Title of Invention

A PROCESS OF STABILIZATION OF A RAMIPRIL AND PHARMACEUTICAL COMPOSITIONS THEREOF

Abstract

A process for the preparation of stabilized armorial compositions, wherein said process comprises; dissolving ramipril in an aqueous solution or dispersion of a weakly basic agent to convert ramipril into a salt/complex form; incorporating a binder into this solution to obtain a blend; granulating said blend; drying the granules at 60°C; grading the said blend; mixing with other pharmaceutically acceptable auxiliaries and compressing the resulting blend in to tablets or filled into capsules- 2. The process as claimed in claim 1, wherein said solution or dispersion of stabilized ramipril is used as a granulating agent for various auxiliaries to obtain oral solid dosage form. 3. The process as claimed in claim, wherein said weakly basic agents are selected from alkali metal compounds. 4. The process as claimed in claim and 3, wherein said alkali metal compounds are selected from sodium bicarbonate, sodium carbonate, sodium lauryl sulphate, potassium bicarbonate or potassium carbonate. 5. The process as claimed in claim 1, wherein said weakly basic agent is an alkaline earth metal compound. 6. The process as claimed in claim 1 and 5, wherein said alkaline earth metal compound i5 selected from the group comprising of magnesium hydroxide, magnesium oxide or calcium carbonate. 7. The process as claimed in claim 1, wherein said alkali metal compound is more preferably sodium bicarbonate. 8. The process as claimed in claim 7, wherein the concentration of said sodium bicarbonate is 0.25-6 parts by weight of ramipril. 9. The process as claimed in claim 8, wherein the concentration of said sodium bicarbonate is 1-1.5 parts by weight of ramipril. 10. The process as claimed in claim 1, wherein said weakly basic agent is a copolymer based on polymethacrylic esters (Eudragit E RTM).

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION [See section 10; rule 13] "A PROCESS OF STABILISATION OF A RAMIPRIL AND PHARMACEUTICAL COMPOSITIONS THEREOF" (a) INDOCO REMEDIES LIMITED, (b) Indoco House, 166 C.S.T. Road, Santacruz (East), MUMBAI-400098, Maharashtra, India (c) Indian Company incorporated under the Companies Act 1956 The following specification describes the nature of the invention and the manner in which it is to be performed: Field of invention: The present invention relates to a process for the preparation of stabilized medicinal substances for the class of ACE inhibitors. More particularly the present invention relates to stabilized solid pharmaceutical composition in the form of tablets or capsules comprising Ramipril as active ingredient. Background of invention: Inhibitors of Angiotensin converting enzyme (ACE) are valuable medicinal agents used to control high blood pressure of various etiologies. 2-[N-[(S)-l-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(lS, 3S, 5S)-2-azabicycIo [3.3.0]-octane-3-caboxylic acid (ramipril) belongs to this class of medicinal agents. Ramipril is administered orally, mainly as solid dosage forms eg; tablets or capsules, for control of high blood pressure. It has been found that ramipril shows a tendency to be unstable in pharmaceutical formulations depending on the auxiliaries used, the manufacturing process and storage conditions. Decomposition is increased by increasing temperature and moisture. It has also been found that a significant cause of decomposition is the mechanical stress associated with the manufacturing process, especially when the active substance is present in a mixture with auxiliaries. US Pat. No. 5,151,433 discloses a stable pharmaceutical composition of ramipri! which comprises coating ramipril agglomerates with a polymeric protective coating. Buffers are mixed either with these coated agglomerates of ramipril or added to the coating dispersion to obtain the required pH of the formulation. However this process involves the use of a fluidized bed coaler or any such process that will ensure a uniform film over the ramipril drug particles, thus making it a lengthy and expensive process. US Pat. No. 6,790,861 discloses use of acid donors such as glycine hydrochloride and glutamic hydrochloride as stabilizers for Spirapril, Ramipril and other ACE inhibitors. These are again expensive excipients. US Pat. No. 6,296,871 describes the use of maleic acid or an edible dessicant as one of the excipients to reduce the rate of degradation of an ACE inhibitor enalapril maleate. Method for preparation of a stable formulation of enalapril maleate by mixing ACE inhibitor with an alcohol to form an alcoholic dispersion of enalapril maleate; mixing a metal compound with an alcoholic dispersion of a ACE inhibitor mixture and mixing the said alcoholic dispersion and metal compound is disclosed in US 2003225124. However, alcohol based formulations have many disadvantages such as it requires flame proof manufacturing facility for industrial application; which leads to increase in costs for facility creation; residual solvent needs to be monitored and safety measures to be taken by person to prevent inhalation of solvent vapors during the manufacturing processes. The present invention is provided to overcome the disadvantages of the prior art by preparing the stabilized Ramipril compositions by using the simple, cost effective and non hazardous manufacturing process. Objective of the invention: It is an object of the present invention to provide a simple, cost effective and industrially viable manufacturing process for the preparation of stable solid pharmaceutical composition in the form of tablets or capsules for the class of ACE inhibitors. Summary of the invention: A process for the preparation of stabilized medicinal substance for the class of ACE inhibitors wherein said process comprises; dissolving the ACE inhibitor in an aqueous solution or dispersion of a weakly basic agent thereby converting ramipril into a salt or complex; incorporating a binder into this solution; granulating said blend; drying the granules at 60°C; grading the said blend; mixing with other pharmaceutically acceptable excipients and compressing the resulting blend in to tablets or filled into capsules. Stabilized pharmaceutical oral solid dosage forms, comprising ACE inhibitor, Ramipril, dissolved or dispersed in a weakly basic agent along with various auxiliaries is disclosed. Detailed description: The present invention provides simple cost effective processes for the preparation of stable oral pharmaceutical compositions of ramipril. The pharmaceutical compositions are solid oral dosage forms comprising ramipril as active ingredient and other pharmaceutical excipients that are well known to persons skilled in the art. Processes for stabilization of medicinal substances, using Ramipril as example, has been described in this invention. The various embodiments of this invention are described herein below. The stabilization processes of the present invention involves preparation of a simple aqueous solution or dispersion of ramipril by dissolving it in an aqueous solution or a dispersion of a weakly basic agent, thereby converting ramipril into a salt or complex and then granulated using various auxiliaries followed by compressing the resulting blend into a tablet or filled into a hard gelatin capsule. In a preferred embodiment Ramipril was converted into salt/complex form by dissolving/dispersing it into a weakly basic agent. A binder is incorporated into this solution/suspension which is then used as a granulating agent for various diluents to 4 give granulates. Granulation is carried out in a conventional granulator. This granulate is dried at about 60°C, graded, mixed with disintegrants, glidants and lubricants. The resulting blend is then compressed into tablets or filled into hard gelatin capsules. The weakly basic agent is selected from alkali metal compounds and alkaline earth metal compounds. Alkali metal compounds are selected from sodium bicarbonate, sodium carbonate, sodium lauryl sulphate, potassium bicarbonate and potassium carbonate, preferably sodium bicarbonate. Alkaline earth metal compounds are selected from magnesium hydroxide, magnesium oxide and calcium carbonate. The weakly basic agent is also a copolymer based on polymethacrylic esters (Eudragit E RTM) or carbomer. The concentration of said sodium bicarbonate is 0.25-6 parts by weight of ramipril, and more preferablyl-1.5 parts by weight of ramipril. The auxiliaries are selected from the group comprising of diluents, carriers, binders, disintegrating agents, glidants, lubricants, colorants, pigments antioxidants and any such substance known in the art. Diluents used are selected from the group comprising of lactose, starch, mannitol, celluloses and any such substance known in the art. Binders used are selected from the group comprising of cellulose derivatives, carbomers, polyvinylpyrollidone, acrylates, starch, gelatin and any such substance known in the art. Disintegrants used are selected from the group comprising of cellulose derivatives, croslinked povidone, starch, croscarmellose sodium, sodium starch glycollate and any such substance known in the art. Glidants and lubricants are selected from the group comprising of talc, magnesium stearate, calcium stearate, sodium stearyl fumarate, zinc stearate, glyceryl monostearate, stearic acid, hydrogenated vegetable oils, waxes and any such substance known in the art. The carriers are selected from the group comprising of cyclodextrins. The stabilized product thus obtained by this process does not require any protective polymeric coating to be formed around the drug particles for stabilization and also resists degradation to any compressional force or any other mode of degradation during tabletting process. In another embodiment, the salt of Ramipril prepared above is further converted into cyclodextrin complex to further enhance its stability, p-cyclodextrin is dissolved in the Ramipril salt solution. The resulting complex can be adsorbed on to auxiliaries to give a directly compressible blend or can be used in a wet granulation formula. Auxilliaries can be used for example lactose, mannitol, microcrystalline cellulose, starch, dibasic calcium phosphate, suitable disintegrants, glidants and lubricants. In another embodiment, Ramiril is intimately blended with metal hydroxides or oxides, such as aluminium hydroxide or magnesium hydroxide, magnesium oxide or with alkaline earth metal silicates. The resulting mixture is granulated with a suitable binder. These granules are used in a directly compressible blend to give a tablet dosage form. The alkaline earth metal hydroxides/ silicates provide a suitable environment to maintain stability of the drug even under the action of mechanical stress. In another embodiment, Ramipril is complexed with ionexchange resin. This complex is then used to formulate a tablet dosage form. Complexation of Ramipril with ionexchange resin improves the stability of the active substance even under compressional force. Ramipril is complexed with Methacrylic acid copolymer. The dispersion containing the said complex is used as a granulating agent for the excipient blend to produce a tablet formulation. 6 Yet, in another embodiment, Ramipril is dispersed in carbopol gel whose pH is adjusted between 6-8 with alkaline organic / inorganic bases. This gel embedded stabilized Ramipril is further used to prepare a tablet dosage form. The stabilized products thus obtained by these processes does not require any protective polymeric coating to be formed around the drug particles for stabilization and also resists degradation to any compressional force or any other mode of degradation during tabletting process. Moreover, ramipril being a potent drug is better distributed in the blend while in solution form as compared to agglomerates, thereby ensuring uniform distribution of ramipril in the pharmaceutical dosage units. The present invention is further illustrated in detail by way of the following examples: Example 1: The weakly basic agent sodium bicarbonate was dissolved in Purified water. Ramipril was added to it and stirred to give a clear solution. Hydroxypropyl methylcellulose was dispersed in this solution. This solution was adsorbed onto a mixture of auxiliaries viz- lactose, mannitol and microcrystalline cellulose. The wet mass was granulated, dried at 60°C, graded and mixed with crospovidone, talc and magnesium stearate. The lubricated blend was then compressed into tablets. Content of ramipril in the stabilized formulations (Formula 1) vs. conventional tablets prepared by direct compression (Formula 2) and tablets prepared by coating ramipril with hydroxypropyl methyl cellulose (Formula 3) and the stability of the said formulations were determined under various stress conditions and the data is given below. Stability data: Ingredients Formula 1 Formula 2 Formula 3 (mg/tab) (mg/tab) (mg/tab) Ramipril (with 5% ovg) 1.32 1.32 1.32 Lactose 21.16 -— — Mannitol 8.50 -— — Microcrystalline cellulose 9.33 73.12 73.03 Sodium bicarbonate 1.32 0.66 — Hydroxypropyl methylcellulose 0.5 -__ 0.09 Colloidal anhydrous silica — 0.2 0.2 Crospovidone 0.965 1.5 1.5 Talc 1.25 2.4 2.4 Magnesium stearate 0.225 0.8 0.8 Colour tartrazine 0.25 ---- — Initial assay values 104.50% 81.00% 73.93%) (non ag coating) 79.55%o (aq coating) Samples heated at 90°C for Ihour 100.64% 5.6.80%) 46.25%) 43.54% 40°C/75%RH,6M 98.45% From the above data it can be concluded that stabilized formulations retain their potency under stress conditions viz. mechanical stress and temperature/ humidity effects, when packed in aluminium pack. Example 2: The weakly basic agent sodium bicarbonate was dissolved in Purified water. Ramipril was added to it and stirred to give a clear solution. Carbomer (0.175 mg/tab) was dispersed in this solution. This solution was adsorbed onto a mixture of auxiliaries viz. lactose, mannitol and microcrystalline cellulose. The wt;t mass was granulated, dried at 60°C, graded and mixed with crospovidone, talc and magnesium stearate. The lubricated blend was then compressed into tablets. 8 Example 3: The weakly basic agent, potassium bicarbonate (1.32 mg/tab) was dissolved in Purified water. Ramipril was added to it and stirred to give a clear solution. This solution was adsorbed onto a mixture of auxiliaries viz. lactose, mannitol and microcrystalline cellulose. The wet mass was granulated, dried at 60°C, graded and mixed with crospovidone, talc and magnesium stearate. The lubricated blend was then compressed into tablets. Example 4: The weakly basic agent, sodium carbonate (1.32 mg/tab) was dissolved in Purified water. Ramipril was added to it and stirred to give a clear solution. This solution was adsorbed onto a mixture of auxiliaries viz. lactose, mannitol and microcrystalline cellulose. The wet mass was granulated, dried at 60°C, graded and mixed with crospovidone, talc and magnesium stearate. The lubricated blend was then compressed into tablets. Example 5: The weakly basic agent, sodium lauryl sulphate (1.32 mg/tab) was dissolved in Purified water. Ramipril was added to it and stirred to give a clear solution. This solution was adsorbed onto a mixture of auxiliaries viz. lactose, mannitol and microcrystalline cellulose. The wet mass was granulated, dried at 60°C, graded and mixed with crospovidone, talc and magnesium stearate. The lubricated blend was then compressed into tablets. Example 6: The weakly basic agent, a copolymer based on polymethacrylic esters (Eudragit E RTM) (1.32 mg/tab) was dispersed in Purified water. Ramipril was added to it and stirred to give a milky white dispersion. This dispersion was adsorbed onto a mixture of auxiliaries viz. lactose, mannitol and microcrystalline cellulose. The wet mass was granulated, dried at 60°C, graded and mixed with crospovidone, talc and magnesium stearate. The lubricated blend was then compressed into tablets. 9 Example 7; The weakly basic agent sodium bicarbonate was dissolved in Purified water. Ramipril was added to it and stirred to give a clear solution. Betacyclodextnn (3.59 mg/tab) was dispersed in this solution. This solution was adsorbed onto a mixture of auxiliaries viz. lactose, mannitol and microcrystalline cellulose. The wet mass was granulated, dried at 60°C, graded and mixed with crospovidone, talc and magnesium stearate. The lubricated blend was then compressed into tablets. Example 8: The weakly basic agent sodium bicarbonate was dissolved in Purified water. Ramipril was added to it and stirred to give a clear solution. Hydroxypropyl betacyclodextnn (4.35 mg/tab) was dispersed in this solution. This solution was adsorbed onto a mixture of auxiliaries viz. lactose, mannitol and microcrystalline cellulose. The wet mass was granulated, dried at 60CC, graded and mixed with crospovidone, talc and magnesium stearate. The lubricated blend was then compressed into tablets. The initial assay values and after heating at 90°C for 1 hr are given below. Example Initial assay values Heating at 90°C for 1 hour Example 2 103.45% 103.45% Example 3 100.48% 100.48% Example 4 101.73% 101.10% Example 5 102.98% 97.54% Example 6 99.95% 98.75% Example 7 106.96% 105.58% Example 8 103.28% 102.26% From the above table it can be concluded that initial assay values of ramipril tablets prepared by the present invention are promising as compared to the direct compression formula. Stability of these formulations on keeping is being studied. We Claim: 1. A process for the preparation of stabilized ramipril compositions, wherein said process comprises; dissolving ramipril in an aqueous solution or dispersion of a weakly basid agent to convert ramipril into a salt/complex form; incorporating a binder into this solution to obtain a blend; granulating said blend; drying the granules at 60°C; grading the said blend; mixing with other pharmaceutically acceptable auxiliaries and compressing the resulting blend in to tablets or filled into capsules- 2. The process as claimed in claim 1, wherein said solution or dispersion of stabilized ramipril is used as a granulating agent for various auxiliaries to obtain oral solid dosage form. 3. The process as claimed in claiml, wherein said weakly basic agents are selected from alkali metal compounds. 4. The process as claimed in claiml and 3, wherein said alkali metal compounds are selected from sodium bicarbonate, sodium carbonate, sodium lauryl sulphate, potassium bicarbonate or potassium carbonate. 5. The process as claimed in claim 1, wherein said weakly basic agent is an alkaline earth metal compound. 6. The process as claimed in claim 1 and 5, wherein said alkaline earth metal compound i5 selected from the group comprising of magnesium hydroxide, magnesium oxide or calcium carbonate. 7. The process as claimed in claim 1, wherein said alkali metal compound is more preferably sodium bicarbonate. 8. The process as claimed in claim 7, wherein the concentration of said sodium bicarbonate is 0.25-6 parts by weight of ramipril. 9. The process as claimed in claim 8, wherein the concentration of said sodium bicarbonate is 1-1.5 parts by weight of ramipril. 10. The process as claimed in claim 1, wherein said weakly basic agent is a copolymer based on polymethacrylic esters (Eudragit E RTM). 11. The process as claimed in claim 2,wherein said auxiliaries are selected from the group comprising of diluents, carriers, binders, disintegrating agents, glidants, lubricants, colorants, pigments and antioxidants. 12. The process as claimed in claim 1 and 11, wherein said diluents are selected from the group comprising of lactose, starch, mannitol, and celluloses. 13. The process as claimed in claim 1 and 11,wherein said binders are selected from the group comprising of cellulose derivatives, carbomers, polyvinylpyrollidone, acrylates, starch and gelatin. 14. The process as claimed in claim land 11 wherein said disintegrating agent are selected from the group comprising of cellulose derivatives, crosslinked povidone, starch, croscarmellose sodium and sodium starch glycollate. 15. The process as claimed in claim 1 and 11 wherein said glidants and lubricants are selected from the group comprising of talc, magnesium stearate, calcium stearate, sodium stearyl fumarate, zinc stearate, glyceryl monostearate, stearic acid, and hydrogenated vegetable oils or mixture thereof. 16. The process as claimed in claim 1 and 11, wherein said carriers are selected from the group comprising of cyclodextrins. 17. Stabilized pharmaceutical oral solid dosage forms, comprising ACE inhibitor, Ramipril in the form of salt/complex, dissolved or dispersed in a weakly basic agent along with suitable pharmaceutical excipients to ensure uniform drug distribution; wherein said dosage forms are resistant to degradation and are substantially free from protective polymeric coating. 18. The stabilized dosage forms as claimed in claim 17, wherein, the solution or dispersion of said ramipril salt/complex is used as a granulating agent for suitable pharmaceutical excipeints to obtain said oral solid dosage form. 19. The stabilized dosage forms as claimed in claim 17, wherein said weakly basic agent is an alkali metal compound. 20. The stabilized dosage forms as claimed in claim 19, wherein said alkali metal compound is selected from the group comprising of sodium bicarbonate, sodium carbonate, sodium lauryl sulphate, potassium bicarbonate and potassium carbonate. 21. The stabilized dosage forms as claimed in claims 19 and 20, wherein said alkali metal compound is more preferably sodium bicarbonate. 22. The stabilized dosage forms as claimed in claim 21, wherein the concentration of said sodium bicarbonate is 0.25-6 parts by weight of ramipril. 23. The stabilized dosage forms as claimed in claim 21, wherein the concentration of said sodium bicarbonate is more preferably 1-1.5 parts by weight of ramipril. 24. The stabilized pharmaceutical composition as claimed in claims 17 and 18, wherein said pharmaceutical excipients are selected from the group comprising of diluents, carriers, binders, disintegrating agents, glidants, lubricants, colorants, pigments and antioxidants. 25. The stabilized dosage forms as claimed in claim 24, wherein said diluents are selected from the group comprising of lactose, starch, mannitol and celluloses. 26. The stabilized dosage forms as claimed in claim 24, wherein said binders are selected from the group comprising of cellulose derivatives, carbomers, polyvinylpyrollidone, acrylates, starch and gelatin or mixture thereof. 27. The stabilized dosage forms as claimed in claim 24, wherein said disintegrating agents are selected from the group comprising of cellulose derivatives, croslinked povidone, starch, croscarmellose sodium and sodium starch glycollate or mixture thereof. 28. The stabilized dosage forms as claimed in claim 24, wherein said glidants and lubricants are selected from the group comprising of talc, magnesium stearate, calcium stearate, sodium stearyl fumarate, zinc stearate, glyceryl monostearate, stearic acid and hydrogenated vegetable oils or mixture thereof. 29. The stabilized dosage forms as claimed in claim 24, wherein said carriers are selected from the group comprising of cyclodextrins.

Documents:

1115-mum-2003-cancelled pages(04-01-2007).pdf

1115-mum-2003-claims(granted)-(04-01-2007).doc

1115-mum-2003-claims(granted)-(04-01-2007).pdf

1115-mum-2003-correspondence(06-07-2006).pdf

1115-mum-2003-correspondence-(ipo)-(26-10-2006).pdf

1115-mum-2003-form 1(04-01-2007).pdf

1115-mum-2003-form 1(21-10-2003).pdf

1115-mum-2003-form 18(04-10-2005).pdf

1115-mum-2003-form 2(granted)-(04-01-2007).doc

1115-mum-2003-form 2(granted)-(04-01-2007).pdf

1115-mum-2003-form 26(02-09-2003).pdf

1115-mum-2003-form 3(21-10-2003).pdf

1115-mum-2003-form 5(21-10-2003).pdf