Bioavailability of curcumin: problems and promises.

PubMed

Anand, Preetha; Kunnumakkara, Ajaikumar B; Newman, Robert A; Aggarwal, Bharat B

2007-01-01

Curcumin, a polyphenolic compound derived from dietary spice turmeric, possesses diverse pharmacologic effects including anti-inflammatory, antioxidant, antiproliferative and antiangiogenic activities. Phase I clinical trials have shown that curcumin is safe even at high doses (12 g/day) in humans but exhibit poor bioavailability. Major reasons contributing to the low plasma and tissue levels of curcumin appear to be due to poor absorption, rapid metabolism, and rapid systemic elimination. To improve the bioavailability of curcumin, numerous approaches have been undertaken. These approaches involve, first, the use of adjuvant like piperine that interferes with glucuronidation; second, the use of liposomal curcumin; third, curcumin nanoparticles; fourth, the use of curcumin phospholipid complex; and fifth, the use of structural analogues of curcumin (e.g., EF-24). The latter has been reported to have a rapid absorption with a peak plasma half-life. Despite the lower bioavailability, therapeutic efficacy of curcumin against various human diseases, including cancer, cardiovascular diseases, diabetes, arthritis, neurological diseases and Crohn's disease, has been documented. Enhanced bioavailability of curcumin in the near future is likely to bring this promising natural product to the forefront of therapeutic agents for treatment of human disease.

Improved oral bioavailability of poorly water-soluble indirubin by a supersaturatable self-microemulsifying drug delivery system.

PubMed

Chen, Zhi-Qiang; Liu, Ying; Zhao, Ji-Hui; Wang, Lan; Feng, Nian-Ping

2012-01-01

Indirubin, isolated from the leaves of the Chinese herb Isatis tinctoria L, is a protein kinase inhibitor and promising antitumor agent. However, the poor water solubility of indirubin has limited its application. In this study, a supersaturatable self-microemulsifying drug delivery system (S-SMEDDS) was developed to improve the oral bioavailability of indirubin. A prototype S-SMEDDS was designed using solubility studies and phase diagram construction. Precipitation inhibitors were selected from hydrophilic polymers according to their crystallization-inhibiting capacity through in vitro precipitation tests. In vitro release of indirubin from S-SMEDDS was examined to investigate its likely release behavior in vivo. The in vivo bioavailability of indirubin from S-SMEDDS and from SMEDDS was compared in rats. The prototype formulation of S-SMEDDS comprised Maisine™ 35-1:Cremophor(®) EL:Transcutol(®) P (15:40:45, w/w/w). Polyvinylpyrrolidone K17, a hydrophilic polymer, was used as a precipitation inhibitor based on its better crystallization-inhibiting capacity compared with polyethylene glycol 4000 and hydroxypropyl methylcellulose. In vitro release analysis showed more rapid drug release from S-SMEDDS than from SMEDDS. In vivo bioavailability analysis in rats indicated that improved oral absorption was achieved and that the relative bioavailability of S-SMEDDS was 129.5% compared with SMEDDS. The novel S-SMEDDS developed in this study increased the dissolution rate and improved the oral bioavailability of indirubin in rats. The results suggest that S-SMEDDS is a superior means of oral delivery of indirubin.

Formulation design for poorly water-soluble drugs based on biopharmaceutics classification system: basic approaches and practical applications.

PubMed

Kawabata, Yohei; Wada, Koichi; Nakatani, Manabu; Yamada, Shizuo; Onoue, Satomi

2011-11-25

The poor oral bioavailability arising from poor aqueous solubility should make drug research and development more difficult. Various approaches have been developed with a focus on enhancement of the solubility, dissolution rate, and oral bioavailability of poorly water-soluble drugs. To complete development works within a limited amount of time, the establishment of a suitable formulation strategy should be a key consideration for the pharmaceutical development of poorly water-soluble drugs. In this article, viable formulation options are reviewed on the basis of the biopharmaceutics classification system of drug substances. The article describes the basic approaches for poorly water-soluble drugs, such as crystal modification, micronization, amorphization, self-emulsification, cyclodextrin complexation, and pH modification. Literature-based examples of the formulation options for poorly water-soluble compounds and their practical application to marketed products are also provided. Classification of drug candidates based on their biopharmaceutical properties can provide an indication of the difficulty of drug development works. A better understanding of the physicochemical and biopharmaceutical properties of drug substances and the limitations of each delivery option should lead to efficient formulation development for poorly water-soluble drugs. Copyright © 2011 Elsevier B.V. All rights reserved.

Carboxylated mesoporous carbon microparticles as new approach to improve the oral bioavailability of poorly water-soluble carvedilol.

PubMed

Zhang, Yanzhuo; Zhi, Zhizhuang; Li, Xue; Gao, Jian; Song, Yaling

2013-09-15

The main objective of this study was to develop carboxylated ordered mesoporous carbon microparticles (c-MCMs) loaded with a poorly water-soluble drug, intended to be orally administered, able to enhance the drug loading capacity and improve the oral bioavailability. A model drug, carvedilol (CAR), was loaded onto c-MCMs via a procedure involving a combination of adsorption equilibrium and solvent evaporation. The physicochemical properties of the drug-loaded composites were systematically studied using scanning electron microscopy (SEM), transmission electron microscopy (TEM), nitrogen adsorption, powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and HPLC. It was found that c-MCM has a high drug loading level up to 41.6%, and higher than that of the mesoporous silica template. Incorporation of CAR in both drug carriers enhanced the solubility and dissolution rate of the drug, compared to the pure crystalline drug. After loading CAR into c-MCMs, its oral bioavailability was compared with the marketed product in dogs. The results showed that the bioavailability of CAR was improved 179.3% compared with that of the commercial product when c-MCM was used as the drug carrier. We believe that the present study will help in the design of oral drug delivery systems for enhanced oral bioavailability of poorly water-soluble drugs. Copyright © 2013 Elsevier B.V. All rights reserved.

Pharmaceutical Dispersion Techniques for Dissolution and Bioavailability Enhancement of Poorly Water-Soluble Drugs.

PubMed

Zhang, Xingwang; Xing, Huijie; Zhao, Yue; Ma, Zhiguo

2018-06-23

Over the past decades, a large number of drugs as well as drug candidates with poor dissolution characteristics have been witnessed, which invokes great interest in enabling formulation of these active ingredients. Poorly water-soluble drugs, especially biopharmaceutical classification system (BCS) II ones, are preferably designed as oral dosage forms if the dissolution limit can be broken through. Minimizing a drug’s size is an effective means to increase its dissolution and hence the bioavailability, which can be achieved by specialized dispersion techniques. This article reviews the most commonly used dispersion techniques for pharmaceutical processing that can practically enhance the dissolution and bioavailability of poorly water-soluble drugs. Major interests focus on solid dispersion, lipid-based dispersion (nanoencapsulation), and liquisolid dispersion (drug solubilized in a non-volatile solvent and dispersed in suitable solid excipients for tableting or capsulizing), covering the formulation development, preparative technique and potential applications for oral drug delivery. Otherwise, some other techniques that can increase the dispersibility of a drug such as co-precipitation, concomitant crystallization and inclusion complexation are also discussed. Various dispersion techniques provide a productive platform for addressing the formulation challenge of poorly water-soluble drugs. Solid dispersion and liquisolid dispersion are most likely to be successful in developing oral dosage forms. Lipid-based dispersion represents a promising approach to surmounting the bioavailability of low-permeable drugs, though the technique needs to traverse the obstacle from liquid to solid transformation. Novel dispersion techniques are highly encouraged to develop for formulation of poorly water-soluble drugs.

Curcumin therapeutic promises and bioavailability in colorectal cancer.

PubMed

Shehzad, A; Khan, S; Shehzad, O; Lee, Y S

2010-07-01

Curcumin, a polyphenol and derivative of turmeric is one of the most commonly used and highly researched phytochemicals. Several research studies have provided interesting insights into the multiple mechanisms by which curcumin may mediate chemotherapy and chemopreventive effects on cancers, including colorectal cancer. Curcumin has the ability to inhibit carcinogenic promotion of colorectal cancer through the modulation of multiple molecular targets such as transcription factors, enzymes, cell cycle proteins, cell surface adhesion proteins, survival pathways and cytokines. A number of clinical trials dealing with curcumin's efficacy and safety revealed poor absorption and low bioavailability. Different factors contributing to the low bioavailability include low plasma level, tissue distribution, rapid metabolism and elimination from the body. Although, curcumin poor absorption and low systemic bioavailability limit its translation into clinics, some of the methods for its use can be approached to enhance the absorption and achieve a therapeutic level of curcumin. Recent clinical trials suggest a potential role for curcumin in regards to colorectal cancer therapy.

Food macromolecule based nanodelivery systems for enhancing the bioavailability of polyphenols.

PubMed

Hu, Bing; Liu, Xixia; Zhang, Chunlan; Zeng, Xiaoxiong

2017-01-01

Diet polyphenols-primarily categorized into flavonoids (e.g., flavonols, flavones, flavan-3-ols, anthocyanidins, flavanones, and isoflavones) and nonflavonoids (with major subclasses of stilbenes and phenolic acids)-are reported to have health-promoting effects, such as antioxidant, antiinflammatory, anticarcinoma, antimicrobial, antiviral, and cardioprotective properties. However, their applications in functional foods or medicine are limited because of their inefficient systemic delivery and poor oral bioavailability. Epigallocatechin-3-gallate, curcumin, and resveratrol are the well-known representatives of the bioactive diet polyphenols but with poor bioavailability. Food macromolecule based nanoparticles have been fabricated using reassembled proteins, crosslinked polysaccharides, protein-polysaccharide conjugates (complexes), as well as emulsified lipid via safe procedures that could be applied in food. The human gastrointestinal digestion tract is the first place where the food grade macromolecule nanoparticles exert their effects on improving the bioavailability of diet polyphenols, via enhancing their solubility, preventing their degradation in the intestinal environment, elevating the permeation in small intestine, and even increasing their contents in the bloodstream. We contend that the stability and structure behaviors of nanocarriers in the gastrointestinal tract environment and the effects of nanoencapsulation on the metabolism of polyphenols warrant more focused attention in further studies. Copyright © 2016. Published by Elsevier B.V.

Oral heparin delivery: design and in vivo evaluation of a stomach-targeted mucoadhesive delivery system.

PubMed

Schmitz, Thierry; Leitner, Verena M; Bernkop-Schnürch, Andreas

2005-05-01

Low molecular weight heparin (LMWH) is an agent of choice in the anti-coagulant therapy and prophylaxis of thrombosis and coronary syndromes. However, the therapeutic use is partially limited due to a poor oral bioavailability. It was therefore the aim of this study to design and evaluate a highly efficient stomach-targeted oral delivery system for LMWH. In order to appraise the influence of the molecular weight on the oral bioavailability, mini-tablets comprising 3 kDa (279 IU) and 6 kDa (300 IU) LMWH, respectively, were generated and tested in vivo in rats. The potential of the test formulations based on thiolated polycarbophil, was evaluated in comparison to hydroxyethylcellulose (HEC) as control carrier matrix. The plasma levels of LMWH after oral versus subcutaneous administration were determined in order to calculate the relative bioavailability. With the delivery system containing 3 kDa LMWH (279 IU) a relative bioavailability of 19.1% was achieved, offering a significantly (p < 0.05) better bioavailability than the control system displaying a relative bioavailability of 8.1% The 6 kDa LMWH (300 IU) formulation displayed a relative bioavailability of 10.7% in contrast to the control displaying a relative bioavailability of 2.1%. In conclusion, these results suggest that mucoadhesive thiolated polymers are a promising tool for the non-invasive stomach-targeted systemic delivery of LMWH as model for a hydrophilic macromolecular polysaccharide. Copyright 2005 Wiley-Liss, Inc

Research progress on berberine with a special focus on its oral bioavailability.

PubMed

Liu, Chang-Shun; Zheng, Yu-Rong; Zhang, Ying-Feng; Long, Xiao-Ying

2016-03-01

The natural product berberine (BBR) has become a potential drug in the treatment of diabetes, hyperlipidemia, and cancer. However, the oral delivery of BBR is challenged by its poor bioavailability. It is necessary to improve the oral bioavailability of BBR before it can be used in many clinical applications. Understanding the pharmacokinetic characteristics of BBR will enable the development of suitable formulas that have improved oral bioavailability. The key considerations for BBR are how to enhance the drug absorption and to avoid the intestinal first-pass effect. This review summarizes the pharmacological activities of BBR and analyzes the factors that lead to its poor oral bioavailability. In particular, the therapeutic potential of BBR in new indications from the aspect of oral bioavailability is discussed. In conclusion, BBR is a promising drug candidate for metabolic disorders and cancer but faces considerable challenges due to its poor oral bioavailability. Copyright © 2016 Elsevier B.V. All rights reserved.

Silica-coated flexible liposomes as a nanohybrid delivery system for enhanced oral bioavailability of curcumin

PubMed Central

Li, Chong; Zhang, Yan; Su, Tingting; Feng, Lianlian; Long, Yingying; Chen, Zhangbao

2012-01-01

We investigated flexible liposomes as a potential oral drug delivery system. However, enhanced membrane fluidity and structural deformability may necessitate liposomal surface modification when facing the harsh environment of the gastrointestinal tract. In the present study, silica-coated flexible liposomes loaded with curcumin (CUR-SLs) having poor water solubility as a model drug were prepared by a thin-film method with homogenization, followed by the formation of a silica shell by the sol-gel process. We systematically investigated the physical properties, drug release behavior, pharmacodynamics, and bioavailability of CUR-SLs. CUR-SLs had a mean diameter of 157 nm and a polydispersity index of 0.14, while the apparent entrapment efficiency was 90.62%. Compared with curcumin-loaded flexible liposomes (CUR-FLs) without silica-coatings, CUR-SLs had significantly higher stability against artificial gastric fluid and showed more sustained drug release in artificial intestinal fluid as determined by in vitro release assays. The bioavailability of CUR-SLs and CUR-FLs was 7.76- and 2.35-fold higher, respectively, than that of curcumin suspensions. Silica coating markedly improved the stability of flexible liposomes, and CUR-SLs exhibited a 3.31-fold increase in bioavailability compared with CUR-FLs, indicating that silica-coated flexible liposomes may be employed as a potential carrier to deliver drugs with poor water solubility via the oral route with improved bioavailability. PMID:23233804

Silica-coated flexible liposomes as a nanohybrid delivery system for enhanced oral bioavailability of curcumin.

PubMed

Li, Chong; Zhang, Yan; Su, Tingting; Feng, Lianlian; Long, Yingying; Chen, Zhangbao

2012-01-01

We investigated flexible liposomes as a potential oral drug delivery system. However, enhanced membrane fluidity and structural deformability may necessitate liposomal surface modification when facing the harsh environment of the gastrointestinal tract. In the present study, silica-coated flexible liposomes loaded with curcumin (CUR-SLs) having poor water solubility as a model drug were prepared by a thin-film method with homogenization, followed by the formation of a silica shell by the sol-gel process. We systematically investigated the physical properties, drug release behavior, pharmacodynamics, and bioavailability of CUR-SLs. CUR-SLs had a mean diameter of 157 nm and a polydispersity index of 0.14, while the apparent entrapment efficiency was 90.62%. Compared with curcumin-loaded flexible liposomes (CUR-FLs) without silica-coatings, CUR-SLs had significantly higher stability against artificial gastric fluid and showed more sustained drug release in artificial intestinal fluid as determined by in vitro release assays. The bioavailability of CUR-SLs and CUR-FLs was 7.76- and 2.35-fold higher, respectively, than that of curcumin suspensions. Silica coating markedly improved the stability of flexible liposomes, and CUR-SLs exhibited a 3.31-fold increase in bioavailability compared with CUR-FLs, indicating that silica-coated flexible liposomes may be employed as a potential carrier to deliver drugs with poor water solubility via the oral route with improved bioavailability.

Preparation and characterization of solid lipid nanoparticles-a review.

PubMed

Parhi, Rabinarayan; Suresh, Padilama

2012-03-01

In the present scenario, most of the developed and new discovered drugs are posing real challenge to the formulation scientists due to their poor aqueous solubility which in turn is responsible for poor bioavailability. One of the approach to overcome above problem is the packaging of the drug in to particulate carrier system. Among various carriers, lipid emerged as very attractive candidate because of its unique property of enhancing the bioavailability of poorly water soluble drugs. Solid lipid, one of the physical forms of lipid, is used to formulate nanoparticles, popularly known as Solid lipid nanoparticles (SLNs), as an alternative carrier system to emulsions, liposomes and polymeric micro- and nano-particles. SLNs combine advantages of the traditional systems but avoid some of their major disadvantages. This paper reviews numerous production techniques for SLNs along with their advantages and disadvantages. Special attention is paid to the characterization of the SLNs by using various analytical tools. It also emphasizes on physical state of lipid (supercooled melts, different lipid modifications).

Improved oral bioavailability of poorly water-soluble indirubin by a supersaturatable self-microemulsifying drug delivery system

PubMed Central

Chen, Zhi-Qiang; Liu, Ying; Zhao, Ji-Hui; Wang, Lan; Feng, Nian-Ping

2012-01-01

Background Indirubin, isolated from the leaves of the Chinese herb Isatis tinctoria L, is a protein kinase inhibitor and promising antitumor agent. However, the poor water solubility of indirubin has limited its application. In this study, a supersaturatable self-microemulsifying drug delivery system (S-SMEDDS) was developed to improve the oral bioavailability of indirubin. Methods A prototype S-SMEDDS was designed using solubility studies and phase diagram construction. Precipitation inhibitors were selected from hydrophilic polymers according to their crystallization-inhibiting capacity through in vitro precipitation tests. In vitro release of indirubin from S-SMEDDS was examined to investigate its likely release behavior in vivo. The in vivo bioavailability of indirubin from S-SMEDDS and from SMEDDS was compared in rats. Results The prototype formulation of S-SMEDDS comprised Maisine™ 35-1:Cremophor® EL:Transcutol® P (15:40:45, w/w/w). Polyvinylpyrrolidone K17, a hydrophilic polymer, was used as a precipitation inhibitor based on its better crystallization-inhibiting capacity compared with polyethylene glycol 4000 and hydroxypropyl methylcellulose. In vitro release analysis showed more rapid drug release from S-SMEDDS than from SMEDDS. In vivo bioavailability analysis in rats indicated that improved oral absorption was achieved and that the relative bioavailability of S-SMEDDS was 129.5% compared with SMEDDS. Conclusion The novel S-SMEDDS developed in this study increased the dissolution rate and improved the oral bioavailability of indirubin in rats. The results suggest that S-SMEDDS is a superior means of oral delivery of indirubin. PMID:22403491

Surface modification of solid lipid nanoparticles for oral delivery of curcumin: Improvement of bioavailability through enhanced cellular uptake, and lymphatic uptake.

PubMed

Baek, Jong-Suep; Cho, Cheong-Weon

2017-08-01

Curcumin has been reported to exhibit potent anticancer effects. However, poor solubility, bioavailability and stability of curcumin limit its in vivo efficacy for the cancer treatment. Solid lipid nanoparticles (SLN) are a promising delivery system for the enhancement of bioavailability of hydrophobic drugs. However, burst release of drug from SLN in acidic environment limits its usage as oral delivery system. Hence, we prepared N-carboxymethyl chitosan (NCC) coated curcumin-loaded SLN (NCC-SLN) to inhibit the rapid release of curcumin in acidic environment and enhance the bioavailability. The NCC-SLN exhibited suppressed burst release in simulated gastric fluid while sustained release was observed in simulated intestinal fluid. Furthermore, NCC-SLN exhibited increased cytotoxicity and cellular uptake on MCF-7 cells. The lymphatic uptake and oral bioavailability of NCC-SLN were found to be 6.3-fold and 9.5-fold higher than that of curcumin solution, respectively. These results suggest that NCC-SLN could be an efficient oral delivery system for curcumin. Copyright © 2017 Elsevier B.V. All rights reserved.

Development of self-nanoemulsifying drug delivery system for oral bioavailability enhancement of valsartan in beagle dogs.

PubMed

Li, Zhenbao; Zhang, Wenjuan; Gao, Yan; Xiang, Rongwu; Liu, Yan; Hu, Mingming; Zhou, Mei; Liu, Xiaohong; Wang, Yongjun; He, Zhonggui; Sun, Yinghua; Sun, Jin

2017-02-01

Valsartan, an angiotensin II receptor antagonist, is widely used to treat high blood pressure in the clinical setting. However, its poor water solubility results in the low oral bioavailability. The aim of this study was to improve dissolution rate and oral bioavailability by developing a self-nanoemulsifying drug delivery system. Saturation solubility of valsartan in various oils, surfactants, and cosurfactants was investigated, and the optimized formulation was determined by central composite design-response surface methodology. The shape of resultant VAL-SNEDDS was spherical with an average diameter of about 27 nm. And the drug loading efficiency is approximately 14 wt%. Differential scanning calorimetry and XRD studies disclosed the molecular or amorphous state of valsartan in VAL-SNEDDS. The dissolution study indicated that the self-nanoemulsifying drug delivery systems (SNEDDS) exhibited significantly enhanced dissolution compared with market capsules (Diovan®) in various media. Furthermore, the stability of formulation revealed that valsartan SNEDDS was stable under low temperature and accelerated test condition. Furthermore, the pharmacokinetics demonstrated that C max and AUC (0-∞) of SNEDDS capsules were about three- and twofold higher than Diovan® in beagle dogs, respectively. Meanwhile, the safety evaluation implied that VAL-SNEDDS was innocuous to beagle dogs during 15 days of continuous administration. Our results suggested that VAL-SNEDDS was a potential and safe delivery system with enhanced dissolution rate and oral bioavailability, as well as offered a strategy for the engineering of poorly water-soluble drugs in the clinical setting.

How does curcumin work with poor bioavailability? Clues from experimental and theoretical studies

NASA Astrophysics Data System (ADS)

Shen, Liang; Liu, Cui-Cui; An, Chun-Yan; Ji, Hong-Fang

2016-02-01

Curcumin is a natural product with multiple biological activities and numerous potential therapeutic applications. However, its poor systemic bioavailability fails to explain the potent pharmacological effects and hinders its clinical application. Using experimental and theoretical approaches, we compared curcumin and its degradation products for its biological activities against Alzheimer’s disease (AD), including the superoxide anion radical (O2.-)-scavenging activity, Aβ fibrils (fAβ) formation-inhibiting activity, and enzymatic inhibition activity. We showed that compared to the parent compound curcumin, the degradation products mixture possessed higher O2.--scavenging activity and stronger inhibition against fAβ formation. The docking simulations revealed that the bioactive degradation products should make important contribution to the experimentally observed enzymatic inhibition activities of curcumin. Given that curcumin is readily degraded under physiological condition, our findings strongly suggested that the degradation products should make important contribution to the diverse biological activities of curcumin. Our novel findings not only provide novel insights into the complex pharmacology of curcumin due to its poor bioavailability, but also open new avenues for developing therapeutic applications of this natural product.

Evaluation of an oral carrier system in rats: bioavailability and gastrointestinal absorption properties of curcumin encapsulated PBCA nanoparticles

NASA Astrophysics Data System (ADS)

Sun, Min; Zhao, Lixia; Guo, Chenyu; Cao, Fengliang; Chen, Huanlei; Zhao, Liyan; Tan, Qi; Zhu, Xiuqing; Zhu, Fanping; Ding, Tingting; Zhai, Yingjie; Zhai, Guangxi

2012-02-01

A new oral delivery system, polybutylcyanoacrylate nanoparticles (PBCNs), was introduced to improve the oral bioavailability of curcumin (CUR), a poorly soluble drug. The formulation was optimized by orthogonal design and the optimal PBCNs loading CUR exhibited a spherical shape under transmission electron microscopy with a range of 40-400 nm. Physicochemical state of CUR in PBCN was investigated by X-ray diffraction and the possible structure changes occurring in CUR after conjugating with polybutylcyanoacrylate were studied with FTIR. The results indicated that CUR in PBCN was in a non-crystalline state and CUR was encapsulated in PBCN without chemical reaction. The oral pharmacokinetic study was conducted in rats and the relative bioavailability of CUR encapsulated PBCNs to the crude CUR was more than 800%. The in situ absorption experiment in rat intestine indicated the absorption was first order with passive diffusion mechanism. The absorption results in various segments of intestine showed that the main absorption sites were ileum and colon. It can be concluded that PBCNs as an oral carrier can significantly improve the oral absorption of a poorly soluble drug.

Rationalizing the selection of oral lipid based drug delivery systems by an in vitro dynamic lipolysis model for improved oral bioavailability of poorly water soluble drugs.

PubMed

Dahan, Arik; Hoffman, Amnon

2008-07-02

As a consequence of modern drug discovery techniques, there has been a consistent increase in the number of new pharmacologically active lipophilic compounds that are poorly water soluble. A great challenge facing the pharmaceutical scientist is making these molecules into orally administered medications with sufficient bioavailability. One of the most popular approaches to improve the oral bioavailability of these molecules is the utilization of a lipid based drug delivery system. Unfortunately, current development strategies in the area of lipid based delivery systems are mostly empirical. Hence, there is a need for a simplified in vitro method to guide the selection of a suitable lipidic vehicle composition and to rationalize the delivery system design. To address this need, a dynamic in vitro lipolysis model, which provides a very good simulation of the in vivo lipid digestion process, has been developed over the past few years. This model has been extensively used for in vitro assessment of different lipid based delivery systems, leading to enhanced understanding of the suitability of different lipids and surfactants as a delivery system for a given poorly water soluble drug candidate. A key goal in the development of the dynamic in vitro lipolysis model has been correlating the in vitro data of various drug-lipidic delivery system combinations to the resultant in vivo drug profile. In this paper, we discuss and review the need for this model, its underlying theory, practice and limitations, and the available data accumulated in the literature. Overall, the dynamic in vitro lipolysis model seems to provide highly useful initial guidelines in the development process of oral lipid based drug delivery systems for poorly water soluble drugs, and it predicts phenomena that occur in the pre-enterocyte stages of the intestinal absorption cascade.

A metabolic way to investigate related hurdles causing poor bioavailability in oral delivery of isoacteoside in rats employing ultrahigh-performance liquid chromatography/quadrupole time-of-flight tandem mass spectrometry.

PubMed

Cui, Qingling; Pan, Yingni; Yan, Xiaowei; Qu, Bao; Liu, Xiaoqiu; Xiao, Wei

2017-02-28

Isoacteoside (ISAT), a phenylethanoid glycoside that acts as the principal bioactive component in traditional Chinese medicines, possesses broad pharmacological effects such as neuroprotective, antihypertensive and hepatoprotective activities. However, its pharmaceutical development has been severely limited due to the poor oral bioavailability. It is essential and significant to investigate related hurdles leading to the poor bioavailability of isoacteoside. Whole animal metabolism studies were conducted in rats, followed by metabolic mechanism including gastrointestinal stability, intestinal flora metabolism and intestinal enzyme metabolism employing the powerful method ultrahigh-performance liquid chromatography combined with quadrupole time-of-flight tandem mass spectrometry (UPLC/QTOF-MS/MS). A simple, rapid and sensitive method has been developed which comprehensively revealed the underlying cause of poor bioavailability of ISAT in a metabolic manner. The prototype of ISAT and its combined metabolites have not been detected in plasma. Furthermore, the residual content of the parent compound in in vitro experiments was approximately 59%, 5% and barely none in intestinal bacteria, intestinal S9 and simulated intestinal juice at 6 h, respectively. The present work has demonstrated that the factors causing the poor bioavailability of isoacteoside should be attributed to the metabolism. In general, the metabolism that resulted from intestinal flora and intestinal enzymes were predominant reasons giving rise to the poor bioavailability of ISAT, which also suggested that metabolites might be responsible for the excellent pharmacological effect of ISAT. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Role of oxate, phytate, tannins and cooking on iron bioavailability from foods commonly consumed in Mexico.

PubMed

Sotelo, Angela; González-Osnaya, Liliana; Sánchez-Chinchillas, Argelia; Trejo, Alberto

2010-02-01

The objectives of this research were to assess the bioavailability of iron in foodstuffs found in the Mexican diet, to provide data on the content of iron absorption inhibitors present in plant origin products and to assess the inhibitory effect of these compounds and of cooking on iron bioavailability; therefore, total content and bioavailable iron, tannins, phytic and oxalic acid were determined in vegetables, cereals, legumes and animal products, before and after cooking. Vegetables, although rich in iron, have poor iron bioavailability and a high content of inhibitory factors; cooking reduced the content of iron and inhibitory factors, whereas in animal products the treatment of cooking did not significantly reduce it. Iron bioavailability, phytate content and the phytate to iron molar ratio predicted poor iron bioavailability and, therefore, a negative impact on the nutritional status of people who rely on them as staple foods could be expected.

Utilizing food effects to overcome challenges in delivery of lipophilic bioactives: structural design of medical and functional foods.

PubMed

McClements, David Julian

2013-12-01

The oral bioavailability of many lipophilic bioactives, such as pharmaceuticals and nutraceuticals, is relatively low due to their poor solubility, permeability and/or chemical stability within the human gastrointestinal tract (GIT). The oral bioavailability of lipophilic bioactives can be improved by designing food matrices that control their release, solubilization, transport and absorption within the GIT. This article discusses the challenges associated with delivering lipophilic bioactive components, the impact of food composition and structure on oral bioavailability and the design of functional and medical foods for improving the oral bioavailability of lipophilic bioactives. Food-based delivery systems can be used to improve the oral bioavailability of lipophilic bioactives. There are a number of potential advantages to delivering lipophilic bioactives using functional or medical foods: greater compliance than conventional delivery forms; increased bioavailability and efficacy; and reduced variability in biological effects. However, food matrices are structurally complex multicomponent materials and research is still needed to identify optimum structures and compositions for particular bioactives.

Significance of excipients to enhance the bioavailability of poorly water-soluble drugs in oral solid dosage forms: A Review

NASA Astrophysics Data System (ADS)

Vadlamudi, Manoj Kumar; Dhanaraj, Sangeetha

2017-11-01

Nowadays most of the drug substances are coming into the innovation pipeline with poor water solubility. Here, the influence of excipients will play a significant role to improve the dissolution of poorly aqueous soluble compounds. The drug substance needs to be dissolved in gastric fluids to get the better absorption and bioavailability of an orally administered drug. Dissolution is the rate-controlling stage for drugs which controls the rate and degree of absorption. Usually, poorly soluble oral administrated drugs show a slower dissolution rate, inconsistent and incomplete absorption which can lead to lower bioavailability. The low aqueous solubility of BCS class II and IV drugs is a major challenge in the drug development and delivery process. Several technologies have been used in an attempt to progress the bioavailability of poorly water-soluble drug compounds which include solid dispersions, lipid-based formulations, micronization, solvent evaporation, co-precipitation, ordered mixing, liquid-solid compacts, solvent deposition inclusion complexation, and steam aided granulation. In fact, most of the technologies require excipient as a carrier which plays a significant role in improving the bioavailability using Hypromellose acetate succinate, Cyclodextrin, Povidone, Copovidone, Hydroxypropyl cellulose, Hydroxypropyl methylcellulose, Crospovidone, Starch, Dimethylacetamide, Polyethylene glycol, Sodium lauryl sulfate, Polysorbate, Poloxamer. Mesoporous silica and so on. This review deliberates about the excipients significance on bioavailability enhancement of drug products in a single platform along with pragmatically proved applications so that user can able to select the right excipients as per the molecule.

Mesoporous materials and nanocrystals for enhancing the dissolution behavior of poorly water-soluble drugs.

PubMed

Santos, Helder A; Peltonen, Leena; Limnell, Tarja; Hirvonen, Jouni

2013-01-01

Advanced drug delivery formulations are presently recognized as promising tools for overcoming the adverse physicochemical properties of conventional drug molecules, such as poor water solubility, which often leads to poor drug bioavailability. Oral drug delivery is considered as the easiest and most convenient route of drug administration. However, via the current trends utilizing combinatorial chemistry and high throughput screening in drug development, new drug molecules are moving towards lipophilic and poorly water-soluble large molecules, and the oral delivery route is becoming increasingly challenging. In this context, formulation of poorly soluble and/or permeable drugs using mesoporous materials and nanocrystals technology have proven to be highly successful due to the greater surface/volume ratio of these systems, resulting in improvements in dissolution and bioavailability, as well as enhanced drug permeability. This review addresses the issues of poorly water-soluble drugs with a major focus on recent developments in the application of the mesoporous materials (e.g., porous silicon and silica) and nanocrystals in drug delivery applications. In addition, we present several recent examples of the significant potential of these materials for the pharmaceutical field.

[Silica-coated ethosome as a novel oral delivery system for enhanced oral bioavailability of curcumin].

PubMed

Li, Chong; Deng, Li; Zhang, Yan; Su, Ting-Ting; Jiang, Yin; Chen, Zhang-Bao

2012-11-01

The aim of this study is to investigate the feasibility of silica-coated ethosome as a novel oral delivery system for the poorly water-soluble curcumin (as a model drug). The silica-coated ethosomes loading curcumin (CU-SE) were prepared by alcohol injection method with homogenization, followed by the precipitation of silica by sol-gel process. The physical and chemical features of CU-SEs, and curcumin release were determined in vitro. The pharmacodynamics and bioavailability measurements were sequentially performed. The mean diameter of CU-SE was (478.5 +/- 80.3) nm and the polydispersity index was 0.285 +/- 0.042, while the mean value of apparent drug entrapment efficiency was 80.77%. In vitro assays demonstrated that CU-SEs were significantly stable with improved release properties when compared with curcumin-loaded ethosomes (CU-ETs) without silica-coatings. The bioavailability of CU-SEs and CU-ETs was 11.86- and 5.25-fold higher, respectively, than that of curcumin suspensions (CU-SUs) in in vivo assays. The silica coatings significantly promoted the stability of ethosomes and CU-SEs exhibited 2.26-fold increase in bioavailablity relative to CU-ETs, indicating that the silica-coated ethosomes might be a potential approach for oral delivery of poorly water-soluble drugs especially the active ingredients of traditional Chinese medicine with improved bioavailability.

Preparation and Pharmacokinetics Evaluation of Solid Self-Microemulsifying Drug Delivery System (S-SMEDDS) of Osthole.

PubMed

Sun, Chaojie; Gui, Yun; Hu, Rongfeng; Chen, Jiayi; Wang, Bin; Guo, Yuxing; Lu, Wenjie; Nie, Xiangjiang; Shen, Qiang; Gao, Song; Fang, Wenyou

2018-05-29

The study was performed aiming to enhance the solubility and oral bioavailability of poorly water-soluble drug osthole by formulating solid self-microemulsifying drug delivery system (S-SMEDDS) via spherical crystallization technique. Firstly, the liquid self-microemulsifying drug delivery system (L-SMEDDS) of osthole was formulated with castor oil, Cremophor RH40, and 1,2-propylene glycol after screening various lipids and emulsifiers. The type and amount of polymeric materials, good solvents, bridging agents, and poor solvents in S-SMEDDS formulations were further determined by single-factor study. The optimal formulation contained 1:2 of ethyl cellulose (EC) and Eudragit S100, which served as matrix forming and enteric coating polymers respectively. Anhydrous ethanol and dichloromethane with a ratio of 5:3 are required to perform as good solvent and bridging agent, respectively, with the addition of 0.08% SDS aqueous solution as poor solvent. The optimized osthole S-SMEDDS had a high yield (83.91 ± 3.31%) and encapsulation efficiency (78.39 ± 2.25%). Secondly, osthole L-SMEDDS was solidified to osthole S-SMEDDS with no significant changes in terms of morphology, particle size, and zeta potential. In vitro release study demonstrated a sustained release of the drug from osthole S-SMEDDS. Moreover, in vivo pharmacokinetic study showed that the T max and mean residence time (MRT (0-t) ) of osthole were significantly prolonged and further confirmed that osthole S-SMEDDS exhibited sustained release effect in rabbits. Comparing with osthole aqueous suspension and L-SMEDDS, osthole S-SMEDDS increased bioavailability by 205 and 152%, respectively. The results suggested that S-SMEDDS was an effective oral solid dosage form, which can improve the solubility and oral bioavailability of poorly water-soluble drug osthole.

Bioavailability enhancement of atovaquone using hot melt extrusion technology.

PubMed

Kate, Laxman; Gokarna, Vinod; Borhade, Vivek; Prabhu, Priyanka; Deshpande, Vinita; Pathak, Sulabha; Sharma, Shobhona; Patravale, Vandana

2016-04-30

Emerging parasite resistance and poor oral bioavailability of anti-malarials are the two cardinal issues which hinder the clinical success of malaria chemotherapy. Atovaquone-Proguanil is a WHO approved fixed dose combination used to tackle the problem of emerging resistance. However, Atovaquone is a highly lipophilic drug having poor aqueous solubility (less than 0.2 μg/ml) thus reducing its oral bioavailability. The aim of the present investigation was to explore hot melt extrusion (HME) as a solvent-free technique to enhance solubility and oral bioavailability of Atovaquone and to develop an oral dosage form for Atovaquone-Proguanil combination. Solid dispersion of Atovaquone was successfully developed using HME. The solid dispersion was characterized for DSC, FTIR, XRD, SEM, and flow properties. It was filled in size 2 hard gelatin capsules. The formulation showed better release as compared to Malarone® tablets, and 3.2-fold and 4.6-fold higher bioavailability as compared to Malarone® tablets and Atovaquone respectively. The enhanced bioavailability also resulted in 100% anti-malarial activity in murine infection model at 1/8(th) therapeutic dose. Thus the developed methodology shows promising potential to solve the problems associated with Atovaquone therapy, namely its high cost and poor oral bioavailability, resulting in increased therapeutic efficacy of Atovaquone. Copyright © 2016 Elsevier B.V. All rights reserved.

Bringing Curcumin to the Clinic in Cancer Prevention: a Review of Strategies to Enhance Bioavailability and Efficacy.

PubMed

Mahran, Rama I; Hagras, Magda M; Sun, Duxin; Brenner, Dean E

2017-01-01

Curcumin is widely available, inexpensive spice that has been used in ancient folk medicine for millennia, especially in India. Curcumin has the pharmacological properties that slow or reverse cellular proliferation and enhance apoptosis and differentiation associated with a diverse array of molecular effects. Despite its effective anticarcinogenesis properties, curcumin's poor solubility, instability, and extensive metabolism result in poor oral bioavailability. Strategies to enhance curcumin delivery include encapsulating or incorporating curcumin in a nanoparticle or microparticle drug delivery system, synthesizing more stable curcumin analogs that resist metabolism while retaining curcumin's pharmacological properties, and adding another natural product that has bioenhancing properties to curcumin or combination of two of these strategies. This review comprehensively explores curcumin's chemistry and pharmacology followed by comparing and contrasting a vast number of strategies designed to enhance curcumin's bioavailability and its therapeutic effects. The review provides insights into which curcumin formulation strategies have the greatest promise to reach clinical application.

Linkage between speciation of Cd in mangrove sediment and its bioaccumulation in total soft tissue of oyster from the west coast of India.

PubMed

Chakraborty, Parthasarathi; Ramteke, Darwin; Gadi, Subhadra Devi; Bardhan, Pratirupa

2016-05-15

This study established a mechanistic linkage between Cd speciation and bioavailability in mangrove system from the west coast of India. High bioaccumulation of Cd was found in the oyster (Crassostrea sp.) even at low Cd loading in the bottom sediment. Bioaccumulation of Cd in the oyster gradually increased with the increasing concentrations of water soluble, exchangeable and carbonate/bicarbonate forms of Cd in the sediments. Fe/Mn oxyhydroxide phase was found to control Cd bioavailability in the sediment system. Cd-associated with sedimentary organic matter was bioavailable and organic ligands in the sediments were poor chelating agents for Cd. This study suggests that bioaccumulation of Cd in oyster (Crassostrea sp.) depends not on the total Cd concentration but on the speciation of Cd in the system. Copyright © 2015 Elsevier Ltd. All rights reserved.

pH-dependent solubility and permeability profiles: A useful tool for prediction of oral bioavailability.

PubMed

Sieger, P; Cui, Y; Scheuerer, S

2017-07-15

pH-dependent solubility - permeability profiles offer a simple way to predict bioavailability after oral application, if bioavailability is only solubility and permeability driven. Combining both pH-dependent solubility and pH-dependent permeability in one diagram provides a pH-window (=ΔpH sol-perm ) from which the conditions for optimal oral bioavailability can be taken. The size of this window is directly proportional to the observed oral bioavailability. A set of 21 compounds, with known absolute human oral bioavailability, was used to establish this correlation. Compounds with ΔpH sol-perm <2 exhibit poor oral bioavailability (<25%). An increase of ΔpH sol-perm by one pH-unit increases oral bioavailability typically by approximately 25%. For compounds where ΔpH sol-perm ≥3 but still showing poor bioavailability, most probably other pharmacokinetic aspects (e.g. high clearance), are limiting exposure. Interestingly, the location of this pH-window seems to have a negligible influence on the observed oral bioavailability. In scenarios, where the bioavailability is impaired by certain factors, like for example proton pump inhibitor co-medication or food intake, the exact position of this pH-window might be beneficial for understanding the root cause. Copyright © 2017 Elsevier B.V. All rights reserved.

Extractive biodegradation and bioavailability assessment of phenanthrene in the cloud point system by Sphingomonas polyaromaticivorans.

PubMed

Pan, Tao; Deng, Tao; Zeng, Xinying; Dong, Wei; Yu, Shuijing

2016-01-01

The biological treatment of polycyclic aromatic hydrocarbons is an important issue. Most microbes have limited practical applications because of the poor bioavailability of polycyclic aromatic hydrocarbons. In this study, the extractive biodegradation of phenanthrene by Sphingomonas polyaromaticivorans was conducted by introducing the cloud point system. The cloud point system is composed of a mixture of (40 g/L) Brij 30 and Tergitol TMN-3, which are nonionic surfactants, in equal proportions. After phenanthrene degradation, a higher wet cell weight and lower phenanthrene residue were obtained in the cloud point system than that in the control system. According to the results of high-performance liquid chromatography, the residual phenanthrene preferred to partition from the dilute phase into the coacervate phase. The concentration of residual phenanthrene in the dilute phase (below 0.001 mg/L) is lower than its solubility in water (1.18 mg/L) after extractive biodegradation. Therefore, dilute phase detoxification was achieved, thus indicating that the dilute phase could be discharged without causing phenanthrene pollution. Bioavailability was assessed by introducing the apparent logP in the cloud point system. Apparent logP decreased significantly, thus indicating that the bioavailability of phenanthrene increased remarkably in the system. This study provides a potential application of biological treatment in water and soil contaminated by phenanthrene.

A Review on Phytosome Technology as a Novel Approach to Improve The Bioavailability of Nutraceuticals

NASA Astrophysics Data System (ADS)

Amin, Tawheed; Bhat, Suman Vikas

2012-08-01

The bioavailability and absorption of water soluble phytoconstituents is erratic due to poor solubility of these constituents in gastrointestinal tract. This can be overcome by a novel delivery system known as phytosome technology in which water soluble phytoconstituents are allowed to react with phospholipids. For better and improved bioavailability, natural phytoconstituents must have a good balance between hydrophilicity (helps in dissolution in gastro-intestinal fluids) and hydrophobicity (helps to cross lipid rich cell membranes). This is achieved through phytosome technology. Phospholipids have a dual solubility and acts as an emulsifier. Phytosome technology acts as a bridge between novel and conventional delivery systems. Many products are available in the market based on this phytosome technology which include popular herbal extracts such as Ginkgo biloba, Silybum marianum, grape seed, olive oil flavonoids etc.

Development of a fortified juice beverage: assessment of iron bioavailability using an established caco-2 cell bioassay

USDA-ARS?s Scientific Manuscript database

Poor iron bioavailability is a contributing factor to the high prevalence of iron deficiency anemia in India, and food fortification with bioavailable iron is one strategy to help address the problem. Validated in vitro methods to measure iron (Fe) bioavailability are useful tools that can be levera...

A novel osmotic pump-based controlled delivery system consisting of pH-modulated solid dispersion for poorly soluble drug flurbiprofen: in vitro and in vivo evaluation.

PubMed

Li, Shujuan; Wang, Xiaoyu; Wang, Yingying; Zhao, Qianqian; Zhang, Lina; Yang, Xinggang; Liu, Dandan; Pan, Weisan

2015-01-01

In this study, a novel controlled release osmotic pump capsule consisting of pH-modulated solid dispersion for poorly soluble drug flurbiprofen (FP) was developed to improve the solubility and oral bioavailability of FP and to minimize the fluctuation of plasma concentration. The pH-modulated solid dispersion containing FP, Kollidon® 12 PF and Na2CO3 at a weight ratio of 1/4.5/0.02 was prepared using the solvent evaporation method. The osmotic pump capsule was assembled by semi-permeable capsule shell of cellulose acetate (CA) prepared by the perfusion method. Then, the solid dispersion, penetration enhancer, and suspending agents were tableted and filled into the capsule. Central composite design-response surface methodology was used to evaluate the influence of factors on the responses. A second-order polynomial model and a multiple linear model were fitted to correlation coefficient of drug release profile and ultimate cumulative release in 12 h, respectively. The actual response values were in good accordance with the predicted ones. The optimized formulation showed a complete drug delivery and zero-order release rate. Beagle dogs were used to be conducted in the pharmacokinetic study. The in vivo study indicated that the relative bioavailability of the novel osmotic pump system was 133.99% compared with the commercial preparation. The novel controlled delivery system with combination of pH-modulated solid dispersion and osmotic pump system is not only a promising strategy to improve the solubility and oral bioavailability of poorly soluble ionizable drugs but also an effective way to reduce dosing frequency and minimize the plasma fluctuation.

Exploring oral nanoemulsions for bioavailability enhancement of poorly water-soluble drugs.

PubMed

Kotta, Sabna; Khan, Abdul Wadood; Pramod, Kannissery; Ansari, Shahid H; Sharma, Rakesh Kumar; Ali, Javed

2012-05-01

More than 40% of new chemical entities discovered are poorly water soluble and suffer from low oral bioavailability. In recent years, nanoemulsions are receiving increasing attention as a tool of delivering these low-bioavailable moieties in an efficient manner. This review gives a brief description about how oral nanoemulsions act as a tool to improve the bioavailability of poorly water-soluble drugs. The recurrent confusion found in the literature regarding the theory behind the formation of nanoemulsions is clarified, along with the difference between nanoemulsion and lyotropic 'microemulsion' phase. This paper gives a clear-cut idea about all possible methods for the preparation of nanoemulsions and the advantages and disadvantages of each method are described. A description of the stability problems of nanoemulsions and their prevention methods is also provided, in addition to a comprehensive update on the patents and research works done in the arena of oral nanoemulsions. Low-energy emulsification techniques can also produce stable nanoemulsions. It is guaranteed that oral nanoemulsions can act as a potential tool for the delivery of poorly water-soluble therapeutic moieties in a very efficient manner.

Formulation and Characterization of Anthocyanins-Loaded Nanoparticles.

PubMed

Dupeyrón, Danay; Kawakami, Monique; Rieumont, Jacques; Carvalho, José Carlos

2017-01-01

Açaí berry, from the Euterpe oleracea Mart. Palm, has been described as the most important fruit in the Brazilian Amazon. Several studies have reported that anthocyanins (ACNs), one of the components of the açaí, have enormous potential for pharmaceuticals applications. However, the bioavailability of anthocyanins is relatively low compared to that of other flavonoids. Then, in the present work, anthocyanins-loaded nanoparticles have been developed to overcome their poor bioavailability. A two-level factorial design with three factors was considered to evaluate the effect of EUDRAGIT ® L100, polyethylene glycol 2000 (PEG 2000) and polysorbate 80 on encapsulation efficiency (EE) of anthocyanins. Also, major parameters of nanoparticles were assessed by using mainly SEM microscopy and Dynamic light scattering. PEG 2000 was the only individual factor that has statistical significance (95% confidence level). The process yields (PY) were found in between 67% and 92%; the particle size and morphology analysis showed two distribution size, one for NPs and another for the agglomerates. The pH-sensitive polymer together with the hydrophilic polymer showed to be suitable as ACNs delivery system. The delayed release profile of ACNs, observed for all formulations, can enhance their poor bioavailability. Nevertheless, ACNs bioavailability in vivo remains to be studied. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Catechin prodrugs and analogs: a new array of chemical entities with improved pharmacological and pharmacokinetic properties.

PubMed

Bansal, Sumit; Vyas, Sandeep; Bhattacharya, Shoumyo; Sharma, Manu

2013-10-11

Extensive research on tea catechins, mainly (-)-epigallocatechin gallate, has shown numerous health promoting effects. However, various clinical studies demonstrated several issues associated with tea catechins which account for their poor systemic bioavailability. In order to improve pharmacological activity and bioavailability of natural tea catechins, two major strategies have been adopted to date which include synthesizing catechin analogs/prodrugs and the development of novel drug delivery systems. In this review, we provide a detailed account of novel synthetic analogs/prodrugs as well as novel drug delivery approaches used for natural tea catechins to make them therapeutically potent drug-like molecules.

Formulation Strategies to Improve the Bioavailability of Poorly Absorbed Drugs with Special Emphasis on Self-Emulsifying Systems

PubMed Central

Gupta, Shweta; Kesarla, Rajesh

2013-01-01

Poorly water-soluble drug candidates are becoming more prevalent. It has been estimated that approximately 60–70% of the drug molecules are insufficiently soluble in aqueous media and/or have very low permeability to allow for their adequate and reproducible absorption from the gastrointestinal tract (GIT) following oral administration. Formulation scientists have to adopt various strategies to enhance their absorption. Lipidic formulations are found to be a promising approach to combat the challenges. In this review article, potential advantages and drawbacks of various conventional techniques and the newer approaches specifically the self-emulsifying systems are discussed. Various components of the self-emulsifying systems and their selection criteria are critically reviewed. The attempts of various scientists to transform the liquid self-emulsifying drug delivery systems (SEDDS) to solid-SEDDS by adsorption, spray drying, lyophilization, melt granulation, extrusion, and so forth to formulate various dosage forms like self emulsifying capsules, tablets, controlled release pellets, beads, microspheres, nanoparticles, suppositories, implants, and so forth have also been included. Formulation of SEDDS is a potential strategy to deliver new drug molecules with enhanced bioavailability mostly exhibiting poor aqueous solubility. The self-emulsifying system offers various advantages over other drug delivery systems having potential to solve various problems associated with drugs of all the classes of biopharmaceutical classification system (BCS). PMID:24459591

Optimizing Oral Bioavailability in Drug Discovery: An Overview of Design and Testing Strategies and Formulation Options.

PubMed

Aungst, Bruce J

2017-04-01

For discovery teams working toward new, orally administered therapeutic agents, one requirement is to attain adequate systemic exposure after oral dosing, which is best accomplished when oral bioavailability is optimized. This report summarizes the bioavailability challenges currently faced in drug discovery, and the design and testing methods and strategies currently utilized to address the challenges. Profiling of discovery compounds usually includes separate assessments of solubility, permeability, and susceptibility to first-pass metabolism, which are the 3 most likely contributors to incomplete oral bioavailability. An initial assessment of absorption potential may be made computationally, and high throughput in vitro assays are typically performed to prioritize compounds for in vivo studies. The initial pharmacokinetic study is a critical decision point in compound evaluation, and the importance of the effect the dosing vehicle or formulation can have on oral bioavailability, especially for poorly water soluble compounds, is emphasized. Dosing vehicles and bioavailability-enabling formulations that can be used for discovery and preclinical studies are described. Optimizing oral bioavailability within a chemical series or for a lead compound requires identification of the barrier limiting bioavailability, and methods used for this purpose are outlined. Finally, a few key guidelines are offered for consideration when facing the challenges of optimizing oral bioavailability in drug discovery. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Considerations for Incorporating Bioavailability in Effect-Directed Analysis and Toxicity Identification Evaluation.

EPA Science Inventory

In order to avoid a bias toward highly toxic but poorly bioavailable compounds in the effect-directed analysis (EDA) of soils and sediments, approaches are discussed to consider bioavailability in EDA procedures. In parallel, complimentary approaches for making toxicity identific...

Nanonization strategies for poorly water-soluble drugs.

PubMed

Chen, Huabing; Khemtong, Chalermchai; Yang, Xiangliang; Chang, Xueling; Gao, Jinming

2011-04-01

Poor water solubility for many drugs and drug candidates remains a major obstacle to their development and clinical application. Conventional formulations to improve solubility suffer from low bioavailability and poor pharmacokinetics, with some carriers rendering systemic toxicities (e.g. Cremophor(®) EL). In this review, several major nanonization techniques that seek to overcome these limitations for drug solubilization are presented. Strategies including drug nanocrystals, nanoemulsions and polymeric micelles are reviewed. Finally, perspectives on existing challenges and future opportunities are highlighted. Published by Elsevier Ltd.

Design and evaluation of oral nanoemulsion drug delivery system of mebudipine.

PubMed

Khani, Samira; Keyhanfar, Fariborz; Amani, Amir

2016-07-01

A nanoemulsion drug delivery system was developed to increase the oral bioavailability of mebudipine as a calcium channel blocker with very low bioavailability profile. The impact of nano-formulation on the pharmacokinetic parameters of mebudipine in rats was investigated. Nanoemulsion formulations containing ethyl oleate, Tween 80, Span 80, polyethylene glycol 400, ethanol and deionized water were prepared using probe sonicator. The optimum formulation was evaluated for physicochemical properties, such as particle size, morphology and stability. The particle size of optimum formulation was 22.8 ± 4.0 nm. Based on the results of this study, the relative bioavailability of mebudipine nanoemulsion was enhanced by about 2.6-, 2.0- and 1.9-fold, respectively, compared with suspension, ethyl oleate solution and micellar solution. In conclusion, nanoemulsion is an interesting option for the delivery of poorly water soluble molecules, such as mebudipine.

Complexation of phytochemicals with cyclodextrin derivatives - An insight.

PubMed

Suvarna, Vasanti; Gujar, Parul; Murahari, Manikanta

2017-04-01

Natural compounds have been attracting huge attention because of their broad therapeutic properties with specificity in their action in human health care as functional foods, pharmaceuticals and nutraceuticals. However poor bioavailability and reduced bioactivity attributed to poor solubility and instability is the major drawback hindering the incorporation of these therapeutically potential molecules in novel drug delivery systems. Based on the findings of reported research investigations; complexation of poorly water soluble phytochemicals with cyclodextrins has emerged to be a promising approach to improve their aqueous solubility, stability, rate of dissolution and bioavailability. The present article summarizes the encapsulation of natural compounds ranging from various flavonoids, phenolic derivatives, coumestans to triterpenes, with cyclodextrin and their derivatives. Also the article highlights the method of complexation, complexation ability, drug solubility, stability, bioavailability and safety aspects of reported natural compounds. Additionally we present the glimpses of patents published in recent 10-15 years to highlight the significance of inclusion of phytochemicals in cyclodextrins. In patents narrated, improvement in stability and solubility of curcumin by complexation with alkyl ether derivative of gamma-cyclodextrin is claimed. Another patent mentioned, complexation of artemisinins with β-cyclodextrin, improved the stability and integrity of peroxide part of artemisinins for long period. On the other hand the complex of dihydromyricetin with γ-CD has shown improved solubility, stability and bioavailability. Thus it can be concluded that phytochemicals have multiple biological activities with broader safety index and improvement of their solubility will be truly beneficial to aid their effective delivery in healthcare. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Carbohydrate-Based Host-Guest Complexation of Hydrophobic Antibiotics for the Enhancement of Antibacterial Activity.

PubMed

Jeong, Daham; Joo, Sang-Woo; Shinde, Vijay Vilas; Cho, Eunae; Jung, Seunho

2017-08-08

Host-guest complexation with various hydrophobic drugs has been used to enhance the solubility, permeability, and stability of guest drugs. Physical changes in hydrophobic drugs by complexation have been related to corresponding increases in the bioavailability of these drugs. Carbohydrates, including various derivatives of cyclodextrins, cyclosophoraoses, and some linear oligosaccharides, are generally used as host complexation agents in drug delivery systems. Many antibiotics with low bioavailability have some limitations to their clinical use due to their intrinsically poor aqueous solubility. Bioavailability enhancement is therefore an important step to achieve the desired concentration of antibiotics in the treatment of bacterial infections. Antibiotics encapsulated in a complexation-based drug delivery system will display improved antibacterial activity making it possible to reduce dosages and overcome the serious global problem of antibiotic resistance. Here, we review the present research trends in carbohydrate-based host-guest complexation of various hydrophobic antibiotics as an efficient delivery system to improve solubility, permeability, stability, and controlled release.

Improved oral bioavailability of glyburide by a self-nanoemulsifying drug delivery system.

PubMed

Liu, Hongzhuo; Shang, Kuimao; Liu, Weina; Leng, Donglei; Li, Ran; Kong, Ying; Zhang, Tianhong

2014-01-01

The present study aimed at the development and characterisation of self-nanoemulsifying drug delivery system (SNEDDS) to improve the oral bioavailability of poorly soluble glyburide. The solubility of glyburide was determined in various oils, surfactants and co-surfactants which were grouped into two different combinations to construct ternary phase diagrams. The formulations were evaluated for emulsification time, droplet size, zeta-potential, electrical conductivity and stability of nanoemulsions. The optimised SNEDDS loading with 5 mg/g glyburide comprised 55% Cremophor® RH 40, 15% propanediol and 30% Miglyol® 812, which rapidly formed fine oil-in-water nanoemulsions with 46 ± 4 nm particle size. Compared with the commercial micronised tablets (Glynase®PresTab®), enhanced in vitro release profiles of SNEDDS were observed, resulting in the 1.5-fold increase of AUC following oral administration of SNEDDS in fasting beagle dogs. These results indicated that SNEDDS is a promising drug delivery system for increasing the oral bioavailability of glyburide.

Enhanced oral bioavailability of fenofibrate using polymeric nanoparticulated systems: physicochemical characterization and in vivo investigation

PubMed Central

Yousaf, Abid Mehmood; Kim, Dong Wuk; Oh, Yu-Kyoung; Yong, Chul Soon; Kim, Jong Oh; Choi, Han-Gon

2015-01-01

Background The intention of this research was to prepare and compare various solubility-enhancing nanoparticulated systems in order to select a nanoparticulated formulation with the most improved oral bioavailability of poorly water-soluble fenofibrate. Methods The most appropriate excipients for different nanoparticulated preparations were selected by determining the drug solubility in 1% (w/v) aqueous solutions of each carrier. The polyvinylpyrrolidone (PVP) nanospheres, hydroxypropyl-β-cyclodextrin (HP-β-CD) nanocorpuscles, and gelatin nanocapsules were formulated as fenofibrate/PVP/sodium lauryl sulfate (SLS), fenofibrate/HP-β-CD, and fenofibrate/gelatin at the optimized weight ratios of 2.5:4.5:1, 1:4, and 1:8, respectively. The three solid-state products were achieved using the solvent-evaporation method through the spray-drying technique. The physicochemical characterization of these nanoparticles was accomplished by powder X-ray diffraction, differential scanning calorimetry, scanning electron microscopy, and Fourier-transform infrared spectroscopy. Their physicochemical properties, aqueous solubility, dissolution rate, and pharmacokinetics in rats were investigated in comparison with the drug powder. Results Among the tested carriers, PVP, HP-β-CD, gelatin, and SLS showed better solubility and were selected as the most appropriate constituents for various nanoparticulated systems. All of the formulations significantly improved the aqueous solubility, dissolution rate, and oral bioavailability of fenofibrate compared to the drug powder. The drug was present in the amorphous form in HP-β-CD nanocorpuscles; however, in other formulations, it existed in the crystalline state with a reduced intensity. The aqueous solubility and dissolution rates of the nanoparticles (after 30 minutes) were not significantly different from one another. Among the nanoparticulated systems tested in this study, the initial dissolution rates (up to 10 minutes) were higher with the PVP nanospheres and HP-β-CD nanocorpuscles; however, neither of them resulted in the highest oral bioavailability. Irrespective of relatively retarded dissolution rate, gelatin nanocapsules showed the highest apparent aqueous solubility and furnished the most improved oral bioavailability of the drug (~5.5-fold), owing to better wetting and diminution in crystallinity. Conclusion Fenofibrate-loaded gelatin nanocapsules prepared using the solvent-evaporation method through the spray-drying technique could be a potential oral pharmaceutical product for administering the poorly water-soluble fenofibrate with an enhanced bioavailability. PMID:25784807

Improved oral bioavailability and therapeutic efficacy of dabigatran etexilate via Soluplus-TPGS binary mixed micelles system.

PubMed

Hu, Mei; Zhang, Jinjie; Ding, Rui; Fu, Yao; Gong, Tao; Zhang, Zhirong

2017-04-01

The clinical use of dabigatran etexilate (DABE) is limited by its poor absorption and relatively low bioavailability. Our study aimed to explore the potential of a mixed micelle system composed of Soluplus ® and D-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS) to improve the oral absorption and bioavailability of DBAE. DBAE was first encapsulated into Soluplus/TPGS mixed micelles by a simple thin film hydration method. The DBAE loaded micelles displayed an average size distribution of around 83.13 nm. The cellular uptake of DBAE loaded micelles in Caco-2 cell monolayer was significantly enhanced by 2-2.6 fold over time as compared with DBAE suspension. Both lipid raft/caveolae and macropinocytosis-mediated the cell uptake of DBAE loaded micelles through P-glycoprotein (P-gp)-independent pathway. Compared with the DBAE suspension, the intestinal absorption of DBAE from DBAE mixed micelles in rats was significantly improved by 8 and 5-fold in ileum at 2 h and 4 h, respectively. Moreover, DBAE mixed micelles were absorbed into systemic circulation via both portal vein and lymphatic pathway. The oral bioavailability of DBAE mixed micelles in rats was 3.37 fold higher than that of DBAE suspension. DBAE mixed micelles exhibited a comparable anti-thrombolytic activity with a thrombosis inhibition rate of 63.18% compared with DBAE suspension in vivo. Thus, our study provides a promising drug delivery system to enhance the oral bioavailability and therapeutic efficacy of DBAE.

Polymorph Impact on the Bioavailability and Stability of Poorly Soluble Drugs.

PubMed

Censi, Roberta; Di Martino, Piera

2015-10-15

Drugs with low water solubility are predisposed to poor and variable oral bioavailability and, therefore, to variability in clinical response, that might be overcome through an appropriate formulation of the drug. Polymorphs (anhydrous and solvate/hydrate forms) may resolve these bioavailability problems, but they can be a challenge to ensure physicochemical stability for the entire shelf life of the drug product. Since clinical failures of polymorph drugs have not been uncommon, and some of them have been entirely unexpected, the Food and Drug Administration (FDA) and the International Conference on Harmonization (ICH) has required preliminary and exhaustive screening studies to identify and characterize all the polymorph crystal forms for each drug. In the past, the polymorphism of many drugs was detected fortuitously or through manual time consuming methods; today, drug crystal engineering, in particular, combinatorial chemistry and high-throughput screening, makes it possible to easily and exhaustively identify stable polymorphic and/or hydrate/dehydrate forms of poorly soluble drugs, in order to overcome bioavailability related problems or clinical failures. This review describes the concepts involved, provides examples of drugs characterized by poor solubility for which polymorphism has proven important, outlines the state-of-the-art technologies and discusses the pertinent regulations.

Nanoparticle-Formulated Curcumin Prevents Posttherapeutic Disease Reactivation and Reinfection with Mycobacterium tuberculosis following Isoniazid Therapy

PubMed Central

Tousif, Sultan; Singh, Dhiraj Kumar; Mukherjee, Sitabja; Ahmad, Shaheer; Arya, Rakesh; Nanda, Ranjan; Ranganathan, Anand; Bhattacharyya, Maitree; Van Kaer, Luc; Kar, Santosh K.; Das, Gobardhan

2017-01-01

Curcumin, the bioactive component of turmeric also known as “Indian Yellow Gold,” exhibits therapeutic efficacy against several chronic inflammatory and infectious diseases. Even though considered as a wonder drug pertaining to a myriad of reported benefits, the translational potential of curcumin is limited by its low systemic bioavailability due to its poor intestinal absorption, rapid metabolism, and rapid systemic elimination. Therefore, the translational potential of this compound is specifically challenged by bioavailability issues, and several laboratories are making efforts to improve its bioavailability. We developed a simple one-step process to generate curcumin nanoparticles of ~200 nm in size, which yielded a fivefold enhanced bioavailability in mice over regular curcumin. Curcumin nanoparticles drastically reduced hepatotoxicity induced by antitubercular antibiotics during treatment in mice. Most interestingly, co-treatment of nanoparticle-formulated curcumin along with antitubercular antibiotics dramatically reduced the risk for disease reactivation and reinfection, which is the major shortfall of current antibiotic treatment adopted by Directly Observed Treatment Short-course. Furthermore, nanoparticle-formulated curcumin significantly reduced the time needed for antibiotic therapy to obtain sterile immunity, thereby reducing the possibility of generating drug-resistant variants of the organisms. Therefore, adjunct therapy of nano-formulated curcumin with enhanced bioavailability may be beneficial to treatment of tuberculosis and possibly other diseases. PMID:28713372

Experimental determination of the oral bioavailability and bioaccessibility of lead particles

PubMed Central

2012-01-01

In vivo estimations of Pb particle bioavailability are costly and variable, because of the nature of animal assays. The most feasible alternative for increasing the number of investigations carried out on Pb particle bioavailability is in vitro testing. This testing method requires calibration using in vivo data on an adapted animal model, so that the results will be valid for childhood exposure assessment. Also, the test results must be reproducible within and between laboratories. The Relative Bioaccessibility Leaching Procedure, which is calibrated with in vivo data on soils, presents the highest degree of validation and simplicity. This method could be applied to Pb particles, including those in paint and dust, and those in drinking water systems, which although relevant, have been poorly investigated up to now for childhood exposure assessment. PMID:23173867

Lipopolysaccharide based oral nanocarriers for the improvement of bioavailability and anticancer efficacy of curcumin.

PubMed

Chaurasia, Sundeep; Patel, Ravi R; Chaubey, Pramila; Kumar, Nagendra; Khan, Gayasuddin; Mishra, Brahmeshwar

2015-10-05

Soluthin MD(®), a unique phosphatidylcholine-maltodextrin based hydrophilic lipopolysaccharide, which exhibits superior biocompatibility and bioavailability enhancer properties for poorly water soluble drug(s). Curcumin (CUR) is a potential natural anticancer drug with low bioavailability due to poor aqueous solubility. The study aims at formulation and optimization of CUR loaded lipopolysaccharide nanocarriers (C-LPNCs) to enhance oral bioavailability and anticancer efficacy in colon-26 tumor-bearing mice in vitro and in vivo. The Optimized C-LPNCs demonstrated favorable mean particle size (108 ± 3.4 nm) and percent entrapment efficiency (65.29 ± 1.0%). Pharmacokinetic parameters revealed ∼130-fold increase in oral bioavailability and cytotoxicity studies demonstrated ∼23-fold reduction in 50% cell growth inhibition when treated with optimized C-LPNCs as compared to pure CUR. In vivo anticancer study performed with optimized C-LPNCs showed significant increase in efficacy compared with pure CUR. Thus, lipopolysaccharide nanocarriers show potential delivery strategy to improve oral bioavailability and anticancer efficacy of CUR in the treatment of colorectal cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.

In vitro-in vivo correlation for wet-milled tablet of poorly water-soluble cilostazol.

PubMed

Jinno, Jun-ichi; Kamada, Naoki; Miyake, Masateru; Yamada, Keigo; Mukai, Tadashi; Odomi, Masaaki; Toguchi, Hajime; Liversidge, Gary G; Higaki, Kazutaka; Kimura, Toshikiro

2008-08-25

The purpose of the present study was to investigate oral bioavailability of an immediate release tablet containing wet-milled crystals of a poorly water-soluble drug, cilostazol, and to establish in vitro-in vivo correlation. Sub-micron sized cilostazol (median diameter: 0.26 microm) was successfully prepared using a beads-mill in water in the presence of a hydrophilic polymer and an anionic surfactant. The milled suspension was solidified with a sugar alcohol as a water-soluble carrier by spray-drying method. The co-precipitate was compressed into an immediate release tablet with common excipients. Oral bioavailability of the wet-milled cilostazol tablet in male beagle dogs was 13-fold higher than the hammer-milled commercial tablet in fasted condition. Food did not increase the oral bioavailability of the wet-milled tablet, while 4-fold increase was found for the commercial tablet. Irrespective to the bioavailability enhancement, in vitro dissolution rate of the wet-milled tablet was even slower than the commercial tablet by the compendial method (USP Apparatus 2). On the other hand, a good correlation was found between the dissolution profiles obtained by a flow-through cell method (USP Apparatus 4, closed-loop system without outlet filter) using a large volume of water and sodium lauryl sulfate (SLS) solution at the concentration lower than the critical micellar concentration (cmc) as dissolution media corresponding to the fasted and fed conditions, respectively.

Nanoparticulation improves bioavailability of Erlotinib.

PubMed

Yang, Kyung Mi; Shin, In Chul; Park, Joo Won; Kim, Kab-Sig; Kim, Dae Kyong; Park, Kyungmoon; Kim, Kunhong

2017-09-01

Nanoparticulation using fat and supercritical fluid (NUFS TM ) is a drug delivery platform technology enabling efficient and effective formulation of poorly soluble drugs. We performed experiments to examine whether NUFS™ could improve poor bioavailability and reduce fed-fasted bioavailability variances of erlotinib (Ert). NUFS-Ert was prepared using NUFS™ technology; its physical properties were characterized, and drug release was measured. Furthermore, in vitro and in vivo efficacy tests and pharmacokinetic analysis were performed. NUFS-Ert nanoparticles had an average size of 250 nm and were stable for 2 months at 40 °C, 4 °C, and room temperature. The dissolution rate of NUFS-Ert increased in bio-relevant dissolution media. NUFS-Ert was more potent in inhibiting EGF signaling and in suppressing the proliferation of A549, a human non-small cell lung cancer cell line. Furthermore, A549 xenografts in BALB/c nude mice treated with NUFS-Ert regressed more efficiently than those in the mice treated with vehicle or Tarceva ® . In addition, experimental lung metastasis was more efficiently inhibited by NUFS-Ert than by Tarceva ® . The relative bioavailability of NUFS-Ert compared with that of Tarceva ® was 550% and the ratio of the area under the concentration-time curve (AUC) of fed state to the AUC of fasted state was 1.8 for NUFS-Ert and 5.8 for Tarceva ® . NUFS-Ert could improve poor bioavailability and reduce fed-fasted bioavailability variances of Ert. NUFS-Ert was more efficacious than Tarceva ® .

Design and optimization of self-nanoemulsifying drug delivery systems for improved bioavailability of cyclovirobuxine D

PubMed Central

Ke, Zhongcheng; Hou, Xuefeng; Jia, Xiao-bin

2016-01-01

Background The main purpose of this research was to design a self-nanoemulsifying drug delivery system (SNEDDS) for improving the bioavailability of cyclovirobuxine D as a poorly water-soluble drug. Materials and methods Solubility trials, emulsifying studies, and pseudo-ternary phase diagrams were used to screen the SNEDDS formulations. The optimized drug-loaded SNEDDS was prepared at a mass ratio of 3:24:38:38 for cyclovirobuxine D, oleic acid, Solutol SH15, and propylene glycol, respectively. The optimized formulation was characterized in terms of physicochemical and pharmacokinetic parameters compared with marketed cyclovirobuxine D tablets. Results The optimized cyclovirobuxine-D-loaded SNEDDS was spontaneously dispersed to form a nanoemulsion with a globule size of 64.80±3.58 nm, which exhibited significant improvement of drug solubility, rapid absorption rate, and enhanced area under the curve, together with increased permeation and decreased efflux. Fortunately, there was a nonsignificant cytotoxic effect toward Caco-2 cells. The relative bioavailability of SNEDDS was 200.22% in comparison with market tablets, in rabbits. Conclusion SNEDDS could be a potential candidate for an oral dosage form of cyclovirobuxine D with improved bioavailability. PMID:27418807

Bioavailability and activity of phytosome complexes from botanical polyphenols: the silymarin, curcumin, green tea, and grape seed extracts.

PubMed

Kidd, Parris M

2009-09-01

Plant-derived polyphenols are increasingly receiving attention as dietary supplements for the homeostatic management of inflammation, to support detoxication, and for anticancer, weight loss, and other benefits. Their pro-homeostatic effects on genes, transcription factors, enzymes, and cell signaling pathways are being intensively explored, but the poor bioavailability of some polyphenols likely contributes to poor clinical trial outcomes. This review covers four polyphenol preparations with poor bioavailability and their complexation into phytosomes to bypass this problem. Silybin and the other silymarin flavonolignans from milk thistle conserve tissue glutathione, are liver-protective, and have anticancer potential. Curcumin and its related diphenolic curcuminoids have potent antioxidant, anti-inflammatory, and anti-carcinogenic properties. The green tea flavan-3-ol catechins have antioxidant, anti-inflammatory, cardio- and neuro-protective effects, and anti-carcinogenic benefits, with fat oxidation effects coupled to weight loss. The complex grape seed proanthocyanidin mix (including catechin and epicatechin monomers and oligomers) counters oxidative stress and protects the circulatory system. For each of these preparations, conversion into phytosomes has improved efficacy without compromising safety. The phytosome technology creates intermolecular bonding between individual polyphenol molecules and one or more molecules of the phospholipid, phosphatidylcholine (PC). Molecular imaging suggests that PC molecule(s) enwrap each polyphenol; upon oral intake the amphipathic PC molecules likely usher the polyphenol through the intestinal epithelial cell outer membrane, subsequently accessing the bloodstream. PC itself has proven clinical efficacy that contributes to phytosome in vivo actions. As a molecular delivery vehicle, phytosome technology substantially improves the clinical applicabilities of polyphenols and other poorly absorbed plant medicinals.

Perspectives on Strategies Using Swellable Polymers in Solid Dispersions for Controlled Drug Release.

PubMed

Tran, Thao T D; Tran, Phuong H L

2017-01-01

Poorly water-soluble drugs, which commonly face the issue of poor absorption and low bioavailability, have been under ongoing research of many formulation scientists for the past few decades. Solid dispersion is one of the most effective strategies in concerns for improving bioavailability of poorly water-soluble drugs. Either application of solid dispersions in dissolution enhancement of poorly water-soluble drugs or the use of swellable polymers in controlled drug release has been reported in pharmaceutical designs widely. However, a review of strategies of using swellable polymers in solid dispersion to take a full advantage of these polymers as a current perspective in facilitating drug bioavailability enhancement is still missing. In this review, we aim to provide a summary of techniques used to formulate a swellable polymer in solid dispersion especially a description of a suitable fabrication method in design of a controlled release solid dispersion. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Improving the dissolution rate of poorly water soluble drug by solid dispersion and solid solution: pros and cons.

PubMed

Chokshi, Rina J; Zia, Hossein; Sandhu, Harpreet K; Shah, Navnit H; Malick, Waseem A

2007-01-01

The solid dispersions with poloxamer 188 (P188) and solid solutions with polyvinylpyrrolidone K30 (PVPK30) were evaluated and compared in an effort to improve aqueous solubility and bioavailability of a model hydrophobic drug. All preparations were characterized by differential scanning calorimetry, powder X-ray diffraction, intrinsic dissolution rates, and contact angle measurements. Accelerated stability studies also were conducted to determine the effects of aging on the stability of various formulations. The selected solid dispersion and solid solution formulations were further evaluated in beagle dogs for in vivo testing. Solid dispersions were characterized to show that the drug retains its crystallinity and forms a two-phase system. Solid solutions were characterized to be an amorphous monophasic system with transition of crystalline drug to amorphous state. The evaluation of the intrinsic dissolution rates of various preparations indicated that the solid solutions have higher initial dissolution rates compared with solid dispersions. However, after storage at accelerated conditions, the dissolution rates of solid solutions were lower due to partial reversion to crystalline form. The drug in solid dispersion showed better bioavailability in comparison to solid solution. Therefore, considering physical stability and in vivo study results, the solid dispersion was the most suitable choice to improve dissolution rates and hence the bioavailability of the poorly water soluble drug.

Bioavailability enhancement of coenzyme Q10: an extensive review of patents.

PubMed

Beg, Sarwar; Javed, Shamama; Kohli, Kanchan

2010-11-01

Coenzyme Q10 (CoQ10) is a major antioxidant principle found in human body which plays a vital role in maintaining several biochemical pathways of body. It acts as a potential mediator in transferring electrons in oxidoreductive reactions of electron transport chain. Chemically, it is a basic quinone containing moiety having a large and high molecular weight structure. Deficiency of this in body leads to several potential disorders like dysfunctions in cellular energetics, neurological degeneration, higher oxidative stress induced damage, breast cancer etc. The high molecular weight and lipophilicity of CoQ10 makes it poorly water soluble and consequently leads to low systemic availability. Several advancements have been made to enhance the bioavailability of CoQ10 using various approaches like size reduction, solubility enhancement (by solid dispersion, prodrug, complexation, ionization) and use of novel drug carriers such as liposomes, microspheres, nanoparticles, nanoemulsions and self-emulsifying system. The primary objective of the present review is to assemble patents representing the various approaches used for enhancement of CoQ10 bioavailability.

Difference and alteration in pharmacokinetic and metabolic characteristics of low-solubility natural medicines.

PubMed

Yan, Shenglei; Liu, Yuying; Feng, Jianfang; Zhao, Hua; Yu, Zhongshu; Zhao, Jing; Li, Yao; Zhang, Jingqing

2018-05-01

Drug metabolism plays vital roles in the absorption and pharmacological activity of poorly soluble natural medicines. It is important to choose suitable delivery systems to increase the bioavailability and bioactivity of natural medicines with low solubility by regulating their metabolism and pharmacokinetics. This review investigates recent developments about the metabolic and pharmacokinetic behavior of poorly soluble natural medicines and their delivery systems. Delivery systems, dosage, administration route and drug-drug interactions alter the metabolic pathway, and bioavailability of low-solubility natural medicines to different degrees. Influencing factors such as formulation, dosage, and administration route are discussed. The metabolic reactions, metabolic enzymes, metabolites and pharmacokinetic behaviors of low-solubility natural medicines, and their delivery systems are systematically reviewed. There are various metabolic situations in the case of low-solubility natural medicines. CYP3A4 and CYP2C are the most common metabolic enzymes, and hydroxylation is the most common metabolic reaction of low solubility natural medicines. The stereo isomeric configuration can have a large influence on metabolism. This review will be useful for physicians and pharmacists to guide more accurate treatment with low-solubility natural medicines by increasing drug efficacies and protecting patients from toxic side effects.

A Helix-Stabilizing Linker Improves Subcutaneous Bioavailability of a Helical Peptide Independent of Linker Lipophilicity.

PubMed

Zhang, Liang; Navaratna, Tejas; Thurber, Greg M

2016-07-20

Stabilized peptides address several limitations to peptide-based imaging agents and therapeutics such as poor stability and low affinity due to conformational flexibility. There is also active research in developing these compounds for intracellular drug targeting, and significant efforts have been invested to determine the effects of helix stabilization on intracellular delivery. However, much less is known about the impact on other pharmacokinetic parameters such as plasma clearance and bioavailability. We investigated the effect of different fluorescent helix-stabilizing linkers with varying lipophilicity on subcutaneous (sc) bioavailability using the glucagon-like peptide-1 (GLP-1) receptor ligand exendin as a model system. The stabilized peptides showed significantly higher protease resistance and increased bioavailability independent of linker hydrophilicity, and all subcutaneously delivered conjugates were able to successfully target the islets of Langerhans with high specificity. The lipophilic peptide variants had slower absorption and plasma clearance than their respective hydrophilic conjugates, and the absolute bioavailability was also lower likely due to the longer residence times in the skin. Their ease and efficiency make double-click helix stabilization chemistries a useful tool for increasing the bioavailability of peptide therapeutics, many of which suffer from rapid in vivo protease degradation. Helix stabilization using linkers of varying lipophilicity can further control sc absorption and clearance rates to customize plasma pharmacokinetics.

Viscoelastic Emulsion Improved the Bioaccessibility and Oral Bioavailability of Crystalline Compound: A Mechanistic Study Using in Vitro and in Vivo Models.

PubMed

Ting, Yuwen; Jiang, Yike; Lan, Yaqi; Xia, Chunxin; Lin, Zhenyu; Rogers, Michael A; Huang, Qingrong

2015-07-06

The oral bioavailability of hydrophobic compound is usually limited by the poor aqueous solubility in the gastrointestinal (GI) tract. Various oral formulations were developed to enhance the systemic concentration of such molecules. Moreover, compounds with high melting temperature that appear as insoluble crystals imposed a great challenge to the development of oral vehicle. Polymethoxyflavone, an emerging category of bioactive compounds with potent therapeutic efficacies, were characterized as having a hydrophobic and highly crystalline chemical structure. To enhance the oral dosing efficiency of polymethoxyflavone, a viscoelastic emulsion system with a high static viscosity was developed and optimized using tangeretin, one of the most abundant polymethoxyflavones found in natural sources, as a modeling compound. In the present study, different in vitro and in vivo models were used to mechanistically evaluate the effect of emulsification on oral bioavailability of tangeretin. In vitro lipolysis revealed that emulsified tangeretin was digested and became bioaccessible much faster than unprocessed tangeretin oil suspension. By simulating the entire human GI tract, TNO's gastrointestinal model (TIM-1) is a valuable tool to mechanistically study the effect of emulsification on the digestion events that lead to a better oral bioavailability of tangeretin. TIM-1 result indicated that tangeretin was absorbed in the upper GI tract. Thus, a higher oral bioavailability can be expected if the compound becomes bioaccessible in the intestinal lumen soon after dosing. In vivo pharmacokinetics analysis on mice again confirmed that the oral bioavailability of tangeretin increased 2.3 fold when incorporated in the viscoelastic emulsion than unformulated oil suspension. By using the combination of in vitro and in vivo models introduced in this work, the mechanism that underlie the effect of viscoelastic emulsion on the oral bioavailability of tangeretin was well-elucidated.

Ocular Drug Delivery Barriers-Role of Nanocarriers in the Treatment of Anterior Segment Ocular Diseases.

PubMed

Bachu, Rinda Devi; Chowdhury, Pallabitha; Al-Saedi, Zahraa H F; Karla, Pradeep K; Boddu, Sai H S

2018-02-27

Ocular drug delivery is challenging due to the presence of anatomical and physiological barriers. These barriers can affect drug entry into the eye following multiple routes of administration (e.g., topical, systemic, and injectable). Topical administration in the form of eye drops is preferred for treating anterior segment diseases, as it is convenient and provides local delivery of drugs. Major concerns with topical delivery include poor drug absorption and low bioavailability. To improve the bioavailability of topically administered drugs, novel drug delivery systems are being investigated. Nanocarrier delivery systems demonstrate enhanced drug permeation and prolonged drug release. This review provides an overview of ocular barriers to anterior segment delivery, along with ways to overcome these barriers using nanocarrier systems. The disposition of nanocarriers following topical administration, their safety, toxicity and clinical trials involving nanocarrier systems are also discussed.

Ocular Drug Delivery Barriers—Role of Nanocarriers in the Treatment of Anterior Segment Ocular Diseases

PubMed Central

Bachu, Rinda Devi; Chowdhury, Pallabitha; Al-Saedi, Zahraa H. F.; Karla, Pradeep K.; Boddu, Sai H. S.

2018-01-01

Ocular drug delivery is challenging due to the presence of anatomical and physiological barriers. These barriers can affect drug entry into the eye following multiple routes of administration (e.g., topical, systemic, and injectable). Topical administration in the form of eye drops is preferred for treating anterior segment diseases, as it is convenient and provides local delivery of drugs. Major concerns with topical delivery include poor drug absorption and low bioavailability. To improve the bioavailability of topically administered drugs, novel drug delivery systems are being investigated. Nanocarrier delivery systems demonstrate enhanced drug permeation and prolonged drug release. This review provides an overview of ocular barriers to anterior segment delivery, along with ways to overcome these barriers using nanocarrier systems. The disposition of nanocarriers following topical administration, their safety, toxicity and clinical trials involving nanocarrier systems are also discussed. PMID:29495528

Formulation of a danazol cocrystal with controlled supersaturation plays an essential role in improving bioavailability.

PubMed

Childs, Scott L; Kandi, Praveen; Lingireddy, Sreenivas Reddy

2013-08-05

Cocrystals have become an established and adopted approach for creating crystalline solids with improved physical properties, but incorporating cocrystals into enabling pre-clinical formulations suitable for animal dosing has received limited attention. The dominant approach to in vivo evaluation of cocrystals has focused on deliberately excluding additional formulation in favor of "neat" aqueous suspensions of cocrystals or loading neat cocrystal material into capsules. However, this study demonstrates that, in order to take advantage of the improved solubility of a 1:1 danazol:vanillin cocrystal, a suitable formulation was required. The neat aqueous suspension of the danazol:vanillin cocrystal had a modest in vivo improvement of 1.7 times higher area under the curve compared to the poorly soluble crystal form of danazol dosed under identical conditions, but the formulated aqueous suspension containing 1% vitamin E-TPGS (TPGS) and 2% Klucel LF Pharm hydroxypropylcellulose improved the bioavailability of the cocrystal by over 10 times compared to the poorly soluble danazol polymorph. In vitro powder dissolution data obtained under non-sink biorelevant conditions correlate with in vivo data in rats following 20 mg/kg doses of danazol. In the case of the danazol:vanillin cocrystal, using a combination of cocrystal, solubilizer, and precipitation inhibitor in a designed supersaturating drug delivery system resulted in a dramatic improvement in the bioavailability. When suspensions of neat cocrystal material fail to return the anticipated bioavailability increase, a supersaturating formulation may be able to create the conditions required for the increased cocrystal solubility to be translated into improved in vivo absorption at levels competitive with existing formulation approaches used to overcome solubility limited bioavailability.

[Bioavailability of antiglaucoma drugs].

PubMed

Demailly, P

2000-05-01

The biodisponibility of antiglaucoma drugs, generally delivered in an aqueous eye-drop solution depends on their capacity to cross the cornea. The structure of the cornea forms a barrier to strongly lipophilic substances and the continuous renewal of the lacrimal film creates a major obstacle, preventing active substances from penetrating the eye. Active substances must thus be delivered in highly concentrated solutions. The systemic bioavailability of antiglaucoma drugs taken orally, for example beta-blockers, is well known, their behavior after eye-drop administration remains poorly elucidated and highly dependent on individual susceptibility. We reviewed the literature on pilocarpine, beta-blockers, adrenergic drugs (dipivalyl-epinephrine, apraclonidine, brimonidine), carbon anhydrase inhibitors (acetazolamide, dorzolamide).

Enhanced oral bioavailability and anticancer efficacy of fisetin by encapsulating as inclusion complex with HPβCD in polymeric nanoparticles.

PubMed

Kadari, Amrita; Gudem, Sagarika; Kulhari, Hitesh; Bhandi, Murali Mohan; Borkar, Roshan M; Kolapalli, Venkata Ramana Murthy; Sistla, Ramakrishna

2017-11-01

Fisetin (FST), a potent anticancer phytoconstituent, exhibits poor aqueous solubility and hence poor bioavailability. The aim of the present study is to improve the oral bioavailability of FST by encapsulating into PLGA NPs (poly-lactide-co-glycolic acid nanoparticles) as a complex of HPβCD (hydroxyl propyl beta cyclodextrin) and to assess its anti-cancer activity against breast cancer cells. FST-HPβCD inclusion complex (FHIC) was prepared and the supramolecular complex formation was characterized by FTIR, DSC, PXRD and 1 H NMR. FHIC encapsulated PLGA nanoparticles (FHIC-PNP) were prepared and were studied for in vitro anticancer activity, cellular uptake, apoptosis and reactive oxygen species generation in MCF-7 human breast cancer cells. Comparative bioavailability of FST was determined after oral administration in C57BL6 mice as pure FST and FHIC-PNP. The results revealed that FHIC-PNP not only enhanced the anti-cancer activity and apoptosis of FST against MCF-7 cells but also improved its oral bioavailability, as demonstrated by increased peak plasma concentration and total drug absorbed.

Lapatinib nano-delivery systems: a promising future for breast cancer treatment.

PubMed

Bonde, Gunjan Vasant; Yadav, Sarita Kumari; Chauhan, Sheetal; Mittal, Pooja; Ajmal, Gufran; Thokala, Sathish; Mishra, Brahmeshwar

2018-05-01

Breast cancer stands the second prominent cause of death among women. For its efficient treatment, Lapatinib (LAPA) was developed as a selective tyrosine kinase inhibitor of receptors, overexpressed by breast cancer cells. Various explored delivery strategies for LAPA indicated its controlled release with enhanced aqueous solubility, improved bioavailability, decreased plasma protein binding, reduced dose and toxicity to the other organs with maximized clinical efficacy, compared to its marketed tablet formulation. Areas covered: This comprehensive review deals with the survey, performed through different electronic databases, regarding various challenges and their solutions attained by fabricating delivery systems like nanoparticles, micelle, nanocapsules, nanochannels, and liposomes. It also covers the synthesis of novel LAPA-conjugates for diagnostic purpose. Expert opinion: Unfortunately, clinical use of LAPA is restricted because of its extensive albumin binding capacity, poor oral bioavailability, and poor aqueous solubility. LAPA is marketed as the oral tablet only. Therefore, it becomes imperative to formulate alternate efficient multiparticulate or nano-delivery systems for administration through non-oral routes, for active/passive targeting, and to scale-up by pharmaceutical scientists followed by their clinical trials by clinical experts. LAPA combinations with capecitabine and letrozole should also be tried for breast cancer treatment.

Enhancement of human oral bioavailability and in vitro antitumor activity of rosuvastatin via spray dried self-nanoemulsifying drug delivery system.

PubMed

Kamel, Amany O; Mahmoud, Azza A

2013-01-01

The purpose of this study was to develop spray dried self-nanoemulsifying drug delivery system (SNEDDS) tablets of rosuvastatin using mannitol as a carrier. SNEDDS were prepared using Capryol 90, poloxamer 407 and Transcutol P or triacetin as oil, surfactant and cosurfactants, respectively. The prepared systems were characterized and their cytotoxicity was evaluated using Caco-2 cell lines. A comparative bioavailability study was performed in human volunteers relative to the conventional commercial product. Results showed better self-nanoemulsifying ability of systems containing triacetin compared to Transcutol P. SNEDDS formed uni-modal nanoemulsion droplet size distributions with droplet size less than 50 nm and polydispersity index values ranging from 0.127 to 0.275. The solubilizing capacity of rosuvastatin was affected by both surfactant and cosurfactant concentrations. Upon spray drying, systems prepared using Transcutol P tended to be soft and tacky and were sticking to the walls of the dryer. The redispersion of rosuvastatin from solid SNEDDS was very fast (100% within 5 minutes). Optimized SNEDDS prepared with triacetin were safe with no cytotoxic effect on Caco-2 cells. The anticancer effect of rosuvastatin was enhanced when incorporated in SNEDDS (IC50 value decreased from 4 to 3 microg/ml) due to the increase in penetration of SNEDDS inside the cells. The relative bioavailability for SNEDDS tablets compared to the commercial tablets was 167%. The effective solubilization, penetration and enhancement in bioavailability of SNEDDS tablets proves their potential as a safe, and effective drug delivery system for poorly-soluble drugs.

Characterization, pharmacokinetics and tissue distribution of chlorogenic acid-loaded self-microemulsifying drug delivery system.

PubMed

Chen, Li; Liu, Chang-Shun; Chen, Qing-Zhen; Wang, Sen; Xiong, Yong-Ai; Jing, Jing; Lv, Jia-Jia

2017-03-30

The purpose of this study was to develop a self-microemulsifying drug delivery system (SMEDDS) to improve the oral bioavailability of Chlorogenic acid (CA), an important bioactive compound from Lonicerae Japonicae Flos with poor permeability. SMEDDS was prepared and characterized by self-emulsifying rate, morphological observation, droplet size determination, stability, in vitro release, in vivo bioavailability and tissue distribution experiments. Results shown that the SMEDDS of CA has a high self-emulsifying rate (>98%) in the dissolution media, and its microemulsion exhibits small droplet size (16.37nm) and good stability. In vitro release test showed a complete release of CA from SMEDDS in 480min. After oral administration in mice, significantly enhanced bioavailability of CA was achieved through SMEDDS (249.4% relative to the CA suspension). Interestingly, SMEDDS significantly changed the tissue distribution of CA and showed a better targeting property to the kidney (2.79 of the relative intake efficiency). It is suggested that SMEDDS improves the oral bioavailability of CA may mainly through increasing its absorption and slowing the metabolism of absorbed CA via changing its distribution from the liver to the kidney. In conclusion, it is indicated that SMEDDS is a promising carrier for the oral delivery of CA. Copyright © 2017 Elsevier B.V. All rights reserved.

A comprehensive overview on the micro- and nano-technological encapsulation advances for enhancing the chemical stability and bioavailability of carotenoids.

PubMed

Soukoulis, Christos; Bohn, Torsten

2018-01-02

Carotenoids are lipophilic secondary plant compounds, and their consumption within fruits and vegetables has been positively correlated with a decreased risk of developing several chronic diseases. However, their bioavailability is often compromised due to incomplete release from the food matrix, poor solubility and potential degradation during digestion. In addition, carotenoids in food products are prone to oxidative degradation, not only lowering the nutritional value of the product but also triggering other quality deteriorative changes, such as formation of lipid pro-oxidants (free radicals), development of discolorations or off-flavor defects. Encapsulation refers to a physicochemical process, aiming to entrap an active substance in structurally engineered micro- or nano-systems, in order to develop an effective thermodynamical and physical barrier against deteriorative environmental conditions, such as water vapor, oxygen, light, enzymes or pH. In this context, encapsulation of carotenoids has shown to be a very effective strategy to improve their chemical stability under common processing conditions including storage. In addition, encapsulation may also enhance bioavailability (via influencing bioaccessibility and absorption) of lipophilic bioactives, via modulating their release kinetics from the carrier system, solubility and interfacial properties. In the present paper, it is aimed to present the state of the art of carotenoid microencapsulation in order to enhance storability and bioavailability alike.

Progress in nanotechnology-based drug carrier in designing of curcumin nanomedicines for cancer therapy: current state-of-the-art.

PubMed

Ahmad, Mohammad Zaki; Alkahtani, Saad Ahmed; Akhter, Sohail; Ahmad, Farhan Jalees; Ahmad, Javed; Akhtar, Mohammad Shabib; Mohsin, Nehal; Abdel-Wahab, Basel A

2016-01-01

Comprehensive pharmacological screening of curcumin (CUR) has given the evidence that it is an excellent naturally occurring therapeutic moiety for cancer. It is very well tolerated with insignificant toxicity even after high doses of oral administration. Irrespective of its better quality as an anticancer agent, therapeutic application of CUR is hampered by its extremely low-aqueous solubility and poor bioavailability, rapid clearance and low-cellular uptake. A simple means of breaking up the restrictive factor of CUR is to perk-up its aqueous solubility, improve its bioavailability, protect it from degradation, and metabolism and potentiate its targeting capacity towards the cancer cell. The development in the field of nanomedicine has made excellent progresses toward enhancing the bioavailability of lipophilic drugs like CUR. Nanoparticles (NPs) are capable to deliver the CUR at specific area and thereby prevent it from physiological degradation and systemic clearance. In recent year, an assortment of nanomedicine-based novel drug delivery system has been designed to potentiate the bioavailability of CUR towards anticancer therapy. In this review, we discuss the recent development in the field of nanoCUR (NanoCur), including polymeric micelles, liposome, polymeric NPs, nanoemulsion, nanosuspension, solid lipid NPs (SLNPs), polymer conjugates, nanogel, etc. in anticancer application.

Role of self-emulsifying drug delivery systems in optimizing the oral delivery of hydrophilic macromolecules and reducing interindividual variability.

PubMed

AboulFotouh, Khaled; Allam, Ayat A; El-Badry, Mahmoud; El-Sayed, Ahmed M

2018-07-01

Self-emulsifying drug delivery systems (SEDDS) have been widely employed to improve the oral bioavailability of poorly soluble drugs. In the past few years, SEDDS were extensively investigated to overcome various barriers encountered in the oral delivery of hydrophilic macromolecules (e.g., protein/peptide therapeutics and plasmid DNA (pDNA)), as well as in lowering the effect of food on drugs' bioavailability. However, the main mechanism(s) by which SEDDS could achieve such promising effects remains not fully understood. This review summarizes the recent progress in the use of SEDDS for protecting protein therapeutics and/or pDNA against enzymatic degradation and increasing the oral bioavailability of various drug substances regardless of the dietary condition. Understanding the underlying mechanism(s) of such promising applications will aid in the future development of rationally designed SEDDS. Entrapment of hydrophilic macromolecules in the oil phase of the formed emulsion is critical for protection of the loaded cargoes against enzymatic degradation and the enhancement of oral bioavailability. On the other hand, drug administration as a preconcentrated solution in the SEDDS preconcentrate allows the process of drug absorption to occur independently of the dietary condition, and thus reducing interindividual variability that results from concomitant food intake. Copyright © 2018 Elsevier B.V. All rights reserved.

Improved Bioavailability of Levodopa Using Floatable Spray-Coated Microcapsules for the Management of Parkinson's Disease.

PubMed

Baek, Jong-Suep; Tee, Jie Kai; Pang, Yi Yun; Tan, Ern Yu; Lim, Kah Leong; Ho, Han Kiat; Loo, Say Chye Joachim

2018-06-01

Oral administration of levodopa (LD) is the gold standard in managing Parkinson's disease (PD). Although LD is the most effective drug in treating PD, chronic administration of LD induces levodopa-induced dyskinesia. A continuous and sustained provision of LD to the brain could, therefore, reduce peak-dose dyskinesia. In commercial oral formulations, LD is co-administrated with an AADC inhibitor (carbidopa) and a COMT inhibitor (entacapone) to enhance its bioavailability. Nevertheless, patients are known to take up to five tablets a day because of poor sustained-releasing capabilities that lead to fluctuations in plasma concentrations. To achieve a prolonged release of LD with the aim of improving its bioavailability, floatable spray-coated microcapsules containing all three PD drugs were developed. This gastro-retentive delivery system showed sustained release of all PD drugs, at similar release kinetics. Pharmacokinetics study was conducted and this newly developed formulation showed a more plateaued delivery of LD that is void of the plasma concentration fluctuations observed for the control (commercial formulation). At the same time, measurements of LD and dopamine of mice administered with this formulation showed enhanced bioavailability of LD. This study highlights a floatable, sustained-releasing delivery system in achieving improved pharmacokinetics data compared to a commercial formulation.

Improving dissolution and oral bioavailability of pranlukast hemihydrate by particle surface modification with surfactants and homogenization

PubMed Central

Ha, Eun-Sol; Baek, In-hwan; Yoo, Jin-Wook; Jung, Yunjin; Kim, Min-Soo

2015-01-01

The present study was carried out to develop an oral formulation of pranlukast hemihydrate with improved dissolution and oral bioavailability using a surface-modified microparticle. Based on solubility measurements, surface-modified pranlukast hemihydrate microparticles were manufactured using the spray-drying method with hydroxypropylmethyl cellulose, sucrose laurate, and water and without the use of an organic solvent. The hydrophilicity of the surface-modified pranlukast hemihydrate microparticle increased, leading to enhanced dissolution and oral bioavailability of pranlukast hemihydrate without a change in crystallinity. The surface-modified microparticles with an hydroxypropylmethyl cellulose/sucrose laurate ratio of 1:2 showed rapid dissolution of up to 85% within 30 minutes in dissolution medium (pH 6.8) and oral bioavailability higher than that of the commercial product, with approximately 2.5-fold and 3.9-fold increases in area under the curve (AUC0→12 h) and peak plasma concentration, respectively. Therefore, the surface-modified microparticle is an effective oral drug delivery system for the poorly water-soluble therapeutic pranlukast hemihydrate. PMID:26150699

Pharmaceutical cocrystals: a novel approach for oral bioavailability enhancement of drugs.

PubMed

Chadha, Renu; Saini, Anupam; Arora, Poonam; Bhandari, Swati

2012-01-01

Solid dosage forms are by far the preferred drug delivery systems. However, these often face the problem of poor and erratic bioavailability during the drug development process. Numerous formulation strategies for drug delivery are currently under development, among which the solid forms such as polymorphs, solvates, salts, and cocrystals have been considered to be the most important for improving dissolution rate and bioavailability. Cocrystallization is a fairly new approach in pharmaceutical industry that can improve the solubility and, consequently, the bioactivity of the active pharmaceutical ingredient (API) without compromising its structural integrity. Pharmaceutical cocrystals have found their place in drug delivery, primarily due to their ability to produce alternative, viable solid forms when a more standard approach of salt and polymorph formation fails to deliver the desired objectives. Over the past few years, a number of papers have been published focusing on a broad range of subjects, from traditional crystal engineering to structure-property relationships of cocrystals. The present review, however, illustrates how the cocrystalline forms of APIs have improved their in vitro dissolution rate and in vivo bioavailability, often correlating well with their improved solubility as well.

Development and evaluation of a novel microemulsion formulation of elacridar to improve its bioavailability

PubMed Central

Sane, Ramola; Mittapalli, Rajendar K.; Elmquist, William F.

2014-01-01

The study objective was to develop a formulation of elacridar to overcome its dissolution-rate limited bioavailability. Elacridar is a P-gp and BCRP inhibitor that has been used to improve the brain distribution of drugs that are substrates of P-gp and BCRP. The chronic use of elacridar is restricted due to poor solubility leading to poor oral bioavailability. A microemulsion formulation using Cremophor EL, Carbitol and Captex 355 (6:3:1) was developed. The elacridar microemulsion was effective in the inhibition of P-gp and Bcrp in MDCKII-transfected cells. FVBn mice were used to determine the bioavailability of elacridar after a 10 mg/kg dose of elacridar in the microemulsion, intraperitoneally and orally; and the absolute bioavailability was determined to be 1.3 and 0.47, respectively. Co-administration of elacridar microemulsion intraperitoneally with oral erlotinib in FVBn mice improved the erlotinib brain penetration three-fold. The current study shows that a microemulsion formulation of elacridar is effective in improving the bioavailability of elacridar and is an effective inhibitor of P-gp and Bcrp; in-vitro and in-vivo. It offers an alternative to the suspension and allows a decrease in the dose required to achieve a significant inhibitory effect at the blood-brain barrier. PMID:23334925

Development of optimized self-nano-emulsifying drug delivery systems (SNEDDS) of carvedilol with enhanced bioavailability potential.

PubMed

Singh, Bhupinder; Khurana, Lalit; Bandyopadhyay, Shantanu; Kapil, Rishi; Katare, O O P

2011-11-01

Carvedilol, a widely prescribed cardiovascular drug for hypertension and congestive heart failure, exhibits low and variable bioavailability owing to poor absorption and extensive hepatic first-pass metabolism. The current research work, therefore, entails formulation development of liquid self-nano-emulsifying drug delivery systems (SNEDDS) to enhance the bioavailability of carvedilol by facilitating its transport via lymphatic circulation. The formulation constituents, i.e. lipids, surfactants, and co-surfactants, were selected on the basis of solubility studies. Pseudo-ternary phase diagrams were constructed to embark upon the selection of blend of lipidic (i.e. Capmul PG8) and hydrophilic components (i.e. Cremophor EL as surfactant and Transcutol HP as co-surfactant) for efficient and robust formulation of SNEDDS. The SNEDDS, systematically optimized employing a central composite design (CCD), were evaluated for various response variables viz drug release parameters, emulsification time, emulsion droplet size, and mean dissolution time. In vitro drug release studies depicted that the release from SNEDDS systems followed a non-Fickian kinetic behavior. The TEM imaging of the optimized formulation affirmed the uniform shape and nano size of the system. Accelerated studies of the optimized formulation indicated high stability of the formulation for 6 months. The in situ perfusion studies carried out in wistar rats construed several fold augmentation in the permeability and absorption potential of the optimized formulation vis-à-vis marketed formulation. Thus, the present studies ratified the potential of SNEDDS in augmenting the oral bioavailability of BCS class II drugs.

A Helix-Stabilizing Linker Improves Subcutaneous Bioavailability of a Helical Peptide Independent of Linker Lipophilicity

PubMed Central

Zhang, Liang; Navaratna, Tejas; Thurber, Greg M.

2016-01-01

Stabilized peptides address several limitations to peptide-based imaging agents and therapeutics such as poor stability and low affinity due to conformational flexibility. There is also active research in developing these compounds for intracellular drug targeting, and significant efforts have been invested to determine the effects of helix stabilization on intracellular delivery. However, much less is known about the impact on other pharmacokinetic parameters such as plasma clearance and bioavailability. We investigated the effect of different fluorescent helix-stabilizing linkers with varying lipophilicity on subcutaneous (SC) bioavailability using the glucagon-like peptide-1 (GLP-1) receptor ligand exendin as a model system. The stabilized peptides showed significantly higher protease resistance and increased bioavailability independent of linker hydrophilicity, and all subcutaneously delivered conjugates were able to successfully target the islets of Langerhans with high specificity. The lipophilic peptide variants had slower absorption and plasma clearance than their respective hydrophilic conjugates, and the absolute bioavailability was also lower likely due to the longer residence times in the skin. The ease and efficiency of double-click helix stabilization chemistries is a useful tool for increasing the bioavailability of peptide therapeutics, many of which suffer from rapid in vivo protease degradation. Helix stabilization using linkers of varying lipophilicity can further control SC absorption and clearance rates to customize plasma pharmacokinetics. PMID:27327034

Novel electrosprayed nanospherules for enhanced aqueous solubility and oral bioavailability of poorly water-soluble fenofibrate

PubMed Central

Yousaf, Abid Mehmood; Mustapha, Omer; Kim, Dong Wuk; Kim, Dong Shik; Kim, Kyeong Soo; Jin, Sung Giu; Yong, Chul Soon; Youn, Yu Seok; Oh, Yu-Kyoung; Kim, Jong Oh; Choi, Han-Gon

2016-01-01

Purpose The purpose of the present research was to develop a novel electrosprayed nanospherule providing the most optimized aqueous solubility and oral bioavailability for poorly water-soluble fenofibrate. Methods Numerous fenofibrate-loaded electrosprayed nanospherules were prepared with polyvinylpyrrolidone (PVP) and Labrafil® M 2125 as carriers using the electrospray technique, and the effect of the carriers on drug solubility and solvation was assessed. The solid state characterization of an optimized formulation was conducted by scanning electron microscopy, powder X-ray diffraction, differential scanning calorimetry, and Fourier transform infrared spectroscopic analyses. Oral bioavailability in rats was also evaluated for the formulation of an optimized nanospherule in comparison with free drug and a conventional fenofibrate-loaded solid dispersion. Results All of the electrosprayed nanospherule formulations had remarkably enhanced aqueous solubility and dissolution compared with free drug. Moreover, Labrafil M 2125, a surfactant, had a positive influence on the solubility and dissolution of the drug in the electrosprayed nanospherule. Increases were observed as the PVP/drug ratio increased to 4:1, but higher ratios gave no significant increases. In particular, an electrosprayed nanospherule composed of fenofibrate, PVP, and Labrafil M 2125 at the weight ratio of 1:4:0.5 resulted in a particle size of <200 nm with the drug present in the amorphous state. It demonstrated the highest solubility (32.51±2.41 μg/mL), an excellent dissolution (~85% in 10 minutes), and an oral bioavailability ~2.5-fold better than that of the free drug. It showed similar oral bioavailability compared to the conventional solid dispersion. Conclusion Electrosprayed nanospherules, which provide improved solubility and bioavailability, are promising drug delivery tools for oral administration of poorly water-soluble fenofibrate. PMID:26834471

Novel electrosprayed nanospherules for enhanced aqueous solubility and oral bioavailability of poorly water-soluble fenofibrate.

PubMed

Yousaf, Abid Mehmood; Mustapha, Omer; Kim, Dong Wuk; Kim, Dong Shik; Kim, Kyeong Soo; Jin, Sung Giu; Yong, Chul Soon; Youn, Yu Seok; Oh, Yu-Kyoung; Kim, Jong Oh; Choi, Han-Gon

2016-01-01

The purpose of the present research was to develop a novel electrosprayed nanospherule providing the most optimized aqueous solubility and oral bioavailability for poorly water-soluble fenofibrate. Numerous fenofibrate-loaded electrosprayed nanospherules were prepared with polyvinylpyrrolidone (PVP) and Labrafil(®) M 2125 as carriers using the electrospray technique, and the effect of the carriers on drug solubility and solvation was assessed. The solid state characterization of an optimized formulation was conducted by scanning electron microscopy, powder X-ray diffraction, differential scanning calorimetry, and Fourier transform infrared spectroscopic analyses. Oral bioavailability in rats was also evaluated for the formulation of an optimized nanospherule in comparison with free drug and a conventional fenofibrate-loaded solid dispersion. All of the electrosprayed nanospherule formulations had remarkably enhanced aqueous solubility and dissolution compared with free drug. Moreover, Labrafil M 2125, a surfactant, had a positive influence on the solubility and dissolution of the drug in the electrosprayed nanospherule. Increases were observed as the PVP/drug ratio increased to 4:1, but higher ratios gave no significant increases. In particular, an electrosprayed nanospherule composed of fenofibrate, PVP, and Labrafil M 2125 at the weight ratio of 1:4:0.5 resulted in a particle size of <200 nm with the drug present in the amorphous state. It demonstrated the highest solubility (32.51±2.41 μg/mL), an excellent dissolution (~85% in 10 minutes), and an oral bioavailability ~2.5-fold better than that of the free drug. It showed similar oral bioavailability compared to the conventional solid dispersion. Electrosprayed nanospherules, which provide improved solubility and bioavailability, are promising drug delivery tools for oral administration of poorly water-soluble fenofibrate.

Does ascorbic acid supplementation affect iron bioavailability in rats fed micronized dispersible ferric pyrophosphate fortified fruit juice?

PubMed

Haro-Vicente, Juan Francisco; Pérez-Conesa, Darío; Rincón, Francisco; Ros, Gaspar; Martínez-Graciá, Carmen; Vidal, Maria Luisa

2008-12-01

Food iron (Fe) fortification is an adequate approach for preventing Fe-deficiency anemia. Poorly water-soluble Fe compounds have good sensory attributes but low bioavailability. The reduction of the particle size of Fe fortificants and the addition of ascorbic acid might increase the bioavailability of low-soluble compounds. The present work aims to compare the Fe absorption and bioavailability of micronized dispersible ferric pyrophosphate (MDFP) (poorly soluble) to ferrous sufate (FS) (highly soluble) added to a fruit juice in presence or absence of ascorbic acid (AA) by using the hemoglobin repletion assay in rats. After a hemoglobin depletion period, four fruit juices comprised of (1) FS, (2) MDFP, (3) FS + AA, (4) MDFP + AA were produced and administered to a different group of rats (n = 18) over 21 days. During the repletion period, Fe balance, hemoglobin regeneration efficiency (HRE), relative bioavailability (RBV) and Fe tissue content were determined in the short, medium and long term. Fe absorption and bioavailability showed no significant differences between fortifying the fruit juice with FS or MDFP. The addition of AA to the juice enhanced Fe absorption during the long-term balance study within the same Fe source. HRE and Fe utilization increased after AA addition in both FS and MDFP groups in every period. Fe absorption and bioavailability from MDFP were comparable to FS added to a fruit juice in rats. Further, the addition of AA enhanced Fe absorption in the long term, as well as Fe bioavailability throughout the repletion period regardless of the Fe source employed.

Nanosizing of drugs: Effect on dissolution rate

PubMed Central

Dizaj, S. Maleki; Vazifehasl, Zh.; Salatin, S.; Adibkia, Kh.; Javadzadeh, Y.

2015-01-01

The solubility, bioavailability and dissolution rate of drugs are important parameters for achieving in vivo efficiency. The bioavailability of orally administered drugs depends on their ability to be absorbed via gastrointestinal tract. For drugs belonging to Class II of pharmaceutical classification, the absorption process is limited by drug dissolution rate in gastrointestinal media. Therefore, enhancement of the dissolution rate of these drugs will present improved bioavailability. So far several techniques such as physical and chemical modifications, changing in crystal habits, solid dispersion, complexation, solubilization and liquisolid method have been used to enhance the dissolution rate of poorly water soluble drugs. It seems that improvement of the solubility properties ofpoorly water soluble drugscan translate to an increase in their bioavailability. Nowadays nanotechnology offers various approaches in the area of dissolution enhancement of low aqueous soluble drugs. Nanosizing of drugs in the form of nanoparticles, nanocrystals or nanosuspensions not requiring expensive facilities and equipment or complicated processes may be applied as simple methods to increase the dissolution rate of poorly water soluble drugs. In this article, we attempted to review the effects of nanosizing on improving the dissolution rate of poorly aqueous soluble drugs. According to the reviewed literature, by reduction of drug particle size into nanometer size the total effective surface area is increased and thereby dissolution rate would be enhanced. Additionally, reduction of particle size leads to reduction of the diffusion layer thickness surrounding the drug particles resulting in the increment of the concentration gradient. Each of these process leads to improved bioavailability. PMID:26487886

Differences in relative bioavailability of traditional Bangladeshi meal plans

USDA-ARS?s Scientific Manuscript database

Background: Iron (Fe) deficiency is the most common nutrient deficiency worldwide. Large intakes of micronutrient-poor staple crops, coupled with low intakes of highly bioavailable dietary Fe is a major cause of this deficiency. Objective: This study examined the Fe concentration and relative Fe ...

Loading amorphous Asarone in mesoporous silica SBA-15 through supercritical carbon dioxide technology to enhance dissolution and bioavailability.

PubMed

Zhang, Zhengzan; Quan, Guilan; Wu, Qiaoli; Zhou, Chan; Li, Feng; Bai, Xuequn; Li, Ge; Pan, Xin; Wu, Chuanbin

2015-05-01

The aim of this study was to load amorphous hydrophobic drug into ordered mesoporous silica (SBA-15) by supercritical carbon dioxide technology in order to improve the dissolution and bioavailability of the drug. Asarone was selected as a model drug due to its lipophilic character and poor bioavailability. In vitro dissolution and in vivo bioavailability of the obtained Asarone-SBA-15 were significantly improved as compared to the micronized crystalline drug. This study offers an effective, safe, and environmentally benign means of solving the problems relating to the solubility and bioavailability of hydrophobic molecules. Copyright © 2015 Elsevier B.V. All rights reserved.

Preparation and optimization of tablets containing a self-nano-emulsifying drug delivery system loaded with rosuvastatin.

PubMed

Salem, Heba F; Kharshoum, Rasha M; Halawa, Abdel Khalek A; Naguib, Demiana M

2018-06-01

Rosuvastatin (ROS) calcium is the latest synthetic drug in the statin group that has an anti-hyperlipidemic activity. It is available as tablets, and its poor aqueous solubility, slow dissolution rate and low-absorption extent result in less than 20% bioavailability and about 80% being excreted unchanged in the feces without absorption. To utilize nanotechnology to reformulate ROS as a self-nano-emulsifying drug delivery system (SNEDDS), and utilizing design optimization to fabricate the SNEDDS as a tablet. The solubility of ROS in different oils, surfactants and co-surfactants was tested. Pseudo-ternary phase diagrams were developed and various SNEDDS formulations were prepared and evaluated regarding globule size, self-emulsification, viscosity and transmittance. The optimized system was examined using transmission electron microscopy. The self-nano-emulsifying tablets were prepared using two types of nano-silica and different percentages of Avicel as a binder and Ac-Di-Sol as a disintegrant. The prepared tablets were evaluated for their physicochemical properties. Bioavailability in human volunteers was assessed. A SNEDDS system was successfully developed with a droplet size range of 15 nm and a composition of 10% Labrafac, 80% Cremophore RH40 and 10% Propylene glycol. The optimized tablet formula contained: hydrophilic nano-silica, 3% Ac-Di-Sol and 30% Avicel. The pharmacokinetic study revealed that the bioavailability was enhanced by more than 2.4-fold compared with the commercially available tablet. Tablets containing SNEDDS loaded with ROS represent a promising novel formula that has higher gastrointestinal absorption and enhanced systemic bioavailability.

Binary lipids-based nanostructured lipid carriers for improved oral bioavailability of silymarin.

PubMed

Shangguan, Mingzhu; Lu, Yi; Qi, Jianping; Han, Jin; Tian, Zhiqiang; Xie, Yunchang; Hu, Fuqiang; Yuan, Hailong; Wu, Wei

2014-02-01

The main purpose of this study was to prepare binary lipids-based nanostructured lipid carriers to improve the oral bioavailability of silymarin, a poorly water-soluble liver protectant. Silymarin-loaded nanostructured lipid carriers were prepared by the method of high-pressure homogenization with glycerol distearates (Precirol ATO-5) and oleic acid as the solid and liquid lipids, respectively, and lecithin (Lipoid E 100) and Tween-80 as the emulsifiers. The silymarin-nanostructured lipid carrier prepared under optimum conditions was spherical in shape with mean particle size of ∼78.87 nm, entrapment efficiency of 87.55%, loading capacity of 8.32%, and zeta potential of -65.3 mV, respectively. In vitro release of silymarin-nanostructured lipid carriers was very limited even after 12 h, while in vitro lipolysis showed fast digestion of nanostructured lipid carriers within 1 h. Relative oral bioavailability of silymarin-nanostructured lipid carriers in Beagle dogs was 2.54- and 3.10-fold that of marketed Legalon® and silymarin solid dispersion pellets, respectively. It was concluded that nanostructured lipid carriers were potential drug delivery systems to improve the bioavailability of silymarin. Other than improved dissolution, alternative mechanisms such as facilitated absorption as well as lymphatic transport may contribute to bioavailability enhancement.

Enhanced bioavailability of opiates after intratracheal administration

DOE Office of Scientific and Technical Information (OSTI.GOV)

Findlay, J.W.A.; Jones, E.C.; McNulty, M.J.

1986-03-01

Several opiate analgesics have low oral bioavailabilities in the dog because of presystemic metabolism. Intratracheal administration may circumvent this first-pass effect. Three anesthetized beagles received 5-mg/kg doses of codeine phosphate intratracheally (i.t.), orally (p.o.) and intravenously (i.v.) in a crossover study. The following drugs were also studied in similar experiments: ethylmorphine hydrochloride (5 mg/kg), pholcodine bitartrate (10 mg/kg, hydrocodone bitartrate (4 mg/kg) and morphine sulfate (2.5 mg/kg). Plasma drug concentrations over the 24- to 48-hr periods after drug administrations were determined by radioimmunoassays. I.t. bioavailabilities (codeine (84%), ethylmorphine (100%), and morphine (87%)) of drugs with poor oral availabilities were allmore » markedly higher than the corresponding oral values (14, 26, and 23%, respectively). I.t. bioavailabilities of pholcodine (93%) and hydrocodone (92%), which have good oral availabilities (74 and 79%, respectively), were also enhanced. In all cases, peak plasma concentrations occurred more rapidly after i.t. (0.08-0.17 hr) than after oral (0.5-2 hr) dosing and i.t. disposition often resembled i.v. kinetics. I.t. administration may be a valuable alternative dosing route, providing rapid onset of pharmacological activity for potent drugs with poor oral bioavailability.« less

Lipid-based nanocarriers as an alternative for oral delivery of poorly water- soluble drugs: peroral and mucosal routes.

PubMed

Silva, A C; Santos, D; Ferreira, D; Lopes, C M

2012-01-01

The hydrophobic character of most drug molecules and their potential for degradation under the hostile environment of the gastrointestinal tract (GIT) constitutes the main obstacle in the development of a successful oral drug delivery system, since these are related to limitations of bioavailability and absorption processes. However, according to the advantages of the oral route, alternative ways of drug administration in the oral cavity should be considered. In this context, it is essential to have a systematic knowledge of the GIT and the oral cavity components, for a better understanding of the processes taking place during the oral administration of drugs. This review gives an overview of those anatomical and physiological features and elucidates about the current approaches employed to enhance the bioavailability of oral poorly water-soluble drugs. Strategies including the uses of lipid-based nanocarriers, such as nanoemulsions, liposomes and lipid nanoparticles are discussed, considering their ability to improve solubility, dissolution kinetics, absorption and, consequently, biopharmaceutical properties. Some toxicological concerns are also highlighted.

Enhancing the solubility and bioavailability of poorly water-soluble drugs using supercritical antisolvent (SAS) process.

PubMed

Abuzar, Sharif Md; Hyun, Sang-Min; Kim, Jun-Hee; Park, Hee Jun; Kim, Min-Soo; Park, Jeong-Sook; Hwang, Sung-Joo

2018-03-01

Poor water solubility and poor bioavailability are problems with many pharmaceuticals. Increasing surface area by micronization is an effective strategy to overcome these problems, but conventional techniques often utilize solvents and harsh processing, which restricts their use. Newer, green technologies, such as supercritical fluid (SCF)-assisted particle formation, can produce solvent-free products under relatively mild conditions, offering many advantages over conventional methods. The antisolvent properties of the SCFs used for microparticle and nanoparticle formation have generated great interest in recent years, because the kinetics of the precipitation process and morphologies of the particles can be accurately controlled. The characteristics of the supercritical antisolvent (SAS) technique make it an ideal tool for enhancing the solubility and bioavailability of poorly water-soluble drugs. This review article focuses on SCFs and their properties, as well as the fundamentals of overcoming poorly water-soluble drug properties by micronization, crystal morphology control, and formation of composite solid dispersion nanoparticles with polymers and/or surfactants. This article also presents an overview of the main aspects of the SAS-assisted particle precipitation process, its mechanism, and parameters, as well as our own experiences, recent advances, and trends in development. Copyright © 2017 Elsevier B.V. All rights reserved.

In vitro and in vivo evaluation of capsaicin-loaded microemulsion for enhanced oral bioavailability.

PubMed

Zhu, Yuan; Zhang, Jiajia; Zheng, Qianfeng; Wang, Miaomiao; Deng, Wenwen; Li, Qiang; Firempong, Caleb Kesse; Wang, Shengli; Tong, Shanshan; Xu, Ximing; Yu, Jiangnan

2015-10-01

Capsaicin, as a food additive, has attracted worldwide concern owing to its pungency and multiple pharmacological effects. However, poor water solubility and low bioavailability have limited its application. This study aims to develop a capsaicin-loaded microemulsion to enhance the oral bioavailability of the anti-neuropathic-pain component, capsaicin, which is poorly water soluble. In this study, the microemulsion consisting of Cremophor EL, ethanol, medium-chain triglycerides (oil phase) and water (external phase) was prepared and characterized (particle size, morphology, stability and encapsulation efficiency). The gastric mucosa irritation test of formulated capsaicin was performed in rats to evaluate its oral feasibility, followed by the pharmacokinetic study in vivo. Under these conditions, the encapsulated capsaicin revealed a faster capsaicin release in vitro coupled with a greater absorption in vivo when compared to the free capsaicin. The oral bioavailability of the formulated capsaicin-loaded microemulsions was 2.64-fold faster than that of free capsaicin. No significant irritation was observed on the mucosa from the pathological section of capsaicin-loaded microemulsion treated stomach. These results indicate that the developed microemulsion represents a safe and orally effective carrier for poorly soluble substances. The formulation could be used for clinical trials and expand the application of capsaicin. © 2014 Society of Chemical Industry.

Total sulfane sulfur bioavailability reflects ethnic and gender disparities in cardiovascular disease.

PubMed

Rajpal, Saurabh; Katikaneni, Pavan; Deshotels, Matthew; Pardue, Sibile; Glawe, John; Shen, Xinggui; Akkus, Nuri; Modi, Kalgi; Bhandari, Ruchi; Dominic, Paari; Reddy, Pratap; Kolluru, Gopi K; Kevil, Christopher G

2018-05-01

Hydrogen sulfide (H 2 S) has emerged as an important physiological and pathophysiological signaling molecule in the cardiovascular system influencing vascular tone, cytoprotective responses, redox reactions, vascular adaptation, and mitochondrial respiration. However, bioavailable levels of H 2 S in its various biochemical metabolite forms during clinical cardiovascular disease remain poorly understood. We performed a case-controlled study to quantify and compare the bioavailability of various biochemical forms of H 2 S in patients with and without cardiovascular disease (CVD). In our study, we used the reverse-phase high performance liquid chromatography monobromobimane assay to analytically measure bioavailable pools of H 2 S. Single nucleotide polymorphisms (SNPs) were also identified using DNA Pyrosequencing. We found that plasma acid labile sulfide levels were significantly reduced in Caucasian females with CVD compared with those without the disease. Conversely, plasma bound sulfane sulfur levels were significantly reduced in Caucasian males with CVD compared with those without the disease. Surprisingly, gender differences of H 2 S bioavailability were not observed in African Americans, although H 2 S bioavailability was significantly lower overall in this ethnic group compared to Caucasians. We also performed SNP analysis of H 2 S synthesizing enzymes and found a significant increase in cystathionine gamma-lyase (CTH) 1364 G-T allele frequency in patients with CVD compared to controls. Lastly, plasma H 2 S bioavailability was found to be predictive for cardiovascular disease in Caucasian subjects as determined by receiver operator characteristic analysis. These findings reveal that plasma H 2 S bioavailability could be considered a biomarker for CVD in an ethnic and gender manner. Cystathionine gamma-lyase 1346 G-T SNP might also contribute to the risk of cardiovascular disease development. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Towards bioavailability-based soil criteria: Past, present and future perspectives

USDA-ARS?s Scientific Manuscript database

Bioavailability has been used as a key indicator in chemical risk assessment, yet it is a poorly quantified risk factor. Worldwide, the framework used to assess potentially contaminated sites is similar and the decisions are based on threshold contaminant concentration. The uncertainty in the defin...

Preparation of novel porous starch microsphere foam for loading and release of poorly water soluble drug.

PubMed

Jiang, Tongying; Wu, Chao; Gao, Yikun; Zhu, Wenquan; Wan, Long; Wang, Zhanyou; Wang, Siling

2014-02-01

Organic porous material is a promising carrier for enhancing the dissolution of poorly water soluble drug. The aim of the present study was to enhance dissolution and oral bioavailability of lovastatin (LV) by preparing a porous starch microsphere foam (PSM) using a novel method, meanwhile, looking into the mechanism of improving dissolution of LV. PSM was prepared by the W/O emulsion-freeze thawing method. The porous structure of PSM was characterized by scanning electron microscopy (SEM) and nitrogen adsorption/desorption analysis. The adsorption role of nanopores on the drug dissolution and physical state of LV was systematically studied by instrumental analysis, and in vitro and in vivo drug dissolution studies. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to evaluate carrier cytotoxicity. The SEM images of PSM showed nanometer-sized pores. Physical state characterization indicated that porous structure effectively limited the degree of crystallinity of LV. The results of in vitro and in vivo tests testified that PSM accelerated the release of LV and enhanced its oral bioavailability in comparison with crude LV and commercial capsules. The loaded PSM powder indicated a good physical stability under storage for 12 months. MTT assay shows PSM has no toxicity for Caco-2 cell. The preparation was a promising method to produce small and uniform PSM with markedly enhanced dissolution rate and oral bioavailability due to the spatial confinement effect of porous structure. The present work demonstrates the significant potential for the use of PSM as a novel delivery system for poorly water soluble drugs.

Orally Bioavailable and Effective Buparvaquone Lipid-Based Nanomedicines for Visceral Leishmaniasis.

PubMed

Smith, Lindsay; Serrano, Dolores R; Mauger, Marion; Bolás-Fernández, Francisco; Dea-Ayuela, Maria Auxiliadora; Lalatsa, Aikaterini

2018-05-24

Nanoenabled lipid-based drug delivery systems offer a platform to overcome challenges encountered with current failed leads in the treatment of parasitic and infectious diseases. When prepared with FDA or EMA approved excipients, they can be readily translated without the need for further toxicological studies, while they remain affordable and amenable to scale-up. Buparvaquone (BPQ), a hydroxynapthoquinone with in vitro activity in the nanomolar range, failed to clinically translate as a viable treatment for visceral leishmaniasis due to its poor oral bioavailability limited by its poor aqueous solubility (BCS Class II drug). Here we describe a self-nanoemulsifying system (SNEDDS) with high loading and thermal stability up to 6 months in tropical conditions and the ability to enhance the solubilization capacity of BPQ in gastrointestinal media as demonstrated by flow-through cell and dynamic in vitro lipolysis studies. BPQ SNEDDS demonstrated an enhanced oral bioavailability compared to aqueous BPQ dispersions (probe-sonicated), resulting in an increased plasma AUC 0-24 by 55% that is 4-fold higher than any previous reported values for BPQ formulations. BPQ SNEDDS can be adsorbed on low molecular glycol chitosan polymers forming solid dispersions that when compressed into tablets allow the complete dissolution of BPQ in gastrointestinal media. BPQ SNEDDS and BPQ solid SNEDDS demonstrated potent in vitro efficacy in the nanomolar range (<37 nM) and were able to near completely inhibit parasite replication in the spleen while also demonstrating 48 ± 48 and 56 ± 23% inhibition of the parasite replication in the liver, respectively, compared to oral miltefosine after daily administration over 10 days. The proposed platform technology can be used to elicit a range of cost-effective and orally bioavailable noninvasive formulations for a range of antiparasitic and infectious disease drugs that are needed for closing the global health innovation gap.

Arsenic speciation dynamics in paddy rice soil-water environment: sources, physico-chemical, and biological factors - A review.

PubMed

Kumarathilaka, Prasanna; Seneweera, Saman; Meharg, Andrew; Bundschuh, Jochen

2018-04-21

Rice is the main staple carbohydrate source for billions of people worldwide. Natural geogenic and anthropogenic sources has led to high arsenic (As) concentrations in rice grains. This is because As is highly bioavailable to rice roots under conditions in which rice is cultivated. A multifaceted and interdisciplinary understanding, both of short-term and long-term effects, are required to identify spatial and temporal changes in As contamination levels in paddy soil-water systems. During flooding, soil pore waters are elevated in inorganic As compared to dryland cultivation systems, as anaerobism results in poorly mobile As(V), being reduced to highly mobile As(III). The formation of iron (Fe) plaque on roots, availability of metal (hydro)oxides (Fe and Mn), organic matter, clay mineralogy and competing ions and compounds (PO 4 3- and Si(OH) 4 ) are all known to influence As(V) and As(III) mobility in paddy soil-water environments. Microorganisms play a key role in As transformation through oxidation/reduction, and methylation/volatilization reactions, but transformation kinetics are poorly understood. Scientific-based optimization of all biogeochemical parameters may help to significantly reduce the bioavailability of inorganic As. Copyright © 2018 Elsevier Ltd. All rights reserved.

Curcumin as a clinically-promising anti-cancer agent: pharmacokinetics and drug interactions.

PubMed

Adiwidjaja, Jeffry; McLachlan, Andrew J; Boddy, Alan V

2017-09-01

Curcumin has been extensively studied for its anti-cancer properties. While a diverse array of in vitro and preclinical research support the prospect of curcumin use as an anti-cancer therapeutic, most human studies have failed to meet the intended clinical expectation. Poor systemic availability of orally-administered curcumin may account for this disparity. Areas covered: This descriptive review aims to concisely summarise available clinical studies investigating curcumin pharmacokinetics when administered in different formulations. A critical analysis of pharmacokinetic- and pharmacodynamic-based interactions of curcumin with concomitantly administered drugs is also provided. Expert opinion: The encouraging clinical results of curcumin administration are currently limited to people with colorectal cancer, given that sufficient curcumin concentrations persist in colonic mucosa. Higher parent curcumin systemic exposure, which can be achieved by several newer formulations, has important implications for optimal treatment of cancers other than those in gastrointestinal tract. Curcumin-drug pharmacokinetic interactions are also almost exclusively in the enterocytes, owing to extensive first pass metabolism and poor curcumin bioavailability. Greater scope of these interactions, i.e. modulation of the systemic elimination of co-administered drugs, may be expected from more-bioavailable curcumin formulations. Further studies are still warranted, especially with newer formulations to support the inclusion of curcumin in cancer therapy regimens.

Creatinine-based non-phospholipid vesicular carrier for improved oral bioavailability of Azithromycin.

PubMed

Ullah, Shafi; Shah, Muhammad Raza; Shoaib, Mohammad; Imran, Muhammad; Shah, Syed Wadood Ali; Ali, Imdad; Ahmed, Farid

2017-06-01

Novel, safe, efficient and cost effective nano-carriers from renewable resources have got greater interest for enhancing solubility and bioavailability of hydrophobic dugs. This study reports the synthesis of a novel biocompatible non-phospholipid human metabolite "Creatinine" based niosomal delivery system for Azithromycin improved oral bioavailability. Synthesized surfactant was characterized through spectroscopic and spectrometric techniques and then the potential for niosomal vesicle formation was evaluated using Azithromycin as model drug. Drug loaded vesicles were characterized for size, polydispersity index (PDI), shape, drug encapsulation efficiency (EE), in vitro release and drug-excipient interaction using zetasizer, atomic force microscope (AFM), LC-MS/MS and FTIR. The biocompatibility of surfactant was investigated through cells cytotoxicity, blood hemolysis and acute toxicity. Azithromycin encapsulated in niosomes was investigated for in vivo bioavailability in rabbits. The vesicles were spherical with 247 ± 4.67 nm diameter hosting 73.29 ± 3.51% of the drug. Surfactant was nontoxic against cell cultures and caused 5.80 ± 0.51% hemolysis at 1000 µg/mL. It was also found safe in mice up to 2.5 g/kg body weight. Synthesized surfactant based niosomal vesicles revealed enhanced oral bioavailability of Azithromycin in rabbits. The results of the present study confirm that the novel surfactant is highly biocompatible and the niosomal vesicles can be efficiently used for improving the oral bioavailability of poor water soluble drugs.

Formulation, optimization, and in vitro/in vivo evaluation of furosemide nanosuspension for enhancement of its oral bioavailability

NASA Astrophysics Data System (ADS)

Sahu, Bhanu P.; Das, Malay K.

2014-04-01

Furosemide is a poorly soluble diuretic used for treatment of hypertension and edema. It has very poor or variable oral bioavailability due to its reduced solubility in gastric fluid and reduced permeability in intestinal fluid. The aim of this study was to prepare nanosuspension of furosemide to enhance its oral bioavailability by increasing its dissolution in stomach where it has better permeability. Full factorial design was used for a systematic approach of formulation and optimization. The nanosuspensions were prepared by precipitation with ultrasonication method. Polyvinyl acetate was used for sterically stabilizing the nanosuspensions. The diffusing drug concentration and stabilizer were used as the factors and the particle size, polydispersity index, and drug release were selected as dependent variables and characterized. The effect of nanoprecipitation on enhancement of oral bioavailability of furosemide nanosuspension was studied by in vitro dissolution and in vivo absorption studies in rats and compared to pure drug. Quality by design using full factorial design provided a systematic approach in optimizing nanosuspensions to produce products with desired quality. Stable nanosuspension were obtained with average size range of the precipitated nanoparticles between 150 and 300 nm and were found to be homogenous showing a narrow polydispersity index of 0.3 ± 0.1. The in vivo studies on rats revealed a significant increase in the oral absorbtion of furosemide in the nanosuspension compared to pure drug. The AUC0→24 and C max values of nanosuspension were approximately 1.38- and 1.68-fold greater than that of pure drug, respectively. Furosemide nanosuspension showed 20.06 ± 0.02 % decrease in systolic blood pressure compared to 13.37 + 0.02 % in plain furosemide suspension, respectively. The improved oral bioavailability and pharmacodynamic effect of furosemide may be due to the improved dissolution of furosemide in simulated gastric fluid which results in enhanced oral systemic absorption of furosemide from stomach region where it has better permeability.

Relative bioavailability of iron and folic acid from a new powdered supplement compared to a traditional tablet in pregnant women

PubMed Central

Hartman-Craven, Brenda; Christofides, Anna; O'Connor, Deborah L; Zlotkin, Stanley

2009-01-01

Background Deficiencies of iron and folic acid during pregnancy can lead to adverse outcomes for the fetus, thus supplements are recommended. Adherence to current tablet-based supplements is documented to be poor. Recently a powdered form of micronutrients has been developed which may decrease side-effects and thus improve adherence. However, before testing the efficacy of the supplement as an alternate choice for supplementation during pregnancy, the bioavailability of the iron needs to be determined. Our objective was to measure the relative bioavailability of iron and folic acid from a powdered supplement that can be sprinkled on semi-solid foods or beverages versus a traditional tablet supplement in pregnant women. Methods Eighteen healthy pregnant women (24 – 32 weeks gestation) were randomized to receive the supplements in a crossover design. Following ingestion of each supplement, the changes (over baseline) in serum iron and folate over 8 hours were determined. The powdered supplement contained 30 mg of iron as micronized dispersible ferric pyrophosphate with an emulsifier coating and 600 μg folic acid; the tablet contained 27 mg iron from ferrous fumarate and 1000 μg folic acid. Results Overall absorption of iron from the powdered supplement was significantly lower than the tablet (p = 0.003). There was no difference in the overall absorption of folic acid between supplements. Based on the differences in the area under the curve and doses, the relative bioavailability of iron from powdered supplement was lower than from the tablet (0.22). Conclusion The unexpected lower bioavailability of iron from the powdered supplement is contrary to previously published reports. However, since pills and capsules are known to be poorly accepted by some women during pregnancy, it is reasonable to continue to explore alternative micronutrient delivery systems and forms of iron for this purpose. Trial Registration ClinicalTrials.gov NCT00789490 PMID:19635145

Lipid-based liquid crystalline nanoparticles as oral drug delivery vehicles for poorly water-soluble drugs: cellular interaction and in vivo absorption

PubMed Central

Zeng, Ni; Gao, Xiaoling; Hu, Quanyin; Song, Qingxiang; Xia, Huimin; Liu, Zhongyang; Gu, Guangzhi; Jiang, Mengyin; Pang, Zhiqing; Chen, Hongzhuan; Chen, Jun; Fang, Liang

2012-01-01

Background Lipid-based liquid crystalline nanoparticles (LCNPs) have attracted growing interest as novel drug-delivery systems for improving the bioavailability of both hydrophilic and hydrophobic drugs. However, their cellular interaction and in vivo behavior have not been fully developed and characterized. Methods In this study, self-assembled LCNPs prepared from soy phosphatidylcholine and glycerol dioleate were developed as a platform for oral delivery of paclitaxel. The particle size of empty LCNPs and paclitaxel-loaded LCNPs was around 80 nm. The phase behavior of the liquid crystalline matrix was characterized using crossed polarized light microscopy and small-angle X-ray scattering, and showed both reversed cubic and hexagonal phase in the liquid crystalline matrix. Transmission electron microscopy and cryofield emission scanning electron microscopy analysis revealed an inner winding water channel in LCNPs and a “ ball-like”/“hexagonal” morphology. Results Cellular uptake of LCNPs in Caco-2 cells was found to be concentration-dependent and time-dependent, with involvement of both clathrin and caveolae/lipid raft-mediated endocytosis. Under confocal laser scanning microscopy, soy phosphatidylcholine was observed to segregate from the internalized LCNPs and to fuse with the cell membrane. An in vivo pharmacokinetic study showed that the oral bioavailability of paclitaxel-loaded LCNPs (13.16%) was 2.1 times that of Taxol® (the commercial formulation of paclitaxel, 6.39%). Conclusion The findings of this study suggest that this LCNP delivery system may be a promising candidate for improving the oral bioavailability of poorly water-soluble agents. PMID:22888230

The bioavailability of iron, zinc, protein and vitamin A is highly variable in French individual diets: Impact on nutrient inadequacy assessment and relation with the animal-to-plant ratio of diets.

PubMed

Perignon, Marlène; Barré, Tangui; Gazan, Rozenn; Amiot, Marie-Josèphe; Darmon, Nicole

2018-01-01

Nutritional adequacy depends on nutrient intakes and bioavailability which strongly varies with the plant- or animal-origin of foods. The aim was to estimate iron, zinc, protein and vitamin A bioavailability from individual diets, and investigate its relation with the animal-to-plant ratio (A/P) of diets. Bioavailability was estimated in 1899 French diets using diet-based algorithms or food-group specific conversion factors. Nutrient inadequacy was estimated based on i) bioavailability calculated in each individual diet and ii) average bioavailability assumed for Western-diets. Mean iron absorption, zinc absorption, protein quality and β-carotene conversion factor were 13%, 30%, 92%, and 17:1, respectively. Bioavailability displayed a high variability between individual diets, poorly explained by their A/P. Using individual bioavailability led to different inadequacy prevalence than with average factors assumed for Western-diets. In this population, the A/P does not seem sufficient to predict nutrient bioavailability and the corresponding recommended intakes. Nutritional adequacy should be assessed using bioavailability accounting for individual diets composition. Copyright © 2016 Elsevier Ltd. All rights reserved.

Enhancement of Oral Bioavailability of Curcumin by a Novel Solid Dispersion System.

PubMed

Hu, Liandong; Shi, Yanjing; Li, Jian Heng; Gao, Na; Ji, Jing; Niu, Feng; Chen, Queting; Yang, Xiaoning; Wang, Shaocheng

2015-12-01

The objective of this study was to improve the solubility and bioavailability of curcumin by a new curcumin dripping pills (Cur-DPs) formulation using melt mixing methods. The optimal formulation consisted of Polyethoxylated 40 hydrogenated castor oil (Cremophor RH40), Poloxamer 188, and Polyethylene glycol 4000 (PEG 4000). Differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier-transform infrared spectroscopy (FT-IR) were used to verify the forming of Cur-DPs. All the physical characterization information proved the formation of Cur-DPs, and the results demonstrated the superiority of the dripping pills in dissolution rates. The pharmacokinetic study of Cur-DPs was performed in rats compared to the pure curcumin suspension. The oral bioavailability of poorly water-soluble curcumin was successfully improved by CUR-DPs. And the stability of prepared Cur-DP was also in a good state in 3 months. These results identified the Cur-DPs was an effective new approach for pharmaceutical application.

Floating lipid beads for the improvement of bioavailability of poorly soluble basic drugs: in-vitro optimization and in-vivo performance in humans.

PubMed

Abouelatta, Samar M; Aboelwafa, Ahmed A; Khalil, Rawia M; ElGazayerly, Omaima N

2015-01-01

The challenge in developing oral drug delivery systems of poorly soluble basic drugs is primarily due to their pH dependent solubility. Cinnarizine (CNZ), a model for a poorly soluble basic drug, has pH dependent solubility; where it dissolves readily at low pH in the stomach and exhibits a very low solubility at pH values greater than 4. It is also characterized by a short half life of 3-6h, which requires frequent daily administration resulting in poor patient compliance. In an attempt to solve these problems, extended release floating lipid beads were formulated. A 2(4) full factorial design was utilized for optimization of the effects of various independent variables; lipid:drug ratio, % Pluronic F-127, % Sterotex, and Gelucire 43/01:Gelucire 50/13 ratio, on the loading efficiency and release of CNZ from the lipid beads. In-vivo pharmacokinetic study of the optimized CNZ-lipid beads compared to Stugeron® (reference standard) was performed in healthy human volunteers. A promising approach for enhancing the bioavailability of the poorly soluble basic drug, CNZ, utilizing novel and simple floating lipid beads was successfully developed. Zero order release profile of CNZ was achieved for 12h. Mean AUC0-24 and AUC0-∞ of the optimized CNZ-loaded lipid beads were 4.23 and 6.04 times that of Stugeron® tablets respectively. Copyright © 2014 Elsevier B.V. All rights reserved.

Solution or suspension - Does it matter for lipid based systems? In vivo studies of chase dosing lipid vehicles with aqueous suspensions of a poorly soluble drug.

PubMed

Larsen, A T; Holm, R; Müllertz, A

2017-08-01

In this study, the potential of co-administering an aqueous suspension with a placebo lipid vehicle, i.e. chase dosing, was investigated in rats relative to the aqueous suspension alone or a solution of the drug in the lipid vehicle. The lipid investigated in the present study was Labrafil M2125CS and three evaluated poorly soluble model compounds, danazol, cinnarizine and halofantrine. For cinnarizine and danazol the oral bioavailability in rats after chase dosing or dosing the compound dissolved in Labrafil M21515CS was similar and significantly higher than for the aqueous suspension. For halofantrine the chase dosed group had a tendency towards a low bioavailability relative to the Labrafil M2125CS solution, but still a significant higher bioavailability relative to the aqueous suspension. This could be due to factors such as a slower dissolution rate in the intestinal phase of halofantrine or a lower solubility in the colloidal structures formed during digestion, but other mechanisms may also be involved. The study thereby supported the potential of chase dosing as a potential dosing regimen in situations where it is beneficial to have a drug in the solid state, e.g. due to chemical stability issues in the lipid vehicle. Copyright © 2017 Elsevier B.V. All rights reserved.

Mesoporous silica-based dosage forms improve bioavailability of poorly soluble drugs in pigs: case example fenofibrate.

PubMed

O'Shea, Joseph P; Nagarsekar, Kalpa; Wieber, Alena; Witt, Vanessa; Herbert, Elisabeth; O'Driscoll, Caitriona M; Saal, Christoph; Lubda, Dieter; Griffin, Brendan T; Dressman, Jennifer B

2017-10-01

Mesoporous silicas (SLC) have demonstrated considerable potential to improve bioavailability of poorly soluble drugs by facilitating rapid dissolution and generating supersaturation. The addition of certain polymers can further enhance the dissolution of these formulations by preventing drug precipitation. This study uses fenofibrate as a model drug to investigate the performance of an SLC-based formulation, delivered with hydroxypropyl methylcellulose acetate succinate (HPMCAS) as a precipitation inhibitor, in pigs. The ability of biorelevant dissolution testing to predict the in vivo performance was also assessed. Fenofibrate-loaded mesoporous silica (FF-SLC), together with HPMCAS, displayed significant improvements in biorelevant dissolution tests relative to a reference formulation consisting of a physical mixture of crystalline fenofibrate with HPMCAS. In vivo assessment in fasted pigs demonstrated bioavailabilities of 86.69 ± 35.37% with combination of FF-SLC and HPMCAS in capsule form and 75.47 ± 14.58% as a suspension, compared to 19.92 ± 9.89% with the reference formulation. A positive correlation was identified between bioavailability and dissolution efficiency. The substantial improvements in bioavailability of fenofibrate from the SLC-based formulations confirm the ability of this formulation strategy to overcome the dissolution and solubility limitations, further raising the prospects of a future commercially available SLC-based formulation. © 2017 Royal Pharmaceutical Society.

Improving Biopharmaceutical Properties of Vinpocetine Through Cocrystallization.

PubMed

Golob, Samuel; Perry, Miranda; Lusi, Matteo; Chierotti, Michele R; Grabnar, Iztok; Lassiani, Lucia; Voinovich, Dario; Zaworotko, Michael J

2016-12-01

Vinpocetine is a poorly water soluble weakly basic drug (pK a  = 7.1) used for the treatment of several cerebrovascular and cognitive disorders. Because existing formulations exhibit poor bioavailability and scarce absorption, a dosage form with improved pharmacokinetic properties is highly desirable. Cocrystallization represents a promising approach to generate diverse novel crystal forms and to improve the aqueous solubility and in turn the oral bioavailability. In this article, a novel ionic cocrystal of vinpocetine is described, using boric acid as a coformer, and fully characterized (by means of differential scanning calorimetry, solid-state nuclear magnetic resonance, powder and single-crystal X-ray diffraction, and powder dissolution test). Pharmacokinetic performance was also tested in a human pilot study. This pharmaceutical ionic cocrystal exhibits superior solubilization kinetics and modulates important pharmacokinetic values such as maximum concentration in plasma (C max ), time to maximum concentration (t max ), and area under the plasma concentration-time curve (AUC) of the poorly soluble vinpocetine and it therefore offers an innovative approach to improve its bioavailability. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Enhanced oral bioavailability of felodipine by novel solid self-microemulsifying tablets.

PubMed

Jing, Boyu; Wang, Zhiyuan; Yang, Rui; Zheng, Xia; Zhao, Jia; Tang, Si; He, Zhonggui

2016-01-01

The novel self-microemulsifying (SME) tablets were developed to enhance the oral bioavailability of a poor water-soluble drug felodipine (FDP). Firstly, FDP was dissolved in the optimized liquid self-microemusifying drug delivery systems (SMEDDS) containing Miglyol® 812, Cremophor® RH 40, Tween 80 and Transcutol® P, and the mixture was solidified with porous silicon dioxide and crospovidone as adsorbents. Then after combining the solidified powders with other excipients, the solid SME tablets were prepared by wet granulation-compression method. The prepared tablets possessed satisfactory characterization; the droplet size of the SME tablets following self-emulsification in water was nearly equivalent to the liquid SMEDDS (68.4 ± 14.0 and 64.4 ± 12.0 nm); differential scanning calorimetry (DSC) and powder X-ray diffractometry (PXRD) analysis demonstrated that FDP in SME tablets had undergone a polymorphism transition from a crystal form to an amorphous state, which was further confirmed by transmission electron microscopy (TEM). A similar dissolution performance of SME tablets and liquid SMEDDS was also obtained under the sink condition (85% within 10 min), both significantly higher than commercial tablets. The oral bioavailability was evaluated for the SME tablets, liquid SMEDDS and commercial conventional tablets in the fasted beagle dogs. The AUC of FDP from the SME tablets was about 2-fold greater than that of conventional tablets, but no significant difference was found when compared with the liquid SMEDDS. Accordingly, these preliminary results suggest that this formulation approach offers a useful large-scale producing method to prepare the solid SME tablets from the liquid SMEDDS for oral bioavailability equivalent enhancement of poorly soluble FDP.

Enhancing the Solubility and Oral Bioavailability of Poorly Water-Soluble Drugs Using Monoolein Cubosomes.

PubMed

Ali, Md Ashraf; Kataoka, Noriko; Ranneh, Abdul-Hackam; Iwao, Yasunori; Noguchi, Shuji; Oka, Toshihiko; Itai, Shigeru

2017-01-01

Monoolein cubosomes containing either spironolactone (SPI) or nifedipine (NI) were prepared using a high-pressure homogenization technique and characterized in terms of their solubility and oral bioavailability. The mean particle size, polydispersity index (PDI), zeta potential, solubility and encapsulation efficiency (EE) values of the SPI- and NI-loaded cubosomes were determined to be 90.4 nm, 0.187, -13.4 mV, 163 µg/mL and 90.2%, and 91.3 nm, 0.168, -12.8 mV, 189 µg/mL and 93.0%, respectively, which were almost identical to those of the blank cubosome. Small-angle X-ray scattering analyses confirmed that the SPI-loaded, NI-loaded and blank cubosomes existed in the cubic space group Im3̄m. The lattice parameters of the SPI- and NI-loaded cubosomes were 147.6 and 151.6 Å, respectively, making them almost identical to that of blank cubosome (151.0 Å). The in vitro release profiles of the SPI- and NI-loaded cubosomes showed that they released less than 5% of the drugs into various media over 12-48 h, indicating that most of the drug remained encapsulated within the cubic phase of their lipid bilayer. Furthermore, the in vivo pharmacokinetic results suggested that these cubosomes led to a considerable increase in the systemic oral bioavailability of the drugs compared with pure dispersions of the same materials. Notably, the stability results indicated that the mean particle size and PDI values of these cubosomes were stable for at least 4 weeks. Taken together, these results demonstrate that monoolein cubosomes represent promising drug carriers for enhancing the solubility and oral bioavailability of poorly water-soluble drugs.

The effect of acidification on the bioavailability and electrochemical lability of zinc in seawater

PubMed Central

Kim, Ja-Myung; Baars, Oliver

2016-01-01

A poorly studied but potentially important consequence of the CO2-induced acidification of the surface ocean is a possible change in the bioavailability of trace metals, which play a critical role in the productivity and population dynamics of marine ecosystems. We report laboratory and field experiments designed to compare quantitatively the effects of acidification on the bioavailability of Zn, a metal essential to the growth of phytoplankton and on the extent of its complexation by model and natural ligands. We observed a good correspondence between the effects of pH on the rate of Zn uptake by a model diatom and the chemical lability of Zn measured by anodic stripping voltammetry (ASV). In model laboratory systems, the chemical lability and the bioavailability of Zn could either increase or decrease at low pH depending on the mix of complexing ligands. In a sample of coastal surface water, we observed similar increases in the ASV-labile and bioavailable Zn concentrations upon acidification, a result contrary to previous observations. These results, which can likely be generalized to other bioactive trace metals, mutatis mutandis, demonstrate the intricacy of the effects of ocean acidification on the chemistry and the ecology of surface seawater. This article is part of the themed issue ‘Biological and climatic impacts of ocean trace element chemistry’. PMID:29035261

A cost-effective method to prepare curcumin nanosuspensions with enhanced oral bioavailability.

PubMed

Wang, Yutong; Wang, Changyuan; Zhao, Jing; Ding, Yanfang; Li, Lei

2017-01-01

Nanosuspension is one of the most promising strategies to improve the oral bioavailability of insoluble drugs. The existing techniques applied to produce nanosuspensions are classified as "bottom-up" or "top-down" methods, or a combination of both. Curcumin (CUR), a Biopharmaceutics Classification System (BCS) class IV substance, is a promising drug candidate in view of its good bioactivity, but its use is limited due to its poor solubility and permeability. In the present study, CUR nanosuspensions were developed to enhance CUR oral bioavailability using a cost-effective method different from conventional techniques. The physicochemical properties of CUR nanosuspensions were characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The crystalline state of CUR in different nanosuspensions analyzed using differential scanning calorimeter (DSC) and X-ray diffraction analysis (PXRD) confirmed its amorphous state. In vitro dissolution degree of the prepared CUR nanosuspensions using TPGS or Brij78 as stabilizer was greatly increased. Pharmacokinetic studies demonstrated that the oral bioavailability of CUR was increased 3.18 and 3.7 times after administration of CUR/TPGS nanosuspensions or CUR/Brij78 nanosuspensions, when compared with the administration of CUR suspension. CUR nanosuspensions produced by our cost-effective method could improve its oral bioavailability. In addition, the low-cost and time-saving method reported here is highly suitable for a fast and inexpensive preparation. Copyright © 2016 Elsevier Inc. All rights reserved.

The effect of acidification on the bioavailability and electrochemical lability of zinc in seawater.

PubMed

Kim, Ja-Myung; Baars, Oliver; Morel, François M M

2016-11-28

A poorly studied but potentially important consequence of the CO 2 -induced acidification of the surface ocean is a possible change in the bioavailability of trace metals, which play a critical role in the productivity and population dynamics of marine ecosystems. We report laboratory and field experiments designed to compare quantitatively the effects of acidification on the bioavailability of Zn, a metal essential to the growth of phytoplankton and on the extent of its complexation by model and natural ligands. We observed a good correspondence between the effects of pH on the rate of Zn uptake by a model diatom and the chemical lability of Zn measured by anodic stripping voltammetry (ASV). In model laboratory systems, the chemical lability and the bioavailability of Zn could either increase or decrease at low pH depending on the mix of complexing ligands. In a sample of coastal surface water, we observed similar increases in the ASV-labile and bioavailable Zn concentrations upon acidification, a result contrary to previous observations. These results, which can likely be generalized to other bioactive trace metals, mutatis mutandis , demonstrate the intricacy of the effects of ocean acidification on the chemistry and the ecology of surface seawater.This article is part of the themed issue 'Biological and climatic impacts of ocean trace element chemistry'. © 2016 The Author(s).

Oral bioavailability assessment and intestinal lymphatic transport of Org 45697 and Org 46035, two highly lipophilic novel immunomodulator analogues.

PubMed

Caliph, Suzanne M; Faassen, W A Fried; Vogel, Gerard M; Porter, Christopher J H

2009-08-01

Org 45697 (MW 600.7, clogP 7.92, soybean oil solubility 50 mg/g) and Org 46035 (MW 601.6, clog P 8.46, soybean oil solubility 40 mg/g) are two poorly water soluble (<0.1 microg/ml), highly lipophilic drug candidates with immunomodulator activity and highly analogous chemical structures. After oral administration to conscious ambulatory rats in an aqueous-based methylcellulose/Tween 80 suspension, the bioavailability of both compounds was low (< 2% of administered dose). However, bioavailability was significantly increased (> 5 fold) after oral administration in a long chain triglyceride lipid (olive oil) formulation. Subsequent studies have explored the potential for solubilising formulations, including lipid-based formulations, to enhance the oral bioavailability of Org 45697 and Org 46035 and secondly to explore the potential contribution of intestinal lymphatic transport to intestinal absorption. The experimental data show that solubilising formulations may provide for significant increases in oral bioavailability for Org 45697 and Org 46035 and that after co-administration with lipid, 35-50% of the absorbed dose may be transported to the systemic circulation via the intestinal lymph. Interestingly, the lymphatic transport of the less lipid soluble analogue, Org 46035 was approximately 40% lower than that of Org 45697 suggesting that relatively subtle differences in lipid solubility can have significant impact on the extent of lymphatic transport.

Role of Components in the Formation of Self-microemulsifying Drug Delivery Systems.

PubMed

Gurram, A K; Deshpande, P B; Kar, S S; Nayak, Usha Y; Udupa, N; Reddy, M S

2015-01-01

Pharmaceutical research is focused in designing novel drug delivery systems to improve the bioavailability of poorly water soluble drugs. Self-microemulsifying drug delivery systems, one among the lipid-based dosage forms were proven to be promising in improving the oral bioavailability of such drugs by enhancing solubility, permeability and avoiding first-pass metabolism via enhanced lymphatic transport. Further, they have been successful in avoiding both inter and intra individual variations as well as the dose disproportionality. Aqueous insoluble drugs, in general, show greater solubility in lipid based excipients, and hence they are formulated as lipid based drug delivery systems. The extent of solubility of a hydrophobic drug in lipid excipients i.e. oil, surfactant and co-surfactant (components of self-microemulsifying drug delivery systems) greatly affects the drug loading and in producing stable self-microemulsifying drug delivery systems. The present review highlighted the influence of physicochemical factors and structural features of the hydrophobic drug on its solubility in lipid excipients and an attempt was made to explore the role of each component of self-microemulsifying drug delivery systems in the formation of stable microemulsion upon dilution.

Preparation and evaluation of a self-emulsifying drug delivery system of etoposide-phospholipid complex.

PubMed

Wu, Zhongbin; Guo, Dan; Deng, Li; Zhang, Yue; Yang, Qiuxia; Chen, Jianming

2011-01-01

The aim of this study was to develop a new phospholipid complex self-emulsifying drug delivery system (PC-SEDDS) to enhance bioavailability of oral etoposide, a drug with poor water solubility. Etoposide-phospholipid complex (EPC) was prepared by reacting etoposide and phospholipid in tetrahydrofuran and confirmed as a phospholipid compound by differential scanning calorimetry (DSC). Solubility of EPC and etoposide was determined in various vehicles. Pseudoternary phase diagrams were constructed to identify the efficient self-emulsification region of EPC-SEDDS, and the effects of oil concentration, drug loading, and aqueous media on droplet size were investigated. The optimal formulation of EPC-SEDDS was EPC:octyl and decyl monoglyceride (ODO):Cremopher EL:PEG-400 (1:20:48:32) (w/w/w/w). Compared with etoposide-phospholipid complex suspension (EPCS) and etoposide suspension (ES), cumulative release of etoposide from EPC-SEDDS increased by 1.31 and 2.65 fold at 24 hours, respectively. Compared with ES, relative bioavailability of EPC-SEDDS, E-SEDDS, and EPCS after oral administration in rats was enhanced by 60.21-, 44.9-, and 8.44- fold, respectively. The synergistic effect between PC and SEDDS contributed to the enhanced bioavailability of etoposide. It was concluded that PC-SEDDS proved to be a potential system for delivering orally administered hydrophobic compounds including etoposide.

Insoluble drug delivery strategies: review of recent advances and business prospects

PubMed Central

Kalepu, Sandeep; Nekkanti, Vijaykumar

2015-01-01

The emerging trends in the combinatorial chemistry and drug design have led to the development of drug candidates with greater lipophilicity, high molecular weight and poor water solubility. Majority of the failures in new drug development have been attributed to poor water solubility of the drug. Issues associated with poor solubility can lead to low bioavailability resulting in suboptimal drug delivery. About 40% of drugs with market approval and nearly 90% of molecules in the discovery pipeline are poorly water-soluble. With the advent of various insoluble drug delivery technologies, the challenge to formulate poorly water soluble drugs could be achieved. Numerous drugs associated with poor solubility and low bioavailabilities have been formulated into successful drug products. Several marketed drugs were reformulated to improve efficacy, safety and patient compliance. In order to gain marketing exclusivity and patent protection for such products, revitalization of poorly soluble drugs using insoluble drug delivery technologies have been successfully adopted by many pharmaceutical companies. This review covers the recent advances in the field of insoluble drug delivery and business prospects. PMID:26579474

Coupling of UDP-glucuronosyltransferases and multidrug resistance-associated proteins is responsible for the intestinal disposition and poor bioavailability of emodin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Wei; Feng, Qian; Li, Ye

2012-12-15

Emodin is a poorly bioavailable but promising plant-derived anticancer drug candidate. The low oral bioavailability of emodin is due to its extensive glucuronidation in the intestine and liver. Caco-2 cell culture model was used to investigate the interplay between UDP-glucuronosyltransferases (UGTs) and efflux transporters in the intestinal disposition of emodin. Bidirectional transport assays of emodin at different concentrations were performed in the Caco-2 monolayers with or without multidrug resistance-associated protein (MRP) and breast cancer resistance protein (BCRP) efflux transporter chemical inhibitors. The bidirectional permeability of emodin and its glucuronide in the Caco-2 monolayers was determined. Emodin was rapidly metabolized tomore » emodin glucuronide in Caco-2 cells. LTC4, a potent inhibitor of MRP2, decreased the efflux of emodin glucuronide and also substantially increased the intracellular glucuronide level in the basolateral-to-apical (B–A) direction. MK-571, chemical inhibitor of MRP2, MRP3, and MRP4, significantly reduced the efflux of glucuronide in the apical-to-basolateral (A–B) and B–A directions in a dose-dependent manner. However, dipyridamole, a BCRP chemical inhibitor demonstrated no effect on formation and efflux of emodin glucuronide in Caco-2 cells. In conclusion, UGT is a main metabolic pathway for emodin in the intestine, and the MRP family is composed of major efflux transporters responsible for the excretion of emodin glucuronide in the intestine. The coupling of UGTs and MRP efflux transporters causes the extensive metabolism, excretion, and low bioavailability of emodin. -- Highlights: ► Glucuronidation is the main reason for the poor oral bioavailability of emodin. ► Efflux transporters are involved in the excretion of emodin glucuronide. ► The intestine is the main organ for metabolism of emodin.« less

Oral bioavailability enhancement of β-lapachone, a poorly soluble fast crystallizer, by cocrystal, amorphous solid dispersion, and crystalline solid dispersion.

PubMed

Liu, Chengyu; Liu, Zhengsheng; Chen, Yuejie; Chen, Zhen; Chen, Huijun; Pui, Yipshu; Qian, Feng

2018-03-01

The aim of this paper was to compare the in vitro dissolution and in vivo bioavailability of three solubility enhancement technologies for β-lapachone (LPC), a poorly water soluble compound with extremely high crystallization propensity. LPC cocrystal was prepared by co-grinding LPC with resorcinol. LPC crystalline and amorphous solid dispersions (CSD and ASD) were obtained by spray drying with Poloxamer 188 and HPMC-AS, respectively. The cocrystal structure was solved by single crystal x-ray diffraction. All formulations were characterized by WAXRD, DSC, POM and SEM. USP II and intrinsic dissolution studies were used to compare the in vitro dissolution of these formulations, and a crossover dog pharmacokinetic study was used to compare their in vivo bioavailability. An 1:1 LPC-resorcinol cocrystal with higher solubility and faster dissolution rate was obtained, yet it converted to LPC crystal rapidly in solution. LPC/HPMC-AS ASD was confirmed to be amorphous and uniform, while the crystal and crystallite sizes of LPC in CSD were found to be ∼1-3 μm and around 40 nm, respectively. These formulations performed similarly during USP II dissolution, while demonstrated dramatically different oral bioavailability of ∼32%, ∼5%, and ∼1% in dogs, for CSD, co-crystal, and ASD, respectively. CSD showed the fastest intrinsic dissolution rate among the three. The three formulations showed poor IVIVC which could be due to rapid and unpredictable crystallization kinetics. Considering all the reasons, we conclude that for molecules with extremely high crystallization tendency that cannot be inhibited by any pharmaceutical excipients, size-reduction technologies such as CSD could be advantageous for oral bioavailability enhancement in vivo than technologies only generating transient but not sustained supersaturation. Copyright © 2018 Elsevier B.V. All rights reserved.

Nanostructured lipid carriers versus microemulsions for delivery of the poorly water-soluble drug luteolin.

PubMed

Liu, Ying; Wang, Lan; Zhao, Yiqing; He, Man; Zhang, Xin; Niu, Mengmeng; Feng, Nianping

2014-12-10

Nanostructured lipid carriers and microemulsions effectively deliver poorly water-soluble drugs. However, few studies have investigated their ability and difference in improving drug bioavailability, especially the factors contributed to the difference. Thus, this study was aimed at investigating their efficiency in bioavailability enhancement based on studying two key processes that occur in NLC and ME during traverse along the intestinal tract: the solubilization process and the intestinal permeability process. The nanostructured lipid carriers and microemulsions had the same composition except that the former were prepared with solid lipids and the latter with liquid lipids; both were evaluated for particle size and zeta potential. Transmission electron microscopy, differential scanning calorimetry, and X-ray diffraction were performed to characterize their properties. Furthermore, in vitro drug release, in situ intestinal absorption, and in vitro lipolysis were studied. The bioavailability of luteolin delivered using nanostructured lipid carriers in rats was compared with that delivered using microemulsions and suspensions. The in vitro analysis revealed different release mechanisms for luteolin in nanostructured lipid carriers and microemulsions, although the in situ intestinal absorption was similar. The in vitro lipolysis data indicated that digestion speed and extent were higher for microemulsions than for nanostructured lipid carriers, and that more of the former partitioned to the aqueous phase. The in vivo bioavailability analysis in rats indicated that the oral absorption and bioavailability of luteolin delivered using nanostructured lipid carriers and microemulsions were higher than those of luteolin suspensions. Nanostructured lipid carriers and microemulsions improved luteolin's oral bioavailability in rats. The rapid lipid digestion and much more drug solubilized available for absorption in microemulsions may contribute to better absorption and higher bioavailability. Copyright © 2014 Elsevier B.V. All rights reserved.

Development of an abiraterone acetate formulation with improved oral bioavailability guided by absorption modeling based on in vitro dissolution and permeability measurements.

PubMed

Solymosi, Tamás; Ötvös, Zsolt; Angi, Réka; Ordasi, Betti; Jordán, Tamás; Semsey, Sándor; Molnár, László; Ránky, Soma; Filipcsei, Genovéva; Heltovics, Gábor; Glavinas, Hristos

2017-10-30

Particle size reduction of drug crystals in the presence of surfactants (often called "top-down" production methods) is a standard approach used in the pharmaceutical industry to improve bioavailability of poorly soluble drugs. Based on the mathematical model used to predict the fraction dose absorbed this formulation approach is successful when dissolution rate is the main rate limiting factor of oral absorption. In case compound solubility is also a major factor this approach might not result in an adequate improvement in bioavailability. Abiraterone acetate is poorly water soluble which is believed to be responsible for its very low bioavailability in the fasted state and its significant positive food effect. In this work, we have successfully used in vitro dissolution, solubility and permeability measurements in biorelevant media to describe the dissolution characteristics of different abiraterone acetate formulations. Mathematical modeling of fraction dose absorbed indicated that reducing the particle size of the drug cannot be expected to result in significant improvement in bioavailability in the fasted state. In the fed state, the same formulation approach can result in a nearly complete absorption of the dose; thereby, further increasing the food effect. Using a "bottom-up" formulation method we improved both the dissolution rate and the apparent solubility of the compound. In beagle dog studies, this resulted in a ≫>10-fold increase in bioavailability in the fasted state when compared to the marketed drug and the elimination of the food effect. Calculated values of fraction dose absorbed were in agreement with the observed relative bioavailability values in beagle dogs. Copyright © 2017 Elsevier B.V. All rights reserved.

Systemic delivery of β-blockers via transdermal route for hypertension

PubMed Central

Ahad, Abdul; Al-Jenoobi, Fahad I.; Al-Mohizea, Abdullah M.; Akhtar, Naseem; Raish, Mohammad; Aqil, Mohd.

2014-01-01

Hypertension is the most common cardiovascular disease worldwide. Moreover, management of hypertension requires long-term treatment that may result in poor patient compliance with conventional dosage forms due to greater frequency of drug administration. Although there is availability of a plethora of therapeutically effective antihypertensive molecules, inadequate patient welfare is observed; this arguably presents an opportunity to deliver antihypertensive agents through a different route. Ever since the transdermal drug delivery came into existence, it has offered great advantages including non-invasiveness, prolonged therapeutic effect, reduced side effects, improved bioavailability, better patient compliance and easy termination of drug therapy. Attempts were made to develop the transdermal therapeutic system for various antihypertensive agents, including β-blockers, an important antihypertensive class. β-blockers are potent, highly effective in the management of hypertension and other heart ailments by blocking the effects of normal amounts of adrenaline in the heart and blood vessels. The shortcomings associated with β-blockers such as more frequent dose administration, extensive first pass metabolism and variable bioavailability, make them an ideal candidate for transdermal therapeutic systems. The present article gives a brief view of different β-blockers formulated as transdermal therapeutic system in detail to enhance the bioavailability as well as to improve patient compliance. Constant improvement in this field holds promise for the long-term success in technologically advanced transdermal dosage forms being commercialized sooner rather than later. PMID:26702253

Enhancement of the bioavailability of an antihypertensive drug by transdermal protransfersomal system: formulation and in vivo study.

PubMed

Morsi, Nadia M; Aboelwafa, Ahmed A; Dawoud, Marwa H S

2018-06-01

Timolol Maleate (TiM), a nonselective β-adrenergic blocker, is a potent highly effective agent for management of hypertension. The drug suffers from poor oral bioavailability (50%) due to its first pass effect and a short elimination half-life of 4 h; resulting in its frequent administration. Transdermal formulation may circumvent these problems in the form of protransfersomes. The aim of this study is to develop and optimize transdermal protransfersomal system of Timolol Maleate by film deposition on carrier method where protransfersomes were converted to transfersomes upon skin hydration following transdermal application under occlusive conditions. Two 2 3 full factorial designs were employed to investigate the influence of three formulation variables which were; phosphatidyl choline: surfactant molar ratio, carrier: mixture and the type of SAA each on particle size, drug entrapment efficiency and release rate. The optimized formulation was evaluated regarding permeation through hairless rat skin and compared with oral administration of aqueous solution on male Wistar rats. Optimized protransfersomal system had excellent permeation rate through shaved rat skin (780.69 μg/cm 2 /h) and showed six times increase in relative bioavailability with prolonged plasma profile up to 72 h. A potential protransfresomal transdermal system was successfully developed and factorial design was found to be a smart tool in its optimization.

Genetically modified Medicago truncatula lacking calcium oxalate has increased calcium bioavailability and partially rescues vitamin D receptor knockout mice phenotypes

USDA-ARS?s Scientific Manuscript database

How the distribution and sequestered form of plant macro/micro-nutrients influence their bioavailability, and ultimately impact human health, is poorly understood. The legume Medicago truncatula has a portion of its tissue calcium sequestered in the form of the calcium oxalate crystal, which reduces...

Impact of crystal polymorphism on the systemic bioavailability of rifaximin, an antibiotic acting locally in the gastrointestinal tract, in healthy volunteers

PubMed Central

Blandizzi, Corrado; Viscomi, Giuseppe Claudio; Scarpignato, Carmelo

2015-01-01

Background Rifaximin is an antibiotic, acting locally in the gastrointestinal tract, which may exist in different crystal as well as amorphous forms. The current marketed rifaximin formulation contains polymorph alpha, the systemic bioavailability of which is very limited. This study compared the pharmacokinetics of this formulation with those of the amorphous form. Methods Amorphous rifaximin was specifically prepared for the study and formulated as the marketed product. Two doses (200 mg and 400 mg) of both formulations were given to two groups of 12 healthy volunteers of either sex according to a single-blind, randomized, two-treatment, single-dose, two-period, cross-over design. Plasma and urine samples were collected at preset times (for 24 hours or 48 hours, respectively) after dosing, and assayed for rifaximin concentrations by high-performance liquid chromatography-mass spectrometry. Results For both dose levels, peak plasma concentration, area under the concentration-time curve, and cumulative urinary excretion were significantly higher after administration of amorphous rifaximin than rifaximin-α. Ninety percent confidence intervals for peak plasma concentration, area under the concentration-time curve, and urinary excretion ratios were largely outside the upper limit of the accepted (0.80–1.25) range, indicating higher systemic bioavailability of the amorphous rifaximin. The few adverse events recorded were not serious and not related to the study medications. Conclusion Rifaximin-α, a crystal polymorph, does differ from the amorphous form, the latter being systemically more bioavailable. In this regard, care must be taken when using – as a medicinal product – a formulation containing even small amounts of amorphous form, which may alter the peculiar pharmacologic properties of this poorly absorbed antibiotic. PMID:25565769

Impact of crystal polymorphism on the systemic bioavailability of rifaximin, an antibiotic acting locally in the gastrointestinal tract, in healthy volunteers.

PubMed

Blandizzi, Corrado; Viscomi, Giuseppe Claudio; Scarpignato, Carmelo

2015-01-01

Rifaximin is an antibiotic, acting locally in the gastrointestinal tract, which may exist in different crystal as well as amorphous forms. The current marketed rifaximin formulation contains polymorph alpha, the systemic bioavailability of which is very limited. This study compared the pharmacokinetics of this formulation with those of the amorphous form. Amorphous rifaximin was specifically prepared for the study and formulated as the marketed product. Two doses (200 mg and 400 mg) of both formulations were given to two groups of 12 healthy volunteers of either sex according to a single-blind, randomized, two-treatment, single-dose, two-period, cross-over design. Plasma and urine samples were collected at preset times (for 24 hours or 48 hours, respectively) after dosing, and assayed for rifaximin concentrations by high-performance liquid chromatography-mass spectrometry. For both dose levels, peak plasma concentration, area under the concentration-time curve, and cumulative urinary excretion were significantly higher after administration of amorphous rifaximin than rifaximin-α. Ninety percent confidence intervals for peak plasma concentration, area under the concentration-time curve, and urinary excretion ratios were largely outside the upper limit of the accepted (0.80-1.25) range, indicating higher systemic bioavailability of the amorphous rifaximin. The few adverse events recorded were not serious and not related to the study medications. Rifaximin-α, a crystal polymorph, does differ from the amorphous form, the latter being systemically more bioavailable. In this regard, care must be taken when using - as a medicinal product - a formulation containing even small amounts of amorphous form, which may alter the peculiar pharmacologic properties of this poorly absorbed antibiotic.

Oral apomorphine delivery from solid lipid nanoparticles with different monostearate emulsifiers: pharmacokinetic and behavioral evaluations.

PubMed

Tsai, Ming-Jun; Huang, Yaw-Bin; Wu, Pao-Chu; Fu, Yaw-Syan; Kao, Yao-Ren; Fang, Jia-You; Tsai, Yi-Hung

2011-02-01

Apomorphine, a dopamine receptor agonist for treating Parkinson's disease, has very poor oral bioavailability (<2%) due to the first-pass effect. The aim of this work was to investigate whether the oral bioavailability and brain regional distribution of apomorphine could be improved by utilizing solid lipid nanoparticles (SLNs). Glyceryl monostearate (GMS) and polyethylene glycol monostearate (PMS) were individually incorporated into SLNs as emulsifiers. It was found that variations in the emulsifiers had profound effects on the physicochemical characteristics. Mean diameters of the GMS and PMS systems were 155 and 63 nm, respectively. More than 90% of the apomorphine was entrapped in the SLNs. The interfacial film was the likely location for most of apomorphine molecules. The PMS system, when incubated in simulated intestinal medium, was found to be more stable in terms of particle size and encapsulation efficiency than the GMS system. Using the GMS and PMS systems to orally administer apomorphine (26 mg/kg) equally enhanced the bioavailability in rats. SLNs showed 12- to 13-fold higher bioavailability than the reference solution. The drug distribution in the striatum, the predominant site of therapeutic action, also increased when using the SLNs. The anti-Parkinsonian activity of apomorphine was evaluated in rats with 6-hydroxydopamine-induced lesions, a model of Parkinson's disease. The contralateral rotation behavior was examined after oral apomorphine delivery. The total number of rotations increased from 20 to 94 and from 20 to 115 when the drug was administered from SLNs containing GMS and PMS, respectively. The experimental results suggest that SLNs may offer a promising strategy for apomorphine delivery via oral ingestion. Copyright © 2010 Wiley-Liss, Inc.

Construction and characterization of curcumin nanoparticles system

NASA Astrophysics Data System (ADS)

Sun, Weitong; Zou, Yu; Guo, Yaping; Wang, Lu; Xiao, Xue; Sun, Rui; Zhao, Kun

2014-03-01

This study was aimed at developing a nanoparticles system for curcumin, a widely used traditional Chinese medicine, but with the disadvantage of poor aqueous solubility. The objective was intended to improve in vitro release characteristics, enhance blood and gastrointestinal stability, increase bioavailability and pharmacological activities. Curcumin nanoparticles system (Cur-NS) was prepared by ionotropic gelation technique. Cur-NS was characterized by particle size, zeta potential, drug entrapment efficiency, drug loading, and physical stability, respectively. Cur-NS presented controlled release properties, and the release properties of Cur from NS were fit non-Fickian mechanism, controlled by the expected diffusional release and the erosion or solubilization from the crosslink layer of polymer carrier. In addition, the pharmacokinetic study in rats revealed a notable improved oral bioavailability of Cur, and the anti-tumor activity in vivo of Cur-NS on tumor growth was investigated. Cur-NS significantly inhibited tumor effect compared with non-vehicle group, thus making it a potential candidate for cancer therapy.

Silymarin liposomes improves oral bioavailability of silybin besides targeting hepatocytes, and immune cells.

PubMed

Kumar, Nitesh; Rai, Amita; Reddy, Neetinkumar D; Raj, P Vasanth; Jain, Prateek; Deshpande, Praful; Mathew, Geetha; Kutty, N Gopalan; Udupa, Nayanabhirama; Rao, C Mallikarjuna

2014-10-01

Silymarin, a hepatoprotective agent, has poor oral bioavailability. However, the current dosage form of the drug does not target the liver and inflammatory cells selectively. The aim of the present study was to develop lecithin-based carrier system of silymarin by incorporating phytosomal-liposomal approach to increase its oral bioavailability and to make it target-specific to the liver for enhanced hepatoprotection. The formulation was prepared by film hydration method. Release of drug was assessed at pH 1.2 and 7.4. Formulation was assessed for in vitro hepatoprotection on Chang liver cells, lipopolysaccharide-induced reactive oxygen species (ROS) production by RAW 267.4 (murine macrophages), in vivo efficacy against paracetamol-induced hepatotoxicity and pharmacokinetic study by oral route in Wistar rat. The formulation showed maximum entrapment (55%) for a lecithin-cholesterol ratio of 6:1. Comparative release profile of formulation was better than silymarin at pH 1.2 and pH 7.4. In vitro studies showed a better hepatoprotection efficacy for formulation (one and half times) and better prevention of ROS production (ten times) compared to silymarin. In in vivo model, paracetamol showed significant hepatotoxicity in Wistar rats assessed through LFT, antioxidant markers and inflammatory markers. The formulation was found more efficacious than silymarin suspension in protecting the liver against paracetamol toxicity and the associated inflammatory conditions. The liposomal formulation yielded a three and half fold higher bioavailability of silymarin as compared with silymarin suspension. Incorporating the phytosomal form of silymarin in liposomal carrier system increased the oral bioavailability and showed better hepatoprotection and better anti-inflammatory effects compared with silymarin suspension. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

A novel oral delivery system consisting in "drug-in cyclodextrin-in nanostructured lipid carriers" for poorly water-soluble drug: vinpocetine.

PubMed

Lin, Congcong; Chen, Fen; Ye, Tiantian; Zhang, Lina; Zhang, Wenji; Liu, Dandan; Xiong, Wei; Yang, Xinggang; Pan, Weisan

2014-04-25

The purpose of this study was to develop a new delivery system based on drug cyclodextrin (CD) complexation and loading into nanostructured lipid carriers (NLC) to improve the oral bioavailability of vinpocetine (VP). Three different CDs and three different methods to obtain solid vinpocetine-cyclodextrin-tartaric acid complexes (VP-CD-TA) were contrasted. The co-evaporation vinpocetine-β-cyclodextrin-tartaric acid loaded NLC (VP-β-CD-TA COE-loaded NLC) was obtained by emulsification ultrasonic dispersion method. VP-β-CD-TA COE-loaded NLC was suitably characterized for particle size, polydispersity index, zeta potential, entrapment efficiency and the morphology. The crystallization of drug in VP-CD-TA and NLC was investigated by differential scanning calorimetry (DSC). The in vitro release study was carried out at pH 1.2, pH 6.8 and pH 7.4 medium. New Zealand rabbits were applied to investigate the pharmacokinetic behavior in vivo. The VP-β-CD-TA COE-loaded NLC presented a superior physicochemical property and selected to further study. In the in vitro release study, VP-β-CD-TA COE-loaded NLC exhibited a higher dissolution rate in the pH 6.8 and pH 7.4 medium than VP suspension and VP-NLC. The relative bioavailability of VP-β-CD-TA COE-loaded NLC was 592% compared with VP suspension and 92% higher than VP-NLC. In conclusion, the new formulation significantly improved bioavailability of VP for oral delivery, demonstrated a perspective way for oral delivery of poorly water-soluble drugs. Copyright © 2014 Elsevier B.V. All rights reserved.

Drug carrier systems for solubility enhancement of BCS class II drugs: a critical review.

PubMed

Kumar, Sumit; Bhargava, Deepak; Thakkar, Arti; Arora, Saahil

2013-01-01

Poor aqueous solubility impedes a drug's bioavailability and challenges its pharmaceutical development. Pharmaceutical development of drugs with poor water solubility requires the establishment of a suitable formulation layout among various techniques. Various approaches have been investigated extensively to improve the aqueous solubility and poor dissolution rate of BCS class II and IV drugs. In this literature review, novel formulation options, particularly for class II drugs designed for applications such as micronization, self-emulsification, cyclodextrin complexation, co-crystallisation, super critical fluid technology, solubilisation by change in pH, salt formation, co-solvents, melt granulation, and solid dispersion, liposomal/niosomal formulations, are discussed in detail to introduce biopharmaceutical challenges and recent approaches to facilitate more efficient drug formulation and development.

Evaluating the ready biodegradability of two poorly water-soluble substances: comparative approach of bioavailability improvement methods (BIMs).

PubMed

Sweetlove, Cyril; Chenèble, Jean-Charles; Barthel, Yves; Boualam, Marc; L'Haridon, Jacques; Thouand, Gérald

2016-09-01

Difficulties encountered in estimating the biodegradation of poorly water-soluble substances are often linked to their limited bioavailability to microorganisms. Many original bioavailability improvement methods (BIMs) have been described, but no global approach was proposed for a standardized comparison of these. The latter would be a valuable tool as part of a wider strategy for evaluating poorly water-soluble substances. The purpose of this study was to define an evaluation strategy following the assessment of different BIMs adapted to poorly water-soluble substances with ready biodegradability tests. The study was performed with two poorly water-soluble chemicals-a solid, anthraquinone, and a liquid, isodecyl neopentanoate-and five BIMs were compared to the direct addition method (reference method), i.e., (i) ultrasonic dispersion, (ii) adsorption onto silica gel, (iii) dispersion using an emulsifier, (iv) dispersion with silicone oil, and (v) dispersion with emulsifier and silicone oil. A two-phase evaluation strategy of solid and liquid chemicals was developed involving the selection of the most relevant BIMs for enhancing the biodegradability of tested substances. A description is given of a BIM classification ratio (R BIM), which enables a comparison to be made between the different test chemical sample preparation methods used in the various tests. Thereby, using this comparison, the BIMs giving rise to the greatest biodegradability were ultrasonic dispersion and dispersion with silicone oil or with silicone oil and emulsifier for the tested solid chemical, adsorption onto silica gel, and ultrasonic dispersion for the liquid one.

Skin permeation mechanism and bioavailability enhancement of celecoxib from transdermally applied nanoemulsion

PubMed Central

Shakeel, Faiyaz; Baboota, Sanjula; Ahuja, Alka; Ali, Javed; Shafiq, Sheikh

2008-01-01

Background Celecoxib, a selective cyclo-oxygenase-2 inhibitor has been recommended orally for the treatment of arthritis and osteoarthritis. Long term oral administration of celecoxib produces serious gastrointestinal side effects. It is a highly lipophilic, poorly soluble drug with oral bioavailability of around 40% (Capsule). Therefore the aim of the present investigation was to assess the skin permeation mechanism and bioavailability of celecoxib by transdermally applied nanoemulsion formulation. Optimized oil-in-water nanoemulsion of celecoxib was prepared by the aqueous phase titration method. Skin permeation mechanism of celecoxib from nanoemulsion was evaluated by FTIR spectral analysis, DSC thermogram, activation energy measurement and histopathological examination. The optimized nanoemulsion was subjected to pharmacokinetic (bioavailability) studies on Wistar male rats. Results FTIR spectra and DSC thermogram of skin treated with nanoemulsion indicated that permeation occurred due to the disruption of lipid bilayers by nanoemulsion. The significant decrease in activation energy (2.373 kcal/mol) for celecoxib permeation across rat skin indicated that the stratum corneum lipid bilayers were significantly disrupted (p < 0.05). Photomicrograph of skin sample showed the disruption of lipid bilayers as distinct voids and empty spaces were visible in the epidermal region. The absorption of celecoxib through transdermally applied nanoemulsion and nanoemulsion gel resulted in 3.30 and 2.97 fold increase in bioavailability as compared to oral capsule formulation. Conclusion Results of skin permeation mechanism and pharmacokinetic studies indicated that the nanoemulsions can be successfully used as potential vehicles for enhancement of skin permeation and bioavailability of poorly soluble drugs. PMID:18613981

Phenazopyridine-phthalimide nano-cocrystal: Release rate and oral bioavailability enhancement.

PubMed

Huang, Yu; Li, Jin-Mei; Lai, Zhi-Hui; Wu, Jun; Lu, Tong-Bu; Chen, Jia-Mei

2017-11-15

Both cocrystal and nanocrystal technologies have been widely used in the pharmaceutical development for poorly soluble drugs. However, the synergistic effects due to the integration of these two technologies have not been well investigated. The aim of this study is to develop a nano-sized cocrystal of phenazopyridine (PAP) with phthalimide (PI) to enhance the release rate and oral bioavailability of PAP. A PAP-PI nano-cocrystal with particle diameter of 21.4±0.1nm was successfully prepared via a sonochemical approach and characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and dynamic light scattering (DLS) analysis. An in vitro release study revealed a significant release rate enhancement for PAP-PI nano-cocrystal as compared to PAP-PI cocrystal and PAP hydrochloride salt. Further, a comparative oral bioavailability study in rats indicated significant improvement in C max and oral bioavailability (AUC 0-∞ ) by 1.39- and 2.44-fold, respectively. This study demonstrated that this novel nano-cocrystal technology can be a new promising option to improve release rate and absorption of poorly soluble compounds in the pharmaceutical industry. Copyright © 2017 Elsevier B.V. All rights reserved.

Bioavailability and bioaccumulation of metal-based engineered nanomaterials in aquatic environments: concepts and processes: chapter 5

USGS Publications Warehouse

Luoma, Samuel N.; Khan, Farhan R.; Croteau, Marie-Noële

2014-01-01

Bioavailability of Me-ENMs to aquatic organisms links their release into the environment to ecological implications. Close examination shows some important differences in the conceptual models that define bioavailability for metals and Me-ENMs. Metals are delivered to aquatic animals from Me-ENMs via water, ingestion, and incidental surface exposure. Both metal released from the Me-ENM and uptake of the nanoparticle itself contribute to bioaccumulation. Some mechanisms of toxicity and some of the metrics describing exposure may differ from metals alone. Bioavailability is driven by complex interaction of particle attributes, environmental transformations, and biological traits. Characterization of Me-ENMs is an essential part of understanding bioavailability and requires novel methodologies. The relative importance of the array of processes that could affect Me-ENM bioavailability remains poorly known, but new approaches and models are developing rapidly. Enough is known, however, to conclude that traditional approaches to exposure assessment for metals would not be adequate to assess risks from Me-ENMs.

Zero-order release and bioavailability enhancement of poorly water soluble Vinpocetine from self-nanoemulsifying osmotic pump tablet.

PubMed

El-Zahaby, Sally A; AbouGhaly, Mohamed H H; Abdelbary, Ghada A; El-Gazayerly, Omaima N

2017-06-08

Solid self-nanoemulsifying (S-SNEDDS) asymmetrically coated osmotic tablets of the poorly water-soluble drug Vinpocetine (VNP) were designed. The aim was to control the release of VNP by the osmotic technology taking advantage of the solubility and bioavailability-enhancing capacity of S-SNEDDS. Liquid SNEDDS loaded with 2.5 mg VNP composed of Maisine™ 35-1, Transcutol ® HP, and Cremophor ® EL was adsorbed on the solid carrier Aeroperl ® . S-SNEDDS was mixed with the osmotic tablet excipients (sodium chloride, Avicel ® , HPMC-K4M, PVP-K30, and Lubripharm ® ), then directly compressed to form the core tablet. The tablets were dip coated and mechanically drilled. A 3 2 *2 1 full factorial design was adopted. The independent variables were: type of coating material (X 1 ), concentration of coating solution (X 2 ), and number of drills (X 3 ). The dependent variables included % release at 2 h (Y 1 ), at 4 h (Y 2 ), and at 8 h (Y 3 ). The in vivo performance of the optimum formula was assessed in rabbits. Zero-order VNP release was obtained by the single drilled 1.5% Opadry ® CA coated osmotic tablets and twofold increase in VNP bioavailability was achieved. The combination of SNEDDS and osmotic pump tablet system was successful in enhancing the solubility and absorption of VNP as well as controlling its release.

Administration of resveratrol: What formulation solutions to bioavailability limitations?

PubMed

Amri, A; Chaumeil, J C; Sfar, S; Charrueau, C

2012-03-10

Resveratrol (3,5,4'-trihydroxystilbene), a naturally occurring polyphenol, has attracted considerable interest for its beneficial potentials for human health, which include anti-oxidant, anti-inflammatory, cardioprotective and anti-tumor activities. However, the in vivo biological effects of resveratrol appear strongly limited by its low bioavailability, which is a barrier to the development of therapeutic applications. In this context, an increasing number of recent studies have aimed at designing novel resveratrol formulations to overcome its poor solubility, limited stability, high metabolization and weak bioavailability. This review outlines physicochemical and pharmacokinetic limitations to resveratrol bioavailability, describes formulations tested for resveratrol administration, controlled release and targeting, and identifies future opportunities for resveratrol delivery. Copyright © 2011 Elsevier B.V. All rights reserved.

Beyond liposomes: Recent advances on lipid based nanostructures for poorly soluble/poorly permeable drug delivery.

PubMed

Teixeira, M C; Carbone, C; Souto, E B

2017-10-01

Solid lipid nanoparticle (SLN), nanostructured lipid carriers (NLC) and hybrid nanoparticles, have gained increasing interest as drug delivery systems because of their potential to load and release drugs from the Biopharmaceutical classification system (BCS) of class II (low solubility and high permeability) and of class IV (low solubility and low permeability). Lipid properties (e.g. high solubilizing potential, biocompatibility, biotolerability, biodegradability and distinct route of absorption) contribute for the improvement of the bioavailability of these drugs for a set of administration routes. Their interest continues to grow, as translated by the number of patents being field worldwide. This paper discusses the recent advances on the use of SLN, NLC and lipid-polymer hybrid nanoparticles for the loading of lipophilic, poorly water-soluble and poorly permeable drugs, being developed for oral, topical, parenteral and ocular administration, also discussing the industrial applications of these systems. A review of the patents filled between 2014 and 2017, concerning the original inventions of lipid nanocarriers, is also provided. Copyright © 2017 Elsevier Ltd. All rights reserved.

Flavonoid interactions during digestion, absorption, distribution and metabolism: a sequential structure-activity/property relationship-based approach in the study of bioavailability and bioactivity.

PubMed

Gonzales, Gerard Bryan; Smagghe, Guy; Grootaert, Charlotte; Zotti, Moises; Raes, Katleen; Van Camp, John

2015-05-01

Flavonoids are a group of polyphenols that provide health-promoting benefits upon consumption. However, poor bioavailability has been a major hurdle in their use as drugs or nutraceuticals. Low bioavailability has been associated with flavonoid interactions at various stages of the digestion, absorption and distribution process, which is strongly affected by their molecular structure. In this review, we use structure-activity/property relationship to discuss various flavonoid interactions with food matrices, digestive enzymes, intestinal transporters and blood proteins. This approach reveals specific bioactive properties of flavonoids in the gastrointestinal tract as well as various barriers for their bioavailability. In the last part of this review, we use these insights to determine the effect of different structural characteristics on the overall bioavailability of flavonoids. Such information is crucial when flavonoid or flavonoid derivatives are used as active ingredients in foods or drugs.

Curcumin, a Compound from Natural Sources, a True Scientific Challenge - A Review.

PubMed

Stanić, Zorka

2017-03-01

Curcumin, a plant-derived polyphenolic compound, naturally present in turmeric (Curcuma longa), has been the subject of intensive investigations on account of its various activities. The implementation of safe, beneficial and highly functional compounds from natural sources in human nutrition/prevention/therapy requires some modifications in order to achieve their multi-functionality, improve their bioavailability and delivery strategies, with the main aim to enhance their effectiveness. The low aqueous solubility of curcumin, its rapid metabolism and elimination from the body, and consequently, poor bioavailability, constitute major obstacles to its application. The main objectives of this review are related to reported strategies to overcome these limitations and, thereby, improve the solubility, stability and bioavailability of curcumin. The effectiveness of curcumin could be greatly improved by using nanoparticle-based carriers. The significance of the quality of a substance delivery system is reflected in the fact that carrying curcumin as a food additive/nutrition also means carrying the active biological product/drug. This review summarizes the state of the art, and highlights some examples and the most significant advances in the field of curcumin research.

Novel delivery system for natural products: Nano-curcumin formulations.

PubMed

Rahimi, Hamid Reza; Nedaeinia, Reza; Sepehri Shamloo, Alireza; Nikdoust, Shima; Kazemi Oskuee, Reza

2016-01-01

Curcumin is extracted from Curcuma longa and regulates the intracellular signal pathways which control the growth of cancerous cell, inflammation, invasion and apoptosis. Curcumin molecules have special intrinsic features that can target the intracellular enzymes, genome (DNA) and messengers (RNA). A wide range of studies have been conducted on the physicochemical traits and pharmacological effects of curcumin on different diseases like cardiovascular diseases, diabetes, cancer, rheumatoid arthritis, Alzheimer's, inflammatory bowel disease (IBD), and even it has wound healing. Oral bioavailability of curcumin is rather poor, which would certainly put some boundaries in the employment of this drug. Bibliographical searches were performed using MEDLINE/ScienceDirect/OVID up to February 2015 using the following keywords (all fields): ("Curcumin" OR "Curcuma longa") AND [(nanoparticles) OR (Nanomicelles) OR (micro emulsions) OR (liposome) OR (phospholipid). Consequently, for any developments of curcumin in the future, analogues of curcumin that have better bioavailability or substitute formulations are needed crucially. These studies indicated that nanotechnology can formulate curcumin effectively, and this nano-formulated curcumin with a potent ability against various cancer cells, were represented to have better efficacy and bioavailability under in vivo conditions.

Chitosan cocrystals embedded alginate beads for enhancing the solubility and bioavailability of aceclofenac.

PubMed

Ganesh, Mani; Jeon, Ung Jin; Ubaidulla, Udhumansha; Hemalatha, Pushparaj; Saravanakumar, Arthanari; Peng, Mei Mei; Jang, Hyun Tae

2015-03-01

Enhanced oral bioavailability of aceclofenac has been achieved using chitosan cocrystals of aceclofenac and its entrapment into alginate matrix a super saturated drug delivery system (SDDS). Prepared SDDS were evaluated by various physiochemical and pharmacological methods. The result revealed that the primary cocrystals enhanced the solubility of the drug and the thick gelled polymer matrix that formed from swelling of calcium alginate beads makes it to release the drug in continuous and sustained manner by supersaturated drug diffusion. The Cmax, Tmax and relative bioavailability for aceclofenac cocrystal and aceclofenac SDDS were 2.06±0.42 μg/ml, 1 h, 159.72±10.84 and 2.01 μg/ml, 1 h, 352.76±12.91, respectively. Anti-inflammatory activity of aceclofenac was significantly improved with the SDDS. With respect to the results, it revealed that the SDDS described herein might be a promising tool for the oral sustained release of aceclofenac and likely for that of various other poorly soluble drugs. Copyright © 2014 Elsevier B.V. All rights reserved.

Dissolution and oral bioavailability enhancement of praziquantel by solid dispersions.

PubMed

Liu, Yanyan; Wang, Tianzi; Ding, Wenya; Dong, Chunliu; Wang, Xiaoting; Chen, Jianqing; Li, Yanhua

2018-06-01

The aim of the present investigation was to enhance the solubility, dissolution, and oral bioavailability of praziquantel (PZQ), a poorly water-soluble BCS II drug (Biopharmaceutical Classification System), using a solid dispersion (SD) technique involving hydrophilic copolymers. The SD formulations were prepared by a solvent evaporation method with PZQ and PEG 4000 (polyethylene glycol 4000), PEG 6000, or P 188 polymers at various weight ratios or a combination of PEG 4000/P 188. The optimized SD formulation, which had the highest solubility in distilled water, was further characterized by its surface morphology, crystallinity, and dissolution in 0.1 M HCl with 0.2% w/v of sodium dodecyl sulfate (SDS). X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR) revealed the amorphous form of PZQ in the SDs. Moreover, at an oral dosage of 5 mg/kg PZQ, the SDs had higher C max values and areas under the curve (AUCs) compared to those of commercial PZQ tablets. Preparation of PZQ-loaded SDs using PEG 4000/P 188 is a promising strategy to improve the oral bioavailability of PZQ.

The effect of Pro NanoLipospheres (PNL) formulation containing natural absorption enhancers on the oral bioavailability of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in a rat model.

PubMed

Cherniakov, Irina; Izgelov, Dvora; Domb, Abraham J; Hoffman, Amnon

2017-11-15

The lipophilic phytocannabinoids cannabidiol (CBD) and Δ 9 -tetrahydrocannabinol (THC) show therapeutic efficacy in various medical conditions. Both molecules are poorly water soluble and subjected to extensive first pass metabolism in the gastrointestinal tract, leading to a limited oral bioavailability of approximately 9%. We have developed an advanced lipid based Self-Emulsifying Drug Delivery System termed Advanced Pro-NanoLiposphere (PNL) pre-concentrate. The PNL is composed of lipid and emulsifying excipients of GRAS status and are known to increase solubility and reduce Phase I metabolism of lipophilic active compounds. Advanced PNLs are PNLs with an incorporated natural absorption enhancers. These molecules are natural alkaloids and phenolic compounds which were reported to inhibit certain phase I and phase II metabolism processes. Here we use piperine, curcumin and resveratrol to formulate the Advanced-PNL formulations. Consequently, we have explored the utility of these Advanced-PNLs on CBD and THC oral bioavailability. Oral administration of CBD-piperine-PNL resulted in 6-fold increase in AUC compared to CBD solution, proving to be the most effective of the screened formulations. The same trend was found in pharmacokinetic experiments of THC-piperine-PNL which resulted in a 9.3-fold increase in AUC as compared to THC solution. Our Piperine-PNL can be used as a platform for synchronized delivery of piperine and CBD or THC to the enterocyte site. This co-localization provides an increase in CBD and THC bioavailability by its effect at the pre-enterocyte and the enterocyte levels of the absorption process. The extra augmentation in the absorption of CBD and THC by incorporating piperine into PNL is attributed to the inhibition of Phase I and phase II metabolism by piperine in addition to the Phase I metabolism and P-gp inhibition by PNL. These novel results pave the way to utilize piperine-PNL delivery system for other poorly soluble, highly metabolized compounds that currently cannot be administered orally. Copyright © 2017. Published by Elsevier B.V.

Enhanced oral bioavailability and anticancer activity of novel curcumin loaded mixed micelles in human lung cancer cells.

PubMed

Patil, Sharvil; Choudhary, Bhavana; Rathore, Atul; Roy, Krishtey; Mahadik, Kakasaheb

2015-11-15

Curcumin has a wide range of pharmacological activities including antioxidant, anti-inflammatory, antidiabetic, antibacterial, wound healing, antiatherosclerotic, hepatoprotective and anti-carcinogenic. However, its clinical applications are limited owing to its poor aqueous solubility, multidrug pump P-gp efflux, extensive in vivo metabolism and rapid elimination due to glucuronidation/sulfation. The objective of the current work was to prepare novel curcumin loaded mixed micelles (CUR-MM) of Pluronic F-127 (PF127) and Gelucire® 44/14 (GL44) in order to enhance its oral bioavailability and cytotoxicity in human lung cancer cell line A549. 3(2) Factorial design was used to assess the effect of formulation variables for optimization of mixed micelle batch. CUR-MM was prepared by a solvent evaporation method. The optimized CUR-MM was evaluated for size, entrapment efficiency (EE), in vitro curcumin release, cytotoxicity and oral bioavailability in rats. The average size of CUR-MM was found to be around 188 ± 3 nm with an EE of about 76.45 ± 1.18% w/w. In vitro dissolution profile of CUR-MM revealed controlled release of curcumin. Additionally, CUR-MM showed significant improvement in cytotoxic activity (3-folds) and oral bioavailability (around 55-folds) of curcumin as compared to curcumin alone. Such significant improvement in cytotoxic activity and oral bioavailability of curcumin when formulated into mixed micelles could be attributed to solubilization of hydrophobic curcumin into micelle core along with P-gp inhibition effect of both, PF127 and GL44. Thus the present work propose the formulation of mixed micelles of PF127 and GL44 which can act as promising carrier systems for hydrophobic drugs such as curcumin with significant improvement in their oral bioavailability. Copyright © 2015 Elsevier GmbH. All rights reserved.

Selenium species-dependent toxicity, bioavailability and metabolic transformations in Caenorhabditis elegans.

PubMed

Rohn, Isabelle; Marschall, Talke Anu; Kroepfl, Nina; Jensen, Kenneth Bendix; Aschner, Michael; Tuck, Simon; Kuehnelt, Doris; Schwerdtle, Tanja; Bornhorst, Julia

2018-05-17

The essential micronutrient selenium (Se) is required for various systemic functions, but its beneficial range is narrow and overexposure may result in adverse health effects. Additionally, the chemical form of the ingested selenium contributes crucially to its health effects. While small Se species play a major role in Se metabolism, their toxicological effects, bioavailability and metabolic transformations following elevated uptake are poorly understood. Utilizing the tractable invertebrate Caenorhabditis elegans allowed for an alternative approach to study species-specific characteristics of organic and inorganic Se forms in vivo, revealing remarkable species-dependent differences in the toxicity and bioavailability of selenite, selenomethionine (SeMet) and Se-methylselenocysteine (MeSeCys). An inverse relationship was found between toxicity and bioavailability of the Se species, with the organic species displaying a higher bioavailability than the inorganic form, yet being less toxic. Quantitative Se speciation analysis with HPLC/mass spectrometry revealed a partial metabolism of SeMet and MeSeCys. In SeMet exposed worms, identified metabolites were Se-adenosylselenomethionine (AdoSeMet) and Se-adenosylselenohomocysteine (AdoSeHcy), while worms exposed to MeSeCys produced Se-methylselenoglutathione (MeSeGSH) and γ-glutamyl-MeSeCys (γ-Glu-MeSeCys). Moreover, the possible role of the sole selenoprotein in the nematode, thioredoxin reductase-1 (TrxR-1), was studied comparing wildtype and trxr-1 deletion mutants. Although a lower basal Se level was detected in trxr-1 mutants, Se toxicity and bioavailability following acute exposure was indistinguishable from wildtype worms. Altogether, the current study demonstrates the suitability of C. elegans as a model for Se species dependent toxicity and metabolism, while further research is needed to elucidate TrxR-1 function in the nematode.

Surface-modified solid lipid nanoparticles for oral delivery of docetaxel: enhanced intestinal absorption and lymphatic uptake

PubMed Central

Cho, Hyun-Jong; Park, Jin Woo; Yoon, In-Soo; Kim, Dae-Duk

2014-01-01

Docetaxel is a potent anticancer drug, but development of an oral formulation has been hindered mainly due to its poor oral bioavailability. In this study, solid lipid nanoparticles (SLNs) surface-modified by Tween 80 or D-alpha-tocopheryl poly(ethylene glycol 1000) succinate (TPGS 1000) were prepared and evaluated in terms of their feasibility as oral delivery systems for docetaxel. Tween 80-emulsified and TPGS 1000-emulsified tristearin-based lipidic nanoparticles were prepared by a solvent-diffusion method, and their particle size distribution, zeta potential, drug loading, and particle morphology were characterized. An in vitro release study showed a sustained-release profile of docetaxel from the SLNs compared with an intravenous docetaxel formulation (Taxotere®). Tween 80-emulsified SLNs showed enhanced intestinal absorption, lymphatic uptake, and relative oral bioavailability of docetaxel compared with Taxotere in rats. These results may be attributable to the absorption-enhancing effects of the tristearin nanoparticle. Moreover, compared with Tween 80-emulsified SLNs, the intestinal absorption and relative oral bioavailability of docetaxel in rats were further improved in TPGS 1000-emulsified SLNs, probably due to better inhibition of drug efflux by TPGS 1000, along with intestinal lymphatic uptake. Taken together, it is worth noting that these surface-modified SLNs may serve as efficient oral delivery systems for docetaxel. PMID:24531717

Design of biodegradable nanoparticles: a novel approach to encapsulating poorly soluble phytochemical ellagic acid

NASA Astrophysics Data System (ADS)

Bala, I.; Bhardwaj, V.; Hariharan, S.; Sitterberg, J.; Bakowsky, U.; Kumar, M. N. V. Ravi

2005-12-01

Nanosizing of poorly water soluble drugs or incorporating them into nanoparticles to increase their solubility and thereby the bioavailability has become a favoured approach today. This work describes a novel method for encapsulating poorly water soluble phytochemical ellagic acid that is also sparingly soluble/insoluble in routine solvents used to prepare nanoparticles.

Bioavailability enhancement of a poorly water-soluble drug by solid dispersion in polyethylene glycol-polysorbate 80 mixture.

PubMed

Joshi, Hemant N; Tejwani, Ravindra W; Davidovich, Martha; Sahasrabudhe, Vaishali P; Jemal, Mohammed; Bathala, Mohinder S; Varia, Sailesh A; Serajuddin, Abu T M

2004-01-09

Oral bioavailability of a poorly water-soluble drug was greatly enhanced by using its solid dispersion in a surface-active carrier. The weakly basic drug (pK(a) approximately 5.5) had the highest solubility of 0.1mg/ml at pH 1.5, < 1 microg/ml aqueous solubility between pH 3.5 and 5.5 at 24+/-1 degrees C, and no detectable solubility (< 0.02 microg/ml) at pH greater than 5.5. Two solid dispersion formulations of the drug, one in Gelucire 44/14 and another one in a mixture of polyethylene glycol 3350 (PEG 3350) with polysorbate 80, were prepared by dissolving the drug in the molten carrier (65 degrees C) and filling the melt in hard gelatin capsules. From the two solid dispersion formulations, the PEG 3350-polysorbate 80 was selected for further development. The oral bioavailability of this formulation in dogs was compared with that of a capsule containing micronized drug blended with lactose and microcrystalline cellulose and a liquid solution in a mixture of PEG 400, polysorbate 80 and water. For intravenous administration, a solution in a mixture of propylene glycol, polysorbate 80 and water was used. Absolute oral bioavailability values from the capsule containing micronized drug, the capsule containing solid dispersion and the oral liquid were 1.7+/-1.0%, 35.8+/-5.2% and 59.6+/-21.4%, respectively. Thus, the solid dispersion provided a 21-fold increase in bioavailability of the drug as compared to the capsule containing micronized drug. A capsule formulation containing 25 mg of drug with a total fill weight of 600 mg was subsequently selected for further development. The selected solid dispersion formulation was physically and chemically stable under accelerated storage conditions for at least 6 months. It is hypothesized that polysorbate 80 ensures complete release of drug in a metastable finely dispersed state having a large surface area, which facilitates further solubilization by bile acids in the GI tract and the absorption into the enterocytes. Thus, the bioavailability of this poorly water-soluble drug was greatly enhanced by formulation as a solid dispersion in a surface-active carrier.

Ordered mesoporous silica to enhance the bioavailability of poorly water-soluble drugs: Proof of concept in man.

PubMed

Bukara, Katarina; Schueller, Laurent; Rosier, Jan; Martens, Mark A; Daems, Tinne; Verheyden, Loes; Eelen, Siemon; Van Speybroeck, Michiel; Libanati, Cristian; Martens, Johan A; Van Den Mooter, Guy; Frérart, Françoise; Jolling, Koen; De Gieter, Marjan; Bugarski, Branko; Kiekens, Filip

2016-11-01

Formulating poorly water soluble drugs using ordered mesoporous silica materials is an emerging approach to tackle solubility-related bioavailability problems. The current study was conducted to assess the bioavailability-enhancing potential of ordered mesoporous silica in man. In this open-label, randomized, two-way cross-over study, 12 overnight fasted healthy volunteers received a single dose of fenofibrate formulated with ordered mesoporous silica or a marketed product based on micronized fenofibrate. Plasma concentrations of fenofibric acid, the pharmacologically active metabolite of fenofibrate, were monitored up to 96h post-dose. The rate (C max /dose increased by 77%; t max reduced by 0.75h) and extent of absorption (AUC 0-24h /dose increased by 54%) of fenofibrate were significantly enhanced following administration of the ordered mesoporous silica based formulation. The results of this study serve as a proof of concept in man for this novel formulation approach. Copyright © 2016 Elsevier B.V. All rights reserved.

Comparative study on solid self-nanoemulsifying drug delivery and solid dispersion system for enhanced solubility and bioavailability of ezetimibe

PubMed Central

Rashid, Rehmana; Kim, Dong Wuk; Yousaf, Abid Mehmood; Mustapha, Omer; Din, Fakhar ud; Park, Jong Hyuck; Yong, Chul Soon; Oh, Yu-Kyoung; Youn, Yu Seok; Kim, Jong Oh; Choi, Han-Gon

2015-01-01

Background The objective of this study was to compare the physicochemical characteristics, solubility, dissolution, and oral bioavailability of an ezetimibe-loaded solid self-nanoemulsifying drug delivery system (SNEDDS), surface modified solid dispersion (SMSD), and solvent evaporated solid dispersion (SESD) to identify the best drug delivery system with the highest oral bioavailability. Methods For the liquid SNEDDS formulation, Capryol 90, Cremophor EL, and Tween 80 were selected as the oil, surfactant, and cosurfactant, respectively. The nanoemulsion-forming region was sketched using a pseudoternary phase diagram on the basis of reduced emulsion size. The optimized liquid SNEDDS was converted to solid SNEDDS by spray drying with silicon dioxide. Furthermore, SMSDs were prepared using the spray drying technique with various amounts of hydroxypropylcellulose and Tween 80, optimized on the basis of their drug solubility. The SESD formulation was prepared with the same composition of optimized SMSD. The aqueous solubility, dissolution, physicochemical properties, and pharmacokinetics of all of the formulations were investigated and compared with the drug powder. Results The drug existed in the crystalline form in SMSD, but was changed into an amorphous form in SNEDDS and SESD, giving particle sizes of approximately 24, 6, and 11 µm, respectively. All of these formulations significantly improved the aqueous solubility and dissolution in the order of solid SNEDDS ≥ SESD > SMSD, and showed a total higher plasma concentration than did the drug powder. Moreover, SESD gave a higher area under the drug concentration time curve from zero to infinity than did SNEDDS and SMSD, even if they were not significantly different, suggesting more improved oral bioavailability. Conclusion Among the various formulations tested in this study, the SESD system would be strongly recommended as a drug delivery system for the oral administration of ezetimibe with poor water solubility. PMID:26491288

Synthesis and evaluation of mesoporous carbon/lipid bilayer nanocomposites for improved oral delivery of the poorly water-soluble drug, nimodipine.

PubMed

Zhang, Yanzhuo; Zhao, Qinfu; Zhu, Wufu; Zhang, Lihua; Han, Jin; Lin, Qisi; Ai, Fengwei

2015-07-01

A novel mesoporous carbon/lipid bilayer nanocomposite (MCLN) with a core-shell structure was synthesized and characterized as an oral drug delivery system for poorly water-soluble drugs. The objective of this study was to investigate the potential of MCLN-based formulation to modulate the in vitro release and in vivo absorption of a model drug, nimodipine (NIM). NIM-loaded MCLN was prepared by a procedure involving a combination of thin-film hydration and lyophilization. Scanning electron microscopy (SEM), transmission electron microscopy (TEM), specific surface area analysis, differential scanning calorimetry (DSC) and X-ray diffraction (XRD) were employed to characterize the NIM-loaded MCLN formulation. The effect of MCLN on cell viability was assessed using the MTT assay. In addition, the oral bioavailability of NIM-loaded MCLN in beagle dogs was compared with that of the immediate-release formulation, Nimotop®. Our results demonstrate that the NIM-loaded MCLN formulation exhibited a typical sustained release pattern. The NIM-loaded MCLN formulation achieved a greater degree of absorption and longer lasting plasma drug levels compared with the commercial formulation. The relative bioavailability of NIM for NIM-loaded MCLN was 214%. MCLN exhibited negligible toxicity. The data reported herein suggest that the MCLN matrix is a promising carrier for controlling the drug release rate and improving the oral absorption of poorly water-soluble drugs.

Preparation, characterization and in vitro/vivo evaluation of tectorigenin solid dispersion with improved dissolution and bioavailability.

PubMed

Shuai, Shuping; Yue, Shanlan; Huang, Qingting; Wang, Wei; Yang, Junyi; Lan, Ke; Ye, Liming

2016-08-01

The purpose of this study was to develop and evaluate a novel amorphous solid dispersion system for tectorigenin (TG). TG is one of isoflavone aglycones extracted from Iris tectorum and flowers of Pueraria thunbergiana, but its poor water solubility and low membrane permeability have severely restricted the clinical application. To increase the aqueous solubility and oral bioavailability of TG, we prepared the solid dispersions of tectorigenin (TG-SD) using a simple solvent evaporation process with TG, polyvinylpyrrolidone (PVP) and PEG4000 at weight ratio of 7:54:9 after tested in several ratios. The prepared solid dispersions of tectorigenin are duly characterized for drug morphological conversion, in vitro dissolution and in vivo bioavailability. The X-ray diffraction (XRD), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM) studies have indicated the morphological conversion of tectorigenin to amorphous form. In vitro release profiles revealed that the % release of TG-SD was achieved 4.35-fold higher than that of the pure drug after 150 min. The oral bioavailability of the solid dispersion in rats was also increased based on AUC0-t and C max of TG-SD, which were 4.8- and 13.1-fold higher than that of TG crystal, respectively. It is worth noting that physical mixture containing TG, PEG4000 and PVP produced a similar level of oral exposure as TG-SD, suggesting that PEG4000 and PVP were able to enhance bioavailability of TG in rats. However, with the reduction of particle size, TG-SD provided the fastest oral absorption compared to physical mixture and pure drug. These results demonstrated that the efficacy of solid dispersions for the enhancement of TG oral bioavailability was by increasing its aqueous solubility and the solid dispersion formulation could be a viable option for enhancing the oral bioavailability of TG.

Bioavailability of indomethacin-saccharin cocrystals.

PubMed

Jung, Min-Sook; Kim, Jeong-Soo; Kim, Min-Soo; Alhalaweh, Amjad; Cho, Wonkyung; Hwang, Sung-Joo; Velaga, Sitaram P

2010-11-01

Pharmaceutical cocrystals are new solid forms with physicochemical properties that appear promising for drug product development. However, the in-vivo bioavailability of cocrystals has rarely been addressed. The cocrystal of indomethacin (IND), a Biopharmaceutical Classification System class II drug, with saccharin (SAC) has been shown to have higher solubility than IND at all pH. In this study, we aimed to evaluate the in-vitro dissolution and in-vivo bioavailability of IND-SAC cocrystals in comparison with IND in a physical mixture and the marketed product Indomee. Scale-up of the cocrystals was undertaken using cooling batch crystallisation without seeding. The chemical and physical purity of the up-scaled material was verified using high-performance liquid chromatography, differential scanning calorimetry and powder X-ray diffraction. The IND-SAC cocrystals and IND plus SAC were mixed with lactose and the formulations were placed into gelatin capsules. In-vitro dissolution studies were then performed using the rotating basket dissolution method. The intrinsic dissolution rate of IND and IND-SAC cocrystals was also determined. Finally, a bioavailability study for the formulations was conducted in beagle dogs. The plasma samples were analysed using high-performance liquid chromatography and the pharmacokinetic data were analysed using standard methodologies.   The bulk cocrystals (i.e. scaled-up material) were chemically and physically pure. The in-vitro dissolution rate of the cocrystals was higher than that of IND and similar to that of Indomee at pH 7.4 and pH 1.2. The in-vivo bioavailability of the IND-SAC cocrystals in dogs was significantly higher (ANOVA, P<0.05) than that of IND but not significantly different from Indomee (ANOVA, P>0.05). The study indicates that the improved aqueous solubility of the cocrystals leads to improved bioavailability of IND. Thus, the cocrystals are a viable alternative solid form that can improve the dissolution rate and bioavailability of poorly soluble drugs. © 2010 The Authors. JPP © 2010 Royal Pharmaceutical Society of Great Britain.

Curcumin Encapsulated in Milk Exosomes Resists Human Digestion and Possesses Enhanced Intestinal Permeability in Vitro.

PubMed

Vashisht, Monika; Rani, Payal; Onteru, Suneel Kumar; Singh, Dheer

2017-11-01

Exosomes, the extracellular secretary nano-vesicles, act as carriers of biomolecules to the target cells. They exhibit several attributes of an efficient drug delivery system. Curcumin, despite having numerous bioactive and therapeutic properties, has limited pharmaceutical use due to its poor water solubility, stability, and low systemic bioavailability. Hence, this study aims to enhance the therapeutic potential of curcumin, a model hydrophobic drug, by its encapsulation into milk exosomes. In the present study, we investigated the stability of free curcumin and exosomal curcumin in PBS and in vitro digestive processes. Additionally, their uptake and trans-epithelial transport were studied on Caco-2 cells. Curcumin in milk exosomes had higher stability in PBS, sustained harsh digestive processes, and crossed the intestinal barrier than free curcumin. In conclusion, the encapsulation of curcumin into the exosomes enhances its stability, solubility, and bioavailability. Therefore, the present study demonstrated that milk exosomes act as stable oral drug delivery vehicles.

Nonionic Surfactant Vesicles in Ocular Delivery: Innovative Approaches and Perspectives

PubMed Central

Sahoo, Ranjan Ku.; Biswas, Nikhil; Guha, Arijit; Sahoo, Nityananda

2014-01-01

With the recent advancement in the field of ocular therapy, drug delivery approaches have been elevated to a new concept in terms of nonionic surfactant vesicles (NSVs), that is, the ability to deliver the therapeutic agent to a patient in a staggered profile. However the major drawbacks of the conventional drug delivery system like lacking of permeability through ocular barrier and poor bioavailability of water soluble drugs have been overcome by the emergence of NSVs. The drug loaded NSVs (DNSVs) can be fabricated by simple and cost-effective techniques with improved physical stability and enhance bioavailability without blurring the vision. The increasing research interest surrounding this delivery system has widened the areas of pharmaceutics in particular with many more subdisciplines expected to coexist in the near future. This review gives a comprehensive emphasis on NSVs considerations, formulation approaches, physicochemical properties, fabrication techniques, and therapeutic significances of NSVs in the field of ocular delivery and also addresses the future development of modified NSVs. PMID:24995280

Elevating bioavailability of curcumin via encapsulation with a novel formulation of artificial oil bodies.

PubMed

Chang, Ming-Tsung; Tsai, Tong-Rong; Lee, Chun-Yann; Wei, Yu-Sheng; Chen, Ying-Jie; Chen, Chun-Ren; Tzen, Jason T C

2013-10-09

Utilization of curcumin has been limited due to its poor oral bioavailability. Oral bioavailability of hydrophobic compounds might be elevated via encapsulation in artificial seed oil bodies. This study aimed to improve oral bioavailability of curcumin via this encapsulation. Unfortunately, curcumin was indissoluble in various seed oils. A mixed dissolvent formula was used to dissolve curcumin, and the admixture was successfully encapsulated in artificial oil bodies stabilized by recombinant sesame caleosin. The artificial oil bodies of relatively small sizes (150 nm) were stably solidified in the forms of powder and tablet. Oral bioavailability of curcumin with or without encapsulation in artificial oil bodies was assessed in Sprague-Dawley male rats. The results showed that encapsulation of curcumin significantly elevated its bioavailability and provided the highest maximum whole blood concentration (Cmax), 37 ± 28 ng/mL, in the experimental animals 45 ± 17 min (t(max)) after oral administration. Relative bioavailability calculated on the basis of the area under the plasma concentration-time curve (AUC) was increased by 47.7 times when curcumin was encapsulated in the artificial oil bodies. This novel formulation of artificial oil bodies seems to possess great potential to encapsulate hydrophobic drugs for oral administration.

Bioavailability of Micronutrients from Plant Foods: An Update.

PubMed

Platel, Kalpana; Srinivasan, Krishnapura

2016-07-26

Deficiencies of iron, zinc, iodine and vitamin A are widespread in the developing countries, poor bioavailability of these micronutrients from plant-based foods being the major reason for their wide prevalence. Diets predominantly vegetarian are composed of components that enhance as well as inhibit mineral bioavailability, the latter being predominant. However, prudent cooking practices and use of ideal combinations of food components can significantly improve micronutrient bioavailability. Household processing such as heat treatment, sprouting, fermentation and malting have been evidenced to enhance the bioavailability of iron and β-carotene from plant foods. Food acidulants amchur and lime are also shown to enhance the bioavailability of not only iron and zinc, but also of β-carotene. Recently indentified newer enhancers of micronutrient bioaccessibility include sulphur compound-rich Allium spices-onion and garlic, which also possess antioxidant properties, β-carotene-rich vegetables-carrot and amaranth, and pungent spices-pepper (both red and black) as well as ginger. Information on the beneficial effect of these dietary compounds on micronutrient bioaccessibility is novel. These food components evidenced to improve the bioavailability of micronutrients are common ingredients of Indian culinary, and probably of other tropical countries. Fruits such as mango and papaya, when consumed in combination with milk, provide significantly higher amounts of bioavailable β-carotene. Awareness of the beneficial influence of these common dietary ingredients on the bioavailability of micronutrients would help in devising dietary strategies to improve the bioavailability of these vital nutrients.

A novel matrix dispersion based on phospholipid complex for improving oral bioavailability of baicalein: preparation, in vitro and in vivo evaluations.

PubMed

Zhou, Yang; Dong, Wujun; Ye, Jun; Hao, Huazhen; Zhou, Junzhuo; Wang, Renyun; Liu, Yuling

2017-11-01

Phospholipid complex is one of the most successful approaches for enhancing oral bioavailability of poorly absorbed plant constituents. But the sticky property of phospholipids results in an unsatisfactory dissolution of drugs. In this study, a matrix dispersion of baicalein based on phospholipid complex (BaPC-MD) was first prepared by a discontinuous solvent evaporation method, in which polyvinylpyrrolidone-K30 (PVP-K30) was employed for improving the dispersibility of baicalein phospholipid complex (BaPC) and increasing dissolution of baicalein. The combination ratio of baicalein and phospholipids in BaPC-MD was 99.39% and baicalein was still in a complete complex state with phospholipid in BaPC-MD. Differential scanning calorimetry (DSC), X-ray diffraction (XRD), scanning electron microscopy (SEM) and Fourier Transform Infrared (FTIR) analyzes demonstrated that baicalein was fully transformed to an amorphous state in BaPC-MD and phospholipid complex formed. The water-solubility and n-octanol solubility of baicalein in BaPC-MD significantly increased compared with those of pure baicalein. Compared with baicalein and BaPC, the cumulative dissolution of BaPC-MD at 120 min increased 2.77- and 1.23-fold, respectively. In vitro permeability study in Caco-2 cells indicated that the permeability of BaPC-MD was remarkably higher than those of baicalein and BaPC. Pharmacokinetic study showed that the average C max of BaPC-MD was significantly increased compared to baicalein and BaPC. AUC 0-14 h of BaPC-MD was 5.01- and 1.91-fold of baicalein and BaPC, respectively. The novel BaPC-MD significantly enhanced the oral bioavailability of baicalein by improving the dissolution and permeability of baicalein without destroying the complexation state of baicalein and phospholipids. The current drug delivery system provided an optimal strategy to significantly enhance oral bioavailability for poorly water-soluble drugs.

Preparation, Characterization and Evaluation of Quetiapine Fumarate Solid Lipid Nanoparticles to Improve the Oral Bioavailability

PubMed Central

Narala, Arjun; Veerabrahma, Kishan

2013-01-01

Quetiapine fumarate is an antipsychotic drug with poor oral bioavailability (9%) due to first-pass metabolism. Present work is an attempt to improve oral bioavailability of quetiapine fumarate by incorporating in solid lipid nanoparticles (SLN). Six quetiapine fumarate SLN formulations were developed using three different lipids by hot homogenisation followed by ultrasonication. The drug excipient compatibility was studied by differential scanning calorimetry (DSC). Stable quetiapine fumarate SLNs having a mean particle size of 200–250 nm with entrapment efficiency varying in between 80% and 92% were developed. The physical stability of optimized formulation F3 was checked at room temperature for 2 months. Comparative bioavailability studies were conducted in male Wistar rats after oral administration of quetiapine fumarate suspension and SLN formulation. The relative bioavailability of quetiapine fumarate from optimized SLN preparation was increased by 3.71 times when compared with the reference quetiapine fumarate suspension. The obtained results are indicative of SLNs as potential lipid carriers for improving the bioavailability of quetiapine fumarate by minimizing first-pass metabolism. PMID:26555970

Nanotechnology-Applied Curcumin for Different Diseases Therapy

PubMed Central

Ghalandarlaki, Negar; Ashkani-Esfahani, Soheil

2014-01-01

Curcumin is a lipophilic molecule with an active ingredient in the herbal remedy and dietary spice turmeric. It is used by different folks for treatment of many diseases. Recent studies have discussed poor bioavailability of curcumin because of poor absorption, rapid metabolism, and rapid systemic elimination. Nanotechnology is an emerging field that is potentially changing the way we can treat diseases through drug delivery with curcumin. The recent investigations established several approaches to improve the bioavailability, to increase the plasma concentration, and to enhance the cellular permeability processes of curcumin. Several types of nanoparticles have been found to be suitable for the encapsulation or loading of curcumin to improve its therapeutic effects in different diseases. Nanoparticles such as liposomes, polymeric nanoparticles, micelles, nanogels, niosomes, cyclodextrins, dendrimers, silvers, and solid lipids are emerging as one of the useful alternatives that have been shown to deliver therapeutic concentrations of curcumin. This review shows that curcumin's therapeutic effects may increase to some extent in the presence of nanotechnology. The presented board of evidence focuses on the valuable special effects of curcumin on different diseases and candidates it for future clinical studies in the realm of these diseases. PMID:24995293

Iron Bioavailability and Provitamin A from Sweet Potato- and Cereal-Based Complementary Foods

PubMed Central

Christides, Tatiana; Amagloh, Francis Kweku; Coad, Jane

2015-01-01

Iron and vitamin A deficiencies in childhood are public health problems in the developing world. Introduction of cereal-based complementary foods, that are often poor sources of both vitamin A and bioavailable iron, increases the risk of deficiency in young children. Alternative foods with higher levels of vitamin A and bioavailable iron could help alleviate these micronutrient deficiencies. The objective of this study was to compare iron bioavailability of β-carotene-rich sweet potato-based complementary foods (orange-flesh based sweet potato (OFSP) ComFa and cream-flesh sweet potato based (CFSP) ComFa with a household cereal-based complementary food (Weanimix) and a commercial cereal (Cerelac®), using the in vitro digestion/Caco-2 cell model. Iron bioavailability relative to total iron, concentrations of iron-uptake inhibitors (fibre, phytates, and polyphenols), and enhancers (ascorbic acid, ß-carotene and fructose) was also evaluated. All foods contained similar amounts of iron, but bioavailability varied: Cerelac® had the highest, followed by OFSP ComFa and Weanimix, which had equivalent bioavailable iron; CFSP ComFa had the lowest bioavailability. The high iron bioavailability from Cerelac® was associated with the highest levels of ascorbic acid, and the lowest levels of inhibitors; polyphenols appeared to limit sweet potato-based food iron bioavailability. Taken together, the results do not support that CFSP- and OFSP ComFa are better sources of bioavailable iron compared with non-commercial/household cereal-based weaning foods; however, they may be a good source of provitamin A in the form of β-carotene. PMID:28231217

The influence of supercritical carbon dioxide (SC-CO2) processing conditions on drug loading and physicochemical properties.

PubMed

Ahern, Robert J; Crean, Abina M; Ryan, Katie B

2012-12-15

Poor water solubility of drugs can complicate their commercialisation because of reduced drug oral bioavailability. Formulation strategies such as increasing the drug surface area are frequently employed in an attempt to increase dissolution rate and hence, improve oral bioavailability. Maximising the drug surface area exposed to the dissolution medium can be achieved by loading drug onto a high surface area carrier like mesoporous silica (SBA-15). The aim of this work was to investigate the impact of altering supercritical carbon dioxide (SC-CO(2)) processing conditions, in an attempt to enhance drug loading onto SBA-15 and increase the drug's dissolution rate. Other formulation variables such as the mass ratio of drug to SBA-15 and the procedure for combining the drug and SBA-15 were also investigated. A model drug with poor water solubility, fenofibrate, was selected for this study. High drug loading efficiencies were obtained using SC-CO(2), which were influenced by the processing conditions employed. Fenofibrate release rate was enhanced greatly after loading onto mesoporous silica. The results highlighted the potential of this SC-CO(2) drug loading approach to improve the oral bioavailability of poorly water soluble drugs. Copyright © 2012 Elsevier B.V. All rights reserved.

Solubilization of poorly water-soluble drugs using solid dispersions.

PubMed

Tran, Thao T-D; Tran, Phuong H-L; Khanh, Tran N; Van, Toi V; Lee, Beom-Jin

2013-08-01

Many new drugs have been discovered in pharmaceutical industry and exposed their surprised potential therapeutic effects. Unfortunately, these drugs possess low absorption and bioavailability since their solubility limitation in water. Solid dispersion (SD) is the current technique gaining so many attractions from scientists due to its effect on improving solubility and dissolution rate of poorly water-soluble drugs. A number of patents including the most recent inventions have been undertaken in this review to address various respects of this strategy in solubilization of poorly watersoluble drugs including type of carriers, preparation methods and view of technologies used to detect SD properties and mechanisms with the aim to accomplish a SD not only effective on enhanced bioavailability but also overcome difficulties associated with stability and production. Future prospects are as well discussed with an only hope that many developments and researches in this field will be successfully reached and contributed to commercial use for treatment as much as possible.

Curcumin-loaded self-nanomicellizing solid dispersion system: part I: development, optimization, characterization, and oral bioavailability.

PubMed

Parikh, Ankit; Kathawala, Krishna; Song, Yunmei; Zhou, Xin-Fu; Garg, Sanjay

2018-05-29

Curcumin (CUR) is considered as one of the most bioactive molecules ever discovered from nature due to its proven anti-inflammatory and antioxidant in both preclinical and clinical studies. Despite its proven safety and efficacy, the clinical translation of CUR into a useful therapeutic agent is still limited due to its poor oral bioavailability. To overcome its limitation and enhance oral bioavailability by improving its aqueous solubility, stability, and intestinal permeability, a novel CUR formulation (NCF) was developed using the self-nanomicellizing solid dispersion strategy. From the initial screening of polymers for their potential to improve the solubility and stability, Soluplus (SOL) was selected. The optimized NCF demonstrated over 20,000-fold improvement in aqueous solubility as a result of amorphization, hydrogen bonding interaction, and micellization determined using differential scanning calorimetry, X-ray diffraction, scanning electron microscopy, Fourier transform infrared spectroscopy, nuclear magnetic resonance, dynamic light scattering, and transmission electron microscopy. Moreover, the greater stabilizing effect in alkaline pH and light was observed. Furthermore, significant enhancement of dissolution and permeability of CUR across everted sacs of rat small intestine were noticed. Pharmacokinetic studies demonstrated that the oral bioavailability of CUR was increased 117 and 17-fold in case of NCF and physical mixture of CUR and SOL compared to CUR suspension. These results suggest NCF identified as a promising new approach for repositioning of CUR for pharmaceutical application by enhancing the oral bioavailability of CUR. The findings herein stimulate further in vivo evaluations and clinical tests of NCF.

Novel gastroretentive sustained-release tablet of tacrolimus based on self-microemulsifying mixture: in vitro evaluation and in vivo bioavailability test.

PubMed

Wang, Yan-ping; Gan, Yong; Zhang, Xin-xin

2011-10-01

To develop a novel gastroretentive drug delivery system based on a self-microemulsifying (SME) lipid mixture for improving the oral absorption of the immunosuppressant tacrolimus. Liquid SME mixture, composed of Cremophor RH40 and monocaprylin glycerate, was blended with polyethylene oxide, chitosan, polyvinylpyrrolidone and mannitol, and then transformed into tablets via granulation, with ethanol as the wetting agent. The tablets were characterized in respect of swelling, bioadhesive and SME properties. In vitro dissolution was conducted using an HCl buffer at pH 1.2. Oral bioavailability of the tablets was examined in fasted beagle dogs. The tablet could expand to 13.5 mm in diameter and 15 mm in thickness during the initial 20 min of contact with the HCl buffer at pH 1.2. The bioadhesive strength was as high as 0.98±0.06 N/cm(2). The SME gastroretentive sustained-release tablets preserved the SME capability of the liquid SME formations under transmission electron microscope. The drug-release curve was fit to the zero-order release model, which was helpful in reducing fluctuations in blood concentration. Compared with the commercially available capsules of tacrolimus, the relative bioavailability of the SME gastroretentive sustained-release tablets was 553.4%±353.8%. SME gastroretentive sustained-release tablets can enhance the oral bioavailability of tacrolimus with poor solubility and a narrow absorption window.

Evaluation of Intestinal Absorption and Bioavailability of a Bergenin-Phospholipid Complex Solid Dispersion in Rats.

PubMed

Gao, Haoshi; Wei, Yue; Xi, Long; Sun, Yuanyuan; Zhang, Tianhong

2018-05-01

Bergenin (BN) is a Biopharmaceutics Classification System class IV (BCS IV) drug with poor hydrophilicity and lipophilicity and is potentially eliminated by the efflux function of P-glycoprotein (P-gp). These factors may explain its low oral bioavailability. In the present study, a BN-phospholipid complex solid dispersion (BNPC-SD) was prepared by solvent evaporation and characterized based on differential scanning calorimetry, powder X-ray diffraction, scanning electron microscopy, infrared diffraction, solubility, octanol-water partition coefficient, and in vitro dissolution. To investigate how P-gp can inhibit BN absorption in vivo, the P-gp inhibitor verapamil was co-administered with BNPC-SD to Sprague Dawley rats. By in situ single-pass intestinal perfusion, the membrane permeability of BN from BNPC-SD was higher than that of BN given alone and was improved further by co-administered verapamil. A pharmacokinetics study was done in Sprague Dawley rats, with plasma BN levels estimated by high-performance liquid chromatography. C max and AUC 0 → t values for BN were significantly higher for BNPC-SD than for BN given alone and were increased further by verapamil. Thus, the relative oral bioavailability of BNPC-SD as well as BNPC-SD co-administered with verapamil was 156.33 and 202.46%, respectively, compared with the value for BN given alone. These results showed that BNPC-SD can increase the oral bioavailability of BCS IV drugs.

Development and Evaluation of High Bioavailable Sustained-Release Nimodipine Tablets Prepared with Monolithic Osmotic Pump Technology.

PubMed

Kong, Hua; Yu, Fanglin; Liu, Yan; Yang, Yang; Li, Mingyuan; Cheng, Xiaohui; Hu, Xiaoqin; Tang, Xuemei; Li, Zhiping; Mei, Xingguo

2018-01-01

Frequent administration caused by short half-life and low bioavailability due to poor solubility and low dissolution rate limit the further application of poorly water-soluble nimodipine, although several new indications have been developed. To overcome these shortcomings, sophisticated technologies had to be used since the dose of nimodipine was not too low and the addition of solubilizers could not resolve the problem of poor release. The purpose of this study was to obtain sustained and complete release of nimodipine with a simple and easily industrialized technology. The expandable monolithic osmotic pump tablets containing nimodipine combined with poloxamer 188 and carboxymethylcellulose sodium were prepared. The factors affecting drug release including the amount of solubilizing agent, expanding agent, retarding agent in core tablet and porogenic agent in semipermeable film were optimized. The release behavior was investigated both in vitro and in beagle dogs. It was proved that the anticipant release of nimodipine could be realized in vitro. The sustained and complete release of nimodipine was also realized in beagles because the mean residence time of nimodipine from the osmotic pump system was longer and Cmax was lower than those from the sustained-release tablets in market while there was no difference in AUC(0-t) of the monolithic osmotic pump tablets and the sustained release tablets in market. It was reasonable to believe that the sustained and complete release of poorly watersoluble nimodipine could be realized by using simple expandable monolithic osmotic pump technology combined with surfactant. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Excipient foods: designing food matrices that improve the oral bioavailability of pharmaceuticals and nutraceuticals.

PubMed

McClements, David Julian; Xiao, Hang

2014-07-25

The oral bioavailability of many lipophilic bioactive agents (pharmaceuticals and nutraceuticals) is limited due to various physicochemical and physiological processes: poor release from food or drug matrices; low solubility in gastrointestinal fluids; metabolism or chemical transformation within the gastrointestinal tract; low epithelium cell permeability. The bioavailability of these agents can be improved by specifically designing food matrices that control their release, solubilization, transport, metabolism, and absorption within the gastrointestinal tract. This article discusses the impact of food composition and structure on oral bioavailability, and how this knowledge can be used to design excipient foods for improving the oral bioavailability of lipophilic bioactives. Excipient foods contain ingredients or structures that may have no bioactivity themselves, but that are able to promote the bioactivity of co-ingested bioactives. These bioactives may be lipophilic drugs in pharmaceutical preparations (such as capsules, pills, or syrups) or nutraceuticals present within food matrices (such as natural or processed foods and beverages).

Fabrication of a Soybean Bowman-Birk Inhibitor (BBI) Nanodelivery Carrier To Improve Bioavailability of Curcumin.

PubMed

Liu, Chun; Cheng, Fenfen; Yang, Xiaoquan

2017-03-22

Curcumin is a poorly water-soluble drug, and its oral bioavailability is very low. Here, a novel self-assembly nanoparticle delivery carrier has been successfully developed by using soybean Bowman-Birk inhibitor (BBI) to improve the solubility, bioaccessibility, and oral absorption of curcumin. BBI is a unique protein, which can be resistant to the pH range and proteolytic enzymes in the gastrointestinal tract (GIT), bioavailable, and not allergenic. The encapsulation efficiencies (EE) and the loading capacities (LC) of curcumin in the curcumin-loaded BBI nanoparticles (Cur-BBI-NPs, size = 90.09 nm, PDI = 0.103) were 86.17 and 10.31%, respectively. The in vitro bioaccessibility of Cur-BBI-NPs was superior to that of curcumin-loaded sodium caseinate (SC) nanoparticles (Cur-SC-NPs) (as control). Moreover, Cur-BBI-NPs significantly enhanced the bioavailability of curcumin in rats compared with Cur-SC-NPs, and the clathrin-mediated endocytosis pathway probably contributed to the favorable bioavailability of Cur-BBI-NPs, as revealed by the cellular uptake inhibition study.

Elucidating the impact of micro-scale heterogeneous bacterial distribution on biodegradation

NASA Astrophysics Data System (ADS)

Schmidt, Susanne I.; Kreft, Jan-Ulrich; Mackay, Rae; Picioreanu, Cristian; Thullner, Martin

2018-06-01

Groundwater microorganisms hardly ever cover the solid matrix uniformly-instead they form micro-scale colonies. To which extent such colony formation limits the bioavailability and biodegradation of a substrate is poorly understood. We used a high-resolution numerical model of a single pore channel inhabited by bacterial colonies to simulate the transport and biodegradation of organic substrates. These high-resolution 2D simulation results were compared to 1D simulations that were based on effective rate laws for bioavailability-limited biodegradation. We (i) quantified the observed bioavailability limitations and (ii) evaluated the applicability of previously established effective rate concepts if microorganisms are heterogeneously distributed. Effective bioavailability reductions of up to more than one order of magnitude were observed, showing that the micro-scale aggregation of bacterial cells into colonies can severely restrict the bioavailability of a substrate and reduce in situ degradation rates. Effective rate laws proved applicable for upscaling when using the introduced effective colony sizes.

Curcumin Nanotechnologies and Its Anticancer Activity.

PubMed

Subramani, Parasuraman Aiya; Panati, Kalpana; Narala, Venkata Ramireddy

2017-04-01

Cancer is one of the leading causes of death worldwide. Curcumin is a well-established anticancer agent in vitro but its efficacy is yet to be proven in clinical trials. Poor bioavailability of curcumin is the principal reason behind the lack of efficiency of curcumin in clinical trials. Many studies prove that the bioavailability of curcumin can be improved by administering it through nanoparticle drug carriers. This review focuses on the efforts made in the field of nanotechnology to improve the bioavailability of curcumin. Nanotechnologies of curcumin come in various shapes and sizes. The simplest curcumin nanoparticle that increased the bioavailability of curcumin is the curcumin-metal complex. On the other hand, we have intricate thermoresponsive nanoparticles that can release curcumin upon stimulation (analogous to a remote control). Future research required for developing potent curcumin nanoparticles is also discussed.

Liposheres as a Novel Carrier for Lipid Based Drug Delivery: Current and Future Directions.

PubMed

Swain, Suryakanta; Beg, Sarwar; Babu, Sitty M

2016-01-01

Researchers are facing challenges to develop robust formulation and to enhance the bioavailability of poorly water-soluble drugs towards clinical applications. The development of new drug molecule alone is not adequate to assure ample pharmacotherapy of various diseases. Considerable results obtained from in vitro studies are not supported by in vivo data due to inadequate plasma drug concentrations. This may occur due to limited drug solubility and absorption. To resolve these problems, development of new drug delivery systems will be a promising approach. One of the promising pharmaceutical strategies is the use of lipospheres drug delivery system to deliver the poorly water-soluble drugs. Therefore, the present review described the methodology for manufacturing of lipospheres and factors influencing the formulation to deliver the drugs to the targeted site. Apart from that, this review also enlisted briefly the various applications of liposphers in medical and biomedical fields and critically discussed the recent patent system.

Nonlinear absorption kinetics of self-emulsifying drug delivery systems (SEDDS) containing tocotrienols as lipophilic molecules: in vivo and in vitro studies.

PubMed

Alqahtani, Saeed; Alayoubi, Alaadin; Nazzal, Sami; Sylvester, Paul W; Kaddoumi, Amal

2013-07-01

Self-emulsifying drug delivery systems (SEDDS) have been broadly used to promote the oral absorption of poorly water-soluble drugs. The purpose of the current study was to evaluate the in vivo oral bioavailability of vitamin E isoforms, δ-tocotrienol (δ-T3) and γ-tocotrienol (γ-T3) administered as SEDDS, as compared to commercially available UNIQUE E® Tocotrienols capsules. Results from studies in rats showed that low dose treatment with δ-T3 (90%) and γ-T3 (10%) formulated SEDDS showed bioavailability of 31.5% and 332%, respectively. However, bioavailability showed a progressive decrease with increased treatment dose that displayed nonlinear absorption kinetics. Additional in vitro studies examining cellular uptake studies in Caco 2 cells revealed that the SEDDS formulation increased passive permeability of δ-T3 and γ-T3 by threefold as compared to the commercial capsule formulation. These studies also showed that free surfactants decreased δ-T3 and γ-T3 absorption. Specifically, combined treatment cremophor EL or labrasol with tocotrienols caused a 60-85% reduction in the cellular uptake of δ-T3 and γ-T3 and these effects appear to result from surfactant-induced inhibition of the δ-T3 and γ-T3 transport protein Niemann-Pick C1-like 1 (NPC1L1). In summary, results showed that SEDDS formulation significantly increases the absorption and bioavailability δ-T3 and γ-T3. However, this effect is self-limiting because treatment with increasing doses of SEDDS appears to be associated with a corresponding increase in free surfactants levels that directly and negatively impact tocotrienol transport protein function and results in nonlinear absorption kinetics and a progressive decrease in δ-T3 and γ-T3 absorption and bioavailability.

Controlled release systems containing solid dispersions: strategies and mechanisms.

PubMed

Tran, Phuong Ha-Lien; Tran, Thao Truong-Dinh; Park, Jun Bom; Lee, Beom-Jin

2011-10-01

In addition to a number of highly soluble drugs, most new chemical entities under development are poorly water-soluble drugs generally characterized by an insufficient dissolution rate and a small absorption window, leading to the low bioavailability. Controlled-release (CR) formulations have several potential advantages over conventional dosage forms, such as providing a uniform and prolonged therapeutic effect to improve patient compliance, reducing the frequency of dosing, minimizing the number of side effects, and reducing the strength of the required dose while increasing the effectiveness of the drug. Solid dispersions (SD) can be used to enhance the dissolution rate of poorly water-soluble drugs and to sustain the drug release by choosing an appropriate carrier. Thus, a CR-SD comprises both functions of SD and CR for poorly water-soluble drugs. Such CR dosage forms containing SD provide an immediately available dose for an immediate action followed by a gradual and continuous release of subsequent doses to maintain the plasma concentration of poorly water-soluble drugs over an extended period of time. This review aims to summarize all currently known aspects of controlled release systems containing solid dispersions, focusing on the preparation methods, mechanisms of action and characterization of physicochemical properties of the system.

Cefuroxime axetil solid dispersion with polyglycolized glycerides for improved stability and bioavailability.

PubMed

Dhumal, Ravindra S; Biradar, Shailesh V; Aher, Suyog; Paradkar, Anant R

2009-06-01

Cefuroxime axetil (CA), a poorly soluble, broad spectrum cephalosporin ester prodrug, is hydrolysed by intestinal esterase prior to absorption, leading to poor and variable bioavailability. The objective was therefore to formulate a stable amorphous solid dispersion of the drug with enhanced solubility and stability against enzymatic degradation. Spray drying was used to obtain a solid dispersion of CA with Gelucire 50/13 and Aerosil 200 (SDCAGA), and a solid dispersion of CA with polyvinyl pyrrolidone (SDCAP); amorphous CA (ACA) was obtained by spray drying CA alone. The formulations were characterized by differential scanning calorimetry, X-ray powder diffraction, scanning electron microscopy and Fourier transform infrared spectroscopy studies, and compared for solubility, dissolution and bioavailability in rats. SDCAP and SDCAGA showed improved solubility and dissolution profiles owing to amorphization and formation of solid dispersions with hydrophilic carriers. The improved stability of amorphous CA in solid dispersions compared to ACA alone was attributed to hydrogen bonding interactions involving the amide of CA with the carbonyl of polyvinyl pyrrolidone in SDCAP, whereas in SDCAGA the interactions were at multiple sites involving the amide and carbonyl of CA with the carbonyl and hydroxyl of Gelucire 50/13. However, SDCAGA showed superior bioavailability compared to SDCAP, ACA and CA. Improvement in physical stability of solid dispersions was attributed to hydrogen bonding, while improvement in bioavailability of SDCAGA compared to SDCAP, in spite of comparable solubility and dissolution profile, may be attributed to Gelucire, which utilizes intestinal esterase for lipolysis, protecting the prodrug from enzymatic degradation to its non-absorbable base form.

Saccharides enhance iron bioavailability to Southern Ocean phytoplankton

PubMed Central

Hassler, Christel S.; Nichols, Carol Mancuso; Butler, Edward C. V.; Boyd, Philip W.

2011-01-01

Iron limits primary productivity in vast regions of the ocean. Given that marine phytoplankton contribute up to 40% of global biological carbon fixation, it is important to understand what parameters control the availability of iron (iron bioavailability) to these organisms. Most studies on iron bioavailability have focused on the role of siderophores; however, eukaryotic phytoplankton do not produce or release siderophores. Here, we report on the pivotal role of saccharides—which may act like an organic ligand—in enhancing iron bioavailability to a Southern Ocean cultured diatom, a prymnesiophyte, as well as to natural populations of eukaryotic phytoplankton. Addition of a monosaccharide (>2 nM of glucuronic acid, GLU) to natural planktonic assemblages from both the polar front and subantarctic zones resulted in an increase in iron bioavailability for eukaryotic phytoplankton, relative to bacterioplankton. The enhanced iron bioavailability observed for several groups of eukaryotic phytoplankton (i.e., cultured and natural populations) using three saccharides, suggests it is a common phenomenon. Increased iron bioavailability resulted from the combination of saccharides forming highly bioavailable organic associations with iron and increasing iron solubility, mainly as colloidal iron. As saccharides are ubiquitous, present at nanomolar to micromolar concentrations, and produced by biota in surface waters, they also satisfy the prerequisites to be important constituents of the poorly defined “ligand soup,” known to weakly bind iron. Our findings point to an additional type of organic ligand, controlling iron bioavailability to eukaryotic phytoplankton—a key unknown in iron biogeochemistry. PMID:21169217

In situ absorption and relative bioavailability studies of zaleplon loaded self-nanoemulsifying powders.

PubMed

Janga, Karthik Y; Jukanti, Raju; Sunkavalli, Sharath; Velpula, Ashok; Bandari, Suresh; Kandadi, Prabhakar; Veerareddy, Prabhakar Reddy

2013-01-01

Self-nanoemulsifying drug delivery systems (SNEDDSs) offer potential as suitable carriers for improved oral delivery of poorly soluble and low bioavailable drugs. To derive self-nanoemulsifying powders (SNEPs), the optimized Z-SNEDDS formulation was adsorbed onto different carriers and based on micromeritics the formulation loaded onto neusilin US2 (SNEP-N) was selected for further characterization. The solid-state characterization (scanning electron microscopy, differential scanning calorimetry and powder X-ray diffraction) studies unravel the transformation of native crystalline state to amorphous and/or molecular state. The higher predictive effective permeability coefficient and fraction absorbed in humans extrapolated from in situ single-pass intestinal absorption study data in rats provide an insight on the potential of SNEPs for augment in absorption across gastrointestinal barrier. Overall a 3.5-fold enhancement in the extent of absorption of zaleplon from SNEP-N formulation proves the feasibility of SNEPs formulation for improved oral delivery of zaleplon.

Drug delivery strategies for poorly water-soluble drugs.

PubMed

Fahr, Alfred; Liu, Xiangli

2007-07-01

The drug candidates coming from combinatorial chemistry research and/or the drugs selected from biologically based high-throughput screening are quite often very lipophilic, as these drug candidates exert their pharmacological action at or in biological membranes or membrane-associated proteins. This challenges drug delivery institutions in industry or academia to develop carrier systems for the optimal oral and parenteral administration of these drugs. To mention only a few of the challenges for this class of drugs: their oral bioavailability is poor and highly variable, and carrier development for parenteral administration is faced with problems, including the massive use of surface-active excipients for solubilisation. Formulation specialists are confronted with an even higher level of difficulties when these drugs have to be delivered site specifically. This article addresses the emerging formulation designs for delivering of poorly water-soluble drugs.

Novel delivery system for natural products: Nano-curcumin formulations

PubMed Central

Rahimi, Hamid Reza; Nedaeinia, Reza; Sepehri Shamloo, Alireza; Nikdoust, Shima; Kazemi Oskuee, Reza

2016-01-01

Objective: Curcumin is extracted from Curcuma longa and regulates the intracellular signal pathways which control the growth of cancerous cell, inflammation, invasion and apoptosis. Curcumin molecules have special intrinsic features that can target the intracellular enzymes, genome (DNA) and messengers (RNA). A wide range of studies have been conducted on the physicochemical traits and pharmacological effects of curcumin on different diseases like cardiovascular diseases, diabetes, cancer, rheumatoid arthritis, Alzheimer’s, inflammatory bowel disease (IBD), and even it has wound healing. Oral bioavailability of curcumin is rather poor, which would certainly put some boundaries in the employment of this drug. Materials and Methods: Bibliographical searches were performed using MEDLINE/ScienceDirect/OVID up to February 2015 using the following keywords (all fields): (“Curcumin” OR “Curcuma longa”) AND [(nanoparticles) OR (Nanomicelles) OR (micro emulsions) OR (liposome) OR (phospholipid). Results: Consequently, for any developments of curcumin in the future, analogues of curcumin that have better bioavailability or substitute formulations are needed crucially. Conclusion: These studies indicated that nanotechnology can formulate curcumin effectively, and this nano-formulated curcumin with a potent ability against various cancer cells, were represented to have better efficacy and bioavailability under in vivo conditions. PMID:27516979

Duloxetine loaded-microemulsion system to improve behavioral activities by upregulating serotonin and norepinephrine in brain for the treatment of depression.

PubMed

Sindhu, Pardeep; Kumar, Shobhit; Iqbal, Babar; Ali, Javed; Baboota, Sanjula

2018-04-01

Duloxetine is a well-known antidepressant molecule which is used in the treatment of depression but due to poor solubility it suffers with the drawback of low oral bioavailability. The objective of present work was to formulate and characterize duloxetine loaded microemulsion to enhance the oral bioavailability. Prepared microemulsion was studied for droplet size, zeta potential, refractive index, polydispersity index (PDI), percentage transmittance, viscosity and in vitro release study. Optimized microemulsion (D1) showed spherical droplets with mean diameter of 35.40 ± 3.11 nm, PDI of 0.170 and zeta potential values of -25.8 mV. Formulation showed good transmittance (greater than 99%), viscosity (0.205 Pa s) and refractive index (1.43 ± 0.01). Increased duloxetine release was obtained with microemulsion in comparison to drug suspension. Behavioral tests like mobility test, tail suspension test and forced swimming test performed in depressed and treated rats with duloxetine microemulsion significantly improved the behavioral activities in comparison to duloxetine suspension. Pharmacokinetic studies showed that microemulsion exhibited 1.8 times increment in bioavailability in comparison to duloxetine suspension. Copyright © 2018 Elsevier Ltd. All rights reserved.

Enhanced Oral Bioavailability of Efavirenz by Solid Lipid Nanoparticles: In Vitro Drug Release and Pharmacokinetics Studies

PubMed Central

Gaur, Praveen Kumar; Mishra, Shikha; Bajpai, Meenakshi; Mishra, Anushika

2014-01-01

Solid lipid nanoparticle is an efficient lipid based drug delivery system which can enhance the bioavailability of poorly water soluble drugs. Efavirenz is a highly lipophilic drug from nonnucleoside inhibitor category for treatment of HIV. Present work illustrates development of an SLN formulation for Efavirenz with increased bioavailability. At first, suitable lipid component and surfactant were chosen. SLNs were prepared and analyzed for physical parameters, stability, and pharmacokinetic profile. Efavirenz loaded SLNs were formulated using Glyceryl monostearate as main lipid and Tween 80 as surfactant. ESLN-3 has shown mean particle size of 124.5 ± 3.2 nm with a PDI value of 0.234, negative zeta potential, and 86% drug entrapment. In vitro drug release study has shown 60.6–98.22% drug release in 24 h by various SLN formulations. Optimized SLNs have shown good stability at 40°C ± 2°C and 75 ± 5% relative humidity (RH) for 180 days. ESLN-3 exhibited 5.32-fold increase in peak plasma concentration (C max⁡) and 10.98-fold increase in AUC in comparison to Efavirenz suspension (ES). PMID:24967360

Solid formulation of a supersaturable self-microemulsifying drug delivery system for valsartan with improved dissolution and bioavailability

PubMed Central

Yeom, Dong Woo; Chae, Bo Ram; Kim, Jin Han; Chae, Jun Soo; Shin, Dong Jun; Kim, Chang Hyun; Kim, Sung Rae; Choi, Ji Ho; Song, Seh Hyon; Oh, Dongho; Sohn, Se Il; Choi, Young Wook

2017-01-01

In order to improve the dissolution and oral bioavailability of valsartan (VST), and reduce the required volume for treatment, we previously formulated a supersaturable self-microemulsifying drug delivery system (SuSMEDDS) composed of VST (80 mg), Capmul® MCM (13.2 mg), Tween® 80 (59.2 mg), Transcutol® P (59.2 mg), and Poloxamer 407 (13.2 mg). In the present study, by using Florite® PS-10 (119.1 mg) and Vivapur® 105 (105.6 mg) as solid carriers, VST-loaded solidified SuSMEDDS (S-SuSMEDDS) granules were successfully developed, which possessed good flow properties and rapid drug dissolution. By introducing croscarmellose sodium (31 mg) as a superdisintegrant, S-SuSMEDDS tablets were also successfully formulated, which showed fast disintegration and high dissolution efficiency. Preparation of granules and tablets was successfully optimized using D-optimal mixture design and 3-level factorial design, respectively, resulting in percentage prediction errors of <10%. In pharmacokinetic studies in rats, the relative bioavailability of the optimized granules was 107% and 222% of values obtained for SuSMEDDS and Diovan® powder, respectively. Therefore, we conclude that novel S-SuSMEDDS formulations offer great potential for developing solid dosage forms of a liquefied formulation such as SuSMEDDS, while improving oral absorption of drugs with poor water solubility. PMID:29212229

Solid formulation of a supersaturable self-microemulsifying drug delivery system for valsartan with improved dissolution and bioavailability.

PubMed

Yeom, Dong Woo; Chae, Bo Ram; Kim, Jin Han; Chae, Jun Soo; Shin, Dong Jun; Kim, Chang Hyun; Kim, Sung Rae; Choi, Ji Ho; Song, Seh Hyon; Oh, Dongho; Sohn, Se Il; Choi, Young Wook

2017-11-07

In order to improve the dissolution and oral bioavailability of valsartan (VST), and reduce the required volume for treatment, we previously formulated a supersaturable self-microemulsifying drug delivery system (SuSMEDDS) composed of VST (80 mg), Capmul ® MCM (13.2 mg), Tween ® 80 (59.2 mg), Transcutol ® P (59.2 mg), and Poloxamer 407 (13.2 mg). In the present study, by using Florite ® PS-10 (119.1 mg) and Vivapur ® 105 (105.6 mg) as solid carriers, VST-loaded solidified SuSMEDDS (S-SuSMEDDS) granules were successfully developed, which possessed good flow properties and rapid drug dissolution. By introducing croscarmellose sodium (31 mg) as a superdisintegrant, S-SuSMEDDS tablets were also successfully formulated, which showed fast disintegration and high dissolution efficiency. Preparation of granules and tablets was successfully optimized using D-optimal mixture design and 3-level factorial design, respectively, resulting in percentage prediction errors of <10%. In pharmacokinetic studies in rats, the relative bioavailability of the optimized granules was 107% and 222% of values obtained for SuSMEDDS and Diovan ® powder, respectively. Therefore, we conclude that novel S-SuSMEDDS formulations offer great potential for developing solid dosage forms of a liquefied formulation such as SuSMEDDS, while improving oral absorption of drugs with poor water solubility.

Novel diindolylmethane derivatives based NLC formulations to improve the oral bioavailability and anticancer effects in triple negative breast cancer

PubMed Central

Godugu, Chandraiah; Doddapaneni, Ravi; Safe, Stephen H.; Singh, Mandip

2017-01-01

The present study demonstrates the promising anticancer effects of novel C-substituted diindolylmethane (DIM) derivatives DIM-10 and DIM-14 in aggressive TNBC models. In vitro studies demonstrated that these compounds possess strong anticancer effects. Caco-2 permeability studies resulted in poor permeability and poor oral bioavailability was demonstrated by pharmacokinetic studies. Nano structured lipid carrier (NLC) formulations were prepared to increase the clinical acceptance of these compounds. Significant increase in oral bioavailability was observed with NLC formulations. Compared to DIM-10, DIM-10 NLC formulation showed increase in Cmax and AUC values by 4.73 and 11.19-folds, respectively. Similar pattern of increase was observed with DIM-14 NLC formulations. In dogs DIM-10 NLC formulations showed an increase of 2.65 and 2.94-fold in Cmax and AUC, respectively. The anticancer studies in MDA-MB-231 orthotopic TNBC models demonstrated significant reduction in tumor volumes in DIM-10 and DIM-14 NLC treated animals. Our studies suggest that NLC formulation of both DIM-10 and 14 is effective in TNBC models. PMID:27586082

Curcumin conjugated silica nanoparticles for improving bioavailability and its anticancer applications.

PubMed

Gangwar, Rajesh K; Tomar, Geetanjali B; Dhumale, Vinayak A; Zinjarde, Smita; Sharma, Rishi B; Datar, Suwarna

2013-10-09

Curcumin, a yellow bioactive component of Indian spice turmeric, is known to have a wide spectrum of biological applications. In spite of various astounding therapeutic properties, it lacks in bioavailability mainly due to its poor solubility in water. In this work, we have conjugated curcumin with silica nanoparticles to improve its aqueous solubility and hence to make it more bioavailable. Conjugation and loading of curcumin with silica nanoparticles was further examined with transmission electron microscope (TEM) and thermogravimetric analyzer. Cytotoxicity analysis of synthesized silica:curcumin conjugate was studied against HeLa cell lines as well as normal fibroblast cell lines. This study shows that silica:curcumin conjugate has great potential for anticancer application.

The influence of droplet size on the stability, in vivo digestion, and oral bioavailability of vitamin E emulsions.

PubMed

Parthasarathi, S; Muthukumar, S P; Anandharamakrishnan, C

2016-05-18

Vitamin E (α-tocopherol) is a nutraceutical compound, which has been shown to possess potent antioxidant and anticancer activity. However, its biological activity may be limited by its poor bioavailability. Colloidal delivery systems have shown wide applications in the food and pharmaceutical industries to deliver lipophilic bioactive compounds. In this study, we have developed conventional and nanoemulsions of vitamin E from food grade ingredients (sunflower oil, saponin, and water) and showed the nanoemulsion formulation increased the oral bioavailability when compared to the conventional emulsion. The mean droplet diameters in the nano and conventional emulsions were 0.277 and 1.285 μm, respectively. The stability of the emulsion formulation after thermal processing, long-term storage at different temperatures, mechanical stress and in plasma was determined. The results showed that the saponin coated nanoemulsion was stable to droplet coalescence during thermal processing (30-90 °C), long-term storage and mechanical stress when compared to the conventional emulsion. The biological fate of the emulsion formulations were studied using male Wistar rats as an animal model. The emulsion droplet stability during passage through the gastrointestinal tract was evaluated by their introduction into rat stomachs. Microscopy was used to investigate the structural changes that occurred during digestion. Both the conventional emulsion and nanoemulsion formulations showed strong evidence of droplet flocculation and coalescence during in vivo digestion. The in vivo oral bioavailability study revealed that vitamin E in a nanoemulsion form showed a 3-fold increase in the AUC when compared to the conventional emulsion. The information reported in this study will facilitate the design of colloidal delivery systems using nanoemulsion formulations.

Custom fractional factorial designs to develop atorvastatin self-nanoemulsifying and nanosuspension delivery systems--enhancement of oral bioavailability.

PubMed

Hashem, Fahima M; Al-Sawahli, Majid M; Nasr, Mohamed; Ahmed, Osama A A

2015-01-01

Poor water solubility of a drug is a major challenge in drug delivery research and a main cause for limited bioavailability and pharmacokinetic parameters. This work aims to utilize custom fractional factorial design to assess the development of self-nanoemulsifying drug delivery systems (SNEDDS) and solid nanosuspensions (NS) in order to enhance the oral delivery of atorvastatin (ATR). According to the design, 14 experimental runs of ATR SNEDDS were formulated utilizing the highly ATR solubilizing SNEDDS components: oleic acid, Tween 80, and propylene glycol. In addition, 12 runs of NS were formulated by the antisolvent precipitation-ultrasonication method. Optimized formulations of SNEDDS and solid NS, deduced from the design, were characterized. Optimized SNEDDS formula exhibited mean globule size of 73.5 nm, zeta potential magnitude of -24.1 mV, and 13.5 μs/cm of electrical conductivity. Optimized solid NS formula exhibited mean particle size of 260.3 nm, 7.4 mV of zeta potential, and 93.2% of yield percentage. Transmission electron microscopy showed SNEDDS droplets formula as discrete spheres. The solid NS morphology showed flaky nanoparticles with irregular shapes using scanning electron microscopy. The release behavior of the optimized SNEDDS formula showed 56.78% of cumulative ATR release after 10 minutes. Solid NS formula showed lower rate of release in the first 30 minutes. Bioavailability estimation in Wistar albino rats revealed an augmentation in ATR bioavailability, relative to ATR suspension and the commercial tablets, from optimized ATR SNEDDS and NS formulations by 193.81% and 155.31%, respectively. The findings of this work showed that the optimized nanocarriers enhance the oral delivery and pharmacokinetic profile of ATR.

Enhancement of oral bioavailability of E804 by self-nanoemulsifying drug delivery system (SNEDDS) in rats.

PubMed

Heshmati, Nasim; Cheng, Xinlai; Eisenbrand, Gerhard; Fricker, Gert

2013-10-01

Indirubin and its derivatives have been shown to interrupt the cell cycle by inhibiting cyclin-dependent kinases, explaining their long-time use in traditional Chinese medicine for the treatment of chronic myelocytic leukemia. A potent derivative of indirubin, indirubin-3'-oxime 2,3-dihydroxypropyl ether (E804), has been shown to block the Src-Stat3 and Src-Stat5 signaling pathway in human cancer cells, inducing apoptosis. The anticancer effects of E804, however, cannot be easily examined in vivo because of its poor water solubility and low absorption. The aim of this study was to develop and evaluate a self-nanoemulsifying drug delivery system (SNEDDS) containing E804 for enhancing its solubility and bioavailability. Solubility of E804 was determined in various vehicles, and pseudoternary phase diagram was used to evaluate the self-emulsifying existence area. The SNEDDS composed of Capmul MCM (oil), Solutol HS 15 (surfactant), and polyethylene glycol 400 (cosurfactant) on the ratio of 20.5:62.5:16 loaded 1.5% of E804. The particle size of droplets was found to be 16.8 and 140 nm, and SNEDDS was stable after freeze-thaw cycles and upon dilution in HCl 0.1 N and pH 7.4 HBSS++. The ability of formulation for absorption enhancement was studied in rats in vivo after oral administration. The results showed that the developed SNEDDS increased the E804 bioavailability 984.23% compared with the aqueous suspension. Our studies for the first time show that the developed SNEDDS can be used as a possible formulation for E804 to improve its solubility and oral bioavailability. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

Pharmacokinetic Evaluation of Improved Oral Bioavailability of Valsartan: Proliposomes Versus Self-Nanoemulsifying Drug Delivery System.

PubMed

Nekkanti, Vijaykumar; Wang, Zhijun; Betageri, Guru V

2016-08-01

The objective of this study was to develop proliposomes and self-nanoemulsifying drug delivery system (SNEDDS) for a poorly bioavailable drug, valsartan, and to compare their in vivo pharmacokinetics. Proliposomes were prepared by thin-film hydration method using different lipids such as soy phosphatidylcholine (SPC), hydrogenated soy phosphatidylcholine (HSPC), distearyl phosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), and dimyristoyl phosphatidylglycerol sodium (DMPG) and cholesterol in various ratios. SNEDDS formulations were prepared using varying concentrations of capmul MCM, labrafil M 2125, and Tween 80. Both proliposomes and SNEDDS were evaluated for particle size, zeta potential, in vitro drug release, in vitro permeability, and in vivo pharmacokinetics. In vitro drug release was carried out in purified water and 0.1 N HCl using USP type II dissolution apparatus. In vitro drug permeation was studied using parallel artificial membrane permeation assay (PAMPA) and everted rat intestinal permeation techniques. Among the formulations, the proliposomes with drug/DMPG/cholesterol in the ratio of 1:1:0.5 and SNEDDS with capmul MCM (16.0% w/w), labrafil M 2125 (64.0% w/w), and Tween 80 (18.0% w/w) showed the desired particle size and zeta potential. Enhanced drug release was observed with proliposomes and SNEDDS as compared to pure valsartan. Valsartan permeability across PAMPA and everted rat intestinal permeation models was significantly higher with proliposomes and SNEDDS. Following single oral administration of proliposomes and SNEDDS, a relative bioavailability of 202.36 and 196.87%, respectively, was achieved compared to pure valsartan suspension. The study results indicated that both proliposomes and SNEDDS formulations are comparable in improving the oral bioavailability of valsartan.

Beyond Yellow Curry: Assessing Commercial Curcumin Absorption Technologies.

PubMed

Douglass, Brad J; Clouatre, Dallas L

2015-01-01

Few natural products have demonstrated the range of protective and therapeutic promise as have turmeric and its principal bioactive components: curcumin, demethoxycurcumin, and bisdemethoxycurcumin. Success in translating this potential into tangible benefits has been limited by inherently poor intestinal absorption, rapid metabolism, and limited systemic bioavailability. Seeking to overcome these limitations, food ingredient formulators have begun to employ a variety of approaches to enhance absorption and bioactivity. Many of these strategies improve upon the age-old practice of consuming turmeric in fat-based sauces, such as in a fat-rich yellow curry. However, there exists uncertainty as to how the various commercially available offerings compare to each other in terms of either uptake or efficacy, and this uncertainty leaves physicians and nutritionists with a dearth of data for making recommendations to interested patients and consumers. Further complicating the issue are recent data suggesting that formulation strategies may not equally enhance the absorption of individual curcuminoids, a significant issue in that these curcuminoids exhibit somewhat different physiologic properties. This review introduces needed order to the curcumin marketplace by examining bioavailability studies on a number of commercial curcumin ingredients and evaluating them on a level playing field. The comparative analysis includes standard pharmacokinetic parameters and a new metric, relative mass efficiency (E). Relative mass efficiency allows for the comparison of different formulations even in cases in which the weight percentage of curcuminoids is vastly different. A hydrophilic carrier dispersed curcuminoid formula exhibits 45.9 times the bioavailability of the standard purified 95 percent curcuminoid preparation and, based on relative mass efficiency, 1.5 times the bioavailability of the next best commercial ingredient, a cyclodextrin complex. Delivery strategies can significantly improve the bioavailability of curcuminoids. Total formula mass is important for making practical formulation decisions about dosing, cost and space.

Preparation and evaluation of Vinpocetine self-emulsifying pH gradient release pellets.

PubMed

Liu, Mengqi; Zhang, Shiming; Cui, Shuxia; Chen, Fen; Jia, Lianqun; Wang, Shu; Gai, Xiumei; Li, Pingfei; Yang, Feifei; Pan, Weisan; Yang, Xinggang

2017-11-01

The main objective of this study was to develop a pH gradient release pellet with self-emulsifying drug delivery system (SEDDS), which could not only improve the oral bioavailability of Vinpocetine (VIN), a poor soluble drug, but reduce the fluctuation of plasma concentration. First, the liquid VIN SEDDS formulation was prepared. Then the self-emulsifying pH gradient release pellets were prepared by extrusion spheronization technique, and formulation consisted by the liquid SEDDS, absorbent (colloidal silicon dioxide), penetration enhancer (sodium chloride), microcrystalline cellulose, ethyl alcohol, and three coating materials (HPMC, Eudragit L30D55, Eudragit FS30D) were eventually selected. Three kinds of coated pellets were mixed in capsules with the mass ratio of 1:1:1. The release curves of capsules were investigated in vitro under the simulated gastrointestinal conditions. In addition, the oral bioavailability and pharmacokinetics of VIN self-emulsifying pH gradient release pellets, commercial tablets and liquid VIN SEDDS were evaluated in Beagle dogs. The oral bioavailability of self-emulsifying pH gradient release pellets was about 149.8% of commercial VIN tablets, and it was about 86% of liquid VIN SEDDS, but there were no significant difference between liquid SEDDS and self-emulsifying pH gradient release pellets. In conclusion, the self-emulsifying pH gradient release pellets could significantly enhance the absorption of VIN and effectively achieve a pH gradient release. And the self-emulsifying pH gradient release pellet was a promising method to improve bioavailability of insoluble drugs.

Novel gastroretentive sustained-release tablet of tacrolimus based on self-microemulsifying mixture: in vitro evaluation and in vivo bioavailability test

PubMed Central

Wang, Yan-ping; Gan, Yong; Zhang, Xin-xin

2011-01-01

Aim: To develop a novel gastroretentive drug delivery system based on a self-microemulsifying (SME) lipid mixture for improving the oral absorption of the immunosuppressant tacrolimus. Methods: Liquid SME mixture, composed of Cremophor RH40 and monocaprylin glycerate, was blended with polyethylene oxide, chitosan, polyvinylpyrrolidone and mannitol, and then transformed into tablets via granulation, with ethanol as the wetting agent. The tablets were characterized in respect of swelling, bioadhesive and SME properties. In vitro dissolution was conducted using an HCl buffer at pH 1.2. Oral bioavailability of the tablets was examined in fasted beagle dogs. Results: The tablet could expand to 13.5 mm in diameter and 15 mm in thickness during the initial 20 min of contact with the HCl buffer at pH 1.2. The bioadhesive strength was as high as 0.98±0.06 N/cm2. The SME gastroretentive sustained-release tablets preserved the SME capability of the liquid SME formations under transmission electron microscope. The drug-release curve was fit to the zero-order release model, which was helpful in reducing fluctuations in blood concentration. Compared with the commercially available capsules of tacrolimus, the relative bioavailability of the SME gastroretentive sustained-release tablets was 553.4%±353.8%. Conclusion: SME gastroretentive sustained-release tablets can enhance the oral bioavailability of tacrolimus with poor solubility and a narrow absorption window. PMID:21927013

Pharmacosomes: An Emerging Novel Vesicular Drug Delivery System for Poorly Soluble Synthetic and Herbal Drugs

PubMed Central

2013-01-01

In the arena of solubility enhancement, several problems are encountered. A novel approach based on lipid drug delivery system has evolved, pharmacosomes. Pharmacosomes are colloidal, nanometric size micelles, vesicles or may be in the form of hexagonal assembly of colloidal drug dispersions attached covalently to the phospholipid. They act as befitting carrier for delivery of drugs quite precisely owing to their unique properties like small size, amphiphilicity, active drug loading, high entrapment efficiency, and stability. They help in controlled release of drug at the site of action as well as in reduction in cost of therapy, drug leakage and toxicity, increased bioavailability of poorly soluble drugs, and restorative effects. There has been advancement in the scope of this delivery system for a number of drugs used for inflammation, heart diseases, cancer, and protein delivery along with a large number of herbal drugs. Hence, pharmacosomes open new challenges and opportunities for improved novel vesicular drug delivery system. PMID:24106615

Nanostructured lipid carriers: versatile oral delivery vehicle

PubMed Central

Poonia, Neelam; Kharb, Rajeev; Lather, Viney; Pandita, Deepti

2016-01-01

Oral delivery is the most accepted and economical route for drug administration and leads to substantial reduction in dosing frequency. However, this route still remains a challenge for the pharmaceutical industry due to poorly soluble and permeable drugs leading to poor oral bioavailability. Incorporating bioactives into nanostructured lipid carriers (NLCs) has helped in boosting their therapeutic functionality and prolonged release from these carrier systems thus providing improved pharmacokinetic parameters. The present review provides an overview of noteworthy studies reporting impending benefits of NLCs in oral delivery and highlights recent advancements for developing engineered NLCs either by conjugating polymers over their surface or modifying their charge to overcome the mucosal barrier of GI tract for active transport across intestinal membrane. PMID:28031979

Detecting ordered small molecule drug aggregates in live macrophages: a multi-parameter microscope image data acquisition and analysis strategy

PubMed Central

Rzeczycki, Phillip; Yoon, Gi Sang; Keswani, Rahul K.; Sud, Sudha; Stringer, Kathleen A.; Rosania, Gus R.

2017-01-01

Following prolonged administration, certain orally bioavailable but poorly soluble small molecule drugs are prone to precipitate out and form crystal-like drug inclusions (CLDIs) within the cells of living organisms. In this research, we present a quantitative multi-parameter imaging platform for measuring the fluorescence and polarization diattenuation signals of cells harboring intracellular CLDIs. To validate the imaging system, the FDA-approved drug clofazimine (CFZ) was used as a model compound. Our results demonstrated that a quantitative multi-parameter microscopy image analysis platform can be used to study drug sequestering macrophages, and to detect the formation of ordered molecular aggregates formed by poorly soluble small molecule drugs in animals. PMID:28270989

Detecting ordered small molecule drug aggregates in live macrophages: a multi-parameter microscope image data acquisition and analysis strategy.

PubMed

Rzeczycki, Phillip; Yoon, Gi Sang; Keswani, Rahul K; Sud, Sudha; Stringer, Kathleen A; Rosania, Gus R

2017-02-01

Following prolonged administration, certain orally bioavailable but poorly soluble small molecule drugs are prone to precipitate out and form crystal-like drug inclusions (CLDIs) within the cells of living organisms. In this research, we present a quantitative multi-parameter imaging platform for measuring the fluorescence and polarization diattenuation signals of cells harboring intracellular CLDIs. To validate the imaging system, the FDA-approved drug clofazimine (CFZ) was used as a model compound. Our results demonstrated that a quantitative multi-parameter microscopy image analysis platform can be used to study drug sequestering macrophages, and to detect the formation of ordered molecular aggregates formed by poorly soluble small molecule drugs in animals.

Solid dispersion tablets of breviscapine with polyvinylpyrrolidone K30 for improved dissolution and bioavailability to commercial breviscapine tablets in beagle dogs.

PubMed

Cong, Wenjuan; Shen, Lan; Xu, Desheng; Zhao, Lijie; Ruan, Kefeng; Feng, Yi

2014-09-01

Breviscapine, one of cardiovascular drugs extracted from a Chinese herb Erigeron breviscapinus, has been frequently used to treat cardiovascular diseases such as hypertension, angina pectoris, coronary heart disease and stroke. However, its poor water solubility and low bioavailability in vivo severely restrict the clinical application. To overcome these drawbacks, breviscapine solid dispersion tablets consisting of breviscapine, polyvinylpyrrolidone K30 (PVP K30), microcrystalline cellulose and crospovidone were appropriately prepared. In vitro dissolution profiles showed that breviscapine released percentage of solid dispersion tablets reached 90 %, whereas it was only 40 % for commercial breviscapine tablets. Comparative pharmacokinetic study between solid dispersion tablets and commercial products was investigated on the normal beagle dogs after oral administration. Results showed that the bioavailability of breviscapine was greatly increased by 3.45-fold for solid dispersion tablets. The greatly improved dissolution rate and bioavailability might be attributed to intermolecular hydrogen bonding reactions between PVP K30 and scutellarin. These findings suggest that our solid dispersion tablets can greatly improve the bioavailability as well as the dissolution rate of breviscapine.

Dry elixir formulations of dexibuprofen for controlled release and enhanced oral bioavailability.

PubMed

Kim, Seo-Ryung; Kim, Jin-Ki; Park, Jeong-Sook; Kim, Chong-Kook

2011-02-14

The objective of this study was to achieve an optimal formulation of dexibuprofen dry elixir (DDE) for the improvement of dissolution rate and bioavailability. To control the release rate of dexibuprofen, Eudragit(®) RS was employed on the surface of DDE resulting in coated dexibuprofen dry elixir (CDDE). Physicochemical properties of DDE and CDDE such as particle size, SEM, DSC, and contents of dexibuprofen and ethanol were characterized. Pharmacokinetic parameters of dexibuprofen were evaluated in the rats after oral administration. The DDE and CDDE were spherical particles of 12 and 19 μm, respectively. The dexibuprofen and ethanol contents in the DDE were dependent on the amount of dextrin and maintained for 90 days. The dissolution rate and bioavailability of dexibuprofen loaded in dry elixir were increased compared with those of dexibuprofen powder. Moreover, coating DDE with Eudragit(®) RS retarded the dissolution rate of dexibuprofen from DDE without reducing the bioavailability. Our results suggest that CDDE may be potential oral dosage forms to control the release and to improve the bioavailability of poorly water-soluble dexibuprofen. Copyright © 2010 Elsevier B.V. All rights reserved.

Pharmaceutical Amorphous Nanoparticles.

PubMed

Jog, Rajan; Burgess, Diane J

2017-01-01

There has been a tremendous revolution in the field of nanotechnology, resulting in the advent of novel drug delivery systems known as nanomedicines for diagnosis and therapy. One of the applications is nanoparticulate drug delivery systems which are used to improve the solubility and oral bioavailability of poorly soluble compounds. This is particularly important because most of the molecules emerging from the drug discovery pipeline in recent years have problems associated with solubility and bioavailability. There has been considerable focus on nanocrystalline materials; however, amorphous nanoparticles have the advantage of synergistic mechanisms of enhancing dissolution rates (due to their nanosize range and amorphous nature) as well as increasing supersaturation levels (due to their amorphous nature). An example of this technology is Nanomorph TM , developed by Soliqus/Abbott, wherein the nanosize drug particles are precipitated in an amorphous form in order to enhance the dissolution rate. This along with other simple and easily scalable manufacturing techniques for amorphous nanoparticles is described. In addition, the mechanisms of formation of amorphous nanoparticles and several physicochemical properties associated with amorphous nanoparticles are critically reviewed. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Bioavailability of curcumin and curcumin glucuronide in the central nervous system of mice after oral delivery of nano-curcumin.

PubMed

Szymusiak, Magdalena; Hu, Xiaoyu; Leon Plata, Paola A; Ciupinski, Paulina; Wang, Zaijie Jim; Liu, Ying

2016-09-10

Curcumin is a bioactive molecule extracted from Turmeric roots that has been recognized to possess a wide variety of important biological activities. Despite its great pharmacological activities, curcumin is highly hydrophobic, which results in poor bioavailability. We have formulated this hydrophobic compound into stable polymeric nanoparticles (nano-curcumin) to enhance its oral absorption. Pharmacokinetic analysis after oral delivery of nano-curcumin in mice demonstrated approximately 20-fold reduction in dose requirement when compared to unformulated curcumin to achieve comparable plasma and central nervous system (CNS) tissue concentrations. This investigation corroborated our previous study of curcumin functionality of attenuating opioid tolerance and dependence, which shows equivalent efficacy of low-dose (20mg/kg) nano-curcumin and high-dose (400mg/kg) pure curcumin in mice. Furthermore, the highly selective and validated liquid chromatography-mass spectrometry (LC-MS) method was developed to quantify curcumin glucuronide, the major metabolite of curcumin. The results suggest that the presence of curcumin in the CNS is essential for prevention and reversal of opioid tolerance and dependence. Copyright © 2016 Elsevier B.V. All rights reserved.

Design and evaluation of self-emulsifying drug delivery systems of Rhizoma corydalis decumbentis extracts.

PubMed

Ma, Hongda; Zhao, Qingchun; Wang, Yongjun; Guo, Tao; An, Ye; Shi, Guobing

2012-10-01

To improve the dissolution and oral absorption of Rhizoma corydalis decumbentis extracts (RCDE), a famous traditional Chinese herbal medicine which contains poorly water-soluble active components, self-emulsifying drug-delivery systems (SEDDS) were designed and evaluated in vitro and in vivo for the first time. Six formulations were prepared, and pseudoternary phase diagrams were constructed to identify the efficient self-emulsication region through the modified visual test. The optimized formulation consisted of 45% Solutol, 40% ethyl oleate, and 15% Transcutol P. The mean droplet size distribution of the optimized SEDDS was less than 100 nm. The release of the active components (protopine and tetrahydropalmatine) in RCDE from SEDDS hard gelatin capsules showed a faster rate in comparison with the commercial tablets. After oral administration of RCDE SEDDS capsules or the commercial tablets to fasted rats, the relative bioavailability of SEDDS capsules for protopine and tetrahydropalmatine was 209.7% and 133.2% compared with commercial tablets, respectively. Our study indicated that SEDDS has the potential to improve the bioavailability of traditional Chinese medicines, in which many active components are hydrophobic, such as RCDE.

In vitro and in vivo studies on the complexes of glipizide with water-soluble β-cyclodextrin-epichlorohydrin polymers.

PubMed

Nie, Shufang; Zhang, Shu; Pan, Weisan; Liu, Yanli

2011-05-01

The purpose of this study was to evaluate the potential of a newly modified cyclodextrin derivative, water-soluble β-cyclodextrin-epichlorohydrin polymer (β-CDP), as an effective drug carrier to enhance the dissolution rate and oral bioavailability of glipizide as a poorly water-soluble model drug. Inclusion complexes of glipizide with β-CDP were prepared by the co-evaporation method and characterized by phase solubility, dissolution, and differential scanning calorimetry. The solubility curve was classified as type A(L), which indicated the formation of 1:1 complex between glipizide and β-CDP. β-CDP had better properties of increasing the aqueous solubility of glipizide compared with HP-β-CD. The dissolution rate of drug from the β-CDP complexes was significantly greater than that of the corresponding physical mixtures indicating that the formation of amorphous complex increased the solubility of glipizide. Moreover, the increment in drug dissolution rate from the glipizide/β-CDP systems was higher than that from the corresponding ones with HP-β-CD, which indicated that β-CDP could provide greater capability of solubilization for poorly soluble drugs. Furthermore, in vivo study revealed that the bioavailability of glipizide was significantly improved by glipizide /β-CDP inclusion complex after oral administration to beagle dogs.

A New Type of Liquid Silymarin Proliposome Containing Bile Salts: Its Preparation and Improved Hepatoprotective Effects.

PubMed

Wang, Mei; Xie, Tingting; Chang, Zhanying; Wang, Ling; Xie, Xiangyun; Kou, Yaohong; Xu, Hongxia; Gao, Xiaoli

2015-01-01

Silymarin, a known extract, is used in the treatment of liver diseases with various origins, but its current administration form cannot target the liver because of its poor oral bioavailability. A new type of oral silymarin proliposome aimed at improving silymarin's poor bioavailability and hepatoprotective effects, is introduced in this work. Silymarin-loaded liquid proliposome were prepared using a simple dissolving process. The morphology, particle size, zeta potential, and entrapment efficiency of the silymarin liposomes were analysed. The everted gut sac transport model was used to measure the intestinal transport of liposomes. The liposomal hepatoprotective activity was evaluated in three types of experimental hepatitis animal models. After staining with haematoxylin and eosin, the livers were microscopically examined to analyse any pathological changes. The prepared silymarin proliposome formed silymarin liposomes with a multilayer liposome structure and improved intestinal transport. In an injured liver, the silymarin liposomes produced a stronger hepatoprotective effect through a significant decrease in both the aminotransferase and MDA levels and a significant increase in the SOD and GSH-PX levels compared to orally administered silymarin tablets. This effect was also confirmed histopathologically. In a word, incorporation of silymarin into a liposomal carrier system increased intestinal absorption and showed better hepatoprotective effects compared to silymarin tablets.

A New Type of Liquid Silymarin Proliposome Containing Bile Salts: Its Preparation and Improved Hepatoprotective Effects

PubMed Central

Chang, Zhanying; Wang, Ling; Xie, Xiangyun; Kou, Yaohong; Xu, Hongxia; Gao, Xiaoli

2015-01-01

Silymarin, a known extract, is used in the treatment of liver diseases with various origins, but its current administration form cannot target the liver because of its poor oral bioavailability. A new type of oral silymarin proliposome aimed at improving silymarin’s poor bioavailability and hepatoprotective effects, is introduced in this work. Silymarin-loaded liquid proliposome were prepared using a simple dissolving process. The morphology, particle size, zeta potential, and entrapment efficiency of the silymarin liposomes were analysed. The everted gut sac transport model was used to measure the intestinal transport of liposomes. The liposomal hepatoprotective activity was evaluated in three types of experimental hepatitis animal models. After staining with haematoxylin and eosin, the livers were microscopically examined to analyse any pathological changes. The prepared silymarin proliposome formed silymarin liposomes with a multilayer liposome structure and improved intestinal transport. In an injured liver, the silymarin liposomes produced a stronger hepatoprotective effect through a significant decrease in both the aminotransferase and MDA levels and a significant increase in the SOD and GSH-PX levels compared to orally administered silymarin tablets. This effect was also confirmed histopathologically. In a word, incorporation of silymarin into a liposomal carrier system increased intestinal absorption and showed better hepatoprotective effects compared to silymarin tablets. PMID:26674103

A Molecular-Level View of the Physical Stability of Amorphous Solid Dispersions

NASA Astrophysics Data System (ADS)

Yuan, Xiaoda

Many pharmaceutical compounds being developed in recent years are poorly soluble in water. This has led to insufficient oral bioavailability of many compounds in vitro. The amorphous formulation is one of the promising techniques to increase the oral bioavailability of these poorly water-soluble compounds. However, an amorphous drug substance is inherently unstable because it is a high energy form. In order to increase the physical stability, the amorphous drug is often formulated with a suitable polymer to form an amorphous solid dispersion. Previous research has suggested that the formation of an intimately mixed drug-polymer mixture contributes to the stabilization of the amorphous drug compound. The goal of this research is to better understand the role of miscibility, molecular interactions and mobility on the physical stability of amorphous solid dispersions. Methods were developed to detect different degrees of miscibility on nanometer scale and to quantify the extent of hydrogen-bonding interactions between the drug and the polymer. Miscibility, hydrogen-bonding interactions and molecular mobility were correlated with physical stability during a six-month period using three model systems. Overall, this research provides molecular-level insights into many factors that govern the physical stability of amorphous solid dispersions which can lead to a more effective design of stable amorphous formulations.

Development of dihydropyridone indazole amides as selective Rho-kinase inhibitors.

PubMed

Goodman, Krista B; Cui, Haifeng; Dowdell, Sarah E; Gaitanopoulos, Dimitri E; Ivy, Robert L; Sehon, Clark A; Stavenger, Robert A; Wang, Gren Z; Viet, Andrew Q; Xu, Weiwei; Ye, Guosen; Semus, Simon F; Evans, Christopher; Fries, Harvey E; Jolivette, Larry J; Kirkpatrick, Robert B; Dul, Edward; Khandekar, Sanjay S; Yi, Tracey; Jung, David K; Wright, Lois L; Smith, Gary K; Behm, David J; Bentley, Ross; Doe, Christopher P; Hu, Erding; Lee, Dennis

2007-01-11

Rho kinase (ROCK1) mediates vascular smooth muscle contraction and is a potential target for the treatment of hypertension and related disorders. Indazole amide 3 was identified as a potent and selective ROCK1 inhibitor but possessed poor oral bioavailability. Optimization of this lead resulted in the discovery of a series of dihydropyridones, exemplified by 13, with improved pharmacokinetic parameters relative to the initial lead. Indazole substitution played a critical role in decreasing clearance and improving oral bioavailability.

Biodegradable in situ gelling system for subcutaneous administration of ellagic acid and ellagic acid loaded nanoparticles: evaluation of their antioxidant potential against cyclosporine induced nephrotoxicity in rats.

PubMed

Sharma, G; Italia, J L; Sonaje, K; Tikoo, K; Ravi Kumar, M N V

2007-03-12

Ellagic acid (EA) is a potent antioxidant marketed as a nutritional supplement. Its pharmacological activity has been reported in wide variety of disease models; however its use has been limited owing to its poor biopharmaceutical properties, thereby poor bioavailability. The objective of the current study was to develop chitosan-glycerol phosphate (C-GP) in situ gelling system for sustained delivery of ellagic acid (EA) via subcutaneous route. EA was incorporated in the system employing propylene glycol (PG) and triethanolamine (TEA) as co-solvents; on the other hand EA loaded PLGA nanoparticles (np) were dispersed in the gelling system using water. These in situ gelling systems were thoroughly characterized for mechanical, rheological and swelling properties. These systems are liquid at room temperature and gels at 37 degrees C. The EA C-GP system showed an initial burst release in vitro with about 85% drug released in 12 h followed by a steady release till 160 h, on the other hand EA nanoparticles entrapped in the C-GP system displayed sustained release till 360 h. The histopathological analysis indicates the absence of inflammation on administration, suggesting that these formulations are safe during the studied period. Furthermore, the antioxidant potential of EA C-GP and EA np C-GP gels has been evaluated against cyclosporine induced nephrotoxicity in rats. The data indicates that formulations were effective against cyclosporine induced nephrotoxicity, where the EA C-GP gels showed activity at 10 times lower dose and the EA np C-GP gels at 150 times lower dose when compared to orally given EA. Formulating nanoparticles of EA and incorporating them in C-GP system results in 15 times lowering of dose in comparison EA C-GP gels which is quite significant. Together, these results indicate that the bioavailability of ellagic acid can be improved by subcutaneous formulations administered as simple EA or EA nps.

Supercritical fluid particle design for poorly water-soluble drugs (review).

PubMed

Sun, Yongda

2014-01-01

Supercritical fluid particle design (SCF PD) offers a number of routes to improve solubility and dissolution rate for enhancing the bioavailability of poorly water-soluble drugs, which can be adopted through an in-depth knowledge of SCF PD processes and the molecular properties of active pharmaceutical ingredients (API) and drug delivery system (DDS). Combining with research experiences in our laboratory, this review focuses on the most recent development of different routes (nano-micron particles, polymorphic particles, composite particles and bio-drug particles) to improve solubility and dissolution rate of poorly water-soluble drugs, covering the fundamental concept of SCF and the principle of SCF PD processes which are typically used to control particle size, shape, morphology and particle form and hence enable notable improvement in the dissolution rate of the poorly water-soluble drugs. The progress of the industrialization of SCF PD processes in pharmaceutical manufacturing environment with scaled-up plant under current good manufacturing process (GMP) specification is also considered in this review.

Formulation and delivery strategies of ibuprofen: challenges and opportunities.

PubMed

Irvine, Jake; Afrose, Afrina; Islam, Nazrul

2018-02-01

Ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), is mostly administered orally and topically to relieve acute pain and fever. Due to its mode of action this drug may be useful in the treatment regimens of other, more chronic conditions, like cystic fibrosis. This drug is poorly soluble in aqueous media and thus the rate of dissolution from the currently available solid dosage forms is limited. This leads to poor bioavailability at high doses after oral administration, thereby increasing the risk of unwanted adverse effects. The poor solubility is a problem for developing injectable solution dosage forms. Because of its poor skin permeability, it is difficult to obtain an effective therapeutic concentration from topical preparations. This review aims to give a brief insight into the status of ibuprofen dosage forms and their limitations, particle/crystallization technologies for improving formulation strategies as well as suggesting its incorporation into the pulmonary drug delivery systems for achieving better therapeutic action at low dose.

New Insight in Improving Therapeutic Efficacy of Antipsychotic Agents: An Overview of Improved In Vitro and In Vivo Performance, Efficacy Upgradation and Future Prospects.

PubMed

Ei Thu, Hnin; Hussain, Zahid; Shuid, Ahmad Nazrun

2018-01-01

Psychotic disorders are recognized as severe mental disorders that rigorously affect patient's personality, critical thinking, and perceptional ability. High prevalence, global dissemination and limitations of conventional pharmacological approaches compel a significant burden to the patient, medical professionals and the healthcare system. To date, numerous orally administered therapies are available for the management of depressive disorders, schizophrenia, anxiety, bipolar disorders and autism spectrum problems. However, poor water solubility, erratic oral absorption, extensive first-pass metabolism, low oral bioavailability and short half-lives are the major factors which limit the pharmaceutical significance and therapeutic feasibility of these agents. In recent decades, nanotechnology-based delivery systems have gained remarkable attention of the researchers to mitigate the pharmaceutical issues related to the antipsychotic therapies and to optimize their oral drug delivery, therapeutic outcomes, and patient compliance. Therefore, the present review was aimed to summarize the available in vitro and in vivo evidences signifying the pharmaceutical importance of the advanced delivery systems in improving the aqueous solubility, transmembrane permeability, oral bioavailability and therapeutic outcome of the antipsychotic agents. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Main approaches for delivering antioxidant vitamins through the skin to prevent skin ageing.

PubMed

Gašperlin, Mirjana; Gosenca, Mirjam

2011-07-01

One of the major contributions to skin photoageing and diseases is oxidative stress, caused by UV radiation inducing reactive oxygen and nitrogen species. Successful prophylaxis and therapy would necessitate control of the oxidant/antioxidant balance at the affected site, which can be achieved through the external supply of endogenous antioxidants. This review discusses possible strategies for dermal delivery of the antioxidant vitamins E and C, as oral supplementation has proved insufficient. These antioxidants have low skin bioavailability, owing to their poor solubility, inefficient skin permeability, or instability during storage. These drawbacks can be overcome by various approaches, such as chemical modification of the vitamins and the use of new colloidal drug delivery systems. New knowledge is included about the importance of: enhancing the endogenous skin antioxidant defense through external supply; the balance between various skin antioxidants; factors that can improve the skin bioavailability of antioxidants; and new delivery systems, such as microemulsions, used to deliver vitamins C and E into the skin simultaneously. A promising strategy for enhancing skin protection from oxidative stress is to support the endogenous antioxidant system, with antioxidants containing products that are normally present in the skin.

Evaluation and selection of bio-relevant dissolution media for a poorly water-soluble new chemical entity.

PubMed

Tang, L; Khan, S U; Muhammad, N A

2001-11-01

The purpose of this work is to develop a bio-relevant dissolution method for formulation screening in order to select an enhanced bioavailable formulation for a poorly water-soluble drug. The methods used included a modified rotating disk apparatus for measuring intrinsic dissolution rate of the new chemical entity (NCE) and the USP dissolution method II for evaluating dissolution profiles of the drug in three different dosage forms. The in vitro dissolution results were compared with the in vivo bioavailability for selecting a bio-relevant medium. The results showed that the solubility of the NCE was proportional to the concentration of sodium lauryl sulfate (SLS) in the media. The apparent intrinsic dissolution rate of the NCE was linear to the rotational speed of the disk, which indicated that the dissolution of the drug is a diffusion-controlled mechanism. The apparent intrinsic dissolution rate was also linear to the surfactant concentration in the media, which was interpreted using the Noyes and Whitney Empirical Theory. Three formulations were studied in three different SLS media using the bulk drug as a reference. The dissolution results were compared with the corresponding bioavailability results in dogs. In the 1% SLS--sink conditions--the drug release from all the formulations was complete and the dissolution results were discriminative for the difference in particle size of the drug in the formulations. However, the data showed poor IVIV correlation. In the 0.5% SLS medium--non-sink conditions--the dissolution results showed the same rank order among the tested formulations as the bioavailability. The best IVIV correlation was obtained from the dissolution in 0.25% SLS medium, an over-saturated condition. The conclusions are: a surfactant medium increases the apparent intrinsic dissolution rate of the NCE linearly due to an increase in solubility. A low concentration of surfactant in the medium (0.25%) is more bio-relevant than higher concentrations of surfactant in the media for the poorly water-soluble drug. Creating sink conditions (based on bulk drug solubilities) by using a high concentration of a surfactant in the dissolution medium may not be a proper approach in developing a bio-relevant dissolution method for a poorly water-soluble drug.

A review on the relationship between food structure, processing, and bioavailability.

PubMed

Sensoy, Ilkay

2014-01-01

This review highlights the effects of processing and food matrix on bioaccessibility and bioavailability of functional components. Human digestive system is reviewed as an element in bioavailability. Methods for bioaccessibility and bioavailability determination are described. Information about the location of functional compounds in the tissue is presented to portray the matrix information. Research data on the effects of food matrix and processing on bioaccessibility and bioavailability are summarized. Finally, trends in the development of functional component delivery systems are included.

Enhanced solubility and bioavailability of sibutramine base by solid dispersion system with aqueous medium.

PubMed

Li, Dong Xun; Jang, Ki-Young; Kang, Wonku; Bae, Kyoungjin; Lee, Mann Hyung; Oh, Yu-Kyoung; Jee, Jun-Pil; Park, Young-Joon; Oh, Dong Hoon; Seo, Youn Gee; Kim, Young Ran; Kim, Jong Oh; Woo, Jong Soo; Yong, Chul Soon; Choi, Han-Gon

2010-01-01

To develop a novel sibutramine base-loaded solid dispersion with improved solubility bioavailability, various solid dispersions were prepared with water, hydroxypropylmethyl cellulose (HPMC), poloxamer and citric acid using spray-drying technique. The effect of HPMC, poloxamer and citric acid on the aqueous solubility of sibutramine was investigated. The physicochemical properties of solid dispersion were investigated using scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and X-ray powder diffraction. The dissolution and pharmacokinetics in rats of solid dispersion were evaluated compared to the sibutramine hydrochloride monohydrate-loaded commercial product (Reductil). The sibutramine base-loaded solid dispersion gave two type forms. Like conventional solid dispersion system, one type appeared as a spherical shape with smooth surface, as the carriers and drug with relatively low melting point were soluble in water and formed it. The other appeared as an irregular form with relatively rough surface. Unlike conventional solid dispersion system, this type changed no crystalline form of drug. Our results suggested that this type was formed by attaching hydrophilic carriers to the surface of drug without crystal change, resulting from changing the hydrophobic drug to hydrophilic form. The sibutramine-loaded solid dispersion at the weight ratio of sibutramine base/HPMC/poloxamer/citric acid of 5/3/3/0.2 gave the maximum drug solubility of about 3 mg/ml. Furthermore, it showed the similar plasma concentration, area under the curve (AUC) and C(max) of parent drug, metabolite I and II to the commercial product, indicating that it might give the similar drug efficacy compared to the sibutramine hydrochloride monohydrate-loaded commercial product in rats. Thus, this solid dispersion system would be useful to deliver poorly water-soluble sibutramine base with enhanced bioavailability.

Higher iron bioavailability of a human-like collagen iron complex.

PubMed

Zhu, Chenhui; Yang, Fan; Fan, Daidi; Wang, Ya; Yu, Yuanyuan

2017-07-01

Iron deficiency remains a public health problem around the world due to low iron intake and/or bioavailability. FeSO 4 , ferrous succinate, and ferrous glycinate chelate are rich in iron but have poor bioavailability. To solve the problem of iron deficiency, following previous research studies, a thiolated human-like collagen-ironcomplex supplement with a high iron content was prepared in an anaerobic workstation. In addition, cell viability tests were evaluated after conducting an MTT assay, and a quantitative analysis of the thiolated human-like collagen-iron digesta samples was performed using the SDS-PAGE method coupled with gel filtration chromatography. The iron bioavailability was assessed using Caco-2 cell monolayers and iron-deficiency anemia mice models. The results showed that (1) one mole of thiolated human-like collagen-iron possessed approximately 35.34 moles of iron; (2) thiolated human-like collagen-iron did not exhibit cytotoxity and (3) thiolated human-like collagen- iron digesta samples had higher bioavailability than other iron supplements, including FeSO 4 , ferrous succinate, ferrous glycine chelate and thiolated human-like collagen-Fe iron. Finally, the iron bioavailability was significantly enhanced by vitamin C. These results indicated that thiolated human-like collagen-iron is a promising iron supplement for use in the future.

Assessment of relative bioavailability of heavy metals in soil using in vivo mouse model and its implication for risk assessment compared with bioaccessibility using in vitro assay.

PubMed

Kang, Yuan; Pan, Weijian; Liang, Siyun; Li, Ning; Zeng, Lixuan; Zhang, Qiuyun; Luo, Jiwen

2016-10-01

There is limited study to simultaneously determine the relative bioavailability of heavy metals such as Cd, Pb, Cu, Cr(VI), and Ni in soil samples. In the present study, the bioaccessibility of heavy metals using in vitro assay was compared with the relative bioavailability of heavy metals using in vivo mouse model. The bioaccessibility of heavy metals ranged from 9.05 ± 0.97 % (Cr) to 42.8 ± 3.52 % (Cd). The uptake profile of heavy metals in soil and solution samples in mouse revealed that the uptake kinetics could be fitted to a two-compartment model. The relative bioavailability of heavy meals ranged from 34.8 ± 7.0 % (Ni) to 131 ± 20.3 % (Cu). Poor correlation between bioaccessibility and relative bioavailability of heavy metals was observed (r (2) = 0.11, p > 0.05). The relative bioavailability of heavy metals was significantly higher than the bioaccessibility of heavy metals (p < 0.05). The present study indicated that the in vitro digestion method should be carefully employed in risk assessment.

Octacosanol educes physico-chemical attributes, release and bioavailability as modified nanocrystals.

PubMed

Sen Gupta, Surashree; Ghosh, Mahua

2017-10-01

Octacosanol is a lesser known nutraceutical with the potential for treatment of several inflammatory diseases, high cholesterol, Parkinson's symptoms and tumour growth along with the capacity to improve athletic performance. But its lipophilicity and large structure inhibits extended solubility in water resulting in poor absorption and a low bioavailability. In the present work, sodium salt of octacosyl sulfate was synthesized. It displayed improved water solubility. Its nanocrystals, synthesized by means of nanoprecipitation technique, enhanced diffusion velocity, antioxidant capacity, shelf-life, penetrability and bioavailability. Particle size of the nanocrystals ranged between 197 and 220nm. Both modified octacosanol and its nanocrystals displayed maximum lipid peroxidation activities at a concentration 1000ppm, but nanocrystals demonstrated higher prevention. From freeze-thaw cycles it was evident that normal octacosanol crystals were far more prone to temperature variations than the nanocrystals. A pronounced increase in release/diffusion rate and bioavailability was observed for the nanocrystals of the modified octacosanol. In vitro release kinetics, bioavailability and bioequivalence were studied. Relative bioavailability for gastric passage and pancreatic passage of nanocrystals was 2.58 times and 1.81 times that of normal crystals respectively. Furthermore the nanocrystals displayed a superior in vitro release rate, while following a non-Fickian mode. Copyright © 2017 Elsevier B.V. All rights reserved.

G5 PAMAM dendrimer versus liposome: a comparison study on the in vitro transepithelial transport and in vivo oral absorption of simvastatin.

PubMed

Qi, Rong; Zhang, Heran; Xu, Lu; Shen, Wenwen; Chen, Cong; Wang, Chao; Cao, Yini; Wang, Yunan; van Dongen, Mallory A; He, Bing; Wang, Siling; Liu, George; Banaszak Holl, Mark M; Zhang, Qiang

2015-07-01

This study compared formulation effects of a dendrimer and a liposome preparation on the water solubility, transepithelial transport, and oral bioavailability of simvastatin (SMV). Amine-terminated G5 PAMAM dendrimer (G5-NH2) was chosen to form SMV/G5-NH2 molecular complexes, and SMV-liposomes were prepared by using a thin film dispersion method. The effects of these preparations on the transepithelial transport were investigated in vitro using Caco-2 cell monolayers. Results indicated that the solubility and transepithelial transport of SMV were significantly improved by both formulations. Pharmacokinetic studies in rats also revealed that both the SMV/G5-NH2 molecular complexes and the SMV-liposomes significantly improved the oral bioavailability of SMV with the liposomes being more effective than the G5-NH2. The overall better oral absorption of SMV-liposomes as compared to SMV/G5-NH2 molecular complexes appeared to arise from better liposomal solubilization and encapsulation of SMV and more efficient intracellular SMV delivery. Various carrier systems have been designed to enhance drug delivery via the oral route. In this study, the authors compared G5 PAMAM dendrimers to liposome preparations in terms of solubility, transepithelial transport, and oral bioavailability of this poorly water-soluble drug. This understanding has improved our knowledge in the further development of drug carrier systems. Copyright © 2015 Elsevier Inc. All rights reserved.

3-aminopropyl functionalized magnesium phyllosilicate as an organoclay based drug carrier for improving the bioavailability of flurbiprofen.

PubMed

Yang, Liang; Choi, Soo-Kyung; Shin, Hyun-Jae; Han, Hyo-Kyung

2013-01-01

This study aimed to develop an oral delivery system using clay-based organic-inorganic hybrid materials to improve the bioavailability of the drug, flurbiprofen, which is poorly soluble in water. 3-aminopropyl functionalized magnesium phyllosilicate (AMP clay) was synthesized by a one-pot direct sol-gel method, and then flurbiprofen (FB) was incorporated into AMP clay (FB-AMP) at different drug/clay ratios. The structural characteristics of AMP and FB-AMP formulation were confirmed by X-ray diffraction, Fourier transform infrared spectroscopy, and transmission electron microscopy. Among tested formulations, FB-AMP(3), dramatically increased the dissolution of FB and achieved rapid and complete drug release within 2 hours. More than 60% of FB was released from FB-AMP(3) after 30 minutes; the drug was completely dissolved in the water within 2 hours. Under the acidic condition (pH 1.2), FB-AMP(3) also increased the dissolution of FB by up to 47.1% within 1 hour, which was three-fold higher than that of untreated FB. Furthermore, following an oral administration of FB-AMP(3) to Sprague-Dawley rats, the peak plasma concentration and area under the plasma concentration-time curve of FB increased two-fold, and the time to reach the peak plasma concentration was shortened compared with that in the untreated FB. This result suggests that the oral drug delivery system using clay-based organic-inorganic hybrid material might be useful to improve the bioavailability of FB.

3-aminopropyl functionalized magnesium phyllosilicate as an organoclay based drug carrier for improving the bioavailability of flurbiprofen

PubMed Central

Yang, Liang; Choi, Soo-Kyung; Shin, Hyun-Jae; Han, Hyo-Kyung

2013-01-01

This study aimed to develop an oral delivery system using clay-based organic–inorganic hybrid materials to improve the bioavailability of the drug, flurbiprofen, which is poorly soluble in water. 3-aminopropyl functionalized magnesium phyllosilicate (AMP clay) was synthesized by a one-pot direct sol-gel method, and then flurbiprofen (FB) was incorporated into AMP clay (FB-AMP) at different drug/clay ratios. The structural characteristics of AMP and FB-AMP formulation were confirmed by X-ray diffraction, Fourier transform infrared spectroscopy, and transmission electron microscopy. Among tested formulations, FB-AMP(3), dramatically increased the dissolution of FB and achieved rapid and complete drug release within 2 hours. More than 60% of FB was released from FB-AMP(3) after 30 minutes; the drug was completely dissolved in the water within 2 hours. Under the acidic condition (pH 1.2), FB-AMP(3) also increased the dissolution of FB by up to 47.1% within 1 hour, which was three-fold higher than that of untreated FB. Furthermore, following an oral administration of FB-AMP(3) to Sprague-Dawley rats, the peak plasma concentration and area under the plasma concentration-time curve of FB increased two-fold, and the time to reach the peak plasma concentration was shortened compared with that in the untreated FB. This result suggests that the oral drug delivery system using clay-based organic–inorganic hybrid material might be useful to improve the bioavailability of FB. PMID:24204143

Perspectives on New Synthetic Curcumin Analogs and their Potential Anticancer Properties

PubMed Central

Vyas, Alok; Dandawate, Prasad; Padhye, Subhash; Ahmad, Aamir; Sarkar, Fazlul

2013-01-01

Curcumin is the active component of dried rhizome of Curcuma longa, a perennial herb belonging to ginger family, cultivated extensively in south and southeastern tropical Asia. It is widely consumed in the Indian subcontinent, south Asia and Japan in traditional food recipes. Extensive research over last few decades has shown that curcumin is a potent anti-inflammatory agent with powerful therapeutic potential against a variety of cancers. It suppresses proliferation and metastasis of human tumors through regulation of various transcription factors, growth factors, inflammatory cytokines, protein kinases and other enzymes. It induces apoptotic cell death and also inhibits proliferation of cancer cells by cell cycle arrest. Pharmacokinetic data has shown that curcumin undergoes rapid metabolism leading to glucuronidation and sulfation in the liver and excretion in the feces, which accounts for its poor systemic bioavailability. The compound has, therefore, been formulated and administered using different drug delivery systems such as liposomes, micelles, polysaccharides, phospholipid complexes and nanoparticles that can overcome the limitation of bioavailability to some extent. Attempts to avoid rapid metabolism of curcumin until now have been met with limited success. This has prompted researchers to look for new synthetic curcumin analogs in order to overcome the drawbacks of limited bioavailability and rapid metabolism, and gain efficacy with reduced toxicity. In this review we provide a summarized account of novel synthetic curcumin formulations and analogs, and the recent progress in the field of cancer prevention and treatment. PMID:23116312

Perspectives on new synthetic curcumin analogs and their potential anticancer properties.

PubMed

Vyas, Alok; Dandawate, Prasad; Padhye, Subhash; Ahmad, Aamir; Sarkar, Fazlul

2013-01-01

Curcumin is the active component of dried rhizome of Curcuma longa, a perennial herb belonging to ginger family, cultivated extensively in south and southeastern tropical Asia. It is widely consumed in the Indian subcontinent, south Asia and Japan in traditional food recipes. Extensive research over last few decades has shown that curcumin is a potent anti-inflammatory agent with powerful therapeutic potential against a variety of cancers. It suppresses proliferation and metastasis of human tumors through regulation of various transcription factors, growth factors, inflammatory cytokines, protein kinases and other enzymes. It induces apoptotic cell death and also inhibits proliferation of cancer cells by cell cycle arrest. Pharmacokinetic data has shown that curcumin undergoes rapid metabolism leading to glucuronidation and sulfation in the liver and excretion in the feces, which accounts for its poor systemic bioavailability. The compound has, therefore, been formulated and administered using different drug delivery systems such as liposomes, micelles, polysaccharides, phospholipid complexes and nanoparticles that can overcome the limitation of bioavailability to some extent. Attempts to avoid rapid metabolism of curcumin until now have been met with limited success. This has prompted researchers to look for new synthetic curcumin analogs in order to overcome the drawbacks of limited bioavailability and rapid metabolism, and gain efficacy with reduced toxicity. In this review we provide a summarized account of novel synthetic curcumin formulations and analogs, and the recent progress in the field of cancer prevention and treatment.

The comparison of different daidzein-PLGA nanoparticles in increasing its oral bioavailability.

PubMed

Ma, Yiran; Zhao, Xinyi; Li, Jian; Shen, Qi

2012-01-01

The aim of this research was to increase the oral bioavailability of daidzein by the formulations of poly(lactic-co-glycolic) acid (PLGA) nanoparticles loaded with daidzein. Amongst the various traditional and novel techniques of preparing daidzein-loaded PLGA nanoparticles, daidzein-loaded phospholipid complexes PLGA nanoparticles and daidzein-loaded cyclodextrin inclusion complexes PLGA nanoparticles were selected. The average drug entrapment efficiency, particle size, and zeta potential of daidzein-loaded phospholipid complexes PLGA nanoparticles and daidzein-loaded cyclodextrin inclusion complexes PLGA nanoparticles were 81.9% ± 5%, 309.2 ± 14.0 nm, -32.14 ± 2.53 mV and 83.2% ± 7.2%, 323.2 ± 4.8 nm, -18.73 ± 1.68 mV, respectively. The morphological characterization of nanoparticles was observed with scanning electron microscopy by stereological method and the physicochemical state of nanoparticles was valued by differential scanning calorimetry. The in vitro drug-release profile of both nanoparticle formulations fitted the Weibull dynamic equation. Pharmacokinetic studies demonstrated that after oral administration of daidzein-loaded phospholipid complexes PLGA nanoparticles and daidzein-loaded cyclodextrin inclusion complexes PLGA nanoparticles to rats at a dose of 10 mg/kg, relative bioavailability was enhanced about 5.57- and 8.85-fold, respectively, compared to daidzein suspension as control. These results describe an effective strategy for oral delivery of daidzein-loaded PLGA nanoparticles and might provide a fresh approach to enhancing the bioavailability of drugs with poor lipophilic and poor hydrophilic properties.

The comparison of different daidzein-PLGA nanoparticles in increasing its oral bioavailability

PubMed Central

Ma, Yiran; Zhao, Xinyi; Li, Jian; Shen, Qi

2012-01-01

The aim of this research was to increase the oral bioavailability of daidzein by the formulations of poly(lactic-co-glycolic) acid (PLGA) nanoparticles loaded with daidzein. Amongst the various traditional and novel techniques of preparing daidzein-loaded PLGA nanoparticles, daidzein-loaded phospholipid complexes PLGA nanoparticles and daidzein-loaded cyclodextrin inclusion complexes PLGA nanoparticles were selected. The average drug entrapment efficiency, particle size, and zeta potential of daidzein-loaded phospholipid complexes PLGA nanoparticles and daidzein-loaded cyclodextrin inclusion complexes PLGA nanoparticles were 81.9% ± 5%, 309.2 ± 14.0 nm, −32.14 ± 2.53 mV and 83.2% ± 7.2%, 323.2 ± 4.8 nm, −18.73 ± 1.68 mV, respectively. The morphological characterization of nanoparticles was observed with scanning electron microscopy by stereological method and the physicochemical state of nanoparticles was valued by differential scanning calorimetry. The in vitro drug-release profile of both nanoparticle formulations fitted the Weibull dynamic equation. Pharmacokinetic studies demonstrated that after oral administration of daidzein-loaded phospholipid complexes PLGA nanoparticles and daidzein-loaded cyclodextrin inclusion complexes PLGA nanoparticles to rats at a dose of 10 mg/kg, relative bioavailability was enhanced about 5.57- and 8.85-fold, respectively, compared to daidzein suspension as control. These results describe an effective strategy for oral delivery of daidzein-loaded PLGA nanoparticles and might provide a fresh approach to enhancing the bioavailability of drugs with poor lipophilic and poor hydrophilic properties. PMID:22346351

Application of carrier and plasticizer to improve the dissolution and bioavailability of poorly water-soluble baicalein by hot melt extrusion.

PubMed

Zhang, Yilan; Luo, Rui; Chen, Yi; Ke, Xue; Hu, Danrong; Han, Miaomiao

2014-06-01

The objective of this study was to develop a suitable formulation for baicalein (a poorly water-soluble drug exhibiting high melting point) to prepare solid dispersions using hot melt extrusion (HME). Proper carriers and plasticizers were selected by calculating the Hansen solubility parameters, evaluating melting processing condition, and measuring the solubility of obtained melts. The characteristic of solid dispersions prepared by HME was evaluated. The dissolution performance of the extrudates was compared to the pure drug and the physical mixtures. Physicochemical properties of the extrudates were characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier transform infrared spectroscopy (FTIR). Relative bioavailability after oral administration in beagle dogs was assessed. As a result, Kollidon VA64 and Eudragit EPO were selected as two carriers; Cremophor RH was used as the plasticizer. The dissolution of all the extrudates was significantly improved. DSC and PXRD results suggested that baicalein in the extrudates was amorphous. FTIR spectroscopy revealed the interaction between drug and polymers. After oral administration, the relative bioavailability of solid dispersions with VA64 and EPO was comparative, about 2.4- and 2.9-fold greater compared to the pure drug, respectively.

Curcumin: A Review of Its' Effects on Human Health.

PubMed

Hewlings, Susan J; Kalman, Douglas S

2017-10-22

Turmeric, a spice that has long been recognized for its medicinal properties, has received interest from both the medical/scientific world and from culinary enthusiasts, as it is the major source of the polyphenol curcumin. It aids in the management of oxidative and inflammatory conditions, metabolic syndrome, arthritis, anxiety, and hyperlipidemia. It may also help in the management of exercise-induced inflammation and muscle soreness, thus enhancing recovery and performance in active people. In addition, a relatively low dose of the complex can provide health benefits for people that do not have diagnosed health conditions. Most of these benefits can be attributed to its antioxidant and anti-inflammatory effects. Ingesting curcumin by itself does not lead to the associated health benefits due to its poor bioavailability, which appears to be primarily due to poor absorption, rapid metabolism, and rapid elimination. There are several components that can increase bioavailability. For example, piperine is the major active component of black pepper and, when combined in a complex with curcumin, has been shown to increase bioavailability by 2000%. Curcumin combined with enhancing agents provides multiple health benefits. The purpose of this review is to provide a brief overview of the plethora of research regarding the health benefits of curcumin.

Preparation, characterization, and scale-up of ketoconazole with enhanced dissolution and bioavailability.

PubMed

Elder, Edmund J; Evans, Jonathan C; Scherzer, Brian D; Hitt, James E; Kupperblatt, Gary B; Saghir, Shakil A; Markham, Dan A

2007-07-01

Many new molecular entities targeted for pharmaceutical applications face serious development challenges because of poor water solubility. Although particle engineering technologies such as controlled precipitation have been shown to enhance aqueous dissolution and bioavailability of poorly water soluble active pharmaceutical ingredients, the data available are the results of laboratory-scale experiments. These technologies must be evaluated at larger scale to ensure that the property enhancement is scalable and that the modified drugs can be processed on conventional equipment. In experiments using ketoconazole as the model drug, the controlled precipitation process was shown to produce kg-scale modified drug powder with enhanced dissolution comparable to that of lab-scale powder. Ketoconazole was demonstrated to be stable throughout the controlled precipitation process, with a residual methanol level below the ICH limit. The modified crystalline powder can be formulated, and then compressed using conventional high-speed tableting equipment, and the resulting tablets showed bioavailability more than double that of commercial tablets. When appropriately protected from moisture, both the modified powder and tablets prepared from the modified powder showed no change in dissolution performance for at least 6 months following storage at accelerated conditions and for at least 18 months following storage at room temperature.

Improving intestinal absorption and oral bioavailability of curcumin via taurocholic acid-modified nanostructured lipid carriers.

PubMed

Tian, Cihui; Asghar, Sajid; Wu, Yifan; Chen, Zhipeng; Jin, Xin; Yin, Lining; Huang, Lin; Ping, Qineng; Xiao, Yanyu

2017-01-01

The expression of multiple receptors on intestinal epithelial cells enables an actively targeted carrier to significantly enhance the oral delivery of payloads. Conjugating the receptors' ligands on the surfaces of a particulate-delivery system allows site-specific targeting. Here, we used taurocholic acid (TCA) as a ligand for uptake of nanostructured lipid carriers (NLCs) mediated by a bile-acid transporter to improve oral bioavailability of curcumin (Cur). First, synthesis of TCA-polyethylene glycol 100-monostearate (S100-TCA) was carried out. Then, the physical and chemical properties of S100-TCA-modified Cur-loaded NLCs (Cur-TCA NLCs) with varying levels of S100-TCA modifications were investigated. Small particle size (<150 nm), high drug encapsulation (>90%), drug loading (about 3%), negative ζ-potential (-7 to -3 mV), and sustained release were obtained. In situ intestinal perfusion studies demonstrated improved absorption rate and permeability coefficient of Cur-TCA NLCs. Depending on the degree of modification, Cur-TCA NLCs displayed about a five- to 15-fold higher area under the curve in rats after oral administration than unmodified Cur NLCs, which established that the addition of S100-TCA to the NLCs boosted absorption of Cur. Further investigations of TCA NLCs might reveal a bright future for effective oral delivery of poorly bioavailable drugs.

Nimodipine nanocrystals for oral bioavailability improvement: preparation, characterization and pharmacokinetic studies.

PubMed

Fu, Qiang; Sun, Jin; Zhang, Dong; Li, Mo; Wang, Yongjun; Ling, Guixia; Liu, Xiaohong; Sun, Yinghua; Sui, Xiaofan; Luo, Cong; Sun, Le; Han, Xiaopeng; Lian, He; Zhu, Meng; Wang, Siling; He, Zhonggui

2013-09-01

This study intended to develop nimodipine (NMD) nanocrystals with different sizes for oral administration and to investigate the relationship between dissolution and pharmacokinetics for NMD nanocrystals and Nimotop(®). NMD nanocrystals were prepared by combination of microprecipitation and high pressure homogenization and were further lyophilized. The particle size, morphology and aqueous solubility of the NMD nanocrystals were determined. With Nimotop(®) as the control, the dissolution rate was evaluated and the pharmacokinetic study was undertaken in beagle dogs. NMD nanocrystals with mean diameters of about 159.0, 503.0 and 833.3 nm were prepared, respectively. The lyophilization didn't affect the particle sizes of the redispersed nanocrystals. The aqueous solubility was significantly improved and displayed a size-dependent manner. The nanocrystals exhibited lower dissolution patterns than Nimotop(®) under non-sink condition, but bioavailability of the two nanocrystals (159.0 and 833.3 nm) was equivalent, about 2.6-fold higher than Nimotop(®). In conclusion, oral nanocrystal drug delivery system was a promising strategy in improving the oral bioavailability of poorly soluble or insoluble drugs. But we could not establish a favorable in vitro in vivo correlation for NMD nanocrystals and Nimotop(®) and thus the oral absorption mechanism of the NMD nanocrystals required further study. Copyright © 2013 Elsevier B.V. All rights reserved.

Nanocrystal for ocular drug delivery: hope or hype.

PubMed

Sharma, Om Prakash; Patel, Viral; Mehta, Tejal

2016-08-01

The complexity of the structure and nature of the eye emanates a challenge for drug delivery to formulation scientists. Lower bioavailability concern of conventional ocular formulation provokes the interest of researchers in the development of novel drug delivery system. Nanotechnology-based formulations have been extensively investigated and found propitious in improving bioavailability of drugs by overcoming ocular barriers prevailing in the eye. The advent of nanocrystals helped in combating the problem of poorly soluble drugs specifically for oral and parenteral drug delivery and led to development of various marketed products. Nanocrystal-based formulations explored for ocular drug delivery have been found successful in achieving increase in retention time, bioavailability, and permeability of drugs across the corneal and conjunctival epithelium. In this review, we have highlighted the ocular physiology and barriers in drug delivery. A comparative analysis of various nanotechnology-based ocular formulations is done with their pros and cons. Consideration is also given to various methods of preparation of nanocrystals with their patented technology. This article highlights the success achieved in conquering various challenges of ocular delivery by the use of nanocrystals while emphasizing on its advantages and application for ocular formulation. The perspectives of nanocrystals as an emerging flipside to explore the frontiers of ocular drug delivery are discussed.

Utilization of nanoemulsions to enhance bioactivity of pharmaceuticals, supplements, and nutraceuticals: Nanoemulsion delivery systems and nanoemulsion excipient systems.

PubMed

Aboalnaja, Khaled Omer; Yaghmoor, Soonham; Kumosani, Taha Abdullah; McClements, David Julian

2016-09-01

The efficacy of many hydrophobic bioactives (pharmaceuticals, supplements, and nutraceuticals) is limited due to their relatively low or highly variable bioavailability. Nanoemulsions consisting of small lipid droplets (r < 100 nm) dispersed in water can be designed to improve bioavailability. The major factors limiting the oral bioavailability of hydrophobic bioactive agents are highlighted: bioaccessibility, absorption and transformation. Two nanoemulsion-based approaches to control these processes and improve bioavailability are discussed: nanoemulsion delivery systems (NDS) and nanoemulsion excipient systems (NES). In NDS, hydrophobic bioactives are dissolved within the lipid phase of oil-in-water nanoemulsions. In NES, the bioactives are present within a conventional drug, supplement, or food, which is consumed with an oil-in-water nanoemulsion. Examples of NDS and NES utilization to improve bioactive bioavailability are given. Considerable progress has been made in nanoemulsion design, fabrication, and testing. This knowledge facilitates the design of new formulations to improve the bioavailability of pharmaceuticals, supplements, and nutraceuticals. NDS and NES must be carefully designed based on the major factors limiting the bioavailability of specific bioactives. Research is still required to ensure these systems are commercially viable, and to demonstrate their safety and efficacy using animal and human feeding studies.

Stimuli-sensitive hydrogels: ideal carriers for chronobiology and chronotherapy.

PubMed

Peppas, Nicholas A; Leobandung, William

2004-01-01

The development of solid-phase peptide synthesis in the early 1960s and recombinant DNA technology in the early 1970s boosted the scientific interest of utilizing proteins and peptides as potential therapeutic agents to battle poorly controlled diseases. While there has been rapid progress in the development and synthesis of new proteins and peptides as potential therapeutic agents, the formulation and development of the associated delivery systems is lacking. The development of delivery systems is equally important due to the problems of stability, low bioavailability and short half-life of proteins and peptides. The main problem in this field is that low stability leads to low bioavailability. In this review we draw attention to chrono-pharmacological drug-delivery systems, which can be used to match the delivery of therapeutic agents with the biological rhythm. They are very important especially in endocrinology and in vaccine therapy. We show that the treatment of hypopituitary dwarfism by administration of human growth-hormone-releasing hormone (GHRH) is more effective when GHRH is administered in a pulsatile manner that exhibits a period characteristic of the patient's circadian rhythm. Here we examine how to design novel chrono-pharmacological drug-delivery systems that should be able to release the therapeutic agents at predetermined intervals.

Recent progress on nanoparticle-based drug delivery systems for cancer therapy

PubMed Central

Xin, Yanru; Yin, Mingming; Zhao, Liyuan; Meng, Fanling; Luo, Liang

2017-01-01

The development of cancer nanotherapeutics has attracted great interest in the recent decade. Cancer nanotherapeutics have overcome several limitations of conventional therapies, such as nonspecific biodistribution, poor water solubility, and limited bioavailability. Nanoparticles with tuned size and surface characteristics are the key components of nanotherapeutics, and are designed to passively or actively deliver anti-cancer drugs to tumor cells. We provide an overview of nanoparticle-based drug delivery methods and cancer therapies based on tumor-targeting delivery strategies that have been developed in recent years. PMID:28884040

Enhanced bioavailability and bioefficacy of an amorphous solid dispersion of curcumin.

PubMed

Chuah, Ai Mey; Jacob, Bindya; Jie, Zhang; Ramesh, Subbarayan; Mandal, Shibajee; Puthan, Jithesh K; Deshpande, Parag; Vaidyanathan, Vadakkanchery V; Gelling, Richard W; Patel, Gaurav; Das, Tapas; Shreeram, Sathyavageeswaran

2014-08-01

Curcumin has been shown to have a wide variety of biological activities for various human diseases including inflammation, diabetes and cancer. However, the poor oral bioavailability of curcumin poses a significant pharmacological barrier to its use therapeutically and/or as a functional food. Here we report the evaluation of the bioavailability and bio-efficacy of curcumin as an amorphous solid dispersion (ASD) in a matrix consisting of hydroxypropyl methyl cellulose (HPMC), lecithin and isomalt using hot melt extrusion for application in food products. Oral pharmacokinetic studies in rats showed that ASD curcumin was ∼13-fold more bioavailable compared to unformulated curcumin. Evaluation of the anti-inflammatory activity of ASD curcumin in vivo demonstrated enhanced bio-efficacy compared to unformulated curcumin at 10-fold lower dose. Thus ASD curcumin provides a more potent and efficacious formulation of curcumin which may also help in masking the colour, taste and smell which currently limit its application as a functional food ingredient. Copyright © 2014 Elsevier Ltd. All rights reserved.

Bioavailability of flavonoids: a review of their membrane transport and the function of bilitranslocase in animal and plant organisms.

PubMed

Passamonti, Sabina; Terdoslavich, Michela; Franca, Raffaella; Vanzo, Andreja; Tramer, Federica; Braidot, Enrico; Petrussa, Elisa; Vianello, Angelo

2009-05-01

Fruits and vegetables are rich in flavonoids, and ample epidemiological data show that diets rich in fruits and vegetables confer protection against cardiovascular, neurodegenerative and inflammatory diseases, and cancer. However, flavonoid bioavailability is reportedly very low in mammals and the molecular mechanisms of their action are still poorly known. This review focuses on membrane transport of flavonoids, a critical determinant of their bioavailability. Cellular influx and efflux transporters are reviewed for their involvement in the absorption of flavonoids from the gastro-intestinal tract and their subsequent tissue distribution. A focus on the mammalian bilirubin transporter bilitranslocase (TCDB 2.A.65.1.1) provides further insight into flavonoid bioavailability and its relationship with plasma bilirubin (an endogenous antioxidant). The general function of bilitranslocase as a flavonoid membrane transporter is further demonstrated by the occurrence of a plant homologue in organs (petals, berries) where flavonoid biosynthesis is most active. Bilitranslocase appears associated with sub-cellular membrane compartments and operates as a flavonoid membrane transporter.

Improving oral bioavailability of acyclovir using nanoparticulates of thiolated xyloglucan.

PubMed

Madgulkar, Ashwini; Bhalekar, Mangesh R; Dikpati, Amrita A

2016-08-01

Acyclovir a BCS class III drug exhibits poor bioavailability due to limited permeability. The intention of this research work was to formulate and characterize thiolated xyloglucan polysaccharide nanoparticles (TH-NPs) of acyclovir with the purpose of increasing its oral bioavailability. Acyclovir-loaded TH-NPs were prepared using a cross-linking agent. Interactions of formulation excipients were reconnoitered using Fourier transform infrared spectroscopy (FT-IR). The formulated nanoparticles were lyophilised by the addition of a cryoprotectant and characterized for its particle size, morphology and stability and optimized using Box Behnken Design.The optimized TH-NP formulation exhibited particle size of 474.4±2.01 and an entrapment efficiency of 81.57%. A marked enhancement in the mucoadhesion was also observed. In-vivo study in a rat model proved that relative bioavailability of acyclovir TH-NPs is ∼2.575 fold greater than that of the marketed acyclovir drug suspension. Copyright © 2016 Elsevier B.V. All rights reserved.

Bioaccessibility and potential bioavailability of phenolic compounds from achenes as a new target for strawberry breeding programs.

PubMed

Ariza, María Teresa; Reboredo-Rodríguez, Patricia; Cervantes, Lucía; Soria, Carmen; Martínez-Ferri, Elsa; González-Barreiro, Carmen; Cancho-Grande, Beatriz; Battino, Maurizio; Simal-Gándara, Jesús

2018-05-15

Strawberry is a major natural source of bioactive compounds. Botanically, strawberry is an aggregate fruit consisting of a fleshy floral receptacle that bears a cluster of real dry fruits (achenes). Existing knowledge on the phenolic composition of achenes and its contribution to that of the whole fruit is limited. Also, the gastric and intestinal bioavailability of phenols is poorly known. In this work, a combination of spectrophotometric and HPLC-DAD methods was used to analyse the phenolic composition of whole fruits and achenes before and after in vitro digestion. Five different phenol families were identified. Also, achenes were found to contribute a sizeable fraction of phenolic acids and hydrolysable tannins in the whole fruit. Because the mere presence of phenolic compounds in a food matrix does not ensure their ready absorption and bioavailability, polyphenol potential bioavailability could be an effective selection criterion for strawberry breeding programs aimed at improving dietary healthiness. Copyright © 2017 Elsevier Ltd. All rights reserved.

Bioavailability of iron from spinach using an in vitro/human Caco-2 cell bioassay model

NASA Technical Reports Server (NTRS)

Rutzke, Corinne J.; Glahn, Raymond P.; Rutzke, Michael A.; Welch, Ross M.; Langhans, Robert W.; Albright, Louis D.; Combs, Gerald F Jr; Wheeler, Raymond M.

2004-01-01

Spinach (Spinacia oleracea) cv Whitney was tested for iron bioavailabilty using an in vitro human intestinal cell culture ferritin bioassay technique previously developed. Spinach was cultured in a growth chamber for 33 days, harvested, and freeze-dried. Total iron in the samples was an average of 71 micrograms/g dry weight. Spinach was digested in vitro (pepsin and 0.1 M HCl followed by pancreatin and 0.1 M NaHCO3) with and without the addition of supplemental ascorbic acid. Caco-2 cell cultures were used to determine iron bioavailability from the spinach mixtures. Production of the iron-binding protein ferritin in the Caco-2 cells showed the supplemental ascorbic acid doubled bioavailability of iron from spinach. The data show fresh spinach is a poor source of iron, and emphasize the importance of evaluation of whole meals rather than single food items. The data support the usefulness of the in vitro/Caco-2 cell ferritin bioassay model for prescreening of space flight diets for bioavailable iron.

The effect of earthworms on the fractionation and bioavailability of heavy metals before and after soil remediation.

PubMed

Udovic, Metka; Lestan, Domen

2007-07-01

The effect of two earthworm species, Lumbricus rubellus and Eisenia fetida, on the fractionation/bioavailability of Pb and Zn before and after soil leaching with EDTA was studied. Four leaching steps with total 12.5 mmol kg(-1) EDTA removed 39.8% and 6.1% of Pb and Zn, respectively. EDTA removed Pb from all soil fractions fairly uniformly (assessed using sequential extractions). Zn was mostly present in the chemically inert residual soil fraction, which explains its poor removal. Analysis of earthworm casts and the remainder of the soil indicated that L. rubellus and E. fetida actively regulated soil pH, but did not significantly change Pb and Zn fractionation in non-remediated and remediated soil. However, the bioavailability of Pb (assessed using Ruby's physiologically based extraction test) in E. fetida casts was significantly higher than in the bulk of the soil. In remediated soil the Pb bioavailability in the simulated stomach phase increased by 5.1 times.

Lipids-based nanostructured lipid carriers (NLCs) for improved oral bioavailability of sirolimus.

PubMed

Yu, Qin; Hu, Xiongwei; Ma, Yuhua; Xie, Yunchang; Lu, Yi; Qi, Jianping; Xiang, Li; Li, Fengqian; Wu, Wei

2016-05-01

The main purpose of this study was to improve the oral bioavailability of sirolimus (SRL), a poorly water-soluble immunosuppressant, by encapsulating into lipids-based nanostructured lipid carriers (NLCs). SRL-loaded NLCs (SRL-NLCs) were prepared by a high-pressure homogenization method with glycerol distearates (PRECIROL ATO-5) as the solid lipid, oleic acid as the liquid lipids, and Tween 80 as the emulsifier. The SRL-NLCs prepared under optimum conditions was spherical in shape with a mean particle size of about 108.3 nm and an entrapment efficiency of 99.81%. In vitro release of SRL-NLCs was very slow, about 2.15% at 12 h, while in vitro lipolysis test showed fast digestion of the NLCs within 1 h. Relative oral bioavailability of SRL-NLCs in Beagle dogs was 1.81-folds that of the commercial nanocrystalline sirolimus tablets Rapamune®. In conclusion, the NLCs show potential to improve the oral bioavailability of SRL.

From nanoemulsions to self-nanoemulsions, with recent advances in self-nanoemulsifying drug delivery systems (SNEDDS).

PubMed

Rehman, Fiza Ur; Shah, Kifayat Ullah; Shah, Shefaat Ullah; Khan, Ikram Ullah; Khan, Gul Majid; Khan, Amjad

2017-11-01

Lipid-based drug delivery systems (LBDDS) are the most promising technique to formulate the poorly water soluble drugs. Nanotechnology strongly influences the therapeutic performance of hydrophobic drugs and has become an essential approach in drug delivery research. Self-nanoemulsifying drug delivery systems (SNEDDS) are a vital strategy that combines benefits of LBDDS and nanotechnology. SNEDDS are now preferred to improve the formulation of drugs with poor aqueous solubility. Areas covered: The review in its first part shortly describes the LBDDS, nanoemulsions and clarifies the ambiguity between nanoemulsions and microemulsions. In the second part, the review discusses SNEDDS and elaborates on the current developments and modifications in this area without discussing their associated preparation techniques and excipient properties. Expert opinion: SNEDDS have exhibit the potential to increase the bioavailability of poorly water soluble drugs. The stability of SNEDDS is further increased by solidification. Controlled release and supersaturation can be achieved, and are associated with increased patient compliance and improved drug loads, respectively. Presence of biodegradable ingredients and ease of large-scale manufacturing combined with a lot of 'drug-targeting opportunities' give SNEDDS a clear distinction and prominence over other solubility enhancement techniques.

Phytobioactive compound-based nanodelivery systems for the treatment of type 2 diabetes mellitus – current status

PubMed Central

Ganesan, Palanivel; Arulselvan, Palanisamy; Choi, Dong-Kug

2017-01-01

Type 2 diabetes mellitus (T2DM) is a major chronic disease that is prevalent worldwide, and it is characterized by an increase in blood glucose, disturbances in the metabolism, and alteration in insulin secretion. Nowadays, food-based therapy has become an important treatment mode for type 2 diabetes, and phytobioactive compounds have gained an increasing amount of attention to this end because they have an effect on multiple biological functions, including the sustained secretion of insulin and regeneration of pancreatic islets cells. However, the poor solubility and lower permeability of these phyto products results in a loss of bioactivity during processing and oral delivery, leading to a significant reduction in the bioavailability of phytobioactive compounds to treat T2DM. Recently, nanotechnological systems have been developed for use as various types of carrier systems to improve the delivery of bioactive compounds and thus obtain a greater bioavailability. Furthermore, carrier systems in most nanodelivery systems are highly biocompatible, with nonimmunologic behavior, a high degree of biodegradability, and greater mucoadhesive strength. Therefore, this review focuses on the various types of nanodelivery systems that can be used for phytobioactive compounds in treating T2DM with greater antidiabetic effects. There is also additional focus on improving the effects of various phytobioactive compounds through nanotechnological delivery to ensure a highly efficient treatment of type 2 diabetes. PMID:28223801

Cyclodextrins in delivery systems: Applications

PubMed Central

Tiwari, Gaurav; Tiwari, Ruchi; Rai, Awani K.

2010-01-01

Cyclodextrins (CDs) are a family of cyclic oligosaccharides with a hydrophilic outer surface and a lipophilic central cavity. CD molecules are relatively large with a number of hydrogen donors and acceptors and, thus in general, they do not permeate lipophilic membranes. In the pharmaceutical industry, CDs have mainly been used as complexing agents to increase aqueous solubility of poorly soluble drugs and to increase their bioavailability and stability. CDs are used in pharmaceutical applications for numerous purposes, including improving the bioavailability of drugs. Current CD-based therapeutics is described and possible future applications are discussed. CD-containing polymers are reviewed and their use in drug delivery is presented. Of specific interest is the use of CD-containing polymers to provide unique capabilities for the delivery of nucleic acids. Studies in both humans and animals have shown that CDs can be used to improve drug delivery from almost any type of drug formulation. Currently, there are approximately 30 different pharmaceutical products worldwide containing drug/CD complexes in the market. PMID:21814436

Improved oral bioavailability of poorly water-soluble glimepiride by utilizing microemulsion technique

PubMed Central

Li, Haiying; Pan, Tingting; Cui, Ying; Li, Xiaxia; Gao, Jiefang; Yang, Wenzhi; Shen, Shigang

2016-01-01

The objective of this work was to prepare an oil/water glimepiride (GM) microemulsion (ME) for oral administration to improve its solubility and enhance its bioavailability. Based on a solubility study, pseudoternary phase diagrams, and Box–Behnken design, the oil/water GMME formulation was optimized and prepared. GMME was characterized by dynamic laser light scattering, zeta potential, transmission electron microscopy, and viscosity. The in vitro drug release, storage stability, pharmacodynamics, and pharmacokinetics of GMME were investigated. The optimized GMME was composed of Capryol 90 (oil), Cremophor RH40 (surfactant), and Transcutol (cosurfactant), and increased GM solubility up to 544.6±4.91 µg/mL. The GMME was spherical in shape. The particle size and its polydispersity index were 38.9±17.46 nm and 0.266±0.057, respectively. Meanwhile, the GMME was physicochemically stable at 4°C for at least 3 months. The short-term efficacy in diabetic mice provided the proof that blood glucose had a consistent and significant reduction at a dose of 375 µg/kg whether via IP injection or IG administration of GMME. Compared with the glimepiride suspensions or glimepiride-meglumine complex solution, the pharmacokinetics of GMME in Wistar rats via IG administration exhibited higher plasma drug concentration, larger area under the curve, and more enhanced oral bioavailability. There was a good correlation of GMME between the in vitro release values and the in vivo oral absorption. ME could be an effective oral drug delivery system to improve bioavailability of GM. PMID:27540291

Biorelevant Dissolution Models for a Weak Base To Facilitate Formulation Development and Overcome Reduced Bioavailability Caused by Hypochlordyria or Achlorhydria.

PubMed

Kou, Dawen; Dwaraknath, Sudharsan; Fischer, Yannick; Nguyen, Daniel; Kim, Myeonghui; Yiu, Hiuwing; Patel, Preeti; Ng, Tania; Mao, Chen; Durk, Matthew; Chinn, Leslie; Winter, Helen; Wigman, Larry; Yehl, Peter

2017-10-02

In this study, two dissolution models were developed to achieve in vitro-in vivo relationship for immediate release formulations of Compound-A, a poorly soluble weak base with pH-dependent solubility and low bioavailability in hypochlorhydric and achlorhydric patients. The dissolution models were designed to approximate the hypo-/achlorhydric and normal fasted stomach conditions after a glass of water was ingested with the drug. The dissolution data from the two models were predictive of the relative in vivo bioavailability of various formulations under the same gastric condition, hypo-/achlorhydric or normal. Furthermore, the dissolution data were able to estimate the relative performance under hypo-/achlorhydric and normal fasted conditions for the same formulation. Together, these biorelevant dissolution models facilitated formulation development for Compound-A by identifying the right type and amount of key excipient to enhance bioavailability and mitigate the negative effect of hypo-/achlorhydria due to drug-drug interaction with acid-reducing agents. The dissolution models use readily available USP apparatus 2, and their broader utility can be evaluated on other BCS 2B compounds with reduced bioavailability caused by hypo-/achlorhydria.

Effects of cooking and food matrix on estimated mineral bioavailability in Mloukhiya, a Mediterranean dish based on jute leaves and meat.

PubMed

Njoumi, Sondos; Bellagha, Sihem; Icard-Vernière, Christèle; Picq, Christian; Amiot, Marie Josèphe; Mouquet-Rivier, Claire

2018-03-01

Traditional Mediterranean plant-based dishes could allow tackling malnutrition while preserving the cultural heritage. To determine the effect of the cooking method on mineral bioavailability, the content in minerals and chelators of Mloukhiya, a Mediterranean dish based on jute leaves (Corchorus olitorius) that contains also meat, was monitored during the whole cooking process. Mineral bioaccessibility was assessed by measuring in vitro dialyzability. Model equation was also used to estimate mineral bioavailability. Comparison of Mloukhiya samples collected at different cooking time points showed that the dish total mineral content did not change despite the exchanges between sauce and meat during cooking. However, iron bioavailability decreased, because 58% of heme iron was degraded after 5h of cooking and non-heme iron showed poor bioaccessibility (1.2%), mainly due to its high content of phenolic compounds. The bioaccessibility of other minerals (zinc, calcium, magnesium and potassium) was high, indicating that the food matrix had no or little effect. The mineral bioavailability values predicted by using mathematical models were of the same order of magnitude as the bioaccessibility values. Copyright © 2017 Elsevier Ltd. All rights reserved.

A microemulsion of puerarin-phospholipid complex for improving bioavailability: preparation, in vitro and in vivo evaluations.

PubMed

Wu, Jun-Yong; Li, Yong-Jiang; Han, Meng; Hu, Xiong-Bin; Yang, Le; Wang, Jie-Min; Xiang, Da-Xiong

2018-08-01

Puerarin is a phytochemical with various pharmacological effects, but poor water solubility and low oral bioavailability limited usage of puerarin. The purpose of this study was to develop a new microemulsion (ME) based on phospholipid complex technique to improve the oral bioavailability of puerarin. Puerarin phospholipid complex (PPC) was prepared by a solvent evaporation method and was characterized by X-ray diffraction and infrared spectroscopy. Pseudo-ternary phase diagrams were constructed to investigate the effects of different oil on the emulsifying performance of the blank ME. Intestinal mucosal injury test was conducted to evaluate safety of PPC-ME, and no sign of damage on duodenum, jejunum and ileum of rats was observed using hematoxylin-eosin staining. In pharmacokinetic study of PPC-ME, a significantly greater C max (1.33 µg/mL) was observed when compared to puerarin (C max 0.55 µg/mL) or PPC (C max 0.70 µg/mL); the relative oral bioavailability of PPC-ME was 3.16-fold higher than puerarin. In conclusion, the ME combined with the phospholipid complex technique was a promising strategy to enhance the oral bioavailability of puerarin.

In vivo efficacy and bioavailability of lumefantrine: Evaluating the application of Pheroid technology.

PubMed

du Plessis, Lissinda H; Govender, Katya; Denti, Paolo; Wiesner, Lubbe

2015-11-01

The oral absorption of compounds with low aqueous solubility, such as lumefantrine, is typically limited by the dissolution rate in the gastro-intestinal tract, resulting in erratic absorption and highly variable bioavailability. In previous studies we reported on the ability of Pheroid vesicles to improve the bioavailability of poorly soluble drugs. In the present study a Pro-Pheroid formulation, a modification of the previous formulation, was applied to improve the solubility of lumefantrine after oral administration and compared to lumefantrine in DMSO:water (1:9 v/v) solution (reference solution). A bioavailability study of lumefantrine was conducted in a mouse model in fed and fasted states. When using the reference solution, the bioavailability of the lumefantrine heavily depended on food intake, resulting in a 2.7 times higher bioavailability in the fed state when compared to the fasted state. It also showed large between-subject variability. When formulated using Pro-Pheroid, the bioavailability of lumefantrine was 3.5 times higher as compared to lumefantrine in the reference solution and fasting state. Pro-Pheroid also dramatically reduced the effects of food intake and the between-subject variability for bioavailability observed with the reference. In vivo antimalarial efficacy was also evaluated with lumefantrine formulated using Pro-Pheroid technology compared to the reference solution. The results indicated that lumefantrine in Pro-Pheroid formulation exhibited improved antimalarial activity in vitro by 46.8%, when compared to the reference. The results of the Peters' 4-day suppressive test indicated no significant difference in the efficacy or mean survival time of the mice in the Pro-Pheroid formulation and reference test groups when compared to the positive control, chloroquine. These findings suggest that using the Pro-Pheroid formulation improves the bioavailability of lumefantrine, eliminates the food effect associated with lumefantrine as well as significantly reduces the between subject variability in bioavailability when compared to the reference solution. Copyright © 2015 Elsevier B.V. All rights reserved.

Iron from nanocompounds containing iron and zinc is highly bioavailable in rats without tissue accumulation

NASA Astrophysics Data System (ADS)

Hilty, Florentine M.; Arnold, Myrtha; Hilbe, Monika; Teleki, Alexandra; Knijnenburg, Jesper T. N.; Ehrensperger, Felix; Hurrell, Richard F.; Pratsinis, Sotiris E.; Langhans, Wolfgang; Zimmermann, Michael B.

2010-05-01

Effective iron fortification of foods is difficult, because water-soluble compounds that are well absorbed, such as ferrous sulphate (FeSO4), often cause unacceptable changes in the colour or taste of foods. Poorly water-soluble compounds, on the other hand, cause fewer sensory changes, but are not well absorbed. Here, we show that poorly water-soluble nanosized Fe and Fe/Zn compounds (specific surface area ~190 m2 g-1) made by scalable flame aerosol technology have in vivo iron bioavailability in rats comparable to FeSO4 and cause less colour change in reactive food matrices than conventional iron fortificants. The addition of Zn to FePO4 and Mg to Fe/Zn oxide increases Fe absorption from the compounds, and doping with Mg also improves their colour. After feeding rats with nanostructured iron-containing compounds, no stainable Fe was detected in their gut wall, gut-associated lymphatics or other tissues, suggesting no adverse effects. Nanosizing of poorly water-soluble Fe compounds sharply increases their absorption and nutritional value.

Use of Polyvinyl Alcohol as a Solubility-Enhancing Polymer for Poorly Water Soluble Drug Delivery (Part 1).

PubMed

Brough, Chris; Miller, Dave A; Keen, Justin M; Kucera, Shawn A; Lubda, Dieter; Williams, Robert O

2016-02-01

Polyvinyl alcohol (PVAL) has not been investigated in a binary formulation as a concentration-enhancing polymer owing to its high melting point/high viscosity and poor organic solubility. Due to the unique attributes of the KinetiSol® dispersing (KSD) technology, PVAL has been enabled for this application and it is the aim of this paper to investigate various grades for improvement of the solubility and bioavailability of poorly water soluble active pharmaceutical ingredients. Solid amorphous dispersions were created with the model drug, itraconazole (ITZ), at a selected drug loading of 20%. Polymer grades were chosen with variation in molecular weight and degree of hydroxylation to determine the effects on performance. Differential scanning calorimetry, powder X-ray diffraction, polarized light microscopy, size exclusion chromatography, and dissolution testing were used to characterize the amorphous dispersions. An in vivo pharmacokinetic study in rats was also conducted to compare the selected formulation to current market formulations of ITZ. The 4-88 grade of PVAL was determined to be effective at enhancing solubility and bioavailability of itraconazole.

Iron from nanocompounds containing iron and zinc is highly bioavailable in rats without tissue accumulation.

PubMed

Hilty, Florentine M; Arnold, Myrtha; Hilbe, Monika; Teleki, Alexandra; Knijnenburg, Jesper T N; Ehrensperger, Felix; Hurrell, Richard F; Pratsinis, Sotiris E; Langhans, Wolfgang; Zimmermann, Michael B

2010-05-01

Effective iron fortification of foods is difficult, because water-soluble compounds that are well absorbed, such as ferrous sulphate (FeSO(4)), often cause unacceptable changes in the colour or taste of foods. Poorly water-soluble compounds, on the other hand, cause fewer sensory changes, but are not well absorbed. Here, we show that poorly water-soluble nanosized Fe and Fe/Zn compounds (specific surface area approximately 190 m(2) g(-1)) made by scalable flame aerosol technology have in vivo iron bioavailability in rats comparable to FeSO(4) and cause less colour change in reactive food matrices than conventional iron fortificants. The addition of Zn to FePO(4) and Mg to Fe/Zn oxide increases Fe absorption from the compounds, and doping with Mg also improves their colour. After feeding rats with nanostructured iron-containing compounds, no stainable Fe was detected in their gut wall, gut-associated lymphatics or other tissues, suggesting no adverse effects. Nanosizing of poorly water-soluble Fe compounds sharply increases their absorption and nutritional value.

In vivo bioavailability and in vitro bioaccessibility of perfluorooctanoic acid (PFOA) in food matrices: correlation analysis and method development.

PubMed

Li, Kan; Li, Chao; Yu, Nan-Yang; Juhasz, Albert L; Cui, Xin-Yi; Ma, Lena Q

2015-01-06

Food is a major source of human exposure to perfluorooctanoic acid (PFOA), however, PFOA bioavailability in food has not been studied. An in vivo mouse model and three in vitro methods (unified BARGE method, UBM; physiologically based extraction test, PBET; and in vitro digestion method, IVD) were used to determine the relative bioavailability and bioaccessibility of PFOA in the presence of 17 foods. PFOA was mixed with foods of different nutritional compositions and fed to mice over a 7-d period. PFOA relative bioavailability was determined by comparing PFOA accumulation in the liver following PFOA exposure via food to that in water. PFOA bioavailability relative to water ranged from 4.30 ± 0.80 to 69.0 ± 11.9% and was negatively correlated with lipid content (r = 0.76). This was possibly due to competitive sorption of free fatty acids with PFOA onto transporters on intestine epithelial cells. Besides, cations in the gastrointestinal tract, such as Ca(2+) and Mg(2+), are capable of complexing PFOA and partitioning to the lipid phase. On the other hand, when assessed using in vitro assays, PFOA bioaccessibility varied with methods, being 8.7-73% (UBM), 9.8-99% (PBET), and 21-114% (IVD). PFOA bioaccessibility was negatively correlated with lipid content when assessed using UBM (r = 0.82); however, a poor correlation with food composition was observed for PBET and IVD (r = 0.01-0.50). When in vivo and in vitro data were compared, a strong correlation was observed for UBM (r = 0.79), but poor relationships were observed for PBET and IVD (r = 0.11-0.22). This was probably because the higher lipolysis ability and presence of Ca(2+) and Mg(2+) in the gastrointestinal fluid of UBM resulted in a lower potential to form stable micelles compared to PBET and IVD. These results indicated that PFOA relative bioavailability was mainly affected by lipid content in foods, and UBM has the potential to determine PFOA bioaccessibility in food samples.

Curcumin AntiCancer Studies in Pancreatic Cancer.

PubMed

Bimonte, Sabrina; Barbieri, Antonio; Leongito, Maddalena; Piccirillo, Mauro; Giudice, Aldo; Pivonello, Claudia; de Angelis, Cristina; Granata, Vincenza; Palaia, Raffaele; Izzo, Francesco

2016-07-16

Pancreatic cancer (PC) is one of the deadliest cancers worldwide. Surgical resection remains the only curative therapeutic treatment for this disease, although only the minority of patients can be resected due to late diagnosis. Systemic gemcitabine-based chemotherapy plus nab-paclitaxel are used as the gold-standard therapy for patients with advanced PC; although this treatment is associated with a better overall survival compared to the old treatment, many side effects and poor results are still present. Therefore, new alternative therapies have been considered for treatment of advanced PC. Several preclinical studies have demonstrated that curcumin, a naturally occurring polyphenolic compound, has anticancer effects against different types of cancer, including PC, by modulating many molecular targets. Regarding PC, in vitro studies have shown potent cytotoxic effects of curcumin on different PC cell lines including MiaPaCa-2, Panc-1, AsPC-1, and BxPC-3. In addition, in vivo studies on PC models have shown that the anti-proliferative effects of curcumin are caused by the inhibition of oxidative stress and angiogenesis and are due to the induction of apoptosis. On the basis of these results, several researchers tested the anticancer effects of curcumin in clinical trials, trying to overcome the poor bioavailability of this agent by developing new bioavailable forms of curcumin. In this article, we review the results of pre-clinical and clinical studies on the effects of curcumin in the treatment of PC.

Neuroprotective properties of curcumin in Alzheimer's disease--merits and limitations.

PubMed

Chin, Dawn; Huebbe, Patricia; Pallauf, Kathrin; Rimbach, Gerald

2013-01-01

As demographics in developed nations shift towards an aging population, neurodegenerative pathologies, especially dementias such as Alzheimer's disease, pose one of the largest challenges to the modern health care system. Since there is yet no cure for dementia, there is great pressure to discover potential therapeutics for these diseases. One popular candidate is curcumin or diferuloylmethane, a polyphenolic compound that is the main curcuminoid found in Curcuma longa (family Zingiberaceae). In recent years, curcumin has been reported to possess anti-amyloidogenic, antiinflammatory, anti-oxidative, and metal chelating properties that may result in potential neuroprotective effects. Particularly, the hydrophobicity of the curcumin molecule hints at the possibility of blood-brain barrier penetration and accumulation in the brain. However, curcumin exhibits extremely low bioavailability, mainly due to its poor aqueous solubility, poor stability in solution, and rapid intestinal first-pass and hepatic metabolism. Despite the many efforts that are currently being made to improve the bioavailability of curcumin, brain concentration of curcumin remains low. Furthermore, although many have reported that curcumin possesses a relatively low toxicity profile, curcumin applied at high doses, which is not uncommon practice in many in vivo and clinical studies, may present certain dangers that in our opinion have not been addressed sufficiently. Herein, the neuroprotective potential of curcumin, with emphasis on Alzheimer's disease, as well as its limitations will be discussed in detail.

Curcumin AntiCancer Studies in Pancreatic Cancer

PubMed Central

Bimonte, Sabrina; Barbieri, Antonio; Leongito, Maddalena; Piccirillo, Mauro; Giudice, Aldo; Pivonello, Claudia; de Angelis, Cristina; Granata, Vincenza; Palaia, Raffaele; Izzo, Francesco

2016-01-01

Pancreatic cancer (PC) is one of the deadliest cancers worldwide. Surgical resection remains the only curative therapeutic treatment for this disease, although only the minority of patients can be resected due to late diagnosis. Systemic gemcitabine-based chemotherapy plus nab-paclitaxel are used as the gold-standard therapy for patients with advanced PC; although this treatment is associated with a better overall survival compared to the old treatment, many side effects and poor results are still present. Therefore, new alternative therapies have been considered for treatment of advanced PC. Several preclinical studies have demonstrated that curcumin, a naturally occurring polyphenolic compound, has anticancer effects against different types of cancer, including PC, by modulating many molecular targets. Regarding PC, in vitro studies have shown potent cytotoxic effects of curcumin on different PC cell lines including MiaPaCa-2, Panc-1, AsPC-1, and BxPC-3. In addition, in vivo studies on PC models have shown that the anti-proliferative effects of curcumin are caused by the inhibition of oxidative stress and angiogenesis and are due to the induction of apoptosis. On the basis of these results, several researchers tested the anticancer effects of curcumin in clinical trials, trying to overcome the poor bioavailability of this agent by developing new bioavailable forms of curcumin. In this article, we review the results of pre-clinical and clinical studies on the effects of curcumin in the treatment of PC. PMID:27438851

On prilled Nanotubes-in-Microgel Oral Systems for protein delivery.

PubMed

de Kruif, Jan Kendall; Ledergerber, Gisela; Garofalo, Carla; Fasler-Kan, Elizaveta; Kuentz, Martin

2016-04-01

Newly discovered active macromolecules are highly promising for therapy, but poor bioavailability hinders their oral use. Microencapsulation approaches, such as protein prilling into microspheres, may enable protection from gastrointestinal (GI) enzymatic degradation. This would increase bioavailability mainly for local delivery to GI lumen or mucosa. This work's purpose was to design a novel architecture, namely a Nanotubes-in-Microgel Oral System, by prilling for protein delivery. Halloysite nanotubes (HNT) were selected as orally acceptable clay particles and their lumen was enlarged by alkaline etching. This chemical modification increased the luminal volume to a mean of 216.3 μL g(-1) (+40.8%). After loading albumin as model drug, the HNT were entrapped in microgels by prilling. The formation of Nanoparticles-in-Microsphere Oral System (NiMOS) yielded entrapment efficiencies up to 63.2%. NiMOS shape was spherical to toroidal, with a diameter smaller than 320 μm. Release profiles depended largely on the employed system and HNT type. Protein stability was determined throughout prilling and after in vitro enzymatic degradation. Prilling did not harm protein structure, and NiMOS demonstrated higher enzymatic protection than pure nanotubes or microgels, since up to 82% of BSA remained unscathed after in vitro digestion. Therefore, prilled NiMOS was shown to be a promising and flexible multi-compartment system for oral (local) macromolecular delivery. Copyright © 2016 Elsevier B.V. All rights reserved.

Improved oral bioavalability of mebudipine upon administration in PhytoSolve and Phosal-based formulation (PBF).

PubMed

Khani, Samira; Keyhanfar, Fariborz

2014-02-01

The aim of this investigation was to examine the efficacy of PhytoSolve and Phosal-based formulation (PBF) to enhance the oral bioavailability of mebudipine, which is a poorly water-soluble calcium channel blocker. The solubility of mebudipine in various oils was determined. PhytoSolve was prepared with a medium-chain triglyceride (MCT) oil (20%), soybean phospholipids (5%), and a 70% fructose solution (75%). The influence of the weight ratio of Phosal 50PG to glycerol in PBF on the mean globule size was studied with dynamic light scattering. The optimized formulation was evaluated for robustness toward dilution, transparency, droplet size, and zeta potential. The in vivo oral absorption of different mebudipine formulations (PhytoSolve, PBF, oily solution, and suspension) were evaluated in rats. The optimized PBF contained Phosal 50PG/glycerol in a 6:4 ratio (w/w). The PBF and PhytoSolve formulations were miscible with water in any ratio and did not demonstrate any phase separation or drug precipitation over 1 month of storage. The mean particle size of PhytoSolve and PBF were 138.5 ± 9.0 and 74.4 ± 2.5 nm, respectively. The in vivo study demonstrated that the oral bioavailability of PhytoSolve and PBF in rats was significantly higher than that of the other formulations. The PhytoSolve and PBF formulations of mebudipine are found to be more bioavailable compared with suspension and oily solutions during an in vivo study in rats. These formulations might be new alternative carriers that increase the oral bioavailability of poorly water-soluble molecules, such as mebudipine.

The pharmacokinetic behavior of the soy isoflavone metabolite S-(-)equol and its diastereoisomer R-(+)equol in healthy adults determined by using stable-isotope-labeled tracers.

PubMed

Setchell, Kenneth Dr; Zhao, Xueheng; Jha, Pinky; Heubi, James E; Brown, Nadine M

2009-10-01

The nonsteroidal estrogen equol occurs as diastereoisomers, S-(-)equol and R-(+)equol, both of which have significant biological actions. S-(-)equol, the naturally occurring enantiomer produced by 20-30% of adults consuming soy foods, has selective affinity for estrogen receptor-beta, whereas both enantiomers modulate androgen action. Little is known about the pharmacokinetics of the diastereoisomers, despite current interest in developing equol as a nutraceutical or pharmaceutical agent. The objective was to compare the pharmacokinetics of S-(-)equol and R-(+)equol by using [13C] stable-isotope-labeled tracers to facilitate the optimization of clinical studies aimed at evaluating the potential of these diastereoisomers in the prevention and treatment of estrogen- and androgen-dependent conditions. A randomized, crossover, open-label study in 12 healthy adults (6 men and 6 women) compared the plasma and urinary pharmacokinetics of orally administered enantiomeric pure forms of S-(-)[2-13C]equol, R-(+)[2-13C]equol, and the racemic mixture. Plasma and urinary [13C]R-equol and [13C]S-equol concentrations were measured by tandem mass spectrometry. Plasma [13C]equol concentration appearance and disappearance curves showed that both enantiomers were rapidly absorbed, attained high circulating concentrations, and had a similar terminal elimination half-life of 7-8 h. The systemic bioavailability and fractional absorption of R-(+)[2-13C]equol were higher than those of S-(-)[2-13C]equol or the racemate. The pharmacokinetics of racemic (+/-)[2-13C]equol were different from those of the individual enantiomers: slower absorption, lower peak plasma concentrations, and lower systemic bioavailability. The high bioavailability of both diastereoisomers contrasts with previous findings for the soy isoflavones daidzein and genistein, both of which have relatively poor bioavailability, and suggests that low doses of equol taken twice daily may be sufficient to achieve biological effects.

Infringement of the barriers of cancer via dietary phytoconstituents capsaicin through novel drug delivery system.

PubMed

Giri, Tapan Kumar; Alexander, Amit; Ajazuddin; Barman, Tapan Kumar; Maity, Subhasis

2016-01-01

Cancer is the major cause of fatality and the number of new cases is increasing incessantly. Conventional therapies and existing anticancer agents cause serious side effects and expand the patient's lifespan by a few years. There is the need to exploit alternative anticancer agents and novel drug delivery system to deliver these agents to the tumor site for the prevention of cancer. Recently, biologically active compounds isolated from plants used for the management of cancer have been the heart of interest. Capsaicin is a major pungent agent present in the chili peppers that is heavily consumed in the world. Capsaicin has demonstrated effectiveness as an anticancer agent, but a restraining factor is its pungency, extremely low aqueous solubility, and poor oral bioavailability which impede its use as an anticancer agent. Many technologies have been developed and applied to conquer this drawback. We bring to light the benefits of this phytoconstituent for treating different types of cancer. We also discussed some of the delivery approaches that have already made an impact by either delivering a drug to target tissue or increasing its bioavailability by many folds.

Preparation and evaluation of high dispersion stable nanocrystal formulation of poorly water-soluble compounds by using povacoat.

PubMed

Yuminoki, Kayo; Seko, Fuko; Horii, Shota; Takeuchi, Haruka; Teramoto, Katsuya; Nakada, Yuichiro; Hashimoto, Naofumi

2014-11-01

In this study, we reported the application of Povacoat®, a hydrophilic polyvinylalcohol copolymer, as a dispersion stabilizer of nanoparticles of poorly water-soluble compounds. In addition, the influence of aggregation of the nanoparticles on their solubility and oral absorption was studied. Griseofulvin (GF) was used as a model compound with poor water solubility and was milled to nanoparticles by wet bead milling. The dispersion stability of GF milled with Povacoat® or the generally used polymers (polyvinylalcohol, hydroxypropylcellulose SSL, and polyvinylpyrrolidone K30) was compared. Milled GF suspended in Povacoat® aqueous solution with D-mannitol, added to improve the disintegration rate of freeze-dried GF, exhibited high dispersion stability without aggregation (D90 = ca. 0.220 μm), whereas milled GF suspended in aqueous solutions of the other polymers aggregated (D90 > 5 μm). Milled GF with Povacoat® showed improved aqueous solubility and bioavailability compared with the other polymers. The aggregation of nanoparticles had significant impact on the solubility and bioavailability of GF. Povacoat® also prevented the aggregation of the various milled poorly water-soluble compounds (hydrochlorothiazide and tolbutamide, etc.) more effectively than the other polymers. These results showed that Povacoat® could have wide applicability to the development of nanoformulations of poorly water-soluble compounds. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Development of rectal self-emulsifying suspension of a moisture-labile water-soluble drug.

PubMed

Kauss, Tina; Gaubert, Alexandra; Tabaran, Luc; Tonelli, Giovanni; Phoeung, Thida; Langlois, Marie-Hélène; White, Nick; Cartwright, Anthony; Gomes, Melba; Gaudin, Karen

2018-01-30

Self-emulsifying drug delivery systems, commonly used for oral delivery of poorly soluble compounds, were used to formulate water soluble but moisture labile compounds for rectal application. The objective was to use the oily phase of the system to formulate a liquid, non-aqueous product while obtaining the advantages of self-emulsification, rapid contact with the rectal mucosa and rapid absorption post-administration. Ceftriaxone was used as a model drug and the human bile salt sodium chenodeoxycholate was used as an absorption enhancer. After preliminary screening of 23 excipients, based on their emulsification ability and emulsion fineness in binary and ternary mixtures, a full factorial design was used to screen different formulations of three preselected excipients. The optimal formulation contained 60% of excipients, namely Capryol 90, Kolliphor EL and Kolliphor PS20 in 4 : 6 : 6 ratio and 40% of a powder blend that included 500 mg of ceftriaxone. Characterization of the system showed that it complied with the requirements for rectal administration, in particular rapid emulsification in a small quantity of liquid. Rabbit bioavailability showed rapid absorption of ceftriaxone, achieving 128% bioavailability compared to powder control formulation. These results demonstrated the potential of self-emulsifying formulations for rectal administration of Class 3 BCS drugs. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

Beyond Yellow Curry: Assessing Commercial Curcumin Absorption Technologies

PubMed Central

Douglass, Brad J.; Clouatre, Dallas L.

2015-01-01

BACKGROUND: Few natural products have demonstrated the range of protective and therapeutic promise as have turmeric and its principal bioactive components: curcumin, demethoxycurcumin, and bisdemethoxycurcumin. Success in translating this potential into tangible benefits has been limited by inherently poor intestinal absorption, rapid metabolism, and limited systemic bioavailability. Seeking to overcome these limitations, food ingredient formulators have begun to employ a variety of approaches to enhance absorption and bioactivity. Many of these strategies improve upon the age-old practice of consuming turmeric in fat-based sauces, such as in a fat-rich yellow curry. However, there exists uncertainty as to how the various commercially available offerings compare to each other in terms of either uptake or efficacy, and this uncertainty leaves physicians and nutritionists with a dearth of data for making recommendations to interested patients and consumers. Further complicating the issue are recent data suggesting that formulation strategies may not equally enhance the absorption of individual curcuminoids, a significant issue in that these curcuminoids exhibit somewhat different physiologic properties. OBJECTIVE: This review introduces needed order to the curcumin marketplace by examining bioavailability studies on a number of commercial curcumin ingredients and evaluating them on a level playing field. METHODS: The comparative analysis includes standard pharmacokinetic parameters and a new metric, relative mass efficiency (E). Relative mass efficiency allows for the comparison of different formulations even in cases in which the weight percentage of curcuminoids is vastly different. RESULTS: A hydrophilic carrier dispersed curcuminoid formula exhibits 45.9 times the bioavailability of the standard purified 95 percent curcuminoid preparation and, based on relative mass efficiency, 1.5 times the bioavailability of the next best commercial ingredient, a cyclodextrin complex. CONCLUSIONS: Delivery strategies can significantly improve the bioavailability of curcuminoids. Total formula mass is important for making practical formulation decisions about dosing, cost and space. PMID:25856323

Vitamin D2 from light-exposed edible mushrooms is safe, bioavailable and effectively supports bone growth in rats.

PubMed

Calvo, M S; Babu, U S; Garthoff, L H; Woods, T O; Dreher, M; Hill, G; Nagaraja, S

2013-01-01

Widespread poor vitamin D status, a health risk for bone disease, increases the need for new food sources of vitamin D. Light-exposed edible mushrooms synthesize vitamin D(2). Bioavailability, safety, and efficacy of high levels of vitamin D(2) from mushrooms to support bone health was established in chronically fed growing rats. Poor vitamin D status from reduced sun exposure is made worse by limited access to vitamin D-containing foods. Exposing white button mushrooms to ultraviolet B (UVB) light markedly increases their vitamin D(2) content, creating a new food source of vitamin D. We used a growing rat model to determine safety, bioavailability, and efficacy in support of bone growth by vitamin D(2) from UVB-exposed mushrooms. We fed 150 weanling female rats one of five diets for 10 weeks, all formulated on AIN-93 G. Control diets contained no mushrooms either with or without vitamin D(3). Other diets contained 2.5% and 5.0% of UVB-exposed or -unexposed mushrooms. Safety of the high levels of vitamin D(2) from mushrooms was assessed by animal growth and by Von Kossa staining for soft tissue calcification. Bioavailability was determined from changes in circulating levels of 25-hydroxyvitamin D [25(OH)D] and parathyroid hormone (PTH). Efficacy in support of bone growth was determined from measures of femur bending properties, size, mineralization, and microarchitecture. Diets containing 2.5% and 5.0% light-exposed mushrooms significantly raised 25(OH)D and suppressed PTH levels compared to control-fed rats or rats fed 5.0% mushroom unexposed to light. Microarchitecture and trabecular mineralization were only modestly higher in the light-treated mushroom-fed rats compared to the controls. Von Kossa staining revealed no soft tissue calcification despite very high plasma 25(OH)D. Vitamin D(2) from UVB-exposed mushrooms is bioavailable, safe, and functional in supporting bone growth and mineralization in a growing rat model without evidence of toxicity.

Enhancement of Curcumin Bioavailability Via the Prodrug Approach: Challenges and Prospects.

PubMed

Ratnatilaka Na Bhuket, Pahweenvaj; El-Magboub, Asma; Haworth, Ian S; Rojsitthisak, Pornchai

2017-06-01

Curcumin is a natural product with many interesting pharmacological properties. However, these are offset by the particularly poor biopharmaceutical properties. The oral bioavailability of curcumin in humans is very low, mainly due to low solubility, poor stability, and extensive metabolism. This has led to multiple approaches to improve bioavailability, including administration of curcumin with metabolism inhibitors, formulation into nanoparticles, modification of the curcumin structure, and development of curcumin prodrugs. In this paper, we focus on the pharmacokinetic outcomes of these approaches. Pharmacokinetic parameters of curcumin after release from prodrugs are dependent on the linker between curcumin and the promoiety, and the release itself may depend on the physiological and enzymatic environment at the site of cleavage. This is an area in which more data are required for rational design of improved linkers. Cytotoxicity of curcumin prodrugs seems to correlate well with cellular uptake in vitro, but the in vivo relevance is uncertain. We conclude that improved experimental and theoretical models of absorption of curcumin prodrugs, development of accurate analytical methods for simultaneous measurement of plasma levels of prodrug and released curcumin, and acquisition of more pharmacokinetic data in animal models for dose prediction in humans are required to facilitate movement of curcumin prodrugs into clinical trials.

In Vitro Release and Bioavailability of Silybin from Micelle-Templated Porous Calcium Phosphate Microparticles.

PubMed

Zhu, Yuan; Wang, Miaomiao; Zhang, Ya; Zeng, Jin; Omari-Siaw, E; Yu, Jiangnan; Xu, Ximing

2016-10-01

Developing a promising carrier for the delivery of poorly water-soluble drugs, such as silybin, to improve oral absorption has become a very worthy of consideration. The goal of this study was to prepare a novel porous calcium phosphate microparticle using povidone-mixed micelles as template while evaluating its in vitro and in vivo properties with silybin as a model drug. The particle characterization, in vitro drug release behavior, and pharmacokinetic parameters of the prepared silybin-loaded calcium phosphate microparticle were investigated. The mean particle size was found to be 3.54 ± 0.32 μm with a rough surface porous structure. Additionally, the silybin-loaded calcium phosphate microparticle compared with the free silybin showed a prolonged 72-h release in vitro and a higher C max (418.5 ± 23.7 ng mL(-1)) with 167.5% oral relative bioavailability. A level A in vitro-in vivo correlation (IVIVC), established for the first time, demonstrated an excellent IVIVC of the formulated silybin in oral administration. In conclusion, this povidone-mixed micelle-based microparticle was successfully prepared to enhance the oral bioavailability of silybin. Therefore, application of this novel porous calcium phosphate microparticle holds a significant potential for the development of poorly water-soluble drugs.

Lycopene Deficiency in Ageing and Cardiovascular Disease

PubMed Central

Petyaev, Ivan M.

2016-01-01

Lycopene is a hydrocarbon phytochemical belonging to the tetraterpene carotenoid family and is found in red fruit and vegetables. Eleven conjugated double bonds predetermine the antioxidant properties of lycopene and its ability to scavenge lipid peroxyl radicals, reactive oxygen species, and nitric oxide. Lycopene has a low bioavailability rate and appears in the blood circulation incorporated into chylomicrons and other apo-B containing lipoproteins. The recent body of evidence suggests that plasma concentration of lycopene is not only a function of intestinal absorption rate but also lycopene breakdown via enzymatic and oxidative pathways in blood and tissues. Oxidative stress and the accumulation of reactive oxygen species and nitric oxide may represent a major cause of lycopene depletion in ageing, cardiovascular disease, and type 2 diabetes mellitus. It has been shown recently that low carotenoid levels, and especially decreased serum lycopene levels, are strongly predictive of all-cause mortality and poor outcomes of cardiovascular disease. However, there is a poor statistical association between dietary and serum lycopene levels which occurs due to limited bioavailability of lycopene from dietary sources. Hence, it is very unlikely that nutritional intervention alone could be instrumental in the correction of lycopene and carotenoid deficiency. Therefore, new nutraceutical formulations of carotenoids with enhanced bioavailability are urgently needed. PMID:26881023

Increasing the dissolution rate and oral bioavailability of the poorly water-soluble drug valsartan using novel hierarchical porous carbon monoliths.

PubMed

Zhang, Yanzhuo; Che, Erxi; Zhang, Miao; Sun, Baoxiang; Gao, Jian; Han, Jin; Song, Yaling

2014-10-01

In the present study, a novel hierarchical porous carbon monolith (HPCM) with three-dimensionally (3D) ordered macropores (∼ 400 nm) and uniform accessible mesopores (∼ 5.2 nm) was synthesized via a facile dual-templating technique using colloidal silica nanospheres and Poloxamer 407 as templates. The feasibility of the prepared HPCM for oral drug delivery was studied. Valsartan (VAL) was chosen as a poorly water-soluble model drug and loaded into the HPCM matrix using the solvent evaporation method. Scanning electron microscopy (SEM) and specific surface area analysis were employed to characterize the drug-loaded HPCM-based formulation, confirming the successful inclusion of VAL into the nanopores of HPCM. Powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) demonstrated that the incorporated drug in the HPCM matrix was in an amorphous state and the VAL formulation exhibited good physical stability for up to 6 months. In vitro tests showed that the dissolution rate of HPCM-based formulation was increased significantly compared with that of crystalline VAL or VAL-loaded 3D ordered macroporous carbon monoliths (OMCMs). Furthermore, a pharmacokinetic study in rats demonstrated about 2.4-fold increase in oral bioavailability of VAL in the case of HPCM-based formulation compared with the commercially available VAL preparation (Valzaar(®)). These results therefore suggest that HPCM is a promising carrier able to improve the dissolution rate and oral bioavailability of the poorly water-soluble drug VAL. Copyright © 2014. Published by Elsevier B.V.

Melt dispersion granules: formulation and evaluation to improve oral delivery of poorly soluble drugs - a case study with valsartan.

PubMed

Chella, Naveen; Tadikonda, Ramarao

2015-06-01

Solid dispersion (SD) technique is a promising strategy to improve the solubility and dissolution of BCS class II drugs. However, only few products are marketed till today based on SD technology due to poor flow properties and stability. The present work was intended to solve these problems by using combination approach, melt dispersion and surface adsorption technologies. The main aim of the present work is to improve the absorption in the stomach (at lower pH) where the absorption window exists for the drug by improving the dissolution, resulting in the enhancement of oral bioavailability of poorly soluble, weakly acidic drug with pH dependant solubility, i.e. valsartan. Melt dispersion granules were prepared in different ratios using different carriers (Gelucire 50/13, PEG 8000 and Pluronic F-68) and lactose as an adsorbent. Similarly, physical mixtures were also prepared at corresponding ratios. The prepared dispersion granules and physical mixtures were characterized by FTIR, DSC and in vitro dissolution studies. DSC studies revealed reduction in the crystallinity with a possibility of presence of amorphous character of drug in the dispersion granules. From dissolution studies, valsartan Gelucire dispersion (GSD4; 1:4 ratio) showed complete drug release in 30 min against the plain drug which showed only 11.31% of drug release in 30 min. Pharmacokinetic studies of optimized formulation in male Wistar rats showed 2.65-fold higher bioavailability and 1.47-fold higher Cmax compared to pure drug. The melt dispersion technology has the potential to improve dissolution and the bioavailability of BCS class II drugs.

Preparation and characterization of intravaginal vardenafil suppositories targeting a complementary treatment to boost in vitro fertilization process.

PubMed

Gomaa, Eman; Abu Lila, Amr S; Hasan, Azza A; Ghazy, Fakhr-Eldin S

2018-01-01

Vaginal route has been recently considered as a potential route for systemic delivery of drugs with poor oral bioavailability. Vardenafil (VDF) is a relatively new phosphodiesterase-5 inhibitor that exhibits a limited oral bioavailability (≈15%) due to extensive first-pass metabolism. In this study, we attempted to enhance the systemic bioavailability of VDF via its formulation within vaginal suppositories. Witepsol H15 and Suppocire NA50 were adopted as lipophilic suppository bases while polyethylene glycol 4000/400 and glycerogelatin were used as hydrophilic suppository bases. The effect of different base types and/or the incorporation of bioadhesive polymer on in vitro release of VDF were evaluated. The in vivo fate and organ biodistribution of VDF following intravaginal (IVG) administration were also investigated. VDF release from water-soluble bases was higher than that from lipophilic bases. The incorporation of bioadhesive polymers, such as Na alginate, remarkably sustained drug release from suppository base. The organ biodistribution study showed a higher C max (32 times) and AUC 0-4h (20 times) of VDF in uterus following IVG administration of conventional suppositories, compared to oral administration of VDF suspension. In addition, cyclic guanosine monophosphate (cGMP) serum levels, used as an indicator of the in vivo activity of VDF, in animals were higher following IVG administration rather than oral administration. This study suggests that IVG administration of VDF might represent a potential alternative to oral route with superior therapeutic benefits especially when targeting the uterus. Copyright © 2017 Elsevier B.V. All rights reserved.

Liposomal curcumin and its application in cancer

PubMed Central

Lee, Robert J; Zhao, Ling

2017-01-01

Curcumin (CUR) is a yellow polyphenolic compound derived from the plant turmeric. It is widely used to treat many types of diseases, including cancers such as those of lung, cervices, prostate, breast, bone and liver. However, its effectiveness has been limited due to poor aqueous solubility, low bioavailability and rapid metabolism and systemic elimination. To solve these problems, researchers have tried to explore novel drug delivery systems such as liposomes, solid dispersion, microemulsion, micelles, nanogels and dendrimers. Among these, liposomes have been the most extensively studied. Liposomal CUR formulation has greater growth inhibitory and pro-apoptotic effects on cancer cells. This review mainly focuses on the preparation of liposomes containing CUR and its use in cancer therapy. PMID:28860764

Liposomal curcumin and its application in cancer.

PubMed

Feng, Ting; Wei, Yumeng; Lee, Robert J; Zhao, Ling

2017-01-01

Curcumin (CUR) is a yellow polyphenolic compound derived from the plant turmeric. It is widely used to treat many types of diseases, including cancers such as those of lung, cervices, prostate, breast, bone and liver. However, its effectiveness has been limited due to poor aqueous solubility, low bioavailability and rapid metabolism and systemic elimination. To solve these problems, researchers have tried to explore novel drug delivery systems such as liposomes, solid dispersion, microemulsion, micelles, nanogels and dendrimers. Among these, liposomes have been the most extensively studied. Liposomal CUR formulation has greater growth inhibitory and pro-apoptotic effects on cancer cells. This review mainly focuses on the preparation of liposomes containing CUR and its use in cancer therapy.

Pharmacokinetics of isochlorgenic acid C in rats by HPLC-MS: Absolute bioavailability and dose proportionality.

PubMed

Huang, Li Hua; Xiong, Xiao Hong; Zhong, Yun Ming; Cen, Mei Feng; Cheng, Xuan Ge; Wang, Gui Xiang; Zang, Lin Quan; Wang, Su Jun

2016-06-05

Isochlorgenic acid C (IAC), one of the bioactive compounds of Lonicera japonica, exhibited diverse pharmacological effects. However, its pharmacokinetic properties and bioavailability remained unresolved. To determine the absolute bioavailability in rats and the dose proportionality on the pharmacokinetics of single oral dose of IAC. A validated HPLC-MS method was developed for the determination of IAC in rat plasma. Plasma concentration versus time data were generated following oral and intravenous dosing. The pharmacokinetic analysis was performed using DAS 3.0 software analysis. Absolute bioavailability in rats was determined by comparing pharmacokinetic data after administration of single oral (5, 10 and 25mgkg(-1)) and intravenous (5mgkg(-1)) doses of IAC. The dose proportionality of AUC(0-∞) and Cmax were analyzed by linear regression. Experimental data showed that absolute oral bioavailability of IAC in rats across the doses ranged between 14.4% and 16.9%. The regression analysis of AUC(0-∞) and Cmax at the three doses (5, 10 and 25mgkg(-1)) indicated that the equations were y=35.23x+117.20 (r=0.998) and y=121.03x+255.74 (r=0.995), respectively. A new HPLC-MS method was developed to determine the bioavailability and the dose proportionality of IAC. Bioavailability of IAC in rats was poor and both Cmax and AUC(0-∞) of IAC had a positive correlation with dose. Evaluation of the pharmacokinetics of IAC will be useful in assessing concentration-effect relationships for the potential therapeutic applications of IAC. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Geochemical partitioning of Cu and Ni in mangrove sediments: relationships with their bioavailability.

PubMed

Chakraborty, Parthasarathi; Ramteke, Darwin; Chakraborty, Sucharita

2015-04-15

Sequential extraction study was performed to determine the concentrations of non-residual metal-complexes in the mangrove sediments from the Divar Island, (west coast of India). Accumulation of metal in the mangrove roots (from the same location) was determined and used as an indicator of bioavailability of metal. An attempt was made to establish a mechanistic linkage between the non-residual metal complexes and their bioavailability in the mangrove system. The non-residual fractions of Cu and Ni were mainly associated with Fe/Mn oxyhydroxide and organic phases in the sediments. A part of these metal fractions were bioavailable in the system. These two phases were the major controlling factors for Ni speciation and their bioavailability in the studied sediments. However, Cu was found to interact more strongly with the organic phases than Ni in the mangrove sediments. Organic phases in the mangrove sediments acted as buffer to control the speciation and bioavailability of Cu in the system. Copyright © 2015 Elsevier Ltd. All rights reserved.

Nano-silymarin provides protection against γ-radiation-induced oxidative stress in cultured human embryonic kidney cells.

PubMed

Adhikari, Manish; Arora, Rajesh

2015-10-01

Radiation can produce biological damage, mainly oxidative stress, via production of free radicals, including reactive oxygen species (ROS). Nanoparticles are of interest as radioprotective agents, particularly due to their high solubility and bioavailability. Silymarin is a hepatoprotective agent but has poor oral bioavailability. Silymarin was formulated as a nanoemulsion with the aim of improving its bioavailability and therapeutic efficacy. In the present study, we evaluated self-nanoemulsifying drug delivery systems (SNEDDS) formulated with surfactants and co-surfactants. Nano-silymarin was characterized by estimating % transmittance, globule size, and polydispersity index, and by transmission electron microscopy (TEM). The nano-silymarin obtained was in the range of 3-8nm diameter. With regard to DNA damage, measured by a plasmid relaxation assay, maximum protection was obtained at 10μg/mL. Cytotoxicity of nano-silymarin to human embryonic kidney (HEK) cells was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. Protective efficacy against γ-radiation was assessed by reduction in micronucleus frequency and ROS generation, using the 2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA) assay. Radiation-induced apoptosis was estimated by microscopic analysis and cell-cycle estimation. Nano-silymarin was radioprotective, supporting the possibility of developing new approaches to radiation protection via nanotechnology. Copyright © 2015 Elsevier B.V. All rights reserved.

The formulation of a nasal nanoemulsion zaleplon in situ gel for the treatment of insomnia.

PubMed

Hosny, Khaled Mohamed; Banjar, Zainy Mohammed

2013-08-01

Zaleplon is a drug used for the treatment of insomnia and is available in tablet form; however, it has two major problems. First, the drug undergoes extensive first pass metabolism, resulting in only 30% bioavailability, and second, the drug has a poor aqueous solubility, which delays the onset of action. The objective of this study is to utilise nanotechnology to formulate zaleplon into a nasal in situ nanoemulsion gel (NEG) to provide a solution for the previously mentioned problems. The solubility of zaleplon in various oils, surfactants and co-surfactants was estimated. Pseudo-ternary phase diagrams were developed and various nanoemulsion (NE) formulations were prepared; these formulations were subjected to visual characterisation, thermodynamic stability study and droplet size and conductivity measurements. Carbopol 934 was used as an in situ gelling agent. The gel strength, pH, gelation time, in vitro release and ex vivo nasal permeation were determined. The pharmacokinetic study of the NEG was carried out in rabbits. Stable NEs were successfully developed with a droplet size range of 35 to 73 nm. A NEG composed of 15% Miglyol, 30% Labrasol and 10% PEG 200 successfully provided the maximum in vitro and ex vivo permeation and enhanced the bioavailability in the rabbits by eightfold, when compared with the marketed tablets. The nasal NEG is a promising novel formula for zaleplon that has higher nasal tissue permeability and enhanced systemic bioavailability.

Polymer blends used to develop felodipine-loaded hollow microspheres for improved oral bioavailability.

PubMed

Pi, Chao; Feng, Ting; Liang, Jing; Liu, Hao; Huang, Dongmei; Zhan, Chenglin; Yuan, Jiyuan; Lee, Robert J; Zhao, Ling; Wei, Yumeng

2018-06-01

Felodipine (FD) has been widely used in anti-hypertensive treatment. However, it has extremely low aqueous solubility and poor bioavailability. To address these problems, FD hollow microspheres as multiple-unit dosage forms were synthesized by a solvent diffusion evaporation method. Particle size of the hollow microspheres, types of ethylcellulose (EC), amounts of EC, polyvinyl pyrrolidone (PVP) and FD were investigated based on an orthogonal experiment of three factors and three levels. In addition, the release kinetics in vitro and pharmacokinetics in beagle dogs of the optimized FD hollow microspheres was investigated and compared with Plendil (commercial FD sustained-release tablets) as a single-unit dosage form. Results showed that the optimal formulation was composed of EC 10 cp :PVP:FD (0.9:0.16:0.36, w/w). The FD hollow microspheres were globular with a hollow structure and have high drug loading (17.69±0.44%) and floating rate (93.82±4.05%) in simulated human gastric fluid after 24h. Pharmacokinetic data showed that FD hollow microspheres exhibited sustained-release behavior and significantly improved relative bioavailability of FD compared with the control. Pharmacodynamic study showed that the FD hollow microspheres could effectively lower blood pressure. Therefore, these findings demonstrated that the hollow microspheres were an effective sustained-release delivery system for FD. Copyright © 2018 Elsevier B.V. All rights reserved.

Improving the oral bioavailability of curcumin using novel organogel-based nanoemulsions.

PubMed

Yu, Hailong; Huang, Qingrong

2012-05-30

Curcumin is a natural bioactive compound with many health-promoting benefits. Its low oral bioavailability limits its application in functional foods. In the present study, novel organogel-based nanoemulsions have been developed for oral delivery of curcumin and improvement of its bioavailability. Recently developed curcumin organogel was used as the oil phase in the curcumin nanoemulsion formulation. Tween 20 was selected as the emulsifier on the basis of maximum in vitro bioaccessibility of curcumin in the nanoemulsion. In vitro lipolysis profile revealed that the digestion of nanoemulsion was significantly faster and more complete than the organogel. Permeation experiments on Caco-2 cell monolayers suggested that digestion-diffusion was the major absorption mechanism for curcumin in the nanoemulsion. Furthermore, in vivo pharmacokinetics analysis on mice confirmed that the oral bioavailability of curcumin in the nanoemulsion was increased by 9-fold compared with unformulated curcumin. This novel formulation approach may also be used for oral delivery of other poorly soluble nutraceuticals with high loading capacity, which has significant impact in functional foods, dietary supplements and pharmaceutical industries.

Improvement of Oral Bioavailability of Lopinavir Without Co-administration of Ritonavir Using Microspheres of Thiolated Xyloglucan.

PubMed

Madgulkar, Ashwini R; Bhalekar, Mangesh R; Kadam, Ashwini A

2018-01-01

Lopinavir is a BCS Class IV drug exhibiting poor bioavailability due to P-gp efflux and limited permeation. The aim of this research was to formulate and characterize microspheres of lopinavir using thiolated xyloglucan (TH-MPs) as carrier to improve its oral bioavailability without co-administration of ritonavir. Thiomeric microspheres were prepared by ionotropic gelation between alginic acid and calcium ions. Interaction studies were performed using Fourier transform infrared spectroscopy (FT-IR). The thiomeric microspheres were characterized for its entrapment efficiency, T 80 , surface morphology, and mucoadhesion employing in vitro wash off test. The microspheres were optimized by 3 2 factorial design. The optimized thiomeric microsphere formulation revealed 93.12% entrapment efficiency, time for 80% drug release (T 80 ) of 358.1 min, and 88% mucoadhesion after 1 h. The permeation of lopinavir from microspheres was enhanced 3.15 times as determined by ex vivo study using everted chick intestine and increased relative bioavailability over 3.22-fold over combination of lopinavir and ritonavir as determined by in vivo study in rat model.

Modulatory effects of silibinin in various cell signaling pathways against liver disorders and cancer - A comprehensive review.

PubMed

Polachi, Navaneethakrishnan; Bai, Guirong; Li, Tingyang; Chu, Yang; Wang, Xiangyang; Li, Shuming; Gu, Ning; Wu, Jiang; Li, Wei; Zhang, Yanjun; Zhou, Shuiping; Sun, He; Liu, Changxiao

2016-11-10

Silibinin, a natural flavanone, derived from the milk thistle plant (Silybum marianum), was illustrated for several medicinal uses such as liver-protective, anti-oxidant, anti-cancer, anti-inflammation and many other. However, silibinin has poor absorbance and bioavailability due to low water solubility, thereby limiting its clinical applications and therapeutic efficiency. To overcome this problem, the combination of silibinin with phosphatidylcholine (PC) as a formulation was used to enhance the solubility and bioavailability. The results indicated that silibinin-PC taken orally markedly enhanced bioavailability and therapeutic efficiency. In addition, a deeper understanding of the signaling pathways modulated by silibinin is important to realize its potential in developing targeted therapies against liver disorders and cancer. Silibinin has been shown to inhibit many cell signaling pathways in preclinical models, demonstrating promising effects against liver disorders and cancer through in vitro and in vivo studies. This review summarizes the pharmacokinetic properties, bioavailability, safety data, clinical activities and modulatory effects of silibinin in different cell signaling pathways against liver disorders and cancer. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Development and evaluation of nitrendipine loaded solid lipid nanoparticles: influence of wax and glyceride lipids on plasma pharmacokinetics.

PubMed

Kumar, Venishetty Vinay; Chandrasekar, Durairaj; Ramakrishna, Sistla; Kishan, Veerabrahma; Rao, Yamsani Madhusudan; Diwan, Prakash Vamanrao

2007-04-20

Nitrendipine is an antihypertensive drug with poor oral bioavailability ranging from 10 to 20% due to the first pass metabolism. For improving the oral bioavailability of nitrendipine, nitrendipine loaded solid lipid nanoparticles have been developed using triglyceride (tripalmitin), monoglyceride (glyceryl monostearate) and wax (cetyl palmitate). Poloxamer 188 was used as surfactant. Hot homogenization of melted lipids and aqueous phase followed by ultrasonication at temperature above the melting point of lipid was used to prepare SLN dispersions. SLN were characterized for particle size, zeta potential, entrapment efficiency and crystallinity of lipid and drug. In vitro release studies were performed in phosphate buffer of pH 6.8 using Franz diffusion cell. Pharmacokinetics of nitrendipine loaded solid lipid nanoparticles after intraduodenal administration to conscious male Wistar rats was studied. Bioavailability of nitrendipine was increased three- to four-fold after intraduodenal administration compared to that of nitrendipine suspension. The obtained results are indicative of solid lipid nanoparticles as carriers for improving the bioavailability of lipophilic drugs such as nitrendipine by minimizing first pass metabolism.

Dissolution and bioavailability enhancement of alpha-asarone by solid dispersions via oral administration.

PubMed

Deng, Li; Wang, Yu; Gong, Tao; Sun, Xun; Zhang, Zhi-Rong

2017-11-01

Alpha (α)-asarone (1-propenyl-2,4,5-methoxybenzol) (ARE) has been extensively used to treat chronic obstructive pulmonary diseases (COPD), bronchial asthma, pneumonia, and epilepsy. Due to its poor solubility and bioavailability, ARE was clinically administered via intravenous injection. However, severe allergies were often reported due to the presence of solublizers in the injection formulation. In our study, we sought to explore the biopharmaceutical classification of ARE, elucidate the mechanisms behind ARE absorption, and to develop a viable formulation to improve the oral bioavailability of ARE. ARE was not a P-glycoprotein substrate, which was absorbed in the passive mode without site specificity in the gastrointestinal tract. Solid dispersions prepared using hydrophilic matrix materials such as Pluronic F68, and polyethylene glycol (PEG) of varying molecular weights (PEG4K, PEG10K, and PEG20K) were proven to significantly improve the dissolution of ARE in vitro and the oral bioavailability of ARE in rats, which represent a promising strategy for the oral administration of ARE and other BCS II compounds.

Bioavailability enhancement of curcumin by complexation with phosphatidyl choline.

PubMed

Gupta, Nishant Kumar; Dixit, Vinod Kumar

2011-05-01

Curcumin is a major constituent of rhizomes of Curcuma longa. Pharmacokinetic studies of curcumin reveal its poor absorption through intestine. Objective of the present study was to enhance bioavailability of curcumin by its complexation with phosphatidyl choline (PC). Complex of curcumin was prepared with PC and characterized on the basis of solubility, melting point, differential scanning calorimetry, thin layer chromatography, and infrared spectroscopic analysis. Everted intestine sac technique was used to study ex vivo drug absorption of curcumin-PC (CU-PC) complex and plain curcumin. Pharmacokinetic studies were performed in rats, and hepatoprotective activity of CU-PC complex was also compared with curcumin and CU-PC physical mixture in isolated rat hepatocytes. Analytical reports along with spectroscopic data revealed the formation of complex. The results of ex vivo study show that CU-PC complex has significantly increased absorption compared with curcumin, when given in equimolar doses. Complex showed enhanced bioavailability, improved pharmacokinetics, and increased hepatoprotective activity as compared with curcumin or CU-PC physical mixture. Enhanced bioavailability of CU-PC complex may be due to the amphiphilic nature of the complex, which greatly enhance the water and lipid solubility of the curcumin. The present study clearly indicates the superiority of complex over curcumin, in terms of better absorption, enhanced bioavailability, and improved pharmacokinetics. Copyright © 2010 Wiley-Liss, Inc.

Pharmacokinetics, oral bioavailability, and metabolic profile of resveratrol and its dimethylether analog, pterostilbene, in rats

PubMed Central

Kapetanovic, Izet M.; Huang, Zhihua; Thompson, Thomas N.; McCormick, David L.

2011-01-01

Purpose Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a naturally occurring polyphenol with a broad range of possible health benefits, including anti-cancer activity. However, the biological activity of resveratrol may be limited by poor absorption and first-pass metabolism: only low plasma concentrations of resveratrol are seen following oral administration, and metabolism to glucuronide and sulfate conjugates is rapid. Methylated polyphenol analogs (such as pterostilbene [3,5-dimethoxy-4′-hydroxy-trans-stilbene], the dimethylether analog of resveratrol) may overcome these limitations to pharmacologic efficacy. The present study was designed to compare the bioavailability, pharmacokinetics, and metabolism of resveratrol and pterostilbene following equimolar oral dosing in rats. Methods The agents were administered orally via gavage for 14 consecutive days at 50 or 150 mg/kg/day for resveratrol and 56 or 168 mg/kg/day for pterostilbene. Two additional groups were dosed once intravenously with 10 and 11.2 mg/kg for resveratrol and pterostilbene, respectively. Plasma concentrations of agents and metabolites were measured using a high-pressure liquid chromatograph-tandem mass spectrometer system. Noncompartmental analysis was used to derive pharmacokinetic parameters. Results Resveratrol and pterostilbene were approximately 20 and 80% bioavailable, respectively. Following oral dosing, plasma levels of pterostilbene and pterostilbene sulfate were markedly greater than were plasma levels of resveratrol and resveratrol sulfate. Although plasma levels of resveratrol glucuronide exceeded those of pterostilbene glucuronide, those differences were smaller than those of the parent drugs and sulfate metabolites. Conclusions When administered orally, pterostilbene demonstrates greater bioavailability and total plasma levels of both the parent compound and metabolites than does resveratrol. These differences in agent pharmacokinetics suggest that the in vivo biological activity of equimolar doses of pterostilbene may be greater than that of resveratrol. PMID:21116625

High drug load, stable, manufacturable and bioavailable fenofibrate formulations in mesoporous silica: a comparison of spray drying versus solvent impregnation methods.

PubMed

Hong, Shiqi; Shen, Shoucang; Tan, David Cheng Thiam; Ng, Wai Kiong; Liu, Xueming; Chia, Leonard S O; Irwan, Anastasia W; Tan, Reginald; Nowak, Steven A; Marsh, Kennan; Gokhale, Rajeev

2016-01-01

Encapsulation of drugs in mesoporous silica using co-spray drying process has been recently explored as potential industrial method. However, the impact of spray drying on manufacturability, physiochemical stability and bioavailability in relation to conventional drug load processes are yet to be fully investigated. Using a 2(3) factorial design, this study aims to investigate the effect of drug-loading process (co-spray drying and solvent impregnation), mesoporous silica pore size (SBA-15, 6.5 nm and MCM-41, 2.5 nm) and percentage drug load (30% w/w and 50% w/w) on material properties, crystallinity, physicochemical stability, release profiles and bioavailability of fenofibrate (FEN) loaded into mesoporous silica. From the scanning electronic microscopy (SEM) images, powder X-ray diffraction and Differential scanning calorimetry measurements, it is indicated that the co-spray drying process was able to load up to 50% (w/w) FEN in amorphous form onto the mesoporous silica as compared to the 30% (w/w) for solvent impregnation. The in vitro dissolution rate of the co-spray dried formulations was also significantly (p = 0.044) better than solvent impregnated formulations at the same drug loading. Six-month accelerated stability test at 40 °C/75 RH in open dish indicated excellent physical and chemical stability of formulations prepared by both methods. The amorphous state of FEN and the enhanced dissolution profiles were well preserved, and very low levels of degradation were detected after storage. The dog data for the three selected co-spray-dried formulations revealed multiple fold increment in FEN bioavailability compared to the reference crystalline FEN. These results validate the viability of co-spray-dried mesoporous silica formulations with high amorphous drug load as potential drug delivery systems for poorly water soluble drugs.

Potential vulnerability of southeast Alaskan wetland soil carbon stocks to climate warming

NASA Astrophysics Data System (ADS)

Fellman, J.; D'Amore, D. V.; Hood, E. W.

2015-12-01

Carbon cycling along the high latitude coastal margins of Alaska is poorly understood relative to boreal and arctic ecosystems. The perhumid coastal temperate rainforest (PCTR) of southeast Alaska has some of the densest carbon stocks (>300 Mg C ha-1) in the world but the fate of these stocks with continued warming will balance on the poorly constrained rates of carbon accumulation and loss. We quantified the rate of dissolved organic carbon (DOC) and carbon dioxide (CO2) production from four different wetland types (rich fen, poor fen, forested wetland and cedar wetland) using controlled laboratory incubations of surface (10 cm) and subsurface (25 cm) soils incubated at 8 ºC and 15 ºC for 37 weeks. This design allowed us to determine the potential vulnerability of wetland soil carbon stocks to climate warming and partition organic matter mineralization into DOC and CO2 fluxes and its controls (e.g., wetland type and temperature). Furthermore, we used fluorescence characterization of DOC and laboratory bioassays to assess how climate warming may impact the quality and bioavailability of DOC delivered to fluvial systems. Soil depth and temperature strongly influenced carbon loss in all four wetland types with the greatest CO2 fluxes observed in the rich fen and greatest DOC fluxes observed in the poor fen. Of the fluxes, CO2 was the most sensitive to incubation temperature but DOC showed more variation with wetland type. Fluxes of DOC and CO2 were positively correlated only during the last few months of the incubation suggesting strong biotic control of DOC production developed as soil organic matter decomposition progressed. Moreover, bioavailable DOC and protein-like fluorescence were greatest in the initial soil extractions but dramatically decreased over the length of the incubations. Our findings suggest that soil organic matter decomposition will increase as the PCTR continues to warm, but this response will also will vary with wetland type.

Evaluation of Iodine Bioavailability in Seaweed Using in Vitro Methods.

PubMed

Domínguez-González, M Raquel; Chiocchetti, Gabriela M; Herbello-Hermelo, Paloma; Vélez, Dinoraz; Devesa, Vicenta; Bermejo-Barrera, Pilar

2017-09-27

Due to the high levels of iodine present in seaweed, the ingestion of a large amount of this type of food can produce excessive intake of iodine. However, the food after ingestion undergoes different chemistry and physical processes that can modify the amount of iodine that reaches the systemic circulation (bioavailability). Studies on the bioavailability of iodine from food are scarce and indicate that the bioavailable amount is generally lower than ingested. Iodine in vitro bioavailability estimation from different commercialized seaweed has been studied using different in vitro approaches (solubility, dialyzability, and transport and uptake by intestinal cells). Results indicate that iodine is available after gastrointestinal digestion for absorption (bioaccessibility: 49-82%), kombu being the seaweed with the highest bioaccessibility. The incorporation of dialysis cell cultures to elucidate bioavailability modifies the estimation of the amount of iodine that may reach the systemic circulation (dialysis, 5-28%; cell culture, ≤3%). The paper discusses advantages and drawbacks of these methodologies for iodine bioavailability in seaweed.

Phase behavior and oral bioavailability of amorphous Curcumin.

PubMed

Pawar, Yogesh B; Shete, Ganesh; Popat, Dharmesh; Bansal, Arvind K

2012-08-30

Amorphous form has been used as a means to improve aqueous solubility and oral bioavailability of poorly water soluble drugs. The objective of present study was to characterize thermodynamic and kinetic parameters of amorphous form of Curcumin (CRM-A). CRM-A was found to be a good glass former with glass transition temperature (T(g)) of 342.64K and critical cooling rate below 1K/min. CRM-A had a moderate tendency of crystallization and exhibited Kauzmann temperature (T(KS)) of 294.23 K. CRM-A was found to be fragile in nature as determined by T(m)/T(g) (1.32), C(p)(1 iq):C(p)(glass) (1.22), strength parameter (D<10), fragility index (m>75), T(K)/T(g) (0.85), and T(g)-T(K) (48.41). Theoretically predicted aqueous solubility advantage of 43.15-folds, was reduced to 17-folds under practical conditions. This reduction in solubility was attributed to water induced devitrification, as evident through PXRD and SEM analysis. Further, oral bioavailability study of CRM-A was undertaken to investigate bioavailability benefits, if any. C(max) was improved by 1.97-folds (statistically significant difference over control). However, oral bioavailability (AUC(0-)(∞)) was improved by 1.45-folds (statistically non significant difference over control). These observations pointed towards role of rapid devitrification of CRM-A in GIT milieu, thus limiting its oral bioavailability advantage. Copyright © 2012 Elsevier B.V. All rights reserved.

Origins and bioavailability of dissolved organic matter in groundwater

USGS Publications Warehouse

Shen, Yuan; Chapelle, Francis H.; Strom, Eric W.; Benner, Ronald

2015-01-01

Dissolved organic matter (DOM) in groundwater influences water quality and fuels microbial metabolism, but its origins, bioavailability and chemical composition are poorly understood. The origins and concentrations of dissolved organic carbon (DOC) and bioavailable DOM were monitored during a long-term (2-year) study of groundwater in a fractured-rock aquifer in the Carolina slate belt. Surface precipitation was significantly correlated with groundwater concentrations of DOC, bioavailable DOM and chromophoric DOM, indicating strong hydrological connections between surface and ground waters. The physicochemical and biological processes shaping the concentrations and compositions of DOM during its passage through the soil column to the saturated zone are conceptualized in the regional chromatography model. The model provides a framework for linking hydrology with the processes affecting the transformation, remineralization and microbial production of DOM during passage through the soil column. Lignin-derived phenols were relatively depleted in groundwater DOM indicating substantial removal in the unsaturated zone, and optical properties of chromophoric DOM indicated lower molecular weight DOM in groundwater relative to surface water. The prevalence of glycine, γ-aminobutyric acid, and d-enantiomers of amino acids indicated the DOM was highly diagenetically altered. Bioassay experiments were used to establish DOC-normalized yields of amino acids as molecular indicators of DOM bioavailability in groundwater. A relatively small fraction (8 ± 4 %) of DOC in groundwater was bioavailable. The relatively high yields of specific d-enantiomers of amino acids indicated a substantial fraction (15–34 %) of groundwater DOC was of bacterial origin.

Enhanced oral bioavailability of glycyrrhetinic acid via nanocrystal formulation.

PubMed

Lei, Yaya; Kong, Yindi; Sui, Hong; Feng, Jun; Zhu, Rongyue; Wang, Wenping

2016-10-01

The purpose of this study was to prepare solid nanocrystals of glycyrrhetinic acid (GA) for improved oral bioavailability. The anti-solvent precipitation-ultrasonication method followed by freeze-drying was adopted for the preparation of GA nanocrystals. The physicochemical properties, drug dissolution and pharmacokinetic of the obtained nanocrystals were investigated. GA nanocrystals showed a mean particle size of 220 nm and shaped like short rods. The analysis results from differential scanning calorimetry and X-ray powder diffraction indicated that GA remained in crystalline state despite a huge size reduction. The equilibrium solubility and dissolution rate of GA nanocrystal were significantly improved in comparison with those of the coarse GA or the physical mixture. The bioavailability of GA nanocrystals in rats was 4.3-fold higher than that of the coarse GA after oral administration. With its rapid dissolution and absorption performance, the solid nanocrystal might be a more preferable formulation for oral administration of poorly soluble GA.

In-situ single pass intestinal permeability and pharmacokinetic study of developed Lumefantrine loaded solid lipid nanoparticles.

PubMed

Garg, Anuj; Bhalala, Kripal; Tomar, Devendra Singh; Wahajuddin

2017-01-10

The present investigation aims to develop lumefantrine loaded binary solid lipid nanoparticles (LF-SLNs) to improve its poor and variable oral bioavailability. The oral bioavailability of LF is poor and variable due to its limited aqueous solubility and P-gp mediated efflux occurring in small intestine. LF-SLNs were prepared using binary lipid mixture of stearic acid and caprylic acid stabilized with TPGS (D-alpha tocopheryl polyethylene glycol 1000 succinate) and Poloxamer 188. Developed LF-SLNs were characterized for particle size distribution, zeta potential, entrapment efficiency, solid state properties and biopharmaceutical properties including in situ intestinal permeability and oral bioavailability. The particle size distribution, zeta potential and entrapment efficiency of optimized batch (LF-SLN7) was found to be 357.7±43.27nm, 25.29±1.15mV and 97.35±0.30%, respectively. DSC thermographs showed loss of crystalline nature of lumefantrine in LF-SLNs. In situ single pass intestinal permeability study (SPIP) study indicated significant enhancement in the effective intestinal permeability of LF from LF-SLN7 as compared to that of control. Pharmacokinetic study also showed significant increase in Cmax and area under curve (AUC0- ∞ ) from LF-SLN7 (3860±521ng/mL and 43181±2557h×ng/mL, respectively) as compared to that of LF-control suspension (1425±563ng/mL and 19586±1537h×ng/mL, respectively). Thus, developed LF-SLNs can be promising to overcome P-gp efflux pump and enhance the oral bioavailability of lumefantrine. Copyright © 2016 Elsevier B.V. All rights reserved.

Assembling nanoparticle coatings to improve the drug delivery performance of lipid based colloids

NASA Astrophysics Data System (ADS)

Simovic, Spomenka; Barnes, Timothy J.; Tan, Angel; Prestidge, Clive A.

2012-02-01

Lipid based colloids (e.g. emulsions and liposomes) are widely used as drug delivery systems, but often suffer from physical instabilities and non-ideal drug encapsulation and delivery performance. We review the application of engineered nanoparticle layers at the interface of lipid colloids to improve their performance as drug delivery systems. In addition we focus on the creation of novel hybrid nanomaterials from nanoparticle-lipid colloid assemblies and their drug delivery applications. Specifically, nanoparticle layers can be engineered to enhance the physical stability of submicron lipid emulsions and liposomes, satbilise encapsulated active ingredients against chemical degradation, control molecular transport and improve the dermal and oral delivery characteristics, i.e. increase absorption, bioavailability and facilitate targeted delivery. It is feasible that hybrid nanomaterials composed of nanoparticles and colloidal lipids are effective encapsulation and delivery systems for both poorly soluble drugs and biological drugs and may form the basis for the next generation of medicines. Additional pre-clinical research including specific animal model studies are required to advance the peptide/protein delivery systems, whereas the silica lipid hybrid systems have now entered human clinical trials for poorly soluble drugs.

Inclusion complex and nanoclusters of cyclodextrin to increase the solubility and efficacy of albendazole

USDA-ARS?s Scientific Manuscript database

Albendazole (ABZ), a benzimidazole widely used to control gastrointestinal parasites is poorly soluble in water, resulting in variable and incomplete bioavailability, which has favored the appearance of parasite resistance and, consequently, clinical ineffectiveness. Among the pharmaceutical techniq...

Preparation of albumin based nanoparticles for delivery of fisetin and evaluation of its cytotoxic activity.

PubMed

Ghosh, Pooja; Singha Roy, Atanu; Chaudhury, Susmitnarayan; Jana, Saikat Kumar; Chaudhury, Koel; Dasgupta, Swagata

2016-05-01

Fisetin is a well known flavonoid that shows several properties such as antioxidant, antiviral and anticancer activities. Its use in the pharmaceutical field is limited due to its poor aqueous solubility which results in poor bioavailability and poor permeability. The aim of our present study is to prepare fisetin loaded human serum albumin nanoparticles to improve its bioavailability. The nanoparticles were prepared by a desolvation method and characterized by spectroscopic and microscopic techniques. The particles were smooth and spherical in nature with an average size of 220 ± 8 nm. The encapsulation efficiency was found to be 84%. The in vitro release profile showed a biphasic pattern and the release rate increases with increase in ionic strength of solution. We have also confirmed the antioxidant activity of the prepared nanoparticles by a DPPH (2,2-diphenyl-1-picrylhydrazyl) assay. Further its anticancer activity was evaluated using MCF-7 breast cancer cell lines. Our findings suggest that fisetin loaded HSA nanoparticles could be used to transfer fisetin to target areas under specific conditions and thus may find use as a delivery vehicle for the flavonoid. Copyright © 2016 Elsevier B.V. All rights reserved.

Soft gelatin capsules (softgels).

PubMed

Gullapalli, Rampurna Prasad

2010-10-01

It is estimated that more than 40% of new chemical entities (NCEs) coming out of the current drug discovery process have poor biopharmaceutical properties, such as low aqueous solubility and/or permeability. These suboptimal properties pose significant challenges for the oral absorption of the compounds and for the development of orally bioavailable dosage forms. Development of soft gelatin capsule (softgel) dosage form is of growing interest for the oral delivery of poorly water soluble compounds (BCS class II or class IV). The softgel dosage form offers several advantages over other oral dosage forms, such as delivering a liquid matrix designed to solubilize and improve the oral bioavailability of a poorly soluble compound as a unit dose solid dosage form, delivering low and ultra-low doses of a compound, delivering a low melting compound, and minimizing potential generation of dust during manufacturing and thereby improving the safety of production personnel. However, due to the very dynamic nature of the softgel dosage form, its development and stability during its shelf-life are fraught with several challenges. The goal of the current review is to provide an in-depth discussion on the softgel dosage form to formulation scientists who are considering developing softgels for therapeutic compounds.

Nanostructured lipid carriers used for oral delivery of oridonin: an effect of ligand modification on absorption.

PubMed

Zhou, Xiaotong; Zhang, Xingwang; Ye, Yanghuan; Zhang, Tianpeng; Wang, Huan; Ma, Zhiguo; Wu, Baojian

2015-02-20

Oridonin (Ori) is a natural compound with notable anti-inflammation and anti-cancer activities. However, therapeutic use of this compound is limited by its poor solubility and low bioavailability. Here a novel biotin-modified nanostructured lipid carrier (NLC) was developed to enhance the bioavailability of Ori. The effect of ligand (biotin) modification on oral absorption of Ori encapsulated in NLCs was also explored. Ori-loaded NLCs (Ori-NLCs) were prepared by the melt dispersion-high pressure homogenization method. Biotin modification of Ori-NLCs was achieved by EDC and NHS in aqueous phase. The obtained biotin-decorated Ori-NLCs (Bio-Ori-NLCs) were 144.9nm in size with an entrapment efficiency of 49.54% and a drug load of 4.81%. Oral bioavailability was enhanced by use of Bio-Ori-NLCs with a relative bioavailability of 171.01%, while the value of non-modified Ori-NLCs was improved to 143.48%. Intestinal perfusion showed that Ori solution unexpectedly exhibited a moderate permeability, indicating that permeability was not a limiting factor of Ori absorption. Ori could be rapidly metabolized that was the main cause of low bioavailability. However, there was a difference in the enhancement of bioavailability between Bio-Ori-NLCs and conventional NLCs. Although severe lipolyses happened both on Bio-Ori-NLCs and non-modified NLCs, the performance of Bio-Ori-NLCs in the bioavailability improvement was more significant. Overall, Bio-Ori-NLCs can further promote the oral absorption of Ori by a ligand-mediated active transport. It may be a promising carrier for the oral delivery of Ori. Copyright © 2014 Elsevier B.V. All rights reserved.

Fabrication and in vivo evaluation of Nelfinavir loaded PLGA nanoparticles for enhancing oral bioavailability and therapeutic effect

PubMed Central

Venkatesh, D. Nagasamy; Baskaran, Mahendran; Karri, Veera Venkata Satyanarayana Reddy; Mannemala, Sai Sandeep; Radhakrishna, Kollipara; Goti, Sandip

2015-01-01

Nelfinavir mesylate (NFV) is an anti-viral drug, used in the treatment of Acquired Immunodeficiency Syndrome (AIDS). Poor oral bioavailability and shorter half-life (3.5–5 h) remain a major clinical limitation of NFV leading to unpredictable drug bioavailability and frequent dosing. In this context, the objective of the present study was to formulate NFV loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), which can increase the solubility and oral bioavailability along with sustained release of the drug. NFV loaded PLGA-NPs were prepared by nanoprecipitation method using PLGA and Poloxomer 407. The prepared NPs were evaluated for particle size, zeta potential, morphology, drug content, entrapment efficiency (EE) and in vitro dissolution studies. Oral bioavailability studies were carried out in New Zealand rabbits by administering developed NFV PLGA-NPs and pure drug suspension. PLGA-NPs prepared by using 1:4 ratio of drug and PLGA, with a stirring rate of 1500 rpm for 4 h. The prepared NPs were in the size of 185 ± 0.83 nm with a zeta potential of 28.7 ± 0.09 mV. The developed NPs were found to be spherical with uniform size distribution. The drug content and EE of the optimized formulation were found to be 36 ± 0.19% and 72 ± 0.47% respectively. After oral administration of NFV PLGA-NPs, the relative bioavailability was enhanced about 4.94 fold compared to NFV suspension as a control. The results describe an effective strategy for oral delivery of NFV loaded PLGA NPs that helps in enhancing bioavailability and reduce the frequency of dosing. PMID:26702262

Pharmacokinetics of dietary cancer chemopreventive compound dibenzoylmethane in rats and the impact of nanoemulsion and genetic knockout of Nrf2 on its disposition.

PubMed

Lin, Wen; Hong, Jin-Liern; Shen, Guoxiang; Wu, Rachel T; Wang, Yuwen; Huang, Mou-Tuan; Newmark, Harold L; Huang, Qingrong; Khor, Tin Oo; Heimbach, Tycho; Kong, Ah-Ng

2011-03-01

The pharmacokinetic disposition of a dietary cancer chemopreventive compound dibenzoylmethane (DBM) was studied in male Sprague-Dawley rats after intravenous (i.v.) and oral (p.o.) administrations. Following a single i.v. bolus dose, the mean plasma clearance (CL) of DBM was low compared with the hepatic blood flow. DBM displayed a high volume of distribution (Vss). The elimination terminal t1/2 was long. The mean CL, Vss and AUC0-∞/dose were similar between the i.v. 10 and 10 mg/kg doses. After single oral doses (10, 50 and 250 mg/kg), the absolute oral bioavailability (F*) of DBM was 7.4%-13.6%. The increase in AUC was not proportional to the oral doses, suggesting non-linearity. In silico prediction of oral absorption also demonstrated low DBM absorption in vivo. An oil-in-water nanoemulsion containing DBM was formulated to potentially overcome the low F* due to poor water solubility of DBM, with enhanced oral absorption. Finally, to examine the role of Nrf2 on the pharmacokinetics of DBM, since DBM activates the Nrf2-dependent detoxification pathways, Nrf2 wild-type (+/+) mice and Nrf2 knockout (-/-) mice were utilized. There was an increased systemic plasma exposure of DBM in Nrf2 (-/-) mice, suggesting that the Nrf2 genotype could also play a role in the pharmacokinetic disposition of DBM. Taken together, the results show that DBM has low oral bioavailability which could be due in part to poor water solubility and this could be overcome by a nanotechnology-based drug delivery system and furthermore the Nrf2 genotype could also play a role in the pharmacokinetics of DBM. Copyright © 2010 John Wiley & Sons, Ltd.

Peptides: important tools for the treatment of central nervous system disorders.

PubMed

Malavolta, Luciana; Cabral, Francisco Romero

2011-10-01

This review shows some classical applications of peptides and suggests there is great promise for the treatment of various central nervous system diseases. Actually, peptides are considered the new generation of biologically active tools because they are key regulators in cellular and intercellular physiological responses, which possess enormous potential for the treatment of various diseases. In spite of their clinical potential, native peptides have seen limited use due to their poor bioavailability and low stability in physiological conditions. Moreover, most peptide or protein pharmaceuticals currently in use are delivered by invasive routes such as via subcutaneous injection. Considerable efforts have been made to design new drugs based on peptides and recent developments in technology and science have provided the means and opportunity to produce a stable as well as controlled-release form of peptide and protein drugs to combat poorly controlled diseases and to increase patients' quality of life. A major challenge in this regard, however, is the delivery of peptides over the blood-brain barrier. This review gives an overview of some strategies used to improve both bioavailability and uptake of peptide drugs for delivery into the brain. Indeed, recent findings suggest that the use of peptides by conjugation to a polymer such as nanoparticles can offer tremendous hope in the treatment of brain disorders. The polymer conjugation improves pharmacokinetics by increasing the molecular mass of proteins and peptides and shielding them from proteolytic enzymes. These new strategies will create new opportunities for the future development of neurotherapeutic drugs. In the present review we have focused our attention on the peptide controlled delivery, summarizing literature reports on the use of peptides and nanotechnology for the treatment and diagnosis of brain disorders. Copyright © 2011 Elsevier Ltd. All rights reserved.

Nanotechnology-based drug delivery systems for the treatment of Alzheimer’s disease

PubMed Central

Fonseca-Santos, Bruno; Gremião, Maria Palmira Daflon; Chorilli, Marlus

2015-01-01

Alzheimer’s disease is a neurological disorder that results in cognitive and behavioral impairment. Conventional treatment strategies, such as acetylcholinesterase inhibitor drugs, often fail due to their poor solubility, lower bioavailability, and ineffective ability to cross the blood–brain barrier. Nanotechnological treatment methods, which involve the design, characterization, production, and application of nanoscale drug delivery systems, have been employed to optimize therapeutics. These nanotechnologies include polymeric nanoparticles, solid lipid nanoparticles, nanostructured lipid carriers, microemulsion, nanoemulsion, and liquid crystals. Each of these are promising tools for the delivery of therapeutic devices to the brain via various routes of administration, particularly the intranasal route. The objective of this study is to present a systematic review of nanotechnology-based drug delivery systems for the treatment of Alzheimer’s disease. PMID:26345528

Poor digestibility of fully hydrogenated soybean oil in rats: a potential benefit of hydrogenated fats and oils.

PubMed

Kaplan, R J; Greenwood, C E

1998-05-01

The digestibility and absorption of dietary triacylglycerols are dependent on a number of factors including their fatty acid profile. Data demonstrating poor bioavailability of dietary stearic acid would suggest that hydrogenated oil sources would have lower digestibility coefficients compared with their native oils. To test this hypothesis, postweanling rats were fed one of four diets, formulated to contain 40% of energy as fat (assuming complete bioavailability), for 14 d. The diets only differed by fat type, containing soybean oil (SBO), fully hydrogenated soybean oil (HSB), medium-chain triglyceride oil (MCT), or hydrogenated coconut oil (HCO). Rats fed HSB consumed more food during the last 6 d (155.2 +/- 2.7 g) than those in each of the other groups (MCT: 118.9 +/- 2. 2 g; HCO: 124.7 +/- 3.2 g; SBO: 123.8 +/- 2.3 g), yet, they did not gain more weight. Two-day fecal excretion was almost three times greater in HSB-fed rats than in rats fed any other diet (P < 0.0001) because HSB was very poorly available. The digestibility coefficients (a measure of bioavailability) of the four fats were: HSB (30.9 +/- 1.3%) < HCO (94.5 +/- 0.4%) < SBO (97.0 +/- 0.4%) < MCT (98.7 +/- 0.2%) (P < 0.0007). All rats compensated for the incomplete availability of the fats, as apparent absorbable energy consumed did not differ among diet groups. The present data suggest that HSB only contributes 11.6 kJ/g (most fats contribute approximately 37.7 kJ/g) and that not only manufactured fat substitutes, such as olestra, but also more conventional fats are incompletely available to the body. Foods that currently contain HSB may contribute much less utilizable fat and energy than presently realized.

Preparation of Spray-Dried Soy Isoflavone-Loaded Gelatin Microspheres for Enhancement of Dissolution: Formulation, Characterization and in Vitro Evaluation

PubMed Central

Panizzon, Gean Pier; Bueno, Fernanda Giacomini; Ueda-Nakamura, Tânia; Nakamura, Celso Vataru; Dias Filho, Benedito Prado

2014-01-01

The most bioactive soy isoflavones (SI), daidzein (DAI) and genistein (GEN) have poor water solubility, which reduces their bioavailability and health benefits and limits their use in industry. The goal of this study was to develop and characterize a new gelatin matrix to microencapsulate DAI and GEN from soy extract (SE) by spray drying, in order to obtain solid dispersions to overcome solubility problems and to allow controlled release. The influences of 1:2 (MP2) and 1:3 (MP3) SE/polymer ratios on the solid state, yield, morphology, encapsulation efficiency, particle size distribution, release kinetics and cumulative release were evaluated. Analyses showed integral microparticles and high drug content. MP3 and MP2 yield were 43.6% and 55.9%, respectively, with similar mean size (p > 0.05), respectively. X-ray diffraction revealed the amorphous solid state of SE. In vitro release tests showed that dissolution was drastically increased. The results indicated that SE microencapsulation might offer a good system to control SI release, as an alternative to improve bioavailability and industrial applications. PMID:25494200

Furosemide Loaded Silica-Lipid Hybrid Microparticles: Formulation Development, in vitro and ex vivo Evaluation.

PubMed

Sambaraj, Swapna; Ammula, Divya; Nagabandi, Vijaykumar

2015-09-01

The main objective of the current research work was to formulate and evaluate furosemide loaded silica lipid hybrid microparticles for improved oral delivery. A novel silica-lipid hybrid microparticulate system is used for enhancing the oral absorption of low solubility and low permeability of (BCS Class IV) drugs. Silica-lipid hybrid microparticles include the drug solubilising effect of dispersed lipids and stabilizing effect of hydrophilic silica particles to increase drug solubilisation, which leads to enhanced oral bioavailability. The slica lipid hybrid (SLH) microparticles were composed of poorly soluble drug (furosemide), dispersion of oil phase (Soya bean oil and miglyol) in lecithin (Phospholipoid 90H), non-ionic surfactant (Polysorbate 80) and adsorbent (Aerosol 380). Saturation solubility studies were performed in different oils and surfactants with increased concentration of drug revealed increased solubility of furosemide. In vitro dissolution studies conducted under simulated gastric medium revealed 2-4 fold increase in dissolution efficiencies for SLH microparticles compared to that of pure drug (furosemide) and marketed formulation Lasix®. Ex vivo studies showed enhanced lipid digestibility, which improved drug permeability. Solid-state characterization of SLH microparticles by X-ray powder diffraction and Fourier transform infrared spectroscopic analysis confirmed non-crystalline nature and more compatibility of furosemide in silica-lipid hybrid microparticles. It can be concluded that the role of lipids and hydrophilic silica based carrier highlighted in enhancing solubility and permeability, and hence the oral bioavailability of poorly soluble drugs.

Furosemide Loaded Silica-Lipid Hybrid Microparticles: Formulation Development, in vitro and ex vivo Evaluation

PubMed Central

Sambaraj, Swapna; Ammula, Divya; Nagabandi, Vijaykumar

2015-01-01

Purpose: The main objective of the current research work was to formulate and evaluate furosemide loaded silica lipid hybrid microparticles for improved oral delivery. A novel silica-lipid hybrid microparticulate system is used for enhancing the oral absorption of low solubility and low permeability of (BCS Class IV) drugs. Silica-lipid hybrid microparticles include the drug solubilising effect of dispersed lipids and stabilizing effect of hydrophilic silica particles to increase drug solubilisation, which leads to enhanced oral bioavailability. Methods: The slica lipid hybrid (SLH) microparticles were composed of poorly soluble drug (furosemide), dispersion of oil phase (Soya bean oil and miglyol) in lecithin (Phospholipoid 90H), non-ionic surfactant (Polysorbate 80) and adsorbent (Aerosol 380). Saturation solubility studies were performed in different oils and surfactants with increased concentration of drug revealed increased solubility of furosemide. Results: In vitro dissolution studies conducted under simulated gastric medium revealed 2-4 fold increase in dissolution efficiencies for SLH microparticles compared to that of pure drug (furosemide) and marketed formulation Lasix®. Ex vivo studies showed enhanced lipid digestibility, which improved drug permeability. Solid-state characterization of SLH microparticles by X-ray powder diffraction and Fourier transform infrared spectroscopic analysis confirmed non-crystalline nature and more compatibility of furosemide in silica-lipid hybrid microparticles. Conclusion: It can be concluded that the role of lipids and hydrophilic silica based carrier highlighted in enhancing solubility and permeability, and hence the oral bioavailability of poorly soluble drugs. PMID:26504763

Albendazole Microcrystal Formulations Based on Chitosan and Cellulose Derivatives: Physicochemical Characterization and In Vitro Parasiticidal Activity in Trichinella spiralis Adult Worms.

PubMed

Priotti, Josefina; Codina, Ana V; Leonardi, Darío; Vasconi, María D; Hinrichsen, Lucila I; Lamas, María C

2017-05-01

The oral route has notable advantages to administering dosage forms. One of the most important questions to solve is the poor solubility of most drugs which produces low bioavailability and delivery problems, a major challenge for the pharmaceutical industry. Albendazole is a benzimidazole carbamate extensively used in oral chemotherapy against intestinal parasites, due to its extended spectrum activity and low cost. Nevertheless, the main disadvantage is the poor bioavailability due to its very low solubility in water. The main objective of this study was to prepare microcrystal formulations by the bottom-up technology to increase albendazole dissolution rate, in order to enhance its antiparasitic activity. Thus, 20 novel microstructures based on chitosan, cellulose derivatives, and poloxamer as a surfactant were produced and characterized by their physicochemical properties and in vitro biological activity. To determine the significance of type and concentration of polymer, and presence or absence of surfactant in the crystals, the variables area under the curve, albendazole microcrystal solubility, and drug released (%) at 30 min were analyzed with a three-way ANOVA. This analysis indicated that the microcrystals made with hydroxyethylcellulose or chitosan appear to be the best options to optimize oral absorption of the active pharmaceutical ingredient. The in vitro evaluation of anthelmintic activity on adult forms of Trichinella spiralis identified system S10A as the most effective, of choice for testing therapeutic efficacy in vivo.

Enhancement of bioavailability of ketoprofen using dry elixir as a novel dosage form.

PubMed

Ahn, H J; Kim, K M; Kim, C K

1998-07-01

To enhance the dissolution rate and bioavailability of poorly water-soluble ketoprofen, a novel oral dosage form of ketoprofen, termed ketoprofen dry elixir, was developed by the spray-drying technique. Ketoprofen, dextrin, and sodium lauryl sulfate were dissolved in an ethanol-water mixture (20:25 w/w) and thereafter spray-dried to form the ketoprofen dry elixir. Comparative studies on the in vitro dissolution and in vivo adsorption of ketoprofen in the form of dry elixir and powder were carried out. Ketoprofen in the dry elixir completely dissolved within 5 min. On the other hand, only about 50.1% of ketoprofen powder alone dissolved during 60 min. The initial dissolution rate of ketoprofen in the dry elixir markedly increased in distilled water at 37 degrees C, becoming fourfold higher than that of ketoprofen powder alone. The maximal plasma concentration of ketoprofen (Cmax) and the area under the concentration-time curve from zero to 8 hr (AUC0-8 hr) after the oral administration of dry elixir increased about 3.2- (24.6 versus 7.6 micrograms/ml) and 2.2-(38.4 versus 17.3 micrograms hr/ml) fold compared with powder alone. It was obvious that ketoprofen dry elixir might be a useful solid dosage form to improve the dissolution rate and bioavailability of poorly water-soluble ketoprofen.

Studies on the bioavailability of the provitamin A carotenoid, beta-carotene, using human exfoliated colonic epithelial cells.

PubMed

Gireesh, T; Nair, P P; Sudhakaran, P R

2004-08-01

The possibility of using exfoliated colonic epithelial cells for assessing the bioavailability of beta-carotene was examined. Analysis of exfoliated colonic epithelial cells showed the presence of beta-carotene and vitamin A. The beta-carotene content was significantly lower in cells from stool samples of subjects on a beta-carotene-poor diet than those receiving a single dose of a beta-carotene supplement. Colonic epithelial cells isolated from stool samples collected daily during a wash-out period while the subjects were on a beta-carotene-poor diet showed a steady decrease in beta-carotene content, reaching the lowest value on day 7. Kinetic analysis showed that a single dose of a beta-carotene supplement in the form of spirulina (Spirulina platensis) or agathi (Sesbania grandiflora) after the wash-out period caused an increase in the beta-carotene content after a lag period of 5-7 d, but the vitamin A levels during these periods were not significantly affected. Analysis of plasma beta-carotene concentration also showed similar changes, which correlated with those of exfoliated colonic cells. A relationship between the beta-carotene content of the diet and that of the colonic epithelial cells suggests that analysis of the beta-carotene content in exfoliated human colonic epithelial cells is a useful non-invasive method to assess the bioavailability of provitamin A beta-carotene.

Ocular delivery systems for topical application of anti-infective agents.

PubMed

Duxfield, Linda; Sultana, Rubab; Wang, Ruokai; Englebretsen, Vanessa; Deo, Samantha; Rupenthal, Ilva D; Al-Kassas, Raida

2016-01-01

For the treatment of anterior eye segment infections using anti-infective agents, topical ocular application is the most convenient route of administration. However, topical delivery of anti-infective agents is associated with a number of problems and challenges owing to the unique structure of the eye and the physicochemical properties of these compounds. Topical ocular drug delivery systems can be classified into two forms: conventional and non-conventional. The efficacy of conventional ocular formulations is limited by poor corneal retention and permeation resulting in low ocular bioavailability. Recently, attention has been focused on improving topical ocular delivery of anti-infective agents using advanced drug delivery systems. This review will focus on the challenges of efficient topical ocular delivery of anti-infective agents and will discuss the various types of delivery systems used to improve the treatment anterior segment infections.

Effects of clay minerals and organic matter in formulated sediments on the bioavailability of sediment-associated uranium to the freshwater midge, Chironomus dilutus.

PubMed

Crawford, Sarah E; Liber, Karsten

2015-11-01

It is well established that bioavailability influences metal toxicity in aquatic ecosystems. However, the factors and mechanisms that influence uranium (U) bioavailability and toxicity in sediment have not been thoroughly evaluated, despite evidence that suggests different sediment components can influence the sorption and interaction of some metals. Given that dissolved U is generally accepted as being the primary bioavailable fraction of U, it is hypothesized that adsorption and interaction of U with different sediment components will influence the bioavailability of U in sediment. We investigated the effects of key sediment physicochemical properties on the bioavailability of U to a model freshwater benthic invertebrate, Chironomus dilutus. Several 10-day spiked sediment bioaccumulation experiments were performed, exposing C. dilutus larvae to a variety of formulated sediments spiked with different concentrations of U (5, 50 and/or 200 mg U/kg d.w.). Mean accumulation of U in C. dilutus larvae decreased significantly from 1195 to 10 mg U/kg d.w. as kaolin clay content increased from 0% to 60% in sediment spiked with 50 mg U/kg d.w. Similarly, higher organic matter content also resulted in a significant reduction of U bioaccumulation in C. dilutus larvae, indicating a reduction in U bioavailability. Concentrations of U in both the overlying water and sediment pore water displayed a strong positive relationship to U bioaccumulation in C. dilutus larvae (r(2) = 0.77, p<0.001 and r(2) = 0.57, p < 0.001, respectively) for all experiments, while total U concentrations in the sediment had a poor relationship to U bioaccumulation (r(2) = 0.10, p = 0.028). Results from this research confirm that sediment clay and organic matter content play a significant role in altering U bioavailability, which is important in informing risk assessments of U contaminated sites and in the development of site-specific sediment quality guidelines for U. Copyright © 2015 Elsevier B.V. All rights reserved.

Bioavailability of rifampicin following concomitant administration of ethambutol or isoniazid or pyrazinamide or a combination of the three drugs.

PubMed

Immanuel, Chandra; Gurumurthy, Prema; Ramachandran, Geetha; Venkatesan, P; Chandrasekaran, V; Prabhakar, R

2003-09-01

Poor bioavailability of rifampicin (R) in combination with other anti-tuberculosis drugs such as isoniazid (H), pyrazinamide (Z), and ethambutol (E) is a subject of much concern for the last few decades. This could be due to an interaction between R and other drugs. An investigation was therefore undertaken to examine the bioavailability of R in the presence of H, Z and E or a combination of the three drugs. The study included eight healthy volunteers, each being investigated on four occasions at weekly intervals once with R alone and with three of the four combinations on the three remaining occasions. A partially balanced incomplete block design was employed and the allocation of R or the drug combinations was random. Plasma concentrations of R at intervals up to 12 h were determined by microbiological assay using Staphylococcus aureus as the test organism. The proportion (%) dose of R as R plus desacetyl R (DR) in urine excreted over the periods 0-8 and 8-12 h was also determined. Bioavailability was expressed as an index (BI) of area under time concentration curve (AUC) calculated from the plasma concentrations or proportion of dose of R excreted as R plus DR in urine with the combinations to that with R alone. The bioavailability indices based on AUC were 0.96 with RE, 0.76 with RH, 1.08 with RZ and 0.65 with REHZ. The indices based on urine estimations (0-8 h) were similar, the values being 0.94, 0.84, 0.94 and 0.75, respectively. A second investigation revealed that the decrease of bioavailability of R with H was not due to the excipients present in H tablets. Isoniazid alone or in combination with E and Z reduces the bioavailability of R. Urinary excretion data offer a simple and non invasive method for the assessment of bioavailability of R.

Use of nanotechnology for improved pharmacokinetics and activity of immunogenic cell death inducers used in cancer chemotherapy.

PubMed

Janicka, Martyna; Gubernator, Jerzy

2017-09-01

Immunogenic cell death inducers (ICD inducers) are a diverse group of therapeutic molecules capable of eliciting an adaptive immune response against the antigens present on the surface of dying cancer cells. Most of these molecules suffer from low bioavailability, high toxicity and poor pharmacokinetics which limit their application. It is believed that nanotechnology, in particular nano-sized nanocarriers, can address most of the issues that limit the use of ICD inducers. Area covered: The mechanism of action of ICD inducers and their limitations is discussed. In addition, we cover the novel possibilities arising from the use of nanotechnology to improve delivery of ICD inducers to the target tissue as well as the restrictions of modern nanotechnology. Expert opinion: At present, nanocarrier formulations suffer from low bioavailability, poor pharmacokinetics and stability issues. Nonetheless, there is a tremendous future for combinatorial immune-pharmacological treatments of human tumors based on nanocarrier delivery of ICD inducers.

A polymeric nanoparticle formulation of curcumin (NanoCurc™) ameliorates CCl4-induced hepatic injury and fibrosis through reduction of pro-inflammatory cytokines and stellate cell activation

PubMed Central

Bisht, Savita; Khan, Mehtab A; Bekhit, Mena; Bai, Haibo; Cornish, Toby; Mizuma, Masamichi; Rudek, Michelle A; Zhao, Ming; Maitra, Amarnath; Ray, Balmiki; Lahiri, Debomoy; Maitra, Anirban; Anders, Robert A

2012-01-01

Plant-derived polyphenols such as curcumin hold promise as a therapeutic agent in the treatment of chronic liver diseases. However, its development is plagued by poor aqueous solubility resulting in poor bioavailability. To circumvent the suboptimal bioavailability of free curcumin, we have developed a polymeric nanoparticle formulation of curcumin (NanoCurc™) that overcomes this major pitfall of the free compound. In this study, we show that NanoCurc™ results in sustained intrahepatic curcumin levels that can be found in both hepatocytes and non-parenchymal cells. NanoCurc™ markedly inhibits carbon tetrachloride-induced liver injury, production of pro-inflammatory cytokines and fibrosis. It also enhances antioxidant levels in the liver and inhibits pro-fibrogenic transcripts associated with activated myofibroblasts. Finally, we show that NanoCurc™ directly induces stellate cell apoptosis in vitro. Our results suggest that NanoCurc™ might be an effective therapy for patients with chronic liver disease. PMID:21691262

Impact of gastrointestinal lipolysis on oral lipid-based formulations and bioavailability of lipophilic drugs.

PubMed

Carrière, Frédéric

2016-06-01

Oil-in-water emulsions are common vehicles for lipids as nutrients and for the delivery of poorly water-soluble drugs. Enhancing oral bioavailability of these drugs using lipid-based formulations (LBF) or self-emulsifying drug delivery systems is one of the current challenges in pharmaceutical industry. Many of the compounds found in LBF (acylglycerols, surfactants with esterified fatty acids, …) are however potential substrates for digestive enzymes. Their digestion (or lipolysis) in the gastrointestinal (GI) tract is critical for drug dissolution and absorption: it can be beneficial (drug solubilization/dispersion) or deleterous (drug precipitation) depending on the drug-LBF association. A better understanding of the fate of LBF in the GI tract is therefore required to engineer efficient lipid-based drug delivery systems. In vitro models for testing simultaneously LBF digestion and drug dispersion are in development to predict drug solubilization and bioavailability, select the best drug-LBF association and obtain better in vitro-in vivo correlations. So far, research in this area has focused on LBF lipolysis under intestinal conditions because the small intestine is the main target for drug delivery and absorption, as well as the main site of digestion by pancreatic enzymes. Lipolysis however starts within the stomach through the action of gastric lipase, the first enzyme involved in fat digestion in humans. In vitro digestion experiments show that most LBFs are submitted to gastric lipolysis, and therefore, both intragastric and intestinal digestions are critical for the fate of LBF and drug solubility. Copyright © 2015 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

PEG-lipid-PLGA hybrid nanoparticles loaded with berberine-phospholipid complex to facilitate the oral delivery efficiency.

PubMed

Yu, Fei; Ao, Mingtao; Zheng, Xiao; Li, Nini; Xia, Junjie; Li, Yang; Li, Donghui; Hou, Zhenqing; Qi, Zhongquan; Chen, Xiao Dong

2017-11-01

The natural product berberine (BBR), present in various plants, arouses great interests because of its numerous pharmacological effects. However, the further development and application of BBR had been hampered by its poor oral bioavailability. In this work, we report on polymer-lipid hybrid nanoparticles (PEG-lipid-PLGA NPs) loaded with BBR phospholipid complex using a solvent evaporation method for enhancing the oral BBR efficiency. The advantage of this new drug delivery system is that the BBR-soybean phosphatidylcholine complex (BBR-SPC) could be used to enhance the liposolubility of BBR and improve the affinity with the biodegradable polymer to increase the drug-loading capacity and controlled/sustained release. The entrapment efficiency of the PEG-lipid-PLGA NPs/BBR-SPC was observed to approach approximately 89% which is more than 2.4 times compared with that of the PEG-lipid-PLGA NPs/BBR. To the best of our knowledge, this is the first report on using polymer material for effective encapsulation of BBR to improve its oral bioavailability. The prepared BBR delivery systems demonstrated a uniform spherical shape, a well-dispersed core-shell structure and a small particle size (149.6 ± 5.1 nm). The crystallographic and thermal analysis has indicated that the BBR dispersed in the PEG-lipid-PLGA NPs matrix is in an amorphous form. More importantly, the enhancement in the oral relative bioavailability of the PEG-lipid-PLGA NPs/BBR-SPC was ∼343% compared with that of BBR. These positive results demonstrated that PEG-lipid-PLGA NPs/BBR-SPC may have the potential for facilitating the oral drug delivery of BBR.

Improved intestinal absorption of a poorly water-soluble oral drug using mannitol microparticles containing a nanosolid drug dispersion.

PubMed

Nishino, Yukiko; Kubota, Aya; Kanazawa, Takanori; Takashima, Yuuki; Ozeki, Tetsuya; Okada, Hiroaki

2012-11-01

A nozzle for a spray dryer that can prepare microparticles of water-soluble carriers containing various nanoparticles in a single step was previously developed in our laboratory. To enhance the solubility and intestinal absorption of poorly water-soluble drugs, we used probucol (PBL) as a poorly water-soluble drug, mannitol (MAN) as a water-soluble carrier for the microparticles, and EUDRAGIT (EUD) as a polymer vehicle for the solid dispersion. PBL-EUD-acetone-methanol and aqueous MAN solutions were simultaneously supplied through different liquid passages of the spray nozzle and dried together. PBL-EUD solid dispersion was nanoprecipitated in the MAN solution using an antisolvent mechanism and rapidly dried by surrounding it with MAN. PBL in the dispersion vehicle was amorphous and had higher physical stability according to powder X-ray diffraction and differential scanning calorimetry analysis. The bioavailability of PBL in PBL-EUD S-100-MAN microparticles after oral administration in rats was markedly higher (14- and 6.2-fold, respectively) than that of the original PBL powder and PBL-MAN microparticles. These results demonstrate that the composite microparticles containing a nanosized solid dispersion of a poorly water-soluble drug prepared using the spray nozzle developed by us should be useful to increase the solubility and bioavailability of drugs after oral administration. Copyright © 2012 Wiley Periodicals, Inc.

Impact of polymer type on bioperformance and physical stability of hot melt extruded formulations of a poorly water soluble drug.

PubMed

Mitra, Amitava; Li, Li; Marsac, Patrick; Marks, Brian; Liu, Zhen; Brown, Chad

2016-05-30

Amorphous solid dispersion formulations have been widely used to enhance bioavailability of poorly soluble drugs. In these formulations, polymer is included to physically stabilize the amorphous drug by dispersing it in the polymeric carrier and thus forming a solid solution. The polymer can also maintain supersaturation and promote speciation during dissolution, thus enabling better absorption as compared to crystalline drug substance. In this paper, we report the use of hot melt extrusion (HME) to develop amorphous formulations of a poorly soluble compound (FaSSIF solubility=1μg/mL). The poor solubility of the compound and high dose (300mg) necessitated the use of amorphous formulation to achieve adequate bioperformance. The effect of using three different polymers (HPMCAS-HF, HPMCAS-LF and copovidone), on the dissolution, physical stability, and bioperformance of the formulations was demonstrated. In this particular case, HPMCAS-HF containing HME provided the highest bioavailability and also had better physical stability as compared to extrudates using HPMCAS-LF and copovidone. The data demonstrated that the polymer type can have significant impact on the formulation bioperformance and physical stability. Thus a thorough understanding of the polymer choice is imperative when designing an amorphous solid dispersion formulation, such that the formulation provides robust bioperformance and has adequate shelf life. Copyright © 2016 Elsevier B.V. All rights reserved.

Mesoporous Silica Molecular Sieve based Nanocarriers: Transpiring Drug Dissolution Research.

PubMed

Pattnaik, Satyanarayan; Pathak, Kamla

2017-01-01

Improvement of oral bioavailability through enhancement of dissolution for poorly soluble drugs has been a very promising approach. Recently, mesoporous silica based molecular sieves have demonstrated excellent properties to enhance the dissolution velocity of poorly water-soluble drugs. Current research in this area is focused on investigating the factors influencing the drug release from these carriers, the kinetics of drug release and manufacturing approaches to scale-up production for commercial manufacture. This comprehensive review provides an overview of different methods adopted for synthesis of mesoporous materials, influence of processing factors on properties of these materials and drug loading methods. The drug release kinetics from mesoporous silica systems, the manufacturability and stability of these formulations are reviewed. Finally, the safety and biocompatibility issues related to these silica based materials are discussed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Self-emulsifying drug delivery systems (SEDDS): formulation development, characterization, and applications.

PubMed

Singh, Bhupinder; Bandopadhyay, Shantanu; Kapil, Rishi; Singh, Ramandeep; Katare, O

2009-01-01

Self-emulsifying drug delivery systems (SEDDS) possess unparalleled potential in improving oral bioavailability of poorly water-soluble drugs. Following their oral administration, these systems rapidly disperse in gastrointestinal fluids, yielding micro- or nanoemulsions containing the solubilized drug. Owing to its miniscule globule size, the micro/nanoemulsifed drug can easily be absorbed through lymphatic pathways, bypassing the hepatic first-pass effect. We present an exhaustive and updated account of numerous literature reports and patents on diverse types of self-emulsifying drug formulations, with emphasis on their formulation, characterization, and systematic optimization strategies. Recent advancements in various methodologies employed to characterize their globule size and shape, ability to encapsulate the drug, gastrointestinal and thermodynamic stability, rheological characteristics, and so forth, are discussed comprehensively to guide the formula-tor in preparing an effective and robust SEDDS formulation. Also, this exhaustive review offers an explicit discussion on vital applications of the SEDDS in bioavailability enhancement of various drugs, outlining an overview on myriad in vitro, in situ, and ex vivo techniques to assess the absorption and/ or permeation potential of drugs incorporated in the SEDDS in animal and cell line models, and the subsequent absorption pathways followed by them. In short, the current article furnishes an updated compilation of wide-ranging information on all the requisite vistas of the self-emulsifying formulations, thus paving the way for accelerated progress into the SEDDS application in pharmaceutical research.

Enhancement of the dissolution rate and bioavailability of fenofibrate by a melt-adsorption method using supercritical carbon dioxide

PubMed Central

Cha, Kwang-Ho; Cho, Kyung-Jin; Kim, Min-Soo; Kim, Jeong-Soo; Park, Hee Jun; Park, Junsung; Cho, Wonkyung; Park, Jeong-Sook; Hwang, Sung-Joo

2012-01-01

Background: The aim of this study was to enhance the bioavailability of fenofibrate, a poorly water-soluble drug, using a melt-adsorption method with supercritical CO2. Methods: Fenofibrate was loaded onto Neusilin® UFL2 at different weight ratios of fenofibrate to Neusilin UFL2 by melt-adsorption using supercritical CO2. For comparison, fenofibrate-loaded Neusilin UFL2 was prepared by solvent evaporation and hot melt-adsorption methods. The fenofibrate formulations prepared were characterized by differential scanning calorimetry, powder x-ray diffractometry, specific surface area, pore size distribution, scanning electron microscopy, and energy-dispersive x-ray spectrometry. In vitro dissolution and in vivo bioavailability were also investigated. Results: Fenofibrate was distributed into the pores of Neusilin UFL2 and showed reduced crystal formation following adsorption. Supercritical CO2 facilitated the introduction of fenofibrate into the pores of Neusilin UFL2. Compared with raw fenofibrate, fenofibrate from the prepared powders showed a significantly increased dissolution rate and better bioavailability. In particular, the area under the drug concentration-time curve and maximal serum concentration of the powders prepared using supercritical CO2 were 4.62-fold and 4.52-fold greater than the corresponding values for raw fenofibrate. Conclusion: The results of this study highlight the usefulness of the melt-adsorption method using supercritical CO2 for improving the bioavailability of fenofibrate. PMID:23118538

Influence of topical anesthesia on tear dynamics and ocular drug bioavailability in albino rabbits.

PubMed

Patton, T F; Robinson, J R

1975-02-01

The bioavailability of topically applied ocular drugs is very poor, due largely to drug loss through drainage and tear turnover. The use of high viscosity solutions or solid matrixes to delay or eliminate drainage is the usual approach for decreasing drug loss but the alternative approach of chemically reducing tear turnover and/or solution drainage has not been investigated. By means of a simple isotopic dilution technique, using radioactive technetium sulfur colloid, the quantitative influence of topical anesthetics on tear production and instilled solution drainage was determined. The reduction in the rate of tear turnover and solution drainage varies for different anesthetics and is dose dependent. The implication of these results for some long accepted clinical procedures is discussed, and questions are raised regarding the present understanding of the mechanisms of tear production. Quantitation of precorneal drug loss through instilled solution drainage and tear turnover permits the establishment of a baseline for ocular drug bioavailability. Aqueous humor drug concentration versus time profiles of radioactive pilocarpine nitrate were obtained, both in the presence and absence of topical anesthesia. The results verify the importance of tear turnover and instilled solution drainage as a major route of drug loss in the eye. Moreover, the success of the present study in improving ocular drug bioavailability by the chemical approach of repressing solution drainage and tear turnover suggests that this approach is viable for improving drug bioavailability.

Soya phospholipid complex of mangiferin enhances its hepatoprotectivity by improving its bioavailability and pharmacokinetics.

PubMed

Bhattacharyya, Sauvik; Ahmmed, Sk Milan; Saha, Bishnu Pada; Mukherjee, Pulok K

2014-05-01

Mangiferin is a xanthonoid present in Mangifera indica. It has been reported for a variety of pharmacological activities, including hepatoprotection. However, the major disadvantage of mangiferin is its reduced biological activity due to poor absorption, low bioavailability and rapid elimination from the body after administration. The aim of this study was to prepare a phospholipid complex of mangiferin to overcome these limitations and to investigate the impact of the complex on hepatoprotective activity and bioavailability. The results showed that the complex has an enhanced hepatoprotective and in vivo antioxidant activity as compared to pure mangiferin at the same dose level (30 and 60 mg kg⁻¹). The complex restored the levels of serum hepatic marker enzymes and liver antioxidant enzymes with respect to carbon tetrachloride-treated animals. The complex also increased the bioavailability of mangiferin in rat serum by 9.75-fold compared to pure mangiferin at the same dose level and enhanced the elimination half-life (t(1/2 el)) from 1.71 ± 0.12 h⁻¹ to 3.52 ± 0.27 h⁻¹. The results suggested that the complexation of mangiferin with soya phospholipid enhanced the hepatoprotection and in vivo antioxidant activity, which may be due to the improved bioavailability and pharmacokinetics of mangiferin in rat serum. © 2013 Society of Chemical Industry.

Effect of amphiphilic graft co-polymer-carrier on physical stability of bosentan nanocomposite: Assessment of solubility, dissolution and bioavailability.

PubMed

Kendre, Prakash N; Chaudhari, Pravin D

2018-05-01

Bosentan is a dual endothelin receptor antagonist used in the treatment of pulmonary arterial hypertension (PAH). But the solubility and bioavailability of this drug are poor, which has restricted the design and development of dosage forms for efficient and successful therapy. The present study was carried out to develop nanocomposites using an amphiphilic graft co-polymer (Soluplus®) as a carrier to enhance the solubility and bioavailability of bosentan. The graft co-polymer-based nanocomposite formulation was prepared using the single-emulsion technique. The nanocomposite was characterised in terms of particle size analysis, solubility, percentage entrapment efficiency, drug-loading capacity, surface morphology, drug content, in vitro dissolution, stability and bioavailability. FT-IR study revealed that there was no interaction between the drug and Soluplus®. DSC analysis of the nanocomposite formulation confirmed that the bosentan was completely encapsulated within a Soluplus®. XRD analysis showed that the drug was converted to an amorphous form irreversibly. SEM images showed that the particles were of size 96-129μm and had slightly smooth to rough textured surface. TEM analysis indicated that the diameters of the prepared bosentan nanocomposite after dispersion in distilled water were 13.69-96.78nm. Statistically significant increases in the solubility, dissolution and bioavailability of the drug were observed. It was confirmed that the use of a graft co-polymer carrier-based nanocomposite formulation is a good approach for efficient delivery of bosentan, the solubility and bioavailability being increased manifold. Copyright © 2017 Elsevier B.V. All rights reserved.

Curcumin Monoglucoside Shows Improved Bioavailability and Mitigates Rotenone Induced Neurotoxicity in Cell and Drosophila Models of Parkinson's Disease.

PubMed

Pandareesh, M D; Shrivash, M K; Naveen Kumar, H N; Misra, K; Srinivas Bharath, M M

2016-11-01

Curcumin (CUR), a dietary polyphenol has diverse pharmacologic effects, but is limited by poor bioavailability. This is probably due to decreased solubility, cellular uptake and stability. In order to enhance its solubility and bioavailability, we synthesized the CUR bioconjugate curcumin monoglucoside (CMG) and tested its bioavailability, neuroprotective and anti-apoptotic propensity against rotenone (ROT) induced toxicity in N27 dopaminergic neuronal cells and Drosophila models. Our results elucidate that CMG showed improved bioavailability than CUR in N27 cells. Pre-treatment with CMG protected against ROT neurotoxicity and exerted antioxidant effects by replenishing cellular glutathione levels and significantly decreasing reactive species. CMG pre-treatment also restored mitochondrial complex I and IV activities inhibited by ROT. ROT-induced nuclear damage was also restored by CMG as confirmed by comet assay. CMG induced anti-apoptotic effects was substantiated by decreased phosporylation of JNK3 and c-jun, which in turn decreased the cleavage of pro-caspase 3. Q-PCR analysis of redox genes showed up-regulation of NOS2 and down-regulation of NQO1 upon ROT exposure and this was attenuated by CMG pre-treatment. Studies in the Drosophila ROT model revealed that, CMG administration showed better survival rate and locomotor activity, improved antioxidant activity and dopamine content than ROT treated group and was comparable with the CUR group. Based on these data, we surmise that CMG has improved bioavailability and offered neuroprotection comparable with CUR, against ROT-induced toxicity both in dopaminergic neuronal cell line and Drosophila models, with therapeutic implications for PD.

Enhancement of oral bioavailability of anti-HIV drug rilpivirine HCl through nanosponge formulation.

PubMed

Zainuddin, Rana; Zaheer, Zahid; Sangshetti, Jaiprakash N; Momin, Mufassir

2017-12-01

To synthesize β cyclodextrin nanosponges using a novel and efficient microwave mediated method for enhancing bioavailability of Rilpivirine HCl (RLP). Belonging to BCS class II RLP has pH dependent solubility and poor oral bioavailability. However, a fatty meal enhances its absorption hence the therapy indicates that the dosage form be consumed with a meal. But then it becomes tedious and inconvenient to continue the therapy for years with having to face the associated gastric side effects such as nausea. Microwave synthesizer was used to mediate the poly-condensation reaction between β-cyclodextrin and cross-linker diphenylcarbonate. Critical parameters selected were polymer to cross-linker ratio, Watt power, reaction time and solvent volume. Characterization studies were performed using FTIR, DSC, SEM, 1 H-NMR and PXRD. Molecular modeling was applied to confirm the possibility of drug entrapment. In vitro drug dissolution followed by oral bioavailability studies was performed in Sprawley rats. Samples were analyzed using HPLC. Microwave synthesis yields para-crystalline, porous nanosponges (∼205 nm). Drug entrapment led to enhancement of solubility and a two-fold increase in drug dissolution (P < 0.001) following Higuchi release model. Enhanced oral bioavailability was observed in fasted Sprawley rats where C max and AUC 0-∞ increases significantly (C max of NS∼ 586 ± 5.91 ng/mL; plain RLP ∼310 ± 5. 74 ng/mL). The approach offers a comfortable dosing zone for AIDs patients, negating the requirement of consuming the formulation in a fed state due to enhancement in drugs' oral bioavailability.

Absolute bioavailability of evacetrapib in healthy subjects determined by simultaneous administration of oral evacetrapib and intravenous [13C8]‐evacetrapib as a tracer

PubMed Central

Aburub, Aktham; Ward, Chris; Hinds, Chris; Czeskis, Boris; Ruterbories, Kenneth; Suico, Jeffrey G.; Royalty, Jane; Ortega, Demetrio; Pack, Brian W.; Begum, Syeda L.; Annes, William F.; Lin, Qun; Small, David S.

2015-01-01

This open‐label, single‐period study in healthy subjects estimated evacetrapib absolute bioavailability following simultaneous administration of a 130‐mg evacetrapib oral dose and 4‐h intravenous (IV) infusion of 175 µg [13C8]‐evacetrapib as a tracer. Plasma samples collected through 168 h were analyzed for evacetrapib and [13C8]‐evacetrapib using high‐performance liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameter estimates following oral and IV doses, including area under the concentration‐time curve (AUC) from zero to infinity (AUC[0‐∞]) and to the last measureable concentration (AUC[0‐tlast]), were calculated. Bioavailability was calculated as the ratio of least‐squares geometric mean of dose‐normalized AUC (oral : IV) and corresponding 90% confidence interval (CI). Bioavailability of evacetrapib was 44.8% (90% CI: 42.2–47.6%) for AUC(0‐∞) and 44.3% (90% CI: 41.8–46.9%) for AUC(0‐tlast). Evacetrapib was well tolerated with no reports of clinically significant safety assessment findings. This is among the first studies to estimate absolute bioavailability using simultaneous administration of an unlabeled oral dose with a 13C‐labeled IV microdose tracer at about 1/1000th the oral dose, with measurement in the pg/mL range. This approach is beneficial for poorly soluble drugs, does not require additional toxicology studies, does not change oral dose pharmacokinetics, and ultimately gives researchers another tool to evaluate absolute bioavailability. PMID:26639670

Absolute bioavailability of evacetrapib in healthy subjects determined by simultaneous administration of oral evacetrapib and intravenous [(13) C8 ]-evacetrapib as a tracer.

PubMed

Cannady, Ellen A; Aburub, Aktham; Ward, Chris; Hinds, Chris; Czeskis, Boris; Ruterbories, Kenneth; Suico, Jeffrey G; Royalty, Jane; Ortega, Demetrio; Pack, Brian W; Begum, Syeda L; Annes, William F; Lin, Qun; Small, David S

2016-05-30

This open-label, single-period study in healthy subjects estimated evacetrapib absolute bioavailability following simultaneous administration of a 130-mg evacetrapib oral dose and 4-h intravenous (IV) infusion of 175 µg [(13) C8 ]-evacetrapib as a tracer. Plasma samples collected through 168 h were analyzed for evacetrapib and [(13) C8 ]-evacetrapib using high-performance liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameter estimates following oral and IV doses, including area under the concentration-time curve (AUC) from zero to infinity (AUC[0-∞]) and to the last measureable concentration (AUC[0-tlast ]), were calculated. Bioavailability was calculated as the ratio of least-squares geometric mean of dose-normalized AUC (oral : IV) and corresponding 90% confidence interval (CI). Bioavailability of evacetrapib was 44.8% (90% CI: 42.2-47.6%) for AUC(0-∞) and 44.3% (90% CI: 41.8-46.9%) for AUC(0-tlast ). Evacetrapib was well tolerated with no reports of clinically significant safety assessment findings. This is among the first studies to estimate absolute bioavailability using simultaneous administration of an unlabeled oral dose with a (13) C-labeled IV microdose tracer at about 1/1000(th) the oral dose, with measurement in the pg/mL range. This approach is beneficial for poorly soluble drugs, does not require additional toxicology studies, does not change oral dose pharmacokinetics, and ultimately gives researchers another tool to evaluate absolute bioavailability. © 2015 The Authors Journal of Labelled Compounds and Radiopharmaceuticals Published by John Wiley & Sons Ltd.

Kinetics of Substrate Biodegradation under the Cumulative Effects of Bioavailability and Self-Inhibition.

PubMed

Gharasoo, Mehdi; Centler, Florian; Van Cappellen, Philippe; Wick, Lukas Y; Thullner, Martin

2015-05-05

Microbial degradation is an important process in many environments controlling for instance the cycling of nutrients or the biodegradation of contaminants. At high substrate concentrations toxic effects may inhibit the degradation process. Bioavailability limitations of a degradable substrate can therefore either improve the overall dynamics of degradation by softening the contaminant toxicity effects to microorganisms, or slow down the biodegradation by reducing the microbial access to the substrate. Many studies on biodegradation kinetics of a self-inhibitive substrate have mainly focused on physiological responses of the bacteria to substrate concentration levels without considering the substrate bioavailability limitations rising from different geophysical and geochemical dynamics at pore-scale. In this regard, the role of bioavailability effects on the kinetics of self-inhibiting substrates is poorly understood. In this study, we theoretically analyze this role and assess the interactions between self-inhibition and mass transfer-limitations using analytical/numerical solutions, and show the findings practical relevance for a simple model scenario. Although individually self-inhibition and mass-transfer limitations negatively impact biodegradation, their combined effect may enhance biodegradation rates above a concentration threshold. To our knowledge, this is the first theoretical study describing the cumulative effects of the two mechanisms together.

Correlations between PAH bioavailability, degrading bacteria, and soil characteristics during PAH biodegradation in five diffusely contaminated dissimilar soils.

PubMed

Crampon, M; Bureau, F; Akpa-Vinceslas, M; Bodilis, J; Machour, N; Le Derf, F; Portet-Koltalo, F

2014-01-01

The natural biodegradation of seven polycyclic aromatic hydrocarbons (PAHs) by native microorganisms was studied in five soils from Normandy (France) from diffusely polluted areas, which can also pose a problem in terms of surfaces and amounts of contaminated soils. Bioavailability tests using cyclodextrin-based extractions were performed. The natural degradation of low molecular weight (LMW) PAHs was not strongly correlated to their bioavailability due to their sorption to geosorbents. Conversely, the very low degradation of high molecular weight (HMW) PAHs was partly correlated to their poor availability, due to their sorption on complexes of organic matter and kaolinites or smectites. A principal component analysis allowed us to distinguish between the respective degradation behaviors of LMW and HMW PAHs. LMW PAHs were degraded in less than 2-3 months and were strongly influenced by the relative percentage of phenanthrene-degrading bacteria over total bacteria in soils. HMW PAHs were not significantly degraded, not only because they were less bioavailable but also because of a lack of degrading microorganisms. Benzo[a]pyrene stood apart since it was partly degraded in acidic soils, probably because of a catabolic cooperation between bacteria and fungi.

Bioavailability and stability of erythromycin delayed release tablets.

PubMed

Ogwal, S; Xide, T U

2001-12-01

Erythromycin is available as the free base, ethylsuccinate, estolate, stearate, gluceptate, and lactobionate derivatives. When given orally erythromycin and its derivatives except the estolate are inactivated to some extent by the gastric acid and poor absorption may result. To establish whether delayed release erythromycin tablets meet the bioequivalent requirement for the market. Sectrophotometric analysis was used to determine the dissolution percentage of the tablets in vitro. High performance liquid chromatography and IBM/XT microcomputer was used to determine the bioavailability and pharmacokinetic parameters in vivo. Dissolution percentage in thirty minutes reached 28.9% and in sixty minutes erythromycin was completely released. The parameters of the delayed release tablets were Tlag 2.3 hr, Tmax.4.5 hr, and Cmax 2.123 g/ml Ka 0.38048 hr(-1) T (1/2) 1.8 hr, V*C/F 49.721 AUC 12.9155. The relative bioavailability of erythromycin delayed release tablet to erythromycin capsules was 105.31% The content, appearance, and dissolution bioavailability of delayed release erythromycin tablets conforms to the United States pharmacopoeia standards. The tablets should be stored in a cool and dry place in airtight containers and the shelf life is temporarily assigned two years.

Oral lipid-based nanoformulation of tafenoquine enhanced bioavailability and blood stage antimalarial efficacy and led to a reduction in human red blood cell loss in mice.

PubMed

Melariri, Paula; Kalombo, Lonji; Nkuna, Patric; Dube, Admire; Hayeshi, Rose; Ogutu, Benhards; Gibhard, Liezl; deKock, Carmen; Smith, Peter; Wiesner, Lubbe; Swai, Hulda

2015-01-01

Tafenoquine (TQ), a new synthetic analog of primaquine, has relatively poor bioavailability and associated toxicity in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals. A microemulsion formulation of TQ (MTQ) with sizes <20 nm improved the solubility of TQ and enhanced the oral bioavailability from 55% to 99% in healthy mice (area under the curve 0 to infinity: 11,368±1,232 and 23,842±872 min·μmol/L) for reference TQ and MTQ, respectively. Average parasitemia in Plasmodium berghei-infected mice was four- to tenfold lower in the MTQ-treated group. In vitro antiplasmodial activities against chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum indicated no change in half maximal inhibitory concentration, suggesting that the microemulsion did not affect the inherent activity of TQ. In a humanized mouse model of G6PD deficiency, we observed reduction in toxicity of TQ as delivered by MTQ at low but efficacious concentrations of TQ. We hereby report an enhancement in the solubility, bioavailibility, and efficacy of TQ against blood stages of Plasmodium parasites without a corresponding increase in toxicity.

Oral lipid-based nanoformulation of tafenoquine enhanced bioavailability and blood stage antimalarial efficacy and led to a reduction in human red blood cell loss in mice

PubMed Central

Melariri, Paula; Kalombo, Lonji; Nkuna, Patric; Dube, Admire; Hayeshi, Rose; Ogutu, Benhards; Gibhard, Liezl; deKock, Carmen; Smith, Peter; Wiesner, Lubbe; Swai, Hulda

2015-01-01

Tafenoquine (TQ), a new synthetic analog of primaquine, has relatively poor bioavailability and associated toxicity in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals. A microemulsion formulation of TQ (MTQ) with sizes <20 nm improved the solubility of TQ and enhanced the oral bioavailability from 55% to 99% in healthy mice (area under the curve 0 to infinity: 11,368±1,232 and 23,842±872 min·μmol/L) for reference TQ and MTQ, respectively. Average parasitemia in Plasmodium berghei-infected mice was four- to tenfold lower in the MTQ-treated group. In vitro antiplasmodial activities against chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum indicated no change in half maximal inhibitory concentration, suggesting that the microemulsion did not affect the inherent activity of TQ. In a humanized mouse model of G6PD deficiency, we observed reduction in toxicity of TQ as delivered by MTQ at low but efficacious concentrations of TQ. We hereby report an enhancement in the solubility, bioavailibility, and efficacy of TQ against blood stages of Plasmodium parasites without a corresponding increase in toxicity. PMID:25759576

Preclinical Bioavailability Strategy for Decisions on Clinical Drug Formulation Development: An In Depth Analysis.

PubMed

Van den Bergh, An; Van Hemelryck, Sandy; Bevernage, Jan; Van Peer, Achiel; Brewster, Marcus; Mackie, Claire; Mannaert, Erik

2018-06-11

The aim of the presented retrospective analysis was to verify whether a previously proposed Janssen Biopharmaceutical Classification System (BCS)-like decision tree, based on preclinical bioavailability data of a solution and suspension formulation, would facilitate informed decision making on the clinical formulation development strategy. In addition, the predictive value of (in vitro) selection criteria, such as solubility, human permeability, and/or a clinical dose number (Do), were evaluated, potentially reducing additional supporting formulation bioavailability studies in animals. The absolute ( F abs,sol ) and relative ( F rel, susp/sol ) bioavailability of an oral solution and suspension, respectively, in rat or dog and the anticipated BCS classification were analyzed for 89 Janssen compounds with 28 of these having F rel,susp/sol and F abs,sol in both rat and dog at doses around 10 and 5 mg/kg, respectively. The bioavailability outcomes in the dog aligned well with a BCS-like classification based upon the solubility of the active pharmaceutical ingredient (API) in biorelevant media, while the alignment was less clear for the bioavailability data in the rat. A retrospective analysis on the clinically tested formulations for a set of 12 Janssen compounds confirmed that the previously proposed animal bioavailability-based decision tree facilitated decisions on the oral formulation type, with the dog as the most discriminative species. Furthermore, the analysis showed that based on a Do for a standard human dose of 100 mg in aqueous and/or biorelevant media, a similar formulation type would have been selected compared to the one suggested by the animal data. However, the concept of a Do did not distinguish between solubility enhancing or enabling formulations and does not consider the API permeability, and hence, it produces the risk of slow and potentially incomplete oral absorption of an API with poor intestinal permeability. In cases where clinical dose estimations are available early in development, the preclinical bioavailability studies and dose number calculations, used to guide formulation selection, may be performed at more relevant doses instead of the proposed standard human dose. It should be noted, however, that unlike in late development, there is uncertainty on the clinical dose estimated in the early clinical phases because that dose is usually only based on in vitro and/or in vivo animal pharmacology models, or early clinical biomarker information. Therefore, formulation strategies may be adjusted based on emerging data supporting clinical doses. In summary, combined early information on in vitro-assessed API solubility and permeability, preclinical suspension/solution bioavailability data in relation to the intravenous clearance, and metabolic pathways of the API can strengthen formulation decisions. However, these data may not always fully distinguish between conventional (e.g., to be taken with food), enhancing, and enabling formulations. Therefore, to avoid overinvestment in complex and expensive enabling technologies, it is useful to evaluate a conventional and solubility (and/or permeability) enhancing formulation under fasted and fed conditions, as part of a first-in-human study or in a subsequent early human bioavailability study, for compounds with high Do, a low animal F rel,susp/sol , or low F abs,sol caused by precipitation of the solubilized API.

In vitro and in vivo studies of pharmacokinetics and antitumor efficacy of D07001-F4, an oral gemcitabine formulation.

PubMed

Hao, Wei-Hua; Wang, Jong-Jing; Hsueh, Shu-Ping; Hsu, Pei-Jing; Chang, Li-Chien; Hsu, Chang-Shan; Hsu, Kuang-Yang

2013-02-01

The chemotherapy agent gemcitabine is currently administered intravenously because the drug has poor oral bioavailability. In order to assess the pharmacokinetics and antitumor activity of D07001-F4, a new self-microemulsifying oral drug delivery system preparation of gemcitabine, this study was performed to compare the effect of D07001-F4 with administered gemcitabine in vitro and in vivo. D07001-F4 pharmacokinetics was examined by evaluation of in vitro deamination of D07001-F4 and gemcitabine hydrochloride by recombinant human cytidine deaminase (rhCDA) and in vivo evaluation of D07001-F4 pharmacokinetics in mice. Antitumor activity was evaluated by comparing the effect of D07001-F4 and gemcitabine hydrochloride in inhibiting growth in nine cancer cell lines and by examining the effect of D07001-F4 and gemcitabine in two xenograft tumor models in mice. In vitro deamination of D07001-F4 by rhCDA was 3.3-fold slower than deamination of gemcitabine hydrochloride. Growth inhibition by D07001-F4 of 7 of the 8 cancer cell lines was increased compared with that seen with gemcitabine hydrochloride, and D07001-F4 inhibited the growth of pancreatic and colon cancer xenografts. In vivo pharmacokinetics showed the oral bioavailability of D07001-F4 to be 34%. D07001-F4 was effective against several cancer types, was metabolized more slowly than gemcitabine hydrochloride, and exhibited enhanced oral bioavailability.

Solubility enhancement and delivery systems of curcumin a herbal medicine: a review.

PubMed

Hani, Umme; Shivakumar, H G

2014-01-01

Curcumin diferuloylmethane is a main yellow bioactive component of turmeric, possess wide spectrum of biological actions. It was found to have anti-inflammatory, antioxidant, anticarcinogenic, antimutagenic, anticoagulant, antifertility, antidiabetic, antibacterial, antifungal, antiprotozoal, antiviral, antifibrotic, antivenom, antiulcer, hypotensive and hypocholesteremic activities. However, the benefits are curtailed by its extremely poor aqueous solubility, which subsequently limits the bioavailability and therapeutic effects of curcumin. Nanotechnology is the available approach in solving these issues. Therapeutic efficacy of curcumin can be utilized effectively by doing improvement in formulation properties or delivery systems. Numerous attempts have been made to design a delivery system of curcumin. Currently, nanosuspensions, micelles, nanoparticles, nano-emulsions, etc. are used to improve the in vitro dissolution velocity and in vivo efficiency of curcumin. This review focuses on the methods to increase solubility of curcumin and various nanotechnologies based delivery systems and other delivery systems of curcumin.

Arsenic mobility and bioavailability in paddy soil under iron compound amendments at different growth stages of rice.

PubMed

Yu, Huan-Yun; Wang, Xiangqin; Li, Fangbai; Li, Bin; Liu, Chuanping; Wang, Qi; Lei, Jing

2017-05-01

Iron (Fe)-based solids can reduce arsenic (As) mobility and bioavailability in soils, which has been well recognized. However, to our knowledge, there are few studies on As uptake at different growth stages of rice under Fe compound amendments. In addition, the formation of Fe plaques at different growth stages of rice has also been rarely reported. Therefore, the present study was undertaken to investigate As mobility and bioavailability in paddy soil under Fe compound amendments throughout the whole growth stage of rice plants. Amendments of poorly crystalline Fe oxides (PC-Fe), FeCl 2 +NaNO 3 and FeCl 2 reduced grain As by 54% ± 3.0%, 52% ± 3.0% and 46% ± 17%, respectively, compared with that of the non-amended control. The filling stage was suggested to be the key stage to take measures to reduce As uptake. At this stage, all soil amendments significantly reduced As accumulation in rice plants. At the maturation stage, PC-Fe amendment significantly reduced mobile pools and increased immobile pools of soil As. Besides, PC-Fe treatment promoted the transformation of Fe fractions from dissolved Fe to adsorbed, poorly crystalline and free Fe oxides. Moreover, significant positive correlations between soil Fe fractions and As fractions were found. Accordingly, we hypothesized that Fe compound amendments might affect the concentration distribution of Fe fractions first and then affect As fractionation in soil and its bioavailability to rice plants indirectly. The formation of Fe plaques varied with growth stages and different treatments. Significantly negative correlations between mobile pools of As and Fe or As in Fe plaques indicated that Fe plaques could immobilize mobile As in soils and thus affect As bioavailability. Overall, the effect of the soil amendments on reduction of As uptake varied with growth stages and different treatments, and further research on the key stage for reducing As uptake is still required. Copyright © 2017 Elsevier Ltd. All rights reserved.

Use of Tunable Whole-Cell Bioreporters to Assess Bioavailable Cadmium and Remediation Performance in Soils

PubMed Central

Yoon, Youngdae; Kim, Sunghoon; Chae, Yooeun; Kang, Yerin; Lee, Youngshim; Jeong, Seung-Woo; An, Youn-Joo

2016-01-01

It is important to have tools to measure the bioavailability to assess the risks of pollutants because the bioavailability is defined as the portions of pollutants showing the biological effects on living organisms. This study described the construction of tunable Escherichia coli whole-cell bioreporter (WCB) using the promoter region of zinc-inducible operon and its application on contaminated soils. It was verified that this WCB system showed specific and sensitive responses to cadmium rather than zinc in the experimental conditions. It was inferred that Cd(II) associates stronger with ZntR, a regulatory protein of zinc-inducible operon, than other metal ions. Moreover, the expression of reporter genes, egfp and mcherry, were proportional to the concentration of cadmium, thereby being a quantitative sensor to monitor bioavailable cadmium. The capability to determine bioavailable cadmium was verified with Cd(II) amended LUFA soils, and then the applicability on environmental systems was investigated with field soils collected from smelter area in Korea before and after soil-washing. The total amount of cadmium was decreased after soil washing, while the bioavailability was increased. Consequently, it would be valuable to have tools to assess bioavailability and the effectiveness of soil remediation should be evaluated in the aspect of bioavailability as well as removal efficiency. PMID:27171374

Use of Tunable Whole-Cell Bioreporters to Assess Bioavailable Cadmium and Remediation Performance in Soils.

PubMed

Yoon, Youngdae; Kim, Sunghoon; Chae, Yooeun; Kang, Yerin; Lee, Youngshim; Jeong, Seung-Woo; An, Youn-Joo

2016-01-01

It is important to have tools to measure the bioavailability to assess the risks of pollutants because the bioavailability is defined as the portions of pollutants showing the biological effects on living organisms. This study described the construction of tunable Escherichia coli whole-cell bioreporter (WCB) using the promoter region of zinc-inducible operon and its application on contaminated soils. It was verified that this WCB system showed specific and sensitive responses to cadmium rather than zinc in the experimental conditions. It was inferred that Cd(II) associates stronger with ZntR, a regulatory protein of zinc-inducible operon, than other metal ions. Moreover, the expression of reporter genes, egfp and mcherry, were proportional to the concentration of cadmium, thereby being a quantitative sensor to monitor bioavailable cadmium. The capability to determine bioavailable cadmium was verified with Cd(II) amended LUFA soils, and then the applicability on environmental systems was investigated with field soils collected from smelter area in Korea before and after soil-washing. The total amount of cadmium was decreased after soil washing, while the bioavailability was increased. Consequently, it would be valuable to have tools to assess bioavailability and the effectiveness of soil remediation should be evaluated in the aspect of bioavailability as well as removal efficiency.

Introduction of 2,4-Dichlorophenoxyacetic acid into soil with solvents and resulting implications for bioavailability to microorganisms

USDA-ARS?s Scientific Manuscript database

Slow equilibration of introduced chemicals through tortuous pore space limits uniform substrate distribution in soil biodegradation studies. The necessity of introducing poorly soluble xenobiotics via organic solvents, the volume of which is minimized to limit toxicity, likely also affects xenobiot...

Polysaccharide-Based Micelles for Drug Delivery

PubMed Central

Zhang, Nan; Wardwell, Patricia R.; Bader, Rebecca A.

2013-01-01

Delivery of hydrophobic molecules and proteins has been an issue due to poor bioavailability following administration. Thus, micelle carrier systems are being investigated to improve drug solubility and stability. Due to problems with toxicity and immunogenicity, natural polysaccharides are being explored as substitutes for synthetic polymers in the development of new micelle systems. By grafting hydrophobic moieties to the polysaccharide backbone, self-assembled micelles can be readily formed in aqueous solution. Many polysaccharides also possess inherent bioactivity that can facilitate mucoadhesion, enhanced targeting of specific tissues, and a reduction in the inflammatory response. Furthermore, the hydrophilic nature of some polysaccharides can be exploited to enhance circulatory stability. This review will highlight the advantages of polysaccharide use in the development of drug delivery systems and will provide an overview of the polysaccharide-based micelles that have been developed to date. PMID:24300453

In vitro and in vivo evaluation of curcumin loaded lauroyl sulphated chitosan for enhancing oral bioavailability.

PubMed

Shelma, R; Sharma, Chandra P

2013-06-05

Curcumin has been demonstrated as a potent anticancer agent but its clinical application has been limited by its poor aqueous solubility and bioavailability. Here we describe encapsulation of curcumin in the lauroyl sulphated chitosan with a view to improve its bioavailability. In vitro antioxidant activity of extract of curcumin loaded matrix was investigated and exhibited dose dependent radical scavenging and reducing activity. Cytotoxicity studies carried out with curcumin loaded carrier on C6 cell line and were found to be toxic. Its in vitro effects on proliferation using the C6 cell lines also studied and observed antiproliferation of C6 cell line. Plasma concentration of curcumin-time profiles from pharmacokinetic studies in rats after oral administration showed a 11.5-fold increased pharmacological availability of curcumin with encapsulated curcumin compared with native curcumin. Overall we demonstrate that the curcumin loaded matrix has shown a superior pharmacological availability in vivo over curcumin. Copyright © 2013 Elsevier Ltd. All rights reserved.

Anti-cancerous efficacy and pharmacokinetics of 6-mercaptopurine loaded chitosan nanoparticles.

PubMed

Kumar, G Prem; Sanganal, Jagadeesh S; Phani, A R; Manohara, C; Tripathi, Syamantak M; Raghavendra, H L; Janardhana, P B; Amaresha, S; Swamy, K B; Prasad, R G S V

2015-10-01

6-Mercaptopurine is a cytotoxic and immunosuppressant drug. The use of this drug is limited due to its poor bioavailability and short plasma half-life. In order to nullify these drawbacks, 6-mercaptopurine-chitosan nanoparticles (6-MP-CNPs) were prepared and evaluated to study the influence of preparation conditions on the physicochemical properties by using DLS, SEM, XRD and FTIR. The in vitro drug release profile at pH 4.8 and 7.4 revealed sustained release patterns for a period of 2 days. The nanoformulations showed enhanced in vitro anti-cancer activities (MTT assay, apoptosis assay, cell cycle arrest and ROS indices) on HT-1080 and MCF-7 cells. In vivo pharmacokinetics profiles of 6-MP-CNPs showed improved bioavailability. Thus, the results of the present study revealed that, the prepared 6-MP-CNPs have a significant role in increasing anti-cancer efficacy, bioavailability and in vivo pharmacokinetics profiles. Copyright © 2015 Elsevier Ltd. All rights reserved.

Role of Marine Snows in Microplastic Fate and Bioavailability.

PubMed

Porter, Adam; Lyons, Brett P; Galloway, Tamara S; Lewis, Ceri

2018-06-19

Microplastics contaminate global oceans and are accumulating in sediments at levels thought sufficient to leave a permanent layer in the fossil record. Despite this, the processes that vertically transport buoyant polymers from surface waters to the benthos are poorly understood. Here we demonstrate that laboratory generated marine snows can transport microplastics of different shapes, sizes, and polymers away from the water surface and enhance their bioavailability to benthic organisms. Sinking rates of all tested microplastics increased when incorporated into snows, with large changes observed for the buoyant polymer polyethylene with an increase in sinking rate of 818 m day -1 and for denser polyamide fragments of 916 m day -1 . Incorporation into snows increased microplastic bioavailability for mussels, where uptake increased from zero to 340 microplastics individual -1 for free microplastics to up to 1.6 × 10 5 microplastics individual -1 when incorporated into snows. We therefore propose that marine snow formation and fate has the potential to play a key role in the biogeochemical processing of microplastic pollution.

Wheat bread enriched with green coffee - In vitro bioaccessibility and bioavailability of phenolics and antioxidant activity.

PubMed

Świeca, Michał; Gawlik-Dziki, Urszula; Dziki, Dariusz; Baraniak, Barbara

2017-04-15

The potential bioaccessibility and bioavailability of phenolics, caffeine and antioxidant activity of wheat bread enriched with green coffee were studied. Supplementation enhanced nutraceutical potential by improving phenolic content and lipid protecting capacity. The simulated-digestion-released phenolics (mainly caffeic acid, syringic acid and vanillic acid) from bread, also caused significant qualitative changes (chlorogenic acids were cleaved and significant amounts of caffeic acid and ferulic acid were determined). Compared to the control, for the bread with 1% and 5% of the functional component the contents of phenolics were 1.6 and 3.33 times higher. Also, an approximately 2.3-fold increase in antioxidant activity was found in bread containing 5% of the supplement. The compounds responsible for antioxidant potential have high bioaccessibility but poor bioavailability. The qualitative composition of the phenolic fraction has a key role in developing the antioxidant potential of bread; however, caffeine and synergism between antioxidants are also important considerations. Copyright © 2016 Elsevier Ltd. All rights reserved.

Design and in vitro evaluation of a new nano-microparticulate system for enhanced aqueous-phase solubility of curcumin.

PubMed

Guzman-Villanueva, Diana; El-Sherbiny, Ibrahim M; Herrera-Ruiz, Dea; Smyth, Hugh D C

2013-01-01

Curcumin, a yellow polyphenol derived from the turmeric Curcuma longa, has been associated with a diverse therapeutic potential including anti-inflammatory, antioxidant, antiviral, and anticancer properties. However, the poor aqueous solubility and low bioavailability of curcumin have limited its potential when administrated orally. In this study, curcumin was encapsulated in a series of novel nano-microparticulate systems developed to improve its aqueous solubility and stability. The nano-microparticulate systems are based entirely on biocompatible, biodegradable, and edible polymers including chitosan, alginate, and carrageenan. The particles were synthesized via ionotropic gelation. Encapsulating the curcumin into the hydrogel nanoparticles yielded a homogenous curcumin dispersion in aqueous solution compared to the free form of curcumin. Also, the in vitro release profile showed up to 95% release of curcumin from the developed nano-microparticulate systems after 9 hours in PBS at pH 7.4 when freeze-dried particles were used.

Mesoporous systems for poorly soluble drugs.

PubMed

Xu, Wujun; Riikonen, Joakim; Lehto, Vesa-Pekka

2013-08-30

Utilization of inorganic mesoporous materials in formulations of poorly water-soluble drugs to enhance their dissolution and permeation behavior is a rapidly growing area in pharmaceutical materials research. The benefits of mesoporous materials in drug delivery applications stem from their large surface area and pore volume. These properties enable the materials to accommodate large amounts of payload molecules, protect them from premature degradation, and promote controlled and fast release. As carriers with various morphologies and chemical surface properties can be produced, these materials may even promote adsorption from the gastrointestinal tract to the systemic circulation. The main concern regarding their clinical applications is still the safety aspect even though most of them have been reported to be safely excreted, and a rather extensive toxicity screening has already been conducted with the most frequently studied mesoporous materials. In addition, the production of the materials on a large scale and at a reasonable cost may be a challenge when considering the utilization of the materials in industrial processes. However, if mesoporous materials could be employed in the industrial crystallization processes to produce hybrid materials with poorly soluble compounds, and hence to enhance their oral bioavailability, this might open new avenues for the pharmaceutical industry to employ nanotechnology in their processes. Copyright © 2012 Elsevier B.V. All rights reserved.

Novel dipeptide nanoparticles for effective curcumin delivery

PubMed Central

Alam, Shadab; Panda, Jiban J; Chauhan, Virander S

2012-01-01

Background: Curcumin, the principal curcuminoid of the popular Indian spice turmeric, has a wide spectrum of pharmaceutical properties such as antitumor, antioxidant, antiamyloid, and anti-inflammatory activity. However, poor aqueous solubility and low bioavailability of curcumin is a major challenge in its development as a useful drug. To enhance the aqueous solubility and bioavailability of curcumin, attempts have been made to encapsulate it in liposomes, polymeric nanoparticles (NPs), lipid-based NPs, biodegradable microspheres, cyclodextrin, and hydrogels. Methods: In this work, we attempted to entrap curcumin in novel self-assembled dipeptide NPs containing a nonprotein amino acid, α, β-dehydrophenylalanine, and investigated the biological activity of dipeptide-curcumin NPs in cancer models both in vitro and in vivo. Results: Of the several dehydrodipeptides tested, methionine-dehydrophenylalanine was the most suitable one for loading and release of curcumin. Loading of curcumin in the dipeptide NPs increased its solubility, improved cellular availability, enhanced its toxicity towards different cancerous cell lines, and enhanced curcumin’s efficacy towards inhibiting tumor growth in Balb/c mice bearing a B6F10 melanoma tumor. Conclusion: These novel, highly biocompatible, and easy to construct dipeptide NPs with a capacity to load and release curcumin in a sustained manner significantly improved curcumin’s cellular uptake without altering its anticancer or other therapeutic properties. Curcumin-dipeptide NPs also showed improved in vitro and in vivo chemotherapeutic efficacy compared to curcumin alone. Such dipeptide-NPs may also improve the delivery of other potent hydrophobic drug molecules that show poor cellular uptake, bioavailability, and efficacy. PMID:22915849

Transporter-targeted cholic acid-cytarabine conjugates for improved oral absorption.

PubMed

Zhang, Dong; Li, Dongpo; Shang, Lei; He, Zhonggui; Sun, Jin

2016-09-10

Cytarabine has a poor oral absorption due to its rapid deamination and poor membrane permeability. Bile acid transporters are highly expressed both in enterocytes and hepatocytes and to increase the oral bioavailability and investigate the potential application of cytarabine for liver cancers, a transporter- recognizing prodrug strategy was applied to design and synthesize four conjugates of cytarabine with cholic acid (CA), chenodeoxycholic acid (CDCA), hyodeoxycholic acid (HDCA) and ursodeoxycholic acid (UDCA). The anticancer activities against HepG2 cells were evaluated by MTT assay and the role of bile acid transporters during cellular transport was investigated in a competitive inhibition experiment. The in vitro and in vivo metabolic stabilities of these conjugates were studied in rat plasma and liver homogenates. Finally, an oral bioavailability study was conducted in rats. All the cholic acid-cytarabine conjugates (40μM) showed potent antiproliferative activities (up to 70%) against HepG2 cells after incubation for 48h. The addition of bile acids could markedly reduce the antitumor activities of these conjugates. The N(4)-ursodeoxycholic acid conjugate of cytarabine (compound 5) exhibited optimal stability (t1/2=90min) in vitro and a 3.9-fold prolonged half-life of cytarabine in vivo. More importantly, compound 5 increased the oral bioavailability 2-fold compared with cytarabine. The results of the present study suggest that the prodrug strategy based on the bile acid transporters is suitable for improving the oral absorption and the clinical application of cytarabine. Copyright © 2016 Elsevier B.V. All rights reserved.

[Bioavailability and factors influencing its rate].

PubMed

Vraníková, Barbora; Gajdziok, Jan

Bioavailability can be defined as the rate and range of active ingredient absorption, when it becomes available in the systemic circulation or at the desired site of drug action, respectively. Drug bioavailability after oral administration is affected by anumber of different factors, including physicochemical properties of the drug, physiological aspects, the type of dosage form, food intake, biorhythms, and intra- and interindividual variability of the human population. This article is the first from the series dealing with the bioavailability and methods leading to its improvement. The aim of the present paper is to provide an overview of aspects influencing the rate of bioavailability after oral administration of the active ingredient. Subsequentarticles will provide detailed descriptions of methods used for dug bioavailability improvement, which are here only summarized.

Effects of oils and pharmaceutical excipients on the bioavailability of ampicillin orally administered, different oily and aqueous suspensions in rabbit.

PubMed

Alhamami, Omran M O

2003-01-01

The in vivo bioavailability and in vitro drug-release studies of ampicillin trihydrate in different oily and aqueous suspensions have been investigated. In addition, partition, solubility, and rheological measurements have also been carried out. The in vivo experimental design was based on a 6 x 6 latin square using the rabbit as the test animal. The bioavailability of ampicillin was determined using the plasma levels, which were measured microbiologically. Results of the study showed that oily and sucrose-containing aqueous formulations enhanced the extent of ampicillin absorption, although not statistically significantly, but was close to the borderline of significance. Ampicillin appears to be absorbed at essentially the same rate from both aqueous and oily formulations. The latter showed plasma-level time curves with biphasic absorption and are likely to produce prolonged plasma concentrations of ampicillin because of the effects of enterohepatic recycling. Viscosity appears to play an insignificant role in the results obtained since the bioavailability parameters correlate poorly with the viscosity except Cmax. It is suggested that enhancement in the bioavailability of ampicillin is due to the decrease in the gut transit rate brought about by the oil which predominates and masks the other effects of viscosity and osmotic effects of sucrose. The existence of a correlation between the in vitro drug-release rate (t50%) and viscosity and the lack of a correlation between in vivo and in vitro parameters support the above suggestion and indicate that traditional dissolution rate tests, such as flask-stirrer method, are unsatisfactory as bioavailability indicators when applied to dosage forms that caused marked changes in physiological factors like GER and biliary excretion.

Ocular delivery systems for poorly soluble drugs: an in-vivo evaluation.

PubMed

Luschmann, C; Herrmann, W; Strauss, O; Luschmann, K; Goepferich, A

2013-10-15

For highly potent but poorly water-soluble drugs like cyclosporine A, the development of aqueous formulations providing an increase of corneal drug tissue levels, and thus of bioavailability, to increase patient compliance is still a challenge. Therefore, we designed two water-based liquid application systems, an in-situ nanosuspension (INS) and a micellar solution (MS), and tested both formulations in vivo at the rabbit cornea for tolerability and the tissue uptake of CsA. The evaluation of the biological tolerability by periodical eye examination during 180 min and quantification in a defined grading system revealed that the INS evoked minimal to no irritations whereas the MS was perfectly tolerated. After the observation period, the rabbits were sacrificed and the corneal tissue levels of CsA were analyzed. The INS and the MS both showed high levels of 1683±430 ngCsA/gcornea and 826±163 ngCsA/gcornea, respectively, and exceeded drug tissue levels reported for Restasis(®) (350 ngCsA/gcornea) and cationic emulsions (750 ngCsA/gcornea). These results marked our INS and MS as outstanding novel approaches for the treatment of inflammatory corneal diseases. Copyright © 2013 Elsevier B.V. All rights reserved.

Design of curcumin-loaded PLGA nanoparticles formulation with enhanced cellular uptake, and increased bioactivity in vitro and superior bioavailability in vivo.

PubMed

Anand, Preetha; Nair, Hareesh B; Sung, Bokyung; Kunnumakkara, Ajaikumar B; Yadav, Vivek R; Tekmal, Rajeshwar R; Aggarwal, Bharat B

2010-02-01

Curcumin, a yellow pigment present in the spice turmeric (Curcuma longa), has been linked with antioxidant, anti-inflammatory, antiproliferative, anticancer, antidiabetic, antirheumatic, and antiviral effects, but its optimum potential is limited by its lack of solubility in aqueous solvents and poor oral bioavailability. We employed a polymer-based nanoparticle approach to improve bioavailability. Curcumin was encapsulated with 97.5% efficiency in biodegradable nanoparticulate formulation based on poly (lactide-co-glycolide) (PLGA) and a stabilizer polyethylene glycol (PEG)-5000. Dynamic laser light scattering and transmission electron microscopy indicated a particle diameter of 80.9 nm. This curcumin, renamed from hereon "as curcumin (NP)", was characterized for its biological activity. In vitro curcumin (NP) exhibited very rapid and more efficient cellular uptake than curcumin. Estrase staining revealed that curcumin (NP) was at least as potent as or more potent than curcumin in inducing apoptosis of leukemic cells and in suppressing proliferation of various tumor cell lines. When examined by electrophoretic gel shift mobility assay, curcumin (NP) was more active than curcumin in inhibiting TNF-induced NF-kappaB activation and in suppression of NF-kappaB-regulated proteins involved in cell proliferation (cyclin D1), invasion (MMP-9), and angiogenesis (VEGF). In mice, curcumin (NP) was more bioavailable and had a longer half-life than curcumin. Overall we demonstrate that curcumin-loaded PLGA nanoparticles formulation has enhanced cellular uptake, and increased bioactivity in vitro and superior bioavailability in vivo over curcumin.

Curcumin-polymeric nanoparticles against colon-26 tumor-bearing mice: cytotoxicity, pharmacokinetic and anticancer efficacy studies.

PubMed

Chaurasia, Sundeep; Chaubey, Pramila; Patel, Ravi R; Kumar, Nagendra; Mishra, Brahmeshwar

2016-01-01

Curcumin (CUR), can inhibit proliferation and induce apoptosis of tumor cells, its extreme insolubility and limited bioavailability restricted its clinical application. An innovative polymeric nanoparticle of CUR has been developed to enhance the bioavailability and anti-cancer efficacy of CUR, in vitro and in vivo. Cationic copolymer Eudragit E 100 was selected as carrier, which can enhance properties of poor bioavailable chemotherapeutic drugs (CUR). The CUR-loaded Eudragit E 100 nanoparticles (CENPs) were prepared by emulsification-diffusion-evaporation method. The in vitro cytotoxicity study of CENPs was carried out using sulphorhodamine B assay. Pharmacokinetic and anti-cancer efficacy of CENPs was investigated in Wister rats as well as colon-26 tumor-bearing mice after oral administration. CENPs showed acceptable particle size and percent entrapment efficiency. In vitro cytotoxicity studies in terms of 50% cell growth inhibition values demonstrated ∼19-fold reduction when treated with CENPs as compared to pure CUR. ∼91-fold increase in Cmax and ∼95-fold increase in AUC0-12h were observed indicating a significant enhancement in the oral bioavailability of CUR when orally administered as CENPs compared to pure CUR. The in vivo anti-cancer study performed with CENPs showed a significant increase in efficacy compared with pure CUR, as observed by tumor volume, body weight and survival rate. The results clearly indicate that the developed polymeric nanoparticles offer a great potential to improve bioavailability and anticancer efficacy of hydrophobic chemotherapeutic drug.

Preparation and evaluation of self-microemulsions for improved bioavailability of ginsenoside-Rh1 and Rh2.

PubMed

Yang, Feifei; Zhou, Jing; Hu, Xiao; Yu, Stephanie Kyoungchun; Liu, Chunyu; Pan, Ruile; Chang, Qi; Liu, Xinmin; Liao, Yonghong

2017-10-01

Due to intestinal cytochrome P450 (CYP450)-mediated metabolism and P-glycoprotein (P-gp) efflux, poor oral bioavailability hinders ginsenoside-Rh1 (Rh1) and ginsenoside-Rh2 (Rh2) from clinical application. In this study, Rh1 and Rh2 were incorporated into two self-microemulsions (SME-1 and SME-2) to improve oral bioavailability. SME-1 contained both CYP450 and P-gp inhibitory excipients while SME-2 only consisted of P-gp inhibitory excipients. Results for release, cellular uptake, transport, and lymph node distribution demonstrated no significant difference between either self-microemulsions in vivo, but were elevated significantly in comparison to the free drug. The pharmaceutical profiles in vivo showed that the bioavailability of Rh1 in SME-1 (33.25%) was significantly higher than that in either SME-2 (21.28%) or free drug (12.92%). There was no significant difference in bioavailability for Rh2 between SME-1 (48.69%) or SME-2 (41.73%), although they both had remarkable increase in comparison to free drug (15.02%). We confirmed that SME containing CYP450 and P-gp inhibitory excipient could distinctively improve the oral availabilities of Rh1 compared to free drug or SME containing P-gp inhibitory excipient. No notable increase was observed between either SME for Rh2, suggesting that Rh2 undergoes P-gp-mediated efflux, but may not undergo distinct CYP450-mediated metabolism.

Oral fast-dissolving films containing lutein nanocrystals for improved bioavailability: formulation development, in vitro and in vivo evaluation.

PubMed

Liu, Chen; Chang, Daoxiao; Zhang, Xinhui; Sui, Hong; Kong, Yindi; Zhu, Rongyue; Wang, Wenping

2017-11-01

Lutein is widely used as diet supplement for prevention of age-related macular degeneration. However, the application and efficacy of lutein in food and nutritional products has been hampered due to its poor solubility and low oral bioavailability. This study aimed to develop and evaluate the formulation of oral fast-dissolving film (OFDF) containing lutein nanocrystals for enhanced bioavailability and compliance. Lutein nanocrystals were prepared by anti-solvent precipitation method and then encapsulated into the films by solvent casting method. The formulation of OFDF was optimized by Box-Behnken Design (BBD) as follows: HPMC 2.05% (w/v), PEG 400 1.03% (w/v), Cremophor EL 0.43% (w/v). The obtained films exhibited uniform thickness of 35.64 ± 1.64 μm and drug content of 0.230 ± 0.003 mg/cm 2 and disintegrated rapidly in 29 ± 8 s. The nanocrystal-loaded films with reconstituted particle size of 377.9 nm showed better folding endurance and faster release rate in vitro than the conventional OFDFs with raw lutein. The microscope images, thermograms, and diffractograms indicated that lutein nanocrystals were highly dispersed into the films. After administrated to SD rats, t max was decreased from 3 h for oral solution formulation to less than 0.8 h for OFDF formulations, and C max increased from 150 ng/mL for solution to 350 ng/mL for conventional OFDF or 830 ng/mL for nanocrystal OFDF. The AUC 0-24h of conventional or nanocrystal OFDF was 1.37 or 2.08-fold higher than that of the oral solution, respectively. These results suggested that drug nanocrystal-loaded OFDF can be applied as a promising approach for enhanced bioavailability of poor soluble drugs like lutein.

Determination of Tangeretin in Rat Plasma: Assessment of Its Clearance and Absolute Oral Bioavailability.

PubMed

Elhennawy, Mai Gamal; Lin, Hai-Shu

2017-12-29

Tangeretin (TAN) is a dietary polymethoxylated flavone that possesses a broad scope of pharmacological activities. A simple high-performance liquid chromatography (HPLC) method was developed and validated in this study to quantify TAN in plasma of Sprague-Dawley rats. The lower limit of quantification (LLOQ) was 15 ng/mL; the intra- and inter-day assay variations expressed in the form of relative standard deviation (RSD) were all less than 10%; and the assay accuracy was within 100 ± 15%. Subsequently, pharmacokinetic profiles of TAN were explored and established. Upon single intravenous administration (10 mg/kg), TAN had rapid clearance ( Cl = 94.1 ± 20.2 mL/min/kg) and moderate terminal elimination half-life ( t 1/2 λz = 166 ± 42 min). When TAN was given as a suspension (50 mg/kg), poor but erratic absolute oral bioavailability (mean value < 3.05%) was observed; however, when TAN was given in a solution prepared with randomly methylated-β-cyclodextrin (50 mg/kg), its plasma exposure was at least doubled (mean bioavailability: 6.02%). It was obvious that aqueous solubility hindered the oral absorption of TAN and acted as a barrier to its oral bioavailability. This study will facilitate further investigations on the medicinal potentials of TAN.

Preparation and in vitro/in vivo evaluation of metformin hydrochloride rectal dosage forms for treatment of patients with type II diabetes.

PubMed

Zaghloul, Abdel-Azim; Lila, Ahmad; Abd-Allah, Fathy; Nada, Aly

2017-06-01

Metformin hydrochloride (MtHCL) is an oral antidiabetic drug and has many other therapeutic benefits. It has poor bioavailability, narrow absorption window and extensive liver metabolism. Moreover, children and elders face difficulty to swallow the commercial oral tablets. Preparation, in vitro/in vivo evaluation of MtHCL suppositories for rectal administration to solve some of these problems. Suppository fatty bases (Witepsol ® , Suppocire ® and Massa ® ; different grades) and PEG bases 1000, 4000 and 6000 (different ratios), were used to prepare rectal suppository formulations each containing 500 mg drug. These were characterized for manufacturing defects, and pharmacotechnical performance and formulations showing superior results were subjected to bioavailability testing in human volunteers compared with the commercial oral tablet (Ref) applying LC-MS/MS developed analytical technique. The preparation method produced suppositories with satisfactory characteristics and free of manufacturing defects. The fatty bases were superior compared with PEG bases regarding the physical characteristics. Three formulations were chosen for bioavailability testing and the results showed comparable bioavailability compared to the Ref. The fatty bases showed superior characteristics compared with the PEG bases. MtHCL formulated in selected fatty bases could be a potential alternative to the commercial oral tablets particularly for pediatric and geriatric patients.

Sildenafil citrate as oral solid lipid nanoparticles: a novel formula with higher bioavailability and sustained action for treatment of erectile dysfunction.

PubMed

Hosny, Khaled M; Aljaeid, Bader M

2014-07-01

The aim of this study was to prepare sildenafil citrate as solid lipid nanoparticles (SLNs), in order to find an innovative way for alleviating the disadvantages associated with commercially available sildenafil citrate tablets. These limitations include poor solubility and extensive first-pass metabolism, resulting in low (40%) bioavailability and short elimination half-life (4 h). SLNs were prepared by hot homogenization followed by ultrasonication. Solubility of sildenafil citrate in different solid lipids was measured, effect of process variables as surfactant type and concentration, homogenization time, ultrasonication time and charge-inducing agent on the particle size, zeta potential and encapsulation efficiency were also determined. Furthermore, in vitro drug release, stability and in vivo pharmacokinetics were studied in rabbits Results: The best SLN formula consisted of 2% precirol ATO5, 0.5% phosphatidylcholine, 2.5% gelucire 44/14, 0.125% stearylamine, had an average particle size of 28.5 nm with 95.34% entrapment efficiency and demonstrated a controlled drug release over 24 h. An in vivo pharmacokinetic study revealed enhanced bioavailability by > 1.87 fold, and the mean residence time was longer than that for the commercially available tablet. SLN could be a promising carrier for sustained/prolonged sildenafil citrate release with enhanced oral bioavailability.

Bioavailability and ecotoxicity of arsenic species in solution culture and soil system: implications to remediation.

PubMed

Bolan, Nanthi; Mahimairaja, Santiago; Kunhikrishnan, Anitha; Seshadri, Balaji; Thangarajan, Ramya

2015-06-01

In this work, bioavailability and ecotoxicity of arsenite (As(III)) and arsenate (As(V)) species were compared between solution culture and soil system. Firstly, the adsorption of As(III) and As(V) was compared using a number of non-allophanic and allophanic soils. Secondly, the bioavailability and ecotoxicity were examined using germination, phytoavailability, earthworm, and soil microbial activity tests. Both As-spiked soils and As-contaminated sheep dip soils were used to test bioavailability and ecotoxicity. The sheep dip soil which contained predominantly As(V) species was subject to flooding to reduce As(V) to As(III) and then used along with the control treatment soil to compare the bioavailability between As species. Adsorption of As(V) was much higher than that of As(III), and the difference in adsorption between these two species was more pronounced in the allophanic than non-allophanic soils. In the solution culture, there was no significant difference in bioavailability and ecotoxicity, as measured by germination and phytoavailability tests, between these two As species. Whereas in the As-spiked soils, the bioavailability and ecotoxicity were higher for As(III) than As(V), and the difference was more pronounced in the allophanic than non-allophanic soils. Bioavailability of As increased with the flooding of the sheep dip soils which may be attributed to the reduction of As(V) to As(III) species. The results in this study have demonstrated that while in solution, the bioavailability and ecotoxicity do not vary between As(III) and As(V), in soils, the latter species is less bioavailable than the former species because As(V) is more strongly retained than As(III). Since the bioavailability and ecotoxicity of As depend on the nature of As species present in the environment, risk-based remediation approach should aim at controlling the dynamics of As transformation.

Plant-microbe interactions as drivers of ecosystem functions relevant for the biodegradation of organic contaminants.

PubMed

Fester, Thomas; Giebler, Julia; Wick, Lukas Y; Schlosser, Dietmar; Kästner, Matthias

2014-06-01

The plant organism and associated microbial communities can be seen as a sunlight driven hotspot for the turnover of organic chemicals. In such environments the fate of a chemical will not only depend on its intrinsic structural stability toward (bio-)chemical reactions and its bioavailability but also on the functional effectiveness and stability of natural microbial communities as main drivers of natural attenuation of chemicals. Recent research demonstrates that interactions between plants and microorganisms are crucial for the biotransformation of organic chemicals, for various processes affecting the bioavailability of such compounds, and for the stability of the affected ecosystem. Practical bioremediation approaches, therefore, should encompass integrated measures targeting functional vegetation as well as functional microbial communities. Good examples for a successful practical approach are constructed wetlands, where an artificial, simplified ecosystem is used for the detoxification of organic contaminants. While such systems have considerable practical success, they are often treated as a black box and a sound mechanistic understanding of functional resilience and of the 'reactive power' of such plant-microbe ecosystems is poor. This situation has to change, if progress in the application of bioremediation is to be made. Copyright © 2014 Elsevier Ltd. All rights reserved.

Nanoformulations of curcumin: an emerging paradigm for improved remedial application

PubMed Central

Gera, Meeta; Sharma, Neelesh; Ghosh, Mrinmoy; Huynh, Do Luong; Lee, Sung Jin; Min, Taesun; Kwon, Taeho; Jeong, Dong Kee

2017-01-01

Curcumin is a natural polyphenol and essential curcuminoid derived from the rhizome of the medicinal plant Curcuma longa (L.) is universally acknowledged as “Wonder drug of life”. It is a vital consumable and restorative herb, commonly keened for several ailments such as cancer, arthritis, pain, bruises, gastrointestinal quandaries, swelling and much more. Despite its enormous curative potential, the poor aqueous solubility and consequently, minimal systemic bioavailability with rapid degradation are some of the major factors which restrict the utilization of curcumin at medical perspective. However, to improve its clinically relevant parameters, nanoformulation of curcumin is emerging as a novel substitute for their superior therapeutic modality. It enhances its aqueous solubility and targeted delivery to the tissue of interest that prompts to enhance the bioavailability, better drug conveyance, and more expeditious treatment. Subsequent investigations are endeavored to enhance the bio-distribution of native curcumin by modifying with felicitous nano-carriers for encapsulation. In this review, we specifically focus on the recent nanotechnology based implementations applied for overcoming the innate constraints of native curcumin and additionally the associated challenges which restrict its potential therapeutic applications both in vivo and in-vitro studies, as well as their detailed mechanism of action, have additionally been discussed. PMID:29029547

Nanoformulations of curcumin: an emerging paradigm for improved remedial application.

PubMed

Gera, Meeta; Sharma, Neelesh; Ghosh, Mrinmoy; Huynh, Do Luong; Lee, Sung Jin; Min, Taesun; Kwon, Taeho; Jeong, Dong Kee

2017-09-12

Curcumin is a natural polyphenol and essential curcuminoid derived from the rhizome of the medicinal plant Curcuma longa ( L .) is universally acknowledged as " Wonder drug of life ". It is a vital consumable and restorative herb, commonly keened for several ailments such as cancer, arthritis, pain, bruises, gastrointestinal quandaries, swelling and much more. Despite its enormous curative potential, the poor aqueous solubility and consequently, minimal systemic bioavailability with rapid degradation are some of the major factors which restrict the utilization of curcumin at medical perspective. However, to improve its clinically relevant parameters, nanoformulation of curcumin is emerging as a novel substitute for their superior therapeutic modality. It enhances its aqueous solubility and targeted delivery to the tissue of interest that prompts to enhance the bioavailability, better drug conveyance, and more expeditious treatment. Subsequent investigations are endeavored to enhance the bio-distribution of native curcumin by modifying with felicitous nano-carriers for encapsulation. In this review, we specifically focus on the recent nanotechnology based implementations applied for overcoming the innate constraints of native curcumin and additionally the associated challenges which restrict its potential therapeutic applications both in vivo and in-vitro studies, as well as their detailed mechanism of action, have additionally been discussed.

Anti-cancer effects of curcumin on head and neck cancers.

PubMed

Gao, Wei; Chan, Jimmy Yu-Wai; Wei, William Ignance; Wong, Thian-Sze

2012-11-01

Head and neck cancer is the sixth large type of cancer in the world. The treatment regimens for head and neck cancer encompass surgery, radiotherapy and chemotherapy. However, all current treatment regimens for head and neck cancer have adverse effects. Therefore, continuing investigations have been undertaken to seek less toxic therapies to reduce treatment morbidity for head and neck cancer. Substantial evidence has demonstrated that curcumin inhibited proliferation, migration, invasion and metastasis and induced apoptosis via modulating multiple signaling pathways in head and neck cancer. Curcumin also suppressed the growth of xenograft derived from head and neck cancer in vivo in animal models. This review summarizes the evidence demonstrating potential use of curcumin as a single chemotherapeutic agent or in combination with other chemotherapeutic agents and radiation to minimize their toxicity in head and neck cancer. Although curcumin has been shown to be safe at doses of 8 g/d in both phase I and phase II clinical trials, its bioavailability is poor. Overcoming the poor bioavailability of curcumin in the near future would facilitate its clinical use.

Enhancing oral bioavailability of quercetin using novel soluplus polymeric micelles

NASA Astrophysics Data System (ADS)

Dian, Linghui; Yu, Enjiang; Chen, Xiaona; Wen, Xinguo; Zhang, Zhengzan; Qin, Lingzhen; Wang, Qingqing; Li, Ge; Wu, Chuanbin

2014-12-01

To improve its poor aqueous solubility and stability, the potential chemotherapeutic drug quercetin was encapsulated in soluplus polymeric micelles by a modified film dispersion method. With the encapsulation efficiency over 90%, the quercetin-loaded polymeric micelles (Qu-PMs) with drug loading of 6.7% had a narrow size distribution around mean size of 79.00 ± 2.24 nm, suggesting the complete dispersibility of quercetin in water. X-ray diffraction (XRD) patterns illustrated that quercetin was in amorphous or molecular form within PMs. Fourier transform infrared spectroscopy (FTIR) indicated that quercetin formed intermolecular hydrogen bonding with carriers. An in vitro dialysis test showed the Qu-PMs possessed significant sustained-release property, and the formulation was stable for at least 6 months under accelerated conditions. The pharmacokinetic study in beagle dogs showed that absorption of quercetin after oral administration of Qu-PMs was improved significantly, with a half-life 2.19-fold longer and a relative oral bioavailability of 286% as compared to free quercetin. Therefore, these novel soluplus polymeric micelles can be applied to encapsulate various poorly water-soluble drugs towards a development of more applicable therapeutic formulations.

Acyclic Cucurbit[n]uril-Type Molecular Container Enables Systemic Delivery of Effective Doses of Albendazole for Treatment of SK-OV-3 Xenograft Tumors.

PubMed

Hettiarachchi, Gaya; Samanta, Soumen K; Falcinelli, Shane; Zhang, Ben; Moncelet, Damien; Isaacs, Lyle; Briken, Volker

2016-03-07

Approximately, 40-70% of active pharmaceutical ingredients (API) are severely limited by their extremely poor aqueous solubility, and consequently, there is a high demand for excipients that can be used to formulate clinically relevant doses of these drug candidates. Here, proof-of-concept studies demonstrate the potential of our recently discovered acyclic cucurbit[n]uril-type molecular container Motor1 (M1) as a solubilizing agent for insoluble drugs. M1 did not induce significant rates of mutations in various Salmonella typhimurium test strains during the Ames test, suggesting low genotoxicity. M1 also has low risk of causing cardiac toxicity in humans since it did not inhibit the human Ether-à-go-go-Related Gene channel as tested on transfected CHO cell lines via patch clamp analysis. Albendazole (ABZ) is a widely used antihelminthic agent but that has also shown promising efficacy against cancerous cells in vitro. However, due to its low aqueous solubility (2.7 μM) and poor pharmacokinetics, ABZ is clinically limited as an anticancer agent. Here we investigated the potential of M1 as a solubilizing excipient for ABZ formulation. A pharmacokinetic study indicated that ABZ escapes the peritoneal cavity resulting in 78% absolute bioavailability, while its active intermediate metabolite, albendazole sulfoxide, achieved 43% absolute bioavailability. The daily dosing of 681 mg/kg M1 complexed with 3.2 mg/kg of ABZ for 14 days did not result in significant weight loss or pathology in Swiss Webster mice. In vivo efficacy studies using this M1·ABZ inclusion complex showed significant decreases in tumor growth rates and increases in survival of mice bearing SK-OV-3 xenograft tumors. In conclusion, we provide substantial new evidence demonstrating that M1 is a safe and efficient excipient that enables in vivo parenteral delivery of poorly water-soluble APIs.

Transdermal delivery of angiotensin II receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACEIs) and others for management of hypertension.

PubMed

Ahad, Abdul; Al-Mohizea, Abdullah Mohammed; Al-Jenoobi, Fahad Ibrahim; Aqil, Mohd

2016-01-01

Angiotensin II receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACEIs) are some of the most commonly prescribed medications for hypertension. Most of all conventional dosage forms of ARBs and ACEIs undergo extensive first-pass metabolism, which significantly reduces bioavailability. Majority of ARBs and ACEIs are inherently short acting due to a rapid elimination half-life. In addition, oral dosage forms of ARBs and ACEIs have many high incidences of adverse effects due to variable absorption profiles, higher frequency of administration and poor patient compliance. Many attempts have been made globally at the laboratory level to investigate the skin permeation and to develop transdermal therapeutic systems of various ARBs, ACEIs and other anti-hypertensives, to circumvent the drawbacks associated with their conventional dosage form. This manuscript presents an outline of the transdermal research specifically in the area of ARBs, ACEIs and other anti-hypertensives reported in various pharmaceutical journals. The transdermal delivery has gained a significant importance for systemic treatment as it is able to avoid first-pass metabolism and major fluctuations of plasma levels typical of repeated oral administration. As we can experience from this review article that transdermal delivery of different ARBs and ACEIs improves bioavailability as well as patient compliance by many folds. In fact, the rationale development of some newer ARBs, ACEIs and other anti-hypertensives transdermal systems will provide new ways of treatment, circumventing current limitations for conventional dosage forms.

Hot-Melt Extrusion: from Theory to Application in Pharmaceutical Formulation.

PubMed

Patil, Hemlata; Tiwari, Roshan V; Repka, Michael A

2016-02-01

Hot-melt extrusion (HME) is a promising technology for the production of new chemical entities in the developmental pipeline and for improving products already on the market. In drug discovery and development, industry estimates that more than 50% of active pharmaceutical ingredients currently used belong to the biopharmaceutical classification system II (BCS class II), which are characterized as poorly water-soluble compounds and result in formulations with low bioavailability. Therefore, there is a critical need for the pharmaceutical industry to develop formulations that will enhance the solubility and ultimately the bioavailability of these compounds. HME technology also offers an opportunity to earn intellectual property, which is evident from an increasing number of patents and publications that have included it as a novel pharmaceutical formulation technology over the past decades. This review had a threefold objective. First, it sought to provide an overview of HME principles and present detailed engineered extrusion equipment designs. Second, it included a number of published reports on the application of HME techniques that covered the fields of solid dispersions, microencapsulation, taste masking, targeted drug delivery systems, sustained release, films, nanotechnology, floating drug delivery systems, implants, and continuous manufacturing using the wet granulation process. Lastly, this review discussed the importance of using the quality by design approach in drug development, evaluated the process analytical technology used in pharmaceutical HME monitoring and control, discussed techniques used in HME, and emphasized the potential for monitoring and controlling hot-melt technology.

Improved Hepatoprotective Effect of Liposome-Encapsulated Astaxanthin in Lipopolysaccharide-Induced Acute Hepatotoxicity

PubMed Central

Chiu, Chun-Hung; Chang, Chun-Chao; Lin, Shiang-Ting; Chyau, Charng-Cherng; Peng, Robert Y.

2016-01-01

Lipopolysaccharide (LPS)-induced acute hepatotoxicity is significantly associated with oxidative stress. Astaxanthin (AST), a xanthophyll carotenoid, is well known for its potent antioxidant capacity. However, its drawbacks of poor aqueous solubility and low bioavailability have limited its utility. Liposome encapsulation is considered as an effective alternative use for the improvement of bioavailability of the hydrophobic compound. We hypothesized that AST encapsulated within liposomes (LA) apparently shows improved stability and transportability compared to that of free AST. To investigate whether LA administration can efficiently prevent the LPS-induced acute hepatotoxicity, male Sprague-Dawley rats (n = six per group) were orally administered liposome-encapsulated AST at 2, 5 or 10 mg/kg-day (LA-2, LA-5, and LA-10) for seven days and then were LPS-challenged (i.p., 5 mg/kg). The LA-10 administered group, but not the other groups, exhibited a significant amelioration of serum glutamic pyruvic transaminase (GPT), glutamic oxaloacetic transaminase (GOT), blood urea nitrogen (BUN), creatinine (CRE), hepatic malondialdehyde (MDA) and glutathione peroxidase (GSH-Px), IL-6, and hepatic nuclear NF-κB and inducible nitric oxide synthase (iNOS), suggesting that LA at a 10 mg/kg-day dosage renders hepatoprotective effects. Moreover, the protective effects were even superior to that of positive control N-acetylcysteine (NAC, 200 mg/kg-day). Histopathologically, NAC, free AST, LA-2 and LA-5 partially, but LA-10 completely, alleviated the acute inflammatory status. These results indicate that hydrophobic AST after being properly encapsulated by liposomes improves bioavailability and can also function as potential drug delivery system in treating hepatotoxicity. PMID:27428953

Optimized sildenafil citrate fast orodissolvable film: a promising formula for overcoming the barriers hindering erectile dysfunction treatment.

PubMed

Hosny, Khaled Mohamed; El-Say, Khalid Mohamed; Ahmed, Osama Abdelhakim

2016-01-01

Sildenafil citrate, a drug used to treat erectile dysfunction, is available in tablet form but has three major problems. First, the drug displays poor aqueous solubility, which delays its onset of action. Second, the drug undergoes extensive first-pass metabolism, resulting in a low (40%) bioavailability. Third, the gastrointestinal effects of sildenafil citrate include dyspepsia and a burning sensation. The objective of this study was to prepare sildenafil citrate using a fast orodissolvable film (ODF) containing the drug in a solid dispersion (SD) to mitigate the abovementioned problems. The solubility of sildenafil citrate in β-cyclodextrin derivatives was estimated, and SDs were prepared and characterized. To develop an ODF that disintegrates rapidly and releases the maximum amount of sildenafil citrate, a 3(3) Box-Behnken experimental design was used to estimate the effects of different concentrations of film forming polymer (X1), the film modifier (X2), and the plasticizer (X3) on the responses, i.e. the disintegration time (Y1) and the amount of drug released (Y2). Pharmacokinetic studies with the optimized (ODF) were conducted on human volunteers. SD prepared using hydroxybutyl-β-cyclodextrin enhanced the solubility of sildenafil citrate by more than eightfold. The Y1 for the optimized ODF was 89 seconds, and the Y2 was 86%; this formula also exhibited a rapid onset of action, and its bioavailability was enhanced by 2.25-fold compared with that of the marketed tablet. The ODF is a promising formulation for sildenafil citrate that results in higher solubility, a rapid onset of action, and enhanced systemic bioavailability.

Radioprotective activity of curcumin-encapsulated liposomes against genotoxicity caused by Gamma Cobalt-60 irradiation in human blood cells.

PubMed

Nguyen, Minh-Hiep; Pham, Ngoc-Duy; Dong, Bingxue; Nguyen, Thi-Huynh-Nga; Bui, Chi-Bao; Hadinoto, Kunn

2017-11-01

While the radioprotective activity of curcumin against genotoxicity has been well established, its poor oral bioavailability has limited its successful clinical applications. Nanoscale formulations, including liposomes, have been demonstrated to improve curcumin bioavailability. The objective of the present work was (1) to prepare and characterize curcumin-encapsulated liposomes (i.e. size, colloidal stability, encapsulation efficiency, and payload), and (2) subsequently to evaluate their radioprotective activity against genotoxicity in human blood cells caused by Gamma Cobalt-60 irradiation. The curcumin-encapsulated liposomes were prepared by lipid-film hydration method using commercial phosphatidylcholine (i.e. Phospholipon ® 90G). The blood cells were obtained from healthy male donors (n = 3) under an approved ethics protocol. The cell uptake and the radioprotective activity of the curcumin-encapsulated liposomes were characterized by fluorescence microscopy and micronucleus assay, respectively. Nanoscale curcumin-encapsulated liposomes exhibiting good physical characteristics and successful uptake by the human blood cells were successfully prepared. The radioprotective activity of the curcumin-encapsulated liposomes was found to be dependent on the curcumin concentration, where an optimal concentration existed (i.e. 30 μg/mL) independent of the irradiation dose, above which the radioprotective activity had become stagnant (i.e. no more reduction in the micronuclei frequency). The present results established for the first time the radioprotective activity of curcumin-encapsulated liposomes in human blood cells, which coupled by its well-established bioavailability, boded well for its potential application as a nanoscale delivery system of other radioprotective phytochemicals.

Soluplus®/TPGS-based solid dispersions prepared by hot-melt extrusion equipped with twin-screw systems for enhancing oral bioavailability of valsartan.

PubMed

Lee, Jae-Young; Kang, Wie-Soo; Piao, Jingpei; Yoon, In-Soo; Kim, Dae-Duk; Cho, Hyun-Jong

2015-01-01

Soluplus(®) (SP) and D-alpha-tocopherol polyethylene glycol 1000 succinate (TPGS)-based solid dispersion (SD) formulations were developed by hot-melt extrusion (HME) to improve oral bioavailability of valsartan (VST). HME process with twin-screw configuration for generating a high shear stress was used to prepare VST SD formulations. The thermodynamic state of the drug and its dispersion in the polymers were evaluated by solid-state studies, including Fourier-transform infrared, X-ray diffraction, and differential scanning calorimetry. Drug release from the SD formulations was assessed at pH values of 1.2, 4.0, and 6.8. Pharmacokinetic study was performed in rats to estimate the oral absorption of VST. HME with a high shear rate produced by the twin-screw system was successfully applied to prepare VST-loaded SD formulations. Drug amorphization and its molecular dispersion in the polymer matrix were verified by several solid-state studies. Drug release from SD formulations was improved, compared to the pure drug, particularly at pH 6.8. Oral absorption of drug in rats was also enhanced in SP and TPGS-based SD groups compared to that in the pure drug group. SP and TPGS-based SDs, prepared by the HME process, could be used to improve aqueous solubility, dissolution, and oral absorption of poorly water-soluble drugs.

Enhanced oral bioavailability of valsartan using a polymer-based supersaturable self-microemulsifying drug delivery system.

PubMed

Yeom, Dong Woo; Chae, Bo Ram; Son, Ho Yong; Kim, Jin Han; Chae, Jun Soo; Song, Seh Hyon; Oh, Dongho; Choi, Young Wook

2017-01-01

A novel, supersaturable self-microemulsifying drug delivery system (S-SMEDDS) was successfully formulated to enhance the dissolution and oral absorption of valsartan (VST), a poorly water-soluble drug, while reducing the total quantity for administration. Poloxamer 407 is a selectable, supersaturating agent for VST-containing SMEDDS composed of 10% Capmul ® MCM, 45% Tween ® 20, and 45% Transcutol ® P. The amounts of SMEDDS and Poloxamer 407 were chosen as formulation variables for a 3-level factorial design. Further optimization was established by weighting different levels of importance on response variables for dissolution and total quantity, resulting in an optimal S-SMEDDS in large quantity (S-SMEDDS_LQ; 352 mg in total) and S-SMEDDS in reduced quantity (S-SMEDDS_RQ; 144.6 mg in total). Good agreement was observed between predicted and experimental values for response variables. Consequently, compared with VST powder or suspension and SMEDDS, both S-SMEDDS_LQ and S-SMEDDS_RQ showed excellent in vitro dissolution and in vivo oral bioavailability in rats. The magnitude of dissolution and absorption-enhancing capacities using quantity-based comparisons was in the order S-SMEDDS_RQ > S-SMEDDS_LQ > SMEDDS > VST powder or suspension. Thus, we concluded that, in terms of developing an effective SMEDDS preparation with minimal total quantity, S-SMEDDS_RQ is a promising candidate.

Improving In Vivo Efficacy of Bioactive Molecules: An Overview of Potentially Antitumor Phytochemicals and Currently Available Lipid-Based Delivery Systems

PubMed Central

Torres, Carlos; Vázquez, Luis; Reglero, Guillermo; Fornari, Tiziana

2017-01-01

Cancer is among the leading causes of morbidity and mortality worldwide. Many of the chemotherapeutic agents used in cancer treatment exhibit cell toxicity and display teratogenic effect on nontumor cells. Therefore, the search for alternative compounds which are effective against tumor cells but reduce toxicity against nontumor ones is of great importance in the progress or development of cancer treatments. In this sense, scientific knowledge about relevant aspects of nutrition intimately involved in the development and progression of cancer progresses rapidly. Phytochemicals, considered as bioactive ingredients present in plant products, have shown promising effects as potential therapeutic/preventive agents on cancer in several in vitro and in vivo assays. However, despite their bioactive properties, phytochemicals are still not commonly used in clinical practice due to several reasons, mainly attributed to their poor bioavailability. In this sense, new formulation strategies are proposed as carriers to improve their bioefficacy, highlighting the use of lipid-based delivery systems. Here, we review the potential antitumoral activity of the bioactive compounds derived from plants and the current studies carried out in animal and human models. Furthermore, their association with lipids as a formulation strategy to enhance their efficacy in vivo is also reported. The development of high effective bioactive supplements for cancer treatment based on the improvement of their bioavailability goes through this association. PMID:28555156

Preparation and in vitro/in vivo characterization of porous sublingual tablets containing ternary kneaded solid system of vinpocetine with î-cyclodextrin and hydroxy Acid.

PubMed

Aburahma, Mona H; El-Laithy, Hanan M; Hamza, Yassin El-Said

2010-01-01

The demand for sublingual tablets has been growing during the previous decades especially for drugs with extensive hepatic first-pass metabolism. Vinpocetine, a widely used neurotropic agent, has low oral bioavailability due to its poor aqueous solubility and marked first-pass metabolism. Accordingly, the aim of this work was to develop tablets for the sublingual delivery of vinpocetine. Initially, the feasibility of improving vinpocetineâs poor aqueous solubility by preparing kneaded solid systems of the drug with Î-Cyclodextrin and hydroxy acids (citric acid and tartaric acid) was assessed. The solid system with improved solubility and dissolution properties was incorporated into porous tablets that rapidly disintegrate permitting fast release of vinpocetine into the sublingual cavity. The pores were induced into these tablets by directly compressing the tabletsâ excipients with a sublimable material, either camphor or menthol, which was eventually sublimated leaving pores. The obtained results demonstrated that the tablets prepared using camphor attained sufficient mechanical strength for practical use together with rapid disintegration and dissolution. In vivo absorption study performed in rabbits indicated that the sublingual administration of the proposed porous tablets containing vinpocetine solid system with Î-Cyclodextrin and tartaric acid could be useful for therapeutic application.

Preparation and In Vitro/In Vivo Characterization of Porous Sublingual Tablets Containing Ternary Kneaded Solid System of Vinpocetine with β-Cyclodextrin and Hydroxy Acid

PubMed Central

Aburahma, Mona H.; El-Laithy, Hanan M.; Hamza, Yassin El-Said

2010-01-01

The demand for sublingual tablets has been growing during the previous decades especially for drugs with extensive hepatic first-pass metabolism. Vinpocetine, a widely used neurotropic agent, has low oral bioavailability due to its poor aqueous solubility and marked first-pass metabolism. Accordingly, the aim of this work was to develop tablets for the sublingual delivery of vinpocetine. Initially, the feasibility of improving vinpocetine’s poor aqueous solubility by preparing kneaded solid systems of the drug with β-Cyclodextrin and hydroxy acids (citric acid and tartaric acid) was assessed. The solid system with improved solubility and dissolution properties was incorporated into porous tablets that rapidly disintegrate permitting fast release of vinpocetine into the sublingual cavity. The pores were induced into these tablets by directly compressing the tablets’ excipients with a sublimable material, either camphor or menthol, which was eventually sublimated leaving pores. The obtained results demonstrated that the tablets prepared using camphor attained sufficient mechanical strength for practical use together with rapid disintegration and dissolution. In vivo absorption study performed in rabbits indicated that the sublingual administration of the proposed porous tablets containing vinpocetine solid system with β-Cyclodextrin and tartaric acid could be useful for therapeutic application. PMID:21179352

Design of microemulsion system suitable for the oral delivery of poorly aqueous soluble beta-carotene.

PubMed

Peng, Cheng; Svirskis, Darren; Lee, Sung Je; Oey, Indrawati; Kwak, Hae-Soo; Chen, Guanyu; Bunt, Craig; Wen, Jingyuan

2017-02-14

Beta-carotene is a potent antioxidant for maintaining human health. However, its oral absorption is low due to poor aqueous solubility of less than 1 μg/ml. A microemulsion delivery system was designed to solubilize beta-carotene toward enhancing its oral bioavailability. From seven pseudoternary diagrams constructed, three systems were selected with large microemulsion areas suitable for oral administration and dilution in the predominately aqueous gastrointestinal fluids. Conductivity and rheology characterization were conducted along four dilution lines within the selected systems. Three pseudoternary-phase diagrams were selected with large microemulsion regions, >60% of the total phase diagram area, which provide microemulsions with higher drug-loading capacity. A phenomenon was observed by which both propylene glycol and Capmul MCM EP stabilize the microstructure of the microemulsions has been proposed based on the characterization studies. An optimal bicontinuous microemulsion formulation was selected comprising 12% orange oil, 24% Capmul MCM, 18% Tween 20, 6% Labrasol, 20% propylene glycol and 20% water, with a high beta-carotene loading capacity of 140.8 μg/ml and droplet size of 117.4 nm. In conclusion, the developed novel microemulsion formulation allows solubilizing beta-carotene and is a promising basis for further development as a functional beverage.

PEG-lipid micelles as drug carriers: physiochemical attributes, formulation principles and biological implication.

PubMed

Gill, Kanwaldeep K; Kaddoumi, Amal; Nazzal, Sami

2015-04-01

PEG-lipid micelles, primarily conjugates of polyethylene glycol (PEG) and distearyl phosphatidylethanolamine (DSPE) or PEG-DSPE, have emerged as promising drug-delivery carriers to address the shortcomings associated with new molecular entities with suboptimal biopharmaceutical attributes. The flexibility in PEG-DSPE design coupled with the simplicity of physical drug entrapment have distinguished PEG-lipid micelles as versatile and effective drug carriers for cancer therapy. They were shown to overcome several limitations of poorly soluble drugs such as non-specific biodistribution and targeting, lack of water solubility and poor oral bioavailability. Therefore, considerable efforts have been made to exploit the full potential of these delivery systems; to entrap poorly soluble drugs and target pathological sites both passively through the enhanced permeability and retention (EPR) effect and actively by linking the terminal PEG groups with targeting ligands, which were shown to increase delivery efficiency and tissue specificity. This article reviews the current state of PEG-lipid micelles as delivery carriers for poorly soluble drugs, their biological implications and recent developments in exploring their active targeting potential. In addition, this review sheds light on the physical properties of PEG-lipid micelles and their relevance to the inherent advantages and applications of PEG-lipid micelles for drug delivery.

Curcumin Nanomedicine: A Road to Cancer Therapeutics

PubMed Central

Yallapu, Murali M.; Jaggi, Meena; Chauhan, Subhash C.

2013-01-01

Cancer is the second leading cause of death in the United States. Conventional therapies cause widespread systemic toxicity and lead to serious side effects which prohibit their long term use. Additionally, in many circumstances tumor resistance and recurrence is commonly observed. Therefore, there is an urgent need to identify suitable anticancer therapies that are highly precise with minimal side effects. Curcumin is a natural polyphenol molecule derived from the Curcuma longa plant which exhibits anticancer, chemo-preventive, chemo- and radio-sensitization properties. Curcumin’s widespread availability, safety, low cost and multiple cancer fighting functions justify its development as a drug for cancer treatment. However, various basic and clinical studies elucidate curcumin’s limited efficacy due to its low solubility, high rate of metabolism, poor bioavailability and pharmacokinetics. A growing list of nanomedicine(s) using first line therapeutic drugs have been approved or are under consideration by the Food and Drug Administration (FDA) to improve human health. These nanotechnology strategies may help to overcome challenges and ease the translation of curcumin from bench to clinical application. Prominent research is reviewed which shows that advanced drug delivery of curcumin (curcumin nanoformulations or curcumin nanomedicine) is able to leverage therapeutic benefits by improving bioavailability and pharmacokinetics which in turn improves binding, internalization and targeting of tumor(s). Outcomes using these novel drug delivery systems have been discussed in detail. This review also describes the tumor-specific drug delivery system(s) that can be highly effective in destroying tumors. Such new approaches are expected to lead to clinical trials and to improve cancer therapeutics. PMID:23116309

Phospholipid-based solid drug formulations for oral bioavailability enhancement: A meta-analysis.

PubMed

Fong, Sophia Yui Kau; Brandl, Martin; Bauer-Brandl, Annette

2015-12-01

Low bioavailability nowadays often represents a challenge in oral dosage form development. Solid formulations composed of drug and phospholipid (PL), which, upon contact with water, eventually form multilamellar liposomes (i.e. 'proliposomes'), are an emerging approach to solve such issue. Regarded as an 'improved' version of liposomes concerning storage stability, the potential and versatility of a range of such formulations for oral drug delivery have been extensively discussed. However, a systematic and quantitative analysis of the studies that applied solid PL for oral bioavailability enhancement is currently lacking. Such analysis is necessary for providing an overview of the research progress and addressing the question on how promising this approach can be on bioavailability enhancement. The current review performed a systematic search of references in three evidence-based English databases, Medline, Embase, and SciFinder, from the year of 1985 up till March 2015. A total of 112 research articles and 82 patents that involved solid PL-based formulations were identified. The majority of such formulations was intended for oral drug delivery (55%) and was developed to address low bioavailability issues (49%). A final of 54 studies that applied such formulations for bioavailability enhancement of 43 different drugs with poor water solubility and/or permeability were identified. These proof-of-concept studies with in vitro (n=31) and/or animal (n=23) evidences have been systematically summarized. Meta-analyses were conducted to measure the overall enhancement power (percent increase compared to control group) of solid PL formulations on drugs' solubility, permeability and oral bioavailability, which were found to be 127.4% (95% CI [86.1, 168.7]), 59.6% (95% CI [30.1, 89.0]), and 18.5% (95% CI [10.1, 26.9]) respectively. Correlations between the enhancement factors and in silico physiochemical properties of drugs were also performed to check if such approach can be used to identify the best candidates for oral solid PL formulation. In addition to scientific literature, 13 solid PL formulation-related patents that addressed the issue of low oral bioavailability have been identified and summarized; whereas no clinical study was identified from the current search. By providing systematic information and meta-analysis on studies that applied the principle of 'proliposomes' for oral bioavailability enhancement, the current review should be insightful for formulation scientists who wish to adopt the PL based approach to overcome the solubility, permeability and bioavailability issues of orally delivered drugs. Copyright © 2015 Elsevier B.V. All rights reserved.

Thymoquinone-based nanotechnology for cancer therapy: promises and challenges.

PubMed

Ballout, Farah; Habli, Zeina; Rahal, Omar Nasser; Fatfat, Maamoun; Gali-Muhtasib, Hala

2018-05-01

Thymoquinone (TQ), the active ingredient of black seed, is a promising anticancer molecule that inhibits cancer cell growth and progression in vitro and in vivo. Despite the promising anticancer activities of TQ, its translation to the clinic is limited by its poor bioavailability and hydrophobicity. As such, we and others encapsulated TQ in nanoparticles to improve its delivery and limit undesirable cytotoxicity. These TQ-nanoparticle formulations showed improved anticancer and anti-inflammatory activities when compared with free TQ. Here, we provide an overview of the various TQ-nanoparticle formulations, highlight their superior efficacy and discuss up-to-date solutions to further enhance TQ bioavailability and anticancer activity, thus improving potential for clinical translation. Copyright © 2018 Elsevier Ltd. All rights reserved.

Is it possible to increase bioavailability but not environmental risk of PAHs in bioremediation?

PubMed

Ortega-Calvo, J J; Tejeda-Agredano, M C; Jimenez-Sanchez, C; Congiu, E; Sungthong, R; Niqui-Arroyo, J L; Cantos, M

2013-10-15

The current poor predictability of end points associated with the bioremediation of polycyclic aromatic hydrocarbons (PAHs) is a large limitation when evaluating its viability for treating contaminated soils and sediments. However, we have seen a wide range of innovations in recent years, such as an the improved use of surfactants, the chemotactic mobilization of bacterial inoculants, the selective biostimulation at pollutant interfaces, rhizoremediation and electrobioremediation, which increase the bioavailability of PAHs but do not necessarily increase the risk to the environment. The integration of these strategies into practical remediation protocols would be beneficial to the bioremediation industry, as well as improve the quality of the environment. Copyright © 2013 Elsevier B.V. All rights reserved.

On definition and use of the term bioavailability.

PubMed

Rescigno, A; Thakur, A K; Marzo, A

1994-10-01

In common usage, the rate of absorption of an active ingredient or its therapeutic moiety is generally not mentioned in the context of bioavailability. In this communication it is shown that exclusion of the rate of absorption may have serious consequence on the interpretation of bioavailability depending on the underlying model for the system under study. In the case of endogenous substances, the term "bioavailability" is ambiguous unless one specifies whether it refers to availability of the exogenous substance only or the sum total of the exogenous and endogenous substances.

Naproxen Microparticulate Systems Prepared Using In Situ Crystallisation and Freeze-Drying Techniques.

PubMed

Solaiman, Amanda; Tatari, Adam Keenan; Elkordy, Amal Ali

2017-07-01

Poor drug solubility and dissolution rate remain to be one of the major problems facing pharmaceutical scientists, with approximately 40% of drugs in the industry categorised as practically insoluble or poorly water soluble. This in turn can lead to serious delivery challenges and poor bioavailability. The aim of this research was to investigate the effects of the surfactants, poloxamer 407 (P407) and caprol® PGE 860 (CAP), at various concentrations (0.1, 0.5, 1 and 3% w/v) on the enhancement of the dissolution properties of poorly water-soluble drug, naproxen, using in situ micronisation by solvent change method and freeze-drying. The extent at which freeze-drying influences the dissolution rate of naproxen microcrystals is investigated in this study by comparison with desiccant-drying. All formulations were evaluated and characterised using particle size analysis and morphology, in vitro dissolution studies, differential scanning calorimetry (DSC), and Fourier transform infra-red (FT-IR) spectroscopy. An increase in poloxamer 407 concentration in freeze-dried formulations led to enhancement of drug dissolution compared to desiccator-dried formulations, naproxen/caprol® PGE 860 formulations and untreated drug. DSC and FT-IR results show no significant chemical interactions between drug and poloxamer 407, with only very small changes to drug crystallinity. On the other hand, caprol® PGE 860 showed some interactions with drug components, alterations to the crystal lattice of naproxen, and poor dissolution profiles using both drying methods, making it a poor choice of excipient.

Pre-systemic metabolism of orally administered drugs and strategies to overcome it.

PubMed

Pereira de Sousa, Irene; Bernkop-Schnürch, Andreas

2014-10-28

The oral bioavailability of numerous drugs is not only limited by poor solubility and/or poor membrane permeability as addressed by the biopharmaceutical classification system (BCS) but also by a pre-systemic metabolism taking place to a high extent in the intestine. Enzymes responsible for metabolic reactions in the intestine include cytochromes P450 (CYP450), transferases, peptidases and proteases. Furthermore, in the gut nucleases, lipases as well as glycosidases influence the metabolic pathway of drugs and nutrients. A crucial role is also played by the intestinal microflora able to metabolize a wide broad of pharmaceutical compounds. Strategies to provide a protective effect towards an intestinal pre-systemic metabolism are based on the co-administration of enzyme inhibitor being optimally immobilized on unabsorbable and undegradable polymeric excipients in order to keep them concentrated there where an inhibitory effect is needed. Furthermore, certain polymeric excipients such as polyacrylates exhibit per se enzyme inhibitory properties. In addition, by incorporating drugs in cyclodextrines, in self-emulsifying drug delivery systems (SEDDS) or liposomes a protective effect towards an intestinal enzymatic attack can be achieved. Being aware of the important role of this pre-systemic metabolism by integrating it in the BCS as third dimension and keeping strategies to overcome this enzymatic barrier in mind, the therapeutic efficacy of many orally given drugs can certainly be substantially improved. Copyright © 2014 Elsevier B.V. All rights reserved.

Design of Curcumin Loaded PLGA Nanoparticles Formulation with Enhanced Cellular Uptake, and Increased Bioactivity in vitro and Superior Bioavailability in vivo

PubMed Central

Anand, Preeta; Nair, Harish B.; Sung, Bokyung; Kunnumakkara, Ajaikumar B.; Yadav, Vivek R.; Tekmal, Rajeshwar R.; Aggarwal, Bharat B.

2011-01-01

Curcumin, a yellow pigment present in the spice turmeric (Curcuma longa), has been linked with antioxidant, anti-inflammatory, anti-proliferative, anticancer, antidiabetic, antirheumatic, and antiviral effects, but its optimum potential is limited by its lack of solubility in aqueous solvents and poor oral bioavailability. We employed a polymer-based nanoparticle approach to improve bioavailability. Curcumin was encapsulated with 97.5% efficiency in biodegradable nanoparticulate formulation based on poly (lactide-co-glycolide) (PLGA) and a stabilizer polyethylene glycol (PEG)-5000. Dynamic laser light scattering and transmission electron microscopy indicated a particle diameter of 80.9 nm. This curcumin, renamed from hereon “as curcumin (NP)”, was characterized for its biological activity. In vitro curcumin (NP) exhibited very rapid (2 h vs > 72 h) and more efficient cellular uptake then curcumin. Estrase staining revealed that curcumin (NP) was at least as potent as or more potent than curcumin in inducing apoptosis of leukemic cells and in suppressing proliferation of various tumor cell lines. When examined by electrophoretic gel shift mobility assay, curcumin (NP) was more active than curcumin in inhibiting TNF-induced NF-κB activation and in suppression of NF-κB-regulated proteins involved in cell proliferation (cyclin D1), invasion (MMP-9), and angiogenesis (VEGF). In mice, curcumin (NP) was more bioavailable and had a longer half-life than curcumin. Overall we demonstrate that curcumin-loaded PLGA nanoparticles formulation has enhanced cellular uptake, and increased bioactivity in vitro and superior bioavailability in vivo over curcumin. PMID:19735646

Pharmacokinetics of Curcumin Diethyl Disuccinate, a Prodrug of Curcumin, in Wistar Rats.

PubMed

Bangphumi, Kunan; Kittiviriyakul, Chuleeporn; Towiwat, Pasarapa; Rojsitthisak, Pornchai; Khemawoot, Phisit

2016-12-01

Curcumin is the major bioactive component of turmeric, but has poor oral bioavailability that limits its clinical applications. To improve the in vitro solubility and alkaline stability, we developed a prodrug of curcumin by succinylation to obtain curcumin diethyl disuccinate, with the goal of improving the oral bioavailability of curcumin. The in vivo pharmacokinetic profile of curcumin diethyl disuccinate was compared with that of curcumin in male Wistar rats. Doses of curcumin 20 mg/kg intravenous or 40 mg/kg oral were used as standard regimens for comparison with the prodrug at equivalent doses in healthy adult rats. Blood, tissues, urine, and faeces were collected from time zero to 48 h after dosing to determine the prodrug level, curcumin level and a major metabolite by liquid chromatography-tandem spectrometry. The absolute oral bioavailability of curcumin diethyl disuccinate was not significantly improved compared with curcumin, with both compounds having oral bioavailability of curcumin less than 1 %. The major metabolic pathway of the prodrug was rapid hydrolysis to obtain curcumin, followed by glucuronidation. Interestingly, curcumin diethyl disuccinate gave superior tissue distribution with higher tissue to plasma ratio of curcumin and curcumin glucuronide in several organs after intravenous dosing at 1 and 4 h. The primary elimination route of curcumin glucuronide occurred via biliary and faecal excretion, with evidence of an entry into the enterohepatic circulation. Curcumin diethyl disuccinate did not significantly improve the oral bioavailability of curcumin due to first pass metabolism in the gastrointestinal tract. Further studies on reduction of first pass metabolism are required to optimise delivery of curcumin using a prodrug approach.

Folic acid conjugation improves the bioavailability and chemosensitizing efficacy of curcumin-encapsulated PLGA-PEG nanoparticles towards paclitaxel chemotherapy.

PubMed

Thulasidasan, Arun Kumar T; Retnakumari, Archana P; Shankar, Mohan; Vijayakurup, Vinod; Anwar, Shabna; Thankachan, Sanu; Pillai, Kavya S; Pillai, Jisha J; Nandan, C Devika; Alex, Vijai V; Chirayil, Teena Jacob; Sundaram, Sankar; Kumar, Gopalakrishnapillai Sankaramangalam Vinod; Anto, Ruby John

2017-12-08

Nanoencapsulation has emerged as a novel strategy to enhance the pharmacokinetic and therapeutic potential of conventional drugs. Recent studies from our lab have established the efficacy of curcumin in sensitizing cervical cancer cells and breast cancer cells towards paclitaxel and 5-FU chemotherapy respectively. Factors that hinder the clinical use of curcumin as a sensitizer or therapeutic agent include its poor bioavailability and retention time. Earlier reports of improvement in bioavailability and retention of drugs upon nanoencapsulation have motivated us in developing various nanoformulations of curcumin, which were found to exhibit significant enhancement in bioavailability and retention time as assessed by our previous in vitro studies. Among the various formulations tested, curcumin-entrapped in PLGA-PEG nanoparticles conjugated to folic acid (PPF-curcumin) displayed maximum cell death. In the present study, we have demonstrated the efficacy of this formulation in augmenting the bioavailability and retention time of curcumin, in vivo , in Swiss albino mice. Further, the acute and chronic toxicity studies proved that the formulation is pharmacologically safe. We have also evaluated its potential in chemosensitizing cervical cancer cells to paclitaxel and have verified the results using cervical cancer xenograft model in NOD-SCID mice. Folic acid conjugation significantly enhanced the efficacy of curcumin in down-regulating various survival signals induced by paclitaxel in cervical cancer cells and have considerably improved its potential in inhibiting the tumor growth of cervical cancer xenografts. The non-toxic nature coupled with improved chemosensitization potential makes PPF-curcumin a promising candidate formulation for clinical trials.

Folic acid conjugation improves the bioavailability and chemosensitizing efficacy of curcumin-encapsulated PLGA-PEG nanoparticles towards paclitaxel chemotherapy

PubMed Central

Shankar, Mohan; Vijayakurup, Vinod; Anwar, Shabna; Thankachan, Sanu; Pillai, Kavya S.; Pillai, Jisha J.; Nandan, C. Devika; Alex, Vijai V.; Chirayil, Teena Jacob; Sundaram, Sankar; Kumar, Gopalakrishnapillai Sankaramangalam Vinod; Anto, Ruby John

2017-01-01

Nanoencapsulation has emerged as a novel strategy to enhance the pharmacokinetic and therapeutic potential of conventional drugs. Recent studies from our lab have established the efficacy of curcumin in sensitizing cervical cancer cells and breast cancer cells towards paclitaxel and 5-FU chemotherapy respectively. Factors that hinder the clinical use of curcumin as a sensitizer or therapeutic agent include its poor bioavailability and retention time. Earlier reports of improvement in bioavailability and retention of drugs upon nanoencapsulation have motivated us in developing various nanoformulations of curcumin, which were found to exhibit significant enhancement in bioavailability and retention time as assessed by our previous in vitro studies. Among the various formulations tested, curcumin-entrapped in PLGA-PEG nanoparticles conjugated to folic acid (PPF-curcumin) displayed maximum cell death. In the present study, we have demonstrated the efficacy of this formulation in augmenting the bioavailability and retention time of curcumin, in vivo, in Swiss albino mice. Further, the acute and chronic toxicity studies proved that the formulation is pharmacologically safe. We have also evaluated its potential in chemosensitizing cervical cancer cells to paclitaxel and have verified the results using cervical cancer xenograft model in NOD-SCID mice. Folic acid conjugation significantly enhanced the efficacy of curcumin in down-regulating various survival signals induced by paclitaxel in cervical cancer cells and have considerably improved its potential in inhibiting the tumor growth of cervical cancer xenografts. The non-toxic nature coupled with improved chemosensitization potential makes PPF-curcumin a promising candidate formulation for clinical trials. PMID:29296172

Enhancement of solubility and bioavailability of ambrisentan by solid dispersion using Daucus carota as a drug carrier: formulation, characterization, in vitro, and in vivo study.

PubMed

Deshmane, Subhash; Deshmane, Snehal; Shelke, Santosh; Biyani, Kailash

2018-06-01

Ambrisentan is an US FDA approved drug, it is the second oral endothelin A receptor antagonist known for the treatment of pulmonary arterial hypertension, but its oral administration is limited due to its poor water solubility. Hence, the objective of the investigation was focused on enhancement of solubility and bioavailability of ambrisentan by solid dispersion technique using natural Daucus carota extract as drug carrier. Drug carrier was evaluated for solubility, swelling index, viscosity, angle of repose, hydration capacity, and acute toxicity test (LD 50 ). Ambrisentan was studied for the saturation solubility, phase solubility, and Gibbs free energy change. Compatibility of drug and the natural carrier was confirmed by DSC, FTIR, and XRD. Solid dispersions were evaluated for drug content, solubility, morphology, in vitro, and in vivo study. Screening of the natural carrier showed the desirable properties like water solubility, less swelling index, less viscosity, and acute toxicity study revealed no any clinical symptoms of toxicity. Drug and carrier interaction study confirmed the compatibility to consider its use in the formulation. Formed particles were found to be spherical with smooth surface. In vitro studies revealed higher drug release from the solid dispersion than that of the physical mixture. Bioavailability study confirms the increased absorption and bioavailability by oral administration of solid dispersion. Hence, it can be concluded that the natural Daucus carota extract can be the better alternative source for the preparation of solid dispersion and/or other dosage forms for improving solubility and bioavailability.

Modified mesoporous silica nanoparticles for enhancing oral bioavailability and antihypertensive activity of poorly water soluble valsartan.

PubMed

Biswas, Nikhil

2017-03-01

The aim was to improve the oral bioavailability and antihypertensive activity of poorly soluble drug valsartan (VAL) by modifying the design and delivery of mesoporous silica nanoparticles (MSNs). The synthesized MSNs were functionalized with aminopropyl groups (AP-MSN) through postsynthesis and coated with pH sensitive polymer Eudragit L100-55 (AP-MSN-L100-55) for pH dependant sustain release of anionic VAL. MSNs were characterized by Brauner-Emmett-Teller (BET) surface area analyzer, zeta sizer, Field Emission Scanning Electron Microscope (FESEM), Powder X-Ray Diffraction (PXRD) and Differential Scanning Calorimetry (DSC). Functionalized MSNs showed highest entrapment efficiency (59.77%) due to strong ionic interaction with VAL. In vitro dissolution of M-MSN [MSN-VAL and AP-MSN-VAL-L100-55 mixed equally] at physiological conditions demonstrated immediate release (MSN-VAL fraction) followed by sustained release (AP-MSN-VAL-L100-55 fraction) of 96% VAL in 960min. The dramatic improvement in dissolution was attributed to the amorphization of crystalline VAL by MSNs as evidenced by DSC and PXRD studies. No noticeable cytotoxicity was observed for MSN, AP-MSN and AP-MSN-L100-55 in MTT assay. Pharmacokinetic study of M-MSN confirmed 1.82 fold increases in bioavailability compared to commercial Diovan tablet in fasted male rabbits. Blood pressure monitoring in rats showed that the morning dosing of Diovan tablet efficiently controlled BP for just over 360min whereas the effect of M-MSN lasted for >840min. Copyright © 2016 Elsevier B.V. All rights reserved.

Soil Quality Assessment Is a Necessary First Step for Designing Urban Green Infrastructure.

PubMed

Montgomery, James A; Klimas, Christie A; Arcus, Joseph; DeKnock, Christian; Rico, Kathryn; Rodriguez, Yarency; Vollrath, Katherine; Webb, Ellen; Williams, Allison

2016-01-01

This paper describes the results of a preliminary project conducted by a team of DePaul University undergraduate students and staff from the Gary Comer Youth Center located on Chicago's South Side. The team assessed soil quality on 116 samples collected among four abandoned residential lots adjacent to the Comer Center. Soil quality data will be used in a follow-up study to determine the suitability of each lot for green infrastructure implementation. Green infrastructure may be a useful approach for providing ecosystem services and mitigating food deserts in inner-city communities. Soil quality on all lots was poor. All soils had pH >8.0, low biological activity, and low N mineralization potential. The soils were rich in available P and had mean total Pb concentrations above the USEPA threshold (400 mg kg) for children's playlots. Mean bioavailable Pb on the largest of the four lots was 12% of total Pb, indicating that most of the total Pb is not bioavailable. This result is encouraging because high bioavailable Pb concentrations are linked with negative health effects, particularly in children. All lots had NO-N concentrations below those considered to be appropriate for plant growth. On the other hand, no significant differences in mean concentrations of the other analytes were found. The poor soil quality in the four lots presents an opportunity to use green infrastructure to enhance ecosystem services, improve community and environmental health, and provide more equitable access to green space. Copyright © by the American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America, Inc.

Natural Compounds and Neuroprotection: Mechanisms of Action and Novel Delivery Systems.

PubMed

Bagli, Eleni; Goussia, Anna; Moschos, Marilita M; Agnantis, Niki; Kitsos, Georgios

Neurodegeneration characterizes pathologic conditions, ranging from Alzheimer's disease to glaucoma, with devastating social and economic effects. It is a complex process implicating a series of molecular and cellular events, such as oxidative stress, mitochondrial dysfunction, protein misfolding, excitotoxicity and inflammation. Natural compounds, because of their broad spectrum of pharmacological and biological activities, could be possible candidates for the management of such multifactorial morbidities. However, their therapeutic potential against neurodegenerative diseases has been hampered by their poor bioavailability and subsequent insufficient delivery to the brain. This article provides an overview of the molecular mechanisms through which natural compounds exert their neuroprotective effects, as well as the development of novel natural compound-loaded delivery systems that could improve their neuroavailability. Copyright © 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Nanocarriers for cancer-targeted drug delivery.

PubMed

Kumari, Preeti; Ghosh, Balaram; Biswas, Swati

2016-01-01

Nanoparticles as drug delivery system have received much attention in recent years, especially for cancer treatment. In addition to improving the pharmacokinetics of the loaded poorly soluble hydrophobic drugs by solubilizing them in the hydrophobic compartments, nanoparticles allowed cancer specific drug delivery by inherent passive targeting phenomena and adopted active targeting strategies. For this reason, nanoparticles-drug formulations are capable of enhancing the safety, pharmacokinetic profiles and bioavailability of the administered drugs leading to improved therapeutic efficacy compared to conventional therapy. The focus of this review is to provide an overview of various nanoparticle formulations in both research and clinical applications with a focus on various chemotherapeutic drug delivery systems for the treatment of cancer. The use of various nanoparticles, including liposomes, polymeric nanoparticles, dendrimers, magnetic and other inorganic nanoparticles for targeted drug delivery in cancer is detailed.

Ocular delivery of macromolecules

PubMed Central

Kim, Yoo-Chun; Chiang, Bryce; Wu, Xianggen; Prausnitz, Mark R.

2014-01-01

Biopharmaceuticals are making increasing impact on medicine, including treatment of indications in the eye. Macromolecular drugs are typically given by physician-administered invasive delivery methods, because non--invasive ocular delivery methods, such as eye drops, and systemic delivery, have low bioavailability and/or poor ocular targeting. There is a need to improve delivery of biopharmaceuticals to enable less-invasive delivery routes, less-frequent dosing through controlled-release drug delivery and improved drug targeting within the eye to increase efficacy and reduce side effects. This review discusses the barriers to drug delivery via various ophthalmic routes of administration in the context of macromolecule delivery and discusses efforts to develop controlled-release systems for delivery of biopharmaceuticals to the eye. The growing number of macromolecular therapies in the eye needs improved drug delivery methods that increase drug efficacy, safety and patient compliance. PMID:24998941

Influence of processing parameters on morphology of polymethoxyflavone in emulsions.

PubMed

Ting, Yuwen; Li, Colin C; Wang, Yin; Ho, Chi-Tang; Huang, Qingrong

2015-01-21

Polymethoxyflavones (PMFs) are groups of compounds isolated from citrus peels that have been documented with wide arrays of health-promoting bioactivities. Because of their hydrophobic structure and high melting point, crystallized PMFs usually have poor systemic bioavailability when consumed orally. To improve the oral efficiency of PMFs, a viscoelastic emulsion system was formulated. Because of the crystalline nature, the inclusion of PMFs into the emulsion system faces great challenges in having sufficient loading capacity and stabilities. In this study, the process of optimizing the quality of emulsion-based formulation intended for PMF oral delivery was systematically studied. With alteration of the PMF loading concentration, processing temperature, and pressure, the emulsion with the desired droplet and crystal size can be effectively fabricated. Moreover, storage temperatures significantly influenced the stability of the crystal-containing emulsion system. The results from this study are a good illustration of system optimization and serve as a great reference for future formulation design of other hydrophobic crystalline compounds.

A new perspective of using sequential extraction: To predict the deficiency of trace elements during anaerobic digestion.

PubMed

Cai, Yafan; Wang, Jungang; Zhao, Yubin; Zhao, Xiaoling; Zheng, Zehui; Wen, Boting; Cui, Zongjun; Wang, Xiaofen

2018-09-01

Trace elements were commonly used as additives to facilitate anaerobic digestion. However, their addition is often blind because of the complexity of reaction conditions, which has impeded their widespread application. Therefore, this study was conducted to evaluate deficiencies in trace elements during anaerobic digestion by establishing relationships between changes in trace element bioavailability (the degree to which elements are available for interaction with biological systems) and digestion performance. To accomplish this, two batch experiments were conducted. In the first, sequential extraction was used to detect changes in trace element fractions and then to evaluate trace element bioavailability in the whole digestion cycle. In the second batch experiment, trace elements (Co, Fe, Cu, Zn, Mn, Mo and Se) were added to the reaction system at three concentrations (low, medium and high) and their effects were monitored. The results showed that sequential extraction was a suitable method for assessment of the bioavailability of trace elements (appropriate coefficient of variation and recovery rate). The results revealed that Se had the highest (44.2%-70.9%) bioavailability, while Fe had the lowest (1.7%-3.0%). A lack of trace elements was not directly related to their absolute bioavailability, but was instead associated with changes in their bioavailability throughout the digestion cycle. Trace elements were insufficient when their bioavailability was steady or increased over the digestion cycle. These results indicate that changes in trace element bioavailability during the digestion cycle can be used to predict their deficiency. Copyright © 2018 Elsevier Ltd. All rights reserved.

Preparation of amorphous cefuroxime axetil nanoparticles by sonoprecipitation for enhancement of bioavailability.

PubMed

Dhumal, Ravindra S; Biradar, Shailesh V; Yamamura, Shigeo; Paradkar, Anant R; York, Peter

2008-09-01

The aim of the present work was to prepare amorphous discreet nanoparticles by sonoprecipitation method for enhancing oral bioavailability of cefuroxime axetil (CA), a poorly water-soluble drug. CA nanoparticles (SONO-CA) were prepared by sonoprecipitation and compared with particles obtained by precipitation without sonication (PPT-CA) and amorphous CA obtained by spray drying. Spray drying present broad particle size distribution (PSD) with mean particle size of 10 microm and low percent yield, whereas, precipitation without sonication resulted in large amorphous aggregates with broad PSD. During sonoprecipitation, particle size and yield improve with an increase in the amplitude of sonication and lowering the operation temperature due to instantaneous supersaturation and nucleation. The overall symmetry and purity of CA molecule was maintained as confirmed by FTIR and HPLC, respectively. All the three methods resulted in the formation of amorphous CA with only sonoprecipitation resulting in uniform sized nanoparticles. Sonoprecipitated CA nanoparticles showed enhanced dissolution rate and oral bioavailability in Wistar rat due to an increased solubility attributed to combination of effects like amorphization and nanonization with increased surface area and reduced diffusion pathway.

Potentiation of the bioavailability of blueberry phenolic compounds by co-ingested grape phenolic compounds in mice, revealed by targeted metabolomic profiling in plasma and feces.

PubMed

Dudonné, Stéphanie; Dal-Pan, Alexandre; Dubé, Pascal; Varin, Thibault V; Calon, Frédéric; Desjardins, Yves

2016-08-10

The low bioavailability of dietary phenolic compounds, resulting from poor absorption and high rates of metabolism and excretion, is a concern as it can limit their potential beneficial effects on health. Targeted metabolomic profiling in plasma and feces of mice supplemented for 15 days with a blueberry extract, a grape extract or their combination revealed significantly increased plasma concentrations (3-5 fold) of blueberry phenolic metabolites in the presence of a co-ingested grape extract, associated with an equivalent decrease in their appearance in feces. Additionally, the repeated daily administration of the blueberry-grape combination significantly increased plasma phenolic concentrations (2-3-fold) compared to animals receiving only a single acute dose, with no such increase being observed with individual extracts. These findings highlight a positive interaction between blueberry and grape constituents, in which the grape extract enhanced the absorption of blueberry phenolic compounds. This study provides for the first time in vivo evidence of such an interaction occurring between co-ingested phenolic compounds from fruit extracts leading to their improved bioavailability.

Solid lipid nanoparticles for enhancing vinpocetine's oral bioavailability.

PubMed

Luo, YiFan; Chen, DaWei; Ren, LiXiang; Zhao, XiuLi; Qin, Jing

2006-08-10

An ultrasonic-solvent emulsification technique was adopted to prepare vinpocetine loaded Glyceryl monostearate (GMS) nanodispersions with narrow size distribution. To increase the lipid load the process was conducted at 50 degrees C, and in order to prepare nanoparticle using an ultrasonic-solvent emulsification technique. The mean particle size and droplet size distribution, drug loading capacity, drug entrapment efficiency (EE%), zeta potential, and long-term physical stability of the SLNs were investigated in detail respectively. Drug release from two sorts of VIN-SLN was studied using a dialysis bag method. A pharmacokinetic study was conducted in male rats after oral administration of 10 mg kg(-1) VIN in different formulations, it was found that the relative bioavailability of VIN in SLNs was significantly increased compared with that of the VIN solution. The amount of surfactant also had a marked effect on the oral absorption of VIN with SLN formulations. The absorption mechanism of the SLN formulations was also discussed. These results indicated that VIN absorption is enhanced significantly by employing SLN formulations. SLNs offer a new approach to improve the oral bioavailability of poorly soluble drugs.

Helicobacter pylori infection and drugs malabsorption.

PubMed

Lahner, Edith; Virili, Camilla; Santaguida, Maria Giulia; Annibale, Bruno; Centanni, Marco

2014-08-14

Drug absorption represents an important factor affecting the efficacy of oral drug treatment. Gastric secretion and motility seem to be critical for drug absorption. A causal relationship between impaired absorption of orally administered drugs and Helicobacter pylori (H. pylori) infection has been proposed. Associations have been reported between poor bioavailability of l-thyroxine and l-dopa and H. pylori infection. According to the Maastricht Florence Consensus Report on the management of H. pylori infection, H. pylori treatment improves the bioavailability of both these drugs, whereas the direct clinical benefits to patients still await to be established. Less strong seems the association between H. pylori infection and other drugs malabsorption, such as delavirdine and ketoconazole. The exact mechanisms forming the basis of the relationship between H. pylori infection and impaired drugs absorption and/or bioavailability are not fully elucidated. H. pylori infection may trigger a chronic inflammation of the gastric mucosa, and impaired gastric acid secretion often follows. The reduction of acid secretion closely relates with the wideness and the severity of the damage and may affect drug absorption. This minireview focuses on the evidence of H. pylori infection associated with impaired drug absorption.

Nanotechnology for delivery of gemcitabine to treat pancreatic cancer.

PubMed

Birhanu, Gebremariam; Javar, Hamid Akbari; Seyedjafari, Ehsan; Zandi-Karimi, Ali

2017-04-01

Pancreatic cancer (PC) is one of the most deadly and quickly fatal human cancers with a 5-year mortality rate close to 100%. Its prognosis is very poor, mainly because of its hostile biological behavior and late onset of symptoms for clinical diagnosis; these bring limitations on therapeutic interventions. Factors contributing for the difficulties in treating PC include: high rate of drug resistance, fast metastasis to different organs, poor prognosis and relapse of the tumor after therapy. After being approved by US FDA 1997, Gemcitabine (Gem) is the first line and the gold standard drug for all stages of advanced PC till now. However, its efficacy is unsatisfactory, mainly due to; its chemical instability and poor cellular uptake, resulting in an extremely short half-life and low bioavailability. To solve this drawbacks and increase the therapeutic outcome important progress has been achieved in the field of nanotechnology and offers a promising and effective alternative. This review mainly focus on the most commonly investigated nanoparticle (NP) delivery systems of Gem for PC treatment and the latest progresses achieved. Novel nanocarriers with better tumor targeting efficiencies and maximum treatment outcome to treat this deadly due are given much attention. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Arsenic bioavailability in soils before and after soil washing: the use of Escherichia coli whole-cell bioreporters.

PubMed

Yoon, Youngdae; Kang, Yerin; Chae, Yooeun; Kim, Sunghoon; Lee, Youngshim; Jeong, Seung-Woo; An, Youn-Joo

2016-02-01

We investigated the quantification of bioavailable arsenic in contaminated soils and evaluation of soil-washing processes in the aspect of bioavailability using a novel bacterial bioreporter developed in present study. The whole-cell bioreporter (WCB) was genetically engineered by fusing the promoter of nik operon from Escherichia coli and green fluorescent protein as a sensing domain and reporter domain. Among eight well-known hazardous heavy metals and metalloid, this system responded specifically to arsenic, thereby inferring association of As(III) with NikR inhibits the repression. Moreover, the response was proportional to the concentration of As(III), thereby it was capable to determine the amount of bioavailable arsenic quantitatively in contaminated soils. The bioavailable portion of arsenic was 5.9 (3.46-10.96) and 0.9 (0.27-1.74) % of total from amended and site soils, respectively, suggesting the bioavailability of arsenic in soils was related to the soil properties and duration of aging. On the other hand, only 1.37 (0.21-2.97) % of total arsenic was extracted into soil solutions and 19.88 (11.86-28.27) % of arsenic in soil solution was bioavailable. This result showed that the soluble arsenic is not all bioavailable and most of bioavailable arsenic in soils is water non-extractable. In addition, the bioavailable arsenic was increased after soil-washing while total amount was decreased, thereby suggesting the soil-washing processes release arsenic associated with soil materials to be bioavailable. Therefore, it would be valuable to have a tool to assess bioavailability and the bioavailability should be taken into consideration for soil remediation plans.

Polymeric Micelles and Alternative Nanonized Delivery Vehicles for Poorly Soluble Drugs

PubMed Central

Lu, Ying; Park, Kinam

2013-01-01

Poorly soluble drugs often encounter low bioavailability and erratic absorption patterns in the clinical setting. Due to the rising number of compounds having solubility issues, finding ways to enhance the solubility of drugs is one of the major challenges in the pharmaceutical industry today. Polymeric micelles, which form upon self-assembly of amphiphilic macromolecules, can act as solubilizing agents for delivery of poorly soluble drugs. This manuscript examines the fundamentals of polymeric micelles through reviews of representative literature and demonstrates possible applications through recent examples of clinical trial developments. In particular, the potential of polymeric micelles for delivery of poorly water-soluble drugs, especially in the areas of oral delivery and in cancer therapy, is discussed. Key considerations in utilizing polymeric micelles’ advantages and overcoming potential disadvantages have been highlighted. Lastly, other possible strategies related to particle size reduction for enhancing solubilization of poorly water-soluble drugs are introduced. PMID:22944304

Computational modeling of human oral bioavailability: what will be next?

PubMed

Cabrera-Pérez, Miguel Ángel; Pham-The, Hai

2018-06-01

The oral route is the most convenient way of administrating drugs. Therefore, accurate determination of oral bioavailability is paramount during drug discovery and development. Quantitative structure-property relationship (QSPR), rule-of-thumb (RoT) and physiologically based-pharmacokinetic (PBPK) approaches are promising alternatives to the early oral bioavailability prediction. Areas covered: The authors give insight into the factors affecting bioavailability, the fundamental theoretical framework and the practical aspects of computational methods for predicting this property. They also give their perspectives on future computational models for estimating oral bioavailability. Expert opinion: Oral bioavailability is a multi-factorial pharmacokinetic property with its accurate prediction challenging. For RoT and QSPR modeling, the reliability of datasets, the significance of molecular descriptor families and the diversity of chemometric tools used are important factors that define model predictability and interpretability. Likewise, for PBPK modeling the integrity of the pharmacokinetic data, the number of input parameters, the complexity of statistical analysis and the software packages used are relevant factors in bioavailability prediction. Although these approaches have been utilized independently, the tendency to use hybrid QSPR-PBPK approaches together with the exploration of ensemble and deep-learning systems for QSPR modeling of oral bioavailability has opened new avenues for development promising tools for oral bioavailability prediction.

Optimization and development of antidiabetic phytosomes by the Box-Behnken design.

PubMed

Rathee, Sushila; Kamboj, Anjoo

2018-06-01

Researchers have extensively reviewed on herbs and natural products for their marked clinical efficacy in some recent years, however, maximum of the newly discovered bioactive constituents offer poor bioavailability due to their large size molecules or to their poor miscibility with oils and lipids, thereby limiting their ability to pass across the lipid-rich outer membranes of the enterocytes of the small intestine. Phytosomes are more bioavailable as compared to herbal extracts owing to their enhanced capacity to cross the bio-membranes and thus reaching the systemic circulation. This study was aimed to investigate the development and optimization of antidiabetic phytosomes using a three-factor, three-level the Box-Behnken design (17 batches). The fruits of Citrullus colocynthis (L.) Momordica balsamina and Momordica dioica were extracted using Soxhlet's apparatus. The phytochemical fingerprint profile of the combined methanolic extracts was done by using high-performance thin layer chromatography (HPTLC). The polynomial quadratic equation analysis was designed to study the response (entrapment efficiency (EE), % yield) of independent significant factors at different levels. Phytosomes were characterized in terms of drug content, particle size, EE, zeta potential and in vitro dissolution. TEM analysis revealed good stability and a spherical, self-closed structure of phytosomes in complex formulations. Average particle size was found to 450 nm. Total flavonoid content was found to be 10.0 ± 0.002 μg/g. Optimized formulation was selected and was prepared using A (1:3), B (60 °C) and C (2.5 h) to give maximum yield and entrapment efficiencies (72% and 92.1 ± 5.1%). Phytosomes were found to have antidiabetic activity comparable to metformin in low dose. HPTLC showed the presence of the phyto-constituent quercetin.

Development of a Video-Microscopic Tool To Evaluate the Precipitation Kinetics of Poorly Water Soluble Drugs: A Case Study with Tadalafil and HPMC.

PubMed

Christfort, Juliane Fjelrad; Plum, Jakob; Madsen, Cecilie Maria; Nielsen, Line Hagner; Sandau, Martin; Andersen, Klaus; Müllertz, Anette; Rades, Thomas

2017-12-04

Many drug candidates today have a low aqueous solubility and, hence, may show a low oral bioavailability, presenting a major formulation and drug delivery challenge. One way to increase the bioavailability of these drugs is to use a supersaturating drug delivery strategy. The aim of this study was to develop a video-microscopic method, to evaluate the effect of a precipitation inhibitor on supersaturated solutions of the poorly soluble drug tadalafil, using a novel video-microscopic small scale setup. Based on preliminary studies, a degree of supersaturation of 29 was chosen for the supersaturation studies with tadalafil in FaSSIF. Different amounts of hydroxypropyl methyl cellulose (HPMC) were predissolved in FaSSIF to give four different concentrations, and the supersaturated system was then created using a solvent shift method. Precipitation of tadalafil from the supersaturated solutions was monitored by video-microscopy as a function of time. Single-particle analysis was possible using commercially available software; however, to investigate the entire population of precipitating particles (i.e., their number and area covered in the field of view), an image analysis algorithm was developed (multiparticle analysis). The induction time for precipitation of tadalafil in FaSSIF was significantly prolonged by adding 0.01% (w/v) HPMC to FaSSIF, and the maximum inhibition was reached at 0.1% (w/v) HPMC, after which additional HPMC did not further increase the induction time. The single-particle and multiparticle analyses yielded the same ranking of the HPMC concentrations, regarding the inhibitory effect on precipitation. The developed small scale method to assess the effect of precipitation inhibitors can speed up the process of choosing the right precipitation inhibitor and the concentration to be used.

Formulation design and photochemical studies on nanocrystal solid dispersion of curcumin with improved oral bioavailability.

PubMed

Onoue, Satomi; Takahashi, Haruki; Kawabata, Yohei; Seto, Yoshiki; Hatanaka, Junya; Timmermann, Barbara; Yamada, Shizuo

2010-04-01

Considerable interest has been focused on curcumin due to its use to treat a wide variety of disorders, however, the therapeutic potential of curcumin could often be limited by its poor solubility, bioavailability, and photostability. To overcome these drawbacks, efficacious formulations of curcumin, including nanocrystal solid dispersion (CSD-Cur), amorphous solid dispersion (ASD-Cur), and nanoemulsion (NE-Cur), were designed with the aim of improving physicochemical and pharmacokinetic properties. Physicochemical properties of the prepared formulations were characterized by scanning/transmission electron microscope for morphological analysis, laser diffraction, and dynamic light scattering for particle size analysis, and polarized light microscope, powder X-ray diffraction and differential scanning calorimetry for crystallinity assessment. In dissolution tests, all curcumin formulations exhibited marked improvement in the dissolution behavior when compared with crystalline curcumin. Significant improvement in pharmacokinetic behavior was observed in the newly developed formulations, as evidenced by 12- (ASD-Cur), 16- (CSD-Cur), and 9-fold (NE-Cur) increase of oral bioavailability. Upon photochemical characterization, curcumin was found to be photoreactive and photodegradable in the solution state, possibly via type 2 photochemical reaction, whereas high photochemical stability was seen in the solid formulations, especially CSD-Cur. On the basis of these observations, taken together with dissolution and pharmacokinetic behaviors, CSD strategy would be efficacious to enhance bioavailability of curcumin with high photochemical stability. 2009 Wiley-Liss, Inc. and the American Pharmacists Association

Sodium Dodecyl Sulfate-Modified Doxorubicin-Loaded Chitosan-Lipid Nanocarrier with Multi Polysaccharide-Lecithin Nanoarchitecture for Augmented Bioavailability and Stability of Oral Administration In Vitro and In Vivo.

PubMed

Su, Chia-Wei; Chiang, Min-Yu; Lin, Yu-Ling; Tsai, Nu-Man; Chen, Yen-Po; Li, Wei-Ming; Hsu, Chin-Hao; Chen, San-Yuan

2016-05-01

For oral anti-cancer drug delivery, a new chitosan-lipid nanoparticle with sodium dodecyl sulfate modification was designed and synthesized using a double emulsification. TEM examination showed that the DOX-loaded nanoparticles, termed D-PL/TG NPs, exhibited a unique core-shell configuration composed of multiple amphiphilic chitosan-lecithin reverse micelles as the core and a triglyceride shell as a physical barrier to improve the encapsulation efficiency and reduce the drug leakage. In addition, the D-PL/TG NPs with sodium dodecyl sulfate modification on the surface have enhanced stability in the GI tract and increased oral bioavailability of doxorubicin. In vitro transport studies performed on Caco-2 monolayers indicated that the D-PL/TG NPs enhanced the permeability of DOX in the Caco-2 monolayers by altering the transport pathway from passive diffusion to transcytosis. The in vivo intestinal absorption assay suggested that the D-PL/TG NPs were preferentially absorbed through the specialized membranous epithelial cells (M cells) of the Peyer's patches, resulting in a significant improvement (8-fold) in oral bioavailability compared to that of free DOX. The experimental outcomes in this work demonstrate that the D-PL/TG NPs provide an exciting opportunity for advances in the oral administration of drugs with poor bioavailability that are usually used in treating tough and chronic diseases.

Preparation, characterization and in vivo evaluation of curcumin self-nano phospholipid dispersion as an approach to enhance oral bioavailability.

PubMed

Allam, Ahmed N; Komeil, Ibrahim A; Fouda, Mohamed A; Abdallah, Ossama Y

2015-07-15

The aim of this study was to examine the efficacy of self-nano phospholipid dispersions (SNPDs) based on Phosal(®) to improve the oral bioavailability of curcumin (CUR). SNPDs were prepared with Phosal(®) 53 and Miglyol 812 at different surfactant ratio. Formulations were evaluated for particle size, polydispersity index, zeta potential, and robustness toward dilution, TEM as well as in vitro drug release. The in vivo oral absorption of selected formulations in comparison to drug suspension was evaluated in rats. Moreover, formulations were assessed for in vitro characteristic changes before and after storage. The SNPDs were miscible with water in any ratio and did not show any phase separation or drug precipitation. All the formulas were monodisperse with nano range size from 158±2.6 nm to 610±6.24 nm. They passed the pharmacopeial tolerance for CUR dissolution. No change in dissolution profile and physicochemical characteristics was detected after storage. CUR-SNPDs are found to be more bioavailable compared with suspension during an in vivo study in rats and in vitro release studies failed to imitate the in vivo conditions. These formulations might be new alternative carriers that enhance the oral bioavailability of poorly water-soluble molecules, such as CUR. Copyright © 2015 Elsevier B.V. All rights reserved.

Biodegradable Poly (Lactic-co-Glycolic Acid)-Polyethylene Glycol Nanocapsules: An Efficient Carrier for Improved Solubility, Bioavailability, and Anticancer Property of Lutein.

PubMed

Arunkumar, Ranganathan; Prashanth, Keelara Veerappa Harish; Manabe, Yuki; Hirata, Takashi; Sugawara, Tatsuya; Dharmesh, Shylaja Mallaiah; Baskaran, Vallikannan

2015-06-01

Lutein bioavailability is limited because of its poor aqueous solubility. In this study, lutein-poly (lactic-co-glycolic acid) (PLGA)-polyethylene glycol (PEG) nanocapsules were prepared to improve the solubility, bioavailability, and anticancer property of lutein. The scanning electron microscopy and dynamic light scattering examination revealed that the nanocapsules are smooth and spherical with size ranging from 80 to 500 nm (mean = 200 nm). In vitro lutein release profile from nanocapsules showed controlled sustainable release (66%) up to 72 h. Aqueous solubility of lutein nanocapsules was much higher by 735-fold than the lutein. Fourier transform infrared spectroscopy analyses showed no chemical interaction among PLGA, PEG, and lutein, indicating possible weak intermolecular forces like hydrogen bonds. X-ray diffraction revealed lutein is distributed in a disordered amorphous state in nanocapsules. Postprandial plasma kinetics (area under the curve) of an oral dose of lutein from nanocapsules was higher by 5.4-fold compared with that of micellar lutein (control). The antiproliferative effect of lutein from nanocapsules (IC50 value, 10.9 μM) was higher (43.6%) than the lutein (IC50 value, 25 μM). Results suggest that PLGA-PEG nanocapsule is an efficient carrier for enhancing hydrophilicity, bioavailability, and anticancer property of lipophilic molecules such as lutein. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Enhancing the bioavailability of resveratrol by combining it with piperine

PubMed Central

Johnson, Jeremy J.; Nihal, Minakshi; Siddiqui, Imtiaz A.; Scarlett, Cameron O.; Bailey, Howard H.; Mukhtar, Hasan; Ahmad, Nihal

2012-01-01

Scope Resveratrol (3,5,4′-trihydroxystilbene) is a phytoalexin shown to possess a multitude of health-promoting properties in pre-clinical studies. However, the poor in vivo bioavailability of resveratrol due to its rapid metabolism is being considered as a major obstacle in translating its effects in humans. In this study, we examined the hypothesis that piperine will enhance the pharmacokinetic parameters of resveratrol via inhibiting its glucuronidation, thereby slowing its elimination. Methods and results Employing a standardized LC/MS assay, we determined the effect of piperine co-administration with resveratrol on serum levels resveratrol and resveratrol-3-O-β-d-glucuronide in C57BL mice. Mice were administered resveratrol (100 mg/kg; oral gavage) or resveratrol (100 mg/kg; oral gavage) + piperine (10 mg/kg; oral gavage), and the serum levels of resveratrol and resveratrol-3-O-β-d-glucuronide were analyzed at different times. We found that the degree of exposure (i.e. AUC) to resveratrol was enhanced to 229% and the maximum serum concentration (Cmax) was increased to 1544% with the addition of piperine. Conclusion Our study demonstrated that piperine significantly improves the in vivo bioavailability of resveratrol. However, further detailed research is needed to study the mechanism of improved bioavailability of resveratrol via its combination with piperine as well as its effect on resveratrol metabolism. PMID:21714124

Bioavailability and Effects of Manufactured TiO2 and Quantum Dot Nanomaterials to Environmental Microorganisms (Invited)

NASA Astrophysics Data System (ADS)

Holden, P. A.; Nadeau, J. L.; Stucky, G.; Priester, J.; Horst, A.; Vukanti, R.; Ge, Y.; Schimel, J.

2010-12-01

Whether through manufacturing processes, waste disposal or the use of consumer goods, manufactured nanomaterials enter soil, sediment and aquatic environments where their impacts are poorly understood. Ecosystem level scale impacts, for example on nutrient cycling and other pollutant biodegradation, are plausible if nanomaterials are bioavailable to, and negatively affect, microbes. Microbes may also contribute to trophic transfer and thus effects to higher organisms. We present data from studies of CdSe quantum dots (QDs) where direct toxicity of these particles and specific entry into bacteria are observed. Effects are similar for planktonic and biofilm bacteria, and biofilm exopolymers do not appear to reduce bioavailability to cells. QDs are taken up whole, retained, but also partially broken down in cells. While nano-TiO2 does not appear to enter cells, negative effects on growth are observed; effects of bacteria on TiO2 agglomerate stability are also observed which could impact nanomaterial transport in the environment. Soil microcosm studies suggest that nano-TiO2 is bioavailable to bacteria as effects on bacterial communities are observed. Taken together, these data support that nanoparticles can affect microorganisms, and thus the processes that they catalyze, and that such effects could manifest in the environment. Still weakly understood are actual environmental exposure levels, and controlling effects mechanisms under environmental conditions.

Enhanced bioavailability of tripterine through lipid nanoparticles using broccoli-derived lipids as a carrier material.

PubMed

Li, Wan; Zhang, Tianpeng; Ye, Yanghuan; Zhang, Xingwang; Wu, Baojian

2015-11-30

Chemotherapy via the oral route remains a considerable challenge due to poor water-solubility and permeability of anticancer agents. This study aimed to construct lipid nanoparticles using broccoli-derived lipids for oral delivery of tripterine (Tri), a natural anticancer candidate, and to enhance its oral bioavailability. Tri-loaded broccoli lipid nanoparticles (Tri-BLNs) were prepared by a solvent-diffusion method. The resulting Tri-BLNs were 75±10 nm in particle size with entrapment efficiency over 98%. In vitro release study indicated that Tri was almost not released from Tri-BLNs (<2%), whereas the lipolytic experiment showed that Tri-BLNs possessed a relatively strong anti-enzymatic degradation ability to Tri-CLNs (Tri-loaded common lipid nanoparticles). In situ single-pass intestinal perfusion manifested that the effective permeability of Tri-BLNs were significantly higher than that of Tri-CLNs. Further, Tri-BLNs exhibited more efficient cellular uptake in MDCK-II cells as evidenced by flow cytometry and confocal microscopy. The relative bioavailability of Tri-BLNs and Tri-CLNs was 494.13% and 281.95% compared with Tri suspensions, respectively. Depending on the ability in enhancement of biomembrane permeability, broccoli-derived lipids as an alternative source should be useful to construct lipid nanoparticles for bettering oral delivery of drugs with low bioavailability. Copyright © 2015 Elsevier B.V. All rights reserved.

Enhanced dissolution and oral bioavailability of valsartan solid dispersions prepared by a freeze-drying technique using hydrophilic polymers.

PubMed

Xu, Wei-Juan; Xie, Hong-Juan; Cao, Qing-Ri; Shi, Li-Li; Cao, Yue; Zhu, Xiao-Yin; Cui, Jing-Hao

2016-01-01

This study aimed to improve the dissolution rate and oral bioavailability of valsartan (VAL), a poorly soluble drug using solid dispersions (SDs). The SDs were prepared by a freeze-drying technique with polyethylene glycol 6000 (PEG6000) and hydroxypropylmethylcellulose (HPMC 100KV) as hydrophilic polymers, sodium hydroxide (NaOH) as an alkalizer, and poloxamer 188 as a surfactant without using any organic solvents. In vitro dissolution rate and physicochemical properties of the SDs were characterized using the USP paddle method, differential scanning calorimetry (DSC), X-ray diffractometry (XRD) and Fourier transform-infrared (FT-IR) spectroscopy, respectively. In addition, the oral bioavailability of SDs in rats was evaluated by using VAL (pure drug) as a reference. The dissolution rates of the SDs were significantly improved at pH 1.2 and pH 6.8 compared to those of the pure drug. The results from DSC, XRD showed that VAL was molecularly dispersed in the SDs as an amorphous form. The FT-IR results suggested that intermolecular hydrogen bonding had formed between VAL and its carriers. The SDs exhibited significantly higher values of AUC 0-24 h and Cmax in comparison with the pure drug. In conclusion, hydrophilic polymer-based SDs prepared by a freeze-drying technique can be a promising method to enhance dissolution rate and oral bioavailability of VAL.

Enhanced Bioavailability of Curcumin Nanoemulsions Stabilized with Phosphatidylcholine Modified with Medium Chain Fatty Acids.

PubMed

Ochoa-Flores, Angélica A; Hernández-Becerra, Josafat A; Cavazos-Garduño, Adriana; Soto-Rodríguez, Ida; Sanchez-Otero, Maria Guadalupe; Vernon-Carter, Eduardo J; García, Hugo S

2017-01-01

Curcumin is a natural, oil-soluble polyphenolic compound with potent anticancer, anti-inflammatory, and antioxidant activities. In its free form, it is very poorly absorbed in the gut due to its very low solubility. The use of nanoemulsions as carrier is a feasible way for improving curcumin bioavailability. To this end, the choice of emulsifying agent for stabilizing the nanoemulsions is of the upmost importance for achieving a desired functionality. Phosphatidylcholine (PC) and phosphatidycholine enriched (PCE) with medium chain fatty acids (42.5 mol %) in combination with glycerol as co-surfactant, were used for preparing oil-in water nanoemulsions coded as NEPC and NEPCE, respectively. NEPCE displayed significantly smaller mean droplet size (30 nm), equal entrapment efficiency (100%), better droplet stability and suffered lower encapsulation efficiency loss (3%) during storage time (120 days, 4ºC) than NEPC. Bioavailability, measured in terms of area under the curve of curcumin concentration versus time, and maximum curcumin plasma concentration, was in general terms significantly higher for NEPCE than for NEPC, and for curcumin coarse aqueous suspension (CCS). Also, NEPCE produced significantly higher curcumin concentrations in liver and lung than NEPC and CCS. These data support the role of phosphatidylcholine enriched with medium chain fatty acids to increase the bioavailability of nanoemulsions for therapeutic applications. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Improved oral bioavailability for lutein by nanocrystal technology: formulation development, in vitro and in vivo evaluation.

PubMed

Chang, Daoxiao; Ma, Yanni; Cao, Guoyu; Wang, Jianhuan; Zhang, Xia; Feng, Jun; Wang, Wenping

2018-08-01

Lutein is a kind of natural carotenoids possessing many pharmacological effects. The application of lutein was limited mainly due to its low oral bioavailability caused by poor aqueous solubility. Nanocrystal formulation of lutein was developed to improve the oral bioavailability in this study. The nanosuspension was prepared by the anti-solvent precipitation-ultrasonication method and optimized by Box-Behnken design, followed by freeze-drying to obtain lutein nanocrystals. The nanocrystals were characterized on their physical properties, in vitro dissolution and in vivo absorption performance. Lutein nanocrystals showed as tiny spheres with an average particle size of 110.7 nm. The result of diffractograms indicated that the percent crystallinity of lutein was 89.4% in coarse powder and then declined in nanocrystal formulation. The saturated solubility of lutein in water increased from 7.3 μg/ml for coarse powder up to 215.7 μg/ml for lutein nanocrystals. The dissolution rate of lutein nanocrystals was significantly higher than that of coarse powder or the physical mixture. The C max and AUC 0-24 h of lutein nanocrystals after oral administration in rats was 3.24 and 2.28 times higher than those of lutein suspension, respectively. These results indicated that the nanocrystal formulation could significantly enhance the dissolution and absorption of lutein and might be a promising approach for improving its oral bioavailability.

Self-microemulsifying drug delivery system improves curcumin dissolution and bioavailability.

PubMed

Wu, Xuemei; Xu, Jianhua; Huang, Xiuwang; Wen, Caixia

2011-01-01

Curcumin has a wide spectrum of biological and pharmacological activities, but it has not yet been approved as a therapeutic agent because of its low solubility and stability in aqueous solution, and the relatively low bioavailability in vivo. To overcome these limitations, self-microemulsifying drug delivery system (SMEDDS) of curcumin was developed. Various oils, surfactants, and cosurfactants were selected to optimize the formulation. Pseudoternary phase diagrams were constructed and orthogonal design was used to compare the oil-in-water (o/w) microemulsion-forming capacity of different oils/surfactants/cosurfactants. The solubility of curcumin in various oils and cosurfactants was determined to find suitable ingredients with a good solubilizing capacity. Droplet size was measured to obtain the concentration of oil, surfactant, and cosurfactant for forming stable microemulsion. Furthermore, its quality and bioavailability in mice were assessed. Pseudoternary phase diagrams and solubility test showed that the formulation of SMEDDS composed of 20% ethanol, 60% Cremophor RH40®, and 20% isopropyl myristate, in which the concentration of curcumin reached 50 mg/mL. Curcumin was released completely from SMEDDS at 10 minutes. The developed SMEDDS formulation improved the oral bioavailability of curcumin significantly, and the relative oral bioavailability of SMEDDS compared with curcumin suspension was 1213%. The SMEDDS can significantly increase curcumin dissolution in vitro and bioavailability in vivo.

SNEDDS curcumin formulation leads to enhanced protection from pain and functional deficits associated with diabetic neuropathy: an insight into its mechanism for neuroprotection.

PubMed

Joshi, Rayanta P; Negi, Geeta; Kumar, Ashutosh; Pawar, Yogesh B; Munjal, Bhushan; Bansal, Arvind K; Sharma, Shyam S

2013-08-01

Curcumin has shown to be effective against various diabetes related complications. However major limitation with curcumin is its low bioavailability. In this study we formulated and characterized self nano emulsifying drug delivery system (SNEDDS) curcumin formulation to enhance its bioavailability and then evaluated its efficacy in experimental diabetic neuropathy. Bioavailability studies were performed in male Sprague Dawley rats. Further to evaluate the efficacy of formulation in diabetic neuropathy various parameters like nerve function and sensorimotor perception were assessed along with study of inflammatory proteins (NF-κB, IKK-β, COX-2, iNOS, TNF-α and IL-6). Nanotechnology based formulation resulted in prolonged plasma exposure and bioavailability. SNEDDS curcumin provided better results against functional, behavioural and biochemical deficits in experimental diabetic neuropathy, when compared with naive curcumin. Further western blot analysis confirmed the greater neuroprotective action of SNEDDS curcumin. SNEDDS curcumin formulation due to higher bioavailability was found to afford enhanced protection in diabetic neuropathy. In this study the authors formulated and characterized a self-emulsifying drug delivery system for formulation to enhance curcumin bioavailability in experimental diabetic neuropathy. Enhanced efficacy was demonstrated in a rat model. Copyright © 2013 Elsevier Inc. All rights reserved.

Respiratory control in aquatic insects dictates their vulnerability to global warming

PubMed Central

Verberk, Wilco C. E. P.; Bilton, David T.

2013-01-01

Forecasting species responses to climatic warming requires knowledge of how temperature impacts may be exacerbated by other environmental stressors, hypoxia being a principal example in aquatic systems. Both stressors could interact directly as temperature affects both oxygen bioavailability and ectotherm oxygen demand. Insufficient oxygen has been shown to limit thermal tolerance in several aquatic ectotherms, although, the generality of this mechanism has been challenged for tracheated arthropods. Comparing species pairs spanning four different insect orders, we demonstrate that oxygen can indeed limit thermal tolerance in tracheates. Species that were poor at regulating oxygen uptake were consistently more vulnerable to the synergistic effects of warming and hypoxia, demonstrating the importance of respiratory control in setting thermal tolerance limits. PMID:23925834

Respiratory control in aquatic insects dictates their vulnerability to global warming.

PubMed

Verberk, Wilco C E P; Bilton, David T

2013-10-23

Forecasting species responses to climatic warming requires knowledge of how temperature impacts may be exacerbated by other environmental stressors, hypoxia being a principal example in aquatic systems. Both stressors could interact directly as temperature affects both oxygen bioavailability and ectotherm oxygen demand. Insufficient oxygen has been shown to limit thermal tolerance in several aquatic ectotherms, although, the generality of this mechanism has been challenged for tracheated arthropods. Comparing species pairs spanning four different insect orders, we demonstrate that oxygen can indeed limit thermal tolerance in tracheates. Species that were poor at regulating oxygen uptake were consistently more vulnerable to the synergistic effects of warming and hypoxia, demonstrating the importance of respiratory control in setting thermal tolerance limits.

Impact of passive permeability and gut efflux transport on the oral bioavailability of novel series of piperidine-based renin inhibitors in rodents.

PubMed

Lévesque, Jean-François; Bleasby, Kelly; Chefson, Amandine; Chen, Austin; Dubé, Daniel; Ducharme, Yves; Fournier, Pierre-André; Gagné, Sébastien; Gallant, Michel; Grimm, Erich; Hafey, Michael; Han, Yongxin; Houle, Robert; Lacombe, Patrick; Laliberté, Sébastien; MacDonald, Dwight; Mackay, Bruce; Papp, Robert; Tschirret-Guth, Richard

2011-09-15

An oral bioavailability issue encountered during the course of lead optimization in the renin program is described herein. The low F(po) of pyridone analogs was shown to be caused by a combination of poor passive permeability and gut efflux transport. Substitution of pyridone ring for a more lipophilic moiety (logD>1.7) had minimal effect on rMdr1a transport but led to increased passive permeability (P(app)>10 × 10(-6) cm/s), which contributed to overwhelm gut transporters and increase rat F(po). LogD and in vitro passive permeability determination were found to be key in guiding SAR and improve oral exposure of renin inhibitors. Copyright © 2011 Elsevier Ltd. All rights reserved.

Haste Makes Waste: The Interplay Between Dissolution and Precipitation of Supersaturating Formulations.

PubMed

Sun, Dajun D; Lee, Ping I

2015-11-01

Contrary to the early philosophy of supersaturating formulation design for oral solid dosage forms, current evidence shows that an exceedingly high rate of supersaturation generation could result in a suboptimal in vitro dissolution profile and subsequently could reduce the in vivo oral bioavailability of amorphous solid dispersions. In this commentary, we outline recent research efforts on the specific effects of the rate and extent of supersaturation generation on the overall kinetic solubility profiles of supersaturating formulations. Additional insights into an appropriate definition of sink versus nonsink dissolution conditions and the solubility advantage of amorphous pharmaceuticals are also highlighted. The interplay between dissolution and precipitation kinetics should be carefully considered in designing a suitable supersaturating formulation to best improve the dissolution behavior and oral bioavailability of poorly water-soluble drugs.

New perspectives of curcumin in cancer prevention

PubMed Central

Park, Wungki; Amin, A.R.M Ruhul; Chen, Zhuo Georgia; Shin, Dong M.

2013-01-01

Numerous natural compounds have been extensively investigated for their potential for cancer prevention over decades. Curcumin, from Curcuma longa, is a highly promising natural compound that can be potentially used for chemoprevention of multiple cancers. Curcumin modulates multiple molecular pathways involved in the lengthy carcinogenesis process to exert its chemopreventive effects through several mechanisms: promoting apoptosis, inhibiting survival signals, scavenging reactive oxidative species (ROS), and reducing the inflammatory cancer microenvironment. Curcumin fulfills the characteristics for an ideal chemopreventive agent with its low toxicity, affordability, and easy accessibility. Nevertheless, the clinical application of curcumin is currently compromised by its poor bioavailability. Here we review the potential of curcumin in cancer prevention, its molecular targets, and action mechanisms. Finally, we suggest specific recommendations to improve its efficacy and bioavailability for clinical applications. PMID:23466484

Mean Annual Temperature Drives Microbial Nitrogen Cycling and Fine Root Nutrient Foraging Across a Tropical Montane Wet Forest Elevation Gradient

NASA Astrophysics Data System (ADS)

Pierre, S.; Litton, C. L. M.; Giardina, C. P.; Sparks, J. P.; Groffman, P. M.; Hewson, I.; Fahey, T. J.

2017-12-01

Mean annual temperature (MAT) is positively correlated with rates of primary production and carbon (C) turnover in forests globally, but the underlying biotic drivers of these relationships remain poorly resolved. We hypothesized that (1) MAT increases nitrifier abundance and thereby nitrate (NO-) bioavailability in soils and (2) increased NO- bioavailability reduces fine root nitrogen (N) demand. We used an ecologically well-constrained natural elevation gradient (13˚C -18˚C) in a tropical wet motane forest on the Island of Hawaii to study to role of MAT in situ. Our previous work showed that MAT drives increased soil NO- bioavailability in situ (r²=0.79, P=0.003), and indicated that the abundance of ammonia oxidizing archaea is strongly and positively correlated with MAT in situ (r²=0.34, P<0.001; Pierre et. al. 2017). Using fertilized fine root ingrowth cores (+N, +P, +N+P, control) across the same MAT gradient, we found that increasing MAT and bulk soil NO- bioavailability produced a significant negative fine root response to the +N+P treatment (P=0.023), and no response to other fertilization treatments. Increasing MAT and soil NO- bioavailability led to increased percent arbuscular mycorrhizal (AM) colonization of fine roots (r²=0.43, P=0.004), but no treatment effect on AM colonization was observed. Our results suggest that N and P generally co-limit fine root foraging across the gradient, while higher MAT and bulk soil NO- bioavailability interact to reduce fine root foraging effort. Further, higher MAT and greater N fertility in soils may reduce the C limitation of AM fungal colonization. We conclude that MAT drives N-rich conditions, which allow for lower N foraging effort, but greater C investment in P acquisition through AM fine root colonization.

Long-Term Effect of Crop Rotation and Fertilisation on Bioavailability and Fractionation of Copper in Soil on the Loess Plateau in Northwest China

PubMed Central

Zang, Yifei; Wei, Xiaorong; Hao, Mingde

2015-01-01

The bioavailability and fractionation of Cu reflect its deliverability in soil. Little research has investigated Cu supply to crops in soil under long-term rotation and fertilisation on the Loess Plateau. A field experiment was conducted in randomized complete block design to determine the bioavailability and distribution of Cu fractions in a Heilu soil (Calcaric Regosol) after 18 years of rotation and fertilisation. The experiment started in 1984, including five cropping systems (fallow control, alfalfa cropping, maize cropping, winter wheat cropping, and grain-legume rotation of pea/winter wheat/winter wheat + millet) and five fertiliser treatments (unfertilised control, N, P, N + P, and N + P + manure). Soil samples were collected in 2002 for chemical analysis. Available Cu was assessed by diethylene triamine pentaacetic acid (DTPA) extraction, and Cu was fractionated by sequential extraction. Results showed that DTPA-Cu was lower in cropping systems compared with fallow control. Application of fertilisers resulted in no remarkable changes in DTPA-Cu compared with unfertilised control. Correlation and path analyses revealed that soil pH and CaCO3 directly affected Cu bioavailability, whereas available P indirectly affected Cu bioavailability. The concentrations of Cu fractions (carbonate and Fe/Al oxides) in the plough layer were lower in cropping systems, while the values in the plough sole were higher under grain-legume rotation relative to fallow control. Manure with NP fertiliser increased Cu fractions bound to organic matter and minerals in the plough layer, and its effects in the plough sole varied with cropping systems. The direct sources (organic-matter-bound fraction and carbonate-bound fraction) of available Cu contributed much to Cu bioavailability. The mineral-bound fraction of Cu acted as an indicator of Cu supply potential in the soil. PMID:26694965

Long-Term Effect of Crop Rotation and Fertilisation on Bioavailability and Fractionation of Copper in Soil on the Loess Plateau in Northwest China.

PubMed

Zang, Yifei; Wei, Xiaorong; Hao, Mingde

2015-01-01

The bioavailability and fractionation of Cu reflect its deliverability in soil. Little research has investigated Cu supply to crops in soil under long-term rotation and fertilisation on the Loess Plateau. A field experiment was conducted in randomized complete block design to determine the bioavailability and distribution of Cu fractions in a Heilu soil (Calcaric Regosol) after 18 years of rotation and fertilisation. The experiment started in 1984, including five cropping systems (fallow control, alfalfa cropping, maize cropping, winter wheat cropping, and grain-legume rotation of pea/winter wheat/winter wheat + millet) and five fertiliser treatments (unfertilised control, N, P, N + P, and N + P + manure). Soil samples were collected in 2002 for chemical analysis. Available Cu was assessed by diethylene triamine pentaacetic acid (DTPA) extraction, and Cu was fractionated by sequential extraction. Results showed that DTPA-Cu was lower in cropping systems compared with fallow control. Application of fertilisers resulted in no remarkable changes in DTPA-Cu compared with unfertilised control. Correlation and path analyses revealed that soil pH and CaCO3 directly affected Cu bioavailability, whereas available P indirectly affected Cu bioavailability. The concentrations of Cu fractions (carbonate and Fe/Al oxides) in the plough layer were lower in cropping systems, while the values in the plough sole were higher under grain-legume rotation relative to fallow control. Manure with NP fertiliser increased Cu fractions bound to organic matter and minerals in the plough layer, and its effects in the plough sole varied with cropping systems. The direct sources (organic-matter-bound fraction and carbonate-bound fraction) of available Cu contributed much to Cu bioavailability. The mineral-bound fraction of Cu acted as an indicator of Cu supply potential in the soil.

Novel resveratrol nanodelivery systems based on lipid nanoparticles to enhance its oral bioavailability

PubMed Central

Neves, Ana Rute; Lúcio, Marlene; Martins, Susana; Lima, José Luís Costa; Reis, Salette

2013-01-01

Introduction Resveratrol is a polyphenol found in grapes and red wines. Interest in this polyphenol has increased due to its pharmacological cardio- and neuroprotective, chemopreventive, and antiaging effects, among others. Nevertheless, its pharmacokinetic properties are less favorable, since the compound has poor bioavailability, low water solubility, and is chemically unstable. To overcome these problems, we developed two novel resveratrol nanodelivery systems based on lipid nanoparticles to enhance resveratrol’s oral bioavailability for further use in medicines, supplements, and nutraceuticals. Methods and materials Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) loaded with resveratrol were successfully produced by a modified hot homogenization technique. These were completely characterized to evaluate the quality of the developed resveratrol-loaded nanoparticles. Results Cryo-scanning electron microscopy morphology studies showed spherical and uniform nanoparticles with a smooth surface. An average resveratrol entrapment efficiency of ~70% was obtained for both SLNs and NLCs. Dynamic light scattering measurements gave a Z-average of 150–250 nm, polydispersity index of ~0.2, and a highly negative zeta potential of around −30 mV with no statistically significant differences in the presence of resveratrol. These characteristics remained unchanged for at least 2 months, suggesting good stability. Differential scanning calorimetry studies confirmed the solid state of the SLNs and NLCs at both room and body temperatures. The NLCs had a less ordered crystalline structure conferred by the inclusion of the liquid lipid, since they had lower values for phase transition temperature, melting enthalpy, and the recrystallization index. The presence of resveratrol induced a disorder in the crystal structure of the nanoparticles, suggesting a favoring of its entrapment. The in vitro release studies on conditions of storage showed a negligible resveratrol release over several hours for both nanosystems and the in vitro simulation of gastrointestinal transit showed that the resveratrol remained mostly associated with the lipid nanoparticles after their incubation in digestive fluids. Conclusion Both nanodelivery systems can be considered suitable carriers for oral administration, conferring protection to the incorporated resveratrol and allowing a controlled release after uptake. PMID:23326193

Experimental Design for Determination of Effects of Superdisintegrant Combinations on Liquisolid System Properties.

PubMed

Vraníková, Barbora; Pavloková, Sylvie; Gajdziok, Jan

2017-03-01

The preparation of liquisolid systems presents a promising and innovative possibility for enhancing dissolution profiles and improving the bioavailability of poorly soluble drugs. This study aims to evaluate the differences in the properties of liquisolid systems containing combinations of 3 commercially used superdisintegrants (sodium starch glycolate, crospovidone, and croscarmellose sodium). Multiple regression models and contour plots were used to study how the amount and the type of superdisintegrant used affected the quality parameters of liquisolid tablets. The results revealed that an increased amount of crospovidone in the mixture improves disintegration and wetting time and enhances drug release from the prepared liquisolid tablets. Moreover, it was observed that a binary blend of crospovidone and sodium starch glycolate improved tablet disintegration. Considering the obtained results, it could be stated that crospovidone showed the best properties to be used as superdisintegrant for the preparation of liquisolid systems containing rosuvastatin. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Dissolved oxygen as an indicator of bioavailable dissolved organic carbon in groundwater

USGS Publications Warehouse

Chapelle, Francis H.; Bradley, Paul M.; McMahon, Peter B.; Kaiser, Karl; Benner, Ron

2012-01-01

Concentrations of dissolved oxygen (DO) plotted vs. dissolved organic carbon (DOC) in groundwater samples taken from a coastal plain aquifer of South Carolina (SC) showed a statistically significant hyperbolic relationship. In contrast, DO-DOC plots of groundwater samples taken from the eastern San Joaquin Valley of California (CA) showed a random scatter. It was hypothesized that differences in the bioavailability of naturally occurring DOC might contribute to these observations. This hypothesis was examined by comparing nine different biochemical indicators of DOC bioavailability in groundwater sampled from these two systems. Concentrations of DOC, total hydrolysable neutral sugars (THNS), total hydrolysable amino acids (THAA), mole% glycine of THAA, initial bacterial cell counts, bacterial growth rates, and carbon dioxide production/consumption were greater in SC samples relative to CA samples. In contrast, the mole% glucose of THNS and the aromaticity (SUVA254) of DOC was greater in CA samples. Each of these indicator parameters were observed to change with depth in the SC system in a manner consistent with active biodegradation. These results are uniformly consistent with the hypothesis that the bioavailability of DOC is greater in SC relative to CA groundwater samples. This, in turn, suggests that the presence/absence of a hyperbolic DO-DOC relationship may be a qualitative indicator of relative DOC bioavailability in groundwater systems.

The atypical genesis and bioavailability of the plant-based small RNA MIR2911: Bulking up while breaking down

USDA-ARS?s Scientific Manuscript database

The uptake of dietary plant small RNAs (sRNAs) in consumers remains controversial, which is mainly due to low dietary content in combination with poor fractional absorption. MIR2911, among all the plant sRNAs including microRNAs, has been shown to be one of the most robustly absorbed sRNAs. Here we ...

Preparation and evaluation of valsartan by a novel semi-solid self-microemulsifying delivery system using Gelucire 44/14.

PubMed

Zhao, Kun; Yuan, Yue; Wang, Hui; Li, Panpan; Bao, Zhihong; Li, Yue

2016-10-01

The aim of the present study was to develop a novel semi-solid self-microemulsifying drug delivery system (SMEDDS) using Gelucire(®) 44/14 as oil with strong solid character to improve the oral bioavailability of poorly soluble drug valsartan. The solubility of valsartan in various excipients was determined, the pseudo-ternary phase diagram was constructed in order to screen the optimal excipients, and DSC analysis was performed to evaluate the melting point of SMEDDS. The optimal drug-loaded SMEDDS formulation was consisted of 30% Gelucire(®) 44/14 (oil), 40% Solutol(®) HS 15 (surfactant), and 30% Transcutol(®) P (cosurfactant) (w/w) with 80 mg valsartan/g excipients. The average droplet sizes of the optimized blank and drug-loaded SMEDDS formulations were 26.20 ± 1.43 and 33.34 ± 2.15 nm, and the melting points of them were 35.6 and 36.8 °C, respectively. The in vitro dissolution rate of optimal semi-solid SMEDDS was increased compared with commercial capsules, resulting in the 2.72-fold and 2.97-fold enhancement of Cmax and AUC0-t after oral administration in rats, respectively. These results indicated that the novel semi-solid SMEDDS formulation could potentially improve the oral bioavailability of valsartan, and the semi-solid SMEDDS was a desirable system than the traditional liquid SMEDDS because it was convenient for preparation, storage and transportation due to semi-solid state at room temperature and melted state at body temperature.

Examination of oral absorption and lymphatic transport of halofantrine in a triple-cannulated canine model after administration in self-microemulsifying drug delivery systems (SMEDDS) containing structured triglycerides.

PubMed

Holm, René; Porter, Christopher J H; Edwards, Glenn A; Müllertz, Anette; Kristensen, Henning G; Charman, William N

2003-09-01

The potential for lipidic self-microemulsifying drug delivery systems (SMEDDS) containing triglycerides with a defined structure, where the different fatty acids on the glycerol backbone exhibit different metabolic fate, to improve the lymphatic transport and the portal absorption of a poorly water-soluble drug, halofantrine, were investigated in fasted lymph cannulated canines. Two different structured triglycerides were incorporated into the SMEDDS; 1,3-dioctanoyl-2-linoleyl-sn-glycerol (C8:0-C18:2-C8:0) (MLM) and 1,3-dilinoyl-2-octanoyl-sn-glycerol (C18:2-C8:0-C18:2) (LML). A previously optimised SMEDDS formulation for halofantrine, comprising of triglyceride, Cremophor EL, Maisine 35-1 and ethanol was selected for bioavailability assessment. The extent of lymphatic transport via the thoracic duct was 17.9% of the dose for the animals dosed with the MLM SMEDDS and 27.4% for LML. Also the plasma availability was affected by the triglyceride incorporated into the multi-component delivery system and availabilities of 56.9% (MLM) and 37.2% (LML) were found. These data indicate that the pharmaceutical scientist can use the structure of the lipid to affect the relative contribution of the two absorption pathways. The MLM formulation produced a total bioavailability of 74.9%, which is higher than the total absorption previously observed after post-prandial administration. This could indicate the utility of disperse lipid-base formulations based on structured triglycerides for the oral delivery of halofantrine, and potentially other lipophilic drugs.

Nanoparticulate strategies for effective delivery of poorly soluble therapeutics.

PubMed

Gokce, Evren H; Ozyazici, Mine; Souto, Eliana B

2010-07-01

The pharmacological activity of a drug molecule depends on its ability to dissolve and interact with its biological target, either through dissolution and absorption, or through dissolution and receptor interaction. The low bioavailability that characterizes poorly water-soluble drugs is usually attributed to the dissolution kinetic profile. Novel strategies to effectively deliver these drugs include nanoparticulate approaches that either increase the surface area of the drug or improve the solubility characteristics of the drug. Nanosizing approaches are based on the production of drug nanocrytals dispersed in an aqueous surfactant solution, whereas other possibilities include drug loading in nanoparticles. Promising nanoparticulate approaches include the development of lipid-based nanocarriers to increase drug solubility followed by enhanced bioavailability. To select the best approach there are, however, some critical considerations to take into account, for example the physicochemical properties of the drug, the possibility to scale-up the production process, the toxicological considerations of the use of solvents and cosolvents, the selection of an environmentally sustainable methodology and the development of a more patient-friendly dosage form. This article addresses these relevant questions and provides feasible examples of novel strategies with respect to relevant administration routes.

Mutually Exclusive Alterations in Secondary Metabolism Are Critical for the Uptake of Insoluble Iron Compounds by Arabidopsis and Medicago truncatula1[C][W

PubMed Central

Rodríguez-Celma, Jorge; Lin, Wen-Dar; Fu, Guin-Mau; Abadía, Javier; López-Millán, Ana-Flor; Schmidt, Wolfgang

2013-01-01

The generally low bioavailability of iron in aerobic soil systems forced plants to evolve sophisticated genetic strategies to improve the acquisition of iron from sparingly soluble and immobile iron pools. To distinguish between conserved and species-dependent components of such strategies, we analyzed iron deficiency-induced changes in the transcriptome of two model species, Arabidopsis (Arabidopsis thaliana) and Medicago truncatula. Transcriptional profiling by RNA sequencing revealed a massive up-regulation of genes coding for enzymes involved in riboflavin biosynthesis in M. truncatula and phenylpropanoid synthesis in Arabidopsis upon iron deficiency. Coexpression and promoter analysis indicated that the synthesis of flavins and phenylpropanoids is tightly linked to and putatively coregulated with other genes encoding proteins involved in iron uptake. We further provide evidence that the production and secretion of phenolic compounds is critical for the uptake of iron from sources with low bioavailability but dispensable under conditions where iron is readily available. In Arabidopsis, homozygous mutations in the Fe(II)- and 2-oxoglutarate-dependent dioxygenase family gene F6′H1 and defects in the expression of PLEIOTROPIC DRUG RESISTANCE9, encoding a putative efflux transporter for products from the phenylpropanoid pathway, compromised iron uptake from an iron source of low bioavailability. Both mutants were partially rescued when grown alongside wild-type Arabidopsis or M. truncatula seedlings, presumably by secreted phenolics and flavins. We concluded that production and secretion of compounds that facilitate the uptake of iron is an essential but poorly understood aspect of the reduction-based iron acquisition strategy, which is likely to contribute substantially to the efficiency of iron uptake in natural conditions. PMID:23735511

Optimized preparation of vinpocetine proliposomes by a novel method and in vivo evaluation of its pharmacokinetics in New Zealand rabbits.

PubMed

Xu, Hongtao; He, Ling; Nie, Shufang; Guan, Jin; Zhang, Xiaoning; Yang, Xinggang; Pan, Weisan

2009-11-16

Free-flowing proliposomes which contained vinpocetine were prepared successfully to increase the oral bioavailability of vinpocetine. In this study the proliposomes were prepared by a novel method which was reported for the first time and the formulation was optimized using the centre composite design (CCD). The optimized formulation was Soybean phosphatidylcholine: 860 mg; cholesterol: 95 mg and sorbitol: 8000 mg. After the proliposomes were contacted with water, the suspension of vinpocetine liposomes formed automatically and the entrapment efficiency was approximately 86.3% with an average particle size of about 300 nm. The physicochemical properties of the proliposomes including SEM, TEM, XRD and FTIR were also detected. HPLC system was applied to study the concentration of vinpocetine in the plasma of the New Zealand rabbits after oral administration of vinpocetine proliposomes and vinpocetine suspension. The pharmacokinetic parameters were calculated by the software program DAS2.0. The concentration-time curves of vinpocetine suspension and vinpocetine proliposomes were much more different. There were two absorption peaks on the concentration-time curves of the vinpocetine proliposomes. The pharmacokinetic parameters of vinpocetine and vinpocetine proliposomes in New Zealand rabbits were T(max) 1 h and 3 h (there was also an absorption peak at 1 h); C(max) 163.82+/-12.28 ng/ml and 166.43+/-21.04 ng/ml; AUC(0-infinity) 1479.70+/-68.51 ng/ml h and 420.70+/-35.86 ng/ml h, respectively. The bioavailability of vinpocetine in proliposomes was more than 3.5 times higher than the vinpocetine suspension. The optimized vinpocetine proliposomes did improve the oral bioavailability of vinpocetine in New Zealand rabbits and offer a new approach to enhance the gastrointestinal absorption of poorly water soluble drugs.

Polyphenols from artichoke heads (Cynara cardunculus (L.) subsp. scolymus Hayek): in vitro bio-accessibility, intestinal uptake and bioavailability.

PubMed

D'Antuono, Isabella; Garbetta, Antonella; Linsalata, Vito; Minervini, Fiorenza; Cardinali, Angela

2015-04-01

Artichoke is a rich source of health promoting compounds such as polyphenols, important for their pharmaceutical and nutritional properties. In this study, the potential for bioavailability of the artichoke polyphenols was estimated by using both in vitro digestion and Caco-2 human intestinal cell models. In vitro digestive recoveries (bio-accessibility) were found to be 55.8% for total artichoke phenolics and in particular, 70.0% for chlorogenic acid, 41.3% for 3,5-O-dicaffeoylquinic acid, and 50.3% for 1,5-O-dicaffeoylquinic acid, highlighting potential sensitivity of these compounds to gastric and small intestinal digestive conditions. Uptake of artichoke polyphenols was rapid with peak accumulation occurring after 30 min with an efficiency of 0.16%, according to the poor uptake of dietary polyphenols. Some compounds, such as coumaric acid, caffeic acid and caffeic acid derivatives, were also detected in the basolateral side assuming extra and intracellular esterase activities on chlorogenic acid. Only apigenin-7-O-glucoside was transported through the Caco-2 monolayer demonstrating its bioavailability to the extent of 1.15% at 60 min. In addition, permeability coefficient (Papp = 2.29 × 10(-5) cm s(-1)), involving apical to basolateral transport of apigenin 7-O-glucoside, was calculated to facilitate estimation of transport through the Caco-2 monolayer. Finally, the mono and dicaffeoylquinic acids present in artichoke heads exert an antioxidant activity on the human low density lipoprotein system correlated to their chemical structure. In conclusion, the utilized in vitro models, although not fully responding to the morphological and physiological features of human in vivo conditions, could be a useful tool for investigating mechanistic effects of polyphenols released from the food matrix.

Manufacturing Amorphous Solid Dispersions with a Tailored Amount of Crystallized API for Biopharmaceutical Testing.

PubMed

Theil, Frank; Milsmann, Johanna; Anantharaman, Sankaran; van Lishaut, Holger

2018-05-07

The preparation of an amorphous solid dispersion (ASD) by dissolving a poorly water-soluble active pharmaceutical ingredient (API) in a polymer matrix can improve the bioavailability by orders of magnitude. Crystallization of the API in the ASD, though, is an inherent threat for bioavailability. Commonly, the impact of crystalline API on the drug release of the dosage form is studied with samples containing spiked crystallinity. These spiked samples possess implicit differences compared to native crystalline samples, regarding size and spatial distribution of the crystals as well as their molecular environment. In this study, we demonstrate that it is possible to grow defined amounts of crystalline API in solid dosage forms, which enables us to study the biopharmaceutical impact of actual crystallization. For this purpose, we studied the crystal growth in fenofibrate tablets over time under an elevated moisture using transmission Raman spectroscopy (TRS). As a nondestructive method to assess API crystallinity in ASD formulations, TRS enables the monitoring of crystal growth in individual dosage forms. Once the kinetic trace of the crystal growth for a certain environmental condition is determined, this method can be used to produce samples with defined amounts of crystallized API. To investigate the biopharmaceutical impact of crystallized API, non-QC dissolution methods were used, designed to identify differences between the various amounts of crystalline materials present. The drug release in the samples manufactured in this fashion was compared to that of samples with spiked crystallinity. In this study, we present for the first time a method for targeted crystallization of amorphous tablets to simulate crystallized ASDs. This methodology is a valuable tool to generate model systems for biopharmaceutical studies on the impact of crystallinity on the bioavailability.

Coamorphous Loratadine-Citric Acid System with Enhanced Physical Stability and Bioavailability.

PubMed

Wang, Jin; Chang, Ruimiao; Zhao, Yanan; Zhang, Jiye; Zhang, Ting; Fu, Qiang; Chang, Chun; Zeng, Aiguo

2017-10-01

Coamorphous systems using citric acid as a small molecular excipient were studied for improving physical stability and bioavailability of loratadine, a BCS class II drug with low water solubility and high permeability. Coamorphous loratadine-citric acid systems were prepared by solvent evaporation technique and characterized by differential scanning calorimetry, X-ray powder diffraction, and Fourier transform infrared spectroscopy. Solid-state analysis proofed that coamorphous loratadine-citric acid system (1:1) was amorphous and homogeneous, had a higher T g over amorphous loratadine, and the intermolecular hydrogen bond interactions between loratadine and citric acid exist. The solubility and dissolution of coamorphous loratadine-citric acid system (1:1) were found to be significantly greater than those of crystalline and amorphous form. The pharmacokinetic study in rats proved that coamorphous loratadine-citric acid system (1:1) could significantly improve absorption and bioavailability of loratadine. Coamorphous loratadine-citric acid system (1:1) showed excellently physical stability over a period of 3 months at 25°C under 0% RH and 25°C under 60% RH conditions. The improved stability of coamorphous loratadine-citric acid system (1:1) could be related to an elevated T g over amorphous form and the intermolecular hydrogen bond interactions between loratadine and citric acid. These studies demonstrate that the developed coamorphous loratadine-citric acid system might be a promising oral formulation for improving solubility and bioavailability of loratadine.

Bioavailability of bioactive food compounds: a challenging journey to bioefficacy

PubMed Central

Rein, Maarit J.; Renouf, Mathieu; Cruz‐Hernandez, Cristina; Actis‐Goretta, Lucas; Thakkar, Sagar K.; da Silva Pinto, Marcia

2013-01-01

Bioavailability is a key step in ensuring bioefficacy of bioactive food compounds or oral drugs. Bioavailability is a complex process involving several different stages: liberation, absorption, distribution, metabolism and elimination phases (LADME). Bioactive food compounds, whether derived from various plant or animal sources, need to be bioavailable in order to exert any beneficial effects. Through a better understanding of the digestive fate of bioactive food compounds we can impact the promotion of health and improvement of performance. Many varying factors affect bioavailability, such as bioaccessibility, food matrix effect, transporters, molecular structures and metabolizing enzymes. Bioefficacy may be improved through enhanced bioavailability. Therefore, several technologies have been developed to improve the bioavailability of xenobiotics, including structural modifications, nanotechnology and colloidal systems. Due to the complex nature of food bioactive compounds and also to the different mechanisms of absorption of hydrophilic and lipophilic bioactive compounds, unravelling the bioavailability of food constituents is challenging. Among the food sources discussed during this review, coffee, tea, citrus fruit and fish oil were included as sources of food bioactive compounds (e.g. (poly)phenols and polyunsaturated fatty acids (PUFAs)) since they are examples of important ingredients for the food industry. Although there are many studies reporting on bioavailability and bioefficacy of these bioactive food components, understanding their interactions, metabolism and mechanism of action still requires extensive work. This review focuses on some of the major factors affecting the bioavailability of the aforementioned bioactive food compounds. PMID:22897361

Pluronic-Functionalized Silica-Lipid Hybrid Microparticles: Improving the Oral Delivery of Poorly Water-Soluble Weak Bases.

PubMed

Rao, Shasha; Richter, Katharina; Nguyen, Tri-Hung; Boyd, Ben J; Porter, Christopher J H; Tan, Angel; Prestidge, Clive A

2015-12-07

A Pluronic-functionalized silica-lipid hybrid (Plu-SLH) microparticle system for the oral delivery of poorly water-soluble, weak base drugs is reported for the first time. A highly effective Plu-SLH microparticle system was composed of Labrasol as the lipid phase, Pluronic F127 as the polymeric precipitation inhibitor (PPI), and silica nanoparticles as the solid carrier. For the model drug cinnarizine (CIN), the Plu-SLH delivery system was shown to offer significant biopharmaceutical advantages in comparison with unformulated drug and drug in the silica-lipid hybrid (SLH) system. In vitro two-phase dissolution studies illustrated significantly reduced pH provoked CIN precipitation and an 8- to 14-fold improvement in the extent of dissolution in intestinal conditions. In addition, under simulated intestinal digesting conditions, the Plu-SLH provided approximately three times more drug solubilization than the SLH. Oral administration in rats resulted in superior bioavailability for Plu-SLH microparticles, i.e., 1.6- and 2.1-fold greater than the SLH and the unformulated CIN, respectively. A physical mixture of Pluronic and SLH (Plu&SLH), having the same composition as Plu-SLH, was also evaluated, but showed no significant increase in CIN absorption when compared to unmodified CIN or SLH. This work represents the first study where different methods of incorporating PPI to formulate solid-state lipid-based formulations were compared for the impact on the biopharmaceutical performance. The data suggest that the novel physicochemical properties and structure of the fabricated Plu-SLH microparticle delivery system play an important role in facilitating the synergistic advantage of Labrasol and Pluronic F127 in preventing drug precipitation, and the Plu-SLH provides efficient oral delivery of poorly water-soluble weak bases.

Causal inference between bioavailability of heavy metals and environmental factors in a large-scale region.

PubMed

Liu, Yuqiong; Du, Qingyun; Wang, Qi; Yu, Huanyun; Liu, Jianfeng; Tian, Yu; Chang, Chunying; Lei, Jing

2017-07-01

The causation between bioavailability of heavy metals and environmental factors are generally obtained from field experiments at local scales at present, and lack sufficient evidence from large scales. However, inferring causation between bioavailability of heavy metals and environmental factors across large-scale regions is challenging. Because the conventional correlation-based approaches used for causation assessments across large-scale regions, at the expense of actual causation, can result in spurious insights. In this study, a general approach framework, Intervention calculus when the directed acyclic graph (DAG) is absent (IDA) combined with the backdoor criterion (BC), was introduced to identify causation between the bioavailability of heavy metals and the potential environmental factors across large-scale regions. We take the Pearl River Delta (PRD) in China as a case study. The causal structures and effects were identified based on the concentrations of heavy metals (Zn, As, Cu, Hg, Pb, Cr, Ni and Cd) in soil (0-20 cm depth) and vegetable (lettuce) and 40 environmental factors (soil properties, extractable heavy metals and weathering indices) in 94 samples across the PRD. Results show that the bioavailability of heavy metals (Cd, Zn, Cr, Ni and As) was causally influenced by soil properties and soil weathering factors, whereas no causal factor impacted the bioavailability of Cu, Hg and Pb. No latent factor was found between the bioavailability of heavy metals and environmental factors. The causation between the bioavailability of heavy metals and environmental factors at field experiments is consistent with that on a large scale. The IDA combined with the BC provides a powerful tool to identify causation between the bioavailability of heavy metals and environmental factors across large-scale regions. Causal inference in a large system with the dynamic changes has great implications for system-based risk management. Copyright © 2017 Elsevier Ltd. All rights reserved.

Particle Size, Surface Area, and Amorphous Content as Predictors of Solubility and Bioavailability for Five Commercial Sources of Ferric Orthophosphate in Ready-To-Eat Cereal.

PubMed

Dickmann, Robin S; Strasburg, Gale M; Romsos, Dale R; Wilson, Lori A; Lai, Grace H; Huang, Hsimin

2016-03-01

Ferric orthophosphate (FePO₄) has had limited use as an iron fortificant in ready-to-eat (RTE) cereal because of its variable bioavailability, the mechanism of which is poorly understood. Even though FePO₄ has desirable sensory properties as compared to other affordable iron fortificants, few published studies have well-characterized its physicochemical properties. Semi-crystalline materials such as FePO₄ have varying degrees of molecular disorder, referred to as amorphous content, which is hypothesized to be an important factor in bioavailability. The objective of this study was to systematically measure the physicochemical factors of particle size, surface area, amorphous content, and solubility underlying the variation in FePO₄ bioavailability. Five commercial FePO₄ sources and ferrous sulfate were added to individual batches of RTE cereal. The relative bioavailability value (RBV) of each iron source, determined using the AOAC Rat Hemoglobin Repletion Bioassay, ranged from 51% to 99% (p < 0.05), which is higher than typically reported. Solubility in dilute HCl accurately predicted RBV (R² = 0.93, p = 0.008). Amorphous content measured by Dynamic Vapor Sorption ranged from 1.7% to 23.8% and was a better determinant of solubility (R² = 0.91; p = 0.0002) than surface area (R² = 0.83; p = 0.002) and median particle size (R² = 0.59; p = 0.12). The results indicate that while solubility of FePO₄ is highly predictive of RBV, solubility, in turn, is strongly linked to amorphous content and surface area. This information may prove useful for the production of FePO₄ with the desired RBV.

Particle Size, Surface Area, and Amorphous Content as Predictors of Solubility and Bioavailability for Five Commercial Sources of Ferric Orthophosphate in Ready-To-Eat Cereal

PubMed Central

Dickmann, Robin S.; Strasburg, Gale M.; Romsos, Dale R.; Wilson, Lori A.; Lai, Grace H.; Huang, Hsimin

2016-01-01

Ferric orthophosphate (FePO4) has had limited use as an iron fortificant in ready-to-eat (RTE) cereal because of its variable bioavailability, the mechanism of which is poorly understood. Even though FePO4 has desirable sensory properties as compared to other affordable iron fortificants, few published studies have well-characterized its physicochemical properties. Semi-crystalline materials such as FePO4 have varying degrees of molecular disorder, referred to as amorphous content, which is hypothesized to be an important factor in bioavailability. The objective of this study was to systematically measure the physicochemical factors of particle size, surface area, amorphous content, and solubility underlying the variation in FePO4 bioavailability. Five commercial FePO4 sources and ferrous sulfate were added to individual batches of RTE cereal. The relative bioavailability value (RBV) of each iron source, determined using the AOAC Rat Hemoglobin Repletion Bioassay, ranged from 51% to 99% (p < 0.05), which is higher than typically reported. Solubility in dilute HCl accurately predicted RBV (R2 = 0.93, p = 0.008). Amorphous content measured by Dynamic Vapor Sorption ranged from 1.7% to 23.8% and was a better determinant of solubility (R2 = 0.91; p = 0.0002) than surface area (R2 = 0.83; p = 0.002) and median particle size (R2 = 0.59; p = 0.12). The results indicate that while solubility of FePO4 is highly predictive of RBV, solubility, in turn, is strongly linked to amorphous content and surface area. This information may prove useful for the production of FePO4 with the desired RBV. PMID:26938556

Oral bioavailability enhancement of raloxifene by developing microemulsion using D-optimal mixture design: optimization and in-vivo pharmacokinetic study.

PubMed

Shah, Nirmal; Seth, Avinashkumar; Balaraman, R; Sailor, Girish; Javia, Ankur; Gohil, Dipti

2018-04-01

The objective of this work was to utilize a potential of microemulsion for the improvement in oral bioavailability of raloxifene hydrochloride, a BCS class-II drug with 2% bioavailability. Drug-loaded microemulsion was prepared by water titration method using Capmul MCM C8, Tween 20, and Polyethylene glycol 400 as oil, surfactant, and co-surfactant respectively. The pseudo-ternary phase diagram was constructed between oil and surfactants mixture to obtain appropriate components and their concentration ranges that result in large existence area of microemulsion. D-optimal mixture design was utilized as a statistical tool for optimization of microemulsion considering oil, S mix , and water as independent variables with percentage transmittance and globule size as dependent variables. The optimized formulation showed 100 ± 0.1% transmittance and 17.85 ± 2.78 nm globule size which was identically equal with the predicted values of dependent variables given by the design expert software. The optimized microemulsion showed pronounced enhancement in release rate compared to plain drug suspension following diffusion controlled release mechanism by the Higuchi model. The formulation showed zeta potential of value -5.88 ± 1.14 mV that imparts good stability to drug loaded microemulsion dispersion. Surface morphology study with transmission electron microscope showed discrete spherical nano sized globules with smooth surface. In-vivo pharmacokinetic study of optimized microemulsion formulation in Wistar rats showed 4.29-fold enhancements in bioavailability. Stability study showed adequate results for various parameters checked up to six months. These results reveal the potential of microemulsion for significant improvement in oral bioavailability of poorly soluble raloxifene hydrochloride.

Comparative preclinical pharmacokinetics study of 3,3′-diindolylmethane formulations: is personalized treatment and targeted chemoprevention in the horizon?

PubMed Central

2013-01-01

Background 3,3′-Diindolylmethane (DIM) is known as an agent of natural origin that provides protection against different cancers due to the broad spectrum of its biological activities in vivo. However, this substance has a very poor biodistribution and absorption in animal tissues. This preclinical trial was conducted to evaluate the pharmacokinetics and bioavailability of various DIM formulations in animal model. Materials and methods The pharmacokinetic parameters of one crystalline DIM formulation and one liquid DIM formulation (oil solution) compared to non-formulated crystalline DIM (control) were tested in 200 rats. The formulations were orally administered to animals by gavage at doses of 200 mg/kg per DIM (crystalline DIM formulation and non-formulated crystalline DIM) and 0.1 mg/kg per DIM (DIM in oil solution). DIM plasma elimination was measured using HPLC method; after that, the area under the curve (AUC), relative bioavailability, and absolute bioavailability were estimated for two formulations in relation to non-formulated crystalline DIM. Results and conclusion The highest bioavailability was achieved by administering liquid DIM (oil solution), containing cod liver oil and polysorbate. The level of DIM in rat blood plasma was about fivefold higher, though the 2,000-fold lower dose was administered compared to crystalline DIM forms. The novel pharmacological DIM substance with high bioavailability may be considered as a promising targeted antitumor chemopreventive agent. It could be used to prevent breast and ovarian cancer development in patients with heterozygous inherited and sporadic BRCA1 gene mutations. Further preclinical and clinical trials are needed to prove this concept. PMID:24325835

Preparation and enhancement of oral bioavailability of curcumin using microemulsions vehicle.

PubMed

Hu, Liandong; Jia, Yanhong; Niu, Feng; Jia, Zheng; Yang, Xun; Jiao, Kuiliang

2012-07-25

A new microemulsions system of curcumin (CUR-MEs) was successfully developed to improve the solubility and bioavailability of curcumin. Several formulations of the microemulsions system were prepared and evaluated using different ratios of oils, surfactants, and co-surfactants (S&CoS). The optimal formulation, which consists of Capryol 90 (oil), Cremophor RH40 (surfactant), and Transcutol P aqueous solution (co-surfactant), could enhance the solubility of curcumin up to 32.5 mg/mL. The pharmacokinetic study of microemulsions was performed in rats compared to the corresponding suspension. The stability of microemulsions after dilution was excellence. Microemulsions have significantly increased the C(max) and area under the curve (AUC) in comparison to that in suspension (p < 0.05). The relative bioavailability of curcumin in microemulsions was 22.6-fold higher than that in suspension. The results indicated that the CUR-MEs could be used as an effective formulation for enhancing the oral bioavailability of curcumin.

Physiologically Based Pharmacokinetic Modeling in Lead Optimization. 1. Evaluation and Adaptation of GastroPlus To Predict Bioavailability of Medchem Series.

PubMed

Daga, Pankaj R; Bolger, Michael B; Haworth, Ian S; Clark, Robert D; Martin, Eric J

2018-03-05

When medicinal chemists need to improve bioavailability (%F) within a chemical series during lead optimization, they synthesize new series members with systematically modified properties mainly by following experience and general rules of thumb. More quantitative models that predict %F of proposed compounds from chemical structure alone have proven elusive. Global empirical %F quantitative structure-property (QSPR) models perform poorly, and projects have too little data to train local %F QSPR models. Mechanistic oral absorption and physiologically based pharmacokinetic (PBPK) models simulate the dissolution, absorption, systemic distribution, and clearance of a drug in preclinical species and humans. Attempts to build global PBPK models based purely on calculated inputs have not achieved the <2-fold average error needed to guide lead optimization. In this work, local GastroPlus PBPK models are instead customized for individual medchem series. The key innovation was building a local QSPR for a numerically fitted effective intrinsic clearance (CL loc ). All inputs are subsequently computed from structure alone, so the models can be applied in advance of synthesis. Training CL loc on the first 15-18 rat %F measurements gave adequate predictions, with clear improvements up to about 30 measurements, and incremental improvements beyond that.

Water soluble biocompatible vesicles based on polysaccharides and oligosaccharides inclusion complexes for carotenoid delivery.

PubMed

Polyakov, Nikolay E; Kispert, Lowell D

2015-09-05

Since carotenoids are highly hydrophobic, air- and light-sensitive hydrocarbon compounds, developing methods for increasing their bioavailability and stability towards irradiation and reactive oxygen species is an important goal. Application of inclusion complexes of "host-guest" type with polysaccharides and oligosaccharides such as arabinogalactan, cyclodextrins and glycyrrhizin minimizes the disadvantages of carotenoids when these compounds are used in food processing (colors and antioxidant capacity) as well as for production of therapeutic formulations. Cyclodextrin complexes which have been used demonstrated enhanced storage stability but suffered from poor solubility. Polysaccharide and oligosaccharide based inclusion complexes play an important role in pharmacology by providing increased solubility and stability of lipophilic drugs. In addition they are used as drug delivery systems to increase absorption rate and bioavailability of the drugs. In this review we summarize the existing data on preparation methods, analysis, and chemical reactivity of carotenoids in inclusion complexes with cyclodextrin, arabinogalactan and glycyrrhizin. It was demonstrated that incorporation of carotenoids into the "host" macromolecule results in significant changes in their physical and chemical properties. In particular, polysaccharide complexes show enhanced photostability of carotenoids in water solutions. A significant decrease in the reactivity towards metal ions and reactive oxygen species in solution was also detected. Copyright © 2015 Elsevier Ltd. All rights reserved.

Perspectives on the recent developments with green tea polyphenols in drug discovery.

PubMed

Li, Feng; Wang, Yongli; Li, Dapeng; Chen, Yilun; Qiao, Xuguang; Fardous, Rania; Lewandowski, Ashton; Liu, Jinbao; Chan, Tak-Hang; Dou, Q Ping

2018-04-24

Increasing evidence has expanded the role of green tea from a traditional beverage to a source of pharmacologically active molecules with diverse health benefits. However, conclusive clinical results are needed to better elucidate the cancer-preventive and therapeutic effects of green tea polyphenols (GTPs). Areas covered: The authors describe GTPs' chemical compositions and metabolic biotransformations, and their recent developments in drug discovery, focusing on their cancer chemopreventive and therapeutic effects. They then review the recent development of GTP-loaded nanoparticles and GTP prodrugs. Expert opinion: GTPs possess potent anticarcinogenic activities through interfering with the initiation, development and progression phases of cancer. There are several challenges (e.g. poor bioavailability) in developing GTPs as therapeutic agents. Use of nanoparticle-based delivery systems has provided unique advantages over purified GTPs. However, there is still a need to determine the actual magnitude and pharmacological mechanisms of GTPs encapsulated in nanoparticles, in order to address newly emerging safety issues associated with the potential 'local overdose' effect. The use of Pro- epigallocatechin gallate (Pro-EGCG) as a prodrug appears to offer improved in vitro stability as well as better in vivo bioavailability and efficacies in a number of animal studies, suggesting its potential as a therapeutic agent for further study and development.

Improving on Nature: The Role of Nanomedicine in the Development of Clinical Natural Drugs.

PubMed

Bilia, Anna Rita; Piazzini, Vieri; Guccione, Clizia; Risaliti, Laura; Asprea, Martina; Capecchi, Giada; Bergonzi, Maria Camilla

2017-03-01

Natural products have been used as a major source of drugs for millennia, and about half of the pharmaceuticals in use today are derived from natural products. However, their efficacy can be limited because of their low hydrophilicity and intrinsic dissolution rate(s), or physical/chemical instability. In addition, they can present scarce absorption, poor pharmacokinetics and bioavailability, scarce biodistribution, first-pass metabolism, trivial penetration and accumulation in the organs of the body, or low targeting efficacy. Novel nanoformulations based on drug delivery systems, namely nanoparticles, micelles, and vesicles, offer significant promise in overcoming these limitations. Nowadays, nanomedicine is crucial in developing appropriate therapeutic treatments of essential drugs, specifically antitumor and antiparasistic agents (i.e., Taxol, vincristine, camptothecin, doxorubicin, artemisinin) and other emerging molecules with pleiotropic functions (i.e., resveratrol, curcumin, salvianolic acid B, honokiol). Additionally, the number of nanoformulations developed with flavonoids, in particular rutin, quercetin, silymarin, and green tea catechins, is constantly increasing, and a significant number of publications have appeared in the last decade pertaining to nanoformulations based on extracts and essential oils. Most of these studies report very promising nanoformulations with sustained release and improved bioavailability at much lower doses than conventional preparations, and in many cases, also a better safety profile. Georg Thieme Verlag KG Stuttgart · New York.

Development of food-grade nanoemulsions and emulsions for delivery of omega-3 fatty acids: opportunities and obstacles in the food industry.

PubMed

Walker, Rebecca; Decker, Eric A; McClements, David Julian

2015-01-01

Consumption of biologically active amounts of omega-3 fatty acids is linked to improved human health, which has partly been attributed to their important role in brain development and cardiovascular health. Western diets are relatively low in omega-3 fatty acids and many consumers turn to supplements or functional foods to increase their intake of these healthy lipids. Fish oil is one of the most widely used sources of omega-3 fatty acid for supplementation and has greater health benefits than plant sources because of its higher concentration of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The incorporation of omega-3 fatty acids into foods and beverages is often challenging due to their low water-solubility, poor oxidative stability, and variable bioavailability. Nanoemulsions offer a promising way to incorporate omega-3 fatty acids into liquid food systems like beverages, dressing, sauces, and dips. Nanoemulsions are colloidal dispersions that contain small oil droplets (r<100 nm) that may be able to overcome many of the challenges of fortifying foods and beverages with omega-3 fatty acids. The composition and fabrication of nanoemulsions can be optimized to increase the chemical and physical stability of oil droplets, as well as to increase the bioavailability of omega-3 fatty acids.

Lipid nanoparticles for cancer therapy: state of the art and future prospects.

PubMed

Lasa-Saracibar, Beatriz; Estella-Hermoso de Mendoza, Ander; Guada, Melissa; Dios-Vieitez, Carmen; Blanco-Prieto, María J

2012-10-01

Cancer is a leading cause of death worldwide and it is estimated that deaths from this disease will rise to over 11 million in 2030. Most cases of cancer can be cured with surgery, radiotherapy or chemotherapy if they are detected at an early stage. However, current cancer therapies are commonly associated with undesirable side effects, as most chemotherapy treatments are cytotoxic and present poor tumor targeting. Lipid nanoparticles (LN) are one of the most promising options in this field. LN are made up of biodegradable generally recognized as safe (GRAS) lipids, their formulation includes different techniques, and most are easily scalable to industrial manufacture. LN overcome the limitations imposed by the need for intravenous administration, as they are mainly absorbed via the lymphatic system when they are administered orally, which improves drug bioavailability. Furthermore, depending on their composition, LN present the ability to cross the blood-brain barrier, thus opening up the possibility of targeting brain tumors. The drawbacks of chemotherapeutic agents make it necessary to invest in research to find safer and more effective therapies. Nanotechnology has opened the door to new therapeutic options through the design of formulations that include a wide range of materials and formulations at the nanometer range, which improve drug efficacy through direct or indirect tumor targeting, increased bioavailability and diminished toxicity.

Treatment with CB2 Agonist JWH-133 Reduces Histological Features Associated with Erectile Dysfunction in Hypercholesterolemic Mice

PubMed Central

Fraga-Silva, Rodrigo Araujo; Costa-Fraga, Fabiana Pereira; Faye, Younouss; Savergnini, Silvia Quintao; Lenglet, Sébastien; Mach, François; Steffens, Sabine; Stergiopulos, Nikolaos; Souza dos Santos, Robson Augusto; da Silva, Rafaela Fernandes

2013-01-01

Hypercholesterolemia is one of the most important risk factors for erectile dysfunction, mostly due to the impairment of oxidative stress and endothelial function in the penis. The cannabinoid system might regulate peripheral mechanisms of sexual function; however, its role is still poorly understood. We investigated the effects of CB2 activation on oxidative stress and fibrosis within the corpus cavernosum of hypercholesterolemic mice. Apolipoprotein-E-knockout mice were fed with a western-type diet for 11 weeks and treated with JWH-133 (selective CB2 agonist) or vehicle during the last 3 weeks. CB2 receptor expression, total collagen content, and reactive oxygen species (ROS) production within the penis were assessed. In vitro corpus cavernosum strips preparation was performed to evaluate the nitric oxide (NO) bioavailability. CB2 protein expression was shown in cavernosal endothelial and smooth muscle cells of wild type and hypercholesterolemic mice. Treatment with JWH-133 reduced ROS production and NADPH-oxidase expression in hypercholesterolemic mice penis. Furthermore, JWH-133 increased endothelial NO synthase expression in the corpus cavernosum and augmented NO bioavailability. The decrease in oxidative stress levels was accompanied with a reduction in corpus cavernosum collagen content. In summary, CB2 activation decreased histological features, which were associated with erectile dysfunction in hypercholesterolemic mice. PMID:24302957

Transdermal delivery of raloxifene HCl via ethosomal system: Formulation, advanced characterizations and pharmacokinetic evaluation.

PubMed

Mahmood, Syed; Mandal, Uttam Kumar; Chatterjee, Bappaditya

2018-05-05

Raloxifene HCl belongs to a class of selective estrogen receptor modulators (SERMs) which is used for the management of breast cancer. The major problem reported with raloxifene is its poor bioavailability which is only up to 2%. The main objective of the present work was to formulate raloxifene loaded ethosomal preparation for transdermal application and compare it with an oral formulation of the drug. Five ethosomal formulations with different concentrations of ethanol and a conventional liposomes formulation were prepared by rotary evaporation method. The prepared systems were characterised by high resolution transmission electron microscopy (HRTEM), force emission electron microscopy (FESEM), atomic force microscopy (AFM), X-ray diffraction (XRD) and 31 P NMR study. All these advanced characterization study established that the ethosome formulation was well defined by its size, shape and its bilayer formation. Transdermal flux of the optimized ethosome formulation was 22.14 ± 0.83 µg/ml/cm 2 which was 21 times higher when compared to the conventional liposomes. Confocal microscopy study revealed an enhanced permeation of coumarin-6 dye loaded ethosomes to much deeper layers of skin when compared with conventional liposomes. The gel was found to be pseudoplastic with elastic behaviour. In-vivo studies on rats showed a higher bioavailability of RXL (157% times) for ethosomal formulation when compared with the oral formulation. In conclusion, RXL loaded ethosomal formulation via transdermal route showed superior drug delivery properties as compared to oral formulation. Copyright © 2018 Elsevier B.V. All rights reserved.

Kaempferol loaded lecithin/chitosan nanoparticles: preparation, characterization, and their potential applications as a sustainable antifungal agent.

PubMed

Ilk, Sedef; Saglam, Necdet; Özgen, Mustafa

2017-08-01

Flavonoid compounds are strong antioxidant and antifungal agents but their applications are limited due to their poor dissolution and bioavailability. The use of nanotechnology in agriculture has received increasing attention, with the development of new formulations containing active compounds. In this study, kaempferol (KAE) was loaded into lecithin/chitosan nanoparticles (LC NPs) to determine antifungal activity compared to pure KAE against the phytopathogenic fungus Fusarium oxysporium to resolve the bioavailability problem. The influence of formulation parameters on the physicochemical properties of KAE loaded lecithin chitosan nanoparticles (KAE-LC NPs) were studied by using the electrostatic self-assembly technique. KAE-LC NPs were characterized in terms of physicochemical properties. KAE has been successfully encapsulated in LC NPs with an efficiency of 93.8 ± 4.28% and KAE-LC NPs showed good physicochemical stability. Moreover, in vitro evaluation of the KAE-LC NP system was made by the release kinetics, antioxidant and antifungal activity in a time-dependent manner against free KAE. Encapsulated KAE exhibited a significantly inhibition efficacy (67%) against Fusarium oxysporium at the end of the 60 day storage period. The results indicated that KAE-LC NP formulation could solve the problems related to the solubility and loss of KAE during use and storage. The new nanoparticle system enables the use of smaller quantities of fungicide and therefore, offers a more environmentally friendly method of controlling fungal pathogens in agriculture.

Inhibitory effect of ebselen on cerebral acetylcholinesterase activity in vitro: kinetics and reversibility of inhibition.

PubMed

Martini, Franciele; Bruning, César Augusto; Soares, Suelen Mendonca; Nogueira, Cristina Wayne; Zeni, Gilson

2015-01-01

Ebselen is a synthetic organoselenium compound that has been considered a potential pharmacological agent with low toxicity, showing antioxidant, anti-inflammatory and neuroprotective effects. It is bioavailable, blood-brain barrier permeant and safe based on cellular toxicity and Phase I-III clinical trials. There is evidence that ebselen inhibits acetylcholinesterase (AChE) activity, an enzyme that plays a key role in the cholinergic system by hydrolyzing acetylcholine (ACh), in vitro and ex vivo. This system has a well-known relationship with cognitive process, and AChE inhibitors, such as donepezil and galantamine, have been used to treat cognitive deficits, mainly in the Alzheimer's Disease (AD). However, these drugs have poor bioavailability and a number of side effects, including gastrointestinal upsets and hepatotoxicity. In this way, this study aimed to evaluate the effect of ebselen on cerebral AChE activity in vitro and to determine the kinetic profile and the reversibility of inhibition by dialysis. Ebselen inhibited the cerebral AChE activity with an IC50 of 29 µM, similar to IC50 found with pure AChE from electric eel, demonstrating a mixed and reversible inhibition of AChE, since it increased Km and decreased Vmax. The AChE activity was recovered within 60 min of dialysis. Therefore, the use of ebselen as a therapeutic agent for treatment of AD should be considered, although memory behavior tasks are needed to support such hypothesis.

Delivery Systems for Birch-Bark Triterpenoids and Their Derivatives in Anticancer Research.

PubMed

Mierina, Inese; Vilskersts, Reinis; Turks, Maris

2018-05-29

Birch-bark triterpenoids and their semi-synthetic derivatives possess a wide range of biological activities including cytotoxic effects on various tumour cell lines. However, due to the low solubility and bioavailability, their medicinal applications are rather limited. The use of various nanotechnology-based drug delivery systems is rapidly developing approach to the solubilisation of insufficiently bioavailable pharmaceuticals. Herein, the drug delivery systems deemed to be applicable for birch-bark triterpenoid structures are reviewed. The aforementioned disadvantages of birch-bark triterpenoids and their semi-synthetic derivatives can be overcome through their incorporation into organic nanoparticles, which include various dendrimeric systems, as well as embedding the active compounds into polymer matrices or complexation with carbohydrate nanoparticles without covalent bonding. Some of the known triterpenoid delivery systems consist of nanoparticles featuring inorganic cores covered with carbohydrates or other polymers. Methods for delivering the title compounds through encapsulation and emulsification into lipophilic media are also suitable. Besides, the birch-bark triterpenoids can form self-assembling systems with increased bio-availability. Even more, the self-assembling systems are used as carriers for delivering other chemotherapeutic agents. Another advantage besides increased bioavailability and anticancer activity is the reduced overall systemic toxicity in most of the cases, when triterpenoids are delivered with any of the carriers. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Absorption Study of Genistein Using Solid Lipid Microparticles and Nanoparticles: Control of Oral Bioavailability by Particle Sizes.

PubMed

Kim, Jeong Tae; Barua, Sonia; Kim, Hyeongmin; Hong, Seong-Chul; Yoo, Seung-Yup; Jeon, Hyojin; Cho, Yeongjin; Gil, Sangwon; Oh, Kyungsoo; Lee, Jaehwi

2017-07-01

In this study, the effect of particle size of genistein-loaded solid lipid particulate systems on drug dissolution behavior and oral bioavailability was investigated. Genistein-loaded solid lipid microparticles and nanoparticles were prepared with glyceryl palmitostearate. Except for the particle size, other properties of genistein-loaded solid lipid microparticles and nanoparticles such as particle composition and drug loading efficiency and amount were similarly controlled to mainly evaluate the effect of different particle sizes of the solid lipid particulate systems on drug dissolution behavior and oral bioavailability. The results showed that genistein-loaded solid lipid microparticles and nanoparticles exhibited a considerably increased drug dissolution rate compared to that of genistein bulk powder and suspension. The microparticles gradually released genistein as a function of time while the nanoparticles exhibited a biphasic drug release pattern, showing an initial burst drug release, followed by a sustained release. The oral bioavailability of genistein loaded in solid lipid microparticles and nanoparticles in rats was also significantly enhanced compared to that in bulk powders and the suspension. However, the bioavailability from the microparticles increased more than that from the nanoparticles mainly because the rapid drug dissolution rate and rapid absorption of genistein because of the large surface area of the genistein-solid lipid nanoparticles cleared the drug to a greater extent than the genistein-solid lipid microparticles did. Therefore, the findings of this study suggest that controlling the particle size of solid-lipid particulate systems at a micro-scale would be a promising strategy to increase the oral bioavailability of genistein.

Enhanced solubility of piperine using hydrophilic carrier-based potent solid dispersion systems.

PubMed

Thenmozhi, Kathavarayan; Yoo, Young Je

2017-09-01

Piperine alkaloid, an important constituent of black pepper, exhibits numerous therapeutic properties, whereas its usage as a drug is limited due to its poor solubility in aqueous medium, which leads to poor bioavailability. Herein, a new method has been developed to improve the solubility of this drug based on the development of solid dispersions with improved dissolution rate using hydrophilic carriers such as sorbitol (Sor), polyethylene glycol (PEG) and polyvinyl pyrrolidone K30 (PVP) by solvent method. Physical mixtures of piperine and carriers were also prepared for comparison. The physicochemical properties of the prepared solid dispersions were examined using SEM, TEM, DSC, XRD and FT-IR. In vitro dissolution profile of the solid dispersions was recorded and compared with that of the pure piperine and physical mixtures. The effect of these carriers on the aqueous solubility of piperine has been investigated. The solid dispersions of piperine with Sor, PEG and PVP exhibited superior performance for the dissolution of piperine with a drug release of 70%, 76% and 89%, respectively after 2 h compared to physical mixtures and pure piperine, which could be due to its transformation from crystalline to amorphous form as well as the attachment of hydrophilic carriers to the surface of poorly water-soluble piperine. Results suggest that the piperine solid dispersions prepared with improved in vitro release exhibit potential advantage in delivering poorly water-soluble piperine as an oral supplement.

Polysaccharides based nanomaterials for targeted anti-cancer drug delivery.

PubMed

Dheer, Divya; Arora, Divya; Jaglan, Sundeep; Rawal, Ravindra K; Shankar, Ravi

2017-01-01

Polysaccharides, an important class of biological polymers, are effectively bioactive, nontoxic, hydrophilic, biodegradable and offer a wide diversity in structure and properties. These can be easily modified chemically and biochemically to enhance the bioadhesion with biological tissues, better stability and can improve bioavailability of drugs. Most of the chemotherapeutic drugs have a narrow therapeutic index, slow drug delivery systems and poor water solubility that usually proves toxic to human bodies. The inherent biocompatibility of these biopolymers have shown enhancement of solubility of some chemotherapeutic drugs which also leads to the preparation of nanomaterials for the delivery of antibiotics, anticancer, proteins, peptides and nucleic acids using several routes of administration. Recently, synthesis and research on polysaccharides based nanomaterials have gained enormous attention as one of the most applicable resources in nanomedicine area. This review article will provide a specific emphasis on polysaccharides as natural biomaterials for targeted anticancer drug delivery system.

Stem cell-extracellular vesicles as drug delivery systems: New frontiers for silk/curcumin nanoparticles.

PubMed

Perteghella, Sara; Crivelli, Barbara; Catenacci, Laura; Sorrenti, Milena; Bruni, Giovanna; Necchi, Vittorio; Vigani, Barbara; Sorlini, Marzio; Torre, Maria Luisa; Chlapanidas, Theodora

2017-03-30

The aim of this work was to develop a novel carrier-in-carrier system based on stem cell-extracellular vesicles loaded of silk/curcumin nanoparticles by endogenous technique. Silk nanoparticles were produced by desolvation method and curcumin has been selected as drug model because of its limited water solubility and poor bioavailability. Nanoparticles were stable, with spherical geometry, 100nm in average diameter and the drug content reached about 30%. Cellular uptake studies, performed on mesenchymal stem cells (MSCs), showed the accumulation of nanoparticles in the cytosol around the nuclear membrane, without cytotoxic effects. Finally, MSCs were able to release extracellular vesicles entrapping silk/curcumin nanoparticles. This combined biological-technological approach represents a novel class of nanosystems, combining beneficial effects of both regenerative cell therapies and pharmaceutical nanomedicine, avoiding the use of viable replicating stem cells. Copyright © 2017 Elsevier B.V. All rights reserved.

Improving the biopharmaceutical attributes of mangiferin using vitamin E-TPGS co-loaded self-assembled phosholipidic nano-mixed micellar systems.

PubMed

Khurana, Rajneet Kaur; Gaspar, Balan Louis; Welsby, Gail; Katare, O P; Singh, Kamalinder K; Singh, Bhupinder

2018-06-01

The current research work encompasses the development, characterization, and evaluation of self-assembled phospholipidic nano-mixed miceller system (SPNMS) of a poorly soluble BCS Class IV xanthone bioactive, mangiferin (Mgf) functionalized with co-delivery of vitamin E TPGS. Systematic optimization using I-optimal design yielded self-assembled phospholipidic nano-micelles with a particle size of < 60 nm and > 80% of drug release in 15 min. The cytotoxicity and cellular uptake studies performed using MCF-7 and MDA-MB-231 cell lines demonstrated greater kill and faster cellular uptake. The ex vivo intestinal permeability revealed higher lymphatic uptake, while in situ perfusion and in vivo pharmacokinetic studies indicated nearly 6.6- and 3.0-folds augmentation in permeability and bioavailability of Mgf. In a nutshell, vitamin E functionalized SPNMS of Mgf improved the biopharmaceutical performance of Mgf in rats for enhanced anticancer potency.

Engineering Synergistically Active and Bioavailable Cost-effective Medicines for Neglected Tropical Diseases; The Role of Excipients.

PubMed

Serrano, Dolores R; Lalatsa, Aikaterini; Dea-Ayuela, M Auxiliadora

2017-07-19

Leishmaniasis is a neglected tropical disease responsible for the ninth largest disease burden in the world threatening 350 million people mostly in developing countries. The lack of efficacy, severe adverse effects, long duration, high cost and parenteral administration of the current therapies result in poor patient compliance and emergence of resistance. Leishmaniasis' unmet need for safer, affordable and more effective treatments is only partly addressed by today's global health product pipeline that focuses on products amenable to rapid clinical development, mainly by reformulating or repurposing existing drugs for new uses. Excipients are necessary for ensuring the stability and bioavailability of currently available antileishmaniasis drugs which in their majority are poorly soluble or have severe side-effects. Thus, selection of excipients that can ensure bioavailability and safety as well as elicit a synergistic effect against the Leishmania parasites without compromising safety will result in a more efficacious, safe and fast to market medicine. We have evaluated the in vitro activity of 30 commercially available generally regarded as safe (GRAS) excipients against different Leishmania spp., their cytotoxicity and potential use for inclusion in novel formulations. Amongst the tested excipients, the compounds with higher selectivity index were Eudragit E100 (cationic triblock copolymer of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate), CTAB (cetyltrimethylammonium bromide, cationic), lauric acid, Labrasol(non-ionic, caprylocaproyl polyoxyl- 8 glycerides) and sodium deoxycholate. An ideal excipient need to possess amphiphilic nature with ionic/polar groups and possess a short or medium fatty acid chain such as lauric (C12), capric C10) or caprylicacid (C8). Inclusion of these excipients and identification of the optimal combination of drug and excipients would lead to a more effective and safer antileishmanial therapies. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Development of lycopene micelle and lycopene chylomicron and a comparison of bioavailability

NASA Astrophysics Data System (ADS)

Jyun Chen, Yi; Inbaraj, Baskaran Stephen; Shiau Pu, Yeong; Chen, Bing Huei

2014-04-01

The objectives of this study were to develop lycopene micelles and lycopene chylomicrons from tomato extracts for the enhancement and comparison of bioavailability. Lycopene micelles and chylomicrons were prepared by a microemulsion technique involving tomato extract, soybean oil, water, vitamin E and surfactant Tween 80 or lecithin in different proportions. The encapsulation efficiency of lycopene was 78% in micelles and 80% in chylomicrons, with shape being roughly spherical and mean particle size being 7.5 and 131.5 nm. A bioavailability study was conducted in rats by both gavage and i.v. administration, with oral bioavailability of lycopene, phytoene and phytofluene being 6.8, 4.3 and 3.1% in micelles and 9.5, 9.4 and 7.1% in chylomicrons, respectively. This outcome reveals higher lycopene bioavailability through incorporation into micelle or chylomicron systems. Both size and shape should be considered for oral bioavailability determination. For i.v. injection, lycopene micelles should be more important than lycopene chylomicrons for future clinical applications.

Aluminum bioavailability from basic sodium aluminum phosphate, an approved food additive emulsifying agent, incorporated in cheese

PubMed Central

Yokel, Robert A.; Hicks, Clair L.; Florence, Rebecca L.

2008-01-01

Oral aluminum (Al) bioavailability from drinking water has been previously estimated, but there is little information on Al bioavailability from foods. It was suggested that oral Al bioavailability from drinking water is much greater than from foods. The objective was to further test this hypothesis. Oral Al bioavailability was determined in the rat from basic [26Al]-sodium aluminum phosphate (basic SALP) in a process cheese. Consumption of ~ 1 gm cheese containing 1.5 or 3% basic SALP resulted in oral Al bioavailability (F) of ~ 0.1 and 0.3%, respectively, and time to maximum serum 26Al concentration (Tmax) of 8 to 9 h. These Al bioavailability results were intermediate to previously reported results from drinking water (F ~ 0.3%) and acidic-SALP incorporated into a biscuit (F ~ 0.1%), using the same methods. Considering the similar oral bioavailability of Al from food vs. water, and their contribution to the typical human’s daily Al intake (~ 95 and 1.5%, respectively), these results suggest food contributes much more Al to systemic circulation, and potential Al body burden, than does drinking water. These results do not support the hypothesis that drinking water provides a disproportionate contribution to total Al absorbed from the gastrointestinal tract. PMID:18436363

Aluminum bioavailability from basic sodium aluminum phosphate, an approved food additive emulsifying agent, incorporated in cheese.

PubMed

Yokel, Robert A; Hicks, Clair L; Florence, Rebecca L

2008-06-01

Oral aluminum (Al) bioavailability from drinking water has been previously estimated, but there is little information on Al bioavailability from foods. It was suggested that oral Al bioavailability from drinking water is much greater than from foods. The objective was to further test this hypothesis. Oral Al bioavailability was determined in the rat from basic [26Al]-sodium aluminum phosphate (basic SALP) in a process cheese. Consumption of approximately 1g cheese containing 1.5% or 3% basic SALP resulted in oral Al bioavailability (F) of approximately 0.1% and 0.3%, respectively, and time to maximum serum 26Al concentration (Tmax) of 8-9h. These Al bioavailability results were intermediate to previously reported results from drinking water (F approximately 0.3%) and acidic-SALP incorporated into a biscuit (F approximately 0.1%), using the same methods. Considering the similar oral bioavailability of Al from food vs. water, and their contribution to the typical human's daily Al intake ( approximately 95% and 1.5%, respectively), these results suggest food contributes much more Al to systemic circulation, and potential Al body burden, than does drinking water. These results do not support the hypothesis that drinking water provides a disproportionate contribution to total Al absorbed from the gastrointestinal tract.

pH-sensitive polymeric nanoparticles to improve oral bioavailability of peptide/protein drugs and poorly water-soluble drugs.

PubMed

Wang, Xue-Qing; Zhang, Qiang

2012-10-01

pH-sensitive polymeric nanoparticles are promising for oral drug delivery, especially for peptide/protein drugs and poorly water-soluble medicines. This review describes current status of pH-sensitive polymeric nanoparticles for oral drug delivery and introduces the mechanisms of drug release from them as well as possible reasons for absorption improvement, with emphasis on our contribution to this field. pH-sensitive polymeric nanoparticles are prepared mainly with polyanions, polycations, their mixtures or cross-linked polymers. The mechanisms of drug release are the result of carriers' dissolution, swelling or both of them at specific pH. The possible reasons for improvement of oral bioavailability include the following: improve drug stability, enhance mucoadhesion, prolong resident time in GI tract, ameliorate intestinal permeability and increase saturation solubility and dissolution rate for poorly water-soluble drugs. As for the advantages of pH-sensitive nanoparticles over conventional nanoparticles, we conclude that (1) most carriers used are enteric-coating materials and their safety has been approved. (2) The rapid dissolution or swelling of carriers at specific pH results in quick drug release and high drug concentration gradient, which is helpful for absorption. (3) At the specific pH carriers dissolve or swell, and the bioadhesion of carriers to mucosa becomes high because nanoparticles turn from solid to gel, which can facilitate drug absorption. Copyright © 2012 Elsevier B.V. All rights reserved.

Polyamidoamine (PAMAM) dendrimers as potential release modulators and oral bioavailability enhancers of vardenafil hydrochloride.

PubMed

Tawfik, Mai Ahmed; Tadros, Mina Ibrahim; Mohamed, Magdy Ibrahim

2018-05-21

Vardenafil hydrochloride (VAR) is an erectile dysfunction treating drug. VAR has a short elimination half-life (4-5 h) and suffers low oral bioavailability (15%). This work aimed to explore the dual potential of VAR-dendrimer complexes as drug release modulators and oral bioavailability enhancers. VAR-dendrimer complexes were prepared by solvent evaporation technique using four dendrimer generations (G4.5, G5, G5.5 and G6) at three concentrations (190 nM, 380 nM and 950 nM). The systems were evaluated for intermolecular interactions, particle size, zeta potential, drug entrapment efficiency percentages (EE%) and drug released percentages after 2 h (Q 2h ) and 24 h (Q 24h ). The results were statistically analyzed, and the system showing the highest desirability was selected for further pharmacokinetic studies in rabbits, in comparison to Levitra ® tablets. The highest desirability (0.82) was achieved with D10 system comprising VAR (10 mg) and G6 (190 nM). It possessed small particle size (113.85 nm), low PDI (0.19), positive zeta potential (+21.53), high EE% (75.24%), promising Q 2 h (41.45%) and Q 24 h (74.05%). Compared to Levitra ® tablets, the significantly (p < 0.01) delayed T max , prolonged MRT (0-∞) and higher relative bioavailability (3.7-fold) could clarify the dual potential of D10 as a sustained release system capable of enhancing VAR oral bioavailability.

Amine functionalized cubic mesoporous silica nanoparticles as an oral delivery system for curcumin bioavailability enhancement

NASA Astrophysics Data System (ADS)

Budi Hartono, Sandy; Hadisoewignyo, Lannie; Yang, Yanan; Meka, Anand Kumar; Antaresti; Yu, Chengzhong

2016-12-01

In the present work, a simple method was used to develop composite curcumin-amine functionalized mesoporous silica nanoparticles (MSN). The nanoparticles were used to improve the bioavailability of curcumin in mice through oral administration. We investigated the effect of particle size on the release profile, solubility and oral bioavailability of curcumin in mice, including amine functionalized mesoporous silica micron-sized-particles (MSM) and MSN (100-200 nm). Curcumin loaded within amine functionalized MSN (MSN-A-Cur) had a better release profile and a higher solubility compared to amine MSM (MSM-A-Cur). The bioavailability of MSN-A-Cur and MSM-A-Cur was considerably higher than that of ‘free curcumin’. These results indicate promising features of amine functionalized MSN as a carrier to deliver low solubility drugs with improved bioavailability via the oral route.

Bioavailability of bioactive food compounds: a challenging journey to bioefficacy.

PubMed

Rein, Maarit J; Renouf, Mathieu; Cruz-Hernandez, Cristina; Actis-Goretta, Lucas; Thakkar, Sagar K; da Silva Pinto, Marcia

2013-03-01

Bioavailability is a key step in ensuring bioefficacy of bioactive food compounds or oral drugs. Bioavailability is a complex process involving several different stages: liberation, absorption, distribution, metabolism and elimination phases (LADME). Bioactive food compounds, whether derived from various plant or animal sources, need to be bioavailable in order to exert any beneficial effects. Through a better understanding of the digestive fate of bioactive food compounds we can impact the promotion of health and improvement of performance. Many varying factors affect bioavailability, such as bioaccessibility, food matrix effect, transporters, molecular structures and metabolizing enzymes. Bioefficacy may be improved through enhanced bioavailability. Therefore, several technologies have been developed to improve the bioavailability of xenobiotics, including structural modifications, nanotechnology and colloidal systems. Due to the complex nature of food bioactive compounds and also to the different mechanisms of absorption of hydrophilic and lipophilic bioactive compounds, unravelling the bioavailability of food constituents is challenging. Among the food sources discussed during this review, coffee, tea, citrus fruit and fish oil were included as sources of food bioactive compounds (e.g. (poly)phenols and polyunsaturated fatty acids (PUFAs)) since they are examples of important ingredients for the food industry. Although there are many studies reporting on bioavailability and bioefficacy of these bioactive food components, understanding their interactions, metabolism and mechanism of action still requires extensive work. This review focuses on some of the major factors affecting the bioavailability of the aforementioned bioactive food compounds. © 2012 Nestec S. A.. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

IMPLICATIONS OF BIOSOLIDS/COMPOST UTILIZATION ON THE RISK OF SOIL METALS

EPA Science Inventory

This presentation summarizes the current work on the fundamental changes in soil mineralogical accomplished by additions of biosolids and P to the system which results in changes in phytoavailability/bioavailability. The concepts of phytoavailability/bioavailability are rather s...

Aluminum bioavailability from tea infusion.

PubMed

Yokel, Robert A; Florence, Rebecca L

2008-12-01

The objective was to estimate oral Al bioavailability from tea infusion in the rat, using the tracer (26)Al. (26)Al citrate was injected into tea leaves. An infusion was prepared from the dried leaves and given intra-gastrically to rats which received concurrent intravenous (27)Al infusion. Oral Al bioavailability (F) was calculated from the area under the (26)Al, compared to (27)Al, serum concentration x time curves. Bioavailability from tea averaged 0.37%; not significantly different from water (F=0.3%), or basic sodium aluminum phosphate (SALP) in cheese (F=0.1-0.3%), but greater than acidic SALP in a biscuit (F=0.1%). Time to maximum serum (26)Al concentration was 1.25, 1.5, 8 and 4.8h, respectively. These results of oral Al bioavailability x daily consumption by the human suggest tea can provide a significant amount of the Al that reaches systemic circulation. This can allow distribution to its target organs of toxicity, the central nervous, skeletal and hematopoietic systems. Further testing of the hypothesis that Al contributes to Alzheimer's disease may be more warranted with studies focusing on total average daily food intake, including tea and other foods containing appreciable Al, than drinking water.

Aluminum bioavailability from tea infusion

PubMed Central

Yokel, Robert A.; Florence, Rebecca L.

2008-01-01

The objective was to estimate oral Al bioavailability from tea infusion in the rat, using the tracer 26Al. 26Al citrate was injected into tea leaves. An infusion was prepared from the dried leaves and given intra-gastrically to rats which received concurrent intravenous 27Al infusion. Oral Al bioavailability (F) was calculated from the area under the 26Al, compared to 27Al, serum concentration × time curves. Bioavailability from tea averaged 0.37%; not significantly different from water (F = 0.3%), or basic sodium aluminum phosphate (SALP) in cheese (F = 0.1 to 0.3%), but greater than acidic SALP in a biscuit (F = 0.1%). Time to maximum serum 26Al concentration was 1.25, 1.5, 8 and 4.8 h, respectively. These results of oral Al bioavailability × daily consumption by the human suggest tea can provide a significant amount of the Al that reaches systemic circulation. This can allow distribution to its target organs of toxicity, the central nervous, skeletal and hematopoietic systems. Further testing of the hypothesis that Al contributes to Alzheimer's disease may be more warranted with studies focusing on total average daily food intake, including tea and other foods containing appreciable Al, than drinking water. PMID:18848597

Bilayer mucoadhesive microparticles for the delivery of metoprolol succinate: Formulation and evaluation.

PubMed

Kumar, Krishan; Dhawan, Neha; Sharma, Harshita; Patwal, Pramod S; Vaidya, Shubha; Vaidya, Bhuvaneshwar

2015-01-01

Metoprolol succinate is a very potent drug for the treatment of hypertension but suffers from poor bioavailability due to its erratic absorption in lower GI tract. Therefore, in the present study, it was hypothesized that by formulating mucoadhesive particles, the residence time in the GIT and release of drug may be prolonged that will enhance the bioavailability of metoprolol succinate. Metoprolol succinate loaded chitosan microparticles were prepared by ionic gelation method. The optimized microparticles were coated with sodium alginate to form a layer over chitosan microparticles to increase the mucoadhesive strength and to release the drug in controlled manner. Coated and uncoated microparticles were evaluated for particle size, zeta potential, morphology, entrapment efficiency, drug loading and in vitro drug release. The coated microparticles showed comparatively less drug release in the 0.1 N HCl while sustained release in PBS (pH 6.8) as compared to uncoated microparticles. The in vivo study on albino rats demonstrated an increase in bioavailability of the coated microparticles as compared to marketed formulation. From the study it can be concluded that alginate coated chitosan microparticles could be a useful carrier for the oral delivery of metoprolol succinate.

Availability of polycyclic aromatic hydrocarbons to earthworms in urban soils and its implications for risk assessment.

PubMed

Cachada, A; Coelho, C; Gavina, A; Dias, A C; Patinha, C; Reis, A P; da Silva, E Ferreira; Duarte, A C; Pereira, R

2018-01-01

Polycyclic aromatic hydrocarbons (PAHs) are a global problem, and in urban soils they can be found at potentially hazard levels. Nevertheless, the real risks that these contaminants pose to the environment are not well known, since the bioavailability of PAHs in urban soils has been poorly studied. Therefore, the bioavailability of PAHs in some selected urban soils from Lisbon (Portugal) was evaluated. Moreover, the applicability of a first screening phase based on total contents of PAHs was assessed. Results show that bioavailability of PAHs is reduced (low levels in earthworms, low accumulation percentages, and low biota-to-soil accumulation factors values), especially in more contaminated soils. The aging of these compounds explains this low availability, and confirms the generally accepted assumption that accumulation of PAHs in urban areas is mostly related with a long-term deposition of contaminated particles. The comparison of measured PAHs concentrations in earthworm tissues with the ones predicted based on theoretical models, reinforce that risks based on total levels are overestimated, but it can be a good initial approach for urban soils. This study also highlights the need of more reliable ecotoxicological data. Copyright © 2017 Elsevier Ltd. All rights reserved.

Fabrication and evaluation of valsartan–polymer– surfactant composite nanoparticles by using the supercritical antisolvent process

PubMed Central

Kim, Min-Soo; Baek, In-hwan

2014-01-01

The aim of this study was to fabricate valsartan composite nanoparticles by using the supercritical antisolvent (SAS) process, and to evaluate the correlation between in vitro dissolution and in vivo pharmacokinetic parameters for the poorly water-soluble drug valsartan. Spherical composite nanoparticles with a mean size smaller than 400 nm, which contained valsartan, were successfully fabricated by using the SAS process. X-ray diffraction and thermal analyses indicated that valsartan was present in an amorphous form within the composite nanoparticles. The in vitro dissolution and oral bioavailability of valsartan were dramatically enhanced by the composite nanoparticles. Valsartan–hydroxypropyl methylcellulose–poloxamer 407 nanoparticles exhibited faster drug release (up to 90% within 10 minutes under all dissolution conditions) and higher oral bioavailability than the raw material, with an approximately 7.2-fold higher maximum plasma concentration. In addition, there was a positive linear correlation between the pharmacokinetic parameters and the in vitro dissolution efficiency. Therefore, the preparation of composite nanoparticles with valsartan–hydroxypropyl methylcellulose and poloxamer 407 by using the SAS process could be an effective formulation strategy for the development of a new dosage form of valsartan with high oral bioavailability. PMID:25404856

Characteristics of Artemether-Loaded Poly(lactic-co-glycolic) Acid Microparticles Fabricated by Coaxial Electrospray: Validation of Enhanced Encapsulation Efficiency and Bioavailability.

PubMed

Mangrio, Farhana Akbar; Dwivedi, Pankaj; Han, Shuya; Zhao, Gang; Gao, Dayong; Si, Ting; Xu, Ronald X

2017-12-04

Artemether is one of the most effective drugs for the treatment of chloroquine-resistant and Plasmodium falciparum strains of malaria. However, its therapeutic potency is hindered by its poor bioavailability. To overcome this limitation, we have encapsulated artemether in poly(lactic-co-glycolic) acid (PLGA) core-shell microparticles (MPs) using the coaxial electrospray method. With optimized process parameters including liquid flow rates and applied electric voltages, experiments are systematically carried out to generate a stable cone-jet mode to produce artemether-loaded PLGA-MPs with an average size of 2 μm, an encapsulation efficiency of 78 ± 5.6%, and a loading efficiency of 11.7%. The in vitro release study demonstrates the sustained release of artemether from the core-shell structure in comparison with that of plain artemether and that of MPs produced by single-axial electrospray without any relevant cytotoxicity. The in vivo studies are performed to evaluate the pharmacokinetic characteristics of the artemether-loaded PLGA-MPs. Our study implies that artemether can be effectively encapsulated in a protective shell of PLGA for controlled release kinetics and enhanced oral bioavailability.

Solid super saturated self-nanoemulsifying drug delivery system (sat-SNEDDS) as a promising alternative to conventional SNEDDS for improvement rosuvastatin calcium oral bioavailability.

PubMed

Abo Enin, Hadel A; Abdel-Bar, Hend Mohamed

2016-11-01

This study aims to illustrate the applicability of solid supersaturated self-nanoemulsifying drug delivery system (sat-SNEDDS) for the improvement of rosuvastatin calcium (RC) oral bioavailability. Different sat-SNEDDS were prepared by incorporating different ratios of RC into SNEDDS using tween80/PEG400 (77.2%) as surfactant/cosurfactant mixture and garlic /olive oil (22.8%) as oil phase. The prepared systems were characterized viz; size, zeta potential, TEM and stability. Various hydrophilic and hydrophobic carriers were employed to solidify the optimized RC sat-SNEDDS. The influence of the carrier was investigated by SEM, XRPD, DSC, flow properties, in vitro precipitation, drug release and oral bioavailability study. The adsorption of the stable positively charged nanocarrier RC sat-SNEDDS onto solid carriers provided free flowing amorphous powder. The carrier could amend the morphological architecture and in vitro release of the RC solid sat-SNEDDS. Hydrophobic carriers as microcrystalline cellulose 102 (MCC) showed superior physical characters and higher dissolution rate over hydrophilic carriers as maltodextrin with respective T 100% 30 min and 45 min. The rapid spontaneous emulsification, the positively nanosized MCC-sat-SNEDDS improved oral bioavailability of RC by 2.1-fold over commercial tablets. Solid MCC-sat-SNEDDS combined dual benefits of sat-SNEDDS and solid dosage form was successfully optimized to improve RC oral bioavailability.

Molecular complexation of curcumin with pH sensitive cationic copolymer enhances the aqueous solubility, stability and bioavailability of curcumin.

PubMed

Kumar, Sunny; Kesharwani, Siddharth S; Mathur, Himanshi; Tyagi, Mohit; Bhat, G Jayarama; Tummala, Hemachand

2016-01-20

Curcumin is a natural dietary compound with demonstrated potential in preventing/treating several chronic diseases in animal models. However, this success is yet to be translated to humans mainly because of its poor oral bioavailability caused by extremely low water solubility. This manuscript demonstrates that water insoluble curcumin (~1μg/ml) forms highly aqueous soluble complexes (>2mg/ml) with a safe pH sensitive polymer, poly(butyl-methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl-methacrylate) when precipitated together in water. The complexation process was optimized to enhance curcumin loading by varying several formulation factors. Acetone as a solvent and polyvinyl alcohol as a stabilizer with 1:2 ratio of drug to polymer yielded complexes with relatively high loading (~280μg/ml) and enhanced solubility (>2mg/ml). The complexes were amorphous in solid and were soluble only in buffers with pHs less than 5.0. Hydrogen bond formation and hydrophobic interactions between curcumin and the polymer were recorded by infrared spectroscopy and nuclear magnetic resonance spectroscopy, respectively. Molecular complexes of curcumin were more stable at various pHs compared to unformulated curcumin. In mice, these complexes increased peak plasma concentration of curcumin by 6 times and oral bioavailability by ~20 times. This is a simple, economic and safer strategy of enhancing the oral bioavailability of curcumin. Copyright © 2015 Elsevier B.V. All rights reserved.

Potentially bioavailable ferrous iron nanoparticles in glacial sediments

NASA Astrophysics Data System (ADS)

Hawkings, J.; Benning, L. G.; Raiswell, R.; Kaulich, B.; Araki, T.; Abyaneh, M.; Koch-Müller, M.; Stockdale, A.; Tranter, M.; Wadham, J.

2017-12-01

Iron (Fe) is an essential nutrient for marine phytoplankton, the primary producers of the ocean. Despite it being the fourth most abundant element in the Earth's crust, it is highly insoluble, due in part to its rapid oxidation from ferric (Fe2+) to ferrous phases (Fe3+), which often leads to the formation of nanoparticulate iron oxyhydroxide phases1. The insoluble nature of Fe in oxygenated waters means Fe limitation of primary producers is prevalent in 30-50% of the world's oceans, including areas of high biological productivity proximal to significant glacial activity (e.g., the Southern Ocean). Glaciers and ice sheets are a significant source of nanoparticulate Fe, which may be important in sustaining the high productivity observed in the near coastal regions proximal to glacial coverage. The reactivity of particulate iron is poorly understood, despite its importance in the ocean Fe inventory. Here we combined geochemical extractions, high-resolution imaging and spectroscopy to investigate the abundance, morphology and valence state of reactive iron in glacial sediments. Our results document the widespread occurrence of amorphous and Fe(II)-rich nanoparticles in glacial meltwaters and icebergs. Fe(II) is thought to be highly bioavailable in marine environments. We argue that glaciers and ice sheets are therefore able to supply potentially bioavailable Fe(II)-containing nanoparticulate material for downstream ecosystems, including those in a marine setting. The flux of bioavailable particulate iron from Arctic glaciers may increase as rising air temperatures lead to higher meltwater export.

Curcumin Cocrystal Micelles-Multifunctional Nanocomposites for Management of Neurodegenerative Ailments.

PubMed

Desai, Preshita P; Patravale, Vandana B

2018-04-01

Curcumin, a potent antioxidant polyphenol with neuroprotective and antiamyloid activities, has significant potential in the treatment of neurodegenerative disorders such as Alzheimer's disease. However, its clinical translation is delayed due to poor bioavailability. For effective use of curcumin in Alzheimer's disease, it is imperative to increase its bioavailability with enhanced delivery at a therapeutic site that is, brain. With this objective, pharmaceutical cocrystals of curcumin were developed and incorporated in micellar nanocarriers for nose-to-brain delivery. For cocrystals, an antioxidant hydrophilic coformer was strategically selected using molecular modeling approach. The cocrystals were formulated using a planetary ball mill, and the process was optimized using 3 2 factorial design followed by characterization using differential scanning calorimetry, X-ray diffraction, and Fourier-transform infrared spectroscopy analysis. The cocrystal micelles exhibited globule size of 28.79 ± 0.86 nm. Further, curcumin cocrystal and co-crystal micelles exhibited a significantly low (p value <0.01) IC 50 concentration for antioxidant activity as compared to curcumin corroborating superior antioxidant performance. In vivo studies revealed about 1.7-fold absolute bioavailability of curcumin cocrystal micelles with C max of 1218.38 ± 58.11 ng/mL and showed significantly high brain distribution even beyond 6 hours of dosing. Thus, the studies confirmed enhanced bioavailability, higher brain uptake, retention, and delayed clearance with curcumin cocrystal micellar nanocarriers. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Nanostructured lipid carriers for oral bioavailability enhancement of raloxifene: Design and in vivo study.

PubMed

Shah, Nirmal V; Seth, Avinash K; Balaraman, R; Aundhia, Chintan J; Maheshwari, Rajesh A; Parmar, Ghanshyam R

2016-05-01

The objective of present work was to utilize potential of nanostructured lipid carriers (NLCs) for improvement in oral bioavailability of raloxifene hydrochloride (RLX). RLX loaded NLCs were prepared by solvent diffusion method using glyceryl monostearate and Capmul MCM C8 as solid lipid and liquid lipid, respectively. A full 3(2) factorial design was utilized to study the effect of two independent parameters namely solid lipid to liquid lipid ratio and concentration of stabilizer on the entrapment efficiency of prepared NLCs. The statistical evaluation confirmed pronounced improvement in entrapment efficiency when liquid lipid content in the formulation increased from 5% w/w to 15% w/w. Solid-state characterization studies (DSC and XRD) in optimized formulation NLC-8 revealed transformation of RLX from crystalline to amorphous form. Optimized formulation showed 32.50 ± 5.12 nm average particle size and -12.8 ± 3.2 mV zeta potential that impart good stability of NLCs dispersion. In vitro release study showed burst release for initial 8 h followed by sustained release up to 36 h. TEM study confirmed smooth surface discrete spherical nano sized particles. To draw final conclusion, in vivo pharmacokinetic study was carried out that showed 3.75-fold enhancements in bioavailability with optimized NLCs formulation than plain drug suspension. These results showed potential of NLCs for significant improvement in oral bioavailability of poorly soluble RLX.

Crystal Engineering of Green Tea Epigallocatechin-3-gallate (EGCg) Cocrystals and Pharmacokinetic Modulation in Rats

PubMed Central

2013-01-01

The most abundant polyphenol in green tea, epigallocatechin-3-gallate (EGCg), has recently received considerable attention due to the discovery of numerous health-promoting bioactivities. Despite reports of its poor oral bioavailability, EGCg has been included in many dietary supplement formulations. Conventional preformulation methods have been employed to improve the bioavailability of EGCg. However, these methods have limitations that hinder the development of EGCg as an effective therapeutic agent. In this study, we have utilized the basic concepts of crystal engineering and several crystallization techniques to screen for various solid crystalline forms of EGCg and evaluated the efficacy of crystal engineering for modulating the pharmacokinetics of EGCg. We synthesized and characterized seven previously undescribed crystal forms of EGCg including the pure crystal structure of EGCg. The aqueous solubility profiles of four new EGCg cocrystals were determined. These cocrystals were subsequently dosed at 100 mg EGCg per kg body weight in rats, and the plasma levels were monitored over the course of eight hours following the single oral dose. Two of the EGCg cocrystals were found to exhibit modest improvements in relative bioavailability. Further, cocrystallization resulted in marked effects on pharmacokinetic parameters including Cmax, Tmax, area under curve, relative bioavailability, and apparent terminal half-life. Our findings suggest that modulation of the pharmacokinetic profile of EGCg is possible using cocrystallization and that it offers certain opportunities that could be useful during its development as a therapeutic agent. PMID:23730870

Changes in Bioavailability of Omega-3 (DHA) through Alpha-Tocopheryl Phosphate Mixture (TPM) after Oral Administration in Rats

PubMed Central

Gavin, Paul D.

2017-01-01

Benefits of Omega-3 Docosahexaenoic acid (DHA) supplements are hindered by their poor solubility and bioavailability. This study investigated the bioavailability of various formulations of Omega-3 and tocopheryl phosphate mixture (TPM), following oral administration in rats, and assessed whether TPM could improve the oral absorption of DHA. The rats were administered with a high (265.7 mg/kg) or low dose (88.6 mg/kg) of DHA. TPM was examined at 1:0.1 w/w (low TPM dose) and 1:0.5 w/w (high TPM dose). Over 24 h, the DHA plasma concentration followed a TPM dose-dependent relationship, reflected in the higher mean Cmax values (78.39 and 91.95 μg/mL) and AUC values (1396.60 and 1560.60) for the low and high TPM, respectively. The biggest difference between the low dose DHA control (LDCont) and TPM formulations was at 4 h after supplementation, where the low and high TPM showed a mean 20% (ns) and 50% (p < 0.05) increase in DHA plasma concentrations versus the control formulation. After correcting for baseline endogenous DHA, the mean plasma DHA at 4 h produced by the LD-HTPM was nearly double (90%) the LDC control (p = 0.057). This study demonstrated that co-administering omega-3 with TPM significantly increases the bioavailability of DHA in the plasma, suggesting potential use for commercially available TPM + DHA fortified products. PMID:28930161