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 CONTAINING AN ALKALINE BUFFERING AGENT
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 stable solid oral dosage form of ramipril or salt thereof containing an alkaline buffering agent.
The following specification particularly describes the invention and the manner in which it is to be performed.
The present invention provides stable solid oral dosage form of ramipril or salt thereof containing an alkaline buffering agent.
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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)-A/-[(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 therefore desirable to increase the stability of ramipril in pharmaceutical compositions. Ramipril capsules are sold in the market under the trade name Altace® capsules.
Several processes (US Patent Nos US 4,587,258; US 5,403,856; US 6,221,368; US 6,979,462 and US Application Nos US 20050202081; US 20050169981) are reported in literature for making solid oral dosage forms of ACE inhibitors.
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US Patent No 5,151,433 provides solid oral pharmaceutical compositions in which ramipril is first coated with a polymeric protective coating and then compressed to get tablets.
PCT Patent Application WO 03/075842 and WO 02/011709 provide a similar approach of having carbonates or bicarbonates as stabilizing agents in ACE inhibitor compositions.
PCT Application WO2005041940 discloses a stable pharmaceutical composition of angiotensin enzyme inhibitors along with meglumine in the form of tablet.
US Patent No 6,555,551 discloses solid oral dosage form of ACE inhibitor which Comprises of mixing an ACE inhibitor with an alcohol to form an alcoholic dispersion; dissolving sodium bicarbonate in water to form a solution; mixing the alcoholic dispersion and a solution and adding excipient to prepare granules.
Present inventors have noticed that when ramipril is simply mixed with a diluent and a glidant and converted into 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 surprisingly found that degradation of ramipril was significantly reduced when composition comprises of a buffering agent. The degradation products after one months of accelerated stability were observed to be less than 1 %, which is also lower as compared with Altace® capsules. The characteristic of the present invention is that there is no need to subject ramipril for protective polymer coating, granulation, drying, or tabletting or to add any hydrophobic or nonvolatile oil ingredient, which in turns minimizes the stress exposure of ramipril, thus retarding the degradation of ramipril. Ramipril is simply admixed with at least
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one pharmaceutically acceptable excipients, a buffering agent and an optional lubricant. The developed procedure is simple and time saving, as it required minimum steps to prepare desired product. The developed product demonstrates desired purity and potency.

In one of the aspects of the present invention there is provided a solid oral dosage formulation comprising ramipril or salt thereof, at least one pharmaceutically accepted excipient, and a buffering agent.

A yet another aspect of the present invention provides a solid oral dosage formulation comprising ramipril or salt thereof, at least one pharmaceutically accepted excipient and tromethamine as buffering agent.
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The buffering agent comprises of sodium dihydrogen phosphate, trisodium citrate dihydrate, and tr/s-(hydroxymethyl)aminomethane (Tromethamine) or the like.
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 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.
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In another aspect of the present invention there is provided a process for preparation of stable solid oral dosage form of ramipril wherein the said process comprises of,
a) mixing ramipril with a buffering agent,
b) blending the mixture of step a) with at least one pharmaceutically acceptable diluent,
c) filling or compressing the resultant blend to get suitable solid oral dosage form.
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
Ramipril was mixed with tromethamine and sifted through ASTM mesh #40. To the mixture was added pre-gelatinized starch, and pre-sifted (through ASTM mesh #60) sodium stearyl fumarate and the blend was mixed in suitable blender. The blend was 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 with pre-gelatinized starch
Ingredient Example 1 Example 2 Example 3 Example 4
mg/cap mg/cap mg/cap mg/cap
Ramipril 10.00 5.00 2.50 1.25
Tromethamine (TRIS 1 Buffer) 14.00 14.00 14.00 14.00
Pre-gelatinized Starch 86.00 91.00 — —
Starch 1500 (partially pre-gelatinized starch) 93.50 94.75
Total weight 110 110 110 110

Table 2. Impurity profile of stabilized solid oral dosage formulation of ramipril:
Details Condition Related Substances
Diketopiperazine Total Unknown Impurities Total Impurities
Example 1 Initial 0.180% 0.00% 0.180%
3 Days 60°C 0.694% 0.262% 1.067%
15 Days 40°C/75%RH 0.214% 0.00% 0.214%
1M40°C/75%RH - - -
Example 3i Initial 0.149 0.00% 0.149%
3 Days 60°C - - -
15 Days 40°C/75%RH 0.196 0.00% 0.196%
1M40°C/75%RH - - -
C) Altace® capsules Initial 2.693 0.064 2.954
3 Days 60°C 5.307 0.138 5.639
15 Days 40°C/75%RH
1M40°C/75%RH - - -
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WE CLAIM:
1. A solid oral dosage formulation comprising ramipril or salt thereof, at least one pharmaceutically accepted excipient, and a buffering agent.
2. A stable solid oral dosage formulation as claimed in claim 1, wherein buffering agent is one or more of sodium dihydrogen phosphate dihydrate, trisodium citrate dihydrate, and tromethamine.
3. A stable solid oral dosage formulation of claim 1 wherein the pharmaceutically acceptable excipient is selected from group comprising of diluents, lubricants, and coloring or flavoring agents.
4. A stable solid oral dosage formulation of claim 3 wherein the diluent is one or more of microcrystalline cellulose, pre-gelatinized starch, starch, mannitol or lactose.
5. A stable solid oral dosage formulation of claim 3, wherein lubricant is one or more of magnesium stearate, calcium stearate, sodium stearyl fumarate, sodium benzoate, stearic acid, hydrogenated vegetable oils or talc.
6. A solid oral dosage formulation comprising ramipril or salt thereof, at least one pharmaceutically accepted excipient and tromethamine as buffering agent.
7. A stable solid oral dosage formulation as claimed in claim 6, wherein tromethamine is used in the range from 0.1 mg to 50 mg.
8. A stable solid oral dosage form of as claimed in claim 6 having less than 1.0% of total impurities in after subjecting for accelerated studies.
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9. A process for preparation of stable solid oral dosage form of ramipril wherein the said process comprises of,
a) mixing ramipril with a buffering agent,
b) blending the mixture of step a) with at least one pharmaceutically acceptable diluent,
c) filling or compressing the resultant blend to get suitable solid oral dosage form.
Dated this OF 28 TH day of February 2006.
For Wockhardt Limited
(Yatendra Kumar) Authorized Signatory
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