WO2011051967A2

WO2011051967A2 - Pharmaceutical compositions comprising mycophenolate and processes for preparing thereof

Info

Publication number: WO2011051967A2
Application number: PCT/IN2010/000688
Authority: WO
Inventors: Arun Prasad; Krishna Prasad; Vermula Sathyanarayana; Ashok Rampal
Original assignee: Alkem Laboratories Ltd
Priority date: 2009-10-23
Filing date: 2010-10-22
Publication date: 2011-05-05
Also published as: WO2011051967A3

Abstract

The present invention relates to a process for preparing 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.

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING YCOPH ENOLATE

AND PROCESSES FOR PREPARING THEREOF

FIELD OF THE INVENTION

The present invention relates to pharmaceutical compositions of mycophenoiate, a salt or a prodrug thereof and processes for preparing thereof

BACKGROUND OF THE INVENTION

Mycophenolic acid (MPA) or mycophenoiate is derived from the fungus Penicilhum stoioniferum. Mycophenoiate is an immunosuppressant drug used for the prophylaxis of organ rejection in patients receiving allogenic renal transplants. It was initially marketed as the prodrug mycophenoiate mofetil (MMF) to improve oral bioavailability. Mycophenoiate mofetil is metabolised in the liver to the active moiety mycophenolic acid. More recently, the salt, mycophenoiate sodium has been introduced.

Mycophenoiate sodium, a mycophenolic acid prodrug, is an inhibitor of T-fymphocyte proliferation. Its chemical name is sodium (E)-6-{4-faydroxy-6-methoxy-7-methyl-3-oxo- lH-2-benzofuran-5-yl)-4-metiiyIhex-4-enoate with molecular formula of C^H^ aOe & molecular weight of 342.31893 [g molj. 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, mycophenoiate 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

l 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. US20050013859A1 relates to ah enteric coated solid dosage form, e.g. a tablet, comprising myeophenofic 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 includ ng 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 mycophenoiate in an acidic medium / stomach.

OBJECT OF THE INVENTION

It is an object of the present invention to provide phannaceutical compositions of mycophenoiate, 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 mycophenoiate, a salt or a prodrug thereof, wherein the compositions are formulated to release at most about 10 % w/w of mycophenoiate in an acidic medium of Ο.Ι ΗΟ, ρΗ Ι.2. It is yet .another object of the present invention to provide enteric coated pharmaceutical compositions of mycophenoiate, a salt or a prodrug thereof, which arc bioequivalent to the commercially available compositions in the United States of America i.e. Myfortic® tablets, wherein the compositions are fonnulated to release at most about 10 % w/w of mycophenoiate in an acidic medium of 0.1 N HC1, pH 1.2.

SUMMARY OF THE INVENTION

The present invention provides enteric coated pharmaceutical compositions of mycophenoiate, a salt or a prodrug thereof, wherein the compositions are formulated to release at most about 10 % w/w of mycophenoiate in an acidic medium of 0.1 N HCL, pH 1.2.

The present invention provides enteric coated pharmaceutical compositions of mycophenoiate, 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 HCl, pH 1.2, comprising;

(b) Depositing a coating layer comprising an enteric polymer s), film forming poIymer(s) 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, 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 "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 NHCI, pH 1.2.

The present invention provides a process for tie 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 mycopheno!ate, 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:

(b) Depositing a coating layer comprising an enteric poiymer(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 HCI, 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 HCI, 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, microcrystalline 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 polymer(s)" as used in the composition of the present invention may be selected from the group comprising ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, sodium carboxymethylcellulose, 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 giycolate, 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 I %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, tri basic 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 thereof, comprising:

(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:

(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 N HCL, 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 sard 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, sah 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 coaler 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

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 aerosil 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 clear 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 !

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

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 a eione/ίΡΑ mixture and stirred till a clear solution was obtained. 2. To the above solution, triethyl citrate was added and stirred for another five TfnTiutes.

3. The solution prepared above was coated on to the core tablets till 7i 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 HCi (Acid stage)

Volume: 750 ml

Appratus: Paddle

Speed: 50 rpm

Media: 6. § pH (Buffer stage)

Volume: 750 ml

Appratus: Paddle Speed: 50 rpm

Thus the composition showed a release of less , than 10% mycophenolate in 0. IN HCI

Stability data:

The composition of example 3 was subjected to stability testing at accelerated conditions. The results are given in table 5.

Table 5

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_s 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 bioequivalence studies at fasting condition are given in below Table 6.

Table 6

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.

Claims

Claims:

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 HC1, 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 the like or mixtures thereof.

4. A process for the preparation of enteric coated pharmaceutical compositions of mycophenolate, a salt or a prodrug thereof, wherem the compositions are formulated to release at most about 10 % w w of mycophenolate in an acidic medium of 0.1 N ΗΟ,ρΗ 1.2, comprising:

(b) Depositing a coating layer comprising an enteric polymer(s) on the said core (a), (c) Depositing a drug coating layer comprising mycophenoiate, 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).