Title of Invention	PHARMACEUTICAL COMPOSITIONS COMPRISING SEVELAMER CARBONATE
Abstract	The present invention discloses pharmaceutical composition comprising phosphate binding polymers such as Sevelamer carbonate substantially free of monovalent anion other than bicarbonate anion. Particularly, monovalent anion content is less than about 0.05% (w/w). Disclosed are compositions comprising wet granulated Sevelamer carbonate free of added metal ions and/or added monovalent anion source.

Title of Invention

PHARMACEUTICAL COMPOSITIONS COMPRISING SEVELAMER CARBONATE

Abstract

The present invention discloses pharmaceutical composition comprising phosphate binding polymers such as Sevelamer carbonate substantially free of monovalent anion other than bicarbonate anion. Particularly, monovalent anion content is less than about 0.05% (w/w). Disclosed are compositions comprising wet granulated Sevelamer carbonate free of added metal ions and/or added monovalent anion source.

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 of 1970) & THE PATENTS RULES, 2003 PROVISIONAL SPECIFICATION (See section 10, rule 13) 1. Title of the invention "Pharmaceutical compositions comprising phosphate- binding polymer1' 2. Applicant(s) Name Nationality Address USV LIMITED Indian company incorporated under Companies Act, 1956 BSD. Marg, Govandi, Mumbai - 400 088 Maharashtra, India 3. Preamble to the description The following specification particularly describes the invention. Technical field of the invention: The present invention relates to pharmaceutical compositions of Sevelamer carbonate in association with pharmaceutically acceptable additives; process for their preparation comprising wet granulation and methods of using such compositions for the control of serum phosphorus in patients with Chronic Kidney Disease(CKD) on dialysis. Background of the invention: Chronic kidney disease (CKD) is a progressive loss of renal function over a period of time. CKD is identified by performing a blood test for creatinine. High levels of creatinine indicates a poor glomerular filtration rate and a decreased capability of the kidneys to excrete waste products. Decreased kidney function leads to high blood pressure due to fluid overload and production of vasoactive hormones and increases the risk of hypertension or congestive cardiac failure; urea accumulation; potassium accumulation; decreased erythropoietin synthesis; edema; hyperphosphatemia due to reduced phosphate excretion; metabolic acidosis. In End-stage renal disease (ESRD) there is a total kidney failure requiring the patients to have renal replacement therapy, either dialysis or transplantation becomes necessary to maintain life. Hemodialysis involves circulation of blood through a filter on a dialysis machine where the blood is cleansed of waste products and excess water. The acid levels and the concentration of various minerals such as sodium and potassium in the blood are normalized and blood is then returned to the body. Patients with chronic kidney disease (CKD) retain phosphorus and can develop hyperphosphatemia. Hyperphosphatemia is a condition where the serum phosphate levels are greater than 5mg/dL in adults or 7mg/dL in children or adolescents. If the condition persists for a long period then it leads to severe abnormalities in calcium and phosphorus metabolism resulting in calcification in joints, lungs and eyes. Hyperphosphatemia plays a role in the development of secondary hyperparathyroidism in renal insufficiency. Treatment of hyperphosphatemia includes reduction in dietary intake of phosphate, inhibition of intestinal phosphate absorption with phosphate binders and removal of phosphate with dialysis. Oral administration of phosphate binders like calcium or aluminium for the treatment of hyperphosphatemia are well known in the art. Most widely used are the calcium salts such as calcium carbonate, calcium acetate, calcium citrate, calcium alginate. These calcium salts when ingested binds to the intestinal phosphate to form insoluble calcium phosphate salts such as calcium hydrogen phosphate, calcium dihydrogen phosphate or tricalcium phosphate and thus prevents the phosphate absorption. However, the drawback associated with this mode of treatment is that due to absorption of high amount of ingested calcium, the patient develops hypercalcemia which inturn results in cardiac arrhythmias, renal failure, and skin and visceral calcification. Sevelamer carbonate is a polymeric amine which binds to phosphates when administered orally. Sevelamer carbonate has the same polymeric structure as Sevelamer hydrochloride in which carbonate replaces chloride as the counterion. Sevelamer carbonate is chemically poly (allylamine-co-NjN'-diallyl-l^-diamino-2-hydroxypropane) carbonate salt. Structure of Sevelamer carbonate is as represented, where 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 Sevelamer carbonate is developed by Genzyme Corporation and marketed under the brand name Renvela™. The prescribing information for Renvela™ is available on www.fda.gov/cder/foi/label/2007/0221271bl.pdf. Renvela™ is indicated for the control of serum phosphorus in patients with chronic kidney disease (CKD) on dialysis. Renvela contains Sevelamer carbonate, a non-absorbed phosphate binding crosslinked polymer, free of metal and calcium. Renvela™ 800mg tablets contain 800mg of Sevelamer carbonate on an anhydrous basis, microcrystalline cellulose, hypromellose, diacetylated monoglycerides, sodium chloride and zinc stearate. Sevelamer carbonate taken with meals has been shown to control serum phosphorus concentrations in patients with CKD who are on dialysis. Sevelamer carbonate 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. Sevelamer carbonate binds the phosphorus in the gastrointestinal tract to facilitate phosphorus excretion in feces, thereby inhibiting phosphorus absorption from the gut, and thereby lowering the plasma phosphorus concentration. Patients with end-stage renal disease (ESRD) retain phosphorus which lead to development of hyperphosphatemia. Control of phosphorus is the primary goal in the care of patients with end-stage renal disease (ESRD). Sevelamer carbonate controls the serum phosphorus in patients with ESRD who are on hemodialysis, without increasing serum calcium levels or contributing an excess calcium load. US5496545 discloses phosphate-binding polymers that are orally administered and useful for the treatment of hyperphosphatemia. US6083495 discloses a class of anion exchange polymers having improved phosphate binding properties and a method of removing phosphate from a patient by ion exchange involving oral administration of a-therapeutically effective amount of a composition containing at least one phosphate-binding polymer. US6696087 discloses a phosphate-binding polymer tablet that contains a large amount of the phosphate-binding polymer having an average particle size of 400um or less, preferably 250jam or less, containing particles of 500u.m or less, preferably 300jam or less, in size at a ratio of 90% or more and having a moisture content of 1 to 14%, together with crystalline cellulose and/or low substituted hydroxypropy lcellulose. US6733780 discloses a direct compression polymer tablet core containing at least about 95% by weight of an aliphatic amine polymer and a method of producing such a tablet core involving the steps of hydrating the aliphatic amine polymer to the desired moisture level; blending with additives in amounts such that the polymer comprises at least about 95% by weight of the resulting blend; and compressing the blend to form the tablet core. WO2006050315 discloses Sevelamer carbonate compositions containing monovalent anion that can prevent or ameliorate acidosis, in particular acidosis in patients with renal disease. According to this document, addition of a monovalent anion source to Sevelamer carbonate prevents the increase in the disintegration time of the tablets and increases the shelf life. WO2007094779 discloses compositions containing aliphatic amine polymers prepared by spray granulation method. Health care professionals have recognized the detrimental effects of high sodium intake on blood pressure control, congestive heart failure and fluid balance in patients with chronic kidney disease. Further, limiting the intake of commonly used metals salts such as those of sodium, calcium, potassium, zinc, aluminium or magnesium will benefit the patients with chronic kidney disease and on haemodialysis. A study on role of salt intake in the progression of chronic kidney disease has been described in Journal of renal nutrition by E Ritz et.al. [Reference: 'Role of sodium intake in the progression of chronic kidney disease' by Department of Internal Medicine, Ruperto Carola University, Heidelberg, Germany; cited in Journal of renal nutrition 2009 Jan;19(l):61-2. by E Ritz et.al] In such a scenario, it would be best to restrict all metal ions, particularly sodium from any medicament to be used in patients with chronic kidney disease. Thus, there exists a need to develop pharmaceutical compositions which are devoid of all metal ions particularly the sodium ions and such a composition can be used safely in patients with chronic kidney disease. Object of Invention: An object of the present invention is to provide pharmaceutical compositions comprising wet granulated Sevelamer carbonate in association with pharmaceutically acceptable additives; characterized in that the composition is substantially free from added metal ions. Another object of the invention is to provide pharmaceutical compositions characterized in that the composition is devoid of crystalline cellulose and/or low substituted hydroxypropyl cellulose. Yet another object of the invention is to provide pharmaceutical compositions comprising wet granulated Sevelamer carbonate in association with pharmaceutically acceptable additives; wherein said additive comprises atleast one polyol selected from the group consisting of inositol, sorbitol, mannitol, isomalt, xylitol, lactitol, erythritol and maltitol. Another object of the invention is to provide pharmaceutical compositions characterized in that the composition is substantially free from monovalent anion source. Another object of the invention is to provide pharmaceutical compositions wherein the composition is free from added metal salt of monovalent anion. Another object of the invention is to provide pharmaceutical compositions characterized in that the composition is substantially free of reducing sugars. Another object of the invention is to provide pharmaceutical compositions comprising wet granulated Sevelamer carbonate in association with pharmaceutically acceptable additives wherein said additive comprises atleast one water soluble material in 1 range of 5.0% to 40.0% by weight of total composition. Summary of Invention: The present invention provides a pharmaceutical composition comprising wet granulated Sevelamer carbonate in association with pharmaceutically acceptable additives; characterized in that the composition is substantially free from added metal ions. The invention also provides a process for preparation of said compositions by wet granulation comprising high shear granulation or spray granulation. In one aspect, the present invention is directed to pharmaceutical compositions; wherein the composition is devoid of crystalline cellulose and/or low substituted hydroxypropyl cellulose. In another aspect, the invention is directed to pharmaceutical compositions of Sevelamer carbonate; wherein said composition comprises atleast one polyol selected from the group consisting of inositol, sorbitol, mannitol, isomalt, xylitol, lactitol, erythritol and maltitol. In another aspect, the invention is directed to pharmaceutical compositions characterized in that the composition is free from agents which compete with Sevelamer for the phosphate binding activity. In another aspect, the invention is directed to pharmaceutical compositions wherein the composition is free from added metal salt of monovalent anion. In another aspect, the invention is directed to pharmaceutical compositions characterized in that the composition is substantially free from monovalent anion source. In another aspect, the invention is directed to pharmaceutical compositions characterized in that the composition is substantially free of reducing sugars. In another aspect, the invention is directed to a process for preparation of pharmaceutical compositions of Sevelamer carbonate comprising wet granulation comprising the steps of: (a) providing a mixture of Sevelamer carbonate and one or more diluents; (b) optionally wetting the mixture of Sevelamer carbonate and diluent(s) using water or macrogol solution; (c) preparing a binder solution by dissolving binder in an organic solvent or mixture of organic solvent and water; (d) granulating the mixture of Sevelamer carbonate and diluent(s) of step (a) or step(b) using binder solution by high shear granulation or spray granulation to form granules; (e) formulating the granules into solid oral dosage forms such as tablets or capsules. Additional aspects and/or advantages of the present invention will be evident from the description that follows. Description of the invention: The present invention provides pharmaceutical compositions comprising wet granulated Sevelamer carbonate in association with pharmaceutically acceptable additives. Pharmaceutical compositions of the present invention are used for the control of serum phosphorus in patients with Chronic Kidney Disease(CKD) on dialysis. Health care professionals have recognized the detrimental effects of high sodium intake on blood pressure control, congestive heart failure and fluid balance in patients with chronic kidney disease. Further, limiting the intake of commonly used metals salts such as that of sodium, calcium, potassium, zinc or magnesium will benefit the patients with chronic kidney disease and on haemodialysis. The inventors of the present invention have now found that by selecting certain types of additives a pharmaceutical composition can be prepared which will be devoid of any adverse effects on patients with chronic kidney disease. In one embodiment, the present invention provides pharmaceutical compositions characterized in that the composition is substantially free from metal ions. More particularly, the invention provides pharmaceutical compositions characterized in that the composition is substantially free from added metal ions. In another embodiment, the present invention provides pharmaceutical composition comprising wet granulated Sevelamer carbonate in association with pharmaceutically acceptable additives; wherein the composition is devoid of crystalline cellulose and/or low substituted hydroxypropyl cellulose. In another embodiment, the present invention provides pharmaceutical compositions comprising wet granulated Sevelamer carbonate in association with pharmaceutically acceptable additives; wherein said additive comprises atleast one polyol selected from the group consisting of inositol, sorbitol, mannitol, isomalt, xylitol, lactitol, erythritol and maltitol. These polyols are safe to be used in patients with diabetes. In one embodiment, the present invention provides pharmaceutical compositions characterized in that the composition is substantially free from monovalent anion source. In . another embodiment, the present invention provides pharmaceutical compositions wherein the composition is free from added metal salt of monovalent anion. Although prior art states that the addition of a monovalent anion source to Sevelamer carbonate prevents the increase in the disintegration time of the tablets and increases the shelf life, the inventors of the present invention have successfully prepared a stable tablet formulation of Sevelamer carbonate by eliminating the incorporation of any monovalent anion source and particularly eliminating the incorporation of sodium chloride. Thus the pharmaceutical compositions of the present invention is devoid of any monovalent anion source. In another embodiment, the present invention provides pharmaceutical compositions comprising wet granulated Sevelamer carbonate in association with pharmaceutically acceptable additives wherein said additive comprises atleast one water soluble material in the range of 5.0% to 40.0% by weight of total composition. In the practice of the present invention, the pharmaceutical composition comprises water soluble materials in the range from about 5.0% to about 40.0% by weight of the total composition. In another embodiment, the present invention provides pharmaceutical compositions characterized in that the composition is substantially free of reducing sugars. Reducing sugars in basic solution, forms aldehyde or ketone and allows the sugar to act as a reducing agent. Some reducing sugars are glucose, fructose, lactose, glyceraldehyde, arabinose and maltose. Monosaccharides that contain ketone groups are known as ketoses and those which contain aldehyde groups are known as aldoses. Sevelamer contains the amine group which under go a Maillard reaction in contact with additives that contain reducing sugars. Maillard reaction is well known in the art. The products of maillard reaction are basically brown pigments. Formation of these brown pigments are indication of chemical instability of the composition. In another embodiment, the invention provides pharmaceutical compositions characterized in that the composition is free from agents which compete with Sevelamer for the phosphate binding activity. These agents contain the phosphate moiety which compete with the Sevelamer for phosphate binding activity. Such agents include calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate. Sevelamer is a phosphate binding polymer and any phosphate containing additive may compete for phosphate binding activity of Sevelamer. The inventors of the present invention have found that exclusion of such phosphate containing additives renders a more effective composition. In one embodiment, the invention provides a process for preparation of pharmaceutical compositions of Sevelamer carbonate comprising wet granulation comprising the steps of: (a) providing a mixture of Sevelamer carbonate and one or more diluents; (b) optionally wetting the mixture of Sevelamer carbonate and diluent(s) using water or macrogol solution; (c) preparing a binder solution by dissolving binder in an organic solvent or mixture of organic solvent and water; (d) granulating the mixture of step(a) or step(b) using binder solution by high shear granulation or spray granulation to form granules; (e) formulating the granules into solid oral dosage forms. In one embodiment, the invention provides use of a composition according to the invention for the manufacture of a medicament for the control of serum phosphorus in patients with chronic kidney disease (CKD) on dialysis. The invention also provides a process for preparation of compositions of Sevelamer carbonate by wet granulation comprising high shear granulation or spray granulation. In one embodiment, the invention provides a process for preparation of Sevelamer carbonate compositions comprising high shear wet granulation comprising the steps of: (a) providing a mixture of Seveiamer carbonate and one or more diluents; (b) optionally wetting the mixture of Seveiamer carbonate and diluent(s) using water or macrogol solution; (c) preparing a binder solution by dissolving binder in an organic solvent or mixture of organic solvent and water; (d) granulating the mixture of step(a) or step(b) using binder solution by high shear granulation or spray granulation to form granulated mass; (e) drying the granulated mass; (f) sizing and milling the dried granulated mass using ball mill or fluid energy mill to form granules of suitable size; (g) blending the milled granules with one or more disintegrants and lubricating the granules; (h) compressing the lubricated granules into tablets and further coating the tablet or (i) filling the lubricated granules of step(g) into capsules. In another embodiment, the invention provides a process for preparation of Seveiamer carbonate compositions comprising spray granulation comprising the steps of: (a) providing a mixture of Seveiamer carbonate and one or more diluents; (b) optionally wetting the mixture of Seveiamer carbonate and diluent(s) using water or macrogol solution; (c) preparing a binder solution by dissolving binder in an organic solvent or mixture of organic solvent and water; (d) spraying the binder solution of step (c) onto the mixture of step(a) or step(b) to form a uniformly fine granulated mass; (e) drying the granulated mass; (f) sizing and milling the dried granulated mass using ball mill or fluid energy mill to form granules of suitable size; (g) blending the milled granules with one or more disintegrants and lubricating the granules (h) compressing the lubricated granules into tablets and further coating the tablet or (i) filling the lubricated granules of step(g) into capsules. Phosphate binding polymer Sevelamer carbonate is insoluble in water but swells in contact with water. Due to this tendency of swelling, formulating Sevelamer by wet granulation becomes difficult. The inventors attempted formulating Sevelamer carbonate by hot melt granulation and hot melt extrusion techniques. However, the results were not satisfactory as very high amount of binder was required and also the granules produced were lacking adequate flow properties. The inventors of the present invention have been successful in developing a process for wet granulation of Sevelamer carbonate by high shear granulation or spray granulation. High shear granulation can be carried out in rapid mixer granulator or planetary mixer and spray granulation can be carried out in fluid bed processor. High shear wet granulation or wet granulation by spraying as practiced by the present invention improves the cohesiveness of particles and provides excellent flowability and compression characteristics to the tablet. As the granules exhibit good flow properties, tablets produced possess uniformity in weight. In practice of the present invention, any commercially available Sevelamer carbonate can be used or Sevelamer carbonate as used in the present invention may be prepared by any conventional processes. In one embodiment, the particles of Sevelamer carbonate are round in shape, particularly spherical or oval in shape. Spherical or oval shaped particles have low bulk density and poor flowability and further resist size reduction. Particles resist deformation and do not rupture or fracture. Due to these characteristics of Sevelamer carbonate, formulating Sevelamer carbonate by direct compression method becomes extremely difficult. In the practice of the present invention, the spherical morphology and hydrophilic nature of active ingredient Sevelamer carbonate presents a special challenge to the formulator. In one embodiment of the invention, the process of preparation of Sevelamer carbonate by wet granulation comprises providing a mixture of Sevelamer carbonate and one or more diluents; wetting the said mixture with water; granulating the wet mixture by wet granulation method using a solvent and preferably by using a binder solution prepared by dissolving the binder in the solvent; the granulation process being carried out in a rapid mixer granulator. Granulated mass is dried to remove the solvent. Dried granules are further milled or pulverized to get granules size less than 425 microns, preferably less than 250 microns and most preferably below 150 microns using a multi-mill initially and then a fluid energy mill or a ball mill; preferably by using a ball mill. Milled or pulverized granules are blended with one or more disintegrants and lubricated using lubricants known in the art and further compressed to provide tablets of required size. Compressed tablets are film coated by non-aqueous coating or aqueous coating or by hydroalcoholic coating. In a preferred embodiment, the process of preparation of Sevelamer carbonate compositions comprises mixing Sevelamer carbonate with one or more diluents; wetting the mixture using a solution of polyethylene glycol 6000 (Macrogol) dissolved in water; preparing a binder solution by dissolving polyvinyl pyrrolidone (Povidone K-30) in an organic solvent (isopropyl alcohol); granulating the wet mixture using the said binder solution and drying the granules. Sizing the dried granules through 100# on vibrosifter after milling with multi-mill and ball mill, blending the milled granules with one or more disintegrants and further lubricating with lubricants and compressing the granules. Core tablets are further film coated by aqueous process till a weight gain of 4.0% to 6.0% is achieved. Sevelamer carbonate is a polymeric material with very poor flowability and is bulky. Wetting with water helps in decreasing the interparticulate distance and increasing the contact area between the particles; thus making the Sevelamer carbonate more amenable for the granulation. Wetting is carried out either in a rapid mixer granulator or a planetary mixer or a fluid bed processor. In the practice of the present invention, wetting of mixture of active and diluent is carried out using about 8.0% to 12.0% by weight of water. Alternatively, the mixture of Sevelamer carbonate and diluent may be made wet using a solution of polyethylene glycol dissolved in water. In an alternate method, polyethylene glycol 6000 may be added into the dry mix as a fine powder during the mixing step. Polyethylene glycols of various grades may be used such as polyethylene glycol 6000 or the like. In the practice of the present invention, granulation is carried out by adding the binder slowly in a thin stream continuously using a peristaltic pump under high speed mixing with the impeller 'on' and chopper 'off. On completion of binder addition, continue mixing at high impeller speed till cohesive granular mass is obtained. If the mass is lumpy then chopper may be used at high speed with impeller also at high speed to obtain uniform wet mass. Drying of wet mass may be carried out using fluidized bed drier or tray drier. Initial drying is performed without application of temperature so as to remove the organic solvent and further the wet mass is dried for sufficient time at about 45°C to 50°C till loss on drying value is achieved in the range of about 8.0% to about 12.0%. If planetary mixer is used for granulation, the wet mass is to be milled on a multi-mill using 8.0 mm screen and then charged for drying. In one embodiment, the process comprises mixing Sevelamer carbonate with one or more diluents; optionally wetting the mixture using water in a rapid mixer granulator; preparing a binder solution by dissolving ethyl cellulose in an organic solvent such as isopropyl alcohol; granulating the mixture of Sevelamer carbonate and diluents using the said binder solution and drying the granules. Sizing the dried granules through 100# on vibrosifter after milling with multi-mill and ball mill and further blending the milled granules with one or more disintegrants and lubricating with lubricants and compressing the granules into tablets. Core tablets are further film coated. In a preferred embodiment, Sevelamer carbonate is mixed with mannitol and made wet using water; granulated using binder solution prepared by dissolving the ethyl cellulose in isopropyl alcohol. Granulation is carried out in a rapid mixer granulator and the granulated mass is dried to remove the organic solvent till loss on drying value in the range of about 8.0% to about 12.0% is achieved. Dried mass is sized using ball mill to achieve granules of required size; blended with one or more disintegrants and further lubricated with lubricants and compressed into tablets. In another embodiment, the process of preparation of Sevelamer carbonate composition comprises providing a mixture of active ingredient Sevelamer carbonate and one or more additives; granulating the mixture by high shear wet granulation or wet granulation by spraying using a solvent and preferably by using a binder solution prepared by dissolving the binder in solvent; the granulation process being carried out in a rapid mixer granulator. Granulated mass is further dried to remove the solvent and a loss on drying value in the range of about 8.0% to about 12.0% is achieved. Dried granules are further milled or pulverized to get granules of size less than 425 microns, preferably less than 250 microns and most preferably 150 microns using a fluid energy mill or a ball mill; preferably by using a ball mill. Milled or pulverized granules are blended with disintegrants and lubricated using lubricants and further compressed to provide tablets of required size or filled into capsules. Compressed tablets may be further coated. In one embodiment, the granules provided by high shear wet granulation or wet granulation by spraying process as described herein are spherical granules of size less than 425 microns, preferably less than 250 microns and most preferably below 150 microns. Although the dried granulated mass can be milled or pulverized using conventional equipments known in the art such as a multimill, co-mill, cadmill or fitzmill, they have limitations when used for size reduction of Sevelamer carbonate granules. Granule size less than 425 microns (40#), preferably less than 250 microns (60#) and most preferably 150 microns (which passes through 100#) is difficult to obtain using such mills. Large granules pose difficulties during compression by decreasing the compressibility of the granules and produces porous tablets with low hardness which consequently exhibit high friability and pose a risk of moisture uptake during aqueous film coating. Oversized granules retained after milling through 0.5mm screen on a conventional mill and sifting on a vibrosifter through 60# and then 100# are milled in a ball mill or fluidized energy mill to obtain particle size less than 425 microns, preferably less than 250 microns and most preferably below 150 microns for the granules. According to the invention, size reduction or pulverization using fluid energy mill or ball mill provides spherical granules of size less than 150microns, which provides an ease in compressibility. Ball milling being the preferred mode for size reduction of granules. In ball milling, the process of size reduction occurs due to combined effect of impact and attrition. In a fluid energy mill, the material is suspended and conveyed at high velocity by air, which is passed through nozzles at 100 to 150 pounds per square inch. The violent turbulence of the air reduces the particle size by interparticulate attrition. Ball mill is preferred interms of output and productivity for large scale batches. In the practice of the present invention comminution techniques comprise grinding in an air- jet mill/impact mill, fluid energy mill, ball mill, vibration mill, mortar mill or pin mill. Milled mass is further sifted through a vibrosifter and oversized particles were milled through a mill preferably a ball mill with stainless steel balls and further sifted through a vibrosifter. Mass is repeatedly milled with ball mill and sifted through vibrosifter till the resultant granules passes through 100#. According to a preferred aspect, granules of the present invention preferably have a particle size of 100% passing through 100#. Particle of size 150microns or less provides satisfactory compression of granules and further provides elegant non-porous, non-friable tablets with a smooth impervious surface which can withstand the rigours of aqueous film coating. In the practice of the present invention, the granule size is controlled and 100% granules passes through 100# and provides tablets which exhibit a smooth impervious surface with a hardness greater than 100 N, friability less than 0.8% and preferably in the range of 0 to 0.5%, disintegration time of about 5 minutes, and a smooth aqueous film coating operation. By controlling the granule size at less than 425 microns, preferably less than 250 microns and most preferably 150 microns(which passes through 100#) elegant tablets are produced. In another embodiment, Sevelamer carbonate tablets may be coated by aqueous or non-aqueous or hydroalcoholic coating. Film coating provides an impervious surface and prevents the ingress of moisture from the aqueous coat. In a preferred embodiment, coating of tablets is done using an aqueous coating method. Aqueous coating of an hydrophilic active ingredient is another difficult process and posed a real challenge to the inventors of the present invention as the Sevelamer has a tendency to swell in presence of water. Aqueous coating has been achieved by having a fine control on the hardness of the cores, which balances the need for a hard core to ensure good coating as well as meets the requirement for disintegration of coated tablets. As the tablet core is hard with an impervious smooth surface, it withstands the aqueous film coating and the polymer Sevelamer carbonate does not swell during coating. Film coating may be carried out using polymers such as polyvinyl alcohol, hydroxyethyl cellulose, ethylcellulose, hydroxypropyl methyl cellulose, methacrylic acid co-polymers. Ready mix coating materials may comprise plasticizers selected from propylene glycol, triacetin or polyethylene glycol. Coating agents may be used in the range of about 3% to about 8% by weight of total composition. Coating composition is devoid of any colouring agent. Tablets may be compressed using suitable punches and dies. According to the invention, tablets may be of oval, elliptical, spherical or caplet shape. Compression can be carried out using equipments known in the art such as a rotary tablet press or any compression machine. Tablets prepared by the process according to the invention meet the specification for disintegration (Limit not more than 30 minutes). Other parameters of tablets such as hardness, friability, and thickness were measured and the results met the standard specifications for tablets. Compositions of Sevelamer carbonate, particularly the tablets may be packed in aluminium strips or by cold formed blister pack, which is a cold process of blister packing, which acts as an excellent moisture barrier with negligible moisture vapor transmission rate and adequate environmental protection during shelf life. According to another embodiment, the spherical granules produced by high shear wet granulation or wet granulation by spraying process may be filled along with suitable additives into hard gelatin capsules of suitable size. Capsule filling can be done using any suitable capsule filling machine. In one embodiment, the pharmaceutical compositions of the present invention comprises Sevelamer carbonate in the range of about 60.0% to about 90.0% by weight of total composition. More particularly, Sevelamer carbonate compositions of the present invention may be provided in dose strength of 800mg. Pharmaceutically acceptable additives that may be used according to the present invention include one or more additives selected from diluents, binders, lubricants, glidants, coating agents, plasticizers and the like. According to the invention, the additives chosen are such that they do not pose any risk for patients with chronic kidney disease. Diluents are substances which usually provide bulk to the composition. Suitable diluents for use in the pharmaceutical composition of the invention include, but are not limited to maize starch, pregelatinized starch, polyols selected from the group consisting of inositol, sorbitol, mannitol, isomalt, xylitol, lactitol, erythritol, maltitol and the like. Most preferred diluent for use in the pharmaceutical composition of the present invention is mannitol and isomalt. Preferably, the composition comprises diluents in an amount of about 0.1% to about 10.0% by total weight of the composition. Additives such as mannitol and isomalt have an advantage of low moisture pick up and satisfactory flow characteristics. Granules containing mannitol get easily dried and they have less tendency to pick up moisture. Mannitol is the most preffered additive as it can be used in an amount of about 0.2% to about 7.0% by total weight of the composition, preferably between 0.4% to 5.0%. Granular and spray dried forms of mannitol are generally used in granulations. Mannitol provides granules which can be easily dried. Sevelamer carbonate being moisture sensitive, mannitol is the preferred diluent as it is not hygroscopic. Various grades of mannitol are available commercially. Preferred grades of mannitol include Pearlitol SD 200 of Roquette, France. Isomalt is hydrogenated isomaltulose which is an equimolar mixture of alpha d glucopyranosido-1,6 sorbitol and alpha-D glucospyranosido-l,6mannitol. Isomalt is a non carcinogenic additive commonly used in pharmaceutical preparations. Isomalt is available in various grades based on the particle size where fine grade viz.GalenlQ 810 is used in the wet granulation. Isomalt is preferably used in the range of about 0.2% to about 7%. Considering the end use of the formulation, mannitol is the preferred diluent. On oral administration, mannitol is not absorbed significantly from the gastrointestinal tract. As diabetes is the leading cause of end-stage renal disease (ESRD) in many cases, the use of sugars as diluents is avoided. Tablet compositions which uses lactose and dextrose as diluents show discoloration as the tablets turn to yellowish brown colour due to Maillard reaction. Similarly dibasic calcium phosphate, tribasic calcium phosphate are also avoided since Sevelamer is a phosphate binding polymer and any phosphate containing diluent may compete for phosphate binding activity of Sevelamer. Binders impart cohesiveness to tablet formulation and ensures that the tablet remain intact after compression. Suitable binders for use in the pharmaceutical composition of the invention include, but are not limited to hydroxy propyl methyl cellulose, hydroxy ethyl cellulose, ethyl cellulose, cellulose derivatives, maize starch, starch derivatives, polyvinylpyrrolidone alone or in combination with polyethylene glycols and the like. Pharmaceutical composition according to the invention comprises binders in an amount of about 3.0% to about 15.0% by total weight of the composition. Binder preferred in the practice of the present invention is ethyl cellulose or polyvinyl pyrrolidone. Different grades of ethyl cellulose having various viscosities are commercially available. Ethyl cellulose of specific grades or blends of different grades may be used to obtain solutions of desired viscosity. Ethyl cellulose having viscosity in the range of 4cps to 22 cps is used; preferred being ethyl cellulose with viscosity of about 5 to 15cps. Preferred grade of ethyl cellulose used for Sevelamer carbonate tablets is Ethocel EC-N 7 Pharm manufactured by Dow chemical company. Ethyl cellulose is not metabolized following oral consumption and therefore a non-calorific substance. Suitable solvents that can be used for preparation of binder solution include isopropyl alcohol, ethanol or dichloromethane. Suitable disintegrants for use in the pharmaceutical composition of the invention include, but are not limited to pregelatinised starch crospovidone and the like. Disintegrants is used in an amount of about 2.0% to about 10.0% by weight of total composition. Lubricants are additives that are used to prevent adhesion of the granules/powder material to the manufacturing equipments such as hoppers. Lubricants reduce the interparticle friction and improves the flow of the gf anules/powder materials and also assist the ejection of the tablet from the tabletttfg die. Suitable lubricants for use in the pharmaceutical composition of the invention include, but are not limited to stearic acid, glyceryl monostearate, glyceryl beher»ate, glyceryl palmitostearate, hydrogenated vegetable oil, mineral oil, polyethylene glycol and the like. Pharmaceutical composition according to the invention comprises lubricants in an amount of about 0.1% to about 3.0% by weight of total composition. In one embodiment, the pharmaceutical compositions of the present invention comprises about 60.0% to 90.0% by weight of Sevelamer carbonate, about 0.1% to about 10.0% by weight of diluent, about 3.0% to about 15.0% by weight of binder, about 2.0% to about 10.0% by weight of disintegrant, about 0.1% to about 3.0% by weight of lubricants and about 3.0% to about 6.0% by weight of coating agents. Suitably the solid dosage form of the present invention is a tablet or a capsule that can be produced on a commercial scale. Compositions prepared by the process as described herein withstand the accelerated stability conditions of temperature and relative humidity and maintain their physical and chemical integrity at accelerated conditions of stability. The features of the present invention can be extended to other aliphatic amine polymers. Some of the aliphatic amine polymers known in the art include colestipol, cholestryramine, orlistat, colesevelam and the like. The present invention further provides use of the compositions of Sevelamer carbonate in the control of serum phosphorus in patients suffering from chronic kidney disease (CK.D) on hemodialysis. In one embodiment, the present invention provides a method for treating a patient suffering from chronic kidney disease (CKD) on hemodialysis comprising administering a therapeutically effective amount of Sevelamer carbonate composition as described herein. Although the present invention makes use of organic solvents such as isopropyl alcohol for granulation, the organic volatile impurity level in the finished product is quite low and is within the permissible limit. (Limit as per ICH guidelines : 5000 ppm) As used herein, the term "composition", unless otherwise defined refers to granules and/or solid oral pharmaceutical dosage forms of the invention that contain Sevelamer carbonate. As used herein, the term "additives" refers to a pharmaceutically acceptable ingredient that is commonly used in the pharmaceutical technology for preparing granules and/or solid oral pharmaceutical dosage forms. As used herein, the term "therapeutically effective amount" refers to an amount sufficient to cause an improvement in a clinically significant condition in the patient or even prevent a disease, disorder or condition in a patient. As used herein, the term "tablet" is intended to encompass compressed pharmaceutical dosage formulations of all shapes and sizes, whether coated or uncoated. The present invention is further illustrated by reference to the following examples which is for illustrative purpose only and does not limit the scope of the invention in any way. Examples: Example 1 Sevelamer carbonate (168g ) was co-sifted with mannitol (Pearlitol SD 200) (4g) and was added to a rapid mixer granulator (RMG). Water (20g) was then added to it and mixed at impeller speed 100 rpm. Ethyl cellulose (16g) was dissolved in hot (45°C) isopropyl alcohol (50 g) and was added to the RMG and the mixture of Sevelamer carbonate and mannitol was granulated at impeller speed 180 rpm without chopper on. Granulated mass was then discharged into bowl of Restch dryer and air dried followed by drying at temperature of about 50°C. Dried mass was milled using multimill/sifter and further using ball mill to obtain granules which passed through 100# S.S.sieve. Granules were blended in a conta blender with Kollidon CLF( 12 g) previously sifted through 60# S.S.sieve and further blended with stearic acid (1 g) previously sifted through 60# S.S.sieve . Lubric¬ated granules were compressed on a conventional tableting machine to produce 800mg tablets of Sevelamer carbonate. Core tablets were film coated by aqueous process till a weight gain in the range of about 4.0% to about 6.0% was achieved. Example 2 Sevelamer carbonate (420 g) was co-sifted with mannitol (Pearlitol SD 200) (lOg) using 20# stainless steel sieve and was transfered into a rapid mixer granulator and mixed for 5minutes at lOOrpm. Binder solution was prepared by dissolving povidone in a mixture of isopropyl alcohol and water (65:35). Binder solution was added to the mixture of Sevelamer carbonate and mannitol and was mixed at im¬peller high speed 180 to 200 rpm with chopper off for sufficient time till a cohes¬ive mass was formed. The mass was air dried for sufficient time in Glatt drier and further dried at temperature of 50°C to 60°C till loss on drying value of about 10% to 12% was achieved. Dried granules were sifted through 100# sieve and the over sized granules were milled using ball mill and the milled mass was sifted through 100# sieve. Sifted granules were blended with presifted Kollidon CLF (sifted through 60#) and stearic acid (sifted through 60#) in a conta blender and was compressed on 0.826 x 0.374 inch capsule shaped punches and dies to obtain tab¬let having weight of 1130 mg per tablet and hardness of about 80 to HON. Com¬pressed tablets were coated using coating solution prepared by dissolving coating ready mix containing HPMC 5 cps and triacetin in water, till weight gain of 4.0% to 6.0 % of the core tablet was achieved. Example 3: Sevelamer carbonate (840 g) was co-sifted with mannitol (Pearlitol SD 200) (20g) using 20 mesh S S Sieve on vibrosifter, and loaded into the rapid mixer granulator and was mixed for about 5 minutes. Binder solution was prepared by dissolving about 80 g Ethocel in 400 g Isopropyl alcohol and was added to the dry mix in the rapid mixer granulator which was pre-wetted with water (110 g). Wet mass was air dried in Glatt drier followed by drying at temperature about 50°C. Dried mass was milled using multimill/sifter and further milled using ball mill to obtain gran¬ules which passed through 100# s.s.sieve. Granules were blended in a conta blender with pregelatinised starch (70.0g) previously sifted through 60# s.s.sieve and further blended with stearic acid (l.Og) previously sifted through 60# s.s.sieve. Lubricated granules were compressed on a conventional tableting ma¬chine to produce Sevelamer carbonate tablets 800mg. Core tablets were film coated by aqueous process till a weight gain in the range of about 4.0% to about 6.0% was achieved. Example 4 Sevelamer carbonate (420 g) was co-sifted with mannitol (Pearlitol SD 200) (lOg) using 20# stainless steel sieve and transfered into a rapid mixer granulator and mixed for 5minutes at lOOrpm. A binder solution was prepared by dissolving povidone in a mixture of isopropyl alcohol and water (100:35 g). The binder solu¬tion was added to the mixture of Sevelamer carbonate and mannitol and was mixed at impeller high speed 180 to 200 rpm with chopper off condition for suffi¬cient time till a cohesive mass was formed. The mass was air dried for sufficient time in Glatt drier and further dried at temperature of 50°C to 60°C till loss on dry¬ing value of about 10% to 12% was achieved. Dried granules were sifted through 100# Sieve and the over sized granules were milled using ball mill and the milled mass was sifted through 100# sieve. Sifted granules were blended with presifted pregelatinised starch 1500 (sifted through 60#) and stearic acid (sifted through 60#) in a conta blender and was compressed on 0.826 x 0.374 inch capsule shaped punches and dies to obtain tablet having weight of 1130 mg per tablet and hard¬ness of about 80 to 140 N. Compressed tablets were Coated using coating solution prepared by dissolving coating ready mix containing HPMC 5 cps and triacetin in water, till weight gain of 4.0% to 6.0 % of the core tablets was achieved. It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and tha.t the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative ^nd not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

Full Text

FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
PROVISIONAL SPECIFICATION
(See section 10, rule 13)
1. Title of the invention
"Pharmaceutical compositions comprising phosphate- binding polymer1'
2. Applicant(s)

Name

Nationality

Address

USV LIMITED

Indian company incorporated under Companies Act, 1956

BSD. Marg, Govandi, Mumbai - 400 088 Maharashtra, India

3. Preamble to the description
The following specification particularly describes the invention.

Technical field of the invention:
The present invention relates to pharmaceutical compositions of Sevelamer carbonate in association with pharmaceutically acceptable additives; process for their preparation comprising wet granulation and methods of using such compositions for the control of serum phosphorus in patients with Chronic Kidney Disease(CKD) on dialysis.
Background of the invention:
Chronic kidney disease (CKD) is a progressive loss of renal function over a period of time. CKD is identified by performing a blood test for creatinine. High levels of creatinine indicates a poor glomerular filtration rate and a decreased capability of the kidneys to excrete waste products. Decreased kidney function leads to high blood pressure due to fluid overload and production of vasoactive hormones and increases the risk of hypertension or congestive cardiac failure; urea accumulation; potassium accumulation; decreased erythropoietin synthesis; edema; hyperphosphatemia due to reduced phosphate excretion; metabolic acidosis.
In End-stage renal disease (ESRD) there is a total kidney failure requiring the patients to have renal replacement therapy, either dialysis or transplantation becomes necessary to maintain life. Hemodialysis involves circulation of blood through a filter on a dialysis machine where the blood is cleansed of waste products and excess water. The acid levels and the concentration of various minerals such as sodium and potassium in the blood are normalized and blood is then returned to the body.
Patients with chronic kidney disease (CKD) retain phosphorus and can develop hyperphosphatemia. Hyperphosphatemia is a condition where the serum phosphate levels are greater than 5mg/dL in adults or 7mg/dL in children or adolescents. If the condition persists for a long period then it leads to severe

abnormalities in calcium and phosphorus metabolism resulting in calcification in joints, lungs and eyes. Hyperphosphatemia plays a role in the development of secondary hyperparathyroidism in renal insufficiency. Treatment of hyperphosphatemia includes reduction in dietary intake of phosphate, inhibition of intestinal phosphate absorption with phosphate binders and removal of phosphate with dialysis.
Oral administration of phosphate binders like calcium or aluminium for the treatment of hyperphosphatemia are well known in the art. Most widely used are the calcium salts such as calcium carbonate, calcium acetate, calcium citrate, calcium alginate. These calcium salts when ingested binds to the intestinal phosphate to form insoluble calcium phosphate salts such as calcium hydrogen phosphate, calcium dihydrogen phosphate or tricalcium phosphate and thus prevents the phosphate absorption. However, the drawback associated with this mode of treatment is that due to absorption of high amount of ingested calcium, the patient develops hypercalcemia which inturn results in cardiac arrhythmias, renal failure, and skin and visceral calcification.
Sevelamer carbonate is a polymeric amine which binds to phosphates when administered orally. Sevelamer carbonate has the same polymeric structure as Sevelamer hydrochloride in which carbonate replaces chloride as the counterion. Sevelamer carbonate is chemically poly (allylamine-co-NjN'-diallyl-l^-diamino-2-hydroxypropane) carbonate salt. Structure of Sevelamer carbonate is as represented,

where 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
Sevelamer carbonate is developed by Genzyme Corporation and marketed under the brand name Renvela™. The prescribing information for Renvela™ is available on www.fda.gov/cder/foi/label/2007/0221271bl.pdf. Renvela™ is indicated for the control of serum phosphorus in patients with chronic kidney disease (CKD) on dialysis. Renvela contains Sevelamer carbonate, a non-absorbed phosphate binding crosslinked polymer, free of metal and calcium. Renvela™ 800mg tablets contain 800mg of Sevelamer carbonate on an anhydrous basis, microcrystalline cellulose, hypromellose, diacetylated monoglycerides, sodium chloride and zinc stearate.
Sevelamer carbonate taken with meals has been shown to control serum phosphorus concentrations in patients with CKD who are on dialysis. Sevelamer carbonate 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. Sevelamer carbonate binds the phosphorus in the gastrointestinal tract to facilitate

phosphorus excretion in feces, thereby inhibiting phosphorus absorption from the gut, and thereby lowering the plasma phosphorus concentration.
Patients with end-stage renal disease (ESRD) retain phosphorus which lead to development of hyperphosphatemia. Control of phosphorus is the primary goal in the care of patients with end-stage renal disease (ESRD). Sevelamer carbonate controls the serum phosphorus in patients with ESRD who are on hemodialysis, without increasing serum calcium levels or contributing an excess calcium load.
US5496545 discloses phosphate-binding polymers that are orally administered and useful for the treatment of hyperphosphatemia.
US6083495 discloses a class of anion exchange polymers having improved phosphate binding properties and a method of removing phosphate from a patient by ion exchange involving oral administration of a-therapeutically effective amount of a composition containing at least one phosphate-binding polymer.
US6696087 discloses a phosphate-binding polymer tablet that contains a large amount of the phosphate-binding polymer having an average particle size of 400um or less, preferably 250jam or less, containing particles of 500u.m or less, preferably 300jam or less, in size at a ratio of 90% or more and having a moisture content of 1 to 14%, together with crystalline cellulose and/or low substituted hydroxypropy lcellulose.
US6733780 discloses a direct compression polymer tablet core containing at least about 95% by weight of an aliphatic amine polymer and a method of producing such a tablet core involving the steps of hydrating the aliphatic amine polymer to the desired moisture level; blending with additives in amounts such that the polymer comprises at least about 95% by weight of the resulting blend; and compressing the blend to form the tablet core.

WO2006050315 discloses Sevelamer carbonate compositions containing monovalent anion that can prevent or ameliorate acidosis, in particular acidosis in patients with renal disease. According to this document, addition of a monovalent anion source to Sevelamer carbonate prevents the increase in the disintegration time of the tablets and increases the shelf life.
WO2007094779 discloses compositions containing aliphatic amine polymers prepared by spray granulation method.
Health care professionals have recognized the detrimental effects of high sodium intake on blood pressure control, congestive heart failure and fluid balance in patients with chronic kidney disease. Further, limiting the intake of commonly used metals salts such as those of sodium, calcium, potassium, zinc, aluminium or magnesium will benefit the patients with chronic kidney disease and on haemodialysis.
A study on role of salt intake in the progression of chronic kidney disease has been described in Journal of renal nutrition by E Ritz et.al. [Reference: 'Role of sodium intake in the progression of chronic kidney disease' by Department of Internal Medicine, Ruperto Carola University, Heidelberg, Germany; cited in Journal of renal nutrition 2009 Jan;19(l):61-2. by E Ritz et.al]
In such a scenario, it would be best to restrict all metal ions, particularly sodium from any medicament to be used in patients with chronic kidney disease.
Thus, there exists a need to develop pharmaceutical compositions which are devoid of all metal ions particularly the sodium ions and such a composition can be used safely in patients with chronic kidney disease.

Object of Invention:
An object of the present invention is to provide pharmaceutical compositions comprising wet granulated Sevelamer carbonate in association with pharmaceutically acceptable additives; characterized in that the composition is substantially free from added metal ions.
Another object of the invention is to provide pharmaceutical compositions characterized in that the composition is devoid of crystalline cellulose and/or low substituted hydroxypropyl cellulose.
Yet another object of the invention is to provide pharmaceutical compositions comprising wet granulated Sevelamer carbonate in association with pharmaceutically acceptable additives; wherein said additive comprises atleast one polyol selected from the group consisting of inositol, sorbitol, mannitol, isomalt, xylitol, lactitol, erythritol and maltitol.
Another object of the invention is to provide pharmaceutical compositions characterized in that the composition is substantially free from monovalent anion source.
Another object of the invention is to provide pharmaceutical compositions wherein the composition is free from added metal salt of monovalent anion.
Another object of the invention is to provide pharmaceutical compositions characterized in that the composition is substantially free of reducing sugars.
Another object of the invention is to provide pharmaceutical compositions comprising wet granulated Sevelamer carbonate in association with pharmaceutically acceptable additives wherein said additive comprises atleast one water soluble material in 1 range of 5.0% to 40.0% by weight of total

composition.
Summary of Invention:
The present invention provides a pharmaceutical composition comprising wet granulated Sevelamer carbonate in association with pharmaceutically acceptable additives; characterized in that the composition is substantially free from added metal ions. The invention also provides a process for preparation of said compositions by wet granulation comprising high shear granulation or spray granulation.
In one aspect, the present invention is directed to pharmaceutical compositions; wherein the composition is devoid of crystalline cellulose and/or low substituted hydroxypropyl cellulose.
In another aspect, the invention is directed to pharmaceutical compositions of Sevelamer carbonate; wherein said composition comprises atleast one polyol selected from the group consisting of inositol, sorbitol, mannitol, isomalt, xylitol, lactitol, erythritol and maltitol.
In another aspect, the invention is directed to pharmaceutical compositions characterized in that the composition is free from agents which compete with Sevelamer for the phosphate binding activity.
In another aspect, the invention is directed to pharmaceutical compositions wherein the composition is free from added metal salt of monovalent anion.
In another aspect, the invention is directed to pharmaceutical compositions characterized in that the composition is substantially free from monovalent anion source.

In another aspect, the invention is directed to pharmaceutical compositions characterized in that the composition is substantially free of reducing sugars.
In another aspect, the invention is directed to a process for preparation of pharmaceutical compositions of Sevelamer carbonate comprising wet granulation comprising the steps of:
(a) providing a mixture of Sevelamer carbonate and one or more diluents;
(b) optionally wetting the mixture of Sevelamer carbonate and diluent(s) using water or macrogol solution;
(c) preparing a binder solution by dissolving binder in an organic solvent or mixture of organic solvent and water;
(d) granulating the mixture of Sevelamer carbonate and diluent(s) of step (a) or step(b) using binder solution by high shear granulation or spray granulation to form granules;
(e) formulating the granules into solid oral dosage forms such as tablets or capsules.
Additional aspects and/or advantages of the present invention will be evident from the description that follows.
Description of the invention:
The present invention provides pharmaceutical compositions comprising wet granulated Sevelamer carbonate in association with pharmaceutically acceptable additives. Pharmaceutical compositions of the present invention are used for the control of serum phosphorus in patients with Chronic Kidney Disease(CKD) on dialysis.
Health care professionals have recognized the detrimental effects of high sodium intake on blood pressure control, congestive heart failure and fluid balance in patients with chronic kidney disease. Further, limiting the intake of commonly

used metals salts such as that of sodium, calcium, potassium, zinc or magnesium will benefit the patients with chronic kidney disease and on haemodialysis.
The inventors of the present invention have now found that by selecting certain types of additives a pharmaceutical composition can be prepared which will be devoid of any adverse effects on patients with chronic kidney disease.
In one embodiment, the present invention provides pharmaceutical compositions characterized in that the composition is substantially free from metal ions. More particularly, the invention provides pharmaceutical compositions characterized in that the composition is substantially free from added metal ions.
In another embodiment, the present invention provides pharmaceutical composition comprising wet granulated Sevelamer carbonate in association with pharmaceutically acceptable additives; wherein the composition is devoid of crystalline cellulose and/or low substituted hydroxypropyl cellulose.
In another embodiment, the present invention provides pharmaceutical compositions comprising wet granulated Sevelamer carbonate in association with pharmaceutically acceptable additives; wherein said additive comprises atleast one polyol selected from the group consisting of inositol, sorbitol, mannitol, isomalt, xylitol, lactitol, erythritol and maltitol. These polyols are safe to be used in patients with diabetes.
In one embodiment, the present invention provides pharmaceutical compositions characterized in that the composition is substantially free from monovalent anion source.
In . another embodiment, the present invention provides pharmaceutical compositions wherein the composition is free from added metal salt of

monovalent anion. Although prior art states that the addition of a monovalent anion source to Sevelamer carbonate prevents the increase in the disintegration time of the tablets and increases the shelf life, the inventors of the present invention have successfully prepared a stable tablet formulation of Sevelamer carbonate by eliminating the incorporation of any monovalent anion source and particularly eliminating the incorporation of sodium chloride. Thus the pharmaceutical compositions of the present invention is devoid of any monovalent anion source.
In another embodiment, the present invention provides pharmaceutical compositions comprising wet granulated Sevelamer carbonate in association with pharmaceutically acceptable additives wherein said additive comprises atleast one water soluble material in the range of 5.0% to 40.0% by weight of total composition. In the practice of the present invention, the pharmaceutical composition comprises water soluble materials in the range from about 5.0% to about 40.0% by weight of the total composition.
In another embodiment, the present invention provides pharmaceutical compositions characterized in that the composition is substantially free of reducing sugars. Reducing sugars in basic solution, forms aldehyde or ketone and allows the sugar to act as a reducing agent. Some reducing sugars are glucose, fructose, lactose, glyceraldehyde, arabinose and maltose. Monosaccharides that contain ketone groups are known as ketoses and those which contain aldehyde groups are known as aldoses. Sevelamer contains the amine group which under go a Maillard reaction in contact with additives that contain reducing sugars. Maillard reaction is well known in the art. The products of maillard reaction are basically brown pigments. Formation of these brown pigments are indication of chemical instability of the composition.
In another embodiment, the invention provides pharmaceutical compositions

characterized in that the composition is free from agents which compete with Sevelamer for the phosphate binding activity. These agents contain the phosphate moiety which compete with the Sevelamer for phosphate binding activity. Such agents include calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate. Sevelamer is a phosphate binding polymer and any phosphate containing additive may compete for phosphate binding activity of Sevelamer. The inventors of the present invention have found that exclusion of such phosphate containing additives renders a more effective composition.
In one embodiment, the invention provides a process for preparation of pharmaceutical compositions of Sevelamer carbonate comprising wet granulation comprising the steps of:
(a) providing a mixture of Sevelamer carbonate and one or more diluents;
(b) optionally wetting the mixture of Sevelamer carbonate and diluent(s) using water or macrogol solution;
(c) preparing a binder solution by dissolving binder in an organic solvent or mixture of organic solvent and water;
(d) granulating the mixture of step(a) or step(b) using binder solution by high shear granulation or spray granulation to form granules;
(e) formulating the granules into solid oral dosage forms.
In one embodiment, the invention provides use of a composition according to the invention for the manufacture of a medicament for the control of serum phosphorus in patients with chronic kidney disease (CKD) on dialysis.
The invention also provides a process for preparation of compositions of Sevelamer carbonate by wet granulation comprising high shear granulation or spray granulation.
In one embodiment, the invention provides a process for preparation of Sevelamer

carbonate compositions comprising high shear wet granulation comprising the steps of:
(a) providing a mixture of Seveiamer carbonate and one or more diluents;
(b) optionally wetting the mixture of Seveiamer carbonate and diluent(s) using water or macrogol solution;
(c) preparing a binder solution by dissolving binder in an organic solvent or mixture of organic solvent and water;
(d) granulating the mixture of step(a) or step(b) using binder solution by high shear granulation or spray granulation to form granulated mass;
(e) drying the granulated mass;
(f) sizing and milling the dried granulated mass using ball mill or fluid energy mill to form granules of suitable size;
(g) blending the milled granules with one or more disintegrants and lubricating the granules;
(h) compressing the lubricated granules into tablets and further coating the
tablet or (i) filling the lubricated granules of step(g) into capsules.
In another embodiment, the invention provides a process for preparation of Seveiamer carbonate compositions comprising spray granulation comprising the steps of:
(a) providing a mixture of Seveiamer carbonate and one or more diluents;
(b) optionally wetting the mixture of Seveiamer carbonate and diluent(s) using water or macrogol solution;
(c) preparing a binder solution by dissolving binder in an organic solvent or mixture of organic solvent and water;
(d) spraying the binder solution of step (c) onto the mixture of step(a) or step(b) to form a uniformly fine granulated mass;
(e) drying the granulated mass;
(f) sizing and milling the dried granulated mass using ball mill or fluid energy

mill to form granules of suitable size; (g) blending the milled granules with one or more disintegrants and
lubricating the granules (h) compressing the lubricated granules into tablets and further coating the
tablet or (i) filling the lubricated granules of step(g) into capsules.
Phosphate binding polymer Sevelamer carbonate is insoluble in water but swells in contact with water. Due to this tendency of swelling, formulating Sevelamer by wet granulation becomes difficult.
The inventors attempted formulating Sevelamer carbonate by hot melt granulation and hot melt extrusion techniques. However, the results were not satisfactory as very high amount of binder was required and also the granules produced were lacking adequate flow properties.
The inventors of the present invention have been successful in developing a process for wet granulation of Sevelamer carbonate by high shear granulation or spray granulation. High shear granulation can be carried out in rapid mixer granulator or planetary mixer and spray granulation can be carried out in fluid bed processor. High shear wet granulation or wet granulation by spraying as practiced by the present invention improves the cohesiveness of particles and provides excellent flowability and compression characteristics to the tablet. As the granules exhibit good flow properties, tablets produced possess uniformity in weight.
In practice of the present invention, any commercially available Sevelamer carbonate can be used or Sevelamer carbonate as used in the present invention may be prepared by any conventional processes.
In one embodiment, the particles of Sevelamer carbonate are round in shape,

particularly spherical or oval in shape. Spherical or oval shaped particles have low bulk density and poor flowability and further resist size reduction. Particles resist deformation and do not rupture or fracture. Due to these characteristics of Sevelamer carbonate, formulating Sevelamer carbonate by direct compression method becomes extremely difficult. In the practice of the present invention, the spherical morphology and hydrophilic nature of active ingredient Sevelamer carbonate presents a special challenge to the formulator.
In one embodiment of the invention, the process of preparation of Sevelamer carbonate by wet granulation comprises providing a mixture of Sevelamer carbonate and one or more diluents; wetting the said mixture with water; granulating the wet mixture by wet granulation method using a solvent and preferably by using a binder solution prepared by dissolving the binder in the solvent; the granulation process being carried out in a rapid mixer granulator. Granulated mass is dried to remove the solvent. Dried granules are further milled or pulverized to get granules size less than 425 microns, preferably less than 250 microns and most preferably below 150 microns using a multi-mill initially and then a fluid energy mill or a ball mill; preferably by using a ball mill. Milled or pulverized granules are blended with one or more disintegrants and lubricated using lubricants known in the art and further compressed to provide tablets of required size. Compressed tablets are film coated by non-aqueous coating or aqueous coating or by hydroalcoholic coating.
In a preferred embodiment, the process of preparation of Sevelamer carbonate compositions comprises mixing Sevelamer carbonate with one or more diluents; wetting the mixture using a solution of polyethylene glycol 6000 (Macrogol) dissolved in water; preparing a binder solution by dissolving polyvinyl pyrrolidone (Povidone K-30) in an organic solvent (isopropyl alcohol); granulating the wet mixture using the said binder solution and drying the granules. Sizing the dried granules through 100# on vibrosifter after milling with multi-mill

and ball mill, blending the milled granules with one or more disintegrants and further lubricating with lubricants and compressing the granules. Core tablets are further film coated by aqueous process till a weight gain of 4.0% to 6.0% is achieved.
Sevelamer carbonate is a polymeric material with very poor flowability and is bulky. Wetting with water helps in decreasing the interparticulate distance and increasing the contact area between the particles; thus making the Sevelamer carbonate more amenable for the granulation. Wetting is carried out either in a rapid mixer granulator or a planetary mixer or a fluid bed processor. In the practice of the present invention, wetting of mixture of active and diluent is carried out using about 8.0% to 12.0% by weight of water. Alternatively, the mixture of Sevelamer carbonate and diluent may be made wet using a solution of polyethylene glycol dissolved in water. In an alternate method, polyethylene glycol 6000 may be added into the dry mix as a fine powder during the mixing step. Polyethylene glycols of various grades may be used such as polyethylene glycol 6000 or the like.
In the practice of the present invention, granulation is carried out by adding the binder slowly in a thin stream continuously using a peristaltic pump under high speed mixing with the impeller 'on' and chopper 'off. On completion of binder addition, continue mixing at high impeller speed till cohesive granular mass is obtained. If the mass is lumpy then chopper may be used at high speed with impeller also at high speed to obtain uniform wet mass.
Drying of wet mass may be carried out using fluidized bed drier or tray drier. Initial drying is performed without application of temperature so as to remove the organic solvent and further the wet mass is dried for sufficient time at about 45°C to 50°C till loss on drying value is achieved in the range of about 8.0% to about 12.0%. If planetary mixer is used for granulation, the wet mass is to be milled on

a multi-mill using 8.0 mm screen and then charged for drying.
In one embodiment, the process comprises mixing Sevelamer carbonate with one or more diluents; optionally wetting the mixture using water in a rapid mixer granulator; preparing a binder solution by dissolving ethyl cellulose in an organic solvent such as isopropyl alcohol; granulating the mixture of Sevelamer carbonate and diluents using the said binder solution and drying the granules. Sizing the dried granules through 100# on vibrosifter after milling with multi-mill and ball mill and further blending the milled granules with one or more disintegrants and lubricating with lubricants and compressing the granules into tablets. Core tablets are further film coated.
In a preferred embodiment, Sevelamer carbonate is mixed with mannitol and made wet using water; granulated using binder solution prepared by dissolving the ethyl cellulose in isopropyl alcohol. Granulation is carried out in a rapid mixer granulator and the granulated mass is dried to remove the organic solvent till loss on drying value in the range of about 8.0% to about 12.0% is achieved. Dried mass is sized using ball mill to achieve granules of required size; blended with one or more disintegrants and further lubricated with lubricants and compressed into tablets.
In another embodiment, the process of preparation of Sevelamer carbonate composition comprises providing a mixture of active ingredient Sevelamer carbonate and one or more additives; granulating the mixture by high shear wet granulation or wet granulation by spraying using a solvent and preferably by using a binder solution prepared by dissolving the binder in solvent; the granulation process being carried out in a rapid mixer granulator. Granulated mass is further dried to remove the solvent and a loss on drying value in the range of about 8.0% to about 12.0% is achieved. Dried granules are further milled or pulverized to get granules of size less than 425 microns, preferably less than 250 microns and most

preferably 150 microns using a fluid energy mill or a ball mill; preferably by using a ball mill. Milled or pulverized granules are blended with disintegrants and lubricated using lubricants and further compressed to provide tablets of required size or filled into capsules. Compressed tablets may be further coated.
In one embodiment, the granules provided by high shear wet granulation or wet granulation by spraying process as described herein are spherical granules of size less than 425 microns, preferably less than 250 microns and most preferably below 150 microns. Although the dried granulated mass can be milled or pulverized using conventional equipments known in the art such as a multimill, co-mill, cadmill or fitzmill, they have limitations when used for size reduction of Sevelamer carbonate granules. Granule size less than 425 microns (40#), preferably less than 250 microns (60#) and most preferably 150 microns (which passes through 100#) is difficult to obtain using such mills. Large granules pose difficulties during compression by decreasing the compressibility of the granules and produces porous tablets with low hardness which consequently exhibit high friability and pose a risk of moisture uptake during aqueous film coating. Oversized granules retained after milling through 0.5mm screen on a conventional mill and sifting on a vibrosifter through 60# and then 100# are milled in a ball mill or fluidized energy mill to obtain particle size less than 425 microns, preferably less than 250 microns and most preferably below 150 microns for the granules.
According to the invention, size reduction or pulverization using fluid energy mill or ball mill provides spherical granules of size less than 150microns, which provides an ease in compressibility. Ball milling being the preferred mode for size reduction of granules. In ball milling, the process of size reduction occurs due to combined effect of impact and attrition. In a fluid energy mill, the material is suspended and conveyed at high velocity by air, which is passed through nozzles at 100 to 150 pounds per square inch. The violent turbulence of the air reduces the

particle size by interparticulate attrition. Ball mill is preferred interms of output and productivity for large scale batches.
In the practice of the present invention comminution techniques comprise grinding in an air- jet mill/impact mill, fluid energy mill, ball mill, vibration mill, mortar mill or pin mill.
Milled mass is further sifted through a vibrosifter and oversized particles were milled through a mill preferably a ball mill with stainless steel balls and further sifted through a vibrosifter. Mass is repeatedly milled with ball mill and sifted through vibrosifter till the resultant granules passes through 100#. According to a preferred aspect, granules of the present invention preferably have a particle size of 100% passing through 100#. Particle of size 150microns or less provides satisfactory compression of granules and further provides elegant non-porous, non-friable tablets with a smooth impervious surface which can withstand the rigours of aqueous film coating.
In the practice of the present invention, the granule size is controlled and 100% granules passes through 100# and provides tablets which exhibit a smooth impervious surface with a hardness greater than 100 N, friability less than 0.8% and preferably in the range of 0 to 0.5%, disintegration time of about 5 minutes, and a smooth aqueous film coating operation. By controlling the granule size at less than 425 microns, preferably less than 250 microns and most preferably 150 microns(which passes through 100#) elegant tablets are produced.
In another embodiment, Sevelamer carbonate tablets may be coated by aqueous or non-aqueous or hydroalcoholic coating. Film coating provides an impervious surface and prevents the ingress of moisture from the aqueous coat.
In a preferred embodiment, coating of tablets is done using an aqueous coating

method. Aqueous coating of an hydrophilic active ingredient is another difficult process and posed a real challenge to the inventors of the present invention as the Sevelamer has a tendency to swell in presence of water. Aqueous coating has been achieved by having a fine control on the hardness of the cores, which balances the need for a hard core to ensure good coating as well as meets the requirement for disintegration of coated tablets. As the tablet core is hard with an impervious smooth surface, it withstands the aqueous film coating and the polymer Sevelamer carbonate does not swell during coating.
Film coating may be carried out using polymers such as polyvinyl alcohol, hydroxyethyl cellulose, ethylcellulose, hydroxypropyl methyl cellulose, methacrylic acid co-polymers. Ready mix coating materials may comprise plasticizers selected from propylene glycol, triacetin or polyethylene glycol. Coating agents may be used in the range of about 3% to about 8% by weight of total composition. Coating composition is devoid of any colouring agent.
Tablets may be compressed using suitable punches and dies. According to the invention, tablets may be of oval, elliptical, spherical or caplet shape. Compression can be carried out using equipments known in the art such as a rotary tablet press or any compression machine. Tablets prepared by the process according to the invention meet the specification for disintegration (Limit not more than 30 minutes). Other parameters of tablets such as hardness, friability, and thickness were measured and the results met the standard specifications for tablets.
Compositions of Sevelamer carbonate, particularly the tablets may be packed in aluminium strips or by cold formed blister pack, which is a cold process of blister packing, which acts as an excellent moisture barrier with negligible moisture vapor transmission rate and adequate environmental protection during shelf life.

According to another embodiment, the spherical granules produced by high shear wet granulation or wet granulation by spraying process may be filled along with suitable additives into hard gelatin capsules of suitable size. Capsule filling can be done using any suitable capsule filling machine.
In one embodiment, the pharmaceutical compositions of the present invention comprises Sevelamer carbonate in the range of about 60.0% to about 90.0% by weight of total composition. More particularly, Sevelamer carbonate compositions of the present invention may be provided in dose strength of 800mg.
Pharmaceutically acceptable additives that may be used according to the present invention include one or more additives selected from diluents, binders, lubricants, glidants, coating agents, plasticizers and the like. According to the invention, the additives chosen are such that they do not pose any risk for patients with chronic kidney disease.
Diluents are substances which usually provide bulk to the composition. Suitable diluents for use in the pharmaceutical composition of the invention include, but are not limited to maize starch, pregelatinized starch, polyols selected from the group consisting of inositol, sorbitol, mannitol, isomalt, xylitol, lactitol, erythritol, maltitol and the like. Most preferred diluent for use in the pharmaceutical composition of the present invention is mannitol and isomalt. Preferably, the composition comprises diluents in an amount of about 0.1% to about 10.0% by total weight of the composition.
Additives such as mannitol and isomalt have an advantage of low moisture pick up and satisfactory flow characteristics. Granules containing mannitol get easily dried and they have less tendency to pick up moisture. Mannitol is the most preffered additive as it can be used in an amount of about 0.2% to about 7.0% by total weight of the composition, preferably between 0.4% to 5.0%.

Granular and spray dried forms of mannitol are generally used in granulations. Mannitol provides granules which can be easily dried. Sevelamer carbonate being moisture sensitive, mannitol is the preferred diluent as it is not hygroscopic. Various grades of mannitol are available commercially. Preferred grades of mannitol include Pearlitol SD 200 of Roquette, France.
Isomalt is hydrogenated isomaltulose which is an equimolar mixture of alpha d glucopyranosido-1,6 sorbitol and alpha-D glucospyranosido-l,6mannitol. Isomalt is a non carcinogenic additive commonly used in pharmaceutical preparations. Isomalt is available in various grades based on the particle size where fine grade viz.GalenlQ 810 is used in the wet granulation. Isomalt is preferably used in the range of about 0.2% to about 7%.
Considering the end use of the formulation, mannitol is the preferred diluent. On oral administration, mannitol is not absorbed significantly from the gastrointestinal tract. As diabetes is the leading cause of end-stage renal disease (ESRD) in many cases, the use of sugars as diluents is avoided.
Tablet compositions which uses lactose and dextrose as diluents show discoloration as the tablets turn to yellowish brown colour due to Maillard reaction.
Similarly dibasic calcium phosphate, tribasic calcium phosphate are also avoided since Sevelamer is a phosphate binding polymer and any phosphate containing diluent may compete for phosphate binding activity of Sevelamer.
Binders impart cohesiveness to tablet formulation and ensures that the tablet remain intact after compression. Suitable binders for use in the pharmaceutical composition of the invention include, but are not limited to hydroxy propyl methyl cellulose, hydroxy ethyl cellulose, ethyl cellulose, cellulose derivatives,

maize starch, starch derivatives, polyvinylpyrrolidone alone or in combination with polyethylene glycols and the like.
Pharmaceutical composition according to the invention comprises binders in an amount of about 3.0% to about 15.0% by total weight of the composition. Binder preferred in the practice of the present invention is ethyl cellulose or polyvinyl pyrrolidone.
Different grades of ethyl cellulose having various viscosities are commercially available. Ethyl cellulose of specific grades or blends of different grades may be used to obtain solutions of desired viscosity. Ethyl cellulose having viscosity in the range of 4cps to 22 cps is used; preferred being ethyl cellulose with viscosity of about 5 to 15cps. Preferred grade of ethyl cellulose used for Sevelamer carbonate tablets is Ethocel EC-N 7 Pharm manufactured by Dow chemical company. Ethyl cellulose is not metabolized following oral consumption and therefore a non-calorific substance. Suitable solvents that can be used for preparation of binder solution include isopropyl alcohol, ethanol or dichloromethane.
Suitable disintegrants for use in the pharmaceutical composition of the invention include, but are not limited to pregelatinised starch crospovidone and the like. Disintegrants is used in an amount of about 2.0% to about 10.0% by weight of total composition.
Lubricants are additives that are used to prevent adhesion of the granules/powder material to the manufacturing equipments such as hoppers. Lubricants reduce the interparticle friction and improves the flow of the gf anules/powder materials and also assist the ejection of the tablet from the tabletttfg die. Suitable lubricants for use in the pharmaceutical composition of the invention include, but are not limited to stearic acid, glyceryl monostearate, glyceryl beher»ate, glyceryl palmitostearate,

hydrogenated vegetable oil, mineral oil, polyethylene glycol and the like. Pharmaceutical composition according to the invention comprises lubricants in an amount of about 0.1% to about 3.0% by weight of total composition. In one embodiment, the pharmaceutical compositions of the present invention comprises about 60.0% to 90.0% by weight of Sevelamer carbonate, about 0.1% to about 10.0% by weight of diluent, about 3.0% to about 15.0% by weight of binder, about 2.0% to about 10.0% by weight of disintegrant, about 0.1% to about 3.0% by weight of lubricants and about 3.0% to about 6.0% by weight of coating agents.
Suitably the solid dosage form of the present invention is a tablet or a capsule that can be produced on a commercial scale.
Compositions prepared by the process as described herein withstand the accelerated stability conditions of temperature and relative humidity and maintain their physical and chemical integrity at accelerated conditions of stability.
The features of the present invention can be extended to other aliphatic amine polymers. Some of the aliphatic amine polymers known in the art include colestipol, cholestryramine, orlistat, colesevelam and the like.
The present invention further provides use of the compositions of Sevelamer carbonate in the control of serum phosphorus in patients suffering from chronic kidney disease (CK.D) on hemodialysis.
In one embodiment, the present invention provides a method for treating a patient suffering from chronic kidney disease (CKD) on hemodialysis comprising administering a therapeutically effective amount of Sevelamer carbonate composition as described herein.

Although the present invention makes use of organic solvents such as isopropyl alcohol for granulation, the organic volatile impurity level in the finished product is quite low and is within the permissible limit. (Limit as per ICH guidelines : 5000 ppm)
As used herein, the term "composition", unless otherwise defined refers to granules and/or solid oral pharmaceutical dosage forms of the invention that contain Sevelamer carbonate.
As used herein, the term "additives" refers to a pharmaceutically acceptable ingredient that is commonly used in the pharmaceutical technology for preparing granules and/or solid oral pharmaceutical dosage forms.
As used herein, the term "therapeutically effective amount" refers to an amount sufficient to cause an improvement in a clinically significant condition in the patient or even prevent a disease, disorder or condition in a patient.
As used herein, the term "tablet" is intended to encompass compressed pharmaceutical dosage formulations of all shapes and sizes, whether coated or uncoated.
The present invention is further illustrated by reference to the following examples which is for illustrative purpose only and does not limit the scope of the invention in any way.
Examples:
Example 1
Sevelamer carbonate (168g ) was co-sifted with mannitol (Pearlitol SD 200) (4g) and was added to a rapid mixer granulator (RMG). Water (20g) was then added to it and mixed at impeller speed 100 rpm. Ethyl cellulose (16g) was dissolved in hot

(45°C) isopropyl alcohol (50 g) and was added to the RMG and the mixture of Sevelamer carbonate and mannitol was granulated at impeller speed 180 rpm without chopper on. Granulated mass was then discharged into bowl of Restch dryer and air dried followed by drying at temperature of about 50°C. Dried mass was milled using multimill/sifter and further using ball mill to obtain granules which passed through 100# S.S.sieve. Granules were blended in a conta blender with Kollidon CLF( 12 g) previously sifted through 60# S.S.sieve and further blended with stearic acid (1 g) previously sifted through 60# S.S.sieve . Lubric¬ated granules were compressed on a conventional tableting machine to produce 800mg tablets of Sevelamer carbonate. Core tablets were film coated by aqueous process till a weight gain in the range of about 4.0% to about 6.0% was achieved.
Example 2
Sevelamer carbonate (420 g) was co-sifted with mannitol (Pearlitol SD 200) (lOg) using 20# stainless steel sieve and was transfered into a rapid mixer granulator and mixed for 5minutes at lOOrpm. Binder solution was prepared by dissolving povidone in a mixture of isopropyl alcohol and water (65:35). Binder solution was added to the mixture of Sevelamer carbonate and mannitol and was mixed at im¬peller high speed 180 to 200 rpm with chopper off for sufficient time till a cohes¬ive mass was formed. The mass was air dried for sufficient time in Glatt drier and further dried at temperature of 50°C to 60°C till loss on drying value of about 10% to 12% was achieved. Dried granules were sifted through 100# sieve and the over sized granules were milled using ball mill and the milled mass was sifted through 100# sieve. Sifted granules were blended with presifted Kollidon CLF (sifted through 60#) and stearic acid (sifted through 60#) in a conta blender and was compressed on 0.826 x 0.374 inch capsule shaped punches and dies to obtain tab¬let having weight of 1130 mg per tablet and hardness of about 80 to HON. Com¬pressed tablets were coated using coating solution prepared by dissolving coating ready mix containing HPMC 5 cps and triacetin in water, till weight gain of 4.0% to 6.0 % of the core tablet was achieved.

Example 3:
Sevelamer carbonate (840 g) was co-sifted with mannitol (Pearlitol SD 200) (20g) using 20 mesh S S Sieve on vibrosifter, and loaded into the rapid mixer granulator and was mixed for about 5 minutes. Binder solution was prepared by dissolving about 80 g Ethocel in 400 g Isopropyl alcohol and was added to the dry mix in the rapid mixer granulator which was pre-wetted with water (110 g). Wet mass was air dried in Glatt drier followed by drying at temperature about 50°C. Dried mass was milled using multimill/sifter and further milled using ball mill to obtain gran¬ules which passed through 100# s.s.sieve. Granules were blended in a conta blender with pregelatinised starch (70.0g) previously sifted through 60# s.s.sieve and further blended with stearic acid (l.Og) previously sifted through 60# s.s.sieve. Lubricated granules were compressed on a conventional tableting ma¬chine to produce Sevelamer carbonate tablets 800mg. Core tablets were film coated by aqueous process till a weight gain in the range of about 4.0% to about 6.0% was achieved.
Example 4
Sevelamer carbonate (420 g) was co-sifted with mannitol (Pearlitol SD 200) (lOg) using 20# stainless steel sieve and transfered into a rapid mixer granulator and mixed for 5minutes at lOOrpm. A binder solution was prepared by dissolving povidone in a mixture of isopropyl alcohol and water (100:35 g). The binder solu¬tion was added to the mixture of Sevelamer carbonate and mannitol and was mixed at impeller high speed 180 to 200 rpm with chopper off condition for suffi¬cient time till a cohesive mass was formed. The mass was air dried for sufficient time in Glatt drier and further dried at temperature of 50°C to 60°C till loss on dry¬ing value of about 10% to 12% was achieved. Dried granules were sifted through 100# Sieve and the over sized granules were milled using ball mill and the milled mass was sifted through 100# sieve. Sifted granules were blended with presifted pregelatinised starch 1500 (sifted through 60#) and stearic acid (sifted through 60#) in a conta blender and was compressed on 0.826 x 0.374 inch capsule shaped

punches and dies to obtain tablet having weight of 1130 mg per tablet and hard¬ness of about 80 to 140 N. Compressed tablets were Coated using coating solution prepared by dissolving coating ready mix containing HPMC 5 cps and triacetin in water, till weight gain of 4.0% to 6.0 % of the core tablets was achieved.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and tha.t the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative ^nd not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

Documents:

142-MUM-2009-ABSTRACT(22-1-2010).pdf

142-MUM-2009-AUSTRALIAN DOCUMENT(4-9-2012).pdf

142-MUM-2009-CLAIMS(22-1-2010).pdf

142-MUM-2009-CLAIMS(AMENDED)-(25-9-2014).pdf

142-MUM-2009-CLAIMS(AMENDED)-(5-3-2013).pdf

142-MUM-2009-CLAIMS(MARKED COPY)-(25-9-2014).pdf

142-MUM-2009-CLAIMS(MARKED COPY)-(5-3-2013).pdf

142-MUM-2009-CORRESPONDENCE(11-1-2012).pdf

142-MUM-2009-CORRESPONDENCE(14-2-2011).pdf

142-MUM-2009-CORRESPONDENCE(16-9-2014).pdf

142-MUM-2009-CORRESPONDENCE(19-12-2013).pdf

142-MUM-2009-CORRESPONDENCE(22-1-2010).pdf

142-MUM-2009-CORRESPONDENCE(27-8-2014).pdf

142-MUM-2009-CORRESPONDENCE(5-3-2010).pdf

142-MUM-2009-CORRESPONDENCE(7-2-2014).pdf

142-MUM-2009-CORRESPONDENCE(7-5-2010).pdf

142-mum-2009-correspondence.pdf

142-MUM-2009-DESCRIPTION(COMPLETE)-(22-1-2010).pdf

142-mum-2009-description(provisional).doc

142-mum-2009-description(provisional).pdf

142-MUM-2009-DRAWING(22-1-2010).pdf

142-MUM-2009-EP DOCUMENT(4-9-2012).pdf

142-mum-2009-form 1.pdf

142-MUM-2009-FORM 18(7-5-2010).pdf

142-mum-2009-form 2(22-1-2010).pdf

142-MUM-2009-FORM 2(TITLE PAGE)-(22-1-2010).pdf

142-mum-2009-form 2(title page).pdf

142-mum-2009-form 2.doc

142-mum-2009-form 2.pdf

142-MUM-2009-FORM 3(11-1-2012).pdf

142-MUM-2009-FORM 3(14-2-2011).pdf

142-MUM-2009-FORM 3(19-12-2013).pdf

142-MUM-2009-FORM 3(4-9-2012).pdf

142-MUM-2009-FORM 3(5-3-2010).pdf

142-MUM-2009-FORM 3(5-3-2013).pdf

142-MUM-2009-FORM 3(7-2-2014).pdf

142-mum-2009-form 3.pdf

142-MUM-2009-FORM 5(22-1-2010).pdf

142-MUM-2009-FORM PCT-IB-373(4-9-2012).pdf

142-MUM-2009-FORM PCT-ISA-237(4-9-2012).pdf

142-MUM-2009-OTHER DOCUMENT(16-9-2014).pdf

142-MUM-2009-OTHER DOCUMENT(19-12-2013).pdf

142-MUM-2009-REPLY TO EXAMINATION REPORT(4-9-2012).pdf

142-MUM-2009-REPLY TO EXAMINATION REPORT(5-3-2013).pdf

142-MUM-2009-REPLY TO HEARING(25-9-2014).pdf

142-MUM-2009-US DOCUMENT(4-9-2012).pdf

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Patent Number

263604

Indian Patent Application Number

142/MUM/2009

PG Journal Number

45/2014

Publication Date

07-Nov-2014

Grant Date

05-Nov-2014

Date of Filing

22-Jan-2009

Name of Patentee

USV LIMITED

Applicant Address

B.S.D MARG, GOVANDI, MUMBAI 400088, MAHARASHTRA, INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	BHIDE YOGESH SHARAD	B.S.D MARG, GOVANDI, MUMBAI 400088, MAHARASHTRA, INDIA.
2	OMRAY ASHOK	B.S.D MARG, GOVANDI, MUMBAI 400088, MAHARASHTRA, INDIA.
3	CHOUDHARY VARSHA SHASHANK	B.S.D MARG, GOVANDI, MUMBAI 400088, MAHARASHTRA, INDIA.

PCT International Classification Number

A61K31/785; A61K47/38; A61K9/20

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA