BAB TRIBLOCK POLYMERS HAVING IMPROVED RELEASE CHARACTERISTICS

• US 20110070188A1
• Filed: 09/20/2010
• Published: 03/24/2011
• Est. Priority Date: 09/18/2009
• Status: Active Grant

• Current Assignee: BTG International Limited (Boston Scientific Corporation)
• Original Assignee: Protherics Salt Lake City, Inc. (Boston Scientific Corporation)
• Inventors: FOWERS, Kirk D., RATHI, Ramesh C., PIAO, Ai-Zhi
• Granted Patent: US 8,753,621 B2
• Time in Patent Office: Days
• US Class Current: 424/85.2
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• 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 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: C08G 63/664 derived from hydroxy carboxylic acids

Abstract

Improved biodegradable and bioabsorbable BAB-block copolymers exhibiting reverse thermal gellation properties, and aqueous polymer compositions including the BAB-block copolymers, are provided. Methods of making the improved BAB-block copolymers and compositions including the same are also provided.

Claims

1. A BAB-block copolymer, said block copolymer comprising:

i) about 60 to 85% by weight of a biodegradable, hydrophobic A-block comprising a biodegradable polyester; and

ii) about 15 to 40% by weight of a biodegradable, hydrophilic B-block comprising a polyethylene glycol, wherein the weight average molecular weight of each B-block is between 300 and 1000 Daltons;

wherein the BAB-block copolymer has a Mw ranging from 5000 to 8000, and is capable of exhibiting reverse thermal gellation properties when formed in an aqueous polymer solution.

2. The block copolymer of claim 1, wherein the A-block content of the copolymer ranges from 65 to 80% and the B-block content of the copolymer ranges from 20 to 35%.

3. The block copolymer of claim 1, wherein the A-block content of the copolymer ranges from 67 to 75% and the B-block content of the copolymer ranges from 25 to 33%.

4. The block copolymer of claim 1, wherein the polyester monomers comprises residues from at least one of D,L-lactide, D-lactide, L-lactide, D,L-lactic acid, D-lactic acid, L-lactic acid, glycolide, glycolic acid, ε

-caprolactone, ε

-hydroxy hexonoic acid, γ

-butyrolactone, γ

-hydroxy butyric acid, δ

-valerolactone, δ

-hydroxy valeric acid, hydrooxybutyric acids, malic acid, or copolymers thereof.

5. The block copolymer of claim 1, wherein the polyester monomers comprises residues from at least one of D,L-lactide, D-lactide, L-lactide, D,L-lactic acid, D-lactic acid, L-lactic acid, glycolide, glycolic acid, ε

-hydroxy hexonoic acid, or copolymers thereof.

16. The block copolymer of claim 1, wherein the number average molecular weight ranges from 3800 to 5000 Daltons.

17. The block copolymer of claim 1, wherein the weight average molecular weight ranges from 5000 to 7000 Daltons.

6. A block copolymer composition comprising the block copolymer of claim and a drug.

7. The block copolymer composition of claim 6, wherein said drug is a polypeptide or protein, nucleic acid or gene, hormone, anti-cancer or anti-cell proliferation agent.

8. The block copolymer composition of claim 7, wherein said polypeptide or protein is oxytocin, vasopressin, adrenocorticotropic hormone, epidermal growth factor, platelet-derived growth factor (PDGF), prolactin, luliberin, luteinizing hormone releasing hormone (LHRH), LHRH agonists, LHRH antagonists, growth hormone (human, porcine, bovine, etc.), growth hormone releasing factor, insulin, erythropoietin, somatostatin, glucagon, interleukin-2 (IL-2), interferon-α

, β

, or γ

, gastrin, tetragastrin, pentagastrin, urogastrone, 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 (GM-CSF), macrophage-colony stimulating factor (M-CSF), heparinase, bone morphogenic protein (BMP), hANP, glucagon-like peptide (GLP-1), interleukin-11 (IL-11), renin, bradykinin, bacitracins, polymyxins, colistins, tyrocidine, gramicidins, cyclosporins and synthetic analogues, modifications and pharmacologically active fragments thereof.

9. The block copolymer of claim 7, wherein said polypeptide or protein is an enzyme, cytokine, antibody or vaccine.

10. The block copolymer of claim 7, wherein said polypeptide or protein is erythropoietin, luteinizing hormone releasing hormone (LHRH), LHRH agonists, LHRH antagonists, growth hormones, tumor necrosis factor (TNF), nerve growth factor (NGF), granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), macrophage-colony stimulating factor (M-CSF), glucagon-like peptide (GLP-1), interleukin-11 (IL-11), cyclosporins and synthetic analogues, modifications or pharmacologically active fragments thereof.

11. The block copolymer of claim 6, wherein the drug is hydrophilic.

12. The block copolymer of claim 6, wherein the drug is Oxytocin, vasopressin, adrenocorticotropic hormone, epidermal growth factor, platelet-derived growth factor (PDGF), pigment epithelial derived factor (PEDF) prolactin, luliberin, luteinizing hormone releasing hormone (LHRH), LHRH agonists, LHRH antagonists, growth hormones, growth hormone releasing factor, insulin, erythropoietin, somatostatin, glucagon, interleukins, interferons, gastrins, secretin, calcitonin, enkephalins, immunoglobulins, endorphins, angiotensins, thyrotropin releasing hormone (TRH), tumor necrosis factors (TNF), nerve growth factors (NGF), granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), macrophage-colony stimulating factor (M-CSF), heparinase, hANP, glucagon-like peptide (GLP-1), bone morphogenic proteins (BMP), antibodies and fragments thereof, enzymes, cytokines, vaccines, goserelin, rapamycin, rituximab, renin, bradykinin, bacitracins, polymyxins, colistins, tyrocidine, gramicidins, cyclosporine or synthetic analogues, modifications or pharmacologically active fragments thereof.

13. The block copolymer of claim 6, wherein said drug is an anti-cancer agent comprising actinomycin D, anastrozole, azacitidine, bevacizumab, bicalutamide, bleomycin, BCNU, bortezomib, camptothecin, capecitabine, carboplatin, cetuximab, daunorubicin, dasatinib, docetaxel, doxorubicin, liposomal, epirubicin, erlotinib, exemestane, gefitinib, gemcitabine, goserelin, imatinib, STI-571, irinotecan, lapatinib, letrozole, leuprolide, methotrexate, mitomycin, oxaliplatin, paclitaxel, pemetrexed, rituximab, sorafenib, sunitinib, tamoxifen, taxotere, tegafur-uracil, temozolomide, trastuzumab, triptorelin, vinorelbine, porcabazine, dacarbazine, altretamine, displatin, mercaptopurine, thioguanine, fludarabine phosphate, cladribine, pentostatin, fluorouracil, cytarabine, azacitidine, vinblastine, vincristine, etoposide, teniposide, topotecan, dactinomycin, idarubincin, plicamycin, flutamide, leuprolide, gasoerelin, aminoglutethimide, amsacrine, hydroxyurea, asparaginase, mitoxantrone, mitotane, retinoic acid derivative, amifostine, carmustine, lomustine, semustine, anti-VEGF and synthetic analogues, modifications or pharmaceutically equivalents thereof.

14. The block copolymer of claim 6, wherein said drug is an anti-cancer agent comprising mitomycin, bleomycin, BCNU, carboplatin, doxorubicin, daunorubicin, methotrexate, paclitaxel, taxotere, actinomycin D, camptothecin, and synthetic analogues, modifications or pharmaceutically equivalents thereof.

15. The block copolymer of claim 6, wherein the drug content of said composition is between about 0.01 and 20% by weight.

18. A BAB-block copolymer, said block copolymer comprising:

i) about 60 to 85% by weight of a biodegradable, hydrophobic A-block comprising a biodegradable polyester; and

ii) about 15 to 40% by weight of a biodegradable, hydrophilic B-block comprising a polyethylene glycol, wherein the weight average molecular weight of each B-block is between 300 and 1000 Daltons;

wherein the BAB-block copolymer has a Mn greater than 3800, and is capable of exhibiting reverse thermal gellation properties when formed in an aqueous polymer solution.

19. (canceled)

20. An aqueous BAB-block copolymer composition, said composition comprising:

i) about 60 to 85% by weight of a biodegradable, hydrophobic A-block comprising a biodegradable polyester; and

ii) about 15 to 40% by weight of a biodegradable, hydrophilic B-block comprising a polyethylene glycol, wherein the weight average molecular weight of each B-block is between 300 and 1000 Daltons;

wherein the BAB-block copolymer composition has a Mw ranging from 5000 to 8000, and exhibits reverse thermal gellation properties.

21-36. -36. (canceled)

37. An aqueous BAB-block copolymer composition, said composition comprising:

i) about 60 to 85% by weight of a biodegradable, hydrophobic A-block comprising a biodegradable polyester; and

ii) about 15 to 40% by weight of a biodegradable, hydrophilic B-block comprising a polyethylene glycol, wherein the weight average molecular weight of each B-block is between 300 and 1000 Daltons;

wherein the BAB-block copolymer composition has a Mn greater than 3800, and exhibits reverse thermal gellation properties.

38. (canceled)

39. A method for the administration of at least one drug to a warm blooded animal in a controlled release form which comprises:

(1) providing an aqueous BAB-block copolymer composition comprising;

i) about 60 to 85% by weight of a biodegradable, hydrophobic A-block comprising a biodegradable polyester; and

ii) about 15 to 40% by weight of a biodegradable, hydrophilic B-block comprising a polyethylene glycol, wherein the weight average molecular weight of each B-block is between 300 and 1000 Daltons;

wherein the BAB-block copolymer composition has a Mw ranging from 5000 to 8000, and exhibits reverse thermal gellation properties; and

(2) administering said composition to a warm blooded animal.

40-55. -55. (canceled)

56. A method of making a BAB-block copolymer composition which comprises:

(1) providing a BAB-block copolymer composition comprising;

i) about 60 to 85% by weight of a biodegradable, hydrophobic A-block comprising a biodegradable polyester; and

ii) about 15 to 40% by weight of a biodegradable, hydrophilic B-block comprising a polyethylene glycol, wherein the weight average molecular weight of each B-block is between 300 and 1000 Daltons;

wherein the BAB-block copolymer composition has a Mw ranging from 5000 to 8000, and is capable of exhibiting reverse thermal gellation properties when formed in an aqueous polymer solution; and

(2) freeze drying said block copolymer, wherein the wherein the block copolymer is capable of exhibiting reference thermal gellation when formed as an aqueous polymer solution.

57-72. -72. (canceled)