Self-Nanoemulsifying Drug Delivery System for Resveratrol: Enhanced Oral Bioavailability and Reduced Physical Fatigue in Rats

PubMed Central

Yen, Ching-Chi; Hsu, Mei-Chich; Wu, Yu-Tse

2017-01-01

Resveratrol (RES), a natural polyphenolic compound, exerts anti-fatigue activity, but its administration is complicated by its low water solubility. To improve RES bioavailability, this study developed a self-nanoemulsifying drug delivery system (SNEDDS) for RES and evaluated its anti-fatigue activity and rat exercise performance by measuring fatigue-related parameters, namely lactate, ammonia, plasma creatinine phosphokinase, and glucose levels and the swimming time to exhaustion. Through solubility and emulsification testing, the optimized SNEDDS composed of Capryol 90, Cremophor EL, and Tween 20 was developed; the average particle size in this formulation, which had favorable self-emulsification ability, was approximately 41.3 ± 4.1 nm. Pharmacokinetic studies revealed that the oral bioavailability of the optimized RES-SNEDDS increased by 3.2-fold compared with that of the unformulated RES-solution. Pretreatment using the RES-SNEDDS before exercise accelerated the recovery of lactate after exercise; compared with the vehicle group, the plasma ammonia level in the RES-SNEDDS group significantly decreased by 65.4%, whereas the glucose level significantly increased by approximately 1.8-fold. Moreover, the swimming time to exhaustion increased by 2.1- and 1.8-fold, respectively, compared with the vehicle and RES-solution pretreatment groups. Therefore, the developed RES-SNEDDS not only enhances the oral bioavailability of RES but may also exert anti-fatigue pharmacological effect. PMID:28841149

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

PubMed

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

2018-06-01

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

SNEDDS curcumin formulation leads to enhanced protection from pain and functional deficits associated with diabetic neuropathy: an insight into its mechanism for neuroprotection.

PubMed

Joshi, Rayanta P; Negi, Geeta; Kumar, Ashutosh; Pawar, Yogesh B; Munjal, Bhushan; Bansal, Arvind K; Sharma, Shyam S

2013-08-01

Curcumin has shown to be effective against various diabetes related complications. However major limitation with curcumin is its low bioavailability. In this study we formulated and characterized self nano emulsifying drug delivery system (SNEDDS) curcumin formulation to enhance its bioavailability and then evaluated its efficacy in experimental diabetic neuropathy. Bioavailability studies were performed in male Sprague Dawley rats. Further to evaluate the efficacy of formulation in diabetic neuropathy various parameters like nerve function and sensorimotor perception were assessed along with study of inflammatory proteins (NF-κB, IKK-β, COX-2, iNOS, TNF-α and IL-6). Nanotechnology based formulation resulted in prolonged plasma exposure and bioavailability. SNEDDS curcumin provided better results against functional, behavioural and biochemical deficits in experimental diabetic neuropathy, when compared with naive curcumin. Further western blot analysis confirmed the greater neuroprotective action of SNEDDS curcumin. SNEDDS curcumin formulation due to higher bioavailability was found to afford enhanced protection in diabetic neuropathy. In this study the authors formulated and characterized a self-emulsifying drug delivery system for formulation to enhance curcumin bioavailability in experimental diabetic neuropathy. Enhanced efficacy was demonstrated in a rat model. Copyright © 2013 Elsevier Inc. All rights reserved.

Effects of crystalline state and self-nanoemulsifying drug delivery system (SNEDDS) on oral bioavailability of the novel anti-HIV compound 6-benzyl-1-benzyloxymethyl-5-iodouracil in rats.

PubMed

Lu, Ying-Yuan; Dai, Wen-Bing; Wang, Xin; Wang, Xiao-Wei; Liu, Jun-Yi; Li, Pu; Lou, Ya-Qing; Lu, Chuang; Zhang, Qiang; Zhang, Guo-Liang

2018-02-01

The objective of this study was to investigate the effect of crystalline state and a formulation of self-nanoemulsifying drug delivery system (SNEDDS) on oral bioavailability of 6-benzyl-1-benzyloxymethyl-5-iodouracil (W-1), a novel non-nucleoside reverse transcriptase inhibitor, in rats. The crystalline states of W-1 were characterized by scanning electron microscope (SEM), differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD). The SNEDDS was formulated by medium-chain lipids, characterized by droplet particle size. The plasma concentrations of W-1 were measured by high performance liquid chromatography (HPLC). The results indicated that W-1 compound were presented as crystalline forms, A and B, the degree of crystallization in form B was higher than that in form A. The SNEDDS of W-1 displayed a significant increase in the dissolution rate than W-1 powder. Furthermore, after oral administration of W-1 (100 mg/kg), the pharmacokinetic parameters of form A, form B, and W-1 SNEDDS were as follows: AUC 0-t 526.4 ± 123.5, 305.1 ± 58.5 and 2297 ± 451 ng h/mL (p < .05, when W-1 SNEDDS were compared with either form A or form B), respectively. With SNEDDS formulation, the relative bioavailabilities were enhanced by 4.36-fold and 7.53-fold over the form A and form B of W-1, respectively. In conclusion, the present results suggested that the crystalline states of W-1 might lead to the lower oral bioavailability, and SNEDDS formulation is a promising strategy of improving bioavailability, in spite of that crystalline states usually carry small lot-to-lot variability.

Self-nanoemulsifying drug delivery systems of tamoxifen citrate: design and optimization.

PubMed

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

2009-10-01

Tamoxifen citrate is an antiestrogen for peroral breast cancer treatment. The drug delivery encounters problems of poor water solubility and vulnerability to enzymatic degradation in both intestine and liver. In the current study, tamoxifen citrate self-nanoemulsifying drug delivery systems (SNEDDS) were prepared in an attempt to circumvent such obstacles. Preliminary screening was carried out to select proper ingredient combinations. All surfactants screened were recognized for their bioactive aspects. Ternary phase diagrams were then constructed and an optimum system was designated. Three tamoxifen SNEDDS were then compared for optimization. The systems were assessed for robustness to dilution, globule size, cloud point, surface morphology and drug release. An optimum system composed of tamoxifen citrate (1.6%), Maisine 35-1 (16.4%), Caproyl 90 (32.8%), Cremophor RH40 (32.8%) and propylene glycol (16.4%) was selected. The system was robust to different dilution volumes and types. It possessed a mean globule size of 150 nm and a cloud point of 80 degrees C. Transmission electron microscopy demonstrated spherical particle morphology. The drug release from the selected formulation was significantly higher than other SNEDDS and drug suspension, as well. Realizing drug incorporation into an optimized nano-sized SNEDD system that encompasses a bioactive surfactant, our results proposed that the prepared system could be promising to improve oral efficacy of the tamoxifen citrate.

Self-nanoemulsifying drug delivery system of nifedipine: impact of hydrophilic-lipophilic balance and molecular structure of mixed surfactants.

PubMed

Weerapol, Yotsanan; Limmatvapirat, Sontaya; Nunthanid, Jurairat; Sriamornsak, Pornsak

2014-04-01

A simple but novel mixed surfactant system was designed to fabricate a self-nanoemulsifying drug delivery system (SNEDDS) based on hydrophilic-lipophilic balance (HLB) value. The impacts of HLB and molecular structure of surfactants on the formation of SNEDDS were investigated. After screening various oils and surfactants, nifedipine (NDP)-loaded liquid SNEDDS was formulated with Imwitor(®) 742 as oil and Tween(®)/Span(®) or Cremophor(®)/Span(®) as mixed surfactant. Droplet size of the emulsions obtained after dispersing SNEDDS containing Tween(®)/Span(®) in aqueous medium was independent of the HLB of a mixed surfactant. The use of the Cremophor(®)/Span(®) blend gave nanosized emulsion at higher HLB. The structure of the surfactant was found to influence the emulsion droplet size. Solid SNEDDS was then prepared by adsorbing NDP-loaded liquid SNEDDS comprising Cremophor(®) RH40/Span(®) 80 onto Aerosil(®) 200 or Aerosil(®) R972 as inert solid carrier. Solid SNEDDS formulations using higher amounts (30-50% w/w) of Aerosil(®) 200 exhibited good flow properties with smooth surface and preserved the self-emulsifying properties of liquid SNEDDS. Differential scanning calorimetry and X-ray diffraction studies of solid SNEDDS revealed the transformation of the crystalline structure of NDP due to its molecular dispersion state. In vitro dissolution study demonstrated higher dissolution of NDP from solid SNEDDS compared with NDP powder.

Enhanced oral bioavailability of lurasidone by self-nanoemulsifying drug delivery system in fasted state.

PubMed

Miao, Yanfei; Sun, Jiqin; Chen, Guoguang; Lili, Ren; Ouyang, Pingkai

2016-08-01

The purpose of this work was to develop a new formulation to enhance the bioavailability and reduce the food effect of lurasidone using self-nanoemulsifying drug delivery systems (SNEDDSs). The formulation of lurasidone-SNEDDS was selected by the solubility and pseudo-ternary phase diagram studies. The prepared lurasidone-SNEDDS formulations were characterized for self-emulsification time, effect of pH and robustness to dilution, droplet size analysis, zeta potential and in vitro drug release. Lurasidone-SNEDDSs were administered to beagle dogs in fed and fasted state and their pharmacokinetics were compared to commercial available tablet as a control. The result showed lurasidone-SNEDDS was successfully prepared using Capmul MCM, Tween 80 and glycerol as oil phase, surfactant and co-surfactant, respectively. In vitro drug release studies indicated that the lurasidone-SNEDDS showed improved drug release profiles and the release behavior was not affected by the medium pH with total drug release of over 90% within 5 min. Pharmacokinetic study showed that the AUC(0-∞) and Cmax for lurasidone-SNEDDS are similar in the fasted and fed state, indicating essentially there is no food effect on the drug absorption. It was concluded that enhanced bioavailability and no food effect of lurasidone had been achieved by using SNEDDS.

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

PubMed

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

2017-11-01

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

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

PubMed

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

2016-08-01

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

Silica encapsulated lipid-based drug delivery systems for reducing the fed/fasted variations of ziprasidone in vitro.

PubMed

Dening, Tahnee J; Rao, Shasha; Thomas, Nicky; Prestidge, Clive A

2016-04-01

Ziprasidone is a poorly water-soluble antipsychotic drug that demonstrates low fasted state oral bioavailability and a clinically significant two-fold increase in absorption when dosed postprandially. Owing to significant compliance challenges faced by schizophrenic patients, a novel oral formulation of ziprasidone that demonstrates improved fasted state absorption and a reduced food effect is of major interest, and is therefore the aim of this research. Three lipid-based drug delivery systems (LBDDS) were developed and investigated: (a) a self-nanoemulsifying drug delivery system (SNEDDS), (b) a solid SNEDDS formulation, and (c) silica-lipid hybrid (SLH) microparticles. SNEDDS was developed using Capmul MCM® and Tween 80®, and solid SNEDDS was fabricated by spray-drying SNEDDS with Aerosil 380® silica nanoparticles as the solid carrier. SLH microparticles were prepared in a similar manner to solid SNEDDS using a precursor lipid emulsion composed of Capmul MCM® and soybean lecithin. The performance of the developed formulations was evaluated under simulated digesting conditions using an in vitro lipolysis model, and pure (unformulated) ziprasidone was used as a control. While pure ziprasidone exhibited the lowest rate and extent of drug solubilization under fasting conditions and a significant 2.4-fold increase in drug solubilization under fed conditions, all three LBDDS significantly enhanced the extent of drug solubilization under fasting conditions between 18- and 43-folds in comparison to pure drug. No significant difference in drug solubilization for the fed and fasted states was observed for the three LBDDS systems. To highlight the potential of LBDDS, mechanism(s) of action and various performance characteristics are discussed. Importantly, LBDDS are identified as an appropriate formulation strategy to explore further for the improved oral delivery of ziprasidone. Copyright © 2016 Elsevier B.V. All rights reserved.

Solid super saturated self-nanoemulsifying drug delivery system (sat-SNEDDS) as a promising alternative to conventional SNEDDS for improvement rosuvastatin calcium oral bioavailability.

PubMed

Abo Enin, Hadel A; Abdel-Bar, Hend Mohamed

2016-11-01

This study aims to illustrate the applicability of solid supersaturated self-nanoemulsifying drug delivery system (sat-SNEDDS) for the improvement of rosuvastatin calcium (RC) oral bioavailability. Different sat-SNEDDS were prepared by incorporating different ratios of RC into SNEDDS using tween80/PEG400 (77.2%) as surfactant/cosurfactant mixture and garlic /olive oil (22.8%) as oil phase. The prepared systems were characterized viz; size, zeta potential, TEM and stability. Various hydrophilic and hydrophobic carriers were employed to solidify the optimized RC sat-SNEDDS. The influence of the carrier was investigated by SEM, XRPD, DSC, flow properties, in vitro precipitation, drug release and oral bioavailability study. The adsorption of the stable positively charged nanocarrier RC sat-SNEDDS onto solid carriers provided free flowing amorphous powder. The carrier could amend the morphological architecture and in vitro release of the RC solid sat-SNEDDS. Hydrophobic carriers as microcrystalline cellulose 102 (MCC) showed superior physical characters and higher dissolution rate over hydrophilic carriers as maltodextrin with respective T 100% 30 min and 45 min. The rapid spontaneous emulsification, the positively nanosized MCC-sat-SNEDDS improved oral bioavailability of RC by 2.1-fold over commercial tablets. Solid MCC-sat-SNEDDS combined dual benefits of sat-SNEDDS and solid dosage form was successfully optimized to improve RC oral bioavailability.

Self-Nanoemulsifying Drug Delivery System of Coenzyme (Q10) with Improved Dissolution, Bioavailability, and Protective Efficiency on Liver Fibrosis.

PubMed

Khattab, Abeer; Hassanin, Lobna; Zaki, Nashwah

2017-07-01

The aim of our investigation is to develop and characterize self-nanoemulsifying drug delivery systems (SNEDDS) of CoQ 10 to improve its water solubility, dissolution rate, and bioavailability, and then evaluate its biochemical and physiological effect on liver cirrhosis in rats compared with CoQ 10 powder. SNEDDS are isotropic and thermodynamically stable mixture of oil, surfactant, co-surfactant, and drug that form an oil/water nanoemulsion when added to aqueous phases with soft agitation. Upon administration, self-nanoemulsifying system becomes in contact with gastrointestinal fluid and forms o/w nanoemulsion by the aid of gastrointestinal motility. When the nanoemulsion is formed in the gastrointestinal tract, it presents the drug in a solubilized form inside small nano-sized droplets that provide a large surface area for enhancing the drug release and absorption. Solubility of CoQ 10 in various oils, surfactants, and co-surfactants were studied to identify the components of SNEDDS; pseudo-ternary phase diagrams were plotted to identify the efficient self-emulsifying regions. CoQ 10 -loaded SNEDDS were prepared using isopropyl myristate as oil; Cremophor El, Labrasol, or Tween80 as surfactant; and Transcutol as co-surfactant. The amount of CoQ 10 in each vehicle was 3%. The formulations that passed thermostability evaluation test were assessed for particle size analysis, morphological characterization, refractive index, zeta potential, viscosity, electroconductivity, drug release profile, as well as ex vivo permeability. Pharmacokinetics and hepatoprotective efficiency of the optimized SNEDDS of CoQ 10 compared with CoQ 10 suspension were performed. Results showed that all optimized formulae have the ability to form a good and stable nanoemulsion when diluted with water; the mean droplet size of all formulae was in the nanometric range (11.7-13.5 nm) with optimum polydispersity index values (0.2-0.21). All formulae showed negative zeta potential (-11.3 to -17.2), and maximum drug loading efficiency. One hundred percent of CoQ 10 was released from most formulae within 30 min. One hundred percent of CoQ 10 was permeated from all formulae through 10 h. The pharmacokinetic study in rabbits revealed a significant increase in bioavailability of CoQ 10 SNEDDS to 2.1-fold compared with CoQ 10 suspension after oral administration. Comparative effect of the optimized formulae on acute liver injury compared with CoQ 10 powder was also studied; it was found that all the liver biochemical markers as alanine transferase (ALT), aspartate amino transferase (AST), alkaline phosphatase (ALP), total protein (TP), and albumin were significantly improved at p < 0.05. Also, histochemical and histopthological studies confirm the biochemical results. Our results suggest the potential use of SNEDDS to increase the solubility of liphophilic drug as poorly water-soluble CoQ 10 and improve its oral absorption, so it can be more efficient to improve liver damage compared to CoQ 10 powder. These results demonstrated that CoQ 10 SNEDDS inhibited thioacetamide (TAA)-induced liver fibrosis mainly through suppression of collagen production.

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

PubMed

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

2014-01-01

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

Lipid-based oral delivery systems for skin deposition of a potential chemopreventive DIM derivative: characterization and evaluation.

PubMed

Boakye, Cedar H A; Patel, Ketan; Patel, Apurva R; Faria, Henrique A M; Zucolotto, Valtencir; Safe, Stephen; Singh, Mandip

2016-10-01

The objective of this study was to explore the oral route as a viable potential for the skin deposition of a novel diindolylmethane derivative (DIM-D) for chemoprevention activity. Various lipid-based oral delivery systems were optimized and compared for enhancing DIM-D's oral bioavailability and skin deposition. Preformulation studies were performed to evaluate the log P and solubility of DIM-D. Microsomal metabolism, P-glycoprotein efflux, and caco-2 monolayer permeability of DIM-D were determined. Comparative evaluation of the oral absorption and skin deposition of DIM-D-loaded various lipid-based formulations was performed in rats. DIM-D showed pH-dependent solubility and a high log P value. It was not a strong substrate of microsomal degradation and P-glycoprotein. SMEDDs comprised of medium chain triglycerides, monoglycerides, and kolliphor-HS15 (36.70 ± 0.42 nm). SNEDDs comprised of long chain triglycerides, cremophor RH40, labrasol, and TPGS (84.00 ± 14.14 nm). Nanostructured lipid carriers (NLC) consisted of compritol, miglyol, and surfactants (116.50 ± 2.12 nm). The blank formulations all showed >70 % cell viability in caco-2 cells. Differential Scanning Calorimetry confirmed the amorphization of DIM-D within the lipid matrices while Atomic Force Microscopy showed particle size distribution similar to the dynamic light scattering data. DIM-D also showed reduced permeation across caco-2 monolayer that was enhanced (p < 0.05) by SNEDDs in comparison to SMEDDs and NLC. Fabsolute for DIM-D SNEDDs, SMEDDs, and NLC was 0.14, 0.04, and 0.007, respectively. SNEDDs caused 53.90, 11.32, and 15.08-fold more skin deposition of DIM-D than the free drug, SMEDDs, and NLC, respectively, at 2 h following oral administration and shows a viable potential for use in skin cancer chemoprevention. Graphical Abstract ᅟ.

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

PubMed

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

2013-10-01

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

Oral self-nanoemulsifying peptide drug delivery systems: impact of lipase on drug release.

PubMed

Mahjub, Reza; Dorkoosh, Farid Abedin; Rafiee-Tehrani, Morteza; Bernkop Schnürch, Andreas

2015-01-01

It was the aim of this study to evaluate the impact of lipases on the release behaviour of a peptide drug from oral self-nanoemulsifying drug delivery systems. Octreotide was ion paired with the anionic surfactants deoxycholate, decanoate, oleate and dodecylsulphate. The lipophilic character of these complexes was characterised by determining the n-octanol/buffer pH 7.4 partition coefficient. In the following the most hydrophilic complex was incorporated in a likely lipase degradable self-nanoemulsifying drug delivery systems (SNEDDS) formulation containing a triglyceride (olive oil; Pharm.Eur.) and in a likely not lipase degradable SNEDDS containing lipids and surfactants without any ester bonds. After 1:100 dilutions in artificial intestinal fluid (AIF), the lipid droplets were characterised regarding size distribution. With these SNEDDS, drug release studies were performed in AIF with and without lipase. Results showed that the most hydrophobic complex can be formed with deoxycholate in an octreotide:anionic surfactant ratio of 1:5. Even 73.1 ± 8.1% of it could be quantified in the n-octanol phase. SNEDDS containing octreotide | olive oil | cremophor EL | propylene glycol (2|57|38|3) and octreotide | liquid paraffin | Brij 35 | propylene glycol | ethanol (2|66.5|25|5|1.5) showed after dilution in AIF, a mean droplet size of 232 ± 53 nm and 235 ± 50 nm, respectively. Drug release studies showed a sustained release of octreotide out of these formulations for at least 24 h, whereas > 80% of the drug was released within 2 h in the presence of lipase in the case of the triglyceride containing SNEEDS. In contrast the release profile from ester-free SNEDDS was not significantly altered (p < 0.05) due to the addition of lipase providing evidence for the stability of this formulation towards lipases. According to these results, SNEDDS could be identified as a useful tool for sustained oral peptide delivery taking an enzymatic degradation by intestinal lipases into considerations.

A combination of complexation and self-nanoemulsifying drug delivery system for enhancing oral bioavailability and anticancer efficacy of curcumin.

PubMed

Shukla, Mahendra; Jaiswal, Swati; Sharma, Abhisheak; Srivastava, Pradeep Kumar; Arya, Abhishek; Dwivedi, Anil Kumar; Lal, Jawahar

2017-05-01

Curcumin, the golden spice from Indian saffron, has shown chemoprotective action against many types of cancer including breast cancer. However, poor oral bioavailability is the major hurdle in its clinical application. In the recent years, self-nanoemulsifying drug delivery system (SNEDDS) has emerged as a promising tool to improve the oral absorption and enhancing the bioavailability of poorly water-soluble drugs. In this context, complexation with lipid carriers like phospholipid has also shown the tremendous potential to improve the solubility and therapeutic efficacy of certain drugs with poor oral bioavailability. In the present investigation, a systematic combination of both the approaches is utilized to prepare the phospholipid complex of curcumin and facilitate its incorporation into SNEDDS. The combined use of both the approaches has been explored for the first time to enhance the oral bioavailability and in turn increase the anticancer activity of curcumin. As evident from the pharmacokinetic studies and in situ single pass intestinal perfusion studies in Sprague-Dawley rats, the optimized SNEDDS of curcumin-phospholipid complex has shown enhanced oral absorption and bioavailability of curcumin. The cytotoxicity study in metastatic breast carcinoma cell line has shown the enhancement of cytotoxic action by 38.7%. The primary tumor growth reduction by 58.9% as compared with the control group in 4T1 tumor-bearing BALB/c mice further supported the theory of enhancement of anticancer activity of curcumin in SNEDDS. The developed formulation can be a potential and safe carrier for the oral delivery of curcumin.

Self-nanoemulsifying drug-delivery system for improved oral bioavailability of rosuvastatin using natural oil antihyperlipdemic.

PubMed

Abo Enin, Hadel A

2015-01-01

The aim is improving the antihyperlipidemic activity of Rosuvastatin Calcium (Rs) through improving its solubility using self-nanoemulsifying drug delivery system (SNEDDS) containing natural oil full of unsaturated fatty acid and omega 3. A 7 × 3(2) full factorial design was adopted for optimization of oil ratio, Surfactant: Co-surfactant (S:CoS) ratio and oil:S/CoS ratio. Ternary phase diagrams were constructed for optimizing the system with drug loading (10 and 20%). The optimized SNEDD systems were evaluated according to their physical evaluation and drug release. Furthermore, the anti-hyperlipidemia efficacy was compared with commercially marketed product on rates followed by clinical study. The system containing Tween 80:PEG 400 (3:1) and olive oil:garlic oil (1:1) as an oily phase has droplet size less than 100 nm, ZP (+23.43 ± 2.58 mV), PDI (<0.02) and cloud point (>90 °C). In vitro drug release studies showed remarkable enhancement of the Rs release from Rs-SNEDDS. The antihyperlipidemic effect of Rs-SNEDDS is greater than that of the commercial tablets and the pure drug on rates and in hyperlipidemic patients. Rs-SNEDDS is a promising drug delivery system for improving the drug solubility and antihyperlipidemic effect using natural oils as (olive oil and garlic oil).

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

PubMed

Kamel, Amany O; Mahmoud, Azza A

2013-01-01

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

Self-Nanoemulsifying Lyophilized Tablets for Flash Oral Transmucosal Delivery of Vitamin K: Development and Clinical Evaluation.

PubMed

El-Say, Khalid M; Ahmed, Tarek A; Ahmed, Osama A A; Hosny, Khaled M; Abd-Allah, Fathy I

2017-09-01

Owing to limited solubility, vitamin K undergoes low bioavailability with large inter-individual variability after oral administration. This article aimed to prepare self-nanoemulsifying lyophilized tablets (SNELTs) for the flash oral transmucosal delivery of vitamin K. Twenty-one formulae of vitamin K self-nanoemulsifying drug delivery systems (SNEDDS) were prepared using different concentrations of vitamin K, Labrasol, and Transcutol according to mixture design. The SNEDDS was loaded on porous carriers and formulated as lyophilized tablets. The release profile and the pharmacokinetic parameters of vitamin K SNELTs were evaluated in comparison with commercial tablets and ampoules on human volunteers. Results revealed that the optimized SNEDDS showed the smallest and most stable nanoemulsion globules. SNELTs were prepared successfully and showed substantial superiority drug release compared with the commercial tablets. Interestingly, SNELTs enhanced both rate and extent of vitamin K absorption as well as relative bioavailability (169.67%) in healthy subjects compared with the commercial tablets. SNELTs revealed promising no significant difference in the area under the curve compared with the commercial intramuscular injection. SNELTs enhanced dissolution and bioavailability that expected to have the strong impact on the efficiency of vitamin K in the prophylaxis and treatment of bleeding disorders in patients with hepatic dysfunction. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

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

PubMed

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

2013-01-01

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

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

PubMed

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

2018-05-24

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

Antidiabetic Activity of Self Nanoemulsifying Drug Delivery System from Bay Leaves (Eugenia polyantha Wight) Ethyl Acetate Fraction

NASA Astrophysics Data System (ADS)

Prihapsara, F.; Harini, M.; Widiyani, T.; Artanti, A. N.; Ani, I. L.

2017-02-01

Insulin resistance is caused by inability of target tissues to insulin response. Bay leaves (Eugenia polyantha Wight) fraction or extract have been used for the treatment of antidibetic mellitus type-2 resistance insulin (ADMRI) but it has low solubility and bioavailability. To overcome these problems, ethyl acetate fraction of bay leaves was formulated into self nanoemulsifying drug delivery system (SNEDDS) using Virgin Coconut Oil (VCO) as a carrier oil. This study aims to produce nanoherbal medicine, determine effect of nanoherbal preparation derived from bay leaves as an anti-ADMRI. The results showed that the optimum SNEDDS formula was tween 80 : PEG 400 : Virgin Coconut Oil (30% : 60% : 10%) in 5 mL. It has emulsification time 13.00 seconds with the average of droplet size value 84.5 nanometer and zeta potential value ± 0.2 mV. Morphological observation showed the nanoemulsion particles has spherical shaped and stable in different pH media. Hypoglycaemic effect of single dose metformin, SNEDDS, combination a-half dose of SNEEDS with metformin value is 28.3%; 15.6%; 34.6% respectively.

Mechanism of enhanced oral absorption of morin by phospholipid complex based self-nanoemulsifying drug delivery system.

PubMed

Zhang, Jinjie; Li, Jianbo; Ju, Yuan; Fu, Yao; Gong, Tao; Zhang, Zhirong

2015-02-02

Phospholipid complex (PLC) based self-nanoemulsifying drug delivery system (PLC-SNEDDS) has been developed for efficient delivery of drugs with poor solubility and low permeability. In the present study, a BCS class IV drug and a P-glycoprotein (P-gp) substrate, morin, was selected as the model drug to elucidate the oral absorption mechanism of PLC-SNEDDS. PLC-SNEDDS was superior to PLC in protecting morin from degradation by intestinal enzymes in vitro. In situ perfusion study showed increased intestinal permeability by PLC was duodenum-specific. In contrast, PLC-SNEDDS increased morin permeability in all intestinal segments and induced a change in the main absorption site of morin from colon to ileum. Moreover, ileum conducted the lymphatic transport of PLC-SNEDDS, which was proven by microscopic intestinal visualization of Nile red labeled PLC-SNEDDS and lymph fluids in vivo. Low cytotoxicity and increased Caco-2 cell uptake suggested a safe and efficient delivery of PLC-SNEDDS. The increased membrane fluidity and disrupted actin filaments were closely associated with the increased cell uptake of PLC-SNEDDS. PLC-SNEDDS could be internalized into enterocytes as an intact form in a cholesterol-dependent manner via clathrin-mediated endocytosis and macropinocytosis. The enhanced oral absorption of morin was attributed to the P-gp inhibition by Cremophor RH and the intact internalization of M-PLC-SNEDDS into Caco-2 cells bypassing P-gp recognition. Our findings thus provide new insights into the development of novel nanoemulsions for poorly absorbed drugs.

Development and optimisation of atorvastatin calcium loaded self-nanoemulsifying drug delivery system (SNEDDS) for enhancing oral bioavailability: in vitro and in vivo evaluation.

PubMed

Kassem, Abdulsalam M; Ibrahim, Hany M; Samy, Ahmed M

2017-05-01

The objective of this study was to develop and optimise self-nanoemulsifying drug delivery system (SNEDDS) of atorvastatin calcium (ATC) for improving dissolution rate and eventually oral bioavailability. Ternary phase diagrams were constructed on basis of solubility and emulsification studies. The composition of ATC-SNEDDS was optimised using the Box-Behnken optimisation design. Optimised ATC-SNEDDS was characterised for various physicochemical properties. Pharmacokinetic, pharmacodynamic and histological findings were performed in rats. Optimised ATC-SNEDDS resulted in droplets size of 5.66 nm, zeta potential of -19.52 mV, t 90 of 5.43 min and completely released ATC within 30 min irrespective of pH of the medium. Area under the curve of optimised ATC-SNEDDS in rats was 2.34-folds higher than ATC suspension. Pharmacodynamic studies revealed significant reduction in serum lipids of rats with fatty liver. Photomicrographs showed improvement in hepatocytes structure. In this study, we confirmed that ATC-SNEDDS would be a promising approach for improving oral bioavailability of ATC.

Self-nanoemulsifying drug delivery systems ameliorate the oral delivery of silymarin in rats with Roux-en-Y gastric bypass surgery

PubMed Central

Chen, Chun-Han; Chang, Cheng-Chih; Shih, Tsung-Hsien; Aljuffali, Ibrahim A; Yeh, Ta-Sen; Fang, Jia-You

2015-01-01

Roux-en-Y gastric bypass (RYGB) is a popular surgery to reduce the body weight of obese patients. Although food intake is restricted by RYGB, drug absorption is also decreased. The purpose of this study was to develop novel self-nanoemulsifying drug delivery systems (SNEDDS) for enhancing the oral delivery of silymarin, which has poor water solubility. The SNEDDS were characterized by size, zeta potential, droplet number, and morphology. A technique of RYGB was performed in Sprague-Dawley rats. SNEDDS were administered at a silymarin dose of 600 mg/kg in normal and RYGB rats for comparison with silymarin aqueous suspension and polyethylene glycol (PEG) 400 solution. Plasma silibinin, the main active ingredient in silymarin, was chosen for estimating the pharmacokinetic parameters. SNEDDS diluted in simulated gastric fluid exhibited a droplet size of 190 nm with a spherical shape. The nanocarriers promoted silibinin availability via oral ingestion in RYGB rats by 2.5-fold and 1.5-fold compared to the suspension and PEG 400 solution, respectively. A significant double-peak concentration of silibinin was detected for RYGB rats receiving SNEDDS. Fluorescence imaging showed a deeper and broader penetration of Nile red, the fluorescence dye, into the gastrointestinal mucosa from SNEDDS than from PEG 400 solution. Histological examination showed that SNEDDS caused more minor inflammation at the gastrointestinal membrane as compared with that caused by PEG 400 solution, indicating a shielding of direct silymarin contact with the mucosa by the nanodroplets. SNEDDS generally showed low-level or negligible irritation in the gastrointestinal tract. Silymarin-loaded SNEDDS were successfully developed to improve the dissolution, permeability, and oral bioavailability of silymarin. To the best of our knowledge, this is the first investigation reporting the usefulness of SNEDDS for improving drug malabsorption elicited by gastric bypass surgery. PMID:25848259

Self-nanoemulsifying drug delivery systems ameliorate the oral delivery of silymarin in rats with Roux-en-Y gastric bypass surgery.

PubMed

Chen, Chun-Han; Chang, Cheng-Chih; Shih, Tsung-Hsien; Aljuffali, Ibrahim A; Yeh, Ta-Sen; Fang, Jia-You

2015-01-01

Roux-en-Y gastric bypass (RYGB) is a popular surgery to reduce the body weight of obese patients. Although food intake is restricted by RYGB, drug absorption is also decreased. The purpose of this study was to develop novel self-nanoemulsifying drug delivery systems (SNEDDS) for enhancing the oral delivery of silymarin, which has poor water solubility. The SNEDDS were characterized by size, zeta potential, droplet number, and morphology. A technique of RYGB was performed in Sprague-Dawley rats. SNEDDS were administered at a silymarin dose of 600 mg/kg in normal and RYGB rats for comparison with silymarin aqueous suspension and polyethylene glycol (PEG) 400 solution. Plasma silibinin, the main active ingredient in silymarin, was chosen for estimating the pharmacokinetic parameters. SNEDDS diluted in simulated gastric fluid exhibited a droplet size of 190 nm with a spherical shape. The nanocarriers promoted silibinin availability via oral ingestion in RYGB rats by 2.5-fold and 1.5-fold compared to the suspension and PEG 400 solution, respectively. A significant double-peak concentration of silibinin was detected for RYGB rats receiving SNEDDS. Fluorescence imaging showed a deeper and broader penetration of Nile red, the fluorescence dye, into the gastrointestinal mucosa from SNEDDS than from PEG 400 solution. Histological examination showed that SNEDDS caused more minor inflammation at the gastrointestinal membrane as compared with that caused by PEG 400 solution, indicating a shielding of direct silymarin contact with the mucosa by the nanodroplets. SNEDDS generally showed low-level or negligible irritation in the gastrointestinal tract. Silymarin-loaded SNEDDS were successfully developed to improve the dissolution, permeability, and oral bioavailability of silymarin. To the best of our knowledge, this is the first investigation reporting the usefulness of SNEDDS for improving drug malabsorption elicited by gastric bypass surgery.

In vitro and in vivo evaluation of self-nanoemulsifying drug delivery systems of cilostazol for oral and parenteral administration.

PubMed

Mahmoud, Dina B; Shukr, Marwa H; Bendas, Ehab R

2014-12-10

The current investigation was aimed to improve the solubility of poorly soluble drug, cilostazol (CLZ). Self-nanoemulsifying drug delivery system (SNEDDS) composed of oil, surfactant and co-surfactant for both oral and parenteral administration of CLZ was formulated. The components for SNEDDS were identified by solubility studies, and pseudo-ternary phase diagrams were plotted to identify the efficient self-emulsification regions. The optimum formula, composed of Capryol 90 as an oil phase, Cremophor EL as a surfactant, and Transcutol HP as a co-surfactant in a ratio of 19.8:30.5:49.7 by weight, was able to solubilize CLZ 2000 times higher than its solubility in water. This formula was able to form grade "A" nanoemulsion when diluted with water, resulted in emulsification time of 50±1.1 s, particle size of 14.3 nm, PDI of 0.5 and % transmittance was 97.40%±0.65. It showed excellent in vitro dissolution of 93.1% and 81.5% after 5 min in 0.3% sodium lauryl sulphate solution and phosphate buffer pH 6.4, respectively when compared with the marketed tablet formulation and drug suspension as the tablets showed only 44.3% and 9.9% while CLZ suspension showed 33.9% and 8.8% in 0.3% sodium lauryl sulphate solution and phosphate buffer pH 6.4, respectively. It was found to be robust to dilution, thermodynamically stable with low viscosity values of 14.20±0.35 cP. In vivo study revealed significant increase in bioavailability of CLZ in rabbits to 3.94 fold compared with the marketed tablet formulation after oral administration. This formula could be sterilized by autoclaving and did not cause significant hemolysis to human blood which indicates its safety for intravenous administration with a 1.12 fold increase in bioavailability compared with its oral administration. Our study illustrated the potential use of SNEDDS of poorly soluble CLZ orally, and its successful administration of parenterally when required in acute cases of myocardial and cerebral infarction. Copyright © 2014 Elsevier B.V. All rights reserved.

A novel solid self-nanoemulsifying drug delivery system (S-SNEDDS) for improved stability and oral bioavailability of an oily drug, 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol.

PubMed

Kim, Kyeong Soo; Yang, Eun Su; Kim, Dong Shik; Kim, Dong Wuk; Yoo, Hye Hyun; Yong, Chul Soon; Youn, Yu Seok; Oh, Kyung Taek; Jee, Jun-Pil; Kim, Jong Oh; Jin, Sung Giu; Choi, Han Gon

2017-11-01

To develop a novel solid self-nanoemulsifying drug delivery system (S-SNEDDS) for a water-insoluble oily drug, 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) with improved stability and oral bioavailability, numerous S-SNEDDS were prepared with surfactant, hydrophilic polymer, antioxidant, and calcium silicate (porous carrier) using the spray-drying method. Their physicochemical properties were evaluated using emulsion droplet size analysis, SEM and PXRD. Moreover, the solubility, dissolution, stability, and pharmacokinetics of the selected S-SNEDDS were assessed compared with the drug and a commercial soft capsule. Sodium lauryl sulfate (SLS) and hydroxypropyl methylcellulose (HPMC) with the highest drug solubility were selected as surfactant and hydrophilic polymer, respectively. Among the antioxidants tested, only butylated hydroxyanisole (BHA) could completely protect the drug from oxidative degradation. The S-SNEDDS composed of PLAG/SLS/HPMC/BHA/calcium silicate at a weight ratio of 1: 0.25: 0.1: 0.0002: 0.5 provided an emulsion droplet size of less than 300 nm. In this S-SNEDDS, the drug and other ingredients might exist in the pores of carrier and attach onto its surface. It considerably improved the drug stability (about 100 vs. 70%, 60 °C for 5 d) and dissolution (about 80 vs. 20% in 60 min) compared to the commercial soft capsule. Moreover, the S-SNEDDS gave higher AUC, C max , and T max values than the commercial soft capsule; in particular, the former improved the oral bioavailability of PLAG by about 3-fold. Our results suggested that this S-SNEDDS provided excellent stability and oral bioavailability of PLAG. Thus, this S-SNEDDS would be recommended as a powerful oral drug delivery system for an oily drug, PLAG.

Self-nanoemulsifying drug delivery system for enhanced bioavailability and improved hepatoprotective activity of biphenyl dimethyl dicarboxylate.

PubMed

El-Laithy, Hanan M

2008-07-01

Biphenyl Dimethyl Dicarboxylate (BDD) is insoluble in aqueous solution and the bioavailability after oral administration is low. Self-nanoemulsifying drug delivery system (SNEDDS) containing BDD has been successfully prepared using carefully selected ingredients which are less affected by pH and ionic strength changes to improve its bioavailability. SNEDDS is an isotropic mixture of lipid, surfactant, and cosurfactant which are spontaneously emulsified in aqueous medium under gentle digestive motility in the gastrointestinal tract. Pseudo ternary phase diagrams composed of various excipients were plotted to identify self -nano -emulsifying area. Droplet size changes upon dilution with aqueous media and in vitro release of BDD from SNEDDS in 0.1N HCl and phosphate buffer (pH 7.4) were studied and compared with commercial chinese pilules and Pennel capsules. The hepatoprotective activity upon oral administration of SNEDDS against carbon tetrachloride-induced oxidative stress in albino rats was assessed by measuring biochemical parameters like serum glutamic oxalacetate transaminase (SGOT), serum glutamic pyruvate transaminase (SGPT) and lactate dehydrogenase (LDH). Results showed that using a proper ratio of Tween 80 to Transcutol as surfactant and co-surfactant respectively and Miglyol 812 as oil to surfactants mixture resulted in production of infinitely diluted formulations in nano droplet size range. BDD self nano emulsified formula composed of 20% Miglyol 812, 60% Tween 80 and 20% Transcutol released 99% of the drug very rapidly within 10-15 minutes regardless of the pH condition. The oral absorption and bioavailability of BDD self nano emulsified formula in albino rats were significantly enhanced (P<0.01) with an average improvement of 1.7 and 6-folds that of commercial chinese pilules and Pennel capsules respectively. This improvement was also confirmed histopathologically in chemically injured rats and by the significant decrease in elevated liver enzymes level.

Controlled release of cyclosporine A self-nanoemulsifying systems from osmotic pump tablets: near zero-order release and pharmacokinetics in dogs.

PubMed

Zhang, Xi; Yi, Yueneng; Qi, Jianping; Lu, Yi; Tian, Zhiqiang; Xie, Yunchang; Yuan, Hailong; Wu, Wei

2013-08-16

It is very important to enhance the absorption simultaneously while designing controlled release delivery systems for poorly water-soluble and poorly permeable drugs (BCS IV). In this study, controlled release of cyclosporine (CyA) was achieved by the osmotic release strategy taking advantage of the absorption-enhancing capacity of self-nanoemulsifying drug delivery systems (SNEDDSs). The liquid SNEDDS consisting of Labrafil M 1944CS, Transcutol P and Cremophor EL was absorbed by the osmotic tablet core excipients (sucrose, lactose monohydrate, polyethylene oxide, and partly pregelatinized starch) and then transformed into osmotic tablets. Near zero-order release could be achieved for CyA-loaded nanoemulsions reconstituted from the SNEDDS. In general, the influencing factor study indicated that the release rate increased with increase of inner osmotic pressure, ratio of osmotic agent to suspending agent, content of pore-forming agent, and size of release orifice, whereas the thickness of the membrane impeded the release of CyA nanoemulsion. Pharmacokinetic study showed steady blood CyA profiles with prolonged Tmax and MRT, and significantly reduced Cmax for self-nanoemulsifying osmotic pump tablet (SNEOPT) in comparison with highly fluctuating profiles of the core tablet and Sandimmune Neoral(®). However, similar oral bioavailability was observed for either controlled release or non-controlled release formulations. It was concluded that simultaneous controlling on CyA release and absorption-enhancing had been achieved by a combination of osmotic tablet and SNEDDS. Copyright © 2013 Elsevier B.V. All rights reserved.

Acute And Subchronic Toxicity Studies Of SNEDDS (Self Nanoemulsifying Drug Delivery Systems) From Ethyl Acetate Extract Of Bay Leaf (Eugenia polyantha W.) with Virgin Coconut Oil As Oil Phase

NASA Astrophysics Data System (ADS)

Prihapsara, F.; Alamsyah, R. I.; Widiyani, T.; Artanti, A. N.

2018-03-01

Bay leaf (Eugenia polyantha) is widely used as an alternative therapy for diabetic and hypercholesterol. However, the administration of the extract has a low oral bioavailability, therefore it is prepared by Self Nanoemulsifying Drug Delivery Systems (SNEDDS) ethyl acetate extract of bay leaf. Therefore, acute and subchronic toxicity test is required. The toxicity test performed was an experimental study, including acute and subchronic toxicity tests. Animal experiments were used using Wistar strain rats. Acute toxicity test using 5 groups (n=5) consisted of 1 control group and 4 groups of SNEDDS dose with 48 mg/kgBW 240 mg/kg, 1200 mg/kg, and 6000 mg/kg, while for subchronic toxicity test with 1 group control and 3 groups of doses of SNEDDS with dose group variation 91.75 mg/kgBW, 183.5 mg/kg, and 367 mg/kg. Duration of observation at acute toxicity test for 14 days while for subcronic toxicity test for 28 days with continuous SNEDDS dosage. The results of the acute toxicity test showed toxic symptoms and obtained median lethal dose (LD50) values from SNEDDS from ethyl acetate extract of bay leaf 1409.30 mg/kgBW belonging to slightly toxic category. Subchronic toxicity studies show that the test drug has minor damage in liver and kidneys and moderate damage in pancreas.

Acute and Subchronic Toxicity of Self Nanoemulsifying Drug Delivery Systems (SNEDDS) from Chloroform Bay Leaf Extract (Eugenia Polyantha W.) with Palm Kernel Oil as A Carrier

NASA Astrophysics Data System (ADS)

Prihapsara, F.; Mufidah; Artanti, A. N.; Harini, M.

2018-03-01

The present study was aimed to study the acute and subchronic toxicity of Self Nanoemulsifying Drug Delivery Systems (SNEDDS) from chloroform bay leaf extract with Palm Kernel Oil as carrier. In acute toxicity test, five groups of rat (n=5/groups) were orally treated with Self Nanoemulsifying Drug Delivery Systems (SNEDDS) from chloroform bay leaf extract with doses at 48, 240, 1200 and 6000 mg/kg/day respectively, then the median lethal dose LD50, advers effect and mortality were recorded up to 14 days. Meanwhile, in subchronic toxicity study, 4 groups of rats (n=6/group) received by orally treatment of SNEDDS from chloroform bay leaf extract with doses at 91.75; 183.5; 367 mg/kg/day respectively for 28 days, and biochemical, hematological and histopatological change in tissue such as liver, kidney, and pancreatic were determined. The result show that LD50 is 1045.44 mg/kg. Although histopathological examination of most of the organs exhibited no structural changes, some moderate damage was observed in high‑ dose group animals (367 mg/kg/day). The high dose of SNEDDS extract has shown mild signs of toxicity on organ function test.

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

PubMed

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

2017-06-08

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

Validated spectrofluorometric method for determination of gemfibrozil in self nanoemulsifying drug delivery systems (SNEDDS)

NASA Astrophysics Data System (ADS)

Sierra Villar, Ana M.; Calpena Campmany, Ana C.; Bellowa, Lyda Halbaut; Trenchs, Monserrat Aróztegui; Naveros, Beatriz Clares

2013-09-01

A spectrofluorometric method has been developed and validated for the determination of gemfibrozil. The method is based on the excitation and emission capacities of gemfibrozil with excitation and emission wavelengths of 276 and 304 nm respectively. This method allows de determination of the drug in a self-nanoemulsifying drug delivery system (SNEDDS) for improve its intestinal absorption. Results obtained showed linear relationships with good correlation coefficients (r2 > 0.999) and low limits of detection and quantification (LOD of 0.075 μg mL-1 and LOQ of 0.226 μg mL-1) in the range of 0.2-5 μg mL-1, equally this method showed a good robustness and stability. Thus the amounts of gemfibrozil released from SNEDDS contained in gastro resistant hard gelatine capsules were analysed, and release studies could be performed satisfactorily.

Validated spectrofluorometric method for determination of gemfibrozil in self nanoemulsifying drug delivery systems (SNEDDS).

PubMed

Sierra Villar, Ana M; Calpena Campmany, Ana C; Bellowa, Lyda Halbaut; Trenchs, Monserrat Aróztegui; Naveros, Beatriz Clares

2013-09-01

A spectrofluorometric method has been developed and validated for the determination of gemfibrozil. The method is based on the excitation and emission capacities of gemfibrozil with excitation and emission wavelengths of 276 and 304 nm respectively. This method allows de determination of the drug in a self-nanoemulsifying drug delivery system (SNEDDS) for improve its intestinal absorption. Results obtained showed linear relationships with good correlation coefficients (r(2)>0.999) and low limits of detection and quantification (LOD of 0.075 μg mL(-1) and LOQ of 0.226 μg mL(-1)) in the range of 0.2-5 μg mL(-1), equally this method showed a good robustness and stability. Thus the amounts of gemfibrozil released from SNEDDS contained in gastro resistant hard gelatine capsules were analysed, and release studies could be performed satisfactorily. Copyright © 2013 Elsevier B.V. All rights reserved.

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

PubMed

Adhikari, Manish; Arora, Rajesh

2015-10-01

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

Analysis of 3D Prints by X-ray Computed Microtomography and Terahertz Pulsed Imaging.

PubMed

Markl, Daniel; Zeitler, J Axel; Rasch, Cecilie; Michaelsen, Maria Høtoft; Müllertz, Anette; Rantanen, Jukka; Rades, Thomas; Bøtker, Johan

2017-05-01

A 3D printer was used to realise compartmental dosage forms containing multiple active pharmaceutical ingredient (API) formulations. This work demonstrates the microstructural characterisation of 3D printed solid dosage forms using X-ray computed microtomography (XμCT) and terahertz pulsed imaging (TPI). Printing was performed with either polyvinyl alcohol (PVA) or polylactic acid (PLA). The structures were examined by XμCT and TPI. Liquid self-nanoemulsifying drug delivery system (SNEDDS) formulations containing saquinavir and halofantrine were incorporated into the 3D printed compartmentalised structures and in vitro drug release determined. A clear difference in terms of pore structure between PVA and PLA prints was observed by extracting the porosity (5.5% for PVA and 0.2% for PLA prints), pore length and pore volume from the XμCT data. The print resolution and accuracy was characterised by XμCT and TPI on the basis of the computer-aided design (CAD) models of the dosage form (compartmentalised PVA structures were 7.5 ± 0.75% larger than designed; n = 3). The 3D printer can reproduce specific structures very accurately, whereas the 3D prints can deviate from the designed model. The microstructural information extracted by XμCT and TPI will assist to gain a better understanding about the performance of 3D printed dosage forms.

Nanoemulsions as self-emulsified drug delivery carriers for enhanced permeability of the poorly water-soluble selective β₁-adrenoreceptor blocker Talinolol.

PubMed

Ghai, Damanjeet; Sinha, Vivek Ranjan

2012-07-01

To enhance the bioavailability of the poorly water-soluble drug talinolol, a self-nanoemulsifying drug delivery system (SNEDDS) comprising 5% (w/v) Brij-721 ethanolic solution (Smix), triacetin, and water, in the ratio of 40:20:40 (% w/w) was developed by constructing pseudo-ternary phase diagrams and evaluated for droplet size, polydispersity index, and surface morphology of nanoemulsions. The effect of nanodrug carriers on drug release and permeability was assessed using stripped porcine jejunum and everted rat gut sac method and compared with hydroalcoholic drug solution, oily solution, and conventional emulsion and suspension. The SNEDDS showed a significant (P < 0.001) increase in drug release, permeability, and in vivo bioavailability as compared to drug suspension. This may be attributed to increased solubility and enhanced permeability of the drug from nanosized emulsion. In this study, a self-nanoemulsifying drug delivery system was utilized to enhance the bioavailability of the poorly water-soluble beta-blocker talinolol. Significant increase in drug release, permeability, and in vivo bioavailability were demonstrated as compared to standard drug suspension. Copyright © 2012 Elsevier Inc. All rights reserved.

Transport of lipid nano-droplets through MDCK epithelial cell monolayer.

PubMed

Khatri, Pulkit; Shao, Jun

2017-05-01

This study aims to investigate the transport of lipid nano-droplets through MDCK epithelial cell monolayer. Nanoemulsions of self-nano-emulsifying drug delivery systems (SNEDDS) labeled with radioactive C18 triglyceride were developed. The effect of droplet size and lipid composition on the transport was investigated. The results showed that the lipid nano-droplet transport through MDCK cell monolayer was as high as 2.5%. The transport of lipid nano-droplets was higher for nanoemulsions of medium chain glycerides than the long chain glycerides. The transport was reduced by more than half when the average lipid nano-droplet size increased from 38nm to 261nm. The droplet size measurement verified the existence of lipid nano-droplets in the receiver chamber only when the nanoemulsions were added to the donor chamber but not when the surfactant or saline solution was added. Cryo-TEM images confirmed the presence of lipid nano-droplets in both donor and receiver chamber at the end of transport study. In conclusion, lipid nano-droplets can be transported through the cell monolayer. This finding may help to further explore the oral and other non-invasive delivery of macromolecules loaded inside SNEDDS. Copyright © 2017 Elsevier B.V. All rights reserved.

Zaleplon loaded bi-layered chronopatch: A novel buccal chronodelivery approach to overcome circadian rhythm related sleep disorder.

PubMed

Farag, Michael M; Abd El Malak, Nevine S; Yehia, Soad A

2018-05-05

The aim of this study was to develop a novel buccal bi-layered chronopatch capable of eliciting pulsatile release pattern of drugs treating diseases with circadian rhythm related manifestation. Zaleplon (ZLP) was used as a model drug intended to induce sleep and to treat middle of night insomnia. The chronopatch was prepared adopting double casting technique. The first layer was composed of a controlled release patch containing ZLP-Precirol melt granules intended to release ZLP in a sustained manner to maintain sleep and to prevent early morning awakening. The second layer was composed of a fast release lyophilized buccal disc containing ZLP loaded SNEDDS (Z-SNEDDS) intended for rapid sleep induction. Pharmacokinetic parameters of ZLP from the chronopatch were compared to those of the immediate release capsule, Siesta®, as reference in Mongrel dogs using a randomized crossover design. The appearance of two peaks having two C max and T max proved the pulsatile release pattern. The increase in relative bioavailability of ZLP from the chronopatch was 2.63 folds. The results revealed the ability of the developed ZLP loaded bi-layered chronopatch to be a candidate for overcoming early morning awakening without middle of night dose administration. Copyright © 2018 Elsevier B.V. All rights reserved.

A comparative study on stress and compliance based structural topology optimization

NASA Astrophysics Data System (ADS)

Hailu Shimels, G.; Dereje Engida, W.; Fakhruldin Mohd, H.

2017-10-01

Most of structural topology optimization problems have been formulated and solved to either minimize compliance or weight of a structure under volume or stress constraints, respectively. Even if, a lot of researches are conducted on these two formulation techniques separately, there is no clear comparative study between the two approaches. This paper intends to compare these formulation techniques, so that an end user or designer can choose the best one based on the problems they have. Benchmark problems under the same boundary and loading conditions are defined, solved and results are compared based on these formulations. Simulation results shows that the two formulation techniques are dependent on the type of loading and boundary conditions defined. Maximum stress induced in the design domain is higher when the design domains are formulated using compliance based formulations. Optimal layouts from compliance minimization formulation has complex layout than stress based ones which may lead the manufacturing of the optimal layouts to be challenging. Optimal layouts from compliance based formulations are dependent on the material to be distributed. On the other hand, optimal layouts from stress based formulation are dependent on the type of material used to define the design domain. High computational time for stress based topology optimization is still a challenge because of the definition of stress constraints at element level. Results also shows that adjustment of convergence criterions can be an alternative solution to minimize the maximum stress developed in optimal layouts. Therefore, a designer or end user should choose a method of formulation based on the design domain defined and boundary conditions considered.

Development of transethosomes formulation for dermal fisetin delivery: Box-Behnken design, optimization, in vitro skin penetration, vesicles-skin interaction and dermatokinetic studies.

PubMed

Moolakkadath, Thasleem; Aqil, Mohd; Ahad, Abdul; Imam, Syed Sarim; Iqbal, Babar; Sultana, Yasmin; Mujeeb, Mohd; Iqbal, Zeenat

2018-05-07

The present study was conducted for the optimization of transethosomes formulation for dermal fisetin delivery. The optimization of the formulation was carried out using "Box-Behnken design". The independent variables were Lipoid S 100, ethanol and sodium cholate. The prepared formulations were characterized for vesicle size, entrapment efficiency and in vitro skin penetration study. The vesicles-skin interaction, confocal laser scanning microscopy and dermatokinetic studies were performed with optimized formulation. Results of the present study demonstrated that the optimized formulation presented vesicle size of 74.21 ± 2.65 nm, zeta potential of -11.0 mV, entrapment efficiency of 68.31 ± 1.48% and flux of 4.13 ± 0.17 µg/cm 2 /h. The TEM image of optimized formulation exhibited sealed and spherical shape vesicles. Results of thermoanalytical techniques demonstrated that the prepared transethosomes vesicles formulation had fluidized the rigid membrane of rat's skin for smoother penetration of fisetin transethosomes. The confocal study results presented well distribution and penetration of Rhodamine B loaded transethosomes vesicles formulation up to deeper layers of the rat's skin as compared to the Rhodamine B-hydro alcoholic solution. Present study data revealed that the developed transethosomes vesicles formulation was found to be a potentially useful drug carrier for fisetin dermal delivery.

Influence of cellulose derivative and ethylene glycol on optimization of lornoxicam transdermal formulation.

PubMed

Shahzad, Yasser; Khan, Qalandar; Hussain, Talib; Shah, Syed Nisar Hussain

2013-10-01

Lornoxicam containing topically applied lotions were formulated and optimized with the aim to deliver it transdermally. The formulated lotions were evaluated for pH, viscosity and in vitro permeation studies through silicone membrane using Franz diffusion cells. Data were fitted to linear, quadratic and cubic models and best fit model was selected to investigate the influence of variables, namely hydroxypropyl methylcellulose (HPMC) and ethylene glycol (EG) on permeation of lornoxicam from topically applied lotion formulations. The best fit quadratic model revealed that low level of HPMC and intermediate level of EG in the formulation was optimum for enhancing the drug flux across silicone membrane. FT-IR analysis confirmed absence of drug-polymer interactions. Selected optimized lotion formulation was then subjected to accelerated stability testing, sensatory perception testing and in vitro permeation across rabbit skin. The drug flux from the optimized lotion across rabbit skin was significantly better that that from the control formulation. Furthermore, sensatory perception test rated a higher acceptability while lotion was stable over stability testing period. Therefore, use of Box-Wilson statistical design successfully elaborated the influence of formulation variables on permeation of lornoxicam form topical formulations, thus, helped in optimization of the lotion formulation. Copyright © 2013 Elsevier B.V. All rights reserved.

Enhanced Ungual Permeation of Terbinafine HCl Delivered Through Liposome-Loaded Nail Lacquer Formulation Optimized by QbD Approach.

PubMed

Shah, Viral H; Jobanputra, Amee

2018-01-01

The present investigation focused on developing, optimizing, and evaluating a novel liposome-loaded nail lacquer formulation for increasing the transungual permeation flux of terbinafine HCl for efficient treatment of onychomycosis. A three-factor, three-level, Box-Behnken design was employed for optimizing process and formulation parameters of liposomal formulation. Liposomes were formulated by thin film hydration technique followed by sonication. Drug to lipid ratio, sonication amplitude, and sonication time were screened as independent variables while particle size, PDI, entrapment efficiency, and zeta potential were selected as quality attributes for liposomal formulation. Multiple regression analysis was employed to construct a second-order quadratic polynomial equation and contour plots. Design space (overlay plot) was generated to optimize a liposomal system, with software-suggested levels of independent variables that could be transformed to desired responses. The optimized liposome formulation was characterized and dispersed in nail lacquer which was further evaluated for different parameters. Results depicted that the optimized terbinafine HCl-loaded liposome formulation exhibited particle size of 182 nm, PDI of 0.175, zeta potential of -26.8 mV, and entrapment efficiency of 80%. Transungual permeability flux of terbinafine HCl through liposome-dispersed nail lacquer formulation was observed to be significantly higher in comparison to nail lacquer with a permeation enhancer. The developed formulation was also observed to be as efficient as pure drug dispersion in its antifungal activity. Thus, it was concluded that the developed formulation can serve as an efficient tool for enhancing the permeability of terbinafine HCl across human nail plate thereby improving its therapeutic efficiency.

Prolonged release matrix tablet of pyridostigmine bromide: formulation and optimization using statistical methods.

PubMed

Bolourchian, Noushin; Rangchian, Maryam; Foroutan, Seyed Mohsen

2012-07-01

The aim of this study was to design and optimize a prolonged release matrix formulation of pyridostigmine bromide, an effective drug in myasthenia gravis and poisoning with nerve gas, using hydrophilic - hydrophobic polymers via D-optimal experimental design. HPMC and carnauba wax as retarding agents as well as tricalcium phosphate were used in matrix formulation and considered as independent variables. Tablets were prepared by wet granulation technique and the percentage of drug released at 1 (Y(1)), 4 (Y(2)) and 8 (Y(3)) hours were considered as dependent variables (responses) in this investigation. These experimental responses were best fitted for the cubic, cubic and linear models, respectively. The optimal formulation obtained in this study, consisted of 12.8 % HPMC, 24.4 % carnauba wax and 26.7 % tricalcium phosphate, had a suitable prolonged release behavior followed by Higuchi model in which observed and predicted values were very close. The study revealed that D-optimal design could facilitate the optimization of prolonged release matrix tablet containing pyridostigmine bromide. Accelerated stability studies confirmed that the optimized formulation remains unchanged after exposing in stability conditions for six months.

Optimized zein nanospheres for improved oral bioavailability of atorvastatin

PubMed Central

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

2015-01-01

Background This work focuses on the development of atorvastatin utilizing zein, a natural, safe, and biocompatible polymer, as a nanosized formulation in order to overcome the poor oral bioavailability (12%) of the drug. Methods Twelve experimental runs of atorvastatin–zein nanosphere formula were formulated by a liquid–liquid phase separation method according to custom fractional factorial design to optimize the formulation variables. The factors studied were: weight % of zein to atorvastatin (X1), pH (X2), and stirring time (X3). Levels for each formulation variable were designed. The selected dependent variables were: mean particle size (Y1), zeta potential (Y2), drug loading efficiency (Y3), drug encapsulation efficiency (Y4), and yield (Y5). The optimized formulation was assayed for compatibility using an X-ray diffraction assay. In vitro diffusion of the optimized formulation was carried out. A pharmacokinetic study was also done to compare the plasma profile of the atorvastatin–zein nanosphere formulation versus atorvastatin oral suspension and the commercially available tablet. Results The optimized atorvastatin–zein formulation had a mean particle size of 183 nm, a loading efficiency of 14.86%, and an encapsulation efficiency of 29.71%. The in vitro dissolution assay displayed an initial burst effect, with a cumulative amount of atorvastatin released of 41.76% and 82.3% after 12 and 48 hours, respectively. In Wistar albino rats, the bioavailability of atorvastatin from the optimized atorvastatin–zein formulation was 3-fold greater than that from the atorvastatin suspension and the commercially available tablet. Conclusion The atorvastatin–zein nanosphere formulation improved the oral delivery and pharmacokinetic profile of atorvastatin by enhancing its oral bioavailability. PMID:26150716

Effect of formulation variables on design, in vitro evaluation of valsartan SNEDDS and estimation of its antioxidant effect in adrenaline-induced acute myocardial infarction in rats.

PubMed

Amin, Maha M; El Gazayerly, Omaima N; Abd El-Gawad, Nabaweya A; Abd El-Halim, Shady M; El-Awdan, Sally A

2016-12-01

Valsartan is a specific angiotensin II antagonist used for the treatment of hypertension. It suffers from low aqueous solubility and high variability in its absorption after oral administration. The aim of this study was to improve the dissolution and thereby the bioavailability of Valsartan through the development of self nano-emulsifying drug delivery systems. Four ternary phase diagrams were constructed to identify the self-emulsification region of Capmul® MCM, Labrafil® M1944, Capryol™ 90 and Labrafac® PG together with Cremophore® RH 40 and Transcutol™ HP as oil, surfactant and co-surfactant, respectively. The effect of oil type, oil and surfactant concentration on droplet size and in vitro Valsartan dissolution were studied. The protective effect of the optimum formula F5 in adrenaline-induced oxidative stress in rats during myocardial infarction was determined. Formula F5 exhibited globule size of (13.95 nm) with 76.07% ± 1.10 of Valsartan dissolved after five minutes compared to Disartan 80 mg capsules (13.43%). Results revealed a significant reduction (p < 0.05) in serum aspartate transaminase, creatine kinase myocardial band and malondialdehyde levels, while a significant increase (p < 0.05) in serum glutathione in F5. Therefore, self nano-emulsifying drug delivery systems could be considered as a promising approach to improve the dissolution and thereby the bioavailability of Valsartan.

Optimization of formulation variables of benzocaine liposomes using experimental design.

PubMed

Mura, Paola; Capasso, Gaetano; Maestrelli, Francesca; Furlanetto, Sandra

2008-01-01

This study aimed to optimize, by means of an experimental design multivariate strategy, a liposomal formulation for topical delivery of the local anaesthetic agent benzocaine. The formulation variables for the vesicle lipid phase uses potassium glycyrrhizinate (KG) as an alternative to cholesterol and the addition of a cationic (stearylamine) or anionic (dicethylphosphate) surfactant (qualitative factors); the percents of ethanol and the total volume of the hydration phase (quantitative factors) were the variables for the hydrophilic phase. The combined influence of these factors on the considered responses (encapsulation efficiency (EE%) and percent drug permeated at 180 min (P%)) was evaluated by means of a D-optimal design strategy. Graphic analysis of the effects indicated that maximization of the selected responses requested opposite levels of the considered factors: For example, KG and stearylamine were better for increasing EE%, and cholesterol and dicethylphosphate for increasing P%. In the second step, the Doehlert design, applied for the response-surface study of the quantitative factors, pointed out a negative interaction between percent ethanol and volume of the hydration phase and allowed prediction of the best formulation for maximizing drug permeation rate. Experimental P% data of the optimized formulation were inside the confidence interval (P < 0.05) calculated around the predicted value of the response. This proved the suitability of the proposed approach for optimizing the composition of liposomal formulations and predicting the effects of formulation variables on the considered experimental response. Moreover, the optimized formulation enabled a significant improvement (P < 0.05) of the drug anaesthetic effect with respect to the starting reference liposomal formulation, thus demonstrating its actually better therapeutic effectiveness.

Development and Optimization of Silver Nanoparticle Formulation for Fabrication

DTIC Science & Technology

2015-08-14

Development and Optimization of Silver Nanoparticle Formulation for Fabrication Publication Type: DJournal/ Paper D Book Chapter ~ Tech Report D...leofPublicationorPresentation: Deve l opment and Optimization of Silver Nanoparticle Formulation for Fabrication 3. Author(s): (List authors starting...fabrication process of silver nanoparticl es could improve future silver containing products , which is i mpor tant to l owering toxicity and improving

Bilayer tablets of Paliperidone for Extended release osmotic drug delivery

NASA Astrophysics Data System (ADS)

Chowdary, K. Sunil; Napoleon, A. A.

2017-11-01

The purpose of this study is to develop and optimize the formulation of paliperidone bilayer tablet core and coating which should meet in vitro performance of trilayered Innovator sample Invega. Optimization of core formulations prepared by different ratio of polyox grades and optimization of coating of (i) sub-coating build-up with hydroxy ethyl cellulose (HEC) and (ii).enteric coating build-up with cellulose acetate (CA). Some important influence factors such as different core tablet compositions and different coating solution ingredients involved in the formulation procedure were investigated. The optimization of formulation and process was conducted by comparing different in vitro release behaviours of Paliperidone. In vitro dissolution studies of Innovator sample (Invega) with formulations of different release rate which ever close release pattern during the whole 24 h test is finalized.

Optimization and characterization of liposome formulation by mixture design.

PubMed

Maherani, Behnoush; Arab-tehrany, Elmira; Kheirolomoom, Azadeh; Reshetov, Vadzim; Stebe, Marie José; Linder, Michel

2012-02-07

This study presents the application of the mixture design technique to develop an optimal liposome formulation by using the different lipids in type and percentage (DOPC, POPC and DPPC) in liposome composition. Ten lipid mixtures were generated by the simplex-centroid design technique and liposomes were prepared by the extrusion method. Liposomes were characterized with respect to size, phase transition temperature, ζ-potential, lamellarity, fluidity and efficiency in loading calcein. The results were then applied to estimate the coefficients of mixture design model and to find the optimal lipid composition with improved entrapment efficiency, size, transition temperature, fluidity and ζ-potential of liposomes. The response optimization of experiments was the liposome formulation with DOPC: 46%, POPC: 12% and DPPC: 42%. The optimal liposome formulation had an average diameter of 127.5 nm, a phase-transition temperature of 11.43 °C, a ζ-potential of -7.24 mV, fluidity (1/P)(TMA-DPH)((¬)) value of 2.87 and an encapsulation efficiency of 20.24%. The experimental results of characterization of optimal liposome formulation were in good agreement with those predicted by the mixture design technique.

Isotretinoin Oil-Based Capsule Formulation Optimization

PubMed Central

Tsai, Pi-Ju; Huang, Chi-Te; Lee, Chen-Chou; Li, Chi-Lin; Huang, Yaw-Bin; Tsai, Yi-Hung; Wu, Pao-Chu

2013-01-01

The purpose of this study was to develop and optimize an isotretinoin oil-based capsule with specific dissolution pattern. A three-factor-constrained mixture design was used to prepare the systemic model formulations. The independent factors were the components of oil-based capsule including beeswax (X 1), hydrogenated coconut oil (X 2), and soybean oil (X 3). The drug release percentages at 10, 30, 60, and 90 min were selected as responses. The effect of formulation factors including that on responses was inspected by using response surface methodology (RSM). Multiple-response optimization was performed to search for the appropriate formulation with specific release pattern. It was found that the interaction effect of these formulation factors (X 1 X 2, X 1 X 3, and X 2 X 3) showed more potential influence than that of the main factors (X 1, X 2, and X 3). An optimal predicted formulation with Y 10 min, Y 30 min, Y 60 min, and Y 90 min release values of 12.3%, 36.7%, 73.6%, and 92.7% at X 1, X 2, and X 3 of 5.75, 15.37, and 78.88, respectively, was developed. The new formulation was prepared and performed by the dissolution test. The similarity factor f 2 was 54.8, indicating that the dissolution pattern of the new optimized formulation showed equivalence to the predicted profile. PMID:24068886

Model-based optimal design of experiments - semidefinite and nonlinear programming formulations

PubMed Central

Duarte, Belmiro P.M.; Wong, Weng Kee; Oliveira, Nuno M.C.

2015-01-01

We use mathematical programming tools, such as Semidefinite Programming (SDP) and Nonlinear Programming (NLP)-based formulations to find optimal designs for models used in chemistry and chemical engineering. In particular, we employ local design-based setups in linear models and a Bayesian setup in nonlinear models to find optimal designs. In the latter case, Gaussian Quadrature Formulas (GQFs) are used to evaluate the optimality criterion averaged over the prior distribution for the model parameters. Mathematical programming techniques are then applied to solve the optimization problems. Because such methods require the design space be discretized, we also evaluate the impact of the discretization scheme on the generated design. We demonstrate the techniques for finding D–, A– and E–optimal designs using design problems in biochemical engineering and show the method can also be directly applied to tackle additional issues, such as heteroscedasticity in the model. Our results show that the NLP formulation produces highly efficient D–optimal designs but is computationally less efficient than that required for the SDP formulation. The efficiencies of the generated designs from the two methods are generally very close and so we recommend the SDP formulation in practice. PMID:26949279

Model-based optimal design of experiments - semidefinite and nonlinear programming formulations.

PubMed

Duarte, Belmiro P M; Wong, Weng Kee; Oliveira, Nuno M C

2016-02-15

We use mathematical programming tools, such as Semidefinite Programming (SDP) and Nonlinear Programming (NLP)-based formulations to find optimal designs for models used in chemistry and chemical engineering. In particular, we employ local design-based setups in linear models and a Bayesian setup in nonlinear models to find optimal designs. In the latter case, Gaussian Quadrature Formulas (GQFs) are used to evaluate the optimality criterion averaged over the prior distribution for the model parameters. Mathematical programming techniques are then applied to solve the optimization problems. Because such methods require the design space be discretized, we also evaluate the impact of the discretization scheme on the generated design. We demonstrate the techniques for finding D -, A - and E -optimal designs using design problems in biochemical engineering and show the method can also be directly applied to tackle additional issues, such as heteroscedasticity in the model. Our results show that the NLP formulation produces highly efficient D -optimal designs but is computationally less efficient than that required for the SDP formulation. The efficiencies of the generated designs from the two methods are generally very close and so we recommend the SDP formulation in practice.

Development of carrier-based formulation of root endophyte Piriformospora indica and its evaluation on Phaseolus vulgaris L.

PubMed

Tripathi, Swati; Das, Aparajita; Chandra, Anil; Varma, Ajit

2015-02-01

Endophytic fungi are plant beneficial rhizospheric microorganisms often applied as bioinoculants for enhanced and disease-free crop production. The objectives of the present work were to develop a carrier-based formulation of root endophyte Piriformospora indica as a bioinoculant. Powder formulation of four different carrier materials viz., talcum powder, clay, sawdust and bioboost (organic supplement) were evaluated and a talc-based formulation was optimized for a longer shelf life with respect to microbial concentration, storage temperature and biological activity. Finally the effect of optimized talc formulation on plant productivity was determined. The application dosages were optimized by studies on plant growth parameters of Phaseolus vulgaris L. plants under green house conditions. Five percent formulation (w/w) of talcum powder was observed to be the most stable at 30 °C with 10(8) CFU g(-1) and effective for a storage period of 6 months. The application of this optimized formulation resulted in increase of growth parameters of P. vulgaris L. and better adaptation of plants under green house conditions.

Development and experimental design of a novel controlled-release matrix tablet formulation for indapamide hemihydrate.

PubMed

Antovska, Packa; Ugarkovic, Sonja; Petruševski, Gjorgji; Stefanova, Bosilka; Manchevska, Blagica; Petkovska, Rumenka; Makreski, Petre

2017-11-01

Development, experimental design and in vitro in vivo correlation (IVIVC) of controlled-release matrix formulation. Development of novel oral controlled delivery system for indapamide hemihydrate, optimization of the formulation by experimental design and evaluation regarding IVIVC on a pilot scale batch as a confirmation of a well-established formulation. In vitro dissolution profiles of controlled-release tablets of indapamide hemihydrate from four different matrices had been evaluated in comparison to the originator's product Natrilix (Servier) as a direction for further development and optimization of a hydroxyethylcellulose-based matrix controlled-release formulation. A central composite factorial design had been applied for the optimization of a chosen controlled-release tablet formulation. The controlled-release tablets with appropriate physical and technological properties had been obtained with a matrix: binder concentration variations in the range: 20-40w/w% for the matrix and 1-3w/w% for the binder. The experimental design had defined the design space for the formulation and was prerequisite for extraction of a particular formulation that would be a subject for transfer on pilot scale and IVIV correlation. The release model of the optimized formulation has shown best fit to the zero order kinetics depicted with the Hixson-Crowell erosion-dependent mechanism of release. Level A correlation was obtained.

Formulation and optimization of zinc-pectinate beads for the controlled delivery of resveratrol.

PubMed

Das, Surajit; Ng, Ka-Yun; Ho, Paul C

2010-06-01

Preventive and therapeutic efficacies of resveratrol on several lower gastrointestinal (GI) diseases (e.g., colorectal cancer, colitis) are well documented. To overcome the problems due to its rapid absorption and metabolism at the upper GI tract, a delayed release formulation of resveratrol was designed to treat these lower GI diseases. The current study aimed to develop a delayed release formulation of resveratrol as multiparticulate pectinate beads by varying different formulation parameters. Zinc-pectinate (Zn-pectinate) beads exhibited better delayed drug release pattern than calcium-pectinate (Ca-pectinate) beads. The effects of the formulation parameters were investigated on shape, size, Zn content, moisture content, drug encapsulation efficiency, swelling-erosion, and resveratrol retention pattern of the formulated beads. Upon optimization of the formulation parameters in relative to the drug release profiles, the optimized beads were further subjected to morphological, chemical interaction, enzymatic degradation, and stability studies. Almost all prepared beads were spherical with approximately 1 mm diameter and efficiently encapsulated resveratrol. The formulation parameters revealed great influence on resveratrol retention and swelling-erosion behavior. In most of the cases, the drug release data more appropriately fitted with zero-order equation. This study demonstrates that the optimized Zn-pectinate beads can encapsulate very high amount of resveratrol and can be used as delayed release formulation of resveratrol.

Applications of fuzzy theories to multi-objective system optimization

NASA Technical Reports Server (NTRS)

Rao, S. S.; Dhingra, A. K.

1991-01-01

Most of the computer aided design techniques developed so far deal with the optimization of a single objective function over the feasible design space. However, there often exist several engineering design problems which require a simultaneous consideration of several objective functions. This work presents several techniques of multiobjective optimization. In addition, a new formulation, based on fuzzy theories, is also introduced for the solution of multiobjective system optimization problems. The fuzzy formulation is useful in dealing with systems which are described imprecisely using fuzzy terms such as, 'sufficiently large', 'very strong', or 'satisfactory'. The proposed theory translates the imprecise linguistic statements and multiple objectives into equivalent crisp mathematical statements using fuzzy logic. The effectiveness of all the methodologies and theories presented is illustrated by formulating and solving two different engineering design problems. The first one involves the flight trajectory optimization and the main rotor design of helicopters. The second one is concerned with the integrated kinematic-dynamic synthesis of planar mechanisms. The use and effectiveness of nonlinear membership functions in fuzzy formulation is also demonstrated. The numerical results indicate that the fuzzy formulation could yield results which are qualitatively different from those provided by the crisp formulation. It is felt that the fuzzy formulation will handle real life design problems on a more rational basis.

High drug loading self-microemulsifying/micelle formulation: design by high-throughput formulation screening system and in vivo evaluation.

PubMed

Sakai, Kenichi; Obata, Kouki; Yoshikawa, Mayumi; Takano, Ryusuke; Shibata, Masaki; Maeda, Hiroyuki; Mizutani, Akihiko; Terada, Katsuhide

2012-10-01

To design a high drug loading formulation of self-microemulsifying/micelle system. A poorly-soluble model drug (CH5137291), 8 hydrophilic surfactants (HS), 10 lipophilic surfactants (LS), 5 oils, and PEG400 were used. A high loading formulation was designed by a following stepwise approach using a high-throughput formulation screening (HTFS) system: (1) an oil/solvent was selected by solubility of the drug; (2) a suitable HS for highly loading was selected by the screenings of emulsion/micelle size and phase stability in binary systems (HS, oil/solvent) with increasing loading levels; (3) a LS that formed a broad SMEDDS/micelle area on a phase diagram containing the HS and oil/solvent was selected by the same screenings; (4) an optimized formulation was selected by evaluating the loading capacity of the crystalline drug. Aqueous solubility behavior and oral absorption (Beagle dog) of the optimized formulation were compared with conventional formulations (jet-milled, PEG400). As an optimized formulation, d-α-tocopheryl polyoxyethylene 1000 succinic ester: PEG400 = 8:2 was selected, and achieved the target loading level (200 mg/mL). The formulation formed fine emulsion/micelle (49.1 nm), and generated and maintained a supersaturated state at a higher level compared with the conventional formulations. In the oral absorption test, the area under the plasma concentration-time curve of the optimized formulation was 16.5-fold higher than that of the jet-milled formulation. The high loading formulation designed by the stepwise approach using the HTFS system improved the oral absorption of the poorly-soluble model drug.

Formulation and evaluation of flurbiprofen microemulsion.

PubMed

Ambade, K W; Jadhav, S L; Gambhire, M N; Kurmi, S D; Kadam, V J; Jadhav, K R

2008-01-01

The purpose of the present study was to investigate the microemulsion formulations for topical delivery of Flurbiprofen (FP) in order to by pass its gastrointestinal adverse effects. The pseudoternary phase diagrams were developed and various microemulsion formulations were prepared using Isopropyl Myristate (IPM), Ethyl Oleate (EO) as oils, Aerosol OT as surfactant and Sorbitan Monooleate as cosurfactant. The transdermal permeability of flurbiprofen from microemulsions containing IPM and EO as two different oil phases was analyzed using Keshary-Chien diffusion cell through excised rat skin. Flurbiprofen showed higher in vitro permeation from IPM as compared to that of from EO microemulsion. Thus microemulsion containing IPM as oil phase were selected for optimization. The optimization was carried out using 2(3) factorial design. The optimized formula was then subjected to in vivo anti-inflammatory study and the performance of flurbiprofen from optimized formulation was compared with that of gel cream. Flurbiprofen from optimized microemulsion formulation was found to be more effective as compared to gel cream in inhibiting the carrageenan induced rat paw edema at all time intervals. Histopathological investigation of rat skin revealed the safety of microemulsion formulation for topical use. Thus the present study indicates that, microemulsion can be a promising vehicle for the topical delivery of flurbiprofen.

Preparation and characterization of sustained-release rotigotine film-forming gel.

PubMed

Li, Xiang; Zhang, Renyu; Liang, Rongcai; Liu, Wei; Wang, Chenhui; Su, Zhengxing; Sun, Fengying; Li, Youxin

2014-01-02

The aim of this study was to develop a film-forming gel formulation of rotigotine with hydroxypropyl cellulose (HPC) and Carbomer 934. To optimize this formulation, we applied the Response Surface Analysis technique and evaluated the gel's pharmacokinetic properties. The factors chosen for factorial design were the concentration of rotigotine, the proportion of HPC and Carbomer 934, and the concentration of ST-Elastomer 10. Each factor was varied over three levels: low, medium and high. The gel formulation was evaluated and optimized according to its accumulated permeation rate (Flux) through Franz-type diffusion. A pharmacokinetic study of rotigotine gel was performed with rabbits. The Flux of the optimized formulation reached the maximum (199.17 μg/cm(2)), which was 3% rotigotine and 7% ST-Elastomer 10 with optimal composition of HPC: Carbomer 934 (5:1). The bioavailability of the optimized formulation compared with intravenous administration was approximately 20%. A film-forming gel of rotigotine was successfully developed using the response surface analysis technique. The results of this study may be helpful in finding an optimum formulation for transdermal delivery of a drug. The product may improve patients' compliance and provide better efficacy. Copyright © 2013 Elsevier B.V. All rights reserved.

Algorithmic Perspectives on Problem Formulations in MDO

NASA Technical Reports Server (NTRS)

Alexandrov, Natalia M.; Lewis, Robert Michael

2000-01-01

This work is concerned with an approach to formulating the multidisciplinary optimization (MDO) problem that reflects an algorithmic perspective on MDO problem solution. The algorithmic perspective focuses on formulating the problem in light of the abilities and inabilities of optimization algorithms, so that the resulting nonlinear programming problem can be solved reliably and efficiently by conventional optimization techniques. We propose a modular approach to formulating MDO problems that takes advantage of the problem structure, maximizes the autonomy of implementation, and allows for multiple easily interchangeable problem statements to be used depending on the available resources and the characteristics of the application problem.

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.

Utilization of a modified special-cubic design and an electronic tongue for bitterness masking formulation optimization.

PubMed

Li, Lianli; Naini, Venkatesh; Ahmed, Salah U

2007-10-01

A unique modification of simplex design was applied to an electronic tongue (E-Tongue) analysis in bitterness masking formulation optimization. Three formulation variables were evaluated in the simplex design, i.e. concentrations of two taste masking polymers, Amberlite and Carbopol, and pH of the granulating fluid. Response of the design was a bitterness distance measured using an E-Tongue by applying a principle component analysis, which represents taste masking efficiency of the formulation. The smaller the distance, the better the bitterness masking effect. Contour plots and polynomial equations of the bitterness distance response were generated as a function of formulation composition and pH. It was found that interactions between polymer and pH reduced the bitterness of the formulation, attributed to pH-dependent ionization and complexation properties of the ionic polymers, thus keeping the drug out of solution and unavailable to bitterness perception. At pH 4.9 and an Amberlite/Carbopol ratio of 1.4:1 (w/w), the optimal taste masking formulation was achieved and in agreement with human gustatory sensation study results. Therefore, adopting a modified simplex experimental design on response measured using an E-Tongue provided an efficient approach to taste masking formulation optimization using ionic binding polymers. (c) 2007 Wiley-Liss, Inc.

Multi-Objective Trajectory Optimization of a Hypersonic Reconnaissance Vehicle with Temperature Constraints

NASA Astrophysics Data System (ADS)

Masternak, Tadeusz J.

This research determines temperature-constrained optimal trajectories for a scramjet-based hypersonic reconnaissance vehicle by developing an optimal control formulation and solving it using a variable order Gauss-Radau quadrature collocation method with a Non-Linear Programming (NLP) solver. The vehicle is assumed to be an air-breathing reconnaissance aircraft that has specified takeoff/landing locations, airborne refueling constraints, specified no-fly zones, and specified targets for sensor data collections. A three degree of freedom scramjet aircraft model is adapted from previous work and includes flight dynamics, aerodynamics, and thermal constraints. Vehicle control is accomplished by controlling angle of attack, roll angle, and propellant mass flow rate. This model is incorporated into an optimal control formulation that includes constraints on both the vehicle and mission parameters, such as avoidance of no-fly zones and coverage of high-value targets. To solve the optimal control formulation, a MATLAB-based package called General Pseudospectral Optimal Control Software (GPOPS-II) is used, which transcribes continuous time optimal control problems into an NLP problem. In addition, since a mission profile can have varying vehicle dynamics and en-route imposed constraints, the optimal control problem formulation can be broken up into several "phases" with differing dynamics and/or varying initial/final constraints. Optimal trajectories are developed using several different performance costs in the optimal control formulation: minimum time, minimum time with control penalties, and maximum range. The resulting analysis demonstrates that optimal trajectories that meet specified mission parameters and constraints can be quickly determined and used for larger-scale operational and campaign planning and execution.

Optimization of controlled release nanoparticle formulation of verapamil hydrochloride using artificial neural networks with genetic algorithm and response surface methodology.

PubMed

Li, Yongqiang; Abbaspour, Mohammadreza R; Grootendorst, Paul V; Rauth, Andrew M; Wu, Xiao Yu

2015-08-01

This study was performed to optimize the formulation of polymer-lipid hybrid nanoparticles (PLN) for the delivery of an ionic water-soluble drug, verapamil hydrochloride (VRP) and to investigate the roles of formulation factors. Modeling and optimization were conducted based on a spherical central composite design. Three formulation factors, i.e., weight ratio of drug to lipid (X1), and concentrations of Tween 80 (X2) and Pluronic F68 (X3), were chosen as independent variables. Drug loading efficiency (Y1) and mean particle size (Y2) of PLN were selected as dependent variables. The predictive performance of artificial neural networks (ANN) and the response surface methodology (RSM) were compared. As ANN was found to exhibit better recognition and generalization capability over RSM, multi-objective optimization of PLN was then conducted based upon the validated ANN models and continuous genetic algorithms (GA). The optimal PLN possess a high drug loading efficiency (92.4%, w/w) and a small mean particle size (∼100nm). The predicted response variables matched well with the observed results. The three formulation factors exhibited different effects on the properties of PLN. ANN in coordination with continuous GA represent an effective and efficient approach to optimize the PLN formulation of VRP with desired properties. Copyright © 2015 Elsevier B.V. All rights reserved.

Development and optimization of a self-microemulsifying drug delivery system for atorvastatin calcium by using D-optimal mixture design.

PubMed

Yeom, Dong Woo; Song, Ye Seul; Kim, Sung Rae; Lee, Sang Gon; Kang, Min Hyung; Lee, Sangkil; Choi, Young Wook

2015-01-01

In this study, we developed and optimized a self-microemulsifying drug delivery system (SMEDDS) formulation for improving the dissolution and oral absorption of atorvastatin calcium (ATV), a poorly water-soluble drug. Solubility and emulsification tests were performed to select a suitable combination of oil, surfactant, and cosurfactant. A D-optimal mixture design was used to optimize the concentration of components used in the SMEDDS formulation for achieving excellent physicochemical characteristics, such as small droplet size and high dissolution. The optimized ATV-loaded SMEDDS formulation containing 7.16% Capmul MCM (oil), 48.25% Tween 20 (surfactant), and 44.59% Tetraglycol (cosurfactant) significantly enhanced the dissolution rate of ATV in different types of medium, including simulated intestinal fluid, simulated gastric fluid, and distilled water, compared with ATV suspension. Good agreement was observed between predicted and experimental values for mean droplet size and percentage of the drug released in 15 minutes. Further, pharmacokinetic studies in rats showed that the optimized SMEDDS formulation considerably enhanced the oral absorption of ATV, with 3.4-fold and 4.3-fold increases in the area under the concentration-time curve and time taken to reach peak plasma concentration, respectively, when compared with the ATV suspension. Thus, we successfully developed an optimized ATV-loaded SMEDDS formulation by using the D-optimal mixture design, that could potentially be used for improving the oral absorption of poorly water-soluble drugs.

Development and optimization of a self-microemulsifying drug delivery system for ator vastatin calcium by using d-optimal mixture design

PubMed Central

Yeom, Dong Woo; Song, Ye Seul; Kim, Sung Rae; Lee, Sang Gon; Kang, Min Hyung; Lee, Sangkil; Choi, Young Wook

2015-01-01

In this study, we developed and optimized a self-microemulsifying drug delivery system (SMEDDS) formulation for improving the dissolution and oral absorption of atorvastatin calcium (ATV), a poorly water-soluble drug. Solubility and emulsification tests were performed to select a suitable combination of oil, surfactant, and cosurfactant. A d-optimal mixture design was used to optimize the concentration of components used in the SMEDDS formulation for achieving excellent physicochemical characteristics, such as small droplet size and high dissolution. The optimized ATV-loaded SMEDDS formulation containing 7.16% Capmul MCM (oil), 48.25% Tween 20 (surfactant), and 44.59% Tetraglycol (cosurfactant) significantly enhanced the dissolution rate of ATV in different types of medium, including simulated intestinal fluid, simulated gastric fluid, and distilled water, compared with ATV suspension. Good agreement was observed between predicted and experimental values for mean droplet size and percentage of the drug released in 15 minutes. Further, pharmacokinetic studies in rats showed that the optimized SMEDDS formulation considerably enhanced the oral absorption of ATV, with 3.4-fold and 4.3-fold increases in the area under the concentration-time curve and time taken to reach peak plasma concentration, respectively, when compared with the ATV suspension. Thus, we successfully developed an optimized ATV-loaded SMEDDS formulation by using the d-optimal mixture design, that could potentially be used for improving the oral absorption of poorly water-soluble drugs. PMID:26089663

Formulation and optimization of solid lipid nanoparticle formulation for pulmonary delivery of budesonide using Taguchi and Box-Behnken design.

PubMed

Emami, J; Mohiti, H; Hamishehkar, H; Varshosaz, J

2015-01-01

Budesonide is a potent non-halogenated corticosteroid with high anti-inflammatory effects. The lungs are an attractive route for non-invasive drug delivery with advantages for both systemic and local applications. The aim of the present study was to develop, characterize and optimize a solid lipid nanoparticle system to deliver budesonide to the lungs. Budesonide-loaded solid lipid nanoparticles were prepared by the emulsification-solvent diffusion method. The impact of various processing variables including surfactant type and concentration, lipid content organic and aqueous volume, and sonication time were assessed on the particle size, zeta potential, entrapment efficiency, loading percent and mean dissolution time. Taguchi design with 12 formulations along with Box-Behnken design with 17 formulations was developed. The impact of each factor upon the eventual responses was evaluated, and the optimized formulation was finally selected. The size and morphology of the prepared nanoparticles were studied using scanning electron microscope. Based on the optimization made by Design Expert 7(®) software, a formulation made of glycerol monostearate, 1.2 % polyvinyl alcohol (PVA), weight ratio of lipid/drug of 10 and sonication time of 90 s was selected. Particle size, zeta potential, entrapment efficiency, loading percent, and mean dissolution time of adopted formulation were predicted and confirmed to be 218.2 ± 6.6 nm, -26.7 ± 1.9 mV, 92.5 ± 0.52 %, 5.8 ± 0.3 %, and 10.4 ± 0.29 h, respectively. Since the preparation and evaluation of the selected formulation within the laboratory yielded acceptable results with low error percent, the modeling and optimization was justified. The optimized formulation co-spray dried with lactose (hybrid microparticles) displayed desirable fine particle fraction, mass median aerodynamic diameter (MMAD), and geometric standard deviation of 49.5%, 2.06 μm, and 2.98 μm; respectively. Our results provide fundamental data for the application of SLNs in pulmonary delivery system of budesonide.

Formulation and optimization of solid lipid nanoparticle formulation for pulmonary delivery of budesonide using Taguchi and Box-Behnken design

PubMed Central

Emami, J.; Mohiti, H.; Hamishehkar, H.; Varshosaz, J.

2015-01-01

Budesonide is a potent non-halogenated corticosteroid with high anti-inflammatory effects. The lungs are an attractive route for non-invasive drug delivery with advantages for both systemic and local applications. The aim of the present study was to develop, characterize and optimize a solid lipid nanoparticle system to deliver budesonide to the lungs. Budesonide-loaded solid lipid nanoparticles were prepared by the emulsification-solvent diffusion method. The impact of various processing variables including surfactant type and concentration, lipid content organic and aqueous volume, and sonication time were assessed on the particle size, zeta potential, entrapment efficiency, loading percent and mean dissolution time. Taguchi design with 12 formulations along with Box-Behnken design with 17 formulations was developed. The impact of each factor upon the eventual responses was evaluated, and the optimized formulation was finally selected. The size and morphology of the prepared nanoparticles were studied using scanning electron microscope. Based on the optimization made by Design Expert 7® software, a formulation made of glycerol monostearate, 1.2 % polyvinyl alcohol (PVA), weight ratio of lipid/drug of 10 and sonication time of 90 s was selected. Particle size, zeta potential, entrapment efficiency, loading percent, and mean dissolution time of adopted formulation were predicted and confirmed to be 218.2 ± 6.6 nm, -26.7 ± 1.9 mV, 92.5 ± 0.52 %, 5.8 ± 0.3 %, and 10.4 ± 0.29 h, respectively. Since the preparation and evaluation of the selected formulation within the laboratory yielded acceptable results with low error percent, the modeling and optimization was justified. The optimized formulation co-spray dried with lactose (hybrid microparticles) displayed desirable fine particle fraction, mass median aerodynamic diameter (MMAD), and geometric standard deviation of 49.5%, 2.06 μm, and 2.98 μm; respectively. Our results provide fundamental data for the application of SLNs in pulmonary delivery system of budesonide. PMID:26430454

Multiple response optimization of processing and formulation parameters of Eudragit RL/RS-based matrix tablets for sustained delivery of diclofenac.

PubMed

Elzayat, Ehab M; Abdel-Rahman, Ali A; Ahmed, Sayed M; Alanazi, Fars K; Habib, Walid A; Sakr, Adel

2017-11-01

Multiple response optimization is an efficient technique to develop sustained release formulation while decreasing the number of experiments based on trial and error approach. Diclofenac matrix tablets were optimized to achieve a release profile conforming to USP monograph, matching Voltaren ® SR and withstand formulation variables. The percent of drug released at predetermined multiple time points were the response variables in the design. Statistical models were obtained with relative contour diagrams being overlaid to predict process and formulation parameters expected to produce the target release profile. Tablets were prepared by wet granulation using mixture of equivalent quantities of Eudragit RL/RS at overall polymer concentration of 10-30%w/w and compressed at 5-15KN. Drug release from the optimized formulation E4 (15%w/w, 15KN) was similar to Voltaren, conformed to USP monograph and found to be stable. Substituting lactose with mannitol, reversing the ratio between lactose and microcrystalline cellulose or increasing drug load showed no significant difference in drug release. Using dextromethorphan hydrobromide as a model soluble drug showed burst release due to higher solubility and formation of micro cavities. A numerical optimization technique was employed to develop a stable consistent promising formulation for sustained delivery of diclofenac.

In vitro/in vivo characterization of nanoemulsion formulation of metronidazole with improved skin targeting and anti-rosacea properties.

PubMed

Yu, Meng; Ma, Huixian; Lei, Mingzhu; Li, Nan; Tan, Fengping

2014-09-01

Topical skin treatment was limited due to the lack of suitable delivery system with significant cutaneous localization and systemic safety. The aim of this study was to develop and optimize a nanoemulsion (NE) to enhance targeting localization of metronidazole (MTZ) in skin layers. In vitro studies were used to optimize NE formulations, and a series of experiments were carried in vitro and in vivo to validate the therapeutic efficacy of MTZ-loaded optimal NE. NE type selection and D-optimal design study were applied to optimize NE formulation with maximum skin retention and minimum skin penetration. Three formulation variables: Oil X1 (Labrafil), Smix X2 (a mixture of Cremophor EL/Tetraethylene glycol, 2:1 w/w) and water X3 were included in D-design. The system was assessed for skin retention Y1, cumulative MTZ amount after 24 h Y2 and droplet size Y3. Following optimization, the values of formulation components (X1, X2 and X3) were 4.13%, 16.42% and 79.45%, respectively. The optimized NE was assessed for viscosity, droplet size, morphological study and in vitro permeation in pig skin. Distributions of MTZ were validated by confocal laser scanning microscopy (CLSM). Active agent of NE transferred into deeper skin and localized in epidermal/dermal layers after 24 h, which showed significant advantages of the optimal NE over Gel. The skin targeting localization and minimal systemic escape of optimal NE was further proved by in vivo study on rat skin. Current in vitro-in vivo correlation (IVIVC) enabled the prediction of pharmacokinetic profile of MTZ from in vitro permeation results. Further, the in vivo anti-rosacea efficacy of optimal formulation was investigated by pharmacodynamics study on mice ear. Copyright © 2014 Elsevier B.V. All rights reserved.

Effect of crospovidone and hydroxypropyl cellulose on carbamazepine in high-dose tablet formulation.

PubMed

Flicker, Felicia; Betz, Gabriele

2012-06-01

The aim of this study was to develop a high-dose tablet formulation of the poorly soluble carbamazepine (CBZ) with sufficient tablet hardness and immediate drug release. A further aim was to investigate the influence of various commercial CBZ raw materials on the optimized tablet formulation. Hydroxypropyl cellulose (HPC-SL) was selected as a dry binder and crospovidone (CrosPVP) as a superdisintegrant. A direct compacted tablet formulation of 70% CBZ was optimized by a 3² full factorial design with two input variables, HPC (0--10%) and CrosPVP (0--5%). Response variables included disintegration time, amount of drug released at 15 and 60 min, and tablet hardness, all analyzed according to USP 31. Increasing HPC-SL together with CrosPVP not only increased tablet hardness but also reduced disintegration time. Optimal condition was achieved in the range of 5--9% HPC and 3--5% CrosPVP, where tablet properties were at least 70 N tablet hardness, less than 1 min disintegration, and within the USP requirements for drug release. Testing the optimized formulation with four different commercial CBZ samples, their variability was still observed. Nonetheless, all formulations conformed to the USP specifications. With the excipients CrosPVP and HPC-SL an immediate release tablet formulation was successfully formulated for high-dose CBZ of various commercial sources.

Computer Optimization of Biodegradable Nanoparticles Fabricated by Dispersion Polymerization.

PubMed

Akala, Emmanuel O; Adesina, Simeon; Ogunwuyi, Oluwaseun

2015-12-22

Quality by design (QbD) in the pharmaceutical industry involves designing and developing drug formulations and manufacturing processes which ensure predefined drug product specifications. QbD helps to understand how process and formulation variables affect product characteristics and subsequent optimization of these variables vis-à-vis final specifications. Statistical design of experiments (DoE) identifies important parameters in a pharmaceutical dosage form design followed by optimizing the parameters with respect to certain specifications. DoE establishes in mathematical form the relationships between critical process parameters together with critical material attributes and critical quality attributes. We focused on the fabrication of biodegradable nanoparticles by dispersion polymerization. Aided by a statistical software, d-optimal mixture design was used to vary the components (crosslinker, initiator, stabilizer, and macromonomers) to obtain twenty nanoparticle formulations (PLLA-based nanoparticles) and thirty formulations (poly-ɛ-caprolactone-based nanoparticles). Scheffe polynomial models were generated to predict particle size (nm), zeta potential, and yield (%) as functions of the composition of the formulations. Simultaneous optimizations were carried out on the response variables. Solutions were returned from simultaneous optimization of the response variables for component combinations to (1) minimize nanoparticle size; (2) maximize the surface negative zeta potential; and (3) maximize percent yield to make the nanoparticle fabrication an economic proposition.

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.

Real-time optimal guidance for orbital maneuvering.

NASA Technical Reports Server (NTRS)

Cohen, A. O.; Brown, K. R.

1973-01-01

A new formulation for soft-constraint trajectory optimization is presented as a real-time optimal feedback guidance method for multiburn orbital maneuvers. Control is always chosen to minimize burn time plus a quadratic penalty for end condition errors, weighted so that early in the mission (when controllability is greatest) terminal errors are held negligible. Eventually, as controllability diminishes, the method partially relaxes but effectively still compensates perturbations in whatever subspace remains controllable. Although the soft-constraint concept is well-known in optimal control, the present formulation is novel in addressing the loss of controllability inherent in multiple burn orbital maneuvers. Moreover the necessary conditions usually obtained from a Bolza formulation are modified in this case so that the fully hard constraint formulation is a numerically well behaved subcase. As a result convergence properties have been greatly improved.

High-throughput screening and stability optimization of anti-streptavidin IgG1 and IgG2 formulations.

PubMed

Alekseychyk, Larysa; Su, Cheng; Becker, Gerald W; Treuheit, Michael J; Razinkov, Vladimir I

2014-10-01

Selection of a suitable formulation that provides adequate product stability is an important aspect of the development of biopharmaceutical products. Stability of proteins includes not only resistance to chemical modifications but also conformational and colloidal stabilities. While chemical degradation of antibodies is relatively easy to detect and control, propensity for conformational changes and/or aggregation during manufacturing or long-term storage is difficult to predict. In many cases, the formulation factors that increase one type of stability may significantly decrease another type under the same or different conditions. Often compromise is necessary to minimize the adverse effects of an antibody formulation by careful optimization of multiple factors responsible for overall stability. In this study, high-throughput stress and characterization techniques were applied to 96 formulations of anti-streptavidin antibodies (an IgG1 and an IgG2) to choose optimal formulations. Stress and analytical methods applied in this study were 96-well plate based using an automated liquid handling system to prepare the different formulations and sample plates. Aggregation and clipping propensity were evaluated by temperature and mechanical stresses. Multivariate regression analysis of high-throughput data was performed to find statistically significant formulation factors that alter measured parameters such as monomer percentage or unfolding temperature. The results of the regression models were used to maximize the stabilities of antibodies under different formulations and to find the optimal formulation space for each molecule. Comparison of the IgG1 and IgG2 data indicated an overall greater stability of the IgG1 molecule under the conditions studied. The described method can easily be applied to both initial preformulation screening and late-stage formulation development of biopharmaceutical products. © 2014 Society for Laboratory Automation and Screening.

Robust Maneuvering Envelope Estimation Based on Reachability Analysis in an Optimal Control Formulation

NASA Technical Reports Server (NTRS)

Lombaerts, Thomas; Schuet, Stefan R.; Wheeler, Kevin; Acosta, Diana; Kaneshige, John

2013-01-01

This paper discusses an algorithm for estimating the safe maneuvering envelope of damaged aircraft. The algorithm performs a robust reachability analysis through an optimal control formulation while making use of time scale separation and taking into account uncertainties in the aerodynamic derivatives. Starting with an optimal control formulation, the optimization problem can be rewritten as a Hamilton- Jacobi-Bellman equation. This equation can be solved by level set methods. This approach has been applied on an aircraft example involving structural airframe damage. Monte Carlo validation tests have confirmed that this approach is successful in estimating the safe maneuvering envelope for damaged aircraft.

Transdermal glimepiride delivery system based on optimized ethosomal nano-vesicles: Preparation, characterization, in vitro, ex vivo and clinical evaluation.

PubMed

Ahmed, Tarek A; El-Say, Khalid M; Aljaeid, Bader M; Fahmy, Usama A; Abd-Allah, Fathy I

2016-03-16

This work aimed to develop an optimized ethosomal formulation of glimepiride then loading into transdermal films to offer lower drug side effect, extended release behavior and avoid first pass effect. Four formulation factors were optimized for their effects on vesicle size (Y1), entrapment efficiency (Y2) and vesicle flexibility (Y3). Optimum desirability was identified and, an optimized formulation was prepared, characterized and loaded into transdermal films. Ex-vivo permeation study for the prepared films was conducted and, the permeation parameters and drug permeation mechanism were identified. Penetration through rat skin was studied using confocal laser microscope. In-vivo study was performed following transdermal application on human volunteers. The percent of alcohol was significantly affecting all the studied responses while the other factors and their interaction effects were varied on their effects on each response. The optimized ethosomal formulation showed observed values for Y1, Y2 and Y3 of 61 nm, 97.12% and 54.03, respectively. Ex-vivo permeation of films loaded with optimized ethosomal formulation was superior to that of the corresponding pure drug transdermal films and this finding was also confirmed after confocal laser microscope study. Permeation of glimepiride from the prepared films was in favor of Higushi-diffusion model and exhibited non-Fickian or anomalous release mechanism. In-vivo study revealed extended drug release behavior and lower maximum drug plasma level from transdermal films loaded with drug ethosomal formulation. So, the ethosomal formulation could be considered a suitable drug delivery system especially when loaded into transdermal vehicle with possible reduction in side effects and controlling the drug release. Copyright © 2016 Elsevier B.V. All rights reserved.

Improved ant colony optimization for optimal crop and irrigation water allocation by incorporating domain knowledge

USDA-ARS?s Scientific Manuscript database

An improved ant colony optimization (ACO) formulation for the allocation of crops and water to different irrigation areas is developed. The formulation enables dynamic adjustment of decision variable options and makes use of visibility factors (VFs, the domain knowledge that can be used to identify ...

[Optimization of Formulation and Process of Paclitaxel PEGylated Liposomes by Box-Behnken Response Surface Methodology].

PubMed

Shi, Ya-jun; Zhang, Xiao-feil; Guo, Qiu-ting

2015-12-01

To develop a procedure for preparing paclitaxel encapsulated PEGylated liposomes. The membrane hydration followed extraction method was used to prepare PEGylated liposomes. The process and formulation variables were optimized by "Box-Behnken Design (BBD)" of response surface methodology (RSM) with the amount of Soya phosphotidylcholine (SPC) and PEG2000-DSPE as well as the rate of SPC to drug as independent variables and entrapment efficiency as dependent variables for optimization of formulation variables while temperature, pressure and cycle times as independent variables and particle size and polydispersion index as dependent variables for process variables. The optimized liposomal formulation was characterized for particle size, Zeta potential, morphology and in vitro drug release. For entrapment efficiency, particle size, polydispersion index, Zeta potential, and in vitro drug release of PEGylated liposomes was found to be 80.3%, (97.15 ± 14.9) nm, 0.117 ± 0.019, (-30.3 ± 3.7) mV, and 37.4% in 24 h, respectively. The liposomes were found to be small, unilamellar and spherical with smooth surface as seen in transmission electron microscopy. The Box-Behnken response surface methodology facilitates the formulation and optimization of paclitaxel PEGylated liposomes.

Tailored nanostructured platforms for boosting transcorneal permeation: Box–Behnken statistical optimization, comprehensive in vitro, ex vivo and in vivo characterization

PubMed Central

Elsayed, Ibrahim; Sayed, Sinar

2017-01-01

Ocular drug delivery systems suffer from rapid drainage, intractable corneal permeation and short dosing intervals. Transcorneal drug permeation could increase the drug availability and efficiency in the aqueous humor. The aim of this study was to develop and optimize nanostructured formulations to provide accurate doses, long contact time and enhanced drug permeation. Nanovesicles were designed based on Box–Behnken model and prepared using the thin film hydration technique. The formed nanodispersions were evaluated by measuring the particle size, polydispersity index, zeta potential, entrapment efficiency and gelation temperature. The obtained desirability values were utilized to develop an optimized nanostructured in situ gel and insert. The optimized formulations were imaged by transmission and scanning electron microscopes. In addition, rheological characters, in vitro drug diffusion, ex vivo and in vivo permeation and safety of the optimized formulation were investigated. The optimized insert formulation was found to have a relatively lower viscosity, higher diffusion, ex vivo and in vivo permeation, when compared to the optimized in situ gel. So, the lyophilized nanostructured insert could be considered as a promising carrier and transporter for drugs across the cornea with high biocompatibility and effectiveness. PMID:29133980

Optimal slew path planning for the Sino-French Space-based multiband astronomical Variable Objects Monitor mission

NASA Astrophysics Data System (ADS)

She, Yuchen; Li, Shuang

2018-01-01

The planning algorithm to calculate a satellite's optimal slew trajectory with a given keep-out constraint is proposed. An energy-optimal formulation is proposed for the Space-based multiband astronomical Variable Objects Monitor Mission Analysis and Planning (MAP) system. The innovative point of the proposed planning algorithm lies in that the satellite structure and control limitation are not considered as optimization constraints but are formulated into the cost function. This modification is able to relieve the burden of the optimizer and increases the optimization efficiency, which is the major challenge for designing the MAP system. Mathematical analysis is given to prove that there is a proportional mapping between the formulation and the satellite controller output. Simulations with different scenarios are given to demonstrate the efficiency of the developed algorithm.

A Matrix-Free Algorithm for Multidisciplinary Design Optimization

NASA Astrophysics Data System (ADS)

Lambe, Andrew Borean

Multidisciplinary design optimization (MDO) is an approach to engineering design that exploits the coupling between components or knowledge disciplines in a complex system to improve the final product. In aircraft design, MDO methods can be used to simultaneously design the outer shape of the aircraft and the internal structure, taking into account the complex interaction between the aerodynamic forces and the structural flexibility. Efficient strategies are needed to solve such design optimization problems and guarantee convergence to an optimal design. This work begins with a comprehensive review of MDO problem formulations and solution algorithms. First, a fundamental MDO problem formulation is defined from which other formulations may be obtained through simple transformations. Using these fundamental problem formulations, decomposition methods from the literature are reviewed and classified. All MDO methods are presented in a unified mathematical notation to facilitate greater understanding. In addition, a novel set of diagrams, called extended design structure matrices, are used to simultaneously visualize both data communication and process flow between the many software components of each method. For aerostructural design optimization, modern decomposition-based MDO methods cannot efficiently handle the tight coupling between the aerodynamic and structural states. This fact motivates the exploration of methods that can reduce the computational cost. A particular structure in the direct and adjoint methods for gradient computation motivates the idea of a matrix-free optimization method. A simple matrix-free optimizer is developed based on the augmented Lagrangian algorithm. This new matrix-free optimizer is tested on two structural optimization problems and one aerostructural optimization problem. The results indicate that the matrix-free optimizer is able to efficiently solve structural and multidisciplinary design problems with thousands of variables and constraints. On the aerostructural test problem formulated with thousands of constraints, the matrix-free optimizer is estimated to reduce the total computational time by up to 90% compared to conventional optimizers.

A Matrix-Free Algorithm for Multidisciplinary Design Optimization

NASA Astrophysics Data System (ADS)

Lambe, Andrew Borean

Multidisciplinary design optimization (MDO) is an approach to engineering design that exploits the coupling between components or knowledge disciplines in a complex system to improve the final product. In aircraft design, MDO methods can be used to simultaneously design the outer shape of the aircraft and the internal structure, taking into account the complex interaction between the aerodynamic forces and the structural flexibility. Efficient strategies are needed to solve such design optimization problems and guarantee convergence to an optimal design. This work begins with a comprehensive review of MDO problem formulations and solution algorithms. First, a fundamental MDO problem formulation is defined from which other formulations may be obtained through simple transformations. Using these fundamental problem formulations, decomposition methods from the literature are reviewed and classified. All MDO methods are presented in a unified mathematical notation to facilitate greater understanding. In addition, a novel set of diagrams, called extended design structure matrices, are used to simultaneously visualize both data communication and process flow between the many software components of each method. For aerostructural design optimization, modern decomposition-based MDO methods cannot efficiently handle the tight coupling between the aerodynamic and structural states. This fact motivates the exploration of methods that can reduce the computational cost. A particular structure in the direct and adjoint methods for gradient computation. motivates the idea of a matrix-free optimization method. A simple matrix-free optimizer is developed based on the augmented Lagrangian algorithm. This new matrix-free optimizer is tested on two structural optimization problems and one aerostructural optimization problem. The results indicate that the matrix-free optimizer is able to efficiently solve structural and multidisciplinary design problems with thousands of variables and constraints. On the aerostructural test problem formulated with thousands of constraints, the matrix-free optimizer is estimated to reduce the total computational time by up to 90% compared to conventional optimizers.

Formulation optimization of transdermal meloxicam potassium-loaded mesomorphic phases containing ethanol, oleic acid and mixture surfactant using the statistical experimental design methodology.

PubMed

Huang, Chi-Te; Tsai, Chia-Hsun; Tsou, Hsin-Yeh; Huang, Yaw-Bin; Tsai, Yi-Hung; Wu, Pao-Chu

2011-01-01

Response surface methodology (RSM) was used to develop and optimize the mesomorphic phase formulation for a meloxicam transdermal dosage form. A mixture design was applied to prepare formulations which consisted of three independent variables including oleic acid (X(1)), distilled water (X(2)) and ethanol (X(3)). The flux and lag time (LT) were selected as dependent variables. The result showed that using mesomorphic phases as vehicles can significantly increase flux and shorten LT of drug. The analysis of variance showed that the permeation parameters of meloxicam from formulations were significantly influenced by the independent variables and their interactions. The X(3) (ethanol) had the greatest potential influence on the flux and LT, followed by X(1) and X(2). A new formulation was prepared according to the independent levels provided by RSM. The observed responses were in close agreement with the predicted values, demonstrating that RSM could be successfully used to optimize mesomorphic phase formulations.

Application of mixture experimental design in the formulation and optimization of matrix tablets containing carbomer and hydroxy-propylmethylcellulose.

PubMed

Petrovic, Aleksandra; Cvetkovic, Nebojsa; Ibric, Svetlana; Trajkovic, Svetlana; Djuric, Zorica; Popadic, Dragica; Popovic, Radmila

2009-12-01

Using mixture experimental design, the effect of carbomer (Carbopol((R)) 971P NF) and hydroxypropylmethylcellulose (Methocel((R)) K100M or Methocel((R)) K4M) combination on the release profile and on the mechanism of drug liberation from matrix tablet was investigated. The numerical optimization procedure was also applied to establish and obtain formulation with desired drug release. The amount of TP released, release rate and mechanism varied with carbomer ratio in total matrix and HPMC viscosity. Increasing carbomer fractions led to a decrease in drug release. Anomalous diffusion was found in all matrices containing carbomer, while Case - II transport was predominant for tablet based on HPMC only. The predicted and obtained profiles for optimized formulations showed similarity. Those results indicate that Simplex Lattice Mixture experimental design and numerical optimization procedure can be applied during development to obtain sustained release matrix formulation with desired release profile.

Formulation and optimization by experimental design of eco-friendly emulsions based on d-limonene.

PubMed

Pérez-Mosqueda, Luis M; Trujillo-Cayado, Luis A; Carrillo, Francisco; Ramírez, Pablo; Muñoz, José

2015-04-01

d-Limonene is a natural occurring solvent that can replace more pollutant chemicals in agrochemical formulations. In the present work, a comprehensive study of the influence of dispersed phase mass fraction, ϕ, and of the surfactant/oil ratio, R, on the emulsion stability and droplet size distribution of d-limonene-in-water emulsions stabilized by a non-ionic triblock copolymer surfactant has been carried out. An experimental full factorial design 3(2) was conducted in order to optimize the emulsion formulation. The independent variables, ϕ and R were studied in the range 10-50 wt% and 0.02-0.1, respectively. The emulsions studied were mainly destabilized by both creaming and Ostwald ripening. Therefore, initial droplet size and an overall destabilization parameter, the so-called turbiscan stability index, were used as dependent variables. The optimal formulation, comprising minimum droplet size and maximum stability was achieved at ϕ=50 wt%; R=0.062. Furthermore, the surface response methodology allowed us to obtain the formulation yielding sub-micron emulsions by using a single step rotor/stator homogenizer process instead of most commonly used two-step emulsification methods. In addition, the optimal formulation was further improved against Ostwald ripening by adding silicone oil to the dispersed phase. The combination of these experimental findings allowed us to gain a deeper insight into the stability of these emulsions, which can be applied to the rational development of new formulations with potential application in agrochemical formulations. Copyright © 2015 Elsevier B.V. All rights reserved.

Preparation of finasteride capsules-loaded drug nanoparticles: formulation, optimization, in vitro, and pharmacokinetic evaluation

PubMed Central

Ahmed, Tarek A

2016-01-01

In this study, optimized freeze-dried finasteride nanoparticles (NPs) were prepared from drug nanosuspension formulation that was developed using the bottom–up technique. The effects of four formulation and processing variables that affect the particle size and solubility enhancement of the NPs were explored using the response surface optimization design. The optimized formulation was morphologically characterized using transmission electron microscopy (TEM). Physicochemical interaction among the studied components was investigated. Crystalline change was investigated using X-ray powder diffraction (XRPD). Crystal growth of the freeze-dried NPs was compared to the corresponding aqueous drug nanosuspension. Freeze-dried NPs formulation was subsequently loaded into hard gelatin capsules that were examined for in vitro dissolution and pharmacokinetic behavior. Results revealed that in most of the studied variables, some of the quadratic and interaction effects had a significant effect on the studied responses. TEM image illustrated homogeneity and shape of the prepared NPs. No interaction among components was noticed. XRPD confirmed crystalline state change in the optimized NPs. An enhancement in the dissolution rate of more than 2.5 times from capsules filled with optimum drug NPs, when compared to capsules filled with pure drug, was obtained. Crystal growth, due to Ostwald ripening phenomenon and positive Gibbs free energy, was reduced following lyophilization of the nanosuspension formulation. Pharmacokinetic parameters from drug NPs were superior to that of pure drug and drug microparticles. In conclusion, freeze-dried NPs based on drug nanosuspension formulation is a successful technique in enhancing stability, solubility, and in vitro dissolution of poorly water-soluble drugs with possible impact on the drug bioavailability. PMID:26893559

Optimization of poorly compactable drug tablets manufactured by direct compression using the mixture experimental design.

PubMed

Martinello, Tiago; Kaneko, Telma Mary; Velasco, Maria Valéria Robles; Taqueda, Maria Elena Santos; Consiglieri, Vladi O

2006-09-28

The poor flowability and bad compressibility characteristics of paracetamol are well known. As a result, the production of paracetamol tablets is almost exclusively by wet granulation, a disadvantageous method when compared to direct compression. The development of a new tablet formulation is still based on a large number of experiments and often relies merely on the experience of the analyst. The purpose of this study was to apply experimental design methodology (DOE) to the development and optimization of tablet formulations containing high amounts of paracetamol (more than 70%) and manufactured by direct compression. Nineteen formulations, screened by DOE methodology, were produced with different proportions of Microcel 102, Kollydon VA 64, Flowlac, Kollydon CL 30, PEG 4000, Aerosil, and magnesium stearate. Tablet properties, except friability, were in accordance with the USP 28th ed. requirements. These results were used to generate plots for optimization, mainly for friability. The physical-chemical data found from the optimized formulation were very close to those from the regression analysis, demonstrating that the mixture project is a great tool for the research and development of new formulations.

[Application of an artificial neural network in the design of sustained-release dosage forms].

PubMed

Wei, X H; Wu, J J; Liang, W Q

2001-09-01

To use the artificial neural network (ANN) in Matlab 5.1 tool-boxes to predict the formulations of sustained-release tablets. The solubilities of nine drugs and various ratios of HPMC: Dextrin for 63 tablet formulations were used as the ANN model input, and in vitro accumulation released at 6 sampling times were used as output. The ANN model was constructed by selecting the optimal number of iterations (25) and model structure in which there are one hidden layer and five hidden layer nodes. The optimized ANN model was used for prediction of formulation based on desired target in vitro dissolution-time profiles. ANN predicted profiles based on ANN predicted formulations were closely similar to the target profiles. The ANN could be used for predicting the dissolution profiles of sustained release dosage form and for the design of optimal formulation.

Formulation development of gastroretentive tablets of lamivudine using the floating-bioadhesive potential of optimized polymer blends.

PubMed

Singh, Bhupinder; Garg, Babita; Chaturvedi, Subhash Chand; Arora, Sharry; Mandsaurwale, Rachana; Kapil, Rishi; Singh, Baljinder

2012-05-01

The current studies entail successful formulation of optimized gastroretentive tablets of lamivudine using the floating-bioadhesive potential of carbomers and cellulosic polymers, and their subsequent in-vitro and in-vivo evaluation in animals and humans. Effervescent floating-bioadhesive hydrophilic matrices were prepared and evaluated for in-vitro drug release, floatation and ex-vivo bioadhesive strength. The optimal composition of polymer blends was systematically chosen using central composite design and overlay plots. Pharmacokinetic studies were carried out in rabbits, and various levels of in-vitro/in-vivo correlation (IVIVC) were established. In-vivo gamma scintigraphic studies were performed in human volunteers using (99m) Tc to evaluate formulation retention in the gastric milieu. The optimized formulation exhibited excellent bioadhesive and floatational characteristics besides possessing adequate drug-release control and pharmacokinetic extension of plasma levels. The successful establishment of various levels of IVIVC substantiated the judicious choice of in-vitro dissolution media for simulating the in-vivo conditions. In-vivo gamma scintigraphic studies ratified the gastroretentive characteristics of the optimized formulation with a retention time of 5 h or more. Besides unravelling the polymer synergism, the study helped in developing an optimal once-a-day gastroretentive drug delivery system with improved bioavailability potential exhibiting excellent swelling, floating and bioadhesive characteristics. © 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society.

Formulation and Optimization of Candesartan Cilexetil Nano Lipid Carrier: In Vitro and In Vivo Evaluation.

PubMed

Paudel, Anjan; Ameeduzzafar; Imam, Syed Sarim; Fazil, Mohd; Khan, Shahroz; Hafeez, Abdul; Ahmad, Farhan Jalees; Ali, Asgar

2017-01-01

The objective of this study was to formulate and optimize Candesartan Cilexetil (CC) loaded nanostructured lipid carriers (NLCs) for enhanced oral bioavailability. Glycerol monostearate (GMS), Oleic acid, Tween 80 and Span 40 were selected as a solid lipid, liquid lipid, surfactant and co- surfactant, respectively. The CC-NLCs were prepared by hot emulsion probe sonication technique and optimized using experimental design approach. The formulated CC-NLCs were evaluated for various physicochemical parameters and further optimized formulation (CC-NLC-Opt) was assessed for in vivo pharmacokinetic and pharmacodynamic activity. The optimized formulation (CC-NLC-Opt) showed particle size (183.5±5.89nm), PDI (0.228±0.13), zeta potential (-28.2±0.99mV), and entrapment efficiency (88.9±3.69%). The comparative in vitro release study revealed that CC-NLC-Opt showed significantly better (p<0.05) release and enhanced permeation as compared to CC-suspension. The in vivo pharmacokinetic study gave many folds increase in oral bioavailability than CC suspension, which was further confirmed by antihypertensive activity in a murine model. Thus, the results of ex vivo permeation, pharmacokinetic study and pharmacodynamics study suggest the potential of CC-NLCs for improved oral delivery. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Optimization of physicochemical and textural properties of pizza cheese fortified with soybean oil and carrot extract.

PubMed

Motevalizadeh, Ehsan; Mortazavi, Seyed Ali; Milani, Elnaz; Hooshmand-Dalir, Moosa Al-Reza

2018-03-01

Response surface methodology (RSM) was used to optimize pizza cheese containing carrot extract. The effects of two important independent variables including soybean oil (5%-20%) and carrot extract (5%-20%) were studied on physicochemical and textural properties of pizza cheese containing carrot extract. According to the results, RSM was successfully used for optimizing formulation of pizza cheese containing carrot juice. Results of this study revealed that oil (A), carrot (B), AB, square term of carrot (B 2 ), B, AB, square term of oil (A 2 ), B 2 , AB, AB, A 2 B, A 2 , A 2 , A, A 2 , A 2 , AB, and AB 2 had the most effect on moisture, acidity, stretch, L*, a*, b*, hardness, meltability, springiness, peroxide value (PV), cohesiveness, chewiness, gumminess, fracture force, adhesiveness force, stiffness, flavor, and overall acceptability, respectively. A formulation upon 20% oil and 10.88% carrot extract was found as the optimal formulation for pizza cheese containing carrot extract. At the optimal formulation, PV, L*, a*, b*, meltability, stretch, cohesiveness, springiness, gumminess, chewiness, adhesive force, flavor, texture, and overall acceptability at the optimum formulation were measured 2.23, 82.51, -3.69, 18.05, 17.86, 85.61, 0.41, 7.874, 23.7, 0.27, 0.61, 3.50, 3.95, and 3.65, respectively.

Fuzzy multiobjective models for optimal operation of a hydropower system

NASA Astrophysics Data System (ADS)

Teegavarapu, Ramesh S. V.; Ferreira, André R.; Simonovic, Slobodan P.

2013-06-01

Optimal operation models for a hydropower system using new fuzzy multiobjective mathematical programming models are developed and evaluated in this study. The models use (i) mixed integer nonlinear programming (MINLP) with binary variables and (ii) integrate a new turbine unit commitment formulation along with water quality constraints used for evaluation of reservoir downstream impairment. Reardon method used in solution of genetic algorithm optimization problems forms the basis for development of a new fuzzy multiobjective hydropower system optimization model with creation of Reardon type fuzzy membership functions. The models are applied to a real-life hydropower reservoir system in Brazil. Genetic Algorithms (GAs) are used to (i) solve the optimization formulations to avoid computational intractability and combinatorial problems associated with binary variables in unit commitment, (ii) efficiently address Reardon method formulations, and (iii) deal with local optimal solutions obtained from the use of traditional gradient-based solvers. Decision maker's preferences are incorporated within fuzzy mathematical programming formulations to obtain compromise operating rules for a multiobjective reservoir operation problem dominated by conflicting goals of energy production, water quality and conservation releases. Results provide insight into compromise operation rules obtained using the new Reardon fuzzy multiobjective optimization framework and confirm its applicability to a variety of multiobjective water resources problems.

Trajectory optimization for lunar rover performing vertical takeoff vertical landing maneuvers in the presence of terrain

NASA Astrophysics Data System (ADS)

Ma, Lin; Wang, Kexin; Xu, Zuhua; Shao, Zhijiang; Song, Zhengyu; Biegler, Lorenz T.

2018-05-01

This study presents a trajectory optimization framework for lunar rover performing vertical takeoff vertical landing (VTVL) maneuvers in the presence of terrain using variable-thrust propulsion. First, a VTVL trajectory optimization problem with three-dimensional kinematics and dynamics model, boundary conditions, and path constraints is formulated. Then, a finite-element approach transcribes the formulated trajectory optimization problem into a nonlinear programming (NLP) problem solved by a highly efficient NLP solver. A homotopy-based backtracking strategy is applied to enhance the convergence in solving the formulated VTVL trajectory optimization problem. The optimal thrust solution typically has a "bang-bang" profile considering that bounds are imposed on the magnitude of engine thrust. An adaptive mesh refinement strategy based on a constant Hamiltonian profile is designed to address the difficulty in locating the breakpoints in the thrust profile. Four scenarios are simulated. Simulation results indicate that the proposed trajectory optimization framework has sufficient adaptability to handle VTVL missions efficiently.

Optimized formulation of solid self-microemulsifying sirolimus delivery systems

PubMed Central

Cho, Wonkyung; Kim, Min-Soo; Kim, Jeong-Soo; Park, Junsung; Park, Hee Jun; Cha, Kwang-Ho; Park, Jeong-Sook; Hwang, Sung-Joo

2013-01-01

Background The aim of this study was to develop an optimized solid self-microemulsifying drug delivery system (SMEDDS) formulation for sirolimus to enhance its solubility, stability, and bioavailability. Methods Excipients used for enhancing the solubility and stability of sirolimus were screened. A phase-separation test, visual observation for emulsifying efficiency, and droplet size analysis were performed. Ternary phase diagrams were constructed to optimize the liquid SMEDDS formulation. The selected liquid SMEDDS formulations were prepared into solid form. The dissolution profiles and pharmacokinetic profiles in rats were analyzed. Results In the results of the oil and cosolvent screening studies, Capryol™ Propylene glycol monocapry late (PGMC) and glycofurol exhibited the highest solubility of all oils and cosolvents, respectively. In the surfactant screening test, D-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) was determined to be the most effective stabilizer of sirolimus in pH 1.2 simulated gastric fluids. The optimal formulation determined by the construction of ternary phase diagrams was the T32 (Capryol™ PGMC:glycofurol:vitamin E TPGS = 30:30:40 weight ratio) formulation with a mean droplet size of 108.2 ± 11.4 nm. The solid SMEDDS formulations were prepared with Sucroester 15 and mannitol. The droplet size of the reconstituted solid SMEDDS showed no significant difference compared with the liquid SMEDDS. In the dissolution study, the release amounts of sirolimus from the SMEDDS formulation were significantly higher than the raw sirolimus powder. In addition, the solid SMEDDS formulation was in a more stable state than liquid SMEDDS in pH 1.2 simulated gastric fluids. The results of the pharmacokinetic study indicate that the SMEDDS formulation shows significantly greater bioavailability than the raw sirolimus powder or commercial product (Rapamune® oral solution). Conclusion The results of this study suggest the potential use of a solid SMEDDS formulation for the delivery of poorly water-soluble drugs, such as sirolimus, through oral administration. PMID:23641156

Optimally Stopped Optimization

NASA Astrophysics Data System (ADS)

Vinci, Walter; Lidar, Daniel

We combine the fields of heuristic optimization and optimal stopping. We propose a strategy for benchmarking randomized optimization algorithms that minimizes the expected total cost for obtaining a good solution with an optimal number of calls to the solver. To do so, rather than letting the objective function alone define a cost to be minimized, we introduce a further cost-per-call of the algorithm. We show that this problem can be formulated using optimal stopping theory. The expected cost is a flexible figure of merit for benchmarking probabilistic solvers that can be computed when the optimal solution is not known, and that avoids the biases and arbitrariness that affect other measures. The optimal stopping formulation of benchmarking directly leads to a real-time, optimal-utilization strategy for probabilistic optimizers with practical impact. We apply our formulation to benchmark the performance of a D-Wave 2X quantum annealer and the HFS solver, a specialized classical heuristic algorithm designed for low tree-width graphs. On a set of frustrated-loop instances with planted solutions defined on up to N = 1098 variables, the D-Wave device is between one to two orders of magnitude faster than the HFS solver.

Novel microemulsion-based gel formulation of tazarotene for therapy of acne.

PubMed

Patel, Mrunali Rashmin; Patel, Rashmin Bharatbhai; Parikh, Jolly R; Patel, Bharat G

2016-12-01

The objective of this study was to develop and evaluate a novel microemulsion based gel formulation containing tazarotene for targeted topical therapy of acne. Psudoternary phase diagrams were constructed to obtain the concentration range of oil, surfactant, and co-surfactant for microemulsion formation. The optimized microemulsion formulation containing 0.05% tazarotene was formulated by spontaneous microemulsification method consisting of 10% Labrafac CC, mixed emulsifiers 15% Labrasol-Cremophor-RH 40 (1:1), 15% Capmul MCM, and 60% distilled water (w/w) as an external phase. All plain and tazarotene-loaded microemulsions were clear and showed physicochemical parameters for desired topical delivery and stability. The permeation profiles of tazarotene through rat skin from optimized microemulsion formulation followed the Higuchi model for controlled permeation. Microemulsion-based gel was prepared by incorporating Carbopol®971P NF in optimized microemulsion formulation having suitable skin permeation rate and skin uptake. Microemulsion-based gel showed desired physicochemical parameters and demonstrated advantage over marketed formulation in improving the skin tolerability of tazarotene indicating its potential in improving its topical delivery. The developed microemulsion-based gel may be a potential drug delivery vehicle for targeted topical delivery of tazarotene in the treatment of acne.

Formulation and characterization of an apigenin-phospholipid phytosome (APLC) for improved solubility, in vivo bioavailability, and antioxidant potential.

PubMed

Telange, Darshan R; Patil, Arun T; Pethe, Anil M; Fegade, Harshal; Anand, Sridhar; Dave, Vivek S

2017-10-15

The apigenin-phospholipid phytosome (APLC) was developed to improve the aqueous solubility, dissolution, in vivo bioavailability, and antioxidant activity of apigenin. The APLC synthesis was guided by a full factorial design strategy, incorporating specific formulation and process variables to deliver an optimized product. The design-optimized formulation was assayed for aqueous solubility, in vitro dissolution, pharmacokinetics, and antioxidant activity. The pharmacological evaluation was carried out by assessing its effects on carbon tetrachloride-induced elevation of liver function marker enzymes in a rat model. The antioxidant activity was assessed by studying its effects on the liver antioxidant marker enzymes. The developed model was validated using the design-optimized levels of formulation and process variables. The physical-chemical characterization confirmed the formation of phytosomes. The optimized formulation demonstrated over 36-fold higher aqueous solubility of apigenin, compared to that of pure apigenin. The formulation also exhibited a significantly higher rate and extent of apigenin release in dissolution studies. The pharmacokinetic analysis revealed a significant enhancement in the oral bioavailability of apigenin from the prepared formulation, compared to pure apigenin. The liver function tests indicated that the prepared phytosome showed a significantly improved restoration of all carbon tetrachloride-elevated rat liver function marker enzymes. The prepared formulation also exhibited antioxidant potential by significantly increasing the levels of glutathione, superoxide dismutase, catalase, and decreasing the levels of lipid peroxidase. The study shows that phospholipid-based phytosome is a promising and viable strategy for improving the delivery of apigenin and similar phytoconstituents with low aqueous solubility. Copyright © 2016 Elsevier B.V. All rights reserved.

Formulation and in vivo assessment of terconazole-loaded polymeric mixed micelles enriched with Cremophor EL as dual functioning mediator for augmenting physical stability and skin delivery.

PubMed

Abd-Elsalam, Wessam H; El-Zahaby, Sally A; Al-Mahallawi, Abdulaziz M

2018-11-01

The aim of the current study was to formulate terconazole (TCZ) loaded polymeric mixed micelles (PMMs) incorporating Cremophor EL as a stabilizer and a penetration enhancer. A 2 3 full factorial design was performed using Design-Expert® software for the optimization of the PMMs which were formulated using Pluronic P123 and Pluronic F127 together with Cremophor EL. To confirm the role of Cremophor EL, PMMs formulation lacking Cremophor EL was prepared for the purpose of comparison. Results showed that the optimal PMMs formulation (F7, where the ratio of total Pluronics to drug was 40:1, the weight ratio of Pluronic P123 to Pluronic F127 was 4:1, and the percentage of Cremophor EL in aqueous phase was 5%) had a high micellar incorporation efficiency (92.98 ± 0.40%) and a very small micellar size (33.23 ± 8.00 nm). Transmission electron microscopy revealed that PMMs possess spherical shape and good dispersibility. The optimal PMMs exhibited superior physical stability when compared with the PMMs formulation of the same composition but lacking Cremophor EL. Ex vivo studies demonstrated that the optimal PMMs formula markedly improved the dermal TCZ delivery compared to PMMs lacking Cremophor EL and TCZ suspension. In addition, it was found that the optimal PMMs exhibited a greater extent of TCZ deposition in the rat dorsal skin relative to TCZ suspension. Moreover, histopathological studies revealed the safety of the optimal PMMs upon topical application to rats. Consequently, PMMs enriched with Cremophor EL, as a stable nano-system, could be promising for the skin delivery of TCZ.

Formulation Optimization of Hot Melt Extruded Abuse Deterrent Pellet Dosage Form Utilizing Design of Experiments (DOE)

PubMed Central

Maddineni, Sindhuri; Battu, Sunil Kumar; Morott, Joe; Majumdar, Soumyajit; Repka, Michael A.

2014-01-01

The objective of the present study was to develop techniques for an abuse-deterrent (AD) platform utilizing hot melt extrusion (HME) process. Formulation optimization was accomplished by utilizing Box-Behnken design of experiments to determine the effect of the three formulation factors: PolyOx™ WSR301, Benecel™ K15M, and Carbopol 71G; each of which was studied at three levels on TR attributes of the produced melt extruded pellets. A response surface methodology was utilized to identify the optimized formulation. Lidocaine Hydrochloride was used as a model drug, and suitable formulation ingredients were employed as carrier matrices and processing aids. All of the formulations were evaluated for the TR attributes such as particle size post-milling, gelling, percentage of drug extraction in water and alcohol. All of the DOE formulations demonstrated sufficient hardness and elasticity, and could not be reduced into fine particles (<150µm), which is a desirable feature to prevent snorting. In addition, all of the formulations exhibited good gelling tendency in water with minimal extraction of drug in the aqueous medium. Moreover, Benecel™ K15M in combination with PolyOx™ WSR301 could be utilized to produce pellets with TR potential. HME has been demonstrated to be a viable technique with a potential to develop novel abuse-deterrent formulations. PMID:24433429

A Mixed Integer Linear Program for Solving a Multiple Route Taxi Scheduling Problem

NASA Technical Reports Server (NTRS)

Montoya, Justin Vincent; Wood, Zachary Paul; Rathinam, Sivakumar; Malik, Waqar Ahmad

2010-01-01

Aircraft movements on taxiways at busy airports often create bottlenecks. This paper introduces a mixed integer linear program to solve a Multiple Route Aircraft Taxi Scheduling Problem. The outputs of the model are in the form of optimal taxi schedules, which include routing decisions for taxiing aircraft. The model extends an existing single route formulation to include routing decisions. An efficient comparison framework compares the multi-route formulation and the single route formulation. The multi-route model is exercised for east side airport surface traffic at Dallas/Fort Worth International Airport to determine if any arrival taxi time savings can be achieved by allowing arrivals to have two taxi routes: a route that crosses an active departure runway and a perimeter route that avoids the crossing. Results indicate that the multi-route formulation yields reduced arrival taxi times over the single route formulation only when a perimeter taxiway is used. In conditions where the departure aircraft are given an optimal and fixed takeoff sequence, accumulative arrival taxi time savings in the multi-route formulation can be as high as 3.6 hours more than the single route formulation. If the departure sequence is not optimal, the multi-route formulation results in less taxi time savings made over the single route formulation, but the average arrival taxi time is significantly decreased.

Development and gamma scintigraphy evaluation of gastro retentive calcium ion-based oral formulation: an innovative approach for the management of gastro-esophageal reflux disease (GERD).

PubMed

Sharma, Braj Gaurav; Khanna, Kushagra; Kumar, Neeraj; Nishad, Dhruv K; Basu, Mitra; Bhatnagar, Aseem

2017-11-01

Calcium chloride is an essential calcium channel agonist which plays an important role in the contraction of muscles by triggering calcium channel. First time hypothesized about its role in the treatment of GER (gastro-esophageal reflux) and vomiting disorder due to its local action. There are two objectives covered in this study as first, the development and optimization of floating formulation of calcium chloride and another objective was to evaluate optimized formulation through gamma scintigraphy in human subjects. Gastro retentive formulation of calcium chloride was prepared by direct compression method. Thirteen tablet formulations were designed with the help of sodium chloride, HPMC-K4M, and carbopol-934 along with effervescing agent sodium bicarbonate and citric acid. Formulation (F8) fitted best for Korsmeyer-Peppas equation with an R 2 value of 0.993. The optimized formulation was radiolabelled with 99m Tc-99 m pertechnetate for its evaluation by gamma scintigraphy. Gastric retention (6 h) was evaluated by gamma scintigraphy in healthy human subjects and efficacy of present formulation confirmed in GER positive human subjects. Gamma scintigraphy results indicated its usefulness in order to manage GERD. Stability studies of the developed formulation were carried out as per ICH guidelines for region IV and found out to be stable for 24 months.

Optimal formulations of local foods to achieve nutritional adequacy for 6–23-month-old rural Tanzanian children

PubMed Central

Raymond, Jofrey; Kassim, Neema; Rose, Jerman W.; Agaba, Morris

2017-01-01

ABSTRACT Background: Achieving nutritional goals of infants and young children while maintaining the intake of local and culture-specific foods can be a daunting task. Diet optimisation using linear goal programming (LP) can effectively generate optimal formulations incorporating local and culturally acceptable foods. Objective: The primary objective of this study was to determine whether a realistic and affordable diet that achieves dietary recommended intakes (DRIs) for 22 selected nutrients can be formulated for rural 6–23-month-old children in Tanzania. Design: Dietary intakes of 400 children aged 6–23 months were assessed using a weighed dietary record (WDR), 24-hour dietary recalls and a 7-days food record. A market survey was also carried out to estimate the cost per 100 g of edible portion of foods that are commonly consumed in the study area. Dietary and market survey data were then used to define LP model parameters for diet optimisation. All LP analyses were done using linear program solver (LiPS) version 1.9.4 to generate optimal food formulations. Results: Optimal formulations that achieved DRIs for 20 nutrients for children aged 6–11 months and all selected nutrients for children aged 12–23 months were successfully developed at a twofold cost of the observed food purchase across age groups. Optimal formulations contained a mixture of ingredients such as wholegrain cereals, Irish potatoes, pulses and seeds, fish and poultry meat as well as fruits and vegetables that can be sourced locally. Conclusions: Our findings revealed that given the available food choices, it is possible to develop optimal formulations that can improve dietary adequacy for rural 6–23-month-old children if food budget for the child’s diets is doubled. These findings suggest the need for setting alternative interventions which can help households increase access to nutrient-dense foods that can fill the identified nutrient gaps. PMID:28814951

D-optimal experimental approach for designing topical microemulsion of itraconazole: Characterization and evaluation of antifungal efficacy against a standardized Tinea pedis infection model in Wistar rats.

PubMed

Kumar, Neeraj; Shishu

2015-01-25

The study aims to statistically develop a microemulsion system of an antifungal agent, itraconazole for overcoming the shortcomings and adverse effects of currently used therapies. Following preformulation studies like solubility determination, component selection and pseudoternary phase diagram construction, a 3-factor D-optimal mixture design was used for optimizing a microemulsion having desirable formulation characteristics. The factors studied for sixteen experimental trials were percent contents (w/w) of water, oil and surfactant, whereas the responses investigated were globule size, transmittance, drug skin retention and drug skin permeation in 6h. Optimized microemulsion (OPT-ME) was incorporated in Carbopol based hydrogel to improve topical applicability. Physical characterization of the formulations was performed using particle size analysis, transmission electron microscopy, texture analysis and rheology behavior. Ex vivo studies carried out in Wistar rat skin depicted that the optimized formulation enhanced drug skin retention and permeation in 6h in comparison to conventional cream and Capmul 908P oil solution of itraconazole. The in vivo evaluation of optimized formulation was performed using a standardized Tinea pedis model in Wistar rats and the results of the pharmacodynamic study, obtained in terms of physical manifestations, fungal-burden score, histopathological profiles and oxidative stress. Rapid remission of Tinea pedis from rats treated with OPT-ME formulation was observed in comparison to commercially available therapies (ketoconazole cream and oral itraconazole solution), thereby indicating the superiority of microemulsion hydrogel formulation over conventional approaches for treating superficial fungal infections. The formulation was stable for a period of twelve months under refrigeration and ambient temperature conditions. All results, therefore, suggest that the OPT-ME can prove to be a promising and rapid alternative to conventional antifungal therapies against superficial fungal infections. Copyright © 2014 Elsevier B.V. All rights reserved.

How to formulate and solve "optimal stand density over time" problems for even-aged stands using dynamic programming.

Treesearch

Chung M. Chen; Dietmar W. Rose; Rolfe A. Leary

1980-01-01

Describes how dynamic programming can be used to solve optimal stand density problems when yields are given by prior simulation or by a new stand growth equation that is a function of the decision variable. Formulations of the latter type allow use of a calculus-based search procedure; they determine exact optimal residual density at each stage.

Design and In-vitro Evaluation of Sustained Release Floating Tablets of Metformin HCl Based on Effervescence and Swelling

PubMed Central

Senjoti, Faria Gias; Mahmood, Syed; Jaffri, Juliana Md; Mandal, Uttam Kumar

2016-01-01

An oral sustained-release floating tablet formulation of metformin HCl was designed and developed. Effervescence and swelling properties were attributed on the developed tablets by sodium bicarbonate and HPMC-PEO polymer combination, respectively. Tablet composition was optimized by response surface methodology (RSM). Seventeen (17) trial formulations were analyzed according to Box-Behnken design of experiment where polymer content of HPMC and PEO at 1: 4 ratio (A), amount of sodium bi-carbonate (B), and amount of SSG (C) were adopted as independent variables. Floating lag time in sec (Y1), cumulative percent drug released at 1 h (Y2) and 12 h (Y3) were chosen as response variables. Tablets from the optimized formulation were also stored at accelerated stability condition (40°C and 75% RH) for 3 months to assess their stability profile. RSM could efficiently optimize the tablet composition with excellent prediction ability. In-vitro drug release until 12 h, floating lag time, and duration of floating were dependent on the amount of three selected independent variables. Optimized tablets remained floating for more than 24 h with a floating lag time of less than 4 min. Based on best fitting method, optimized formulation was found to follow Korsmeyer-Peppas release kinetic. Accelerated stability study revealed that optimized formulation was stable for three months without any major changes in assay, dissolution profile, floating lag time and other physical properties. PMID:27610147

A formulation and analysis of combat games

NASA Technical Reports Server (NTRS)

Heymann, M.; Ardema, M. D.; Rajan, N.

1984-01-01

Combat which is formulated as a dynamical encounter between two opponents, each of whom has offensive capabilities and objectives is outlined. A target set is associated with each opponent in the event space in which he endeavors to terminate the combat, thereby winning. If the combat terminates in both target sets simultaneously, or in neither, a joint capture or a draw, respectively, occurs. Resolution of the encounter is formulated as a combat game; as a pair of competing event constrained differential games. If exactly one of the players can win, the optimal strategies are determined from a resulting constrained zero sum differential game. Otherwise the optimal strategies are computed from a resulting nonzero sum game. Since optimal combat strategies may frequently not exist, approximate or delta combat games are also formulated leading to approximate or delta optimal strategies. The turret game is used to illustrate combat games. This game is sufficiently complex to exhibit a rich variety of combat behavior, much of which is not found in pursuit evasion games.

Structural design using equilibrium programming formulations

NASA Technical Reports Server (NTRS)

Scotti, Stephen J.

1995-01-01

Solutions to increasingly larger structural optimization problems are desired. However, computational resources are strained to meet this need. New methods will be required to solve increasingly larger problems. The present approaches to solving large-scale problems involve approximations for the constraints of structural optimization problems and/or decomposition of the problem into multiple subproblems that can be solved in parallel. An area of game theory, equilibrium programming (also known as noncooperative game theory), can be used to unify these existing approaches from a theoretical point of view (considering the existence and optimality of solutions), and be used as a framework for the development of new methods for solving large-scale optimization problems. Equilibrium programming theory is described, and existing design techniques such as fully stressed design and constraint approximations are shown to fit within its framework. Two new structural design formulations are also derived. The first new formulation is another approximation technique which is a general updating scheme for the sensitivity derivatives of design constraints. The second new formulation uses a substructure-based decomposition of the structure for analysis and sensitivity calculations. Significant computational benefits of the new formulations compared with a conventional method are demonstrated.

Two alternative ways for solving the coordination problem in multilevel optimization

NASA Technical Reports Server (NTRS)

Sobieszczanski-Sobieski, Jaroslaw

1991-01-01

Two techniques for formulating the coupling between levels in multilevel optimization by linear decomposition, proposed as improvements over the original formulation, now several years old, that relied on explicit equality constraints which were shown by application experience as occasionally causing numerical difficulties. The two new techniques represent the coupling without using explicit equality constraints, thus avoiding the above diffuculties and also reducing computational cost of the procedure. The old and new formulations are presented in detail and illustrated by an example of a structural optimization. A generic version of the improved algorithm is also developed for applications to multidisciplinary systems not limited to structures.

Horsetail matching: a flexible approach to optimization under uncertainty

NASA Astrophysics Data System (ADS)

Cook, L. W.; Jarrett, J. P.

2018-04-01

It is important to design engineering systems to be robust with respect to uncertainties in the design process. Often, this is done by considering statistical moments, but over-reliance on statistical moments when formulating a robust optimization can produce designs that are stochastically dominated by other feasible designs. This article instead proposes a formulation for optimization under uncertainty that minimizes the difference between a design's cumulative distribution function and a target. A standard target is proposed that produces stochastically non-dominated designs, but the formulation also offers enough flexibility to recover existing approaches for robust optimization. A numerical implementation is developed that employs kernels to give a differentiable objective function. The method is applied to algebraic test problems and a robust transonic airfoil design problem where it is compared to multi-objective, weighted-sum and density matching approaches to robust optimization; several advantages over these existing methods are demonstrated.

Design and statistical optimization of glipizide loaded lipospheres using response surface methodology.

PubMed

Shivakumar, Hagalavadi Nanjappa; Patel, Pragnesh Bharat; Desai, Bapusaheb Gangadhar; Ashok, Purnima; Arulmozhi, Sinnathambi

2007-09-01

A 32 factorial design was employed to produce glipizide lipospheres by the emulsification phase separation technique using paraffin wax and stearic acid as retardants. The effect of critical formulation variables, namely levels of paraffin wax (X1) and proportion of stearic acid in the wax (X2) on geometric mean diameter (dg), percent encapsulation efficiency (% EE), release at the end of 12 h (rel12) and time taken for 50% of drug release (t50), were evaluated using the F-test. Mathematical models containing only the significant terms were generated for each response parameter using the multiple linear regression analysis (MLRA) and analysis of variance (ANOVA). Both formulation variables studied exerted a significant influence (p < 0.05) on the response parameters. Numerical optimization using the desirability approach was employed to develop an optimized formulation by setting constraints on the dependent and independent variables. The experimental values of dg, % EE, rel12 and t50 values for the optimized formulation were found to be 57.54 +/- 1.38 mum, 86.28 +/- 1.32%, 77.23 +/- 2.78% and 5.60 +/- 0.32 h, respectively, which were in close agreement with those predicted by the mathematical models. The drug release from lipospheres followed first-order kinetics and was characterized by the Higuchi diffusion model. The optimized liposphere formulation developed was found to produce sustained anti-diabetic activity following oral administration in rats.

Construction and cellular uptake behavior of redox-sensitive docetaxel prodrug-loaded liposomes.

PubMed

Ren, Guolian; Jiang, Mengjuan; Guo, Weiling; Sun, Bingjun; Lian, He; Wang, Yongjun; He, Zhonggui

2018-01-01

A redox-responsive docetaxel (DTX) prodrug consisting of a disulfide linkage between DTX and vitamin E (DTX-SS-VE) was synthesized in our laboratory and was successfully formulated into liposomes. The aim of this study was to optimize the formulation and investigate the cellular uptake of DTX prodrug-loaded liposomes (DPLs). The content of DTX-SS-VE was determined by ultrahigh-performance liquid chromatography (UPLC). The formulation and process were optimized using entrapment efficiency (EE), drug-loading (DL), particle size and polydispersity index (PDI) as the evaluation indices. The optimal formulation was as follows: drug/lipid ratio of 1:12, cholesterol/lipid ratio of 1:10, hydration temperature of 40 °C, sonication power and time of 400 W and 5 min. The EE, DL and particle size of the optimized DPLs were 97.60 ± 0.03%, 7.09 ± 0.22% and 93.06 ± 0.72 nm, respectively. DPLs had good dilution stability under the physiological conditions over 24 h. In addition, DPLs were found to enter tumor cells via different pathways and released DTX from the prodrug to induce apoptosis. Taken together, the optimized formulation and process were found to be a simple, stable and applicable method for the preparation of DPLs that could successfully escape from lysosomes.

Chlorogenic acid stabilized nanostructured lipid carriers (NLC) of atorvastatin: formulation, design and in vivo evaluation.

PubMed

Khan, Saba; Baboota, Sanjula; Ali, Javed; Narang, R S; Narang, Jasjeet K

2016-01-01

The present work was aimed at developing an optimized oral nanostructured lipid carrier (NLC) formulation of poorly soluble atorvastatin Ca (AT Ca) and assessing its in vitro release, oral bioavailability and pharmacodynamic activity. In this study, chlorogenic acid, a novel excipient having synergistic cholesterol lowering activity was utilized and explored in NLC formulation development. The drug-loaded NLC formulations were prepared using a high pressure homogenization technique and optimized by the Box-Behnken statistical design using the Design-Expert software. The optimized NLC formulation was composed of oleic acid and stearic acid as lipid phase (0.9% w/v), poloxamer 188 as surfactant (1% w/v) and chlorogenic acid (0.05% w/v). The mean particle size, polydispersity index (PDI) and % drug entrapment efficiency of optimized NLC were 203.56 ± 8.57 nm, 0.27 ± 0.028 and 83.66 ± 5.69, respectively. In vitro release studies showed that the release of drug from optimized NLC formulations were markedly enhanced as compared to solid lipid nanoparticles (SLN) and drug suspension. The plasma concentration time profile of AT Ca in rats showed 3.08- and 4.89-fold increase in relative bioavailability of developed NLC with respect to marketed preparation (ATORVA® tablet) and drug suspension, respectively. Pharmacodynamic study suggested highly significant (**p < 0.01) reduction in the cholesterol and triglyceride values by NLC in comparison with ATORVA® tablet. Therefore, the results of in vivo studies demonstrated promising prospects for successful oral delivery of AT Ca by means of its chlorogenic acid integrated NLC.

Optimization of caseinate-coated simvastatin-zein nanoparticles: improved bioavailability and modified release characteristics.

PubMed

Ahmed, Osama A A; Hosny, Khaled M; Al-Sawahli, Majid M; Fahmy, Usama A

2015-01-01

The current study focuses on utilization of the natural biocompatible polymer zein to formulate simvastatin (SMV) nanoparticles coated with caseinate, to improve solubility and hence bioavailability, and in addition, to modify SMV-release characteristics. This formulation can be utilized for oral or possible depot parenteral applications. Fifteen formulations were prepared by liquid-liquid phase separation method, according to the Box-Behnken design, to optimize formulation variables. Sodium caseinate was used as an electrosteric stabilizer. The factors studied were: percentage of SMV in the SMV-zein mixture (X1), ethanol concentration (X2), and caseinate concentration (X3). The selected dependent variables were mean particle size (Y1), SMV encapsulation efficiency (Y2), and cumulative percentage of drug permeated after 1 hour (Y3). The diffusion of SMV from the prepared nanoparticles specified by the design was carried out using an automated Franz diffusion cell apparatus. The optimized SMV-zein formula was investigated for in vivo pharmacokinetic parameters compared with an oral SMV suspension. The optimized nanosized SMV-zein formula showed a 131 nm mean particle size and 89% encapsulation efficiency. In vitro permeation studies displayed delayed permeation characteristics, with about 42% and 85% of SMV cumulative amount released after 12 and 48 hours, respectively. Bioavailability estimation in rats revealed an augmentation in SMV bioavailability from the optimized SMV-zein formulation, by fourfold relative to SMV suspension. Formulation of caseinate-coated SMV-zein nanoparticles improves the pharmacokinetic profile and bioavailability of SMV. Accordingly, improved hypolipidemic activities for longer duration could be achieved. In addition, the reduced dosage rate of SMV-zein nanoparticles improves patient tolerability and compliance.

Gastroretentive behavior of orally administered radiolabeled tamarind seed formulations in rabbits validated by gamma scintigraphy.

PubMed

Razavi, Mahboubeh; Karimian, Hamed; Yeong, Chai Hong; Fadaeinasab, Mehran; Khaing, Si Lay; Chung, Lip Yong; Mohamad Haron, Didi Erwandi B; Noordin, Mohamed Ibrahim

2017-01-01

This study aimed to formulate floating gastroretentive tablets containing metformin hydrochloric acid (HCl), using various grades of hydrogel such as tamarind powders and xanthan to overcome short gastric residence time of the conventional dosage forms. Different concentrations of the hydrogels were tested to determine the formulation that could provide a sustained release of 12 h. Eleven formulations with different ratios of tamarind seed powder/tamarind kernel powder (TKP):xanthan were prepared. The physical parameters were observed, and in vitro drug-release studies of the prepared formulations were carried out. Optimal formulation was assessed for physicochemical properties, thermal stability, and chemical interaction followed by in vivo gamma scintigraphy study. MKP3 formulation with a TKP:xanthan ratio of 3:2 was found to have 99.87% release over 12 h. Furthermore, in vivo gamma scintigraphy study was carried out for the optimized formulation in healthy New Zealand White rabbits, and the pharmacokinetic parameters of developed formulations were obtained. 153 Sm 2 O 3 was used to trace the profile of release in the gastrointestinal tract of the rabbits, and the drug release was analyzed. The time ( T max ) at which the maximum concentration of metformin HCl in the blood ( C max ) was observed, and it was extended four times for the gastroretentive formulation in comparison with the formulation without polymers. C max and the half-life were found to be within an acceptable range. It is therefore concluded that MKP3 is the optimal formulation for sustained release of metformin HCl over a period of 12 h as a result of its floating properties in the gastric region.

Gastroretentive behavior of orally administered radiolabeled tamarind seed formulations in rabbits validated by gamma scintigraphy

PubMed Central

Razavi, Mahboubeh; Karimian, Hamed; Yeong, Chai Hong; Fadaeinasab, Mehran; Khaing, Si Lay; Chung, Lip Yong; Mohamad Haron, Didi Erwandi B; Noordin, Mohamed Ibrahim

2017-01-01

This study aimed to formulate floating gastroretentive tablets containing metformin hydrochloric acid (HCl), using various grades of hydrogel such as tamarind powders and xanthan to overcome short gastric residence time of the conventional dosage forms. Different concentrations of the hydrogels were tested to determine the formulation that could provide a sustained release of 12 h. Eleven formulations with different ratios of tamarind seed powder/tamarind kernel powder (TKP):xanthan were prepared. The physical parameters were observed, and in vitro drug-release studies of the prepared formulations were carried out. Optimal formulation was assessed for physicochemical properties, thermal stability, and chemical interaction followed by in vivo gamma scintigraphy study. MKP3 formulation with a TKP:xanthan ratio of 3:2 was found to have 99.87% release over 12 h. Furthermore, in vivo gamma scintigraphy study was carried out for the optimized formulation in healthy New Zealand White rabbits, and the pharmacokinetic parameters of developed formulations were obtained. 153Sm2O3 was used to trace the profile of release in the gastrointestinal tract of the rabbits, and the drug release was analyzed. The time (Tmax) at which the maximum concentration of metformin HCl in the blood (Cmax) was observed, and it was extended four times for the gastroretentive formulation in comparison with the formulation without polymers. Cmax and the half-life were found to be within an acceptable range. It is therefore concluded that MKP3 is the optimal formulation for sustained release of metformin HCl over a period of 12 h as a result of its floating properties in the gastric region. PMID:28031701

Use of nonlinear programming to optimize performance response to energy density in broiler feed formulation.

PubMed

Guevara, V R

2004-02-01

A nonlinear programming optimization model was developed to maximize margin over feed cost in broiler feed formulation and is described in this paper. The model identifies the optimal feed mix that maximizes profit margin. Optimum metabolizable energy level and performance were found by using Excel Solver nonlinear programming. Data from an energy density study with broilers were fitted to quadratic equations to express weight gain, feed consumption, and the objective function income over feed cost in terms of energy density. Nutrient:energy ratio constraints were transformed into equivalent linear constraints. National Research Council nutrient requirements and feeding program were used for examining changes in variables. The nonlinear programming feed formulation method was used to illustrate the effects of changes in different variables on the optimum energy density, performance, and profitability and was compared with conventional linear programming. To demonstrate the capabilities of the model, I determined the impact of variation in prices. Prices for broiler, corn, fish meal, and soybean meal were increased and decreased by 25%. Formulations were identical in all other respects. Energy density, margin, and diet cost changed compared with conventional linear programming formulation. This study suggests that nonlinear programming can be more useful than conventional linear programming to optimize performance response to energy density in broiler feed formulation because an energy level does not need to be set.

Optimization-Based Selection of Influential Agents in a Rural Afghan Social Network

DTIC Science & Technology

2010-06-01

nonlethal targeting model, a nonlinear programming ( NLP ) optimization formulation that identifies the k US agent assignment strategy producing the greatest...leader social network, and 3) the nonlethal targeting model, a nonlinear programming ( NLP ) optimization formulation that identifies the k US agent...NATO Coalition in Afghanistan. 55 for Afghanistan ( [54], [31], [48], [55], [30]). While Arab tribes tend to be more hierarchical, Pashtun tribes are

Enhanced Solubility and Dissolution Rate of Lacidipine Nanosuspension: Formulation Via Antisolvent Sonoprecipitation Technique and Optimization Using Box-Behnken Design.

PubMed

Kassem, Mohamed A A; ElMeshad, Aliaa N; Fares, Ahmed R

2017-05-01

Lacidipine (LCDP) is a highly lipophilic calcium channel blocker of poor aqueous solubility leading to poor oral absorption. This study aims to prepare and optimize LCDP nanosuspensions using antisolvent sonoprecipitation technique to enhance the solubility and dissolution of LCDP. A three-factor, three-level Box-Behnken design was employed to optimize the formulation variables to obtain LCDP nanosuspension of small and uniform particle size. Formulation variables were as follows: stabilizer to drug ratio (A), sodium deoxycholate percentage (B), and sonication time (C). LCDP nanosuspensions were assessed for particle size, zeta potential, and polydispersity index. The formula with the highest desirability (0.969) was chosen as the optimized formula. The values of the formulation variables (A, B, and C) in the optimized nanosuspension were 1.5, 100%, and 8 min, respectively. Optimal LCDP nanosuspension had particle size (PS) of 273.21 nm, zeta potential (ZP) of -32.68 mV and polydispersity index (PDI) of 0.098. LCDP nanosuspension was characterized using x-ray powder diffraction, differential scanning calorimetry, and transmission electron microscopy. LCDP nanosuspension showed saturation solubility 70 times that of raw LCDP in addition to significantly enhanced dissolution rate due to particle size reduction and decreased crystallinity. These results suggest that the optimized LCDP nanosuspension could be promising to improve oral absorption of LCDP.

Application of Box-Behnken design for preparation of levofloxacin-loaded stearic acid solid lipid nanoparticles for ocular delivery: Optimization, in vitro release, ocular tolerance, and antibacterial activity.

PubMed

Baig, Mirza Salman; Ahad, Abdul; Aslam, Mohammed; Imam, Syed Sarim; Aqil, Mohd; Ali, Asgar

2016-04-01

The aim of the present study was to develop and optimize levofloxacin loaded solid lipid nanoparticles for the treatment of conjunctivitis. Box-Behnken experimental design was applied for optimization of solid lipid nanoparticles. The independent variables were stearic acid as lipid (X1), Tween 80 as surfactant (X2) and sodium deoxycholate as co-surfactant (X3) while particle size (Y1) and entrapment efficiency (Y2) were the dependent variables. Further in vitro release and antibacterial activity in vitro were also performed. The optimized formulation of levofloxacin provides particle size of 237.82 nm and showed 78.71% entrapment efficiency and achieved flux 0.2,493 μg/cm(2)/h across excised goat cornea. In vitro release study showed prolonged drug release from the optimized formulation following Korsmeyer-Peppas model. Antimicrobial study revealed that the developed formulation possesses antibacterial activity against Staphylococcus aureus, and Escherichia coli equivalent to marketed eye drops. HET-CAM test demonstrated that optimized formulation was found to be non-irritant and safe for topical ophthalmic use. Our results concluded that solid lipid nanoparticles are an efficient carrier for ocular delivery of levofloxacin and other drugs. Copyright © 2015 Elsevier B.V. All rights reserved.

Algorithms for bilevel optimization

NASA Technical Reports Server (NTRS)

Alexandrov, Natalia; Dennis, J. E., Jr.

1994-01-01

General multilevel nonlinear optimization problems arise in design of complex systems and can be used as a means of regularization for multi-criteria optimization problems. Here, for clarity in displaying our ideas, we restrict ourselves to general bi-level optimization problems, and we present two solution approaches. Both approaches use a trust-region globalization strategy, and they can be easily extended to handle the general multilevel problem. We make no convexity assumptions, but we do assume that the problem has a nondegenerate feasible set. We consider necessary optimality conditions for the bi-level problem formulations and discuss results that can be extended to obtain multilevel optimization formulations with constraints at each level.

Integrated aerodynamic/dynamic optimization of helicopter rotor blades

NASA Technical Reports Server (NTRS)

Chattopadhyay, Aditi; Walsh, Joanne L.; Riley, Michael F.

1989-01-01

An integrated aerodynamic/dynamic optimization procedure is used to minimize blade weight and 4 per rev vertical hub shear for a rotor blade in forward flight. The coupling of aerodynamics and dynamics is accomplished through the inclusion of airloads which vary with the design variables during the optimization process. Both single and multiple objective functions are used in the optimization formulation. The Global Criteria Approach is used to formulate the multiple objective optimization and results are compared with those obtained by using single objective function formulations. Constraints are imposed on natural frequencies, autorotational inertia, and centrifugal stress. The program CAMRAD is used for the blade aerodynamic and dynamic analyses, and the program CONMIN is used for the optimization. Since the spanwise and the azimuthal variations of loading are responsible for most rotor vibration and noise, the vertical airload distributions on the blade, before and after optimization, are compared. The total power required by the rotor to produce the same amount of thrust for a given area is also calculated before and after optimization. Results indicate that integrated optimization can significantly reduce the blade weight, the hub shear and the amplitude of the vertical airload distributions on the blade and the total power required by the rotor.

A Comparative Theoretical and Computational Study on Robust Counterpart Optimization: II. Probabilistic Guarantees on Constraint Satisfaction

PubMed Central

Li, Zukui; Floudas, Christodoulos A.

2012-01-01

Probabilistic guarantees on constraint satisfaction for robust counterpart optimization are studied in this paper. The robust counterpart optimization formulations studied are derived from box, ellipsoidal, polyhedral, “interval+ellipsoidal” and “interval+polyhedral” uncertainty sets (Li, Z., Ding, R., and Floudas, C.A., A Comparative Theoretical and Computational Study on Robust Counterpart Optimization: I. Robust Linear and Robust Mixed Integer Linear Optimization, Ind. Eng. Chem. Res, 2011, 50, 10567). For those robust counterpart optimization formulations, their corresponding probability bounds on constraint satisfaction are derived for different types of uncertainty characteristic (i.e., bounded or unbounded uncertainty, with or without detailed probability distribution information). The findings of this work extend the results in the literature and provide greater flexibility for robust optimization practitioners in choosing tighter probability bounds so as to find less conservative robust solutions. Extensive numerical studies are performed to compare the tightness of the different probability bounds and the conservatism of different robust counterpart optimization formulations. Guiding rules for the selection of robust counterpart optimization models and for the determination of the size of the uncertainty set are discussed. Applications in production planning and process scheduling problems are presented. PMID:23329868

Designing CAF-adjuvanted dry powder vaccines: spray drying preserves the adjuvant activity of CAF01.

PubMed

Ingvarsson, Pall Thor; Schmidt, Signe Tandrup; Christensen, Dennis; Larsen, Niels Bent; Hinrichs, Wouter Leonardus Joseph; Andersen, Peter; Rantanen, Jukka; Nielsen, Hanne Mørck; Yang, Mingshi; Foged, Camilla

2013-05-10

Dry powder vaccine formulations are highly attractive due to improved storage stability and the possibility for particle engineering, as compared to liquid formulations. However, a prerequisite for formulating vaccines into dry formulations is that their physicochemical and adjuvant properties remain unchanged upon rehydration. Thus, we have identified and optimized the parameters of importance for the design of a spray dried powder formulation of the cationic liposomal adjuvant formulation 01 (CAF01) composed of dimethyldioctadecylammonium (DDA) bromide and trehalose 6,6'-dibehenate (TDB) via spray drying. The optimal excipient to stabilize CAF01 during spray drying and for the design of nanocomposite microparticles was identified among mannitol, lactose and trehalose. Trehalose and lactose were promising stabilizers with respect to preserving liposome size, as compared to mannitol. Trehalose and lactose were in the glassy state upon co-spray drying with the liposomes, whereas mannitol appeared crystalline, suggesting that the ability of the stabilizer to form a glassy matrix around the liposomes is one of the prerequisites for stabilization. Systematic studies on the effect of process parameters suggested that a fast drying rate is essential to avoid phase separation and lipid accumulation at the surface of the microparticles during spray drying. Finally, immunization studies in mice with CAF01 in combination with the tuberculosis antigen Ag85B-ESAT6-Rv2660c (H56) demonstrated that spray drying of CAF01 with trehalose under optimal processing conditions resulted in the preservation of the adjuvant activity in vivo. These data demonstrate the importance of liposome stabilization via optimization of formulation and processing conditions in the engineering of dry powder liposome formulations. Copyright © 2013 Elsevier B.V. All rights reserved.

Combined mixture-process variable approach: a suitable statistical tool for nanovesicular systems optimization.

PubMed

Habib, Basant A; AbouGhaly, Mohamed H H

2016-06-01

This study aims to illustrate the applicability of combined mixture-process variable (MPV) design and modeling for optimization of nanovesicular systems. The D-optimal experimental plan studied the influence of three mixture components (MCs) and two process variables (PVs) on lercanidipine transfersomes. The MCs were phosphatidylcholine (A), sodium glycocholate (B) and lercanidipine hydrochloride (C), while the PVs were glycerol amount in the hydration mixture (D) and sonication time (E). The studied responses were Y1: particle size, Y2: zeta potential and Y3: entrapment efficiency percent (EE%). Polynomial equations were used to study the influence of MCs and PVs on each response. Response surface methodology and multiple response optimization were applied to optimize the formulation with the goals of minimizing Y1 and maximizing Y2 and Y3. The obtained polynomial models had prediction R(2) values of 0.645, 0.947 and 0.795 for Y1, Y2 and Y3, respectively. Contour, Piepel's response trace, perturbation, and interaction plots were drawn for responses representation. The optimized formulation, A: 265 mg, B: 10 mg, C: 40 mg, D: zero g and E: 120 s, had desirability of 0.9526. The actual response values for the optimized formulation were within the two-sided 95% prediction intervals and were close to the predicted values with maximum percent deviation of 6.2%. This indicates the validity of combined MPV design and modeling for optimization of transfersomal formulations as an example of nanovesicular systems.

Transungual Gel of Terbinafine Hydrochloride for the Management of Onychomycosis: Formulation, Optimization, and Evaluation.

PubMed

Thatai, Purva; Sapra, Bharti

2017-08-01

The present study was aimed to optimize, develop, and evaluate microemulsion and microemulsion-based gel as a vehicle for transungual drug delivery of terbinafine hydrochloride for the treatment of onychomycosis. D-optimal mixture experimental design was adopted to optimize the composition of microemulsion having amount of oil (X 1 ), Smix (mixture of surfactant and cosurfactant; X 2 ), and water (X 3 ) as the independent variables. The formulations were assessed for permeation (micrograms per square centimeter per hour; Y 1 ), particle size (nanometer; Y 2 ), and solubility of the drug in the formulation (milligrams per milliliter; Y 3 ). The microemulsion containing 3.05% oil, 24.98% Smix, and 71.96% water was selected as the optimized formulation. The microemulsion-based gel showed better penetration (∼5 folds) as well as more retention (∼9 fold) in the animal hoof as compared to the commercial cream. The techniques used to screen penetration enhancers (hydration enhancement factor, ATR-FTIR, SEM, and DSC) revealed the synergistic effect of combination of urea and n-acetyl cysteine in disruption of the structure of hoof and hence, leading to enhanced penetration of drug.

Evaluation of Beeswax Influence on Physical Properties of Lipstick Using Instrumental and Sensory Methods.

PubMed

Kasparaviciene, Giedre; Savickas, Arunas; Kalveniene, Zenona; Velziene, Saule; Kubiliene, Loreta; Bernatoniene, Jurga

2016-01-01

The aim of this study was to optimize the lipsticks formulation according to the physical properties and sensory attributes and investigate the relationship between instrumental and sensory analyses and evaluate the influence of the main ingredients, beeswax and oil, with analysis of lipsticks properties. Central composite design was used to optimize the mixture of oils and beeswax and cocoa butter for formulation of lipsticks. Antioxidant activity was evaluated by DPPH free radical scavenging method spectrophotometrically. Physical properties of lipsticks melting point were determined in a glass tube; the hardness was investigated with texture analyzer. Sensory analysis was performed with untrained volunteers. The optimized mixture of sea buckthorn oil and grapeseed oil mixture ratio 13.96 : 6.18 showed the highest antioxidative activity (70 ± 0.84%) and was chosen for lipstick formulation. According to the sensory and instrumental analysis results, optimal ingredients amounts for the lipstick were calculated: 57.67% mixture of oils, 19.58% beeswax, and 22.75% cocoa butter. Experimentally designed and optimized lipstick formulation had good physical properties and high scored sensory evaluation. Correlation analysis showed a significant relationship between sensory and instrumental evaluations.

Evaluation of Beeswax Influence on Physical Properties of Lipstick Using Instrumental and Sensory Methods

PubMed Central

Kasparaviciene, Giedre; Savickas, Arunas; Kalveniene, Zenona; Velziene, Saule; Kubiliene, Loreta

2016-01-01

The aim of this study was to optimize the lipsticks formulation according to the physical properties and sensory attributes and investigate the relationship between instrumental and sensory analyses and evaluate the influence of the main ingredients, beeswax and oil, with analysis of lipsticks properties. Central composite design was used to optimize the mixture of oils and beeswax and cocoa butter for formulation of lipsticks. Antioxidant activity was evaluated by DPPH free radical scavenging method spectrophotometrically. Physical properties of lipsticks melting point were determined in a glass tube; the hardness was investigated with texture analyzer. Sensory analysis was performed with untrained volunteers. The optimized mixture of sea buckthorn oil and grapeseed oil mixture ratio 13.96 : 6.18 showed the highest antioxidative activity (70 ± 0.84%) and was chosen for lipstick formulation. According to the sensory and instrumental analysis results, optimal ingredients amounts for the lipstick were calculated: 57.67% mixture of oils, 19.58% beeswax, and 22.75% cocoa butter. Experimentally designed and optimized lipstick formulation had good physical properties and high scored sensory evaluation. Correlation analysis showed a significant relationship between sensory and instrumental evaluations. PMID:27994631

Tracking trade transactions in water resource systems: A node-arc optimization formulation

NASA Astrophysics Data System (ADS)

Erfani, Tohid; Huskova, Ivana; Harou, Julien J.

2013-05-01

We formulate and apply a multicommodity network flow node-arc optimization model capable of tracking trade transactions in complex water resource systems. The model uses a simple node to node network connectivity matrix and does not require preprocessing of all possible flow paths in the network. We compare the proposed node-arc formulation with an existing arc-path (flow path) formulation and explain the advantages and difficulties of both approaches. We verify the proposed formulation model on a hypothetical water distribution network. Results indicate the arc-path model solves the problem with fewer constraints, but the proposed formulation allows using a simple network connectivity matrix which simplifies modeling large or complex networks. The proposed algorithm allows converting existing node-arc hydroeconomic models that broadly represent water trading to ones that also track individual supplier-receiver relationships (trade transactions).

Pasteurization as a tool to control the bio-burden in solid herbal dosage forms: A pilot study of formulating Ashoka tablets with an industrial perspective.

PubMed

Pushpalatha, Hulikal Basavarajaiah; Pramod, Kumar; Sundaram, Ramachandran; Shyam, Ramakrishnan

2014-10-01

Irradiation and use of preservatives are routine procedures to control bio-burden in solid herbal dosage forms. Use of steam or pasteurization is even though reported in the literature, not many studies are available with respect to its application in reducing the bio-burden in herbal drug formulations. Hence, we undertook a series of studies to explore the suitability of pasteurization as a method to reduce bio-burden during formulation and development of herbal dosage forms, which will pave the way for preparing preservative-free formulations. Optimized Ashoka (Saraca indica) tablets were formulated and developed. The optimized formula was then subjected to pasteurization during formulation, with an aim to keep the microbial count well within the limits of pharmacopoeial standards. Then, three variants of the optimized Ashoka formulation - with preservative, without preservative and formulation without preservative and subjected to pasteurization, were compared by routine in-process parameters and stability studies. The results obtained indicate that Ashoka tablets manufactured by inclusion of the pasteurization technique not only showed the bio-burden to be within the limits of pharmacopoeial standards, but also exhibited the compliance with other parameters, such as stability and quality. The outcome of this pilot study shows that pasteurization can be employed as a distinctive method for reducing bio-burden during the formulation and development of herbal dosage forms, such as tablets.

New scale-down methodology from commercial to lab scale to optimize plant-derived soft gel capsule formulations on a commercial scale.

PubMed

Oishi, Sana; Kimura, Shin-Ichiro; Noguchi, Shuji; Kondo, Mio; Kondo, Yosuke; Shimokawa, Yoshiyuki; Iwao, Yasunori; Itai, Shigeru

2018-01-15

A new scale-down methodology from commercial rotary die scale to laboratory scale was developed to optimize a plant-derived soft gel capsule formulation and eventually manufacture superior soft gel capsules on a commercial scale, in order to reduce the time and cost for formulation development. Animal-derived and plant-derived soft gel film sheets were prepared using an applicator on a laboratory scale and their physicochemical properties, such as tensile strength, Young's modulus, and adhesive strength, were evaluated. The tensile strength of the animal-derived and plant-derived soft gel film sheets was 11.7 MPa and 4.41 MPa, respectively. The Young's modulus of the animal-derived and plant-derived soft gel film sheets was 169 MPa and 17.8 MPa, respectively, and both sheets showed a similar adhesion strength of approximately 4.5-10 MPa. Using a D-optimal mixture design, plant-derived soft gel film sheets were prepared and optimized by varying their composition, including variations in the mass of κ-carrageenan, ι-carrageenan, oxidized starch and heat-treated starch. The physicochemical properties of the sheets were evaluated to determine the optimal formulation. Finally, plant-derived soft gel capsules were manufactured using the rotary die method and the prepared soft gel capsules showed equivalent or superior physical properties compared with pre-existing soft gel capsules. Therefore, we successfully developed a new scale-down methodology to optimize the formulation of plant-derived soft gel capsules on a commercial scale. Copyright © 2017 Elsevier B.V. All rights reserved.

Production and storage stability of formulated chicken nuggets using konjac flour and shiitake mushrooms.

PubMed

Akesowan, Adisak

2016-10-01

Formulated chicken nuggets which are low in fat and, high in dietary fiber and free from phosphate were developed by adding various levels of a konjac flour/xanthan gum (KF/XG) (3:1) mixture (0.2-1.5 %, w/w) and shiitake powder (SP) (1-4 %, w/w). A central composite rotatable design was used to investigate the influence of variables on the physical and sensory properties of nuggets and to optimize the formulated nugget formulation. The addition of the KF/XG mixture and SP was effective in improving nugget firmness and increasing hedonic scores for color, taste, flavor and overall acceptability. The nugget became darker with more SP was added. Optimal nuggets with 0.39 % KF/XG mixture and 1.84 % SP had reduced fat, higher dietary fiber and amino acids. After frozen (-18 ± 2 °C) storage, optimal formulated nuggets showed slower decreased in moisture, hardness and chewiness compared to standard nuggets. Konjac flour and SP also lowered lipid oxidation in frozen formulated nuggets. A slight change in sensory score was observed in both nuggets were microbiologically safe after frozen storage for 75 days.

Dynamically Reconfigurable Approach to Multidisciplinary Problems

NASA Technical Reports Server (NTRS)

Alexandrov, Natalie M.; Lewis, Robert Michael

2003-01-01

The complexity and autonomy of the constituent disciplines and the diversity of the disciplinary data formats make the task of integrating simulations into a multidisciplinary design optimization problem extremely time-consuming and difficult. We propose a dynamically reconfigurable approach to MDO problem formulation wherein an appropriate implementation of the disciplinary information results in basic computational components that can be combined into different MDO problem formulations and solution algorithms, including hybrid strategies, with relative ease. The ability to re-use the computational components is due to the special structure of the MDO problem. We believe that this structure can and should be used to formulate and solve optimization problems in the multidisciplinary context. The present work identifies the basic computational components in several MDO problem formulations and examines the dynamically reconfigurable approach in the context of a popular class of optimization methods. We show that if the disciplinary sensitivity information is implemented in a modular fashion, the transfer of sensitivity information among the formulations under study is straightforward. This enables not only experimentation with a variety of problem formations in a research environment, but also the flexible use of formulations in a production design environment.

Development and optimization of apigenin-loaded transfersomal system for skin cancer delivery: in vitro evaluation.

PubMed

Jangdey, Manmohan Singh; Gupta, Anshita; Saraf, Shailendra; Saraf, Swarnlata

2017-11-01

The aim of this work is to apply Box-Behnken design to optimize the transfersomes were formulated by modified rotary evaporation sonication technique using surfactant Tween 80. The response surface methodology was used having three-factored with three levels. The prepared formulations were characterized for vesicle shape, size, entrapment efficiency (%), stability, and in vitro permeation. The result showed that drug entrapment of 84.24% with average vesicle size of 35.41 nm and drug loading of 8.042%. Thus, optimized formulation was found good stability and is a promising approach to improve the permeability of apigenin in sustained release for prolonged period of time.

Preliminary Structural Design Using Topology Optimization with a Comparison of Results from Gradient and Genetic Algorithm Methods

NASA Technical Reports Server (NTRS)

Burt, Adam O.; Tinker, Michael L.

2014-01-01

In this paper, genetic algorithm based and gradient-based topology optimization is presented in application to a real hardware design problem. Preliminary design of a planetary lander mockup structure is accomplished using these methods that prove to provide major weight savings by addressing the structural efficiency during the design cycle. This paper presents two alternative formulations of the topology optimization problem. The first is the widely-used gradient-based implementation using commercially available algorithms. The second is formulated using genetic algorithms and internally developed capabilities. These two approaches are applied to a practical design problem for hardware that has been built, tested and proven to be functional. Both formulations converged on similar solutions and therefore were proven to be equally valid implementations of the process. This paper discusses both of these formulations at a high level.

Optimality approaches to describe characteristic fluvial patterns on landscapes

PubMed Central

Paik, Kyungrock; Kumar, Praveen

2010-01-01

Mother Nature has left amazingly regular geomorphic patterns on the Earth's surface. These patterns are often explained as having arisen as a result of some optimal behaviour of natural processes. However, there is little agreement on what is being optimized. As a result, a number of alternatives have been proposed, often with little a priori justification with the argument that successful predictions will lend a posteriori support to the hypothesized optimality principle. Given that maximum entropy production is an optimality principle attempting to predict the microscopic behaviour from a macroscopic characterization, this paper provides a review of similar approaches with the goal of providing a comparison and contrast between them to enable synthesis. While assumptions of optimal behaviour approach a system from a macroscopic viewpoint, process-based formulations attempt to resolve the mechanistic details whose interactions lead to the system level functions. Using observed optimality trends may help simplify problem formulation at appropriate levels of scale of interest. However, for such an approach to be successful, we suggest that optimality approaches should be formulated at a broader level of environmental systems' viewpoint, i.e. incorporating the dynamic nature of environmental variables and complex feedback mechanisms between fluvial and non-fluvial processes. PMID:20368257

A chance constraint estimation approach to optimizing resource management under uncertainty

Treesearch

Michael Bevers

2007-01-01

Chance-constrained optimization is an important method for managing risk arising from random variations in natural resource systems, but the probabilistic formulations often pose mathematical programming problems that cannot be solved with exact methods. A heuristic estimation method for these problems is presented that combines a formulation for order statistic...

Optimizing habitat location for black-tailed prairie dogs in southwestern South Dakota

Treesearch

John Hof; Michael Bevers; Daniel W. Uresk; Gregory L. Schenbeck

2002-01-01

A spatial optimization model was formulated and used to maximize black-tailed prairie dog populations in the Badlands National Park and the Buffalo Gap National Grassland in South Dakota. The choice variables involved the strategic placement of limited additional protected habitat. Population dynamics were captured in formulations that reflected exponential population...

The Auburn Engineering Technical Assistance Program investigation of polyvinyl alcohol film developments pertaining to radioactive particle decontamination and industrial waste minimization

NASA Astrophysics Data System (ADS)

Mole, Tracey Lawrence

In this work, an effective and systematic model is devised to synthesize the optimal formulation for an explicit engineering application in the nuclear industry, i.e. radioactive decontamination and waste reduction. Identification of an optimal formulation that is suitable for the desired system requires integration of all the interlacing behaviors of the product constituents. This work is unique not only in product design, but also in these design techniques. The common practice of new product development is to design the optimized product for a particular industrial niche and then subsequent research for the production process is conducted, developed and optimized separately from the product formulation. In this proposed optimization design technique, the development process, disposal technique and product formulation is optimized simultaneously to improve production profit, product behavior and disposal emissions. This "cradle to grave" optimization approach allowed a complex product formulation development process to be drastically simplified. The utilization of these modeling techniques took an industrial idea to full scale testing and production in under 18 months by reducing the number of subsequent laboratory trials required to optimize the formula, production and waste treatment aspects of the product simultaneously. This particular development material involves the use of a polymer matrix that is applied to surfaces as part of a decontamination system. The polymer coating serves to initially "fix" the contaminants in place for detection and ultimate elimination. Upon mechanical entrapment and removal, the polymer coating containing the radioactive isotopes can be dissolved in a solvent processor, where separation of the radioactive metallic particles can take place. Ultimately, only the collection of divided solids should be disposed of as nuclear waste. This creates an attractive alternative to direct land filling or incineration. This philosophy also provides waste generators a way to significantly reduce waste and associated costs, and help meet regulatory, safety and environmental requirements. In order for the polymeric film exhibit the desired performance, a combination of discrete constraints must be fulfilled. These interacting characteristics include the choice of polymer used for construction, drying time, storage constraints, decontamination ability, removal behavior, application process, coating strength and dissolvability processes. Identification of an optimized formulation that is suitable for this entire decontamination system requires integration of all the interlacing characteristics of the coating composition that affect the film behavior. A novel systematic method for developing quantitative values for theses qualitative characteristics is being developed in order to simultaneously optimize the design formulation subject to the discrete product specifications. This synthesis procedure encompasses intrinsic characteristics vital to successful product development, which allows for implementation of the derived model optimizations to operate independent of the polymer film application. This contribution illustrates the optimized synthesis example by which a large range of polymeric compounds and mixtures can be completed. (Abstract shortened by UMI.)

Formulation and Optimization of Multiparticulate Drug Delivery System Approach for High Drug Loading.

PubMed

Shah, Neha; Mehta, Tejal; Gohel, Mukesh

2017-08-01

The aim of the present work was to develop and optimize multiparticulate formulation viz. pellets of naproxen by employing QbD and risk assessment approach. Mixture design with extreme vertices was applied to the formulation with high loading of drug (about 90%) and extrusion-spheronization as a process for manufacturing pellets. Independent variables chosen were level of microcrystalline cellulose (MCC)-X 1 , polyvinylpyrrolidone K-90 (PVP K-90)-X 2 , croscarmellose sodium (CCS)-X 3 , and polacrilin potassium (PP)-X 4 . Dependent variables considered were disintegration time (DT)-Y 1 , sphericity-Y 2 , and percent drug release-Y 3 . The formulation was optimized based on the batches generated by MiniTab 17 software. The batch with maximum composite desirability (0.98) proved to be optimum. From the evaluation of design batches, it was observed that, even in low variation, the excipients affect the pelletization property of the blend and also the final drug release. In conclusion, pellets with high drug loading can be effectively manufactured and optimized systematically using QbD approach.

A formulation and analysis of combat games

NASA Technical Reports Server (NTRS)

Heymann, M.; Ardema, M. D.; Rajan, N.

1985-01-01

Combat is formulated as a dynamical encounter between two opponents, each of whom has offensive capabilities and objectives. With each opponent is associated a target in the event space in which he endeavors to terminate the combat, thereby winning. If the combat terminates in both target sets simultaneously or in neither, a joint capture or a draw, respectively, is said to occur. Resolution of the encounter is formulated as a combat game; namely, as a pair of competing event-constrained differential games. If exactly one of the players can win, the optimal strategies are determined from a resulting constrained zero-sum differential game. Otherwise the optimal strategies are computed from a resulting non-zero-sum game. Since optimal combat strategies frequencies may not exist, approximate of delta-combat games are also formulated leading to approximate or delta-optimal strategies. To illustrate combat games, an example, called the turret game, is considered. This game may be thought of as a highly simplified model of air combat, yet it is sufficiently complex to exhibit a rich variety of combat behavior, much of which is not found in pursuit-evasion games.

Evaluation of polyvinyl alcohols as mucoadhesive polymers for mucoadhesive buccal tablets prepared by direct compression.

PubMed

Ikeuchi-Takahashi, Yuri; Ishihara, Chizuko; Onishi, Hiraku

2017-09-01

The purpose of the present work was to evaluate polyvinyl alcohols (PVAs) as a mucoadhesive polymer for mucoadhesive buccal tablets prepared by direct compression. Various polymerization degree and particle diameter PVAs were investigated for their usability. The tensile strength, in vitro adhesive force, and water absorption properties of the tablets were determined to compare the various PVAs. The highest values of the tensile strength and the in vitro adhesive force were observed for PVAs with a medium viscosity and small particle size. The optimal PVA was identified by a factorial design analysis. Mucoadhesive tablets containing the optimal PVA were compared with carboxyvinyl polymer and hydroxypropyl cellulose formulations. The optimal PVA gives a high adhesive force, has a low viscosity, and resulted in relatively rapid drug release. Formulations containing carboxyvinyl polymer had high tensile strengths but short disintegration times. Higher hydroxypropyl cellulose concentration formulations had good adhesion forces and very long disintegration times. We identified the optimal characteristics of PVA, and the usefulness of mucoadhesive buccal tablets containing this PVA was suggested from their formulation properties.

Optimization of caseinate-coated simvastatin-zein nanoparticles: improved bioavailability and modified release characteristics

PubMed Central

Ahmed, Osama AA; Hosny, Khaled M; Al-Sawahli, Majid M; Fahmy, Usama A

2015-01-01

The current study focuses on utilization of the natural biocompatible polymer zein to formulate simvastatin (SMV) nanoparticles coated with caseinate, to improve solubility and hence bioavailability, and in addition, to modify SMV-release characteristics. This formulation can be utilized for oral or possible depot parenteral applications. Fifteen formulations were prepared by liquid–liquid phase separation method, according to the Box–Behnken design, to optimize formulation variables. Sodium caseinate was used as an electrosteric stabilizer. The factors studied were: percentage of SMV in the SMV-zein mixture (X1), ethanol concentration (X2), and caseinate concentration (X3). The selected dependent variables were mean particle size (Y1), SMV encapsulation efficiency (Y2), and cumulative percentage of drug permeated after 1 hour (Y3). The diffusion of SMV from the prepared nanoparticles specified by the design was carried out using an automated Franz diffusion cell apparatus. The optimized SMV-zein formula was investigated for in vivo pharmacokinetic parameters compared with an oral SMV suspension. The optimized nanosized SMV-zein formula showed a 131 nm mean particle size and 89% encapsulation efficiency. In vitro permeation studies displayed delayed permeation characteristics, with about 42% and 85% of SMV cumulative amount released after 12 and 48 hours, respectively. Bioavailability estimation in rats revealed an augmentation in SMV bioavailability from the optimized SMV-zein formulation, by fourfold relative to SMV suspension. Formulation of caseinate-coated SMV-zein nanoparticles improves the pharmacokinetic profile and bioavailability of SMV. Accordingly, improved hypolipidemic activities for longer duration could be achieved. In addition, the reduced dosage rate of SMV-zein nanoparticles improves patient tolerability and compliance. PMID:25670883

Optimization of helicopter airframe structures for vibration reduction considerations, formulations and applications

NASA Technical Reports Server (NTRS)

Murthy, T. Sreekanta

1988-01-01

Several key issues involved in the application of formal optimization technique to helicopter airframe structures for vibration reduction are addressed. Considerations which are important in the optimization of real airframe structures are discussed. Considerations necessary to establish relevant set of design variables, constraints and objectives which are appropriate to conceptual, preliminary, detailed design, ground and flight test phases of airframe design are discussed. A methodology is suggested for optimization of airframes in various phases of design. Optimization formulations that are unique to helicopter airframes are described and expressions for vibration related functions are derived. Using a recently developed computer code, the optimization of a Bell AH-1G helicopter airframe is demonstrated.

The optimal location of piezoelectric actuators and sensors for vibration control of plates

NASA Astrophysics Data System (ADS)

Kumar, K. Ramesh; Narayanan, S.

2007-12-01

This paper considers the optimal placement of collocated piezoelectric actuator-sensor pairs on a thin plate using a model-based linear quadratic regulator (LQR) controller. LQR performance is taken as objective for finding the optimal location of sensor-actuator pairs. The problem is formulated using the finite element method (FEM) as multi-input-multi-output (MIMO) model control. The discrete optimal sensor and actuator location problem is formulated in the framework of a zero-one optimization problem. A genetic algorithm (GA) is used to solve the zero-one optimization problem. Different classical control strategies like direct proportional feedback, constant-gain negative velocity feedback and the LQR optimal control scheme are applied to study the control effectiveness.

Systematic Development of Transethosomal Gel System of Piroxicam: Formulation Optimization, In Vitro Evaluation, and Ex Vivo Assessment.

PubMed

Garg, Varun; Singh, Harmanpreet; Bhatia, Amit; Raza, Kaisar; Singh, Sachin Kumar; Singh, Bhupinder; Beg, Sarwar

2017-01-01

Piroxicam is used in the treatment of rheumatoid arthritis, osteoarthritis, and other inflammatory diseases. Upon oral administration, it is reported to cause ulcerative colitis, gastrointestinal irritation, edema and peptic ulcer. Hence, an alternative delivery system has been designed in the form of transethosome. The present study describes the preparation, optimization, characterization, and ex vivo study of piroxicam-loaded transethosomal gel using the central composite design. On the basis of the prescreening study, the concentration of lipids and ethanol was kept in the range of 2-4% w/v and 0-40% v/v, respectively. Formulation was optimized by measuring drug retention in the skin, drug permeation, entrapment efficiency, and vesicle size. Optimized formulation was incorporated in hydrogel and compared with other analogous vesicular (liposomes, ethosomes, and transfersomes) gels for the aforementioned responses. Among the various lipids used, soya phosphatidylcholine (SPL 70) and ethanol in various percentages were found to affect drug retention in the skin, drug permeation, vesicle size, and entrapment efficiency. The optimized batch of transethosome has shown 392.730 μg cm -2 drug retention in the skin, 44.312 μg cm -2  h -1 drug permeation, 68.434% entrapment efficiency, and 655.369 nm vesicle size, respectively. It was observed that the developed transethosomes were found superior in all the responses as compared to other vesicular formulations with improved stability and highest elasticity. Similar observations were noted with its gel formulation.

Evidence-Based Design of Fixed-Dose Combinations: Principles and Application to Pediatric Anti-Tuberculosis Therapy.

PubMed

Svensson, Elin M; Yngman, Gunnar; Denti, Paolo; McIlleron, Helen; Kjellsson, Maria C; Karlsson, Mats O

2018-05-01

Fixed-dose combination formulations where several drugs are included in one tablet are important for the implementation of many long-term multidrug therapies. The selection of optimal dose ratios and tablet content of a fixed-dose combination and the design of individualized dosing regimens is a complex task, requiring multiple simultaneous considerations. In this work, a methodology for the rational design of a fixed-dose combination was developed and applied to the case of a three-drug pediatric anti-tuberculosis formulation individualized on body weight. The optimization methodology synthesizes information about the intended use population, the pharmacokinetic properties of the drugs, therapeutic targets, and practical constraints. A utility function is included to penalize deviations from the targets; a sequential estimation procedure was developed for stable estimation of break-points for individualized dosing. The suggested optimized pediatric anti-tuberculosis fixed-dose combination was compared with the recently launched World Health Organization-endorsed formulation. The optimized fixed-dose combination included 15, 36, and 16% higher amounts of rifampicin, isoniazid, and pyrazinamide, respectively. The optimized fixed-dose combination is expected to result in overall less deviation from the therapeutic targets based on adult exposure and substantially fewer children with underexposure (below half the target). The development of this design tool can aid the implementation of evidence-based formulations, integrating available knowledge and practical considerations, to optimize drug exposures and thereby treatment outcomes.

Evaluating tretinoin formulations in the treatment of acne.

PubMed

Kircik, Leon H

2014-04-01

Topical tretinoin has been a standard treatment for acne vulgaris for more than 4 decades. While tretinoin has demonstrated proven efficacy in the treatment of acne lesions, it also is associated with the potential for skin irritation. Newer formulations have been designed to optimize both the drug concentration and the delivery vehicle with the aim to enable clinicians to provide increasingly effective acne treatment that minimizes irritation. These therapies include formulations with varying concentrations of tretinoin and vehicles that utilize a microsponge delivery system, hydrogels and micronized tretinoin, or propolymers. The purpose of this review is to evaluate different formulations and combinations of tretinoin in the treatment of acne vulgaris. While these advanced formulations were designed for controlled release of active ingredient, and have the potential to reduce cutaneous irritation relative to standard tretinoin cream and gel formulations, there is a need for comparative studies to evaluate the relative benefits of each of these advanced tretinoin formulations in optimizing acne treatment.

Strong diffusion formulation of Markov chain ensembles and its optimal weaker reductions

NASA Astrophysics Data System (ADS)

Güler, Marifi

2017-10-01

Two self-contained diffusion formulations, in the form of coupled stochastic differential equations, are developed for the temporal evolution of state densities over an ensemble of Markov chains evolving independently under a common transition rate matrix. Our first formulation derives from Kurtz's strong approximation theorem of density-dependent Markov jump processes [Stoch. Process. Their Appl. 6, 223 (1978), 10.1016/0304-4149(78)90020-0] and, therefore, strongly converges with an error bound of the order of lnN /N for ensemble size N . The second formulation eliminates some fluctuation variables, and correspondingly some noise terms, within the governing equations of the strong formulation, with the objective of achieving a simpler analytic formulation and a faster computation algorithm when the transition rates are constant or slowly varying. There, the reduction of the structural complexity is optimal in the sense that the elimination of any given set of variables takes place with the lowest attainable increase in the error bound. The resultant formulations are supported by numerical simulations.

Green clay and aloe vera peel-off facial masks: response surface methodology applied to the formulation design.

PubMed

O'Reilly Beringhs, André; Rosa, Julia Macedo; Stulzer, Hellen Karine; Budal, Rosane Maria; Sonaglio, Diva

2013-03-01

This article describes the optimization of a peel-off facial mask formulation. An investigation was carried out on the parameters of the formulation that most affect the desirable characteristics of peel-off facial masks. Cereal alcohol had a significant effect on the drying time at concentrations of 1-12% (w/w). The applicability of the evaluated formulations was influenced by both carbomer (0-2.4%; w/w) and polyvinyl alcohol (PVA; 2.5-17.5%; w/w) content due to their ability to alter the formulation viscosity. Inverse concentrations of carbomer and PVA led to formulations with optimum viscosity for facial application. Film-forming performance was influenced only by the PVA concentration, achieving maximum levels at concentrations of around 11% (w/w). The optimized formulation, determined mathematically, contained 13% (w/w) PVA and 10% (w/w) cereal alcohol with no addition of carbomer. This formulation provided high levels of applicability and film-forming performance, the lowest drying time possible and excellent homogeneity of the green clay particles and aloe vera before and after drying. The preliminary stability study indicated that the optimized formulation is stable under normal storage conditions. The microbiological stability evaluation indicated that the preservative was efficient in terms of avoiding microbial growth. RSM was shown to be a useful statistical tool for the determination of the behavior of different compounds and their concentrations for the responses studied, allowing the investigation of the optimum conditions for the production of green clay and aloe vera peel-off facial masks.

Optimally Stopped Optimization

NASA Astrophysics Data System (ADS)

Vinci, Walter; Lidar, Daniel A.

2016-11-01

We combine the fields of heuristic optimization and optimal stopping. We propose a strategy for benchmarking randomized optimization algorithms that minimizes the expected total cost for obtaining a good solution with an optimal number of calls to the solver. To do so, rather than letting the objective function alone define a cost to be minimized, we introduce a further cost-per-call of the algorithm. We show that this problem can be formulated using optimal stopping theory. The expected cost is a flexible figure of merit for benchmarking probabilistic solvers that can be computed when the optimal solution is not known and that avoids the biases and arbitrariness that affect other measures. The optimal stopping formulation of benchmarking directly leads to a real-time optimal-utilization strategy for probabilistic optimizers with practical impact. We apply our formulation to benchmark simulated annealing on a class of maximum-2-satisfiability (MAX2SAT) problems. We also compare the performance of a D-Wave 2X quantum annealer to the Hamze-Freitas-Selby (HFS) solver, a specialized classical heuristic algorithm designed for low-tree-width graphs. On a set of frustrated-loop instances with planted solutions defined on up to N =1098 variables, the D-Wave device is 2 orders of magnitude faster than the HFS solver, and, modulo known caveats related to suboptimal annealing times, exhibits identical scaling with problem size.

Dynamics and control of DNA sequence amplification

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

Marimuthu, Karthikeyan; Chakrabarti, Raj, E-mail: raj@pmc-group.com, E-mail: rajc@andrew.cmu.edu; Division of Fundamental Research, PMC Advanced Technology, Mount Laurel, New Jersey 08054

2014-10-28

DNA amplification is the process of replication of a specified DNA sequence in vitro through time-dependent manipulation of its external environment. A theoretical framework for determination of the optimal dynamic operating conditions of DNA amplification reactions, for any specified amplification objective, is presented based on first-principles biophysical modeling and control theory. Amplification of DNA is formulated as a problem in control theory with optimal solutions that can differ considerably from strategies typically used in practice. Using the Polymerase Chain Reaction as an example, sequence-dependent biophysical models for DNA amplification are cast as control systems, wherein the dynamics of the reactionmore » are controlled by a manipulated input variable. Using these control systems, we demonstrate that there exists an optimal temperature cycling strategy for geometric amplification of any DNA sequence and formulate optimal control problems that can be used to derive the optimal temperature profile. Strategies for the optimal synthesis of the DNA amplification control trajectory are proposed. Analogous methods can be used to formulate control problems for more advanced amplification objectives corresponding to the design of new types of DNA amplification reactions.« less

Optimal Operation System of the Integrated District Heating System with Multiple Regional Branches

NASA Astrophysics Data System (ADS)

Kim, Ui Sik; Park, Tae Chang; Kim, Lae-Hyun; Yeo, Yeong Koo

This paper presents an optimal production and distribution management for structural and operational optimization of the integrated district heating system (DHS) with multiple regional branches. A DHS consists of energy suppliers and consumers, district heating pipelines network and heat storage facilities in the covered region. In the optimal management system, production of heat and electric power, regional heat demand, electric power bidding and sales, transport and storage of heat at each regional DHS are taken into account. The optimal management system is formulated as a mixed integer linear programming (MILP) where the objectives is to minimize the overall cost of the integrated DHS while satisfying the operation constraints of heat units and networks as well as fulfilling heating demands from consumers. Piecewise linear formulation of the production cost function and stairwise formulation of the start-up cost function are used to compute nonlinear cost function approximately. Evaluation of the total overall cost is based on weekly operations at each district heat branches. Numerical simulations show the increase of energy efficiency due to the introduction of the present optimal management system.

Formulation and statistical optimization of self-microemulsifying drug delivery system of eprosartan mesylate for improvement of oral bioavailability.

PubMed

Dangre, Pankaj; Gilhotra, Ritu; Dhole, Shashikant

2016-10-01

The present investigation is aimed to design a statistically optimized self-microemulsifying drug delivery system (SMEDDS) of eprosartan mesylate (EM). Preliminary screening was carried out to find a suitable combination of various excipients for the formulation. A 3(2) full factorial design was employed to determine the effect of various independent variables on dependent (response) variables. The independent variables studied in the present work were concentration of oil (X 1) and the ratio of S mix (X 2), whereas the dependent variables were emulsification time (s), globule size (nm), polydispersity index (pdi), and zeta potential (mV), and the multiple linear regression analysis (MLRA) was employed to understand the influence of independent variables on dependent variables. Furthermore, a numerical optimization technique using the desirability function was used to develop a new optimized formulation with desired values of dependent variables. The optimized SMEDDS formulation of eprosartan mesylate (EMF-O) by the above method exhibited emulsification time, 118.45 ± 1.64 s; globule size, 196.81 ± 1.29 nm; zeta potential, -9.34 ± 1.2 mV, and polydispersity index, 0.354 ± 0.02. For the in vitro dissolution study, the optimized formulation (EMF-O) and pure drug were separately entrapped in the dialysis bag, and the study indicated higher release of the drug from EMF-O. In vivo pharmacokinetic studies in Wistar rats using PK solver software revealed 2.1-fold increment in oral bioavailability of EM from EMF-O, when compared with plain suspension of pure drug.

Understanding and optimizing the dual excipient functionality of sodium lauryl sulfate in tablet formulation of poorly water soluble drug: wetting and lubrication.

PubMed

Aljaberi, Ahmad; Chatterji, Ashish; Dong, Zedong; Shah, Navnit H; Malick, Waseem; Singhal, Dharmendra; Sandhu, Harpreet K

2013-01-01

To evaluate and optimize sodium lauryl sulfate (SLS) and magnesium stearate (Mg.St) levels, with respect to dissolution and compaction, in a high dose, poorly soluble drug tablet formulation. A model poorly soluble drug was formulated using high shear aqueous granulation. A D-optimal design was used to evaluate and model the effect of granulation conditions, size of milling screen, SLS and Mg.St levels on tablet compaction and ejection. The compaction profiles were generated using a Presster(©) compaction simulator. Dissolution of the kernels was performed using a USP dissolution apparatus II and intrinsic dissolution was determined using a stationary disk system. Unlike kernels dissolution which failed to discriminate between tablets prepared with various SLS contents, the intrinsic dissolution rate showed that a SLS level of 0.57% was sufficient to achieve the required release profile while having minimal effect on compaction. The formulation factors that affect tablet compaction and ejection were identified and satisfactorily modeled. The design space of best factor setting to achieve optimal compaction and ejection properties was successfully constructed by RSM analysis. A systematic study design helped identify the critical factors and provided means to optimize the functionality of key excipient to design robust drug product.

Solid dispersions of the penta-ethyl ester prodrug of diethylenetriaminepentaacetic acid (DTPA): Formulation design and optimization studies

PubMed Central

Yang, Yu-Tsai; Di Pasqua, Anthony J.; Zhang, Yong; Sueda, Katsuhiko; Jay, Michael

2015-01-01

The penta-ethyl ester prodrug of diethylenetriaminepentaacetic acid (DTPA), which exists as an oily liquid, was incorporated into a solid dispersion for oral administration by the solvent evaporation method using blends of polyvinylpyrrolidone (PVP), Eudragit® RL PO and α-tocopherol. D-optimal mixture design was used to optimize the formulation. Formulations that had a high concentration of both Eudragit® RL PO and α-tocopherol exhibited low water absorption and enhanced stability of the DTPA prodrug. Physicochemical properties of the optimal formulation were evaluated using Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC). In vitro release of the prodrug was evaluated using the USP Type II apparatus dissolution method. DSC studies indicated that the matrix had an amorphous structure, while FTIR spectrometry showed that DTPA penta-ethyl ester and excipients did not react with each other during formation of the solid dispersion.. Dissolution testing showed that the optimized solid dispersion exhibited a prolonged release profile, which could potentially result in a sustained delivery of DTPA penta-ethyl to enhance bioavailability. In conclusion, DTPA penta-ethyl ester was successfully incorporated into a solid matrix with high drug loading and improved stability compared to prodrug alone. PMID:24047113

Improved pharmacokinetics and antihyperlipidemic efficacy of rosuvastatin-loaded nanostructured lipid carriers.

PubMed

Rizwanullah, Md; Amin, Saima; Ahmad, Javed

2017-01-01

In the present study, rosuvastatin calcium-loaded nanostructured lipid carriers were developed and optimized for improved efficacy. The ROS-Ca-loaded NLC was prepared using melt emulsification ultrasonication technique and optimized by Box-Behnken statistical design. The optimized NLC composed of glyceryl monostearate (solid lipid) and capmul MCM EP (liquid lipid) as lipid phase (3% w/v), poloxamer 188 (1%) and tween 80 (1%) as surfactant. The mean particle size, polydispersity index (PDI), zeta potential (ζ) and entrapment efficiency (%) of optimized NLC formulation was observed to be 150.3 ± 4.67 nm, 0.175 ± 0.022, -32.9 ± 1.36 mV and 84.95 ± 5.63%, respectively. NLC formulation showed better in vitro release in simulated intestinal fluid (pH 6.8) than API suspension. Confocal laser scanning showed deeper permeation of formulation across rat intestine compared to rhodamine B dye solution. Pharmacokinetic study on female albino Wistar rats showed 5.4-fold increase in relative bioavailability with NLC compared to API suspension. Optimized NLC formulation also showed significant (p < 0.01) lipid lowering effect in hyperlipidemic rats. Therefore, NLC represents a great potential for improved efficacy of ROS-Ca after oral administration.

Enhancement of dissolution and oral bioavailability of lacidipine via pluronic P123/F127 mixed polymeric micelles: formulation, optimization using central composite design and in vivo bioavailability study.

PubMed

Fares, Ahmed R; ElMeshad, Aliaa N; Kassem, Mohamed A A

2018-11-01

This study aims at preparing and optimizing lacidipine (LCDP) polymeric micelles using thin film hydration technique in order to overcome LCDP solubility-limited oral bioavailability. A two-factor three-level central composite face-centered design (CCFD) was employed to optimize the formulation variables to obtain LCDP polymeric micelles of high entrapment efficiency and small and uniform particle size (PS). Formulation variables were: Pluronic to drug ratio (A) and Pluronic P123 percentage (B). LCDP polymeric micelles were assessed for entrapment efficiency (EE%), PS and polydispersity index (PDI). The formula with the highest desirability (0.959) was chosen as the optimized formula. The values of the formulation variables (A and B) in the optimized polymeric micelles formula were 45% and 80%, respectively. Optimum LCDP polymeric micelles had entrapment efficiency of 99.23%, PS of 21.08 nm and PDI of 0.11. Optimum LCDP polymeric micelles formula was physically characterized using transmission electron microscopy. LCDP polymeric micelles showed saturation solubility approximately 450 times that of raw LCDP in addition to significantly enhanced dissolution rate. Bioavailability study of optimum LCDP polymeric micelles formula in rabbits revealed a 6.85-fold increase in LCDP bioavailability compared to LCDP oral suspension.

Shortening the decade-long gap between adult and paediatric drug formulations: a new framework based on the HIV experience in low- and middle-income countries.

PubMed

Penazzato, Martina; Lewis, Linda; Watkins, Melynda; Prabhu, Vineet; Pascual, Fernando; Auton, Martin; Kreft, Wesley; Morin, Sébastien; Vicari, Marissa; Lee, Janice; Jamieson, David; Siberry, George K

2018-02-01

Despite the coordinated efforts by several stakeholders to speed up access to HIV treatment for children, development of optimal paediatric formulations still lags 8 to 10 years behind that of adults, due mainly to lack of market incentives and technical complexities in manufacturing. The small and fragmented paediatric market also hinders launch and uptake of new formulations. Moreover, the problems affecting HIV similarly affect other disease areas where development and introduction of optimal paediatric formulations is even slower. Therefore, accelerating processes for developing and commercializing optimal paediatric drug formulations for HIV and other disease areas is urgently needed. The Global Accelerator for Paediatric Formulations (GAP-f) is an innovative collaborative model that will accelerate availability of optimized treatment options for infectious diseases, such as HIV, tuberculosis and viral hepatitis, affecting children in low- and middle-income countries (LMICs). It builds on the HIV experience and existing efforts in paediatric drug development, formalizing collaboration between normative bodies, research networks, regulatory agencies, industry, supply and procurement organizations and funding bodies. Upstream, the GAP-f will coordinate technical support to companies to design and study optimal paediatric formulations, harmonize efforts with regulators and incentivize manufacturers to conduct formulation development. Downstream, the GAP-f will reinforce coordinated procurement and communication with suppliers. The GAP-f will be implemented in a three-stage process: (1) development of a strategic framework and promotion of key regulatory efficiencies; (2) testing of feasibility and results, building on the work of existing platforms such as the Paediatric HIV Treatment Initiative (PHTI) including innovative approaches to incentivize generic development and (3) launch as a fully functioning structure. GAP-f is a key partnership example enhancing North-South and international cooperation on and access to science and technology and capacity building, responding to Sustainable Development Goal (SDG) 17.6 (technology) and 17.9. (capacity-building). By promoting access to the most needed paediatric formulations for HIV and high-burden infectious diseases in low-and middle-income countries, GAP-f will support achievement of SDG 3.2 (infant mortality), 3.3 (end of AIDS and combat other communicable diseases) and 3.8 (access to essential medicines), and be an essential component of meeting the global Start Free, Stay Free, AIDS Free super-fast-track targets. © 2018 World Health Organization; licensee IAS.

Performance Analysis and Design Synthesis (PADS) computer program. Volume 1: Formulation

NASA Technical Reports Server (NTRS)

1972-01-01

The program formulation for PADS computer program is presented. It can size launch vehicles in conjunction with calculus-of-variations optimal trajectories and can also be used as a general-purpose branched trajectory optimization program. In the former use, it has the Space Shuttle Synthesis Program as well as a simplified stage weight module for optimally sizing manned recoverable launch vehicles. For trajectory optimization alone or with sizing, PADS has two trajectory modules. The first trajectory module uses the method of steepest descent; the second employs the method of quasilinearization, which requires a starting solution from the first trajectory module.

Glabridin nanosuspension for enhanced skin penetration: formulation optimization, in vitro and in vivo evaluation.

PubMed

Wang, W P; Hul, J; Sui, H; Zhao, Y S; Feng, J; Liu, C

2016-05-01

Glabridin, a polyphenolic flavonoid from licorice, has inspired great interest for its antioxidant, anti-inflammatory and skin-lightening activities. However, low water solubility and poor stability of glabridin impedes its topical application in cosmetic products and therapies of dermal diseases. The purpose of this study was to develop a nanosuspension formulation of glabridin to improve its skin permeation. Glabridin nanosuspensions were prepared using anti-solvent precipitation-homogenization method, and Box-Behnken design was adopted to investigate the effects of crucial formulation variables on particle size and to optimize the nanosuspension formulation. The optimal formulation consisted of 0.25% glabridin, 0.47% Poloxamer 188 and 0.11% Polyvinylpyrrolidone K30, and the obtained nanosuspension showed an average particle size of 149.2 nm with a polydispersity index of 0.254. Furthermore, the nanosuspension exhibited significantly enhanced drug permeation flux of glabridin through rat skin with no lag phase both in vitro and in vivo, compared to the coarse suspension and physical mixture. The glabridin nanosuspension showed no significant particle aggregates and a drug loss of 5.46% after storage for 3 months at room temperature. With its enhanced skin penetration, the nanosuspension might be a more preferable formulation for topical administration of poorly soluble glabridin.

Optimization of Primary Drying in Lyophilization during Early Phase Drug Development using a Definitive Screening Design with Formulation and Process Factors.

PubMed

Goldman, Johnathan M; More, Haresh T; Yee, Olga; Borgeson, Elizabeth; Remy, Brenda; Rowe, Jasmine; Sadineni, Vikram

2018-06-08

Development of optimal drug product lyophilization cycles is typically accomplished via multiple engineering runs to determine appropriate process parameters. These runs require significant time and product investments, which are especially costly during early phase development when the drug product formulation and lyophilization process are often defined simultaneously. Even small changes in the formulation may require a new set of engineering runs to define lyophilization process parameters. In order to overcome these development difficulties, an eight factor definitive screening design (DSD), including both formulation and process parameters, was executed on a fully human monoclonal antibody (mAb) drug product. The DSD enables evaluation of several interdependent factors to define critical parameters that affect primary drying time and product temperature. From these parameters, a lyophilization development model is defined where near optimal process parameters can be derived for many different drug product formulations. This concept is demonstrated on a mAb drug product where statistically predicted cycle responses agree well with those measured experimentally. This design of experiments (DoE) approach for early phase lyophilization cycle development offers a workflow that significantly decreases the development time of clinically and potentially commercially viable lyophilization cycles for a platform formulation that still has variable range of compositions. Copyright © 2018. Published by Elsevier Inc.

A new experimental design method to optimize formulations focusing on a lubricant for hydrophilic matrix tablets.

PubMed

Choi, Du Hyung; Shin, Sangmun; Khoa Viet Truong, Nguyen; Jeong, Seong Hoon

2012-09-01

A robust experimental design method was developed with the well-established response surface methodology and time series modeling to facilitate the formulation development process with magnesium stearate incorporated into hydrophilic matrix tablets. Two directional analyses and a time-oriented model were utilized to optimize the experimental responses. Evaluations of tablet gelation and drug release were conducted with two factors x₁ and x₂: one was a formulation factor (the amount of magnesium stearate) and the other was a processing factor (mixing time), respectively. Moreover, different batch sizes (100 and 500 tablet batches) were also evaluated to investigate an effect of batch size. The selected input control factors were arranged in a mixture simplex lattice design with 13 experimental runs. The obtained optimal settings of magnesium stearate for gelation were 0.46 g, 2.76 min (mixing time) for a 100 tablet batch and 1.54 g, 6.51 min for a 500 tablet batch. The optimal settings for drug release were 0.33 g, 7.99 min for a 100 tablet batch and 1.54 g, 6.51 min for a 500 tablet batch. The exact ratio and mixing time of magnesium stearate could be formulated according to the resulting hydrophilic matrix tablet properties. The newly designed experimental method provided very useful information for characterizing significant factors and hence to obtain optimum formulations allowing for a systematic and reliable experimental design method.

Learning Incoherent Sparse and Low-Rank Patterns from Multiple Tasks

PubMed Central

Chen, Jianhui; Liu, Ji; Ye, Jieping

2013-01-01

We consider the problem of learning incoherent sparse and low-rank patterns from multiple tasks. Our approach is based on a linear multi-task learning formulation, in which the sparse and low-rank patterns are induced by a cardinality regularization term and a low-rank constraint, respectively. This formulation is non-convex; we convert it into its convex surrogate, which can be routinely solved via semidefinite programming for small-size problems. We propose to employ the general projected gradient scheme to efficiently solve such a convex surrogate; however, in the optimization formulation, the objective function is non-differentiable and the feasible domain is non-trivial. We present the procedures for computing the projected gradient and ensuring the global convergence of the projected gradient scheme. The computation of projected gradient involves a constrained optimization problem; we show that the optimal solution to such a problem can be obtained via solving an unconstrained optimization subproblem and an Euclidean projection subproblem. We also present two projected gradient algorithms and analyze their rates of convergence in details. In addition, we illustrate the use of the presented projected gradient algorithms for the proposed multi-task learning formulation using the least squares loss. Experimental results on a collection of real-world data sets demonstrate the effectiveness of the proposed multi-task learning formulation and the efficiency of the proposed projected gradient algorithms. PMID:24077658

Learning Incoherent Sparse and Low-Rank Patterns from Multiple Tasks.

PubMed

Chen, Jianhui; Liu, Ji; Ye, Jieping

2012-02-01

We consider the problem of learning incoherent sparse and low-rank patterns from multiple tasks. Our approach is based on a linear multi-task learning formulation, in which the sparse and low-rank patterns are induced by a cardinality regularization term and a low-rank constraint, respectively. This formulation is non-convex; we convert it into its convex surrogate, which can be routinely solved via semidefinite programming for small-size problems. We propose to employ the general projected gradient scheme to efficiently solve such a convex surrogate; however, in the optimization formulation, the objective function is non-differentiable and the feasible domain is non-trivial. We present the procedures for computing the projected gradient and ensuring the global convergence of the projected gradient scheme. The computation of projected gradient involves a constrained optimization problem; we show that the optimal solution to such a problem can be obtained via solving an unconstrained optimization subproblem and an Euclidean projection subproblem. We also present two projected gradient algorithms and analyze their rates of convergence in details. In addition, we illustrate the use of the presented projected gradient algorithms for the proposed multi-task learning formulation using the least squares loss. Experimental results on a collection of real-world data sets demonstrate the effectiveness of the proposed multi-task learning formulation and the efficiency of the proposed projected gradient algorithms.

Preparation, Optimization, In vitro Evaluation and Ex vivo Permeation Studies of Finasteride loaded gel Formulations Prepared by using Response Surface Methodology.

PubMed

Khan, Muhammad Zia Ullah; Makreski, Petre; Murtaza, Ghulam

2018-05-02

The aim of present explorative study was to prepare and optimize finasteride loaded topical gel formulations by using three factor [propylene glycol (PG), Tween® 80, and sodium lauryl sulphate (SLS)], five level central composite design. Optimized finasteride topical gel formulation (F4), containing PG, Tween® 80, and SLS in a concentration of 0.8 mg, 0.4 mg and 0.2 mg, respectively, showed 6-fold higher values of cumulative drug release, flux, partition coefficient, input rate, lag time, and diffusion coefficient, when compared to control formulation without permeation enhancer. Finally, it can be concluded that finasteride permeation was enhanced by PG, tween® 80 and SLS individually, while in combination only PG along with tween® 80 had synergistic and more pronounced effect on flux, permeability coefficient and input rate while antagonistic effect on lag time and diffusion coefficient was observed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Design and synthesis of a novel multifunctional stabilizer for highly stable uc(dl)-tetrahydropalmatine nanosuspensions and in vitro study

NASA Astrophysics Data System (ADS)

Yan, Beibei; Wang, Yancai; Wang, Lulu; Zhou, Yuqi; Shang, Xueyun; Zhao, Juan; Liu, Yangyang; Du, Juan

2018-05-01

The present study aimed to prepare stable uc(dl)-tetrahydropalmatine (uc(dl)-THP) nanosuspensions of optimized formulation with PEGylated chitosan as a multifunctional stabilizer using the antisolvent precipitation method. A central composite design project of three factors and five-level full factorial (53) was applied to design the experimental program, and response surface methodology analysis was used to optimize the experimental conditions. The effects of critical influencing factors such as PEGylated chitosan concentration, operational temperature, and ultrasonic energy on particle size and zeta potential were investigated. Under the optimization nanosuspension formulation, the particle size was 269 nm and zeta potential was at 37.4 mV. Also, the uc(dl)-THP nanosuspensions maintained good physical stability after 2 months, indicating the potential ability of the multifunctional stabilizer for stable nanosuspension formulation. Hence, the present findings indicated that PEGylated chitosan could be used as the ideal stabilizer to form a physically stable nanosuspension formulation.

Closed-form recursive formula for an optimal tracker with terminal constraints

NASA Technical Reports Server (NTRS)

Juang, J.-N.; Turner, J. D.; Chun, H. M.

1984-01-01

Feedback control laws are derived for a class of optimal finite time tracking problems with terminal constraints. Analytical solutions are obtained for the feedback gain and the closed-loop response trajectory. Such formulations are expressed in recursive forms so that a real-time computer implementation becomes feasible. Two examples are given to illustrate the validity and usefulness of the formulations.

Assessment of Aprotinin Loaded Microemulsion Formulations for Parenteral Drug Delivery: Preparation, Characterization, in vitro Release and Cytotoxicity Studies.

PubMed

Okur, Neslihan Üstündağ; Özdemir, Derya İlem; Kahyaoğlu, Şennur Görgülü; Şenyiğit, Zeynep Ay; Aşıkoğlu, Makbule; Genç, Lütfi; Karasulu, H Yeşim

2015-01-01

The object of the current study was to prepare novel microemulsion formulations of aprotinin for parenteral delivery and to compare in vitro characteristics and release behaviour of different Technetium-99m ((99m)Tc)-Aprotinin loaded microemulsion formulations. In addition, cytotoxicity of microemulsion formulation was evaluated with cell culture studies on human immortalized pancreatic duct epithelial-like cells. For this aim, firstly, pseudo-ternary phase diagrams were plotted to detect the formulation region and optimal microemulsions were characterized for their thermodynamic stability, conductivity, particle size, zeta potential, viscosity, pH and in vitro release properties. For in vitro release studies aprotinin was labelled with (99m)Tc and labelling efficiency, radiochemical purity and stability of the radiolabeled complex were determined by several chromatography techniques. Radiolabeling efficiency of (99m)Tc-Aprotinin was found over than 90% without any significant changes up to 6 hours after labelling at room temperature. After that, in vitro release studies of (99m)Tc-Aprotinin loaded microemulsions were performed with two different methods; dissolution from diffusion cells and dialysis bags. Both methods showed that release rate of (99m)Tc- Aprotinin from microemulsion could be controlled by microemulsion formulations. Drug release from the optimized microemulsion formulations was found lower compared to drug solution at the end of six hours. According to stability studies, the optimized formulation was found to be stable over a period of 12 months. Also, human immortalized pancreatic duct epithelial-like cells were used to evaluate the cytotoxicity of optimum formulation. Developed microemulsion did not reveal cytotoxicity. In conclusion the present study indicated that the M1-APT microemulsion is appropriate for intravenous application of aprotinin.

Integrated structure/control law design by multilevel optimization

NASA Technical Reports Server (NTRS)

Gilbert, Michael G.; Schmidt, David K.

1989-01-01

A new approach to integrated structure/control law design based on multilevel optimization is presented. This new approach is applicable to aircraft and spacecraft and allows for the independent design of the structure and control law. Integration of the designs is achieved through use of an upper level coordination problem formulation within the multilevel optimization framework. The method requires the use of structure and control law design sensitivity information. A general multilevel structure/control law design problem formulation is given, and the use of Linear Quadratic Gaussian (LQG) control law design and design sensitivity methods within the formulation is illustrated. Results of three simple integrated structure/control law design examples are presented. These results show the capability of structure and control law design tradeoffs to improve controlled system performance within the multilevel approach.

Multi-Stage Convex Relaxation Methods for Machine Learning

DTIC Science & Technology

2013-03-01

Many problems in machine learning can be naturally formulated as non-convex optimization problems. However, such direct nonconvex formulations have...original nonconvex formulation. We will develop theoretical properties of this method and algorithmic consequences. Related convex and nonconvex machine learning methods will also be investigated.

Optimization and characterization of stable lipid-based, oxygen-filled microbubbles by mixture design.

PubMed

Polizzotti, Brian D; Thomson, Lindsay M; O'Connell, Daniel W; McGowan, Francis X; Kheir, John N

2014-08-01

Tissue hypoxia is a final common pathway that leads to cellular injury and death in a number of critical illnesses. Intravenous injections of self-assembling, lipid-based oxygen microbubbles (LOMs) can be used to deliver oxygen gas, preventing organ injury and death from systemic hypoxemia. However, current formulations exhibit high polydispersity indices (which may lead to microvascular obstruction) and poor shelf-lives, limiting the translational capacity of LOMs. In this study, we report our efforts to optimize LOM formulations using a mixture response surface methodology (mRSM). We study the effect of changing excipient proportions (the independent variables) on microbubble diameter and product loss (the dependent variables). By using mRSM analysis, the experimental data were fit using a reduced Scheffé linear mixture model. We demonstrate that formulations manufactured from 1,2-distearoyl-sn-glycero-3-phosphocholine, corn syrup, and water produce micron-sized microbubbles with low polydispersity indices, and decreased product loss (relative to previously described formulations) when stored at room temperature over a 30-day period. Optimized LOMs were subsequently tested for their oxygen-releasing ability and found to have similar release kinetics as prior formulations. © 2014 Wiley Periodicals, Inc.

Plasma Transfusion: History, Current Realities, and Novel Improvements.

PubMed

Watson, Justin J J; Pati, Shibani; Schreiber, Martin A

2016-11-01

Traumatic hemorrhage is the leading cause of preventable death after trauma. Early transfusion of plasma and balanced transfusion have been shown to optimize survival, mitigate the acute coagulopathy of trauma, and restore the endothelial glycocalyx. There are a myriad of plasma formulations available worldwide, including fresh frozen plasma, thawed plasma, liquid plasma, plasma frozen within 24 h, and lyophilized plasma (LP). Significant equipoise exists in the literature regarding the optimal plasma formulation. LP is a freeze-dried formulation that was originally developed in the 1930s and used by the American and British military in World War II. It was subsequently discontinued due to risk of disease transmission from pooled donors. Recently, there has been a significant amount of research focusing on optimizing reconstitution of LP. Findings show that sterile water buffered with ascorbic acid results in decreased blood loss with suppression of systemic inflammation. We are now beginning to realize the creation of a plasma-derived formulation that rapidly produces the associated benefits without logistical or safety constraints. This review will highlight the history of plasma, detail the various types of plasma formulations currently available, their pathophysiological effects, impacts of storage on coagulation factors in vitro and in vivo, novel concepts, and future directions.

In situ gelling dorzolamide loaded chitosan nanoparticles for the treatment of glaucoma.

PubMed

Katiyar, Shefali; Pandit, Jayamanti; Mondal, Rabi S; Mishra, Anil K; Chuttani, Krishna; Aqil, Mohd; Ali, Asgar; Sultana, Yasmin

2014-02-15

The most important risk associated with glaucoma is the onset and progression of intraocular pressure. The objective of this study was to formulate in situ gel of chitosan nanoparticles to enhance the bioavailability and efficacy of dorzolamide in the glaucoma treatment. Optimized nanoparticles were spherical in shape (particle size: 164 nm) with a loading efficiency of 98.1%. The ex vivo release of the optimized in situ gel nanoparticle formulation showed a sustained drug release as compared to marketed formulation. The gamma scintigraphic study of prepared in situ nanoparticle gel showed good corneal retention compared to marketed formulation. HET-CAM assay of the prepared formulation scored 0.33 in 5 min which indicates the non-irritant property of the formulation. Thus in situ gel of dorzolamide hydrochloride loaded nanoparticles offers a more intensive treatment of glaucoma and a better patient compliance as it requires fewer applications per day compared to conventional eye drops. Copyright © 2013 Elsevier Ltd. All rights reserved.

Optimization of storage condition for maintaining long-term viability of nematophagous fungus Esteya vermicola as biocontrol agent against pinewood nematode.

PubMed

Xue, Jian Jie; Hou, Jin Gang; Zhang, Yong An; Wang, Chun Yan; Wang, Zhen; Yu, Jiao Jiao; Wang, Yun Bo; Wang, Yu Zhu; Wang, Qing Hua; Sung, Chang Keun

2014-11-01

The fungus, Esteya vermicola has been proposed as biocontrol agent against pine wilting disease caused by Bursaphelenchus xylophilus. In this study, we reported the effects of temperature and different additives on the viability and biocontrol efficacy of E. vermicola formulated by alginate-clay. The viability of the E. vermicola formulation was determined for six consecutive months at temperature ranged from -70 to 25 °C. The fresh conidia without any treatment were used as control. Under the optimal storage conditions with E. vermicola alginate-clay formulation, the results suggested that E. vermicola alginate-clay formulation with a long shelf life could be a non-vacuum-packed formulation that contains 2 % sodium alginate and 5 % clay at 4 °C. Three conidial formulations prepared with additives of 15 % glycerol, 0.5 % yeast extract and 0.5 % herbal extraction, respectively significantly improved the shelf life. In addition, these tested formulations retained the same biocontrol efficacy as the fresh conidial against pinewood nematode. This study provided a tractable and low-cost method to preserve the shelf life of E. vermicola.

Quality by design case study 1: Design of 5-fluorouracil loaded lipid nanoparticles by the W/O/W double emulsion - Solvent evaporation method.

PubMed

Amasya, Gulin; Badilli, Ulya; Aksu, Buket; Tarimci, Nilufer

2016-03-10

With Quality by Design (QbD), a systematic approach involving design and development of all production processes to achieve the final product with a predetermined quality, you work within a design space that determines the critical formulation and process parameters. Verification of the quality of the final product is no longer necessary. In the current study, the QbD approach was used in the preparation of lipid nanoparticle formulations to improve skin penetration of 5-Fluorouracil, a widely-used compound for treating non-melanoma skin cancer. 5-Fluorouracil-loaded lipid nanoparticles were prepared by the W/O/W double emulsion - solvent evaporation method. Artificial neural network software was used to evaluate the data obtained from the lipid nanoparticle formulations, to establish the design space, and to optimize the formulations. Two different artificial neural network models were developed. The limit values of the design space of the inputs and outputs obtained by both models were found to be within the knowledge space. The optimal formulations recommended by the models were prepared and the critical quality attributes belonging to those formulations were assigned. The experimental results remained within the design space limit values. Consequently, optimal formulations with the critical quality attributes determined to achieve the Quality Target Product Profile were successfully obtained within the design space by following the QbD steps. Copyright © 2016 Elsevier B.V. All rights reserved.

Sonic Boom Mitigation Through Aircraft Design and Adjoint Methodology

NASA Technical Reports Server (NTRS)

Rallabhandi, Siriam K.; Diskin, Boris; Nielsen, Eric J.

2012-01-01

This paper presents a novel approach to design of the supersonic aircraft outer mold line (OML) by optimizing the A-weighted loudness of sonic boom signature predicted on the ground. The optimization process uses the sensitivity information obtained by coupling the discrete adjoint formulations for the augmented Burgers Equation and Computational Fluid Dynamics (CFD) equations. This coupled formulation links the loudness of the ground boom signature to the aircraft geometry thus allowing efficient shape optimization for the purpose of minimizing the impact of loudness. The accuracy of the adjoint-based sensitivities is verified against sensitivities obtained using an independent complex-variable approach. The adjoint based optimization methodology is applied to a configuration previously optimized using alternative state of the art optimization methods and produces additional loudness reduction. The results of the optimizations are reported and discussed.

[Study on optimization of formulation of Danggui Liuhuang effervescent granules].

PubMed

Zheng, Ping; Meng, Li-Juan; Sun, Guo-Ping; Wang, Wen-Zhong

2011-03-01

To optimize the formulation of Danggui Liuhuang effervescent granules. By means of quadratic regression rotation-orthogonal combination design, the effect of the proper proportion between citric acid and sodium bicarbonate, as well as the proper quantity of polyethylene glycol 6000 and sodium cyclamate on the dissolubility and pH of effervescent granules was studied. The best formulation was as follows: citric acid: sodium bicarbonate = 0.75: 1, the percentage of polyethylene glycol 6000 and cyclamate was 3.25% and 0.89%, respectively. The dissolubility and pH of the effervescent granules are better and the taste is satisfactory.

Global, Multi-Objective Trajectory Optimization With Parametric Spreading

NASA Technical Reports Server (NTRS)

Vavrina, Matthew A.; Englander, Jacob A.; Phillips, Sean M.; Hughes, Kyle M.

2017-01-01

Mission design problems are often characterized by multiple, competing trajectory optimization objectives. Recent multi-objective trajectory optimization formulations enable generation of globally-optimal, Pareto solutions via a multi-objective genetic algorithm. A byproduct of these formulations is that clustering in design space can occur in evolving the population towards the Pareto front. This clustering can be a drawback, however, if parametric evaluations of design variables are desired. This effort addresses clustering by incorporating operators that encourage a uniform spread over specified design variables while maintaining Pareto front representation. The algorithm is demonstrated on a Neptune orbiter mission, and enhanced multidimensional visualization strategies are presented.

Complex Systems Simulation and Optimization | Computational Science | NREL

Science.gov Websites

account. Stochastic Optimization and Control: Formulation and implementation of advanced optimization and account uncertainty. Contact Wesley Jones Group Manager, Complex Systems Simulation and Optimiziation

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

Hart, William; Laird, Carl; Siirola, John

Pyomo provides a rich software environment for formulating and analyzing optimization applications. Pyomo supports the algebraic specification of complex sets of objectives and constraints, which enables optimization solvers to exploit problem structure to efficiently perform optimization.

Power plant maintenance scheduling using ant colony optimization: an improved formulation

NASA Astrophysics Data System (ADS)

Foong, Wai Kuan; Maier, Holger; Simpson, Angus

2008-04-01

It is common practice in the hydropower industry to either shorten the maintenance duration or to postpone maintenance tasks in a hydropower system when there is expected unserved energy based on current water storage levels and forecast storage inflows. It is therefore essential that a maintenance scheduling optimizer can incorporate the options of shortening the maintenance duration and/or deferring maintenance tasks in the search for practical maintenance schedules. In this article, an improved ant colony optimization-power plant maintenance scheduling optimization (ACO-PPMSO) formulation that considers such options in the optimization process is introduced. As a result, both the optimum commencement time and the optimum outage duration are determined for each of the maintenance tasks that need to be scheduled. In addition, a local search strategy is presented in this article to boost the robustness of the algorithm. When tested on a five-station hydropower system problem, the improved formulation is shown to be capable of allowing shortening of maintenance duration in the event of expected demand shortfalls. In addition, the new local search strategy is also shown to have significantly improved the optimization ability of the ACO-PPMSO algorithm.

Development of an ANN optimized mucoadhesive buccal tablet containing flurbiprofen and lidocaine for dental pain.

PubMed

Hussain, Amjad; Syed, Muhammad Ali; Abbas, Nasir; Hanif, Sana; Arshad, Muhammad Sohail; Bukhari, Nadeem Irfan; Hussain, Khalid; Akhlaq, Muhammad; Ahmad, Zeeshan

2016-06-01

A novel mucoadhesive buccal tablet containing flurbiprofen (FLB) and lidocaine HCl (LID) was prepared to relieve dental pain. Tablet formulations (F1-F9) were prepared using variable quantities of mucoadhesive agents, hydroxypropyl methyl cellulose (HPMC) and sodium alginate (SA). The formulations were evaluated for their physicochemical properties, mucoadhesive strength and mucoadhesion time, swellability index and in vitro release of active agents. Release of both drugs depended on the relative ratio of HPMC:SA. However, mucoadhesive strength and mucoadhesion time were better in formulations, containing higher proportions of HPMC compared to SA. An artificial neural network (ANN) approach was applied to optimise formulations based on known effective parameters (i.e., mucoadhesive strength, mucoadhesion time and drug release), which proved valuable. This study indicates that an effective buccal tablet formulation of flurbiprofen and lidocaine can be prepared via an optimized ANN approach.

Systematic evaluation of common lubricants for optimal use in tablet formulation.

PubMed

Paul, Shubhajit; Sun, Changquan Calvin

2018-05-30

As an essential formulation component for large-scale tablet manufacturing, the lubricant preserves tooling by reducing die-wall friction. Unfortunately, lubrication also often results in adverse effects on tablet characteristics, such as prolonged disintegration, slowed dissolution, and reduced mechanical strength. Therefore, the choice of lubricant and its optimal concentration in a tablet formulation is a critical decision in tablet formulation development to attain low die-wall friction while minimizing negative impact on other tablet properties. Three commercially available tablet lubricants, i.e., magnesium stearate, sodium stearyl fumerate, and stearic acid, were systematically investigated in both plastic and brittle matrices to elucidate their effects on reducing die-wall friction, tablet strength, tablet hardness, tablet friability, and tablet disintegration kinetics. Clear understanding of the lubrication efficiency of commonly used lubricants as well as their impact on tablet characteristics would help future tablet formulation efforts. Copyright © 2018 Elsevier B.V. All rights reserved.

Design, optimization and characterization of coenzyme Q10- and D-panthenyl triacetate-loaded liposomes

PubMed Central

Çelik, Burak; Sağıroğlu, Ali Asram; Özdemir, Samet

2017-01-01

Coenzyme Q10 (CoQ10) is a lipid-soluble molecule found naturally in many eukaryotic cells and is essential for electron transport chain and energy generation in mitochondria. D-Panthenyl triacetate (PTA) is an oil-soluble derivative of D-panthenol, which is essential for coenzyme A synthesis in the epithelium. Liposomal formulations that encapsulate both ingredients were prepared and optimized by applying response surface methodology for increased stability and skin penetration. The optimum formulation comprised 4.17 mg CoQ10, 4.22 mg PTA and 13.95 mg cholesterol per 100 mg of soy phosphatidylcholine. The encapsulation efficiency of the optimized formulation for CoQ10 and PTA was found to be 90.89%±3.61% and 87.84%±4.61%, respectively. Narrow size distribution was achieved with an average size of 161.6±3.6 nm, while a spherical and uniform shape was confirmed via scanning electron microscopy and transmission electron microscopy images. Cumulative release of 90.93% for PTA and 24.41% for CoQ10 was achieved after 24 hours of in vitro release study in sink conditions. Physical stability tests indicated that the optimized liposomes were suitable for storage at 4°C for at least 60 days. The results suggest that the optimized liposomal formulation would be a promising delivery system for both ingredients in various topical applications. PMID:28744121

Rapidly absorbed orodispersible tablet containing molecularly dispersed felodipine for management of hypertensive crisis: development, optimization and in vitro/in vivo studies.

PubMed

Basalious, Emad B; El-Sebaie, Wessam; El-Gazayerly, Omaima

2013-01-01

A liquisolid orodispersible tablet of felodipine, a BCS Class II drug, was developed to improve drug dissolution and absorption through the buccal mucosa for management of hypertensive crisis. A 24 full-factorial design was applied to optimize felodipine liquisolid systems (FLSs) having acceptable flow properties and possessing enhanced drug dissolution rates. Four formulation variables; The liquid type, X1 (PG or PEG), drug concentration, X2 (10% and 20%), type of coat, X3 (Aerosil® and Aeroperl®) and excipients ratio, X4 (10 and 20) were included in the design. The systems were assessed for dissolution and flow properties. Following optimization, the formulation components (X1, X2, X3 and X4) were PEG, 10%, Aerosil® and 20, respectively. The optimized FLS was compressed into felodipine liquisolid orodispersible tablet using Prosolv® as carrier material (FLODT-2). The in vitro and in vivo disintegration times of FLODT-2 were 9 and 7 s, respectively. The in vivo pharmacokinetic study using human volunteers showed a significant increase in dissolution and absorption rates of the formulation of FLODT-2 compared to soft gelatin capsules filled with felodipine solution in PEG under the same conditions. Our results proposed that the optimized FLODT formulation could be promising to manage hypertensive crisis.

Formulation development and optimization of sustained release matrix tablet of Itopride HCl by response surface methodology and its evaluation of release kinetics

PubMed Central

Bose, Anirbandeep; Wong, Tin Wui; Singh, Navjot

2012-01-01

The objective of this present investigation was to develop and formulate sustained release (SR) matrix tablets of Itopride HCl, by using different polymer combinations and fillers, to optimize by Central Composite Design response surface methodology for different drug release variables and to evaluate drug release pattern of the optimized product. Sustained release matrix tablets of various combinations were prepared with cellulose-based polymers: hydroxy propyl methyl cellulose (HPMC) and polyvinyl pyrolidine (pvp) and lactose as fillers. Study of pre-compression and post-compression parameters facilitated the screening of a formulation with best characteristics that underwent here optimization study by response surface methodology (Central Composite Design). The optimized tablet was further subjected to scanning electron microscopy to reveal its release pattern. The in vitro study revealed that combining of HPMC K100M (24.65 MG) with pvp(20 mg)and use of LACTOSE as filler sustained the action more than 12 h. The developed sustained release matrix tablet of improved efficacy can perform therapeutically better than a conventional tablet. PMID:23960836

Image gathering and processing - Information and fidelity

NASA Technical Reports Server (NTRS)

Huck, F. O.; Fales, C. L.; Halyo, N.; Samms, R. W.; Stacy, K.

1985-01-01

In this paper we formulate and use information and fidelity criteria to assess image gathering and processing, combining optical design with image-forming and edge-detection algorithms. The optical design of the image-gathering system revolves around the relationship among sampling passband, spatial response, and signal-to-noise ratio (SNR). Our formulations of information, fidelity, and optimal (Wiener) restoration account for the insufficient sampling (i.e., aliasing) common in image gathering as well as for the blurring and noise that conventional formulations account for. Performance analyses and simulations for ordinary optical-design constraints and random scences indicate that (1) different image-forming algorithms prefer different optical designs; (2) informationally optimized designs maximize the robustness of optimal image restorations and lead to the highest-spatial-frequency channel (relative to the sampling passband) for which edge detection is reliable (if the SNR is sufficiently high); and (3) combining the informationally optimized design with a 3 by 3 lateral-inhibitory image-plane-processing algorithm leads to a spatial-response shape that approximates the optimal edge-detection response of (Marr's model of) human vision and thus reduces the data preprocessing and transmission required for machine vision.

Formulation development and optimization of sustained release matrix tablet of Itopride HCl by response surface methodology and its evaluation of release kinetics.

PubMed

Bose, Anirbandeep; Wong, Tin Wui; Singh, Navjot

2013-04-01

The objective of this present investigation was to develop and formulate sustained release (SR) matrix tablets of Itopride HCl, by using different polymer combinations and fillers, to optimize by Central Composite Design response surface methodology for different drug release variables and to evaluate drug release pattern of the optimized product. Sustained release matrix tablets of various combinations were prepared with cellulose-based polymers: hydroxy propyl methyl cellulose (HPMC) and polyvinyl pyrolidine (pvp) and lactose as fillers. Study of pre-compression and post-compression parameters facilitated the screening of a formulation with best characteristics that underwent here optimization study by response surface methodology (Central Composite Design). The optimized tablet was further subjected to scanning electron microscopy to reveal its release pattern. The in vitro study revealed that combining of HPMC K100M (24.65 MG) with pvp(20 mg)and use of LACTOSE as filler sustained the action more than 12 h. The developed sustained release matrix tablet of improved efficacy can perform therapeutically better than a conventional tablet.

Effect of Mixing Time and Storage Condition on Characterization of Heparinoid Admixtures with Corticosteroids.

PubMed

Sugiyama, Ikumi; Takahashi, Namiki; Sadzuka, Yasuyuki

2016-01-01

In dermatologic therapy, several external preparations formulated as ointments or creams are prescribed. And they are often admixture to improve patient compliance. In this study, we prepared admixtures of moisturizer with steroids and examined their usability and the amount of principal agent in formulations, particularly focusing on the moisturizer content. Four heparinoid semisolid formulations were selected: Hirudoid ® soft ointment 0.3% (Formulation A) and 3 generic agents [(Besoften ® oil-based cream 0.3% (Formulation B), Kuradoido ® ointment 0.3% (Formulation C), and Hepadaerm ointment 0.3% (Formulation D)], and Antebate ® ointment 0.05% (Formulation E) were used as steroids. Formulation A and B are water-in-oil emulsions, and Formulation C and D are oil-in-water emulsions. Admixtures looked like to be mixed uniformly by visual observation. In the examination of heparinoid amount, admixture A+E and B+E were mixed uniformly. On the other hand, admixture C+E was remarkable un-uniformly. It was speculated that the emulsification of formulation C was broken. The phenomenon was supported by the result of malleability. After 8 weeks storage, the heparinoid ratio in each formulation could be expressed as follows: Admixture B≥Admixture A>Admixture C=Admixture D. A suitable storage temperature was 4°C. The results of physicochemical data analysis reveal the formulations composed of water-in-oil cream, i.e., Formulation A and Formulation B, to be the optimal choices for mixing with steroid ointments. Mixing time and storage conditions may be optimized to solve pharmaceutical problems. Moreover, understanding the emulsion type and character of semisolid formulations can expand the range of formulation options.

Optimal rail container shipment planning problem in multimodal transportation

NASA Astrophysics Data System (ADS)

Cao, Chengxuan; Gao, Ziyou; Li, Keping

2012-09-01

The optimal rail container shipment planning problem in multimodal transportation is studied in this article. The characteristics of the multi-period planning problem is presented and the problem is formulated as a large-scale 0-1 integer programming model, which maximizes the total profit generated by all freight bookings accepted in a multi-period planning horizon subject to the limited capacities. Two heuristic algorithms are proposed to obtain an approximate optimal solution of the problem. Finally, numerical experiments are conducted to demonstrate the proposed formulation and heuristic algorithms.

Date seed oil loaded niosomes: development, optimization and anti-inflammatory effect evaluation on rats.

PubMed

Soliman, Mahmoud S; Abd-Allah, Fathy I; Hussain, Talib; Saeed, Noha M; El-Sawy, Hossam S

2018-07-01

An optimized date seed oil (DSO) loaded niosomes was formulated. Maximize the extract anti-inflammatory efficacy and govern its release characteristics from nanoparticles for osteoarthritis prevention and treatment purposes. By using Box-Behnken Design, the effect of three formulation factors on the entrapment efficiency percentage (Y 1 ), initial DSO release percentage after 2 h (Y 2 ), and cumulative DSO release percentage of DSO after 12 h (Y 3 ), were optimized and studied. The optimized DSO formulation was specified, elaborated, particle size and zeta potential assessed, examined morphologically under electron and light microscope, and in vivo evaluated via carrageenan-induced rat paw edema study. 65.89%, 18.39%, and 58.27% were the measured responses of the optimized niosomes for Y 1 , Y 2 , and Y 3 , respectively. The vesicular structure of the optimized DSO loaded nano-vesicles with nano-size range and good stability features were confirmed. Furthermore, a distinguished anti-inflammatory activity in both prompt and sustained effectiveness were exhibited via the optimized DSO niosomes. Interestingly, the delayed efficacy outcomes of the extract loaded nanoparticles showed a similarity profile as well as the negative control group outcomes. To emphasize, DSO loading in niosomes revealed a significant enhancement toward inflammation alleviation, which offers a promising implement in osteoarthritis remediation and prohibition.

Nanoemulsion: for improved oral delivery of repaglinide.

PubMed

Akhtar, Juber; Siddiqui, Hefazat Hussain; Fareed, Sheeba; Badruddeen; Khalid, Mohammad; Aqil, Mohammed

2016-07-01

Repaglinide (RPG) is a fast-acting prandial glucose regulator. It acts by stimulating insulin release from pancreatic β-cells. Recurrent dosing of RPG before each meal is burdensome remedy. Hence the plan of the present study was to evaluate nanoemulsion as a hopeful carrier for RPG for persistent hypoglycemic effect. The drug was incorporated into oil phase of nanoemulsion to give improved biopharmaceutical properties as compared to the lipid-based systems. Pseudo ternary phase diagrams were prepared by aqueous titration method. Formulations were selected at a difference of 5% w/w of oil from the o/w nanoemulsion region of phase diagrams. The optimized nanoemulsion formulation constituted sefsol-218 (5% v/v) as an oil phase, 30% v/v of Tween-80 and transcutol as a surfactant and co-surfactant to restrain nanodroplet size and low viscosity and distilled water (65%). In vitro dissolution studies showed higher drug release (98.22%), finest droplet size (76.23 nm), slightest polydispersity value (0.183), least viscosity (21.45 cps) and immeasurable dilution capability from the nanoemulsion as compared with existing oral tablet formulation. The optimized RPG nanoemulsion formulation showed better hypoglycemic effect in comparison to tablet formulation in experimental diabetic rats. No significant variations were also observed in the optimized formulation when subjected to accelerated stability study at different temperature and relative humidity over a period of 3 months.

Mixture experiment methods in the development and optimization of microemulsion formulations

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

Furlanetto, Sandra; Cirri, Marzia; Piepel, Gregory F.

2011-06-25

Microemulsion formulations represent an interesting delivery vehicle for lipophilic drugs, allowing for improving their solubility and dissolution properties. This work developed effective microemulsion formulations using glyburide (a very poorly-water-soluble hypoglycaemic agent) as a model drug. First, the area of stable microemulsion (ME) formations was identified using a new approach based on mixture experiment methods. A 13-run mixture design was carried out in an experimental region defined by constraints on three components: aqueous, oil, and surfactant/cosurfactant. The transmittance percentage (at 550 nm) of ME formulations (indicative of their transparency and thus of their stability) was chosen as the response variable. Themore » results obtained using the mixture experiment approach corresponded well with those obtained using the traditional approach based on pseudo-ternary phase diagrams. However, the mixture experiment approach required far less experimental effort than the traditional approach. A subsequent 13-run mixture experiment, in the region of stable MEs, was then performed to identify the optimal formulation (i.e., having the best glyburide dissolution properties). Percent drug dissolved and dissolution efficiency were selected as the responses to be maximized. The ME formulation optimized via the mixture experiment approach consisted of 78% surfactant/cosurfacant (a mixture of Tween 20 and Transcutol, 1:1 v/v), 5% oil (Labrafac Hydro) and 17% aqueous (water). The stable region of MEs was identified using mixture experiment methods for the first time.« less

Topology synthesis and size optimization of morphing wing structures

NASA Astrophysics Data System (ADS)

Inoyama, Daisaku

This research demonstrates a novel topology and size optimization methodology for synthesis of distributed actuation systems with specific applications to morphing air vehicle structures. The main emphasis is placed on the topology and size optimization problem formulations and the development of computational modeling concepts. The analysis model is developed to meet several important criteria: It must allow a rigid-body displacement, as well as a variation in planform area, with minimum strain on structural members while retaining acceptable numerical stability for finite element analysis. Topology optimization is performed on a semi-ground structure with design variables that control the system configuration. In effect, the optimization process assigns morphing members as "soft" elements, non-morphing load-bearing members as "stiff' elements, and non-existent members as "voids." The optimization process also determines the optimum actuator placement, where each actuator is represented computationally by equal and opposite nodal forces with soft axial stiffness. In addition, the configuration of attachments that connect the morphing structure to a non-morphing structure is determined simultaneously. Several different optimization problem formulations are investigated to understand their potential benefits in solution quality, as well as meaningfulness of the formulations. Extensions and enhancements to the initial concept and problem formulations are made to accommodate multiple-configuration definitions. In addition, the principal issues on the external-load dependency and the reversibility of a design, as well as the appropriate selection of a reference configuration, are addressed in the research. The methodology to control actuator distributions and concentrations is also discussed. Finally, the strategy to transfer the topology solution to the sizing optimization is developed and cross-sectional areas of existent structural members are optimized under applied aerodynamic loads. That is, the optimization process is implemented in sequential order: The actuation system layout is first determined through multi-disciplinary topology optimization process, and then the thickness or cross-sectional area of each existent member is optimized under given constraints and boundary conditions. Sample problems are solved to demonstrate the potential capabilities of the presented methodology. The research demonstrates an innovative structural design procedure from a computational perspective and opens new insights into the potential design requirements and characteristics of morphing structures.

Application of rotatable central composite design in the preparation and optimization of poly(lactic-co-glycolic acid) nanoparticles for controlled delivery of paclitaxel.

PubMed

Kollipara, Sivacharan; Bende, Girish; Movva, Snehalatha; Saha, Ranendra

2010-11-01

Polymeric carrier systems of paclitaxel (PCT) offer advantages over only available formulation Taxol® in terms of enhancing therapeutic efficacy and eliminating adverse effects. The objective of the present study was to prepare poly (lactic-co-glycolic acid) nanoparticles containing PCT using emulsion solvent evaporation technique. Critical factors involved in the processing method were identified and optimized by scientific, efficient rotatable central composite design aiming at low mean particle size and high entrapment efficiency. Twenty different experiments were designed and each formulation was evaluated for mean particle size and entrapment efficiency. The optimized formulation was evaluated for in vitro drug release, and absorption characteristics were studied using in situ rat intestinal permeability study. Amount of polymer and duration of ultrasonication were found to have significant effect on mean particle size and entrapment efficiency. First-order interactions of amount of miglyol with amount of polymer were significant in case of mean particle size, whereas second-order interactions of polymer were significant in mean particle size and entrapment efficiency. The developed quadratic model showed high correlation (R(2) > 0.85) between predicted response and studied factors. The optimized formulation had low mean particle size (231.68 nm) and high entrapment efficiency (95.18%) with 4.88% drug content. The optimized formulation showed controlled release of PCT for more than 72 hours. In situ absorption study showed faster and enhanced extent of absorption of PCT from nanoparticles compared to pure drug. The poly (lactic-co-glycolic acid) nanoparticles containing PCT may be of clinical importance in enhancing its oral bioavailability.

Terbinafine Hydrochloride Trans-ungual Delivery via Nanovesicular Systems: In Vitro Characterization and Ex Vivo Evaluation.

PubMed

Elsherif, Noha Ibrahim; Shamma, Rehab Nabil; Abdelbary, Ghada

2017-02-01

Treating a nail infection like onychomycosis is challenging as the human nail plate acts as a formidable barrier against all drug permeation. Available oral and topical treatments have several setbacks. Terbinafine hydrochloride (TBH), belonging to the allylamine class, is mainly used for treatment of onychomycosis. This study aims to formulate TBH in a nanobased spanlastic vesicular carrier that enables and enhances the drug delivery through the nail. The nanovesicles were formulated by ethanol injection method, using either Span® 60 or Span® 65, together with Tween 80 or sodium deoxycholate as an edge activator. A full factorial design was implemented to study the effect of different formulation and process variables on the prepared TBH-loaded spanlastic nanovesicles. TBH entrapment efficiency percentages, particle size diameter, percentage drug released after 2 h and 8 h were selected as dependent variables. Optimization was performed using Design-Expert® software to obtain an optimized formulation with high entrapment efficiency (62.35 ± 8.91%), average particle size of 438.45 ± 70.5 nm, and 29.57 ± 0.93 and 59.53 ± 1.73% TBH released after 2 and 8 h, respectively. The optimized formula was evaluated using differential scanning calorimetry and X-ray diffraction and was also morphologically examined using transmission electron microscopy. An ex vivo study was conducted to determine the permeation and retainment of the optimized formulation in a human cadaver nail plate, and confocal laser scanning microscope was used to show the extent of formulation permeation. In conclusion, the results confirmed that spanlastics exhibit promising results for the trans-ungual delivery of TBH.

A novel experimental design method to optimize hydrophilic matrix formulations with drug release profiles and mechanical properties.

PubMed

Choi, Du Hyung; Lim, Jun Yeul; Shin, Sangmun; Choi, Won Jun; Jeong, Seong Hoon; Lee, Sangkil

2014-10-01

To investigate the effects of hydrophilic polymers on the matrix system, an experimental design method was developed to integrate response surface methodology and the time series modeling. Moreover, the relationships among polymers on the matrix system were studied with the evaluation of physical properties including water uptake, mass loss, diffusion, and gelling index. A mixture simplex lattice design was proposed while considering eight input control factors: Polyethylene glycol 6000 (x1 ), polyethylene oxide (PEO) N-10 (x2 ), PEO 301 (x3 ), PEO coagulant (x4 ), PEO 303 (x5 ), hydroxypropyl methylcellulose (HPMC) 100SR (x6 ), HPMC 4000SR (x7 ), and HPMC 10(5) SR (x8 ). With the modeling, optimal formulations were obtained depending on the four types of targets. The optimal formulations showed the four significant factors (x1 , x2 , x3 , and x8 ) and other four input factors (x4 , x5 , x6 , and x7 ) were not significant based on drug release profiles. Moreover, the optimization results were analyzed with estimated values, targets values, absolute biases, and relative biases based on observed times for the drug release rates with four different targets. The result showed that optimal solutions and target values had consistent patterns with small biases. On the basis of the physical properties of the optimal solutions, the type and ratio of the hydrophilic polymer and the relationships between polymers significantly influenced the physical properties of the system and drug release. This experimental design method is very useful in formulating a matrix system with optimal drug release. Moreover, it can distinctly confirm the relationships between excipients and the effects on the system with extensive and intensive evaluations. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Remediation System Design Optimization: Field Demonstration at the Umatilla Army Deport

NASA Astrophysics Data System (ADS)

Zheng, C.; Wang, P. P.

2002-05-01

Since the early 1980s, many researchers have shown that the simulation-optimization (S/O) approach is superior to the traditional trial-and-error method for designing cost-effective groundwater pump-and-treat systems. However, the application of the S/O approach to real field problems has remained limited. This paper describes the application of a new general simulation-optimization code to optimize an existing pump-and-treat system at the Umatilla Army Depot in Oregon, as part of a field demonstration project supported by the Environmental Security Technology Certification Program (ESTCP). Two optimization formulations were developed to minimize the total capital and operational costs under the current and possibly expanded treatment plant capacities. A third formulation was developed to minimize the total contaminant mass of RDX and TNT remaining in the shallow aquifer by the end of the project duration. For the first two formulations, this study produced an optimal pumping strategy that would achieve the cleanup goal in 4 years with a total cost of 1.66 million US dollars in net present value. For comparison, the existing design in operation was calculated to require 17 years for cleanup with a total cost of 3.83 million US dollars in net present value. Thus, the optimal pumping strategy represents a reduction of 13 years in cleanup time and a reduction of 56.6 percent in the expected total expenditure. For the third formulation, this study identified an optimal dynamic pumping strategy that would reduce the total mass remaining in the shallow aquifer by 89.5 percent compared with that calculated for the existing design. In spite of their intensive computational requirements, this study shows that the global optimization techniques including tabu search and genetic algorithms can be applied successfully to large-scale field problems involving multiple contaminants and complex hydrogeological conditions.

Continued research on selected parameters to minimize community annoyance from airplane noise

NASA Technical Reports Server (NTRS)

Frair, L.

1981-01-01

Results from continued research on selected parameters to minimize community annoyance from airport noise are reported. First, a review of the initial work on this problem is presented. Then the research focus is expanded by considering multiobjective optimization approaches for this problem. A multiobjective optimization algorithm review from the open literature is presented. This is followed by the multiobjective mathematical formulation for the problem of interest. A discussion of the appropriate solution algorithm for the multiobjective formulation is conducted. Alternate formulations and associated solution algorithms are discussed and evaluated for this airport noise problem. Selected solution algorithms that have been implemented are then used to produce computational results for example airports. These computations involved finding the optimal operating scenario for a moderate size airport and a series of sensitivity analyses for a smaller example airport.

Simulation of global oceanic upper layers forced at the surface by an optimal bulk formulation derived from multi-campaign measurements.

NASA Astrophysics Data System (ADS)

Garric, G.; Pirani, A.; Belamari, S.; Caniaux, G.

2006-12-01

order to improve the air/sea interface for the future MERCATOR global ocean operational system, we have implemented the new bulk formulation developed by METEO-FRANCE (French Meteo office) in the MERCATOR 2 degree global ocean-ice coupled model (ORCA2/LIM). A single bulk formulation for the drag, temperature and moisture exchange coefficients is derived from an extended consistent database gathering 10 years of measurements issued from five experiments dedicated to air-sea fluxes estimates (SEMAPHORE, CATCH, FETCH, EQUALANT99 and POMME) in various oceanic basins (from Northern to equatorial Atlantic). The available database (ALBATROS) cover the widest range of atmospheric and oceanic conditions, from very light (0.3 m/s) to very strong (up to 29 m/s) wind speeds, and from unstable to extremely stable atmospheric boundary layer stratification. We have defined a work strategy to test this new formulation in a global oceanic context, by using this multi- campaign bulk formulation to derive air-sea fluxes from base meteorological variables produces by the ECMWF (European Centre for Medium Range and Weather Forecast) atmospheric forecast model, in order to get surface boundary conditions for ORCA2/LIM. The simulated oceanic upper layers forced at the surface by the previous air/sea interface are compared to those forced by the optimal bulk formulation. Consecutively with generally weaker transfer coefficient, the latter formulation reduces the cold bias in the equatorial Pacific and increases the too weak summer sea ice extent in Antarctica. Compared to a recent mixed layer depth (MLD) climatology, the optimal bulk formulation reduces also the too deep simulated MLDs. Comparison with in situ temperature and salinity profiles in different areas allowed us to evaluate the impact of changing the air/sea interface in the vertical structure.

Closed-form recursive formula for an optimal tracker with terminal constraints

NASA Technical Reports Server (NTRS)

Juang, J. N.; Turner, J. D.; Chun, H. M.

1986-01-01

Feedback control laws are derived for a class of optimal finite time tracking problems with terminal constraints. Analytical solutions are obtained for the feedback gain and the closed-loop response trajectory. Such formulations are expressed in recursive forms so that a real-time computer implementation becomes feasible. An example involving the feedback slewing of a flexible spacecraft is given to illustrate the validity and usefulness of the formulations.

Formulation Development and Evaluation of Fast Disintegrating Tablets of Salbutamol Sulphate for Respiratory Disorders

PubMed Central

Sharma, Deepak

2013-01-01

Recent developments in fast disintegrating tablets have brought convenience in dosing to pediatric and elderly patients who have trouble in swallowing tablets. The objective of the present study was to prepare the fast disintegrating tablet of salbutamol sulphate for respiratory disorders for pediatrics. As precision of dosing and patient's compliance become important prerequisites for a long-term treatment, there is a need to develop a formulation for this drug which overcomes problems such as difficulty in swallowing, inconvenience in administration while travelling, and patient's acceptability. Hence, the present investigation were undertaken with a view to develop a fast disintegrating tablet of salbutamol sulphate which offers a new range of products having desired characteristics and intended benefits. Superdisintegrants such as sodium starch glycolate was optimized. Different binders were optimized along with optimized superdisintegrant concentration. The tablets were prepared by direct compression technique. The tablets were evaluated for hardness, friability, weight variation, wetting time, disintegration time, and uniformity of content. Optimized formulation was evaluated by in vitro dissolution test, drug-excipient compatibility, and accelerated stability study. It was concluded that fast disintegrating tablets of salbutamol sulphate were formulated successfully with desired characteristics which disintegrated rapidly; provided rapid onset of action; and enhanced the patient convenience and compliance. PMID:23956881

Initial Results of an MDO Method Evaluation Study

NASA Technical Reports Server (NTRS)

Alexandrov, Natalia M.; Kodiyalam, Srinivas

1998-01-01

The NASA Langley MDO method evaluation study seeks to arrive at a set of guidelines for using promising MDO methods by accumulating and analyzing computational data for such methods. The data are collected by conducting a series of re- producible experiments. In the first phase of the study, three MDO methods were implemented in the SIGHT: framework and used to solve a set of ten relatively simple problems. In this paper, we comment on the general considerations for conducting method evaluation studies and report some initial results obtained to date. In particular, although the results are not conclusive because of the small initial test set, other formulations, optimality conditions, and sensitivity of solutions to various perturbations. Optimization algorithms are used to solve a particular MDO formulation. It is then appropriate to speak of local convergence rates and of global convergence properties of an optimization algorithm applied to a specific formulation. An analogous distinction exists in the field of partial differential equations. On the one hand, equations are analyzed in terms of regularity, well-posedness, and the existence and unique- ness of solutions. On the other, one considers numerous algorithms for solving differential equations. The area of MDO methods studies MDO formulations combined with optimization algorithms, although at times the distinction is blurred. It is important to

Optimization of primaquine diphosphate tablet formulation for controlled drug release using the mixture experimental design.

PubMed

Duque, Marcelo Dutra; Kreidel, Rogério Nepomuceno; Taqueda, Maria Elena Santos; Baby, André Rolim; Kaneko, Telma Mary; Velasco, Maria Valéria Robles; Consiglieri, Vladi Olga

2013-01-01

A tablet formulation based on hydrophilic matrix with a controlled drug release was developed, and the effect of polymer concentrations on the release of primaquine diphosphate was evaluated. To achieve this purpose, a 20-run, four-factor with multiple constraints on the proportions of the components was employed to obtain tablet compositions. Drug release was determined by an in vitro dissolution study in phosphate buffer solution at pH 6.8. The polynomial fitted functions described the behavior of the mixture on simplex coordinate systems to study the effects of each factor (polymer) on tablet characteristics. Based on the response surface methodology, a tablet composition was optimized with the purpose of obtaining a primaquine diphosphate release closer to a zero order kinetic. This formulation released 85.22% of the drug for 8 h and its kinetic was studied regarding to Korsmeyer-Peppas model, (Adj-R(2) = 0.99295) which has confirmed that both diffusion and erosion were related to the mechanism of the drug release. The data from the optimized formulation were very close to the predictions from statistical analysis, demonstrating that mixture experimental design could be used to optimize primaquine diphosphate dissolution from hidroxypropylmethyl cellulose and polyethylene glycol matrix tablets.

Optimization of Thermal Object Nonlinear Control Systems by Energy Efficiency Criterion.

NASA Astrophysics Data System (ADS)

Velichkin, Vladimir A.; Zavyalov, Vladimir A.

2018-03-01

This article presents the results of thermal object functioning control analysis (heat exchanger, dryer, heat treatment chamber, etc.). The results were used to determine a mathematical model of the generalized thermal control object. The appropriate optimality criterion was chosen to make the control more energy-efficient. The mathematical programming task was formulated based on the chosen optimality criterion, control object mathematical model and technological constraints. The “maximum energy efficiency” criterion helped avoid solving a system of nonlinear differential equations and solve the formulated problem of mathematical programming in an analytical way. It should be noted that in the case under review the search for optimal control and optimal trajectory reduces to solving an algebraic system of equations. In addition, it is shown that the optimal trajectory does not depend on the dynamic characteristics of the control object.

Recent experience in simultaneous control-structure optimization

NASA Technical Reports Server (NTRS)

Salama, M.; Ramaker, R.; Milman, M.

1989-01-01

To show the feasibility of simultaneous optimization as design procedure, low order problems were used in conjunction with simple control formulations. The numerical results indicate that simultaneous optimization is not only feasible, but also advantageous. Such advantages come at the expense of introducing complexities beyond those encountered in structure optimization alone, or control optimization alone. Examples include: larger design parameter space, optimization may combine continuous and combinatoric variables, and the combined objective function may be nonconvex. Future extensions to include large order problems, more complex objective functions and constraints, and more sophisticated control formulations will require further research to ensure that the additional complexities do not outweigh the advantages of simultaneous optimization. Some areas requiring more efficient tools than currently available include: multiobjective criteria and nonconvex optimization. Efficient techniques to deal with optimization over combinatoric and continuous variables, and with truncation issues for structure and control parameters of both the model space as well as the design space need to be developed.

Discrete-time entropy formulation of optimal and adaptive control problems

NASA Technical Reports Server (NTRS)

Tsai, Yweting A.; Casiello, Francisco A.; Loparo, Kenneth A.

1992-01-01

The discrete-time version of the entropy formulation of optimal control of problems developed by G. N. Saridis (1988) is discussed. Given a dynamical system, the uncertainty in the selection of the control is characterized by the probability distribution (density) function which maximizes the total entropy. The equivalence between the optimal control problem and the optimal entropy problem is established, and the total entropy is decomposed into a term associated with the certainty equivalent control law, the entropy of estimation, and the so-called equivocation of the active transmission of information from the controller to the estimator. This provides a useful framework for studying the certainty equivalent and adaptive control laws.

Microfluidics: a transformational tool for nanomedicine development and production.

PubMed

Garg, Shyam; Heuck, Gesine; Ip, Shell; Ramsay, Euan

2016-11-01

Microfluidic devices are mircoscale fluidic circuits used to manipulate liquids at the nanoliter scale. The ability to control the mixing of fluids and the continuous nature of the process make it apt for solvent/antisolvent precipitation of drug-delivery nanoparticles. This review describes the use of numerous microfluidic designs for the formulation and production of lipid nanoparticles, liposomes and polymer nanoparticles to encapsulate and deliver small molecule or genetic payloads. The advantages of microfluidics are illustrated through examples from literature comparing conventional processes such as beaker and T-tube mixing to microfluidic approaches. Particular emphasis is placed on examples of microfluidic nanoparticle formulations that have been tested in vitro and in vivo. Fine control of process parameters afforded by microfluidics, allows unprecedented optimization of nanoparticle quality and encapsulation efficiency. Automation improves the reproducibility and optimization of formulations. Furthermore, the continuous nature of the microfluidic process is inherently scalable, allowing optimization at low volumes, which is advantageous with scarce or costly materials, as well as scale-up through process parallelization. Given these advantages, microfluidics is poised to become the new paradigm for nanomedicine formulation and production.

Design sensitivity analysis of boundary element substructures

NASA Technical Reports Server (NTRS)

Kane, James H.; Saigal, Sunil; Gallagher, Richard H.

1989-01-01

The ability to reduce or condense a three-dimensional model exactly, and then iterate on this reduced size model representing the parts of the design that are allowed to change in an optimization loop is discussed. The discussion presents the results obtained from an ongoing research effort to exploit the concept of substructuring within the structural shape optimization context using a Boundary Element Analysis (BEA) formulation. The first part contains a formulation for the exact condensation of portions of the overall boundary element model designated as substructures. The use of reduced boundary element models in shape optimization requires that structural sensitivity analysis can be performed. A reduced sensitivity analysis formulation is then presented that allows for the calculation of structural response sensitivities of both the substructured (reduced) and unsubstructured parts of the model. It is shown that this approach produces significant computational economy in the design sensitivity analysis and reanalysis process by facilitating the block triangular factorization and forward reduction and backward substitution of smaller matrices. The implementatior of this formulation is discussed and timings and accuracies of representative test cases presented.

Scale up, optimization and stability analysis of Curcumin C3 complex-loaded nanoparticles for cancer therapy

PubMed Central

2012-01-01

Background Nanoparticle based delivery of anticancer drugs have been widely investigated. However, a very important process for Research & Development in any pharmaceutical industry is scaling nanoparticle formulation techniques so as to produce large batches for preclinical and clinical trials. This process is not only critical but also difficult as it involves various formulation parameters to be modulated all in the same process. Methods In our present study, we formulated curcumin loaded poly (lactic acid-co-glycolic acid) nanoparticles (PLGA-CURC). This improved the bioavailability of curcumin, a potent natural anticancer drug, making it suitable for cancer therapy. Post formulation, we optimized our process by Reponse Surface Methodology (RSM) using Central Composite Design (CCD) and scaled up the formulation process in four stages with final scale-up process yielding 5 g of curcumin loaded nanoparticles within the laboratory setup. The nanoparticles formed after scale-up process were characterized for particle size, drug loading and encapsulation efficiency, surface morphology, in vitro release kinetics and pharmacokinetics. Stability analysis and gamma sterilization were also carried out. Results Results revealed that that process scale-up is being mastered for elaboration to 5 g level. The mean nanoparticle size of the scaled up batch was found to be 158.5 ± 9.8 nm and the drug loading was determined to be 10.32 ± 1.4%. The in vitro release study illustrated a slow sustained release corresponding to 75% drug over a period of 10 days. The pharmacokinetic profile of PLGA-CURC in rats following i.v. administration showed two compartmental model with the area under the curve (AUC0-∞) being 6.139 mg/L h. Gamma sterilization showed no significant change in the particle size or drug loading of the nanoparticles. Stability analysis revealed long term physiochemical stability of the PLGA-CURC formulation. Conclusions A successful effort towards formulating, optimizing and scaling up PLGA-CURC by using Solid-Oil/Water emulsion technique was demonstrated. The process used CCD-RSM for optimization and further scaled up to produce 5 g of PLGA-CURC with almost similar physicochemical characteristics as that of the primary formulated batch. PMID:22937885

Scale up, optimization and stability analysis of Curcumin C3 complex-loaded nanoparticles for cancer therapy.

PubMed

Ranjan, Amalendu P; Mukerjee, Anindita; Helson, Lawrence; Vishwanatha, Jamboor K

2012-08-31

Nanoparticle based delivery of anticancer drugs have been widely investigated. However, a very important process for Research & Development in any pharmaceutical industry is scaling nanoparticle formulation techniques so as to produce large batches for preclinical and clinical trials. This process is not only critical but also difficult as it involves various formulation parameters to be modulated all in the same process. In our present study, we formulated curcumin loaded poly (lactic acid-co-glycolic acid) nanoparticles (PLGA-CURC). This improved the bioavailability of curcumin, a potent natural anticancer drug, making it suitable for cancer therapy. Post formulation, we optimized our process by Reponse Surface Methodology (RSM) using Central Composite Design (CCD) and scaled up the formulation process in four stages with final scale-up process yielding 5 g of curcumin loaded nanoparticles within the laboratory setup. The nanoparticles formed after scale-up process were characterized for particle size, drug loading and encapsulation efficiency, surface morphology, in vitro release kinetics and pharmacokinetics. Stability analysis and gamma sterilization were also carried out. Results revealed that that process scale-up is being mastered for elaboration to 5 g level. The mean nanoparticle size of the scaled up batch was found to be 158.5±9.8 nm and the drug loading was determined to be 10.32±1.4%. The in vitro release study illustrated a slow sustained release corresponding to 75% drug over a period of 10 days. The pharmacokinetic profile of PLGA-CURC in rats following i.v. administration showed two compartmental model with the area under the curve (AUC0-∞) being 6.139 mg/L h. Gamma sterilization showed no significant change in the particle size or drug loading of the nanoparticles. Stability analysis revealed long term physiochemical stability of the PLGA-CURC formulation. A successful effort towards formulating, optimizing and scaling up PLGA-CURC by using Solid-Oil/Water emulsion technique was demonstrated. The process used CCD-RSM for optimization and further scaled up to produce 5 g of PLGA-CURC with almost similar physicochemical characteristics as that of the primary formulated batch.

Solid lipid nanoparticles as vesicles for oral delivery of olmesartan medoxomil: formulation, optimization and in vivo evaluation.

PubMed

Nooli, Mounika; Chella, Naveen; Kulhari, Hitesh; Shastri, Nalini R; Sistla, Ramakrishna

2017-04-01

Olmesartan medoxomil (OLM) is an antihypertensive drug with low oral bioavailability (28%) resulting from poor aqueous solubility, presystemic metabolism and P-glycoprotein mediated efflux. The present investigation studies the role of lipid nanocarriers in enhancing the OLM bioavailability through oral delivery. Solid lipid nanoparticles (SLN) were prepared by solvent emulsion-evaporation method. Statistical tools like regression analysis and Pareto charts were used to detect the important factors effecting the formulations. Formulation and process parameters were then optimized using mean effect plot and contour plots. The formulations were characterized for particle size, size distribution, surface charge, percentage of drug entrapped in nanoparticles, drug-excipients interactions, powder X-ray diffraction analysis and drug release in vitro. The optimized formulation comprised glyceryl monostearate, soya phosphatidylcholine and Tween 80 as lipid, co-emulsifier and surfactant, respectively, with an average particle size of 100 nm, PDI 0.291, zeta potential of -23.4 mV and 78% entrapment efficiency. Pharmacokinetic evaluation in male Sprague Dawley rats revealed 2.32-fold enhancement in relative bioavailability of drug from SLN when compared to that of OLM plain drug on oral administration. In conclusion, SLN show promising approaches as a vehicle for oral delivery of drugs like OLM.

Pharmacokinetics of IDX184, a liver-targeted oral prodrug of 2'-methylguanosine-5'-monophosphate, in the monkey and formulation optimization for human exposure.

PubMed

Pan-Zhou, Xin-Ru; Mayes, Benjamin A; Rashidzadeh, Hassan; Gasparac, Rahela; Smith, Steven; Bhadresa, Sanjeev; Gupta, Kusum; Cohen, Marita Larsson; Bu, Charlie; Good, Steven S; Moussa, Adel; Rush, Roger

2016-10-01

IDX184 is a phosphoramidate prodrug of 2'-methylguanosine-5'-monophosphate, developed to treat patients infected with hepatitis C virus. A mass balance study of radiolabeled IDX184 and pharmacokinetic studies of IDX184 in portal vein-cannulated monkeys revealed relatively low IDX184 absorption but higher exposure of IDX184 in the portal vein than in the systemic circulation, indicating >90 % of the absorbed dose was subject to hepatic extraction. Systemic exposures to the main metabolite, 2'-methylguanosine (2'-MeG), were used as a surrogate for liver levels of the pharmacologically active entity 2'-MeG triphosphate, and accordingly, systemic levels of 2'-MeG in the monkey were used to optimize formulations for further clinical development of IDX184. Capsule formulations of IDX184 delivered acceptable levels of 2'-MeG in humans; however, the encapsulation process introduced low levels of the genotoxic impurity ethylene sulfide (ES), which necessitated formulation optimization. Animal pharmacokinetic data guided the development of a tablet with trace levels of ES and pharmacokinetic performance equal to that of the clinical capsule in the monkey. Under fed conditions in humans, the new tablet formulation showed similar exposure to the capsule used in prior clinical trials.

[Optimization of formulations for dietetic pastry products].

PubMed

Villarroel, M; Uquiche, E; Brito, G; Cancino, M

2000-03-01

Optimized formulations of dietetic pastry products such as cake and sponge cake premixes were formulated using the surface response methodology. % Emulsifier agent and baking time were the selected independent variables for cake, as well as % emulsifier agent % chlorinated flour the variables selected for sponge cake. Three different level of each variable summing up thirteen experimental formulae of each product were assessed to optimize the variables that could have some influence in the sensory characteristics of these dietetic products. The total sensory quality was determined for both dietetic products using the composite scoring test and a panel of 18 trained judges. Looking at the contour graphic and considering economic aspects the best combination of variables for cake formulation was 2% emulsifier agent and 48 minutes for baking time, With respect to sponge cake, the best combination was 6% emulsifier agent and 48% chlorinated flour. Shelf life studies showed that both dietetic formulations remained stable during storage conditions of 75 days at 30 degrees C. During this period, significant differences in sensory characteristics were not found (p < 0.05). Data of peroxide values were kept under the critical value reported for detection of organoleptic rancidity. Reported values of hedonic test showed that these dietetics pastry products had good acceptability, and open up marketing opportunities for new products with potential health benefits to consumers.

Network-optimized congestion pricing : a parable, model and algorithm

DOT National Transportation Integrated Search

1995-05-31

This paper recites a parable, formulates a model and devises an algorithm for optimizing tolls on a road network. Such tolls induce an equilibrium traffic flow that is at once system-optimal and user-optimal. The parable introduces the network-wide c...

R&D 100, 2016: Pyomo 4.0 – Python Optimization Modeling Objects

ScienceCinema

Hart, William; Laird, Carl; Siirola, John

2018-06-13

Pyomo provides a rich software environment for formulating and analyzing optimization applications. Pyomo supports the algebraic specification of complex sets of objectives and constraints, which enables optimization solvers to exploit problem structure to efficiently perform optimization.

AN OPTIMAL MAINTENANCE MANAGEMENT MODEL FOR AIRPORT CONCRETE PAVEMENT

NASA Astrophysics Data System (ADS)

Shimomura, Taizo; Fujimori, Yuji; Kaito, Kiyoyuki; Obama, Kengo; Kobayashi, Kiyoshi

In this paper, an optimal management model is formulated for the performance-based rehabilitation/maintenance contract for airport concrete pavement, whereby two types of life cycle cost risks, i.e., ground consolidation risk and concrete depreciation risk, are explicitly considered. The non-homogenous Markov chain model is formulated to represent the deterioration processes of concrete pavement which are conditional upon the ground consolidation processes. The optimal non-homogenous Markov decision model with multiple types of risk is presented to design the optimal rehabilitation/maintenance plans. And the methodology to revise the optimal rehabilitation/maintenance plans based upon the monitoring data by the Bayesian up-to-dating rules. The validity of the methodology presented in this paper is examined based upon the case studies carried out for the H airport.

Maximizing overall liking results in a superior product to minimizing deviations from ideal ratings: an optimization case study with coffee-flavored milk

PubMed Central

Li, Bangde; Hayes, John E.; Ziegler, Gregory R.

2015-01-01

In just-about-right (JAR) scaling and ideal scaling, attribute delta (i.e., “Too Little” or “Too Much”) reflects a subject’s dissatisfaction level for an attribute relative to their hypothetical ideal. Dissatisfaction (attribute delta) is a different construct from consumer acceptability, operationalized as liking. Therefore, we hypothesized minimizing dissatisfaction and maximizing liking would yield different optimal formulations. The objective of this research was to compare product optimization strategies, i.e. maximizing liking vis-à-vis minimizing dissatisfaction. Coffee-flavored dairy beverages (n = 20) were formulated using a fractional mixture design that constrained the proportions of coffee extract, milk, sucrose, and water. Participants (n = 388) were randomly assigned to one of three research conditions, where they evaluated 4 of the 20 samples using an incomplete block design. Samples were rated for overall liking and for intensity of the attributes sweetness, milk flavor, thickness and coffee flavor. Where appropriate, measures of overall product quality (Ideal_Delta and JAR_Delta) were calculated as the sum of the absolute values of the four attribute deltas. Optimal formulations were estimated by: a) maximizing liking; b) minimizing Ideal_Delta; or c) minimizing JAR_Delta. A validation study was conducted to evaluate product optimization models. Participants indicated a preference for a coffee-flavored dairy beverage with more coffee extract and less milk and sucrose in the dissatisfaction model compared to the formula obtained by maximizing liking. That is, when liking was optimized, participants generally liked a weaker, milkier and sweeter coffee-flavored dairy beverage. Predicted liking scores were validated in a subsequent experiment, and the optimal product formulated to maximize liking was significantly preferred to that formulated to minimize dissatisfaction by a paired preference test. These findings are consistent with the view that JAR and ideal scaling methods both suffer from attitudinal biases that are not present when liking is assessed. That is, consumers sincerely believe they want ‘dark, rich, hearty’ coffee when they do not. This paper also demonstrates the utility and efficiency of a lean experimental approach. PMID:26005291

Long-Acting Phospholipid Gel of Exenatide for Long-Term Therapy of Type II Diabetes.

PubMed

Hu, Mei; Zhang, Yu; Xiang, Nanxi; Zhong, Ying; Gong, Tao; Zhang, Zhi-Rong; Fu, Yao

2016-06-01

This study aimed to develop a sustained-release formulation of exenatide (EXT) for the long-term therapeutic efficacy in the treatment of type II diabetes. In this study, we present an injectable phospholipid gel by mixing biocompatible phospholipid S100, medium chain triglyceride (MCT) with 85% (w/w) ethanol. A systemic pre-formulation study has been carried out to improve the stability of EXT during formulation fabrication. With the optimized formulation, the pharmacokinetic profiles in rats were studied and two diabetic animal models were employed to evaluate the therapeutic effect of EXT phospholipid gel via a single subcutaneous injection versus repeated injections of normal saline and EXT solution. With optimized formulation, sustained release of exenatide in vivo for over three consecutive weeks was observed after one single subcutaneous injection. Moreover, the pharmacodynamic study in two diabetic models justified that the gel formulation displayed a comparable hypoglycemic effect and controlled blood glucose level compared with exenatide solution treated group. EXT-loaded phospholipid gel represents a promising controlled release system for long-term therapy of type II diabetes.

Optimization of nanostructured lipid carriers for topical delivery of nimesulide using Box-Behnken design approach.

PubMed

Moghddam, Seyedeh Marziyeh Mahdavi; Ahad, Abdul; Aqil, Mohd; Imam, Syed Sarim; Sultana, Yasmin

2017-05-01

The aim of the present study was to develop and optimize topically applied nimesulide-loaded nanostructured lipid carriers. Box-Behnken experimental design was applied for optimization of nanostructured lipid carriers. The independent variables were ratio of stearic acid: oleic acid (X 1 ), poloxamer 188 concentration (X 2 ) and lecithin concentration (X 3 ) while particle size (Y 1 ) and entrapment efficiency (Y 2 ) were the chosen responses. Further, skin penetration study, in vitro release, confocal laser scanning microscopy and stability study were also performed. The optimized nanostructured lipid carriers of nimesulide provide reasonable particle size, flux, and entrapment efficiency. Optimized formulation (F9) with mean particle size of 214.4 ± 11 nm showed 89.4 ± 3.40% entrapment efficiency and achieved mean flux 2.66 ± 0.09 μg/cm 2 /h. In vitro release study showed prolonged drug release from the optimized formulation following Higuchi release kinetics with R 2 value of 0.984. Confocal laser scanning microscopy revealed an enhanced penetration of Rhodamine B-loaded nanostructured lipid carriers to the deeper layers of the skin. The stability study confirmed that the optimized formulation was considerably stable at refrigerator temperature as compared to room temperature. Our results concluded that nanostructured lipid carriers are an efficient carrier for topical delivery of nimesulide.

Finding optimal vaccination strategies under parameter uncertainty using stochastic programming.

PubMed

Tanner, Matthew W; Sattenspiel, Lisa; Ntaimo, Lewis

2008-10-01

We present a stochastic programming framework for finding the optimal vaccination policy for controlling infectious disease epidemics under parameter uncertainty. Stochastic programming is a popular framework for including the effects of parameter uncertainty in a mathematical optimization model. The problem is initially formulated to find the minimum cost vaccination policy under a chance-constraint. The chance-constraint requires that the probability that R(*)

Evaluating the effects of real power losses in optimal power flow based storage integration

DOE PAGES

Castillo, Anya; Gayme, Dennice

2017-03-27

This study proposes a DC optimal power flow (DCOPF) with losses formulation (the `-DCOPF+S problem) and uses it to investigate the role of real power losses in OPF based grid-scale storage integration. We derive the `- DCOPF+S problem by augmenting a standard DCOPF with storage (DCOPF+S) problem to include quadratic real power loss approximations. This procedure leads to a multi-period nonconvex quadratically constrained quadratic program, which we prove can be solved to optimality using either a semidefinite or second order cone relaxation. Our approach has some important benefits over existing models. It is more computationally tractable than ACOPF with storagemore » (ACOPF+S) formulations and the provably exact convex relaxations guarantee that an optimal solution can be attained for a feasible problem. Adding loss approximations to a DCOPF+S model leads to a more accurate representation of locational marginal prices, which have been shown to be critical to determining optimal storage dispatch and siting in prior ACOPF+S based studies. Case studies demonstrate the improved accuracy of the `-DCOPF+S model over a DCOPF+S model and the computational advantages over an ACOPF+S formulation.« less

Selective Optimization

DTIC Science & Technology

2015-07-06

NUMBER 5b. GRANT NUMBER AFOSR FA9550-12-1-0154 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Shabbir Ahmed and Santanu S. Dey 5d. PROJECT NUMBER 5e. TASK...standard mixed-integer programming (MIP) formulations of selective optimization problems. While such formulations can be attacked by commercial...F33615-86-C-5169. 5b. GRANT NUMBER. Enter all grant numbers as they appear in the report, e.g. AFOSR-82-1234. 5c. PROGRAM ELEMENT NUMBER. Enter

Multitrace/singletrace formulations and Domain Decomposition Methods for the solution of Helmholtz transmission problems for bounded composite scatterers

NASA Astrophysics Data System (ADS)

Jerez-Hanckes, Carlos; Pérez-Arancibia, Carlos; Turc, Catalin

2017-12-01

We present Nyström discretizations of multitrace/singletrace formulations and non-overlapping Domain Decomposition Methods (DDM) for the solution of Helmholtz transmission problems for bounded composite scatterers with piecewise constant material properties. We investigate the performance of DDM with both classical Robin and optimized transmission boundary conditions. The optimized transmission boundary conditions incorporate square root Fourier multiplier approximations of Dirichlet to Neumann operators. While the multitrace/singletrace formulations as well as the DDM that use classical Robin transmission conditions are not particularly well suited for Krylov subspace iterative solutions of high-contrast high-frequency Helmholtz transmission problems, we provide ample numerical evidence that DDM with optimized transmission conditions constitute efficient computational alternatives for these type of applications. In the case of large numbers of subdomains with different material properties, we show that the associated DDM linear system can be efficiently solved via hierarchical Schur complements elimination.

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.

Stacking-sequence optimization for buckling of laminated plates by integer programming

NASA Technical Reports Server (NTRS)

Haftka, Raphael T.; Walsh, Joanne L.

1991-01-01

Integer-programming formulations for the design of symmetric and balanced laminated plates under biaxial compression are presented. Both maximization of buckling load for a given total thickness and the minimization of total thickness subject to a buckling constraint are formulated. The design variables that define the stacking sequence of the laminate are zero-one integers. It is shown that the formulation results in a linear optimization problem that can be solved on readily available software. This is in contrast to the continuous case, where the design variables are the thicknesses of layers with specified ply orientations, and the optimization problem is nonlinear. Constraints on the stacking sequence such as a limit on the number of contiguous plies of the same orientation and limits on in-plane stiffnesses are easily accommodated. Examples are presented for graphite-epoxy plates under uniaxial and biaxial compression using a commercial software package based on the branch-and-bound algorithm.

Energy-modeled flight in a wind field

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

Feldman, M.A.; Cliff, E.M.

Optimal shaping of aerospace trajectories has provided the motivation for much modern study of optimization theory and algorithms. Current industrial practice favors approaches where the continuous-time optimal control problem is transcribed to a finite-dimensional nonlinear programming problem (NLP) by a discretization process. Two such formulations are implemented in the POST and the OTIS codes. In the present paper we use a discretization that is specially adapted to the flight problem of interest. Among the unique aspects of the present discretization are: a least-squares formulation for certain kinematic constraints; the use of an energy ideas to enforce Newton`s Laws; and, themore » inclusion of large magnitude horizontal winds. In the next section we shall provide a description of the flight problem and its NLP representation. Following this we provide some details of the constraint formulation. Finally, we present an overview of the NLP problem.« less

Formulation and evaluation of herbal anti-acne moisturizer.

PubMed

Rasheed, Arun; Shama, Shaik Neelufar; Joy, Jyothi Mulanjananiyil; Reddy, Bobbu Sravya; Roja, Chirra

2012-10-01

The moisture content present in human skin makes it look young and the use of moisturizer results in fastening the moisture with a surface film of oil. Acne vulgaris is one of the most commonly seen diseases among the youth. The present study is focused on the use of herbs as moisturizer for acne treatment. The anti-acne moisturizer was formulated from herbal crude extracts and investigated the physico-chemical parameters as well as antibacterial activity of the formulation. The study revealed that ethanol extract of Andrographis paniculata, Glycyrrhiza glabra, Ocimum sanctum, Azadiracta indica and Green tea possessed the potential for inhibiting acne. It was observed that the optimal formula of anti-acne moisturizer was satisfactorily effective to control acne inducing bacteria i.e., Staphylococcus epidermis and Propionibacterium. The physico-chemical parameters of the formulation were also optimal with no signs of irritation.

Process optimization and photostability of silymarin nanostructured lipid carriers: effect on UV-irradiated rat skin and SK-MEL 2 cell line.

PubMed

Singh, Pooja; Singh, Mahendra; Kanoujia, Jovita; Arya, Malti; Saraf, Shailendra K; Saraf, Shubhini A

2016-10-01

The objective of the present work was to formulate a novel stable delivery system which would not only overcome the solubility issue of silymarin, but also help to increase the therapeutic value by better permeation, anticancer action and reduced toxicity. This was envisaged through the recent developments in nanotechnology, combined with the activity of the phytoconstituent silymarin. A 2(3) full factorial design based on three independent variables was used for process optimization of nanostructured lipid carriers (NLC). Developed formulations were evaluated on the basis of particle size, morphology, in vitro drug release, photostability and cell line studies. Optimized silymarin-NLC was incorporated into carbopol gel and further assessed for rheological parameters. Stable behaviour in presence of light was proven by photostability testing of formulation. Permeability parameters were significantly higher in NLC as compared to marketed phytosome formulation. The NLC based gel described in this study showed faster onset, and prolonged activity up to 24 h and better action against edema as compared to marketed formulation. In case of anticancer activity of silymarin-NLC against SK-MEL 2 cell lines, silymarin-NLC proved to possess anticancer activity in a dose-dependent manner (10-80 μM) and induced apoptosis at 80 μM in SK-MEL 2 cancer cells. This work documents for the first time that silymarin can be formulated into nanostructured lipoidal carrier system for enhanced permeation, greater stability as well as anticancer activity for skin.

Rival framings: A framework for discovering how problem formulation uncertainties shape risk management trade-offs in water resources systems

NASA Astrophysics Data System (ADS)

Quinn, J. D.; Reed, P. M.; Giuliani, M.; Castelletti, A.

2017-08-01

Managing water resources systems requires coordinated operation of system infrastructure to mitigate the impacts of hydrologic extremes while balancing conflicting multisectoral demands. Traditionally, recommended management strategies are derived by optimizing system operations under a single problem framing that is assumed to accurately represent the system objectives, tacitly ignoring the myriad of effects that could arise from simplifications and mathematical assumptions made when formulating the problem. This study illustrates the benefits of a rival framings framework in which analysts instead interrogate multiple competing hypotheses of how complex water management problems should be formulated. Analyzing rival framings helps discover unintended consequences resulting from inherent biases of alternative problem formulations. We illustrate this on the monsoonal Red River basin in Vietnam by optimizing operations of the system's four largest reservoirs under several different multiobjective problem framings. In each rival framing, we specify different quantitative representations of the system's objectives related to hydropower production, agricultural water supply, and flood protection of the capital city of Hanoi. We find that some formulations result in counterintuitive behavior. In particular, policies designed to minimize expected flood damages inadvertently increase the risk of catastrophic flood events in favor of hydropower production, while min-max objectives commonly used in robust optimization provide poor representations of system tradeoffs due to their instability. This study highlights the importance of carefully formulating and evaluating alternative mathematical abstractions of stakeholder objectives describing the multisectoral water demands and risks associated with hydrologic extremes.

A novel pH-sensitive interferon-β (INF-β) oral delivery system for application in multiple sclerosis.

PubMed

Kondiah, Pierre P D; Tomar, Lomas K; Tyagi, Charu; Choonara, Yahya E; Modi, Girish; du Toit, Lisa C; Kumar, Pradeep; Pillay, Viness

2013-11-18

pH-sensitive microparticles were prepared using trimethyl-chitosan (TMC), poly(ethylene glycol)dimethacrylate (PEGDMA) and methacrylic acid (MAA) by free radical suspension polymerization, for the oral delivery of interferon-β (INF-β). The microparticles were subsequently compressed into a suitable oral tablet formulation. A Box-Behnken experimental design was employed for generating a series of formulations with varying concentrations of TMC (0.05-0.5 g/100 mL) and percentage crosslinker (polyethylene glycol diacrylate) (3-8%, w/w of monomers), for establishment of an optimized TMC-PEGDMA-MAA copolymeric microparticles. For pragmatism, insulin was initially employed as the model peptide for undertaking the preliminary experimentation and the optimized formulation was subsequently evaluated using INF-β. The prepared copolymeric microparticulate system was characterized for its morphological, porositometric and mucoadhesive properties. The optimized microparticles with 0.5 g/100 mL TMC and 3% crosslinker had an INF-β loading efficiency of 53.25%. The in vitro release of INF-β was recorded at 74% and 3% in intestinal (pH 6.8) and gastric (pH 1.2) pH from the oral tablet formulation, respectively. The tablet was further evaluated for plasma concentration of INF-β in the New Zealand White rabbit, and compared to a known subcutaneous formulation. The system showed an astounding effective release profile over 24h with higher INF-β plasma concentrations compared with the subcutaneous injection formulation. Copyright © 2013 Elsevier B.V. All rights reserved.

Vitamin B12-Loaded Buccoadhesive Films as a Noninvasive Supplement in Vitamin B12 Deficiency: In Vitro Evaluation and In Vivo Comparative Study With Intramuscular Injection.

PubMed

Mohamad, Soad A; Sarhan, Hatem A; Abdelkader, Hamdy; Mansour, Heba F

2017-07-01

This study aimed to formulate and evaluate vitamin B12-loaded buccal mucoadhesive hydrogel films. Various film formulations were prepared using chitosan and polyvinyl alcohol. The prepared films were characterized for thickness, weight variation, drug content, percentage moisture uptake and moisture content, surface pH, mechanical properties, in vitro release, and mucoadhesion. Vitamin B12 bioavailability from the optimized formulation was studied on rabbits by the aid of enzyme-linked immunosorbent assay. Neuroton ® I.M. injection was used for comparison. The films had acceptable mechanical and mucoadhesion properties. The percentages of moisture content of the optimized formulation were 3.2 ± 0.95, whereas the percentage drug released was 98.59 ± 1.41% at the end of 40 min. FTIR revealed the incidence of drug/polymer interaction. Differential scanning calorimetry revealed the possibility of the dispersion of cyanocobalamin in a molecular state with complete amorphization in the polymers. The estimated AUC 0-8h showed 1.5-fold increases in the bioavailability of cyanocobalamin from the optimized formulation compared with the marketed I.M. injection. These findings warrant that vitamin B12 buccal film formulation can be considered as an effective alternative portal with noninvasive and more convenient characteristics compared with the I.M. injection dosage form. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Affordable Window Insulation with R-10/inch Rating

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

Jenifer Marchesi Redouane Begag; Je Kyun Lee; Danny Ou

2004-10-15

During the performance of contract DE-FC26-00-NT40998, entitled ''Affordable Window Insulation with R-10/inch Value'', research was conducted at Aspen Aerogels, Inc. to develop new transparent aerogel materials suitable for window insulation applications. The project requirements were to develop a formulation or multiple formulations that have high transparency (85-90%) in the visible region, are hydrophobic (will not opacify with exposure to water vapor or liquid), and have at least 2% resiliency (interpreted as recoverable 2% strain and better than 5% strain to failure in compression). Results from an unrelated project showed that silica aerogels covalently bonded to organic polymers exhibit excellent mechanicalmore » properties. At the outset of this project, we believed that such a route is the best to improve mechanical properties. We have applied Design of Experiment (DOE) techniques to optimize formulations including both silica aerogels and organically modified silica aerogels (''Ormosils''). We used these DOE results to optimize formulations around the local/global optimization points. This report documents that we succeeded in developing a number of formulations that meet all of the stated criteria. We successfully developed formulations utilizing a two-step approach where the first step involves acid catalyzed hydrolysis and the second step involves base catalyzed condensation to make the gels. The gels were dried using supercritical CO{sub 2} and we were able to make 1 foot x 1 foot x 0.5 inch panels that met the criteria established.« less

Mixture experiment methods in the development and optimization of microemulsion formulations.

PubMed

Furlanetto, S; Cirri, M; Piepel, G; Mennini, N; Mura, P

2011-06-25

Microemulsion formulations represent an interesting delivery vehicle for lipophilic drugs, allowing for improving their solubility and dissolution properties. This work developed effective microemulsion formulations using glyburide (a very poorly-water-soluble hypoglycaemic agent) as a model drug. First, the area of stable microemulsion (ME) formations was identified using a new approach based on mixture experiment methods. A 13-run mixture design was carried out in an experimental region defined by constraints on three components: aqueous, oil and surfactant/cosurfactant. The transmittance percentage (at 550 nm) of ME formulations (indicative of their transparency and thus of their stability) was chosen as the response variable. The results obtained using the mixture experiment approach corresponded well with those obtained using the traditional approach based on pseudo-ternary phase diagrams. However, the mixture experiment approach required far less experimental effort than the traditional approach. A subsequent 13-run mixture experiment, in the region of stable MEs, was then performed to identify the optimal formulation (i.e., having the best glyburide dissolution properties). Percent drug dissolved and dissolution efficiency were selected as the responses to be maximized. The ME formulation optimized via the mixture experiment approach consisted of 78% surfactant/cosurfacant (a mixture of Tween 20 and Transcutol, 1:1, v/v), 5% oil (Labrafac Hydro) and 17% aqueous phase (water). The stable region of MEs was identified using mixture experiment methods for the first time. Copyright © 2011 Elsevier B.V. All rights reserved.

Application of Pharmacokinetic and Pharmacodynamic Analysis to the Development of Liposomal Formulations for Oncology

PubMed Central

Ait-Oudhia, Sihem; Mager, Donald E.; Straubinger, Robert M.

2014-01-01

Liposomal formulations of anticancer agents have been developed to prolong drug circulating lifetime, enhance anti-tumor efficacy by increasing tumor drug deposition, and reduce drug toxicity by avoiding critical normal tissues. Despite the clinical approval of numerous liposome-based chemotherapeutics, challenges remain in the development and clinical deployment of micro- and nano-particulate formulations, as well as combining these novel agents with conventional drugs and standard-of-care therapies. Factors requiring optimization include control of drug biodistribution, release rates of the encapsulated drug, and uptake by target cells. Quantitative mathematical modeling of formulation performance can provide an important tool for understanding drug transport, uptake, and disposition processes, as well as their role in therapeutic outcomes. This review identifies several relevant pharmacokinetic/pharmacodynamic models that incorporate key physical, biochemical, and physiological processes involved in delivery of oncology drugs by liposomal formulations. They capture observed data, lend insight into factors determining overall antitumor response, and in some cases, predict conditions for optimizing chemotherapy combinations that include nanoparticulate drug carriers. PMID:24647104

Conceptual design and multidisciplinary optimization of in-plane morphing wing structures

NASA Astrophysics Data System (ADS)

Inoyama, Daisaku; Sanders, Brian P.; Joo, James J.

2006-03-01

In this paper, the topology optimization methodology for the synthesis of distributed actuation system with specific applications to the morphing air vehicle is discussed. The main emphasis is placed on the topology optimization problem formulations and the development of computational modeling concepts. For demonstration purposes, the inplane morphing wing model is presented. The analysis model is developed to meet several important criteria: It must allow large rigid-body displacements, as well as variation in planform area, with minimum strain on structural members while retaining acceptable numerical stability for finite element analysis. Preliminary work has indicated that addressed modeling concept meets the criteria and may be suitable for the purpose. Topology optimization is performed on the ground structure based on this modeling concept with design variables that control the system configuration. In other words, states of each element in the model are design variables and they are to be determined through optimization process. In effect, the optimization process assigns morphing members as 'soft' elements, non-morphing load-bearing members as 'stiff' elements, and non-existent members as 'voids.' In addition, the optimization process determines the location and relative force intensities of distributed actuators, which is represented computationally as equal and opposite nodal forces with soft axial stiffness. Several different optimization problem formulations are investigated to understand their potential benefits in solution quality, as well as meaningfulness of formulation itself. Sample in-plane morphing problems are solved to demonstrate the potential capability of the methodology introduced in this paper.

Solid-perforated panel layout optimization by topology optimization based on unified transfer matrix.

PubMed

Kim, Yoon Jae; Kim, Yoon Young

2010-10-01

This paper presents a numerical method for the optimization of the sequencing of solid panels, perforated panels and air gaps and their respective thickness for maximizing sound transmission loss and/or absorption. For the optimization, a method based on the topology optimization formulation is proposed. It is difficult to employ only the commonly-used material interpolation technique because the involved layers exhibit fundamentally different acoustic behavior. Thus, an optimization method formulation using a so-called unified transfer matrix is newly proposed. The key idea is to form elements of the transfer matrix such that interpolated elements by the layer design variables can be those of air, perforated and solid panel layers. The problem related to the interpolation is addressed and bench mark-type problems such as sound transmission or absorption maximization problems are solved to check the efficiency of the developed method.

Optimization of methazolamide-loaded solid lipid nanoparticles for ophthalmic delivery using Box-Behnken design.

PubMed

Wang, Fengzhen; Chen, Li; Jiang, Sunmin; He, Jun; Zhang, Xiumei; Peng, Jin; Xu, Qunwei; Li, Rui

2014-09-01

The purpose of the present study was to optimize methazolamide (MTZ)-loaded solid lipid nanoparticles (SLNs) which were used as topical eye drops by evaluating the relationship between design factors and experimental data. A three factor, three-level Box-Behnken design (BBD) was used for the optimization procedure, choosing the amount of GMS, the amount of phospholipid, the concentration of surfactant as the independent variables. The chosen dependent variables were entrapment efficiency, dosage loading, and particle size. The generated polynomial equations and response surface plots were used to relate the dependent and independent variables. The optimal nanoparticles were formulated with 100 mg GMS, 150 mg phospholipid, and 1% Tween80 and PEG 400 (1:1, w/v). A new formulation was prepared according to these levels. The observed responses were close to the predicted values of the optimized formulation. The particle size was 197.8 ± 4.9 nm. The polydispersity index of particle size was 0.239 ± 0.01 and the zeta potential was 32.7 ± 2.6 mV. The entrapment efficiency and dosage loading were about 68.39% and 2.49%, respectively. Fourier transform infrared spectroscopy (FT-IR) study indicated that the drug was entrapped in nanoparticles. The optimized formulation showed a sustained release followed the Peppas model. MTZ-SLNs showed significant prolonged decreasing intraocular pressure effect comparing with MTZ solution in vivo pharmacodynamics studies. The results of acute eye irritation study indicated that MTZ-SLNs and AZOPT both had no eye irritation. Furthermore, the MTZ-SLNs were suitable to be stored at low temperature (4 °C).

Implications of Preference and Problem Formulation on the Operating Policies of Complex Multi-Reservoir Systems

NASA Astrophysics Data System (ADS)

Quinn, J.; Reed, P. M.; Giuliani, M.; Castelletti, A.

2016-12-01

Optimizing the operations of multi-reservoir systems poses several challenges: 1) the high dimension of the problem's states and controls, 2) the need to balance conflicting multi-sector objectives, and 3) understanding how uncertainties impact system performance. These difficulties motivated the development of the Evolutionary Multi-Objective Direct Policy Search (EMODPS) framework, in which multi-reservoir operating policies are parameterized in a given family of functions and then optimized for multiple objectives through simulation over a set of stochastic inputs. However, properly framing these objectives remains a severe challenge and a neglected source of uncertainty. Here, we use EMODPS to optimize operating policies for a 4-reservoir system in the Red River Basin in Vietnam, exploring the consequences of optimizing to different sets of objectives related to 1) hydropower production, 2) meeting multi-sector water demands, and 3) providing flood protection to the capital city of Hanoi. We show how coordinated operation of the reservoirs can differ markedly depending on how decision makers weigh these concerns. Moreover, we illustrate how formulation choices that emphasize the mean, tail, or variability of performance across objective combinations must be evaluated carefully. Our results show that these choices can significantly improve attainable system performance, or yield severe unintended consequences. Finally, we show that satisfactory validation of the operating policies on a set of out-of-sample stochastic inputs depends as much or more on the formulation of the objectives as on effective optimization of the policies. These observations highlight the importance of carefully considering how we abstract stakeholders' objectives and of iteratively optimizing and visualizing multiple problem formulation hypotheses to ensure that we capture the most important tradeoffs that emerge from different stakeholder preferences.

Optimizing the taste-masked formulation of acetaminophen using sodium caseinate and lecithin by experimental design.

PubMed

Hoang Thi, Thanh Huong; Lemdani, Mohamed; Flament, Marie-Pierre

2013-09-10

In a previous study of ours, the association of sodium caseinate and lecithin was demonstrated to be promising for masking the bitterness of acetaminophen via drug encapsulation. The encapsulating mechanisms were suggested to be based on the segregation of multicomponent droplets occurring during spray-drying. The spray-dried particles delayed the drug release within the mouth during the early time upon administration and hence masked the bitterness. Indeed, taste-masking is achieved if, within the frame of 1-2 min, drug substance is either not released or the released amount is below the human threshold for identifying its bad taste. The aim of this work was (i) to evaluate the effect of various processing and formulation parameters on the taste-masking efficiency and (ii) to determine the optimal formulation for optimal taste-masking effect. Four investigated input variables included inlet temperature (X1), spray flow (X2), sodium caseinate amount (X3) and lecithin amount (X4). The percentage of drug release amount during the first 2 min was considered as the response variable (Y). A 2(4)-full factorial design was applied and allowed screening for the most influential variables i.e. sodium caseinate amount and lecithin amount. Optimizing these two variables was therefore conducted by a simplex approach. The SEM and DSC results of spray-dried powder prepared under optimal conditions showed that drug seemed to be well encapsulated. The drug release during the first 2 min significantly decreased, 7-fold less than the unmasked drug particles. Therefore, the optimal formulation that performed the best taste-masking effect was successfully achieved. Copyright © 2013 Elsevier B.V. All rights reserved.

Melt-in-Mouth Multi-particulate System for the Treatment of ADHD: A Convenient Platform for Pediatric Use.

PubMed

Patadia, Jalashri; Tripathi, Rahul; Joshi, Amita

2016-08-01

Generally, pellets obtained from extrusion/spheronization, containing microcrystalline cellulose (MCC), do not disintegrate. An attempt has been made to develop melt-in-mouth pellets of taste-masked atomoxetine hydrochloride, using extrusion-spheronization, for pediatric patients. Melt-in-mouth pellets were prepared using extrusion-spheronization method and optimized using 3(3) FFD. MCC (X1, %), mannitol (X2, %) and Indion 414: Pharmaburst 500 ratio (X3, ratio) were the factors (independent variables) studied, whereas responses studied (dependent variables) were friability (Y1, %), yield (Y2, %) shape (Y3, roundness) in vitro disintegration time (Y4, seconds). The optimized formulation obtained from FFD was characterized for friability, shape and morphology, in vitro disintegration time, porosity, moisture uptake, in vitro release study and in vivo taste and disintegration time in healthy human volunteers. Randomized, two-treatment, two-sequence, two-period, single dose, crossover sensory evaluation study of taste-masked melt-in-mouth pellet was carried out in 10 healthy human subjects. A statistically significant polynomial mathematical relationship was generated between the factors and responses to obtain an optimized formulation. The optimized formulation was characterized (in vitro and in vivo) and exhibited a rapid drug release in vitro attributed to fast disintegration of pellets and high solubility of drug in 0.1 N HCl and buffer (pH 6.8). In vivo, 40% of volunteers ranked taste-masked optimized formulation as slightly bitter while 60% ranked it as no taste. The optimized pellets were conveniently administered in volunteers and exhibited rapid in-vivo disintegration in the oral cavity. Melt-in-mouth pellets can be a used as a platform technology for administering drugs to paediatric patients accurately and conveniently resulting in patient compliance.

Physicochemical and microstructural properties of a novel edible film synthesized from Balangu seed mucilage.

PubMed

Sadeghi-Varkani, Atina; Emam-Djomeh, Zahra; Askari, Gholamreza

2018-03-01

This paper reports the synthesis of a novel edible film from Balangu seed mucilage (BSM) as a new carbohydrate source. Optimal formulation of the proposed edible film was found through fabricating several distinct films with different concentrations of BSM and glycerol. The effect of these formulation variables on the physical, mechanical, thermal, barrier, and microstructural properties of the manufactured films was then investigated. Optimal formulation of the BSM edible film was then determined based on the measured mechanical and barrier characteristics. These characteristics were found to deteriorate with an excessive use of glycerol which caused non-homogeneity of the films as observed through scanning electron micrographs. In-depth analysis of the optimal BSM film properties was performed through investigating its oxygen permeability, Fourier transform infrared spectroscopy, atomic force microscopy, X-ray diffraction, and water sorption isotherm. The superior mechanical and barrier characteristics of the obtained optimal BSM edible film make it a potential candidate for packaging that aim at an extended shelf-life. Copyright © 2017 Elsevier B.V. All rights reserved.

A novel concept of overcoming the skin barrier using augmented liquid nanocrystals: Box-Behnken optimization, ex vivo and in vivo evaluation.

PubMed

Said, Mayada; Elsayed, Ibrahim; Aboelwafa, Ahmed A; Elshafeey, Ahmed H

2018-06-18

Agomelatine suffers from extensive inactivation through 1 st pass effect with a limited oral bioavailability (5%). The aim of this study was to formulate and optimize liquid nanocrystals (LNC) containing agomelatine to enhance the transdermal permeation of the drug. The independent factors of the employed Box-Behnken design were the Pluronic F127, deoxycholic acid sodium salt and propylene glycol percentages. On the other hand, particle size, polydispersity index, zeta potential, entrapment efficiency, cumulative amount permeated at certain time intervals and permeation enhancement ratio were considered as dependent responses. The optimized formulation was composed of 1.5% Pluronic F127 and 1.5% deoxycholic acid sodium salt and it was found to have significantly higher AUC 0-24h , AUC 0-∞ and elimination t 1/2 than that of the employed reference indicating the enhancement of the drug permeation. The obtained findings indicated the ability of the optimized LNC formulation to improve the drug bioavailability after its transdermal application. Copyright © 2018 Elsevier B.V. All rights reserved.

Substitution of modified starch with hydrogen peroxide-modified rice bran in salad dressing formulation: physicochemical, texture, rheological and sensory properties.

PubMed

Maani, Bahareh; Alimi, Mazdak; Shokoohi, Shirin; Fazeli, Fatemeh

2017-06-01

Rice bran samples were treated under different conditions including hydrogen peroxide content (1, 4, and 7 wt%) and media pH (10.5, 11.5, and 12.5). Water holding capacity and color measurement results showed acceptable improvements compared with the untreated native bran confirmed by Fourier transform infrared analysis. Optimization of modification conditions upon characterization results suggested the introduction of 7% hydrogen peroxide at pH = 12.5. Accordingly, 1, 2 and 3 wt% of the rice bran treated under the optimized conditions, was used in salad dressing formulation; as for .3 wt% of modified starch in the formulation of blank sample, 1 wt% of treated rice bran dietary fiber was substituted. Biopolymer swelling and formation of a stable viscous gel network promoted by the chemical treatment of lignocellulosic rice bran restrict the mobility of oil droplets dispersed in the continuous phase which would consequently retard the emulsion instability phenomena. This effect was also confirmed by flow behavior and viscoelastic characterization results. Salad dressing samples containing 1 and 2 wt% treated rice bran showed acceptable physicochemical, rheological and organoleptic properties besides superior nutritional characteristics compared with the commercial modified starch traditionally used in salad dressing formulations. Despite recommended consumption of dietary fibers, addition of unprocessed lignocellulosic materials to food products usually raise negative effects in sensory, color, and texture quality. This study investigates the modification of rice bran, the byproduct of brown rice milling, to substitute modified starch traditionally used in salad dressing formulations to achieve optimum properties desirable for the final product. Optimization of modification conditions upon characterization of the formulated samples in this study would suggest new improved formulation for the commercial product. © 2016 Wiley Periodicals, Inc.

A novel ropivacaine-loaded in situ forming implant prolongs the effect of local analgesia in rats

PubMed Central

Lu, Lei; Zhang, Wei; Wu, Xin; Wang, Xiaoyu; Zhang, Min; Zhu, Quangang; Ding, Xueying; Xu, Zhiyun

2012-01-01

Introduction Prolonged postoperative analgesia cannot be achieved by a single injection of local anesthetic solution. The objective of this study was to optimize the formulation of a ropivacaine hydrochloride (Ropi-HCl) loaded in situ forming implant (ISI) by addition of different co-solvents, and evaluate the in vitro release of Ropi-HCl, and the analgesic effect and toxicity of the optimized formulation in rats. Material and methods Triacetin (TA), benzyl benzoate (BB) and polyethylene glycol 400 (PEG 400) were used as additives and added to the solvent of N-methyl-2-pyrrolidone (NMP). Drug release to the surface and inner structural properties of the formed implant were evaluated by scanning electron microscopy (SEM). The analgesic effect was determined by injection near the rat sciatic nerve. Results The solvent system added with TA or BB significantly decreased the burst release, whereas PEG 400 increased the Ropi-HCl burst release from the formulation. Over 70% of the incorporated Ropi-HCl was released from all formulations in 14 days in the in vitro assay. The SEM showed that the surface of NMP-BB formulation was less porous and more homogeneous, compared with the other formulations. Compared with Ropi-HCl injection, the optimized formulation (NMP-BB) significantly prolonged the analgesic effect in 48 h (p < 0.05), with a mild degree of motor block from 3 h to 12 h. Histological evaluation of the injection site revealed only mild inflammatory infiltration without obvious pathological nerve alterations. Conclusions The biodegradable Ropi-HCl-loaded ISI system with NMP-BB may prove to be an attractive and safe alternative for the delivery of parenteral local anesthetics to prolong pain relief. PMID:24049519

Pharmaceutical applications of cyclodextrins: effects on drug permeation through biological membranes.

PubMed

Loftsson, Thorsteinn; Brewster, Marcus E

2011-09-01

Cyclodextrins are useful solubilizing excipients that have gained currency in the formulator's armamentarium based on their ability to temporarily camouflage undesirable physicochemical properties. In this context cyclodextrins can increase oral bioavailability, stabilize compounds to chemical and enzymatic degradation and can affect permeability through biological membranes under certain circumstances. This latter property is examined herein as a function of the published literature as well as work completed in our laboratories.   Cyclodextrins can increase the uptake of drugs through biological barriers if the limiting barrier component is the unstirred water layer (UWL) that exists between the membrane and bulk water. This means that cyclodextrins are most useful when they interact with lipophiles in systems where such an UWL is present and contributes significantly to the barrier properties of the membrane. Furthermore, these principles are used to direct the optimal formulation of drugs in cyclodextrins. A second related critical success factor in the formulation of cyclodextrin-based drug product is an understanding of the kinetics and thermodynamics of complexation and the need to optimize the cyclodextrin amount and drug-to-cyclodextrin ratios. Drug formulations, especially those targeting compartments associated with limited dissolution (i.e. the eye, subcutaneous space, etc.), should be carefully designed such that the thermodynamic activity of the drug in the formulation is optimal meaning that there is sufficient cyclodextrin to solubilize the drug but not more than that. Increasing the cyclodextrin concentration decreases the formulation 'push' and may reduce the bioavailability of the system. A mechanism-based understanding of cyclodextrin complexation is essential for the appropriate formulation of contemporary drug candidates. © 2011 The Authors. JPP © 2011 Royal Pharmaceutical Society.

Optimization and formulation design of gels of Diclofenac and Curcumin for transdermal drug delivery by Box-Behnken statistical design.

PubMed

Chaudhary, Hema; Kohli, Kanchan; Amin, Saima; Rathee, Permender; Kumar, Vikash

2011-02-01

The aim of this study was to develop and optimize a transdermal gel formulation for Diclofenac diethylamine (DDEA) and Curcumin (CRM). A 3-factor, 3-level Box-Behnken design was used to derive a second-order polynomial equation to construct contour plots for prediction of responses. Independent variables studied were the polymer concentration (X(1)), ethanol (X(2)) and propylene glycol (X(3)) and the levels of each factor were low, medium, and high. The dependent variables studied were the skin permeation rate of DDEA (Y(1)), skin permeation rate of CRM (Y(2)), and viscosity of the gels (Y(3)). Response surface plots were drawn, statistical validity of the polynomials was established to find the compositions of optimized formulation which was evaluated using the Franz-type diffusion cell. The permeation rate of DDEA increased proportionally with ethanol concentration but decreased with polymer concentration, whereas the permeation rate of CRM increased proportionally with polymer concentration. Gels showed a non-Fickian super case II (typical zero order) and non-Fickian diffusion release mechanism for DDEA and CRM, respectively. The design demonstrated the role of the derived polynomial equation and contour plots in predicting the values of dependent variables for the preparation and optimization of gel formulation for transdermal drug release. Copyright © 2010 Wiley-Liss, Inc.

Solid dispersions in the development of a nimodipine floating tablet formulation and optimization by artificial neural networks and genetic programming.

PubMed

Barmpalexis, Panagiotis; Kachrimanis, Kyriakos; Georgarakis, Emanouil

2011-01-01

The present study investigates the use of nimodipine-polyethylene glycol solid dispersions for the development of effervescent controlled release floating tablet formulations. The physical state of the dispersed nimodipine in the polymer matrix was characterized by differential scanning calorimetry, powder X-ray diffraction, FT-IR spectroscopy and polarized light microscopy, and the mixture proportions of polyethylene glycol (PEG), polyvinyl-pyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC), effervescent agents (EFF) and nimodipine were optimized in relation to drug release (% release at 60 min, and time at which the 90% of the drug was dissolved) and floating properties (tablet's floating strength and duration), employing a 25-run D-optimal mixture design combined with artificial neural networks (ANNs) and genetic programming (GP). It was found that nimodipine exists as mod I microcrystals in the solid dispersions and is stable for at least a three-month period. The tablets showed good floating properties and controlled release profiles, with drug release proceeding via the concomitant operation of swelling and erosion of the polymer matrix. ANNs and GP both proved to be efficient tools in the optimization of the tablet formulation, and the global optimum formulation suggested by the GP equations consisted of PEG=9%, PVP=30%, HPMC=36%, EFF=11%, nimodipine=14%. Copyright © 2010 Elsevier B.V. All rights reserved.

Formulation Development and Evaluation of Fast Disintegrating Tablets of Salbutamol Sulphate, Cetirizine Hydrochloride in Combined Pharmaceutical Dosage Form: A New Era in Novel Drug Delivery for Pediatrics and Geriatrics

PubMed Central

Sharma, Deepak; Singh, Gurmeet; Kumar, Dinesh; Singh, Mankaran

2015-01-01

The objective of the present study was to prepare the fast disintegrating tablet of Salbutamol Sulphate, Cetirizine Hydrochloride in combined tablet dosage form for respiratory disorders such as bronchitis, asthma, and coughing for pediatrics and geriatrics. The tablets were prepared by direct compression technique. Superdisintegrant such as Sodium Starch Glycolate was optimized as 4% on the basis of least disintegration time. Different binders such as MCC and PVP K-30 were optimized along with optimized superdisintegrant concentration. 1% MCC was selected as optimum binder concentration on the basis of least disintegration time. The tablets were evaluated for hardness, friability, weight variation, wetting time, disintegration time, and drug content uniformity. Optimized formulation was further evaluated by in vitro dissolution test, drug-excipient compatibility, and accelerated stability study. Percent weight variation and content uniformity were within the acceptable limit. The friability was less than 1%. The wetting time and disintegration time were practically good for all formulations. FTIR studies and accelerated stability study showed that there was no interaction between the drug and excipients. It was concluded that, by employing commonly available pharmaceutical excipients such as superdisintegrants, hydrophilic and swellable excipients and proper filler, a fast disintegrating tablet of Salbutamol Sulphate, Cetirizine Hydrochloride in combined tablet dosage form, were formulated successfully with desired characteristics. PMID:25810924

Risk based approach for design and optimization of stomach specific delivery of rifampicin.

PubMed

Vora, Chintan; Patadia, Riddhish; Mittal, Karan; Mashru, Rajashree

2013-10-15

The research envisaged focuses on risk management approach for better recognizing the risks, ways to mitigate them and propose a control strategy for the development of rifampicin gastroretentive tablets. Risk assessment using failure mode and effects analysis (FMEA) was done to depict the effects of specific failure modes related to respective formulation/process variable. A Box-Behnken design was used to investigate the effect of amount of sodium bicarbonate (X1), pore former HPMC (X2) and glyceryl behenate (X3) on percent drug release at 1st hour (Q1), 4th hour (Q4), 8th hour (Q8) and floating lag time (min). Main effects and interaction plots were generated to study effects of variables. Selection of the optimized formulation was done using desirability function and overlay contour plots. The optimized formulation exhibited Q1 of 20.9%, Q4 of 59.1%, Q8 of 94.8% and floating lag time of 4.0 min. Akaike information criteria and Model selection criteria revealed that the model was best described by Korsmeyer-Peppas power law. The residual plots demonstrated no existence of non-normality, skewness or outliers. The composite desirability for optimized formulation computed using equations and software were 0.84 and 0.86 respectively. FTIR, DSC and PXRD studies ruled out drug polymer interaction due to thermal treatment. Copyright © 2013 Elsevier B.V. All rights reserved.

In vitro anticancer evaluation of 5-fluorouracil lipid nanoparticles using B16F10 melanoma cell lines

NASA Astrophysics Data System (ADS)

Shenoy, Vikram S.; Gude, Rajiv P.; Murthy, Rayasa S. Ramachandra

2013-05-01

The present study is aimed to investigate the formulation and in vitro anticancer activities of solid lipid nanoparticles (SLNs) of 5-fluorouracil (5-FU) prepared using glyceryl monostearate (GMS) and cetyl palmitate (CP) by hot homogenization method. The lipids were selected based on the partition coefficient of 5-FU in lipids. The lipid nanoparticles were optimized for process and formulation parameters. The optimized nanoparticles were characterized for their zeta potential, morphology, release kinetics, and anticancer activity. Higher entrapments were achieved using a combination of emulsifiers. The zeta potential of the optimized CP and GMS SLN formulation were -8.26 and -9.35 mV, respectively. Both the optimized formulations were spherical. The in vitro release studies of SLNs of both the lipid carriers followed Peppas-Korsenmeyer equation when carried out at pH 3.5 and 7.4. The chemosensitivity assay carried out in B16F10 cell lines revealed that CP SLNs had better cytotoxicity than 5-FU solution and GMS SLNs at 48 h of incubation. Subtoxic concentration of 5-FU-loaded CP SLNs (0.12 μg/mL) possessed comparable antimigrational activity, colony inhibition activity, and cytopathic as that of 5-FU solution effects. The results indicated that encapsulating 5-FU in CP would be a promising delivery system for delivering 5-FU.

Design and Optimization of Floating Drug Delivery System of Acyclovir

PubMed Central

Kharia, A. A.; Hiremath, S. N.; Singhai, A. K.; Omray, L. K.; Jain, S. K.

2010-01-01

The purpose of the present work was to design and optimize floating drug delivery systems of acyclovir using psyllium husk and hydroxypropylmethylcellulose K4M as the polymers and sodium bicarbonate as a gas generating agent. The tablets were prepared by wet granulation method. A 32 full factorial design was used for optimization of drug release profile. The amount of psyllium husk (X1) and hydroxypropylmethylcellulose K4M (X2) were selected as independent variables. The times required for 50% (t50%) and 70% (t70%) drug dissolution were selected as dependent variables. All the designed nine batches of formulations were evaluated for hardness, friability, weight variation, drug content uniformity, swelling index, in vitro buoyancy, and in vitro drug release profile. All formulations had floating lag time below 3 min and constantly floated on dissolution medium for more than 24 h. Validity of the developed polynomial equation was verified by designing two check point formulations (C1 and C2). The closeness of predicted and observed values for t50% and t70% indicates validity of derived equations for the dependent variables. These studies indicated that the proper balance between psyllium husk and hydroxypropylmethylcellulose K4M can produce a drug dissolution profile similar to the predicted dissolution profile. The optimized formulations followed Higuchi's kinetics while the drug release mechanism was found to be anomalous type, controlled by diffusion through the swollen matrix. PMID:21694992

Design and optimization of floating drug delivery system of acyclovir.

PubMed

Kharia, A A; Hiremath, S N; Singhai, A K; Omray, L K; Jain, S K

2010-09-01

The purpose of the present work was to design and optimize floating drug delivery systems of acyclovir using psyllium husk and hydroxypropylmethylcellulose K4M as the polymers and sodium bicarbonate as a gas generating agent. The tablets were prepared by wet granulation method. A 3(2) full factorial design was used for optimization of drug release profile. The amount of psyllium husk (X1) and hydroxypropylmethylcellulose K4M (X2) were selected as independent variables. The times required for 50% (t(50%)) and 70% (t(70%)) drug dissolution were selected as dependent variables. All the designed nine batches of formulations were evaluated for hardness, friability, weight variation, drug content uniformity, swelling index, in vitro buoyancy, and in vitro drug release profile. All formulations had floating lag time below 3 min and constantly floated on dissolution medium for more than 24 h. Validity of the developed polynomial equation was verified by designing two check point formulations (C1 and C2). The closeness of predicted and observed values for t(50%) and t(70%) indicates validity of derived equations for the dependent variables. These studies indicated that the proper balance between psyllium husk and hydroxypropylmethylcellulose K4M can produce a drug dissolution profile similar to the predicted dissolution profile. The optimized formulations followed Higuchi's kinetics while the drug release mechanism was found to be anomalous type, controlled by diffusion through the swollen matrix.

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.

Bioavailability enhancement of baclofen by gastroretentive floating formulation: statistical optimization, in vitro and in vivo pharmacokinetic studies.

PubMed

Thakar, Krishna; Joshi, Garima; Sawant, Krutika K

2013-06-01

The study was aimed to improve bioavailability of baclofen by developing gastroretentive floating drug delivery system (GFDDS). Preliminary optimization was done to select various release retardants to obtain minimum floating lag time, maximum floating duration and sustained release. Optimization by 3(2) factorial design was done using Polyox WSR 303 (X1) and HPMC K4M (X2) as independent variables and cumulative percentage drug released at 6 h (Q6h) as dependent variable. Optimized formulation showed floating lag time of 4-5 s, floated for more than 12 h and released the drug in sustained manner. In vitro release followed zero ordered kinetics and when fitted to Korsemeyer Peppas model, indicated drug release by combination of diffusion as well as chain relaxation. In vivo floatability study confirmed floatation for more than 6 h. In vivo pharmacokinetic studies in rabbits showed Cmax of 189.96 ± 13.04 ng/mL and Tmax of 4 ± 0.35 h for GFDDS. The difference for AUC(0-T) and AUC(0-∞) between the test and reference formulation was statistically significant (p > 0.05). AUC(0-T) and AUC(0-∞) for GFDDS was 2.34 and 2.43 times greater than the marketed formulation respectively. GFDDS provided prolonged gastric residence and showed significant increase in bioavailability of baclofen.

Genetic algorithms - What fitness scaling is optimal?

NASA Technical Reports Server (NTRS)

Kreinovich, Vladik; Quintana, Chris; Fuentes, Olac

1993-01-01

A problem of choosing the best scaling function as a mathematical optimization problem is formulated and solved under different optimality criteria. A list of functions which are optimal under different criteria is presented which includes both the best functions empirically proved and new functions that may be worth trying.

Optimal Water-Power Flow Problem: Formulation and Distributed Optimal Solution

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

Dall-Anese, Emiliano; Zhao, Changhong; Zamzam, Admed S.

This paper formalizes an optimal water-power flow (OWPF) problem to optimize the use of controllable assets across power and water systems while accounting for the couplings between the two infrastructures. Tanks and pumps are optimally managed to satisfy water demand while improving power grid operations; {for the power network, an AC optimal power flow formulation is augmented to accommodate the controllability of water pumps.} Unfortunately, the physics governing the operation of the two infrastructures and coupling constraints lead to a nonconvex (and, in fact, NP-hard) problem; however, after reformulating OWPF as a nonconvex, quadratically-constrained quadratic problem, a feasible point pursuit-successivemore » convex approximation approach is used to identify feasible and optimal solutions. In addition, a distributed solver based on the alternating direction method of multipliers enables water and power operators to pursue individual objectives while respecting the couplings between the two networks. The merits of the proposed approach are demonstrated for the case of a distribution feeder coupled with a municipal water distribution network.« less

Formulation of image fusion as a constrained least squares optimization problem

PubMed Central

Dwork, Nicholas; Lasry, Eric M.; Pauly, John M.; Balbás, Jorge

2017-01-01

Abstract. Fusing a lower resolution color image with a higher resolution monochrome image is a common practice in medical imaging. By incorporating spatial context and/or improving the signal-to-noise ratio, it provides clinicians with a single frame of the most complete information for diagnosis. In this paper, image fusion is formulated as a convex optimization problem that avoids image decomposition and permits operations at the pixel level. This results in a highly efficient and embarrassingly parallelizable algorithm based on widely available robust and simple numerical methods that realizes the fused image as the global minimizer of the convex optimization problem. PMID:28331885

Evaluation of acetylated moth bean starch as a carrier for controlled drug delivery

PubMed Central

Singh, Akhilesh V.; Nath, Lila K.

2012-01-01

The present investigation concerns with the development of controlled release tablets of lamivudine using acetylated moth bean starch. The acetylated starch was synthesized with acetic anhydride in pyridine medium. The acetylated moth bean starch was tested for acute toxicity and drug–excipient compatibility study. The formulations were evaluated for physical characteristics like hardness, friability, % drug content and weight variations. The in vitro release study showed that the optimized formulation exhibited highest correlation (R) value in case of Higuchi kinetic model and the release mechanism study proved that the formulation showed a combination of diffusion and erosion process. There was a significant difference in the pharmacokinetic parameters (Tmax, Cmax, AUC, Vd, T1/2 and MDT) of the optimized formulation as compared to the marketed conventional tablet Lamivir®, which proved controlled release potential of acetylated moth bean starch. PMID:22210486

On solving three-dimensional open-dimension rectangular packing problems

NASA Astrophysics Data System (ADS)

Junqueira, Leonardo; Morabito, Reinaldo

2017-05-01

In this article, a recently proposed three-dimensional open-dimension rectangular packing problem is considered, in which the objective is to find a minimal volume rectangular container that packs a set of rectangular boxes. The literature has tackled small-sized instances of this problem by means of optimization solvers, position-free mixed-integer programming (MIP) formulations and piecewise linearization approaches. In this study, the problem is alternatively addressed by means of grid-based position MIP formulations, whereas still considering optimization solvers and the same piecewise linearization techniques. A comparison of the computational performance of both models is then presented, when tested with benchmark problem instances and with new instances, and it is shown that the grid-based position MIP formulation can be competitive, depending on the characteristics of the instances. The grid-based position MIP formulation is also embedded with real-world practical constraints, such as cargo stability, and results are additionally presented.

Implicit methods for efficient musculoskeletal simulation and optimal control

PubMed Central

van den Bogert, Antonie J.; Blana, Dimitra; Heinrich, Dieter

2011-01-01

The ordinary differential equations for musculoskeletal dynamics are often numerically stiff and highly nonlinear. Consequently, simulations require small time steps, and optimal control problems are slow to solve and have poor convergence. In this paper, we present an implicit formulation of musculoskeletal dynamics, which leads to new numerical methods for simulation and optimal control, with the expectation that we can mitigate some of these problems. A first order Rosenbrock method was developed for solving forward dynamic problems using the implicit formulation. It was used to perform real-time dynamic simulation of a complex shoulder arm system with extreme dynamic stiffness. Simulations had an RMS error of only 0.11 degrees in joint angles when running at real-time speed. For optimal control of musculoskeletal systems, a direct collocation method was developed for implicitly formulated models. The method was applied to predict gait with a prosthetic foot and ankle. Solutions were obtained in well under one hour of computation time and demonstrated how patients may adapt their gait to compensate for limitations of a specific prosthetic limb design. The optimal control method was also applied to a state estimation problem in sports biomechanics, where forces during skiing were estimated from noisy and incomplete kinematic data. Using a full musculoskeletal dynamics model for state estimation had the additional advantage that forward dynamic simulations, could be done with the same implicitly formulated model to simulate injuries and perturbation responses. While these methods are powerful and allow solution of previously intractable problems, there are still considerable numerical challenges, especially related to the convergence of gradient-based solvers. PMID:22102983

Artificial neural networks to model formulation-property correlations in the process of inline-compounding on an injection moulding machine

NASA Astrophysics Data System (ADS)

Moritzer, Elmar; Müller, Ellen; Martin, Yannick; Kleeschulte, Rainer

2015-05-01

Today the global market poses great challenges for industrial product development. Complexity, diversity of variants, flexibility and individuality are just some of the features that products have to offer today. In addition, the product series have shorter lifetimes. Because of their high capacity for adaption, polymers are increasingly able to displace traditional materials such as wood, glass and metals from various fields of application. Polymers can only be used to substitute other materials, however, if they are optimally suited to the applications in question. Hence, product-specific material development is becoming increasingly important. Integrating the compounding step in the injection moulding process permits a more efficient and faster development process for a new polymer formulation, making it possible to create new product-specific materials. This process is called inline-compounding on an injection moulding machine. The entire process sequence is supported by software from Bayer Technology called Product Design Workbench (PDWB), which provides assistance in all the individual steps from data management, via analysis and model compilation, right through to the optimization of the formulation and the design of experiments. The software is based on artificial neural networks and can model the formulation-property correlations and thus enable different formulations to be optimized. In the study presented, the workflow and the modelling with the software are presented.

Formulation, optimization, and evaluation of self-emulsifying drug delivery systems of nevirapine

PubMed Central

Chintalapudi, Ramprasad; Murthy, T. E. G. K.; Lakshmi, K. Rajya; Manohar, G. Ganesh

2015-01-01

Background: The aim of the present study was to formulate and optimize the self-emulsifying drug delivery systems (SEDDS) of nevirapine (NVP) by use of 22 factorial designs to enhance the oral absorption of NVP by improving its solubility, dissolution rate, and diffusion profile. SEDDS are the isotropic mixtures of oil, surfactant, co-surfactant and drug that form oil in water microemulsion when introduced into the aqueous phase under gentle agitation. Materials and Methods: Solubility of NVP in different oils, surfactants, and co-surfactants was determined for the screening of excipients. Pseudo-ternary phase diagrams were constructed by the aqueous titration method, and formulations were developed based on the optimum excipient combinations with the help of data obtained through the maximum micro emulsion region containing combinations of oil, surfactant, and co-surfactant. The formulations of SEDDS were optimized by 22 factorial designs. Results: The optimum formulation of SEDDS contains 32.5% oleic acid, 44.16% tween 20, and 11.9% polyethylene glycol 600 as oil, surfactant, and co-surfactant respectively. The SEDDS was evaluated for the following drug content, self-emulsification time, rheological properties, zeta potential, in vitro diffusion studies, thermodynamic stability studies, and in vitro dissolution studies. An increase in dissolution was achieved by SEDDS compared to pure form of NVP. Conclusion: Overall, this study suggests that the dissolution and oral bioavailability of NVP could be improved by SEDDS technology. PMID:26682191

Quality by design approach for optimizing the formulation and physical properties of extemporaneously prepared orodispersible films.

PubMed

Visser, J Carolina; Dohmen, Willem M C; Hinrichs, Wouter L J; Breitkreutz, Jörg; Frijlink, Henderik W; Woerdenbag, Herman J

2015-05-15

The quality by design (QbD) approach was applied for optimizing the formulation of extemporaneously prepared orodispersible films (ODFs) using Design-Expert® Software. The starting formulation was based on earlier experiments and contained the film forming agents hypromellose and carbomer 974P and the plasticizer glycerol (Visser et al., 2015). Trometamol and disodium EDTA were added to stabilize the solution. To optimize this formulation a quality target product profile was established in which critical quality attributes (CQAs) such as mechanical properties and disintegration time were defined and quantified. As critical process parameters (CPP) that were evaluated for their effect on the CQAs the percentage of hypromellose and the percentage of glycerol as well as the drying time were chosen. Response surface methodology (RMS) was used to evaluate the effects of the CPPs on the CQAs of the final product. The main factor affecting tensile strength and Young's modulus was the percentage of glycerol. Elongation at break was mainly influenced by the drying temperature. Disintegration time was found to be sensitive to the percentage of hypromellose. From the results a design space could be created. As long as the formulation and process variables remain within this design space, a product is obtained with desired characteristics and that meets all set quality requirements. Copyright © 2015 Elsevier B.V. All rights reserved.

Development of functional beverages from blends of Hibiscus sabdariffa extract and selected fruit juices for optimal antioxidant properties.

PubMed

Ogundele, Oluwatoyin M A; Awolu, Olugbenga O; Badejo, Adebanjo A; Nwachukwu, Ifeanyi D; Fagbemi, Tayo N

2016-09-01

The demand for functional foods and drinks with health benefit is on the increase. The synergistic effect from mixing two or more of such drinks cannot be overemphasized. This study was carried out to formulate and investigate the effects of blends of two or more of pineapple, orange juices, carrot, and Hibiscus sabdariffa extracts (HSE) on the antioxidant properties of the juice formulations in order to obtain a combination with optimal antioxidant properties. Experimental design was carried out using optimal mixture model of response surface methodology which generated twenty experimental runs with antioxidant properties as the responses. The DPPH (1,1-diphenyl-2-picrylhydrazyl) and ABTS [2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid)] radical scavenging abilities, ferric reducing antioxidant potential (FRAP), vitamin C, total phenolics, and total carotenoids contents of the formulations were evaluated as a test of antioxidant property. In all the mixtures, formulations having HSE as part of the mixture showed the highest antioxidant potential. The statistical analyzes, however, showed that the formulations containing pineapple, carrot, orange, and HSE of 40.00, 16.49, 17.20, and 26.30%, respectively, produced optimum antioxidant potential and was shown to be acceptable to a research laboratory guidance panel, thus making them viable ingredients for the production of functional beverages possessing important antioxidant properties with potential health benefits.

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

PubMed Central

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

2017-01-01

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

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

PubMed

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

2017-11-07

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

Formulation Optimization and Ex Vivo and In Vivo Evaluation of Celecoxib Microemulsion-Based Gel for Transdermal Delivery.

PubMed

Cao, Mengyuan; Ren, Lili; Chen, Guoguang

2017-08-01

Celecoxib (CXB) is a poorly aqueous solubility sulfonamide non-steroidal anti-inflammatory drug (NSAID). Hence, the formulation of CXB was selected for solubilization and bioavailability. To find out suitable formulation for microemulsion, the solubility of CXB in triacetin (oil phase), Tween 80 (surfactant), and Transcutol-P (co-surfactant) was screened respectively and optimized by using orthogonal experimental design. The Km value and concentration of oil, S mix , and water were confirmed by pseudo-ternary phase diagram studies and central composite design. One percent carbopol 934 was added to form CXB microemulsion-based gel. The final formulation was evaluated for its appearance, pH, viscosity, stability, drug content determination, globule size, and zeta potential. Its ex vivo drug permeation and the in vivo pharmacokinetic was investigated. Further research was performed to ensure the safety and validity by skin irritation study and in vivo anti-inflammatory activity study. Ex vivo permeation study in mice was designed to compare permeation and transdermal ability between microemulsion formulation and conventional gel. The results revealed that optimized microemulsion-based gel gained higher permeation based on smaller globule size and high drug loading of microemulsion. Transdermal ability was also greatly improved. Bioavailability was compared to market Celebrex® by the in vivo pharmacokinetic study in rabbits. The results indicated that CXB microemulsion-based gel had better bioavailability than Celebrex®.

PD-PK evaluation of freeze-dried atorvastatin calcium-loaded poly-ε-caprolactone nanoparticles.

PubMed

Ahmed, Iman S; El-Hosary, Rania; Shalaby, Samia; Abd-Rabo, Marwa M; Elkhateeb, Dalia G; Nour, Samia

2016-05-17

In this work lyophilized poly-ε-caprolactone nanoparticles (NPs) loaded with atorvastatin calcium (AC) were developed in an attempt to improve the in-vivo performance of AC following oral administration. The individual and combined effects of several formulation variables were previously investigated using step-wise full factorial designs in order to produce optimized AC-NPs with predetermined characteristics including particle size, drug loading capacity, drug release profile and physical stability. Four optimized formulations were further subjected in this work to lyophilization to promote their long-term physical stability and were fully characterized. The pharmacodynamics (PD)/pharmacokinetics (PK) properties of two optimized freeze-dried AC-NPs formulations showing acceptable long-term stability were determined and compared to a marketed AC immediate release tablet (Lipitor(®)) in albino rats. PD results revealed that the two tested formulations were equally effective in reducing low density lipoproteins (LDL) and triglycerides (TG) levels when given in reduced doses compared to Lipitor(®) and showed no adverse effects. PK results, on the other hand, revealed that the two freeze-dried AC-NPs formulations were of significantly lower bioavailability compared to Lipitor(®). Taken together the PD and PK results demonstrate that the improved efficacy obtained at reduced doses from the freeze-dried AC-NPs could be due to increased concentration of AC in the liver rather than in the plasma. Copyright © 2016 Elsevier B.V. All rights reserved.

QbD for pediatric oral lyophilisates development: risk assessment followed by screening and optimization.

PubMed

Casian, Tibor; Iurian, Sonia; Bogdan, Catalina; Rus, Lucia; Moldovan, Mirela; Tomuta, Ioan

2017-12-01

This study proposed the development of oral lyophilisates with respect to pediatric medicine development guidelines, by applying risk management strategies and DoE as an integrated QbD approach. Product critical quality attributes were overviewed by generating Ishikawa diagrams for risk assessment purposes, considering process, formulation and methodology related parameters. Failure Mode Effect Analysis was applied to highlight critical formulation and process parameters with an increased probability of occurrence and with a high impact on the product performance. To investigate the effect of qualitative and quantitative formulation variables D-optimal designs were used for screening and optimization purposes. Process parameters related to suspension preparation and lyophilization were classified as significant factors, and were controlled by implementing risk mitigation strategies. Both quantitative and qualitative formulation variables introduced in the experimental design influenced the product's disintegration time, mechanical resistance and dissolution properties selected as CQAs. The optimum formulation selected through Design Space presented ultra-fast disintegration time (5 seconds), a good dissolution rate (above 90%) combined with a high mechanical resistance (above 600 g load). Combining FMEA and DoE allowed the science based development of a product with respect to the defined quality target profile by providing better insights on the relevant parameters throughout development process. The utility of risk management tools in pharmaceutical development was demonstrated.

Development of modified-release tablets of zolpidem tartrate by biphasic quick/slow delivery system.

PubMed

Mahapatra, Anjan Kumar; Sameeraja, N H; Murthy, P N

2015-06-01

Zolpidem tartrate is a non-benzodiazepine analogue of imidazopyridine of sedative and hypnotic category. It has a short half-life with usual dosage regimen being 5 mg, two times a day, or 10 mg, once daily. The duration of action is considered too short in certain circumstances. Thus, it is desirable to lengthen the duration of action. The formulation design was implemented by preparing extended-release tablets of zolpidem tartrate using the biphasic delivery system technology, where sodium starch glycolate acts as a superdisintegrant in immediate-release part and hydroxypropyl methyl cellulose as a release retarding agent in extended-release core. Tablets were prepared by direct compression. Both the core and the coat contained the drug. The pre-compression blends were evaluated for angle of repose, bulk density, and compressibility index. The tablets were evaluated for thickness, hardness, weight variation test, friability, and in vitro release studies. No interaction was observed between zolpidem tartrate and excipients from the Fourier transform infrared spectroscopy and differential scanning calorimetry analysis. The results of all the formulations prepared were compared with reference product Stilnoct®. Optimized formulations showed release patterns that match the United States Pharmacopeia (USP) guidelines for zolpidem tartrate extended-release tablets. The mechanism of drug release was studied using different mathematical models, and the optimized formulation has shown Fickian diffusion. Accelerated stability studies were performed on the optimized formulation.

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.

Statistical optimization of tretinoin-loaded penetration-enhancer vesicles (PEV) for topical delivery.

PubMed

Bavarsad, Neda; Akhgari, Abbas; Seifmanesh, Somayeh; Salimi, Anayatollah; Rezaie, Annahita

2016-02-29

The aim of this study was to develop and optimize deformable liposome for topical delivery of tretinoin. Liposomal formulations were designed based on the full factorial design and prepared by fusion method. The influence of different ratio of soy phosphatidylcholine and transcutol (independent variables) on incorporation efficiency and drug release in 15 min and 24 h (responses) from liposomal formulations was evaluated. Liposomes were characterized for their vesicle size and Differential Scanning Calorimetry (DSC) was used to investigate changes in their thermal behavior. The penetration and retention of drug was determined using mouse skin. Also skin histology study was performed. Particle size of all formulations was smaller than 20 nm. Incorporation efficiency of liposomes was 79-93 %. Formulation F7 (25:5) showed maximum drug release. Optimum formulations were selected based on the contour plots resulted by statistical equations of drug release in 15 min and 24 h. Solubility properties of transcutol led to higher skin penetration for optimum formulations compared to tretinoin cream. There was no significant difference between the amount of drug retained in the skin by applying optimum formulations and cream. Histopatological investigation suggested optimum formulations could decrease the adverse effect of tretinoin in liposome compared to conventional cream. According to the results of the study, it is concluded that deformable liposome containing transcutol may be successfully used for dermal delivery of tretinoin.

The Effects of Screw Configuration and Polymeric Carriers on Hot-Melt Extruded Taste-Masked Formulations Incorporated into Orally Disintegrating Tablets

PubMed Central

Morott, Joseph T.; Pimparade, Manjeet; Park, Jun-Bom; Worley, Chelsea P.; Majumdar, Soumyajit; Lian, Zhuoyang; Pinto, Elanor; Bi, Yunxia; Durig, Thomas; Repka, Michael A.

2015-01-01

The primary aim of this research was to produce successfully taste masked formulations of Sildenafil Citrate (SC) using hot-melt extrusion (HME) technology. Multiple screw configurations and polymeric carriers were evaluated for their effects on taste masking efficiency, which was assessed by both E-tongue analysis and in vitro dissolution in simulated salivary fluid (SSF, pH 6.8 artificial saliva). The screw configurations were further assessed for their effects on the morphology of the API using PXRD, FT-IR and mid-infrared chemical imaging. It was determined that the screw configuration had a profound effect on the taste masking efficiency of the formulations as a result of altering the physical state of the API. Selected extruded formulations using ethylcellulose (EC) with a pore former were further formulated into orally disintegrating tablets (ODTs), which were optimized by varying the grade and percentage of the superdisintegrant used. An optimized disintegration time of approximately 8 seconds was achieved. The final ODT formulation exhibited excellent taste masking properties with over 85% drug release in gastric media as well as physical tablet properties. Interestingly, friability, which tends to be a common concern when formulating ODTs, was well within the acceptable limits (<1%) for common tablets. PMID:25410968

Improved Stability of a Model IgG3 by DoE-Based Evaluation of Buffer Formulations

DOE PAGES

Chavez, Brittany K.; Agarabi, Cyrus D.; Read, Erik K.; ...

2016-01-01

Formulating appropriate storage conditions for biopharmaceutical proteins is essential for ensuring their stability and thereby their purity, potency, and safety over their shelf-life. Using a model murine IgG3 produced in a bioreactor system, multiple formulation compositions were systematically explored in a DoE design to optimize the stability of a challenging antibody formulation worst case. The stability of the antibody in each buffer formulation was assessed by UV/VIS absorbance at 280 nm and 410 nm and size exclusion high performance liquid chromatography (SEC) to determine overall solubility, opalescence, and aggregate formation, respectively. Upon preliminary testing, acetate was eliminated as a potentialmore » storage buffer due to significant visible precipitate formation. An additional 2 4full factorial DoE was performed that combined the stabilizing effect of arginine with the buffering capacity of histidine. From this final DoE, an optimized formulation of 200 mM arginine, 50 mM histidine, and 100 mM NaCl at a pH of 6.5 was identified to substantially improve stability under long-term storage conditions and after multiple freeze/thaw cycles. Therefore, our data highlights the power of DoE based formulation screening approaches even for challenging monoclonal antibody molecules.« less

Optimization of beam orientation in radiotherapy using planar geometry

NASA Astrophysics Data System (ADS)

Haas, O. C. L.; Burnham, K. J.; Mills, J. A.

1998-08-01

This paper proposes a new geometrical formulation of the coplanar beam orientation problem combined with a hybrid multiobjective genetic algorithm. The approach is demonstrated by optimizing the beam orientation in two dimensions, with the objectives being formulated using planar geometry. The traditional formulation of the objectives associated with the organs at risk has been modified to account for the use of complex dose delivery techniques such as beam intensity modulation. The new algorithm attempts to replicate the approach of a treatment planner whilst reducing the amount of computation required. Hybrid genetic search operators have been developed to improve the performance of the genetic algorithm by exploiting problem-specific features. The multiobjective genetic algorithm is formulated around the concept of Pareto optimality which enables the algorithm to search in parallel for different objectives. When the approach is applied without constraining the number of beams, the solution produces an indication of the minimum number of beams required. It is also possible to obtain non-dominated solutions for various numbers of beams, thereby giving the clinicians a choice in terms of the number of beams as well as in the orientation of these beams.

When is a research question not a research question?

PubMed

Mayo, Nancy E; Asano, Miho; Barbic, Skye Pamela

2013-06-01

Research is undertaken to answer important questions yet often the question is poorly expressed and lacks information on the population, the exposure or intervention, the comparison, and the outcome. An optimal research question sets out what the investigator wants to know, not what the investigator might do, nor what the results of the study might ultimately contribute. The purpose of this paper is to estimate the extent to which rehabilitation scientists optimally define their research questions. A cross-sectional survey of the rehabilitation research articles published during 2008. Two raters independently rated each question according to pre-specified criteria; a third rater adjudicated all discrepant ratings. The proportion of the 258 articles with a question formulated as methods or expected contribution and not as what knowledge was being sought was 65%; 30% of questions required reworking. The designs which most often had poorly formulated research questions were randomized trials, cross-sectional and measurement studies. Formulating the research question is not purely a semantic concern. When the question is poorly formulated, the design, analysis, sample size calculations, and presentation of results may not be optimal. The gap between research and clinical practice could be bridged by a clear, complete, and informative research question.

Modern Vaccines/Adjuvants Formulation Session 6: Vaccine &Adjuvant Formulation & Production 15-17 May 2013, Lausanne, Switzerland.

PubMed

Fox, Christopher B

2013-09-01

The Modern Vaccines/Adjuvants Formulation meeting aims to fill a critical gap in current vaccine development efforts by bringing together formulation scientists and immunologists to emphasize the importance of rational formulation design in order to optimize vaccine and adjuvant bioactivity, safety, and manufacturability. Session 6 on Vaccine and Adjuvant Formulation and Production provided three examples of this theme, with speakers emphasizing the need for extensive physicochemical characterization of adjuvant-antigen interactions, the rational formulation design of a CD8+ T cell-inducing adjuvant based on immunological principles, and the development and production of a rabies vaccine by a developing country manufacturer. Throughout the session, the practical importance of sound formulation and manufacturing design accompanied by analytical characterization was highlighted.

Muffins Elaborated with Optimized Monoglycerides Oleogels: From Solid Fat Replacer Obtention to Product Quality Evaluation.

PubMed

Giacomozzi, Anabella S; Carrín, María E; Palla, Camila A

2018-06-01

This study demonstrates the effectiveness of using oleogels from high oleic sunflower oil (HOSO) and monoglycerides as solid fat replacers in a sweet bakery product. Firstly, a methodology to obtain oleogels with desired properties based on mathematical models able to describe relationships between process and product characteristics variables followed by multi-objective optimization was applied. Later, muffins were prepared with the optimized oleogels and their physicochemical and textural properties were compared with those of muffins formulated using a commercial margarine (Control) or only HOSO. Furthermore, the amount of oil released from muffins over time (1, 7, and 10 days) was measured to evaluate their stability. The replacement of commercial margarine with the optimized oleogels in muffin formulation led to the obtention of products with greater spreadability, higher specific volume, similar hardness values, and a more connected and homogeneous crumb structure. Moreover, these products showed a reduction of oil migration of around 50% in contrast to the Control muffins after 10 days of storage, which indicated that the optimized oleogels can be used satisfactorily to decrease oil loss in this sweet baked product. Fat replacement with the optimized monoglycerides oleogels not only had a positive impact on the quality of the muffins, but also allowed to improve their nutritional profile (without trans fat and low in saturated fat). The food industry demands new ways to reduce the use of saturated and trans fats in food formulations. To contribute to this search, oleogels from high oleic sunflower oil and saturated monoglycerides were prepared under optimized conditions in order to obtain a product with similar functionality to margarine, and its potential application as a semisolid fat ingredient in muffins was evaluated. Muffins formulated with oleogels showed an improved quality compare with those obtained using a commercial margarine with the added benefit of a healthier nutritional profile. © 2018 Institute of Food Technologists®.

Optimization of sustained release aceclofenac microspheres using response surface methodology.

PubMed

Deshmukh, Rameshwar K; Naik, Jitendra B

2015-03-01

Polymeric microspheres containing aceclofenac were prepared by single emulsion (oil-in-water) solvent evaporation method using response surface methodology (RSM). Microspheres were prepared by changing formulation variables such as the amount of Eudragit® RS100 and the amount of polyvinyl alcohol (PVA) by statistical experimental design in order to enhance the encapsulation efficiency (E.E.) of the microspheres. The resultant microspheres were evaluated for their size, morphology, E.E., and in vitro drug release. The amount of Eudragit® RS100 and the amount of PVA were found to be significant factors respectively for determining the E.E. of the microspheres. A linear mathematical model equation fitted to the data was used to predict the E.E. in the optimal region. Optimized formulation of microspheres was prepared using optimal process variables setting in order to evaluate the optimization capability of the models generated according to IV-optimal design. The microspheres showed high E.E. (74.14±0.015% to 85.34±0.011%) and suitably sustained drug release (minimum; 40% to 60%; maximum) over a period of 12h. The optimized microspheres formulation showed E.E. of 84.87±0.005 with small error value (1.39). The low magnitudes of error and the significant value of R(2) in the present investigation prove the high prognostic ability of the design. The absence of interactions between drug and polymers was confirmed by Fourier transform infrared (FTIR) spectroscopy. Differential scanning calorimetry (DSC) and X-ray powder diffractometry (XRPD) revealed the dispersion of drug within microspheres formulation. The microspheres were found to be discrete, spherical with smooth surface. The results demonstrate that these microspheres could be promising delivery system to sustain the drug release and improve the E.E. thus prolong drug action and achieve the highest healing effect with minimal gastrointestinal side effects. Copyright © 2014 Elsevier B.V. All rights reserved.

Statistically designed nonionic surfactant vesicles for dermal delivery of itraconazole: characterization and in vivo evaluation using a standardized Tinea pedis infection model.

PubMed

Kumar, Neeraj; Goindi, Shishu

2014-09-10

The study aims to statistically develop a hydrogel of itraconazole loaded nonionic surfactant vesicles (NSVs) for circumventing the shortcomings and adverse effects of currently used therapies. Influential factors were screened using first-order Taguchi design, thereafter, optimization was performed via D-optimal design involving screened factors (surfactant type, content and molar ratio of cholesterol: surfactant). Response variables investigated were percent drug entrapment, vesicle size, drug skin retention and permeation in 6h. Suspensions of NSVs were gelled to improve topical applicability. Characterization of formulations was performed using vesicle shape, size, surface charge, texture analysis and rheology behavior. Ex vivo studies in rat skin depicted that optimized formulation augmented drug skin retention and permeation in 6h than conventional cream and oily solution of itraconazole. Standardized Tinea pedis model in Wistar rats exhibited in vivo antifungal efficacy of optimized formulation, observed in terms of physical manifestations, fungal-burden score and histopathological profiles. Also, a unique investigation involving studying local oxidative stress of infected paw skins as an indicator of fungal infection was performed. Rapid alleviation of infection in animals treated with optimized hydrogel was observed in comparison to commonly prescribed therapies. Therefore, the optimized NSVs may be a promising and efficient alternative to available antifungal therapies. Copyright © 2014 Elsevier B.V. All rights reserved.

Enhanced Multiobjective Optimization Technique for Comprehensive Aerospace Design. Part A

NASA Technical Reports Server (NTRS)

Chattopadhyay, Aditi; Rajadas, John N.

1997-01-01

A multidisciplinary design optimization procedure which couples formal multiobjectives based techniques and complex analysis procedures (such as computational fluid dynamics (CFD) codes) developed. The procedure has been demonstrated on a specific high speed flow application involving aerodynamics and acoustics (sonic boom minimization). In order to account for multiple design objectives arising from complex performance requirements, multiobjective formulation techniques are used to formulate the optimization problem. Techniques to enhance the existing Kreisselmeier-Steinhauser (K-S) function multiobjective formulation approach have been developed. The K-S function procedure used in the proposed work transforms a constrained multiple objective functions problem into an unconstrained problem which then is solved using the Broyden-Fletcher-Goldfarb-Shanno (BFGS) algorithm. Weight factors are introduced during the transformation process to each objective function. This enhanced procedure will provide the designer the capability to emphasize specific design objectives during the optimization process. The demonstration of the procedure utilizes a computational Fluid dynamics (CFD) code which solves the three-dimensional parabolized Navier-Stokes (PNS) equations for the flow field along with an appropriate sonic boom evaluation procedure thus introducing both aerodynamic performance as well as sonic boom as the design objectives to be optimized simultaneously. Sensitivity analysis is performed using a discrete differentiation approach. An approximation technique has been used within the optimizer to improve the overall computational efficiency of the procedure in order to make it suitable for design applications in an industrial setting.

The anatomy of choice: active inference and agency.

PubMed

Friston, Karl; Schwartenbeck, Philipp; Fitzgerald, Thomas; Moutoussis, Michael; Behrens, Timothy; Dolan, Raymond J

2013-01-01

This paper considers agency in the setting of embodied or active inference. In brief, we associate a sense of agency with prior beliefs about action and ask what sorts of beliefs underlie optimal behavior. In particular, we consider prior beliefs that action minimizes the Kullback-Leibler (KL) divergence between desired states and attainable states in the future. This allows one to formulate bounded rationality as approximate Bayesian inference that optimizes a free energy bound on model evidence. We show that constructs like expected utility, exploration bonuses, softmax choice rules and optimism bias emerge as natural consequences of this formulation. Previous accounts of active inference have focused on predictive coding and Bayesian filtering schemes for minimizing free energy. Here, we consider variational Bayes as an alternative scheme that provides formal constraints on the computational anatomy of inference and action-constraints that are remarkably consistent with neuroanatomy. Furthermore, this scheme contextualizes optimal decision theory and economic (utilitarian) formulations as pure inference problems. For example, expected utility theory emerges as a special case of free energy minimization, where the sensitivity or inverse temperature (of softmax functions and quantal response equilibria) has a unique and Bayes-optimal solution-that minimizes free energy. This sensitivity corresponds to the precision of beliefs about behavior, such that attainable goals are afforded a higher precision or confidence. In turn, this means that optimal behavior entails a representation of confidence about outcomes that are under an agent's control.

Optimized Solvent for Energy-Efficient, Environmentally-Friendly Capture of CO{sub 2} at Coal-Fired Power Plants

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

Farthing, G. A.; Rimpf, L. M.

The overall goal of this project, as originally proposed, was to optimize the formulation of a novel solvent as a critical enabler for the cost-effective, energy-efficient, environmentally-friendly capture of CO{sub 2} at coal-fired utility plants. Aqueous blends of concentrated piperazine (PZ) with other compounds had been shown to exhibit high rates of CO{sub 2} absorption, low regeneration energy, and other desirable performance characteristics during an earlier 5-year development program conducted by B&W. The specific objective of this project was to identify PZ-based solvent formulations that globally optimize the performance of coal-fired power plants equipped with CO{sub 2} scrubbing systems. Whilemore » previous solvent development studies have tended to focus on energy consumption and absorber size, important issues to be sure, the current work seeks to explore, understand, and optimize solvent formulation across the full gamut of issues related to commercial application of the technology: capital and operating costs, operability, reliability, environmental, health and safety (EH&S), etc. Work on the project was intended to be performed under four budget periods. The objective of the work in the first budget period has been to identify several candidate formulations of a concentrated PZ-based solvent for detailed characterization and evaluation. Work in the second budget period would generate reliable and comprehensive property and performance data for the identified formulations. Work in the third budget period would quantify the expected performance of the selected formulations in a commercial CO{sub 2} scrubbing process. Finally, work in the fourth budget period would provide a final technology feasibility study and a preliminary technology EH&S assessment. Due to other business priorities, however, B&W has requested that this project be terminated at the end of the first budget period. This document therefore serves as the final report for this project. It is the first volume of the two-volume final report and summarizes Budget Period 1 accomplishments under Tasks 1-5 of the project, including the selection of four solvent formulations for further study.« less

Formulation Optimization of Human Insulin Loaded Microspheres for Controlled Oral Delivery Using Response Surface Methodology.

PubMed

Agrawal, Gauravkuma; Wakte, Pravin; Shelke, Santosh

2017-01-01

The objectives of the present investigation were to prepare recombinant human insulin entrapped Eudragit-S100 microspheres containing protease inhibitors and to precisely analyze the outcome of different formulation variables on the microspheres properties using a response surface methodology to develop an optimized formulation with desirable features. A central composite design was employed to produce microspheres of therapeutic protein by w/o/w multiple emulsion solvent evaporation technique using Eudragit S-100 as coating material and polyvinyl alcohol as a stabilizer. The effect of formulation variables (independent variables) that is levels of Eudragit S-100 (X1), therapeutic protein (X2), volumes of inner aqueous phase (X3) and external aqueous phase (X4) on dependant variables, that are encapsulation efficiency (Y1), drug release at pH 1.2 after 2 h (Y2) and drug release at pH 7.4 after of 2 h (Y3) were evaluated. The significant terms in the mathematical models were generated for each response parameter using multiple linear regression analysis and analysis of variance. All the formulation variables except the volume of external aqueous phase (X4) exerted a significant effect (P <0.05) on drug encapsulation efficiency (Y1) whereas first two variables, namely the levels of Eudragit S-100 (X1) and therapeutic protein (X2) materialized as the determining factors which significantly influenced drug release at pH 1.2 after 2 h (Y2) and drug release at pH 7.4 after of 2 h (Y3). The formulation was numerically optimized by framing the constraints on the dependent and independent variables using the desirability approach. The experimental values for Y1 and Y2 of optimized formulation were found to be 77.65% and 3.64%, respectively which were quite closer to results suggested by software. The results recorded indicate that the recombinant human insulin loaded Eudragit S-100 microspheres containing aprotinin have the benefits of higher loading efficiency, pH responsive and prolonged release characteristics, which may help to carry insulin to the optimum site of absorption. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Enhancement of oral bioavailability of atorvastatin calcium by self-emulsifying drug delivery systems (SEDDS).

PubMed

Kadu, Pawan J; Kushare, Sachin S; Thacker, Dhaval D; Gattani, Surendra G

2011-02-01

The aim of the present study was to formulate a self-emulsifying drug delivery system of atorvastatin calcium and its characterization including in vitro and in vivo potential. The solubility of atorvastatin calcium was determined in various vehicles such as Captex 355, Captex 355 EP/NF, Ethyl oleate, Capmul MCM, Capmul PG-8, Gelucire 44/14, Tween 80, Tween 20, and PEG 400. Pseudoternary phase diagrams were plotted on the basis of solubility data of drug in various components to evaluate the microemulsification region. Formulation development and screening was carried out based on results obtained from phase diagrams and characteristics of resultant microemulsion. Prepared formulations were tested for microemulsifying properties and evaluated for clarity, precipitation, viscosity determination, drug content and in vitro dissolution. The optimized formulation further evaluated for particle size distribution, zeta potential, stability studies and in vivo potential. In vivo performance of the optimized formulation was evaluated using a Triton-induced hypercholesterolemia model in male Albino Wistar rats. The formulation significantly reduced serum lipid levels as compared with atorvastatin calcium. Thus studies illustrated the potential use for the delivery of hydrophobic drug such as atorvastatin calcium by oral route.

Spray-drying nanocapsules in presence of colloidal silica as drying auxiliary agent: formulation and process variables optimization using experimental designs.

PubMed

Tewa-Tagne, Patrice; Degobert, Ghania; Briançon, Stéphanie; Bordes, Claire; Gauvrit, Jean-Yves; Lanteri, Pierre; Fessi, Hatem

2007-04-01

Spray-drying process was used for the development of dried polymeric nanocapsules. The purpose of this research was to investigate the effects of formulation and process variables on the resulting powder characteristics in order to optimize them. Experimental designs were used in order to estimate the influence of formulation parameters (nanocapsules and silica concentrations) and process variables (inlet temperature, spray-flow air, feed flow rate and drying air flow rate) on spray-dried nanocapsules when using silica as drying auxiliary agent. The interactions among the formulation parameters and process variables were also studied. Responses analyzed for computing these effects and interactions were outlet temperature, moisture content, operation yield, particles size, and particulate density. Additional qualitative responses (particles morphology, powder behavior) were also considered. Nanocapsules and silica concentrations were the main factors influencing the yield, particulate density and particle size. In addition, they were concerned for the only significant interactions occurring among two different variables. None of the studied variables had major effect on the moisture content while the interaction between nanocapsules and silica in the feed was of first interest and determinant for both the qualitative and quantitative responses. The particles morphology depended on the feed formulation but was unaffected by the process conditions. This study demonstrated that drying nanocapsules using silica as auxiliary agent by spray drying process enables the obtaining of dried micronic particle size. The optimization of the process and the formulation variables resulted in a considerable improvement of product yield while minimizing the moisture content.

Development of Self Emulsifying Formulations of Poorly Soluble Naproxen for Enhanced Drug Delivery.

PubMed

Penjuri, Subhash C B; Saritha, Damineni; Ravouru, Nagaraju; Poreddy, Srikanth R

2016-01-01

The objective of this investigation was to develop a self emulsifying drug delivery system (SEDDS) of naproxen, a poorly water soluble drug, which could improve its solubility and oral bioavailability. The recent patents on SEDDS of abiraterone acetate (WO2014/009434 A1) and tamoxifen (WO2013/0080083) helped in selecting the naproxen and excipients. Phase diagrams were constructed and the formulations were taken from the micro emulsion region. Formulations were subjected to thermodynamic stability, dispersibility and precipitation tests for optimization. Physico chemical characterization was carried out by FTIR and DSC studies. The selected SEDDS consisted of IPM+labrafac lipophile WL 1349, tween 80, PEG 400 and naproxen. The optimized formulation has globule size- 187.6 nm, zeta potential- -9.81 mv, viscosity- 1.772 cps and infinite dilution ability. In vitro drug release was 98.21% and was found to be significantly different from the marketed product and plain drug. After oral administration in rats the SEDDS of naproxen showed anti inflammatory activity (69.82%) which was much improved as compared to the marketed formulation. The Cmax, AUC0t of naproxen was boosted with SEDDS to 133.63 g/ml and 698.29 hr. g/ml respectively. The optimized formulation was found to be stable for 6 months during stability studies conducted according to the ICH Q1A (R2) guidelines. Thus this developed self emulsifying drug delivery system may be a useful tool to enhance the solubility of oral poorly water soluble drug naproxen. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Optimization and physicochemical characterization of a cationic lipid-phosphatidylcholine mixed emulsion formulated as a highly efficient vehicle that facilitates adenoviral gene transfer.

PubMed

Kim, Soo-Yeon; Lee, Sang-Jin; Kim, Jin-Ki; Choi, Han-Gon; Lim, Soo-Jeong

2017-01-01

Cationic lipid-based nanoparticles enhance viral gene transfer by forming electrostatic complexes with adenoviral vectors. We recently demonstrated the superior complexation capabilities of 1,2-dioleoyl-3-trimethylammonium propane (DOTAP) emulsion compared with a liposomal counterpart but the cytotoxicity of DOTAP emulsions remained a challenge. The present study is aimed at formulating an emulsion capable of acting as a highly effective viral gene transfer vehicle with reduced cytotoxicity and to physicochemically characterize the structures of virus-emulsion complexes in comparison with virus-liposome complexes when the only difference between emulsions and liposomes was the presence or absence of inner oil core. The emulsion formulation was performed by 1) reducing the content of DOTAP while increasing the content of zwitterionic lipid 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), and 2) optimizing the oil content. The complexation capability of formulated DOTAP:DMPC mixed emulsions was similar to those of emulsions containing DOTAP alone while displaying significantly lower cytotoxicity. The complexation capabilities of the DOTAP:DMPC mixed emulsion were serum-compatible and were monitored in a variety of cell types, whereas its liposomal counterpart was totally ineffective. Characterization by scanning electron microscopy, transmission electron microscopy, atomic force microscopy, and dynamic light scattering studies indicated that the optimized emulsions spontaneously surrounded the virus particles to generate emulsions that encapsulated the viral particles, whereas viral particles merely attached to the surfaces of the counterpart liposomes to form multiviral aggregates. Overall, these studies demonstrated that optimized DOTAP:DMPC mixed emulsions are potentially useful for adenoviral gene delivery due to less cytotoxicity and the unique ability to encapsulate the viral particle, highlighting the importance of nanoparticle formulation.

Optimization and physicochemical characterization of a cationic lipid-phosphatidylcholine mixed emulsion formulated as a highly efficient vehicle that facilitates adenoviral gene transfer

PubMed Central

Kim, Soo-Yeon; Lee, Sang-Jin; Kim, Jin-Ki; Choi, Han-Gon; Lim, Soo-Jeong

2017-01-01

Cationic lipid-based nanoparticles enhance viral gene transfer by forming electrostatic complexes with adenoviral vectors. We recently demonstrated the superior complexation capabilities of 1,2-dioleoyl-3-trimethylammonium propane (DOTAP) emulsion compared with a liposomal counterpart but the cytotoxicity of DOTAP emulsions remained a challenge. The present study is aimed at formulating an emulsion capable of acting as a highly effective viral gene transfer vehicle with reduced cytotoxicity and to physicochemically characterize the structures of virus-emulsion complexes in comparison with virus–liposome complexes when the only difference between emulsions and liposomes was the presence or absence of inner oil core. The emulsion formulation was performed by 1) reducing the content of DOTAP while increasing the content of zwitterionic lipid 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), and 2) optimizing the oil content. The complexation capability of formulated DOTAP:DMPC mixed emulsions was similar to those of emulsions containing DOTAP alone while displaying significantly lower cytotoxicity. The complexation capabilities of the DOTAP:DMPC mixed emulsion were serum-compatible and were monitored in a variety of cell types, whereas its liposomal counterpart was totally ineffective. Characterization by scanning electron microscopy, transmission electron microscopy, atomic force microscopy, and dynamic light scattering studies indicated that the optimized emulsions spontaneously surrounded the virus particles to generate emulsions that encapsulated the viral particles, whereas viral particles merely attached to the surfaces of the counterpart liposomes to form multiviral aggregates. Overall, these studies demonstrated that optimized DOTAP:DMPC mixed emulsions are potentially useful for adenoviral gene delivery due to less cytotoxicity and the unique ability to encapsulate the viral particle, highlighting the importance of nanoparticle formulation. PMID:29070949

Preparation, characterization and optimization of sildenafil citrate loaded PLGA nanoparticles by statistical factorial design

PubMed Central

2013-01-01

Background and the aim of the study The objective of the present study was to formulate and optimize nanoparticles (NPs) of sildenafil-loaded poly (lactic-co-glycolic acid) (PLGA) by double emulsion solvent evaporation (DESE) method. The relationship between design factors and experimental data was evaluated using response surface methodology. Method A Box-Behnken design was made considering the mass ratio of drug to polymer (D/P), the volumetric proportion of the water to oil phase (W/O) and the concentration of polyvinyl alcohol (PVA) as the independent agents. PLGA-NPs were successfully prepared and the size (nm), entrapment efficiency (EE), drug loading (DL) and cumulative release of drug from NPs post 1 and 8 hrs were assessed as the responses. Results The NPs were prepared in a spherical shape and the sizes range of 240 to 316 nm. The polydispersity index of size was lower than 0.5 and the EE (%) and DL (%) varied between 14-62% and 2-6%, respectively. The optimized formulation with a desirability factor of 0.9 was selected and characterized. This formulation demonstrated the particle size of 270 nm, EE of 55%, DL of 3.9% and cumulative drug release of 79% after 12 hrs. In vitro release studies showed a burst release at the initial stage followed by a sustained release of sildenafil from NPs up to 12 hrs. The release kinetic of the optimized formulation was fitted to Higuchi model. Conclusions Sildenafil citrate NPs with small particle size, lipophilic feature, high entrapment efficiency and good loading capacity is produced by this method. Characterization of optimum formulation, provided by an evaluation of experimental data, showed no significant difference between calculated and measured data. PMID:24355133

pH responsive alginate polymeric rafts for controlled drug release by using box behnken response surface design

PubMed Central

Abbas, Ghulam; Hanif, Muhammad; Khan, Mahtab Ahmad

2017-01-01

Abstract Aim of the present work was to develop alginate raft forming tablets for controlled release pantoprazole sodium sesquihydrate (PSS). Box behnken design was used to optimize 15 formulations with three independent and three dependent variables. Physical tests of all formulations were within pharmacopoeial limits. Raft was characterized by their strength, thickness, resilience, acid neutralizing capacity, floating lag time and total floating time. Raft strength, thickness and resilience of optimized formulation AR9 were 7.43 ± 0.019 g, 5.8 ± 0.245 cm and greater than 480 min, respectively. Buffering and neutralizing capacity were 11.2 ± 1.01 and 6.5 ± 0.56 meq, respectively. Dissolution studies were performed by using simulated gastric fluid pH 1.2 and cumulative percentage release of optimized formulation AR9 was found 98%. First order release kinetics were followed and non-fickian diffusion was observed as value of n was greater than 0.45 in korsmeyer-peppas model. PSS, polymers, tablets and rafts were further characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffractometry (XRD) and differential scanning calorimetry (DSC). FTIR spectra of PSS, polymers and raft of optimized formulation AR9 showed peaks at 3223.09, 1688.17, 1586.67, 1302.64 and 1027.74 cm−1 due to –OH stretching, ester carbonyl group (C=O) stretching, existence of water and carboxylic group in raft, C–N stretching and –OH bending vibration showed no interaction between them. XRD showed diffraction lines indicates crystalline nature of PSS. DSC thermogram showed endothermic peaks at 250 °C for PSS. The developed raft was suitable for controlled release delivery of PSS. PMID:29491774

QbD-Oriented Development and Characterization of Effervescent Floating-Bioadhesive Tablets of Cefuroxime Axetil.

PubMed

Bansal, Sanjay; Beg, Sarwar; Garg, Babita; Asthana, Abhay; Asthana, Gyati S; Singh, Bhupinder

2016-10-01

The objective of the present studies was systematic development of floating-bioadhesive gastroretentive tablets of cefuroxime axetil employing rational blend of hydrophilic polymers for attaining controlled release drug delivery. As per the QbD-based approach, the patient-centric target product profile and quality attributes of tablet were earmarked, and preliminary studies were conducted for screening the suitability of type of polymers, polymer ratio, granulation technique, and granulation time for formulation of tablets. A face-centered cubic design (FCCD) was employed for optimization of the critical material attributes, i.e., concentration of release controlling polymers, PEO 303 and HPMC K100 LV CR, and evaluating in vitro buoyancy, drug release, and ex vivo mucoadhesion strength. The optimized formulation was embarked upon through numerical optimization, which yield excellent floatation characteristic with drug release control (i.e., T 60% > 6 h) and bioadhesion strength. Drug-excipient compatibility studies through FTIR and P-XRD revealed the absence of any interaction between the drug and polymers. In vivo evaluation of the gastroretentive characteristics through X-ray imaging and in vivo pharmacokinetic studies in rabbits revealed significant extension in the rate of drug absorption (i.e., T max, K a, and MRT) from the optimized tablet formulation as compared to the marketed formulation. Successful establishment of various levels of in vitro/in vivo correlations (IVIVC) substantiated high degree of prognostic ability of in vitro dissolution conditions in predicting the in vivo performance. In a nutshell, the studies demonstrate successful development of the once-a-day gastroretentive formulations of cefuroxime axetil with controlled drug release profile and improved compliance.

Optimization of coupled systems: A critical overview of approaches

NASA Technical Reports Server (NTRS)

Balling, R. J.; Sobieszczanski-Sobieski, J.

1994-01-01

A unified overview is given of problem formulation approaches for the optimization of multidisciplinary coupled systems. The overview includes six fundamental approaches upon which a large number of variations may be made. Consistent approach names and a compact approach notation are given. The approaches are formulated to apply to general nonhierarchic systems. The approaches are compared both from a computational viewpoint and a managerial viewpoint. Opportunities for parallelism of both computation and manpower resources are discussed. Recommendations regarding the need for future research are advanced.

Simulation and optimization of volume holographic imaging systems in Zemax.

PubMed

Wissmann, Patrick; Oh, Se Baek; Barbastathis, George

2008-05-12

We present a new methodology for ray-tracing analysis of volume holographic imaging (VHI) systems. Using the k-sphere formulation, we apply geometrical relationships to describe the volumetric diffraction effects imposed on rays passing through a volume hologram. We explain the k-sphere formulation in conjunction with ray tracing process and describe its implementation in a Zemax UDS (User Defined Surface). We conclude with examples of simulation and optimization results and show proof of consistency and usefulness of the proposed model.

Optimization of the sources in local hyperthermia using a combined finite element-genetic algorithm method.

PubMed

Siauve, N; Nicolas, L; Vollaire, C; Marchal, C

2004-12-01

This article describes an optimization process specially designed for local and regional hyperthermia in order to achieve the desired specific absorption rate in the patient. It is based on a genetic algorithm coupled to a finite element formulation. The optimization method is applied to real human organs meshes assembled from computerized tomography scans. A 3D finite element formulation is used to calculate the electromagnetic field in the patient, achieved by radiofrequency or microwave sources. Space discretization is performed using incomplete first order edge elements. The sparse complex symmetric matrix equation is solved using a conjugate gradient solver with potential projection pre-conditionning. The formulation is validated by comparison of calculated specific absorption rate distributions in a phantom to temperature measurements. A genetic algorithm is used to optimize the specific absorption rate distribution to predict the phases and amplitudes of the sources leading to the best focalization. The objective function is defined as the specific absorption rate ratio in the tumour and healthy tissues. Several constraints, regarding the specific absorption rate in tumour and the total power in the patient, may be prescribed. Results obtained with two types of applicators (waveguides and annular phased array) are presented and show the faculties of the developed optimization process.

Optimal control and optimal trajectories of regional macroeconomic dynamics based on the Pontryagin maximum principle

NASA Astrophysics Data System (ADS)

Bulgakov, V. K.; Strigunov, V. V.

2009-05-01

The Pontryagin maximum principle is used to prove a theorem concerning optimal control in regional macroeconomics. A boundary value problem for optimal trajectories of the state and adjoint variables is formulated, and optimal curves are analyzed. An algorithm is proposed for solving the boundary value problem of optimal control. The performance of the algorithm is demonstrated by computing an optimal control and the corresponding optimal trajectories.

Optimization Under Uncertainty for Wake Steering Strategies

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

Quick, Julian; Annoni, Jennifer; King, Ryan N

2017-08-03

This presentation covers the motivation for this research, optimization under the uncertainty problem formulation, a two-turbine case, the Princess Amalia Wind Farm case, and conclusions and next steps.

Computational experiments in the optimal slewing of flexible structures

NASA Technical Reports Server (NTRS)

Baker, T. E.; Polak, Lucian Elijah

1989-01-01

Numerical experiments on the problem of moving a flexible beam are discussed. An optimal control problem is formulated and transcribed into a form which can be solved using semi-infinite optimization techniques. All experiments were carried out on a SUN 3 microcomputer.

Truss topology optimization with simultaneous analysis and design

NASA Technical Reports Server (NTRS)

Sankaranarayanan, S.; Haftka, Raphael T.; Kapania, Rakesh K.

1992-01-01

Strategies for topology optimization of trusses for minimum weight subject to stress and displacement constraints by Simultaneous Analysis and Design (SAND) are considered. The ground structure approach is used. A penalty function formulation of SAND is compared with an augmented Lagrangian formulation. The efficiency of SAND in handling combinations of general constraints is tested. A strategy for obtaining an optimal topology by minimizing the compliance of the truss is compared with a direct weight minimization solution to satisfy stress and displacement constraints. It is shown that for some problems, starting from the ground structure and using SAND is better than starting from a minimum compliance topology design and optimizing only the cross sections for minimum weight under stress and displacement constraints. A member elimination strategy to save CPU time is discussed.

An integrated prediction and optimization model of biogas production system at a wastewater treatment facility.

PubMed

Akbaş, Halil; Bilgen, Bilge; Turhan, Aykut Melih

2015-11-01

This study proposes an integrated prediction and optimization model by using multi-layer perceptron neural network and particle swarm optimization techniques. Three different objective functions are formulated. The first one is the maximization of methane percentage with single output. The second one is the maximization of biogas production with single output. The last one is the maximization of biogas quality and biogas production with two outputs. Methane percentage, carbon dioxide percentage, and other contents' percentage are used as the biogas quality criteria. Based on the formulated models and data from a wastewater treatment facility, optimal values of input variables and their corresponding maximum output values are found out for each model. It is expected that the application of the integrated prediction and optimization models increases the biogas production and biogas quality, and contributes to the quantity of electricity production at the wastewater treatment facility. Copyright © 2015 Elsevier Ltd. All rights reserved.

Numerical solution of a conspicuous consumption model with constant control delay☆

PubMed Central

Huschto, Tony; Feichtinger, Gustav; Hartl, Richard F.; Kort, Peter M.; Sager, Sebastian; Seidl, Andrea

2011-01-01

We derive optimal pricing strategies for conspicuous consumption products in periods of recession. To that end, we formulate and investigate a two-stage economic optimal control problem that takes uncertainty of the recession period length and delay effects of the pricing strategy into account. This non-standard optimal control problem is difficult to solve analytically, and solutions depend on the variable model parameters. Therefore, we use a numerical result-driven approach. We propose a structure-exploiting direct method for optimal control to solve this challenging optimization problem. In particular, we discretize the uncertainties in the model formulation by using scenario trees and target the control delays by introduction of slack control functions. Numerical results illustrate the validity of our approach and show the impact of uncertainties and delay effects on optimal economic strategies. During the recession, delayed optimal prices are higher than the non-delayed ones. In the normal economic period, however, this effect is reversed and optimal prices with a delayed impact are smaller compared to the non-delayed case. PMID:22267871

[Preparation and quality control of pyridostigmine bromide orally disintegrating tablet].

PubMed

Zhang, Li; Tan, Qun-you; Cheng, Xun-guan; Wang, Hong; Hu, Ni-ni; Zhang, Jing-qing

2012-05-01

To prepare orally disintegrating tablets containing pyridostigmine bromide and optimize formulations. Solid dispersion was prepared using solvent evaporation-deposition method. The formulation was optimized by central composite design-response surface methodology (RSM plus CCD) with disintegration time as a reference parameter. The orally disintegrating tablets showed integrity and were smooth with desirable taste and feel in mouth. The disintegration time was less than 30 s. The cumulative drug dissolution was around 8.5% (around 2.5 mg which was less than bitterness threshold of pyridostigmine bromide of 3 mg) within 5 min in water while the cumulative drug dissolution was higher than 95% within 2 min in 0.1 N HCl. The orally disintegrating tablets are reasonable in formulation, feasible in technology and patient-friendly.

Global dynamic optimization approach to predict activation in metabolic pathways.

PubMed

de Hijas-Liste, Gundián M; Klipp, Edda; Balsa-Canto, Eva; Banga, Julio R

2014-01-06

During the last decade, a number of authors have shown that the genetic regulation of metabolic networks may follow optimality principles. Optimal control theory has been successfully used to compute optimal enzyme profiles considering simple metabolic pathways. However, applying this optimal control framework to more general networks (e.g. branched networks, or networks incorporating enzyme production dynamics) yields problems that are analytically intractable and/or numerically very challenging. Further, these previous studies have only considered a single-objective framework. In this work we consider a more general multi-objective formulation and we present solutions based on recent developments in global dynamic optimization techniques. We illustrate the performance and capabilities of these techniques considering two sets of problems. First, we consider a set of single-objective examples of increasing complexity taken from the recent literature. We analyze the multimodal character of the associated non linear optimization problems, and we also evaluate different global optimization approaches in terms of numerical robustness, efficiency and scalability. Second, we consider generalized multi-objective formulations for several examples, and we show how this framework results in more biologically meaningful results. The proposed strategy was used to solve a set of single-objective case studies related to unbranched and branched metabolic networks of different levels of complexity. All problems were successfully solved in reasonable computation times with our global dynamic optimization approach, reaching solutions which were comparable or better than those reported in previous literature. Further, we considered, for the first time, multi-objective formulations, illustrating how activation in metabolic pathways can be explained in terms of the best trade-offs between conflicting objectives. This new methodology can be applied to metabolic networks with arbitrary topologies, non-linear dynamics and constraints.

Synthesis and characterization of emamectin-benzoate slow-release microspheres with different surfactants.

PubMed

Wang, Yan; Wang, Anqi; Wang, Chunxin; Cui, Bo; Sun, Changjiao; Zhao, Xiang; Zeng, Zhanghua; Shen, Yue; Gao, Fei; Liu, Guoqiang; Cui, Haixin

2017-10-06

Pesticide slow-release formulations provide a way to increase the efficiency of active components by reducing the amount of pesticide that needs to be applied. Slow-release formulations also increase the stability and prolong the control effect of photosensitive pesticides. Surfactants are an indispensable part of pesticide formulations, and the choice of surfactant can strongly affect formulation performance. In this study, emamectin-benzoate (EMB) slow-release microspheres were prepared by the microemulsion polymerization method. We explored the effect of different surfactants on the particle size and dispersity of EMB in slow-release microspheres. The results indicated that the samples had uniform spherical shapes with an average diameter of 320.5 ±5.24 nm and good dispersity in the optimal formulation with the polymeric stabilizer polyvinyl alcohol (PVA) and composite non-ionic surfactant polyoxyethylene castor oil (EL-40). The optimal EMB pesticide slow-release microspheres had excellent anti-photolysis performance, stability, controlled release properties, and good leaf distribution. These results demonstrated that EMB slow-release microspheres are an attractive candidate for improving pesticide efficacy and prolonging the control effect of EMB in the environment.

Wireless Sensor Network Optimization: Multi-Objective Paradigm.

PubMed

Iqbal, Muhammad; Naeem, Muhammad; Anpalagan, Alagan; Ahmed, Ashfaq; Azam, Muhammad

2015-07-20

Optimization problems relating to wireless sensor network planning, design, deployment and operation often give rise to multi-objective optimization formulations where multiple desirable objectives compete with each other and the decision maker has to select one of the tradeoff solutions. These multiple objectives may or may not conflict with each other. Keeping in view the nature of the application, the sensing scenario and input/output of the problem, the type of optimization problem changes. To address different nature of optimization problems relating to wireless sensor network design, deployment, operation, planing and placement, there exist a plethora of optimization solution types. We review and analyze different desirable objectives to show whether they conflict with each other, support each other or they are design dependent. We also present a generic multi-objective optimization problem relating to wireless sensor network which consists of input variables, required output, objectives and constraints. A list of constraints is also presented to give an overview of different constraints which are considered while formulating the optimization problems in wireless sensor networks. Keeping in view the multi facet coverage of this article relating to multi-objective optimization, this will open up new avenues of research in the area of multi-objective optimization relating to wireless sensor networks.

Distance Metric Learning via Iterated Support Vector Machines.

PubMed

Zuo, Wangmeng; Wang, Faqiang; Zhang, David; Lin, Liang; Huang, Yuchi; Meng, Deyu; Zhang, Lei

2017-07-11

Distance metric learning aims to learn from the given training data a valid distance metric, with which the similarity between data samples can be more effectively evaluated for classification. Metric learning is often formulated as a convex or nonconvex optimization problem, while most existing methods are based on customized optimizers and become inefficient for large scale problems. In this paper, we formulate metric learning as a kernel classification problem with the positive semi-definite constraint, and solve it by iterated training of support vector machines (SVMs). The new formulation is easy to implement and efficient in training with the off-the-shelf SVM solvers. Two novel metric learning models, namely Positive-semidefinite Constrained Metric Learning (PCML) and Nonnegative-coefficient Constrained Metric Learning (NCML), are developed. Both PCML and NCML can guarantee the global optimality of their solutions. Experiments are conducted on general classification, face verification and person re-identification to evaluate our methods. Compared with the state-of-the-art approaches, our methods can achieve comparable classification accuracy and are efficient in training.

Application of fuzzy theories to formulation of multi-objective design problems. [for helicopters

NASA Technical Reports Server (NTRS)

Dhingra, A. K.; Rao, S. S.; Miura, H.

1988-01-01

Much of the decision making in real world takes place in an environment in which the goals, the constraints, and the consequences of possible actions are not known precisely. In order to deal with imprecision quantitatively, the tools of fuzzy set theory can by used. This paper demonstrates the effectiveness of fuzzy theories in the formulation and solution of two types of helicopter design problems involving multiple objectives. The first problem deals with the determination of optimal flight parameters to accomplish a specified mission in the presence of three competing objectives. The second problem addresses the optimal design of the main rotor of a helicopter involving eight objective functions. A method of solving these multi-objective problems using nonlinear programming techniques is presented. Results obtained using fuzzy formulation are compared with those obtained using crisp optimization techniques. The outlined procedures are expected to be useful in situations where doubt arises about the exactness of permissible values, degree of credibility, and correctness of statements and judgements.

Robust Control Design for Systems With Probabilistic Uncertainty

NASA Technical Reports Server (NTRS)

Crespo, Luis G.; Kenny, Sean P.

2005-01-01

This paper presents a reliability- and robustness-based formulation for robust control synthesis for systems with probabilistic uncertainty. In a reliability-based formulation, the probability of violating design requirements prescribed by inequality constraints is minimized. In a robustness-based formulation, a metric which measures the tendency of a random variable/process to cluster close to a target scalar/function is minimized. A multi-objective optimization procedure, which combines stability and performance requirements in time and frequency domains, is used to search for robustly optimal compensators. Some of the fundamental differences between the proposed strategy and conventional robust control methods are: (i) unnecessary conservatism is eliminated since there is not need for convex supports, (ii) the most likely plants are favored during synthesis allowing for probabilistic robust optimality, (iii) the tradeoff between robust stability and robust performance can be explored numerically, (iv) the uncertainty set is closely related to parameters with clear physical meaning, and (v) compensators with improved robust characteristics for a given control structure can be synthesized.

Optimization of conditions for probiotic curd formulation by Enterococcus faecium MTCC 5695 with probiotic properties using response surface methodology.

PubMed

Ramakrishnan, Vrinda; Goveas, Louella Concepta; Prakash, Maya; Halami, Prakash M; Narayan, Bhaskar

2014-11-01

Enterococcus faecium MTCC 5695 possessing potential probiotic properties as well as enterocin producing ability was used as starter culture. Effect of time (12-24 h) and inoculum level (3-7 % v/v) on cell growth, bacteriocin production, antioxidant property, titrable acidity and pH of curd was studied by response surface methodology (RSM). The optimized conditions were 26.48 h and 2.17%v/v inoculum and the second order model validated. Co cultivation studies revealed that the formulated product had the ability to prevent growth of foodborne pathogens that affect keeping quality of the product during storage. The results indicated that application of E. faecium MTCC 5695 along with usage of optimized conditions attributed to the formation of highly consistent well set curd with bioactive and bioprotective properties. Formulated curd with potential probiotic attributes can be used as therapeutic agent for the treatment of foodborne diseases like Traveler's diarrhea and gastroenteritis which thereby help in improvement of bowel health.

The fluid dynamic approach to equidistribution methods for grid generation and adaptation

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

Delzanno, Gian Luca; Finn, John M

2009-01-01

The equidistribution methods based on L{sub p} Monge-Kantorovich optimization [Finn and Delzanno, submitted to SISC, 2009] and on the deformation [Moser, 1965; Dacorogna and Moser, 1990, Liao and Anderson, 1992] method are analyzed primarily in the context of grid generation. It is shown that the first class of methods can be obtained from a fluid dynamic formulation based on time-dependent equations for the mass density and the momentum density, arising from a variational principle. In this context, deformation methods arise from a fluid formulation by making a specific assumption on the time evolution of the density (but with some degreemore » of freedom for the momentum density). In general, deformation methods do not arise from a variational principle. However, it is possible to prescribe an optimal deformation method, related to L{sub 1} Monge-Kantorovich optimization, by making a further assumption on the momentum density. Some applications of the L{sub p} fluid dynamic formulation to imaging are also explored.« less

An Optimization-Based Approach to Determine Requirements and Aircraft Design under Multi-domain Uncertainties

NASA Astrophysics Data System (ADS)

Govindaraju, Parithi

Determining the optimal requirements for and design variable values of new systems, which operate along with existing systems to provide a set of overarching capabilities, as a single task is challenging due to the highly interconnected effects that setting requirements on a new system's design can have on how an operator uses this newly designed system. This task of determining the requirements and the design variable values becomes even more difficult because of the presence of uncertainties in the new system design and in the operational environment. This research proposed and investigated aspects of a framework that generates optimum design requirements of new, yet-to-be-designed systems that, when operating alongside other systems, will optimize fleet-level objectives while considering the effects of various uncertainties. Specifically, this research effort addresses the issues of uncertainty in the design of the new system through reliability-based design optimization methods, and uncertainty in the operations of the fleet through descriptive sampling methods and robust optimization formulations. In this context, fleet-level performance metrics result from using the new system alongside other systems to accomplish an overarching objective or mission. This approach treats the design requirements of a new system as decision variables in an optimization problem formulation that a user in the position of making an acquisition decision could solve. This solution would indicate the best new system requirements-and an associated description of the best possible design variable variables for that new system-to optimize the fleet level performance metric(s). Using a problem motivated by recorded operations of the United States Air Force Air Mobility Command for illustration, the approach is demonstrated first for a simplified problem that only considers demand uncertainties in the service network and the proposed methodology is used to identify the optimal design requirements and optimal aircraft sizing variables of new, yet-to-be-introduced aircraft. With this new aircraft serving alongside other existing aircraft, the fleet of aircraft satisfy the desired demand for cargo transportation, while maximizing fleet productivity and minimizing fuel consumption via a multi-objective problem formulation. The approach is then extended to handle uncertainties in both the design of the new system and in the operations of the fleet. The propagation of uncertainties associated with the conceptual design of the new aircraft to the uncertainties associated with the subsequent operations of the new and existing aircraft in the fleet presents some unique challenges. A computationally tractable hybrid robust counterpart formulation efficiently handles the confluence of the two types of domain-specific uncertainties. This hybrid formulation is tested on a larger route network problem to demonstrate the scalability of the approach. Following the presentation of the results obtained, a summary discussion indicates how decision-makers might use these results to set requirements for new aircraft that meet operational needs while balancing the environmental impact of the fleet with fleet-level performance. Comparing the solutions from the uncertainty-based and deterministic formulations via a posteriori analysis demonstrates the efficacy of the robust and reliability-based optimization formulations in addressing the different domain-specific uncertainties. Results suggest that the aircraft design requirements and design description determined through the hybrid robust counterpart formulation approach differ from solutions obtained from the simplistic deterministic approach, and leads to greater fleet-level fuel savings, when subjected to real-world uncertain scenarios (more robust to uncertainty). The research, though applied to a specific air cargo application, is technically agnostic in nature and can be applied to other facets of policy and acquisition management, to explore capability trade spaces for different vehicle systems, mitigate risks, define policy and potentially generate better returns on investment. Other domains relevant to policy and acquisition decisions could utilize the problem formulation and solution approach proposed in this dissertation provided that the problem can be split into a non-linear programming problem to describe the new system sizing and the fleet operations problem can be posed as a linear/integer programming problem.

Baseline LAW Glass Formulation Testing

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

Kruger, Albert A.; Mooers, Cavin; Bazemore, Gina

2013-06-13

The major objective of the baseline glass formulation work was to develop and select glass formulations that are compliant with contractual and processing requirements for each of the LAW waste streams. Other objectives of the work included preparation and characterization of glasses with respect to the properties of interest, optimization of sulfate loading in the glasses, evaluation of ability to achieve waste loading limits, testing to demonstrate compatibility of glass melts with melter materials of construction, development of glass formulations to support ILAW qualification activities, and identification of glass formulation issues with respect to contract specifications and processing requirements.

The effect of parking orbit constraints on the optimization of ballistic planetary trajectories

NASA Technical Reports Server (NTRS)

Sauer, C. G., Jr.

1984-01-01

The optimization of ballistic planetary trajectories is developed which includes constraints on departure parking orbit inclination and node. This problem is formulated to result in a minimum total Delta V where the entire constrained injection Delta V is included in the optimization. An additional Delta V is also defined to allow for possible optimization of parking orbit inclination when the launch vehicle orbit capability varies as a function of parking orbit inclination. The optimization problem is formulated using primer vector theory to derive partial derivatives of total Delta V with respect to possible free parameters. Minimization of total Delta V is accomplished using a quasi-Newton gradient search routine. The analysis is applied to an Eros rendezvous mission whose transfer trajectories are characterized by high values of launch asymptote declination during particular launch opportunities. Comparisons in performance are made between trajectories where parking orbit constraints are included in the optimization and trajectories where the constraints are not included.

Formulation and Evaluation of Long Circulating Liposomal Amphotericin B: A Scinti-kinetic Study using 99mTc in BALB/C Mice

PubMed Central

Jadhav, M. P.; Nagarsenker, Mangal S.; Gaikwad, R. V.; Samad, A.; Kshirsagar, Nilima A.

2011-01-01

In the present study, we formulated long circulating liposomes for amphotericin B and characterized them. The formulation was optimized using 23 factorial designs. Pegylated liposomal formulation showed favorable results with reference to particle size (247.33±9.60 nm), percent entrapment efficiency (94.55±3.34%). TEM studies revealed that the liposomes were essentially spherical, hollow, and appeared like powder puff structures. From DSC study it was concluded that the pegylated formulation containing Amp B showed better stability and membrane integrity of the formulation. During the stability studies the formulation was found to be stable. When subjected to gamma scintigraphy kinetic tracer studies the formulation showed longer residence time in the blood in BALB/C mice. PMID:22131622

New displacement-based methods for optimal truss topology design

NASA Technical Reports Server (NTRS)

Bendsoe, Martin P.; Ben-Tal, Aharon; Haftka, Raphael T.

1991-01-01

Two alternate methods for maximum stiffness truss topology design are presented. The ground structure approach is used, and the problem is formulated in terms of displacements and bar areas. This large, nonconvex optimization problem can be solved by a simultaneous analysis and design approach. Alternatively, an equivalent, unconstrained, and convex problem in the displacements only can be formulated, and this problem can be solved by a nonsmooth, steepest descent algorithm. In both methods, the explicit solving of the equilibrium equations and the assembly of the global stiffness matrix are circumvented. A large number of examples have been studied, showing the attractive features of topology design as well as exposing interesting features of optimal topologies.

Benchmarking optimization software with COPS.

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

Dolan, E.D.; More, J.J.

2001-01-08

The COPS test set provides a modest selection of difficult nonlinearly constrained optimization problems from applications in optimal design, fluid dynamics, parameter estimation, and optimal control. In this report we describe version 2.0 of the COPS problems. The formulation and discretization of the original problems have been streamlined and improved. We have also added new problems. The presentation of COPS follows the original report, but the description of the problems has been streamlined. For each problem we discuss the formulation of the problem and the structural data in Table 0.1 on the formulation. The aim of presenting this data ismore » to provide an approximate idea of the size and sparsity of the problem. We also include the results of computational experiments with the LANCELOT, LOQO, MINOS, and SNOPT solvers. These computational experiments differ from the original results in that we have deleted problems that were considered to be too easy. Moreover, in the current version of the computational experiments, each problem is tested with four variations. An important difference between this report and the original report is that the tables that present the computational experiments are generated automatically from the testing script. This is explained in more detail in the report.« less

Development of Probiotic Formulation for the Treatment of Iron Deficiency Anemia.

PubMed

Korčok, Davor Jovan; Tršić-Milanović, Nada Aleksandar; Ivanović, Nevena Djuro; Đorđević, Brižita Ivan

2018-04-01

Probiotics are increasingly more present both as functional foods, and in pharmaceutical preparations with multiple levels of action that contribute to human health. Probiotics realize their positive effects with a proper dose, and by maintaining a declared number of probiotics cells by the expiration date. Important precondition for developing a probiotic product is the right choice of clinically proven probiotic strain, the choice of other active components, as well as, the optimization of the quantity of active component of probiotic per product dose. This scientific paper describes the optimization of the number of probiotics cells in the formulation of dietary supplement that contains probiotic culture Lactobacillus plantarum 299v, iron and vitamin C. Variations of the quantity of active component were analyzed in development batches of the encapsulated probiotic product categorized as dietary supplement with the following ingredients: probiotic culture, sucrosomal form of iron and vitamin C. Optimal quantity of active component L. plantarum of 50 mg, was selected. The purpose of this scientific paper is to select the optimal formulation of probiotic culture in a dietary supplement that contains iron and vitamin C, and to also determine its expiration date by the analysis of the number of viable probiotic cells.

Pharmaceutical development and optimization of azithromycin suppository for paediatric use.

PubMed

Kauss, Tina; Gaubert, Alexandra; Boyer, Chantal; Ba, Boubakar B; Manse, Muriel; Massip, Stephane; Léger, Jean-Michel; Fawaz, Fawaz; Lembege, Martine; Boiron, Jean-Michel; Lafarge, Xavier; Lindegardh, Niklas; White, Nicholas J; Olliaro, Piero; Millet, Pascal; Gaudin, Karen

2013-01-30

Pharmaceutical development and manufacturing process optimization work was undertaken in order to propose a potential paediatric rectal formulation of azithromycin as an alternative to existing oral or injectable formulations. The target product profile was to be easy-to-use, cheap and stable in tropical conditions, with bioavailability comparable to oral forms, rapidly achieving and maintaining bactericidal concentrations. PEG solid solution suppositories were characterized in vitro using visual, HPLC, DSC, FTIR and XRD analyses. In vitro drug release and in vivo bioavailability were assessed; a study in rabbits compared the bioavailability of the optimized solid solution suppository to rectal solution and intra-venous product (as reference) and to the previous, non-optimized formulation (suspended azithromycin suppository). The bioavailability of azithromycin administered as solid solution suppositories relative to intra-venous was 43%, which compared well to the target of 38% (oral product in humans). The results of 3-month preliminary stability and feasibility studies were consistent with industrial production scale-up. This product has potential both as a classical antibiotic and as a product for use in severely ill children in rural areas. Industrial partners for further development are being sought. Copyright © 2012 Elsevier B.V. All rights reserved.

Pharmaceutical development and optimization of azithromycin suppository for paediatric use

PubMed Central

Kauss, Tina; Gaubert, Alexandra; Boyer, Chantal; Ba, Boubakar B.; Manse, Muriel; Massip, Stephane; Léger, Jean-Michel; Fawaz, Fawaz; Lembege, Martine; Boiron, Jean-Michel; Lafarge, Xavier; Lindegardh, Niklas; White, Nicholas J.; Olliaro, Piero; Millet, Pascal; Gaudin, Karen

2013-01-01

Pharmaceutical development and manufacturing process optimization work was undertaken in order to propose a potential paediatric rectal formulation of azithromycin as an alternative to existing oral or injectable formulations. The target product profile was to be easy-to-use, cheap and stable in tropical conditions, with bioavailability comparable to oral forms, rapidly achieving and maintaining bactericidal concentrations. PEG solid solution suppositories were characterized in vitro using visual, HPLC, DSC, FTIR and XRD analyses. In vitro drug release and in vivo bioavailability were assessed; a study in rabbits compared the bioavailability of the optimized solid solution suppository to rectal solution and intra-venous product (as reference) and to the previous, non-optimized formulation (suspended azithromycin suppository). The bioavailability of azithromycin administered as solid solution suppositories relative to intra-venous was 43%, which compared well to the target of 38% (oral product in humans). The results of 3-month preliminary stability and feasibility studies were consistent with industrial production scale-up. This product has potential both as a classical antibiotic and as a product for use in severely ill children in rural areas. Industrial partners for further development are being sought. PMID:23220079

Optimization of Premix Powders for Tableting Use.

PubMed

Todo, Hiroaki; Sato, Kazuki; Takayama, Kozo; Sugibayashi, Kenji

2018-05-08

Direct compression is a popular choice as it provides the simplest way to prepare the tablet. It can be easily adopted when the active pharmaceutical ingredient (API) is unstable in water or to thermal drying. An optimal formulation of preliminary mixed powders (premix powders) is beneficial if prepared in advance for tableting use. The aim of this study was to find the optimal formulation of the premix powders composed of lactose (LAC), cornstarch (CS), and microcrystalline cellulose (MCC) by using statistical techniques. Based on the "Quality by Design" concept, a (3,3)-simplex lattice design consisting of three components, LAC, CS, and MCC was employed to prepare the model premix powders. Response surface method incorporating a thin-plate spline interpolation (RSM-S) was applied for estimation of the optimum premix powders for tableting use. The effect of tablet shape identified by the surface curvature on the optimization was investigated. The optimum premix powder was effective when the premix was applied to a small quantity of API, although the function of premix was limited in the case of the formulation of large amount of API. Statistical techniques are valuable to exploit new functions of well-known materials such as LAC, CS, and MCC.

Optimization of Robust HPLC Method for Quantitation of Ambroxol Hydrochloride and Roxithromycin Using a DoE Approach.

PubMed

Patel, Rashmin B; Patel, Nilay M; Patel, Mrunali R; Solanki, Ajay B

2017-03-01

The aim of this work was to develop and optimize a robust HPLC method for the separation and quantitation of ambroxol hydrochloride and roxithromycin utilizing Design of Experiment (DoE) approach. The Plackett-Burman design was used to assess the impact of independent variables (concentration of organic phase, mobile phase pH, flow rate and column temperature) on peak resolution, USP tailing and number of plates. A central composite design was utilized to evaluate the main, interaction, and quadratic effects of independent variables on the selected dependent variables. The optimized HPLC method was validated based on ICH Q2R1 guideline and was used to separate and quantify ambroxol hydrochloride and roxithromycin in tablet formulations. The findings showed that DoE approach could be effectively applied to optimize a robust HPLC method for quantification of ambroxol hydrochloride and roxithromycin in tablet formulations. Statistical comparison between results of proposed and reported HPLC method revealed no significant difference; indicating the ability of proposed HPLC method for analysis of ambroxol hydrochloride and roxithromycin in pharmaceutical formulations. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

[Optimization and characterization of curcumin-piperine dual drug loaded self-microemulsifying drug delivery system by simplex lattice design].

PubMed

Li, Qiu-Ping; Dai, Jun-Dong; Zhai, Wen-Wen; Jiang, Qiao-Li

2014-10-01

The objective of the study was to prepare and evaluate the quality of curcumin-piperinedual drug loaded self-microemulsifying drug delivery system(Cur-PIP-SMEDDS). Simplex lattice design was constructed using optimal oil phase, surfactant and co-surfactant concentration as independent variables, and the curcumin and piperine were used as model drugs to optimize Cur-PIP-SMEDDS formulation. In the present study, the drug loadings of curcumin and piperine, mean particle size of Cur-PIP-SMEDDS were made as indicators, and the experiment design, model building and response surface analysis were established using Design Expert 8. 06 software to optimize and verify the composition of SMEDDS formulation. The quality of Cur-PIP-SMEDDS was evaluated by observing the appearance status, transmission electron microscope micrographs and determining particle diameter, electric potential, drug entrapment efficiency and drug loading of it. As a result, the optimal formulation of SMEDDS was CapryoL 90-Cremophor RH40-TranscutoL HP (10:60:30). The appearance of Cur-PIP-SMEDDS remained clarified and transparent, and the microemulsion droplets appeared spherical without aggregation with uniform particle size distribution. The mean size of microemulsion droplet formed from Cur-PIP-SMEDDS was 15.33 nm, the drug loading of SMEDDS for Cur and PIP were 40.90 mg · g(-1) and 0.97 mg · g(-1), respectively, the drug entrapment efficiency were 94.98% and 90.96%, respectively. The results show that Cur-PIP-SMEDDS can increase the solubility and stability of curcumin significantly, in the expectation of enhancing the bioavailability of it. Taken together, these findings can provide the reference to a preferable choice of the Cur formulation and contribute to therapeutic application in clinical research.

Optimization of liposomal topotecan for use in treating neuroblastoma.

PubMed

Chernov, Lina; Deyell, Rebecca J; Anantha, Malathi; Dos Santos, Nancy; Gilabert-Oriol, Roger; Bally, Marcel B

2017-06-01

The purpose of this work was to develop an optimized liposomal formulation of topotecan for use in the treatment of patients with neuroblastoma. Drug exposure time studies were used to determine that topotecan (Hycamtin) exhibited great cytotoxic activity against SK-N-SH, IMR-32 and LAN-1 neuroblastoma human cell lines. Sphingomyelin (SM)/cholesterol (Chol) and 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)/Chol liposomes were prepared using extrusion methods and then loaded with topotecan by pH gradient and copper-drug complexation. In vitro studies showed that SM/Chol liposomes retained topotecan significantly better than DSPC/Chol liposomes. Decreasing the drug-to-lipid ratio engendered significant increases in drug retention. Dose-range finding studies on NRG mice indicated that an optimized SM/Chol liposomal formulation of topotecan prepared with a final drug-to-lipid ratio of 0.025 (mol: mol) was better tolerated than the previously described DSPC/Chol topotecan formulation. Pharmacokinetic studies showed that the optimized SM/Chol liposomal topotecan exhibited a 10-fold increase in plasma half-life and a 1000-fold increase in AUC 0-24 h when compared with Hycamtin administered at equivalent doses (5 mg/kg). In contrast to the great extension in exposure time, SM/Chol liposomal topotecan increased the life span of mice with established LAN-1 neuroblastoma tumors only modestly in a subcutaneous and systemic model. The extension in exposure time may still not be sufficient and the formulation may require further optimization. In the future, liposomal topotecan will be assessed in combination with high-dose radiotherapy such as 131 I-metaiodobenzylguanidine, and immunotherapy treatment modalities currently used in neuroblastoma therapy. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Optimization and characterization of spray-dried IgG formulations: a design of experiment approach.

PubMed

Faghihi, Homa; Najafabadi, Abdolhosein Rouholamini; Vatanara, Alireza

2017-10-24

The purpose of the present study is to optimize a spray-dried formulation as a model antibody regarding stability and aerodynamic property for further aerosol therapy of this group of macromolecules. A three-factor, three-level, Box-Behnken design was employed milligrams of Cysteine (X 1 ), Trehalose (X 2 ), and Tween 20 (X 3 ) as independent variables. The dependent variables were quantified and the optimized formulation was prepared accordingly. SEC-HPLC and FTIR-spectroscopy were conducted to evaluate the molecular and structural status of spray-dried preparations. Particle characterization of optimized sample was performed with the aid of DSC, SEM, and TSI examinations. Experimental responses of a total of 17 formulations resulted in yield values, (Y 1 ), ranging from 21.1 ± 0.2 to 40.2 ± 0.1 (%); beta-sheet content, (Y 2 ), from 66.22 ± 0.19 to 73.78 ± 0.26 (%); amount of aggregation following process, (Y 3 ), ranging from 0.11 ± 0.03 to 0.95 ± 0.03 (%); and amount of aggregation upon storage, (Y 4 ), from 0.81 ± 0.01 to 3.13 ± 0.64 (%) as dependent variables. Results-except for those of the beta sheet content-were fitted to quadratic models describing the inherent relationship between main factors. Co-application of Cysteine and Tween 20 preserved antibody molecules from molecular degradation and improved immediate and accelerated stability of spry-dried antibodies. Validation of the optimization study indicated high degree of prognostic ability of response surface methodology in preparation of stable spray-dried IgG. Graphical abstract Spray drying of IgG in the presence of Trehalose, Cysteine and Tween 20.

Optimization of carboxylate-terminated poly(amidoamine) dendrimer-mediated cisplatin formulation.

PubMed

Kulhari, Hitesh; Pooja, Deep; Singh, Mayank K; Chauhan, Abhay S

2015-02-01

Abstract Cisplatin is mainly used in the treatment of ovarian, head and neck and testicular cancer. Poor solubility and non-specific interactions causes hurdles in the development of successful cisplatin formulation. There were few reports on poly(amidoamine) (PAMAM) dendrimer-cisplatin complexes for anticancer treatment. But the earlier research was mainly focused on therapeutic effect of PAMAM dendrimer-cisplatin complex, with less attention paid on the formulation development of these complexes. Objective of the present study is to optimize and validate the carboxylate-terminated, EDA core PAMAM dendrimer-based cisplatin formulation with respect to various variables such as dendrimer core, generation, drug entrapment, purification, yield, reproducibility, stability, storage and in-vitro release. Dendrimer-cisplatin complex was prepared by an efficient method which significantly increases the % platinum (Pt) content along with the product yield. Dendrimers showed reproducible (∼27%) platinum loading by weight. Variation in core and generations does not produce significant change in the % Pt content. Percentage Pt content of dendrimeric formulation increases with increase in drug/dendrimer mole ratio. Formulation with low drug/dendrimer mole ratio showed delayed release compared to the higher drug/dendrimer mole ratio; these dendrimer formulations are stable in room temperature. In vitro release profiles of the stored dendrimer-cisplatin samples showed comparatively slow release of cisplatin, which may be due to formation of strong bond between cisplatin and dendrimer. This study will contribute to create a fine print for the formulation development of PAMAM dendrimer-cisplatin complexes.

Development and evaluation of in situ gel of pregabalin

PubMed Central

Madan, Jyotsana R; Adokar, Bhushan R; Dua, Kamal

2015-01-01

Aim and Background: Pregabalin (PRG), an analog of gamma-aminobutyric acid, reduces the release of many neurotransmitters, including glutamate, and noradrenaline. It is used for the treatment of epilepsy; simple and complex partial convulsion. The present research work aims to ensure a high drug absorption by retarding the advancement of PRG formulation through the gastrointestinal tract. The work aims to design a controlled release PRG formulation which is administered as liquid and further gels in the stomach and floats in gastric juice. Materials and Methods: In situ gelling formulations were prepared using sodium alginate, calcium chloride, sodium citrate, hydroxypropyl methylcellulose (HPMC) K100M, and sodium bicarbonate. The prepared formulations were evaluated for solution viscosity, drug content, in vitro gelling studies, gel strength, and in vitro drug release. The final formulation was optimized using a 32 full factorial design. Results: The formulation containing 2.5% w/v sodium alginate and 0.2% w/v calcium chloride were considered optimum since it showed minimum floating lag time (18 s), optimum viscosity (287.3 cps), and gel strength (4087.17 dyne/cm2). The optimized formulation follows Korsmeyer-Peppas kinetic model with n value 0.3767 representing Fickian diffusion mechanism of drug release. Conclusion: Floating in situ gelling system of PRG can be formulated using sodium alginate as a gelling polymer and calcium chloride as a complexing agent to control the drug release for about 12 h for the treatment of epilepsy. PMID:26682193

Formulation and evaluation of voriconazole ophthalmic solid lipid nanoparticles in situ gel.

PubMed

Pandurangan, Dinesh Kumar; Bodagala, Prathima; Palanirajan, Vijayaraj Kumar; Govindaraj, Saravanan

2016-01-01

In the present investigation, solid lipid nanoparticles (SLNs)-loaded in situ gel with voriconazole drug was formulated. Further, the formulation was characterized for pH, gelling capacity, entrapment efficiency, in vitro drug release, drug content, and viscosity. Voriconazole is an antifungal drug used to treat various infections caused by yeast or other types of fungi. Film hydration technique was used to prepared SLNs from lecithin and cholesterol. Based on the entrapment efficiency 67.2-97.3% and drug release, the optimized formulation NF1 of SLNs was incorporated into in situ gels. The in situ gels were prepared using viscosity-enhancing polymers such as Carbopol and (hydroxypropyl)methyl cellulose (HPMC). Formulated SLN in situ gel formulations were characterized, which showed pH 4.9-7.1, drug content 65.69-96.3%, and viscosity (100 rpm) 120-620 cps. From the characterizations given above, F6 was optimized and evaluated for microbial assay and ocular irritation studies. Microbial assay was conducted by the cup-plate method using Candida albicans as the test organism. An ocular irritation study was conducted on albino rabbits. The results revealed that there was no ocular damage to the cornea, conjunctiva, or iris. Stability studies were carried out on the F6 formulation for 3 months, which showed that the formulation had good stability. These results indicate that the studied SLNs-loaded in situ gel is a promising vehicle for ocular delivery.

Formulation, functional evaluation and ex vivo performance of thermoresponsive soluble gels - A platform for therapeutic delivery to mucosal sinus tissue.

PubMed

Pandey, Preeti; Cabot, Peter J; Wallwork, Benjamin; Panizza, Benedict J; Parekh, Harendra S

2017-01-01

Mucoadhesive in situ gelling systems (soluble gels) have received considerable attention recently as effective stimuli-transforming vectors for a range of drug delivery applications. Considering this fact, the present work involves systematic formulation development, optimization, functional evaluation and ex vivo performance of thermosensitive soluble gels containing dexamethasone 21-phosphate disodium salt (DXN) as the model therapeutic. A series of in situ gel-forming systems comprising the thermoreversible polymer poloxamer-407 (P407), along with hydroxypropyl methyl cellulose (HPMC) and chitosan were first formulated. The optimized soluble gels were evaluated for their potential to promote greater retention at the mucosal surface, for improved therapeutic efficacy, compared to existing solution/suspension-based steroid formulations used clinically. Optimized soluble gels demonstrated a desirable gelation temperature with Newtonian fluid behaviour observed under storage conditions (4-8°C), and pseudoplastic fluid behaviour recorded at nasal cavity/sinus temperature (≈34°C). The in vitro characterization of formulations including rheological evaluation, textural analysis and mucoadhesion studies of the gel form were investigated. Considerable improvement in mechanical properties and mucoadhesion was observed with incorporation of HPMC and chitosan into the gelling systems. The lead poloxamer-based soluble gels, PGHC4 and PGHC7, which were carried through to ex vivo permeation studies displayed extended drug release profiles in conditions mimicking the human nasal cavity, which indicates their suitability for treating a range of conditions affecting the nasal cavity/sinuses. Copyright © 2016 Elsevier B.V. All rights reserved.

Formulation design space for stable, pH sensitive crystalline nifedipine nanoparticles.

PubMed

Jog, Rajan; Unachukwu, Kenechi; Burgess, Diane J

2016-11-30

Enteric coated formulations protect drugs from degrading in the harsh environment of the stomach (acidic pH and enzymes), and promotes drug delivery to and absorption into the duodenum and/or later parts of the intestine. Four DoE models were applied to optimize formulation parameters for the preparation of pH sensitive nifedipine nanoparticles. Stability studies were performed on the optimized formulations to monitor any possible variation in particle size distribution, homogeneity index, surface charge and drug release (pH 1.2 and pH 6.8). Stability studies were performed for 3 months at 4°C, 25°C and 40°C. A combination of Eudragit ® L 100-55 and polyvinyl alcohol was determined to be the most effective in stabilizing the nanoparticle suspension. The average particle size distribution, polydispersity index and surface charge of the optimized pH sensitive nifedipine nanoparticles were determined to be 131.86±8.21nm, 0.135±0.008 and -7.631±0.146mV, respectively. Following three months storage, it was observed that the formulations stored at 4°C were stable in terms of particle size distribution, polydispersity index, surface charge, drug loading and drug release, whereas those stored at 25°C and 40°C were relatively unstable. A predictive model to prepare stable pH sensitive nifedipine nanoparticles, was successfully developed using multiple linear regression analysis. Copyright © 2016 Elsevier B.V. All rights reserved.

Application of Artificial Neural Networks in the Design and Optimization of a Nanoparticulate Fingolimod Delivery System Based on Biodegradable Poly(3-Hydroxybutyrate-Co-3-Hydroxyvalerate).

PubMed

Shahsavari, Shadab; Rezaie Shirmard, Leila; Amini, Mohsen; Abedin Dokoosh, Farid

2017-01-01

Formulation of a nanoparticulate Fingolimod delivery system based on biodegradable poly(3-hydroxybutyrate-co-3-hydroxyvalerate) was optimized according to artificial neural networks (ANNs). Concentration of poly(3-hydroxybutyrate-co-3-hydroxyvalerate), PVA and amount of Fingolimod is considered as the input value, and the particle size, polydispersity index, loading capacity, and entrapment efficacy as output data in experimental design study. In vitro release study was carried out for best formulation according to statistical analysis. ANNs are employed to generate the best model to determine the relationships between various values. In order to specify the model with the best accuracy and proficiency for the in vitro release, a multilayer percepteron with different training algorithm has been examined. Three training model formulations including Levenberg-Marquardt (LM), gradient descent, and Bayesian regularization were employed for training the ANN models. It is demonstrated that the predictive ability of each training algorithm is in the order of LM > gradient descent > Bayesian regularization. Also, optimum formulation was achieved by LM training function with 15 hidden layers and 20 neurons. The transfer function of the hidden layer for this formulation and the output layer were tansig and purlin, respectively. Also, the optimization process was developed by minimizing the error among the predicted and observed values of training algorithm (about 0.0341). Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Efficacy and Physicochemical Evaluation of an Optimized Semisolid Formulation of Povidone Iodine Proposed by Extreme Vertices Statistical Design; a Practical Approach

PubMed Central

Lotfipour, Farzaneh; Valizadeh, Hadi; Shademan, Shahin; Monajjemzadeh, Farnaz

2015-01-01

One of the most significant issues in pharmaceutical industries, prior to commercialization of a pharmaceutical preparation is the "preformulation" stage. However, far too attention has been paid to verification of the software assisted statistical designs in preformulation studies. The main aim of this study was to report a step by step preformulation approach for a semisolid preparation based on a statistical mixture design and to verify the predictions made by the software with an in-vitro efficacy bioassay test. Extreme vertices mixture design (4 factors, 4 levels) was applied for preformulation of a semisolid Povidone Iodine preparation as Water removable ointment using different PolyEthylenGlycoles. Software Assisted (Minitab) analysis was then performed using four practically assessed response values including; Available iodine, viscosity (N index and yield value) and water absorption capacity. Subsequently mixture analysis was performed and finally, an optimized formulation was proposed. The efficacy of this formulation was bio-assayed using microbial tests in-vitro and MIC values were calculated for Escherichia coli, pseudomonaaeruginosa, staphylococcus aureus and Candida albicans. Results indicated the acceptable conformity of the measured responses. Thus, it can be concluded that the proposed design had an adequate power to predict the responses in practice. Stability studies, proved no significant change during the one year study for the optimized formulation. Efficacy was eligible on all tested species and in the case of staphylococcus aureus; the prepared semisolid formulation was even more effective. PMID:26664368

Chronotherapeutically Modulated Pulsatile System of Valsartan Nanocrystals-an In Vitro and In Vivo Evaluation.

PubMed

Biswas, Nikhil; Kuotsu, Ketousetuo

2017-02-01

The objective was to improve the dissolution of valsartan by developing valsartan nanocrystals and design a pulsed release system for the chronotherapy of hypertension. Valsartan nanocrystals were prepared by sonication-anti-solvent precipitation method and lyophilized to obtain dry powder. Nanocrystals were directly compressed to minitablets and coated to achieve pulsatile valsartan release. Pharmacokinetic profiles of optimized and commercial formulations were compared in rabbit model. The mean particle size and PDI of the optimized nanocrystal batch V4 was reported as 211 nm and 0.117, respectively. DSC and PXRD analysis confirmed the crystalline nature of valsartan in nanocrystals. The dissolution extent of valsartan was markedly enhanced with both nanocrystals and minitablets as compared to pure valsartan irrespective of pH of the medium. Core minitablet V4F containing 5% w/w polyplasdone XL showed quickest release of valsartan, over 90% within 15 min. Coated formulation CV4F showed two spikes in release profile after successive lag times of 235 and 390 min. The pharmacokinetic study revealed that the bioavailability of optimized formulation (72.90%) was significantly higher than the commercial Diovan tablet (30.18%). The accelerated stability studies showed no significant changes in physicochemical properties, release behavior, and bioavialability of CV4F formulation. The formulation was successfully designed to achieve enhanced bioavailability and dual pulsatile release. Bedtime dosing will more efficiently control the circadian spikes of hypertension in the morning.

Studies on a novel doughnut-shaped minitablet for intraocular drug delivery.

PubMed

Choonara, Yahya E; Pillay, Viness; Carmichael, Trevor; Danckwerts, Michael P

2007-12-28

The objective of this study was to evaluate the effect of 2 independent formulation variables on the drug release from a novel doughnut-shaped minitablet (DSMT) in order to optimize formulations for intraocular drug delivery. Formulations were based on a 3(2) full-factorial design. The 2 independent variables were the concentration of Resomer (% wt/wt) and the type of Resomer grade (RG502, RG503, and RG504), respectively. The evaluated response was the drug release rate constant computed from a referenced marketed product and in vitro drug release data obtained at pH 7.4 in simulated vitreous humor. DSMT devices were prepared containing either of 2 model drugs, ganciclovir or foscarnet, using a Manesty F3 tableting press fitted with a novel central-rod, punch, and die setup. Dissolution data revealed biphasic drug release behavior with 55% to 60% drug released over 120 days. The inherent viscosity of the various Resomer grades and the concentration were significant to achieve optimum release rate constants. Using the resultant statistical relationships with the release rate constant as a response, the optimum formulation predicted for devices formulated with foscarnet was 70% wt/wt of Resomer RG504, while 92% wt/wt of Resomer RG503 was ideal for devices formulated with ganciclovir. The results of this study revealed that the full-factorial design was a suitable tool to predict an optimized formulation for prolonged intraocular drug delivery.

Formulation and optimization of fast dissolving intraoral drug delivery system for clobazam using response surface methodology

PubMed Central

Bala, Rajni; Khanna, Sushil; Pawar, Pravin K.

2013-01-01

Clobazam is a newer 1,5-benzodiazepine used for the treatment of epilepsy. It is better tolerated and less sedating than other benzodiazepines. Absorption of the drug can be impacted by oral fast dissolving dosage form; this may have implications for epilepsy in pediatrics and those having difficulty in swallowing tablets/capsules resulting in improved patient compliance. The purpose of the present investigation was to formulate and optimize clobazam oro-dissolving tablets by direct compression method using response surface methodology (RSM). Oro-dispersible tablets of clobazam were prepared by direct compression method using crospovidone (2-6%) as a superdisintegrant, microcrystalline cellulose (MCC) (20-40%) was used as diluents along with directly compressible mannitol to enhance mouth feel. A 32 full factorial design was applied to investigate the combined effect of two formulation variables: amount of crospovidone and MCC over the independent variables disintegration time, wetting time and percent drug release. Disintegration time showed by all formulations was found to be in the range of 24.3-193 s based on evaluation parameters the formulation containing 6% of crospovidone and 30% of MCC showed promising performance against all other formulations. The results demonstrated that the RSM could efficiently be applied for the formulation of clobazam oro-dispersible tablets; therefore, constitute an advance in the management of epileptic attacks. PMID:24083203

Program to Optimize Simulated Trajectories (POST). Volume 1: Formulation manual

NASA Technical Reports Server (NTRS)

Brauer, G. L.; Cornick, D. E.; Habeger, A. R.; Petersen, F. M.; Stevenson, R.

1975-01-01

A general purpose FORTRAN program for simulating and optimizing point mass trajectories (POST) of aerospace vehicles is described. The equations and the numerical techniques used in the program are documented. Topics discussed include: coordinate systems, planet model, trajectory simulation, auxiliary calculations, and targeting and optimization.

Analytical and Computational Properties of Distributed Approaches to MDO

NASA Technical Reports Server (NTRS)

Alexandrov, Natalia M.; Lewis, Robert Michael

2000-01-01

Historical evolution of engineering disciplines and the complexity of the MDO problem suggest that disciplinary autonomy is a desirable goal in formulating and solving MDO problems. We examine the notion of disciplinary autonomy and discuss the analytical properties of three approaches to formulating and solving MDO problems that achieve varying degrees of autonomy by distributing the problem along disciplinary lines. Two of the approaches-Optimization by Linear Decomposition and Collaborative Optimization-are based on bi-level optimization and reflect what we call a structural perspective. The third approach, Distributed Analysis Optimization, is a single-level approach that arises from what we call an algorithmic perspective. The main conclusion of the paper is that disciplinary autonomy may come at a price: in the bi-level approaches, the system-level constraints introduced to relax the interdisciplinary coupling and enable disciplinary autonomy can cause analytical and computational difficulties for optimization algorithms. The single-level alternative we discuss affords a more limited degree of autonomy than that of the bi-level approaches, but without the computational difficulties of the bi-level methods. Key Words: Autonomy, bi-level optimization, distributed optimization, multidisciplinary optimization, multilevel optimization, nonlinear programming, problem integration, system synthesis

Tailoring the mucoadhesive and sustained release characteristics of mesalamine loaded formulations for local treatment of distal forms of ulcerative colitis.

PubMed

Ali, Hany S M; Hanafy, Ahmed F; El Achy, Samar N

2016-10-10

Direct delivery of sustained therapeutic levels of mesalamine (MS) via rectal systems to manage distal forms of ulcerative colitis was studied. The High molecular weight hydroxypropyl methylcellulose (HPMC K4M) polymer was combined with hydrophilic surfactants to control polymer hydration process allowing optimization of the mucoadhesive and controlled drug release properties for the rectal systems. Physical mixtures and granules of MS and HPMC K4M were prepared and in vitro characterized using scanning electron microscope, differential scanning calorimetry and X-ray diffraction techniques. Rectal formulations were prepared utilizing MS-HPMC K4M mixtures in different polyethylene glycol (PEG) combination bases. The developed rectal formulations were investigated for physical, mucoadhesion, in-vitro drug release and swelling characteristics. Results revealed acceptable physical characteristics of the prepared formulations with good content uniformity and minimum weight variation. Sustained release patterns of MS form HPMC K4M based formulations were observed. Formulations prepared using high proportions of the polymer or PEG 400 showed higher extent of mucoadhesion, swelling and greatly extended drug release time. Efficacy of an optimized formulation was assessed using the acetic acid induced colitis model in rats and compared to a reference polymer-free formulation of the drug. Clinical evaluation included bleeding from rectum, consistency of animal stool and colon/body weight ratio. Furthermore, histopathological analysis was carried out to evaluate the degree of inflammation and mucosal damage. Overall results showed a significant enhancement in the clinical pictures and colon histopathology of animals treated by the sustained release mucoadhesive formulation compared to the reference polymer free formulation and the non-treated colitis group. Copyright © 2016 Elsevier B.V. All rights reserved.

A novel folate-modified self-microemulsifying drug delivery system of curcumin for colon targeting.

PubMed

Zhang, Lin; Zhu, Weiwei; Yang, Chunfen; Guo, Hongxia; Yu, Aihua; Ji, Jianbo; Gao, Yan; Sun, Min; Zhai, Guangxi

2012-01-01

The objective of this study was to prepare, characterize, and evaluate a folate-modified self-microemulsifying drug delivery system (FSMEDDS) with the aim to improve the solubility of curcumin and its delivery to the colon, facilitating endocytosis of FSMEDDS mediated by folate receptors on colon cancer cells. Ternary phase diagrams were constructed in order to obtain the most efficient self-emulsification region, and the formulation of curcumin-loaded SMEDDS was optimized by a simplex lattice experiment design. Then, three lipophilic folate derivatives (folate-polyethylene glycol-distearoylphosphatidylethanolamine, folate-polyethylene glycol-cholesteryl hemisuccinate, and folate-polyethylene glycol-cholesterol) used as a surfactant were added to curcumin-loaded SMEDDS formulations. An in situ colon perfusion method in rats was used to optimize the formulation of FSMEDDS. Curcumin-loaded FSMEDDS was then filled into colon-targeted capsules and the in vitro release was investigated. Cytotoxicity studies and cellular uptake studies was used in this research. The optimal formulation of FSMEDDS obtained with the established in situ colon perfusion method in rats was comprised of 57.5% Cremophor(®) EL, 32.5% Transcutol(®) HP, 10% Capryol™ 90, and a small amount of folate-polyethylene glycol-cholesteryl hemisuccinate (the weight ratio of folate materials to Cremophor EL was 1:100). The in vitro release results indicated that the obtained formulation of curcumin could reach the colon efficiently and release the drug immediately. Cellular uptake studies analyzed with fluorescence microscopy and flow cytometry indicated that the FSMEDDS formulation could efficiently bind with the folate receptors on the surface of positive folate receptors cell lines. In addition, FSMEDDS showed greater cytotoxicity than SMEDDS in the above two cells. FSMEDDS-filled colon-targeted capsules are a potential carrier for colon delivery of curcumin.

Single Layer Extended Release Two-in-One Guaifenesin Matrix Tablet: Formulation Method, Optimization, Release Kinetics Evaluation and Its Comparison with Mucinex® Using Box-Behnken Design.

PubMed

Morovati, Amirhosein; Ghaffari, Alireza; Erfani Jabarian, Lale; Mehramizi, Ali

2017-01-01

Guaifenesin, a highly water-soluble active (50 mg/mL), classified as a BCS class I drug. Owing to its poor flowability and compressibility, formulating tablets especially high-dose one, may be a challenge. Direct compression may not be feasible. Bilayer tablet technology applied to Mucinex®, endures challenges to deliver a robust formulation. To overcome challenges involved in bilayer-tablet manufacturing and powder compressibility, an optimized single layer tablet prepared by a binary mixture (Two-in-one), mimicking the dual drug release character of Mucinex ® was purposed. A 3-factor, 3-level Box-Behnken design was applied to optimize seven considered dependent variables (Release "%" in 1, 2, 4, 6, 8, 10 and 12 h) regarding different levels of independent one (X 1 : Cetyl alcohol, X 2 : Starch 1500 ® , X 3 : HPMC K100M amounts). Two granule portions were prepared using melt and wet granulations, blended together prior to compression. An optimum formulation was obtained (X 1 : 37.10, X 2 : 2, X 3 : 42.49 mg). Desirability function was 0.616. F2 and f1 between release profiles of Mucinex® and the optimum formulation were 74 and 3, respectively. An n-value of about 0.5 for both optimum and Mucinex® formulations showed diffusion (Fickian) control mechanism. However, HPMC K100M rise in 70 mg accompanied cetyl alcohol rise in 60 mg led to first order kinetic (n = 0.6962). The K values of 1.56 represented an identical burst drug releases. Cetyl alcohol and starch 1500 ® modulated guaifenesin release from HPMC K100M matrices, while due to their binding properties, improved its poor flowability and compressibility, too.

Single Layer Extended Release Two-in-One Guaifenesin Matrix Tablet: Formulation Method, Optimization, Release Kinetics Evaluation and Its Comparison with Mucinex® Using Box-Behnken Design

PubMed Central

Morovati, Amirhosein; Ghaffari, Alireza; Erfani jabarian, Lale; Mehramizi, Ali

2017-01-01

Guaifenesin, a highly water-soluble active (50 mg/mL), classified as a BCS class I drug. Owing to its poor flowability and compressibility, formulating tablets especially high-dose one, may be a challenge. Direct compression may not be feasible. Bilayer tablet technology applied to Mucinex®, endures challenges to deliver a robust formulation. To overcome challenges involved in bilayer-tablet manufacturing and powder compressibility, an optimized single layer tablet prepared by a binary mixture (Two-in-one), mimicking the dual drug release character of Mucinex® was purposed. A 3-factor, 3-level Box-Behnken design was applied to optimize seven considered dependent variables (Release “%” in 1, 2, 4, 6, 8, 10 and 12 h) regarding different levels of independent one (X1: Cetyl alcohol, X2: Starch 1500®, X3: HPMC K100M amounts). Two granule portions were prepared using melt and wet granulations, blended together prior to compression. An optimum formulation was obtained (X1: 37.10, X2: 2, X3: 42.49 mg). Desirability function was 0.616. F2 and f1 between release profiles of Mucinex® and the optimum formulation were 74 and 3, respectively. An n-value of about 0.5 for both optimum and Mucinex® formulations showed diffusion (Fickian) control mechanism. However, HPMC K100M rise in 70 mg accompanied cetyl alcohol rise in 60 mg led to first order kinetic (n = 0.6962). The K values of 1.56 represented an identical burst drug releases. Cetyl alcohol and starch 1500® modulated guaifenesin release from HPMC K100M matrices, while due to their binding properties, improved its poor flowability and compressibility, too. PMID:29552045

Formulation of Saudi Propolis into Biodegradable Chitosan Chips for Vital Pulpotomy.

PubMed

Balata, Gihan F; Abdelhady, Mohamed I S; Mahmoud, Ghada M; Matar, Moustafa A; Abd El-Latif, Amani N

2018-01-01

Propolis has been widely used to treat oral cavity disorders, such as endodontal and periodontal diseases and microbial infections. The study aimed at the formulation of commercial Saudi propolis into biodegradable chitosan chips and evaluation of its effectiveness as a pulpotomy agent. The standardization of 80% ethanolic propolis extract was performed regarding its total phenolic content, total flavonoid content, quantitative estimation of main polyphenolic constituents and antioxidant activity. Chitosan chips containing propolis extract were prepared by the solvent/ casting method. The investigated variables were % of chitosan polymer (2, 2.5 and 3%), % of plasticizer (1, 5 and 10%) and incorporation of different concentrations of hydroxypropyl methylcellulose (5, 10 and 20% of polymer weight). The chips were characterized for weight and thickness uniformity, content uniformity, pH, percentage moisture loss, swelling index, tensile strength and in vitro propolis release. The optimal propolis chip formulation was further investigated in dogs regarding the short term response of primary dental pulp to propolis chips compared with the most commonly used formocresol preparation. The prepared films were flexible and demonstrated satisfactory physicochemical characteristics. The optimal formulation showed an initial release of about 41.7% of the loaded propolis followed by a sustained release extended up to 7 days. The kinetics study demonstrated that propolis release was controlled by Fick´s diffusion. The optimal propolis chip formulation resulted in less pulpal inflammation compared to formocresol, and produced hard tissue formation in all specimens. Formulation of commercial Saudi propolis as a biodegradable chitosan chip is an effective alternative to the commercially available chemical agents for the treatment of vital pulpotomy. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Dynamic modeling and optimization for space logistics using time-expanded networks

NASA Astrophysics Data System (ADS)

Ho, Koki; de Weck, Olivier L.; Hoffman, Jeffrey A.; Shishko, Robert

2014-12-01

This research develops a dynamic logistics network formulation for lifecycle optimization of mission sequences as a system-level integrated method to find an optimal combination of technologies to be used at each stage of the campaign. This formulation can find the optimal transportation architecture considering its technology trades over time. The proposed methodologies are inspired by the ground logistics analysis techniques based on linear programming network optimization. Particularly, the time-expanded network and its extension are developed for dynamic space logistics network optimization trading the quality of the solution with the computational load. In this paper, the methodologies are applied to a human Mars exploration architecture design problem. The results reveal multiple dynamic system-level trades over time and give recommendation of the optimal strategy for the human Mars exploration architecture. The considered trades include those between In-Situ Resource Utilization (ISRU) and propulsion technologies as well as the orbit and depot location selections over time. This research serves as a precursor for eventual permanent settlement and colonization of other planets by humans and us becoming a multi-planet species.

Formulation for Simultaneous Aerodynamic Analysis and Design Optimization

NASA Technical Reports Server (NTRS)

Hou, G. W.; Taylor, A. C., III; Mani, S. V.; Newman, P. A.

1993-01-01

An efficient approach for simultaneous aerodynamic analysis and design optimization is presented. This approach does not require the performance of many flow analyses at each design optimization step, which can be an expensive procedure. Thus, this approach brings us one step closer to meeting the challenge of incorporating computational fluid dynamic codes into gradient-based optimization techniques for aerodynamic design. An adjoint-variable method is introduced to nullify the effect of the increased number of design variables in the problem formulation. The method has been successfully tested on one-dimensional nozzle flow problems, including a sample problem with a normal shock. Implementations of the above algorithm are also presented that incorporate Newton iterations to secure a high-quality flow solution at the end of the design process. Implementations with iterative flow solvers are possible and will be required for large, multidimensional flow problems.

The anatomy of choice: active inference and agency

PubMed Central

Friston, Karl; Schwartenbeck, Philipp; FitzGerald, Thomas; Moutoussis, Michael; Behrens, Timothy; Dolan, Raymond J.

2013-01-01

This paper considers agency in the setting of embodied or active inference. In brief, we associate a sense of agency with prior beliefs about action and ask what sorts of beliefs underlie optimal behavior. In particular, we consider prior beliefs that action minimizes the Kullback–Leibler (KL) divergence between desired states and attainable states in the future. This allows one to formulate bounded rationality as approximate Bayesian inference that optimizes a free energy bound on model evidence. We show that constructs like expected utility, exploration bonuses, softmax choice rules and optimism bias emerge as natural consequences of this formulation. Previous accounts of active inference have focused on predictive coding and Bayesian filtering schemes for minimizing free energy. Here, we consider variational Bayes as an alternative scheme that provides formal constraints on the computational anatomy of inference and action—constraints that are remarkably consistent with neuroanatomy. Furthermore, this scheme contextualizes optimal decision theory and economic (utilitarian) formulations as pure inference problems. For example, expected utility theory emerges as a special case of free energy minimization, where the sensitivity or inverse temperature (of softmax functions and quantal response equilibria) has a unique and Bayes-optimal solution—that minimizes free energy. This sensitivity corresponds to the precision of beliefs about behavior, such that attainable goals are afforded a higher precision or confidence. In turn, this means that optimal behavior entails a representation of confidence about outcomes that are under an agent's control. PMID:24093015

Multiobjective topology optimization of trabecular Bone Structure in the spine and the femur: Implications for biomimcry

NASA Astrophysics Data System (ADS)

Elbanna, Ahmed; Peetz, Darin

Bone is classically considered to be a self-optimizing structure in accordance with Wolff's law. However, while the structure's ability to adapt to changing stress patterns has been well documented, whether it is fully optimal for compliance is less certain (Sigmund, 2002). Given the complexity of many biological systems, it is expected that this structure serves several purposes. We present a multi-objective topology optimization formulation for trabecular bone in the human body at two locations: the vertebrae and the femur. We account for the effect of different conflicting objectives such as maximization of stiffness, maximization of surface area, and minimization of buckling susceptibility. Our formulation enables us to determine the relative role of each of these objective in optimizing the structure. Moreover, it provides an opportunity to explore what structural features have to evolve to meet a certain objective requirements that may have been absent otherwise. For example, inclusion of stability considerations introduce numerous horizontal and diagonal members in the topology in the case of human vertebrae under vertical loading. However, the stability is found to play a lesser role in the case of the femur bone optimization. Our formulation enables investigation of bone adaptation at different locations of the body as well as under different loading and boundary conditions (e.g. healthy and diseased discs for the case of the spine). We discuss the implications of our findings on developing design rules for bio-inspired and bio-mimetic architectured materials. National Science Foundation: CMMI.

Preventing Aggregation of Recombinant Interferon beta-1b in Solution by Additives: Approach to an Albumin-Free Formulation

PubMed Central

Mahjoubi, Najmeh; Fazeli, Mohammad Reza; Dinarvand, Rassoul; Khoshayand, Mohammad Reza; Fazeli, Ahmad; Taghavian, Mohammad; Rastegar, Hossein

2015-01-01

Purpose: Aggregation suppressing additives have been used to stabilize proteins during manufacturing and storage. Interferonβ-1b is prone to aggregation because of being non-glycosylated. Aggregation behavior of albumin-free formulations of recombinant IFNβ-1b was explored using additives such as n-dodecyl-β-D-maltoside, Tween 20, arginine, glycine, trehalose and sucrose at different pH. Methods: Fractional factorial design was applied to select major factors affecting aggregation in solutions. Box-Behnken technique was used to optimize the best concentration of additives and protein. Results: Quadratic model was the best fitted model for particle size, OD350 and OD280/OD260. The optimal conditions of 0.2% n-Dodecyl-β-D-maltoside, 70 mM arginine, 189 mM trehalose and protein concentration of 0.50 mg/ml at pH 4 were achieved. A potency value of 91% ± 5% was obtained for the optimized formulation. Conclusion: This study shows that the combination of n-Dodecyl-β-D-maltoside, arginine and trehalose would demonstrate a significant stabilizing and anti-aggregating effect on the liquid formulation of interferonβ-1b. It can not only reduce the manufacturing costs but will also ease patient compliance. PMID:26819922

Nutritional and sensory characteristics of gluten-free quinoa (Chenopodium quinoa Willd)-based cookies development using an experimental mixture design.

PubMed

Brito, Isabelle L; de Souza, Evandro Leite; Felex, Suênia Samara Santos; Madruga, Marta Suely; Yamashita, Fábio; Magnani, Marciane

2015-09-01

The aim of this study was to develop a gluten-free formulation of quinoa (Chenopodium quinoa Willd.)-based cookies using experimental design of mixture to optimize a ternary mixture of quinoa flour, quinoa flakes and corn starch for parameters of colour, specific volume and hardness. Nutritional and sensory aspects of the optimized formulation were also assessed. Corn starch had a positive effect on the lightness of the cookies, but increased amounts of quinoa flour and quinoa flakes in the mixture resulted in darker product. Quinoa flour showed a negative effect on the specific volume, producing less bulky cookies, and quinoa flour and quinoa flakes had a positive synergistic effect on the hardness of the cookies. According the results and considering the desirability profile for colour, hardness and specific volume in gluten-free cookies, the optimized formulation contains 30 % quinoa flour, 25 % quinoa flakes and 45 % corn starch. The quinoa-based cookie obtained was characterized as a product rich in dietary fibre, a good source of essential amino acids, linolenic acid and minerals, with good sensory acceptability. These findings reports for the first time the application of quinoa processed as flour and flakes in mixture with corn starch as an alternative ingredient for formulations of gluten-free cookies-type biscuits.

A logical approach to optimize the nanostructured lipid carrier system of irinotecan: efficient hybrid design methodology

NASA Astrophysics Data System (ADS)

Mohan Negi, Lalit; Jaggi, Manu; Talegaonkar, Sushama

2013-01-01

Development of an effective formulation involves careful optimization of a number of excipient and process variables. Sometimes the number of variables is so large that even the most efficient optimization designs require a very large number of trials which put stress on costs as well as time. A creative combination of a number of design methods leads to a smaller number of trials. This study was aimed at the development of nanostructured lipid carriers (NLCs) by using a combination of different optimization methods. A total of 11 variables were first screened using the Plackett-Burman design for their effects on formulation characteristics like size and entrapment efficiency. Four out of 11 variables were found to have insignificant effects on the formulation parameters and hence were screened out. Out of the remaining seven variables, four (concentration of tween-80, lecithin, sodium taurocholate, and total lipid) were found to have significant effects on the size of the particles while the other three (phase ratio, drug to lipid ratio, and sonication time) had a higher influence on the entrapment efficiency. The first four variables were optimized for their effect on size using the Taguchi L9 orthogonal array. The optimized values of the surfactants and lipids were kept constant for the next stage, where the sonication time, phase ratio, and drug:lipid ratio were varied using the Box-Behnken design response surface method to optimize the entrapment efficiency. Finally, by performing only 38 trials, we have optimized 11 variables for the development of NLCs with a size of 143.52 ± 1.2 nm, zeta potential of -32.6 ± 0.54 mV, and 98.22 ± 2.06% entrapment efficiency.

Designing herbicide formulation characteristics to maximize efficacy and minimize rice injury in paddy environments.

PubMed

Cryer, S A; Mann, R K; Erhardt-Zabik, S; Keeney, F N; Handy, P R

2001-06-01

Mathematical descriptors, coupled with experimental observations, are used to quantify differential uptake of an experimental herbicide in Japonica and Indica rice (Oryza sativa, non-target) and barnyardgrass (Echinochloa crus-galli, target). Partitioning, degradation, plant uptake and metabolism are described using mass-balance conservation equations in the form of kinetic approximations. Estimated environmental concentrations, governed by the pesticide formulation, are described using superimposed analytical solutions for the one-dimensional diffusion equation in spherical coordinates and by a finite difference representation of the two-dimensional diffusion equation in Cartesian coordinates. Formulation attributes from granules include active ingredient release rates, particle sizes, pesticide loading, and granule spacing. The diffusion model for pesticide transport is coupled with the compartment model to follow the fate and transport of a pesticide from its initial application location to various environmental matrices of interest. Formulation effects, partitioning and degradation in the various environmental matrices, differential plant uptake and metabolism, and dose-response information for plants are accounted for. This novel model provides a mechanism for selecting formulation delivery systems that optimize specific attributes (such as weed control or the therapeutic index) for risk-assessment procedures. In this report we describe how this methodology was used to explore the factors affecting herbicide efficacy and to define an optimal release rate for a granule formulation.

Nanosized ethosomes-based hydrogel formulations of methoxsalen for enhanced topical delivery against vitiligo: formulation optimization, in vitro evaluation and preclinical assessment.

PubMed

Garg, Bhawna Jain; Garg, Neeraj K; Beg, Sarwar; Singh, Bhupinder; Katare, Om Prakash

2016-01-01

The present investigation aimed for the development and characterization of ethosomes-based hydrogel formulations of methoxsalen for enhanced topical delivery and effective treatment against vitiligo. The ethosomes were prepared by central composite design (CCD) and characterized for various quality attributes like vesicle shape, size, zeta potential, lamellarity, drug entrapment and drug leaching. The optimized ethosomes were subsequently incorporated int Carbopol® 934 gel and characterized for drug content, rheological behavior, texture profile, in vitro release, ex vivo skin permeation and retention, skin photosensitization and histopathological examination. Ethosomes were found to be spherical and multilamellar in structures having nanometric size range with narrow size distribution, and high encapsulation efficiency. Ethosomal formulations showed significant skin permeation and accumulation in the epidermal and dermal layers. The fluorescence microscopy study using 123 Rhodamine exhibited enhanced permeation of the drug-loaded ethosomes in the deeper layers of skin. Also, the developed formulation showed insignificant phototoxicity and erythema vis-à-vis the conventional cream. The results were cross-validated using histopathological examination of skin segments. In a nutshell, the ethosomes-based hydrogel formulation was found to be a promising drug delivery system demonstrating enhanced percutaneous penetration of methoxsalen with reduced phototoxicity and erythema, thus leading to improved patient compliance for the treatment against vitiligo.

Optimizing novel implant formulations for the prolonged release of biopharmaceuticals using in vitro and in vivo imaging techniques.

PubMed

Beyer, Susanne; Xie, Li; Schmidt, Mike; de Bruin, Natasja; Ashtikar, Mukul; Rüschenbaum, Sabrina; Lange, Christian M; Vogel, Vitali; Mäntele, Werner; Parnham, Michael J; Wacker, Matthias G

2016-08-10

As a rapidly growing class of therapeutics, biopharmaceuticals have conquered the global market. Despite the great potential from a therapeutic perspective, such formulations often require frequent injections due to their short half-life. Aiming to establish a parenteral dosage form with prolonged release properties, a biodegradable implant was developed, based on a combination of nanoencapsulation of protein-heparin complexes, creation of a slow release matrix by freeze-drying, and compression using hyaluronan and methylcellulose. In order to investigate this novel delivery system, formulations containing IFN-β-1a and trypsinogen as model proteins were developed. No degradation of the proteins was observed at any stage of the formulation processing. The potential of the delivery system was evaluated in vivo and in vitro after fluorescence-labeling of the biopharmaceuticals. An optimized agarose gel was utilized as in vitro release medium to simulate the subcutaneous environment in a biorelevant manner. In addition, the formulations were administered to female SJL mice and release was innovatively tracked by fluorescence imaging, setting up an in vitro-in vivo correlation. A prolonged time of residence of approximately 12days was observed for the selected formulation design. Copyright © 2016 Elsevier B.V. All rights reserved.

Formulation strategies for optimizing the morphology of polymeric bulk heterojunction organic solar cells: a brief review

NASA Astrophysics Data System (ADS)

Vongsaysy, Uyxing; Bassani, Dario M.; Servant, Laurent; Pavageau, Bertrand; Wantz, Guillaume; Aziz, Hany

2014-01-01

Polymeric bulk heterojunction (BHJ) organic solar cells represent one of the most promising technologies for renewable energy with a low fabrication cost. Control over BHJ morphology is one of the key factors in obtaining high-efficiency devices. This review focuses on formulation strategies for optimizing the BHJ morphology. We address how solvent choice and the introduction of processing additives affect the morphology. We also review a number of recent studies concerning prediction methods that utilize the Hansen solubility parameters to develop efficient solvent systems.

Formulation and Stability of Solutions.

PubMed

Akers, Michael J

2016-01-01

Ready-to-use solutions are the most preferable and most common dosage forms for injectable and topical ophthalmic products. Drugs formulated as solution almost always have chemical and physical stability challenges as well as solubility limitations and the need to prevent inadvertent microbial contamination issues. The first in this series of articles took us through a discussion of optimizing the physical stability of solutions. This article concludes this series of articles with a discussion on foreign particles, protein aggregation, and immunogenicity; optimizing microbiological activity; and osmolality (tonicity) agents, and discusses how these challenges and issues are addressed.

New Mathematical Strategy Using Branch and Bound Method

NASA Astrophysics Data System (ADS)

Tarray, Tanveer Ahmad; Bhat, Muzafar Rasool

In this paper, the problem of optimal allocation in stratified random sampling is used in the presence of nonresponse. The problem is formulated as a nonlinear programming problem (NLPP) and is solved using Branch and Bound method. Also the results are formulated through LINGO.

Improving oral bioavailability of acyclovir using nanoparticulates of thiolated xyloglucan.

PubMed

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

2016-08-01

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

A Mathematical Formulation of the SCOLE Control Problem. Part 2: Optimal Compensator Design

NASA Technical Reports Server (NTRS)

Balakrishnan, A. V.

1988-01-01

The study initiated in Part 1 of this report is concluded and optimal feedback control (compensator) design for stability augmentation is considered, following the mathematical formulation developed in Part 1. Co-located (rate) sensors and (force and moment) actuators are assumed, and allowing for both sensor and actuator noise, stabilization is formulated as a stochastic regulator problem. Specializing the general theory developed by the author, a complete, closed form solution (believed to be new with this report) is obtained, taking advantage of the fact that the inherent structural damping is light. In particular, it is possible to solve in closed form the associated infinite-dimensional steady-state Riccati equations. The SCOLE model involves associated partial differential equations in a single space variable, but the compensator design theory developed is far more general since it is given in the abstract wave equation formulation. The results thus hold for any multibody system so long as the basic model is linear.

Application of hanging drop technique to optimize human IgG formulations.

PubMed

Li, Guohua; Kasha, Purna C; Late, Sameer; Banga, Ajay K

2010-01-01

The purpose of this work is to assess the hanging drop technique in screening excipients to develop optimal formulations for human immunoglobulin G (IgG). A microdrop of human IgG and test solution hanging from a cover slide and undergoing vapour diffusion was monitored by a stereomicroscope. Aqueous solutions of IgG in the presence of different pH, salt concentrations and excipients were prepared and characterized. Low concentration of either sodium/potassium phosphate or McIlvaine buffer favoured the solubility of IgG. Addition of sucrose favoured the stability of this antibody while addition of NaCl caused more aggregation. Antimicrobial preservatives were also screened and a complex effect at different buffer conditions was observed. Dynamic light scattering, differential scanning calorimetry and size exclusion chromatography studies were performed to further validate the results. In conclusion, hanging drop is a very easy and effective approach to screen protein formulations in the early stage of formulation development.

The Capability Portfolio Analysis Tool (CPAT): A Mixed Integer Linear Programming Formulation for Fleet Modernization Analysis (Version 2.0.2).

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

Waddell, Lucas; Muldoon, Frank; Henry, Stephen Michael

In order to effectively plan the management and modernization of their large and diverse fleets of vehicles, Program Executive Office Ground Combat Systems (PEO GCS) and Program Executive Office Combat Support and Combat Service Support (PEO CS&CSS) commis- sioned the development of a large-scale portfolio planning optimization tool. This software, the Capability Portfolio Analysis Tool (CPAT), creates a detailed schedule that optimally prioritizes the modernization or replacement of vehicles within the fleet - respecting numerous business rules associated with fleet structure, budgets, industrial base, research and testing, etc., while maximizing overall fleet performance through time. This paper contains a thor-more » ough documentation of the terminology, parameters, variables, and constraints that comprise the fleet management mixed integer linear programming (MILP) mathematical formulation. This paper, which is an update to the original CPAT formulation document published in 2015 (SAND2015-3487), covers the formulation of important new CPAT features.« less

A Mathematical Optimization Problem in Bioinformatics

ERIC Educational Resources Information Center

Heyer, Laurie J.

2008-01-01

This article describes the sequence alignment problem in bioinformatics. Through examples, we formulate sequence alignment as an optimization problem and show how to compute the optimal alignment with dynamic programming. The examples and sample exercises have been used by the author in a specialized course in bioinformatics, but could be adapted…

Single Mothers and Their Infants: Factors Associated with Optimal Parenting.

ERIC Educational Resources Information Center

Barratt, Marguerite Stevenson; And Others

1991-01-01

Examined factors that might influence optimal early parenting by Caucasian single mothers (n=53). Results indicated optimal parenting was linked with older maternal age, fewer maternal psychological symptoms, and less difficult infant temperament. Recommends particular needs of single mother should be considered when formulating public policy.…

Final Report. Baseline LAW Glass Formulation Testing, VSL-03R3460-1, Rev. 0

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

Muller, Isabelle S.; Pegg, Ian L.; Gan, Hao

2015-06-18

The major objective of the baseline glass formulation work was to develop and select glass formulations that are compliant with contractual and processing requirements for each of the LAW waste streams. Other objectives of the work included preparation and characterization of glasses with respect to the properties of interest, optimization of sulfate loading in the glasses, evaluation of ability to achieve waste loading limits, testing to demonstrate compatibility of glass melts with melter materials of construction, development of glass formulations to support ILAW qualification activities, and identification of glass formulation issues with respect to contract specifications and processing requirements.

Shuttle program. MCC Level C formulation requirements: Entry guidance and entry autopilot

NASA Technical Reports Server (NTRS)

Harpold, J. C.; Hill, O.

1980-01-01

A set of preliminary entry guidance and autopilot software formulations is presented for use in the Mission Control Center (MCC) entry processor. These software formulations meet all level B requirements. Revision 2 incorporates the modifications required to functionally simulate optimal TAEM targeting capability (OTT). Implementation of this logic in the MCC must be coordinated with flight software OTT implementation and MCC TAEM guidance OTT. The entry guidance logic is based on the Orbiter avionics entry guidance software. This MCC requirements document contains a definition of coordinate systems, a list of parameter definitions for the software formulations, a description of the entry guidance detailed formulation requirements, a description of the detailed autopilot formulation requirements, a description of the targeting routine, and a set of formulation flow charts.

Hybrid Optimization in Urban Traffic Networks

DOT National Transportation Integrated Search

1979-04-01

The hybrid optimization problem is formulated to provide a general theoretical framework for the analysis of a class of traffic control problems which takes into account the role of individual drivers as independent decisionmakers. Different behavior...

Meshless methods in shape optimization of linear elastic and thermoelastic solids

NASA Astrophysics Data System (ADS)

Bobaru, Florin

This dissertation proposes a meshless approach to problems in shape optimization of elastic and thermoelastic solids. The Element-free Galerkin (EFG) method is used for this purpose. The ability of the EFG to avoid remeshing, that is normally done in a Finite Element approach to correct highly distorted meshes, is clearly demonstrated by several examples. The shape optimization example of a thermal cooling fin shows a dramatic improvement in the objective compared to a previous FEM analysis. More importantly, the new solution, displaying large shape changes contrasted to the initial design, was completely missed by the FEM analysis. The EFG formulation given here for shape optimization "uncovers" new solutions that are, apparently, unobtainable via a FEM approach. This is one of the main achievements of our work. The variational formulations for the analysis problem and for the sensitivity problems are obtained with a penalty method for imposing the displacement boundary conditions. The continuum formulation is general and this facilitates 2D and 3D with minor differences from one another. Also, transient thermoelastic problems can use the present development at each time step to solve shape optimization problems for time-dependent thermal problems. For the elasticity framework, displacement sensitivity is obtained in the EFG context. Excellent agreements with analytical solutions for some test problems are obtained. The shape optimization of a fillet is carried out in great detail, and results show significant improvement of the EFG solution over the FEM or the Boundary Element Method solutions. In our approach we avoid differentiating the complicated EFG shape functions, with respect to the shape design parameters, by using a particular discretization for sensitivity calculations. Displacement and temperature sensitivities are formulated for the shape optimization of a linear thermoelastic solid. Two important examples considered in this work, the optimization of a thermal fin and of a uniformly loaded thermoelastic beam, reveal new characteristics of the EFG method in shape optimization applications. Among other advantages of the EFG method over traditional FEM treatments of shape optimization problems, some of the most important ones are shown to be: elimination of post-processing for stress and strain recovery that directly gives more accurate results in critical positions (near the boundaries, for example) for shape optimization problems; nodes movement flexibility that permits new, better shapes (previously missed by an FEM analysis) to be discovered. Several new research directions that need further consideration are exposed.

Review: Optimization methods for groundwater modeling and management

NASA Astrophysics Data System (ADS)

Yeh, William W.-G.

2015-09-01

Optimization methods have been used in groundwater modeling as well as for the planning and management of groundwater systems. This paper reviews and evaluates the various optimization methods that have been used for solving the inverse problem of parameter identification (estimation), experimental design, and groundwater planning and management. Various model selection criteria are discussed, as well as criteria used for model discrimination. The inverse problem of parameter identification concerns the optimal determination of model parameters using water-level observations. In general, the optimal experimental design seeks to find sampling strategies for the purpose of estimating the unknown model parameters. A typical objective of optimal conjunctive-use planning of surface water and groundwater is to minimize the operational costs of meeting water demand. The optimization methods include mathematical programming techniques such as linear programming, quadratic programming, dynamic programming, stochastic programming, nonlinear programming, and the global search algorithms such as genetic algorithms, simulated annealing, and tabu search. Emphasis is placed on groundwater flow problems as opposed to contaminant transport problems. A typical two-dimensional groundwater flow problem is used to explain the basic formulations and algorithms that have been used to solve the formulated optimization problems.

Wireless Sensor Network Optimization: Multi-Objective Paradigm

PubMed Central

Iqbal, Muhammad; Naeem, Muhammad; Anpalagan, Alagan; Ahmed, Ashfaq; Azam, Muhammad

2015-01-01

Optimization problems relating to wireless sensor network planning, design, deployment and operation often give rise to multi-objective optimization formulations where multiple desirable objectives compete with each other and the decision maker has to select one of the tradeoff solutions. These multiple objectives may or may not conflict with each other. Keeping in view the nature of the application, the sensing scenario and input/output of the problem, the type of optimization problem changes. To address different nature of optimization problems relating to wireless sensor network design, deployment, operation, planing and placement, there exist a plethora of optimization solution types. We review and analyze different desirable objectives to show whether they conflict with each other, support each other or they are design dependent. We also present a generic multi-objective optimization problem relating to wireless sensor network which consists of input variables, required output, objectives and constraints. A list of constraints is also presented to give an overview of different constraints which are considered while formulating the optimization problems in wireless sensor networks. Keeping in view the multi facet coverage of this article relating to multi-objective optimization, this will open up new avenues of research in the area of multi-objective optimization relating to wireless sensor networks. PMID:26205271

The random fractional matching problem

NASA Astrophysics Data System (ADS)

Lucibello, Carlo; Malatesta, Enrico M.; Parisi, Giorgio; Sicuro, Gabriele

2018-05-01

We consider two formulations of the random-link fractional matching problem, a relaxed version of the more standard random-link (integer) matching problem. In one formulation, we allow each node to be linked to itself in the optimal matching configuration. In the other one, on the contrary, such a link is forbidden. Both problems have the same asymptotic average optimal cost of the random-link matching problem on the complete graph. Using a replica approach and previous results of Wästlund (2010 Acta Mathematica 204 91–150), we analytically derive the finite-size corrections to the asymptotic optimal cost. We compare our results with numerical simulations and we discuss the main differences between random-link fractional matching problems and the random-link matching problem.

Formulation and pharmacokinetics of diclofenac lipid nanoemulsions for parenteral application.

PubMed

Ramreddy, Srividya; Kandadi, Prabhakar; Veerabrahma, Kishan

2012-01-01

The objective of the present study was to formulate and determine the pharmacokinetics of stable o/w parenteral lipid nanoemulsions (LNEs) of diclofenac acid used to treat arthritic conditions. The LNEs of diclofenac acid with a mean size ranging from 200 to 240 nm and a zeta potential of -29.4 ± 1.04 mV (negatively charged LNEs) and 62.1 ± 3.5 (positively charged LNEs) emulsions were prepared by hot homogenization and ultrasonication process. The influence of formulation variables, such as the change in proportion of cholesterol, was studied, and optimized formulations were developed. The optimized formulations were relatively stable during centrifugal stress, dilution stress, and storage. The drug content and entrapment efficiency were determined using high-performance liquid chromatography. The in vitro drug release was carried out in phosphate-buffered saline pH 7.4 and cumulative amount of drug released was estimated using a UV-visible spectro-photometer. During in vivo pharmacokinetic studies in male Wistar rats, diclofenac serum concentration from LNEs was higher than that of Voveran injection and was detectable up to 12 h. Diclofenac in LNEs showed improved pharmacokinetic profile with increase in area under the curve, elimination half-life and mean residence time in comparison to Voveran. Our aim was to prepare and determine the pharmacokinetics of injectable lipid nanoemulsions of diclofenac acid for treating arthritic conditions by reducing the frequency of dosing and pain at site of injection. The nanoemulsions of diclofenac acid were prepared by homogenization and ultrasonication process. The sizes and charges of oil globules were determined. The effect of cholesterol on stability of emulsion was studied, and an optimized preparation was developed. The optimized formulations were stable during centrifugation, dilution, and storage. The total amount of drug in emulsion and percentage amount of drug present in emulsion globules were determined using high-performance liquid chromatography. The drug release from preparation was carried out in phosphate-buffered saline pH 7.4. The cumulative amount of drug released was estimated using a spectrophotometer. The time course of the released drug in rat serum was determined. Diclofenac concentrations from lipid nanoemulsions were higher than that of Voveran injection (solution form) in serum.

Optimal strategies for electric energy contract decision making

NASA Astrophysics Data System (ADS)

Song, Haili

2000-10-01

The power industry restructuring in various countries in recent years has created an environment where trading of electric energy is conducted in a market environment. In such an environment, electric power companies compete for the market share through spot and bilateral markets. Being profit driven, electric power companies need to make decisions on spot market bidding, contract evaluation, and risk management. New methods and software tools are required to meet these upcoming needs. In this research, bidding strategy and contract pricing are studied from a market participant's viewpoint; new methods are developed to guide a market participant in spot and bilateral market operation. A supplier's spot market bidding decision is studied. Stochastic optimization is formulated to calculate a supplier's optimal bids in a single time period. This decision making problem is also formulated as a Markov Decision Process. All the competitors are represented by their bidding parameters with corresponding probabilities. A systematic method is developed to calculate transition probabilities and rewards. The optimal strategy is calculated to maximize the expected reward over a planning horizon. Besides the spot market, a power producer can also trade in the bilateral markets. Bidding strategies in a bilateral market are studied with game theory techniques. Necessary and sufficient conditions of Nash Equilibrium (NE) bidding strategy are derived based on the generators' cost and the loads' willingness to pay. The study shows that in any NE, market efficiency is achieved. Furthermore, all Nash equilibria are revenue equivalent for the generators. The pricing of "Flexible" contracts, which allow delivery flexibility over a period of time with a fixed total amount of electricity to be delivered, is analyzed based on the no-arbitrage pricing principle. The proposed algorithm calculates the price based on the optimality condition of the stochastic optimization formulation. Simulation examples illustrate the tradeoffs between prices and scheduling flexibility. Spot bidding and contract pricing are not independent decision processes. The interaction between spot bidding and contract evaluation is demonstrated with game theory equilibrium model and market simulation results. It leads to the conclusion that a market participant's contract decision making needs to be further investigated as an integrated optimization formulation.

Design and Evaluation of Topical Diclofenac Sodium Gel Using Hot Melt Extrusion Technology as a Continuous Manufacturing Process with Kolliphor® P407.

PubMed

Pawar, Jaywant; Narkhede, Rajkiran; Amin, Purnima; Tawde, Vaishali

2017-08-01

The aim of the present context was to develop and evaluate a Kolliphor® P407-based transdermal gel formulation of diclofenac sodium by hot melt extrusion (HME) technology; central composite design was used to optimize the formulation process. In this study, we have explored first time ever HME as an industrially feasible and continuous manufacturing technology for the manufacturing of gel formulation using Kolliphor® P407 and Kollisolv® PEG400 as a gel base. Diclofenac sodium was used as a model drug. The HME parameters such as feeding rate, screw speed, and barrel temperature were crucial for the semisolid product development, and were optimized after preliminary trials. For the processing of the gel formulation by HME, a modified screw design was used to obtain a uniform product. The obtained product was evaluated for physicochemical characterization such as differential scanning calorimetry (DSC), X-ray diffraction (XRD), pH measurement, rheology, surface tension, and texture profile analysis. Moreover, it was analyzed for general appearance, spreadibility, surface morphology, and drug content. The optimized gel formulation showed homogeneity and transparent film when applied on a glass slide under microscope, pH was 7.02 and uniform drug content of 100.04 ± 2.74 (SD = 3). The DSC and XRD analysis of the HME gel formulation showed complete melting of crystalline API into an amorphous form. The Kolliphor® P407 and Kollisolv® PEG400 formed excellent gel formulation using HME with consistent viscoelastic properties of the product. An improved drug release was found for the HME gel, which showed a 100% drug release than that of a marketed product which showed only 88% of drug release at the end of 12 h. The Flux value of the HME gel was 106 than that of a marketed formulation, which showed only about 60 value, inferring a significant difference (P < 0.05) at the end of 1 h. This study demonstrates a novel application of the hot melt extrusion process for manufacturing of topical semisolid products.

[Effect of increased protein content on nutritional and sensory quality of cookies].

PubMed

Pérez, Santiago Rafael; Osella, Carlos Alberto; Torre, Maria Adela de la; Sánchez, Hugo Diego

2008-12-01

The objective of this work was to study the effect of soy flour and whey protein concentrate (WPC) on cookies quality. An optimal recipe showing improved protein quality and content as well as acceptable sensory quality was defined taking into account the results obtained. Rotary moulded cookie formulation adaptable to lamination and cutting in pilot plant was used. Wheat flour from this formulation was partially replaced by whey protein concentrate and full fat soy flour. Second order models were employed to generate response surfaces for: total protein, lysine by 16 grams of total nitrogen, lysine by 100 grams of sample, loss of lysine during processing and sensory evaluation of cookies. We could obtain an effect on available lysine value when water content was increased in the formulation because a delay in the Maillard reaction. The optimal formulation contains 13% of full fat soy flour, 3% of whey protein concentrate and 23% of water. The results demonstrated that the protein content and the protein quality of the supplemented flours were increased when soy flour was added in the formulation of cookies. On other hand, protein content was increased but protein quality was decreased when WPC was used, because of available lysine loss.

Development and Evaluation of Taste Masked Granular Formulation of Satranidazole by Melt Granulation Technique

PubMed Central

Pawar, Harshal Ashok; Joshi, Pooja Rasiklal

2014-01-01

Drugs from nitroimidazole category are generally bitter in taste. Oral formulation with bitter taste is not palatable. Geriatrics and pediatrics patients usually suffer from swallowing difficulties. Many other patients in some disease conditions avoid swallowing tablets. Satranidazole is a new nitro-imidazole derivative with bitter taste and is available in market as film coated tablet. The purpose of this research was to mask the bitter taste of Satranidazole by coating complexation with low melting point wax and Eudragit EPO. Different types of wax (glyceryl monostearate, stearic acid and cetyl alcohol) were tried for taste masking. The drug to stearic acid ratio 1 : 2 was found to be optimum on the basis of taste evaluation and in vitro release. The formulated granules were found to possess good flow property. FTIR studies confirmed that there was no interaction between drug and excipients. Scanning Electron Microscopy of drug and the optimized batch of granules was performed. The in vitro release of drug from granules was compared with marketed tablet formulation. The taste masked granules of optimized batch showed 87.65% release of drug in 1 hr which is comparable to that of marketed tablet formulation. PMID:26556200

A novel transdermal nanoethosomal gel of betahistine dihydrochloride for weight gain control: in-vitro and in-vivo characterization

PubMed Central

El-Menshawe, Shahira F; Ali, Adel Ahmed; Halawa, Abdelkhalk Ali; Srag El-Din, Ahmed SG

2017-01-01

Background Betahistine dihydrochloride (BDH) is a histamine analog used to control weight gain, with short elimination half-life and gastric irritation as side effects. Objective The aim of the current investigation is to formulate and optimize a topical BDH ethosomal gel for weight gain control. Materials and methods Box–Behnken design was applied to study the effect of independent variables: phosphatidylcholine (PC), propylene glycol (PG), and ethanol on vesicle size; entrapment efficiency; % drug release; and flux. The morphology and zeta potential of the optimized formulation were evaluated. The % drug release, flux, and pharmacodynamics of the optimized formulation gel were studied. Results The size and entrapment efficiency percent had a direct positive relationship with the concentration of PC and negative relationship with ethanol and PG. The % drug release and flux decreased with increasing PC and PG, while ethanol enhanced both responses. Regression modeling indicated a good correlation between dependent and independent variables, where F16 was chosen as the optimized formulation. F16 showed well-defined spherical vesicles and zeta potential of −24 mV, and % release from the gel exceeded 99.5% over 16 h with the flux of 0.28 mg/cm2/h. Food intake and weight gain of rats were significantly decreased after transdermal application of the BDH ethosomal gel when compared with control, placebo, and BDH gel. The histopathological findings proved the absence of inflammation and decrease in adipose tissue. Conclusion Results obtained showed a significant, sustained transdermal absorption of BDH ethosomal gel and, consequently, a decrease in food intake and weight gain. PMID:29238164

Commentary: Why Pharmaceutical Scientists in Early Drug Discovery Are Critical for Influencing the Design and Selection of Optimal Drug Candidates.

PubMed

Landis, Margaret S; Bhattachar, Shobha; Yazdanian, Mehran; Morrison, John

2018-01-01

This commentary reflects the collective view of pharmaceutical scientists from four different organizations with extensive experience in the field of drug discovery support. Herein, engaging discussion is presented on the current and future approaches for the selection of the most optimal and developable drug candidates. Over the past two decades, developability assessment programs have been implemented with the intention of improving physicochemical and metabolic properties. However, the complexity of both new drug targets and non-traditional drug candidates provides continuing challenges for developing formulations for optimal drug delivery. The need for more enabled technologies to deliver drug candidates has necessitated an even more active role for pharmaceutical scientists to influence many key molecular parameters during compound optimization and selection. This enhanced role begins at the early in vitro screening stages, where key learnings regarding the interplay of molecular structure and pharmaceutical property relationships can be derived. Performance of the drug candidates in formulations intended to support key in vivo studies provides important information on chemotype-formulation compatibility relationships. Structure modifications to support the selection of the solid form are also important to consider, and predictive in silico models are being rapidly developed in this area. Ultimately, the role of pharmaceutical scientists in drug discovery now extends beyond rapid solubility screening, early form assessment, and data delivery. This multidisciplinary role has evolved to include the practice of proactively taking part in the molecular design to better align solid form and formulation requirements to enhance developability potential.

Lower irritation microemulsion-based rotigotine gel: formulation optimization and in vitro and in vivo studies.

PubMed

Wang, Zheng; Mu, Hong-Jie; Zhang, Xue-Mei; Ma, Peng-Kai; Lian, Sheng-Nan; Zhang, Feng-Pu; Chu, Sheng-Ying; Zhang, Wen-Wen; Wang, Ai-Ping; Wang, Wen-Yan; Sun, Kao-Xiang

2015-01-01

Rotigotine is a potent and selective D1, D2, and D3 dopaminergic receptor agonist. Due to an extensive first-pass effect, it has a very low oral bioavailability (approximately 0.5% in rats). The present investigation aimed to develop a microemulsion-based hydrogel for transdermal rotigotine delivery with lower application site reactions. Pseudoternary phase diagrams were constructed to determine the region of oil in water (o/w)-type microemulsion. Central composite design was used to support the pseudoternary phase diagrams and to select homogeneous and stable microemulsions with an optimal amount of rotigotine permeation within 24 hours. In vitro skin permeation experiments were performed, using Franz diffusion cells, to compare rotigotine-loaded microemulsions with rotigotine solutions in oil. The optimized formulation was used to prepare a microemulsion-based hydrogel, which was subjected to bioavailability and skin irritancy studies. The selected formulations of rotigotine-loaded microemulsions had enhanced flux and permeation coefficients compared with rotigotine in oil. The optimum microemulsion contained 68% water, 6.8% Labrafil(®), 13.44% Cremophor(®) RH40, 6.72% Labrasol(®), and 5.04% Transcutol(®) HP; the drug-loading rate was 2%. To form a microemulsion gel, 1% Carbomer 1342 was added to the microemulsion. The bioavailability of the rotigotine-loaded microemulsion gel was 105.76%±20.52% with respect to the marketed rotigotine patch (Neupro(®)). The microemulsion gel irritated the skin less than Neupro. A rotigotine microemulsion-based hydrogel was successfully developed, and an optimal formulation for drug delivery was identified. This product could improve patient compliance and have broad marketability.

A Sparse Representation-Based Deployment Method for Optimizing the Observation Quality of Camera Networks

PubMed Central

Wang, Chang; Qi, Fei; Shi, Guangming; Wang, Xiaotian

2013-01-01

Deployment is a critical issue affecting the quality of service of camera networks. The deployment aims at adopting the least number of cameras to cover the whole scene, which may have obstacles to occlude the line of sight, with expected observation quality. This is generally formulated as a non-convex optimization problem, which is hard to solve in polynomial time. In this paper, we propose an efficient convex solution for deployment optimizing the observation quality based on a novel anisotropic sensing model of cameras, which provides a reliable measurement of the observation quality. The deployment is formulated as the selection of a subset of nodes from a redundant initial deployment with numerous cameras, which is an ℓ0 minimization problem. Then, we relax this non-convex optimization to a convex ℓ1 minimization employing the sparse representation. Therefore, the high quality deployment is efficiently obtained via convex optimization. Simulation results confirm the effectiveness of the proposed camera deployment algorithms. PMID:23989826

An introduction to optimal power flow: Theory, formulation, and examples

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

Frank, Stephen; Rebennack, Steffen

The set of optimization problems in electric power systems engineering known collectively as Optimal Power Flow (OPF) is one of the most practically important and well-researched subfields of constrained nonlinear optimization. OPF has enjoyed a rich history of research, innovation, and publication since its debut five decades ago. Nevertheless, entry into OPF research is a daunting task for the uninitiated--both due to the sheer volume of literature and because OPF's ubiquity within the electric power systems community has led authors to assume a great deal of prior knowledge that readers unfamiliar with electric power systems may not possess. This articlemore » provides an introduction to OPF from an operations research perspective; it describes a complete and concise basis of knowledge for beginning OPF research. The discussion is tailored for the operations researcher who has experience with nonlinear optimization but little knowledge of electrical engineering. Topics covered include power systems modeling, the power flow equations, typical OPF formulations, and common OPF extensions.« less

[Optimization of calcium alginate floating microspheres loading aspirin by artificial neural networks and response surface methodology].

PubMed

Zhang, An-yang; Fan, Tian-yuan

2010-04-18

To investigate the preparation and optimization of calcium alginate floating microspheres loading aspirin. A model was used to predict the in vitro release of aspirin and optimize the formulation by artificial neural networks (ANNs) and response surface methodology (RSM). The amounts of the material in the formulation were used as inputs, while the release and floating rate of the microspheres were used as outputs. The performances of ANNs and RSM were compared. ANNs were more accurate in prediction. There was no significant difference between ANNs and RSM in optimization. Approximately 90% of the optimized microspheres could float on the artificial gastric juice over 4 hours. 42.12% of aspirin was released in 60 min, 60.97% in 120 min and 78.56% in 240 min. The release of the drug from the microspheres complied with Higuchi equation. The aspirin floating microspheres with satisfying in vitro release were prepared successfully by the methods of ANNs and RSM.

Nonlinear programming extensions to rational function approximation methods for unsteady aerodynamic forces

NASA Technical Reports Server (NTRS)

Tiffany, Sherwood H.; Adams, William M., Jr.

1988-01-01

The approximation of unsteady generalized aerodynamic forces in the equations of motion of a flexible aircraft are discussed. Two methods of formulating these approximations are extended to include the same flexibility in constraining the approximations and the same methodology in optimizing nonlinear parameters as another currently used extended least-squares method. Optimal selection of nonlinear parameters is made in each of the three methods by use of the same nonlinear, nongradient optimizer. The objective of the nonlinear optimization is to obtain rational approximations to the unsteady aerodynamics whose state-space realization is lower order than that required when no optimization of the nonlinear terms is performed. The free linear parameters are determined using the least-squares matrix techniques of a Lagrange multiplier formulation of an objective function which incorporates selected linear equality constraints. State-space mathematical models resulting from different approaches are described and results are presented that show comparative evaluations from application of each of the extended methods to a numerical example.

Formulation and evaluation of novel controlled release of topical pluronic lecithin organogel of mefenamic acid.

PubMed

Jhawat, Vikas; Gupta, Sumeet; Saini, Vipin

2016-11-01

In the present study, pluronic lecithin based organogels (PLO gels) were formulated as topical carrier for controlled delivery of mefenamic acid. Ten organogel formulations were prepared by a method employing lecithin as lipophilic phase and pluronic F-127 as hydrophilic phase in varying concentrations to study various parameters using in vitro diffusion study and in vivo studies. All formulations were found to be off-white, homogenous, and reluctant to be washed easily and have pH value within the range of 5.56-5.80 which is nonirritant. Polymer concentration increased in formulations of F1 to F5 (lecithin) and F6 to F10 (pluronic) resulted in decrease of the gelation temperature, increase of viscosity and reduction of spreadability of gels having polymer tendency to form rigid 3D network. Organogels with higher viscosity were found to be more stable and retard the drug release from the gel. The formulations of F2 and F3 were selected for kinetic studies and stability studies, as they found to have all physical parameters within acceptable limits, highest percent drug content and exhibited highest drug release in eight hours. The order of drug release from various formulations was found to be F2 > F3 > F10 > F4 > F1 > F9 > F8 > F5 > F7 > F6. The optimized formulation F2 was found to follow zero order rate kinetics showing controlled release of the drug from the formulations. In vivo anti-inflammatory activity of optimized mefenamic acid organogel (F2) against a standard marketed preparation (Volini gel) was found satisfactory and significant.

Sustained release of intravitreal flurbiprofen from a novel drug-in-liposome-in-hydrogel formulation.

PubMed

Pachis, K; Blazaki, S; Tzatzarakis, M; Klepetsanis, P; Naoumidi, E; Tsilimbaris, M; Antimisiaris, S G

2017-11-15

A novel Flurbiprofen (FLB)-in-liposome-in-hydrogel formulation was developed, as a method to sustain the release and increase the ocular bioavailability of FLB following intravitreal injection. For this, FLB loading into liposomes was optimized and liposomes were entrapped in thermosensitive hydrogels consisted of Pluronic F-127 (P). FLB solution, liposomes, and FLB dissolved in hydrogel were also used as control formulations. Actively loaded liposomes were found to be optimal for high FLB loading and small size, while in vitro studies revealed that P concentration of 18% (w/v) was best to retain the integrity of the hydrogel-dispersed liposome, compared to a 20% concentration. The in vitro release of FLB was significantly sustained when FLB-liposomes were dispersed in the hydrogel compared to hydrogel dissolved FLB, as well as the other control formulations. In vivo studies were carried out in pigmented rabbits which were injected through a 27G needle with 1mg/mL FLB in the different formulation-types. Ophthalmic examinations after intravitreal injection of all FLB formulations, revealed no evidence of inflammation, hemorrhage, uveitis or endophthalmitis. Pharmacokinetic analysis results confirm that the hybrid drug delivery system increases the bioavailability (by 1.9 times compared to solution), and extends the presence of the drug in the vitreous cavity, while liposome and hydrogel formulations demonstrate intermediate performance. Furthermore the hybrid system increases MRT of FLB in aqueous humor and retina/choroid tissues, compared to all the control formulations. Currently the potential therapeutic advances of FLB sustained release formulations for IVT administration are being evaluated. Copyright © 2017 Elsevier B.V. All rights reserved.

Intravesical Toll-like receptor 7 agonist R-837: Optimization of its formulation in an orthotopic mouse model of bladder cancer

PubMed Central

Hayashi, Tomoko; Crain, Brian; Corr, Maripat; Chan, Michael; Cottam, Howard B; Maj, Roberto; Barberis, Alcide; Leoni, Lorenzo; Carson, Dennis A

2013-01-01

Objective To study the immune response caused by the intravesical administration of the immunomodulator R-837 in various formulations and to estimate its therapeutic potential for bladder cancer. Methods Female C57BL/6 mice were intravesically treated with different formulations of R-837, a Toll-like receptor 7 agonist used for treating genital warts and skin malignancy. The tested formulation mixtures contained different ratios of lactic acid, a thermosensitive poloxamer polymer (Lutrol F127) and 2-(hydroxypropyl)-β-cyclodextrin (HPβCD). Induction of tumor necrosis factor α (TNFα) and keratinocyte-derived chemokine (KC) was analyzed by Luminex microbeads assay. The therapeutic potential of intravesical administration of R-837 was assessed in an orthotopic, syngeneic mouse model of bladder cancer using MB49 cells. Results Intravesical administration of R-837 in lactic acid alone induced systemic and bladder TNFα and KC in a dose-dependent manner. Formulations including poloxamer decreased systemic absorption of R-837 and significantly reduced systemic and local induction of KC. Addition of HPβCD in the poloxamer formulation particularly reversed levels of systemic and local levels of TNFα and KC. Histological examination showed that poloxamer-HPβCD formulation allowed infiltration of mononuclear cells into urothelium and lamina propria. In studies using orthotopic mouse bladder cancer, the tumor loads in R-837-treated mice were significantly lower than those in vehicle-treated or non-treated mice. Conclusion The optimized poloxamer-HPβCD formulation of R-837 shows therapeutic potential for bladder cancer while avoiding adverse side-effects. PMID:20337728

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

PubMed

Khani, Samira; Keyhanfar, Fariborz

2014-02-01

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

Blended near-optimal alternative generation, visualization, and interaction for water resources decision making

NASA Astrophysics Data System (ADS)

Rosenberg, David E.

2015-04-01

State-of-the-art systems analysis techniques focus on efficiently finding optimal solutions. Yet an optimal solution is optimal only for the modeled issues and managers often seek near-optimal alternatives that address unmodeled objectives, preferences, limits, uncertainties, and other issues. Early on, Modeling to Generate Alternatives (MGA) formalized near-optimal as performance within a tolerable deviation from the optimal objective function value and identified a few maximally different alternatives that addressed some unmodeled issues. This paper presents new stratified, Monte-Carlo Markov Chain sampling and parallel coordinate plotting tools that generate and communicate the structure and extent of the near-optimal region to an optimization problem. Interactive plot controls allow users to explore region features of most interest. Controls also streamline the process to elicit unmodeled issues and update the model formulation in response to elicited issues. Use for an example, single-objective, linear water quality management problem at Echo Reservoir, Utah, identifies numerous and flexible practices to reduce the phosphorus load to the reservoir and maintain close-to-optimal performance. Flexibility is upheld by further interactive alternative generation, transforming the formulation into a multiobjective problem, and relaxing the tolerance parameter to expand the near-optimal region. Compared to MGA, the new blended tools generate more numerous alternatives faster, more fully show the near-optimal region, and help elicit a larger set of unmodeled issues.

Topology optimization of reduced rare-earth permanent magnet arrays with finite coercivity

NASA Astrophysics Data System (ADS)

Teyber, R.; Trevizoli, P. V.; Christiaanse, T. V.; Govindappa, P.; Rowe, A.

2018-05-01

The supply chain risk of rare-earth permanent magnets has yielded research efforts to improve both materials and magnetic circuits. While a number of magnet optimization techniques exist, literature has not incorporated the permanent magnet failure process stemming from finite coercivity. To address this, a mixed-integer topology optimization is formulated to maximize the flux density of a segmented Halbach cylinder while avoiding permanent demagnetization. The numerical framework is used to assess the efficacy of low-cost (rare-earth-free ferrite C9), medium-cost (rare-earth-free MnBi), and higher-cost (Dy-free NdFeB) permanent magnet materials. Novel magnet designs are generated that produce flux densities 70% greater than the segmented Halbach array, albeit with increased magnet mass. Three optimization formulations are then explored using ferrite C9 that demonstrates the trade-off between manufacturability and design sophistication, generating flux densities in the range of 0.366-0.483 T.

An Investigation to Manufacturing Analytical Services Composition using the Analytical Target Cascading Method.

PubMed

Tien, Kai-Wen; Kulvatunyou, Boonserm; Jung, Kiwook; Prabhu, Vittaldas

2017-01-01

As cloud computing is increasingly adopted, the trend is to offer software functions as modular services and compose them into larger, more meaningful ones. The trend is attractive to analytical problems in the manufacturing system design and performance improvement domain because 1) finding a global optimization for the system is a complex problem; and 2) sub-problems are typically compartmentalized by the organizational structure. However, solving sub-problems by independent services can result in a sub-optimal solution at the system level. This paper investigates the technique called Analytical Target Cascading (ATC) to coordinate the optimization of loosely-coupled sub-problems, each may be modularly formulated by differing departments and be solved by modular analytical services. The result demonstrates that ATC is a promising method in that it offers system-level optimal solutions that can scale up by exploiting distributed and modular executions while allowing easier management of the problem formulation.

Application of multi-objective optimization to pooled experiments of next generation sequencing for detection of rare mutations.

PubMed

Zilinskas, Julius; Lančinskas, Algirdas; Guarracino, Mario Rosario

2014-01-01

In this paper we propose some mathematical models to plan a Next Generation Sequencing experiment to detect rare mutations in pools of patients. A mathematical optimization problem is formulated for optimal pooling, with respect to minimization of the experiment cost. Then, two different strategies to replicate patients in pools are proposed, which have the advantage to decrease the overall costs. Finally, a multi-objective optimization formulation is proposed, where the trade-off between the probability to detect a mutation and overall costs is taken into account. The proposed solutions are devised in pursuance of the following advantages: (i) the solution guarantees mutations are detectable in the experimental setting, and (ii) the cost of the NGS experiment and its biological validation using Sanger sequencing is minimized. Simulations show replicating pools can decrease overall experimental cost, thus making pooling an interesting option.

Physicochemical and microbiological stability studies of extemporaneous antihypertensive pediatric suspensions for hospital use.

PubMed

Mendes, Cassiana; Costa, Ana Paula; Oliveira, Paulo Renato; Tagliari, Monika Piazzon; Silva, Marcos Antônio Segatto

2013-01-01

Extemporaneous suspensions of the antihypertensive agents furosemide, spironolactone and hydrochlorothiazide for pediatric use have been prepared at University Hospital (Federal University of Santa Catarina - Brazil). The aim of this work was to investigate the physicochemical and microbiological stability of these suspensions over the estimated shelf-life period of seven days and, if necessary, to optimize the formulations by improving the chemical stability. The pediatric suspensions were prepared using drug raw material and were stored at 25 ± 2°C and 5 ± 3°C. Chemical stability was evaluated by HPLC assay of the suspensions for drug content. Physical stability was evaluated by sedimentation volume, redispersibility, particle size, and zeta potential. Viable bacterial and fungal contaminations were assessed according to the official compendium. Furosemide and spironolactone suspensions as prepared herein can be stored for 7 days. However, the hydrochlorothiazide suspension formulation at pH 6.5 demonstrated poor chemical stability and was optimized by adjusting the pH to 3.3 where the drug exhibited acceptable stability. The optimized formulation demonstrated to be stable over the required period of 7 days.

Parameter Optimization for Turbulent Reacting Flows Using Adjoints

NASA Astrophysics Data System (ADS)

Lapointe, Caelan; Hamlington, Peter E.

2017-11-01

The formulation of a new adjoint solver for topology optimization of turbulent reacting flows is presented. This solver provides novel configurations (e.g., geometries and operating conditions) based on desired system outcomes (i.e., objective functions) for complex reacting flow problems of practical interest. For many such problems, it would be desirable to know optimal values of design parameters (e.g., physical dimensions, fuel-oxidizer ratios, and inflow-outflow conditions) prior to real-world manufacture and testing, which can be expensive, time-consuming, and dangerous. However, computational optimization of these problems is made difficult by the complexity of most reacting flows, necessitating the use of gradient-based optimization techniques in order to explore a wide design space at manageable computational cost. The adjoint method is an attractive way to obtain the required gradients, because the cost of the method is determined by the dimension of the objective function rather than the size of the design space. Here, the formulation of a novel solver is outlined that enables gradient-based parameter optimization of turbulent reacting flows using the discrete adjoint method. Initial results and an outlook for future research directions are provided.

Optimal cure cycle design of a resin-fiber composite laminate

NASA Technical Reports Server (NTRS)

Hou, Jean W.; Sheen, Jeenson

1987-01-01

A unified computed aided design method was studied for the cure cycle design that incorporates an optimal design technique with the analytical model of a composite cure process. The preliminary results of using this proposed method for optimal cure cycle design are reported and discussed. The cure process of interest is the compression molding of a polyester which is described by a diffusion reaction system. The finite element method is employed to convert the initial boundary value problem into a set of first order differential equations which are solved simultaneously by the DE program. The equations for thermal design sensitivities are derived by using the direct differentiation method and are solved by the DE program. A recursive quadratic programming algorithm with an active set strategy called a linearization method is used to optimally design the cure cycle, subjected to the given design performance requirements. The difficulty of casting the cure cycle design process into a proper mathematical form is recognized. Various optimal design problems are formulated to address theses aspects. The optimal solutions of these formulations are compared and discussed.

Removal of xylenol orange from its aqueous solution using SDS self-microemulsifying systems: optimization by Box-Behnken statistical design.

PubMed

Shakeel, Faiyaz; Haq, Nazrul; Alanazi, Fars K; Alsarra, Ibrahim A

2014-04-01

The aim of present study was to develop and evaluate sodium dodecyl sulfate (SDS) self-microemulsifying systems (SMES) for the removal of an anionic dye xylenol orange (XO) from its bulk aqueous media via liquid-liquid adsorption. The composition of SDS SMES was optimized by Box-Behnken statistical design for the maximum removal of XO from its aqueous solution. Various SDS formulations were prepared by spontaneous emulsification method and characterized for thermodynamic stability, self-microemulsification efficiency, droplet size, and viscosity. Adsorption studies were conducted at 8, 16, and 24 h by mixing small amounts of SDS formulations with relatively large amounts of bulk aqueous solution of XO. Droplet size and viscosity of SDS formulations were significantly influenced by oil phase concentration (triacetin), while surfactant concentration had little impact on droplet size and viscosity. However, the percentage of removal of XO was influenced by triacetin concentration, surfactant concentration, and adsorption time. Based on lowest droplet size (35.97 nm), lowest viscosity (29.62 cp), and highest percentage of removal efficiency (89.77 %), formulation F14, containing 2 % w/w of triacetin and 40 % w/w of surfactant mixture (20 % w/w of SDS and 20 % w/w of polyethylene glycol 400), was selected as an optimized formulation for the removal of XO from its bulk aqueous media after 16 h. These results indicated that SDS SMES could be suitable alternates of solid-liquid adsorption for the removal of toxic dyes such as XO from its aqueous solution through liquid-liquid adsorption.

Influence of some formulation variables on the optimization of pH-dependent, colon-targeted, sustained-release mesalamine microspheres.

PubMed

El-Bary, Ahmed Abd; Aboelwafa, Ahmed A; Al Sharabi, Ibrahim M

2012-03-01

The aim of this work was to understand the influence of different formulation variables on the optimization of pH-dependent, colon-targeted, sustained-release mesalamine microspheres prepared by O/O emulsion solvent evaporation method, employing pH-dependent Eudragit S and hydrophobic pH-independent ethylcellulose polymers. Formulation variables studied included concentration of Eudragit S in the internal phase and the ratios between; internal to external phase, drug to Eudragit S and Eudragit S to ethylcellulose to mesalamine. Prepared microspheres were evaluated by carrying out in vitro release studies and determination of particle size, production yield, and encapsulation efficiency. In addition, morphology of microspheres was examined using optical and scanning electron microscopy. Emulsion solvent evaporation method was found to be sensitive to the studied formulation variables. Particle size and encapsulation efficiency increased by increasing Eudragit S concentration in the internal phase, ratio of internal to external phase, and ratio of Eudragit S to the drug. Employing Eudragit S alone in preparation of the microspheres is only successful in forming acid-resistant microspheres with pulsatile release pattern at high pH. Eudragit S and ethylcellulose blend microspheres were able to control release under acidic condition and to extend drug release at high pH. The stability studies carried out at 40°C/75% RH for 6 months proved the stability of the optimized formulation. From the results of this investigation, microencapsulation of mesalamine in microspheres using blend of Eudragit S and ethylcellulose could constitute a promising approach for site-specific and controlled delivery of drug in colon.

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.

Formulation and evaluation of optimized oxybenzone microsponge gel for topical delivery.

PubMed

Pawar, Atmaram P; Gholap, Aditya P; Kuchekar, Ashwin B; Bothiraja, C; Mali, Ashwin J

2015-01-01

Background. Oxybenzone, a broad spectrum sunscreen agent widely used in the form of lotion and cream, has been reported to cause skin irritation, dermatitis, and systemic absorption. Aim. The objective of the present study was to formulate oxybenzone loaded microsponge gel for enhanced sun protection factor with reduced toxicity. Material and Method. Microsponge for topical delivery of oxybenzone was successfully prepared by quasiemulsion solvent diffusion method. The effects of ethyl cellulose and dichloromethane were optimized by the 3(2) factorial design. The optimized microsponges were dispersed into the hydrogel and further evaluated. Results. The microsponges were spherical with pore size in the range of 0.10-0.22 µm. The optimized formulation possesses the particle size and entrapment efficiency of 72 ± 0.77 µm and 96.9 ± 0.52%, respectively. The microsponge gel showed the controlled release and was nonirritant to the rat skin. In creep recovery test it had shown highest recovery indicating elasticity. The controlled release of oxybenzone from microsponge and barrier effect of gel result in prolonged retention of oxybenzone with reduced permeation activity. Conclusion. Evaluation study revealed remarkable and enhanced topical retention of oxybenzone for prolonged period of time. It also showed the enhanced sun protection factor compared to the marketed preparation with reduced irritation and toxicity.

Optimization of edible coating formulations for improving postharvest quality and shelf life of pear fruit using response surface methodology.

PubMed

Nandane, A S; Dave, Rudri K; Rao, T V Ramana

2017-01-01

The effect of composite edible films containing soy protein isolate (SPI) in combination with additives like hydroxypropyl methylcellulose (HPMC) and olive oil on 'Babughosha' pear ( Pyrus communis L.) stored at ambient temperature (28 ± 5 °C and 60 ± 10% RH) was evaluated using Response surface methodology (RSM). A total of 30 edible coating formulations comprising of SPI (2-6%, w/v), olive oil (0.7-1.1%, v/v), HPMC (0.1-0.5%, w/v) and potassium sorbate (0-0.4% w/v) were evaluated for optimizing the most suitable combination. Quality parameters like weight loss%, TSS, pH and titrable acidity of the stored pears were selected as response variables for optimization. The optimization procedure was carried out using RSM. It was observed that the response variables were mainly effected by concentration of SPI and olive oil in the formulation. Edible coating comprising of SPI 5%, HPMC 0.40%, olive oil 1% and potassium sorbate 0.22% was found to be most suitable combination for pear fruit with predicted values of response variables indicated as weight loss% 3.50, pH 3.41, TSS 11.13 and TA% 0.513.

Oral bioavailability enhancement of raloxifene by developing microemulsion using D-optimal mixture design: optimization and in-vivo pharmacokinetic study.

PubMed

Shah, Nirmal; Seth, Avinashkumar; Balaraman, R; Sailor, Girish; Javia, Ankur; Gohil, Dipti

2018-04-01

The objective of this work was to utilize a potential of microemulsion for the improvement in oral bioavailability of raloxifene hydrochloride, a BCS class-II drug with 2% bioavailability. Drug-loaded microemulsion was prepared by water titration method using Capmul MCM C8, Tween 20, and Polyethylene glycol 400 as oil, surfactant, and co-surfactant respectively. The pseudo-ternary phase diagram was constructed between oil and surfactants mixture to obtain appropriate components and their concentration ranges that result in large existence area of microemulsion. D-optimal mixture design was utilized as a statistical tool for optimization of microemulsion considering oil, S mix , and water as independent variables with percentage transmittance and globule size as dependent variables. The optimized formulation showed 100 ± 0.1% transmittance and 17.85 ± 2.78 nm globule size which was identically equal with the predicted values of dependent variables given by the design expert software. The optimized microemulsion showed pronounced enhancement in release rate compared to plain drug suspension following diffusion controlled release mechanism by the Higuchi model. The formulation showed zeta potential of value -5.88 ± 1.14 mV that imparts good stability to drug loaded microemulsion dispersion. Surface morphology study with transmission electron microscope showed discrete spherical nano sized globules with smooth surface. In-vivo pharmacokinetic study of optimized microemulsion formulation in Wistar rats showed 4.29-fold enhancements in bioavailability. Stability study showed adequate results for various parameters checked up to six months. These results reveal the potential of microemulsion for significant improvement in oral bioavailability of poorly soluble raloxifene hydrochloride.

Mixed Integer Programming and Heuristic Scheduling for Space Communication

NASA Technical Reports Server (NTRS)

Lee, Charles H.; Cheung, Kar-Ming

2013-01-01

Optimal planning and scheduling for a communication network was created where the nodes within the network are communicating at the highest possible rates while meeting the mission requirements and operational constraints. The planning and scheduling problem was formulated in the framework of Mixed Integer Programming (MIP) to introduce a special penalty function to convert the MIP problem into a continuous optimization problem, and to solve the constrained optimization problem using heuristic optimization. The communication network consists of space and ground assets with the link dynamics between any two assets varying with respect to time, distance, and telecom configurations. One asset could be communicating with another at very high data rates at one time, and at other times, communication is impossible, as the asset could be inaccessible from the network due to planetary occultation. Based on the network's geometric dynamics and link capabilities, the start time, end time, and link configuration of each view period are selected to maximize the communication efficiency within the network. Mathematical formulations for the constrained mixed integer optimization problem were derived, and efficient analytical and numerical techniques were developed to find the optimal solution. By setting up the problem using MIP, the search space for the optimization problem is reduced significantly, thereby speeding up the solution process. The ratio of the dimension of the traditional method over the proposed formulation is approximately an order N (single) to 2*N (arraying), where N is the number of receiving antennas of a node. By introducing a special penalty function, the MIP problem with non-differentiable cost function and nonlinear constraints can be converted into a continuous variable problem, whose solution is possible.

Optimization of a Nanomedicine-based Pc 4-PDT Strategy for Targeted Treatment of EGFR-Overexpressing Cancers

PubMed Central

Master, Alyssa M.; Livingston, Megan; Oleinick, Nancy L.; Gupta, Anirban Sen

2012-01-01

The current clinical mainstays for cancer treatment, namely, surgical resection, chemotherapy and radiotherapy, can cause significant trauma, systemic toxicity, and functional/cosmetic debilitation of tissue, especially if repetitive treatment becomes necessary due to tumor recurrence. Hence there is significant clinical interest in alternate treatment strategies like photodynamic therapy (PDT) which can effectively and selectively eradicate tumors and can be safely repeated if needed. We have previously demonstrated that the second-generation photosensitizer Pc 4 can be formulated within polymeric micelles, and these micelles can be specifically targeted to EGFR-overexpressing cancer cells using GE11 peptide ligands, to enhance cell-specific Pc 4 delivery and internalization. In the current study, we report on the in vitro optimization of the EGFR-targeting, Pc 4 loading of the micellar nanoformulation, along with optimization of the corresponding photoirradiation conditions to maximize Pc 4 delivery, internalization and subsequent PDT-induced cytotoxicity in EGFR-overexpressing cells in vitro. In our studies, absorption and fluorescence spectroscopy were used to monitor the cell-specific uptake of the GE11-decorated Pc 4-loaded micelles and the cytotoxic singlet oxygen production from the micelle-encapsulated Pc 4, to determine the optimum ligand density and Pc 4 loading. It was found that the micelle formulations bearing 10 mole% of GE11-modified polymer component resulted in the highest cellular uptake in EGFR-overexpressing A431 cells within the shortest incubation periods. Also, the loading of ~50 μg Pc 4 per mg of polymer in these micellar formulations resulted in the highest levels of singlet oxygen production. When formulations bearing these optimized parameters were tested in vitro on A431 cells for PDT effect, a formulation dose containing 400 nM Pc 4 and photoirradiation duration of 400 seconds at a fluence of 200 mJ/cm2 yielded close to 100% cell death. PMID:22775587

Transbuccal delivery of chlorpheniramine maleate from mucoadhesive buccal patches.

PubMed

Sekhar, K Chandra; Naidu, K V S; Vishnu, Y Vamshi; Gannu, Ramesh; Kishan, V; Rao, Y Madhusudan

2008-01-01

This article describes buccal permeation of chlorpheniramine maleate (CPM) and its transbuccal delivery using mucoadhesive buccal patches. Permeation of CPM was calculated in vitro using porcine buccal membrane and in vivo in healthy humans. Buccal formulations were developed with hydroxyethylcellulose (HEC) and evaluated for in vitro release, moisture absorption, mechanical properties, and bioadhesion, and optimized formulation was subjected for bioavailability studies in healthy human volunteers. In vitro flux of CPM was calculated to be 0.14 +/- 0.03 mg.h(-1).cm(-2) and buccal absorption also was demonstrated in vivo in human volunteers. In vitro drug release and moisture absorbed were governed by HEC content and formulations exhibited good tensile and mucoadhesive properties. Bioavailability from optimized buccal patch was 1.46 times higher than the oral dosage form and the results showed statistically significant difference.

Integrated control-structure design

NASA Technical Reports Server (NTRS)

Hunziker, K. Scott; Kraft, Raymond H.; Bossi, Joseph A.

1991-01-01

A new approach for the design and control of flexible space structures is described. The approach integrates the structure and controller design processes thereby providing extra opportunities for avoiding some of the disastrous effects of control-structures interaction and for discovering new, unexpected avenues of future structural design. A control formulation based on Boyd's implementation of Youla parameterization is employed. Control design parameters are coupled with structural design variables to produce a set of integrated-design variables which are selected through optimization-based methodology. A performance index reflecting spacecraft mission goals and constraints is formulated and optimized with respect to the integrated design variables. Initial studies have been concerned with achieving mission requirements with a lighter, more flexible space structure. Details of the formulation of the integrated-design approach are presented and results are given from a study involving the integrated redesign of a flexible geostationary platform.

Optimization of the formulation and technology of pearl millet based 'ready-to-reconstitute' kheer mix powder.

PubMed

Bunkar, Durga Shankar; Jha, Alok; Mahajan, Ankur

2014-10-01

The objective of this study was to optimize the process of manufacturing instant kheer mix based on pearl millet instead of rice. Dairy whitener, pearl millet and powdered sugar were the responses studied by employing the 3-factor Central Composite Rotatable Design. The formulation with 15 g sugar, 30 g dairy whitener and 20 g pearl millet was found suitable for obtaining dry kheer mix. The analyses were based on scores of consistency, cohesiveness, viscosity and overall acceptability. The reconstituted product from the formulated kheer mix had an overall acceptability score of 7.66 and desirability index of 0.7663. The moisture, fat, protein, carbohydrate and ash contents of the dry mix product were 2.8, 4.38, 5.84, 85.88 and 1.1 %, respectively.

An Efficacious Multi-Objective Fuzzy Linear Programming Approach for Optimal Power Flow Considering Distributed Generation.

PubMed

Warid, Warid; Hizam, Hashim; Mariun, Norman; Abdul-Wahab, Noor Izzri

2016-01-01

This paper proposes a new formulation for the multi-objective optimal power flow (MOOPF) problem for meshed power networks considering distributed generation. An efficacious multi-objective fuzzy linear programming optimization (MFLP) algorithm is proposed to solve the aforementioned problem with and without considering the distributed generation (DG) effect. A variant combination of objectives is considered for simultaneous optimization, including power loss, voltage stability, and shunt capacitors MVAR reserve. Fuzzy membership functions for these objectives are designed with extreme targets, whereas the inequality constraints are treated as hard constraints. The multi-objective fuzzy optimal power flow (OPF) formulation was converted into a crisp OPF in a successive linear programming (SLP) framework and solved using an efficient interior point method (IPM). To test the efficacy of the proposed approach, simulations are performed on the IEEE 30-busand IEEE 118-bus test systems. The MFLP optimization is solved for several optimization cases. The obtained results are compared with those presented in the literature. A unique solution with a high satisfaction for the assigned targets is gained. Results demonstrate the effectiveness of the proposed MFLP technique in terms of solution optimality and rapid convergence. Moreover, the results indicate that using the optimal DG location with the MFLP algorithm provides the solution with the highest quality.

An Efficacious Multi-Objective Fuzzy Linear Programming Approach for Optimal Power Flow Considering Distributed Generation

PubMed Central

Warid, Warid; Hizam, Hashim; Mariun, Norman; Abdul-Wahab, Noor Izzri

2016-01-01

This paper proposes a new formulation for the multi-objective optimal power flow (MOOPF) problem for meshed power networks considering distributed generation. An efficacious multi-objective fuzzy linear programming optimization (MFLP) algorithm is proposed to solve the aforementioned problem with and without considering the distributed generation (DG) effect. A variant combination of objectives is considered for simultaneous optimization, including power loss, voltage stability, and shunt capacitors MVAR reserve. Fuzzy membership functions for these objectives are designed with extreme targets, whereas the inequality constraints are treated as hard constraints. The multi-objective fuzzy optimal power flow (OPF) formulation was converted into a crisp OPF in a successive linear programming (SLP) framework and solved using an efficient interior point method (IPM). To test the efficacy of the proposed approach, simulations are performed on the IEEE 30-busand IEEE 118-bus test systems. The MFLP optimization is solved for several optimization cases. The obtained results are compared with those presented in the literature. A unique solution with a high satisfaction for the assigned targets is gained. Results demonstrate the effectiveness of the proposed MFLP technique in terms of solution optimality and rapid convergence. Moreover, the results indicate that using the optimal DG location with the MFLP algorithm provides the solution with the highest quality. PMID:26954783

A General-Purpose Optimization Engine for Multi-Disciplinary Design Applications

NASA Technical Reports Server (NTRS)

Patnaik, Surya N.; Hopkins, Dale A.; Berke, Laszlo

1996-01-01

A general purpose optimization tool for multidisciplinary applications, which in the literature is known as COMETBOARDS, is being developed at NASA Lewis Research Center. The modular organization of COMETBOARDS includes several analyzers and state-of-the-art optimization algorithms along with their cascading strategy. The code structure allows quick integration of new analyzers and optimizers. The COMETBOARDS code reads input information from a number of data files, formulates a design as a set of multidisciplinary nonlinear programming problems, and then solves the resulting problems. COMETBOARDS can be used to solve a large problem which can be defined through multiple disciplines, each of which can be further broken down into several subproblems. Alternatively, a small portion of a large problem can be optimized in an effort to improve an existing system. Some of the other unique features of COMETBOARDS include design variable formulation, constraint formulation, subproblem coupling strategy, global scaling technique, analysis approximation, use of either sequential or parallel computational modes, and so forth. The special features and unique strengths of COMETBOARDS assist convergence and reduce the amount of CPU time used to solve the difficult optimization problems of aerospace industries. COMETBOARDS has been successfully used to solve a number of problems, including structural design of space station components, design of nozzle components of an air-breathing engine, configuration design of subsonic and supersonic aircraft, mixed flow turbofan engines, wave rotor topped engines, and so forth. This paper introduces the COMETBOARDS design tool and its versatility, which is illustrated by citing examples from structures, aircraft design, and air-breathing propulsion engine design.

JPL Innovation Foundry

NASA Technical Reports Server (NTRS)

Sherwood, Brent; McCleese, Daniel J.

2012-01-01

NASA supports the community of mission principal investigators by helping them ideate, mature, and propose concepts for new missions. As NASA's Federally Funded Research and Development Center (FFRDC), JPL is a primary resource for providing this service. The environmental context for the formulation lifecycle evolves continuously. Contemporary trends include: more competitors; more-complex mission ideas; scarcer formulation resources; and higher standards for technical evaluation. Derived requirements for formulation support include: stable, clear, reliable methods tailored for each stage of the formulation lifecycle; on-demand access to standout technical and programmatic subject-matter experts; optimized, outfitted facilities; smart access to learning embodied in a vast oeuvre of prior formulation work; hands-on method coaching. JPL has retooled its provision of integrated formulation lifecycle support to PIs, teams, and program offices in response to this need. This mission formulation enterprise is the JPL Innovation Foundry.

Power optimization of wireless media systems with space-time block codes.

PubMed

Yousefi'zadeh, Homayoun; Jafarkhani, Hamid; Moshfeghi, Mehran

2004-07-01

We present analytical and numerical solutions to the problem of power control in wireless media systems with multiple antennas. We formulate a set of optimization problems aimed at minimizing total power consumption of wireless media systems subject to a given level of QoS and an available bit rate. Our formulation takes into consideration the power consumption related to source coding, channel coding, and transmission of multiple-transmit antennas. In our study, we consider Gauss-Markov and video source models, Rayleigh fading channels along with the Bernoulli/Gilbert-Elliott loss models, and space-time block codes.

Development and characterization of floating spheroids of atorvastatin calcium loaded NLC for enhancement of oral bioavailability.

PubMed

Sharma, Kritika; Hallan, Supandeep Singh; Lal, Bharat; Bhardwaj, Ankur; Mishra, Neeraj

2016-09-01

The obejctive of the present study was to investigate the potential use of floating spheroids of Atorvastatin Calcium (ATS) Loaded nanostructured lipid carriers (NLCs). The final formula of floating spheroids was optimized on the basis of shape (spherical), diameter (0.47 mm), lag time (20 s), and floating time (> 32 h). The results were further confirmed by different pharmacokinetic parameters-it was observed that the developed optimized floating ATS spheroid-loaded NLCs formulation has significantly improved relative bioavailability, that is, 3.053-folds through oral route in comparison to marketed formulation.

Study of aerodynamic surface control of space shuttle boost and reentry, volume 1

NASA Technical Reports Server (NTRS)

Chang, C. J.; Connor, C. L.; Gill, G. P.

1972-01-01

The optimization technique is described which was used in the study for applying modern optimal control technology to the design of shuttle booster engine reaction control systems and aerodynamic control systems. Complete formulations are presented for both the ascent and reentry portions of the study. These formulations include derivations of the 6D perturbation equations of motion and the process followed in the control and blending law selections. A total hybrid software concept applied to the study is described in detail. Conclusions and recommendations based on the results of the study are included.

Formulation procedure and spectral data for a coatings system optimally employing the high intrinsic reflectance of barium sulphate

NASA Technical Reports Server (NTRS)

Schutt, J. B.; Stromberg, E.; Shai, C. M.; Arens, J. F.

1972-01-01

The use of polyvinyl alcohol as a binder for barium sulphate does not allow the intrinsically high reflectance of this material in the near vacuum ultraviolet to be optimally employed. In an effort to better utilize this property, completely inorganic coatings systems are described, where from the intrinsically high reflectance of barium sulphate in this spectral region can be gotten. Potassium sulphate turns out to be the preferred binder. Compositions, formulating procedures, and application techniques are included. For completeness, absolute and relative reflectance data are included for intra- and intersystem comparisons.

Absence of Degradation of Tretinoin When Benzoyl Peroxide is Combined with an Optimized Formulation of Tretinoin Gel (0.05%)

PubMed Central

Pillai, Radhakrishnan; Moore, Robert

2010-01-01

Background: Clinicians have been reluctant to prescribe benzoyl peroxide concurrently with topical tretinoin due to a belief that the benzoyl peroxide may cause oxidation and degradation of the tretinoin molecule, thereby reducing its effectiveness. However, benzoyl peroxide-induced degradation of tretinoin may not necessarily apply to all topical tretinoin formulations. Objective: To evaluate the potential for benzoyl peroxide-induced degradation of an optimized aqueous gel formulation of tretinoin (0.05%). Methods: Tretinoin gel (0.05%) and benzoyl peroxide gel (6.26% premix concentration to produce 5% benzoyl peroxide in a fixed combination clindamycin product) were mixed together (1:1) at 32ºC and samples assayed after 1, 2, 3, 5, and 7 hours. Each sample was analyzed for tretinoin (expressed as % tretinoin remaining) and its degradation product content. Results: No loss of tretinoin was observed over the seven-hour time period. When tretinoin gel (0.05%) was combined with benzoyl peroxide, 100 percent of the initial tretinoin concentration remained after seven hours. There was no increase in the degradation products of tretinoin. Conclusions: There was no benzoyl peroxide-induced degradation of tretinoin when the optimized formulation of tretinoin gel (0.05%) was admixed with benzoyl peroxide gel (6.26%). Although the direct clinical significance of these results is unknown, clinicians may feel comfortable using this particular combination concurrently without concerns about tretinoin oxidation and degradation. PMID:20967192

Development of loteprednol etabonate-loaded cationic nanoemulsified in-situ ophthalmic gel for sustained delivery and enhanced ocular bioavailability.

PubMed

Patel, Nirav; Nakrani, Happy; Raval, Mihir; Sheth, Navin

2016-11-01

A novel cationic nanoemulsified in-situ ophthalmic gel of loteprednol etabonate (LE) was developed to improve the permeability and retention time of formulations for overall improvement of drug's ocular bioavability. Capryol 90 (oil phase), tween 80 (surfactant) and transcutol P (cosurfactant) was selected as formulation excipients to construct pseudoternary phase diagrams and nanoemulsion region was recognized from diagrams. Spontaneous emulsification method was used to manufacture LE nanoemulsion and it was optimized using 3 2 factorial design by considering the amount of oil and the ratio of surfactant to cosurfactant (S mix ) as independent variables and evaluated for various physicochemical properties. Optimized NE was dispersed in Poloxamer 407 and 188 solution to form nanoemulsified sols that were predictable to transform into in-situ gels at corneal temperature. Drug pharmacokinetics of sterilized optimized in situ NE gel, NE-ISG2 [0.69% w/w Capryol 90, 0.99%w/w S mix (3:1), 13% Poloxamer 407, 4% w/w Poloxamer 188] and marketed formulation were assessed in rabbit aqueous humor. The in-situ gels were clear, shear thinning in nature and displayed zero-order drug release kinetics. NE-ISG2 showed the minimum ocular irritation potential and significantly (p < 0.01) higher C max and AUC (0-10 h) , delayed T max , extended mean residence time and improved (2.54-fold times) bioavailability compared to marketed formulation.

Efficient methods for overlapping group lasso.

PubMed

Yuan, Lei; Liu, Jun; Ye, Jieping

2013-09-01

The group Lasso is an extension of the Lasso for feature selection on (predefined) nonoverlapping groups of features. The nonoverlapping group structure limits its applicability in practice. There have been several recent attempts to study a more general formulation where groups of features are given, potentially with overlaps between the groups. The resulting optimization is, however, much more challenging to solve due to the group overlaps. In this paper, we consider the efficient optimization of the overlapping group Lasso penalized problem. We reveal several key properties of the proximal operator associated with the overlapping group Lasso, and compute the proximal operator by solving the smooth and convex dual problem, which allows the use of the gradient descent type of algorithms for the optimization. Our methods and theoretical results are then generalized to tackle the general overlapping group Lasso formulation based on the l(q) norm. We further extend our algorithm to solve a nonconvex overlapping group Lasso formulation based on the capped norm regularization, which reduces the estimation bias introduced by the convex penalty. We have performed empirical evaluations using both a synthetic and the breast cancer gene expression dataset, which consists of 8,141 genes organized into (overlapping) gene sets. Experimental results show that the proposed algorithm is more efficient than existing state-of-the-art algorithms. Results also demonstrate the effectiveness of the nonconvex formulation for overlapping group Lasso.

Development and evaluation of paclitaxel nanoparticles using a quality-by-design approach.

PubMed

Yerlikaya, Firat; Ozgen, Aysegul; Vural, Imran; Guven, Olgun; Karaagaoglu, Ergun; Khan, Mansoor A; Capan, Yilmaz

2013-10-01

The aims of this study were to develop and characterize paclitaxel nanoparticles, to identify and control critical sources of variability in the process, and to understand the impact of formulation and process parameters on the critical quality attributes (CQAs) using a quality-by-design (QbD) approach. For this, a risk assessment study was performed with various formulation and process parameters to determine their impact on CQAs of nanoparticles, which were determined to be average particle size, zeta potential, and encapsulation efficiency. Potential risk factors were identified using an Ishikawa diagram and screened by Plackett-Burman design and finally nanoparticles were optimized using Box-Behnken design. The optimized formulation was further characterized by Fourier transform infrared spectroscopy, X-ray diffractometry, differential scanning calorimetry, scanning electron microscopy, atomic force microscopy, and gas chromatography. It was observed that paclitaxel transformed from crystalline state to amorphous state while totally encapsulating into the nanoparticles. The nanoparticles were spherical, smooth, and homogenous with no dichloromethane residue. In vitro cytotoxicity test showed that the developed nanoparticles are more efficient than free paclitaxel in terms of antitumor activity (more than 25%). In conclusion, this study demonstrated that understanding formulation and process parameters with the philosophy of QbD is useful for the optimization of complex drug delivery systems. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

Improvement of skin condition in striae distensae: development, characterization and clinical efficacy of a cosmetic product containing Punica granatum seed oil and Croton lechleri resin extract

PubMed Central

Bogdan, Cătălina; Iurian, Sonia; Tomuta, Ioan; Moldovan, Mirela

2017-01-01

Striae distensae are a frequent skin condition associated with pregnancy, weight change or lack of skin elasticity. The aim of this research was to obtain a topical product containing herbal active ingredients with documented antioxidant and anti-inflammatory activity (Punica granatum seed oil and Croton lechleri resin extract) and demonstrate its positive effect on prevention and treatment of striae distensae. First, the cream base formulation was optimized through experimental design. Secondly, the cream containing the two active ingredients was investigated in an interventional nonrandomized clinical trial. The clinical outcome was assessed through biophysical parameters and ultrasonographic evaluation. The state of the skin was evaluated by biophysical measurements and ultrasonography at the beginning of the study and after 3 and 6 weeks. The experimental design was successfully used to set the best ranges for the technological and formulation factors to obtain a cosmetic formulation with optimal characteristics. The study of clinical efficacy on the optimal formulation revealed an increase in the dermis thickness, hydration and elasticity values in both groups after 6 weeks of cream application. The new oil-in-water cream containing P. granatum seed oil and C. lechleri resin extract can be helpful in the prevention or improving of skin changes associated with striae. PMID:28280300

Subwavelength elastic joints connecting torsional waveguides to maximize the power transmission coefficient

NASA Astrophysics Data System (ADS)

Lee, Joong Seok; Lee, Il Kyu; Seung, Hong Min; Lee, Jun Kyu; Kim, Yoon Young

2017-03-01

Joints with slowly varying tapered shapes, such as linear or exponential profiles, are known to transmit incident wave power efficiently between two waveguides with dissimilar impedances. This statement is valid only when the considered joint length is longer than the wavelengths of the incident waves. When the joint length is shorter than the wavelengths, however, appropriate shapes of such subwavelength joints for efficient power transmission have not been explored much. In this work, considering one-dimensional torsional wave motion in a cylindrical elastic waveguide system, optimal shapes or radial profiles of a subwavelength joint maximizing the power transmission coefficient are designed by a gradient-based optimization formulation. The joint is divided into a number of thin disk elements using the transfer matrix approach and optimal radii of the disks are determined by iterative shape optimization processes for several single or bands of wavenumbers. Due to the subwavelength constraint, the optimized joint profiles were found to be considerably different from the slowly varying tapered shapes. Specifically, for bands of wavenumbers, peculiar gourd-like shapes were obtained as optimal shapes to maximize the power transmission coefficient. Numerical results from the proposed optimization formulation were also experimentally realized to verify the validity of the present designs.

Efficient computation of optimal actions.

PubMed

Todorov, Emanuel

2009-07-14

Optimal choice of actions is a fundamental problem relevant to fields as diverse as neuroscience, psychology, economics, computer science, and control engineering. Despite this broad relevance the abstract setting is similar: we have an agent choosing actions over time, an uncertain dynamical system whose state is affected by those actions, and a performance criterion that the agent seeks to optimize. Solving problems of this kind remains hard, in part, because of overly generic formulations. Here, we propose a more structured formulation that greatly simplifies the construction of optimal control laws in both discrete and continuous domains. An exhaustive search over actions is avoided and the problem becomes linear. This yields algorithms that outperform Dynamic Programming and Reinforcement Learning, and thereby solve traditional problems more efficiently. Our framework also enables computations that were not possible before: composing optimal control laws by mixing primitives, applying deterministic methods to stochastic systems, quantifying the benefits of error tolerance, and inferring goals from behavioral data via convex optimization. Development of a general class of easily solvable problems tends to accelerate progress--as linear systems theory has done, for example. Our framework may have similar impact in fields where optimal choice of actions is relevant.

Design of optimal groundwater remediation systems under flexible environmental-standard constraints.

PubMed

Fan, Xing; He, Li; Lu, Hong-Wei; Li, Jing

2015-01-01

In developing optimal groundwater remediation strategies, limited effort has been exerted to solve the uncertainty in environmental quality standards. When such uncertainty is not considered, either over optimistic or over pessimistic optimization strategies may be developed, probably leading to the formulation of rigid remediation strategies. This study advances a mathematical programming modeling approach for optimizing groundwater remediation design. This approach not only prevents the formulation of over optimistic and over pessimistic optimization strategies but also provides a satisfaction level that indicates the degree to which the environmental quality standard is satisfied. Therefore the approach may be expected to be significantly more acknowledged by the decision maker than those who do not consider standard uncertainty. The proposed approach is applied to a petroleum-contaminated site in western Canada. Results from the case study show that (1) the peak benzene concentrations can always satisfy the environmental standard under the optimal strategy, (2) the pumping rates of all wells decrease under a relaxed standard or long-term remediation approach, (3) the pumping rates are less affected by environmental quality constraints under short-term remediation, and (4) increased flexible environmental standards have a reduced effect on the optimal remediation strategy.

Isolation, characterization and investigation of Plantago ovata husk polysaccharide as superdisintegrant.

PubMed

Pawar, Harshal; Varkhade, Chhaya

2014-08-01

Psyllium husk (Plantago ovata, Family: Plantaginaceae) contains a high proportion of hemicellulose, composed of a xylan backbone linked with arabinose, rhamnose, and galacturonic acid units (arabinoxylans). Polysaccharide was isolated from Psyllium husk using solvent precipitation method. The isolated polysaccharide was evaluated for various physicochemical parameters. The rheological behavior of polysaccharide (1% w/v in water) was studied using Brookfield viscometer. Polysaccharide derived from the husk of P. ovata was investigated as superdisintegrant in the fast dissolving tablets. Valsartan, an antihypertensive drug, was selected as a model drug. The tablets of Valsartan were prepared separately using different concentrations (1, 2.5, 5, 7.5% w/w) of isolated Plantago ovata (P. ovata) husk polysaccharide (Natural) and crospovidone as a synthetic superdisintegrant by direct compression method. The prepared tablets were evaluated for various pre-compression and post-compression parameters. The drug excipient interactions were characterized by FTIR studies. The formulation F4 containing7.5% polysaccharide showed rapid wetting time and disintegration time as compared to formulation prepared using synthetic superdisintegrant at the same concentration level. Hence batch F4 was considered as optimized formulation. The stability studies were performed on formulation F4. The disintegration time and in vitro drug release of the optimized formulation was compared with the marketed formulation (Conventional tablets). Copyright © 2014 Elsevier B.V. All rights reserved.

Optimization design combined with coupled structural-electrostatic analysis for the electrostatically controlled deployable membrane reflector

NASA Astrophysics Data System (ADS)

Liu, Chao; Yang, Guigeng; Zhang, Yiqun

2015-01-01

The electrostatically controlled deployable membrane reflector (ECDMR) is a promising scheme to construct large size and high precision space deployable reflector antennas. This paper presents a novel design method for the large size and small F/D ECDMR considering the coupled structure-electrostatic problem. First, the fully coupled structural-electrostatic system is described by a three field formulation, in which the structure and passive electrical field is modeled by finite element method, and the deformation of the electrostatic domain is predicted by a finite element formulation of a fictitious elastic structure. A residual formulation of the structural-electrostatic field finite element model is established and solved by Newton-Raphson method. The coupled structural-electrostatic analysis procedure is summarized. Then, with the aid of this coupled analysis procedure, an integrated optimization method of membrane shape accuracy and stress uniformity is proposed, which is divided into inner and outer iterative loops. The initial state of relatively high shape accuracy and uniform stress distribution is achieved by applying the uniform prestress on the membrane design shape and optimizing the voltages, in which the optimal voltage is computed by a sensitivity analysis. The shape accuracy is further improved by the iterative prestress modification using the reposition balance method. Finally, the results of the uncoupled and coupled methods are compared and the proposed optimization method is applied to design an ECDMR. The results validate the effectiveness of this proposed methods.

Formulation and Statistical Optimization of Culture Medium for Improved Production of Antimicrobial Compound by Streptomyces sp. JAJ06

PubMed Central

Arul Jose, Polpass; Sivakala, Kunjukrishnan Kamalakshi; Jebakumar, Solomon Robinson David

2013-01-01

Streptomyces sp. JAJ06 is a seawater-dependent antibiotic producer, previously isolated and characterised from an Indian coastal solar saltern. This paper reports replacement of seawater with a defined salt formulation in production medium and subsequent statistical media optimization to ensure consistent as well as improved antibiotic production by Streptomyces sp. JAJ06. This strain was observed to be proficient to produce antibiotic compound with incorporation of chemically defined sodium-chloride-based salt formulation instead of seawater into the production medium. Plackett-Burman design experiment was applied, and three media constituents, starch, KBr, and CaCO3, were recognised to have significant effect on the antibiotic production of Streptomyces JAJ06 at their individual levels. Subsequently, Response surface methodology with Box-Behnken design was employed to optimize these influencing medium constituents for the improved antibiotic production of Streptomyces sp. JAJ06. A total of 17 experiments were conducted towards the construction of a quadratic model and a second-order polynomial equation. Optimum levels of medium constituents were obtained by analysis of the model and numerical optimization method. When the strain JAJ06 was cultivated in the optimized medium, the antibiotic activity was increased to 173.3 U/mL, 26.8% increase as compared to the original (136.7 U/mL). This study found a useful way to cultivate Streptomyces sp. JAJ06 for enhanced production of antibiotic compound. PMID:24454383

Verifiable Adaptive Control with Analytical Stability Margins by Optimal Control Modification

NASA Technical Reports Server (NTRS)

Nguyen, Nhan T.

2010-01-01

This paper presents a verifiable model-reference adaptive control method based on an optimal control formulation for linear uncertain systems. A predictor model is formulated to enable a parameter estimation of the system parametric uncertainty. The adaptation is based on both the tracking error and predictor error. Using a singular perturbation argument, it can be shown that the closed-loop system tends to a linear time invariant model asymptotically under an assumption of fast adaptation. A stability margin analysis is given to estimate a lower bound of the time delay margin using a matrix measure method. Using this analytical method, the free design parameter n of the optimal control modification adaptive law can be determined to meet a specification of stability margin for verification purposes.

Human motion planning based on recursive dynamics and optimal control techniques

NASA Technical Reports Server (NTRS)

Lo, Janzen; Huang, Gang; Metaxas, Dimitris

2002-01-01

This paper presents an efficient optimal control and recursive dynamics-based computer animation system for simulating and controlling the motion of articulated figures. A quasi-Newton nonlinear programming technique (super-linear convergence) is implemented to solve minimum torque-based human motion-planning problems. The explicit analytical gradients needed in the dynamics are derived using a matrix exponential formulation and Lie algebra. Cubic spline functions are used to make the search space for an optimal solution finite. Based on our formulations, our method is well conditioned and robust, in addition to being computationally efficient. To better illustrate the efficiency of our method, we present results of natural looking and physically correct human motions for a variety of human motion tasks involving open and closed loop kinematic chains.

Bioactive characteristics and optimization of tamarind seed protein hydrolysate for antioxidant-rich food formulations.

PubMed

Bagul, Mayuri B; Sonawane, Sachin K; Arya, Shalini S

2018-04-01

Tamarind seed has been a source of valuable nutrients such as protein (contains high amount of many essential amino acids), essential fatty acids, and minerals which are recognized as additive to develop perfect balanced functional foods. The objective of present work was to optimize the process parameters for extraction and hydrolysis of protein from tamarind seeds. Papain-derived hydrolysates showed a maximum degree of hydrolysis (39.49%) and radical scavenging activity (42.92 ± 2.83%) at optimized conditions such as enzyme-to-substrate ratio (1:5), hydrolysis time (3 h), hydrolysis temperature (65 °C), and pH 6. From this study, papain hydrolysate can be considered as good source of natural antioxidants in developing food formulations.

Modeling and analysis of power processing systems: Feasibility investigation and formulation of a methodology

NASA Technical Reports Server (NTRS)

Biess, J. J.; Yu, Y.; Middlebrook, R. D.; Schoenfeld, A. D.

1974-01-01

A review is given of future power processing systems planned for the next 20 years, and the state-of-the-art of power processing design modeling and analysis techniques used to optimize power processing systems. A methodology of modeling and analysis of power processing equipment and systems has been formulated to fulfill future tradeoff studies and optimization requirements. Computer techniques were applied to simulate power processor performance and to optimize the design of power processing equipment. A program plan to systematically develop and apply the tools for power processing systems modeling and analysis is presented so that meaningful results can be obtained each year to aid the power processing system engineer and power processing equipment circuit designers in their conceptual and detail design and analysis tasks.

Optimizing the sequence of diameter distributions and selection harvests for uneven-aged stand management

Treesearch

Robert G. Haight; J. Douglas Brodie; Darius M. Adams

1985-01-01

The determination of an optimal sequence of diameter distributions and selection harvests for uneven-aged stand management is formulated as a discrete-time optimal-control problem with bounded control variables and free-terminal point. An efficient programming technique utilizing gradients provides solutions that are stable and interpretable on the basis of economic...

On optimal strategies in event-constrained differential games

NASA Technical Reports Server (NTRS)

Heymann, M.; Rajan, N.; Ardema, M.

1985-01-01

Combat games are formulated as zero-sum differential games with unilateral event constraints. An interior penalty function approach is employed to approximate optimal strategies for the players. The method is very attractive computationally and possesses suitable approximation and convergence properties.

Optimal timber harvest scheduling with spatially defined sediment objectives

Treesearch

Jon Hof; Michael Bevers

2000-01-01

This note presents a simple model formulation that focuses on the spatial relationships over time between timber harvesting and sediment levels in water runoff courses throughout the watershed being managed. A hypothetical example is developed to demonstrate the formulation and show how sediment objectives can be spatially defined anywhere in the watershed. Spatial...

A comprehensive linear programming tool to optimize formulations of ready-to-use therapeutic foods: An application to Ethiopia

USDA-ARS?s Scientific Manuscript database

Ready-to-use therapeutic food (RUTF) is the standard of care for children suffering from noncomplicated severe acute malnutrition (SAM). The objective was to develop a comprehensive linear programming (LP) tool to create novel RUTF formulations for Ethiopia. A systematic approach that surveyed inter...

Wildlife Conservation Planning Using Stochastic Optimization and Importance Sampling

Treesearch

Robert G. Haight; Laurel E. Travis

1997-01-01

Formulations for determining conservation plans for sensitive wildlife species must account for economic costs of habitat protection and uncertainties about how wildlife populations will respond. This paper describes such a formulation and addresses the computational challenge of solving it. The problem is to determine the cost-efficient level of habitat protection...

Formulation of diazepam containing rectal suppositories and experiences of their biopharmaceutical study.

PubMed

Regdon, G; Bácskay, I; Kata, M; Selmeczi, B; Szikszay, M; Sánta, A; Bálint, G S

1994-05-01

Methodology and the results of the in vitro membrane diffusion and in vivo bioavailability studies are presented. The results confirm a correlation between in vitro and in vivo findings. Hydrophilic macrogol-mixture with great molecular mass can be recommended as the optimal vehicle for formulation of diazepam suppositories.

Development of antibrowning and antimicrobial formulations to minimize listeria monocytogenes contamination and inhibit browning of fresh-cut "Granny Smith" apples

USDA-ARS?s Scientific Manuscript database

In recent years, there have been a number of Listeria monocytogenes recalls involving fresh-cut apples, probably contaminated during treatments with antibrowning solutions. In the present study, we used response surface methodology to develop and optimize formulations for reducing L. monocytogenes ...

Compositional Models of Glass/Melt Properties and their Use for Glass Formulation

DOE PAGES

Vienna, John D.; USA, Richland Washington

2014-12-18

Nuclear waste glasses must simultaneously meet a number of criteria related to their processability, product quality, and cost factors. The properties that must be controlled in glass formulation and waste vitrification plant operation tend to vary smoothly with composition allowing for glass property-composition models to be developed and used. Models have been fit to the key glass properties. The properties are transformed so that simple functions of composition (e.g., linear, polynomial, or component ratios) can be used as model forms. The model forms are fit to experimental data designed statistically to efficiently cover the composition space of interest. Examples ofmore » these models are found in literature. The glass property-composition models, their uncertainty definitions, property constraints, and optimality criteria are combined to formulate optimal glass compositions, control composition in vitrification plants, and to qualify waste glasses for disposal. An overview of current glass property-composition modeling techniques is summarized in this paper along with an example of how those models are applied to glass formulation and product qualification at the planned Hanford high-level waste vitrification plant.« less

Effect of handling characteristics on minimum time cornering with torque vectoring

NASA Astrophysics Data System (ADS)

Smith, E. N.; Velenis, E.; Tavernini, D.; Cao, D.

2018-02-01

In this paper, the effect of both passive and actively-modified vehicle handling characteristics on minimum time manoeuvring for vehicles with 4-wheel torque vectoring (TV) capability is studied. First, a baseline optimal TV strategy is sought, independent of any causal control law. An optimal control problem (OCP) is initially formulated considering 4 independent wheel torque inputs, together with the steering angle rate, as the control variables. Using this formulation, the performance benefit using TV against an electric drive train with a fixed torque distribution, is demonstrated. The sensitivity of TV-controlled manoeuvre time to the passive understeer gradient of the vehicle is then studied. A second formulation of the OCP is introduced where a closed-loop TV controller is incorporated into the system dynamics of the OCP. This formulation allows the effect of actively modifying a vehicle's handling characteristic via TV on its minimum time cornering performance of the vehicle to be assessed. In particular, the effect of the target understeer gradient as the key tuning parameter of the literature-standard steady-state linear single-track model yaw rate reference is analysed.

Alginate coated chitosan nanogel for the controlled topical delivery of Silver sulfadiazine.

PubMed

El-Feky, Gina S; El-Banna, Sally T; El-Bahy, G S; Abdelrazek, E M; Kamal, Mustafa

2017-12-01

Burn wounds environment favors the growth of micro-organisms causing delay in wound healing. The traditional treatment with antimicrobial creams offer inaccurate doses. The aim of the present study is to formulate and evaluate different silver sulfadiazine loaded nanogel formulations. A factorial design experiment was used for the identification of critical process parameters and for the optimization of the respective process conditions. The prepared drug loaded nanogels were characterized for their particle size, zeta potential, entrapment efficiency and swelling index in order to demonstrate their physicochemical properties, in addition, FTIR, TEM, SEM and in vitro release were used for characterization. The release profile of all tested nanogels showed an initial burst followed by a slow and continuous release rate. An optimum nanogel formulation was predicted by the JMP ® software according to the stated prediction expressions and was composed of 0.4% sodium alginate (ALG) and 0.414% Silver sulfadiazine (SSD). The optimized formulation showed higher therapeutic efficacy in vivo when compared to market product. Copyright © 2017 Elsevier Ltd. All rights reserved.

Release of Liposomal Contents by Cell-Secreted Matrix Metalloproteinase-9

PubMed Central

Banerjee, Jayati; Hanson, Andrea J.; Gadam, Bhushan; Elegbede, Adekunle I.; Tobwala, Shakila; Ganguly, Bratati; Wagh, Anil; Muhonen, Wallace W.; Law, Benedict; Shabb, John B.; Srivastava, D. K.; Mallik, Sanku

2011-01-01

Liposomes have been widely used as a drug delivery vehicle and currently, more than 10 liposomal formulations are approved by the Food and Drug Administration for clinical use. However, upon targeting, the release of the liposome-encapsulated contents is usually slow. We have recently demonstrated that contents from appropriately-formulated liposomes can be rapidly released by the cancer-associated enzyme matrix metalloproteinase-9 (MMP-9). Herein, we report our detailed studies to optimize the liposomal formulations. By properly selecting the lipopeptide, the major lipid component and their relative amounts, we demonstrate that the contents are rapidly released in the presence of cancer-associated levels of recombinant human MMP-9. We observed that the degree of lipid mismatch between the lipopepides and the major lipid component profoundly affects the release profiles from the liposomes. By utilizing the optimized liposomal formulations, we also demonstrate that cancer cells (HT-29) which secrete low levels of MMP-9 failed to release significant amount of the liposomal contents. Metastatic cancer cells (MCF7) secreting high levels of the enzyme rapidly release the encapsulated contents from the liposomes. PMID:19601658

Optimizing Research to Speed Up Availability of Pediatric Antiretroviral Drugs and Formulations.

PubMed

Penazzato, Martina; Gnanashanmugam, Devasena; Rojo, Pablo; Lallemant, Marc; Lewis, Linda L; Rocchi, Francesca; Saint Raymond, Agnes; Ford, Nathan; Hazra, Rohan; Giaquinto, Carlo; Belew, Yodit; Gibb, Diana M; Abrams, Elaine J

2017-06-01

Globally 1.8 million children are living with human immunodeficiency virus (HIV), yet only 51% of those eligible actually start treatment. Research and development (R&D) for pediatric antiretrovirals (ARVs) is a lengthy process and lags considerably behind drug development in adults. Providing safe, effective, and well-tolerated drugs for children remains critical to ensuring scale-up globally. We review current approaches to R&D for pediatric ARVs and suggest innovations to enable simplified, faster, and more comprehensive strategies to develop optimal formulations. Several approaches could be adopted, including focusing on a limited number of prioritized formulations and strengthening existing partnerships to ensure that pediatric investigation plans are developed early in the drug development process. Simplified and more efficient mechanisms to undertake R&D need to be put in place, and financing mechanisms must be made more sustainable. Lessons learned from HIV should be shared to support progress in developing pediatric formulations for other diseases, including tuberculosis and viral hepatitis. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Analytical instrumentation infrastructure for combinatorial and high-throughput development of formulated discrete and gradient polymeric sensor materials arrays

NASA Astrophysics Data System (ADS)

Potyrailo, Radislav A.; Hassib, Lamyaa

2005-06-01

Multicomponent polymer-based formulations of optical sensor materials are difficult and time consuming to optimize using conventional approaches. To address these challenges, our long-term goal is to determine relationships between sensor formulation and sensor response parameters using new scientific methodologies. As the first step, we have designed and implemented an automated analytical instrumentation infrastructure for combinatorial and high-throughput development of polymeric sensor materials for optical sensors. Our approach is based on the fabrication and performance screening of discrete and gradient sensor arrays. Simultaneous formation of multiple sensor coatings into discrete 4×6, 6×8, and 8×12 element arrays (3-15μL volume per element) and their screening provides not only a well-recognized acceleration in the screening rate, but also considerably reduces or even eliminates sources of variability, which are randomly affecting sensors response during a conventional one-at-a-time sensor coating evaluation. The application of gradient sensor arrays provides additional capabilities for rapid finding of the optimal formulation parameters.

Development of surface stabilized candesartan cilexetil nanocrystals with enhanced dissolution rate, permeation rate across CaCo-2, and oral bioavailability.

PubMed

Jain, Sanyog; Reddy, Venkata Appa; Arora, Sumit; Patel, Kamlesh

2016-10-01

Candesartan cilexetil (CC), an ester prodrug of candesartan, is BCS class II drug with extremely low aqueous solubility limiting its oral bioavailability. The present research aimed to develop a nanocrystalline formulation of CC with improved saturation solubility in gastrointestinal fluids and thereby, exhibiting enhanced oral bioavailability. CC nanocrystals were prepared using a low energy antisolvent precipitation methodology. A combination of hydroxypropyl methylcellulose (HPMC) and Pluronic® F 127 (50:50 w/w) was found to be optimum for the preparation of CC nanocrystals. The particle size, polydispersity index (PDI), and zeta potential of optimized formulation was found to be 159 ± 8.1 nm, 0.177 ± 0.043, and -23.7 ± 1.02 mV, respectively. Optimized formulation was found to possess irregular, plate-like morphology as evaluated by scanning electron microscopy and crystalline as evaluated by differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD). A significant increase in saturation solubility and dissolution rate of the optimized nanosuspension was observed at all the tested pH conditions. Optimized CC nanocrystals exhibited a storage stability of more than 3 months when stored under cold and room temperature conditions. In vitro Caco-2 permeability further revealed that CC nanocrystals exhibited nearly 4-fold increase in permeation rate compared to the free CC. In vivo oral bioavailability studies of optimized CC nanocrystals in murine model revealed 3.8-fold increase in the oral bioavailability and twice the C max as compared with the free CC when administered orally. In conclusion, this study has established a crystalline nanosuspension formulation of CC with improved oral bioavailability in murine model. Graphical Abstract Antisolvent precipitation methodology for the preparation of Candesartan Cilexetil nanocrystals for enhanced solubility and oral bioavailability.

Freeze drying optimization of polymeric nanoparticles for ocular flurbiprofen delivery: effect of protectant agents and critical process parameters on long-term stability.

PubMed

Ramos Yacasi, Gladys Rosario; Calpena Campmany, Ana Cristina; Egea Gras, María Antonia; Espina García, Marta; García López, María Luisa

2017-04-01

The stabilization of flurbiprofen loaded poly-ɛ-caprolactone nanoparticles (FB-PɛCL-NPs) for ocular delivery under accurate freeze-drying (FD) process provides the basis for a large-scale production and its commercial development. Optimization of the FD to improve long-term stability of ocular administration's FB-PɛCL-NPs. FB-PɛCL-NPs were prepared by solvent displacement method with poloxamer 188 (P188) as stabilizer. Freezing and primary drying (PD) were studied and optimized through freeze-thawing test and FD microscopy. Design of experiments was used to accurate secondary drying (SD) conditions and components concentration. Formulations were selected according to desired physicochemical properties. Furthermore, differential scanning calorimetry (DSC) and X-ray diffraction (XRD) were used to study interactions components. Optimized FB-PɛCL-NPs, stabilized with 3.5% (w/w) P188 and protected with 8% (w/w) poly(ethylene glycol), was submitted to precooling at +10 °C for 1 h, freezing at -50 °C for 4 h, PD at +5 °C and 0.140 mbar for 24 h and a SD at +45 °C during 10 h. These conditions showed 188.4 ± 1.3 nm, 0.087 ± 0.014, 85.5 ± 1.4%, 0.61 ± 0.12%, -16.4 ± 0.1 mV and 325 ± 7 mOsm/kg of average size, polydispersity index, entrapment efficiency, residual moisture, surface charge and osmolality, respectively. It performed a long-term stability >12 months. DSC and XRD spectra confirmed adequate chemical interaction between formulation components and showed a semi-crystalline state after FD. An optimal freeze dried ocular formulation was achieved. Evidently, the successful design of this promising colloidal system resulted from rational cooperation between a good formulation and the right conditions in the FD process.

Behavior learning in differential games and reorientation maneuvers

NASA Astrophysics Data System (ADS)

Satak, Neha

The purpose of this dissertation is to apply behavior learning concepts to incomplete- information continuous time games. Realistic game scenarios are often incomplete-information games in which the players withhold information. A player may not know its opponent's objectives and strategies prior to the start of the game. This lack of information can limit the player's ability to play optimally. If the player can observe the opponent's actions, it can better optimize its achievements by taking corrective actions. In this research, a framework to learn an opponent's behavior and take corrective actions is developed. The framework will allow a player to observe the opponent's actions and formulate behavior models. The developed behavior model can then be utilized to find the best actions for the player that optimizes the player's objective function. In addition, the framework proposes that the player plays a safe strategy at the beginning of the game. A safe strategy is defined in this research as a strategy that guarantees a minimum pay-off to the player independent of the other player's actions. During the initial part of the game, the player will play the safe strategy until it learns the opponent's behavior. Two methods to develop behavior models that differ in the formulation of the behavior model are proposed. The first method is the Cost-Strategy Recognition (CSR) method in which the player formulates an objective function and a strategy for the opponent. The opponent is presumed to be rational and therefore will play to optimize its objective function. The strategy of the opponent is dependent on the information available to the opponent about other players in the game. A strategy formulation presumes a certain level of information available to the opponent. The previous observations of the opponent's actions are used to estimate the parameters of the formulated behavior model. The estimated behavior model predicts the opponent's future actions. The second method is the Direct Approximation of Value Function (DAVF) method. In this method, unlike the CSR method, the player formulates an objective function for the opponent but does not formulates a strategy directly; rather, indirectly the player assumes that the opponent is playing optimally. Thus, a value function satisfying the HJB equation corresponding to the opponent's cost function exists. The DAVF method finds an approximate solution for the value function based on previous observations of the opponent's control. The approximate solution to the value function is then used to predict the opponent's future behavior. Game examples in which only a single player is learning its opponent's behavior are simulated. Subsequently, examples in which both players in a two-player game are learning each other's behavior are simulated. In the second part of this research, a reorientation control maneuver for a spinning spacecraft will be developed. This will aid the application of behavior learning and differential games concepts to the specific scenario involving multiple spinning spacecraft. An impulsive reorientation maneuver with coasting will be analytically designed to reorient the spin axis of the spacecraft using a single body fixed thruster. Cooperative maneuvers of multiple spacecraft optimizing fuel and relative orientation will be designed. Pareto optimality concepts will be used to arrive at mutually agreeable reorientation maneuvers for the cooperating spinning spacecraft.

Robust Optimization and Sensitivity Analysis with Multi-Objective Genetic Algorithms: Single- and Multi-Disciplinary Applications

DTIC Science & Technology

2007-01-01

multi-disciplinary optimization with uncertainty. Robust optimization and sensitivity analysis is usually used when an optimization model has...formulation is introduced in Section 2.3. We briefly discuss several definitions used in the sensitivity analysis in Section 2.4. Following in...2.5. 2.4 SENSITIVITY ANALYSIS In this section, we discuss several definitions used in Chapter 5 for Multi-Objective Sensitivity Analysis . Inner

Brain targeted oral delivery of doxycycline hydrochloride encapsulated Tween 80 coated chitosan nanoparticles against ketamine induced psychosis: behavioral, biochemical, neurochemical and histological alterations in mice.

PubMed

Yadav, Monu; Parle, Milind; Sharma, Nidhi; Dhingra, Sameer; Raina, Neha; Jindal, Deepak Kumar

2017-11-01

To develop statistically optimized brain targeted Tween 80 coated chitosan nanoparticulate formulation for oral delivery of doxycycline hydrochloride for the treatment of psychosis and to evaluate its protective effect on ketamine induced behavioral, biochemical, neurochemical and histological alterations in mice. 3 2 full factorial design was used to optimize the nanoparticulate formulation to minimize particle size and maximize entrapment efficiency, while independent variables chosen were concentration of chitosan and Tween 80. The optimized formulation was characterized by particle size, drug entrapment efficiency, Fourier transform infrared, Transmission electron microscopy analysis and drug release behavior. Pure doxycycline hydrochloride (25 and 50 mg/kg, p.o.) and optimized doxycycline hydrochloride encapsulated Tween 80 coated chitosan nanoparticles (DCNP opt ) (equivalent to 25 mg/kg doxycycline hydrochloride, p.o.) were explored against ketamine induced psychosis in mice. The experimental studies for DCNP opt , with mean particle size 237 nm and entrapment efficiency 78.16%, elucidated that the formulation successfully passed through blood brain barrier and exhibited significant antipsychotic activity. The underlying mechanism of action was further confirmed by behavioral, biochemical, neurochemical estimations and histopathological study. Significantly enhanced GABA and GSH level and diminished MDA, TNF-α and dopamine levels were observed after administration of DCNP opt at just half the dose of pure doxycycline hydrochloride, showing better penetration of doxycyline hydrochloride in the form of Tween 80 coated nanoparticles through blood brain barrier. This study demonstrates the hydrophilic drug doxycycline hydrochloride, loaded in Tween 80 coated chitosan nanoparticles, can be effectively brain targeted through oral delivery and therefore represents a suitable approach for the treatment of psychotic symptoms.

Preparation and evaluation of microemulsion-based transdermal delivery of Cistanche tubulosa phenylethanoid glycosides

PubMed Central

Yang, Jianhua; Xu, Huanhuan; Wu, Shanshan; Ju, Bowei; Zhu, Dandan; Yan, Yao; Wang, Mei; Hu, Junping

2017-01-01

The primary aim of the present study was to develop a novel microemulsion (ME) formulation to deliver phenylethanoid glycoside (PG) for use in skin lighteners and sunscreens. The oil phase was selected on the basis of drug solubility, while the surfactant and cosurfactant were screened and selected on the basis of their solubilizing capacity and the efficiency with which they formed MEs. Pseudoternary phase diagrams were constructed to evaluate ME regions and five formulations of oil-in-water MEs were selected as vehicles. In vitro skin permeation experiments were performed to optimize the ME formulation and to evaluate its permeability in comparison to that of saline solution. The physicochemical properties of the optimized ME and the permeating ability of PG delivered by this ME were also investigated. The optimized ME formulation was composed of isopropyl myristate (7%, w/w), Cremorphor EL (21%, w/w), propylene glycol (7%, w/w) and water (65%, w/w). The cumulative amount of PG that permeated through excised mouse skin when carried by ME was ~1.68 times that when PG was carried by saline solution only. The cumulative amount of PG in the microemulsion (4149.650±37.3 µg·cm−2) was significantly greater than that of PG in the saline solution (2288.63±20.9 µg·cm−2). Furthermore, the permeability coefficient indicated that optimized microemulsion was a more efficient carrier for transdermal delivery of PG than the control solution (8.87±0.49 cm/hx10−3 vs. 5.41±0.12 cm/hx10−3). Taken together, the permeating ability of ME-carried PG was significantly increased compared with saline solution. PMID:28138704

Lower irritation microemulsion-based rotigotine gel: formulation optimization and in vitro and in vivo studies

PubMed Central

Wang, Zheng; Mu, Hong-Jie; Zhang, Xue-Mei; Ma, Peng-Kai; Lian, Sheng-Nan; Zhang, Feng-Pu; Chu, Sheng-Ying; Zhang, Wen-Wen; Wang, Ai-Ping; Wang, Wen-Yan; Sun, Kao-Xiang

2015-01-01

Background Rotigotine is a potent and selective D1, D2, and D3 dopaminergic receptor agonist. Due to an extensive first-pass effect, it has a very low oral bioavailability (approximately 0.5% in rats). Purpose The present investigation aimed to develop a microemulsion-based hydrogel for transdermal rotigotine delivery with lower application site reactions. Methods Pseudoternary phase diagrams were constructed to determine the region of oil in water (o/w)-type microemulsion. Central composite design was used to support the pseudoternary phase diagrams and to select homogeneous and stable microemulsions with an optimal amount of rotigotine permeation within 24 hours. In vitro skin permeation experiments were performed, using Franz diffusion cells, to compare rotigotine-loaded microemulsions with rotigotine solutions in oil. The optimized formulation was used to prepare a microemulsion-based hydrogel, which was subjected to bioavailability and skin irritancy studies. Results The selected formulations of rotigotine-loaded microemulsions had enhanced flux and permeation coefficients compared with rotigotine in oil. The optimum microemulsion contained 68% water, 6.8% Labrafil®, 13.44% Cremophor® RH40, 6.72% Labrasol®, and 5.04% Transcutol® HP; the drug-loading rate was 2%. To form a microemulsion gel, 1% Carbomer 1342 was added to the microemulsion. The bioavailability of the rotigotine-loaded microemulsion gel was 105.76%±20.52% with respect to the marketed rotigotine patch (Neupro®). The microemulsion gel irritated the skin less than Neupro. Conclusion A rotigotine microemulsion-based hydrogel was successfully developed, and an optimal formulation for drug delivery was identified. This product could improve patient compliance and have broad marketability. PMID:25609965

Pharmaceutical development of a parenteral formulation of the novel anti-tumor agent carzelesin (U-80,244).

PubMed

Jonkman-de Vries, J D; de Graaff-Teulen, M J; Henrar, R E; Kettenes-van den Bosch, J J; Bult, A; Beijnen, J H

1994-01-01

The aim of this study was to design a parenteral dosage form for the investigational cytotoxic drug carzelesin. A stable formulation in PET (Polyethylene glycol 400/absolute ethanol/Tween 80, 6:3:1, v/v/v) was developed. The prototype, containing 0.50 mg carzelesin in 2.0 ml PET formulation, was found to be the optimal formulation in terms of solubility, stability and dosage requirements in phase I clinical trials. Quality control of the formulation showed that the pharmaceutical preparation of carzelesin in PET is not negatively influenced by the manufacturing process. Shelf life studies demonstrated that the formulation is stable for at least 1 year, when stored at -30 degrees C in the dark. In addition, the stability of carzelesin in the PET formulation is discussed as a function of temperature, additives and after dilution in infusion fluids.

Variational estimate method for solving autonomous ordinary differential equations

NASA Astrophysics Data System (ADS)

Mungkasi, Sudi

2018-04-01

In this paper, we propose a method for solving first-order autonomous ordinary differential equation problems using a variational estimate formulation. The variational estimate is constructed with a Lagrange multiplier which is chosen optimally, so that the formulation leads to an accurate solution to the problem. The variational estimate is an integral form, which can be computed using a computer software. As the variational estimate is an explicit formula, the solution is easy to compute. This is a great advantage of the variational estimate formulation.

Formulation, optimization and evaluation of curcumin-β-cyclodextrin-loaded sponge for effective drug delivery in thermal burns chemotherapy.

PubMed

Kaur, Navdeep; Garg, Tarun; Goyal, Amit K; Rath, Goutam

2016-09-01

The present study was designed to determine the role of curcumin-β-cyclodextrin-loaded sponge on burn wound healing in rats. Curcumin-β-cyclodextrin complex was prepared by the solvent evaporation encapsulation method. Molecular inclusion complex of curcumin-β-cyclodextrin was incorporated into gelatin sponge. The developed sponge was characterized for drug entrapment, drug release and morphology. The biological activity of optimized formulation was determined on burn wounds which were made on rats. The burn wound healing efficacy was analyzed through physical and histological changes observed at the wound sites. There was a significant decrease in rate of wound contraction in experimental groups then the control group. Curcumin-β-cyclodextrin-loaded sponge treated wound was found to heal in rate comparable to marketed formulation with no sign of adverse consequence. The result clearly substantiates the beneficial effects of curcumin-β-cyclodextrin-loaded sponge in the acceleration of wound healing.

Solution formulation development and efficacy of MJC13 in a preclinical model of castration-resistant prostate cancer.

PubMed

Liang, Su; Bian, Xiaomei; Liang, Dong; Sivils, Jeffrey C; Neckers, Leonard M; Cox, Marc B; Xie, Huan

2016-01-01

MJC13, a novel FKBP52 targeting agent, has potential use for the treatment of castration-resistant prostate cancer. The purpose of this work was to develop a solution formulation of MJC13, and obtain its efficacy profile in a human prostate cancer xenograft mouse model. Preformulation studies were conducted to evaluate the physicochemical properties. Co-solvent systems were evaluated for aqueous solubility and tolerance. A human prostate cancer xenograft mouse model was established by growing 22Rv1 prostate cancer cells in C.B-17 SCID mice. The optimal formulation was used to study the efficacy of MJC13 in this preclinical model of castrate-resistant prostate cancer. We found that MJC13 was stable (at least for 1 month), highly lipophilic (logP = 6.49), poorly soluble in water (0.28 µg/mL), and highly plasma protein bound (>98%). The optimal formulation consisting of PEG 400 and Tween 80 (1:1, v/v) allowed us to achieve a MJC13 concentration of 7.5 mg/mL, and tolerated an aqueous environment. After twice weekly intratumoral injection with 10 mg/kg MJC13 in this formulation for four consecutive weeks, tumor volumes were significantly reduced compared to vehicle-treated controls.

The Effects of Lipoplex Formulation Variables on the Protein Corona and Comparisons with in vitro Transfection Efficiency

PubMed Central

Betker, Jamie L.; Gomez, Joe; Anchordoquy, Thomas J.

2013-01-01

The use of lipoplexes for the intracellular delivery of nucleic acids typically involves the optimization of several parameters that are known to affect delivery. Researchers commonly vary charge ratio, and often incorporate different amounts of helper lipids (e.g., cholesterol) to optimize formulations for transfection in cell culture and in vivo. The results of such experiments are often interpreted in the context of nuclease resistance and cell association, but effects on the protein corona are usually not considered. While many studies have demonstrated that lipoplex structure and function can be dramatically compromised in the presence of serum, little attention has been paid to the adsorption of specific proteins and how this might be affected by formulation parameters. In this study, we characterize changes in the protein corona that occur as DOTAP-based lipoplexes are formulated with different amounts of cholesterol and prepared at different charge ratios. Our results demonstrate a significant effect of lipid composition on both total protein adsorption as well as the individual proteins from fetal calf serum that are associated with lipoplexes. In addition, we show that PEGylation increases protein adsorption with our formulations; effects that depend on the type of PEG conjugate employed in the lipoplex. Attempts to identify a specific protein responsible for enhancing transfection were unsuccessful. PMID:23920037

Development of an Injectable Slow-Release Metformin Formulation and Evaluation of Its Potential Antitumor Effects.

PubMed

Baldassari, Sara; Solari, Agnese; Zuccari, Guendalina; Drava, Giuliana; Pastorino, Sara; Fucile, Carmen; Marini, Valeria; Daga, Antonio; Pattarozzi, Alessandra; Ratto, Alessandra; Ferrari, Angelo; Mattioli, Francesca; Barbieri, Federica; Caviglioli, Gabriele; Florio, Tullio

2018-03-02

Metformin is an antidiabetic drug which possesses antiproliferative activity in cancer cells when administered at high doses, due to its unfavorable pharmacokinetics. The aim of this work was to develop a pharmacological tool for the release of metformin in proximity of the tumor, allowing high local concentrations, and to demonstrate the in vivo antitumor efficacy after a prolonged metformin exposition. A 1.2% w/w metformin thermoresponsive parenteral formulation based on poloxamers P407 and P124, injectable at room temperature and undergoing a sol-gel transition at body temperature, has been developed and optimized for rheological, thermal and release control properties; the formulation is easily scalable, and proved to be stable during a 1-month storage at 5 °C. Using NOD/SCID mice pseudo-orthotopically grafted with MDA-MB-231/luc + human breast cancer cells, we report that multiple administrations of 100 mg of the optimized metformin formulation close to the tumor site cause tissue accumulation of the drug at levels significantly higher than those observed in plasma, and enough to exert antiproliferative and pro-apoptotic activities. Our results demonstrate that this formulation is endowed with good stability, tolerability, thermal and rheological properties, representing a novel tool to be pursued in further investigations for adjuvant cancer treatment.

Compatibility Condition in Theory of Solid Mechanics (Elasticity, Structures, and Design Optimization)

NASA Technical Reports Server (NTRS)

Patnaik, Surya N.; Pai, Shantaram S.; Hopkins, Dale A.

2007-01-01

The strain formulation in elasticity and the compatibility condition in structural mechanics have neither been understood nor have they been utilized. This shortcoming prevented the formulation of a direct method to calculate stress. We have researched and understood the compatibility condition for linear problems in elasticity and in finite element analysis. This has lead to the completion of the method of force with stress (or stress resultant) as the primary unknown. The method in elasticity is referred to as the completed Beltrami-Michell formulation (CBMF), and it is the integrated force method (IFM) in structures. The dual integrated force method (IFMD) with displacement as the primary unknown has been formulated. IFM and IFMD produce identical responses. The variational derivation of the CBMF yielded the new boundary compatibility conditions. The CBMF can be used to solve stress, displacement, and mixed boundary value problems. The IFM in structures produced high-fidelity response even with a modest finite element model. The IFM has influenced structural design considerably. A fully utilized design method for strength and stiffness limitation has been developed. The singularity condition in optimization has been identified. The CBMF and IFM tensorial approaches are robust formulations because of simultaneous emphasis on the equilibrium equation and the compatibility condition.

Solution Formulation Development and Efficacy of MJC13 in a Preclinical Model of Castrate-Resistant Prostate Cancer

PubMed Central

Liang, Su; Bian, Xiaomei; Liang, Dong; Sivils, Jeffrey C.; Neckers, Leonard M.; Cox, Marc B.; Xie, Huan

2015-01-01

MJC13, a novel FKBP52 targeting agent, has potential use for the treatment of castrate-resistant prostate cancer. The purpose of this work was to develop a solution formulation of MJC13, and obtain its efficacy profile in a human prostate cancer xenograft mouse model. Preformulation studies were conducted to evaluate the physicochemical properties. Co-solvent systems were evaluated for aqueous solubility and tolerance. A human prostate cancer xenograft mouse model was established by growing 22Rv1 prostate cancer cells in C.B-17 SCID mice. The optimal formulation was used to study the efficacy of MJC13 in this preclinical model of castrate-resistant prostate cancer. We found that MJC13 was stable (at least for 1 month), very lipophilic (logP = 6.49), poorly soluble in water (0.28 μg/mL), and highly plasma protein bound (> 98%). The optimal formulation consisting of PEG 400 and Tween 80 (1:1, v/v) allowed us to achieve a MJC13 concentration of 7.5 mg/mL, and tolerated an aqueous environment. After twice weekly intratumoral injection with 10 mg/kg MJC13 in this formulation for 4 consecutive weeks, tumor volumes were significantly reduced compared to vehicle-treated controls. PMID:25380396

Maximizing the Therapeutic Efficacy of Imatinib Mesylate-Loaded Niosomes on Human Colon Adenocarcinoma Using Box-Behnken Design.

PubMed

Kassem, Mohammed A; El-Sawy, Hossam S; Abd-Allah, Fathy I; Abdelghany, Tamer M; El-Say, Khalid M

2017-01-01

This research purposed to formulate an optimized imatinib mesylate (IM)-loaded niosomes to improve its chemotherapeutic efficacy. The influence of 3 formulation factors on niosomal vesicular size (Y 1 ), zeta potential (Y 2 ), entrapment capacity percentage (Y 3 ), the percentage of initial drug release after 2 h (Y 4 ), and the percentage of cumulative drug release after 24 h (Y 5 ) were studied and optimized using Box-Behnken design. Optimum desirability was specified and the optimized formula was prepared, stability tested, morphologically examined, checked for vesicular bilayer formation and evaluated for its in vitro cytotoxicity on 3 different cancer cell lines namely MCF-7, HCT-116, and HepG-2 in addition to 1 normal cell line to ensure its selectivity against cancer cells. The actual responses of the optimized IM formulation were 425.36 nm, -62.4 mV, 82.96%, 18.93%, and 89.45% for Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 , respectively. The optimized IM-loaded niosomes confirmed the spherical vesicular shape imaged by both light and electron microscopes and further proven by differential scanning calorimetry. Moreover, the optimized formula exhibited improved stability on storage at 4 ± 2°C and superior efficacy on MCF7, HCT-116, and HepG2 as IC 50 values were 6.7, 16.4, and 7.3 folds less than those of free drug, respectively. Interestingly, IC 50 of the optimized formula against normal cell line was ranged from 3 to 11 folds higher than in different cancer cells indicating a higher selectivity of the optimized formula to cancer cells. In conclusion, the incorporation of IM in niosomes enhanced its efficacy and selectivity toward cancer cells, presenting a promising tool to fight cancer using this approach. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Review of extended-release formulations of Tramadol for the management of chronic non-cancer pain: focus on marketed formulations

PubMed Central

Kizilbash, Arshi; Ngô-Minh, Cường

2014-01-01

Patients with chronic non-malignant pain report impairments of physical, social, and psychological well-being. The goal of pain management should include reducing pain and improving quality of life. Patients with chronic pain require medications that are able to provide adequate pain relief, have minimum dosing intervals to maintain efficacy, and avoid breakthrough pain. Tramadol has proven efficacy and a favourable safety profile. The positive efficacy and safety profile has been demonstrated historically in numerous published clinical studies as well as from post-marketing experience. It is a World Health Organization “Step 2” opioid analgesic that has been shown to be effective, well-tolerated, and valuable, where treatment with strong opioids is not required. A number of extended release formulations of Tramadol are available in Canada and the United States. An optimal extended release Tramadol formulation would be expected to provide consistent pain control with once daily dosing, few sleep interruptions, flexible dosing schedules, and no limitation on taking with meals. Appropriate treatment options should be based on the above proposed attributes. A comparative review of available extended release Tramadol formulations shows that these medications are not equivalent in their pharmacokinetic profile and this may have implications for selecting the optimal therapy for patients with pain syndromes where Tramadol is an appropriate analgesic agent. Differences in pharmacokinetics amongst the formulations may also translate into varied clinical responses in patients. Selection of the appropriate formulation by the health care provider should therefore be based on the patient’s chronic pain condition, needs, and lifestyle. PMID:24711710

Formulation development and in vitro evaluation of solidified self-microemulsion in the form of tablet containing atorvastatin calcium.

PubMed

Ali, Kazi Asraf; Mukherjee, Biswajit; Bandyopadhyay, Amal Kumar

2013-11-01

The objective of our present study was to prepare solid self-microemulsion in the form of tablet of a poorly water soluble drug, Atorvastatin calcium (ATNC) to increase the solubility, dissolution rate, and minimize the hazards experienced from liquid emulsions. Self-microemulsifying ATNC tablet was formulated mainly by using self-emulsifying base, solidifying agent silicon dioxide and sodium starch glycolate as tablet disintegrant. Self-emulsifying base containing Transcutol P, Gelucire 44/14, and Lutrol F68 with their ratios in the formulation, were best selected by solubility study and ternary phase diagram in different vehicles. Particle size of microemulsion from tablet, physical parameters of the tablet and drug content has been checked. In vitro drug release rate has been carried out in phosphate buffer medium (pH 6.8). Physicochemical characterization of the drug in the optimized formulation has been performed to check drug-excipient incompatibility, if any. Average particle diameter of the emulsions formed from the tablet was found to be below 100 nm in case of formulation F4 and F5, which indicated microemulsions has been formed. In vitro drug release from the formulations F3, F4, and F5 was found to be >90%, indicated the enhancement of solubility of ATNC compared to parent drug. Differential thermal analysis (DTA), Powder X-ray Diffraction (X-RD) and Fourier transform infra red (FTIR) study proved the identity of the drug in the optimized formulation. The tablet form of self-microemulsifying (SME) drug delivery is good for solubility enhancement.

Formulation and evaluation of sublingual tablets containing Sumatriptan succinate

PubMed Central

Prajapati, Shailesh T; Patel, Parth B; Patel, Chhagan N

2012-01-01

Objective: Sumatriptan succinate is a selective 5-hydroxytryptamine-1 receptor agonist effective in the acute treatment of migraine headaches, having low bioavailability of about 15% orally due to first-pass metabolism. The purpose of this research was to mask the intensely bitter taste of Sumatriptan succinate and to formulate fast-acting, taste-masked sublingual tablet formulation. Materials and Methods: Taste masking was performed by solid dispersion method with mannitol and ion exchange with Kyron T 114 because it releases the drug in salivary pH. The resultant batches were evaluated for in-vivo taste masking as well compatability study (Fourier transform infrared (FTIR) and differential scanning calorimetry (DSC)). For a better feel in the mouth, menthol and sweetener Na saccharine were added to the tablet formulation. The tablets were prepared by direct compression and evaluated for weight variation, thickness, friability, drug content, hardness, disintegration time, wetting time, in vitro drug release, and in vitro permeation study. Results and Discussion: Optimized batches disintegrated in vitro within 28-34 s. Maximum drug release could be achieved with in 10 min for the solid dispersion batches and 14-15 min for the ion-exchange batches with Kyron T 114. The optimized tablet formulation showed better taste and the formulated sublingual tablets may act as a potential alternate for the Sumatriptan succinate oral tablet. Conclusion: Sumatriptan succinate can be successfully taste-masked by both the solid dispersion method using mannitol by the melting method and Ion exchange resin with Kyron T114. It was also concluded that prepared formulation improve bioavailability by prevention of first pass metabolism. PMID:23373008

Quality by Design approach for an in situ gelling microemulsion of Lorazepam via intranasal route.

PubMed

Shah, Vidhi; Sharma, Mukesh; Pandya, Radhika; Parikh, Rajesh K; Bharatiya, Bhavesh; Shukla, Atindra; Tsai, Hsieh-Chih

2017-06-01

The present study illustrates the application of the concept of Quality by Design for development, optimization and evaluation of Lorazepam loaded microemulsion containing ion responsive In situ gelator gellan gum and carbopol 934. A novel approach involving interactions between surfactant and polymer was employed to achieve controlled drug release and reduced mucociliary clearance. Microemulsion formulated using preliminary solubility study and pseudo ternary phase diagrams showed significantly improved solubilization capacity of Lorazepam with 54.31±6.07nm droplets size. The effect of oil to surfactant/cosurfactant ratio and concentration of gelling agent on the drug release and viscosity of microemulsion gel (MEG) was evaluated using a 3 2 full factorial design. The gel of optimized formulation (MEG 1 ) showed a drug release up to 6h of 97.32±1.35% of total drug loaded. The change in shear-dependent viscosity for different formulations on interaction with Simulated Nasal Fluid depicts the crucial role of surfactant-polymer interactions on the gelation properties along with calcium ions binding on the polymer chains. It is proposed that the surfactant-polymer interactions in the form of a stoichiometric hydrogen bonding between oxyethylene and carboxylic groups of the polymers used, provides exceptional ME stability and adhesion properties. Compared with the marketed formulation, optimized MEG showed improved pharmacodynamic activity. Ex vivo diffusion studies revealed significantly higher release for MEG compared to microemulsion and drug solution. MEG showed higher flux and permeation across goat nasal mucosa. According to the study, it could be concluded that formulation would successfully provide the rapid onset of action, and decrease the mucociliary clearance due to formation of in situ gelling mucoadhesive system. Copyright © 2017 Elsevier B.V. All rights reserved.

Development of a novel alginate-polyvinyl alcohol-hydroxyapatite hydrogel for 3D bioprinting bone tissue engineered scaffolds.

PubMed

Bendtsen, Stephanie T; Quinnell, Sean P; Wei, Mei

2017-05-01

Three-dimensional printed biomaterials used as personalized tissue substitutes have the ability to promote and enhance regeneration in areas of defected tissue. The challenge with 3D printing for bone tissue engineering remains the selection of a material with optimal rheological properties for printing in addition to biocompatibility and capacity for uniform cell incorporation. Hydrogel biomaterials may provide sufficient printability to allow cell encapsulation and bioprinting of scaffolds with uniform cell distribution. In this study, a novel alginate-polyvinyl alcohol (PVA)-hydroxyapatite (HA) hydrogel formulation with optimal rheological properties for 3D bioprinting of mouse calvaria 3T3-E1 (MC3T3) cells into scaffolds of high shape fidelity has been developed. A systematic investigation was conducted to determine the effect of varying concentrations of alginate, phosphate, calcium, and the PVA-HA suspension in the formulation on the resulting viscosity and thus printability of the hydrogel. HA, the main mineral component in natural bone, was incorporated into the hydrogel formulation to create a favorable bone-forming environment due to its excellent osteoconductivity. Degradation studies in α-MEM cell culture media showed that the 3D printed alginate-PVA-HA scaffolds remained in-tact for 14 days. MC3T3 cells were well distributed and encapsulated throughout the optimal hydrogel formulation and expressed high viability through the completion of the 3D printing process. Thus, the development of this novel, osteoconductive, biodegradable, alginate-PVA-HA formulation and its ability to 3D bioprint tissue engineered scaffolds make it a promising candidate for treating personalized bone defects. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1457-1468, 2017. © 2017 Wiley Periodicals, Inc.

Repurposing rosiglitazone, a PPAR-γ agonist and oral antidiabetic, as an inhaled formulation, for the treatment of PAH.

PubMed

Rashid, Jahidur; Alobaida, Ahmad; Al-Hilal, Taslim A; Hammouda, Samia; McMurtry, Ivan F; Nozik-Grayck, Eva; Stenmark, Kurt R; Ahsan, Fakhrul

2018-06-28

Peroxisome-proliferator-activated-receptor-gamma (PPAR-γ) is implicated, in some capacity, in the pathogenesis of pulmonary arterial hypertension (PAH). Rosiglitazone, an oral antidiabetic and PPAR-γ agonist, has the potential to dilate pulmonary arteries and to attenuate arterial remodeling in PAH. Here, we sought to test the hypothesis that rosiglitazone can be repurposed as inhaled formulation for the treatment of PAH. We have tested this conjecture by preparing and optimizing poly(lactic-co-glycolic) acid (PLGA) based particles of rosiglitazone, assessing the drug particles for pulmonary absorption, investigating the efficacy of the plain versus particulate drug formulation in improving the respiratory hemodynamics in PAH animals, and finally studying the effect of the drug in regulating the molecular markers associated with PAH pathogenesis. The optimized particles were slightly porous and spherical, and released 87.9% ± 6.7% of the drug in 24 h. The elimination half-life of the drug formulated in PLGA particles was 2.5-fold greater than that of the plain drug administered via the same route at the same dose. The optimized formulation, given via the pulmonary route, produced pulmonary selective vasodilation in PAH animals, but oral rosiglitazone had no effect in pulmonary hemodynamics. Rosiglitazone ameliorates the pathogenesis of PAH by balancing the molecular regulators involved in the vasoconstriction and vasodilation of human pulmonary arterial smooth muscle cells. All in all, data generated using intact animal and cellular models point to the conclusion that PLGA particles of an antidiabetic drug can be used for the treatment of a different disease, PAH. Copyright © 2018 Elsevier B.V. All rights reserved.

Conceptuation, formulation and evaluation of sustained release floating tablets of captopril compression coated with gastric dispersible hydrochlorothiazide using 23 factorial design

PubMed Central

Sirisha, Pathuri Lakshmi; Babu, Govada Kishore; Babu, Puttagunta Srinivasa

2014-01-01

Ambulatory blood pressure monitoring is regarded as the gold standard for hypertensive therapy in non-dipping hypertension patients. A novel compression coated formulation of captopril and hydrochlorothiazide (HCTZ) was developed in order to improve the efficacy of antihypertensive therapy considering the half-life of both drugs. The synergistic action using combination therapy can be effectively achieved by sustained release captopril (t1/2= 2.5 h) and fast releasing HCTZ (average t1/2= 9.5 h). The sustained release floating tablets of captopril were prepared by using 23 factorial design by employing three polymers i.e., ethyl cellulose (EC), carbopol and xanthan gum at two levels. The formulations (CF1-CF8) were optimized using analysis of variance for two response variables, buoyancy and T50%. Among the three polymers employed, the coefficients and P values for the response variable buoyancy and T50% using EC were found to be 3.824, 0.028 and 0.0196, 0.046 respectively. From the coefficients and P values for the two response variables, formulation CF2 was optimized, which contains EC polymer alone at a high level. The CF2 formulation was further compression coated with optimized gastric dispersible HCTZ layer (HF9). The compression coated tablet was further evaluated using drug release kinetics. The Q value of HCTZ layer is achieved within 20 min following first order release whereas the Q value of captopril was obtained at 6.5 h following Higuchi model, from which it is proved that rapid release HCTZ and slow release of captopril is achieved. The mechanism of drug release was analyzed using Peppas equation, which showed an n >0.90 confirming case II transportation mechanism for drug release. PMID:25006552

Existence of Optimal Controls for Compressible Viscous Flow

NASA Astrophysics Data System (ADS)

Doboszczak, Stefan; Mohan, Manil T.; Sritharan, Sivaguru S.

2018-03-01

We formulate a control problem for a distributed parameter system where the state is governed by the compressible Navier-Stokes equations. Introducing a suitable cost functional, the existence of an optimal control is established within the framework of strong solutions in three dimensions.

Current advances on polynomial resultant formulations

NASA Astrophysics Data System (ADS)

Sulaiman, Surajo; Aris, Nor'aini; Ahmad, Shamsatun Nahar

2017-08-01

Availability of computer algebra systems (CAS) lead to the resurrection of the resultant method for eliminating one or more variables from the polynomials system. The resultant matrix method has advantages over the Groebner basis and Ritt-Wu method due to their high complexity and storage requirement. This paper focuses on the current resultant matrix formulations and investigates their ability or otherwise towards producing optimal resultant matrices. A determinantal formula that gives exact resultant or a formulation that can minimize the presence of extraneous factors in the resultant formulation is often sought for when certain conditions that it exists can be determined. We present some applications of elimination theory via resultant formulations and examples are given to explain each of the presented settings.

Optimization of Aspergillus niger rock phosphate solubilization in solid-state fermentation and use of the resulting product as a P fertilizer

PubMed Central

Mendes, Gilberto de Oliveira; da Silva, Nina Morena Rêgo Muniz; Anastácio, Thalita Cardoso; Vassilev, Nikolay Bojkov; Ribeiro, José Ivo; da Silva, Ivo Ribeiro; Costa, Maurício Dutra

2015-01-01

A biotechnological strategy for the production of an alternative P fertilizer is described in this work. The fertilizer was produced through rock phosphate (RP) solubilization by Aspergillus niger in a solid-state fermentation (SSF) with sugarcane bagasse as substrate. SSF conditions were optimized by the surface response methodology after an initial screening of factors with significant effect on RP solubilization. The optimized levels of the factors were 865 mg of biochar, 250 mg of RP, 270 mg of sucrose and 6.2 ml of water per gram of bagasse. At this optimal setting, 8.6 mg of water-soluble P per gram of bagasse was achieved, representing an increase of 2.4 times over the non-optimized condition. The optimized SSF product was partially incinerated at 350°C (SB-350) and 500°C (SB-500) to reduce its volume and, consequently, increase P concentration. The post-processed formulations of the SSF product were evaluated in a soil–plant experiment. The formulations SB-350 and SB-500 increased the growth and P uptake of common bean plants (Phaseolus vulgaris L.) when compared with the non-treated RP. Furthermore, these two formulations had a yield relative to triple superphosphate of 60% (on a dry mass basis). Besides increasing P concentration, incineration improved the SSF product performance probably by decreasing microbial immobilization of nutrients during the decomposition of the remaining SSF substrate. The process proposed is a promising alternative for the management of P fertilization since it enables the utilization of low-solubility RPs and relies on the use of inexpensive materials. PMID:26112323

Energy optimization for upstream data transfer in 802.15.4 beacon-enabled star formulation

NASA Astrophysics Data System (ADS)

Liu, Hua; Krishnamachari, Bhaskar

2008-08-01

Energy saving is one of the major concerns for low rate personal area networks. This paper models energy consumption for beacon-enabled time-slotted media accessing control cooperated with sleeping scheduling in a star network formulation for IEEE 802.15.4 standard. We investigate two different upstream (data transfer from devices to a network coordinator) strategies: a) tracking strategy: the devices wake up and check status (track the beacon) in each time slot; b) non-tracking strategy: nodes only wake-up upon data arriving and stay awake till data transmitted to the coordinator. We consider the tradeoff between energy cost and average data transmission delay for both strategies. Both scenarios are formulated as optimization problems and the optimal solutions are discussed. Our results show that different data arrival rate and system parameters (such as contention access period interval, upstream speed etc.) result in different strategies in terms of energy optimization with maximum delay constraints. Hence, according to different applications and system settings, different strategies might be chosen by each node to achieve energy optimization for both self-interested view and system view. We give the relation among the tunable parameters by formulas and plots to illustrate which strategy is better under corresponding parameters. There are two main points emphasized in our results with delay constraints: on one hand, when the system setting is fixed by coordinator, nodes in the network can intelligently change their strategies according to corresponding application data arrival rate; on the other hand, when the nodes' applications are known by the coordinator, the coordinator can tune the system parameters to achieve optimal system energy consumption.

Optimization of Aspergillus niger rock phosphate solubilization in solid-state fermentation and use of the resulting product as a P fertilizer.

PubMed

Mendes, Gilberto de Oliveira; da Silva, Nina Morena Rêgo Muniz; Anastácio, Thalita Cardoso; Vassilev, Nikolay Bojkov; Ribeiro, José Ivo; da Silva, Ivo Ribeiro; Costa, Maurício Dutra

2015-11-01

A biotechnological strategy for the production of an alternative P fertilizer is described in this work. The fertilizer was produced through rock phosphate (RP) solubilization by Aspergillus niger in a solid-state fermentation (SSF) with sugarcane bagasse as substrate. SSF conditions were optimized by the surface response methodology after an initial screening of factors with significant effect on RP solubilization. The optimized levels of the factors were 865 mg of biochar, 250 mg of RP, 270 mg of sucrose and 6.2 ml of water per gram of bagasse. At this optimal setting, 8.6 mg of water-soluble P per gram of bagasse was achieved, representing an increase of 2.4 times over the non-optimized condition. The optimized SSF product was partially incinerated at 350°C (SB-350) and 500°C (SB-500) to reduce its volume and, consequently, increase P concentration. The post-processed formulations of the SSF product were evaluated in a soil-plant experiment. The formulations SB-350 and SB-500 increased the growth and P uptake of common bean plants (Phaseolus vulgaris L.) when compared with the non-treated RP. Furthermore, these two formulations had a yield relative to triple superphosphate of 60% (on a dry mass basis). Besides increasing P concentration, incineration improved the SSF product performance probably by decreasing microbial immobilization of nutrients during the decomposition of the remaining SSF substrate. The process proposed is a promising alternative for the management of P fertilization since it enables the utilization of low-solubility RPs and relies on the use of inexpensive materials. © 2015 The Authors. Microbial Biotechnology published by John Wiley & Sons Ltd and Society for Applied Microbiology.

A guided search genetic algorithm using mined rules for optimal affective product design

NASA Astrophysics Data System (ADS)

Fung, Chris K. Y.; Kwong, C. K.; Chan, Kit Yan; Jiang, H.

2014-08-01

Affective design is an important aspect of new product development, especially for consumer products, to achieve a competitive edge in the marketplace. It can help companies to develop new products that can better satisfy the emotional needs of customers. However, product designers usually encounter difficulties in determining the optimal settings of the design attributes for affective design. In this article, a novel guided search genetic algorithm (GA) approach is proposed to determine the optimal design attribute settings for affective design. The optimization model formulated based on the proposed approach applied constraints and guided search operators, which were formulated based on mined rules, to guide the GA search and to achieve desirable solutions. A case study on the affective design of mobile phones was conducted to illustrate the proposed approach and validate its effectiveness. Validation tests were conducted, and the results show that the guided search GA approach outperforms the GA approach without the guided search strategy in terms of GA convergence and computational time. In addition, the guided search optimization model is capable of improving GA to generate good solutions for affective design.

Formulation optimization and evaluation of jackfruit seed starch-alginate mucoadhesive beads of metformin HCl.

PubMed

Nayak, Amit Kumar; Pal, Dilipkumar

2013-08-01

The present study deals with the formulation optimization of jackfruit (Artocarpus heterophyllus Lam., family: Moraceae) seed starch (JFSS)-alginate mucoadhesive beads containing metformin HCl through ionotropic gelation using 3(2) factorial design. The effect of sodium alginate to JFSS ratio and CaCl2 concentration on the drug encapsulation efficiency (DEE, %), and cumulative drug release at 10h (R10h, %) was optimized. The optimized beads containing metformin HCl showed DEE of 97.48±3.92%, R10h of 65.70±2.22%, and mean diameter of 1.16±0.11mm. The in vitro drug release from these beads was followed controlled-release (zero-order) pattern with super case-II transport mechanism. The beads were also characterized by SEM and FTIR. The swelling and degradation of these beads were influenced by pH of the test medium. The optimized beads also exhibited good mucoadhesivity and significant hypoglycemic effect in alloxan-induced diabetic rats over prolonged period after oral administration. Copyright © 2013 Elsevier B.V. All rights reserved.

Observations Regarding Use of Advanced CFD Analysis, Sensitivity Analysis, and Design Codes in MDO

NASA Technical Reports Server (NTRS)

Newman, Perry A.; Hou, Gene J. W.; Taylor, Arthur C., III

1996-01-01

Observations regarding the use of advanced computational fluid dynamics (CFD) analysis, sensitivity analysis (SA), and design codes in gradient-based multidisciplinary design optimization (MDO) reflect our perception of the interactions required of CFD and our experience in recent aerodynamic design optimization studies using CFD. Sample results from these latter studies are summarized for conventional optimization (analysis - SA codes) and simultaneous analysis and design optimization (design code) using both Euler and Navier-Stokes flow approximations. The amount of computational resources required for aerodynamic design using CFD via analysis - SA codes is greater than that required for design codes. Thus, an MDO formulation that utilizes the more efficient design codes where possible is desired. However, in the aerovehicle MDO problem, the various disciplines that are involved have different design points in the flight envelope; therefore, CFD analysis - SA codes are required at the aerodynamic 'off design' points. The suggested MDO formulation is a hybrid multilevel optimization procedure that consists of both multipoint CFD analysis - SA codes and multipoint CFD design codes that perform suboptimizations.

Formulation and Evaluation of Optimized Oxybenzone Microsponge Gel for Topical Delivery

PubMed Central

Pawar, Atmaram P.; Gholap, Aditya P.; Kuchekar, Ashwin B.; Bothiraja, C.; Mali, Ashwin J.

2015-01-01

Background. Oxybenzone, a broad spectrum sunscreen agent widely used in the form of lotion and cream, has been reported to cause skin irritation, dermatitis, and systemic absorption. Aim. The objective of the present study was to formulate oxybenzone loaded microsponge gel for enhanced sun protection factor with reduced toxicity. Material and Method. Microsponge for topical delivery of oxybenzone was successfully prepared by quasiemulsion solvent diffusion method. The effects of ethyl cellulose and dichloromethane were optimized by the 32 factorial design. The optimized microsponges were dispersed into the hydrogel and further evaluated. Results. The microsponges were spherical with pore size in the range of 0.10–0.22 µm. The optimized formulation possesses the particle size and entrapment efficiency of 72 ± 0.77 µm and 96.9 ± 0.52%, respectively. The microsponge gel showed the controlled release and was nonirritant to the rat skin. In creep recovery test it had shown highest recovery indicating elasticity. The controlled release of oxybenzone from microsponge and barrier effect of gel result in prolonged retention of oxybenzone with reduced permeation activity. Conclusion. Evaluation study revealed remarkable and enhanced topical retention of oxybenzone for prolonged period of time. It also showed the enhanced sun protection factor compared to the marketed preparation with reduced irritation and toxicity. PMID:25789176

Optimum design of bolted composite lap joints under mechanical and thermal loading

NASA Astrophysics Data System (ADS)

Kradinov, Vladimir Yurievich

A new approach is developed for the analysis and design of mechanically fastened composite lap joints under mechanical and thermal loading. Based on the combined complex potential and variational formulation, the solution method satisfies the equilibrium equations exactly while the boundary conditions are satisfied by minimizing the total potential. This approach is capable of modeling finite laminate planform dimensions, uniform and variable laminate thickness, laminate lay-up, interaction among bolts, bolt torque, bolt flexibility, bolt size, bolt-hole clearance and interference, insert dimensions and insert material properties. Comparing to the finite element analysis, the robustness of the method does not decrease when modeling the interaction of many bolts; also, the method is more suitable for parametric study and design optimization. The Genetic Algorithm (GA), a powerful optimization technique for multiple extrema functions in multiple dimensions search spaces, is applied in conjunction with the complex potential and variational formulation to achieve optimum designs of bolted composite lap joints. The objective of the optimization is to acquire such a design that ensures the highest strength of the joint. The fitness function for the GA optimization is based on the average stress failure criterion predicting net-section, shear-out, and bearing failure modes in bolted lap joints. The criterion accounts for the stress distribution in the thickness direction at the bolt location by applying an approach utilizing a beam on an elastic foundation formulation.

Analyzing the Effect of Multi-fuel and Practical Constraints on Realistic Economic Load Dispatch using Novel Two-stage PSO

NASA Astrophysics Data System (ADS)

Chintalapudi, V. S.; Sirigiri, Sivanagaraju

2017-04-01

In power system restructuring, pricing the electrical power plays a vital role in cost allocation between suppliers and consumers. In optimal power dispatch problem, not only the cost of active power generation but also the costs of reactive power generated by the generators should be considered to increase the effectiveness of the problem. As the characteristics of reactive power cost curve are similar to that of active power cost curve, a nonconvex reactive power cost function is formulated. In this paper, a more realistic multi-fuel total cost objective is formulated by considering active and reactive power costs of generators. The formulated cost function is optimized by satisfying equality, in-equality and practical constraints using the proposed uniform distributed two-stage particle swarm optimization. The proposed algorithm is a combination of uniform distribution of control variables (to start the iterative process with good initial value) and two-stage initialization processes (to obtain best final value in less number of iterations) can enhance the effectiveness of convergence characteristics. Obtained results for the considered standard test functions and electrical systems indicate the effectiveness of the proposed algorithm and can obtain efficient solution when compared to existing methods. Hence, the proposed method is a promising method and can be easily applied to optimize the power system objectives.

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

PubMed

Aungst, Bruce J

2017-04-01

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

Chitosan Nanoparticles of Gamma-Oryzanol: Formulation, Optimization, and In vivo Evaluation of Anti-hyperlipidemic Activity.

PubMed

Rawal, Tejal; Mishra, Neha; Jha, Abhishek; Bhatt, Apurva; Tyagi, Rajeev K; Panchal, Shital; Butani, Shital

2018-05-01

The elevated blood levels of cholesterol and low-density lipoproteins result in hyperlipidemia. The available expensive prophylactic treatments are kindred with severe side effects. Therefore, we fabricated the polymeric nanoparticles of gamma-oryzanol to achieving the improved efficacy of drug. The nanoparticles were prepared by ionic gelation method and optimized using 2 3 full factorial design taking drug/polymer ratio (X 1 ), polymer/cross linking agent ratio (X 2 ), and stirring speed (X 3 ) as independent variables. The average particle size, percentage entrapment efficiency, and in vitro drug release at 2, 12, and 24 h were selected as response parameters. The factorial batches were statistically analyzed and optimized. The optimized nanoparticles were characterized with respect to particle size (141 nm) and zeta potential (+ 6.45 mV). Results obtained with the prepared and characterized formulation showed 83% mucoadhesion towards the intestinal mucosa. The in vitro findings were complemented well by in vivo anti-hyperlipidemic activity of developed formulation carried out in Swiss albino mouse model. The in vivo studies showed improved atherogenic index, malondialdehyde, and superoxide dismutase levels in poloxamer-407-induced hyperlipidemic animals when treated with oryzanol and gamma-oryzanol nanoformulation. Based on our findings, we believe that chitosan-mediated delivery of gamma-oryzanol nanoparticles might prove better in terms of anti-hyperlipidemic therapeutics.

In vitro and in vivo evaluation of gastro-retentive carvedilol loaded chitosan beads using Gastroplus™.

PubMed

Praveen, Radhakrishnan; Prasad Verma, Priya Ranjan; Venkatesan, Jayachandran; Yoon, Dong-Han; Kim, Se-Kwon; Singh, Sandeep Kumar

2017-09-01

The objective of present investigation was to develop gastro-retentive controlled release system of carvedilol using biological macromolecule, chitosan. 3 2 full factorial design was adopted for optimization of tripolyphosphate (X 1 ) and curing time (X 2 ). Bead stability in 0.1N HCl, buoyancy duration, density, drug loading, dissolution efficiency and cumulative percentage release at 8th hour were evaluated as dependent variables. The levels of X 1 and X 2 of optimized formulation having maximum desirability was found to 2.0% w/v and 62.66min, respectively. The in silico predicted responses and observed response were found to be in good agreement (percent bias error: -13.295 to +13.269). SEM images showed numerous pores in the cross sectional image that renders buoyancy. AUC 0-∞ of optimized formulation was 1.47 times higher as compared to suspension corroborating enhanced extent of absorption. T max and mean residence time were significantly higher from optimized formulation vis a vis suspension. In silico study indicated maximum regional absorption from the duodenum (94.1%) followed by jejunum (5.6%). Wagner-Nelson and Loo-Reigelman method were the preferred deconvolution approach over numerical deconvolution to establish IVIVC. In conclusion, the study showed that gastro-retentive controlled release system prepared using chitosan could be a potential drug carrier of carvedilol with improved bioavailability. Copyright © 2017 Elsevier B.V. All rights reserved.

Profile shape optimization in multi-jet impingement cooling of dimpled topologies for local heat transfer enhancement

NASA Astrophysics Data System (ADS)

Negi, Deepchand Singh; Pattamatta, Arvind

2015-04-01

The present study deals with shape optimization of dimples on the target surface in multi-jet impingement heat transfer. Bezier polynomial formulation is incorporated to generate profile shapes for the dimple profile generation and a multi-objective optimization is performed. The optimized dimple shape exhibits higher local Nusselt number values compared to the reference hemispherical dimpled plate optimized shape which can be used to alleviate local temperature hot spots on target surface.