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Ep 2236513 B1 (19) TZZ ¥_¥_T (11) EP 2 236 513 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07K 1/32 (2006.01) C07K 7/56 (2006.01) 02.10.2013 Bulletin 2013/40 (21) Application number: 10157468.9 (22) Date of filing: 24.03.2010 (54) An improved purification process for lipopeptides Verbessertes Reinigungsverfahren für Lipopeptide Procédé de purification amélioré pour lipopeptides (84) Designated Contracting States: (74) Representative: Jones, Helen M.M. AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Gill Jennings & Every LLP HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL The Broadgate Tower PT RO SE SI SK SM TR 20 Primrose Street London EC2A 2ES (GB) (30) Priority: 24.03.2009 IN MU06762009 (56) References cited: (43) Date of publication of application: US-A- 5 166 135 US-B1- 6 183 736 06.10.2010 Bulletin 2010/40 • ARIMA K ET AL: "Surfactin, a crystalline (73) Proprietor: CADILA HEALTHCARE LIMITED peptidelipid surfactant produced by Bacillus Ahmedebad 380 015, subtilis: Isolation, characterization and its Gujarat (IN) inhibition of fibrin clot formation" BIOCHEMICAL AND BIOPHYSICAL RESEARCH (72) Inventors: COMMUNICATIONS, ACADEMIC PRESS INC. • Gurnani, Menka ORLANDO, FL, US LNKD- DOI: 10.1016/0006-291X 380 015, Gujarat (IN) (68)90503-2, vol. 31, no. 3, 10 May 1968 • Maurya, Rajkumar (1968-05-10), pages 488-494, XP024830992 ISSN: 380 015, Gujarat (IN) 0006-291X [retrieved on 1968-05-10] Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 236 513 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 236 513 B1 Description Field of the Invention 5 [0001] The present invention relates to the improved process for purification of lipopeptide compounds, and in particular certain Echinocandin-type compounds, by using salt-adsorbent complex complex(s). In a further embodiment, it also includes appropriate combination of solvents for binding and elution of compound from the salt-adsorbent complex complex(s). 10 Background [0002] Echinocandin lipopeptides are natural products that have shown potent fungicidal activity against Aspergillus and Candida sp. and protect animals from fungicidal infection by inhibiting the enzyme β (1, 3)- D- Glucan synthase, thereby disturbing the integrity of the fungal cell wall. Echinocandin family compounds are natural products such as 15 Echinocandin B, Echinocandin C, Mulundocandin, Sporiofungin A, Pneumocandin A0, and Pneumocandin B0. Their isolation, structure elucidation and biological evaluation have been reported by Schmartz et al in "Cutaneous Antifungal Agents, 1993, pp375- 394". The natural Echinocandin products are used as a precursor for semi- synthetic lipopeptides such as Anidulafungin, Micafungin, Caspofungin. [0003] Anidulafungin is a semisynthetic lipopeptide Echinocandin B derivative developed by Eli Lilly/Versicor as an 20 antifungal agent for intravenous administration. Anidulafungin is disclosed in U.S. Pat. Nos. 5,965,525 and 6,384,013. Cilofungin is an Echinocandin lipopeptide disclosed by Eli Lilly in U.S. Pat. No. 4,293,489 for use as an antifungal agent. Micafungin (FUNGARD) is an Echinocandin-like lipopeptide developed by Fujisawa, as an antifungal agent for intrave- nous administration. Micafungin is disclosed in U.S. Pat. No. 6,107,. Daptomycin (CIDECIN) is a semisynthetic lipopeptide derivative developed by Cubist as an antibacterial agent. Daptomycin is disclosed by Eli Lilly in U.S. Pat. No. 4,537,717. 25 [0004] Pneumocandin B0 is produced as a secondary metabolite by fermentation of the fungusGlarea lozoyensis (U.S. Patent 5, 194, 377 and 5, 202, 309) which is precursor for Caspofuingin acetate (CANCIDAS), a semisynthetic lipopeptide Echinocandin B derivative currently being sold in US as an antifungal agent for intravenous administration. [0005] US5, 166, 135 discloses a procedure for the purification of Echinocandin B, comprising extraction of Echinoc- andin B from the growth broth using an organic solvent and a further purification step. 30 [0006] ARIMA et al. (1968) BIOCHEM. BIOPHYS. RES. COMM. 31,488-494 discloses a method purification of a lipopeptide, surfactin, from a nutrient broth. Surfactin is produced in a fair amount in the culture fluids of several strains of B. subtilis. [0007] US6, 183, 736 discloses two lipopeptides A1 and A2 produced by Bacillus subtilis and their use as an antifungal agent against Aspergillus flavus. Both peptides are cyclic, acidic and have a broad range of antifungal and antimicrobial 35 activity. Both peptides belong to the Bacillomycin D family. A purification method of these lipopeptides is disclosed. [0008] The purification of Echinocandin lipopeptide compounds is a technical challenge despite intense research effort directed at controlling distribution and amount of various analogues produced by organism during fermentation. The organism can produce, in addition to desired compound, 20 or more Echinocandin- type compounds including Pneumo- candin A0 and C0. Furthermore, these lipopeptides have unique solubility properties; they are essentially insoluble in 40 water and most pure solvents, but dissolve in alcohols and some aqueous/ organic solvent mixture. Moreover, it is difficult, if not impossible, to purify them by crystallization. [0009] Therefore, the separation of any desired product like Pneumocandin B0 from its key analog impurities like pneumocandin C0, pneumocandin B5 and pneumocandin E0 is very cumbersome and expensive because all of them comprise a cyclic hexapeptide coupled with dimethylmyristate side chain. 45 [0010] Several efforts have been made to separate desired Pneumocandins from culture broth and to purify it by using various processes to obtain good productivity of highly purified Pneumocandins. [0011] US 4,874,843 describes the use of non- functional resin in reversed mode to purify Echinocandin- type products. Even though the process improved the purity of products derived from fermentation process, further improvements are still needed to remove contaminants that are difficult to separate from both the intermediate and final pharmaceutical 50 compounds. [0012] The use of SP-207, HP-20 resin and reverse phase HPLC are described for the separation of pneumocandin B0. (U.S. 5,162,211 and Robert E. Schwartz, The Journal of Antibiotics, Vol. 45, No. 12 1853-1866, 1992). R. E. Schwartz et.al.(1992) describe large scale whole broth methanol extract purification by use of fluidized bed of SP- 207 followed by HP 20 column and then again use SP- 207 for further material concentration and then purification of the same over silica 55 column. This process has disadvantage that the purification method is very complicated because of being multi-step process. Furthermore, SP-207 and HP-20 are capital expensive to use at large scale production. Another disadvantage is that process is very time consuming and a major amount of desired product is lost in the transfer of sample from one column to another that decreases the yield of product of interest and makes the recovery of product poor. 2 EP 2 236 513 B1 [0013] US 6,610,822 describes the purification process for Pneumocandin B0 where two phase, multi solvent system and back extraction steps have been used to maintain the polarity balance of the solution in which the compound is purified. The process comprises use of multiple solvents like isobutyl alcohol (IBA), methanol, n-heptane, water and acetonitrile, which is used in the extraction and purification of Pneumocandin B0. The problem associated with the said 5 process is that recovery and reuse of multisolvent system involves critical monitoring as the process depends upon exact ratio of solvents to bring about polarity shift as described earlier. The process has low productivity, overall yield 69% and purity obtained is 61.4%. [0014] US 2008/0108806 also describes purification of Echinocandin-type compounds such as pneumocandins, by two-phase system, first to remove non polar impurities and then extraction of compound followed by crystallization and 10 precipitation The first extraction is performed using non- polar or weakly polar water immiscible organic solvent followed by second extraction using water immiscible alcohols. The second extraction is followed by concentration and crystal- lization/precipitation. The crystallization/precipitation process by addition of antisolvent is facilitated using solid carriers. The process describes use of solid carriers to precipitate compound from the concentrated solution. This process also has low productivity. 15 [0015] US patent no. 6,506,726 and 6,590,073 describe purification of echinocandin type compounds, especially of deacylated echinocandin B by chromatography. [0016] EP1157030 describes formation of crystalline complex between echinocandin- type compounds and carbohy- drate. The patent describes enhanced stability and water solubility for these complexes. [0017] Since the potency of the final pharmaceutical product is dependent upon the purity of intermediates used to 20 make the final product, therefore the improvements in purity at any stage of the manufacturing process is highly desirable. Ideally, the contaminants should be removed at the earliest stage possible in the
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