WO2011025467A1

WO2011025467A1 - Solid dosage forms comprising telmisartan

Info

Publication number: WO2011025467A1
Application number: PCT/TR2010/000168
Authority: WO
Inventors: Bilgic Mahmut
Original assignee: Bilgic Mahmut
Priority date: 2009-08-24
Filing date: 2010-08-13
Publication date: 2011-03-03
Also published as: TR200906506A2

Abstract

The present invention is related to monolayer oral dosage forms comprising telmisartan and hydrochlorothiazide as active agents and the compositions of these forms and the preparation method of these dosage forms.

Description

SOLID DOSAGE FORMS COMPRISING TELMISART AN Field of the Invention

The present invention relates to stable oral dosage forms comprising telmisartan and hydrochlorothiazide as an active agent. Background of the Invention

Telmisartan was described in the patent numbered EP502314 for the first time and was indicated for use in the treatment of hypertension and was described as an angiotensin II receptor antagonist. Chemical name of this molecule shown with the chemical structure indicated in Formula 1, is known as 4'-[(l,4'-dimethyl-2'-propyl [2,6'-bi-lH-benzimidazole]- 1 '-yl)methyl]-[l , 1 '-bifenyl]-2-carboxylic acid.

FORMULA I

When its physical features are considered, telmisartan is a white or light yellow solid and in sense of its solubility, although it can not be dissolved in water and strong acids, it is observed that it can be dissolved in strong bases.

Hydrochlorothiazide which is also known as "HCTZ" or "HCT" in short has the chemical structure shown with Formula 2 as seen below. It is a diuretic drug and its chemical name is known as 6-chloro-3,4-dihydro-2H-l,2,4-benzothiadiazine-7-sulfonamide 1,1 -dioxide. Hydrochlorothiazide is in the form of an odorless white powder and it has low solubility in water.

FORMULA II It's known that both diuretic and angiotensin II receptor antagonists are effective on renin- angiotensin system. Angiotensin II receptor antagonists decrease blood pressure by blocking angiotensin receptor. Diuretics decrease both sodium amount and liquid volume by regulating sodium balance. As explained in patent applications numbered WO 2006/063737 and US 2006/0159747, generally more than one anti-hypertensive drugs should be used in order to obtain blood pressure in the desired level for treatment of hypertension. Combination of telmisartan/hydrochlorothiazide is preferred due to its synergic effect.

Although the usage of telmisartan/hydrochlorothiazide combination has an important role in treatment of hypertension, it is known that telmisartan's solubility is very low between pH

1-7 which is the physiological pH value of gastrointenstinal tract and it is required that basic agents such as meglumin, diethanolamin, sodium hydroxide, sodium bicarbonate are used in tablet formulations to solve this problem. On the other hand, hydrochlorothiazide is not stable and degrades under alkali conditions, so it causes a lot of problems about development of formulation retaled to the said product.

Bilayer tablet forms are described in European patent numbered EP 1467712 for the purpose of solving this problem. The described method include preparing different formulations where different matrices for each active agent are prepared and the compositions are then pressed on top of each other to solve the incompatibility problem of these two agents. In the patent application numbered WO 2007/060170 tablet compositions characterized by the ratio of stabilizing agent to telmisartan and ratio of emulsifier and water soluble dilutent to total weight of tablet are described.

Although it is possible to solve this problem with bilayer tablet, considering that more energy and work power are required to prepare these kinds of tablets, it is clearly seen that formulations of stable telmisartan/hydrochlorothiazide should be developed,.

Summary of the Invention

The present invention relates to the preparation of stable monolayer tablet formulations comprising telmisartan/hydrochlorothiazide combination. Surprisingly, it is seen that tablet formulations comprising buffering agent in the range of 1-20% with respect to the tablet weight in addition to basic agent, has tablet solubility in the desired level and degradation of hydrochlorothiazide present in the tablet is prevented without the requirement of the production of bilayer tablet.

Accordingly, the first aspect of the invention is the stable oral tablet formulations comprising telmisartan and hydrochlorothiazide. The second aspect of the invention is to use buffering agent in the range of 1-20% in the formulation of monolayer oral tablet including telmisartan and hydrochlorothiazide.

Another aspect of the invention is the presence of the water soluble diluent in the range of 60-90% by the total tablet weight in tablet formulation comprising a combination of telmisartan/hydrochlorothiazide that is prepared for oral application. Detailed Description of the Invention

Surprisingly, it is seen that solubility and stability are increased when the formulation given below is used in monolayer tablets comprising telmisartan and hydrochlorothiazide as active agents.

Considering that the total of the whole components is 100%; The monolayer tablet formulation wherein;

- The ratio of telmisartan weight to final tablet weight is in the range of 1-25%

- The ratio of hydrochlorothiazide weight to final tablet weight is in the range of 0,1-10% The ratio of weight of water solvable diluent to final tablet weight is in the range of 60-90%

- The ratio of buffering agent weight to final tablet weight is in the range of 1-20%

- The ratio of basic agent weight to final tablet weight is in the range of 0.01-5% and other excipients are optionally present in the range of 1-20% with respect to the final tablet weight.

Pharmaceutical composition that is subject of the present invention is preferably formulated for oral tablet dosage form. Accordingly, another aspect of the invention is pharmaceutical compositions comprising telmisartan and hydrochlorothiazide as active agent and in addition to that the pharmaceutical composition may further comprise at least one water soluble diluent, basic agent and buffering agent in the ratios given above, and the formulation optionally comprises binding agent, dispersing agent, lubricant, glidant and other pharmaceutical acceptable excipients. Telmisartan used as an active agent is in stable form and is optionally in the crystal form.

Water soluable diluents used in the formulation can be chosen from a group comprising lactose, maltitol, magnesium oxide, magnesium carbonate, maltose, mannitol, maltose, strach, sucrose, xylitol but it should not be limited by these. The buffering agent used in the formulation can be chosen from a group comprising 3-

{[tris(hydroxymethyl) methyl]amino} propane sulfonic acid, N,N-bis(2-hydroxyethyl) glycine, tris(hidroxymethyl)methylamin, N-tris (hydorxymethyl) methylglycine, malic asit, potassium citrate, citric asit, 4-2-hydroxyethyl-l-piperazinethane sulfonic acid, 2- {[tris(hydroxymethyll)methyl] amino }ethanesulfonic acid, 3-(N-morpholine)propansulfonic acid, piperazine-N,N'-bis(2-ethanesulfonic asid), 2-(N- morpholine) ethanesulfonic acid but it should not be limited by these.

Basic agent used in the formulation can be chosen from the group comprising potassium bicarbonate, potassium citrate, potassium hydoxide, ammonia, sodium bicarbonate, sodium hydroxide. In the mentioned formulation, binding agents that can optionally be used can be chosen from the group comprising methyl cellulose, maize starch, polyvinylpyrrolidone, crystalized cellulose, hydroxymethyl cellulose but should not be limited by these.

Dispersing agents that will be optionally used in the formulation can be chosen from the group comprising croscarmellose sodium, crospovidone, microcrystalline celluose, hydroxypropyl celluose, povidone, sodium alginate, starch but it should not be limited by these.

Lubricants that will be optionally used in the formulation can be chosen from the group comprising calcium stearate, glyceryl monostearate, magnessium monostearate, polyethylene glycol, sodium lauryl sulfoacetate, potassium benzoate, stearic acid, magnessium stearate, polyvinyl alcohol but it should not be limited by these.

Glidants that will be optionally used in the formulation can be chosen from the group comprising celluose, silicon dioxide, magnessium silicate and starch but it should not be limited by these.

Other than the ones that are mentioned above, additional excipients such as preservatives, coloring agents, antioxidants, anti-adhesion substances, substances for demolding, silica flow modulators can be present in the formulation but additional excipients should not be limited by these.

Telmisartan is present in an amount in the range of 1-25%, preferably in the range of % 5-20 and more preferably in the range of 8-15% by weight of the tablet. Hydrochlorothiazide is present in an amount in the range of 0,1-10%, preferably in range of

0,5-8% and more preferably in the range of 1-5% by weight of the tablet.

Preferably, water soluble diluent is present in an amount in the range of 60-90% by weight of the tablet.

Buffering agent is present in an amount in the range of 1-20%, preferably in the range of % 1-10, more preferably in the range of 1 -5% by weight of tablet.

Preferably, binding agent is present in an amount in the range of 0,1-5%, dispersing agent is present in an amount in the range of 0,1-5% by weight, lubricant is present in an amount in the range of 0,1-3% by weight, glidant is present in an amount in the range of 0,05-2% by weight, basic agent is present in an amount in the range of 0,1-0,8% by weight and coloring agent is present in an amount in the range of 0,01-0,05% by weight of the tablet.

Pharmaceutical composition of the invention, for instance, can be prepared by the methods of dry-blending or wet-granulation or with a method comprising both of them, by using standart technics and manufacturing processes commonly known in technology.

Not limited by this example, a method for the preparation of monolayer pharmaceutical composition that is subject of the invention can include the steps shown below: a) granulating the diluent by granulation solution that comprises telmisartan, basic agent and buffering agent and drying the granules;

b) Dry-blending of the hydrochlorothiazide and other pharmaceutical acceptable excipients; c) Combining the mixture resulting from the steps a and b and compressing them. Considering the above mentioned processes, another aspect of the invention is to form a method to prepare stable monolayer tablet formulations including telmisartan and hydrochlorothiazide, this method includes usage of at least one buffering agent and 60-90% of diluent by weight of the tablet formulation. Example :

(1) Ammonia and ethyl alcohol are mixed, telmisartan is added to the obtained solution and mixed, and then polyvinylpyrrolidon is added and mixed and finally, Tris(hydroxymethyl)methylamine is added and mixed. Mannitol is transferred to the fluidized bed and granulated with the solution including telmisartan. The obtained granule is dried and sieved. (2) Hydrochlorothiazide, mannitol, Aerosil 200, starch RX 1500 and red iron oxide are mixed in stirrer and sieved. (3) The mixture obtained in step 1 and step 2 are blended and then magnesium stearate is added and mixed. The obtained mixture is fed to the tablet pressing machine and pressed as a tablet.

Claims

1. A stable and monolayered pharmaceutical composition comprising telmisartan and hydrochlorothiazide, characterized in that the composition comprises buffering agent in an amount in the range of 1-20% by weight

2. The pharmaceutical composition comprising telmisartan and hydrochlorothiazide according to claim 1, characterized in that the buffering agent used is present in an amount in the range of 1-20%, preferably in the range of 1-10% and more preferably in the range of 1-5% by weight.

3. The pharmaceutical composition comprising telmisartan and hydrochlorothiazide according to claim 1, characterized in that the buffering agent used is chosen from the group comprising 3- {[tris(hydroxyrnethyl)methyl] amino} propane sulfonic acid, N,N-bis(2- hydroxyethyl) glycine, tris(hidroxyrnethyl)methylamin, N-tris(hydorxymethyl) methylglycine, malic asit, potassium citrate, citric asit, 4-2-hydroxyethyl-l-piperazinethane sulfonic acid, 2-{[tris(hydroxymethyll)methyl]amino}ethanesulfonic acid, 3-(N- morpholine)propansulfonic acid, piperazine-N,N'-bis(2-ethanesulfonic asid), 2-(N- morpholine) ethanesulfonic acid.

4. The pharmaceutical composition according to any of the previous claims, characterized in that telmisartan that is used as an active agent is preferably in the crystal form.

5. The pharmaceutical composition comprising telmisartan and hydrochlorothiazide according to claim 1, characterized in that said composition additionally comprises at least one water soluble diluent, binding agent, dispersing agent, lubricant, glidant, basic agent, coloring agent, buffering agent and preferably other pharmaceutically acceptable excipients.

6. The pharmaceutical composition according to any of the previous claims, characterized in that active agent is present in an amount in the range of 1-35% by weight, preferably in the range of 3-30% and more preferably in the range of 5-25% by weight of the tablet.

7. The pharmaceutical composition comprising telmisartan and hydrochlorothiazide according to any of the previous claims, characterized in that telmisartan is present in an amount in the range of 1-25%, preferably 5-20% and more preferably in the range of 8-15% by weight of the tablet.

8. The pharmaceutical composition comprising telmisartan and hydrochlorothiazide according to any of the previous claims, characterized in that hydrochlorothiazide is present in an amount in the range of 0,1-10%, preferably 0,5-8% and more preferably 1-5% by weight of the tablet.

9. The pharmaceutical composition according to any of the previous claims, characterized in that with respect to the total tablet weight there are a) at least one binding agent in an amount in the range of % 0,1-5 b) at least one dispersing agent in an amount in the range of % 0,1-5 c) at least one lubricant in an amount in the range of % 0,1-3 d) a glidant in an amount in the range of % 0,05-2 e) a basic agent in an amount in the range of % 0,1-0,8 f) a coloring agent in an amount in the range of % 0,01-0,05 and g) at least one buffering agent in an amount in the range of % 1-20, preferably in the range of % 1-10 and more preferably in the range of % 1-5.

10. The pharmaceutical composition according to any of the previous claims, characterized in that at least one water soluble diluent is present in an amount range of % 60-90 with respect to the total tablet weight.

11. The pharmaceutical composition according to any of the previous claims, characterized in that water soluble diluent is chosen from the group comprising; maltilol, magnesium oxide, magnesium carbonate, maltose, mannitol, sorbitol, starch, sucrose, xylitol.

12. Water soluble diluent according to claim 11, wherein said water soluble diluent is mannitol or lactose or a mixture of these..

13. The pharmaceutical composition according to any of the preceding claims, characterized in that binding agent is chosen from the group comprising methyl cellulose, maize starch, polyvinylpyrrolidone, crystalline cellulose, hydroxymethyl cellulose.

14. The pharmaceutical composition according to claim 13, characterized in that the preferred binding agent is polyvinyl pyrrolidine or starch or mixture of both.

15. The pharmaceutical composition according to any of the preceding claims, characterized in that dispersing agent is chosen from the group comprising crosscarmellose sodium, crospovidone, microcrystalline cellulose, hydroxypropyl cellulose, povidone, sodium alginate, starch.

16. The pharmaceutical composition according to claim 15, characterized in that preferred dispersing agent is microcrystalline cellulose or starch or mixture of them.

17. The pharmaceutical composition according to any of the preceding claims, characterized in that lubricant is chosen from the group comprising, calcium stearate, glyceryl, monostearate, magnesium monostearate, polyethylene glycol, sodium lauryl sulfate, potassium benzoate, stearic acid, magnesium stearate, polyvinyl alcohol.

18. The pharmaceutical composition according to claim 17, characterized in that preferred lubricant is magnesium stearate.

19. The pharmaceutical composition according to any of the preceding claims, characterized in that glidant is chosen from the group comprising, cellulose, silicone dioxide, magnesium silicate and starch.

20. The pharmaceutical composition according to claim 19, characterized in that preferred glidant is silicone dioxide.

21. The pharmaceutical composition according to any of the preceding claims, characterized in that basic agent is chosen from the group comprising potassium bicarbonate, potassium citrate, potassium hydroxide, ammonia, sodium bicarbonate, sodium hydroxide.

22. The pharmaceutical composition according to claim 21, characterized in that preferred basic agent is ammonia.

23. A process for the preparation of monolayer pharmaceutical composition according to any of the preceding claims, characterized in that said process comprises the steps of a) granulation of the diluents with granulation solution comprising telmisartan, basic agent and buffering agent and drying them, b) Dry-blending the hydrochlorothiazide and other pharmaceutical acceptable excipients c) combining the mixtures obtained from steps a and b and pressing them.