[Comparative study on transdermal osmosis in vitro of Aconitum brachypodium liniment, gel and patcher].

PubMed

Lin, Ya-ping; Zhao, Ying; Zhang, Yong-ping; Liang, Guang-yi

2007-02-01

To study the transdermal osmosis process of Aconitum brachypodum's liniment, gel and patcher to provide basis for selecting dosage form and controlling the quality. Taking the cumulate rate of transdermal as index, a imitated Fick's diffusion device was used for the investigating the transdermal osmosis course of the three preparations. The best transdermal mathematics models are obtained and the relations between the transdermal course and the release course are analysed. The three preparations have different characteristics of transdermal osmosis course. The liniment meets dynamics 0 order process, the gel and the patcher meet dynamic 0 order process of non-corroded drug system. And the relation is good cubic equation between their transdermal course and release course. The transdermal osmosis experiment in vitro for three preparations can provide basis for selecting dosage form and the quality control in future studies.

3D printing applications for transdermal drug delivery.

PubMed

Economidou, Sophia N; Lamprou, Dimitrios A; Douroumis, Dennis

2018-06-15

The role of two and three-dimensional printing as a fabrication technology for sophisticated transdermal drug delivery systems is explored in literature. 3D printing encompasses a family of distinct technologies that employ a virtual model to produce a physical object through numerically controlled apparatuses. The applicability of several printing technologies has been researched for the direct or indirect printing of microneedle arrays or for the modification of their surface through drug-containing coatings. The findings of the respective studies are presented. The range of printable materials that are currently used or potentially can be employed for 3D printing of transdermal drug delivery (TDD) systems is also reviewed. Moreover, the expected impact and challenges of the adoption of 3D printing as a manufacturing technique for transdermal drug delivery systems, are assessed. Finally, this paper outlines the current regulatory framework associated with 3D printed transdermal drug delivery systems. Copyright © 2018 Elsevier B.V. All rights reserved.

Transdermal drug delivery: feasibility for treatment of superficial bone stress fractures.

PubMed

Aghazadeh-Habashi, Ali; Yang, Yang; Tang, Kathy; Lőbenberg, Raimar; Doschak, Michael R

2015-12-01

Transdermal drug delivery offers the promise of effective drug therapy at selective sites of pathology whilst reducing systemic exposure to the pharmaceutical agents in off-target organs and tissues. However, that strategy is often limited to cells comprising superficial tissues of the body (rarely to deeper bony structures) and mostly indicated with small hydrophobic pharmacological agents, such as steroid hormones and anti-inflammatory gels to skin, muscle, and joints. Nonetheless, advances in transdermal liposomal formulation have rendered the ability to readily incorporate pharmacologically active hydrophilic drug molecules and small peptide biologics into transdermal dosage forms to impart the effective delivery of those bioactive agents across the skin barrier to underlying superficial tissue structures including bone, often enhanced by some form of electrical, chemical, and mechanical facilitation. In the following review, we evaluate transdermal drug delivery systems, with a particular focus on delivering therapeutic agents to treat superficial bone pain, notably stress fractures. We further introduce and discuss several small peptide hormones active in bone (such as calcitonins and parathyroid hormone) that have shown potential for transdermal delivery, often under the added augmentation of transdermal drug delivery systems that employ lipo/hydrophilicity, electric charge, and/or microprojection facilitation across the skin barrier.

Spray-on transdermal drug delivery systems.

PubMed

Ibrahim, Sarah A

2015-02-01

Transdermal drug delivery possesses superior advantages over other routes of administration, particularly minimizing first-pass metabolism. Transdermal drug delivery is challenged by the barrier nature of skin. Numerous technologies have been developed to overcome the relatively low skin permeability, including spray-on transdermal systems. A transdermal spray-on system (TSS) usually consists of a solution containing the drug, a volatile solvent and in many cases a chemical penetration enhancer. TSS promotes drug delivery via the complex interplay between solvent evaporation and drug-solvent drag into skin. The volatile solvent carries the drug into the upper layers of the stratum corneum, and as the volatile solvent evaporates, an increase in the thermodynamic activity of the drug occurs resulting in an increased drug loading in skin. TSS is easily applied, delivering flexible drug dosage and associated with lower incidence of skin irritation. TSS provides a fast-drying product where the volatile solvent enables uniform drug distribution with minimal vehicle deposition on skin. TSS ensures precise dose administration that is aesthetically appealing and eliminates concerns of residual drug associated with transdermal patches. Furthermore, it provides a better alternative to traditional transdermal products due to ease of product development and manufacturing.

Experimental motion sickness - Efficacy of transdermal scopolamine plus ephedrine

NASA Technical Reports Server (NTRS)

Graybiel, A.; Cramer, D. B.; Wood, C. D.

1981-01-01

A double-blind, placebo-controlled study compared the efficacy of transdermal therapeutic system-scopolamine administered alone and combined with ephedrine sulfate given orally in doses of 12.5, 25, and 50 mg. Eight normal male students were exposed to stressful accelerations in a slow-rotation room after receiving 10 apparently identical treatments comprising the four drugs and six placebos. Efficacy of the drug was defined in terms of the placebo range and categorized as beneficial, inconsequential, or detrimental. None of the effects was detrimental. Overall beneficial effects were 60% for transdermal therapeutic system-scopolamine (plus placebo) and 57% for the three transdermal therapeutic system-scopolamine plus ephedrine combinations.

Effect of Penetration Enhancers on the Percuaneous Delivery of Hormone Replacement Actives.

PubMed

Trimble, John O; Light, Bob

2017-01-01

Transdermal compositions for hormone replacement are comprised of exogenous hormones that are biochemically similar to those produced endogenously by the ovaries or elsewhere in the body. In this work, estradiol, estriol, and testosterone were loaded in transdermal vehicles, prepared using one of three selected penetration enhancer mixtures: Vehicle 1 (olive oil and oleic acid), Vehicle 2 (isopropyl palmitate and lecithin), and Vehicle 3 (isopropyl myristate and lecithin). The influence of penetration enhancers on transdermal delivery was evaluated using Franz-type diffusion cells and Normal Human 3D Model of Epidermal Tissue. Results showed that drug delivery is affected by the penetration enhancer used in the transdermal composition. Copyright© by International Journal of Pharmaceutical Compounding, Inc.

Poly(lactic-co-glycolic) acid drug delivery systems through transdermal pathway: an overview.

PubMed

Naves, Lucas; Dhand, Chetna; Almeida, Luis; Rajamani, Lakshminarayanan; Ramakrishna, Seeram; Soares, Graça

2017-05-01

In past few decades, scientists have made tremendous advancement in the field of drug delivery systems (DDS), through transdermal pathway, as the skin represents a ready and large surface area for delivering drugs. Efforts are in progress to design efficient transdermal DDS that support sustained drug release at the targeted area for longer duration in the recommended therapeutic window without producing side-effects. Poly(lactic-co-glycolic acid) (PLGA) is one of the most promising Food and Drug Administration approved synthetic polymers in designing versatile drug delivery carriers for different drug administration routes, including transdermal drug delivery. The present review provides a brief introduction over the transdermal drug delivery and PLGA as a material in context to its role in designing drug delivery vehicles. Attempts are made to compile literatures over PLGA-based drug delivery vehicles, including microneedles, nanoparticles, and nanofibers and their role in transdermal drug delivery of different therapeutic agents. Different nanostructure evaluation techniques with their working principles are briefly explained.

Electron beam processed transdermal delivery system for administration of an anti-anginal agent

NASA Astrophysics Data System (ADS)

Kotiyan, P. N.; Vavia, P. R.; Bharadwaj, Y. K.; Sabarwal, S.; Majali, A. B.

2002-12-01

Electron beam irradiation was used to synthesize a matrix type transdermal system of isosorbide dinitrate, an effective anti-anginal agent. The drug was dissolved in two monomeric systems, 2-ethylhexyl acrylate (EHA) and 2-ethylhexyl acrylate : methyl methacrylate (9 : 1). The solutions were then directly irradiated on a backing membrane (Scotchpak ®1006) at different doses to get transdermal patches. The developed systems were evaluated for residual monomer content, equilibrium weight swelling ratio, weight uniformity, thickness uniformity, drug content, peel strength, in vitro release and skin permeation kinetics. They possessed excellent tack and adhesive properties. In the case of isosorbide dinitrate-EHA systems, an increase in the peel strength values with respect to the skin was observed with increasing radiation doses. The systems exhibited promising skin permeation kinetics favorable for transdermal drug delivery. The radiation stability of the drug in the pure solid state form was also assessed.

Conductive polymer nanotube patch for fast and controlled ex vivo transdermal drug delivery.

PubMed

Nguyen, Thao M; Lee, Sebin; Lee, Sang Bok

2014-10-01

To uptake and release hydrophilic model drugs and insulin in a novel conductive polymer (CP) nanotube transdermal patch. The externally controlled transdermal delivery of model drugs and insulin were tested ex vivo and results were compared with CP films. The unique intrinsic properties of CPs provide electrostatic interaction between the model drugs and polymer backbone. When a pulsed potential was applied, the drug delivery release profile mimics that of injection delivery. With a constant potential applied, the release rate constants of the patch system were up to three-times faster than the control (0 V) and released approximately 80% more drug molecules over 24 h. The CP nanotube transdermal patch represents a new and promising drug method, specifically for hydrophilic molecules, which have been a large obstacle for conventional transdermal drug delivery systems.

Natural oils as skin permeation enhancers for transdermal delivery of olanzapine: in vitro and in vivo evaluation.

PubMed

Aggarwal, Geeta; Dhawan, Sanju; HariKumar, S L

2012-03-01

The feasibility of development of transdermal delivery system of olanzapine utilizing natural oils as permeation enhancers was investigated. Penetration enhancing potential of corn (maize) oil, groundnut oil and jojoba oil on in vitro permeation of olanzapine across rat skin was studied. The magnitude of flux enhancement factor with corn oil, groundnut oil and jojoba oil was 7.06, 5.31 and 1.9 respectively at 5mg/ml concentration in solvent system. On the basis of in vitro permeation studies, eudragit based matrix type transdermal patches of olanzapine were fabricated using optimized concentrations of natural oils as permeation enhancers. All transdermal patches were found to be uniform with respect to physical characteristics. The interaction studies carried out by comparing the results of ultraviolet, HPLC and FTIR analyses for the pure drug, polymers and mixture of drug and polymers indicated no chemical interaction between the drug and excipients. Corn oil containing unsaturated fatty acids was found to be promising natural permeation enhancer for transdermal delivery of olanzapine with greatest cumulative amount of drug permeated (1010.68 μg/cm²/h) up to 24 h and caused no skin irritation. The fabricated transdermal patches were found to be stable. The pharmacokinetic characteristics of the final optimized matrix patch (T2) were determined after transdermal application to rabbits. The calculated relative bioavailability of TDDS was 113.6 % as compared to oral administration of olanzapine. The therapeutic effectiveness of optimized transdermal system was confirmed by tranquillizing activity in rotarod and grip mice model.

Relative efficacy of the proposed Space Shuttle antimotion sickness medications

NASA Astrophysics Data System (ADS)

Hordinsky, J. R.; Schwartz, E.; Beier, J.; Martin, J.; Aust, G.

1982-07-01

Space motion sickness has been estimated as affecting between 1/3 and 1/2 of all space flight participants. NASA has at the moment proposed a combination of promethazine and ephedrine ( P/E) and one of scopolamine and dextroamphetamine ( S/D), both given orally, as well as a transdermally applied scopolamine (TAS), as preventive and ameliorative measures. The reported double-blind study tests the early phase actions and efficacy of the transdermal scopolamine (Transderm ™-V of ALZA Corporation) and compares these in detail to the oral medications. Motion sickness resistance was tested by standardized head movements while accelerating at 0.2°/sec 2 to a maximum rotation of 240°/sec, with an intermediate plateau of 10 min at 180°/sec. To permit weighting motion sickness protection against other system influences, cardiovascular, psychological (subjective and objective), and visual parameter changes were documented for the three therapeutic modes. The relative impact of the various modalities on operational and experimental components of space missions is discussed. A comparison to intramuscularly administered promethazine (a backup therapeutic mode suggested for Space Shuttle use) is also included.

Transdermal film-loaded finasteride microplates to enhance drug skin permeation: Two-step optimization study.

PubMed

Ahmed, Tarek A; El-Say, Khalid M

2016-06-10

The goal was to develop an optimized transdermal finasteride (FNS) film loaded with drug microplates (MIC), utilizing two-step optimization, to decrease the dosing schedule and inconsistency in gastrointestinal absorption. First; 3-level factorial design was implemented to prepare optimized FNS-MIC of minimum particle size. Second; Box-Behnken design matrix was used to develop optimized transdermal FNS-MIC film. Interaction among MIC components was studied using physicochemical characterization tools. Film components namely; hydroxypropyl methyl cellulose (X1), dimethyl sulfoxide (X2) and propylene glycol (X3) were optimized for their effects on the film thickness (Y1) and elongation percent (Y2), and for FNS steady state flux (Y3), permeability coefficient (Y4), and diffusion coefficient (Y5) following ex-vivo permeation through the rat skin. Morphological study of the optimized MIC and transdermal film was also investigated. Results revealed that stabilizer concentration and anti-solvent percent were significantly affecting MIC formulation. Optimized FNS-MIC of particle size 0.93μm was successfully prepared in which there was no interaction observed among their components. An enhancement in the aqueous solubility of FNS-MIC by more than 23% was achieved. All the studied variables, most of their interaction and quadratic effects were significantly affecting the studied variables (Y1-Y5). Morphological observation illustrated non-spherical, short rods, flakes like small plates that were homogeneously distributed in the optimized transdermal film. Ex-vivo study showed enhanced FNS permeation from film loaded MIC when compared to that contains pure drug. So, MIC is a successful technique to enhance aqueous solubility and skin permeation of poor water soluble drug especially when loaded into transdermal films. Copyright © 2016 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

Navigating sticky areas in transdermal product development.

PubMed

Strasinger, Caroline; Raney, Sam G; Tran, Doanh C; Ghosh, Priyanka; Newman, Bryan; Bashaw, Edward D; Ghosh, Tapash; Shukla, Chinmay G

2016-07-10

The benefits of transdermal delivery over the oral route to combat such issues of low bioavailability and limited controlled release opportunities are well known and have been previously discussed by many in the field (Prausnitz et al. (2004) [1]; Hadgraft and Lane (2006) [2]). However, significant challenges faced by developers as a product moves from the purely theoretical to commercial production have hampered full capitalization of the dosage forms vast benefits. While different technical aspects of transdermal system development have been discussed at various industry meetings and scientific workshops, uncertainties have persisted regarding the pharmaceutical industry's conventionally accepted approach for the development and manufacturing of transdermal systems. This review provides an overview of the challenges frequently faced and the industry's best practices for assuring the quality and performance of transdermal delivery systems and topical patches (collectively, TDS). The topics discussed are broadly divided into the evaluation of product quality and the evaluation of product performance; with the overall goal of the discussion to improve, advance and accelerate commercial development in the area of this complex controlled release dosage form. Published by Elsevier B.V.

Future of the transdermal drug delivery market--have we barely touched the surface?

PubMed

Watkinson, Adam C; Kearney, Mary-Carmel; Quinn, Helen L; Courtenay, Aaron J; Donnelly, Ryan F

2016-01-01

Transdermal drug delivery is the movement of drugs across the skin for absorption into the systemic circulation. Transfer of the drug can occur via passive or active means; passive transdermal products do not disrupt the stratum corneum to facilitate delivery whereas active technologies do. Due to the very specific physicochemical properties necessary for successful passive transdermal drug delivery, this sector of the pharmaceutical industry is relatively small. There are many well-documented benefits of this delivery route however, and as a result there is great interest in increasing the number of therapeutic substances that can be delivered transdermally. This review discusses the various transdermal products that are currently/have been marketed, and the paths that led to their success, or lack of. Both passive and active transdermal technologies are considered with the advantages and limitations of each highlighted. In addition to marketed products, technologies that are in the investigative stages by various pharmaceutical companies are reviewed. Passive transdermal drug delivery has made limited progress in recent years, however with the ongoing intense research into active technologies, there is great potential for growth within the transdermal delivery market. A number of active technologies have already been translated into marketed products, with other platforms including microneedles, rapidly progressing towards commercialisation.

Heat: A Highly Efficient Skin Enhancer for Transdermal Drug Delivery.

PubMed

Szunerits, Sabine; Boukherroub, Rabah

2018-01-01

Advances in materials science and bionanotechnology have allowed the refinements of current drug delivery systems, expected to facilitate the development of personalized medicine. While dermatological topical pharmaceutical formulations such as foams, creams, lotions, gels, etc., have been proposed for decades, these systems target mainly skin-based diseases. To treat systemic medical conditions as well as localized problems such as joint or muscle concerns, transdermal delivery systems (TDDSs), which use the skin as the main route of drug delivery, are very appealing. Over the years, these systems have shown to offer important advantages over oral as well as intravenous drug delivery routes. Besides being non-invasive and painless, TDDSs are able to deliver drugs with a short-half-life time more easily and are well adapted to eliminate frequent administrations to maintain constant drug delivery. The possibility of self-administration of a predetermined drug dose at defined time intervals makes it also the most convenient personalized point-of-care approach. The transdermal market still remains limited to a narrow range of drugs. While small and lipophilic drugs have been successfully delivered using TDDSs, this approach fails to deliver therapeutic macromolecules due to size-limited transport across the stratum corneum , the outermost layer of the epidermis. The low permeability of the stratum corneum to water-soluble drugs as well as macromolecules poses important challenges to transdermal administration. To widen the scope of drugs for transdermal delivery, new procedures to enhance skin permeation to hydrophilic drugs and macromolecules are under development. Next to iontophoresis and microneedle-based concepts, thermal-based approaches have shown great promise to enhance transdermal drug delivery of different therapeutics. In this inaugural article for the section "Frontiers in Bioengineering and Biotechnology," the advances in this field and the handful of examples of thermal technologies for local and systemic transdermal drug delivery will be discussed and put into perspective.

Heat: A Highly Efficient Skin Enhancer for Transdermal Drug Delivery

PubMed Central

Szunerits, Sabine; Boukherroub, Rabah

2018-01-01

Advances in materials science and bionanotechnology have allowed the refinements of current drug delivery systems, expected to facilitate the development of personalized medicine. While dermatological topical pharmaceutical formulations such as foams, creams, lotions, gels, etc., have been proposed for decades, these systems target mainly skin-based diseases. To treat systemic medical conditions as well as localized problems such as joint or muscle concerns, transdermal delivery systems (TDDSs), which use the skin as the main route of drug delivery, are very appealing. Over the years, these systems have shown to offer important advantages over oral as well as intravenous drug delivery routes. Besides being non-invasive and painless, TDDSs are able to deliver drugs with a short-half-life time more easily and are well adapted to eliminate frequent administrations to maintain constant drug delivery. The possibility of self-administration of a predetermined drug dose at defined time intervals makes it also the most convenient personalized point-of-care approach. The transdermal market still remains limited to a narrow range of drugs. While small and lipophilic drugs have been successfully delivered using TDDSs, this approach fails to deliver therapeutic macromolecules due to size-limited transport across the stratum corneum, the outermost layer of the epidermis. The low permeability of the stratum corneum to water-soluble drugs as well as macromolecules poses important challenges to transdermal administration. To widen the scope of drugs for transdermal delivery, new procedures to enhance skin permeation to hydrophilic drugs and macromolecules are under development. Next to iontophoresis and microneedle-based concepts, thermal-based approaches have shown great promise to enhance transdermal drug delivery of different therapeutics. In this inaugural article for the section “Frontiers in Bioengineering and Biotechnology,” the advances in this field and the handful of examples of thermal technologies for local and systemic transdermal drug delivery will be discussed and put into perspective. PMID:29497609

Transdermal scopolamine in the prevention of motion sickness - Evaluation of the time course of efficacy

NASA Technical Reports Server (NTRS)

Homick, J. L.; Reschke, M. F.; Degioanni, J.; Cintron-Trevino, N. M.; Kohl, R. L.

1983-01-01

This study evaluated the time course of efficacy of transdermal scopolamine in the prevention of motion sickness induced by exposure to coriolis stimulation in a rotating chair. We measured levels of efficacy, quantified side effects and symptoms, and determined inter- and intra-subject variability following use of transdermal scopolamine. The response to transdermal scopolamine was highly variable, although overall we recorded a 40 percent improvement in test scores 16-72 h after application of the transdermal system. This variability could not be explained solely by the levels of scopolamine present in the blood. The improvement was not due to the artifactual repression by scopolamine of selected symptoms of motion sickness. An unexpectedly high incidence of side effects was reported. It was concluded that the therapeutic use of transdermal scopolamine be evaluated individually and that individuals be cautioned that subsequent usage may not always be effective.

Transdermal delivery of biomacromolecules using lipid-like nanoparticles

NASA Astrophysics Data System (ADS)

Bello, Evelyn A.

The transdermal delivery of biomacromolecules, including proteins and nucleic acids, is challenging, owing to their large size and the penetration-resistant nature of the stratum corneum. Thus, an urgent need exists for the development of transdermal delivery methodologies. This research focuses on the use of cationic lipid-like nanoparticles (lipidoids) for the transdermal delivery of proteins, and establishes an in vitro model for the study. The lipidoids used were first combinatorially designed and synthesized; afterwards, they were employed for protein encapsulation in a vesicular system. A skin penetration study demonstrated that lipidoids enhance penetration depth in a pig skin model, overcoming the barrier that the stratum corneum presents. This research has successfully identified active lipidoids capable of efficiently penetrating the skin; therefore, loading proteins into lipidoid nanoparticles will facilitate the transdermal delivery of proteins. Membrane diffusion experiments were used to confirm the results. This research has confirmed that lipidoids are a suitable material for transdermal protein delivery enhancement.

Recent Advances in Skin Penetration Enhancers for Transdermal Gene and Drug Delivery.

PubMed

Amjadi, Morteza; Mostaghaci, Babak; Sitti, Metin

2017-01-01

There is a growing interest in transdermal delivery systems because of their noninvasive, targeted, and on-demand delivery of gene and drugs. However, efficient penetration of therapeutic compounds into the skin is still challenging largely due to the impermeability of the outermost layer of the skin, known as stratum corneum. Recently, there have been major research activities to enhance the skin penetration depth of pharmacological agents. This article reviews recent advances in the development of various strategies for skin penetration enhancement. We show that approaches such as ultrasound waves, laser, and microneedle patches have successfully been employed to physically disrupt the stratum corneum structure for enhanced transdermal delivery. Rather than physical approaches, several non-physical route have also been utilized for efficient transdermal delivery across the skin barrier. Finally, we discuss some clinical applications of transdermal delivery systems for gene and drug delivery. This paper shows that transdermal delivery devices can potentially function for diverse healthcare and medical applications while further investigations are still necessary for more efficient skin penetration of gene and drugs. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

On the Road to Development of an in Vitro Permeation Test (IVPT) Model to Compare Heat Effects on Transdermal Delivery Systems: Exploratory Studies with Nicotine and Fentanyl.

PubMed

Shin, Soo Hyeon; Ghosh, Priyanka; Newman, Bryan; Hammell, Dana C; Raney, Sam G; Hassan, Hazem E; Stinchcomb, Audra L

2017-09-01

At elevated temperatures, the rate of drug release and skin permeation from transdermal delivery systems (TDS) may be higher than at a normal skin temperature. The aim of this study was to compare the effect of heat on the transdermal delivery of two model drugs, nicotine and fentanyl, from matrix-type TDSs with different formulations, using in vitro permeation tests (IVPT). IVPT experiments using pig skin were performed on two nicotine and three fentanyl TDSs. Both continuous and transient heat exposures were investigated by applying heat either for the maximum recommended TDS wear duration or for short duration. Continuous heat exposure for the two nicotine TDSs resulted in different effects, showing a prolonged heat effect for one product but not the other. The J max enhancement ratio due to the continuous heat effect was comparable between the two nicotine TDS, but significantly different (p < 0.05) among the three fentanyl TDSs. The J max enhancement ratios due to transient heat exposure were significantly different for the two nicotine TDSs, but not for the three fentanyl TDSs. Furthermore, the transient heat exposure affected the clearance of drug from the skin depot after TDS removal differently for two drugs, with fentanyl exhibiting a longer heat effect. This exploratory work suggests that an IVPT study may be able to discriminate differences in transdermal drug delivery when different TDS are exposed to elevated temperatures. However, the clinical significance of IVPT heat effects studies should be further explored by conducting in vivo clinical studies with similar study designs.

Biomaterials as novel penetration enhancers for transdermal and dermal drug delivery systems.

PubMed

Chen, Yang; Wang, Manli; Fang, Liang

2013-01-01

The highly organized structure of the stratum corneum provides an effective barrier to the drug delivery into or across the skin. To overcome this barrier function, penetration enhancers are always used in the transdermal and dermal drug delivery systems. However, the conventional chemical enhancers are often limited by their inability to delivery large and hydrophilic molecules, and few to date have been routinely incorporated into the transdermal formulations due to their incompatibility and local irritation issues. Therefore, there has been a search for the compounds that exhibit broad enhancing activity for more drugs without producing much irritation. More recently, the use of biomaterials has emerged as a novel method to increase the skin permeability. In this paper, we present an overview of the investigations on the feasibility and application of biomaterials as penetration enhancers for transdermal or dermal drug delivery systems.

Nanoparticle-Enabled Transdermal Drug Delivery Systems for Enhanced Dose Control and Tissue Targeting.

PubMed

Palmer, Brian C; DeLouise, Lisa A

2016-12-15

Transdermal drug delivery systems have been around for decades, and current technologies (e.g., patches, ointments, and creams) enhance the skin permeation of low molecular weight, lipophilic drugs that are efficacious at low doses. The objective of current transdermal drug delivery research is to discover ways to enhance skin penetration of larger, hydrophilic drugs and macromolecules for disease treatment and vaccination. Nanocarriers made of lipids, metals, or polymers have been successfully used to increase penetration of drugs or vaccines, control drug release, and target drugs to specific areas of skin in vivo. While more research is needed to identify the safety of nanocarriers, this technology has the potential to expand the use of transdermal routes of administration to a wide array of therapeutics. Here, we review the current state of nanoparticle skin delivery systems with special emphasis on targeting skin diseases.

Nanoparticle enabled transdermal drug delivery systems for enhanced dose control and tissue targeting

PubMed Central

Palmer, Brian C.; DeLouise, Lisa A.

2017-01-01

Transdermal drug delivery systems have been around for decades, and current technologies (e.g. patches, ointments, and creams) enhance the skin permeation of low molecular weight, lipophilic drugs that are efficacious at low doses. The objective of current transdermal drug delivery research is to discover ways to enhance skin penetration of larger, hydrophilic drugs and macromolecules for disease treatment and vaccination. Nanocarriers made of lipids, metals, or polymers have been successfully used to increase penetration of drugs or vaccines, control drug release, and target drugs to specific areas of skin in vivo. While more research is needed to identify the safety of nanocarriers, this technology has the potential to expand the use of transdermal routes of administration to a wide array of therapeutics. Here, we review the current state of nanoparticle skin delivery systems with special emphasis on targeting skin diseases. PMID:27983701

Transdermal drug delivery

PubMed Central

Prausnitz, Mark R.; Langer, Robert

2009-01-01

Transdermal drug delivery has made an important contribution to medical practice, but has yet to fully achieve its potential as an alternative to oral delivery and hypodermic injections. First-generation transdermal delivery systems have continued their steady increase in clinical use for delivery of small, lipophilic, low-dose drugs. Second-generation delivery systems using chemical enhancers, non-cavitational ultrasound and iontophoresis have also resulted in clinical products; the ability of iontophoresis to control delivery rates in real time provides added functionality. Third-generation delivery systems target their effects to skin’s barrier layer of stratum corneum using microneedles, thermal ablation, microdermabrasion, electroporation and cavitational ultrasound. Microneedles and thermal ablation are currently progressing through clinical trials for delivery of macromolecules and vaccines, such as insulin, parathyroid hormone and influenza vaccine. Using these novel second- and third-generation enhancement strategies, transdermal delivery is poised to significantly increase impact on medicine. PMID:18997767

Advanced Analgesic Drug Delivery and Nanobiotechnology.

PubMed

Stoicea, Nicoleta; Fiorda-Diaz, Juan; Joseph, Nicholas; Shabsigh, Muhammad; Arias-Morales, Carlos; Gonzalez-Zacarias, Alicia A; Mavarez-Martinez, Ana; Marjoribanks, Stephen; Bergese, Sergio D

2017-07-01

Transdermal administration of analgesic medications offers several benefits over alternative routes of administration, including a decreased systemic drug load with fewer side effects, and avoidance of drug degradation by the gastrointestinal tract. Transdermal administration also offers a convenient mode of drug administration over an extended period of time, particularly desirable in pain medicine. A transdermal administration route may also offer increased safety for drugs with a narrow therapeutic window. The primary barrier to transdermal drug absorption is the skin itself. Transdermal nanotechnology offers a novel method of achieving enhanced dermal penetration with an extended delivery profile for analgesic drugs, due to their small size and relatively large surface area. Several materials have been used to enhance drug duration and transdermal penetration. The application of nanotechnology in transdermal delivery of analgesics has raised new questions regarding safety and ethical issues. The small molecular size of nanoparticles enables drug delivery to previously inaccessible body sites. To ensure safety, the interaction of nanoparticles with the human body requires further investigation on an individual drug basis, since different formulations have unique properties and side effects.

Ion-exchange and iontophoresis-controlled delivery of apomorphine.

PubMed

Malinovskaja, Kristina; Laaksonen, Timo; Kontturi, Kyösti; Hirvonen, Jouni

2013-04-01

The objective of this study was to test a drug delivery system that combines iontophoresis and cation-exchange fibers as drug matrices for the controlled transdermal delivery of antiparkinsonian drug apomorphine. Positively charged apomorphine was bound to the ion-exchange groups of the cation-exchange fibers until it was released by mobile counter-ions in the external solution. The release of the drug was controlled by modifying either the fiber type or the ionic composition of the external solution. Due to high affinity of apomorphine toward the ion-exchanger, a clear reduction in the in vitro transdermal fluxes from the fibers was observed compared to the respective fluxes from apomorphine solutions. Changes in the ionic composition of the donor formulations affected both the release and iontophoretic flux of the drug. Upon the application of higher co-ion concentrations or co-ions of higher valence in the donor formulation, the release from the fibers was enhanced, but the iontophoretic steady-state flux was decreased. Overall, the present study has demonstrated a promising approach using ion-exchange fibers for controlling the release and iontophoretic transdermal delivery of apomorphine. Copyright © 2012 Elsevier B.V. All rights reserved.

Combined use of monopolar radiofrequency and transdermal drug delivery in the treatment of melasma.

PubMed

Cameli, Norma; Abril, Elva; Mariano, Maria; Berardesca, Enzo

2014-07-01

Melasma is a common acquired pigmentary disorder that has a considerable psychological impact on the patient. The recurrent and refractory nature of this condition makes it difficult for treatment. We aim to evaluate the efficacy and safety of a combined system that simultaneously uses monopolar radiofrequency (RF) and transdermal drug delivery of phytocomplex containing 1% kojic acid in the treatment of melasma. Fifty patients affected by melasma underwent 6 sessions of treatment at 1-week intervals. The outcome was evaluated before treatment (T0) and 1 month (T1) and 6 months (T2) after treatment using the Melasma Area and Severity Index score, a Mexameter, and Visioface devices for digital and ultraviolet computerized image analysis of skin color. The image analysis showed that hyperpigmentation was significantly reduced at T1 and T2 compared with baseline. Melasma Area and Severity Index score, the average melanin score, and the average erythema values showed a significant reduction. No side effects were observed or reported. This study describes the first report of improvement in melasma through the combined use of monopolar RF with transdermal delivery of depigmenting agents. This could be a safe, tolerable, and effective alternative tool for the treatment of melasma.

Recent trends in the transdermal delivery of therapeutic agents used for the management of neurodegenerative diseases.

PubMed

Ita, Kevin

2017-06-01

With the increasing proportion of the global geriatric population, it becomes obvious that neurodegenerative diseases will become more widespread. From an epidemiological standpoint, it is necessary to develop new therapeutic agents for the management of Alzheimer's disease, Parkinson's disease, multiple sclerosis and other neurodegenerative disorders. An important approach in this regard involves the use of the transdermal route. With transdermal drug delivery systems (TDDS), it is possible to modulate the pharmacokinetic profiles of these medications and improve patient compliance. Transdermal drug delivery has also been shown to be useful for drugs with short half-life and low or unpredictable bioavailability. In this review, several transdermal drug delivery enhancement technologies are being discussed in relation to the delivery of medications used for the management of neurodegenerative disorders.

Current and emerging lipid-based systems for transdermal drug delivery.

PubMed

Singla, Sumeet K; Sachdeva, Vishal

2015-01-01

Developing a transdermal drug delivery system is a challenging task considering the selective permeability of the skin and the physicochemical properties the drug must possess to permeate through the skin. Lipid-based drug delivery systems have contributed a great deal in this direction in the last few decades, and thereby have helped to expand the range of therapeutic molecules that can be delivered through the skin in a safe and effective manner. Additionally, vesicular delivery systems such as nanoparticles and emulsions have also played important roles in providing alternative novel approaches for drug delivery. In this article, we will discuss some of the current and future lipid-based systems for transdermal drug delivery along with the associated challenges.

Rivastigmine Transdermal Patch

MedlinePlus

... also used to treat dementia in people with Parkinson's disease (a brain system disease with symptoms of slowing ... cure Alzheimer's disease or dementia in people with Parkinson's disease. Continue to use transdermal rivastigmine even if you ...

Peptide-chaperone-directed transdermal protein delivery requires energy.

PubMed

Ruan, Renquan; Jin, Peipei; Zhang, Li; Wang, Changli; Chen, Chuanjun; Ding, Weiping; Wen, Longping

2014-11-03

The biologically inspired transdermal enhanced peptide TD1 has been discovered to specifically facilitate transdermal delivery of biological macromolecules. However, the biological behavior of TD1 has not been fully defined. In this study, we find that energy is required for the TD1-mediated transdermal protein delivery through rat and human skins. Our results show that the permeation activity of TD1-hEGF, a fusion protein composed of human epidermal growth factor (hEGF) and the TD1 sequence connected with a glycine-serine linker (GGGGS), can be inhibited by the energy inhibitor, rotenone or oligomycin. In addition, adenosine triphosphate (ATP), the essential energetic molecule in organic systems, can effectively facilitate the TD1 directed permeation of the protein-based drug into the skin in a dose-dependent fashion. Our results here demonstrate a novel energy-dependent permeation process during the TD1-mediated transdermal protein delivery that could be valuable for the future development of promising new transdermal drugs.

Promotion of the transdermal delivery of protein drugs by N-trimethyl chitosan nanoparticles combined with polypropylene electret.

PubMed

Tu, Ye; Wang, Xinxia; Lu, Ying; Zhang, He; Yu, Yuan; Chen, Yan; Liu, Junjie; Sun, Zhiguo; Cui, Lili; Gao, Jing; Zhong, Yanqiang

We recently reported that electret, which was prepared by a corona charging system with polypropylene film, could enhance the transdermal delivery of several drugs of low molecular weight. The aim of this study was to investigate whether electret could enhance the transdermal delivery of protein drugs by N -trimethyl chitosan nanoparticles (TMC NPs) prepared by an ionic gelation method. A series of experiments were performed, including in vitro skin permeation assays and anti-inflammatory effects, to evaluate the transdermal delivery of protein drugs by TMC NPs in the presence of electret. The results showed that in the presence of electret, the transdermal delivery of protein drugs in TMC NPs was significantly enhanced, as demonstrated by in vitro permeation studies and confocal laser scanning microscopy. Notably, superoxide dismutase-loaded TMC NPs combined with electret exhibited the best inhibitory effect on the edema of the mouse ear. TMC NPs combined with electret represent a novel platform for the transdermal delivery of protein drugs.

Promotion of the transdermal delivery of protein drugs by N-trimethyl chitosan nanoparticles combined with polypropylene electret

PubMed Central

Tu, Ye; Wang, Xinxia; Lu, Ying; Zhang, He; Yu, Yuan; Chen, Yan; Liu, Junjie; Sun, Zhiguo; Cui, Lili; Gao, Jing; Zhong, Yanqiang

2016-01-01

We recently reported that electret, which was prepared by a corona charging system with polypropylene film, could enhance the transdermal delivery of several drugs of low molecular weight. The aim of this study was to investigate whether electret could enhance the transdermal delivery of protein drugs by N-trimethyl chitosan nanoparticles (TMC NPs) prepared by an ionic gelation method. A series of experiments were performed, including in vitro skin permeation assays and anti-inflammatory effects, to evaluate the transdermal delivery of protein drugs by TMC NPs in the presence of electret. The results showed that in the presence of electret, the transdermal delivery of protein drugs in TMC NPs was significantly enhanced, as demonstrated by in vitro permeation studies and confocal laser scanning microscopy. Notably, superoxide dismutase-loaded TMC NPs combined with electret exhibited the best inhibitory effect on the edema of the mouse ear. TMC NPs combined with electret represent a novel platform for the transdermal delivery of protein drugs. PMID:27822034

Methylphenidate Transdermal System in Adult ADHD and Impact on Emotional and Oppositional Symptoms

ERIC Educational Resources Information Center

Marchant, Barrie K.; Reimherr, Frederick W.; Robison, Reid J.; Olsen, John L.; Kondo, Douglas G.

2011-01-01

Objective: This trial evaluated the effect of methylphenidate transdermal system (MTS) on the full spectrum of adult symptoms (attention-disorganization, hyperactivity-impulsivity, emotional dysregulation [ED], and oppositional-defiant disorder [ODD]) found in this disorder. Method: This placebo-controlled, double-blind, flexible-dose, crossover…

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.

Disproportionality analysis of buprenorphine transdermal system and cardiac arrhythmia using FDA and WHO postmarketing reporting system data.

PubMed

Sessler, Nelson E; Walker, Ekaterina; Chickballapur, Harsha; Kacholakalayil, James; Coplan, Paul M

2017-01-01

Positive-controlled clinical studies have shown a dose dependent effect of buprenorphine transdermal system on QTc interval prolongation. This study provides assessment of the buprenorphine transdermal system and cardiac arrhythmia using US FDA and WHO postmarketing reporting databases. Disproportionality analysis of spontaneously reported adverse events to assess whether the reporting rate of cardiac arrhythmia events was disproportionately elevated relative to expected rates of reporting in both FDA and WHO databases. Cardiac arrhythmia events were identified using the standardized Medical Dictionary for Regulatory Activities query for torsade de pointes and/or QT prolongation (TdP/QTP). The threshold for a signal of disproportionate adverse event reporting was defined as the lower 90% confidence limit ≥ 2 of the Empiric Bayes geometric mean in FDA database and as the lower 95% confidence limit of the Informational Component >0 in WHO database. There were 124 (<1%) and 77 (2%) cardiac arrhythmia event cases associated with buprenorphine transdermal as compared to 3206 (12%) and 2913 (14%) involving methadone in the FDA and WHO databases, respectively. In the FDA database methadone was associated with a signal of disproportionate reporting for TdP/QTP (EB05 3.26); however, buprenorphine transdermal was not (EB05 0.33). In the WHO database methadone was associated with a signal of disproportionate reporting for TdP/QTP (IC025 2.66); however, buprenorphine transdermal was not (IC025 -0.88). Similar trends were observed in sensitivity analyses by age, gender, and specific terms related to ventricular arrhythmia. The signal identified in the transdermal buprenorphine thorough QTc study, which led to a dose limitation in its US label, does not translate into a signal of increased risk for cardiac arrhythmia in real world use, as assessed by this method of analyzing post-market surveillance data.

Gold nanorods in an oil-base formulation for transdermal treatment of type 1 diabetes in mice

NASA Astrophysics Data System (ADS)

Nose, Keisuke; Pissuwan, Dakrong; Goto, Masahiro; Katayama, Yoshiki; Niidome, Takuro

2012-05-01

Efficient transdermal insulin delivery to the systemic circulation would bring major benefit to diabetic patients. We investigated the possibility of using gold nanorods (GNRs) that formed a complex with an edible surfactant and insulin (INS) in an oil phase to form a solid-in-oil (SO) formulation (SO-INS-GNR) for transdermal treatment of diabetes. Diabetic mice comprised the model for our study. In vitro, there was high penetration of insulin through the stratum corneum (SC) and the dermis in mouse skin treated with an SO-INS-GNR complex plus near-infrared (NIR) light irradiation. Blood glucose levels in the diabetic mice were significantly decreased after treatment with SO-INS-GNR plus irradiation. To our knowledge, this is the first study to use gold nanorods for systemic insulin delivery through the skin. The use of an SO-INS-GNR complex combined with NIR irradiation may provide the possibility of transdermal insulin delivery to diabetic patients.Efficient transdermal insulin delivery to the systemic circulation would bring major benefit to diabetic patients. We investigated the possibility of using gold nanorods (GNRs) that formed a complex with an edible surfactant and insulin (INS) in an oil phase to form a solid-in-oil (SO) formulation (SO-INS-GNR) for transdermal treatment of diabetes. Diabetic mice comprised the model for our study. In vitro, there was high penetration of insulin through the stratum corneum (SC) and the dermis in mouse skin treated with an SO-INS-GNR complex plus near-infrared (NIR) light irradiation. Blood glucose levels in the diabetic mice were significantly decreased after treatment with SO-INS-GNR plus irradiation. To our knowledge, this is the first study to use gold nanorods for systemic insulin delivery through the skin. The use of an SO-INS-GNR complex combined with NIR irradiation may provide the possibility of transdermal insulin delivery to diabetic patients. Electronic supplementary information (ESI) available. See DOI: 10.1039/c2nr30651d

Modular reservoir concept for MEMS-based transdermal drug delivery systems

NASA Astrophysics Data System (ADS)

Cantwell, Cara T.; Wei, Pinghung; Ziaie, Babak; Rao, Masaru P.

2014-11-01

While MEMS-based transdermal drug delivery device development efforts have typically focused on tightly-integrated solutions, we propose an alternate conception based upon a novel, modular drug reservoir approach. By decoupling the drug storage functionality from the rest of the delivery system, this approach seeks to minimize cold chain storage volume, enhance compatibility with conventional pharmaceutical practices, and allow independent optimization of reservoir device design, materials, and fabrication. Herein, we report the design, fabrication, and preliminary characterization of modular reservoirs that demonstrate the virtue of this approach within the application context of transdermal insulin administration for diabetes management.

Transdermal delivery of scopolamine by natural submicron injectors: in-vivo study in pig.

PubMed

Shaoul, Esther; Ayalon, Ari; Tal, Yossi; Lotan, Tamar

2012-01-01

Transdermal drug delivery has made a notable contribution to medical practice, but has yet to fully achieve its potential as an alternative to oral delivery and hypodermic injections. While transdermal delivery systems would appear to provide an attractive solution for local and systemic drug delivery, only a limited number of drugs can be delivered through the outer layer of the skin. The most difficult to deliver in this way are hydrophilic drugs. The aquatic phylum Cnidaria, which includes sea anemones, corals, jellyfish and hydra, is one of the most ancient multicellular phyla that possess stinging cells containing organelles (cnidocysts), comprising a sophisticated injection system. The apparatus is folded within collagenous microcapsules and upon activation injects a thin tubule that immediately penetrates the prey and delivers its contents. Here we show that this natural microscopic injection system can be adapted for systemic transdermal drug delivery once it is isolated from the cells and uploaded with the drug. Using a topically applied gel containing isolated natural sea anemone injectors and the muscarinic receptor antagonist scopolamine, we found that the formulated injectors could penetrate porcine skin and immediately deliver this hydrophilic drug. An in-vivo study in pigs demonstrated, for the first time, rapid systemic delivery of scopolamine, with T(max) of 30 minutes and C(max) 5 times higher than in controls treated topically with a scopolamine-containing gel without cnidocysts. The ability of the formulated natural injection system to penetrate a barrier as thick as the skin and systemically deliver an exogenous compound presents an intriguing and attractive alternative for hydrophilic transdermal drug delivery.

Transdermal Delivery of Scopolamine by Natural Submicron Injectors: In-Vivo Study in Pig

PubMed Central

Shaoul, Esther; Ayalon, Ari; Tal, Yossi; Lotan, Tamar

2012-01-01

Transdermal drug delivery has made a notable contribution to medical practice, but has yet to fully achieve its potential as an alternative to oral delivery and hypodermic injections. While transdermal delivery systems would appear to provide an attractive solution for local and systemic drug delivery, only a limited number of drugs can be delivered through the outer layer of the skin. The most difficult to deliver in this way are hydrophilic drugs. The aquatic phylum Cnidaria, which includes sea anemones, corals, jellyfish and hydra, is one of the most ancient multicellular phyla that possess stinging cells containing organelles (cnidocysts), comprising a sophisticated injection system. The apparatus is folded within collagenous microcapsules and upon activation injects a thin tubule that immediately penetrates the prey and delivers its contents. Here we show that this natural microscopic injection system can be adapted for systemic transdermal drug delivery once it is isolated from the cells and uploaded with the drug. Using a topically applied gel containing isolated natural sea anemone injectors and the muscarinic receptor antagonist scopolamine, we found that the formulated injectors could penetrate porcine skin and immediately deliver this hydrophilic drug. An in-vivo study in pigs demonstrated, for the first time, rapid systemic delivery of scopolamine, with Tmax of 30 minutes and Cmax 5 times higher than in controls treated topically with a scopolamine-containing gel without cnidocysts. The ability of the formulated natural injection system to penetrate a barrier as thick as the skin and systemically deliver an exogenous compound presents an intriguing and attractive alternative for hydrophilic transdermal drug delivery. PMID:22363770

The development of the rotigotine transdermal patch: a historical perspective.

PubMed

Waters, Cheryl

2013-08-01

The rotigotine transdermal system is a dopamine receptor agonist delivered over a 24-hour period. It is approved for the treatment of idiopathic Parkinson's disease (PD). This article reviews the development of the rotigotine transdermal system, including rotigotine's receptor profile, steady-state pharmacokinetics, and metabolism. Preclinical studies of rotigotine in animal models of PD and proof-of-concept studies in patients with PD are reviewed. These preclinical and clinical studies established this system as an effective method for providing continuous rotigotine delivery across the skin providing the basis for continued clinical development of rotigotine for the treatment of early and advanced PD. Copyright © 2013 Elsevier Inc. All rights reserved.

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.

Transdermal delivery and cutaneous targeting of antivirals using a penetration enhancer and lysolipid prodrugs.

PubMed

Diblíková, Denisa; Kopečná, Monika; Školová, Barbora; Krečmerová, Marcela; Roh, Jaroslav; Hrabálek, Alexandr; Vávrová, Kateřina

2014-04-01

In this work, we investigate prodrug and enhancer approaches for transdermal and topical delivery of antiviral drugs belonging to the 2,6-diaminopurine acyclic nucleoside phosphonate (ANP) group. Our question was whether we can differentiate between transdermal and topical delivery, i.e., to control the delivery of a given drug towards either systemic absorption or retention in the skin. The in vitro transdermal delivery and skin concentrations of seven antivirals, including (R)- and (S)-9-[2-(phosphonomethoxy)propyl]-2,6-diaminopurine (PMPDAP), (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]-2,6-diaminopurine ((S)-HPMPDAP), its 8-aza analog, and their cyclic and hexadecyloxypropyl (HDP) prodrugs, was investigated with and without the penetration enhancer dodecyl-6-(dimethylamino)hexanoate (DDAK) using human skin. The ability of ANPs to cross the human skin barrier was very low (0.5-1.4 nmol/cm(2)/h), and the majority of the compounds were found in the stratum corneum, the uppermost skin layer. The combination of antivirals and the penetration enhancer DDAK proved to be a viable approach for transdermal delivery, especially in case of (R)-PMPDAP, an anti-HIV effective drug (30.2 ± 2.3 nmol/cm(2)/h). On the other hand, lysophospholipid-like HDP prodrugs, e.g., HDP-(S)-HPMPDAP, reached high concentrations in viable epidermis without significant systemic absorption. By using penetration enhancers or lysolipid prodrugs, it is possible to effectively target systemic diseases by the transdermal route or to target cutaneous pathologies by topical delivery.

Iontophoresis: A Potential Emergence of a Transdermal Drug Delivery System

PubMed Central

Dhote, Vinod; Bhatnagar, Punit; Mishra, Pradyumna K.; Mahajan, Suresh C.; Mishra, Dinesh K.

2012-01-01

The delivery of drugs into systemic circulation via skin has generated much attention during the last decade. Transdermal therapeutic systems propound controlled release of active ingredients through the skin and into the systemic circulation in a predictive manner. Drugs administered through these systems escape first-pass metabolism and maintain a steady state scenario similar to a continuous intravenous infusion for up to several days. However, the excellent impervious nature of the skin offers the greatest challenge for successful delivery of drug molecules by utilizing the concepts of iontophoresis. The present review deals with the principles and the recent innovations in the field of iontophoretic drug delivery system together with factors affecting the system. This delivery system utilizes electric current as a driving force for permeation of ionic and non-ionic medications. The rationale behind using this technique is to reversibly alter the barrier properties of skin, which could possibly improve the penetration of drugs such as proteins, peptides and other macromolecules to increase the systemic delivery of high molecular weight compounds with controlled input kinetics and minimum inter-subject variability. Although iontophoresis seems to be an ideal candidate to overcome the limitations associated with the delivery of ionic drugs, further extrapolation of this technique is imperative for translational utility and mass human application. PMID:22396901

In vivo real-time monitoring system of electroporation mediated control of transdermal and topical drug delivery.

PubMed

Blagus, Tanja; Markelc, Bostjan; Cemazar, Maja; Kosjek, Tina; Preat, Veronique; Miklavcic, Damijan; Sersa, Gregor

2013-12-28

Electroporation (EP) is a physical method for the delivery of molecules into cells and tissues, including the skin. In this study, in order to control the degree of transdermal and topical drug delivery, EP at different amplitudes of electric pulses was evaluated. A new in vivo real-time monitoring system based on fluorescently labeled molecules was developed, for the quantification of transdermal and topical drug delivery. EP of the mouse skin was performed with new non-invasive multi-array electrodes, delivering different amplitudes of electric pulses ranging from 70 to 570 V, between the electrode pin pairs. Patches, soaked with 4 kDa fluorescein-isothiocyanate labeled dextran (FD), doxorubicin (DOX) or fentanyl (FEN), were applied to the skin before and after EP. The new monitoring system was developed based on the delivery of FD to and through the skin. FD relative quantity was determined with fluorescence microscopy imaging, in the treated region of the skin for topical delivery and in a segment of the mouse tail for transdermal delivery. The application of electric pulses for FD delivery resulted in enhanced transdermal delivery. Depending on the amplitude of electric pulses, it increased up to the amplitude of 360 V, and decreased at higher amplitudes (460 and 570 V). Topical delivery steadily enhanced with increasing the amplitude of the delivered electric pulses, being even higher than after tape stripping used as a positive control. The non-invasive monitoring of the delivery of DOX, a fluorescent chemotherapeutic drug, qualitatively and quantitatively confirmed the effects of EP at 360 and 570 V pulse amplitudes on topical and transdermal drug delivery. Delivery of FEN at 360 and 570 V pulse amplitudes verified the observed effects as obtained with FD and DOX, by the measured physiological responses of the mice as well as FEN plasma concentration. This study demonstrates that with the newly developed non-invasive multi-array electrodes and with the varying electric pulse amplitude, the amount of topical and transdermal drug delivery to the skin can be controlled. Furthermore, the newly developed monitoring system provides a tool for rapid real-time determination of both, transdermal and topical delivery, when the delivered molecule is fluorescent. © 2013 Elsevier B.V. All rights reserved.

Methylphenidate Transdermal System in Adults with Past Stimulant Misuse: An Open-Label Trial

ERIC Educational Resources Information Center

McRae-Clark, Aimee L.; Brady, Kathleen T.; Hartwell, Karen J.; White, Kathleen; Carter, Rickey E.

2011-01-01

Objective: This 8-week, open-label trial assessed the efficacy of methylphenidate transdermal system (MTS) in 14 adult individuals diagnosed with ADHD and with a history of stimulant misuse, abuse, or dependence. Method: The primary efficacy endpoint was the Wender-Reimherr Adult ADHD Scale (WRAADS), and secondary efficacy endpoints included the…

Dissolving and biodegradable microneedle technologies for transdermal sustained delivery of drug and vaccine

PubMed Central

Hong, Xiaoyun; Wei, Liangming; Wu, Fei; Wu, Zaozhan; Chen, Lizhu; Liu, Zhenguo; Yuan, Weien

2013-01-01

Microneedles were first conceptualized for drug delivery many decades ago, overcoming the shortages and preserving the advantages of hypodermic needle and conventional transdermal drug-delivery systems to some extent. Dissolving and biodegradable microneedle technologies have been used for transdermal sustained deliveries of different drugs and vaccines. This review describes microneedle geometry and the representative dissolving and biodegradable microneedle delivery methods via the skin, followed by the fabricating methods. Finally, this review puts forward some perspectives that require further investigation. PMID:24039404

Magnetophoresis for enhancing transdermal drug delivery: Mechanistic studies and patch design

PubMed Central

Murthy, S. Narasimha; Sammeta, Srinivasa M.; Bower, C.

2017-01-01

Magnetophoresis is a method of enhancement of drug permeation across the biological barriers by application of magnetic field. The present study investigated the mechanistic aspects of magnetophoretic transdermal drug delivery and also assessed the feasibility of designing a magnetophoretic transdermal patch system for the delivery of lidocaine. In vitro drug permeation studies were carried out across the porcine epidermis at different magnetic field strengths. The magnetophoretic drug permeation “flux enhancement factor” was found to increase with the applied magnetic field strength. The mechanistic studies revealed that the magnetic field applied in this study did not modulate permeability of the stratum corneum barrier. The predominant mechanism responsible for magnetically mediated drug permeation enhancement was found to be “magnetokinesis”. The octanol/water partition coefficient of drugs was also found to increase when exposed to the magnetic field. A reservoir type transdermal patch system with a magnetic backing was designed for in vivo studies. The dermal bioavailability (AUC0–6 h) from the magnetophoretic patch system in vivo, in rats was significantly higher than the similarly designed nonmagnetic control patch. PMID:20728484

A Transdermal Drug Delivery System Based on LIGA Technology and Soft Lithography

NASA Astrophysics Data System (ADS)

Matteucci, Marco; Perennes, Frederic; Marmiroli, Benedetta; Di Fabrizio, Enzo

2007-01-01

This report presents a transdermal drug delivery system based on LIGA fabricated microparts. It is a portable device combining a magnetically actuated micro gear pump with a microneedle array. The fluidic behaviour of the system is analyzed in order to predict its performance according to the dimension of the microparts and then compared to experimental data. The manufacturing process of both micropump and microneedle array are described.

Long-Term Effects of Methylphenidate Transdermal Delivery System Treatment of ADHD on Growth

ERIC Educational Resources Information Center

Faraone, Stephen V.; Giefer, Eldred E.

2007-01-01

Objective: To examine the long-term effects of the methylphenidate transdermal system (MTS) on the growth of children being treated for attention-deficit/hyperactivity disorder. Method: Height, weight, and body mass index (BMI) were measured in 127 children ages 6 to 12 at longitudinal assessments for up to 36 months of treatment with MTS. These…

A Randomized, Double-Blind, Placebo-Controlled, Laboratory Classroom Assessment of Methylphenidate Transdermal System in Children with ADHD

ERIC Educational Resources Information Center

McGough, James J.; Wigal, Sharon B.; Abikoff, Howard; Turnbow, John M.; Posner, Kelly; Moon, Eliot

2006-01-01

Objective: This study evaluates the efficacy, duration of action, and tolerability of methylphenidate transdermal system (MTS) in children with ADHD. Method: Participants were dose optimized over 5 weeks utilizing patch doses of 10, 16, 20, and 27 mg applied in the morning and worn for 9 hours. Following optimization, 80 participants were…

Enhancement of transdermal protein delivery by photothermal effect of gold nanorods coated on polysaccharide-based hydrogel.

PubMed

Haine, Aung Thu; Koga, Yuki; Hashimoto, Yuta; Higashi, Taishi; Motoyama, Keiichi; Arima, Hidetoshi; Niidome, Takuro

2017-10-01

Transdermal protein delivery is a useful and attractive method for protein therapy and dermal vaccination. However, this delivery method is restricted by the low permeability of the stratum corneum. The purpose of this study was to develop a transdermal delivery system for enhancement of protein permeability into the skin. First, we prepared a transparent gel patch made of polysaccharides with gold nanorods on the gel surface and fluorescein isothiocyanate-modified ovalbumin (FITC-OVA) inside. Next, the gel patch was placed on mouse skin to allow contact with the coated gold nanorods, and irradiated by a continuous-wave laser. The laser irradiation heated the gold nanorods and the skin temperature increased to 43°C, resulting in enhanced translocation of FITC-OVA into the skin. These results confirmed the capability of the transdermal protein delivery system to perforate the stratum corneum and thus facilitate the passage of proteins across the skin. Copyright © 2017 Elsevier B.V. All rights reserved.

A comparative study on the transdermal penetration effect of gaseous and aqueous plasma reactive species

NASA Astrophysics Data System (ADS)

Liu, Xin; Gan, Lu; Ma, Mingyu; Zhang, Song; Liu, Jingjing; Chen, Hongxiang; Liu, Dawei; Lu, Xinpei

2018-02-01

To improve the depth of plasma active species in the skin, it is very important to develop skin disease treatment using plasma. In this article, an air plasma source was used to work directly with the skin of a mouse. A tortuous pathway, hair follicles, electroporation and a microneedle do not aid the transdermal delivery of gaseous plasma active species, therefore these gaseous plasma active species cannot penetrate mouse skin with a thickness of ~0.75 mm. The plasma activated water (PAW) produced by the air plasma source was used to study the transdermal penetration of the aqueous plasma activated species. This aqueous plasma activated species can penetrate the skin through hair follicles, intercellular and transcellular routes. The pH of the PAW did not affect the penetration efficiency of the aqueous plasma active species.

Transdermal absorption of memantin--effect of chemical enhancers, iontophoresis, and role of enhancer lipophilicity.

PubMed

del Rio-Sancho, S; Serna-Jiménez, C E; Calatayud-Pascual, M A; Balaguer-Fernández, C; Femenía-Font, A; Merino, V; López-Castellano, A

2012-09-01

The transdermal administration of memantine may have advantages with respect to oral therapy when treating advanced stages of Alzheimer's disease. With the ultimate objective of administrating memantine through a transdermal patch, the absorption of the drug across skin was evaluated by means of in vitro permeation studies. The effect of several chemical enhancers was studied in order to enhance percutaneous absorption of the memantine. The iontophoretic transdermal transport of memantine hydrochloride using a current density of 0.5 mA/cm(2) was also investigated. Results demonstrated that pre-treatment of the skin with R-(+)-limonene, laurocapram, decenoic acid, or oleic acid produced a statistically significant increment in the transdermal flux of memantine hydrochloride with respect to the control. Iontophoresis exhibited the greatest ability to enhance the flux of drug with respect to the control; nevertheless, the results obtained with R-(+)-limonene indicate that this compound could be of great use as a percutaneous enhancer in a memantine transdermal delivery system. In this study, the relationship between enhancement activity and lipophilicity was also studied. Satisfactory correlations have been obtained between the optimum lipophilicity of the enhancer and n-octanol/water partition coefficients of drugs. This relationship is a very useful tool that could allow to reduce time and to optimize the selection of appropriate enhancers for transdermal formulations. Copyright © 2012 Elsevier B.V. All rights reserved.

Identification and assessment of permeability enhancing vehicles for transdermal delivery of glucosamine hydrochloride.

PubMed

Han, In Hee; Choi, Sung-Up; Nam, Dae Young; Park, Young Mi; Kang, Myung Joo; Kang, Kyoung Hoon; Kim, Yong Min; Bae, Gunho; Oh, Il Young; Park, Jong Hyeok; Ye, Jin Soo; Choi, Yoon Bae; Kim, Duk Ki; Lee, Jaehwi; Choi, Young Wook

2010-02-01

As an initial step to develop the transdermal delivery system of glucosamine hydrochloride (GL-HCl), the permeation study across the rat skin in vitro was performed to identify the most efficient vehicle with regard to the ability to deliver GL-HCl transdermally. The GL-HCl formulations such as o/w cream, liposome suspension, liposomal gel, and liquid crystalline vehicles were prepared and compared for transdermal flux of GL-HCl. The liquid crystalline vehicles were more effective in increasing the skin permeation of GL-HCl than o/w cream and liposomal vehicles. Of the liquid crystalline vehicles tested, the permeation enhancing ability of the cubic phase was greater than that of the hexagonal phase when the nanoparticle dispersion was used. The skin permeation enhancing ability of the cubic nanoparticles for GL-HCl was further increased by employing both oleic acid and polyethylene glycol 200. Therefore, the cubic liquid crystalline nanodispersion containing oleic acid and PEG 200 can provide a possibility of clinical application of transdermal GL-HCl.

A comparison of a novel testosterone bioadhesive buccal system, striant, with a testosterone adhesive patch in hypogonadal males.

PubMed

Korbonits, Márta; Slawik, Marc; Cullen, Derek; Ross, Richard J; Stalla, Günter; Schneider, Harald; Reincke, Martin; Bouloux, Pierre M; Grossman, Ashley B

2004-05-01

A novel delivery system has been developed for testosterone replacement. This formulation, COL-1621 (Striant), a testosterone-containing buccal mucoadhesive system, has been shown in preliminary studies to replace testosterone at physiological levels when used twice daily. Therefore, the current study compared the steady-state pharmacokinetics and tolerability of the buccal system with a testosterone-containing skin patch (Andropatch or Androderm) in an international multicenter study of a group of hypogonadal men. Sixty-six patients were randomized into two groups; one applied the buccal system twice daily, whereas the other applied the transdermal patch daily, in each case for 7 d. Serum total testosterone and dihydrotestosterone concentrations were measured at d 1, 3 or 4, and 6, and serially over the last 24 h of the study. Pharmacokinetic parameters for each formulation were calculated, and the two groups were compared. The tolerability of both formulations was also evaluated. Thirty-three patients were treated with the buccal preparation, and 34 were treated with the transdermal patch. The average serum testosterone concentration over 24 h showed a mean of 18.74 nmol/liter (SD =; 5.90) in the buccal system group and 12.15 nmol/liter (SD =; 5.55) in the transdermal patch group (P < 0.01). Of the patients treated with the buccal system, 97% had average steady-state testosterone concentrations within the physiological range (10.41-36.44 nmol/liter), whereas only 56% of the transdermal patch patients achieved physiological total testosterone concentrations (P < 0.001 between groups). Testosterone concentrations were within the physiological range in the buccal system group for a significantly greater portion of the 24-h treatment period than in the transdermal patch group (mean, 84.9% vs. 54.9%; P < 0.001). Testosterone/dihydrotestosterone ratios were physiological and similar in both groups. Few patients experienced major adverse effects from either treatment. No significant local tolerability problems were noted with the buccal system, other than a single patient withdrawal. We conclude that this buccal system is superior to the transdermal patch in achieving testosterone concentrations within the normal range. It may, therefore, be a valuable addition to the range of choices for testosterone replacement therapy.

Preparation and the in vitro evaluation of nanoemulsion system for the transdermal delivery of granisetron hydrochloride.

PubMed

Zheng, Wen-wu; Zhao, Ling; Wei, Yu-meng; Ye, Yun; Xiao, Shun-han

2010-08-01

The objective of this study was to develop and evaluate nanoemulsion system for transdermal delivery of granisetron hydrochloride. Pseudo-ternary phase diagram was constructed to ascertain the concentration range of components of nanoemulsion composed of isopropyl myristate (IPM) as an oil phase, tween 85 as surfactant, ethanol as cosurfactant, water as aqueous phase. The effects of the content of IPM as an oil phase and n-methyl pyrrolidone (NMP) as transdermal enhancer on rat skin permeation of granisetron hydrochloride nanoemulsion were studied in vitro. The results showed that the mean particle size of nanoemulsion ranged from 50.4+/-1.5 to 82.4+/-0.9 nm with homogeneous size distribution. The resulted optimum formulation composed of 2.5% granisetron hydrochloride, 4% IPM, 40% tween 85/ethanol (1 : 1) and 10% NMP showed that the skin permeation rate was the highest (85.39+/-2.90 microg/cm(2)/h) and enhancement of drug permeability was 4.1-fold for transdermal delivery of granisetron hydrochloridein comparison with the control group (20% of tween 85 and 20% of ethanol micelle solution containing 2.5% of granisetron hydrochloride without IPM), and cumulative permeation amount was the highest (891.8+/-2.86 microg/cm(2)) with the shortest lag time (0.11+/-0.02 h) and was stable for at least 12 months. Therefore, the nanoemulsion system developed in this study offers a promising vehicle for the transdermal delivery system of granisetron hydrochloride, which may be as effective as oral or intravenous dosage forms and avoid some difficulties associated with these dosage forms.

Expanding the domain of drug delivery for HIV prevention: exploration of the transdermal route.

PubMed

Puri, Ashana; Sivaraman, Arunprasad; Zhang, Wei; Clark, Meredith R; Banga, Ajay K

2017-01-01

Constant efforts for HIV prevention using antiretroviral drugs, pre- and postexposure prophylactic agents, and microbicides are being made by researchers. Drug-delivery systems such as oral tablets and coitally dependent vaginal gels are short acting, require daily application, and are associated with user adherence issues, whereas the coitally independent systems such as injectables and biodegradable implants are long acting, lasting several months, during which time the termination of prophylaxis is impractical in case of adverse effects. An effective drug-delivery system to be used for an intermediate duration, if available, would be an attractive alternative option for users in terms of adherence. Transdermal delivery systems, overcoming most of the limitations of the other routes of administration and aiming to provide sustained delivery of drugs through skin, may be explored for HIV prevention. Passive and physical enhancement techniques may be designed strategically to improve the transdermal delivery of HIV preventive agents.

Preparation and characterization of metoprolol tartrate containing matrix type transdermal drug delivery system.

PubMed

Malipeddi, Venkata Ramana; Awasthi, Rajendra; Ghisleni, Daniela Dal Molim; de Souza Braga, Marina; Kikuchi, Irene Satiko; de Jesus Andreoli Pinto, Terezinha; Dua, Kamal

2017-02-01

The present study aimed to develop matrix-type transdermal drug delivery system (TDDS) of metoprolol tartrate using polyvinyl pyrrolidone (PVP) and polyvinyl alcohol (PVA). The transdermal films were evaluated for physical parameters, Fourier transform infrared spectroscopy analysis (FTIR), differential scanning calorimetry (DSC), in vitro drug release, in vitro skin permeability, skin irritation test and stability studies. The films were found to be tough, non-sticky, easily moldable and possess good tensile strength. As the concentration of PVA was increased, the tensile strength of the films was also increased. Results of FTIR spectroscopy and DSC revealed the absence of any drug-polymer interactions. In vitro release of metoprolol followed zero-order kinetics and the mechanism of release was found to be diffusion rate controlled. In vitro release studies of metoprolol using Keshary-Chein (vertical diffusion cell) indicated 65.5 % drug was released in 24 h. In vitro skin permeation of metoprolol transdermal films showed 58.13 % of the drug was released after 24 h. In vitro skin permeation of metoprolol followed zero-order kinetics in selected formulations. The mechanism of release was found to be diffusion rate controlled. In a 22-day skin irritation test, tested formulation of transdermal films did not exhibit any allergic reactions, inflammation, or contact dermatitis. The transdermal films showed good stability in the 180-day stability study. It can be concluded that the TDDS of MPT can help in bypassing the first-pass effect and will provide patient improved compliance, without sacrificing the therapeutic advantages of the drugs.

Novel engineered systems for oral, mucosal and transdermal drug delivery.

PubMed

Li, Hairui; Yu, Yuan; Faraji Dana, Sara; Li, Bo; Lee, Chi-Ying; Kang, Lifeng

2013-08-01

Technological advances in drug discovery have resulted in increasing number of molecules including proteins and peptides as drug candidates. However, how to deliver drugs with satisfactory therapeutic effect, minimal side effects and increased patient compliance is a question posted before researchers, especially for those drugs with poor solubility, large molecular weight or instability. Microfabrication technology, polymer science and bioconjugate chemistry combine to address these problems and generate a number of novel engineered drug delivery systems. Injection routes usually have poor patient compliance due to their invasive nature and potential safety concerns over needle reuse. The alternative non-invasive routes, such as oral, mucosal (pulmonary, nasal, ocular, buccal, rectal, vaginal), and transdermal drug delivery have thus attracted many attentions. Here, we review the applications of the novel engineered systems for oral, mucosal and transdermal drug delivery.

Effects of transdermal estrogen replacement therapy on cardiovascular risk factors.

PubMed

Menon, Dileep V; Vongpatanasin, Wanpen

2006-01-01

The prevalence of hypertension and cardiovascular disease increases dramatically after menopause in women, implicating estrogen as having a protective role in the cardiovascular system. However, recent large clinical trials have failed to show cardiovascular benefit, and have even demonstrated possible harmful effects, of opposed and unopposed estrogen in postmenopausal women. While these findings have led to a revision of guidelines such that they discourage the use of estrogen for primary or secondary prevention of heart disease in postmenopausal women, many investigators have attributed the negative results in clinical trials to several flaws in study design, including the older age of study participants and the initiation of estrogen late after menopause.Because almost all clinical trials use oral estrogen as the primary form of hormone supplementation, another question that has arisen is the importance of the route of estrogen administration with regards to the cardiovascular outcomes. During oral estrogen administration, the concentration of estradiol in the liver sinusoids is four to five times higher than that in the systemic circulation. This supraphysiologic concentration of estrogen in the liver can modulate the expression of many hepatic-derived proteins, which are not observed in premenopausal women. In contrast, transdermal estrogen delivers the hormone directly into the systemic circulation and, thus, avoids the first-pass hepatic effect.Although oral estrogen exerts a more favorable influence than transdermal estrogen on traditional cardiovascular risk factors such as high- and low-density lipoprotein-cholesterol levels, recent studies have indicated that oral estrogen adversely influences many emerging risk factors in ways that are not seen with transdermal estrogen. Oral estrogen significantly increases levels of acute-phase proteins such as C-reactive protein and serum amyloid A; procoagulant factors such as prothrombin fragments 1+2; and several key enzymes involved in plaque disruption, while transdermal estrogen does not have these adverse effects.Whether the advantages of transdermal estrogen with regards to these risk factors will translate into improved clinical outcomes remains to be determined. Two ongoing clinical trials, KEEPS (Kronos Early Estrogen Prevention Study) and ELITE (Early versus Late Intervention Trial with Estradiol) are likely to provide invaluable information regarding the role of oral versus transdermal estrogen in younger postmenopausal women.

An update on pharmacological, pharmacokinetic properties and drug-drug interactions of rotigotine transdermal system in Parkinson's disease and restless legs syndrome.

PubMed

Elshoff, Jan-Peer; Cawello, Willi; Andreas, Jens-Otto; Mathy, Francois-Xavier; Braun, Marina

2015-04-01

This narrative review reports on the pharmacological and pharmacokinetic properties of rotigotine, a non-ergolinic D₃/D₂/D₁ dopamine receptor agonist approved for the treatment of early- and advanced-stage Parkinson's disease (PD) and moderate to severe restless legs syndrome (RLS). Rotigotine is formulated as a transdermal patch providing continuous drug delivery over 24 h, with a plasma concentration profile similar to that of administration via continuous intravenous infusion. Absolute bioavailability after 24 h transdermal delivery is 37 % of the applied rotigotine dose. Following a single administration of rotigotine transdermal system (24-h patch-on period), most of the absorbed drug is eliminated in urine and feces as sulphated and glucuronidated conjugates within 24 h of patch removal. The drug shows a high apparent volume of distribution (>2500 L) and a total body clearance of 300-600 L/h. Rotigotine transdermal system provides dose-proportional pharmacokinetics up to supratherapeutic dose rates of 24 mg/24 h, with steady-state plasma drug concentrations attained within 1-2 days of daily dosing. The pharmacokinetics of rotigotine transdermal patch are similar in healthy subjects, patients with early- or advanced-stage PD, and patients with RLS when comparing dose-normalized area under the plasma concentration-time curve (AUC) and maximum plasma drug concentration (Cmax), as well as half-life and other pharmacokinetic parameters. Also, it is not influenced in a relevant manner by age, sex, ethnicity, advanced renal insufficiency, or moderate hepatic impairment. No clinically relevant drug-drug interactions were observed following co-administration of rotigotine with levodopa/carbidopa, domperidone, or the CYP450 inhibitors cimetidine or omeprazole. Also, pharmacodynamics and pharmacokinetics of an oral hormonal contraceptive were not influenced by rotigotine co-administration. Rotigotine was generally well tolerated, with an adverse event profile consistent with dopaminergic stimulation and use of a transdermal patch. These observations, combined with the long-term efficacy demonstrated in clinical studies, support the use of rotigotine as a continuous non-ergot D₃/D₂/D₁ dopamine receptor agonist in the treatment of PD and RLS.

The pros and cons of transdermal nicotine therapy.

PubMed

Gourlay, S

1994-02-07

To review current knowledge of the efficacy, safety and cost of transdermal nicotine therapy for smoking cessation. 1. Published and unpublished reports of randomised, double-blind trials of at least 12 weeks' duration, in smokers motivated to cease smoking, identified by a search of the MEDLINE database, article and book bibliographies, Current contents, and by a request to the Medical Department of Ciba-Geigy (Australia) Ltd. 2. A clinical trial of 1500 smokers using transdermal nicotine (S Gourlay, unpublished data). Transdermal nicotine more than doubles the success rates of smoking cessation attempts in motivated subjects who smoke at least 10-15 cigarettes per day (odds ratio 12 months after quitting, 2.3; 95% confidence interval, 1.6-3.4). Application site reactions are not uncommon (erythema or burning < or = 16%, transient itch < or = 50%) and cause discontinuation of therapy in up to 10% of subjects. Sleep disturbance due to nocturnal nicotine absorption occurs in up to 13% of subjects when patches are worn overnight. Smoking or nicotine chewing gum used concurrently with transdermal nicotine could raise peak nicotine levels but is unlikely to adversely affect individuals with established tolerance to nicotine. Smoking and (theoretically) nicotine replacement therapies should be avoided in pregnancy or patients with unstable coronary artery disease. In such patients, the risk-benefit ratio of nicotine replacement therapies may be favourable for nicotine-dependent smokers unable to cease smoking by alternative methods. Transdermal nicotine is an effective smoking cessation therapy for motivated, nicotine-dependent smokers. As most smokers can cease smoking on their own, and the patches are costly, they should be recommended only for smokers who are unable to quit by simpler means and those likely to suffer severe nicotine withdrawal symptoms.

Traversing the Skin Barrier with Nano-emulsions.

PubMed

Burger, Cornel; Shahzad, Yasser; Brummer, Alicia; Gerber, Minja; du Plessis, Jeanetta

2017-01-01

In recent years, colloidal delivery systems based on nano-emulsion are gaining popularity; being used for encapsulation and delivery of many drugs. This review therefore aims at summarizing various methods of nano-emulsion formulation and their use as a topical and transdermal delivery vehicle for a number of active pharmaceutical ingredients from different pharmacological classes. This article represents a systematic review of nano-emulsions for topical and transdermal drug delivery. A vast literature was searched and critically analysed. Nano-emulsions are thermokinetically stable dispersion systems, which have been used in topical and transdermal delivery of a number of pharmaceutically active compounds. Nano-emulsions have a narrow droplet size range with tuneable surface properties, which make them an ideal delivery vehicle. Nanoemulsions have a number of advantages over conventional emulsions, including easy preparation using various low and high energy methods, optical transparency, high solubilisation capacity, high stability to droplet aggregation and the ability to penetrate the skin; thus allowing the transdermal delivery of drugs. This review indicated that nano-emulsions are promising vehicle for entrapping various drugs and are suitable for traversing the skin barrier for systemic effects. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Dendrimer-coupled sonophoresis-mediated transdermal drug-delivery system for diclofenac.

PubMed

Huang, Bin; Dong, Wei-Jiang; Yang, Gao-Yi; Wang, Wei; Ji, Cong-Hua; Zhou, Fei-Ni

2015-01-01

The purpose of the present study was to develop a novel transdermal drug-delivery system comprising a polyamidoamine dendrimer coupled with sonophoresis to enhance the permeation of diclofenac (DF) through the skin. The novel transdermal drug-delivery system was developed by using a statistical Plackett-Burman design. Hairless male Wistar rat skin was used for the DF-permeation study. Coupling media concentration, ultrasound-application time, duty cycle, distance from probe to skin, and a third-generation polyamidoamine-dendrimer concentration were selected as independent variables, while in vitro drug release was selected as a dependent variable. Independent variables were found to be statistically significant (P<0.05). DF gel without dendrimer and ultrasound treatment to skin (passive delivery, run 13) showed 56.69 µg/cm(2) cumulative drug permeated through the skin, while the DF-dendrimer gel without sonophoresis treatment (run 14) showed 257.3 µg/cm(2) cumulative drug permeated through the skin after 24 hours. However, when the same gel was applied to sonophoresis-treated skin, drastic permeation enhancement was observed. In the case of run 3, the cumulative drug that permeated through the skin was 935.21 µg/cm(2). It was concluded that dendrimer-coupled sonophoresis-mediated transdermal drug delivery system has the potential to enhance the permeation of DF through the skin.

In Silico Modelling of Transdermal and Systemic Kinetics of Topically Applied Solutes: Model Development and Initial Validation for Transdermal Nicotine.

PubMed

Chen, Tao; Lian, Guoping; Kattou, Panayiotis

2016-07-01

The purpose was to develop a mechanistic mathematical model for predicting the pharmacokinetics of topically applied solutes penetrating through the skin and into the blood circulation. The model could be used to support the design of transdermal drug delivery systems and skin care products, and risk assessment of occupational or consumer exposure. A recently reported skin penetration model [Pharm Res 32 (2015) 1779] was integrated with the kinetic equations for dermis-to-capillary transport and systemic circulation. All model parameters were determined separately from the molecular, microscopic and physiological bases, without fitting to the in vivo data to be predicted. Published clinical studies of nicotine were used for model demonstration. The predicted plasma kinetics is in good agreement with observed clinical data. The simulated two-dimensional concentration profile in the stratum corneum vividly illustrates the local sub-cellular disposition kinetics, including tortuous lipid pathway for diffusion and the "reservoir" effect of the corneocytes. A mechanistic model for predicting transdermal and systemic kinetics was developed and demonstrated with published clinical data. The integrated mechanistic approach has significantly extended the applicability of a recently reported microscopic skin penetration model by providing prediction of solute concentration in the blood.

Role of the Na(+)/K(+)-ATPase beta-subunit in peptide-mediated transdermal drug delivery.

PubMed

Wang, Changli; Ruan, Renquan; Zhang, Li; Zhang, Yunjiao; Zhou, Wei; Lin, Jun; Ding, Weiping; Wen, Longping

2015-04-06

In this work, we discovered that the Na(+)/K(+)-ATPase beta-subunit (ATP1B1) on epidermal cells plays a key role in the peptide-mediated transdermal delivery of macromolecular drugs. First, using a yeast two-hybrid assay, we screened candidate proteins that have specific affinity for the short peptide TD1 (ACSSSPSKHCG) identified in our previous work. Then, we verified the specific binding of TD1 to ATP1B1 in yeast and mammalian cells by a pull-down ELISA and an immunoprecipitation assay. Finally, we confirmed that TD1 mainly interacted with the C-terminus of ATP1B1. Our results showed that the interaction between TD1 and ATP1B1 affected not only the expression and localization of ATP1B1, but also the epidermal structure. In addition, this interaction could be antagonized by the exogenous competitor ATP1B1 or be inhibited by ouabain, which results in the decreased delivery of macromolecular drugs across the skin. The discovery of a critical role of ATP1B1 in the peptide-mediated transdermal drug delivery is of great significance for the future development of new transdermal peptide enhancers.

A novel male contraceptive pill-patch combination: oral desogestrel and transdermal testosterone in the suppression of spermatogenesis in normal men.

PubMed

Hair, W M; Kitteridge, K; O'Connor, D B; Wu, F C

2001-11-01

This study investigated the effect of transdermal T and oral desogestrel on the reproductive axis of healthy men. Twenty-three men were randomized to 1 of 3 treatment groups and received a daily transdermal T patch plus oral desogestrel at a dose of 75, 150, or 300 microg/d for 24 wk. Baseline blood and semen samples were obtained and then every 4 wk thereafter for 32 wk. The outcome measures were sperm density and plasma levels of FSH, LH, total and free T. The results show a dose-dependent suppression of spermatogenesis and gonadotropins. Seven of the 17 subjects became azoospermic. Desogestrel (300 microg daily) in combination with 5 mg daily transdermal T was the most effective (57% azoospermic), whereas a dose of 75 microg was ineffective (0% azoospermic). Total and free plasma T were reduced by approximately 30%. High density lipoprotein cholesterol was significantly reduced. No serious side-effects were encountered. We conclude that daily self-administered desogestrel with transdermal T is capable of suppressing the male reproductive axis, although the efficacy was less marked and less consistent than injectable regimens. The lower efficacy is likely to be due to failure of the transdermal T system to maintain circulating T levels consistently in the required range.

Skin Pretreatment With Conventional Non-Fractional Ablative Lasers Promote the Transdermal Delivery of Tranexamic Acid.

PubMed

Hsiao, Chien-Yu; Sung, Hsin-Ching; Hu, Sindy; Huang, Chun-Hsun

2016-07-01

Laser pretreatment of skin can be used to enable drugs used in dermatology to penetrate the skin to the depth necessary for their effect to take place. To compare the permeation of tranexamic acid after conventional non-fractionated ablative Er:YAG and CO2 laser pretreatment in a laser-aided transdermal delivery system. An erbium-doped yttrium aluminium garnet (Er:YAG) and a CO2 laser were used to pretreat dorsal porcine skin. Scanning electron microscopy was used to examine disruption of the skin surface. Confocal laser scanning microscopy was used to determine the depth of penetration of a reporter molecule (fluorescein isothiocyanate) into the skin. A Franz diffusion assembly was used to examine fluency-related increases in transdermal delivery of transexamic acid. Transdermal delivery of tranexamic acid increased as Er:YAG laser fluency increased. Transdermal delivery was higher when CO2 laser pretreatment was used than when Er:YAG laser pretreatment was used, but a "ceiling effect" was present and increasing the wattage did not cause a further increase in delivery. CO2 laser pretreatment also caused more extensive and deeper skin disruption than Er:YAG laser pretreatment. For conventional, non-fractionated ablative laser pretreatment, the Er:YAG laser would be an optimal choice to enhance transdermal penetration of transexamic acid.

A novel nano-carrier transdermal gel against inflammation.

PubMed

Chaudhary, Hema; Kohli, Kanchan; Kumar, Vikash

2014-04-25

The objective was to develop a stable, reproducible and patient non-infringing novel transdermal drug delivery system "nano-carrier transdermal gel" (NCTG) in combination of partial dose replacement of diclofenac diethylamine (DDEA) by curcumin (CRM). The drug content of gel was 99.30 and 97.57% for DDEA and CRM. Plasma samples were analyzed by liquid chromatography with triple-quadrupole tandem mass spectrometer (LC-MS/MS). Data were integrated with Analyst™ and analyzed by WinNonlin; stability parameters were analyzed using Tukey-Kramer multiple comparison test. Its average skin irritation scored 0.49 concluded to be non-irritant, safe for human use and in vivo studies revealed significantly greater extent of absorption and highly significant inhibition (%) of carrageenan induced paw edema. The results also demonstrated that encapsulation of drugs in nano-carrier increases its biological activity due to superior skin penetration potential. Hence, a novel once day transdermal gel of nano-carrier (nano-transfersomes; deformable vesicular) is achieved, to increase systemic availability, subsequent reduction in dose and toxicity of DDEA was developed for the treatment of inflammation. Copyright © 2014 Elsevier B.V. All rights reserved.

Immune modulation using transdermal photodynamic therapy

NASA Astrophysics Data System (ADS)

Levy, Julia G.; Chowdhary, R. K.; Ratkay, Leslie G.; Waterfield, Douglas; Obochi, Modestus; Leong, Simon; Hunt, David W. C.; Chan, Agnes H.

1995-01-01

The photosensitizer benzoporphyrin derivative monoacid ring A (VerteporfinR or BPD) has maximum absorption characteristics (690 nm) and biodistribution characteristics which permit activation of the drug in capillaries of the skin without causing skin photosensitivity (transdermal PDT). This permits targeting of cells in the circulation for selective ablation. Since BPD has been shown to accumulate preferentially in activated lymphocytes and monocytes, studies have been undertaken to determine the effect of transdermal PDT on murine models for rheumatoid arthritis (the MRL/lpr adjuvant enhanced model) and multiple sclerosis (the experimental allergic encephalomyelitis (EAE) model in PL mice). Localized transdermal PDT with BPD was found to be completely successful in preventing the development of adjuvant enhanced arthritis in the MRL/lpr mouse as well as improving the underlying arthritic condition of these animals. In the EAE model, in which an adoptive transfer system was used, it was found that transdermal PDT of recipients was effective in preventing EAE if treatments were implemented up to 24 hours after cell transfer but was not effective if given later, indicating the requirement for circulating T cells for effective treatment.

In vivo microdialysis for the evaluation of transfersomes as a novel transdermal delivery vehicle for cinnamic acid.

PubMed

Zhang, Yong-Tai; Xu, Yue-Ming; Zhang, Su-Juan; Zhao, Ji-Hui; Wang, Zhi; Xu, Ding-Qin; Feng, Nian-Ping

2014-03-01

In this study, cinnamic acid-loaded transfersomes were prepared and dermal microdialysis sampling was used in Sprague-Dawley rats to compare the amount of drug released into the skin using transfersomes as transdermal carriers with that released on using conventional liposomes. The formulation of cinnamic acid-loaded transfersomes was optimized by a uniform design through in vitro transdermal permeation studies. Hydration time was confirmed as a significant factor influencing the entrapment efficiency of transfersomes, further affecting their transdermal flux in vitro. The fluxes of cinnamic acid from transfersomes were all higher than those from conventional liposomes, and the flux from the optimal transfersome formulation was 3.01-fold higher than that from the conventional liposomes (p < 0.05). An in vivo microdialysis sampling method revealed that the dermal drug concentrations from transfersomes applied on various skin regions were much lower than those required with conventional liposomes. After the administration of drug-containing transfersomes and liposomes on abdominal skin regions of rats for a period of 10 h, the Cmax of cinnamic acid from the compared liposomes was 3.21 ± 0.25 μg/mL and that from the transfersomes was merely 0.59 ± 0.02 μg/mL. The results suggest that transfersomes can be used as carriers to enhance the transdermal delivery of cinnamic acid, and that these vehicles may penetrate the skin in the complete form, given their significant deformability.

Transdermal granisetron.

PubMed

Duggan, Sean T; Curran, Monique P

2009-01-01

Granisetron is a highly selective serotonin 5-HT(3) receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting. The transdermal granisetron system delivers continuous granisetron (3.1 mg/day) into the systemic circulation (via passive diffusion) for up to 7 days. In a large phase III trial in cancer patients receiving multi-day (3-5 days) moderately or highly emetogenic chemotherapy, transdermal granisetron applied 24-48 hours prior to chemotherapy and remaining in place for 7 days was noninferior to oral granisetron 2 mg once daily administered for 3-5 days 1 hour prior to chemotherapy. Efficacy was assessed according to the proportion of patients achieving complete response (no vomiting and/or retching, no more than mild nausea, no rescue medication) from the first day, until 24 hours after the start of the last day, of administration of the chemotherapy regimen. In a phase II trial in patients with cancer receiving single-day, moderately-emetogenic chemotherapy, transdermal granisetron applied at least 24 hours prior to chemotherapy and removed after 5 days was as effective as a single oral dose of granisetron 2 mg in achieving total control (no nausea, no vomiting/retching, no use of rescue medication and no study withdrawal) during the delayed (24-120 hours; primary endpoint) period after chemotherapy. Transdermal granisetron was generally well tolerated in clinical trials, with few adverse events being treatment related.

Transdermal deferoxamine prevents pressure-induced diabetic ulcers

PubMed Central

Duscher, Dominik; Neofytou, Evgenios; Wong, Victor W.; Maan, Zeshaan N.; Rennert, Robert C.; Januszyk, Michael; Rodrigues, Melanie; Malkovskiy, Andrey V.; Whitmore, Arnetha J.; Galvez, Michael G.; Whittam, Alexander J.; Brownlee, Michael; Rajadas, Jayakumar; Gurtner, Geoffrey C.

2015-01-01

There is a high mortality in patients with diabetes and severe pressure ulcers. For example, chronic pressure sores of the heels often lead to limb loss in diabetic patients. A major factor underlying this is reduced neovascularization caused by impaired activity of the transcription factor hypoxia inducible factor-1 alpha (HIF-1α). In diabetes, HIF-1α function is compromised by a high glucose-induced and reactive oxygen species-mediated modification of its coactivator p300, leading to impaired HIF-1α transactivation. We examined whether local enhancement of HIF-1α activity would improve diabetic wound healing and minimize the severity of diabetic ulcers. To improve HIF-1α activity we designed a transdermal drug delivery system (TDDS) containing the FDA-approved small molecule deferoxamine (DFO), an iron chelator that increases HIF-1α transactivation in diabetes by preventing iron-catalyzed reactive oxygen stress. Applying this TDDS to a pressure-induced ulcer model in diabetic mice, we found that transdermal delivery of DFO significantly improved wound healing. Unexpectedly, prophylactic application of this transdermal delivery system also prevented diabetic ulcer formation. DFO-treated wounds demonstrated increased collagen density, improved neovascularization, and reduction of free radical formation, leading to decreased cell death. These findings suggest that transdermal delivery of DFO provides a targeted means to both prevent ulcer formation and accelerate diabetic wound healing with the potential for rapid clinical translation. PMID:25535360

(-)-Epigallocatechin gallate (EGCG)-nanoethosomes as a transdermal delivery system for docetaxel to treat implanted human melanoma cell tumors in mice.

PubMed

Liao, Bingwu; Ying, Hao; Yu, Chenhuan; Fan, Zhaoyang; Zhang, Weihua; Shi, John; Ying, Huazhong; Ravichandran, Nagaiya; Xu, Yongquan; Yin, Junfeng; Jiang, Yongwen; Du, Qizhen

2016-10-15

(-)-Epigallocatechin-3-O-gallate (EGCG), a versatile natural product in fresh tea leaves and green tea, has been investigated as a preventative treatment for cancers and cardiovascular disease. The objective of this study was to develop EGCG-nanoethosomes for transdermal delivery and to evaluate them for treating subcutaneously implanted human melanoma cell tumors. EGCG-nanoethosomes, composed of 0.2% EGCG, 2% soybean phosphatidylcholine, 30% ethanol, 1% Tween-80 and 0.1% sugar esters, were prepared and characterized using laser transmission electron microscopy. These nanoethosomes were smoother and more compact than basic-nanoethosomes with the same components except for EGCG. The effectiveness of transdermal delivery by EGCG-nanoethosomes was demonstrated in an in vitro permeability assay system using mouse skin. The inhibitory effect of docetaxel (DT) loaded in EGCG-nanoethosomes (DT-EGCG-nanoethosomes) was analyzed by monitoring growth of a subcutaneously implanted tumor from A-375 human melanoma cells in mice. Mice treated with DT-EGCG-nanoethosomes exhibited a significant therapeutic effect, with tumors shrinking, on average, by 31.5% of initial volumes after 14 d treatment. This indicated a potential for treating skin cancer. In a pharmacokinetic study, transdermal delivery by DT-EGCG-nanoethosomes enabled sufficient DT exposure to the tumor. Together, these findings indicated that EGCG-nanoethosomes have great potential as drug carriers for transdermal delivery. Copyright © 2016 Elsevier B.V. All rights reserved.

Controlled release of optimized electroporation enhances the transdermal efficiency of sinomenine hydrochloride for treating arthritis in vitro and in clinic

PubMed Central

Feng, Shun; Zhu, Lijun; Huang, Zhisheng; Wang, Haojia; Li, Hong; Zhou, Hua; Lu, Linlin; Wang, Ying; Liu, Zhongqiu; Liu, Liang

2017-01-01

Sinomenine hydrochloride (SH) is an ideal drug for the treatment of rheumatoid arthritis and osteoarthritis. However, high plasma concentration of systemically administered SH can release histamine, which can cause rash and gastrointestinal side effects. Topical delivery can increase SH concentration in the synovial fluid without high plasma level, thus minimizing systemic side effects. However, passive diffusion of SH was found to be inefficient because of the presence of the stratum corneum layer. Therefore, an effective method is required to compensate for the low efficiency of SH passive diffusion. In this study, transdermal experiments in vitro and clinical tests were utilized to explore the optimized parameters for electroporation of topical delivery for SH. Fluorescence experiment and hematoxylin and eosin staining analysis were performed to reveal the mechanism by which electroporation promoted permeation. In vitro, optimized electroporation parameters were 3 KHz, exponential waveform, and intensity 10. Using these parameters, transdermal permeation of SH was increased by 1.9–10.1 fold in mice skin and by 1.6–47.1 fold in miniature pig skin compared with passive diffusion. After the electroporation stimulation, the intercellular intervals and epidermal cracks in the skin increased. In clinical tests, SH concentration in synovial fluid was 20.84 ng/mL after treatment with electroporation. Therefore, electroporation with optimized parameters could significantly enhance transdermal permeation of SH. The mechanism by which electroporation promoted permeation was that the electronic pulses made the skin structure looser. To summarize, electroporation may be an effective complementary method for transdermal permeation of SH. The controlled release of electroporation may be a promising clinical method for transdermal drug administration. PMID:28670109

Transdermal Drug Delivery: Opportunities and Challenges for Controlled Delivery of Therapeutic Agents Using Nanocarriers.

PubMed

Kurmi, Balak Das; Tekchandani, Pawan; Paliwal, Rishi; Paliwal, Shivani Rai

2017-01-01

Transdermal drug delivery represents an extremely attractive and innovative route across the skin owing to the possibility for achieving systemic effect of drugs. The present scenario demands a special focus on developing safe medicine with minimized toxic adverse effects related to most of the pharmacologically active agents. Transdermal drug delivery would be a focal paradigm which provides patient convenience, first-pass hepatic metabolism avoidance, local targeting and reduction in toxic effect related to various categories of drugs like, analgesics, antiinflammatory, antibiotics, antiviral, anaesthetic, anticancer etc. Even this route has challenges due to highly organized structure of skin which acts as a main barrier to penetration of drug via the skin. Several alternative possible strategies are available which overcome these barriers, including use of penetration enhancer, eletroporation, iontophoresis and various nanotechnologically developed nanocarrier systems. The latest one includes employing liposome, dendrimers, nanoparticles, ethosome, carbon nanotube and many more to avoid associated limitations of conventional formulations. Numerous transdermal products such as Estrasorb, Diractin, VivaGel®, Daytrana®, Aczone, Sileryst® are available in the market having a novel strategy to achieve higher penetration of drugs. This encourages formulation fraternity to develop structurally deformable and stable nanocarriers as an alternative approach for controlled and reliable drug delivery across the skin barrier. In this review, we will discuss nanocarriers mediated approaches that come-up with the solutions to the different challenges towards transdermal drug delivery, its clinical importance and latest insight to research in it. The reports presented in this review confirm the wide application of nanocarriers for transdermal delivery of drug/gene. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Local transdermal therapy to the breast for breast cancer prevention and DCIS therapy: preclinical and clinical evaluation.

PubMed

Lee, Oukseub; Ivancic, David; Allu, Subhashini; Shidfar, Ali; Kenney, Kara; Helenowski, Irene; Sullivan, Megan E; Muzzio, Miguel; Scholtens, Denise; Chatterton, Robert T; Bethke, Kevin P; Hansen, Nora M; Khan, Seema A

2015-12-01

Women at high risk of breast cancer and those with carcinoma in situ need non-toxic, well-tolerated preventive interventions. One promising approach is drug delivery through the breast skin (local transdermal therapy, LTT). Our goal was to test novel drugs for LTT, to establish that LTT is applicable to non-steroidal drugs. Athymic nude rats were treated with oral tamoxifen, transdermal 4-hydroxytamoxifen (4-OHT) or endoxifen gel applied daily to the axillary mammary gland for 6 weeks (Study 1). Study 2 was identical to Study 1, testing transdermal telapristone acetate (telapristone) gel versus subcutaneous implant. At euthanasia, mammary glands and blood were collected. In Study 3, consenting women requiring mastectomy were randomized to diclofenac patch applied to the abdomen or the breast for 3 days preoperatively. At surgery, eight tissue samples per breast were collected from predetermined locations, along with venous blood. Drug concentrations were measured using liquid chromatography-tandem mass spectroscopy. Mammary tissue concentrations of 4-OHT, endoxifen, and telapristone were significantly higher in the axillary glands of the gel-treated animals, compared to inguinal glands or to systemically treated animals. Plasma concentrations were similar in gel and systemically treated animals. The clinical trial showed significantly higher mammary concentrations when diclofenac was applied to the breast skin versus the abdominal skin, but concentrations were variable. These results demonstrate that lipophilic drugs can be developed for LTT; although the nude rat is suitable for testing drug permeability, delivery is systemic. In human, however, transdermal application to the breast skin provides local delivery.

Microprocessor-controlled iontophoretic drug delivery of 5-fluorouracil: pharmacodynamic and pharmacokinetic study.

PubMed

Chandrashekar, N S; Shobha Rani, R H

2007-01-01

The purpose of this study was to fabricate monolithic 5-fluorouracil (5-FU) transdermal patch with microprocessor- controlled iontophoretic delivery, to evaluate the pharmacodynamic effects on Dalton's lymphoma ascites (DLA) induced in Balb/c mice, and to study pharmacokinetics in rabbits. The transdermal patches were prepared by solvent casting method; a reprogrammable microprocessor was developed and connected to the patches. DLA cells were injected to the hind limb of Balb/c mice (10 animals/group). In the first group of mice 5-FU was administered i.v. (12 mg/kg). In the second group of mice, transdermal patches (20 mg/patch/animal) were installed and kept for 10 consecutive days, while the third (control) group was kept without any treatment. The tumor diameter was measured every 5th day for 30 days, and the animal survival time and death pattern were studied. The electric current density protocol of 0.5 mA/cm(2) for 30 min was used in the pharmacokinetic study in rabbits. There was a significant reduction in tumor volume in the animals treated with monolithic matrix 5-FU transdermal patch compared to untreated controls and i.v. therapy. Tumor volume of the control animals was 5.8 cm(3) on the 30th day, while in 5-FU with transdermal patch delivery animals it was only 0.23 cm(3) (p <0.05). DLA cells tumor-bearing mice treated with 5-FU with transdermal patch had significantly increased lifespan (ILS). Control animals survived only 21+/-1 days after the tumor inoculation, while i.v. 5-FU and 5-FU patches animals survived 24+/-2.7 days and 39.5+/-1.87 days with ILS of 25.58% and 88.09%, respectively (p <0.01). There was significant sustained release of 5-FU through microprocessor-controlled patches and half-life was significantly higher (p <0.05) compared to the i.v. route. Cytotoxic concentration of 5-FU can be achieved through the transdermal drug delivery and effective therapeutic drug concentration can be maintained up to 24 h, with less toxicity. A new generation of transdermal drug delivery systems based on microprocessor-controlled iontophoresis is in the late stages of development and promises to enhance the treatment of local and systemic medical conditions. The incorporation of microprocessor into these systems has been an important advancement to ensure safe and efficient administration of a wide variety of drugs.

Ethosomes as delivery system for transdermal administration of vinpocetine.

PubMed

Mao, Yan-Ting; Hua, Hai-Ying; Zhang, Xiang-Guo; Zhu, Dong-Xue; Li, Feng; Gui, Zhen-Hua; Zhao, Yong-Xing

2013-05-01

The purpose of the present study was to develop a novel transdermal vinpocetine patch containing a stable formulation and with good entrapment efficiency, and percutaneous absorption which via ethosome. Ethosome was found to be a more efficient delivery carrier with high encapsulation capacities (79.5% +/- 1.8%) and nanometric size (180.7 +/- 1.5 nm). In vitro percutaneous permeation experiments demonstrated that the permeation of vinpocetine through abdominal skin of Sprague Dawley was significantly increased when ethosome was used. The vinpocetine transdermal fluxes from ethosome gel (3.56 +/- 0.13 microg/cm2/h) were 6.72 and 3.10 times higher than that of vinpocetine gel solution and vinpocetine aueous solution, respectively. Furthermore, the AUC(0 --> infinity), and eliminiation half-life by the transdermal administration were significantly higher than those by the intragastric administration (P < 0.01). The study demonstrated that ethosome is a promising vesicular carrier for enhancing percutaneous absorption of vinpocetine.

Transdermal and transbuccal drug delivery systems: enhancement using iontophoretic and chemical approaches.

PubMed

Hu, Longsheng; Silva, Sérgio M C; Damaj, Bassam B; Martin, Richard; Michniak-Kohn, Bozena B

2011-12-12

We investigated the enhancement effect of chemical enhancers and iontophoresis on the in vitro transdermal and transbuccal delivery of lidocaine HCl (LHCl), nicotine hydrogen tartrate (NHT), and diltiazem HCl (DHCl) using porcine skin and buccal tissues. Dodecyl 2-(N,N-dimethylamino) propionate (DDAIP), dodecyl-2-(N,N-dimethylamino) propionate hydrochloride (DDAIP HCl), N-(4-bromobenzoyl)-S,S-dimethyliminosulfurane (Br-iminosulfurane), and azone (laurocapram) were used as chemical enhancers. The study results showed that the application of iontophoresis at either 0.1 mA or 0.3 mA significantly enhanced transdermal and transmucosal delivery of LHCl, NHT and DHCl. It was also demonstrated that iontophoresis had a more pronounced enhancement effect on transdermal delivery than on transbuccal delivery of LHCl, NHT and DHCl. In addition, DDAIP HCl was found to be the most effective enhancer for transbuccal delivery of LHCl and NHT. Copyright © 2011 Elsevier B.V. All rights reserved.

Infrared free electron laser enhanced transdermal drug delivery

NASA Astrophysics Data System (ADS)

Awazu, Kunio; Uchizono, Takeyuki; Suzuki, Sachiko; Yoshikawa, Kazushi

2005-08-01

It is necessary to control enhancement of transdermal drug delivery with non-invasive. The present study was investigated to assess the effectivity of enhancing the drug delivery by irradiating 6-μm region mid infrared free electron laser (MIR-FEL). The enhancement of transdermal drug (lidocaine) delivery of the samples (hairless mouse skin) irradiated with lasers was examined for flux (μg/cm2/h) and total penetration amount (μg/cm2) of lidocaine by High performance Liquid Chromatography (HPLC). The flux and total amount penatration date was enhanced 200-300 fold faster than the control date by the laser irradiation. FEL irradiating had the stratum corneum, and had the less thermal damage in epidermis. The effect of 6-μm region MIR-FEL has the enhancement of transdermal drug delivery without removing the stratum corneum because it has the less thermal damage. It leads to enhancement drug delivery system with non-invasive laser treatment.

Transdermal Delivery of Drugs with Microneedles—Potential and Challenges

PubMed Central

Ita, Kevin

2015-01-01

Transdermal drug delivery offers a number of advantages including improved patient compliance, sustained release, avoidance of gastric irritation, as well as elimination of pre-systemic first-pass effect. However, only few medications can be delivered through the transdermal route in therapeutic amounts. Microneedles can be used to enhance transdermal drug delivery. In this review, different types of microneedles are described and their methods of fabrication highlighted. Microneedles can be fabricated in different forms: hollow, solid, and dissolving. There are also hydrogel-forming microneedles. A special attention is paid to hydrogel-forming microneedles. These are innovative microneedles which do not contain drugs but imbibe interstitial fluid to form continuous conduits between dermal microcirculation and an attached patch-type reservoir. Several microneedles approved by regulatory authorities for clinical use are also examined. The last part of this review discusses concerns and challenges regarding microneedle use. PMID:26131647

The fentanyl HCl patient-controlled transdermal system (PCTS): an alternative to intravenous patient-controlled analgesia in the postoperative setting.

PubMed

Sinatra, Raymond

2005-01-01

Inadequate pain control in the postoperative period not only contributes to patient discomfort, but also causes physiological changes that may result in increased risk of myocardial ischaemia, deep vein thrombosis and pulmonary embolism. These events complicate postoperative recovery and may lead to longer hospital stays as well as increased healthcare costs. Patient-controlled analgesia (PCA) has emerged as an effective way for patients to manage their pain, allowing self-administration of small doses of analgesics to maintain a certain level of pain control. PCA is most commonly delivered via an intravenous (IV) or epidural route, and while patient satisfaction is higher with PCA than with conventional methods of analgesic administration, the invasiveness, costs and risk of errors associated with currently available modalities may limit their utility. These systems also require significant healthcare resources, as nurses must manually program the pumps to deliver the correct amount of medication. Several new PCA modalities are being developed to address these limitations. These systems deliver drug through a variety of routes, including nasal transmucosal and transdermal. Most notably, a self-contained, credit card-sized, transdermal PCA system is currently in the final stages of development. The fentanyl HCl patient-controlled transdermal system (PCTS; IONSYS, Ortho-McNeil Pharmaceutical, Inc., Raritan, NJ) uses an imperceptible, low-intensity direct current to transfer fentanyl on demand across the skin into the systemic circulation. This compact system is patient-activated, can be applied to the patient's upper arm or chest, and is designed to manage moderate-to-severe pain requiring opioid analgesia. The system delivers a preprogrammed amount of fentanyl HCI over 10 minutes, for a total of 80 doses, or for 24 hours, whichever occurs first. The on-demand dosing and pharmacokinetics of this system differentiate it from the passive transdermal formulation of fentanyl designed for the management of chronic pain. Clinical studies have shown that the fentanyl HCl PCTS is effective in the management of acute postoperative pain. These studies have also demonstrated that the system is safe and well tolerated by patients.

Properties and in vitro drug release of hyaluronic acid-hydroxyethyl cellulose hydrogels for transdermal delivery of isoliquiritigenin.

PubMed

Kong, Bong Ju; Kim, Ayoung; Park, Soo Nam

2016-08-20

In the present study, the properties of hydrogel systems based on hyaluronic acid (HA)-hydroxyethyl cellulose (HEC) were investigated for effective transdermal delivery of isoliquiritigenin (ILTG). Hydrogels were synthesized by chemical cross-linking, and network structures were characterised using scanning electron microscopy (SEM) and surface area analyser. Texture properties and swelling of HA-HEC hydrogels were found to be closely linked to cross-linker concentration and swelling medium. Water in HA-HEC hydrogels was found to exist mostly in the form of free water. The viscoelasticity and the network stabilization of the hydrogels were analysed via rheological studies. The release kinetics of the hydrogel followed Fickian diffusion mechanism. In an in vitro skin penetration study, the system substantially improved the delivery of ILTG into the skin. These results indicate that the hydrogel system composed of HA and HEC has potential as a transdermal delivery system, with cross-linking density and the swelling medium influencing the properties. Copyright © 2016 Elsevier Ltd. All rights reserved.

Microneedles for enhanced transdermal and intraocular drug delivery.

PubMed

Moffatt, Kurtis; Wang, Yujing; Raj Singh, Thakur Raghu; Donnelly, Ryan F

2017-10-01

Microneedle mediated delivery based research has garnered great interest in recent years. In the past, the initial focus was delivery of macromolecules of biological origin, however the field has now broadened its scope to include transdermal delivery of conventional low molecular weight drug molecules. Great success has been demonstrated utilising this approach, particularly in the field of vaccine delivery. Current technological advances have permitted an enhancement in design formulation, allowing delivery of therapeutic doses of small molecule drugs and biomolecules, aided by larger patch sizes and scalable manufacture. In addition, it has been recently shown that microneedles are beneficial in localisation of drug delivery systems within targeted ocular tissues. Microneedles have the capacity to modify the means in which therapeutics and formulations are delivered to the eye. However, further research is still required due to potential drawbacks and challenges. Indeed, no true microneedle-based transdermal or ocular drug delivery system has yet been marketed. Some concerns have been raised regarding regulatory issues and manufacturing processes of such systems, and those in the field are now actively working to address them. Microneedle-based transdermal and ocular drug delivery systems have the potential to greatly impact not only patient benefits, but also industry, and through diligence, innovation and collaboration, their true potential will begin to be realised within the next 3-5 years. Copyright © 2017 Elsevier Ltd. All rights reserved.

Transdermal Photopolymerization for Minimally Invasive Implantation

NASA Astrophysics Data System (ADS)

Elisseeff, J.; Anseth, K.; Sims, D.; McIntosh, W.; Randolph, M.; Langer, R.

1999-03-01

Photopolymerizations are widely used in medicine to create polymer networks for use in applications such as bone restorations and coatings for artificial implants. These photopolymerizations occur by directly exposing materials to light in "open" environments such as the oral cavity or during invasive procedures such as surgery. We hypothesized that light, which penetrates tissue including skin, could cause a photopolymerization indirectly. Liquid materials then could be injected s.c. and solidified by exposing the exterior surface of the skin to light. To test this hypothesis, the penetration of UVA and visible light through skin was studied. Modeling predicted the feasibility of transdermal polymerization with only 2 min of light exposure required to photopolymerize an implant underneath human skin. To establish the validity of these modeling studies, transdermal photopolymerization first was applied to tissue engineering by using "injectable" cartilage as a model system. Polymer/chondrocyte constructs were injected s.c. and transdermally photopolymerized. Implants harvested at 2, 4, and 7 weeks demonstrated collagen and proteoglycan production and histology with tissue structure comparable to native neocartilage. To further examine this phenomenon and test the applicability of transdermal photopolymerization for drug release devices, albumin, a model protein, was released for 1 week from photopolymerized hydrogels. With further study, transdermal photpolymerization potentially could be used to create a variety of new, minimally invasive surgical procedures in applications ranging from plastic and orthopedic surgery to tissue engineering and drug delivery.

Fabrication, appraisal, and transdermal permeation of sildenafil citrate-loaded nanostructured lipid carriers versus solid lipid nanoparticles

PubMed Central

Elnaggar, Yosra SR; El-Massik, Magda A; Abdallah, Ossama Y

2011-01-01

Although sildenafil citrate (SC) is used extensively for erectile dysfunction, oral delivery of SC encounters many obstacles. Furthermore, the physicochemical characteristics of this amphoteric drug are challenging for delivery system formulation and transdermal permeation. This article concerns the assessment of the potential of nanomedicine for improving SC delivery and transdermal permeation. SC-loaded nanostructured lipid carriers (NLCs) and solid lipid nanoparticles (SLNs) were fabricated using a modified high-shear homogenization technique. Nanoparticle optimization steps included particle size analysis, entrapment efficiency (EE) determination, freeze-drying and reconstitution, differential scanning calorimetry, in vitro release, stability study and high-performance liquid chromatography analysis. Transdermal permeation of the nanocarriers compared with SC suspension across human skin was assessed using a modified Franz diffusion cell assembly. Results revealed that SLNs and NLCs could be optimized in the nanometric range (180 and 100 nm, respectively) with excellent EE (96.7% and 97.5%, respectively). Nanoparticles have significantly enhanced in vitro release and transdermal permeation of SC compared with its suspensions. Furthermore, transdermal permeation of SC exhibited higher initial release from both SLN and NLC formulations followed by controlled release, with promising implications for faster onset and longer drug duration. Nanomedicines prepared exhibited excellent physical stability for the study period. Solid nanoparticles optimized in this study successfully improved SC characteristics, paving the way for an efficient topical Viagra® product. PMID:22238508

Patient-controlled analgesia: therapeutic interventions using transdermal electro-activated and electro-modulated drug delivery.

PubMed

Indermun, Sunaina; Choonara, Yahya E; Kumar, Pradeep; Du Toit, Lisa C; Modi, Girish; Luttge, Regina; Pillay, Viness

2014-02-01

Chronic pain poses a major concern to modern medicine and is frequently undertreated, causing suffering and disability. Patient-controlled analgesia, although successful, does have limitations. Transdermal delivery is the pivot to which analgesic research in drug delivery has centralized, especially with the confines of needle phobias and associated pain related to traditional injections, and the existing limitations associated with oral drug delivery. Highlighted within is the possibility of further developing transdermal drug delivery for chronic pain treatment using iontophoresis-based microneedle array patches. A concerted effort was made to review critically all available therapies designed for the treatment of chronic pain. The drug delivery systems developed for this purpose and nondrug routes are elaborated on, in a systematic manner. Recent developments and future goals in transdermal delivery as a means to overcome the individual limitations of the aforementioned delivery routes are represented as well. The approval of patch-like devices that contain both the microelectronic-processing mechanism and the active medicament in a small portable device is still awaited by the pharmaceutical industry. This anticipated platform may provide transdermal electro-activated and electro-modulated drug delivery systems a feasible attempt in chronic pain treatment. Iontophoresis has been proven an effective mode used to administer ionized drugs in physiotherapeutic, diagnostic, and dermatological applications and may be an encouraging probability for the development of devices and aids in the treatment of chronic pain. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

Perspectives on Transdermal Electroporation

PubMed Central

Ita, Kevin

2016-01-01

Transdermal drug delivery offers several advantages, including avoidance of erratic absorption, absence of gastric irritation, painlessness, noninvasiveness, as well as improvement in patient compliance. With this mode of drug administration, there is no pre-systemic metabolism and it is possible to increase drug bioavailability and half-life. However, only a few molecules can be delivered across the skin in therapeutic quantities. This is because of the hindrance provided by the stratum corneum. Several techniques have been developed and used over the last few decades for transdermal drug delivery enhancement. These include sonophoresis, iontophoresis, microneedles, and electroporation. Electroporation, which refers to the temporary perturbation of the skin following the application of high voltage electric pulses, has been used to increase transcutaneous flux values by several research groups. In this review, transdermal electroporation is discussed and the use of the technique for percutaneous transport of low and high molecular weight compounds described. This review also examines our current knowledge regarding the mechanisms of electroporation and safety concerns arising from the use of this transdermal drug delivery technique. Safety considerations are especially important because electroporation utilizes high voltage pulses which may have deleterious effects in some cases. PMID:26999191

Anti-cancer vaccination by transdermal delivery of antigen peptide-loaded nanogels via iontophoresis.

PubMed

Toyoda, Mao; Hama, Susumu; Ikeda, Yutaka; Nagasaki, Yukio; Kogure, Kentaro

2015-04-10

Transdermal vaccination with cancer antigens is expected to become a useful anti-cancer therapy. However, it is difficult to accumulate enough antigen in the epidermis for effective exposure to Langerhans cells because of diffusion into the skin and muscle. Carriers, such as liposomes and nanoparticles, may be useful for the prevention of antigen diffusion. Iontophoresis, via application of a small electric current, is a noninvasive and efficient technology for transdermal drug delivery. Previously, we succeeded in the iontophoretic transdermal delivery of liposomes encapsulating insulin, and accumulation of polymer-based nanoparticle nanogels in the stratum corneum of the skin. Therefore, in the present study, we examined the use of iontophoresis with cancer antigen gp-100 peptide KVPRNQDWL-loaded nanogels for anti-cancer vaccination. Iontophoresis resulted in the accumulation of gp-100 peptide and nanogels in the epidermis, and subsequent increase in the number of Langerhans cells in the epidermis. Moreover, tumor growth was significantly suppressed by iontophoresis of the antigen peptide-loaded nanogels. Thus, iontophoresis of the antigen peptide-loaded nanogels may serve as an effective transdermal delivery system for anti-cancer vaccination. Copyright © 2015 Elsevier B.V. All rights reserved.

Efficacy of a Methylphenidate Transdermal System versus t.i.d. Methylphenidate in a Laboratory Setting

ERIC Educational Resources Information Center

Pelham, William E.; Waxmonsky, James G.; Schentag, Jerome; Ballow, Charles H.; Panahon, Carlos J.; Gnagy, Elizabeth M.; Hoffman, Martin T.; Burrows-MacLean, Lisa; Meichenbaum, David L.; Forehand, Gregory L.; Fabiano, Gregory A.; Tresco, Katy E.; Lopez-Williams, Andy; Coles, Erika K.; Gonzalez, Mario A.

2011-01-01

Objective: To test the efficacy and tolerability of the methylphenidate transdermal formulation (MTS) against immediate-release methylphenidate (IR MPH) and placebo in a 12-hr analog classroom setting. Method: A total of nine boys ages 6 to 9 years, medicated with MPH for ADHD, complete a within-subject, double-blind study. For the purpose of the…

Critical attributes of transdermal drug delivery system (TDDS)--a generic product development review.

PubMed

Ruby, P K; Pathak, Shriram M; Aggarwal, Deepika

2014-11-01

Bioequivalence testing of transdermal drug delivery systems (TDDS) has always been a subject of high concern for generic companies due to the formulation complexity and the fact that they are subtle to even minor manufacturing differences and hence should be clearly qualified in terms of quality, safety and efficacy. In recent times bioequivalence testing of transdermal patches has gained a global attention and many regulatory authorities worldwide have issued recommendations to set specific framework for demonstrating equivalence between two products. These current regulatory procedures demand a complete characterization of the generic formulation in terms of its physicochemical sameness, pharmacokinetics disposition, residual content and/or skin irritation/sensitization testing with respect to the reference formulation. This paper intends to highlight critical in vitro tests in assessing the therapeutic equivalence of products and also outlines their valuable applications in generic product success. Understanding these critical in vitro parameters can probably help to decode the complex bioequivalence outcomes, directing the generic companies to optimize the formulation design in reduced time intervals. It is difficult to summarize a common platform which covers all possible transdermal products; hence few case studies based on this approach has been presented in this review.

Effect of electron beam irradiation on bacterial cellulose membranes used as transdermal drug delivery systems

NASA Astrophysics Data System (ADS)

Stoica-Guzun, Anicuta; Stroescu, Marta; Tache, Florin; Zaharescu, Traian; Grosu, Elena

2007-12-01

Ionizing radiation is an effective energetic source for polymer surfaces modification in order to obtain transdermal systems with different controlled release properties. In this work, gamma rays have been applied to induce changes in bacterial cellulose membranes. Permeation of drug (tetracycline) was theoretically and experimentally investigated starting from the effect of γ-irradiation on membranes permeability. Release and permeation of drug from irradiated and non-irradiated membranes have been performed using a diffusion cell.

Studies on optimizing in vitro transdermal permeation of ondansetron hydrochloride using nerodilol, carvone, and limonene as penetration enhancers.

PubMed

Krishnaiah, Yellela S R; Raju, Vengaladasu; Shiva Kumar, Mantri; Rama, Bukka; Raghumurthy, Vanambattina; Ramana Murthy, Kolapalli V

2008-01-01

The present investigation was carried out to formulate a terpene-based hydroxypropyl cellulose (HPC) gel drug reservoir system for its optimal transdermal permeation of ondansetron hydrochloride. The HPC gel formulations containing ondansetron hydrochloride (3% w/w) and selected concentrations of either nerodilol (0% w/w, 1% w/w, 2% w/w, 3% w/w, and 4% w/w), carvone (0% w/w, 2% w/w, 4% w/w, 8% w/w, and 10% w/w), or limonene (0% w/w, 2% w/w, 3% w/w, and 4% w/w) were prepared and subjected to in vitro permeation of the drug across rat epidermis. All the 3 terpene enhancers increased the transdermal permeation of ondansetron hydrochloride. The optimal transdermal permeation was observed with 3% w/w of nerodilol (175.3 +/- 3.1 microg/cm(2.)h), 8% w/w of carvone (87.4 +/- 1.6 microg/cm(2.)h), or 3% w/w of limonene (181.9 +/- 0.9 microg/cm(2.)h). The enhancement ratio (ER) in drug permeability with 3% w/w nerodilol, 8% w/w carvone, and 3% w/w limonene were 21.6, 10.8, and 22.5, respectively, when compared with that obtained without a terpene enhancer (control). However, there was 1.04-, 2.09-, and 2.17-fold increase in the optimal drug flux obtained with carvone, nerodilol, and limonene, respectively, when compared with the desired drug flux (84 microg/cm(2.)h). It was concluded that the HPC gel drug reservoir systems containing either 3% w/w nerodilol or 3% w/w limonene act as optimal formulations for use in the design of membrane-controlled transdermal therapeutic system (TTS) of ondansetron hydrochloride.

Transdermal delivery of AT1 receptor antagonists reduce blood pressure and reveals a vasodilatory effect in kidney blood vessels.

PubMed

Michalatou, Michaila; Androutsou, Maria Eleni; Antonopoulos, Markos; Vlahakos, Demetrios V; Agelis, George; Zulli, Anthony; Qaradakhi, Tawar; Mikkelsen, Kathleen; Apostolopoulos, Vasso; Matsoukas, John

2018-04-19

The Renin Angiotensin System (RAS) is pharmacologically targeted to reduce blood pressure, and patient compliance to oral medications is a clinical issue. The mechanisms of action of angiotensin receptor blockers (ARBs) in reducing blood pressure are not well understood, and is purported to be via a reduction of angiotensin II signaling. We aimed to develop a transdermal delivery method for ARBs (losartan potassium and valsartan) and to determine if ARBs reveal a vasodilatory effect of the novel RAS peptide, alamandine. In addition we determined the anti-hypertensive effects of the transdermal delivery patch. In vitro and in vivo experiments were performed to develop an appropriate therapeutic system, promising an alternative and more effective therapy in the treatment of hypertension. A variety of penetration enhancers were selected such as isopropyl myristate, propylene glycol, transcutol and dimenthyl sulfoxide to obtain a constant release of drugs through human skin. Small resistance vessels (kidney interlobar arteries) were mounted in organ baths and incubated with an ARB. Vasodilatory curves to alamandine were constructed Results: The in vivo studies demonstrates that systemic absorption of valsartan and losartan potassium using the appropriate formulations provides a steady state release and anti-hypertensive effect even after 24 hours of transdermal administration. No apparent skin irritations (erythema, edema) were observed with the tested formulations. We also show that blocking the AT1 receptor of rabbit interlobar arteries in vitro reveals a vasodilatory effect of alamandine. This study reveals potential mechanism of AT1 receptor blockade via alamandine, and is an important contribution in developing a favorable, convenient and painless antihypertensive therapy of prolonged duration through transdermal delivery of AT1 blockers. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Blind Deconvolution for Distributed Parameter Systems with Unbounded Input and Output and Determining Blood Alcohol Concentration from Transdermal Biosensor Data.

PubMed

Rosen, I G; Luczak, Susan E; Weiss, Jordan

2014-03-15

We develop a blind deconvolution scheme for input-output systems described by distributed parameter systems with boundary input and output. An abstract functional analytic theory based on results for the linear quadratic control of infinite dimensional systems with unbounded input and output operators is presented. The blind deconvolution problem is then reformulated as a series of constrained linear and nonlinear optimization problems involving infinite dimensional dynamical systems. A finite dimensional approximation and convergence theory is developed. The theory is applied to the problem of estimating blood or breath alcohol concentration (respectively, BAC or BrAC) from biosensor-measured transdermal alcohol concentration (TAC) in the field. A distributed parameter model with boundary input and output is proposed for the transdermal transport of ethanol from the blood through the skin to the sensor. The problem of estimating BAC or BrAC from the TAC data is formulated as a blind deconvolution problem. A scheme to identify distinct drinking episodes in TAC data based on a Hodrick Prescott filter is discussed. Numerical results involving actual patient data are presented.

Multiscale modeling of transdermal drug delivery

NASA Astrophysics Data System (ADS)

Rim, Jee Eun

2006-04-01

This study addresses the modeling of transdermal diffusion of drugs, to better understand the permeation of molecules through the skin, and especially the stratum corneum, which forms the main permeation barrier of the skin. In transdermal delivery of systemic drugs, the drugs diffuse from a patch placed on the skin through the epidermis to the underlying blood vessels. The epidermis is the outermost layer of the skin and can be further divided into the stratum corneum (SC) and the viable epidermis layers. The SC consists of keratinous cells (corneocytes) embedded in the lipid multi-bilayers of the intercellular space. It is widely accepted that the barrier properties of the skin mostly arises from the ordered structure of the lipid bilayers. The diffusion path, at least for lipophilic molecules, seems to be mainly through the lipid bilayers. Despite the advantages of transdermal drug delivery compared to other drug delivery routes such as oral dosing and injections, the low percutaneous permeability of most compounds is a major difficulty in the wide application of transdermal drug delivery. In fact, many transdermal drug formulations include one or more permeation enhancers that increase the permeation of the drug significantly. During the last two decades, many researchers have studied percutaneous absorption of drugs both experimentally and theoretically. However, many are based on pharmacokinetic compartmental models, in which steady or pseudo-steady state conditions are assumed, with constant diffusivity and partitioning for single component systems. This study presents a framework for studying the multi-component diffusion of drugs coupled with enhancers through the skin by considering the microstructure of the stratum corneum (SC). A multiscale framework of modeling the transdermal diffusion of molecules is presented, by first calculating the microscopic diffusion coefficient in the lipid bilayers of the SC using molecular dynamics (MD). Then a homogenization procedure is performed over a model unit cell of the heterogeneous SC, resulting in effective diffusion parameters. These effective parameters are the macroscopic diffusion coefficients for the homogeneous medium that is "equivalent" to the heterogeneous SC, and thus can be used in finite element simulations of the macroscopic diffusion process.

Effect of different penetration enhancers on diclofenac permeation across horse skin.

PubMed

Ferrante, M; Andreeta, A; Landoni, M F

2010-12-01

Diclofenac is a hydrophilic non-steroidal anti-inflammatory drug widely used in humans and animals. Previous reports have shown that this compound has low percutaneous absorption in horses. The effect of five penetration enhancers (10% urea, 15% and 20% oleic acid and 5% and 10% d-limonene) on the percutaneous absorption of diclofenac diethylamine through horse skin was evaluated in vitro using Franz-type diffusion cells. All tested penetration enhancers induced a significant increase in diclofenac diethylamine permeation, with limonene showing the highest enhancing effect at the lowest concentration (5%) applied. The presence of the permeation enhancers did not affect lag-time. This is the first in vitro study of the effects of penetration enhancers on transdermal permeation of diclofenac diethylamine across horse skin. The results suggested that urea, limonene and 5% oleic acid were useful for enhancing the transdermal absorption of diclofenac diethylamine and may assist in the development of a transdermal formulation of diclofenac diethylamine for use in horses. Copyright © 2009. Published by Elsevier Ltd.

The viscoelastic evaluation of transdermal adhesive systems and the influence of excipients

NASA Astrophysics Data System (ADS)

Wick, Steven Marshall

1998-12-01

The transdermal dosage form requires simultaneous consideration of both drug delivery and adhesion to skin in order to achieve the desired therapeutic effect. A transdermal system with inadequate adhesion performance will produce a variable and unpredictable systemic blood level profile. It is therefore of paramount importance that the adhesive performance be fully contemplated within the development of a total transdermal system. An experimental strategy was developed within this thesis which utilizes a sequential combination of a dynamic stress followed by a static shear stress evaluation Within the dynamic stress evaluation, a sinusoidal stress of constant frequency, over a frequency of 0.065 to 64 Hz was applied normal to the surface of an adhesive system. The static shear stress apparatus (CIRUSS) applies a constant shear stress for a defined time interval (three minutes) followed by an instantaneous removal of the applied shear stress. The mechanical behavior of two distinct adhesive polymers (silicone and acrylate) was modeled as a one-dimensional four-parameter solid and five-parameter solid respectively for the two adhesive systems. The effects of several additives were examined including ethyl oleate, glyceryl monolaurate, an amine oxide, Teflon and a macromer. In addition, the effect of branching and cross-linking was examined using the acrylate adhesive system. A physical interpretation of the mechanical behavior was proposed associating the deformation within an adhesive system with the disruption of the hydrogen bonding network as well as the covalent bonds within the polymer backbone. The collected data was consistent with the author's postulate. The presented results verify the utility of the aforementioned sequential evaluation strategy in characterizing adhesive viscoelastic performance.

Transdermal Bioavailability in Rats of Lidocaine in the Forms of Ionic Liquids, Salts, and Deep Eutectic.

PubMed

Berton, Paula; Di Bona, Kristin R; Yancey, Denise; Rizvi, Syed A A; Gray, Marquita; Gurau, Gabriela; Shamshina, Julia L; Rasco, Jane F; Rogers, Robin D

2017-05-11

Tuning the bioavailability of lidocaine was explored by its incorporation into the ionic liquid lidocainium docusate ([Lid][Doc]) and the deep eutectic Lidocaine·Ibuprofen (Lid·Ibu) and comparing the transdermal absorption of these with the crystalline salt lidocainium chloride ([Lid]Cl). Each form of lidocaine was dissolved in a vehicle cream and topically applied to Sprague-Dawley rats. The concentrations of the active pharmaceutical ingredients (APIs) in blood plasma were monitored over time as an indication of systemic absorption. The concentration of lidocaine in plasma varied between applied API-based creams, with faster and higher systemic absorption of the hydrogen bonded deep eutectic Lid·Ibu than the absorption of the salts [Lid]Cl or [Lid][Doc]. Interestingly, a differential transdermal absorption was observed between lidocaine and ibuprofen when Lid·Ibu was applied, possibly indicating different interactions with the tissue components.

Transdermal Bioavailability in Rats of Lidocaine in the Forms of Ionic Liquids, Salts, and Deep Eutectic

PubMed Central

2017-01-01

Tuning the bioavailability of lidocaine was explored by its incorporation into the ionic liquid lidocainium docusate ([Lid][Doc]) and the deep eutectic Lidocaine·Ibuprofen (Lid·Ibu) and comparing the transdermal absorption of these with the crystalline salt lidocainium chloride ([Lid]Cl). Each form of lidocaine was dissolved in a vehicle cream and topically applied to Sprague–Dawley rats. The concentrations of the active pharmaceutical ingredients (APIs) in blood plasma were monitored over time as an indication of systemic absorption. The concentration of lidocaine in plasma varied between applied API-based creams, with faster and higher systemic absorption of the hydrogen bonded deep eutectic Lid·Ibu than the absorption of the salts [Lid]Cl or [Lid][Doc]. Interestingly, a differential transdermal absorption was observed between lidocaine and ibuprofen when Lid·Ibu was applied, possibly indicating different interactions with the tissue components. PMID:28523100

Partial ablation of stratum corneum by UV (193-nm) or IR (2.94-μm) pulsed lasers to enhance transdermal drug delivery rate

NASA Astrophysics Data System (ADS)

Fujiwara, Ai; Hinokitani, Toshihiro; Goto, Kenichi; Arai, Tsunenori

2004-07-01

To develop the noninvasive transdermal drug delivery system, pulsed lasers (argon-fluoride excimer laser (ArF laser) and erbium:yittrium aluminum garnet laser (Er:YAG laser)) were used to partially ablate the stratum corneum (SC), the upper layer of the skin. Because of the barrier function of the SC to drug permeation, the number of drugs especially macromolecules used in transdermal drug delivery system without skin irritation has been limited. Ultrastructural changes on the SC surface of ablated Yucatan micropig skin in vitro were observed with Environmental Scanning Electron Microscope. The result indicated that the structural changes varied according to each laser sources and irradiation conditions (laser fluences and numbers of pulses). Many granular structures of about 2 μm in diameter were observed in the ablated sites on ArF laser with lower fluence exposure (30 mJ/cm2, 200 pulses), and plane structures in the sites with higher fluence exposure (80 mJ/cm2, 80 pulses). In contrast, the ablation of Er:YAG laser created some pores of about 20 μm across on the surface of the SC. Under the irradiation condition of partial ablation, the skin permeability of macromolecule compound was enhanced. This partial SC ablation by pulsed laser could be possible candidate of the noninvasive transdermal drug delivery system with good physiological conditions of skin.

Lipid based noninvasive vesicular formulation of cytarabine: Nanodeformable liposomes.

PubMed

Raj, Rakesh; Raj, Pooja Mongia; Ram, Alpana

2016-06-10

Leukemia is the common cause of death and worldwide incidence of this disease is increasing. Chemotherapy is the first choice for leukemia treatment, but the major limitations of standard therapy are its side effects and poor patient compliances. Therefore it is imperative to look for a therapeutic system with lesser side effects urgently to address the underlying causes of poor treatment outcomes. In such a scenario transdermal route for delivery of chemotherapeutic drugs could be a better alternative to provide sustained drug level, enhanced activity, self administration and better patient compliances. The present work is focus on the design of nanolipid based transdermal carrier, deformable liposomes bearing cytarabine as a model drug for effective delivery of drug with enhanced transdermal flux. Developed nanocarriers were characterized for their size, morphology, entrapment efficiency, skin penetration and irritation. It could be concluded that nanodeformable liposomes accentuated transdermal flux of cytarabine and could provide a new strategy for leukemia. Copyright © 2016 Elsevier B.V. All rights reserved.

Nanoethosomes for transdermal delivery of tropisetron HCl: multi-factorial predictive modeling, characterization, and ex vivo skin permeation.

PubMed

Abdel Messih, Hanaa A; Ishak, Rania A H; Geneidi, Ahmed S; Mansour, Samar

2017-06-01

The aim of the present work is to exclusively optimize and model the effect of phospholipid type either egg phosphatidylcholine (EPC) or soybean phosphatidylcholine (SPC), together with other formulation variables, on the development of nano-ethosomal systems for transdermal delivery of a water-soluble antiemetic drug. Tropisetron HCl (TRO) is available as hard gelatin capsules and IV injections. The transdermal delivery of TRO is considered as a novel alternative route supposing to improve BAV as well as patient convenience. TRO-loaded ethanolic vesicular systems were prepared by hot technique. The effect of formulation variables were optimized through a response surface methodology using 3 × 2 2 -level full factorial design. The concentrations of both PC (A) and ethanol (B) and PC type (C) were the factors, while entrapment efficiency (Y 1 ), vesicle size (Y 2 ), polydispersity index (Y 3 ), and zeta potential (Y 4 ) were the responses. The drug permeation across rat skin from selected formulae was studied. Particle morphology, drug-excipient interactions, and vesicle stability were also investigated. The results proved the critical role of all formulation variables on ethosomal characteristics. The suggested models for all responses showed good predictability. Only the concentration of phospholipid, irrespective to PC type, had a significant effect on the transdermal flux (p < 0.01). The ethosomal vesicles were unilamellar with a nearly spherical shape. EPC-based ethosomes proved good stability. The study suggests the applicability of statistical modeling as a promising tool for prediction of ethosomal characteristics. The ethanolic vesicles were considered as novel potential nanocarriers for accentuated transdermal TRO delivery.

Transdermal thiol-acrylate polyethylene glycol hydrogel synthesis using near infrared light

NASA Astrophysics Data System (ADS)

Chung, Solchan; Lee, Hwangjae; Kim, Hyung-Seok; Kim, Min-Gon; Lee, Luke P.; Lee, Jae Young

2016-07-01

Light-induced polymerization has been widely applied for hydrogel synthesis, which conventionally involves the use of ultraviolet or visible light to activate a photoinitiator for polymerization. However, with these light sources, transdermal gelation is not efficient and feasible due to their substantial interactions with biological systems, and thus a high power is required. In this study, we used biocompatible and tissue-penetrating near infrared (NIR) light to remotely trigger a thiol-acrylate reaction for efficient in vivo gelation with good controllability. Our gelation system includes gold nanorods as a photothermal agent, a thermal initiator, diacrylate polyethylene glycol (PEG), and thiolated PEG. Irradiation with a low-power NIR laser (0.3 W cm-2) could induce gelation via a mixed-mode reaction with a small increase in temperature (~5 °C) under the optimized conditions. We also achieved successful transdermal gelation via the NIR-assisted photothermal thiol-acryl reactions. This new type of NIR-assisted thiol-acrylate polymerization provides new opportunities for in situ hydrogel formation for injectable hydrogels and delivery of drugs/cells for various biomedical applications.Light-induced polymerization has been widely applied for hydrogel synthesis, which conventionally involves the use of ultraviolet or visible light to activate a photoinitiator for polymerization. However, with these light sources, transdermal gelation is not efficient and feasible due to their substantial interactions with biological systems, and thus a high power is required. In this study, we used biocompatible and tissue-penetrating near infrared (NIR) light to remotely trigger a thiol-acrylate reaction for efficient in vivo gelation with good controllability. Our gelation system includes gold nanorods as a photothermal agent, a thermal initiator, diacrylate polyethylene glycol (PEG), and thiolated PEG. Irradiation with a low-power NIR laser (0.3 W cm-2) could induce gelation via a mixed-mode reaction with a small increase in temperature (~5 °C) under the optimized conditions. We also achieved successful transdermal gelation via the NIR-assisted photothermal thiol-acryl reactions. This new type of NIR-assisted thiol-acrylate polymerization provides new opportunities for in situ hydrogel formation for injectable hydrogels and delivery of drugs/cells for various biomedical applications. Electronic supplementary information (ESI) available: FE-SEM image of thiol-acrylate hydrogels; UV/Vis spectra of Ellman's assay; the temperature increase during transdermal photothermal hydrogelation. See DOI: 10.1039/c6nr01956k

Current and emerging formulation strategies for the effective transdermal delivery of HIV inhibitors.

PubMed

Ham, Anthony S; Buckheit, Robert W

2015-02-01

Current and emerging formulation strategies for skin permeation are poised to open the transdermal drug delivery to a broader range of small molecule compounds that do not fit the traditional requirements for successful transdermal drug delivery, allowing the development of new patch technologies to deliver antiretroviral drugs that were previously incapable of being delivered through transdermal means. Transdermal drug delivery offers several distinct advantages over traditional dosage forms. Current antiretroviral drugs used for the treatment of HIV infection include a variety of highly active small molecule compounds with significantly limited skin permeability, and thus new and novel means of enhancing transport through the skin are needed. Current and emerging formulation strategies are poised to open the transdermal drug delivery to a broader range of compounds that do not fit the traditional requirements for successful transdermal drug delivery, allowing the development of new patch technologies to deliver antiretroviral drugs that were previously incapable of being delivered through transdermal means. Thus, with continuing research into skin permeability and patch formulation strategies, there is a large potential for antiretroviral transdermal drug delivery.

Current and emerging formulation strategies for the effective transdermal delivery of HIV inhibitors

PubMed Central

Ham, Anthony S; Buckheit, Robert W

2015-01-01

Current and emerging formulation strategies for skin permeation are poised to open the transdermal drug delivery to a broader range of small molecule compounds that do not fit the traditional requirements for successful transdermal drug delivery, allowing the development of new patch technologies to deliver antiretroviral drugs that were previously incapable of being delivered through transdermal means. Transdermal drug delivery offers several distinct advantages over traditional dosage forms. Current antiretroviral drugs used for the treatment of HIV infection include a variety of highly active small molecule compounds with significantly limited skin permeability, and thus new and novel means of enhancing transport through the skin are needed. Current and emerging formulation strategies are poised to open the transdermal drug delivery to a broader range of compounds that do not fit the traditional requirements for successful transdermal drug delivery, allowing the development of new patch technologies to deliver antiretroviral drugs that were previously incapable of being delivered through transdermal means. Thus, with continuing research into skin permeability and patch formulation strategies, there is a large potential for antiretroviral transdermal drug delivery. PMID:25690088

Initial study of transdermal oxybutynin for treating hyperhidrosis.

PubMed

Millán-Cayetano, José Francisco; Del Boz, Javier; Toledo-Pastrana, Tomas; Nieto-Guindo, Miriam; García-Montero, Pablo; de Troya-Martín, Magdalena

2017-06-01

Oral oxybutynin for treating hyperhidrosis is effective and safe. Its side-effects are mild but frequent so we consider whether transdermal oxybutynin (considered to have a better side-effect profile) could be an alternative for treating hyperhidrosis. During 2015, a prospective study was conducted. Epidemiological variables, effectiveness (using the Hyperhidrosis Disease Severity Scale) and tolerance to transdermal oxybutynin were compiled concerning two different groups (patients previously treated or untreated with oral oxybutynin), at baseline, and at 3 and 12 months. Seven previously treated and six previously untreated patients were included. Five patients in the first group discontinued the treatment within 3 months. Of the two remaining patients, one reported ineffectiveness and the other obtained an excellent response but discontinued due to local irritation. Among the untreated patients, two showed no response and four experienced improvement (three with "partial response" and one with "excellent response"). All patients discontinued treatment within 12 months. No major adverse effects were observed. The absence of active metabolites after transdermal oxybutynin could result in less effectiveness than oral oxybutynin, although it is usually well tolerated. In conclusion, transdermal oxybutynin could have low effectiveness for the treatment of hyperhidrosis in patients following intolerance to oral oxybutynin but could provide good results in patients who have never tried systemic drugs. © 2017 Japanese Dermatological Association.

The molecular assembly of the ionic liquid/aliphatic carboxylic acid/aliphatic amine as effective and safety transdermal permeation enhancers.

PubMed

Kubota, Koji; Shibata, Akira; Yamaguchi, Toshikazu

2016-04-30

In spite of numerous advantages, transdermal drug delivery systems are unfeasible for most drugs because of the barrier effect of the stratum corneum. Ionic liquids were recently used to enhance transdermal drug delivery by improving drug solubility. In the present study, safe and effective ionic liquids for transdermal absorption were obtained as salts generated by a neutralization reaction between highly biocompatible aliphatic carboxylic acids (octanoic acid or isostearic acid) and aliphatic amines (diisopropanolamine or triisopropanolamine) (Medrx Co., Ltd., 2009). The mechanism of skin permeability enhancement by ionic liquids was investigated by hydrophilic phenol red and hydrophobic tulobuterol. Further, the skin permeation enhancing effect was remarkably superior in the acid excess state rather than the neutralization state. Infrared absorption spectrum analysis confirmed that ionic liquids/aliphatic carboxylic acid/aliphatic amine are coexisting at all mixing states. In the acid excess state, ionic liquids interact with aliphatic carboxylic acids via hydrogen bonds. Thus, the skin permeation enhancing effect is not caused by the ionic liquid alone. The "liquid salt mixture," referred to as a complex of ingredients coexisting with ionic liquids, forms a molecular assembly incorporating hydrophilic drug. This molecular assembly was considered an effective and safety enhancer of transdermal drug permeation. Copyright © 2016. Published by Elsevier B.V.

Assessment of simvastatin niosomes for pediatric transdermal drug delivery.

PubMed

Zidan, Ahmed S; Hosny, Khaled M; Ahmed, Osama A A; Fahmy, Usama A

2016-06-01

The prevalence of childhood dyslipidemia increases and is considered as an important risk factor for the incidence of cardiovascular disease in the adulthood. To improve dosing accuracy and facilitate the determination of dosing regimens in function of the body weight, the proposed study aims at preparing transdermal niosomal gels of simvastatin as possible transdermal drug delivery system for pediatric applications. Twelve formulations were prepared to screen the influence of formulation and processing variables on critical niosomal characteristics. Nano-sized niosomes with 0.31 μm number-weighted size displayed highest simvastatin release rate with 8.5% entrapment capacity. The niosomal surface coverage by negative charges was calculated according to Langmuir isotherm with n = 0.42 to suggest that the surface association was site-independent, probably producing surface rearrangements. Hypolipidemic activities after transdermal administration of niosomal gels to rats showed significant reduction in cholesterol and triglyceride levels while increasing plasma high-density lipoproteins concentration. Bioavailability estimation in rats revealed an augmentation in simvastatin bioavailability by 3.35 and 2.9 folds from formulation F3 and F10, respectively, compared with oral drug suspension. Hence, this transdermal simvastatin niosomes not only exhibited remarkable potential to enhance its bioavailability and hypolipidemic activity but also considered a promising pediatric antihyperlipidemic formulation.

Interview with faz chowdhury.

PubMed

Chowdhury, Faz

2014-06-01

Faz Chowdhury is the Chief Executive Officer of Nemaura Pharma (Loughborough, UK), a pharmaceutical drug-delivery company developing patented formulation technologies alongside transdermal systems. Having originally trained as a pharmaceutical scientist, Dr Chowdhury received his PhD in Nanomedicine from the University of Oxford (Oxford, UK). With recognized expertise in the pharmaceutical industry and the holder of more than 15 patents on drug-delivery systems, Dr Chowdhury discussed the challenges faced in microneedle-based drug delivery, an area widely expected to revolutionize the transdermal field over the coming years. Interview conducted by James Potticary, Commissioning Editor.

Minimization of CYP2D6 Polymorphic Differences and Improved Bioavailability via Transdermal Administration: Latrepirdine Example.

PubMed

Chew, Marci L; Mordenti, Joyce; Yeoh, Thean; Ranade, Gautam; Qiu, Ruolun; Fang, Juanzhi; Liang, Yali; Corrigan, Brian

2016-08-01

Transdermal delivery has the potential to offer improved bioavailability by circumventing first-pass gut and hepatic metabolism. This study evaluated the pharmacokinetics of oral immediate release and transdermal latrepirdine in extensive and poor CYP2D6 metabolizers (EM/PM). Latrepirdine transdermal solution was prepared extemporaneously. The solution was applied with occlusive dressing to upper or middle back for 24 h. Each subject received a single dose of 8.14 mg oral, 5 mg transdermal, and 10 mg transdermal (EMs only) latrepirdine free base in a fixed sequence. Twelve EMs and 7 PMs (50-79 years) enrolled and completed the study. Latrepirdine was well tolerated following both routes of administration. Dose-normalized latrepirdine total exposures were approximately 11-fold and 1.5-fold higher in EMs and PMs, respectively following administration of transdermal relative to oral. Differences between EM and PM latrepirdine exposures were decreased, with PMs having 1.9- and 2.7-fold higher peak and total exposures, respectively, following transdermal administration compared to 11- and 20-fold higher exposures, respectively, following oral administration. Transdermal delivery can potentially mitigate the large intersubject differences observed with compounds metabolized primarily by CYP2D6. Transdermal delivery was readily accomplished in the clinic using an extemporaneously prepared solution [NCT00990613].

Enantioselective penetration enhancing effect of carvone on the in vitro transdermal permeation of nicorandil.

PubMed

Krishnaiah, Yellela S R; Nada, Aly

2012-01-01

The objective was to investigate the difference in penetration enhancing effect of R-carvone, S-carvone and RS-carvone on the in vitro transdermal drug permeation. In vitro permeation studies were carried out across neonatal rat epidermis from 2%w/v HPMC (hydroxypropyl methylcellulose) gel containing 4%w/v of nicorandil (a model drug) and a selected concentration (12%w/v) of either R-carvone, S-carvone or RS-carvone against a control. The stratum corneum (SC) of rats was treated with vehicle (70%v/v ethanol-water) or ethanolic solutions of 12%w/v R-carvone, S-carvone or RS-carvone. The enhancement ratio (ER) of R-carvone, S-carvone and RS-carvone when compared to control was about 37.1, 31.2 and 29.9, respectively indicating enantioselective penetration enhancing effect of carvone enantiomers. Furthermore, there was a significant decrease in the lag time required to produce a steady-state flux of nicorandil with S-carvone when compared to R-carvone and RS-carvone. DSC and FT-IR studies indicate that the investigated enantiomers of carvone exhibit a difference in their ability to affect the cellular organization of SC lipids and proteins thereby showing enantioselective transdermal drug permeation. It was concluded that R-carvone exhibited a higher penetration enhancing activity on transdermal permeation of nicorandil when compared to its S-isomer or racemic mixture.

Hydrogel-thickened nanoemulsions based on essential oils for topical delivery of psoralen: Permeation and stability studies.

PubMed

Barradas, Thaís Nogueira; Senna, Juliana Perdiz; Cardoso, Stephani Araujo; Nicoli, Sara; Padula, Cristina; Santi, Patrizia; Rossi, Francesca; de Holanda E Silva, K Gyselle; Mansur, Claudia R Elias

2017-07-01

Nanoemulsions (NE) have attracted much attention due to their as dermal delivery systems for lipophilic drugs such as psoralens. However, NE feature low viscosity which might be unsuitable for topical application. In this work, we produced hydrogel-thickened nanoemulsions (HTN) using chitosan as thickening polymer to overcome the low viscosity attributed to NE. The aim of this study is to develop and characterize oil-in-water (o/w) HTN based on sweet fennel and clove essential oil to transdermal delivery of 8-methoxsalen (8-MOP). NE components (oil, surfactant) were selected on the basis of solubility and droplet size and processed in a high-pressure homogenizer (HPH). Drug loaded NE and HTN were characterized for particle size, stability under storage and centrifugation, rheological behavior, transdermal permeation and skin accumulation. Transdermal permeation of 8-MOP from HTN was determined by using Franz diffusion cell. Transdermal permeation from HTN using clove essential oil showed strong dependency chitosan molecular weight. On the other hand, HTN using sweet fennel oil showed an unexpected pH-dependent behavior not fully understood at the moment. These results need further investigation, nevertheless HTN revealed to be interesting and complex dermal delivery systems for poorly soluble drugs. Copyright © 2016. Published by Elsevier B.V.

Transdermal Drug Delivery: Innovative Pharmaceutical Developments Based on Disruption of the Barrier Properties of the stratum corneum

PubMed Central

Zaid Alkilani, Ahlam; McCrudden, Maelíosa T.C.; Donnelly, Ryan F.

2015-01-01

The skin offers an accessible and convenient site for the administration of medications. To this end, the field of transdermal drug delivery, aimed at developing safe and efficacious means of delivering medications across the skin, has in the past and continues to garner much time and investment with the continuous advancement of new and innovative approaches. This review details the progress and current status of the transdermal drug delivery field and describes numerous pharmaceutical developments which have been employed to overcome limitations associated with skin delivery systems. Advantages and disadvantages of the various approaches are detailed, commercially marketed products are highlighted and particular attention is paid to the emerging field of microneedle technologies. PMID:26506371

Comparison of transdermal diclofenac patch with oral diclofenac as an analgesic modality following multiple premolar extractions in orthodontic patients: A cross over efficacy trial

PubMed Central

Bhaskar, Hemant; Kapoor, Pranav; Ragini

2010-01-01

Aims: This study was performed to compare the degree of post operative analgesia, patient compliance, and frequency of adverse events with the use of oral diclofenac tablets and transdermal diclofenac patch following multiple premolar extractions in patients undergoing orthodontic treatment. Materials and Methods: Twenty young pre-orthodontic patients requiring bilateral maxillary and mandibular first premolar extractions were selected for the study. The right maxillary and mandibular first premolars were extracted first and 50 mg oral diclofenac sodium tablets were prescribed to be taken thrice a day for three days. In the next appointment, the contralateral first premolars were extracted and a 100 mg transdermal diclofenac patch was applied once a day for three days. Pain relief and pain intensity with both the diclofenac formulations was recorded for each of the three postoperative days using 5-point Verbal Pain Intensity and Pain Relief Score Charts. Results and Conclusions: Statistical analyses revealed that there was a gradual increase in pain relief scores and a gradual decrease in pain intensity scores with the use of oral diclofenac tablets as well as with the transdermal patch. However, subjects reported that they were more comfortable using the transdermal patch particularly due to the once-a-day application and lesser frequency of systemic adverse effects. Results of this study indicate that the transdermal diclofenac patch provides as potent analgesia as the oral diclofenac tablets with the added advantage of better patient compliance and may be used for routine post extraction analgesia. PMID:22114407

Taro corms mucilage/HPMC based transdermal patch: an efficient device for delivery of diltiazem hydrochloride.

PubMed

Sarkar, Gunjan; Saha, Nayan Ranjan; Roy, Indranil; Bhattacharyya, Amartya; Bose, Madhura; Mishra, Roshnara; Rana, Dipak; Bhattacharjee, Debashis; Chattopadhyay, Dipankar

2014-05-01

The aim of this work is to examine the effectiveness of mucilage/hydroxypropylmethylcellulose (HPMC) based transdermal patch (matrix type) as a drug delivery device. We have successfully extracted mucilage from Colocasia esculenta (Taro) corms and prepared diltiazem hydrochloride incorporated mucilage/HPMC based transdermal patches using various wt% of mucilage by the solvent evaporation technique. Characterization of both mucilage and transdermal patches has been done by several techniques such as Molisch's test, organoleptic evaluation of mucilage, mechanical, morphological and thermal analysis of transdermal patches. Skin irritation test is studied on hairless Albino rat skin showing that transdermal patches are apparently free of potentially hazardous skin irritation. Fourier transform infrared analysis shows that there is no interaction between drug, mucilage and HPMC while scanning electron microscopy shows the surface morphology of transdermal patches. In vitro drug release time of mucilage-HPMC based transdermal patches is prolonged with increasing mucilage concentration in the formulation. Copyright © 2014 Elsevier B.V. All rights reserved.

Nano-proniosomes enhancing the transdermal delivery of mefenamic acid.

PubMed

Wen, Ming Ming; Farid, Ragwa M; Kassem, Abeer A

2014-12-01

Mefenamic acid (MA) is a BCS II class NSAID drug. It is available only in the form of tablets, capsules, and pediatric suspensions. Oral administration of MA is associated with severe gastrointestinal side effects. The aim of this study was to develop a convenient and low-cost transdermal drug delivery system for MA using proniosome as a novel carrier without the addition of penetration enhancers. The formulation factors, such as the presence of cholesterol, types of lecithin, and surfactants were investigated for their influence on the entrapment efficiency, rate of hydration, vesicle size, and zeta potential, in vitro drug release and skin permeation in order to optimize the proniosomal formulations with the minimum dose of the drug. Furthermore, the in vivo anti-inflammatory effect was evaluated on a formalin-induced rat paw edema model. The results showed that the type of surfactants had higher impact on the entrapment efficiency than the type of lecithins, with the highest in Span 80 (82.84%). The release of MA from Span 80 proniosomal gel was significantly affected by the type of lecithin used. The addition of cholesterol significantly increased both the drug release and the skin permeation flux of MA. Zeta potential showed a stable A4 noisomal suspension. DSC revealed the molecular dispersion of MA into the loaded proniosomes. In vivo study of the treatment group with MA proniosome gel showed a significant inhibition of rat paw edema compared with the same gel without the drug (control). The results of this study suggest that proniosomes are promising nano vesicular carriers and safe alternatives to enhance the transdermal delivery of MA.

An update on the application of physical technologies to enhance intradermal and transdermal drug delivery.

PubMed

Herwadkar, Anushree; Banga, Ajay K

2012-03-01

A large number of biopharmaceuticals and other macromolecules are being developed for therapeutic applications. Conventional oral delivery is not always possible due to first-pass metabolism and degradation in the GI tract. Parenteral delivery is invasive and has poor patient compliance. Transdermal delivery provides one attractive route of administration. Transdermal administration can achieve the continuous and non-invasive delivery of drugs. However, passive transdermal delivery is restricted to small lipophilic molecules. Active physical-enhancement technologies are being investigated to increase the scope of transdermal delivery to hydrophilic molecules and macromolecules. Recent developments in transdermal technologies, such as microporation, iontophoresis and sonophoresis can enable therapeutic delivery of many drug molecules, biopharmaceuticals, cosmeceuticals and vaccines. This review provides an update of recent developments in transdermal delivery focusing on physical-enhancement technologies.

Chemistry, manufacturing and controls in passive transdermal drug delivery systems.

PubMed

Goswami, Tarun; Audett, Jay

2015-01-01

Transdermal drug delivery systems (TDDS) are used for the delivery of the drugs through the skin into the systemic circulation by applying them to the intact skin. The development of TDDS is a complex and multidisciplinary affair which involves identification of suitable drug, excipients and various other components. There have been numerous problems reported with respect to TDDS quality and performance. These problems can be reduced by appropriately addressing chemistry, manufacturing and controls requirements, which would thereby result in development of robust TDDS product and processes. This article provides recommendations on the chemistry, manufacturing and controls focusing on the unique technical aspects of TDDS.

Transdermal rivastigmine: management of cutaneous adverse events and review of the literature.

PubMed

Greenspoon, Jill; Herrmann, Nathan; Adam, David N

2011-07-01

Alzheimer's disease is a chronic neurodegenerative disorder resulting in part from the degeneration of cholinergic neurons in the brain. Rivastigmine, a cholinesterase inhibitor, is commonly used as a treatment for dementia due to its ability to moderate cholinergic neurotransmission; however, treatment with oral rivastigmine can lead to gastrointestinal adverse effects such as nausea and vomiting. Transdermal administration of rivastigmine can minimize these adverse effects by providing continuous delivery of the medication, while maintaining the effectiveness of the oral treatment. While the transdermal form of rivastigmine has been found to have fewer systemic adverse effects compared with the oral form, cutaneous reactions, such as contact dermatitis, can lead to discontinuation of the drug in its transdermal form. Lack of patient compliance with regard to applying the patch to the designated site, applying the patch for the correct length of time or rotating patch application sites increases the risk of cutaneous adverse reactions. This article outlines the diagnosis and management of irritant contact dermatitis and allergic contact dermatitis secondary to transdermal rivastigmine. The large majority of reactions to transdermal patches are of an irritant type, which can be diagnosed clinically by the presence of a pruritic, erythematous, eczematous plaque strictly confined to the borders of the patch. In contrast, an allergic reaction can be differentiated by the presence of vesicles and/or oedema, erythema beyond the boundaries of the transdermal patch and lack of improvement of the lesion 48 hours after removal of the offending treatment. By encouraging the patient to follow a regular rotation schedule for the patch, and using lipid-based emollients for irritant dermatitis and pre- and post-treatment topical corticosteroids for allergic dermatitis, cutaneous reactions can often be alleviated and patients can continue with their medication regimen. Other simple changes to a patient's treatment routine, including minimizing the use of harsh soaps, avoiding recently shaven or damaged areas of skin and carefully removing the patch after use, can help to further decrease the risk of dermatitis development.

Optimization of a jet-propelled particle injection system for the uniform transdermal delivery of drug/vaccine.

PubMed

Liu, Yi; Kendall, Mark A F

2007-08-01

A jet-propelled particle injection system, the biolistics, has been developed and employed to accelerate micro-particles for transdermal drug delivery. We have examined a prototype biolistic device employing a converging-diverging supersonic nozzle (CDSN), and found that the micro-particles were delivered with a wide velocity range (200-800 m/s) and spatial distribution. To provide a controllable system for transdermal drug delivery, we present a contoured shock-tube (CST) concept and its embodiment device. The CST configuration utilizes a quasi-steady, quasi-one dimensional and shock-free supersonic flow to deliver the micro-particles with an almost uniform velocity (the mean velocity and the standard deviation, 699 +/- 4.7 m/s) and spatial distribution. The transient gas and particle dynamics in both prototype devices are interrogated with the validated computational fluid dynamics (CFD) approach. The predicted results for static pressure and Mach number histories, gas flow structures, particle velocity distributions and gas-particle interactions are presented and interpreted. The implications for clinical uses are discussed. (c) 2007 Wiley Periodicals, Inc.

Rationalising polymer selection for supersaturated film forming systems produced by an aerosol spray for the transdermal delivery of methylphenidate.

PubMed

Edwards, A; Qi, S; Liu, F; Brown, M B; McAuley, W J

2017-05-01

Film forming systems offer a number of advantages for topical and transdermal drug delivery, in particular enabling production of a supersaturated state which can greatly improve drug absorption and bioavailability. However the suitability of individual film forming polymers to stabilise the supersaturated state and optimise delivery of drugs is not well understood. This study reports the use of differential scanning calorimetry (DSC) to measure the solubility of methylphenidate both as the free base and as the hydrochloride salt in two polymethacrylate copolymers, Eudragit RS (EuRS) and Eudragit E (EuE) and relates this to the ability of films formed using these polymers to deliver methylphenidate across a model membrane. EuRS provided greater methylphenidate delivery when the drug was formulated as the free base in comparison EuE because the lower solubility of the drug in EuRS provided a higher degree of drug saturation in the polymeric film. In contrast EuE provided greater delivery of methylphenidate hydrochloride as EuRS could not prevent its crystallisation from a supersaturated state. Methylphenidate flux across the membrane could be directly related to degree of saturation of the drug in the film formulation as estimated by the drug solubility in the individual polymers demonstrating the importance of drug solubility in the polymer included in film forming systems for topical/transdermal drug delivery. In addition DSC has been demonstrated to be a useful tool for determining the solubility of drugs in polymers used in film forming systems and the approaches outlined here are likely to be useful for predicting the suitability of polymers for particular drugs in film forming transdermal drug delivery systems. Copyright © 2017. Published by Elsevier B.V.

Fractional Ablative Laser Followed by Transdermal Acoustic Pressure Wave Device to Enhance the Drug Delivery of Aminolevulinic Acid: In Vivo Fluorescence Microscopy Study.

PubMed

Waibel, Jill S; Rudnick, Ashley; Nousari, Carlos; Bhanusali, Dhaval G

2016-01-01

Topical drug delivery is the foundation of all dermatological therapy. Laser-assisted drug delivery (LAD) using fractional ablative laser is an evolving modality that may allow for a greater precise depth of penetration by existing topical medications, as well as more efficient transcutaneous delivery of large drug molecules. Additional studies need to be performed using energy-driven methods that may enhance drug delivery in a synergistic manner. Processes such as iontophoresis, electroporation, sonophoresis, and the use of photomechanical waves aid in penetration. This study evaluated in vivo if there is increased efficacy of fractional CO2 ablative laser with immediate acoustic pressure wave device. Five patients were treated and biopsied at 4 treatment sites: 1) topically applied aminolevulinic acid (ALA) alone; 2) fractional ablative CO2 laser and topical ALA alone; 3) fractional ablative CO2 laser and transdermal acoustic pressure wave device delivery system; and 4) topical ALA with transdermal delivery system. The comparison of the difference in the magnitude of diffusion with both lateral spread of ALA and depth diffusion of ALA was measured by fluorescence microscopy. For fractional ablative CO2 laser, ALA, and transdermal acoustic pressure wave device, the protoporphyrin IX lateral fluorescence was 0.024 mm on average vs 0.0084 mm for fractional ablative CO2 laser and ALA alone. The diffusion for the acoustic pressure wave device was an order of magnitude greater. We found that our combined approach of fractional ablative CO2 laser paired with the transdermal acoustic pressure wave device increased the depth of penetration of ALA.

Microneedle-based drug delivery systems for transdermal route.

PubMed

Pierre, Maria Bernadete Riemma; Rossetti, Fabia Cristina

2014-03-01

Transdermal delivery offers an attractive, noninvasive administration route but it is limited by the skin's barrier to penetration. Minimally invasive techniques, such as the use of microneedles (MNs), bypass the stratum corneum (SC) barrier to permit the drug's direct access to the viable epidermis. These novel micro devices have been developed to puncture the skin for the transdermal delivery of hydrophilic drugs and macromolecules, including peptides, DNA and other molecules, that would otherwise have difficulty passing the outermost layer of the skin, the SC. Using the tools of the microelectronics industry, MNs have been fabricated with a range of sizes, shapes and materials. MNs have been shown to be robust enough to penetrate the skin and dramatically increase the skin permeability of several drugs. Moreover, MNs have reduced needle insertion pain and tissue trauma and provided controlled delivery across the skin. This review focuses on the current state of the art in the transdermal delivery of drugs using various types of MNs and developments in the field of microscale devices, as well as examples of their uses and clinical safety.

Photoacoustic study of percutaneous absorption of Carbopol and transdermic gels for topic use in skin

NASA Astrophysics Data System (ADS)

Rossi, R. C. P.; de Paiva, R. F.; da Silva, M. D.; Barja, P. R.

2008-01-01

Topical medicine application has been used to treat a good number of pathological processes. Its efficacy is associated to an efficient penetration of the drug in the internal skin layers, promoting systemic effects and excluding the possibility of drug degradation by the digestive tract and hepatic elimination. This work analyzes the penetration kinetics of two soluble bases employed as vehicles for topic application: superficial gel (Carbopol 940) and transdermic (transdermal) gel. Analysis was performed with the photoacoustic technique, based upon the absorption of modulated light by a sample with subsequent conversion of the absorbed energy in heat, generating acoustic waves in the air layer adjacent to the sample. Each of the two vehicles was evaluated through in vivo (human skin) and in vitro application. Measurements in vitro employed samples of VitroSkin (synthetic material with properties similar to those of real skin, employed in the pharmaceutical industry research). Results show that the permeation was faster for the transdermal gel, both for in vivo and in vitro measurements, indicating that in vitro measurements may be utilized in qualitative, comparative permeation studies.

Transdermal optogenetic peripheral nerve stimulation

NASA Astrophysics Data System (ADS)

Maimon, Benjamin E.; Zorzos, Anthony N.; Bendell, Rhys; Harding, Alexander; Fahmi, Mina; Srinivasan, Shriya; Calvaresi, Peter; Herr, Hugh M.

2017-06-01

Objective: A fundamental limitation in both the scientific utility and clinical translation of peripheral nerve optogenetic technologies is the optical inaccessibility of the target nerve due to the significant scattering and absorption of light in biological tissues. To date, illuminating deep nerve targets has required implantable optical sources, including fiber-optic and LED-based systems, both of which have significant drawbacks. Approach: Here we report an alternative approach involving transdermal illumination. Utilizing an intramuscular injection of ultra-high concentration AAV6-hSyn-ChR2-EYFP in rats. Main results: We demonstrate transdermal stimulation of motor nerves at 4.4 mm and 1.9 mm depth with an incident laser power of 160 mW and 10 mW, respectively. Furthermore, we employ this technique to accurately control ankle position by modulating laser power or position on the skin surface. Significance: These results have the potential to enable future scientific optogenetic studies of pathologies implicated in the peripheral nervous system for awake, freely-moving animals, as well as a basis for future clinical studies.

Management of chemotherapy-induced nausea and vomiting in patients receiving multiple-day highly or moderately emetogenic chemotherapy: role of transdermal granisetron.

PubMed

Coluzzi, Flaminia; Mattia, Consalvo

2016-08-01

Granisetron transdermal delivery system (GTDS) is the first 5-HT3 drug to be transdermally delivered and represents a convenient alternative to oral and intravenous antiemetics for the treatment of chemotherapy-induced nausea and vomiting. GTDS is effective and well tolerated in patients receiving multiple-day moderate-to-highly emetogenic chemotherapy. In this setting noninferiority studies showed similar efficacy when GTDS was compared with intravenous and oral granisetron and intravenous palonosetron. GTDS has shown good cardiovascular safety; however, special caution is needed in patients at risk for developing excessive QTc interval prolongation and arrhythmias. So far, GTDS has been investigated for intravenous prevention in comparison with granisetron and palonosetron; however, further prospects open the route to future clinical investigations.

Current advances in transdermal delivery of drugs for Alzheimer's disease.

PubMed

Nguyen, Thuy Trang; Giau, Vo Van; Vo, Tuong Kha

2017-01-01

Alzheimer's disease (AD) is a common, progressive, fatal neurodegenerative disorder, which will play an increasingly important role both socially and financially in the aging populations. Treatments for AD show modest improvements in cognition and global functioning among patients. Furthermore, the oral administration of treating AD has had some drawbacks that decrease the medication adherence and efficacy of the therapy. Transdermal drugs are proposed as an alternative remedy to overcome the disadvantages of current pharmaceutical dosage options for this chronic disorder. They could have different strengths, such as offering a stable diffusion of active substance, avoiding the first pass metabolism, and reducing system adverse reactions. This article reviews the technical principles, novel techniques of transdermal delivery drug, and prospects for future development for the management of cognitive and behavioral dysfunctions in AD patients.

Design, formulation and optimization of valsartan transdermal gel containing iso-eucalyptol as novel permeation enhancer: preclinical assessment of pharmacokinetics in Wistar albino rats.

PubMed

Ahad, Abdul; Aqil, Mohd; Kohli, Kanchan; Sultana, Yasmin; Mujeeb, Mohd

2014-08-01

The aim of this study was to develop and optimize a transdermal gel formulation of valsartan using Box-Behnken design and to evaluate it for pharmacokinetic study. The independent variables were Carbopol 940 (X1), PEG 400 (X2) and ethanol (X3) while valsartan flux (Y1), Tlag (Y2) and gel viscosity (Y3) were the dependent variables. Iso-eucalyptol was added in all gel formulations as permeation enhancer except for control gel. It was observed that the permeation rate of valsartan significantly increased in direct proportion to the ethanol concentration, but significantly decreased in direct proportion to polymer concentration. Lag time and viscosity decreased in reverse proportion to ethanol concentration. The optimized valsartan gel formulation (VGF-OPT) yielded flux of 143.27 ± 7.11 µg/cm(2)/h and 27.55 ± 2.51 µg/cm(2)/h across rat and human cadaver skin, respectively. In vivo pharmacokinetic study of VGF-OPT-transdermal therapeutic system containing iso-eucalyptol showed a significant increase in the bioavailability (2.52 times) compared with oral formulation of valsartan by virtue of better permeation through Wistar rat skin. It was concluded that the developed transdermal gel accentuates the flux of valsartan and could be used as an antihypertensive dosage form for effective transdermal delivery of valsartan.

Recent developments in skin mimic systems to predict transdermal permeation.

PubMed

Waters, Laura J

2015-01-01

In recent years there has been a drive to create experimental techniques that can facilitate the accurate and precise prediction of transdermal permeation without the use of in vivo studies. This review considers why permeation data is essential, provides a brief summary as to how skin acts as a natural barrier to permeation and discusses why in vivo studies are undesirable. This is followed by an in-depth discussion on the extensive range of alternative methods that have been developed in recent years. All of the major 'skin mimic systems' are considered including: in vitro models using synthetic membranes, mathematical models including quantitative structure-permeability relationships (QSPRs), human skin equivalents and chromatographic based methods. All of these model based systems are ideally trying to achieve the same end-point, namely a reliable in vitro-in vivo correlation, i.e. matching non-in vivo obtained data with that from human clinical trials. It is only by achieving this aim, that any new method of obtaining permeation data can be acknowledged as a potential replacement for animal studies, for the determination of transdermal permeation. In this review, the relevance and potential applicability of the various models systems will also be discussed.

TRANSDERMAL NITROGLYCERIN FOR THE TREATMENT OF PRETERM LABOR: A SYSTEMATIC REVIEW AND META-ANALYSIS

PubMed Central

CONDE-AGUDELO, Agustín; ROMERO, Roberto

2014-01-01

OBJECTIVE To evaluate the efficacy and safety of transdermal nitroglycerin as tocolytic agent in women with preterm labor. STUDY DESIGN Systematic review and meta-analysis of randomized controlled trials. RESULTS Thirteen studies (1302 women) were included. Two studies evaluated transdermal nitroglycerin versus placebo (N=186), 9 evaluated transdermal nitroglycerin versus β2-adrenergic-receptor agonists (N=1024), and 1 each evaluated transdermal nitroglycerin versus nifedipine (N=50) and transdermal nitroglycerin versus magnesium sulfate (N=42). There were no significant differences between transdermal nitroglycerin and placebo for delivery within 48 hours of initiation of treatment or before 28, 34 or 37 weeks’ gestation, adverse neonatal outcomes, and neurodevelopmental status at 24 months of age. Nevertheless, one study found a marginally significant reduction in the risk of a composite outcome of significant neonatal morbidity and perinatal mortality (3/74 [4.1%] versus 11/79 [13.9%]; relative risk 0.29, 95% confidence interval 0.08–1.00). When compared with β2-adrenergic-receptor agonists, transdermal nitroglycerin was associated with a significant reduction in the risk of preterm birth <34 and <37 weeks’ gestation, admission to the neonatal intensive care unit, use of mechanical ventilation, and maternal side effects. There were no significant differences between transdermal nitroglycerin and nifedipine and magnesium sulfate in delivery within 48 hours of treatment and pregnancy prolongation, respectively. Overall, women receiving transdermal nitroglycerin had a higher risk of headache. CONCLUSION Although transdermal nitroglycerin appears to be more effective than β 2-adrenergic-receptor agonists, the current evidence does not support its routine use as tocolytic agent for the treatment of preterm labor. Further additional double-blind placebo-controlled trials are needed. PMID:23891631

Development of an Injectable Salmon Fibrinogen-Thrombin Matrix to Enhance Healing of Compound Fractures of Extremities

DTIC Science & Technology

2012-09-01

first responder. Many factors may contribute to non-union of fractures, including nutritional or hormonal status, age of the patient, and presence of...of transdermal 420 fentanyl (100 µg/h) in Yucatan minipigs, plasma fentanyl concentration peaked within 48 hours, 421 with peak concentrations...3rd, Morse BC. 2001. Evaluation of a transdermal fentanyl system in 612 yucatan miniature pigs. Contemp Top Lab Anim Sci 40:12-16. 613 50. Wolfe

In Vitro Drug Transfer Due to Drug Retention in Human Epidermis Pretreated with Application of Marketed Estradiol Transdermal Systems.

PubMed

Krishnaiah, Yellela S R; Pavurala, Naresh; Yang, Yang; Manda, Prashanth; Katragadda, Usha; Yang, Yongsheng; Shah, Rakhi; Fang, Guodong; Khan, Mansoor A

2017-08-01

Study objective was to assess skin-to-skin drug transfer potential that may occur due to drug retention in human epidermis (DRE) pretreated with application of estradiol transdermal drug delivery systems (TDDS) and other estradiol transdermal dosage forms (gels and sprays). TDDS (products-A, B, and C) with varying formulation design and composition, and other estradiol transdermal products (gel and spray) were applied to heat separated human epidermis (HSE) and subjected to in vitro drug permeation study. Amounts of DRE were quantified after 24 h. The DRE with product-B was significantly (P < 0.001) higher than that with product-C, product-A, gel, and spray. However, products-A and C, gel, and spray showed almost the same (P > 0.05) amounts of DRE. A separate in vitro permeation study was carried out to determine amounts of drug transferred from drug-retaining epidermis to untreated HSE. The amounts of drug transferred, due to DRE after 8 h, with product-C were significantly (P < 0.001) higher than those with products-A and B, gel, and spray. The in vitro study results indicate a high potential of skin-to-skin drug transfer due to the DRE after labeled period of using estradiol TDDS, though the clinical relevance of these findings is yet to be determined.

Rheology-A pre-formulation tool for evaluating mechanical and thermal properties of transdermal formulations

NASA Astrophysics Data System (ADS)

Modi, Nisarg

Rheological characterization of pharmaceutical gel is of importance as it provides fundamental information required for the assessment of some of the final properties of a product such as viscosity, elasticity, quality and physical storage stability. The effect of formulation and process variables on product characteristics such as consistency, drug release, and physical stability can also be attained. Moreover, some of the transdermal patch problems such as leaking from reservoir patch or cold flow in matrix patch can also be estimated using rheological characterization. During this research, various tests were employed to characterize the mechanical properties of gel such as oscillation test (Frequency and Amplitude Sweep), flow and viscosity curves and yield point measurements, as well as temperature sweep and temperature ramp test. The present studies evaluate rheological properties of hydroxypropyl cellulose (Klucel HF) gels prepared containing fatty acids with different carbon chain length at different homogenization speed. A controlled stress rheometer was used to study the effect of different number of carbon chain fatty acids, homogenization speed and storage period on the rheological properties and microstructure of transdermal gels. The studies demonstrated that as the carbon chain length increased (C10-C 18) the thixotropic area decreased, which suggested that the stability of gel structure was increased with increase in carbon chain of fatty acids. Cohesive Energy was affected by the homogenization speed and carbon chain of fatty acids. There was decreased in cohesive energy as increase in carbon chain of fatty acids. Temperature sweep data revealed that gels prepared with oleic acid (C18) at 25000 RPM gave the best thermal stability after the longest storage period (60-Days) compare to the capric(C10) acid and Lauirc (C12) acid. There was only 31% decreased in temperature loop area for oleic (C18) acid as compare to 54% and 86% for capric (C10) acid and lauric acid (C12) respectively. During different mixing speeds at initial time period (t=0), oleic acid showed lowest temperature loop area, which was not affected by storage period. Furthermore, by applying power law model to frequency sweep data, mechanical propereties of transdermal gels were evaluated. Transdermal gels are "physical gels" in nature which showed both frequency dependency and also had a cross-over point. Moreover, the value of n is less than 1. Time Temperature superposition principle can apply to the rheological data of Transdermal gels to obtain the thermal properties of formulations. Thermal properties of transdermal gels are very difficult to measure using traditional DSC equipment. By applying TTS principle, frequency sweep data were obtained between 5-50 °C and extrapolated to achieve the glass transition temperature, free volume and thermal expansion co-efficient of the formulations. Last but not least, In-vitro studies using human cadaver skin showed that Capric acid is the best permeability enhancing agent for escitalopram oxalate in current formulations. Furthermore, increase in carbon chain length of fatty acids decreased the permeability enhancing effect of Escitalopram Oxalate through human cadaver skin during In-vitro diffusion studies.

Structure-activity relationship of chemical penetration enhancers in transdermal drug delivery.

PubMed

Kanikkannan, N; Kandimalla, K; Lamba, S S; Singh, M

2000-06-01

Transdermal drug delivery (TDD) is the administration of therapeutic agents through intact skin for systemic effect. TDD offers several advantages over the conventional dosage forms such as tablets, capsules and injections. Currently there are about eight drugs marketed as transdermal patches. Examples of such products include nitroglycerin (angina pectoris), clonidine (hypertension), scopolamine (motion sickness), nicotine (smoking cessation), fentanil (pain) and estradiol (estrogen deficiency). Since skin is an excellent barrier for drug transport, only potent drugs with appropriate physicochemical properties (low molecular weight, adequate solubility in aqueous and non-aqueous solvents, etc) are suitable candidates for transdermal delivery. Penetration enhancement technology is a challenging development that would increase significantly the number of drugs available for transdermal administration. The permeation of drugs through skin can be enhanced by physical methods such as iontophoresis (application of low level electric current) and phonophoresis (use of ultra sound energy) and by chemical penetration enhancers (CPE). In this review, we have discussed about the CPE which have been investigated for TDD. CPE are compounds that enhance the permeation of drugs across the skin. The CPE increase skin permeability by reversibly altering the physicochemical nature of the stratum corneum, the outer most layer of skin, to reduce its diffusional resistance. These compounds increase skin permeability also by increasing the partition coefficient of the drug into the skin and by increasing the thermodynamic activity of the drug in the vehicle. This review compiles the various CPE used for the enhancement of TDD, the mechanism of action of different chemical enhancers and the structure-activity relationship of selected and extensively studied enhancers such as fatty acids, fatty alcohols and terpenes. Based on the chemical structure of penetration enhancers (such as chain length, polarity, level of unsaturation and presence of some special groups such as ketones), the interaction between the stratum corneum and penetration enhancers may vary which will result in significant differences in penetration enhancement. Our review also discusses the various factors to be considered in the selection of an appropriate penetration enhancer for the development of transdermal delivery systems.

Nicotine patches improve mood and response speed in a lexical decision task.

PubMed

Gentry, M V; Hammersley, J J; Hale, C R; Nuwer, P K; Meliska, C J

2000-01-01

The effects of smoking a cigarette or wearing a transdermal nicotine patch on mood and lexical decision-making were tested in eight smokers. Each participant was tested after 4 hours of smoking abstinence, under 4 conditions: placebo (very low nicotine) cigarette, nicotine cigarette, placebo patch, and nicotine patch. Relative to placebo, wearing the nicotine patch reduced Profile of Mood States (POMS) Total Mood Disturbance and Fatigue/Inertia scores, while increasing the speed of some types of lexical decisions. Smoking a nicotine cigarette did not affect reaction times, but unexpectedly decreased the accuracy of Word/ Nonword lexical decisions. Thus, transdermal nicotine may improve mood and facilitate longterm memory search and/or attentional processes in nicotine-deprived smokers.

Pluronic® F-127 and Pluronic Lecithin Organogel (PLO): main features and their applications in topical and transdermal administration of drugs.

PubMed

Almeida, Hugo; Amaral, Maria Helena; Lobão, Paulo; Lobo, José Manuel Sousa

2012-01-01

Topical drug treatment aims at providing high concentrations of drugs at the site of application so as to avoid adverse systemic effects associated with oral administration. Smart polymers, or stimuli-responsive polymers, are able to respond to a stimulus by showing physical or chemical changes in their behaviour as, for example, the delivery of the drug carried by them. The thermo-responsive nature of Pluronic® F-127 (Basf, Ludwigshafen, Germany) makes it an excellent candidate for the delivery of drugs at various application sites. In recent years, PF-127, and later, Pluronic lecithin organogels (PLO), have attracted particular interest in the design of dermal and transdermal delivery systems with a view to promoting, improving or retarding drug permeation through the skin, bearing in mind that for topical delivery systems, accumulation in the skin with minimal permeation is desired, while for systemic delivery, the opposite behaviour is preferred. In this review, we discuss the properties and characteristics of PF-127 and Pluronic lecithin organogels (PLO), and present many examples and advantages of the application of these polymeric systems in topical and transdermal administration of drugs. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

The role of surfactants in the formulation of elastic liposomal gels containing a synthetic opioid analgesic.

PubMed

Singh, Sima; Vardhan, Harsh; Kotla, Niranjan G; Maddiboyina, Balaji; Sharma, Dinesh; Webster, Thomas J

2016-01-01

Transdermal drug delivery systems have made significant contributions to the medical community, but have yet to completely substitute oral or parenteral delivery. Recently, various strategies have been used to augment the transdermal delivery of therapeutics. Primarily, they include iontophoresis, electrophoresis, sonophoresis, chemical permeation enhancers, microneedles, and vesicular systems. Among these strategies, elastic liposomes appear promising. Elastic vesicle scaffolds have been developed and evaluated as novel topical and transdermal delivery systems, with an infrastructure consisting of hydrophobic and hydrophilic moieties together, and as a result, such scaffolds can accommodate drug molecules with a wide range of solubility. High deformability of these vesicles provides for better penetration of intact vesicles. This system is much more efficient at delivering low- and high-molecular-weight drugs to the skin in terms of quantity and depth. In this work, elastic liposomes of Tramadol HCl were prepared using a solvent evaporation method with different surfactants and were characterized using microscopy, and particle size, shape, drug content, ex vivo release, and zeta potential were also calculated. The prepared elastic liposomes were found to be in the range of 152.4 nm with a zeta potential of -22.4 mV; the entrapment efficiencies of the selected formulation was found to be 79.71%±0.27%. All formulations in the form of a gel were evaluated for physicochemical properties and were found to be homogeneous with no grittiness, and the pH of all formulations was found to be neutral. The optimized selected elastic liposomal formulation followed the Higuchi equation and Fickian diffusion and released the drug for a period of 24 hours. The overall results provide much promise for the continued investigation of deformable vesicles as transdermal drug carriers.

The role of surfactants in the formulation of elastic liposomal gels containing a synthetic opioid analgesic

PubMed Central

Singh, Sima; Vardhan, Harsh; Kotla, Niranjan G; Maddiboyina, Balaji; Sharma, Dinesh; Webster, Thomas J

2016-01-01

Transdermal drug delivery systems have made significant contributions to the medical community, but have yet to completely substitute oral or parenteral delivery. Recently, various strategies have been used to augment the transdermal delivery of therapeutics. Primarily, they include iontophoresis, electrophoresis, sonophoresis, chemical permeation enhancers, microneedles, and vesicular systems. Among these strategies, elastic liposomes appear promising. Elastic vesicle scaffolds have been developed and evaluated as novel topical and transdermal delivery systems, with an infrastructure consisting of hydrophobic and hydrophilic moieties together, and as a result, such scaffolds can accommodate drug molecules with a wide range of solubility. High deformability of these vesicles provides for better penetration of intact vesicles. This system is much more efficient at delivering low- and high-molecular-weight drugs to the skin in terms of quantity and depth. In this work, elastic liposomes of Tramadol HCl were prepared using a solvent evaporation method with different surfactants and were characterized using microscopy, and particle size, shape, drug content, ex vivo release, and zeta potential were also calculated. The prepared elastic liposomes were found to be in the range of 152.4 nm with a zeta potential of −22.4 mV; the entrapment efficiencies of the selected formulation was found to be 79.71%±0.27%. All formulations in the form of a gel were evaluated for physicochemical properties and were found to be homogeneous with no grittiness, and the pH of all formulations was found to be neutral. The optimized selected elastic liposomal formulation followed the Higuchi equation and Fickian diffusion and released the drug for a period of 24 hours. The overall results provide much promise for the continued investigation of deformable vesicles as transdermal drug carriers. PMID:27114707

Treatment with subcutaneous and transdermal fentanyl: results from a population pharmacokinetic study in cancer patients.

PubMed

Oosten, Astrid W; Abrantes, João A; Jönsson, Siv; de Bruijn, Peter; Kuip, Evelien J M; Falcão, Amílcar; van der Rijt, Carin C D; Mathijssen, Ron H J

2016-04-01

Transdermal fentanyl is effective for the treatment of moderate to severe cancer-related pain but is unsuitable for fast titration. In this setting, continuous subcutaneous fentanyl may be used. As data on the pharmacokinetics of continuous subcutaneous fentanyl are lacking, we studied the pharmacokinetics of subcutaneous and transdermal fentanyl. Furthermore, we evaluated rotations from the subcutaneous to the transdermal route. Fifty-two patients treated with subcutaneous and/or transdermal fentanyl for moderate to severe cancer-related pain participated. A population pharmacokinetic model was developed and evaluated using non-linear mixed-effects modelling. For rotations from subcutaneous to transdermal fentanyl, a 1:1 dose conversion ratio was used while the subcutaneous infusion was continued for 12 h (with a 50 % tapering after 6 h). A 6-h scheme with 50 % tapering after 3 h was simulated using the final model. A one-compartment model with first-order elimination and separate first-order absorption processes for each route adequately described the data. The estimated apparent clearance of fentanyl was 49.6 L/h; the absorption rate constant for subcutaneous and transdermal fentanyl was 0.0358 and 0.0135 h(-1), respectively. Moderate to large inter-individual and inter-occasion variability was found. Around rotation from subcutaneous to transdermal fentanyl, measured and simulated plasma fentanyl concentrations rose and increasing side effects were observed. We describe the pharmacokinetics of subcutaneous and transdermal fentanyl in one patient cohort and report several findings that are relevant for clinical practice. Further research is warranted to study the optimal scheme for rotations from the subcutaneous to the transdermal route.

Machine learning study for the prediction of transdermal peptide

NASA Astrophysics Data System (ADS)

Jung, Eunkyoung; Choi, Seung-Hoon; Lee, Nam Kyung; Kang, Sang-Kee; Choi, Yun-Jaie; Shin, Jae-Min; Choi, Kihang; Jung, Dong Hyun

2011-04-01

In order to develop a computational method to rapidly evaluate transdermal peptides, we report approaches for predicting the transdermal activity of peptides on the basis of peptide sequence information using Artificial Neural Network (ANN), Partial Least Squares (PLS) and Support Vector Machine (SVM). We identified 269 transdermal peptides by the phage display technique and use them as the positive controls to develop and test machine learning models. Combinations of three descriptors with neural network architectures, the number of latent variables and the kernel functions are tried in training to make appropriate predictions. The capacity of models is evaluated by means of statistical indicators including sensitivity, specificity, and the area under the receiver operating characteristic curve (ROC score). In the ROC score-based comparison, three methods proved capable of providing a reasonable prediction of transdermal peptide. The best result is obtained by SVM model with a radial basis function and VHSE descriptors. The results indicate that it is possible to discriminate between transdermal peptides and random sequences using our models. We anticipate that our models will be applicable to prediction of transdermal peptide for large peptide database for facilitating efficient transdermal drug delivery through intact skin.

Engineering approaches to transdermal drug delivery: a tribute to contributions of prof. Robert Langer.

PubMed

Mitragotri, S

2013-01-01

Transdermal drug delivery continues to provide an advantageous route of drug administration over injections. While the number of drugs delivered by passive transdermal patches has increased over the years, no macromolecule is currently delivered by the transdermal route. Substantial research efforts have been dedicated by a large number of researchers representing varied disciplines including biology, chemistry, pharmaceutics and engineering to understand, model and overcome the skin's barrier properties. This article focuses on engineering contributions to the field of transdermal drug delivery. The article pays tribute to Prof. Robert Langer, who pioneered the engineering approach towards transdermal drug delivery. Over a period spanning nearly 25 years since his first publication in the field of transdermal drug delivery, Bob Langer has deeply impacted the field by quantitative analysis and innovative engineering. At the same time, he has inspired several generations of engineers by collaborations and mentorship. His scientific insights, innovative technologies, translational efforts and dedicated mentorship have transformed the field. © 2013 S. Karger AG, Basel.

Current advances in transdermal delivery of drugs for Alzheimer's disease

PubMed Central

Nguyen, Thuy Trang; Giau, Vo Van; Vo, Tuong Kha

2017-01-01

Alzheimer's disease (AD) is a common, progressive, fatal neurodegenerative disorder, which will play an increasingly important role both socially and financially in the aging populations. Treatments for AD show modest improvements in cognition and global functioning among patients. Furthermore, the oral administration of treating AD has had some drawbacks that decrease the medication adherence and efficacy of the therapy. Transdermal drugs are proposed as an alternative remedy to overcome the disadvantages of current pharmaceutical dosage options for this chronic disorder. They could have different strengths, such as offering a stable diffusion of active substance, avoiding the first pass metabolism, and reducing system adverse reactions. This article reviews the technical principles, novel techniques of transdermal delivery drug, and prospects for future development for the management of cognitive and behavioral dysfunctions in AD patients. PMID:28706327

Chemical Leukoderma Associated with Methylphenidate Transdermal System: Data From the US Food and Drug Administration Adverse Event Reporting System.

PubMed

Cheng, Carmen; La Grenade, Lois; Diak, Ida-Lina; Brinker, Allen; Levin, Robert L

2017-01-01

To identify and characterize cases of chemical leukoderma, an underrecognized adverse event, associated with the methylphenidate transdermal system (MTS) reported to the US Food and Drug Administration Adverse Event Reporting System (FAERS). We searched the Food and Drug Administration Adverse Event Reporting System for reports of chemical leukoderma associated with MTS, received by the Food and Drug Administration from April 6, 2006 to December 23, 2014. We identified 51 cases of chemical leukoderma reported with the use of MTS. The median age was 11 years; 43 cases reported leukoderma at or near the application site only, and 7 reported leukoderma at other parts of the body in addition to the application site; 1 case did not provide enough information to confirm the affected site. The time to onset ranged from 2 months to 4 years after the initiation of MTS. MTS was discontinued in 31 cases. Thirteen patients were prescribed treatment for repigmentation. Three cases reported continued spread of leukoderma after MTS was discontinued. Nineteen cases were diagnosed as vitiligo, including 5 cases reporting histologic features consistent with vitiligo. Leukoderma was persistent in all cases. The median follow-up interval after the discontinuation of MTS in 23 cases was 14 months. As outlined in recent changes to the prescribing information for MTS, health care professionals need to be aware of the potential risk of chemical leukoderma caused by MTS, especially given that chemical leukoderma is often misdiagnosed as idiopathic vitiligo. MTS should be discontinued at the earliest sign of pigment loss and other treatment options considered. Published by Elsevier Inc.

Pharmacokinetics of a granisetron transdermal system for the treatment of chemotherapy-induced nausea and vomiting.

PubMed

Howell, Julian; Smeets, Jean; Drenth, Henk-Jan; Gill, David

2009-12-01

To determine the pharmacokinetic (PK) profile of granisetron transdermal formulation and examine its possible relationship with age, gender, and renal function. This article describes a Phase I PK study and a post hoc pooled population PK analysis. The Phase I study was a randomized, cross-over study that assessed PK parameters of three granisetron patch sizes and oral granisetron. The pooled population PK analysis included data from three trials in healthy subjects (n = 48) and from Phase II and III studies in patients with cancer (n = 793). The population PK model was used to investigate granisetron exposure and its possible relationship with age, gender, and renal function. Following oral dosing, plasma granisetron concentration was quantifiable at 1 h, and maximal mean concentration (4.7 ng/mL) was reached 2 h after administration. With transdermal application, maximal concentration was reached 48 h post-application; t(1/2) was 36 h. With oral dosing, overall exposure after 5 days was 306 ng/mL.h, and C(avg) 2.6 ng/mL. This corresponded to an AUC(0-infinity) for the 52 cm(2) patch of 420 ng/mL.h and C(avg) 2.2 ng/mL over 6 days. Clearance was not affected by age, gender, weight, or renal function. The 52 cm( 2) granisetron patch achieves a similar exposure to that of a 2 mg oral dose and provides continuous delivery of granisetron over 6 days. The patch may have utility in treating chemotherapy-induced nausea and vomiting where prolonged drug delivery is advantageous. No dose adjustments would be needed based on age or renal function.

P-Glycoprotein in skin contributes to transdermal absorption of topical corticosteroids.

PubMed

Hashimoto, Naoto; Nakamichi, Noritaka; Yamazaki, Erina; Oikawa, Masashi; Masuo, Yusuke; Schinkel, Alfred H; Kato, Yukio

2017-04-15

ATP binding cassette transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), are expressed in skin, but their involvement in transdermal absorption of clinically used drugs remains unknown. Here, we examined their role in transdermal absorption of corticosteroids. Skin and plasma concentrations of dexamethasone after dermal application were reduced in P-gp and BCRP triple-knockout (Mdr1a/1b/Bcrp -/- ) mice. The skin concentration in Mdr1a/1b/Bcrp -/- mice was reduced in the dermis, but not in the epidermis, indicating that functional expression of these transporters in skin is compartmentalized. Involvement of these transporters in dermal transport of dexamethasone was also supported by the observation of a higher epidermal concentration in Mdr1a/1b/Bcrp -/- than wild-type mice during intravenous infusion. Transdermal absorption after dermal application of prednisolone, but not methylprednisolone or ethinyl estradiol, was also lower in Mdr1a/1b/Bcrp -/- than in wild-type mice. Transport studies in epithelial cell lines transfected with P-gp or BCRP showed that dexamethasone and prednisolone are substrates of P-gp, but are minimally transported by BCRP. Thus, our findings suggest that P-gp is involved in transdermal absorption of at least some corticosteroids in vivo. P-gp might be available as a target for inhibition in order to deliver topically applied drugs and cosmetics in a manner that minimizes systemic exposure. Copyright © 2017 Elsevier B.V. All rights reserved.

Estradiol Transdermal Patch

MedlinePlus

Most brands of estradiol transdermal patches are used to treat hot flushes (hot flashes; sudden strong feelings of heat ... different medication that does not contain estrogen. Most brands of estradiol transdermal patches are also sometimes used ...

Iontophoretic transdermal drug delivery: a multi-layered approach.

PubMed

Pontrelli, Giuseppe; Lauricella, Marco; Ferreira, José A; Pena, Gonçalo

2017-12-11

We present a multi-layer mathematical model to describe the transdermal drug release from an iontophoretic system. The Nernst-Planck equation describes the basic convection-diffusion process, with the electric potential obtained by solving the Laplace's equation. These equations are complemented with suitable interface and boundary conditions in a multi-domain. The stability of the mathematical problem is discussed in different scenarios and a finite-difference method is used to solve the coupled system. Numerical experiments are included to illustrate the drug dynamics under different conditions. © The authors 2016. Published by Oxford University Press on behalf of the Institute of Mathematics and its Applications. All rights reserved.

Hydrogels containing redispersible spray-dried melatonin-loaded nanocapsules: a formulation for transdermal-controlled delivery

NASA Astrophysics Data System (ADS)

Hoffmeister, Cristiane RD; Durli, Taís L.; Schaffazick, Scheila R.; Raffin, Renata P.; Bender, Eduardo A.; Beck, Ruy CR; Pohlmann, Adriana R.; Guterres, Sílvia S.

2012-05-01

The aim of the present study was to develop a transdermal system for controlled delivery of melatonin combining three strategies: nanoencapsulation of melatonin, drying of melatonin-loaded nanocapsules, and incorporation of nanocapsules in a hydrophilic gel. Nanocapsules were prepared by interfacial deposition of the polymer and were spray-dried using water-soluble excipients. In vitro drug release profiles were evaluated by the dialysis bag method, and skin permeation studies were carried out using Franz cells with porcine skin as the membrane. The use of 10% ( w/ v) water-soluble excipients (lactose or maltodextrin) as spray-drying adjuvants furnished redispersible powders (redispersibility index approximately 1.0) suitable for incorporation into hydrogels. All formulations showed a better controlled in vitro release of melatonin compared with the melatonin solution. The best controlled release results were achieved with hydrogels prepared with dried nanocapsules (hydrogels > redispersed dried nanocapsules > nanocapsule suspension > melatonin solution). The skin permeation studies demonstrated a significant modulation of the transdermal melatonin permeation for hydrogels prepared with redispersible nanocapsules. In this way, the additive effect of the different approaches used in this study (nanoencapsulation, spray-drying, and preparation of semisolid dosage forms) allows not only the control of melatonin release, but also transdermal permeation.

Ultradeformable Liposomes: a Novel Vesicular Carrier For Enhanced Transdermal Delivery of Procyanidins: Effect of Surfactants on the Formation, Stability, and Transdermal Delivery.

PubMed

Chen, Rencai; Li, Rongli; Liu, Qian; Bai, Chao; Qin, Benlin; Ma, Yue; Han, Jing

2017-07-01

The aims of this work were to develop a novel vesicular carrier, procyanidins, ultradeformable liposomes (PUDLs), to expand the applications for procyanidins, and increase their stability and transdermal delivery. In this study, we prepared procyanidins ultradeformable liposomes using thin film hydration method and evaluated their encapsulation efficiency, vesicle deformability, storage stability, and skin permeation in vitro. The influence of different surfactants on the properties of PUDLs was also investigated. The results obtained showed that the PUDLs containing Tween 80 had a high entrapment efficiency (80.27 ± 0.99%), a small particle size (140.6 ± 19 nm), high elasticity, and prolonged drug release. Compared with procyanidins solution, the stability of procyanidins in PUDLs improved significantly when stored at 4, 25, and 30°C. The penetration rate of PUDLs was 6.25-fold greater than that of procyanidins solution. Finally, the results of our study suggested that PUDLs could increase the transdermal flux, prolong the release and improve the stability of procyanidins, and could serve as an effective dermal delivery system for procyanidins.

Low temperature fabrication of biodegradable sugar glass microneedles for transdermal drug delivery applications.

PubMed

Martin, C J; Allender, C J; Brain, K R; Morrissey, A; Birchall, J C

2012-02-28

Transdermal drug delivery is limited by the barrier properties of the outer skin layer. Microneedles (MNs) effectively circumvent the skin barrier to offer this route as a potential alternative to oral and parenteral delivery of therapeutics. Biodegradable microneedles offer particular advantages however processing commonly requires elevated temperatures that may adversely affect heat-labile molecules and macromolecules. In this study, solid amorphous sugar glasses containing low residual quantities of water were created by dehydration of trehalose and sucrose sugar combination solutions. Biodegradable sugar glass MNs were fabricated following optimisation of a simple and novel low temperature vacuum deposition micromoulding methodology. These had absolute morphological fidelity to silicon master structures and demonstrated sufficient structural rigidity to efficiently penetrate excised human breast skin. Sugar glass MNs incorporating a marker compound dissolved rapidly and completely in situ releasing dye into deeper skin layers. The biological activity of a model macromolecule was partially retained over extended storage following incorporation into sugar glass. This is the first demonstration that MNs created from amorphous sugar glasses can be used for incorporating and delivering molecules, and potentially biologically active macromolecules, via the transdermal route. Copyright © 2011 Elsevier B.V. All rights reserved.

Evaluation in vitro and in vivo of dimethicone transdermal therapeutic systems. Influence of propylene glycol on drug release.

PubMed

Ritschel, W A; Nayak, P M

1987-03-01

Coumarin-containing transdermal drug delivery systems were studied in vitro for drug release and in vivo in rats for drug absorption. The matrix of the transdermal delivery system, dimethicone, was a commercially available silicone elastomer. The devices containing 1, 3 and 5% coumarin released in vitro 8.8 (87.4%), 23.4 (74.5%) and 31.6 mg (63.3%) of drug within 24 h. The device containing 5% coumarin was selected for further studies in which 5, 10, 20, 30, 50 and 70% propylene glycol was added. Up to 20% propylene glycol content did not change the amount released. The preparations with 30, 50 and 70% propylene glycol released 69.3, 73.6 and 87.9%, respectively. The 50 and 70% preparations were physically not acceptable. Only the preparations containing 5% coumarin without propylene glycol and 5% coumarin and 30% propylene glycol in the elastomer were evaluated in vivo. The area under the blood level-time curve of the propylene glycol-containing system was twice that of the device without propylene glycol. Blood levels were maintained between about 2 micrograms/ml and 5 micrograms/ml during the time the device was kept on the skin (24 h).

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.

Dissolving polymeric microneedle arrays for electrically assisted transdermal drug delivery.

PubMed

Garland, Martin J; Caffarel-Salvador, Ester; Migalska, Katarzyna; Woolfson, A David; Donnelly, Ryan F

2012-04-10

It has recently been proposed that the combination of skin barrier impairment using microneedles (MNs) coupled with iontophoresis (ITP) may broaden the range of drugs suitable for transdermal delivery, as well as enabling the rate of delivery to be achieved with precise electronic control. However, no reports exist on the combination of ITP with in situ drug loaded polymeric MN delivery systems. Furthermore, although a number of studies have highlighted the importance of MN design for transdermal drug delivery enhancement, to date, there has been no systematic investigation of the influence of MN geometry on the performance of polymeric MN arrays which are designed to remain in contact with the skin during the period of drug delivery. As such, for the first time, this study reports on the effect of MN heigth and MN density upon the transdermal delivery of small hydrophilic compounds (theophylline, methylene blue, and fluorescein sodium) across neonatal porcine skin in vitro, with the optimised MN array design evaluated for its potential in the electrically faciliatated delivery of peptide (bovine insulin) and protein (fluorescein isothiocyanate-labelled bovine serum albumin (FTIC-BSA)) macromolecules. The results of the in vitro drug release investigations revealed that the extent of transdermal delivery was dependent upon the design of the MN array employed, whereby an increase in MN height and an increase in MN density led to an increase in the extent of transdermal drug delivery achieved 6h after MN application. Overall, the in vitro permeation studies revealed that the MN design containing 361 MNs/cm(2) of 600 μm height resulted in the greatest extent of transdermal drug delivery. As such, this design was evaluated for its potential in the MN mediated iontophoretic transdermal delivery. Whilst the combination of MN and ITP did not further enhance the extent of small molecular weight solute delivery, the extent of peptide/protein release was significantly enhanced when ITP was used in combination of the soluble PMVE/MA MN arrays. For example, the cumulative amount of insulin permeated across neonatal porcine skin at 6h was found to be approximately 150 μg (3.25%), 227 μg (4.85%) and 462 μg (9.87%) for ITP, MN, and MN/ITP delivery strategies, respectively. Similarly, the cumulative amount of FTIC-BSA delivered across neonatal porcine skin after a 6h period was found to be approximately 110 μg (4.53%) for MN alone and 326 μg (13.40%) for MN in combination with anodal ITP (p<0.001). As such, drug loaded soluble PMVE/MA MN arrays show promise for the electrically controlled transdermal delivery of biomacromolecules in a simple, one-step approach. Copyright © 2012 Elsevier B.V. All rights reserved.

Effects of vehicles and enhancers on transdermal delivery of clebopride.

PubMed

Rhee, Yun-Seok; Huh, Jai-Yong; Park, Chun-Woong; Nam, Tae-Young; Yoon, Koog-Ryul; Chi, Sang-Cheol; Park, Eun-Seok

2007-09-01

The effects of vehicles and penetration enhancers on the skin permeation of clebopride were evaluated using Franz type diffusion cells fitted with excised rat dorsal skins. The binary vehicle system, diethylene glycol monoethyl ether/isopropyl myristate (40/60, w/w), significantly enhanced the skin permeation rate of clebopride. The skin permeation enhancers, oleic acid and ethanol when used in the binary vehicle system, resulted in relatively high clebopride skin permeation rates. A gel formulation consisting of 1.5% (w/w) clebopride, 5% (w/w) oleic acid, and 7% (w/w) gelling agent with the binary vehicle system resulted in a permeation rate of 28.90 microg/cm2/h. Overall, these results highlight the potential of clebopride formulation for the transdermal route.

Basics and recent advances in peptide and protein drug delivery

PubMed Central

Bruno, Benjamin J; Miller, Geoffrey D; Lim, Carol S

2014-01-01

While the peptide and protein therapeutic market has developed significantly in the past decades, delivery has limited their use. Although oral delivery is preferred, most are currently delivered intravenously or subcutaneously due to degradation and limited absorption in the gastrointestinal tract. Therefore, absorption enhancers, enzyme inhibitors, carrier systems and stability enhancers are being studied to facilitate oral peptide delivery. Additionally, transdermal peptide delivery avoids the issues of the gastrointestinal tract, but also faces absorption limitations. Due to proteases, opsonization and agglutination, free peptides are not systemically stable without modifications. This review discusses oral and transdermal peptide drug delivery, focusing on barriers and solutions to absorption and stability issues. Methods to increase systemic stability and site-specific delivery are also discussed. PMID:24228993

Effect of nerodilol and carvone on in vitro permeation of nicorandil across rat epidermal membrane.

PubMed

Krishnaiah, Yellela S R; Al-Saidan, Saleh M; Chandrasekhar, Dantam V; Rama, Bukka

2006-04-01

The objective of the study was to investigate the effect of nerodilol and carvone on the in vitro transdermal delivery of nicorandil so as to fabricate a membrane-moderated transdermal therapeutic system. The in vitro permeation studies were carried across the rat epidermal membrane from the hydroxypropyl methylcellulose (HPMC) gels (prepared with 70:30 v/v ethanol-water) containing selected concentrations of a terpene such as nerodilol (0%w/w, 4%w/w, 8%w/w, 10%w/w, or 12%w/w) or carvone (0%w/w, 4%w/w, 8%w/w, 12%w/w, or 16%w/w). The amount of nicorandil permeated (Q(24)) from HPMC gel drug reservoir without a terpene was 3424.6+/-51.4 microg/cm(2), and the corresponding flux of the drug was 145.5+/-2.2 microg/cm(2). h. The flux of nicorandil increased with an increase in terpene concentration in HPMC gel. It was increased ranging from 254.9+/-3.1 to 375.7+/-3.2 microg/cm(2).h or 207.6+/-4.7 to 356.7+/-15.3 microg/cm(2). h from HPMC gels containing nerodilol (4%w/w to 12%w/w) or carvone (4%w/w to 16%w/w), respectively. Nerodilol increased the flux of nicorandil by about 2.62-folds whereas carvone increased the flux of the drug by about 2.49-folds across the rat epidermal membrane. The results of the Fourier Transform Infrared (FT-IR) study indicated that the enhanced in vitro transdermal delivery of nicorandil might be due to the partial extraction of stratum corneum lipids by nerodilol or carvone. It was concluded that the terpenes, nerodilol and carvone, produced a marked penetration enhancing effect on the transdermal delivery of nicorandil that could be used in the fabrication of membrane-moderated transdermal therapeutic systems.

Ultrasound mediated transdermal insulin delivery in pigs using a lightweight transducer.

PubMed

Park, E J; Werner, Jacob; Smith, Nadine Barrie

2007-07-01

In previous studies, ultrasound mediated transdermal drug delivery has shown a promising potential as a method for noninvasive drug administration. For prospective future human application, this study was designed to determine the feasibility of lightweight cymbal transducer array as a practical device for noninvasive transdermal insulin delivery in large pigs. Six Yorkshire pigs (100-140 lbs) were divided into two groups. As the control (n = 3), the first group did not receive any ultrasound exposure with the insulin. The second group (n = 3) was treated with ultrasound and insulin at 20 kHz with an I(sptp) = 100 mW/cm(2) at a 20% duty cycle for 60 min. With the pigs in lateral recumbency after anesthesia, the ultrasound transducer with insulin was placed on the axillary area of the pig. At the beginning and every 15 min up to 90 min, the blood glucose level was determined using a glucose monitoring system. To compare the results of individual animals, the change of blood glucose level was normalized to each animal's initial glucose value at the start of the experiment. Although each animal had a different initial glucose level, the mean and standard error for the six animals was 146 +/- 13 mg/dl. For the control group, the blood glucose level increased to 31 +/- 21 mg/dl compared to the initial baseline over the 90 min experiment. However for the ultrasound with insulin treated group, the glucose level decreased to -72 +/- 5 mg/dl at 60 min (p < 0.05) and continued to decrease to -91 +/- 23 mg/dl in 90 min (p < 0.05). The results indicate the feasibility of ultrasound mediated transdermal insulin delivery using the cymbal transducer array in animal with a similar size and weight to a human. Based on these result, the cymbal array has potential as a practical ultrasound system for noninvasive transdermal insulin delivery for diabetes management.

Fabrication, Physicochemical Characterization, and Performance Evaluation of Biodegradable Polymeric Microneedle Patch System for Enhanced Transcutaneous Flux of High Molecular Weight Therapeutics.

PubMed

Shah, Viral; Choudhury, Bijaya Krushna

2017-11-01

A revolutionary paradigm shift is being observed currently, towards the use of therapeutic biologics for disease management. The present research was focused on designing an efficient dosage form for transdermal delivery of α-choriogonadotropin (high molecular weight biologic), through biodegradable polymeric microneedles. Polyvinylpyrrolidone-based biodegradable microneedle arrays loaded with high molecular weight polypeptide, α-choriogonadotropin, were fabricated for its systemic delivery via transdermal route. Varied process and formulation parameters were optimized for fabricating microneedle array, which in turn was expected to temporally rupture the stratum corneum layer of the skin, acting as a major barrier to drug delivery through transdermal route. The developed polymeric microneedles were optimized on the basis of quality attributes like mechanical strength, axial strength, insertion ratio, and insertion force analysis. The optimized polymeric microneedle arrays were characterized for in vitro drug release studies, ex vivo drug permeation studies, skin resealing studies, and in vivo pharmacokinetic studies. Results depicted that fabricated polymeric microneedle arrays with mechanical strength of above 5 N and good insertion ratio exhibited similar systemic bioavailability of α-choriogonadotropin in comparison to marketed subcutaneous injection formulation of α-choriogonadotropin. Thus, it was ultimately concluded that the designed drug delivery system can serve as an efficient tool for systemic delivery of therapeutic biologics, with an added benefit of overcoming the limitations of parenteral delivery, achieving better patient acceptability and compliance.

Transdermal nicotine patches for eosinophilic pustular folliculitis.

PubMed

Yoshifuku, Asuka; Higashi, Yuko; Matsushita, Shigeto; Kawai, Kazuhiro; Kanekura, Takuro

2013-09-01

We previously reported the clinical effectiveness of transdermal nicotine patches for the treatment of skin disorders with eosinophilic infiltration such as Kimura's disease, erythema nodosum and eosinophilic pustular folliculitis (EPF). We assessed the efficacy and safety of transdermal nicotine patches for EPF. We treated eight patients with EPF with transdermal nicotine patches and evaluated the treatment response by performing overall lesional assessment. Excellent 77and good responses were obtained in five and one patient(s), respectively. In the other two patients, the lesions remained unchanged. No severe adverse effects were observed. Our results suggest that transdermal nicotine patches may be useful and safe in the treatment of EPF. © 2013 Japanese Dermatological Association.

Transdermal granisetron: a guide to its use in preventing nausea and vomiting induced by chemotherapy.

PubMed

Keating, Gillian M; Duggan, Sean T; Curran, Monique P

2012-09-01

Transdermal granisetron (Sancuso®) is effective in the prevention of nausea and vomiting in patients with cancer who are receiving moderately or highly emetogenic chemotherapy for 3-5 days. Transdermal granisetron is noninferior to oral granisetron in this indication, and is generally well tolerated in this indication. Thus, transdermal granisetron provides a convenient option for the prevention of chemotherapy-induced nausea and vomiting, with the potential to improve patient compliance.

Interpretation of urine drug testing results in patients using transdermal buprenorphine preparations for the treatment of chronic noncancer pain.

PubMed

Markman, John D; Barbosa, William A; Gewandter, Jennifer S; Frazer, Maria; Rast, Shirley; Dugan, Michelle; Nandigam, Kiran; Villareal, Armando; Kwong, Tai C

2015-06-01

To determine whether the prevailing liquid chromatography and tandem mass spectroscopy assay (LC-MS/MS) assay designed to monitor buprenorphine compliance of the sublingual formulation used in the substance abuse treatment setting can be extrapolated to the transdermal formulation used in the chronic pain treatment setting, which is 1000-fold less concentrated. Retrospective chart review. Self-reported compliant patients using the transdermal or sublingual formulations of buprenorhphine. Transdermal patch application was also visually confirmed during clinic visits. Urine drug test results from a LC-MS/MS were compared between samples from transdermal and sublingual patients. While all sublingual patients tested positive for at least one metabolite of buprenorphine, only 69% of the transdermal patients did so. In addition, the most abundant metabolite in the transdermal patients was buprenorphine-glucuronide, as compared with norbuprenorphine-glucuronide in sublingual patients. These data suggest that currently available urine drug tests for buprenorphine, including the more expensive LC-MS/MS based assays, may not be sufficiently sensitive to detect the metabolites from transdermal buprenorphine patients. This study highlights the need to evaluate the value and sensitivity of urine drug tests given the wide range of buprenorphine dosing in clinical practice. These results underscore the need for additional cost benefit analyses comparing different confirmatory drug testing techniques including many commercially available drug testing options. © 2014 Wiley Periodicals, Inc. Wiley Periodicals, Inc.

Caregiver Preference and Treatment Compliance in Patients with Mild-to-Moderate Alzheimer's Disease in South Korea: RECAP Study Results.

PubMed

Lee, Kang Joon; Cho, Seong-Jin; Kim, Byeong Chae; Park, Minseok; Lee, Jae-Hong

2017-02-01

The aim of this study was to assess caregiver preference and treatment compliance with oral and transdermal medications in a "real-world" setting in patients with mild-to-moderate Alzheimer's disease (AD) in South Korea. Real-world evaluation of compliance and preference in Alzheimer's disease treatment (RECAP) was a 24-week, multicenter, prospective, non-interventional study in patients with AD treated with oral or transdermal therapy. Here, we report data from patients living in South Korea. Eligible patients were grouped into one of two treatment cohorts: oral (donepezil, galantamine, rivastigmine, or memantine) or transdermal (rivastigmine patch). Caregiver preference, patient compliance, and physician preference were assessed at week 24 (end of the study). Safety was assessed by reported adverse events (AEs). A total of 398 patients were enrolled (oral 51.8%; transdermal 48.2%) and 79.4% completed the study. Caregivers of patients that were exposed to either the oral or transdermal monotherapy showed a preference for the treatment to which the patients were exposed (both p < 0.0001). However, caregivers of patients that were exposed to both forms of treatments reported a higher preference for transdermal monotherapy (65.9%; p < 0.0041). Patients in both treatment cohorts showed good compliance, with an overall mean (SD) score of 8.84 (1.514) (a median of 9). Of the 15 participating physicians, eight indicated their preference for transdermal therapy and seven preferred oral therapy at week 24. A total of 133 (33.4%) patients reported at least one AE during the study period (oral: 60 patients; transdermal: 73 patients). The study showed higher caregiver preference for transdermal monotherapy over oral monotherapy when patients with AD were exposed to both forms of treatment and good patient compliance for both oral and transdermal treatments.

The effects of chemical and physical penetration enhancers on the percutaneous permeation of lidocaine through equine skin

PubMed Central

2014-01-01

Background The effect of physical and chemical permeation enhancers on in vitro transdermal permeation of lidocaine was investigated in the horse. Therefore, the effect of six vehicles (phosphate-buffered saline (PBS), 50% ethanol, 50% propylene glycol, 50% isopropylalcohol, 50% isopropylalcohol/isopropylmyristate and 50% dimethylsulfoxide) was examined as well as the effect of microneedle pretreatment with different needle lengths on transdermal drug delivery of lidocaine. The skin was obtained from the thorax of six Warmblood horses and was stored up to two weeks at - 20°C. Franz-type diffusion cells were used to study the transdermal permeation through split skin (600 μm thickness). The amount of lidocaine in the receptor fluid was determined by UV–VIS high-performance liquid chromatography. Results All investigated vehicle supplementations diminished the transdermal flux of lidocaine through equine skin in comparison to pure PBS except dimethylsulfoxide, which resulted in comparable permeation rates to PBS. The maximum flux (Jmax) was 1.6-1.8 fold lower for lidocaine applied in 50% ethanol, propylene glycol, isopropylalcohol and isopropylalcohol/isopropylmyristate. A significant higher Jmax of lidocaine was observed when lidocaine was applied in PBS onto microneedle pretreated skin with similar permeation rates in both needle lengths. After 6 hours, 1.7 fold higher recovery rates were observed in the microneedle pretreated skin samples than in the untreated control samples. The lagtimes were reduced to 20–50% in the microneedle pretreated skin samples. Conclusion Microneedles represent a promising tool for transdermal lidocaine application in the horse with a rapid systemic bioavailability. PMID:24950611

Design, formulation and optimization of novel soft nano-carriers for transdermal olmesartan medoxomil delivery: In vitro characterization and in vivo pharmacokinetic assessment.

PubMed

Kamran, Mohd; Ahad, Abdul; Aqil, Mohd; Imam, Syed Sarim; Sultana, Yasmin; Ali, Asgar

2016-05-30

Olmesartan is a hydrophobic antihypertensive drug with a short biological half-life, and low bioavailability, presents a challenge with respect to its oral administration. The objective of the work was to formulate, optimize and evaluate the transdermal potential of novel vesicular nano-invasomes, containing above anti-hypertensive agent. To achieve the above purpose, soft carriers (viz. nano-invasomes) of olmesartan with β-citronellene as potential permeation enhancer were developed and optimized using Box-Behnken design. The physicochemical characteristics e.g., vesicle size, shape, entrapment efficiency and skin permeability of the nano-invasomes formulations were evaluated. The optimized formulation was further evaluated for in vitro drug release, confocal microscopy and in vivo pharmacokinetic study. The optimum nano-invasomes formulation showed vesicles size of 83.35±3.25nm, entrapment efficiency of 65.21±2.25% and transdermal flux of 32.78±0.703 (μg/cm(2)/h) which were found in agreement with the predicted value generated by Box-Behnken design. Confocal laser microscopy of rat skin showed that optimized formulation was eventually distributed and permeated deep into the skin. The pharmacokinetic study presented that transdermal nano-invasomes formulation showed 1.15 times improvement in bioavailability of olmesartan with respect to the control formulation in Wistar rats. It was concluded that the response surfaces estimated by Design Expert(®) illustrated obvious relationship between formulation factors and response variables and nano-invasomes were found to be a proficient carrier system for transdermal delivery of olmesartan. Copyright © 2016 Elsevier B.V. All rights reserved.

A review of compliance to treatment in Alzheimer's disease: potential benefits of a transdermal patch.

PubMed

Small, Gary; Dubois, Bruno

2007-11-01

Following prescribed medication regimens is essential for the effective treatment of any medical condition. Unfortunately, patients often fail to follow recommendations, and treatment non-compliance represents a widespread, often underestimated problem, placing tremendous burden on the healthcare system. Compliance in Alzheimer's disease (AD), a chronic neurodegenerative disease typically afflicting older adults, is especially challenging. To review factors contributing to poor treatment compliance in AD, considering the prominent role care givers often play in treatment management; and acknowledging strategic approaches, particularly modern transdermal patches, to improve compliance in this particularly susceptible population. Articles were identified by searching MEDLINE in November 2006 (search limits: 1987-2007) using the terms: compliance; Alzheimer's; treatment; and transdermal. Additional resources included bibliographies of identified articles. Strategic approaches to improving treatment compliance include: simplifying treatment regimens, using reminder packaging, and developing more patient- or caregiver-friendly modes of administration. To date, AD therapies have been administered orally. However, recent developments in alternative modes of drug delivery, such as transdermal patches, may offer effective, well-tolerated treatment options with the potential to enhance compliance. A patch containing rivastigmine (Exelon), an established cholinesterase inhibitor, has been developed and demonstrated to have good efficacy and tolerability in patients with AD. In addition, initial caregiver experience suggests preference for the patch over oral administration. Transdermal patches may be an effective way to optimize treatment compliance for AD, as well as an increasing number of other chronic conditions that typically afflict the older population, offering the possibility of more sustained clinical benefits.

Drug crystallization - implications for topical and transdermal delivery.

PubMed

Hadgraft, Jonathan; Lane, Majella E

2016-06-01

Crystallization of actives in skin following topical application was suggested by studies in the 1950s and 1960s but is poorly understood. In contrast, the problem of crystallization of actives on skin and in transdermal formulations has been known for many years. With respect to crystallization in skin, this review describes early reports of a skin 'reservoir' and possible reasons underlying its genesis. Techniques to study crystallization on and in skin and in transdermal patches are outlined. The role of the vehicle in skin delivery is emphasised. Studies which have investigated permeation from crystalline particles are described. Approaches to limit crystallization of actives are discussed. Using supersaturation and antinuclean polymers, control of crystal size is possible; controlled release from crystals is also employed in transdermal patches. Drug crystallization has significant implications for topical and transdermal delivery. Approaches have been developed to counteract the issue for transdermal patches but crystallization in and on the skin for other formulations remains unresolved. Greater knowledge of residence time of excipients and their interaction with skin at the molecular level is critical in order to address the problem. This will lay the foundations for better design of topical/transdermal formulations.

Oleic acid-enhanced transdermal delivery pathways of fluorescent nanoparticles

NASA Astrophysics Data System (ADS)

Lo, Wen; Ghazaryan, Ara; Tso, Chien-Hsin; Hu, Po-Sheng; Chen, Wei-Liang; Kuo, Tsung-Rong; Lin, Sung-Jan; Chen, Shean-Jen; Chen, Chia-Chun; Dong, Chen-Yuan

2012-05-01

Transdermal delivery of nanocarriers provides an alternative pathway to transport therapeutic agents, alleviating pain, improving compliance of patients, and increasing overall effectiveness of delivery. In this work, enhancement of transdermal delivery of fluorescent nanoparticles and sulforhodamine B with assistance of oleic acid was visualized utilizing multiphoton microscopy (MPM) and analyzed quantitatively using multi-photon excitation-induced fluorescent signals. Results of MPM imaging and MPM intensity-based spatial depth-dependent analysis showed that oleic acid is effective in facilitating transdermal delivery of nanoparticles.

Converting from Transdermal to Buccal Formulations of Buprenorphine: A Pharmacokinetic Meta-Model Simulation in Healthy Volunteers.

PubMed

Priestley, Tony; Chappa, Arvind K; Mould, Diane R; Upton, Richard N; Shusterman, Neil; Passik, Steven; Tormo, Vicente J; Camper, Stephen

2017-09-29

 To develop a model to predict buprenorphine plasma concentrations during transition from transdermal to buccal administration.  Population pharmacokinetic model-based meta-analysis of published data.  A model-based meta-analysis of available buprenorphine pharmacokinetic data in healthy adults, extracted as aggregate (mean) data from published literature, was performed to explore potential conversion from transdermal to buccal buprenorphine. The time course of mean buprenorphine plasma concentrations following application of transdermal patch or buccal film was digitized from available literature, and a meta-model was developed using specific pharmacokinetic parameters (e.g., absorption rate, apparent clearance, and volumes of distribution) derived from analysis of pharmacokinetic data for intravenously, transdermally, and buccally administered buprenorphine.  Data from six studies were included in this analysis. The final transdermal absorption model employed a zero-order input rate that was scaled to reflect a nominal patch delivery rate and time after patch application (with decline in rate over time). The transdermal absorption rate constant became zero following patch removal. Buccal absorption was a first-order process with a time lag and bioavailability term. Simulations of conversion from transdermal 20 mcg/h and 10 mcg/h to buccal administration suggest that transition can be made rapidly (beginning 12 hours after patch removal) using the recommended buccal formulation titration increments (75-150 mcg) and schedule (every four days) described in the product labeling.  Computer modeling and simulations using a meta-model built from data extracted from publications suggest that rapid and straightforward conversion from transdermal to buccal buprenorphine is feasible. © 2017 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Myth or Reality-Transdermal Magnesium?

PubMed

Gröber, Uwe; Werner, Tanja; Vormann, Jürgen; Kisters, Klaus

2017-07-28

In the following review, we evaluated the current literature and evidence-based data on transdermal magnesium application and show that the propagation of transdermal magnesium is scientifically unsupported. The importance of magnesium and the positive effects of magnesium supplementation are extensively documented in magnesium deficiency, e.g., cardiovascular disease and diabetes mellitus. The effectiveness of oral magnesium supplementation for the treatment of magnesium deficiency has been studied in detail. However, the proven and well-documented oral magnesium supplementation has become questioned in the recent years through intensive marketing for its transdermal application (e.g., magnesium-containing sprays, magnesium flakes, and magnesium salt baths). In both, specialist and lay press as well as on the internet, there are increasing numbers of articles claiming the effectiveness and superiority of transdermal magnesium over an oral application. It is claimed that the transdermal absorption of magnesium in comparison to oral application is more effective due to better absorption and fewer side effects as it bypasses the gastrointestinal tract.

Myth or Reality—Transdermal Magnesium?

PubMed Central

Gröber, Uwe; Werner, Tanja; Vormann, Jürgen

2017-01-01

In the following review, we evaluated the current literature and evidence-based data on transdermal magnesium application and show that the propagation of transdermal magnesium is scientifically unsupported. The importance of magnesium and the positive effects of magnesium supplementation are extensively documented in magnesium deficiency, e.g., cardiovascular disease and diabetes mellitus. The effectiveness of oral magnesium supplementation for the treatment of magnesium deficiency has been studied in detail. However, the proven and well-documented oral magnesium supplementation has become questioned in the recent years through intensive marketing for its transdermal application (e.g., magnesium-containing sprays, magnesium flakes, and magnesium salt baths). In both, specialist and lay press as well as on the internet, there are increasing numbers of articles claiming the effectiveness and superiority of transdermal magnesium over an oral application. It is claimed that the transdermal absorption of magnesium in comparison to oral application is more effective due to better absorption and fewer side effects as it bypasses the gastrointestinal tract. PMID:28788060

Influence of Transcutol CG on the skin accumulation and transdermal permeation of ultraviolet absorbers.

PubMed

Godwin, Donald A; Kim, Nae-Hwa; Felton, Linda A

2002-01-01

The objective of this study was to determine the influence of Transcutol CG concentration on the transdermal permeation and skin accumulation of two ultraviolet (UV) absorbers, 2-hydroxy-4-methoxybenzophenone (oxybenzone) and 2-octyl-4-methoxycinnamate (cinnamate). The concentration of the UV absorber was held constant at 6% (w/w) for all vehicle systems while the concentration of Transcutol CG was varied from 0 to 50% (w/w). Data showed that both UV absorbers exhibited increases in skin accumulation with increasing concentrations of Transcutol CG. Skin accumulation of oxybenzone was significantly (P<0.05) greater than that of cinnamate for all formulations investigated. Oxybenzone skin accumulation ranged from 22.9+/-2.8 microg/mg (0% Transcutol CG) to 80.8+/-27.2 microg/mg (50% Transcutol CG). Cinnamate skin accumulation ranged from 9.0+/-0.9 microg/mg to 39.8+/-12.2 microg/mg at 0 and 50% Transcutol CG, respectively. No significant differences were found in the transdermal permeation of oxybenzone or cinnamate for any of the formulations tested. The results of this study demonstrate that the inclusion of Transcutol CG in sunscreen formulations increases the skin accumulation of the UV absorbers oxybenzone and cinnamate without a concomitant increase in transdermal permeation.

A UHPLC-UV Method to Quantify Skin Deposition and Transdermal Permeation of Tizanidine Hydrochloride

PubMed Central

del Río-Sancho, Sergio; Merino, Virginia; López-Castellano, Alicia; Kalia, Yogeshvar N.

2016-01-01

Tizanidine hydrochloride is an α2-adrenergic agonist used for the symptomatic relief of spasticity associated with multiple sclerosis or with spinal cord injury or disease. The objective of this study was to develop an isocratic, robust and sensitive ultra-high performance liquid chromatography method using UV detection for use in a project to develop a transdermal therapeutic system to deliver tizanidine across the skin. Isocratic separation was achieved using a C18 column and a mobile phase comprising a 80:20 mixture of 0.004% trifluoroacetic acid in water and MeCN (pH* 3.2) at a flow rate of 0.2 mL min−1. Tizanidine eluted at 1.499 min and the total run time was 2 min. The method was specific, robust and the response was accurate, precise and linear from 17.4 to 290 ng mL−1. In contrast to existing methods, the method developed here was validated over a concentration range so as to include the low concentrations frequently observed in transdermal permeation studies and in samples extracted from the cutaneous matrix. Its suitability for use in transdermal permeation studies was subsequently tested and confirmed in preliminary experiments using porcine skin in vitro. PMID:26892401

High-dose transdermal nicotine replacement for tobacco cessation.

PubMed

Brokowski, Laurie; Chen, Jiahui; Tanner, Sara

2014-04-15

The safety and efficacy of high-dose transdermal nicotine-replacement therapy (NRT) for the treatment of tobacco-use cessation were reviewed. Transdermal nicotine doses of 7, 14, and 21 mg daily are approved by the Food and Drug Administration for use in tobacco cessation. However, studies have suggested that these doses are more adequate for people who smoke fewer than 20 cigarettes per day. A literature search was conducted to identify English-language studies that evaluated the use of transdermal nicotine doses of ≥42 mg daily. A total of 11 articles were identified, representing 10 separate trials. In terms of safety, the majority of the trials had no reports of serious adverse events related to transdermal NRT at doses of ≥42 mg daily. A dose-response relationship with adverse events occurred in most trials. In terms of efficacy, a numerically higher abstinence rate was achieved with high-dose transdermal NRT in all trials but 1. However, none of the studies showed significant differences in final abstinence rates at follow-up. Some reasons why statistical significance was not achieved in these trials may be related to the limitations of these trials, such as their small samples and the lack of a power calculation. A more robust trial is needed to support higher nicotine transdermal doses in tobacco cessation and to help elucidate which patient population would be most suitable for their use. The safety and efficacy of high-dose transdermal NRT for tobacco cessation have not been established in the medical literature.

Influence of menthol and pressure-sensitive adhesives on the in vivo performance of membrane-moderated transdermal therapeutic system of nicardipine hydrochloride in human volunteers.

PubMed

Krishnaiah, Y S R; Satyanarayana, V; Bhaskar, P

2003-05-01

A membrane-moderated transdermal therapeutic system of nicardipine hydrochloride was developed using 2% w/w hydroxypropylcellulose (HPC) gel as a reservoir system containing 5% w/w of menthol as a penetration enhancer. The permeability flux of nicardipine hydrochloride through the ethylene vinyl acetate (EVA) copolymer membrane was found to increase with an increase in vinyl acetate content in the copolymer. The effect of various pressure-sensitive adhesives (MA-31, MA-38 or TACKWHITE A 4MED on the permeability of nicardipine hydrochloride through EVA 2825 membrane (28% w/w vinyl acetate) or EVA 2825 membrane/skin composite was also studied. The results showed that nicardipine hydrochloride permeability through EVA 2825 membrane coated with TACKWHITE A 4MED/skin composite was higher than that coated with MA-31 or MA-38. Thus, a new transdermal therapeutic system for nicardipine hydrochloride was formulated using EVA 2825 membrane coated with a pressure-sensitive adhesive TACKWHITE A 4MED, and 2% w/w HPC gel as reservoir containing 5% w/w of menthol as a penetration enhancer. In vivo studies in healthy human volunteers indicated that the TTS of nicardipine hydrochloride, designed in the present study, provided steady-state plasma concentration of the drug with minimal fluctuations for 26h with improved bioavailability in comparison with the immediate release capsule dosage form.

Numerical modelling of transdermal delivery from matrix systems: parametric study and experimental validation with silicone matrices.

PubMed

Snorradóttir, Bergthóra S; Jónsdóttir, Fjóla; Sigurdsson, Sven Th; Másson, Már

2014-08-01

A model is presented for transdermal drug delivery from single-layered silicone matrix systems. The work is based on our previous results that, in particular, extend the well-known Higuchi model. Recently, we have introduced a numerical transient model describing matrix systems where the drug dissolution can be non-instantaneous. Furthermore, our model can describe complex interactions within a multi-layered matrix and the matrix to skin boundary. The power of the modelling approach presented here is further illustrated by allowing the possibility of a donor solution. The model is validated by a comparison with experimental data, as well as validating the parameter values against each other, using various configurations with donor solution, silicone matrix and skin. Our results show that the model is a good approximation to real multi-layered delivery systems. The model offers the ability of comparing drug release for ibuprofen and diclofenac, which cannot be analysed by the Higuchi model because the dissolution in the latter case turns out to be limited. The experiments and numerical model outlined in this study could also be adjusted to more general formulations, which enhances the utility of the numerical model as a design tool for the development of drug-loaded matrices for trans-membrane and transdermal delivery. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Transdermal therapeutic systems for memantine delivery. Comparison of passive and iontophoretic transport.

PubMed

Del Río-Sancho, S; Serna-Jiménez, C E; Sebastián-Morelló, M; Calatayud-Pascual, M A; Balaguer-Fernández, C; Femenía-Font, A; Kalia, Y N; Merino, V; López-Castellano, A

2017-01-30

Memantine is a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist used in the treatment of moderate to severe dementia including the symptoms of Alzheimer's disease (AD). It is administered orally but compliance, swallowing problems and the routine use of multiple medications in elderly AD patients means that an alternative route of administration would be of interest. The aim of the present study was to develop memantine hydrochloride occlusive transdermal therapeutic systems (TTS) for passive and iontophoretic delivery across the skin. Polyvinyl pyrrolidone (PVP) and a mixture with polyvinyl alcohol (PVA) were employed as polymeric matrices. The study involved the TTS characterization in addition to quantification of the memantine transport across porcine skin in vitro. The evaluation of the TTS physical properties suggested that systems were made more mechanically resistant by including PVA (6%) or high concentrations of PVP (24%). Moreover, a linear correlation was observed between the concentration of PVP and the bioadhesion of the systems. Drug delivery experiments showed that the highest transdermal flux provided by a passive TTS (PVP 24% w/w limonene) was 8.89±0.81μgcm -2 h -1 whereas the highest iontophoretic transport was 46.4±3.6μgcm -2 h -1 . These innovative TTS would enable two dosage regimens that could lead to therapeutic plasma concentrations. Copyright © 2016 Elsevier B.V. All rights reserved.

Matrix-type transdermal films to enhance simvastatin ex vivo skin permeability.

PubMed

El-Say, Khalid M; Ahmed, Osama A A; Aljaeid, Bader M; Zidan, Ahmed S

2017-06-01

This study aimed at employing Plackett-Burman design in screening formulation variables that affect quality of matrix-type simvastatin (SMV) transdermal film. To achieve this goal, 12 formulations were prepared by casting method. The investigated variables were Eudragit RL percentage, polymer mixture percentage, plasticizer type, plasticizer percentage, enhancer type, enhancer percentage and dichloromethane fraction in organic phase. The films were evaluated for physicochemical properties and ex vivo SMV permeation. SMV initial, delayed flux, diffusivity and permeability coefficient were calculated on the delayed flux phase with constraint to minimize the initial flux and approaching steady-state flux. The obtained results revealed flat films with homogeneous distribution of SMV within the films. Thickness values changed from 65 to 180 μm by changing the factors' combinations. Most of the permeation profiles showed sustained release feature with fast permeation phase followed by slow phase. Analysis of variance (ANOVA) showed significant effects (p < 0.05) of the investigated variables on the responses with Prob > F values of 0.0147, 0.0814, 0.0063 and 0.0142 for the initial and delayed fluxes, permeability coefficients and diffusivities, respectively. The findings of screening study showed the importance of the significant variables to be scaled up for full optimization study as a promising alternative drug delivery system.

Pharmacokinetics of 2 Formulations of Transdermal Fentanyl in Cynomolgus Macaques (Macaca fascicularis)

PubMed Central

Carlson, Amy M; Kelly, Richard; Fetterer, David P; Rico, Pedro J; Bailey, Emily J

2016-01-01

Fentanyl is a μ-opioid agonist that often is used as the analgesic component for balanced anesthesia in both human and veterinary patients. Minimal information has been published regarding appropriate dosing, and the pharmacokinetics of fentanyl are unknown in NHP. The pharmacokinetic properties of 2 transdermal fentanyl delivery methods, a solution (2.6 and 1.95 mg/kg) and a patch (25 µg/h), were determined when applied topically to the dorsal scapular area of cynomolgus macaques (Macaca fascicularis). Serum fentanyl concentrations were analyzed by using liquid chromatography–mass spectrometry. Compared with the patch, the transdermal fentanyl solution generated higher drug concentrations over longer time. Adverse reactions occurred in the macaques that received the transdermal fentanyl solution at 2.6 mg/kg. Both preparations showed significant interanimal variability in the maximal serum drug levels, time to achieve maximal fentanyl levels, elimination half-life, and AUC values. Both the maximal concentration and the time at which this concentration occurred were increased in macaques compared with most other species after application of the transdermal fentanyl patch and compared with dogs after application of the transdermal fentanyl solution. The pharmacokinetic properties of transdermal fentanyl in macaques are markedly different from those in other veterinary species and preclude its use as a long-acting analgesic drug in NHP. PMID:27423151

Rotigotine Transdermal Patch: A Review in Restless Legs Syndrome.

PubMed

Garnock-Jones, Karly P

2016-07-01

Rotigotine transdermal patch (Leganto(®), Neupro(®)) is indicated for the treatment of restless legs syndrome (RLS); this article reviews the pharmacological properties of rotigotine transdermal patch and its clinical efficacy and tolerability in patients with RLS. The transdermal patch allows for a continuous, stable release of rotigotine (avoiding first-pass metabolism), which in turn leads to continuous receptor stimulation, believed to closely mimic physiological striatal dopamine receptor function. In short-term and 6-month studies, especially at the higher dosages of 2 and 3 mg/24 h, rotigotine transdermal patch was generally associated with a significantly greater improvement in IRLS total score and CGI-S total score than placebo, and rotigotine recipients were generally more likely to respond to treatment and enter remission. In noncomparative extension studies, efficacy was sustained for ≤5 years. Rotigotine transdermal patch is generally well tolerated, and appears to have a tolerability profile that is similar to that of other non-ergolinic dopamine-receptor agonists. The most common adverse events in clinical trials included application-site reactions, nausea, headache and asthenic conditions. The drug has a relatively low risk of clinically significant augmentation of restless legs syndrome symptoms. In conclusion, rotigotine transdermal patch offers continuous administration of the drug in a daily treatment, and is a useful treatment option in patients with RLS.

Comparison between transdermal nitroglycerin and sildenafil citrate in intrauterine growth restriction: effects on uterine, umbilical and fetal middle cerebral artery pulsatility indices.

PubMed

Trapani, A; Gonçalves, L F; Trapani, T F; Franco, M J; Galluzzo, R N; Pires, M M S

2016-07-01

To evaluate the effects of transdermal nitroglycerin (GTN) and sildenafil citrate on Doppler velocity waveforms of the uterine (UtA), umbilical (UA) and fetal middle cerebral (MCA) arteries in pregnancies with intrauterine growth restriction (IUGR). This was a prospective study of 35 singleton pregnancies (gestational age, 24-31 weeks) with IUGR and abnormal UtA and UA Doppler waveforms. We compared maternal arterial blood pressure and Z-scores of the pulsatility index (PI) of UtA, UA and fetal MCA before and after application of a transdermal GTN patch (average dose, 0.4 mg/h), oral sildenafil citrate (50 mg) or placebo. Statistical analysis was performed by ANOVA for paired samples. There was a significant decrease in UtA-PI after application of GTN (21.0%) and sildenafil citrate (20.4%). A significant reduction in UA-PI was also observed for both GTN (19.1%) and sildenafil citrate (18.2%). There was no difference in UtA- and UA-PI when the GTN and sildenafil groups were compared. No changes in Doppler velocimetry were observed in the placebo group and no significant change in MCA-PI was observed in any group. Maternal arterial blood pressure decreased with administration of both GTN and sildenafil citrate in those with pre-eclampsia. The use of transdermal GTN or sildenafil citrate in pregnancies with IUGR is associated with a significant reduction in both UtA and UA Doppler PI, as well as maternal arterial blood pressure. Neither drug affected the MCA-PI. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Short-term treatment with transdermal nicotine affects the function of canine saphenous veins.

PubMed

Clouse, W D; Rud, K S; Hurt, R D; Miller, V M

2000-01-01

Experiments were designed to determine the effects of nicotine treatment on the functions of saphenous veins used for coronary artery bypass grafts in dogs. Dogs received either no treatment or transdermal nicotine for 5 weeks at doses of 11 mg, 22 mg or 44 mg/day. Saphenous veins were removed and suspended for the measurement of isometric force in organ chambers. Endothelium was removed mechanically from some rings. N(G)-mono-methyl-L-arginine (L-NMMA; 10(-4) M) was used to inhibit the production of nitric oxide. Contractions to alpha2-adrenergic stimulation were decreased in veins from dogs treated with a 22-mg/day dose of transdermal nicotine. In addition, endothelium-dependent relaxations to adenosine-diphosphate (10(-8)-10(-4) M) and the calcium ionophore A23,187 (10(-8)-10(-6) M) were decreased in veins from dogs with a 22-mg/day dose and increased in veins from dogs treated with a 44-mg/day dose. These relaxations were inhibited by L-NMMA. Plasma concentrations of oxidized products of nitric oxide were decreased only in dogs treated with 22 mg/day of nicotine. The relaxation of rings without endothelium (direct response on the smooth muscle) to nitric oxide were not altered by nicotine treatment. These results suggest that the short-term treatment of dogs with intermediate (22 mg/day) but not low (11 mg/day) or high (44 mg/day) doses of transdermal nicotine decreases the endothelial function of veins used for coronary artery bypass grafts. Therefore, changes in plasma products of nitric oxide and endothelium-dependent relaxations mediated by nitric oxide are related to the dose of nicotine treatment.

Optimization of Microemulsion Based Transdermal Gel of Triamcinolone.

PubMed

Jagdale, Swati; Chaudhari, Bhagyashree

2017-01-01

Triamcinolone is a long acting corticosteroid used in the treatment of arthritis, eczema, psoriasis and similar conditions which cause inflammation. Triamcinolone has half-life of 88min. Prolonged oral use is associated with gastrointestinal adverse effects as peptic ulcer, abdominal distention and ulcerative esophagitis as described in various patents. Microemulgel offers advantage of better stability, better loading capacity and controlled release especially for drug with short half life. Objective of the present study was to optimize microemulgel based transdermal delivery of triamcinolone. Saturated solubility of triamcinolone in various oils, surfactants and co-surfactants is estimated. Pseudo-ternary phase diagrams were constructed to determine the region of transparent microemulsion. Microemulsion was evaluated for globule size (FE-SEM, zetasizer), % transmittance, pH, viscosity, conductivity etc. Design of experiment was used to optimize microemulsion based gel. Carbopol 971P and HPMC K100M were used as independent variables. Microemulsion based gel was evaluated for in-vitro as well as ex-vivo parameters. Microemulsion was formulated with oleic acid, lauroglycol FCC and propylene glycol. PDI 0.197 indicated microemulsion is mono-disperse. 32 factorial design gave batch F8 as optimized. Design expert suggested drug release; gel viscosity and bio-adhesive strength were three significant dependant factors affecting the transdermal delivery. F8 showed drug release 92.62.16±1.22% through egg membrane, 95.23±1.44% through goat skin after 8hr and Korsmeyer-Peppas release model was followed. It can be concluded that a stable, effective controlled release transdermal microemulgel was optimised for triamcinolone. This would be a promising tool to deliver triamcinolone with enhanced bioavailability and reduced dosing frequency. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

In vitro determination of transdermal permeation of synthetic musks and estimated dermal uptake through usage of personal care products.

PubMed

Zhang, Xiaolan; Yu, Yuling; Gu, Yue; Li, Xiaojing; Zhang, Xinyu; Yu, Yingxin

2017-04-01

Synthetic musks, chemical constituents of personal care products, enter the human body through dermal contact. Elucidation of the mechanisms underlying transdermal permeation of synthetic musks should enhance our understanding of their uptake and distribution in human skin and allow accurate evaluation of associated human exposure. Here, the transdermal permeation dynamics and distribution of galaxolide (HHCB) and tonalide (AHTN) were investigated using an in vitro skin diffusion model. The transdermal permeation amounts of HHCB and AHTN increased rapidly during the first 6 h. The applied HHCB and AHTN amounts did not affect percutaneous absorption rates. HHCB and AHTN remained primarily in the stratum corneum, accounting for 70.0% and 70.3% of the totals during the 24-h period, respectively. The percutaneous absorption rate of both chemicals was ∼11%. HHCB, AHTN, musk ketone, musk xylene, and Musk-T were detected in 29 personal care products. The average total concentrations of the musks were 3990, 54.0, 17.7, and 9.8 μg g -1 in perfume, shampoo, lotion, and shower gel, respectively. Among the four product categories, HHCB was dominant (57.4%-99.6%), followed by AHTN. The data clearly indicate that polycyclic and nitro musks are most commonly used in personal care products. The total estimated dermal intake (51.6 μg kg -1 bw  day -1 ) was markedly higher than total dermal uptake (5.9 μg kg -1 bw  day -1 ) when percutaneous absorption rates of the chemicals were added into the calculation. Uptake of HHCB and AHTN via dermal contact of personal care products was significantly higher than that from dust inhalation calculated according to earlier literature data. Copyright © 2017 Elsevier Ltd. All rights reserved.

Development of a Real-Time Repeated-Measures Assessment Protocol to Capture Change over the Course of a Drinking Episode

PubMed Central

Luczak, Susan E.; Rosen, I. Gary; Wall, Tamara L.

2015-01-01

Aims: We report on the development of a real-time assessment protocol that allows researchers to assess change in BrAC, alcohol responses, behaviors, and contexts over the course of a drinking event. Method: We designed a web application that uses timed text messages (adjusted based on consumption pattern) containing links to our website to obtain real-time participant reports; camera and location features were also incorporated into the protocol. We used a transdermal alcohol sensor device along with software we designed to convert transdermal data into estimated BrAC. Thirty-two college students completed a laboratory session followed by a 2-week field trial. Results: Results for the web application indicated we were able to create an effective tool for obtaining repeated measures real-time drinking data. Participants were willing to monitor their drinking behavior with the web application, and this did not appear to strongly affect drinking behavior during, or 6 weeks following, the field trial. Results for the transdermal device highlighted the willingness of participants to wear the device despite some discomfort, but technical difficulties resulted in limited valid data. Conclusion: The development of this protocol makes it possible to capture detailed assessment of change over the course of naturalistic drinking episodes. PMID:25568142

Transdermal iontophoresis of ranitidine: an opportunity in paediatric drug therapy.

PubMed

Djabri, Asma; Guy, Richard H; Delgado-Charro, M Begoña

2012-10-01

The objective of this study was to examine the use of transdermal iontophoresis for the delivery of ranitidine hydrochloride in children. Constant, direct current, anodal iontophoresis of ranitidine was performed in vitro across dermatomed pig skin. The effect of donor vehicle, current intensity, and drug concentration were first examined using aqueous solutions. It was found that drug delivery was higher at pH 7 (donor: 5mM Tris) than pH 5.6 (donor: water). In the presence of low levels of competing background electrolyte, ranitidine delivery increased linearly with applied current but was independent of the donor drug concentration. The second part of the study evaluated two Pluronic(®) F-127 gels as potential vehicles for ranitidine delivery. The formulations were characterised in terms of apparent viscosity, conductivity and passive permeation measurements. Iontophoretic delivery of ranitidine was only slightly affected when delivered from the gels relative to aqueous solutions. Overall the results demonstrated that therapeutic paediatric doses of ranitidine (neonates: 0.09-0.17 μmol/kg h; 1 month to 12 years: 0.36-0.71 μmol/kg h) could be easily achieved by transdermal iontophoresis with simple gel patches of practical surface area (0.2-1.5 cm(2)/kg). Copyright © 2012 Elsevier B.V. All rights reserved.

A randomized, 14-day, double-blind study evaluating conversion from hydrocodone/acetaminophen (Vicodin) to buprenorphine transdermal system 10 μg/h or 20 μg/h in patients with osteoarthritis pain.

PubMed

Ripa, Steven R; McCarberg, Bill H; Munera, Catherine; Wen, Warren; Landau, Craig J

2012-06-01

The objective of this study was to evaluate continued pain control and tolerability of converting patients from Vicodin (hydrocodone/acetaminophen; HCD/APAP) to the buprenorphine transdermal system (BTDS). Adult patients with pain from osteoarthritis receiving a stable dosage of HCD/APAP (i.e., 15 - 30 mg hydrocodone/day) were switched to an equivalent or near-equivalent dosage of open-label Vicodin for 7 days. Patients maintaining acceptable analgesia were stratified based on their Vicodin dosage and randomized to receive either titratable BTDS 10 μg/h or fixed-dose BTDS 20 μg/h. The primary efficacy variable was completion of the 14-day double-blind phase. Tolerability was assessed. A total of 84.3% of patients met the primary end point, completion of the 14-day double-blind phase (167/198 patients, 95% CI 79.3 - 89.4). Adverse events were consistent with those associated with the use of opioid analgesics and transdermal patches. There was a similar analgesic and tolerability profile when patients treated with Vicodin for osteoarthritis pain were switched to 7-day BTDS treatment.

Development of novel formulations to enhance in vivo transdermal permeation of tocopherol.

PubMed

Nada, Aly H; Zaghloul, Abdelazim A; Hedaya, Mohsen M; Khattab, Ibrahim S

2014-09-01

Tocopherol represents a big challenge for transdermal permeation owing to its extreme hydrophobicity and large molecular mass. The aim of the present study was to develop alpha-tocopherol (T) topical formulations and evaluate their ex vivo and in vivo permeation. Franz diffusion cells were used for ex vivo permeation, and neonatal rats were used for in vivo permeation. Seven gel formulations and 21 liquid formulations were investigated for physical stability, viscosity and permeation of T. Analysis of T was performed by a validated HPLC method using a UV detector. The ex vivo permeation from gel and emulsion formulations was very poor (0.001-0.015%). Highest permeation was observed from monophasic liquid formulations containing dimethyl sulfoxide (DMSO), tocopheryl polyethylene glycols (TPGs), propylene glycol, ethanol and 9.5% T. The in vivo results demonstrated higher retention in the epidermis compared to subcutaneous tissues, 1377 and 1.13 μg g⁻¹, respectively. Increasing T concentration from 4.8 to 9.5% did not increase the amount permeated or % of T retained. It was concluded that simple solutions of T in the presence of DMSO and TPGs were more promising systems for effective transdermal permeation compared to gel, emulsion or oleaginous systems.

Assay of 6-gingerol in CO2 supercritical fluid extracts of ginger and evaluation of its sustained release from a transdermal delivery system across rat skin.

PubMed

Chen, Yan; Zhang, Cuiping; Zhang, Mei; Fu, Xiaobing

2014-07-01

Ginger has been widely used as healthy food condiment as well as traditional Chinese medicine since antiquity. Multiple potentials of ginger for treatment of various ailments have been revealed. However, the biological half-life of 6-gingerol (a principal pungent ingredient of ginger) is only 7.23 minutes while taken orally. Delivery of ginger compositions by routes other than oral have scarcely been reported. Therefore, we studied a noninvasive transdermal drug delivery system (TDDS) of ginger to bypass hepatic first pass metabolism, avoid gastrointestinal degradation and achieve long persistent release of effective compositions. After establishment of a HPLC analysis method of 6-gingerol, assays of 6-gingerol were performed to compare two kinds of ginger extracts. Then, the characteristics of transdermal delivery of 6-gingerol in TDDS were exhibited. The results showed that the contents of 6-gingerol in two kinds of ginger extracts were significantly different. The maximal delivery percentage of 6-gingerol across rat skin at 20 h was more than 40% in different TDDS formulations. TDDS may provide long-lasting delivery of ginger compounds.

Stereomicroscopic imaging technique for the quantification of cold flow in drug-in-adhesive type of transdermal drug delivery systems.

PubMed

Krishnaiah, Yellela S R; Katragadda, Usha; Khan, Mansoor A

2014-05-01

Cold flow is a phenomenon occurring in drug-in-adhesive type of transdermal drug delivery systems (DIA-TDDS) because of the migration of DIA coat beyond the edge. Excessive cold flow can affect their therapeutic effectiveness, make removal of DIA-TDDS difficult from the pouch, and potentially decrease available dose if any drug remains adhered to pouch. There are no compendial or noncompendial methods available for quantification of this critical quality attribute. The objective was to develop a method for quantification of cold flow using stereomicroscopic imaging technique. Cold flow was induced by applying 1 kg force on punched-out samples of marketed estradiol DIA-TDDS (model product) stored at 25°C, 32°C, and 40°C/60% relative humidity (RH) for 1, 2, or 3 days. At the end of testing period, dimensional change in the area of DIA-TDDS samples was measured using image analysis software, and expressed as percent of cold flow. The percent of cold flow significantly decreased (p < 0.001) with increase in size of punched-out DIA-TDDS samples and increased (p < 0.001) with increase in cold flow induction temperature and time. This first ever report suggests that dimensional change in the area of punched-out samples stored at 32°C/60%RH for 2 days applied with 1 kg force could be used for quantification of cold flow in DIA-TDDS. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Transdermal permeation of WIN 55,212-2 and CP 55,940 in human skin in vitro.

PubMed

Valiveti, Satyanarayana; Kiptoo, Paul K; Hammell, Dana C; Stinchcomb, Audra L

2004-06-18

Synthetic cannabinoids have a promising future as treatments for nausea, appetite modulation, pain, and many neurological disorders. Transdermal delivery is a convenient and desirable dosage form for these drugs and health conditions. The aim of the present study was to investigate the in vitro transdermal permeation of two synthetic cannabinoids, WIN 55,212-2 and CP 55,940. Transdermal flux, drug content in the skin, and lag times were measured in split-thickness human abdominal skin in flow-through diffusion cells with receiver solutions of 4% bovine serum albumin (BSA) or 0.5% Brij 98. Differential thermal analysis (DSC) was performed in order to determine heats of fusion, melting points, and relative thermodynamic activities. The in vitro diffusion studies in 0.5% Brij 98 indicated that WIN 55,212-2 diffuses across human skin faster than CP 55,940. The WIN 55,212-2 skin disposition concentration levels were also significantly higher than that of CP 55,940. Correspondingly, CP 55,940 was significantly metabolized in the skin. WIN 55,212-2 flux and skin disposition were significantly lower into 4% BSA than into 0.5% Brij 98 receiver solutions. There was no significant difference in the flux, lag time, and drug content in the skin of CP 55,940 in 4% BSA versus 0.5% Brij 98 receiver solutions. The DSC studies showed that CP 55,940 had a significantly lower melting point, smaller heat of fusion, and corresponding higher calculated thermodynamic activity than the more crystalline WIN 55,212-2 mesylate salt. The permeation results indicated that WIN 55,212-2 mesylate, CP 55,940, and other potent synthetic cannabinoids with these physicochemical properties could be ideal candidates for the development of a transdermal therapeutic system. Copyright 2004 Elsevier B.V.

The effect of transdermal scopolamine for the prevention of postoperative nausea and vomiting.

PubMed

Antor, María A; Uribe, Alberto A; Erminy-Falcon, Natali; Werner, Joseph G; Candiotti, Keith A; Pergolizzi, Joseph V; Bergese, Sergio D

2014-01-01

Postoperative nausea and vomiting (PONV) is one of the most common and undesirable complaints recorded in as many as 70-80% of high-risk surgical patients. The current prophylactic therapy recommendations for PONV management stated in the Society of Ambulatory Anesthesia (SAMBA) guidelines should start with monotherapy and patients at moderate to high risk, a combination of antiemetic medication should be considered. Consequently, if rescue medication is required, the antiemetic drug chosen should be from a different therapeutic class and administration mode than the drug used for prophylaxis. The guidelines restrict the use of dexamethasone, transdermal scopolamine, aprepitant, and palonosetron as rescue medication 6 h after surgery. In an effort to find a safer and reliable therapy for PONV, new drugs with antiemetic properties and minimal side effects are needed, and scopolamine may be considered an effective alternative. Scopolamine is a belladonna alkaloid, α-(hydroxymethyl) benzene acetic acid 9-methyl-3-oxa-9-azatricyclo non-7-yl ester, acting as a non-selective muscarinic antagonist and producing both peripheral antimuscarinic and central sedative, antiemetic, and amnestic effects. The empirical formula is C17H21NO4 and its structural formula is a tertiary amine L-(2)-scopolamine (tropic acid ester with scopine; MW = 303.4). Scopolamine became the first drug commercially available as a transdermal therapeutic system used for extended continuous drug delivery during 72 h. Clinical trials with transdermal scopolamine have consistently demonstrated its safety and efficacy in PONV. Thus, scopolamine is a promising candidate for the management of PONV in adults as a first line monotherapy or in combination with other drugs. In addition, transdermal scopolamine might be helpful in preventing postoperative discharge nausea and vomiting owing to its long-lasting clinical effects.

Rotigotine transdermal system: a short review

PubMed Central

Bunten, Sabine; Happe, Svenja

2006-01-01

Rotigotine (Neupro®) is a new non-ergolinic dopamine agonist transdermal patch that can be applied once daily. To date, it is approved for the treatment of early Parkinson’s disease as monotherapy and has been shown to be effective in the treatment of advanced-stage Parkinson’s disease and restless legs syndrome in several clinical trials. This review gives an overview of physical, chemical, and pharmaceutical characteristics, pharmacokinetics, biotransformation and elimination, drug interactions, and adverse events of rotigotine. Further, the rationale for the treatment of Parkinson’s disease and restless legs syndrome with rotigotine is discussed. PMID:19412491

A study on the gas-solid particle flows in a needle-free drug delivery device

NASA Astrophysics Data System (ADS)

Rasel, Md. Alim Iftekhar; Taher, Md. Abu; Kim, H. D.

2013-08-01

Different systems have been used over the years to deliver drug particles to the human skin for pharmaceutical effect. Research has been done to improve the performance and flexibility of these systems. In recent years a unique system called the transdermal drug delivery has been developed. Transdermal drug delivery opened a new door in the field of drug delivery as it is more flexible and offers better performance than the conventional systems. The principle of this system is to accelerate drug particles with a high speed gas flow. Among different transdermal drug delivery systems we will concentrate on the contour shock tube system in this paper. A contoured shock tube is consists of a rupture chamber, a shock tube and a supersonic nozzle section. The drug particles are retained between a set of bursting diaphragm. When the diaphragm is ruptured at a certain pressure, a high speed unsteady flow is initiated through the shock tube which accelerates the particles. Computational fluid dynamics is used to simulate and analyze the flow field. The DPM (discrete phase method) is used to model the particle flow. As an unsteady flow is initiated though the shock tube the drag correlation proposed by Igra et al is used other than the standard drag correlation. The particle velocities at different sections including the nozzle exit are investigated under different operating conditions. Static pressure histories in different sections in the shock tube are investigated to analyze the flow field. The important aspects of the gas and particle dynamics in the shock tube are discussed and analyzed in details.

Conductive polymer nanotube patch for fast and controlled in vivo transdermal drug delivery

NASA Astrophysics Data System (ADS)

Nguyen, Thao M.

Transdermal drug delivery has created new applications for existing therapies and offered an alternative to the traditional oral route where drugs can prematurely metabolize in the liver causing adverse side effects. Opening the transdermal delivery route to large hydrophilic drugs is one of the greatest challenges due to the hydrophobicity of the skin. However, the ability to deliver hydrophilic drugs using a transdermal patch would provide a solution to problems of other delivery methods for hydrophilic drugs. The switching of conductive polymers (CP) between redox states cause simultaneous changes in the polymer charge, conductivity, and volume—properties that can all be exploited in the biomedical field of controlled drug delivery. Using the template synthesis method, poly(3,4-ethylenedioxythiophene (PEDOT) nanotubes were synthesized electrochemically and a transdermal drug delivery patch was successfully designed and developed. In vitro and in vivo uptake and release of hydrophilic drugs were investigated. The relationship between the strength of the applied potential and rate of drug release were also investigated. Results revealed that the strength of the applied potential is proportional to the rate of drug release; therefore one can control the rate of drug release by controlling the applied potential. The in vitro studies focused on the kinetics of the drug delivery system. It was determined that the drug released mainly followed zero-order kinetics. In addition, it was determined that applying a releasing potential to the transdermal drug delivery system lead to a higher release rate constant (up to 7 times greater) over an extended period of time (˜24h). In addition, over 24 hours, an average of 80% more model drug molecules were released with an applied potential than without. The in vivo study showed that the drug delivery system was capable of delivering model hydrophilic drugs molecules through the dermis layer of the skin within 30 minutes, while the control showed no visible drugs at the same depth. Most importantly, it was determined that the delivery of drugs into the blood stream was stable within 20 minutes. The functionalization of CP was also studied in order to enhance the properties and drug loading capabilities of the polymers. The co-polymerization of poly(3,4-(2-methylene)propylenedioxythiophene) (PMProDot) with polystyrene (PS) and polyvinylcarbazole (PVK) through the highly reactive methylene group was achieved. The modified PMProDot nanotubes demonstrated response times that were two times faster than without modification. The modification of PEDOT nanotubes with polydopamine, a biocompatible polymer, was also investigated and achieved. In depth characterization of functionalized CP demonstrate the ability to fine tune the properties of the polymer in order to achieve the required therapeutic drug release profile.

Transdermal flunixin meglumine minimally alters neutrophil functionality in beef heifers administered a respiratory disease challenge

USDA-ARS?s Scientific Manuscript database

The objectives were to determine the effects of altering time of transdermal flunixin meglumine (BTD; Banamine Transdermal, Merck Animal Health) administration relative to a viral-bacterial challenge in beef heifers. Thirty-two heifers (170 ± 21.1 kg BW) were assigned to one of four treatments: 1) C...

Acute metabolic responses to a combined viral-bacterial respiratory disease challenge in heifers administered transdermal flunixin meglumine

USDA-ARS?s Scientific Manuscript database

A trial was conducted to determine effects of altering time of transdermal flunixin meglumine (BTD; Banamine Transdermal, Merck Animal Health, Summit, NJ) administration relative to a viral-bacterial respiratory disease challenge in beef heifers. Thirty-two healthy heifers (170±21.1 kg BW) were assi...

Hydrogel-Forming Microneedle Arrays for Enhanced Transdermal Drug Delivery

PubMed Central

Donnelly, Ryan F; Singh, Thakur Raghu Raj; Garland, Martin J; Migalska, Katarzyna; Majithiya, Rita; McCrudden, Cian M; Kole, Prashant Laxman; Mahmood, Tuan Mazlelaa Tuan; McCarthy, Helen O; Woolfson, A David

2012-01-01

Unique microneedle arrays prepared from crosslinked polymers, which contain no drug themselves, are described. They rapidly take up skin interstitial fluid upon skin insertion to form continuous, unblockable, hydrogel conduits from attached patch-type drug reservoirs to the dermal microcirculation. Importantly, such microneedles, which can be fabricated in a wide range of patch sizes and microneedle geometries, can be easily sterilized, resist hole closure while in place, and are removed completely intact from the skin. Delivery of macromolecules is no longer limited to what can be loaded into the microneedles themselves and transdermal drug delivery is now controlled by the crosslink density of the hydrogel system rather than the stratum corneum, while electrically modulated delivery is also a unique feature. This technology has the potential to overcome the limitations of conventional microneedle designs and greatly increase the range of the type of drug that is deliverable transdermally, with ensuing benefits for industry, healthcare providers and, ultimately, patients. PMID:23606824

Effects of Transdermal Testosterone on Natriuretic Peptide Levels in Women: A Randomized Placebo-Controlled Pilot Study

PubMed Central

Lin, Eleanor; McCabe, Elizabeth; Newton-Cheh, Christopher; Bloch, Kenneth; Buys, Emmanuel; Wang, Thomas; Miller, Karen K.

2011-01-01

Objective To investigate whether testosterone administration alters natriuretic peptide levels in women. Design Three-month, double-blind, randomized, placebo-controlled study. Setting Clinical research center. Patients 51 women with hypoandrogenemia due to hypopituitarism. Intervention Transdermal testosterone (300 mcg daily) or placebo patch. Main Outcome Measure N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. Results NT-proBNP levels decreased in the transdermal testosterone group compared with placebo over three months (p = 0.009). The difference between groups remained significant after controlling for baseline age, systolic blood pressure, body mass index, and homeostasis model of assessment-insulin resistance (p = 0.008). Change in NT-proBNP over three months was inversely associated with change in free testosterone levels (ρ = −0.41, p = 0.01). Conclusions Testosterone administration to women results in decreased natriuretic peptide levels, suggesting that testosterone may be an inverse regulator of the natriuretic peptide system. Clinical Trials Registration Number NCT00027430 PMID:22137497

Effect of stratum corneum heterogeneity, anisotropy, asymmetry and follicular pathway on transdermal penetration.

PubMed

Barbero, Ana M; Frasch, H Frederick

2017-08-28

The impact of the complex structure of the stratum corneum on transdermal penetration is not yet fully described by existing models. A quantitative and thorough study of skin permeation is essential for chemical exposure assessment and transdermal delivery of drugs. The objective of this study is to analyze the effects of heterogeneity, anisotropy, asymmetry, follicular diffusion, and location of the main barrier of diffusion on percutaneous permeation. In the current study, the solution of the transient diffusion through a two-dimensional-anisotropic brick-and-mortar geometry of the stratum corneum is obtained using the commercial finite element program COMSOL Multiphysics. First, analytical solutions of an equivalent multilayer geometry are used to determine whether the lipids or corneocytes constitute the main permeation barrier. Also these analytical solutions are applied for validations of the finite element solutions. Three illustrative compounds are analyzed in these sections: diethyl phthalate, caffeine and nicotine. Then, asymmetry with depth and follicular diffusion are studied using caffeine as an illustrative compound. The following findings are drawn from this study: the main permeation barrier is located in the lipid layers; the flux and lag time of diffusion through a brick-and-mortar geometry are almost identical to the values corresponding to a multilayer geometry; the flux and lag time are affected when the lipid transbilayer diffusivity or the partition coefficients vary with depth, but are not affected by depth-dependent corneocyte diffusivity; and the follicular contribution has significance for low transbilayer lipid diffusivity, especially when flux between the follicle and the surrounding stratum corneum is involved. This study demonstrates that the diffusion is primarily transcellular and the main barrier is located in the lipid layers. Published by Elsevier B.V.

Effects of Once-Daily Oral and Transdermal Methylphenidate on Sleep Behavior of Children with ADHD

ERIC Educational Resources Information Center

Faraone, Stephen V.; Glatt, Stephen J.; Bukstein, Oscar G.; Lopez, Frank A.; Arnold, L. Eugene; Findling, Robert L.

2009-01-01

Objective: Methylphenidate is a leading first-line treatment for ADHD (AD/HD). This stimulant has long been suspected to adversely affect sleeping patterns of treated individuals, especially children. There are few studies on the effects of recently developed longer-acting methylphenidate treatments, such as once-daily oral or transdermal…

Population pharmacokinetic model of transdermal nicotine delivered from a matrix-type patch.

PubMed

Linakis, Matthew W; Rower, Joseph E; Roberts, Jessica K; Miller, Eleanor I; Wilkins, Diana G; Sherwin, Catherine M T

2017-12-01

Nicotine addiction is an issue faced by millions of individuals worldwide. As a result, nicotine replacement therapies, such as transdermal nicotine patches, have become widely distributed and used. While the pharmacokinetics of transdermal nicotine have been extensively described using noncompartmental methods, there are few data available describing the between-subject variability in transdermal nicotine pharmacokinetics. The aim of this investigation was to use population pharmacokinetic techniques to describe this variability, particularly as it pertains to the absorption of nicotine from the transdermal patch. A population pharmacokinetic parent-metabolite model was developed using plasma concentrations from 25 participants treated with transdermal nicotine. Covariates tested in this model included: body weight, body mass index, body surface area (calculated using the Mosteller equation) and sex. Nicotine pharmacokinetics were best described with a one-compartment model with absorption based on a Weibull distribution and first-order elimination and a single compartment for the major metabolite, cotinine. Body weight was a significant covariate on apparent volume of distribution of nicotine (exponential scaling factor 1.42). After the inclusion of body weight in the model, no other covariates were significant. This is the first population pharmacokinetic model to describe the absorption and disposition of transdermal nicotine and its metabolism to cotinine and the pharmacokinetic variability between individuals who were administered the patch. © 2017 The British Pharmacological Society.

A mechanics approach to the study of pressure sensitive adhesives and human skin for transdermal drug delivery applications

NASA Astrophysics Data System (ADS)

Taub, Marc Barry

Transdermal drug delivery is an alternative approach to the systemic delivery of pharmaceuticals where drugs are administered through the skin and absorbed percutaneously. This method of delivery offers several advantages over more traditional routes; most notably, the avoidance of the fast-pass metabolism of the liver and gut, the ability to offer controlled release rates, and the possibility for novel devices. Pressure sensitive adhesives (PSAs) are used to bond transdermal drug delivery devices to the skin because of their good initial and long-term adhesion, clean removability, and skin and drug compatibility. However, an understanding of the mechanics of adhesion to the dermal layer, together with quantitative and reproducible test methods for measuring adhesion, have been lacking. This study utilizes a mechanics-based approach to quantify the interfacial adhesion of PSAs bonded to selected substrates, including human dermal tissue. The delamination of PSA layers is associated with cavitation in the PSA followed by the formation of an extensive cohesive zone behind the debond tip. A quantitative metrology was developed to assess the adhesion and delamination of PSAs, such that it could be possible to easily distinguish between the adhesive characteristics of different PSA compositions and to provide a quantitative basis from which the reliability of adhesive layers bonded to substrates could be studied. A mechanics-based model was also developed to predict debonding in terms of the relevant energy dissipation mechanisms active during this process. As failure of transdermal devices may occur cohesively within the PSA layer, adhesively at the interface between the PSA and the skin, or cohesively between the corneocytes that comprise the outermost layer of the skin, it was also necessary to explore the mechanical and fracture properties of human skin. The out-of-plane delamination of corneocytes was studied by determining the strain energy release rate during debonding of cantilever-beam specimens containing thin layers of human dermal tissue at their midline. Finally, the interfacial adhesion of PSAs bonded to human skin was studied and the mechanics model that was developed for PSA failure was extended to provide the capability for in vivo reliability predictions for transdermal systems bonded to human skin.

Acute immunological responses to a combined viral-bacterial respiratory disease challenge in heifers administered transdermal flunixin meglumine

USDA-ARS?s Scientific Manuscript database

Time of flunixin meglumine transdermal (FTD; Finadyne Transdermal, Merck Animal Health, Summit, NJ) administration relative to a viral-bacterial challenge was evaluated in beef heifers. Thirty-two beef heifers (170 ± 21.1 kg BW) were randomly assigned to one of four treatments: 1) Control (CON), rec...

Efficacy and tolerability of transdermal granisetron for the control of chemotherapy-induced nausea and vomiting associated with moderately and highly emetogenic multi-day chemotherapy: a randomized, double-blind, phase III study.

PubMed

Boccia, Ralph V; Gordan, Lucio N; Clark, Gemma; Howell, Julian D; Grunberg, Steven M

2011-10-01

A novel transdermal formulation of granisetron (the granisetron transdermal delivery system (GTDS)) has been developed to deliver granisetron continuously over 7 days. This double-blind, phase III, non-inferiority study compared the efficacy and tolerability of the GTDS to daily oral granisetron for the control of chemotherapy-induced nausea and vomiting (CINV). Six hundred forty-one patients were randomized to oral (2 mg/day, 3-5 days) or transdermal granisetron (one GTDS patch, 7 days), before receiving multi-day chemotherapy. The primary endpoint was complete control of CINV (no vomiting/retching, no more than mild nausea, no rescue medication) from chemotherapy initiation until 24 h after final administration. The prespecified non-inferiority margin was 15%. Five hundred eighty-two patients were included in the per protocol analysis. The GTDS displayed non-inferiority to oral granisetron: complete control was achieved by 60% of patients in the GTDS group, and 65% in the oral granisetron group (treatment difference, -5%; 95% confidence interval, -13-3). Both treatments were well tolerated, the most common adverse event being constipation. The GTDS provides effective, well-tolerated control of CINV associated with moderately or highly emetogenic multi-day chemotherapy. It offers a convenient alternative route for delivering granisetron for up to 7 days that is as effective as oral granisetron.

Development and physical characterization of polymer-fish oil bigel (hydrogel/oleogel) system as a transdermal drug delivery vehicle.

PubMed

Rehman, Khurram; Mohd Amin, Mohd Cairul Iqbal; Zulfakar, Mohd Hanif

2014-01-01

Polymer-Fish oil bigel (hydrogel/oleogel colloidal mixture) was developed by using fish oil and natural (sodium alginate) and synthetic (hydroxypropyl methylcellulose) polymer for pharmaceutical purposes. The bigels were closely monitored and thermal, rheological and mechanical properties were compared with the conventional hydrogels for their potential use as an effective transdermal drug delivery vehicle. Stability of the fish oil fatty acids (especially eicosapentanoic acid, EPA and docosahexanoic acid, DHA) was determined by gas chromatography and the drug content (imiquimod) was assessed with liquid chromatography. Furthermore, in vitro permeation study was conducted to determine the capability of the fish oil-bigels as transdermal drug delivery vehicle. The bigels showed pseudoplastic rheological features, with excellent mechanical properties (adhesiveness, peak stress and hardness), which indicated their excellent spreadability for application on the skin. Bigels prepared with mixture of sodium alginate and fish oil (SB1 and SB2), and the bigels prepared with the mixture of hydroxypropyl methylcellulose and fish oil (HB1-HB3) showed high cumulative permeation and drug flux compared to hydrogels. Addition of fish oil proved to be beneficial in increasing the drug permeation and the results were statistically significant (p < 0.05, one-way Anova, SPSS 20.0). Thus, it can be concluded that bigel formulations could be used as an effective topical and transdermal drug delivery vehicle for pharmaceutical purposes.

Development of liposomal and microemulsion formulations for transdermal delivery of clonazepam: effect of randomly methylated β-cyclodextrin.

PubMed

Mura, Paola; Bragagni, Marco; Mennini, Natascia; Cirri, Marzia; Maestrelli, Francesca

2014-11-20

Transdermal administration of clonazepam, a poorly water-soluble benzodiazepine, is an interesting strategy for overcoming the drawbacks of its oral administration. With this aim, two nano-carrier formulations, based on ultra-deformable liposomes and microemulsions, have been developed to favour clonazepam transdermal delivery. Considering the solubilizing power of methyl-βcyclodextrin (Me-βCD) toward clonazepam and its potential positive influence on transdermal drug delivery, the effect of its addition to these formulations was investigated. Artificial lipophilic membranes simulating the skin allowed a rapid evaluation of the drug permeation properties from the systems, compared with those from an aqueous drug suspension, with or without Me-βCD. The best formulations were further characterized by permeation through excised rabbit ear skin. All the formulations increased drug permeability, ranging from 2-fold (liposomes without Me-βCD), up to over 4-fold (microemulsions containing Me-βCD). The different formulations allowed for pointing out different possible permeation enhancing mechanisms of Me-βCD: increase in drug solubility and thermodynamic activity in the vehicle, when added to the drug aqueous suspension; interactions with the vesicle bilayer, in case of liposomal formulations; interactions with the skin membrane lipids, as evidenced in experiments with excised rabbit ear for microemulsions containing Me-βCD, that were then selected for further in vivo studies. Copyright © 2014. Published by Elsevier B.V.

Microneedles for Transdermal Biosensing: Current Picture and Future Direction.

PubMed

Ventrelli, Letizia; Marsilio Strambini, Lucanos; Barillaro, Giuseppe

2015-12-09

A novel trend is rapidly emerging in the use of microneedles, which are a miniaturized replica of hypodermic needles with length-scales of hundreds of micrometers, aimed at the transdermal biosensing of analytes of clinical interest, e.g., glucose, biomarkers, and others. Transdermal biosensing via microneedles offers remarkable opportunities for moving biosensing technologies and biochips from research laboratories to real-field applications, and envisages easy-to-use point-of-care microdevices with pain-free, minimally invasive, and minimal-training features that are very attractive for both developed and emerging countries. In addition to this, microneedles for transdermal biosensing offer a unique possibility for the development of biochips provided with end-effectors for their interaction with the biological system under investigation. Direct and efficient collection of the biological sample to be analyzed will then become feasible in situ at the same length-scale of the other biochip components by minimally trained personnel and in a minimally invasive fashion. This would eliminate the need for blood extraction using hypodermic needles and reduce, in turn, related problems, such as patient infections, sample contaminations, analysis artifacts, etc. The aim here is to provide a thorough and critical analysis of state-of-the-art developments in this novel research trend, and to bridge the gap between microneedles and biosensors. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Transdermal anti-nuclear kappaB siRNA therapy for atopic dermatitis using a combination of two kinds of functional oligopeptide.

PubMed

Ibaraki, Hisako; Kanazawa, Takanori; Takashima, Yuuki; Okada, Hiroaki; Seta, Yasuo

2018-05-05

Nucleic acid-based targeting of nuclear factor kappaB (NF-κB) is gaining attention as a treatment option for skin diseases like atopic dermatitis (AD). Transdermal administration improves patient quality of life because of non-invasive; however, siRNA delivery into the skin can be challenging owing to the barrier of tight junctions in the granular layer. Therefore, we aimed to develop a delivery system of siRNA for topical skin application using functional peptides. We previously reported that combined treatment with a cytoplasm-responsive stearylated-arginine-rich peptide (STR-CH 2 R 4 H 2 C) and a tight junction opening peptide (AT1002) showed high siRNA permeability in the skin of AD-induced and normal mice. Here, we used murine macrophage RAW264.7 cells to examine siRNA permeation and the therapeutic effect of anti-NF-κB (RelA) siRNA (siRelA) complexed with STR-CH 2 R 4 H 2 C and AT1002 for AD-induced mice. We showed that significantly higher siRNA cellular uptake occurs after this treatment as well as decreased TNF-α and IL-6 expression. Additionally, we showed that effective siRNA transdermal delivery occurs with the suppression of the tight junction protein ZO-1. Moreover, topical skin application of siRelA with STR-CH 2 R 4 H 2 C and AT1002 improved AD-like symptoms in model mice. Thus, the combined treatment of STR-CH 2 R 4 H 2 C and AT1002 could serve as an effective transdermal siRNA therapeutic system for AD. Copyright © 2018 Elsevier B.V. All rights reserved.

Pharmacokinetics, safety, and tolerability of rotigotine transdermal system in healthy Japanese and Caucasian subjects following multiple-dose administration.

PubMed

Cawello, Willi; Kim, Seong Ryul; Braun, Marina; Elshoff, Jan-Peer; Masahiro, Takeuchi; Ikeda, Junji; Funaki, Tomoo

2016-08-01

Rotigotine is a dopamine receptor agonist indicated for the treatment of Parkinson's disease and moderate-to-severe restless legs syndrome. Continuous transdermal delivery of rotigotine via a silicon-based patch maintains stable plasma concentrations over 24 h. The objective of the study was to evaluate the pharmacokinetics, safety, and tolerability of a multiple-dose schedule of rotigotine transdermal patch in Japanese and Caucasian subjects. In this open-label, repeated-dose, parallel-group study (ClinicalTrials.gov: NCT01854216), healthy male and female subjects of Japanese or Caucasian ethnic origin were matched by gender, body mass index, and age. Subjects underwent a 9-day patch application period. 12 Japanese and 12 Caucasian subjects were included in the pharmacokinetic analyses. Mean apparent doses (actual amount of drug delivered) increased proportionally with rotigotine nominal dosages (1, 2, and 4 mg/24 h) and were similar for both ethnic groups, with large inter-individual variability. Mean plasma concentration-time profiles for unconjugated rotigotine were similar in both ethnic groups at day 3 for each dosage. Peak concentrations (C max,ss) and area under the concentration-time curves from pre-dose to the concentration measured 24 h after administration of patch (AUC(0-24,ss)) showed similar exposure in both groups; higher values in Japanese subjects were explained by differences in body weight. For total rotigotine, C max,ss and AUC(0-24,ss) values were higher in Caucasian subjects and could be explained by small differences in apparent dose. Rotigotine was generally well tolerated following multiple applications up to 4 mg/24 h. These findings suggest similar dosage requirements for rotigotine transdermal system in Japanese and Caucasian populations.

Influence of domperidone on pharmacokinetics, safety and tolerability of the dopamine agonist rotigotine

PubMed Central

Braun, Marina; Cawello, Willi; Boekens, Hilmar; Horstmann, Rolf

2009-01-01

AIMS To evaluate the influence of the antiemetic agent domperidone on steady-state pharmacokinetics, safety and tolerability of multiple-dose treatment of the transdermally applied non-ergolinic dopamine agonist rotigotine. METHODS Sixteen healthy male subjects (mean age 30.3 years) participated in a randomized, two-way crossover clinical trial. Treatment A consisted of transdermal rotigotine patch (2 mg (24 h)−1, 10 cm2, total drug content 4.5 mg) applied daily for 4 days, and concomitant oral domperidone (10 mg t.i.d.) for 5 days. For treatment B, subjects received only transdermal rotigotine treatment (daily for 4 days). Pharmacokinetic variables describing systemic exposure and renal elimination of rotigotine and metabolites, and safety and tolerability of the treatment were assessed. RESULTS The primary steady-state pharmacokinetic parameters (Cmax,ss and AUC(0–24),ss) were similar with or without co-administration of domperidone. Geometric mean ratios were close to 1 and respective 90% confidence intervals were within the acceptance range of bioequivalence (0.8, 1.25): Cmax,ss 0.96 (0.86, 1.08) and AUC(0–24),ss 0.97 (0.87, 1.08). tmax,ss, t1/2, secondary parameters calculated on days 4/5 after repeated patch application (Cmin,ss, Cave,ss, AUC(0–tz)) and renal elimination for unconjugated rotigotine and its metabolites were also similar with and without comedication of domperidone. A reduction in the dopaminergic side-effect nausea was seen with domperidone comedication. CONCLUSIONS No changes of pharmacokinetic parameters describing systemic exposure and renal elimination of rotigotine were observed when domperidone was administered concomitantly with rotigotine. The lack of pharmacokinetic interactions indicates that a dose adjustment of rotigotine transdermal patch is not necessary with concomitant use of domperidone. PMID:19094160

Long-term safety and tolerability of rotigotine transdermal system in patients with early-stage idiopathic Parkinson's disease: a prospective, open-label extension study.

PubMed

Elmer, Lawrence W; Surmann, Erwin; Boroojerdi, Babak; Jankovic, Joseph

2012-06-01

This prospective, open-label extension (SP702; NCT00594165) of a 6-month double-blind, randomized study investigated the long-term safety and tolerability of rotigotine transdermal system in early Parkinson's disease (PD). Patients with early-stage idiopathic PD received transdermal rotigotine for up to 6 years at optimal dose (up to 16 mg/24h). Adjunctive levodopa was allowed. Primary outcomes included adverse events (AEs) and extent of rotigotine exposure. Other outcomes included time to levodopa, incidence of dyskinesias, and efficacy using the Unified Parkinson's Disease Rating Scale (UPDRS) II+III total score. Of 217 patients entering the open-label study, 47% were still in the study upon closure; 24% withdrew because of AEs and 6% because of lack of efficacy. The median exposure to rotigotine was 1910 days (≈ 5 years, 3 months; range 1-2188 days). Most common AEs were somnolence (23% per patient-year), falls (17%), peripheral edema (14%), nausea (12%), and application site reactions (ASRs; 12%). 3% withdrew because of ASRs. 26% patients did not initiate levodopa; of those who did, fewer than half started levodopa in the first year. Dyskinesias were reported by 25% patients; the majority (83%) reported their first episode after initiating levodopa. Mean UPDRS II+III total scores remained below double-blind baseline for up to 2 years of open-label treatment. This is the longest interventional study of rotigotine conducted to date. Transdermal rotigotine was generally well tolerated for up to 6 years; AEs reported were similar to those observed in shorter studies and led to discontinuation in only 24% patients. Copyright © 2012 Elsevier Ltd. All rights reserved.

Transdermal nitroglycerin for the treatment of preterm labor: a systematic review and metaanalysis.

PubMed

Conde-Agudelo, Agustín; Romero, Roberto

2013-12-01

The purpose of this study was to evaluate the efficacy and safety of transdermal nitroglycerin as a tocolytic agent in women with preterm labor. We conducted a systematic review and metaanalysis of randomized controlled trials. Thirteen studies were included (1302 women) comparing transdermal nitroglycerin vs placebo (2 studies; n = 186); β2-adrenergic receptor agonists (9 studies; n = 1024); nifedipine (1 study; n = 50); and magnesium sulfate (1 study; n = 42). There were no significant differences between transdermal nitroglycerin and placebo for delivery within 48 hours of the initiation of treatment or at <28, <34, or <37 weeks of gestation, adverse neonatal outcomes, and neurodevelopmental status at 24 months of life. Nevertheless, 1 study found a marginally significant reduction in the risk of a composite outcome of major neonatal morbidity and perinatal death (3/74 [4.1%] vs 11/79 [13.9%]; relative risk, 0.29; 95% confidence interval, 0.08-1.00). When compared with β2-adrenergic receptor agonists, transdermal nitroglycerin was associated with a significant reduction in the risk of preterm birth at <34 and <37 weeks of gestation, admission to the neonatal intensive care unit, use of mechanical ventilation, and maternal side effects. There were no significant differences between transdermal nitroglycerin and nifedipine and magnesium sulfate in delivery within 48 hours of treatment and pregnancy prolongation, respectively. Overall, women who received transdermal nitroglycerin had a higher risk of headache. Although transdermal nitroglycerin appears to be more effective than β2-adrenergic receptor agonists, the current evidence does not support its routine use as a tocolytic agent for the treatment of preterm labor. Further double-blind placebo-controlled trials are needed. Copyright © 2013 Mosby, Inc. All rights reserved.

Transcriptional transactivator peptide modified lidocaine-loaded nanoparticulate drug delivery system for topical anesthetic therapy.

PubMed

Wang, Yan; Wang, Shenhui; Shi, Pengcai

2016-11-01

For the topical anesthetic, transcriptional transactivator peptide (TAT) modified lidocaine (LID) loaded nanostructured lipid carriers (TAT-NLCs-LID) were prepared and then used for improving transdermal delivery of local anesthetic drug. In this study, TAT was conjugated with Distearoyl phosphatidylethanolamine-(polyethylene glycol) 2000 -maleimide (DSPE-PEG 2000 -Mal) to obtain TAT-PEG 2000 -DSPE. TAT-NLCs-LID were successfully prepared and characterized by determination of their particle size, morphology, drug encapsulation efficiency and in vitro drug release behavior. The skin permeation of LID-LNPs was examined using a Franz diffusion cell mounted with depilated mouse skin in vitro and in vivo anesthesia effect was evaluated on mice. The results showed that TAT-NLCs-LID have substantially small mean diameter (157.9 nm) and high encapsulation efficiency (81.8%). From the in vitro skin permeation results, transdermal flux of TAT-NLCs-LID was about several times higher than that of LID solution and NLCs-LID. In vivo anesthesia effect evaluation illustrated that TAT-NLCs-LID can enhance the transdermal delivery of LID by reducing the pain threshold in mice. These results indicate that the novel TAT containing drug delivery system is very useful for overcoming the barrier function of the skin and could deliver anesthetic through the skin. TAT-NLCs-LID could function as promising topical anesthetic system.

Development of a Two-Dimensional Model for Predicting Transdermal Permeation with the Follicular Pathway: Demonstration with a Caffeine Study.

PubMed

Kattou, Panayiotis; Lian, Guoping; Glavin, Stephen; Sorrell, Ian; Chen, Tao

2017-10-01

The development of a new two-dimensional (2D) model to predict follicular permeation, with integration into a recently reported multi-scale model of transdermal permeation is presented. The follicular pathway is modelled by diffusion in sebum. The mass transfer and partition properties of solutes in lipid, corneocytes, viable dermis, dermis and systemic circulation are calculated as reported previously [Pharm Res 33 (2016) 1602]. The mass transfer and partition properties in sebum are collected from existing literature. None of the model input parameters was fit to the clinical data with which the model prediction is compared. The integrated model has been applied to predict the published clinical data of transdermal permeation of caffeine. The relative importance of the follicular pathway is analysed. Good agreement of the model prediction with the clinical data has been obtained. The simulation confirms that for caffeine the follicular route is important; the maximum bioavailable concentration of caffeine in systemic circulation with open hair follicles is predicted to be 20% higher than that when hair follicles are blocked. The follicular pathway contributes to not only short time fast penetration, but also the overall systemic bioavailability. With such in silico model, useful information can be obtained for caffeine disposition and localised delivery in lipid, corneocytes, viable dermis, dermis and the hair follicle. Such detailed information is difficult to obtain experimentally.

Prevention of peripheral side-effects of transdermal hyoscine by adjunctive therapy with low dosage of pyridostigmine.

PubMed Central

Ziv, I; Versano, D; Ruach, M; Izraeli, S; Almog, S; Alhalel, A; Alkalay, M; Menahem, S; Tochner, Z

1992-01-01

1. The value of low dosage of pyridostigmine (30 mg three times daily) in preventing peripheral anti-muscarinic side effects of a transdermal controlled-release formulation of hyoscine, was tested in a double-blind placebo-controlled study, involving 47 healthy subjects. 2. Salivary excretion was repeatedly measured during 48 h of combined therapy of two transdermal hyoscine patches with pyridostigmine and 14 h after its cessation. Blood acetylcholinesterase activity was also measured, serving as an index of pyridostigmine bioavailability. 3. The adjunctive therapy with pyridostigmine was highly effective in preventing the substantial impairment in salivary flow caused by the transdermal formulation. An associated 23% inhibition of blood acetylcholinesterase activity was observed. 4. Small doses of pyridostigmine may therefore have a role in increasing the tolerability of transdermal hyoscine therapy. In some patients this drug combination might also allow some increment of the hyoscine dose. PMID:1524963

Organogels in Drug Delivery: A Special Emphasis on Pluronic Lecithin Organogels.

PubMed

Alsaab, Hashem; Bonam, Sindhu Prabha; Bahl, Dherya; Chowdhury, Pallabita; Alexander, Kenneth; Boddu, Sai Hs

2016-01-01

Organogels have emerged as an alternative carrier for small and macromolecules via transdermal, oral, rectal and ophthalmic routes. Pluronic lecithin organogels (PLO gels) are lecithin-based organogels widely used in compounding pharmacies as a vehicle for enhancing the transdermal permeability of many therapeutic drugs. However, the scientific and systematic evidence in support of how well PLO gels help in transdermal delivery is scanty. Recently, some clinical studies have reported nearly complete lack of bioavailability of certain topically administered drugs from PLO gels. The present review aims at summarizing gels and organogels, with a focus on the use of PLO gels in transdermal drug delivery. A special emphasis is placed on controversies looming over the use of PLO gels as a delivery platform for drugs via transdermal route. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

A novel local anesthetic system: transcriptional transactivator peptide-decorated nanocarriers for skin delivery of ropivacaine.

PubMed

Chen, Chuanyu; You, Peijun

2017-01-01

Barrier properties of the skin and physicochemical properties of drugs are the main factors for the delivery of local anesthetic molecules. The present work evaluates the anesthetic efficacy of drug-loaded nanocarrier (NC) systems for the delivery of local anesthetic drug, ropivacaine (RVC). In this study, transcriptional transactivator peptide (TAT)-decorated RVC-loaded NCs (TAT-RVC/NCs) were successfully fabricated. Physicochemical properties of NCs were determined in terms of particle size, zeta potential, drug encapsulation efficiency, drug-loading capacity, stability, and in vitro drug release. The skin permeation of NCs was examined using a Franz diffusion cell mounted with depilated mouse skin in vitro, and in vivo anesthetic effect was evaluated in mice. The results showed that TAT-RVC/NCs have a mean diameter of 133.2 nm and high drug-loading capacity of 81.7%. From the in vitro skin permeation results, it was observed that transdermal flux of TAT-RVC/NCs was higher than that of RVC-loaded NCs (RVC/NCs) and RVC injection. The evaluation of in vivo anesthetic effect illustrated that TAT-RVC/NCs can enhance the transdermal delivery of RVC by reducing the pain threshold in mice. These results indicate that TAT-decorated NCs systems are useful for overcoming the barrier function of the skin, decreasing the dosage of RVC and enhancing the anesthetic effect. Therefore, TAT-decorated NCs can be used as an effective transdermal delivery system for local anesthesia.

Novel non-ionic surfactant proniosomes for transdermal delivery of lacidipine: optimization using 2(3) factorial design and in vivo evaluation in rabbits.

PubMed

Soliman, Sara M; Abdelmalak, Nevine S; El-Gazayerly, Omaima N; Abdelaziz, Nabaweya

2016-06-01

Proniosomes offer a versatile vesicle drug delivery concept with potential for delivery of drugs via transdermal route. To develop proniosomal gel using cremophor RH 40 as non-ionic surfactant containing the antihypertensive drug lacidipine for transdermal delivery so as to avoid its extensive first pass metabolism and to improve its permeation through the skin. Proniosomes containing 1% lacidipine were prepared by the coacervation phase separation method, characterized, and optimized using a 2(3) full factorial design to define the optimum conditions to produce proniosomes with high entrapment efficiency, minimal vesicle size, and high-percentage release efficiency. The amount of cholesterol (X1), the amount of soya lecithin (X2), and the amount of cremophor RH 40 (X3) were selected as three independent variables. The system F4 was found to fulfill the maximum requisite of an optimum system because it had minimum vesicle size, maximum EE, maximum release efficiency, and maximum desirability. The optimized system (F4) was then converted to proniosomal gel using carbopol 940 (1% w/w). In vitro permeation through excised rabbit skin study revealed higher flux (6.48 ± 0.45) for lacidipine from the optimized proniosomal gel when compared with the corresponding emulgel (3.04 ± 0.13) mg/cm(2)/h. The optimized formulation was evaluated for its bioavailability compared with commercial product. Statistical analysis revealed significant increase in AUC (0 - α) 464.17 ± 113.15 ng h/ml compared with 209.02 ± 47.35 ng h/ml for commercial tablet. Skin irritancy and histopathological investigation of rat skin revealed its safety. Cremophor RH 40 proniosomal gel could be considered as very promising nanocarriers for transdermal delivery of lacidipine.

Current and future technological advances in transdermal gene delivery.

PubMed

Chen, Xianfeng

2017-12-19

Transdermal gene delivery holds significant advantages as it is able to minimize the problems of systemic administration such as enzymatic degradation, systemic toxicity, and poor delivery to target tissues. This technology has the potential to transform the treatment and prevention of a range of diseases. However, the skin poses a great barrier for gene delivery because of the "bricks-and-mortar" structure of the stratum corneum and the tight junctions between keratinocytes in the epidermis. This review systematically summarizes the typical physical and chemical approaches to overcome these barriers and facilitate gene delivery via skin for applications in vaccination, wound healing, skin cancers and skin diseases. Next, the advantages and disadvantages of different approaches are discussed and the insights for future development are provided. Copyright © 2017 Elsevier B.V. All rights reserved.

Laser-assisted delivery of topical methotrexate - in vitro investigations.

PubMed

Taudorf, Elisabeth Hjardem

2016-06-01

Ablative fractional lasers (AFXL) are increasingly used to treat dermatological disorders and to facilitate laser-assisted topical drug delivery. In this thesis, laser-tissue interactions generated by stacked pulses with a miniaturized low-power 2,940 nm AFXL were characterized (study I). Knowledge of the correlation between laser parameters and tissue effects was used to deliver methotrexate (MTX) topically through microscopic ablation zones (MAZs) of precise dimensions. MTX is a well-known chemotherapeutic and anti-inflammatory drug that may cause systemic adverse effects, and topical delivery is thus of potential benefit. The impact of MAZ depth (study II) and transport kinetics (study III) on MTX deposition in skin as well as transdermal permeation was determined in vitro. Quantitative analyses of dermal and transdermal MTX concentrations were performed by high performance liquid chromatography (HPLC) (study II & III), while qualitative analyses of MTX biodistribution in skin were illustrated and semi-quantified by fluorescence microscopy (study II & III) and desorption electro spray mass spectrometry imaging (DESI-MSI) (study III). Laser-tissue interactions generated by AFXL: AFXL-exposure generated a variety of MAZ-dimensions. MAZ depth increased linearly with the logarithm of total energy delivered by stacked pulses, but was also affected by variations in power, pulse energy, pulse duration, and pulse repetition rate. Coagulation zones lining MAZs increased linearly with the applied total energy, while MAZ width increased linearly with the logarithm of stacked pulses. Results were gathered in a mathematical model estimating relations between laser parameters and specific MAZ dimensions. Impact of MAZ depth on AFXL-assisted topical MTX delivery: Pretreatment by AFXL facilitated topical MTX delivery to all skin layers. Deeper MAZs increased total MTX deposition in skin compared to superficial MAZs and altered the intradermal biodistribution profile towards maximum accumulation in deeper skin layers. Biodistribution of MTX occurred throughout the skin without being compromised by coagulation zones of varying thickness. The ratio of skin deposition versus transdermal permeation was constant, regardless of MAZ depth. Impact of transport kinetics on AFXL-assisted topical MTX delivery: MTX accumulated rapidly in AFXL-processed skin. MTX was detectable in mid-dermis after 15 min. and saturated the skin after 7 h at a ten-fold increased MTX-concentration compared to intact skin. Transdermal permeation stayed below 1.5% of applied MTX before skin saturation, and increased afterwards up to 8.0% at 24h. MTX distributed radially into the coagulation zone within 15 min of application and could be detected in surrounding skin at 1.5 h. Upon skin saturation, MTX had distributed in an entire mid-dermal skin section. In conclusion, adjusting laser parameters and application time may enable targeted treatments of dermatological disorders and potentially pose a future alternative to systemic MTX in selected dermatological disorders.

Evaluation of the pharmacodynamics and pharmacokinetics of brucine following transdermal administration.

PubMed

Chen, Jun; Hu, Wei; Qu, Ye-Qing; Dong, Jie; Gu, Wei; Gao, Ying; Fang, Yun; Fang, Fang; Chen, Zhi-Peng; Cai, Bao-Chang

2013-04-01

Before the design of brucine-containing transdermal formulations, the pharmacodynamics and pharmacokinetics of brucine following transdermal administration should be evaluated. In this study, the effect of addition of ethanol on solubility of bruicne was investigated and 20% ethanol was added into PBS to obtain 10mg/mL brucine solution. Then three transdermal doses (10, 20 and 40 mg/kg) were administered to mice to evaluate pharmacological activity. It had been demonstrated that brucine possessed analgesic and anti-inflammatory activity in a dose-dependent manner. Cytotoxicities of brucine against various tumor cells including skin tumor cell were also compared in vitro. Brucine was found to possess antitumor activity in a concentration and time-dependent manner and gastrointestinal tumor cells seemed to be more sensitive to brucine. Then in vitro skin permeation behavior and in vivo pharmacokinetics following transdermal administration were further investigated. The cumulative amounts of brucine across mouse skin in vitro were found to be higher than 90%. The absolute bioavailability of brucine was determined to be 40.83%. And compared with intravenous administration, MRT and T1/2 values were increased about 8~12-fold by transdermal route. Moreover, fluctuations of drug levels were found to be significantly decreased in tissues, especially in brain. Finally, no dermal toxicity of brucine was observed. The results of this study indicated that transdermal administration might be beneficial for the sustained efficacy and reduced toxicity of brucine. Copyright © 2013 Elsevier B.V. All rights reserved.

Transdermal fentanyl: pharmacology and toxicology.

PubMed

Nelson, Lewis; Schwaner, Robert

2009-12-01

To evaluate the underlying pharmacology, safety, and misuse/abuse of transdermal fentanyl, one of the cornerstone pharmacotherapies for patients with chronic pain. Literature was identified through searches of Medline (PubMed) and several textbooks in the areas of pharmacology, toxicology, and pain management. A bibliographical review of articles identified by these searches was also performed. Search terms included combinations of the following: fentanyl, transdermal, patch, pharmacology, kinetics, toxicity, and poisoning. All pertinent clinical trials, retrospective studies, and case reports relevant to fentanyl pharmacology and transdermal fentanyl administered by any route and published in English were identified. Each was reviewed for data regarding the clinical pharmacology, abuse, misuse, and safety of transdermal fentanyl. Data from these studies and information from review articles and pharmaceutical prescribing information were included in this review. Fentanyl is a high-potency opioid that has many uses in the treatment of both acute and chronic pain. Intentional or unintentional misuse, as well as abuse, may lead to significant clinical consequences, including death. Both the US Food and Drug Administration (FDA) and Health Canada have warned of potential pitfalls associated with transdermal fentanyl, although these have not been completely effective in preventing life-threatening adverse events and fatalities related to its inappropriate use. Clinically consequential adverse effects may occur unexpectedly with normal use of transdermal fentanyl, or if misused or abused. Misuse and therapeutic error may be largely preventable through better education at all levels for both the prescriber and patient. The prevention of intentional misuse or abuse may require regulatory intervention.

Rotigotine transdermal patch for the treatment of Parkinson's Disease.

PubMed

Perez-Lloret, Santiago; Rey, María Verónica; Ratti, Pietro Lucca; Rascol, Olivier

2013-02-01

Rotigotine, a non-ergot dopamine agonist, has been developed as a novel transdermal formulation. The rotigotine transdermal patch has received EMEA marketing authorization for the treatment of adult patients with early or advanced Parkinson's disease (PD) or with moderate to severe restless legs syndrome (RLS). FDA originally granted a marketing authorization for early PD, which was later suspended, and is now studying the authorization for RLS. The aim of this review is to review the pharmacokinetics, pharmacodynamics as well as the clinical efficacy and tolerability of the rotigotine transdermal patch in PD. Source material was identified using a PubMed search for the term 'rotigotine' and PD. Articles published up to January 2011 or abstract submitted to most relevant international neurology congresses were reviewed. The rotigotine transdermal patch is efficacious for the treatment of PD. Tolerability profile appears to be well within the range of that observed with other non-ergot dopamine agonists in PD. Application-site reactions were the most frequent adverse event, and they were considered mild to moderate in the majority of cases. The rotigotine transdermal patch offers a safe and efficacious alternative for the treatment of PD. Further studies should focus on the possibility that continuous dopamine stimulation by means of the transdermal patch has any influence on levodopa-related motor complications. © 2012 The Authors Fundamental and Clinical Pharmacology © 2012 Société Française de Pharmacologie et de Thérapeutique.

Self-Assembled Cubic Liquid Crystalline Nanoparticles for Transdermal Delivery of Paeonol

PubMed Central

Li, Jian-Chun; Zhu, Na; Zhu, Jin-Xiu; Zhang, Wen-Jing; Zhang, Hong-Min; Wang, Qing-Qing; Wu, Xiao-Xiang; Wang, Xiu; Zhang, Jin; Hao, Ji-Fu

2015-01-01

Background The aim of this study was to optimize the preparation method for self-assembled glyceryl monoolein-based cubosomes containing paeonol and to characterize the properties of this transdermal delivery system to improve the drug penetration ability in the skin. Material/Methods In this study, the cubic liquid crystalline nanoparticles loaded with paeonol were prepared by fragmentation of glyceryl monoolein (GMO)/poloxamer 407 bulk cubic gel by high-pressure homogenization. We evaluated the Zeta potential of these promising skin-targeting drug-delivery systems using the Malvern Zeta sizer examination, and various microscopies and differential scanning calorimetry were also used for property investigation. Stimulating studies were evaluated based on the skin irritation reaction score standard and the skin stimulus intensity evaluation standard for paeonol cubosomes when compared with commercial paeonol ointment. In vitro tests were performed on excised rat skins in an improved Franz diffusion apparatus. The amount of paeonol over time in the in vitro penetration and retention experiments both was determined quantitatively by HPLC. Results Stimulating studies were compared with the commercial ointment which indicated that the paeonol cubic liquid crystalline nanoparticles could reduce the irritation in the skin stimulating test. Thus, based on the attractive characteristics of the cubic crystal system of paeonol, we will further exploit the cosmetic features in the future studies. Conclusions The transdermal delivery system of paeonol with low-irritation based on the self-assembled cubic liquid crystalline nanoparticles prepared in this study might be a promising system of good tropical preparation for skin application. PMID:26517086

Behavior Therapy and the Transdermal Nicotine Patch: Effects on Cessation Outcome, Affect, and Coping.

ERIC Educational Resources Information Center

Cinciripini, Paul M.; And Others

1996-01-01

Process and outcome of a smoking cessation program using behavior therapy along (BT) or behavior therapy plus the nicotine patch (BTP) was studied in 64 participants. Abstinence was significantly higher for the BTP group from the end of behavioral treatment (79% vs. 63%) through the three-month follow-up, with the effects weakening at the six- and…

Idiopathic scrotal calcinosis.

PubMed

Celik, Orcun; Ipekci, Tumay; Kazimoglu, Hatem

2013-12-01

Idiopathic scrotal calcinosis is a rare scrotal benign disease. Its distinct features are painless, non-pruritic, semi-soft palpable calcific transdermal nodules. We report a 42-year-old-man with asymptomatic multiple calcified scrotal skin nodules for 10 years. Under spinal anesthesia, the affected scrotal skin was excised and the nodules removed. We aim to explain the etiology, pathophysiology, diagnosis, and treatment modalities of this rare disease.

Evolution of stimulants to treat ADHD: transdermal methylphenidate

PubMed Central

Patrick, Kennerly S.; Straughn, Arthur B.; Perkins, Jeb S.; González, Mario A.

2009-01-01

Objective The following comprehensive review describes the evolution of stimulant drug formulations used in the treatment of attention-deficit/hyperactivity disorder (ADHD). Emphasis is placed on the basic and clinical pharmacology of the dl-methylphenidate (MPH) transdermal system (MTS). Methods The pharmacokinetic and pharmacodynamic literature pertaining to MPH and amphetamine enantiomers was reviewed in the context of ADHD therapy and MTS as a treatment option. Results MTS incorporates MPH into an adhesive monolithic matrix, using the free base form of the drug to facilitate transdermal absorption. MTS technology minimizes contact dermatitis by eliminating to need for percutaneous penetration enhancers. After a lag time of approximately 2 h, plasma concentrations of the therapeutic d-MPH isomer become detectable, then continuously rise over the course of the recommended 9 h wear time. Concentrations of l-MPH typically attain 40−50% that of d-MPH (vs. 1−2% following oral MPH). Unauthorized MTS removal poses some misuse liability and over 50% of MTS drug content remains in the discarded system. Conclusions While liquid or chewable MPH formulations overcome potential swallowing difficulties, as do sprinkled once-daily extended-release (ER) MPH products, only MTS addresses swallowing difficulties while also offering a flexible individualized MPH exposure time in a once-daily MPH regimen. PMID:19051222

Efficacy of rivastigmine tartrate, transdermal system, in Alzheimer's disease.

PubMed

Nieto, Rachel A; Deardorff, William James; Grossberg, George T

2016-01-01

As the most common major neurocognitive disorder, Alzheimer's disease (AD) will play an increasingly important role both socially and financially as the population ages. Approved treatments for AD are symptomatic in nature and show modest improvements in cognition and global functioning among patients with AD. This article focuses on the pharmacokinetics, pharmacodynamics, efficacy, and safety of the transdermal patch form of the cholinesterase inhibitor rivastigmine. The rivastigmine transdermal system is approved for the treatment of patients with mild, moderate, and severe AD. Three randomized trials have shown the rivastigmine patch to be efficacious and tolerable across all stages of AD. The rivastigmine patch offers several advantages over the capsule form, including decreased peak to trough plasma fluctuations, reduced rates of nausea and vomiting, better treatment adherence, higher probability of reaching the target dose, ease of administration, and greater satisfaction among caregivers. These factors may be especially important in patients with severe AD, in which patients are more vulnerable to adverse side effects from higher doses. While the patch is more expensive than generic therapies, patient populations that may benefit from the patch include those that are particularly sensitive to GI side effects, have chronic gastrointestinal problems, have difficulty swallowing medications, or have failed to respond with high doses of other generic options.

Efficacy and safety of a transdermal contraceptive system.

PubMed

Smallwood, G H; Meador, M L; Lenihan, J P; Shangold, G A; Fisher, A C; Creasy, G W

2001-11-01

To evaluate the efficacy, cycle control, compliance, and safety of a transdermal contraceptive system that delivers norelgestromin 150 microg and ethinyl estradiol 20 microg daily. In this open-label, 73-center study, 1672 healthy, ovulatory, sexually active women received ORTHO EVRA/EVRA for six (n = 1171) or 13 cycles (n = 501). The treatment regimen for each cycle was three consecutive 7-day patches (21 days) followed by 1 patch-free week. The overall and method-failure probabilities of pregnancy through 13 cycles were 0.7% and 0.4%, respectively. The incidence of breakthrough bleeding was low throughout the study. Perfect compliance (21 consecutive days of dosing, followed by a 7-day drug-free interval; no patch could be worn for more than 7 days) was achieved in 90% of subject cycles; only 1.9% of patches detached completely. Adverse events were typical of hormonal contraception, and most were mild-to-moderate in severity and not treatment limiting. The most common adverse events resulting in discontinuation were application site reactions (1.9%), nausea (1.8%), emotional lability (1.5%), headache (1.1%), and breast discomfort (1.0%). The transdermal contraceptive patch provides effective contraception and cycle control, and is well tolerated. The weekly change schedule for the contraceptive patch is associated with excellent compliance and wearability characteristics.

Design of a transdermal delivery system for aspirin as an antithrombotic drug.

PubMed

Ammar, H O; Ghorab, M; El-Nahhas, S A; Kamel, R

2006-12-11

Aspirin has become the gold standard to which newer antiplatelet drugs are compared for reducing risks of cardiovascular diseases, while keeping low cost. Oral aspirin has a repertoire of gastrointestinal side effects even at low doses and requires high frequent dosing because it undergoes extensive presystemic metabolism. Transdermal delivery offers an alternative route that bypasses the gut and may be more convenient and safer for aspirin delivery especially during long-term use. This study comprised formulation of aspirin in different topical bases. Release studies revealed that hydrocarbon gel allowed highest drug release. In vitro permeation studies revealed high drug permeation from hydrocarbon gel. Several chemical penetration enhancers were monitored for augmenting the permeation from this base. Combination of propylene glycol and alcohol showed maximum enhancing effect and, hence, was selected for biological investigation. The biological performance of the selected formulation was assessed by measuring the inhibition of platelet aggregation relevant to different dosage regimens aiming to minimize both drug dose and frequency of application. The results demonstrated the feasibility of successfully influencing platelet function and revealed that the drug therapeutic efficacy in transdermal delivery system is dose independent. Biological performance was re-assessed after storage and the results revealed stability and persistent therapeutic efficacy.

Microneedle-based drug delivery systems: Microfabrication, drug delivery, and safety

PubMed Central

Donnelly, Ryan F.; Raj Singh, Thakur Raghu; Woolfson, A. David

2010-01-01

Many promising therapeutic agents are limited by their inability to reach the systemic circulation, due to the excellent barrier properties of biological membranes, such as the stratum corneum (SC) of the skin or the sclera/cornea of the eye and others. The outermost layer of the skin, the SC, is the principal barrier to topically-applied medications. The intact SC thus provides the main barrier to exogenous substances, including drugs. Only drugs with very specific physicochemical properties (molecular weight < 500 Da, adequate lipophilicity, and low melting point) can be successfully administered transdermally. Transdermal delivery of hydrophilic drugs and macromolecular agents of interest, including peptides, DNA, and small interfering RNA is problematic. Therefore, facilitation of drug penetration through the SC may involve by-pass or reversible disruption of SC molecular architecture. Microneedles (MNs), when used to puncture skin, will by-pass the SC and create transient aqueous transport pathways of micron dimensions and enhance the transdermal permeability. These micropores are orders of magnitude larger than molecular dimensions, and, therefore, should readily permit the transport of hydrophilic macromolecules. Various strategies have been employed by many research groups and pharmaceutical companies worldwide, for the fabrication of MNs. This review details various types of MNs, fabrication methods and, importantly, investigations of clinical safety of MN. PMID:20297904

Ultrasound mediated transdermal drug delivery.

PubMed

Azagury, Aharon; Khoury, Luai; Enden, Giora; Kost, Joseph

2014-06-01

Transdermal drug delivery offers an attractive alternative to the conventional drug delivery methods of oral administration and injections. However, the stratum corneum serves as a barrier that limits the penetration of substances to the skin. Application of ultrasound (US) irradiation to the skin increases its permeability (sonophoresis) and enables the delivery of various substances into and through the skin. This review presents the main findings in the field of sonophoresis in transdermal drug delivery as well as transdermal monitoring and the mathematical models associated with this field. Particular attention is paid to the proposed enhancement mechanisms and future trends in the fields of cutaneous vaccination and gene therapy. Copyright © 2014 Elsevier B.V. All rights reserved.

[Cost-effective analysis of rotation from sustained-release morphine tablet to transdermal fentanyl of matrix type or sustained-release oxycodone tablet].

PubMed

Ise, Yuya; Wako, Tetsuya; Miura, Yoshihiko; Katayama, Shirou; Shimizu, Hisanori

2009-12-01

The present study was undertaken to determine the pharmacoeconomics of switching from sustained-release morphine tablet to matrix type (MT) of transdermal fontanel or sustained-release Oxycodone tablet. Cost-effective analysis was performed using a simulation model along with decision analysis. The analysis was done from the payer's perspective. The cost-effective ratio/patient of transdermal MT fontanel (22, 539 yen)was lower than that of sustained -release Oxycodone tablet (23, 630 yen), although a sensitivity analysis could not indicate that this result was reliable. These results suggest the possibility that transdermal MT fontanel was much less expensive than a sustained-release Oxycodone tablet.

Transdermal nicotine mixed natural rubber-hydroxypropylmethylcellulose film forming systems for smoking cessation: in vitro evaluations.

PubMed

Pichayakorn, Wiwat; Suksaeree, Jirapornchai; Boonme, Prapaporn; Taweepreda, Wirach; Amnuaikit, Thanaporn; Ritthidej, Garnpimol C

2014-08-27

Abstract Novel film forming polymeric dispersions for transdermal nicotine delivery were prepared from deproteinized natural rubber latex (DNRL) blended with hydroxypropylmethylcellulose (HPMC) and dibutyl phthalate (DBP) or glycerin (GLY) as plasticizer. The preliminary molecular compatibility of ingredients was observed by Fourier transform infrared spectroscopy, differential scanning calorimetry and X-ray diffractometry characterizations. All film forming polymeric dispersions were elegant in appearance and smooth in texture without agglomeration. Their pH was 7-8. In addition, their viscosity and spreadability showed good characteristics depended on HPMC and plasticizers blended. The transparent in situ dry films with good strength and elasticity were also confirmed by peeling-off. The nicotine release from them revealed an initial fast release that was similar to the release from a concentrated nicotine solution, and followed by slow release pattern from the in situ films. GLY blended formulation produced a higher amount of nicotine permeation through the in vitro pig skin than DBP blends. Ethanol mixing also enhanced nicotine permeation, but it affected the integrity of in situ films. The nicotine release and skin permeation kinetics were by a diffusion mechanism that was confirmed by the Higuchi's model. These formulations were safe without producing any severe skin irritation. However, for the stability they needed to be stored at 4 °C in tightly sealed containers.

Evaluations of imidazolium ionic liquids as novel skin permeation enhancers for drug transdermal delivery.

PubMed

Zhang, Ding; Wang, Huai-Ji; Cui, Xiu-Ming; Wang, Cheng-Xiao

2017-06-01

In this work, imidazolium ionic liquids (imidazolium ILs) were employed as the novel chemical permeation enhancers (CPEs) and their performances and mechanisms of action were deeply investigated. Testosterone was used as a model drug to investigate the transdermal delivery enhancement of twenty imdidazolium ILs. The results suggested that the promotion activity connected to the structure and composition of the ILs. The quantitative structure-activity relationship (QSAR) model revealed a good linearity between the electronic properties of ILs and their enhancements. Furthermore, the transepidermal water loss (TEWL) and scanning laser confocal microscope (CLSM) examinations showed the strong improvement of ILs on skin barrier permeability, which were well correlated with the drug penetration profiles. The total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) and atomic force microscope (AFM) evaluations of skins indicated that the ILs can disrupt the regular and compact arrangements of the corneocytes, change the surface properties of stratum corneum, and make the skin structure more permeable. Our work demonstrated the significant skin permeation promotion profiles of the imidazolium ILs, which are of great potential in transdermal drug delivery systems.

Hybrid electrospun chitosan-phospholipids nanofibers for transdermal drug delivery.

PubMed

Mendes, Ana C; Gorzelanny, Christian; Halter, Natalia; Schneider, Stefan W; Chronakis, Ioannis S

2016-08-20

Chitosan (Ch) polysaccharide was mixed with phospholipids (P) to generate electrospun hybrid nanofibers intended to be used as platforms for transdermal drug delivery. Ch/P nanofibers exibithed average diameters ranging from 248±94nm to 600±201nm, depending on the amount of phospholipids used. Fourier Transformed Infra-Red (FTIR) spectroscopy and Dynamic Light Scattering (DLS) data suggested the occurrence of electrostatic interactions between amine groups of chitosan with the phospholipid counterparts. The nanofibers were shown to be stable for at least 7days in Phosphate Buffer Saline (PBS) solution. Cytotoxicity studies (WST-1 and LDH assays) demonstrated that the hybrid nanofibers have suitable biocompatibility. Fluorescence microscopy, also suggested that L929 cells seeded on top of the CH/P hybrid have similar metabolic activity comparatively to the cells seeded on tissue culture plate (control). The release of curcumin, diclofenac and vitamin B12, as model drugs, from Ch/P hybrid nanofibers was investigated, demonstrating their potential utilization as a transdermal drug delivery system. Copyright © 2016 Elsevier B.V. All rights reserved.

Complications of oral exposure to fentanyl transdermal delivery system patches.

PubMed

Prosser, Jane M; Jones, Brent E; Nelson, Lewis

2010-12-01

Fentanyl is a synthetic opioid available therapeutically as an intravenous, transbucal, or transdermal preparation. It is also used as a drug of abuse through a variety of different methods, including the oral abuse of transdermal fentanyl patches. This is a series of patients with oral fentanyl patch exposure reported to our center and represents the first series of oral fentanyl patch exposures collected outside of the postmortem setting. In this series, we examined the New York Poison Control Center database for all cases of oral abuse of fentanyl reported between January 2000 and April 2008. Twenty cases were reported, nine were asymptomatic or had symptoms of opioid withdrawal; 11 had symptoms of opioid intoxication. Eight patients were administered naloxone and all showed improvement in clinical status. Only one case resulted in a confirmed fatality-this patient had an orally adherent patch discovered at intubation. Oral exposure may result in life-threatening toxicity. Patients should be closely assessed and monitored for the opioid toxidrome, and if symptomatic, should be managed with opioid antagonists and ventilatory support.

Transdermal delivery of lercanidipine hydrochloride: effect of chemical enhancers and ultrasound.

PubMed

Shetty, Pallavi K; Suthar, Neelam A; Menon, Jyothsna; Deshpande, Praful B; Avadhani, Kiran; Kulkarni, Raghavendra V; Mutalik, Srinivas

2013-08-01

The effects of permeation enhancers and sonophoresis on the transdermal permeation of lercanidipine hydrochloride (LRDP) across mouse skin were investigated. Parameters including drug solubility, partition coefficient, drug degradation and drug permeation in skin were determined. Tween-20, dimethyl formamide, propylene glycol, poly ethylene glycol (5% v/v) and different concentration of ethanol were used for permeation enhancement. Low frequency ultrasound was also applied in the presence and absence of permeation enhancers to assess its effect on augmenting the permeation of drug. All the permeation enhancers, except propylene glycol, increased the transdermal permeation of LRDP. Sonophoresis significantly increased the cumulative amount of LRDP permeating through the skin in comparison to passive diffusion. A synergistic effect was noted when sonophoresis was applied in presence of permeation enhancers. The results suggest that the formulation of LRDP with an appropriate penetration enhancer may be useful in the development of a therapeutic system to deliver LRDP across the skin for a prolonged period (i.e., 24 h). The application of ultrasound in association with permeation enhancers could further serve as non-oral and non-invasive drug delivery modality for the immediate therapeutic effect.

Microemulsion Transdermal Formulation for Simultaneous Delivery of Valsartan and Nifedipine: Formulation by Design.

PubMed

Sood, Jatin; Sapra, Bharti; Tiwary, Ashok K

2017-08-01

The objective of the study was to optimize the proportion of different components for formulating oil in water microemulsion formulation meant for simultaneous transdermal delivery of two poorly soluble antihypertensive drugs. Surface response methodology of Box-Behnken design was utilized to evaluate the effect of two oils (Captex 500 - x1 and Capmul MCM - x2) and surfactant (Acrysol EL135 - x3) on response y1 (particle size), y2 (solubility of valsartan), and y3 (solubility of nifedipine). The important factors which significantly affected the responses were identified and validated using ANOVA. The model was diagnosed using normal plot of residuals and Box-Cox plot. The design revealed an inverse correlation between particle size and concentration of Capmul MCM and Acrysol EL 135. However, an increase in concentration of Captex 500 led to an increase in particle size of microemulsion. Solubility of valsartan decreased while that of nifedipine increased with increase in concentration of Captex 500. Capmul MCM played a significant role in increasing the solubility of valsartan. The effect of Acrysol EL 135 on solubility of both drugs, although significant, was only marginal as compared to that of Captex 500 and Capmul MCM. The optimized microemulsion was able to provide an enhancement ratio of 27.21 and 63.57-fold for valsartan and nifedipine, respectively, with respect to drug dispersion in aqueous surfactant system when evaluated for permeation studies. The current studies candidly suggest the scope of microemulsion systems for solubilizing as well as promoting the transport of both drugs across rat skin at an enhanced permeation rate.

Prodrugs for transdermal drug delivery - trends and challenges.

PubMed

Ita, Kevin B

2016-09-01

Prodrugs continue to attract significant interest in the transdermal drug delivery field. These moieties can confer favorable physicochemical properties on transdermal drug delivery candidates. Alkyl chain lengthening, pegylation are some of the strategies used for prodrug synthesis. It is usually important to optimize partition coefficient, water and oil solubilities of drugs. In this review, progress made in the field of prodrugs for percutaneous penetration is highlighted and the challenges discussed.

A case of overdose via tattoo.

PubMed

Borg, Roberta; Ashton, Antony

2015-08-01

Transdermal fentanyl patches are used frequently for the management of both acute and chronic pain. Adverse events with their use, in particular overdose, are not uncommon. We describe a case of fentanyl overdose from transdermal patch placed over a five-day old tattoo. The report will review the pharmacology of transdermal fentanyl and the physiology of tattooing, as well as the potential link between the two, which may have lead to the overdose.

Epirubicin-loaded superparamagnetic iron-oxide nanoparticles for transdermal delivery: cancer therapy by circumventing the skin barrier.

PubMed

Rao, Yue-feng; Chen, Wei; Liang, Xing-guang; Huang, Yong-zhuo; Miao, Jing; Liu, Lin; Lou, Yan; Zhang, Xing-guo; Wang, Ben; Tang, Rui-kang; Chen, Zhong; Lu, Xiao-yang

2015-01-14

The transdermal administration of chemotherapeutic agents is a persistent challenge for tumor treatments. A model anticancer agent, epirubicin (EPI), is attached to functionalized superparamagnetic iron-oxide nanoparticles (SPION). The covalent modification of the SPION results in EPI-SPION, a potential drug delivery vector that uses magnetism for the targeted transdermal chemotherapy of skin tumors. The spherical EPI-SPION composite exhibits excellent magnetic responsiveness with a saturation magnetization intensity of 77.8 emu g(-1) . They feature specific pH-sensitive drug release, targeting the acidic microenvironment typical in common tumor tissues or endosomes/lysosomes. Cellular uptake studies using human keratinocyte HaCaT cells and melanoma WM266 cells demonstrate that SPION have good biocompatibility. After conjugation with EPI, the nanoparticles can inhibit WM266 cell proliferation; its inhibitory effect on tumor proliferation is determined to be dose-dependent. In vitro transdermal studies demonstrate that the EPI-SPION composites can penetrate deep inside the skin driven by an external magnetic field. The magnetic-field-assisted SPION transdermal vector can circumvent the stratum corneum via follicular pathways. The study indicates the potential of a SPION-based vector for feasible transdermal therapy of skin cancer. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Size-dependent penetration of nanoemulsions into epidermis and hair follicles: implications for transdermal delivery and immunization

PubMed Central

Su, Rui; Fan, Wufa; Yu, Qin; Dong, Xiaochun; Qi, Jianping; Zhu, Quangang; Zhao, Weili; Wu, Wei; Chen, Zhongjian; Li, Ye; Lu, Yi

2017-01-01

Nanoemulsions have been widely applied to dermal and transdermal drug delivery. However, whether and to what depth the integral nanoemulsions can permeate into the skin is not fully understood. In this study, an environment-responsive dye, P4, was loaded into nanoemulsions to track the transdermal translocation of the nanocarriers, while coumarin-6 was embedded to represent the cargoes. Particle size has great effects on the transdermal transportation of nanoemulsions. Integral nanoemulsions with particle size of 80 nm can diffuse into but not penetrate the viable epidermis. Instead, these nanoemulsions can efficiently fill the whole hair follicle canals and reach as deep as 588 μm underneath the dermal surfaces. The cargos are released from the nanoemulsions and diffuse into the surrounding dermal tissues. On the contrary, big nanoemulsions, with mean particle size of 500 nm, cannot penetrate the stratum corneum and can only migrate along the hair follicle canals. Nanoemulsions with median size, e.g. 200 nm, show moderate transdermal permeation effects among the three-size nanoemulsions. In addition, colocalization between nanoemulsions and immunofluorescence labeled antigen-presenting cells was observed in the epidermis and the hair follicles, implying possible capture of nanoemulsions by these cells. In conclusion, nanoemulsions are advantageous for transdermal delivery and potential in transcutaneous immunization. PMID:28465469

Effect of casting solvent on crystallinity of ondansetron in transdermal films.

PubMed

Pattnaik, Satyanarayan; Swain, Kalpana; Mallick, Subrata; Lin, Zhiqun

2011-03-15

The purpose of the present investigation is to assess the influence of casting solvent on crystallinity of ondansetron hydrochloride in transdermal polymeric matrix films fabricated using povidone and ethyl cellulose as matrix forming polymers. Various casting solvents like chloroform (CHL), dichloromethane (DCM), methanol (MET); and mixture of chloroform and ethanol (C-ETH) were used for fabrication of the transdermal films. Analytical tools like scanning electron microscopy (SEM), X-ray diffraction (XRD) studies, differential scanning calorimetry (DSC), etc. were utilized to characterize the crystalline state of ondansetron in the film. Recrystallisation was observed in all the transdermal films fabricated using the casting solvents other than chloroform. Long thin slab-looking, long wire-like or spherulite-looking crystals with beautiful impinged boundaries were observed in SEM. Moreover, XRD revealed no crystalline peaks of ondansetron hydrochloride in the transdermal films prepared using chloroform as casting solvent. The significantly decreased intensity and sharpness of the DSC endothermic peaks corresponding to the melting point of ondansetron in the formulation (specifically in CHL) indicated partial dissolution of ondansetron crystals in the polymeric films. The employed analytical tools suggested chloroform as a preferred casting solvent with minimum or practically absence of recrystallization indicating a relatively amorphous state of ondansetron in transdermal films. Copyright © 2011 Elsevier B.V. All rights reserved.

Rotigotine transdermal system: developing continuous dopaminergic delivery to treat Parkinson's disease and restless legs syndrome.

PubMed

Benitez, Arturo; Edens, Heather; Fishman, Jesse; Moran, Kimberly; Asgharnejad, Mahnaz

2014-11-01

Rotigotine is a nonergoline dopamine receptor agonist with structural similarity to dopamine. Rotigotine binds to the D1 through D5 dopamine receptors, having several times more affinity than dopamine does to the D2 and D3 receptors. Although rotigotine was demonstrated to restore locomotor activity in animal models of Parkinson's disease (PD), the rapid metabolism of rotigotine limited the development of an orally administered formulation. Rotigotine's high lipid solubility and extended duration of action when applied to the skin in experimental models of PD suggested that rotigotine was a candidate for transdermal application. The constant transdermal delivery of rotigotine over 24 h is hypothesized to approximate continuous agonist-receptor stimulation, which conceptually more closely mimics physiologic striatal dopamine receptor function. Randomized clinical studies have demonstrated rotigotine's efficacy, safety, and tolerability in patients with early- and advanced-stage PD, including improvements in motor symptoms and off-time. Although the etiology is unknown, restless legs syndrome (RLS) is thought to involve dopaminergic dysregulation. Randomized clinical studies also have demonstrated the efficacy of rotigotine in improving the symptoms of moderate-to-severe primary RLS. This review examines rotigotine's developmental history for transdermal administration leading to its approval for the treatment of early- and advanced-stage PD and moderate-to-severe primary RLS. © 2014 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals Inc. on behalf of The New York Academy of Sciences.

Tramadol and the risk of fracture in an elderly female population: a cost utility assessment with comparison to transdermal buprenorphine.

PubMed

Hirst, Alexander; Knight, Chris; Hirst, Matt; Dunlop, Will; Akehurst, Ron

2016-03-01

Opioid treatment for chronic pain is a known risk factor for falls and/or fractures in elderly patients. The latter cause a significant cost to the National Health Service and the Personal Social Services in the UK. Tramadol has a higher risk of fractures than some other opioid analgesics used to treat moderate-to-severe pain and, in the model described here, we investigate the cost effectiveness of transdermal buprenorphine treatment compared with tramadol in a high-risk population. A model was developed to assess the cost effectiveness of tramadol compared with transdermal buprenorphine over a 1-year time horizon and a patient population of high-risk patients (female patients age 75 or older). To estimate the total cost and quality-adjusted life years (QALYs) of treatment, published odds ratios are used in combination with the published incidence rates of four types of fracture: hip, wrist, humerus and other. The model shows tramadol to be associated with 1,058 more fractures per 100,000 patients per year compared with transdermal buprenorphine, resulting in transdermal buprenorphine being cost-effective with an incremental cost-effectiveness ratio of less than £7,000 compared with tramadol. Sensitivity analysis found this result to be robust. In the UK data, there is uncertainty regarding the transdermal buprenorphine odds ratios for fractures. Odds ratios published in Danish and Swedish studies show similar point estimates but are associated with less uncertainty. Transdermal buprenorphine is cost-effective compared to tramadol at a willingness-to-pay threshold of £20,000 per QALY.

Transdermal nicotine for induction of remission in ulcerative colitis.

PubMed

McGrath, J; McDonald, J W D; Macdonald, J K

2004-10-18

Ulcerative colitis is largely a disease of nonsmokers. Intermittent smokers often experience improvement in their symptoms while smoking. Nonsmokers with ulcerative colitis who begin smoking may go into remission. Randomized controlled trials were developed to test the efficacy of transdermal nicotine for the induction of remission in ulcerative colitis. (1) To determine the efficacy of transdermal nicotine for induction of remission in ulcerative colitis. (2) To assess adverse events associated with transdermal nicotine therapy for ulcerative colitis The MEDLINE (via PubMed) and EMBASE databases were searched using the search criteria "ulcerative colitis" and "transdermal nicotine" or "nicotine" to identify relevant papers published between 1970 and December 2003. Manual searches of reference lists from potentially relevant papers were performed to identify additional studies. Abstracts from major gastroenterological meetings were searched to identify research submitted in abstract form only. The Cochrane Central Register of Controlled Trials and the Cochrane Inflammatory Bowel Disease Group Specialized Trials Register were also searched. We included only randomized controlled trials in which patients with active mild to moderate ulcerative colitis were randomly allocated to receive transdermal nicotine (15 to 25 mg/day) or a placebo or another treatment (corticosteroids or mesalamine). Data extraction and assessment of the methodological quality of each trial were independently performed by each author. Any disagreement among reviewers was resolved by consensus. The primary outcome measure was the number of patients achieving clinical or sigmoidoscopic remission as defined by the primary studies (e.g. no symptoms of ulcerative colitis), and expressed as a percentage of the patients randomized (intention to treat analysis). Secondary outcomes included clinical response, adverse events and withdrawal because of adverse events. Seven studies were identified, five of which met the inclusion criteria. A meta-analysis of two trials in which 71 patients were randomized to nicotine and 70 to placebo showed a statistically significant benefit for nicotine treatment. After four to six weeks of treatment 19 of 71 patients treated with transdermal nicotine were in clinical remission compared to 9 of 70 treated with placebo (OR=2.56, 95% CI 1.02-6.45). In the same group of patients improvement or remission was noted in 29 of the 71 patients assigned to nicotine compared to 14 of 70 patients assigned to placebo (OR=2.72, 95% CI 1.28 - 5.81). For patients with left sided colitis the odds ratio was 2.31 (95% CI 1.05-5.10). When transdermal nicotine was compared to standard medical therapy no significant benefit for nicotine was observed. After four to six weeks of standard therapy (oral prednisone or mesalamine), 34 of 63 patients were in clinical or sigmoidoscopic remission compared to 33 of 66 patients treated with transdermal nicotine (OR=0.77, 95% CI 0.37-1.60). A meta-analysis of all five studies which included 137 patients treated with transdermal nicotine and 133 patients treated with a placebo or standard therapy demonstrated no statistically significant benefit of nicotine therapy (OR=1.23; 95% CI 0.71-2.14). Patients treated with transdermal nicotine were significantly more likely to withdrawal due to adverse events than patients treated with placebo or standard medical therapy (OR=5.82, 95% CI, 1.66 - 20.47) and were significantly more likely to suffer from an adverse event than patients treated with placebo or standard medical therapy (OR=3.54, 95% CI, 2.07 - 6.08). The results of this review provide evidence that transdermal nicotine is superior to placebo for the induction of remission in patient's with ulcerative colitis. The review did not identify any significant advantage for transdermal nicotine therapy compared to standard medical therapy. Adverse events associated with transdermal nicotine are significant and limit its use in some patients.

Synchronization of skin ablation and microjet injection for an effective transdermal drug delivery

NASA Astrophysics Data System (ADS)

Jang, Hun-jae; Yeo, Seonggu; Yoh, Jack J.

2016-04-01

An Er:YAG laser with 2940-nm wavelength and 150-µs pulse duration was built for the purpose of combined ablation and microjet injection. A shorter pulse duration compared to common erbium lasers in dentistry is desirable for a synchronization of skin ablation and subsequent microjet injection into target skin for transdermal injection of liquid dose. A single laser beam is split into two for an optimal energy of pre-ablation of skin and the residual energy allocated to a microjet ejection. A newly designed injector consists of an L-shaped chamber and a parabolic mirror in a single unit, and the handheld laser is a part of an integrated system requiring no optical fiber. Through various injection tests using the porcine skin, the effectiveness of the new delivery system is herein evaluated.

Microneedle-mediated transdermal bacteriophage delivery

PubMed Central

Ryan, Elizabeth; Garland, Martin J.; Singh, Thakur Raghu Raj; Bambury, Eoin; O’Dea, John; Migalska, Katarzyna; Gorman, Sean P.; McCarthy, Helen O.; Gilmore, Brendan F.; Donnelly, Ryan F.

2012-01-01

Interest in bacteriophages as therapeutic agents has recently been reawakened. Parenteral delivery is the most routinely-employed method of administration. However, injection of phages has numerous disadvantages, such as the requirement of a health professional for administration and the possibility of cross-contamination. Transdermal delivery offers one potential means of overcoming many of these problems. The present study utilized a novel poly (carbonate) (PC) hollow microneedle (MN) device for the transdermal delivery of Escherichia coli-specific T4 bacteriophages both in vitro and in vivo. MN successfully achieved bacteriophage delivery in vitro across dermatomed and full thickness skin. A concentration of 2.67 × 106 PFU/ml (plaque forming units per ml) was detected in the receiver compartment when delivered across dermatomed skin and 4.0 × 103 PFU/ml was detected in the receiver compartment when delivered across full thickness skin. An in vivo study resulted in 4.13 × 103 PFU/ml being detected in blood 30 min following initial MN-mediated phage administration. Clearance occurred rapidly, with phages being completely cleared from the systemic circulation within 24 h, which was expected in the absence of infection. We have shown here that MN-mediated delivery allows successful systemic phage absorption. Accordingly, bacteriophage-based therapeutics may now have an alternative route for systemic delivery. Once fully-investigated, this could lead to more widespread investigation of these interesting therapeutic viruses. PMID:22750416

In vitro and in vivo evaluation of a novel testosterone transdermal delivery system (TTDS) using palm oil base

PubMed Central

Haron, Didi Erwandi Mohamad; Chik, Zamri; Noordin, Mohamed Ibrahm; Mohamed, Zahurin

2015-01-01

Objective (s): Transdermal preparations for testosterone are becoming popular because of their unique advantages such as avoidance of first-pass effect, convenience, improved bioavailability, and reduction of systemic side effects. A novel testosterone transdermal delivery system (TDDS) was developed using a palm oil base called HAMIN™ (a commercial product) and tested using in vitro and in vivo skin permeability test methods. Materials and Methods: The physical characteristics of the formulation such as particle size and viscosity were determined by using Franz diffusion cell and Brookfield viscometer, respectively. In vivo skin permeability test was performed on healthy rabbits through the skin. Testosterone in serum was analyzed using the validated Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) technique. Results: In vitro study showed that the cumulative amount of testosterone diffused was between 40 to 1400 ngcm-² over a period of five hr after application of TDDS through the artificial Strat-M™ membrane. In the in vivo rabbit skin permeability test, the results indicated that testosterone was well absorbed with a mean Cmax and Tmax of 60.94 ngml-1 and 2.29 hr after application of TDDS while no increase was observed in placebo treatment. Particle size analysis ranged from 79.4 nm to 630.0 nm for placebo and 97 to 774.0 nm for TDDS. Conclusion: The formulation was successfully prepared using HAMIN™, which has demonstrated great potential for topical delivery of testosterone. PMID:26877845

Physicochemical properties of pH-sensitive hydrogels based on hydroxyethyl cellulose-hyaluronic acid and for applications as transdermal delivery systems for skin lesions.

PubMed

Kwon, Soon Sik; Kong, Bong Ju; Park, Soo Nam

2015-05-01

We investigated the physicochemical properties of pH-sensitive hydroxyethyl cellulose (HEC)/hyaluronic acid (HA) complex hydrogels containing isoliquiritigenin (ILTG), and discussed potential applications as transdermal delivery systems for the treatment of skin lesions caused by pH imbalance. HA has skin compatibility and pH functional groups and HEC serves as scaffold to build hydrogels with varied HCE:HA mass ratio. Hydrogels were synthesized via chemical cross-linking, and three-dimensional network structures were characterized via scanning electron microscopy (SEM). The swelling properties and polymer ratios of the hydrogels were investigated at pH values in the range 1-13. HECHA13 (i.e., an HEC:HA mass ratio of 1:3) was found to have optimal rheological and adhesive properties, and was used to investigate the drug release efficiency as a function of pH; the efficiency was greater than 70% at pH 7. Antimicrobial activity assays against Propionibacterium acnes were conducted to take advantage of the pH-sensitive properties of HECHA13. At pH 7, we found that HECHA13, which contained ILTG, inhibited the growth of P. acnes. Furthermore, HECHA13 was found to exhibit excellent permeability into the skin, which penetrated mostly via the hair follicle. These results indicate that this pH-sensitive hydrogel is effective as a transdermal delivery system for antimicrobial therapeutics, with potential applications in the treatment of acne. Copyright © 2015 Elsevier B.V. All rights reserved.

Development of antimigraine transdermal delivery systems of pizotifen malate.

PubMed

Serna-Jiménez, C E; del Rio-Sancho, S; Calatayud-Pascual, M A; Balaguer-Fernández, C; Femenía-Font, A; López-Castellano, A; Merino, V

2015-08-15

The aim of this study was to develop and evaluate a transdermal delivery system of pizotifen malate. Pizotifen is frequently used in the preventive treatment of migraine, but is also indicated in eating disorders. In the course of the project, the effects of chemical enhancers such as ethanol, 1,8-cineole, limonene, azone and different fatty acids (decanoic, decenoic, dodecanoic, linoleic and oleic acids) were determined, first using a pizotifen solution. Steady state flux, diffusion and partition parameters were estimated by fitting the Scheuplein equation to the data obtained. Among the chemical enhancers studied, decenoic acid showed the highest enhancement activity, which seemed to be due to the length of its alkyl chain and unsaturation at the 9th carbon. The influence of iontophoresis and the involvement of electrotransport in said process was determined. The absorption profile obtained with iontophoresis was similar to that obtained with fatty acids and terpenes, though skin deposition of the drug was lower with the former. Transdermal delivery systems (TDS) of pizotifen were manufactured by including chemical enhancers, decenoic acid or oleic acid, and were subsequently characterized. When the results obtained with solutions were compared with those obtained with the TDS, a positive enhancement effect was observed with the latter with respect to the partitioning and diffusion of the drug across the skin. Our findings endorse the suitability of our TDS for delivering therapeutic amounts of pizotifen malate. Copyright © 2015 Elsevier B.V. All rights reserved.

Progress in the use of microemulsions for transdermal and dermal drug delivery.

PubMed

Ita, Kevin

2017-06-01

Transdermal drug delivery continues to attract considerable interest in the scientific community. However, due to the hindrance provided by the stratum corneum, it is not possible to deliver most medications in therapeutically significant amounts. One of the ways of increasing the penetration of drugs across the skin is through the use of microemulsions (MEs). This review focuses on the role of MEs in enhancing topical and transdermal drug delivery.

Nanocrystal cellulose as drug excipient in transdermal patch for wound healing: an overview

NASA Astrophysics Data System (ADS)

Zuki, S. A. Mohd; Rahman, N. Abd; Abu Bakar, N. F.

2018-03-01

Wound must be carefully treated to avoid serious infection that needs costly treatment. Method to enhance the recovery of the wound is crucial to have effective wound treatment. One of the technologies in wound treatment is transdermal patch that has the benefits of being non-invasive, easy to handle and permits constant drug dosage. In order to obtain a good controlled drug release, drug excipient needs to be investigated. Recently, natural Nanocrystal Cellulose (NCC) which can be synthesized from animal, algae, microorganism or plant has been actively used in drug delivery system as excipient. The application of NCC is advantageous due to its large surface area, biodegradable, non-toxic and abundance source.

Cellular interactions of a lipid-based nanocarrier model with human keratinocytes: Unravelling transport mechanisms.

PubMed

Silva, Elisabete; Barreiros, Luísa; Segundo, Marcela A; Costa Lima, Sofia A; Reis, Salette

2017-04-15

Knowledge of delivery system transport through epidermal cell monolayer is vital to improve skin permeation and bioavailability. Recently, nanostructured lipid carriers (NLCs) have gained great attention for transdermal delivery due to their biocompatibility, high drug payload, occlusive properties and skin hydration effect. However, the nanocarriers transport related mechanisms in epidermal epithelial cells are not yet understood. In this research, the internalization and transport pathways of the NLCs across the epidermal epithelial cell monolayer (HaCaT cells) were investigated. The 250nm sized witepsol/miglyol NLCs, prepared by hot homogenization had reduced cytotoxicity and no effect on the integrity of cell membrane in human HaCaT keratinocytes. The internalization was time-, concentration- and energy-dependent, and the uptake of NLCs was a vesicle-mediated process by macropinocytosis and clathrin-mediated pathways. 3% of NLCs were found at the apical membrane side of the HaCaT monolayer through exocytosis mechanism. Additionally, the endoplasmic reticulum, Golgi apparatus and microtubules played crucial roles in the transport of NLCs out of HaCaT cells. NLCs were transported intact across the human keratinocytes monolayer, without disturbing the tight junction's structure. From the transcytosis data only approximately 12% of the internalized NLCs were passed from the apical to the basolateral side. The transcytosis of NLCs throughout the HaCaT cell monolayer towards the basolateral membrane side requires the involvement of the endoplasmic reticulum, Golgi apparatus and microtubules. Our findings may contribute to a systematic understanding of NLCs transport across epidermal epithelial cell monolayers and their optimization for clinical transdermal application. Transdermal drug delivery is a challenging and growing area of clinical application. Lipid nanoparticles such as nanostructured lipid carriers (NLCs) have gained wide interest for transdermal drug delivery. However these nanocarriers' interactions with epidermal epithelial barrier are yet unknown. Unveiling the mechanisms involved in NLCs transport across the epidermal epithelial monolayers will contribute with valuable information to achieve enhanced skin permeability, superior bioavailability and consequently improved therapeutic effect. With our present work we could certainly provide researchers and clinicians guidance for the design of optimized transdermal delivery systems, based on the nanomaterials and biological interactions. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Microemulsions based transdermal drug delivery systems.

PubMed

Vadlamudi, Harini C; Narendran, Hyndavi; Nagaswaram, Tejeswari; Yaga, Gowri; Thanniru, Jyotsna; Yalavarthi, Prasanna R

2014-01-01

Since the discovery of microemulsions by Jack H Schulman, there has been huge progress made in applying microemulsion systems in plethora of research and industrial process. Microemulsions are optically isotropic systems consisting of water, oil and amphiphile. These systems are beneficial due to their thermodynamic stability, optical clarity, ease of preparation, higher diffusion and absorption rates. Moreover, it has been reported that the ingredients of microemulsion can effectively overcome the diffusion barrier and penetrate through the stratum corneum of the skin. Hence it becomes promising for both transdermal and dermal drug delivery. However, low viscosity of microemulsion restrains its applicability in pharmaceutical industry. To overcome the above drawback, the low viscous microemulsions were added to viscous gel bases to potentiate its applications as topical drug delivery systems so that various drug related toxic effects and erratic drug absorption can be avoided. The present review deals with the microemulsions, various techniques involved in the development of organic nanoparticles. The review emphasized on microemulsion based systems such as hydrogels and organogels. The physicochemical characteristics, mechanical properties, rheological and stability principles involved in microemulsion based viscous gels were also explored.

Transdermal Nitroglycerin Delivery Using Acrylic Matrices: Design, Formulation, and In Vitro Characterization

PubMed Central

Ramazani Saadat Abadi, Ahmad

2014-01-01

Nitroglycerin (TNG) transdermal drug delivery systems (TDDSs) with different acrylic pressure-sensitive adhesives (PSAs) and chemical permeation enhancers (CPEs) were prepared. The effects of PSAs and CPEs types and concentrations on skin permeation and in vitro drug release from devices were evaluated using the dissolution method as well as the modified-jacketed Franz diffusion cells fitted with excised rat abdominal skin. It was demonstrated that the permeation rate or steady state flux (J ss) of the drug through the excised rat skin was dependent on the viscosity and type of acrylic PSA as well as the type of CPE. Among different acrylic PSAs, Duro-Tak 2516 and Duro-Tak 2054 showed the highest and Duro-Tak 2051 showed the lowest J ss. Among the various CPEs, propylene glycol and cetyl alcohol showed the highest and the lowest enhancement of the skin permeation of TNG, respectively. The adhesion properties of devices such as 180° peel strength and probe tack values were obtained. It was shown that increasing the concentration of CPE led to reduction in the adhesion property of PSA. Moreover, after optimization of the formulation, it was found that the use of 10% PG as a CPE and 25% nitroglycerin loading in Duro-Tak 2054 is an effective monolithic DIAP for the development of a transdermal therapeutic system for nitroglycerin. PMID:24511396

Transdermal delivery of alprazolam from a monolithic patch: formulation based on in vitro characterization.

PubMed

Soler, L I; Boix, A; Lauroba, J; Colom, H; Domenech, J

2012-10-01

Alprazolam, a benzodiazepine widely used for the treatment of psychiatric disorders, has been aimed to be formulated in a transdermal delivery system (TDS) prototype. A series of TDS prototypes dosed in all cases at 0.35 mg·cm(-2) of alprazolam were prepared as a monolithic drug in adhesive matrix using acrylic pressure-sensitive adhesives (PSA) of acrylate vinyl acetate (Duro-tack(®)). The effects of several permeation enhancers as azone, transcutol, propylene glycol, dodecyl alcohol, decyl alcohol, diethanolamine, N-methyl pyrrolidone and lauric acid were studied. Prototypes have been characterized based on adhesion parameters (peel adhesion and shear adhesion), in vitro human skin permeation and in vitro drug release according to European Pharmacopoeia for the selected prototype. Best results show that a combination of permeation enhancers from different chemical groups is able to provide almost a 33 fold increase in the transdermal alprazolam flux of an aqueous saturated dispersion (from 0.054 ± 0.019 to 1.76 ± 0.21 μg h.cm(-2)). Based on these in vitro flux data, a predictive simulation of the achievable plasmatic levels was performed assuming a constant systemic infusion of drug. In summary, it is possible to obtain a prototype of a TDS of alprazolam with adequate adhesive properties (peel adhesion and shear adhesion) and able to predict sustained therapeutic plasmatic levels.

Transdermal permeation of trimetazidine from nerodilol-based HPMC gel drug reservoir system across rat epidermis.

PubMed

Krishnaiah, Yellela S; Al-Saidan, Saleh M

2008-01-01

To study the in vitro transdermal permeation of trimetazidine from hydroxypropylmethyl cellulose (HPMC) gel drug reservoir system using nerodilol as a penetration enhancer. An HPMC gel containing selected concentrations of nerodilol (0, 2, 4 or 5% w/v) and 2.5% w/v of trimetazidine was prepared, and subjected to in vitro permeation studies across rat epidermis. The amount of trimetazidine permeated at different time intervals (1, 2, 4, 8, 12, 18 and 24 h) was estimated, and the data were analyzed to calculate various permeation parameters. There was an increase in the amount of trimetazidine (8,719.7 +/- 153.3 microg/cm(2))permeated across the rat epidermis up to 24 h (Q(24)) with an increase in nerodilol concentration (5% w/v) in HPMC gel drug reservoir. However, no significant difference (p > 0.05) was observed in the amount of drug permeated (Q(24)) with 5% w/v of nerodilol when compared to that obtained with 4% w/v of nerodilol (8,484.5 +/- 165.8 microg/cm(2)). Nerodilol, at a concentration of 4% w/v enhanced the flux of trimetazidine across rat epidermis by about 1.96 times when compared to control. The HPMC gel drug reservoir containing 4% w/v of nerodilol showed optimal transdermal permeation of trimetazidine. (c) 2007 S. Karger AG, Basel.

Comparative evaluation of rivastigmine permeation from a transdermal system in the Franz cell using synthetic membranes and pig ear skin with in vivo-in vitro correlation.

PubMed

Simon, Alice; Amaro, Maria Inês; Healy, Anne Marie; Cabral, Lucio Mendes; de Sousa, Valeria Pereira

2016-10-15

In the present study, in vitro permeation experiments in a Franz diffusion cell were performed using different synthetic polymeric membranes and pig ear skin to evaluate a rivastigmine (RV) transdermal drug delivery system. In vitro-in vivo correlations (IVIVC) were examined to determine the best model membrane. In vitro permeation studies across different synthetic membranes and skin were performed for the Exelon(®) Patch (which contains RV), and the results were compared. Deconvolution of bioavailability data using the Wagner-Nelson method enabled the fraction of RV absorbed to be determined and a point-to-point IVIVC to be established. The synthetic membrane, Strat-M™, showed a RV permeation profile similar to that obtained with pig ear skin (R(2)=0.920). Studies with Strat-M™ resulted in a good and linear IVIVC (R(2)=0.991) when compared with other synthetic membranes that showed R(2) values less than 0.90. The R(2) for pig ear skin was 0.982. Strat-M™ membrane was the only synthetic membrane that adequately simulated skin barrier performance and therefore it can be considered to be a suitable alternative to human or animal skin in evaluating transdermal drug transport, potentially reducing the number of studies requiring human or animal samples. Copyright © 2016 Elsevier B.V. All rights reserved.

A thermal microjet system with tapered micronozzles fabricated by inclined UV lithography for transdermal drug delivery

NASA Astrophysics Data System (ADS)

Yoon, Yong-Kyu; Park, Jung-Hwan; Lee, Jeong-Woo; Prausnitz, Mark R.; Allen, Mark G.

2011-02-01

Transdermal drug delivery can be enabled by various methods that increase the permeability of the skin's outer barrier of stratum corneum, including skin exposure to heat and chemical enhancers, such as ethanol. Combining these approaches for the first time, in this study we designed a microdevice consisting of an array of microchambers filled with ethanol that is vaporized using an integrated microheater and ejected through a micronozzle contacting the skin surface. In this way, we hypothesize that the hot ethanol vapor can increase skin permeability upon contacting the skin surface. The tapered micronozzle and the microchamber designed for this application were realized using proximity-mode inclined rotational ultraviolet lithography, which facilitates easy fabrication of complex three-dimensional structures, convenient integration with other functional layers, low fabrication cost, and mass production. The resulting device had a micronozzle with an orifice inner and outer diameter of 220 and 320 µm, respectively, and an extruded height of 250 µm. When the microchamber was filled with an ethanol gel and activated, the resulting ethanol vapor jet increased the permeability of human cadaver epidermis to a model compound, calcein, by approximately 17 times, which is attributed to thermal and chemical disruption of stratum corneum structure. This thermal microjet system can serve as a tool not only for transdermal drug delivery, but also for a variety of biomedical applications.

Oral and transdermal drug delivery systems: role of lipid-based lyotropic liquid crystals.

PubMed

Rajabalaya, Rajan; Musa, Muhammad Nuh; Kifli, Nurolaini; David, Sheba R

2017-01-01

Liquid crystal (LC) dosage forms, particularly those using lipid-based lyotropic LCs (LLCs), have generated considerable interest as potential drug delivery systems. LCs have the physical properties of liquids but retain some of the structural characteristics of crystalline solids. They are compatible with hydrophobic and hydrophilic compounds of many different classes and can protect even biologicals and nucleic acids from degradation. This review, focused on research conducted over the past 5 years, discusses the structural evaluation of LCs and their effects in drug formulations. The structural classification of LLCs into lamellar, hexagonal and micellar cubic phases is described. The structures of these phases are influenced by the addition of surfactants, which include a variety of nontoxic, biodegradable lipids; these also enhance drug solubility. LLC structure influences drug localization, particle size and viscosity, which, in turn, determine drug delivery properties. Through several specific examples, we describe the applications of LLCs in oral and topical drug formulations, the latter including transdermal and ocular delivery. In oral LLC formulations, micelle compositions and the resulting LLC structures can determine drug solubilization and stability as well as intestinal transport and absorption. Similarly, in topical LLC formulations, composition can influence whether the drug is retained in the skin or delivered transdermally. Owing to their enhancement of drug stability and promotion of controlled drug delivery, LLCs are becoming increasingly popular in pharmaceutical formulations.

Oral and transdermal drug delivery systems: role of lipid-based lyotropic liquid crystals

PubMed Central

Rajabalaya, Rajan; Musa, Muhammad Nuh; Kifli, Nurolaini; David, Sheba R

2017-01-01

Liquid crystal (LC) dosage forms, particularly those using lipid-based lyotropic LCs (LLCs), have generated considerable interest as potential drug delivery systems. LCs have the physical properties of liquids but retain some of the structural characteristics of crystalline solids. They are compatible with hydrophobic and hydrophilic compounds of many different classes and can protect even biologicals and nucleic acids from degradation. This review, focused on research conducted over the past 5 years, discusses the structural evaluation of LCs and their effects in drug formulations. The structural classification of LLCs into lamellar, hexagonal and micellar cubic phases is described. The structures of these phases are influenced by the addition of surfactants, which include a variety of nontoxic, biodegradable lipids; these also enhance drug solubility. LLC structure influences drug localization, particle size and viscosity, which, in turn, determine drug delivery properties. Through several specific examples, we describe the applications of LLCs in oral and topical drug formulations, the latter including transdermal and ocular delivery. In oral LLC formulations, micelle compositions and the resulting LLC structures can determine drug solubilization and stability as well as intestinal transport and absorption. Similarly, in topical LLC formulations, composition can influence whether the drug is retained in the skin or delivered transdermally. Owing to their enhancement of drug stability and promotion of controlled drug delivery, LLCs are becoming increasingly popular in pharmaceutical formulations. PMID:28243062

Human Growth Hormone Delivery with a Microneedle Transdermal System: Preclinical Formulation, Stability, Delivery and PK of Therapeutically Relevant Doses

PubMed Central

Ameri, Mahmoud; Kadkhodayan, Miryam; Nguyen, Joe; Bravo, Joseph A.; Su, Rebeca; Chan, Kenneth; Samiee, Ahmad; Daddona, Peter E.

2014-01-01

This study evaluated the feasibility of coating formulated recombinant human growth hormone (rhGH) on a titanium microneedle transdermal delivery system, Zosano Pharma (ZP)-hGH, and assessed preclinical patch delivery performance. Formulation rheology and surface activity were assessed by viscometry and contact angle measurement. rhGH liquid formulation was coated onto titanium microneedles by dip-coating and drying. The stability of coated rhGH was determined by size exclusion chromatography-high performance liquid chromatography (SEC-HPLC). Preclinical delivery and pharmacokinetic studies were conducted in female hairless guinea pigs (HGP) using rhGH coated microneedle patches at 0.5 and 1 mg doses and compared to Norditropin® a commercially approved rhGH subcutaneous injection. Studies demonstrated successful rhGH formulation development and coating on microneedle arrays. The ZP-hGH patches remained stable at 40 °C for six months with no significant change in % aggregates. Pharmacokinetic studies showed that the rhGH-coated microneedle patches, delivered with high efficiency and the doses delivered indicated linearity with average Tmax of 30 min. The absolute bioavailability of the microneedle rhGH patches was similar to subcutaneous Norditropin® injections. These results suggest that ZP-transdermal microneedle patch delivery of rhGH is feasible and may offer an effective and patient-friendly alternative to currently marketed rhGH injectables. PMID:24838219

Case report of severe bradycardia due to transdermal fentanyl.

PubMed

Hawley, Pippa

2013-09-01

This case report describes a patient who developed severe bradycardia due to transdermal fentanyl. There have been no prior case reports of this occurring in palliative care, but the frequency of association of fentanyl with bradycardia in the anesthesia setting suggests it may be more common than realized. Palliative care settings often have a policy of not routinely checking vital signs, and symptoms of bradycardia could be misinterpreted as the dying process. A patient with recurrent ovarian cancer was admitted with nausea and abdominal pain due to bowel obstruction and fever from a urinary tract infection. A switch from injectable hydromorphone to transdermal fentanyl resulted in symptomatic severe bradycardia within 36 h, without any other signs of opioid toxicity and with good analgesic effect. The fentanyl patch was removed. Atropine was not required. The patient made an uneventful recovery. Transdermal buprenorphine was subsequently used satisfactorily for long-term background pain control, with additional hydromorphone when needed. The delayed absorption of fentanyl via the transdermal route makes early identification of fentanyl-induced bradycardia key to prompt reversal. Patients with resting or relative bradycardia may be at higher than average risk.

Application of a buprenorphine transdermal patch for the perioperative analgesia in patients who underwent simple lumbar discectomy

PubMed Central

Tang, Jian; Fan, Jin; Yao, Yilun; Cai, Weihua; Yin, Guoyong; Zhou, Wei

2017-01-01

Abstract This study aimed to investigate the perioperative analgesic effect of a buprenorphine transdermal patch in patients who underwent simple lumbar discectomy. In total, 96 patients were randomly divided into parecoxib intravenous injection (Group A), oral celecoxib (Group B), and buprenorphine transdermal patch groups (Group C). The pain status, degree of satisfaction, adverse effects, and condition in which the patient received tramadol hydrochloride for uncontrolled pain were recorded on the night before surgery, postoperative day 1, postoperative day 3, and postoperative day 5. The degree of patient satisfaction in Group C was higher than that in Groups A and B, with minimal adverse effects. The buprenorphine transdermal patch had a better perioperative analgesic effect in patients who underwent simple lumbar discectomy. PMID:28514299

Correlation between the transdermal characteristics of pseudoephedrine and amygdalin in majiepingchuan in vitro.

PubMed

Kong, Hui; Qu, Huihua; Qu, Baoping; Zeng, Wenhao; Zhao, Yan; Wang, Xueqian; Wang, Qingguo

2016-04-01

To analyze the transdermal profile of pseudoephedrine and amygdalin in the Traditional Chinese Medicine majiepingchuan in rat skin and to reveal their interaction. A Franz diffusion cell was used in vitro to evaluate the transdermal parameters of cumulative transdermal flux (Q(tot)), cumulative transmission (T(tot)), and mean penetration rate (Kp) of pseudoephedrine and amygdalin in majiepingchuan. Linear regression analyses of Q(tot) over time of pseudoephedrine vs amygdalin and their ratios was adopted for correlation evaluation. At 1, 2, 4, 6, and 8 h, the Q(tot), T(tot) and Kp of pseudoephedrine showed a good correlation with that of amygdalin. There was a small difference in the ratios of Q(tot), T(tot) and Kp between pseudoephedrine and amygdalin, and a correlation between them.

Photoactivated Composite Biomaterial for Soft Tissue Restoration in Rodents and in Humans

PubMed Central

Nahas, Zayna; Reid, Branden; Coburn, Jeannine M.; Axelman, Joyce; Chae, Jemin J.; Guo, Qiongyu; Trow, Robert; Thomas, Andrew; Hou, Zhipeng; Lichtsteiner, Serge; Sutton, Damon; Matheson, Christine; Walker, Patricia; David, Nathaniel; Mori, Susumu; Taube, Janis M.; Elisseeff, Jennifer H.

2015-01-01

Soft tissue reconstruction often requires multiple surgical procedures that can result in scars and disfiguration. Facial soft tissue reconstruction represents a clinical challenge because even subtle deformities can severely affect an individual’s social and psychological function. We therefore developed a biosynthetic soft tissue replacement composed of poly(ethylene glycol) (PEG) and hyaluronic acid (HA) that can be injected and photocrosslinked in situ with transdermal light exposure. Modulating the ratio of synthetic to biological polymer allowed us to tune implant elasticity and volume persistence. In a small-animal model, implanted photocrosslinked PEG-HA showed a dose-dependent relationship between increasing PEG concentration and enhanced implant volume persistence. In direct comparison with commercial HA injections, the PEG-HA implants maintained significantly greater average volumes and heights. Reversibility of the implant volume was achieved with hyaluronidase injection. Pilot clinical testing in human patients confirmed the feasibility of the transdermal photocrosslinking approach for implantation in abdomen soft tissue, although an inflammatory response was observed surrounding some of the materials. PMID:21795587

Development of a real-time repeated-measures assessment protocol to capture change over the course of a drinking episode.

PubMed

Luczak, Susan E; Rosen, I Gary; Wall, Tamara L

2015-03-01

We report on the development of a real-time assessment protocol that allows researchers to assess change in BrAC, alcohol responses, behaviors, and contexts over the course of a drinking event. We designed a web application that uses timed text messages (adjusted based on consumption pattern) containing links to our website to obtain real-time participant reports; camera and location features were also incorporated into the protocol. We used a transdermal alcohol sensor device along with software we designed to convert transdermal data into estimated BrAC. Thirty-two college students completed a laboratory session followed by a 2-week field trial. Results for the web application indicated we were able to create an effective tool for obtaining repeated measures real-time drinking data. Participants were willing to monitor their drinking behavior with the web application, and this did not appear to strongly affect drinking behavior during, or 6 weeks following, the field trial. Results for the transdermal device highlighted the willingness of participants to wear the device despite some discomfort, but technical difficulties resulted in limited valid data. The development of this protocol makes it possible to capture detailed assessment of change over the course of naturalistic drinking episodes. Published by Oxford University Press on behalf of Medical Council on Alcohol 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Effect of isopropyl myristate on the viscoelasticity and drug release of a drug-in-adhesive transdermal patch containing blonanserinEffect of isopropyl myristate on the viscoelasticity and drug release of a drug-in-adhesive transdermal patch containing blonanserinretain-->.

PubMed

Zhao, Chunyi; Quan, Peng; Liu, Chao; Li, Qiaoyun; Fang, Liang

2016-11-01

The purpose of this study was to investigate the effect of isopropyl myristate (IPM), a penetration enhancer, on the viscoelasticity and drug release of a drug-in-adhesive transdermal patch containing blonanserin. The patches were prepared with DURO-TAK ® 87-2287 as a pressure-sensitive adhesive (PSA) containing 5% ( w / w ) of blonanserin and different concentrations of IPM. An in vitro release experiment was performed and the adhesive performance of the drug-in-adhesive patches with different concentrations of IPM was evaluated by a rolling ball tack test and a shear-adhesion test. The glass transition temperature ( T g ) and rheological parameters of the drug-in-adhesive layers were determined to study the effect of IPM on the mechanical properties of the PSA. The results of the in vitro release experiment showed that the release rate of blonanserin increased with an increasing concentration of IPM. The rolling ball tack test and shear-adhesion test showed decreasing values with increasing IPM concentration. The results were interpreted on the basis of the IPM-induced plasticization of the PSA, as evidenced by a depression of the glass transition temperature and a decrease in the elastic modulus. In conclusion, IPM acted as a plasticizer on DURO-TAK ® 87-2287, and it increased the release of blonanserin and affected the adhesive properties of the PSA.

Transdermal Protein Delivery Using Choline and Geranate (CAGE) Deep Eutectic Solvent.

PubMed

Banerjee, Amrita; Ibsen, Kelly; Iwao, Yasunori; Zakrewsky, Michael; Mitragotri, Samir

2017-08-01

Transdermal delivery of peptides and other biological macromolecules is limited due to skin's inherent low permeability. Here, the authors report the use of a deep eutectic solvent, choline and geranate (CAGE), to enhance topical delivery of proteins such as bovine serum albumin (BSA, molecular weight: ≈66 kDa), ovalbumin (OVA, molecular weight: ≈45 kDa) and insulin (INS, molecular weight: 5.8 kDa). CAGE enhances permeation of BSA, OVA, and insulin into porcine skin ex vivo, penetrating deep into the epidermis and dermis. Studies using tritium-labeled BSA and fluorescein isothiocyanate labeled insulin show significantly enhanced delivery of proteins into and across porcine skin, penetrating the skin in a time-dependent manner. Fourier transform IR spectra of porcine stratum corneum (SC) samples before and after incubation in CAGE show a reduction in peak area attributed to SC lipid content, suggesting lipid extraction from the SC. Circular dichroism confirms that CAGE does not affect insulin's secondary conformation. In vivo studies in rats show that topical application of 10 U insulin dispersed in CAGE (25 U kg -1 insulin dose) leads to a highly significant 40% drop in blood glucose levels in 4 h that is relatively sustained for 12 h. Taken together, these studies demonstrate that CAGE is a promising vehicle for transdermal delivery of therapeutic proteins; specifically, as a noninvasive delivery alternative to injectable insulin for the treatment of diabetes. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Solid‐in‐oil nanodispersions for transdermal drug delivery systems

PubMed Central

Kitaoka, Momoko; Wakabayashi, Rie; Kamiya, Noriho

2016-01-01

Abstract Transdermal administration of drugs has advantages over conventional oral administration or administration using injection equipment. The route of administration reduces the opportunity for drug evacuation before systemic circulation, and enables long‐lasting drug administration at a modest body concentration. In addition, the skin is an attractive route for vaccination, because there are many immune cells in the skin. Recently, solid‐in‐oil nanodisperison (S/O) technique has demonstrated to deliver cosmetic and pharmaceutical bioactives efficiently through the skin. S/O nanodispersions are nanosized drug carriers designed to overcome the skin barrier. This review discusses the rationale for preparation of efficient and stable S/O nanodispersions, as well as application examples in cosmetic and pharmaceutical materials including vaccines. Drug administration using a patch is user‐friendly, and may improve patient compliance. The technique is a potent transcutaneous immunization method without needles. PMID:27529824

Solid-in-oil nanodispersions for transdermal drug delivery systems.

PubMed

Kitaoka, Momoko; Wakabayashi, Rie; Kamiya, Noriho; Goto, Masahiro

2016-11-01

Transdermal administration of drugs has advantages over conventional oral administration or administration using injection equipment. The route of administration reduces the opportunity for drug evacuation before systemic circulation, and enables long-lasting drug administration at a modest body concentration. In addition, the skin is an attractive route for vaccination, because there are many immune cells in the skin. Recently, solid-in-oil nanodisperison (S/O) technique has demonstrated to deliver cosmetic and pharmaceutical bioactives efficiently through the skin. S/O nanodispersions are nanosized drug carriers designed to overcome the skin barrier. This review discusses the rationale for preparation of efficient and stable S/O nanodispersions, as well as application examples in cosmetic and pharmaceutical materials including vaccines. Drug administration using a patch is user-friendly, and may improve patient compliance. The technique is a potent transcutaneous immunization method without needles. © 2016 The Authors. Biotechnology Journal published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Quantitative characterization of chitosan in the skin by Fourier-transform infrared spectroscopic imaging and ninhydrin assay: application in transdermal sciences.

PubMed

Nawaz, A; Wong, T W

2016-07-01

The chitosan has been used as the primary excipient in transdermal particulate dosage form design. Its distribution pattern across the epidermis and dermis is not easily accessible through chemical assay and limited to radiolabelled molecules via quantitative autoradiography. This study explored Fourier-transform infrared spectroscopy imaging technique with built-in microscope as the means to examine chitosan molecular distribution over epidermis and dermis with the aid of histology operation. Fourier-transform infrared spectroscopy skin imaging was conducted using chitosan of varying molecular weights, deacetylation degrees, particle sizes and zeta potentials, obtained via microwave ligation of polymer chains at solution state. Both skin permeation and retention characteristics of chitosan increased with the use of smaller chitosan molecules with reduced acetyl content and size, and increased positive charge density. The ratio of epidermal to dermal chitosan content decreased with the use of these chitosan molecules as their accumulation in dermis (3.90% to 18.22%) was raised to a greater extent than epidermis (0.62% to 1.92%). A larger dermal chitosan accumulation nonetheless did not promote the transdermal polymer passage more than the epidermal chitosan. A small increase in epidermal chitosan content apparently could fluidize the stratum corneum and was more essential to dictate molecular permeation into dermis and systemic circulation. The histology technique aided Fourier-transform infrared spectroscopy imaging approach introduces a new dimension to the mechanistic aspect of chitosan in transdermal delivery. © 2015 The Authors Journal of Microscopy © 2015 Royal Microscopical Society.

Impact of various progestins with or without transdermal testosterone on gonadotropin levels for non-invasive hormonal male contraception: a randomized clinical trial.

PubMed

Zitzmann, M; Rohayem, J; Raidt, J; Kliesch, S; Kumar, N; Sitruk-Ware, R; Nieschlag, E

2017-05-01

Although several progestins have been tested for hormonal male contraception, the effects of dosage and nature of various progestins on gonadotropin suppression combined with and without additional testosterone has not been performed in a comparative trial. The aim of this study was to evaluate the differential impact of four oral or transdermal progestins on the suppression of gonadotropins in healthy men: oral: cyproterone acetate (CPA), levonorgestrel (LNG), norethisterone acetate (NETA), and transdermal: Nestorone ® (NES), all in combination with transdermal testosterone (T). Randomized clinical trial testing was performed with four progestins at two doses each. After a 2-week progestin-only treatment, transdermal T was added for further 4 weeks and was followed by a 3-week recovery period. Progestin-dose per day: CPA 10 mg/20 mg, NES 2 mg/3 mg/dose e.g. 200/300 μg/day absorbed, NETA 5 mg/10 mg, LNG 120 μg/240 μg. From an andrology outpatient clinic, 56 healthy men aged 18-50 years, with body mass index ≤33 kg × m -2 were included in the study. Serum concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were studied. Secondary outcome measure included were serum testosterone concentrations, sperm concentrations, and safety parameters. Intergroup comparisons demonstrated that CPA and LNG had the strongest effect on LH/FSH suppression. Nevertheless, every substance showed significant inhibitory effects on gonadotropin secretion, especially in combination with transdermal T. A decrease in hematocrit and insulin sensitivity as well as cholesterol subfractions and triglycerides was uniformly seen for every group. The combination of oral or transdermal progestins with a transdermal testosterone preparation is able to suppress gonadotropins. Further dose titration studies with sperm suppression as an end-point should be conducted to determine the lowest effective dose for hormonal male contraception. © 2017 American Society of Andrology and European Academy of Andrology.

Self-assembly formation of palm-based esters nano-emulsion: A molecular dynamics study

NASA Astrophysics Data System (ADS)

Abdul Rahman, Mohd. Basyaruddin; Huan, Qiu-Yi; Tejo, Bimo A.; Basri, Mahiran; Salleh, Abu Bakar; Rahman, Raja Noor Zaliha Abdul

2009-10-01

Palm-oil esters (POEs) are unsaturated and non-ionic esters that can be prepared by enzymatic synthesis from palm oil. Their nano-emulsion properties possess great potential to act as drug carrier for transdermal drug delivery system. A ratio of 75:5:20 (water/POEs/Span20) was chosen from homogenous region in the phase diagram of our previous experimental work to undergo molecular dynamics simulation. A 15 ns molecular dynamics simulation of nano-emulsion system (water/POEs/Span20) was carried out using OPLS-AA force field. The aggregations of the oil and surfactant molecules are observed throughout the simulation. After 8 ns of simulation, the molecules start to aggregate to form one spherical micelle where the POEs molecules are surrounded by the non-ionic surfactant (Span20) molecules with an average size of 4.2 ± 0.05 nm. The size of the micelle and the ability of palm-based nano-emulsion to self-assemble suggest that this nano-emulsion can potentially use in transdermal drug delivery system.

A high aspect ratio SU-8 fabrication technique for hollow microneedles for transdermal drug delivery and blood extraction

NASA Astrophysics Data System (ADS)

Chaudhri, Buddhadev Paul; Ceyssens, Frederik; De Moor, Piet; Van Hoof, Chris; Puers, Robert

2010-06-01

Protein drugs, e.g. hormonal drugs, cannot be delivered orally to a patient as they get digested in the gastro-intestinal (GI) tract. Thus, it is imperative that these kinds of drugs are delivered transdermally through the skin. To provide for real-time feedback as well as to test independently for various substances in the blood, we also need a blood sampling system. Microneedles can perform both these functions. Further, microneedles made of silicon or metal have the risk of breaking inside the skin thereby leading to complications. SU-8, being approved of as being biocompatible by the Food and Drug Agency (FDA) of the United States, is an attractive alternative because firstly it is a polymer material, thereby reducing the chances of breakages inside the skin, and secondly it is a negative photoresist, thereby leading to ease of fabrication. Thus, here we present very tall (around 1600 µm) SU-8 polymer-based hollow microneedles fabricated by a simple and repeatable process, which are a very good candidate for transdermal drug delivery as well as blood extraction. The paper elaborates on the details that allow the fabrication of such extreme aspect ratios (>100).

Increased skin permeation efficiency of imperatorin via charged ultradeformable lipid vesicles for transdermal delivery

PubMed Central

Lin, Hongwei; Xie, Qingchun; Huang, Xin; Ban, Junfeng; Wang, Bo; Wei, Xing

2018-01-01

Aim The aim of this work was to develop a novel vesicular carrier, ultradeformable liposomes (UDLs), to expand the applications of the Chinese herbal medicine, imperatorin (IMP), and increase its transdermal delivery. Methods In this study, we prepared IMP-loaded UDLs using the thin-film hydration method and evaluated their encapsulation efficiency, vesicle deformability, skin permeation, and the amounts accumulated in different depths of the skin in vitro. The influence of different charged surfactants on the properties of the UDLs was also investigated. Results The results showed that the UDLs containing cationic surfactants had high entrapment efficiency (60.32%±2.82%), an acceptable particle size (82.4±0.65 nm), high elasticity, and prolonged drug release. The penetration rate of IMP in cationic-UDLs was 3.45-fold greater than that of IMP suspension, which was the highest value among the vesicular carriers. UDLs modified with cationic surfactant also showed higher fluorescence intensity in deeper regions of the epidermis. Conclusion The results of our study suggest that cationic surfactant-modified UDLs could increase the transdermal flux, prolong the release of the drug, and serve as an effective dermal delivery system for IMP. PMID:29467573

Controlled Transdermal Iontophoresis by Polypyrrole/Poly(Acrylic Acid) Hydrogel

NASA Astrophysics Data System (ADS)

Chansai, Phithupha; Sirivat, Anuvat

2008-03-01

Transdermal drug delivery system delivers a drug into a body at desired site and rate. The conductive polymer-hydrogel blend between polypyrrole (PPy) doped with anionic drug and poly(acrylic acid) (PAA) were developed as a matrix/carrier of drug for the transdermal drug delivery in which the characteristic releases depend on the electrical field applied. The PAA films and their blend films were prepared by solution casting using ethylene glycol dimethacrylate (EGDMA) as a crosslinking agent. A mechanical blending of PPy particles and PAA matrix was then carried out. Drug diffusions in the blended PPy/PAA hydrogel and the non-blended one were investigated and determined by using a modified Franz-diffusion cell with an acetate buffer, pH 5.5, at 37 0C, for a period of 48 hours to determine the effects of crosslinking ratio and electric field strength. Amounts of the released drug were measured by UV-Visible spectrophotometry. The diffusion coefficient of drug was determined through the Higuchi equation via different conditions, with and without an electric field. Moreover, thermal properties and electrical conductivity of the polypyrrole and drug-loaded polypyrrole were investigated by means of the thermogravimetric analysis and by using a two-point probe meter, respectively.

Fractional derivatives in the diffusion process in heterogeneous systems: The case of transdermal patches.

PubMed

Caputo, Michele; Cametti, Cesare

2017-09-01

In this note, we present a simple mathematical model of drug delivery through transdermal patches by introducing a memory formalism in the classical Fick diffusion equation based on the fractional derivative. This approach is developed in the case of a medicated adhesive patch placed on the skin to deliver a time released dose of medication through the skin towards the bloodstream.The main resistance to drug transport across the skin resides in the diffusion through its outermost layer (the stratum corneum). Due to the complicated architecture of this region, a model based on a constant diffusivity in a steady-state condition results in too simplistic assumptions and more refined models are required.The introduction of a memory formalism in the diffusion process, where diffusion parameters depend at a certain time or position on what happens at preceeding times, meets this requirement and allows a significantly better description of the experimental results.The present model may be useful not only for analyzing the rate of skin permeation but also for predicting the drug concentration after transdermal drug delivery depending on the diffusion characteristics of the patch (its thickness and pseudo-diffusion coefficient). Copyright © 2017 Elsevier Inc. All rights reserved.

Increased skin permeation efficiency of imperatorin via charged ultradeformable lipid vesicles for transdermal delivery.

PubMed

Lin, Hongwei; Xie, Qingchun; Huang, Xin; Ban, Junfeng; Wang, Bo; Wei, Xing; Chen, Yanzhong; Lu, Zhufen

2018-01-01

The aim of this work was to develop a novel vesicular carrier, ultradeformable liposomes (UDLs), to expand the applications of the Chinese herbal medicine, imperatorin (IMP), and increase its transdermal delivery. In this study, we prepared IMP-loaded UDLs using the thin-film hydration method and evaluated their encapsulation efficiency, vesicle deformability, skin permeation, and the amounts accumulated in different depths of the skin in vitro. The influence of different charged surfactants on the properties of the UDLs was also investigated. The results showed that the UDLs containing cationic surfactants had high entrapment efficiency (60.32%±2.82%), an acceptable particle size (82.4±0.65 nm), high elasticity, and prolonged drug release. The penetration rate of IMP in cationic-UDLs was 3.45-fold greater than that of IMP suspension, which was the highest value among the vesicular carriers. UDLs modified with cationic surfactant also showed higher fluorescence intensity in deeper regions of the epidermis. The results of our study suggest that cationic surfactant-modified UDLs could increase the transdermal flux, prolong the release of the drug, and serve as an effective dermal delivery system for IMP.

Reduction of nicotine self-administration by chronic nicotine infusion with H1 histamine blockade in female rats.

PubMed

Levin, Edward D; Hall, Brandon J; Chattopadhyay, Autri; Slade, Susan; Wells, Corinne; Rezvani, Amir H; Rose, Jed E

2016-08-01

Chronic nicotine infusion via transdermal patches has been widely shown to assist with smoking cessation. In particular, transdermal nicotine treatment prior to quitting smoking helps reduce ad libitum smoking and aids cessation Rose et al. (Nicotine Tob Res 11:1067-75, 2009). However, despite this success, the majority of smokers who use transdermal nicotine fail to permanently quit smoking. Additional treatments are needed. Tobacco addiction does not just depend on nicotinic receptor systems; a variety of neural systems are involved, including dopamine, norepinepherine, serotonin, and histamine. Given the involvement of a variety of neural systems in the circuits of addiction, combination therapy may offer improved efficacy for successful smoking cessation beyond single treatments alone. We have found that pyrilamine, an H1 histamine antagonist, significantly decreases nicotine self-administration in rats. The current study was conducted to confirm the effect of chronic nicotine infusion on ongoing nicotine self-administration and resumed access after enforced abstinence and to determine the interaction of chronic nicotine with an H1 antagonist treatment. Chronic nicotine infusion via osmotic minipump (2.5 and 5 mg/kg/day for 28 days) significantly reduced nicotine self-administration in a dose-dependent manner. Chronic nicotine infusion also reduced the resumption of nicotine self-administration after enforced abstinence. Chronic pyrilamine infusion (25 mg/kg/day for 14 days) also significantly reduced nicotine self-administration. The combination of chronic nicotine and pyrilamine reduced nicotine self-administration to a greater extent than treatment with either drug alone.

Transdermal delivery of heparin: Physical enhancement techniques.

PubMed

Ita, Kevin

2015-12-30

Thromboembolic complications are the most common preventable cause of mortality and morbidity in trauma patients. Thrombosis is also the common cause of ischemic heart disease (acute coronary syndrome), stroke, and venous thromboembolism. Heparin, as a potent anticoagulant, has been used in clinical practice for more than five decades and remains the major medicine for the prevention and treatment of venous thromboembolism. However it binds to the endothelium and has a high affinity for plasma proteins resulting in a short half-life and unpredictable bioavailability. Transdermal drug delivery can address the problems of short half-life and unpredictable bioavailability. Other advantages of transdermal drug delivery include convenience, improved patient compliance, prompt termination of dosing and avoidance of the first-pass effect. This review focuses on different approaches used for transdermal delivery of heparin. Copyright © 2015 Elsevier B.V. All rights reserved.

Influence of peptide dendrimers and sonophoresis on the transdermal delivery of ketoprofen.

PubMed

Manikkath, Jyothsna; Hegde, Aswathi R; Kalthur, Guruprasad; Parekh, Harendra S; Mutalik, Srinivas

2017-04-15

The aim of this study was to determine the individual and combined effects of peptide dendrimers and low frequency ultrasound on the transdermal permeation of ketoprofen. Arginine terminated peptide dendrimers of varying charges (4 + , 8 + and 16 + , named as A4. A8 and A16 respectively) were synthesized and characterized. Ketoprofen was subjected to passive, peptide dendrimer-assisted and sonophoretic permeation studies (with and without dendrimer application) across Swiss albino mouse skin, both in vitro and in vivo. The studies revealed that the synthesized peptide dendrimers considerably increased the transdermal permeation of ketoprofen and displayed enhancement ratios of up to 3.25 (with A16 dendrimer), compared to passive diffusion of drug alone in vitro. Moreover, the combination of peptide dendrimer treatment and ultrasound application worked in synergy and gave enhancement ratios of up to 1369.15 (with ketoprofen-A16 dendrimer complex). In vivo studies demonstrated that dendrimer and ultrasound-assisted permeation of drug achieved much higher plasma concentration of drug, compared to passive diffusion. Comparison of transdermal and oral absorption studies revealed that transdermal administration of ketoprofen with A8 dendrimer showed comparable absorption and plasma drug levels with oral route. The excised mouse skin after in vivo permeation study with dendrimers and ultrasound did not show major toxic reactions. This study demonstrates that arginine terminated peptide dendrimers combined with sonophoresis can effectively improve the transdermal permeation of ketoprofen. Copyright © 2017 Elsevier B.V. All rights reserved.

Formulation, in vitro and in vivo evaluation of transdermal patches containing risperidone.

PubMed

Aggarwal, Geeta; Dhawan, Sanju; Hari Kumar, S L

2013-01-01

The efficacy of oral risperidone treatment in prevention of schizophrenia is well known. However, oral side effects and patient compliance is always a problem for schizophrenics. In this study, risperidone was formulated into matrix transdermal patches to overcome these problems. The formulation factors for such patches, including eudragit RL 100 and eudragit RS 100 as matrix forming polymers, olive oil, groundnut oil and jojoba oil in different concentrations as enhancers and amount of drug loaded were investigated. The transdermal patches containing risperidone were prepared by solvent casting method and characterized for physicochemical and in vitro permeation studies through excised rat skin. Among the tested preparations, formulations with 20% risperidone, 3:2 ERL 100 and ERS 100 as polymers, mixture of olive oil and jojoba oil as enhancer, exhibited greatest cumulative amount of drug permeated (1.87 ± 0.09 mg/cm(2)) in 72 h, so batch ROJ was concluded as optimized formulation and assessed for pharmacokinetic, pharmacodynamic and skin irritation potential. The pharmacokinetic characteristics of the optimized risperidone patch were determined using rabbits, while orally administered risperidone in solution was used for comparison. The calculated relative bioavailability of risperidone transdermal patch was 115.20% with prolonged release of drug. Neuroleptic efficacy of transdermal formulation was assessed by rota-rod and grip test in comparison with control and marketed oral formulations with no skin irritation. This suggests the transdermal application of risperidone holds promise for improved bioavailability and better management of schizophrenia in long-term basis.

Comparison of estrus synchronization by controlled internal drug release device (CIDR) and adhesive transdermal progestin patch in postpartum beef cows.

PubMed

Kajaysri, Jatuporn; Chumchoung, Chaiwat; Wutthiwitthayaphong, Supphathat; Suthikrai, Wanvipa; Sangkamanee, Praphai

2017-09-15

Estrous synchronization with progesterone based protocols has been essentially used in cattle industry. Although intravaginal devices have been commonly used, this technique may induce vaginitis. This study aimed at examining the efficiency of novel transdermal progestin patch on follicle development and comparing the progestin patch versus CIDR device on estrous synchronization, complication at treated site and pregnancy in beef cattle. In experiment 1, seven beef cows were treated with an adhesive transdermal progestin patch on the ventral surface of the proximal part of the tail for 7 days. The cows were daily examined the follicular development using ultrasonography starting on Day 0 till 3 days after hormone removal. Experiment 2, forty beef cows were divided into two equal groups (20 cows per group). The cows randomly allocated to received either vaginal insertion of CIDR (n = 20) or treated with an adhesive transdermal progestin patch (n = 20). The levels of plasma progesterone during the experiment and the numbers of standing estrous cows were recorded. Timed artificial inseminated (TAI) was performed at 60 h after CIDR or patch termination. Pregnancy rates were determined at 60 days after TAI. Experiment 1 revealed that the novel transdermal progestin patch could efficiently control follicular growth. All the seven treated cows had dominant follicle upon dermal patch removal indicating the effectiveness of the progestin patch. In experiment 2, the percentages of cows exhibited standing estrus were similar between transdermal patch (72.22%) and CIDR (70.00%). The levels of plasma progesterone during CIDR treatment were significantly higher (4.06 ± 1.65 ng/mL on Day 1 and 3.62 ± 1.60 ng/mL on Day 7) compared with transdermal patch (2.60 ± 1.43 ng/mL on Day 1 and 1.81 ± 1.57 ng/mL on Day 7). Three cows treated with CIDR (15%) developed vaginitis while none of cows had physically dermal reaction at adhesive site. Cows synchronized with these two protocols had similar pregnancy rates (50.00%) following fixed time artificial insemination. It is concluded that transdermal progestin patch was equally effective in estrus synchronization as compared with traditional CIDR. However, the transdermal patch demonstrated less complication. This device should therefore be considered as an alternative method for estrus synchronization in postpartum beef cattle. Copyright © 2017 Elsevier Inc. All rights reserved.

In vivo skin penetration of macromolecules in irritant contact dermatitis.

PubMed

Abdel-Mottaleb, Mona M A; Lamprecht, Alf

2016-12-30

Recently, a selective preferential accumulation of polymeric nanoparticles (in the size range around 100nm) has been observed in the follicular system of dermatitis skin. The present investigation aimed at clearly investigating the effect of irritant contact dermatitis on the barrier permeability for colloidal systems below this size range, namely quantum dots and hydrophilic macromolecules. Irritant dermatitis was induced in mice and the penetrability of quantum dots (5nm) and hydrophilic dextran molecules has been tracked in both healthy and inflamed skin using confocal laser scanning microscopy. The selective accumulation of the quantum dots was clearly observed in inflamed skin while hydrophilic dextran behaved similarly in both healthy and inflamed skin. The therapeutic potential for the transdermal delivery of peptide drugs through inflamed skin has been also tested in rats. Results revealed that the transdermal permeation of insulin and calcitonin was not significantly enhanced in dermatitis compared to healthy skin. On the other side, permeation through stripped skin was significantly higher. However, the effect was limited and shorter compared to the SC injection where t min was 0.5h and 2h with a 70% and 46% reduction in blood glucose levels for the stripped skin and the SC injection respectively. Similarly, t min was 4h and 8h with area under the curve of 161±65% and 350±97% for the stripped skin and the SC injection respectively. In conclusion, the changes in skin permeability accompanied with skin inflammation did not affect its permeability to peptide drugs. Our findings also underline that experiments with the tape stripped skin model as a surrogate for inflamed skin can risk misleading conclusions due to significant difference of skin permeability between the tape stripped skin and inflamed skin. Copyright © 2016 Elsevier B.V. All rights reserved.

Transdermal drug delivery of insulin with ultradeformable carriers.

PubMed

Cevc, Gregor

2003-01-01

For a long time, scientists believed that macromolecules can only be introduced through the skin with a hypodermic needle or some other harsh treatment that locally damages the skin barrier. It is now clear that macromolecules can be administered epicutaneously, so that insulin, for example, can exhibit therapeutic effects in patients with type 1 diabetes mellitus. When carriers are employed for the purpose, the drugs must be associated with specifically designed vehicles in the form of highly deformable aggregates and applied on the skin non-occlusively. Using such optimised carriers, so-called Transfersomes, ensures reproducible and efficient transcutaneous carrier and drug transport. Insulin-loaded Transfersomes, for example, can deliver the drug through the non-compromised skin barrier with a reproducible drug effect that resembles closely that of an ultralente insulin injected under the skin; the pharmacokinetic and pharmacodynamic properties of the injected and transdermal insulin are also comparable. The efficacy of transcutaneously delivered insulin in Transfersomes is not affected by the previous therapy, similar results having been measured in patients normally receiving intensified insulin therapy or a continuous subcutaneous infusion of insulin solution. Systemic normoglycaemia that lasts at least 16 hours has been achieved using a single non-invasive, epicutaneous administration of insulin in Transfersomes. Experience with other drugs suggests that the biodistribution of injected and transcutaneously delivered drugs can be very similar. This notwithstanding, Transfersomes can be designed and applied so as to mediate site-specific drug delivery into peripheral musculoskeletal tissues or into the skin, as may be desired.

Design, Synthesis of Novel Lipids as Chemical Permeation Enhancers and Development of Nanoparticle System for Transdermal Drug Delivery

PubMed Central

Shah, Punit P.; Etukala, Jagan Reddy; Vemuri, Adithi; Singh, Mandip

2013-01-01

In the present study, we designed and developed novel lipids that include (Z)-1-(Octadec-9-en-1-yl)-pyrrolidine (Cy5T), 1, 1-Di-((Z)-octadec-9-en-1-yl)pyrrolidin-1-ium iodide (Cy5), (Z)-1-(Octadec-9-en-1-yl)-piperidine (Cy6T), and 1, 1-Di-((Z)-octadec-9-en-1-yl) piperidin-1-ium iodide (Cy6) to enhance the transdermal permeation of some selected drugs. Firstly, we evaluated the transdermal permeation efficacies of these lipids as chemical permeation enhancers in vehicle formulations for melatonin, ß-estradiol, caffeine, α-MSH, and spantide using franz diffusion cells. Among them Cy5 lipid was determined to be the most efficient by increasing the transdermal permeation of melatonin, ß-estradiol, caffeine, α-MSH, and spantide by 1.5 to 3.26-fold more at the epidermal layer and 1.3 to 2.5-fold more at the dermal layer, in comparison to either NMP or OA. Hence we developed a nanoparticle system (cy5 lipid ethanol drug nanoparticles) to evaluate any further improvement in the drug penetration. Cy5 lipid formed uniformly sized nanoparticles ranging from 150–200 nm depending on the type of drug. Further, Cy5 based nanoparticle system significantly (p<0.05) increased the permeation of all the drugs in comparison to the lipid solution and standard permeation enhancers. There were about 1.54 to 22-fold more of drug retained in the dermis for the Cy5 based nanoparticles compared to OA/NMP standard enhancers and 3.87 to 66.67-fold more than lipid solution. In addition, epifluorescent microscopic analysis in rhodamine-PE permeation studies confirmed the superior permeation enhancement of LEDs (detection of fluorescence up to skin depth of 340 μm) more than lipid solution, which revealed fluorescence up to skin depth of only 260 μm. In summary the present findings demonstrate that i) cationic lipid with 5 membered amine heterocyclic ring has higher permeating efficacy than the 6 membered amine hertocyclic ring. ii) The nanoparticle system prepared with Cy5 showed significant (p<0.05) increase in the permeation of the drugs than the control penetration enhancers, oleic acid and NMP. PMID:24349315

Efficacy and Safety of Oral Diclofenac Sustained release Versus Transdermal Diclofenac Patch in Chronic Musculoskeletal Pain: A Randomized, Open Label Trial.

PubMed

Shinde, Viraj Ashok; Kalikar, Mrunalini; Jagtap, Satyajeet; Dakhale, Ganesh N; Bankar, Mangesh; Bajait, Chaitali S; Motghare, Vijay M; Pashilkar, Ashlesha A; Raghute, Latesh B; Khamkar, Ajita D

2017-01-01

To compare the efficacy, safety, and tolerability of transdermal patches of diclofenac sodium with oral diclofenac sustained release (SR) in patients of chronic musculoskeletal MSK pain conditions. The eligible patients were given either transdermal diclofenac patch or tablet diclofenac SR. Pain was assessed at 2 and 4 weeks using a visual analog scale. Adverse events were recorded. Patients with 18-65 years old of either gender with score of ≥4 on a 11-item numeric rating scale-numeric version of visual analog scale for pain with diagnosis of primary osteoarthritis (OA) of the knee or hand of at least 3 months duration, with independent radiological confirmation of OA or having pain associated with other MSK conditions such as soft-tissue rheumatism, cervical and lumbar back pain, and fibromyalgia, of at least 3 months duration were included in this study. Transdermal diclofenac diethylamine patch and tablet diclofenac sodium sustained release (SR) do not significantly differ in the reduction of numerical rating scores at the end of 4 weeks (P = 0.8393). Transdermal diclofenac was equi-efficacious as tablet diclofenac sodium SR in reducing pain due to chronic MSK pain conditions.

Non-Ablative Fractional Laser to Facilitate Transdermal Delivery.

PubMed

Ganti, Sindhu S; Banga, Ajay K

2016-11-01

The advances in laser technology have led to its rapidly expanding applications in dermatology. This study aims at the novel use of a non-ablative fractional laser to enhance transdermal permeation of diclofenac sodium and sumatriptan succinate. The effects of the laser on skin were characterized visually with dye binding, scanning electron microscopy, pore permeability index, and histology. In vitro transdermal permeation of drugs through laser treated and untreated human dermatomed skin was analyzed over 24 h and quantified by HPLC. Drug transport through untreated skin resulted in transdermal delivery of 72.61 μg/cm 2 ± 50.35 and 22.80 ± 0.64 μg/cm 2 of diclofenac sodium and sumatriptan succinate, respectively. Laser treatment of skin significantly increased (p < 0.005) delivery of diclofenac sodium to 575.66 ± 207.18 μg/cm 2 and sumatriptan succinate to 498.32 ± 97.54 μg/cm 2 . This is a first of its kind study that demonstrates the use of 1410 nm non-ablative fractional laser to enhance transdermal permeation of 2 small molecular weight drugs. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Combination strategies for enhancing transdermal absorption of sumatriptan through skin.

PubMed

Femenía-Font, A; Balaguer-Fernández, C; Merino, V; López-Castellano, A

2006-10-12

The aim of the present work was to characterize in vitro sumatriptan transdermal absorption through human skin and to investigate the effect of chemical enhancers and iontophoresis applied both individually and in combination. A secondary objective was to compare the results obtained with those in porcine skin under the same conditions, in order to characterize the relationship between the two skin models and validate the porcine model for further research use. Transdermal flux of sumatriptan was determined in different situations: (a) after pre-treatment of human skin with ethanol, Azone (1-dodecyl-azacycloheptan-2-one), polyethylene glycol 600 and R-(+)-limonene, (b) under iontophoresis application (0.25 and 0.50 mA/cm(2)) and (c) combining chemical pre-treatment and iontophoresis at 0.50 mA/cm(2) current density. All the strategies applied enhance sumatriptan transdermal absorption. A linear relationship between the fluxes in the two skin models in the different conditions assayed can be established. The combination of both strategies, Azone and iontophoresis, proved to be the most effective of the techniques for enhancing the transdermal absorption of sumatriptan. The flux obtained with porcine skin in vitro is approximately double that obtained in human skin.

Chemoprevention of Breast Cancer by Transdermal Delivery of α-Santalol through Breast Skin and Mammary Papilla (Nipple).

PubMed

Dave, Kaushalkumar; Alsharif, Fahd M; Islam, Saiful; Dwivedi, Chandradhar; Perumal, Omathanu

2017-09-01

Almost all breast cancers originate from epithelial cells lining the milk ducts in the breast. To this end, the study investigated the feasibility of localized transdermal delivery of α-santalol, a natural chemopreventive agent to the breast. Different α-santalol formulations (cream, solution and microemulsion) were developed and the in vitro permeability was studied using excised animal (porcine and rat) and human breast skin/mammary papilla (nipple). The in vivo biodistribution and efficacy studies were conducted in female rats. A chemical carcinogenesis model of breast cancer was used for the efficacy studies. Phospholipid based α-santalol microemulsion showed the highest penetration through the nipple and breast skin. Delivery of α-santalol through the entire breast (breast skin and nipple) in vivo in rats resulted in significantly higher concentration in the mammary gland compared to transdermal delivery through the breast skin or nipple. There was no measurable α-santalol concentration in the blood. Transdermal delivery of α-santalol reduced the tumor incidence and tumor multiplicity. Furthermore, the tumor size was significantly reduced with α-santalol treatment. The findings from this study demonstrate the feasibility of localized transdermal delivery of α-santalol for chemoprevention of breast cancer.

Rapid pain relief using transdermal film forming polymeric solution of ketorolac.

PubMed

Ammar, H O; Ghorab, M; Mahmoud, A A; Makram, T S; Ghoneim, A M

2013-01-01

Ketorolac is one of the most potent nonsteroidal anti-inflammatory drugs and is an attractive alternative to opioids for pain management. Development and evaluation of transdermal ketorolac film forming polymeric solution. Eudragits(®) RLPO, RSPO and E100 as well as polyvinyl pyrrolidone K30 dissolved in ethanol were used as film forming solutions. In vitro experiments were conducted to optimize formulation parameters. Different permeation enhancers were monitored for potentiality of enhancing drug permeation across excised pigskin. The use of 10% oleic acid, Lauroglycol(®) 90 or Azone(®) with 5% Eudragit(®) RSPO, showed the highest enhancement effect on ketorolac skin permeation and showed faster analgesic effect compared to the ketorolac tablet. The formula comprising 5% Eudragit(®) RSPO and 10% Lauroglycol(®) 90 showed the greatest pharmacodynamic effect and thus was subjected to pharmacokinetic studies. The pharmacodynamic and pharmacokinetic results didn't run paralleled to each other, as the ketorolac tablets showed higher plasma concentrations compared to the selected ketorolac transdermal formulation. This might be due to the induction of analgesia by the available ethanol in the transdermal preparation. Optimized transdermal ketorolac formulation showed marked ability to ensure fast and augmented analgesic effect that is an essential request in pain management.

Photoacoustic microscopy imaging for microneedle drug delivery

NASA Astrophysics Data System (ADS)

Moothanchery, Mohesh; Seeni, Razina Z.; Xu, Chenjie; Pramanik, Manojit

2018-02-01

The recent development of novel transdermal drug delivery systems (TDDS) using microneedle technology allows micron-sized conduits to be formed within the outermost skin layers attracting keen interest in skin as an interface for localized and systemic delivery of therapeutics. In light of this, researchers are using microneedles as tools to deliver nanoparticle formulations to targeted sites for effective therapy. However, in such studies the use of traditional histological methods are employed for characterization and do not allow for the in vivo visualization of drug delivery mechanism. Hence, this study presents a novel imaging technology to characterize microneedle based nanoparticle delivery systems using optical resolution-photoacoustic microscopy (OR-PAM). In this study in vivo transdermal delivery of gold nanoparticles using microneedles in mice ear and the spatial distribution of the nanoparticles in the tissue was successfully illustrated. Characterization of parameters that are relevant in drug delivery studies such as penetration depth, efficiency of delivered gold nanoparticles were monitored using the system. Photoacoustic microscopy proves an ideal tool for the characterization studies of microneedle properties and the studies shows microneedles as an ideal tool for precise and controlled drug delivery.

Implantable and transdermal polymeric drug delivery technologies for the treatment of central nervous system disorders.

PubMed

Govender, Thiresen; Choonara, Yahya E; Kumar, Pradeep; Bijukumar, Divya; du Toit, Lisa C; Modi, Girish; Naidoo, Dinesh; Pillay, Viness

2017-06-01

The complexity of the brain and the membranous blood-brain barrier (BBB) has proved to be a significant limitation to the systemic delivery of pharmaceuticals to the brain rendering them sub-therapeutic and ineffective in the treatment of neurological diseases. Apart from this, lack of innovation in product development to counteract the problem is also a major contributing factor to a poor therapeutic outcome. Various innovative strategies show potential in treating some of the neurological disorders; however, drug delivery remains the most popular. To attain therapeutic drug levels in the central nervous system, large, intolerable systemic doses are generally administered. The major factors responsible for the success maintenance therapy of neurological diseases included controlled and sustained release of neurotherapeutics, reduced frequency of administration, higher bioavailability, and patient compliances. Conventional oral or injectable formulations cannot satisfy all the requirements in many circumstances. This article reviews the therapeutic implantable polymeric and transdermal devices employed in an attempt to effectively achieve therapeutic quantities of drug across the BBB over a prolonged period, to improve patient disease prognosis.

The Efficacy and Tolerability of the Clonidine Transdermal Patch in the Treatment for Children with Tic Disorders: A Prospective, Open, Single-Group, Self-Controlled Study.

PubMed

Song, Pan-Pan; Jiang, Li; Li, Xiu-Juan; Hong, Si-Qi; Li, Shuang-Zi; Hu, Yue

2017-01-01

To evaluate the efficacy and tolerability of a clonidine transdermal patch in the treatment of children with tic disorders (TD) and to establish a predictive model for patients. Forty-one patients who met the inclusion criteria entered into 12 weeks of prospective, open, single-group, self-controlled treatment with a clonidine transdermal patch. The Yale Global Tic Severity Scale (YGTSS) was employed before therapy (baseline) and at 4, 8, and 12 weeks after therapy. (1) The total effect rates of treatment with a clonidine transdermal patch were 29.27, 53.66, and 63.41% at 4, 8, and 12 weeks, respectively. Compared with the baseline, the differences were significant at three different observation periods. (2) Compared to the level of 25% reduction, there were significant decreases in the score-reducing rate of motor tic and total tic severities at 12 weeks. (3) If the disease course was ≤24 months and the motor tic score was <16 at the baseline, there was an effective rate of 100% for treatment with the clonidine transdermal patch. If the disease course was ≤24 months and the motor tic score was >16, there was an effective rate of 57.1%. If the disease course was >24 months and the clinical classification was chronic TD, there was an effective rate of 62.5%. If the disease course was >24 months and the clinical classification was Tourette's syndrome, 90% of the patients were invalid. (4) The main adverse events were rash, slight dizziness, and headache. (1) When patients were pretreated with a D2-dopamine receptor antagonist that was ineffective or not tolerated well, switching to a clonidine transdermal patch treatment was effective and safe. (2) A clonidine transdermal patch could be a first-line medication for mild and moderate TD cases that are characterized by motor tics.

Effect of formulation pH on transdermal penetration of antiemetics formulated in poloxamer lecithin organogel.

PubMed

Woodall, Rachel; Arnold, John J; McKay, Doug; Asbill, C Scott

2013-01-01

The purpose of this study was to assess the impact of altering formulation pH on the transdermal penetration of several commonly used antiemetic, weakly basic drugs incorporated into poloxamer lecithin organogel vehicle. Poloxamer lecithin organogel formulations containing promethazine hydrochloride (25 mg/mL), metoclopramide hydrochloride (10 mg/mL), and ondansetron hydrochloride (8 mg/mL) were examined for both drug release and transdermal penetration across porcine skin in modified Franz diffusion cells for a period of 24 hours. For the transdermal studies, each antiemetic drug was formulated at a pH above and below their acid dissociation constant (pKa) in an attempt to assure that the drug would be primarily in their respective ionized or non-ionized states. In addition, drug content in skin was assessed at the end of the 24-hour experiment. Drug content analysis was determined via high-performance liquid chromatography. As a percent of total drug release from the poloxamer lecithin organogel vehicle, promethazine hydrochloride demonstrated the most transdermal drug penetration after 24 hours (30.2% +/- 20.2%), followed by ondansetron hydrochloride (2.7% +/- 1.1%) and metoclopramide hydrochloride (1.8% +/- 1.6%). Subsequently, the pH of the Pluronic F-127 gel was adjusted in order to ensure that each antiemetic drug would be primarily in its unionized state. The transdermal permeation of each antiemetic drug primarily in its unionized state increased over that observed with the drug primarily in its ionized state after 24 hours (promethazine: 1.6-fold increase; metoclopramide: 1.3-fold increase; ondansetron: 1.8-fold increase). A similar trend was noted in the amount of each drug found in the skin after 24 hours (promethazine: 1.2-fold increase; metoclopramide: 2.4-fold increase; ondansetron: 3.0-fold increase). These results suggest that proper optimization of drug ionization state may be a useful strategy for compounding pharmacists to increase the efficacy of drugs intended for inclusion in transdermal formulations.

Design, development, physicochemical, and in vitro and in vivo evaluation of transdermal patches containing diclofenac diethylammonium salt.

PubMed

Arora, Priyanka; Mukherjee, Biswajit

2002-09-01

In this study, matrix-type transdermal patches containing diclofenac diethylamine were prepared using different ratios of polyvinylpyrrolidone (PVP) and ethylcellulose (EC) by solvent evaporation technique. The drug matrix film of PVP and EC was casted on a polyvinylalcohol backing membrane. All the prepared formulations were subjected to physical studies (moisture content, moisture uptake, and flatness), in vitro release studies and in vitro skin permeation studies. In vitro permeation studies were performed across cadaver skin using a modified diffusion cell. Variations in drug release profiles among the formulations studied were observed. Based on a physicochemical and in vitro skin permeation study, formulation PA4 (PVP/EC, 1:2) and PA5 (PVP/EC, 1:5) were chosen for further in vivo experiments. The antiinflammatory effect and a sustaining action of diclofenac diethylamine from the two transdermal patches selected were studied by inducing paw edema in rats with 1% w/v carrageenan solution. When the patches were applied half an hour before the subplantar injection of carrageenan in the hind paw of male Wistar rats, it was observed that formulation PA4 produced 100% inhibition of paw edema in rats 12 h after carrageenan insult, whereas in the case of formulation PA5, 4% mean paw edema was obtained half an hour after the carrageenan injection and the value became 19.23% 12 h after the carrageenan insult. The efficacy of transdermal patches was also compared with the marketed Voveran gel and it was found that PA4 transdermal patches produced a better result as compared with the Voveran gel. Hence, it can be reasonably concluded that diclofenac diethylamine can be formulated into the transdermal matrix type patches to sustain its release characteristics and the polymeric composition (PVP/EC, 1:2) was found to be the best choice for manufacturing transdermal patches of diclofenac diethylamine among the formulations studied. Copyright 2002 Wiley-Liss, Inc.

Sex hormone-binding globulin and antithrombin III activity in women with oral ultra-low-dose estradiol.

PubMed

Matsui, Sumika; Yasui, Toshiyuki; Kasai, Kana; Keyama, Kaoru; Yoshida, Kanako; Kato, Takeshi; Uemura, Hirokazu; Kuwahara, Akira; Matsuzaki, Toshiya; Irahara, Minoru

2017-07-01

Oral oestrogen increases the risk of venous thromboembolism (VTE) and increases production of sex hormone-binding globulin (SHBG) in a dose-dependent manner. SHBG has been suggested to be involved in venous thromboembolism. We examined the effects of oral ultra-low-dose oestradiol on circulating levels of SHBG and coagulation parameters, and we compared the effects to those of transdermal oestradiol. Twenty women received oral oestradiol (500 μg) every day (oral ultra-low-dose group) and 20 women received a transdermal patch (50 μg) as a transdermal group. In addition, the women received dydrogesterone continuously (5 mg) except for women who underwent hysterectomy. Circulating SHBG, antithrombin III (ATIII) activity, d-dimer, thrombin-antithrombin complex and plasmin-α2 plasmin inhibitor complex were measured before and 3 months after the start of treatment. SHBG was significantly increased at 3 months in the oral ultra-low-dose group, but not in the transdermal group. However, percent changes in SHBG were not significantly different between the two groups. In both groups, ATIII was significantly decreased at 3 months. In conclusion, even ultra-low-dose oestradiol orally increases circulating SHBG level. However, the magnitude of change in SHBG caused by oral ultra-low-dose oestradiol is small and is comparable to that caused by transdermal oestradiol. Impact statement Oral oestrogen replacement therapy increases production of SHBG which may be related to increase in VTE risk. However, the effect of oral ultra-low-dose oestradiol on SHBG has not been clarified. Even ultra-low-dose oestradiol orally increases circulating SHBG levels, but the magnitude of change in SHBG caused by oral ultra-low-dose oestradiol is small and is comparable to that caused by transdermal oestradiol. VTE risk in women receiving oral ultra-low-dose oestradiol may be comparable to that in women receiving transdermal oestradiol.

Transdermal permeation of drugs with differing lipophilicity: Effect of penetration enhancer camphor.

PubMed

Xie, Feng; Chai, Jia-Ke; Hu, Quan; Yu, Yong-Hui; Ma, Li; Liu, Ling-Ying; Zhang, Xu-Long; Li, Bai-Ling; Zhang, Dong-Hai

2016-06-30

The aim of the present study was to investigate the potential application of (+)-camphor as a penetration enhancer for the transdermal delivery of drugs with differing lipophilicity. The skin irritation of camphor was evaluated by in vitro cytotoxicity assays and in vivo transdermal water loss (TEWL) measurements. A series of model drugs with a wide span of lipophilicity (logP value ranging from 3.80 to -0.95), namely indometacin, lidocaine, aspirin, antipyrine, tegafur and 5-fluorouracil, were tested using in vitro transdermal permeation experiments to assess the penetration-enhancing profile of camphor. Meanwhile, the in vivo skin microdialysis was carried out to further investigate the enhancing effect of camphor on the lipophilic and hydrophilic model drugs (i.e. lidocaine and tegafur). SC (stratum corneum)/vehicle partition coefficient and Fourier transform infrared spectroscopy (FTIR) were performed to probe the regulation action of camphor in the skin permeability barrier. It was found that camphor produced a relatively low skin irritation, compared with the frequently-used and standard penetration enhancer laurocapram. In vitro skin permeation studies showed that camphor could significantly facilitate the transdermal absorption of model drugs with differing lipophilicity, and the penetration-enhancing activities were in a parabola curve going downwards with the drug logP values, which displayed the optimal penetration-enhancing efficiency for the weak lipophilic or hydrophilic drugs (an estimated logP value of 0). In vivo skin microdialysis showed that camphor had a similar penetration behavior on transdermal absorption of model drugs. Meanwhile, the partition of lipophilic drugs into SC was increased after treatment with camphor, and camphor also produced a shift of CH2 vibration of SC lipid to higher wavenumbers and decreased the peak area of the CH2 vibration, probably resulting in the alteration of the skin permeability barrier. This suggests that camphor might be a safe and effective penetration enhancer for transdermal drug delivery. Copyright © 2016 Elsevier B.V. All rights reserved.

Evaluating transdermal alcohol measuring devices

DOT National Transportation Integrated Search

2007-11-01

This report is an evaluation study of two types of transdermal devices that detect alcohol at the skin surface representing two types of electrochemical sensing technology. The AMS SCRAM ankle device and the Giner WrisTAS wrist device were worn...

Status of surfactants as penetration enhancers in transdermal drug delivery

PubMed Central

Som, Iti; Bhatia, Kashish; Yasir, Mohd.

2012-01-01

Surfactants are found in many existing therapeutic, cosmetic, and agro-chemical preparations. In recent years, surfactants have been employed to enhance the permeation rates of several drugs via transdermal route. The application of transdermal route to a wider range of drugs is limited due to significant barrier to penetration across the skin which is associated with the outermost stratum corneum layer. Surfactants have effects on the permeability characteristics of several biological membranes including skin. They have the potential to solubilize lipids within the stratum corneum. The penetration of the surfactant molecule into the lipid lamellae of the stratum corneum is strongly dependent on the partitioning behavior and solubility of surfactant. Surfactants ranging from hydrophobic agents such as oleic acid to hydrophilic sodium lauryl sulfate have been tested as permeation enhancer to improve drug delivery. This article reviews the status of surfactants as permeation enhancer in transdermal drug delivery of various drugs. PMID:22368393

Nanoethosomes mediated transdermal delivery of vinpocetine for management of Alzheimer's disease.

PubMed

Moghaddam, Atefeh Afshar; Aqil, Mohd; Ahmad, Farhan J; Ali, Mushir M; Sultana, Yasmin; Ali, Asgar

2015-12-01

To develop and statistically optimize nanoethosomal formulation for transdermal delivery of vinpocetine as an anti-Alzheimer's drug. Box-Behnken experimental design was applied for optimization of nanoethosomes. The independent variables were phospholipid (X 1 ), Tween 80 (X 2 ) and Ethanol (X 3 ) while entrapment efficiency (Y 1 ), particle sizes (Y 2 ), elasticity (Y 3 ) and flux (Y 4 ) were the dependent variables. Optimized nanoethosomal vinpocetine formulation with mean particle size 50.57 ± 26.11 nm showed 97.51 ± 0.86% entrapment efficiency, achieved mean transdermal flux 925.60 ± 39.80 µg/cm 2 /h and elasticity of 86.61 ± 2.88. Ex-vivo study of nanoethosomal formulation showed a significant increase flux and entrapment efficiency compared with control vinpocetine solution. Our results suggest that nanoethosome is an efficient carrier for transdermal delivery of vinpocetine as compared to its oral form.

76 FR 51038 - Guidance for Industry on Residual Drug in Transdermal and Related Drug Delivery Systems...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-17

... a larger amount of the drug substance than what is intended to be delivered to the patient. This... patient, but also to others, including family members, caregivers, children, and pets. For example...

Topical Non-Iontophoretic Application of Acetylcholine and Nitroglycerin via a Translucent Patch: A New Means for Assessing Microvascular Reactivity

PubMed Central

Schonberger, Robert B.; Worden, William S.; Shahmohammadi, Kaveh; Menn, Kirsten; Silverman, Tyler J.; Stout, Robert G.; Shelley, Kirk H.; Silverman, David G.

2007-01-01

Objective: Assessments of endothelial cell function with acetylcholine have typically used systemic, regional intra-arterial, or iontophoretic delivery of drug. Each of these techniques induces systemic and/or local changes that compromise their safety or effectiveness. Using translucent drug preparations applied under laser Doppler flowmetry (LDF) probes, we tested whether local vasodilation can be induced with non-iontophoretic transdermal delivery of acetylcholine and how such dilation would compare to the dilation achieved with topical nitroglycerin in healthy volunteers. Methods: Ten subjects without known vascular disease were recruited for LDF monitoring at sites of drug application for this preliminary investigation. Topical acetylcholine chloride, nitroglycerin, and placebo were applied via translucent patches to the forehead directly below LDF probes. Results: LDF readings increased by 406 percent (245 percent to 566 percent) and 36 percent (26 percent to 46 percent), respectively, at the acetylcholine and placebo sites (p = .005 by Wilcoxon Signed Rank Test (WSRT) for acetylcholine vs. placebo); and they increased by 365 percent (179 percent to 550 percent) at the nitroglycerin site (p = .005 by WSRT for nitroglycerin vs. placebo; p = .6 vs. acetylcholine). Conclusion: Transdermal delivery of acetylcholine can induce significant local vasodilatory responses comparable to those achieved with nitroglycerin without requiring iontophoresis. The means of transdermal delivery and monitoring described herein may constitute a new minimally invasive way to interrogate the microvasculature and thereby assess the microcirculatory changes induced by various disorders and therapeutic interventions. PMID:17876370

A novel non-imaging optics based Raman spectroscopy device for transdermal blood analyte measurement

PubMed Central

Kong, Chae-Ryon; Barman, Ishan; Dingari, Narahara Chari; Kang, Jeon Woong; Galindo, Luis; Dasari, Ramachandra R.; Feld, Michael S.

2011-01-01

Due to its high chemical specificity, Raman spectroscopy has been considered to be a promising technique for non-invasive disease diagnosis. However, during Raman excitation, less than one out of a million photons undergo spontaneous Raman scattering and such weakness in Raman scattered light often require highly efficient collection of Raman scattered light for the analysis of biological tissues. We present a novel non-imaging optics based portable Raman spectroscopy instrument designed for enhanced light collection. While the instrument was demonstrated on transdermal blood glucose measurement, it can also be used for detection of other clinically relevant blood analytes such as creatinine, urea and cholesterol, as well as other tissue diagnosis applications. For enhanced light collection, a non-imaging optical element called compound hyperbolic concentrator (CHC) converts the wide angular range of scattered photons (numerical aperture (NA) of 1.0) from the tissue into a limited range of angles accommodated by the acceptance angles of the collection system (e.g., an optical fiber with NA of 0.22). A CHC enables collimation of scattered light directions to within extremely narrow range of angles while also maintaining practical physical dimensions. Such a design allows for the development of a very efficient and compact spectroscopy system for analyzing highly scattering biological tissues. Using the CHC-based portable Raman instrument in a clinical research setting, we demonstrate successful transdermal blood glucose predictions in human subjects undergoing oral glucose tolerance tests. PMID:22125761

Innovative polymeric system (IPS) for solvent-free lipophilic drug transdermal delivery via dissolving microneedles.

PubMed

Dangol, Manita; Yang, Huisuk; Li, Cheng Guo; Lahiji, Shayan Fakhraei; Kim, Suyong; Ma, Yonghao; Jung, Hyungil

2016-02-10

Lipophilic drugs are potential drug candidates during drug development. However, due to the need for hazardous organic solvents for their solubilization, these drugs often fail to reach the pharmaceutical market, and in doing so highlight the importance of solvent free systems. Although transdermal drug delivery systems (TDDSs) are considered prospective safe drug delivery routes, a system involving lipophilic drugs in solvent free or powder form has not yet been described. Here, we report, for the first time, a novel approach for the delivery of every kind of lipophilic drug in powder form based on an innovative polymeric system (IPS). The phase transition of powder form of lipophilic drugs due to interior chemical bonds between drugs and biodegradable polymers and formation of nano-sized colloidal structures allowed the fabrication of dissolving microneedles (DMNs) to generate a powerful TDDS. We showed that IPS based DMN with powder capsaicin enhances the therapeutic effect for treatment of the rheumatic arthritis in a DBA/1 mouse model compared to a solvent-based system, indicating the promising potential of this new solvent-free platform for lipophilic drug delivery. Copyright © 2016 Elsevier B.V. All rights reserved.

Contingency Management for Alcohol Use Reduction: A Pilot Study using a Transdermal Alcohol Sensor*

PubMed Central

Barnett, Nancy P.; Tidey, Jennifer; Murphy, James G.; Swift, Robert; Colby, Suzanne M.

2011-01-01

Background Contingency management (CM) has not been thoroughly evaluated as a treatment for alcohol abuse or dependence, in part because verification of alcohol use reduction requires frequent in-person breath tests. Transdermal alcohol sensors detect alcohol regularly throughout the day, providing remote monitoring and allowing for rapid reinforcement of reductions in use. Methods The purpose of this study was to evaluate the efficacy of CM for reduction in alcohol use, using a transdermal alcohol sensor to provide a continuous measure of alcohol use. Participants were 13 heavy drinking adults who wore the Secure Continuous Remote Alcohol Monitoring (SCRAM) bracelet for three weeks and provided reports of alcohol and drug use using daily web-based surveys. In Week 1, participants were asked to drink as usual; in Weeks 2 and 3, they were reinforced on an escalating schedule with values ranging from $5-$17 per day on days when alcohol use was not reported or detected by the SCRAM. Results Self-reports of percent days abstinent and drinks per week, and transdermal measures of average and peak transdermal alcohol concentration and area under the curve declined significantly in Weeks 2-3. A nonsignificant but large effect size for reduction in days of tobacco use also was found. An adjustment to the SCRAM criteria for detecting alcohol use provided an accurate but less conservative method for use with non-mandated clients. Conclusion Results support the efficacy of CM for alcohol use reductions and the feasibility of using transdermal monitoring of alcohol use for clinical purposes. PMID:21665385

Contingency management for alcohol use reduction: a pilot study using a transdermal alcohol sensor.

PubMed

Barnett, Nancy P; Tidey, Jennifer; Murphy, James G; Swift, Robert; Colby, Suzanne M

2011-11-01

Contingency management (CM) has not been thoroughly evaluated as a treatment for alcohol abuse or dependence, in part because verification of alcohol use reduction requires frequent in-person breath tests. Transdermal alcohol sensors detect alcohol regularly throughout the day, providing remote monitoring and allowing for rapid reinforcement of reductions in use. The purpose of this study was to evaluate the efficacy of CM for reduction in alcohol use, using a transdermal alcohol sensor to provide a continuous measure of alcohol use. Participants were 13 heavy drinking adults who wore the Secure Continuous Remote Alcohol Monitoring (SCRAM) bracelet for three weeks and provided reports of alcohol and drug use using daily web-based surveys. In Week 1, participants were asked to drink as usual; in Weeks 2 and 3, they were reinforced on an escalating schedule with values ranging from $5 to $17 per day on days when alcohol use was not reported or detected by the SCRAM. Self-reports of percent days abstinent and drinks per week, and transdermal measures of average and peak transdermal alcohol concentration and area under the curve declined significantly in Weeks 2-3. A nonsignificant but large effect size for reduction in days of tobacco use also was found. An adjustment to the SCRAM criteria for detecting alcohol use provided an accurate but less conservative method for use with non-mandated clients. Results support the efficacy of CM for alcohol use reductions and the feasibility of using transdermal monitoring of alcohol use for clinical purposes. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Evaluation of the Percutaneous Absorption of Ketamine HCl, Gabapentin, Clonidine HCl, and Baclofen, in Compounded Transdermal Pain Formulations, Using the Franz Finite Dose Model.

PubMed

Bassani, August S; Banov, Daniel

2016-02-01

This study evaluates the ability of four commonly used analgesics (ketamine HCl, gabapentin, clonidine HCl, and baclofen), when incorporated into two transdermal compounding bases, Lipoderm and Lipoderm ActiveMax, to penetrate human cadaver trunk skin in vitro, using the Franz finite dose model. In vitro experimental study. Methods. Ketamine HCl 5% w/w, gabapentin 10% w/w, clonidine HCl 0.2% w/w, and baclofen 2% w/w were compounded into two transdermal bases, Lipoderm and Lipoderm ActiveMax. Each compounded drug formulation was tested on skin from three different donors and three replicate skin sections per donor. The Franz finite dose model was used in this study to evaluate the percutaneous absorption and distribution of drugs within each formulation. Rapid penetration to peak flux was detected for gabapentin and baclofen at approximately 1 hour after application. Clonidine HCl also had a rapid penetration to peak flux occurring approximately 1 hour after application and had a secondary peak at approximately 40 hours. Ketamine HCl exhibited higher overall absorption rates than the other drugs, and peaked at 6–10 hours. Similar patterns of drug distribution within the skin were also observed using both transdermal bases. This study suggests that the combination of these 4 analgesic drugs can be successfully delivered transdermally, using either Lipoderm or Lipoderm ActiveMax. Compounded transdermal drug preparations may then provide physicians with an alternative to traditional oral pain management regimens that can be personalized to the specific patient with the potential for enhanced pain control.

In vivo immunomodulatory, cumulative skin irritation, sensitization and effect of d-limonene on permeation of 6-mercaptopurine through transdermal drug delivery.

PubMed

Chandrashekar, N S; Hiremath, Shobha Rani Rajeev

2008-04-01

Using skin as a port for systemic drug administration, transdermal drug delivery has expanded greatly over the last two decades. Our aim was to formulate the single layer drug-in-adhesive transdermal patch for 6-mercaptopurine (6-MP). In vitro permeation study was carried out using modified Franz diffusion cell with and without of different concentration of d-limonene in human cadaver skin. In vivo immunomodulatory was carried out in mice, cumulative skin irritation, sensitization and patch adherence study was done in both mice and human subjects. 6-MP flux increased from 43+/-12.2 microg/cm2h (control) to 162.8+/-32.2 microg/cm2h (6% w/v d-limonene) data was significant (p<0.05), with decrease in the lag time to 35+/-9.3 min compared to control of 90 +/-15.3 min. In vivo immunomodulatory effect was shown in the Balb/c mice with 100 mumol/kg/body wt of animal for 5d (one dose/d) of d-limonene. WBC count of 13469 cells/mm peak was observed on 12th day, bone marrow cells of 26.3 x 10(6) cells/femur and alpha-esterase positive cells of 1259+/-328.4 cells/4000 bone marrow cells. Cumulative skin irritation, sensitisation and patch adherence in animals and human subjects showed no skin irritation and sensitization. Patch adhesion was greater than 90.0% respectively in both human subjects and mice. The percentage of human subjects with adhesive residue was significantly less with scores of zero. d-Limonene proved as good chemical enhancer by increasing in the skin permeability with shortened the lag time. It proved that therapeutic amount of 6-MP can be delivered through transdermal drug delivery.

Fatal intravenous fentanyl abuse: four cases involving extraction of fentanyl from transdermal patches.

PubMed

Tharp, Amy M; Winecker, Ruth E; Winston, David C

2004-06-01

The transdermal fentanyl system delivers a specific dose at a constant rate. Even after the prescribed application time has elapsed, enough fentanyl remains within a patch to provide a potentially lethal dose. Death due to the intravenous injection of fentanyl extracted from transdermal patches has not been previously reported. We present 4 cases in which the source of fentanyl was transdermal patches and was injected. In all of these cases, the victim was a white male who died at home. Case 1 was a 35-year-old with no known history of drug use, who was found by his wife on the floor of his workshop. Police recovered a fentanyl patch, needle, and syringe at the scene. Case 2 was a 38-year-old with a known history of drug use whose family claimed that he was in a treatment program that used fentanyl patches for unknown reasons. His brother found him dead in bed, and law enforcement officers found a hypodermic needle beside the body; a ligature around his left hand, and apparent needle marks between his first and second digits were also noted. Case 3 was a 42-year-old with a recent attempted suicide via overdose who was found dead at his home. An empty box of fentanyl patches, Valium, Ritalin, and 2 syringes were found at the scene. Case 4 was a 39-year-old found by his mother, who admitted to removing a needle with attached syringe from the decedent's arm. Medications at the scene included hydrocodone, alprazolam, zolpidem, and fentanyl patches. All reported deaths were attributed to fentanyl intoxication, with blood concentrations ranging from 5 to 27 microg/L.

75 FR 45640 - Draft Guidance for Industry on Residual Drug in Transdermal and Related Drug Delivery Systems...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-03

... drug substance than what is intended to be delivered to the patient. This excess amount of drug... issue not only to the patient, but also to others including family members, caregivers, children, and...

An Overview of Clinical and Commercial Impact of Drug Delivery Systems

PubMed Central

Anselmo, Aaron C.; Mitragotri, Samir

2014-01-01

Drug delivery systems are widely researched and developed to improve the delivery of pharmaceutical compounds and molecules. The last few decades have seen a marked growth of the field fueled by increased number of researchers, research funding, venture capital and the number of start-ups. Collectively, the growth has led to novel systems that make use of micro/nano-particles, transdermal patches, inhalers, drug reservoir implants and antibody-drug conjugates. While the increased research activity is clearly an indication of proliferation of the field, clinical and commercial translation of early-stage research ideas is critically important for future growth and interest in the field. Here, we will highlight some of the examples of novel drug delivery systems that have undergone such translation. Specifically, we will discuss the developments, advantages, limitations and lessons learned from: (i) microparticle-based depot formulations, (ii) nanoparticle-based cancer drugs, (iii) transdermal systems, (iv) oral drug delivery systems, (v) pulmonary drug delivery, (vi) implants and (vii) antibody-drug conjugates. These systems have impacted treatment of many prevalent diseases including diabetes, cancer and cardiovascular diseases, among others. At the same time, these systems are integral and enabling components of products that collectively generate annual revenues exceeding US $100 billion. These examples provide strong evidence of the clinical and commercial impact of drug delivery systems. PMID:24747160

From the Cover: Microfabricated needles for transdermal delivery of macromolecules and nanoparticles: Fabrication methods and transport studies

NASA Astrophysics Data System (ADS)

McAllister, Devin V.; Wang, Ping M.; Davis, Shawn P.; Park, Jung-Hwan; Canatella, Paul J.; Allen, Mark G.; Prausnitz, Mark R.

2003-11-01

Arrays of micrometer-scale needles could be used to deliver drugs, proteins, and particles across skin in a minimally invasive manner. We therefore developed microfabrication techniques for silicon, metal, and biodegradable polymer microneedle arrays having solid and hollow bores with tapered and beveled tips and feature sizes from 1 to 1,000 μm. When solid microneedles were used, skin permeability was increased in vitro by orders of magnitude for macromolecules and particles up to 50 nm in radius. Intracellular delivery of molecules into viable cells was also achieved with high efficiency. Hollow microneedles permitted flow of microliter quantities into skin in vivo, including microinjection of insulin to reduce blood glucose levels in diabetic rats. transdermal drug delivery | skin | microelectromechanical systems | solid microneedle | hollow needle injection

Pharmacokinetics, safety and tolerability of a novel tocopheryl phosphate mixture/oxycodone transdermal patch system: a Phase I study.

PubMed

Gavin, Paul D; Simon, Lee S; Schlagheck, Thomas; Smith, Alisha J; Shakib, Sepehr

2017-07-01

To characterize the pharmacokinetic profile and evaluate the safety and tolerability of a transdermal oxycodone patch containing tocopheryl phosphate mixture (TPM). Eleven healthy subjects received a single application of three TPM/oxycodone patches applied to the torso for 72 h. Oxycodone was detected 8.0 ± 2.7-h postpatch administration, reaching a mean maximum plasma concentration of 3.41 ± 1.34 ng/ml at 49.3 ± 21.2 h. The safety profile was consistent with the application method and known side-effect profile of oxycodone and naltrexone. No treatment-limiting skin irritation was observed. A 3-day application of the TPM/oxycodone patch demonstrated an acceptable safety profile and was well tolerated by healthy subjects, with limited dermal irritation following application.

Enhancement of Permeation in Transdermal Drug Delivery System by 6μm Wavelength Area Using an MIR-FEL

NASA Astrophysics Data System (ADS)

Uchizono, T.; Ishii, K.; Iwao, Y.; Itou, Y.; Maruo, H.; Hori, M.; Awazu, K.

2005-03-01

Ablation of the stratum corneum (SC) by pulsed-laser irradiation is one method of enhancing transdermal drug delivery (TD). For non-invasive laser TD treatment, we have tried to enhance TD without ablation of the SC using an MIR-FEL (6-μm wavelength) (FEL : free electron laser). Lidocaine was used as the drug in this study. The enhancement of TD was measured by HPLC. It was found that the lidocaine TD of the sample irradiated by MIR-FEL was enhanced 10 fold faster than the non-irradiated sample with a flux at 0.5 μg/cm2/h, measured by HPLC. We have demonstrated the effectiveness of TD enhancement by an MIR-FEL (6-μm wavelength) irradiation.

Tamoxifen citrate loaded ethosomes for transdermal drug delivery system: preparation and characterization.

PubMed

Sarwa, Khomendra Kumar; Suresh, Preeti K; Debnath, Manabendra; Ahmad, Mohammad Zaki

2013-08-01

Long term tamoxifen citrate therapy is imperative to treat several dermatological and hormonal sensitive disorders. Successful oral and parenteral administration of tamoxifen citrate has been challenging since it undergoes enzymatic degradation and has poor aqueous solubility issues. In the present work, tamoxifen citrate loaded ethosomes were prepared and characterized for transdermal applications. The prepared formulations were characterized for morphological features, particle size distribution, calorimetric attributes, zeta potential and drug entrapment. Permeation profile of prepared ethosomes was compared with liposomes and hydroethonalic solution across cellophane membrane and human cadaver skin. Results of the permeation studies indicate that ethosomes were able to deliver >90% drug within 24 hours of application, while liposomes and hydroethanolic solution delivered only 39.04% and 36.55% respectively. Skin deposition and stability studies are also reported.

Transdermal Scopolamine Withdrawal Syndrome Case Report in the Pediatric Cerebral Palsy Population.

PubMed

Chowdhury, Nasim A; Sewatsky, Mary Laura; Kim, Heakyung

2017-08-01

Sialorrhea in children with cerebral palsy (CP) results in aspiration, decreased social integration, and poor quality of life. Management options include transdermal anticholinergics such as the scopolamine patch. A controlled clinical trial has proven botulinum toxin (BTX) injections into the salivary glands are an effective alternative to transdermal anticholinergics with a safer side effect profile. Multiple studies of the injections in diverse populations demonstrate reduction in saliva production with improvement in quality of life and decrease in hospitalization-associated costs. The authors describe a 15-year-old boy with spastic quadriplegic CP who developed emesis, nausea, and lethargy 1 day after the first injection of botulinum toxin A (BTX-A) to his salivary glands for sialorrhea management. The authors ascribed his symptoms to scopolamine withdrawal. Given the lack of exposure in the medical literature, there is minimal awareness of the withdrawal syndrome from transdermal scopolamine in children with or without CP, resulting in delayed diagnosis and potential complications. Treatment of the withdrawal syndrome has been successful with meclizine though safety and efficacy has not been established in children younger than 12 despite frequent clinical and over-the-counter use. Prompt diagnosis of the transdermal scopolamine withdrawal syndrome can result in quicker treatment and a shorter hospital stay.

Efficacy and Safety of Oral Diclofenac Sustained release Versus Transdermal Diclofenac Patch in Chronic Musculoskeletal Pain: A Randomized, Open Label Trial

PubMed Central

Shinde, Viraj Ashok; Kalikar, Mrunalini; Jagtap, Satyajeet; Dakhale, Ganesh N.; Bankar, Mangesh; Bajait, Chaitali S.; Motghare, Vijay M.; Pashilkar, Ashlesha A.; Raghute, Latesh B.; Khamkar, Ajita D.

2017-01-01

Introduction: To compare the efficacy, safety, and tolerability of transdermal patches of diclofenac sodium with oral diclofenac sustained release (SR) in patients of chronic musculoskeletal MSK pain conditions. Materials and Methods: The eligible patients were given either transdermal diclofenac patch or tablet diclofenac SR. Pain was assessed at 2 and 4 weeks using a visual analog scale. Adverse events were recorded. Patients with 18–65 years old of either gender with score of ≥4 on a 11-item numeric rating scale-numeric version of visual analog scale for pain with diagnosis of primary osteoarthritis (OA) of the knee or hand of at least 3 months duration, with independent radiological confirmation of OA or having pain associated with other MSK conditions such as soft-tissue rheumatism, cervical and lumbar back pain, and fibromyalgia, of at least 3 months duration were included in this study. Results: Transdermal diclofenac diethylamine patch and tablet diclofenac sodium sustained release (SR) do not significantly differ in the reduction of numerical rating scores at the end of 4 weeks (P = 0.8393). Conclusion: Transdermal diclofenac was equi-efficacious as tablet diclofenac sodium SR in reducing pain due to chronic MSK pain conditions. PMID:29472748

Mechanisms of gastroprotection by transdermal nitroglycerin in the rat

PubMed Central

Calatayud, Sara; Sanz, María-Jesús; Canet, Amparo; Bello, Regina; de Rojas, Francisco Díaz; Esplugues, Juan V

1999-01-01

Nitric oxide (NO) donors prevent experimentally-induced gastric mucosal damage, but their clinical utility is limited by short duration of action or unsuitability of the pharmaceutical form employed. This study analyses the gastroprotection elicited by a clinically used mode of continuous administration of an NO donor, namely the nitroglycerin patch. Application to rats of a transdermal patch that releases doses of nitroglycerin comparable to those used in man (40, 80, 160 and 400 ng min−1 rat−1) reduced gastric damage induced by indomethacin (25 mg kg−1, p.o. or s.c.). The nitroglycerin patch (160 ng  min−1 rat−1) also diminished damage by oral administration (1 ml) of acidified bile salts (100 mg kg−1 taurocholic acid in 150 mM HCl) or 50% ethanol. Transdermal nitroglycerin (160 ng min−1 rat−1) did not influence basal gastric blood flow, as measured by lasser-doppler flowmetry, but prevented its reduction by indomethacin. Transdermal nitroglycerin (160 ng min−1 rat−1) prevented in vivo leukocyte rolling and adherence in the rat mesentery microvessels superfused with indomethacin, as evaluated by intravital microscopy. The transdermal nitroglycerin patch protects the gastric mucosa from damage by mechanisms that involve maintenance of mucosal blood flow and reduction of leukocyte-endothelial cell interaction. PMID:10455256

Superiority of liquid crystalline cubic nanocarriers as hormonal transdermal vehicle: comparative human skin permeation-supported evidence.

PubMed

Mohyeldin, Salma M; Mehanna, Mohammed M; Elgindy, Nazik A

2016-08-01

The aim of this investigation was to explore the feasibility of various nanocarriers to enhance progesterone penetration via the human abdominal skin. Four progesterone-loaded nanocarriers; cubosomes, nanoliposomes, nanoemulsions and nanomicelles were formulated and characterized regarding particle size, zeta potential, % drug encapsulation and in vitro release. Structural elucidation of each nanoplatform was performed using transmission electron microscopy. Ex vivo skin permeation, deposition ability and histopathological examination were evaluated using Franz diffusion cells. Each nanocarrier was fabricated with a negative surface, nanometric size (≤ 270 nm), narrow size distribution and reasonable encapsulation efficiency. In vitro progesterone release showed a sustained release pattern for 24 h following a non-Fickian transport diffusion mechanism. All nanocarriers exhibited higher transdermal flux relative to free progesterone. Cubosomes revealed a higher skin penetration with transdermal steady flux of 48.57.10(-2) ± 0.7 µg/cm(2) h. Nanoliposomes offered a higher percentage of skin progesterone deposition compared to other nanocarriers. Based on the histopathological examination, cubosomes and nanoliposomes were found to be biocompatible for transdermal application. Confocal laser scanning microscopy confirmed the ability of fluoro-labeled cubosomes to penetrate through the whole skin layers. The elaborated cubosomes proved to be a promising non-invasive nanocarrier for transdermal hormonal delivery.

Do local meteorological conditions influence skin irritation caused by transdermal rivastigmine? A retroprospective, pilot study.

PubMed

Segers, Kurt; Cytryn, Ephraim; Surquin, Murielle

2012-06-01

This retrospective study aimed to evaluate the incidence of transdermal rivastigmine treatment withdrawal secondary to adverse skin reactions among the patients from our Memory Clinic. In addition, we tested whether climatic conditions might have an influence on skin irritations leading to eventual treatment disruption. We performed a retrospective review of patients from the Brugmann University Hospital Memory Clinic having started transdermal rivastigmine between June 2008 and December 2010. Local meteorological data were provided by the Royal Meteorological Institute of Belgium. A total of 26.9% of the patients experienced adverse skin reactions at the rivastigmine application site, leading to treatment discontinuation in 19.2% of the cases. Rivastigmine cutaneous tolerability was not found to be related to demographic parameters, Mini Mental Status Examination score, or type of dementia. High temperature and low air humidity during the first month of treatment were found to be associated with a higher incidence of skin reactions and secondary treatment disruption. Transdermal rivastigmine induced a higher incidence of cutaneous adverse events than previously reported in a prospective clinical trial. Moreover, it seems that meteorological conditions favoring skin perspiration (high temperature and low air humidity) during the first month of treatment might have an influence on transdermal rivastigmine skin tolerability.

Transdermal Delivery of Iron Using Soluble Microneedles: Dermal Kinetics and Safety.

PubMed

Modepalli, Naresh; Shivakumar, H Nanjappa; McCrudden, Maeliosa T C; Donnelly, Ryan F; Banga, Ajay; Murthy, S Narasimha

2016-03-01

Currently, the iron compounds are administered via oral and parenteral routes in patients of all ages, to treat iron deficiency. Despite continued efforts to supplement iron via these conventional routes, iron deficiency still remains the most prevalent nutritional disorder all over the world. Transdermal replenishment of iron is a novel, potential approach of iron replenishment. Ferric pyrophosphate (FPP) was found to be a suitable source of iron for transdermal replenishment. The safety of FPP was assessed in this project by challenging the dermal fibroblast cells with high concentration of FPP. The cell viability assay and reactive oxygen species assay were performed. The soluble microneedle array was developed, incorporated with FPP and the kinetics of free iron in the skin; extracellular fluid following dermal administration of microneedle array was investigated in hairless rats. From the cell based assays, FPP was selected as one of the potential iron sources for transdermal delivery. The microneedles were found to dissolve in the skin fluid within 3 hours of administration. The FPP concentration in the dermal extracellular fluid declined after complete dissolution of the microneedle array. Overall, the studies demonstrated the safety of FPP for dermal delivery and the feasibility of soluble microneedle approach for transdermal iron replenishment therapy. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Pharmacokinetics of multiple doses of transdermal flunixin meglumine in adult Holstein dairy cows.

PubMed

Kleinhenz, M D; Gorden, P J; Smith, J S; Schleining, J A; Kleinhenz, K E; Wulf, L L; Sidhu, P K; Rea, D; Coetzee, J F

2018-06-01

A transdermal formulation of the nonsteroidal anti-inflammatory drug, flunixin meglumine, has been approved in the United States and Canada for single-dose administration. Transdermal flunixin meglumine was administered to 10 adult Holstein cows in their second or third lactation at the label dose of 3.33 mg/kg every 24 hr for three total treatments. Plasma flunixin concentrations were determined using high-pressure liquid chromatography with mass spectroscopy (HPLC-MS). Pharmacokinetic analysis was completed on each individual animal with noncompartmental methods using computer software. The time to maximum drug concentration (Tmax) was 2.81 hr, and the maximum drug concentration was 1.08 μg/ml. The mean terminal half-life (T½) was determined to be 5.20 hr. Clearance per fraction absorbed (Cl/F) was calculated to be 0.294 L/hr kg -1 , and volume of distribution of fraction (Vz/F) absorbed was 2.20 L/kg. The mean accumulation factor was 1.10 after three doses. This indicates changes in dosing may not be required when giving multiple doses of flunixin transdermal. Further work is required to investigate the clinical efficacy of transdermal flunixin after multiple daily doses. © 2018 John Wiley & Sons Ltd.

Nanoemulsion as pharmaceutical carrier for dermal and transdermal drug delivery: Formulation development, stability issues, basic considerations and applications.

PubMed

Rai, Vineet Kumar; Mishra, Nidhi; Yadav, Kuldeep Singh; Yadav, Narayan Prasad

2018-01-28

The use of nanoemulsion in augmenting dermal and transdermal effectiveness of drugs has now well established. The development of nanoemulsion based semisolid dosage forms is an active area of present research. However, thickening or liquid-to-semisolid conversion of the nanoemulsions provides opportunities to the formulation scientist to explore novel means of solving instability issues during transformation. Extending knowledge about the explicit role of nature/magnitude of zeta potential, types of emulsifiers and selection of appropriate semisolid bases could place these versatile carriers from laboratory to industrial scale. This article reviews the progressive advancement in the delivery of medicament via nanoemulsion with special reference to the dermal and transdermal administration. It is attempted to explore the most suitable semi solid dosage form for the particular type of nanoemulsion (o/w, w/o and others) and effect of particle size and zeta potential on the delivery of drugs through dermal or transdermal route. Finally, this review also highlights the basic principles and fundamental considerations of nanoemulsion manufacture, application of nanoemulsion based semisolid dosage forms in the dermal/transdermal administration and basic considerations during the nanoemulsion absorption into and through skin. Copyright © 2017 Elsevier B.V. All rights reserved.

Transdermal absorption of natural progesterone from alcoholic gel formulations with hydrophilic surfactant.

PubMed

Matsui, Rakan; Ueda, Osamu; Uchida, Shinya; Namiki, Noriyuki

2015-06-01

The aim of this study was to evaluate the in vitro skin permeation and in vivo transdermal absorption of natural progesterone (Prog) from alcoholic gel-based transdermal formulations containing Prog dissolved stably at a concentration of 3%. 3% Prog dissolved gel formulations were prepared containing with water, ethanol, 1,3-butylene glycol, carboxyvinylpolymer, diisopropanolamine, polyoxyethylene (2) oleylether and benzyl alcohol. The gel formulations added different hydrophilic surfactants and isopropyl myristate or propylene glycol dicaprylate (PGDC) as oily solvents were applied in vitro permeation study through excised rat skin on unocclusive condition. The gel formulations added polyoxyethylene (20) oleylether (Oleth-20) as hydrophilic surfactant and PGDC were applied in vivo single- and repeated-dose transdermal absorption study of rat on unocclusive condition. The results of evaluation of the gel formulations by an in vitro skin permeation study revealed a high flux of Prog from the formulation containing Oleth-20 and Oleth-20 with PGDC. The results of single and repeated in vivo transdermal absorption studies confirmed that good plasma levels of Prog were achieved and maintained by Oleth-20 and PGDC containing gel formulation. The Oleth-20 and PGDC containing ethanolic gel formulation seemed to have the ability to maintain a high activity of Prog and high diffusivity or solubility of Prog in the epidermis on the practical formulation application.

Transdermal solid delivery of epigallocatechin-3-gallate using self-double-emulsifying drug delivery system as vehicle: Formulation, evaluation and vesicle-skin interaction.

PubMed

Hu, Caibiao; Gu, Chengyu; Fang, Qiao; Wang, Qiang; Xia, Qiang

2016-02-01

The present study investigated a self-double-emulsifying drug delivery system loaded with epigallocatechin-3-gallate to improve epigallocatechin-3-gallate skin retention. The long chain solid lipids (cetostearyl alcohol) and macadamia oil were utilized as a carrier to deliver the bioactive ingredient. Response surface methodology was used to optimize the formulation, and the solid lipid to total lipid weight ratio, concentration of epigallocatechin-3-gallate and hydrophilic surfactant on skin retention were found to be the principal factors. The optimum formulation with high encapsulation efficiency (95.75%), self-double-emulsification performance (99.58%) and skin retention (87.24%) were derived from the fitted models and experimentally examined, demonstrating a reasonable agreement between experimental and predicted values. Epigallocatechin-3-gallate-self-double-emulsifying drug delivery system was found to be stable for 3 months. Transdermal studies could explain a higher skin diffusion of epigallocatechin-3-gallate from the self-double-emulsifying drug delivery system compared with EGCG aqueous solution. In vitro cytotoxicity showed that epigallocatechin-3-gallate-self-double-emulsifying drug delivery system did not exert hazardous effect on L929 cells up to 1:10. © The Author(s) 2015.

Drug Delivery Through the Skin: Molecular Simulations of Barrier Lipids to Design more Effective Noninvasive Dermal and Transdermal Delivery Systems for Small Molecules Biologics and Cosmetics

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

J Torin Huzil; S Sivaloganathan; M Kohandel

The delivery of drugs through the skin provides a convenient route of administration that is often preferable to injection because it is noninvasive and can typically be self-administered. These two factors alone result in a significant reduction of medical complications and improvement in patient compliance. Unfortunately, a significant obstacle to dermal and transdermal drug delivery alike is the resilient barrier that the epidermal layers of the skin, primarily the stratum corneum, presents for the diffusion of exogenous chemical agents. Further advancement of transdermal drug delivery requires the development of novel delivery systems that are suitable for modern, macromolecular protein andmore » nucleotide therapeutic agents. Significant effort has already been devoted to obtain a functional understanding of the physical barrier properties imparted by the epidermis, specifically the membrane structures of the stratum corneum. However, structural observations of membrane systems are often hindered by low resolutions, making it difficult to resolve the molecular mechanisms related to interactions between lipids found within the stratum corneum. Several models describing the molecular diffusion of drug molecules through the stratum corneum have now been postulated, where chemical permeation enhancers are thought to disrupt the underlying lipid structure, resulting in enhanced permeability. Recent investigations using biphasic vesicles also suggested a possibility for novel mechanisms involving the formation of complex polymorphic lipid phases. In this review, we discuss the advantages and limitations of permeation-enhancing strategies and how computational simulations, at the atomic scale, coupled with physical observations can provide insight into the mechanisms of diffusion through the stratum corneum.« less

The safety and tolerability of rotigotine transdermal system over a 6-year period in patients with early-stage Parkinson's disease.

PubMed

Giladi, Nir; Boroojerdi, Babak; Surmann, Erwin

2013-09-01

This open-label extension (SP716; NCT00599196) of a 6-month, double-blind, randomized study (SP513) investigated the safety and tolerability of rotigotine transdermal system over up to ~6 years in patients with Parkinson's disease (PD; early-stage PD at double-blind enrollment). Eligible patients completing the 6-month study received optimal dose open-label rotigotine (≤ 16 mg/24 h) for up to ~6 years. Adjunctive levodopa was permitted. Primary outcomes included adverse events (AEs) and extent of rotigotine exposure. Analysis of adjunctive levodopa use, dyskinesias [unified Parkinson's disease rating scale (UPDRS) IV], and efficacy (UPDRS II + III total score) were also assessed. Of 381 patients enrolled in the open-label extension, 52 % were still in the study at time of closure; 24 % withdrew because of AEs and 6 % because of lack of efficacy. Patients received rotigotine for a median duration of 1,564.5 days (~4 years, 3 months; range 5-2, 145 days). 69 % of patients started supplemental levodopa; median time to levodopa was 485 days (~1 year, 4 months). Most common AEs (% per patient-year) were somnolence (18 %), application site reactions (12 %), nausea (9 %), peripheral edema (7 %), and fall (7 %). AEs indicative of impulsive-compulsive behavior were recorded in 25 (7 %) patients. Dyskinesias were experienced by 65 (17 %) patients; the majority [47 of 65 (72 %)] reported first dyskinesia after starting levodopa. Mean UPDRS II + III total scores remained below double-blind baseline for 4 years (assessment of all patients). In conclusion, rotigotine was generally well tolerated for up to ~6 years in patients with early-stage PD. The AEs reported were in line with previous studies of rotigotine transdermal system, with typical dopaminergic side effects and application site reactions seen.

Methylphenidate Transdermal System: A Multisite, Open-Label Study of Dermal Reactions in Pediatric Patients Diagnosed With ADHD

PubMed Central

Squires, Liza; Li, Yunfeng; Civil, Richard; Paller, Amy S.

2010-01-01

Objective: To characterize dermal reactions and examine methylphenidate (MPH) sensitization in subjects receiving methylphenidate transdermal system (MTS). Method: This multicenter, open-label, dose-optimization study utilized MTS doses of 10, 15, 20, and 30 mg in children aged 6 to 12 years, inclusive (N = 305), with a DSM-IV-TR primary diagnosis of attention-deficit/hyperactivity disorder. The study was conducted between January 8, 2007, and August 23, 2007. Subjects wore MTS on their hips for 9 hours per day, alternating sides daily for a total of 7 weeks. Assessments included the Experience of Discomfort scale, Transdermal System Adherence scale, and Dermal Response Scale (DRS; 0 = no irritation, 7 = strong reaction). On-study reevaluations were conducted to characterize DRS scores ≥ 4. Epicutaneous allergy patch testing was conducted for DRS scores ≥ 6, persistent DRS scores ≥ 4, DRS score increase following an assessment of ≥ 4, or DRS scores of 4 or 5 following elective discontinuation. Results: Approximately half of subjects experienced definite erythema at the patch site that generally dissipated within 24 hours. Four subjects experienced a DRS score of 4 (1%): erythema in 1 subject resolved on study treatment, 2 cases resolved poststudy and subjects tolerated oral MPH, and 1 subject discontinued treatment. The latter subject was referred for patch testing and was diagnosed with allergic contact sensitization to MPH. Conclusions: Few severe dermal effects were seen with MTS treatment. Dermal reactions were characterized as contact dermatitis and dissipated rapidly. On patch testing, 1 subject (0.3%) manifested sensitization to MPH. Trial Registration: clinicaltrials.gov Identifier: NCT00434213 PMID:21494336

Transdermal Nicotine for Smoking Cessation.

ERIC Educational Resources Information Center

Hughes, John R.; Glaser, Mitchell

1993-01-01

Discusses the use of transdermal nicotine (TN) in smoking cessation and its value as an effective procedure. The article reveals that, compared to a placebo, TN has double the quit rate percentages, and less than 5% of smokers quit TN due to side effects. (GLR)

Skin permeation of D-limonene-based nanoemulsions as a transdermal carrier prepared by ultrasonic emulsification.

PubMed

Lu, Wen-Chien; Chiang, Been-Huang; Huang, Da-Wei; Li, Po-Hsien

2014-03-01

Nanoemulsions can be used for transporting pharmaceutical phytochemicals in skin-care products because of their stability and rapid permeation properties. However, droplet size may be a critical factor aiding permeation through skin and transdermal delivery efficiency. We prepared D-limonene nanoemulsions with various droplet sizes by ultrasonic emulsification using mixed surfactants of sorbitane trioleate and polyoxyethylene (20) oleyl ether under different hydrophilic-lipophilic balance (HLB) values. Droplet size decreased with increasing HLB value. With HLB 12, the droplet size was 23 nm, and the encapsulated ratio peaked at 92.3%. Transmission electron microscopy revealed spherical droplets and the gray parts were D-limonene precipitation incorporated in spherical droplets of the emulsion system. Franz diffusion cell was used to evaluate the permeation of D-limonene nanoemulsion through rat abdominal skin; the permeation rate depended on droplet size. The emulsion with the lowest droplet size (54 nm) achieved the maximum permeation rate. The concentration of D-limonene in the skin was 40.11 μL/cm(2) at the end of 360 min. Histopathology revealed no distinct voids or empty spaces in the epidermal region of permeated rat skin, so the D-limonene nanoemulsion may be a safe carrier for transdermal drug delivery. Copyright © 2013 Elsevier B.V. All rights reserved.

Synchronous electrical stimulation of laryngeal muscles: an alternative for enhancing recovery of unilateral recurrent laryngeal nerve paralysis.

PubMed

Garcia Perez, Alejandro; Hernández López, Xochiquetzal; Valadez Jiménez, Víctor Manuel; Minor Martínez, Arturo; Ysunza, Pablo Antonio

2014-07-01

Although electrical stimulation of the larynx has been widely studied for treating voice disorders, its effectiveness has not been assessed under safety and comfortable conditions. This article describes design, theoretical issues, and preliminary evaluation of an innovative system for transdermal electrical stimulation of the larynx. The proposed design includes synchronization of electrical stimuli with laryngeal neuromuscular activity. To study whether synchronous electrical stimulation of the larynx could be helpful for improving voice quality in patients with dysphonia due to unilateral recurrent laryngeal nerve paralysis (URLNP). A 3-year prospective study was carried out at the Instituto Nacional de Rehabilitacion in the Mexico City. Ten patients were subjected to transdermal current electrical stimulation synchronized with the fundamental frequency of the vibration of the vocal folds during phonation. The stimulation was triggered during the phase of maximum glottal occlusion. A complete acoustic voice analysis was performed before and after the period of electrical stimulation. Acoustic analysis revealed significant improvements in all parameters after the stimulation period. Transdermal synchronous electrical stimulation of vocal folds seems to be a safe and reliable procedure for enhancing voice quality in patients with (URLNP). Copyright © 2014 The Voice Foundation. Published by Mosby, Inc. All rights reserved.

Management of an oral ingestion of transdermal fentanyl patches: a case report and literature review.

PubMed

Faust, Andrew C; Terpolilli, Ralph; Hughes, Darrel W

2011-01-01

Purpose. Fentanyl is available as a transdermal system for the treatment of chronic pain in opioid-tolerant patients; however, it carries a black box warning due to both the potency of the product and the potential for abuse. In this report, we describe a case of transbuccal and gastrointestinal ingestion of fentanyl patches and the management of such ingestion. Summary. A 32-year-old man was brought to the emergency department (ED) via emergency medical services for toxic ingestion and suicide attempt. The patient chewed and ingested two illegally purchased transdermal fentanyl patches. In the ED, the patient was obtunded, dizzy and drowsy. Initial vital signs showed the patient to be afebrile and normotensive with a heart rate of 63, respiratory rate of 16, and oxygen saturation of 100% on 2 liters nasal cannula after administration of 2 milligrams of intravenous naloxone. The patient was treated with whole bowel irrigation and continuous intravenous naloxone infusion for approximately 48 hours without complications. Conclusion. Despite numerous case reports describing oral ingestion of fentanyl patches, information on the management of such intoxication is lacking. We report successful management of such a case utilizing whole bowel irrigation along with intravenous push and continuous infusion naloxone.

Management of an Oral Ingestion of Transdermal Fentanyl Patches: A Case Report and Literature Review

PubMed Central

Faust, Andrew C.; Terpolilli, Ralph; Hughes, Darrel W.

2011-01-01

Purpose. Fentanyl is available as a transdermal system for the treatment of chronic pain in opioid-tolerant patients; however, it carries a black box warning due to both the potency of the product and the potential for abuse. In this report, we describe a case of transbuccal and gastrointestinal ingestion of fentanyl patches and the management of such ingestion. Summary. A 32-year-old man was brought to the emergency department (ED) via emergency medical services for toxic ingestion and suicide attempt. The patient chewed and ingested two illegally purchased transdermal fentanyl patches. In the ED, the patient was obtunded, dizzy and drowsy. Initial vital signs showed the patient to be afebrile and normotensive with a heart rate of 63, respiratory rate of 16, and oxygen saturation of 100% on 2 liters nasal cannula after administration of 2 milligrams of intravenous naloxone. The patient was treated with whole bowel irrigation and continuous intravenous naloxone infusion for approximately 48 hours without complications. Conclusion. Despite numerous case reports describing oral ingestion of fentanyl patches, information on the management of such intoxication is lacking. We report successful management of such a case utilizing whole bowel irrigation along with intravenous push and continuous infusion naloxone. PMID:21629807

Corticosteroid transdermal delivery significantly improves arthritis pain and functional disability.

PubMed

Iannitti, Tommaso; McDermott, Michael F; Laurino, Carmen; Malagoli, Andrea; Palmieri, Beniamino

2017-02-01

Arthritis is characterized by pain and functional limitation affecting the patients' quality of life. We performed a clinical study to investigate the efficacy of a betamethasone valerate medicated plaster (Betesil) in improving pain and functional disability in patients with arthritis and osteoarthritis. We enrolled 104 patients affected by osteoarthritis (n = 40) or arthritis (n = 64) in different joints. Patients received diclofenac sodium cream (2 g, four times a day) or a 2.25-mg dose of Betesil applied to the painful joint every night before bedtime for 10 days. Pain and functional disability were assessed, by the Visual Analogue Scale (VAS) and Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) scores. Redness was assessed by clinical inspection, and edema by the "fovea sign" method. C-reactive protein (CRP) was also measured; CRP can be used to cost-effectively monitor the pharmacological treatment efficacy and is increased during the acute-phase response, returning to physiological values after tissue recovery and functional restoration. All measurements were at baseline and at 10-day follow-up. At 10-day follow-up, a greater improvement in VAS and WOMAC pain and WOMAC stiffness and functional limitation scores from baseline was observed in patients treated with Betesil compared with diclofenac (all p < 0.01). At 10-day follow-up, improvement in redness, edema, and CRP levels from baseline was also greater in patients treated with Betesil compared with diclofenac (all p < 0.01). This study demonstrates the safety and efficacy of transdermal delivery of betamethasone valerate in patients affected by arthritis and osteoarthritis.

Whey protein/polysaccharide-stabilized emulsions: Effect of polymer type and pH on release and topical delivery of salicylic acid.

PubMed

Combrinck, Johann; Otto, Anja; du Plessis, Jeanetta

2014-06-01

Emulsions are widely used as topical formulations in the pharmaceutical and cosmetic industries. They are thermodynamically unstable and require emulsifiers for stabilization. Studies have indicated that emulsifiers could affect topical delivery of actives, and this study was therefore designed to investigate the effects of different polymers, applied as emulsifiers, as well as the effects of pH on the release and topical delivery of the active. O/w emulsions were prepared by the layer-by-layer technique, with whey protein forming the first layer around the oil droplets, while either chitosan or carrageenan was subsequently adsorbed to the protein at the interface. Additionally, the emulsions were prepared at three different pH values to introduce different charges to the polymers. The active ingredient, salicylic acid, was incorporated into the oil phase of the emulsions. Physical characterization of the resulting formulations, i.e., droplet size, zeta potential, stability, and turbidity in the water phase, was performed. Release studies were conducted, after which skin absorption studies were performed on the five most stable emulsions, by using Franz type diffusion cells and utilizing human, abdominal skin membranes. It was found that an increase in emulsion droplet charge could negatively affect the release of salicylic acid from these formulations. Contrary, positively charged emulsion droplets were found to enhance dermal and transdermal delivery of salicylic acid from emulsions. It was hypothesized that electrostatic complex formation between the emulsifier and salicylic acid could affect its release, whereas electrostatic interaction between the emulsion droplets and skin could influence dermal/transdermal delivery of the active.

Selection and use of crystallization inhibitors for matrix-type transdermal drug-delivery systems containing sex steroids.

PubMed

Lipp, R

1998-12-01

The purpose of this study was to stabilize transdermal drug-delivery systems (TDDS) highly loaded with sex steroids against recrystallization of drugs during storage. To facilitate the selection of potential crystallization inhibitors a drug-excipient interaction test was also established. Analysis of the thermal behaviour of 1:1 steroid-excipient mixtures by differential scanning calorimetry (DSC) revealed that oestradiol and gestodene interact strongly with silicone dioxide and povidones, e.g. povidone K12. The addition of povidone K12 to polyacrylate-based matrix TDDS containing either 3% oestradiol or 2% gestodene resulted in stable systems which did not recrystallize during storage at 25 degrees C for more than 5 years. Significant recrystallization was, on the other hand, observed in non-stabilized reference patches even after 1 to 2 months storage. The DSC screening model proved very effective for selection of inhibitors of the crystallization of sex steroids in matrix TDDS. The crystallization inhibitor approach is a highly versatile stabilization tool for matrix patches containing high concentrations of sex steroids.

Nano-transfersomal formulations for transdermal delivery of asenapine maleate: in vitro and in vivo performance evaluations.

PubMed

Shreya, A B; Managuli, Renuka S; Menon, Jyothsna; Kondapalli, Lavanya; Hegde, Aswathi R; Avadhani, Kiran; Shetty, Pallavi K; Amirthalingam, Muthukumar; Kalthur, Guruprasad; Mutalik, Srinivas

2016-09-01

Asenapine maleate (ASPM) is an antipsychotic drug for the treatment of schizophrenia and bipolar disorder. Extensive metabolism makes the oral route inconvenient for ASPM. The objective of this study is to increase ASPM bioavailability via transdermal route by improving the skin permeation using combined strategy of chemical and nano-carrier (transfersomal) based approaches. Transfersomes were prepared by the thin film hydration method using soy-phosphatidylcholine (SPC) and sodium deoxycholate (SDC). Transfersomes were characterized for particle size, polydispersity index (PDI), zeta potential (ZP), entrapment efficiency, surface morphology, and in vitro skin permeation studies. Various chemical enhancers were screened for skin permeation enhancement of ASPM. Optimized transfersomes were incorporated into a gel base containing suitable chemical enhancer for efficient transdermal delivery. In vivo pharmacokinetic study was performed in rats to assess bioavailability by transdermal route against oral administration. Optimized transfersomes with drug:SPC:SDC weight ratio of 5:75:10 were spherical with an average size of 126.0 nm, PDI of 0.232, ZP of -43.7 mV, and entrapment efficiency of 54.96%. Ethanol (20% v/v) showed greater skin permeation enhancement. The cumulative amount of ASPM permeated after 24 h (Q24) by individual effect of ethanol and transfersome, and in combination was found to be 160.0, 132.9, and 309.3 μg, respectively, indicating beneficial synergistic effect of combined approach. In vivo pharmacokinetic study revealed significant (p < 0.05) increase in bioavailability upon transdermal application compared with oral route. Dual strategy of permeation enhancement was successful in increasing the transdermal permeation and bioavailability of ASPM.

[Preparation and transdermal permeation of triptolide and ferulic acid ethosomes gel in vitro].

PubMed

Tao, Ling; He, Liang-Fei; Guan, Yong-Mei; Chen, Li-Hua; Zhu, Wei-Feng; Jin, Chen; Wu, Lu

2018-03-01

The aim of this study was to prepare triptolide and ferulic acid ethosomes gel, investigate its transdermal permeation, and compare the results with ordinary gel and cream. Improved Franz diffusion cell method was used in the transdermal delivery experiment with rat abdominal skin as in vitro model. The receptor fluid at different time points was collected; ferulic acid concentration was determined by high performance liquid chromatography (HPLC) and triptolide concentration was determined by liquid chromatography-electrospray ionization mass spectrometry (LC-MS/MS). Then the penetration rate, transdermal volume and skin reserve of three dosage forms (hydroplasy gel, ordinary gel, and cream) to investigate the transdermal properties of ferulic acid and triptolide in vitro of triptolide and ferulic acid ethosomes gel. The results showed that the steady penetration rate of ferulic acid was 5.268 5, 8.990 9, 12.042 0 μg·cm⁻² ·h⁻¹ respectively in triptolide and ferulic acid ethosomes gel, ordinary gel and cream; the skin retention was (30.234 8±1.525 4), (20.402 6±0.402 6), (7.635 3±1.094 2) μg·cm⁻² . The steady-state permeation rate of triptolide was 67.238 0, 67.238 0 ng·cm⁻² ·h⁻¹ in triptolide and ferulic acid ethosomes gel, about 1.24 times of cream and 3.28 times of ordinary gel; the skin retention was (371.351 4±35.317 1) ng·cm⁻², about 3.35 times of cream and 5.25 times of ordinary gel. Therefore, the ethosomes gel showed good transdermal absorption property and it may be good for clinical safety administration. Copyright© by the Chinese Pharmaceutical Association.

Genetic, pathological and physiological determinants of transdermal fentanyl pharmacokinetics in 620 cancer patients of the EPOS study.

PubMed

Barratt, Daniel T; Bandak, Benedikte; Klepstad, Pål; Dale, Ola; Kaasa, Stein; Christrup, Lona L; Tuke, Jonathan; Somogyi, Andrew A

2014-04-01

This study aimed to investigate whether CYP3A4/5 genetic variants, together with clinical and patient factors, influence serum fentanyl and norfentanyl concentrations and their ratio in cancer pain patients receiving transdermal fentanyl. CYP3A4*22 and CYP3A5*3 polymorphisms were analysed in 620 cancer pain patients receiving transdermal fentanyl (12.5-700 μg/h) from the European Pharmacogenetic Opioid Study. Using stepwise linear regression, CYP3A4/5 genetic variability was examined in combination with patient factors relating to organ drug elimination function and ABCB1 genetics for their association with serum fentanyl and norfentanyl concentrations and metabolic ratio (MR) (norfentanyl : fentanyl). Delivery rate-adjusted serum fentanyl concentrations (0.0012-1.1 nmol/l/μg.h) and MRs (0.08-499) varied widely. Only 43% of variability in serum fentanyl concentrations was accounted for by delivery rate and less than 50% by CYP3A4/5 genotypes and clinical variables (delivery rate, sex, comedications, kidney disease, BMI, serum albumin). CYP3A4*22 and CYP3A5*3 variants, CYP3A inhibitors and variables relating to liver and kidney function (serum albumin, glomerular filtration rate, kidney disease, BMI) were associated with MR, but accounted for only 14% of variability. Serum fentanyl concentrations and MR vary considerably between cancer pain patients on transdermal fentanyl patches. CYP3A4*22 and CYP3A5*3 genotypes, and multiple clinical factors, combine to influence transdermal fentanyl pharmacokinetics, but accounted for only a small proportion of variability in this study. Identification of the remaining factors determining serum fentanyl concentrations, and their relationship to efficacy and adverse effects may aid in improving the safety and effectiveness of transdermal fentanyl.

Sonophoresis Using Ultrasound Contrast Agents: Dependence on Concentration.

PubMed

Park, Donghee; Song, Gillsoo; Jo, Yongjun; Won, Jongho; Son, Taeyoon; Cha, Ohrum; Kim, Jinho; Jung, Byungjo; Park, Hyunjin; Kim, Chul-Woo; Seo, Jongbum

2016-01-01

Sonophoresis can increase skin permeability to various drugs in transdermal drug delivery. Cavitation is recognized as the predominant mechanism of sonophoresis. Recently, a new logical approach to enhance the efficiency of transdermal drug delivery was tried. It is to utilize the engineered microbubble and its resonant frequency for increase of cavitation activity. Actively-induced cavitation with low-intensity ultrasound (less than ~1 MPa) causes disordering of the lipid bilayers and the formation of aqueous channels by stable cavitation which indicates a continuous oscillation of bubbles. Furthermore, the mutual interactions of microbubble determined by concentration of added bubble are also thought to be an important factor for activity of stable cavitation, even in different characteristics of drug. In the present study, we addressed the dependence of ultrasound contrast agent concentration using two types of drug on the efficiency of transdermal drug delivery. Two types of experiment were designed to quantitatively evaluate the efficiency of transdermal drug delivery according to ultrasound contrast agent concentration. First, an experiment of optical clearing using a tissue optical clearing agent was designed to assess the efficiency of sonophoresis with ultrasound contrast agents. Second, a Franz diffusion cell with ferulic acid was used to quantitatively determine the amount of drug delivered to the skin sample by sonophoresis with ultrasound contrast agents. The maximum enhancement ratio of sonophoresis with a concentration of 1:1,000 was approximately 3.1 times greater than that in the ultrasound group without ultrasound contrast agent and approximately 7.5 times greater than that in the control group. These results support our hypothesis that sonophoresis becomes more effective in transdermal drug delivery due to the presence of engineered bubbles, and that the efficiency of transdermal drug delivery using sonophoresis with microbubbles depends on the concentration of microbubbles in case stable cavitation is predominant.

Absorption of Transdermal Fluoxetine Compounded in a Lipoderm Base Compared to Oral Fluoxetine in Client-owned Cats.

PubMed

Eichstadt, Lauren R; Corriveau, Lorraine A; Moore, George E; Knipp, Gregory T; Cooper, Bruce R; Gwin, Wilson E

2017-01-01

The objective of this study was to compare serum concentrations of transdermal fluoxetine compounded in Lipoderm base versus commercially available oral fluoxetine tablets. Sixteen clinically healthy, client-owned cats that were at least one year of age were enrolled. Cats weighed between three and seven kilograms, had no comorbidities, and were behavior medication naïve. Cats were recruited from January 2016 through April 2016. Eight cats were assigned to each medication group based on owner preference. The cats received either oral (1 mg/kg) or transdermal (5 mg/kg; maximum 25 mg daily) fluoxetine compounded in a transdermal base (PCCA Lipoderm), administered daily for 60 days. Serum levels of fluoxetine and norfluoxetine were assessed as a surrogate for relative efficacy. Serum was collected and analyzed by high-performance liquid chromatography-mass spectrometry/mass spectrometry at baseline and days 5, 10, 30, 45, and 60 post-drug start. Adverse effects were monitored during physical exams, speaking with owners, and laboratory analysis of liver function tests at baseline and days 5, 30, and 60 post-drug start. Serum fluoxetine concentrations significantly differed between the treatment groups at days 45 and 60 post-drug start. Norfluoxetine concentrations significantly differed at days 30, 45, and 60 post-drug start. Blood concentrations of fluoxetine and norfluoxetine significantly differed between oral and transdermal routes after 30 days of treatment. Oral fluoxetine concentrations were consistently higher. Transdermal fluoxetine appeared to be well-tolerated, but a lack of knowledge regarding effective blood levels makes it unclear if a clinical effective response would be obtained at the blood concentrations achieved. Copyright© by International Journal of Pharmaceutical Compounding, Inc.

LC-MS/MS analysis of fentanyl and norfentanyl in a fatality due to application of multiple Durogesic transdermal therapeutic systems.

PubMed

Coopman, Vera; Cordonnier, Jan; Pien, Karen; Van Varenbergh, Dirk

2007-07-04

Fentanyl is a potent synthetic narcotic analgesic administered in the form of a transdermal patch for the management of chronic pain. A 78-year-old woman with a history of cancer was found dead in bed. She was lying on her back. The external examination revealed 10 Durogesic transdermal therapeutic systems (100 microg/h fentanyl) on the body. Liquid-liquid extraction and liquid chromatography tandem mass spectrometry with electrospray source in positive ionization mode was applied for the quantitation of fentanyl and its major metabolite norfentanyl in the post-mortem samples. Fentanyl-d5 and norfentanyl-d5 were used as internal standards. Multiple reaction monitoring was used for specific detection. Calibration was performed by addition of standard solutions to drug-free matrix (blood, urine and liver) prior to extraction. The method showed good linearity for fentanyl and norfentanyl over a concentration range of 5-150 microg/L in reconstituted extracts with coefficients of determination equal or greater than 0.998. Percent mean within-day precision and accuracy of 0.9-1.0% and 99.4-101.1% for fentanyl and 2.0-4.5% and 93.1-101.0% for norfentanyl were obtained. Mean extraction recoveries varied between 95.5% and 100.3% for fentanyl and 39.2-57.4% for norfentanyl. The following fentanyl (norfentanyl) concentration in the post-mortem samples were measured; 28.6 microg/L (3.0 microg/L) in right and 28.2 microg/L (3.5 microg/L) in left subclavian blood, 21.3 microg/L (<2 microg/L) in right and 20.9 microg/L (<2 microg/L) in left femoral blood, 37.6 microg/L (4.2 microg/L) in right and 33.9 microg/L (4.4 microg/L) in left ventricular blood, 282.9 microg/L (121.2 microg/L) in urine, 688.2 microg/L in stomach contents, 122.5 microg/L (25.4 microg/L) in bile, 19.5 microg/L (< 2 microg/L) in vitreous humour, 203.0 microg/kg (26.6 microg/kg) in liver and 78.6 microg/kg (46.3 microg/kg) in kidney. We concluded that the woman's death was caused by acute intoxication with fentanyl. The manner of death was presumed to be suicide due to excessive administered Durogesic transdermal therapeutic systems.

A comparative multicenter study of two transdermal estradiol replacement therapies in the treatment of postmenopausal symptoms.

PubMed

Van Leusden, H A; Albertyn, G; Verlaine, C; Van Ruymbeke, J

1993-01-01

Comparison of the effects of treatment of two transdermal therapeutic systems for estrogen replacement therapy with regard to efficacy, tolerability, and acceptance. Open randomized. Multicenter. A study population of 104 postmenopausal women was randomized on a 1:1 basis to treatment with one of two estradiol patches, System (Cilag) and Estraderm (Ciba-Geigy). Systolic and diastolic BP, hot flushes, night sweating, fatigue, insomnia, depression, nervousness, headache, vaginal discomfort (efficacy variables); bleeding, dermatological symptoms, comfort and adhesiveness of patch, and other possible causes of discontinuation (tolerability); general evaluation by patient (acceptance). Considering all efficacy variables, 53% of Systen and 46% of Estraderm patients found the therapy satisfactory. Tolerability was somewhat higher in the Systen group. Adhesiveness of the patch was significantly better for Systen. Overall, 79% of Systen patients and 62% of Estraderm patients evaluated treatment as "good" or "very good." The majority of patients in both groups found the patch very comfortable or only slightly obtrusive.

Antimotion-sickness efficacy of scopolamine 12 and 72 hours after transdermal administration

NASA Technical Reports Server (NTRS)

Graybiel, A.; Cramer, D. B.; Wood, C. D.

1982-01-01

The antimotion sickness remedy, transdermal therapeutic system-scopolamine, administered in this experiment was scheduled to deliver 1.0 mg of scopolamine over a period of 3 d, and this paper compares its efficacy 12 and 72 h after administration. In a double-blind study, six male college students were individually exposed to a standardized provocative test in a slow rotation room after six apparently identical treatments comprising four placebos and two medications. Efficacy was categorized as beneficial, inconsequential, or detrimental. None of the responses was detrimental. Following the first administration of the therapeutic system, there were four beneficial responses after 12 h but none was beneficial after 72 h. Following the second treatment regimen, there were four beneficial responses after 12 h and three beneficial responses after 72 h. Great individual differences were demonstrated, two subjects accounting for six beneficial responses and two accounting for only one beneficial response. The difference in efficacy after 12 and 72 h has practical and theoretical significance.

Non-invasive, transdermal, path-selective and specific glucose monitoring via a graphene-based platform

NASA Astrophysics Data System (ADS)

Lipani, Luca; Dupont, Bertrand G. R.; Doungmene, Floriant; Marken, Frank; Tyrrell, Rex M.; Guy, Richard H.; Ilie, Adelina

2018-06-01

Currently, there is no available needle-free approach for diabetics to monitor glucose levels in the interstitial fluid. Here, we report a path-selective, non-invasive, transdermal glucose monitoring system based on a miniaturized pixel array platform (realized either by graphene-based thin-film technology, or screen-printing). The system samples glucose from the interstitial fluid via electroosmotic extraction through individual, privileged, follicular pathways in the skin, accessible via the pixels of the array. A proof of principle using mammalian skin ex vivo is demonstrated for specific and `quantized' glucose extraction/detection via follicular pathways, and across the hypo- to hyper-glycaemic range in humans. Furthermore, the quantification of follicular and non-follicular glucose extraction fluxes is clearly shown. In vivo continuous monitoring of interstitial fluid-borne glucose with the pixel array was able to track blood sugar in healthy human subjects. This approach paves the way to clinically relevant glucose detection in diabetics without the need for invasive, finger-stick blood sampling.

Numerical simulations of crystal growth in a transdermal drug delivery system

NASA Astrophysics Data System (ADS)

Zeng, Jianming; Jacob, Karl I.; Tikare, Veena

2004-02-01

Grain growth by precipitation and Ostwald ripening in an unstressed matrix of a dissolved crystallizable component was simulated using a kinetic Monte Carlo model. This model was used previously to study Ostwald ripening in the high crystallizable component regime and was shown to correctly simulate solution, diffusion and precipitation. In this study, the same model with modifications was applied to the low crystallizable regime of interest to the transdermal drug delivery system (TDS) community. We demonstrate the model's utility by simulating precipitation and grain growth during isothermal storage at different supersaturation conditions. The simulation results provide a first approximation for the crystallization occurring in TDS. It has been reported that for relatively higher temperature growth of drug crystals in TDS occurs only in the middle third of the polymer layer. The results from the simulations support these findings that crystal growth is limited to the middle third of the region, where the availability of crystallizable components is the highest, for cluster growth at relatively high temperature.

Innovative formulations for the delivery of levothyroxine to the skin.

PubMed

Padula, Cristina; Nicoli, Sara; Santi, Patrizia

2009-05-08

The aim of this work was to realize innovative transdermal formulations containing sodium levothyroxine in view of topical administration. Permeation experiments were performed in vitro, using rabbit ear skin as barrier. At the end of the permeation experiments levothyroxine retained in the skin was extracted and quantified by HPLC. Formulations tested were microemulsions and transdermal films. Microemulsions containing isopropyl myristate and isobutanol were shown to be able to increase levothyroxine solubility by the inclusion in reverse micelles. However, the inclusion in reversed micelles reduced the drug release to a significant extent, and consequently skin retention, compared to aqueous solutions. When the microemulsion was included in the transdermal film, drug retention was increased, probably for the enhancer effect of its excipients. The transdermal film proposed in this work could be an interesting alternative to semisolid formulations for the ease of use and the control in the amount of active applied. Additional benefit can be obtained if the film is used in occlusive conditions.

Nonaqueous gel for the transdermal delivery of a DTPA penta-ethyl ester prodrug.

PubMed

Zhang, Yong; Sadgrove, Matthew P; Sueda, Katsuhiko; Yang, Yu-Tsai; Pacyniak, Erik K; Kagel, John R; Braun, Brenda A; Zamboni, William C; Mumper, Russell J; Jay, Michael

2013-04-01

Diethylenetriamine pentaacetic acid penta-ethyl ester, designated as C2E5, was successfully incorporated into a nonaqueous gel for transdermal delivery. The thermal and rheological properties of a formulation containing 40% C2E5, 20% ethyl cellulose, and 40% Miglyol 840® prepared using the solvent evaporation method demonstrated that the gel had acceptable content uniformity and flow properties. In vitro studies showed that C2E5 was steadily released from the gel at a rate suitable for transdermal delivery. Topical application of the gel at a 200 mg C2E5/kg dose level in rats achieved significantly higher plasma exposures of several active metabolites compared with neat C2E5 oil at the same dose level. The results suggest that transdermal delivery of a chelator prodrug is an effective radionuclide decorporation strategy by delivering chelators to the circulation with a pharmacokinetic profile that is more consistent with the biokinetic profile of transuranic elements in contaminated individuals.

Development and evaluation of transdermal organogels containing nicorandil.

PubMed

Madan, J R; Sagar, Banode; Chellappan, Dinesh K; Dua, Kamal

2013-01-01

The objective of the study was to formulate a transdermal product containing Nicorandil as a model drug, because it has been first drug of choice to treat angina and hypertension. A further objective was to reduce its side effects. The transdermal product was prepared using various synthetic and natural gelling agents such as Carbopol 934p, Carbopol 974p, HPMC K15M and HPMC K100M. Various penetration enhancers were incorporated to enhance the diffusion across the rat skin. A further objective was to formulate organogels and minimize the concentration of penetration enhancer to 50% of the concentration used in gels and yet to achieve the maximum drug release. The prepared formulations were evaluated for their physical appearance, viscosity, spreadability, drug content and freeze thaw cycle. Based on in vitro studies across rat skin and human cadaver skin it was concluded that Nicrorandil transdermal organogel formulation using HPMC K100M with 2% w/w Transcutol-P shows increase in cumulative diffusion of Nicorandil amongst all other formulations.

Recent Advances in Lipid-Based Vesicles and Particulate Carriers for Topical and Transdermal Application.

PubMed

Jain, Shashank; Patel, Niketkumar; Shah, Mansi K; Khatri, Pinak; Vora, Namrata

2017-02-01

In the recent decade, skin delivery (topical and transdermal) has gained an unprecedented popularity, especially due to increased incidences of chronic skin diseases, demand for targeted and patient compliant delivery, and interest in life cycle management strategies among pharmaceutical companies. Literature review of recent publications indicates that among various skin delivery systems, lipid-based delivery systems (vesicular carriers and lipid particulate systems) have been the most successful. Vesicular carriers consist of liposomes, ultradeformable liposomes, and ethosomes, while lipid particulate systems consist of lipospheres, solid lipid nanoparticles, and nanostructured lipid carriers. These systems can increase the skin drug transport by improving drug solubilization in the formulation, drug partitioning into the skin, and fluidizing skin lipids. Considering that lipid-based delivery systems are regarded as safe and efficient, they are proving to be an attractive delivery strategy for the pharmaceutical as well as cosmeceutical drug substances. However, development of these delivery systems requires comprehensive understanding of physicochemical characteristics of drug and delivery carriers, formulation and process variables, mechanism of skin delivery, recent technological advancements, specific limitations, and regulatory considerations. Therefore, this review article encompasses recent research advances addressing the aforementioned issues. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Pharmacokinetics of continuous once-a-week combination 17β-Estradiol/Low- or high-dose levonorgestrel transdermal delivery systems in postmenopausal women.

PubMed

Karara, Adel H; Harrison, Lester I; Melikian, Armen P; Poola, Nagaraju; Morrison, Dennis; Bourg, Dale; Bourg, Linda; Zurth, Christian

2014-05-01

Two open-label, randomized, two-period, crossover studies were performed to determine the safety, delivery rates, and pharmacokinetic properties of a combination estradiol (E2)/levonorgestrel (LNG) transdermal delivery system (TDS). Study 1 enrolled 24 postmenopausal women who received a single TDS containing 4.4 mg E2 and 1.39 mg of LNG (E2/LNG Low) or E2 0.050 mg/24 hours TDS and 0.090 mg LNG oral tablet. Study 2 enrolled 44 postmenopausal women who received either E2/LNG Low or TDS containing 4.4 mg E2 and 2.75 mg LNG (E2/LNG High) weekly for a period of 4 weeks. E2, estrone (E1), LNG, and sex hormone-binding globulin (SHBG) serum concentrations were determined. Overall, both E2/LNG TDS were well tolerated and had excellent adhesion properties. The average daily delivery for E2/LNG Low was 0.045 mg for E2 and 0.0132 mg for LNG. Following weekly delivery of E2/LNG Low or High for 4 weeks, the combination of E2 with two different strengths of LNG did not alter the pharmacokinetic profile of E2. SHBG, total cholesterol, and triglycerides concentrations significantly decreased compared to baseline. Both E2/LNG Low and High TDSs were well tolerated and provided continuous drug delivery over 7 days supporting the benefits of the transdermal route of administration in optimally delivering hormonal therapy. © 2014, The American College of Clinical Pharmacology.

Dry Gel Containing Optimized Felodipine-Loaded Transferosomes: a Promising Transdermal Delivery System to Enhance Drug Bioavailability.

PubMed

Kassem, Mohammed Ali; Aboul-Einien, Mona Hassan; El Taweel, Mai Magdy

2018-04-30

Felodipine has a very low bioavailability due to first-pass metabolism. The aim of this study was to enhance its bioavailability by transdermal application. Felodipine-loaded transferosomes were prepared by thin-film hydration using different formulation variables. An optimized formula was designed using statistical experimental design. The independent variables were the used edge activator, its molar ratio to phosphatidylcholine, and presence or absence of cholesterol. The responses were entrapment efficiency of transferosomes, their size, polydispersity index, zeta potential, and percent drug released after 8 h. The optimized formula was subjected to differential scanning calorimetry studies and its stability on storage at 4°C for 6 months was estimated. This formula was improved by incorporation of different permeation enhancers where ex vivo drug flux through mice skin was estimated and the best improved formula was formulated in a gel and lyophilized. The prepared gel was subjected to in vivo study using Plendil® tablets as a reference. According to the calculated desirability, the optimized transferosome formula was that containing sodium deoxycholate as edge activator at 5:1 M ratio to phosphatidylcholine and no cholesterol. The thermograms of this formula indicated the incorporation of felodipine inside the prepared vesicles. None of the tested parameters differed significantly on storage. The lyophilized gel of labrasol-containing formula was chosen for in vivo study. The relative bioavailability of felodipine from the designed gel was 1.7. In conclusion, topically applied lyophilized gel containing felodipine-loaded transferosomes is a promising transdermal delivery system to enhance its bioavailability.

The effect of inhalant anesthetic and body temperature on peri-anesthetic serum concentrations of transdermally administered fentanyl in dogs.

PubMed

Pettifer, Glenn R; Hosgood, Giselle

2004-04-01

To determine whether moderate hypothermia during anesthesia significantly affects the serum concentration of transdermally delivered fentanyl and whether halothane or isoflurane affect these concentrations. Randomized cross-over experimental trial. Six mature, healthy Beagles (three males, three females) weighing 10.6 +/- 0.43 kg. A 50-microg hour(-1) fentanyl patch was applied 36 hours prior to anesthesia. Anesthesia was induced at time 0 (t = 0). Each dog received four treatments: isoflurane + normothermia (ISO-NORM), isoflurane + hypothermia (ISO-HYPO), halothane + normothermia (HAL-NORM), and halothane + hypothermia (HAL-HYPO). Dogs were intubated and maintained at 1.5 times MAC. Animals in the hypothermia treatments were cooled to 35 degrees C during anesthesia. Serum fentanyl analysis was performed at -36, -24, -12, 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 18, and 26 hours. Direct arterial blood pressures and arterial blood gases were monitored. The mean body temperatures (+/-SEM) during the anesthetic period for the four treatments were: ISO-NORM = 37.7 +/- 0.07 degrees C, ISO-HYPO = 35.8 +/- 0.1 degrees C, HAL-NORM = 37.7 +/- 0.06 degrees C, and HAL-HYPO = 35.8 +/- 0.13 degrees C. The mean (+/-SEM) serum fentanyl concentrations (SFC) for both hypothermia treatments were significantly lower than baseline concentrations at t = 1 hour and persisted for the duration of anesthesia for the ISO-HYPO treatment but only from t = 1 to 2 hours for the HAL-HYPO treatment. Serum fentanyl concentrations returned to baseline within one hour of the end of anesthesia, regardless of body temperature. There were no significant differences between treatments for systolic or diastolic blood pressure but mean blood pressures were higher during normothermia versus hypothermia during the last hour of anesthesia. Hypothermia during inhalation anesthesia produced a significant reduction in SFC using transdermal administration and was more protracted with isoflurane than halothane anesthesia. While significant reductions in SFC occurred, the SFC were still within the range believed to confer analgesia.

Characterization and In Vitro Permeation Study of Cubic Liquid Crystal Containing Sinomenine Hydrochloride.

PubMed

Chu, Xiaoqin; Li, Qian; Gui, Shuangying; Li, Zhengguang; Cao, Jiaojiao; Jiang, Jianqin

2018-05-08

This study developed a new transdermal delivery system for the improved delivery of sinomenine hydrochloride (SH). The delivery system utilized the advantages of lyotropic liquid crystals (LLC) creating an adaptable system that offers a variety of options for the field of transdermal delivery. The formulation was prepared, characterized, and evaluated for its skin penetration in vitro. In the study, the appearance of samples was characterized by visual observation, and these LLC gels were colorless and transparent. Polarizing light microscopy (PLM) and small-angle X-ray diffraction (SAXS) were used to analyze the internal structures of gels, and the gels displayed a cubic double-diamond (P n 3 m ) internal structure with a dark field of vision. The Franze diffusion cell was used to evaluate its skin penetration. There were several factors which might influence the skin penetration of drugs, such as drug loading, water content, and the layer spacing of the LLC. In our case, drug concentration gradient played a more powerful role. The result of in vitro permeation studies demonstrated that the drug concentration was higher; the cumulative osmotic quantity of SH (Q) was greater. Therefore, the system was a promising formulation for successful percutaneous delivery of SH through the skin.

Enhancing the transdermal delivery of rigid nanoparticles using the simultaneous application of ultrasound and sodium lauryl sulfate

PubMed Central

Lopez, Renata F.V.; Seto, Jennifer E.; Blankschtein, Daniel; Langer, Robert

2010-01-01

The potential of rigid nanoparticles to serve as transdermal drug carriers can be greatly enhanced by improving their skin penetration. Therefore, the simultaneous application of ultrasound and sodium lauryl sulfate (referred to as US/SLS) was evaluated as a skin pre-treatment method for enhancing the passive transdermal delivery of nanoparticles. We utilized inductively-coupled plasma mass spectrometry and an improved application of confocal microscopy to compare the delivery of 10- and 20-nm cationic, neutral, and anionic quantum dots (QDs) into US/SLS-treated and untreated pig split-thickness skin. Our findings include: (a) ~0.01% of the QDs penetrate the dermis of untreated skin (which we quantify for the first time), (b) the QDs fully permeate US/SLS-treated skin, (c) the two cationic QDs studied exhibit different extents of skin penetration and dermal clearance, and (d) the QD skin penetration is heterogeneous. We discuss routes of nanoparticle skin penetration and the application of the methods described herein to address conflicting literature reports on nanoparticle skin penetration. We conclude that US/SLS treatment significantly enhances QD transdermal penetration by 500–1300%. Our findings suggest that an optimum surface charge exists for nanoparticle skin penetration, and motivate the application of nanoparticle carriers to US/SLS-treated skin for enhanced transdermal drug delivery. PMID:20971504

Enhancing the transdermal delivery of rigid nanoparticles using the simultaneous application of ultrasound and sodium lauryl sulfate.

PubMed

Lopez, Renata F V; Seto, Jennifer E; Blankschtein, Daniel; Langer, Robert

2011-01-01

The potential of rigid nanoparticles to serve as transdermal drug carriers can be greatly enhanced by improving their skin penetration. Therefore, the simultaneous application of ultrasound and sodium lauryl sulfate (referred to as US/SLS) was evaluated as a skin pre-treatment method for enhancing the passive transdermal delivery of nanoparticles. We utilized inductively coupled plasma mass spectrometry and an improved application of confocal microscopy to compare the delivery of 10- and 20-nm cationic, neutral, and anionic quantum dots (QDs) into US/SLS-treated and untreated pig split-thickness skin. Our findings include: (a) ∼0.01% of the QDs penetrate the dermis of untreated skin (which we quantify for the first time), (b) the QDs fully permeate US/SLS-treated skin, (c) the two cationic QDs studied exhibit different extents of skin penetration and dermal clearance, and (d) the QD skin penetration is heterogeneous. We discuss routes of nanoparticle skin penetration and the application of the methods described herein to address conflicting literature reports on nanoparticle skin penetration. We conclude that US/SLS treatment significantly enhances QD transdermal penetration by 500-1300%. Our findings suggest that an optimum surface charge exists for nanoparticle skin penetration, and motivate the application of nanoparticle carriers to US/SLS-treated skin for enhanced transdermal drug delivery. Copyright © 2010 Elsevier Ltd. All rights reserved.

Influence of hydroxypropyl-beta-cyclodextrin on the transdermal permeation and skin accumulation of oxybenzone.

PubMed

Felton, Linda A; Wiley, Cody J; Godwin, Donald A

2002-10-01

The objective of the present study was to determine the effects of hydroxypropyl-beta-cyclodextrin (HPCD) concentration on the transdermal permeation and skin accumulation of a model ultraviolet (UV) absorber, oxybenzone. The concentration of oxybenzone was held constant at 2.67 mg/mL for all formulations, while the HPCD concentrations varied from 0 to 20% (w/w). Complexation of oxybenzone by HPCD was demonstrated by differential scanning calorimetry. A modified Franz cell apparatus was used in the transdermal experiments, with aliquots of the receptor fluid assayed for oxybenzone by high-performance liquid chromatography. From the permeation data, flux of the drug was calculated. Skins were removed from the diffusion cells at specified time points over a 24-hr period and the oxybenzone content in the skin determined. The aqueous solubility of oxybenzone increased linearly with increasing HPCD concentration, following a Higuchi AL-type complexation. The stability constant of the reaction was calculated from the phase-solubility diagram and found to be 2047 M-1. As the concentration of HPCD was increased from 0 to 10%, transdermal permeation and skin accumulation of oxybenzone increased. Maximum flux occurred at 10% HPCD, where sufficient cyclodextrin was added to completely solubilize all oxybenzone. When the concentration of HPCD was increased to 20%, both transdermal permeation and skin accumulation decreased. These data suggest the formation of a drug reservoir on the surface of the skin.

Preparation and characterization of marine sponge collagen nanoparticles and employment for the transdermal delivery of 17beta-estradiol-hemihydrate.

PubMed

Nicklas, Martina; Schatton, Wolfgang; Heinemann, Sascha; Hanke, Thomas; Kreuter, Jörg

2009-09-01

Transdermal administration of estradiol offers advantages over oral estrogens for hormone replacement therapy regarding side effects by bypassing the hepatic presystemic metabolism. The objective of this study was to develop nanoparticles of Chondrosia reniformis sponge collagen as penetration enhancers for the transdermal drug delivery of 17beta-estradiol-hemihydrate in hormone replacement therapy. Collagen nanoparticles were prepared by controlled alkaline hydrolysis and characterized using atomic force microscopy and photon correlation spectroscopy. Estradiol-hemihydrate was loaded to the nanoparticles by adsorption to their surface, whereupon a drug loading up to 13.1% of sponge collagen particle mass was found. After incorporation of drug-loaded nanoparticles in a hydrogel, the estradiol transdermal delivery from the gel was compared with that from a commercial gel that did not contain nanoparticles. Saliva samples in postmenopausal patients showed significantly higher estradiol levels after application of the gel with nanoparticles. The area under the curve (AUC) for estradiol time-concentration curves over 24 hours was 2.3- to 3.4-fold higher and estradiol levels 24 hours after administration of estradiol were at least twofold higher with the nanoparticle gel. The hydrogel with estradiol-loaded collagen nanoparticles enabled a prolonged estradiol release compared to a commercial gel and yielded a considerably enhanced estradiol absorption. Consequently, sponge collagen nanoparticles represent promising carriers for transdermal drug delivery.

Essential oil-mediated glycerosomes increase transdermal paeoniflorin delivery: optimization, characterization, and evaluation in vitro and in vivo.

PubMed

Zhang, Kai; Zhang, Yongtai; Li, Zhe; Li, Nana; Feng, Nianping

2017-01-01

In this study, a novel glycerosome carrier containing essential oils was prepared for topical administration of paeoniflorin (PF) to enhance its transdermal drug delivery and improve drug absorption in the synovium. The formulation of glycerosomes was optimized by a uniform design, and the final vehicle was composed of 5% (w/v) phospholipid, 0.6% (w/v) cholesterol, and 10% (v/v) glycerol, with 2% (v/v) Speranskia tuberculata essential oil (STO) as the transdermal enhancer. The in vitro transdermal flux of PF loaded in the STO-glycerosomes was 1.4-fold, 1.6-fold, and 1.7-fold higher than those of glycerosomes, liposomes, and tinctures, respectively. In vivo studies showed that the use of STO-glycerosomes was associated with a 3.1-fold greater accumulation of PF in the synovium than that of common glycerosomes. This finding was confirmed by in vivo imaging studies, which found that the fluorescence intensity of Cy5.5-loaded STO-glycerosomes in mice knee joints was 1.8-fold higher than that of the common glycerosomes 5 h after administration. The glycerosomes mediated by STO exhibited considerable skin permeability as well as improved drug absorption in the synovium, indicating that STO-glycerosomes may be a potential PF transdermal delivery vehicle for the treatment of rheumatoid arthritis caused by synovium lesions.

Oral and transdermal DL-methylphenidate-ethanol interactions in C57BL/6J mice: potentiation of locomotor activity with oral delivery.

PubMed

Bell, Guinevere H; Griffin, William C; Patrick, Kennerly S

2011-12-01

Many abusers of dl-methylphenidate co-abuse ethanol. The present animal study examined behavioral effects of oral or transdermal DL-methylphenidate in combination with a high, depressive dose of ethanol to model co-abuse. Locomotor activity of C57BL/6J mice was recorded for 3 h following dosing with either oral DL-methylphenidate (7.5 mg/kg) or transdermal DL-methylphenidate (Daytrana®;1/4 of a 12.5 cm(2) patch; mean dose 7.5 mg/kg), with or without oral ethanol (3 g/kg). Brains were enantiospecifically analyzed for the isomers of methylphenidate and the transesterification metabolite ethylphenidate. An otherwise depressive dose of ethanol significantly potentiated oral DL-methylphenidate induced increases in total distance traveled for the first 100 min (p<0.05). Transdermal DL-methylphenidate increased total distance traveled after a latency of 80 min, though this effect was not potentiated by concomitant ethanol. Mean 3 h brain D-methylphenidate concentrations were significantly elevated by ethanol in both the oral (65% increase) and transdermal (88% increase) groups. The corresponding L-ethylphenidate concentrations were 10 ng/g and 130 ng/g. Stimulant induced motor activity in rodents may correlate with abuse liability. Potentiation of DL-methylphenidate motor effects by concomitant ethanol carries implications regarding increased abuse potential of DL-methylphenidate when combined with ethanol. Copyright © 2011 Elsevier Inc. All rights reserved.

Essential oil-mediated glycerosomes increase transdermal paeoniflorin delivery: optimization, characterization, and evaluation in vitro and in vivo

PubMed Central

Zhang, Kai; Zhang, Yongtai; Li, Zhe; Li, Nana; Feng, Nianping

2017-01-01

In this study, a novel glycerosome carrier containing essential oils was prepared for topical administration of paeoniflorin (PF) to enhance its transdermal drug delivery and improve drug absorption in the synovium. The formulation of glycerosomes was optimized by a uniform design, and the final vehicle was composed of 5% (w/v) phospholipid, 0.6% (w/v) cholesterol, and 10% (v/v) glycerol, with 2% (v/v) Speranskia tuberculata essential oil (STO) as the transdermal enhancer. The in vitro transdermal flux of PF loaded in the STO-glycerosomes was 1.4-fold, 1.6-fold, and 1.7-fold higher than those of glycerosomes, liposomes, and tinctures, respectively. In vivo studies showed that the use of STO-glycerosomes was associated with a 3.1-fold greater accumulation of PF in the synovium than that of common glycerosomes. This finding was confirmed by in vivo imaging studies, which found that the fluorescence intensity of Cy5.5-loaded STO-glycerosomes in mice knee joints was 1.8-fold higher than that of the common glycerosomes 5 h after administration. The glycerosomes mediated by STO exhibited considerable skin permeability as well as improved drug absorption in the synovium, indicating that STO-glycerosomes may be a potential PF transdermal delivery vehicle for the treatment of rheumatoid arthritis caused by synovium lesions. PMID:28503066

Recent Advances in Protein and Peptide Drug Delivery: A Special Emphasis on Polymeric Nanoparticles

PubMed Central

Patel, Ashaben; Patel, Mitesh; Yang, Xiaoyan; Mitra, Ashim K.

2015-01-01

Proteins and peptides are widely indicated in many diseased states. Parenteral route is the most commonly employed method of administration for therapeutic proteins and peptides. However, requirement of frequent injections due to short in vivo half-life results in poor patient compliance. Non-invasive drug delivery routes such as nasal, transdermal, pulmonary, and oral offer several advantages over parenteral administration. Intrinsic physicochemical properties and low permeability across biological membrane limit protein delivery via non-invasive routes. One of the strategies to improve protein and peptide absorption is by delivering through nanostructured delivery carriers. Among nanocarriers, polymeric nanoparticles (NPs) have demonstrated significant advantages over other delivery systems. This article summarizes the application of polymeric NPs for protein and peptide drug delivery following oral, nasal, pulmonary, parenteral, transdermal, and ocular administrations. PMID:25106908

Characterization of starch Pickering emulsions for potential applications in topical formulations.

PubMed

Marku, Diana; Wahlgren, Marie; Rayner, Marilyn; Sjöö, Malin; Timgren, Anna

2012-05-30

The aim of this work has been to characterize starch based Pickering emulsions as a first step to evaluate their possible use as vehicles for topical drug delivery. A minor phase study of emulsions with high oil content has been performed. Emulsion stability against coalescence over eight weeks and after mild centrifugation treatment has been studied. The particle size, rheological properties and in vitro skin penetration of emulsions containing three different oils (Miglyol, paraffin and sheanut oil) was investigated. It was shown that it is possible to produce oil in water starched stabilised Pickering emulsions with oil content as high as 56%. Furthermore, this emulsions show good stability during storage over eight weeks and towards mild centrifugation. The particle size of the systems are only dependent on the ratio between oil and starch and for liquid oils the type of oil do not affect the particle size. The type of oil also affects the cosmetic and rheological properties of the creams but did not affect the transdermal diffusion in in vitro tests. However, it seems as if the Pickering emulsions affected the transport over the skin, as the flux was twice that of what has been previously reported for solutions. Copyright © 2012 Elsevier B.V. All rights reserved.

Oppositional Defiant Disorder in Adults with ADHD

ERIC Educational Resources Information Center

Reimherr, Frederick W.; Marchant, Barrie K.; Olsen, John L.; Wender, Paul H.; Robison, Reid J.

2013-01-01

Objective: Oppositional defiant disorder (ODD) is the most common comorbid condition in childhood ADHD. This trial was prospectively designed to explore ODD symptoms in ADHD adults. Method: A total of 86 patients in this placebo-controlled, double-blind trial of methylphenidate transdermal system (MTS) were categorized based on the presence of ODD…

Transdermal granisetron versus palonosetron for prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: a multicenter, randomized, open-label, cross-over, active-controlled, and phase IV study.

PubMed

Seol, Young Mi; Kim, Hyo Jeong; Choi, Young Jin; Lee, Eun Mi; Kim, Yang Soo; Oh, Sung Yong; Koh, Su Jin; Baek, Jin Ho; Lee, Won Sik; Joo, Young Don; Lee, Hyun Gi; Yun, Eun Young; Chung, Joo Seop

2016-02-01

Palonosetron is the second-generation 5-hydroxytryptamine 3 receptor antagonist (5-HT3RA) that has shown better efficacy than the first-generation 5-HT3RA for prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately emetogenic chemotherapy (MEC). Granisetron transdermal delivery system (GTDS), a novel transdermal formulation, was developed to deliver granisetron continuously over 7 days. This study compared the efficacy and tolerability of the GTDS to palonosetron for the control of CINV following MEC. A total of 196 patients were randomized to GP or PG group. In this multicenter, randomized, open-label, cross-over, active-controlled, Phase IV study, GP group was assigned to receive transdermal granisetron (one GTDS patch, 7 days) in the first chemotherapy cycle, palonosetron (iv 0.25 mg/day, 1 days) in the second chemotherapy cycle before receiving MEC, and PG group was assigned to receive palonosetron in the first cycle and GTDS in the second cycle. Primary endpoint was the percentage of chemotherapy cycles achieving complete response (CR; defined as no emetic episodes and no rescue medication use) during the acute phase (0-24 h in post-chemotherapy; non-inferiority comparison with palonosetron). Total 333 cycles (165 in GTDS and 168 in palonosetron) were included in the per protocol analysis. The GTDS cycles showed non-inferiority to palonosetron cycles during the acute phase: CR was achieved by 124 (75.2 %) patients in the GTDS cycles and 134 (79.8 %) patients in the palonosetron cycles (treatment difference, -4.6 %; 95 % confidence interval, -13.6-4.4). There was no significant difference in CR rate during acute phase after the end of the first and second chemotherapy cycle between GP and PG group (p = 0.405, p = 0.074). Patients' satisfaction, assessed using Functional Living Index-Emesis (FLI-E), GTDS cycle were higher than those of palonosetron cycle in GP group (FLI-E score; median 1549.5 in GTDS cycle, median 1670.0 in palonosetron cycle). Both treatments were well tolerated and safe. Transdermal granisetron is a good alternative therapeutic option to palonosetron for preventing CINV after MEC.

An overview of clinical and commercial impact of drug delivery systems.

PubMed

Anselmo, Aaron C; Mitragotri, Samir

2014-09-28

Drug delivery systems are widely researched and developed to improve the delivery of pharmaceutical compounds and molecules. The last few decades have seen a marked growth of the field fueled by increased number of researchers, research funding, venture capital and the number of start-ups. Collectively, the growth has led to novel systems that make use of micro/nano-particles, transdermal patches, inhalers, drug reservoir implants and antibody-drug conjugates. While the increased research activity is clearly an indication of proliferation of the field, clinical and commercial translation of early-stage research ideas is critically important for future growth and interest in the field. Here, we will highlight some of the examples of novel drug delivery systems that have undergone such translation. Specifically, we will discuss the developments, advantages, limitations and lessons learned from: (i) microparticle-based depot formulations, (ii) nanoparticle-based cancer drugs, (iii) transdermal systems, (iv) oral drug delivery systems, (v) pulmonary drug delivery, (vi) implants and (vii) antibody-drug conjugates. These systems have impacted treatment of many prevalent diseases including diabetes, cancer and cardiovascular diseases, among others. At the same time, these systems are integral and enabling components of products that collectively generate annual revenues exceeding US $100 billion. These examples provide strong evidence of the clinical and commercial impact of drug delivery systems. Copyright © 2013 Elsevier B.V. All rights reserved.

Simple amides of oleanolic acid as effective penetration enhancers.

PubMed

Bednarczyk-Cwynar, Barbara; Partyka, Danuta; Zaprutko, Lucjusz

2015-01-01

Transdermal transport is now becoming one of the most convenient and safe pathways for drug delivery. In some cases it is necessary to use skin penetration enhancers in order to allow for the transdermal transport of drugs that are otherwise insufficiently skin-permeable. A series of oleanolic acid amides as potential transdermal penetration enhancers was formed by multistep synthesis and the synthesis of all newly prepared compounds is presented. The synthetized amides of oleanolic acid were tested for their in vitro penetration promoter activity. The above activity was evaluated by means of using the Fürst method. The relationships between the chemical structure of the studied compounds and penetration activity are presented.

Simple Amides of Oleanolic Acid as Effective Penetration Enhancers

PubMed Central

Bednarczyk-Cwynar, Barbara; Partyka, Danuta; Zaprutko, Lucjusz

2015-01-01

Transdermal transport is now becoming one of the most convenient and safe pathways for drug delivery. In some cases it is necessary to use skin penetration enhancers in order to allow for the transdermal transport of drugs that are otherwise insufficiently skin-permeable. A series of oleanolic acid amides as potential transdermal penetration enhancers was formed by multistep synthesis and the synthesis of all newly prepared compounds is presented. The synthetized amides of oleanolic acid were tested for their in vitro penetration promoter activity. The above activity was evaluated by means of using the Fürst method. The relationships between the chemical structure of the studied compounds and penetration activity are presented. PMID:26010090

Three dimensional transient multifield analysis of a piezoelectric micropump for drug delivery system for treatment of hemodynamic dysfunctions.

PubMed

Nisar, Asim; Afzulpurkar, Nitin; Tuantranont, Adisorn; Mahaisavariya, Banchong

2008-12-01

In this paper, we present design of a transdermal drug delivery system for treatment of cardiovascular or hemodynamic disorders such as hypertension. The system comprises of integrated control electronics and microelectromechanical system devices such as micropump, micro blood pressure sensor and microneedle array. The objective is to overcome the limitations of oral therapy such as variable absorption profile and the need for frequent dosing, by fabricating a safe, reliable and cost effective transdermal drug delivery system to dispense various pharmacological agents through the skin for treatment of hemodynamic dysfunction such as hypertension. Moreover, design optimization of a piezoelectrically actuated valveless micropump is presented for the drug delivery system. Because of the complexity in analysis of piezoelectric micropump, which involves structural and fluid field couplings in a complicated geometrical arrangement, finite element (FE) numerical simulation rather than an analytical system has been used. The behavior of the piezoelectric actuator with biocompatible polydimethylsiloxane membrane is first studied by conducting piezoelectric analysis. Then the performance of the valveless micropump is analyzed by building a three dimensional electric-solid-fluid model of the micropump. The effect of geometrical dimensions on micropump characteristics and efficiency of nozzle/diffuser elements of a valveless micropump is investigated in the transient analysis using multiple code coupling method. The deformation results of the membrane using multifield code coupling analysis are in good agreement with analytical as well as results of single code coupling analysis of a piezoelectric micropump. The analysis predicts that to enhance the performance of the micropump, diffuser geometrical dimensions such as diffuser length, diffuser neck width and diffuser angle need to be optimized. Micropump flow rate is not strongly affected at low excitation frequencies from 10 to 200 Hz. The excitation voltage is the more dominant factor that affects the flow rate of the micropump as compared with the excitation frequency. However, at extremely high excitation frequencies beyond 8,000 Hz, the flow rate drops as the membrane exhibits multiple bending peaks which is not desirable for fluid flow. Following the extensive numerical analysis, actual fabrication and performance characterization of the micropump is presented. The performance of the micropump is characterized in terms of piezoelectric actuator deflection and micropump flow rate at different operational parameters. The set of multifield simulations and experimental measurement of deflection and flow rate at varying voltage and excitation frequency is a significant advance in the study of the electric-solid-fluid coupled field effects as it allows transient, three dimensional piezoelectric and fluid analysis of the micropump thereby facilitating a more realistic multifield analysis. The results of the present study will also help to conduct relevant strength duration tests of integrated drug delivery device with micropump and microneedle array in future.

A novel, non-invasive transdermal fluid sampling methodology: IGF-I measurement following exercise

USDA-ARS?s Scientific Manuscript database

This study tested the hypothesis that transdermal fluid (TDF) provides a more sensitive and accurate measure of exercise-induced increases in insulin-like growth factor-I (IGF-I) than serum, and that these increases are detectable proximal, but not distal, to the exercising muscle. A novel, noninvas...

Effect of micropatterning induced surface hydrophobicity on drug release from electrospun cellulose acetate nanofibers

NASA Astrophysics Data System (ADS)

Adepu, Shivakalyani; Gaydhane, Mrunalini K.; Kakunuri, Manohar; Sharma, Chandra S.; Khandelwal, Mudrika; Eichhorn, Stephen J.

2017-12-01

Sustained release and prevention of burst release for low half-life drugs like Diclofenac sodium is crucial to prevent drug related toxicity. Electrospun nanofibers have emerged recently as potential carrier materials for controlled and sustained drug release. Here, we present a facile method to prevent burst release by tuning the surface wettability through template assisted micropatterning of drug loaded electrospun cellulose acetate (CA) nanofibers. A known amount of drug (Diclofenac sodium) was first mixed with CA and then electrospun in the form of a nanofabric. This as-spun network was hydrophilic in nature. However, when electrospinning was carried out through non-conducting templates, viz nylon meshes with 50 and 100 μm size openings, two kinds of hydrophobic micro-patterned CA nanofabrics were produced. In vitro transdermal testing of our nanofibrous mats was carried out; these tests were able to show that it would be possible to create a patch for transdermal drug release. Further, our results show that with optimized micro-patterned dimensions, a zero order sustained drug release of up to 12 h may be achieved for the transdermal system when compared to non-patterned samples. This patterning caused a change in the surface wettability, to a hydrophobic surface, resulting in a controlled diffusion of the hydrophilic drug. Patterning assisted in controlling the initial burst release, which is a significant finding especially for low half-life drugs.

Wearable/disposable sweat-based glucose monitoring device with multistage transdermal drug delivery module

PubMed Central

Lee, Hyunjae; Song, Changyeong; Hong, Yong Seok; Kim, Min Sung; Cho, Hye Rim; Kang, Taegyu; Shin, Kwangsoo; Choi, Seung Hong; Hyeon, Taeghwan; Kim, Dae-Hyeong

2017-01-01

Electrochemical analysis of sweat using soft bioelectronics on human skin provides a new route for noninvasive glucose monitoring without painful blood collection. However, sweat-based glucose sensing still faces many challenges, such as difficulty in sweat collection, activity variation of glucose oxidase due to lactic acid secretion and ambient temperature changes, and delamination of the enzyme when exposed to mechanical friction and skin deformation. Precise point-of-care therapy in response to the measured glucose levels is still very challenging. We present a wearable/disposable sweat-based glucose monitoring device integrated with a feedback transdermal drug delivery module. Careful multilayer patch design and miniaturization of sensors increase the efficiency of the sweat collection and sensing process. Multimodal glucose sensing, as well as its real-time correction based on pH, temperature, and humidity measurements, maximizes the accuracy of the sensing. The minimal layout design of the same sensors also enables a strip-type disposable device. Drugs for the feedback transdermal therapy are loaded on two different temperature-responsive phase change nanoparticles. These nanoparticles are embedded in hyaluronic acid hydrogel microneedles, which are additionally coated with phase change materials. This enables multistage, spatially patterned, and precisely controlled drug release in response to the patient’s glucose level. The system provides a novel closed-loop solution for the noninvasive sweat-based management of diabetes mellitus. PMID:28345030

Investigations on the viscoelastic performance of pressure sensitive adhesives in drug-in-adhesive type transdermal films.

PubMed

Wolff, Hans-Michael; Irsan; Dodou, Kalliopi

2014-08-01

We aimed to investigate the effect of solubility parameter and drug concentration on the rheological behaviour of drug-in-adhesive films intended for transdermal application. Films were prepared over a range of drug concentrations (5%, 10% and 20% w/w) using ibuprofen, benzoic acid, nicotinic acid and lidocaine as model drugs in acrylic (Duro-Tak 87-4287 and Duro-Tak 87900A) or silicone (Bio-PSA 7-4301 and Bio-PSA 7-4302) pressure sensitive adhesives (PSAs). Saturation status of films was determined using light microscopy. Viscoelastic parameters were measured in rheology tests at 32°C. Subsaturated films had lower viscoelastic moduli whereas saturated films had higher moduli than the placebo films and/or a concentration-dependent increase in their modulus. Saturation concentration of each drug in the films was reflected by decreasing/increasing viscoelastic patterns. The viscoelastic windows (VWs) of the adhesive and drug-in-adhesive films clearly depicted the effect of solubility parameter differences, molar concentration of drug in the adhesive film and differences in PSA chemistry. Drug solubility parameters and molar drug concentrations have an impact on rheological patterns and thus on the adhesive performance of tested pressure sensitive adhesives intended for use in transdermal drug delivery systems. Use of the Flory equation in its limiting form was appropriate to predict drug solubility in the tested formulations.

[Local effects of transdermal treatment with rotigotine].

PubMed

Bermejo, Pedro Emilio; Zea, María Ascensión; Alba-Alcántara, Lucía; Ruiz-Huete, Cristina

2013-04-01

Rotigotine is the first transdermal non-ergolinic dopaminergic agonist used in the treatment of Parkinson's disease. It has several important advantages such as once-daily administration, absence of interactions with food, steady levels in plasma and continuous dopaminergic stimulation. Although its systemic side effects are similar to those seen in other dopaminergic agonists, rotigotine also has local side effects derived from the site of application. The aim of this paper is to review those local problems. A retrospective analysis was carried out in order to identify the first 165 patients treated with rotigotine. Patients with intracranial lesions, psychiatric pathology or dementia were excluded. Patients were evaluated before and at two, four and six months after beginning treatment with rotigotine. In all, 94 males and 71 females were identified, with an average age of 65.2 and an average rotigotine daily dose of 11.3 mg. Local side effects were present in 21 patients and they were usually mild. Two patients abandoned the treatment because of these local adverse events, presenting erythema and prurigo. Thirty patients complained about lack of adherence of the patch, specially when it was hot, and 36 about the formation of wrinkles in the patch. None of these problems was associated to motor fluctuations or other complications. Local complications of transdermal rotigotine are mild but frequent. We consider it is necessarily to take them into account to get a better treatment of patients suffering from Parkinson's disease.

In vitro-ex vivo correlations between a cell-laden hydrogel and mucosal tissue for screening composite delivery systems

PubMed Central

Blakney, Anna K.; Little, Adam B.; Jiang, Yonghou; Woodrow, Kim A.

2017-01-01

Composite delivery systems where drugs are electrospun in different layers and vary the drug stacking-order are posited to affect bioavailability. We evaluated how the formulation characteristics of both burst- and sustained-release electrospun fibers containing three physicochemically diverse drugs: dapivirine (DPV), maraviroc (MVC) and tenofovir (TFV) affect in vitro and ex vivo release. We developed a poly(hydroxyethyl methacrylate) (pHEMA) hydrogel release platform for the rapid, inexpensive in vitro evaluation of burst- and sustained-release topical or dermal drug delivery systems with varying microarchitecture. We investigated properties of the hydrogel that could recapitulate ex vivo release into nonhuman primate vaginal tissue. Using a DMSO extraction protocol and HPLC analysis, we achieved >93% recovery from the hydrogels and >88% recovery from tissue explants for all three drugs. We found that DPV loading, but not stacking order (layers of fiber containing a single drug) or microarchitecture (layers with isolated drug compared to all drugs in the same layer) impacted the burst release in vitro and ex vivo. Our burst-release formulations showed a correlation for DPV accumulation between the hydrogel and tissue (R2=0.80), but the correlation was not significant for MVC or TFV. For the sustained release formulations, the PLGA/PCL content did not affect TFV release in vitro or ex vivo. Incorporation of cells into the hydrogel matrix improved the correlation between hydrogel and tissue explant release for TFV. We expect that this hydrogel tissue mimic maybe a promising preclinical model to evaluate topical or transdermal drug delivery systems with complex microarchitectures. PMID:28222612

Exploitation of sub-micron cavitation nuclei to enhance ultrasound-mediated transdermal transport and penetration of vaccines.

PubMed

Bhatnagar, Sunali; Kwan, James J; Shah, Apurva R; Coussios, Constantin-C; Carlisle, Robert C

2016-09-28

Inertial cavitation mediated by ultrasound has been previously shown to enable skin permeabilisation for transdermal drug and vaccine delivery, by sequentially applying the ultrasound then the therapeutic in liquid form on the skin surface. Using a novel hydrogel dosage form, we demonstrate that the use of sub-micron gas-stabilising polymeric nanoparticles (nanocups) to sustain and promote cavitation activity during simultaneous application of both drug and vaccine results in a significant enhancement of both the dose and penetration of a model vaccine, Ovalbumin (OVA), to depths of 500μm into porcine skin. The nanocups themselves exceeded the penetration depth of the vaccine (up to 700μm) due to their small size and capacity to 'self-propel'. In vivo murine studies indicated that nanocup-assisted ultrasound transdermal vaccination achieved significantly (p<0.05) higher delivery doses without visible skin damage compared to the use of a chemical penetration enhancer. Transdermal OVA doses of up to 1μg were achieved in a single 90-second treatment, which was sufficient to trigger an antigen-specific immune response. Furthermore, ultrasound-assisted vaccine delivery in the presence of nanocups demonstrated substantially higher specific anti-OVA IgG antibody levels compared to other transdermal methods. Further optimisation can lead to a viable, safe and non-invasive delivery platform for vaccines with potential use in a primary care setting or personalized self-vaccination at home. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Synthesis of conjugated chitosan and its effect on drug permeation from transdermal patches.

PubMed

Satheeshababu, B K; Shivakumar, K L

2013-03-01

The aim of this study was to synthesis the conjugated chitosan by covalent attachment of thiol moieties to the cationic polymer, mediated by a carbodiimide to improve permeation properties of chitosan. Thioglycolic acid was covalently attached to chitosan by the formation of amide bonds between the primary amino groups of the polymer and the carboxylic acid groups of thioglycolic acid. Hence, these polymers are called as thiomers or thiolated polymers. Conjugation of chitosan was confirmed by Fourier transform-infrared and differential scanning calorimetric analysis. Matrix type transdermal patches of carvedilol were prepared using the different proportions of chitosan and chitosan-thioglycolic acid conjugates (2:0, 1.7:0.3, 1.4:0.6, 1:1, 0.6:1.4 and 0.3:1.7) by solvent casting technique. Prepared matrix type patches were evaluated for their physicochemical characterization followed by in vitro evaluation. Selected formulations were subjected for their ex vivo studies on Wistar albino rat skin and human cadaver skin using the modified Franz diffusion cell. As the proportion of conjugated chitosan increased, the transdermal patches showed increased drug permeation. The mechanism of drug release was found to be nonFickian profiles. The present study concludes that the transdermal patches of carvedilol using conjugated chitosan with different proportions of chitosan were successfully developed to provide improved drug permeation. The transdermal patches can be a good approach to improve drug bioavailability by bypassing the extensive hepatic first-pass metabolism of the drug.

[Post marketing surveillance study with an analgesic (transdermal buprenorphine patch) in patients with moderate to severe chronic pain].

PubMed

Tschirner, M; Ritzdorf, I; Brünjes, R

2008-09-18

To obtain information on the efficacy, tolerability and safetyofa transdermal buprenorphine patch (Transtec PRO) in patients with moderate to severe chronic pain. In addition it should be evaluated to what extent the two fixed patch change days per weekare simplifyingthe therapy. In this prospective multi-center post marketing surveillance study patients with chronic cancer and non-cancer pain were treated with transdermal buprenorphine for up to eight weeks. The evaluation included pain intensity, the dosage of the applied analgesics and additional therapies, the renal function (by serum creatinine) and adverse events. 3654 patients were treated for a mean of 50.4 days. Using the NRS-11 the mean pain intensity decreased from 6.3 at the time when patients were switched to the transdermal buprenorphine patch to 2.6 at the last treatment evaluation. The matrix patch was safe and well tolerated also in patients with advanced renal insufficiency. Adverse events were reported in 6.7% of the patients. 89.3% of the physicians quoted to prefer transdermal buprenorphine with the two fixed patch change days per week compared to the pre-treatment. The buprenorphine-containing matrix patch was effective and well tolerated in patients with moderate to severe chronic cancer and noncancer pain. From the physicians view the two fixed patch change days per week facilitate the guidance of therapy. In patients with advanced renal insufficiency a dose adjustment is not necessary.

From high doses of oral rivastigmine to transdermal rivastigmine patches: user experience and satisfaction among caregivers of patients with mild to moderate Alzheimer disease.

PubMed

Reñé, R; Ricart, J; Hernández, B

2014-03-01

Rivastigmine, a treatment for mild to moderate Alzheimer disease (AD), is the first cholinesterase inhibitor to be available in the transdermal format. We aim to describe user experience and satisfaction with the rivastigmine patch, as well as any clinical changes perceived in patients. Observational, cross-sectional, multicentre study with 239 investigators and 1851 informal caregivers of patients with mild to moderate AD. Patients were treated with transdermal rivastigmine patches for ≥ 6 months and had previously received high doses of oral rivastigmine. Mean caregiver age was 59.8±14.4 years and 70.9% were women. They spent 10.0±7.1hours per day providing care and 79.8% lived with the patient. Patch instructions were described as easy to follow by 97.1% of the caregivers and 92.1% of them rated patch application as easy or very easy. The most commonly cited disadvantage was adhesion problems (26.8%). Discontinuation of treatment was due to cutaneous reactions in most cases. Overall, 76.5% of the caregivers were satisfied or very satisfied with transdermal treatment and 77.4% considered that its interference with daily activities was minimal or null. The patch was preferred to oral treatment by 94.3% of caregivers. Clinical Global Impression of Change ratings improved according to 61.3% of the caregivers and 53% of the investigators. Few caregivers reported medication forgetfulness. Most caregivers of patients with mild to moderate AD preferred the transdermal format of rivastigmine to the oral format. Caregivers also reported overall satisfaction, ease of use, and reduced impact on daily activities for transdermal rivastigmine format, in addition to patient improvement compared to their condition under the previous treatment. Copyright © 2012 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

Therapeutic serum phenobarbital concentrations obtained using chronic transdermal administration of phenobarbital in healthy cats.

PubMed

Delamaide Gasper, Joy A; Barnes Heller, Heidi L; Robertson, Michelle; Trepanier, Lauren A

2015-04-01

Seizures are a common cause of neurologic disease, and phenobarbital (PB) is the most commonly used antiepileptic drug. Chronic oral dosing can be challenging for cat owners, leading to poor compliance. The purpose of this study was to determine if the transdermal administration of PB could achieve serum PB concentrations of between 15 and 45 μg/ml in healthy cats. Nineteen healthy cats were enrolled in three groups. Transdermal PB in pluronic lecithin organogel (PLO) was applied to the pinnae for 14 days at a dosage of 3 mg/kg q12h in group 1 (n = 6 cats) and 9 mg/kg q12h in group 2 (n = 7 cats). Transdermal PB in Lipoderm Activemax was similarly applied at 9 mg/kg q12h for 14 days in group 3 (n = 6 cats). Steady-state serum PB concentrations were measured at trough, and at 2, 4 and 6 h after the morning dose on day 15. In group 1, median concentrations ranged from 6.0-7.5 μg/ml throughout the day (observed range 0-11 μg/ml). Group 2 median concentrations were 26.0 μg/ml (observed range 18.0-37.0 μg/ml). For group 3, median concentrations ranged from 15.0-17.0 μg/ml throughout the day (range 5-29 μg/ml). Side effects were mild. One cat was withdrawn from group 2 owing to ataxia and sedation. These results show therapeutic serum PB concentrations can be achieved in cats following chronic transdermal administration of PB in PLO at a dosage of 9 mg/kg q12h. More individual variation was noted using Lipoderm Activemax. Transdermal administration may be an alternative for cats that are difficult to medicate orally. © ISFM and AAFP 2014.

[Dose-finding for treatment with a transdermal fentanyl patch : Titration with oral transmucosal fentanyl citrate and morphine sulfate].

PubMed

Mücke, M; Conrad, R; Marinova, M; Cuhls, H; Elsner, F; Rolke, R; Radbruch, L

2016-12-01

To date, no studies investigating titration with oral transmucosal fentanyl for the dose-finding of transdermal fentanyl treatment have been published. In an open randomized study 60 patients with chronic malignant (n = 39) or nonmalignant pain (n = 21), who required opioid therapy according to step three of the guidelines of the World Health Organization (WHO), were investigated. In two groups of 30 patients each titration with immediate release morphine (IRM) or oral transmucosal fentanyl citrate (OTFC) was undertaken. For measurement purposes the Brief Pain Inventory (BPI) and Minimal Documentation System (MIDOS) were used. After a 24-h titration phase, in which patients documented the intensity of pain, nausea, and tiredness, treatment with transdermal fentanyl was evaluated over a 10-day period by means of the necessary dose adaptation (responder ≤ 1 dose adaptation; conversion formula 1:1 [OTFC group] vs 100:1 [IRM group]).The pain reduction over the first 24 h (titration phase) did not differ significantly between the groups. The number of responders (17 OTFC vs. 21 IRM) over the 10-day period did not show any difference either. In both groups there was a significant reduction in pain intensity (p < 0.001). Over the course of the study, there were significantly more drop-outs because of adverse effects in the OTFC group than in the IRM group (8 vs 1, p = 0.028).Oral transmucosal fentanyl citrate can be applied for the titration of transdermal fentanyl, but it does not show any clinically relevant advantage. For example, the risk of side effects-induced drop-outs was greater in the present study. Whether the unnecessary opioid switching to treat chronic pain and breakthrough pain is advantageous with regard to minimizing conversion errors cannot be definitively answered within the scope of this study.

Caregivers' and physicians' attitudes to rotigotine transdermal patch versus oral Parkinson's disease medication: an observational study.

PubMed

Sieb, Jörn Peter; Themann, Peter; Warnecke, Tobias; Lauterbach, Thomas; Berkels, Reinhard; Grieger, Frank; Lorenzl, Stefan

2015-05-01

To provide real-world data on caregiver and physician perceptions of the advantages and disadvantages of rotigotine transdermal patch (Neupro * ) versus oral Parkinson's Disease (PD) medication. Cross-sectional, non-interventional study in routine clinical practice in Germany (NCT01330290). Patients had PD with documented need for care, and had received rotigotine transdermal patch as add-on to oral PD treatment for ≥1 month. Caregivers/nurses and physicians assessed rotigotine transdermal patch versus oral PD medications using questionnaires. Specific questions regarding the possible benefits of transdermal application were asked and comprised questions on: swallowing dysfunction, nausea/vomiting, monitoring therapy, once daily application, application independently from meals, application to sleeping patients, caregiving efforts (caregivers only) and clinical aspects (physicians only). Each question was assessed on a 5 point scale ranging from -2 (major disadvantage) to 2 (major advantage) compared with oral treatment. Primary outcomes were mean total scores of all questions for caregivers/nurses and physicians who provided responses for ≥4 questions. As there are no validated tools to assess physician/caregiver preference in the PD setting, there is no reference against which the current findings can be compared; this study serves to pilot the questionnaires. Questionnaire responses from 128 caregivers/nurses and 41 physicians were documented for 147 patients. One hundred (68%) patients had a caregiving family member; 40 (27%) were cared for by a nurse. Mean PD duration was 8.2 (SD 6.3) years; 136 (93%) patients were taking levodopa. Mean total score of caregivers'/nurses' questionnaires was 1.32 (SD 0.67) and of physicians' questionnaires was 1.46 (0.32) indicating a perceived advantage of rotigotine transdermal patch over oral PD therapy. Mean scores for individual questions were in the range 1.03-1.54 for caregivers/nurses and 1.15-1.87 for physicians. When given a choice about rationale to prescribe, physicians cited pharmaceutical form (patch) in 139 (95%) cases and active agent (rotigotine) in 89 (61%) cases. Caregivers/nurses and physicians perceived advantages with rotigotine transdermal patch compared to an oral PD medication as add-on therapy in patients with PD; advantages were observed in aspects of medical treatment as well as in everyday situations of caregiving of PD patients.

In vitro permeation of levothyroxine across the skin.

PubMed

Padula, Cristina; Pappani, Alice; Santi, Patrizia

2008-02-12

The aim of this work was to investigate the in vitro transdermal permeation characteristics of sodium levothyroxine, in view of its topical application. Permeation experiments were performed in vitro, using rabbit ear skin as barrier. At the end of the experiments levothyroxine retained in the skin was extracted and quantified by HPLC. The formulations tested were solutions and a commercial cream. The use of dimethyl beta-cyclodextrin as solubilizing agent increased to a significant extent levothyroxine solubility, but reduced its skin accumulation. Skin stripping before drug application produced a considerable increase in the amount retained and levothyroxine was found also in the receptor compartment. The application of the commercial cream in occlusive conditions increased to a significant extent drug retention in the skin. In conclusion, levothyroxine skin administration is promising in view of a localized effect, because it was retained in the skin. On the contrary, transdermal administration in view of systemic effect does not represent a concrete possibility.

Evaluation of Microemulsion and Lamellar Liquid Crystalline Systems for Transdermal Zidovudine Delivery.

PubMed

Carvalho, André Luis Menezes; Silva, José Alexsandro da; Lira, Ana Amélia Moreira; Conceição, Tamara Matos Freire; Nunes, Rogéria de Souza; de Albuquerque Junior, Ricardo Luiz Cavalcanti; Sarmento, Victor Hugo Vitorino; Leal, Leila Bastos; de Santana, Davi Pereira

2016-07-01

This study proposed to investigate and to compare colloidal carrier systems containing Zidovudine (3'-azido-3'-deoxythymidine) (AZT) for transdermal administration and optimization of antiretroviral therapy. Microemulsion (ME) and lamellar phase (LP) liquid crystal were obtained and selected from pseudoternary diagrams previously developed. Small-angle X-ray scattering and rheology analysis confirmed the presence of typical ME and liquid crystalline structures with lamellar arrangement, respectively. Both colloidal carrier systems, ME, and LP remained stable, homogeneous, and isotropic after AZT addition. In vitro permeation study (using pig ear skin) showed that the amount of permeated drug was higher for ME compared to the control and LP, obtaining a permeation enhancing effect on the order of approximately 2-fold (p < 0.05). Microscopic examination after in vivo skin irritation studies using mice suggested few histological changes in the skin of animals treated with the ME compared to the control group (hydrogel). Thus, ME proved to be adequate and have promising effects, being able to promote the drug permeation without causing apparent skin irritation. On the order hand, LP functioned as a drug reservoir reducing AZT partitioning into the skin. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

A statistical experimental design approach to evaluate the influence of various penetration enhancers on transdermal drug delivery of buprenorphine.

PubMed

Taghizadeh, S Mojtaba; Moghimi-Ardakani, Ali; Mohamadnia, Fatemeh

2015-03-01

A series of drug-in-adhesive transdermal drug delivery systems (patch) with different chemical penetration enhancers were designed to deliver drug through the skin as a site of application. The objective of our effort was to study the influence of various chemical penetration enhancers on skin permeation rate and adhesion properties of a transdermal drug delivery system using Box-Behnken experimental design. The response surface methodology based on a three-level, three-variable Box-Behnken design was used to evaluate the interactive effects on dependent variables including, the rate of skin permeation and adhesion properties, namely peel strength and tack value. Levulinic acid, lauryl alcohol, and Tween 80 were used as penetration enhancers (patch formulations, containing 0-8% of each chemical penetration enhancer). Buprenorphine was used as a model penetrant drug. The results showed that incorporation of 20% chemical penetration enhancer into the mixture led to maximum skin permeation flux of buprenorphine from abdominal rat skin while the adhesion properties decreased. Also that skin flux in presence of levulinic acid (1.594 μg/cm(2) h) was higher than Tween 80 (1.473 μg/cm(2) h) and lauryl alcohol (0.843 μg/cm(2) h), and in mixing these enhancers together, an additional effect was observed. Moreover, it was found that each enhancer increased the tack value, while levulinic acid and lauryl alcohol improved the peel strength but Tween 80 reduced it. These findings indicated that the best chemical skin penetration enhancer for buprenorphine patch was levulinic acid. Among the designed formulations, the one which contained 12% (wt/wt) enhancers exhibited the highest efficiency.

Rotigotine and specific non-motor symptoms of Parkinson's disease: post hoc analysis of RECOVER.

PubMed

Ray Chaudhuri, K; Martinez-Martin, Pablo; Antonini, Angelo; Brown, Richard G; Friedman, Joseph H; Onofrj, Marco; Surmann, Erwin; Ghys, Liesbet; Trenkwalder, Claudia

2013-07-01

Non-motor symptoms of Parkinson's disease (PD) represent major causes of morbidity. RECOVER, a randomized controlled trial of rotigotine transdermal system, was the first prospective controlled trial to use the Non-Motor Symptoms Scale (NMSS) as an exploratory outcome for assessment of treatment effects on non-motor symptoms in PD. Rotigotine improved NMSS total score compared with placebo, and the "Sleep/fatigue" and "Mood/apathy" domains. This post hoc analysis further characterizes the effects of rotigotine on sleep/fatigue and mood/apathy. Patients with PD and unsatisfactory early-morning motor impairment were randomized to transdermal patches of rotigotine (2-16 mg/24 h) or placebo. Treatment was titrated to optimal dose over 1-8 weeks, maintained for 4 weeks. The NMSS was assessed at baseline and end of treatment. Post hoc analyses are presented for individual items of the "Sleep/fatigue" and "Mood/apathy" domains. The interpretation of p-values is considered exploratory in nature. Of 287 patients randomized, NMSS data were available for 267 patients (178 rotigotine, 89 placebo). Within the "Sleep/fatigue" domain there was a significant difference, in favor of rotigotine, in change from baseline score in 1 of 5 items: "fatigue (tiredness) or lack of energy" (ANCOVA, p < 0.0001). Within the "Mood/apathy" domain, there were significant differences in favor of rotigotine in 4 of 7 items: "lost interest in surroundings" (p < 0.0001), "lost interest in doing things" (p < 0.0001), "seems sad or depressed" (p < 0.01), and "difficulty experiencing pleasure" (p < 0.05). Rotigotine transdermal system may improve non-motor symptoms such as fatigue, symptoms of depression, anhedonia, and apathy in patients with PD; further prospective controlled studies are required to confirm this post hoc analysis. Copyright © 2013 Elsevier Ltd. All rights reserved.

Effects of Internet-Based Voucher Reinforcement and a Transdermal Nicotine Patch on Cigarette Smoking

ERIC Educational Resources Information Center

Glenn, Irene M.; Dallery, Jesse

2007-01-01

Nicotine replacement products are commonly used to promote smoking cessation, but alternative and complementary methods may increase cessation rates. The current experiment compared the short-term effects of a transdermal nicotine patch to voucher-based reinforcement of smoking abstinence on cigarette smoking. Fourteen heavy smokers (7 men and 7…

[Study on the pharmacokinetics Oxytropis falcate total flavonoids ointment in rats].

PubMed

Li, Wei-Dong; Chen, Zhi-Peng; Qu, Min-Ming; Liu, Dan; Xiao, Yan-Yu; Cai, Bao-Chang

2011-09-01

To study the pharmacokinetics of Oxytropis falcate total flavonoids ointment after transdermal administration in rats. The content of 2',4'-dihydroxychalcone (TFC) in plasma was determined by high performance liquid chromatography. The concentration was determined at various time and the data was processed by 3P97. TFC behaved as a one-compartment and a two-compartment model after transdermal administration of total Oxytropis falcate total flavonoids ointment and solution, respectively. And the C(max) of ointment was improved about 3 times compared with that of the solution. The results show that the ointment possesses sustained release property and significantly prolong the degradation half life of TFC. The ointment is benefit to improve the analgesic and anti-inflammatory activity after transdermal administration.

MAOIs and transdermal delivery.

PubMed

Vandenberg, Chad M

2012-09-01

Although not currently considered a first-line treatment for depression due to safety and tolerability concerns, MAOIs are effective antidepressants, particularly for atypical or treatment-resistant depression. FDA-approved oral MAOIs inhibit both MAO-A and MAO-B; inhibition of MAO-A in the brain is required for an antidepressant effect, but inhibition in the intestinal tract can allow excessive absorption of tyramine, which can lead to hypertensive crisis. A transdermal formulation of selegiline delivers the medication directly into the circulatory system, bypassing the first-pass metabolism of the GI system and substantially reducing the risk for tyramine-related adverse events. The skin patch allows for a lower dose of the drug to achieve an antidepressant effect, maintains a steady dose of the medication over 24 hours, and avoids the need for dietary restrictions at the minimum effective dose of 6 mg/24 hours. MAOIs are useful treatment options for patients who have not responded to first-line treatments, and understanding their mechanism of action can help clinicians to accurately and safely prescribe these medications. © Copyright 2012 Physicians Postgraduate Press, Inc.

Photoacoustic evaluation of the penetration of piroxicam gel applied with phonophoresis into human skin

NASA Astrophysics Data System (ADS)

Silveira, F. L. F. D.; Barja, P. R.; Acosta-Avalos, D.

2010-03-01

The photoacoustic (PA) technique has been increasingly employed in biomedical studies, allowing in vivo skin measurements not easily performed with other techniques. It is possible to use PA measurements to evaluate transdermal delivery of products topically applied through manual massage or phonophoresis, that is the utilization of ultrasound waves to enhance drug absorption. The aim of this study was to analyze the influence of the period of phonophoresis application in the transdermal penetration of piroxicam gel. In vivo PA measurements employed a tungsten lamp as light source and a thin aluminum foil closing the PA chamber. The PA signals of the arm (i) clean; and (ii) after phonophoresis were utilized to estimate the concentration of piroxicam into skin. For all (4) volunteers, drug concentration in skin after phonophoresis application was the same for the different application times employed; in this way, phonophoresis for one minute seemed to be sufficient to enhance piroxicam penetration into skin. The actual amount of drug delivered into tissue depends on the person, suggesting a dependency with the skin type, which affects the PA signal level [2]. We conclude that drug delivery depends not only on the application method, but also on the specific skin type.

Using cyclodextrin complexation to enhance secondary photoprotection of topically applied ibuprofen.

PubMed

Godwin, Donald A; Wiley, Cody J; Felton, Linda A

2006-01-01

Each year millions of people are overexposed to the sun resulting in photodamage of the skin. Secondary photoprotection is the application of medicinal agents to the body after sun exposure to reduce this damage. The objective of this study was to determine the affects of hydroxypropyl-beta-cyclodextrin (HPCD) complexation on the secondary photoprotective properties of topically applied ibuprofen. Complexation of ibuprofen by HPCD was demonstrated by differential scanning calorimetry, while solubilities were determined using HPLC. A linear (r2>0.999) relationship was found between ibuprofen solubility and HPCD concentration. For subsequent experiments, the concentration of ibuprofen was held constant at the solubility in 10% HPCD (10.6 mg/ml), while the HPCD concentration varied from 0 to 20% (w/w). In vitro transdermal permeation experiments demonstrated a parabolic relationship between transdermal kinetic parameters and HPCD concentration, with maximum values for both flux and skin accumulation occurring with the 10% HPCD formulation. In vivo experiments were performed by exposing hairless mice to UV radiation and applying ibuprofen-HPCD formulations topically at various times following UV exposure. Edema and epidermal lipid damage data demonstrated that application of ibuprofen-HPCD formulations within 1h of UV exposure provided significant photoprotection.

Enhancing topical analgesic administration: review and prospect for transdermal and transbuccal drug delivery systems.

PubMed

Sanz, Roser; Calpena, Ana C; Mallandrich, Mireia; Clares, Beatriz

2015-01-01

Topical administration is an appealing method for drug delivery due to its non-invasiveness, self-controlled application, avoidance of first-pass metabolism in the liver and reduction of systemic side effects compared to other conventional routes such as oral and parenteral. However, topical administration must overcome the permeable barriers that skin and mucosa represent for the drug to achieve its desired therapeutic effect. Penetration of drugs through human skin is mainly impaired by the stratum corneum- the uppermost keratinized skin layer. In contrast, the stratified squamous epithelium (a nonkeratinized tissue) represents the major physical barrier for transbuccal drug administration in humans. Different technologies have been studied to enhance the bioavailability or local effects of drugs administered through skin and buccal mucosa. Those technologies involve the use of physical or chemical enhancers and new dosage forms such as vesicles, cyclodextrins, nanoparticles and other complex systems. Combinations of these technologies may further increase drug delivery in some cases. As analgesia is one of the main therapeutic effects sought through topical administration, this paper focuses on the review of drug delivery systems to improve the topical and transdermal/transbuccal drug delivery of substances with known analgesic action. A discussion of their possibilities and limitations is also included.

Predictors of relapse in patients with major depressive disorder in a 52-week, fixed dose, double blind, randomized trial of selegiline transdermal system (STS).

PubMed

Jang, Saeheon; Jung, Sungwon; Pae, Chiun; Kimberly, Blanchard Portland; Craig Nelson, J; Patkar, Ashwin A

2013-12-01

We investigated patient and disease characteristics predictive of relapse of MDD during a 52-week placebo controlled trial of selegiline transdermal system (STS) to identify patient characteristics relevant for STS treatment. After 10 weeks of open-label stabilization with STS, 322 remitted patients with MDD were randomized to 52-weeks of double-blind treatment with STS (6 mg/24h) or placebo (PLB). Relapse was defined as Hamilton Depression Rating Scale (HAMD-17) score of ≥ 14 and a CGI-S score of ≥ 3 with at least 2-point increase from the beginning of the double blind phase on 2 consecutive visits. Cox's proportional hazards regression was used to examine the effect of potential predictors (age, sex, age at onset of first MDD, early response pattern, number of previous antidepressant trials, severity of index episode, number of previous episodes, melancholic features, atypical features and anxious feature) on outcome. Exploratory analyses examined additional clinical variables (medical history, other psychiatric history, and individual items of HAM-D 28) on relapse. For all predictor variables analyzed, treatment Hazard Ratio (HR=0.48~0.54) was significantly in favor of STS (i.e., lower relapse risk than PLB). Age of onset was significantly predictive of relapse. Type, duration, and severity of depressive episodes, previous antidepressant trials, or demographic variables did not predict relapse. In additional exploratory analysis, eating disorder history and suicidal ideation were significant predictors of relapse after controlling for the effect of treatment in individual predictor analysis. While age of onset, eating disorder history and suicidal ideation were significant predictors, the majority of clinical and demographic variables were not predictive of relapse. Given the post-hoc nature of analysis, the findings need confirmation from a prospective study. It appears that selegiline transdermal system was broadly effective in preventing relapse across different subtypes and symptoms clusters of MDD. © 2013 Published by Elsevier B.V.

A comparative study of vitamin E TPGS/HPMC supersaturated system and other solubilizer/polymer combinations to enhance the permeability of a poorly soluble drug through the skin.

PubMed

Ghosh, Indrajit; Michniak-Kohn, Bozena

2012-11-01

In transdermal drug delivery systems (TDDS), it is a challenge to achieve stable and prolonged high permeation rates across skin, because the concentration of the drug dissolved in the matrix has to be high in order to maintain zero order release kinetics of the drug. In case of poorly soluble drugs, due to thermodynamic challenges, there is a high tendency for the drug to nucleate immediately after formulating or even during storage. The present study focuses on the efficiency of vitamin E TPGS/HPMC supersaturated solution and other solubilizer/polymer systems to improve the solubility of the drug and inhibit crystal growth in the transdermal formulation. Effect of several solubilizers, for example, Pluronic F-127, vitamin E TPGS and co-solvent, for example, propylene glycol (PG) were studied on the supersaturated systems of ibuprofen as model drug. Various stabilizers such as hydroxylpropyl methylcellulose (HPMC 3 cps) and polyvinylpyrrolidone (PVP K-30) were examined to evaluate their crystal inhibitory effects. Different analytical tools were used in this study to detect the growth of crystals in the systems. Vitamin E TPGS and HPMC 3 cps formulation produced the highest permeation rate of the drug as compared to other systems. In addition, the onset of crystallization time was shown to be longer with this formulation as compared to other solubilizer/polymer combinations.

Transdermal Scopolamine and Acute Postoperative Urinary Retention in Pelvic Reconstructive Surgery.

PubMed

Propst, Katie; OʼSullivan, David M; Tulikangas, Paul K

2016-01-01

To evaluate the relationship between perioperative use of transdermal scopolamine and the rate of urinary retention after stress urinary incontinence and pelvic organ prolapse procedures in women. This is a retrospective, cohort study; the primary outcome is the rate of acute postoperative urinary retention. Study candidates were adult female patients who underwent pelvic reconstructive surgery at a tertiary care center. Subjects were excluded if preoperative postvoid residual urine volume was greater than 150 mL, preoperative urodynamic testing was not performed, or if a postoperative trial of void was not performed. Subjects were grouped based on preoperative use of transdermal scopolamine. Patients were selected consecutively until 138 subjects per group was reached. Differences in rates of acute postoperative urinary retention were evaluated using a chi-square test. Group demographics were evaluated using t tests and χ tests. Two hundred seventy-six subjects were included in the analysis, 138 received a transdermal scopolamine patch in the perioperative period and 138 did not. The overall rate of acute postoperative urinary retention was 25.3%. There was no significant difference in the rate of acute postoperative urinary retention between the study groups (scopolamine, 26.8%; no scopolamine, 23.9%; P = 0.580). Demographics of the 2 groups were compared; patients who received scopolamine patch were younger (P = 0.001), received a greater amount of intravenous fluids (P = 0.007), and underwent a greater percentage of incontinence procedures (P = 0.048). Otherwise, there were no differences between the groups. Transdermal scopolamine is not a risk factor for acute postoperative urinary retention after pelvic reconstructive procedures.

The efficacy and safety of a novel lipophilic formulation of methimazole for the once daily transdermal treatment of cats with hyperthyroidism.

PubMed

Hill, K E; Gieseg, M A; Kingsbury, D; Lopez-Villalobos, N; Bridges, J; Chambers, P

2011-01-01

Previous studies on transdermal methimazole have used pluronic lecithin organogel as the vehicle. This might not be the most suitable vehicle for a lipophilic drug, such as methimazole. Once daily transdermal administration of a novel lipophilic formulation of methimazole is as safe and effective as oral carbimazole in treating hyperthyroidism in cats. Forty-five client-owned cats diagnosed with hyperthyroidism. Prospective study. Cats with newly diagnosed, untreated hyperthyroidism were treated with carbimazole (5 mg p.o., q12h) or methimazole (10 mg) applied to the inner pinnae q24h. Cats were examined after 0, 1, 4, 8, and 12 weeks of treatment. Clinical signs, body weight, systolic blood pressure, hematologic, serum biochemical and urine parameters, total serum thyroxine concentrations (TT4), and serum methimazole concentrations were recorded. No significant differences between groups were detected at day 0. Both formulations were effective in treating hyperthyroidism. No significant differences were detected in thyroxine concentrations, body weight, blood pressure, heart rate, alkaline phosphatase, alanine aminotransferase, creatinine, urea, and urine specific gravity (USG) between groups. The serum methimazole concentrations correlated poorly with TT4-concentrations in both groups. In this 12-week trial, once daily application of a novel formulation of transdermal methimazole applied to the pinnae was as effective and safe as twice daily oral carbimazole in the treatment of cats with hyperthyroidism. This novel formulation and transdermal application could have practical advantages to some pet owners. Copyright © 2011 by the American College of Veterinary Internal Medicine.

Microdose transdermal estrogen therapy for relief of vulvovaginal symptoms in postmenopausal women.

PubMed

Bachmann, Gloria A; Schaefers, Matthias; Uddin, Alkaz; Utian, Wulf H

2009-01-01

The aim of this study was to investigate the effectiveness of microdose transdermal 17beta-estradiol (E2) therapy in postmenopausal women with moderate to severe vulvovaginal symptoms. This report is based on a subset of 121 women who reported most bothersome moderate or severe vulvovaginal symptoms at baseline, from a previous randomized, double-blind, placebo-controlled, multicenter study of 425 healthy, symptomatic, postmenopausal women. Recruits had experienced at least 7 moderate or severe hot flushes daily for at least 1 week or at least 50 moderate or severe hot flushes per week for at least 1 week. Effects on coprimary efficacy variables have been reported previously. Participants received low-dose transdermal E2 plus levonorgestrel (n = 43; nominal delivery 0.023 mg/d E2/0.0075 mg/d levonorgestrel), microdose E2 (n = 42; nominal delivery 0.014 mg/d), or placebo (n = 36) for 12 weeks. Secondary efficacy variables reported herein include mean change from baseline in vaginal pH and vaginal maturation index, the proportion of women with symptoms of vulvar and vaginal atrophy at baseline and week 12, and the proportion of women with moderate-to-severe symptoms of vulvar and vaginal atrophy. Microdose transdermal E2 treatment was associated with a consistent benefit versus placebo in women with vulvovaginal atrophy. There was a statistically significant difference between both E2 versus placebo for changes in vaginal pH and vaginal maturation index. Microdose transdermal E2 offers a useful addition to the therapeutic armamentarium for postmenopausal women in whom vulvovaginal symptoms are particularly troublesome.

Preliminary Experience with Transdermal Oxybutynin Patches for Hyperhidrosis.

PubMed

Bergón-Sendín, M; Pulido-Pérez, A; Sáez-Martín, L C; Suárez-Fernández, R

2016-12-01

Hyperhidrosis is very common and has a considerable impact on patients' quality of life. While oral oxybutynin is associated with good response rates, adverse effects are common and frequently cause patients to stop treatment. Following the recent launch of oxybutynin in a transdermal patch formulation in Spain, we undertook a preliminary study to assess treatment response and adverse effects in patients with hyperhidrosis. This prospective study of 25 patients treated twice weekly with transdermal oxybutynin patches over 10 weeks assessed treatment response on 2 subjective scales: the Hyperhidrosis Disease Severity Scale (HDSS) and a visual analog scale (VAS) for sweating. Sixty percent of patients showed an improvement in HDSS scores. VAS scores improved in all cases, and 68% of patients achieved a reduction of 3 points or more. Just 2 patients (8%) experienced treatment-related adverse effects (irritant dermatitis at the patch application site in both cases). Although our results are based on a small sample, they suggest that transdermal oxybutynin could be a useful option for the treatment of hyperhidrosis and that it has an excellent safety and tolerability profile. Copyright © 2016 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.

Dermal and transdermal delivery of pharmaceutically relevant macromolecules.

PubMed

Münch, S; Wohlrab, J; Neubert, R H H

2017-10-01

The skin offers an attractive way for dermal and transdermal drug delivery that is why the drug still needs certain qualities to transcend the outermost layer of the skin, the stratum corneum. The requirements are: drugs with a maximum molecular weight of 1kDa, high lipophilicity and a certain polarity. This would restrict the use of a transdermal delivery of macromolecules, which would make the drug more effective in therapeutic administration. Various studies have shown that macromolecules without support do not penetrate the human skin. This effect can be achieved using physical and chemical methods, as well as biological peptides. The most popular physical method is the use of microneedles to create micropores in the skin and release the active agent in different sections. But also, other methods have been tested. Microjets, lasers, electroporation, sonophoresis and iontophoresis are also promising methods to successfully deliver dermal and transdermal macromolecules. Additionally, there are different penetration enhancer groups and biological peptides, which are also considered to be interesting approaches of enabling macromolecules to travel along the skin. All these methods will be described and evaluated in this review article. Copyright © 2017 Elsevier B.V. All rights reserved.

Heat effects on drug delivery across human skin

PubMed Central

Hao, Jinsong; Ghosh, Priyanka; Li, S. Kevin; Newman, Bryan; Kasting, Gerald B.; Raney, Sam G.

2016-01-01

Introduction Exposure to heat can impact the clinical efficacy and/or safety of transdermal and topical drug products. Understanding these heat effects and designing meaningful in vitro and in vivo methods to study them are of significant value to the development and evaluation of drug products dosed to the skin. Areas covered This review provides an overview of the underlying mechanisms and the observed effects of heat on the skin and on transdermal/topical drug delivery, thermoregulation and heat tolerability. The designs of several in vitro and in vivo heat effect studies and their results are reviewed. Expert opinion There is substantial evidence that elevated temperature can increase transdermal/topical drug delivery. However, in vitro and in vivo methods reported in the literature to study heat effects of transdermal/topical drug products have utilized inconsistent study conditions, and in vitro models require better characterization. Appropriate study designs and controls remain to be identified, and further research is warranted to evaluate in vitro-in vivo correlations and the ability of in vitro models to predict in vivo effects. The physicochemical and pharmacological properties of the drug(s) and the drug product, as well as dermal clearance and heat gradients may require careful consideration. PMID:26808472

Piezoelectric control of needle-free transdermal drug delivery.

PubMed

Stachowiak, Jeanne C; von Muhlen, Marcio G; Li, Thomas H; Jalilian, Laleh; Parekh, Sapun H; Fletcher, Daniel A

2007-12-04

Transdermal drug delivery occurs primarily through hypodermic needle injections, which cause pain, require a trained administrator, and may contribute to the spread of disease. With the growing number of pharmaceutical therapies requiring transdermal delivery, an effective, safe, and simple needle-free alternative is needed. We present and characterize a needle-free jet injector that employs a piezoelectric actuator to accelerate a micron-scale stream of fluid (40-130 microm diameter) to velocities sufficient for skin penetration and drug delivery (50-160 m/s). Existing jet injectors, powered by compressed springs and gases, are not widely used due to painful injections and poor reliability in skin penetration depth and dose. In contrast, our device offers electronic control of the actuator expansion rate, resulting in direct control of jet velocity and thus the potential for more precise injections. We apply a simple fluid-dynamic model to predict the device response to actuator expansion. Further, we demonstrate that injection parameters including expelled volume, jet pressure, and penetration depth in soft materials vary with actuator expansion rate, but are highly coupled. Finally, we discuss how electronically-controlled jet injectors may enable the decoupling of injection parameters such as penetration depth and dose, improving the reliability of needle-free transdermal drug delivery.

Quantitative study of electrophoretic and electroosmotic enhancement during alternating current iontophoresis across synthetic membranes.

PubMed

Yan, Guang; Li, S Kevin; Peck, Kendall D; Zhu, Honggang; Higuchi, William I

2004-12-01

One of the primary safety and tolerability limitations of direct current iontophoresis is the potential for electrochemical burns associated with the necessary current densities and/or application times required for effective treatment. Alternating current (AC) transdermal iontophoresis has the potential to eliminate electrochemical burns that are frequently observed during direct current transdermal iontophoresis. Although it has been demonstrated that the intrinsic permeability of skin can be increased by applying low-to-moderate AC voltages, transdermal transport phenomena and enhancement under AC conditions have not been systematically studied and are not well understood. The aim of the present work was to study the fundamental transport mechanisms of square-wave AC iontophoresis using a synthetic membrane system. The model synthetic membrane used was a composite Nuclepore membrane. AC frequencies ranging from 20 to 1000 Hz and AC fields ranging from 0.25 to 0.5 V/membrane were investigated. A charged permeant, tetraethyl ammonium, and a neutral permeant, arabinose, were used. The transport studies showed that flux was enhanced by increasing the AC voltage and decreasing AC frequency. Two theoretical transport models were developed: one is a homogeneous membrane model; the other is a heterogeneous membrane model. Experimental transport data were compared with computer simulations based on these models. Excellent agreement between model predictions and experimental data was observed when the data were compared with the simulations from the heterogeneous membrane model. (c) 2004 Wiley-Liss, Inc. and the American Pharmacists Association

Development of w/o microemulsion for transdermal delivery of iodide ions.

PubMed

Lou, Hao; Qiu, Ni; Crill, Catherine; Helms, Richard; Almoazen, Hassan

2013-03-01

The objective of this study was to develop a water-in-oil (w/o) microemulsion which can be utilized as a transdermal delivery for iodide ions. Several w/o microemulsion formulations were prepared utilizing Span 20, ethanol, Capryol 90®, and water. The selected formulations had 5%, 10%, 15%, 20%, and a maximum of 23% w/w water content. Potassium iodide (KI) was incorporated in all formulations at 5% w/v. Physicochemical characterizations were conducted to evaluate the structure and stability. These studies included: mean droplet size, pH, viscosity, conductivity, and chemical stability tests. In vitro human skin permeation studies were conducted to evaluate the diffusion of the iodide ion through human skin. The w/o microemulsion formulations were stable and compatible with iodide ions with water content ranging from 5% to 23% w/w. The addition of KI influenced the physicochemical properties of microemulsion as compared to blank microemulsion formulations. In vitro human skin permeation studies indicated that selected formulations improved iodide ion diffusion significantly as compared to control (KI solution; P value<0.05). Iodide ions were entrapped within the aqueous core of w/o microemulsion. Span 20, ethanol and Capryol 90 protected the iodide ions against oxidation and formed a stable microemulsion. It is worth to note that according to Hofmeister series, iodide ions tend to lower the interfacial tension between water and oil and consequently enhance overall stability. This work illustrates that microemulsion system can be utilized as a vehicle for the transdermal administration of iodide.

Diffusion profile of macromolecules within and between human skin layers for (trans)dermal drug delivery.

PubMed

Römgens, Anne M; Bader, Dan L; Bouwstra, Joke A; Baaijens, Frank P T; Oomens, Cees W J

2015-10-01

Delivering a drug into and through the skin is of interest as the skin can act as an alternative drug administration route for oral delivery. The development of new delivery methods, such as microneedles, makes it possible to not only deliver small molecules into the skin, which are able to pass the outer layer of the skin in therapeutic amounts, but also macromolecules. To provide insight into the administration of these molecules into the skin, the aim of this study was to assess the transport of macromolecules within and between its various layers. The diffusion coefficients in the epidermis and several locations in the papillary and reticular dermis were determined for fluorescein dextran of 40 and 500 kDa using a combination of fluorescent recovery after photobleaching experiments and finite element analysis. The diffusion coefficient was significantly higher for 40 kDa than 500 kDa dextran, with median values of 23 and 9 µm(2)/s in the dermis, respectively. The values only marginally varied within and between papillary and reticular dermis. For the 40 kDa dextran, the diffusion coefficient in the epidermis was twice as low as in the dermis layers. The adopted method may be used for other macromolecules, which are of interest for dermal and transdermal drug delivery. The knowledge about diffusion in the skin is useful to optimize (trans)dermal drug delivery systems to target specific layers or cells in the human skin. Copyright © 2015 Elsevier Ltd. All rights reserved.

Simple and cost-effective fabrication of solid biodegradable polymer microneedle arrays with adjustable aspect ratio for transdermal drug delivery using acupuncture microneedles

NASA Astrophysics Data System (ADS)

Cha, Kyoung Je; Kim, Taewan; Jea Park, Sung; Kim, Dong Sung

2014-11-01

Polymer microneedle arrays (MNAs) have received much attention for their use in transdermal drug delivery and microneedle therapy systems due to the advantages they offer, such as low cost, good mechanical properties, and a versatile choice of materials. Here, we present a simple and cost-effective method for the fabrication of a biodegradable polymer MNA in which the aspect ratio of each microneedle is adjustable using commercially available acupuncture microneedles. In our process, a master template with acupuncture microneedles, whose shape will be the final MNA, was carefully prepared by fixing them onto a plastic substrate with selectively drilled holes which, in turn, determine the aspect ratios of the microneedles. A polylactic acid (PLA; a biodegradable polymer) MNA was fabricated by a micromolding process with a polydimethylsiloxane (PDMS) mold containing the cavity of the microneedles, which was obtained by the PDMS replica molding against the master template. The mechanical force and degradation behavior of the replicated PLA MNA were characterized with the help of a compression test and an accelerated degradation test, respectively. Finally, the transdermal drug delivery performance of the PLA MNA was successfully simulated by two different methods of penetration and staining, using the skin of a pig cadaver. These results indicated that the proposed method can be effectively used for the fabrication of polymer MNAs which can be used in various microneedle applications.

Enhanced Transdermal Delivery by Combined Application of Dissolving Microneedle Patch on Serum-Treated Skin.

PubMed

Kim, Suyong; Dangol, Manita; Kang, Geonwoo; Lahiji, Shayan F; Yang, Huisuk; Jang, Mingyu; Ma, Yonghao; Li, Chengguo; Lee, Sang Gon; Kim, Chang Hyun; Choi, Young Wook; Kim, So Jeong; Ryu, Ja Hyun; Baek, Ji Hwoon; Koh, Jaesuk; Jung, Hyungil

2017-06-05

Dissolving microneedle (DMN), a transdermal drug delivery system in which drugs are encapsulated in a biodegradable polymeric microstructure, is designed to dissolve after skin penetration and release the encapsulated drugs into the body. However, because of limited loading capacity of drugs within microsized structures, only a small dosage can be delivered, which is often insufficient for patients. We propose a novel DMN application that combines topical and DMN application simultaneously to improve skin permeation efficiency. Drugs in pretreated topical formulation and encapsulated drugs in DMN patch are delivered into the skin through microchannels created by DMN application, thus greatly increasing the delivered dose. We used 4-n-butylresorcinol to treat human hyperpigmentation and found that sequential application of serum formulation and DMNs was successful. In skin distribution experiments using Alexa Fluor 488 and 568 dyes as model drugs, we confirmed that the pretreated serum formulation was delivered into the skin through microchannels created by the DMNs. In vitro skin permeation and retention experiments confirmed that this novel combined application delivered more 4-n-butylresorcinol into the skin than traditional DMN-only and serum-only applications. Moreover, this combined application showed a higher efficacy in reducing patients' melanin index and hyperpigmented regions compared with the serum-only application. As combined application of DMNs on serum-treated skin can overcome both dose limitations and safety concerns, this novel approach can advance developments in transdermal drug delivery.

Diclofenac Loaded Lipid Nanovesicles Prepared by Double Solvent Displacement for Skin Drug Delivery.

PubMed

Sala, M; Locher, F; Bonvallet, M; Agusti, G; Elaissari, A; Fessi, H

2017-09-01

Herein, we detail a promising strategy of nanovesicle preparation based on control of phospholipid self-assembly: the Double Solvent Displacement. A systematic study was conducted and diclofenac as drug model encapsulated. In vitro skin studies were carried out to identify better formulation for dermal/transdermal delivery. This method consists in two solvent displacements. The first one, made in a free water environment, has allowed triggering a phospholipid pre-organization. The second one, based on the diffusion into an aqueous phase has led to liposome formation. Homogeneous liposomes were obtained with a size close to 100 nm and a negative zeta potential around -40 mV. After incorporation of acid diclofenac, we obtained nanoliposomes with a size between 101 ± 45 and 133 ± 66 nm, a zeta potential between 34 ± 2 and 49 ± 3 mV, and the encapsulation efficiency (EE%) was between 58 ± 3 and 87 ± 5%. In vitro permeation studies showed that formulation with higher EE% dispayed the higher transdermal passage (18,4% of the applied dose) especially targeting dermis and beyond. Our results suggest that our diclofenac loaded lipid vesicles have significant potential as transdermal skin drug delivery system. Here, we produced cost effective lipid nanovesicles in a merely manner according to a process easily transposable to industrial scale. Graphical Abstract ᅟ.

Preparation, optimization, and evaluation of Zaltoprofen-loaded microemulsion and microemulsion-based gel for transdermal delivery.

PubMed

Mishra, Ratnesh; Prabhavalkar, Kedar S; Bhatt, Lokesh Kumar

2016-12-01

Zaltoprofen, a non-steroidal anti-inflammatory drug, has potent inhibitory action against nociceptive responses. However, gastrointestinal ulcer accompanied with anemia due to the bleeding are most cited side effects associated with it. Due to this, administration of Zaltoprofen is not suitable for individuals with gastric ulcer. Thus, there is unmet need to develop an alternative delivery system that will be easy to administer and can avoid ulcerogenic side effects associated with it. Present study was aimed to prepare and evaluate microemulsion (ME) and microemulsion-based gel formulation of Zaltoprofen for transdermal delivery. Pseudo-ternary phase diagrams were utilized to prepare ME formulations. Effect of surfactant and co-surfactant mass ratio on the ME formation and permeation of ME were evaluated and formulation was optimized. Permeation studies were performed using excised pigskin was studied. Efficacy of optimized formulations was evaluated in rat model of inflammation and pain. Composition of optimized formulation was 1% (w/w) Zaltoprofen, 20% (w/w) Capryol 90, 50% (w/w) Smix (2:1, Cremophor RH 40 and Transcutol P). Optimized formulation showed globule size of 22.11 nm, polydispersity index of 0.251 and zeta potential of -11.4 mV. ME gel was found safe in skin irritation study. Significant analgesic activity and anti-inflammatory activity of ME gel was observed in hot plate test and rat paw edema test, respectively. In conclusion, results of present study suggest that ME could be a promising formulation for transdermal administration of Zaltoprofen.

Microprocessor controlled transdermal drug delivery.

PubMed

Subramony, J Anand; Sharma, Ashutosh; Phipps, J B

2006-07-06

Transdermal drug delivery via iontophoresis is reviewed with special focus on the delivery of lidocaine for local anesthesia and fentanyl for patient controlled acute therapy such as postoperative pain. The role of the microprocessor controller in achieving dosimetry, alternating/reverse polarity, pre-programmed, and sensor-based delivery is highlighted. Unique features such as the use of tactile signaling, telemetry control, and pulsatile waveforms in iontophoretic drug delivery are described briefly.

Improvement in bioavailability of transdermally applied flurbiprofen using tulsi (Ocimum sanctum) and turpentine oil.

PubMed

Charoo, Naseem Ahmad; Shamsher, Areeg Anwer Ali; Kohli, Kanchan; Pillai, Krishna; Rahman, Ziyaur

2008-09-01

Penetration enhancing potential of tulsi and turpentine oil on transdermal delivery of flurbiprofen, a potent non-steroidal anti-inflammatory agent, was investigated. The transdermal permeation rate of flurbiprofen across the rat abdominal skin from binary solvent mixture composition of propylene glycol (PG):isopropyl alcohol (IPA) (30:70%, v/v) was 98.88 microg/cm(2)/h, significantly higher than other binary solvent mixtures. The corresponding steady state plasma concentration, 0.71 microg/ml, was much lower than required steady state plasma concentration of 3-5 microg/ml. Hence influence of tulsi and turpentine oil in the optimized binary solvent mixture along with the increased drug load on the flurbiprofen permeation was evaluated. The magnitude of the flux enhancement factor with turpentine oil and tulsi oil was 2.4 and 2.0 respectively at 5% (v/v) concentration beyond which there was no significant increase in the flux. Addition of 2% (w/v) hydroxypropyl methylcellulose (HPMC), as a thickening agent, resulted in desired consistency for the fabrication of patch with insignificant effect on permeation rate of flurbiprofen. The reservoir type of transdermal patch formulation, fabricated by encapsulating the flurbiprofen reservoir solution within a shallow compartment moulded from polyester backing film and microporous ethyl vinyl acetate membrane, did not modulate the skin permeation of flurbiprofen through rat skin in case of turpentine formulations whereas flux of formulations with tulsi oil was significantly altered. The influence of penetration enhancer and solvents on the anatomical structure of the rat skin was studied. Enhancement properties exhibited by turpentine oil and tulsi oil in optimized binary solvent mixture were superior as compared to solvent treated and normal control groups with negligible skin irritation. The fabricated transdermal patches were found to be stable. The bioavailability of flurbiprofen with reference to orally administered flurbiprofen in albino rats was found to increase by 2.97, 3.80 and 5.56 times with transdermal patch formulation without enhancer, tulsi and turpentine oil formulations, respectively. The results were confirmed by pharmacodynamic studies in rat edema inflammation model.

Induction of a robust immune response against avian influenza virus following transdermal inoculation with H5-DNA vaccine formulated in modified dendrimer-based delivery system in mouse model.

PubMed

Bahadoran, Azadeh; Ebrahimi, Mehdi; Yeap, Swee Keong; Safi, Nikoo; Moeini, Hassan; Hair-Bejo, Mohd; Hussein, Mohd Zobir; Omar, Abdul Rahman

2017-01-01

This study was aimed to evaluate the immunogenicity of recombinant plasmid deoxyribonucleic acid (DNA), pBud-H5-green fluorescent protein (GFP)-interferon-regulatory factor (IRF)3 following delivery using polyamidoamine (PAMAM) dendrimer and transactivator of transcription (TAT)-conjugated PAMAM dendrimer as well as the effect of IRF3 as the genetic adjuvant. BALB/c mice were vaccinated transdermally with pBud-H5-GFP, PAMAM/pBud-H5-GFP, TAT-PAMAM/pBud-H5-GFP, and TAT-PAMAM/pBud-H5-GFP-IRF3. The expression analysis of H5 gene from the blood by using quantitative real-time reverse transcriptase polymerase chain reaction confirmed the ability of PAMAM dendrimer as a carrier for gene delivery, as well as the ability of TAT peptide to enhance the delivery efficiency of PAMAM dendrimer. Mice immunized with modified PAMAM by TAT peptide showed higher hemagglutination inhibition titer, and larger CD3 + /CD4 + T cells and CD3 + /CD8 + T cells population, as well as the production of cytokines, namely, interferon (IFN)-γ, interleukin (IL)-2, IL-15, IL-12, IL-6, and tumor necrosis factor-α compared with those immunized with native PAMAM. These results suggest that the function of TAT peptide as a cell-penetrating peptide is able to enhance the gene delivery, which results in rapid distribution of H5 in the tissues of the immunized mice. Furthermore, pBud-H5-GFP co-expressing IRF3 as a genetic adjuvant demonstrated the highest hemagglutination inhibition titer besides larger CD3 + /CD4 + and CD3 + /CD8 + T cells population, and strong Th1-like cytokine responses among all the systems tested. In conclusion, TAT-PAMAM dendrimer-based delivery system with IRF3 as a genetic adjuvant is an attractive transdermal DNA vaccine delivery system utilized to evaluate the efficacy of the developed DNA vaccine in inducing protection during challenge with virulent H5N1 virus.

Automicroneedle therapy system combined with topical tretinoin shows better regenerative effects compared with each individual treatment.

PubMed

Kim, J H; Park, H Y; Jung, M; Choi, E H

2013-01-01

Regenerative therapy is a relatively new dermatological field. However, the currently available topical agents are unsuitable for transdermal drug delivery because of their high molecular weight and low liposolubility. Therefore, a more effective transdermal drug delivery system is needed in order to achieve better therapeutic effects with these agents. A recently introduced microneedle therapy system (MTS), which is a mechanical method for making minute holes in the skin, improves transdermal delivery. A recently developed refinement of this technique, the automicroneedle therapy system (AMTS), has several advantages over the traditional MTS, as it can achieve consistent results because of its automatic punching method. To evaluate the cutaneous effects of an AMTS in combination with topical tretinoin. Twelve hairless mice were divided into two groups, and the dorsal skin of each mouse was marked down the centre. The first group was treated with the AMTS plus 0.025% tretinoin on one side of the back, and with 0.025% tretinoin only on the other side. The other group was treated with the AMTS and vehicle on one side, while the other side was left untreated. The effects on cutaneous regeneration and the treatment side-effects were evaluated by functional assessment including transepidermal water loss and skin hydration, and by histopathology including epidermal and dermal thickness, and density of collagen fibres. Western blotting and real-time reverse transcriptase PCR were also performed to determine protein and mRNA expression of procollagen type 1 and matrix metalloproteinase-13. Compared with the individual treatments (the AMTS alone or tretinoin alone) the combination of tretinoin plus the AMTS produced greater dermal regeneration as a result of increased proliferation of collagen fibres. This combination therapy did not result in treatment-related adverse effects. An AMTS combined with topical tretinoin is a safe and effective method for skin regeneration, which works by increasing collagen production, and might be a new therapeutic option for regenerative therapy. © The Author(s). CED © 2012 British Association of Dermatologists.

In vitro-ex vivo correlations between a cell-laden hydrogel and mucosal tissue for screening composite delivery systems.

PubMed

Blakney, Anna K; Little, Adam B; Jiang, Yonghou; Woodrow, Kim A

2016-11-01

Composite delivery systems where drugs are electrospun in different layers and vary the drug stacking-order are posited to affect bioavailability. We evaluated how the formulation characteristics of both burst- and sustained-release electrospun fibers containing three physicochemically diverse drugs: dapivirine (DPV), maraviroc (MVC) and tenofovir (TFV) affect in vitro and ex vivo release. We developed a poly(hydroxyethyl methacrylate) (pHEMA) hydrogel release platform for the rapid, inexpensive in vitro evaluation of burst- and sustained-release topical or dermal drug delivery systems with varying microarchitecture. We investigated properties of the hydrogel that could recapitulate ex vivo release into nonhuman primate vaginal tissue. Using a dimethyl sulfoxide extraction protocol and high-performance liquid chromatography analysis, we achieved >93% recovery from the hydrogels and >88% recovery from tissue explants for all three drugs. We found that DPV loading, but not stacking order (layers of fiber containing a single drug) or microarchitecture (layers with isolated drug compared to all drugs in the same layer) impacted the burst release in vitro and ex vivo. Our burst-release formulations showed a correlation for DPV accumulation between the hydrogel and tissue (R 2 =   0.80), but the correlation was not significant for MVC or TFV. For the sustained-release formulations, the PLGA/PCL content did not affect TFV release in vitro or ex vivo. Incorporation of cells into the hydrogel matrix improved the correlation between hydrogel and tissue explant release for TFV. We expect that this hydrogel-tissue mimic may be a promising preclinical model to evaluate topical or transdermal drug delivery systems with complex microarchitectures.

Separate and Combined Effects of Very Low Nicotine Cigarettes and Nicotine Replacement in Smokers with Schizophrenia and Controls

PubMed Central

Rohsenow, Damaris J.; Kaplan, Gary B.; Swift, Robert M.; AhnAllen, Christopher G.

2013-01-01

Introduction: The prevalence of smoking among people with schizophrenia in the United States is about 3 times that of the general population. Novel approaches are needed to reduce rates of smoking-related morbidity and mortality among these smokers. Methods: This study used a within-subjects design to investigate the separate and combined effects of sensorimotor replacement for smoking (very low nicotine content [VLNC] cigarettes vs. no cigarettes) and transdermal nicotine replacement (42 mg nicotine [NIC] vs. placebo [PLA] patches) in smokers with schizophrenia (SS; n = 30) and control smokers without psychiatric illness (CS; n = 26). Each session contained a 5-hr controlled administration period in which participants underwent the following conditions, in counterbalanced order: VLNC + NIC, VLNC + PLA, no cigarettes + NIC, no cigarettes + PLA, usual-brand cigarettes + no patches. Next, participants completed measures of cigarette craving, nicotine withdrawal, smoking habit withdrawal, and cigarette subjective effects, followed by a 90-min period of ad libitum usual-brand smoking. Results: Smoking VLNC cigarettes during the controlled administration periods reduced cigarette craving, nicotine withdrawal symptoms, habit withdrawal symptoms, and usual-brand smoking in SS and CS relative to the no cigarette conditions. VLNC cigarettes were well accepted by both groups and did not affect psychiatric symptom levels in SS. Transdermal nicotine significantly reduced cigarette craving but did not affect usual-brand smoking. Conclusions: These findings suggest that reducing the nicotine content of cigarettes to nonaddictive levels may be a promising approach for reducing nicotine dependence among people with schizophrenia. PMID:22517190

Transdermal Alcohol Concentration Data Collected During a Contingency Management Program to Reduce At-Risk Drinking

PubMed Central

Dougherty, Donald M.; Karns, Tara E.; Mullen, Jillian; Liang, Yuanyuan; Lake, Sarah L.; Roache, John D.; Hill-Kapturczak, Nathalie

2017-01-01

Background Recently, we demonstrated that transdermal alcohol monitors could be used in a contingency management procedure to reduce problematic drinking; the frequency of self-reported heavy/moderate drinking days decreased and days of no to low drinking increased. These effects persisted for three months after intervention. In the current report, we used the transdermal alcohol concentration (TAC) data collected prior to and during the contingency management procedure to provide a detailed characterization of objectively measured alcohol use. Methods Drinkers (n = 80) who frequently engaged in risky drinking behaviors were recruited and participated in three study phases: a 4-week Observation phase where participants drank as usual; a 12-week Contingency Management phase where participants received $50 each week when TAC did not exceed 0.03 g/dl; and a 3-month Follow-up phase where self-reported alcohol consumption was monitored. Transdermal monitors were worn during the first two phases, where each week they recived $105 for visiting the clinic and wearing the monitor. Outcomes focused on using TAC data to objectively characterize drinking and were used to classify drinking levels as either no, low, moderate, or heavy drinking as a function of weeks and day of week. Results Compared to the Observation phase, TAC data indicated that episodes of heavy drinking days during the Contingency Management phase were reduced and episodes of no drinking and low to moderate drinking increased. Conclusions These results lend further support for linking transdermal alcohol monitoring with contingency management interventions. Collectively, studies to date indicate that interventions like these may be useful for both abstinence and moderation-based programs. PMID:25582388

Development of Tat-Conjugated Dendrimer for Transdermal DNA Vaccine Delivery.

PubMed

Bahadoran, Azadeh; Moeini, Hassan; Bejo, Mohd Hair; Hussein, Mohd Zobir; Omar, Abdul Rahman

In order to enhance cellular uptake and to facilitate transdermal delivery of DNA vaccine, polyamidoamine (PAMAM) dendrimers conjugated with HIV transactivator of transcription (TAT) was developed. First, the plasmid DNA (pIRES-H5/GFP) nanoparticle was formulated using PAMAM dendrimer and TAT peptide and then characterized for surface charge, particle size, DNA encapsulation and protection of the pIRES-H5/GFP DNA plasmid to enzymatic digestion. Subsequently, the potency of the TAT-conjugated dendrimer for gene delivery was evaluated through in vitro transfection into Vero cells followed by gene expression analysis including western blotting, fluorescent microscopy and PCR. The effect of the TAT peptide on cellular uptake of DNA vaccine was studied by qRT-PCR and flow cytometry. Finally, the ability of TAT-conjugated PAMAM dendrimer for transdermal delivery of the DNA plasmid was assessed through artificial membranes followed by qRT-PCR and flow cytometry. TAT-conjugated PAMAM dendrimer showed the ability to form a compact and nanometre-sized polyplexes with the plasmid DNA, having the size range of 105 to 115 nm and a positive charge of +42 to +45 mV over the N/P ratio of 6:1(+/-).  In vitro transfection analysis into Vero cells confirms the high potency of TAT-conjugated PAMAM dendrimer to enhance the cellular uptake of DNA vaccine.  The permeability value assay through artificial membranes reveals that TAT-conjugated PAMAM has more capacity for transdermal delivery of the DNA compared to unmodified PAMAM dendrimer (P<0.05). The findings of this study suggest that TAT-conjugated PAMAM dendrimer is a promising non-viral vector for transdermal use.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Effects of oral and transdermal estrogen on IGF1, IGFBP3, IGFBP1, serum lipids, and glucose in patients with hypopituitarism during GH treatment: a randomized study.

PubMed

Isotton, Ana Lúcia; Wender, Maria Celeste Osorio; Casagrande, Alessandra; Rollin, Guilherme; Czepielewski, Mauro Antônio

2012-02-01

To evaluate the effects of oral estradiol and transdermal 17β-estradiol on serum concentrations of IGF1 and its binding proteins in women with hypopituitarism. Prospective, comparative study. Eleven patients with hypopituitarism were randomly allocated to receive 2 mg oral estradiol (n=6) or 50 μg/day of transdermal 17β-estradiol (n=5) for 3 months. The oral estrogen group showed a significant reduction in IGF1 levels (mean: 42.7%±41.4, P=0.046); no difference was observed in the transdermal estrogen group. There was a significant increase in IGFBP1 levels (mean: 170.2%±230.9, P=0.028) in the oral group, but not in the transdermal group. There was no significant difference within either group in terms of median IGFBP3 levels. In relation to lipid profiles, there was a significant increase in mean high-density lipoprotein cholesterol levels in the oral group after 3 months of treatment, (27.8±9.3, P=0.003). We found no differences in the anthropometric measurements, blood pressure, heart rate, glucose, insulin, C-peptide, or the homeostasis model assessment index after treatment. Our preliminary data indicate that different estrogen administration routes can influence IGF1 and IGFBP1 levels. These findings in patients with hypopituitarism have an impact on their response to treatment with GH, since patients receiving oral estrogen require increased GH dosage. These results suggest that oral estrogens may reduce the beneficial effects of GH replacement on fat and protein metabolism, body composition, and quality of life.

Quantifying alcohol consumption: Self-report, transdermal assessment, and prediction of dependence symptoms.

PubMed

Simons, Jeffrey S; Wills, Thomas A; Emery, Noah N; Marks, Russell M

2015-11-01

Research on alcohol use depends heavily on the validity of self-reported drinking. The present paper presents data from 647 days of self-monitoring with a transdermal alcohol sensor by 60 young adults. We utilized a biochemical measure, transdermal alcohol assessment with the WrisTAS, to examine the convergent validity of three approaches to collecting daily self-report drinking data: experience sampling, daily morning reports of the previous night, and 1-week timeline follow-back (TLFB) assessments. We tested associations between three pharmacokinetic indices (peak concentration, area under the curve (AUC), and time to reach peak concentration) derived from the transdermal alcohol signal and within- and between- person variation in alcohol dependence symptoms. The WrisTAS data corroborated 85.74% of self-reported drinking days based on the experience sampling data. The TLFB assessment and combined experience sampling and morning reports agreed on 87.27% of drinking days. Drinks per drinking day did not vary as a function of wearing or not wearing the sensor; this indicates that participants provided consistent reports of their drinking regardless of biochemical verification. In respect to self-reported alcohol dependence symptoms, the AUC of the WrisTAS alcohol signal was associated with dependence symptoms at both the within- and between- person level. Furthermore, alcohol dependence symptoms at baseline predicted drinking episodes characterized in biochemical data by both higher peak alcohol concentration and faster time to reach peak concentration. The results support the validity of self-report alcohol data, provide empirical data useful for optimal design of daily process sampling, and provide an initial demonstration of the use of transdermal alcohol assessment to characterize drinking dynamics associated with risk for alcohol dependence. Copyright © 2015 Elsevier Ltd. All rights reserved.

Safety and efficacy of transdermal buprenorphine versus oral tramadol for the treatment of post-operative pain following surgery for fracture neck of femur: A prospective, randomised clinical study.

PubMed

Desai, Sameer N; Badiger, Santhoshi V; Tokur, Shreesha B; Naik, Prashanth A

2017-03-01

Transdermal buprenorphine, which is used in chronic pain management, has rarely been studied for use in acute pain management. The aim of this study was to compare the safety and efficacy of transdermal buprenorphine patch to oral tramadol for post-operative analgesia, following proximal femur surgeries. Fifty adult patients undergoing surgery for hip fracture under spinal anaesthesia were included in this study. One group (Group TDB) received transdermal buprenorphine 10 mcg/h patch applied a day before the surgery and other group received oral tramadol 50 mg three times a day for analgesia (Group OT). They were allowed to take diclofenac and paracetamol tablets for rescue analgesia. Pain scores at rest, on movement, rescue analgesic requirement and side effects were compared between the groups over 7 days. Chi-square and independent sample t -test were used for categorical and continuous variables, respectively. Resting pain scores and pain on movement were significantly lower in TDB Group on all 7 days starting from 24 h post-operatively. Rescue analgesic requirement was significantly lower in TDB Group compared to OT Group. All the patients needed rescue analgesic in OT Group whereas 68% of the patients needed the same in TDB Group. Incidence of vomiting was less and satisfaction scores were much higher in TDB Group as compared to OT Group (79% vs. 66%, P < 0.001). Transdermal buprenorphine can be safely used for post-operative analgesia and is more efficacious in reducing post-operative pain after 24 hours, with fewer side effects when compared to oral tramadol.

Transdermal alcohol concentration data collected during a contingency management program to reduce at-risk drinking.

PubMed

Dougherty, Donald M; Karns, Tara E; Mullen, Jillian; Liang, Yuanyuan; Lake, Sarah L; Roache, John D; Hill-Kapturczak, Nathalie

2015-03-01

Recently, we demonstrated that transdermal alcohol monitors could be used in a contingency management procedure to reduce problematic drinking; the frequency of self-reported heavy/moderate drinking days decreased and days of no to low drinking increased. These effects persisted for three months after intervention. In the current report, we used the transdermal alcohol concentration (TAC) data collected prior to and during the contingency management procedure to provide a detailed characterization of objectively measured alcohol use. Drinkers (n=80) who frequently engaged in risky drinking behaviors were recruited and participated in three study phases: a 4-week Observation phase where participants drank as usual; a 12-week Contingency Management phase where participants received $50 each week when TAC did not exceed 0.03g/dl; and a 3-month Follow-up phase where self-reported alcohol consumption was monitored. Transdermal monitors were worn during the first two phases, where each week they recived $105 for visiting the clinic and wearing the monitor. Outcomes focused on using TAC data to objectively characterize drinking and were used to classify drinking levels as either no, low, moderate, or heavy drinking as a function of weeks and day of week. Compared to the Observation phase, TAC data indicated that episodes of heavy drinking days during the Contingency Management phase were reduced and episodes of no drinking and low to moderate drinking increased. These results lend further support for linking transdermal alcohol monitoring with contingency management interventions. Collectively, studies to date indicate that interventions like these may be useful for both abstinence and moderation-based programs. Copyright © 2015. Published by Elsevier Ireland Ltd.

The Effect of Ultralow-Dose Transdermal Estradiol on Urinary Incontinence in Postmenopausal Women

PubMed Central

Waetjen, L. Elaine; Brown, Jeanette S.; Vittinghoff, Eric; Ensrud, Kristine E.; Pinkerton, JoAnn; Wallace, Robert; Macer, Judith L.; Grady, Deborah

2006-01-01

OBJECTIVE To estimate the effect of 2 years of treatment with ultralow-dose transdermal estradiol (E2) on incontinence in postmenopausal women. METHODS Ultra Low Dose Transdermal estRogen Assessment (ULTRA) was a multicenter, randomized, double-blinded, placebo-controlled trial of unopposed ultralow-dose (0.014 mg/d) transdermal E2 for prevention of osteoporosis in 417 postmenopausal women aged 60 to 80 years. Frequency of incontinence episodes was assessed at baseline and after 4 months and 2 years of treatment using a self-reported questionnaire. We used an intention-to-treat analysis to compare change in incontinence frequency, improved (decreased 2 or more episodes per week), unchanged (increased or decreased no more than 1 episode per week), or worsened (increased 2 or more episodes per week) between the E2 and placebo groups among women with and without at least weekly incontinence at baseline. RESULTS At baseline, the prevalence of at least weekly incontinence was similar between E2 and placebo groups (43%). After 2 years, there was no difference between groups in the proportions of women with incontinence at baseline whose incontinence improved, worsened, or was unchanged. The odds ratio for worsening incontinence in the E2 compared with placebo group was 1.35 (95% confidence interval 0.75–2.42. In women without incontinence at baseline, the odds of developing at least weekly incontinence after 2 years in the E2 compared with placebo group was not significant (odds ratio 1.2, 95% confidence interval 0.7–2.2). CONCLUSION Two years of treatment with unopposed ultralow-dose transdermal E2 did not substantially change the frequency of incontinence symptoms or alter the risk of developing at least weekly incontinence. PMID:16260511

Quantifying alcohol consumption: Self-report, transdermal assessment, and prediction of dependence symptoms☆

PubMed Central

Simons, Jeffrey S.; Wills, Thomas A.; Emery, Noah N.; Marks, Russell M.

2015-01-01

Research on alcohol use depends heavily on the validity of self-reported drinking. The present paper presents data from 647 days of self-monitoring with a transdermal alcohol sensor by 60 young adults. We utilized a bio chemical measure, transdermal alcohol assessment with the WrisTAS, to examine the convergent validity of three approaches to collecting daily self-report drinking data: experience sampling, daily morning reports of the previous night, and 1-week timeline follow-back (TLFB) assessments. We tested associations between three pharmacokinetic indices (peak concentration, area under the curve (AUC), and time to reach peak concentration) derived from the transdermal alcohol signal and within- and between-person variation in alcohol dependence symptoms. The WrisTAS data corroborated 85.74% of self-reported drinking days based on the experience sampling data. The TLFB assessment and combined experience sampling and morning reports agreed on 87.27% of drinking days. Drinks per drinking day did not vary as a function of wearing or not wearing the sensor; this indicates that participants provided consistent reports of their drinking regardless of biochemical verification. In respect to self-reported alcohol dependence symptoms, the AUC of the WrisTAS alcohol signal was associated with dependence symptoms at both the within- and between-person level. Furthermore, alcohol dependence symptoms at baseline predicted drinking episodes characterized in biochemical data by both higher peak alcohol concentration and faster time to reach peak concentration. The results support the validity of self-report alcohol data, provide empirical data useful for optimal design of daily process sampling, and provide an initial demon stration of the use of transdermal alcohol assessment to characterize drinking dynamics associated with risk for alcohol dependence. PMID:26160523

Programmable carbon nanotube membrane-based transdermal nicotine delivery with microdialysis validation assay.

PubMed

Gulati, Gaurav Kumar; Chen, Tao; Hinds, Bruce Jackson

2017-01-01

To evaluate the performance of switchable carbon nanotubes (CNT) membrane devices for transdermal nicotine delivery, we have developed an in-vitro microdialysis method that allow us to detect variable transdermal fluxes of nicotine through CNT devices and can be applied directly to in-vivo studies. Microdialysis membranes were placed beneath the porcine skin and its nicotine levels increased 6-8 times when the CNT membrane on skin was turned from OFF to ON state by application of bias. Fluxes in the ON state were approximately 3 times that of commercial nicotine patches and switching times were less than two hours, thus suggesting the improved therapeutic potential of our device. Blue tooth enabled CNT devices that can be programmed by smartphone and coupled with remote counseling application for enhanced smoking cessation treatments. Copyright © 2016. Published by Elsevier Inc.

Drug profile: transdermal rivastigmine patch in the treatment of Alzheimer disease.

PubMed

Emre, Murat; Bernabei, Roberto; Blesa, Rafael; Bullock, Roger; Cunha, Luis; Daniëls, Hugo; Dziadulewicz, Edward; Förstl, Hans; Frölich, Lutz; Gabryelewicz, Tomasz; Levin, Oleg; Lindesay, James; Martínez-Lage, Pablo; Monsch, Andreas; Tsolaki, Magda; van Laar, Teus

2010-08-01

Cholinesterase inhibitors constitute one of the mainstays of treatment of Alzheimer disease (AD). Gastrointestinal side effects, difficulty accessing therapeutic doses and poor patient compliance have been identified as barriers to effective treatment with these substances. The rivastigmine transdermal patch provides continuous delivery of drug through the skin into the bloodstream, avoiding the fluctuations in plasma concentration associated with oral administration. This pharmacokinetic profile is associated with reduced side effects, resulting in easier access to expected target doses. These benefits, along with other practical advantages of the transdermal patch, may contribute to enhanced patient compliance. Here, we present a review of the current literature on rivastigmine patch, and offer advice based on our own collective clinical experience. Rivastigmine patch provides an efficient option for managing patients with AD, to be considered among the first line therapies for the disease.

Enhancement of transdermal delivery of ibuprofen using microemulsion vehicle.

PubMed

Hu, Liandong; Hu, Qiaofeng; Yang, Jianxue

2014-10-01

The objective of this study was to find a stable microemulsion vehicle for transdermal delivery of ibuprofen to improve the skin permeability. Microemulsion was prepared using different sorts of oils, surfactants and co-surfactants. Pseudo-ternary phase diagrams were used to evaluate the microemulsion domain. The effects of oleic acid and surfactant mixture on skin permeation of ibuprofen were evaluated with excised skins. The optimum formulation F3 consisting of 6% oleic acid, 30% Cremophor RH40/Transcutol P (2:1, w/w) and 59% water phase, showed a high permeation rate of 42.98 µg/cm(2)/hr. The mean droplet size of microemulsion was about 43 nm and no skin irritation signs were observed on the skin of rabbits. These results indicated that this novel microemulsion is a useful formulation for the transdermal delivery of ibuprofen.

An Exploratory Trial of Transdermal Nicotine for Aggression and Irritability in Adults with Autism Spectrum Disorder.

PubMed

Lewis, Alan S; van Schalkwyk, Gerrit Ian; Lopez, Mayra Ortiz; Volkmar, Fred R; Picciotto, Marina R; Sukhodolsky, Denis G

2018-03-13

Nicotinic acetylcholine receptors (nAChRs), particularly the α7 nAChR, are implicated in the pathophysiology of both autism spectrum disorder (ASD) and aggressive behavior. We explored the feasibility, tolerability, and preliminary efficacy of targeting nAChRs using transdermal nicotine to reduce aggressive symptoms in adults with ASD. Eight subjects were randomized in a double-blind crossover trial of 7 mg transdermal nicotine or placebo, each for 1 week. All participants tolerated nicotine treatment well. Five subjects contributed data to the primary outcome, Aberrant Behavior Checklist-Irritability (ABC-I) subscale change from baseline, which was improved by nicotine compared to placebo. Sleep ratings were also improved by nicotine and correlated with ABC-I improvement. These findings support further investigation of nAChR agonists for aggression and sleep in ASD.

Comparison of abuse, suspected suicidal intent, and fatalities related to the 7-day buprenorphine transdermal patch versus other opioid analgesics in the National Poison Data System.

PubMed

Coplan, Paul M; Sessler, Nelson E; Harikrishnan, Venkatesh; Singh, Richa; Perkel, Charles

2017-01-01

Prescription opioid related abuse, suicide and death are significant public health problems. This study compares rates of poison center calls categorized as intentional abuse, suspected suicidal intent or fatality for the 7-day buprenorphine transdermal system/patch (BTDS) with other extended-release and long-acting (ER/LA) opioids indicated for chronic pain. Retrospective 24-month cohort study using National Poison Data System data from July 2012 through June 2014. BTDS was introduced in the United States in January 2011. Numbers and rates of calls of intentional abuse, suspected suicidal intent and fatalities were evaluated for BTDS, ER morphine, ER oxycodone, fentanyl patch, ER oxymorphone and methadone tablets/capsules, using prescription adjustment to account for community availability. Rate ratios (RR) and 95% confidence intervals (CI) were calculated. Absolute numbers and prescription-adjusted rates of intentional abuse and suspected suicidal intent with BTDS were significantly lower (p < .0001) than for all other ER/LA opioid analgesics examined. No fatalities associated with BTDS exposure were reported. This post-marketing evaluation of BTDS indicates infrequent poison center calls for intentional abuse and suspected suicidal intent events, suggesting lower rates of these risks with BTDS compared to other ER/LA opioids.

Microemulsion for simultaneous transdermal delivery of benzocaine and indomethacin: in vitro and in vivo evaluation.

PubMed

El Maghraby, Gamal M; Arafa, Mona F; Osman, Mohamed A

2014-12-01

This study investigated simultaneous transdermal delivery of indomethacin and benzocaine from microemulsion. Eucalyptus oil based microemulsion was used with Tween 80 and ethanol being employed as surfactant and cosurfactant, respectively. A microemulsion formulation comprising eucalyptus oil, polyoxyethylene sorbitan momooleate (Tween 80), ethanol and water (20:30:30:20) was selected. Indomethacin (1% w/w) and benzocaine (20% w/w) were incorporated separately or combined into this formulation before in vitro and in vivo evaluation. Application of indomethacin microemulsion enhanced the transdermal flux and reduced the lag time compared to saturated aqueous control. The same trend was evident for benzocaine microemulsion. Simultaneous application of the two drugs in microemulsion provided similar enhancement pattern. The in vivo evaluation employed the pinprick method and revealed rapid anesthesia after application of benzocaine microemulsion with the onset being 10 min and the action lasting for 50 min. For indomethacin microemulsion, the analgesic effect was recorded after 34.5 min and lasted for 70.5 min. Simultaneous application of benzocaine and indomethacin provided synergistic effect. The onset of action was achieved after 10 min and lasted for 95 min. The study highlighted the potential of microemulsion formulation in simultaneous transdermal delivery of two drugs.

Exposure to Fentanyl After Transdermal Patch Administration for Cancer Pain Management.

PubMed

Bista, Sudeep R; Haywood, Alison; Hardy, Janet; Norris, Ross; Hennig, Stefanie

2016-06-01

This study aimed to describe exposure after fentanyl transdermal patch administration in patients with advanced cancer to quantify variability around the exposure. Patients (n  =  56) with advanced cancer who received transdermal fentanyl (Durogesic®; median dose, 50 μg/h; range, 12-200 μg/h) provided venous blood samples (n  =  163) at various times (0.5-72 hours) during several patch application intervals. Plasma fentanyl concentration was determined (median, 0.9 μg/L; range, 0.04-9.7 μg/L) by high-performance liquid chromatography coupled to tandem mass spectrometry. Pharmacokinetic analysis was performed using nonlinear mixed-effects modeling with NONMEM. A 1-compartment distribution model with first-order absorption and elimination described fentanyl exposure after transdermal patch administration. Fentanyl apparent clearance (between-subject variability [BSV], %) was estimated at 122 L/h/70 kg and 38.5%, respectively. The absorption rate constant was 0.013 h(-1) . Between-occasion variability on apparent clearance was 22.0%, which was lower than BSV, suggesting predictable exposure within the same patient and justifying therapeutic drug monitoring. Except for weight-based dosing, no other patient characteristic could be identified to guide initial fentanyl dose selection in patients with advanced cancer. © 2015, The American College of Clinical Pharmacology.

De Novo Design of Skin-Penetrating Peptides for Enhanced Transdermal Delivery of Peptide Drugs.

PubMed

Menegatti, Stefano; Zakrewsky, Michael; Kumar, Sunny; De Oliveira, Joshua Sanchez; Muraski, John A; Mitragotri, Samir

2016-03-09

Skin-penetrating peptides (SPPs) are attracting increasing attention as a non-invasive strategy for transdermal delivery of therapeutics. The identification of SPP sequences, however, currently performed by experimental screening of peptide libraries, is very laborious. Recent studies have shown that, to be effective enhancers, SPPs must possess affinity for both skin keratin and the drug of interest. We therefore developed a computational process for generating and screening virtual libraries of disulfide-cyclic peptides against keratin and cyclosporine A (CsA) to identify SPPs capable of enhancing transdermal CsA delivery. The selected sequences were experimentally tested and found to bind both CsA and keratin, as determined by mass spectrometry and affinity chromatography, and enhance transdermal permeation of CsA. Four heptameric sequences that emerged as leading candidates (ACSATLQHSCG, ACSLTVNWNCG, ACTSTGRNACG, and ACSASTNHNCG) were tested and yielded CsA permeation on par with previously identified SPP SPACE (TM) . An octameric peptide (ACNAHQARSTCG) yielded significantly higher delivery of CsA compared to heptameric SPPs. The safety profile of the selected sequences was also validated by incubation with skin keratinocytes. This method thus represents an effective procedure for the de novo design of skin-penetrating peptides for the delivery of desired therapeutic or cosmetic agents. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Biochemical enhancement of transdermal delivery with magainin peptide: modification of electrostatic interactions by changing pH.

PubMed

Kim, Yeu-Chun; Late, Sameer; Banga, Ajay K; Ludovice, Peter J; Prausnitz, Mark R

2008-10-01

Magainin is a naturally occurring, pore-forming peptide that has recently been shown to increase skin permeability. This study tested the hypothesis that electrostatic forces between magainin peptides and drugs mediate drug transport across the skin. Electrostatic interaction between positively charged magainin and a negatively charged model drug, fluorescein, was attractive at pH 7.4 and resulted in a 35-fold increase in delivery across human epidermis in vitro when formulated with 2% N-lauroylsarcosine in 50% ethanol. Increasing to pH 10 or 11 largely neutralized magainin's charge, which eliminated enhancement due to magainin. Shielding electrostatic interactions with 1-2M NaCl solution similarly eliminated enhancement. Showing the opposite dependence on pH, electrostatic interaction between magainin and a positively charged anti-nausea drug, granisetron, was largely neutralized at pH 10 and resulted in a 92-fold increase in transdermal delivery. Decreasing to pH 5 increased magainin's positive charge, which repelled granisetron and progressively decreased transdermal flux. Circular dichroism analysis, multi-photon microscopy, and FTIR spectroscopy showed no significant pH effect on magainin secondary structure, magainin deposition in stratum corneum, or stratum corneum lipid order, respectively. We conclude that magainin increases transdermal delivery by a mechanism involving electrostatic interaction between magainin peptides and drugs.

The Rule of Five for Non-Oral Routes of Drug Delivery: Ophthalmic, Inhalation and Transdermal

PubMed Central

Choy, Young Bin; Prausnitz, Mark R.

2011-01-01

The Rule of Five predicts suitability of drug candidates, but was developed primarily using orally administered drugs. Here, we test whether the Rule of Five predicts drugs for delivery via non-oral routes, specifically ophthalmic, inhalation and transdermal. We assessed 111 drugs approved by FDA for those routes of administration and found that >98% of current non-oral drugs have physicochemical properties within the limits of the Rule of Five. However, given the inherent bias in the dataset, this analysis was not able to assess whether drugs with properties outside those limits are poor candidates. Indeed, further analysis indicates that drugs well outside the Rule of Five limits, including hydrophilic macromolecules, can be delivered by inhalation. In contrast, drugs currently administered across skin fall within more stringent limits than predicted by the Rule of Five, but new transdermal delivery technologies may make these constraints obsolete by dramatically increasing skin permeability. The Rule of Five does appear to apply well to ophthalmic delivery. We conclude that although current non-oral drugs mostly have physicochemical properties within the Rule of Five thresholds, the Rule of Five should not be used to predict non-oral drug candidates, especially for inhalation and transdermal routes. PMID:20967491

Biochemical enhancement of transdermal delivery with magainin peptide: Modification of electrostatic interactions by changing pH

PubMed Central

Kim, Yeu-Chun; Late, Sameer; Banga, Ajay K.; Ludovice, Peter J.; Prausnitz, Mark R.

2008-01-01

Magainin is a naturally occurring, pore-forming peptide that has recently been shown to increase skin permeability. This study tested the hypothesis that electrostatic forces between magainin peptides and drugs mediate drug transport across the skin. Electrostatic interaction between positively charged magainin and a negatively charged model drug, fluorescein, was attractive at pH 7.4 and resulted in a 35 fold increase in delivery across human epidermis in vitro when formulated with 2% N-lauroylsarcosine in 50% ethanol. Increasing to pH 10 or 11 largely neutralized magainin’s charge, which eliminated enhancement due to magainin. Shielding electrostatic interactions with 1–2 M NaCl solution similarly eliminated enhancement. Showing the opposite dependence on pH, electrostatic interaction between magainin and a positively charged anti-nausea drug, granisetron, was largely neutralized at pH 10 and resulted in a 59 fold increase in transdermal delivery. Decreasing to pH 5 increased magainin’s positive charge, which repelled granisetron and progressively decreased transdermal flux. Circular dichroism analysis, multi-photon microscopy, and FTIR spectroscopy showed no significant pH effect on magainin secondary structure, magainin deposition in stratum corneum, or stratum corneum lipid order, respectively. We conclude that magainin increases transdermal delivery by a mechanism involving electrostatic interaction between magainin peptides and drugs. PMID:18601987

Skin models for the testing of transdermal drugs

PubMed Central

Abd, Eman; Yousef, Shereen A; Pastore, Michael N; Telaprolu, Krishna; Mohammed, Yousuf H; Namjoshi, Sarika; Grice, Jeffrey E; Roberts, Michael S

2016-01-01

The assessment of percutaneous permeation of molecules is a key step in the evaluation of dermal or transdermal delivery systems. If the drugs are intended for delivery to humans, the most appropriate setting in which to do the assessment is the in vivo human. However, this may not be possible for ethical, practical, or economic reasons, particularly in the early phases of development. It is thus necessary to find alternative methods using accessible and reproducible surrogates for in vivo human skin. A range of models has been developed, including ex vivo human skin, usually obtained from cadavers or plastic surgery patients, ex vivo animal skin, and artificial or reconstructed skin models. Increasingly, largely driven by regulatory authorities and industry, there is a focus on developing standardized techniques and protocols. With this comes the need to demonstrate that the surrogate models produce results that correlate with those from in vivo human studies and that they can be used to show bioequivalence of different topical products. This review discusses the alternative skin models that have been developed as surrogates for normal and diseased skin and examines the concepts of using model systems for in vitro–in vivo correlation and the demonstration of bioequivalence. PMID:27799831

Development and in vitro evaluation of potential electromodulated transdermal drug delivery systems based on carbon nanotube buckypapers.

PubMed

Schwengber, Alex; Prado, Héctor J; Bonelli, Pablo R; Cukierman, Ana L

2017-07-01

Buckypapers based on different types of carbon nanotubes with and without the addition of four model drugs, two of basic nature (clonidine hydrochloride, selegiline hydrochloride) and the others of acidic character (flurbiprofen, ketorolac tromethamine) were prepared and characterized. The influence of the conditions employed in the preparation of the buckypapers (dispersion time and solvents used in the preparation, as well as the type of carbon nanotubes used and the characteristics of the drug involved) on their conductivity was especially examined. The in vitro performance of the drug loaded buckypapers as passive and active transdermal drug release systems, the latter being modulated by means of the application of electric voltages, was studied. Passive drug loaded buckypapers presented characteristic release profiles, also depending on the drug used, which indicate differences in the drug-carbon nanotubes non-covalent interactions. Application of electrical biases of appropriate polarities enabled the modulation of the drug release profiles in any desired direction. Different mathematical models were fitted to passive and electromodulated experimental release data for the four model drugs. Among these models, the most appropriate for data description was a two-compartment pseudo-second-order one. Copyright © 2017 Elsevier B.V. All rights reserved.

Design, modeling and simulation of MEMS-based silicon Microneedles

NASA Astrophysics Data System (ADS)

Amin, F.; Ahmed, S.

2013-06-01

The advancement in semiconductor process engineering and nano-scale fabrication technology has made it convenient to transport specific biological fluid into or out of human skin with minimum discomfort. Fluid transdermal delivery systems such as Microneedle arrays are one such emerging and exciting Micro-Electro Mechanical System (MEMS) application which could lead to a total painless fluid delivery into skin with controllability and desirable yield. In this study, we aimed to revisit the problem with modeling, design and simulations carried out for MEMS based silicon hollow out of plane microneedle arrays for biomedical applications particularly for transdermal drug delivery. An approximate 200 μm length of microneedle with 40 μm diameter of lumen has been successfully shown formed by isotropic and anisotropic etching techniques using MEMS Pro design tool. These microneedles are arranged in size of 2 × 4 matrix array with center to center spacing of 750 μm. Furthermore, comparisons for fluid flow characteristics through these microneedle channels have been modeled with and without the contribution of the gravitational forces using mathematical models derived from Bernoulli Equation. Physical Process simulations have also been performed on TCAD SILVACO to optimize the design of these microneedles aligned with the standard Si-Fabrication lines.

Enhanced in Vivo Delivery of 5-Fluorouracil by Ethosomal Gels in Rabbit Ear Hypertrophic Scar Model

PubMed Central

Wo, Yan; Zhang, Zheng; Zhang, Yixin; Zhang, Zhen; Wang, Kan; Mao, Xiaohui; Su, Weijie; Li, Ke; Cui, Daxiang; Chen, Jun

2014-01-01

Applying Ethosomal Gels (EGs) in transdermal drug delivery systems has evoked considerable interest because of their good water-solubility and biocompatibility. However, there has not been an explicit description of applying EGs as a vehicle for hypertrophic scars treatment. Here, a novel transdermal EGs loaded with 5-fluorouracil (5-FU EGs) was successfully prepared and characterized. The stability assay in vitro revealed that 5-FU EGs stored for a period of 30 days at 4 ± 1 °C had a better size stability than that at 25 ± 1 °C. Furthermore, using confocal laser scanning microscopy, EGs labeled with Rhodamine 6 G penetrated into the deep dermis of the hypertrophic scar within 24 h in the rabbit ear hypertrophic model suggested that the EGs were an optional delivery carrier through scar tissues. In addition, the value of the Scar Elevation Index (SEI) of 5-FU EGs group in the rabbit ear scar model was lower than that of 5-FU Phosphate Buffered Saline gel and Control groups. To conclude, these results suggest that EGs delivery system loaded 5-fluorouracil is a perfect candidate drug for hypertrophic scars therapy in future. PMID:25501333

Dual drug-loaded nanoparticles on self-integrated scaffold for controlled delivery

PubMed Central

Bennet, Devasier; Marimuthu, Mohana; Kim, Sanghyo; An, Jeongho

2012-01-01

Antioxidant (quercetin) and hypoglycemic (voglibose) drug-loaded poly-D,L-lactideco-glycolide nanoparticles were successfully synthesized using the solvent evaporation method. The dual drug-loaded nanoparticles were incorporated into a scaffold film using a solvent casting method, creating a controlled transdermal drug-delivery system. Key features of the film formulation were achieved utilizing several ratios of excipients, including polyvinyl alcohol, polyethylene glycol, hyaluronic acid, xylitol, and alginate. The scaffold film showed superior encapsulation capability and swelling properties, with various potential applications, eg, the treatment of diabetes-associated complications. Structural and light scattering characterization confirmed a spherical shape and a mean particle size distribution of 41.3 nm for nanoparticles in the scaffold film. Spectroscopy revealed a stable polymer structure before and after encapsulation. The thermoresponsive swelling properties of the film were evaluated according to temperature and pH. Scaffold films incorporating dual drug-loaded nanoparticles showed remarkably high thermoresponsivity, cell compatibility, and ex vivo drug-release behavior. In addition, the hybrid film formulation showed enhanced cell adhesion and proliferation. These dual drug-loaded nanoparticles incorporated into a scaffold film may be promising for development into a transdermal drug-delivery system. PMID:22888222

Transdermal delivery of paeonol using cubic gel and microemulsion gel

PubMed Central

Luo, Maofu; Shen, Qi; Chen, Jinjin

2011-01-01

Background The aim of this study was to develop new systems for transdermal delivery of paeonol, in particular microemulsion gel and cubic gel formulations. Methods Various microemulsion vehicles were prepared using isopropyl myristate as an oil phase, polyoxyethylated castor oil (Cremophor® EL) as a surfactant, and polyethylene glycol 400 as a cosurfactant. In the optimum microemulsion gel formulation, carbomer 940 was selected as the gel matrix, and consisted of 1% paeonol, 4% isopropyl myristate, 28% Cremophor EL/polyethylene glycol 400 (1:1), and 67% water. The cubic gel was prepared containing 3% paeonol, 30% water, and 67% glyceryl monooleate. Results A skin permeability test using excised rat skins indicated that both the cubic gel and microemulsion gel formulations had higher permeability than did the paeonol solution. An in vivo pharmacokinetic study done in rats showed that the relative bioavailability of the cubic gel and microemulsion gel was enhanced by about 1.51-fold and 1.28-fold, respectively, compared with orally administered paeonol suspension. Conclusion Both the cubic gel and microemulsion gel formulations are promising delivery systems to enhance the skin permeability of paeonol, in particular the cubic gel. PMID:21904450

Ethinyl estradiol and levonorgestrel in a transdermal contraceptive delivery system.

PubMed

Sriprasert, Intira; Stanczyk, Frank Z; Archer, David F

2015-01-01

The new transdermal contraceptive delivery system (TCDS) developed by Agile Therapeutics containing ethinyl estradiol and levonorgestrel (EE/LNG) is a reversible contraceptive method that maintains stable serum levels of both estrogen and progestin, and has efficacy similar to that of combination oral contraceptives (COC). We provided information of this new TCDS compared with the only TCDS available on the market that contains EE and norelgestromin, and has a higher EE exposure than a COC with 35 µg of EE potentially increasing the risk of venous thromboembolism. The article will summarize finding from clinical studies Phase I, II and III of EE/LNG TCDS. The development of the lower dose EE/LNG TCDS has demonstrated less EE exposure. The serum levels of EE and LNG were stable and comparable between various application sites and daily life conditions. Moreover, the EE/LNG TCDS showed comparable efficacy among obese and non-obese users. However, the Pearl index of this EE/LNG TCDS is questionable and the problem of compliance is a potential confounder of the results. The current Phase III efficacy study will contribute to a further evaluation of compliance and efficacy and will be completed in 2016.

Optimization of naltrexone diclofenac codrugs for sustained drug delivery across microneedle-treated skin.

PubMed

Ghosh, Priyanka; Lee, DoMin; Kim, Kyung Bo; Stinchcomb, Audra L

2014-01-01

The purpose of this work was to optimize the structure of codrugs for extended delivery across microneedle treated skin. Naltrexone, the model compound was linked with diclofenac, a nonspecific cyclooxygenase inhibitor to enhance the pore lifetime following microneedle treatment and develop a 7 day transdermal system for naltrexone. Four different codrugs of naltrexone and diclofenac were compared in terms of stability and solubility. Transdermal flux, permeability and skin concentration of both parent drugs and codrugs were quantified to form a structure permeability relationship. The results indicated that all codrugs bioconverted in the skin. The degree of conversion was dependent on the structure, phenol linked codrugs were less stable compared to the secondary alcohol linked structures. The flux of naltrexone across microneedle treated skin and the skin concentration of diclofenac were higher for the phenol linked codrugs. The polyethylene glycol link enhanced solubility of the codrugs, which translated into flux enhancement. The current studies indicated that formulation stability of codrugs and the flux of naltrexone can be enhanced via structure design optimization. The polyethylene glycol linked naltrexone diclofenac codrug is better suited for a 7 day drug delivery system both in terms of stability and drug delivery.

Response to rivastigmine transdermal patch or memantine plus rivastigmine patch is affected by apolipoprotein E genotype in Alzheimer patients.

PubMed

Han, Hyun Jeong; Kim, Byeong C; Lee, Jun-Young; Ryu, Seung-Ho; Na, Hae Ri; Yoon, Soo Jin; Park, Hyun Young; Shin, Joon Hyun; Cho, Soo-Jin; Yi, Hyon-Ah; Choi, Mun Seong; Heo, Jae-Hyeok; Park, Kyung Won; Kim, Kwang K; Choi, Seong Hye

2012-01-01

The apolipoprotein E (APOE) genotype in response to pharmacological treatments in patients with Alzheimer's disease (AD) remains a matter of controversy. This analysis investigated the effect of the APOE genotype on the clinical response to rivastigmine transdermal patch monotherapy or memantine plus rivastigmine patch in patients with mild to moderate AD. Two hundred and six (n = 206) patients with probable AD and Mini-Mental State Examination (MMSE) scores of 10-20 were randomized to rivastigmine patch monotherapy or memantine plus rivastigmine patch for 24 weeks. Of the 206 patients with probable AD, 146 patients who consented to genetic testing for APOE were included and assessed for this subgroup study. There were no significant differences on MMSE, NPI, ADAS-cog, ADCS-ADL, CDR-SB, NPI and FAB between rivastigmine patch monotherapy and memantine plus rivastigmine patch according to the APOE genotype. However, patients with moderately severe AD (MMSE ≤15) who were APOE ε4 carriers showed higher responder rates on ADCS-ADL with memantine plus rivastigmine patch compared to rivastigmine patch monotherapy. Moderately severe AD patients with the APOE ε4 allele may respond more favorably to memantine plus rivastigmine patch than ε4 noncarriers. Copyright © 2012 S. Karger AG, Basel.

Nausea and vomiting in pregnancy: a review of the pathology and compounding opportunities.

PubMed

Zur, Eyal

2013-01-01

Nausea and vomiting in pregnancy can have serious adverse effects on the quality of a woman's life, affecting her occupational, social, and domestic functioning, and her general well-being; therefore, it is very important to treat this condition appropriately and effectively. Evidence-based algorithms support the use of oral pyridoxine alone or combined with doxylamine as first-line treatment. Promethazine or dimenhydrinate, known as a second-line treatment, should be added to the first-line treatment or should be added only to pyridoxine according to different algorithms. In most of the world, there is a lack of approved medicines using this combination approach known as the first-line treatment. Therefore, compounding pharmacists should supply the demand by compounding 10-mg pyridoxine hydrochloride and 10-mg doxylamine succinate slow-release capsules. Since transdermal promethazine does not exist world wide, and, since this medicine has significant added values compared to the oral/rectal dosage forms, compounding pharmacists should offer physicians transdermal promethazine as a second-line therapy in nausea and vomiting in pregnancy. This review summarizes the nausea and vomiting in pregnancy problems and discusses the compounding opportunities that exist in this common and wide-spread pathology in order to improve a woman's quality of life.

Clinical pharmacology and efficacy of rotigotine (Neupro® patch) in the treatment of restless leg syndrome.

PubMed

Ferini-Strambi, Luigi; Marelli, Sara; Galbiati, Andrea

2016-08-01

Restless legs syndrome/Willis Ekbom disease (RLS/WED) is a sensorimotor disorder characterized by unpleasant sensations in the legs accompanied by an urge to move them, that typically occurs and tend to worsen in the evening/night or during period of inactivity. Standard medications for RLS/WED are dopamine agonists and calcium channel α-2-δ ligands. The clinical spectrum of RLS/WED is very broad, ranging from individuals suffering from the disease during limited periods up to those severely affected, with daily symptoms. In such cases a long-acting drug like rotigotine should be considered. The clinical pharmacology and efficacy of rotigotine was examined to evaluate the evidence supporting its use in RLS/WED. The rotigotine transdermal patch provides constant delivery of the drug, maintaining a stable plasma concentration over 24 hours by means of a single daily application. Several randomized, double-blind, placebo-controlled trials have demonstrated the efficacy of rotigotine in improving moderate-to-severe RLS/WED symptoms. Rotigotine is generally well tolerated. The most common adverse effects were application-site reactions, dose-dependent, more frequently reported in the first period of treatment. Incidence of augmentation in RLS/WED patients treated with oral dopamine agonists is higher when compared with the use of transdermal rotigotine.

[Effects of penetration enhancers on curcumin transdermal drug delivery].

PubMed

Gao, Zhen-Shen; Wang, Lan; Zhang, Mei

2012-01-01

To study the effects of penetration enhancers and their combinations on the curcumine transdermal drug delivery (CUR-TDDS). The penetration rate of curcumin through rat skin in vitro was measured using Valia-Chien diffusion cells, and orthogonal design method was set up for experimental design. The optimum penetration enhancers were: 3% hydroxypropyl beta cyclodextrins (HP-beta-CD), 9% borneol and 3% peppermint oil. The HP-beta-CD has the most potent enhancing effect.

Hemozoin-generated vapor nanobubbles for transdermal reagent- and needle-free detection of malaria

PubMed Central

Lukianova-Hleb, Ekaterina Y.; Campbell, Kelly M.; Constantinou, Pamela E.; Braam, Janet; Olson, John S.; Ware, Russell E.; Sullivan, David J.; Lapotko, Dmitri O.

2014-01-01

Successful diagnosis, screening, and elimination of malaria critically depend on rapid and sensitive detection of this dangerous infection, preferably transdermally and without sophisticated reagents or blood drawing. Such diagnostic methods are not currently available. Here we show that the high optical absorbance and nanosize of endogenous heme nanoparticles called “hemozoin,” a unique component of all blood-stage malaria parasites, generates a transient vapor nanobubble around hemozoin in response to a short and safe near-infrared picosecond laser pulse. The acoustic signals of these malaria-specific nanobubbles provided transdermal noninvasive and rapid detection of a malaria infection as low as 0.00034% in animals without using any reagents or drawing blood. These on-demand transient events have no analogs among current malaria markers and probes, can detect and screen malaria in seconds, and can be realized as a compact, easy-to-use, inexpensive, and safe field technology. PMID:24379385

Hemozoin-generated vapor nanobubbles for transdermal reagent- and needle-free detection of malaria.

PubMed

Lukianova-Hleb, Ekaterina Y; Campbell, Kelly M; Constantinou, Pamela E; Braam, Janet; Olson, John S; Ware, Russell E; Sullivan, David J; Lapotko, Dmitri O

2014-01-21

Successful diagnosis, screening, and elimination of malaria critically depend on rapid and sensitive detection of this dangerous infection, preferably transdermally and without sophisticated reagents or blood drawing. Such diagnostic methods are not currently available. Here we show that the high optical absorbance and nanosize of endogenous heme nanoparticles called "hemozoin," a unique component of all blood-stage malaria parasites, generates a transient vapor nanobubble around hemozoin in response to a short and safe near-infrared picosecond laser pulse. The acoustic signals of these malaria-specific nanobubbles provided transdermal noninvasive and rapid detection of a malaria infection as low as 0.00034% in animals without using any reagents or drawing blood. These on-demand transient events have no analogs among current malaria markers and probes, can detect and screen malaria in seconds, and can be realized as a compact, easy-to-use, inexpensive, and safe field technology.

Fentanyl by continuous subcutaneous infusion for the management of cancer pain: a retrospective study.

PubMed

Watanabe, S; Pereira, J; Hanson, J; Bruera, E

1998-11-01

Twenty-two patients who received fentanyl by continuous subcutaneous infusion for treatment of cancer pain were evaluated retrospectively. No local toxicities were noted. Five patients were switched from transdermal fentanyl due to uncontrolled pain; three achieved stability, accompanied by improvement in visual analogue scores for pain. Seventeen patients were switched from other opioids due to toxicity; 10 achieved stability, with documented improvement in toxicity in seven. The median dose ratio of opioid prior to switchover (mg/day) to fentanyl at stabilization (mg/day) was 85.4 (range 65-112.5) for morphine and 23.0 (range 10.7-29.7) for hydromorphone. Of six stable patients switched from subcutaneous to transdermal fentanyl, four maintained stability. We conclude that fentanyl by continuous subcutaneous infusion is a useful alternative for cancer patients who experience uncontrolled pain while receiving transdermal fentanyl or who experience toxicity on other opioids.

Transdermal rivastigmine in the treatment of Alzheimer's disease: current and future directions.

PubMed

Amanatkar, Hamid Reza; Grossberg, George Thomas

2014-10-01

Despite the fact that the prevalence of Alzheimer's disease (AD) is exponentially increasing, we have not yet been able to develop a new treatment to modify the course of the disease. This vacuum makes the traditional cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonist the only accessible pharmacotherapy options for the treatment of this disease. Among these medications, the only available transdermal patch at this time is the rivastigmine patch. This patch provides significantly lower gastrointestinal adverse effects. A higher tolerability rate provides the option for physicians to continue treatment with higher doses of rivastigmine in advanced stages of AD. Moreover, ease of use, easy-to-follow schedule, less administration time spent by the caregiver result in greater adherent to the treatment. This article aims to provide a comprehensive drug profile for transdermal rivastigmine, to review currently available treatment options, and to try to anticipate future treatment directions for AD.

An analytical procedure for the determination of aluminum used in antiperspirants on human skin in Franz™ diffusion cell.

PubMed

Guillard, Olivier; Fauconneau, Bernard; Favreau, Frédéric; Marrauld, Annie; Pineau, Alain

2012-04-01

A local case report of hyperaluminemia (aluminum concentration: 3.88 µmol/L) in a woman using an aluminum-containing antiperspirant for 4 years raises the question of possible transdermal uptake of aluminum salt as a future public health problem. Prior to studying the transdermal uptake of three commercialized cosmetic formulas, an analytical assay of aluminum (Al) in chlorohydrate form (ACH) by Zeeman Electrothermal Atomic Absorption Spectrophotometer (ZEAAS) in a clean room was optimized and validated. This analysis was performed with different media on human skin using a Franz(™) diffusion cell. The detection and quantification limits were set at ≤ 3 µg/L. Precision analysis as within-run (n = 12) and between-run (n = 15-68 days) yield CV ≤ 6%. The high analytic sensitivity (2-3 µg/L) and low variability should allow an in vitro study of the transdermal uptake of ACH.

Enhancement of transdermal delivery of ibuprofen using microemulsion vehicle

PubMed Central

Hu, Liandong; Hu, Qiaofeng; Yang, Jianxue

2014-01-01

Objective(s): The objective of this study was to find a stable microemulsion vehicle for transdermal delivery of ibuprofen to improve the skin permeability. Materials and Methods: Microemulsion was prepared using different sorts of oils, surfactants and co-surfactants. Pseudo-ternary phase diagrams were used to evaluate the microemulsion domain. The effects of oleic acid and surfactant mixture on skin permeation of ibuprofen were evaluated with excised skins. Results: The optimum formulation F3 consisting of 6% oleic acid, 30% Cremophor RH40/Transcutol P (2:1, w/w) and 59% water phase, showed a high permeation rate of 42.98 µg/cm2/hr. The mean droplet size of microemulsion was about 43 nm and no skin irritation signs were observed on the skin of rabbits. Conclusion: These results indicated that this novel microemulsion is a useful formulation for the transdermal delivery of ibuprofen. PMID:25729544

[Analysis on preparation and characterization of asiaticoside-loaded flexible nanoliposomes].

PubMed

Ren, Yan; He, Xing-Dong; Shang, Bei-Cheng; Bao, Xiu-Kun; Wang, Yan-Fang; Ma, Ji-Sheng

2013-10-01

Asiaticoside is a compound extracted from traditional Chinese medicine Centella asiatica, and mainly used in wound healing and scar repair in clinical, with notable efficacy. However, its poor transdermal absorption and short action time restrict its wide application. In this experiment, the reserve-phase-extrusion-lyophilization method was conducted to prepare the lyophilized asiaticoside-loaded flexible nanoliposomes (LAFL). Its characteristics including electron microscope structure, particle size, Zeta potential, entrapment rate, drug-loading rate, stability and drug release were determined with the intelligent transdermal absorption instrument. LAFL were white spheroids, with pH, particle size and zeta potential of 7. 03, 70. 14 nm and - 36. 5 mV, respectively. The average entrapment rate of the 3 batch samples were 31. 43% , and the average asiaticoside content in 1 mg lyophilized simple was 0. 134 mg. The results indicated that LAFL have good physicochemical properties and pharmaceutical characteristics, with an improved transdermal performance.

Estimation of maximum transdermal flux of nonionized xenobiotics from basic physicochemical determinants

PubMed Central

Milewski, Mikolaj; Stinchcomb, Audra L.

2012-01-01

An ability to estimate the maximum flux of a xenobiotic across skin is desirable both from the perspective of drug delivery and toxicology. While there is an abundance of mathematical models describing the estimation of drug permeability coefficients, there are relatively few that focus on the maximum flux. This article reports and evaluates a simple and easy-to-use predictive model for the estimation of maximum transdermal flux of xenobiotics based on three common molecular descriptors: logarithm of octanol-water partition coefficient, molecular weight and melting point. The use of all three can be justified on the theoretical basis of their influence on the solute aqueous solubility and the partitioning into the stratum corneum lipid domain. The model explains 81% of the variability in the permeation dataset comprised of 208 entries and can be used to obtain a quick estimate of maximum transdermal flux when experimental data is not readily available. PMID:22702370

Use of lipolanthionine peptide, a toll-like receptor 2 inhibitor, enhances transdermal delivery efficiency.

PubMed

Chen, Bin; Liu, Da-Lie; Pan, Wen-Yan; Yang, Xiao-Hui; Shou, Jia-Bao; Wu, Ju-Hua; Mao, Qing-Long; Wang, Jia

2014-08-01

The transdermal delivery system (TDS) is able to obtain a systemic therapeutic effect by administration through the skin, which has low side effects and is able to maintain a sustained blood concentration. However, due to the barrier presented by the stratum corneum, numerous drugs have poor percutaneous permeability. Therefore, the improvement of skin permeability is key to TDS. The main method of promoting transdermal absorption is through the usage of penetration enhancers. Dimethyl sulfoxide (DMSO) is a commonly used penetration enhancer, which has anti‑inflammatory analgesic effects and is able to penetrate the skin. Retinoic acid (RA) and lipolanthionine peptide (LP) may also benefit the permeation efficiency of TDS. Therefore, the present study examined the function of DMSO, RA and LP as penetration enhancers in TDS. Firstly, the optimum concentration of DMSO was confirmed by detecting the expression of the LacZ gene in vitro. Secondly, different combinations of LP, RA and DMSO were applied to mouse skin to analyze the penetration enhancer combination with the greatest efficacy. All the animals were divided into five groups: The RA + LP + DMSO + pORF‑LacZ group, the RA + DMSO + pORF‑LacZ group, the LP + DMSO + pORF‑LacZ group, the DMSO + pORF-LacZ group and the control group. Skin was soaked in combinations of LP, RA and DMSO for seven days and then the pORF‑LacZ plasmids were daubed onto the skin once daily three days. On the 11th day, all the animals were sacrificed by cervical dislocation and the skin and blood samples were collected. The blood samples were used to detect the expression of the LacZ gene by quantitative polymerase chain reaction and the skin samples were used to detect the expression of claudin‑4 and zonula occluden‑1 (ZO‑1) proteins by immunohistochemistry and western blot analysis. The results demonstrated that the combination of LP, RA and DMSO exhibited the greatest transdermal delivery efficiency, which verified that RA and LP were able to increase the penetration effects. Following treatment with LP, the symptoms of dermal edema were relieved and the capillaries contracted, which suggested that LP was a safe and effective penetration enhancer able to reduce the side‑effects caused by DMSO. The present study provides a guideline for the synthesis of novel penetration enhancers.

Lidocaine self-sacrificially improves the skin permeation of the acidic and poorly water-soluble drug etodolac via its transformation into an ionic liquid.

PubMed

Miwa, Yasushi; Hamamoto, Hidetoshi; Ishida, Tatsuhiro

2016-05-01

Poor transdermal penetration of active pharmaceutical ingredients (APIs) impairs both bioavailability and therapeutic benefits and is a major challenge in the development of transdermal drug delivery systems. Here, we transformed a poorly water-soluble drug, etodolac, into an ionic liquid in order to improve its hydrophobicity, hydrophilicity and skin permeability. The ionic liquid was prepared by mixing etodolac with lidocaine (1:1, mol/mol). Both the free drug and the transformed ionic liquid were characterized by differential scanning colorimetry (DSC), infrared spectroscopy (IR), and saturation concentration measurements. In addition, in vitro skin-permeation testing was carried out via an ionic liquid-containing patch (Etoreat patch). The lidocaine and etodolac in ionic liquid form led to a relatively lower melting point than either lidocaine or etodolac alone, and this improved the lipophilicity/hydrophilicity of etodolac. In vitro skin-permeation testing demonstrated that the Etoreat patch significantly increased the skin permeation of etodolac (9.3-fold) compared with an etodolac alone patch, although an Etoreat patch did not increase the skin permeation of lidocaine, which was consistent with the results when using a lidocaine alone patch. Lidocaine appeared to self-sacrificially improve the skin permeation of etodolac via its transformation into an ionic liquid. The data suggest that ionic liquids composed of approved drugs may substantially expand the formulation preparation method to meet the challenges of drugs which are characterized by poor rates of transdermal absorption. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Perioperative analgesia with a buprenorphine transdermal patch for hallux valgus surgery: a prospective, randomized, controlled study

PubMed Central

Xu, Can; Li, Mingqing; Wang, Chenggong; Li, Hui; Liu, Hua

2018-01-01

Purpose Hallux valgus surgery often results in significant postoperative pain. Adequate control of pain is essential for patient satisfaction and improves the outcome of the procedure. This study aimed to investigate the perioperative analgesic effect of a buprenorphine transdermal patch in patients who underwent hallux valgus surgery. Patients and methods A total of 90 patients were randomly divided into the following three groups based on the perioperative analgesic method: flurbiprofen axetil intravenous injection (Group F), oral celecoxib (Group C), and buprenorphine transdermal delivery system (BTDS) (Group BTDS). The pain status, degree of satisfaction, adverse effects, and administration of tramadol hydrochloride for uncontrolled pain were recorded on the night before surgery, postoperative day 1, postoperative day 2, and postoperative day 3. Results The BTDS could effectively control perioperative pain for patients undergoing hallux valgus surgery. The analgesic effect of the BTDS was better than that of oral celecoxib. In addition, statistically significant differences were not observed in the visual analog scale (VAS) scores, adverse effects, and rescue analgesia between the patients who received the BTDS and the patients who received the flurbiprofen axetil intravenous injection. However, the degree of patient satisfaction of the BTDS group was significantly higher (P<0.05) than that of the other two groups. Conclusion The BTDS (a preemptive analgesia regimen) could exert an analgesic effect during the perioperative period for patients who had received hallux valgus surgery, and this effect is beneficial for sustaining postoperative physiological and psychological states and promoting functional rehabilitation. PMID:29731664

Pharmacokinetics of Drugs in Cachectic Patients: A Systematic Review

PubMed Central

Trobec, Katja; Kerec Kos, Mojca; von Haehling, Stephan; Springer, Jochen; Anker, Stefan D.; Lainscak, Mitja

2013-01-01

Cachexia is a weight-loss process caused by an underlying chronic disease such as cancer, chronic heart failure, chronic obstructive pulmonary disease, or rheumatoid arthritis. It leads to changes in body structure and function that may influence the pharmacokinetics of drugs. Changes in gut function and decreased subcutaneous tissue may influence the absorption of orally and transdermally applied drugs. Altered body composition and plasma protein concentration may affect drug distribution. Changes in the expression and function of metabolic enzymes could influence the metabolism of drugs, and their renal excretion could be affected by possible reduction in kidney function. Because no general guidelines exist for drug dose adjustments in cachectic patients, we conducted a systematic search to identify articles that investigated the pharmacokinetics of drugs in cachectic patients. PMID:24282510

Limonene enhances the in vitro and in vivo permeation of trimetazidine across a membrane-controlled transdermal therapeutic system.

PubMed

Krishnaiah, Yellela S; Al-Saidan, Saleh M

2008-01-01

The objective of the study was to design membrane-controlled transdermal therapeutic system (TTS) for trimetazidine. The optimization of (i) concentration of ethanol-water solvent system, (ii) HPMC concentration of drug reservoir and (iii) limonene concentration in 2% w/v HPMC gel was done based on the in vitro permeation of trimetazidine across excised rat epidermis. A limonene-based membrane-controlled TTS of trimetazidine was fabricated and evaluated for its in vivo drug release in rabbit model. The in vitro permeation of trimetazidine from water, ethanol and selected concentrations (25, 50 and 75% v/v) of ethanol-water co-solvent systems showed that 50% v/v of ethanol-water solvent system provided an optimal transdermal flux of 233.1+/-3.8 microg/cm(2.)h. The flux of the drug decreased to 194.1+/-7.4 microg/cm(2.)h on adding 2% w/v of HPMC to ethanolic (50% v/v ethanol-water) solution of trimetazidine. However, on adding selected concentrations of limonene (0, 2, 4, 6 and 8% w/v) to 2% w/v HPMC gel drug reservoir, the flux of the drug increased to 365.5+/-7.1 microg/cm(2.)h. Based on these results, 2% w/v HPMC gel drug reservoir containing 6% w/v of limonene was chosen as an optimal formulation for studying the influence of rate-controlling EVA2825 membrane and adhesive-coated EVA2825 membrane. The flux of the drug across EVA2825 membrane (mean thickness 31.2 microm) decreased to 285.8+/-2.2 microg/cm(2.)h indicating that the chosen membrane was effective as rate-controlling membrane. On applying an adhesive coat (mean thickness 10.2 microm) to EVA2825 membrane, the drug flux further decreased to 212.4+/-2.6 microg/cm(2.)h. However, the flux of the drug across adhesive-coated EVA2825 membrane-rat epidermis composite was 185.9+/-2.9 microg/cm(2.)h, which is about 2-times higher than the desired flux. The fabricated limonene-based TTS patch of trimetazidine showed a mean steady state plasma concentration of 71.5 ng/mL for about 14 h with minimal fluctuation when tested in rabbits. It was concluded from the investigation that the limonene-based TTS patch of trimetazidine provided constant drug delivery across the skin in rabbit model.

Transdermal power transfer for recharging implanted drug delivery devices via the refill port.

PubMed

Evans, Allan T; Chiravuri, Srinivas; Gianchandani, Yogesh B

2010-04-01

This paper describes a system for transferring power across a transdermal needle into a smart refill port for recharging implantable drug delivery systems. The device uses a modified 26 gauge (0.46 mm outer diameter) Huber needle with multiple conductive elements designed to couple with mechanical springs in the septum of the refill port of a drug delivery device to form an electrical connection that can sustain the current required to recharge a battery during a reservoir refill session. The needle is fabricated from stainless steel coated with Parylene, and the refill port septum is made from micromachined stainless steel contact springs and polydimethylsiloxane. The device properties were characterized with dry and wet ambient conditions. The needle and port pair had an average contact resistance of less than 2 Omega when mated in either environment. Electrical isolation between the system, the liquid in the needle lumen, and surrounding material has been demonstrated. The device was used to recharge a NiMH battery with currents up to 500 mA with less than 15 degrees C of resistive heating. The system was punctured 100 times to provide preliminary information with regard to device longevity, and exhibited about 1 Omega variation in contact resistance. The results suggest that this needle and refill port system can be used in an implant to enable battery recharging. This allows for smaller batteries to be used and ultimately increases the volume efficiency of an implantable drug delivery device.

Pharmacokinetics of rotigotine transdermal system in adolescents with idiopathic restless legs syndrome (Willis-Ekbom disease).

PubMed

Elshoff, Jan-Peer; Hudson, John; Picchietti, Daniel L; Ridel, Keith; Walters, Arthur S; Doggett, Kimberly; Moran, Kimberly; Oortgiesen, Marga; Ramirez, Francisco; Schollmayer, Erwin

2017-04-01

To investigate the pharmacokinetics (PK) of rotigotine transdermal system in adolescents with moderate-to-severe idiopathic restless legs syndrome (RLS). This multicenter, open-label, dose-escalation study enrolled patients ≥13 to <18 years of age. Rotigotine transdermal patches were applied daily and up-titrated weekly: 0.5, 1, 2, 3 mg/24 h. Blood samples were collected on the final day of each dose step. Primary PK variables were the apparent total body clearance (CL/f; L/h) and volume of distribution at steady state (V SS /f; L) of unconjugated rotigotine for each dose step, calculated for the PK per-protocol set (PKPPS). Other PK, safety, and efficacy variables (International RLS Study Group Rating Scale [IRLS]; Clinical Global Impressions Item 1 [CGI-1]) were assessed. Of 24 patients who received rotigotine, 23 completed all dose steps and 17 formed the PKPPS. Least-squares mean (95% confidence interval) CL/f and V SS /f values were broadly similar across all dose steps (CL/f: 0.5 mg/24 h: 676.86 [408.50-1121.51]; 1 mg/24 h: 671.72 [459.11-982.80]; 2 mg/24 h: 937.56 [658.50-1334.89]; 3 mg/24 h: 1088.77 [723.47-1638.53]; V SS /f: 5403.16 [2850.67-10,241.17]; 6220.79 [3842.05-10,072.28]; 7114.01 [4547.88-11,128.07]; 6037.92 [3598.36-10,131.41]). Among 23 patients with efficacy data, mean IRLS and CGI-1 scores improved at each dosage level. Adverse events reported by ≥3 patients were nausea (seven) and application site reactions (four). Key PK properties of rotigotine in adolescent patients with moderate-to-severe idiopathic RLS were comparable to those previously observed in adults. Rotigotine improved RLS symptoms and was well tolerated. ClinicalTrials.gov: NCT01495793. Copyright © 2016 Elsevier B.V. All rights reserved.

Next generation Er:YAG fractional ablative laser

NASA Astrophysics Data System (ADS)

Heinrich, A.; Vizhanyo, A.; Krammer, P.; Summer, S.; Gross, S.; Bragagna, T.; Böhler, C.

2011-03-01

Pantec Biosolutions AG presents a portable fractional ablative laser system based on a miniaturized diode pumped Er:YAG laser. The system can operate at repetition rates up to 500 Hz and has an incorporated beam deflection unit. It is smaller, lighter and cost efficient compared to systems based on lamp pumped Er:YAG lasers and incorporates a skin layer detection to guarantee precise control of the microporation process. The pulse parameters enable a variety of applications in dermatology and in general medicine, as demonstrated by first results on transdermal drug delivery of FSH (follicle stimulating hormone).

Rotigotine transdermal system as add-on to oral dopamine agonist in advanced Parkinson's disease: an open-label study.

PubMed

Kim, Jong-Min; Chung, Sun Ju; Kim, Jae Woo; Jeon, Beom Seok; Singh, Pritibha; Thierfelder, Stephan; Ikeda, Junji; Bauer, Lars

2015-02-28

Achieving optimal symptom control with minimal side effects is a major goal in clinical practice. Dual-agent dopamine receptor agonist (DA) therapy in Parkinson's disease (PD) may represent a promising approach to treatment, as the combination of different pharmacokinetic/pharmacological profiles may result in a lesser need for high dosages and, accordingly, may be well tolerated. The objective of the current study was to investigate safety and efficacy of rotigotine transdermal system as add-on to oral DA in patients with advanced PD inadequately controlled with levodopa and low-dose oral DA. PD0015 was an open-label, multinational study in patients with advanced-PD and sleep disturbance or early-morning motor impairment. Patients were titrated to optimal dose rotigotine (≤8 mg/24 h) over 1-4 weeks and maintained for 4-7 weeks (8-week treatment). Dosage of levodopa and oral DA (pramipexole ≤1.5 mg/day, ropinirole ≤6.0 mg/day) was stable. Primary variable was Clinical Global Impressions (CGI) item 4: side effects, assessing safety. Other variables included adverse events (AEs), Patient Global Impressions of Change (PGIC), Unified Parkinson's Disease Rating Scale (UPDRS) II and III, Parkinson's Disease Sleep Scale (PDSS-2), Pittsburgh Sleep Quality Index (PSQI), and "off" time. Of 90 patients who received rotigotine, 79 (88%) completed the study; 5 (6%) withdrew due to AEs. Most (83/89; 93%) had a CGI-4 score <3 indicating that rotigotine add-on therapy did not interfere with functioning; 6 (7%) experienced drug-related AEs that interfered with functioning (score ≥3). AEs occurring in ≥5% were application site pruritus (13%), dizziness (10%), orthostatic hypotension (10%), nausea (8%), dyskinesia (8%), and nasopharyngitis (6%). Numerical improvements in motor function (UPDRS III), activities of daily living (UPDRS II), sleep disturbances (PDSS-2, PSQI), and reduction in "off" time were observed. The majority (71/88; 81%) improved on PGIC. Addition of rotigotine transdermal system to low-dose oral DA in patients with advanced-PD was feasible and may be associated with clinical benefit. ClinicalTrials.gov identifier NCT01723904 . Trial registration date: November 6, 2012.

Factors Associated with Greater Adherence to and Satisfaction with Transdermal Rivastigmine in Patients with Alzheimer's Disease and Their Caregivers.

PubMed

Riepe, Matthias; Weinman, John; Osae-Larbi, Judith; Mulick Cassidy, Amy; Knox, Sean; Chaves, Ricardo; Müller, Beate

2015-01-01

Adherence to cholinesterase inhibitors is important in order to maximise treatment efficacy. This study aimed to investigate patient and caregiver factors associated with adherence to and satisfaction with transdermal rivastigmine treatment. Sociodemographic, clinical and psychosocial data were collected from 127 patients and their caregivers during the first follow-up visit after prescription. At the second follow-up, data were collected on 110 of the dyads. Adherence to and satisfaction with the treatment were assessed using the Medication Adherence Report Scale and an adapted version of the Alzheimer's Disease Caregiver Preference Questionnaire. 66.2% of the caregivers reported being adherent to, and 77.0% were satisfied with, the patch at the second follow-up. Factors predicting higher adherence at the second follow-up were caregivers' greater frequency of contact with patients, greater satisfaction with the information received about the patch, better tolerability of the patch and living at home with their caregivers. Greater concerns of the caregivers about the patch and the patients' belief in 'other' causes of their Alzheimer's disease predicted a lower adherence at the second follow-up. Assessing and addressing caregivers' concerns about transdermal rivastigmine, improving doctor-patient/caregiver communication to increase caregiver satisfaction with information about the patch as well as providing education and support around patients' beliefs and tolerability of the patch could improve adherence to transdermal rivastigmine. © 2015 S. Karger AG, Basel.

Enhancement of skin permeation of flurbiprofen via its transdermal patches using isopulegol decanoate (ISO-C10) as an absorption enhancer: pharmacokinetic and pharmacodynamic evaluation.

PubMed

Chen, Yang; Quan, Peng; Liu, Xiaochang; Guo, Wenjia; Song, Wenting; Cun, Dongmei; Wang, Zhongyan; Fang, Liang

2015-09-01

The study aimed to prepare a transdermal patch for flurbiprofen using isopulegol decanoate (ISO-C10) as a permeation enhancer, and to evaluate the in-vitro and in-vivo percutaneous permeation of the drug, as well as the pharmacodynamic efficacy of the formulation. The permeation experiments were conducted on rabbit skin, and the pharmacokinetic profiles and synovial fluid drug concentration were measured after in-vivo transdermal administration. A deconvolution approach was employed to analyse the correlation between the in-vitro and in-vivo drug permeation. The anti-inflammatory and analgesic effects were, respectively, assessed using the adjuvant arthritis model and the acetic acid induced pain model. ISO-C10 could increase the in-vitro permeation of flurbiprofen from 46.22 ± 5.65 μg/cm(2) to 101.07 ± 10.85 μg/cm(2) . The in-vivo absorption of the drug was also improved by the enhancer, and a good linear correlation was observed between the in-vitro and in-vivo drug permeation. Meanwhile, the ISO-C10 contained patches increased the drug disposition in synovial fluid and enhanced the pharmacodynamic efficacy of the formulation. ISO-C10 would be a promising permeation enhancer for improving the in-vitro and in-vivo delivery of flurbiprofen from its transdermal patches. © 2015 Royal Pharmaceutical Society.

Nanovesicles for transdermal delivery of felodipine: Development, characterization, and pharmacokinetics

PubMed Central

Yusuf, Mohd; Sharma, Vijay; Pathak, Kamla

2014-01-01

Aim: The research traces development of nanovesicles to attain enhanced transdermal delivery of felodipine and also investigates parameters for optimization of variable membrane compositions containing soya- and egg lecithin and edge activator. Materials and Methods: Rotary evaporation sonication method was employed to obtain tranfersomal formulation that was characterized for vesicle shape and size, polydispersity index (PDI), zeta potential, entrapment and loading efficiency, deformability index and in vitro skin permeation. Results: Spherical nanovesicles of 75.71 ± 5.4 nm with PDI 0.228 and zeta potential of −49.8 were adjudged as the best formulation (MF8). MF8 displayed maximum entrapment and loading efficiency with a high deformability index of 119.68. In vitro permeation across rat skin by MF8 reported 256% enhancement in permeation (flux = 23.72 ± 0.64) when compared with transdermal control formulation and followed zero order kinetics (Case-II). Pharmacokinetic studies revealed that transdermal administration, in contrast to oral delivery provided relatively constant, sustained blood concentration with minimal plasma fluctuation, rapid and prolonged peak time. The relative bioavailability of felodipine was found 358.42% versus oral administration that was well supported by the outcomes of confocal laser scanning microscopic studies that suggested rapid permeation of drugs to across dermal layers. Conclusion: The results conclude that composition variation and method of preparation elicited significant effect on the vesicle characteristic and proved the transcendency of felodipine loaded transfersomes. PMID:25126525

[In vitro transdermal delivery of the active fraction of xiangfusiwu decoction based on principal component analysis].

PubMed

Li, Zhen-Hao; Liu, Pei; Qian, Da-Wei; Li, Wei; Shang, Er-Xin; Duan, Jin-Ao

2013-06-01

The objective of the present study was to establish a method based on principal component analysis (PCA) for the study of transdermal delivery of multiple components in Chinese medicine, and to choose the best penetration enhancers for the active fraction of Xiangfusiwu decoction (BW) with this method. Improved Franz diffusion cells with isolated rat abdomen skins were carried out to experiment on the transdermal delivery of six active components, including ferulic acid, paeoniflorin, albiflorin, protopine, tetrahydropalmatine and tetrahydrocolumbamine. The concentrations of these components were determined by LC-MS/MS, then the total factor scores of the concentrations at different times were calculated using PCA and were employed instead of the concentrations to compute the cumulative amounts and steady fluxes, the latter of which were considered as the indexes for optimizing penetration enhancers. The results showed that compared to the control group, the steady fluxes of the other groups increased significantly and furthermore, 4% azone with 1% propylene glycol manifested the best effect. The six components could penetrate through skin well under the action of penetration enhancers. The method established in this study has been proved to be suitable for the study of transdermal delivery of multiple components, and it provided a scientific basis for preparation research of Xiangfusiwu decoction and moreover, it could be a reference for Chinese medicine research.

Preparation and characterization of cyanocobalamin (vit B12) microemulsion properties and structure for topical and transdermal application.

PubMed

Salimi, Anayatollah; Sharif Makhmal Zadeh, Behzad; Moghimipour, Eskandar

2013-07-01

The objective of this study was to design a topical microemulsion of Vit B12 and to study the correlation between internal structure and physicochemical properties of the microemulsions. Microemulsions are thermodynamically stable mixtures of water, oil, surfactants and usually cosurfactants with several advantages for topical and transdermal drug delivery. The formulation of microemulsions for pharmaceutical use requires a clear understanding of the properties and microstructures of the microemulsions. In this study, phase behavior and microstructure of traditional and novel microemulsions of Vit B12 have been investigated by Small-angle X-ray (SAXS), differential scanning calorimetery (DSC) and measuring density, particle size, conductivity and surface tension. WO and bicontinuous microemulsion with different microstructures were found in novel and traditional formulations. In this study, amount of water, surfactant concentration, oil/ surfactant ratio and physicochemical properties of cosurfactants influenced the microstructures. In both formulations, water behavior was affected by the concentration of the surfactant. Water Solubilization capacity and enthalpy of exothermic peak of interfacial and free water of traditional formulations were more than novel ones. This means that the affinity of water to interfacial film is dependent on the surfactant properties.   This study showed that both microemulsions provided good solubility of Vit B12 with a wide range of internal structure. Low water solubilization capacity is a common property of microemulsions that can affect drug release and permeability through the skin.  Based on Vit B12 properties, specially, intermediate oil and water solubility, better drug partitioning into the skin may be obtained by traditional formulations with wide range of structure and high amount of free and bounded water.    

Experimental design and optimization of raloxifene hydrochloride loaded nanotransfersomes for transdermal application.

PubMed

Mahmood, Syed; Taher, Muhammad; Mandal, Uttam Kumar

2014-01-01

Raloxifene hydrochloride, a highly effective drug for the treatment of invasive breast cancer and osteoporosis in post-menopausal women, shows poor oral bioavailability of 2%. The aim of this study was to develop, statistically optimize, and characterize raloxifene hydrochloride-loaded transfersomes for transdermal delivery, in order to overcome the poor bioavailability issue with the drug. A response surface methodology experimental design was applied for the optimization of transfersomes, using Box-Behnken experimental design. Phospholipon(®) 90G, sodium deoxycholate, and sonication time, each at three levels, were selected as independent variables, while entrapment efficiency, vesicle size, and transdermal flux were identified as dependent variables. The formulation was characterized by surface morphology and shape, particle size, and zeta potential. Ex vivo transdermal flux was determined using a Hanson diffusion cell assembly, with rat skin as a barrier medium. Transfersomes from the optimized formulation were found to have spherical, unilamellar structures, with a homogeneous distribution and low polydispersity index (0.08). They had a particle size of 134±9 nM, with an entrapment efficiency of 91.00%±4.90%, and transdermal flux of 6.5±1.1 μg/cm(2)/hour. Raloxifene hydrochloride-loaded transfersomes proved significantly superior in terms of amount of drug permeated and deposited in the skin, with enhancement ratios of 6.25±1.50 and 9.25±2.40, respectively, when compared with drug-loaded conventional liposomes, and an ethanolic phosphate buffer saline. Differential scanning calorimetry study revealed a greater change in skin structure, compared with a control sample, during the ex vivo drug diffusion study. Further, confocal laser scanning microscopy proved an enhanced permeation of coumarin-6-loaded transfersomes, to a depth of approximately160 μM, as compared with rigid liposomes. These ex vivo findings proved that a raloxifene hydrochloride-loaded transfersome formulation could be a superior alternative to oral delivery of the drug.

Experimental design and optimization of raloxifene hydrochloride loaded nanotransfersomes for transdermal application

PubMed Central

Mahmood, Syed; Taher, Muhammad; Mandal, Uttam Kumar

2014-01-01

Raloxifene hydrochloride, a highly effective drug for the treatment of invasive breast cancer and osteoporosis in post-menopausal women, shows poor oral bioavailability of 2%. The aim of this study was to develop, statistically optimize, and characterize raloxifene hydrochloride-loaded transfersomes for transdermal delivery, in order to overcome the poor bioavailability issue with the drug. A response surface methodology experimental design was applied for the optimization of transfersomes, using Box-Behnken experimental design. Phospholipon® 90G, sodium deoxycholate, and sonication time, each at three levels, were selected as independent variables, while entrapment efficiency, vesicle size, and transdermal flux were identified as dependent variables. The formulation was characterized by surface morphology and shape, particle size, and zeta potential. Ex vivo transdermal flux was determined using a Hanson diffusion cell assembly, with rat skin as a barrier medium. Transfersomes from the optimized formulation were found to have spherical, unilamellar structures, with a homogeneous distribution and low polydispersity index (0.08). They had a particle size of 134±9 nM, with an entrapment efficiency of 91.00%±4.90%, and transdermal flux of 6.5±1.1 μg/cm2/hour. Raloxifene hydrochloride-loaded transfersomes proved significantly superior in terms of amount of drug permeated and deposited in the skin, with enhancement ratios of 6.25±1.50 and 9.25±2.40, respectively, when compared with drug-loaded conventional liposomes, and an ethanolic phosphate buffer saline. Differential scanning calorimetry study revealed a greater change in skin structure, compared with a control sample, during the ex vivo drug diffusion study. Further, confocal laser scanning microscopy proved an enhanced permeation of coumarin-6-loaded transfersomes, to a depth of approximately160 μM, as compared with rigid liposomes. These ex vivo findings proved that a raloxifene hydrochloride-loaded transfersome formulation could be a superior alternative to oral delivery of the drug. PMID:25246789

The transdermal formulation of rivastigmine improves caregiver burden and treatment adherence of patients with Alzheimer's disease under daily practice conditions

PubMed Central

Adler, G; Mueller, B; Articus, K

2014-01-01

Background Rivastigmine is the only cholinesterase inhibitor (ChEI) available as transdermal patch. The patch was developed to improve gastrointestinal tolerability and treatment adherence to higher dosages as compared with oral medication. Preferences of patients and caregivers for the patch were reported; however, neither patient compliance nor caregiver burden has yet been measured under routine practice conditions. Methods This was a prospective, multi-centre, observational study in patients with Alzheimer's disease treated with rivastigmine patch in Germany. To compare the transdermal with oral dosage forms, physicians were asked to enrol patients who recently switched from oral to transdermal medication. Beyond effectiveness and tolerability, outcome measures were drug adherence evaluated by the Morisky questionnaire, and caregiver burden, measured as the daily time expenditure for dressing the patient, controlling appearance and administration of medication. Results In total, 1104 outpatients (57.5% female gender; mean age 77 ± 7 years) were enrolled in 220 sites. After 6 months of treatment, 67.5% of patients had an improved Clinical Global Impression and the Mini-Mental State Examination score increased from 19.0 ± 5.1 to 20.0 ± 5.2 (p < 0.001); 84.1% of patients were still on treatment, 64.6% on the target dose of 9.5 mg/day. Compliance and patient satisfaction with therapy continuously increased over the study period and average time savings of caregivers added up to 20 min/day. In general, tolerability was deemed good and there were no unexpected adverse events. Conclusions Transdermal rivastigmine is an effective treatment alternative, which may improve adherence and treatment satisfaction of the patient and relieve the caregiver. Controlled parallel-group trials are warranted. Clinical trials registration: none (observational study). PMID:24588972

The transdermal formulation of rivastigmine improves caregiver burden and treatment adherence of patients with Alzheimer's disease under daily practice conditions.

PubMed

Adler, G; Mueller, B; Articus, K

2014-04-01

Rivastigmine is the only cholinesterase inhibitor (ChEI) available as transdermal patch. The patch was developed to improve gastrointestinal tolerability and treatment adherence to higher dosages as compared with oral medication. Preferences of patients and caregivers for the patch were reported; however, neither patient compliance nor caregiver burden has yet been measured under routine practice conditions. This was a prospective, multi-centre, observational study in patients with Alzheimer's disease treated with rivastigmine patch in Germany. To compare the transdermal with oral dosage forms, physicians were asked to enrol patients who recently switched from oral to transdermal medication. Beyond effectiveness and tolerability, outcome measures were drug adherence evaluated by the Morisky questionnaire, and caregiver burden, measured as the daily time expenditure for dressing the patient, controlling appearance and administration of medication. In total, 1104 outpatients (57.5% female gender; mean age 77 ± 7 years) were enrolled in 220 sites. After 6 months of treatment, 67.5% of patients had an improved Clinical Global Impression and the Mini-Mental State Examination score increased from 19.0 ± 5.1 to 20.0 ± 5.2 (p < 0.001); 84.1% of patients were still on treatment, 64.6% on the target dose of 9.5 mg/day. Compliance and patient satisfaction with therapy continuously increased over the study period and average time savings of caregivers added up to 20 min/day. In general, tolerability was deemed good and there were no unexpected adverse events. Transdermal rivastigmine is an effective treatment alternative, which may improve adherence and treatment satisfaction of the patient and relieve the caregiver. Controlled parallel-group trials are warranted. none (observational study). © 2014 Novartis Pharma GmbH. International Journal of Clinical Practice published by John Wiley & Sons Ltd.

Early Postmenopausal Transdermal 17β-Estradiol Therapy and Amyloid-β Deposition.

PubMed

Kantarci, Kejal; Lowe, Val J; Lesnick, Timothy G; Tosakulwong, Nirubol; Bailey, Kent R; Fields, Julie A; Shuster, Lynne T; Zuk, Samantha M; Senjem, Matthew L; Mielke, Michelle M; Gleason, Carey; Jack, Clifford R; Rocca, Walter A; Miller, Virginia M

2016-05-07

It remains controversial whether hormone therapy in recently postmenopausal women modifies the risk of Alzheimer's disease (AD). To investigate the effects of hormone therapy on amyloid-β deposition in recently postmenopausal women. Participants within 5-36 months past menopause in the Kronos Early Estrogen Prevention Study, a randomized, double blinded placebo-controlled clinical trial, were randomized to: 1) 0.45 mg/day oral conjugated equine estrogens (CEE); 2) 50μg/day transdermal 17β-estradiol; or 3) placebo pills and patch for four years. Oral progesterone (200 mg/day) was given to active treatment groups for 12 days each month. 11C Pittsburgh compound B (PiB) PET imaging was performed in 68 of the 118 participants at Mayo Clinic approximately seven years post randomization and three years after stopping randomized treatment. PiB Standard unit value ratio (SUVR) was calculated. Women (age = 52-65) randomized to transdermal 17β-estradiol (n = 21) had lower PiB SUVR compared to placebo (n = 30) after adjusting for age [odds ratio (95% CI) = 0.31(0.11-0.83)]. In the APOEɛ4 carriers, transdermal 17β-estradiol treated women (n = 10) had lower PiB SUVR compared to either placebo (n = 5) [odds ratio (95% CI) = 0.04(0.004-0.44)], or the oral CEE treated group (n = 3) [odds ratio (95% CI) = 0.01(0.0006-0.23)] after adjusting for age. Hormone therapy was not associated with PiB SUVR in the APOEɛ4 non-carriers. In this pilot study, transdermal 17β-estradiol therapy in recently postmenopausal women was associated with a reduced amyloid-β deposition, particularly in APOEɛ4 carriers. This finding may have important implications for the prevention of AD in postmenopausal women, and needs to be confirmed in a larger sample.