FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
8B
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
"IMPROVED COMPOSITION OF AMLODIPINE BESYLATE"
We, BA RESEARCH INDIA LIMITED, of BA Research House, Opposite "Pushparaj Towers", Nr. Judges Bungalows, Bodakdev, Ahmedabad-380 054, Gujarat, India
The following specification particularly describes the nature of the invention and the manner in which it is to be performed.

FIELD OF INVENTION
The present invention relates to pharmaceutical dosage forms of Amlodipine besylate and processes for their preparation. The formulation or the composition comprises Amlodipine and PEG micornized and distributed on an inert excipient.
BACKGROUND OF THE INVENTION
Amlodipine is a long acting calcium channel blocker marketed by Pfizer as
amlodipine besylate under the trade name Norvasc(R). It is available as oral tablets in strengths of 2.5 mg, 5 mg, and 10 mg, and is indicated for the treatment of hypertension, chronic stable angina and vasospastic angina. Norvasc(R) tablets are formulated using microcrystalline cellulose, dibasic calcium pnosphate anhydrous, sodium starch glycolate, and magnesium stearate as various excipients.
The preparation of amlodipine base is described in U.S. Patent No. 4,572,909. Further, U.S. Patent No. 4,879,303 discloses that free base compositions that include microcrystalline cellulose and dicalcium phosphate as diluents excessively stick to the tablet punches during processing and are not suitable in making solid dosage forms for oral administration. The patent teaches that the amlodipine besylate salt can be used to make solid dosage forms and those solid dosage forms can include microcrystalline cellulose and dibasic calcium phosphate. U.S. Patent Application No. 2003/0022922 discloses that to reduce the stickiness of the tablet, amlodipine free base should be incorporated into the tablet composition in the form of particulates having an average particle size of 150-350 urn; and a preferred excipient is a combination of calcium phosphate and microcrystalline cellulose. A capsule dosage form also is disclosed in this patent application as containing amlodipine base, microcrystalline cellulose, predried potato starch, and magnesium stearate. The microcrystalline cellulose makes up approximately 74% (w/w) of the capsule dosage form.
Amlodipine is highly hygroscopic and absorbs moisture, which leads to degradation. One of the major routes of degradation is via the catalytic oxidative process, which is pH dependent. WO2006059217, which is incorporated as reference in its entirety, describes several degradation products of Amlodipine and also described a formulation providing for a stable oral dosage form of Amlodipine. Due to the instability of Amlodipine, there exists a need to prepare a formulation of Amlodipine which is stable and which may have the additional beneficial effect of improved bioavailability. We herein disclose such an improved formulation. EMBODIMENTS OF THE INVNTION
In an embodiment there is provided an improved formulation of Amlodipine.
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In a second embodiment there is provided a process allowing to increase the bioavailability of Amlodipine and its derivatives using the formulation of the present invention.
A further embodiment of the invention involves a process for preparing the formulation of Amlodipine, the process comprising the co-precipitation of Amlodipine and polyethylene glycol from a solution, into a very high surface obtained by means of the micronization of an inert excipient or in precipitating polyethylene glycol on a homogenous mixture of Amlodipine and an inert excipient, both being micronized. The above and other inventive embodiments are further described below.
DETAILED DESCRIPTION
According to the present invention, a solution of Amlodipine and polyethylene glycol of high molecular weight is made in a solvent(s) and the solution is dispersed on a micronized inert excipient which is preferably soluble in the gastrointestinal juices.
The surfactant property of the polyethylene glycol of high molecular weight is therefore utilized to be able to "wet" the microparticles of the inert excipient with the solution, and spread it over all of the very high surface available so that, when the solvent evaporates, the Amlodipine crystals which precipitate are tiny and remain as such due to the impossibility of swelling or aggregation between each other. It was also noted that it is possible to micronize Amlodipine, mixing it with the micronized inert excipient and then "wet" such a mixture with a polyethylene glycol solution. When the solvent evaporates, polyethylene glycol precipitates in very fine particles and in intimate contact with the Amlodipine particles. In both cases one obtains a granulate of Amlodipine and polyethylene glycol finely and homogeneously dispersed in the micronized inert excipient, thus having the same characteristics. It is important, moreover, that the inert excipient is easily soluble in the gastrointestinal juices so as to leave the Amlodipine microcrystals free after swallowing.
The obtained granulate is finally mixed with the excipients suitable to the manufacture of the desired solid forms of dosage: preferably tablets. Testing the bioavailability, it was surprisingly found that these tablets have the characteristics of a retard product and have a bioavailability equivalent to of the oral forms on the market.
In the process specified in the present invention, polyethylene glycols with a molecular weight exceeding 2000, and preferably between 4000 and 6000, are used. The ratio between active substance and polyethylene glycol may vary in the interval between 20:80 and 80:20, and preferably 40:60 and 60:40.
Amlodipine and polyethylene glycol may be dissolved in suitable solvent(s) and
successively this is evaporated to obtain the co-precipitate. Preferably, however, the solution
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is mixed, for example in a kneader, with a micronized inert excipient which is preferably soluble in the gastrointestinal juices, thereby obtaining a granulate, which is successively dried. In this phase, the co-precipitation of the active substance with the polyethylene glycol in intimate mixture with the inert excipient(s), is obtained. As already mentioned, alternatively one may add in the kneader a polyethylene glycol solution to a homogeneous mixture of Amlodipine and inert excipient, where both Amlodipine and the excipient(s) are micronized. Illustrative but non-limiting examples of the said micronized inert excipients include sucrose, lactose, glucose, fructose, levulose, mannitol, sorbitol, glycocoll, xylitol, pentaerythrite, maltodextrine. The ratio between co-precipitate and inert excipient(s) may vary, but, the preferred range is between 1:20 and 1:4.
The granulate of active substance, polyethylene glycol and micronized inert excipient may be used directly for the preparation of tablets, preferably adding a lubricanting agent.
It was also found that a further prolongation of the retardant effect can be obtained if substances which, when in contact with the gastrointestinal juices, swell again and successively dissolve themselves slowly such as hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, carboxyvinyl polymers, xanthan gum, alone or in combination, in quantities varying between 5% and 50% of the tablet weight and preferably between 10 and 30%, are added to the granulate prepared in the manners hereinbefore specified.
The invention is further exemplified by the following non-limiting examples. These examples are provided for the purpose of illustration only and represents some of the preferred modes of carrying out the invention as is perceived by the inventor. It must be appreciated that several other obvious processes may be available for preparing the formulations of the present invention. Such obvious alternatives, including obvious alternative formulating agents, should be construed to be within the scope of the present invention and the examples should be considered in an inclusive way rather than an exclusive way. Example 1:
The following solutions were prepared:

Components Solution 1 (g) Solution 2 (g)
Amlodipine 110 100
PEG 4000 110 100
Acetone 1010 920
Deionized water 190 190
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The formulations are prepared as follows:
Amlodipine is dissolved in acetone and PEG in water, using a suitable vessel equipped with stirrer. The Amlodipine acetonic solution and the aqueous PEG 4000 solution are then mixed in such a way so as to obtain the solutions indicated in the table. 3.9 kg of micronized lactose placed in a kneader with horizontal blades, to which 1.42 kg of solution I is added.
When the solution is homogeneously distributed, the mixture is desiccated at 45 °C for 2 hours. It is granulated with an oscillating granulator provided with an inox ASTM No. 8 stainless steel metal wire mesh and desiccation is completed.
The evaporation of the solvent causes the co-precipitation of the active substance and polyethylene glycol in fine form and homogeneously dispersed in the inert excipient.
The granulate thus obtained is ground so as to be able to proceed with the subsequent application of the active substance and polyethylene glycol solution.
Afterwards, the operations specified hereinbefore are repeated with solution II. After the last blending, the dried product is granulated through a inox ASTM No. 25 stainless steel wire mesh. Preparation of tablets:
4.5 kg of granulate and 75 g of magnesium stearate are mixed for 15 min. in a cubic mixer. A chromed punch with a capsular shape having a 15 mm length, a 6 mm width and a 5 mm bending radius, is used for the preparation of the tablets. Example 2: The following solutions were prepared:

Components Solution 1 (g) Solution 2 (g)
Amlodipine 220 180
PEG 6000 220 180
Acetone 1010 920
Methylene chloride 3170 2650
Amlodipine and methylene chloride are placed in a suitable vessel equipped with stirrer, and stirred until complete dissolution. Polyethylene glycol is added and stirred until complete dissolution. 5.2 kg of micronized mannitol is placed in a kneader and mixed with 3.6 kg of solution was added by pouring in about 2 min. After finishing the addition the solution is terminated, mixing is continued for another 4-5 min. During the latter operation, evaporation of methylene chloride is carried out by suction.
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The mixture is distributed on the grid of a stove, in a thin layer, and is dried with a single circulation of air at room temperature for about 2 hours until the almost total elimination of the methylene chloride.
Then granulation is done with an oscillating granulator provided with a inox ASTM No. 8 stainless steel mesh. The granulate is again distributed on the same grid and is dried with air circulation at 45 °C. for over 2-3 hours.
After having ground the granulate, the operations are repeated using solution II operating with the same method.
After the last blending, the dried granulate must be granulated with the oscillating granulator provided with inox steel ASTM No. 25 wire mesh. Preparation of tablets: In a cubic mixer 60 kg of granulate
1 kg of stearate magnesium 8 kg of hydroxypropylmethylcellulosa (Methocel E 4 M) are placed and mixed for 15 min. A chromed capsule-shaped punch having 17.5 mm length, 7 mm width and 7 mm bending radius is used for the preparation of the tablets. Example 3:
In a suitable vessel equipped with stirrer 1100 g of deionized water are charged with 300 g PEG and dissolved under agitation. In a cube mixer 3900 g of micronized lactose and 300 g of micronized Amlodipine are intimately mixed.
Such a mixture is charged in a kneader with horizontal blades and is wetted with the PEG aqueous solution. When the solution is homogeneously distributed, the mixture is transferred to a stove with forced air circulation where it is dried for 2 hours at 45 °C. Granulation is effected with an oscillating granulator provided with a inox ASTM No. 8 stainless steel metal wire mesh and dessication is completed. Tablets are then prepared as described in Example 1. Pharmacokinetic study:
The formulation of the present invention was compared with the commercially
available formulation in a single dose, crossover, randomized comparative pharmacokinetic
study performed in 48 healthy volunteers.
It was found that
63 % subjects achieved Tmax later in test product compare to reference product;
50% of subjects have higher Cmax compare to ref product
52 % of the subjects had attended a greater ti/2 compared to the reference product.
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This data indicates that the formulation is a retard formulation but achieves comparable bioequivalence as the commercially available product.
While the invention has been described by way of examples and in terms of the preferred embodiments, it is to be understood that the invention is not limited to the disclosed embodiments. On the contrary, it is intended to cover various modifications as would be apparent to those skilled in the art. Therefore, the scope of the appended claims should be accorded the broadest interpretation so as to encompass all such modifications.

We claim:
1. A solid pharmaceutical composition comprising
- amlodipine besylate as active principle;
- polyethylene glycol;
- one or more inert excipient;
wherein the active principle and polyethylene glycol are micronized and precipitated on the micronized inert excipient or polyethylene glycol is precipitated on the mixture of active principle and inert excipient the product beingin the form of very fine particles having an extremely high total specific surface.
2. A composition as claimed in claim 1 in the form of a sustained release tablet.
3. A composition as claimed in claim 1 wherein the micronized inert excipient is chosen from sucrose, lactose, glucose, fructose, levulose, mannitol, sorbitol, glycocoll, xylitol, pentaerythrite, and maltodextrine.
4. A composition as claimed in any preceding claim optionally comprising a rate retarding agent selected from hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, carboxyvinyl polymers, xanthan gum, in quantities varying in weight between 5% and 50% of the tablet.
5. A composition as claimed in any preceding claim wherein the ratio between active principle and polyethylene glycol varies between 20:80 and 80:20, preferably between 40:60 and 60:40.
6. A composition as claimed in any preceding claim wherein the polyethylene glycol has a molecular weight between 4000 and 6000.
7. A composition as claimed in any preceding claim wherein a co-precipitate is obtained in at least one phase.
8. A composition as claimed in claim 1 in the form of a tablet, characterized by the fact that there is at least one type of hydroxypropylmethylcellulose present among the excipients.
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9. A form of oral administration based on Amlodipine besylatee containing a solid pharmaceutical formulation as specified in claim 1.
10. A composition as claimed in claim 1, characterized by the fact that the ratio between the propylene glycol plus active principle and the micronized inert excipient varies between 1:20 and 1:4.
Dated this the 3rd day of September 2007


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Abstract
IMPROVED COMPOSITION OF AMLODIPINE BESYLATE
The present invention relates to pharmaceutical dosage forms of Amlodipine besylate and processes for their preparation.
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