Technological approaches to improve the bioavailability of the poor soluble substance Candesartan Cilexetil in mini-tablets

Introduction. The polypill in the form of a hard gelatin capsule containing mini-tablets of the original antihypertensive combination is being developed at the Saint-Petersburg State Chemical and Pharmaceutical University. One of the components of the polypill is Candesartan, which has high antihypertensive activity and organoprotective properties. The active pharmaceutical ingredient (API) of Candesartan Cilexetil is characterized by low solubility in water and gastrointestinal tract media, therefore increasing the solubility of this substance can lead to a significant improving the bioavailability. Aim. Comparative analysis of technological approaches to increasing the bioavailability of the poor soluble API Сandesartan Сilexetil in a mini-tablet dosage form. Materials and methods. API Сandesartan Сilexetil, β-cyclodextrin (β-CD), copolymer of polyvinylpyrrolidone and vinyl acetate and excipients for the production of mini-tablets, such as diluents, binders, disintegrant, dusting components were used. The release profiles of Candesartan Cilexetil from the developed mini-tablets were assessed in comparison with the original drug Atacand®, 8 mg tablets. The complex of candesartan cilexetil with β-CD in a 1 : 1 ratio was prepared by three methods: dry mixing, paste method and lyophilization. A solid dispersion (SD) of candesartan was obtained by hot melt extrusion. The API complexes with β-CD and SD were characterized by FTIR-spectroscopy and differential scanning calorimetry. Tablet mixtures were produced by dry mixing and wet granulation technology. Mini-tablets were obtained on a laboratory automatic single-punch tablet press. Quality control of the mini-tablets was conducted by the methods of State Pharmacopoeia of the Russian Federation XV ed. and United State Pharmacopeia methods. Results and discussion. Comparative analysis of technological approaches to increasing the bioavailability of Candesartan Cilexetil showed, that preparation of a complex including API with β-CD in a 1 : 1 ratio using the paste method with further using of wet granulation technology allowed to obtain mini-tablets with improved release of poor soluble API compared to the original drug. On the contrary, the use of TDS in mini-tablet technology led to a slower release of API compared to the original drug. The developed mini-tablets of Candesartan composition № 7 met pharmacopoeial requirements by all acceptance criteria. Conclusion. The creation of complex of Candesartan Cilexetil with β-CD by the paste method with further using of wet granulation technology is the optimal technological approach to increasing the bioavailability of the poor soluble API Candesartan Cilexetil in mini-tablets.