Biodegradable poly(alkylene oxide)-poly(p-dioxanone) block copolymer soluble in organic solvents, and drug delivery composition comprising same

• US 6,599,519 B1
• Filed: 06/28/2001
• Issued: 07/29/2003
• Est. Priority Date: 07/20/1999
• Status: Expired due to Term

• Current Assignee: Samyang Biopharmaceuticals Corporation (Samyang Holdings Corporation)
• Original Assignee: Samyang Corporation (Samyang Holdings Corporation)
• Inventors: Seo, Min-Hyo, Choi, In-Ja
• Primary Examiner(s): Spear, James M.
• Assistant Examiner(s): FUBARA, BLESSING M
• Application Number:
  US09/763,921
• Time in Patent Office: 761 Days
• Field of Search: 424/426, 424/400, 424/402, 424/451, 424/184.1, 424/422, 424/423, 424/489, 424/486, 424/487, 424/484, 606/230, 525/408, 525/409, 525/411, 525/413, 525/415, 528/354, 528/421, 514/44, 514/169, 514/54.07, 514/254, 514/9
• US Class Current: 424/426
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5153 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: C08G 63/664 derived from hydroxy carboxylic acids
• CPC Class Codes: Y10S 977/906 Drug delivery

Abstract

The present invention relates to a biocompatible and biodegradable block copolymer of poly(alkylene oxide) and poly(p-dioxanone), which is soluble in organic solvents, and a drug delivery composition comprising the same.

Claims

1. A block copolymer comprising one or more poly(alkylene oxide) blocks and one or more blocks of a p-dioxanone homopolymer or copolymer, wherein:

(a) the block copolymer has a solubility in an organic solvent of 33.3 to 1,000 mg/ml; and

(b) the poly(alkylene oxide) blocks comprise between 25% to 80% by weight of the block copolymer.

2. The block of claim 1, wherein the poly(alkylene oxide) blocks comprises between 30 to 75% by weight of the block copolymer.

3. The block copolymer of claim 1 having an average molecular weight of between 625 to 2,000,000 Daltons.

4. The block copolymer of claim 1, wherein the total molecular weight of the poly(alkylene oxide) blocks is within range from 200 to 500,000 Daltons.

5. The block copolymer of claim 1, wherein the poly(alkylene oxide) is a member selected from the group consisting of poly(ethylene oxide), random copolymers of ethylene oxide and propylene oxide and block copolymers of poly(ethylene oxide) and poly(propylene oxide) and monoalkoxy-terminated derivatives thereof.

6. The block copolymer claim 1, wherein the p-dioxanone copolymer is a copolymer of 1,4-dioxane-2-one and a member selected from the group consisting of glycolic acid, lactic acid, and caprolactone.

7. The block copolymer of claim 6, wherein the p-dioxanone copolymer contains at least 5 mole percent of repeating units derived from 1,4-dioxane-2-one based on the total amount of monomers used in preparing said copolymer.

8. The block copolymer of claim 1, wherein the block copolymer is a diblock or triblock copolymer.

9. The block copolymer of claim 1 wherein said block copolymer is selected from the group consisting of RO—

A—

B—

OH, RO—

B—

A—

B—

OR, RO—

A—

B—

A—

OR and RO—

(A—

B)_n—

OR, wherein R is hydrogen, an alkyl or acyl group having 1˜

20 carbon atoms, n is an integer of 2 to 100;

A is a hydrophillic poly(alkylene oxide) block selected from the group consisting of poly(ethylene oxide), random copolymers of ethylene oxide and propylene oxide and block copolymers of poly(ethylene oxide) and poly(propylene oxide); and

B is a hydrophobic block selected from the group consisting of poly(p-dioxanone), a block or random copolymer of 1,4-dioxanone and at least one comonomer selected from the group consisting of lactic acid, glycolic acid and carprolactone.

10. The block copolymer claim 1, wherein the organic solvent is a member selected from the group consisting of methylene chloride, chloroform, ethanol, methanol, isopropanol, butanol, acetic acid, formic acid, ethyl acetate, methyl acetate, acetonitrile, acetone, 1,4-dioxane, N,N-dimethyl formamide, N,N-dimethyl acetamide, dimethyl sulfoxide, N-methylpyrrolidone, or a mixture thereof.

11. A bioactive agent delivery composition comprising the block copolymer of claim 1 and a bioactive agent encased therein.

12. The composition of claim 11, wherein the bioactive agent is a member selected from the group consisting of peptides or proteins, anti-cancer agents, antiphlogistic anodyme agents, anti-biotic agents, anti-bacterial agents, hormones, genes and vaccines.

13. The composition of claim 1, wherein the bioactive agent is selected from the group consisting of paclitaxel, cisplatin, carboplatin, doxorubicin, camtotecin, 5-fluorouracil, cytosine arabinoside, methotrexate, indomethacin, probiprofen, ketoprofen, piroxicam, diclofenac, cyclosporine, etraconazole, ketoconazole, tetracycline, minocycline, doxycycline, ofloxacin, ciprofloxacin, gentamicin, amphotericin B human growth hormone, pig growth hormone, bovine growth hormone, leukocyte increasing factors, erythrocyte increasing agent, osteogenetic protein, platelet sensitive agent, epithelial cell growth factor, brain growth factor, leuprorelin acetate, goserelin acetate, insulin, glucagon, octreotide, calcitonin, decapeptyl, follicle-stimulating hormone, interferon, testosterone, progesterone, estradiol, estrogen.

14. A drug formulation for subcutaneous implantation of intravenous injection comprising the composition of claim 11.

15. A drug formulation for subcutaneous implantation or intravenous injection comprising a bioactive agent delivery composition comprising a block copolymer comprising one or more poly(alkylene oxide) blocks and one or more blocks of a p-dioxanone homopolymer or copolymer, wherein:

(a) the block copolymer is soluble in an organic solvent; and

(b) the poly(alkylene oxide) blocks comprise between 25 to 85% by weight of the block copolymer;

and a bioactive agent encased therein, wherein said composition is in the form of a microsphere, microcapsule, film, strip, fiber, gel or solution.

16. A drug formation for subcutaneous implantation or intravenous injection comprising a bioactive agent delivery composition comprising a block copolymer comprising one or more poly(alkylene oxide) blocks and one or more blocks of a p-dioxanone homopolymer or copolymer, wherein:

(a) the block copolymer is soluble in an organic solvent; and

(b) the poly(alkylene oxide) blocks comprise between 25 to 80% by weight of the block copolymer;

and a bioactive agent encased therein, wherein said composition is in the form of a nanosphere, nanocapsule or polymeric micelle.