Thermogelling biodegradable aqueous polymer solution

• US 6,841,617 B2
• Filed: 04/11/2001
• Issued: 01/11/2005
• Est. Priority Date: 09/28/2000
• Status: Expired due to Term

• Current Assignee: Battelle Memorial Institute
• Original Assignee: Battelle Memorial Institute
• Inventors: Jeong, Byeong Moon, Gutowska, Anna
• Primary Examiner(s): Yoon, Tae H.
• Application Number:
  US09/833,460
• Publication Number:
  US 20020173586A1
• Time in Patent Office: 1,371 Days
• Field of Search: 524/845, 524/504, 524/505, 524/601, 528/354, 424/78.17, 424/486
• US Class Current: 524/845
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• 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: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 5/10 of the posterior pituitary hormones, e.g. oxytocin, ADH
• CPC Class Codes: C08G 63/664 derived from hydroxy carboxylic acids

Abstract

Disclosed is a thermogelling biodegradable aqueous polymer solution useful in providing a bioactive agent delivery system. The present invention provides a thermogelling biodegradable aqueous polymer solution with a polyethylene glycol (PEG) block and a biodegradable polyester block, where the blocks are linked to form a polymer of a general structure comprising the formula of A_n(B), where n is greater than 2 and A is selected from the group consisting of a polyethylene glycol block and a biodegradable polyester block, B is selected from the group consisting of a polyethylene glycol block and a biodegradable polyester block, and A is different from B.

Claims

1. A thermogelling biodegradable aqueous polymer solution, comprising:

a. a biodegradable graft polymer, comprising;

i. a polyethylene glycol (PEG) block, and

ii. a biodegradable polyester block, wherein

iii. said blocks are linked to form a polymer of a general structure comprising the formula of A_n(B), where n is greater than 2 and A is selected from the group consisting of a polyethylene glycol block and a biodegradable polyester block, B is selected from the group consisting of a polyethylene glycol block and a biodegradable polyester block, and A is different from B;

and

b. an aqueous solution.

2. A thermogelling biodegradable aqueous polymer solution according to claim 1 wherein n is between 3 and 10.

3. A thermogelling biodegradable aqueous polymer solution according to claim 1 wherein said polyethylene glycol (PEG) has a weight average molecular weight of between about 300 and 20,000.

4. A thermogelling biodegradable aqueous polymer solution according to claim 1 wherein said polyethylene glycol (PEG) has a weight average molecular weight of between about 500 and 10,000.

5. A thermogelling biodegradable aqueous polymer solution according to claim 1 wherein said polyester block has a weight average molecular weight of between about 1,000 and 30,000.

6. A thermogelling biodegradable aqueous polymer solution according to claim 1 wherein said polyester block has a weight average molecular weight of between about 1,000 and 10,000.

7. A thermogelling biodegradable aqueous polymer solution according to claim 1, wherein said biodegradable polyester block is selected from the group consisting of poly(DL-lactic acid), poly(L-lactic acid), poly(glycolic acid), poly(ε

-caprolactone), poly(γ

-butyrolactone), poly(γ

-valerolactone), poly(β

-hydroxybutyric acid), and their copolymers or terpolymers.

8. A thermogelling biodegradable aqueous polymer solution according to claim 7, wherein said copolymers and/or terpolymers are selected from the group consisting of poly(DL-lactic acid-co-glycolic acid), poly(L-lactic acid-co-glycolic acid), poly(ε

-caprolactone-co-DL-lactic acid), copoly(ε

-caprolactone-co-DL-lactic acid-glycolic acid).

9. A biodegradable bioactive agent delivery system, comprising:

a. an effective amount of bioactive agent contained in;

b. a thermogelling biodegradable aqueous polymer solution comprising

i. a biodegradable graft polymer, comprising a polyethylene glycol (PEG) block, a biodegradable polyester block, wherein said blocks are linked to form a polymer of a general structure comprising the formula A_n(B), where n is greater than 2 and A is selected from the group consisting of a polyethylene glycol block and a biodegradable polyester block, B is selected from the group consisting of a polyethylene glycol block and a biodegradable polyester block, and A is different from B, and

ii. an aqueous solution.

10. A biodegradable bioactive agent delivery system according to claim 9 wherein said bioactive agent is a drug.

11. A biodegradable bioactive agent delivery system according to claim 10 wherein said drug is selected from the group consisting of anti-cancer agents, hormones, antibiotics, narcotic antagonists, analgesics, anti-inflammatory agents, anti-depressants, anti-epileptics, anti-malarial agents, immunoactivators, growth factors, radioprotection agents, vaccines, gene therapy agents, oligonucleotides, antisense, peptides and proteins, and combinations thereof.

12. A biodegradable bioactive agent delivery system according to claim 10 wherein said drug is an anti-cancer agent.

13. A biodegradable bioactive agent delivery system according to claim 12 wherein said anti-cancer agent is a member selected from the group consisting of adriamycin, mitomycin, bleomycin, cisplatin, carboplatin, doxorubicin, daunorubicin, 5-fluouroacil, methotrexate, taxol, taxotere, and actinomycin D.

14. A biodegradable bioactive agent delivery system according to claim 10 wherein said drug is a polypeptide.

15. A biodegradable bioactive agent delivery system according to claim 14 wherein said polypeptide is a member selected from the group consisting of oxytocin, vasopressin, adrenocorticotropic growth factor (PDGF), prolactin, luliberin or luteinising hormone releasing hormone (LHRH), growth hormone, growth hormone releasing factor, insulin, somatostatin, glucagons, interleukin-2 (IL-2), interferon-α

,β

,γ

(IFN-α

,β

,γ

), gastrin, tetragastrin, pentagastrin, urogastroine, secretin, cacitonin, enkephalins, endorphins, angiotensins, thyrotropin releasing hormone (TRH), tumor necrosis factor (TNF), nerve growth factor (NGF), granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (M-CSF), rennin, bradykinin, bacitracins, alpha-1 antitrypsin, platelet derived growth factor, albumin, anti-thrombin III, glucocerebrosidase, DNAse, tissue plasminogen activator, calcitonin, clotting factors VII, VIII, and IX, LHRH antagonists, insulin, erythropoietin, polymixins, colistins, tyrocidin, gramicidines, and synthetic analogues, modifications and pharmacologically active fragments thereof, monoclonal antibodies and soluble vaccines.

16. A biodegradable bioactive agent delivery system according to claim 9 wherein said therapeutic agent is a cell.

17. A biodegradable bioactive agent delivery system according to claim 9 wherein said thermogelling biodegradable aqueous polymer solution provides as a solubilizer.