FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(Section 10 and Rule 13)
PHARMACEUTICAL COMPOSITION COMPRISING MYCOPHENOLATE SODIUM
Glenmark Generics Limited
an Indian Company, registered under the Indian company's Act 1957
and having its registered office at
B/2, Mahalaxmi Chambers, 22 Bhulabhai Desai Road,
Mumbai - 400 026
The following specification particularly describes the invention and the manner in which it is to be performed

FIELD OF INVENTION:
The present invention relates to an enteric coated tablet comprising acicular mycophenolic acid or pharmaceutically acceptable salt thereof, more particularly mycophenolate sodium and at-least a pharmaceutically acceptable excipient.
BACKGROUND & PRIOR ART:
Mycophenolic acid (MPA) was first isolated in 1896 from Penicillium species, and was known to have anti-psoriatic, anti-tumor, anti-viral and immunosuppressive activity. Allison et al (Syntex) during 1980 considered MPA as immunosuppressive agent. They postulated that depletion of GMP by inhibiting inosine monophosphate dehydrogenase (IMPD) might result in an antiproliferative effect on lymphocytes to a greater extent than that on other cell types, given that lymphocytes use de novo purine synthesis, whereas other cell depend more on purine salvage. MPA was found to be a noncompetitive reversible inhibitor of eukaryotic but not prokaryotic IMP dehydrogenase. However, the in vitro studies demonstrated that only free MPA is available to inhibit IMPDH, and hence the immunosuppressive effect is achieved only by the freely available MPA.
On oral administration, Mycophenolic acid showed a poor bioavailability, due to the complexation in gastro-intestinal lumen, narrow absorption window and metabolism prior to absorption, therefore the MPA was found to be unsuitable for the purpose of direct oral administration. The problems pertaining to the bioavailability of Mycophenolic acid led to the development of its pro-drug called Mycophenolate mofetil (MMF) which is the morpholinoethyl ester of the MPA. It was found that on oral administration to a patient, mycophenolate mofetil hydrolyzes into mycophenolic acid (MPA) in vivo, and improves the bioavailability of MPA, and enhances the efficacy. Subsequently MMF was commercially made available in form of tablet,
capsule, oral suspension and injection under the brand name CELLCEPT . Mycophenolate mofetil, although widely used for a long time, was found to cause certain gastro-intestinal side effects such as diarrhea and burning sensation in patient.
The literature provides compositions which overcome the abovementioned gasterointestinal problems associated with the therapy of Mycophenolate mofetil. US patents 6025391, 6172107

and 6306900 of Novartis, provide capsules comprising mycophenolate sodium. The capsules enclosing mycophenolate sodium, were coated in a manner to prevent the release of mycophenolate Sodium in the stomach but to release the mycophenolate sodium in the upper part of the intestinal tract.
US patent application published as US20050013859 and US20100210717 describes an enteric coated tablets comprising high drug load of mycophenolate sodium. The high drug loading in the application means mycophenolate sodium in amount of at-least 20% to about 95% by weight based on the total weight of the tablet including enteric coating. The application exemplifies enteric coated tablet comprising mycophenolate sodium present in an amount of above 45% more particularly above 50% by weight based on total weight of the tablet including the enteric coating.
The crystals of mycophenolate sodium, due to its acicular crystal nature, are associated with certain drawbacks such as a low bulk density, a poor flow property and low compressibility. The acicular crystals exhibit crystal growth preferably in any one direction and have an aspect ratio (ratio of length and the width) significantly higher than 1:1. This results in poor flow of mycophenolate sodium crystals during the tablet manufacturing process. It is well established in pharmaceutical technology, that a good flow property is a prerequisite for the successful formulation of a tablet. Further due to the acicular nature, the crystals of mycophenolate sodium have low bulk density which result in tablet having inadequate hardness and friability. Apart from being an acicular crystal nature substance, the high dose of mycophenolate sodium i.e. equivalent to 180 & 360 mg of mycophenolic acid, also causes difficulties with respect to the preparation of the tablet of suitable size and the drug release pattern.
In past, attempts have been made to modify first the acicular nature of mycophenolate sodium crystals by means of special techniques, followed by incorporating the modified crystals into the pharmaceutical composition such as Tablets. US Patent 8008511 of Novartis provides the modified acicular crystals of mycophenolate sodium, having an aspect ratio of about 10:1 to 1:1 and a bulk density of above about 200 kg/m3. The mycophenolate sodium of aspect ratio of 2:1 was more preferred. The desired aspect ratio was prepared by employing special processes. The

aforesaid method of modifying the acicular crystals of mycophenolate sodium requires special techniques and arrangements which make the whole process complex and cumbersome.
Considering the variety of problems associated with the mycophenolate sodium, such as acicular crystal nature and high dose requirement, there is a need of an enteric coated tablet comprising non-modified acicular mycophenolate sodium having an acceptable size, hardness, release pattern and prepared with the routine simple pharmaceutical techniques.
SUMMARY OF THE INVENTION:
The present invention provides an enteric coated tablet comprising acicular mycophenolate sodium in an amount of about 35% to 45% by weight of the tablet.
In one of the preferred embodiment, the present invention provides an enteric coated tablet comprising acicular mycophenolate sodium in an amount of 35% to 45% by weight of the tablet and at-least one pharmaceutically acceptable excipient, such that the enteric coated tablet releases not more than 5% of mycophenolate in 750 ml of 0.1 N HC1 (USP type II apparatus at 100 rpm) for 120 minutes and releases more than 90% of mycophenolate in 1000 ml of pH 6.8 buffer (USP type II apparatus at 100 rpm) in 60 minutes.
In another embodiment, the present invention provides an enteric coated tablet comprising acicular mycophenolate sodium in an amount of 35% to 45% by weight of the tablet and anhydrous lactose present in the intra-granular portion in an amount of about 40 - 60%> and in the extra-granular portion in an amount of about 40 - 60% of the total anhydrous lactose present in the tablet.
In one more embodiment, the present invention provides an enteric coated tablet comprising acicular mycophenolate sodium in an amount of about 40% by weight of the tablet and anhydrous lactose in the intra-granular and extra-granular portion wherein weight ratio of anhydrous lactose present in the intra-granular and extra-granular portion is about 1:1.

In yet another embodiment, the present invention provides a process of preparing an enteric coated tablet of mycophenolate sodium comprising acicular mycophenolate sodium in an amount of 35% to 45% by weight of the tablet and at-least one pharmaceutically acceptable excipient.
DETAILED DESCRIPTION OF INVENTION:
The various abbreviations used in the present applications like MP A, MPS, MMF, MPAG, AcMPAG respectively refers to mycophenolic acid, mycophenolate sodium, mycophenolate mofetil, mycophenolic acid glucuronide, and acetylated mycophenolic acid glucuronide.
As used herein, the term "pharmaceutically acceptable salts of Mycophenolic acid" shall refer to salts prepared from pharmaceutically acceptable non toxic bases or acids including inorganic or organic bases and inorganic or organic acids. In a preferred embodiment, the term "pharmaceutically acceptable salts of Mycophenolic acid" used in the present application refers to a mono-sodium salt of mycophenolic acid also termed as "mycophenolate sodium".
The term "tablet weight" or "weight of tablet" refers to weight of the tablet including the enteric coat.
As discussed earlier, mycophenolic acid or its pharmaceutically acceptable salt preferably the mycophenolate sodium is associated with several drawbacks like an acicular crystal nature, a low bulk density, poor flow and low compressibility. This results in tablet of inadequate hardness, friability and a low mechanical stability. The acicular crystals of mycophenolate sodium have the ratio between the length and the width, the so-called aspect ratio significantly higher than 1:1 and these crystals are needle, rod or capillary shaped. Because of such shape, these crystals display poor processability and inefficient processing during formulation process. These crystal particle having an elongated shape and small particle size may cause tablet weight variation, unacceptable blend uniformity, and difficulty in filling dies in a tableting machine.
The acicular crystals of mycophenolate sodium have been modified in US8008511 which discloses mycophenolate sodium crystals with an aspect ratio of about 10:1 to 1:1 and a bulk density of above 200 kg/m .

Inventors of the present invention surprisingly found that an enteric coated tablet comprising non-modified acicular mycophenolate sodium in an amount of about 35 % to 45 % and anhydrous lactose in an amount of about 5% to 50% by weight of the tablet optionally with other pharmaceutically acceptable excipient provides an excellent dissolution and mechanical stability.
In a major aspect, the present invention provides an enteric coated tablet comprising acicular mycophenolate sodium in an amount of 35% to 45% by weight of the tablet and anhydrous lactose present in the intra-granular portion in an amount of about 40-60% and in the extra-granular portion in an amount of about 40-60% of the total anhydrous lactose present in the tablet.
In another aspect, the present invention provides an enteric coated tablet comprising acicular mycophenolate sodium in an amount of 35% to 45% by weight of the tablet and anhydrous lactose in the intra-granular portion in an amount of about 50% of the total lactose of the tablet while the remaining percentage of anhydrous lactose is present in the extra-granular portion.
In a specific aspect, the present invention provides an enteric coated tablet comprising acicular mycophenolate sodium in an amount of about 40% by weight of the tablet and anhydrous lactose in the intra-granular and extra-granular portion wherein weight ratio of anhydrous lactose present in the intra-granular and extra-granular portion is about 1:1.
In one more aspect, the present invention provides an enteric coated tablet comprising acicular mycophenolate sodium in an amount of 35% to 45%; intra-granular anhydrous lactose about 15%; extra-granular anhydrous lactose about 15%; a binder about 1 to 15%, a disintegrating agent about 0.5 to 15%; a glidants about 0.1 to 10 % and a lubricant about 0.1 to 10 % of the total tablet weight.
In one more aspect, the present invention provides a process of preparing an enteric coated tablet of acicular mycophenolate sodium, wherein the intra-granular portion comprising the acicular mycophenolate sodium is intimately mixed with anhydrous lactose and optionally other pharmaceutically acceptable excipient in a rapid mixer granulator and the resulting mass is granulated using a non-aqueous solvent. This intra-granular portion is then mixed with extra-granular portion comprising anhydrous lactose and optionally other pharmaceutically acceptable

excipient, lubricated and compressed into a core tablet. The core tablet is then coated with an enteric coating solution until a desired build up is achieved.
In one more aspect of the present invention, the non-aqueous solvent used to granulate the intra-granular component is selected from the group comprising of but not limited isopropyl alcohol, methylene dichloride, ethanol, acetone and the likes; wherein ethanol is most preferred. However, it is well within the scope of present invention to use a mixture of more than one nonaqueous solvent in various proportions, and the non-aqueous solvent can be suitably diluted for a better granulation.
In one more aspect, the enteric coating solution comprises an enteric polymer, a plasticizer and a coloring aid, wherein the enteric polymer is present in amount of 2 - 15%, more preferably in amount of 5-10% of the tablet weight.
In a preferred aspect, the enteric coated tablet of the present invention comprises enteric coating over the core tablet, wherein the enteric coating is about 5-15 % by weight of the core tablet.
In one more aspect, the pharmaceutically acceptable excipient used in the enteric coated tablet of present invention comprising acicular mycophenolate sodium can be selected from the group comprising of but not limited to diluent(s) selected from the group comprising of, but not limited to anhydrous lactose, sugar, starches, modified starches, mannitol, sorbitol, inorganic salts like dicalcium phosphate, cellulose derivatives (e.g. microcrystalline cellulose), calcium sulfate, xylitol, lactitol and the likes; binder(s) selected from the group comprising of, but not limited to polyvinylpyrrolidone, lactose, starches, modified starches, sugars, gum acacia, gum tragacanth, guar gum, pectin, wax binders, microcrystalline cellulose, methylcellulose, carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, crospovidone, polyethylene glycol, polyvinyl alcohol, gelatin, sodium alginate and the likes; disintegrating agent(s) selected from the group comprising of, but not limited to crospovidone, crosscarmallose sodium, polyvinylpyrrolidone, modified starch, sodium starch glycolate, corn starch, microcrystalline cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose and the likes; lubricant(s) selected from the group comprising of, but not limited to magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, carnauba wax,

hydrogenated vegetable oils, mineral oil, polyethylene glycols, sodium stearyl fumarate and the likes.
The enteric coating comprises enteric polymer(s) selected from the group comprising of but not limited to hydroxypropyl methyl cellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), polyvinyl acetyl phthalate (PVAP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), vinyl copolymers, acrylic acid copolymers and derivatives thereof such as methacrylic acid, methyl methacrylate copolymer and the likes; a plasticizer(s) selected from the group comprising of but not limited to triacetin, polyethylene glycol 400, triethyl citrate, diethyl phthalate, dibutyl sebacetate, hydrogenated vegetable oil and the likes. The solvent used to prepare the enteric coating solution is non-aqueous solvent selected from the group comprising of but not limited isopropyl alcohol, methylene dichloride, ethanol and the likes; wherein ethanol is most preferred, which may be suitably diluted.
In a preferred aspect, the enteric coated tablet of the present invention releases not more than 5% of mycophenolate in 750 ml of 0.1 N HC1 (USP type II apparatus at 100 rpm) for 120 minutes and releases more than 90% of mycophenolate in 1000 ml of pH 6.8 buffer (USP type II apparatus at 100 rpm) in 60 minutes.
The enteric coated tablet of the present invention comprising acicular mycophenolate sodium exhibits adequate hardness and friability, an acceptable mechanical stability and the release of mycophenolate from the tablet is comparable to the release pattern of Myfortic®.
Throughout this specification it is to be understood that the words "comprise" and "include" and variations such as "comprises", "comprising", "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
While the present invention is disclosed by reference to the preferred embodiments and example below, it is understood that these example are intended in an illustrative rather than in a limiting sense. It is contemplated that modifications and combinations will readily occur to those skilled in the art, which modifications and combinations will be within the spirit of the invention and the scope of the following claims.

Example-1: In a preferred embodiment, below examples illustrates an enteric coated tablet comprising mycophenolic acid or its salt: Table: 1

Ingredient 180 mg 360 mg
Intra-Granular
Mycophenolate sodium 192.400 384.800
Povidone K 30 10.000 20.000
Colloidal silicon dioxide 6.600 13.200
Lactose anhydrous 76.250 152.500
Crospovidone 32.500 65.000
Ethanol Qs Qs
Water Qs Qs
Extra-Granular
Lactose anhydrous 66.250 132.500
Crospovidone 32.500 65.000
Starch 10.250 20.500
Magnesium stearate 3.250 6.500
Enteric coat
Hydroxypropylmethylcellulose phthalate (HPMCP) 35.000 70.000
Triacetin 1.600 3.200
Titanium dioxide 3.239 5.686
Iron oxide yellow 0.136 0.272
FD&C Blue no. 2 Al. Lake (lake indigo carmine) 0.025 NA
FD&C Yellow no. 6 Al. Lake (Sunset yellow) NA 0.840
Iron oxide red NA 0.002
Ethanol Qs Qs
Water Qs Qs
Total 470.000 940.000
Process of preparation:
Weighed and sifted required quantities of mycophenolate sodium, povidone K30, and Colloidal silicon dioxide, crospovidone, lactose anhydrous through sieve # 30. The blend obtained was mixed in rapid mixer granulator and granulated with ethanol and dried in a fluidized bed processor till loss on drying (LOD) comes between 0.8 -1.5%. The obtained granules were shifted through suitable sieve and mixed with passed # 30 lactose anhydrous, crospovidone and starch mixed blend for 10-15 minute. The magnesium stearate is passed through sieve # 60 and was added to above blend and mixed for 5 minute. The resulting mass was compressed into core tablets using suitable

tooling. The enteric coating solution was prepared by adding coating material to ethanol and stirred for 5 minute under over head stirrer and water was added in suitable ratio under stirring to get a clear solution. The resulting solution was sprayed on the compressed tablets until a desired build up was achieved.
Dissolution Profile:
(I) Drug release at 0.1 N HC1 (750 ml) in USP type II apparatus at 100 rpm:
Table: 2

Time (rain) % Drug dissolve in 0.1 N HC1
Myfortic® Enteric coated tablet of example 1
120 0 0
The enteric coated tablet prepared as per example -1 of the present application shows no drug release for 120 minutes in 0.1 N HC1 (750 ml) in USP type II apparatus at 50 & 100 rpm. This indicates that the enteric coat doesn't disintegrate in the acidic pH environment of stomach and hence no drug release occurs in stomach.
(II)Drug release at pH 6.8 buffer (1000 ml) in USP type II apparatus at 100 rpm: Table: 3

Time (min) % Drug dissolve in pH 6.8 buffer
Myfortic® Enteric coated tablet of example 1
10 1 10
20 51 61
30 91 98
45 99 100
60 99 100
The release pattern of mycophenolate from the enteric coated tablet of example 1 of present invention, at pH 6.8 (1000 ml) in USP type II apparatus, 100 rpm is found comparable to the release pattern of Myfortic .

Stability Test:
I) The enteric coated tablet of example-1 of present invention was found to be stable when exposed to 40°C and 75% relative humidity for two months, as depicted below:
Table: 4

Enteric coated tablet of example 1
Initial 1 month 40°C/75%RH 2 month
40°C / 75% RH
NA HDPE HDPE
Assay (%) 98.9 100.2 99.1
Related Substances
5-7-Dihydroxy 4-methyl phalide Below 0.01% Below 0.01% Below 0.01%
Single Max 0.03 0.03 0.03
Total Impurity 0.06 0.06 0.06
II) The dissolution test of one month and two month stability samples of the enteric coated tablet of example 1 of present invention exhibited a dissolution profile matching with the initial samples.
Table: 5

Initial 1 month
40°C / 75% RH 2 month 40°C / 75% RH
Time (min) % Drug dissolve in 0.1 N HC1 (750 ml)/USP II apparatus at 100 rpm
120 0 0 0
Time (min) % Drug dissolve in pH 6.8 buffer (1000 ml)/USP II apparatus at 100 rpm
60 min 93 95 90
Physical Test:
The physical test results of the enteric coated tablet of example 1 of the present invention are found comparable to the marketed product Myfortic .
Table: 6

Parameters tested Enteric coated tablet of example 1
Disintegration time of core tablet 9-11 minutes
Tablet Hardness (Kp) 12-17Kp
Friability at 100 Revolutions Less than 0.1 % w/w

Claims:
We claim
1) An enteric coated tablet comprising acicular mycophenolate sodium in an amount of about 35% to 45% by weight of the tablet and at-least one pharmaceutically acceptable excipient.
2) An enteric coated tablet of claim 1, wherein the pharmaceutically acceptable excipient is anhydrous lactose present in the intra-granular portion in an amount of about 40 - 60% and in the extra-granular portion in an amount of about 40 - 60% of the total anhydrous lactose present in the tablet, optionally with other pharmaceutically acceptable excipient.
3) An enteric coated tablet of claim 1, wherein the tablet releases not more than 5% of mycophenolate in 750 ml of 0.1 N HO (USP type II apparatus at 100 rpm) for 120 minutes and releases more than 90%o of mycophenolate in 1000 ml of pH 6.8 buffer (USP type II apparatus at 100 rpm) in 60 minutes.
4) An enteric cOated tablet comprising acicular mycophenolate sodium in an amount of about 40%) by weight of the tablet and anhydrous lactose in the intra-granular and extra-granular portion optionally with other pharmaceutically acceptable excipient, wherein the weight ratio of anhydrous lactose in the intra-granular and extra-granular portion is about 1:1.
5) An enteric coated tablet of claim 4, wherein the tablet comprises acicular mycophenolate sodium in an amount of about 40%, intra-granular lactose about 15% and extra-granular lactose about 15%> by weight of the tablet optionally with other pharmaceutically acceptable excipient.
6) An enteric coated tablet of claim 1 and 4, prepared by a process comprising the steps of:
i) Preparing an intra-granular portion by intimately mixing the acicular mycophenolate
sodium with anhydrous lactose and optionally other pharmaceutically acceptable
excipient and granulating the mass using a non-aqueous solvent. ii) Preparing an extra-granular portion by blending anhydrous lactose and optionally other
pharmaceutically acceptable excipient. iii) Mixing the granules with the extra-granular blend, lubricating the mixture and
compressing it into a core tablet. iv) The core tablet is then coated with an enteric coating until a desired build up is achieved.