CA2435301A1 - Multi-arm block copolymers as drug delivery vehicles - Google Patents

Multi-arm block copolymers as drug delivery vehicles Download PDF

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CA2435301A1
CA2435301A1 CA002435301A CA2435301A CA2435301A1 CA 2435301 A1 CA2435301 A1 CA 2435301A1 CA 002435301 A CA002435301 A CA 002435301A CA 2435301 A CA2435301 A CA 2435301A CA 2435301 A1 CA2435301 A1 CA 2435301A1
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block copolymer
polymer segment
arm block
poly
central core
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CA2435301C (en
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Xuan Zhao
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Nektar Therapeutics
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/724—Cyclodextrins
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/91—Polymers modified by chemical after-treatment
    • C08G63/914—Polymers modified by chemical after-treatment derived from polycarboxylic acids and polyhydroxy compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • A61K31/77—Polymers containing oxygen of oxiranes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/593—Polyesters, e.g. PLGA or polylactide-co-glycolide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/26—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds
    • C08G65/2603—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds the other compounds containing oxygen
    • C08G65/2606—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds the other compounds containing oxygen containing hydroxyl groups
    • C08G65/2609—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds the other compounds containing oxygen containing hydroxyl groups containing aliphatic hydroxyl groups
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G81/00—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L71/00—Compositions of polyethers obtained by reactions forming an ether link in the main chain; Compositions of derivatives of such polymers
    • C08L71/02—Polyalkylene oxides
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2650/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G2650/22—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterised by the initiator used in polymerisation
    • C08G2650/24—Polymeric initiators
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L2205/00—Polymer mixtures characterised by other features
    • C08L2205/05—Polymer mixtures characterised by other features containing polymer components which can react with one another

Abstract

The invention provides multi-arm block copolymers useful as drug delivery vehicles comprising a central core molecule, such as a residue of a polyol, and at least three copolymer arms covalently attached to the central core molecule, each copolymer arm comprising an inner hydrophobic polymer segment covalently attached to the central core molecule and an outer hydrophilic polymer segment covalently attached to the hydrophobic polymer segment, wherein the central core molecule and the hydrophobic polymer segment define a hydrophobic core region. The solubility of hydrophobic biologically active agents can be improved by entrapment within the hydrophobic core region of the block copolymer. The invention further includes pharmaceutical compositions including such block copolymers, methods of making such copolymers and pharmaceutical compositions, and methods of using the block copolymers as drug delivery vehicles.

Claims (66)

1. A multi-arm block copolymer useful as a drug delivery vehicle, comprising:
a central core molecule comprising a residue of a polyol, and at least three copolymer arms covalently attached to the central core molecule, each copolymer arm comprising an inner hydrophobic polymer segment covalently attached to the central core molecule and an outer hydrophilic polymer segment covalently attached to the hydrophobic polymer segment, at least one of the hydrophobic and hydrophilic polymer segments comprising at least one degradable linkage, wherein the central core molecule and the hydrophobic polymer segment define a hydrophobic core region.
2. The multi-arm block copolymer of Claim 1, wherein the central core molecule is a residue of a polyol selected from the group consisting of glycerol, sorbitol, pentaerythritol, and glycerol oligomers.
3. The multi-arm block copolymer of Claim 1, wherein the central core molecule is a residue of hexaglycerol.
4. The multi-arm block copolymer of Claim 1, wherein the central core molecule is a residue of hydroxypropyl-.beta.-cyclodextrin.
5. The multi-arm block copolymer of Claim 1, wherein the inner hydrophobic polymer segment is selected from the group consisting of a poly(hydroxyester), a poly(alkylene oxide) other than poly(ethylene glycol), or a copolymer thereof.
6. The multi-arm block copolymer of Claim 1, wherein the inner hydrophobic polymer segment is poly(propylene glycol).
7. The multi-arm block copolymer of Claim 1, wherein the inner hydrophobic polymer segment is a poly(hydroxyester) selected from the group consisting of poly(lactide), poly(glycolide), poly(lactide)/(glycolide) copolymer, poly(butyrolactide), and polycaprolactone.
8. The multi-arm block copolymer of Claim 1, wherein the outer hydrophilic polymer segment comprises poly(ethylene glycol).
9. The multi-arm block copolymer of Claim 1, wherein each hydrophobic and hydrophilic polymer segment has a molecular weight of about 500 Da to about 100,000 Da.
10. The multi-arm block copolymer of Claim 1, wherein the hydrophobic polymer segment has a molecular weight of about 10,000 Da to about 40,000 Da.
11. The multi-arm block copolymer of Claim 1, wherein the hydrophilic polymer segment has a molecular weight of about 1,000 Da to about 20,000 Da.
12. The multi-arm block copolymer of Claim 1, wherein the central core molecule is attached to at least 5 copolymer arms.
13. The multi-arm block copolymer of Claim 1, wherein the central core molecule is attached to at least 8 copolymer arms.
14. The multi-arm block copolymer of Claim 1, wherein the central core molecule is attached to at least 10 copolymer arms.
15. The multi-arm block copolymer of Claim 1, wherein at least one targeting moiety is covalently attached to at least one hydrophilic polymer segment.
16. The multi-arm block copolymer of Claim 15, wherein the targeting moiety is a bisphosphonate.
17. The multi-arm block copolymer of Claim 1, wherein at least one capping group is covalently attached to at least one hydrophilic polymer segment.
18. The multi-arm block copolymer of Claim 17, wherein the capping group is selected from the group consisting of alkoxy, hydroxyl, protected hydroxyl, active ester, active carbonate, acetal, aldehyde, aldehyde hydrates, alkyl or aryl sulfonate, halide, disulfide, alkenyl, acrylate, methacrylate, acrylamide, active sulfone, amine, protected amine, hydrazide, protected hydrazide, thiol, protected thiol, carboxylic acid, protected carboxylic acid, isocyanate, isothiocyanate, maleimide, vinylsulfone, dithiopyridine, vinylpyridine, iodoacetamide, epoxide, glyoxals, diones, mesylates, tosylates, or tresylate.
19. The multi-arm block copolymer of Claim 1, having the structure:
A(-O-B-O-C-D)n wherein:
A is a central core molecule comprising a residue of a polyol, O is oxygen, B is a hydrophobic polymer segment, C is a hydrophilic polymer segment, D is a capping group, and n is 3 to about 25.
20. The multi-arm block copolymer of Claim 19, wherein each D is alkoxy.
21. The multi-arm block copolymer of Claim 19, wherein each D is hydroxy.
22. The multi-arm block copolymer of Claim 19, wherein each D is selected from the group consisting of alkoxy, hydroxyl, protected hydroxyl, active ester, active carbonate, acetal, aldehyde, aldehyde hydrates, alkyl or aryl sulfonate, halide, disulfide, alkenyl, acrylate, methacrylate, acrylamide, active sulfone, amine, protected amine, hydrazide, protected hydrazide, thiol, protected thiol, carboxylic acid, protected carboxylic acid, isocyanate, isothiocyanate, maleimide, vinylsulfone, dithiopyridine, vinylpyridine, iodoacetamide, epoxide, glyoxals, diones, mesylates, tosylates, or tresylate.
23. The multi-arm block copolymer of Claim 19, wherein A is a residue of a polyol selected from the group consisting of glycerol, sorbitol, pentaerythritol, hydroxypropyl-.beta.-cyclodextrin, and glycerol oligomers.
24. The multi-arm block copolymer of Claim 19, wherein B is selected from the group consisting of a poly(hydroxyester), a poly(alkylene oxide) other than poly(ethylene glycol), or a copolymer thereof.
25. The multi-arm block copolymer of Claim 19, wherein B is poly(propylene oxide).
26. The multi-arm block copolymer of Claim 19, wherein B is a poly(hydroxyester) selected from the group consisting of poly(lactide), poly(glycolide), poly(lactide)/(glycolide) copolymer, poly(butyrolactide), and polycaprolactone.
27. The multi-arm block copolymer of Claim 19, wherein at least one of B
and C comprises at least one degradable linkage.
28. The multi-arm block copolymer of Claim 19, wherein C comprises poly(ethylene glycol).
29. The multi-arm block copolymer of Claim 19, wherein C comprises a hydrolyzable linkage selected from the group consisting of esters, carbonates, imines, hydrazone, phosphate esters, orthoesters, peptides, or acetals.
30. The multi-arm block copolymer of Claim 1, having the structure:
(E-C-O-B-O-)p A(-O-B-O-C-D)m, wherein:
A is a central core molecule moiety comprising a residue of a polyol, O is oxygen, B is a hydrophobic polymer segment, C is a hydrophilic polymer segment, D is a hydroxyl or alkoxy group, p is at least 1, the sum of m and p is from 3 to about 25, and E is a functional group selected from the group consisting of active ester, active carbonate, acetal, aldehyde, aldehyde hydrates, alkyl or aryl sulfonate, halide, disulfide, alkenyl, acrylate, methacrylate, acrylamide, active sulfone, amine, protected amine, hydrazide, protected hydrazide, thiol, protected thiol, carboxylic acid, protected carboxylic acid, isocyanate, isothiocyanate, maleimide, vinylsulfone, dithiopyridine, vinylpyridine, iodoacetamide, epoxide, glyoxals, diones, mesylates, tosylates, or tresylate.
31. The multi-arm block copolymer of Claim 1, having the structure:
(T-C-O-B-O-)p A(-O-B-O-C-D)m wherein:
A is a central core molecule moiety comprising a residue of a polyol, O is oxygen, B is a hydrophobic polymer segment, C is a hydrophilic polymer segment, D is a capping group, p is at least 1, the sum of m and p is from 3 to about 25, and T is a targeting moiety.
32. The multi-arm block copolymer of Claim 31, wherein T is selected from the group consisting of a protein, an antibody, an antibody fragment, a peptide, a carbohydrate, a lipid, an oligonucleotide, DNA, RNA, and a small molecule having molecular weight less than 2000 Daltons.
33. The multi-arm block copolymer of Claim 31, wherein T is a bisphosphonate.
34. A multi-arm block copolymer useful as a drug delivery vehicle, comprising:

a central core molecule comprising a residue of a polyol, and at least five copolymer arms covalently attached to the central core molecule, each copolymer arm comprising an inner hydrophobic polymer segment covalently attached to the central core molecule and an outer hydrophilic polymer segment covalently attached to the hydrophobic polymer segment, wherein the central core molecule and the hydrophobic polymer segment define a hydrophobic core region.
35. The multi-arm block copolymer of Claim 34, wherein the central core molecule is a residue of a polyol selected from the group consisting of glycerol, sorbitol, pentaerythritol, and glycerol oligomers.
36. The multi-arm block copolymer of Claim 34, wherein the inner hydrophobic polymer segment is selected from the group consisting of a poly(hydroxyester), a poly(alkylene oxide) other than poly(ethylene glycol), or a copolymer thereof.
37. The multi-arm block copolymer of Claim 34, wherein the inner hydrophobic polymer segment is a poly(hydroxyester) selected from the group consisting of poly(lactide), poly(glycolide), poly(lactide)/(glycolide) copolymer, and polycaprolactone.
38. The multi-arm block copolymer of Claim 34, wherein at least one of the inner hydrophobic polymer segment and the outer hydrophilic polymer segment comprises at least one degradable linkage.
39. The multi-arm block copolymer of Claim 34, wherein the outer hydrophilic polymer segment comprises poly(ethylene glycol).
40. The multi-arm block copolymer of Claim 34, wherein the central core molecule is attached to at least 8 copolymer arms.
41. The multi-arm block copolymer of Claim 34, wherein the central core molecule is attached to at least 10 copolymer arms.
42. The multi-arm block copolymer of Claim 34, wherein at least one targeting moiety is covalently attached to at least one hydrophilic polymer segment.
43. The multi-arm block copolymer of Claim 42, wherein the targeting moiety is a bisphosphonate.
44. The multi-arm block copolymer of Claim 34, wherein at least one capping group is covalently attached to at least one hydrophilic polymer segment.
45. The multi-arm block copolymer of Claim 44, wherein the capping group is selected from the group consisting of alkoxy, hydroxyl, protected hydroxyl, active ester, active carbonate, acetal, aldehyde, aldehyde hydrates, alkyl or aryl sulfonate, halide, disulfide, alkenyl, acrylate, methacrylate, acrylamide, active sulfone, amine, protected amine, hydrazide, protected hydrazide, thiol, protected thiol, carboxylic acid, protected carboxylic acid, isocyanate, isothiocyanate, maleimide, vinylsulfone, dithiopyridine, vinylpyridine, iodoacetamide, epoxide, glyoxals, diones, mesylates, tosylates, or tresylate.
46. A pharmaceutical composition, comprising:
a multi-arm block copolymer, the block copolymer comprising a central core molecule comprising a residue of a polyol, and at least three copolymer arms covalently attached to the central core molecule, each copolymer arm comprising an inner hydrophobic polymer segment covalently attached to the central core molecule and an outer hydrophilic polymer segment covalently attached to the hydrophobic polymer segment, wherein the central core molecule and the hydrophobic polymer segment define a hydrophobic core region, and at least one biologically active agent entrapped within the hydrophobic core region of the multi-arm block copolymer.
47. The pharmaceutical composition of Claim 46, wherein the biologically active agent is selected from the group consisting of 3,4-di-[1-methyl 6-nitro-indolyl]-1H-pyrrole-2,5-dione (MNIPD), simvastatin, indomethacin, pivaloyloxymethyl butyrate, cyclosporin A, paclitaxel, analogs thereof, and pharmaceutically acceptable salts thereof.
48. The pharmaceutical composition of Claim 46, wherein the central core molecule is a residue of a polyol selected from the group consisting of glycerol, sorbitol, pentaerythritol, hydroxypropyl-.beta.-cyclodextrin, and glycerol oligomers.
49. The pharmaceutical composition of Claim 46, wherein the inner hydrophobic polymer segment is selected from the group consisting of a poly(hydroxyester), a poly(alkylene oxide) other than polyethylene glycol), or a copolymer thereof.
50. The pharmaceutical composition of Claim 46, wherein the inner hydrophobic polymer segment is poly(propylene glycol).
51. The pharmaceutical composition of Claim 46, wherein the inner hydrophobic polymer segment is a poly(hydroxyester) selected from the group consisting of poly(lactide), poly(glycolide), poly(lactide)/(glycolide) copolymer, poly(butyrolactide), and polycaprolactone.
52. The pharmaceutical composition of Claim 46, wherein at least one of the inner hydrophobic polymer segment and the outer hydrophilic polymer segment comprises at least one degradable linkage.
53. The pharmaceutical composition of Claim 46, wherein the outer hydrophilic polymer segment comprises poly(ethylene glycol).
54. The pharmaceutical composition of Claim 46, wherein each hydrophobic and hydrophilic polymer segment has a molecular weight of about 500 Da to about 100,000 Da.
55. The pharmaceutical composition of Claim 46, wherein the hydrophobic polymer segment has a molecular weight of about 10,000 Da to about 40,000 Da.
56. The pharmaceutical composition of Claim 46, wherein the hydrophilic polymer segment has a molecular weight of about 1,000 Da to about 20,000 Da.
57. The pharmaceutical composition of Claim 46, wherein the central core molecule is attached to at least 5 copolymer arms.
58. The pharmaceutical composition of Claim 46, wherein the central core molecule is attached to at least 8 copolymer arms.
59. The pharmaceutical composition of Claim 46, wherein at least one targeting moiety is covalently attached to at least one hydrophilic polymer segment.
60. A method of preparing a pharmaceutical composition, comprising:
providing a multi-arm block copolymer, the block copolymer comprising a central core molecule comprising a residue of a polyol, and at least three copolymer arms covalently attached to the central core molecule, each copolymer arm comprising an inner hydrophobic polymer segment covalently attached to the central core molecule and an outer hydrophilic polymer segment covalently attached to the hydrophobic polymer segment, wherein the central core molecule and the hydrophobic polymer segment define a hydrophobic core region, and entrapping a biologically active agent within the hydrophobic core region of the multi-arm block copolymer.
61. The method of Claim 60, wherein said entrapping step comprises dissolving the multi-arm block copolymer and biologically active agent in an organic solvent to form a mixture and drying the mixture to form a solid pharmaceutical composition.
62. The method of Claim 60, wherein said entrapping step comprises suspending the biologically active agent in an aqueous solution of the multi-arm block copolymer and subjecting the solution to ultrasonication.
63. The method of Claim 60, wherein said entrapping step comprises mixing the biologically active agent and multi-arm block copolymer in solid form, heating the mixture to form a melt, and stirring the mixture to intimately mix the biologically active moiety and the multi-arm block copolymer.
64. A method of delivering a biologically active agent to a mammal, comprising:~
administering a therapeutically effective amount of a pharmaceutical composition to the mammal, the pharmaceutical composition comprising:
a multi-arm block copolymer, the block copolymer comprising a central core molecule comprising a residue of a polyol, and at least three copolymer arms covalently attached to the central core molecule, each copolymer arm comprising an inner hydrophobic polymer segment covalently attached to the central core molecule and an outer hydrophilic polymer segment covalently attached to the hydrophobic polymer segment, wherein the central core molecule and the hydrophobic polymer segment define a hydrophobic core region, and at least one biologically active agent entrapped within the hydrophobic core region of the multi-arm block copolymer.
65. The method of Claim 64, wherein the biologically active agent is selected from the group consisting of 3,4-di-[1-methyl 6-nitro-3-indolyl]-1H-pyrrole-2,5-dione (MNIPD), simvastatin, indomethacin,, pivaloyloxymethyl butyrate, cyclosporin A, paclitaxel, analogs thereof, and pharmaceutically acceptable salts thereof.
66. The method of Claim 64, wherein said administering step comprises administering by oral, buccal, rectal, topical, nasal, ophthalmic, parenteral, or inhalation routes.
CA2435301A 2001-01-19 2002-01-22 Multi-arm block copolymers as drug delivery vehicles Expired - Lifetime CA2435301C (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US26275401P 2001-01-19 2001-01-19
US60/262,754 2001-01-19
PCT/US2002/021872 WO2003000777A2 (en) 2001-01-19 2002-01-22 Multi-arm block copolymers as drug delivery vehicles

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CA2435301A1 true CA2435301A1 (en) 2003-01-03
CA2435301C CA2435301C (en) 2010-04-13

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US (6) US6730334B2 (en)
EP (1) EP1373366B1 (en)
JP (1) JP4078300B2 (en)
KR (1) KR100851270B1 (en)
AT (1) ATE313586T1 (en)
AU (1) AU2002326369B2 (en)
CA (1) CA2435301C (en)
DE (1) DE60208172T2 (en)
ES (1) ES2254717T3 (en)
MX (1) MXPA03006449A (en)
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