FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
PATENTS RULES, 2006
COMPLETE SPECIFICATION (SECTION 10; RULE 13)
"PHARMACEUTICAL COMPOSITIONS COMPRISING MYCOPHENOLATE AND PROCESSES FOR PREPARING 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

FIELD OF THE INVENTION
The present invention relates to pharmaceutical compositions of mycophenolate, a salt or a prodrug thereof and processes for preparing thereof.
BACKGROUND OF THE INVENTION
Mycophenolic acid (MPA) or mycophenolate is derive++d from the fungus Penicillium stoloniferum. Mycophenolate is an immunosuppressant drug used for the prophylaxis of organ rejection in patients receiving allogenic renal transplants. It was initially marketed as the prodrug mycophenolate mofetil (MMF) to improve oral bioavailability. Mycophenolate mofetil is metabolised in the liver to the active moiety mycophenolic acid. More recently, the salt, mycophenolate sodium has been introduced.
Mycophenolate sodium, a mycophenolic acid prodrug, is an inhibitor of T-lymphocyte proliferation. Its chemical name is sodium (E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-lH-2-benzofuran-5-yl)-4-methylhex-4-enoate with molecular formula of C17H19NaO6 & molecular weight of 342.31893 [g/mol]. It is an uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase, the enzyme that controls the rate of synthesis of guanine monophosphate in the de novo pathway of purine synthesis used in the proliferation of B and T lymphocytes. An immunosuppressant that has drastically decreased the incidence of acute rejection in solid transplant recipients, mycophenolate is increasingly utilized as a steroid sparing treatment in immune-mediated disorders including immunoglobulin A, nephropathy, small vessel vasculitides, and psoriasis. Also its increasing applications in treating lupus nephritis compared to cyclophosphamide bolus therapy, a regimen with risk of bone marrow suppression, infertility, and malignancy have been demonstrated with more frequent complete response and less frequent complications. Mycophenolate is potent and can be used in place of the older anti-proliferative azathioprine. It is usually used as part of a three compound regimen of immunosuppressants, also including a calcineurin inhibitor (cyclosporin or tacrolimus). Mycophenolic acid is commonly marketed under the trade names CellCept® (mycophenolate mofetil; Roche) and Myfortic® (mycophenolate sodium; Novartis).

United States Patent Nos. 6306900, 6172107, 602539 describe a pharmaceutical composition comprising a mycophenolate salt & the composition being adapted to prevent release of mycophenolate in the stomach & to release mycophenolate in the upper part of the intestinal tract.
United States Patent Application No. US200500I3859A1 relates to an enteric coated solid dosage form, e.g. a tablet, comprising mycophenolic acid or mycophenolate salt and a process for its production, wherein the mycophenolic acid or mycophenolate salt is present in an amount of from about 20% to about 95% by weight based on the total weight of the solid dosage form including the enteric coating. It also claims that the tablet has a round shape with specific dimensions.
United States Patent Application No. US20080206322AI relates to a novel composition, of mycophenolic acid, a salt or a prodrug thereof in a modified release form. It discloses a formulation wherein the active agent is released and provided for absorption over a longer period of time than from a conventional dosage form, i.e. it provides a sustained, retard, continuous, gradual, prolonged or pulsatile release and therefore alters drug plasma levels distinctively versus an immediate release formulation.
Despite the above mentioned formulations of mycophenolate, there still exists a need for commercially acceptable dosage forms for oral administration with comparable bioavailability. Surprisingly we have found that pharmaceutical compositions of mycophenolate of the present invention are bioequivalent to the commercially available compositions in the United States of America i.e. Myfortic® tablets, in spite of releasing some amount of the mycophenolate in an acidic medium / stomach.
OBJECT OF THE INVENTION
It is an object of the present invention to provide pharmaceutical compositions of mycophenolate, a salt or a prodrug thereof and processes for preparing thereof.

It is an object of the present invention to provide enteric coated pharmaceutical compositions of mycophenolate, a salt or a prodrug thereof wherein the compositions are formulated to release at most about 10 % w/w of mycophenolate in an acidic medium of 0.1NHCl,PHl.2.
ft is yet another object of the present invention to provide enteric coated pharmaceutical compositions of mycophenolate, a salt or a prodrug thereof, which are bioequivalent to the commercially available compositions in the United States of America i.e. Myfortic® tablets, wherein the compositions are formulated to release at most about 10 % w/w of mycophenolate in an acidic medium of 0.1 N HCI, pH 1.2.
SUMMARY OF THE INVENTION
The present invention provides enteric coated pharmaceutical compositions of mycophenolate, a salt or a prodrug thereof, wherein the compositions are formulated to release at most about 10 % w/w of mycophenolate in an acidic medium of 0.1 N HCl, pH
1.2.
The present invention provides enteric coated pharmaceutical compositions of mycophenolate, a salt or a prodrug thereof, which are bioequivalent to the commercially available composition in the United States of America i.e. Myfortic® tablets, wherein the compositions are formulated to release at most about 10 % w/w of mycophenolate in an acidic medium of 0.1 N HCl, pH 1.2.
The present invention provides a process for the preparation of enteric coated pharmaceutical compositions of mycophenolate, a salt or a prodrug thereof, wherein the compositions are formulated to release at most about 10 % w/w of mycophenolate in an acidic medium of 0.1 NHC1, pH 1.2, comprising:
(a) Providing a core comprising mycophenolate, a salt or a prodrug thereof and one or more pharmaceutically acceptable excipients,

(b) Depositing a coating layer comprising an enteric polymers) on the said core (a),
(c) Depositing a drug coating layer comprising mycophenolate, a salt or a prodrug thereof, a film forming polymer(s) and one or more pharmaceutically acceptable excipients on the said enteric coat (b), and optionally (d) depositing a coating layer comprising a film forming polymer(s) on the said drug coating layer (c).
The present invention also provides a process for the preparation of enteric coated pharmaceutical compositions of mycophenolate, a salt or a prodrug thereof, wherein the compositions are formulated to release at most about 10 % w/w of mycophenolate in an acidic medium of 0.1 N HCI, pH 1.2, comprising:
(a) Providing a core comprising mycophenolate, a salt or a prodrug thereof and one or more pharmaceutically acceptable excipients,
(b) Depositing a coating layer comprising an enteric poiymer(s), film forming polymers) and one or more pharmaceutically acceptable excipients on the said core (a).
DETAILED DESCRIPTION OF THE INVENTION
Before the present process 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, aiJ 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 "enteric coating" as used herein means a pharmaceutical composition in which a dosage form is coated with a material to provide minimum dissolution in an acidic medium / stomach & allows complete dissolution in the small intestine.
The term "acidic medium" refers to 0.1N Hydrochloric acid (HC1) of pH-1.2 buffer solution, which is employed as in vitro dissolution medium to test the release of a drug for the first 2 hours in gastric juice / stomach.
We have now surprisingly found that pharmaceutical compositions of mycophenolate of the present invention are bioequivalent to the commercially available compositions in the

United States of America i.e. Myfortic® tablets, in spite of releasing some amount of the mycophenolate in an acidic medium / stomach.
The present invention provides enteric coated pharmaceutical compositions of mycophenolate, a salt or a prodrug thereof wherein the compositions are formulated to release at most about 10 % w/w of mycophenolate in an acidic medium of 0.1 N HC1, pH 1.2.
The present invention provides enteric coated pharmaceutical compositions of mycophenolate, a salt or a prodrug thereof, which are bioequivalent to the commercially available composition in the United States of America i e. Myfortic® tablets, wherein the compositions are formulated to release at most about 10 % w/w of mycophenolate in an acidic medium of 0.1 N HC1, pH 1.2.
The present invention provides a process for the preparation of enteric coated pharmaceutical compositions of mycophenolate, a salt or a prodrug thereof, wherein the compositions are formulated to release at most about 10 % w/w of mycophenolate in an acidic medium of 0.1 N HC1, pH 1.2, comprising:
(a) Providing a core comprising mycophenolate, a salt or a prodrug thereof and one or more pharmaceutically acceptable excipients,
(b) Depositing a coating layer comprising an enteric polymer(s) on the said core (a),
(c) Depositing a drug coating layer comprising mycophenolate, a salt or a prodrug thereof a film forming polymer(s) and one or more pharmaceutically acceptable excipients on the said enteric coat (b), and optionally (d) depositing a coating layer comprising a film forming polymer(s) on the said drug coating layer (c).
The present invention also provides a process for the preparation of enteric coated pharmaceutical compositions of mycophenolate, a salt or a prodrug thereof, wherein the compositions are formulated to release at most about 10 % w/w of mycophenolate in an acidic medium of 0.1 N HC1, pH 1.2, comprising:

(a) Providing a core comprising mycophenolate, a salt or a prodrug thereof and one or more pharmaceutically acceptable excipients,
(b) Depositing a coating layer comprising an enteric polymer(s), film forming polymer(s) and one or more pharmaceutically acceptable excipients on the said core (a).
In one of the embodiments, the present invention relates to enteric coated pharmaceutical compositions of mycophenolate, a salt or a prodrug thereof, wherein the compositions are formulated to release at most about 10 % w/w of mycophenolate in an acidic medium of 0.1 N HC1, pH 1.2, by outermost coating layer comprising drug loading or by diffusion mechanism. Without wishing to be bound by theory it is thought that "diffusion mechanism" refers to a type of passive transport (non-energy requiring) involving the movement of small molecules from an area where they are highly concentrated to an area where they are less concentrated. By adding film forming polymer(s) to aqueous enteric polymer(s), it is possible to provide pores in the coating layer due to the solubility of film formers in an acidic medium. Thus, a small amount of drug is released practically exclusively via pores by the diffusion mechanism. The above cited methods result in enteric coated pharmaceutical compositions of mycophenolate, a salt or a prodrug thereof; being formulated to release at most about 10 % w/w of mycophenolate in an acidic medium of 0.1 N HC1, pH 1.2, wherein the composition is bioequivalent to the commercially available mycophenolate tablets i.e. Myfortic®.
The term "core" is used as it is generally used in the pharmaceutical industry. The core is the innermost part, on which some layers of the different compositions are placed. The core may include tablet such as compressed tablets, spheroids, pellets and the like comprising one or more of sugar like glucose, mannitol, lactose, xylitol, dextrose, and sucrose; a non-pareil seed, macrocrystalline cellulose, celphere, sand silicon dioxide, glass, plastic, polystyrene, hydroxypropyl methylcellulose and the like and mixtures thereof. The core may be prepared by techniques such as granulation or extrusion-spheronization. The particularly preferable core of the present invention may be compressed tablets and the said core may be prepared by the methods known to a person skilled in the art.

The term "mycophenolate, a salt or a prodrug thereof refers to mycophenolic acid, any pharmaceutically acceptable salt of mycophenolic acid as mono- or disodium salt, preferably monosodium salt or a prodrug thereof like mycophenolate mofetil. A particularly preferred is mycophenolate sodium. In the present invention for pharmaceutical compositions of mycophenolate and a process for preparing thereof the therapeutic effective amount of mycophenolate, a salt or a prodrug thereof that may be used is in the range from about 10 % to about 70 % w/w, preferably from about 40 % to about 60 % w/w.
The "enteric polymer(s)" as used in the composition of the present invention may comprise a suitable pH-dependent polymer selected from a group comprising hydroxypropyl methyl cellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), polyvinyl acetyl phthalate (PVAP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), vinyl copolymers, acrylic acid and copolymers and derivatives thereof such as methacrylic acid/methyl methacrylate copolymer and the like or mixtures thereof. The polymer may be used either alone or in combination with other polymers & particularly preferable enteric polymer is hydroxypropyl methyl cellulose phthalate (HPMCP). The enteric polymer may be used in the present invention in amounts ranging from about 2 %w/w to about 30 %w/w of the composition.
The "film forming polymers)" as used in the composition of the present invention may be selected from the group comprising ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, sodium carboxy methylcellulose, methylcellulose, shellac; and the like and mixtures thereof wherein particularly preferable film forming polymer is hydroxypropyl methylcellulose in the range from about 1 % to about 10% w/w.
The present pharmaceutical compositions of mycophenolate, a salt or a prodrug thereof may include one or more pharmaceutically acceptable excipients such as diluents,

binders, disintegrants, lubricants, glidants, plasticizers, and coloring agents in the core and coating layers.
The diluent used in the composition of the present invention may be selected from powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, anhydrous 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. The diluent may be present in an amount ranging from about 5 %w/w to about 30 %w/w of the composition.
The disintegrant used in the composition of the present invention may be selected from croscarmellose sodium, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, microcrystalline cellulose, cross- linked polyvinylpyrrolidone also known as crosspovidone, sodium alginate and the like and mixtures thereof. The disintegrant may be used in an amount ranging from about 5 %w/w to about 15 %w/w of the composition.
The binder used in the composition of the present invention may be selected from hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomers, carboxymethylcellulose sodium, dextrin, methylcellulose, shellac, zein, gelatin, polymethacrylates, polyvinyl pyrrolidone, maize starch, pregelatinized starch, sodium alginate, gums, synthetic resins and the like. The binder may be present in an amount ranging from about 1 %w/w to about 30 %w/w of the composition.
The lubricant used in the composition of the present invention may be selected from metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyethylene glycols, corn starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc, and the like and mixtures thereof. The glidant used in the composition of the present invention may be selected from talc, colloidal silicon dioxide, magnesium

trisilicate, powdered cellulose, starch, tribasic calcium phosphate; and mixtures thereof. The lubricant or glidant may be present in an amount ranging from about 0.25 %w/w to about 5 %w/w of the composition.
Suitable plasticizers that may be used in the formulations of the present invention include one or more of polyethylene glycol 400, triethyl citrate, triacetin, diethyl phthalate, dibutyl sebacetate, hydrogenated vegetable oil such as lubritab, polyoxyethylene alkyl ethers such as cremophor and the like and mixtures thereof The plasticizers may be present in the composition of the present invention in an amount ranging from about 0.5 % w/w to about 15 % w/w of the coating polymer.
In one embodiment, the present invention provides a process for the preparation of enteric coated pharmaceutical compositions of mycophenolate, a salt or a prodrug there of comprising:
(a) Providing a core comprising mycophenolate, a salt or a prodrug thereof and one or more pharmaceutically acceptable excipients,
(b) Depositing a coating layer comprising an enteric polymer(s) on the said core (a),
(c) Depositing a drug coating layer comprising mycophenolate, a salt or a prodrug thereof a film forming polymer(s) and one or more pharmaceutically acceptable excipients on the said enteric coat (b), and optionally (d) depositing a coating layer comprising a film forming polymer(s) on the said drug coating layer (c), wherein the compositions are formulated to release at most about 10 % w/w of mycophenolate in an acidic medium of 0.1 N HC1, pH 1.2.
In the preferred embodiments, the said step (a) relates to the core, which is preferably a tablet prepared by compression comprising mycophenolate, a salt or a prodrug thereof and one or more pharmaceutically acceptable excipients such as diluents, binders, disintegrants, glidants and lubricants. The said step (b) comprises an enteric polymer(s) solution with one or more pharmaceutically acceptable excipients, which is sprayed on to the said core until the desired build up is achieved. The said step (c) relates to the drug coating layer comprising mycophenolate, a salt or a prodrug thereof a film forming

polymer(s) and optionally the coating layer (d) comprising a film forming polymer(s) with one or more pharmaceutically acceptable excipients like diluents, glidants or lubricant and plasticizers, which is sprayed on to the said enteric coat of step (b) until the desired build up is achieved.
In another embodiment, the present invention provides a process for the preparation of enteric coated pharmaceutical compositions of mycophenolate, a salt or a prodrug thereof, comprising:
(a) Providing a core comprising mycophenolate, a salt or a prodrug thereof and one or more pharmaceutically acceptable excipients,
(b) Depositing a coating layer comprising an enteric polymer(s), film forming polymer(s) and one or more pharmaceutically acceptable excipients on the said core (a), wherein the compositions are formulated to release at most about 10 % w/w of mycophenolate in an acidic medium of 0.1 NHC1, pH 1.2.
In the preferred embodiments, the said step (a) relates to the core, which is preferably a tablet prepared by compression comprising mycophenolate, a salt or a prodrug thereof and one or more pharmaceutically acceptable excipients such as diluents, binders, disintegrants, glidants and lubricants. The said step (b) comprises an enteric polymer(s) and film forming polymer(s) solution with one or more pharmaceutically acceptable excipients, which is sprayed on to the said core until the desired build up is achieved.
The pharmaceutical compositions as described herein may be prepared by different techniques. The core tablet may be prepared by the conventional processes such as wet granulation, dry granulation or direct compression, preferably by wet granulation. In wet granulation, mycophenolate, salt or prodrug thereof is mixed with suitable pharmaceutically acceptable excipients and granulated, followed by screening and drying of the damp mass. The dried mass may be screened, lubricated and compressed. Then the coating layer comprising the enteric polymer(s) and/or film forming polymer(s) is sprayed on to the said core until the desired build up is achieved. This process may be carried out in a coating pan wherein the cores are coated with a solution of one or more

sealant polymers. The enteric coated layer may then optionally be coated with one or more coating layers comprising the mycophenolate, salt or prodrug thereof, the film forming polymer and one or more suitable pharmaceutically acceptable excipients. This solution of the coating layer is sprayed on the enteric coated tablets again until the desired build up is achieved.
In one of the embodiments of the invention, the process can be carried out continuously in a single equipment or in another embodiment of the invention, the process is a batch process, but can be preferably carried out in a single equipment, where representative samples are sampled at the end of each stage. Appropriate equipments, such as a coating pan or a tangential spray coater can be used for manufacturing oral pharmaceutical formulation comprising mycophenolate, salt or prodrug thereof using the above process.
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
The pharmaceutical compositions of the present invention may be prepared as given in table 1.
Table 1

Name of Ingredients Quantity (Mg/Tab) Quantity
(Mg/Tab) %w/w
Mycophenolate Sodium 182 = 170.63 364 = 341.25 51.03
Lactose anhydrous 45 90 12.61
Crospovidone 32.S 65 9.67
Povidone k-30 20 40 5.60
Maize starch 10.25 20.5 2.87
Aerosil 7 14 1.96
Mg Stearate 3.25 6.5 0.91
Total 300mg 600 ms 84.11

Enteric coating
HPMCP 26.4 52.8 7.4
Platicizer (PEG/Dia cetylated monoglyceride) 2.64 5.28 0.74
Talc 3.96 7.92 1.11
IPA q.s q.s
DCM q.s q.s
Total 333 mg 666 mg 93.36
Drug loading
Mycophenolate Sodium 10 20 2.8
HPMC 5 10 1.4
PEG 400 0.5 1 0.14
talc 1.15 2.3 0.32
Total 351.65 mg 703-30 mg 98.03
Film coating 7 14 1.55
Total tablet wt 356.65 mg 713.30 mg 100
The pharmaceutical composition comprising mycophenolate, salt or prodrug thereof is prepared by a process as follows:
Core tablet:
All raw materials were sifted through 40 #. The Mycophenolate Sodium and acrosil were
mixed intra granulalry for 10 minutes in RMG. This blend was granulated by a solution
of povidone prepared in required quantity of ethanol The wet mass was dried at 45°C for
30 minutes till the LOD reached less than 2%w/w. Then extra granular excipients like
lactose, crospovidone and maize starch were mixed with obtained granules for 25
minutes. The above blend was compressed using 16.9mm-8.2mm punch.
Enteric coating:
Enteric polymer HPMCP was dissolved in ethanol & acetone (1; 1) solution under stirring
to get a dear solution, to this clear solution plasticizer PEG 400, talc. The resulting
solution was sprayed on the compressed tablets until desired build up was achieved.
Drug Loading:
HPMC was dissolved in water under stirring to get a clear solution. To this clear solution
Mycophenolate Sodium, plasticizer PEG 400 & talc were added. The resulting solution
was sprayed on the enteric coated tablets until desired build up was achieved.
Film Coating:

HPMC was dissolved in water under stirring to get a clear solution. To this clear solution suitable color, plasticizer & talc were added. The resulting solution was sprayed on the drug loading layer until desired build up was achieved.
EXAMPLE-2
The pharmaceutical compositions of the present invention may be prepared as given in table 2.
Table 2

Name of Ingredients Quantity (Mg/Tab) Quantity (Mg/Tab) % w/w
Mycophenolate Sodium 192.4-180 384.8= 360 52.85
Lactose anhydrous 45 90 12.36
Crospovidone 32.5 65 8.92
Povidone k-30 20 40 5.49
Maize starch 10.25 20.5 2.81
Aerosil 6.6 13.2 1.813
Mg stearate 3.25 6.5 0.892
Total 310 mg 620 mg 85.16
Enteric coating
HPMCP 33 66 9.06
HPMC 16.5 33 4.53
PEG 2.475 4.95 0.679
Talc 2.025 4.05 0.556
IPA q.s q.s
DCP q.s q.s
Enteric coating 54 108 14.83
Total tablet wt 364 mg 728 mg 100
The pharmaceutical composition comprising mycophenolate, salt or prodrug thereof is prepared by a process as per the process given in example 1. However, this process did not use drug loading and film coating layer, instead for enteric coating, enteric polymer HPMCP dissolved in IPA, film forming polymer HPMC were mixed with dibasic

calcium phosphate, plasticizer PEG 400 & talc. The resulting solution was sprayed on the compressed tablets until desired build up was achieved.
EXAMPLE-3
The pharmaceutical compositions of the present invention may be prepared as given in table 3.
Table 3

Ingredients mg/tab % w/w
Intra Granular
Mycophenolate sodium 364.8 48.64
Colloidal silicon dioxide 13.2 1.76
povidone K 30 25 3.33
Crospovidone 20 2.67
Ethanol q.s
Extra granular
Corn starch 25.5 3.4
lactose monohydrate 90 12
Crospovidone 55 7.33
magnesium stearate 6.5 0.87
Total core 600
Enteric coating
HPMCP HP-50 65 8.67
Triethyl citrate 6 0.8
Acetone q.s
IPA q.s
Total weight 671
Drug coating
Mycophenolate sodium 20 2.67
povidone K 30 5 0.67
Crospovidone 35 4.67
Talc 5 0.67
Ethanol q.s
Total weight 736
Film coating
Opadry pink 14 1.87
water q.s
Total weight 750 100 |

The pharmaceutical compositions of the present invention may be prepared by the process given below;
Core tablet mfg:
1. All the intra granular material were sifted and granulated with Ethanol in RMG.
2. The granulated material was dried in fluid bed drier till the required LOD was achieved (LOD; 1.5 to 3.0%).
3. The dried granules were sifted through 20 mesh and the retails were milled through multimill using 1mm screen and sifted through 20 mesh.
4. The granules of step3 were mixed with extra granular material except magnesium stearate and blended for 30 minutes.
5. Magnesium stearate was added to the granules prepared above and blended for another 5 minutes.
6. The tablets were compressed using suitable punches.
Enteric coating:
1. The HPMCP was dissolved in acctonc/IPA mixture and stirred till a clear solution was obtained.
2. To the above solution, triethyl citrate was added and stirred for another five minutes.
3. The solution prepared above was coated on to the core tablets till 71 mg build up was achieved.
Drug coating:
1. The required quantity of povidone was dissolved in ethanol and stirred till a clear solution was achieved.
2. To the above solution was added, mycophenolate sodium, talc and crospovidone and the entire dispersion was passed through a colloidal mill.
3. The above dispersion was coated on the tablet till 65 mg build up was achieved.

Film coating:
1. The coating material was dispersed in water and stirred for 45 min.
2. The above dispersion was filtered.
3. The above dispersion was coated on to the tablets till 14 mg build up was achieved.
Dissolution data:
The composition of example 3 was subjected to dissolution testing. The results are given in table 4.
Table 4
Dissolution data:
Media: 0.1 N HC1 (Acid stage)
Volume: 750 ml
Appratus: Paddle
Speed: 50 rpm

Time tab-1 tab-2 tab-3 Mean
2hr 3 2.5 2.5 2.7
Media: 6.8 pH (Buffer stage)
Volume: 750 ml
Appratus. Paddle
Speed: 50 rpm

Time tab-1 tab-2 tab-3 Mean
60 min 92.1 104.8 93.1 96.7
Thus the composition showed a release of less than 10% mycophenolate in 0.1N HC1
Stability data:
The composition of example 3 was subjected to stability testing at accelerated conditions. The results are given in table 5.
Table 5

stability Initial 40°C/75% RH
1M 2M 3M

Assay 102.33 103.59 101.57 103.49
Related substances
Single highest 0.046 0.045 0.043 0.045
Total 0.128 0.147 0.127 0.129
The results show that the composition of example 3 was stable.
Bio-Equivalence study:
The composition prepared in example 3 above, was subjected to bioequivalence studies. An open label, two way crossover comparative bioavailability of the composition of the present invention i.e. composition of example 360 mg vs Myfortic of Novartis, United States of America under fasting conditions was carried out.
Study design: A balanced, open label, randomized, two-treatment, two-period, two sequence, single dose, crossover comparative bioavailability study under fasting conditions.
Study duration: Approximately 7 days including a washout period of at least 5 days between the two periods.
Investigational products: The test product was the Mycophenolate acid delayed release tablet composition of the present invention (Mycophenolic acid delayed release tablet 360 mg) prepared in example 3, whereas the Reference product was Myfortic (Mycophenolic acid delayed release tablet 360 mg) tablets.
Number of subjects: 14 healthy adult, human subjects
Drug administration: After an overnight fast of at least 10 hours, subjects were dosed in sitting posture with 240ml of water at ambient temperature. In each study period a single dose of Mycophenolate acid delayed release tablet 360 mg was administered to the subjects. Subjects receiving the test product in one study period received the reference product (Myfortic 360 mg) in the other period.

Blood Sample Collection: 0.0, 0.16, 0.33, 0.5, 0.67, 0.83, 1.0, 1.25, 1.5, 2, 4, 4, 6, 8, 12, 16, 24, 36, 48, hours.
Plasma samples of all the subjects completing the study were analyzed and the same were used in pharmacokinetic and statistical study.
The results of the above bioequivaience studies at fasting condition are given in below Table 6.
Table 6

PARAMETER T/R C.I Lower C.I_Upper
C max 81.0 80.0 94.0
AUC(0-t) 106.0 100.0 111.0
AUC(0-α) 98.0 95.0 118.0
It can be seen that the composition of the present invention is bioequivalent to the commercially available Myfortic tablet in the United States of America.
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 preferred by way of example to facilitate comprehension of the invention and should not be construed to limit the scope thereof

We claim:
1. Enteric coated pharmaceutical compositions of mycophenolate, a salt or a prodrug thereof, wherein the compositions are formulated to release at most about 10%w/w of mycophenolate in an acidic medium of 0.1 N HO, pH 1.2.
2. Enteric coated pharmaceutical compositions as in claim 1, which are bioequivalent to the commercially available composition in the United States of America i.e. Myfortic® tablets.
3. Enteric coated pharmaceutical compositions as in claim 1, wherein the enteric polymer(s) is selected from a group comprising hydroxypropyl methyl cellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), polyvinyl acetyl phthalate (PVAP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), vinyl copolymers, acrylic acid and copolymers and derivatives thereof such as methacrylic acid/methyl methacrylate copolymer and me like or mixtures thereof.
4. A process for the preparation of enteric coated pharmaceutical compositions of mycophenolate, a salt or a prodrug thereof wherein the compositions are formulated to release at most about 10 % w/w of mycophenolate in an acidic medium of 0.1 N HC1, pH 1.2, comprising:

(a) Providing a core comprising mycophenolate, a salt or a prodrug thereof and one or more pharmaceutically acceptable excipients,
(b) Depositing a coating layer comprising an enteric polymer(s) on the said core (a),

(c) Depositing a drug coating layer comprising mycophenolate, a salt or a prodrug thereof, a film forming polymer(s) and one or more pharmaceutically acceptable excipients on the said enteric coat (b), and optionally (d) depositing a coating layer comprising a film forming polymer(s) on the said drug coating layer (c).