Preparation and characterization of tablet formulation based on solid dispersion of glimepiride and poly(ester amide) hyperbranched polymer.

The feasibility of incorporating a solid dispersion containing poorly soluble antidiabetic drug glimepiride and poly(ester amide) hyperbranched polymer into a tablet using a direct-compression tabletting technique was investigated. Tablet cores were additionally coated with hydroxypropyl methylcellulose phthalate in order to protect the extremely hygroscopic solid dispersion from atmospheric moisture. Preliminary stability studies show that glimepiride, which is in amorphous form within solid dispersion, is chemically stable, even if tablets are exposed to elevated temperature and/or moisture. In-vitro dissolution studies show some impact of storage conditions on the tablet cores disintegration time and, consequently, drug release rate. Glimepiride solubility also deteriorates somewhat, most probably due to its partial recrystallization. Storage conditions much less affect the physical stability of coated tablets, which was ascribed to reduced tablet hygroscopicity due to the presence of protecting coating. The hyperbranched polymers are rather new and complex macromolecules. Therefore, we addressed also the biocompatibility of hyperbranched polymer, i.e., its impact on haemolysis of the red blood cells. The concentration required for the haemolytic effect on the red blood cells is around 100-times higher than its expected gastrointestinal luminal concentration, which makes the occurrence of hyperbranched polymer mediated cytotoxicity very unlikely.

Determination of the interaction between glimepiride and hyperbranched polymers in solid dispersions.

Solid dispersions of glimepiride, belonging to the sulfonylurea group of antidiabetic drugs, and poly(ester amide) hyperbranched polymers of different chemical compositions were prepared in order to improve glimepiride's poor water solubility. X-ray powder diffraction results show that glimepiride is in noncrystalline form, indicating that drug molecules are molecularly dispersed within the amorphous hyperbranched polymers. Nuclear magnetic resonance spectroscopy and Fourier transform-infrared spectroscopy results reveal the complex formation between the glimepiride drug and the particular hyperbranched polymer, which was confirmed also by quantum chemical calculations. The complex is stabilized by a hydrogen-bond interaction between the NH group of the sulfonylurea segment of glimepiride and the carbonyls of the amide and ester bonds of the hyperbranched polymers. The slightly acidic proton of the NH group of the sulfonylurea segment of glimepiride is also involved in an interaction with the tertiary amino functional groups of the hyperbranched polymer. As a consequence, the loading capacity is higher for the hyperbranched polymer with the tertiary amino groups. Owing to a complex formation between glimepiride and a particular hyperbranched polymer, glimepiride's water solubility and its dissolution rate are considerably improved relative to the pure glimepiride drug.

Hyperbranched poly(esteramides) as solubility enhancers for poorly water-soluble drug glimepiride.

The aim of this work was to study the feasibility of using hyperbranched polymers with highly branched structure and a large number of functional groups as solubilization enhancers for poorly water-soluble drugs. Antidiabetic drug glimepiride was used as a model drug and commercially available hyperbranched poly(esteramide)s as drug carriers. The results of in vitro dissolution studies showed significantly enhanced aqueous-solubility of glimepiride in the form of solid dispersions with hyperbranched poly(esteramide)s as compared to pure glimepiride in crystalline or amorphous form. The results of IR spectroscopic measurements revealed that improved solubility is a consequence of a complex formation between glimepiride and hyperbranched polymer. HB poly(esteramide)s with carbonyls of ester (O)-C=O and amide (N)-C=O groups serve mainly as a source of proton acceptor groups to which NH groups of glimepiride establish hydrogen bonds. Due to complex formation, glimepiride is within solid dispersions with HB polymers amorphous up to concentration of 5% (w/w) as revealed by X-ray powder diffraction measurements. Above this limit, glimepiride crystallizes as a separate phase during solvent evaporation.

Novel pyrazinone and pyridinone thrombin inhibitors incorporating weakly basic heterobicyclic P(1)-arginine mimetics.

The design, synthesis and biological activity of new thrombin inhibitors with a pyridinone or pyrazinone core and different heterobicyclic P(1) arginine side-chain mimetics are described. The arginine side-chain mimetics used in this study are (+/-)-4,5,6,7-tetrahydro-2H-indazol-5-ylmethanamine and both enantiomers thereof, (+/-)-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine and the corresponding R enantiomer. Compound 25, the most potent in the series of pyrazinone inhibitors, exhibited a K(i) of 41 nM in vitro and high selectivity against trypsin and factor Xa.