FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule l3)
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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This patent application is patent of addition to our co-pending Indian Patent Application No 74/MUM/2006 dated January 17, 2006.
Ramipril is a 2-aza-bicyclo [3.3.0]-octane-3-carboxylic acid derivative. Chemically
ramipril is (2S,3aS,6aS)-1 [(S)-/V-[(S)-1 -Carboxy-3-phenylpropyl]alanyl]
octahydrocyclopenta[b] 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

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 acid, 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.
In another aspect of the present invention there is provided a process for preparation of solid oral dosage form comprising ramipril or salt thereof, wherein the said process comprises of,
a) pre-coating at least one pharmaceutically acceptable excipient with film forming agent,
b) drying the coated particles obtained in step a),
c) blending the dried coated particles of step b) with ramipril or salt thereof to get the solid oral dosage form.
The film-forming agent is selected from the group of cellulose ethers or gelatin. The resultant coated particles of the excipient are subjected for drying. The dried
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coated particles are then mixed with ramipril having an optional lubricant. The resultant blend is subjected either for filling in empty capsule shell or sachets.
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 either hydroxypropyl methylcellulose solution or gelatin. The quantity of hydroxypropyl methylcellulose is taken 3% or 5% w/w of pre-gelatinized starch or the quantity of gelatin is taken 3% w/w of pregelatinized starch. The resultant granules are dried. Ramipril is optionally 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 pregelatinized 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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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 with gelatin.
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 of claim 1, wherein lubricant is one or more of magnesium stearate, calcium stearate, sodium stearyl fumarate, sodium benzoate, stearic acid, hydrogenated vegetable oils or talc.
5. The pharmaceutical composition as claimed in 1, wherein the said composition is capsules or sachets.
6. A process for preparation of solid oral dosage form comprising ramipril or salt thereof, wherein the said process comprises of,
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a) pre-coating at least one pharmaceutically acceptable excipient with film forming agent,
b) drying the coated particles obtained in step a),
c) blending the dried coated particles of step b) with ramipril or salt thereof to get the solid oral dosage form.
7. A process of claim 9 wherein pharmaceutically acceptable excipient is pre-gelatinized starch.