FIELD OF THE INVENTION

The present invention relates to a solid oral pharmaceutical composition comprising telmisartan or pharmaceutically acceptable salts thereof and amiodipine or pharmaceutically acceptable salts thereof and a process for preparation of composition therof. More specifically, the invention relates to a stable pharmaceutical composition comprising telmisartan or pharmaceutically acceptable salts thereof and amiodipine or pharmaceutically acceptable salts thereof with pharmaceutically acceptable excipients.

BACKGROUND OF THE INVENTION

Telmisartan, the chemical name of which is 2-(4-{[4-methyl-6-(1 -methylbenzimidazol-2- yl)-2-propylbenzimidazol-1 -yl]-methyl}-phenyl)-benzoic acid having the below structure is an angiotensin II receptor antagonist useful for the treatment of hypertension that was originally disclosed in EP0502314. Telmisartan is commercially available in particular in its free acid form, which is poorly soluble in neutral or acidic media. Thus, telmisartan is typically formulated together with a basic agent or in the form of a basic salt for improved solubility.

Calcium channel blockers, such as amiodipine, nifedipine, nimodipine, nilvadipine, manidipine, barnidipine, nitrendipine, benidipine, nicardipine, lercanidipine, nisoldipine, efonidipine, cilnidipine, azelnidipine, felodipine, aranidipine and pranidipine, exert antihypertensive action by reducing the availability of calcium ions for muscular contraction and therefore, resulting in decreased peripheral vascular resistance and reduced blood pressure.

Amiodipine, the chemical name of which is 3-ethyl 5-methyl 2-[(2-aminoethoxy)methyl]- 4-(2-chlorophenyl)-6-methyl-1 ,4-dihydropyridine-3,5-dicarboxylate having the below structure is a long-acting calcium channel blocker (dihydropyridine class) used as an antihypertensive and in the treatment of angina that was originally disclosed in EP0089167. Amiodipine is commercially available in the form of maleate, besylate or mesylate salt. It is known that amiodipine and/or pharmaceutically acceptable salts thereof are susceptible to hydrolysis when exposed to an alkaline medium.

Stangier, J. et al, "Pharmacokinetics of repeated oral doses of amiodipine and amiodipine plus telmisartan in healthy volunteers", Journal of Clinical Pharmacology, vol. 40 (12), part 1 , December 2000, pages 1347-1354, discloses the concomitant administration of tablets of telmisartan and tablets of amiodipine.

However, a combination of active ingredients is not without drawbacks. Certain physical properties of the drugs and specifically stability, present a challenge in developing composition suitable for preparing a tablet having reduced levels of total impurities on long term stability.

It is known in the art that amiodipine is susceptible to hydrolysis when exposed to basic agents that are commonly used together with the free acid form of telmisartan. Combination therapy of telmisartan with calcium channel blocker such as amiodipine is marketed by Boehringer Ingelheim under the brand name TWYNSTA®, for the treatment of hypertension.

WO 2006/048208 discloses the stability problem caused by the incompatibility of amiodipine with basic constituents of the telmisartan composition by preparing a bi-layer pharmaceutical tablet comprising a first layer of telmisartan in substantially amorphous form in a dissolving tablet matrix and a second layer of amiodipine in a disintegrating or eroding tablet matrix. According to this document, the term 'dissolving tablet matrix' refers to a pharmaceutical tablet base composition having instant release (fast dissolution) characteristics that readily dissolves in a physiological aqueous medium' and the term disintegrating or eroding tablet matrix' refers to a pharmaceutical tablet base composition having instant release characteristics that readily disintegrates or erodes in a physiological aqueous medium'. The dissolving tablet matrix is described to have neutral or basic properties, with a basic tablet matrix being preferred. It comprises a basic agent, a water soluble diluent and optionally other excipients and adjuvants. As preferred disintegrants used to prepare a disintegrating or eroding tablet matrix the following group of disintegrants is listed: croscarmellose sodium (crosslinked carboxymethylcellulose sodium), sodium starch glycolate, crospovidone (crosslinked polyvinylpyrrolidone), corn starch, pregelatinized starch, low-substituted hydroxypropylcellulose and microcrystalline cellulose. Particularly preferred are sodium starch glycolate and crospovidone.

WO 2008/146178 discloses a pharmaceutical composition comprising a telmisartan blend layer having a disintegrating matrix and amiodipine tablets having a disintegrating matrix which amiodipine tablets are inlayed in an inert excipients layer representing a disintegrating matrix as well.

WO 2012/055941 discloses a solid pharmaceutical composition comprising telmisartan or a pharmaceutically acceptable derivative thereof, optionally one or more basifying agents and at least one calcium channel blocker. More specifically the invention discloses a pharmaceutical composition comprising telmisartan and amiodipine that comprises at least one non-hygroscopic filler and/or at least one non-hygroscopic binder that do not exhibit a disintegrating effect, and/or at least one hydrophilic lubricant.

The composition of above prior arts involve complex process and/or specialized excipients in solving the compatibility and/or stability concerns involved in the preparation of combination of telmisartan and amiodipine besylate.

Thus, there is a need to develop a simple and convenient process of achieving stability of amiodipine besylate while it is present in a combination with telmisartan.

Hence, the present invention provides a single layer stable composition comprising telmisartan or pharmaceutically acceptable salts thereof and amiodipine or pharmaceutically acceptable salts thereof present in a fixed dose combination dosage form of the pharmaceutical composition with pharmaceutically acceptable excipients.

SUMMARY OF THE INVENTION

The present invention relates to pharmaceutical composition comprising telmisartan or pharmaceutically acceptable salts thereof and amiodipine or pharmaceutically acceptable salts thereof, including pharmaceutically acceptable excipients and mixtures thereof, wherein telmisartan and amiodipine besylate are present as a fixed dose combination in a single or mono layer tablet dosage form.

The present invention also relates to process for preparation of pharmaceutical composition comprising telmisartan or pharmaceutically acceptable salts thereof and amiodipine or pharmaceutically acceptable salts thereof, including its pharmaceutically acceptable excipients and mixtures thereof, wherein telmisartan and amiodipine besylate are present as a fixed dose combination in a tablet dosage form.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a single layer stable pharmaceutical composition comprising telmisartan or pharmaceutically acceptable salts thereof and amiodipine or pharmaceutically acceptable salts thereof, including pharmaceutically acceptable excipients and also relates to process for preparation of oral fixed dose combination in a tablet dosage form containing the same.

In an embodiment, the invention relates to a fixed dose combination solid oral pharmaceutical composition comprising

(a) Granules comprising amiodipine or a pharmaceutically acceptable salt thereof; and with pharmaceutically acceptable excipients;

(b) Granules comprising telmisartan or a pharmaceutical acceptable salt thereof; and with pharmaceutically acceptable excipients.

The term 'fixed dose combination comprises telmisartan or pharmaceutically acceptable salts thereof and amiodipine or pharmaceutically acceptable salts thereof and/or pharmaceutical excipients are blended and compressed together optionally with other pharmaceutical excipients in the form of tablet.'

The invention further relates to a single layer pharmaceutical composition containing granule (a) and granule (b) which is stable over its shelf-life and also capable to match the required dissolution profile of marketed products Twynsta ^® .

The pharmaceutical excipients which used herein may be selected from the group consisting of one or more diluents, one or more binders, one or more lubricants, one or more disintegrants, one or more glidants, one or more surfactants, one or more basic agents and the like.

The amiodipine granules of the present invention do not contain any non-hygroscopic filler. More specifically, the amiodipine granules of the present invention are devoid of any non-hygroscopic filler. The non-hygroscopic fillers such as monosaccharides, oligosaccharides, sugar alcohols and mixtures thereof. It also contains about 3% to about 9% of disintegrant by weight of the amiodipine granules. More preferably, the amount of disintegrant in amiodipine granules ranges between about 5% to about 8%.

Pharmaceutically acceptable excipients suitable for use in the present invention include, without limitation, diluents or fillers, disintegrants, glidants, lubricants, binders, surfactants and combinations thereof. Suitable diluents include, without limitation, microcrystalline cellulose (e.g., cellulose MK GR), mannitol, lactose, sucrose or other sugars or sugar derivatives, PEG 400, Aerosil and combinations thereof.

Suitable binders include, without limitation, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, pregelatinized starch and combinations thereof.

Suitable disintegrant include, without limitation, crospovidone, pregelatinized starch, sodium starch glycolate, hydroxypropyl starch, corn starch, carboxymethylcellulose sodium and calcium, cross-linked carboxymethylcellulose sodium, polacrilin potassium, low-substituted hydroxypropylcellulose, sodium and calcium alginate, docusate sodium, methylcellulose, agar, guar gum, chitosan and alginic acid.

Suitable glidants include, without limitation, colloidal silicon dioxide (e.g., Aerosil 200), magnesium trisilicate, powdered cellulose, starch, talc and combinations thereof.

Suitable lubricants include, without limitation, magnesium stearate, aluminum or calcium silicate, stearic acid, PEG 4000-8000, talc and combinations thereof.

Suitable basic or basifying agents include, without limitation, ammonia, NaOH, KOH, Ca(OH)2, Na2C03 , K2C0 ₃ , NaHC0 ₃ , KHC0 ₃ , Na ₃ P0 ₄ , K3P0 ₄ , Na2HP0 ₄ , K2HP0 ₄ , choline, tert-butylamine, ethanolamine, meglumine, piperazine, diethylamine, L-arginine and mixtures thereof.

Suitable surfactants include, without limitation, include anionic, cationic, ampholytic and non-ionic surfactants such as sodium lauryl sulfate, cetrimide, N-dodecyl N, N- dimethylbetaine, polysorbates (such as Tweens®), poloxamers and mixtures thereof.

A pharmaceutical composition according to an embodiment of the present invention is intended for the treatment of hypertension and comprises composition as described herein together with suitable pharmaceutical excipients.

Thus, in particular, the present invention is directed to a pharmaceutical composition (especially an oral solid dosage form, particularly a tablet) comprising telmisartan, amiodipine besylate and one or more pharmaceutical excipients, particularly one or more diluents, one or more binders, one or more disintegrants, one or more glidants, one or more basic agent and/or one or more lubricants.

In more particular, the present invention is directed to a pharmaceutical composition (especially an oral solid dosage form, particularly a tablet) comprising telmisartan and optionally pharmaceutical excipients, amlodipine besylate and optionally pharmaceutical excipients and disintegrants selected from the group consisting of croscarmellose sodium, pregelatinized starch, crospovidone as disintegrant and one or more further pharmaceutical excipients

Typical pharmaceutical composition of this invention may comprise telmisartan granules 1 -20% by weight and amlodipine besylate granules 1 -5% by weight, diluents (e.g. mannitol) 1 -70% by weight, binders (e.g. povidone, HPC) 1 -10%, disintegrants (crospovidone, corn starch, cross carmellose sodium) 1 -20%, basic agents (e.g. sodium hydroxide, meglumine) 1 -10%, glidants (e.g. Aerosil 200) 0.1 -5% & lubricant (e.g. magnesium stearate) 0.1 -10% by weight of tablet.

In one of the preferred embodiment of the present invention, the telmisartan granules contain mannitol, povidone, meglumine, sodium hydroxide or optionally with any other pharmaceutically acceptable excipients.

In another preferred embodiment of the present invention, the amlodipine granules contain microcrystalline cellulose, hydroxypropyl cellulose, corn starch, polyethylene glycol or optionally with any other pharmaceutically acceptable excipients.

The amount of the telmisartan and amlodipine besylate in the pharmaceutical composition according to this invention corresponds to the respective dosage ranges as provided herein before. For example, a pharmaceutical composition comprises telmisartan in an amount of 40 mg to 80 mg and amlodipine besylate in an amount of 5 mg to 10 mg.

In another aspect, the further embodiment of the present invention provides a process for preparation of composition, blends or dosage forms of this invention, such as e.g. by using methods known to one skilled in the art and/or in a manner as described herein, for example they may be obtained by processes comprising using (e.g. mixing, spraying, drying, blending and/or compressing) the components. As well as the present invention further provides compositions, blends or dosage forms obtainable by these methods or processes and/or obtainable from the components, ingredients, pre- mixtures and/or mixtures mentioned hereinbefore and hereinafter.

In a further aspect of the present invention, the present invention provides a stable pharmaceutical composition, blend or dosage form of this invention which is substantially free of or only marginally comprises impurities and/or degradation products.

Dosage Forms for the composition of this Invention:

A typical fixed dose combination tablet preparation of this invention comprises telmisartan or pharmaceutically acceptable salts thereof and amlodipine or pharmaceutically acceptable salts thereof, one or more diluents, one or more binders, one or more disintegrant, one or more glidants, one or more basic agents and one or more lubricants.

In a preferred embodiment of the present invention, the present invention is directed to a stable oral solid pharmaceutical composition, preferably a tablet comprising or made from telmisartan, amlodipine (particularly amlodipine besylate) and one or more pharmaceutical excipients, particularly one or more diluents (e.g. mannitol, microcrystalline cellulose), one or more disintegrants (e.g. croscarmellose sodium, corn starch, crospovidone), one or more binders (e.g. povidone, hydroxypropyl cellulose), one or more basic agent (e.g. sodium hydroxide, meglumine), one or more glidants (e.g. colloidal anhydrous silica/aerosil) and/or one or more lubricants (e.g. magnesium stearate), as well as, optionally, one or more glidants (e.g. talc) and optionally, a coating agent e.g. comprising one or more film-coating agents (e.g. hypromellose, hydroxypropyl cellulose).

A process for preparation of tablet of this invention comprises compression of one or more final blends in form of granules/pellets. Granules of the (final) blend(s) according to this invention may be prepared by methods well-known to one skilled in the art (e.g. high shear wet granulation or fluid bed granulation or top spray granulation).

Granules according to this invention as well as details of granulation processes (including their separate steps) for the preparation of granules of this invention is described by way of example in the following examples.

Further embodiments, features and advantages of the present invention may become apparent from the following examples. The following examples serve to illustrate, by way of example, the principles of the invention without restricting it.

An illustrative granulation process for the preparation of composition containing granules/pellets:

I. Preparation of Amlodipine Besylate containing granule/pellet:

a. Preparing a solution of hydroxy propyl cellulose into the solvent, add slowly required qty. of corn starch into the same solution with continuous stirring until it got dissolved and then Amlodipine Besylate is added to the same solution with continuous stirring;

b. Spray the above drug containing solution on to the cellphere (Inert bead) to obtain a granule;

c. Dry the granule further at 30-35°C;

d. Seal coat the granules obtained in above step by using solution of hydroxy propyl cellulose prepared by ethanol;

e. Dry the granule further at 30-35°C;

f. Optionally, other excipients are added to the drug loaded granule.

II. Preparation of Telmisartan containing granule/pellet:

a. Dissolve Meglumine followed by Povidone K-25 in of Purified water under stirring to get clear solution;

b. Dissolve Sodium hydroxide followed by Telmisartan in of Purified Water under stirring to get clear solution; c. Add Solution Meglumine-Povidone K-25 solution to Telmisartan -Sodium hydroxide solution under stirring and mix.

d. Spray the above drug containing solution on to the Mannitol to obtain a granule;

e. Carry out the drying to get the LOD is NMT 2.00 % w/w;

f. Optionally, other excipients are added to the drug loaded granule of above step.

III. Blending/Mixing & Lubrication:

a. Mix the granules of above step (i) & (ii) in a blender.

b. Optionally, other excipients are added to the mixture of above drug loaded granules (i) & (ii);

c. Add pharmaceutically acceptable lubricant to the above mixture of drug loaded granules and mix.

IV. Compression:

a. Compress the lubricated blend in to tablets as per the desired compression parameters.

Exam le 1: Telmisartan and Amiodipine Besylate Tablet

Process for the preparation of composition containing telmisartan and amlodipine besylate

Granulation/Drug Coating (Amlodipine Besylate): Take required qty. of dehydrated alcohol (Ethyl alcohol anhydrous). Add slowly required qty. of hydroxy propyl cellulose (Pre-sifted from suitable sieve) into the solvent. Then add slowly required qty. of corn starch (Pre-sifted from suitable sieve) into the same with continuous stirring until it gets dissolved. Amlodipine Besylate is sifted through suitable sieve and added to the above solution of with continuous stirring. Load the required qty. of cell sphere pellets into the GPCG 1.1 , Spray the drug dispersion of above step onto the cell sphere pellets with continuous stirring and dry the pellets further at 30-35°C. Seal Coating stage: Take required qty of ethanol and add required qty. of hydroxy propyl cellulose (Klucel EF) with continuous stirring until it gets dissolved. Load required qty. of drug loaded pellets into GPCG 1.1 . Spray the seal coating solution onto the drug loaded pellets. Dry the pellets further at 30-35 °C. Drug Loaded Pellets were sifted to get the desired size pellets.

Granulation/Drug Coating (Telmisartan): Dissolve meglumine followed by Povidone K-25 in (1/4 quantity) of Purified water under stirring to get clear solution (part A). Dissolve Sodium hydroxide followed by Telmisartan in (3/4 quantity) of Purified Water under stirring to get clear solution (Part B). Add Solution (Part A) to Solution (Part B) under continuous stirring and mixing. Pass the above solution of through 100 # S.S sieve or Nylon bolting cloth. Granulation and drying: Sift Mannitol (Pearlitol SD 200) through 40 # S.S Sieve using vibratory sifter, Load Sifted material in Fluid bed equipment. Granulate the premix of above step by top spray process using the drug solution. Carry out the drying to get the LOD is NMT 2.00 % w/w. Drug Loaded Pellets were sifted to get the desired size pellets.

Mixing: Mixing of both the granules/pellets of telmisartan and amlodipine mesylate in a blender.

Pre-lubrication: Add extragnular sifted mannitol (Pearlitol SD 200), pregelatinized starch -1500 and cross-carmellose sodium to the mixed granules/pellets in a blender. Lubrication: Add sifted magnesium Stearate to the above blend in a blender and mix. Compression: Compress the above lubricated blend in to tablets as per the desired compression parameters.

Example 2: Telmisartan and Amiodipine Besylate Tablet

Magnesium stearate Lubricant 1 .00 1 .00 1.00 1.00

Total 1 100.00 100.00 100.00 100.00

Manufacturing method for Example 2 is similar as described above in example 1.

Example 3: Telmisartan and Amiodipine Besylate Tablet

Cross carmellose sodium Disintegrai it 5.33 5.33 5.33 5.33

Magnesium stearate Lubricant 0.56 0.56 0.56 0.56 Total 100.00 100.00 100.00 100.00

Manufacturing method for Example 3 is similar as described above in example 1. Example 4: Telmisartan and Amiodipine Besylate Table

Sodium Stearyl

19 Fumarate 0.83 0.83 0.83 0.83

LUDrication

20 Magnesium stearate 0.69 0.69 0.69 0.69

Comparative stability data: i) For Telmisartan 80 mg and Amiodipine 10 mg tablets (40°C/75%RH 3 months Alu-Alu)

ii) For Telmisartan 40 mg and Amiodipine 5 mg tablets (40°C/75%RH 6 months Alu-Alu)

Total 0.08 0.06 0.12 0.1 1

Hi) For Telmisartan 40 mg and Amiodipine 10 mg tablets (40°C/75%RH 6 months Alu-Alu)

For Telmisartan 80 mg and Amiodipine 5 mg tablets (40°C/75%RH 6 months Alu-Alu)

*ND: Not detected

Reference: Twynsta Monolayer tablet: Example 4