WO2009034540A1

WO2009034540A1 - Pharmaceutical composition of sevelamer

Info

Publication number: WO2009034540A1
Application number: PCT/IB2008/053671
Authority: WO
Inventors: Swati Aggarwal; Rohit Lowalekar; Romi Barat Singh
Original assignee: Ranbaxy Laboratories Ltd
Current assignee: Ranbaxy Laboratories Ltd
Priority date: 2007-09-11
Filing date: 2008-09-11
Publication date: 2009-03-19
Anticipated expiration: 2010-03-11

Abstract

This invention relates to a pharmaceutical composition for oral administration comprising sevelamer or pharmaceutically acceptable salt thereof in an amount less than 80% by weight of composition wherein the composition is free of crystalline cellulose and low-substituted hydroxypropyl cellulose.

Description

PHARMACEUTICAL COMPOSITION OF SEVELAMER

Field of the Invention

This invention relates to pharmaceutical compositions for oral administration comprising sevelamer or pharmaceutically acceptable salts thereof in an amount less than 80% by weight of composition, wherein the composition is free of crystalline cellulose and low-substituted hydroxypropyl cellulose.

Also, it relates to pharmaceutical compositions in the form of tablets, comprising sevelamer or pharmaceutically acceptable salt thereof; and hydroxypropyl cellulose; wherein the tablet is free of crystalline cellulose and low- substituted hydroxypropyl cellulose and has a tablet disintegration time of less than 5 minutes.

Background of the Invention

Sevelamer is a phosphate binding polymer indicated for the control of serum phosphorus in patients with Chronic Kidney Disease (CKD) on hemodialysis. It binds phosphorus in the gastrointestinal tract to facilitate phosphorus excretion in feces, by inhibiting phosphorus absorption from the gut, and thereby lowering the plasma phosphorus concentration. The use of sevelamer and its pharmaceutical compositions, and processes for its preparation are disclosed in U.S. Patent No. 5,496,545.

Currently, sevelamer hydrochloride and sevelamer carbonate are being marketed under the trade name of Renagel® and Renvela® respectively. The recommended starting dose of sevelamer is 800 to 1600 mg. The high dose and the hygroscopic nature of sevelamer make it difficult to formulate it in a suitably dosage form.

U.S. Patent No. 6,733,780 discloses a tablet comprising a core and a coating wherein at least 95% by weight of the core comprises sevelamer. Further, it discloses water-based coating for sevelamer tablets. U.S. Publication 2002/0054903 discloses a tablet comprising a compressed tablet core comprising at least about 80% of sevelamer.

U.S. Patent No. 6,383,518 discloses a tablet comprising a phosphate binding polymer having an average particle size of 400 μm or less together with crystalline cellulose and low-substituted hydroxypropyl cellulose. Further, it discloses that crystalline cellulose and low- substituted hydroxypropyl cellulose are desired to obtain a tablet disintegration time of less than 15 minutes, which is not obtained by using additives other than low- substituted hydroxypropyl cellulose or crystalline cellulose.

Summary of the Invention An alternate pharmaceutical composition for an oral administration comprising sevelamer or pharmaceutically acceptable salts thereof in an amount less than 80% by weight of composition wherein the composition is free of crystalline cellulose and low- substituted hydroxypropyl cellulose is presented herein.

Also presented herein is a pharmaceutical composition in the form of a tablet comprising sevelamer or pharmaceutically acceptable salts thereof and hydroxypropyl cellulose wherein the pharmaceutical composition is found to have desired hardness and disintegratability.

In one of the aspects, there is provided a pharmaceutical composition for oral administration comprising: a) less than 80% w/w of sevelamer or pharmaceutically acceptable salts thereof; and b) pharmaceutically acceptable inert excipients; wherein the composition is free of crystalline cellulose and low-substituted hydroxypropyl cellulose. In another aspect, there is provided a pharmaceutical composition for oral administration comprising: a) from about 40 to 75% w/w of sevelamer or pharmaceutically acceptable salts thereof; and b) from about 25 to 60% w/w of pharmaceutically acceptable inert excipients; wherein the composition is free of crystalline cellulose and low-substituted hydroxypropyl cellulose.

In another aspect, there is provided a pharmaceutical composition for oral administration comprising: a) from about 50 to 75% by weight of sevelamer or pharmaceutically acceptable salts thereof; b) from about 5 to 40% by weight of diluents selected from, for example, dextrates, dextrins, dextrose, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, sucrose, and the like; and c) from about 0.1 tol0% by weight of other pharmaceutically acceptable inert excipients; wherein the composition is free of crystalline cellulose and low-substituted hydroxypropyl cellulose. In another aspect, there is provided a process for the preparation of a pharmaceutical composition for oral administration comprising the steps of: i) blending sevelamer or pharmaceutically acceptable salts thereof with pharmaceutically acceptable inert excipients; ii) optionally granulating the blend; iii) lubricating the blend or granules; iv) compressing the blend or granules into suitably sized tablets; and v) optionally coating the tablets; wherein sevelamer or salts is present in an amount less than 80% by weight of composition and the composition is free of crystalline cellulose and low-substituted hydroxypropyl cellulose.

In another aspect, there is provided a method for the control of serum phosphorus in patients with Chronic Kidney Disease (CKD) on hemodialysis comprising administering a pharmaceutical composition for oral administration comprising: a) less than 80% w/w of sevelamer or pharmaceutically acceptable salts thereof; and b) pharmaceutically acceptable inert excipients; wherein the composition is free of crystalline cellulose and low-substituted hydroxypropyl cellulose. In another aspect, there is provided a pharmaceutical composition in the form of a tablet comprising: a) sevelamer or pharmaceutically acceptable salts thereof; and b) hydroxypropyl cellulose; wherein the tablet is free of crystalline cellulose and low-substituted hydroxypropyl cellulose and has a tablet disintegration time of less than 5 minutes.

In another aspect, there is provided a pharmaceutical composition in the form of a tablet comprising: a) less than 80 % w/w of sevelamer or pharmaceutically acceptable salts thereof; and b) about 1 to 10% w/w of hydroxypropyl cellulose; wherein the tablet is free of crystalline cellulose and low-substituted hydroxypropyl cellulose and has a disintegration time of less than 5 minutes.

In another aspect, there is provided a pharmaceutical composition in the form of a tablet comprising: a) about 40-75% w/w of sevelamer or pharmaceutically acceptable salts thereof; and b) about 1 to 10% w/w of a low-viscosity hydroxypropyl cellulose; wherein the tablet is free of crystalline cellulose and low-substituted hydroxypropyl cellulose and has a disintegration time of less than 5 minutes.

In another aspect, there is provided a pharmaceutical composition in the form of a tablet comprising: a) about 40-70% w/w of sevelamer or pharmaceutically acceptable salts thereof; b) about 1 to 10% w/w of a low-viscosity hydroxypropyl cellulose; and c) about 5 to 20% w/w of mannitol; wherein the tablet is free of crystalline cellulose and low-substituted hydroxypropyl cellulose and has a disintegration time of less than 5 minutes. In another aspect, there is provided a pharmaceutical composition in the form of a tablet comprising: a) sevelamer or pharmaceutically acceptable salts thereof; b) a low-viscosity hydroxypropyl cellulose; and c) a medium-viscosity hydroxypropyl cellulose; wherein the tablet is free of crystalline cellulose and low-substituted hydroxypropyl cellulose and has a disintegration time of less than 5 minutes.

In another aspect, there is provided a pharmaceutical composition in the form of a tablet comprising sevelamer or pharmaceutically acceptable salt thereof and hydroxypropyl cellulose alone or in combination with other binders selected from, for example, methyl cellulose, hydroxyl propyl methycellulose, povidone, pregelatinized starch, carboxymethyl cellulose and copovidone; wherein the tablet is free of crystalline cellulose and low- substituted hydroxypropyl cellulose and has a disintegration time of less than 5 minutes. In another aspect, there is provided a process for the preparation of a pharmaceutical composition in the form of a tablet comprising the steps of: i) blending sevelamer or pharmaceutically acceptable salts thereof, hydroxypropyl cellulose along with other pharmaceutically acceptable excipients; ii) optionally, granulating the blend of step i); iii) lubricating, the blend of step i) or granules of step ii); iv) compressing, the blend or granules of step iii) into a suitably sized tablet; and v) optionally, coating the tablet of step iv); wherein the tablet is free of crystalline cellulose and low-substituted hydroxypropyl cellulose and the tablet has a disintegration time of less than 5 minutes.

In another aspect, there is provided a method for the control of serum phosphorus in patients with Chronic Kidney Disease (CKD) on hemodialysis comprising administering a pharmaceutical composition in the form of a tablet comprising: a) sevelamer or pharmaceutically acceptable salts thereof; and b) hydroxypropyl cellulose; wherein the tablet is free of crystalline cellulose and low- substituted hydroxypropyl cellulose and has a disintegration time of less than 5 minutes. Detailed Description of the Invention

The term "sevelamer" as used herein includes hydrated or anhydrate form of sevelamer. The pharmaceutically acceptable salts thereof include hydrochloride, carbonate, hydrobromide, phosphate, sulfate and the like. The compressibility of sevelamer is dependent on moisture content of sevelamer, hence to obtain desired compressibility, sevelamer may be hydrated to a desired moisture content, which may vary from about 1 to about 14%, in particular about 6-9%. The moisture level of hydrated or anhydrate API may be determined by the Karl Fischer method. Further, it was observed that no hydration of sevelamer would be required with compositions containing less than about 70% of sevelamer. The tablet compositions comprise sevelamer or salts in amounts less than 80% by weight of the composition. In particular, the tablet can comprise about 40 to 75% w/w of sevelamer or salts, more particularly of about 50-75% w/w of sevelamer or salts.

The term "free of as used herein refers to the non-detectability of crystalline cellulose and low-substituted hydroxypropyl cellulose in the pharmaceutical compositions. The term "low- substituted hydroxypropyl cellulose" is well known to those of skill in the art of pharmaceutical formulation, as evidenced by the following definition in "The Handbook of Pharmaceutical Excipients;" 4^th Edition; eds. Rowe et al, p. 294-6, (2003): "a low- substituted hydroxypropyl ether of cellulose. When dried at 105⁰C for one hour, it contains not less than 5.0%, and not more than 16.0% of hydroxypropyl groups." Disintegration time of tablets of the present invention was determined using USP-

30 disintegration time apparatus and was found to be less than 5 minutes, in particular 0.1- 3.25 minutes. Further, it was observed that tablets according to the invention showing hardness exceeding 15kp, disintegrated in less than 5 minutes.

The pharmaceutical composition may further comprise one or more pharmaceutically acceptable inert excipients. The term "pharmaceutically acceptable inert excipients" as used herein includes binders, diluents, disintegrants, lubricants, glidants, surfactants and coating additives.

Examples of binders include methyl cellulose, hydroxyl propyl methylcellulose, povidone, pregelatinized starch, carboxymethyl cellulose, ethyl cellulose, polyvinyl alcohol, hydroxypropyl cellulose and copovidone; in particular hydroxypropyl cellulose.

Hydroxypropyl cellulose is used in the composition as a binder. It may be present in amounts of about 1-10% w/w. Hydroxypropyl cellulose may be selected from the various grades such as a low- viscosity, a medium- viscosity or combination thereof, in particular low- viscosity. The various marketed grades of low-viscosity hydroxypropyl cellulose include Klucel® JF, Klucel® LF, having viscosity 150-400 and 75-150 mpas of 5% aqueous solution respectively and Klucel® EF, having viscosity 200-600 mpas of 10% aqueous solution. The various marketed grades of medium-viscosity hydroxypropyl cellulose include Klucel® MF and Klucel® GF, having viscosity 4000-6500 mpas and 150-400 mpas of 2% aqueous solution respectively. Hydroxypropyl cellulose may be present either alone or in combination with other binders selected from, for example, methyl cellulose, hydroxyl propyl methylcellulose, povidone, pregelatinized starch, carboxymethyl cellulose and copovidone. In particular, hydroxypropyl methylcellulose and polyvinyl pyrrolidone may be present in an amount of about 1-5 % w/w. Examples of diluents include dextrates, dextrins, dextrose, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, sucrose, and the like.

Examples of disintegrants include starch, crospovidone and the like.

Examples of lubricants and glidants include colloidal anhydrous silica, silicon dioxide (Aerosil® 200), stearic acid, magnesium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acids, microcrystalline wax, yellow beeswax, white beeswax and the like.

Surfactants include polyethoxylated fatty acids and its derivatives, for example polyethylene glycol 400 distearate, polyethylene glycol - 20 dioleate, polyethylene glycol 4 -150 mono dilaurate, polyethylene glycol -20 glyceryl stearate; alcohol - oil transesterification products, for example polyethylene glycol - 6 corn oil; polyglycerized fatty acids, for example polyglyceryl - 6 pentaoleate; propylene glycol fatty acid esters, for example propylene glycol monocaprylate; mono and diglycerides for example glyceryl ricinoleate; sterol and sterol derivatives; sorbitan fatty acid esters and its derivatives, for example polyethylene glycol - 20 sorbitan monooleate, sorbitan monolaurate; polyethylene glycol alkyl ether or phenols, for example polyethylene glycol - 20 cetyl ether, polyethylene glycol - 10 - 100 nonyl phenol; sugar esters, for example sucrose monopalmitate; polyoxyethylene - polyoxypropylene block copolymers known as "poloxamer".

The pharmaceutical composition of the invention may optionally be coated with a film forming polymer along with other coating additives, which may include both functional and nonfunctional coating. Suitably coating additives may include one or more of plasticizers, coloring agents, opacifiers, solvents and lubricants/glidants.

Examples of film-forming polymers include ethyl cellulose, hydroxypropyl methylcellulose, methylcellulose, carboxy methylcellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate; waxes such as polyethylene glycol; methacrylic acid polymers such as Eudragit® RL and RS; gums such as xanthan gum, and the like. Alternatively, commercially available coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry® may also be used for coating. Examples of plasticizers include acetylated triacetin, triethyl citrate, tributyl citrate, glycerol tributyrate, diacetylated monoglyceride, polyethylene glycols, propylene glycol, sesame oil, acetyl tributyl citrate, acetyl triethyl citrate, diethyl oxalate, diethyl phthalate, diethyl maleate, diethyl fumarate, dibutyl succinate, diethylmalonate, dioctyl phthalate, dibutyl sebacate, and the like. Examples of opacifiers include titanium dioxide and the like.

Examples of coloring agents include Iron oxide, Ferric Oxide Yellow, Lake of Tartrazine, Allura Red, Lake of Quinoline Yellow, Lake of Erythrosine.

A polymer solution or dispersion may be prepared in various solvents, including water, ethanol, isopropyl alcohol, acetone, ether or mixtures thereof. The composition may be coated using techniques such as spray coating in conventional coating pan or fluidized bed processor, or dip coating.

The coating options that can be used for the coating of the composition may include, for example: i) hydroxypropyl methylcellulose, diacetylated monoglyceride and purified water; or ii) polyvinyl alcohol, xanthan gum, lecithin, talc, titanium dioxide and purified water; or iii) hydroxypropyl methylcellulose, polyethylene glycol, talc, titanium dioxide, isopropyl alcohol and dichloromethane.

Tablets may be prepared by conventional methods like direct compression or dry granulation or wet granulation, in particular non-aqueous granulation.

According to one of the embodiments, the tablet is prepared by direct compression process, the process comprising the steps of: i) hydrating sevelamer or salts by exposing sevelamer or salts to the atmosphere for 1-2 hours till the moisture level is at a desired level; ii) blending hydrated sevelamer or salts with pharmaceutically acceptable inert excipients; iii) lubricating the blend; iv) compressing the blend into a suitably sized tablet; and v) optionally, coating the tablet.

According to another embodiment, the tablet is prepared by direct compression process, the process comprising the steps of: i) blending sevelamer or salts with pharmaceutically acceptable inert excipients; ii) lubricating the blend; iii) compressing the blend into a suitably sized tablet; and iv) optionally, coating the tablet. According to another embodiment, the tablet is prepared by dry granulation process, the process comprising the steps of: i) blending sevelamer or salts with pharmaceutically acceptable inert excipients; ii) granulating the above blend using slugging or roller compaction; iii) optionally blending with pharmaceutically acceptable inert extragranular excipients; iv) lubricating the granules/blend; v) compressing the lubricated granule/blend into suitably sized tablet cores; and vi) optionally, coating the tablet cores.

According to another embodiment, the tablet is prepared by direct compression process, the process comprising the steps of: i) blending sevelamer or salts with hydroxypropyl cellulose and other pharmaceutically acceptable inert excipients; ii) lubricating the blend of step i); iii) compressing the blend of step ii) into suitably sized tablet; and iv) optionally, coating the tablet of step iii).

According to another embodiment, the tablet is prepared by dry granulation process, the process comprising the steps of i) blending sevelamer or salts with hydroxypropyl cellulose and other pharmaceutically acceptable inert excipients; ii) granulating the blend of step i) using slugging or roller compaction; iii) optionally, blending granules of step ii) with pharmaceutically acceptable inert extragranular excipients; iv) lubricating the granules of step ii) or blend of step iii); v) compressing the lubricated granules or blend of step iv) into suitably sized tablet core; and vi) optionally, coating the tablet core of step v).

According to another embodiment, the tablet is prepared by direct compression process, the process comprising the steps of: i) hydrating sevelamer by exposing sevelamer or salts to the atmosphere for 1-2 hours or by spraying water to achieve the desired moisture level; ii) blending the hydrated sevelamer or salts of step i) with hydroxypropyl cellulose and other pharmaceutically acceptable inert excipients; iii) lubricating the blend of step ii); iv) compressing the blend step iii) into suitably sized tablet; and v) optionally, coating the tablet of step iv).

The following examples are representative of the invention, but do not limit the scope of the claims.

EXAMPLES

Example 1

Process:

1. Sevelamer HCl, silicon dioxide and lactose were blended together.

2. The blend of step 1 was lubricated with stearic acid and compressed into suitably sized tablets. Example 2

Process:

1. Sevelamer HCl (initial moisture content of 2.35%) was hydrated by exposing it to atmosphere for 1-2 hours to obtain a moisture level of 6.72%.

2. Hydrated Sevelamer HCl, silicon dioxide and lactose were blended together.

3. The blend of step 2 was lubricated with stearic acid and compressed into suitably sized tablets.

Example 3

Process:

1. Sevelamer HCl, hydroxypropyl cellulose (low- viscosity), silicon dioxide and lactose were blended together.

2. The blend of step 1 was lubricated with stearic acid and compressed into suitably sized tablets. Example 4

Process:

1. Sevelamer HCl, copovidone, lactose and hydroxypropyl cellulose (low-viscosity) were blended together.

2. The blend of step 1 was lubricated with stearic acid and compressed into suitably sized tablets.

Example 5

Process:

1. Sevelamer hydrochloride, povidone, lactose and hydroxypropyl cellulose (low- viscosity) were blended together.

2. The blend of step 1 was lubricated with stearic acid and compressed into suitably sized tablets. Example 6

Process:

1. Sevelamer hydrochloride, copovidone, lactose, hydroxypropyl cellulose (low- viscosity) and hydroxypropyl cellulose (medium- viscosity) were blended together.

Example 7

Process:

1. Sevelamer hydrochloride, povidone, mannitol, silicon dioxide, hydroxypropyl cellulose (low-viscosity) and pregelatinized starch were blended together.

2. The blend of step 1 was lubricated with stearic acid and compressed into suitably sized tablets. Example 8

Process:

1. Sevelamer hydrochloride, povidone, mannitol, silicon dioxide, hydroxypropyl cellulose (low-viscosity) and crospovidone were blended together.

Example 9

Process:

1. Sevelamer hydrochloride, povidone, mannitol, silicon dioxide, hydroxypropyl cellulose (low- viscosity) and corn starch were blended together.

2. The blend of step 1 was lubricated with stearic acid and compressed into suitably sized tablets. Table 1 summarizes the results of disintegration testing and hardness testing of each tablet prepared as per Examples 3-9. The disintegration time of each tablet was determined using USP-30 disintegration time apparatus and hardness of each tablet was measured with a Schleuniger Hardness Tester.

Table 1: Disintegration time and hardness of tablets of Example (Expl) 3-9

While particular embodiments have been described above, it will be apparent that various modifications and combinations of the formulations detailed in the text can be made without departing from the spirit and scope of the invention. For example, exemplary tablet formulations are described below.

Example 10

Process:

1. Blend Sevelamer HCl, Silicon dioxide and mannitol together.

2. Lubricate the blend of step 1 with stearic acid.

3. Compress the lubricated blend of step 2 into suitably sized tablets. Example 11

Process:

1. Blend Sevelamer HCl, silicon dioxide and pregelatinized starch together.

2. Lubricate the blend of step 1 with stearic acid.

3. Compress the lubricated blend of step 2 into suitably sized tablets.

Example 12

Process:

1. Blend Sevelamer HCl, copovidone, lactose, mannitol, povidone, hydroxypropyl methyl cellulose, hydroxypropyl cellulose (low-viscosity) and hydroxypropyl cellulose (medium-viscosity) together.

2. Lubricate blend of step 1 with stearic acid

3. Compress blend of step 2 into a suitably sized tablets. Example 13

Process:

1. Blend sevelamer carbonate, hydroxypropyl cellulose (low-vicosity), silicon dioxide and lactose together.

2. Lubricate blend of step 1 with stearic acid and compress into a suitably sized tablets.

Example 14

Process:

1. Blend sevelamer carbonate, copovidone, lactose, hydroxypropyl cellulose (low- viscosity) and hydroxypropyl cellulose (medium- viscosity) were blended together.

2. Lubricate the blend of step 1 with stearic acid and compress into suitably sized tablets.

Claims

CLAIMS 1. A pharmaceutical composition for oral administration comprising: a) less than about 80% w/w of sevelamer or pharmaceutically acceptable salts thereof; and b) pharmaceutically acceptable inert excipients; wherein the composition is free of crystalline cellulose and low-substituted hydroxypropyl cellulose.

2. The pharmaceutical composition according to the claim 1 wherein the sevelamer is present in an amount of about 40-75 % by weight of the composition.

3. The pharmaceutical composition according to the claim 1 wherein the pharmaceutical acceptable salts are selected from carbonate and hydrochloride.

4. The pharmaceutical composition according to claim 1 wherein the pharmaceutical acceptable inert excipients are selected from the group consisting of binders, diluents, disintegrants, lubricants, glidants, surfactants and coating additives.

5. The pharmaceutical composition according to the claim 1 wherein the pharmaceutical acceptable inert excipients are present in an amount of about 20 to about 60 % by weight of the composition.

6. The pharmaceutical composition according to claim 1 wherein said pharmaceutical composition is in the form of tablet.

7. A pharmaceutical composition in the form of a tablet comprising: a) sevelamer or pharmaceutically acceptable salts thereof; and b) hydroxypropyl cellulose; wherein the tablet is free of crystalline cellulose and low-substituted hydroxypropyl cellulose and has a disintegration time of less than 5 minutes.

8. The pharmaceutical composition according to claim 7 wherein the hydroxypropyl cellulose is present in an amount of about 1-10% by weight of the composition.

9. The pharmaceutical composition according to claim 7 wherein the hydroxypropyl cellulose is selected from low- viscosity hydroxypropyl cellulose, medium-viscosity hydroxypropyl cellulose or mixture thereof.

10. The pharmaceutical composition according to claim 7 further comprising mannitol in an amount of 5-20% by weight of the composition.

11. The pharmaceutical composition according to claim 7 wherein the hydroxypropyl cellulose is present in combination with other binders selected from the group consisting of methyl cellulose, hydroxypropyl methylcellulose, povidone, pregelatinized starch, carboxymethyl cellulose and copovidone.

12. The pharmaceutical composition according to claim 7 wherein the tablet is prepared by a process comprising the steps of: i) blending sevelamer or pharmaceutically acceptable salt thereof, hydroxypropyl cellulose along with other pharmaceutically acceptable excipients; ii) optionally, granulating the blend of step i); iii) lubricating, the blend of step i) or granules of step ii); iv) compressing, the blend or granules of step iii) into a suitably sized tablet; and v) optionally, coating the tablet of step iv).