FORM 2
THE PATENT ACT 1970 (39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:

STABLE SOLID ORAL DOSAGE FORMULATION OF RAMIPRIL

2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra (East),
Mumbai - 400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides solid oral dosage formulation comprising of ramipril or salt thereof, wherein ramipril is mixed with at least one pharmaceutically accepted excipient, which is coated with film forming agent, in a manner to stabilize the ramipril in said pharmaceutical composition.
The following specification particularly describes the invention and the manner in which it is to be performed._______________________________________
The present invention provides solid oral dosage formulation comprising ramipril or salt thereof, wherein ramipril is mixed with at least one pharmaceutically accepted excipient, which is coated with film forming agent, in a manner to stabilize the ramipril in said pharmaceutical composition.

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Ramipril is a 2-aza-bicyclo [3.3.0]-octane-3-carboxylic acid derivative. Chemically ramipril is (2S,3aS,6aS) -1[(S)-N-[(S) -1-Carboxy-3-phenylpropyl]alanyl] octahydrocyclopentafjb] pyrrole-2-carboxylic acid, 1-ethyl ester; of Formula I.

Ramipril is indicated for the treatment of hypertension and its mechanism of action is by inhibiting angiotensin-converting enzyme (ACE). Ramipril and other ACE inhibitors are reported to be effective antihypertensive drugs, but they are often susceptible for degradation due to cyclisation, hydrolysis or oxidation. Ramipril is believed to degrade into two main products: diketopiperazine and ramiprilat. Decomposition during manufacture and storage may adversely affect the effectiveness of the drug product in terms of its purity and potency. It is therefore desirable to increase the stability of ramipril in pharmaceutical compositions.
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US Patent No 4,587,258 discloses a process for synthesis of ramipril and pharmaceutical composition as being useful as antihypertensive agents and in the treatment of congestive heart failure and of glaucoma.
US Patent No 5,403,856 disclose compositions of angiotensin-converting enzyme inhibitors prepared by using suitable pharmaceutical excipients for oral or parental administration for the treatment of cardiac insufficiency.
US Patent Application No 20050069586 provide solid oral pharmaceutical compositions comprising an intimate admixture, which is formed by granulation, comprising ramipril and effective amount of a lubricant and at least one non-lubricant excipient.
US Patent No 6,221,368 discloses solid oral dosage compositions comprising of ACE inhibitor along with a binder and conventional additives by extrusion process,
US Patent No 6,979,462 provides solid oral pharmaceutical compositions in which active compound is admixed with non-volatile oils and pharmaceutically accepted excipients.

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Present inventors have noticed that when ramipril is simply mixed with a diluent and a glidant and converted in to a solid oral dosage form, ramipril slowly degrades leading to more than 20% of degradation products within one or two months of stability.
While developing a stable oral solid dosage form of ramipril the present inventors, it was surprisingly found that when the diluent which used in the dosage form of ramipril is coated with film forming agent and then mixed with ramipril the degradation of ramipril was significantly reduced. The degradation products after three months of accelerated stability were observed to be less than 2%. The characteristic of the present invention is that there is no need to subject the drug for granulation, drying, or tabletting or to add any hydrophobic or non-volatile oil ingredient, which in turns minimizes the stress exposure of ramipril, thus retarding the degradation of ramipril. Ramipril is simply admixed with at least one pharmaceutically acceptable excipient, which is coated with film forming agents and a lubricant. The developed product demonstrates desired purity and potency.
In one of the aspects of the present invention there is provided the solid oral dosage formulation comprising ramipril or salt thereof, at least one pharmaceutically accepted excipient which is pre-coated and a lubricant.

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The pharmaceutically acceptable excipients can be selected from the group of diluents, lubricants, film forming agents, and coloring or flavoring agents. The stable solid oral dosage formulation can be capsules or sachets.
The diluent can be one or more of microcrystalline cellulose, mannitol, starch, lactose and pre-gelatinized starch. The diluent is coated with film forming agent. The lubricants can be one or more of talc, magnesium stearate, calcium stearate, polyethylene glycol, hydrogenated vegetable oils, stearic aci-d, sodium stearyl fumarate and sodium benzoate. Suitable coloring or flavoring agents include those approved for use by the United States Food and Drug Administration (FDA) and are well known to those skilled in the art. 4

The film forming agent can be selected from the group of cellulose ethers include one or more of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose and other suitable cellulose ethers or from poly (meth)acrylates and copolymers thereof with (meth)acrylic acid.
In another aspect of the present invention the diluent is coated with film forming agent selected from the group of cellulose ethers. The resultant coated particles of the diluent are subjected for drying. The dried coated particles are then mixed with ramipril and a lubricant. The resultant blend is subjected either for filling in empty capsule shell or sachets.

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In further aspect of the present invention there is provided a stable solid oral dosage form of ramipril which having total impurities less than 1.0% after subjecting for accelerated studies at 40°C ± 5°C 0nd 75% RH± 5% RH for 3 months.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Examples
The composition of the batches is provided in Table 1.
The pregelatinized starch is coated with hydroxypropyl methylcellulose solution. The quantity of hydroxypropyl methylcellulose is taken 3% or 5% w/w of pre¬gelatinized starch. The resultant granules are dried. Ramipril is mixed with sodium stearyl fumarate (SSF) and passed through ASTM mesh #40. The mixture of ramipril and sodium stearyl fumarate is added to the pre-coated pre¬gelatinized starch granules and mixed in suitable blender. The blend is either filled in empty capsule shell or filled in empty sachets. Table 1 provides compositions of present invention.
Table 2 provides the data showing total impurity profile of ramipril observed during accelerated stability studies and studies at room temperature for capsules prepared as per the Formula provided in Table 1.

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Table 1: A. Example of ramipril capsules prepared by using pregelatinized starch coated with 3% HPMC.
Table 1: B. Example of ramipril capsules prepared by using pregelatinized starch coated with 5% HPMC.

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Table 2. Impurity profile of stabilized solid oral dosage formulation of
ramipril:
A. Impurity profile of ramipril capsules prepared by using pregelatinized
starch coated with 5% HPMC.
B. Impurity profile of ramipril capsules prepared by using pregelatinized starch coated with 3% HPMC.

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WE CLAIM:
1. A stable solid oral dosage formulation comprising of ramipril and its salt thereof, wherein ramipril is mixed with at least one pharmaceutically accepted excipient, which is pre-coated and a lubricant.
2. A stable solid oral dosage formulation of claim 1 wherein pharmaceutically acceptable excipient is selected from group comprising of diluents, lubricants, film forming agents and coloring or flavoring agents.
3. A stable solid oral dosage formulation of claim 2 wherein the diluent is one or more of microcrystalline cellulose, pregelatinized starch, starch, mannitol or lactose.
4. A stable solid oral dosage formulation as claimed in claim 1, wherein the pharmaceutically accepted excipient is coated with film forming agent.
5. A stable solid oral dosage formulation as claimed in claim 4, wherein film forming agent is one or more of hydroxypropyl methylcellulose, ethylcellulose, methyl cellulose or hydroxypropyl cellulose or poly methyl meth(acrylate) derivatives.
6. A stable solid oral dosage formulation of claim 1, wherein lubricant is one or more of magnesium stearate, calcium stearate, sodium stearyl

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fumarate, sodium benzoate, stearic acid, hydrogenated vegetable oils or talc.
7. The pharmaceutical composition as claimed in 1, wherein the said composition is capsules or sachets.
8. A stable solid oral dosage form of ramipril having less than 1.0% of total impurities after subjecting for accelerated studies.
9. A process for preparation of stable solid oral dosage form of ramipril or salt thereof wherein the said process comprises of
a) pre-coating pharmaceuticaily acceptable excipient with film forming agent,
b) adding ramipril or salt thereof and a lubricant to the pre-coated granules of pharmaceuticaily acceptable excipient.
10. A process of claim 9 wherein pharmaceuticaily acceptable excipient is pre-gelatinized starch.

For Wockhardt Limited

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