WO2014002011A1

WO2014002011A1 - Micronized particles of olmesartan medoxomil and pharmaceutical composition thereof

Info

Publication number: WO2014002011A1
Application number: PCT/IB2013/055213
Authority: WO
Inventors: Rajesh Kshirsagar; Jayadev Patil; Vijay KARWA
Original assignee: Micro Labs Limited
Priority date: 2012-06-26
Filing date: 2013-06-25
Publication date: 2014-01-03
Also published as: WO2014002011A9

Abstract

The present invention provides micronized particles of Olmesartan Medoxomil having d_0.9 value less than 10µm. Further, the present invention provides an easy, fast, cost effective and reliable process of direct compression or dry granulation for preparation of pharmaceutical composition comprising therapeutically effective amount of Olmesartan Medoxomil having d_0.9 less than 10µm.

Description

MICRONIZED PARTICLES OF OLMESARTAN MEDOXOMIL AND PHARMACEUTICAL COMPOSITION THEREOF

TECHNICAL FIELD OF THE INVENTION

The present invention relates to pharmaceutical composition comprising micronized particles of Olmesartan Medoxomil and process for preparation of pharmaceutical composition comprising Olmesartan Medoxomil.

BACKGROUND OF THE INVENTION

Olmesartan Medoxomil chemically known as ((5-methyl-2-oxo-1 ,3-dioxolen-4- yl)methyl 4-(1-hydroxy-1-methylethyl) -2-propyl-1 -[2'- (1 H-tetrazol-5-yl) biphenyl-4- ylmethyl]imidazole-5-carboxylate) is known to be an excellent angiotensin II receptor blocker, and is useful as a treatment drug or a preventive drug for hypertension, heart disease and the like.

The pharmaceutical formulation currently approved for the administration of Olmesartan Medoxomil is a film-coated tablet, commercially available under the brand name Benicar^®. These tablets are being marketed by Daiichi Sankyo and are covered by U.S. Patent No. 5,616,599. It discloses Olmesartan Medoxomil and other related imidazoles. It also describes a process for the preparation of imidazole derivatives useful for the synthesis of Olmesartan.

WO 2007/047838 relates to a process of preparing Olmesartan Medoxomil having decreased impurities and a particle size distribution such that the d₀.g is less than 250 μηη.

WO 2008/1 17707 relates to ground crystals of Olmesartan Medoxomil having particle size distribution such that the d₀.g is less than 75 μηη, preferably less than 66 μηη and most preferably less than 57 μηη.

WO 2007/128478 relates to oral solid pharmaceutical compositions containing Olmesartan Medoxomil, optionally in combination with Hydrochlorothiazide. Compositions comprising Olmesartan Medoxomil having different particle size distributions were tested. It was found that satisfactory dissolutions are achieved with particle sizes having d₀.9 less than 140 μηη, and d₀.5 ~ 50 μηη, preferably d₀.g with 100- 140 μηη while decreasing the particle sizes by micronization to d₀.g -Ι Ομηη did not have an effect.

Thus, there is still unmet need to develop a pharmaceutical composition comprising Olmesartan Medoxomil having particle size less than 10μηι, to manufacture cost effective and stable compositions with acceptable dissolution profile. SUMMARY OF THE INVENTION

In one aspect the present invention provides the micronized particles of Olmesartan Medoxomil having d₀.g less than 10μηη.

In yet another aspect the present invention provides a pharmaceutical composition comprising therapeutically effective amount of Olmesartan Medoxomil having d₀.g less than 10μηι.

In yet another aspect the present invention provides a process for production of pharmaceutical composition comprising therapeutically effective amount of Olmesartan Medoxomil having d₀.g less than 10μηι.

In yet another aspect the present invention provides a direct compression process for production of pharmaceutical composition comprising therapeutically effective amount of Olmesartan Medoxomil having d₀.g less than 10μηι.

In yet another aspect the present invention provides a dry granulation process for production of pharmaceutical composition comprising therapeutically effective amount of Olmesartan Medoxomil having d₀.g less than 10μηι.

BRIEF DESCRIPTION OF THE DRAWING

Fig. 1 Graphical representation of dissolution profile for formulation of Example-4 and reference product Benicar^®40 mg in 900 ml, Phosphate Buffer pH-6.8 (OGD Media), Apparatus USP Type II (Paddle), 50 RPM, at 37 ± 0.5°C.

Fig. 2 Graphical representation of dissolution profile for formulation of Example-4 and reference product Benicar^®40 mg in 900 ml, 0.1 N HCI, Apparatus USP Type II (Paddle), 50 RPM, at 37 ± 0.5°C.

Fig. 3 Graphical representation of linear mean plot of Olmesartan Medoxomil (Test Product-T and Reference Product- R) plasma concentration Vs Time for all subjects under Fasting condition. (n= 13). DETAILED DESCRIPTION OF THE INVENTION

The present invention provides the micronized particles of Olmesartan Medoxomil having d₀.g less than 10μηη and pharmaceutical composition comprising therapeutically effective amount of Olmesartan Medoxomil.

The term "Olmesartan Medoxomil", as used herein, includes crystalline or amorphous Olmesartan Medoxomil. In the compositions of the present invention, Olmesartan Medoxomil may be utilized in an amount ranging from 2% to 80% (w/w) based on the total weight of the pharmaceutical composition.

As used herein, the phrase "micronized Olmesartan Medoxomil" means particles of Olmesartan Medoxomil having d₀.g less than Ι Ομηη.

The term "do.g", as used herein, with reference to the size of micronized Olmesartan Medoxomil particles, indicates that about 90% of particles measured have a size less than the defined d₀.g value, and that about 10% of particles measured have a size greater than the defined d₀.g value.

The phrase "therapeutically effective amount", as used herein, means a dosage that is sufficient to provide the specific pharmacological response for which the Olmesartan Medoxomil is being administered. The "therapeutically effective amount" will vary depending on the severity of the disease, age, weight, physical condition and the responsiveness of the subject.

"Cmax" as used herein, means maximum plasma concentration of Olmesartan Medoxomil, produced by the oral administration of the composition of the invention or the immediate release (IR) comparator.

"AUCo-t" as used herein, means area under the plasma concentration-time curve, as calculated by the trapezoidal rule over the complete dosing interval for the formulation.

"AUC0-∞" as used herein, means area under the plasma concentration-time curve, as calculated by the trapezoidal rule from time zero to time infinity (AUC _0-~), where AUC o-~ = AUC o-t + Ct/λζ, Ct is the last measurable drug concentration and λζ is the terminal or elimination rate constant calculated according to an appropriate method. As used herein the term "tablet" is intended to encompass compressed pharmaceutical dosage forms of all shape and size, whether coated or uncoated. The particle size distribution of Olmesartan Medoxomil particles of the present invention may be determined using an optical microscopic method, sedimentation techniques, for example, pipette analysis using an Andreason pipette, sedimentation scales, photo sedimentometers or sedimentation in a centrifugal force field, pulse methods, for example, using a Coulter counter, or sorting by means of gravitational or centrifugal force, sieve analysis, laser diffraction or ultrasound attenuation spectroscopy. The particle size distribution of Olmesartan Medoxomil particles of the present invention is particularly determined through laser diffraction using a Malvern^® Mastersizer laser diffraction instrument.

The pharmaceutical composition that includes therapeutically effective amount of micronized Olmesartan Medoxomil may further comprise one or more pharmaceutically acceptable excipients selected from a group comprising diluents, binders, disintegrants, lubricants, coloring agents, flavoring agents or any other excipients known in the art.

Suitable examples of diluents include corn starch, lactose, white sugar, sucrose, sugar compressible, sugar confectioners, glucose, sorbitol, calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose, fructose, kaolin, lactitol, mannitol, starch, pregelatinized starch or mixtures thereof.

Suitable examples of binders include polyvinylpyrrolidone, starch mucilage, pregelatinized starch, sodium alginate, alginic acid, acacia mucilage, tragacanth, hydroxypropylmethyl cellulose, carboxymethylcellulose sodium, carboxymethylcellulose calcium, cellulose, ethyl cellulose, polyethylene glycol, hydroxyethyl cellulose, hydroxy propyl cellulose, methyl cellulose, polymethacrylates, carboxyvinyl polymers, carbopols, and combinations thereof.

Suitable examples of disintegrants include cross-linked polyvinylpyrrolidone, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose (crosscarmellose sodium), calcium carboxymethyl cellulose, alginic acid and alginates, pregelatinised starch, starch and starch derivatives, low-substituted hydroxypropyl cellulose and combinations thereof.

Suitable examples of lubricants and glidants include colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acids, microcrystalline wax, yellow beeswax, white beeswax or mixtures thereof.

Coloring agents and flavoring agents may be selected from any FDA approved colors and flavors for oral use.

The pharmaceutical composition comprising therapeutically effective amount of micronized Olmesartan Medoxomil may optionally contain surfactants/wetting agents. Surfactants/wetting agents include both non-ionic and ionic (cationic, anionic and zwitterionic) surfactants suitable for use in pharmaceutical compositions. These include polyethoxylated fatty acid esters, polyethylene glycol fatty acid esters, alcohol-oil transesterification products, polyglycerized fatty acids, polyethylene glycol sorbitan fatty acid esters, sugar esters, polyoxyethylene-polyoxypropylene block copolymers, ionic surfactants, derivatives of fat soluble vitamins, and mixtures thereof. Suitable examples include sodium lauryl sulphate, sodium dodecyl sulphate, polyoxyethylene castor oil derivatives, for example, tweens, polyoxyethylene- polyoxypropylene block copolymers, for example, poloxamer, or mixtures thereof. The present invention further provides pharmaceutical composition that includes therapeutically effective amount of micronized Olmesartan Medoxomil, wherein the composition may be in the form of tablets, dispersible tablets, capsules, granules, beads, pellets, powder, suspension, emulsion, syrups or elixirs. Particularly, the compositions of the present invention are formulated into tablets, capsules or dispersible tablets. Further, the tablets may be film-coated.

The tablets may be coated using a sugar-based agent, an agent for water-soluble film-coating base, enteric film-coating agent or a modified release film-coating agent. The coating agent may also contain a plasticizer.

Suitable examples of coating agents include but not limited to polyvinyl alcohol, hydroxypropyl methylcellulose, carboxymethyl cellulose and like.

Preferably coating is carried out using coating agents such as Opadry^®. Opadry^® contains hydroxypropyl methyl cellulose, plasticizers selected from triacetin, triethyl citrate, polyethylene glycol, antitacking agent such as Talc, opacifiers such as titanium dioxide. Preferred Opadry^® are Opadry^® White 03A580003 which contains Hypromellose, Talc &Titanium dioxide, Opadry^® Yellow 03A520003 which contains Hypromellose, Talc, Titanium dioxide & Iron oxide yellow, Opadry^® Pink 03A540021 which contains Hypromellose, Titanium dioxide, Talc, Iron oxide red and Iron oxide yellow, Opadry^® II Brown 85F565047 which contains Polyvinyl alcohol, Polyethylene glycol, Titanium dioxide, Talc, Red iron oxide, Black iron oxide and Yellow iron oxide, Opadry^® II pink 85F540084 which contains Polyvinyl alcohol, Polyethylene glycol, Titanium dioxide, Talc, Red iron oxide and Yellow iron oxide , Opadry^® 03A570000 Beige and Opadry^® 03A570001 Beige which contains Hypromellose, titanium dioxide, Talc, Iron oxide red and Iron oxide yellow. Solvents that may be used for coating include purified water.

The oral pharmaceutical composition comprising therapeutically effective amount of micronized Olmesartan Medoxomil may be prepared by using the conventional techniques, for example, either by direct compression, or first slugging some of the ingredients, milling the slugs, blending with the remaining ingredients and then compressing as appropriate. These compositions may also be prepared using wet granulation techniques. More preferably these compositions are prepared by using direct compression process or dry granulation process.

In one aspect the present invention provides the micronized particles of Olmesartan Medoxomil having d₀.9 less than 10μηι.

In yet another aspect the present invention provides a pharmaceutical composition comprising therapeutically effective amount of Olmesartan Medoxomil having d₀.g less than 10μηι. In yet another aspect the present invention provides a pharmaceutical composition for the treatment or prophylaxis of hypertension or of a cardiovascular disease by administering to a patient in need thereof.

In yet another aspect the present invention provides a pharmaceutical composition comprising therapeutically effective amount of Olmesartan Medoxomil having d₀.g less than Ι Ομηη in combination with one or more antihypertensive agent.

In yet another aspect the antihypertensive agent is selected from group comprising of diuretics like bumetanide, ethacrynic acid, furosemide, torsemide, epitizide, Hydrochlorothiazide, chlorothiazide, bendroflumethiazide, indapamide, chlorthalidone, metolazone, amiloride, triamterene, spironolactone, Adrenergic receptor antagonists like atenolol, metoprolol, nadolol, oxprenolol, pindolol, propranolol, Timolol, doxazosin, phentolamine, indoramin, phenoxybenzamine, prazosin, terazosin, tolazoline, bucindolol, carvedilol, labetalol, Calcium channel blockers like Amiodipine, felodipine, isradipine, lercanidipine, nicardipine, nifedipine, nimodipine, nitrendipine, diltiazem, verapamil, ACE inhibitors like captopril, enalapril, fosinopril, lisinopril, perindopril, quinapril, Ramipril, trandolapril, benazepril, Angiotensin II receptor antagonists like candesartan, eprosartan, irbesartan, losartan, Olmesartan, telmisartan, valsartan, Aldosterone antagonists like eplerenone and spironolactone and Alpha-2 agonists like Clonidine, Guanabenz, Methyldopa, Moxonidine or its pharmaceutically acceptable salts, esters, hydrates, solvates, polymorphs, pro-drugs, or mixtures thereof and the like.

In yet another aspect the present invention provides a pharmaceutical composition comprising therapeutically effective amount of Olmesartan Medoxomil having d₀.g less than 10μηι in combination with one or more of thiazide diuretics, β-blockers, calcium channel blockers, rennin inhibitors or ACE inhibitors.

In yet another aspect the present invention provides a pharmaceutical composition comprising therapeutically effective amount of Olmesartan Medoxomil having d₀.9 less than 10μηι in combination with Hydrochlorothiazide.

In yet another aspect the present invention provides a pharmaceutical composition comprising therapeutically effective amount of Olmesartan Medoxomil having d₀.g less than 10μηι in combination with Amiodipine or its pharmaceutically acceptable salts, polymorphs, Hydrates, solvates thereof.

In yet another aspect the present invention provides a pharmaceutical composition comprising therapeutically effective amount of Olmesartan Medoxomil having d₀.9 less than 10μηι in combination with Amiodipine Besylate.

In yet another aspect the present invention provides a pharmaceutical composition comprising therapeutically effective amount of Olmesartan Medoxomil having d₀.g less than 10μηι in combination with Amlodipine or its pharmaceutically acceptable salts, polymorphs, Hydrates, solvates thereof and Hydrochlorothiazide.

In yet another aspect the present invention provides a pharmaceutical composition comprising therapeutically effective amount of Olmesartan Medoxomil having d₀.g less than 10μηη in combination with Amlodipine Besylate and Hydrochlorothiazide. In yet another aspect the present invention provides a process for production of pharmaceutical composition comprising therapeutically effective amount of Olmesartan Medoxomil having d₀.g less than 10μηη.

In yet another aspect the present invention provides a process for production of pharmaceutical composition comprising therapeutically effective amount of Olmesartan Medoxomil having d₀.g less than 10μηη and one or more pharmaceutically acceptable excipient, comprising steps of:

a. Sift individually Olmesartan Medoxomil and one or more pharmaceutically acceptable excipients;

b. Co-sift sifted Olmesartan Medoxomil along with sifted one or more pharmaceutically acceptable excipients;

c. Load co-sifted material of step-b to a suitable blender and blend for 20 minutes at 15 rpm.

d. Add above sifted lubricant of step -a to step-c and mix for 5 minutes at 15 rpm. e. Compress the above lubricated blend in to tablets using a suitable compression technique.

f. Film coat the compressed tablets using aqueous solution of Opadry^® White.

In yet another aspect the present invention provides a direct compression process for production of pharmaceutical composition comprising therapeutically effective amount of Olmesartan Medoxomil having d₀.g less than 10μηη.

In yet another aspect the present invention provides a dry granulation process for production of pharmaceutical composition comprising therapeutically effective amount of Olmesartan Medoxomil having d₀.g less than 10μηη.

Dry granulation process may be carried out using either by slugging or roller compaction technique. Preferably roller compaction technique is used.

Advantageously, direct compression or dry granulation process avoid the use of solvents (e.g. water) allowing for formulation of solvent sensitive drugs.

Furthermore, dry granulation or direct compression is the fastest, simple and most cost effective way of tablet preparation.

In yet another aspect the present invention provides a pharmaceutical composition comprising therapeutically effective amount of Olmesartan Medoxomil having d₀.g 6.78 μηι which gives dissolution profile which is similar to the dissolution profile of Innovator product (Benicar^®).

In yet preferred aspect the present invention provides a tablet formulation comprising therapeutically effective amount of Olmesartan Medoxomil having d₀.g 6.78 μηη which gives dissolution profile which is similar to the dissolution profile of Innovator product (Benicar^®).

In a particular embodiment, the dissolution profile is determined in 900 ml, Phosphate Buffer pH-6.8, Apparatus USP Type II (Paddle), 50 RPM, at 37 ± 0.5°C, which gives dissolution profile which matches with the dissolution profile of Innovator product (Benicar^®).

In a particular embodiment, the dissolution profile is also determined in 900 ml, 0.1 N HCI, Apparatus USP Type II (Paddle), 50 RPM, at 37 ± 0.5°C, which gives dissolution profile which matches with the dissolution profile of Innovator product (Benicar^®).

In yet another embodiment, the compositions, formulations and active pharmaceutical agents described herein are thermally stable at room temperature, at 25 ^°C with relative humidity 60% or at 30 ^°C with relative humidity 65% for at least 3 months when packaged into HDPE bottle with rayon coil and Alu-Alu Strip pack. In yet another embodiment, the compositions, formulations and active pharmaceutical agents described herein are thermally stable even at accelerated conditions of stability i.e. at 40 ^°C with relative humidity 75% for at least 3 months when packaged into HDPE bottle with rayon coil and Alu-Alu Strip pack.

The following examples illustrate preferred embodiments in accordance with the present invention without limiting the scope or spirit of the invention.

Examples Example 1 , 2, 3 & 4

Examples 1 , 2, 3 & 4 are tablets comprising Olmesartan Medoxomil having d₀.9, 73.13 μηη, 34.91 μηη, 13.68 μηη & 6.78 μηη prepared using dry granulation method respectively,

5 L- Hydroxy propyl cellulose (LH-1 1 ) 80.00

6 Magnesium Stearate 1 .60

Lubrication

7 Magnesium Stearate 2.00

Core Tablet Weight 424.00

8 Opadry^® White (03A580003) 12.00

10 Purified Water Q.S.

Coated Tablet Weight 436.00

Manufacturing procedure:

1 . Olmesartan Medoxomil was individually sieved through ASTM #20 mesh and collected separately. Lactose Monohydrate (Super tab SD 1 1 ), Microcrystalline Cellulose (Avicel pH 102) and Hydroxy Propyl Cellulose (SSL) were individually sieved through 40# sieve. L- Hydroxy propyl cellulose (LH-1 1 ) was individually sieved through ASTM # 30 mesh and Magnesium Stearate (I^st & II^nd Part) was separately sieved through ASTM #60 mesh and collected in suitable polybags.

2. Previously sifted Olmesartan Medoxomil was sieved along with sifted Lactose Monohydrate (Super tab 1 1 SD) through ASTM # 30 mesh.

3. Co-sifted material of step-2 was added to a suitable blender along with sifted Microcrystalline cellulose (Avicel pH 102), Hydroxy Propyl Cellulose (SSL), L- Hydroxy propyl cellulose (LH-1 1 ) and blended for 15 minutes at slow speed (15 rpm). 4. Above Sifted Magnesium Stearate (I^st Part) was added to Step-3 and mixed for 5 minutes at slow speed (15 rpm) and collected in separate double polythene bags. 5. Lubricated Blend of Step-4 was processed in Roll Compactor and the flakes were collected in double polythene bags.

6. The compact material of step 5 was sieved through vibratory sifter equipped with ASTM # 20 sieve. The # 20 retains of above step were passed through multi mill equipped with suitable screen with knives which forwarded at "SLOW" speed, further milled granules were passed through vibratory sifter equipped with ASTM # 20 sieve.

7. Sifted Magnesium Stearate (II^nd Part) was transferred into octagonal blender previously loaded with step 6 materials and mixed for 5 mins at slow speed (15 rpm).

8. The lubricated blend as obtained in step-7 was compressed into tablets using a suitable compression machine and punches and film coated using aqueous solution of Opadry^® White as per above mentioned formula.

Comparison of in-vitro dissolution profile:

The tablets of Olmesartan Medoxomil prepared as per the compositions of examples 1 ,2,3 & 4 were subjected to dissolution studies in 900 ml of 0.05 M phosphate buffer (pH 6.8) at 37 °C ± 0.5 ^°C using USP apparatus II with paddle speed at 50 rpm. Table 1 provides comparative dissolution profile.

Table 1 : The dissolution of formulation 1 , 2, 3 & 4 in 900 ml, Phosphate Buffer pH- 6.8 (OGD Media), Apparatus USP Type II (Paddle), 50 RPM, at 37 ± 0.5°C.

Comparative dissolution profile of the examples 1 , 2, 3 & 4 indicate that as the particle size of Olmesartan Medoxomil decreases the dissolution increases.

Table 2: The dissolution of formulation prepared according to Example 4 and reference product Benicar^®40 mg was carried out in 900 ml, Phosphate Buffer pH-6.8 (OGD Media), Apparatus USP Type II (Paddle), 50 RPM, at 37 ± 0.5°C , the dissolution profile is as follows and shown in Fig. 1

Table 3: The dissolution of formulation prepared according to Example 4 and reference product Benicar^®40 mg was carried out in 900 ml, 0.1 N HCI, Apparatus USP Type II (Paddle), 50 RPM, at 37 ± 0.5°C , the dissolution profile is as follows and shown in Fig. 2

Example 5

Manufacturing procedure:

1 . Olmesartan Medoxomil, Hydroxy Propyl Cellulose, Lactose Monohydrate, Microcrystalline Cellulose, and L-Hydroxy Propyl Cellulose were sieved through 40 # sieve and collected separately and Magnesium Stearate was sieved separately through 60 # sieve and collected in suitable polybags.

2. Sifted Olmesartan Medoxomil was co-sifted along with sifted Hydroxy Propyl Cellulose, Lactose Monohydrate, Microcrystalline Cellulose, and L-Hydroxy Propyl Cellulose through 40 # sieve.

3. Co-sifted materials of step-2 were added to a suitable blender and blended for 20 minutes at 15 rpm. 4. Sifted Magnesium Stearate was added to Step-3 and mixed for 5 minutes at 15 rpm.

5. Lubricated blend as obtained in step-4 was compressed into tablets using a suitable compression machine and punches.

6. The compressed tablets as obtained in step-5 were then coated using aqueous solution of Opadry^® White as per above mentioned formula.

Example 6:

Manufacturing procedure:

1. Olmesartan Medoxomil was sieved through ASTM # 40 mesh. Lactose Monohydrate (Pharmatose 200M) was sieved through ASTM # 40 mesh. Hydroxy Propyl Cellulose (Klucel LF) was sieved through ASTM # 30 mesh. L- Hydroxy propyl cellulose (LH-1 1 ) was sieved through ASTM # 40 mesh. Microcrystalline Cellulose (Avicel pH 1 12) was sieved through ASTM #40 mesh and Magnesium Stearate was sieved separately through ASTM #60 mesh and collected in suitable polybags.

2. Sifted Olmesartan Medoxomil, Lactose Monohydrate (Pharmatose 200M), Hydroxy Propyl cellulose (Klucel LF), L- Hydroxy propyl cellulose (LH-1 1 ), Microcrystalline Cellulose (Avicel pH 1 12) were mixed for 10 minutes and sifted through ASTM # 40 mesh. Then, sifted Magnesium Stearate was added to it and mixed for 5 minutes.

3. The blend of step-2 was passed through Roll Compactor. The flakes were collected and the obtained flakes were passed through Multimill with 1.5 mm screen. The milled granules were sifted through ASTM # 30 mesh. 4. Microcrystalline Cellulose (Avicel pH 1 12) and L- Hydroxy propyl cellulose (LH-1 1 ) were sieved through ASTM # 40 mesh and added to granules as obtained in step 3 and mixed for 10 minutes.

5. Above sifted Magnesium Stearate was added to blend as obtained in step-4 and mixed for 5 minutes.

6. The lubricated blend as obtained in step-5 was compressed into tablets using a suitable compression machine and punches and film coated using aqueous solution of Opadry^® White as per above mentioned formula.

Example 7:

Manufacturing procedure:

1 . Olmesartan Medoxomil was sieved through 20 # sieve and collected separately, further Hydroxy Propyl Cellulose, Lactose Monohydrate, Microcrystalline Cellulose, and L-Hydroxy Propyl Cellulose were sieved through 40 # sieve and collected separately and Magnesium Stearate was sieved separately through 60 # sieve and collected in suitable polybags.

2. Previously sifted Olmesartan Medoxomil was co-sifted with previously sifted Lactose Monohydrate (Super tab 1 1 SD) through 30 # sieve.

3. Co-sifted material of step-2 was added to a suitable blender along with previously sifted Hydroxy Propyl Cellulose, Microcrystalline Cellulose, and L-Hydroxy Propyl

Cellulose and blended for 20 minutes at 15 rpm. 4. Previously sifted Magnesium Stearate was added to Step-3 and mixed for 5 minutes at 15 rpm.

6. The compressed tablets as obtained in step-5 were then coated using aqueous solution of Opadry^® White (for 40 mg and 20 mg strength) and Opadry^® Yellow (for 5 mg strength) as per above mentioned formula.

Example 8

Manufacturing procedure:

2. Previously sifted Olmesartan Medoxomil was co-sifted with previously sifted Lactose Monohydrate (Super tab 1 1 SD) through ASTM # 30 mesh.

3. Co-sifted material of step-2 was added to a suitable blender along with sifted microcrystalline cellulose (Avicel pH 102), Hydroxy Propyl Cellulose (SSL), L- Hydroxy propyl cellulose (LH-1 1 ) and blend for 15 minutes at slow speed (15 rpm). 4. Above sifted Magnesium Stearate (I^st Part) was added to Step-3 and mixed for 5 minutes at slow speed (15 rpm) and collected in separate double polythene bags. 5. Lubricated Blend of Step-4 was processed in Roll Compactor and the flakes were collected in double polythene bags.

8. The lubricated blend as obtained in step-7 was compressed into tablets using a suitable compression machine and punches and film coated using aqueous solution of Opadry^® White (for 20 mg strength) and Opadry^® Yellow (for 5 mg strength) as per above mentioned formula.

Example 9

Manufacturing procedure:

1 . Olmesartan Medoxomil and Hydrochlorothiazide were individually sieved through ASTM # 20 sieve and collected separately. Lactose Monohydrate (Super tab SD 1 1 ), Microcrystalline Cellulose (Avicel pH 102), Hydroxy Propyl Cellulose (SSL), L- Hydroxy propyl cellulose (LH-1 1 ) were individually sieved through ASTM # 40 sieve and collected in suitable polybags. Magnesium stearate (I^st & II^nd Part) separately sieved through ASTM # 60 sieve and collected in suitable polybags.

2. Olmesartan Medoxomil was geometrically mixed along with sifted Lactose Monohydrate (Super tab 1 1 SD) in a double Polybag and then sifted through ASTM #30 sieve. Further, Hydrochlorothiazide was geometrically mixed with microcrystalline cellulose (Avicel pH 102) and then sifted though ASTM # 30 sieve.

3. Co-sifted materials of step 2 were loaded to a suitable blender along with sifted Hydroxy Propyl Cellulose (SSL), Intragranular portion of L- Hydroxy propyl cellulose (LH-1 1 ) and blended for 20 minutes at slow speed (15 rpm).

4. Sifted magnesium stearate (I^st Part) was added to blend of step-3 and mixed for 5 minutes at slow speed (15 rpm) and collected in separate double polythene bags.

5. The lubricated Blend of Step-4 was processed in Roll Compactor and the obtained flakes were collected in double polythene bags.

6. The compact material of step 5 was sieved through vibratory sifter equipped with ASTM # 20 sieve. The ASTM # 20 retains of this step were passed through multi mill equipped with suitable screen with knives which forwarded at "MEDIUM" speed, further milled granules were passed through vibratory sifter equipped with ASTM # 20 sieve.

7. The blend of step 6 was prelubricated with extragranular portion of L- hydroxy propyl cellulose LH-1 1 in suitable octagonal blender for 5 mins at slow speed (15 rpm).

8. The blend of step 7 was lubricated with sifted magnesium stearate (II^nd Part) into octagonal blender and mixed for 5 mins at slow speed (15 rpm).

9. The lubricated blend as obtained in step-8 was compressed into tablets using a suitable compression machine and punches and film coated using aqueous solution of Opadry^® Pink as per above mentioned formula. Example 10

Manufacturing procedure:

1 . Olmesartan Medoxomil and Amiodipine Besylate were individually sieved through ASTM # 20 and collected separately. Pregelatinized starch, Silicified Microcrystalline

Cellulose, Croscarmellose sodium were individually sieved through ASTM # 40 and collected separately. Magnesium Stearate was separately sieved through ASTM # 60 sieve and collected in suitable polybags.

2. Previously sifted Olmesartan Medoxomil was co-sifted with sifted Pregelatinized starch through ASTM # 30 mesh. Further, Amiodipine Besylate was geometrically mixed along with sifted silicified Microcrystalline Cellulose then sifted through ASTM # 30 mesh.

3. Co-sifted and geometrically mixed materials (Olmesartan Medoxomil part and Amiodipine Besylate Part) of step 2 were loaded to a suitable blender along with sifted Croscarmellose sodium and blended for 20 minutes at 15 rpm.

4. Sifted Magnesium Stearate was added to the blend of step 3 and mixed for 5 minutes at 15 rpm and collected in separate double polythene bags.

5. The lubricated blend of step 4 was processed in Roll Compactor and the obtained flakes were collected in double polythene bags.

6. The compacted material of step 5 was sieved through vibratory sifter equipped with ASTM # 20.

7. The blend of step 6 was prelubricated with extragranular portion of Croscarmellose sodium in suitable octagonal blender for 5 mins at slow speed (15 rpm). 8. The blend of step 7 was lubricated with sifted Magnesium Stearate in suitable octagonal blender for 5 mins at slow speed (15 rpm).

9. The lubricated blend as obtained in step 8 was compressed into tablets using a suitable compression machine and punches and film coated using aqueous solution of Opadry^® Brown as per above mentioned formula. Example 11

Manufacturing procedure:

1 . Olmesartan Medoxomil, Amiodipine Besylate and Hydrochlorothiazide were sifted separately through 20# sieve. Pregelatinised starch, Silicified MCC, Croscarmellose sodium were individually sifted through 40 # sieve and separately collected. Further Magnesium Stearate was separately sifted through 60 # sieve and collected in suitable polybags.

2. Previously sifted Olmesartan Medoxomil was co-sifted along with sifted Pregelatinized starch through ASTM # 30 mesh. Further, Amiodipine Besylate was geometrically mixed with half quantity of silicified MCC which was then passed through ASTM # 30 mesh. Further, Hydrochlorothiazide was geometrically mixed with remaining quantity of silicified MCC which was then passed through ASTM # 30 mesh.

3. The co-sifted & geometrical mixed material (Olmesartan Medoxomil part, Amiodipine Besylate Part and Hydrochlorothiazide Part) of step-2 was loaded to a suitable blender along with sifted cross carmellose sodium and blended for 20 minutes at 15 rpm. 4. The blend as obtained in step-3 was lubricated with sifted Magnesium Stearate for 5 minutes at 15 rpm and collected in separate double polythene bags.

5. The Lubricated Blend as obtained in step-4 was processed in Roll Compactor and the obtained flakes were collected in double polythene bags.

6. The compact material as obtained in step-5 was sifted through vibratory sifter equipped with ASTM # 20. Further the # 20 retains as obtained in step-5 were passed through multi mill equipped with 1 .0 mm screen with knives and forwarded at "SLOW" speed, further milled granules were passed through vibratory sifter equipped with ASTM # 20.

7. Croscarmellose sodium was sifted through 40 # sieve and collected separately. Further Magnesium Stearate was sifted through 60 # sieve and collected separately.

8. Sifted Croscarmellose sodium was mixed with step-6 in to octagonal blender for 5 mins at slow speed (15 rpm).

9. The blend as obtained in step-8 was lubricated with sifted Magnesium Stearate into octagonal blender for 5 mins at slow speed (15 rpm).

10. The lubricated blend as obtained in step-9 was compressed into tablets using a suitable compression machine and punches and finally film coated using aqueous solution of Opadry^® Pink as per above mentioned formula.

Example 12

Pharmacokinetic study of Olmesartan Medoxomil and Hydrochlorothiazide tablet

This study was open label, balanced, randomized, two-treatment, two-period, two- sequence, single oral dose, crossover, bioequivalence study with 7 days washout period between the successive dosing days.

The two formulations compared were the Test Product-T of present invention (Olmesartan Medoxomil and Hydrochlorothiazide 40 mg / 25 mg Tablets) (treatment A), and Reference product-R [Benicar HCT^® (Olmesartan Medoxomil / Hydrochlorothiazide 40 mg / 25 mg Tablets)] (treatment B).

In total, 14 healthy adult human volunteers (aged 18-45 years and of body mass index within 18.5 to 24.9 kg/m²' not weighing less than 60 kg) entered in the study and thirteen subjects among the total of 14 completed the study.

Blood samples were collected at the following times: the pre-dose sample was collected within one hour prior to drug administration and the post dose samples were collected at 0.33 ,0.66, 1 , 1.25, 1.5, 1 .75, 2, 2.25, 2.5, 2.75, 3, 3.5, 4, 5, 6, 8, 12,16,24,36 and 48 hours after dosing. Plasma samples were analyzed for Olmesartan Medoxomil and Hydrochlorothiazide concentrations using a validated two 5 separate LC-MS / MS methods. The results of the pharmacokinetic analyses are

shown in fig.3

Under the single dose fasting conditions of this study, the formulation of the tablets of the present invention and Benicar HCT^® 40 mg / 25 mg were bioequivalent, having comparative rates of absorption and comparative extent of absorption.

10 The 90% confidence intervals of test Vs Reference were observed as 91 .68 % to

1 13.32 % for AUC_0-t, 91.83 % to 1 13.60 % for AUC₀-_∞ and 95.93 % to 1 1 1.99% for Cmax and matching with the regulatory agencies bioequivalence acceptance criteria. The formulation of the present invention was therefore, found to be bioequivalent to Benicar HCT^® 40 mg / 25 mg formulation (Daiichi Sankyo). Thus, the formulation of

15 the present invention is clearly suitable and effective for oral administration of

Olmesartan Medoxomil and Hydrochlorothiazide. ible 4: Olmesartan Medoxomil Tablets 40mg packaged in HDPE Bottle with Rayon coil finished prod lalysis data-initial and on stability

20

roduct: Olmesartan Medoxomil Tablets 40mg prepared according to Example 4

ack : HDPE Bottle with Rayon coil

White biconvex oval shaped, film coated tablet debossed with '95' on one site T on otr escription

sides.

5st parameters 1 M 2 M 3 M 3M 3M

Initial

40°C/75%RH 40°C/75%RH 40°C/75%RH 25°C/60%RH 30°C/65%F escription Limits As above As above As above As above As above As above

Not less

than 90.0

% and not

ssay % more than 97.5 99.3 99.9 100.9 97.2 99.3

1 10.0 % of

the label

claim.

elated

jbstances

ipurity-A Not more 0.049 0.043 0.331 0.434 0.285 0.280

)lmesartan) than 1.5%

ighest Not more

0.079 0.079 0.090 0.086 0.078 0.080 n known than 0.2 %

Dtal Not more

0.433 0.475 0.776 0.904 0.618 0.672 ipurities than 3.0 %

Tolerance: Not less than 70 % (Q) of the labeled amount of Olmesartan Medoxomil is dissolved in issolution

minutes.

issolution Time % Release % Release % Release % Release % Release % Release ondition:

)0ml 5 43 49 43 52 54 44 hosphate 10 60 61 58 61 63 56 uffer pH-6.8, 15 66 65 64 65 68 62

SP Type II 20 70 68 67 68 70 66 >addle), 30 74 71 69 71 74 72 ) RPM

45 79 75 75 74 76 76

60 81 78 77 76 77 79 3 5: Olmesartan Medoxomil Tablets 40mg packaged in Alu-Alu Strip Pack finished product /s s data-initial and on stability

duct: Olmesartan Medoxomil Tablets 40mg prepared according to Example 4

:k : Alu-Alu Strip Pack

Claims

We claim:

1 . A pharmaceutical composition comprising micronized particles of Olmesartan Medoxomil having d₀.g less than 10 μηη and one or more pharmaceutically acceptable excipients, wherein the in-vitro dissolution of Olmesartan Medoxomil of said composition is greater than 80% in 30 minutes when measured in USP

Type II (Paddle) Apparatus at 50 rpm using 900 ml of pH-6.8 Phosphate Buffer at 37 ± 0.5°C.

2. The pharmaceutical composition of claim 1 , wherein the micronized particles of Olmesartan Medoxomil are present in an amount of about 2% to about 80% by weight of the composition.

3. The pharmaceutical composition of claim 1 , further comprising one or more pharmaceutically acceptable excipients are selected from a group comprising diluents, binders, disintegrants, lubricants, glidants, surfactants, coloring agents or flavoring agents.

4. The pharmaceutical composition of claim 1 , wherein the composition is in the form of a tablet and/or capsule.

5. The pharmaceutical composition of claim 4, wherein the composition is prepared by direct compression or dry granulation of olmesartan Medoxomil with one or more excipients.

6. The pharmaceutical composition of claim 1 , wherein the composition is used for the treatment or prophylaxis of hypertension or of a cardiovascular disease by administering to a patient in need thereof.

7. The pharmaceutical composition of claim 1 , wherein the composition further comprises one or more anti-hypertensive agent.

8. The pharmaceutical composition of claim 7, wherein the additional antihypertensive agent comprises one or more of thiazide diuretics, β-blockers, calcium channel blockers, rennin inhibitors or ACE inhibitors.

9. A pharmaceutical composition comprising micronized particles of Olmesartan Medoxomil having d₀.g less than 10 μηη, Hydrochlorothiazide and one or more pharmaceutically acceptable excipients, wherein the in-vitro dissolution of Olmesartan Medoxomil of said composition is greater than 80% in 30 minutes when measured in USP Type II (Paddle) Apparatus at 50 rpm using 900 ml of pH-6.8 Phosphate Buffer at 37 ± 0.5°C.

10. The pharmaceutical composition of claim 9, wherein the composition is in the form of a tablet and/or capsule.

1 1. The pharmaceutical composition of claim 10, wherein the composition is prepared by direct compression or dry granulation of olmesartan Medoxomil with one or more excipients.

12. The pharmaceutical composition of claim 9, wherein the composition is used for the treatment or prophylaxis of hypertension or of a cardiovascular disease by administering to a patient in need thereof.

13. A pharmaceutical composition comprising micronized particles of Olmesartan Medoxomil having d₀.g less than 10 μηη, Amlodipine Besylate and one or more pharmaceutically acceptable excipients, wherein the in-vitro dissolution of Olmesartan Medoxomil of said composition is greater than 80% in 30 minutes when measured in USP Type II (Paddle) Apparatus at 50 rpm using 900 ml of pH-6.8 Phosphate Buffer at 37 ± 0.5°C.

14. The pharmaceutical composition of claim 13, wherein the composition is in the form of a tablet and/or capsule.

15. The pharmaceutical composition of claim 14, wherein the composition is prepared by direct compression or dry granulation of olmesartan Medoxomil with one or more excipients.

16. The pharmaceutical composition of claim 13, wherein the composition is used for the treatment or prophylaxis of hypertension or of a cardiovascular disease by administering to a patient in need thereof.

17. A pharmaceutical composition comprising micronized particles of Olmesartan Medoxomil having d₀.g less than 10 μηη, Hydrochlorothiazide, Amlodipine Besylate and one or more pharmaceutically acceptable excipients, wherein the in-vitro dissolution of Olmesartan Medoxomil of said composition is greater than 80% in 30 minutes when measured in USP Type II (Paddle) Apparatus at 50 rpm using 900 ml of pH-6.8 Phosphate Buffer at 37 ± 0.5°C.

18. The pharmaceutical composition of claim 17, wherein the composition is in the form of a tablet and/or capsule.

19. The pharmaceutical composition of claim 18, wherein the composition is prepared by direct compression or dry granulation of olmesartan Medoxomil with one or more excipients.

20. The pharmaceutical composition of claim 17, wherein the composition is used for the treatment or prophylaxis of hypertension or of a cardiovascular disease by administering to a patient in need thereof.

21. A pharmaceutical composition comprising micronized particles of Olmesartan Medoxomil having d₀.g between 4 μηη to 8 μηη and one or more pharmaceutically acceptable excipients. Fig. 3 Graphical representation of linear mean plot of Olmesartan Medoxomil (Test Product-T and Reference Product- R) plasma concentration Vs Time for all subjects under Fasting condition. (n= 13).