Form 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULE 2003
PROVISIONAL SPECIFICATION
[See section 10 and rule 13]
1. TITLE OF THE INVENTION
"Alkylated crosslinked polymer"
2. APPLICANT
(1) NAME: USV LIMITED
(2) NATIONALITY: Indian Company incorporated under the
Companies ACT 1956
(3) ADDRESS: B.S.D. Marg, Station Road, Govandi, Mumbai 400 088,
Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention.


Technical Field:
The present invention relates to the process for preparation of Colesevelam hydrochloride, an antilipemic agent. The present invention also relates to novel pharmaceutical compositions comprising wet granulated Colesevelam or pharmaceutically acceptable salts thereof together with suitable pharmaceutically acceptable excipients. Further, the invention relates to a novel process for preparation of Colesevelam or pharmaceutically acceptable salts thereof comprising wet granulation.
Background of the invention:
Colesevelam hydrochloride is a non-absorbed, polymeric, lipid-lowering and glucose-lowering agent intended for oral administration. Colesevelam hydrochloride is a high-capacity bile acid-binding molecule, marketed as Welchol™ by Genzyme Corporation. The chemical name (IUPAC) of Colesevelam hydrochloride is allylamine polymer with l-chloro-2,3-epoxypropane, [6-(allylamino)-hexyl]trimethylammonium chloride and N-allydecylamine, hydrochloride of Formula I.

ai
Formula-I wherein (a) represents allyl amine monomer units that have not been alkylated by either of the 1-bromodecane or (6-bromohexyl)-trimethylamrnonium bromide alkylating agents
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or cross-linked by epichlorohydrin; (b) represents allyl amine units that have undergone crosslinking with epichlorohydrin; (c) represents allyl amine units that have been alkylated with a decyl group; (d) represents allyl amine units that have been alkylated with a (6-trimethylammonium) hexyl group, and m represents a number > 100 to indicate an extended polymer network. A small amount of the amines are dialkylated, and are not depicted in the formula above. No regular order of the groups is implied by the structure; cross-linking and alkylation are expected to occur randomly along the polymer chains. A large amount of the amines are protonated. The polymer is depicted in the hydrochloride form; a small amount of the halides are bromide.
Colesevelam is developed by Genzyme. Colesevelam is marketed in United states by Daiichi Sankyo under the brand name Welchol®. Welchol® is supplied as off-white, oval, film-coated, solid tablet containing 625 mg colesevelam hydrochloride. The inactive ingredients in Welchol® are magnesium stearate, microcrystalline cellulose, silicon dioxide, hydroxypropyl methylcellulose and acetylated monoglyceride. Colesevelam is marketed in Europe under the brand name Cholestagel.
Colesevelam is a bile acid sequestrant and is administered orally. Colesevelam has been shown to lower LDL cholesterol a mean of 19 % and a dose of 3.8 g/d. Colesevelam is indicated as an adjunct to diet and exercise to reduce elevated low-density lipoprotein cholesterol (LDL-C) in patients with primary hyperlipidemia as monotherapy or in combination with an hydroxymethyl-glutaryl-coenzyme A (HMG CoA) reductase inhibitor. Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when response to diet and non-pharmacological interventions alone has been inadequate. Colesevelam is also indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Colesevelam hydrochloride is a non-absorbed, lipid-lowering polymer which binds the bile acids in the intestine and impedes their reabsorption. As the bile acid pool becomes depleted, the hepatic enzyme, cholesterol 7-a-hydroxylase, is upregulated, which increases the conversion of cholesterol to bile acids. This causes an increased demand for cholesterol in the liver cells, resulting in the dual effect of increasing transcription and activity of the cholesterol biosynthetic enzyme, HMG-CoA reductase, and increasing the number of hepatic low-density lipoprotein receptors. These compensatory effects result in
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increased clearance of LDL-C from the blood, resulting in decreased serum LDL-C levels (ref: www.fda.gov/cder/foi/label/2008/021176s0171bl.pdf).
US5693675 (equivalent to US5679717) describes process fox preparation of polyallylamine hydrochloride which comprises addition of crosslinked poly(allylamine), (6-bromohexyl) trimethylammonium bromide and 1-bromodecane to a stirred solution of methanol and sodium hydroxide followed by heating the mixture with stirring. The mixture was then allowed to cool to room temperature, filtered and washed twice with methanol, twice with NaCl solution, thrice with deionized water and then with isopropanol. The obtained solid was dried in a vacuum oven at 50°C and then ground to pass through an 80 mesh sieve. The chloride content of polymer according to the process disclosed herein does not matches with Welchol™ tablet. Comparative analysis of Colesevelam HC1 prepared by this process (US5693675) and Welchol™ tablet is as follows,

Sr.No. Parameters Welchol™ tablet US 5693675 Present invention
01 BBC (mM/gm) 4.0 3.07 4.07
02 Chloride (meq/gm) 5.96 2.03 5.45
03 Bromide (meq/gm) 0.09 0.35 Less than 0.1
US5607669 describes process for alkylating the cross linked amine polymer which comprises reaction of crosslinked amine polymer with 6-bromohexyl trimethylammonium bromide and 1-bromodecane. After completion of alkylation, the polymer was treated with methanol, washed twice with 2M sodium chloride solution and thrice with deionized water, total six washings were given to the polymer. The calculated yield of the product is 1.5 times with respect to cross linked polyallylamine.
US7148319 describes process for the alkylation of crosslinked polymers which comprises optionally deprotonating the gelled polymers obtained by polymerization and crosslinking a) in water, an organic solvent or in an organic solvent/water mixture by addition of a base, b) optionally washing the polymers one or more times with water, an organic solvent or an organic solvent/water mixture, then c) adding one or more alkylators at atmospheric or elevated pressure at a temperature of between 5 and 160° C to the gel suspension which is stirred in water, an organic solvent or in an organic solvent/water mixture and after a mixing time of 1 to 60 minutes adding the base continually or in plural portions in such a way that the pH is between 8 and 13.5 and d) subsequently
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carrying out the reprotonation by means of concentrated acid, optionally after one or more washing steps, to get the product. In this patent alkylation is carried out on gelled polymer, Sevelamer which was prepared in situ. After completion of alkylation, polymer was treated with methanol (4 times), 2M sodium chloride solution in water (7 times) and deionized water (6 times). Hence total 17 washings were given to the polymer which is time consuming, thus this process is not economically viable.
US7105631 relates to an alkylation process which comprises cutting the crude gel into defined shape and washing the cross linking polymer (Sevelamer) gel with methanol. The obtained mass was then alkylated in methanol by adding one or/and more alkylators at 5-90°C under pressure in presence of base and optionally reprotonating followed by washing with methanol, subsequently with aqueous sodium chloride solution and finally with water to get the product. In this patent, alkylation is carried out on gelled polymer, which was prepared in situ. After completion of alkylation, polymer was treated with methanol (4 times), 2M sodium chloride solution in water (7 times) and deionized water (6 times). Hence total 17 washings were given to the polymer on a pressure suction filter. WO2005065291 discloses tablets, capsules, sachets and papers that have an aliphatic amine polymer-containing core having an enteric coating that targets the release of aliphatic amine polymers to one or more specific intestinal regions. Prior art discloses various formulations of Colesevelam Hydrochloride by methods involving direct compression.
Object of Invention:
An object of the invention is to provide a simple, industrially feasible and cost effective process for preparation of Colesevelam hydrochloride in high yield and having consistency in chloride content and bile binding capacity.
Another object of the present invention is to provide Colesevelam hydrochloride with chloride content in the range of 4.77-7.15 meq/gm, bromide content in the range of not more than about O.lmeq/gm and bile binding capacity in the range of 3.2-4.8 mM/gm
Another object of the invention is to provide novel pharmaceutical compositions comprising wet granulated Colesevelam or pharmaceutically acceptable salts thereof together with suitable pharmaceutically acceptable excipients.
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Another object of the invention is to provide a novel process for preparation of pharmaceutical compositions of Colesevelam or phannaceutically acceptable salts thereof comprising wet granulation.
Another object of the invention is to provide novel compositions comprising less than 80.0% by weight of Colesevelam or phannaceutically acceptable salts thereof.
Another object of the invention is to provide a novel process for preparation of Colesevelam or phannaceutically acceptable salts thereof comprising high shear or spray granulation.
Summary of Invention:
The present invention discloses an improved process for preparation of Colesevelam hydrochloride which comprises,
a) reacting 1,6-dibromohexane and trimethylamine gas at low temperature to get 6-bromohexyl trimethylammonium bromide;
b) alkylating Sevelamer hydrochloride using 6-bromohexyl trimethylammonium bromide and 1-bromodecane in presence of base to get the bromide salt of Sevelamer;
c) converting the obtained bromide salt into chloride salt using sodium chloride solution;
d) treating the reaction mass with acid and
e) isolating Colesevelam hydrochloride.
The present invention discloses novel pharmaceutical compositions comprising wet granulated Colesevelam or phannaceutically acceptable salts thereof together with suitable phannaceutically acceptable excipients. Further disclosed is a novel process for preparation of said compositions comprising wet granulation.
According to one embodiment, the present invention provides a process for preparation of compositions of Colesevelam or phannaceutically acceptable salts thereof comprising high shear granulation.
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According to another embodiment, the present invention provides a process for preparation of compositions of Colesevelam or pharmaceutically acceptable salts thereof comprising spray granulation.
According to the present invention, the process for preparation of pharmaceutical
compositions of Colesevelam or pharmaceutically acceptable salts thereof comprising wet
granulation comprises the steps of:
l)preparing a mixture of Colesevelam or pharmaceutically acceptable salts thereof and
one or more pharmaceutically acceptable additives;
2)granulating the mixture by high shear granulation or spray granulation to form granules;
3)compressing the granules into tablets or filling the granules into hard gelatin/cellulose
capsules.
According to one embodiment of the present invention, the process for preparation of pharmaceutical compositions of Colesevelam or pharmaceutically acceptable salts thereof comprising wet granulation comprises the steps of:
(1) preparing a mixture of Colesevelam or pharmaceutically acceptable salts thereof and one or more diluents;
(2) preparing a binder solution by dissolving the binder in a mixture of organic solvent and water;
(3) granulating the mixture of step (1) using binder solution by high shear granulation or spray granulation to form granulated mass;
(4) drying the granulated mass;
(5) milling the dried granulated mass using ball mill or fluid energy mill to form granules of suitable size;
(6) lubricating the milled granules;
(7) compressing the lubricated granules into tablets or filling the lubricated granules into capsules;
(8) coating the compressed tablets.
Detailed description of the invention:
The present invention describes process for the preparation of Colesevelam hydrochloride having chloride content in the range of 4.77-7.15 meq/gm, bromide content in the range
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of not more than about 0.l meq/gm and bile binding capacity in the range of 3.2-4.8
mM/gm.
According to the present invention, process for preparation of Colesevelam hydrochloride
comprises the following steps,
a) reacting 1,6-dibromohexane and trimethylamine at low temperature to get 6-bromohexyl trimethylammonium bromide;
b) alkylating Sevelamer hydrochloride using 6-bromohexyl trimethylammonium bromide and 1-bromodecane in presence of base to get the bromide salt of Sevelamer;
c) converting the obtained bromide salt into chloride salt using sodium chloride solution;
d) treating the reaction mass with acid and
e) isolating Colesevelam hydrochloride.
The low temperature is in the range of -10° C to 30° C, preferably -10° C to 0° C The reaction is represented in the following reaction schemes :
Stage-1 : Preparation of 6-bromohexyl trimethylammonium bromide
/ THF
N
/ 0 to-10C
1,6-Dibromohexane Trimethylamine 6-Bromohexyltrimethylammoniiim bromide
Scheme 1
In stage 1, process for preparation of 6-bromohexyltrimethylammonium bromide
(Quaternisation) comprises reaction of 1,6-dibromohexane with trimethylamine in suitable organic solvent at -10 to 0°C. The separated product is filtered in nitrogen atmosphere since product formed is hygroscopic in nature and dried under vacuum at 25 to 60°C, preferably 40 to 45°C. The second crop of the product is obtained by stirring the mother liquor for several hours.
The obtained 6-bromohexyltrimethylammonium bromide (bromide content 25.6%) is
used as such for alkylation of polyallylamine hydrochloride.
The solvent used is selected from ether, hydrocarbon, ester, ketone preferably

tetrahydrofuran. The reaction is carried out at the temperature range of-10° C to 30° C,
preferably -10° C to 0° C for 12 to 60 hours, preferably 48 hours.
Mole ratio of 1,6-dibromohexane to trimethylamine is in the range of 1: 0.9 to 1: 1.2,
preferably 1:1.06.
Stage- 2 : Preparation of Colesevelam hydrochloride
1) 'MeOH
2) NaOH
r ^sewUmhydircHoriia

Scheme 2
In stage 2, process for preparation of Colesevelam hydrochloride comprises partially
deprotonating Sevelamer hydrochloride using base in organic solvent and adding alkylating agents to the obtained reaction mass. The reaction mass is refluxed at 60-65° C for several hours, optionally under pressure. After the completion of reaction, the obtained material is filtered, washed with organic solvent by vigorous stirring followed by two to three times washing with sodium chloride solution to get complete bromide exchange with chloride ions. The polymer thus obtained is treated with acid to get the product with desired chloride content. The product is washed two to three times with purified water to remove any inorganic impurities and dried either on rotary evaporator or fluidized bed dryer at an elevated temperature preferably at 40-90° C for 8 to 24 hrs.
The base used for alkylation is selected from alkali or alkaline earth metal hydroxides,
preferably sodium hydroxide.
The organic solvent used for the reaction is selected from alcohol such as methanol,
ethanol, isopropanol preferably methanol.
The alkylating agents used are 6-bromohexyl trimethylammonium bromide and 1-
bromodecane. The acid is used is hydrochloric acid, preferably dilute hydrochloric acid.
Advantages of the present invention: 1) The process of the present invention provides Colesevelam hydrochloride in a yield which is higher than that obtained by the prior art process of US5607669.

2) The polymer obtained by the process of prior art (US7148319 and US7105631) was washed more than 10 times whereas in the present invention only less number of washings are required (7 times) to yield a product with consistent chloride content and bile binding capacity.
3) The process of the present invention is an efficient, non- tedious, non-laborious cost effective and commercially viable process as Sevelamer hydrochloride used in the present process is in the dry powder form instead of gelled polymer as used in prior art.
In another embodiment the alkylation reaction of 6-bromohexyl trimethylammonium bromide with Sevelamer is carried out under pressure and after the completion of alkylation reaction the product obtained is filtered either using Buchner funnel assembly or by centrifuging. The obtained wet cake is then washed with alcoholic solvent and filtered either using Buchner funnel assembly or by centrifuging.
In another embodiment, the bromide counterion exchange with chloride ion is carried out by vigorous stirring of wet cake in aqueous sodium chloride solution, optionally one or more times at temperature from 10°C- 40°C preferably at 25°C-35° C. The wet cake thus obtained is treated with aqueous hydrochloric acid solution, preferably 0.1N hydrochloric acid, at temperature from 10°C-40°C preferably at 25°C-35°C to get the product with desired chloride content. Finally the wet cake is further stirred vigorously preferably, one or more times, in purified water at temperature from 10°C- 40° C preferably at 25° C -35° C to remove inorganic impurities in the desired product. The obtained wet cake is dried on rotary evaporator or fluidized bed dryer at an elevated temperature of 60 °C to 95°C.
The present invention describes novel pharmaceutical compositions useful for the treatment of primary hyperlipidemia comprising wet granulated Colesevelam or pharmaceutically acceptable salt thereof. Particularly, the pharmaceutically acceptable salt is a hydrochloride salt of Colesevelam. The invention further describes a novel process for preparation of Colesevelam compositions; the said process comprising wet granulation. More specifically, the invention describes a novel process for preparation of Colesevelam or pharmaceutically acceptable salts thereof comprising high shear granulation or spray granulation.
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The present invention describes novel compositions comprising about 50.0% to 80.0% by weight of wet granulated Colesevelam or a pharmaceutically acceptable salt thereof.
The phosphate binding polymer Colesevelam hydrochloride is water insoluble. However, it swells in contact with water and due to this tendency of swelling of the active ingredient Colesevelam hydrochloride, formulating Colesevelam hydrochloride by wet granulation becomes difficult. According to the invention, the particles of Colesevelam hydrochloride are round in shape, particularly spherical or oval in shape. Spherical or oval shaped particles have low bulk density and poor flowability and further resist size reduction. Particles resist deformation and do not rupture or fracture. Due to these characteristics of Colesevelam hydrochloride, formulating Colesevelam hydrochloride by direct compression method becomes extremely difficult. In the practice of the present invention, the spherical morphology and hydrophilic nature of active ingredient Colesevelam hydrochloride presents a special challenge to the formulator.
Attempts were made to prepare compositions of Colesevelam hydrochloride by hot melt granulation and hot melt extrusion techniques. However, the results were not satisfactory as it employed very high quantity of binder and granules which were produced lacked adequate flow properties. The inventors of the present invention tried out several ways for formulating Colesevelam hydrochloride and has successfully developed formulations by high shear granulation which provides improved cohesiveness of particles, excellent flowability and compression characteristics. High shear granulation was performed using rapid mixer granulator or planetary mixer. Further, the inventors also successfully developed formulations by fluid bed processing technique/spray granulation.
According to the present invention, the process for preparation of compositions of Colesevelam or pharmaceutically acceptable salts thereof comprising wet granulation comprises the steps of:
(1) preparing a mixture of Colesevelam or pharmaceutically acceptable salts thereof and one or more diluents;
(2) optionally wetting the mixture of step (1) using water or solution of polyethylene glycol;
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(3) preparing a binder solution by dissolving the binder in a mixture of organic solvent and water;
(4) granulating the mixture of step (1) or step (2) using binder solution by high shear granulation or spray granulation to form granulated mass;
(5) drying the granulated mass;
(6) milling the dried granulated mass using ball mill or fluid energy mill to form granules of suitable size;
(7) lubricating the milled granules;
(8) compressing the lubricated granules into tablets or filling the lubricated granules into capsules;
(9) coating the compressed tablets.
According to one embodiment of the invention, the process of preparation of compositions of Colesevelam hydrochloride by high shear granulation comprises providing a mixture of active ingredient Colesevelam hydrochloride and one or more diluents; granulating the dry mix by wet granulation method using mixture of a organic solvent and purified water and preferably by using a binder solution prepared by dissolving the binder in the mixture of organic solvent and purified water; the granulation process being carried out in a rapid mixer granulator. Granulated mass is dried to remove the organic solvent and further dried at temperature of 50°C to 60°C till loss on drying value of about 5% to 12% is achieved. Dried granules are further milled or pulverized to get granules size less than 425 microns and preferably less than 250 microns using a multi-mill initially and then a fluid energy mill or a ball mill and preferably using a ball mill. Milled or pulverized granules are lubricated using lubricants known in the art and further compressed to provide tablets of required size. Compressed tablets are film coated by non-aqueous coating or aqueous coating or by hydro-alcoholic coating.
According to another embodiment, the spherical granules produced by the high shear granulation/spray granulation process may be filled along with suitable excipients into hard gelatin/cellulose capsules of suitable size. Capsule filling can be done using a suitable capsule filling machine.
Colesevelam hydrochloride is not a free flowing powder and is bulky. Wetting with
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purified water helps in decreasing the interparticulate distance and increasing the contact area between the particles; thus making the Colesevelam hydrochloride more amenable for granulation. Alternatively, the mixture of active and diluent may be made wet using a solution of polyethylene glycol dissolved in purified water. In an alternate method, polyethylene glycol 6000 may be added into the dry mix as a fine powder during the mixing step. Polyethylene glycols of various grades may be used such as polyethylene glycol 6000 or the like. Wetting is carried out either in a rapid mixer granulator or a planetary mixer. In the practice of the present invention, wetting of mixture of Colesevelam and diluent is carried out using about 9% to 15% by weight of purified water.
According to one embodiment, the process of preparation of Colesevelam hydrochloride compositions comprises mixing Colesevelam hydrochloride with one or more diluents; wetting the mixture using a solution of polyethylene glycol 6000 (Macrogol) dissolved in purified water; preparing a binder solution by dissolving polyvinyl pyrrolidone (Povidone K-30) in an organic solvent (isopropyl alcohol); granulating the wet mixture using the said binder solution and drying the granules. Sizing the dried granules through 60# on vibrosifter after milling with multi-mill and ball mill. The dried granules are blended using lubricants known in the art and the lubricated granules are further compressed into tablets. The core tablets are further film coated by aqueous coating process till a weight gain of 4.0% to 6.0% is achieved.
In the practice of the present invention, wet granulation is carried out by adding the hydro-alcoholic binder solution slowly in a thin stream continuously using a peristaltic pump under high speed mixing with the impeller 'on' and chopper 'off'. On completion of addition of binder, mixing is continued at high impeller speed till cohesive granular mass is obtained. If the mass is lumpy then chopper may be used at high speed with impeller also at high speed to obtain uniform wet mass. If planetary mixer is used for granulation, the wet mass is to be milled on a multi-mill using 8.0 mm screen and then charged for drying.
In the practice of the present invention, high shear granulation improves the cohesiveness of particles and provides excellent flowability and compression characteristics to the
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tablet. As the granules exhibit good flow properties, the tablets produced possess uniformity in weight. Further, the practice of the present invention also favours spray granulation. Drying of wet mass may be carried out using fluidized bed drier or tray drier. Initial drying is performed without application of temperature so as to remove the organic solvent and further the wet mass is dried for sufficient time at about 45°C to 50°C till loss on drying value is achieved in the range of about 5.0% to about 12.0%.
According to another embodiment, the process comprises mixing Colesevelam hydrochloride with one or more diluents; optionally wetting the mixture using purified water in a rapid mixer granulator; preparing a binder solution by dissolving ethyl cellulose in an organic solvent such as isopropyl alcohol; granulating the mixture of Colesevelam hydrochloride and diluents using the said binder solution and drying the granules. Sizing the dried granules through 60# on vibrosifter after milling with multi-mill and ball mill and further blending with commonly used lubricants and compressing the granules. Core tablets are further film coated.
According to another embodiment, Colesevelam hydrochloride is mixed with mannitol and made wet using purified water; granulated using binder solution prepared by dissolving the ethyl cellulose in isopropyl alcohol. Granulation is carried out in a rapid mixer granulator and the granulated mass is dried to remove the organic solvent till loss on drying of about 5.0% to about 12.0% is achieved. Dried mass is sized using ball mill to achieve granules of required size; lubricated using lubricants and compressed into tablets.
According to another embodiment of the invention, the process of preparation of Colesevelam hydrochloride composition comprises providing a mixture of active ingredient Colesevelam hydrochloride and one or more excipients; granulating the mixture by high shear granulation using a organic solvent and preferably by using a binder solution prepared by dissolving the binder in the organic solvent; the granulation process being carried out in a rapid mixer granulator. Granulated mass is further dried to remove the orgamc solvent and futher dried till a loss on drying value in the range of about 3.0% to 5.0% (which is similar to moisture content of active Colesevelam hydrochloride) is achieved. Dried granules are further milled or pulverized to get granules size of 425 microns and preferably less than 250microns. Milling may be carried out
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using a fluid energy mill or a ball mill and preferably by using a ball mill. Milled or pulverized granules are lubricated using lubricants known in the art and further compressed to provide tablets of required size or filled into capsules. Compressed tablets may be further coated.
According to one embodiment, the granules provided by high shear granulation process as described herein are spherical granules of size less than 425 microns and preferably less than 250microns. Although the dried granulated mass can be milled or pulverized using conventional equipments known in the art such as a multimill, co-mill, cadmill or fitzmill, they have limitations when used for size reduction of Colesevelam hydrochloride granules. Granule size below 425 microns (which passes through 40#) is difficult to obtain using such mills. Large granules pose difficulties during compression by decreasing the compressibility of the granules and produces porous tablets with low hardness, which consequently exhibit high friability and pose a risk of moisture uptake during aqueous film coating. Oversized granules retained after milling through 0.5mm screen on a conventional mill and sifting on a vibrosifter through 60# are milled in a ball mill or fluidized energy mill to obtain a particle size below 425 microns and preferably below 250microns for the granules.
In the practice of the present invention, size reduction or pulverization using fluid energy mill or ball mill provides spherical granules of size less than 425microns, which provides ease in compressibility. Ball milling being the preferred mode for size reduction of granules. Ball mill is preferred in terms of output and productivity for large scale batches. In ball milling, the process of size reduction occurs due to combined effect of impact and attrition. In a Fluid energy mill, the material is suspended and conveyed at high velocity by air, which is passed through nozzles at 100 to 150 pounds per square inch. The violent turbulence of the air reduces the particle size by inter-particulate attrition.
Milled mass is further sifted through a vibrosifter and oversized particles were milled through a mill preferably a ball mill with stainless steel balls and further sifted through a vibrosifter. The grinding media in the ball mill could range from Ytrria stabilized Zirconia systems, Glass, Porcelain, stainless steel, and the like. Mass is repeatedly milled with ball mill and sifted through vibrosifter till the resultant granules passed through 60#.
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According to a preferred aspect, granules of the present invention preferably have a particle size of 100% passing through 60#. Particle of size 250microns or less provides satisfactory compression of granules and further provides elegant non-porous, non-friable tablets with a smooth impervious surface, which can withstand the rigors of aqueous film coating. In the practice of the present invention, the granule size is controlled and 100% granules passes through 60# and provides tablets which exhibit a smooth impervious surface with a high hardness, low friability of less than 1.0% and preferably in the range of 0 to 0.8%, low disintegration time, and a smooth aqueous film coating operation. By controlling the granule size at less than 425 microns (which passes through 40#) and preferably less than 250 microns (which passes through 60#), elegant tablets are produced.
Tablets may be compressed using suitable punches and dies. Tablets may be of oval, elliptical, spherical or caplet shape. Compression can be carried out using equipments known in the art such as a rutery- tablet press. Tablets prepared by the process according to the invention meet the specification for disintegration (Limit not more than 30 minutes). Other parameters of tablets such as hardness, friability, and thickness, were measured and the results met the standard specifications for tablets.
According to another embodiment of the invention the Colesevelam hydrochloride tablets may be coated by aqueous or non-aqueous or hydroalcoholic coating. Film coating provides an impervious surface and prevents the ingress of moisture from the aqueous coat.
In one embodiment, coating of tablets is done using an aqueous coating method. Aqueous coating of hydrophilic active ingredient is another difficult process and posed a real challenge to the inventors of the present invention as the Colesevelam hydrochloride has a tendency to swell in presence of water. Aqueous coating has been achieved by having a fine control on the hardness of the cores, which balances the need for a hard core to ensure good coating as well as meets the requirement for disintegration of coated tablets. As the tablet core is hard with an impervious smooth surface, it withstands the aqueous film coating and the polymer Colesevelam hydrochloride does not swell during coating.
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According to one embodiment, the present invention provides novel pharmaceutical compositions comprising less than 80.0% by weight of Colesevelam or pharmaceutically acceptable salts thereof.
According to one embodiment, the compositions of the present invention comprises the active ingredient Colesevelam hydrochloride in the range of about 50% to about 80% by weight of total composition. More particularly, Colesevelam hydrochloride compositions of the present invention may be provided in dose strength of 625 mg.
According to a one aspect of the present invention, the composition contains about 50.0% to about 80.0% by weight of Colesevelam hydrochloride, 5.0% to 20.0% by weight of diluent, 5.0% to 30.0% by weight of binder, 0.25% to 5.0% by weight of glidant, 0.25% to 5.0% by weight of lubricants and about 3.8 to 6.0% by weight of coating agents.
Compositions of present invention may include one or more pharmaceutically acceptable excipients selected from diluents, binders, lubricants, glidants, colorants, coating agents, plasticizers and the like.
Diluents are substances which usually provides bulk to the composition. Diluents which may be used for preparation of Colesevelam hydrochloride compositions as per the invention include, but are not limited to maize starch, microcrystalline cellulose of various grades like Avicel PH 101, 112, 102), pregelatinized starch, manmtol, calcium carbonate, calcium sulfate and the like. Mannitol being the preferred diluent. Diluents may be used in the range of about 5% to about 20% by weight of total composition. Considering the end use of the formulation, mannitol is the preferred diluent. On oral administration, mannitol is not absorbed significantly from the gastrointestinal tract. Granular and spray dried forms of mannitol are generally used in granulations. Mannitol provides granules which can be easily dried. Colesevelam hydrochloride being hygroscopic, manmtol is the preferred diluent as it is not hygroscopic. Various grades of mannitol are available commercially. Preferred grades of mannitol include Pearlitol SD 200 of Roquette, France.
Binders impart cohesiveness to tablet formulation and ensures that the tablet remain intact
after compression. Binders which may be used for preparation of Colesevelam
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hydrochloride compositions as per the invention include, but are not limited to hydroxy propyl methyl cellulose, hydroxy propyl cellulose, hydroxy ethyl cellulose, ethyl cellulose, cellulose derivatives, maize starch, polyvinylpyrrolidone alone or in combination with polyethylene glycols and the like. Binders may be used in the range of about 5% to about 20% by weight of total composition. Binder preferred in the practice of the present invention is ethyl cellulose and polyvinyl pyrrolidone. Different grades of ethyl cellulose having various viscosities are commercially available. Ethyl cellulose of specific grades or blends of different grades may be used to obtain solutions of desired viscosity. Ethyl cellulose having viscosity in the range of 4cps to 22 cps is used; preferred being ethycellulose with viscosity of about 5 to I5cps. The preferred grade of ethylcellulose used for Colesevelam hydrochloride tablets is Ethocel EC-N 7 Pharm manufactured by Dow chemical company. Ethylcellulose is not metabolized following oral consumption and therefore a noncalorific substance.
According to the invention, one or more binders may be used for preparing the binding solution for wet granulation. Solvents that may be used as per the invention include, isopropyl alcohol, ethanol, dichloromethane, water or mixtures thereof. The preferred solvent being isopropyl alcohol alone or a mixture of isopropyl alcohol and water. The organic solvent/water solution is a solution of about 50.0% to 90.0% organic solvent and about 10.0% to 50.0% water. The ratio of organic solvent to water may be 50:50 or 75:25 or 80:20 or 90:10.
Lubricants which may be used for preparation of Colesevelam hydrochloride compositions as per the invention include, but are not limited to stearic acid, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, zinc stearate, magnesium stearate, sodium stearyl fumarate, calcium stearyl fumarate, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium lauryl sulphate, and the like. Glidants which may be used include colloidal silicon dioxide, talc and the like. Lubricants and glidants may be used in the range of about 0.25% to about 5% by weight of total composition.
Film coating may be carried out using polymers such as polyvinyl alcohol, hydroxyethyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and methacrylic acid co¬polymers. Ready mix coating materials may comprise plasticizers selected from
propylene glycol, triacetin or polyethylene glycol. Coating agents may be used in the
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range of about 3.0% to about 8.0% by weight of total composition.
Composition prepared by the process as described herein has a water content of about 5.0% to about 12%, particularly about 7.0% to about 10.0%. Although the present invention makes use of organic solvents such as isopropyl alcohol for granulation, the organic volatile impurity level in the finished product is quite low and is within the permissible limit.(Limit as per ICH guidelines: 5000 ppm)
Compositions of Colesevelam hydrochloride, particularly the tablets may be packed in aluminium strips or by cold formed blister pack, which is a cold process of blister packing, which acts as an excellent moisture barrier with negligible moisture vapor transmission rate and adequate environmental protection during shelf life. Alternatively the bulk pack in HDPE containers also should suffice to maintain the quality and integrity.
Compositions prepared by the novel process as described herein withstand the accelerated stability conditions of temperature and relative humidity and maintain their physical and chemical integrity at accelerated conditions of stability.
According to one embodiment, the present invention provides a method of treating a patient suffering from hyperlipidemia comprising administering to the patient a wet granulated Colesevelam hydrochloride pharmaceutical composition comprising a therapeutically effective amount of colesevelam hydrochloride.
The present invention is further illustrated by reference to the following examples which does not limit the scope of the invention in any way.
Examples:
Example 1 : Preparation of Sevelamer hydrochloride
50 g Poly(allylamine hydrochloride) and 75 ml water were mixed at 25 to 35°C to get a clear solution. The solution was further cooled to 5 to 15°C and 13.68 g sodium hydroxide solution in water (Qty of sodium hydroxide pellets used was 65-70 % by mole of Polyal-lylamine hydrochloride) was added to the reaction mass at 5 to 15°C and stirred for 30 minutes, 400 ml toluene and 2g SPAN-85 were added to it at 5 to 15°C. The temperature
19

of the reaction mixture was then raised to 20 to 25°C and maintained for 15 min. The re¬action mixture was filtered to remove any extraneous matter at 25 to 35°C. The tempera¬ture of the filtrate was further raised to 55 to 60°C and maintained for 15 minutes. 4.5 g epichlorohydrin (Qty of Epichlorohydrin used was 5-12 % by wt of Polyallylamine hy¬drochloride) was added at constant temperature of 55 to 60°C to reaction mixture and maintained for 3 hr at 55 to 60°C. The reaction mixture was cooled to 25 to 35°C and product was isolated by centrifugation. The wet cake was further sludged with water (3x750 ml) for 45 min at 25 to 50°C, filtered and dried in FBD at 25 to 90°C. Chloride content - 4.45 meq/gm
Phosphate binding capacity by IC method - 5.97 mmol/gm. Degree of cross linking -16.4 % Yield - 77.0 % w/w
Example 2 : Preparation of 6-bromohexyltrimethylammonium bromide
lkg 1,6-dibromohexane was stirred in 3L of tetrahydrofuran (THF) and 242g of trimethylamine was slowly purged into reaction mass at -10 to 0° C for 2-3 hrs. The reaction mass was further stirred for 48 hrs and the separated solid was immediately filtered, washed with 2L tetrahydrofuran, suck dried and then dried in vacuum oven at 40-45° C till constant weight was obtained. 1.047 kg 6-bromohexyltrimethylammonium bromide was obtained. Yield - 104 % w/w
Example 3 : Preparation of 6-bromohexyltrimethylammonium bromide :
1 kg 1,6-dibromohexane was stirred in 3L tetrahydrofuran (THF) and 242 gm trimethylamine was slowly purged into reaction mass at -10 to 0°C for 2-3 hrs. The reaction mass was stirred for 3 hrs and the separated solid was immediately filtered and washed with 2L tetrahydrofuran (THF). The material thus obtained was suck dried first and then dried in vacuum oven at 40-45°C till constant weight was obtained. 783g 6-' bromohexyltrimethylammonium bromide was obtained. Yield - 78.3 % w/w
Example 4 Preparation of Colesevelam hydrochloride:
50g of Sevelamer hydrochloride, 88 g 6-bromohexyltrimethylammonium bromide and
52.5 g 1-bromodecane were added to a solution of 22.5 gm of sodium hydroxide
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dissolved in 1.35 L methanol under stirring. The reaction mass was refluxed for 22 hrs. After the completion of reaction, the reaction mass was cooled to room temperature and filtered. The wet cake thus obtained was stirred in 3.65 L (2 M) sodium chloride solution in water for 2 hrs and filtered. The material was further stirred in 3.65 L (2 M) sodium chloride solution in water for 2 hrs and filtered. The wet cake thus obtained was stirred in 3.65 L (0.1 N) HCl solution in water for 1 hr and filtered. The wet cake was further stirred twice in 3.65 L purified water for 1 hr, filtered, suck dried and further dried at 90-95°C under vacuum either on rotary evaporator or fluidized bed dryer till constant weight of the material was obtained. 99 gm Colesevelam hydrochloride was obtained. Bile binding capacity - 4.12 mmol/g. Yield -198 % w/w
Example 5 : Preparation of Colesevelam hydrochloride:
50 g of Sevelamer hydrochloride, 88 g 6-bromohexyItrimethylammonium bromide and 52.5 g 1 -bromodecane were added to a solution of 22.5 g sodium hydroxide dissolved in 1.35 L methanol and the reaction mass was refluxed for 6hrs. Then reaction mass was cooled to room temperature and filtered the material. The wet cake obtained was stirred in 3.65 L (2M) sodium chloride solution in water for 2 hrs twice and filtered. The wet cake thus obtained was further stirred in 3.65 L (0.1 N) HCl solution in water for 1 hr and filtered. The material was stirred in 3.65 L purified water for lhr twice, filtered, suck dried and then dried at 90-95° C under vacuum either on rotary evaporator or fluidized bed dryer till constant weight of the material was obtained. 97 gm Colesevelam hydrochloride was obtained. Bile binding capacity- 3.93 mmol/g and Yield-194 % w/w
Example 6 : Preparation of Colesevelam hydrochloride:
To a solution of 22.5 gm sodium hydroxide dissolved in 1.35 L methanol, 50 gm of Sevelamer hydrochloride, 88 gm 6-bromohexyltrimethylammonium bromide and 52.5 gm 1-bromodecane were added and the reaction mass was refluxed for 12hrs. Then the reaction mass was cooled to room temperature and filtered. The wet cake obtained was stirred in 3.65 L (2M) sodium chloride solution in water for 2hrs twice and filtered. The obtained wet cake was stirred in 3.65 L (0.1 N) HCl solution in water for lhr, filtered and stirred in 3.65 L purified water for 1 hr twice and was filtered. The material thus obtained
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was suck dried and then dried at 90-95° C under vacuum either on rotary evaporator or fluidized bed dryer till constant weight of the material was obtained. 102g Colesevelam hydrochloride was obtained. Bile binding capacity- 3.66 mmol/g and Yield- 204 % \y/w.
Example 7 : Preparation of Colesevelam hydrochloride:
50 g of Sevelamer hydrochloride, 88 g 6-bromohexyltrimethylammonium bromide and 52.5 g 1-bromodecane were added to a solution of 22.5 g sodium hydroxide dissolved in 1.35 L methanol and the reaction mass was refluxed for 4 hrs. After the completion of reaction the reaction mass was cooled to room temperature and filtered. The obtained wet cake was stirred twice in 3.65 L (2 M) sodium chloride solution in water for 2 hrs and filtered. The wet cake was further stirred in 3.65 L (0.1 N) HC1 solution in water for 1 hr and the obtained material was filtered. The wet cake was further stirred in 3.65 L purified water for Ihr and filtered and again stirred in 3.65 L purified water for 1 hr. The material was filtered, suck dried and further dried at 90-950 C under vacuum either on rotary evaporator or fluidized bed dryer till constant weight of the material was obtained. 90 g Colesevelam hydrochloride was obtained. Bile binding capacity - 4.65 mmol/g and Yield - 180 % w/w
Example 8 : Preparation of Colesevelam hydrochloride:
50 g of Sevelamer hydrochloride, 88 g 6-bromohexyltrimethylammonium bromide and 52.5 g 1-bromodecane were added to a solution of 22.5 g sodium hydroxide dissolved in 1.35 L methanol and the reaction mass was refluxed for 29 hrs. Then reaction mass was cooled to room temperature and filtered. The wet cake obtained was stirred in 3.65 L (2M) sodium chloride solution in water for 2 hrs and filtered. The obtained material was again stirred in 3.65 L (2M) sodium chloride solution in water for 2 hrs and filtered. The wet cake thus obtained was stirred in 3.65 L (0.1 N) HC1 solution in water for lhr, filtered and further stirred twice in 3.65 L purified water for lhr- and filtered. The material thus obtained was first suck dried and then dried at 90-95°C under vacuum either on rotary evaporator or fluidized bed dryer till constant weight of the material was obtained. 92g Colesevelam hydrochloride was obtained. Bile binding capacity - 3.64 mmol/g and Yield - 184 % -w/w
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Example 9 : Preparation of Colesevelam hydrochloride:
To a solution of 11.25 gm sodium hydroxide dissolved in 0.675 L methanol, 25 gm Sevelamer hydrochloride, 44 gm 6-bromohexyltrimethylammonium bromide were added and the reaction mass was refluxed for Ihr. 26.25 gm 1-bromodecane was added to the reaction mass at reflux temperature and stirred at reflux for 18 hrs. Then the reaction mass was cooled to room temperature and filtered. The wet cake was stirred in 2.82 L (2M) sodium chloride solution in water for 2hrs and the material was filtered off and this is repeated again and the material was filtered. The wet cake obtained was stirred in 1.82 L (0.1 N) HC1 solution in water for lhr and filtered off. The material obtained was stirred in 1.82 L purified water for lhr and the material was filtered. This step was repeated again. The material obtained was first suck dried and then dried at 90-95° C under vacuum either on rotary evaporator or fluidized bed dryer till constant weight of the material was obtained. 52.5 gm Colesevelam hydrochloride was obtained. Bile binding capacity 3.43 mmol/gm and Yield - 210 % w/w
Example 10 : Preparation of Colesevelam hydrochloride:
11.25 g sodium hydroxide was dissolved in 0.675 L methanol under stirring and 25 g Sevelamer hydrochloride, 44 g 6-bromohexyltrimethylarnmonium bromide were added and the reaction mass was refluxed for 30 min. 26.25 g 1-bromodecane was added to the obtained reaction mass at reflux temperature and stirred at reflux for 18 hrs. The reaction mass was cooled to room temperature and filtered. The wet cake obtained was stirred in 1.82 L (2M) sodium chloride solution in water for 2 hrs and filtered. The sodium chloride treatment was repeated once more and the obtained material was stirred in 1.82 L (0.1 N) HC1 solution in water for 1 hr. Material was filtered and stirred in 1.82 L purified water for lhr, twice. The material was filtered, suck dried and then dried at 90-95°C under vacuum either on rotary evaporator or fluidized bed dryer till constant weight of the material is obtained. 52.5 g Colesevelam hydrochloride was obtained. Bile binding capacity - 3.58 mmol/g and Yield-210 %w/w
Example 11 : Preparation of Colesevelam hydrochloride:
11.25 gm sodium hydroxide was dissolved in 0.675 L methanol under stirring and 25 gm
Sevelamer hydrochloride, 44 gm 6-bromohexyltrirnethylammonium bromide were added
and the reaction mass was refluxed for 2 hrs. 26.25 g 1-bromodecane was added to the
23

reaction mixture at reflux temperature and stirred at reflux for 18 hr. The reaction mass was cooled to room temperature and filtered. The wet cake was stirred in 1.82 L (2M) sodium chloride solution in water for 2hrs twice and the material was filtered. The wet cake obtained was stirred in 1.82 L (0.1 N) HCl solution in water for lhr and filtered. The obtained material was again stirred in 1.82 L purified water for lhr twice. The material obtained was filtered, suck dried and further dried at 90-95°C under vacuum either on rotary evaporator or fluidized bed dryer till constant weight of the material was obtained. 53.5 g Colesevelam hydrochloride was obtained. Bile binding capacity 3.55 mmol/g and Yield - 214 % w/w
Example 12 : Preparation of Colesevelam hydrochloride:
22.5 g sodium hydroxide was dissolved in 1.35 L methanol under stirring and 50 g Sevelamer hydrochloride, 88 g 6-bromohexyltrimethylammonium bromide and 64.14 gm 1-bromodecane were added and refluxed for 22 hrs. The reaction mass was cooled to room temperature and filtered. The wet cake was stirred in 3.65 L (2M) sodium chloride solution in water for 2hrs twice and filtered. The material was further stirred in 3.65 L (0.1 N) HCl solution in water for 1 hr and filtered. The obtained material was stirred in 3.65 L purified water for lhr twice and filtered. The material obtained was suck dried and then dried at 90-95°C under vacuum either on rotary evaporator or fluidized bed dryer till constant weight of the material was obtained. 90 g Colesevelam hydrochloride was obtained. Bile binding capacity - 3.32 mmol/g and Yield- 180% w/w
Example 13 : Preparation of Colesevelam hydrochloride:
31gm sodium hydroxide was dissolved in 1.35 L methanol under stirring and 88 gm 6-bromohexyltrimethylammonium bromide and 64.14 gm 1-bromodecane were added. This reaction mass was refluxed for 22 hrs. Then reaction mass was cooled to room temperature and filtered. The wet cake was stirred in 3.65 L (2 M) sodium chloride solution in water for 2 hrs and filtered. 3.65 L (2 M) sodium chloride solution in water was added to the obtained material for 2hr and filtered. The wet cake was stirred in 3.65 L (0.1 N) HCl solution in water for 1 hr and filtered. The obtained material was stirred in 3.65 L purified water twice for 1 hr and filtered. The material was suck dried and dried at 90-95°C under vacuum either on rotary evaporator or fluidized bed dryer till constant
24

weight of the material was obtained. 90gm Colesevelam hydrochloride was obtained. Bile binding capacity - 3.64 mmole/gm and Yield - 180%w/w
Example 14

Ingredients Quantity (g)
Core
Colesevelam hydrochloride 164.473
Mannitol 3.327
Polyvinyl pyrrolidone (Povidone 30) 22.500
Purified water 26.400
Isopropyl alcohol 50.000
Colloidal silicon dioxide 2.200
Magnesium stearate 1.100
Film-coating
Ready mix film coating material 8.800
Total 228.800
Procedure: Colesevelam hydrochloride was co-sifted with mannitol (Pearlitol SD 200) using 20# stainless steel sieve and transfered into a rapid mixer granulator and mixed for 5minutes at l00rpm. Binder solution was prepared by dissolving povidone in a mixture of isopropyl alcohol and water. The binder solution was added to the Colesevelam-mannitol mixture and mixed at impeller high speed 180 to 200 rpm with chopper off condition for sufficient time till a cohesive mass is formed. The mass was air dried for sufficient time in Glatt drier and further dried at temperature of 50°C to 60°C till loss on drying value of about 10% to 12% was achieved. The dried granules were sifted through 60# Sieve. The over sized granules were milled using ball mill and the milled mass was sifted through 60# sieve. The sifted granules were blended with presifted colloidal silicon dioxide (sifted through 40#) and magnesium stearate (sifted through 60#) in a conta blender and compressed on 0.75 x 0.35 inch elliptical punches and dies to obtain tablet having weight of 880mg per tablet and hardness of about 50 to 100 N. The compressed tablets were coated using coating solution prepared by dissolving coating ready mix containing HPMC 5 cps and Triacetin in purified water, till weight gain of 4.0% of the core tablets (weight of coated tablets 915.200 mg) is achieved.
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Example 15
Ingredients Quantity (g)
Core
Colesevelam hydrochloride 657.892
Mannitol 13.308
Polyvinyl pyrrolidone (Povidone 30) 90.000
Purified water 105.600
Isopropyl alcohol 100.000
Colloidal silicon dioxide 8.800
Magnesium stearate 4.400
Film-coating
Ready mix film coating material 35.200
Total 915.200
Procedure: Colesevelam hydrochloride was co-sifted with mannitol (Pearlitol SD 200) using 20# S. S. Sieve and transfered into Uniglatt fluid bed processor and mixed for 10 minutes. Binder solution was prepared by dissolving povidone in a mixture of isopropyl alcohol and water. The binder solution was sprayed on to the Colesevelam-mannitol mixture in the Uniglatt by top spray mechanism. The mass was dried at temperature of 50°C to 60°C for sufficient time till loss on drying value of about 10% to 12% was achieved. The dried granules were sifted through 60# Sieve. The over sized granules were milled using ball mill and the milled mass was sifted through 60# sieve. The sifted granules were blended with presifted colloidal silicon dioxide (sifted through 40#) and magnesium stearate (sifted through 60#) in a conta blender and compressed on 0.75 x 0.35 inch elliptical punches and dies to obtain tablet having weight of 880mg per tablet and hardness of about 50 to 100 N. The compressed tablets were coated using coating solution prepared by dissolving coating ready mix containing HPMC 5 cps and Triacetin in purified water, till weight gain of 4.0% of the core tablets (weight of coated tablets 915.200 mg) is achieved.
Example 16

Ingredients Quantity (g)
Core
Colesevelam hydrochloride 164.474
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Mannitol 9.777
Purified water 21.250
Ethyl cellulose 13.813
Isopropyl alcohol 55.250
Colloidal silicon dioxide 2.125
Magnesium stearate 1.063
Film-coating
Ready mix film coating material 8.800
Total 221.300
Procedure: Colesevelam hydrochloride was co-sifted with mannitol (Pearlitol SD 200) using 20# S. S. Sieve and transfered into a rapid mixer granulator and mixed for 5minutes at l00rpm. Purified water was added into the rapid mixer granulator and mixed for about 3 minutes at impeller speed of 100 rpm. Binder solution was prepared by dissolving ethyl cellulose in isopropyl alcohol by warming at about 45°-50°C. The binder solution at 45°-50°C was added to the Colesevelam-mannitol mixture and mixed at impeller high speed 180 to 200rpm with chopper off condition for sufficient time till a cohesive mass is formed. The mass was air dried for sufficient time in Glatt drier and further dried at temperature of 50 to 60°C till loss on drying value of about 10% to 12% was achieved. The dried granules were sifted through 60# Sieve. The over sized granules were milled using ball mill and the milled mass was sifted through 600# sieve. The sifted granules were blended with presifted colloidal silicon dioxide (sifted through 40#) and magnesium stearate (sifted through 60#) in a conta blender and compressed on 0.75 x 0.35 inch elliptical punches and dies to obtain tablet having weight of 880mg per tablet and hardness of about 50 to 100 N. The compressed tablets were coated using coating solution prepared by dissolving coating ready mix containing HPMC 5 cps and Triacetin in purified water, till weight gain of 4.0% of the core tablets (weight of coated tablets 885.200 mg) is achieved.
Example 17

Ingredients Quantity (g)
Core
Colesevelam hydrochloride 164.474
27

Mannitol
9.787
Polyvinyl pyrrolidone (Povidone 30) 7.500
Purified water 21.250
Ethyl cellulose 13.813
Isopropyl alcohol 55.25
Colloidal silicon dioxide 55.250
Magnesium stearate 2.125
Film-coating
Ready mix film coating material 8.800
Total 228.810
Procedure: Colesevelam hydrochloride was co-sifted with mannitol (Pearlitol SD 200) using 20# S. S. Sieve and transfered into a rapid mixer granulator and mixed for 5minutes at lOOrpm. The binder solution was prepared by dissolving povidone in water. The povidone solution was added into the rapid mixer granulator and was mixed for about 5 minutes at impeller speed 100 rpm. The second binder solution was prepared by dissolving ethyl cellulose in isopropyl alcohol by warming at about 45°-50°C. The binder solution at 45°-50°C was added to the Colesevelam-mannitol mixture and mixed at impeller high speed 180 to 200rpm with chopper off condition for sufficient time till a cohesive mass is formed. The mass was air dried for sufficient time in Glatt drier and further dried at temperature of 50 to 60°C till loss on drying value of about 10% to 12% was achieved. The dried granules were sifted through 60# Sieve. The over sized granules were milled using ball mill and the milled mass was sifted through 60# sieve. The sifted granules were blended with presifted colloidal silicon dioxide (sifted through 40#) and magnesium stearate (sifted through 60#) in a conta blender and compressed on 0.75 x 0.35 inch elliptical punches and dies to obtain tablet having weight of 880.04mg per tablet and hardness of about 50 to 100 N. The compressed tablets were coated using coating solution prepared by dissolving coating ready mix containing HPMC 5 cps and Triacetin in purified water, till weight gain of 4.0% of the core tablets (weight of coated tablets 915.240 mg) is achieved.
Example 18
Ingredients Quantity (g)
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Core
Colesevelam hydrochloride 164.474
Mannitol 2.727
Polyethylene glycol 6000 5.000
Purified water 22.000
Polyvinyl pyrrolidone (Povidone 30) 22.5000
Isopropyl alcohol 56.250
Colloidal silicon dioxide 2.200
Magnesium stearate 1.100
Film-coating
Ready mix film coating material 8.800
Total 228.800
Procedure: Colesevelam hydrochloride was co-sifted with mannitol (Pearlitol SD 200) using 20# S. S. Sieve and transfered into a rapid mixer granulator and mixed for 5minutes at lOOrpm. The wetting solution was prepared by dissolving polyethylene glycol 6000 in water. This wetting solution was added into the rapid mixer granulator and mixed for about 5 minutes at impeller speed of 100 rpm. The binder solution was prepared by dissolving povidone in a mixture of isopropyl alcohol and water. The binder solution was added to the Colesevelam-mannitol mixture and mixed at impeller high speed 180 to 200rpm with chopper off condition for sufficient time till a cohesive mass is formed. The mass was air dried for sufficient time in Glatt drier and further dried at temperature of 50 to 60°C till loss on drying value of about 10% to 12% was achieved. The dried granules were sifted through 60# Sieve. The over sized granules were milled using ball mill and the milled mass was sifted through 60# sieve. The sifted granules were blended with presifted colloidal silicon dioxide (sifted through 40#) and magnesium stearate (sifted through 60#) for about 5 minutes in a conta blender and compressed on 0.75 x 0.35 inch elliptical punches and dies to obtain tablet having weight of 880mg per tablet and hardness of about 50 to 100 N. The compressed tablets were coated using coating solution prepared by dissolving coating ready mix containing HPMC 5 cps and Triacetin in purified water, till weight gain of 4.0% of the core tablets (weight of coated tablets 915.200 mg) is achieved.
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While the present invention is described above in connection with preferred or illustrative embodiments, these embodiments are not intended to be exhaustive or limiting of the invention. Rather, the invention is intended to cover all alternatives, modifications and equivalents included within its spirit and scope, as defined by the appended claims.
Dated this 01st day of September 2008

Dr. K. Gl Rajend ran Head Knowledge Cell USV Limited
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