Thermogelling oligopeptide polymers

• US 7,087,244 B2
• Filed: 04/16/2002
• Issued: 08/08/2006
• Est. Priority Date: 09/28/2000
• Status: Expired due to Term

• Current Assignee: Battelle Memorial Institute
• Original Assignee: Battelle Memorial Institute
• Inventors: Jeong, Byeongmoon, Gutowska, Anna
• Primary Examiner(s): Yoon, Tae H.
• Application Number:
  US10/124,614
• Publication Number:
  US 20040077780A1
• Time in Patent Office: 1,575 Days
• Field of Search: 524/845, 524/504, 524/505, 523/200, 528/271, 424/486, 424/499
• US Class Current: 424/486
• 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: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C08G 63/664 derived from hydroxy carboxylic acids
• CPC Class Codes: C08H 1/00 Macromolecular products derived from proteins food proteins A23; glue, gelatine C09H

Abstract

Disclosed is a thermogelling biodegradable aqueous polymer solution useful in providing a bioactive agent delivery system. A thermogelling biodegradable aqueous polymer solution may comprise a biocompatible block and a biodegradable polypeptide block, where the blocks are linked to form a polymer of a general structure comprising the formula of C_nD_m, wherein n is equal to or greater than 1, m is equal to or greater than 1, C is a biodegradable polypeptide block, and D is a biocompatible soluble polymer having a chain length such that if D is not biodegradable, D may be eliminated through a glomeruli filtration system.

Claims

1. A thermogelling, biodegradable polymer comprising:

i. a biocompatible polymer block; and

ii. a polypeptide block,

iii. wherein the biocompatible polymer and the polypeptide blocks are linked to form a copolymer that undergoes a solution-to-gel transition in response to an increase in temperature from a temperature below the gelling temperature of the copolymer to about body temperature and has a general structure satisfying the formula C_nD_m, wherein n is equal to or greater than 1, m is equal to or greater than 1, C is a biodegradable polypeptide block, D is a biocompatible soluble polymer having a chain length such that if D is not biodegradable, D may be eliminated through a glomeruli filtration system, and C is different from D.

2. The thermogelling, biodegradable polymer of claim 1, wherein the polymer is in a powder form.

3. The thermogelling, biodegradable polymer of claim 1, wherein D comprises a biodegradable polymer.

4. The thermogelling, biodegradable polymer of claim 1, wherein C comprises an enzymatically biodegradable polypeptide and D comprises a biodegradable polymer.

5. The thermogelling, biodegradable polymer of claim 1, wherein C is a polypeptide block comprising at least two amino acids, wherein at least one of the amino acids is hydrophilic relative to the other amino acid of the polypeptide block.

6. The thermogelling, biodegradable polymer of claim 1, wherein D comprises a polyethylene glycol block.

7. The thermogelling, biodegradable polymer of claim 1, wherein n is between 1 and 20.

8. The thermogelling, biodegradable polymer of claim 1, wherein n and m are each between 1 and 20.

9. The thermogelling, biodegradable polymer of claim 6, wherein the polyethylene glycol has a weight average molecular weight of from about 300 to about 20,000.

10. The thermogelling, biodegradable polymer of claim 6, wherein the polyethylene glycol block has a weight average molecular weight of from about 500 to about 10,000.

11. The thermogelling, biodegradable polymer of claim 1, wherein the polypeptide block has a weight average molecular weight of from about 300 to about 30,000.

12. The thermogelling, biodegradable polymer of claim 1, wherein the polypeptide block has a weight average molecular weight of from about 500 to about 10,000.

13. The thermogelling, biodegradable polymer of claim 1, wherein the thermogelling, biodegradable polymer does not raise a pH value of a surrounding solution as the polymer biodegrades.

14. The thermogelling, biocompatible polymer of claim 1, further comprising a bioactive agent.

15. A biocompatible, bioactive agent delivery system, comprising:

an effective amount of bioactive agent contained in a thermogelling, aqueous polymer solution, the polymer solution comprising,

i. a biocompatible polymer block;

ii. a biodegradable polypeptide block, wherein the biocompatible polymer and the polypeptide blocks are linked to form a polymer that undergoes a solution-to-gel transition in response to an increase in temperature from a temperature below the gelling temperature of the polymer to about 37°

C. and has a general structure satisfying the formula C_nD_m, wherein n is equal to or greater than 1, m is equal to or greater than 1, C is a biodegradable polypeptide block, D is a biocompatible soluble polymer having a chain length such that if D is not biodegradable, D may be eliminated through a glomeruli filtration system; and

iii. an aqueous solvent.

16. The biocompatible, bioactive agent delivery system of claim 15, wherein the bioactive agent is a drug.

17. The biocompatible, bioactive agent delivery system of claim 15, wherein the bioactive agent is selected from the group consisting essentially 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, proteins, cells, and combinations thereof.

18. The biocompatible, bioactive agent delivery system of claim 16, wherein the drug is 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, calcitonin, 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, 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.

19. The biocompatible, bioactive agent delivery system of claim 15, wherein the bioactive agent is a cell.

20. The biocompatible, bioactive agent delivery system of claim 15, wherein the thermogelling, biodegradable aqueous polymer does not raise a pH value of a surrounding solution as the polymer biodegrades.

21. A thermogelling, biodegradable polymer drug delivery system comprising:

i. a biocompatible polymer block;

ii. a polypeptide block,

iii. wherein the biocompatible polymer and the polypeptide blocks are linked to form a polymer that undergoes a solution-to-gel transition in response to an increase in temperature from about room temperature to about body temperature and has a general structure satisfying the formula C_nD_m, wherein n is equal to or greater than 1, m is equal to or greater than 1, D is a biocompatible soluble polymer having a chain length such that if D is not biodegradable, D may be eliminated through a glomeruli filtration system, and C is a biodegradable polypeptide block comprising at least two amino acids, wherein at least one of the amino acids is hydrophilic relative to the other amino acid; and

iv. an effective amount of a bioactive agent.

22. The thermogelling, biodegradable polymer of claim 21, wherein D comprises a polyethylene glycol block.

23. The thermogelling, biodegradable polymer of claim 22, wherein the polyethylene glycol block has a weight average molecular weight of from about 300 to about 20,000.

24. The thermogelling, biodegradable polymer of claim 21, wherein D is different from C.

25. The thermogelling, biodegradable polymer of claim 21, wherein C is enzymatically biodegradable.