Prodrugs of etoposide and etoposide analogs
First Claim
Patent Images
1. A prodrug comprising:
- (a) at least one therapeutic compound; and
(b) one or more PEG polymers and/or oligomers, each joined to a bonding site on the therapeutic compound by a hydrolyzable bond, said PEG polymers and/or oligomers each;
(i) comprising a straight or branched PEG segment consisting of 2 to 25 polyethylene glycol units; and
(ii) comprising a salt-forming moiety.
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Abstract
The present invention provides amphiphilic prodrugs comprising a therapeutic compound conjugated to an PEG-oligomer/polymer and methods for using said prodrugs to enable oral drug delivery and/or delivery of drugs across the blood brain barrier into the central nervous system.
114 Citations
105 Claims
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1. A prodrug comprising:
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(a) at least one therapeutic compound; and
(b) one or more PEG polymers and/or oligomers, each joined to a bonding site on the therapeutic compound by a hydrolyzable bond, said PEG polymers and/or oligomers each;
(i) comprising a straight or branched PEG segment consisting of 2 to 25 polyethylene glycol units; and
(ii) comprising a salt-forming moiety. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13)
(a) a prodrug of claim 1; and
(b) a pharmaceutically acceptable carrier.
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12. The pharmaceutical composition of claim 11 in a form suitable for oral administration.
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13. The pharmaceutical composition of claim 11 in a form selected from the group consisting of:
- tablets, capsules, caplets, gelcaps, pills, liquid solutions, suspensions or elixirs, powders, lozenges, micronized particles and osmotic delivery systems.
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14. A prodrug comprising a therapeutic compound joined by hydrolysable bond(s) to one or more PEG oligomer(s) selected from the group consisting of:
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wherein n is from 1 to 7, m is from 2 to 25, and R is hydrogen or a lower alkyl;
wherein n is from 1 to 6, p is from 2 to 8, m is from 2 to 25, and R is hydrogen or a lower alkyl;
wherein n is from 1 to 6, m and r are each independently from 2 to 25, and R is hydrogen or a lower alkyl;
wherein n is from 1 to 6, p is from 2 to 8, m is from 2 to 25 and R is hydrogen or lower alkyl;
wherein n is from 1 to 6, p is from 2 to 25, m is from 2 to 8, R is hydrogen or lower alkyl, and X is a negative ion;
wherein n is from 1 to 6, p is from 2 to 8, m is from 2 to 25, and R1 and R2 are each independently lower alkyl;
wherein n is from 1 to 6, p is from 2 to 8 and m is from 2 to 25;
wherein n is from 1 to 5, m is from 2 to 25, X−
is a negative ion, and wherein R1 and R2 are each independently hydrogen or lower alkyl; and
wherein n is from 1 to 6, m is from 2 to 25 and X−
is a negative ion.- View Dependent Claims (15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58)
(a) a prodrug of claim 14; and
(b) a pharmaceutically acceptable carrier.
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21. The pharmaceutical composition of claim 20 in a form suitable for oral administration.
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22. The pharmaceutical composition of claim 20 in a form selected from the group consisting of:
- tablets, capsules, caplets, gelcaps, pills, liquid solutions, suspensions or elixirs, powders, lozenges, micronized particles and osmotic delivery systems.
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23. The prodrug of claim 14 wherein the therapeutic compound is joined by hydrolyzable bond(s) to one or more PEG oligomer(s) having the formula:
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wherein n is from 1 to 7, m is from 2 to 25, and R is hydrogen or a lower alkyl.
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24. The prodrug of claim 23 wherein the therapeutic compound comprises etoposide.
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25. The prodrug of claim 23 wherein the therapeutic compound comprises a etoposide analog which retains some or all of the therapeutic activity of etoposide.
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26. The prodrug of claim 23 wherein the therapeutic compound is derivatized by 1, 2, 3 or 4 of the polyethylene glycol oligomer(s).
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27. The prodrug of claim 14 wherein the therapeutic compound is joined by hydrolyzable bond(s) to one or more PEG oligomer(s) having the formula:
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wherein n is from 1 to 6, p is from 2 to 8, m is from 2 to 25, and R is hydrogen or a lower alkyl.
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28. The prodrug of claim 27 wherein the therapeutic compound comprises etoposide.
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29. The prodrug of claim 27 wherein the therapeutic compound comprises a etoposide analog which retains some or all of the therapeutic activity of etoposide.
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30. The prodrug of claim 27 wherein the therapeutic compound is derivatized by 1, 2, 3 or 4 of the polyethylene glycol oligomer(s).
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31. The prodrug of claim 14 wherein the therapeutic compound is joined by hydrolyzable bond(s) to one or more PEG oligomer(s) having the formula:
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wherein n is from 1 to 6, m and r are each independently from 2 to 25, and R is hydrogen or a lower alkyl.
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32. The prodrug of claim 31 wherein the therapeutic compound comprises etoposide.
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33. The prodrug of claim 31 wherein the therapeutic compound comprises a etoposide analog which retains some or all of the therapeutic activity of etoposide.
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34. The prodrug of claim 31 wherein the therapeutic compound is derivatized by 1, 2, 3 or 4 of the polyethylene glycol oligomer(s).
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35. The prodrug of claim 14 wherein the therapeutic compound is joined by hydrolyzable bond(s) to one or more PEG oligomer(s) having the formula:
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wherein n is from 1 to 6, p is from 2 to 8, m is from 2 to 25 and R is hydrogen or lower alkyl.
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36. The prodrug of claim 35 wherein the therapeutic compound comprises etoposide.
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37. The prodrug of claim 35 wherein the therapeutic compound comprises a etoposide analog which retains some or all of the therapeutic activity of etoposide.
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38. The prodrug of claim 35 wherein the therapeutic compound is derivatized by 1, 2, 3 or 4 of the polyethylene glycol oligomer(s).
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39. The prodrug of claim 14 wherein the therapeutic compound is joined by hydrolyzable bond(s) to one or more PEG oligomer(s) having the formula:
-
wherein n is from 1 to 6, p is from 2 to 8, m is from 2 to 25, R is hydrogen or lower alkyl, and X−
is a negative ion.
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40. The prodrug of claim 39 wherein the therapeutic compound comprises etoposide.
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41. The prodrug of claim 39 wherein the therapeutic compound comprises a etoposide analog which retains some or all of the therapeutic activity of etoposide.
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42. The prodrug of claim 39 wherein the therapeutic compound is derivatized by 1, 2, 3 or 4 of the polyethylene glycol oligomer(s).
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43. The prodrug of claim 14 wherein the therapeutic compound is joined by hydrolyzable bond(s) to one or more PEG oligomer(s) having the formula:
-
wherein n is from 1 to 6, p is from 2 to 8, m is from 2 to 25, and R1 and R2 are each independently a lower alkyl.
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44. The prodrug of claim 43 wherein the therapeutic compound comprises etoposide.
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45. The prodrug of claim 43 wherein the therapeutic compound comprises a etoposide analog which retains some or all of the therapeutic activity of etoposide.
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46. The prodrug of claim 43 wherein the therapeutic compound is derivatized by 1, 2, 3 or 4 of the polyethylene glycol oligomer(s).
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47. The prodrug of claim 14 wherein the therapeutic compound is joined by hydrolyzable bond(s) to one or more PEG oligomer(s) having the formula:
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wherein n is from 1 to 6, p is from 2 to 8 and m is from 2 to 25.
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48. The prodrug of claim 47 wherein the therapeutic compound comprises etoposide.
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49. The prodrug of claim 47 wherein the therapeutic compound comprises a etoposide analog which retains some or all of the therapeutic activity of etoposide.
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50. The prodrug of claim 47 wherein the therapeutic compound is derivatized by 1, 2, 3 or 4 of the PEG oligomer(s).
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51. The prodrug of claim 14 wherein the therapeutic compound is joined by hydrolyzable bond(s) to one or more PEG oligomer(s) having the formula:
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wherein n is from 1 to 5, m is from 2 to 25, X−
is a negative ion, and wherein R1 and R2 are each independently hydrogen or lower alkyl.
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52. The prodrug of claim 51 wherein the therapeutic compound comprises etoposide.
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53. The prodrug of claim 51 wherein the therapeutic compound comprises a etoposide analog which retains some or all of the therapeutic activity of etoposide.
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54. The prodrug of claim 51 wherein the therapeutic compound is derivatized by 1, 2, 3 or 4 of the PEG oligomer(s).
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55. The prodrug of claim 14 wherein the therapeutic compound is joined by hydrolyzable bond(s) to one or more PEG oligomer(s) having the formula:
-
wherein n is from 1 to 6, m is from 2 to 25 and X−
is a negative ion.
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56. The prodrug of claim 55 wherein the therapeutic compound comprises etoposide.
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57. The prodrug of claim 55 wherein the therapeutic compound comprises a etoposide analog which retains some or all of the therapeutic activity of etoposide.
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58. The prodrug of claim 55 wherein the therapeutic compound is derivatized by 1, 2, 3 or 4 of the PEG oligomer(s).
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59. A prodrug comprising a therapeutic compound joined by hydrolyzable bond(s) to one or more PEG oligomer(s) having the formula:
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wherein n and p are each independently from 1 to 6, m is from 2 to 25 and X+ is a positive ion. - View Dependent Claims (60, 61, 62)
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63. An epipodophyllotoxin prodrug in salt form comprising:
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(a) an epipodophyllotoxin;
(b) an oligomer joined to a bonding site on the epipodophyllotoxin by a hydrolyzable bond, said oligomer comprising;
(i) a straight or branched PEG segment consisting of 2 to 25 polyethylene glycol units; and
(ii) a salt forming moiety; and
(c) a positive or negative ion associated with the salt forming moiety to provide the epipodophyllotoxin prodrug in salt form. - View Dependent Claims (64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80)
wherein n and p are each independently from 1 to 6, m is from 2 to 25 and X+ is a positive ion.
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78. A pharmaceutical composition comprising:
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(a) a epipodophyllotoxin prodrug in salt form of claim 63; and
(b) a pharmaceutically acceptable carrier.
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79. The pharmaceutical composition of claim 78 in a form suitable for oral administration.
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80. The pharmaceutical composition of claim 78 in a form selected from the group consisting of:
- tablets, capsules, gelcaps, pills, liquid solutions, suspension, elixirs, powders, lozenges, micronized particles and osmotic delivery systems.
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81. A epipodophyllotoxin prodrug in salt form comprising:
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(a) an epipodophyllotoxin;
(b) an oligomer joined to a bonding site on the epipodophyllotoxin by a hydrolyzable bond, wherein the oligomer is;
wherein n is from 1 to 6, p is from 2 to 8, m is from 2 to 25, R is hydrogen or lower alkyl, and X−
is a negative ion.
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82. An epipodophyllotoxin prodrug in salt form comprising:
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(a) an epipodophyllotoxin;
(b) an oligomer joined to a bonding site on the epipodophyllotoxin by a hydrolyzable bond, wherein the oligomer is;
wherein n is from 1 to 5, m is from 2 to 25, X−
is a negative ion, and wherein R1 and R2 are each independently hydrogen or lower alkyl.
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83. An epipodophyllotoxin prodrug in salt form comprising:
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(a) an epipodophyllotoxin;
(b) an oligomer joined to a bonding site on the epipodophyllotoxin by a hydrolyzable bond, wherein the oligomer is;
wherein n is from 1 to 6, m is from 2 to 25 and X−
is a negative ion.
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84. An etoposide prodrug comprising:
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(a) an etoposide;
(b) an oligomer joined to a bonding site on the etoposide by a hydrolyzable bond, said oligomer comprising a straight or branched PEG segment consisting of 2 to 25 polyethylene glycol units. - View Dependent Claims (85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96)
(a) a prodrug of claim 84; and
(b) a pharmaceutically acceptable carrier.
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95. The pharmaceutical composition of claim 94 in a form suitable for oral administration.
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96. The pharmaceutical composition of claim 94 in a form selected from the group consisting of:
- tablets, capsules, caplets, gelcaps, pills, liquid solutions, suspensions or elixirs, powders, lozenges, micronized particles, and osmotic delivery systems.
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97. An etoposide prodrug comprising:
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(a) an etoposide; and
(b) an oligomer joined to a bonding site on the etoposide by a hydrolyzable bond, said oligomer comprising a straight or branched PEG segment consisting of 1 to 25 polyethylene glycol units. - View Dependent Claims (98, 99)
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100. An etoposide prodrug comprising:
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(a) an etoposide therapeutic compound selected from the group consisting of etoposide and an etoposide analog which retains some or all of the therapeutic activity of etoposide; and
(b) an oligomer joined to a bonding site on the etoposide therapeutic compound by a hydrolyzable bond, said oligomer comprising a straight or branched PEG segment consisting of 1 to 25 polyethylene glycol units. - View Dependent Claims (101, 102)
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103. An etoposide prodrug comprising an etoposide coupled at each of the three hydroxy bonding sites of the etoposide to an oligomer having the following structure:
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104. An etoposide prodrug comprising an etoposide coupled at each of the three hydroxy bonding sites of the etoposide to an oligomer having the following structure:
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105. An etoposide prodrug comprising an etoposide coupled at each of the three hydroxy bonding sites of the etoposide to an oligomer having the following structure:
Specification