For most of the drugs neither of the approaches used alone improve dissolution characteristics. The reduction of particle size of hydrophobic drugs also lead to increased surface charges (static charges) resulting in the agglomeration of the partices, especially in an aqueous media because of thermodynamic repulsion. This results in significant decrease in the effective or exposed surface area available for dissolution. This tendency of micronized particles to agglomerate is generally reduced by the addition of a surfactant.
PCT application WO/2007/047838 filed by Dr. Reddy's relates to a process of preparing olmesartan medoxomil having lesser impurities and a particle size distribution such that d09 is less than 250 urn.
PCT application WO/2008/117707 filed by Daichii Sankyo relates to ground crystals of olmesartan medoxomil having particle size distribution such that d0.9 is less than 75 urn, preferably less than 66 urn and most preferably less than 57 urn.
The present inventors have found that further reduction of the particle size of olmesartan medoxomil (i.e. less than 50 urn), even without addition of a surfactant leads to remarkably improved solubility characteristics and as a result, a pharmaceutical composition having an improved dissolution profile can be obtained.
SUMMARY OF THE INVENTION
The present invention relates to pharmaceutical compositions comprising micronized olmesartan medoxomil and processes thereof.
One of the aspects of the present invention provides the pharmaceutical composition comprising micronized particles of olmesartan medoxomil having d0.9 less than 50 urn.
According to another embodiment the present invention relates to pharmaceutical composition comprising micronized particles of olmesartan medoxomil having do.g between 1pm to 50 urn.
According to yet another embodiment the present invention relates to pharmaceutical composition comprising micronized particles of olmesartan medoxomil having do.g between 2pm to 25 urn.
According to still another embodiment the present invention relates to pharmaceutical composition comprising micronized particles of olmesartan medoxomil having do.g between 4pm to 10 pm.
In still another embodiment the pharmaceutical composition according to the present invention is in the form of a tablet, dispersible tablet, capsule, granule, pellet, bead, powder, suspension, elixir or syrup. More particularly the composition of the present invention is in the form of a tablet.
According to yet another embodiment pharmaceutical composition of the present invention further comprises one or more pharmaceutically acceptable excipients selected from the group comprising diluents, binders, disintegrants, lubricants, coloring agents or flavoring agents.
According to still another embodiment the pharmaceutical composition of the present invention comprises micronized olmesartan medoxomil in an amount of 2 % to 80 % by weight of the composition.
Another aspect of the present invention provides micronized particles of olmesartan medoxomil having do.g less than 50 pm.
Another embodiment of the present invention relates to micronized particles of olmesartan medoxomil having d09 between 1pm to 50 pm.
Yet another embodiment of the present invention relates to micronized particles of olmesartan medoxomil having do g between 2pm to 25 pm.
Still another embodiment of the present invention relates to micronized particles of olmesartan medoxomil having do 9 between 4pm to 10 urn.
According to yet another aspect pharmaceutical composition comprising micronized particles of olmesartan medoxomil is prepared by blending olmesartan medoxomil with one or more pharmaceutically acceptable excipients. Further blend is either directly compressed or formulated into granules using wet or dry granulation techniques.
In another aspect there is provided a method for the treatment or prophylaxis of hypertension or of a cardiovascular disease by administering to a person in need thereof a pharmaceutical composition of the present invention.
According to yet another aspect composition of the present invention can also be administered in combination with another antihypertensive agent.
According to one of the embodiments another antihypertensive drug includes thiazide diuretics, (3-blockers, calcium channel blockers, rennin inhibitor, and ACE inhibitors.
Another aspect of the present invention relates to pharmaceutical composition comprising micronized olmesartan medoxomil particles and hydrochlorothiazide wherein said micronized olmesartan particles have d09 less than 50 urn.
According to yet another aspect the present invention relates to pharmaceutical composition comprising micronized olmesartan medoxomil particles and amlodipine wherein said micronized olmesartan particles have d0 9 less than 50 urn.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a novel pharmaceutical composition comprising micronized olmesartan medoxomil and processes thereof.
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 d0.9 less than 50 urn, particularly between 1 urn to 50 urn, more particularly between 2 urn to 25 urn. Most particularly it relates to olmesartan medoxomil particles having do.g between 4um to 10 urn.
The term "do.9" as used herein with reference to the size of micronized olmesartan medoxomil particles, indicate that about 90 volume % of particles measured have a size less than the defined do.9 value, and that about 10 volume % of particles measured have a size greater than the defined do.9 value.
The phrase "therapeutically effective amount" as used herein means the 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.
The particle size distribution of olmesartan medoxomil particles of the present invention may be determined using optical microscopic method, sedimentation techniques for example pipette analysis using an Andreassen pipette, sedimentation scales, photosedimentometers 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 by Laser diffraction using a Malvern® Mastersizer laser diffraction instrument.
The pharmaceutical composition comprising micronized olmesartan medoxomil may further comprise one or more pharmaceutically acceptable excipients selected from a group comprising but not limited to diluents, binders, disintegrants, lubricants, coloring agents, flavoring agents or any other excipients known in the art.
Suitable examples of diluents include, but are not limited to, 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, but are not limited to polyvinylpyrrolidone, starch mucilage, pregelatinized starch, sodium alginate, alginic acid, acacia mucilage, tragacanth, hydroxypropylmethyl cellulose, carboxymethylcellulose sodium, carboxymethylcellulose calcium, microcrystalline cellulose, ethyl cellulose, polyethylene glycol, hydroxyethyl cellulose, hydroxy propyl cellulose, methyl cellulose, polymethacrylates, carboxyvinyl polymers, carbopols, and combinations thereof.
Suitable examples of disintegrants include, but are not limited to, 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.
TECHNICAL FIELD OF THE INVENTION
The present invention relates to pharmaceutical compositions comprising micronized particles of olmesartan medoxomil and processes thereof.
BACKGROUND OF THE INVENTION
Olmesartan medoxomil, chemically described as (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate, is widely used for the treatment of hypertension and related diseases and conditions due to its ability to inhibit the angiotensin-converting enzyme. Olmesartan medoxomil is a prodrug, which is hydrolyzed to olmesartan during absorption from the gastrointestinal tract.
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 Daichii Sankyo and are covered by a patent, US 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.
Olmesartan medoxomil is practically insoluble in water. This leads to low rate of dissolution of olmesartan medoxomil in aqueous media (including gastrointestinal fluids), which results in inadequate bioavailability after oral ingestion.
Two most common approches employed in prior art to increase the dissolution rate of a poorly soluble drug is either reduction of the particle size of the drug or addition of a surfactant. Reduction of particle size leads to increased surface area and addition of surfactant improves the surface propertries of the drug particles thereby improving the dissolution characteristics of a poorly soluble drug.
Examples of lubricants and glidants include, but are not limited to, 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 compositions of the present invention may optionally contain surfactants.
Surfactants/wetting agents include both non-ionic and ionic (cationic, anionic and zwitterionic) surfactants suitable for use in pharmaceutical compositions. These include but are not limited to, 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 comprising micronized olmesartan medoxomil, wherein the said composition may be in the form of tablets, dispersible tablets, capsules, granules, beads, pellets, powder, suspension, emulsion, syrups 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.
The oral pharmaceutical compositions of the present invention 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.
The pharmaceutical composition according to the present invention comprising micronized olmesartan medoxomil may be administered for the treatment or prophylaxis of hypertension or of a cardiocascular disease.
Further, pharmaceutical compositions described herein can also be administered in combination with other antihypertensive agents selected from thiazide diuretics, (3-blockers, calcium channel blockers, rennin inhibitors or ACE inhibitors.
The following examples represent various embodiments according to the present invention. The examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention, as many variations thereof are possible without departing from the spirit and scope of the invention.
EXAMPLES 1,2, 3 &4
Tablets comprising olmesartan medoxomil having dog 116 urn, 67 urn, 22 urn & 6 um respectively
(TABLE REMOVED)
Process:
(i) Olmesartan medoxomil and microcrystalline cellulose were sieved and blended together.
(ii) Lactose monohydrate and L-hydroxypropylcellulose were sieved and mixed with the blend of step (i).
(iii) Hydroxy propyl cellulose was dissolved in purified water. (iv) Blend of step (ii) was granulated using the binder solution of step (iii). (v) Granules of step (iv) were dried in a fluidized bed dryer. (vi) Dried granules of step (v) were sieved, (vii) Magnesium stearate was mixed with granules of step (vi). (viii) Finally the blend of step (vii) was compressed into tablets. (ix) The coating material was dispersed in purified water to prepare coating solution.
(x) The compressed tablets were then coated using coating solution of step (ix).
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 1000 ml of phosphate buffer (pH 6.8) at 37 °C using USP apparatus II with paddle speed at 50 rpm. Table 1 provides comparative dissolution profile.
(TABLE REMOVED)
Comparative dissolution profile of the examples 1, 2, 3 & 4 indicate that as the particle size of olmesartan medoxomil decreases the dissolution percentage increases.

WE CLAIM:
1. A pharmaceutical composition comprising micronized particles of olmesartan medoxomil having do.g less than 50 urn and one or more pharmaceutically acceptable excipients.
2. The pharmaceutical composition of claim 1 wherein said micronized particles of olmesartan medoxomil have d0. 9 between 2 urn to 25 urn.
3. The pharmaceutical composition of claim 1 wherein said micronized particles of olmesartan medoxomil have d0.9 between 4 urn to 10 urn.
4. The pharmaceutical composition according to claim 1 wherein olmesartan medoxomil is present in an amount of about 2% to about 80% by weight of the composition.
5. The pharmaceutical composition of claim 1 wherein said composition is in the form of a tablet, dispersible tablet, capsule, granule, pellet, bead, powder, suspension, elixir or syrup.
6. The pharmaceutical composition of claim 1 wherein said one or more pharmaceutical^ acceptable excipients are selected from a group comprising diluents, binders, d is integrants, lubricants, coloring agents or flavoring agents.
7. Olmesartan medoxomil particles having d0.9 less than 50 urn.
8. Olmesartan medoxomil particles according to claim 7 wherein said particles have d0.9 between 2 urn to 25 urn.
9. Olmesartan medoxomil particles according to claim 7 wherein said particles have d0.9between 4 urn to 10 urn.
10. A pharmaceutical composition comprising therapeutically effective amount of micronized olmesartan medoxomil substantially as described and illustrated herein.