FORMULATION DEVELOPMENT AND IN VIVO EVALUATION OF PIOGLITAZONE INCLUSION COMPLEXES: A FACTORIAL STUDY
DOI:
https://doi.org/10.22159/ijap.2018v10i3.24558Keywords:
Pioglitazone, Nil, Poloxamer 407, PVP K30, Solubility, Dissolution rate, Factorial study, PharmacokineticsAbstract
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.
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