Process of manufacture of novel drug delivery system: multilayer tablet composition of thiazolidinedione and biguanides

A bi-layered pharmaceutical dosage form for once a day administration comprising,

• a) a first layer comprising granules of at least one non-biodegradable inert polymer and a biguanide, or a pharmaceutically acceptable salt thereof, of particle size less than 100 microns for pH independent prolonged in-vitro release of the biguanide or a pharmaceutical acceptable salt thereof, wherein the non-biodegradable inert polymer is present in an amount of at least 35% by weight of biguanide in the dosage form;
• and
• b) a second layer for immediate release comprising (i) one or more active pharmaceutical ingredients, or pharmaceutical acceptable salts thereof, selected from thiazolidinediones, sulfonyl ureas, alpha-glucosidase inhibitors, aldose reductase inhibitors, statins squalene synthesis inhibitors, fibrates, angiotensin converting enzymes inhibitors, and LDL catabolism enhancers and (ii) a non-biodegradable inert polymer;
• wherein the content of non-biodegradable inert polymer in the second layer is not more than 1.2% by weight of the second layer, and the dosage form provides monophasic prolonged release of the biguanide.

A method of treating diabetes in a mammal in need thereof, comprising administering a bi-layer tablet dosage form to the mammal once a day, wherein the tablet dosage form comprises,

• a) a first layer comprising granules of at least one non-biodegradable inert polymer and a biguanide, or a pharmaceutically acceptable salt thereof, of particle size less than 100 microns for pH independent prolonged in-vitro release of the biguanide or pharmaceutical acceptable salts thereof, wherein the non-biodegradable inert polymer is present in an amount of at least 35% by weight of biguanide in the dosage form;
• and
• b) a second layer for immediate release comprising (i) one or more active pharmaceutical ingredients, or pharmaceutical acceptable salts thereof, selected from thiazolidinediones, sulfonyl ureas, alpha-glucosidase inhibitors, aldose reductase inhibitors, statins, squalene synthesis inhibitors, fibrates, angiotensin converting enzymes inhibitor inhibitors, and LDL catabolism enhancers and (ii) a non-biodegradable inert polymer;
• wherein the content of non-biodegradable inert polymer in the second layer is not more than 1.2% by weight of the second layer, and the dosage form provides monophasic prolonged release of the biguanide.