WO2010106557A2

WO2010106557A2 - Stable pharmaceutical formulations comprising anhydrous lanthanum carbonate and process for preparation thereof

Info

Publication number: WO2010106557A2
Application number: PCT/IN2010/000163
Authority: WO
Inventors: Rajesh Jain; Sarabjit Singh; Paramjit Singh; Pirthi Pal Singh
Original assignee: Panacea Biotec Limited
Priority date: 2009-03-20
Filing date: 2010-03-19
Publication date: 2010-09-23
Also published as: WO2010106557A3

Abstract

The present invention discloses the premix pharmaceutical formulation comprising anhydrous lanthanum carbonate. The present invention further relates to a stable pharmaceutical formulation comprising a therapeutically effective amount of anhydrous lanthanum carbonate and pharmaceutically acceptable carrier and/or excipients, with the proviso that the said formulation is substantially free of monosaccharides or disaccharides. Further the said formulation is substantially free of amino acids and/or stabilizers. The process of preparing such formulations is also described.

Description

STABLE PHARMACEUTICAL FORMULATIONS COMPRISING ANHYDROUS LANTHANUM CARBONATE AND PROCESS FOR PREPARATION THEREOF

FIELD OF THE INVENTION The present invention relates to the premix pharmaceutical formulation comprising anhydrous lanthanum carbonate.

The present invention relates to a stable pharmaceutical formulation comprising anhydrous lanthanum carbonate and a pharmaceutically acceptable carrier and/or excipients and the process for the preparation of pharmaceutical formulation comprising anhydrous lanthanum carbonate.

BACKGROUND OF THE INVENTION

Hyperphosphatemia is a particular problem of patients with chronic renal insufficiency or chronic kidney disease (CKD). Approximately 70% of patients with End Stage Renal Disease (ESRD) on renal dialysis therapy require treatment for hyperphosphatemia. This condition can lead to severe bone problems and metastatic calcification of skin and major organs and is associated with significant morbidity and mortality. Elevated phosphate levels are treated using a combination of dietary restrictions and phosphate-binding agents.

Another problem of patients with chronic renal insufficiency is secondary hyperparathyroidism. It is also important in patients with chronic renal insufficiency to avoid and treat secondary hyperparathyroidism.

Certain forms of lanthanum carbonate have been used to treat hyperphosphatemia in patients with renal failure (see, e.g., JP 1876384).

Japanese Published Patent Application Number 62-145024 (Asahi Chemical Ind. KK) discloses that rare earth carbonates, bicarbonates or organic acid compounds may be used as phosphate binding agents. The application relates to the use of lanthanum carbonate, although in the tests described, cerium organic acid salts and carbonate gave better phosphate ion extraction than lanthanum carbonate. The patent application does not disclose the use of anhydrous lanthanum carbonate as phosphate binding agent.

United States Patent Number 5,968,976 describes the use of La₂(CO₃ )3.xH₂O, where x has a value of 3 to 6, for the preparation of a medicament for the treatment of hyperphosphataemia by administration into the gastrointestinal tract. The patent discloses that phosphate binding capacity of lanthanum carbonate hydrate having 3 to 6 water molecules is better and quicker than the other hydrates, specifically octahydrate and monohydrate. The patent does not suggest the use of anhydrous lanthanum carbonate in the composition and for the treatment of hyperphosphataemia. United States Patent 7,381,428 describes the stabilized lanthanum carbonate compositions comprising a monosaccharide or disaccharide as stabilizing agent, and to the treatment of subjects having hyperphosphatemia by administering a pharmaceutical composition containing a therapeutically effective amount of a stabilized lanthanum carbonate. The patent discloses that the lanthanum carbonate has a tendency to degrade to lanthanum hydroxycarbonate due to moisture and heat and can be stabilized using monosaccharide or disaccharide as stabilizer in the composition.

The inventors of the present invention have found that the use of monosaccharides or disaccharides as the stabilizing agent increases the bulk of the formulation as they are to be used in higher amount. The use of higher amount of the excipients leads to the higher tablet weight and for a drug product like lanthanum carbonate having very high dose i.e. 1700mg the tablet weight goes upto 4gm or 5gms. This decreases patient compliance and increases the cost of the formulation.

United States Patent Application 2008/0125394 relates to a continuous slow release oral pharmaceutical compositions of substances capable of binding phosphorus, which when administered during fasting periods provides an improved treatment of hyperphosphatemia by binding the phosphorous secreted in the saliva and other gastric secretions. The patent application does not disclose the use of anhydrous lanthanum carbonate in the immediate release oral pharmaceutical composition.

United States Patent 7,465,465 describes a pharmaceutical formulation in a tablet or in a powder form comprising a pharmaceutically effective amount of a lanthanum compound produced by dry granulation or direct compression process. The patent discloses that with the drugs having a specific hydration status, granulating with water or solvents and drying is not advisable as this can affect the hydration status of the drug.

The prior art as discussed above discloses the use of direct compression and dry granulation for the preparation of tablet formulation comprising lanthanum carbonate to maintain the hydration status of lanthanum carbonate and to avoid decarboxylation. But, the direct compression and dry granulation processes are very difficult for a drug having high proportion in the dosage form.

PCT application WO2007/1 15973 relates to the alimentary or dietary component comprising phosphate binding agents. The patent application does not suggest the use of anhydrous lanthanum carbonate in the composition.

PCT application WO2006/050314 relates to a method for reducing serum phosphate in a subject in need thereof comprising administering once per day to said subject a phosphate binder, wherein the phosphate binder has a phosphate binding capacity of at least 52 mmole. The patent application further relates to a once-per-day phosphate binder formulation that is substantially equivalent to the standard formulation requiring three times per day dosing for controlling serum phosphate.

PCT application WO2006/044657 relates to compositions and formulations of phosphate binders that can be used for the treatment of diseases such as End Stage Renal Disease and Chronic Renal Insufficiency. Specifically, it is directed to compositions comprising lanthanum-based compounds such as lanthanum carbonate hydroxides and lanthanum oxycarbonates, which bind phosphate and can be formulated to provide for a reduced pill burden relative to other phosphate binders. The patent application does not suggest the use of anhydrous lanthanum carbonate in the composition.

PCT application WO2004/016553 relates to rare earth metal compounds of porous nature. The patent application further relates to the method of making the rare earth metal compounds and methods of using said rare earth metal compounds. The patent application specifically relates to the lanthanum oxychloride, anhydrous lanthanum oxycarbonate, and hydrated lanthanum oxycarbonate having porous structure and improved phosphate binding capacity. The patent application does not suggest the use of anhydrous lanthanum carbonate in the composition.

PCT application WO2009/1 18760 relates to stable, solid oral pharmaceutical composition comprising Lanthanum carbonate having more than-6 molecules of water per molecule of lanthanum carbonate and pharmaceutically acceptable carriers or diluents, wherein said carrier or diluent excludes monosaccharide/s or disaccharide/s, such that the composition has comparable in-vitro dissolution profile similar to that of Fosrenol®. The patent application discloses the use of various other diluents such as microcrystalline cellulose in the composition. The patent application does not suggest the use of anhydrous lanthanum carbonate in the composition.

Indian patent application IN2475/CHE/2007 relates to stabilized lanthanum carbonate composition comprising lanthanum carbonate in low hydration state having less than 3 molecules of water and aminoacid as diluent/stabilizer. The application discloses the stabilized high drug loaded pharmaceutical composition comprising lanthanum carbonate in low hydration state having less than three molecules of water and aminoacid as diluent/stabilizer. The applicant discloses the use of aminoacids as the essential component i.e. diluent or stabilizer for getting the stabilized lanthanum carbonate composition. There is no enabled disclosure for lanthanum carbonate composition without the use of aminoacid as diluent/stabilizer.

Lanthanum carbonate has a tendency to degrade to lanthanum hydroxycarbonate and lanthanum oxycarbonates. This process is accelerated by moisture and heat. There is a need in the art to prevent this degradation because current regulatory requirements preclude detectable decarboxylated products of lanthanum carbonate for administration to patients.

There exists an unmet need of stabilized pharmaceutical formulation comprising anhydrous lanthanum carbonate and pharmaceutically acceptable carrier and/or excipients.

The inventors of present invention have surprisingly found that Lanthanum Carbonate formulation can be stabilized without the use of monosaccharide or disaccharide or amino acids which is substantially free of lanthanum hydroxycarbonate or other related impurities in the final formulation.

SUMMARY:

The present invention relates to a stable pharmaceutical formulation comprising a therapeutically effective amount of anhydrous lanthanum carbonate and pharmaceutically acceptable carrier and/or excipients, with the proviso that the said formulation is substantially free of monosaccharides or disaccharides. The stable pharmaceutical formulation of said invention is also substantially free of amino acids and/or stabilizers.

The present invention also relates to processes for the preparation of anhydrous lanthanum carbonate as well as for the pharmaceutical formulation comprising this anhydrous lanthanum carbonate. Further, it relates to use of this formulation for the treatment of a disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the formulation of the present invention.

The formulation of present invention is such that it contains anhydrous lanthanum carbonate as an active ingredient instead of the hydrated lanthanum carbonate of the marketed product Fosrenol®, but still has higher stability, comparable dissolution profile & higher in vitro phosphate binding capacity in contrast to the belief in the art that it is not possible to have such a stable & efficacious formulation using anhydrous lanthanum carbonate.

BRIEF DESCRIPTION OF DRAWINGS:

Fig 1 and Fig 2 gives XRPD (x-ray powder diffraction) pattern of anhydrous lanthanum carbonate (Example 1) and chewable tablet formulation G of Table-7 respectively at 40 ± 2°C / 75 ±,5% RH on 0 day, 1 month, 2 month and 3 month in comparison with standard anhydrous lanthanum carbonate, lanthanum carbonate tetrahydrate, Fosrenol® tablet composition, lanthanum carbonate octahydrate, Lanthanum hydroxycarbonate polymorph I, Lanthanum hydroxycarbonate polymorph II, Lanthanum oxycarbonate.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to a stable pharmaceutical formulation comprising anhydrous lanthanum carbonate and pharmaceutically acceptable carrier and/or excipients.

The present invention relates to a stable pharmaceutical formulation comprising anhydrous lanthanum carbonate and pharmaceutically acceptable carrier and/or excipients, with the proviso that the said formulation is substantially free of monosaccharides or disaccharides.

The present invention further relates to the stable pharmaceutical formulation comprising anhydrous lanthanum carbonate and pharmaceutically acceptable carrier and/or excipients, with the proviso that said formulation are substantially free of monosaccharides or disaccharides, wherein the formulation is prepared by wet granulation.

The present invention further relates to the stable pharmaceutical formulation comprising anhydrous lanthanum carbonate and pharmaceutically acceptable carrier and/or excipients, with the proviso that said formulation is substantially free of monosaccharides or disaccharides, wherein the formulation is prepared by wet granulation. The present invention further relates to the stable pharmaceutical formulation comprising anhydrous lanthanum carbonate and pharmaceutically acceptable carrier and/or excipients, with the proviso that said formulation is substantially free of monosaccharides or disaccharides, wherein the composition is substantially free of aminoacid. The present invention further relates to the stable pharmaceutical formulation comprising anhydrous lanthanum carbonate and pharmaceutically acceptable carrier and/or excipients, with the proviso that said formulation is substantially free of monosaccharides or disaccharides, wherein the composition is substantially free of stabilizer.

Prior arts as discussed above discloses the lanthanum carbonate compositions with the use of aminoacid and stabilizers which contributes to the total weight of the formulation and thus increases the total weight of the composition. Inventors of the present invention have found a stable lanthanum carbonate formulation comprising anhydrous lanthanum carbonate which is substantially free of stabilizer and aminoacid. The moisture content of the stabilizers and aminoacid or the hydrophilic behavior of the stabilizers and aminoacid can affect the stability of the lanthanum carbonate in the formulation. The use of anhydrous lanthanum carbonate in the composition which is substantially free of stabilizers and aminoacid helps in achieving the stable formulation and the total weight of the formulation is also reduced leading to increased patient compliance and reduced cost because of smaller dosage form.

The present invention further relates to the stable pharmaceutical formulation comprising anhydrous lanthanum carbonate and pharmaceutically acceptable carrier and/or excipients, with the proviso that said formulation does not contain monosaccharides or disaccharides, wherein the total weight of the formulation is less than 60% of the total weight of the marketed formulation of lanthanum carbonate (Fosrenol®).

The present invention further relates to the stable pharmaceutical formulation comprising anhydrous lanthanum carbonate and pharmaceutically acceptable carrier and/or excipients, wherein the formulation comprises atleast 65% w/w of anhydrous lanthanum carbonate, with the proviso that said formulation is substantially free of monosaccharides or disaccharides.

Prior art discloses lanthanum carbonate tablet formulation having 10-40% of elemental lanthanum and having the tablet weight ranging between lgm for 250mg strength to 4.2gms for lOOOmg strength. The higher tablet weight decreases the patient compliance and also increases the cost of the tablet because of the use of high amount of excipients. The present invention further relates to the stable pharmaceutical formulation comprising anhydrous lanthanum carbonate and pharmaceutically acceptable carrier and/or excipients, wherein the formulation comprises atleast 65% w/w of anhydrous lanthanum carbonate, with the proviso that said formulation is substantially free of monosaccharides or disaccharides, wherein the composition is substantially free of aminoacid.

The present invention further relates to the stable pharmaceutical formulation comprising anhydrous lanthanum carbonate and pharmaceutically acceptable carrier and/or excipients, wherein the formulation comprises atleast 65% w/w of anhydrous lanthanum carbonate, with the proviso that said formulation is substantially free of monosaccharides or disaccharides, wherein the composition is substantially free of stabilizer.

The present invention further relates to the stable pharmaceutical formulation comprising anhydrous lanthanum carbonate and pharmaceutically acceptable carrier and/or excipients, wherein the formulation comprises atleast 65% w/w of anhydrous lanthanum carbonate, with the proviso that said formulation is substantially free of monosaccharides or disaccharides, wherein the total weight of the formulation is less than 60% of the total weight of the marketed formulation of lanthanum carbonate (Fosrenol®).

The present invention further relates to the stable pharmaceutical formulation comprising anhydrous lanthanum carbonate and a pharmaceutically acceptable carrier and/or excipients, wherein the formulation comprises anhydrous lanthanum carbonate and binder in the ratio of 4:1 to 70:1 w/w.

The inventors of the present invention have found that the ratio of anhydrous lanthanum carbonate and binder is very critical for getting good quality product i.e. less friable and stable formulation of anhydrous lanthanum carbonate. For a drug having high dose the selection of binders and the ratio of drug to binder significantly affects the strength of the formulation. The inventors of the present invention have found that the use of anhydrous lanthanum carbonate and binder in the ratio of 4: 1 to 70: 1 w/w provides the formulation with higher strength, lesser friability, and improved stability.

The present invention also relates to a premix composition comprising anhydrous lanthanum carbonate and pharmaceutically acceptable carrier and/or excipients. The present invention further relates to a premix composition comprising anhydrous lanthanum carbonate and pharmaceutically acceptable carrier and/or excipients with the proviso that the said composition is substantially free of monosaccharide or disaccharide.

The present invention also relates to a premix composition comprising anhydrous lanthanum carbonate and pharmaceutically acceptable carrier and/or excipients, wherein the composition comprises atleast 65% w/w of anhydrous lanthanum carbonate, with the proviso that said composition is substantially free of monosaccharides or disaccharides.

The present invention further relates to a pharmaceutical formulation comprising a premix composition and pharmaceutically acceptable external excipients wherein the formulation comprises atleast 65% w/w of the premix composition. Inventors of the present invention have found that the preparation of lanthanum carbonate formulation with prior art method requires large amount of excipients to form a stable dosage form. The dosage form prepared by the prior art methods provide coarser particles of the lanthanum carbonate which leads to segregation of particles during the dry mixing before compression. The coarser particles also lead to the slower phosphate binding as compared to the finer or porous particles. Inventors of the present invention have found that the anhydrous lanthanum carbonate formulation prepared by the process of the present invention provides lanthanum carbonate particles of lesser bulk density and of porous nature, resulting in increased surface area and hence faster phosphate binding.

Inventors of the present invention have surprisingly found that the reaction temperature condition is the critical parameter for getting the desired hydration levels of lanthanum carbonate and the stirring conditions during the reaction is the critical parameter for achieving the desired particle size of lanthanum carbonate.

Anhydrous lanthanum carbonate particles according to the present invention are prepared by simple chemical reaction process under the controlled temperature and stirring conditions. Anhydrous lanthanum carbonate particles of the present invention are prepared by reacting lanthanum chloride with sodium carbonate under constant stirring at about 1-1000 rpm and at the temperature range of about -10 to 20⁰C. Inventors of the present invention have found that the reaction conducted at -10 to 2O⁰C and with the constant stirring at about 1-1000 rpm results in anhydrous lanthanum carbonate particles with lower bulk density and hence faster phosphate binding due to increased surface area too. The bulk density of the resulting anhydrous lanthanum carbonate ranges between 0.05 to 0.5 g/ml, preferably 0.1 to 0.3 g/ml.

Another aspect of the present invention relates to process for preparation of anhydrous lanthanum carbonate comprising the steps of: a) adding lanthanum salt solution and alkali or alkaline earth metal carbonate solution under constant stirring in a container. b) filtering the residue of step a) and washing with water miscible solvent(s) to obtain the wet cake. c) drying the wet cake to get the anhydrous lanthanum carbonate.

Another aspect of the present invention relates to process for preparation of anhydrous lanthanum carbonate comprising the steps of: a) adding lanthanum salt solution and alkali or alkaline earth metal carbonate solution under constant stirring of about 1-1000 rpm at -10 to 20⁰C temperature in a container. b) filtering the residue of step a) and washing with water miscible solvent(s) to obtain the wet cake c) drying the wet cake to get the anhydrous lanthanum carbonate.

Another aspect of the present invention relates to process for preparation of anhydrous lanthanum carbonate comprising the steps of: a) adding lanthanum salt solution and alkali or alkaline earth metal carbonate solution under constant stirring in a container, optionally containing colloidal silicon dioxide dispersion, at about 1-1000 rpm and -10 to 2O⁰C b) filtering the residue of step a) and washing with water, ethanol, methanol, isopropyl alcohol, acetone, water and isopropyl alcohol or others and mixtures thereof to obtain the wet cake c) drying the wet cake to get the anhydrous lanthanum carbonate.

Another aspect of the present invention relates to a stable pharmaceutical formulation comprising anhydrous lanthanum carbonate and pharmaceutically acceptable carrier and/or excipients, with the proviso that the said formulation is substantially free of monosaccharide or disaccharide wherein the anhydrous lanthanum carbonate is prepared by the process comprising the steps of: a) adding lanthanum salt solution and alkali or alkaline earth metal carbonate solution under constant stirring in a container. b) filtering the residue of step a) and washing with water miscible solvent(s) to obtain the wet cake. c) drying the wet cake to get the anhydrous lanthanum carbonate.

Another aspect of the present invention relates to a stable pharmaceutical formulation comprising anhydrous lanthanum carbonate and pharmaceutically acceptable carrier and/or excipients, with the proviso that the said formulation is substantially free of monosaccharide or disaccharide wherein the anhydrous lanthanum carbonate is prepared by the process comprising the steps of: a) adding lanthanum salt solution and alkali or alkaline earth metal carbonate solution under constant stirring in a container. b) filtering the residue of step a) and washing with water miscible solvent(s) to obtain the wet cake. c) drying the wet cake to get the anhydrous lanthanum carbonate. wherein the formulation comprises atleast 65% w/w of anhydrous lanthanum carbonate

Another aspect of the present invention relates to a stable pharmaceutical formulation comprising anhydrous lanthanum carbonate and pharmaceutically acceptable carrier and/or excipients, with the proviso that the said formulation is substantially free of monosaccharide or disaccharide wherein the anhydrous lanthanum carbonate is prepared by the process comprising the steps of: a) adding lanthanum salt solution and alkali or alkaline earth metal carbonate solution under constant stirring of about 1-1000 rpm at -10 to 2O⁰C temperature in a container. b) filtering the residue of step a) and washing with water miscible solvent(s) to obtain the wet cake c) drying the wet cake to get the anhydrous lanthanum carbonate.

Another aspect of the present invention relates to a stable pharmaceutical formulation comprising anhydrous lanthanum carbonate and pharmaceutically acceptable carrier and/or excipients, with the proviso that the said formulation is substantially free of monosaccharide or disaccharide wherein the anhydrous lanthanum carbonate is prepared by the process comprising the steps of: a) adding lanthanum salt solution and alkali or alkaline earth metal carbonate solution under constant stirring in a container, optionally containing colloidal silicon dioxide dispersion, at about 1-1000 rpm and -10 to 20⁰C b) filtering the residue of step a) and washing with water or isopropyl alcohol or mixtures thereof to obtain the wet cake c) drying the wet cake to get the anhydrous lanthanum carbonate.

Another aspect of the present invention relates to a stable pharmaceutical formulation comprising anhydrous lanthanum carbonate and pharmaceutically acceptable carrier and/or excipients, with the proviso that the said formulation is substantially free of monosaccharide or disaccharide wherein the formulation is prepared by the process comprising the steps of: a) mixing the anhydrous lanthanum carbonate with pharmaceutically acceptable carrier and/or excipients; b) granulating the blend of step a) with water miscible solvent; c) drying the granules; d) optionally mixing the granules with external excipients; e) compression of granules to form tablet or filling the granules in the capsule shell.

Another aspect of the present invention relates to a stable pharmaceutical formulation comprising anhydrous lanthanum carbonate and pharmaceutically acceptable carrier and/or excipients, with the proviso that the said formulation is substantially free of monosaccharide or disaccharide wherein the formulation is prepared by the process comprising the steps of: a) mixing the anhydrous lanthanum carbonate with pharmaceutically acceptable carrier and/or excipients; b) granulating the blend of step a) with water or isopropyl alcohol; c) drying the granules; d) optionally mixing the granules with external excipients; e) compression of granules to form tablet or filling the granules in the capsule shell.

Another aspect of the present invention relates to a stable pharmaceutical formulation comprising anhydrous lanthanum carbonate and pharmaceutically acceptable carrier and/or excipients selected from a group comprising binder, sweetener, diluent, disintegrants, glidant, lubricant, antioxidant, flavoring agent, coloring agent, surface stabilizer, Anticapping agent or the like or combinations thereof, with the proviso that the said formulation is substantially free of monosaccharide or disaccharide wherein the formulation is prepared by the process comprising the steps of: a) mixing the anhydrous lanthanum carbonate with pharmaceutically acceptable carrier and/or excipients; b) granulating the blend of step a) with water or isopropyl alcohol; c) drying the granules; d) optionally mixing the granules with external excipients; e) compression of granules to form tablet or filling the granules in the capsule shell.

Another aspect of the present invention relates to a stable pharmaceutical formulation comprising anhydrous lanthanum carbonate and pharmaceutically acceptable carrier and/or excipients, with the proviso that the said formulation is substantially free of monosaccharide or disaccharide wherein the formulation is prepared by the process comprising the steps of: a) mixing the anhydrous lanthanum carbonate with sweetener and binder; b) granulating the blend of step a) with water or isopropyl alcohol; c) drying the granules; d) optionally mixing the granules with external excipients; e) compression of granules to form tablet or filling the granules in the capsule shell.

Another aspect of the present invention relates to a stable pharmaceutical formulation comprising anhydrous lanthanum carbonate and pharmaceutically acceptable carrier and/or excipients, with the proviso that the said formulation is substantially free of monosaccharide or disaccharide wherein the formulation is prepared by the process comprising the steps of: a) mixing the anhydrous lanthanum carbonate with sucralose and hydroxypropyl cellulose; b) granulating the blend of step a) with water or isopropyl alcohol; c) drying the granules; d) optionally mixing the granules with external excipients; e) compression of granules to form tablet or filling the granules in the capsule shell.

Another aspect of the present invention relates to a stable pharmaceutical formulation comprising anhydrous lanthanum carbonate and pharmaceutically acceptable carrier and/or excipients, with the proviso that the said formulation is substantially free of monosaccharide or disaccharide wherein the formulation is prepared by the process comprising the steps of: a) adding lanthanum salt solution and alkali or alkaline earth metal carbonate solution under constant stirring in a container. b) filtering the residue of step a) and washing with water miscible solvent(s) to obtain the wet cake. c) granulating the wet cake of step b) using binder d) drying the granules; e) optionally mixing the granules with external excipients f) compressing the granules to form tablet or filling the granules into the capsule or sachet. The present invention also relates to a stable pharmaceutical formulation comprising anhydrous lanthanum carbonate and pharmaceutically acceptable carrier and/or excipients, wherein the formulation is prepared by the process comprising the steps of: a) adding lanthanum salt solution and alkali or alkaline earth metal carbonate solution under constant stirring of about 1-1000 rpm at -10 to 20⁰C temperature in a container. b) filtering the residue of step a) and washing with water miscible solvent(s) to obtain the wet cake c) granulating the wet cake of step b) using binder d) drying the granules; e) optionally mixing the granules with external excipients f) compressing the granules to form tablet or filling the granules into the capsule or sachet.

The present invention also relates to a stable pharmaceutical formulation comprising anhydrous lanthanum carbonate and pharmaceutically acceptable carrier and/or excipients, with the proviso that the said formulation is substantially free of monosaccharide or disaccharide wherein the formulation is prepared by the process comprising the steps of: a) adding lanthanum salt solution and alkali or alkaline earth metal carbonate solution under constant stirring of about 1-1000 rpm at -10 to 20⁰C temperature in a container b) filtering the residue of step a) and washing with water miscible solvent(s) to obtain the wet cake c) granulating the wet cake of step b) using binder d) drying the granules; e) optionally mixing the granules with external excipients f) compressing the granules to form tablet or filling the granules into the capsule or sachet, wherein the formulation comprises atleast 65% w/w of anhydrous lanthanum carbonate. The present invention also relates to a stable pharmaceutical formulation comprising anhydrous lanthanum carbonate and pharmaceutically acceptable carrier and/or excipients, with the proviso that the said formulation is substantially free of monosaccharide or disaccharide wherein the formulation is prepared by the process comprising the steps of: a) adding lanthanum salt solution and alkali or alkaline earth metal carbonate solution under constant stirring in a container, optionally containing colloidal silicon dioxide dispersion, at about 1-1000 rpm at -10 to 20⁰C b) filtering the residue of step a) and washing with water or isopropyl alcohol or mixtures thereof to obtain the wet cake c) granulating the wet cake of step b) using plasdone or hydroxypropyl cellulose or mixtures thereof. d) drying the granules; e) optionally mixing the granules with disintegrant, glidant or lubricant or mixtures thereof f) compressing the granules to form tablet.

The present invention also relates to a premix composition comprising anhydrous lanthanum carbonate, binder, optionally a stabilizer and pharmaceutically acceptable carrier and/or excipients, with the proviso that the said composition does not contain monosaccharide or disaccharide wherein the composition is prepared by the process comprising the steps of: a) adding lanthanum salt solution and alkali or alkaline earth metal carbonate solution under constant stirring in a container; b) filtering the residue of step a) and washing with water miscible solvent(s) to obtain the wet cake; c) adding binder to the wet cake c) drying the wet cake to form premix.

The present invention also relates to a premix composition comprising anhydrous lanthanum carbonate and a surface stabilizer, with the proviso that the said composition does not contain monosaccharide or disaccharide wherein the composition is prepared by the process comprising the steps of: a) adding lanthanum salt solution and alkali or alkaline earth metal carbonate solution under constant stirring in a container containing dispersion of surface stabilizer; b) filtering the residue of step a) and washing with water miscible solvent(s) to obtain the wet cake; c) adding binder to the wet cake c) drying the wet cake to form premix.

The present invention also relates to a premix composition comprising anhydrous lanthanum carbonate and pharmaceutically acceptable carrier and/or excipients, with the proviso that the said composition is substantially free of monosaccharide or disaccharide wherein the composition is prepared by the process comprising the steps of: a) adding lanthanum salt solution and alkali or alkaline earth metal carbonate solution under constant stirring in a container b) filtering the residue of step a) and washing with water or isopropyl alcohol or mixtures thereof to obtain the wet cake c) granulating the wet cake of step b) using binder, and d) drying the granules to form premix.

The present invention also relates to a premix composition comprising anhydrous lanthanum carbonate and pharmaceutically acceptable carrier and/or excipients, with the proviso that the said composition is substantially free of monosaccharide or disaccharide wherein the composition is prepared by the process comprising the steps of: a) adding lanthanum salt solution and alkali or alkaline earth metal carbonate solution under constant stirring of about 1-1000 rpm at -10 to 20⁰C temperature in a container b) filtering the residue of step a) and washing with water miscible solvent(s) to obtain the wet cake c) granulating the wet cake of step b) using binder and d) drying the granules to form a premix wherein the composition comprises atleast 65% w/w of anhydrous lanthanum carbonate

The present invention also relates to a premix composition comprising anhydrous lanthanum carbonate and pharmaceutically acceptable carrier and/or excipients, with the proviso that the said composition is does not contain monosaccharide or disaccharide wherein the composition is prepared by the process comprising the steps of: a) adding lanthanum salt solution and alkali or alkaline earth metal carbonate solution under constant stirring in a container optionally containing colloidal silicon dioxide dispersion at about 1-1000 rpm at -10 to 20⁰C b) filtering the residue of step a) and washing with water or isopropyl alcohol or mixtures thereof to obtain the wet cake c) granulating the wet cake of step b) using plasdone or hydroxypropyl cellulose or mixtures thereof. d) drying the granules to form a premix.

In an aspect, the present invention also relates to a stable pharmaceutical formulation comprising a therapeutically effective amount of anhydrous lanthanum carbonate and pharmaceutically acceptable carrier and/or excipients, with the proviso that the said formulation does not contain monosaccharides or disaccharides.

The anhydrous lanthanum carbonate formed from the reaction of reactants produces anhydrous lanthanum carbonate in the dispersion. The particle size of the anhydrous lanthanum carbonate in the dispersion phase ranges from lOOnm to 100 μm.

Inventors of the present invention have surprisingly found that the selection of surface stabilizer and the ratio of reactants to surface stabilizer, during dispersion stage greatly affect the particle size of the anhydrous lanthanum carbonate in dispersion phase and the bulk density of the powder. Use of surface stabilizer during the dispersion phase prevents aggregation of particles at dispersion phase and granulation. It further reduces the bulk density of the powder and thereby providing more surface area for rapid binding of phosphate ions.

It is found that the use of reactants to surface stabilizer ratio ranging from 0.3:1 to 300: 1 in the dispersion phase results in more uniform and stable dispersion of the lanthanum carbonate. The use of the specific ratio of reactants to surface stabilizer also results in the porous particles of the anhydrous lanthanum carbonate in the granules and hence increases the surface area for phosphate binding.

In yet another aspect the stable pharmaceutical formulation of the present invention results in faster phosphate binding. The phosphate ions released from the food product will bind immediately with the lanthanum ions resulting in less chance of phosphate ions getting absorbed in the blood. Reactant according the present invention means the substances which react to produce lanthanum carbonate as final product. The reactants include lanthanum base, it salts and alkali or alkaline earth metal carbonate.

Solution of lanthanum salt and alkali or alkaline earth metal carbonate can be prepared by any method known in the art. Preferably solution of lanthanum salt and alkali or alkaline earth metal carbonate can be prepared by simple mixing the lanthanum salt and alkali or alkaline earth metal carbonate with water miscible solvents in separate containers.

A water-miscible solvent according to the present invention means all the solvents which are miscible with water including water. Water miscible solvents include, but not limited to, water, alcohol, formic acid, dimethyl sulfoxide, dimethyl formamide, acetonitrile, acetone, dichloromethane, tetrahydrofuran, 1 ,4-dioxane, pyridine, furfuryl alcohol, tetrahydro furfuryl alcohol or the like or combinations thereof.

The term "lanthanum carbonate" according to the present invention includes anhydrous lanthanum carbonate, its polymorphic forms, or derivatives thereof. "Lanthanum salts" according to the present invention includes all the salts of lanthanum metal for example, lanthanum chloride, lanthanum oxide, lanthanum acetate or the like or combinations thereof and their hydrates or derivatives thereof. Preferred lanthanum salt is lanthanum chloride heptahydrate.

The term "alkali or alkaline earth metal carbonate" according to the present invention includes, but is not limited to; carbonate salt of any of the alkali or alkaline earth metal as per the periodic table. Alkali or alkaline earth metal carbonate include, but are not limited to, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, or the like or combinations thereof. Preferred alkaline earth metal carbonate is sodium carbonate. The term "premix" according to the present invention refers to a mixture of active ingredient, and pharmaceutically acceptable carriers and/or excipients including but not limited to surface stabilizer, binder and optionally glidant/lubricant. The Premix is such that it is a form (as granules, powder, pellets or others) which includes a binder during the manufacturing of the active ingredient and is thus such that it can be directly compressed into a tablet without subjecting to further granulation using optionally other excipients like lubricants, sweeteners and others and like. "Monosaccharides" according to the present invention includes glyceraldehyde, erythrose, threose, ribose, lyxose, xylose, arabinose, allose, talose, gulose, mannose, glucose, idose, galactose, altrose, dihydroxyacetone, erythrulose, ribulose, xyloketose, psicose, tagatose, sorbose, fructose, sorbitol, xylitol, inositol, erythritol, and mannitol in either the D- or L- configuration.

"Disaccharides" according to the present invention include sucrose as such, lactose (including anhydrous lactose and lactose monohydrate), maltose, isomaltose, cellobiose, trehalose, maltitol, isomalt, and lactitol.

The term "substantially free of according to the present invention means that the composition may contain the said substance in an amount less than or equal to 10%, preferably less than or equal to 5% and most preferably less than or equal to 1%.

"Pharmaceutically acceptable carrier and/or excipients" according to the present invention can be any auxiliary substance suitable for making a dosage form or formulation. Preferably, the excipients used in the formulation administered by the present invention should be suitable for oral administration, especially to renally impaired subjects. Pharmaceutically acceptable carrier and/or excipients according to the present invention include but not limited to diluent, binder, disintegrant, glidant, lubricant, antioxidant, flavoring agent, coloring agent, sweetener, surface stabilizer, anti-capping agent or the like or combinations thereof.

Diluents according to the present invention means an inert substance used to increases the bulk of the composition. Diluents include, but are not limited to, microcrystalline cellulose, calcium sulphate, starch, calcium carbonate, magnesium oxide, magnesium carbonate, or the like or combinations thereof. The total amount of diluents can be used from about 0 % to about 55%, preferably in the range of about 0% to about 35% and more preferably in the range of about 0% to about 25% by weight of the composition. In another embodiment of the present invention the stable pharmaceutical formulation is substantially free of diluents.

Binders help to bind the active ingredient and other excipients together. Binders used in the composition include binders commonly used in solid pharmaceutical compositions. Binders include, but are not limited to, polyvinyl pyrrolidone, polyethylene oxide, acacia, alginic acid, carbomer, sodium carboxymethylcellulose, dextrin, maltose, povidone, starch, gelatin, glucose, guar gum, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methylcellulose, ethylcellulose, methylcellulose, methacrylate copolymers, natural gums and the like or combinations thereof. The total amount of binder ranges from about 2 % to about 55%, preferably in the range of about 5% to about 45% and more preferably in the range of about 5% to about 35% by weight of the composition. Disintegrants helps in faster disintegration of dosage form and can increase dissolution. Examples of suitable disintegrants are, but not limited to, starch, hydroxypropyl cellulose low substituted, pregelatinized starch, sodium starch glycolate, hydroxypropyl starch, sodium carboxymethylcellulose, calcium carboxymethyl cellulose, crosslinked sodium carboxymethylcellulose, clays, microcrystalline cellulose, sodium alginate and other alginates, guar gum and other gums, docusate sodium, magnesium aluminium silicate, surfactants, effervescent mixtures, hydrous aluminum silicate, crospovidone, and others as known in the art or combinations thereof. The total amount of disintegrant ranges from about 0% to about 25%, preferably in the range of about 0% to about 20% and more preferably in the range of about 0% to about 15% by weight of the composition. Anticapping agent can be added to the composition for preventing the capping problem, if any, during tablet formulation. Anticapping agent includes, but are not limited to, hydroxypropyl cellulose, hydroxypropyl cellulose low-substituted, or the like or combinations thereof. The total amount of anti-capping agent ranges from about 0% to about 10%, preferably in the range of about 0% to about 8% by weight of the composition. A lubricant can be added to the composition for ease in processing, e.g., to reduce adhesion to the equipment used during processing, and to ease release of the product from a punch or dye during tableting. Useful lubricants can be chosen from, but are not limited to, for example, magnesium stearate, talc, polyethylene glycol, silica, colloidal anhydrous silica, colloidal silicon dioxide, hydrogenated vegetable oil, glyceryl behenate, glyceryl monostearate, calcium stearate, mineral oil, sodium stearyl fumarate, stearic acid, sodium lauryl sulfate, and zinc stearate or the combinations thereof. One or more lubricants can be present in a formulation. The total lubricant amount ranges from about 0.001% to about 6.0%, preferably in the range of about 0.001% to about 5.0%, and more preferably in the range of about 0.001% to about 4.0% by weight of the composition. Glidant can be added to improve the flowability of a pharmaceutical composition and improve the accuracy of dosing. Useful glidant can be chosen from, but are not limited to, colloidal Silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, silica, colloidal anhydrous silica, calcium silicate, magnesium silicate and tribasic calcium phosphate and the like or combinations thereof. One or more glidant can be present in a formulation. The total amount of glidant ranges from about 0.001% to about 6.0%, preferably in the range of about 0.001% to about 5.0%, and more preferably in the range of about 0.001% to about 4.0% by weight of the composition.

It may also be advantageous to incorporate an antioxidant, for example, ascorbic acid, alpha tocopherol or butylated hydroxyanisole in the formulation to enhance its storage life. One or more antioxidants can be present in the formulation.

Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that can be included in the composition of the present invention include natural, semi-synthetic or synthetic flavors, for example but not limited to, maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid and the like or combinations thereof.

Coloring agents make the dosage form more acceptable to the patients and helps in easy identification of the preferable brand. Coloring agents include, but not limited to, all FD&C dyes and colors, red oxide, titanium oxide or combinations thereof.

Sweeteners make the dosage form more palatable to the patients. Sweeteners include but not limited to sucralose, acesulfam potassium, sodium saccharin, aspartame, mono ammonium glycyrrhizinate or the like or combinations thereof. The total amount of sweetener ranges from about 0.0001% to about 2.0%, preferably in the range of about 0.001% to about 1.50%, and more preferably in the range of about 0.001% to about 1.0% by weight of the composition.

Useful surface stabilizers, which are known in the art and described, are believed to include those which physically adhere to the surface of the active agent. The surface stabilizer is adsorbed on the surface of the particulate active agent in an amount sufficient to maintain an effective average particle size for the active agent. One or more surface stabilizers can be employed in the compositions and methods of the invention.

Suitable surface stabilizers are selected from a group of various inorganic hydrophilic substances, polymers, low molecular weight oligomers, natural products, and surfactants. Such excipients include hydroxypropylmethyl cellulose, carboxy methyl cellulose, carbopols, polaxamers, guar gum, xanthan gum, tweens, spans, and metal oxides etc. The total amount of surface stabilizer ranges from about 0.001% to about 10.0%, preferably in the range of about 0.001% to about 8.0%, and more preferably in the range of about 0.001% to about 4.0% by weight of the composition. Preferred surface stabilizer is colloidal silicon dioxide.

"External excipient" according to the present invention includes, but are not limited to, disintegrant, diluents, glidant, lubricant, antioxidant, flavoring agent, coloring agent, sweetener, binder, anti-capping agent.

"Stabilizer" according to the present invention means any substance which stabilizes lanthanum carbonate w.r.t hydration level and impurities including lanthanum hydroxycarbonate and lanthanum oxy carbonate. The hydration level of the lanthanum compound can be measured by any method known in the art, including thermo-gravimetric analysis (TGA) or Differential Scanning Calorimetry (DSC).

In the present invention, the granulation step results in particles that are free flowing and have good characteristics for tableting. The term "free flowing" means ease of handling as in, for example, measuring, introducing into packages, or feeding into tableting or encapsulating equipment. Free flowing materials exhibit low cohesion and have the ability to keep moving consistently under the force of gravity without any applied agitation.

Flow properties of a formulation may be evaluated by a number of methods known in the art. One way of characterizing formulation properties of a powdered material is by bulk density measurements. Carr's Compressibility Index is a simple test to evaluate flowability by comparing both the initial and final (tapped) bulk volumes and the rate of packing down.

Compressibility Index (%) = [(tapped density-initial density )/tapped density]^χ 100

Granules prepared in the present invention, have a Carr's Compressibility Index of less than about 35%; more preferably less than about 30%; even more preferably less than about 25%. The Hausner ratio is defined in the Metals Handbook, Vol. 7, 9th Ed. p. 285 (1984) as the tap density divided by the bulk density where the densities are in common units of measure. The Hausner ratio is a number that is correlated to the flowability of a powder or granular material. The granules prepared in present invention have a Hausner ratio of less than 1.35, preferably less than 1.25.

The tablets prepared from the granulation of the present invention exhibit acceptable physical characteristics including good friability and hardness. The resistance of a tablet to chipping, abrasion, or breakage under conditions of storage and transportation depends on its friability. The desired hardness may vary, depending on factors such as tablet size and shape.

The lanthanum carbonate formulation can be orally administered to subjects in accordance with this invention in dosage forms varying from about 125 to about 2000 mg lanthanum carbonate as elemental lanthanum per meal. A typical dosage for an adult can be, e.g., 375 mg-6000 mg daily. More preferably, the dosage is 375-3750 mg/day. The dose can be divided and taken with each meal, for example a 250, 500, 750, or 1000 mg elemental lanthanum per tablet, e.g., three times per day. Serum plasma levels can be monitored weekly and dosages can be modified until an optimal serum phosphate level is reached. Administration may be conducted in an uninterrupted regimen; such a regimen may be a long term regimen, e.g., a permanent regimen, for treating chronic conditions.

The lanthanum carbonate formulations can be orally administered, for example, in the form of tablets, capsules, chewable formulations, or the like. Frequently, due to their renal problems, subjects with hyperphosphatemia need to limit their liquid intake. Therefore, a lanthanum carbonate formulation that can be taken with no or limited amounts of liquid is desirable. For example, a lanthanum carbonate formulation, in the form of, e.g., beads, chewed or crushed tablets, powder, or sieved granules, may be sprinkled on food.

It will be understood that the type of lanthanum carbonate formulation and the duration of the treatment will vary depending on the requirements for treatment of individual subjects. The precise dosage regimen will be determined by the attending physician or veterinarian who will, inter alia, consider factors such as body weight, age a nd specific symptoms. The physician or veterinarian may titrate the dosage of lanthanum carbonate administered to a subject to determine the correct dosage for treatment. For example, a physician can measure phosphate levels in a patient, prescribe a particular lanthanum carbonate dosage to the patient for a week, and evaluate after the week if the dosage is appropriate by remeasuring phosphate levels in the patient. The pharmaceutical composition of the present invention can be administered to the animals, including companion animals in an amount effective to mitigate hyperphosphatemia.

It must be noted that as used in the specification and the appended claims, the singular forms 'a', 'an' and 'the' include plural references unless the context clearly indicates otherwise. It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent or patent application were specifically and individually indicated to be so incorporated by reference.

The following examples are merely illustrative of the present invention and they should not be considered as limiting the scope of the invention in any way.

Example-1 Process for the preparation of anhydrous lanthanum carbonate: Table-1

1. Aqueous dispersion of colloidal silicon dioxide was prepared by transferring the said amount of colloidal silicon dioxide into water and stirred to make slurry. 2. This aqueous dispersion was charged into the reaction vessel and stirred in a anchor type stirrer. The reaction mixture was cooled and maintained at controlled temperature conditions. 3. Aqueous solution of lanthanum chloride and sodium carbonate were added into the reaction mixture above at a controlled rate.

4. The dispersion obtained in step 3 above was centrifuged and washed with water miscible solvents mentioned in 8 & 6 in table 1 to form a wet cake. 4. Wet cake was dried at 120 ⁰C for 12 h.

Example-2

Preparation of lanthanum carbonate chewable tablet from anhydrous lanthanum carbonate premix composition Step 1. Process for preparing anhydrous lanthanum carbonate premix composition Table-2

1. Anhydrous lanthanum carbonate was synthesized as described in steps 1 to 4 of Example 1 using the ingredients from 1 to 7 above in table-2.

2. Binders (either dry powder or solution) were mixed to the wet cake (selected from ingredients 8, 9, or 10 as per the composition in table-2).

3. The powder/granules thus obtained were dried at 120 ⁰C for 12 h to obtain the premix composition. Step 2. Process for preparation of lanthanum carbonate tablet from the above premix composition

Table-3

1. All the ingredients mentioned in table-3 above were weighed as per the quantities mentioned above

2. Premix composition (obtained form table-2) comprising the anhydrous lanthanum carbonate was blended with low substituted hydroxypropyl cellulose (LHPC-LHl 1 ), colloidal silicon dioxide, and magnesium stearate.

3. The above blend was compressed to form chewable tablets.

Example-3

Determination of Hausner's Ratio & Carr's Compressibility index

Granules of anhydrous lanthanum carbonate were prepared as per the formulation mentioned in table-4 below to determine the flow properties like Carr's Compressibility index and Hausner's Ratio. Table-4

S. Ingredients Quantity (g)

No.

A B C D E

1 Anhydrous lanthanum carbonate 1.65 1.65 1.65 1.65 1.65

2 0.4058 0.3058 0.28 0.23 0.18

Hydroxypropyl Cellulose

3 Sucralose 0.0042 0.0042 0.0042 0.0042 0.0042

4 * * * * *

Isopropyl alcohol

5 Low-substituted hydroxypropyl

0 0.1 0.1258 0.1758 0.2258 cellulose(LHPC-LHl l )

6 Colloidal silicon dioxide 0.02 0.02 0.02 0.02 0.02

7 Magnesium stearate 0.01 0.01 0.01 0.01 0.01 8 Talc 0.01 0.01 0.01 0.01 0.01

I Tablet weight 2.1 2.1 2.1 2.1 2.1

Hausner's Ratio 1.235 1.250 1.250 1.282 1.333

Carr's Compressibility index 19 20 20 22 25

*lsopropyl alcohol-Lost during processing

1. Ingredients 1, 2, 3 were weighed as per quantities mentioned in table-4 for each formulation & mixed to form a blend.

2. The blend was granulated using isopropyl alcohol.

3. The granules obtained were dried & mixed with ingredients no. 5, 6, 7, & 8 to obtain lubricated granules.

4. Flow properties like Carr's Compressibility index and Hausner's Ratio were determined using the granules as obtained in step 3.

Example-4

Preparation of lanthanum carbonate chewable tablets (250 mg, 500 mg, and 1000 mg)

A process similar to that described in Example 3 was followed to prepare lanthanum carbonate chewable tablet of Example 4.

TabIe-5

For 250 mg elemental lanthanum tablets Jngredient __ ___ Quantity (g/tablet)

A B C D E F G H

¹ Lanthanum carbonate 0.4125 0.4125 0.4125 0.4125 0.4125 0.4125 0.4125 0.4125 [ Hydroxypropyl

0.07 0.07 0.07 0.07 0.1025 0.05145 0.10145 0.06395 i cellulose

; Sucralose 0.000525 0.00105 0.00105 0.00105 Lactose anhydrous 0.035 0.035 0.035 0.031975

Isopropyl alcohol* Low-substituted 0.0475 0.05 0.05 hydroxypropyl cellulose crospovidone_ 0.0475 Colloidal silicon

0.005 0.005 0.005 0.005 0.005 0.005 0.005 0.005 dioxide

Talc 0.0025 0.0025 0.0025 0.0025 0.0025 0.0025 0.0025

Magnesium stearate 0.0025 0.0025 0.0025 0.0025 0.0025 0.0025 0.0025 0.0025

TABLET WEIGHT 0.525 ^■ 0.575 0.575 0.525 0.525 0.525 0.525 0.5375

* Isopropyl alcohol-Lost during processing Table-6

For 500 mg elemental lanthanum tablets

Lactose anhydrous 0.07 0.07 0.07 • 0.06395 - - - l Isopropyl alcohol , - - - - - - -

' Low-substituted '

- - 0.095 - 0.1 - 0.1 ; hydroxypropyl cellulose I i crospovidone - 0.095 - I r- _ _ - - -

Colloidal silicon dioxide 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01

Talc - 0.005 0.005 , 0.005 0.005 0.005 0.005 0.005

Magnesium stearate 0.005 0.005 0.005 0.005 0 005 0.005 0.005 0.005

TABLET WEIGHT ^! 1.05 1.15 1.15 , 1.05 1.05 1 05 1.05 1 075

*Isoprόpyl alcohol-Lost during processing

Table-7

For 1000 mg elemental lanthanum tablets

Ingredient Quantity (g/tablet)

A B C D E F G H

Lanthanum carbonate 1.65 1.65 1.65 1.65 1.65 1.65 1.65 1 65

Hydroxypropyl cellulose 0.28 0.28 0.28 0.28 0.41 0.2058 0.4058 0.2558

Sucralose - - - 0.0021 - 0 0042 0.0042 0.0042

Lactose anhydrous 0.14 0.14 0.14 0.1279 - - - -

Isopropyl alcohol Low-substituted

- - 0.19 I 0.2 0.2 hydroxypropyl cellulose t {• I crospovidone - 0.19 - - -

Colloidal silicon dioxide 0.02 0.02 0.02 ¹ 0.02 * 0.02 ' 0.02 0.02 0.02

Talc - 0.01 0.01 0.01 0.01 0.01 0.01 0 01

Magnesium stearate 0.01 0.01 0.01 0.01 0 01 0.01 0 01 0 01

TABLET WEIGHT 2.1 2.3 2.3 2 1 2.1 2.1 2.1 2 15

^♦Isopropyl alcohol-Lost during processing

Exam pie- 5

Comparative dissolution study of formulations of F and G of table 7 with Fosrenol® The dissolution test was carried out using USP II apparatus at 100 rpm, 900 ml of 0.25N HCl at 37 ± 0.5 ⁰C. TabIe-8

The in-vitro dissolution profile obtained illustrates that the lanthanum carbonate formulation

G exhibits comparative release with the marketed formulation and formulation F is exhibiting faster dissolution than that of the marketed lanthanum carbonate preparation (Fosrenol®).

Example-6

Comparative phosphate binding studies: Example 1, formulations G of TabIe-7 and

Fosrenol®

The anhydrous lanthanum carbonate of example 1 and tablet formulation G of table-7 were compared with the marketed lanthanum carbonate formulation (Fosrenol®) for phosphate binding capacity.

Procedure: Standard stock solution of Phosphate ions was prepared with final concentration of 50 mg/L of phosphate ion. At 0 time point weighed quantity of lanthanum carbonate powder from different formulations (all passed through 100 mesh) were added to Phosphate ion solution under stirring condition. Lanthanum binding to phosphate ions was allowed for

1, 3, 5, 10, 30, and 60 minutes. After stipulated time intervals free phosphate ions were measured using Quantofix® Phosphate Kit.

Table-9

Tablet formulation ₅0 5 5 5

The in vitro phosphate binding data indicates that the formulation of present invention exhibit better phosphate binding kinetics than Fosrenol®.

Example-7 Stability studies:

Stability study of anhydrous lanthanum carbonate and lanthanum carbonate chewable tablets , 1000 mg was carried out in sealed HDPE container and this sealed HDPE containers were stored in accelerated stability condition at 40°C/75% relative humidity and XRPD was performed on tablets withdrawn at specified intervals of 1, 2 and 3 months. Table-8 and Table-9 below provide the stability data for the same at various conditions indicated in the tables.

1. Stability data of anhydrous lanthanum carbonate of Example 1 Table-10

Condition O day I M 2M 3M

40/75 WOWP WOWP WOWP

Appearance 30/65 WOWP WOWP WOWP

WOWP

25/60 WOWP WOWP WOWP

60 ⁰C WOWP WOWP WOWP

O day I M 2M 3M

40/75 100.18 100.01 100.07

Assay (%) 30/65 100.03 100.15 99.99

100 6

25/60 100.1 100.08 100.28

60 ⁰C 99.82 99.57 100.12

O day IM 2M 3M

40/75 1.15 1.40 1.10

Moisture 30/65 1.19 1.30 1.30 Content (%) 1.50 25/60 1.18 1.40 1.40

60 ⁰C 1.1 1 1.25 1.00

O day I M 2M 3M

40/75 0.76 0.58 1.05

Loss on Drying 30/65 0.59 0.48 0.97 (%) 0.96 25/60 0.68 0.65 0.96

60 ⁰C 0.57 0.29 0.48 ^♦ WOWP= White to off white colored powder 2. Stability data of anhydrous lanthanum carbonate tablet formulation G of table- 7 Table -11

O day 15 D I M 2M 3M

40/75 - WOWT WOWT WOWT

Appearance 30/65 - WOWT WOWT WOWT

WOWT

25/60 - WOWT WOWT WOWT

60 ⁰C WOWT WOWT WOWT WOWT

O day 15 D I M 2M 3M

40/75 - 99.81 97.78 99.1

Assay (%) 30/65 go Qf. - 99.67 97.24 98.37

25/60 - 98.98 98.34 98.21

60 ⁰C 100.43 99.48 99.08 98.92

O day 15 D I M 2M 3M

40/75 - 0.8 0.9 0.95

LOD (%) 30/65 - 0.73 1.28 1.16

U (\.7 / 11

25/60 - 0.97 1.1 1 0.91

60 °C 0.74 1.63 0.78 0.58

* WOWT= White to off white colored tablet

The XRPD graphs are depicted in Figure 1 and 2, summarizing the stability test results of Example 1 and tablet formulation G of Table-7.

The figures clearly illustrate that anhydrous lanthanum carbonate and the tablet formulation is stable even at accelerated conditions for 3 months and the impurities or degradation products like Lanthanum oxycarbonate, Lanthanum hydroxycarbonate polymorph II, Lanthanum hydroxycarbonate polymorph I, Lanthanum carbonate octahydrate, Lanthanum carbonate tetrahydrate are absent over the entire storage period.

Claims

We Claim:

1. A premix composition comprising anhydrous lanthanum carbonate and pharmaceutically acceptable carrier and/or excipients, with the proviso that the said composition does not contain monosaccharide or disaccharide.

2. A stable pharmaceutical formulation comprising a premix composition according to claim 1 and pharmaceutically acceptable external excipients wherein

(i) the formulation comprises atleast 65% w/w of the premix composition; wherein the premix composition comprises atleast 65% w/w of anhydrous lanthanum carbonate and

(ii) the total weight of the formulation is less than 60% of the total weight of marketed lanthanum carbonate formulation (FOSRENOL)

3. A stable pharmaceutical formulation comprising a therapeutically effective amount of anhydrous lanthanum carbonate and pharmaceutically acceptable carrier and/or excipients, with the proviso that the said formulation is substantially free of monosaccharides or disaccharides.

4. A stable pharmaceutical formulation according to claim 2 and 3 wherein said formulation is substantially free of amino acid and/or a stabilizer.

5. A stable pharmaceutical formulation according to claim 2 and 3 wherein said formulation comprises binder as a pharmaceutically acceptable carrier and/or excipients and wherein anhydrous lanthanum carbonate and binder is in the ratio of 4: 1 to 70: 1 w/w.

6. A stable pharmaceutical formulation according to claim 3 wherein

(i) the formulation comprises atleast 65% w/w of anhydrous lanthanum carbonate and

(ii) the total weight of the formulation is less than 60% of the total weight of marketed lanthanum carbonate formulation (FOSRENOL) . (iii)

7. A stable pharmaceutical formulation according to claim 3 wherein the formulation is prepared by wet granulation.

8. A stable pharmaceutical formulation according to claim 3 wherein the anhydrous lanthanum carbonate is prepared by a process comprising the steps of: a) adding lanthanum salt solution and alkali or alkaline earth metal carbonate solution under constant stirring in a container. b) filtering the residue of step a) and washing with water miscible solvent(s) to obtain wet cake. c) drying the wet cake to get the anhydrous lanthanum carbonate.

9. The process according to claim 8 wherein the stirring is done at 1 -1000 rpm at -10 to 20^°C temperature in a container.

10. The process according to claim 8 wherein the water miscible solvent(s) is selected from water, ethanol, methanol, isopropyl alcohol, acetone and isopropyl alcohol or others and mixtures thereof.

1 1. The process according to claim 8 wherein the step (a) optionally comprises surface stabilizer selected form the group of inorganic hydrophilic substances, polymers, low molecular weight oligomers, natural products, surfactants and the like and wherein the surface stabilizer preferably is colloidal silicon dioxide in an amount ranging from about 0.001% to about 10.0%; of about 0.001% to about 8.0%, or about 0.001% to about 4.0% by weight of the composition.

12. The process according to claim 8 wherein lanthanum salt includes all salts of lanthanum metal including but not limited to lanthanum chloride, lanthanum oxide, lanthanum acetate or the like or combinations thereof and their hydrates or derivatives thereof; preferably the lanthanum salt is lanthanum chloride heptahydrate and wherein alkali or alkaline earth metal carbonate include, but are not limited to, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, or the like or combinations thereof; preferably sodium carbonate.

13. A stable pharmaceutical formulation comprising a therapeutically effective amount of anhydrous lanthanum carbonate and pharmaceutically acceptable carrier and/or excipients, with the proviso that the said formulation does not contain monosaccharides or disaccharides; wherein the formulation is prepared by the process comprising the steps of: a) mixing the anhydrous lanthanum carbonate with pharmaceutically acceptable carrier and/or excipients; b) granulating the blend of step (a) with water miscible solvent(s); c) drying the granules; d) optionally mixing the granules with external excipients; e) compressing the granules to form tablet or filling the granules in the capsule shell

14. A stable pharmaceutical formulation according to claim 3 wherein the said formulation has better phosphate binding capacity to that of the marketed formulation FOSRENOL.

15. A stable pharmaceutical formulation according to claim 3 wherein the said formulation has equivalent or faster in-vitro dissolution profile as described in specification that that of the marketed formulation FOSRENOL.