Title of Invention	"A PROCESS FOR THE PREPARATION OF STABLE TABLETS OF FOSINOPRIL SODIUM"
Abstract	The present invention relates to a process for the preparation of stable tablets of fosinopril sodium with or without diuretic(s).

Full Text

The present invention relates to a process for the preparation of stable tablets of fosinopril sodium with or without diuretic(s). Fosinopril sodium is an angiotensin converting enzyme inhibitor. Fosinopril sodium alone or in combination with thiazide diuretics is indicated for the treatment of hypertension. Fosinopril sodium is also used as an adjunctive therapy when added to conventional therapy including diuretics with or without digitalis for the management of heart failure. Fosinopril sodium has low bulk density, poor flow property and sticking tendency to metal surfaces. Combination of such characteristics makes processing of tablets highly problematic, demanding the incorporation of suitable lubricants and glidants in the formulation. Added to these, the hydrolytic nature of fosinopril sodium further complicates the selection of other inert pharmaceutical excipients, particularly lubricants. Conventional fosinopril sodium tablets were prepared using magnesium stearate as lubricant. However, these tablets were highly moisture sensitive and only marginally stable. Therefore, in order to achieve reasonable shelf lives, these required sophisticated protective packaging. United States Patent Number 5,006,344 discloses that by eliminating magnesium stearate as the lubricant during the tabletting of fosinopril sodium and instead employing either sodium stearyl fumarate or hydrogenated vegetable oil tablets with improved stability were obtained. In the present invention, we have discovered that use of talc in combination with colloidal silicon dioxide as lubricant during the tableting process, surprisingly increase the stability of the tablet and provide reasonably long shelf lives. Therefore, the present invention relates to process for preparation of stable tablet by wet or dry granulation or direct compression as herein described comprising fosinopril sodium alone or in combination with a diuretic as herein described, and other pharmaceutically acceptable excipients selected from a group consisting of lubricant, diluent, disintegrant, binder, coloring and flavoring agent as herein described wherein the lubricant is a combination of talc and colloidal silicon dioxide in a concentration range of 0.25-5% w/w and 0.25 to 10% w/w of the tablet respectively. Conventionally colloidal silicon dioxide and talc are used as glidants but to our surprise the combination of two showed excellent lubricant properties. The tablets thus prepared by the process of the present invention had improved shelf stability. Colloidal silicon dioxide or talc used individually in higher concentrations may also provide proper lubrication during processing of tablets and stability during storage. However, higher concentrations of lubricant would increase the tablet weight and may also exceed the permissible daily intake. Further, higher concentration of lubricant may also hamper the bioavailability of drug from the tablets. The combination of colloidal silicon dioxide and talc on the other hand has synergistic action and is therefore effective in reasonably low amounts. When used in combination the amount of talc may vary from about 0.25% to about 5% by weight, whereas that of colloidal silicon dioxide may vary from about 0.25% to about 10% by weight with respect to the total weight of tablet. Present invention is further evident from the stability results generated at 40°C and 75% relative humidity over a time period of three months and at 60°C for one week (Table 1 &2). For the purpose of the present invention the tablets may contain fosinopril sodium alone or in combination with diuretics. Suitable diuretics include chlorthalidone, thiazide diuretics, furosemide, triameterene, amiloride, spironolactone, and salts thereof. Thiazide diuretics may be selected from the group consisting of bendroflumethazide, benzthiazide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methylclothiazide, polythiazide, trichlormethiazide, chlorthalidone, indapamide, metolazone and quinethazone. In addition to the actives (fosinopril sodium and optional diuretic), lubricants (talc and colloidal silicon dioxide), tablets prepared according to present invention may contain other pharmaceutically acceptable excipients such as diluents, disintegrants, binders, coloring agents and flavoring agents. Diluents of the present invention may be selected from calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, cellulose- microcrystalline, cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners and mixtures thereof. Binders of the present invention may be selected from methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arable, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, alginate and the like. Disintegrant of the present invention may be selected from low substituted hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, croscarmellose sodium A-type (Ac-di-sol), starch, crystalline cellulose, hydroxypropyl starch, partly pregelatinized starch and the like. Coloring agents and flavoring agents may be selected from any FDA approved color and flavor which are compatible with all the other ingredients of the tablet. The fosinopril sodium tablets of this invention can be prepared by conventional tablet making techniques such as wet granulation, dry granulation and direct compression. For the wet granulation process, the fosinopril sodium alone or in combination with diuretics are blended with the diluent and disintegrant. This blend is then granulated with a solution of the binder in a solvent. The granules are then dried and sieved. The dried granules are mixed with talc and colloidal silicon dioxide and compressed into tablets. In the direct compression process, the fosinopril sodium alone or in combination with diuretics is blended with the diluent, disintegrant and binder. The blend is then mixed with talc and colloidal silicon dioxide and compressed into tablets. For dry granulation process, fosinopril sodium alone or in combination with diuretics is blended with diluent, binder and disintegrant and compressed to form slugs. These slugs are milled to form granules. These granules are then mixed with talc and colloidal silicon dioxide and compressed into tablets. The invention is further illustrated by the following examples but they should not be construed as limiting the scope of the invention anyway. Example 1 (Table Removed) Process: 1. Fosinopril sodium is blended with lactose, microcrystalline cellulose and a part of crospovidone. 2. The above blend is granulated with povidone solution in isopropyl alcohol. 3. The granules were dried at 60°C. 4. The dried granules were sieved and blended with crospovidone, talc and colloidal silicon dioxide and compressed into tablets. Example 2 (Table Removed) Process: Same as for Example-1 Example 3 (Table Removed) Process: Same as for Example-1 Fosinopril tablets prepared as per Example-1 were tested for the initial amount of fosinopril sodium using HPLC. These samples were then kept at 40°C and 75% relative humidity for three months and at 60°C for one week. Amount of fosinopril at the end of first, second and third month was measured. Table-1 Stability results generated at 40°C and 75% relative humidity over a time period of three months. Table-2 Stability results generated at 60°C for one week (Table Removed) WE CLAIM : 1. A process for preparation of stable tablet by wet or dry granulation or direct compression as herein described comprising fosinoprll sodium alone or In combination with a diuretic as herein described, and other pharmaceutlcally acceptable exclplents selected from a group consisting of lubricant, diluent, dislntegrant, binder, coloring and flavoring agent as herein described wherein the lubricant is a combination of talc and colloidal silicon dioxide in a concentration range of 0.25-5% w/w and 0.25 to 10% w/w of the tablet respectively. 2. The process according to claim 1 wherein the diuretics may be selected from chlorthalidone, thiazide diuretics, furosemide, triameterene, amilorlde, spironolactone, and salts thereof. 3. The process according to claim 2 wherein the thiazide diuretic are selected from the group consisting of bendroflumethazide, benzthiazide, bendroflumethlazlde, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methylclothlazlde, polythiazlde, trichlormethiazlde, chlorthalidone, indapamide, metolazone and quinethazone. 4. The process according to claim 3 wherein the thiazide diuretic Is hydrochlorothiazide. 5. The process according to claim 1 wherein the diluent may be selected from group consisting of calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribaslc, calcium sulfate, cellulose-mlcrocrystalllne, cellulose powdered, dextrates, dextrins, dextrose exclplents, fructose, kaolin, lactltol, lactose, mannltol, sorbitol, starch, starch pregelatinlzed, sucrose, sugar compressible, sugar confectioners and the like. 6. The process according to claim 5 wherein the diluent is lactose. 7. The process according to claim 1 wherein the binder may be selected from methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arable, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, alginate and the like. 8. The process according to claim 7 wherein the binder is povidone. 9. The process according to claim 1 wherein the disintegrant may be selected from low substituted hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, croscarmellose sodium, starch, crystalline cellulose, hydroxypropyl starch, partly pregelatinized starch and the like. 10.The process according to claim 9 wherein the disintegrant is croscarmellose sodium. 11. A process for preparation of stable tablet comprising fosinopril sodium as described and illustrated by the examples herein.

Documents:

814-del-2002-abstract.pdf

814-del-2002-claims cancelled.pdf

814-del-2002-claims.pdf

814-del-2002-complete specification(granted).pdf

814-del-2002-correspondence-others.pdf

814-del-2002-correspondence-po.pdf

814-del-2002-description (complete).pdf

814-del-2002-form-1.pdf

814-del-2002-form-2.pdf