FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
[Section 10, and Rule 13]
PROCESS FOR PREPARATION OF A
STABLE PHARMACEUTICAL COMPOSITION
CONTAINING AMLODIPINE AND
VALSARTAN
Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near Dinesh Hall, Ahmedabad 380 009, Gujarat, India
The following specification describes the invention:

FIELD OF THE INVENTION
The present invention relates to a stable pharmaceutical composition comprising amiodipine and valsartan; and process for preparation thereof.
BACKGROUND OF THE INVENTION
Amiodipine, a calcium channel blocker, and its salts are disclosed in U.S. Patent No. 4,572,909. Further, the besylate salt of amiodipine is disclosed in U.S. Patent No. 4,879,303. It is known that amiodipine is hygroscopic in nature and may degrade in presence of moisture. One of the major routes of degradation is known to be pH-dependent catalytic oxidative process. One of the major related substance produced by degradation is 3-ethyl-5-methyl 2-[(2-aminoethoxy) methyl]-4-(2-chlorophenyl)-6-methylpyridine-3, 5-dicarboxylate ("Impurity D" of Formula (I)), which is typically a cause of concern with respect to stability of amiodipine formulation.

YYV
o a

o o

Amiodipine Impurity D (I)
Valsartan, chemically designated as N-(1-oxopentyl)-N-[[2'-(1H-tetrazol-5-yl) [1, 1'-biphenyl]-4-yl] methyl]-L-valine, is disclosed in U.S. Patent No. 5,399,578, as an angiotensin II receptor antagonist useful for the treatment of hypertension and chronic heart failure. Valsartan is generally manufactured and supplied in the free acid form, such as Diovan® marketed by Novartis.
Combination of amiodipine and valsartan has been known to provide synergistic effect in the treatment of cardiovascular disorders such as hypertension. It would be desirable to prepare a fixed dose pharmaceutical combination of amiodipine and valsartan, to increase compliance for patients taking such a combination. The fixed-dose combination of amiodipine and valsartan is disclosed in US Patent No. 6,395,728. Such a combination is marketed by Novartis in USA under the brand-name Exforge®.

The PCT Application WO 2007/022113 assigned to Novartis discloses bilayer, multilayer tablets of amiodipine and valsartan. It also discloses dry granulation process for preparing a solid dosage form of amiodipine and valsartan.
The PCT Application WO 2007/001065 assigned to Sankyo discloses wet granulation process for preparing a solid dosage form containing an angiotensin II receptor antagonist and a calcium channel blocker. It discloses that the tablets containing olmesartan and amiodipine prepared by wet granulation show better dissolution profile than the tablets prepared by direct compression.
The PCT Application WO 2007/001067 assigned to Sankyo discloses a solid dosage form containing an angiotensin II receptor antagonist and a calcium channel blocker, wherein both active ingredients are not intimately mixed with each other. It also discloses bilayer, multilayer and dry-coated tablet dosage form. It is described therein that dissolution properties of a solid dosage form comprising an angiotensin II receptor antagonist and a calcium channel blocker may be improved by separately blending each active ingredient to form particles and then mixing the particles comprising each active ingredient such that they are not intimately mixed in the dosage form.
The PCT application WO 2007/001066 assigned to Sankyo discloses a composition comprising an angiotensin II receptor antagonist, a calcium channel blocker and at least one substance selected from a hydrophilic polymer, an acidic substance and a fluidizing agent. It provides a composition with improved dissolution properties.
Being an unstable compound, amiodipine requires well-directed stability approaches to formulate pharmaceutical compositions with reasonable stability. It has been surprisingly found that a pharmaceutical composition of a combination of amiodipine and valsartan can be prepared without the need of physical separation of the two active ingredients and without compromising the stability. The stable composition has a high content uniformity of amiodipine.


SUMMARY OF THE INVENTION
One aspect discloses a stable pharmaceutical composition comprising
(i) valsartan,
(ii) amiodipine,
(iii) at least one pharmaceutically acceptable excipient; wherein the valsartan is present intragranularly and the amiodipine is present in extragranularly.
Another aspect discloses a process for preparing a stable pharmaceutical composition, wherein the process comprises:
(i) mixing valsartan and at least one pharmaceutically acceptable excipient;
(ii) granulating the mixture of step (i) with a solvent or binder solution;
(iii) drying the granules obtained in step (ii);
(iv) mixing amiodipine and at least one pharmaceutically acceptable excipient with the granules of step (iii);
(v) optionally lubricating the mixture of step (iv); and
(vi) compressing the mixture of step (iv) or step (v) to obtain the composition.
Another aspect discloses a process for preparing a stable pharmaceutical composition, wherein the process comprises:
(i) mixing valsartan, diluent, and optionally a disintegrant;
(ii) granulating the mixture of step (i) with a binder solution;
(iii) drying the granules obtained in step (ii);
(iv) mixing the granules of step (iii) with amiodipine, diluent, disintegrant and optionally a glidant;
(v) optionally lubricating the mixture of step (iv); and
(vi) compressing the mixture of step (iv) or step (v) to obtain the composition, wherein the combined amount of valsartan and amiodipine is less than 35 % by weight of the composition.


DETAILED DESCRIPTION OF THE INVENTION
The term "stable pharmaceutical composition" as used herein refers to the composition of amiodipine and valsartan wherein the impurities do not exceed the regulatory requirement of country of interest. For example, stable pharmaceutical composition refers to compositions comprising amiodipine impurity D less than 0.2% w/w, preferably less than 0.05%, single unknown impurity less than 0.2% and total impurity less than 2%, preferably less than 1% w/w, when stored at 40°C and 75% relative humidity (RH) over a period of time, such as for a period of one month.
The term "amiodipine" as used herein includes amiodipine free base, or pharmaceutically acceptable acid addition salts thereof or mixtures thereof. It also covers anhydrous form, hydrous form, different crystalline forms, amorphous form, enantiomers of amiodipine or pharmaceutically acceptable acid addition salts thereof or mixtures thereof. Amiodipine may be present in an amount ranging from 1 mg to 25 mg in the composition.
The term "valsartan" as described herein includes valsartan free acid or pharmaceutically acceptable salts, hydrates, solvates, polymorphs and enantiomers thereof, or mixtures thereof. Valsartan may be in a crystalline or amorphous form, or mixtures thereof. Valsartan as described herein may be of varying particle size, for example it may be in micronized or non-micronized form. Valsartan may be present in an amount ranging from 20 mg to 320 mg in the composition.
Amiodipine and valsartan, in combination, may be present in an amount less than 35% by weight of the composition. Both the active ingredients are not physically separated from each other. Amiodipine is used in 0.5 to 2 % by weight of total composition. It may be difficult to maintain consistency in dose of amiodipine in each tablet because of low dose of amiodipine in tablet. Content Uniformity Testing is useful for assessing the consistency of active content within individual units post-manufacturing. Content uniformity testing involves using a content/potency assay to determine the content of active material contained in multiple different samples collected throughout the batch. The composition as described herein has a high content uniformity of amiodipine with a relative standard deviation of less than 4%.


The pharmaceutical compositions as described herein may comprise one or more pharmaceutical^ acceptable excipients selected from diluent, disintegrant, binder, lubricant, and such like.
Diluent may be selected from powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, corn starch, maize starch, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, dextrose, kaolin, magnesium carbonate, magnesium oxide; sugars such as lactose and sucrose; sugar alcohols such as mannitol, sorbitol or erythritol, and the like; or mixtures thereof. In one embodiment, the diluent is a mixture of lactose and microcrystalline cellulose. It is known that amlodipine may undergo degradation or form an adduct in the presence of lactose. However, by careful process manipulation, such instability is reduced in the compositions as described herein. Lactose, when used, is preferably in the spray-dried form. The diluent may be present in an amount ranging from 1 to 90% by weight of the composition.
Disintegrant may be selected from croscarmellose sodium, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, microcrystalline cellulose, cross-linked polyvinylpyrrolidone or mixtures thereof. The disintegrant may be present in an amount ranging from 1 % to 10 % by weight of the composition.
Binder may be selected from hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomers, dextrin, ethyl cellulose, methylcellulose, shellac, zein, gelatin, polymethacrylates, polyvinylpyrrolidone, pregelatinized starch, sodium alginate, gums, synthetic resins, and such like. The binder may be present in an amount ranging from 0.1 % to 10 % by weight of the composition. Alternatively, solvents selected from water, isopropyl alcohol, ethanol, methylene chloride or combinations thereof may be used as a binder.
Glidant / lubricant may be selected from talc, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; silicon dioxide, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate, polyethylene glycols, sodium stearyl fumarate, magnesium trisilicate; or mixtures thereof.


The lubricant / glidant may be present in an amount ranging from 0.1 % to 5 % by weight of the composition.
The pharmaceutical compositions may additionally comprise excipients such as colorants selected from known F.D. & C. and D. & C. dyes, and the like.
The pharmaceutical composition may be prepared using wet granulation. For example, valsartan and at least one pharmaceutically acceptable excipient may be mixed together. The mixture may be granulated by using a solvent. Alternatively, the mixture may be granulated with a binder solution prepared by dissolving a binder in appropriate solvent. The granules may be dried. The dried granules may be mixed with amlodipine and at least one pharmaceutically acceptable excipient. The mixture may be lubricated and the lubricated mixture may be compressed to form tablets. The tablets may be optionally coated with a film-coat comprising film-forming polymer such as hydroxypropyl methylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, polyvinyl pyrrolidone, and the like. The coating may also comprise of a plasticizer such as glyceryltriacetate, dibutyl sebacate, diethylphthalate, polyethylene glycol, propylene glycol, glycerol, castor oil, copolymers of propylene oxide and ethylene oxide, or mixtures thereof. Such compositions are also available under the brand name of Opadry® or Lustreclear®, sold by Colorcon.
One embodiment discloses, a stable tablet may be prepared by:
mixing valsartan and at least one pharmaceutically acceptable excipient;
granulating the mixture with purified water;
drying the granules;
mixing amlodipine and at least one pharmaceutically acceptable excipient with the
dried granules;
compressing the mixture into tablets and coating the tablets.
Another embodiment discloses, a stable tablet may be prepared by:
mixing valsartan, and at least one pharmaceutically acceptable excipient; granulating the mixture with a binder solution; drying the granules;


mixing amlodipine, at least one pharmaceutical^ acceptable excipient with the dried
granules;
compressing the mixture into tablets and coating the tablets.
The pharmaceutical compositions as described herein may be illustrated by the following examples which are not to be construed as limiting the scope of the invention:
EXAMPLES 1 AND 2

EXAMPLE 1 EXAMPLE 2
Ingredients Quantity (mg/tablet) Quantity (mg/tablet)
Valsartan 320.00 160.00
Amlodipine besylate 13.88 6.94
Microcrystalline cellulose 227.02 113.51
Lactose monohydrate 340.00 170.00
Croscarmellose sodium 45.50 22.75
Dibasic calcium phosphate 15.00 7.50
Polyvinyl pyrrolidone 20.00 10.00
Magnesium stearate 8.60 4.30
Talc 10.00 5.00
Purified water q.s. q.s.
Total 1000.00 500.00
PROCEDURE: Valsartan, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium and dibasic calcium phosphate were sifted and mixed. Binder solution was prepared by dissolving polyvinyl pyrrolidone in purified water. The mixture was granulated with the binder solution. The granules were dried. The dried granules were blended with amlodipine besylate, microcrystalline cellulose and talc. The blend was lubricated with magnesium stearate. The lubricated blend was compressed into tablets using appropriate tooling.


The tablets of Example 1 were exposed to a temperature of 40°C and 75% relative humidity for 1 month and were analyzed for the amount of impurities. The results are depicted in Table 1.
Table 1: Amount of impurities in tablets of Example 1

Condition Impurity D ofamlodipine(%w/w) Single unknown impurity (%w/w) Total impurity (%w/w)
Initial 0.00 0.15 0.30
15 days(40°C, 75% RH) 0.00 0.15 0.32
1 Month(40°C, 75% RH) 0.02 0.15 0.48
The tablets of Example 1 were tested for content uniformity of amlodipine by sampling 10 tablets and performing assay as per known technique. The results are depicted in Table 2. As is evident from the relative standard deviation values, the composition of Example 1 have excellent content uniformity of amlodipine.
Table 2: Content uniformity data of amlodipine in Tablets

Parameters Example 1 Example 2
Assay (Mean) 95.5 99.1
Relative Standard Deviation (RSD) 2.15 1.15


COMPARATIVE EXAMPLE

Ingredients Quantity (mg/tablet)
Valsartan 320.00
Amlodipine besylate 13.88
Microcrystalline cellulose 227.02
Lactose monohydrate 340.00
Croscarmellose sodium 45.50
Dibasic calcium phosphate 15.00
Polyvinyl pyrrolidone 20.00
Magnesium stearate 8.60
Talc 10.00
Purified water q.s.
Total 1000.00
PROCEDURE: Valsartan, amlodipine besylate, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium and dibasic calcium phosphate were sifted and mixed. Binder solution was prepared by dissolving polyvinyl pyrrolidone in purified water. The mixture was granulated with the binder solution. The granules were dried. The dried granules were blended with microcrystalline cellulose and talc. The blend was lubricated with magnesium stearate. The lubricated blend was compressed into tablets using appropriate tooling.
The tablets of Comparative Example were analyzed for the amount of impurities and the comparative results with tablets of Example 1 are depicted in Table 3.
Table 3: Initial amount of impurities in Tablets of Example 1 and Comparative Example at 25°C

Condition Impurity D ofamlodipine(%w/w) Single unknown impurity (%w/w) Total impurity (%w/w)
Example 1 0.00 0.15 0.30
Comparative Example 0.00 0.57 1.09


As is evident from Table 3, level of single unknown impurity and total impurity significantly decreases when amiodipine and valsartan are not mixed with each other during granulation step.

ABSTRACT OF THE INVENTION
The present invention relates to a stable pharmaceutical composition of amiodipine and valsartan and a process for preparation thereof.