WO2014068507A1

WO2014068507A1 - Solid oral pharmaceutical compositions of telmisartan, essentially free of surfactants

Info

Publication number: WO2014068507A1
Application number: PCT/IB2013/059807
Authority: WO
Inventors: Meghana SHETYE; Prasad Patil; Manish Grover; Shripad Jathar
Original assignee: Abbott Healthcare Pvt. Ltd.
Priority date: 2012-11-02
Filing date: 2013-10-31
Publication date: 2014-05-08

Abstract

The present invention discloses a solid oral pharmaceutical composition comprising telmisartan or pharmaceutically acceptable salts thereof, wherein the said compositions are essentially free of surfactants. The present invention further relates to a pharmaceutical composition in the form of tablets comprising telmisartan and process of preparing the same.

Description

SOLID ORAL PHARMACEUTICAL COMPOSITIONS OF TELMI SARTAN,

ESSENTIALLY FREE OF SURFACTANTS

FIELD OF THE INVENTION:

The present invention is related to solid oral pharmaceutical compositions comprising telmisartan or pharmaceutically acceptable salts thereof for the treatment of hypertension and other medical indications, wherein the said composition is in the form of tablet dosage form. More specifically, the solid oral compositions of telmisartan are essentially free of surfactants, and yet have the desired dissolution and friability properties. The present invention also provides the process of preparing the tablet dosage forms of the present invention, comprising telmisartan or phannaceutically acceptable salts thereof, and essentially free of surfactants.

BACKGROUND OF THE INVENTION:

Telmisartan (chemical name 2-(4- { [4-niethyl-6-( 1 -methyl- 1 H - 1 ,3 -benzodiazol-2-yl)-2- propyl-lH-1 ,3-benzodiazol-l -yl]methyl}phenyl)benzoic acid) is an angiotensin ΙΪ receptor antagonist (angiotensin receptor blocker) used in the management of hypertension. Telmisartan is an angiotensin II receptor blocker that shows high affinity for the angiotensin li receptor type 1 (ATI), with a binding affinity 3000 times greater for AT I than AT2. In addition to blocking the RAs, telmisartan acts as a selective modulator of peroxisome proliferator-activated receptor gamma (PFAR-γ), a central regulator of insulin and glucose metabolism. Teimisartan's dual mode of action may provide protective benefits against the vascular and renal damage caused by diabetes and cardiovascular disease (CVD). The usually effective dose of telmisartan is 40-80 mg once daily. Some patients may already benefit at a daily dose of 20 mg. In cases where the target blood pressure is not achieved, telmisartan dose can be increased to a maximum of 80 mg once daily. Telmisartan is available in free acid form. It exists in two polymorphic forms having different melting point. Under the influence of heat and humidity, the lower melting polymorph B transforms into the higher melting polymorph A. Both forms are characterised by a very poor solubility in aqueous systems at the physiological pH range of the gastro-intestinal tract of between pH 1 to 7. Pharmaceutical formulations of telmisartan are often alkaline and commonly include a basic sohibilisation agent such as meglumine. In addition, dissolution rates are enhanced by the inclusion of surfactants or emulsifiers to the solid dosage forms. Telmisartan-only tablets are known especially from EP 1 545 467 but require relatively complex manufacture and inclusion of surfactant, solubiiiser and other components to achieve satisfactory formulation. Furthermore, the addition of surfactant to the formulation can soften the tablet product, increasing the risk of damage during handling, Patient compliance can be reduced by any formulation that, is overtly damaged,

PCT application number WO 2004028505 discloses the pharmaceutical composition comprising basic agent and telmisartan in the ratio of 1:1 to 10: 1 , and essentially contains a surfactant or emulsifier in an amount of 1 to 20 wt%, 25 to 70 wt% of water soluble diluent, and optionally 0 to 20 wt% of further excipients. Further, the said PCT application discloses the process of preparation of the pharmaceutical compositions and final formulations in the form of tablets and capsules.

PCT application number WO 2009135646 discloses the surfactant-free granulate comprising amorphous telmisartan or a salt thereof, at least one filler, and optionally, hydrochlorothiazide, wherein telmisartan or a salt thereof has not been spray-dried.

Indian application number IN 948/DEL/2009 discloses the pharmaceutical composition of telmisartan comprising water-soluble diluents in an amount from about 75% to about 90%. The said pharmaceutical composition also contains the basic agent and the surfactant.

Indian application number IN 381/MUM/2009 discloses a pharmaceutical composition comprising: telmisartan, a basic agent, a disintegrating agent, and at least one diluent selected from water soluble and wa ter insoluble diluents, wherein the amount of water soluble diluents is less than 10% by weight of the pharmaceutical composition, and the composition is devoid of any surfactant.

Thus, there is need in the art to provide the pharmaceutical composition comprising telmisartan or pharmaceutically acceptable salts thereof, which is easy to manufacture, less prone to damage or breakage, comparatively cheaper and bioequivalent. OBJECT AND SUMMARY OF THE INVENTION:

It is an objective of the present invention to provide a solid oral pharmaceutical composition of telmisartan that avoids use of surfactants and yet has the desired friability and dissolution properties. In one aspect, the present invention provides a pharmaceutical composition in the form of tablet comprising telmisartan, wherein the said composition is essentially free of surfactants,

The further aspect of the present invention provides a process of preparing a pharmaceutical composition in the form of tablet comprising telmisartan, wherein the said composition is essentially free of surfactants.

In one specific aspect, the present invention provides a solid, oral pharmaceutical composition of telmisartan comprising; from about 5% to 25% by weight of telmisartan, more than 50% by weight of water insoluble diluent, from about 0.1% to 5.0% by weight of a binder, and pharmaceutically acceptable excipients, wherein the said composition is essentially tree of surfactants. In further aspects, the compositions of the present invention comprise more than 60% by weight, or more than 70% by weight of water insoluble diluent. in the compositions of the present invention, the water insoluble diluent is selected from pregeiatinized starch, microcrystalline cellulose, dicalcium phosphate, calcium sulphate, calcium carbonate, calcium silicate, tribasic calcium phosphate, light magnesium oxide and mixtures thereof. The binder in the present invention is polyvinyl pyrrolidone (Povidone). The pharmaceutically acceptable excipients in the present invention are selected from basic agents, disintegrants, lubricants, glidants, colorants, or a combination thereof.

In another aspect, the present invention provides a solid oral composition of telmisartan comprising; 5%> to 25 %> by weight of telmisartan, more than 50% by weight of microcrystalline cellulose or combination of microcrystalline cellulose and light magnesium oxide, 0.1% to 5.0% by weight of a binder, one or more lubricants, one or more basic agents, and one or more disintegrants, wherein the said composition is essentially free of surfactants. In further aspects, the compositions of the present invention comprise more than 60% by weight, or more than 70% by weight of microcrystalline cellulose or combination of microcrystalline cellulose and light magnesium oxide. The basic agent used in the compositions of the present invention is selected from alkali metal hydroxides such as NaOH, KOH, NaHC0₃, K .C^{( )} _;. Na₂C0₃, K ^{( '( )};. NaHP0₄, K2HPO4, basic amino acids such as arginine, and combinations thereof. The disintegrant used in the compositions of the present invention is selected from sodium starch glycolate

crospovidone, croscarmel!ose sodium, carboxy methyl cellulose, dried com starch and combinations thereof. The lubricant used in the compositions of the present invention is selected from stearic acid, magnesium stearate, sodium stearylfumarate, glycerol tribehenate and combinations thereof. In a further aspect, the present invention provides a telmisartan composition in the form of tablet consisting of; 5% to 25% by weight of telmisartan, more than 50% by weight of microcrystalline cellulose or a combination of microcrystalline cellulose and light magnesium oxide, 1% to 2% by weight of sodium hydroxide, 0.1 % to 1.0%) by weight of povidone K- 30, 5% to 25% by weight of a disintegrant selected from sodium starch giycollate, croscarmeliose sodium or a combination thereof, and 0.1% to 2% by weight of magnesium stearate. In further aspects, the compositions of the present invention comprise more than 60% by weight, or more than 70% by weight of microcrystalline cellulose or combination of microcrystalline cellulose and light magnesium oxide, In some specific compositions of the present invention, the amount of binder is 0.1% to 2.0% by weight.

The present invention also provides that the compositions of the present invention are prepared using dry granulation or wet granulation or direct compression methods.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention provides solid oral pharmaceutical compositions of telmisartan. Telmisartan is very less soluble in water and hence, the dissolution of telmisartan is difficult. To address this problem, the use of surfactants has been advised. However, the use of surfactants makes the tablets friable and the tablets comprising surfactants are liable for physical damage during transportation and patient handling. The present invention provides tablets of telmisartan that are essentially free of surfactants, and have negligible friability, and yet retain the desired dissolution properties. The present invention provides the solid, oral pharmaceutical compositions of telmisartan comprising telmisartan, a water insoluble diluent and a binder, with other pharmaceutically acceptable excipients, which has negligible friability and desired dissolution properties. In the present invention, high amounts of water insoluble diluents are used to achieve the desired compositions. When high amounts of water insoluble diluents are used, high amounts of binder is also required. However, the present invention provides compositions of telmisartan comprising high amounts of water insoluble diluents, but low amounts of binders, and yet achieve the desired friability and dissolution properties. The term "telmisartan" herein refers to telmisartan in the form of freebase or its pharmaceutically acceptable salt(s), hydrate(s), solvate(s) and physiologically functional derivative(s) and precursors thereof. The term also includes all polymorphic forms, whether crystalline or amorphous. The reference to "% by weight" refers to a percentage amount by weight of the composition, unless recited otherwise.

The reference to "essentially free" for a component refers to absence of, or avoidance of use of such component in the composition,

In one embodiment, the present invention provides a telmisartan composition in the form of tablet comprising:

a) telmisartan,

b) a water insoluble diluent,

c) a binder, and

d) one or more other pharmaceutically acceptable excipients,

wherein the said composition is essentially free of surfactants. in yet another embodiment, the present invention provides a process of preparing telmisartan composition in the form of tablet comprising:

a) telmisartan,

b) a water insoluble diluent,

c) a binder, and d) one or more other pharmaceutically acceptable excipients,

wherein the said composition is essentially free of surfactants, and wherein the process is selected from dry granulation or wet granulation or direct compression.

In yet another embodiment, the present invention provides a method of treatment of hypertension using a teimisartan composition in the form of tablet comprising:

a) teimisartan,

b) a water insoluble diluent,

c) a binder, and

d) one or more other pharmaceutically acceptable excipients,

wherein the said composition is essentially free of surfactants,

In yet another embodiment, the present invention provides a teimisartan composition in the form of tablet comprising:

a) 5% to 25 % by weight of teimisartan,

b) more than 50% by weight of a water insoluble diluent,

c) 0,1% to 5.0% by weight of a binder, and

d) one or more other pharmaceutically acceptable excipients,

wherein the said composition is essentially free of surfactants.

a) 5% to 25 % by weight of teimisartan,

b) more than 60% by weight of a water insoluble diluent,

c) 0.1% to 5.0% by weight of a binder, and

d) one or more other pharmaceutically acceptable excipients,

wherein the said composition is essentially free of surfactants.

a) 5% to 25 % by weight of teimisartan,

b) more than 70% by weight of water insoluble diluent,

c) 0.1% to 5.0% by weight of a binder, and

d) one or more other pharmaceutically acceptable excipients, wherein the said composition is essentially free of surfactants.

In yet another embodiment, the present invention provides a telmisartan composition in the form of tablet comprising:

a) 5% to 25 % by weight of telmisartan,

b) more than 50% by weight of water insoluble diluent selected from microcrystallme cellul ose or a combination of microcrystallme cellulose and light magnesium oxide,

c) 0,1% to 5.0%> by weight of a binder, and

d) one or more other pharmaceutically acceptable excipients,

wherein the said composition is essentially free of surfactants.

a) 5%> to 25 % by weight of telmisartan,

b) more than 50%» by weight of microcrystallme cellulose or combination of rnicrocrystalline cellulose and light magnesium oxide,

c) 0.1% to 5.0%> by weight of a binder,

d) one or more basic agent/pH adjuster,

e) one or more disintegrants, and

f) one or more lubricants,

wherein the said composition is essentially free of surfactants.

a) 5% to 25 % by weigh; of telmisartan,

b) more than 50% by weight of microcrystallme cellulose or combination of rnicrocrystalline cellulose and light magnesium oxide,

c) 0.1% to 5.0%) by weight of povidone K-30,

d) sodium hydroxide,

e) a disintegrant selected from sodium starch giycoliate, croscarmellose sodium or both, and

f) a lubricant such as magnesium stearate. The water insoluble diluents used in the present invention are selected from but are not limited to pregelatiiiized starch or microcrystalline cellulose, dicalcium phosphate, calcium sulphate, calcium carbonate, calcium silicate, tribasic calcium phosphate, and the like, light magnesium oxide, and mixtures thereof. The binder in the present invention is polyvinyl pyrrolidone (Povidone).

The other excipients may be selected from but not limited to basic agents, disintegrants, lubricants, glidents, and the combinations thereof. The examples of suitable basic agents or pH adjusters used in the present invention are selected from, but not limited to, alkali metai hydroxides such as NaOH, KOI L NaHCQ₃, K4CO₃, Na₂C0₃, K₂CO₃, NaHP0₄, K₂HP0₄, basic amino acids such as arginine, and combinations thereof. The disintegrants in the present invention are selected from, but not limited to, sodium starch glycol;! lc (primogel^®), crospovidoiie, croscarniellose sodium, carboxy methyl cellulose, dried corn starch, and combinations thereof.

The lubricants in the present invention are selected from, but not limited to, stearic acid, magnesium stearate, sodium stearylfumarate, glycerol tribehenate and combinations thereof.

The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the present invention, The examples should not be read as limiting the scope of the present invention.

Example 1:

Method of preparation:

Telmisartan. light magnesium oxide, primogel, avicel 101 were sifted through 20 mesh. The blend was further mixed in RMG for 10 minutes. Sodium hydroxide was dissolved in water and povidone was dispersed in isopropyl alcohol and were added to the dry mix in the blend. Wet mass thus formed was dried to form the granules. The dried granules were sized through 20 mesh, lubricated and compressed to form tablets.

Example No: 2

Table No: 2

Method of preparation:

Telmisartan, light magnesium oxide, primogel, avicel 101 were sifted through 20 mesh. The blend was further mixed in RMG for 10 minutes. Sodium hydroxide was dissolved in water and povidone was dispersed in isopropyl alcohol, and were further added to the dry mix in the blend, wet mass was dried to form the granules. The dried granules were sized through 20 mesh, lubricated and compressed to form tablets.

Example No: 3

Table No: 3

Method of preparation:

Primogel and avicel 101 were sifted through 30 mesh. The blend was further mixed in RMG for 10 minutes. Sodium hydroxide was dissolved in water, Telmisartan was dissolved in the solution of sodium hydroxide and povidone was further dispersed in the above solution. The solution was further added to the dry mix in the blend, wet mass was dried to form the granules. The dried granules were sized through 30 mesh, lubricated and compressed to form tablets.

Example No: 4

Table No: 4

Method of preparation:

Primogel and avicel 101 were sifted through 30 mesh. The blend was further mixed in RMG for 10 minutes. Sodium hydroxide was dissolved in water. Meglumine and telmisartari were dissolved in the solution of sodium hydroxide and povidone was further dispersed in the above solution. The solution was further added to the dry mix in the blend, wet mass was dried to form the granules. The dried granules were sized through 30 mesh, lubricated and compressed to form tablets.

Example 5:

Table No: 5

Method of preparation:

Primogel, avicel 101, light magnesium oxide, povidone were sifted through 30 mesh. The blend was further mixed in RMG for 10 minutes. Sodium hydroxide was dissolved in water. Telmisartaii was dissolved in the solution of sodium hydroxide. The solution containing telmisartan was further added to the dry mix in the blend, w^ret mass w^ras dried to form the granules. The dried granules were sized through 30 mesh, lubricated and compressed to form tablets.

Three batches of the various strengths were taken as per the composition of table no, 5 and were subjected to the stability studies. The results obtained are presented in table no. 6.

Note:

IM = 1 Month; 2M = 2 Months; 3M = 3 Months; 6M = 6 Months

Claims

We Claim:

1. A solid oral composition of telmisartan comprising:

a) from about 5% to 25% by weight of telmisartan or pharmaceutically acceptable salts thereof,

b) more than 50% by weight of water insoluble diluent,

c) from about 0.1 % to 5.0% by weight of a binder, and

d) pharmaceutically acceptable excipients,

wherein the said composition is essentially free of surfactants.

2. The composition according to claim 1, wherein the amount of water insoluble diluent is more than 60% by weight.

3. The composition according to claim 1 , wherein the amount of water insoluble diluent is more than 70% by weight.

4. The composition according to claim 1, wherein the amount of binder is from about 0.1% to 2.0% by weight.

5. The composition according to claim 1 , wherein the water insoluble diluents are selected from pregeiatinized starch, macrocrystalline cellulose, di calcium phosphate, calcium sulphate, calcium carbonate, calcium silicate, tribasic calcium phosphate, light magnesium oxide and mixtures thereof.

6. The composition according to claim 1, wherein the binder is polyvinyl pyrrolidone (Povidone).

7. The composition according to claim 1 , wherein the pharmaceutically acceptable excipients are selected from basic agents, disintegrants, lubricants, glidants, colorants, or a combination thereof.

8. The composition according to claim 7, wherein the basic agent is selected from alkali metal hydroxides such as NaOH, KOH, NaHCi¾, K4CO₃, Na₂CQ₃, K₂C0₃, NaHPC>4, K₂HPO₄, basic amino acids such as arginine and combinations thereof.

9. The composition according to claim 7, wherein the disintegrant is selected from sodium starch glycolate, crospovidone, croscaniiellose sodium, sodium carboxy methyl cellulose, dried corn starch and combinations thereof.

10. The composition according to claim 7, wherein the lubricant is selected from stearic acid, magnesium stearate, sodium stearyl fumarate, glycerol tribehenate and combinations thereof.

11. A solid oral composition of telmisartan comprising: a) 5% to 25% by weight of teSniisartan or pharmaceuticaiiy acceptable salts thereof,

b) more than 50% by weight of microcrystalline cellulose or combination of microcrystalline cellulose and l ight magnesium oxide,

c) 0.1 % to 5 , 0% by weight of a binder,

d) one or more lubricants,

e) one or more basic agents, and

f) one or more disintegrants,

wherein the said composition is essentially free of surfactants.

12. The composition according to claim 11, comprising more than 60% by weight of microciystailine cellulose or combination of microcrystalline cellulose and. light magnesium oxide.

13. The composition according to claim 11, comprising more than 70% by weight of microcrystalline cellulose or combination of microcrystalline cellulose and light magnesium oxide.

14. The composition according to claim 11, wherein the amount of binder is from 0.1% to 2.0% by weight.

15. A telmisartan composition in the form of tablet consisting of:

a) 5% to 25%) by weight of telmisartan or pharmaceutically acceptable salts thereof,

b) more than 50% by weight of microcrystalline cellulose or a combination of microcrystalline cellulose and light magnesium oxide,

c) 1% to 2% by weight of sodium hydroxide,

d) 0.1% to 1.0% by weight of povidone K-30,

e) 5%) to 25% by weight of a disintegrant selected from sodium starch giycoliate, croscarmeliose sodium or a combination thereof, and

f) 0.1 % to 2% of magnesium stearate,

16. The composition according to claim 15, consisting more than 60% by weight of microcrystalline cellulose or combination of microcrystalline cellulose and light magnesium oxide.

17. The composition according to claim 15, consisting more than 70% by weight of microcrystalline cellulose or combination of microcrystalline cellulose and light magnesium oxide.

18. The composition according to any of the preceding claims, wherein the compositions are prepared using dry granulation or wet granulation or direct compression methods.