Methods for preparing purified lipopeptides
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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.
47 Citations
187 Claims
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1-56. -56. (canceled)
- 57. A crystalline or crystal-like lipopeptide or a salt thereof wherein the lipopeptide is selected from the group consisting of a daptomycin, an A54145, an A-21978C analog, and a daptomycin-related lipopeptide.
- 77. A pharmaceutical composition comprising a crystalline or crystal-like lipopeptide antibiotic and a pharmaceutically acceptable carrier, wherein the lipopeptide antibiotic is selected from the group consisting of a daptomycin, an A54145, an A-21978C analog, and a daptomycin-related lipopeptide.
- 85. A formulation comprising a crystalline or crystal-like lipopeptide antibiotic and a pharmaceutically acceptable carrier, wherein the lipopeptide antibiotic is selected from the group consisting of daptomycin, A54145, an A-21978C analog, and a daptomycin-related lipopeptide.
- 90. A method for administering a crystalline or crystal-like lipopeptide, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, wherein the lipopeptide is selected from the group consisting of a daptomycin, an A54145 and a daptomycin-related lipopeptide, comprising the step of administering to a patient in need thereof a therapeutically effective amount of the crystalline or crystal-like lipopeptide, the pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof.
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99. A method for storing a lipopeptide, wherein the lipopeptide is selected from the group consisting of a daptomycin, an A54145, an A-21978C analog, and a daptomycin-related lipopeptide, comprising the steps of
a) providing a dissolved solution of a lipopeptide; -
b) crystallizing or precipitating the lipopeptide;
c) collecting and drying the lipopeptide; and
d) storing the lipopeptide;
wherein the crystalline or crystal-like lipopeptide is more stable than an amorphous form of the lipopeptide. - View Dependent Claims (101, 102, 108, 109, 110, 111)
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100. A method for manufacturing a crystalline or crystal-like lipopeptide, wherein the lipopeptide is selected from the group consisting of a daptomycin, an A54145, an A-21978C analog, and a daptomycin-related lipopeptide, comprising the steps of
a) providing an amorphous form of a lipopeptide; -
b) crystallizing or precipitating the lipopeptide; and
c) collecting the crystalline or crystal-like lipopeptide. - View Dependent Claims (103, 104, 105, 106, 107)
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- 112. A method for preparing daptomycin, comprising the steps of providing an amorphous form of daptomycin and crystallizing the daptomycin from a crystallization solution comprising a cation from a salt, a buffer, an organic precipitant, and a low molecular weight alcohol.
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133. A method for preparing a crystalline or crystal-like daptomycin, comprising the steps of
a) providing a solution comprising daptomycin, a salt comprising a monovalent or divalent cation, a pH buffering agent and a low molecular weight or polyhydric alcohol; - and
b) allowing the daptomycin to crystallize or precipitate from the solution to obtain a crystalline or crystal-like daptomycin preparation, respectively. - View Dependent Claims (134, 135, 136, 137, 138, 139, 142, 143, 144, 145, 146, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163)
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140. A method for preparing a crystalline or crystal-like daptomycin, comprising the steps of
a) providing a solution comprising daptomycin, a pH buffering agent that is a salt comprising a monovalent or divalent cation, and a low molecular weight or polyhydric alcohol; - and
b) allowing the daptomycin to crystallize or precipitate from the solution to obtain a crystalline or crystal-like daptomycin preparation, respectively. - View Dependent Claims (141, 147, 148, 149, 150)
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164. A method for preparing a purified daptomycin, comprising the steps of
a) providing a solution comprising daptomycin, a pH buffering agent that is a salt comprising a monovalent or divalent cation, and a low molecular weight or polyhydric alcohol; - and
b) allowing the daptomycin to crystallize or precipitate from the solution to obtain a purified daptomycin preparation. - View Dependent Claims (165, 166, 167, 168)
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- 169. A method of preparing a crystalline form of a lipopeptide which comprises combining the lipopeptide with a crystallization solution comprising at least one cation and at least one alcohol chosen from the group consisting of polyhydric alcohols and low molecular weight alcohols and combinations thereof, wherein the lipopeptide is chosen from the group consisting of daptomycin and daptomycin analogs.
- 180. A method for administering to a subject in need thereof a crystalline lipopeptide or salt thereof, wherein the crystalline or crystal-like lipopeptide is chosen from the group consisting of crystalline daptomycin and crystalline A-21978C analogs, which comprises administering to the subject a pharmaceutical composition comprising the crystalline or crystal-like lipopeptide or salt thereof and a pharmaceutically acceptable carrier.
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186. A method of storing a lipopeptide selected from the group consisting of daptomyin and A-21978C analogs which comprises preparing the lipopeptide in crystalline form and storing the crystalline or crystal-like lipopeptide.
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187. In a method for preparing a lipopeptide selected from the group consisting of daptomycin and A-21978C analogs, the improvement which comprises preparing the lipopeptide in crystalline form.
Specification