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  Methods for preparing purified lipopeptidesUSPTO Application #: 20060014674Title: Methods for preparing purified lipopeptides Abstract: The present invention relates to crystalline and crystal-like forms of lipopeptides, including daptomycin, a lipopeptide antibiotic with potent bactericidal activity against gram-positive bacteria, including strains that are resistant to conventional antibiotics. The present invention relates to methods of purifying lipopeptides, including daptomycin, a lipopeptide antibiotic with potent bactericidal activity against gram-positive bacteria, including strains that are resistant to conventional antibiotics. The present invention also relates to pharmaceutical compositions comprising the purified form of the lipopeptide and methods of using these compositions. (end of abstract) Agent: Fish & Richardson PC - Minneapolis, MN, US Inventors: Dennis Keith, Jan-Ji Lai, Chandrika Govardhan, Nazer Khalaf USPTO Applicaton #: 20060014674 - Class: 514009000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai, Cyclopeptides The Patent Description & Claims data below is from USPTO Patent Application 20060014674. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] The present application claims the benefit of U.S. Provisional Application No. 60/256,268, filed Dec. 18, 2000; Ser. No. 60/274,741, filed Mar. 9, 2001; Ser. No. filed Dec. 13, 2001; and Ser. No. filed Dec. 13, 2001, the contents of which are incorporated herein by reference. TECHNICAL FIELD OF THE INVENTION [0002] The present invention relates to crystalline and crystalline-like forms of lipopeptides, including daptomycin, a lipopeptide antibiotic with potent bactericidal activity against gram positive bacteria, including strains that are resistant to conventional antibiotics. The present invention also relates to processes for preparing crystalline or crystal-like forms of the lipopeptide and to methods of purifying lipopeptides including daptomycin. The present invention also relates to pharmaceutical compositions comprising the purified form of the lipopeptide and methods of using these compositions. BACKGROUND OF THE INVENTION [0003] The rapid increase in the incidence of gram-positive infections--including those caused by antibiotic-resistant bacteria--has sparked renewed interest in the development of novel classes of antibiotics. One such class is the lipopeptide antibiotics, which includes daptomycin. Daptomycin has potent bactericidal activity in vitro against clinically relevant gram-positive bacteria that cause serious and life-threatening diseases. These bacteria include, but are not limited to, resistant pathogens, such as vancomycin-resistant enterococci (VRE), methicillin-resistant Staphylococcus aureus (MRSA), glycopeptide intermediary susceptible Staphylococcus aureus (GISA), coagulase-negative staphylococci (CNS), and penicillin-resistant Streptococcus pneumoniae (PRSP), for which there are very few therapeutic alternatives. See, e.g., Tally et al., 1999, Exp. Opin. Invest. Drugs 8:1223-1238. Daptomycin's inhibitory effect is a rapid, concentration-dependent bactericidal effect in vitro and in vivo, and a relatively prolonged concentration-dependent post-antibiotic effect in vivo. [0004] Daptomycin is described by Baltz in Biotechnology of Antibiotics, 2nd Ed., ed. W. R. Strohl (New York: Marcel Dekker, Inc.), 1997, pp. 415-435. Daptomycin, also known as LY 146032, is a cyclic lipopeptide antibiotic that can be derived from the fermentation of Streptomyces roseosporus. Daptomycin is a member of the factor A-21978C.sub.0 type antibiotics of S. roseosporus and is comprised of a decanoyl side chain linked to the N-terminal tryptophan of a cyclic 13-amino acid peptide (FIG. 1). Daptomycin has an excellent profile of activity because it is highly effective against most gram-positive bacteria; it is highly bactericidal and fast-acting; it has a low resistance rate and is effective against antibiotic-resistant organisms. The compound is currently being developed in a variety of formulations to treat serious infections caused by bacteria, including, but not limited to, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). [0005] A number of U.S. patents describe A-21978C.sub.0 antibiotics and daptomycin-related lipopeptides including daptomycin (LY 146032). These patents also describe methods of producing and isolating the A-21978C.sub.0 antibiotics and daptomycin-related lipopeptides. [0006] U.S. Pats. RE32,333, RE32,455, 4,800,157, 4,874,843, and 4,885,243 describe methods of synthesizing and isolating daptomycin from fermentation cultures of Streptomyces roseosporus. U.S. Pats. RE32,310, RE32,311, 4,537,717, 4,482,487 and 4,524,135 describe A-21978C.sub.0 antibiotics and methods of deacylating the A-21978C.sub.0 antibiotic and reacylating the peptide nucleus and antibiotic derivatives made by this process. U.S. Pat. No. 5,912,226 (hereafter the '226 patent) describes the identification and isolation of two impurities produced during the manufacture of daptomycin, anhydro-daptomycin and the .beta.-isomer form of daptomycin. None of these U.S. patents discloses a method for precipitating or crystallizing a lipopeptide in a manner to increase purity of the lipopeptide. [0007] U.S. Pat. No. 4,439,425 (hereafter the '425 patent) discloses a crystalline lipopeptide and a method of crystallizing the lipopeptide. The lipopeptide disclosed in the '425 patent is structurally dissimilar from daptomycin and daptomycin-related lipopeptides. U.S. Pat. No. 5,336,756 (hereafter the '756 patent) also discloses a crystalline cyclic lipopeptide comprising a hexapeptide. The crystalline cyclic lipopeptide disclosed in the '756 patent is also structurally dissimilar from daptomycin and daptomycin-related lipopeptides. The '756 patent discloses that the lipopeptide, an echinocandin-type compound, can be obtained when aqueous n-propanol is employed as the crystallizing solvent. See, e.g., cols. 1-2 of the '756 patent. Neither the '425 patent nor the '756 patent disclose methods of crystallizing or precipitating daptomycin or a daptomycin-related lipopeptide, nor do they disclose methods of crystallizing or precipitating lipopeptides produced by Streptomyces. [0008] It would be advantageous to develop a method of crystallizing or precipitating daptomycin and daptomycin-related lipopeptides to provide an improved purification method for these lipopeptides. In addition, a crystalline or highly purified precipitated form of daptomycin or other daptomycin-related lipopeptide would be useful in formulating pharmaceutical compositions for treating bacterial infections. Further, a crystalline or highly purified precipitated form of daptomycin or daptomycin-related lipopeptide would be useful in a method to make a sterile product, particularly bulk sterile product. Thus, there is a need for methods to produce crystalline or precipitated daptomycin and daptomycin-related lipopeptides and the crystalline or precipitated forms of the lipopeptides produced thereby. However, there has been no simple and robust method that has been effective in crystallizing or precipitating daptomycin or a daptomycin-related lipopeptide that results in a lipopeptide that is more pure after crystallization or precipitation than before. SUMMARY OF THE INVENTION [0009] The instant invention addresses these problems by providing crystalline and crystalline-like forms of lipopeptides, particularly daptomycin and daptomycin-related lipopeptides and methods for producing them. In one embodiment, the invention provides methods for crystallizing lipopeptides. In another embodiment, the methods provide a lipopeptide that is more pure after crystallization or precipitation than before crystallization or precipitation. [0010] The invention also provides robust processes for producing and purifying lipopeptides comprising, inter alia, crystallizing or precipitating lipopeptides. In one embodiment, the crystallizing or precipitating steps of the processes are used to purify the lipopeptides. In another embodiment, the processes are used for large-scale and/or commercial production of lipopeptides, preferably daptomycin. [0011] The invention further provides highly purified crystalline or crystal-like forms of daptomycin and daptomycin-related lipopeptides. In one embodiment, the crystalline or crystal-like forms of the lipopeptides may be used in pharmaceutical compositions. In another embodiment, the invention comprises methods of using the pharmaceutical compositions. BRIEF DESCRIPTION OF THE DRAWINGS [0012] FIG. 1 shows the structure of daptomycin. [0013] FIG. 2 shows a photomicrograph of urchin-like crystal or crystal-like particle of daptomycin produced by the method described in Example 12. [0014] FIG. 3 shows a photomicrograph of needle-like crystals of daptomycin. [0015] FIG. 4 shows a photomicrograph of rod-like crystals of daptomycin. [0016] FIG. 5 shows photomicrographs of daptomycin samples at 100.times. magnification. Photomicrographs of amorphous daptomycin are shown using plane transmitted light (A) and using crossed polarized light (B). Photomicrographs of daptomycin crystals are shown using plane transmitted light (C and E) and using crossed polarized light (D and F). The daptomycin crystals were produced by the protocol disclosed in Example 7. [0017] FIG. 6 shows an x-ray powder diffraction pattern for amorphous daptomycin. [0018] FIG. 7 shows an x-ray powder diffraction pattern for a daptomycin crystal produced by the protocol described in Example 7. [0019] FIG. 8 shows an x-ray powder diffraction pattern for a second sample of a daptomycin crystal produced by the protocol described in Example 7. Continue reading... Full patent description for Methods for preparing purified lipopeptides Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Methods for preparing purified lipopeptides patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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