Pharmaceutical compositions, dosage forms and methods for oral administration of epothilones

A kit for use in a method of increasing the biovailability of orally administered epothilones which comprises:

• (i) a first component comprising one or more epothilones of Formula:
• 13
• G is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo,
• 14
• W is O or NR16;
• X is O;
• S;
• CHR17;
• or H, R18
• Y is selected from the group consisting of O;
• H, H;
• H, OR22;
• OR23, OR23;
• NOR24;
• H, NOR25;
• H, HNR26R27;
• NHNR28R29;
• H,NHNR30R31 or CHR32, where OR23, OR23 can be a cyclic ketal;
• B1 and B2 are selected from the group consisting of H, OR33, OCOR34, OCONR35R36, NR37R38, or NR39CONR40R41
• D is selected from the group consisting of NR42R43 or heterocyclo;
• R1, R2, R3, R4, and R5 are selected from H, lower alkyl;
• R8, R9, R10 and R11 are selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo or substituted heterocyclo;
• R17, R18, R22, and R23 are selected from the group consisting of H, alkyl, and substituted alyl;
• R24, R25, R26, R28, R30, R32, R33, R34, R35, R36, R37, R39, R40, R41, R42, R51, R52, R53, and R61 are selected from the group of H, alkyl, substituted alkyl, aryl or substituted aryl;
• R12, R,16, R27, R29, R31, R38, and R43 are selected from the group consisting of H, alkyl, substituted alkyl, substituted aryl, cycloalkyl, heterocyclo, R51C=O, R52OC=O, R53SO2, hydroxy, and O-alkyl or O-substituted alkyl;
• or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug thereof;
• and
• (ii) a second component comprising a pharmaceutically acceptable acid neutralizing buffer,
• wherein the first component and the second component are provided as an oral dosage form or as a pharmaceutical composition that can be reconstituted with a solvent to provide a liquid oral dosage.

A pharmaceutical composition suitable for oral administration to a mammal comprising:

• (i) one or more epothilones of Formula:
• 15
• wherein:
• G is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo,
• 16
• W is O or NR16;
• X is O;
• S;
• CHR17;
• or H, R18;
• Y is selected from the group consisting of O;
• H, H;
• H, OR22;
• OR23, OR23;
• NOR24;
• H, NOR25;
• H, HNR26R27;
• NHNR28R29;
• H, NHNR30R31 or CHR32, where OR23, R23 can be a cyclic ketal;
• B1 and B2 are selected from the group consisting of H, OR33, OCOR34, OCONR35R36, NR37R38, or NR39CONR40R41
• D is selected from the group consisting of NR42R43 or heterocyclo;
• R1, R2, R3, R4, and R5 are selected from H, lower alkyl;
• R8, R9, R10 and R11 are selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo or substituted heterocyclo;
• R17, R18, R22, and R23 are selected from the group consisting of H, alkyl, and substituted alkyl;
• R24, R25, R26, R28, R30, R32, R33, R34, R3s, R36, R37, R39, R40, R41, R42, R51, R52, R53, and R61 are selected from the group of H, alkyl, substituted alkyl, aryl or substituted alyl;
• R12, R16, R27, R29, R31, R38, and R43, are selected from the group consisting of H, alkyl, substituted alkyl, substituted aryl, cycloalkyl, heterocyclo, R51C=O, R52OC=O, R53SO2, hydroxy, and O-alkyl or O-substituted alkyl;
• or a pharmaceutically acceptable salt, solvate, clathrate, hydrate or prodrug thereof, in solid form;
• and
• (ii) a solid pharmaceutically acceptable acid neutralizing buffer in an amount sufficient to reduce decomposition of the one or more epothilones, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug thereof when the pharmaceutical composition is reconstituted with a solvent to provide a liquid oral dosage form.

A liquid oral dosage form suitable for oral administration to a mammal comprising:

• (i) one or more epothilones of Formula:
• 17
• wherein:
• G is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo,
• 18
• W is O or NR16;
• X is O;
• S;
• CHR17;
• or H, R18;
• Y is selected from the group consisting of O;
• H, H;
• H, OR22;
• OR23, OR23;
• NOR24;
• H, NOR25;
• H, HNR26R27;
• NHNR28R29;
• H, NHNR30R31 or CHR32, where OR23, OR23 can be a cyclic ketal;
• B1 and B2 are selected from the group consisting of H, OR33, OCOR34, OCONR35R36, NR37R38, or NR39CONR40R41
• D is selected from the group consisting of NR42R43 or heterocyclo;
• R1, R2, R3, R4, and R5 are selected from H, lower alkyl;
• R8, R9, R10 and R11 are selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo or substituted heterocyclo;
• R17, R18, R22, and R23 are selected from the group consisting of H, allyl, and substituted alkyl;
• R24, R25, R26, R28, R30, R32, R33, R34, R35, R36, R37, R39, R40, R41, R42, R51, R52, R53, and R61 are selected from the group of H, alkyl, substituted alkyl, aryl or substituted aryl;
• R12, R16, R27, R29, R31, R38, and R43, are selected from the group consisting of H, alkyl, substituted alkyl, substituted aryl, cycloalkyl, heterocyclo, R51C=O, R52OC=O, R53SO2, hydroxy, and O-alkyl or O-substituted alkyl;
• or a pharmaceutically acceptable salt, solvate, clathrate, hydrate or prodrug thereof, and
• (ii) a pharmaceutically acceptable liquid carrier.

An article of manufacture which comprises:

• (a) a sealable container suitable to carry a liquid or solid pharmaceutical;
• (b) one or more epothilones or a pharmaceutically acceptable salt, solvate, clathrate, hydrate or prodrug thereof;
• and
• (c) a pharmaceutically acceptable carrier suitable to deliver the epothilone orally.

A dispersible buffered tablet which comprises:

• (i) one or more epothilones of Formula:
• 19
• wherein:
• G is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo,
• 20
• W is O or NR16;
• X is O;
• S;
• CHR17;
• or H, R18;
• Y is selected from the group consisting of O;
• H, H;
• H, OR22;
• OR23, OR23;
• NOR24;
• H, NOR25;
• H, HNR26R27;
• NHNR28R29;
• H, NHNR30R31 or CHR32, where OR23, OR23 can be a cyclic ketal;
• B1 and B2 are selected from the group consisting of H, OR33, OCOR34, OCONR35R36, NR37R38, or NR39CONR40R41
• D is selected from the group consisting of NR42R43 or heterocyclo;
• R1, R2, R3, R4, and R5 are selected from H, lower alkyl;
• R8, R9, R10 and R11 are selected from the group consisting of, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo or substituted heterocyclo;
• R17, R18, R22, and R23 are selected from the group consisting of H, alkyl, and substituted alkyl;
• R24, R25, R26, R28, R30, R32, R33, R34, R35, R36, R37, R39, R40, R41, R42, R51, R52, R53, and R61 are selected from the group of H, alkyl, substituted alkyl, aryl or substituted aryl;
• R12, R16, R27, R29, R31, R38, and R43, are selected from the group consisting of H, alkyl, substituted alkyl, substituted aryl, cycloalkyl, heterocyclo, R51C=O, R52OC=O, R53SO2, hydroxy, and O-alkyl or O-substituted alkyl;
• or a pharmaceutically acceptable salt, solvate, clathrate, hydrate or prodrug thereof;
• and
• (ii) buffer components which are suitable to neutralize gastric fluids for a time sufficient to allow said epothilone to be absorbed.