Field of the invention

The technical field of the present invention relates to a solid dosage form comprising angiotensin II receptor blocker (ARB) and diuretic. More particularly, the present invention relates to a solid dosage form comprising telmisartan and hydrochlorothiazide.

Background of the invention

Angiotensin II receptor blockers (ARB's) are widely used for the treatment of hypertension and various cardiovascular diseases. ARB's act by antagonizing Angiotensin II receptor, and are therefore useful in regulating and moderating angiotensin induced hypertension, congestive heart failure, renal failure. Such ARB's include telmisartan, valsartan, losartan, irbesartan, candesartan and eprosartan which are disclosed in US 5,591,762, US 5,399,578, US 5,138,069, US 5,270,317, US 5,196,444, and US 5,185,351. These ARB's are also commercially available in combination with diuretics such as hydrochlorothiazide.

Chemically telmisartan is designated as 4'-[(l,4'-dimethyl-2'-propyl [2,6'-bi-lH-benzimidazol]-1'-yl) methyl]-[l,l'-biphenyl]-2-carboxylic acid and is commercially marketed under the trade name Micardis® and Micardis HCT in combination with hydrochlorothiazide in the United States. Commercially Micardis HCT tablets are available as biconvex two layered, uncoated tablets containing telmisartan and hydrochlorothiazide as active ingredients and sodium hydroxide, meglumine, povidone, sorbitol, magnesium stearate, lactose monohydrate, microcrystalline cellulose, maize starch, sodium starch glycolate and iron oxides as inactive ingredients.

As disclosed in US 2005/0089575, the conventional approach of making a powder mixture or co-granulate of telmisartan and HCTZ was not feasible due to the incompatibility of HCTZ with basic compounds such as meglumine. To overcome this, US '575 discloses bilayer tablet comprising first layer containing telmisartan in a dissolving tablet matrix and a second layer containing hydrochlorothiazide in a disintegrating tablet matrix and further discloses process for the preparation of telmisartan layer by spray dried granulation.

The following patents /patent publications further disclose compositions of telmisartan in combination with hydrochlorothiazide.

US 2004/0110813 discloses composition comprising telmisartan dispersed in a dissolving matrix comprising a basic agent, surfactant, 25 % to 70 wt. % of a water-soluble diluent and further discloses spray dried granulation or fluid bed granulation process for the preparation of telmisartan composition.

US 2007/0116759 discloses composition comprising telmisartan, surfactant, basic agent and less than 25% of diluent.

US 2008/0113023 discloses a bilayer tablet comprising a first layer containing telmisartan dispersed in a dissolving matrix comprising a basic agent, a surfactant and 25 to 70 wt. % of a water-soluble diluent, and a second layer containing a diuretic in a disintegrating tablet matrix. This patent publication further discloses fluid bed granulation process for the preparation of the tablets.

US 2009/0202636 Al discloses that bilayer tablets described in US '575 requires special tableting machinery which is expensive and to overcome this US '636 discloses mono layered tablet composition comprising first unit selected from the group consisting of granules, pellets and tablet cores comprising telmisartan, with optional film coating applied to said first unit, and at least one second unit, selected from the group consisting of granules, pellets, and a mixture of powders, comprising hydrochlorothiazide. This patent publication further discloses tablet core comprising telmisartan coated with hydrochlorothiazide.

US 2009/0142398 discloses composition comprising telmisartan dispersed in disintegrating matrix comprising disintegrant, basic agent, water insoluble diluent. And further discloses water insoluble diluent selected from microcrystalline cellulose, di- or tri-basic calcium phosphate, meglumine oxide, crystalline cellulose, powdered cellulose, anhydrous silicic acid, calcium carbonate, calcium sulphate, magnesium silicate, magnesium trisilicate, magnesium aluminium metasilicate kaolin, starch and starch derivatives, magnesium carbonate, magnesium oxide and silicified microcrystalline cellulose.

WO 2009/058950 discloses bilayer tablet comprising first portion comprising telmisartan in a dissolving matrix and a second portion containing hydrochlorothiazide in a dissolving matrix.

EP 1 970 053 Al discloses tablet layer comprising telmisartan, a basic agent and sorbitol, characterized in that the sorbitol has a specific surface area of between 0.75-3.5 m2/g.
IN 1761/MUM/2007 discloses mono layer tablet comprising telmisartan and hydrochlorothiazide.

WO 2009/115301 Al discloses bilayered tablet comprising first layer containing telmisartan in a dissolving matrix and the second layer containing in a dissolving matrix and the pharmaceutical composition is substantially free of disintegrants.

WO 2009/135646 A2 discloses surfactant free granulate comprising amorphous telmisartan, filler and optionally hydrochlorothiazide prepared by fluid bed processing. This patent publication further discloses inert cores coated with telmisartan.

WO 2010/012248 Al discloses composition comprising telmisartan granules prepared by granulating sorbitol with the solution / dispersion comprising telmisartan, meglumine, povidone and sodium hydroxide and further blending telmisartan granules with sorbitol and lubricant and then compressed to tablets.

WO 2010/063995 A2 discloses that the bilayer tablet has the disadvantage that its two constituent layers have a propensity to separate. To overcome this and to provide more mechanically stable tablets than prior art bilayered tablets, WO '995 discloses a mantle tablet in which the inner core comprising telmisartan in dissolving matrix and a mantle comprising diuretic in disintegrating matrix or vice versa.

WO 2010/063997 Al discloses formulation comprising telmisartan and more than 60% by weight of water soluble diluent, wherein said formulation is substantially free of surfactant and emulsifier. This patent publication discloses process for the preparation of the formulation by fluid bed granulation.

IN 2745/MUM/2009 discloses mono layer tablet comprising telmisartan granules and hydrochlorothiazide granules prepared by fluid bed granulation, wherein said tablet is essentially free of surfactant. It further discloses bilayered tablet comprising telmisartan in one layer and hydrochlorothiazide in another layer, wherein hydrochlorothiazide layer is free from disintegrant.

WO 2010/081824 Al discloses single unit dosage form comprising core comprising telmisartan and film coating comprising hydrochlorothiazide and a copolymer of polyvinyl alcohol with polyethylene glycol.

IN 381/MUM/2009 discloses surfactant free composition comprising telmisartan prepared by granulating microcrystalline cellulose, crospovidone using telmisartan solution, drying the granules and further blending the dried granules with crospovidone, sodium starch glycolate, talc and magnesium stearate followed by compression.

The above prior art reference discloses different ways of stabilizing telmisartan and hydrochlorothiazide components i.e. by separating them into layers such as telmisartan in dissolving matrix and hydrochlorothiazide in disintegrating matrix or telmisartan in disintegrating matrix and hydrochlorothiazide in dissolving matrix or both telmisartan and hydrochlorothiazide in dissolving matrix or telmisartan core coated with hydrochlorothiazide. None of the prior art references discloses bilayer tablet comprising both telmisartan and hydrochlorothiazide in disintegrating matrix.

Objective of the invention

Accordingly, the main objective of present invention is to provide solid dosage form comprising telmisartan and hydrochlorothiazide, which comply with the reference product in terms of in vivo parameters like Cmax, tmax and AUC and in vitro parameters like dissolution.

Yet another objective of the present invention is to provide simple and efficient process for preparing solid dosage form of comprising telmisartan and hydrochlorothiazide on a commercial scale.

Summary of the invention

Accordingly, the present invention provides a stable bilayer tablet comprising: (i) first layer comprising telmisartan in a disintegrating matrix comprises

(a) intragranular portion comprising telmisartan and one or more pharmaceutically acceptable excipients,

(b) extragranular portion comprising about 10% to 25% of water insoluble diluent by weight of first layer and one or more pharmaceutically acceptable excipients,

(ii) second layer comprising hydrochlorothiazide in a disintegrating matrix comprises

(a) intragranular portion comprising hydrochlorothiazide and one or more
pharmaceutically acceptable excipients,

(b) extragranular portion comprising one or more pharmaceutically
acceptable excipients.

Detailed description of the invention

In another embodiment, the pharmaceutically acceptable excipients are selected from diluents, basic agent, binder, disintegrant, glidant, colorant and lubricant.

The disintegrating matrix as used in present invention refers to matrix comprising of excipients that readily swells and is capable of disintegrating into small particles in an aqueous medium.

The presence of both layers in a disintegrating matrix allow for the rapid disintegration of the matrix into finer granules thereby enabling faster dissolution rate of telmisartan and hydrochlorothiazide.

In another embodiment, the intragranular portion of the first layer comprising telmisartan is optionally coated with polymers selected from cellulose derivatives, povidone and polyethylene glycol. The amount of polymer may range from about 5% to 20% by weight of intragranular portion.

In another embodiment, the extragranular portion of the first layer may be in the form of powder comprising blend of excipients or as granules.

In another embodiment, telmisartan present in the dosage form may be in crystalline or amorphous form.

In another embodiment, a stable bilayer tablet comprising: (i) first layer comprising telmisartan in a disintegrating matrix, said disintegrating matrix comprising

(a) intragranular portion comprising 5.0% to 25% of telmisartan, 20% to 70% of
diluent, 4% to 10% of basic agent, 1% to 10% of binder and 1% to 15% of disintegrant;

(b) extragranular portion comprising 10% to 25% of water insoluble diluent, 1% to 5% of disintegrant and 0.5% to 5% of lubricant based on the weight of first layer,

(ii) second layer comprising hydrochlorothiazide in a disintegrating matrix, said disintegrating matrix comprising

(a) intragranular portion comprising 5.0% to 15% of hydrochlorothiazide, 40% to 85% of diluent, 1% to 10% of binder and 0% to 5% of disintegrant,

(b) extragranular portion comprising 1% to 10% of disintegrant and 0.1% to 5% of lubricant based on the weight of second layer.

Suitable diluents used according to the present invention are selected from water soluble or water insoluble or combination thereof. Suitable water soluble diluents include sucrose, dextrose, lactose, mannitol, sorbitol and the like and water insoluble diluents include starch, microcrystalline cellulose, silicified microcrystalline cellulose, calcium silicate and the like or combination thereof. The amount of diluent may range from about 20% to 75% by weight.

Suitable basic agents used according to the present invention are selected from the group comprising of sodium hydroxide and potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate, meglumine and the like or combination thereof. The amount of basic agent may range from about 2% to 10% by weight.

Suitable binders used according to the present invention are selected from the group comprising of hydroxypropylmethylcellulose, maize starch, povidone, hydroxypropylcellulose, pregelatinized starch and the like or combination thereof. The amount of binder may range from about 1% to 10% by weight.

Suitable disintegrants used according to the present invention are selected from starch, crospovidone, sodium starch glycolate, croscarmellose sodium and the like or combination thereof. The amount of disintegrant may range from about 1% to 15% by weight.

Suitable glidants of the present invention include magnesium silicate, talc, colloidal silicon dioxide, starch and the like.

Suitable lubricants used according to the present invention are selected from magnesium stearate, hydrogenated castor oil, calcium stearate, sodium stearyl fumarate, talc, vegetable oils, stearic acid, fumaric acid, glyceryl behenate and the like.

In another embodiment, there is provided a process for the preparation of a stable bilayer tablet comprising: (i) first layer comprising telmisartan in a disintegrating matrix comprises

(a) intragranular portion comprising telmisartan and one or more pharmaceutically acceptable excipients,

(b) extragranular portion comprising about 10% to 25% of water insoluble diluent by weight of first layer and one or more pharmaceutically acceptable excipients

(ii) second layer comprising hydrochlorothiazide in a disintegrating matrix comprises

(a) intragranular portion comprising hydrochlorothiazide and one or more
pharmaceutically acceptable excipients,

(b) extragranular portion comprising one or more pharmaceutically
acceptable excipients, comprising the steps of:

(i) granulating the blend of excipients with a solution comprising telmisartan,

(ii) drying the granules of step (i) and

(iii) blending the dried granules of step (ii) with extragranular excipients or
granules,

(iv) granulating hydrochlorothiazide and one or more intragranular excipients
using aqueous/nonaqueous binder solution,

(v) drying the granules of step (iv) and

(vi) blending the dried granules of step (v) with extragranular excipients,

(vii) compressing the blend of step (iii) and step (vi) using bilayer tablet compression machine.

The solvents used for granulation are selected from water, isopropyl alcohol, ethanol, methylene chloride, acetone and the like or mixture thereof.

In another embodiment, a stable bilayer tablet comprising (i) first layer comprising telmisartan in a disintegrating matrix, wherein said disintegrating matrix comprises telmisartan, water insoluble diluent and one or more pharmaceutically acceptable excipients and (ii) second layer comprising hydrochlorothiazide in a disintegrating matrix.

In a preferred embodiment, a stable bilayer tablet dosage form comprising (i) first layer comprising telmisartan in a disintegrating matrix, said disintegrating matrix comprising

(a) intragranular portion comprising 5.0% to 25% of telmisartan; 20% to 70% of diluent selected from lactose, microcrystalline cellulose, calcium silicate or combination thereof; 4% to 10% of basic agent selected from sodium hydroxide, meglumine or combination thereof; 1% to 10% of binder selected from povidone or pregelatinised starch and 1% to 15% of disintegrant selected from croscarmellose sodium or sodium starch glycolate;

(b) extra granular portion comprising 10% to 25% of water insoluble diluent selected from microcrystalline cellulose, calcium silicate or combination thereof; 1% to 5% of disintegrant selected from croscarmellose sodium or sodium starch glycolate and 0.5% to 5% of lubricant selected from magnesium stearate or sodium stearyl fumarate based on the weight of first layer, (ii) second layer comprising hydrochlorothiazide in a disintegrating matrix, said disintegrating matrix comprising

(a) intragranular portion comprising 5.0% to 15% of hydrochlorothiazide; 40% to 85% of diluent selected from lactose, microcrystalline cellulose or combination thereof; 1% to 10% of binder selected from povidone or pregelatinised starch and 0% to 5% of disintegrant;

(b) extra granular portion comprising 1% to 10% of disintegrant selected from croscarmellose sodium or sodium starch glycolate and 0.1% to 5% of lubricant selected from magnesium stearate or sodium stearyl fumarate based on the weight of second layer.

In another embodiment, the bilayer tablet of present invention is optionally coated with a solution / suspension of film coating polymers and one or more excipients such as lactose, titanium dioxide, solubilizing agent and antisticking agent.

Suitable film coating polymers used according to the present invention are selected from ethylcellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose and the like or mixtures thereof.

Suitable anti-sticking agents used according to the present invention are selected from talc, magnesium stearate and the like or a mixture thereof.

In yet another embodiment, the present invention also provides method of treating hypertension, congestive heart failure, angina, and myocardial infarction by administering bilayered tablet prepared according to present invention.

The following examples further exemplify the invention and are not intended to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.

Example 1

The processing steps involved in manufacturing telmisartan and
hydrochlorothiazide dosage form given in example 1 are given below:

Telmisartan granules

i) telmisartan was dissolved in aqueous solution of povidone, sodium hydroxide
and meglumine,

ii) microcrystalline cellulose, lactose and croscarmellose were sifted and
blended,

iii) the blend of step (ii) was granulated with a solution of step (i) in fluid bed
granulator,

iv) dried the granules obtained in step (iii),

v) calcium silicate, microcrystalline cellulose and croscarmellose sodium were
sifted and blended,

vi) granulating the blend (v) with water,

vii) the granules of step (vi) were dried,

viii) blending the granules of step (iv) and step (vii),

ix) the granules of step (viii) were lubricated with magnesium stearate Hydrochlorothiazide granules

x) hydrochlorothiazide, lactose, microcrystalline cellulose, pregelatinised starch
and ferric oxide were sifted and blended,

xi) granulating the blend of step (x) with water,

xii) dried the granules of step (xi) and then blended with sodium starch glycolate,

xiii) the granules of step (xii) were lubricated with magnesium stearate,

xiv) compressed the blended granules of step (ix) and granules of step (xiii)
using bilayer tablet compression machine.

Example 2



The processing steps involved in manufacturing telmisartan and
hydrochlorothiazide dosage form given in example 2 are given below:

Telmisartan granules

i) telmisartan was dissolved in aqueous solution of povidone, sodium hydroxide
and meglumine,

ii) microcrystalline cellulose, lactose and croscarmellose were sifted and
blended,

iii) the blend of step (ii) was granulated with a solution of step (i) in fluid bed
granulator,

iv) dried the granules obtained in step (iii),

v) the dried granules of step (iv) were blended with calcium silicate,
microcrystalline cellulose and croscarmellose sodium were sifted and blended,

vi) the granules of step (v) were lubricated with magnesium stearate,
Hydrochlorothiazide granules

vii) hydrochlorothiazide, lactose, microcrystalline cellulose, pregelatinised
starch and ferric oxide were sifted and blended,

viii) granulating the blend of step (vii) with water,

ix) dried the granules of step (viii) and then blended with sodium starch
glycolate,

x) the granules of step (ix) were lubricated with magnesium stearate,

xi) compressed the blended granules of step (vi) and granules of step (x) using
bilayer tablet compression machine.

Example 3

The processing steps involved in manufacturing telmisartan and
hydrochlorothiazide dosage form given in example 2 are given below:

Telmisartan granules

i) telmisartan was dissolved in aqueous solution of povidone, sodium hydroxide
and meglumine,

ii) microcrystalline cellulose, lactose and croscarmellose were sifted and
blended,

iii) the blend of step (ii) was granulated with a solution of step (i) in fluid bed
granulator,

iv) dried the granules obtained in step (iii),

v) coating the dried granules with aqueous solution of povidone,

vi) calcium silicate, microcrystalline cellulose and croscarmellose sodium were
sifted and blended,

vii) the blend of step (vi) was then made into slugs and then sieved to granules,

viii) blending the granules of step (v) and step (vii),

ix) the granules of step (viii) were lubricated with magnesium stearate

Hydrochlorothiazide granules

x) hydrochlorothiazide, lactose, microcrystalline cellulose, pregelatinised starch
and ferric oxide were sifted and blended,

xi) granulating the blend of step (x) with water,

xii) dried the granules of step (xi) and then blended with sodium starch
glycolate,

xiii) the granules of step (xii) were lubricated with magnesium stearate,

xiv) compressed the blended granules of step (ix) and granules of step (xiii)
using bilayer tablet compression machine.

Stability Data: Tablets prepared according to example 3 were stored at 40°C / 75% RH for three months and then tested by HPLC to determine the amount of impurities. The stability data of telmisartan is given in table 1 and the stability data for hydrochlorothiazide is given in table 2.

Table 1


Table 2

The dissolution profile of telmisartan and hydrochlorothiazide tablets prepared according to the present invention was carried out in 900 ml of pH 7.5 phosphate buffer solution as medium Apparatus USP II, Paddle, @ 75 rpm speed. The release profile (% of drug released in minutes) is given in table 3.

Table 3

Claims

1. A stable bilayer tablet comprising:

(i) first layer comprising telmisartan in a disintegrating matrix comprises

(a) intragranular portion comprising telmisartan and one or more
pharmaceutically acceptable excipients,

(b) extragranular portion comprising about 10% to 25% of water insoluble
diluent by weight of first layer and one or more pharmaceutically acceptable
excipients,

(ii) second layer comprising hydrochlorothiazide in a disintegrating matrix comprises

(a) intragranular portion comprising hydrochlorothiazide and one or more pharmaceutically acceptable excipients,

(b) extragranular portion comprising one or more pharmaceutically acceptable excipients.

2. The tablet of claim 1, wherein the pharmaceutically acceptable excipients are selected from diluents, basic agent, binder, disintegrant, glidant, colorant and lubricant.

3. The tablet of claim 1, wherein the intragranular portion of the first layer comprising telmisartan is optionally coated.

4. The tablet of claim 1, wherein the water insoluble diluent is selected from starch, microcrystalline cellulose, silicified microcrystalline cellulose, calcium silicate or combination thereof.

5. The tablet of claim 2, wherein the diluent is selected from water soluble or water insoluble or combination thereof.

6. The tablet of claim 5, wherein the water soluble diluent is selected from sucrose, dextrose, lactose, mannitol, sorbitol or combination thereof.

7. The tablet of claim 2, wherein the basic agent is selected from sodium hydroxide and potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate, meglumine or combination thereof.

8. A stable bilayer tablet comprising

(i) first layer comprising telmisartan in a disintegrating matrix, wherein said disintegrating matrix comprises telmisartan, water insoluble diluent and one or more pharmaceutically acceptable excipients and (ii) second layer comprising hydrochlorothiazide in a disintegrating matrix.

9. A stable bilayer tablet comprising:

(i) first layer comprising telmisartan in a disintegrating matrix, said disintegrating matrix comprising

(a) intragranular portion comprising 5.0% to 25% of telmisartan, 20% to 70% of diluent, 4% to 10% of basic agent, 1% to 10% of binder and 1% to 15% of disintegrant;

(b) extragranular portion comprising 10% to 25% of water insoluble diluent, 1% to 5% of disintegrant and 0.5% to 5% of lubricant based on the weight of first layer,

(ii) second layer comprising hydrochlorothiazide in a disintegrating matrix, said disintegrating matrix comprising

(a) intragranular portion comprising 5.0% to 15% of hydrochlorothiazide, 40% to 85% of diluent, 1% to 10% of binder and 0% to 5% of disintegrant,

(b) extragranular portion comprising 1% to 10% of disintegrant and 0.1% to 5% of lubricant based on the weight of second layer.

10. A process for the preparation of a stable bilayer tablet of claim 1,
comprising the steps of:

(i) granulating the blend of excipients with a solution comprising telmisartan,

(ii) drying the granules of step (i) and

(iii) blending the dried granules of step (ii) with extragranular excipients or
granules,

(iv) granulating hydrochlorothiazide and one or more intragranular excipients
using aqueous/nonaqueous binder solution,

(v) drying the granules of step (iv) and

(vi) blending the dried granules of step (v) with extragranular excipients,

(vii) compressing the blend of step (iii) and step (vi) using bilayer tablet compression machine.