Hydrolysis-promoting hydrophobic taxane derivatives

• US 6,482,850 B2
• Filed: 08/29/2001
• Issued: 11/19/2002
• Est. Priority Date: 09/12/1995
• Status: Expired due to Fees

• Current Assignee: Cephalon France (Teva Pharmaceutical Industries Limited)
• Original Assignee: The Liposome Company
• Inventors: Ahmad, Imran, Bhattacharya, Soumendu, Ali, Shaukat, Janoff, Andrew S., Mayhew, Eric, Franklin, J. Craig, Koehane, Gil
• Primary Examiner(s): Trinh, Ba K.
• Application Number:
  US09/940,672
• Publication Number:
  US 20020052518A1
• Time in Patent Office: 447 Days
• Field of Search: 549/510, 549/511, 514/449
• US Class Current: 514/449
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 305/14 condensed with carbocyclic rings or ring systems

Abstract

Provided herein is a taxane having a hydrocarbon attached at the 2′ and/or 7 positions, the hydrocarbon'"'"'s alpha position being occupied by a “hydrolysis-promoting group” (“HPG”). In one embodiment, the hydrolysis promoting group is stereospecifically attached to the α-carbon of the hydrophobic taxane. The Substitution of an HPG for the methylene unit ordinarily occupying the alpha position allows for enhanced in vivo hydrolysis of the hydrocarbon-taxane bond, and hence, for enhanced taxane therapeutic activity. Also provided herein are taxane-containing compositions, and methods of administering taxanes to animals, including those afflicted with cancers or inflammatory diseases.

Claims

1. A taxane having the formula:

wherein;

A¹ is H or a group having the formula Z—

C(O)NHCH(C₆H₅)CH(OR)C(O)—

;

Z is phenyl, benzyloxy, t-butoxy or CH(CH₃)=C(CH₃)—

;

A² is H or CH₃C(O)—

;

A³ is H or OH;

R and R¹ are independently H or an acyl group having an α

carbon atom substituted with a hydrolysis-promoting group;

wherein the α

carbon atom of said acyl group has an (R) configuration, an (S) configuration or a mixture of (R) and (S) configurations;

wherein the hydrolysis-promoting group is an atom or group of atoms more electronegative than hydrogen, provided that when the hydrolysis-promoting group comprises an oxygen or sulfur atom directly attached to the α

carbon atom of said acyl group, the hydrolysis-promoting group does not comprise a —

C(O)O—

radical;

with the proviso that (a) when R¹ is H, A¹ is Z—

C(O)NHCH(C₆H₅)CH(OR)C(O)— and

R is said acyl group, (b) when R is H, R¹ is said acyl group and (c) when A¹ is H, R¹ is said acyl group.

2. The taxane of claim 1, wherein said acyl group having the α

carbon atom substituted with the hydrolysis-promoting group is —

Y¹Y², wherein;

—

Y¹ is a group having the formula —

C(O)CHX¹(CH₂)_n1(CH=CH)_n2(CH₂)_n3(CH=CH)_n4(CH₂)_n5(CH=CH)_n6(CH₂)_n7(CH=CH)_n8(CH₂)_n9;

the sum of n1+2n2+n3+2n4+n5+2n6+n7 +2n8 +n9 is equal an integer of from 1 to 21, with each of n2, n4, n6 and n8 being independently zero or 1;

n1 is equal to zero or an integer of from 1 to 21;

n3 is equal to zero or an integer of from 1 to 18;

n5 is equal to zero or an integer of from 1 to 15;

n7 is equal to zero or an integer of from 1 to 12;

n9 is equal to zero or an integer of from 1 to 9;

where each of n1 to n9 can be the same or different;

Y² is methyl, carboxyl or hydroxymethyl; and

X¹ is a hydrolysis-promoting group selected from the group consisting of F, Cl, Br and I.

3. The taxane of claim 1, wherein said acyl group is at least 6, 12 or 16 carbon atoms long.

4. The taxane of claim 2, wherein n2, n4, n6 and n8 are zero.

5. The taxane of claim 2, wherein Y² is methyl.

6. The taxane of claim 5, wherein —

Y¹Y² is —

C(O)CHX¹(CH₂)₃CH₃, —

C(O)CHX¹(CH₂)₅CH₃, —

C(O)CHX¹(CH₂)₉CH₃, —

C(O)CHX¹(CH₂)₁₁CH₃, —

C(O)CHX¹(CH₂)₁₃CH₃ or —

C(O)CHX¹(CH₂)₁₅CH₃.

7. The taxane of claim 2, wherein at least one of n2, n4, n6 and n8 is one.

8. The taxane of claim 7, wherein —

Y¹ is —

C(O)CHX¹(CH₂)_n1CH=CH(CH₂)_n3, wherein

n1 is zero or an integer of from 1 to 18;

n3 is zero or an integer of from 1 to 18 ; and

the sum of n1 and n3 is equal to an integer of from 1 to 19.

9. The taxane of claim 8, wherein Y² is methyl.

10. The taxane of claim 1, wherein A¹ is a group having the formula Z—

C(O)NHCH(C₆H₅)CH(OR)C(O)—

.

11. The taxane of claim 10, wherein R¹ is H.

12. The taxane of claim 11, wherein Y² is methyl.

13. The taxane of claim 10, wherein R is H.

14. The taxane of claim 13, wherein Y² is methyl.

15. The taxane of claim 10, wherein Z is phenyl.

16. The taxane of claim 10, wherein X¹ is Br.

17. The taxane of claim 1, wherein X¹ is Br.

18. The taxane of claim 1, wherein A² is CH₃C(O)—

and A³ is H.

19. The taxane of claim 18, wherein Y² is methyl.

20. The taxane of claim 10, wherein A² is CH₃C(O)—

and A³ is H.

21. The taxane of claim 1, wherein the α

carbon atom of the acyl group substituted with the hydrolysis-promoting group has the (R) configuration.

22. The taxane of claim 1, wherein the α

carbon atom of the acyl group substituted with the hydrolysis-promoting group has the (S) configuration.

23. The taxane of claim 1, wherein the α

carbon atom of the acyl group substituted with the hydrolysis-promoting group has a mixture of the (R) and (S) configurations.

24. A pharmaceutical composition comprising the taxane of claim 1 and a pharmaceutically acceptable medium.

25. The composition of claim 24, wherein the pharmaceutically acceptable medium is a substance selected from the group consisting of a polyoxyethylated derivative of castor oil, polysorbate (Tween) 80, dimethyl sulfoxide, carboxymethyl cellulose, hydroxypropylcellulose, polyethylene glycol, triacetin, soybean oil, lecithin, soy lipid, combination thereof and lipid carrier.

26. The composition of claim 25, wherein the pharmaceutically acceptable medium is a polyoxyethylated derivative of castor oil.

27. The composition of claim 26, wherein the pharmaceutically acceptable medium is USP/NF Polyoxyl 35 Castor Oil.

28. The composition of claim 24, wherein the pharmaceutically acceptable medium is a lipid carrier.

29. The composition of claim 28, wherein the lipid carrier is selected from the group consisting of fatty acids, phospholipids, lipoproteins, micelles, lipid complexes or liposomes.

30. The composition of claim 29, wherein the pharmaceutically acceptable medium is a liposome.

31. The composition of claim 30, wherein the liposome is multilamellar.

32. The composition of claim 30, wherein the liposome comprises a lipid component which comprises a saturated lipid.

33. The composition of claim 32, wherein the saturated lipid is a saturated phosphatidylcholine.

34. The composition of claim 33, wherein the saturated phosphatidylcholine is dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine and distearoyl phosphatidylcholine.

35. The composition of claim 34, wherein the saturated phosphatidylcholine is dimyristoyl phosphatidylcholine.

36. A pharmaceutical composition comprising the taxane of claim 2 and a pharmaceutically acceptable medium, which medium is a liposome, wherein the sum of n1, 2n2, n3, 2n4, n5, 2n6, n7, 2n8 and n9 is an integer of from 3 to 21.

37. The composition of claim 36, wherein the sum of n1, 2n2, n3, 2n4, n5, 2n6, n7, 2n8 and n9 is an integer of from 9 to 21.

38. The composition of claim 37, wherein the sum of n1, 2n2, n3, 2n4, n5, 2n6, n7, 2n8 and n9 is an integer of from 13 to 21.

39. The composition of claim 28, wherein the acyl group substituted with the hydrolysis-promoting group is an acyl chain of at least 6 carbon atoms in length substituted with the hydrolysis-promoting group.

40. The composition of claim 39, wherein the acyl group substituted with the hydrolysis-promoting group is an acyl chain of at least 12 carbon atoms in length substituted with the hydrolysis-promoting group.

41. The composition of claim 40, wherein the acyl group substituted with the hydrolysis-promoting group is an acyl chain of at least 16 carbon atoms in length substituted with the hydrolysis-promoting group.

42. The composition of claim 28, wherein the acyl group substituted with the hydrolysis-promoting group comprises no C=C and/or C≡

C bond.

43. The composition of claim 30, wherein the liposome is multilamellar.

44. The composition of claim 26, wherein the weight ratio of the taxane to the polyoxyethylated derivative of castor oil is from about 13 to about 30 parts per thousand.

45. The composition of claim 27, wherein the acyl group substituted with the hydrolysis-promoting group at the α

carbon atom is a C₁₆ acyl chain, which hydrolysis-promoting group is Br.

46. A liposome comprising

(i) a lipid component;

and

(ii) the taxane of claim 1.

47. The liposome of claim 46 comprising the lipid component and the taxane of claim 44.

48. The liposome of claim 46, wherein the lipid component comprises a saturated acyl chain lipid.

49. The liposome of claim 48, wherein the saturated acyl chain lipid is a phosphatidylcholine.

50. The liposome of claim 49, wherein the phosphatidylcholine is selected from the group consisting of dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine and distearoyl phosphatidylcholine.

51. The liposome of claim 46, wherein the phosphatidylcholine is dimyristoyl phosphatidylcholine.

52. The liposome of claim 46, which is multilamellar.

53. A method for treating cancer in an animal in need of the treatment, comprising administering a cancer treating effective amount of the taxane of claim 1 to said animal.

54. A method for treating cancer in an animal in need of the treatment, comprising administering a cancer treating effective amount of the composition of claim 24 to said animal.

55. The method of claim 53, wherein said animal is a human.

56. The method of claim 54, wherein said animal is a human.

57. The method of claim 53, wherein said cancer is a cancer of the brain, stomach, lung, colon, prostate, breast, ovary, head or neck of said animal.

58. The method of claim 53, wherein said cancer is a leukemia, lymphoma, carcinoma or sarcoma.

59. The method of claim 54, wherein said cancer is a cancer of the brain, stomach, lung, colon, prostate, breast, ovary, head or neck of said animal.

60. The method of claim 54, wherein said cancer is a leukemia, lymphoma, carcinoma or sarcoma.

61. A method for treating an inflammatory disease in an animal in need of the treatment, comprising administering an inflammatory disease treating effective amount of the taxane of claim 1 to said animal.

62. A method for treating an inflammatory disease in an animal in need of the treatment, comprising administering an inflammatory disease treating effective amount of the composition of claim 24 to said animal.

63. The method of claim 61, wherein said animal is a human.

64. The method of claim 62, wherein said animal is a human.

65. The method of claim 61, wherein said inflammatory disease is arthritis.

66. The method of claim 62, wherein said inflammatory disease is arthritis.

67. A taxane having the formula:

wherein;

A¹ is H or a group having the formula Z—

C(O)NHCH(C₆H₅)CH(OR)C(O)—

;

A² is H or CH₃C(O)—

;

Z is phenyl, benzyloxy, t-butoxy or CH(CH₃)=C(CH₃)—

;

A³ is H;

each of R and R¹ is independently H or a group having the formula —

Y¹Y²;

provided that at least one of R and R¹ is not H and provided that when A¹ is H, R¹ is not H;

—

Y¹ is a group having the formula —

C(O)CHX¹(CH₂)_n1(CH═

CH)_n2(CH₂)_n3(CH═

CH)_n4(CH₂)_n5(CH═

CH)_n6(CH₂)_n7(CH═

CH)_n8(CH₂)_n9;

the sum of n1+2n2+n3+2n4+n5+2n6+n7+2n8+n9 is equal to an integer of from 1 to 21, with each of n2, n4, n6 and n8 being independently zero or 1;

n1 is equal to zero or an integer of from 1 to 21;

n3 is equal to zero or an integer of from 1 to 18;

n5 is equal to zero or an integer of from 1 to 15;

n7 is equal to zero or an integer of from 1 to 12;

n9 is equal to zero or an integer of from 1 to 9;

where each of n1 to n9 can be the same or different at each occurrence;

X¹ is a hydrolysis-promoting group; and

Y² is methyl, carboxyl or hydroxymethyl.

68. The taxane of claim 67, wherein A¹ is Z—

C(O)NHCH(C₆H₅)CH(OR)C(O)—

.

69. The taxane of claim 68, wherein R¹ is H.

70. The taxane of claim 69, wherein R is a group having the formula Y¹CH₃.

71. The taxane of claim 70, wherein R¹ is —

C(O)CHX¹(CH₂)₃CH₃, —

C(O)CHX¹(CH₂)₅CH₃, —

C(O)CHX¹(CH₂)₉CH₃ or —

C(O)CHX¹(CH₂)₁₃CH₃.

72. The taxane of claim 68, wherein R is H.

73. The taxane of claim 72, wherein R¹ is a group having the formula Y¹CH₃.

74. The taxane of claim 73, wherein R¹ is —

C(O)CHX¹(CH₂)₃CH₃, —

C(O)CHX¹ (CH₂)₅CH₃, —

C(O)CHX¹(CH₂)₉CH₃ or —

C(O)CHX¹(CH₂)₁₃CH₃.

75. The taxane of claim 67, wherein X¹ is F, Cl, Br, I, the group —

OC₆H₄X² or the group —

C(O)X² and wherein X² is F, Cl, Br, I, CN, NO₂ or NH₃⁺.

76. The taxane of claim 68, wherein Z is C₆H₅.

77. The taxane of claim 76, wherein A² is CH₃C(O)—

.

78. The taxane of claim 77, wherein R¹ is H and R is —

C(O)CHX¹(CH₂)₃CH₃, —

C(O)CHX¹(CH₂)₅CH₃, —

C(O)CHX¹(CH₂)₉CH₃ or —

C(O)CHX¹(CH₂)₁₃CH₃.

79. The taxane of claim 78, wherein X¹ is F, Cl, Br or I.

80. The taxane of claim 77, wherein R is H and R¹ is —

C(O)CHX¹(CH₂)₃CH₃, —

C(O)CHX¹(CH₂)₅CH₃, —

C(O)CHX¹(CH₂)₉CH₃ or —

C(O)CHX¹(CH₂)₁₃CH₃.

81. The taxane of claim 80, wherein X¹ is F, Cl, Br or I.

82. A composition comprising the taxane of claim 67 and a pharmaceutically acceptable medium.

83. The composition of claim 82, wherein the pharmaceutically acceptable medium comprises a lipid carrier and wherein the taxane is associated with the lipid carrier.

84. The composition of claim 83, wherein the lipid carrier is a fatty acid, phospholipid, lipoprotein, micelle, lipid complex or liposome.

85. A method of administering a taxane to an animal which comprises administering the composition of claim 82 to the animal.

86. The method of claim 85, wherein the animal is afflicted with a cancer and wherein an anticancer effective amount of the taxane is administered.

87. The method of claim 86, wherein the anticancer effective amount of the taxane is from about 0.1 mg per kg of body weight of the animal to about 1000 mg per kg.

88. The method of claim 86, wherein the taxane is associated with a liposome.

89. The method of claim 86, wherein A¹ is C₆H₅C(O)NHCH(C₆H₅)CH(OR)C(O)—

, A² is CH₃C(O)—

, and one of R or R¹ is —

C(O)CHX¹(CH₂)₃CH₃, —

C(O)CHX¹(CH₂)₅CH₃, —

C(O)CHX¹(CH₂)₉CH₃or —

C(O)CHX¹(CH₂)₁₃CH₃.

90. The method of claim 86, wherein the cancer is a lung, colon, brain, breast, ovarian, prostate or stomach cancer, or a leukemia, lymphoma, sarcoma or carcinoma.

91. A liposome which comprises:

(i) a lipid component comprising a saturated acyl chain lipid;

(ii) a taxane having the formula;

wherein;

A¹ is H or a group having the formula Z—

C(O)NHCH(C₆H₅)CH(OR)C(O)—

;

Z is phenyl, t-butoxy or CH(CH₃)═

C(CH₃)—

;

A² is H or CH₃C(O)—

;

A³ is H;

each of R and R¹ is independently H or a group having the formula —

Y¹Y²;

provided that at least one of R and R¹ is not H and provided that (a) when A¹ is H, R¹ is not H, or (B) when A¹ is Z—

C(O)NHCH(C₆C₅)CH(OR)C(O)—

and R is H, R¹ is not H;

—

Y¹ is a group having the formula —

C(O)CHX¹(CH₂)_n1(CH═

CH)_n2(CH₂)_n3(CH═

H)_n4(CH₂)_n5(CH═

CH)_n6(CH₂)_n7(CH═

CH)_n8(CH₂)_n9;

the sum of n1+2n2+n3+2n4+n5+2n6+n7+2n8+n9 is equal an integer of from 1 to 21, with each of n2, n4, n6 and n8 being independently zero or 1;

n1 is equal to zero or an integer of from 1 to 21;

n3 is equal to zero or an integer of from 1 to 18;

n5 is equal to zero or an integer of from 1 to 15;

n7 is equal to zero or an integer of from 1 to 12;

n9 is equal to zero or an integer of from 1 to 9;

where each of n1 to n9 can be the same or different at each occurrence;

X¹ is a hydrolysis-promoting group; and

Y² is methyl, carboxyl or hydroxymethyl.

92. The liposome of claim 91, which is a multilamellar liposome.

93. The liposome of claim 92, wherein the multilamellar liposome has substantially equal intermolecular solute distribution.

94. The liposome of claim 91, wherein the saturated acyl chain lipid is a phosphatidylcholine selected from the group consisting of dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine and distearoyl phosphatidylcholine.

95. The liposome of claim 91, wherein A¹ is C₆C₅C(O)NHCH(C₆C₅)CH(OR)C(O)—

and A² is CH₃C(O)—

.

96. The liposome of claim 95, wherein R¹ is H and R is —

C(O)CHX¹(CH₂)₃CH₃, —

C(O)CHX¹(CH₂)₅CH₃, —

C(O)CHX¹(CH₂)₉CH₃ or —

C(O)CHX¹(CH₂)₁₃CH₃.

97. The liposome of claim 96, wherein X¹ is Br.

98. The liposome of claim 95, wherein R is H and R¹ is —

C(O)CHX¹(CH₂)₃CH₃, —

C(O)CHX¹(CH₂)₅CH₃, —

C(O)CHX¹(CH₂)₉CH₃ or —

C(O)CHX¹(CH₂)₁₃CH₃.

99. The liposome of claim 98, wherein X¹ is Br.

100. The liposome of claim 91, wherein the saturated acyl chain lipid is a phosphatidylcholine selected from the group consisting of dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine and distearoyl phosphatidylcholine;

and wherein R¹ is H and R is —

C(O)CHBr(CH₂)₃CH₃, —

C(O)CHBr(CH₂)₅CH₃, —

C(O)CHBr(CH₂)₉CH₃, —

C(O)CHBr(CH₂)₁₁CH₃, —

C(O)CHBr(CH₂)₁₃CH₃ or —

C(O)CHBr(CH₂)₁₅CH₃,

or wherein R is H and R¹ is —

C(O)CHBr(CH₂)₃CH₃, —

C(O)CHBr(CH₂)₅CH₃, —

C(O)CHBr(CH₂)₉CH₃, —

C(O)CHBr(CH₂)₁₁CH₃, —

C(O)CHBr(CH₂)₁₃CH₃ or —

C(O)CHBr(CH₂)₁₅CH₃.

101. A taxane having the formula:

wherein;

A¹ is H or a group having the formula Z—

C(O)NHCH(C₆C₅)CH(OR)C(O)—

;

A² is H or CH₃C(O)—

;

A³ is H or OH;

Z is phenyl, benzyloxy, t-butoxy or CH(CH₃)═

C(CH₃)—

;

each of R and R¹ is independently H or a group having the formula —

Y¹Y²;

provided that at least one of R and R¹ is not H and provided that when A¹ is H, R¹ is not H;

—

Y¹ is a group having the formula —

C(O)CHX¹(CH₂)_n1(CH═

CH)_n2(CH₂)_n3(CH═

CH)_n4(CH₂)_n5(CH═

CH)_n6(CH₂)_n7(CH═

CH)_n8(CH₂)_n9;

the sum of n1 +2n2+n3 +2n4 +n5 +2n6 +n7 +2n8 +n9 is equal to an integer of from 1 to 21, with each of n2, n4, n6 and n8 being independently zero or 1;

n1 is equal to zero or an integer of from 1 to 21;

n3 is equal to zero or an integer of from 1 to 18;

n5 is equal to zero or an integer of from 1 to 15;

n7 is equal to zero or an integer of from 1 to 12;

n9 is equal to zero or an integer of from 1 to 9;

where each of n1 to n9 can be the same or different at each occurrence;

X¹ is a hydrolysis-promoting group; and

Y¹² is methyl, carboxyl or hydroxymethyl;

wherein the carbon atom to which X¹is attached has a stereospecific configuration selected from the group consisting of an (R) configuration, an (S) configuration and a mixture of (R) and (S) configurations.

102. The taxane of claim 101, wherein A¹ is a group having the formula Z—

C(O)NHCH(C₆H₅)CH(OR)C(O)—

.

103. The taxane of claim 102, wherein R¹ is H.

104. The taxane of claim 103, wherein R is a group having the formula Y¹CH₃.

105. The taxane of claim 104, wherein R¹ is —

C(O)CHX¹(CH₂)₃CH₃, —

C(O)CHX¹(CH₂)₅CH₃, —

C(O)CHX¹(CH₂)₉CH₃ or —

C(O)CHX¹(CH₂)₁₃CH₃.

106. The taxane of claim 102, wherein R is H.

107. The taxane of claim 106, wherein R¹ is a group having the formula Y¹CH₃.

108. The taxane of claim 107, wherein R is —

C(O)CHX¹(CH₂)₃CH₃, —

C(O)CHX¹(CH₂)₅CH₃, —

C(O)CHX¹(CH₂)₉CH₃ or —

C(O)CHX¹(CH₂)₁₃CH₃.

109. The taxane of claim 108, wherein X¹ is F, Cl, Br, I, the group —

OC₆H₄X² or the group —

C(O)X² and wherein X² is F, Cl, Br, I, CN, NO₂ or NH₃⁺.

110. The taxane of claim 102, wherein Z is C₆H₅.

111. The taxane of claim 110, wherein A² is CH₃C(O)—

and A³ is H.

112. The taxane of claim 111, wherein R¹ is H and R is —

C(O)CHX¹(CH₂)₃CH₃, —

C(O)CHX¹(CH₂)₅CH₃, —

C(O)CHX¹(CH₂)₉CH₃ or —

C(O)CHX¹(CH₂)₁₃CH₃.

113. The taxane of claim 112, wherein X¹ is F, Cl, Br or I.

114. The taxane of claim 111, wherein R is H and R¹ is —

C(O)CHX¹(CH₂)₃CH₃, —

C(O)CHX¹(CH₂)₅CH₃, —

C(O)CHX¹(CH₂)₉CH₃ or —

C(O)CHX¹(CH₂)₁₃CH₃.

115. The taxane of claim 114, wherein X¹ is F, Cl, Br or I.

116. The taxane of claim 101, wherein the carbon atom to which X¹ is attached has an (R) configuration.

117. The taxane of claim 101, wherein the carbon atom to which X¹ is attached has an (S) configuration.

118. The taxane of claim 101, wherein the carbon atom to which X¹ is attached has a mixture of (R) and (S) configurations.

119. A composition comprising the taxane of claim 101 and a pharmaceutically acceptable medium.

120. The composition of claim 119, wherein the pharmaceutically acceptable medium comprises a polyoxyethylated derivative of castor oil.

121. The composition of claim 120, wherein the weight ratio of the taxane to the polyoxyethylated derivative of castor oil is from about 13 to about 30 parts per thousand.

122. The composition of claim 120, wherein the sum of n1+2n2+n3+2n4+n5+2n6+n7+2n8+n9 is an integer of from 3 to 21.

123. The composition of claim 122, wherein the sum of n1+2n2+n3+2n4+n5+2n6+n7+2n8+n9 is an integer of from 9 to 21.

124. The composition of claim 122, wherein the sum of n1+2n2+n3+2n4+n5+2n6+n7+2n8+n9 is an integer of from 13 to 21.

125. The composition of claim 120, wherein Y¹ is —

C(O)CHBr(CH₂)₁₃CH₃.

126. A method of administering a taxane to an animal which comprises administering to the animal a treatment effective amount of a composition comprising the taxane of claim 101 and a pharmaceutically acceptable carrier.

127. The method of claim 126, wherein the pharmaceutically acceptable carrier comprises a polyoxyethylated derivative of castor oil.

128. The method of claim 126, wherein the animal is afflicted with a cancer and wherein an anti-cancer effective amount of the composition is administered.