WO2021101461A1

WO2021101461A1 - Oral solid pharmaceutical compositions comprising lanthanum carbonate octahydrate

Info

Publication number: WO2021101461A1
Application number: PCT/TR2019/050978
Authority: WO
Inventors: Ersin Yildirim; Bayram Kanik; Tansel AKTAŞ; Fatma ÖZTÜRK; Seda BIYIK
Original assignee: Santa Farma İlaç Sanayi̇ A.Ş.
Priority date: 2019-11-21
Filing date: 2019-11-21
Publication date: 2021-05-27
Also published as: EP4061340A1; EP4061340A4

Abstract

The subject invention provides an oral solid pharmaceutical composition prepared by dry granulation method with slugging process, comprising Lanthanum carbonate, preferably Lanthanum carbonate octahydrate as an active ingredient, lubricant and flow agent as excipients, wherein the compression force in slugging process is between 10 to 24 kP, and the ratio of lubricant/flow agent used before and after slugging process is 7:1 respectively.

Description

ORAL SOLID PHARMACEUTICAL COMPOSITIONS COMPRISING LANTHANUM CARBONATE OCTAHYDRATE

FIELD OF INVENTION The present invention relates to an oral solid pharmaceutical composition comprising Lanthanum Carbonate, preferably Lanthanum Carbonate Octahydrate with optimized characteristics of powder flowability and compressibility to obtain a pharmaceutical composition prepared by dry granulation method with improved dissolution profile.

BACKGROUND OF THE INVENTION Hyperphosphatemia occurs when the blood stores high levels of inorganic phosphate. This condition is prevalent in patients with severe kidney dysfunction, including chronic renal insufficiency and end stage renal disease. Therefore, 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 also lead to severe bone problems and metastatic calcification of skin and major organs and is associated with significant morbidity and mortality.

Similar to calcium, phosphate is found in bones and teeth and absorption occurs efficiently with consistent Vitamin D intake. Under normal conditions, the kidneys excrete phosphate. However in those patients with hyperphosphatemia, the kidneys are unable to remove the phosphate and dialysis proves to be ineffective in phosphate removal. Therefore, conventional dialysis fails to reduce levels of phosphate in the blood, so that the levels rise in time. According to the literature data, aluminium salts, or calcium salts can be used to to control phosphate levels by the oral administration. However, with the known toxic effects of aluminium, aluminium-based therapy tends to be avoided. In the case of calcium salts, calcium is absorbed rather readily from the gut, and in turn causes hypercalcaemia.

JP 62-145024 discloses that rare earth carbonates, bicarbonates or organic acid compounds may be used as phosphate binding agents. According to the published application prepares La2(C03)3.xH20, ie the monohydrate. EP1785141 relates to stabilized Lanthanum carbonate compositions comprising lanthanum carbonate having the general formula La₂(C0₃)₃.xH₂0, wherein x has a value from 0 and 10, and at least one pharmaceutically acceptable monosaccharide or disaccharide stabilizing agent to stabilize the lanthanum carbonate against decarboxylation to lanthanum hydroxycarbonate for treating subjects having hyperphosphatemia. In this innovation discloses that stabilized lanthanum carbonate composition degrades into lanthanum hydroxycarbonate at a slower rate compared to lanthanum carbonate alone or not in the presence of other materials.

EP1389102 relates to a method of preventing or treating urolithiasis by administering rare Lanthanum carbonate with 4 or 5 moles of water per mole, to bind dietary oxalate and preventing its absorption into the gastrointestinal tract.

EP0817639 discloses a pharmaceutical composition for the treatment of hyperphosphatemia comprising Lanthanum carbonate hydrate where Lanthanum carbonate has 3 to 6 molecules of water wherein the pharmaceutical composition consists of a pharmaceutically acceptable diluent or carrier for administration to the gastrointestinal tract.

The innovative product is currently marketed in the form of chewable tablets and sachets under the name LOSRENOL^® in the strength of 250 mg, 500 mg, 750 mg and 1000 mg of lanthanum wherein product contains lanthanum in the form of the lanthanum carbonate (2:3) hydrate with molecular formula La₂(C0₃)₃.xH₂0, wherein x is on average 4-5 moles of water.

The LOSRENOL^® is indicated in adult patients as a phosphate binding agent for use in the control of hyperphosphataemia in chronic renal failure patients on haemodialysis or continuous ambulatory peritoneal dialysis (CAPD). Losrenol is also indicated in adult patients with chronic kidney disease not on dialysis with serum phosphate levels 1.78 mmol/L in whom a low phosphate diet alone is insufficient to control serum phosphate levels. In vitro studies have shown that in the physiologically relevant pH range of 3 to 5 in gastric fluid, Lanthanum binds approximately 97% of the available phosphate when Lanthanum is present in a two-fold molar excess to phosphate.

The active ingredient in LOSRENOL^® is the lanthanum carbonate which is as a phosphate binder is dependent on the high affinity of lanthanum (La) ions for dietary phosphate. The La ions are released from the carbonate salt in the acid environment of the upper gastrointestinal tract. Insoluble lanthanum phosphate is formed which reduces the absorption of phosphate from the gastrointestinal tract. If the composition is intended to be a chewable composition, palatability and "mouth feel" are extremely important factors in formulating high dose insoluble drugs. Insoluble materials usually have both an unpleasant mouth feel and an unpalatable taste due to chalkiness, grittiness, & dryness properties of these materials. It is known that tablet blends may be dry mixed, dry granulated or wet-granulated before tabletting. The choice of the processing procedure depends on the properties of the drug and the excipients preferred. When the drug has poor flow characteristics and is required in high doses, then direct compression can be difficult due to ameliorating the flow problems with adding higher proportion of excipients. However, generally when the drug has moisture- sensitive properties, the manufacturing proces is thought to be dry granulation.

In the state of art, there are many patents/patent applications which are summarized below.

EP1660104 relates to a pharmaceutical chewable tablet composition comprising the amount of lanthanum, as the element is about from 10 to 40 wt%, the amount of the diluents is about from 40 to 80% by weight and the amount of the blending(s) or lubricant(s) is about from 0.1 to 5.0% by weight of the composition wherein the composition is prepared without using wet granulation or drying process. This invention also discloses the lanthanum tablet composition produced through a process of powder blending the lanthanum compound and an excipient in a mixer to form a mixture. The mixture is then either compressing into a slug material or roller compacting into a strand material. The compressed or compacted material is then milled into a free flowing mixture and compressed into a tablet.

W02007054782 relates to stabilized Lanthanum carbonate compositions comprising a pharmaceutically effective amount of lanthanum carbonate having the general formula La2(CO3)3.xH2O, wherein x has a value from 0 and 10, and a monosaccharide or disaccharide stabilizing agent wherein it is presented in an amount of at least about 1% by weight based on the total weight of the composition for the treatment of hyperphosphatemia.

W02010106557 relates to the premix pharmaceutical composition comprising anhydrous Lanthanum carbonate and pharmaceutically acceptable carrier and/or excipients wherein said composition does not contain monosaccharide or disaccharide. EP2133084 relates to a palatable, sprinklable lanthanum carbonate compositions in the form of beads, a powder or sieved granules wherein the composition compositions contain Lanthanum as the element, diluent, blending or flow agent(s) and lubricant(s).

EP2172205 relates to pharmaceutical chewable tablet composition comprising %26.5 of Lanthanum carbonate, 69.3% dextrates, 2.0% colloidal anhydrous silica, 1.7% purified talc and 0.5% magnesium stearate by the weight of the total composition, also wherein the lanthanum carbonate is hydrated having a water content with an average value of 4 moles of water.

EP2792363 relates to pharmaceutical chewable tablet composition discloses used various amount of the Lanthanum as the element, diluent, blending or flow agent(s) and lubricant(s) in the total composition and at least one chewable pharmaceutically acceptable excipient.

W02009118760 relates to a pharmaceutical composition for the treatment of hyperphosphataemia comprising Lanthanum carbonate having more than 6 molecules of water per molecule of lanthanum carbonate and pharmaceutically acceptable carrier or diluent, wherein said carrier or diluent excludes monosaccharide(s) or disaccharide(s) wherein the stabilized composition is prepared by wet granulation process.

EP2389070 relates to stable, disintegrable pharmaceutical dosage form comprising Lanthanum carbonate with at least one pharmaceutically acceptable excipient(s).

WO201 1051968 relates to pharmaceutical compositions of Lanthanum carbonate comprising diluents in an amount ranging from about 30 % w/w to about 40 % w/w of the composition.

Many pharmaceutical compositions for solid compositions comprising hydrate form of Lanthanum carbonate are explained in the prior art documents stated above. Generally, hydrate form of Lanthanum carbonate is chosen as having 3 to 6 molecules of water.

The present invention relates to an oral solid pharmaceutical composition comprising Lanthanum carbonate, preferably octahydrate with optimized characteristics of powder flowability and compressibility to obtain a pharmaceutical composition manufacrured by dry granulation method with improved dissolution profile. SUMMARY OF THE INVENTION

The object of this invention is to develop an oral solid pharmaceutical composition comprising Lanthanum, which is used in the treatment of hyperphosphataemia.

The present invention relates to a specific composition for use in treating hyperphosphataemia is a patient in need thereof such a lanthanum carbonate composition.

Another object of the present invention is to provide compositions comprising the lanthanum carbonate in a desired hydration state where the general formula of the lanthanum carbonate is La2(CO3)3.xH2O where x has a value of 8.

The present invention is also related to Lanthanum carbonate octahydrate which presents specific 2-theta values at 10.3°±0.2°, 19.7°±0.2° and 27.1°±0.2°.

According to the state of the art, Lanthanum carbonate is known to be hard to work during the manufacturing process where some difficulties such as dehydration (changes of octahydrate to patented tri to hexa-hydrate), poor flowability or palatability will come about as a challange. Furthermore, octahydrate from of the Lanthanum carbonate is only used for obtaining the desired lanthanum carbonate with 3 to 6 molecules of water form not as a main active ingredient.

Thus, it is objective of the present invention is to provide a pharmacautical composition comprising octahydrate form of the Lanthanum carbonate exibits improved flowability and compressibility. Another object of the present invention is to provide an oral solid composition pharmaceutical composition comprising Lanthanum carbonate octahydrate form and one or more acceptable excipients. It is prepared by using optimised dry granulation method.

Another object of the present invention is to provide an oral solid pharmaceutical composition comprising Lanthanum carbonate octahydrate such that it constitutes 50% by weight of the total composition, and diluent, flow agent and lubricant wherein said lubricant consists of the magnesium stearate, talc and silicon dioxide. DETAILED DESCRIPTION OF THE INVENTION

Flow agent can be selected from magnesium stearate, talc, polyethylene glycol, silica, silicon dioxide, hydrogenated vegetable oils, glyceryl behenate and glyceryl monostearate or a mixture thereof, preferably the flow agent a mixture of silicon dioxide and talc. Preferably, silicon dioxide and talc is used before slugging process.

Lubricant can be selected from magnesium stearate, talc, polyethylene glycol, silica and colloidal anhydrous silica or a mixture thereof, preferably the lubricant is mixture of magnesium stearate and talc. Preferably, magnesium stearate is used after slugging process.

In another embodiment, the composition may further comprise diluent as excipient. The diluent is preferably selected from dextrates, corn syrup, oligosaccharide, isomaltooligosaccharide, glucose, lycasin, xylitol, lactitol, erythritol, mannitol, isomaltose, polydextrose, dextrin, starch, fructose, xylitol, maltodextrin, maltitol, isomalt, lactose, sorbitol, microcrystalline cellulose, sucrose based diluent-binders, confectioner's sugar, calcium sulfate dihydrate, calcium lactate trihydrate, hydrolysed starches, dextrose, inositol, hydrolyzed cereal solids, amylose or glycine. More preferably, the diluent is dextrate.

The present invention also provides an oral solid pharmaceutical composition wherein the formulation in %w/w by the weight of the total composition is as stated below:

The present invention further provides a process for the manufacture of an oral solid pharmaceutical composition comprising Lanthanum carbonate, preferably Lanthanum carbonate octahydrate as an active ingredient, wherein the process comprises the following steps: i. Lanthanum carbonate, preferably Lanthanum carbonate octahydrate, Silicon dioxide and Dextrate were screened through a proper sieve and stirred, ii. Talc was screened through a proper sieve and then added to the powder blend prepared in Step i and stirred, iii. The prepared blend in Step ii was compressed by slugging process, iv. The compressed tablets were sifted through a proper sieve, v. Magnesium stearate was screened through a proper sieve and added to the powder blend prepared in Step iv, vi. Preferably, the final blend was compressed into tablets.

The subject invention also provides oral solid pharmaceutical compositions prepared by dry granulation method with slugging process, comprising Lanthanum carbonate, preferably Lanthanum carbonate octahydrate as an active ingredient, lubricant and flow agent as excipients, wherein the compression force in slugging process is between 10 to 24 kP, and the ratio of lubricant/flow agent used before and after slugging process is 7:1 respectively, for use in the treatment of hyperphosphataemia.

The oral compositions described in the invention are in a high hydration form with optimized characteristics of powder flowability and compressibility to present proper dissolution profile.

The term an "oral dosage form" refers to a pharmaceutical composition or composition that has been shaped or sized suitable for oral administration. Preferably the oral dosage form is in the form of a tablet, coated tablet, chewable tablets, capsule, pill, powder, sachets or granule. The oral dosage form of the present invention can be filled in sachets or chewable tablets. Preferably, it is chewable tablet and sachet.

The term of the “high hydration” state for the present invention means Lanthanum carbonate salt having more than six molecules of water, in between seven to ten, and preferably eight molecules of water such as octahydrate form of Lanthanum carbonate. However, FOSRENOL^® is the innovative product that contains Lanthanum carbonate in low hydration form wherein product contains lanthanum in the form of the lanthanum carbonate (2:3) hydrate with molecular formula La₂(C0₃)₃.xH₂0, wherein x is on average 4-5 moles of water.

Thus, the objective of this invention is related to prepare a pharmaceutical composition that contains Lanthanum carbonate octahydrate (molecular formula La₂(C0₃)₃.xH₂0, wherein x is 8, which is in a high hydration form and still has same in-vitro phosphate binding capacity as the innovative product FOSRENOL^®.

Preferably, Lanthanum carbonate or Lanthanum carbonate octahydrate used in the composition and process is in crystalline form having specific 2- theta values at 10.3°±0.2°, 19.7°±0.2° and 27.1°±0.2°. In the state of the art, a pharmaceutical composition comprising hydrate forms of Lanthanum carbonate encounters with difficulties in pharmaceutical properties.

Having poor flow characteristic of Lanthanum carbonate is known during the manufacturing process. Thus, before embarking on the studies, flowability of powder form of the Lanthanum carbonate octahydrate is determined by performing analytical method in accordance with USP <1174> wherein the compressibility index and Hausner ratio correspond to the ratio of tapped density to bulk density.

The compressibility index and Hausner ratio were calculated as 35.00 and 1.538, respectively wherein bulk density was 0.563 g/ml and top density was 0.866 g/ml.

Table 1 given below shows scaling of flowability depending on the value of the Compressibility index and Hausner ratio.

Table 1. Scale of Flowability

Based on the results of scale of flowability, Lanthanum carbonate octahydrate has “very poor” flow characteristic that represents a challenge when preparing compositions that have high drug load, as is the case for lanthanum carbonate while maintaining a dose size that is acceptable and palatable to the patient.

Lanthanum carbonate is known to be used in high drug load wherein the drug product loaded with 250 mg to 1000 mg Lantanum as the only active ingredient.

Preparation methods for the compositions comprising Lanthanum carbonate were investigated by using conventional methods such as direct compression, wet granulation or dry granulation.

In wet granulation, generally active ingredient is mixed with diluents, optional solubilizers and various other excipients and granulated, followed by screening and drying of the damp mass. However, Lanthanum carbonate is known as a specific hydration status, granulating with water or solvents and drying can affect the hydration status of the drug substance. Thus, the wet granulation is not preferred as the manufacturing method.

According to the characterization of active ingredient, direct compression and dry granulation (slugging or roller compaction) could be more proper to use as a manufacturing method to improve flow characteristic of Lanthanum carbonate.

Dry granulation is usually described as a method of controlled crushing of precompacted powders densified by either slugging or passing the material between two counter-rotating rolls. More specifically, powdered components that may contain very fine particles are typically mixed prior to being compacted to yield hard slugs which are then ground and sieved before the addition of other ingredients and final compression to form tablets. No liquids are used in the dry granulation process, the issues related to wet granulation are avoided.

Direct compression may only be applied to materials that do not need to be granulated before tableting. Direct compression requires only two principal steps; i.e., the mixing of all the ingredients and the compression of this mixture. However, when the drug has poor flow characteristics and is in a high dose, direct compression can be difficult due to poor flow.

In a preferred embodiment of the present invention is to provide a pharmaceutical compositions containing Lanthanum carbonate or Lanthanum carbonate octahydrate wherein the preparation methods and ingredients of the composition do not have an effect on hydration status. In a preferred embodiment of the present invention is to provide a pharmaceutical compositions containing Lanthanum carbonate by using dry granulation method wherein provided for the manufacture of tablets containing the active ingredient, diluents, flow agent and lubricants selected as to be the most suitable ones with respect to the intended form of administration.

Ingredients of composition and manufacturing method were designed to be similar with the example given in EP1660104 patent which is Composition I is presented below to evaluate the flowability and compressibility of the composition.

Composition I: Composition for Drug product prepared by using direct compression

In this process, a solid oral dosage form was composed of Lanthanum carbonate octahydrate wherein detailed manufacturing steps are as presented below:

1. Lanthanum carbonate octahydrate and Silicon dioxide were screened through a proper sieve and stirred.

2. Dextrate was screened through a proper sieve and then added to the powder blend prepared in Step 1 and stirred.

3. Magnesium stearate was screened through a proper sieve and added to the powder blend prepared in Step 2 and stirred to obtain a uniform final blend.

After getting final blend, at first the flowability of the final blend was determined by performing analytical method in accordance with USP <1174>. The compressibility index and Hausner ratio were calculated as 31.61 and 1.462, respectively based on the results of bulk and tapped densities were 0.595 g/ml and 0.870 g/ml.

Based on the results of scale of flowability, the final blend had “very poor” flow characteristic that was not suitable for the compression. An appropriate flowability was not achieved by direct compression method and yield of the lanthanum carbonate octahydrate. The prepared pharmaceutical composition comprising Lanthanum carbonate octahydrate wherein it constitutes 50% weight by the total weight of the composition. Thus, the manufacturing process of the pharmaceutical composition comprising Lanthanum carbonate octahydrate was changed from direct compression to dry granulation in order to improve bonds between powder particles by avoiding exposure of heat or moisture.

In dry granulation process, the tablet ingredients are not exposed to moisture, solvents and heat. Thus, Lanthanum carbonate which is sensitive to moisture, solvent and/or heat can be used in this process. Dry granulation can be carried out by slugging or by roller compaction. Slugging is a double compression process. It is a pre-compression process for the formation of extra-large tablets (slugs), usually of variable weight, due to poor flow of the drug powder. The resulting slugs are subsequently broken down into granules, which are recompressed to obtain the final tablets. The procedure is applicable to the dry granulation of hydrolysable drugs, such as Lanthanum carbonate, which are not amenable to wet granulation.

To be able to achieve binding effect in the composition, the amounts of Dextrate, Silicon dioxide and Magnesium stearate were justified during manufacturing process to be performed successfully.

Composition II: Composition for Drug product prepared by using dry granulation

In this embodiment of the present invention, a solid dosage form was composed of Lanthanum carbonate octahydrate wherein detailed manufacturing steps are as presented below:

1. Lanthanum carbonate, preferably Lanthanum carbonate octahydrate and Silicon dioxide were screened through a proper sieve and stirred. 2. Dextrate was screened through a proper sieve and then added to the powder blend prepared in Step 1 and stirred.

3. Half amount of Magnesium stearate was screened through a proper sieve and added to the powder blend prepared in Step 2 4. The prepared blend in Step 2 was compressed by slugging process.

5. The compressed tablets were sifted through a proper sieve.

6. The remaining amount of the Magnesium stearate was screened through a proper sieve and added to the powder blend prepared in Step 5.

It was observed that; the flowability of the granules in slug compression process was improved from the degree of the “very poor” to “passable”. However, there is still a need for slug compression process to be improved.

At first, the flowability of the blend before slugging process was determined by performing analytical method in accordance with USP <1174>.

The compressibility index and Hausner ratio were calculated as 21.50 and 1.284, respectively based on the results of bulk and tapped densities were 0.853 g/ml and 1.087 g/ml.

An improvement was needed in the composition by using the same manufacturing method. Therefore, Composition II was re-designed by doing modifications below.

Adding different type of lubricant which has also flow agent properties

According to Handbook of Pharmaceutical Excipients, talc is primarily used in solid-dosage forms and is often used as a lubricant or a flow agent in compositions. Talc provides some essential lubricity for pharmaceutical operations because of its hydrophobicity and weakly- bonded sheet structure. Based on this information, Talc was preferred as the added lubricant.

Justification of Silicon dioxide amount in the Composition II due to adding new type of lubricant/flow agent Amount of Silicon dioxide was decreased due to use of excessive concentration of total amount of the lubricant. Excessive amount of lubricant can cause a decrease in dissolution rate. Total amount of Magnesium stearate was used after slugging process due to adding new type of lubricant/flow agent before slugging process.

It was considered that use of Talc and Silicon dioxide before slugging process provides successful slugging process. Therefore, Magnesium stearate was planned to be used after the slugging process to obtain successful final product. The amount of Magnesium stearate was decreased from 5% to 1% w/w. The proportion of lubricant /flow agent in the composition could also be adjusted.

Total amount of the lubricant and flow agent used in Composition II was kept constant as 8% w/w. In addition, the amount of active ingredient and diluent was also same as Composition II.

Composition III: Talc added composition with adjusting the amount of other excipients

1. Lanthanum carbonate, preferably Lanthanum carbonate octahydrate, Silicon dioxide and Dextrate were screened through a proper sieve and stirred.

2. Talc was screened through a proper sieve and then added to the powder blend prepared in Step 1 and stirred.

3. The prepared blend in Step 2 was compressed by slugging process.

4. The compressed tablets were sifted through a proper sieve.

5. Magnesium stearate was screened through a proper sieve and added to the powder blend prepared in Step 4.

6. Preferably, the final blend was compressed into tablets. It was observed that, the flowability of the final granules before slugging process were better to lead slugging compression to be achieved.

Thus, the flowability of the final blend was determined by measuring in accordance with USP <1174>. The compressibility index and Hausner ratio were calculated as 18.00 and 1.22, respectively based on the results of bulk and tapped densities which were 0.93 g/ml and 1.134 g/ml.

Based on the results of scale of flowability, the final blend before slugging process presented “fair” flow characteristic that was suitable for the further process of the tablet compression or filling granules into sachets. Tablets were subjected to in vitro dissolution study. The conditions of dissolution study are set by US FDA, based on the information dissolution media is 0.25N HC1. Other conditions are defined as; Volume of dissolution media is 900 ml, temperature of study is 37°C±0.5°C, rotation speed is 10 dpm, apparatus is paddle and the duration of dissolution study is 60 minutes. Dissolution apparatus is Biodiss apparatus-3.

A graph was generated based on the results in Table 2, illustrated as Figure I.

Based on the table above, dissolution profiles of reference product and Composition III were quite different. The problem was investigated; as a result, it was considered that the difference between dissolution profiles raised from compression force of the slugging process. Optimized the slugging pressure causes an increase in dissolution rate. This was probably due to fracturing of the harder granules into smaller particles with greater specific surface area. However, controlling the slugging pressure is critical parameter as excessive pressure will produce very hard granules that are difficult to deform during the recompression stage resulting in soft tablets.

According to the information above, slugging compression was considered to be optimized in Composition III. The slugging compression force of Composition III was between 6 to 10 kP. This compression force was increased to get proper dissolution profile. The range of slugging compression forces were investigated regarding obtaining successful to be successful. The effect of the different slugging compression forces was given at the Table 2.

Table 2: The results of dissolution study conducted on tablets obtained with Composition III with modified compression force in slugging process

The comparative dissolution results of Composition III obtained with three different compression forces and Reference drug product were shown in Table 2.

A graph was generated based on the results in Table 2, illustrated as Figure II.

Three different scale of slugging forces were evaluated; 6-10 kP, 10-14 kP and 14-24 kP. The comparative dissolution profiles indicated that slugging compression pressure was directly in related with dissolution characterises.

Composition III prepared with 6-10 kP slugging compression forces were not similar with the reference product. However, Composition III B and C prepared with 10-14 kP and 14-24 kP were very similar to reference product. One of the critical issue is the amount and manufacturing stage of the lubricant/flow agent in the composition. In addition, another critical issue is slugging compression force. In the embodiment of the present invention, total amount of lubricant/flow agent is 8% w/w which is proportionally used in before and after slugging process. 7% of this amount is used before slugging process, remaining part is used after slugging process. This improvement provides workable powder blend characteristics with the problems of flowability and compressibility.

In the embodiment of the present invention, the slugging compression force is between 10-24 kP to get improved dissolution profile.

In the embodiment of the present invention, oral solid pharmaceutical composition prepared by slugging process including the critical parameters mentioned above comprises XRD pattern same as active ingredient. XRD of lanthanum carbonate octahydrate is given in Figure III.

While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.

Claims

1. An oral solid pharmaceutical composition prepared by dry granulation method with slugging process, comprising Lanthanum carbonate, preferably Lanthanum carbonate octahydrate as an active ingredient, lubricant and flow agent as excipients, wherein -the compression force in slugging process is between 10 to 24 kP,

-the weight ratio of lubricant/flow agent used before and after slugging process is 7:1.

2. An oral solid pharmaceutical composition according to claim 1, wherein the flow agent is selected from magnesium stearate, talc, polyethylene glycol, silica, silicon dioxide, hydrogenated vegetable oils, glyceryl behenate and glyceryl monostearate or a mixture thereof.

3. An oral solid pharmaceutical composition according to claim 2, the flow agent is silicon dioxide and talc.

4. An oral solid pharmaceutical composition according to claim 1, wherein the lubricant is selected from magnesium stearate, talc, polyethylene glycol, silica and colloidal anhydrous silica or a mixture thereof.

5. An oral solid pharmaceutical composition according to claim 4, wherein the lubricant is magnesium stearate.

6. An oral solid pharmaceutical composition according to any of the preceeding claims, wherein the composition further comprises diluent as excipient.

7. An oral solid pharmaceutical composition according to claim 6, wherein the diluent is selected from dextrates, com syrup, oligosaccharide, isomaltooligosaccharide, glucose, lycasin, xylitol, lactitol, erythritol, mannitol, isomaltose, polydextrose, dextrin, starch, fructose, xylitol, maltodextrin, maltitol, isomalt, lactose, sorbitol, microcrystalline cellulose, sucrose based diluent-binders, confectioner's sugar, calcium sulfate dihydrate, calcium lactate trihydrate, hydrolysed starches, dextrose, inositol, hydrolyzed cereal solids, amylose or glycine.

8. An oral solid pharmaceutical composition according to claim 7, wherein the diluent is dextrate.

9. An oral solid pharmaceutical composition according to any of the preceeding claims, wherein the total amount of the silicon dioxide and talc is the amount of lubricant/flow agent before slugging process.

10. An oral solid pharmaceutical composition according to any of the preceeding claims, wherein the amount of the magnesium stearate is the amount of lubricant/flow agent after slugging process.

11. An oral solid pharmaceutical composition comprising Lanthanum carbonate, preferably Lanthanum carbonate octahydrate according to claim 1, wherein

-the compression force in slugging process is between 10 to 24 kP, -the weight ratio of the total amount of the silicon dioxide and talc used before slugging process and the amount of the magnesium stearate added after slugging process is 7:1.

12. An oral solid pharmaceutical composition according to any of the preceeding claims, wherein the formulation in w/w % is as stated below:

13. A process for the manufacture of an oral solid pharmaceutical composition comprising Lanthanum carbonate, preferably Lanthanum carbonate octahydrate as an active ingredient, wherein the process comprises the following steps: i. Lanthanum carbonate, preferably Lanthanum carbonate octahydrate, Silicon dioxide and Dextrate were screened through a proper sieve and stirred, ii. Talc was screened through a proper sieve and then added to the powder blend prepared in Step i and stirred, iii. The prepared blend in Step ii was compressed by slugging process, iv. The compressed tablets were sifted through a proper sieve, v. Magnesium stearate was screened through a proper sieve and added to the powder blend prepared in Step iv, vi. Preferably, the final blend was compressed into tablets.

14. An oral solid pharmaceutical composition prepared by dry granulation method with slugging process according to any preceding claims for use in the treatment of hyperphosphataemia.