FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
PATENTS RULES, 2006
PROVISIONAL SPECIFICATION (SECTION 10; RULE 13)
STABILISED DOSAGE FORMS OF AMLODIPINE BESYLATE AND PROCESS FOR THEIR PREPARATION"
ALKEM LABORATORIES LIMITED, A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956, HAVING ITS CORPORATE OFFICE AT ALKEM HOUSE, DEVASHISH, ADJACENT TO MATULYA CENTRE, S.B.MARG, LOWER PAREL, MUMBAI - 400013, MAHARASHTRA, INDIA.
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED:

ABSTRACT
The technical field of present invention relates to stable solid dosage forms of amlodipine and process of preparation thereof which is free from alkalizers and which reduces the levels of total impurities and especially impurity D on stability.
BACKGROUND OF THE INVENTION
Amlodipine is 3-ethyl-5-methyl-2-(2-aminoethoxy-methyl)-4-(2-chlorophenyl) 6-methyl-l,4-dihydro-3,5-pyridine dicarboxylate This compound is used for the preparation of a medicament having calcium channel blocking activity that is useful, inter alia, in the management of hypertension, congestive heart failure and angina pectoris. Various formulations of amlodipine besylate are described as follows:
For example; U.S. Pat. No. 4,879,303 and corresponding EP 244 944 Edward Davison describes the commercial product of amlodipine (NORVASCO® by Pfizer, Inc.) which contains amlodipine besylate. This patent discloses a single form of amlodipine besylate, namely a crystalline anhydrous besylate salt of amlodipine. The inactive ingredients in the Norvasc tablets include microcrystalline cellulose, dibasic calcium phosphate anhydrous, sodium starch glycolate, and magnesium stearate.
For example WO Patent No 04075825A2, Nagaprasad relates to stable solid dosage forms of amlodipine base and process of preparation which it free of dicalcium phosphate. The stable amlodipine solid dosage form includes amlodipine base, microcrystalline cellulose, is substantially free of dicalcium phosphate, and has less than about 0.5% concentration (w/w) of Impurity D after three months at 40°C and 75% relative humidity.
For example WO Patent No 03051364A1 Fekete relates to amlodipine bezylate tablets with improved stability of the active ingredient and reduced in weight containing
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microcrystalline cellulose, a lubricant and a disintegrating agent. The invention also relates to a process for the preparation of the said tablets.
It is well known that microcrystalline cellulose also absorbs the moisture and amlodipine degrades and generates impurity in presence of moisture.
SUMMARY OF THE INVENTION
While the amlodipine salt form disclosed in the above patents is suitable for a commercial product, but they suffer from some drawbacks in terms of stability, and impurity profiling. Further it has been disclosed in the prior art that free base compositions which include microcrystalline cellulose as diluents leads to process related issues.
Moreover literature discloses that Amlodipine is highly hydroscopic and absorbs moisture, which leads to degradation via the catalytic oxidative process, which is pH dependent. The major related substances produced are {3-ethyl 5-methyl (4RS) 4-(2-chlorophenyl)-6-methyl-2-[[2-[[2(methylcarbamoyl) benzoyl&rsqb,amino]ethoxy]methyl]-l,4-dihydropyridine-3,5 dicarboxylate}("ImpurityB”){3-ethyl-5-methyl-2-[(2-aminoethoxy)methyl]4-(2-chlorophenyl)-6-methylpyridine-3,5 dicarboxylate} ("Impurity D"); and {3- ethyl 5-methyl (4RS) 4-(2-chlorophenyl)-2[[2-(l,3-dioxo- dihydro-2H-isoindol-2-yl) ethoxy]methyl]-6-methyl-l,4-dihydropyridine-3, 5 dicarboxylate} ("Impurity A"), along with some unknown impurities. It is also known in the prior art literature that the presence of dicalcium phosphate in amlodipine formulation triggers the degradation of amlodipine which is more pronounced at a pH below 6.0.Hence removal of dicalcium phosphate from the composition provides more stable formulation.
To overcome the problems associated with the prior arts, an intensive and thorough research resulted in providing the most advantageous solid formulation in terms of both stability and processing characteristics. This includes amlodipine which contains pregelatinised starch along with mannitol to overcome the shortcomings of
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microcrystalline cellulose. Besides this, the present invention is also free from alkalizers and microcrystalline cellulose which resulted in reduced levels of Impurity D and total impurities.
DETAILED DESCRIPTION OF INVENTION
The present invention relates to stable solid dosage forms of amlodipine and process of preparation thereof which is free from alkalizers and microcrystalline cellulose which results in reduced levels of Impurity D and total impurities.
Another aspect of the invention includes use of pregelatinised starch along with mannitol to improve the processing of the formulation.
The term "stable" as used herein refers to chemical stability of amlodipine in solid dosage forms.
The dosage form may include one or more pharmaceutical excipients selected from diluents, binders, desiccants, disintegrants, coloring agents, flavoring agents, surfactants, lubricants/glidants, plasticizers and preservatives.
Examples of disintegrants include sodium starch glycolate, croscarmellose sodium, crospovidone, low substituted hydroxypropyl cellulose, and the like.
Examples of binders include dry and wet binders like methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arable, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, and the like.
Examples of diluents include dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, mannitol, sorbitol, xyletol, and other polyols, starch starch pregelatinized, sucrose, sugar compressible sugar confectioners, and the like.
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Examples of lubricants and glidants include colloidal silicon dioxide, magnesium stearate, and colloidal anhydrous silica, stearic acid, magnesium stearate, and calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, fumarates and the like.
Examples of coloring agents include any FDA approved colors for oral use.
The following examples illustrate the invention: Examples 1

INGREDIENTS Percentage w/w
Amlodipine Besylate 3.48%
Mannitol 61.52%
Pregelatinised Starch 30 %
Aerosol 200 2%
Magnesium Stearate 1%
Sodium Starch Glycollate 2%
Examples 2

INGREDIENTS Percentage w/w
Amlodipine Besylate 3.48 %
Mannitol 30%
Pregelatinised Starch 61.52%
Aerosol 200 2%
Magnesium Stearate 1%
Sodium Starch Glycollate 2%
The stable amlodipine tablets are prepared by a process that includes the steps of
a) Blending an effective amount of amlodipine besylate, pregelatinised starch, aerosil 200
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& sodium starch glycollate
(b) Mixing the above blend with mannitol.
(c) Lubricating the blend with magnesium stearate.
(d) Directly compressing the blend in a suitable tableting machine.
The tablets obtained above were subjected to stability evaluation on both enclosed and open exposure at 40°C and 75% relative humidity.
The formulation was also subjected to stress studies like autoclaving.
All the above studies indicated that amlodipine tablets without dicalcium phosphate and microcrystalline cellulose are more stable and had significantly lower levels of total impurities especially impurity D.


Dated this 13th day of June 2006.

Sanjay Kher
Applicants' Patent Agent.

To:
The Controller of Patents, Patent Office,
Mumbai 400 037

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