FIELD OF THE INVENTION
The present invention relates to pharmaceutical composition of telmisartan comprising a water soluble diluent in an amount more than 70 percent by weight of the composition.
BACKGROUND OF THE INVENTION
Telmisartan is a non-peptide angiotensin II receptor (type AT1) antagonist developed for the treatment of hypertension and for treating other cardiovascular disorders including cardiac insufficiency, ischaemic peripheral circulation disorders, myocardial ischaemia (angina). Its chemical name is 4'-[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)- benzimidazol-1-ylmethyl]-biphenyl-2-carboxylic acid. It may be used alone or in combination with other hypertensive agents, such as hydrochlorthiazide. EP 0502314 discloses telmisartan and the physiologically acceptable salts thereof can also be used to treat cardiac insufficiency, ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), diabetic neuropathy, glaucoma, gastrointestinal diseases, bladder diseases, and to prevent progression of cardiac insufficiency after myocardial infarct.
Telmisartan is commercially marketed under the trade name Micardis® and available as 20, 40 and 80 mg tablets for oral administration. It is generally manufactured and supplied in free acid form. As disclosed in WO 00/43370, crystalline telmisartan exists in two polymorphic forms having different melting points. Under the influence of heat and humidity, the lower melting point polymorph B transforms irreversible into the higher melting polymorph A. Both forms are characterized by a very poor solubility in aqueous systems at the physiological pH range of the gastro-intestinal tract of between pH 1 to 7.
WO 00/27397 discloses spray-dried granules comprising telmisartan and tablets comprising these granules.
US 2004/0110813 discloses that the solubility of telmisartan can be increased several hundred fold by a pharmaceutical composition comprising 3 to 50 wt%. of telmisartan dispersed in a dissolving matrix comprising a) a basic agent wherein the molar ratio of basic agent: telmisartan = 1:1 to 10:1, b) a surfactant or emulsifier in an amount of about 1 to 20% of the final composition, c) 25 to 70% of a water soluble diluent, and d) optionally 0 to 20% of further excipients and/or adjuvants.
WO 07/061415 discloses a pharmaceutical composition comprising telmisartan and less than 25% of water soluble diluents.
SUMMARY OF THE INVENTION
We have now developed a pharmaceutical composition of telmisartan comprising a water soluble diluent in an amount more than 70 percent by weight of the composition.
According to one of the aspect, there is provided a pharmaceutical composition of telmisartan comprising a water soluble diluent in an amount more than 70 percent by weight of the composition.
In another aspect, there is provided a pharmaceutical composition of telmisartan comprising a water soluble diluent in an amount about 75-90 percent by weight of the composition.
According to another aspect, there is provided a process for the preparation of a pharmaceutical composition comprising the steps of-
(a) blending the spray dried telmisartan with a water soluble diluent,
(b) lubricating the blend of step (a),
(c) compressing the blend into suitable sized tablets;
wherein the composition comprises more than 70% of water soluble diluent.
According to another aspect, there is provided a process for the preparation of a pharmaceutical composition comprising the steps of-
(a) dissolving telmisartan along with one or more basic agents in water,
(b) spray-drying the solution of step a) to obtain spray-dried telmisartan,
(c) blending spray-dried telmisartan with a water soluble diluent,
(d) lubricating the blend of step (c),
(e) compressing the blend into suitable sized tablets
wherein the composition comprises more than 70% of water soluble diluent.
In another aspect, there is provided a method for the treatment of hypertension, the method comprising: orally administering to a subject a pharmaceutical composition of telmisartan comprising a water soluble diluent in an amount more than 70 percent by weight of the composition.
DETAILED DESCRIPTION
The term 'telmisartan' as employed herein is intended to include isomers, cis and trans forms of telmisartan or mixture thereof or any pharmaceutically acceptable salts such as alkali metal (e.g. sodium and potassium) salts and alkaline earth metal (e.g. calcium and magnesium) salts. Telmisartan may be used in any polymorphic form such as Form A or Form B.
The term "water-soluble diluent" as used herein refers to a compound, used in the art as diluent, for use in a pharmaceutical composition which is soluble in an aqueous environment. Suitable water-soluble diluents for use in the pharmaceutical composition of the present invention include lactose, sucrose, glucose, maltodextrin, mannitol, potassium chloride, sodium chloride, sorbitol, erythritol and xylitol.
The total amount of the water-soluble diluent is more than 70% by weight of the total composition. In a preferred embodiment of the invention, the relative amount of the water-soluble diluent is preferably from about 75% to about 90% by weight of the pharmaceutical composition.
The term 'pharmaceutical composition' as used herein includes solid dosage forms such as tablet, capsule, pill and the like.
The pharmaceutical composition may further comprise one or more pharmaceutically acceptable excipients which include binders, surfactants, lubricants/glidants, disintegrants, basic agents, plasticizers, opacifiers, coloring agents, plasticizers and the like.
Specific examples of suitable basic agents include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline carbonates and bicarbonates such as sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate; alkaline phosphates such as disodium hydrogen phosphate, dipotassium hydrogen phosphate; basic amino acids such as arginine; and Meglumine (N-methyl-D-glucamine). The amount of basic agent may vary from about 0.05-15% by weight of the total composition.
The surfactants may be ionic or non-ionic. Specific examples of surfactants include poloxamers or pluronics, polyethylene glycols, polyethylene glycol monostearate, polyglycerized fatty acids, polysorbates, sodium lauryl sulfate, polyethoxylated and hydrogenated castor oil. Suitable poloxamers may have an average molecular weight of about 2000 to 12000, preferably 4000 to 10000, most preferred 6000 to 10000. Examples of specific poloxamers are poloxamer 182LF, poloxamer 331 and poloxamer 188. The amount of surfactant may vary from about 0.1-15% by weight of the total composition.
Specific examples of binders include cellulose derivatives such as methyl cellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose; polyvinylpyrrolidone (povidone), polymethacrylates, gelatin, guar gum, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, starch, propylene glycol, and the like.
Suitable examples of lubricants/glidants include stearic acid, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, glyceryl monostearate, glyceryl palmitostearate,
hydrogenated vegetable oil, mineral oil, sodium lauryl sulfate, talc, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and the like.
Suitable examples of disintegrants include sodium starch glycolate, pregelatinized starch, powdered cellulose, crospovidone, croscarmellose sodium, microcrystalline cellulose, sodium carboxymethylcellulose and dried corn starch.
The composition may be further coated with a functional or non functional coating. The coating composition may comprise pharmaceutically acceptable excipients such as plasticizers, opacifiers and coloring agents. Examples of plasticizers include acetylated triacetin, triethyl citrate, tributyl citrate, glycerol tributyrate, diacetylated monoglyceride, polyethylene glycols, propylene glycol, sesame oil, acetyl tributyl citrate, acetyl triethyl citrate, diethyl oxalate, diethyl phthalate, diethyl maleate, diethyl fumarate, dibutyl succinate, diethylmalonate, dioctyl phthalate, dibutyl sebacate, and the like.
Examples of opacifiers include titanium dioxide and the like.
Examples of coloring agents include Iron oxide, Ferric oxide yellow, Lake of Tartrazine, Allura red, Lake of Quinoline yellow, Lake of Erythrosine.
According to one of the embodiment, there is provided a process of the preparation of telmisartan
by spray drying, comprising the steps of:
i) dissolving sodium hydroxide in purified water,
ii) dissolving polyvinylpyrrolidone and meglumine in solution of step i),
iii) dissolving telmisartan in solution of step ii) under stirring, iv) spray-drying the solution of step iii) to obtain spray-dried telmisartan.
According to another embodiment, there is provided a process for the preparation of
pharmaceutical composition comprising the steps of-
i) dissolving telmisartan along with one or more basic agents in water,
ii) spray-drying the solution of step i) to obtain spray-dried telmisartan,
iii) blending the spray-dried telmisartan of step ii) with a water-soluble diluent,
iv) lubricating the blend of step iii)
v) compressing the blend into suitable size tablets or filing into suitable size capsules.
According to yet another embodiment, there is provided a process for the preparation of a
pharmaceutical composition comprising the steps of-
i) blending the spray-dried telmisartan with a water-soluble diluent and a surfactant,
ii) lubricating the blend of step i),
iii) compressing the final blend into suitable sized tablets.
According to another embodiment, there is provided a process for the preparation of a pharmaceutical composition comprising the steps of-
i) blending the spray dried telmisartan with sorbitol and poloxamer,
ii) lubricating the blend of step i),
iii) compressing the final blend into suitable sized tablets.
The following examples are representative of the invention, but are not to be construed as limiting the scope of the claims.
Examples Example 1

(Table Removed)
Procedure:
1. Sodium hydroxide was dissolved in purified water.
2. Povidone and Meglumine were dissolved in solution of step 1.
3. Telmisartan was dissolved in solution of step 2 under stirring.
4. The solution of step 3 was spray dried under suitable temperature conditions.
5. Spray dried telmisartan of step 4 was blended with Poloxamer and Sorbitol.
6. The blend of step 5 was lubricated and compressed into suitable sized tablets.
Example 2

(Table Removed)
Procedure:
1. Sodium hydroxide was dissolved in purified water.
2. Povidone and Meglumine were dissolved in solution of step 1.
3. Telmisartan was dissolved in solution of step 2 under stirring.
4. The solution of step 3 was spray dried under suitable temperature conditions.
5. Spray dried telmisartan of step 4 was blended with Sorbitol.
6. The blend of step 5 was lubricated and compressed into suitable sized tablets.
Dissolution data:
Telmisartan tablets of Example 1 and 2 were subjected to in-vitro dissolution studies using an Apparatus II (Paddle Method) as described in the European Pharmacopoeia II. In these tests, the dissolution of the tablets of example 1 and 2 was compared with dissolution of the reference tablet formulation (Micardis®). The study was conducted at a paddle speed of 75 rpm, at a temperature of 37°C, in a phosphate buffer of pH 7.5. The results of these dissolution tests are presented in table 1.
Table 1: Dissolution data of above examples

(Table Removed)

WE CLAIM:
1. A pharmaceutical composition of telmisartan comprising a water-soluble diluent in an amount from about 75% to about 90% of the total weight of the composition.
2. The pharmaceutical composition according to claim 1 wherein the water soluble diluent is selected from the group consisting of lactose, sucrose, glucose, maltodextrin, mannitol, potassium chloride, sodium chloride, sorbitol, erythritol and xylitol.
3. The pharmaceutical composition according to claim 1 wherein the composition is a tablet or capsule.
4. The pharmaceutical composition according to claim 1 wherein the composition further comprises pharmaceutically acceptable excipients selected from the group consisting of binders, surfactants, lubricants/glidants, disintegrants, basic agents, plasticizers, opacifiers, coloring agents and plasticizers.
5. The pharmaceutical composition according to claim 4 wherein the surfactant is selected from the group consisting of poloxamers, polyethylene glycols, polyethylene glycol monostearate, polyglycerized fatty acids, polysorbates, sodium lauryl sulfate, polyethoxylated and hydrogenated castor oil.
6. The pharmaceutical composition according to claim 4, wherein the basic agent is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, arginine and Meglumine.
7. The pharmaceutical composition according to any of the preceding claims wherein the composition comprises

a) about 5-20 wt.% of Telmisartan,
b) about 75-90 wt. % of water soluble diluent,
c) about 0.05-15 wt. % of basic agents, and
d) about 0.1-15 wt. % of surfactant.
8. The pharmaceutical composition according to any of the preceding claims wherein the
composition comprises
a) about 5-20 wt.% of Telmisartan,
b) about 75-90 wt% of Sorbitol,
c) about 0.05- 5 wt.% of Sodium hydroxide, and
d) about 0.1 - 5 wt. % of Poloxamer.
9. The pharmaceutical composition according to any of the preceding claims, wherein the
composition is prepared by a process comprising the steps of:
a) dissolving telmisartan along with one or more basic agents in water,
b) spray-drying the aqueous solution of step a) to obtain spray-dried telmisartan,
c) blending the spray dried telmisartan with a water soluble diluent and optionally other pharmaceutically acceptable excipients,
d) lubricating the blend of step (c), and
e) compressing the blend into suitable sized tablets or filing into suitable size capsules.
10. The pharmaceutical composition of telmisartan as used and exemplified herein.