FORMULATION DEVELOPMENT AND IN VIVO EVALUATION OF PIOGLITAZONE INCLUSION COMPLEXES: A FACTORIAL STUDY

Objective: The objective of the study was to evaluate the individual main effects and combined (or interaction) effects of cyclodextrin (β cyclodextrin), surfactant (Poloxamer 407) and polyvinylpyrrolidone K30 (PVP K30) on the solubility and dissolution rate of pioglitazone in a series of 23 factorial experiments. The inclusion complexes were evaluated for pharmacokinetics and in vivo performance in comparison to pioglitazone pure drug.Methods: Among the various approaches complexation with cyclodextrins has gained good acceptance in recent years in the industry for enhancing the solubility and dissolution rate of poorly soluble drugs. As per the phase solubility studies, a 23 factorial study was used to prepare the solid inclusion complexes and evaluated for the interactions and in vitro drug release. The best combinations were selected for in vivo performance in healthy albino rabbits. From the time versus plasma concentration data, various pharmacokinetic parameters such as peak concentration (Cmax), time at which peak occurred (Tmax), area under the curve (AUC), elimination rate constant (Kel), biological half-life (t1/2), percent absorbed to various times and absorption rate constant (Ka) were calculated in each case.Results: The solubility of pioglitazone in eight selected fluids containing β cyclodextrin (βCD), Poloxamer 407 and PVP K30 as per 23 factorial studies was determined. Combination of βCD with Poloxamer 407 and PVP K30 resulted in a much higher enhancement (13.85-7.06 folds) in the solubility of pioglitazone than the βCD alone. Solid inclusion complexes of pioglitazone-βCD were prepared with and without Poloxamer 407 and PVP K30 by kneading method as per 23- factorial design. Analysis of variance (ANOVA) indicated that the individual main effects of βCD, Poloxamer 407 and PVP K30 and their combined effects in enhancing the solubility and dissolution rate (K1) were highly significant (P<0.01). The t1/2 value of pioglitazone estimated (6.92-7.46 h) in the present study was in good agreement with the literature reported value of 6-10 h. Pioglitazone was absorbed slowly when given orally with an absorption rate constant (Ka) of 0.629 h-1 and a peak plasma concentration (Cmax) of 11.40±0.7 µg/ml was observed at 4.0 h after administration. All the pharmacokinetic parameters namely Cmax, Tmax, Ka and (AUC)0∞ indicated rapid and higher absorption and bioavailability of pioglitazone when administered as βCD complexes. A 3.43 and 4.67 fold increase in the absorption rate (Ka) and a 1.49 and 1.67 fold increase in (AUC)0∞ was observed respectively with pioglitazone-βCD (1:2) and pioglitazone-βCD (1:2)-Poloxamer 407 (2%) complexes when compared to pioglitazone pure drug.Conclusion: Combination of βCD with Poloxamer 407 gave higher rates of absorption and bioavailability of pioglitazone than is possible with βCD alone. Hence the combination of βCD with Poloxamer 407 is recommended to enhance the absorption and bioavailability of pioglitazone, a BCS class II drug

Evaluation of olibanum resin as a new microencapsulating agent for aceclofenac controlled release microcapsules

ABSTRACT The objective of the study is to evaluate olibanum resin, a natural resin as a coat for controlled release microcapsules of aceclofenac. Olibanum resin coated microcapsules were prepared by an emulsion-solvent evaporation method employing different proportions of core and coat and the microcapsules were evaluated for size, drug content and microencapsulation efficiency, wall thickness, surface character by SEM and drug release kinetics. The olibanum resin coated microcapsules prepared were found to be discrete, spherical, and free flowing. Drug content was uniform (c.v.≤ 0.13%) in each batch of microcapsules and the microencapsulation efficiency was in the range 95.74-99.03%. Aceclofenac release from the olibanum resin coated microcapsules was slow and spread over a period of 24 h and depended on core: coat ratio, wall thickness and size of the microcapsules. Drug release from these microcapsules was majorly by non-fickian diffusion. Good linear relationships were observed between wall thickness of the microcapsules and release rate (K 0 ) and (K 1 ). Microcapsules prepared employing chloroform as solvent for olibanum exhibited higher release rates when compared to those prepared employing dichloromethane as solvent. Olibanum resin was found to be a new and efficient microencapsulating agent for controlled release microcapsules and the olibanum resin coated microcapsules exhibited good controlled release characteristics and were found suitable for oral controlled release of aceclofenac over 24 h

Enhancement of Dissolution Rate of Valdecoxib by Solid Dispersion in Starch Phosphate and Gelucire -A Factorial Study

ABSTRACT Valdecoxib, a widely prescribed anti-inflammatory and analgesic drug belongs to class II under BCS and exhibit low and variable oral bioavailability due to its poor aqueous solubility. As such it needs enhancement in the dissolution rate and bioavailability to derive its maximum therapeutic efficacy. The objective of the present study is to prepare and evaluate solid dispersions of valdecoxib in combined carriers, a water dispersible new modified starch namely starch phosphate and a water soluble surfactant namely Gelucire 50/13 for enhancing the dissolution rate and dissolution efficiency of valdecoxib in a 2 2 factorial study. The individual and combined effects of the starch phosphate (Factor A) and Gelucire 50/13 (Factor B) in enhancing the dissolution rate and dissolution efficiency of valdecoxib were evaluated in a 2 2 factorial study. Solid dispersions of valdecoxib in starch phosphate (a new modified starch) and Gelucire 50/13 (surfactant) alone and in combination were prepared as per 2 2 factorial design by kneading method and were evaluated for dissolution rate and dissolution efficiency. The dissolution rate (K 1 ) and dissolution efficiency (DE 30 ) of valdecoxib could be significantly enhanced by solid dispersion in starch phosphate (a water dispersible modified starch) and Gelucire 50/13 (a surfactant). ANOVA indicated that the individual effects of starch phosphate (factor A) and Gelucire 50/13 (factor B) in enhancing the dissolution rate (K 1 ) and dissolution efficiency (DE 30 ) were highly significant (P < 0.01) and the combined (interaction) effects of the two factors were also significant (P<0.05). A 19.70, 22.31 and 45.63 fold increase in the dissolution rate (K 1 ) and a 20.46, 21.03 and 32.90 fold increase in the dissolution efficiency (DE 30 ) was observed respectively with solid dispersions SD a , SD b and SD a b when compared to F1 (valdecoxib pure drug). The combination of starch phosphate (a water dispersible modified starch) and Gelucire 50/13 (a surfactant) gave a markedly higher enhancement in the dissolution rate (K 1 ) and dissolution efficiency (DE 30 ) of valdecoxib than is possible with them individually. Hence solid dispersion of valdecoxib in combined carriers consisting of starch phosphate and Gelucire 50/13 is recommended to enhance the dissolution rate and dissolution efficiency of valdecoxib, a BCS class II drug