Drug Discov Ther. 2008;2(2):94-107.

Formulation and hypoglycemic activity of pioglitazone-cyclodextrin inclusion complexes.

Elbary AA, Kassem MA, Abou Samra MM, Khalil RM


Pioglitazone is a thiazolidinedione derivative used for the treatment of type 2 diabetes. The drug's poor aqueous solubility and slow dissolution rate are the main causes of its limited therapeutic action in some cases. The aim of the present study is to formulate a more soluble product of pioglitazone at physiological pH. The potential interaction of pioglitazone with cyclodextrins and water-soluble polymers was investigated to enhance the drug's bioavailability and improve its efficacy. The interaction of pioglitazone with β-cyclodextrin, HP-β-cyclodextrin, and dimethyl-β- cyclodextrin was evaluated by spectrophotometric and solubility methods. Both methods revealed the formation of 1:1 inclusion complexes. The phase solubility diagram of pioglitazone-cyclodextrin systems with or without water-soluble polymers was classified as the AL type. The solubilization strength of cyclodextrins and the apparent stability constant of systems increased upon addition of water-soluble polymers. Inclusion complexes of pioglitazone in cyclodextrins with or without watersoluble polymers were prepared by the kneading method. Binary systems were characterized and confirmed by IR spectroscopy, X-ray diffractometry, and thermogravimetric analysis. The dissolution rates of pioglitazone, pioglitazone-cyclodextrin physical mixtures, pioglitazone-cyclodextrin complexes, and ternary systems containing watersoluble polymers were determined using a USP dissolution tester; results revealed enhanced dissolution properties of cyclodextrin complexes compared to drug and physical mixtures, and all of the ternary systems displayed higher dissolution efficiency than corresponding binary systems. The permeation of pioglitazone and pioglitazonecyclodextrin complexes through a cellulose membrane with and without water-soluble polymers (PVP and HPMC) present increased and the release pattern follows the kinetics of a Higuchi equation. Assessment of the hypoglycemic effect of the free drug and its cyclodextrin complexes in normal rats via measurement of blood glucose levels (BGL) after administration of a single oral dose revealed that the hypoglycemic effect of pioglitazone-cyclodextrin complexes was greater than that of the free drug and that a pioglitazone-DM β-cyclodextrin complex had the greatest effect. In conclusion, the physicochemical and biological properties of pioglitazone improved as a result of complexation with cyclodextrins, and the improvement of physicochemical properties was more prominent after water-soluble polymers were associated with pioglitazone-cyclodextrin systems.

KEYWORDS: Cyclodextrins, Water-soluble polymers, Dissolution rate, Complexation, Solubility

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