Technical Field of the Invention
The present invention relates to solid oral dosage forms comprising granules of mycophenolate mofetil, the said granules having increased bulk density. The invention also discloses process for preparation of such granules and solid dosage forms therefrom.
Background of the Invention
Mycophenolate mofetil, the morpholinoethyl ester of mycophenolic acid, chemically designated as 2-morpholinoethyl (E) - 6- (1, 3- dihydro - 4 - hydroxy - 6 - methoxy - 7 -methyl - 3 - oxo - 5 - isobenzofuranyl) - 4 - methyl - 4 -hexenoate is an inosine monophosphate dehydrogenase (IMPDH) inhibitor. It is rapidly absorbed after oral administration and is hydrolyzed to its active metabolite, mycophenolic acid. Mycophenolic acid is a potent, selective, uncompetitive and reversible inhibitor of IMPDH, and therefore inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation into DNA. Mycophenolate mofetil has been disclosed in US Patent Numbers 4,753,935; 4,786,637; 4,808,592; 4,868,153; 4,948,793; 4,952,579 and 4,992,467. These patents also relate to the use of mycophenolate mofetil in anti-tumour, immunosuppressive, autoimmune, anti-viral, anti-arthritic and/or anti-psoriatic activities. Mycophenolate mofetil is indicated for use in the prophylaxis of organ rejection in patients receiving allogeneic renal, cardiac or hepatic transplants and should be administered concomitantly with cyclosporine and corticosteroids.
Presently, Roche Pharmaceuticals Inc., USA commercializes Mycophenolate mofetil in the United States of America and other countries under the brand name CELLCEPT® as 500mg tablet, 250mg capsule and 200 mg/mL suspension. Although a diverse range of dosage form of mycophenolate mofetil has been widely marketed, the low bulk density and inherent fluffiness of the drug substance has always been a drawback from the manufacturing point of view as it leads to difficulty in handling, increased chances of fine generation leading to cross-contamination and higher degree of variation in content uniformity. The US Patent Number 5,688,529 discusses a high dose suspension formulation of mycophenolate mofetil, wherein granules or powder blend formulation of mycophenolate mofetil is prepared for constitution with water to give a high dose oral suspension. Nonetheless, solid dosage forms have been more popular and preferred over liquid dosage forms, owing to ease of handling, accurate dosing as well as due to patient compliance and also from the stability point of view. Solid dosage forms comprising mycophenolate mofetil have also been described in the art. The US Patent Numbers 5,455,045 and 5,554,384 describe high dose formulations and

processes of manufacturing of pharmaceutical formulations containing mycophenolate mofetil, wherein the drug substance is melted into a liquid at above its melting point, then supercooled and finally filled as a liquid into a solid pharmaceutical dosage form. However, such processes are complex, time consuming and not cost efficient.
Thus, there still exists a need to formulate a cost-effective method of preparation of solid oral dosage forms comprising mycophenolate mofetil, involving conventional granulation techniques known in the art, wherein the granules so prepared have an increased bulk density which in turn would help in achieving more acceptable dosage forms, for example in case of capsules, a higher fill weight can be attained.
Summary of the Invention
In one general aspect, it relates to a solid oral pharmaceutical composition comprising high bulk density mycophenolate mofetil granules, the said granules comprising a therapeutically effective amount of mycophenolate mofetil and one or more pharmaceutically acceptable excipient(s), wherein the said granules have an apparent bulk density in the range of about 0.35 g/mL to about 0.55 g/mL and a tapped density in the range of about 0.55 g/ml_ to about 0.75g/mLIn another general aspect, it relates to a solid oral pharmaceutical composition comprising high bulk density mycophenolate mofetil granules, wherein the said granules comprise of a therapeutically effective amount of mycophenolate mofetil and one or more pharmaceutically acceptable excipient(s) selected from the group comprising of diluent(s), binder(s), disintegrant(s), lubricant(s) and glidant(s), wherein the said granules have an apparent bulk density in the range of about 0.35 g/mL to about 0.55 g/mL and a tapped density in the range of about 0.55 g/mL to about 0.75 g/mL.
In one embodiment of the above aspects, the high bulk density mycophenolate mofetil granules comprise of binder which is present in the range of about 1% to about 10% by weight of the composition.
In another general aspect, it relates to a process of preparation of high bulk density mycophenolate mofetil granules wherein the process is wet granulation.
In another general aspect, it relates to a process of preparation of high bulk density mycophenolate mofetil granules wherein the process comprises of the following steps:

a) Mycophenolate mofetil is blended with one or more of the pharmaceutically
acceptable excipient(s), selected from the group comprising of diluents, binders and
disintegrants, in a suitable mixer;
b) the blend of step (a) is granulated with binder solution;
c) the granules of step (b) are dried and sized; and
d) the sized granules of step (c) are mixed with one or more of the pharmaceutically
acceptable excipient(s) selected from diluents, disintegrants, lubricants and glidants.
In another general aspect, it relates to a process of preparation of high bulk density mycophenolate mofetil granules wherein the process comprises of the following steps:
a) Mycophenolate mofetil is blended with one or more of the pharmaceutically
acceptable excipient(s), selected from the group comprising of diluents, binders and
disintegrants, in a suitable mixer;
b) the blend of step (a) is granulated with polyvinylpyrrolidone solution;
c) the granules of step (b) are dried and sized; and
d) the sized granules of step (c) are mixed with one or more of the pharmaceutically
acceptable excipient(s) selected from diluents, disintegrants, lubricants and glidants.
In one embodiment of the above aspects, the high bulk density mycophenolate mofetil granules are filled into hard gelatin capsules or compressed into tablets.
Detailed Description of the Invention
The bulk density of a drug substance or a formulation in powder form is a measure of the degree of packing or conversely the amount of space between the particles in the powder. As per the Handbook of Pharmaceutical Excipients, the apparent/loose/poured bulk density of a drug substance or formulation can be determined by pouring drug substance or formulation of known weight into a graduated cylinder. Tapped density is determined by mechanically tapping the drug substance or formulation in a graduated cylinder until it no longer settles. The apparent bulk density and the tapped density of mycophenolate mofetil are in the range of about 0.21 to about 0.25 g/mL and about 0.35 to about 0.37 g/mL respectively, which is very low from a manufacturing perspective, as discussed hereinbefore. Accordingly, granules of increased bulk density comprising of mycophenolate mofetil have been provided, wherein the apparent bulk density of the mycophenolate mofetil granules is in the range of about 0.35 g/mL to about 0.55 g/mL and the tapped density of the same is in the range of about 0.55 g/mL to about 0.75 g/mL.

Mycophenolate mofetil, as referred to herein means mycophenolate mofetil or a pharmaceutically acceptable form of mycophenolate mofetil, including without limitation, its free form, and its pharmaceutically acceptable salts, enantiomers, solvates, hydrates, polymorphs and complexes thereof. The term "pharmacologically effective amount", as used herein, is understood to mean the amount of active agent which stops or reduces the progress of the condition to be treated or which otherwise completely or partly cures or acts palliatively on the condition. Such an amount can be routinely determined by experimentation. Mycophenolate mofetil may comprise from about 5% to about 95% by weight of the granules.
The granules of high bulk density containing mycophenolate mofetil may contain one or more pharmaceutically acceptable excipients. The "pharmaceutically acceptable excipients" as recited herein includes conventional pharmaceutical additives known in the art, such as diluent(s), binder(s), disintegrant(s), lubricants(s), granulating solvent(s), glidants(s) or combinations thereof.
According to the present invention, the use of a suitable binder is critical, as it imparts compressibility and flow property to the granules and happens to be instrumental in increasing the bulk density of the mycophenolate mofetil containing granules. Binders that may be used, includes, without limitation, polyvinylpyrrolidone, cellulose, methylcellulose, hydroxymethylcellulose, carboxymethylcellulose sodium, carboxymethylcellulose calcium, hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, microcrystalline cellulose, polypropylpyrrolidone, gelatin, gum Arabic, gum acacia, polyethylene glycols, starch, pregelatinized starch, polyvinylpyrrolidone/vinyl acetate copolymer, acrylates such as Eudragits, carboxy vinyl polymers such as carbomers and other such materials routinely used in the art of solid dosage form manufacturing. The binder(s) may be used in the range of about 1% to about 10%, preferably about 2% to about 5% by weight of the granules.
Diluents may be selected depending upon the compatibility with the active ingredient, and may be exemplified as, but are not limited to, saccharides like lactose, dextrose, sucrose, fructose, maltose; sugars like mannitol, erythritol, sorbitol, xylitol and lactitol; cellulose derivatives like powdered cellulose, microcrystalline cellulose; starch and pregelatinized starch; dicalcium phosphate, tribasic calcium phosphate, calcium sulphate, calcium carbonate, kaolin and the like. The diluent(s) may comprise about 1% to about 40% by weight of the granules.

Disintegrants may be selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crosslinked polyvinylpyrrolidone, corn starch, potato starch, pregelatinized starch, low-substituted hydroxypropylcellulose, alginates, carboxymethyl starches, methacrylic acid divinylbenzene copolymer salts and microcrystalline cellulose. The disintegrant(s) may comprise about 1% to about 20% by weight of the granules.
Lubricants include magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, powdered stearic acid, magnesium oleate, calcium palmitate, potassium laureate, sodium suberate, vegetable oil, mineral oil and the like. Glidants may be selected from talc, colloidal silicon dioxide, corn starch and the like. Suitable lubricant /glidants may be present in an amount of about 0.1% to about 3% by weight of the granules. Other additional excipients like sweeteners, flavouring agents, colouring agents can also be included.
Suitable granulating solvents may be used to prepare binder solution which include without limitation, water, ethanol, methanol, isopropyl alcohol, methylene chloride, acetone and the like.
The granules of high bulk density as described herein may be prepared by conventional granulation techniques, namely aqueous or non-aqueous wet granulation, melt granulation or roller compactation.
Rapid Mixer Granulators give excellent mixing and uniform granules may be prepared at lower operating cost along with higher productivity. Other High Shear Mixer Granulators like those available from Zanchetta may also be used for the preparation of high bulk density mycophenolate mofetil granules.
In one embodiment, the granules are prepared by wet granulation technique, and comprises of the following steps:
a) Mycophenolate mofetil is blended with one or more of the pharmaceutically
acceptable excipient(s), selected from the group comprising diluent(s), binder(s)
and disintegrant(s), in a suitable mixer.
b) The blend of step (a) is granulated with a binder solution.
c) The granules of step (b) are dried and sized.
d) The sized granules of step (c) are mixed with one or more of the pharmaceutically
acceptable excipient(s) selected from diluent(s); disintegrant(s), lubricant(s) and
glidant(s).

In another embodiment, the granules are prepared by wet granulation technique, and comprises of the following steps:
a) Mycophenolate mofetil is blended with one or more of the pharmaceutically
acceptable excipient(s), selected from the group comprising diluent(s), binder(s) and
disintegrant(s), in a suitable mixer.
b) The blend of step (a) is granulated with polyvinylpyrrolidone solution.
c) The granules of step (b) are dried and sized.
d) The sized granules of step (c) are mixed with one or more of the pharmaceutically
acceptable excipient(s) selected from diluent(s); disintegrant(s), lubricant(s) and
glidant(s).
In another embodiment, the granules are prepared by wet granulation technique, and comprises of the following steps:
a) Mycophenolate mofetil is blended with one or more of the pharmaceutically
acceptable excipient(s), selected from the group comprising diluent(s), binder(s) and
disintegrant(s) in a Rapid Mixer Granulator.
b) The blend of step (a) is granulated with polyvinylpyrrolidone solution.
c) The granules of step (b) are dried and sized.
d) The sized granules of step (c) are mixed with one or more of the pharmaceutically
acceptable excipient(s) selected from diluent(s); disintegrant(s), lubricant(s) and
glidant(s).
In another embodiment, the granules are prepared by wet granulation technique, and comprises of the following steps:
a) Mycophenolate mofetil is blended with one or more of the pharmaceutically
acceptable excipient(s), selected from the group comprising diluent(s), binder(s) and
disintegrant(s), in a Zanchetta Granulator.
b) The blend of step (a) is granulated with polyvinylpyrrolidone solution.
c) The granules of step (b) are dried and sized.
d) The sized granules of step (c) are mixed with one or more of the pharmaceutically
acceptable excipient(s) selected from diluent(s); disintegrant(s), lubricant(s) and
glidant(s).
The granules so prepared may be optionally compressed into tablets or filled into capsules using appropriate tooling. The tablets may be coated using conventional coating ingredients known to a skilled artisan. In one particular embodiment, the granules so formed are filled into capsules of size 1 or 0 having respective volumes of 0.5 and 0.68 mLsing

commercially available capsule filling machinery, in anotner embodiment, the granules are compressed into tablets and further coated using commercially available coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry®.
The granules of high bulk density comprising a therapeutically effective amount of mycophenolate mofetil, as described herein is further illustrated by the following examples but it should not be construed as limiting the scope of the invention(Table Removed)
(
Table Removed Procedures: Example 1
Mycophenolate mofetil was mixed with a portion of polyvinylpyrrolidone, pregelatinized starch, and a portion of Croscarmellose sodium in a Zanchetta Granulator and granulated with an aqueous solution of the remaining portion of polyvinylpyrrolidone. The wet mass was dried, suitably sized, and then blended with the remaining portion of Croscarmellose sodium and magnesium stearate. The final blend was filled into size "1" capsules using appropriate tooling.
Example 2
Mycophenolate mofetil was mixed with pregelatinized starch and a portion of Croscarmellose sodium in a Rapid Mixer Granulator and granulated with an aqueous solution of

polyvinylpyrrolidone. The wet mass was dried, suitably sized, and then blended with the remaining portion of croscarmellose sodium and magnesium stearate. The final blend was filled into size "1" capsules using appropriate tooling.
Example 3
Mycophenolate mofetil was mixed with pregelatinized starch and a portion of croscarmellose sodium in a Zanchetta Granulator and granulated with a hydroalcoholic solution (50:50) of polyvinylpyrrolidone. The wet mass was dried, suitably sized, and then blended with the remaining portion of croscarmellose sodium and magnesium stearate. The final blend was filled into size "0" capsules using appropriate tooling.
Example 4
Mycophenolate mofetil was mixed with pregelatinized starch and a portion of croscarmellose sodium in a Zanchetta Granulator and granulated with an aqueous solution of polyvinylpyrrolidone. The wet mass was dried, suitably sized, and then blended with the remaining portion of croscarmellose sodium and magnesium stearate. The final blend was filled into size "1" capsules using appropriate tooling.
Example 5
Mycophenolate mofetil was mixed with pregelatinized starch and a portion of croscarmellose sodium in a Zanchetta Granulator and granulated with an aqueous solution of polyvinylpyrrolidone. The wet mass was dried, suitably sized, and then blended with the remaining portion of croscarmellose sodium, magnesium stearate, colloidal silicon dioxide and talc. The final blend was filled into size "0" capsules using appropriate tooling.
Example 6
Mycophenolate mofetil was mixed with microcrystalline cellulose in a Zanchetta Granulator and granulated with an aqueous solution of polyvinylpyrrolidone. The wet mass was dried, suitably sized, and then blended with croscarmellose sodium, rnicrocrystalline cellulose, and magnesium stearate. The final blend was then compressed into tablets using appropriate tooling, and was film coated to obtain the final formulation.
Capsules of Examples 1-5 and tablets of Example 6 were subjected to dissolution studies in a USP II Apparatus in 0.1 N HCI (900mL). The temperature and agitation were set at 37°C±0.5°C and 40rpm, respectively for the capsules and for the tablets the agitation was 5Orpm. Dissolution profiles of these capsules and the tablet are given in Table 1.

able1: In-vitro release pattern of mycophenolate mofetil capsules as per composition of Examples 1-5 and tablet as per the composition of Example 6, in USP II apparatus in 900mL of 0.1 N HCI

(Table Removed) The apparent bulk density and tapped density of the granules present in mycophenolate mofetil capsules as prepared in Examples 1-5 and that of the granules prepared in Example 6 prior to compression are given in Table 2.
Table 2: Data for the Apparent Bulk Density and Tapped Density of the mycophenolate mofetil granules as prepared in Examples 1-6

(Table Removed)The theoretical and actual fill weight of the mycophenolate mofetil capsules prepared as per Examples 1-5 are provided in Table 3.
Table 3: Comparative data of the theoretical and actual fill weights of the mycophenolate mofetil capsules as prepared in Examples 1-5
(Table Removed)

We Claim:
1. A solid oral pharmaceutical composition comprising high bulk density mycophenolate
mofetil granules, the said granules comprising a therapeutically effective amount of
mycophenolate mofetil and one or more pharmaceutically acceptable excipient(s),
wherein the said granules have an apparent bulk density in the range of about 0.35
g/mL to about 0.55 g/mL and a tapped density in the range of about 0.55 g/mL to
about 0.75 g/mL.
2. The solid oral pharmaceutical composition according to claim 1 wherein the
pharmaceutically acceptable excipient(s) include one or more of diluent(s), binder(s),
disintegrant(s), lubricant(s) and glidant(s) as described herein.
3. The solid oral pharmaceutical composition according to claim 2 wherein the amount
of the binder is in the range of about 1% to about 10% by weight of the composition.
4. The solid oral pharmaceutical composition according to claim 2 the pharmaceutically
acceptable excipient(s) include one or more of microcrystalline cellulose,
polyvinylpyrrolidone, croscarmellose sodium and pregelatinized starch.
5. A process of preparation of high bulk density mycophenolate mofetil granules of
claim 1 by wet granulation.
6. A process of preparation according to claim 5 wherein the process comprises of the
following steps:

a) Mycophenolate mofetil is blended with one or more of the pharmaceutically
acceptable excipient(s), selected from the group comprising of diluents, binders and
disintegrants, in a suitable mixer;
b) the blend of step (a) is granulated with a binder solution;
c) the granules of step (b) are dried and sized; and
d) the sized granules of step (c) are mixed with one or more of the pharmaceutically
acceptable excipient(s) selected from diluents, disintegrants, lubricants and glidants.
7. The process of preparation according to claim 6 wherein the high bulk density
mycophenolate mofetil granules are filled into hard gelatin capsules.

8. The process of preparation according to claim 6 wherein the high bulk density
mycophenolate mofetil granules are compressed into tablets.
9. The solid oral pharmaceutical composition comprising high bulk density
mycophenolate mofetil granules and process for the preparation thereof substantially
as described and illustrated by examples herein.