Title of Invention

PROCESS FOR PREPARATION OF SEVELAMER CARBONATE

Abstract The present invention provides process for preparation of amine polymer or salts thereof used as an antihyperphosphatemic agent.
Full Text 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
"Process for preparation of Sevelamer Carbonate"

(a) NAME: USV LIMITED
(b) NATIONALITY: Indian Company incorporated under the
Companies ACT 1956
(c) 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 Poly (allylamine-co-N,N'-diallyl-l,3-diamino-2-hydroxypropane) carbonate salt (Sevelamer carbonate) of Formula-I, an antihyperphosphatemic agent.

a, b = number of primary amine groups a + b = 9
c = number of crosslinking groups c = 1
m = large number to indicate extended polymer network
Background of the invention:
Sevelamer carbonate is non-absorbable polymer marketed as Renvela™ by Genzyme Corporation. It is known chemically as poly(allylamine-cj)-N,N'-diallyl-l,3-diamino-2-hydroxypropane) carbonate salt. It was developed as a pharmaceutical alternative to Sevelamer hydrochloride (Renagel®). Renvela™ contains Sevelamer carbonate, a non-absorbed phosphate binding crosslinked polymer, free of metal and calcium. It contains multiple amines separated by one carbon from the polymer backbone. These amines exist in a protonated form in the intestine and interact with phosphate molecules through ionic and hydrogen bonding. By binding phosphate -in the dietary tract and decreasing

absorption, Sevelamer carbonate lowers the phosphate concentration in the serum. Sevelamer carbonate is an anion exchange resin with the same polymeric structure as Sevelamer hydrochloride in which carbonate replaces chloride as the counterion. While the counterions differ for the two salts, the polymer itself, the active moiety, is the same. The protonated amines can be indirectly measured as carbonate content in meq/gm. Renvela™ is used in End Stage Renal Disease (ESRD) which leads to hyperphosphatemia due to retention of phosphorous. This condition can lead to ectopic calcification. Renvela™ binds dietory phosphate in GI tract and thus controls the serum phosphate levels. The potency of Renvela™ is measured in terms of its Phosphate Binding Capacity (PBC) by Phosphate Assay (PA). Treatment of hyperphosphatemia includes reduction in dietary intake of phosphate, inhibition of intestinal phosphate absorption with phosphate binders, and removal of phosphate with dialysis. Sevelamer carbonate taken with meals has been shown to control serum phosphorus concentrations in patients with CKD who are on dialysis. Currently Sevelamer hydrochloride is used to cure hyperphosphatemia. As a consequence ESRD patients still need a high dosage of Renagel® to meet clinical end-points, leading to adverse effect such as gastrointestinal discomfort and problems with patient compliance. But systemic acidosis development or worsening of pre-existing acidosis has been reported in many patients on long term dialysis who are given Sevelamer hydrochloride (Perit Dial Int. 2002, 22, 737-738, Nephron 2002, 92, 499-500, Kidney Int. 2004, 66, S39-S45, Ren. Fail 2005, 27,143-147).
Administration of Sevelamer hydrochloride adds to metabolic acid load because the resin remove some bicarbonate or bicarbonate precursor (mainly short chain fatty acid ) from the body and replaces with chloride. Each molecule of chloride contributed to the body in equivalent to a molecule of hydrochloric acid added to the body, so the tendency of patients on long term haemodialysis to acidosis is inevitably increased when they take Sevelamer hydrochloride (Kidney Int., 2005;67: 776-777)
This problem can be countered by an increase in the dialysate concentration of bicarbonate used in each dialysis session. But a more fundamental solution, suitable for both dialyzed and no-dialyzed patients, would be the administration of Sevelamer free base, or any other suitable resin, not as the chloride but as body suitable counterion such


as bicarbonate. Anion exchange resins have traditionally been synthesized in the chloride form, but the chloride in the current Sevelamer preparation is of no benefit to patients with renal failure. A change in the formulation of Sevelamer from its current chloride form to Sevelamer attached to bicarbonate would convert an acid load into a mild alkali load. (Cli. Sci. 1963; 24:187-200)
US 6858203 relates to phosphate-binding polymers provided for removing phosphate from the gastrointestinal tract. These polymers are useful for the treatment of hyperphosphatemia.
WO 2006/050315 describes pharmaceutical compositions comprising a carbonate salt of an aliphatic amine polymer wherein the monovalent anion can prevent or ameliorate acidosis, in particular acidosis in patients with renal disease.
HPLC Ion Chromatography PA method is used for the determination of PBC of Sevelamer HC1 which can be adopted for determining the carbonate content from Sevelamer carbonate (J R Mazzeo et al, J. Pharm. Biomed. Anal. 19 (1999) 911-915)
Our co-pending application number 1402/MUM/2006 dated 1 September 2006 discloses process for preparation of Sevelamer HC1 having phosphate binding capacity in the range of about 5.0 meq/gm to about 6.0 meq/gm and chloride content in the range of about 4.5 to about 5.5 meq/gm.
Although prior art mentioned above discussed advantages of Sevelamer carbonate over Sevelamer hydrochloride, however there is no process disclosed in the prior art for the preparation of Sevelamer carbonate. Thus there remains need for commercially viable and industrially useful process for the preparation of Sevelamer carbonate having consistency in phosphate binding capacity, degree of cross linking and carbonate content.
Object of Invention:
An object of the present invention process is to provide process for preparation of Sevelamer carbonate.


Another object of present invention is to provide simple process for preparation of Sevelamer carbonate having consistency in carbonate content and phosphate binding capacity.
Summary of Invention:
According to one aspect of the invention Sevelamer carbonate is prepared from Sevelamer hydrochloride which comprises the steps of;
a) treating Sevelamer hydrochloride with base to obtain Sevelamer base and
b) combining obtained Sevelamer base with suitable carbonate source to get Sevelamer carbonate.


According to second aspect of the present invention process for preparation of Sevelamer carbonate comprises;
a) treating polyallylamine hydrochloride with base to obtain polyallylamine base;
b) combining polyallylamine base with suitable carbonate source to get polyallylamine carbonate and
c) crosslinking the obtained polyallylamine carbonate with crosslinking agent to get Sevelamer carbonate.


According to third aspect of the present invention process for preparation of Sevelamer carbonate comprises
a) treating allylamine free base with a suitable carbonate source to get allylamine carbonate ;
b) converting the obtained allylamine carbonate into polyallylamine carbonate and
c) crosslinking obtained polyallylamine carbonate with crosslinking agent to get Sevelamer carbonate.

Detailed description of the invention:
The present invention provides process for the preparation of Sevelamer carbonate. According to one embodiment Sevelamer carbonate is prepared by reacting Sevelamer base with with a suitable carbonate source.
Sevelamer base used is prepared by neutralizing Sevelamer hydrochloride in presence of base. The base used is sodium hydroxide which can be used in solid or in solution form. Any remaining excess base and unwanted salt formed during process can be removed by

repeated washing of final insoluble polymer with sufficient quantity of water under vigorous stirring.
Preferably, Sevelamer base is suspended in purified water at atmospheric pressure and combined with suitable carbonate source followed by vigorous stirring to get fine dispersion of aqueous phase during the reaction. The obtained carbonate polymer cake is washed with water to remove inorganic salts and the wet cake is dried on rotary evaporator or in Fluidised Bed Dryer at an elevated temperature preferably at 60-90° C. The carbonate source used is selected from carbon dioxide gas, carbonic acid prepared in situ by dissolving carbon dioxide gas in water, by using dry ice for gas generation and alkali metal or alkaline earth metal salts such as sodium carbonate, potassium carbonate, calcium carbonate, sodium bicarbonate and the like. The reaction is represented by the following reaction scheme 1:


According to another embodiment of the invention process to manufacture Sevelamer carbonate comprises treating the polyallylamine hydrochloride with base in presence of suitable solvent. The inorganic salts formed during the synthesis of polyallylamine base is separated by filtration. Solvent is distilled out from the filtrate and the sticky polymeric mass is dissolved in water and carbon dioxide gas is purged under pressure or at atmospheric pressure to get polyallylamine carbonate. The aqueous solution of polyallylamine carbonate is poured into suitable solvent to get the solid. The separated solid is filtered and the wet cake is dried at an elevated temperature. The polyallylamine carbonate is crosslinked by partially neutralizing with base either solid or as aqueous solution in suitable solvent in presence of dispersing agent like sorbitane trioleate (SPAN-85). The carbonate polymer cake is washed with water to remove inorganic salts and the wet cake is dried on rotary evaporator or in Fluidised Bed Dryer at an elevated temperature preferably at 60-90°C. The reaction is represented by the following reaction scheme 2:


In another embodiment of the present invention process for preparation of Sevelamer carbonate comprises converting allylamine to its carbonate salt by treating into an aqueous solution of allylamine with suitable carbonate source.
The aqueous solution of allylamine carbonate is subjected to polymerization in presence of suitable polymerizing agent under inert atmosphere. The aqueous solution of polyallylamine carbonate is added to a suitable solvent to get the solid which is filtered. The polyallylamine carbonate is partially neutralized with base and suspended in suitable solvent in presence of dispersing agent. The suspension is heated to elevated temperature of about 40°C to about 150°C, preferably 55 to 60°C followed by treatment with crosslinking agent maintaining elevated temperature till cross linking is complete. The reaction mixture is cooled at 25° to 35°C and filtered. The polymer gel is added in organic solvent and filtered. The carbonate polymer cake is washed with water to remove inorganic salts and drying the wet cake on rotary evaporator or in Fluidised Bed Dryer at an elevated temperature preferably at 50-95° C to remove any moisture present.
The base is used in an amount of 65 to 70 mole % by weight of polyallylamine carbonate.
The dispersing agent used is selected from trioleate surfactants, preferably sorbitane trioleate ( SPAN-85). Suitable solvent used can be selected from aliphatic or aromatic hydrocarbon. Aromatic hydrocarbon is selected from benzene, toluene, xylene, chlorobenzene, nitrobenzene and the like or the mixtures thereof.
The crosslinking agent is used in the range of about 5 % to about 12 % by weight of Polyallylamine carbonate.
The organic solvent used in crosslinking is selected from acetone, methanol, ethanol, isopropanol, butanol or mixtures thereof.
The reaction is represented by the following reaction scheme 3:



Example 1
10 gm Sevelamer base was suspended in 200 ml water and stirred. Carbon dioxide gas was purged at 25-35°C for 8 hrs using dry ice. The obtained material was filtered and washed with 100 ml water [3x100] and the wet cake was dried on rotavapor at 90-95° C till constant weight of dried polymer was obtained. Off white colored Sevelamer carbonate (11.5 gm) was obtained which can be sieved through 30 mesh for uniformity of

the sample.
Degree of crosslinking - 16.4 %
Yield-115 % w/w
Solid state 13C NMR shows prominent peak at 164 ppm which is for carbon of carbonate.
Example 2
10 gm Sevelamer base was added to 200 ml water and reacted with carbon dioxide gas under pressure at 25-35° C for 7- 8 hrs with stirring. The obtained material was filtered and washed with 100 ml water thrice [3x100]. The wet cake thus obtained was dried on rotavapor at 90-95° C till constant weight of dried polymer was obtained. Off white colored Sevelamer carbonate (11.3 gm) was obtained which can be sieved through 30 mesh for uniformity of the sample. Degree of crosslinking - 16.4 % Yield - 113% w/w Solid state 13C NMR shows prominent peak at 164 ppm which is for carbon of carbonate.
Example 3
Sevelamer base (7 gm) was added to 150 ml water and reacted with carbon dioxide gas under pressure at 60-65° C for 7- 8 hrs with stirring. The material obtained was filtered and washed with 100 ml purified water thrice [3x100]. The wet cake thus obtained was dried on rotavapor at 90-95° C till constant weight of dried polymer was obtained. Off white colored Sevelamer carbonate (9.3 gm) was obtained which can be sieved through 30 mesh for uniformity of the sample. Degree of crosslinking - 16.4 % Yield- 120 % w/w Solid state l3C NMR shows prominent peak at 164 ppm which is for carbon of carbonate.
Example 4
Sodium hydroxide pellets (41 gm) were dissolved in 600 ml methanol at 25-35° C and polyallylamine hydrochloride (100 gm) was added to it followed by stirring for 5-6 hrs at temperature 25-35° C. Reaction mass was filtered through hyflobed and filtrate was

concentrated to reduce to half volume and the separated inorganic salt was filtered off over hyflobed. Filtrate was concentrated completely under vacuum. Sticky mass (61 gm) was obtained. Yield -61 %w/w
Example 5
Polyallylamine base (27.5 gm) dissolved in 100 ml water was charged into 1 L SS 316 autoclave and reacted with carbon dioxide gas under pressure (5.0 Kg/cm2). Initially 2-3 Kg/cm2 gas was consumed by the reaction mass and exotherm was observed from 28 C to 35° C. Then 5 Kg/cm2 pressure was maintained for 5-6 hours. After completion of the reaction the reaction mass was slowly added to 700 methanol and stirred for 3-4 hours. The separated solid (31 gm) was filtered, washed with 50 ml methanol and dried at 40-50° C in vacuum oven.
Yield -112 %w/w
Example 6
Polyallylamine carbonate (20 gm) was dissolved in 30 ml water and cooled at 5-15° C under stirring. The aqueous sodium hydroxide solution [dissolving 4.23 gm sodium hydroxide pellets into 4.2 ml of water] was added to reaction mass dropwise at 10-15° C with continued stirring for 30 minutes. 101 ml toluene and 0.6 ml SPAN-85 was added to it and heated at 55-60° C. Epichlorohydrin (1.06 gm) was added to the reaction mass followed by stirring and heating for 3hrs. The reaction mass was cooled at 25-35° C and filtered through Buchner funnel. The obtained wet cake was added to 1L acetone followed by stirring for 1 hour to get solid which was filtered through Buchner funnel. The aqueous organic washings were repeated for 7-10 times till polymer is free from excess alkalinity and the obtained wet cake (9 gm) was dried at 40-50° C on rotavapor and then at 90-95° C till constant weight of polymer is obtained.
Yield - 45 % w/w
Solid state 13C NMR shows prominent peak at 164 ppm which is for carbon of carbonate.


Example 7
Polyallylamine carbonate (20 gm) is dissolved in 30 ml water and cooled at 5-15° C under stirring. The aqueous sodium hydroxide solution [dissolving 4.23 gm sodium hydroxide pellets into 4.2 ml of purified water] is added to reaction mass dropwise at 10-15° C with continued stirring for 30 minutes. 150 ml water and 0.6 ml SPAN-85 is added to it and heated at 60-80° C. Epichlorohydrin (1.06 gm) is added followed by stirring and heating is continued for 3 hours. The reaction mass is cooled at 25-35° C and filtered through Buchner funnel. The obtained wet cake is added to 1 L acetone followed by stirring for 1 hour to get solid which is filtered through Buchner funnel. This aqueous organic washings were repeated for 7-10 times till the polymer is free from excess alkalinity and the obtained wet cake (9 gm) was dried at 40-50° C on rotavapor and/or Fluidised bed dryer then at 90-95° C till constant weight of polymer is obtained.
Example 8
Polyallylamine carbonate (20 gm) is dissolved in 30 ml water and cooled at 5-15° C under stirring. The aqueous sodium hydroxide solution [dissolving 4.23 gm sodium hydroxide pellets into 4.2 ml of purified water] is added to reaction mass dropwise at 10-15° C with continued stirring for 30 minutes. 150 ml water and 0.6 ml SPAN-85 is added to it and heated at 60-80° C. Epichlorohydrin (1.06 gm) is added . Stirring and heating is continued for 3 hours. The reaction mass is cooled at 25-35° C and filtered through Buchner funnel. The obtained wet cake is repeatedly washed with purified water to remove alkalinity completely. Then it is either filtered or water is evaporated completely to get the desired product.
Example 9
In 1L SS 316 autoclave, 75 gm allylamine and 200 ml water was charged reacted with carbon dioxide gas under pressure (5 Kg/cm2) and maintained for 3- 4 hours followed by stirring. Nitrogen gas was purged for 15 minutes. 9.8 gm VA-086 was added to the


reaction mass and stirred at 70-80°C for 12 hours. This solution was added to 1L methanol under stirring. Separated material (90 gm) was filtered and washed with 100 ml methanol, suck dried and dried in vacuum oven at 50-60°C. 90 gm of polyallylamine carbonate was obtained.
Yield -120 % w/w
Example 10
Polyallylamine carbonate (20 gm) dissolved in 30 ml water was cooled at 5-15° C under stirring and sodium hydroxide solution [dissolving 4.23 gm sodium hydroxide pellets into 4.2 ml of purified water] was added to reaction mass dropwise at 10-15° C followed by continued stirring for 30 minutes. 101 ml toluene and 0.6 ml SPAN-85 was added to it and heated at 55-60° C. Epichlorohydrin (1.06 gm) was added and reaction mass was stirred and heated for 3 hours. Then it was cooled to 25-35° C and filtered through Buchner funnel. Wet cake was added to 1 to 1.5 L acetone followed by stirring for 1 hour to get solid which was filtered through Buchner funnel. The washings were repeated for 7-10 times till polymer is free from excess alkalinity. Wet cake (9 gm) was dried at 40-50° C on rotavapor and then at 90-95° C till constant weight of polymer is obtained.
Yield-45 % w/w
Example 11
Sevelamer hydrochloride (10 gm) was added to 200 ml water and 10 % aqueous sodium bicarbonate solution was added to it at 25-35° C for 7- 8 hrs with stirring. The material obtained was filtered and washed with 100 ml purified water thrice and the wet cake was dried on rotavapor at 90-95° C till constant weight of dried polymer is obtained. Off white colored Sevelamer carbonate (7.5 gm) was obtained which can be sieved through 30 mesh for uniformity of the sample.
Yield - 75 % w/w
Solid state 13C NMR shows prominent peak at 164'ppm which is for carbon of carbonate.


The above description is not intended to detail all modifications and variations of the invention. It will be appreciated by those skilled in the art that changes can be made to the embodiments described above without departing from the inventive concept. It is understood, therefore, that the invention is not limited to the particular embodiments described above, but is intended to cover modifications that are within the spirit and scope of the invention, as defined by the language of the following claims.




Documents:

00826-MUM-2008-FORM 3(26-11-2009).pdf

826-MUM-2008-ABSTRACT(6-4-2009).pdf

826-MUM-2008-AUSTRALIAN DOCUMENT(13-7-2012).pdf

826-MUM-2008-CLAIMS(6-4-2009).pdf

826-MUM-2008-CLAIMS(AMENDED)-(19-2-2014).pdf

826-MUM-2008-CLAIMS(AMENDED)-(5-2-2013).pdf

826-MUM-2008-CLAIMS(MARKED COPY)-(19-2-2014).pdf

826-MUM-2008-CLAIMS(MARKED COPYD)-(5-2-2013).pdf

826-MUM-2008-CORRESPONDENCE(14-2-2011).pdf

826-MUM-2008-CORRESPONDENCE(20-11-2009).pdf

826-MUM-2008-CORRESPONDENCE(20-12-2012).pdf

826-MUM-2008-CORRESPONDENCE(26-11-2009).pdf

826-MUM-2008-CORRESPONDENCE(6-4-2009).pdf

826-MUM-2008-CORRESPONDENCE(7-2-2014).pdf

826-MUM-2008-CORRESPONDENCE(7-5-2010).pdf

826-mum-2008-correspondence-received.pdf

826-mum-2008-description (provisional).pdf

826-MUM-2008-DESCRIPTION(COMPLETE)-(6-4-2009).pdf

826-mum-2008-diagram.doc

826-MUM-2008-DRAWING(6-4-2009).pdf

826-MUM-2008-EP DOCUMENT(13-7-2012).pdf

826-MUM-2008-FORM 18(26-11-2009).pdf

826-mum-2008-form 2(6-4-2009).pdf

826-MUM-2008-FORM 2(TITLE PAGE)-(6-4-2009).pdf

826-MUM-2008-FORM 2(TITLE PAGE)-(PROVISIONAL)-(8-4-2008).pdf

826-MUM-2008-FORM 3(13-7-2012).pdf

826-MUM-2008-FORM 3(14-2-2011).pdf

826-MUM-2008-FORM 3(20-12-2012).pdf

826-MUM-2008-FORM 3(26-11-2009).pdf

826-MUM-2008-FORM 3(7-2-2014).pdf

826-MUM-2008-FORM 3(7-5-2010).pdf

826-MUM-2008-FORM 3(8-4-2008).pdf

826-MUM-2008-FORM 5(6-4-2009).pdf

826-MUM-2008-FORM PCT-ISA-206(26-11-2009).pdf

826-MUM-2008-FORM PCT-ISA-237(13-7-2012).pdf

826-MUM-2008-FORM PCT-ISA-373(13-7-2012).pdf

826-mum-2008-form-1.pdf

826-mum-2008-form-2.doc

826-mum-2008-form-2.pdf

826-mum-2008-form-3.pdf

826-MUM-2008-OTHER DOCUMENT(7-2-2014).pdf

826-MUM-2008-PETITION UNDER RULE 137(5-2-2013).pdf

826-MUM-2008-REPLY TO EXAMINATION REPORT(13-7-2012).pdf

826-MUM-2008-REPLY TO EXAMINATION REPORT(5-2-2013).pdf

826-MUM-2008-REPLY TO HEARING(19-2-2014).pdf

826-MUM-2008-US DOCUMENT(13-7-2012).pdf

826-MUM-2008-US DOCUMENT(20-12-2012).pdf


Patent Number 259632
Indian Patent Application Number 826/MUM/2008
PG Journal Number 13/2014
Publication Date 28-Mar-2014
Grant Date 20-Mar-2014
Date of Filing 08-Apr-2008
Name of Patentee USV LIMITED
Applicant Address B.S.D. MARG, STATION ROAD, GOVANDI, MUMBAI
Inventors:
# Inventor's Name Inventor's Address
1 SATHE DHANANJAY GOVIND 202/A-1, GOLDEN PARK, L.B.S. MARG, PANCHPAKHADI, THANE 400602
2 MONDKAR HARISH KASHINATH 5/22, SAMANT BLOCKS, CAMA ROAD, ANDHERI (W), MUMBAI 400058
3 JADHAV TANAJI SHAMRAO SUNDARAM APARTMENT PLOT NO. 160-161, FLAT NO. A-101, SECTOR-6, NERUL NAVI MUMBAI 400706
4 PATIL SAMADHAN DAULAT C-49, NILESHWARI PALACE, DEVI CHOWK, SHASTRI NAGAR, DOMBIVLI (W), 421202
PCT International Classification Number C08F8/44; A61K47/00; C08F8/40
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA