Multiblock biodegradable hydrogels for drug delivery and tissue treatment

• US 6,201,065 B1
• Filed: 07/26/1996
• Issued: 03/13/2001
• Est. Priority Date: 07/28/1995
• Status: Expired due to Term

• Current Assignee: Genzyme Corporation (Sanofi )
• Original Assignee: Focal PLLC
• Inventors: Pathak, Chandrashekhar P., Sawhney, Amarpreet S., Avila, Luis Z., Kieras, Mark T., Barman, Shikha P., Coury, Arthur J., Philbrook, C. Michael
• Primary Examiner(s): YOON, TAE H
• Application Number:
  US08/692,914
• Time in Patent Office: 1,691 Days
• Field of Search: 528/300, 525/79, 525/90, 525/941, 524/504, 524/505, 524/916, 424/486, 424/487
• US Class Current: 525/90
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• 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 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• 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 9/1075 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 9/1274 Non-vesicle bilayer structures, e.g. liquid crystals, tubules, cubic phases, cochleates; Sponge phases
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5138 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5146 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
• CPC Class Codes: A61K 9/7015 Drug-containing film-forming compositions, e.g. spray-on
• CPC Class Codes: A61L 15/58 Adhesives
• CPC Class Codes: A61L 15/60 Liquid-swellable gel-forming materials, e.g. super-absorbents
• CPC Class Codes: A61L 24/0031 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 24/0042 Materials resorbable by the body
• CPC Class Codes: A61L 24/046 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds A61L24/043 takes precedence
• CPC Class Codes: C08G 63/00 Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule polyester-amides C08G69/44; polyester-imides C08G73/16
• CPC Class Codes: C08G 65/329 with organic compounds
• CPC Class Codes: C08L 2666/14 Macromolecular compounds according to C08L59/00 - C08L87/00; Derivatives thereof
• CPC Class Codes: C08L 71/00 Compositions of polyethers obtained by reactions forming an ether link in the main chain of polyacetals C08L59/00; of epoxy resins C08L63/00; of polythioether-ethers C08L81/02; of polyether-sulfones C08L81/06; Compositions of derivatives of such polymers
• CPC Class Codes: C08L 71/02 : Polyalkylene oxides
• CPC Class Codes: Y10S 424/13 : Burn treatment
• CPC Class Codes: Y10S 524/916 : Hydrogel compositions
• CPC Class Codes: Y10S 525/941 : Polymer mixture containing block copolymer is mixed or reacted with chemical treating agent

Abstract

Gel-forming macromers including at least four polymeric blocks, at least two of which are hydrophobic and at least one of which is hydrophilic, and including a crosslinkable group are provided. The macromers can be covalently crosslinked to form a gel on a tissue surface in vivo. The gels formed from the macromers have a combination of properties including thermosensitivity and lipophilicity, and are useful in a variety of medical applications including drug delivery and tissue coating.

Claims

1. A macromer which is capable of forming a gel, the macromer comprising a total of five or ten covalently linked polymeric blocks, wherein:

a) at least one polymer block is hydrophilic and each hydrophilic polymer block individually has a water solubility of at least 1 gram/liter;

b) at least two blocks are sufficiently hydrophobic to cause the macromer to aggregate to form micelles in an aqueous continuous phase;

c) the macromer comprises at least one crosslinkable group;

d) the macromer comprises at least one thermally sensitive region; and

e) a solution of the macromer is capable of gelling or crosslinking to produce a hydrogel with a temperature dependent volume.

2. The macromer of claim 1 wherein the crosslinkable groups are separated by at least one degradable linkage capable of degrading under physiological conditions.

5. A solution of a macromer of claim 1, further comprising a biologically active material.

6. The macromer of claim 1 wherein the rate of release of a drug incorporated in the hydrogel is dependent upon the volume of the hydrogel.

7. The macromer of claim 1 wherein the macromer is capable of thermoreversible gelation in an aqueous solution of the macromer at a concentration of at least 2% by weight, and wherein the gelation temperature is between about 0°

C. and about 65°

C.

8. The macromer of claim 1 wherein the macromer has an optically anisotropic phase at a concentration at or below the maximal solubility of the macromer in an aqueous solution, at a temperature between about 0 and 65°

C.

9. The macromer of claim 1, further comprising at least one ionically charged moiety covalently attached to the macromer.

10. The macromer of claim 1 wherein the macromer has a phase transition temperature in the range of 0 to 100°

C., and wherein the transition temperature is affected by a property selected from the group consisting of the ionic composition of an aqueous solution of the macromer and the concentration of macromer in the aqueous solution.

11. A mixture comprising the macromer of claim 1 and a hydrophobic material non-covalently associated with the macromer.

12. The mixture of claim 11, wherein the hydrophobic material is selected from the group consisting of a hydrocarbon, a lipid, a fatty acid, and a sterol.

13. The macromer of claim 1 wherein the crosslinkable group is selected from the group consisting of an ethylenically unsaturated group, an epoxide, an isocyanate, an isothiocyanate, an aldehyde, an amine, a sulfonic acid and a carboxylic acid.

14. The macromer of claim 1 wherein the hydrophobic blocks are the same or different and are selected from the group consisting of polypropylene oxide, polybutylene oxide, hydrophobic mixed poly(alkylene oxides), and oligomers of hydroxy acids, lactones, amino acids, anhydrides, orthoesters, phosphazenes, and phosphates.

15. The macromer of claim 1 wherein the hydrophilic blocks are the same or different and are selected from the group consisting of poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol), poly(vinylpyrrolidone), poly(ethyloxazoline), polysaccharides and amino acid polymers.

16. The macromer of claim 2 wherein the degradable linkage groups are the same or different and are selected from the group consisting of poly(alpha-hydroxy acids), poly(amino acids), poly(anhydrides), poly(orthoesters), poly(phosphazines), poly(phosphoesters), and polylactones.

17. The macromer of claim 1 wherein at least two hydrophobic blocks are separated by a hydrophilic block.

18. The macromer of claim 1 wherein each hydrophobic block is separated by a hydrophilic block from any other hydrophobic block.

19. The macromer of claim 1 wherein the dry macromer absorbs at least about 10% in weight of water.

20. The macromer of claim 1 wherein the molecular weight of the macromer is at least 1000 Daltons.

21. The macromer of claim 1 wherein the molecular weight of the macromer is at least 2000 Daltons.

22. The macromer of claim 1 wherein the molecular weight of the macromer is at least 4000 Daltons.

23. The macromer of claim 1 further comprising at least two hydrophilic blocks.

24. The macromer of claim 1 provided in a pharmaceutically acceptable carrier.

25. The macromer of claim 24 wherein the macromer is provided in a carrier suitable for parenteral administration.

26. The macromer of claim 1, wherein the thermally sensitive region is selected from the group consisting of poloxamers, meroxapols, poloxamines, polyvinyl alcohol, polyvinyl-pyrrolidone, polyacrylic acids, esters, amides, celluloses, peptides and proteins, dextrans and other polysaccharides, polyalkylene oxides, and natural gums.

3. A macromer which is capable of forming a gel, the macromer comprising at least four covalently linked polymeric blocks, wherein:

a) at least one polymer block is hydrophilic and each hydrophilic polymer block individually has a water solubility of at least 1 gram/liter;

b) at least two blocks are sufficiently hydrophobic to cause the macromer to aggegate to form micelles in an aqueous continuous phase;

c) the macromer comprises at least one crosslinkable group;

d) the macromer comprises at least one thermally sensitive region;

e) a solution of the macromer is capable of gelling or crosslinking to produce a hydrogel with a temperature dependent volume; and

f) at least one hydrophobic block is separated from any crosslinkable group by at least one hydrophilic block.

4. A macromer which is capable of forming a gel, the macromer comprising at least four covalently linked polymeric blocks, wherein:

a) at least one polymer block is hydrophilic and each hydrophilic polymer block individually has a water solubility of at least 1 gram/liter;

b) at least two blocks are sufficiently hydrophobic to cause the macromer to aggregate to form micelles in an aqueous continuous phase;

c) the macromer comprises at least one crosslinkable group;

d) the macromer comprises at least one thermally sensitive region;

e) a solution of the macromer is capable of gelling or crosslinking to produce a hydrogel with a temperature dependent volume; and

f) the macromer comprises at least two chemically distinct hydrophobic blocks.

27. A macromer which is capable of forming a gel, the macromer comprising at least four covalently linked polymeric blocks, wherein:

a) at least one polymer block is hydrophilic and each hydrophlilc polymer block individually has a water solubility of at least 1 gram/liter;

b) at least two blocks are sufficiently hydrophobic to cause the macromer to aggregate to form micelles in an aqueous continuous phase;

c) the macromer comprises at least one crosslinkable group;

d) the macromer comprises at least one thermally sensitive region;

e) a solution of the macromer is capable of gelling or crosslinking to produce a hydrogel with a temperature dependent volume; and

f) the thermally sensitive region comprises a poloxamer backbone extended with oligolactate moities, wherein the poloxamer-lactate copolymer is terminated by acrylate moieties.

28. A macromer which is capable of forming a gel, the macromer comprising at least four covalently linked polymeric blocks, wherein:

a) at least one polymer block is hydrophilic and each hydrophilic polymer block individually has a water solubility of at least 1 gram/liter;

b) at least two blocks are sufficiently hydrophobic to cause the macromer to aggregate to form micelles in an aqueous continuous phase;

c) the macromer comprises at least one crosslinkable group;

d) the macromer comprises at least one thermally sensitive region;

e) a solution of the macromer is capable of gelling or crosslinking to produce a hydrogel with a temperature dependent volume; and

f) the thermally sensitive region comprises an acrylate capped polyglycolide derivatized poloxamer of about 30% polypropylene oxide content.