FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
STABLE SOLID ORAL DOSAGE FORMULATION OF TRANDOLAPRIL AND PROCESS OF MAKING THE SAME
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 a stable solid oral dosage formulation comprising trandolapril or salt thereof in admixture with pharmaceutically acceptable excipients, wherein the said formulation is prepared by direct compression method.
The following specification particularly describes the invention and the manner in which it is to be performed.

4. DESCRIPTION
The present invention provides a stable solid oral dosage formulation comprising trandolapril or salt thereof in admixture with pharmaceutically acceptable excipients, wherein the said formulation is prepared by direct compression method.
Trandolapril is the ethyl ester prodrug of a nonsulfhydryl angiotensin converting enzyme (ACE) inhibitor, trandolaprilat. It is commercially available under the trade name of MAVIK®. Trandolapril is chemically described as (2S,3aR,7aS)-1-[(S)-N-[(S)-1-Carboxy-3-phenylpropyl]alanyl] hexahydro-2-indo-linecarboxylic acid, 1-ethyl ester (Formula I), it is indicated for the treatment of hypertension and heart failure post myocardial infarction or left-ventricular dysfunction post myocardial infarction.

US Patent No 4,933,361 disclose compound trandolapril and its salts thereof.
EP Patent No. 280,999 and US patent no 4,743,450 discloses a pharmaceutical composition containing an ACE inhibitor which is susceptible to cyclization,
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hydrolysis, and discoloration, an alkali or alkaline earth metal carbonate to inhibit cyclization and discoloration, and a saccharide to inhibit hydrolysis.
US patent no 4,830,853 discloses a pharmaceutical composition containing an ACE inhibitor which is susceptible to oxidative attack resulting in discoloration and a color stabilizing amount of one or more of ascorbic acid and/or sodium ascorbate.
US patent no. 4,793,998 discloses a pharmaceutical composition containing an ACE inhibitor which is susceptible to decomposition by cyclization, hydrolysis and oxidative attack, an ascorbic acid-containing stabilizer to inhibit cyclization and/or hydrolysis and optionally one or more components which do not significantly interfere in the function of component stabilizer.
US patent no 6,555,551 discloses a method of preparing a stable formulation of ACE inhibitor by mixing the drug with an alcohol followed by blending with metal compound dispersion. This dispersion is mixed with excipients and granulated.
US application no 20050142196 discloses a stable pharmaceutical composition comprising an ACE inhibitor or a pharmaceutical acceptable salt thereof, an alkali or alkaline earth metal carbonate, and a low-substituted hydroxypropyl cellulose.
US application no. 2005118259 discloses a pharmaceutical formulation comprising trandolapril, an alkali or alkaline earth metal carbonate an insoluble alkaline-earth metal salt of hydrogen phosphate; with the proviso that the formulation does not contain a substantial amount of a saccharide compound.
US application no 2004171669 discloses coated granules of angiotensin-converting enzyme inhibitor, wherein the granule comprise microcrystals, binders and optionally a diluent.
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PCT application no WO05082420 discloses a pharmaceutical composition comprising an ACE inhibitor, or a pharmaceutically acceptable salt or derivative thereof, and a C16-C28 glyceride.
Several other stable pharmaceutical compositions containing trandolapril are known in the prior art such as US Patent No. 6417196, US 6,300,361, US 6,300,362, US application No 2005069586; PCT application nos. WO2005041940, WO2005011737, WO2003059388 and WO2003075842.
It is well known in the prior art that trandolapril have an ester 3{CO-O) and an amide (CO-N) bond and such bonds are susceptible to hydrolysis leading to the formation of hydrolytic degradation products. Moreover, due to the molecular structure trandolapril is susceptible to cyclization to form diketopiperazine degradation products. Various ways to minimize the degradation of trandolapril in pharmaceutical compositions have been advocated. Despite of the efforts to stabilize trandolapril, there remains a long-standing need for development of stable pharmaceutical compositions comprising trandolapril or a pharmaceutically acceptable salt or derivative thereof and methods of preparing the same.
The present inventors while developing a stable oral solid dosage form of trandolapril have surprisingly found a method for preparing a stable pharmaceutical composition comprising trandolapril or pharmaceutically salts thereof in admixture with pharmaceutically acceptable excipients wherein the said composition is prepared by direct compression. The direct compression method provides
• A stable composition
• Ease of manufacturing
• Cost effectiveness
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• Reduction in the formation of diketopiperazine degradation products and other unknown impurities when compared to tablets prepared by wet granulation method
• Reduction in the level of diketopiperazine degradation products and other unknown impurities when compared to commercially available Mavik® tablet
• A formulation that exhibits a dissolution profile such that within 30 minutes 90% or more of Trandolapril is released and exhibits similar dissolution profile as that of Mavik® tablet (commercially available Trandolapril tablets)
The present inventors have also surprisingly found that the presence of pregelatinized starch and colloidal silicon dioxide increases the amount of unknown impurities and diketopiperazine degradation products. While working on the development of trandolapril tablet, the present inventors have surprisingly found that the use of low moisture grade starch (LOD less than 2 %), povidone and hypromellose help in stabilizing the formulation against formation of Diketopiperazine and unknown impurity.
In one of the aspects of the present invention there is provided a stable pharmaceutical composition comprising Trandolapril or pharmaceutically acceptable salts thereof in admixture with pharmaceutically acceptable excipients wherein the said composition is prepared by direct compression method.
In yet another aspect of the present invention there is provided a method for preparing pharmaceutical composition comprising Trandolapril or pharmaceutically acceptable salts thereof wherein the said method comprises the step of
a) mixing trandolapril with suitable solubilizer or binder
b) adding pharmaceutically acceptable excipients to blend of step a)
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c) optionally blending the mixture obtained in step b) with a colorant and disintegrant.
The pharmaceutical composition comprises of trandolapril as an active ingredient. The pharmaceutical composition can be prepared by direct compression method. The method of preparing pharmaceutical composition involves preparing a color blend comprising Maize starch and a suitable colorant like Iron oxide red, iron oxide yellow or Iron oxide brown. Separately blending trandolapril with suitable solubilizer or binder like povidone, followed by adding suitable pharmaceutically acceptable excipients like lactose, HPMC. The obtained blend is mixed with color blend and then lubricated. The lubricated blend is compressed to form a tablet using suitable tooling.
The tablets obtained by the above process exhibits a dissolution profile such that within 30 minutes 90% or more of Trandolapril is released and also exhibits similar dissolution profile as that of Mavik® tablet (commercially available Trandolapril tablets) in 500 ml of water as dissolution medium at 50 rpm.
The pharmaceutical composition can be granule, powder, sachet, capsule or compressed to form tablets. The pharmaceutical composition is meant for oral administration.
Suitable colorant can be one or more of Iron oxide red, iron oxide yellow or Iron oxide brown, colors approved by US FDA and the like
Suitable disintegrant can be one or more of maize starch, carboxymethylcellulose calcium, starch, croscarmellose sodium, crospovidone, sodium starch glycolate and the like.
Suitable solubilizer can be one or more of Povidone and the like
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Suitable binders can be one or more of starch, sugars, gums, low molecular weight hydroxypropylmethyl cellulose, polyvinyl pyrrolidone and hydroxypropyl cellulose.
The pharmaceutically acceptable excipients can be selected from the group of diluents, filler, lubricants, binder and the like. Suitable diluent can be one or more of microcrystalline cellulose, mannitol, starch, lactose, pregelatinized starch and the like. Suitable filler can be one or more of lactose, dicalcium phosphate, microcrystalline cellulose, mannitol and the like. Suitable lubricants can be one or more of talc, magnesium stearate, calcium stearate, polyethylene glycol, hydrogenated vegetable oils, stearic acid, sodium stearyl fumarate, sodium benzoate and the like. Suitable binders can be one or more of starch, sugars, gums, low molecular weight hydroxypropylmethyl cellulose, polyvinyl pyrrolidone and hydroxypropyl cellulose.
Accelerated condition refers to the storage of composition at temperature of 40°C and 75% Relative Humidity.
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.
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Examples 1-3
Table 1: Composition of trandolapril tablet with low moisture grade maize starch prepared by direct compression method

S.No Ingredients Example 1Qty / Tab(mg) Example 2Qty / Tab(mg) Example 3Qty / Tab(mg)
1. Trandolapril 4.00 2.00 1.00
2. Maize Starch (Low moisture grade) 20.00 10.00 5.00
3. Iron oxide red — — 0.0125
4. Iron oxide yellow — 0.025 —
5. Iron oxide brown 0.050 — —
6. Lactose anhydrous 162.95 81.475 40.738
7. Povidone (PVP K 30) 7.00 3.50 1.75
8. Hypromellose 4.00 2.00 1.00
9. Sodium Stearyl Fumarate 2.00 1.00 0.50
Total 200.0 100.0 50.0
Procedure: Mix Maize starch (Low moisture grade) with Iron oxide red for 1 mg tablet, Mix Maize starch (Low moisture grade) with iron oxide yellow for 2 mg tablet and Mix Maize starch (Low moisture grade) with Iron oxide brown for 4 mg tablet to prepare a color blend. Trandolapril is mixed with Povidone (PVP K 30) followed by addition of Hypromellose and Lactose anhydrous (Blend A). Color blend is added to Blend A. The obtained mixture is blended in suitable blender and then lubricated with sodium stearyl fumarate. The blend is compressed to form a tablet using suitable tooling.
Table 2: Stability data showing percentage of total unknown, diketopiperazine (DKP) and total impurities in trandolapril tablet composition (1 mg) as shown in
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table 1 (Example 3) and Mavik® tablet (1 mg: commercially available trandolapril tablet) at accelerated condition for 3 months.

Stability condition Trandolapril Tablet 1 mg (Example 3) Mavik® tablet (1mg)
Total unknown DKP Total Impurities Total unknown DKP Total Impurities
Initial 0.00 0.034 0.034 0.00 0.665 0.665
1 M 40°C/75%RH 0.070 0.736 0.806 0.00 1.130 1.130
2 M 40°C/75%RH 0.050 0.907 0.957 — — —
3 M 40°C/75%RH 0.00 1.269 1.353 0.00 1.829 1.829
Table 3: Stability data showing percentage of total unknown, diketopiperazine (DKP) and total impurities in trandolapril tablet composition (4 mg) as shown in table 1 (Example 1) and Mavik® tablet (4mg: commercially available trandolapril tablet) at accelerated condition for 3 months.

Stability condition Trandolapril Tablet 4 mg (Example 1) Mavik® tablet (4mg)
Total unknown DKP Total Impurities Total unknown DKP Total Impurities
Initial 0.00 0.053 0.053 0.00 0.489 0.489
1 M 40°C/75%RH 0.104 0.405 0.509 0.00 0.726 0726
2 M 40°C/75%RH 0.083 0.599 0.682 0.00 0.878 0.878
3 M 40°C/75%RH 0.072 0.898 0.898 0.00 1.100 1.100
Example 4 - 6
Table 4: Composition of trandolapril tablet prepared by wet granulation method

S.No Ingredients Example 4Qty / Tab(mg) Example 5Qty / Tab(mg) Example 6Qty / Tab(mg)
Intragranular Ingredients
1. Trandolapril 4.00 2.00 1.00
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2. Sodium Stearyl Fumarate 1.50 0.75 0.375
3. Maize Starch 98.0 49.0 24.50
4. Hypromellose 4.00 2.00 1.00
5. Povidone 8.00 4.00 2.00
6. Pregelatinized starch 60.0 30.00 15.00
Extragranular Ingredients
7. Colloidal Silicon Dioxide 3.00 1.50 0.75
8. Pregelatinized Starch 20.0 10.0 5.00
9. Sodium Stearyl Fumarate 1.50 0.75 0.375
Total 200.0 100.0 50.0
Procedure: Trandolapril is granulated with a solution of sodium stearyl fumarate (Granule A). Separately maize starch, hypromellose and pregelatinized starch are granulated using Povidone solution (Granule B). Granule A is mixed with Granule B. The obtained granules are mixed with colloidal silicon dioxide and pregelatinized starch followed by lubricating the granules with sodium stearyl fumarate. The lubricated granules are compressed to form tablet using a suitable tooling.
Table 5: Stability data showing percentage of- total unknown, diketopiperazine (DKP) and total impurities in trandolapril tablet composition (1 mg and 4 mg) as shown in table 4 (Example 6 and 4) prepared by wet granulation and stability is done at accelerated condition for 3 months.

Stability condition Trandolapril Tablet 1 mg (Example 6) Trandolapril Tablet 4 mg (Example 4)
Total unknown DKP Total Impurities Total unknown DKP Total Impurities
Initial 0.034 0.056 0.091 0.042 0.038 0.079
15 days 0.05 0.358 0.413 0.039 0.333 0.372
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40°C/75%RH
1 M 40°C/75%RH 0.229 0.974 1.203 0.118 0.848 0.967
2 M 40°C/75%RH 0.492 2.028 2.520 0.792 1.980 2.772
3 M 40°C/75%RH 3.497 3.581 7.078 1.396 3.629 5.025
Example 7 - 9
Table 6: Composition of trandolapril tablet with Pregelatinized Starch & Colloidal Silicon Dioxide prepared by direct compression method

S.No Ingredients Example 7Qty / Tab(mg) Example 8Qty / Tab(mg) Example 9Qty / Tab(mg)
1. Trandolapril 4.00 2.00 1.00
2. Sodium Stearyl Fumarate 1.50 0.75 0.375
3. Maize Starch 98.0 49.0 24.50
4. Hypromellose 4.00 2.00 1.00
5. Povidone 8.00 4.00 2.00
6. Pregelatinized starch 80.0 40.00 20.00
7. Colloidal Silicon Dioxide 3.00 1.50 0.75
8. Sodium Stearyl Fumarate 1.50 0.75 0.375
Total 200.0 100.0 50.0
Procedure: Mix Trandolapril and sodium stearyl fumarate (Mixture 1). Separately mix maize starch, hypromellose, povidone and pregelatinized starch (Mixture 2). Add mixture 2 to Mixture 1 followed by lubrication with colloidal silicon dioxide and sodium stearyl fumarate. The lubricated mixture is compressed to form tablet using a suitable tooling.
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Table 7: Stability data showing percentage of total unknown, diketopiperazine (DKP) and total impurities in trandolapril tablet composition (1 mg and 4 mg) as shown in table 6 (Example 9 and 7) prepared by direct compression and stability is carried out at accelerated condition for 3 months.

Stability condition Trandolapril Tablet 1 mg (Example 9) Trandolapril Tablet 4 mg (Example 7)
Total unknown DKP Total Impurities Total unknown DKP Total Impurities
Initial 0.040 0.039 0.780 0.032 0.037 0.069
15 days 40°C/75%RH 0.040 0.425 0.465 0.044 0.313 0.357
1 M 40°C/75%RH 0.473 0.893 1.366 0.283 0.678 0.961
2 M 40°C/75%RH 0.939 1.837 2.776 0.640 1.574 2.214
3 M 40°C/75%RH 1.491 2.904 4.395 3.988 2.689 6.677
Table 8: Drug release data of Trandolapril tablets 4 mg (Example 1) and MAVIK® tablet 4 mg.

Time (min) MAVIK® tablet% DrugDissolved Example 1% DrugDissolved
0 0 0
5 34.0 44.0
10 60.0 62.0
15 79.0 76.0
30 45 60 91.0 93.0 94.0 94.0 97.0 97.0
For determination of drug release, USP Type 2 Apparatus, 50 rpm is used wherein 500ml of water is used as a medium.
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WE CLAIM:
1. A stable pharmaceutical composition comprising Trandolapril or pharmaceutical^ acceptable salts thereof in admixture with pharmaceutically acceptable excipients wherein the said composition is prepared by direct compression method.
2. A method for preparing pharmaceutical composition comprising Trandolapril or pharmaceutically acceptable salts thereof wherein the said method comprises the step of

a) mixing trandolapril with suitable solubilizer or binder
b) adding pharmaceutically acceptable excipients to blend of step a)
c) optionally blending the mixture obtained in step b) with a colorant and disintegrant.

3. A stable pharmaceutical composition and a method for preparing pharmaceutical composition as per claim 1 and 2, wherein pharmaceutically acceptable excipient is selected from a group comprising one or more of diluent, filler, lubricant, binder, disintegrant, colorant, solubilizer.
4. A method for preparing pharmaceutical composition as per claim 2, wherein solubilizer is Povidone.
5. A method for preparing pharmaceutical composition as per claim 2, wherein binder is selected from a group comprising of one or more of starch, sugars, gums, low molecular weight hydroxypropylmethyl cellulose, polyvinyl pyrrolidone and hydroxypropyl cellulose.
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6. A method for preparing pharmaceutical composition as per claim 2, wherein colorant is selected from a group comprising of one or more of Iron oxide red, iron oxide yellow or Iron oxide brown, colors approved by US FDA.
7. A method for preparing pharmaceutical composition as per claim 2, wherein disintegrant is selected from a group comprising of one or more of maize starch, carboxymethylcellulose calcium, starch, croscarmellose sodium, crospovidone, sodium starch glycolate.
8. A stable pharmaceutical composition as per claim 1 wherein the said composition is meant for oral administration
9. A stable pharmaceutical composition as per claim 1 wherein the said composition is powder, granule, sachet, capsule, tablet
10. A stable pharmaceutical composition as per claim 1 wherein the said composition exhibits a dissolution profile such that within 30 minutes 90% or more of Trandolapril is released in 500 ml of water at 50 rpm
Dated this 31st day of August, 2006.
For Wockhardt Limited

(Mandar ftodgule) Authorized Signatory