CA2706292A1

CA2706292A1 - A stable pharmaceutical formulation comprising telmisartan and hydrochlorothiazide

Info

Publication number: CA2706292A1
Application number: CA2706292A
Authority: CA
Inventors: Naresh Talwar; Dean Sebastian; Mathew Philip
Original assignee: Pharmascience Inc
Current assignee: Pharmascience Inc
Priority date: 2010-05-28
Filing date: 2010-05-28
Publication date: 2011-11-28
Also published as: CA2801020A1; WO2011147026A3; WO2011147026A2

Abstract

The present invention is directed to a stable pharmaceutical formulation comprising telmisartan or a pharmaceutically acceptable salt and a diuretic dispersed in a matrix, said matrix comprising: at least one disintegrant in an amount ranging from 0.5 %-20% by weight; a dissolution enhancing agent present in a molar ratio of dissolution enhancing agent to telmisartan of from 1:1 to 10:1; a water-insoluble diluent in an amount ranging from 15%-75% by weight; and at least one other pharmaceutically acceptable excipient /or adjuvant in an amount ranging from 0 - 25% by weight.

Description

A STABLE PHARMACEUTICAL FORMULATION COMPRISING
TELMISARTAN AND HYDROCHLOROTHIAZIDE

FIELD OF THE INVENTION

The present invention relates to a pharmaceutical tablet formulation comprising two active ingredients. More specifically the present invention relates to a formulation comprising Telmisartan, which is an angiotensin II receptor antagonist, and Hydrochlorothiazide, a diuretic, and methods of manufacturing thereof.

BACKGROUND OF THE INVENTION

Telmisartan was first disclosed in European Patent No. 0 502 314 as an angiotensin II
receptor antagonist and is indicated for treatment of mild to moderate essential hypertension in patients.

Its chemical name is 4'-[[4-methyl-6-(1-methyl-2-benzimidazolyl)-2-propyl-1-benzimidazolyl]methyl]-2-biphenylcarboxylic acid, with molecular formula C33H30N402, having following structure:

Telmisartan is a white to off-white, odorless crystalline powder. It is practically insoluble in water and in the pH range of 3 to 7, sparingly soluble in strong acid (except HCI) and soluble in strong base.

As disclosed in W02000/43370 (Canadian Patent No. 2,352,436) crystalline telmisartan exists in two polymorphic forms having different melting points. Under the influence of heat and humidity, the lower melting polymorph B transforms irreversibly into the higher melting polymorph A.

Telmisartan is an orally active, AT1 selective angiotensin II receptor antagonist. By selectively blocking the binding of angiotensin II to the AT1 receptors, telmisartan inhibits the vasoconstrictor and aldosterone-secreting effects of angiotensin II.

Telmisartan blocks ATI receptors, and has essentially no affinity for the AT2 receptors. AT2 receptors have been found in many tissues; to date, they have not been found to be associated with cardiovascular homeostasis. Telmisartan does not inhibit angiotensin converting enzyme (ACE, also known as kininase II), the enzyme that converts angiotensin I
to angiotensin II and degrades bradykinin, nor does it affect renin or other hormone receptors or ion channels involved in cardiovascular regulation of blood pressure and sodium homeostasis. In hypertensive patients, antagonism of angiotensin II AT1 receptors results in two to three-fold increases in plasma renin and angiotensin II
plasma concentrations. Long term effects of increased AT2 receptor stimulation by angiotensin II
are unknown. Telmisartan is known on the market under the trade name Micardis by Boehringer Ingelheim Corporation.

Hydrochlorothiazide (HCTZ) is an orally administered thiazide diuretic which was first disclosed in the patent US 3163645 and is indicated in treatment of edema and hypertension. The chemical name is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, molecular formula is C7HBCIN304S2 with following structure:

H2N S`N
N
iH
Hydrochlorothiazide is a white to practically white, crystalline powder which is slightly soluble in water and freely soluble in sodium hydroxide solution.

Combination of Telmisartan and Hydrochlorothiazide is commercially available under the trade name Micardis Plus and is indicated for use in the treatment of hypertension.
However, particularly with a combination of Telmisartan or a pharmaceutically acceptable salt thereof and HCTZ, this approach was not feasible due to the incompatibility of HCTZ
with basic compounds such as, e.g., meglumine (N-methyl-D-glucamine) which is a conventional component of Telmisartan formulations and the reduced dissolution rate of HCTZ from the dissolving matrix as compared with dissolution from a disintegrating tablet.
Formulations using a combination of these two drugs are described in the following patents:
W02003/059327 (Canadian Patent No. 2,472,392), W02004/096215 (Canadian Patent Application No. 2,524,091), W02006063737 (Canadian Patent Application No.
2,589,493), W02007/060170 (Canadian Patent Application No. 2,625,404), W02007/144175 (Canadian Patent Application No. 2,654,890), W02009/058950, and W02009/115301.
W02003/059327 (Canadian Patent No. 2,472,392) discloses a bilayer pharmaceutical tablet comprising a first layer containing Telmisartan in substantially amorphous form in a dissolving tablet matrix and a second layer containing a diuretic in a disintegrating tablet matrix. This bilayer tablet structure overcomes the stability problem caused by the incompatibility of a diuretic like HCTZ with basic constituents of the Telmisartan formulation.
At the same time such a formulation provides for immediate release of the diuretic from the fast disintegrating matrix. However bilayer tablets as per W003/059327 (CA2472392) tend to be slightly hygroscopic and, therefore, need to be packaged using a moisture-proof packaging material such as aluminium foil blister packs, or polypropylene tubes and HDPE
bottles which preferably contain a desiccant.

Several approaches to overcome the incompatibility problem have been reported in W02003/059327 (Canadian Patent No. 2,472,392). In one approach HCTZ particle was coated in a fluidized-bed granulator with a polymer solution containing water soluble polymers like hydroxypropylcellulose, hydroxypropylmethylcellulose or polyvinylpyrrolidone, thereby reducing the contact surface area of the HCTZ particles with the Telmisartan formulation during mixing and compressing. However, by this means it was not possible to reduce the surface contact area of HCTZ with the Telmisartan formulation in a compressed tablet to a degree sufficient to achieve the desired prolonged shelf life W02004/096215 relates to a medicament formulation of the crystalline sodium salt of 4'-[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl) benzimidazol-1 -ylmethyl]biphenyl-2-carboxylic acid (Telmisartan) and methods for production thereof. The patent discloses pharmaceutical compositions containing the telmisartan sodium salt and a diuretic.

W02006/063737 discloses a pharmaceutical composition comprising telmisartan and hydrochlorothiazide for the treatment of hypertension in patients with an insufficient blood pressure reduction upon treatment either with an angiotensin II receptor antagonist, or a pharmaceutical composition of an angiotensin II receptor antagonist and a low dose of hydrochlorothiazide, wherein the pharmaceutical composition contains the component telmisartan in a dissolving tablet matrix having instant release characteristics and wherein the diuretic hydrochlorothiazide forms is in a separate layer in a disintegrating pharmaceutical matrix.

W02007/144175 discloses a stable formulation of telmisartan and hydrochlorothiazide having both substances in separate units is prepared, exhibiting exceptional stability when subjecting to stress conditions.

W02009/058950 (Dr. Reddy's Laboratories) discloses the pharmaceutical tablets comprising a first layer formulated for immediate release of telmisartan from a dissolving matrix and a second layer formulated for immediate release of hydrochlorothiazide from a dissolving matrix, methods for producing tablets and methods of use for treating hypertension.

The PCT application WO 2009/115301 discloses the solid pharmaceutical composition comprising at least two layers, wherein the first layer contains a non-peptide angiotensin II
receptor antagonist or a pharmaceutically acceptable salt thereof in a dissolving matrix and the second layer contains a diuretic or a pharmaceutically acceptable salt thereof, characterized in that the second layer contains the diuretic or the pharmaceutically acceptable salt thereof in a dissolving matrix and the pharmaceutical composition is substantially free of disintegrants.

It is often desirable to combine multiple active ingredients in a single pharmaceutical composition. Inclusion of multiple ingredients in a single composition generally reduces costs and provides the convenience of consuming a single medication rather than multiple medications for treating individual symptoms. However, a combination of ingredients, especially the stability of a composition might be compromised due to incompatibility between two active ingredients.

The solid pharmaceutical composition according to the present invention, preferably in the form of a tablet, provides an immediate release of the non-peptide angiotensin II receptor antagonist, in particular of the poorly water soluble Telmisartan or pharmaceutically acceptable salts thereof, and also provides an immediate release of a diuretic from the tablet matrix. At the same time the tablet structure overcomes the stability problem caused by the incompatibility of diuretics, like HCTZ, with basic excipients of the conventional Telmisartan formulation, e.g. meglumine.

It is known from the literature that telmisartan has very poor aqueous solubility in the physiological pH range of the gastrointestinal tract between pH 1 and 7, and is soluble in strong base. On the other hand, hydrochlorothiazide degrades in alkaline conditions i.e undergoes alkaline hydrolysis in the presence of heat and moisture. The major degradation product of Hydrochlorothiazide is 4-amino-6-chloro-1,3-benzenesulfonamide ("DSA") It is advantageous to administer both drugs concomitantly or even better to administer a composition comprising both, to treat hypertension.

Difficulty results from the fact that both active substances need to be released from the composition substantially simultaneously. Preparation of fixed dose combinations of telmisartan and hydrochlorothiazide with adequate stability poses a challenge to formulators. Hence there is need for simple and stable fixed dose compositions containing telmisartan and hydrochlorothiazide.

SUMMARY OF THE INVENTION

A first object of the present invention is to provide a stable pharmaceutical formulation comprising telmisartan or a pharmaceutically acceptable salt and a diuretic dispersed in a matrix, said matrix comprising:
- at least one disintegrant in an amount ranging from 0.5 %-20% by weight;
- a dissolution enhancing agent present in a molar ratio of dissolution enhancing agent to telmisartan of from 1:1 to 10:1;
- a water-insoluble diluent in an amount ranging from 15%-75% by weight; and at least one other pharmaceutically acceptable excipient /or adjuvant in an amount ranging from 0 - 25% by weight.

Preferably, the diuretic is HCTZ.

Preferably, the formulation according to the present invention comprises a surfactant or emulsifier present in an amount ranging from 0.5% -10% by weight.

According to another aspect of the present invention, there is provided a stable pharmaceutical formulation according to claim 1 wherein the in vitro dissolution rate of said formulation is at least 80% w/w of telmisartan dissolved within 30 minutes and at least 80 %
of the diuretic dissolved within 30 minutes as measured by using USP type II
apparatus at 75 rpm in 900ml of pH 7.5 phosphate buffer.

Preferably, the disintegrant is selected from the group consisting of:
crospovidone, croscarmellose sodium, sodium starch glycolate, starch, modified starch and a combination thereof. More preferably, the disintegrant is croscarmellose sodium.

The dissolution enhancing agent is preferably selected from the group consisting of:
NaHCO3, KHCO3i NA2CO3, Na2HPO4, K2HPO4, tromethamine, triethanolamine, MgO, and MgCO3. More preferably, the dissolution enhancing agent is MgO.

Preferably, the formulation further comprises a solubilizing agent selected from the group consisting of: alkali metal hydroxide such as NaOH and KOH. More preferably, the solubilizing agent is NaOH.

Preferably, the water insoluble diluent is selected from the group consisting of:
microcrystalline cellulose, di- or tri-basic calcium phosphate, crystalline cellulose, powdered cellulose, anhydrous silicic acid, calcium carbonate, calcium sulphate, magnesium silicate, magnesium trisilicate, magnesium aluminium metasilicate (Neusilin), kaolin, starch, starch derivatives, and co-processed excipients. Also preferably, the co-processed excipient is selected from the group consisting of: Ludipress( (mixture of lactose and 3.2% Povidone K30), Cellactose( (mixture of lactose and cellulose), and Silicified MCC
Prosolv (mixture of microcrystalline cellulose and silicon dioxide). More preferably, the co-processed excipient is silicified microcrystalline cellulose Prosoly .

Preferably, the formulation comprises less than 0.5% wt of 4-amino-6-chloro-1,3 benzenedisulfonamide (DSA) impurity in comparison to the initial HCTZ content when exposed to 40 C/75% relative humidity conditions in Blister as well as HDPE
pack. Also preferably, the formulation according to claim 1, wherein the in vitro dissolution rate remains similar to the initial value for telmisartan and for the diuretic on stabiliy as measured by using USP type II apparatus at 75 rpm in 900m1 of pH 7.5 phosphate buffer.

According to another aspect of the present invention, there is provided a wet granulation process preferably a low shear granulation process for preparing the stable pharmaceutical composition.

According to another aspect of the present invention, there is provided a process for the preparation of a stable pharmaceutical formulation according to claim 1 comprising: an angiotensin II receptor antagonist, a diuretic and a dissolution enhancing agent in a matrix, wherein said process comprises the following steps:
(1) - preparation of granulation solution;
(2) - dry mixing;
(3) - granulation;
(4) - lubrication; and (5) - compression.

When the process has for starting material a salt form of an angiotensin II
receptor antagonist said process comprises a dry mixing step and direct compression.

According to another aspect of the present invention, there is provided a use of a stable pharmaceutical formulation containing two active ingredients in a single layer, in an immediate release form for the treatment or prevention of hypertension.

Preferably, the formulation is in the form of a monolithic tablet or a single layer tablet. Also preferably, the formulation is in the form of a bilayer tablet dosage form wherein a first layer is a placebo layer and the second layer contains the angiotensin II receptor antagonist or a pharmaceutically acceptable salt thereof, and a diuretic.

According to another aspect of the present invention further relates to stable formulation comprising telmisartan or acceptable salts and Hydrochlorothiazide, wherein the telmisartan or acceptable salt is in substantially amorphous form.

DETAILED DESCRIPTION OF THE INVENTION

An object of the present invention provides a pharmaceutical formulation comprising two active ingredients, wherein the in vitro dissolution rate of said formulation provides at least 80% of a first active ingredient dissolved within 30 minutes and at least 80 %
of a second active ingredient dissolved within 30 minutes as measured by USP type II
apparatus at 75 rpm in 900ml of pH 7, 5 phosphate buffer.

According to another object of the present invention there is provided a pharmaceutical formulation comprising a combination of Telmisartan and Hydrochlorothiazide (HCTZ) in a single layer, preferably with Magnesium Oxide, but does not degrade or contribute to degradation of HCTZ, and a manufacturing process in order to get suitable stability properties, without need of expensive packing.

In a preferred embodiment of the invention, there is provided bilayer pharmaceutical formulation comprising two active ingredients, wherein the first active ingredient is Telmisartan or a pharmaceutically acceptable salt thereof, which is practically insoluble in water (pH 3- 9), soluble in strong base. Preferably, the second active ingredient is hydrochlorothiazide, which is soluble in sodium hydroxide solution, slightly soluble in water.
The term "active ingredient" refers to an agent or substance that has measurable specified or selected physiologic activity when administered to a subject in a pharmaceutically significant or effective amount. The active agent can be a therapeutic, a prophylactic, or a diagnostic agent. These terms of art are well-known in the pharmaceutical and medicinal arts.

The term "stability" refers to the extent to which a product retains, within specified limits and throughout its period of storage and use, the same properties and characteristics that it possessed at the time of its manufacture. There are five general types of stability defined by the United States Pharmacopoeia: Chemical, Physical, Microbiological, Therapeutic and Toxicological.

Additionally, the formulation of the present invention preferably further comprises pharmaceutically acceptable excipients. Excipients are added to the composition for a variety of purposes. One or more pharmaceutically acceptable excipients may be present in the composition of the present invention, such as for example diluents, binders, lubricants, disintegrants, glidants, acidifying agents.

Particularly preferred, as pharmaceutically acceptable excipients to use in the present invention are: povidone, sodium hydroxide, isopropyl alcohol, silicified MCC90 (Prosoly ), colloidal silicon dioxide (Aerosil ), dibasic calcium phosphate Hydrous, croscarmellose sodium, magnesium oxide heavy, magnesium stearate, microcrystalline cellulose and iron oxides.

Suitable diluents include for example pharmaceutically acceptable inert fillers such as microcrystalline cellulose, lactose, pregelatinized starch, dibasic calcium phosphate, saccharides, and/or mixtures of the foregoing.

Suitable binders may be selected from amongst povidone, Copovidone, alginic acid; sodium alginate; cellulose derivatives such as hydroxypropyl methylcellulose, hydroxy propyl cellulose, hydroxy ethyl cellulose, methylcellulose and ethyl cellulose;
gelatin; and starch or starch derivatives.

Suitable lubricants are selected from the group consisting of: Mg-, Al- or Ca-stearate, stearic acid, sodium stearyl fumarate, talc, sodium benzoate, glyceryl mono fatty acid, glyceryl monostearate hydrogenated vegetable oil, polyethylene glycol,and mixtures thereof.

Suitable disintegrants may be selected from one or more compounds such as:
croscarmellose sodium, sodium starch glycolate, maize starch, CMC-Ca, CMC-Na, microcrystalline cellulose, cross-linked PVP, alginic acid, sodium alginate, pregelatinized starch and low-substituted hydroxy propyl cellulose.

Suitable dissolution enhancing agents are preferably selected from the group consisting of:
NaHCO3i KHCO3, NA2CO3, Na2HPO4, K2HPO4, tromethamine, triethanolamine, MgO, and MgCO3. More preferably, the dissolution enhancing agent is MgO.

Suitable anti-adherents may be selected from one or more compounds that are capable of preventing stickiness to surfaces of the punches. Examples of anti-adherents include silicon-containing compounds such as colloidal silicon dioxide, magnesium trisilicate and talc.

According to another object of the invention, there is pharmaceutical formulation comprising Telmisartan or a pharmaceutically acceptable salt thereof and a second active ingredient, wherein at least 60 % of Telmisartan is dissolved within 5 minutes as measured by USP
Paddle Method at 75 rpm at pH 7,5 dissolution phosphate buffer at 37 C. Also, preferably at least 80 % of Telmisartan is dissolved within 10 minutes as measured by USP
Paddle Method at 75 rpm at pH 7,5 dissolution phosphate buffer at 37 C. Also, preferably at least 90 % of Telmisartan is dissolved within 30 minutes as measured by USP Paddle Method at 75 rpm at pH 7,5 dissolution phosphate buffer at 37 C.

According to another object of the invention, there is provided a pharmaceutical formulation comprising Telmisartan or a pharmaceutically acceptable salt thereof and Hydrochlorothiazide, wherein at least 55 % of Hydrochlorothiazide is dissolved within 5 minutes as measured by USP Paddle Method at 75 rpm at pH 7,5 dissolution phosphate buffer at 37 C. Also, preferably at least 75 % of Hydrochlorothiazide is dissolved within 10 minutes as measured by USP Paddle Method at 75 rpm at pH 7,5 dissolution phosphate buffer at 37 C. Also, preferably at least 80 % of Hydrochlorothiazide is dissolved within 30 minutes as measured by USP Paddle Method at 75 rpm at pH 7,5 dissolution phosphate buffer at 37 C. Also, preferably at least 85 % of Hydrochlorothiazide is dissolved within 60 minutes as measured by USP Paddle Method at 75 rpm at pH 7,5 dissolution phosphate buffer at 37 C.

According to another object of the invention, there is provided a process for the preparation of a pharmaceutical formulation containing two active ingredients in a single layer comprising the following steps:
(1) - dissolving Telmisartan in purified water with sodium hydroxide;
(2) - dissolving binder in isopropyl alcohol;

(3) - mixing the content of step (1) with the content of step (2);
(4) - blending pharmaceutical excipients;
(5) - granulating the blend of step (4) with the content of step (3);
(6) - drying the wet granules obtained from step (5);
(7) - screening the dried granules obtained from step (6);
(8) - mixing the granules of step (7) with additional pharmaceutically acceptable excipients;
(9) - preparing a mixture of a second active ingredient and pharmaceutically acceptable excipients;
(10) - adding the content of step (9) to the content of step (8); and (11) - compressing the blend of step (10).

According to another object of the invention, there is provided a process for the preparation of a pharmaceutical formulation comprising two active ingredients, wherein the in vitro dissolution rate of the said formulation provides at least 80 % of a first active ingredient dissolved within 30 minutes and at least 80 % of a second active ingredient dissolved within 30 minutes as measured by USP Paddle Method at 75 rpm at pH 7, 5 dissolution phosphate buffer at 37 C, wherein said process comprises the following steps:
(1) - dissolving Telmisartan in purified water with sodium hydroxide;
(2) - dissolving, povidone (K-30) in isopropyl alcohol;
(3) - mixing the solution of step (1) with the solution of step (2);
(4) - dry mixing the following pharmaceutical excipients: silicified MCC
90(Prosolv ), dibasic calcium phosphate hydrous, croscarmellose sodium and colloidal silicon dioxide;
(5) - screening the content obtained from step (4) and then blending;
(6) - adding to the blend of step (5) to the granulation solution of step (3);
(7) - drying the wet granules in a fluid bed drier;
(8) - screening the dried granules obtained from step (7);
(9) - mixing the granules of step (8) with magnesium oxide heavy and the colloidal silicon dioxide (Aerosil ) and screening the obtained mixture;
(10) - screening Hydrochlorothiazide, microcrystalline cellulose PH102 (Avicel ) and croscarmellose sodium, and blending with the granules of step (9);
(11) - dispersing a portion of blend with magnesium stearate and screening;

(12) - blending the content of step (11) together with the granules of step (9);

(13) - separately screening the microcrystalline cellulose, yellow iron oxide, colloidal silicon dioxide and croscarmellose sodium, through #40 sieve (400pm) and blending the content;

(14) - screening magnesium stearate and blending with the blend of step (12);

(15) - compressing the lubricated blend of step (14) and the blend of step (12), using a bilayer compression machine.

Preferably, the process for the preparation of a pharmaceutical formulation comprises two active ingredients - Telmisartan and Hydrochlorothiazide, the pharmaceutically acceptable excipients: povidone, sodium hydroxide, isopropyl alcohol, silicified MCC90 (Prosoly ), colloidal silicon dioxide (Aerosil ), dibasic calcium phosphate hydrous, croscarmellose sodium, magnesium oxide heavy, magnesium stearate, microcrystalline cellulose and colorants.

Preferably, the granulation solution is prepared by dissolving gradually Telmisartan under stirring in purified water with sodium hydroxide. More preferably, wherein isopropyl alcohol and povidone (K-30) is dissolved in a separate vessel. Then, the content of solution of step (1) is mixed with the content of the solution of step (2).

Preferably, the obtained content is dry mixed and then screened with the following pharmaceutical excipients: silicified MCC 90 (Prosolv ), dibasic calcium phosphate hydrous, croscarmellose sodium and colloidal silicon dioxide.

Preferably, to the blend of step (5) is added to the content of step (3) and the granulation is carried out in a ribbon blender.

Preferably, the wet granules are dried in a fluid bed drier at inlet temperature of 50 C 5 C
until a loss on drying value of 3.8% 0.4% is obtained on a moisture analyzer set at 105 C
for 10 minutes.

Preferably, the dried granules obtained from step (7) are screened through a comill equipped with 0.039R screen (1000 pm).

Preferably, the granules of step (8) are mixed with magnesium oxide heavy and colloidal silicon dioxide (Aerosil ) and screened through #30 sieve (600pm).

Preferably, Hydrochlorothiazide, microcrystalline cellulose PH102 (Avicel ) and croscarmellose sodium are screened through #40 sieve (400pm), added to the granules of step (9) and blended for 20 minutes.

Preferably, a portion of the blend obtained from step (10) is dispersed with magnesium stearate, and then screened manually through #40 sieve (400pm) and blended for minutes.

Preferably, microcrystalline cellulose PH102, yellow iron oxide, colloidal silicon dioxide and croscarmellose sodium are screened through #40 sieve (400pm) and blended for minutes.

Preferably, magnesium stearate is passed through a 40 (400pm) mesh screen, is introduced into the bin blender and blended for 3 minutes with mixture obtained from step (12), prior to compression.

Preferably, the lubricated blend is compressed using capsule shaped tooling at average weight of 700 mg on a stokes bilayer compression machine.

According to another object of the invention, there is provided a process for the preparation of a pharmaceutical formulation containing two active ingredients in a single layer, wherein said process comprises the following steps:
(1) - preparation of granulation solution;
(2) - dry mixing;
(3) - granulation;
(4) - lubrication; and (5) - compression.

Preferably, the step of preparation of a granulation solution further comprises dissolving Telmisartan under stirring in purified water with sodium hydroxide.

Preferably, the step of preparation of a granulation solution further comprises dissolving povidone (K-30) in Isopropyl Alcohol.

Preferably, the step of preparation of a granulation solution further comprises mixing the content of step (1) with the content of step (2) for 15 minutes.

Preferably, the step of dry mixing further comprises: dry mixing silicified MCC 90 (Prosolv ), dibasic calcium phosphate hydrous, croscarmellose sodium and colloidal silicon dioxide in a ribbon blender for 5 min.

Preferably, the step of dry mixing further comprises screening the content obtained from step (2) through a comill equipped with 0.045R screen (1190 pm) and then mix for 5 minutes to yield an excipient blend.

Preferably, the step of granulation further comprises adding to the blend obtained from the dry mixing step the granulation solution.

Preferably, the step of granulation further comprises drying the wet granules in a fluid bed drier at an inlet temperature of 50 C 5 C till a loss on drying value of 3.8% 0.4% is obtained on a moisture analyzer set at 105 C for 10 minutes.

Preferably, the step of granulation further comprises screening the dried granules through a comill equipped with 0.039R screen (1000 pm).

Preferably, the step of lubrication comprises mixing magnesium oxide heavy and the colloidal silicon dioxide (Aerosil ) and screening through #30 sieve (600pm).

Preferably, the step of lubrication further comprises screening Hydrochlorothiazide, microcrystalline cellulose PH102 (Avicel(D) and croscarmellose sodium, through #40 sieve (400pm) and adding to the granules of Telmisartan and blending to yield a HCTZ
blend.
Preferably, the step of lubrication further comprises dispersing a portion of the HCTZ blend with magnesium stearate and screening the obtained content through #40 sieve (400pm) to yield a lubricated HCTZ blend.

Preferably, the step of lubrication further comprises adding the lubricated HCTZ blend to the Telmisartan granules and blending for 3 minutes to yield the actives blend.

Preferably, the step of blending placebo blend further comprises screening microcrystalline cellulose, yellow or red iron oxide, colloidal silicon dioxide and croscarmellose sodium, through #40 sieve (400pm) and blending the content for 15 minutes to obtain an excipient placebo blend.

Preferably, the step of compression further comprises compressing the excipient blend and actives blend, to form a bilayer pharmaceutical formulation.

According to another object of the present invention, there is provided the use of a pharmaceutical formulation containing two active ingredients in a single layer, in an immediate release form, for the treatment or prevention of hypertension.

While several embodiments of the invention have been described, it will be understood that the present invention is capable of further modifications and this application is intended to cover any variations uses or adaptations of the invention following in general the principles of the invention and including such departures from the present disclosure as to come within knowledge customary practices in the art to which the invention pertains, as may be applied to the essential features herein before set forth and falling within the scope of the invention.
The following examples illustrate the preferred embodiment and various aspects of the present invention.

Example 1 IMMEDIATE RELEASE DOSAGE FORM OF TELMISARTAN/HCTZ ACCORDING TO A
PREFERRED EMBODIMENT OF THE PRESENT INVENTION

1. Preparation Of Granulating Solution:

1. In a vessel to purified water was added sodium hydroxide and dissolved under stirring.
The required quantity of Telmisartan was added gradually and dissolved under stirring.

2. In another vessel to isopropyl alcohol was added Povidone (K-30) and dissolved under stirring.

3. The granulation solution is prepared by adding to the content of Telmisartan solution (1) the Povidone K30 solution (2) and mixing for 15 minutes.

Dry Mixing 4. Silicified MCC 90 (Prosoly ), Dibasic Calcium phosphate Hydrous, Croscarmellose sodium and Colloidal Silicon Dioxide (Aerosil ) was introduced into a ribbon blender and blended for 5 minutes. The blend was screened through a comill screen 0.045R
(1190 pm). This blend was reintroduced into the ribbon blender and blended for minutes.

Granulation 5. The blend of step 4 was granulated with solution of step 3 in a ribbon blender.

6. The wet granules were dried in a fluid bed drier at an inlet temperature of till a Loss on drying value of 3.8% 0.4% is obtained on a moisture analyzer set at 105 C for 10 minutes.

7. The dried granules were screened through a co mill screen 0.039R screen (1000 pm) for further processing.

Lubrication 8. The dried screened granules of step 7 was added to a bin blender.

9. Magnesium oxide heavy and Colloidal Silicon Dioxide (Aerosil ) were dispersed and screened through #30 sieve (600pm).This sieved dispersion was added to the bin blender of step 8.

10. Hydrochlorothiazide, Microcrystalline Cellulose PH102 (Avicel(D)and croscarmellose sodium was screened through #40 sieve (400pm).This sieved dispersion was introduced into the bin blender of step 8 and blended for 20 minutes.

11. Magnesium stearate was dispersed with a portion of the blend of step 10 in a polyethylene bag and screened manually through #40 sieve (400pm).This sieved dispersion was introduced into the bin blender of step 8 and blended for 3 minutes.

II. Manufacturing of Yellow Placebo Blend 12. Microcrystalline Cellulose PH 102 (Avicel ), Yellow oxide iron, Colloidal Silicon Dioxide (Aerosil ) and croscarmellose sodium was screened through #40 sieve (400pm) and introduced into the bin blender and blended for 15 minutes.

13. Magnesium stearate was screened through #40 sieve (400pm) and introduced into the bin blender of step 12 and blended for 3 minutes.

Compression 14. The lubricated blend of step 11 and stepl 3 was compressed using capsule shaped tooling at an average weight of 700 mg on a stokes bilayer compression machine.

The formulation of Example 1 is set out in Table 1 below.
Table 1 Formulation according to the present invention No. Ingredient mg/Tablet (Telmisartan and Hydrochlorothiazide granules) 1 Telmisartan 80.0 2 Sodium Hydroxide 6.624 3 Povidione (k30) 4.80 4 Purified water 110.0*
Isopropyl Alcohol 12.7**
6 Silicified MCC 90 ( Prosoly ) 168.0 No. Ingredient mg/Tablet 7 Colloidal Silicon Dioxide (Aerosil ) 4.8 8 Dibasic Calcium phosphate Hydrous 72.0 9 Croscarmellose Sodium 19.2 Magnesium Oxide Heavy 24.0 11 Colloidal Silicon Dioxide (Aerosil ) 2.4 12 Hydrochlorothiazide 25.0 13 Microcrystalline Cellulose PH 102 (Avicel ) 70.23 14 Croscarmellose Sodium 19.2 Magnesium Stearate 3.75 Total 500.0 Yellow Placebo granules 16 Microcrystalline Cellulose PH 102 (Avicel ) 194.65 17 Yellow oxide iron 0.35 18 Colloidal Silicon Dioxide (Aerosil ) 0.5 19 Croscarmellose sodium 4.0 Magnesium Stearate 0.5 Total 200.0 Total of both layers 700.0 * & **: Evaporates during processing. Does not appear in the final formulation.
Dissolution:

The tablets obtained from Example 1 were subsequently tested for in vitro dissolution rate, measured by Apparatus II (USP Paddle Method), using the following parameters:
Speed: 75 rpm Media: 900 ml pH 7.5 Phosphate buffer Temperature: 37 C.
The dissolution results are set out in Table 2 and 3 below.

Table II and III provides a comparative dissolution of telmisartan and hydrochlorothiazide from Micardis Plus 80/25 mg where Telmisartan and Hydrochlorothiazide are dispersed in two separate layers) versus formulation of present invention (where Telmisartan and hydrochlorothiazide are dispersed in a single layer) Table II
Media :900 ml,7.5 Phosphate buffer Apparatus: USP Type II
RPM : 75 Micardis Plus 80/25 mg Time Lot no :810094 Example 1 minutes % Telmisartan Dissolved % Telmisartan Dissolved Table III :
Media :900m1, 7.5 Phosphate buffer Apparatus: USP Type II
RPM : 75 Micardis Plus 80/25 mg Time Lot No :810094 Example 1 % Hydrochlorothiazide % Hydrochlorothiazide min Dissolved Dissolved Stability Stability of formulation of present invention (Examplel) was evaluated in two types of packaging at 40 C /75% RH conditions. The following parameters were evaluated.
1) Degradation of Telmisartan and Hydrochlorothiazide in the formulation as per the present invention.
2) Dissolution of Telmisartan and Hydrochlorothiazide in the formulation as per the present invention.
3) Moisture content of the formulation as per the present invention.

The results of degradation, dissolution and Moisture content are tabulated in Tables IV, V, VI, VII, VIII and IX.

Pack I: HDPE pack with desiccant ( Trisorb ) Pack II: Cold forming ALU/ALU blisters.

Table IV: Degradation of formulation of Example I in HDPE bottles at 40 C/75%
RH
Pack I : HDPE pack with desiccant (Trisorb ) Lot No: Formulation as per Example 1 Parameter Initial (T=0) 1 Month 2 Months Moisture content (%) 3.71% 3.58% 3.34%
Degradation of Telmisartan Known Impurities Comp 3 - - -Comp 4 - - -Comp 5 - - -Comp 6 0.07% 0.07% 0.06%
Comp 7 - - -Unknown RRT % RRT % RRT %
Impurities 0.87 0.03 0.87 0.03 1.40 0.03 1.41 0.03 1.40 0.03 1.41 0.10 1.42 0.07 1.41 0.09 Degradation of Hydrochlorothiazide Known Impurities Comp 1* 0.07% 0.07% 0.06%
Comp 2 0.04% 0.04% 0.04%
Unknown Impurities RRT % RRT % RRT %
2.60 0.04 2.58 0.04 2.58 0.05 * DSA Impurity Table V: Dissolution of Telmisartan from formulation as per example 1 in HDPE
pack at 40 C/75% RH
Media :900 ml,7.5 Phosphate buffer Apparatus: USP Type II
RPM : 75 T=0 I Month 2 Months Time % Telmisartan % Telmisartan % Telmisartan in minutes Dissolved Dissolved Dissolved Table VI: Dissolution of Hydrochlorothiazide from formulation as per example 1 in HDPE
pack at 40 C/75% RH
Media :900ml, 7.5 Phosphate buffer Apparatus: USP Type II
RPM : 75 T=0 I Month 2 Months Hydrochlorothiazide Hydrochlorothiazide Hydrochlorothiazide Time Dissolved Dissolved Dissolved Table VII: Comparative Degradation of Example I and Micardis Plus in ALU/ALU
Blisters at 40 C/75% RH.
Pack If : ALU/ALU Blister pack Example I Micardis Plus 80/25 mg Lot No 810094 Parameter Initial (T=0) 1Month 2 Months Initial (T=0) 1Month Moisture 3.71% 3.8% 3.5% 1.74% 1.71%
content (%) Degradation of Telmisartan Known Impurities Comp 3 - - - - -Comp 4 - - - - -Comp 5 - - - - -Comp 6 0.07% 0.07% 0.06% - -Comp 7 - - -Unknown RRT % RRT % RRT % RRT % RRT %
Impurities 0.87 0.03 0.87 0.03 0.87 0.03 1.46 0.03 1.46 0.03 1.41 0.03 1.41 0.09 1.40 0.04 1.47 0.04 1.47 0.03 1.42 0.07 1.41 0.10 Degradation of Hydrochlorothiazide Known Impurities Comp l 0.07% 0.06% 0.07% 0.10% 0.12%
Comp 2 0.04% 0.04% 0.04% 0.03% 0.03%
Unknown RRT % RRT % RRT % RRT % RRT %
Impurities 2.60 0.04 2.58 0.04 2.60 0.05 2.58 0.05 2.58 0.05 Table VIII: Dissolution of Telmisartan from formulation as per example 1 in ALU/ALU Blister pack at 40 C/75% RH

Media :900m1, 7.5 Phosphate buffer Apparatus: USP Type II
RPM : 75 T=0 1 Month 2 Months Time in %Telmisartan % Telmisartan %Telmisartan minutes Dissolved Dissolved Dissolved Table IX: Dissolution of Hydrochlorothiazide from formulation as per example 1 in ALU/ALU
Blister pack at 40 C/75% RH
Media :900m1,7.5 Phosphate buffer Apparatus: USP Type II
RPM : 75 T=0 I Month 2 Months % Hydrochlorothiazide % Hydrochlorothiazide % Hydrochlorothiazide Time Dissolved Dissolved Dissolved Based on the data from the above tables the following can be concluded:

1) From Tables IV & VII the formulation as per the present invention has comparable stability in both blister as well as HDPE pack with that of the reference product (Micardis Plus 80/25 mg).

2) From Tables V, VI, VIII and IX the dissolution rate of Hydrochlorothiazide and Telmisartan from formulation as per-the present invention is not affected on stability.

Claims

1. A stable pharmaceutical formulation comprising telmisartan or a pharmaceutically acceptable salt and a diuretic dispersed in a matrix, said matrix comprising:
- at least one disintegrant in an amount ranging from 0.5 %-20% by weight;
- a dissolution enhancing agent present in a molar ratio of dissolution enhancing agent to telmisartan of from 1:1 to 10:1;
- a water-insoluble diluent in an amount ranging from 15%-75% by weight; and - at least one other pharmaceutically acceptable excipient /or adjuvant in an amount ranging from 0 - 25% by weight.

2. The stable pharmaceutical formulation according to claim 1 wherein the diuretic is hydrochlorothiazide.

3. A stable pharmaceutical formulation according to claim 1 or 2, further comprising a surfactant or emulsifier present in an amount ranging from 0.5% -10% by weight.

4. A stable pharmaceutical formulation according to claim 1 wherein the in vitro dissolution rate of said formulation is at least 80% w/w of telmisartan dissolved within 30 minutes and at least 80 % of the diuretic dissolved within 30 minutes as measured by using USP type II apparatus at 75 rpm in 900m1 of pH 7,5 phosphate buffer.

5. The formulation according to claim 1 wherein the disintegrant is selected from the group consisting of: crospovidone, croscarmellose sodium, sodium starch glycolate, starch, modified starch and a combination thereof.

6. The formulation according to claim 5 wherein the disintegrant is croscarmellose sodium.

7. The formulation according to claim 1 wherein the dissolution enhancing agent is selected from the group consisting of: NaHCO3, KHCO3, NA2CO3, Na2HPO4, K2HPO4, tromethamine, triethanolamine, MgO, and MgCO3.

8. The formulation according to any one of claims 1 to 7, wherein the dissolution enhancing agent is MgO.

9. The formulation according to any one of claims 1 to 8, further comprising a solubilizing agent selected from the group consisting of alkali metal hydroxides such as NaOH and KOH.

10. The formulation according to claim 9, where the solubilizing agent is NaOH.

11. The formulation according to claim 1, wherein the water insoluble diluent is selected from the group consisting of: microcrystalline cellulose, di- or tri-basic calcium phosphate, crystalline cellulose, powdered cellulose, anhydrous silicic acid, calcium carbonate, calcium sulphate, magnesium silicate, magnesium trisilicate, magnesium aluminium metasilicate (Neusilin), kaolin, starch, starch derivatives, and co-processed excipients.

12. The formulation according to claim 11, wherein the co-processed excipient is selected from the group consisting of: Ludipress® (mixture of lactose and 3.2%
Povidone K30), Cellactose® (mixture of lactose and cellulose), and Silicified MCC
Prosolv® (mixture of microcrystalline cellulose and silicon dioxide).

13. The formulation according to claim 11 or 12 wherein the co-processed excipient is silicified microcrystalline cellulose (Prosolv®).

14. The formulation according to claim 13, wherein the composition further comprises at least one pharmaceutically acceptable excipient selected from the group consisting of:
binders, lubricants, flow agents, adsorbants, crystallization retarders, anti-adherents, pH
modifiers and coloring agents.

15. The formulation according to any one of claims 1 to 14, further comprising less than 0.5% wt of 4-amino-6-chloro-1,3 benzenedisulfonamide (DSA) impurity in comparison to the initial HCTZ content.

16. The formulation according to claim 1, wherein the in vitro dissolution rate remains similar to the initial value for telmisartan and for the diuretic as measured by using USP type II apparatus at 75 rpm in 900ml of pH 7, 5 phosphate buffer.

17. A low shear granulation process for preparing a stable pharmaceutical composition as per claim 1.

18. A process for the preparation of a stable pharmaceutical formulation according to claim 1 comprising: an angiotensin II receptor antagonist, a diuretic and a dissolution enhancing agent in a matrix, wherein said process comprises the following steps:
(1) - preparation of granulation solution;
(2) - dry mixing;
(3) - granulation;
(4) - lubrication; and (5) - compression.

19. A process for the preparation of a stable pharmaceutical formulation containing a pharmaceutically acceptable salt form of an angiotensin II receptor antagonist, a diuretic and a dissolution enhancing agent in a matrix, wherein said process comprises a step of dry blending and direct compression.

20. Use of a stable pharmaceutical formulation containing two active ingredients in a single layer, in an immediate release form, according to any one of claims 1 to 16 for the treatment or prevention of hypertension.

21. The formulation according to any one of claims 1 to 16, in the form of a monolithic tablet or a single layer tablet.

22. The formulation according to any one of claims 1 to 16, in the form of a bilayer tablet dosage form wherein a first layer is a placebo layer and the second layer contains the angiotensin II receptor antagonist or a pharmaceutically acceptable salt thereof, and a diuretic.