Treatment of cancers, tumors and malignancies using amphiphilic prodrugs
View Patent ↗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.
1. A method of treating a mammalian subject having a disease condition selected from the group consisting of cancers, tumors, and malignancies, said method comprising administering to the subject of an effective disease treating amount of a prodrug comprising:
(a) at least one therapeutic compound selected from the group consisting of a therapeutic compound comprising etoposide and a therapeutic compound comprising an etoposide analog which retains some or all of the therapeutic activity of etoposide; 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 1 to 25 polyethylene glycol units; and
(ii) comprising a salt-forming moiety.
2. The method of claim 1 wherein the PEG oligomer has a number of PEG units selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, and 9.
3. The method of claim 1 wherein the therapeutic compound is derivatized by from 1 up to the maximum number of sites of attachment for the PEG oligomer(s).
4. The method of claim 1 wherein the prodrug is administered by a route of administration which comprises an oral route of administration.
5. The method of claim 1 wherein the prodrug is administered by a route of administration which comprises a parenteral route of administration.
6. The method of claim 1 wherein the disease condition comprises a condition selected from the group consisting of small cell lung cancer, non-small cell lung cancer, testicular cancer, lymphoma, leukemia, ovarian cancer, and gastric cancer.
7. The method of claim 1 wherein the prodrug is administered as a component of a pharmaceutical composition comprising:
(a) the prodrug; and
(b) a pharmaceutically acceptable carrier.
8. The method of claim 7 wherein the pharmaceutical composition is in a form suitable for oral administration.
9. The method of claim 7 wherein the pharmaceutical composition is in a form suitable for parenteral administration.
10. A method of treating a mammalian subject having a disease condition selected from the group consisting of cancers, tumors and malignancies, said method comprising administering to the subject of an effective disease treating amount of a prodrug comprising a therapeutic compound selected from the group consisting of a therapeutic compound comprising etoposide and a therapeutic compound comprising an etoposide analog which retains some or all of the therapeutic activity of etoposide and wherein the therapeutic compound is joined by hydrolyzable bond(s) to one or more PEG oligomer(s) selected from the group consisting of:
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 a lower alkyl;
wherein n is from 1 to 6, p is from 2 to 8, m is from 2 to 25, X − is a negative ion 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 1 and R 2 are each independently hydrogen or a lower alkyl;
wherein n is from 1 to 6, p is from 2 to 8 and m is from 2 to 25;
wherein n and p are each independently from 1 to 6, m is from 2 to 25 and X + is a positive ion;
wherein n is from 1 to 5, m is from 2 to 25, and wherein R 1 and R 2 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.
11. The method of claim 10 wherein the one or more PEG oligomer(s) each has 2, 3, 4 or 5 PEG units.
12. The method of claim 10 wherein the therapeutic compound is derivatized by from 1 up to the maximum number of sites of attachment for the PEG oligomer(s).
13. The method of claim 10 wherein the prodrug is delivered by a route of administration which comprises an oral route of administration.
14. The method of claim 10 wherein the prodrug is delivered by a route of administration which comprises an parenteral route of administration.
15. The method of claim 10 wherein the disease condition is selected from the group consisting of cancers, tumors and malignancies.
16. The method of claim 10 wherein the disease condition comprises a condition selected from the group consisting of small cell lung cancer, non-small cell lung cancer, testicular cancer, lymphoma, leukemia, ovarian cancer, and gastric cancer.
17. The method of claim 10 wherein the prodrug is administered as a component of a pharmaceutical composition comprising:
(a) the prodrug; and
(b) a pharmaceutically acceptable carrier.
18. The method of claim 17 wherein the pharmaceutical composition is formulated for oral administration.
19. The method of claim 17 wherein the pharmaceutical composition is formulated for parenteral administration.
20. The method of claim 10 wherein the PEG oligomer has a formula:
wherein n is from 1 to 7, m is from 2 to 25, and R is hydrogen or a lower alkyl.
21. The method of claim 10 wherein the PEG oligomer has a formula:
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.
22. The method of claim 10 wherein the PEG oligomer has a formula:
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.
23. The method of claim 10 wherein the PEG oligomer has a formula:
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.
24. The method of claim 10 wherein the PEG oligomer has a formula:
wherein n is from 1 to 6, p is from 2 to 8, m is from 2 to 25, X − is a negative ion and R is hydrogen or a lower alkyl.
25. The method of claim 10 wherein the PEG oligomer has a formula:
wherein n is from 1 to 6, p is from 2 to 8, m is from 2 to 25, and R 1 and R 2 are each independently hydrogen or a lower alkyl.
26. The method of claim 10 wherein the PEG oligomer has a formula:
wherein n is from 1 to 6, p is from 2 to 8 and m is from 2 to 25.
27. The method of claim 10 wherein the PEG oligomer has a formula:
wherein n and p are each independently from 1 to 6, m is from 2 to 25 and X + is a positive ion.
28. The method of claim 10 wherein the PEG oligomer has a formula:
wherein n is from 1 to 5, m is from 2 to 25, and wherein R 1 and R 2 are each independently hydrogen or lower alkyl.
29. The method of claim 10 wherein the PEG oligomer has a formula:
wherein n is from 1 to 6, m is from 2 to 25 and X − is a negative ion.
30. The method of claim 1 wherein the therapeutic compound is etoposide.
31. The method of claim 1 wherein the therapeutic compound is an etoposide analog which retains some or all of the therapeutic activity of etoposide.
32. The method of claim 10 wherein the therapeutic compound is etoposide.
33. The method of claim 10 wherein the therapeutic compound is an etoposide analog which retains some or all of the therapeutic activity of etoposide.
34. The method of claim 1 wherein the therapeutic compound is derivatized by 1 PEG oligomer.