Pharmaceutical compositions, dosage forms and methods for oral administration of epothilones
First Claim
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1. A method of increasing the bioavailability of orally administered epothilones comprising orally administering to a human one or more epothilones of Formula:
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wherein;
G is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, 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 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 orally administering one or more pharmaceutically acceptable acid neutralizing buffers.
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Abstract
The invention relates to methods of increasing the bioavailability of orally administered epothilones. Epothilones administered by the methods of the invention are sufficiently bioavailable to have a pharmacological effect The invention further relates to pharmaceutical compositions, pharmaceutical dosage forms, and kits for use in the methods of the invention.
82 Citations
52 Claims
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1. A method of increasing the bioavailability of orally administered epothilones comprising orally administering to a human one or more epothilones of Formula:
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wherein; G is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, 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 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 orally administering one or more pharmaceutically acceptable acid neutralizing buffers. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19)
(a) orally administering an aqueous solution of a pharmaceutically acceptable acid neutralizing buffer comprising anhydrous dibasic sodium phosphate, sodium citrate dihydrate, and anhydrous citric acid;
(b) orally administering the one or more epothilones or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug thereof as a solution of propylene glycol; and
(c) orally administering an aqueous solution of a pharmaceutically acceptable acid neutralizing buffer comprising anhydrous dibasic sodium phosphate, sodium citrate dihydrate, and anhydrous citric acid.
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19. The method of claim 18, wherein the epothilone is [1S-[1R*,3R*(E),7R*,10S*,11R*,16S*]]-7,11-dihydroxy 8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl-17-oxa-4-azabicyclo[14.1.0]heptadecane-5,9-dione.
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20. A kit for use in a method of increasing the biovailability of orally administered epothilones which comprises:
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(i) a first component comprising one or more epothilones of Formula;
G is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, W is O or NR16;
X is O;
S;
CHR17;
or H, R18Y 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, 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, 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 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. - View Dependent Claims (21, 22, 23, 24, 25, 26, 27, 49, 50, 51, 52)
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28. A pharmaceutical composition suitable for oral administration to a mammal comprising:
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(i) one or more epothilones of Formula;
wherein;
G is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, 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 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, 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. - View Dependent Claims (29, 30, 31, 32, 33, 34, 35, 36)
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37. A liquid oral dosage form suitable for oral administration to a mammal comprising:
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(i) one or more epothilones of Formula;
wherein;
G is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, 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 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. - View Dependent Claims (38, 39, 40, 41, 42, 43, 44, 45, 46)
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47. An article of manufacture which comprises:
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(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.
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48. A dispersible buffered tablet which comprises:
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(i) one or more epothilones of Formula;
wherein;
G is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, 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 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.
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Specification