FIELD OF INVENTION
This invention relates to stabilized lanthanum carbonate composition wherein lanthanum compound is in low hydration state, More particularly, the present invention is directed to a chewable pharmaceutical composition comprising lanthanum carbonate having less than three molecules of water, preferably in anhydrous form. It also relates to a methods for making and methods of manufacturing the composition.
BACKGROUND OF THE INVENTION AND RELATED PRIOR ART
Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of the common general knowledge in the field.
The invention relates to a solid dosage composition comprising lanthanum compound preferably Lanthanum carbonate and to methods for making such composition.
Lanthanum is a rare earth element with an atomic number of 57. The properties of lanthanum make this agent a good candidate as a useful phosphate binder. It has a high affinity for binding phosphorous and in the form of its carbonate salt, has a low solubility that limits gastrointestinal absorption. In addition, the phosphate binding is independent of pH, it possesses a low toxic potential based on the LD50, it is palatable, abundant, and has limited effects on serum electrolyte concentrations (Hutchison, A J et al. (1998) Perit. Dial. Int. 18 (Suppl2):S38.
Lanthanum carbonate has a tendency to degrade via decarboxylation to lanthanum hydroxycarbonate as shown:
La2(C03)3 + H2O ► 2LaOHC03 + CO2
The hydroxycarbonate product results from electrophihc or nucleophihc attack on the carbonyl moiety of lanthanum carbonate. This process is accelerated in the presence of

moisture or heat and appears to be self-catalyzing. Hence, even a very small amount of lanthanum hydroxycarbonate in lanthanum carbonate compositions causes rapid and excessive degradation. Furthermore, there is a need in the art to prevent this degradation since, as noted above, current regulatory requirements preclude detectable decarboxylation for administration to patients. As a i"esult, compositions that eliminate or substantially retard degradation are highly preferred.
Lanthanum carbonate having the general formula La2(C03)3 has been approved by FDA to treat hyperphosphatemia in end stage renal disease (ESRD) subjects and it currently being market under the brand name Fosrenol® by Shire Pharmaceuticals, Wayne, PA.
Hyperphosphatemia is a particular problem of patients with chronic renal insufficiency or chronic kidney disease (CKD), using dialysis equipment and with about 70% of patients with ESRD. Chronic kidney disease (CKD) can be defined as either (1) having kidney damage as defined by structural or functional abnormalities of the kidney for 3 months or longer with or without a decreased glomerular filti'ation rate (GFR) or (2) having a GFR of less than 60 mL/min/1.73 m2 for 3 months or longer with or without kidney damage. Structural or functional abnormalities are manifested by symptoms such as either pathologic abnormalities or markers of kidney damage, including abnormalities identified in imaging studies or the composition of blood or urine.
Conventional dialysis fails to reduce levels of phosphate in the blood, so that the levels rise in time. This condition can lead to severe bone problems and excess serum phosphate precipitates serum calcium causing widespread ectopic extra-skeletal calcification. Unwanted calcium deposits can occur in cardiovascular tissue, resulting in an increased risk of cardiovascular complications and is associated with significant morbidity and mortality. Additionally, increased serum phosphate decreases intestinal calcium absorption. These two mechanisms work concurrently to reduce serum calcium levels.
Elevated phosphate levels can be treated using a combination of dietary restrictions and phosphate-binding agents. It is known to control phosphate levels by the oral administration

of aluminium salts, or calcium salts, due to 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. Another problem of patients with chronic renal insufilciency is secondary hyperparathyroidism. It is also important in patients with chronic renal insufficiency to avoid and treat secondary hyperparathyroidism.
Japanese published patent application number JP62145024 (Asahi Chemical Ind) discloses that rare earth carbonates, bicarbonates or organic acid compounds may be used as phosphate binding agents. One example of said published application relates to the use of lanthanum carbonate, and example 11 of said SLpplication prepares La2(C03)3.H20 i.e. the monohydrate form of lanthanum carbonate. U.S. 2007/0104799 discloses a method to treat a subject with symptoms of chronic kidney disease (CKD), who does not have ESRD, by orally administering a pharmaceutical composition containing therapeutically effective amount of a non-toxic lanthanum compounds.
U.S. 5,968,976 (assigned to Shire Pharmaceuticals) discloses a pharmaceutical composition comprising a lanthanum carbonate hydrate having the formula La2(C03)3-xH20, where x has a value between 3 to 6, to treat hyperphosphatemia in ESRD subjects. Processes for preparing this composition and a method to treat hyperphosphatemia in ESRD subjects using this composition are also described.
U.S. 2005/079135 and U.S. 2006,^0121127 disclose a stabilized lanthanum carbonate compositions, where Lanthanum carbonate is in hydrated state and the composition is stabilized by incorporating monosaccharide or disaccharide as stabilizing agent.
In view of the prior art, there lies a need to provide a stable and cost effective oral pharmaceutical formulations comprising Lanthanum carbonate, which is in low hydration state and where the production of lanthanum hydroxycarbonate is reduced during the shelf life of the product and the provides high drug load composition.

We have now found a stable, cost effective solid oral dosage form of Lanthanum carbonate where Lanthanum is in low hydration state, containing less than three molecules of water, preferably anhydrous.
OBJECTS OF THE INVENTION
Due to their renal problems patients with end stage renal disease or chronic kidney diseases need to limit their liquid intake. There is therefore a need for a formulation of a lanthanum compound that can be taken with no or limited amount of liquid. It is also known that moisture catalyzes the formation of lanthanum hydroxycarbonate in a composition. The currently marketed formulations of lanthanum carbonate shows tablets with low friability (tablets breaks easily while handling), which lead to poor patient compliance, during administration, and poor stability during transport. Hence there is a need to make a Lanthanum carbonate composition containing (a) lanthanum carbonate is in low hydration state, (b) where the generation of hydroxycarbonate impurity in the formulation is minimized, (c) the formulation has high drug loading and at the same time (d) the formulation has improved physical parameters (like low friability for tablets).
The present invention is related to a stable, solid oral dosage form comprising a) Lanthanum carbonate having less than three molecules of water; b) optionally atleast one pharmaceutically acceptable excipient and c) pharmaceutically acceptable diluents, where the composition contains more than 50% w/w of Lanthanum carbonate to the total weight of the dosage form.
According to one aspect of the invention there is also provided a process to making stable Lanthanum carbonate composition with low hydration state and high dose of Lanthanum ions.
Another object of the present invention is to provide a bioequivalent composition as that of commercially available chewable tablets being marketed under the brand name of FOSRENOL®. Lanthanum carbonate tablets of 500mg, 750mg and lOOOmg strengths.

Another object of the present invention is to stabilize the composition containing Lanthanum carbonate by limiting water molecules in its hydration state, so as to decrease the production of lanthanum hydroxycarbonate, which even in small amount is not desirable in the composition.
In one embodiment, the object of the present invention is to stabilize the composition containing Lanthanum carbonate in a low hydration state without use of sugars.
In one embodiment, the invention relates to such a method for treating hyperphosphatemia in a renal failure patient, including but not limited to a patient receiving dialysis and a patient with end-stage renal disease (ESRI)), comprising administering a therapeutically effective amount of a lanthanum compound.
In one embodiment, the invention relates to such a method for treating a chronic kidney disease patient comprising administering a therapeutically effective amount of a lanthanum compound.
In another embodiment, the invention relates to a method for controlling hyperparathyroidism in a patient with chronic renal insufficiency comprising administering a therapeutically effective amount of a lanthanum compound, preferably lanthanum carbonate.
This invention relates to a method for controlling hyperphosphatemia in a patient comprising administering a therapeutically effective amount of a lanthanum carbonate in a chewable formulation.
In one embodiment of the invention, the pharmaceutical composition is prepared by a process comprising: (a) Mixing Lanthanum carbonate and diluents in a blender (b) Granulating the blend of step [a] to form granules (c) optionally Milling the granules and blending the granules with colloidal silicon dioxide and a lubricant and (d) Compressing the blend of step [c] to form tablets.

In a further aspect, the excipients include diluents, binders, and lubricants/glidants. It is understood that other agents such as disintegrant, colors, flavors/ sweeteners can be added to the formulation.
SUMMARY OF THE INVENTION
The present invention is related to a stable solid oral composition comprising a) Lanthanum carbonate having less than three molecules of water; b) optionally atleast one pharmaceutically acceptable excipient and c) pharmaceutically acceptable diluents, where the formulation contains more than 50% w/w of Lanthanum carbonate to the total weight of the dosage form.
In particular. Lanthanum carbonate containing less than three molecules of water, preferably it is in anhydrous form, where such composition will have a high drug load.
An additional aspect of the present invention includes process for the preparation of lanthanum carbonate composition. In particular, the processes involve preparation of a solid composition form of Lanthanum carbonate; the composition can be a chewable tablet.
As presently contemplated, in one broad form, the invention provides a process to make a pharmaceutical composition comprising the following steps:
(a) Mixing Lanthanum carbonate with low hydration state and at least one pharmaceutically acceptable additive,
(b) Granulating the blend of step [a] to form granules,
(c) Lubricating the blend of step [b] with a lubricant and
(d) Compressing the blend to form tablets
Embodiments of the oral composition may include one or more of the following features. For example, the oral composition ma> contain Lanthanum carbonate in tri-hydrate form or in dihydrate form or in mono-hydrate ibrm and preferably in anhydrous form.

Other aspects of the present invention include use of this composition 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 compositions of the present invention.
The composition may include one or more pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients may be one or more of diluents, surfactants, lubricants, glidants, coloring agents and optionally binders, disintegrants.
DETAILED DESCRIPTION INCLUDING PREFERRED EMBODIMENTS OF THE INVENTION:
The inventors have recognized that there exists a need for a stable formulation with high drug load and low moisture content. The present invention is directed to a composition and a process for obtaining the composition. It should be noted that the hydration state of the lanthanum compound present in the formulation of the present invention is relevant to the biological properties of the product. It is therefore desirable to have low number of water molecules, particularly less than three molecules of water, preferably in anhydrous form, so that composition contains high drug load, while maintaining a dose size that is acceptable and palatable to the patient.
These commercially available tablets containing 500 mg of lanthanum carbonate has a weight of 2069 mg, tablets containing 750 mg of lanthanum carbonate has a weight of 3155 mg and tablets containing 1000 mg of lanthanum carbonate has a weight of 4183 mg. In these commercial tablets, the weight of lanthanum carbonate is always less than 25 % w/w to the total weight of the dosage form. As these tablets have high amount of inactive ingredients, the size of tablets is too large and hence patients may face inconvenience in swallowing the chewed tablet particles.
In the present invention we have formulated tablets containing 500 mg, 750 mg and 1000 mg of lanthanum carbonate, where the weight of lanthanum carbonate is above 50 % w/w to the total weight of the dosage form and tablets containing 500 mg of lanthanum carbonate has a

weight of 1300 mg, tablets containing 750 mg of lanthanum carbonate has a weight of 1950 mg and tablets containing 1000 mg of lanthanum carbonate has a weight of 2600 mg [above weights approximate and may vary by a very small margin, on production scale].
Hence tablets prepared according to the invention are less bulky and smaller in dimensions.
Solid oral composition according to the invention provide for the administration of the active substance in a palatable oral forni than was heretofore possible for a given unit dose of active agent.
In a stable solid composition according to the invention the active agent is present in the amount of from 500 - 1000 mg e.g. 500 mg, 750 mg or 1000 mg.
The solid oral composition may further comprise pharmaceutically acceptable additives known in the art. The term 'pharmaceutically acceptable additive' includes 'pharmaceutically acceptable excipient' within its ambit and the singular term includes plural as well. The pharmaceutically acceptable excipients may be one or more of diluents, surfactants, lubricants, glidants, coloring agents and optionally binders, disintegrants.
Fillers or diluents, includes calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, mannitol, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, and the like can be used. The pharmaceutically inert diluent may be used in an amount of about 10% to about 40% by weight of the total weight of the dosage form.
Amino acids include one or more compounds selected from alanine, arginine, aspartic acid, asparagine, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine; preferably glycine and lysine.

Sweeteners are often used to impart a pleasant flavor to the composition. Suitable sweeteners for use in the present invention include natural sweeteners such as sucrose, dextrose, fructose, invert sugar, mannitol, sorbitol, and the like, as well as synthetic sweeteners such as saccharin, aspartame, acesulfam potassium, cyclamates, and other commercial artificial sweeteners well-known to those of skill in the art.
Disintegrants, which include but are not limited to, cross linked polyvinylpyrolidone (Crospovidone, polyplasdone XL, Kollidon CL), croscarmellose sodium; croscarmellose calcium; cellulose products such as microcrystalline cellulose and its salts, microfine cellulose, low substituted hydroxypropylcellulose and mixtures thereof. Most preferably disintegrants are crosslinked polyvinylpyrrolidone, crosslinked carboxymethylcellulose and crosslinked sodium carboxymethylcellulose.
Binders/ Granulating agent includes, but are not limited to, alkyl celluloses such as methyl
cellulose, ethyl cellulose, hydroxyalkylcelluloses such as hydroxypropylcellulose, low
substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium
carboxymethylcellulose, microcrystalline cellulose, gelatin, polyvinylpyrrolidone and eudragits.
Examples of suitable non-aqueous solvents employed as granulating fluids in the preparation of dosage forms include methylene chloride, isopropyl alcohol, acetone, methanol, ethanol and the like.
Glidants improve the flowability of the powder making up the tablet during production. Glidants can be selected from selected from the group consisting of: silicon dioxide, colloidal silicon dioxide, fumed silicon dioxide, sodium aluminosilicate, calcium silicate, powdered cellulose, microcrystalline cellulose, com starch, sodium benzoate, calcium carbonate, magnesium carbonate, asbestos free talc, metallic stearates, calcium stearate, magnesium stearate, zinc stearate, stearowet C, starch, starch 1500, magnesium lauryl sulfate, or magnesium oxide, where colloidal silicon dioxide is the preferred glidant.

Lubricants may be selected from the group of magnesium stearate, calcium stearate, sodium stearyl ilimarate, stearic acid, hydrogenated cottonseed oil, sodium benzoate, sodium lauryl sulfate, polyethylene glycol, talc etc.
The amount of each type of additive employed, e.g. glidant, binder, disintegrant, filler or diluent and lubricant may vary within ranges conventional in the art.
It is a characteristic of the present solid oral compositions that they contain Lanthanum carbonate in a low hydration state, containing less than 3 molecules of water, preferably anhydrous form. The total amount of additives in a given unit dosage may be about 50 % or less by weight based on the total ^veight of the solid oral dosage form, more particularly about 40 % or less.
In a preferred embodiment, there is provided a process of making the stable solid oral compositions as hereinabove described comprising the steps of (a) Mixing Lanthanum carbonate and diluents in a blender (b) Mixing the blend of step [a] with colloidal silicon dioxide and talc (c) Lubricating the blend of step [b] with a lubricant and (d) Compressing the blend to form tablets. The compi-ession of granulate to tablet cores can be carried out in a conventional tabletting machine, eccentric tabletting machine or a rotary compression machine.
The following examples further exemplify the invention and are not intended to limit the scope of the invention.
Examples 1: (Lanthanum Carbonate in Anhydrous form)

Sr.
No Ingredients Unit weight (mg) % weight

250 500 750 1000

1 Lanthanum carbonate 41L96 823.91 1235.87 1647.83 63.38
2 Glycine 50 100 150 200 7.69
3 AvicelCE 15 87.5 175 262.5 350 13.46
4 Aspartame 12.5 25 37.5 50 1.92
5 Hydroxypropylcellulose 37.5 75 112.5 150 5.77

6 Non aqueous solvent q.s q.s q.s q.s
7 Colloidal silicon Dioxide 39.54 79.09 118.63 158.17 6.08
8 Talc 5.5 11 16.5 22 0.85
9 Magnesium Stearate 5.5 11 16.5 22 0.85
Total weight (mg) 650.00 1300.00 1950.00 2600.00 100.00
Manufacturing Procedure:
1. Ingredients 1, 2 and 3 are mixed together and sifted through U 25 mesh, Step 1 is loaded to RMG and dry mixed for 20 minutes.
2. Preparation of binder solution : Hydroxypropylcellulose is added to isopropyl alcohol under continues stirring to get clear solution
3. Step 1 is granulated using binder solution of step 2 in RMG to get uniform granules and wet mass is milled using suitable mill fitted with suitable sieve
4. Wet granules are dried at 40°C for the period about 45 minutes.
5. Dried granules of step 4 is sifted through suitable sieve
6. step 5 was blended with the ingredients 4, 7, 8, and 9 in bin blender for the period of 20 minutes
7. Blend of step 6 is compressed using suitable tooling
Examples 2: (Lanthanum Carbonate in Anhydrous form)

Sr. No Ingredients Unit weight (mg) % weight

250 500 750 1000

1 Lanthanum carbonate 411.96 823.91 1235,87 1647.83 63.38
2 Glycine 50 100 150 200 7.69
3 prosolv SMCC 87.5 175 262.5 350 13.46
4 Aspartame 12.5 25 37.5 50 1.92
5 Hydroxypropylcellulose 37.5 75 112.5 150 5.77
6 Isopropyl alcohol q.s q.s q.s q.s
7 Colloidal silicon Dioxide 39.54 79.09 118.63 158.17 6.08
8 Talc 5.5 11 16.5 22 0.85
9 Magnesium Stearate 5.5 11 16.5 22 0.85
Total weight (mg) 650.00 1300.00 1950.00 2600.00 100.00
Manufacturing Procedure:

1. Ingredients 1, 2 and 3 are mixed together and sifted through # 25 mesh. Step 1 is loaded to RMG and dry mixed for 20 minutes.
2. Preparation of binder solution : Hydroxypropylcellulose is added to isopropyl alcohol under continues stirring to get clear solution
3. Step 1 is granulated using binder solution of step 2 in RMG to get uniform granules and wet mass is milled using suitable mill fitted with suitable sieve
4. Wet granules are dried at 40°C for the period about 45 minutes.
5. Dried granules of step 4 is sifted through suitable sieve
6. step 5 was blended with the ingredients 4, 7, 8, and 9 in bin blender for the period of 20 minutes
7. Blend of step -6 is compressed using suitable tooling

Examples 3: (Lanthanum Carbonate in Anhydrous form)

Sr.
No Ingredients Unit weight (mg) % weight

250 500 750 1000

1 Lanthanum carbonate 411.96 823.91 1235.87 1647.83 63.38
2 Glycine 50 100 150 200 7.69
3 MCC 87.5 175 262.5 350 13.46
4 Aspartame 12.5 25 37.5 50 1.92
5 Hydroxypropylcellulose 37.5 75 112.5 150 5.77
6 Isopropyl alcohol q.s q.s q.s q.s
7 Colloidal silicon Dioxide 39.54 79.09 118.63 158.17 6.08
8 Talc 5.5 11 16.5 22 0.85
9 Magnesium Stearate 5.5 11 16.5 22 0.85
Total weight (mg) 650.00 1300,00 1950.00 2600.00 100.00
Manufacturing Procedure:
1. Ingredients 1, 2 and 3 are mixed together and sifted through # 25 mesh, Step 1 is loaded to RMG and dry mixed for 20 minutes.
2. Preparation of binder solution : Hydroxypropylcellulose is added to isopropyl alcohol under continues stirring to get clear solution
3. Step -1 is granulated using binder solution of step 2 in RMG to get uniform granules and wet mass is milled using suitable mill fitted with suitable sieve
4. Wet granules are dried at 40°(!! for the period about 45 minutes.
5. Dried granules of step 4 is sifted through suitable sieve
6. step 5 was blended with the ingredients 4, 7, 8, and 9 in bin blender for the period of 20 minutes
7. Blend of step 6 is compressed using suitable tooling
Dissolution Study: The dissolution test is done using USP II apparatus (Modified) at 10 RPM, 900 ml of 0.25 N HCl at 37 ± 0.5 °C.
Table 1: Results of the dissolution study of Example 2 with FOSRENOL®

Time (min) % Drug Release
FOSRENOL (1000 mg) EXAMPLE 2 (1000 mg)
10 59 55
20 82 78

30 89 90
45 99 96
60 99 100
Table 2: Height/ Diameter ratio of I'OSRENOL® tablets (Lanthanum Carbonate tetra hydrate)

Strength (mg) Weight of tablets in (mg) Diameter
(mm)
A Height (mm) B Ratio (B/A)
500 2069 18.06 5.02 0.277
750 3155 20.08 6.24 0.310
1000 4183 22.11 6.91 0.3125
Table 2: Height/ Diameter ratio of test tablets (with less than three molecule of water)

Strength
(mg) Weight of tablets in (mg) Diameter
(mm) A Height
(mm)B Ratio (B/A)
500 1300 10- 13 3.5- 5.5 0.35-0.42
750 1950 12- 15 4.5 - 6.5 0.37-0.43
1000 2600 14- 16 5.5 - 7.5 0.39- 0.46

Claims:
1. A solid oral composition comprising:
(a) therapeutically effective amount of lanthanum carbonate in low hydration state;
(b) an amino-acid or a pharmaceutically acceptable salt thereof;
(c) optionally other pharmaceutically acceptable additives;
wherein said tablet composition comprises atleast 50% by weight of lanthanum carbonate.
2. The composition according to claim 1, wherein lanthanum carbonate is present in an anhydrous form.
3. The composition according to claim 1, wherein said amino acid is selected from a group comprising alanine, arginine, aspartic acid, asparagine, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucinc, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.
4. A pharmaceutical composition according to claim 1, wherein percentage of lanthanum carbonate released from said dosage composition in-vitro dissolution is comparable to that of lanthanum carbonate formulation marketed under the trade name of FOSRENOL®.
5. A process of preparing a pharmaceutical composition of lanthanum carbonate in the form of chewable tablet comprising:
a) wet granulating lanthanum carbonate, an amino acid, atleast one diluent or filler, and optionally other pharmaceutically acceptable additive, with a non-aqueous binder solution to form granulate, b) optionally milling said granulate;
c) optionally mixing one or more lubricant to obtain a final blend; and
d) compressing said final blend to get the chewable tablet.
6. The process according to claim 7, wherein said non-aqueous solvent used for preparing
binder solution is selected from methylene chloride, isopropyl alcohol, acetone, methanol,
ethanol and the like.

7. The method as claimed in claim 7, wherein said binder is selected from the group
comprising alkyl celluloses such as methyl cellulose, ethyl cellulose, hydroxyalkylcelluloses
such as hydroxypropylcellulose, low substituted hydroxypropylcellulose,
hydroxypropylmethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose,
gelatin, polyvinylpyrrolidone and Eudragits.
8. The pharmaceutical composition according to claim 1 used for treating
hyperphosphatemia, chronic kidney disease and controlling hyperparathyroidism in humans.