EP2321335A1 - Procédé de traitement d'oligopeptides cycliques préparés par voie microbiologique - Google Patents

Procédé de traitement d'oligopeptides cycliques préparés par voie microbiologique

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Publication number
EP2321335A1
EP2321335A1 EP09781252A EP09781252A EP2321335A1 EP 2321335 A1 EP2321335 A1 EP 2321335A1 EP 09781252 A EP09781252 A EP 09781252A EP 09781252 A EP09781252 A EP 09781252A EP 2321335 A1 EP2321335 A1 EP 2321335A1
Authority
EP
European Patent Office
Prior art keywords
cyclosporin
ether
weight
butyl ether
extractant
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.)
Withdrawn
Application number
EP09781252A
Other languages
German (de)
English (en)
Inventor
Stephan Bertel
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.)
Sandoz AG
Original Assignee
Sandoz 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
Application filed by Sandoz AG filed Critical Sandoz AG
Priority to EP09781252A priority Critical patent/EP2321335A1/fr
Publication of EP2321335A1 publication Critical patent/EP2321335A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/14—Extraction; Separation; Purification
    • C07K1/145—Extraction; Separation; Purification by extraction or solubilisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64—Cyclic peptides containing only normal peptide links
    • C07K7/645—Cyclosporins; Related peptides

Definitions

  • the present invention relates to processes for the processing of microbiologically produced, nonpolar, cyclic oligopeptides comprising the step a) extraction of the resulting in the microbiological production total fermentation pulp with a liquid, water-immiscible, ether-containing extractant, wherein the amount of extractant is sufficient to to form a two-phase system with the whole fermentation pulp, as well as new solvates of cyclosporin A and methyl t-butyl ether.
  • Cyclic oligopeptides in particular undecapeptides have long been u. a. known as microbiological metabolites. Of the undecapeptides cyclosporins in particular have gained importance.
  • Cyclosporins in particular cyclosporin A, are in fact valuable pharmaceutical active substances which can be used as immunosuppressants, in particular in organ transplants.
  • cyclosporins are suitable for the treatment of diseases such. As diabetes and psoriasis, and numerous autoimmune diseases such. Rheumatoid arthritis and chronic inflammation.
  • Cyclosporins, in particular cyclosporin A are also suitable for controlling diseases caused as a result of their inhibitory action against the human immunodeficiency virus (HIV).
  • HAV human immunodeficiency virus
  • a pharmacological effect of cyclosporins, in particular cyclosporin A for the sensitization of cancer cells to chemotherapeutic agents such.
  • B Vincistin or Daunorubicin be detected.
  • the neuroprotective or regenerative properties of cyclosporins, in particular cyclosporin A in various neurological indications such. As Alzheimer's, amyotrophic lateral sclerosis or Parkinson's
  • cyclic undecapeptides such as cyclosporins
  • cyclosporin A can be produced by means of a strain of the fungus species Cylindrocarpon lucidum Booth or a strain of the fungus species Tolypocladium inflatum Garns.
  • This strain of the fungus species Tolypocladium was originally referred to as a strain of the fungal species Trichoderma polysporum, which was deposited with the United States Department of Agriculture (Northern Research and Development Division), Peoria, IL, USA under the number NRRL 8044.
  • strains for the microbiological production of cyclosporins are strains of the fungus species Tolypocladium geodes, Tolypocladium cylindrosporum and Tolypocladium sp. LeA3, the latter being deposited under the Budapest Treaty at the Custodian of the Central Bureau of Meat Cultures in Holland under number CBS 630.92.
  • DOS 2455859 or DD-B-298276 known methods for the isolation of cyclosporins, in particular cyclosporin A, from the total fermentation pulp, d. H. from the culture broth, either the biomass with product can be separated from the culture broth by filtration or centrifugation or the whole fermentation broth, i. H. without separation of the biomass, be worked up.
  • the separated biomass is subjected to the metabolic products of a preferably repeated extraction with methanol or acetone and the separated extract is preferably concentrated to an aqueous residue to z. With ethylene chloride or chloroform, preferably to be extracted several times.
  • the culture filtrate separated from the biomass is preferably likewise extracted accordingly.
  • the culture broth i. H. the total fermentation porridge, u. a. extracted with the abovementioned solvents, ethylene chloride or chloroform and the separated organic phase after concentration several times at different, stationary column fillings with different eluents for further work-up.
  • Sephadex LH-20 as a stationary column material with methanol as the eluent or alumina as a column material with toluene / ethyl acetate as the eluent in question.
  • a corresponding chromatographic work-up can also be carried out in the first-mentioned work-up variant, wherein the residue obtained from the ethylene chloride or chloroform extracts using the column material silica gel in combination with the eluent chloroform and the column material Sephadex LH-20 in combination with the eluent purified methanol and in the desired products, preferably cyclosporin A, further separated.
  • the object was to provide technologically advantageous, environmentally compatible and efficient work-up procedures for microbiologically produced, cyclic oligopeptides, in particular undecapeptides such as cyclosporins, with a very good exploitation and purity of the products.
  • the task was to reduce the number of organic solvents used and to achieve their recyclability, so u. a. to make the reprocessing process ecologically more efficient.
  • This object is achieved by providing the method according to the invention for the processing of microbiologically produced, nonpolar, cyclic oligopeptides, comprising the step a) extraction of the resulting in the microbiological production total fermentation broth with a liquid, water-immiscible, ether-containing extractant, wherein the Extract of the extractant is sufficient to form a two-phase system with the total fermentation pulp.
  • microbiologically prepared, non-polar, cyclic oligopeptides having preferably 5 to 15 peptide bonds can be worked up.
  • oligopeptide according to the invention is to be understood as an organic compound comprising a certain number of peptide bonds, wherein only two consecutive nitrogen atoms of the ring system are preferably separated by two intervening carbon atoms.
  • nonpolar, cyclic oligopeptides of 8 to 13 amino acids, particularly preferably undecapeptides can be isolated with the aid of the workup process according to the invention. This process is very particularly preferably suitable for working up the microbiologically produced, nonpolar undecapeptides, such as cyclosporins, very particularly preferably cyclosporin A.
  • non-polar cyclic oligopeptides in particular undecapeptides as cyclosporins are to be understood according to the invention, which, as lipophilic compounds have a water solubility of ⁇ 0.1 g / l of water at 25 0 C.
  • the desired products can be obtained by extraction.
  • the total fermentation broth is mixed with a liquid, water-immiscible, ether-containing extractant, wherein the amount of the extractant is sufficient to form a two-phase system with the total fermentation pulp.
  • Particles from the fermentation process in the aforementioned system are present, which are present in the aqueous phase.
  • a liquid extractant immiscible with water is understood to mean an extractant which has at least one miscibility gap at 20 ° C. with water at which the liquid extractant is at least incompletely miscible or incompletely soluble with the water such that a phase separation occurs.
  • ether-containing, water-immiscible extractants used according to the invention preferably have a density of at most 0.9 g / cm 3 , preferably a density of from 0.6 to 0.85 g / cm 3 , particularly preferably from 0.7 to 0.8 g / cm 3 , each measured at 20 0 C, on.
  • the ether-containing extractant consists essentially of one or more ethers, most preferably at least one ether of the general formula
  • R 1 and R 2 independently of one another, is a linear or branched alkyl radical having Ci to C 5 and at least one of the radicals Ri and R 2 has at least 3 C-atoms, preferably at least 4 C-atoms.
  • Particularly preferred ethers which can be used for the extraction, at least one ether selected from the group comprising di-isopropyl ether, di-n-propyl ether, di-t-butyl ether, di-iso-butyl ether, methyl t-butyl ether, ethyl t-butyl ether, propyl t-butyl ether and n-butyl t-butyl ether, with the use of methyl t-butyl ether being particularly preferred.
  • Another object of the present invention is therefore also the use of liquid, water-immiscible, ether-containing extractant, preferably having a density of at most 0.9 g / cm 3 , measured at 20 0 C, as a means for extraction of microbiologically produced, nonpolar cyclic oligopeptides, preferably undecapeptides, more preferably cyclosporins, most preferably cyclosporin A from the total fermentation broth obtained in the microbiological production.
  • the ethers listed above preferably come in such quantities used to form a 2-phase system with the total fermentation pulp.
  • the extraction of the total fermentation broth in particular in the isolation and workup of cyclosporins, more preferably cyclosporin A, at a pH of 7 to 9, preferably 7.5 to 8.5.
  • water-soluble wetting agents e.g. Polyacrylate-based
  • water-soluble wetting agents e.g. Polyacrylate-based
  • the extraction is carried out several times. Most preferably, the total extraction pulp is extracted twice with the ethereal extractant.
  • the extraction of the total fermentation paste is preferably carried out with the ether-containing, water-immiscible extractant at room temperature, more preferably at 20 to 30 0 C.
  • the extraction of the total fermentation pulp can be carried out in customary apparatuses, the extracts obtained during the extraction being combined after separation of the aqueous phase with the biomass for further work-up.
  • the process step a) is followed by a further process step b) according to which the residual water content present in the extract is reduced to less than 1% by weight, preferably to less than 0.3% by weight.
  • the extract is preferably washed with an aqueous solution, preferably with water, in order to remove any residues of biomass which may be present.
  • an azeotropic distillation can be carried out. Not only is the residual water content reduced to the desired level in the extract, but also the concentration of the microbiologically produced products, preferably the cyclosporins, particularly preferably the cyclosporin A, is increased.
  • a Cyclosporingehalt is preferably adjusted from 10 to 35 wt.%.
  • the azeotropic distillation in step b) makes it possible not only to adjust the residual water content in the extract to the desired, low water content, but also to set a concentration of the extract which is advantageous for the subsequent crystallization of the worked-up product, the product preferably being used as cyclosporin ether. Solvate is crystallized.
  • the inventive method for working up of microbiologically produced products preferably cyclosporins, more preferably cyclosporin A, a further step c), according to the concentrated in step b), the residual water content largely freed extract by cooling to temperatures of -10 0 C. to 15 0 C, preferably to temperatures of -5 0 C to 10 0 C, for crystallization as an ether solvate product, preferably cyclosporin ether solvate is cooled.
  • the crystals preferably the cyclosporin ether solvate crystals, may be washed with an organic solvent in which the crystals dissolve only slowly, for further purification.
  • the cyclosporin ether solvate crystals can be separated by known chromatographic purification and crystallization in suitable known solvents in the cyclosporins A-Z (see also WO97 / 46575, EP0725076, EP0888382).
  • Another object of the present invention is the use of crystalline cyclosporin ether solvates in the industrial scale Production of Cyclosporines, preferably Cyclosporin A.
  • Cyclosporines preferably Cyclosporin A.
  • the crystalline cyclosporin-ether-solvate crystals obtained according to the invention are suitable.
  • a particularly preferred embodiment of the present invention is a process for working up microbiologically produced non-polar cyclosporins, preferably cyclosporin A, comprising the steps of a) extraction of the total fermentation pulp obtained in the microbiological production of cyclosporines with a liquid, water-immiscible ether-containing Extracting agent, wherein the amount of the extractant is sufficient to form a two-phase system with the total fermentation pulp, b) reducing the residual water content dissolved in the extract to less than
  • step a) may optionally be washed with an aqueous solution prior to this lowering of the residual water content, and c) crystallizing the cyclosporins as cyclosporin ether Solvates, wherein preferably before the crystallization of the extract obtained in step b) to a Cyclosporingehalt of 10 to 25 wt.%, Based on the total extract, and for crystallization of the concentrated extract to temperatures of -10 0 C to 15 0 C, preferably -5 0 C to 10 0 C, is cooled.
  • reaction conditions for the individual process steps likewise apply to the workup of nonpolar cyclosporins which has been preferred according to the invention and which have been prepared microbiologically, in particular for the workup and isolation of cyclosporin A.
  • ether-containing extraction agent used preferably ethers of the general formula given above.
  • crystals are also particularly suitable for being separated into the cyclosporins A-Z by further recrystallization in a known manner and / or by chromatographic work-up with known columnar materials in combination with known, suitable eluents.
  • cyclosporin A with a content of less than 0.05% by weight of isocyclosporin A, preferably with a content of 0.04 to 0.05% by weight of isocyclosporin A.
  • the cyclosporin A which is obtainable by the work-up method according to the invention, is also distinguished by a lower content of cyclosporin H and cyclosporin T.
  • Another object of the present invention is therefore also cyclosporin A, wherein the total content of cyclosporin H and cyclosporin T less than 0.5 wt.%, Preferably from 0.1 to 0.4 wt.% Is.
  • cyclosporin A having a content of 0.04 to 0.005 wt.% Isocyclosporin A, wherein the additional total content of cyclosporin H and cyclosporin T from 0.01 to 4 wt.% Is.
  • This cyclosporin A with the low contents of by-products is preferably obtainable by the work-up and further treatment of cyclosporin A-methyl-t-butyl-ether-solvate crystals obtained according to the invention.
  • the cyclosporin ether solvate crystals not only with an excellent purity and with yields of more than 90%, preferably> 95%, with the aid of the preferred work-up method of nonpolar, microbiologically produced cyclosporines according to the invention, but also with a very good handling of the crystals, since at least 90% of the crystals have a crystal size> 10 microns and the median particle size distribution is about 60 microns.
  • 3 ⁇ 1 g of the sample were dispersed in 60 ml of water and measured after addition of the dispersing unit Hydro 2000S at a stirring speed of 2000 rpm using the "Mastersizer 2000" measuring instrument from Malvern. used by the device manufacturer. The above values are average values over 3 such measurements.
  • Another object of the present invention is therefore crystalline cyclosporin A-methyl-t-butyl ether solvate, of which at least 90% of the crystals have a crystal size> 10 microns, preferably the median size distribution is between 30 .mu.m and 100 .mu.m, preferably between 40 .mu.m and 80 .mu.m.
  • the process according to the invention is particularly suitable for working up microbiologically produced cyclosporin A as crystalline cyclosporin A-methyl-t-butyl ether solvate.
  • Such crystals could be clearly determined by means of X-ray powder diffractograms.
  • X-ray powder diffractograms were obtained on an AXS Bruker X-ray powder diffractometer D-8 using the following environmental sampling parameters: tube anode: Cu; Generator voltage: 4OkV; Generator current: 40 mA; Initial angle: 2 ° 2-theta; Final angle: 40 ° 2-theta; Step size: 0.01 ° 2-theta; Time per step: 2 seconds.
  • the typical accuracy of the 2-theta values is in the range of ⁇ 0.1 ° 2-theta. Therefore, a diffraction peak (vertex) recorded at 5.0 ° 2-theta may appear between 4.9 and 5.1 ° 2-theta on most X-ray diffractometers at standard conditions.
  • Another object of the present invention is therefore crystalline cyclosporin A-methyl-t-butyl ether solvate containing an X-ray powder diffractogram comprising peaks at 2 theta angles of 7.0 ° +/- 0.1 °, 8.2 ° + / - 0.1 °, 11, 0 ° +/- 0.1 ° and 20.5 ° +/- 0.1 °, in particular additionally comprising vertices at 2 theta angles of 7.3 ° +/- 0, 1 M 1, 8 ° +/- 0.1 M 3.3 ° +/- 0.1 ° and 16.5 ° +/- 0.1 °.
  • the invention also relates to the following items:
  • a process for the processing of microbiologically produced, non-polar, cyclic oligopeptides comprising the step a) extraction of the resulting in microbiological production total fermentation pulp with a liquid, water-immiscible at 25 0 C, ether-containing extractant, wherein the amount of the extractant sufficient to form a two-phase system with the total fermentation pulp.
  • step b) is carried out by azeotropic distillation.
  • step b) A method according to item 5 or 6, wherein the extract obtained in step a) is washed with an aqueous solution prior to further processing in step b).
  • Ri and R 2 independently of one another, is a linear or branched alkyl radical having Ci to C 5 and at least one of the radicals Ri or R 2 has at least 3 C-atoms, preferably at least 4 C-atoms.
  • at least one ether selected from the group consisting of di-isopropyl ether, di-n-propyl ether, di-t-butyl ether, diisobutyl ether, methyl t-butyl ether, ethyl t- butyl ether, propyl t-butyl ether and n-butyl t-butyl ether is used.
  • step c) the concentrated extract to a temperature of -10 0 C to 15 ° C is cooled.
  • step c) cyclosporin ether solvate crystals with organic solvents in which the cyclosporin ether solvate crystals dissolve only slowly, are washed.
  • a method according to any one of items 1 to 16 characterized in that the extraction with the ether-containing extractant at room temperature, preferably at 20 to 30 0 C, is performed. 18.
  • Cyclosporin A with a content of less than 0.05% by weight of isocyclosporin A, preferably with a content of 0.04-0.005% by weight of isocyclosporin A.
  • Cyclosporin A wherein the total content of cyclosporin H and cyclosporin T is less than 0.5% by weight, preferably from 0.1 to 0.4% by weight.
  • Cyclosporin A with a content of 0.04-0.005% by weight of isocyclosporin A, the additional total content of cyclosporin H and cyclosporin T being from 0.1-0.4% by weight.
  • FIG. 1 X-ray powder diffractogram of crystalline cyclosporin A-methyl-t-butyl ether solvate
  • FIG. 2 Infrared spectrum of crystalline cyclosporin A-methyl-t-butyl ether solvate
  • cyclosporin A-containing fermentation broth as can be obtained, for example, by fermentation of Tolypocladium inflatum, were extracted twice with 2000 ml of methyl tert-butyl ether (MTBE) in the presence of 4000 ppm of the polyacrylate Clahant MD07 / 049.
  • the ether phases were separated in a separatory funnel and combined.
  • the cyclosporin A-containing ether phase was washed once with 200 ml of water having a pH of about 7 in the separating funnel and the ether phase was concentrated after filtration by azeotropic distillation at a temperature of about 53 ° C, so that a cyclosporin concentration of 150g / kg was reached.
  • the temperature was then lowered to a value just below the boiling point and kept at this temperature for 2 hours, with fresh MTBE being discharged through the distillation head. Thereafter, the solution was concentrated under normal pressure at 53 ° C, so that a cyclosporin concentration of 300 g / kg was achieved.
  • the residual water content which before the azeotropic distillation was about 1.4% by weight, was now below 0.1% by weight.
  • the solution was carefully cooled, in 120 minutes from 53 ° C to 45 ° C, in another 60 minutes at 40 0 C, in another 60 minutes at 30 0 C and in another 60 minutes at 0 ° C.
  • White, crystalline cyclosporin A - MTBE solvate was obtained in a total theoretical yield of about 82%.
  • FIG. 2 An infrared spectrum of the crystals obtained is shown in FIG. 2, a powder X-ray diffractogram (XRPD) of the resulting crystals is shown in FIG.
  • the evaluation at the interference microscope showed highly crystalline material with large, birefringent crystals, with an average particle size of about 65 ⁇ m.
  • Example 2 Large-scale extraction of cyclosporin A from fermentation broth
  • 510kg of cyclosporin A-containing fermentation broth were extracted twice with 510 l each of methyl tert-butyl ether (MTBE), to which was added 2.6kg of the polyacrylate Clariant MD07 / 049.
  • the ether phases were separated in a 3001 separator in the run and combined.
  • the cyclosporin A-containing ether phase was washed once with 700 l of pure water having a pH of about 7, the phases were separated again in the separator and the ether phase was concentrated by azeotropic distillation in a 10001 thin-film evaporator at a temperature of about 53 ° C, so a cyclosporin concentration of 100 g / kg was reached.
  • the temperature was then lowered to a value just below the boiling point and kept at this temperature for 2 hours, with fresh MTBE being discharged through the distillation head. Thereafter, the solution was concentrated under normal pressure at 53 ° C, so that a cyclosporin concentration of 300 g / kg was reached.
  • the residual water content which before the azeotropic distillation was about 1.4% by weight, was now below 0.1% by weight.
  • the solution was then carefully cooled, in 120 minutes from 53 ° C to 45 ° C, in another 60 minutes at 40 0 C, in another 60 minutes at 30 0 C and in another 60 minutes at 0 ° C. 8.55 kg of white, crystalline cyclosporin A-MTBE solvate were obtained in a total theoretical yield of about 87%.
  • the content of isocyclosporin A was 0.008% by weight, the total content of cyclosporin H and cyclosporin T was 0.28% by weight, which meant a highly significant reduction in the content of these impurities as compared to a butyl acetate extraction process.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Peptides Or Proteins (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

La présente invention porte sur un procédé de traitement d'oligopeptides cycliques, apolaires, préparés par voie microbiologique, comprenant l'étape a) d'extraction de la bouillie de fermentation totale obtenue lors de la préparation microbiologique, avec un agent d'extraction contenant de l'éther, liquide et non miscible à l'eau, la quantité de l'agent d'extraction étant suffisante pour former avec la bouillie totale de fermentation un système diphasique. L'invention concerne également de nouveaux produits de solvatation à base de cyclosporine A et de méthyl-tert-butyléther.
EP09781252A 2008-07-29 2009-07-29 Procédé de traitement d'oligopeptides cycliques préparés par voie microbiologique Withdrawn EP2321335A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP09781252A EP2321335A1 (fr) 2008-07-29 2009-07-29 Procédé de traitement d'oligopeptides cycliques préparés par voie microbiologique

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP08161348A EP2151450A1 (fr) 2008-07-29 2008-07-29 Procédé de préparation d'oligopeptides cycliques microbiologiques
EP09781252A EP2321335A1 (fr) 2008-07-29 2009-07-29 Procédé de traitement d'oligopeptides cycliques préparés par voie microbiologique
PCT/EP2009/059826 WO2010012786A1 (fr) 2008-07-29 2009-07-29 Procédé de traitement d'oligopeptides cycliques préparés par voie microbiologique

Publications (1)

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EP2321335A1 true EP2321335A1 (fr) 2011-05-18

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EP09781252A Withdrawn EP2321335A1 (fr) 2008-07-29 2009-07-29 Procédé de traitement d'oligopeptides cycliques préparés par voie microbiologique

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US (1) US8691770B2 (fr)
EP (2) EP2151450A1 (fr)
JP (1) JP2011529476A (fr)
CN (1) CN102164944A (fr)
WO (1) WO2010012786A1 (fr)

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CN104877013B (zh) * 2015-06-03 2018-04-20 兰州大学 环孢菌素t及其制备方法和应用
CN108148118B (zh) * 2017-12-12 2021-07-09 陈秀明 一种环孢菌素h的分离纯化方法

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DE2455859C2 (de) * 1973-12-06 1983-12-15 Sandoz-Patent-GmbH, 7850 Lörrach Das Antibiotikum Cyclosporin A (S 7481/F-1), seine Herstellung und Verwendung
US4144138A (en) * 1978-01-18 1979-03-13 Texaco Inc. Recovery of ethers
DD298276A5 (de) 1988-10-11 1992-02-13 Institut Fuer Mikrobiologie Und Experimentelle Therapie,De Verfahren zur herstellung von cyclosporin a
HU201577B (en) 1988-12-20 1990-11-28 Gyogyszerkutato Intezet Process for producing cyclosporin antibiotics
ES2078374T3 (es) 1991-04-06 1995-12-16 Dresden Arzneimittel Procedimiento para la produccion por fermentacion y aislamiento de ciclosporina a, y nuevas cepas formadoras de ciclosporina.
FI92334C (fi) 1992-12-30 1994-10-25 Leiras Oy Menetelmä syklosporiinien tuottamiseksi ja menetelmässä käytettävä uusi Tolypocladium-kanta
UA49803C2 (uk) * 1994-06-03 2002-10-15 Дж.Д. Сьорль Енд Ко Спосіб лікування ретровірусних інфекцій
EP0725076B1 (fr) 1995-02-01 2001-06-06 National Research Development Corporation of India Procédé de préparation de la cyclosporine A de l'espèce tolypocladium
DE19611094C2 (de) 1996-03-21 1999-06-17 Dresden Arzneimittel Verfahren zur Reinigung von Cyclosporin A und/oder verwandten Cyclosporinen aus einem Cyclosporin-haltigen Rohextrakt unter Anwendung chromatographischer Verfahren mit Kieselgel als Adsorbens
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US20110124575A1 (en) 2011-05-26
JP2011529476A (ja) 2011-12-08
EP2151450A1 (fr) 2010-02-10
US8691770B2 (en) 2014-04-08
WO2010012786A1 (fr) 2010-02-04
CN102164944A (zh) 2011-08-24

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