Field of the invention

The technical field of the present invention relates to solid dosage form
comprising combination of angiotensin II receptor blocker (ARB) and calcium channel blocker (CCB). More particularly, the present invention relates to solid dosage form comprising combination of valsartan and amlodipine.

Background of the invention

Angiotensin II receptor blockers and calcium channel blockers (CCBs) 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. Commercially available ARB's include valsartan marketed under the trade name Diovan®, losartan marketed under the trade name Cozaar®, irbesartan marketed under the trade name Avapro®, candesartan marketed under the trade name Atacand®, telmisartan marketed under the trade name Micardis® and eprosartan marketed under the trade name Teventen®' which are disclosed in US 5,399,578, US 5,138,069, US 5,270,317, US 5,196,444, US 5,591,762 and US 5,185,351.

These ARB's are also commercially available in combination with diuretics such as hydrochlorothiazide.

Apart from the combination of ARB's with diuretics, ARB's are also available in combination with CCB's. CCB's act by inhibiting the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle and cause reduction in peripheral vascular resistance and reduction in blood pressure. Commercially available calcium channel blocker includes amlodipine, nifedipine, nimodipine, manidipine, nicardipine, lercanidipine, nisoldipine, felodipine and their pharmaceutically acceptable salts thereof.

Combination of CCB and ARB provides synergistic effect in the treatment of cardiovascular disorders such as hypertension, congestive heart failure, angina, myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction and stroke.

Combination of amlodipine and valsartan is being marketed as tablets under the trade name Exforge® in the United States containing 5/160, 5/320, 10/160 and 10/320 mg of amlodipine and valsartan as active ingredients and excipients such as colloidal silicon dioxide, crospovidone, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, Iron oxides, hypromellose, polyethylene glycol, talc and titanium dioxide. As per SBA of Exforge® tablets 5/160mg, 10/160 mg are formulated as monolayered tablets. However, for 5/320mg and 10/320mg strengths, the valsartan component of fixed combination was not bioequivalent to the free combination, to achieve bioequivalence 5/320mg and 10/320mg strengths are formulated as bilayered tablets.

Combination of olmesartan and amlodipine is being marketed as tablets under the trade name Azor® in the United States containing 5/20, 5/40, 10/20, and 10/40 mg of amlodipine and olmesartan as active ingredients and excipients such as silicified microcrystalline cellulose, pregelatinised starch, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, macrogol, titanium dioxide, talc and iron oxides.

Triple combination of ARB, CCB with diuretics are commercially available in US under the brand names Exforge HCT® and Tribenzor®. Exforge HCT® is a combination of amlodipine besylate, valsartan and hydrochlorothiazide and Tribenzor® contains amlodipine besylate, olmesartan medoxomil and hydrochlorothiazide.

Given below are the patents/patent publications, which disclose pharmaceutical compositions of valsartan and its combination with amlodipine:

US 5,399,578 discloses tablet composition comprising valsartan, lactose, potato starch, gelatin, talc, magnesium stearate, colloidal silicon dioxide prepared by wet granulation using ethanol as solvent. This patent further discloses tablets composition comprising valsartan coated with hypromellose, shellac.

US 6,294,197, US 6,485,745 and US 6,858,228 discloses compaction process for preparing a compressed solid dosage form comprising an effective amount of valsartan and at least one additive, wherein the active agent is present in an amount of more than 35% by weight based on the total weight of the compressed solid dosage form.

US 6,395,728 discloses composition comprising combination of amlodipine and valsartan prepared by means of conventional mixing, granulating, sugar-coating, dissolving or lyophilizing processes. US '728 further discloses formulation of valsartan (80mg) and amlodipine (5mg) prepared by roller compaction.

US 2005/0208130 discloses a tablet comprising more than about 65% by weight of valsartan or a pharmaceutically acceptable salt thereof or hydrate thereof, microcrystalline cellulose, and crospovidone, wherein the tablet has a maximum valsartan concentration (Cmax) of about 0.77 mg/1 to 3.5 mg/1 and further discloses the process of preparing a tablet by compaction.

US 2008/0171086 discloses solid dosage forms of valsartan and amlodipine in the form of monolayer tablets prepared by blending valsartan and amlodipine with other excipients and compacting the blend followed by milling and compressing into tablets or bilayared tablet prepared by compressing valsartan granules and amlodipine blend or valsartan granules and amlodipine granules compressed into bilayered tablet, wherein the granules of valsartan and amlodipine are prepared by compaction.

EP 1 680 095 Al discloses directly tabletted formulation containing 30-60% by weight of valsartan, 40-60% by weight of microcrystalline cellulose and 3-10% by weight of sodium carboxymethyl cellulose, 0.5 -2% by weight of colloidal silicon dioxide and 0.5-4% by weight of magnesium stearate.

WO 95/24901 discloses capsule dosage form comprising valsartan, microcrystalline cellulose, polyvidone, sodium lauryl sulfate, crospovidone and magnesium stearate prepared by wet granulation.

WO 2005/089720 discloses compaction process for preparing a tablet comprising valsartan, and at least two disintegrants, wherein the at least two disintegrants are present intragranularly, extragranularly or both.

WO 2006/113631 discloses solid dispersions of valsartan with different solubility enhancing agents.

WO 2007/077581 discloses oral solid dosage form comprising valsartan and at least one particle separating agent prepared by melt granulation.

WO 2007/052307 discloses compaction process for preparing a stable solid oral dosage form comprising an effective amount of valsartan and pharmaceutically acceptable additives suitable for the preparation of solid oral dosage forms, wherein the active agent is present in an amount less than 35% by weight based on the total weight of the solid oral dosage form.

WO 2009/084003 discloses single layer composition comprising amlodipine and valsartan prepared by blending amlodipine and valsartan with additives, subjecting the blend to slugging/compaction, sifting the compacted mass into granules and compressing the granules to monolayered tablet.

IN 2775/DEL/2007 discloses dosage form comprising valsartan and amlodipine, wherein the active ingredients are present in an amount less than 35% by weight and further discloses process for the preparation of said dosage form by compaction.

US 2010/0003321 discloses monolayer, bilayer tablet comprising valsartan, amlodipine and hydrochlorothiazide.

IN 855/MUM/2008 discloses monolayered composition comprising valsartan granules prepared by wet granulation and amlodipine powder.

CN 101485657 discloses the formulation comprising valsartan, amlodipine, filler, disintegrating agent, flow aid and lubricant prepared by granulating valsartan and excipients using roller compaction and then mixing the valsartan granules with amlodipine and pressing into tablets.

CN 101507715 discloses monolayered tablet comprising valsartan granules prepared by granulating valsartan, microcrystalline cellulose, croscarmellose sodium using water and amlodipine granules prepared by granulating amlodipine, microcrystalline cellulose, starch, croscarmellose sodium using hydroxypropylmethylcellulose solution.

CN 101647797 discloses composition comprising 5 parts by weight of amlodipine benzosulfonate, 80 parts by weight of valsartan, 60 parts by weight of microcrystalline cellulose, 4.7-13.2 parts by weight of croscarmellose sodium, 4.8 parts by weight of silicon dioxide and 1.6 parts by weight of magnesium stearate prepared by direct compression.

CN 101987098 discloses composition comprising valsartan 80-320, amlodipine 5-20, microcrystalline cellulose 100-400, croscarmellose sodium 15-60, and magnesium stearate 3-12 prepared by dry method.

The above prior art references disclose various compositions of valsartan and amlodipine prepared by compaction in the form of monolayer or bilayered tablets. Still, there exists a need to develop alternate process for the preparation of bioequivalent composition comprising amlodipine and valsartan.

Objective of the invention

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

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

Summary of the invention

Accordingly, the present invention provides a monolayer tablet comprising:

(a) valsartan granules comprising valsartan or its pharmaceutically acceptable salts thereof and colloidal silicondioxide,
(b) amlodipine granules comprising amlodipine and its pharmaceutically
acceptable salts thereof and
(c) one or more pharmaceutically acceptable excipients, wherein said granules are prepared by wet granulation process.

Detailed description of the invention

In another embodiment of the present invention, valsartan granules and the amlodipine granules further comprise one or more pharmaceutically acceptable excipients.

In another embodiment the one or more pharmaceutically acceptable excipients include diluent, binder, disintegrant, glidant and lubricant.

In another embodiment, the solid dosage form comprising valsartan is present either in crystalline or amorphous form.

In another embodiment, the particle size of valsartan used in the present invention is in the range of about 5 to 40 um.

In another embodiment, the amount of valsartan used in the present invention is about 20% to 50% preferably 25% to 35% by weight of compressed solid dosage form.

In another embodiment, amlodipine is present in the form of besylate salt in an amount of about 1% to 20% w/w.

Suitable diluents used according to the present invention are selected from sucrose, dextrose, lactose, mannitol, sorbitol, starch, microcrystalline cellulose, silicified microcrystalline cellulose and the like or combination thereof.

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.

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 1% to about 5% by weight of compressed dosage form.

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 fumerate, talc, vegetable oils, stearic acid, fumaric acid, glyceryl behenate and the like. The amount of lubricant may range from 0.1% to about 5% by weight of compressed dosage form.

In another embodiment, the tablet may further comprise diuretic selected from amiloride, chlorthalidone, furosemide, hydrochlorothiazide and indapamide.

In another embodiment, diuretic may be present either in valsartan granules or in amlodipine granules.

In another embodiment, valsartan granules comprises based on weight of tablet; 20% to about 50% of valsartan, 0% to about 10% of diuretic, 5% to about 40% of diluent, 0% to about 10% of disintegrant, 0.5% to about 5.0% of binder and 0.1% to about 5% of colloidal silicondioxide.

In another embodiment, amlodipine granules comprises based on weight of tablet; 1% to about 10% of amlodipine, 0% to about 10% of diuretic, 10% to about 25% of diluent, 0% to about 10% of disintegrant, 1% to about 10% of binder and 0% to about 5% of glidant.

In another embodiment, valsartan granules and amlodipine granules are then blended with one or more excipients such as disintegrant and lubricant.

In another embodiment, there is provided a process for the preparation of a mono layer tablet comprising valsartan and amlodipine prepared by the process comprising the steps of:

i) granulating valsartan, colloidal silicon dioxide and one or more excipients using aqueous/nonaqueous binder solution, ii) drying the granules of step (i),
iii) granulating amlodipine and one or more excipients using aqueous/nonaqueous binder solution, iv) drying the granules of step (iii),
v) blending the dried granules of step (ii) & step (iv) with one or more excipients and
vi) compressing the blend into mono layer tablets.

The solvents used for granulation include methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water and the like or mixtures thereof.

In another embodiment, valsartan granules comprises based on weight of tablet; 20% to about 50% of valsartan; 5% to about 40% of diluent selected from microcrystalline cellulose or lactose; 0% to about 10% of disintegrant selected from sodium starch glycolate or croscarmellose sodium; 0.5% to about 5.0% of binder selected from povidone or pregelatinised starch and 0.1% to about 5% colloidal silicon dioxide.

In another embodiment, valsartan granules comprises based on weight of tablet; 20% to about 50% of valsartan; 0% to about 10% of hydrochlorothiazide, 5% to about 40% of diluent selected from microcrystalline cellulose or lactose; 0% to about 10% of disintegrant selected from sodium starch glycolate or croscarmellose sodium; 0.5% to about 5.0% of binder selected from povidone or pregelatinised starch and 0.1% to about 5% of colloidal silicon dioxide.

In another embodiment, amlodipine granules comprises based on weight of tablet; 1% to about 10%'of amlodipine; 0% to about 10% of hydrochlorothiazide, 10% to about 25% of diluent selected from microcrystalline cellulose or lactose; 0% to about 10% of disintegrant elected from sodium starch glycolate or croscarmellose sodium; 1% to about 10% of binder selected from povidone or pregelatinised starch and 0% to about 5% of glidant selected from colloidal silicon dioxide or starch.

In a preferred embodiment, there is provided a process for the preparation of monolayer tablet comprising valsartan and amlodipine prepared by the process comprising the steps of:

i) granulating 20% to about 50% of valsartan, 5% to about 40% of diluent and 0.1% to about 5% of colloidal silicondioxide using 0.5% to about 5.0% of aqueous/nonaqueous binder solution, ii) drying the granules of step (i),
iii) granulating 1% to about 10% of amlodipine, 10% to about 25% of diluents and 0% to about 5% of glidant using 1% to about 10% of aqueous/nonaqueous binder solution, iv) drying the granules of step (iii) v) blending the dried granules of step (ii) & step (iv) with 1% to about 5% of disintegrant and 0.1% to 3% of lubricant and vi) compressing the blend into monolayer tablets.

In another preferred embodiment, there is provided a process for the preparation of monolayer tablet comprising valsartan and amlodipine prepared by the process comprising the steps of:

i) granulating 20% to about 50% of valsartan, 5% to about 40% of diluent selected from microcrystalline cellulose or lactose and 0.1% to about 5% of colloidal silicon dioxide; using 0.5% to about 5.0% of aqueous/nonaqueous binder solution selected from povidone or pregelatinised starch, ii) drying the granules of step (i), iii) granulating 1% to about 10% of amlodipine, 10% to about 25% of diluent selected from microcrystalline cellulose or lactose and 0% to about 5% of glidant selected from colloidal silicon dioxide or starch; using 1% to about 10% of aqueous/nonaqueous binder solution selected from povidone or pregelatinised starch, iv) drying the granules of step (iii) v) blending the dried granules of step (ii) & step (iv) with 1% to about 5% of disintegrant selected from sodium starch glycolate and croscarmellose sodium and 0.1% to 3% of lubricant selected from magnesium stearate and talc and vi) compressing the blend into monolayer tablets.

In another embodiment, the tablets of the present invention may be uncoated or optionally coated.
In yet another embodiment of the present invention, film coating composition comprises 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.

In yet another embodiment, the present invention also provides method of treating hypertension, congestive heart failure, angina, and myocardial infarction by administering solid dosage forms 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: Monolayer Tablet of Valsartan and Amlodipine

The processing steps involved in manufacturing valsartan and amlodipine tablets given in example 1 & 2 are given below:

i) valsartan, microcrystalline cellulose, colloidal silicon dioxide were sifted and blended,
ii) binder solution of povidone in water was prepared, iii) granulated the blended material of step (i) with binder solution of step (ii), iv) dried the granules obtained in step (iii), v) amlodipine besylate and microcrystalline cellulose was sifted and blended, vi) binder solution of pregelatinised starch in water was prepared, vii) granulated the blended material of step (v) with binder solution of step (vi), viii) dried the granules obtained in step (vii), ix) the granules of step (iv) and step (viii) were then blended with sodium starch glycolate, x) lubricated the blend of step (ix) with magnesium stearate and xi) the lubricated blend was compressed to obtain mono layer tablets.

Example 2: Monolayer Tablet of Valsartan and Amlodipine

Example 3: Monolayer Tablet of Valsartan Amlodipine and Hydrochlorothiazide

The processing steps involved in manufacturing valsartan amlodipine and hydrochlorothiazide tablets given in example 3 is given below:
i) valsartan, microcrystalline cellulose, colloidal silicon dioxide, sodium starch glycolate were sifted and blended,
ii) binder solution of povidone in water was prepared, iii) granulated the blended material of step (i) with binder solution of step (ii), iv) dried the granules obtained in step (iii), v) amlodipine besylate, hydrochlorothiazide microcrystalline cellulose and
pregelatinised was sifted and blended, vi) granulated the blended material of step (v) with water, vii) dried the granules obtained in step (vi), viii) the granules of step (iv) and step (vii) were then blended with sodium starch glycolate, ix) lubricated the blend of step (viii) with magnesium stearate and x) the lubricated blend was compressed to obtain mono layer tablets.

Tablets prepared according to Example 2 were stored at 40°C/75% RH in HDPE bottles with silica gel for six months and then tested by HPLC to determine the amount of impurities related to valsartan and amlodipine. The stability data related to valsartan is given in table 1 and the stability data related to amlodipine is given in table 2.

Table 1

Claims

1. A monolayer tablet comprising:

(a) valsartan granules comprising valsartan or its pharmaceutically acceptable salts thereof and colloidal silicondioxide,

(b) amlodipine granules comprising amlodipine and its pharmaceutically acceptable salts thereof and

(c) one or more pharmaceutically acceptable excipients, wherein said granules are prepared by wet granulation process.

2. The tablet of claim 1, wherein the excipients include diluent, binder, disintegrant, glidant and lubricant.

3. The tablet of claim 1, further comprises diuretic in valsartan granules or amlodipine granules.

4. The tablet of claim 1, wherein valsartan granules comprises based on weight of tablet; 20% to about 50% of valsartan, 0% to about 10% of diuretic, 5% to about 40% of diluent, 0% to about 10% of disintegrant, 0.5% to about 5.0% of binder and 0.1% to about 5% of colloidal silicondioxide.

5. The tablet of claim 1, wherein amlodipine granules comprises based on weight of tablet; 1% to about 10% of amlodipine, 0% to about 10% of diuretic, 10% to about 25% of diluent, 0% to about 10% of disintegrant, 1% to about 10% of binder and 0% to about 5% of glidant.

6. The tablet of claim 2, wherein the diluent is selected from sucrose, dextrose, lactose, mannitol, sorbitol, starch, microcrystalline cellulose, silicified microcrystalline cellulose or combination thereof.

7. The tablet of claim 2, wherein the binder is selected from hydroxypropylmethylcellulose, maize starch, povidone, hydroxypropylcellulose, pregelatinized starch or combination thereof.

8. The tablet of claim 2, wherein the disintegrant is selected from starch, crospovidone, sodium starch glycolate, croscarmellose sodium or combination thereof.

9. A process for the preparation of a mono layer tablet comprising valsartan and amlodipine prepared by the process comprising the steps of:

i) granulating valsartan, colloidal silicondioxide and one or more excipients using aqueous/nonaqueous binder solution,
ii) drying the granules of step (i), iii) granulating amlodipine and one or more excipients using
aqueous/nonaqueous binder solution, iv) drying the granules of step (iii), v) blending the dried granules of step (ii) & step (iv) with one or more excipients and vi) compressing the blend into mono layer tablets.

10. The tablet of claim 9, wherein the solvents used for granulation is selected from methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water or mixtures thereof.