Porous carrier based floating granular delivery system of repaglinide

A floating granular delivery system consisting of calcium silicate (CS) as porous carrier; repaglinide (Rg), an oral hypoglycemic agent; and hydroxypropyl methylcellulose K4M (HPMC K4M), ethyl cellulose (EC) and carbopol 940 (CP940) as matrix forming polymers was prepared and evaluated for its gastro-retentive and controlled release properties. The effect of various formulation and process variables on the particle morphology, micromeritic properties, in vitro floating behavior, drug content (%) and in vitro drug release was studied. The transit of floating granules of optimized formulation in the gastrointestinal (GI) tract was monitored by gamma scintigraphy in albino rabbits. The optimized formulation was compared in vivo with lactose granules (RgSCLG) prepared from identical polymers with their optimized composition ratio. Repaglinide-loaded optimized formulation was orally administered to albino rabbits and blood samples collected were used to determine pharmacokinetic parameters of Rg from floating granular formulation. Results were compared with pharmacokinetic parameters of marketed tablet formulation of Rg. The optimized formulation (RgSCG4) demonstrated favorable in vitro floating and release characteristics. Prolonged gastric residence time (GRT) of over 6 hr was achieved in all subjects for calcium silicate based floating granules of Rg. The relative bioavailability of Rg-loaded floating granules increased 3.8-fold in comparison to that of its marketed capsule. The designed system, combining excellent buoyant ability and suitable drug release pattern, offered clear advantages in terms of increased bioavailability of repaglinide.     

Design and development of nanoemulsion drug delivery system of amlodipine besilate for improvement of oral bioavailability

Nanoemulsion (NE) of amlodipine besilate (AB) was developed by spontaneous emulsification method with the aim to enhance the solubility and oral bioavailability of AB and to achieve localized delivery of drug at target site. Pseudoternary phase diagrams were constructed to identify the NE region. The selected formulations from NE region were subjected to droplet size analysis, partitioning study and in vitro drug release. The partition coefficient was calculated and correlated with percent dissolution efficiency as a tool to predict in vitro drug release from NEs. The release of drug from NEs was significantly higher (p < 0.01) than the marketed tablet formulation. The optimal formulation contained 15% Labrafil M, 35% [Tween 80: ethanol (2:1)], and 50% by weight aqueous phase (NE3) was characterized by transmission electron microscopy (TEM) and for thermodynamic stability. The pharmacokinetics and biodistribution studies of the optimized radiolabeled formulation (99mTc-labeled) in mice (p.o.) demonstrated a relative bioavailability of 475% against AB suspension. In almost all the tested organs, the uptake of AB from NE was significantly higher (p < 0.05) than AB suspension especially in heart with a drug targeting index of 44.1%, also confirming the efficacy of nanosized formulation at therapeutic site. A three times increase in the overall residence time of NE further signifies the advantage of NEs as drug carriers for enhancing bioavailability of AB.     

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

Objectives: The study was aimed to improve bioavailability of baclofen by developing gastroretentive floating drug delivery system (GFDDS).

Methods: Preliminary optimization was done to select various release retardants to obtain minimum floating lag time, maximum floating duration and sustained release. Optimization by 3² 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.

Results: 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 C_max of 189.96?±?13.04?ng/mL and T_max 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.

Conclusion: GFDDS provided prolonged gastric residence and showed significant increase in bi oavailability of baclofen.     

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

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

Mucoadhesive elementary osmotic pump tablets of trimetazidine for controlled drug delivery and reduced variability in oral bioavailability

The objectives of this work was preparation and evaluation of the mucoadhesive elementary osmotic pump tablets of trimetazidine hydrochloride to achieve desired controlled release action and augmentation of oral drug absorption. The drug-loaded core tablets were prepared employing the suitable tableting excipients and coated with polymeric blend of ethyl cellulose and hydroxypropyl methylethylcellulose E5 (4:1). The prepared tablets were characterized for various quality control tests and in vitro drug release. Evaluation of drug release kinetics through model fitting suggested the Fickian mechanism of drug release, which was regulated by osmosis and diffusion as the predominant mechanism. Evaluation of mucoadhesion property using texture analyzer suggested good mucoadhesion potential of the developed osmotic systems. Solid state characterization using Fourier-transform infrared spectroscopy, differential scanning calorimetry and powder X-ray diffraction spectroscopy confirmed the absence of any physiochemical incompatibilities between drug and excipients. Scanning electron microscopy analysis showed the smooth surface appearance of the coated tablets with intact polymeric membrane without any fracture. In vivo pharmacokinetic studies in rabbits revealed 3.01-fold enhancement in the oral bioavailability vis-à-vis the marketed formulation (Vastarel MR®). These studies successfully demonstrate the bioavailability enhancement potential of the mucoadhesive elementary osmotic pumps as novel therapeutic systems for other drugs too.     

Design and optimization of gastric floating sustained-release mini-tablets of alfuzosin hydrochloride based on a factorial design: in vitro/in vivo evaluation

Abstract

The purpose of this research was to develop multiple-unit gastric floating mini-tablets and to evaluate the possibility of using these mini-tablets as a delivery system to improve the drug absorption for drugs with a narrow absorption window. Mini-tablets were prepared using hydroxypropyl methylcellulose (HPMC K100M) and carbopol 971P as release retarding agents and sodium bicarbonate (NaHCO₃) as gas-forming agent. The properties of the prepared mini-tablets in terms of floating characteristic parameters and in vitro release were evaluated. Furthermore, in vivo gastric retention study in rats and in vivo pharmacokinetic study in rabbits of the optimized formulation were performed. The optimized mini-tablets containing 45% HPMC K100M, 15% stearyl alcohol, 13% carbopol 971P, and 12% NaHCO₃ were found to float immediately within 1?min and duration more than 9?h. The in vivo gastric retention study results indicated that the mini-tablets could retain in the stomach for more than 6.67?h. Furthermore, the AUC_0?t of the floating mini-tablets (6849.83?±?753.80?h ng·mL^?1) was significantly higher than that of marketed sustained-release tablets XATRAL®XL (4970.16?±?924.60?h ng·mL^?1). All these results illustrated that the gastric floating mini-tablets might be a promising drug delivery system for drugs with a narrow absorption window.     

Preparation and pharmacokinetics study on gastro-floating sustained-release tablets of troxipide

The purpose of this research aimed at preparing gastro-floating sustained-release tablets of troxipide and a further study on in vitro release and in vivo bioavailability. Under the circumstances of direct powder compression, the floating tablets were successfully prepared with HPMC as main matrix material, Carbopol as assistant matrix material, octadecanol as floating agent and sodium bicarbonate as foaming agent to float by gas-forming. The floating time and accumulative release amount as evaluation indexes were utilized to perform pre-experiment screening and single-factor test, respectively, while central composite design response surface method was applied for formulation optimization, followed by in vivo pharmacokinetic study in beagles after oral administration for floating tablets and commercial tablets used as the control. The results indicated that the floating sustained-release tablets held a better capability for floating and drug release and more satisfactory pharmacokinetic parameters, such as a lower C_max, a prolonged T_max, but an equivalent bioavailability calculated by AUC_0–24 compared to commercial tablets. So a conclusion was finally drawn that the floating sustained-release tablets possessing a good release property could be suitable for demands of design.     

Enhanced oral bioavailability of isradipine via proniosomal systems

The objective of the present research was to develop a proniosomal formulation of isradipine and to evaluate the influence of proniosomal systems on the oral bioavailability of the drug in albino Wistar rats. Proniosomes were prepared by film deposition on carrier’s method using various molar ratios of nonionic surfactants such as span20, span40, span60, and span80 with cholesterol as membrane stabilizing agent and dicetylphosphate as a charge inducer. The formation of niosomes and surface morphology of proniosome formulations were studied by optical and scanning electron microscopy (SEM), respectively. The prepared proniosomes have shown higher dissolution of isradipine compared with pure drug powder. Fourier transform infrared spectroscopy, differential scanning calorimetry, and powder X-ray diffractometry studies were performed to understand the solid state properties of the drug. Ex vivo permeation enhancement assessed from flux, permeability coefficient, and enhancement ratio were significantly higher for proniosomes compared with control. The pharmacokinetic parameters were evaluated in male albino Wistar rats and a significant enhancement in the bioavailability (2.3-fold) was observed from optimized proniosome formulation compared with control (oral suspension). The stability study reveals that the proniosome formulations are stable when stored at 4°C.     

Development of dorzolamide hydrochloride in situ gel nanoemulsion for ocular delivery

Background: Several in situ gel-forming systems have been developed to prolong the precorneal residence time of a drug and to improve ocular bioavailability. Poloxamer 407 with its thermoreversible gelation and surface active properties was utilized to formulate a novel dorzolamide hydrochloride in situ gel nanoemulsion (NE) delivery system for ocular use. Objective: Improvement of both ocular bioavailability and duration of action for dorzolamide hydrochloride was the aim of this study. Methods: Physicochemical properties, in vitro drug release studies and biological evaluation of the prepared NEs were investigated. Results: The optimum formulation of in situ gel NE consisted of Triacetin (7.80%), Poloxamer 407 (13.65%), Poloxamer 188 (3.41%), Miranol C2M (4.55%), and water (70.59%). Biological evaluation of the designed dorzolamide formulation on normotensive albino rabbits indicated that this formulation had better biological performance, faster onset of action, and prolonged effect relative to either drug solution or the market product. The formula showed a superior pharmacodynamic activity compared to the in situ gel dorzolamide eye drops. This indicated the effectiveness of the in situ gel properties of poloxamer 407, besides formulating the drug in an NE form for improving the therapeutic efficacy of the drug. Conclusion: These results demonstrate the superiority of in situ gel NE to conventional ocular eye drops and in situ gels to enhance ocular drug bioavailability.     

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

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.     

Novel instantly-dispersible nanocarrier powder system (IDNPs) for intranasal delivery of dapoxetine hydrochloride: in-vitro optimization,ex-vivo permeation studies,and in-vivo evaluation

Dapoxetine (D) suffers from poor oral bioavailability (42%) due to extensive metabolism in the liver. The aim of this study was to enhance the bioavailability of D via preparing instantly-dispersible nanocarrier powder system (IDNPs) for intranasal delivery of D. IDNPs were prepared using the thin film hydration technique, followed by freeze-drying to obtain easily reconstituted powder providing rapid and ready method of administration. The produced nanocarrier systems were evaluated for drug content, entrapment efficiency percentage, particle size, polydispersity index, zeta potential, and drug payload. The optimized nanocarrier system was morphologically evaluated via transmission electron microscopy and the optimized freeze-dried IDNPs were evaluated for ex-vivo permeation and in-vivo pharmacokinetic studies in rabbits following intranasal and oral administration. The relative bioavailability of D after intranasal administration of freeze-dried IDNPs was about 235.41% compared to its corresponding oral nanocarrier formulation. The enhanced D permeation and improved bioavailability suggest that IDNPs could be a promising model for intranasal delivery of drugs suffering from hepatic first pass effect.     

Development of a directly compressible poly(ethylene oxide) matrix for the sustained-release of dihydrocodeine bitartrate

The purpose of this study was to design and evaluate a directly compressible hydrophilic poly(ethylene oxide) (PEO) matrix for the oral sustained delivery of dihydrocodeine bitartrate (DHCT). A direct compression method was used to prepare PEO matrices, and the amount of PEO in the matrices was varied to optimize in vitro DHCT release profiles. In vitro release studies indicated that the matrices containing 20%-70% w/w of PEO with molecular weight of 5.0 x 10(6) showed a similar release profile, as estimated with DT50%, to that exhibited by a marketed product, DHC Continus. In vivo bioavailability study revealed that the difference in the pharmacokinetic parameters such as AUC0-30 and Tmax of the selected sustained-release formulation containing 60% w/w of PEO 5.0 x 10(6) and DHC Continus was statistically insignificant (p > 0.05). Thus, it could be concluded that the extent of bioavailability of the sustained-release formulation developed here was similar to that of DHC Continus although Cmax values of these two preparations were significantly different (p < 0.05). From the data obtained in this research, hydrophilic PEO matrices were found to be a novel sustained-release carrier for the oral delivery of DHCT.     

Development of zolmitriptan transfersomes by Box–Behnken design for nasal delivery: in vitro and in vivo evaluation

The aim was to prepare an optimized zolmitriptan (ZT)-loaded transfersome formulation using Box–Behnken design for improving the bioavailability by nasal route for quick relief of migraine and further to compare with a marketed nasal spray. Here, three factors were evaluated at three levels. Independent variables include: amount of soya lecithin (X₁), amount of drug (X₂) and amount of tween 80 (X₃). The dependent responses were vesicle size (Y₁), flexibility index (Y₂) and regression coefficient of drug release kinetics (Y₃). Prepared formulations were evaluated for physical characters and an optimal system was identified. Further, in vivo pharmacokinetic study was performed in male wistar rats to compare the amount of drug in systemic circulation after intranasal administration. Optimized ZT-transfersome formulation containing 82.74?mg of lecithin (X₁), 98.37?mg of zolmitriptan (X₂) and 32.2?mg of Tween 80 (X₃) and had vesicle size of 93.3?nm, flexibility index of 20.25 and drug release regression coefficient of 0.992. SEM picture analysis revealed that the vesicles were spherical in morphology and had a size more than 1?µm. The formulations were found to be physically stable upon storage at room temperature up to 2?months period, as there were no significant changes noticed in size and ZP. The nasal bioavailability of optimized transfersome formulation was found to be increased by 1.72 times than that of marketed nasal spray (Zolmist^®). The design and development of zolmitriptan as transfersome provided improved nasal delivery over a conventional nasal spray for a better therapeutic effect.     

Thermal sintering: a novel technique used in the design,optimization and biopharmaceutical evaluation of propranolol HCl gastric floating tablets

The objective of the present investigation was to study the applicability of thermal sintering technique for the development of gastric floating tablets of propranolol HCl. Formulations were prepared using four independent variables, namely (i) polymer quantity, (ii) sodium bicarbonate concentration, (iii) sintering temperature and (iv) sintering time. Floating lag time and t₉₅ were taken as dependent variables. Tablets were prepared by the direct compression method and were evaluated for physicochemical properties, in vitro buoyancy and dissolution studies. From the drug release studies, it was observed that drug retarding property mainly depends upon the sintering temperature and time of exposure. The statistically optimized formulation (PTSso) was characterized by Fourier transform infrared spectroscopy and differential scanning calorimetry studies, and no significant chemical interaction between drug and polymer was observed. Optimized formulation was stable at accelerated conditions for a period of six months. PTSso was evaluated for in vivo buoyancy studies in humans for both fed and fasted states and found that gastric residence time of the floating tablets were enhanced by fed stage but not in fasted state. Optimized formulation PTSso and commercial formulation Ciplar LA 80 were subjected to bioavailability studies in healthy human volunteers by estimating pharmacokinetic parameters such as C_max, T_max, area under curve (AUC), elimination rate constant (K_el), biological half-life (t_1/2) and mean residence time (MRT). There was a significant increase in the bioavailability of the propranolol HCl from PTSso formulation, which was evident from increased AUC levels and larger MRT values than Ciplar LA 80.     

In vitro and in vivo studies on a novel solid dispersion of repaglinide using polyvinylpyrrolidone as the carrier

In order to improve the dissolution and absorption of the water insoluble drug repaglinide, a solid dispersion was developed by solvent method using polyvinylpyrrolidone K30 (PVP K30) as the hydrophilic carrier for the first time. Studies indicated that both solubility and the dissolution rate of repaglinide were significantly increased in the solid dispersion system compared with that of repaglinide raw material or physical mixtures. The repaglinide solid dispersions with PVP K30 solid state was characterized by polarizing microscopy, differential scanning calorimetry (DSC), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FT-IR). DSC and XRD studies indicated that repaglinide existed in an amorphous form in the solid dispersion. FT-IR analysis demonstrated the presence of intermolecular hydrogen bonding between repaglinide and PVP K30 in the solid dispersion. In the in situ gastrointestinal perfusion experiment, solid dispersion was shown to remarkably enhance the absorption of repaglinide in stomach and all segments of intestine. In vivo pharmacokinetic study in rats showed that immediate and complete release of repaglinide from the solid dispersion resulted in rapid absorption that significantly increased the bioavailability and the maximum plasma concentration over repaglinide raw material. These results demonstrated PVP K30 was an appropriate carrier for solid dispersion of repaglinide, with increased dissolution and oral absorption.     

Use of sorbitol as pharmaceutical excipient in the present day formulations – issues and challenges for drug absorption and bioavailability

Sorbitol is a popular sugar alcohol which has been used as an excipient in formulations of various drugs. Although from a safety perspective the presence of sorbitol in drug formulations does not raise a concern, reports have emerged and these suggest that sorbitol in drug formulations may alter oral absorption and bioavailability of certain drugs. The focus of this article was to review the published literature of various drugs where pharmacokinetic data has been reported for the drug alone versus drug administered with sorbitol and provide perspectives on the pharmacokinetic findings. Interestingly, for BCS class I drugs such as theophylline, metoprolol, the oral absorption, and bioavailability were generally not affected by sorbitol. However, theophylline oral absorption and bioavailability were decreased when sustained release formulation was used in place of immediate release formulation. For drugs such as risperidone (BCS class II) and lamivudine and ranitidine (BCS class III), the solution formulations showed diminished oral bioavailability in presence of sorbitol, whereas cimetidine and acyclovir (BCS class III), did not show any changes in pharmacokinetic profiles due to sorbitol. Finally, the presence of activated charcoal with sorbitol showed different pharmacokinetic outcome for BCS class I and II drugs.     

Buccoadhesive films for once-a-day administration of rivastigmine: systematic formulation development and pharmacokinetic evaluation

Context: Rivastigmine, an anti-Alzheimer’s drug, suffers from major predicaments like low oral bioavailability, severe GI adverse effects related to rapid fluctuations in drug plasma levels, and high frequency of dosing.

Objective: The present investigation aims at developing buccoadhesive films capable of delivering the drug in vivo in a sustained manner. Augmentation of drug bioavailability by the avoidance of first-pass effect through the buccal route and reduction in GI side effects would be other key advantages of this system.

Methods: Buccoadhesive films of rivastigmine were systematically designed and evaluated for in vitro drug release, ex vivo buccal permeation and ex vivo buccoadhesive strength. Optimal composition of the polymer blends was rationally chosen using a central composite design and overlay plot. In vivo pharmacokinetic studies were carried out in rabbits, and attempts were made to establish in vitro/ in vivo correlations (IVIVC).

Results: Besides possessing the requisite drug release regulation, the optimized formulation exhibited excellent buccoadhesion, and buccal permeation. Pharmacokinetic studies indicated extension of plasma drug levels and level A of IVIVC was successfully established.

Discussion: Excellent buccal bioadhesion and transmucosal permeation, coupled with drug release control, ratify the potential of the optimized formulation to deliver the drug in a controlled and site-specific manner. Successful establishment of IVIVC substantiated the judicious choice of in vitro dissolution media for simulating the in vivo conditions.

Conclusion: Besides unraveling the polymer synergism, the study helped in developing an optimal once-a-day buccoadhesive drug delivery system exhibiting excellent trans-buccal permeation and buccoadhesive characteristics with improved bioavailability potential.     

Nanosuspension of efavirenz for improved oral bioavailability: formulation optimization,in vitro,in situ and in vivo evaluation

Context: Nanosuspensions (NSs) of poorly water-soluble drugs are known to increase the oral bioavailability.

Objectives: The purpose of this study was to develop NS of efavirenz (EFV) and to investigate its potential in enhancing the oral bioavailability of EFV.

Materials and methods: EFV NS was prepared using the media milling technique. The Box–Behnken design was used for optimization of the factors affecting EFV NS. Sodium lauryl sulfate and PVP K30 were used to stabilize the NS. Freeze-dried NS was completely re-dispersed with double-distilled filtered water.

Results: Mean particle size and zeta potential of the optimized NS were found to be 320.4?±?3.62?nm and –32.8?±?0.4 mV, respectively. X-ray diffraction and differential scanning calorimetric analysis indicated no phase transitions. Rate and extent of drug dissolution in the dissolution medium for NS was significantly higher compared to marketed formulation. The parallel artificial membrane permeability assay revealed that NS successfully enhanced the permeation of EFV. Results of in situ absorption studies showed a significant difference in absorption parameters such as K_a, t_1/2 and uptake percentages between lyophilized NS and marketed formulation of EFV. Oral bioavailability of EFV in rabbits resulting from NS was increased by 2.19-fold compared to the marketed formulation.

Conclusion: Thus, it can be concluded that NS formulation of EFV can provide improved oral bioavailability due to enhanced solubility, dissolution velocity, permeability and hence absorption.     

Controlled Theophylline Release from Microcapsules of Acrylic & Methacrylic Acid Ester Copolymer

The goal of this work was to develop a suitable method for microencapsulation of theophylline using copolymer of acrylate and methacrylate ester (EUDRAGIT) as the coating material. The effect of protective colloids on the process of microencapsulation was evaluated. The in vitro studies revealed significant control of drug release for the developed dosage form. Individually, the polymer coated drug particles of different core: coat ratio and different proportions of protective colloids were found to influence the pharmacokinetic parameters as revealed from the in vivo bioavailability studies in gastric-emptying controlled rabbits. In vivo bioavailability data were compared using Westlake's confidence limit.     

Oral bioavailability enhancement of raloxifene by developing microemulsion using D-optimal mixture design: optimization and in-vivo pharmacokinetic study

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.