Cyclodextrin-based polymers for therapeutics delivery

• US 20080058427A1
• Filed: 07/25/2007
• Published: 03/06/2008
• Est. Priority Date: 09/06/2002
• Status: Active Grant

• Current Assignee: Cerulean Pharma Inc. (Daré Bioscience, Inc.)
• Original Assignee: Insert Therapeutics, Inc. (Arrowhead Pharmaceuticals, Inc.)
• Inventors: Khin, Kay, Davis, Mark, Cheng, Jianjun
• Granted Patent: US 8,110,179 B2
• Time in Patent Office: Days
• US Class Current: 514/772.1
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61K 47/58 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
• CPC Class Codes: A61K 47/59 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
• 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 47/61 the organic macromolecular compound being a polysaccharide or a derivative thereof
• CPC Class Codes: A61K 47/6951 using cyclodextrin cyclodextrins used as simple excipients A61K47/40
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C08B 30/00 Preparation of starch, degraded or non-chemically modified starch, amylose, or amylopectin
• CPC Class Codes: C08B 31/00 Preparation of derivatives of starch derivatives of amylose C08B33/00; derivatives of amylopectin C08B35/00
• CPC Class Codes: C08B 37/0012 Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
• CPC Class Codes: C08F 220/282 and containing two or more oxygen atoms
• CPC Class Codes: C08G 69/44 Polyester-amides
• CPC Class Codes: C08G 81/02 : at least one of the polymers being obtained by reactions involving only carbon-to-carbon unsaturated bonds
• CPC Class Codes: G16H 20/10 : relating to drugs or medications, e.g. for ensuring correct administration to patients
• CPC Class Codes: G16H 70/40 : relating to drugs, e.g. their side effects or intended usage
• CPC Class Codes: Y02A 90/10 : Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation

Abstract

The present invention relates to novel compositions of therapeutic cyclodextrin containing polymeric compounds designed as a carrier for small molecule therapeutics delivery and pharmaceutical compositions thereof. These cyclodextrin-containing polymers improve drug stability and solubility, and reduce toxicity of the small molecule therapeutic when used in vivo. Furthermore, by selecting from a variety of linker groups and targeting ligands the polymers present methods for controlled delivery of the therapeutic agents. The invention also relates to methods of treating subjects with the therapeutic compositions described herein. The invention further relates to methods for conducting pharmaceutical business comprising manufacturing, licensing, or distributing kits containing or relating to the polymeric compounds described herein.

Claims

1-35. -35. (canceled)

36. A water-soluble, cyclodextrin-containing polymer with a linear polymer chain, wherein a plurality of bioactive moieties are covalently attached to the polymer through attachments that are cleaved under biological conditions to release the bioactive moieties, wherein administration of the polymer to a patient results in release of the bioactive moieties.

37. The polymer of claim 36, wherein the polymer comprises cyclodextrin moieties in pendant side chains of the polymer.

38. The polymer of claim 36, wherein the polymer comprises cyclodextrin moieties in the linear polymer chain.

39. The polymer of claim 38, wherein the polymer comprises cyclodextrin moieties alternating with linker moieties in the polymer chain.

40. The polymer of claim 39, wherein a plurality of the linker moieties are attached to bioactive moieties, wherein the linker moieties are cleaved under biological conditions.

41. The polymer of claim 36, wherein the polymer further comprises a plurality of linker moieties that are attached to bioactive moieties, wherein the linker moieties are cleaved under biological conditions.

42. The polymer of any one of claims 40-41, wherein each linker moiety represents a hydrocarbylene group wherein one or more methylene groups is optionally replaced by a group Y (provided that none of the Y groups are adjacent to each other), wherein each Y, independently for each occurrence, is selected from, substituted or unsubstituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or —

O—

, C(═

X) (wherein X is NR₁, O or S), —

OC(O) —

, —

C(═

O)O, —

NR₁—

, —

NR₁CO—

, —

C(O) NR₁—

, —

S(O)_n—

(wherein n is 0, 1, or

     2), —

OC(O) —

NR₁, —

NR₁—

C(O) —

NR₁—

, —

NR₁—

C(NR₁) —

NR₁—

, and —

B(OR₁)—

; and

R₁, independently for each occurrence, represents H or a lower alkyl.

43. The polymer of any one of claims 40-41, wherein each linker moiety represents an amino acid or peptide, or derivative thereof.

44. The polymer of claim 36, wherein the bioactive moieties are small molecules, peptides, proteins, polymers, or a combination thereof that have therapeutic activity.

45. The polymer of claim 36, wherein the bioactive moieties are hydrophobic and have a log P>

0.4.

46. The polymer of claim 36, wherein the bioactive moieties have low aqueous solubility.

47. The polymer of any one of claims 40-41, wherein a plurality of linker moieties include an ester, amide, carbonate, carbamate, or a combination thereof, which is cleaved under biological conditions.

48. The polymer of claim 36, wherein the bioactive moieties are anti-cancer, anti-fungal, anti-bacterial, anti-mycotic, anti-viral therapeutic agents, or a combination thereof.

49. The polymer of claim 36, wherein the bioactive moieties are a receptor agonists.

50. The polymer of claim 36, wherein the bioactive moieties are a receptor antagonists.

51. The polymer of claim 36, wherein the polymer is biodegradable or bioerodable.

52. The polymer of claim 36, wherein the polymer has a number average (Me) molecular weight between about 1,000 to about 500,000 amu.

53. The polymer of claim 52, wherein the polymer has a number average (M_n) molecular weight between about 5,000 to about 200,000 amu.

54. The polymer of claim 53, wherein the polymer has a number average (M_n) molecular weight between about 10,000 to about 100,000 amu.

55. A pharmaceutical preparation comprising a pharmaceutical excipient and a polymer of claim 36, or a pharmaceutically acceptable ester, salt, or hydrate thereof.

56. The polymer of claim 36, wherein the bioactive moieties are selected from anorexics, antiarthritics, antiasthmatic agents, anticonvulsants, antidepressants;

antihistamines, anti-inflammatory agents, antinauseants, antineoplastics, antipruritics, antipsychotics, antipyretics, antispasmodics, cardiovascular preparations, antihypertensives, diuretics, vasodilators, central nervous system stimulants, cough and cold preparations, decongestants, diagnostics, hormones, bone growth stimulants and bone resorption inhibitors, immunosuppressives, muscle relaxants, psychostimulants, sedatives, tranquilizers, anti-inflammatory agents, anti-epileptics, anesthetics, hypnotics, sedatives, neuroleptic agents, antidepressants, anxiolytics, anticonvulsant agents, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergics, antiarrhythmics, and antihypertensive agents.

57. The polymer of claim 36, wherein the bioactive moiety makes up at least about 5% by weight of the compound.

58. The polymer of claim 57, wherein the bioactive moiety makes up at least about 20% by weight of the compound.

59. The polymer of claim 58, wherein the bioactive moiety makes up at least about 35% by weight of the compound.

60. The polymer of claim 36, wherein the polymer is water-soluble.

61. The polymer of claim 36, wherein at least one occurrence of a cyclodextrin moiety is oxidized.

62. The polymer of claim 61, wherein a plurality of cyclodextrin moieties are oxidized.

63. A method for delivering one or more bioactive moieties comprising administering to a patient in need thereof a therapeutically effective amount of one or more of the polymers of claim 36.

64. A method of preparing the polymer of claim 36, comprising reacting monomers M-L-CD and M-L-D and optionally M-L-T, wherein CD represents a cyclodextrin molecule or derivative thereof;

L, independently for each occurrence, is absent or represents a linker group;

D, independently for each occurrence, represents the same or different therapeutic agent or prodrugs thereof;

T, independently for each occurrence, represents the same or different targeting ligand or precursor thereof; and

M represents a monomer subunit bearing one or more reactive moieties capable of undergoing a polymerization reaction with one or more other M in the monomers in the reaction mixture, under conditions that promote polymerization of the monomers.

65. A method of preparing the polymer of claim 36 comprising reacting a polymer P, the polymer bearing a plurality of reactive groups, with grafting agents X-L-CD and Y-L-D and, optionally, Z-L-T, wherein CD represents a cyclodextrin molecule or derivative thereof;

L, independently for each occurrence, is absent or represents a linker group;

D, independently for each occurrence, represents the same or different therapeutic agent or prodrugs thereof;

T, independently for each occurrence, represents the same or different targeting ligand or precursor thereof;

X, independently for each occurrence, represents a reactive group capable of forming a covalent bond with a reactive group of the polymer; and

Y and Z, independently for each occurrence, represent inclusion hosts or reactive groups capable of forming a covalent bond with a reactive group of the polymer or inclusion complexes with CD moieties grafted to the polymer,

under conditions that cause the grafting agents to form covalent bonds and/or inclusion complexes with the polymer or moieties grafted to the polymer.

66. A pharmaceutical dosage form comprising a therapeutically effective amount of one or more compounds represented by Formula I:

67. The dosage form of claim 66, wherein the polymer chain comprises n′

units of U, wherein n′

represents an integer in the range of 1 to about 30,000; and

U is represented by the general formula;

70. The dosage form of claim 66, wherein the linker group represents a hydrocarbylene group wherein one or more methylene groups is optionally replaced by a group Y (provided that none of the Y groups are adjacent to each other), wherein each Y, independently for each occurrence, is selected from, substituted or unsubstituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or —

O—

, C(═

X) (wherein X is NR₁, O or S), —

OC(O) —

, —

C(═

O)O, —

NR₁—

, —

NR₁CO—

, —

C(O) NR₁—

, —

S(O)_n—

(wherein n is 0, 1, or

     2), —

OC(O) —

NR₁, —

NR₁—

C(O)—

NR₁—

, —

NR₁—

C(NR₁)—

NR₁—

, and —

B(OR₁) —

; and

R₁, independently for each occurrence, represents H or a lower alkyl.

71. The dosage form of claim 66, wherein the linker group represents an amino acid or peptide, or derivative thereof.

72. The dosage form of claim 66, wherein the therapeutic agent or targeting ligand is covalently bonded to the linker group via a biohydrolyzable bond.

73. The dosage form of claim 72, wherein the biohydrolyzable bond is selected from an ester, amide, carbonate, or a carbamate.

74. The dosage form of claim 66, wherein the compound is water soluble.

75. The dosage form of claim 66, wherein at least one occurrence of CD or a cyclodextrin moiety is oxidized.

76. The dosage form of claim 66, wherein P comprises cyclodextrin moieties and wherein the cyclodextrin moieties of P alternate with linker moieties in the polymer chain.

77. The dosage form of claim 76, wherein a plurality of the linker moieties are attached to therapeutic agents or prodrugs thereof that are cleaved under biological conditions.

68. A pharmaceutical dosage form comprising a therapeutically effective amount of one or more compounds represented by Formula II:

69. A pharmaceutical dosage form comprising a therapeutically effective amount of one or more compounds represented by Formula III:

78. A pharmaceutical dosage form comprising a linear, water-soluble, cyclodextrin-containing polymer, the polymer comprising cyclodextrin moieties alternating with linker moieties in the polymer chain, wherein a plurality of bioactive moieties are covalently attached to the polymer through attachments to the linker moieties that are cleaved under biological conditions to release the bioactive moieties, wherein administration of the polymer to a patient results in release of the bioactive moieties.