WO1998004279A1 - Pharmaceutical compositions for the treatment of transplant rejection, autoimmune or inflammatory conditions comprising cyclosporin a and 40-0-(2-hydroxiethyl)-rapamycin - Google Patents

Pharmaceutical compositions for the treatment of transplant rejection, autoimmune or inflammatory conditions comprising cyclosporin a and 40-0-(2-hydroxiethyl)-rapamycin Download PDF

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Publication number
WO1998004279A1
WO1998004279A1 PCT/EP1997/004123 EP9704123W WO9804279A1 WO 1998004279 A1 WO1998004279 A1 WO 1998004279A1 EP 9704123 W EP9704123 W EP 9704123W WO 9804279 A1 WO9804279 A1 WO 9804279A1
Authority
WO
WIPO (PCT)
Prior art keywords
rapamycin
cyclosporin
hydroxyethyl
transcription inhibitor
administration
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP1997/004123
Other languages
English (en)
French (fr)
Inventor
Gerhard Zenke
Hendrik J. Schuurman
Barbara Haeberlin
Armin Meinzer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis AG
Original Assignee
Ciba Geigy AG
Novartis AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=26309775&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO1998004279(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority claimed from GBGB9615942.1A external-priority patent/GB9615942D0/en
Priority claimed from GBGB9705684.0A external-priority patent/GB9705684D0/en
Priority to DK01131018T priority Critical patent/DK1208847T3/da
Priority to DE69714861T priority patent/DE69714861T2/de
Priority to DK97937526T priority patent/DK0956034T3/da
Priority to EP97937526A priority patent/EP0956034B1/en
Priority to AU40124/97A priority patent/AU730781B2/en
Application filed by Ciba Geigy AG, Novartis AG filed Critical Ciba Geigy AG
Priority to JP50851398A priority patent/JP3942641B2/ja
Priority to CA2261666A priority patent/CA2261666C/en
Priority to SI9730389T priority patent/SI0956034T1/xx
Priority to NZ333657A priority patent/NZ333657A/xx
Priority to US09/230,618 priority patent/US6239124B1/en
Priority to AT97937526T priority patent/ATE222502T1/de
Priority to HK00102877.4A priority patent/HK1023720B/en
Publication of WO1998004279A1 publication Critical patent/WO1998004279A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • 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
    • 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
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention thus provides products and methods for co-administration of an IL-2 transcription inhibitor (e.g., cyclosporin A or FK506) and 40-O-(2-hydroxyethyl)-rapamycin, especially cyclosporin A and 40-O-(2-hydroxyethyl)-rapamycin, at synergistically effective dosages, e.g.,
  • compositions under 6 above also include compositions suitable for topical administration e.g., in the form of a dermal cream, ointment, gel or like preparation, especially in combination or association with penetration enhancing agents, e.g., for the treatment of autoimmune or inflammatory conditions of the skin, as well as composition in the form of an ocular cream, gel or eye-drop preparation, e.g. for the purposes of application to the eye, and inhalable compositions, e.g., for use in treatment of autoimmune or inflammatory conditions of the lungs and airways.
  • penetration enhancing agents e.g., for the treatment of autoimmune or inflammatory conditions of the skin
  • an ocular cream, gel or eye-drop preparation e.g. for the purposes of application to the eye
  • inhalable compositions e.g., for use in treatment of autoimmune or inflammatory conditions of the lungs and airways.
  • Suitable surfactants include reaction products of natural or hydrogenated vegetable oils and ethylene glycol, e.g., polyethoxylated castor oils available for example under the trade mark CREMOPHOR (H.P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende füre, Vol. 1, 3rd edition, 1989) e.g. CREMOPHOR RH 40 or EL; polyoxyethylene-glycerol- fatty acid esters, e.g. available under the trade mark TAGAT, e.g. TAGAT TO; and polyoxyethylene sorbitan fatty acid esters, e.g.
  • a solid dispersion in the form of a simple eutectic mixture, solid solution or solid micellar solution, glass suspension or glass solution of active agent/complex association may be formed which contains the IL-2 transcription inhibitor, e.g. cyclosporin A, with 40-O-(2-hydroxyethyl)-rapamycin in fine to molecularly dispersed form.
  • a solid dispersion is formed which is a co-precipitate of the H -2 transcription inhibitor, e.g. cyclosporin A, with 40-O-(2-hydroxyethyl)-rapamycin and a carrier medium e.g.
  • the invention provides a pharmaceutical composition in the form of a microemulsion or a microemulsion preconcentrate, or a solid dispersion, e.g. as described herein, comprising (i) a rapamycin, e.g. rapamycin or 40-O-(2-hydroxyethyl)-rapamycin, and (ii) an IL-2 transcription inhibitor, e.g. cyclosporin A or FK 506, preferably in a synergistic ratio, e.g. as described above, for use in treatment or prevention of a condition as described above, e.g., the treatment or prevention of an autoimmune or inflammatory condition, or transplant rejection, especially chronic rejection or xenograft rejection, for example,
  • a pharmaceutical composition in the form of a microemulsion or a microemulsion preconcentrate, or a solid dispersion, e.g. as described herein, comprising (i) a rapamycin, e.g. rapamycin or 40-
  • Synergy is shown between the 40-O-(2-hydroxyethyl)-rapamycin and cyclosporin A in the two-way mouse mixed lymphocyte reaction.
  • Spleen cells of BALB/c and CBA mice (1 x 10 from each strain) are cultured in duplicate in flat-bottom 96-well microtiter plates in the absence or presence of serially diluted compound in serum-free medium. After four days, 3 H-thymidine is added. Sixteen hours later, the cells are harvested and 3 H-thymidine incorporation is measured by liquid scintillation counting. Cell proliferation is assessed in the absence of compounds (100% value) or in the presence of serially diluted compounds or combinations of compounds.
  • the maximum 3 H thymidine incorporation (100% value) is around 240 x 10 3 cpm, and the background 3 H-thymidine incorporation in unstimulated cells is around 5 x 10 3 cpm.
  • Drug concentrations at which the maximum proliferative response is inhibited by 70% are calculated using a four- parameter logistic function.
  • the IC 70 is 21 nM for cyclosporin A and 0.3 nM for 40-O-(2- hydroxyethyl)-rapamycin.
  • EXAMPLE 2 Synergism between 40-O-(2-hydroxyethyl)-rapamycin and cyclosporin A in vivo
  • Synergism in vivo is shown using orthotopic kidney and heterotopic heart allotransplantation models in male Lewis rats (RT1 ' haplotype) using donor organs from male DA rats (RTl a haplotype).
  • the termination point in long term survivors is 100 days.
  • the graft is removed at autopsy, fixed in buffered formalin, and embedded in paraffin.
  • Four micron thick sections stained with hematoxylin and eosin are read for signs of rejection and scored as "no rejection”, or “marginal”, “slight”, “moderate”, or “severe” cellular rejection based on the extent of mononuclear cell infiltration and damage to the parenchyma (tubules in the kidney, myocytes in the heart).
  • Cyclosporin A (NEORAL) and/or 40-O-(2-hydroxyethyl)-rapamycin are given daily orally in a microemulsion preconcentrate vehicle. Allograft survival data and histology are presented in Table 1. The minimum effective dose of cyclosporine A giving long term allograft survival is 5.0 mg/kg body weight, with a slight rejection in graft histology. For 40-O-(2-hydroxyethyl)- rapamycin, a dose of 5.0 mg kg must be given for long term survival of a kidney allograft; this dose is not fully effective for heart allograft.
  • a dose of 1.0 or 2.0 mg kg cyclosporin A is combined with dosages of 0.5, 1.0 or 2.0 mg/kg 40-O-(2-hydroxyethyl)-rapamycin.
  • Long term survival of the kidney allograft is seen at the lowest dosages of both compound; long term survival of the heart allograft at 1.0 mg/kg of each compound.
  • the histology of the long term surviving allografts is improved.
  • the index of synergy for the kidney transplant model is about 0.3 (1.0 mg/kg cyclosporin A) to 0.5 (2.0 mg/kg cyclosporin A), and for heart transplant, ⁇ 0.5 (1.0 mg/kg cyclosporin A) and ⁇ 0.7 (2.0 mg kg cyclosporin A).
  • the in vivo synergy of the compounds is even greater than would be predicted from the in vitro results.
  • a soft gelatin capsule suitable for oral administration is prepared containing the following composition in a 500mg dosage
  • the composition is stable and no precipitation is observed.
  • Soft gelatin capsules suitable for oral administration are prepared containing the following compositions, each in a 500mg dosage
  • a solid dispersion formulation is prepared containing the following components in parts by weight:
  • the components are dissolved in a 1 : 1 absolute ethanol/acetone mixture.
  • the solvents are evaporated and the resulting dry residue milled to a fine powder with mean particle size around 0.1 to 0.4 mm.
  • the fine powder is tabletted or filled into hard capsules.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Dermatology (AREA)
  • Pulmonology (AREA)
  • Rheumatology (AREA)
  • Transplantation (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Graft Or Block Polymers (AREA)
  • Medicinal Preparation (AREA)
PCT/EP1997/004123 1996-07-30 1997-07-29 Pharmaceutical compositions for the treatment of transplant rejection, autoimmune or inflammatory conditions comprising cyclosporin a and 40-0-(2-hydroxiethyl)-rapamycin Ceased WO1998004279A1 (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
US09/230,618 US6239124B1 (en) 1996-07-30 1997-07-29 Pharmaceutical compositions for the treatment of transplant rejection or autoimmune or inflammatory conditions comprising cyclosporin A and 40-0-(2-hydroxyethyl)-rapamycin
HK00102877.4A HK1023720B (en) 1996-07-30 1997-07-29 Pharmaceutical compositions for the treatment of transplant rejection, autoimmune or inflammatory conditions comprising cyclosporin a and 40-0-(2-hydroxyethyl)-rapamycin
AT97937526T ATE222502T1 (de) 1996-07-30 1997-07-29 Kombinationspräparat mit hemmender wirkung auf die abstossung von transplantaten, autoimmunerkrankungen und entzündungen, welches cyclosporin a und 40-0-(2-hydroxyethyl)-rapamycin enthält
CA2261666A CA2261666C (en) 1996-07-30 1997-07-29 Pharmaceutical compositions for the treatment of transplant rejection, autoimmune or inflammatory conditions comprising cyclosporin a and 40-0-(2-hydroxiethyl)-rapamycin
DK97937526T DK0956034T3 (da) 1996-07-30 1997-07-29 Farmaceutiske præparater til behandling af transplantatafstødning, autoimmune eller inflammatoriske tilstande omfattende cyclosporin A og 40-O-(2-hydroxyethyl)-rapamycin
EP97937526A EP0956034B1 (en) 1996-07-30 1997-07-29 Pharmaceutical compositions for the treatment of transplant rejection, autoimmune or inflammatory conditions comprising cyclosporin a and 40-0-(2-hydroxyethyl)-rapamycin
AU40124/97A AU730781B2 (en) 1996-07-30 1997-07-29 Pharmaceutical compositions for the treatment of transplant rejection, autoimmune or inflammatory conditions comprising cyclosporin A and 40-0-(2-hydroxiethyl)-rapamycin
DK01131018T DK1208847T3 (da) 1996-07-30 1997-07-29 Farmaceutiske præparater til behandling af transplantatafstödning samt autoimmune eller inflammatoriske tilstande
JP50851398A JP3942641B2 (ja) 1996-07-30 1997-07-29 サイクロスポリンａおよび４０―ｏ―（２―ヒドロキシエチル）―ラパマイシンを含む移植拒絶、自己免疫疾患または炎症性状態の処置用医薬組成物
DE69714861T DE69714861T2 (de) 1996-07-30 1997-07-29 Kombinationspräparat mit hemmender wirkung auf die abstossung von transplantaten, autoimmunerkrankungen und entzündungen, welches cyclosporin a und 40-0-(2-hydroxyethyl)-rapamycin enthält
SI9730389T SI0956034T1 (en) 1996-07-30 1997-07-29 Pharmaceutical compositions for the treatment of transplant rejection, autoimmune or inflammatory conditions comprising cyclosporin a and 40-0-(2-hydroxyethyl)-rapamycin
NZ333657A NZ333657A (en) 1996-07-30 1997-07-29 A pharmaceutical composition comprising cyclosporin A and 40-O-(2-hydroxyethyl)-rapamycin

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB9615942.1 1996-07-30
GBGB9615942.1A GB9615942D0 (en) 1996-07-30 1996-07-30 Organic compounds
GBGB9705684.0A GB9705684D0 (en) 1997-03-18 1997-03-18 Organic compounds
GB9705684.0 1997-03-18

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US09/230,618 A-371-Of-International US6239124B1 (en) 1996-07-30 1997-07-29 Pharmaceutical compositions for the treatment of transplant rejection or autoimmune or inflammatory conditions comprising cyclosporin A and 40-0-(2-hydroxyethyl)-rapamycin
US09/758,301 Continuation US6455518B2 (en) 1996-07-30 2001-01-11 Pharmaceutical compositions for the treatment of transplant rejection, autoimmune or inflammatory conditions comprising cyclosporin a and 40-O-(2-hydroxyethyl)-rapamycin

Publications (1)

Publication Number Publication Date
WO1998004279A1 true WO1998004279A1 (en) 1998-02-05

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ID=26309775

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1997/004123 Ceased WO1998004279A1 (en) 1996-07-30 1997-07-29 Pharmaceutical compositions for the treatment of transplant rejection, autoimmune or inflammatory conditions comprising cyclosporin a and 40-0-(2-hydroxiethyl)-rapamycin

Country Status (14)

Country Link
US (2) US6239124B1 (enExample)
EP (2) EP1208847B8 (enExample)
JP (2) JP3942641B2 (enExample)
AT (2) ATE222502T1 (enExample)
AU (1) AU730781B2 (enExample)
CA (1) CA2261666C (enExample)
CY (1) CY2391B1 (enExample)
DE (2) DE69736750T2 (enExample)
DK (2) DK1208847T3 (enExample)
ES (2) ES2182112T3 (enExample)
NZ (1) NZ333657A (enExample)
PT (2) PT1208847E (enExample)
SI (1) SI1208847T1 (enExample)
WO (1) WO1998004279A1 (enExample)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2786771A1 (fr) * 1998-12-07 2000-06-09 Novartis Ag Procede de stabilisation d'un macrolide poly-ene et composition pharmaceutique contenant un tel compose
WO2000045834A3 (en) * 1999-02-05 2000-12-21 Univ Pittsburgh Use of aerosolized cyclosporine for prevention and treatment of pulmonary disease
WO2000067773A3 (en) * 1999-05-10 2001-06-28 Novartis Ag Combinations of immunosupressive agents for the treatment or prevention of graft rejections
WO2006095173A2 (en) 2005-03-11 2006-09-14 Biotica Technology Limited Medical uses of 39-desmethoxyrapamycin and analogues thereof
EP1967520A2 (en) 2002-07-16 2008-09-10 Biotica Technology Limited Production of polyketides and other natural products
US7648996B2 (en) 2005-03-11 2010-01-19 Biotica Technology Limited 39-desmethoxy derivatives of rapamycin
US7803808B2 (en) 2004-08-11 2010-09-28 Wyeth Llc Production of polyketides and other natural products
EP2258415A3 (en) * 2001-09-10 2011-03-23 Abbott Laboratories Medical devices containing rapamycin analogs
EP2255836A3 (en) * 2001-09-10 2011-04-06 Abbott Laboratories Medical devices containing rapamycin analogs
EP2583678A2 (en) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Small molecule immunopotentiators and assays for their detection
WO2013093493A1 (en) 2011-12-23 2013-06-27 Biotica Technology Limited Novel rapamycin analogue
EP2671583A4 (en) * 2011-01-31 2014-09-03 Univ Osaka EXTERNALLY USED MEDICAMENT FOR THE TREATMENT OF SKIN DISEASES AND MANUFACTURING METHOD THEREFOR
WO2018148508A1 (en) 2017-02-10 2018-08-16 Mount Tam Biotechnologies, Inc. Rapamycin analog

Families Citing this family (70)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE198041T1 (de) * 1993-09-28 2000-12-15 Scherer Gmbh R P Herstellung von weichgelatinekapseln
US5858401A (en) * 1996-01-22 1999-01-12 Sidmak Laboratories, Inc. Pharmaceutical composition for cyclosporines
ATE222502T1 (de) * 1996-07-30 2002-09-15 Novartis Ag Kombinationspräparat mit hemmender wirkung auf die abstossung von transplantaten, autoimmunerkrankungen und entzündungen, welches cyclosporin a und 40-0-(2-hydroxyethyl)-rapamycin enthält
US20030199425A1 (en) * 1997-06-27 2003-10-23 Desai Neil P. Compositions and methods for treatment of hyperplasia
GB9825632D0 (en) * 1998-11-23 1999-01-13 Novartis Ag Organic compounds
US20040102425A1 (en) * 2000-11-03 2004-05-27 Barr Alexander Stephen Selective glucocorticoid receptor agonists
US20020127263A1 (en) * 2001-02-27 2002-09-12 Wenda Carlyle Peroxisome proliferator-acitvated receptor gamma ligand eluting medical device
US8741378B1 (en) 2001-06-27 2014-06-03 Advanced Cardiovascular Systems, Inc. Methods of coating an implantable device
US20040137066A1 (en) * 2001-11-26 2004-07-15 Swaminathan Jayaraman Rationally designed therapeutic intravascular implant coating
US6641611B2 (en) * 2001-11-26 2003-11-04 Swaminathan Jayaraman Therapeutic coating for an intravascular implant
US20080145402A1 (en) * 2001-09-10 2008-06-19 Abbott Cardiovascular Systems Inc. Medical Devices Containing Rapamycin Analogs
US20030054042A1 (en) * 2001-09-14 2003-03-20 Elaine Liversidge Stabilization of chemical compounds using nanoparticulate formulations
CA2461730C (en) * 2001-10-19 2012-05-15 Isotechnika Inc. Novel cyclosporin analog microemulsion preconcentrates
CN100512809C (zh) * 2001-10-25 2009-07-15 阿特罗吉尼克斯公司 化合物在制备用于慢性移植排斥的药物中的用途
US6939376B2 (en) 2001-11-05 2005-09-06 Sun Biomedical, Ltd. Drug-delivery endovascular stent and method for treating restenosis
US7682387B2 (en) * 2002-04-24 2010-03-23 Biosensors International Group, Ltd. Drug-delivery endovascular stent and method for treating restenosis
US7109169B2 (en) * 2002-06-28 2006-09-19 Hobai Ion A Method for treating heart failure by inhibiting the sarcolemmal sodium/calcium exchange
BR0314013A (pt) * 2002-09-06 2005-07-12 Abbott Lab Equipamento médico contendo inibidor de hidratação
AU2003272471B2 (en) * 2002-09-18 2010-10-07 Trustees Of The University Of Pennsylvania Method of inhibiting choroidal neovascularization
US8202530B2 (en) * 2002-09-27 2012-06-19 Advanced Cardiovascular Systems, Inc. Biocompatible coatings for stents
AR043504A1 (es) * 2003-03-17 2005-08-03 Novartis Ag Composiciones farmaceuticas que comprenden rapamicina para el tratamiento de enfermedades inflamatorias
US7160867B2 (en) 2003-05-16 2007-01-09 Isotechnika, Inc. Rapamycin carbohydrate derivatives
BRPI0414000B8 (pt) * 2003-08-29 2021-05-25 Lifecycle Pharma As composição farmacêutica sólida oral de liberação prolongada contendo tacrolimus na forma de uma dispersão sólida, forma de dosagem, e, uso da composição farmacêutica
JP2007505932A (ja) 2003-09-18 2007-03-15 マクサイト， インコーポレイテッド 経強膜送達
US8709469B2 (en) 2004-06-30 2014-04-29 Abbott Cardiovascular Systems Inc. Anti-proliferative and anti-inflammatory agent combination for treatment of vascular disorders with an implantable medical device
US8021849B2 (en) * 2004-11-05 2011-09-20 Siemens Healthcare Diagnostics Inc. Methods and kits for the determination of sirolimus in a sample
AU2006213673A1 (en) * 2005-02-09 2006-08-17 Santen Pharmaceutical Co., Ltd. Formulations for ocular treatment
US8663639B2 (en) 2005-02-09 2014-03-04 Santen Pharmaceutical Co., Ltd. Formulations for treating ocular diseases and conditions
JP2008530145A (ja) * 2005-02-15 2008-08-07 ワイス 経口投与可能なｃｃｉ−７７９製剤
US8735394B2 (en) 2005-02-18 2014-05-27 Abraxis Bioscience, Llc Combinations and modes of administration of therapeutic agents and combination therapy
CN103285395A (zh) * 2005-02-18 2013-09-11 阿布拉科斯生物科学有限公司 治疗剂的组合和给予方式以及联合治疗
BRPI0609432A2 (pt) * 2005-03-21 2010-04-06 Macusight Inc sistemas de distribuição de fármacos para tratamento de doenças ou condições
EA200702216A1 (ru) * 2005-04-12 2008-08-29 Элан Фарма Интернэшнл Лимитед Композиции в форме наночастиц с контролируемым высвобождением, содержащие циклоспорин
US7189582B2 (en) * 2005-04-27 2007-03-13 Dade Behring Inc. Compositions and methods for detection of sirolimus
US20100004738A1 (en) * 2005-04-29 2010-01-07 Atrium Medical Corporation Drug delivery coating for use with a medical device and methods of treating vascular injury
US20070043096A1 (en) * 2005-07-18 2007-02-22 Horizon Therapeutics, Inc. Unit dose form with ibuprofen-famotidine admixture
US8067451B2 (en) 2006-07-18 2011-11-29 Horizon Pharma Usa, Inc. Methods and medicaments for administration of ibuprofen
US20080020040A1 (en) * 2006-07-18 2008-01-24 Horizon Therapeutics, Inc. Unit dose form for administration of ibuprofen
US20080021078A1 (en) * 2006-07-18 2008-01-24 Horizon Therapeutics, Inc. Methods and medicaments for administration of ibuprofen
BRPI0707612B8 (pt) 2006-02-09 2021-05-25 Macusight Inc vaso lacrado e formulações líquidas contidas no mesmo
US8222271B2 (en) 2006-03-23 2012-07-17 Santen Pharmaceutical Co., Ltd. Formulations and methods for vascular permeability-related diseases or conditions
US8067033B2 (en) 2007-11-30 2011-11-29 Horizon Pharma Usa, Inc. Stable compositions of famotidine and ibuprofen
WO2008027963A2 (en) * 2006-08-31 2008-03-06 Horizon Therapeutics, Inc. Nsaid dose unit formulations with h2-receptor antagonists and methods of use
US8661630B2 (en) 2008-05-21 2014-03-04 Abbott Cardiovascular Systems Inc. Coating comprising an amorphous primer layer and a semi-crystalline reservoir layer
DE102008060549A1 (de) 2008-12-04 2010-06-10 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Wirkstoff-Peptid-Konstrukt zur extrazellulären Anreicherung
US11304960B2 (en) 2009-01-08 2022-04-19 Chandrashekar Giliyar Steroidal compositions
BR112012024442A2 (pt) 2010-03-29 2017-03-21 Abraxis Bioscience Llc métodos de tratamento de câncer
CA2794147A1 (en) 2010-03-29 2011-10-06 Abraxis Bioscience, Llc Use of a composition comprising nanoparticles comprising a taxane and an albumin to improve uptake of chemotherapeutics by tumors and for treating a cancer that is highly fibrotic and/or has a dense stroma
US8685433B2 (en) 2010-03-31 2014-04-01 Abbott Cardiovascular Systems Inc. Absorbable coating for implantable device
RU2576609C2 (ru) 2010-06-04 2016-03-10 АБРАКСИС БАЙОСАЙЕНС, ЭлЭлСи Способы лечение рака поджелудочной железы
US9034858B2 (en) 2010-11-30 2015-05-19 Lipocine Inc. High-strength testosterone undecanoate compositions
US20180153904A1 (en) 2010-11-30 2018-06-07 Lipocine Inc. High-strength testosterone undecanoate compositions
US9358241B2 (en) 2010-11-30 2016-06-07 Lipocine Inc. High-strength testosterone undecanoate compositions
US20120148675A1 (en) 2010-12-10 2012-06-14 Basawaraj Chickmath Testosterone undecanoate compositions
US8809562B2 (en) 2011-06-06 2014-08-19 Chevron Phillips Chemical Company Lp Use of metallocene compounds for cancer treatment
US9220759B2 (en) 2012-02-23 2015-12-29 Abbott Cardiovascular Systems Inc. Treatment of diabetic patients with a drug eluting stent and adjunctive therapy
US9220584B2 (en) 2012-03-30 2015-12-29 Abbott Cardiovascular Systems Inc. Treatment of diabetic patients with a stent and locally administered adjunctive therapy
EP2705856A1 (en) 2012-09-07 2014-03-12 Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. Compounds for the treatment of neurodegenerative disorders
WO2014117035A1 (en) 2013-01-24 2014-07-31 Transderm, Inc. COMPOSITIONS FOR TRANSDERMAL DELIVERY OF mTOR INHIBITORS
BR112016006378A2 (pt) 2013-09-24 2017-08-01 Giner Inc sistema para tratamento de gás de um implante de célula
US20170246187A1 (en) 2014-08-28 2017-08-31 Lipocine Inc. (17-ß)-3-OXOANDROST-4-EN-17-YL TRIDECANOATE COMPOSITIONS AND METHODS OF THEIR PREPARATION AND USE
WO2016033556A1 (en) 2014-08-28 2016-03-03 Lipocine Inc. BIOAVAILABLE SOLID STATE (17-β)-HYDROXY-4-ANDROSTEN-3-ONE ESTERS
WO2016205423A2 (en) 2015-06-15 2016-12-22 Lipocine Inc. Composition and method for oral delivery of androgen prodrugs
US20180321258A1 (en) * 2015-11-06 2018-11-08 The Trustees Of Columbia University In The City Of New York Exosomal Protein Profiling for Detection of Cardiac Transplant Rejection
WO2018093956A1 (en) 2016-11-15 2018-05-24 Giner, Inc. Percutaneous gas diffusion device suitable for use with a subcutaneous implant
US11559530B2 (en) 2016-11-28 2023-01-24 Lipocine Inc. Oral testosterone undecanoate therapy
CA3049402A1 (en) 2017-01-06 2018-07-12 Palvella Therapeutics Llc Anhydrous compositions of mtor inhibitors and methods of use
JP7199632B2 (ja) 2017-05-04 2023-01-06 ガイナー，インク． 堅牢なインプラント可能なガス送達装置ならびにそれを含む方法、システムおよび装置
US11000513B2 (en) 2018-07-02 2021-05-11 Palvella Therapeutics, Inc. Anhydrous compositions of mTOR inhibitors and methods of use
US12150945B2 (en) 2018-07-20 2024-11-26 Lipocine Inc. Liver disease

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0401747A2 (en) * 1989-06-06 1990-12-12 Roy Calne Use of rapamycin and derivatives and prodrugs thereof in the manufacture of a medicament for inhibiting transplant rejection in mammals
WO1994009010A1 (en) * 1992-10-09 1994-04-28 Sandoz Ltd. O-alkylated rapamycin derivatives and their use, particularly as immunosuppressants
WO1997025977A1 (en) * 1996-01-19 1997-07-24 Novartis Ag Pharmaceutical compositions

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4894366A (en) 1984-12-03 1990-01-16 Fujisawa Pharmaceutical Company, Ltd. Tricyclo compounds, a process for their production and a pharmaceutical composition containing the same
US5286731A (en) 1991-09-17 1994-02-15 American Home Products Corporation Method of treating immunoinflammatory bowel disease
US5286730A (en) * 1991-09-17 1994-02-15 American Home Products Corporation Method of treating immunoinflammatory disease
ATE138807T1 (de) 1992-03-27 1996-06-15 American Home Prod 29-demethoxyrapamycin zur induktion der immunosuppression
GB2278780B (en) 1993-05-27 1998-10-14 Sandoz Ltd Macrolide formulations
GB9606452D0 (en) 1996-03-27 1996-06-05 Sandoz Ltd Organic compounds
ATE222502T1 (de) * 1996-07-30 2002-09-15 Novartis Ag Kombinationspräparat mit hemmender wirkung auf die abstossung von transplantaten, autoimmunerkrankungen und entzündungen, welches cyclosporin a und 40-0-(2-hydroxyethyl)-rapamycin enthält
ATE474590T1 (de) * 1999-05-10 2010-08-15 Paolo Brenner Kombination von immunsuppressiven substanzen zur behandlung oder vorbeugung von transplantat abstossungen

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0401747A2 (en) * 1989-06-06 1990-12-12 Roy Calne Use of rapamycin and derivatives and prodrugs thereof in the manufacture of a medicament for inhibiting transplant rejection in mammals
WO1994009010A1 (en) * 1992-10-09 1994-04-28 Sandoz Ltd. O-alkylated rapamycin derivatives and their use, particularly as immunosuppressants
WO1997025977A1 (en) * 1996-01-19 1997-07-24 Novartis Ag Pharmaceutical compositions

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
SCHULER W. ET AL: "SDZ-RAD, A NEW RAPAMYCIN DERIVATIVE. Pharmacological properties in vitro and in vivo", TRANSPLANTATION, vol. 64, no. 1, 15 July 1997 (1997-07-15), pages 36 - 42, XP002048032 *
SHUURMAN H.J. ET AL: "SDZ-RAD, A NEW RAPAMYCIN DERIVATIVE. SYNERGISM WITH CYCLOSPORINE", TRANSPLANTATION, vol. 64, no. 1, 15 July 1997 (1997-07-15), pages 32 - 35, XP002048030 *
TU Y. ET AL: "The synergistic effects of cyclosporine, sirolimus, and brequinar on heart allograft survival in mice", TRANSPLANTATION, 1995, 59/2 (177-183), USA, XP002048031 *

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Publication number Priority date Publication date Assignee Title
US7572804B2 (en) 1998-12-07 2009-08-11 Novartis Ag Macrolides
US7741338B2 (en) 1998-12-07 2010-06-22 Novartis Ag Macrolides
EP2269651A3 (en) * 1998-12-07 2011-03-09 Novartis AG Stabilisation of macrolides
BE1012869A3 (fr) * 1998-12-07 2001-04-03 Novartis Ag Procede de stabilisation d'un macrolide poly-ene et composition pharmaceutique contenant un tel compose.
EP2279751A3 (en) * 1998-12-07 2011-02-16 Novartis AG Stabilisation of macrolides
FR2786771A1 (fr) * 1998-12-07 2000-06-09 Novartis Ag Procede de stabilisation d'un macrolide poly-ene et composition pharmaceutique contenant un tel compose
US6605613B2 (en) 1998-12-07 2003-08-12 Novartis Ag Macrolides
RU2243769C2 (ru) * 1998-12-07 2005-01-10 Новартис Аг Стабилизация макролидов
US6852729B2 (en) 1998-12-07 2005-02-08 Novartis Ag Macrolides
WO2000033878A3 (en) * 1998-12-07 2000-11-02 Novartis Ag Stabilization of macrolides
EP1743657A3 (en) * 1998-12-07 2007-03-28 Novartis AG Stabilisation of macrolides
US7297703B2 (en) 1998-12-07 2007-11-20 Novartis Ag Macrolides
US8158110B2 (en) 1999-02-05 2012-04-17 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Use of aerosolized cyclosporine for prevention and treatment of pulmonary disease
WO2000045834A3 (en) * 1999-02-05 2000-12-21 Univ Pittsburgh Use of aerosolized cyclosporine for prevention and treatment of pulmonary disease
EP1980263A1 (en) * 1999-05-10 2008-10-15 Novartis AG Combinations of immunosuppressive agents for the treatment or prevention of graft rejections
JP2002544167A (ja) * 1999-05-10 2002-12-24 ノバルティス アクチエンゲゼルシャフト 有機化合物
WO2000067773A3 (en) * 1999-05-10 2001-06-28 Novartis Ag Combinations of immunosupressive agents for the treatment or prevention of graft rejections
US8435520B2 (en) 1999-05-10 2013-05-07 Paolo Brenner Combinations of immunosuppressive agents for the treatment or prevention of graft rejections
EP2255836A3 (en) * 2001-09-10 2011-04-06 Abbott Laboratories Medical devices containing rapamycin analogs
US10058641B2 (en) 2001-09-10 2018-08-28 Abbott Laboratories Medical devices containing rapamycin analogs
EP2258415A3 (en) * 2001-09-10 2011-03-23 Abbott Laboratories Medical devices containing rapamycin analogs
EP2277898A2 (en) 2002-07-16 2011-01-26 Biotica Technology Limited Rapamycin analogues
EP1967520A2 (en) 2002-07-16 2008-09-10 Biotica Technology Limited Production of polyketides and other natural products
EP2583678A2 (en) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Small molecule immunopotentiators and assays for their detection
US7803808B2 (en) 2004-08-11 2010-09-28 Wyeth Llc Production of polyketides and other natural products
US8008318B2 (en) 2005-03-11 2011-08-30 Biotica Technology Limited 39-desmethoxy derivatives of rapamycin
US7648996B2 (en) 2005-03-11 2010-01-19 Biotica Technology Limited 39-desmethoxy derivatives of rapamycin
WO2006095173A2 (en) 2005-03-11 2006-09-14 Biotica Technology Limited Medical uses of 39-desmethoxyrapamycin and analogues thereof
EP2671583A4 (en) * 2011-01-31 2014-09-03 Univ Osaka EXTERNALLY USED MEDICAMENT FOR THE TREATMENT OF SKIN DISEASES AND MANUFACTURING METHOD THEREFOR
WO2013093493A1 (en) 2011-12-23 2013-06-27 Biotica Technology Limited Novel rapamycin analogue
WO2018148508A1 (en) 2017-02-10 2018-08-16 Mount Tam Biotechnologies, Inc. Rapamycin analog

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ATE340586T1 (de) 2006-10-15
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DE69714861D1 (de) 2002-09-26
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AU730781B2 (en) 2001-03-15
JP2000505806A (ja) 2000-05-16
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US6239124B1 (en) 2001-05-29
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