FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
PATENTS RULES, 2006
PROVISIONAL SPECIFICATION (SECTION 10; RULE 13)
"STABLE PHARMACEUTICAL COMPOSITIONS OF LANTHANUM CARBONATE AND PROCESS FOR THE PREPARATION THEREOF"


ALKEM LABORATORIES LIMITED, A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956, HAVING ITS CORPORATE. OFFICE AT ALKEM HOUSE, DEVASHISH, ADJACENT TO MATULYA CENTRE, S.B.MARG, LOWER PAREL, MUMBAI - 400013, MAHARASHTRA, INDIA.
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED:


ABSTRACT:
The technical field of the present invention relates to stable pharmaceutical compositions comprising lanthanum carbonate & process for the preparation of the same.
BACKGROUND OF THE INVENTION:
Lanthanum is a rare earth element of transition group IIIb of the periodic table. It was discovered by Carl Gustaf Mosander in 1839. Its name derived from the Greek fanthamin, meaning "to be concealed", indicating that it is difficult to isolate. Lanthanum carbonate, La2(CO3)3, salt formed by lanthanum(IH) cations and carbonate anions, is a non-calcium, non-aluminum containing phosphate binder. It is an ore of lanthanum metal, along with monazite with an atomic numbeT 57 and an atomic weight of 139.
Lanthanum carbonate binds phosphate optimally at pH 3-5, while retaining binding activity across the full range of pH 1-7. It is, therefore, able to bind phosphate efficiently at the low pH of the stomach as well as the higher values in the duodenum and jejunum, unlike calcium carbonate. Thus, following administration with food, lanthanum carbonate forms a compound of low aqueous solubility (i.e., lanthanum phosphate) which does not readily pass through the lining of the gastrointestinal tract into the blood. As a consequence, phosphate absorption from the diet is decreased. Dietary phosphate bound to lanthanum carbonate is excreted in the feces, with a resultant lowering of serum phosphorus and urinary phosphorus excretion. In United States., the FDA approved Fosrenol® (lanthanum carbonate) indicating reduction in serum phosphate levels in patients with end-stage renal disease (ESRD), is now available to patients having appeared on the market during early 2005. Apart from medicinal, lanthanum carbonate is also used for the tinting of glass, for water treatment, or as a catalyst for hydrocarbon cracking.


U.S. Patent No. 5968976 discloses that selected lanthanum carbonate hydrates with 3 to 6 molecules of water of crystallization, may be administered into the gastrointestinal tract, to treat hyperphosphataemia in patients with renal failure.
U.S. Patent No. 7381428 & U.S. Patent application No. 20080187602A1 disclose stabilized lanthanum carbonate compositions containing a monosaccharide or disaccharide stabilizing agent and subjects having hyperphosphatemia can be treated by administering a pharmaceutical composition containing a therapeutically effective amount of the stabilized lanthanum carbonate formulation.
U.S. Patent No. 7465465 & U.S. Patent application No. 20090017133A1 relate to a chewable lanthanum formulation comprising a pharmaceutically effective amount of a lanthanum compound; and at least one chewable pharmaceutically acceptable excipient. This invention also discloses a pharmaceutical formulation of a lanthanum compound in a tablet or in a powder form produced by a process comprising the steps of: a) powder blending the lanthanum compound and at least one pharmaceutically acceptable excipient in a mixer to form a mixture; or b) powder blending the lanthanum compound and excipients, compressing the resulting combination into a slug material or roller compacting the resulting combination into a strand material, and milling the prepared material into a free flowing mixture; and c) compressing the resulting mixture into a tablet or filing up the resulting mixture in a appropriate container.
U.S. Patent No. 20080125394A1 relates to medicaments useful for reducing phosphorus serum level, especially in those subjects affected from hyperphosphatemia. It discloses pharmaceutical compositions comprising a phosphorus compound binding agent and at least one pharmaceutically acceptable vehicle and/or excipients, to be administered by oral route in fasting periods, in order to absorb phosphorus compounds from fluids of the enteric tract, especially from saliva.
In the above cited prior art patents / applications, high unit doses of lanthanum carbonate necessitate blend lubrication, glidant addition and facilitated die filling to ensure efficient


tablet production at plant scale. Also when presented as a chewable tablet, the cohesivity of lanthanum carbonate inhibits flow under gravity, paddle-feed being indicated to ensure reproducible die fill and consistent tablet mass.
The present invention has been made in view of overcoming the aforementioned problems. In the patent search for this application, no other prior art was identified which incorporated the use of specific lubricant as specified herein to provide stability to the lanthanum carbonate composition.
OBJECT OF THE INVENTION:
It is an object of the present invention to provide stable pharmaceutical compositions comprising lanthanum carbonate and a lubricant selected from sodium stearyl fumarate, zinc stearate, calcium stearate, stearic acid or mixtures thereof.
It is another object of the present invention to provide process for the preparation of a stable lanthanum carbonate pharmaceutical composition by using a lubricant selected from sodium stearyl fumarate, zinc stearate, calcium stearate, stearic acid or mixtures thereof.
At least one of the preceding objects is met, in whole or in part, by a process providing the use of a lubricant selected from sodium stearyl fumarate, zinc stearate, calcium stearate, stearic acid or mixtures thereof to prepare stable pharmaceutical compositions
comprising lanthanum carbonate.
SUMMARY OF THE INVENTION:
The present invention relates to stable pharmaceutical compositions comprising lanthanum carbonate and a lubricant selected from sodium stearyl fumarate, zinc stearate, calcium stearate, stearic acid or mixtures thereof.


Additionally, the present invention also relates to a process for the preparation of a stable lanthanum carbonate pharmaceutical composition by using a lubricant selected from sodium stearyl fumarate, zinc stearate, calcium stearate, stearic acid or mixtures thereof
More particularly, the present invention relates to stable pharmaceutical compositions comprising lanthanum carbonate by using sodium stearyl fumarate as a lubricant and a process for the preparation thereof.
DESCRIPTION OF THE INVENTION:
Before the present compositions and methods are described, it is to be understood that this invention is not limited to particular compounds, formulas or steps described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein


are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.
It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds and reference to "the step" includes reference to one or more step and equivalents thereof known to those skilled in the art, and so forth.
The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.
The term "stable" as used herein refers to chemical stability of lanthanum carbonate in solid dosage forms wherein there is no change in impurities percentages and dissolution profile when kept at 40°C / 75% RH for 3 months.
We have surprisingly found that it is possible to achieve stable pharmaceutical compositions comprising lanthanum carbonate by process providing the use of a lubricant selected from sodium stearyl fumarate, zinc stearate, calcium stearate, stearic acid or mixtures thereof.
Additionally, the present invention also relates to a process for the preparation of a stable lanthanum carbonate pharmaceutical composition by using a lubricant selected from sodium stearyl fumarate, zinc stearate, calcium stearate, stearic acid or mixtures thereof.
More particularly, the present invention relates to stable pharmaceutical compositions comprising lanthanum carbonate by using sodium stearyl fumarate as a lubricant and a process for the preparation thereof


As used herein, lanthanum carbonate refers to all polymorphs and hydrated forms of lanthanum carbonate and anhydrous lanthanum carbonate of the general formula:
La2(C03)3.xH20
where x has a value from 0 to 10, preferably x has an average value of 8. For example, the stable pharmaceutical composition of the invention may include from about 30% w/w to about 50% w/w of lanthanum carbonate by weight of the composition.
Lanthanum carbonate has a tendency to degrade via decarboxylation to lanthanum hydroxycarbonate as shown:
La2(C03)3 + nH20 -> 2LaOHC03 + C02 + (n -1)H20
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. Further, conditions sufficient to bring about decarboxylation of these materials may be present during their manufacture as well as during storage in a formulated or unformulated state.
Accordingly, the present invention relates to the use of a lubricant selected from sodium stearyl fumarate, zinc stearate, calcium stearate, stearic acid or mixtures thereof, providing the stable pharmaceutical compositions comprising lanthanum carbonate. Lubricants of the present invention, particularly, sodium stearyl fumarate is relatively inert and therefore avoids incompatibilities with lanthanum carbonate which results in a better stability. It has a high melting point and is therefore the preferred lubricant for high speed direct compression. While using magnesium stearate during force-feed die filling, over blending is most common resulting prolong tablet wetting and break-up and also affecting disintegration. Sodium stearyl fumarate has superior tablet hardness and lower ejection force at equivalent compression force and also it is more hydrophilic than magnesium stearate, therefore it accelerates the disintegration and shows less retardant effect on the dissolution rate. Surprisingly, it was identified that the present


pharmaceutical compositions prepared by using a lubricant as specified herein, were less 'moisture sensitive and more stable. The lubricants of the present invention may be used in the stable pharmaceutical composition of the present invention in amounts ranging from about 0.5 % w/w to about 5 % w/w, preferably from about 2 % w/w to about 3.5 % w/w of the composition.
The stable pharmaceutical compositions of the present invention may further comprise conventional pharmaceutically acceptable excipients. Conventional pharmaceutical excipients include those which function in a dosage form, for example, as a diluent or sweetening agent, binder, glidant, disintegrants, colors and flavors.
Diluents / sweetening agents that may be included in the composition include, but are not limited to, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, starch, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, dextrates, dextrin, dextrose, kaolin, magnesium carbonate, magnesium oxide, sugars such as sucrose; sugar alcohols such as mannitol, sorbitol, erythritol; and mixtures thereof, preferably mattitol, which may act as a stabilizing agent. Diluent may generally be added to increase the bulk volume of the powder to facilitate granulation or compression. One or more diluents/sweetening agents can be present in the composition. The diluents/sweetening agents may be present in the composition in an amount of from about 10 % w/w to about 60 % w/w, preferably from about 35 % w/w to about 45 % w/w.
Binding agents which may be employed include, but are not limited to, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carbomers, carboxymethylcellulose sodium, Hydroxypropyl p-cyclodextrin, dextrin, methylcellulose, shellac, zein, gelatin, polymethacrylates, polyvinyl pyrrolidone, pregelatinized starch, potato starch, sodium alginate, gums, synthetic resins and the like and the mixtures thereof The binding agent may be present in the composition in an amount of from about 2 % w/w to about 15 % w/w, preferably from about 5 % w/w to about 10.5 % w/w.


Disintegrants that may be used in the composition include, but are not limited to, cross povidone, cross carrnellose sodium, sodium starch glycolate and the like and the mixtures thereof. The disintegrants may be present in the composition in an amount of from about 0.001 % w/w to about 10 % w/w, preferably from about 0.05% w/w to about 5% w/w.
Alternatively, antioxidants may also be incorporated in the composition to enhance its storage stability, for example, ascorbic acid, alpha tocopherol or butylated hydroxyanisole. One or more antioxidants can be present in the composition. The total antioxidant amount can be from about 0.0001% to 1.0%, preferably from about 0.001% to about 0.1%, and most desirably from about 0.005% to 0.05% by weight of the composition.
The term "pharmaceutical composition" as used herein includes solid oral dosage forms such as powder, beads, granules, tablets, capsules, chewable compositions and the like, that in turn may be prepared by conventional methods known to a person skilled in the art.
As discussed above, the pharmaceutical compositions of the present invention may be prepared by conventional techniques such as dry admixing, wet granulation, dry granulation or direct compression. In dry admixing, lanthanum carbonate is mixed with sodium stearyl fumarate and various excipients in a mixer to form a mixture. In wet granulation, lanthanum carbonate is mixed with sodium stearyl fumarate and various excipients and granulated, followed by screening and drying of the damp mass. The dried mass may be screened, lubricated. Dry granulation can be done by two processes: (1) slugging, which involves mixing the lanthanum carbonate with sodium stearyl fumarate and the excipients, slugging, dry screening, again lubricating with sodium stearyl fumarate, or (2) roller compaction process. The granules obtained by the said granulating processes, can either be filled in capsules or compressed into tablets. Direct compression involves compressing tablets directly from the physical mixture of lanthanum carbonate, sodium stearyl fumarate and the excipients. Alternatively the pharmaceutical compositions of the present invention may be obtained by preparing placebo granules comprising the sodium stearyl fumarate and pharmaceutical^ acceptable excipients, and


mixing these with lanthanum carbonate to obtain a blend, which may be compressed into tablets. These methods provide compositions of lanthanum carbonate that are stable.
The following examples are intended to illustrate the scope of the present invention in all its aspects but not to limit it thereto.
EXAMPLE 1-2
The stable pharmaceutical composition comprising lanthanum carbonate may be prepared as given in Table 1 and Table 2.
Table 1

Name of Ingredients Quantity (Mg/Tab) %w/w
Intra Granular
Lanthanum carbonate octahydrate 2183.406 49.06
Maltitol 2176.594 48.91
Sodium Steryl Fumarate 45.0 1.01
Extra Granular
Sodium Steryl Fumarate 45.0 1.01
Total 4450.0 100
Table 2

Name of Ingredients Quantity (Mg/Tab) %w/w
Intra Granular
Lanthanum carbonate octahydrate 2183.406 49.06
Maltitol 1966.594 44.19
Potato Starch/ Hydroxypropylmethyl
cellulose 3 CPS/ Hydroxy propyl p-
cyclodextrin 200.0 4.49
Sodium Steryl Fumarate 50.0 1.12
Extra Granular
Sodium Steryl Fumarate 50.0 1.12
Total 4450.0 100


Lanthanum Carbonate Octahydrate, and Maltitol (for table 1), Lanthanum Carbonate Octahydrate, Maltitol, Potato starch/ Hydroxypropylmethyl cellulose 3 CPS/ Hydroxy propyl B-cyclodextrin (for table 2) were sifted through # 30 and mixed for 10 minutes in a RMG. Sodium steryl fumarate was sifted through 40# and mixed with it for further 5 mm. The above dry mix was slugged by using 22.0 mm flat punch. After slugging, it was deslugged by Multimill using 2.5 mm screen at slow speed. The milled granules were passed through 16# to get uniform granules. Sodium Steryl Fumarate (extra granular) was sifted through 40# and mixed with deslugged granules for 5 min. The above obtained blend was compressed with their respective punches.
EXAMPLE 3
The stable pharmaceutical composition as prepared in example 1 (table 1) was subjected to dissolution. The results are given in Table 3.
Media : 0.25 NHCl
Apparatus : USP Type II
Agitation : 50 RPM
Volume ; 900 ml
Table 3

Time in min Fosrenol® Tablet Composition of example -1 (table 1)

(% drug release) (% drug release)
20 min 51.8 67
40 min 92.8 91.8
60 min 103.3 98
Although the invention has been described in terms of particular embodiments and applications, one of ordinary skill in the art, in light of this teaching, can generate additional embodiments and modifications without departing from the spirit of or exceeding the scope of the claimed invention. It should be emphasized that the above-


described embodiments of the present invention, particularly any "preferred" embodiments, are merely possible examples of the invention of implementations, merely set forth for a clear understanding of the principles of the invention. Accordingly, it is to be understood that the drawings and descriptions herein are proffered by way of example to facilitate comprehension of the invention and should not be construed to limit the scope thereof.
Dated this 20th day of April 2009

To:
The Controller of Patents, Patent Office, Mumbai400 037