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WO2009047799A1 - Forme posologique pharmaceutique à usage oral unitaire solide à haute dose de mycophénolate de sodium et son procédé de fabrication - Google Patents

Forme posologique pharmaceutique à usage oral unitaire solide à haute dose de mycophénolate de sodium et son procédé de fabrication Download PDF

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Publication number
WO2009047799A1
WO2009047799A1 PCT/IN2008/000651 IN2008000651W WO2009047799A1 WO 2009047799 A1 WO2009047799 A1 WO 2009047799A1 IN 2008000651 W IN2008000651 W IN 2008000651W WO 2009047799 A1 WO2009047799 A1 WO 2009047799A1
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WIPO (PCT)
Prior art keywords
active agent
composition according
composition
mycophenolate sodium
dosage form
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PCT/IN2008/000651
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English (en)
Inventor
Rajesh Jain
Sukhjeet Singh
Sampath Kumar Devarajan
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Panacea Biotec Limited
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Publication of WO2009047799A1 publication Critical patent/WO2009047799A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • the present invention relates to high dose solid unit oral pharmaceutical dosage form compositions comprising mycophenolate sodium as active agent in an amount of from greater than about 720 mg to about 1500 mg, preferably from about 800 mg to about 1440 mg calculated as mycophenolic acid, and one or more pharmaceutically acceptable excipient(s).
  • the dosage form compositions are meant for once-a-day or twice-a-day administration and provide the active agent in an extended release form which is released in a sustained manner in-vivo for a prolonged duration.
  • the invention is also directed to process of manufacturing the high dose formulations, and prophylactic and/or therapeutic methods of using such dosage forms.
  • composition of the present invention are easy to formulate, safe, effective and well-tolerated, and are useful for the management such as prophylaxis, amelioration and/or treatment of immunosuppressant indicated disease(s)/disorder(s) especially for the treatment or prevention of organ, tissue or cellular allograft or xenograft rejection, e.g. after transplant, or the management of immune-mediated diseases (autoimmune diseases).
  • autoimmune diseases immune-mediated diseases
  • MPA Mycophenolic acid
  • Mycophenolate sodium having a molecular weight of 342.32.
  • Mycophenolate sodium is a white to off-white crystalline powder and is highly soluble in aqueous media at physiological pH and practically insoluble in 0.1N HCl.
  • a derivative of MPA such as mycophenolate mofetil (MMF) had been introduced commercially in the United States and elsewhere under the brand name CellCept® as an immunosuppressant in the immediate release form as 250 mg capsules or 500 mg oral tablets for the treatment or prevention of organ or tissue transplant rejection.
  • a pharmaceutical delayed release composition comprising mycophenolate sodium under the brand name Myfortic® has been approved for marketing in the United States.
  • Myfortic® is available for oral use as delayed release (enteric coated) tablets containing 180 mg or 360 mg of mycophenolic acid.
  • the recommended dose of Myfortic® is 720 mg administered twice daily (1440 mg total daily dose).
  • MPA is required in daily doses in the order of 2.0 grams to as much as 3.5 or 4.0 grams per day or even 5.0 grams per day depending upon the patient and the disease state being treated.
  • immediate release tablet compositions containing 500 mg equivalent of MPA a patient receiving a 3.0 gram daily dose is required to take six tablets each day, giving rise to patient" inconvenience and noncompliance.
  • at least two tablets of the delayed release product (Myfortic®) needs to be administered twice daily which leads to patient compliance concerns. Therefore, a need still exists to provide single unit high dose oral formulations for MPA particularly in view of its relatively high daily doses.
  • US Patent No. 5554384 discloses high dose pharmaceutical formulation preferably as a capsule comprising a therapeutically effective amount of an active agent selected from the group consisting of mycophenolate mofetil and mycophenolic acid, said active agent having been heated to a first temperature above its melting point, cooled to a second temperature below its melting point at which second temperature said active agent remained liquefied, and filled into a pharmaceutical dosage form while in said cooled liquefied state.
  • an active agent selected from the group consisting of mycophenolate mofetil and mycophenolic acid
  • the preferred formulations disclosed in the said patent comprise 96% w/w mycophenolate mofetil and 4% w/w croscarmellose sodium, most preferably in a size 1 hard gelatin capsule containing 500 mg active agent, in a size 0 hard gelatin capsule containing 750 mg active agent, or in a size 00 hard gelatin capsule containing 1000 mg active agent.
  • Such types of formulations involve cumbersome manufacturing procedure and also require special equipments. Further, such compositions primarily provide an immediate release of the active agent, since the claimed process of preparing the formulation makes the incorporation of rate controlling polymeric materials very difficult.
  • the said patent does not disclose any modified release composition such as a delayed or sustained release composition comprising mycophenolate sodium as active agent; nor does it disclose any compositions comprising a substantially high dose of mycophenolate sodium in a single unit dosage form particularly for providing extended release of the active agent.
  • US Patent Nos. 5,455,045, 6,025,391 and 6,172,107 describe a pharmaceutical composition comprising a mycophenolate salt, the composition being adapted to prevent release of the mycophenolate salt in the stomach and to release the mycophenolate salt in the upper part of the intestinal tract.
  • PCT Publication No. WO2006024479 discloses a composition comprising mycophenolic acid, a salt or a prodrug thereof in a modified release form. Such compositions are intended to improve the drug distribution in the intestine, and to delay the delivery of the drug substance to the intestinal tract. Multiparticulate systems such as granules, pellets, beads and minitablets are disclosed. Also disclosed are coated pellets and granules compressed into rapid disintegrating tablets. However no single unit dosage form either uncoated or coated for providing a sustained release of mycophenolate sodium particularly throughout the GIT is disclosed. Another PCT Publication No.
  • WO2005034916 describes a composition comprising mycophenolic acid, a salt or a prodrug thereof in multiparticulate form such that the compositions disintegrate or dissolve in the mouth, stomach or small intestine to give multiparticles, wherein the multiparticles are enteric coated.
  • PCT Publication No. WO20Q3032978 describe an enteric coated solid dosage form comprising a pharmacologically effective amount of mycophenolic acid or mycophenolate salt, wherein the mycophenolic acid or mycophenolate salt is present in an amount of from 20-95% by weight based on the total weight of the solid dosage form including the enteric coating.
  • compositions described in said PCT publications comprise substantially low unit dose of mycophenolate sodium compared to the daily dose requirement for treatment/prophylaxis of a disease/disorder using the said active agent. Therefore more than one unit of the dosage form composition needs to be administered to a patient at a time and hence such composition lacks patient compliance. Further, such compositions also need to be administered more that once-a-day due to the lower single unit content of the active agent.
  • compositions of present invention are preferably single unit dosage forms containing high dose of mycophenolate sodium which can be administered as a single dose once daily or twice daily, and provides an extended prophylactic and/or therapeutic concentration of the active agent devoid of any substantial toxicity, thus demonstrating a significant advancement over prior art.
  • the inventors of the present invention have invented extended release high dose solid unit oral pharmaceutical dosage form compositions of mycophenolate sodium, characterized in that mycophenolate sodium is released in a sustained manner, alleviating or at least reducing the chances of causing any associated side effects without compromising the bioavailability of active agent. Further, the active agent mycophenolate sodium is well absorbed orally and and/or the variation of its absorbability is substantially alleviated when made into compositions according to the present invention.
  • a high dosage strength solid unit oral dosage form e.g., a tablet of mycophenolate sodium having satisfactory dissolution and bioavailability has apparently not been successfully developed prior to the present invention. This may be due in part to the pH dependent solubility, poor compressibility, poor flow properties and low bulk density of the said drug which makes it difficult to be formulated into a solid single unit dosage form.
  • the formulation of high dose solid unit dosage form comprising mycophenolate sodium theoretically requires the use of high quantities of excipients, especially rate controlling polymers particularly when a sustained release product is desired.
  • the inventors of the present invention have done extensive research and experimentation to alleviate the drawbacks existing in the prior art and to develop novel high dose solid unit oral pharmaceutical dosage form compositions comprising mycophenolate sodium having particularly desirable bioavailability characteristics and which are well-tolerated, stable, and convenient to administer, thus demonstrating a significant advancement over prior art.
  • modified release compositions comprising mycophenolate sodium as the active agent in a high dose solid unit oral pharmaceutical dosage form for once-a-day or twice-a-day administration, wherein the said composition provides a better patient compliance by reducing the frequency of dosage form administration and/or, reducing the number of unit dosage form to be administered, and wherein the said compositions upon administration leads to lesser episodes of allograft or xenograft transplant rejections.
  • the modified release composition may be in the form of an extended release composition providing a sustained release of the active agent throughout the gastrointestinal tract (GIT).
  • It is a further objective of the present invention to provide high dose solid unit oral pharmaceutical dosage form compositions comprising mycophenolate sodium as active agent in an amount of from greater than about 720 mg to about 1500 mg, preferably from greater than about 800 mg to about 1440 mg, more preferably about 1080 mg calculated as mycophenolic acid, and one or more pharmaceutically acceptable excipient(s).
  • the dosage form compositions provide the active agent in an extended release form which is released in a sustained manner in-vivo for a prolonged duration.
  • It is another objective of the present invention to provide high dose solid unit oral pharmaceutical dosage form compositions comprising mycophenolate sodium as active agent in an amount of from greater than about 720 mg to about 1500 mg, preferably from greater than about 800 mg to about 1440 mg, more preferably about 1080 mg calculated as mycophenolic acid, and one or more pharmaceutically acceptable excipient(s), wherein the dosage form is coated using such composition which aids in providing a sustained release of the active agent.
  • It is a preferred objective of the present invention to provide high dose solid unit oral pharmaceutical dosage form compositions comprising mycophenolate sodium as active agent in an amount of about 1080 mg calculated as mycophenolic acid, and one or more pharmaceutically acceptable excipient(s), wherein the said active agent is present in an extended release form proving a sustained release of the active agent for a prolonged duration.
  • It is another preferred objective of the present invention to provide high dose solid unit oral pharmaceutical dosage form compositions comprising mycophenolate sodium as active agent in an amount of about 1080 mg calculated as mycophenolic acid, and one or more pharmaceutically acceptable excipient(s), wherein the total daily dose of mycophenolate sodium can be provided in a single unit dose such as a single once-a-day tablet or at the most two unit doses such as two tablets, are easier to manufacture and involves a low formulation cost.
  • It is another objective of the present invention to provide high dose solid unit oral pharmaceutical dosage form compositions comprising mycophenolate sodium as active agent, optionally alongwith one or more pharmaceutically acceptable excipient(s), wherein the said composition is made in the form of a single unit dosage form or' a multiple unit dosage form comprising greater than about 720 mg of active agent calculated as mycophenolic acid, and wherein the said single unit dosage form or a multiple unit dosage form is administrable at a dosing interval of at least about 12 hours.
  • composition of the present invention which comprises treating mycophenolate sodium with one or more release controlling material(s), alongwith optionally one or more pharmaceutically acceptable excipient(s), and formulating into a suitable dosage form.
  • composition of the present invention which comprises treating mycophenolate sodium with at least one release controlling material(s) optionally with one or more other pharmaceutically acceptable excipient(s), and formulating into a suitable dosage form.
  • composition of the present invention for the management such as prophylaxis, amelioration and/or treatment of immunosuppressant indicated diseas ⁇ )/disorder(s) especially for the treatment or prevention of organ, tissue or cellular allograft or xenograft rejection, e.g. after transplant, or the management of immune-mediated diseases (autoimmune diseases), which comprises administering to a subject in need thereof the composition comprising a pharmaceutically effective amount of the active agent mycophenolate sodium.
  • autoimmune diseases immune-mediated diseases
  • autoimmune diseases immune-mediated diseases
  • It is yet another objective of the present invention to provide high dose solid unit oral pharmaceutical dosage form compositions comprising mycophenolate sodium as active agent in an amount of from greater than about 720 mg to about 1500 mg, preferably from greater than about 800 mg to about 1440 mg, more preferably about 1080 mg calculated as mycophenolic acid, and one or more pharmaceutically acceptable excipient(s), wherein the said dosage form is used concomitantly or during therapy with at least one another immunosuppressant such as cyclosporine, and/or another active agent such as corticosteroid.
  • novel high dose solid unit oral pharmaceutical dosage form compositions of the present invention such as a single once-a-day tablet comprising mycophenolate sodium possess particularly desirable bioavailability characteristics, are well-tolerated, stable, convenient to administer, easier to manufacture involving a low formulation cost, and are useful particularly for prevention or treatment of native or transgenic organ, tissue or cellular allograft transplant rejection, immune-mediated and/or inflammatory disease.
  • the novel compositions are patient-friendly particularly for administration of mycophenolate sodium to pediatric/geriatric patients, and provide a simple and reliable posology for administration of mycophenolate sodium.
  • the present invention provides modified release compositions comprising mycophenolate sodium as the active agent in a high dose solid unit oral pharmaceutical dosage form for once-a-day or twice-a- day administration.
  • the novel compositions provide a better patient compliance by reducing the frequency of dosage form administration and also resulting in lesser episodes of allograft or xenograft transplant rejections.
  • the present invention provides effective, safe and tolerable high dose solid unit oral pharmaceutical dosage form compositions of mycophenolate sodium wherein the total daily dose of mycophenolate sodium can be provided in a single unit dose such as a single once-a-day tablet or at the most two unit doses such as two tablets, are easier to manufacture, and involves a low formulation cost, and wherein the single unit dosage forms have particularly an acceptable size for oral administration.
  • the development of a modified release composition particularly extended release dosage form for mycophenolate sodium is challenging due to the pH-dependent solubility of the drug i.e. high solubility of the drug in pH above 6.0 and poor solubility in pH below 6.0. Furthermore, it is challenging to develop extended release dosage forms of mycophenolate sodium comprising high dose of the active agent that are robust, and whose dissolution behavior does not depend on the state of digestion or dosage form transit through the gastrointestinal tract.
  • the inventors of the present invention have been able to develop such high dose solid unit oral pharmaceutical dosage form compositions of mycophenolate sodium thus demonstrating a significant advancement over the prior art.
  • the present invention provides a stable high dose solid unit oral extended release pharmaceutical dosage form compositions of mycophenolate sodium such as matrix tablets which could provide substantially linear drug release for a prolonged duration of time during the transit through varying pHs of the gastro-intestinal tract.
  • Difficulties in formulation of oral solid dosage forms such as tablets comprising mycophenolate sodium can be for example due to the low bulk density of active agent resulting in e.g. low mechanical stability of the solid dosage form and/or unfavorable size particularly when a high amount of excipients is added to improve the mechanical stability properties. Tablets with inferior mechanical properties are liable to crumbling, edge chipping or breaking. These difficulties are even greater when it is intended to make an oral solid dosage form comprising a high dose of mycophenolate sodium particularly due to the high drug loading and scope for using a proportionately lesser quantity of excipients. Unfortunately use of lesser quantity of excipients makes it more difficult to obtain particularly a single unit compressed solid dosage form.
  • the drug mycophenolate sodium possesses very poor flow properties, poor compressibility and also develops static charges while processing which makes the formulation of a dosage form all the more challenging.
  • developing high dose modified release composition particularly extended release unit dosage forms such as tablet formulations for mycophenolate sodium is very challenging and requires extensive research and experimentation.
  • the present invention provides easy, convenient and reproducible method to manufacture particularly single unit high dose extended release dosage forms comprising mycophenolate sodium.
  • the dosage form composition of the present invention is preferably designed in such a manner that it will not restrict the drug release to certain GIT pHs; instead it will facilitate release of drug through different pHs, which is very important for a desirable extended release dosage form.
  • the present invention provides pharmaceutically acceptable high dose oral solid dosage forms, e.g. in the form of tablets of mycophenolate sodium in an easily administrable size and mechanically stable form with a high drug loading.
  • Oral dosage forms being particularly convenient to administer and stable, may be obtained, e.g. by preparation of tablets by compression methods. More specifically, the tablets of the invention may be prepared by granulation followed by compression methods.
  • the present invention provides unit high dose modified release compositions comprising mycophenolate sodium as active agent suitable for use in situations where a sustained effect of said active agent for a prolonged duration is desirable in order to develop compositions suitable for administration less frequently such as once or twice daily.
  • the compositions are also capable of providing an initial rapid effect followed by a sustained effect of the active agent for use in certain situations where such combined effect is desirable.
  • the high dose solid unit oral pharmaceutical dosage form of the present invention when made into the modified release compositions are safe, predictable and reliable, and are also very storage stable because an immediate release due to accidental damaging of e.g. the coating or capsule may result in undesired high plasma concentrations, so-called dose dumping, which could cause undesired side effects.
  • the storage stability of the extended release compositions of the present invention is very beneficial from a technical point of view since even a minor change in the release rate and/or release pattern may have a significant impact on the in-vivo performance of the composition.
  • the modified release pharmaceutical composition has been disclosed which at the same time can be produced in an easy, cheap and reliable manner and which provides a suitable profile for release of active agent (under acidic, neutral and basic conditions) resulting in an extended period of about 12 to 24 hours.
  • high dose single unit oral pharmaceutical dosage form compositions comprising mycophenolate sodium as active agent, optionally alongwith one or more pharmaceutically acceptable excipient(s), wherein the said composition is made in the form of a single unit dosage form or a multiple unit dosage form comprising greater than about 720 mg of active agent calculated as mycophenolic acid.
  • the present invention provides high dose solid unit oral pharmaceutical dosage form compositions comprising mycophenolate sodium as active agent in an amount of from greater than about 720 mg to about 1500 mg, preferably from greater than about 800 mg to about 1440 mg, more preferably about 1080 mg calculated as mycophenolic acid, and one or more pharmaceutically acceptable excipient(s).
  • the dosage form compositions provide the active agent in an extended release form which is released in a sustained manner in-vivo for a prolonged duration.
  • the present invention provides high dose solid unit oral pharmaceutical dosage form compositions comprising mycophenolate sodium as active agent in an amount of from greater than about 720 mg to about 1500 mg, preferably from greater than about 800 mg to about 1440 mg, more preferably about 1080 mg calculated as mycophenolic acid, and one or more pharmaceutically acceptable excipient(s), wherein the dosage form is coated using such composition which aids in providing a sustained release of the active agent.
  • the present invention provides high dose solid unit oral pharmaceutical dosage form compositions comprising mycophenolate sodium as active agent in an amount of about 1080 mg calculated as mycophenolic acid, and one or more pharmaceutically acceptable excipient(s), wherein the said active agent is present in an extended release form providing a sustained release of the active agent for a prolonged duration.
  • the present invention provides high dose solid unit oral pharmaceutical dosage form compositions comprising mycophenolate sodium as active agent in an amount of about 1080 mg calculated as mycophenolic acid, and one or more pharmaceutically acceptable excipient(s), wherein the total daily dose of mycophenolate sodium can be provided in a single unit dose such as a single once-a-day tablet or at the most two unit doses such as two tablets, that are easier to manufacture, and involves a low formulation cost.
  • the present invention provides high dose solid unit oral pharmaceutical dosage form compositions comprising mycophenolate sodium as active agent, optionally alongwith one or more pharmaceutically acceptable excipient(s), wherein the said composition is made in the form of a single unit dosage form or a multiple unit dosage form comprising greater than about 720 mg of active agent calculated as mycophenolic acid, and wherein the said single unit dosage form or a multiple unit dosage form is administrable at a dosing interval of at least about 12 hours.
  • the recommended daily dose of Mycophenolate mofetil is 1 g to 3 g.
  • the total daily dose of Mycophenolic acid in patients is 1440 mg which may extend upto a maximum of 2160 mg.
  • patients are administered with four Myfortic® 180 mg tablets or two 360 mg tablet twice daily (1440 mg daily dose).
  • a daily dose of 1 g to 3 g of Mycophenolate mofetil ( 1 g of Mycophenolate mofetil equivalent to 720 mg of MPA) is recommended for renal/ organ transplantation patients.
  • Such a type of dosage regimen causes a lot of inconvenience for patients, and there are always chances that a dose is missed or a patient does not take so many tablets at a time.
  • the present invention provides high dose solid unit oral pharmaceutical dosage form compositions comprising mycophenolate sodium as active agent, optionally alongwith one or more pharmaceutically acceptable excipient(s), wherein the said composition is made in the form of a single unit dosage form or a multiple unit dosage form comprising greater than about 720 mg of active agent calculated as mycophenolic acid.
  • the present invention provides high dose single unit modified release dosage form compositions comprising mycophenolate sodium as the active agent particularly as solid oral dosage forms, wherein the said dosage forms exhibit a sustained release of active agent throughout the GIT such that only a sufficient amount of the active agent is released in the lower part and/or proximal part of the gastro-intestinal tract so as to reduce the drug related gastrointestinal side effects without compromising the systemic bioavailability of the active agent.
  • the high dose single unit modified release dosage form composition of the present invention is prepared by using formulation techniques aimed at releasing the immunosuppressant active agent in a manner such that the bioavailability of the dosage form thus obtained is at least comparable to a conventional immediate release dosage form.
  • the release of mycophenolate sodium from the dosage form of the present invention is controlled in such a manner by using one or more release controlling materials alongwith one or more pharmaceutically acceptable excipient(s) so that therapeutically effective plasma concentration of the active agent can be obtained without any undesirable side effects for an extended period of time thus leading to improved patient compliance.
  • the high dose single unit modified release dosage form composition comprises mycophenolate sodium as active agent in an amount of at least 30% by weight of the composition.
  • the high dose single unit modified release composition is an extended release pharmaceutical composition according to the present invention which comprises mycophenolate sodium as the active agent in an amount of about 30% to about 99% by weight of the composition alongwith one or more release controlling material(s) in an amount of about 1% to about 70% by weight of the composition and one or pharmaceutically acceptable excipient(s) in an amount of about 0.5% to about 70% by weight of composition.
  • the active agent of the present invention is mycophenolate sodium, e.g. mono or di-sodium salt, preferably mono-sodium salt.
  • the release controlling material(s) useful in the present invention preferably comprises a polymeric material selected from but not limited to the group comprising pH dependent polymers such as alginates, carbomers, cellulose propionate (lower, medium or higher molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose triacetate or methacrylic acid polymers or a mixture thereof used either alone or in combination thereof; pH independent polymers such as acrylate or methacrylate polymers, or cellulosic polymers; soluble or insoluble polymers; swellable polymers; hydrophilic polymers; hydrophobic polymers; ionic polymers such as calcium carboxymethylcellulose or sodium carboxymethylcellulose; non-ionic polymers such as hydroxypropyl methylcellulose and its various pharmaceutically acceptable grades (e.g.
  • pH dependent polymers such as alginates, carbomers, cellulose propionate (lower, medium or higher molecular weight), cellulose acetate propionate, cellulose acetate buty
  • Methocel® KlOOM CR Methocel® KlOOM CR
  • synthetic or natural polysaccharide selected from the group comprising alkylcelluloses, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitrocelluloses, dextrin, agar, carrageenan, pectin, furcellaran, starch and starch derivatives, and mixtures thereof; cellulosic polymer, methacrylate polymer, carboxyvinyl polymer and its various pharmaceutically acceptable grades (e.g.
  • Carbopol 71G Copolymers of acrylate and methacrylates with quarternary ammonium group (Eudragit®), polyvinylpyrrolidone (PVP), polyvinylpyrrolidone- polyvinylacetate polymer (PVP-PVA) copolymer, ethylcellulose, cellulose acetate, poly(alkyl methacrylate), poly ⁇ sodecyl methacrylate), poly ⁇ auryl methacrylate), poly(phenyl methacrylate), poly(alkyl acrylate), poly(octadecyl acrylate), poly(ethylene), poly(alkylene), poly(alkylene oxide), poly(alkylene terephthalate), poly( vinyl isobutyl ether), polyvinyl acetate), polyvinyl chloride) and polyurethane or a mixture thereof used either alone or in combination thereof.
  • PVP polyvinylpyrrolidone
  • PVP-PVA polyvinylpyrroli
  • the release controlling material(s) useful in the present invention is a gum selected from but not limited to a group comprising xanthan gum, guar gum, gum arabic, carrageenan gum, karaya gum, locust bean gum, acacia gum, tragacanth gum, agar and the like or mixtures thereof used alone or in combination thereof.
  • the release controlling material(s) useful in the present invention is a lipid agent selected from but not limited to a group comprising glyceryl behenate such as Compritol® ATO888, Compritol® HD ATO 5, and the like; hydrogenated vegetable oil such as hydrogenated castor oil e.g.
  • the pharmaceutically acceptable excipient(s) useful in the composition of the present invention are selected from but not limited to a group of excipients generally known to persons skilled in the art e.g.
  • diluents such as lactose (Pharmatose DCL 21), starch, mannitol, sorbitol, dextrose, microcrystalline cellulose, dibasic calcium phosphate, sucrose-based diluents, confectioner's sugar, monobasic calcium sulfate monohydrate, calcium sulfate dihydrate, calcium lactate trihydrate, dextrates, inositol, hydrolyzed cereal solids, amylose, powdered cellulose, calcium carbonate, glycine, and bentonite; disintegrants; binders; fillers; bulking agent; organic acid(s); colorants; stabilizers; preservatives; lubricants; glidants/antiadherants; chelating agents; vehicles; bulking agents; stabilizers; preservatives; hydrophilic polymers; solubility enhancing agents such as glycerin, various grades of polyethylene oxides, transcutol and glycofiirol; tonic
  • the disintegrants useful in the present invention include but not limited to starch or its derivatives, partially pregelatinized maize starch (Starch 1500®), croscarmellose sodium, sodium starch glycollate, clays, celluloses, alginates, pregelatinized corn starch, crospovidone, gums and the like used either alone or in combination thereof.
  • the lubricants useful in the present invention include but not limited to talc, magnesium stearate, calcium stearate, sodium stearate, stearic acid, hydrogenated vegetable oil, glyceryl behenate, glyceryl behapate, waxes, Stearowet, boric acid, sodium benzoate, sodium acetate, sodium chloride, DL-leucine, polyethylene glycols, sodium oleate, sodium lauryl sulfate, magnesium lauryl sulfate and the like used either alone or in combination thereof.
  • the anti-adherents or glidants useful in the present invention are selected from but not limited to a group comprising talc, corn starch, DL-leucine, sodium lauryl sulfate, and magnesium, calcium and sodium stearates, and the like or mixtures thereof.
  • the compositions may additionally comprise an antimicrobial preservative such as benzyl alcohol.
  • the composition may additionally comprise a conventionally known antioxidant such as ascorbyl palmitate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate and/or ⁇ -tocopherol.
  • the dosage form of the present invention additionally comprises at least one wetting agent(s) such as a surfactant selected from a group comprising anionic surfactants, cationic surfactants, non-ionic surfactants, zwitterionic surfactants, or mixtures thereof.
  • the wetting agents are selected from but not limited to a group comprising oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium oleate, sodium lauryl sulfate and the like, or mixtures thereof.
  • the dosage form of the present invention additionally comprises at least one complexing agent such as cyclodextrin selected from a group comprising but not limited to alpha-cyclodextrin, beta-cyclodextrin, betahydroxy-cyclodextrin, gamma-cyclodextrin, and hydroxypropyl beta-cyclodextrin, or the like.
  • the dosage form of the present invention additionally comprises of lipid(s) selected from but not limited to glyceryl behenate such as Compritol® ATO888, Compritol® ATO 5, and the like; hydrogenated vegetable oil such as hydrogenated castor oil e.g.
  • Lubritab® glyceryl palmitostearate such as Precirol® ATO 5 and the like, or mixtures thereof used either alone or in combination thereof. It will be appreciated that any given excipient may serve more than one function in the compositions according to the present invention.
  • the present invention provides high dose single unit extended release pharmaceutical composition comprising mycophenolate sodium as the active agent; at least one pH independent polymer(s) and at least one lipid agent(s) as release controlling materials, optionally with one or more other pharmaceutically acceptable excipient(s).
  • the present invention provides high dose single unit extended release pharmaceutical composition comprising mycophenolate sodium as the active agent; at least one pH independent polymer(s) and at least one gum(s) as release controlling materials, optionally with one or more other pharmaceutically acceptable excipient(s).
  • Oral delivery of the high dose single unit pharmaceutical compositions of the present invention can include extended release formulations, providing prolonged or sustained delivery of the drug to the gastrointestinal tract by any number of mechanisms.
  • Such prolonged or sustained release mechanisms can include, but are not limited to, pH sensitive release from the dosage form based on the changing pH of the gastro-intestinal tract; slow erosion of a tablet or capsule; retention in the stomach based on the physical properties of the formulation; bioadhesion of the dosage form to the mucosal lining of the intestinal tract; or enzymatic release of the active agent mycophenolate sodium from the dosage form.
  • the intended effect is to extend the time period over which the active agent is delivered to site of action by manipulation of dosage form.
  • Suitable matrix forming materials are waxes e.g., carnauba, bees wax, paraffin wax, ceresine, shellac wax, fatty acids, and fatty alcohols; oils, hardened oils or fats e.g., hardened rapeseed oil, castor oil, beef tallow, palm oil, and soya bean oil; polymers e.g., hydroxypropyl cellulose, hydroxyethyl cellulose, polyvinylpyrrolidone, hydroxypropyl methyl cellulose, polyethylene glycol, methacrylates (PMMA), polycarbophils and carbomers; alginates; gums e.g.
  • waxes e.g., carnauba, bees wax, paraffin wax, ceresine, shellac wax, fatty acids, and fatty alcohols
  • oils hardened oils or fats e.g., hardened rapeseed oil, castor oil, beef tallow, palm oil, and soya bean
  • xanthan gum and other carrier materials known to those of ordinary skill in the art.
  • suitable matrix tableting materials include, but are not limited to, microcrystalline cellulose, powdered cellulose, hydroxypropyl cellulose, and ethyl cellulose.
  • Other types of extended release compositions may achieve controlled release by use of granulates, coated powders, pellets, or the like, by use of multi-layering, and/or by use of suitable coatings. Still other extended release compositions include an osmotic pump, or combinations of the above.
  • Extended release compositions can be made by one or more techniques such as mixing, prilling, spray drying, pan coating, granulation, melt granulation, wurster coating, tangential coating, top spraying, tableting, extruding, coacervation and the like.
  • the particle size of the extended release components other than active agent in the dosage form depends on the technology used. The particle sizes can range from submicron to 1000 micron for powder technologies (mixtures, spray drying, dispersions, and the like); 5-1900 microns for coating technologies (top spray, bottom spray, spray drying, extrusion, layering, and the like); and 0.1 microns to 50 mm for tableting technologies.
  • the compositions can comprise the active agent in a micronized form. Where the composition is in the form of a pellet product, the pellets can be presented in a sachet, capsule or tablet.
  • a plurality of elements containing active agent, or cores are prepared by extrusion/spheronization, or by layering the active agent (or a blend of active agent with other carrier materials) onto inert carriers by various processes.
  • the cores can contain the active agent at the required potency according to the active agent dose, required size, required presentation, and subsequent processes (coating and the like).
  • the cores can contain active agent in the range of about 0.1% to about 100%, depending on the required dose, potency, manufacturing method, and other properties.
  • the controlled release form can be in the form of coated beads or granules of the active agent.
  • the controlled release portion of the dose can be provided by a controlled release core as described above, or a controlled release core that is further modified by overcoating.
  • the extended release compositions provide a therapeutic effect over a period greater than about 12 hours, with a sustained therapeutic effect for a period of about 12 to 24 hours being especially preferred.
  • composition of the present invention is in the form of a tablet
  • aqueous media such as in the gastrointestinal tract
  • the tablet surface wets and the release controlling material(s) begins to partially hydrate forming an outer gel layer.
  • This outer gel layer becomes fully hydrated and begins to erode into the aqueous fluids. Water continues to permeate toward the core of the tablet permitting another gel layer to form beneath the dissolving outer gel layer.
  • These successive concentric gel layers sustain uniform release of the active agent by diffusion from the gel layer and exposure through tablet erosion. Changes in the tablet size and shape can affect the surface to volume ratio of the tablet and therefore the active agent release kinetics from the hydrophilic matrix of the tablet.
  • the amount of mycophenolate sodium to be incorporated into the pharmaceutical composition of the present invention can vary over a wide range depending on known factors such as, for example, the intended use i.e. prophylactic or therapeutic, disease/disorder to be treated, the severity of the disease/disorder, the patient's body weight, the dosage form, the chosen route of administration and the number of administration per day. However, selection of optimum amount is simple and routine for a person skilled in the art. Typically the amount of mycophenolate sodium would be equivalent to about 720 mg to about 1500 mg of mycophenolic acid in a unit dose.
  • the compositions of the present invention comprising mycophenolate sodium as active agent, releases the active agent throughout the gastro-intestinal tract (GIT).
  • GIT gastro-intestinal tract
  • the compositions are designed in such a manner so as to release a sufficient amount of the active agent in the lower part of the GIT and a substantial amount of the active agent in the upper part of the intestine, e.g. in the duodenum, jejunum and/or ileum.
  • the release of mycophenolate sodium from the dosage form compositions of the present invention are designed in such a manner so that the said active is absorbed continuously throughout the GIT thus producing desired concentrations of the active in the blood and at the same time devoid of any substantial gastro-intestinal side effects associated with the active agent.
  • compositions release the active agent in a manner such that it is effective, safe and well-tolerated particularly for immunosuppressive indications especially for the treatment or prevention of organ, tissue or cellular allograft or xenograft rejection, e.g. after transplant, or the treatment or prevention of immune-mediated diseases.
  • the compositions of the present invention may be formulated to disintegrate or erode relatively slowly in the lower part of the GIT such as the stomach as compared to its disintegration or erosion in the upper part of the GIT.
  • the present invention provides a modified release pharmaceutical composition
  • a modified release pharmaceutical composition comprising particulate mycophenolate sodium having a D 90 particle size of about 0.001 to about 1000 microns, in an amount equivalent to about 720 mg to about 1500 mg of mycophenolic acid, at least one release controlling material(s), optionally alongwith one or more pharmaceutically acceptable excipient(s).
  • the pharmaceutical composition according to the present invention comprises about 30% to about 99% by weight of mycophenolate sodium; about 0.001% to about 70% by weight of diluent(s); about 1% to about 70% by weight of release controlling material(s); about 0.1% to about 10% by weight of binder(s); and optionally about 0.1% to about 40% by weight of at least one lipophilic material(s) and optionally 0.01% to about 10% by weight of a lubricant.
  • the lipophilic material(s) is present intragranularly or extragranularly or both intra and extragranularly, but more preferably extragranularly, alongwith the lubricant(s).
  • the pharmaceutical composition according to the present invention comprises mycophenolate sodium in an amount equivalent to about 720 mg to about 1500 mg by weight of mycophenolic acid; about 0 mg to about 2000 mg by weight of diluent(s); about 1 mg to about 1000 mg by weight of release controlling polymer(s); about 0.1 mg to about 500 mg by weight of binder(s); and optionally about 1 mg to about 1000 mg by weight of at least one lipophilic material(s) and optionally about 1 mg to about 500 mg by weight of a lubricant(s).
  • the release controlling material is an acrylate or a methacrylate polymer or copolymer, or a mixture of such polymers.
  • the binder is an acrylate or a methacrylate polymer or copolymer, or a mixture of such polymers.
  • the pharmaceutical composition comprises one or more material(s) selected from but not limited to a group comprising of a lipophilic material such as glyceryl behenate, an acrylate or a methacrylate polymer or copolymer such as Eudragit®; a cellulosic polymer such as hydroxypropyl methylcellulose; a gum such as xanthan gum; or suitable mixtures thereof.
  • a lipophilic material such as glyceryl behenate, an acrylate or a methacrylate polymer or copolymer such as Eudragit®
  • a cellulosic polymer such as hydroxypropyl methylcellulose
  • a gum such as xanthan gum
  • one or more of a material such as glyceryl behenate, an acrylate or a methacrylate polymer or copolymer such as Eudragit®, a cellulosic polymer such as hydroxypropyl methylcellulose, a gum such as xanthan gum, or mixtures thereof, is present as a lubricant composition which is added extragranularly to make the composition according to the present invention.
  • the pharmaceutical composition is a coated or uncoated solid unit dosage form such as tablet.
  • the modified release compositions of the present invention comprises a core and at least one coating such that the active agent mycophenolate sodium is either present in the core or the coat or in both.
  • the coating also contributes in extending the release of the active agent from the compositions.
  • the coating is applied on the core compositions from a solution and/or suspension preferably in an aqueous or an organic solvent.
  • film-forming agents which are suitable for use in the coating composition in accordance with the present invention are agents selected from the group comprising of cellulose derivatives such as, e.g., ethylcellulose, cellulose acetate, cellulose propionate, cellulose butyrate, cellulose valerate, cellulose acetate propionate; methacrylic polymers; acrylic polymers such as, e.g., polymethyl methacrylate; vinyl polymers such as, e.g., polyvinyl acetate, polyvinyl formal, polyvinyl butyryl, vinyl chloride-vinyl acetate copolymer, vinyl acetate polymers and copolymers such as Kollicoat®SR 30D which is polyvinyl acetate (-27% w/w) stabilized with polyvinylpyrrolidone (-2-5% w/w) and sodium lauryl sulfate (-0.3% w/w), copolymer of polyvinyl alcohol-polyethylene glycol (Kolli
  • the coating is not an enteric coating, but the coating composition is such that it controls the release of the active agent thus aiding the extended release of the active agent.
  • the acrylic polymer is comprised of one or more ammonio methacrylate copolymers.
  • the acrylic coating is an acrylic resin lacquer used in the form of an aqueous dispersion, such as that which is commercially available from Rohm Pharma under the tradename Eudragit®.
  • the acrylic coating comprises a mixture of two acrylic resin lacquers such as Eudragit® RL 3OD and Eudragit® RS 3OD, which are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups.
  • Eudragit® RIVRS mixtures are insoluble in water and in digestive fluids.
  • coatings formed from the same are swellable and permeable in aqueous solutions and digestive fluids.
  • Other polymers such as Eudragit® RL e.g. Eudragit® RLPO, and Eudragit® RS e.g. Eudragit® RSPO or their suitable mixtures can be used to obtain the extended release composition of the present invention having a desirable dissolution profile.
  • a mixture of Eudragit® polymer and a cellulosic polymer such as hydroxypropyl methylcellulose can be used as the coating material.
  • an extended release composition may also be prepared by using a retardant coating based on Eudragit® NE 3OD, which is a neutral resin.
  • ethylcellulose or water-soluble coating materials such as water- soluble cellulose derivatives, e.g. hydroxypropylcellulose, carboxymethylcellulose, methylcellulose, propylcellulose, hydroxyethylcellulose, carboxyethylcellulose, carboxymethyl hydroxyethylcellulose, hydroxymelhylcellulose, carboxymethyl ethylcellulose, methylhydroxy propylcellulose or hydroxypropyl methylcellulose may be employed in the present invention.
  • water- soluble cellulose derivatives e.g. hydroxypropylcellulose, carboxymethylcellulose, methylcellulose, propylcellulose, hydroxyethylcellulose, carboxyethylcellulose, carboxymethyl hydroxyethylcellulose, hydroxymelhylcellulose, carboxymethyl ethylcellulose, methylhydroxy propylcellulose or hydroxypropyl methylcellulose
  • the amount of coating applied is adapted so as to obtain a predetermined dissolution characteristic of the novel extended release composition.
  • the percentage by weight of the coating on the individual unit dosage form is about 2-30% w/w of the composition.
  • the amount of coating applied depends on the predetermined dissolution characteristics of the particular core composition and the desired release profile. However, the amount of coating applied is such that there will be no rupturing problems.
  • the coating may be admixed with various excipients selected from but not limited to a group comprising plasticizers, anti-adhesives such as, e.g., colloidal silicon dioxide, inert fillers, and pigments in a manner known per se.
  • Tackiness of the water-dispersible film-forming substances may be overcome by simply incorporating an anti-adhesive in the coating.
  • the anti-adhesive is preferably a finely divided, substantially insoluble, pharmaceutically acceptable non-wetting powder having anti-adhesive properties in the coating.
  • anti-adhesives are metallic stearates such as magnesium stearate or calcium stearate, microcrystalline cellulose, or mineral substances such as calcite, substantially water-insoluble calcium phosphates or substantially water-insoluble calcium sulphates, colloidal silica, titanium dioxide, barium sulphates, hydrogenated aluminium silicates, hydrous aluminium potassium silicates and talc, or mixtures thereof.
  • plasticizers for use in accordance with present invention .
  • plasticizers include triacetin, acetylated monoglyceride, rape oil, olive oil, sesame oil, acetyl tributyl citrate, acetyl triethyl citrate, glycerin, sorbitol, diethyloxalate, diethylmalate, diethylmaleate, diethylfumarate, diethylsuccinate, diethylmalonate, dioctylphthalate, dibutylsebacetate, triethylcitrate, tributylcitrate, glyceroltributyrate, polyethyleneglycol, propyleneglycol, 1,2-propyleneglycol, dibutyl sebacate, diethyl sebacate, and mixtures thereof.
  • the plasticizer is normally incorporated in an amount of less than about 20% by weight, calculated on dry matter content of coating composition.
  • the coating may further comprise, especially in aqueous dispersions, one or more thickening agents to avoid sedimentation of suspended excipients, e.g. HPMC 3 cps or 6 cps and optionally anti-sticking agent e.g. colloidal silicon dioxide, a synthetic amorphous silicic acid such as Syloid 244 FP, talc, or glycerine monostearate, or their mixtures.
  • compositions of the present invention comprising a substantially high dose of mycophenolate sodium in a single unit system that are safe, tolerable, effective and easy-to- manufacture had not been achieved earlier which was one of the major limitation of the prior art; however the inventors of the present invention have been able to alleviate said limitation(s) of the prior art and formulate novel compositions comprising a substantially high dose of mycophenolate sodium by virtue of extensive research and experimentation.
  • the drug levels are maintained above the lower level of the prophylactic/therapeutic plasma concentration for longer periods of time.
  • the oral extended release high dose compositions of the present invention are well-absorbed and possess other inherent advantages over conventional, immediate release dosage forms.
  • a less frequent dosing of the medicament, as is required by a sustained release dosage form increases the resultant patient compliance, provides a more sustained drug blood level response, and effects therapeutic action with less ingestion of a drug, thereby mitigating many potential side effects.
  • By providing a slow and steady release of mycophenolate sodium over time absorbed drug concentration spikes are mitigated or eliminated by affecting a smoother and more sustained blood level response.
  • the extended release composition results in a uniform and constant dissolution of mycophenolate sodium from the pharmaceutical formulation and is thus effective for an extended period of time. Further, the extended release compositions are easy to formulate and the process of preparation is reproducible.
  • the extended release compositions comprising mycophenolate sodium in a high dose as active agent in accordance with the invention characteristically releases the active agent in a sustained manner and the pharmaceutical activity maintains for a long period.
  • the frequency of administration of mycophenolate sodium can be decreased. More particularly, it has become possible to provide a pharmaceutical formulation containing mycophenolate sodium which may be administered only once a day. Furthermore, it has become possible according to the present invention to provide a pharmaceutical composition which is free from the risk for undesired effects caused by a transiently excessive concentration of the active agent and insures an expression of pharmacological efficacy over a sufficiently extended time period.
  • composition of the present invention which comprises treating mycophenolate sodium with one or more release controlling material(s), alongwith optionally one or more pharmaceutically acceptable excipient(s), and formulating into a suitable dosage form.
  • a process of preparation of the modified release composition of the present invention which comprises treating the active agent mycophenolate sodium alongwith at least one release controlling material(s) which is hydrophilic or hydrophobic or mixtures thereof optionally alongwith one or more pharmaceutically acceptable excipient(s), and formulating into a suitable dosage form.
  • the pharmaceutical composition of the present invention comprising mycophenolate sodium in a high dose is preferably formulated as an oral dosage form such as tablets, capsules, and the like.
  • the composition of the present invention is in the form of tablets.
  • the tablets can be prepared by either direct compression, dry compression (slugging), or by granulation.
  • the granulation technique is either aqueous or non-aqueous.
  • the non-aqueous solvent used is selected from a group comprising ethanol, isopropyl alcohol, acetone or methylene chloride.
  • the compositions of the present invention are in the form of compressed tablets, molded tablets, or products prepared by extrusion or film cast technique, and the like.
  • the composition of the present invention may be in the particulate form such a powder, granules, beads, pellets, mini-tablets or the like, preferably made into a single unit dosage form such as a tablet or capsule.
  • the compositions may be coated with a 'functional coating'.
  • 'functional coating' it is herein implied that the coating composition does not comprise of a enteric polymer but comprises a part of the active agent(s) and/or the composition comprises excipient(s) which aid in controlling the rate of release of the active agent(s) independent of the pH through GIT pHs and/or the composition comprises additionally another active agent which is different from the active agent present in the core composition.
  • the coating composition employed may be an aqueous, non-aqueous or a hydro-alcoholic system.
  • the solvents used to prepare a non-aqueous coating composition is selected from but not limited to a group comprising dehydrated alcohol, isopropyl alcohol, methylene chloride, acetone or any other solvent known to the art for such use, or mixtures thereof.
  • the coating composition can include an antitack agent such as talc, kaolin, titanium dioxide, silicon dioxide, alumina, starch, polacrilin potassium, microcrystalline cellulose or the like.
  • the composition comprises a high dose of mycophenolate sodium and comparatively lesser excipients
  • the mechanical strength of the composition according to the present invention is sufficiently high to withstand normal handling of a pharmaceutical composition and to enable the composition to be coated using traditional coating equipments well known to a person skilled in the art.
  • the pharmaceutical compositions of the present invention are intended for once-a-day or twice-a-day administration, preferably for once-a-day administration.
  • the once-a-day composition releases mycophenolate sodium in a desired manner so as to maintain prophylactic and/or therapeutic levels of the active agent in the plasma for extended period of time devoid of any substantial drug related toxicity, and also can be prepared in an easy and cost-effective manner.
  • the ..present -invention provides , once ⁇ a-day modified release ⁇ compositions ⁇ comprising mycophenolate sodium in high dose such that the inter- and intra-patient variability is alleviated or reduced.
  • the modified release mycophenolate sodium compositions of the present invention are stable, possess appreciable bioavailability characteristics, and are well-tolerated and safe.
  • the oral compositions comprising mycophenolate sodium for prophylactic and/or therapeutic use can release the drug in a desired manner such as to maintain prophylactic/therapeutic levels of the drug in the plasma for extended period of time but without causing drug related toxicity; and which can be prepared in an easy and cost-effective manner.
  • the single unit dosage form composition of the present invention comprising a high dose of mycophenolate sodium is a tablet.
  • oral solid dosage forms e.g. effervescent tablets, fast dispersible tablets, matrix tablets, minitablets, pulsed release tablets, pellets, capsules, granulates or powders, e.g. in a sachet or a bottle, may be produced and are encompassed within the scope of this invention.
  • the tablets of the present invention are, despite the high drug loading of at least about 10% by weight based on the total weight of the tablet, are convenient to administer. Furthermore, the tablets are stable, e.g. during storage, handling or packaging, effective and well-tolerated.
  • the tablets have improved mechanical properties; e.g. when uncoated tablets are scored, they are easy to divide to produce e.g. half doses.
  • the tablets obtained are stable both during the production process and during storage, e.g. for 2 years or even 3 years in conventional packaging.
  • the present invention provides an oral solid dosage form, e.g. tablet, wherein the mycophenolate sodium salt is in anhydrous or crystalline form or a mixture of both forms.
  • the tablet according to the present invention it is a characteristic of the tablet according to the present invention that despite the high content of mycophenolate sodium, it contains only a relatively small amount of pharmaceutically acceptable excipient(s). This advantageously results in a mechanically stable tablet having a size amenable to oral administration.
  • the total amount of one or more pharmaceutically acceptable excipient(s) in a given unit dosage form according to the present invention may be not more than about 80% by weight based on the total weight of the tablet.
  • the absolute amounts of each pharmaceutically acceptable excipient(s) and their relative amounts are dependent on the desired properties of the tablet and may also be chosen by routine experimentation.
  • the tablet may be chosen to exhibit accelerated release of the active agent mycophenolate sodium or an extended release of the said active agent.
  • the tablet is chosen to -exhibit an extended release of the mycophenolate sodium over a prolonged time period.
  • compositions may be in the form of oral osmotic systems (OROS), coated tablets, matrix tablets, press-coated tablets, rapidly disintegrating tablets and the like.
  • OROS oral osmotic systems
  • the compositions comprising a high dose of mycophenolate sodium may be preferably made as coated tablets.
  • the tablet compositions of the present invention may also be produced by direct compression of mycophenolate sodium and one or more pharmaceutically acceptable excipient(s). Alternatively granulation techniques such as melt granulation, wet granulation (aqueous or organic solvent) or roller compaction may be performed, followed by the compression step. Optionally the tablets may be film-coated using conventional coating equipments and methods.
  • the activity and characteristics of the high dose solid unit oral pharmaceutical dosage form compositions comprising mycophenolate sodium of the present invention may be indicated in standard animal trials e.g. observing the kidney allograft reaction in rat may be employed. Additionally, clinical trials e.g. observing the first acute rejection episodes or treatment failure six months after transplant of kidneys or maintaining a rejection-free state within 6 months after initiation of treatment with the invention might be conducted to substantiate the animal experiments.
  • the composition of the present invention additionally comprises at least one other active agent(s).
  • the other active agent useful in the present invention may be any agent known to the art that can be administered in combination with a immunosuppressant such as an active agent(s) selected from but not limited to a group comprising cardiovascular drug, respiratory drug, sympathomimetic drug, cholinomimetic drug, adrenergic agonist, adrenergic antagonist, analgesic/antipyretic, anesthetic, antiasthamatic, antibiotic, antidepressant, antidiabetic, antifungal, antihypertensive, anti-inflammatory, antineoplastic, antianxiety agent, antipsychotic, immunosuppressant, antimigraine agent, sedative/hypnotic, antianginal agent, antiarrhythmic, antiarthritic agent, antigout agent, anticoagulant, thrombolytic agent, antifibrinolytic agent, hemorheologic agent, antiplatelet agent, anticonvulsant, antiparkin
  • the other active agent useful in the present invention alongwith mycophenolate sodium is an immunosuppressant such as cyclosporine or a corticosteroid.
  • the present invention provides a method of immunosuppressing a subject which comprises administering a solid dosage form according to the present invention, e.g. a tablet, to a subject in need of such immunosuppression, optionally with the simultaneous, sequential or separate administration of another immunosuppressant or immunomodulatory compound, such as cyclosporine and/or a steroid.
  • the high dose solid unit oral pharmaceutical dosage form compositions comprising mycophenolate sodium are provided in unit dosage form wherein the core comprises mycophenolate sodium mixed in suitable proportions alongwith pharmaceutically acceptable excipients and may be prepared by any of the methods well-known in the pharmaceutical art.
  • the present invention provides use of the pharmaceutical composition comprising a high dose of mycophenolate sodium according to the present invention in reducing the variability in absorption of mycophenolate sodium throughout the gastro-intestinal tract by providing a substantially uniform sustained release in-vivo and also reducing the chances of causing any associated gastrointestinal side effects without compromising the bioavailability of said active agent.
  • a method of using the composition of the present invention comprising a high dose of mycophenolate sodium for the management such as prophylaxis, amelioration and/or treatment of immunosuppressant indicated disease(s)/disorder(s) especially for the treatment or prevention of organ, tissue or cellular allograft or xenograft rejection, e.g. after transplant, or the management of immune-mediated diseases (autoimmune diseases), which comprises administering to a subject in need thereof the composition comprising a pharmaceutically effective amount of mycophenolate sodium as the active agent.
  • autoimmune diseases immune-mediated diseases
  • the pharmaceutical composition comprising pharmaceutically effective amount of mycophenolate sodium as the active agent for the preparation of a medicament for the management such as prophylaxis, amelioration and/or treatment of immunosuppressant indicated disease(s)/disorder(s) especially for organ, tissue or cellular allograft or xenograft rejection, e.g. after transplant, or the management of immune-mediated diseases (autoimmune diseases).
  • a medicament for the management such as prophylaxis, amelioration and/or treatment of immunosuppressant indicated disease(s)/disorder(s) especially for organ, tissue or cellular allograft or xenograft rejection, e.g. after transplant, or the management of immune-mediated diseases (autoimmune diseases).
  • compositions of the present invention comprising a high dose of mycophenolate sodium are useful in the treatment and/or prevention of native or transgenic organ, tissue or cellular allograft or xenograft transplant rejection, e.g. for the treatment of recipients of e.g. heart, lung, combined heart-lung, liver, kidney, pancreatic, skin, pancreatic islet cell, neural cell or corneal transplant; including treatment and prevention of acute rejection; treatment and prevention of hyperacute rejection, e.g. as associated with xenograft rejection; and treatment and prevention of - chronic rejection r e.gr as-associated -with-graft- vessel disease.
  • the compositions of the -invention are also indicated for the treatment and prevention of graft-versus-host disease, such as following bone marrow transplantation.
  • compositions of the present invention comprising a high dose of mycophenolate sodium in a single unit system are also useful in the treatment and/or prevention of autoimmune diseases, e.g. immune-mediated diseases and inflammatory conditions, in particular inflammatory conditions with an etiology including an immunological component such as arthritis (for example rheumatoid arthritis, arthritis chronica progrediente and arthritis deformans) and rheumatic diseases.
  • autoimmune diseases e.g. immune-mediated diseases and inflammatory conditions, in particular inflammatory conditions with an etiology including an immunological component such as arthritis (for example rheumatoid arthritis, arthritis chronica progrediente and arthritis deformans) and rheumatic diseases.
  • compositions of the invention include, autoimmune hematological disorders, including, but not limited to hemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, sclerodoma, Wegener granulosis, dermatomyositis, polymyositis, chronic active hepatitis, primary bilary cirrhosis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, pemphigus, idiophatic sprue, inflammatory bowel diseases (including e.g.
  • ulcerative colitis and Crohn's disease endocrine ophthalmophathy
  • Graves disease sarcoidosis, multiple sclerosis, primary biliary cirrhosis, juvenile diabetes (diabetes mellitus type I), non-infectious uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis, vasculitides, glomerulonephritides (with and without nephrotic syndrome, e.g. including idiophatic nephrotic syndrome or minimal change nephropathy) and juvenile dermatomyositis.
  • step (ii) Polyvinyl pyrrolidone (PVP K-30) was weighed and dissolved in isopropyl alcohol under stirring, iii) The blend of step (iii) was granulated using the solution of step (ii), dried and passed through suitable sieves to obtain granules, iv) Step (iii) granules were lubricated with mesh #40 passed magnesium stearate and compressed to obtain tablets.
  • PVP K-30 Polyvinyl pyrrolidone
  • step (i) Mycophenolate sodium, lactose anhydrous, hydroxypropyl methylcellulose, polyethylene oxide and polyvinyl pyrrolidone k-90 were weighed and mixed together, ii) Polyvinylpyrrolidone K-30 was dissolved in isopropyl alcohol, iii) The blend of step (i) was granulated with the material of step (ii) and then passed through sieve of mesh size # 12 followed by drying. iv) The dried material was passed through sieve of mesh size # 24. v) The material of step (iv) was lubricated with sieve of mesh size # 60 passed magnesium stearate for 5 mins. vi) The lubricated granules of step (v) were compressed into tablet.

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Abstract

L'invention porte sur des compositions de forme posologique pharmaceutique à usage oral unitaire solide à haute dose comprenant, comme agent actif, une quantité de mycophénolate de sodium se situant entre plus de 720 mg environ et 1500 mg environ, de préférence entre 800 mg et 1 440 mg environ, calculée comme acide mycophénolique ; et un ou plusieurs excipients pharmaceutiquement acceptables. Plus spécifiquement, les compositions de forme posologique sont destinées à être administrées une ou deux fois par jour et délivrent un agent actif à libération prolongée libéré de façon soutenue in vivo pendant une durée prolongée. L'invention porte également sur un procédé de fabrication des formulations à haute dose et sur des procédés prophylactiques et/ou thérapeutiques d'utilisation de telles formes posologiques. La composition de la présente invention est facile à formuler, efficace, bien tolérée et ne présente pas de danger. Ladite composition est utile pour la gestion -prophylaxie et amélioration, par exemple- et/ou pour le traitement de maladies/troubles requérant des immunosuppresseurs, notamment pour le traitement ou la prévention d'un rejet d'allogreffe ou de xénogreffe d'organe, de tissu ou de cellule après transplantation, par exemple, ou pour la gestion de maladies immunoinduites (maladies autoimmunes).
PCT/IN2008/000651 2007-10-08 2008-10-08 Forme posologique pharmaceutique à usage oral unitaire solide à haute dose de mycophénolate de sodium et son procédé de fabrication WO2009047799A1 (fr)

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Cited By (14)

* Cited by examiner, † Cited by third party
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WO2011046546A1 (fr) * 2009-10-13 2011-04-21 Teva Pharmaceutical Industries Ltd. Compositions à libération retardée
BE1018740A3 (nl) * 2010-08-10 2011-07-05 Oystershell Nv Samenstelling voor de behandeling van vochtige epitheliale oppervlakken.
CN102793658A (zh) * 2012-08-23 2012-11-28 无锡福祈制药有限公司 一种含有麦考酚酸或麦考酚酸盐的骨架型制剂及其包衣片
US8361971B2 (en) 2010-06-07 2013-01-29 Telik, Inc. Tablet formulation of ezatiostat
US8759303B2 (en) 2010-06-07 2014-06-24 Telik, Inc. Compositions and methods for treating myelodysplastic syndrome
US8841476B2 (en) 2010-06-07 2014-09-23 Telik, Inc. Preparation of crystalline ezatiostat hydrochloride ansolvate form D
WO2014167442A1 (fr) 2013-03-26 2014-10-16 Wockhardt Limited Compositions pharmaceutiques comprenant de l'acide mycophénolique ou des sels de celui-ci
US8920838B2 (en) 2006-08-03 2014-12-30 Horizon Pharma Ag Delayed-release glucocorticoid treatment of rheumatoid disease
WO2018093289A1 (fr) * 2016-11-17 2018-05-24 Общество с ограниченной ответственностью "Изварино Фарма" Formulation orale solide et procédé de fabrication correspondant
CN110787206A (zh) * 2019-12-23 2020-02-14 卓和药业集团有限公司 一种含有麦考酚钠的药物组合物及其制备方法
RU2723255C2 (ru) * 2018-11-14 2020-06-09 Общество с ограниченной ответственностью "Изварино Фарма" Экструдат с микофенолятом натрия для получения пероральной твердой лекарственной формы
CN114569570A (zh) * 2022-03-15 2022-06-03 浙江长典药物技术开发有限公司 一种吗替麦考酚酯及制备方法
CN115192597A (zh) * 2022-08-08 2022-10-18 青海大学 用于防治肺动脉高压的药物组合物、其制备方法及应用
CN117442580A (zh) * 2023-12-21 2024-01-26 泊诺(天津)创新医药研究有限公司 一种高生物利用度麦考酚钠肠溶片及其制备方法

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WO1994026266A1 (fr) * 1993-05-13 1994-11-24 Syntex (U.S.A.) Inc. Formules a dose eleves
WO2006024479A2 (fr) * 2004-08-31 2006-03-09 Novartis Ag Compositions pharmaceutiques
WO2007093364A1 (fr) * 2006-02-15 2007-08-23 Sanofi-Aventis Nouvelles aryldihydroisoquinolinones à substitution azacyclyle, leur procédé de préparation et leur utilisation comme médicaments

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9504699B2 (en) 2006-08-03 2016-11-29 Hznp Limited Delayed-release glucocorticoid treatment of rheumatoid disease
US8920838B2 (en) 2006-08-03 2014-12-30 Horizon Pharma Ag Delayed-release glucocorticoid treatment of rheumatoid disease
WO2011046546A1 (fr) * 2009-10-13 2011-04-21 Teva Pharmaceutical Industries Ltd. Compositions à libération retardée
US8759303B2 (en) 2010-06-07 2014-06-24 Telik, Inc. Compositions and methods for treating myelodysplastic syndrome
US8841476B2 (en) 2010-06-07 2014-09-23 Telik, Inc. Preparation of crystalline ezatiostat hydrochloride ansolvate form D
US8361971B2 (en) 2010-06-07 2013-01-29 Telik, Inc. Tablet formulation of ezatiostat
BE1018740A3 (nl) * 2010-08-10 2011-07-05 Oystershell Nv Samenstelling voor de behandeling van vochtige epitheliale oppervlakken.
CN102793658A (zh) * 2012-08-23 2012-11-28 无锡福祈制药有限公司 一种含有麦考酚酸或麦考酚酸盐的骨架型制剂及其包衣片
WO2014167442A1 (fr) 2013-03-26 2014-10-16 Wockhardt Limited Compositions pharmaceutiques comprenant de l'acide mycophénolique ou des sels de celui-ci
WO2018093289A1 (fr) * 2016-11-17 2018-05-24 Общество с ограниченной ответственностью "Изварино Фарма" Formulation orale solide et procédé de fabrication correspondant
RU2723255C2 (ru) * 2018-11-14 2020-06-09 Общество с ограниченной ответственностью "Изварино Фарма" Экструдат с микофенолятом натрия для получения пероральной твердой лекарственной формы
CN110787206A (zh) * 2019-12-23 2020-02-14 卓和药业集团有限公司 一种含有麦考酚钠的药物组合物及其制备方法
CN114569570A (zh) * 2022-03-15 2022-06-03 浙江长典药物技术开发有限公司 一种吗替麦考酚酯及制备方法
CN114569570B (zh) * 2022-03-15 2023-03-24 浙江长典药物技术开发有限公司 一种吗替麦考酚酯及制备方法
CN115192597A (zh) * 2022-08-08 2022-10-18 青海大学 用于防治肺动脉高压的药物组合物、其制备方法及应用
CN117442580A (zh) * 2023-12-21 2024-01-26 泊诺(天津)创新医药研究有限公司 一种高生物利用度麦考酚钠肠溶片及其制备方法
CN117442580B (zh) * 2023-12-21 2024-04-05 泊诺(天津)创新医药研究有限公司 一种高生物利用度麦考酚钠肠溶片及其制备方法

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