Indian Patents. 251100:A NOVEL FORMULATION OF SEVELAMER HYDROCHLORIDE

Title of Invention	A NOVEL FORMULATION OF SEVELAMER HYDROCHLORIDE
Abstract	Disclosed herein is an improved process for preparation of Sevelamer hydrochloride having phosphate binding capacity of 4.7 to 6.4mmol/g. further, the invention discloses Sevelamer hydrochloride compositions and a novel process for preparation of said compositions comprising high shear non-aqueous granulation.

Full Text	Form 2 THE PATENTS ACT, 1970 (39 of 1970) & THE PATENTS RULE 2003 PROVISIONAL SPECIFICATION [See section 10 and rule 131 1. TITLE OF THE INVENTION "A Novel formulation of Sevelamer HC1" 2. APPLICANT (a) NAME: USV LIMITED (b) NATIONALITY: Indian Company incorporated under the Companies ACT 1956 (c) ADDRESS: B.S.D. Marg, Govandi, Mumbai 400 088, Maharashtra, India 3. PREAMBLE TO THE DESCRIPTION The following specification describes the nature of this invention and the manner in which it is to be performed. 1 A Novel formulation of Sevelamer HC1 Technical field: The present invention relates to a novel process of preparation of Sevelamer HC1. Background and Prior art: Sevelamer hydrochloride is poly (allylamine hydrochloride) crosslinked with epichlorohydrin in which forty percent of the amines are protonated. It is known chemically as poly (allylamine-co-N,N'-diallyl-l,3-diamino-2-hydroxypropane) hydrochloride. Sevelamer hydrochloride taken with meals has been shown to decrease serum phosphorus concentrations in patients with ESRD who are on hemodialysis. Sevelamer hydrochloride treatment also results in a lowering of low- density lipoprotein (LDL) and total serum cholesterol levels. Sevelamer hydrochloride is indicated for the control of serum phosphorus in patients with Chronic Kidney Disease (CKD) on hemodialysis (www.fda.gov/cder/foi/label/2000/211791bl.pdf). In hemodialysis patients, Sevelamer hydrochloride decreases the incidence of hypercalcemic episodes relative to patients on calcium treatment. US5496545 and US 6509013 disclose the use of Sevelamer HC1 for phosphate binding but do not describe any specific formulation. In W09844933 to Chugai, a tablet containing a phosphate binding polymer is described. Particle size and moisture content of polymer is also disclosed. A direct compression tablet containing Sevelamer HC1 is described in WO01028527 to Genzyme Corporation. It further discloses that atleast 95% of the core comprises 2 an aliphatic polymer, which is hydrated and a water-based coating made of HPMC and plasticizer and diacetylated monoglyceride. WO02085378 discloses a low salt formulation of Sevelamer, wherein the chloride ion content is about 4% to 12 %. However the prior art uses a dry granulation method, and further states that wet granulation is impossible to achieve. Although the prior art states that tabletting of such a polymer is impossible by granulation, the present invention has successfully granulated the Sevelamer hydrochloride using a non-aqueous binder solution and then the granules have been successfully compressed into 400 and 800 mg tablets. Summary of the Invention: The present invention relates to a process for preparing a pharmaceutical composition comprising Sevelamer Hydrochloride. The process comprises: l)Hydrating a mixture of the polymer and excipient 2)Granulating the hydrated mixture with non-aqueous binder solution 3)Partially drying the granulated mass to remove the non-aqueous solvent but retain sufficient amount of moisture 4)Blending the dried mass with commonly used lubricants 5) Compressing the blend The compressed tablets are further coated by non-aqueous/ aqueous/ hydroalcoholic coating. Detailed Description: In an embodiment of the present invention, phosphate binding polymer as disclosed in this application is water-insoluble, but is hydrophilic and swells in contact with 3 water. By virtue of its amorphous nature and the spherical shape of its particles, it resists compression. The particles resist deformation and do not rupture or fracture. Hence compressing the blend to make a tablet is extremely difficult. In a further embodiment of the present invention Sevelamer Hydrochloride is spherical in shape and hence: l)resists size reduction 2)cannot be micronised 3)has poor flow, low bulk density 4)cannot be directly compressed (lacks compressibility) The polymer is hydrophilic and swells in water (though water-insoluble). For such a hydrophilic polymer (with spherical particles), aqueous film coating would be difficult. But the tabletting process in the current invention gives tablets with a sufficiently impervious surface, which prevents the ingress of moisture from the aqueous coat. In another embodiment of the present invention the pharmaceutical composition comprising Sevelamer Hydrochloride may be coated with a non-aqueous or hydrolcoholic coatings. The tablet core and film coat composition provided a robust formulation, which withstands the accelerated stability conditions of temperature and relative humidity. The tablets maintain their physical and chemical integrity at accelerated conditions of stability. The percentage of Sevelamer in the core ranges from 66% to 80% of the blend. The pharmaceutically acceptable excipients include fillers, binders, glidants, 4 lubricants, coating agents, plasticisers. A preferred embodiment of the invention comprises: (a)about 5 to 21% of fillers (b)about 3 to 15 % of binders (c)about 0.25 to 3% of glidants (d)about 0.25 to 3% of lubricants (e)about 3 to 6% of coating agents In a preferred embodiment the tablets may comprise: (a) Fillers: Lactose, Maize Starch, Microcrystalline Cellulose, Pregelatinized starch, mannitol (b) Binders: Hydroxy propyl methylcellulose, Hydroxy propyl cellulose, Hydroxy ethyl cellulose, Ethyl cellulose, Maize Starch, Polyvinylpyrrolidone, Polyethylene Glycols (c) Glidants: Silicon Dioxide (d) Lubricants: Stearic Acid, Magnesium Stearate, Sodium stearyl fumarate, Calcium stearyl fumarate. (e) Coating: Polyvinyl Alcohol, Hydroxy ethyl cellulose, Ethyl cellulose, Hydroxy propyl methyl cellulose, Methacrylic acid co-polymers The ready mix coating material may comprise plasticizers selected from triacetin or polyethylene glycols. The present invention provides a method of preparing a tablet comprising a wet granulation process. The method of producing the tablet core comprises the steps of: l)Hydrating a mixture of the polymer and excipient 2)Granulating the hydrated mixture with non-aqueous binder solution 5 3)Partially drying the granulated mass to remove the non-aqueous solvent but retain sufficient amount of moisture 4)Blending the dried mass with commonly used lubricants 5)Compressing the blend The compressed tablets were further coated by non-aqueous/ aqueous/ hydroalcoholic coating. Preferred mode for carrying out the invention: Sevelamer Hydrochloride and excipient cellulose were mixed together in a suitable mixing equipment. The resultant mixture was hydrated either with plain purified water or with a solution of macrogol in water. The preferred macrogol is PEG6000. The hydration process was carried out in a suitable mixing equipment. The hydrated Sevelamer Hydrochloride + cellulose mass was granulated with a suitable granulating agent preferably Povidone K-30 or Ethyl cellulose dissolved in a non-aqueous solvents preferably isopropyl alcohol. The wet mass was dried in a suitable drying equipment such that the non aqueous solvent is evaporated but Sevelamer Hydrochloride maintains its hydrated state and the resultant mass was then granulated. The granules were then lubricated with known lubricants preferably colloidal silicon dioxide, stearic acid, sodium stearyl fumarate or calcium stearate. The lubricated blend was then compressed using suitable punches and dies which may be oval / elliptical / capsule shaped / spherical and maybe concave or plain. The core tablets were then film coated with hydroxypropyl methyl cellulose and triacetin based clear coat either by non-aqueous (isopropyl acohol + methylene dichloride), aqueous (water) or hydro-alcoholic (isopropyl alcohol + water) coating. 6 The tablets meet the specifications for disintegration and phosphate binding capacity. The specifications are: DT NMT 30 minutes, Phosphate binding capacity; 2.79-3.41meq/gm(3.1±10%) Hard gelatin capsules containing the active compound with or without added excipients may be prepared in a similar manner. EXAMPLES Referential Example: Preparation of Sevelamer Hydrochloride: Stage I- Poly allylamine hydrochloride: Allylamine is added to hydrochloric acid by maintaining the temperature 5 to 15°C. The pH is adjusted to 1 to 2 and the solution is stirred for 30 min. The recovery of acidic water at temp below 90°C is carried out under vacuum to get allylamine hydrochloride salt and the recovery till approx. about 1 volume of water based on input allylamine is distilled out to get thick mass. Cool the reaction mass to 25 to 35°C. Water is added to get uniform slurry for 40 to 45 min and the reaction mass ^ is heated to 80 to 85°C. VA-086, an initiator is added in 2 lots. 1st lot of VA-086 is added in about 4 hrs at 80 to 85°C. The reaction mixture is maintained at 80 to 85°C for a further 8 hrs. 2nd lot of VA-086 is added in about 2 hrs at 80 to 85°Cand the reaction mixture is maintained for a further 10 hrs at 80 to 85°C. The mass is cooled to 40 to 50°C and the solution is slowly charged to Methanol (quenching). Two successive washings of Methanol are given to the wet cake of polyallylamine HC1 by stirring at 25 to 35°C for 45 min. The resultant mass is dried at 65 to 70°C under vacuum. Stage II- Sevelamer hydrochloride: 7 Polyallylamine hydrochloride and water are mixed at 25 to 35°C to get a clear solution. The solution is further cooled to 5 to 15°C and sodium hydroxide is added to the solution at 5 to 15°C and stirred for 30 min. Toluene and SPAN-85 are added to it at 5 to 15°C. The temperature is then raised to 20 to 25°C and maintained for 15 min. The reaction mixture is filtered to remove any extraneous matter at 25 to 35°C. Epichlorohydrin is added at 25 to 35°C to reaction mixture and the reaction mixture is stirred for 15 min and the temperature is raised to 58 to 60°C and maintained for 3hrs. The reaction mixture is cooled to 25 to 35°C and the product is isolated by centrifugation. The cake is further sludged and washed twice with water with stirring for 45 min at 25 to 35°C. The wet cake is finally sludged and washed with isopropanol to remove water. The material is dried at temperature 60 to 65 °C for 2 hrs and further raise the temperature to 85 to 90°C and dry the material till LOD complies. Example 1: Disperse hydroxypropyl methylcellulose (HPMC) E-15 (7.5gm) in 100 ml purified water. Granulate 100 gm of Sevelamer with this binder. Dry it in a tray dryer. The mass is then lubricated it with colloidal silicon dioxide 2.0 gm and stearic acid 1.5 gm and the blend is compressed in tablets. Example 2: Dissolve povidone K-90 (8gm) in isopropyl alcohol (IPA) (83gm). Granulate Sevelamer hydrochloride with this solution. Dry it in a tray dryer. Lubricate the mass with l gm of colloidal silicon dioxide and 3gm of stearic acid. Compress the blend into a tablet. Example 3: Dissolve povidone K-90 (8gm) in purified water (116gm). Load Sevelamer hydrochloride in Kenwood Mixer and dry mix for 3 min and granulate the mass with 8 the povidone K-90/ purified water solution. Dry it in a tray dryer. Lubricate the mass with colloidal silicon dioxide (l gm) and stearic acid (3gm). Compress the blend into tablets. Example 4: Dissolve povidone K-90 (6gm) in isopropyl alcohol (IPA) (35gm). Load Sevelamer hydrochloride in Kenwood mixer and dry mix it for 3 min and granulate this mass with the povidone/IPA solution and Dry it in a tray dryer. Lubricate the mass with colloidal silicon dioxide (0.5gm) and stearic acid (1.5gm) and the resultant blend is compressed in to tablets. Example 5: Disperse l0gm of povidone K-90 in 70gm of purified water under stirring. Separately make a paste of maize starch (6gm) in purified water (120gm) and add this to povidone solution, cool it for 5 minutes. Load Sevelamer hydrochloride (200gm) and Avicel PH 101(25gm) into the Kenwood mixer and dry mix it for 3 min. Granulate the resultant mass with the mixture of binder solution and dry it in a tray dryer. Lubricate the resultant mass with colloidal silicon dioxide (1.74gm) and stearic acid (2.86gm) and compress the resultant blend into tablets. Example 6: Sevelamer is loaded in RMG (Rapid Mixer Granulator) and dry mixed for 5 min. Disperse 18gm of povidone K-90 in 90gm of isopropyl alcohol under stirring. Soak 9gm of polyethylene glycol in l0gm of purified water. Mix both the dispersions. Granulate the dry mass with the povidone/isopropanol and polyethylene glycol solution and dry it in a tray dryer. The mass is then lubricated it with colloidal silicon dioxide (1.95gm) and stearic acid (3.9gm). Compress the resultant blend into tablets. Example 7: 9 Sevelamer hydrochloride is loaded in RMG, and dry mixed for 5 min. Povidone K-90 (13.12 gm) is dispersed in 90gm of isopropyl alcohol under stirring. Soak 7.5gm of polyethylene glycol in 50gm of water. Granulate the dry mass with the povidone isopropyl alcohol and polyethylene glycol solution and dry it in a tray dryer. Lubricate the mass with 1.125gm of colloidal silicon dioxide and 2.25g of stearic acid. The resultant blend is compressed in to tablets. Example 8: 202gm of Sevelamer hydrochloride and 30gm of Avicel pH 101 are loaded in RMG and dry mixed for 5 min. 20gm of povidone K-30 is dispersed in 50gm of isopropyl alcohol under stirring. Soak l0gm of polyethylene glycol in 10 gm of water. Granulate the dry mass with the povidone isopropyl alcohol and polyethylene glycol solution and dry it in a tray dryer. The resultant mass is lubricated with 1.5 gm of colloidal silicon dioxide and 2.55gm of stearic acid. The resultant blend is compressed into tablets. Example 9: 202gm of Sevelamer hydrochloride and 36.20gm of Avicel pH 101 are loaded in RMG and dry mixed for 5 min. Disperse 12.75gm of ethyl cellulose in 50gm of weighed amount of warm isopropyl alcohol (up to 45°C) under stirring. Granulate the dry mass with the ethyl cellulose solution and dry it in a tray dryer. Sift the dried mass through 20 mesh and lubricate it with 1.125gm of colloidal silicon dioxide and 2.25gm of stearic acid. The resultant blend is compressed into tablets and further coated. The tablets are then coated with ready-mix coating material containing hydroxypropylmethylcellulose, triacetin, and titanium dioxide dispersed in purified water. Example 10: 10 Sevelamer hydrochloride (164.8gm) and 84.4gm of B -cyclodextrin are sieved and loaded in Kenwood Mixer. 5gm of purified water is added and dry mixed for 5 min. Disperse 17.2 gm of povidone K-30 in 40gm of isopropyl alcohol, under stirring. Similarly soak 11.6gm of polyethylene glycol in the 15 gm of water. Granulate the dry mass with povidone, isopropanol and polyethylene glycol solution and dry it in a tray dryer. The resultant mass is lubricated with 1.68gm of colloidal silicon dioxide and 2.32gm of stearic acid. The resultant blend is compressed into tablets and further coated. The coating solution is prepared by dispersing 160 gm of ready mix coating material containing HPMC 2910, triacetin in mixture of isopropyl alcohol (l000gm) and methylene dichloride (1500gm). Example 11: Sevelamer hydrochloride (164.8gm) and Avicel PH 101 (34.2gm) are loaded in Kenwood Mixer. Disperse 17.4gm of povidone K-30 in 40gm of isopropyl alcohol under stirring. Soak 15gm polyethylene glycol in 47gm water. The dry mass is then granulated with povidone/isopropyl alcohol and polyethylene glycol solution and dried it in a tray dryer. Lubricate the mass with 1.68gm of colloidal silicon dioxide and 2.32gm of stearic acid. The resultant blend is compressed into tablets and further coated. The coating solution is prepared with ready mix coating material containing hydroxypropylmethyl cellulose 2910, triacetin dispersed in isopropanol (l000gm) and methylene dichloride (1500gm) under stirring. Example 12: 165.6 gm of Sevelamer hydrochloride and 47.6 gm of Avicel PH 101 are loaded in RMG and dry mix for 5 min. Disperse 11.6gm of ethyl cellulose in 50g of isopropyl alcohol. Granulate the dry mass with the ethyl cellulose solution dry it in a tray dryer. The dried mass is lubricated with 1.68gm colloidal silicon dioxide and 2.32gm of 11 stearic acid. The resultant blend is compressed in to tablets. The tablets are then coated with ready mix coating material containing HPMC 2910 and triacetin. Example 13: 408gm of Sevelamer hydrochloride and Avicel PH 101 (96gm) are loaded in Kenwood Mixer. 45gm of povidone K-30 is dispersed in 45gm isopropyl alcohol under stirring. Similarly soak 45gm of polyethylene glycol in 60gm of purified water. Granulate the dry mass with the povidone/isopropyl alcohol and polyethylene glycol solution and dry it in a tray dryer. The resultant mass is lubricated with 3gm of colloidal silicon dioxide and stearic acid. The resultant blend is then compressed in to tablets and further coated. The coating solution is prepared as a ready mix coating material containing hydroxypropylmefhylcellulose 2910, triacetin dispersed in isopropyl alcohol (l000gm) and methylene chloride (2000gm) under stirring. Example 14: 408gm of Sevelamer hydrochloride and 52gm of Avicel PH 101 are loaded in Kenwood Mixer and dry mixed for 5 min. 37.5gm ethyl cellulose is dispersed in 150gm of isopropyl alcohol under stirring. The dry mass is granulated with purified water and ethyl cellulose solution and dried it in a tray dryer. The dried mass is lubricated with 1.25gm of colloidal silicon dioxide and 1.25gm of stearic acid. The resultant blend is compressed in to tablets and further coated. The coating solution is prepared as a ready mix coating material containing HPMC 2910, triacetin dispersed in isopropanol (l000gm) and methylene dichloride (2000gm) under stirring. Example 15: Sevelamer hydrochloride (408gm) and Avicel PH 101 (29.5gm) are sieved through 30 mesh and load the sifted mass in Kenwood Mixer. 15gm of Klucel LF is dispersed 12 in 45gm of isopropyl alcohol under stirring. Soak 45gm polyethylene glycol in the 60gm of water. The dry mass is then granulated with the Klucel LF/ isopranol and polyethylene solution and dried in a tray dryer. The granules are lubricated with 1.25gm of colloidal silicon dioxide and 1.25gm of stearic acid. The resultant blend is compressed into tablets and further coated. The coating solution is prepared as a ready mix coating material containing HPMC 2910, triacetin dispersed in isopropanol (l000gm) and methylene dichloride (2000gm) under stirring. Example 16: Sevelamer hydrochloride (163.2gm) and 112.9gm of Avicel PH 112 are lubricated with 5.4gm of colloidal silicon dioxide and 1.8gm of stearic acid. Example 17: 202gm of Sevelamer hydrochloride and Avicel pH 101 are loaded in Kenwood Mixer and dry mix for 5 min. Disperse 30gm ethyl cellulose in 150gm of isopropyl alcohol under stirring. The dry mass is granulated with purified water and ethyl cellulose solution and dried in a tray dryer. The dried mass is lubricated with 0.625gm colloidal silicon dioxide and 0.625gm stearic acid. The resultant blend is compressed into tablets and further coated. The coating solution is prepared as a ready mix coating material containing HPMC 2910, triacetin dispersed in isopropanol (l000gm) and methylene dichloride (1500gm) under stirring. Example 18: Sevelamer hydrochloride (408gm) and 101.81gm of Avicel pH 101 are loaded in Kenwood Mixer. Disperse 60gm of Povidone K-30 in 240gm of isopropyl alcohol, under stirring. Similarly soak 45gm polyethylene glycol in 80gm of purified water. The dry mass is then granulated with the povidone/isopropanol and polyethylene-water solution and dry in a tray dryer. The dried mass is multimilled and then 13 lubricated with 3gm of colloidal silicon dioxide and 3gm of stearic acid. The resultant blend is compressed into tablets and further coated. The coating solution is prepared as a ready mix coating material containing HPMC 2910 + triacetin dispersed in isopropanol (l000gm) and methylene dichloride (2000gm) under stirring. Example 19: 408gm of Sevelamer hydrochloride and Avicel pH 101 (27gm) are loaded in Kenwood Mixer, dry mix for 5 min. Disperse 60gm of ethyl cellulose in 300g of warm isopropyl alcohol (up to 45°C) under stirring. The dry mass is granulated with 60gm of purified water and ethyl cellulose solution and dry in a tray dryer. The dried mass is lubricated with 2.5gm of colloidal silicon dioxide and 2.5gm of stearic acid. The resultant blend is compressed in to tablets and further coated. The coating solution is prepared as a ready mix coating material containing hydroxypropylmethyl cllulose 2910 + triacetin dispersed in isopropyl alcohol (l000gm) and methylene dichloride (1500gm) under stirring. Example 20: Sevelamer hydrochloride (408gm) and Avicel pH 101 (27gm) are loaded in Kenwood Mixer. 60gm of HPMC E-5 is dispersed in 220gm of isopropyl alcohol, under stirring. The dry mass is granulated with the HPMC E-5 and polyethylene glycol solution and dried it in a tray dryer. The dried mass are multimilled and further lubricated with 2.5gm of colloidal silicon dioxide and 2.5gm of stearic acid. The resultant blend is compressed into tablets and further coated. Example 21: 810gm of Sevelamer hydrochloride and Avicel pH 101 (186gm) are loaded in RMG, dry mixed for 5 min. 102gm of Povidone K-30 is dispersed in 300gm of isopropyl alcohol under stirring. Similarly soak 90gm of polyethylene glycol in 110gm of 14 water. The dry mass is granulated with the povidone /isopropyl alcohol and polyethylene glycol solution and dry in a FBD. The granules are multimilled and then lubricated with 6gm of colloidal silicon dioxide and 6gm of stearic acid. The resultant blend is compressed into tablets and further coated. The coating solution is prepared as a ready mix coating material containing hydroxy propylmethylcellulose 2910 + Triacetin dispersed in isopropanol (144gm) + purified water (816.48gm) under stirring. Example 22: Sevelamer hydrochloride (810gm) and Avicel pH 101 (95gm) are loaded in a RMG and dry mixed for 5 min. 85gm of ethyl cellulose is dispersed in 264.6 gm of IPA under stirring. The dry mass is granulated with purified water (85gm) and the ethyl cellulose solution. The wet mass is sifted and dried in a Glatt drier. The dried mass is sieved through 20 mesh and lubricated with 5gm of colloidal silicon dioxide and 5gm of stearic acid. The resultant blend is compressed into tablets and further coated. The coating solution is prepared as a ready mix coating material containing HPMC 2910 + Triacetin dispersed in IPA (144g) under stirring. The coating solution is prepared as a ready mix coating material containing HPMC 2910 + Triacetin dispersed in Purified Water (816.48g) under stirring. The tablets were thus coated by non-aqueous and aqueous method. Example 23: Sevelamer hydrochloride (1620gm) and 372gm of Avicel pH 101 are loaded the sifted mass in RMG. 204 gm of povidone K-30 is dispersed in 560 gm of isopropyl alcohol under stirring. Soak 180gm of polyethylene glycol 6000 in 220 g of purified water. The dry mass is granulated with the povidone-isopropyl alcohol and polyethylene glycol solution and dried it in a fluid bed dryer. The dried mass is multimilled and then lubricated with 12gm of colloidal silicon dioxide and 12gm stearic acid. The resultant blend is compressed into tablets and further coated. 15 The core tablets are film coated with a 6% solution of ready mix coating material containing hydroxypropylmethylcellulose 2910 + Triacetin. Example 24: 945.6 gm of Sevelamer hydrochloride and 110.6 gm of Avicel pH 101 are loaded in RMG and dry mix for 5 min. 99.23gm of ethyl cellulose is dispersed into 333.8gm of isopropyl alcohol. The dry mass is granulated with purified water (99.23 gm) and the ethyl cellulose solution. The wet mass is dried in a Glatt drier and lubricated with 5.778gm of colloidal silicon dioxide and stearic acid 5.778gm. The resultant blend is compressed into tablets and further coated. The core tablets are film coated with a 6% solution of ready mix coating material containing hydroxypropylmethylcellulose 2910 + Triacetin in purified water. Dated this the 1st day of September, 2006 Rajendran ledge Cell SV Limited 16 Abstract: The present invention provides a method of producing a tablet comprising a wet granulation process utilizing a binding agent for improving the compressibility of the hydrophilic aliphatic amine polymer. 17

Full Text

Form 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULE 2003
PROVISIONAL SPECIFICATION
[See section 10 and rule 131
1. TITLE OF THE INVENTION
"A Novel formulation of Sevelamer HC1"
2. APPLICANT
(a) NAME: USV LIMITED
(b) NATIONALITY: Indian Company incorporated under the
Companies ACT 1956
(c) ADDRESS: B.S.D. Marg, Govandi, Mumbai 400 088,
Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the nature of this invention and the
manner in which it is to be performed.
1

A Novel formulation of Sevelamer HC1
Technical field:
The present invention relates to a novel process of preparation of Sevelamer HC1.
Background and Prior art:
Sevelamer hydrochloride is poly (allylamine hydrochloride) crosslinked with
epichlorohydrin in which forty percent of the amines are protonated. It is known
chemically as poly (allylamine-co-N,N'-diallyl-l,3-diamino-2-hydroxypropane)
hydrochloride. Sevelamer hydrochloride taken with meals has been shown to
decrease serum phosphorus concentrations in patients with ESRD who are on
hemodialysis. Sevelamer hydrochloride treatment also results in a lowering of low-
density lipoprotein (LDL) and total serum cholesterol levels. Sevelamer
hydrochloride is indicated for the control of serum phosphorus in patients with
Chronic Kidney Disease (CKD) on hemodialysis
(www.fda.gov/cder/foi/label/2000/211791bl.pdf). In hemodialysis patients, Sevelamer hydrochloride decreases the incidence of hypercalcemic episodes relative to patients on calcium treatment.
US5496545 and US 6509013 disclose the use of Sevelamer HC1 for phosphate binding but do not describe any specific formulation.
In W09844933 to Chugai, a tablet containing a phosphate binding polymer is described. Particle size and moisture content of polymer is also disclosed.
A direct compression tablet containing Sevelamer HC1 is described in WO01028527 to Genzyme Corporation. It further discloses that atleast 95% of the core comprises
2

an aliphatic polymer, which is hydrated and a water-based coating made of HPMC and plasticizer and diacetylated monoglyceride.
WO02085378 discloses a low salt formulation of Sevelamer, wherein the chloride ion content is about 4% to 12 %.
However the prior art uses a dry granulation method, and further states that wet granulation is impossible to achieve.
Although the prior art states that tabletting of such a polymer is impossible by granulation, the present invention has successfully granulated the Sevelamer hydrochloride using a non-aqueous binder solution and then the granules have been successfully compressed into 400 and 800 mg tablets.
Summary of the Invention:
The present invention relates to a process for preparing a pharmaceutical composition
comprising Sevelamer Hydrochloride. The process comprises:
l)Hydrating a mixture of the polymer and excipient
2)Granulating the hydrated mixture with non-aqueous binder solution
3)Partially drying the granulated mass to remove the non-aqueous solvent but retain sufficient amount of moisture
4)Blending the dried mass with commonly used lubricants
5) Compressing the blend
The compressed tablets are further coated by non-aqueous/ aqueous/ hydroalcoholic
coating.
Detailed Description:
In an embodiment of the present invention, phosphate binding polymer as disclosed in this application is water-insoluble, but is hydrophilic and swells in contact with
3

water. By virtue of its amorphous nature and the spherical shape of its particles, it resists compression. The particles resist deformation and do not rupture or fracture. Hence compressing the blend to make a tablet is extremely difficult.
In a further embodiment of the present invention Sevelamer Hydrochloride is spherical in shape and hence:
l)resists size reduction
2)cannot be micronised
3)has poor flow, low bulk density
4)cannot be directly compressed (lacks compressibility)
The polymer is hydrophilic and swells in water (though water-insoluble). For such a hydrophilic polymer (with spherical particles), aqueous film coating would be difficult. But the tabletting process in the current invention gives tablets with a sufficiently impervious surface, which prevents the ingress of moisture from the aqueous coat.
In another embodiment of the present invention the pharmaceutical composition comprising Sevelamer Hydrochloride may be coated with a non-aqueous or hydrolcoholic coatings.
The tablet core and film coat composition provided a robust formulation, which withstands the accelerated stability conditions of temperature and relative humidity. The tablets maintain their physical and chemical integrity at accelerated conditions of stability.
The percentage of Sevelamer in the core ranges from 66% to 80% of the blend.
The pharmaceutically acceptable excipients include fillers, binders, glidants,
4

lubricants, coating agents, plasticisers.
A preferred embodiment of the invention comprises: (a)about 5 to 21% of fillers (b)about 3 to 15 % of binders (c)about 0.25 to 3% of glidants (d)about 0.25 to 3% of lubricants (e)about 3 to 6% of coating agents
In a preferred embodiment the tablets may comprise:
(a) Fillers: Lactose, Maize Starch, Microcrystalline Cellulose, Pregelatinized starch, mannitol
(b) Binders: Hydroxy propyl methylcellulose, Hydroxy propyl cellulose, Hydroxy ethyl cellulose, Ethyl cellulose, Maize Starch, Polyvinylpyrrolidone, Polyethylene Glycols
(c) Glidants: Silicon Dioxide
(d) Lubricants: Stearic Acid, Magnesium Stearate, Sodium stearyl fumarate, Calcium stearyl fumarate.
(e) Coating: Polyvinyl Alcohol, Hydroxy ethyl cellulose, Ethyl cellulose, Hydroxy propyl methyl cellulose, Methacrylic acid co-polymers
The ready mix coating material may comprise plasticizers selected from triacetin or polyethylene glycols.
The present invention provides a method of preparing a tablet comprising a wet granulation process.
The method of producing the tablet core comprises the steps of: l)Hydrating a mixture of the polymer and excipient 2)Granulating the hydrated mixture with non-aqueous binder solution
5

3)Partially drying the granulated mass to remove the non-aqueous solvent but
retain sufficient amount of moisture
4)Blending the dried mass with commonly used lubricants
5)Compressing the blend
The compressed tablets were further coated by non-aqueous/ aqueous/ hydroalcoholic coating.
Preferred mode for carrying out the invention:
Sevelamer Hydrochloride and excipient cellulose were mixed together in a suitable mixing equipment. The resultant mixture was hydrated either with plain purified water or with a solution of macrogol in water. The preferred macrogol is PEG6000. The hydration process was carried out in a suitable mixing equipment.
The hydrated Sevelamer Hydrochloride + cellulose mass was granulated with a suitable granulating agent preferably Povidone K-30 or Ethyl cellulose dissolved in a non-aqueous solvents preferably isopropyl alcohol.
The wet mass was dried in a suitable drying equipment such that the non aqueous solvent is evaporated but Sevelamer Hydrochloride maintains its hydrated state and the resultant mass was then granulated.
The granules were then lubricated with known lubricants preferably colloidal silicon dioxide, stearic acid, sodium stearyl fumarate or calcium stearate. The lubricated blend was then compressed using suitable punches and dies which may be oval / elliptical / capsule shaped / spherical and maybe concave or plain.
The core tablets were then film coated with hydroxypropyl methyl cellulose and triacetin based clear coat either by non-aqueous (isopropyl acohol + methylene dichloride), aqueous (water) or hydro-alcoholic (isopropyl alcohol + water) coating.
6

The tablets meet the specifications for disintegration and phosphate binding capacity. The specifications are: DT NMT 30 minutes, Phosphate binding capacity; 2.79-3.41meq/gm(3.1±10%)
Hard gelatin capsules containing the active compound with or without added excipients may be prepared in a similar manner.
EXAMPLES
Referential Example:
Preparation of Sevelamer Hydrochloride:
Stage I- Poly allylamine hydrochloride:
Allylamine is added to hydrochloric acid by maintaining the temperature 5 to 15°C. The pH is adjusted to 1 to 2 and the solution is stirred for 30 min. The recovery of acidic water at temp below 90°C is carried out under vacuum to get allylamine hydrochloride salt and the recovery till approx. about 1 volume of water based on input allylamine is distilled out to get thick mass. Cool the reaction mass to 25 to 35°C. Water is added to get uniform slurry for 40 to 45 min and the reaction mass ^ is heated to 80 to 85°C. VA-086, an initiator is added in 2 lots. 1st lot of VA-086 is added in about 4 hrs at 80 to 85°C. The reaction mixture is maintained at 80 to 85°C for a further 8 hrs. 2nd lot of VA-086 is added in about 2 hrs at 80 to 85°Cand the reaction mixture is maintained for a further 10 hrs at 80 to 85°C. The mass is cooled to 40 to 50°C and the solution is slowly charged to Methanol (quenching). Two successive washings of Methanol are given to the wet cake of polyallylamine HC1 by stirring at 25 to 35°C for 45 min. The resultant mass is dried at 65 to 70°C under vacuum.
Stage II- Sevelamer hydrochloride:
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Polyallylamine hydrochloride and water are mixed at 25 to 35°C to get a clear solution. The solution is further cooled to 5 to 15°C and sodium hydroxide is added to the solution at 5 to 15°C and stirred for 30 min. Toluene and SPAN-85 are added to it at 5 to 15°C. The temperature is then raised to 20 to 25°C and maintained for 15 min. The reaction mixture is filtered to remove any extraneous matter at 25 to 35°C. Epichlorohydrin is added at 25 to 35°C to reaction mixture and the reaction mixture is stirred for 15 min and the temperature is raised to 58 to 60°C and maintained for 3hrs. The reaction mixture is cooled to 25 to 35°C and the product is isolated by centrifugation. The cake is further sludged and washed twice with water with stirring for 45 min at 25 to 35°C. The wet cake is finally sludged and washed with isopropanol to remove water. The material is dried at temperature 60 to 65 °C for 2 hrs and further raise the temperature to 85 to 90°C and dry the material till LOD complies.
Example 1:
Disperse hydroxypropyl methylcellulose (HPMC) E-15 (7.5gm) in 100 ml purified water. Granulate 100 gm of Sevelamer with this binder. Dry it in a tray dryer. The mass is then lubricated it with colloidal silicon dioxide 2.0 gm and stearic acid 1.5 gm and the blend is compressed in tablets.
Example 2:
Dissolve povidone K-90 (8gm) in isopropyl alcohol (IPA) (83gm). Granulate Sevelamer hydrochloride with this solution. Dry it in a tray dryer. Lubricate the mass with l gm of colloidal silicon dioxide and 3gm of stearic acid. Compress the blend into a tablet.
Example 3:
Dissolve povidone K-90 (8gm) in purified water (116gm). Load Sevelamer hydrochloride in Kenwood Mixer and dry mix for 3 min and granulate the mass with
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the povidone K-90/ purified water solution. Dry it in a tray dryer. Lubricate the mass with colloidal silicon dioxide (l gm) and stearic acid (3gm). Compress the blend into tablets.
Example 4:
Dissolve povidone K-90 (6gm) in isopropyl alcohol (IPA) (35gm). Load Sevelamer hydrochloride in Kenwood mixer and dry mix it for 3 min and granulate this mass with the povidone/IPA solution and Dry it in a tray dryer. Lubricate the mass with colloidal silicon dioxide (0.5gm) and stearic acid (1.5gm) and the resultant blend is compressed in to tablets.
Example 5:
Disperse l0gm of povidone K-90 in 70gm of purified water under stirring. Separately make a paste of maize starch (6gm) in purified water (120gm) and add this to povidone solution, cool it for 5 minutes. Load Sevelamer hydrochloride (200gm) and Avicel PH 101(25gm) into the Kenwood mixer and dry mix it for 3 min. Granulate the resultant mass with the mixture of binder solution and dry it in a tray dryer. Lubricate the resultant mass with colloidal silicon dioxide (1.74gm) and stearic acid (2.86gm) and compress the resultant blend into tablets.
Example 6:
Sevelamer is loaded in RMG (Rapid Mixer Granulator) and dry mixed for 5 min. Disperse 18gm of povidone K-90 in 90gm of isopropyl alcohol under stirring. Soak 9gm of polyethylene glycol in l0gm of purified water. Mix both the dispersions. Granulate the dry mass with the povidone/isopropanol and polyethylene glycol solution and dry it in a tray dryer. The mass is then lubricated it with colloidal silicon dioxide (1.95gm) and stearic acid (3.9gm). Compress the resultant blend into tablets.
Example 7:
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Sevelamer hydrochloride is loaded in RMG, and dry mixed for 5 min. Povidone K-90 (13.12 gm) is dispersed in 90gm of isopropyl alcohol under stirring. Soak 7.5gm of polyethylene glycol in 50gm of water. Granulate the dry mass with the povidone isopropyl alcohol and polyethylene glycol solution and dry it in a tray dryer. Lubricate the mass with 1.125gm of colloidal silicon dioxide and 2.25g of stearic acid. The resultant blend is compressed in to tablets.
Example 8:
202gm of Sevelamer hydrochloride and 30gm of Avicel pH 101 are loaded in RMG and dry mixed for 5 min. 20gm of povidone K-30 is dispersed in 50gm of isopropyl alcohol under stirring. Soak l0gm of polyethylene glycol in 10 gm of water. Granulate the dry mass with the povidone isopropyl alcohol and polyethylene glycol solution and dry it in a tray dryer. The resultant mass is lubricated with 1.5 gm of colloidal silicon dioxide and 2.55gm of stearic acid. The resultant blend is compressed into tablets.
Example 9:
202gm of Sevelamer hydrochloride and 36.20gm of Avicel pH 101 are loaded in RMG and dry mixed for 5 min. Disperse 12.75gm of ethyl cellulose in 50gm of weighed amount of warm isopropyl alcohol (up to 45°C) under stirring. Granulate the dry mass with the ethyl cellulose solution and dry it in a tray dryer. Sift the dried mass through 20 mesh and lubricate it with 1.125gm of colloidal silicon dioxide and 2.25gm of stearic acid. The resultant blend is compressed into tablets and further coated.
The tablets are then coated with ready-mix coating material containing hydroxypropylmethylcellulose, triacetin, and titanium dioxide dispersed in purified water.
Example 10:
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Sevelamer hydrochloride (164.8gm) and 84.4gm of B -cyclodextrin are sieved and loaded in Kenwood Mixer. 5gm of purified water is added and dry mixed for 5 min. Disperse 17.2 gm of povidone K-30 in 40gm of isopropyl alcohol, under stirring. Similarly soak 11.6gm of polyethylene glycol in the 15 gm of water. Granulate the dry mass with povidone, isopropanol and polyethylene glycol solution and dry it in a tray dryer. The resultant mass is lubricated with 1.68gm of colloidal silicon dioxide and 2.32gm of stearic acid. The resultant blend is compressed into tablets and further coated.
The coating solution is prepared by dispersing 160 gm of ready mix coating material containing HPMC 2910, triacetin in mixture of isopropyl alcohol (l000gm) and methylene dichloride (1500gm).
Example 11:
Sevelamer hydrochloride (164.8gm) and Avicel PH 101 (34.2gm) are loaded in Kenwood Mixer. Disperse 17.4gm of povidone K-30 in 40gm of isopropyl alcohol under stirring. Soak 15gm polyethylene glycol in 47gm water. The dry mass is then granulated with povidone/isopropyl alcohol and polyethylene glycol solution and dried it in a tray dryer. Lubricate the mass with 1.68gm of colloidal silicon dioxide and 2.32gm of stearic acid. The resultant blend is compressed into tablets and further coated.
The coating solution is prepared with ready mix coating material containing hydroxypropylmethyl cellulose 2910, triacetin dispersed in isopropanol (l000gm) and methylene dichloride (1500gm) under stirring.
Example 12:
165.6 gm of Sevelamer hydrochloride and 47.6 gm of Avicel PH 101 are loaded in RMG and dry mix for 5 min. Disperse 11.6gm of ethyl cellulose in 50g of isopropyl alcohol. Granulate the dry mass with the ethyl cellulose solution dry it in a tray dryer. The dried mass is lubricated with 1.68gm colloidal silicon dioxide and 2.32gm of
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stearic acid. The resultant blend is compressed in to tablets. The tablets are then coated with ready mix coating material containing HPMC 2910 and triacetin.
Example 13:
408gm of Sevelamer hydrochloride and Avicel PH 101 (96gm) are loaded in Kenwood Mixer. 45gm of povidone K-30 is dispersed in 45gm isopropyl alcohol under stirring. Similarly soak 45gm of polyethylene glycol in 60gm of purified water. Granulate the dry mass with the povidone/isopropyl alcohol and polyethylene glycol solution and dry it in a tray dryer. The resultant mass is lubricated with 3gm of colloidal silicon dioxide and stearic acid. The resultant blend is then compressed in to tablets and further coated.
The coating solution is prepared as a ready mix coating material containing hydroxypropylmefhylcellulose 2910, triacetin dispersed in isopropyl alcohol (l000gm) and methylene chloride (2000gm) under stirring.
Example 14:
408gm of Sevelamer hydrochloride and 52gm of Avicel PH 101 are loaded in Kenwood Mixer and dry mixed for 5 min. 37.5gm ethyl cellulose is dispersed in 150gm of isopropyl alcohol under stirring. The dry mass is granulated with purified water and ethyl cellulose solution and dried it in a tray dryer. The dried mass is lubricated with 1.25gm of colloidal silicon dioxide and 1.25gm of stearic acid. The resultant blend is compressed in to tablets and further coated.
The coating solution is prepared as a ready mix coating material containing HPMC 2910, triacetin dispersed in isopropanol (l000gm) and methylene dichloride (2000gm) under stirring.
Example 15:
Sevelamer hydrochloride (408gm) and Avicel PH 101 (29.5gm) are sieved through 30 mesh and load the sifted mass in Kenwood Mixer. 15gm of Klucel LF is dispersed
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in 45gm of isopropyl alcohol under stirring. Soak 45gm polyethylene glycol in the 60gm of water. The dry mass is then granulated with the Klucel LF/ isopranol and polyethylene solution and dried in a tray dryer. The granules are lubricated with 1.25gm of colloidal silicon dioxide and 1.25gm of stearic acid. The resultant blend is compressed into tablets and further coated.
The coating solution is prepared as a ready mix coating material containing HPMC 2910, triacetin dispersed in isopropanol (l000gm) and methylene dichloride (2000gm) under stirring.
Example 16:
Sevelamer hydrochloride (163.2gm) and 112.9gm of Avicel PH 112 are lubricated
with 5.4gm of colloidal silicon dioxide and 1.8gm of stearic acid.
Example 17:
202gm of Sevelamer hydrochloride and Avicel pH 101 are loaded in Kenwood Mixer and dry mix for 5 min. Disperse 30gm ethyl cellulose in 150gm of isopropyl alcohol under stirring. The dry mass is granulated with purified water and ethyl cellulose solution and dried in a tray dryer. The dried mass is lubricated with 0.625gm colloidal silicon dioxide and 0.625gm stearic acid. The resultant blend is compressed into tablets and further coated.
The coating solution is prepared as a ready mix coating material containing HPMC 2910, triacetin dispersed in isopropanol (l000gm) and methylene dichloride (1500gm) under stirring.
Example 18:
Sevelamer hydrochloride (408gm) and 101.81gm of Avicel pH 101 are loaded in
Kenwood Mixer. Disperse 60gm of Povidone K-30 in 240gm of isopropyl alcohol, under stirring. Similarly soak 45gm polyethylene glycol in 80gm of purified water. The dry mass is then granulated with the povidone/isopropanol and polyethylene-water solution and dry in a tray dryer. The dried mass is multimilled and then
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lubricated with 3gm of colloidal silicon dioxide and 3gm of stearic acid. The resultant blend is compressed into tablets and further coated.
The coating solution is prepared as a ready mix coating material containing HPMC 2910 + triacetin dispersed in isopropanol (l000gm) and methylene dichloride (2000gm) under stirring.
Example 19:
408gm of Sevelamer hydrochloride and Avicel pH 101 (27gm) are loaded in Kenwood Mixer, dry mix for 5 min. Disperse 60gm of ethyl cellulose in 300g of warm isopropyl alcohol (up to 45°C) under stirring. The dry mass is granulated with 60gm of purified water and ethyl cellulose solution and dry in a tray dryer. The dried mass is lubricated with 2.5gm of colloidal silicon dioxide and 2.5gm of stearic acid. The resultant blend is compressed in to tablets and further coated. The coating solution is prepared as a ready mix coating material containing hydroxypropylmethyl cllulose 2910 + triacetin dispersed in isopropyl alcohol (l000gm) and methylene dichloride (1500gm) under stirring.
Example 20:
Sevelamer hydrochloride (408gm) and Avicel pH 101 (27gm) are loaded in Kenwood Mixer. 60gm of HPMC E-5 is dispersed in 220gm of isopropyl alcohol, under stirring. The dry mass is granulated with the HPMC E-5 and polyethylene glycol solution and dried it in a tray dryer. The dried mass are multimilled and further lubricated with 2.5gm of colloidal silicon dioxide and 2.5gm of stearic acid. The resultant blend is compressed into tablets and further coated.
Example 21:
810gm of Sevelamer hydrochloride and Avicel pH 101 (186gm) are loaded in RMG, dry mixed for 5 min. 102gm of Povidone K-30 is dispersed in 300gm of isopropyl alcohol under stirring. Similarly soak 90gm of polyethylene glycol in 110gm of
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water. The dry mass is granulated with the povidone /isopropyl alcohol and polyethylene glycol solution and dry in a FBD. The granules are multimilled and then lubricated with 6gm of colloidal silicon dioxide and 6gm of stearic acid. The resultant blend is compressed into tablets and further coated.
The coating solution is prepared as a ready mix coating material containing hydroxy propylmethylcellulose 2910 + Triacetin dispersed in isopropanol (144gm) + purified water (816.48gm) under stirring.
Example 22:
Sevelamer hydrochloride (810gm) and Avicel pH 101 (95gm) are loaded in a RMG and dry mixed for 5 min. 85gm of ethyl cellulose is dispersed in 264.6 gm of IPA under stirring. The dry mass is granulated with purified water (85gm) and the ethyl cellulose solution. The wet mass is sifted and dried in a Glatt drier. The dried mass is sieved through 20 mesh and lubricated with 5gm of colloidal silicon dioxide and 5gm of stearic acid. The resultant blend is compressed into tablets and further coated. The coating solution is prepared as a ready mix coating material containing HPMC 2910 + Triacetin dispersed in IPA (144g) under stirring.
The coating solution is prepared as a ready mix coating material containing HPMC 2910 + Triacetin dispersed in Purified Water (816.48g) under stirring. The tablets were thus coated by non-aqueous and aqueous method.
Example 23:
Sevelamer hydrochloride (1620gm) and 372gm of Avicel pH 101 are loaded the sifted mass in RMG. 204 gm of povidone K-30 is dispersed in 560 gm of isopropyl alcohol under stirring. Soak 180gm of polyethylene glycol 6000 in 220 g of purified water. The dry mass is granulated with the povidone-isopropyl alcohol and polyethylene glycol solution and dried it in a fluid bed dryer. The dried mass is multimilled and then lubricated with 12gm of colloidal silicon dioxide and 12gm stearic acid. The resultant blend is compressed into tablets and further coated.
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The core tablets are film coated with a 6% solution of ready mix coating material containing hydroxypropylmethylcellulose 2910 + Triacetin.
Example 24:
945.6 gm of Sevelamer hydrochloride and 110.6 gm of Avicel pH 101 are loaded in
RMG and dry mix for 5 min. 99.23gm of ethyl cellulose is dispersed into 333.8gm of isopropyl alcohol. The dry mass is granulated with purified water (99.23 gm) and the ethyl cellulose solution. The wet mass is dried in a Glatt drier and lubricated with 5.778gm of colloidal silicon dioxide and stearic acid 5.778gm. The resultant blend is compressed into tablets and further coated.
The core tablets are film coated with a 6% solution of ready mix coating material containing hydroxypropylmethylcellulose 2910 + Triacetin in purified water.
Dated this the 1st day of September, 2006

Rajendran
ledge Cell
SV Limited

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Abstract:
The present invention provides a method of producing a tablet comprising a wet granulation process utilizing a binding agent for improving the compressibility of the hydrophilic aliphatic amine polymer.
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A NOVEL FORMULATION OF SEVELAMER HYDROCHLORIDE

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