WO2011128910A2 - Formulation pharmaceutique solide pour administration médicamenteuse à base de sirolimus - Google Patents

Formulation pharmaceutique solide pour administration médicamenteuse à base de sirolimus Download PDF

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Publication number
WO2011128910A2
WO2011128910A2 PCT/IN2011/000107 IN2011000107W WO2011128910A2 WO 2011128910 A2 WO2011128910 A2 WO 2011128910A2 IN 2011000107 W IN2011000107 W IN 2011000107W WO 2011128910 A2 WO2011128910 A2 WO 2011128910A2
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Prior art keywords
formulation
sirolimus
complexing agent
wetting agent
present
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Ceased
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PCT/IN2011/000107
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WO2011128910A3 (fr
Inventor
Saibal Chakravorty
Amit Kumar Jain
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RPG Life Sciences Ltd
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RPG Life Sciences Ltd
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Publication of WO2011128910A3 publication Critical patent/WO2011128910A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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

Definitions

  • a drug delivery solid dosage formulation of Sirolimus A drug delivery solid dosage formulation of Sirolimus.
  • the present invention relates to drug delivery formulation of Sirolimus.
  • the drug Sirolimus may also be referred- to as rapamycin is an antibiotic macrolide produced by actinomycete bacterium - Sterptomyces hygroscopicus. It was initially identified as antifungal agent capable of inhibiting growth of fungi such as Candida albicans and Microsporum gypseum. It is also reported to have antibiotic properties [US Patent No. 3,929,992 (US'992). It is also a potent immunosuppressant in preventing organ transplant rejection. Its immunosuppressant activities have been described in US Patent No. 5, 100,899.
  • tacrolimus Although it is a structural analogue of tacrolimus, it acts somewhat differently and has different side-effects.
  • Sirolimus is also effective against autoimmuno diseases, solid tumors, and adult T-Cell Leukemia or Lymphoma, and is capable of acting as anti- inflammatory drug. It has been found to be capable of inhibiting T-lymphocyte activation and proliferation that occurs in response to antigenic and cytokine (interleukin IL-2, IL-4 and IL-5). It stimulates distinctly different from other immunosuppressants.
  • Sirolimus is capable of preventing B cell differentiation into plasma cells, reducing production of IgM, IgG, and IgA antibodies.
  • FKBP-12 FK Binding Protein 12
  • the Sirolimus is insoluble in water, but freely soluble in organic solvents particularly, benzyl alcohol, chloroform, acetone and acetonitrile. Therefore, it has very poor dissolution and bioavailability.
  • organic solvents particularly, benzyl alcohol, chloroform, acetone and acetonitrile. Therefore, it has very poor dissolution and bioavailability.
  • Sirolimus is taken in the form of oral solution, its bioavailability is just 14% and in case it is taken in the form of a tablet its mean bioavailability is about 27%.
  • the fat contents in food have been found to increase its bioavailability, but due to added disadvantages of fat contents these are not desirable in food contents.
  • the present invention aims to provide an improved drug delivery system for a drug, particularly for an immunosuppressant drug, more particularly for Sirolimus which is capable of overcoming at least some of the above described disadvantages, limitations and drawbacks of prior art.
  • main object of the present invention is to provide a drug delivery solid dosage formulation of Sirolimus having improved dissolution.
  • the present invention relates to a drug delivery solid dosage formulation of Sirolimus as immunosuppressant drug, wherein the formulation has improved dissolution, bioavailability, and is independent of fat content in the physiological system, and wherein the sirolimus is surface treated with a complexing agent and wetting agent in dissolved state, and wherein the complexing agent is hydoxypropyl ⁇ - cyclodextrin (Kleptose HPB) and the wetting agent is selected from a group comprising polysorbate 80, sodium lauryl sulphate [SLS], propylene glycol, polyoxyl 40 hydrogenated castor oil (cremophor RH 40) and mixture thereof.
  • the complexing agent is hydoxypropyl ⁇ - cyclodextrin (Kleptose HPB)
  • the wetting agent is selected from a group comprising polysorbate 80, sodium lauryl sulphate [SLS], propylene glycol, polyoxyl 40 hydrogenated castor oil (
  • the Sirolimus is dissolved in an organic solvent, preferably in acetone.
  • the solvent for complexing agent is selected from a group comprising polyethylene glycol, ethyl alcohol and propylene glycol.
  • the solvent for complexing agent is preferably propylene glycol, which in present invention has been found to act not only as solvent for complexing agent, but also act as wetting agent. This dual purpose of propylene glycol has been found to improve the dissolution of Sirolimus in the formulation of present invention.
  • the wetting agent is preferably propylene glycol or polyoxyl 40 hydrogenated castor oil (Cremophor RH40), more preferably polyoxyl 40 hydrogenated castor oil (Cremophor RH40).
  • the solutions of Sirolimus in acetone and complexing agent in propylene glycol are mixed and to this solution a wetting agent is added which results in formation of a complex which has been surprisingly found to have enhanced dissolution inspite of Sirolimus being insoluble in water, and during the bioavailability studies it has been found to have improved bioavailability.
  • the complex resulted by surface treatment of Sirolimus with complexing agent and wetting agent in dissolved state is adsorbed or spreaded on a filler selected from a group comprising microcrystalline cellulose, powdered cellulose, polyols, binders and mixture thereof.
  • a filler selected from a group comprising microcrystalline cellulose, powdered cellulose, polyols, binders and mixture thereof.
  • the binder selected in accordance with present invention acts as filler as well as binder.
  • the formulation may optionally comprise disintegrant.
  • the binder is selected from a group comprising hydroxypropyl cellulose (Klucel LF Pharm), polyvinyl pyrrolidone, hydroxypropylmethyl cellulose, and mixture thereof.
  • the binder is preferably hydroxypropyl cellulose (Klucel LF Pharm) having a viscosity of 75 to 150 cps at 25°C in a 5% aqueous solution, which has been found to further enhance the compressibility of the dosage form to tablet.
  • the polyols is selected from group comprising pearlitol, sorbitol, mannitol, particularly the a- form of spray dried mannitol, and mixture thereof.
  • the polyols is preferably pearlitol, which is more preferably pearlitol SD 200, which has been found to further enhance the flowability of powder to compress to a tablet as well as it adsorb complex solution for improved dissolution.
  • the disintegrant is selected from a group comprising crosslinked polyvinyl pyrrolidone and Low- substituted Hydroxypropyl Cellulose (L-HPC, grade : LH-21), and mixture thereof.
  • the disintegrant is preferably Low-substituted Hydroxypropyl Cellulose (L-HPC, grade: LH-21) having a hydroxypropoxyl content of about 10.0 - 12.9%, which has been found to further enhance the dissolution by way of reducing the disintegration with faster drug release.
  • L-HPC Low-substituted Hydroxypropyl Cellulose
  • the dried powder obtained after adsorption or spreading on filler is lubricated to compress to tablets for film coating with a compound selected from a group comprising colloidal silicon dioxide (Aerosil 200) and magnesium stearate, and mixture thereof.
  • a compound selected from a group comprising colloidal silicon dioxide (Aerosil 200) and magnesium stearate, and mixture thereof is lubricated to compress to tablets for film coating with a compound selected from a group comprising colloidal silicon dioxide (Aerosil 200) and magnesium stearate, and mixture thereof.
  • the present invention also relates to a method for preparation of drug delivery solid dosage formulation of sirolimus comprising steps of:- a) preparing solutions of sirolimus in a solvent and of complexing agent in another solvent;
  • step-b) mixing solutions from step-a) and adding thereto a wetting agent resulting in formation of a complex of sirolimus, complexing agent and wetting agent; and c) adsorbing the complex from step-b) in dissolved state on a filler and allowing to dry to a powder form which is compressed to a tablet form;
  • complexing agent is hydoxypropyl ⁇ - cyclodextrin;
  • wetting agent is selected from a group comprising polysorbate 80, sodium lauryl sulphate [SLS], propylene glycol, polyoxyl 40 hydrogenated castor oil (cremophor RH 40) and mixture thereof.
  • the solution of Sirolimus is prepared in an organic solvent, preferably in acetone.
  • the solution of complexing agent is prepared in a solvent selected from group comprising polyethylene glycol and propylene glycol.
  • the solvent for complexing agent is preferably propylene glycol, which has been found to act not only as solvent for complexing agent, but also act as wetting agent. This dual purpose of propylene glycol has been found to improve the dissolution of Sirolimus in the formulation of present invention.
  • the wetting agent is preferably propylene glycol or polyoxyl 40 hydrogenated castor oil (Cremophor RH40), more preferably polyoxyl 40 hydrogenated castor oil (Cremophor RH40).
  • the filler is selected from a group comprising microcrystalline cellulose, powdered cellulose, polyols, binders and mixture thereof.
  • the binder acts as filler as well as binder.
  • the formulation may optionally comprise disintegrants.
  • the binder is selected from a group comprising hydroxypropyl cellulose (Klucel LF Pharm), polyvinyl pyrrolidone, and hydroxypropyl methyl cellulose, and mixture thereof.
  • the binder is preferably hydroxypropyl cellulose (Klucel LF Pharm), which has been found to enhance the compressibility of the dosage from to tablet.
  • the polyols is selected from group comprising pearlitol, sorbitol, and mannitol, particularly the a- form of spray dried mannitol, and mixture thereof.
  • the polyols is preferably pearlitol, which is more preferably pearlitol SD 200, which has been found to further enhance the flowability of Powder to compress to a tablet as well as it adsorb complex solution for improved dissolution.
  • the dried powder obtained after adsorption or spreading on filler is lubricated to compress to tablets for film coating with a compound selected from a group comprising colloidal silicon dioxide (Aerosil 200) and magnesium stearate, and mixture thereof.
  • a compound selected from a group comprising colloidal silicon dioxide (Aerosil 200) and magnesium stearate, and mixture thereof is lubricated to compress to tablets for film coating with a compound selected from a group comprising colloidal silicon dioxide (Aerosil 200) and magnesium stearate, and mixture thereof.
  • the tablet form from step - c) is further processed for film coating with opadry containing hydroxypropyle methyl cellulose having a viscosity of about 5 to 6 mps of 2 % w/v aqueous solution.
  • the film tablet obtained in accordance with present invention has been surprisingly and unexpectedly found to have improved dissolution and easy to swallow with water.
  • the drug delivery solid dosage formulation of Sirolimus is easy to be manufactured on mass scale production.
  • Sirolimus and the complexing agent - hydroxypropyl ⁇ - cyclodextrin are taken in a weight ratio varying from about 1 : 0.5 to about 4 : 2 w/w.
  • Sirolimus and the wetting agent which in accordance with present invention is preferably Cremophor RH 40 are taken in a weight ratio varying from about 0.5 : 2.25 to about 3 : 13.5 w/w.
  • Sirolimus, complexing agent [hydroxypropyl ⁇ - cyclodextrin (Kleptose HPB)] and the wetting agent [cremophor RH 40] are respectively taken in a weight ratio varying from about 0.5 : 0.25 : 2.25 to about 4 : 2 : 18 w/w.
  • the complexing agent [hydroxypropyl ⁇ - cyclodextrin (Kleptose HPB)], the wetting agent [Cremophor RH 40] and the solvent for complexing agent [propylene glycol] are respectively taken in a weight ratio varying from about 0.5 : 4.5 : 10 to about 4 : 36 : 40 w/w.
  • Sirolimus the wetting agent [Cremophor RH 40], the complexing agent [hydroxypropyl ⁇ - cyclodextrin (Kleptose HPB)] and the solvent [propylene glycol] are mixed, respectively, in a weight ratio of about 1 : 4.5 : 0.5 : 10 w/w.
  • the combination of binder to disintegrant where the binder is hydroxypropyl cellulose (Klucel LF Pharm) having a viscosity of 75 to 150 cps at 25°C in a 5% aqueous solution and disintegrant is low-substituted hydroxypropyl cellulose (L-HPC grade-LH- 21) having a hydroxypropoxyl content of about 10.0 - 12.9% is in the weight ratio of about 0.33 : 0.47 to about 4:5.64 w/w.
  • the binder is hydroxypropyl cellulose (Klucel LF Pharm) having a viscosity of 75 to 150 cps at 25°C in a 5% aqueous solution
  • disintegrant is low-substituted hydroxypropyl cellulose (L-HPC grade-LH- 21) having a hydroxypropoxyl content of about 10.0 - 12.9% is in the weight ratio of about 0.33 : 0.47 to about 4:5.64 w
  • microcrystalline cellulose may vary from about 40% to about 60% of the formulation.
  • Polyol which is preferably Pearlitol SD 200 may vary from about 10% to 30% w/w of the formulation.
  • Sirolimus acts as immunosuppressant drug.
  • the formulation comprises complex of Sirolimus as immunosupprasant drug in acetone, hydroxypropyl ⁇ - cyclodextrin as complexing agent in propylene glycol used as solvent as well as wetting agent.
  • the formulation comprises complex of Sirolimus as immunosupprasant drug in acetone, hydroxypropyl ⁇ - cyclodextrin as complexing agent in propylene glycol, Cremophor RH 40 as wetting agent.
  • formulation comprising complex of Sirolimus as immunosupprasant drug in acetone, hydroxypropyl ⁇ - cyclodextrin as complexing agent in propylene glycol used as solvent as well as wetting agent [Formulation - I] does demonstrate better in-vitro dissolution and better in-vivo bioavailability, however the formulation comprising complex of Sirolimus as immunosupprasant drug in acetone, hydroxypropyl ⁇ - cyclodextrin as complexing agent in propylene glycol, Cremophor RH 40 as wetting agent [Formulation - II], surprisingly and unexpectedly demonstrate further enhanced in-vivo bioavailability, confirming surprising and unexpected results for the formulations [Formulation - I and Formulation - II] of the present invention particularly for the formulation comprising complex of Sirolimus as immunosupprasant drug in acetone, hydroxypropyl ⁇ - cyclodextrin as complexing agent in propylene glycol,
  • formulations of present invention for a period upto day 14 at a dose of 2.0 mg per animal.
  • the formulation of Exp.03 comprising complex of Sirolimus as immunosuppressant drug in acetone, hydroxypropyl ⁇ - cyclodextrin as complexing agent in propylene glycol, Cremophor RH 40 as wetting agent - the most preferred embodiment of the present invention
  • formulation of Exp.04 comprising complex of Sirolimus as immunosupprasant drug in acetone, hydroxypropyl ⁇ - cyclodextrin as complexing agent in propylene glycol used as solvent as well as wetting agent - one of the preferred embodiments of the present invention were compared for the in-vivo bioavailability, using rat model of male and female gender, with that of Rapamune [of Batch No. D66317 of Wyeth Pharmaceuticals Ltd].
  • a 0.5 ml of blood was collected with EDTA as an anticoagulant in each of above experiment.
  • a screw capped plastic test tube a 0.5 ml of whole blood, 1.0 ml of ZnS0 4 (50 gms/lit) and 1.0 ml of acetone was added. It was mixed with Vortex Mixer for 20 seconds and then centrifiiged at 2600g at room temperature for 5.0 minutes. The supernatant was collected in a glass centrifuge tube. A 200 ⁇ NaOH (200 mmol / lit) was added to the supernatant. The tube was mixed with Vortex Mixer for 30 seconds. A 2.0 ml of 1-chlorobutane was added to it and again mixed with Vortex Mixer for 1.0 minute.
  • the supernatant was collected and was dried under nitrogen for 30 minutes.
  • the dry extract was reconstituted with 150 ⁇ of Mobile Phase and 500 ⁇ hexane.
  • the content was mixed with Vortex Mixer for 30 seconds and then centrifiiged at 2600g at Room Temperature for 2.0 minutes.
  • the hexane layer was discarded and the content of the tube was dried under nitrogen for 1.0 minute to remove any residue of hexane.
  • the 20 ⁇ extract was then injected to the HPLC column.
  • the mobile phase used was Acetonitrile : Water in the ratio of 95:05 with flow rate of 1.0 ml/ minute.
  • the analysis was conducted at 278 nm. The peak was detected at 4.73 to 4.87.
  • the pharmacokinetic experimental data for formulation of Exp. 03 and of reference formulation - Rapamune are given in Table III; and for formulation of Exp. 04 and of reference formulation - Rapamune are given in Table IV, wherein CI is Clearance, AUC is Area Under Curve, VSS is Volume of distribution at steady state, Cmax is concentration maximum in blood and Tmax is time maximum for reaching maximum concentration in blood.
  • Exp. 03 of present invention containing 2.0 mg Sirolimus when dosed in 100 gm male rat showed a Cmax of 35.03 ug/ml at 1.0 hour, and the clearance calculated was 5.709 ⁇ g/min/kg in male.
  • Exp. 03 of present invention containing 2.0 mg Sirolimus when dosed in 100 gm female rat showed a Cmax of 6.4 ⁇ g/ml at 1.0 hour, and the clearance calculated was 31.25 ⁇ g/min/kg in female.
  • the formulation of Exp. 04 of present invention containing 2.0 mg Sirolimus when dosed in 100 gm male rat showed a Cmax of 24.56 ⁇ g/ml at 1.0 hour, and the clearance calculated was 8.141 ⁇ g/min/k:g in male.
  • the formulation of Exp. 04 of present invention containing 2.0 mg Sirolimus when dosed in 100 gm female rat showed a Cmax of 3.2 ⁇ g ml at 0.5 hour, and the clearance calculated was 82.918 ⁇ g/min/kg in female.
  • Rapamune may have demonstrated better in-vitro dissolution, but its in-vivo bioavailability is much poorer than the formulations of present invention, particularly the formulations of Exp 03 and Exp 04 of the present invention.

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  • Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne une formulation pharmaceutique solide pour administration médicamenteuse à base de Sirolimus, présentant une dissolution in vitro et une biodisponibilité in vivo améliorées, le Sirolimus étant traité en surface avec un agent complexant et un agent mouillant à l'état dissous, ainsi que son procédé de préparation.
PCT/IN2011/000107 2010-03-02 2011-02-23 Formulation pharmaceutique solide pour administration médicamenteuse à base de sirolimus Ceased WO2011128910A2 (fr)

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IN534/MUM/2010 2010-03-02
IN534MU2010 2010-03-02

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015121836A1 (fr) 2014-02-14 2015-08-20 Druggability Technologies Ip Holdco Limited Complexes de sirolimus et leur dérivés, leur procédé de préparation et compositions pharmaceutiques les contenant
JP2017122083A (ja) * 2016-01-06 2017-07-13 日本化薬株式会社 ラパマイシン誘導体を含有する医薬組成物及びその製造方法
CN110585159A (zh) * 2019-09-12 2019-12-20 杭州华东医药集团新药研究院有限公司 一种含有西罗莫司的片剂
CN112641733A (zh) * 2020-12-30 2021-04-13 北京华氏开元医药科技有限公司 一种西罗莫司缓释微丸及其制备方法

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US3929992A (en) 1972-09-29 1975-12-30 Ayerst Mckenna & Harrison Rapamycin and process of preparation
US5100899A (en) 1989-06-06 1992-03-31 Roy Calne Methods of inhibiting transplant rejection in mammals using rapamycin and derivatives and prodrugs thereof
US5989591A (en) 1997-03-14 1999-11-23 American Home Products Corporation Rapamycin formulations for oral administration

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CN101366715A (zh) * 2007-08-15 2009-02-18 上海医药工业研究院 一种雷帕霉素组合物及其制备方法
CN101129362B (zh) * 2007-08-16 2010-10-06 江苏信孚药业有限公司 西罗莫司分散片及其制备方法
US20090130210A1 (en) * 2007-09-11 2009-05-21 Raheja Praveen Pharmaceutical compositions of sirolimus
CN101361703B (zh) * 2008-09-24 2010-11-03 宋洪涛 西罗莫司缓控释制剂及其制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3929992A (en) 1972-09-29 1975-12-30 Ayerst Mckenna & Harrison Rapamycin and process of preparation
US5100899A (en) 1989-06-06 1992-03-31 Roy Calne Methods of inhibiting transplant rejection in mammals using rapamycin and derivatives and prodrugs thereof
US5989591A (en) 1997-03-14 1999-11-23 American Home Products Corporation Rapamycin formulations for oral administration

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015121836A1 (fr) 2014-02-14 2015-08-20 Druggability Technologies Ip Holdco Limited Complexes de sirolimus et leur dérivés, leur procédé de préparation et compositions pharmaceutiques les contenant
JP2017122083A (ja) * 2016-01-06 2017-07-13 日本化薬株式会社 ラパマイシン誘導体を含有する医薬組成物及びその製造方法
CN110585159A (zh) * 2019-09-12 2019-12-20 杭州华东医药集团新药研究院有限公司 一种含有西罗莫司的片剂
CN110585159B (zh) * 2019-09-12 2021-11-02 杭州华东医药集团新药研究院有限公司 一种含有西罗莫司的片剂
CN112641733A (zh) * 2020-12-30 2021-04-13 北京华氏开元医药科技有限公司 一种西罗莫司缓释微丸及其制备方法

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