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


Surya Prakasarao Kovvasu, Kpr Chowdary

Abstract


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)0indicated 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)0was 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.


Keywords


Pioglitazone; β Cyclodextrin; Poloxamer 407; PVP K30; Solubility; Dissolution rate; Factorial study; Pharmacokinetics.

References


Archontaki HA, Vertzoni MV, Athanassiou MH. Study on the inclusion complexes of bromazepam with beta-hydroxypropyl-cyclodextrins. J Pharm Biomed Anal 2002;28:761–9.

Arima H, Yunomae K, Miyake K, Irie T, Hirayama F, Uekama K. Comparative studies of the enhancing effects of cyclodextrins on the solubility and oral bioavailability of tacrolimus in rats. J Pharm Sci 2001;90:690–701.

Thompson DO. Cyclodextrins- enabling excipients: their present and future use in pharmaceuticals. Critical Rev Ther Drug Carrier Sys 1997; 14.

Hedges AR. Industrial applications of cyclodextrins. Chem Rev 1998;98:2035-44.

Kurmi R, Mishra DK, Jain DK.Solid dispersion: a novel means of solubility enhancement. J Crit Rev 2016;3:1-8.

Manimaran V, Damodharan N, Mothilal M, Rajkumar K, Chalackal RM. Enhancement of dissolution rate of glibenclamide by solid dispersion technology. Int J Current Pharma Res 2010;2:14-7.

Dumortier G, Grossiord JL, Agnely F, Chaumeil JC. A review of Poloxamer 407 pharmaceutical and pharmacological characteristics. Pharma Res 2006;23:2709-28.

Patel TB, Patel D, Patel TB, Makwana SH, Patel TR. Formulation and characterization of solid dispersions containing glibenclamide. Int J Pharm Pharma Sci 2010;2:138-41.

Chowdary KPR, Prakasarao KS. Formulation development of etoricoxib tablets employing HP β cyclodextrin-Poloxamer 407-PVP K30: a factorial study. Asian J Pharma Clin Res 2012;5:161-4.

Boddu P, Cherakapu VL, Ponukumati UD. Application of solid dispersion technique in solubility and dissolution rate enhancement of nateglinide. Asian J Pharma Clin Res 2017;10:231-8.

Ikasari ED, Fudholi A, Martono S, Marchaban. Investigation of nifedipine solid dispersion with solvent PVP K30. Int J Pharm Pharma Sci 2015;7:389-92.

Kurmi R, Mishra DK, Jain DK. Solid dispersion: a novel means of solubility enhancement. J Crit Rev 2016;3:1-8.

Chowdary KPR, Prakasarao KS. A factorial study on the effects of HP β cyclodextrin, Poloxamer 407 and PVP K30 on the solubility and dissolution rate of pioglitazone. Der Pharmacia Lettre 2011;3:154-9.

Higuchi T, Connors K. Phase-solubility techniques. Adv Anal Chem Instr 1965;4:117-22.

Chowdary KPR, Prakasarao KS. Formulation development of pioglitazone tablets employing β cyclodextrin-Poloxamer 407-PVP K30: a factorial study. Scholars Res Lib 2011;3:24-30.

Joner M, Farb A, Cheng Q, Finn AV, Acampado E, Burke AP et al. Pioglitazone inhibits in-stent restenosis in atherosclerotic rabbits by targeting transforming growth factor-β and MCP-1. Arterio Thromb Vasc Biology 2007;27:182-9.

Galibsaheb V, Chowdary KPR. HPLC estimation of pioglitazone in formulations and in pharmacokinetic studies. Asian J Chem 2011;23:4500-2.

Wagner JG, Nelson E.Percent absorbed time plots derived from blood level and/or urinary excretion data. J Pharma Sci 1963;52:610-1.

Wagner JG, Nelson E. Kinetic analysis of blood levels and urinary excretion in the absorptive phase after single doses of drug. J Pharma Sci 1964;53:1392-1403.

Khan K. The concept of dissolution efficiency. J Pharm Pharmacol 1975;27:48-9.

Eckland D, Danhof M. Clinical pharmacokinetics of pioglitazone. Exp Clin Endoc Diab 2000;108:234-42.




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