FORM 2
THE PATENTS ACT, 1970
(39 OF 1970) &
THE PATENT RULES, 2003
PROVISIONAL SPECIFICATION
(See section 10; rule 13)
STABLE ORAL DOSAGE FORM
SUN PHARMACEUTICAL INDUSTRIES LTD.
A company incorporated under the laws of India having their office at ACME PEA/A. ANDHERl-KURLA ROAD. ANDHERI (E), MUMBAl-400059, MAHARASHTRA. INDIA.
I lie following specification describes the nature of this invention.

the present invention relates to a stable, oral dosage form comprising therapeutically effective amounts of amlodipine or its pharmaceutical!) acceptable salt and olmesartan or its pharmaceutical!) acceptable salt.
BACKGROUND OF THE INVENTION
currcnllv. calcium channel blockers and angiotensin II receptor antagonists are widely used clinicall) as medicaments for the treatment and prophylaxis of hypertension.
Inited Stales patent application number US20060252805 (herein after referred to as "805) relates to a pharmaceutical composition comprising pharmaceutically effective amounts of the following active ingredients:
(A) Lin angiotensin II receptor antagonist which is (5-methyl-2-o\o-l ..i-dioxolen-4-y 1) methyl S-(I-hydroxy- l-methylethyl)-2-propy l-[12'-( lh-telrazol-5-yl)biphenyl-4-y l)methy I [imidadol-5-carbo\y kite and
(B) a calcium channel blocker is amiodipine.
united Slates patent application number WS20060009502 (lierein after referred to as "502) claims a pharmaceutical composition comprising pharmaceuticallv effective amounts of the following active ingredients:
(A) an angiotensin II receptor antagonist selected from the group consisting of a compound having a formula (I), a pharmacologically acceptable ester thereof and a pharmacological!) acceptable sail thereof:

and (11) a calcium channel blocker selected from the group consisting of 1.4-dihydropyridine compound and a pharmacological!) acceptable salt thereof.
I'd patent publication. WO200700 1065 (hereinafter referred to as publication "065) disclosed that prior art compositions made b) direct compression hud poor dissolution characteristics and claims a method comprising a step ol preparing by wet granulation, a composition comprising an angiotensin II receptor antagonist and a calcium channel blocker to achieve improved dissolution ol' angiotensin II receptor antagonist.

PCT patent publication. W0200700I066 (hereinafter referred to as publication '066) claims a pharmaceutical composition comprising an angiotensin II receptor antagonist, a calcium channel blocker and at least one substance selected from a hydrophilie polymer, an acidic substance and a lluidi/ing agent. the patent application states that a combination of the angiotensin II receptor antagonist and a calcium channel blocker with additional hydrophilie polymer, acidic substance or fluidizing agent affords improved dissolution properties, file composition in the form of tablets may be made by any method known in the art including direct compression.
PCT patent publication. WO200700 1067 (hereinafter referred to as publication "067) claims a solid dosage form with improved dissolution wherein the angiotensin II receptor antagonist and the calcium channel blocker are not intimately mixed ra ther each of the active ingredient is mixed separate!) with pharmaceutical excipients and isolated from each o ther by granulation or compression of at least one or both the mixtures, flic compositions can be made in the form of tablets by any of the methods known in the art including direct compression.
None of the above mentioned prior arts disclose whe ther the compositions retain both amlodipine besylate or olmesartan mcdoxomil without appreciable degradation. the free base anilodipinc and olmcsartan are drugs with ester function and arc susceptible to hydrolysis. Yeung ct al in the journal publication entitled Liquid chromatography assay for amlodipine: chemical stability and pharmacokinetics in rabbits J. pharm. Biomed. Anal, vol.So.1) (7), Qii^._So.__56.3-7.!...Ul!)}LI. provides a liquid chromatography method for studying the stability of amlodipine besylate. C'elebier et al. in the journal publication titled Determination of olmesartan medoxomil in tablets by UV-Vis spectrophotometry. I'harmazie vol. 62(6): page No. 419-422 (2007) discusses the analytical method for determination of stability of olmesartan medoxomil in the pharmaceutical dosage forms.
OHEJCTS OK THE INVENTION
ll was the object of the present invention to provide dosage forms having adequate rates of dissolution and chemical stability of both amlodipine besylate and olmesartan medoxomil.
It was also the object of the present invention to provide dosage forms by processes that do not necessarily require separation of the amlodipine besylate and olmesartan medoxomil.
It was the object of the present invention to provide dosage forms that require few steps for manufacture into tablet dosage form.
ll was further an object of the present invention to provide dosage forms that do not necessarily require wet granulation as a means for improving dissolution but instead can be made by dry granulation or direct compression thus avoiding the energy intensive steps of drying and also minimizing the moisture content in the final dosatte form.

SUMMARY OF THE INVENTION
the present invention provides a stable, oral, solid dosage form consisting essential!) of an intimate mixture of therapeutically effective amounts of ainlodipine or its pharmaccutically acceptable salt and therapeutical!) effective amounts ol' olmesartan or its pharmaceutical!) acceptable salt and pharmaceutical!) acceptable disintegrants. diluents and lubricants, the solid dosage form being free of Indrophilic or hydrophobic binders.
DETAILED DESCRIPTION OF THE INVENTION
I lie present invention provides a stable, oral, solid dosage form consisting essential!) of an intimate mixture ol therapeutieat effective amounts ol' amlodipine or its pharmaceutical!) acceptable salt and llicrapeuticall) effective amounts olmesartan or its pharmaceutical!) acceptable salt and one or more pharmaceutical!) acceptable diluents, disintegrants and lubricants, the said solid dosage form being free of h_v drophilic or hydrophobic binders.
I he present invention provides dosage forms having adequate rales of dissolution and chemical stability of both amlodipine besylate and olmesartan medoxomil. the term "adequate rate of dissolution' as used herein, means that tile dissolution of each active ingredient is more than SO % in about 45 minutes. I he term "without appreciable degradation" as used herein general. means that the total impurities of active ingredients and known impurities do not exceed the acceptable limits ol the labeled amount of active ingredient during the shell life of the product or when kept at accelerated stability conditions for example, at 40 " C r 2 " C and 75 % t 5 % relative humidity for a period of three months in closed containers, with or without desiceants.
In one embodiment of the present invention, the pharmaceutical I) acceptable salt of amlodipine is amlodipine lies) late and the pharmaceutical!) acceptable salt of olmesartan is olmesartan medoxomil. I he amount of amlodipine bes) late used in the dosage form of the present invention ranges from about I nig to about 100 mg by weight the dosage form. the amount of olmesartan medoxomil used in the dosage form of the present invention ranges from about 1 mg to about 100 nig. In the preferred embodiment, the amount of ainlodipine besvlale ranges from about 5 nig to about 20 mg and the amount of olmesartan medoxomil ranges from about 10 mg to about 50 nig per unit dosage form.
According to the present invention, the amlodipine or its pharmaecuticallv acceptable salt are "intimate!) mixed' toge ther, flic term "intimately mixed" as used herein means that the two drugs are mixed and blended and are capable of coming in contact with each o ther.
the oral, solid, dosage form of the present invention is free of Indrophilic or hydrophobic binders. I he term 'binder' used herein is known in the art and connotes an excipicni that promotes binding of particles to form strong aggregates such as granules, pellets, slugs, pills or tablets, flic Kxamples of the Indrophilic binders include, bul are not limited to. cellulose derivatives such as low molecular weight grades of In droxv prop) I methyl cellulose, methyl cellulose, hvdroxyprop) 1 cellulose and sodium


carboxv niclhv I eeliulose: svn thetic polvmers sueh as polyvinylpyrrolidone, aminoalkvl methaerv late copolvmcr. carboxiyvinyl polvmcr. polyvinyl alcohol and polyethylene glvcol): gum Arabic, agar, gelatin and sodium alginate and mixtures thereof. the term hydrophilie or hydrophobic binder does not include diluents that have the ability to consolidate upon compression, for example, dirccll) compressible diluents such as dircctl) compressible grades of mieroei')stalline cellulose, sprav dried lactose, mannitol and the like.
examples ol diluents that may be used in the oral dosage form of the present invention includes, but arc not limited to. microervstalline cellulose, starch, sugars and the like and mixture thereof. I he amount of diluent that nun be used ma\ range from about 5 % to about 95 % by weight of the oral dosage form.
In one preferred embodiment, mierocrystalline cellulose is used as the diluent. Microervstalline cellulose is a purified. partially deloplv meri/ed cellulose, that occurs as a while, odorless, tasteless and crystalline powder composed of porous particles. It is commercially available in different particle sixes and moisture grades which have different properties and specifications. It is available commercial!) under the brand names Avicel by FMC Corporation. Pmbocef1' b\ Kdward Mendell Co. Inc and Vicacel'' by .1.1 Kellcnniaiei and Sohne Cimbll. these commercially available brands are available with varying mean panicle si/e. and moisture content, for example. Avicel ''' by l-'MC Corporation, is available as Avicel I'll-101 with a nominal mean particle si/e of 50 microns. Avicel PI I-102 with a nominal mean particle size of 100 microns. Avicel PH 103 with a nominal mean particle si/e of 50 microns and moisture content ol less than TO "<>. Avicel I'll-105 with a nominal mean panicle si/e of 20 microns and moisture content of less than 5.0 %. Avicel PH 112 with a nominal mean particle si/e of 100 microns and moisture content of less than 1.5 %. Avicel 113 with a nominal mean panicle si/e of 50 microns and moisture content of less than 1.5 %. Avicel 1-200 with a nominal mean particle si/e of 1 80 microns and moisture content of less than 5.0 %. Avicel PI 1-30 I with a nominal mean particle si/e of 50 microns and moisture content of less than 5.0 %. Avicel PI 1-302 with a nominal mean particle si/e of 100 microns and moisture content of less than 5.0 %. Embocel 50M with a nominal mean particle si/e of 51 microns and moisture content of less than 5.0 %. Embocel 90M with a nominal mean particle si/e of 91 microns and moisture content of less than 5.0 %.. the Vivacel brand is available as Vivacel 101. 102. 12 and 20 with the nominal mean particle si/e of 50. 100. ISO and 20 microns respective!), with a moisture content of less than 5 %. In one preferred embodiment, where the oral dosage form is prepared by slugging, the microervstalline cellulose having mean panicle in the range o\' 150 mms to about 200 mrns, preferably a grade having mean particle si/e of about 180 urns is used.
Examples of disintegrants used in the oral, solid dosage form of the present invention include, but are not limned to. Microcrysialline cellulose, croscarmellose sodium, cross linked polyvinyl pyrrolidone. sodium starch glycolate. starch and its derivatives such as partially gelatinized starch, low substituted hydroxy 1 prop) I cellulose, ion exchange resins like polacrillin potassium, effervescent couple such as sodium bicarbonate and citric acid and the like and mixtures thereof. One preferred embodiment ol the present invention uses croscarmellose sodium as the disintegrants. the amount of disintegranls that ma) be used

ranges from about 0.9% to about 50 % by weight ol' the dosage form, preferably from about I % to about in "(. by weight of the oral dosage form.
Examples of lubricants, that are used in the solid dosage form of the present invention, include, but are not limited to. the group comprising of sodium lauryl sulfate, laic, magnesium starch. sodium stearyl fumarate. stearic acid, glyceryl behenate. hydrogenated vegetable oil. zinc stearate and the like and mixtures thereof. the amount of lubricants used may range from about 0.1 % to about 2 % by weight of the dosage form.
According to one embodiment of the present invention, the oral, solid, dosage form comprises one or more antioxidants. I he antioxidants may be selected from the group comprising butylated hydroxy anisole. hilly kited hydroxy toluene and the like and mixtures thereof, in one preferred embodiment, the amount of butyl led hydroxy I toluene that may be used in the oral dosage form ranges from about 0.01 % to about 2 "i. by weight of the unit dosage form, preferably 0.05 % to about 0.5 % by weight of the unit dosage form.
I he oral, solid dosage form of the present invention may be in the form of powders, pills, pellets, tablets, powder filled into capsules, sachets, granules, slugs, compacts. In one preferred embodiment of the present invention, the solid dosage form is in the form of compressed tablets.
I he present invention provides dosage forms that require few steps for manufacture into tablet dosage form. In one preferred embodiment, the present invention provides a solid oral dosage form that does not necessarily require wet granulation as a means for improving dissolution. Instead, a dry granulation or direct compression which avoids the energy intensive steps of drying and also minimizing the moisture content in the final dosage form may be utilized.
Although the oral dosage form of the present invention may be prepared by any suitable method such as wet granulation, dry granulation or direct compression: dry granulation processes such as slugging and roller compaction are preferred.
In one embodiment of the present invention, the oral dosage form is prepared by roller compaction, den rally. in roller compaction, the blend of powders is led to two counter-rotating rolls which draw the powder between the rolls due to friction and compact the powder. I'he compacts formed by roller compaction are usually referred to as 'ribbons'. I'he ribbons are further milled into smaller granules and then may be tilled into capsules, or converted into tablets by compressing the milled compacts.
In an alternative embodiment of the present invention, the oral dosage form may be prepared by the process of slugging. the term 'slugging' as used herein means that the intimate mixture of the two active ingredients is converted into larger particles without the use of any solvent. In a preferred embodiment ol the present invention, the oral dosage form is prepared by mixing together the two drugs and the


pharmaceutical!) acceptable excipients and converting the powder blend into slugs of sizes ol'. for example, about 10 mm to about 20 mm round diameter, preferably about 15 mm in diameter using round punches. I he slugs are, fur there milled into smaller granules and then nun be 111 led into capsules, or com cried into tablets by compressing the milled slugs.
In one embodiment of the present invention, the amlodipine besylate is mixed with an alcoholic solution of butylated hydroxy! toluene (HUT). the alcohol is evaporated to get a dry amlodipine besylate with Hill. This mixture of amlodipine besylate and HUT is further mixed with olmesartan or its pharmaceutically acceptable salt to get an "intimate mixture' of the said two drugs. This intimate mixture may be further mixed with other excipients such as disintegrants. lubricants and then com cried into compact .ii slugs. I he compacts or slugs may be further milled and converted into granules. these granules may be filled into capsules, or max be compressed into tables.
In an anther embodiment of the present invention, an inert excipient such as diluent, disintegrants or lubricant or mixtures thereof, is mixed with an alcoholic solution of butylated hydroxy 1 toluene. I he alcohol is evaporated to get a dry excipient with the antioxidant. This mixture of the excipient and antioxidant is further mixed with the blend of amlodipine or its pharmaceutical!) acceptable salt and olmesartan or its pharmaceutical!) acceptable salt to get an "intimate mixture' of the said two drugs. This intimate mixture may be further mixed with other excipients and converted into compacts or slugs flic compacts or slugs may be further milled and converted into granules, these granules may be filled into capsules, or may be compressed into tablets.
flic examples that follow do not limit the scope of the invention and are merely used as illustrations.
EXAMPLE 1

Butylated hydroxy I toluene was dissolved in isopropyl alcohol. Croscarmellose sodium (half portion) was welled with the alcoholic solution of butylated hydroxyl toluene. the wet mass was dried, flic specified amounts of olmesartan mcdoxomil. lactose anhydrous, colloidal silicon dioxide (half amount) and microcrvstallinc cellulose was dried individually through AS'I'M U 40 mesh and mixed and then blended for about 20 minutes. This blend was mixed with the specified amount ol amlodipine besylate I he mixture was further mixed in a blender for 10 minutes. Magnesium stearalc was added to the above

blend and blended lor further 5 minutes. I his lubricated mixture was slugged using 16 mm round plain punches at a target weight of 1400 mg. the slugs were milled through clit mill fitted with 2.00 mm screen at slow speed with knives forward, fhe remaining half portion of both croscarmellosc sodium and colloidal silicon dioxide were sifted through AS I M # 40 mesh. Magnesium stearale was silted through ■ 80 AS IM mesh. the slugs were mixed with the blend of erosearmellose sodium, colloidal silicon dioxide and lubricated with magnesium stearate and compressed into tablets using suitable punches. the cure tablets were coated with aqueous dispersion of Opadry II white in purified water.
I he tablets prepared according to example I were subjected to in vitro dissolution in USP t\ pe 2 apparatus (paddle) in 000 ml of pi I 6.8 phosphate buffer rotating at 50 rpm. the dissolution was tested in peak dissolution vessel. I he results of dissolution are tabulated in table 2.
I able 2: in vitro dissolution in peak veesal dissolution of tablets of example 1

in minutes % ol amiodipine released % of olmesartan medoxomil released
10 92 78
20 95 87
.it) 95 91
45 60 97or 94 95
EXAMPLE: 2
fable 3

ngredicnls % b_\ weight of the coated tablet
Imesartan medoxomil 12.94
ictose anh\drous 44.33
licroenslullinc cellulose (A\ieel Pll 200) 22.56
loscarmcllosc sodium 9.7
mlodipine bes_\ laicnits lated In drox\toluene 4.48 0.129
olloidal silicon dioxide 1 1.6 1
umncsium stearale . _ 1,28 _.__^
)padr\ coaling r 2 91
Butylated hydroxyl toluene was dissolved in isopropyl alcohol. Croscarmellosc sodium (half portion) was wetted with the alcoholic solution of butylated hydroxyl toluene. the wet mass was dried and mixed with the specified amounts ol olmesartan medoxomil. lactose anhydrous, colloidal silicon dioxide (half amount) and microcrystalline cellulose. the material was mixed in a blender for 10 minutes. Magnesium stearale was added to the above blend and blended for further 5 minutes. I his material was slugged using 16 mm round plain punches at a target weight ol 1400 mg. fhe slugs were milled through clit mill lined with 2.00 mm screen at slow speed with knives forward, fhe remaining half portion of croscarmellosc sodium, colloidal silicon dioxide and amiodipine besylate were silted through AS I'M « 40 mesh. 'I he remaining amount of magnesium stearate was sifted through # 80 ASTM mesh. the slugs were mixed with the blend of croscarmellosc sodium, colloidal silicon dioxide and amiodipine bes)late an lubricated with magnesium stearale and compressed into tablets using suitable punches. the core tablets were coated with aqueous dispersion of ()pad II while in purified water.


the tablets prepared according lo example 2 were subjected to in vitro dissolution in I :SI> ly pe 2 apparatus in 900 ml of pi I 6.8 phosphate buffer rotating at 50 rpm. Ihe dissolution was tested in peak dissolution vessel. the results of dissolution Lire tabulated in table 4.
table 4: in vitro dissolution in peak vessel dissolution of tablets of example 2

n minutes % of amlodipine released % of olmesartan medoxomil released
10 93 78
20 95 89
30 97 90
45 96 91
60 98 92
EXAMPLE 3
fable 5

Ingredients % by weight ofihe coaled ablet
olmesartan medoxomil 9.24 ■-
lactose anhvdrous 36.73
mieroerystallinc cellulose (Aviccl Pll 102) 36.73
low substituted hydroxypropyl cellulose 9.70
Amlodipine besy late 3.21
Colloidal silicon dioxide 1.85
Mamiesiuni stearate 0.9.3__...
Opadry 11 Im coating
.All the listed ingredients except magnesium stearate were silted through 40 mesh. Magnesium stearale was sifted through AS IM # 60 mesh. Olmesartan medoxomil was mixed with part of following excisions: lactose anhydrous. microcrystalline cellulose, low substituted hydroxy propyl cellulose and colloidal silicon dioxide in a blender for 20 minutes. This blend was lubricated with part of sifted magnesium stearale and slugged. the slugs were milled. Sifted amlodipine busy laic, part of the following ingredients namely microcrystalline cellulose, lactose anhydrous, colloidal silicon dioxide were mixed with Ihe milled slugs. This blend was compressed into tablets. the cores were coaled with III'MC based ()padr\ film coaling.
Ihe tablets prepared according lo example 3 were subjected to in vitro dissolution in I SI' type 2 apparatus in 900 ml of pi I 6.8 phosphate buffer rotating at 50 rpm. I'he dissolution was tested in peak dissolution vessel. the results of dissolution are tabulated in table 6.
fable 6: in vilro dissolution in peak vessel dissolution of tablets ol' Example 3

Time in minutes % of amlodipine released % of olmesartan medoxomil released
1020 ~" 30 89 91 93 75 83 87
45 94 89
f'"~ ~w> 93 90


EXAMPLE 4
Table 7

Ingredients % b\ weight of the coaled tablet
olmesartan medoxomil laciose anh_\drous 1 1.42 47.40
microcn, stallinc cellulose (A\ ieel PI 1 200) 23.50
crosearmellosc sodium 0.7(>
amlodipine besylate 1.08
hui\ laled hydrox) toluene 0.057
colloidal silicon dioxide maiiiiesium slcaralc 1.61 L28~
Opadt) coaling 2.01
all the listed ingredients except magnesium scarlet were sifted through 40 mesh. Magnesium stearale was si lied through AS I'M •■/ 60 mesh. Olmesartan medoxomil was mixed with the specified amounts ol following cxcipients: lactose anhydrous. micron stallion cellulose and a portion of the colloidal silicon dioxide and portion of crosearmellosc sodium in a blender for 20 minutes. This blend was lubricated with part of stilled magnesium scarlet and slugged. Ihe slugs were milled butylated hydroxyl draw I toluene was disrobed in isopropyl alcohol. Amlodipine besylated was welled with this solution. Ihe wet mass was dried in tray drier till the isopropyl alcohol was evaporated completed). Amlodipine bes> laic irealcd with Hill was mixed with pair of the following ingredients namely\. colloidal silicon dioxide and crosearmellosc sodium and mixed with the milled slugs. Magnesium started was added to this mixture and blended for 5-10 minutes. This blend was compressed into tablets using suitable punches. I he cores were coated with ()padr> film coating.
Ihe tablets prepared according to example 4 were subjected lo in vitro dissolution in I SI' l_\ pc 2 apparatus in 000 ml of pi I 6.8 phosphate buffer rotating at 50 rpm. the dissolution was tested in peak dissolution veesal. the results of dissolution are tabulated in table 8.
able 8: in vitro dissolution in peak vessel dissolution of tables ol 'Example 4

I ime in miiuiles I "» of amlodipine released
" 10 "' " " _ ?]^~~ZZ
20 ' ~~
(,2
os"
45
08 08

"<> of olmcsartan medoxomil released
_ S.i
01
03 04 04