Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1995-02-22
1997-09-23
Tsang, Cecilia J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 9, 514885, 530317, A61K 3800, A61K 3812, C07K 500, C07K 700
Patent
active
056704780
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention concerns medical preparations for internal use, or for another use, containing poly-N-methylated monocyclic undecapeptides called cyclosporins.
BACKGROUND ART
This group of stucturally similar peptides called cyclosporins is produced by some deuteromycetes, such as e.g. Tolypocladium inflatum (Swiss pat. 589 716 and 603 790) or Tolypocladium terricola (Matha et al., Cytobios 69, 163-170, 1992). Besides cyclosporin A (=cyclosporin) of formula I a number of structurally similar natural cyclosporins was isolated (Traber et al., Helv. Chim. Acta 65, 1655-1667, 1982). Modified cyclosporins which were prepared by partial synthesis were described also in EPA 0216 122 or in Czechoslovak patent 277 472. ##STR1##
Especially immunosuppressive properties of systemically administered cyclosporin are used in therapy or during organ transplants or bone marrow transplants. It is also applicable in treatment of broad range of autoimmune diseases of inflammatory etiology and also as antiparasitic treatment. Cyclosporin is used e.g. in rheumatic diseases (rheumatoid polyarthritis), hematologic diseases (aplastic anemia, idiopathic thrombocytopenia), gastric disorders (ulcerating colitis, Crohn disease), dermatic diseases (psoriasis, sclerodermia) and eye diseases (uveitis). Also topical applications have been tested e.g. in treatment of psoriasis, uveitis and allopecia.
Bioavailability of cyclosporin varies between 20-50% for currently available dosage formulations (Wood A. J., et al., Transplant Proc., 15, suppl. 2409, 1983). There are significant differences between groups of patients. E.g. there is a low bioavailability in liver acceptors, and increased bioavailability in bone marrow transplantation. The interpersonal variability of biovailability is considerably greater, ranging from a few percent to 90%. This is complicated also by the presence of significant variations in the course of the treatment.
Effective immunosuppressive treatment requires keeping a certain level of cyclosporin in blood and maintaining this level in certain range. The range required is always specific depending upon therapeutic goal. E.g. in cases of graft rejection or in treatment of autoimmune disease, it is necessary to take into account application of another immunosuppressant at the same time. When formulating medical drugs with cyclosporins, it is important to take into account their high lipophilicity. Solubility of these drugs in water varies usually from 1.6-2.3 mg/100 ml and does not exceed 4 mg/100 ml. Cyclosporins are not sufficiently resorbed from usual carriers in both liquid or solid state. This problem is solved in Swiss patent 636013 by using sezame oil and/or non-ionogenic tenside and/or reesterified non-ionogenic triglyceride and/or a mixture containing one or more lecithins, reeesterified non-ionogenic triglycerides or ethyloleate and/or neutral oil.
Another Swiss patent 641356 is trying to improve resorption of cyclosporins by adding transesterification products of triglycerides with polyethylenglycols and/or saturated triglyceride of fatty acid and/or mono or diglycerides.
Therapeutically suitable concentrations of cyclosporins in liquid carriers show low stability towards precipitations from the solutions and the solutions are usually badly tolerated. Injection preparations containing a non-ionogenic tenside (Cremophor EL) can develop the anaphylactic reaction (Lorenc W. et al.: Agents and Actions 12, 64-80, 1982) and cause washing out of additives from plastic parts of devices for parenteral applications.
An oral formualtion with transesterification product of triglyceride with polyethylenglycols (Labrafil.RTM. M1944 CS) forms an emulsion of v/o type in which phases are easily separated.
Insufficient tolerance of injection cyclosporin preparations containing non-ionogenic tensides was solved in a French patent 2608427 by preparing a lyophilisate for ad hoc formulation of sub-microne suspension. However, this process is energy-consuming when working with larger volumes of carrier c
REFERENCES:
patent: 3951945 (1976-04-01), Heesen et al.
patent: 4388307 (1983-06-01), Cavanak
patent: 4996193 (1991-02-01), Hewitt et al.
Descotes et al., Immunotoxicity Screening of Drugs & Chemicals: Value of Contact Hypersensitivity of Picryl Chloride in the Mouse, 1985, pp. 303-305.
Matha et al., The Mosquitocidal Activity of Conidia of Tolypocladium tundrense and Tolypocladium terricola, 1992, pp. 163-170, Great Britain.
Traber et al., Isolation & Structure Determination of the New Cyclosporins E, F, G, H and I, 1982, pp. 1655-1677.
Lorenz et al., Histamine release & hypotensive reactions in dogs by solubilizing agents & fatty acids: Analysis of various components in cremophor El and development of a compound with reduced toxicity, 1982, vol. 12, pp. 64-80.
Wood et al., Cyclosporine: Pharmacokinetics, Metabolism and Drug Interactions. Transplantation Proc. XV, 4, Suppl. 1, 2409-2412, 1983, Switzerland.
Markovic Lubos
Pavelek Zdenek
Stuchlik Milan
Borin Michael
Galena a.s.
Tsang Cecilia J.
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