FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
(SECTION 10 and Rule 13)
TITLE OF THE INVENTION "COMPOSITIONS OF ALIPHATIC AMINE POLYMERS"
Encore Pharmaceuticals Limited, an Indian company, registered under the Indian Company's Act 1957 and
having its registered office at
Emcure House, T-184, M.I.D.C., Bhosari, Pune-411026, India.
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION

FIELD OF THE INVENTION
The present invention relates to pharmaceutical compositions comprising aliphatic amine polymer. Particularly, the present invention relates to pharmaceutical compositions comprising aliphatic amine polymers selected from sevelamer hydrochloride, sevelamer carbonate and colesevelam hydrochloride; and methods of preparing pharmaceutical compositions thereof.
BACKGROUND OF THE INVENTION
Hyperphosphatemia is a disease associated with acute and chronic renal failure and occurs when the serum phosphorus level is greater than 5 mg/dL (1.6 mmol/L), usually in the form of inorganic phosphorus. Hyperphosphatemia involves decreased Calcium ions due to increased serum phosphorus, increased parathyroid hormone secretion, and associated sequelae. Therapeutic efforts directed toward the control of hyperphosphatemia include dialysis, dietary phosphate reduction, and oral administration of phosphate-binding agents.
Phosphate binding agents act to reduce serum phosphorus ingested through the diet and include calcium, aluminium and magnesium salts or ion exchange polymers such as aliphatic amine polymers. Calcium and aluminum based phosphate binders have been widely used effectively to bind with intestinal phosphate and prevent absorption by forming insoluble calcium or aluminum salts. Calcium carbonate and calcium acetate are the most commonly used calcium based phosphate binders. However, side effects associated with these agents limit their effectiveness. Therefore, treatment with these agents requires frequent monitoring of serum calcium or aluminum levels.
Therefore, aliphatic amine polymers are one of the most preferred and widely used therapeutic drug for the treatment of hyperphosphataemia. These polymers provide an effective treatment for decreasing the serum level of phosphate, without concomitantly increasing the absorption of any clinically undesirable materials. Examples of aliphatic amine polymer which have found place in clinical practice include sevelamer, a polymeric phosphate binder intended for oral administration and colsevelam, a bile acid sequestrant.

Sevelamer hydrochloride is a poly(allylamine hydrochloride) crosslinked with epichlorohydrin in which forty percent of the amines are apparently protonated. Sevelamer carbonate is another therapeutically useful agent, with the same polymeric structure as sevelamer hydrochloride, in which carbonate replaces chloride as the counterion. Colesevelam is another aliphatic amine polymer, which is indicated as an adjunct to diet and exercise to reduce elevated low-density lipoprotein cholesterol in patients with primary hyperlipidemia as monotherapy and to improve glycemic control in adults with type 2 diabetes mellitus. Colesevelam hydrochloride has almost all of its amines protonated and contains about 21% chloride by weight.
Currently all these aliphatic amine polymers are available in dosage forms suitable for oral administration. These polymers are hydrophilic in nature but insoluble in water. The solubility profile coupled with complex polymer structure pose difficulties while formulating the suitable dosage forms for oral administration. The researches have tried to overcome these difficulties and reported various formulations for these aliphatic amine polymers, as follows:
Tyler et al in US 6,733,780 discloses a direct compression polymer tablet core containing at least about 95% by weight of an aliphatic amine polymer and a method of producing such a tablet core involving the steps of hydrating the aliphatic amine polymer to the desired moisture level; blending with additives in amounts such that the polymer comprises at least about 95% by weight of the resulting blend; and compressing the blend to form the tablet core.
Matsuda et al in US 6,383,518 and in US 6,696,087 discloses a phosphate-binding polymer tablet that contains a phosphate-binding polymer having an average particle size of 400 |o, or less, preferably 250 p, or less, and having a moisture content of 1 to 14%, together with crystalline cellulose and/or low substituted hydroxy propyl cellulose.
Bhagat et al in US 7,985,418 discloses sevelamer carbonate compositions containing monovalent anion that can prevent or ameliorate acidosis, in particular acidosis in patients with renal disease. According to this document, addition of a monovalent anion source, especially sodium chloride, to sevelamer carbonate prevents the increase in the disintegration time of the tablets and increases the shelf life.
Hrakovsky et al in US 7,749,536 discloses compositions containing aliphatic amine polymers prepared by spray granulation method wherein the granulating solution is ethanol/water

solution prepared from about 82% to about 95% of 95% ethanol and about 5% to about 18% water. US 7,846,425 of Hegde et al discloses use of non-aqueous solvent for preparing granulating liquid.
Lynch et al in US 2010/0166861 disclose use of copovidone for preparation of tablet and discloses that sevelamer, or a salt thereof, does not readily lend itself to compression into tablet form, and therefore copovidone, which may be used as a binding agent, and is believed to provide cohesiveness to the composition during the compression stages of the tableting process. Copovidone is also believed to act as a disintegrant to aid in the breakup and dispersion of the active ingredient after oral consumption of the tablet by a patient.
Jobdevairakkam et al in US 2010/0330175 discloses that controlling particle size of hydrated cross-linked polyallylamine salts is generally more difficult than controlling particle size of a substantially dry material as the hydrated material upon milling causes lump formation where as size reduction of the dried cross-linked polyallylamine salts having low water content from about 0.1% to 3% is much more straight forward and easier for scale up operations. Hence document suggests use of dried cross-linked polyallylamine along with poly hydroxy compounds.
Osinga et al in WO 2011/047700 discloses use of lactose monohydrate to make the tablet, whereas Lloret et al in WO 2010/0149794 disclose starch as suitable excipient for the preparation of sevelamer tablet formulations.
From the above, it would be evident that there is plethora of reports, at times completely divergent, relating to a formulation of aliphatic amine polymer leaving a person bewildered. Further, the hygroscopic nature of these polymers associated with serious volume gain during uptake of water thereby limiting the choice of excipients and tableting process has vexed researches in this field.
In addition to this, Health care professionals around the world are extremely cautious regarding excipients used in the tablet formulation as commonly used metal salts such as those of sodium, calcium, potassium, aluminium or magnesium have detrimental effects of high sodium intake on blood pressure control, congestive heart failure and fluid balance in patients with chronic kidney disease.

Thus, there exists a need to develop pharmaceutical compositions of aliphatic amine polymers which are safe to administer to patients and are convenient to manufacture.
OBJECTS OF THE INVENTION
It is therefore an object of the present invention to provide a simple formulation of aliphatic amine polymers suitable for oral administration.
Another object of the present invention is to provide a simple tablet formulation of polyallyl amine polymers.
Yet another object of the present invention is to provide a simple, commercially viable process for preparation of tablet formulation of polyallyl amine polymers.
SUMMARY OF THE INVENTION
The present invention relates to a solid oral dosage formulation containing aliphatic amine polymer or pharmaceutically acceptable salt thereof. The formulation, preferably a tablet, contains suitable excipients such as diluents along with the aliphatic amine polymer. The judicious selection of diluent in the pharmaceutical composition of the present invention, results in a formulation having desired characteristics.
In one aspect of the present invention, the formulation comprises aliphatic amine polymer selected from the group consisting of sevelamer hydrochloride, sevelamer carbonate and colesevelam hydrochloride. More preferably, the aliphatic amine polymer is sevelamer carbonate.
In another aspect of the present invention, the aliphatic amine polymer is present in an amount ranging from about 60% to 95% by weight of the tablet core. The therapeutic dose of these aliphatic amine polymers is very high, and hence it is recommended to have the amounts of the active ingredient as high as possible so as to reduce the total size of the tablet.
In still another aspect, the invention provides a tablet formulation comprising sevelamer carbonate and a diluent, wherein the amount of sevelamer carbonate present in the tablet is from about 60% to 95% by weight of the tablet core.

In a further aspect, the present invention provides a film coated pharmaceutical composition comprising aliphatic amine polymer and at least one excipient such as diluents. The formulation may contain other excipients that are normally employed in such pharmaceutical compositions, the only qualifications being that they must not deleteriously affect the stability of the pharmaceutical composition and should result in a pharmaceutical composition with short disintegration time, high drug load, and sufficient hardness.
In a yet further aspect, the present invention also provides a process for making such solid oral dosage forms comprising aliphatic amine polymers and diluents. The method comprises the step of compressing the blend of aliphatic amine polymer and excipient to form the tablet core. The tablet core can further include one or more suitable excipients. Preferably, a direct compression method is employed for preparation of solid oral dosage forms of aliphatic amine polymer.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a solid oral dosage formulation containing aliphatic amine polymer or pharmaceutically acceptable salt thereof. The formulation also contains suitable excipients such as diluents along with the aliphatic amine polymer.
The aliphatic amine polymer can be any of the aliphatic amine polymer described in U.S. Pat. Nos. 5,496,545; 5,667,775; 5,703,188; 5,679,717; 5,693,675, 5,607,669;'and 5,618,530, each of which is hereby incorporated herein by reference in its entirety. Preferably, the aliphatic amine polymer is selected from sevelamer hydrochloride (HO), sevelamer carbonate and colesevelam hydrochloride. More preferably, the aliphatic amine polymer is sevelamer carbonate.
Typically, the present invention relates to pharmaceutical compositions comprising a tablet core comprising sevelamer carbonate in a range of from about 60% to about 95%, preferably form about 70% to about 90% by weight and more preferably from about 80 to 85% by weight of tablet core. For the purpose of present invention, the quantity of aliphatic amine polymer to be incorporated in the tablet is determined based on the moisture content present in the aliphatic amine polymer.

The judicious selection of the diluent makes the formulation simple, convenient and easy to manufacture and helps to achieve the desired properties of the formulation viz., short disintegration time, high drug load, and sufficient hardness.
The present inventors have found that the diluents selected from the group consisting of non reducing sugar or modified sugar or combinations thereof helps to achieve the abovementioned desired properties of the formulation.
The non-reducing sugar is preferably a non-reducing disaccharide. The non-reducing disaccharides are those disaccharides in which the components bond through an acetal linkage between their anomeric centers and neither monosaccharide has a free hemiacetal unit. Sucrose and trehalose are the examples of non-reducing disaccharides. The preferred non-reducing sugar is trehalose.
The modified sugars are commonly of two kinds, deoxy and amino. In deoxy sugars a hydroxy group (-OH) is replaced by a hydrogen (-H) or a hydroxy methyl group (-CH2OH) by a methyl group (-CH3). The former typically occurs at C2 and the latter at C6. In amino sugars the hydroxy group (-OH) is replaced by he amino group (-NH2), commonly at C2 position. The amino group may subsequently be acetylated to give the N-acetyl derivative.
The preferred examples of modified sugars are confectioner's sugar or compressible sugar. Confectioner's sugar, which is also known as powdered sugar or icing sugar, is very fine sugar. This sugar is granulated sugar ground to a smooth powder and then sifted. It contains about 3% cornstarch. Compressible sugar contains sucrose and maltodextrin or dried glucose syrup. It contains 95.0 to 98.0% of sucrose and 2 to 5% of dried glucose syrup or maltodextrin. It may contain a suitable lubricant, invert sugar or suitable colouring matter.
The role of excipients in the immediate release tablet comprising aliphatic amine polymer is generally to bind the composition in the tabletting process into a sufficiently hard and stable tablet simultaneously allowing sufficiently rapid disintegration of the tablet matrix in the stomach environment. The present inventors have found that these properties could be achieved by using non reducing sugar or modified sugar as diluents. The diluent is present in an amount ranging form about 5% to about 30 % and most preferably from 10-25 % of the

tablet composition. By using these excipients as diluent, the obtained composition possesses sufficient hardness making it suitable for film coating.
In addition to diluents, the pharmaceutical composition of the present invention optionally may also contain one or more excipients that are normally employed in such pharmaceutical compositions, the only qualifications being that they must not deleteriously affect the stability of the pharmaceutical composition. Examples of such excipients are binders, disintegrant, lubricant, glidants. A combination of excipients may also be used. Such excipients are known to those skilled in the art, and thus, only few representative examples for each class of excipient are mentioned herein below:
Disintegrant may be, for example, croscarmellose sodium, crospovidone, sodium starch glycolate, bentonite, sodium alginate, or the like. Lubricants may be, for example, talc, magnesium stearate, calcium stearate, or the like. Glidants may be, for example, colloidal silicone dioxide, talc or the like.
A typical pharmaceutical composition of the aliphatic amine polymer can be administered orally in the form of tablets, pills, capsules.
The pharmaceutical compositions of the present invention can be prepared by any of the conventionally employed tablet processing techniques such as dry granulation, wet granulation or direct compression process. A typical process comprises of the following steps:
1. Mixing of active agents along with diluents;
2. Lubricating the above blend with suitable lubricant; and
3. Compressing the blend of step 2 on suitable punches to get the tablet.
In the above process, active agents and excipients can be passed through the appropriate mesh size either independently or collectively. Mixing can be done by using the process known in the art such as by using blender or mixer. Punches used for compression could be used from those known in the art.
The formulation of the present invention may be optionally further coated with a seal coating agent that may or may not contain a colorant. Suitable seal coatings agent include cellulosic

materials such as naturally occurring cellulose and synthetic cellulose derivatives such as hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxy ethyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxymethyl cellulose (CMC), sodium CMC, cellulose triacetate, cellulose sulphate sodium salt, and the like; acrylic polymers and vinyl polymers, for example polymethyl methacrylate, poly ethyl methacrylate, poly butyl methacrylate, poly isobutyl methacrylate, poly hexyl methacrylate, poly phenyl methacrylate, poly methyl acrylate, poly isopropyl acrylate, poly isobutyl acrylate, poly octadecyl acrylate, poly ethylene, poly ethylene low density poly ethylene, high density poly propylene, poly ethylene glycol, poly ethylene oxide, poly ethylene terephthalate, polyvinyl alcohol, polyvinyl isobutyl ether, polyvinyl acetate, poly vinyl chloride, polyvinyl pyrrolidone, and the like; proteinaceous materials such as gelatin, polypeptides and natural and synthetic shellacs and waxes; and combinations of the forgoing.
The seal coating material can be an immediate release coating chosen to provide a coated tablet having substantially the same dissolution properties as the corresponding uncoated tablet. An exemplary seal coating material includes hydroxypropyl methyl cellulose.
Typically, the tablet core is contacted with the coating solution until the weight of the tablet core has increased by an amount ranging from about 4% to about 6%, indicating the deposition of a suitable coating on the tablet core to form a coated tablet. In one embodiment, the quantity of seal coating material should not be so high that the coating material impedes the release profile of the active agent when ingested or evaluated for dissolution profile.
Suitable methods can be used to apply the seal coating to the tablets. Processes such as simple or complex coacervation, interfacial polymerization, liquid drying, thermal and ionic gelation, spray drying, spray chilling, fluidized bed coating, pan coating, electrostatic deposition, may be used. A substantially continuous nature of the coating may be achieved, for example, by spray drying from a suspension or dispersion of the coating composition including a polymer in a solvent in a drying gas having a low dew point.
When a solvent is used to apply the coating, the solvent is preferably an organic solvent. The solvent may be selected from alcohols such as methanol, ethanol, halogenated hydrocarbons

such as dichloromethane, cyclohexane, and combinations comprising one or more of the foregoing solvents.
The principles, preferred embodiments, and modes of operation of the present invention have been described in the foregoing specification. The invention which is intended to be protected herein, however, is not to be construed limited to the particular forms disclosed, since these are to be regarded as illustrative rather than restrictive. Variations and changes may be made by those skilled in the art, without departing from the spirit of the invention.
The invention is further explained with the help of following illustrative examples, however, in no way these examples should be construed as limiting the scope of the invention.
EXAMPLES:
A. Sevelamer Carbonate:
Preparation of 800 mg Sevelamer Carbonate Direct Compression Tablet Cores
Example -1:

Sr.No Ingredients mg/tab
1 Sevelamer Carbonate® 856.00
2 Confectioner's Sugar . 175.50
3 Zinc Stearate 3.50
4 Colloidal Silicon dioxide 15.00
Weight of Core Tablet 1050
@ The given quantity is by considering a LOD of 7 %w/w Example -2:

Sr.No Ingredients mg/tab
1 S evelamer Carbonate® 856.00
2 Compressible Sugar 175.50
3 Zinc Stearate 3.50
4 Colloidal Silicon dioxide 15.00
Weight of Core Tablet 1050
® The given quantity is by considering a LOD of 7 %w/w

Example- 3:

Sr.No Ingredients mg/tab
1 Sevelamer Carbonate® 856.00
2 Trehalose 175.50
3 Zinc Stearate 3.50
4 Colloidal Silicon dioxide 15.00
Weight of Core Tablet 1050
@ The given quantity is by considering a LOD of 7 %w/w
All the mentioned ingredients were weight accurately. Confectioner's sugar or compressible sugar or trehalose and colloidal silicon dioxide were sifted through suitable screen in mechanical sifter. Sevelamer Carbonate was also sifted through suitable screen in mechanical sifter. Sevelamer carbonate was mixed with other excipients in a blender for a desired time period. The obtained material was lubricated with zinc stearate and the final blend was compressed to get tablets using defined tooling and desired tablet parameters.
B. Colesevelam Hydrochloride:
Preparation of 625 mg Colesevelam Hydrochloride Direct Compression Tablet Cores:
Example -1:

Sr.No Ingredients mg/tab
1 ColeSevelam Hydrochloride® 657.89
2 Trehalose 201.55
3 Zinc Stearate 2.89
4 Colloidal Silicon dioxide 12.5
Weight of Core Tablet 875
@ The given quantity is by considering a LOD of 5 %w/w

Example-2:

Sr.No Ingredients mg/tab
1 ColeSevelam Hydrochloride® 657.89
2 Compressible Sugar 201.55
3 Zinc Stearate 2.89
4 Colloidal Silicon.dioxide 12.5
Weight of Core Tablet 1000
@ The given quantity is by considering a LOD of 5 %w/w
All the mentioned ingredients were weighed accurately. Compressible sugar or trehalose and colloidal silicon dioxide were sifted through suitable screen in mechanical sifter. Colesevelam Hydrochloride was also sifted through suitable screen in mechanical sifter. Colesevelam Hydrochloride was mixed with other excipients in a blender for a desired time period. The obtained material was lubricated with zinc stearate and the final blend was compressed to get tablets using defined tooling and desired tablet parameters.
C. Sevelamer Hydrochloride:
Preparation of 800 mg Sevelamer Hydrochloride Direct Compression Tablet Cores:
Example-1:

Sr.No Ingredients mg/tab
1 Sevelamer Hydrochloride® 856.00
2 Trehalose 125.50
3 Zinc Stearate 3.50
4 Colloidal Silicon dioxide 15.00
Weight of Core Tablet 1000
@ The given quantity is by considering a LOD of 7 %w/w

Example-2;

Sr.No Ingredients mg/tab
1 Sevelamer Hydrochloride ® 856.00
2 Compressible Sugar 125.50
3 Zinc Stearate 3.50
4 Colloidal Silicon dioxide 15.00
Weight of Core Tablet 1000
@ The given quantity is by considering a LOD of 7 %w/w
All the mentioned ingredients were weighed accurately. Compressible sugar or trehalose and colloidal silicon dioxide were sifted through suitable screen in mechanical sifter. Sevelamer Hydrochloride was also sifted through suitable screen in mechanical sifter. Sevelamer Hydrochloride was mixed with other excipients in a blender for a desired time period. The obtained material was lubricated with zinc stearate and the final blend was compressed to get tablets using defined tooling and desired tablet parameters.
D. Characterization of Tablet Cores
The tablets prepared as described above were off-white, modified capsule shaped, compressed tablets. The variation of the tablets prepared from each blend with respect to weight, thickness, friability, hardness, disintegration time and density was assessed. Standard methods in the art were employed for each of the measurements. The results indicate that the hardness, friability, thickness, and disintegration behavior of the tablets all met industry-standard criteria.
E. Coating of Sevelamer Carbonate Tablet Cores
Compressed core tablets prepared as described in Example 1, 2 and 3 were coated in a coating pan with an aqueous coating solution having a solids composition comprising:

Sr.No
Ingredients %w/w
1 Hypromellose 3cps 35.0
2 Hydroxy Propyl Cellulose 30.0
3 Titanium Dioxide 20.0
4 Polyethylene Glycol 400 10.0
5 Hypromellose 50 cps 5.0

The coating solution was applied to the compressed cores until a weight gain of approximately 4 to 6% was achieved. Stability studies—controlled room temperature, accelerated conditions,—for the coated Sevelamer carbonate tablets were conducted in accordance with those procedures known in the art and described in the following references: International Committee on Harmonization (ICH) guidance "Q1A—Stability Testing of New Drug Substances and Products" (June 1997); and ICH guidance "QIC—Stability Testing for New Dosage Forms" (November 1996. The results (not shown) indicate that the coated tablets all met industry standard criteria.

WE CLAIM:
1. A solid pharmaceutical composition for oral administration comprising:
(a) an aliphatic amine polymer or its pharmaceutically acceptable salts;
(b) a diluent, selected from the group comprising non-reducing sugars or modified sugars or combinations thereof; and
(c) pharmaceutically acceptable excipients.

2. The solid pharmaceutical composition as claimed in claim 1, wherein the aliphatic amine polymer is sevelamer hydrochloride, sevelamer carbonate or colesevelam.
3. The solid pharmaceutical composition as claimed in claim 1, wherein the aliphatic amine polymer is sevelamer carbonate.
4. The solid pharmaceutical composition as claimed in claim 1, wherein the aliphatic amine polymer is present in an amount ranging from about 60% to 95% by weight of the tablet core.
5. The solid pharmaceutical composition as claimed in claim 1, wherein the non-reducing sugar is a non-reducing disaccharide.
6. The solid pharmaceutical composition as claimed in claim 5, wherein the non-reducing disaccharides is selected from the group comprising sucrose and trehalose.
7. The solid pharmaceutical composition as claimed in claim 1, wherein the modified sugar is selected from the group consisting of confectioner's sugar or compressible sugar.
8. The solid pharmaceutical composition as claimed in claim 1, wherein the diluent is present in an amount ranging from about 5% to 30% by weight of the tablet core.
9. The solid pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical acceptable excipients are selected from the group consisting of one or more binding agent, one or more disintegrant, one or more lubricant, one or more glidant, and mixtures thereof.

10. A process for preparing the pharmaceutical composition comprising the steps of:
(a) direct blending of aliphatic amine polymers with the diluents selected from the group comprising non-reducing sugars or modified sugars or combinations thereof; and other pharmaceutically acceptable excipients;
(b) lubricating the blend;
(c) compressing the blend into a tablet; and
(d) optionally coating the tablet.