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Publication Date: 2010-Jul-28
Document File: 4 page(s) / 43K

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The Prior Art Database

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FORMULATION CONTAINING a thienopyridine antiplatelet prodrug

2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (PG), is a thienopyridine antiplatelet prodrug for the prevention of atherothrombotic events in patients with acute coronary syndromes, including unstable angina and myocardial infarction.

The aim of our work was to prepare a pharmaceutical composition comprising PG or its pharmaceutically acceptable salts as the active pharmaceutical ingredient, prepared in the absence of water. Prolonged exposure of the PG to air and moisture result in some chemical degradation of the active pharmaceutical ingredient. It has been found out that the stability problem can be solved by using a dry technological processes (i.e. processed in the absence of water, preferably in the absence of a solvent). The solvent free method can be a direct compression method or a solvent free granulation method such as roller compaction, slugging, melt extrusion or melt granulation.

Tablets were produced by direct compression method by mixing the active ingredient PG (2-8 %), a lactose-free dilluent e.g. microcrystalline cellulose, mannitol, xylitol or any mixture thereof (70-90%), optionally an acidic solubility enhancer like. fumaric acid, citric acid, adipic acid, succinic acid (0.1-5%), a surfactant e.g. sodium lauryl sulphate or different types of poloxamers (0.1-3%) and a disintegrant e.g. croscarmelose sodium, sodium starch glycolate, crospovidone or any mixture thereof (0.5-15%) in a conic or high-shear mixer. Finally, a lubricant e.g. magnesium stearate or sodium stearyl fumarate (0.1-3%) was admixed to obtain the compression mixture which was compressed into round or oval tablets on an automatic rotary compressing machine using a main compression pressure between 2-25 kN. Alternatively, tablets could be produced via dry granulation step (roller compaction or slugging), where PG, a part of the diluent, part of the disintegrant and optionally part of lubricant were mixed in appropriate mixer and dry compacted on roller compactor. The obtained ribbons were milled and sieved to obtain a granulate with desired particle size distribution. The rest of diluent and disintegrant were admixed to the granulate obtained by dry granulation to prepare a homogenous mixture. Finally, the rest of lubricant was admixed to obtain homogeneous mixture. The obtained homogenous mixture was compressed into tablets. In one of the embodiments the directly compressed or dry granulated tablet composition comprised 10 mg of PG, 30 – 50 mg of microcrystalline cellulose, 100 – 130 mg of xylitol or mannitol, 2-4 mg of fumaric acid, 1-3 mg of sodium lauryl sulphate, 7 – 9 mg of crospovidone or croscarmelose sodium and 1-3 mg of magnesium stearate. In a second variety, the directly compressed or dry granulated tablet composition comprised 10 mg of PG, 90 – 100 mg of microcrystalline cellulose, 70 - 90 mg of xylitol or mannitol, 2-4 mg of fuma...