Biodegradable multi-block polymeric composition capable of sol-gel trainsition and pharmaceutical composition comprising the same

• US 20070161753A1
• Filed: 08/01/2005
• Published: 07/12/2007
• Est. Priority Date: 08/02/2004
• Status: Active Grant

• Current Assignee: Samyang Holdings Corporation
• Original Assignee: Samyang Corporation (Samyang Holdings Corporation)
• Inventors: Seo, Min-Hyo
• Granted Patent: US 7,655,735 B2
• Time in Patent Office: Days
• US Class Current: 525/242
• CPC Class Codes: A61K 38/193 Colony stimulating factors [CSF]
• CPC Class Codes: A61K 38/212 IFN-alpha
• CPC Class Codes: A61K 38/27 Growth hormone [GH], i.e. somatotropin
• 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 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• 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: C07K 14/56 IFN-alpha
• CPC Class Codes: C07K 14/61 Growth hormone [GH], i.e. somatotropin
• CPC Class Codes: C08G 2261/126 block
• CPC Class Codes: C08G 63/672 Dicarboxylic acids and dihydroxy compounds
• CPC Class Codes: C08G 65/3322 acyclic
• CPC Class Codes: C08G 65/3326 aromatic
• CPC Class Codes: C08G 65/3344 containing oxygen in addition to sulfur
• CPC Class Codes: C08G 65/3353 containing oxygen in addition to phosphorus

Abstract

The present invention relates to an ionic multi-block copolymer composition comprising tri-block copolymers having a polypropyleneoxide or polybutyleneoxide block positioned between two polyethyleneoxide blocks and the tri-block copolymers are connected through dicarboxylic acid linkages forming a multi-block copolymer having a weight average molecular weight of more than 40,000 Dalton. The higher weight average molecular weight enables the hydrolgel formed from the multi-block copolymer of the present invention to maintain its gel status for more than several days.

Claims

1. A multi-block copolymer comprising at least two ABA-type tri-block copolymers which are covalently connected through a biodegradable dicarboxylic linkage, wherein A is a polyethyleneoxide block, B is a polypropyleneoxide block, a polybutyleneoxide block or a combination thereof, and wherein said multi-block copolymer has an hydroxyl or ionic group at both terminal ends.

2. The multi-block copolymer composition according to claim 1, the unit number of ethyleneoxide, and propyleneoxide or butyleneoxide is within the range from 2 to 2000, respectively.

3. The multi-block copolymer composition according to claim 1, wherein the unit ratio between A and B block ranges form 0.2:

1 to 40;

1.

4. The multi-block copolymer composition according to claim 1, wherein the ionic group is a member selected from the group consisting of monovalent or divalent metal salt of —

SO₃⁻

, —

PO₃²⁻

, and —

C(═

O)—

R—

C(═

O)—

O⁻

.

5. The multi-block copolymer according to claim 1, has a weight average molecular weight ranging from 40,000 to 1,000,000 Daltons.

6. The multi-block copolymer composition according claim 1, wherein the biodegradable dicarboxylic linkage is derived from a member selected from the group consisting of oxalic acid, malonic acid, malic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, sebacoyl acid, suberic acid, and dodecanoic acid fumaric acid, maleic acid, phthalic acid and terephthalic acid.

15. A composition comprising a multi-block copolymer according to one of the claim from 1 or 7.

16. The composition according to claim 15, wherein the multi-block copolymer composition is in a form selected from the group consisting of gels, microspheres, nano-particles, stripes, rods and films.

17. A pharmaceutical composition comprising the composition according to claim 15 and an effective amount of a bioactive agent.

18. The pharmaceutical composition according to claim 17, wherein the bioactive agent is within the range from 0.01% to 50%.

19. The pharmaceutical composition according to claim 17, wherein the bioactive agent is a protein or a peptide.

20. The pharmaceutical composition according to claim 19, wherein the protein or peptide is in its natural form or is modified by a polymer.

21. The pharmaceutical composition according to claim 19, wherein the protein is selected from the group consisting of growth hormone (GH), interferon (IFN), granulocyte colony stimulation factor (G-CSF), granulocyte macrophage colony stimulating factor (GMCSF), erythropoietin (EPO), interleukin (IL), fibroblast growth factor, follicle stimulating hormone (FSH), macrophage colony stimulating factor (M-CSF), nerve growth factor (NGF), octreotide, insulin, insulin-like growth factor (IGF), calcitonin, tumor necrosis factor (TNF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), bone morphogenetic protein (BMP), tissue plasminogen activator (TPA), thrombopoietin (TPO), tissue growth factor and tumor necrosis factor (TNF).

22. The pharmaceutical composition according to claim 17, wherein the composition is in a form selected from the group consisting of gels, microspheres, nanoparticles, stripes, rods and films.

23. The pharmaceutical composition according to claim 17, comprising 0.5 to 50% of the composition according to claim 17 in an aqueous medium.

24. The pharmaceutical composition according to claim 17, wherein the composition further comprises at least one member selected from the group consisting of PEG, hyaluronic acid, dextran, gelatin, collagen, chitosan, poloxamer 407, poloxamer 188, methylcellulose (MC), ethylcellulose (EC), hydroxyethylcellulose (HEC), methylhydroxyethylcellulose (MHEC), hydroxymethylcellulose, hydroxypropylmethylcellulose (HPMC) and hydroxypropylcellulose.

7. A multi-block copolymer represented by the following formula:

M-X—

O—

[PEO—

Y—

PEO—

C(═

O)—

R—

C(═

O)—

O]_n—

PEO—

Y—

PEO—

O—

X-M

wherein PEO is a polyethylene oxide block,

Y is PPO or PBO or combinations of PPO and PBO, wherein PPO is a polypropylene oxide block and PBO is a polybutylene oxide block,

X is H or an anion group,

n is an integer ranging from 1 to 100,

R is —

(CH₂)_m—

or an aryl having Cm′

, where m is an integer ranging from 0 to 20, m′

is an integer ranging from 6 to 12, and M is H or a cation group, with the proviso that M and X cannot both be H, and M cannot be present when X is H.

8. The multi-block copolymer according to claim 7, wherein X is an anion group selected from the group consisting of —

SO₃⁻

, —

PO₃²⁻

and —

C(═

O)—

R—

C(═

O)—

O⁻

.

9. The multi-block copolymer according to claim 7, wherein M is a cation selected from the group consisting of Li, Na, K, Ag, Au, Ca, Mg, Zn, Fe, Cu, Co and Ni.

10. The multi-block copolymer according to claim 7, has a weight average molecular weight ranging from 40,000 to 1,000,000 Daltons.

11. The multi-block copolymer according to claim 7, wherein the unit ratio between the PEO and Y ranges from 0.2:

1 to 40;

1.

12. The multi-block copolymer according to claim 7, wherein Y has a weight average molecular weight ranging from 1,000 to 20,000 Daltons.

13. The multi-block copolymer according to claim 7, wherein Y is a poloxamer.

14. The multi-block copolymer according to claim 7, wherein R is biodegradable dicarboxylic linkage is derived from a member selected from the group consisting of oxalic acid, malonic acid, malic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, sebacoyl acid, suberic acid, and dodecanoic acid, fumaric acid, maleic acid, phthalic acid and terephthalic acid.

25. A method for a preparing the multi-block copolymer according to claim 7 having terminal hydroxyl ends comprising:

1) preparing a reaction solution containing a predetermined amount of PEO—

Y—

PEO, slowly adding 0.5 to 1.0 equivalents of dicarboxylic acid dihalide based on 1 equivalent of terminal end hydroxyl groups of the PEO—

Y—

PEO to the reaction solution and allowing the reaction to proceed for a predetermined number of hours;

2) adding an additional 0.1 equivalents of PEO—

Y—

PEO to the above reaction solution to react until the reaction is completed;

3) precipitating the produced multi-block copolymer in an ether or hexane solvent and then dissolving the precipate in alcohol; and

4) slowly adding ether or hexane so that the volume ratio of alcohol/ether or hexane is 1/1 to 1/20 to precipitate the multi-block copolymer.

26. A method for a preparing the multi-block copolymer according to claim 7 having terminal carboxylic ends comprising:

1) preparing a reaction solution containing a predetermined amount of PEO—

Y—

PEO, slowly adding 0.5 to 1.0 equivalents of dicarboxylic acid dihalide based on 1 equivalent of the terminal end hydroxyl groups of the PEO—

Y—

PEO to the reaction solution and allowing the reaction to proceed for a predetermined number of hours;

2) adding more than 1 equivalent of additional dicarboxylic acid dihalide based on an equivalent of hydroxyl groups of the PEO—

Y—

PEO terminal end to the reaction solution to react until the reaction is completed;

3) precipitating the produced multi-block copolymer in an ether or hexane solvent and then dissolving the precipitate in alcohol; and

4) slowly adding ether or hexane so that a volume ratio of alcohol/ether or hexane is 1/1 to 1/20 to precipitate the multi-block copolymer.

27. A method for preparing a multi-block copolymer according to claim 7 which has metal carboxylate salts at both terminal ends of the multi-block copolymer comprising:

1) dissolving the multi-block copolymer produced from claim 26 in a solvent capable of being mixed with water, and

2) neutralizing the multi-block solution with sodium carbonate, sodium bicarbonate, calcium chloride, zinc chloride, magnesium chloride, iron chloride, copper chloride, silver nitrate, potassium chloride, or lithium chloride.

28. A method for preparing the multiblock copolymer according to claim 7 having a sulfuric acid, phosphoric acid, or metal salt thereof at its polymer terminal end, comprising:

1) dissolving the multi-block copolymer of claim 25 in a solvent and reacting the solution with a sulfate trioxide pyridine complex, C₅H₅NSO₃, or a phosphorous oxychloride, POCl₃; and

2) optionally neutralizing the reaction mixture with sodium carbonate, sodium bicarbonate calcium chloride, zinc chloride, magnesium chloride, iron chloride, copper chloride, silver nitrate, potassium chloride, or lithium chloride to prepare a multi-block copolymer having a metal salt at its polymer terminal end.

29. The method according to claim 25, wherein PEO—

Y—

PEO is a poloxamer.

30. The method according to claim 26, wherein PEO—

Y—

PEO is a poloxamer.

31. The method according to claim 25, wherein PEO—

Y—

PEO is purified by dissolving it in methylenechloride followed by precipitation in hexane, or separating it by layer-separation in an n-propanol/H₂O solvent.

32. The method according to claim 26, wherein PEO—

Y—

PEO is purified by dissolving it in methylenechloride followed by precipitation in hexane, or separating it by layer-separation in an n-propanol/H₂O solvent.