FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"MULTILAYER PHARMACEUTICAL COMPOSITION"
2. APPLICANT:
(a) NAME: CIPLA LTD.
(b)NATIONALITY: Indian Company incorporated under the Companies Act, 1956
(c) ADDRESS: 289, Bellasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra, India.
3.PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the nature of invention and the manner in which it is to be performed.

Field of the Invention:
The present invention relates to a multilayer pharmaceutical composition comprising aliphatic amine polymers with one or more pharmaceutical excipients, its method of preparation and use of the said pharmaceutical composition for treatment or prophylaxis of a patient suffering from hyperphosphatemia or chronic kidney disease or related disorders.
Background and Prior art:
Aliphatic amine polymers are useful as active pharmaceutical ingredients for use in
pharmaceutical compositions. A particularly interesting aliphatic amine polymer is
sevelamer, a polymeric phosphate binder intended for oral administration. Sevelamer
hydrochloride is a poly(allylamine hydrochloride) crosslinked with epichlorohydrin in
which forty percent of the amines are apparently protonated. It is known chemically as
poly(allylamine-co-N,N'-diallyl-l,3-diamino-2-hydroxypropane) hydrochloride.
Sevelamer hydrochloride is hydrophiltc, but insoluble in water. The reported structure of Sevelamer HC1 is represented below:

a, b = number of primary amine groups a + b = 9
c = number of cross linking groups c = I
n = fraction of protonated amines n = 0.4
m = large number to indicate extended polymer network
Sevelamer HC1 is currently being marketed by Genzyme Corporation as Renagel®, in the form of 400mg and 800mg tablets, for the treatment of patients with Chronic Kidney Disease (CKD) which are on hemodialysis. The recommended starting dose of Sevelamer

is 800 to 1600mg. Renagel® is indicated for the control of serum phosphorus in such CKD patients. The commercially available Sevelamer tablets also contain the following inactive ingredients; hypromellose, diacetylated monoglyceride, colloidal silicon dioxide, and stearic acid.
Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.
U.S. Pat. No. 5,496,545 discloses a method of removing phosphate from a patient by ion exchange, which involves oral administration of a therapeutically effective amount of a composition containing at least one phosphate-binding polymer that is non-toxic and stable once ingested.
WO01/28527 discloses a tablet core which comprises at least about 95% by weight of an aliphatic amine polymer and a process of producing the tablet by hydrating the aliphatic amine polymer to the desired moisture level; blending the aliphatic amine polymer with the excipients in amounts such that the polymer comprises at least about 95% by weight of the resulting blend; and compressing the blend to form tablet core. Tablet is coated with a water based coating.
U.S. Publication 2002/0054903 discloses a tablet comprising a compressed tablet core comprising at least about 80% of sevelamer.
U.S. Patent No. 6,383,518 discloses a tablet comprising a phosphate binding polymer having an average particle size of 400 µm or less together with crystalline cellulose and low-substituted hydroxypropyl cellulose.
U.S. Patent No. 6,733,780 B1 and U.S. Patent Application 2005/0260236 Al discloses method of producing a direct compressible composition of a polymer tablet core.
WO2009034540 discloses a pharmaceutical composition for an oral administration comprising sevelamer or pharmaceutically acceptable salts thereof in an amount less than

80% by weight of composition wherein the composition is free of crystalline cellulose and low- substituted hydroxypropyl cellulose is presented herein.
EP1818048 Bl discloses pharmaceutical compositions comprising aliphatic amine polymers, such as for example Sevelamer HCI, as the active pharmaceutical ingredient and methods of preparing pharmaceutical compositions thereof such as for example Sevelamer HCI Film Coated Tablets employing wet granulation. The aliphatic amine polymers are wet granulated using ethanol/water solution containing about 82% to about 95% ethanol and about 5% to about 18% water.
U.S. Publication 2009/280178 discloses a process for preparation of sevelamer hydrochloride having phosphate binding capacity of 4.7 to 6.4 mmol/g. The patent application also suggest that the said composition if prepared using lactose and dextrose as diluents shows discoloration; as the tablets turn to yellowish brown colour due to Maillard reaction, hence the composition should be devoid of diluents such as reducing sugars which undergoes Maillard reaction.
EP0997148 discloses tablets which contain phosphate-binding polymers having an average particle size of 400 urn or less and 90% of particles are less than 500 urn together with crystalline cellulose and/or hydroxypropylcellulose with low degree substitution. Further, the patent discloses that a phosphate binding polymer when compressed alone results in a tablet having poor hardness.
It may well be acknowledged that Sevelamer, being hygroscopic in nature, requires sufficient amount of diluents (e.g. cellulose derivatives) to be present in intimate contact with this moisture sensitive drug to help maintain the stability of the drug product. Although, this problem can be overcome by use of suitable diluents like cellulose derivatives (e.g. microcrystalline cellulose), due consideration is required with the choice of other excipients to formulate a stable drug product (an example of Maillard reaction as discussed above).
The prior art discloses various formulations of Sevelamer by methods involving direct compression, or convention granulation techniques and utilizing conventional excipients.

However, there is not much disclosure about how to formulate a stable oral composition of aliphatic amine polymer (e.g. Sevelamer) using conventional excipients which may undergo Maillard reaction with the polymer. Maillard reaction is the reaction in which an amine compound turns brown by reacting with reductive sugars such as glucose [Maillard, L.C., Compt. Rend. Soc. Biol., 72:599 (1912); thereby degrading the drug product. Concurrently, such excipients are also essential in order to achieve the desired drug release from the formulation.
Thus, there exists a need to develop a pharmaceutical composition of aliphatic amine polymers (e.g. Sevelamer) comprising one or more conventional excipients which remain stable over the storage period.
Object of the Invention:
The object of the present invention is to provide a pharmaceutical composition of aliphatic amine polymer with conventional pharmaceutical excipients, which composition remains stable during the formulation and over the storage period.
Another object of the present invention is to provide a pharmaceutical composition of aliphatic amine polymer having desired drug release pattern.
Yet another object of the present invention is to provide a simple manufacturing process for manufacturing the said pharmaceutical composition comprising aliphatic amine polymer/s.
Summary of the Invention:
According to one aspect of the present invention, there is provided a multilayer pharmaceutical composition comprising at least one functional layer comprising at least one aliphatic amine polymer; and at least one non-functional layer comprising one or more pharmaceutical excipients.
According to another aspect of the present invention, there is provided a process of manufacturing a multilayer pharmaceutical composition comprising at least one

functional layer comprising at least one aliphatic amine polymer; and at least one nonfunctional layer comprising one or more pharmaceutical excipients.
According to yet another aspect of the present invention, there is provided a bilayer pharmaceutical composition comprising a functional layer comprising atleast one aliphatic amine polymer and a non-functional layer comprising one or more pharmaceutical excipients.
According to further aspect of the present invention, there is provided a process of manufacturing a bilayer pharmaceutical composition comprising a functional layer comprising atleast one aliphatic amine polymer and a non-functional layer comprising one or more pharmaceutical excipients.
According to another aspect of the present invention, there is provided a method of
improving the stability of the oral pharmaceutical compostion comprising aliphatic
amine polymer by formulating a multilayer pharmaceutical composition comprising at least one functional layer comprising at least one aliphatic amine polymer and at least one non-functional layer comprising one or more pharmaceutical excipients.
According to another aspect of the present invention, there is provided a method of preventing or treating a patient suffering from hyperphosphatemia or chronic kidney disease which comprise administering the said pharmaceutical composition of aliphatic amine polymer to the patients in need thereof.
Detailed description:
As discussed above, when aliphatic amine polymers (e.g. Sevelamer) are formulated with parmaceutical excipients (including cellulose derivatives which act as diluents and excipients) which are prone to undergo Maillard reaction with the amine drug; it results in discoloration of the drug product. Surprisingly, the present inventors have found that if such amine drug and excipients are formulated in separate layers, the formulation not only exhibits desired drug release pattern but also renders the composition stable over the storage period.

It was also found that, in spite of the diluents (e.g. cellulose) and the active being in intimate contact with each other, there was no active/ product degradation.
According to one embodiment of the present invention, the multilayer pharmaceutical composition may comprise at least one functional layer comprising at least one aliphatic amine polymer and at least one non-functional layer comprising one or more pharmaceutical excipients.
According to another embodiment of the present invention, the multilayer pharmaceutical composition may be a bilayer or trilayer composition or a core coated composition.
The bilayer pharmaceutical composition, according to the present invention may comprise a functional layer comprising at least one aliphatic amine polymer and a nonfunctional layer comprising one or more pharmaceutical excipients.
The core coated tablet, according to the present invention comprises (i) a compressed core comprising at least one aliphatic amine polymer acting as a functional layer and (ii) at least one coating around the core, the coat comprising one or more pharmaceutical excipients acting as non-functional layer.
Preferably, according to the present invention, the functional layer comprises Sevelamer and the non-functional layer comprises one or more pharmaceutical excipients comprising diluents, binders, disintegrants, glidants, lubricants, sweeteners, colorants, flavoring agents etc
The term "functional layer" used throughout the description means blend or granules comprising atleast one aliphatic amine polymer such as sevelamer and optionally one or more pharmaceutical excipients such as. but not limited to anti-adherents/ diluents, lubricants etc.
The term "non-functional layer" used throughout the description means blend or granules devoid of aliphatic amine polymer or other active agent and comprising at least one pharmaceutical excipient which is prone to cause Maillard reaction in presence of the

aliphatic amine polymer such as sevelamer. The said non-functional layer may also comprise other pharmaceutical excipients such as, but not limited to lubricants, diluents, disintegrants, anti-adherents.
The terms "aliphatic amine polymer" and "Sevelamer" are used throughout the description in broad sense to include not only the aliphatic amine polymer and sevelamer per se respectively but also their pharmaceutical!)' acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs. The preferable pharmaceutically acceptable salts of sevelamer include the hydrochloride and carbonate.
The phosphate binding capacity of an aliphatic amine polymer is an indicator of therapeutic effectiveness of the phosphate binding polymer. According to present invention, the aliphatic amine polymer in the said composition has a phosphate binding capacity ranging from 5.5 - 6.5 mmols/ gm.
In a further embodiment, the multilayer composition according to the present invention comprises aliphatic amine polymer (e.g. Sevelamer) having average particle size of not more than 400 µM, preferably not more than 250 urn.
In a further embodiment, the multilayer composition according to the present invention comprises aliphatic amine polymer (e.g. Sevelamer) ranging from 55 to 80% w/w of the composition.
According to the present invention, pharmaceutical excipients which are prone to cause Maillard reaction in presence of aliphatic amine polymers may comprise lactose, glucose, maltose, fructose, dextrose, starch and its derivatives; excipients which may contain reducing sugar in the form of impurity such as cellulose and its derivatives such as methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, microcrystalline cellulose, starch and its derivatives such as pregelatinised starch.

The multilayer pharmaceutical composition, according to the present invention may comprise one or more pharmaceutical excipients that may be present in either of the layer(s) such as, but are not limited to: fillers or diluents, surfactants, disintegrants, binders, lubricants, glidants, sweeteners, colorants, flavoring agents.
Suitable diluents that may be employed according to the present invention may comprise saccharides, including monosaccharides, disaccharides, polysaccharides and sugar alcohols such as arabinose, lactose, dextrose, sucrose, fructose, maltose, mannitol, erythritol, sorbitol, xylitol lactitol, The formulation may incorporate one or more bulking agents such as powdered cellulose, purified sugar and derivatives thereof. Diluents may be used in the range of about 5% to about 50% by weight of total composition.
Suitable disintegrating agents that may be employed according to the present invention may comprise croscarmellose sodium, crospovidone, sodium starch glycollate, corn starch, potato starch, maize starch, pregelatinised starch and modified starches, calcium silicates, low substituted hydroxy- propylcellulose. Disintegrating agents may be used in the range of about 0.5% to about 10% by weight of total composition.
Suitable binders that may be employed according to the present invention may comprise copovidone, celluloses such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, starches and other pharmaceutically acceptable substances with cohesive properties. Binders may be used in the range of about 3.0% to about 15.0% by weight of total composition.
Suitable surface active agents that may be employed according to the present invention may comprise anionic surfactants, non-ionic surfactants, cationic surfactants, and amphoteric surfactants.
Suitable nonionic surfactants may comprise sorbitan fatty acid esters, glycerol fatty acid esters, glycerol, decaglycerin fatty acid esters, polyglycerin fatty acid esters, propylene glycol fatty acid esters, pentaerythritol fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene sorbitol fatty acid esters, polyoxyethylene glycerin fatty acid esters, polyethylene glycol fatty acid esters, sucrose fatty acid esters, polyoxyethylene

alkyl ethers, polyoxyethylene phytosterols, polyoxyethylene phytostanols, polyoxyethylene polyoxypropylene glycol, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene lanolin, polyoxyethylene lanolin alcohol, beeswax derivatives, polyoxyethylene alkylamines and polyoxyethylene fatty acid amides or mixtures thereof.
Suitable anionic surfactants may comprise alkyl sulfates, polyoxyethylene alkyl ether sulfates, N-acylamino acid or salts thereof, and polyoxyethylene alkyl ether phosphates or mixtures thereof.
Suitable cationic surfactants may comprise alkyl ammonium salts and alkylbenzyl ammonium salts or mixtures thereof.
Suitable amphoteric surfactants may comprise betaine acetate and lecithin or mixtures thereof.
Suitable lubricants and/or glidants that may be employed according to the present invention may comprise stearic acid and its derivatives or esters like sodium stearate, magnesium stearate and calcium stearate and the corresponding esters such as sodium stearate fumarate; talc and silicon dioxide respectively. Lubricants and/or glidants may be used in the range of about 0.1% to about 5.0% by weight of total composition.
According to a further embodiment of the present invention, there is provided a process of manufacturing the multilayer pharmaceutical composition, which process comprises:
(1) blending the aliphatic amine polymer optionally with one or more pharmaceutical excipients to form the drug blend;
(2) blending one or more pharmaceutical excipients to form excipient blend;
(3) compressing the above blends to form multilayer tablet.
According to another embodiment of the present invention, there is further provided a process of manufacturing the multilayer pharmaceutical composition, wherein the drug blend of step (I) is compressed to form the functional layer which is then compressed with the excipient blend to form multilayer tablet.

The present invention may be manufactured through various techniques or processes known in the art which includes, but are not limited to direct compression, dry/wet granulation, melt granulation (e.g. hot melt granulation), melt extrusion, spray drying and solvent/ solution evaporation.
It will be well acknowledged to the person skilled in the art that Sevelamer hydrochloride is very hygroscopic and swell upon contact with water and such swelling of the aliphatic amine complicates formulating the active pharmaceutical ingredient in a pharmaceutical composition. Thus, although compressibility is apparently dependant on the degree of hydration, simply adding water to sevelamer results in a swollen material which swollen material is impossible to use to press into tablets. Thus, dry granulation or direct compression may be employed as the granulation technique for aliphatic amine polymer layer (the drug layer). Alternatively, wet granulation of the drug layer may also be carried out by using hydroalcoholic solution containing about 80% to about 95% ethanol and about 5% to about 20% water.
As part of exemplification, there is provided a process of manufacturing a multilayer pharmaceutical composition which process comprises,
a) at least one functional layer comprising aliphatic amine polymers (e.g. Sevelamer) optionally wet granulated with one or more pharmaceutical excipients,
b) at least one non-functional layer devoid of aliphatic amine polymer and comprising one or more pharmaceutical excipient;
wherein the said functional layer is granulated with a hydroalcoholic solution (e.g. ethanol/water solution) wherein the said hydroalcoholic solution incorporates about 80% to about 95% alcohol (95%) and about 5% to about 20% water.
The moisture content of the aliphatic amine polymer, excipient and/ or composition may be controlled in the range of 0.5 to 15%, preferably between 1 to 10% to achieve the multilayer composition of desired stability.
According to the present invention, the functional layer comprising Sevelamer may be processed through dry/ wet granulation, melt granulation, direct compression, melt

extrusion and the like and the non-functional layer comprising pharmaceutical excipient may be processed through dry/ wet/ melt granulation, melt extrusion and the like.
According to alternative embodiment, the said pharmaceutical composition may be seal coated and finally film coated.
The seal coating material may comprise polyvinylacetate, polyvinyl alcohol-polyethylene glycol copolymer, acrylate polymers such as ethyl acrylate and methyl acrylate or its copolymer, HPMC 6 CPS, or HPMC 6 CPS to HPMC 15CPS grade. The HPMC component of the seal coating may be mixed with solvents such as methylene chloride and isopropyl alcohol or mixtures thereof. The seal coating may also comprise talc. Preferably the seal coating ingredient is polyvinyl alcohol-polyethylene glycol copolymer which provides a moisture resistant coating to the bilayer composition of the present invention.
The formulation may be coated with Ready colour mix systems (such as Opadry colour mix systems).
According to the present invention there is provided a bilayer pharmaceutical composition for treating a patient suffering from hyperphosphatemia and chronic kidney disease comprising administering a therapeutically effective amount of Sevelamer in the said composition. Patients suffering from chronic kidney disease (CK.D) are frequently treated with hemodialysis. In such patients, which are treated with hemodialysis, it is important to control the phosphorus content in their serum. Sevelamer binds phosphorus and is therefore used as a phosphorus scavenger in the blood stream of patients to control serum phosphorus content.
Preferably, the treatment of a patient undergoing hemodialysis comprises administering a therapeutically effective amount of Sevelamer according to the present invention to control the serum phosphorus content in such patient.
The following example is for the purpose of illustration of the invention only and is not intended in any way to limit the scope of the present invention.

Examples:
Formula for Sevelamer Bilayer tablet: (A) Layer 1: Sevelamer Hydrochloride

Sr. No. Ingredients Qty/Unit Qty/ Batch
1 Sevelamer hydrochloride 856.00 85.60
2 Colloidal anhydrous silica 8.00 0.80
3 Stearic acid 4.00 0.40
Total 868.00 86.80
(B) Layer 2: Placebo layer

Sr. No. Ingredients Qty/ Unit Qty/ Batch
1 Microcrystalline cellulose 312.00 31.20
2 Pregelatinised starch 8.00 0.80
3 Stearic acid 2.00 0.20
Total 322.00 32.20
Film coating solution:

Sr. No, Ingredients Qty/ Unit Qty/ Batch
1 Kollicoat protect 40.00 4.00
2 Purified talc 5.00 0.50
3 Isopropyl alcohol q. s. q. s.
4 Purified water q. s. q. s.
Manufacturing Process:
(1) Sevelamer hydrochloride, colloidal anhydrous silica and part quantity of stearic acid were blended to obtain sevelamer blend.

(2) Microcrystalline cellulose and pregelatinised starch were mixed with remaining
quantity of stearic acid to obtain excipient blend.
(3) Finally both the blends were directly compressed together to form bilayer tablets.
It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by the preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and such modifications and variations are considered to be falling within the scope of the invention.
It is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of "including," "comprising," or "having" and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.
It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a polymer" includes a single polymer as well as two or more different polymers; reference to a "plasticizer" refers to a single plasticizer or to combinations of two or more plasticizer, and the like.

We claim,
1. A multilayer pharmaceutical composition comprising:
(a) at least one functional layer comprising at least one aliphatic amine polymer, and
(b) at least one non-functional layer comprising one or more pharmaceutical excipients.

2. A multilayer pharmaceutical composition according to claim 1, wherein the aliphatic amine polymer is Sevelamer or pharmaceutically acceptable salts, solvates, hydrates, enantiomers, derivatives, polymorphs or prodrugs thereof.
3. A multilayer pharmaceutical composition according to any preceding claim, wherein the moisture content of the aliphatic amine polymer and/ or composition is from 0.5 to
15%.
4. A multilayer pharmaceutical composition according to claim 1, wherein at least one non-functional layer comprises at least one pharmaceutical excipient which is prone to cause Maillard reaction in presence of amine compounds.
5. A multilayer pharmaceutical composition according to any preceding claim, wherein the multilayer pharmaceutical composition is a bilayer or trilayer composition or a core coated composition.
6. A bilayer pharmaceutical composition comprising:

(a) a functional layer comprising Sevelamer or its pharmaceutically acceptable salt, and
(b) a non-functional layer comprising one or more pharmaceutical excipients which are prone to undergo Maillard reaction in presence of amine compounds.

7. A bilayer pharmaceutical composition according to claim 6, wnerem the moisture content of the aliphatic amine polymer and/ or composition is from 0.5 to 15%.
8. A process of manufacturing the multilayer pharmaceutical composition which process comprises:
(a) blending the aliphatic amine polymer optionally with one or more pharmaceutical excipients to form the drug blend in one or more layer;

(b) blending one or more pharmaceutical excipients to form the excipient blend in one or more layer;
(c) compressing the above blends together to form multilayer tablet.

9. A process of manufacturing the multilayer pharmaceutical composition according to claim 8, wherein the drug blend of step (a) is compressed to form the functional layer which is then compressed with the excipient blend to form multilayer tablet.
10. A process of manufacturing the multilayer pharmaceutical composition which process comprises:

(a) granulating the aliphatic amine polymer with one or more pharmaceutical excipients to form one or more functional layer;
(b) blending one or more pharmaceutical excipients to form one or more nonfunctional layer;
(c) compressing the above layers to form multilayer tablet.
11. A process of manufacturing the multilayer pharmaceutical composition according to claim 10, wherein the functional layer is granulated with hydroalcoholic solution comprising about 80% to about 95% alcohol (95%) and about 5% to about 20% water.
12. A bilayer pharmaceutical composition substantially herein described with reference to the accompanying examples.