Title of Invention	PHARMACEUTICAL FORMULATION CONTAINING ACE INHIBITOR
Abstract	ABSTRACT: The present invention relates to stable pharmaceutical compositions for the oral administration of ACE inhibitor(s). It also relates to the novel process of preparing the stable pharmaceutical composition for the oral administration of the ACE inhibitor(s).

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FIELD OF INVENTION The present invention relates to stable pharmaceutical compositions comprising angiotensin converting enzyme (ACE) inhibitor(s), which are susceptible to degradation, and processes for the preparation thereof. More particularly, the invention relates to the preparation of a stable pharmaceutical composition comprising ramiprii and pharmaceutical iy acceptable excipients and its process of preparation. BACKGROUND OF THE INVENTION AND RELATED PRIOR ART Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of the common general knowledge in the field. Angiotensin Converting Enzyme (ACE) inhibitors, which are useful as anti¬hypertensives, are susceptible to certain types of degradation. ACE inhibitors such as ramiprii, quinapril, enalapril, spirapril, lisinopril, benazepril and structurally related drugs can undergo cyclization via internal nucleophilic attack to form substituted diketopiperazines. These drugs can also degrade via hydrolysis (of the side-chain ester group) and oxidation, to form products having unwanted coloration. It has been found that a significant cause of such degradations can be the mechanical stress associated with the manufacturing process of pharmaceutical composition such as compression and other related processes. The stability of pharmaceutical compositions containing ACE inhibitors can also be negatively influenced by the choice of tabletting auxiliaries and its storage conditions. Ramiprii (2S, 3aS, 6aS)-l[(S)-N- [(S)-l-carboxy- 3-phenylpropyl]alanyl]octahydro cyclopenta[b]pyrrole -2-carboxylic acid, 1-ethyl ester is an important ACE inhibitors. As ramiprii is an unstable molecule, numbers of research activities have been directed towards stabilizing the molecule in the pharmaceutical formulations and thus overcoming the inherent stability problem. US5442008 and US5151433 state that this instability can be influenced by several factors, such as mechanical stress, compression, manufacturing processes, excipients, storage conditions, heat and moisture. Consequently, Ramipril needs special care when formulating into pharmaceutical preparations to minimize the decomposition of Ramipril into degradation products. They disclose a method of making Ramipril formulation by coating the drug with a polymeric coat [3 to 25% polymer w/w of the drug] to form agglomerates and then compressing the agglomerates so formed. US4743450 discloses that stable compositions containing ACE inhibitors can be produced using certain additives as stabilizers. Specifically, this patent discloses that the inorganic salts of metals of Group 1 and 11 of the Periodic Table act as stabilizers of ACE inhibitor containing formulations susceptible to certain types of degradation. US2005202081 discloses use of inert cores which are coated with a seal coat polymer layer. Ramipril is layered upon this coated core and a final film coat is put above the drug layer, thereby preventing direct contact of Ramipril with the excipients in the compressed tablet. Interestingly, this application states that the core should be inert or contain a drug other than Ramipril. Purportedly, this is to prevent Ramipril from degradation due to mechanical stress. The focus of all of the above patents/applications is to provide ramipril composition that prevents the drug from degradation arising from mechanical stress resulting from compression. The inventors have now surprisingly found that stable formulations of ramipril can be prepared wherein ramipril can withstand compression forces without leading to substantial degradation. They have developed a process for making a stable composition, wherein certain part of the ramipril is contained in the core and the rest is coated on to the core, preferably to a compressed core, as a film coat, thereby avoiding degradation induced by mechanical stress. The process can be easily scaled up using the conventional tabletting excipients and suitable coating equipment. OBJECTS OF THE INVENTION It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative. The object of the present invention is to provide a process for the preparation of a stable composition for oral administration of ACE inhibitor(s) comprising a core, preferably a compressed core containing a part of ramipril by weight, and the rest being coated on to the core as a film coat of the same. A further objective of the invention is to provide a process for the preparation of a stable composition for oral administration of ACE inhibitor(s) wherein the process comprises coating a part of the ramipril with a polymer and incorporating the coated ramipril in a core. The core is coated further with a seal/sub-coat and followed by further coating the rest of the ramipril onto the coated core. Optionally the ramipril coated core can be coated with a protective film coat. DETAILED DESCRIPTION INCLUDING PREFERRED EMBODIMENTS OF THE INVENTION: Disclosed herein is a stable pharmaceutical composition for oral administration of ACE inhibitor(s) comprising: i) a core, preferably a compressed core, comprising an ACE inhibitor and pharmaceutical excipients; ii) a seal/sub-coat on the core; and iii) ACE inhibitor coat layered on the seal coat layer. iv) Optionally, a protective film coat on the drug coat layer. The invention also covers a process for the preparation of a stable pharmaceutical composition for oral administration of ACE inhibitor(s) comprising preparing a compressed core of an ACE inhibitor and pharmaceutical excipients, applying a seal/sub coat on the core and disposing a layer of ACE inhibitor dispersion onto the coated core. The drug in the core component may be used uncoated or it may be coated with a polymer/cellulose derivative or commercial film-former. In the preferred embodiment, the active ingredient, for example, an ACE inhibitor, which is susceptible to degradation, is divided into two parts. A part of the total quantity, preferably around 0.01-3% w/w, more preferably around 0. l-l%w/w of the total drug is coated with polymers belonging to the group consisting of cellulose derivatives, gums, polyvinylpyrrolidone derivatives, and starch to form a film coating over the drug particles and then the coated drug particles are mixed with diluent and other additives and compressed to form a tablet core. The above tablet core is provided with a seal/sub-coat in order to prevent the following ACE inhibitor layer coming in direct contact with the tabletting auxiliaries. The remaining other part of the ACE inhibitor, preferably 97.0-99.99%w/w, or more preferably 99.0-99.9%w/w of the total drug in the composition is coated on the tablet core with polymers belonging to the group consisting of cellulose derivatives, gums, polyvinylpyrrolidone derivatives, and starch to form a film coating. The drug coated layer may optionally be further coated with a protective outer film coating layer such as commercially available Opadry® and the like to improve the aesthetic appeal and protect the tablet from the atmospheric humidity and other harsh conditions. The core of the present invention is preferably a compressed core, which could be optionally inert or contain an active ingredient from about 0.01-3%w/w, preferably 0. l-l%w/w. The core may also be a sugar or starch particle such as non-pareil sugar seeds, or the like. The compressed core may comprise diluents and other additives known to the persons skilled in the art such as binders, disintegrants, lubricants and glidants. The compressed core can be prepared by conventional techniques such as direct compression, wet granulation and dry granulation. The ACE inhibitor in the tablet core may be uncoated or coated with polymers belonging to the group consisting of cellulose derivatives, gums, polyvinylpyrrolidone derivatives, and starch. The diluent may be, for example, any pharmaceutically acceptable, non-toxic diluent. Particular examples include lactose, dextrose, sucrose, maltose, microcrystalline cellulose, starch, calcium hydrogen phosphate, mannitol and the like. Binders may be, for example, starch, sugars, gums, low molecular weight hydroxypropyl methylcelluiose, hydroxypropylcellulose or the like. Disintegrant may be, for example, croscarmeilose sodium, crospovidone, sodium starch glycolate, bentonite, sodium alginate, or the like. Lubricants may be, for example, talc, magnesium stearate, calcium stearate, hydrogenated vegetable oils, stearic acid, sodium stearyl fumarate, sodium benzoate or the like. Glidants may be, for example, colloidal silicon dioxide, talc or the like. A seal/sub coat is applied on to the tablet core which separates the tablet core from the ACE inhibitor layer. The seal coat is prepared with the solution or dispersion of the polymers selected from the group of cellulose derivatives, starch, sugars, gums, polyvinylpyrrolidone derivatives, alginate derivatives, zein, shellac, and the like. The solution or the dispersion comprises from about 2% to about 30%w/w of the polymer in the suitable solvent. The solvents for the polymer solution or dispersion are selected from the group consisting of water, isopropyl alcohol, ethanol, acetone, methylene chloride and mixtures thereof. The seal/sub coat may optionally contain plasticizer such as polyethylene glycol, triethylcitrate, triacetin, dibutyl phthalate, diethyl phthalate, dimethyl phthalate, benzyl benzoate, butyl and glycol esters of fatty acids, oleic acid, cetyl alcohol, stearyl alcohol, castor oil, dimethicone, simethicone and the like. Similarly, an outer coat may optionally be given on the ACE inhibitor layer. The seal/sub coat and outer protective film coat may have the same composition also. Though the examples below refer to ACE inhibitor drug- ramipril, the process can also be applied to other drugs that are susceptible to mechanical stress-induced or mechanical stress-related degradation. The ACE inhibitor may be micronized, and solubilised/dispersed in a solvent to which film forming polymer(s) is added. The film-forming polymer may be, for example, hydroxypropylcellulose, hydroxypropyimethylcellulose, hydroxyethylcellulose, ethylcellulose, cellulose acetate, polyvinylpyrrolidone, gelatin, LustreClear (combination of microcrystalline cellulose and carrageenan), combinations of polyvinylalcohol and polyvinylacetate, and the like. The ACE inhibitor, in the above layer is preferably from about 97.0-99.99%w/w, or more preferably from about 99.0-99.9%w/w of the total drug in the composition. The ACE inhibitor(s) layer may also contain pigments, colorants, antifoaming agents, waxes, monoglycerides, emulsifiers, surfactants or other additives. The solution or the dispersion of the ACE inhibitor(s) comprises from about 2% to about 30%w/w of the polymer in the suitable solvent. The solvents for the above solution or dispersion are selected from the group consisting of water, isopropyl alcohol, ethanol, acetone, methylene chloride and mixtures thereof. Drug coating solution can be prepared in a multitude of ways known in the art. Alternatively drug can be coated on cores by dusting a powder containing drug and simultaneous spray of coating solution prepared using suitable agent and solvent. It may also further contain plasticizer such as polyethylene glycol, triethylcitrate, triacetin, dibutyl phthalate, diethyl phthalate, dimethyl phthalate, benzyl benzoate, butyl and glycol esters of fatty acids, oleic acid, cetyl alcohol, stearyl alcohol, castor oil, dimethicone, simethicone and the like. Similarly and optionally, the ACE inhibitor(s) layer is further coated with an outer protective film coating layer such as commercially available Opadry® and the like to improve the aesthetic appeal and protect the tablet from the atmospheric humidity and other harsh conditions. The present invention is further illustrated by way of below, non-limiting examples, through which a convenient, reproducible stable pharmaceutical composition of the ACE inhibitor may be obtained using the process of the present invention. Manufacturing Process: 1. Sift ingredient no. 1, 2, 3 & 4 through #30 mesh and blend for 15 minutes in blender. 2. Sift ingredient no. 5 # 40 mesh, add in material of step 1 and blend for 5 minutes. 3. Compress the core tablets of respective strengths. 4. Disperse ingredient no. 6 in water with continuous stirring. 5. Coat the core tablets of step 3 with the coating dispersion of step 4. 6. Disperse ingredient no. 9 & 10 in water with continuous stirring. 7. Add Ramipril in coating dispersion of step 6 with continuous stirring. 8. Coat the coated tablets of step 5 with Ramipril coating dispersion of step 7. 9. Disperse ingredient no. 12 in water with continuous stirring to get a homogenous coating suspension. Stability Data of the ramipril composition prepared according to the preferred embodiments of the invention is given below: The above stability data shows that the process of the present invention can be used to prepare a stable composition of the ACE inhibitor(s) wherein a part of the drug is contained in the tablet core and the rest is coated on the tablet core with the optional seal/sub coat in between the two layers. CLAIMS: 1. A pharmaceutical composition for oral administration of ACE inhibitor(s) comprising: i) a core comprising a part of the total ACE inhibitor; ii) a seal/sub-coat over the core; iii) a drug layer comprising the remaining part of the ACE inhibitor over the seal/sub-coat; iv) optionally a protective film coat over the drug layer. 2. A pharmaceutical composition for oral administration of ACE inhibitor(s) comprising: i) a core comprising from about 0.01-3%w/w of the total ACE inhibitor, ii) a seal/sub-coat from about 0.1-5% w/w over the core; iii) a drug layer comprising from about 97-99.9%w/w of the ACE inhibitor over the seal/sub-coat; iv) optionally a protective film coat over the drug layer from about 0.1 -5%w/w. 3. The composition according to claim 1 wherein the ACE inhibitor is selected from the group consisting of ramipril, quinapril, enalapril, spirapril, lisonipril, benzapril and structurally related compounds, their pharmaceutically acceptable salts and esters and their mixtures thereof. 4. A process of preparing a pharmaceutical composition for oral administration of ACE inhibitor(s) comprising: a) coating a part of ACE inhibitor with suitable polymer(s) and mixing with one or more pharmaceutically acceptable excipients; b) compressing the ingredients of step(a) to form a core; c) optionally, coating the core with a seal/sub-coat with suitable polymer(s); d) coating the rest of the ACE inhibitor on to the coated core of step(c); e) optionally, coating a drug coated core with a protective film coat. 5. A process of preparing a pharmaceutical composition for oral administration of ACE inhibitor(s) comprising: a) mixing a part of ACE inhibitor with one or more pharmaceutically acceptable excipients; b) compressing the ingredients of step(a) to form a core; c) optionally, coating the core with a seal/sub-coat with suitable polymer(s); d) coating the rest of the ACE inhibitor on to the coated core of step(c); e) optionally, coating a drug coated core with a protective film coat. 6. The process according to claim 4 wherein the film forming polymer(s) for coating the drug is selected from the group consisting of cellulose derivatives, gums, polyvinylpyrrolidone derivatives, starch, gelatin and combination thereof. 7. The process according to claim 4 or 5 wherein the seal/sub-coat comprises a solution or dispersion of the film former selected from the group consisting of cellulose derivatives, starch, sugars, gums, polyvinylpyrrolidone derivatives, alginate derivatives, zein, shellac, and their combinations in the solvent system chosen from water, isopropyl alcohol, ethanol, acetone, methylene chloride and mixtures thereof. 8. The process according to claim 4 or 5, wherein the ACE inhibitor coating layer comprises ACE inhibitor and film forming polymer. 9. The process according to claim 7 wherein the film forming polymer(s) is selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose. ethylcellulose, cellulose acetate, polyvinylpyrrolidone, gelatin, LustreClear® (combination of microcrystalline cellulose and carrageenan) and a combination of polyvinyl alcohol and polyvinyl acetate. 10. The process according to claim 7 wherein the ACE inhibitor coating solution/dispersion is made with solvents selected from the group consisting of water, isopropyl alcohol, ethanol, acetone, methylene chloride or mixtures thereof.

Documents:

1398-CHE-2007 AMENDED CLAIMS 18-01-2013.pdf

1398-CHE-2007 CORRESPONDENCE OTHERS 08-11-2012.pdf

1398-CHE-2007 CORRESPONDENCE OTHERS 05-12-2012.pdf

1398-CHE-2007 CORRESPONDENCE OTHERS 18-01-2013.pdf

1398-CHE-2007 CORRESPONDENCE OTHERS 24-12-2012.pdf

1398-CHE-2007 CORRESPONDENCE OTHERS 17-12-2012.pdf

1398-CHE-2007 FORM-13 26-04-2011.pdf

1398-CHE-2007 FORM-13 16-11-2011.pdf

1398-CHE-2007 AMENDED CLAIMS 02-07-2012.pdf

1398-CHE-2007 CORRESPONDENCE OTHERS 02-07-2012.pdf

1398-che-2007 abstract.pdf

1398-che-2007 claims.pdf

1398-che-2007 correspondence-others.pdf

1398-che-2007 correspondence-po.pdf

1398-che-2007 description (complete).pdf

1398-che-2007 description (provisional).pdf

1398-che-2007 form-1.pdf

1398-che-2007 form-3.pdf

1398-che-2007 form-5.pdf