High purity lipopeptides
DC CAFCFirst Claim
1. A composition comprising essentially pure daptomycin purified by a process comprising the steps of:
- (a) subjecting daptomycin to conditions forming a daptomycin aggregate; and
(b) obtaining the essentially pure daptomycin from the daptomycin aggregate.
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Abstract
The invention discloses highly purified daptomycin and to pharmaceutical compositions comprising this compound. The invention discloses a method of purifying daptomycin comprising the sequential steps of anion exchange chromatography, hydrophobic interaction chromatography and anion exchange chromatography. The invention also discloses a method of purifying daptomycin by modified buffer enhanced anion exchange chromatography. The invention also discloses an improved method for producing daptomycin by fermentation of Streptomyces roseosporus. The invention also discloses high pressure liquid chromatography methods for analysis of daptomycin purity. The invention also discloses lipopeptide micelles and methods of making the micelles. The invention also discloses methods of using lipopeptide micelles for purifying lipopeptide antibiotics, such as daptomycin. The invention also discloses using lipopeptide micelles therapeutically.
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Citations
192 Claims
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1. A composition comprising essentially pure daptomycin purified by a process comprising the steps of:
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(a) subjecting daptomycin to conditions forming a daptomycin aggregate; and (b) obtaining the essentially pure daptomycin from the daptomycin aggregate. - View Dependent Claims (2)
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3. A composition comprising daptomycin that is substantially free of anhydro-daptomycin and substantially free of β
- -isomer of daptomycin, the daptomycin being purified by a process comprising the steps of;
(a) subjecting daptomycin to conditions forming a daptomycin aggregate; and (b) obtaining the daptomycin that is substantially free of anhydro-daptomycin or substantially free of β
-isomer of daptomycin from the daptomycin aggregate. - View Dependent Claims (4, 5, 6, 7)
- -isomer of daptomycin, the daptomycin being purified by a process comprising the steps of;
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8. A composition comprising purified daptomycin that is substantially free of each of impurities 1 to 14 defined by peaks 1-14 shown in
FIG. 12 , the purified daptomycin being obtained by a process comprising the steps of:-
(a) subjecting daptomycin to conditions forming a daptomycin aggregate; (b) subjecting the daptomycin aggregate to conditions forming monomeric daptomycin; and (c) obtaining the daptomycin from the monomeric daptomycin, the daptomycin aggregate or a combination thereof. - View Dependent Claims (9)
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10. A pharmaceutical composition comprising essentially pure daptomycin purified by a process comprising the steps of:
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(a) forming micelles comprising daptomycin; (b) converting the micelles to a non-micellar daptomycin composition comprising daptomycin in a non-micellar state; and (c) obtaining the purified daptomycin from the micelles, the non-micellar daptomycin composition, or a combination thereof. - View Dependent Claims (11, 12, 13, 14, 15, 16, 17, 18, 19, 20)
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21. A composition comprising daptomycin of greater than or about 93% purity relative to daptomycin impurities that arise in fermentation or purification of daptomycin, and wherein the daptomycin impurities comprise impurities 1-14 defined by peaks 1-14 shown in
FIG. 12 , and the daptomycin is obtained by a process comprising the step of forming a micelle comprising daptomycin.
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49. A purified daptomycin composition comprising daptomycin of greater than or about 93% purity relative to impurities 1-14 defined by peaks 1-14 shown in
FIG. 12 , the daptomycin being obtained by a process comprising the step of forming an aggregate comprising daptomycin.
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50. A composition comprising purified daptomycin obtained from a daptomycin aggregate, the purified daptomycin selected from the group consisting of:
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(a) essentially pure daptomycin, (b) daptomycin that is substantially free of anhydro-daptomycin and substantially free of β
-isomer of daptomycin,(c) daptomycin that is essentially free of anhydro-daptomycin and substantially free of β
-isomer of daptomycin,(d) daptomycin that is free of anhydro-daptomycin and substantially free of β
-isomer of daptomycin,(e) daptomycin that is substantially free of each of impurities 1 to 14 defined by peaks 1-14 shown in FIG. 12 , and(f) daptomycin that is essentially free of each of impurities 1 to 14 defined by peaks 1-14 shown in FIG. 12 . - View Dependent Claims (165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175)
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176. A purified daptomycin composition of greater than or 93% purity relative to impurities 1-14 defined by peaks 1-14 shown in
FIG. 12 , the purified daptomycin composition obtained by a process comprising the steps of:-
(a) subjecting daptomycin to conditions forming daptomycin micelles and (b) obtaining the purified daptomycin from the daptomycin micelles. - View Dependent Claims (177, 178, 179)
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180. A purified daptomycin composition of greater than or about 93% purity relative to impurities 1-14 defined by peaks 1-14 shown in
FIG. 12 , the purified daptomycin composition obtained by a process comprising the steps of:-
(a) subjecting an aqueous solution comprising daptomycin at or above the critical daptomycin micelle concentration to a pH of 3.0 to 4.8 at a temperature of about 2-15 degrees C. to form a daptomycin preparation; and (b) obtaining the purified daptomycin from the daptomycin preparation obtained in step (a). - View Dependent Claims (181, 182)
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183. A purified daptomycin composition of greater than or about 93% purity relative to impurities 1-14 defined by peaks 1-14 shown in
FIG. 12 , wherein the percent purity is measured by HPLC analysis, and the purified daptomycin composition is obtained from a lipopeptide aggregate comprising daptomycin.
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191. A purified daptomycin composition of greater than or about 93% purity relative to impurities 1-14 defined by peaks 1-14 shown in
FIG. 12 , wherein the percent purity is measured by HPLC analysis, and the purified daptomycin composition is obtained by a process comprising the steps of:-
(a) fermenting a culture of Streptomyces roseosporus to produce daptomycin; (b) contacting the daptomycin from step (a) with an anion exchange resin; (c) eluting the daptomycin from the anion exchange resin in step (b) with a solvent having a pH of about 6.0-6.5 to obtain a daptomycin solution; (d) adjusting the pH of the daptomycin solution from step (c) to about 3.0 to 4.8 and a temperature to about 2-15 degrees C. to obtain a daptomycin aggregate solution comprising daptomycin aggregates; and (e) filtering the daptomycin aggregate solution to separate daptomycin aggregates from the daptomycin aggregate solution; and (f) obtaining the purified daptomycin from the daptomycin aggregates. - View Dependent Claims (192)
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Specification