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WO1990000540A1 - Utilisation de metabolites ou d'analogues de la vitamine d pour la prevention de rejet de greffes - Google Patents

Utilisation de metabolites ou d'analogues de la vitamine d pour la prevention de rejet de greffes Download PDF

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Publication number
WO1990000540A1
WO1990000540A1 PCT/DK1989/000142 DK8900142W WO9000540A1 WO 1990000540 A1 WO1990000540 A1 WO 1990000540A1 DK 8900142 W DK8900142 W DK 8900142W WO 9000540 A1 WO9000540 A1 WO 9000540A1
Authority
WO
WIPO (PCT)
Prior art keywords
dihydroxyvitamin
prevention
use according
homo
vitamin
Prior art date
Application number
PCT/DK1989/000142
Other languages
English (en)
Inventor
Lise Binderup
Original Assignee
Leo Pharmaceutical Products Ltd. A/S (Løvens Kemiske Fabrik Produktionsaktieselskab)
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
Application filed by Leo Pharmaceutical Products Ltd. A/S (Løvens Kemiske Fabrik Produktionsaktieselskab) filed Critical Leo Pharmaceutical Products Ltd. A/S (Løvens Kemiske Fabrik Produktionsaktieselskab)
Publication of WO1990000540A1 publication Critical patent/WO1990000540A1/fr

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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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems

Definitions

  • the present invention relates to a method for the prevention of graft rejection, and to the preparation of a pharmaceutical preparation for the treatment of patients having undergone transplantation of various organs and tissue.
  • the preferred drug for prevention of graft rejection in the clinic is cyclosporin A, but the use of this com- pound is limited by its adverse effect, e.g. nephro- toxicity.
  • l ⁇ ,25-dihydroxyvitamin D reflex in the following also referred to as l ⁇ ,25-(OH)_D 3
  • immunosuppresive agents prolongs skin graft survival in mice (Jordan, S.C., Shibuka, R., Mullen, Y. : Abstract Seventh workshop of vitamin D, Collinso Mirage, California, April 24-29 (1988), p. 67).
  • the dose of l ⁇ ,25-(OH) 2 D 3 which can be administered is limited by a high mortality rate in mice given more than the minimal active dose thus limiting the potential use of this com ⁇ pound in treatment of diseases characterized by graft versus host or host versus graft rejection, especially in the prevention of graft rejection in humans.
  • Such compounds can be given in a higher and more ef ⁇ fective dose than l ⁇ ,25-(OH)-D 3 without side effects caused by hypercalcemia. Furthermore, these compounds are well tolerated and do not give rise to adverse effects, such as the nephro- toxicity caused by cyclosporin A.
  • vitamin D metabolites and analogues for use in the present pharmaceutical preparations are listed below.
  • the treatment may be performed with the vitamin D compound or analogue alone or in combination with an immunosuppresive agent such as cyclosporin A, a steroid such as prednisone, azathioprine, cyclophosphamide or anti- lymphocyte serum.
  • an immunosuppresive agent such as cyclosporin A, a steroid such as prednisone, azathioprine, cyclophosphamide or anti- lymphocyte serum.
  • the present compounds are intended for use in pharma ⁇ ceutical preparations which are useful in the treatment of human disorders as described above.
  • the amount required of the active compound for thera- Treatment effect will, of course, vary both with the partic ⁇ ular compound and the route of administration.
  • the com ⁇ pounds of the invention can, as mentioned above, be admini ⁇ stered by the parenteral, enteral or topical route. When the active compound is well absorbed when given enterally, this is the preferred form of administration in the sys ⁇ temic treatment of the said disorder.
  • the active compound While it is possible for an active compound to be administered alone as the raw chemical, it is preferable to present it as a pharmaceutical preparation. Conveniently, the active compound comprises from 0.1 ⁇ g/g to 1 mg/g of the preparation.
  • dosage unit a unitary, i.e. a single dose which is capable of being administered to a patient, and which may be readily handled and packed, re ⁇ maining as a physically and chemically stable unit dose comprising either the active material as such or a mixture of it with solid or liquid pharmaceutical diluents or car- riers.
  • the preparations of the present invention comprise an active compound in association with a pharmaceutically ac ⁇ ceptable carrier therefore and optionally other therapeutic ingredient(s).
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the preparations and not deleterious to the recipient thereof.
  • the preparations include e.g. those in a form suit ⁇ able for oral, rectal, parenteral (including subcutaneous, and intravenous), and topical administration.
  • the preparations may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active compound into association with the carrier which constitutes one or more accessory ingre- promo- promotes.
  • the preparations are prepared by uni ⁇ formly and intimately bringing the active compound into association with a liquid carrier or a finely divided, solid carrier or both, and then, if necessary, shaping the prod ⁇ uct into the desired preparation.
  • Preparations of the present invention suitable for oral administration may be in the form of discrete units as capsules, sachets, tablets or lozenges, each containing a predetermined amount of the active compound; in the form of a powder or granules; in the form of a solution or a sus ⁇ pension in an aqueous liquid or non-aqueous liquid; or in the form of an oil-in-water emulsion or a water-in-oil emulsion.
  • the active compound may also be administered in the form of a bolus, electuary or paste.
  • a tablet may be made by compressing or moulding the active compound optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by comp ⁇ ressing, in a suitable machine, the active compound in a free-flowing form such as a powder or granules, optionally mixed by a binder, lubricant, inert diluent, surface active or dispersing agent.
  • Moulded tablets may be made by mould ⁇ ing, in a suitable machine, a mixture of the powdered active compound and suitable carrier moistened with an inert liquid diluent.
  • Preparations for rectal administration may be in the form of a suppository incorporating the active compound and a carrier such as cocoa butter, or in the form of an enema.
  • Preparations suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active compound which is preferably isotonic with the blood of the recipient.
  • Preparations suitable for topical administration in- elude liquid or semi-liquid preparations such as liniments, lotions, applicants, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or sus ⁇ pensions such as drops.
  • the preparations of this invention may include one or more additional ingredients such as diluents, buffers, flavour ⁇ ing agents, binders, surface active agents, thickeners, lubricants, preservatives, e.g. methyl hydroxybenzoate (including anti-oxidants), emulsifying agents and the like.
  • additional ingredients such as diluents, buffers, flavour ⁇ ing agents, binders, surface active agents, thickeners, lubricants, preservatives, e.g. methyl hydroxybenzoate (including anti-oxidants), emulsifying agents and the like.
  • the preparations may further contain other therapeu- tically active compounds usually applied in the above mentioned treatment.
  • ointments, creams, or lo ⁇ tions containing from 1-500 ⁇ g/g of the vitamin D analogues or metabolites are administered.
  • the oral preparations are formulated, preferably as tablets, capsules, or drops, con- taining from 0.5-1000 ⁇ g of the vitamin D analogues or metabolites, per dosage unit.
  • the present invention further concerns a method for treating patients in risk of experiencing graft rejection, said method consisting of administering to a patient in need of treatment an effective amount of one or more of the above mentioned vitamin D analogues or metabolites, alone or in combination with one or more other therapeutically active compounds usually applied in such treatment.
  • the treatment with the present compounds and/or with further therapeutically active compounds may be simultaneous or with intervals.
  • MC-903 In 1 g almond oil was dissolved 1 mg MC 903. To this solution was added 40 g of mineral oil and 20 g of self- -emulsifying beeswax. The mixture was heated to liquify. After the addition of 40 ml hot water, the mixture was mixed well. The resulting cream contains approximately 10 ⁇ g of MC 903 per gram of cream.
  • Example 2 Capsules containing 22-oxa-l ⁇ ,25-dihv- droxyvitamin D 3 22-oxa-l ⁇ ,25-dihydroxyvitamin D 3 was suspended in arachis oil to a final concentration of 50 ⁇ g 22-oxa-l ⁇ ,25- -dihydroxyvitamin D 3 /ml oil. 10 Parts by weight of gela ⁇ tine, 5 parts by weight glycerine, 0.08 parts by weight potassium sorbate, and 14 parts by weight distilled water were mixed together with heating and formed into soft gela ⁇ tine capsules.
  • each capsule contained 5 ⁇ g 22-oxa-l ⁇ ,25-di- hydroxyvitamin D 3 .

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé de prévention de rejet de greffe, ainsi qu'une préparation pharmaceutique destinée au traitement de patients ayant subi une transplantation de divers organes et tissus. La préparation contient un métabolite ou un analogue de vitamine D n'ayant qu'une activité modérée sur le métabolisme de calcium par comparaison avec la 1α,25-dihydroxyvitamine D3, mais ayant conservé la capacité d'activer des récepteurs pour la 1α,25-dihydroxyvitamine D3 non associée à l'absorption de calcium.
PCT/DK1989/000142 1988-07-12 1989-06-08 Utilisation de metabolites ou d'analogues de la vitamine d pour la prevention de rejet de greffes WO1990000540A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB8816505.5 1988-07-12
GB888816505A GB8816505D0 (en) 1988-07-12 1988-07-12 Novel treatment

Publications (1)

Publication Number Publication Date
WO1990000540A1 true WO1990000540A1 (fr) 1990-01-25

Family

ID=10640270

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DK1989/000142 WO1990000540A1 (fr) 1988-07-12 1989-06-08 Utilisation de metabolites ou d'analogues de la vitamine d pour la prevention de rejet de greffes

Country Status (2)

Country Link
GB (1) GB8816505D0 (fr)
WO (1) WO1990000540A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998055127A1 (fr) * 1997-06-06 1998-12-10 Wisconsin Alumni Research Foundation Utilisation de composes de la vitamine d pour eviter les rejets de greffes

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4226788A (en) * 1979-03-28 1980-10-07 Wisconsin Alumni Research Foundation 24,24-Difluoro-1α,25-dihydroxycholecalciferol
US4341774A (en) * 1979-08-10 1982-07-27 Chugai Seiyaku Kabushiki Kaisha Method for suppressing abnormal rise in immunological function and agent useful therefor
WO1985000819A1 (fr) * 1983-08-18 1985-02-28 Wisconsin Alumni Research Foundation 23,23-DIFLUORO-1alpha, 25-DIHYDROXY-VITAMINE D3
WO1987000834A1 (fr) * 1985-08-02 1987-02-12 Leo Pharmaceutical Products Ltd. A/S Nouveaux analogues de la vitamine d
US4749710A (en) * 1985-05-01 1988-06-07 Hoffmann-La Roche Inc. Immunosuppressive agents

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4226788A (en) * 1979-03-28 1980-10-07 Wisconsin Alumni Research Foundation 24,24-Difluoro-1α,25-dihydroxycholecalciferol
US4341774A (en) * 1979-08-10 1982-07-27 Chugai Seiyaku Kabushiki Kaisha Method for suppressing abnormal rise in immunological function and agent useful therefor
WO1985000819A1 (fr) * 1983-08-18 1985-02-28 Wisconsin Alumni Research Foundation 23,23-DIFLUORO-1alpha, 25-DIHYDROXY-VITAMINE D3
US4749710A (en) * 1985-05-01 1988-06-07 Hoffmann-La Roche Inc. Immunosuppressive agents
WO1987000834A1 (fr) * 1985-08-02 1987-02-12 Leo Pharmaceutical Products Ltd. A/S Nouveaux analogues de la vitamine d

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
BIOCHEMICAL PHARMACOLOGY, Vol. 37, No. 5, 1988, LISE BINDERUP et al.: "Effects of a novel vitamin D analogue MC 903 on cell proliferation and differentiation in vitro and on calcium metabolism in vivo", pages 889-895. *
CHEM. PHARM. BULL., Vol. 35, No. 10, 1987, NOBUO IKEKAWA et al.: "26,27-diethyl-l alpha,25-dihydroxyvitamin D3 and 24,24-difluoro-24-homo-1,alpha,25-dihydroxy vitamin D3: Highly potent inducer for differentiation of human leukemia cells HL-60", pages 4362-4365. *
CHEMICAL ABSTRACTS, Vol. 107, No. 23, 7 December 1987, (Columbus, Ohio, USA); IKEKAWA NOBUO: "A process for the preparation of 24a,24a-difluoro-l alpha,25-dihydroxy-24-homovitamin D3", see page 622, abstract 217935w; & WO,A,8703282, 4 June 1987. *
FEBS LETTERS, Vol. 226, No. 1, December 1987, JUNKO ABE et al.: "Synthetic analogues of vitamin D3 with an oxygen atom in the side chain skeleton", pages 58-62. *
TETRAHEDRON, Vol. 43, No. 20, 1987, MARTIN J. CALVERLEY: "Synthesis of MC 903, a biologically active vitamin D metabolite analogue", pages 4609-4619. *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998055127A1 (fr) * 1997-06-06 1998-12-10 Wisconsin Alumni Research Foundation Utilisation de composes de la vitamine d pour eviter les rejets de greffes
US6071897A (en) * 1997-06-06 2000-06-06 Wisconsin Alumni Research Foundation Use of vitamin D compounds to prevent transplant rejection

Also Published As

Publication number Publication date
GB8816505D0 (en) 1988-08-17

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