Water soluble paclitaxel prodrugs

• US 5,977,163 A
• Filed: 03/11/1997
• Issued: 11/02/1999
• Est. Priority Date: 03/12/1996
• Status: Expired due to Term

• Current Assignee: PG-TXL Company, L.P.
• Original Assignee: PG-TXL Company, L.P.
• Inventors: Li, Chun, Yu, Dong-Fang, Yang, David J., Wallace, Sidney
• Primary Examiner(s): Dees, Jose' G.
• Assistant Examiner(s): Hartley, Michael G.
• Application Number:
  US08/815,104
• Time in Patent Office: 966 Days
• Field of Search: 424/1.65, 424/9.36, 424/9.364, 534/10, 534/11, 534/12, 534/13, 534/14, 534/15, 534/16, 514/449, 546/196, 548/5.25, 549/510, 549/511, 527/200
• US Class Current: 514/449
• CPC Class Codes: A61K 2121/00 Preparations for use in therapy
• CPC Class Codes: A61K 2123/00 Preparations for testing in vivo
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 47/547 Chelates, e.g. Gd-DOTA or Zinc-amino acid chelates; Chelate-forming compounds, e.g. DOTA or ethylenediamine being covalently linked or complexed to the pharmacologically- or therapeutically-active agent
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 47/645 Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
• CPC Class Codes: A61K 51/0497 conjugates with a carrier being an organic compounds
• CPC Class Codes: A61L 2300/416 Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
• CPC Class Codes: A61L 2300/606 Coatings
• CPC Class Codes: A61L 31/10 Macromolecular materials
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

Disclosed are water soluble compositions of paclitaxel and docetaxel formed by conjugating the paclitaxel or docetaxel to a water soluble chelator, polyethylene glycol or polymer such as poly (1-glutamic acid) or poly (1-aspartic acid). Also disclosed are methods of using the compositions for treatment of tumors, auto-immune disorders such as rheumatoid arthritis and for prediction of paclitaxel uptake by tumors and radiolabeled DTPA-paclitaxel tumor imaging. Other embodiments include the coating of implantable stents for prevention of restenosis.

Claims

1. A pharmaceutical composition comprising a conjugate comprising an anti-tumor or drug conjugated to a water soluble polyglutamic acid polymer, wherein said polymer has a molecular weight of greater than or equal to about 5,000, wherein said drug is conjugated to said polymer so as to provide a drug conjugate having a higher water solubility than the unconjugated drug, the ability to accumulate in a tumor, and wherein said anti-tumor drug is paclitaxel, docetaxel, etopside, teniposide, camptothecin or epothilone.

2. The pharmaceutical composition of claim 1, wherein said polyglutamic acid polymer is poly (1-glutamic acid), poly (d-glutamic acid) or poly (dl-glutamic acid).

3. The pharmaceutical composition of claim 1, wherein said water soluble polymer is further defined as a copolymer with polycaprolactone, polyglycolic acid, polylactic acid, polyacrylic acid, poly(2-hydroxyethyl 1-glutamine), carboxymethyl dextran, hyaluronic acid, human serum albumin, polyalginic acid or a combination thereof.

4. The pharmaceutical composition of claim 1, wherein said conjugate comprises paclitaxel.

5. The pharmaceutical composition of claim 4, wherein said conjugate comprises up to 35% paclitaxel.

6. The pharmaceutical composition of claim 5, wherein said pharmaceutical composition contains 15-25% paclitaxel.

7. The pharmaceutical composition of claim 1, wherein the drug conjugate of said pharmaceutical composition has a molecular weight of about 45,000 to about 55,000.

8. The pharmaceutical composition of claim 1, wherein said water soluble polymer has a molecular weight of about 20,000 to about 80,000.

9. The pharmaceutical composition of claim 8, wherein said water soluble polymer has a molecular weight of about 30,000 to about 60,000.

10. The pharmaceutical composition of claim 1, wherein the water soluble polymer is conjugated to the 2'"'"'-or the 7-hydroxyl of paclitaxel or docetaxel.

11. The pharmaceutical composition of claim 1, wherein said pharmaceutical composition is dispersed in a pharmaceutically acceptable carrier solution.

12. A pharmaceutical composition comprising a conjugate comprising paclitaxel conjugated at its 2'"'"'-or 7-hydroxyl group to a water soluble polyglutamic acid polymer, wherein said polymer has a molecular weight of greater than or equal to about 5,000, said conjugate having a higher water solubility than unconjugated paclitaxel, and having the ability to accumulate in a tumor.

13. The pharmaceutical composition of claim 12, wherein said polyglutamic acid polymer is poly (1-glutamic acid), poly (d-glutamic acid) or poly (dl-glutamic acid).

14. The pharmaceutical composition of claim 12, wherein said water soluble polymer is further defined as a copolymer with polycaprolactone, polyglycolic acid, polylactic acid, polyacrylic acid, poly(2-hydroxyethyl 1-glutamine), carboxymethyl dextran, hyaluronic acid, human serum albumin, polyalginic acid or a combination thereof.

15. The pharmaceutical composition of claim 12, wherein said paclitaxel is up to 35% of the total weight of said pharmaceutical composition.

16. The pharmaceutical composition of claim 15, wherein said pharmaceutical composition contains 15-25% paclitaxel.

17. The pharmaceutical composition of claim 12, wherein the drug conjugate of said pharmaceutical composition has a molecular weight of about 45,000 to about 55,000.

18. The pharmaceutical composition of claim 12, wherein said water soluble polymer has a molecular weight of about 20,000 to about 80,000.

19. The pharmaceutical composition of claim 18, wherein said water soluble polymer has a molecular weight of about 30,000 to about 60,000.

20. The pharmaceutical composition of claim 12, wherein said pharmaceutical composition is dispersed in a pharmaceutically acceptable carrier solution.

21. A pharmaceutical composition comprising a conjugate comprising an anti-tumor drug conjugated to a water soluble polymer comprising a polyglutamic acid polymer, wherein said polyglutamic acid polymer has a molecular weight of about 20,000 to about 80,000, and wherein said drug is conjugated to said water soluble polymer so as to provide a drug conjugate having a higher water solubility than the unconjugated drug, the ability to accumulate in a tumor, and wherein said anti-tumor drug is paclitaxel, docetaxel, etopside, teniposide, camptothecin or epothilone.

22. A pharmaceutical composition comprising a conjugate of paclitaxel conjugated at its 2'"'"'-or 7-hydroxyl group to a water soluble polymer comprising a polyglutamic acid polymer, wherein said polyglutamic acid polymer has a molecular weight of about 20,000 to about 80,000, and wherein said conjugate has a higher water solubility than unconjugated paclitaxel, and has the ability to accumulate in a tumor.