CLIAMS:We Claim-

1. An oral delayed release pharmaceutical composition comprising less than of about 45% of mycophenolic acid or salts by total weight of composition, lactose and microcrystalline cellulose (MCC) and one or more pharmaceutically acceptable excipients; wherein the ratio of the amount of lactose to MCC is in the range of about 1.0: 6.0 to about 6.0: 1.0.

2. The oral delayed release pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable excipients comprise one or more delayed release polymers.

3. The oral delayed release pharmaceutical composition of claim 2, wherein the delayed release polymer comprises water soluble polymer and water insoluble polymer.

4. The oral delayed release pharmaceutical composition of claim 2, wherein the delayed release polymer is present in the form of a coating or in the matrix.

5. The oral delayed release pharmaceutical composition of claim 1, wherein the composition is in the form a tablet or a capsule.

6. The oral delayed release pharmaceutical composition of claim 1, wherein the composition retains at least 90% potency of mycophenolic acid or salts thereof in the when stored at 400C and 25% relative humidity for 3 months.

7. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable excipients comprise diluent, binder, disintegrant, glidant, lubricant, and others.

8. Use of the delayed pharmaceutical composition of claim 1 for the preparation of medicament for preventing/treating of organ rejection in patients receiving allogeneic renal transplants.

Dated this 26th day of March 2013 For Wockhardt Limited

(Dr. Mandar Kodgule)
Authorized Signatory
,TagSPECI:Description

The present invention relates to a delayed release pharmaceutical composition comprising less than of about 45% of mycophenolic acid or salts by total weight of composition and one or more pharmaceutically acceptable excipients. The invention also includes process of preparing such composition and their use in prophylaxis of organ rejection in patients receiving allogeneic renal transplants.

Mycophenolic acid (MPA) is an immunosuppressive agent. Mycophenolic acid was first isolated in the 19th century and has reported activity as an anti-tumor, anti-viral, immunosuppressive, anti-psoriatic, and anti-inflammatory agent. As the sodium salt, MPA is chemically designated as (E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoic acid sodium salt and has the following structural formula:

Mycophenolic acid has poor bioavailability caused by undetermined factors such as drug complexation in the gastro-intestinal lumen, a narrow absorption window, and metabolism before absorption etc. Thus the morpholinoethyl ester of mycophenolic acid was prepared known as mycophenolate mofetil (MMF) which have considerable higher bioavailability than MPA (100% for MMF and 43% for MPA). However, the patient compliance with mycophenolate mofetil is not ideal because of side-effects, such as gastro-intestinal side effects, which has resulted in development of various delayed release formulations that by passes the stomach environment.

Further, mycophenolic acid as the sodium salt is a white to off-white, crystalline powder and is highly soluble in aqueous media at physiological pH and practically insoluble in 0.1 N hydrochloric acid.

As a consequence of the above solubility, the mycophenolate sodium has a tendency to precipitate in the stomach due to acidic environment. Consequently, this precipitation adversely affects the bioavailability of the active ingredient. It is therefore desirable that dissolution of mycophenolate compositions is prevented in the stomach and instead dissolution is delayed until the intestine in which the pH is more basic.

Thus, it has been necessary to develop pharmaceutical compositions comprising a mycophenolate salt that prevents release of the active ingredient in the stomach and instead provides it release in the upper intestinal tract.

Mycophenolic acid as delayed release formulation comprising mycophenolate sodium was approved in United States. It is commercially available in 180 mg or 360 mg strengths under the proprietary name Myfortic® and marketed by Novartis.

Myfortic® is indicated for the prophylaxis of organ rejection in patients receiving allogeneic renal transplants, administered in combination with cyclosporine and corticosteroids.

The sodium salt of mycophenolic acid was disclosed specifically in first time in South African Patent 68/4959.

U.S. Patent No. 6,025,391 discloses pharmaceutical compositions which have been modified to release pharmaceutically acceptable mycophenolate salt in the upper part of the intestinal tract. The patent discloses a composition comprising an enteric coated pharmaceutically acceptable mycophenolate salt. The patent further exemplifies an enteric coated capsule containing mycophenolate sodium particles mixed with silicon dioxide, lactose and magnesium stearate.

U.S. Patent No. 6,172,107 & 6,306,900 discloses a pharmaceutical composition comprising a mycophenolate salt, the composition being adopted to release mycophenolate in the upper part of the intestinal tract. The delayed release of the active ingredient is provided by compositions having an enteric coating.

PCT Publication No. WO 2007/093346 discloses the use of mycophenolic acid in immunosuppression, particularly for prevention or treatment of transplant rejection and immuno-mediated and/or inflammatory diseases, wherein mycophenolic acid, the salt or the prodrug thereof is administered with an initial intensified dosage regimen. The application also discloses an enteric coated composition of mycophenolate, or a salt or a prodrug thereof.

PCT Publication No. WO 2009/047799 discloses high dose extended release pharmaceutical compositions comprising mycophenolate sodium as active agent in an amount of from greater than 720 mg to about 1500 mg and one or more pharmaceutically acceptable excipients. The dosage forms are meant for once or twice a day administration and provide in-vivo release of the drug in a sustained manner for a prolonged duration.

US Patent publication No. 20100210717 discloses a solid dosage form, e.g. a tablet, comprising mycophenolic acid or a mycophenolate salt and a process of its production. The application discloses both accelerated and delayed release compositions. The application further discloses enteric coated tablets comprising a pharmacologically effective amount of mycophenolic acid or mycophenolate salt present in an amount of from about 20% to about 95% by weight based on the total weight of the tablet.

US Patent publication No. 20110086102 discloses a matrix controlled delayed release pharmaceutical composition comprising an active pharmaceutical ingredient including mycophenolic acid, or its pharmaceutically acceptable salt, or combinations thereof. The composition disclosed in the application does not contain enteric coating.

Attempts have been made in the arts to prevent dissolution of mycophenolate compositions in the stomach, and provide release of mycophenolate in the upper part of the intestinal tract, mainly by employing either enteric coating or by formulating the dosage form in the form of a delayed release providing matrix.

Further the nature of pharmaceutically acceptable excipients or their amount used in such composition may have significant effect on the release profile of the drug from the dosage form.

Thus, there still exists an enduring need to develop an improved delayed release pharmaceutical composition of mycophenolic acid or pharmaceutically acceptable salt thereof which can provide an alternative to existing formulation of mycophenolic acid and exhibit desired release profile.

The inventors of the present invention have surprisingly found that by using less than of about 45% of mycophenolic acid or salts thereof by total weight of composition and certain pharmaceutically acceptable excipients in legitimate amount, the delayed release dosage form of mycophenolate or its salt with desired release profile can be prepared.

In particular, the inventors have found that by using less than of about 45% of mycophenolic acid or salts thereof by total weight of composition and lactose to microcrystalline cellulose (MCC) in the amount ratio of about 1.0: 6.0 to about 6.0: 1.0; the pharmaceutical composition being well tolerated, convenient to administer, achieves the desired dissolution parameters and provides the desired release profile.

In one general aspect, there is provided an oral delayed release pharmaceutical composition comprising less than of about 45% of mycophenolic acid or salts by total weight of composition and one or more pharmaceutically acceptable excipients.

In another general aspect, there is provided an oral delayed release pharmaceutical composition comprising less than of about 45% of mycophenolic acid or salts by total weight of composition, lactose and microcrystalline cellulose (MCC); wherein the ratio of the amount of lactose to MCC is in the range of about 1.0: 6.0 to about 6.0: 1.0.

In another general aspect, there is provided an oral delayed release pharmaceutical composition comprising less than of about 45% of mycophenolic acid or salts by total weight of composition, lactose and microcrystalline cellulose (MCC); wherein the ratio of the amount of lactose to MCC is in the range of about 1.0: 6.0 to about 6.0: 1.0 and the composition achieves the desired dissolution profile.

In another general aspect, there is provided an oral delayed release pharmaceutical composition of mycophenolic acid or salts thereof comprising lactose and microcrystalline cellulose (MCC), and one or more pharmaceutically acceptable excipients, wherein the ratio of the amount of lactose to MCC is in the range of about 1.0: 6.0 to about 6.0: 1.0 and the composition achieves the desired dissolution profile.

In another general aspect, there is provided an oral delayed release tablet comprising less than of about 45% of mycophenolic acid or salts by total weight of composition, lactose and microcrystalline cellulose (MCC); wherein the ratio of the amount of lactose to MCC is in the range of about 1.0: 6.0 to about 6.0: 1.0 and the composition achieves the desired dissolution profile.

In another general aspect, there is provided an oral delayed release capsule comprising less than of about 45% of mycophenolic acid or salts by total weight of composition, lactose and microcrystalline cellulose (MCC); wherein the ratio of the amount of lactose to MCC is in the range of about 1.0: 6.0 to about 6.0: 1.0 and the composition achieves the desired dissolution profile.

In another general aspect, there is provided an oral delayed release pharmaceutical composition comprising less than of about 45% of mycophenolic acid or salts by total weight of composition and one or more pharmaceutically acceptable excipients, characterized that the composition is bioequivalent to delayed release formulation of mycophenolic acid marketed under the trade name Myfortic®.

In another general aspect, there is provided an oral pharmaceutical composition of mycophenolic acid or salts thereof comprising less than of about 45% of mycophenolic acid or salts by total weight of composition, characterized that the composition retains at least 90% potency of mycophenolic acid or salts thereof when stored at 25°C and 40% relative humidity or at 400C and 25% relative humidity for 3 months.

In another general aspect, there is provided a process for the preparation of an oral pharmaceutical composition of mycophenolic acid or salts thereof, which process comprises mixing of mycophenolic acid or salts thereof with one or more pharmaceutically acceptable excipients, subjecting the obtained blend for granulation and compression to form tablet followed by coating with delayed release polymer.

In another general aspect, there is provided a process for the preparation of an oral pharmaceutical composition of mycophenolic acid or salts thereof, which process comprises mixing of mycophenolic acid or salts thereof with one or more pharmaceutically acceptable excipients intra-granularly and extra-granularly, subjecting the obtained blend for granulation and compression to form tablet followed by coating with delayed release polymers.

In another general aspect, there is provided an oral pharmaceutical composition comprising composition comprising less than of about 45% of mycophenolic acid or salts by total weight of composition and one or more pharmaceutically acceptable excipients, used for the prophylaxis / treatment of organ rejection in patients receiving allogeneic renal transplants, administered in combination with cyclosporine and corticosteroids.

The term "delayed release", as used herein, comprises any pharmaceutically acceptable composition that prevents the release of the active agent in the stomach and provides, preferably in the upper part of the intestinal tract and allows the resorption of the active agent through the walls of the intestinal tract.

The term “mycophenolic acid” used throughout the specification refers to not only mycophenolic acid per se, but also mycophenolate sodium salts, other pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof. The active pharmaceutical ingredient, in the context of the present invention is selected from the group comprising mycophenolic acid, a pharmaceutically acceptable salt thereof and combinations thereof, such as mycophenolate sodium or mycophenolate mofetyl. Most preferably, the active pharmaceutical ingredient is mycophenolate sodium.

The pharmaceutical composition of the present invention are described with particular reference to tablets, other types of oral solid dosage forms but not limited effervescent tablets, fast dispersible tablets, matrix tablets, minitablets, multilayer tablets, pulsed release tablets, pellets, capsules, granulates or powder form, may be produced and are encompassed within the scope of this invention.

The pharmaceutical compositions of the present invention can be prepared by any conventional process. The compositions can be prepared by conventional granulation techniques such as wet granulation or direct compression or dry granulation. Preferably, the compositions are prepared using wet granulation.

In one embodiment of the invention in which the pharmaceutical composition is a tablet the invention provides a process for preparing a pharmaceutical composition of the invention comprising: (i) mixing the mycophenolic acid or mycophenolate salt and pharmaceutically acceptable excipients, (ii) subjecting a mixture obtained in step (i) to granulation (iii) compressing the granulates obtained in step (ii) and pharmaceutically acceptable additives to form the tablet. The obtained tablets were coated with delayed release polymers.

The polymer used for modifying the release of mycophenolic acid or salts thereof includes but not limited to water soluble or water insoluble polymer. The delayed release polymer comprises but not limited to cellulose ester derivatives, cellulose ethers, acrylic resins such as methylacrylate copolymers, copolymers of maleic acid and phthalic acid derivatives, shellac, hydroxypropylmethylcellulose acetate succinate, or polyvinylacetate phthalate.

Representative examples of delayed release polymer comprises but not limited to cellulose acetate phthalate and trimellitate; methacrylic acid copolymers derived from methacrylic acid and esters thereof and especially hydroxypropyl methylcellulose phthalate.

Polymethacrylates include but not limited to those of molecular weight above 100,000 daltons based on methacrylic acid and methyl or ethyl methacrylate in a ratio of about 1:1.

Typical cellulose acetate phthalates have an acetyl content of 17-26% and a phthalate content of from 30-40% with a viscosity of ca. 45-90 cP.

Typical cellulose acetate trimellitates have an acetyl content of 17-26%, trimellityl content from 25-35% with a viscosity of ca. 15-20 cS.

Examples of suitable hydroxypropyl methylcellulose phthalates (HPMCP) are the hydroxypropyl content of from 6-10%, a methoxy content of from 20-24%, a phthalyl content of from 21-27%.

The delayed release polymers as per the present invention may be present in the form of a coating or in the matrix.

Suitable solvents for the delayed release coating includes but not limited to aqueous solvents, organic solvents or mixture thereof. Examples of suitable organic solvents alcohol such as ethanol or a mixture of alcohols, a ketone such as acetone, halogenated hydrocarbons for example methylene chloride or mixtures of such solvents, example ethanol/acetone.

The term "pharmaceutically acceptable excipients" includes a pharmaceutically acceptable material, composition or vehicle, suitable for administering an active pharmaceutical ingredient. Each excipient should be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Excipients include diluents, binders, disintegrants, glidants, lubricants, flavoring, and others.

Diluents increase the bulk of a solid pharmaceutical composition. Exemplary diluents for solid compositions include, but are not limited to, microcrystalline cellulose, microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates, potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.

Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Exemplary binders for solid pharmaceutical compositions include, but are not limited to, acacia, alginic acid, carbomer, carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone, pregelatinized starch, sodium alginate and starch.

Disintegrants increase the dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach, for example. Exemplary disintegrants include, but are not limited to alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate and starch.

Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Exemplary excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.

A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Exemplary lubricants include, but are not limited to, magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Example 1:
Sr. No. Ingredients mg/tab (360 mg) Percentage(%)
Tablet (Uncoated core)
1 Mycophenolate sodium 384.70 39.58
2 Lactose anhydrous 180.30 18.55
3 Microcrystalline cellulose 138.00 14.19
4 Pregelatinised starch 80.00 8.23
5 Crospovidone 72.00 7.41
6 Povidone K 30 27.00 2.78
7 Isopropyl Alcohol : Methylene chloride (1:1) q. s.
8 Crospovidone 45.00 4.63
9 Colloidal silicon dioxide 9.00 0.93
10 Magnesium stearate 9.00 0.93
Total (core tab) 900.00
Coating
11 HPMC Phthalate 63.30 6.51
12 Iron oxide Red 0.40 0.04
13 Iron oxide Yellow 0.40 0.04
14 FD&C blue no. 2 (Indigocarmine lake) 0 0
15 Titanium dioxide 3.50 0.36
16 Triethyl Citrate 4.40 0.45
17 MDC:IPA (1:1 w/w) q. s.
Total 972.00 100.0

Process:
The mycophenolate sodium, lactose anhydrous, pregelatinised starch, crospovidone & microcrystalline cellulose were Co-sifted through suitable sieve & mixed. Binder solution was prepared by dissolving the povidone in mixture of Isopropyl alcohol & methylene chloride and mixed with previously obtained blend. The obtained wet mass formed was dried in achieve loss on drying (LOD) below 2 %. Dried granules were again passed through suitable mesh. The obtained granules were lubricated with previously sieved magnesium stearate and then compressed into tablets. The obtained uncoated tablets were finally coated with hydroxyl propylmethyl cellulose pthalate.

Example 2:
Sr. No. Ingredients mg/tab (360 mg) Percentage(%)
Tablet (Uncoated core)
Intragranular
1 Mycophenolate sodium 384.70 39.58
2 Lactose anhydrous 180.30 18.55
3 Microcrystalline cellulose 78.00 8.02
4 Pregelatinised starch 80.00 8.23
5 Crospovidone 27.00 2.78
6 Povidone K 30 27.00 2.78
7 Isopropyl Alcohol : Methylene chloride (1:1) q. s.
Extragranular
8 Microcrystalline cellulose 60.00 6.17
9 Crospovidone 45.00 4.63
10 Colloidal silicon dioxide 9.00 0.93
11 Magnesium stearate 9.00 0.93
Total (core tab) 900.00
Coating
12 HPMC Pthalate 63.30 6.51
13 Iron oxide Red 0.40 0.04
14 Iron oxide Yellow 0.40 0.04
15 FD&C blue no. 2 (Indigocarmine lake) 0 0
16 Titanium dioxide 3.50 0.36
17 Triethyl Citrate 4.40 0.45
18 MDC:IPA (1:1 w/w) q. s.
Total (coated tab) 972.00 100.0

Process:
The mycophenolate sodium, lactose anhydrous, pregelatinised starch, crospovidone & microcrystalline cellulose were Co-sifted through suitable sieve & mixed. Binder solution was prepared by dissolving the povidone in mixture of Isopropyl alcohol & methylene chloride and mixed with previously obtained blend. The obtained wet mass formed was dried in achieve loss on drying (LOD) below 2 %. Dried granules were again passed through suitable mesh. The microcrystalline cellulose, crospovidone and colloidal silicon dioxide were passed through suitable mesh and mixed extra granularly with intragranular formed granules. The obtained granules were lubricated with previously sieved magnesium stearate and then compressed into tablets. The obtained uncoated tablets were finally coated with hydroxyl propylmethyl cellulose pthalate.

Example 3:

Sr. No. Ingredients mg/tab
Intragranular
1 Mycophenolate sodium 384.70
2 Lactose anhydrous 90.00
3 Microcrystalline cellulose 108.30
4 Pregelatinised starch 80.00
5 Crospovidone 27.00
6 Povidone K 30 27.00
7 Isopropyl Alcohol :Methylene chloride (1:1) q. s.
Extragranular
8 Microcrystalline cellulose 120.00
9 Crospovidone 45.00
10 Colloidal silicon dioxide 9.00
11 Magnesium stearate 9.00
Total (core tab) 900.00
Coating
12 HPMC Pthalate (HP 55) 63.30
13 Iron oxide Red 0.40
14 Iron oxide Yellow 0.40
15 Titanium dioxide 3.50
16 Triethyl Citrate 4.40
17 MDC:IPA (1:1 w/w) q. s.
Total (coated tab) 972.00

Process:
The mycophenolate sodium, lactose anhydrous, pregelatinised starch, crospovidone & microcrystalline cellulose were Co-sifted through suitable sieve & mixed. Binder solution was prepared by dissolving the povidone in mixture of Isopropyl alcohol & methylene chloride and mixed with previously obtained blend. The obtained wet mass formed was dried in achieve loss on drying (LOD) below 2 %. Dried granules were again passed through suitable mesh. The obtained granules were lubricated with previously sieved magnesium stearate and then compressed into tablets. The obtained uncoated tablets were finally coated with hydroxyl propylmethyl cellulose pthalate.

Example 4:
Sr. No. Ingredients mg/tab
Intragranular
1 Mycophenolate sodium 384.70
2 Lactose anhydrous 45.00
3 Microcrystalline cellulose 198.30
4 Pregelatinised starch 80.00
5 Crospovidone 27.00
6 Povidone K 30 27.00
7 Isopropyl Alcohol :Methylene chloride (1:1) q. s.
Extragranular
8 Microcrystalline cellulose 75.00
9 Crospovidone 45.00
10 Colloidal silicon dioxide 9.00
11 Magnesium stearate 9.00
Total (core tab) 900.00
Coating
12 HPMC Pthalate 63.30
13 Iron oxide Red 0.40
14 Iron oxide Yellow 0.40
15 Titanium dioxide 3.50
16 Triethyl Citrate 4.40
17 MDC:IPA (1:1 w/w) q. s.
Total (coated tab) 972.00

Process:
The mycophenolate sodium, lactose anhydrous, pregelatinised starch, crospovidone & microcrystalline cellulose were Co-sifted through suitable sieve & mixed. Binder solution was prepared by dissolving the povidone in mixture of Isopropyl alcohol & methylene chloride and mixed with previously obtained blend. The obtained wet mass formed was dried in achieve loss on drying (LOD) below 2 %. Dried granules were again passed through suitable mesh. The obtained granules were lubricated with previously sieved magnesium stearate and then compressed into tablets. The obtained uncoated tablets were finally coated with hydroxyl propylmethyl cellulose pthalate.