Claims for Patent: 6,309,633

Summary for Patent: 6,309,633

Title:	Amphiphilic drug-oligomer conjugates with hydroyzable lipophile components and methods for making and using the same
Abstract:	The invention provides a drug-oligomer conjugate having the following general formula: ##STR1## wherein D is a therapeutic drug moiety; H and H\' are each a hydrophilic moiety, independently selected from the group consisting of straight or branched PEG polymers having from 2 to 130 PEG subunits, and sugars; L is a lipophilic moiety selected from the group consisting of alkyl groups having 2-26 carbon atoms, cholesterol, adamantane and fatty acids; o is a number from 1 to the maximum number of covalent bonding sites on H; m+n+p together have a value of at least one and not exceeding the total number of covalent bonding sites on D for the --H\', --L and --H--L substituents; the H--L bond(s) are hydrolyzable and the D--L\' bond(s), when present, are hydrolyzable; the conjugate being further characterized by one of the following: (i) m is 0 and p is at least 1; (ii) n is 0 and p is at least 1; (iii) m and n are each 0 and p is at least 1; (iv) p is 0 and m and n are each at least 1. The therapeutic drug moiety is preferably a therapeutic protein or peptide, preferably insulin or a functional equivalent thereof.
Inventor(s):	Ekwuribe; Nnochiri (Cary, NC), Ramaswamy; Muthukumar (Cary, NC), Rajagopalan; Jayanthi Sethuraman (Cary, NC)
Assignee:	Nobex Corporation (Research Triangle Park, NC)
Application Number:	09/336,548
Patent Claims:	1. A drug-oligomer conjugate having the following general formula: wherein D is a therapeutic drug moiety; H is a hydrophilic moiety, independently selected from the group consisting of straight or branched PEG polymers having from 2 to 130 PEG subunits, and sugars; L is a lipophilic moiety selected from the group consisting of alkyl groups having 2-24 carbon atoms, cholesterol, adamantane and fatty acids; S is a spacer group selected from the group consisting of sugars, carbohydrates and glycerol; n is a number from 1 to the maximum number of covalent bonding sites at which S can form a bond with H; o is a number from 1 to the maximum number of covalent bonding sites at which L can form a bond with S; p is a number from 1 to the maximum number of covalent bonding sites at which --[(H--Sn)--Lo] can form a bond with D; and the S--H bond is hydrolyzable. 2. The drug-oligomer conjugate of claim 1 wherein L is selected so as to render the D--[(H--S.sub.n)--L.sub.o ].sub.p conjugate inactive prior to hydrolysis of the S--H bond. 3. The drug-oligomer conjugate of claim 1 wherein the L--S bond is hydrolyzable, and wherein L is selected so as to render the D--[(H--S.sub.n)--L.sub.o ].sub.p conjugate inactive prior to hydrolysis of the S--L bond. 4. The drug-oligomer conjugate of claim 1 wherein D is insulin or a functional equivalent thereof. 5. A drug-oligomer conjugate having the following general formula: wherein D is a therapeutic drug moiety; H and H' are hydrophilic moieties, individually selected from the group consisting of straight or branched PEG polymers having from 2 to 130 PEG subunits, and sugars; L is a lipophilic moiety selected from the group consisting of alkyl groups having 2-24 carbon atoms, cholesterol, adamantane and fatty acids; S is a spacer group selected from the group consisting of sugars, carbohydrates and glycerol; n is a number from 1 to the maximum number of covalent bonding sites at which S can form a bond with H; q is a number from 1 to the maximum number of covalent bonding sites at which H' can form a bond with S; o is a number from 1 to the maximum number of covalent bonding sites at which L can form a bond with S; p is a number from 1 to the maximum number of covalent bonding sites at which --[(H--S.sub.n --H'.sub.q)--L.sub.o ] can form a bond with D; and the H--S bond is hydrolyzable. 6. The drug oligomer conjugate of claim 5 wherein L is selected so as to render the D--[(H--S.sub.n --H'.sub.q)--L.sub.o ].sub.p conjugate inactive prior to hydrolysis of the H--S bond. 7. The drug-oligomer conjugate of claim 5 wherein the S--H' bond is hydrolyzable, and wherein L is selected so as to render the D--[(H--S.sub.n --H'.sub.q)--L.sub.o ].sub.p conjugate inactive prior to hydrolysis of the S--H' bond. 8. The drug-oligomer conjugate of claim 5 wherein the H'--L bond is hydrolyzable, and wherein L is selected so as to render the D--[(H--S.sub.n --H'.sub.q)--L.sub.o ].sub.p conjugate inactive prior to hydrolysis of the H'--L bond. 9. The drug-oligomer conjugate of claim 5 wherein the H'--L bond is non-hydrolyzable, and wherein the (H--S.sub.n --H'.sub.q)--L.sub.o oligomer comprises an H'--L subunit selected from the group consisting of: wherein n=3 to 25 and m=1 to 7; wherein n=3 to 25 and m=1 to 6; wherein m=0 to 5 and R=cholesterol or adamantane; wherein m=1 to 7; and wherein m=1 to 7 and X=NH. 10. The drug-oligomer conjugate of claim 5 wherein D is insulin or a functional equivalent thereof. 11. A drug-oligomer conjugate having the following general formula: D--[(H--H'.sub.q --S.sub.n)--L.sub.o ].sub.p (Formula 13) wherein D is a therapeutic drug moiety; H and H' are hydrophilic moieties, individually selected from the group consisting of straight or branched PEG polymers having from 2 to 130 PEG subunits, and sugars; L is a lipophilic moiety selected from the group consisting of alkyl groups having 2-24 carbon atoms, cholesterol, and fatty acids; S is a spacer group selected from the group consisting of sugars, carbohydrates and glycerol; q is a number from 1 to the maximum number of covalent bonding sites at which H' can form a bond with H; n is a number from 1 to the maximum number of covalent bonding sites at which S can form a bond with H'; o is a number from 1 to the maximum number of covalent bonding sites at which L can form a bond with S; p is a number from 1 to the maximum number of covalent bonding sites at which --[(H--H'.sub.q --S.sub.n)--L.sub.o ] can form a bond with D; and the H--S bond is hydrolyzable. 12. The drug-oligomer conjugate of claim 11 wherein D is insulin or a functional equivalent thereof. 13. The drug-oligomer conjugate of claim 11 wherein D is insulin or a functional equivalent thereof and H is PEG.sub.2-7. 14. The drug-oligomer conjugate of claim 11 wherein D is insulin or a functional equivalent thereof and H is PEG.sub.3. 15. A drug-oligomer conjugate having the following general formula: wherein D is a therapeutic drug moiety; H and H' are hydrophilic moieties, individually selected from the group consisting of straight or branched PEG polymers having from 2 to 130 PEG subunits, and sugars; L is a lipophilic moiety selected from the group consisting of alkyl groups having 2-24 carbon atoms, cholesterol, and fatty acids; the H--H' bond is hydrolyzable and the H'--L bond is not hydrolyzable; q is a number from 1 to the maximum number of covalent bonding sites at which H' can form a bond with H; o is a number from 1 to the maximum number of covalent bonding sites at which L can form a bond with H'; and p is a number from 1 to the maximum number of covalent bonding sites at which --[(H--H'.sub.q)--L.sub.o ] can form a bond with D. 16. The drug-oligomer conjugate of claim 15 wherein D, H, H' and L are selected and arranged such that the drug-oligomer conjugate is amphiphilic. 17. The drug-oligomer conjugate of claim 15 wherein D is insulin or a functional equivalent thereof and H is PEG.sub.2-7. 18. The drug-oligomer conjugate of claim 15 wherein D is insulin or a functional equivalent thereof and H is PEG.sub.3. 19. The drug-oligomer conjugate of claim 16 wherein D is insulin or a functional equivalent thereof and H is PEG.sub.2-7. 20. The drug-oligomer conjugate of claim 16 wherein D is insulin or a functional equivalent thereof and H is PEG.sub.3. 21. A drug-oligomer conjugate having the following general formula: ##STR14## wherein D is a therapeutic drug moiety; H and H' are each a hydrophilic moiety, independently selected from the group consisting of straight or branched PEG polymers having from 2 to 130 PEG subunits, and sugars; the H--L bond(s) are hydrolyzable and the D--L' bond(s), when present, are hydrolysable; L and L' are each a lipophilic moiety, independently selected from the group consisting of alkyl groups having 2-26 carbon atoms, cholesterol, adamantane and fatty acids; o is a number from 1 to the maximum number of covalent bonding sites on H; and m+n+p together have a value of at least one and not exceeding the total number of covalent bonding sites on D for the --H', --L' and --H--L substituents, and wherein m and n are each at least 1. 22. The drug-oligomer conjugate of claim 21 wherein p is 0 and m and n are each at least 1. 23. The drug-oligomer conjugate of claim 21 wherein p is at least 1 and m and n are each at least 1. 24. The drug-oligomer conjugate of claim 21 wherein the D--H and D--H' bonds, when present, are non-hydrolyzable. 25. The drug-oligomer conjugate of claim 21 wherein m and n are each at least 1, H is PEG.sub.2-7, L is a fatty acid having 12-22 carbon atoms, and D is insulin or a functional equivalent of insulin. 26. A drug-oligomer conjugate having the following general formula: ##STR15## wherein D is a therapeutic drug moiety; H and H' are each a hydrophilic moiety, independently selected from the group consisting of straight or branched PEG polymers having from 2 to 130 PEG subunits, and sugars; the H--L bond(s) are hydrolyzable and the D--L' bond(s), when present, are hydrolysable; L and L' are each a lipophilic moiety, independently selected from the group consisting of alkyl groups having 2-24 carbon atoms, cholesterol, adamantane and fatty acids: o is a number from 1 to the maximum number of covalent bonding sites on H; m+n+p together have a value of at least one and not exceeding the total number of covalent bonding sites on D for the --H', --L' and --H--L substituents, and wherein m and n are each at least 1; and wherein the D--H and D--H' bonds, when present, are independently selected from the group consisting of carbamate, amide and secondary amine. 27. The drug-oligomer conjugate of claim 26 wherein m and n are each at least 1 and p=0. 28. A drug-oligomer conjugate having the following general formula: ##STR16## wherein D is a therapeutic drug moiety; H and H' are each a hydrophilic moiety, independently selected from the group consisting of straight or branched PEG polymers having from 2 to 130 PEG subunits, and sugars; the H--L bond(s) are hydrolyzable and the D--L' bond(s), when present, are hydrolysable; L and L' are each a lipophilic moiety, independently selected from the group consisting of alkyl groups having 2-24 carbon atoms, cholesterol, adamantane and fatty acids; o is a number from 1 to the maximum number of covalent bonding sites on H; m+n+p together have a value of at least one and not exceeding the total number of covalent bonding sites on D for the --H', --L' and --H--L substituents, and wherein m and n are each at least 1; and wherein the H--L bond is selected from the group consisting of ester and carbonate. 29. The drug-oligomer conjugate of claim 28 wherein m and n are each at least 1 and p=0. 30. The drug-oligomer conjugate of claim 28 wherein the D--L' bond is present and is selected from the group consisting of ester and carbonate. 31. The drug-oligomer conjugate of claim 28 wherein D is a biologically active peptide. 32. A drug-oligomer conjugate having the following general formula: ##STR17## wherein D is a therapeutic drug moiety; H and H' are each a hydrophilic moiety, independently selected from the group consisting of straight or branched PEG polymers having from 2 to 130 PEG subunits, and sugars; the H--L bond(s) are hydrolyzable and the D--L' bond(s), when present, are hydrolysable; L and L' are each a lipophilic moiety, independently selected from the group consisting of alkyl groups having 2-24 carbon atoms, cholesterol, adamantane and fatty acids; o is a number from 1 to the maximum number of covalent bonding sites on H; m+n+p together have a value of at least one and not exceeding the total number of covalent bonding sites on D for the --H', --L' and --H--L substituents, and wherein m and n are each at least 1; and wherein the therapeutic drug moiety has at least one available moiety for conjugation selected from the group consisting of --NH2; --OH and --SH, and wherein at least one of the available moieties is conjugated to the H--L moiety. 33. The drug-oligomer conjugate of claim 32 wherein m and n are each at least 1 and p=0. 34. The drug-oligomer conjugate of claim 32 wherein the therapeutic drug moiety is selected from the group consisting of: adrenocorticotropic hormone; ebiratide; angiotensin; angiotensin II; asparaginase; atrial natriuretic peptides; atrial sodium diuretic peptides; bacitracin; beta-endorphins; blood coagulation factors VII, VIII and IX; blood thymic factor; bone morphogenic factor; bone morphogenic protein; bradykinin; caerulein; calcitonin gene related polypeptide; calcitonins; CCK-8; cell growth factors; EGF; TGF-alpha; TGF-beta; acidic FGF; basic FGF; chemokines; cholecystokinin; cholecystokinin-8; cholecystokinin-pancreozymin; colistin; colony-stimulating factors; GMCSF; MCSF; corticotropin-releasing factor; cytokines; desmopressin; dipeptide; dismutase; dynorphin; eledoisin; endorphins; endothelin; endothelin-antagonistic peptides; endotherins; enkephalins; epidermal growth factor; erythropoietin; follicle-stimulating hormone; gallanin; gastric inhibitory polypeptide; gastrin-releasing polypeptide; gastrins; G-CSF; glucagon; glutathione peroxidase; glutathio-peroxidase; gonadotropin; gramicidin; gramicidines; growth factor; growth hormone-releasing factor; growth hormones; h-ANP; hormone releasing hormone; human chorionic gonadotrophin; human chorionic gonadotrophin .beta.-chain; human placental lactogen; insulin; insulin-like growth factors; IGF-I; IGF-II; interferons; interleukins; intestinal polypeptide; kallikrein; kyotorphin; luliberin; luteinizing hormone; luteinizing hormone-releasing hormone; lysozyme chloride; melanocyte-stimulating hormone; melanophore stimulating hormone; mellitin; motilin; muramyl; muramyldipeptide; nerve growth factor; nerve nutrition factors; NT-3; NT-4; CNTF; GDNF; BDNF; neuropeptide Y; neurotensin; oxytocin; pancreastatin; pancreatic polypeptide; pancreozymin; parathyroid hormone; pentagastrin; polypeptide YY; pituitary adenyl cyclase-activating polypeptides; platelet derived growth factor; polymixin B; prolactin; protein synthesis stimulating polypeptide; PTH-related protein; relaxin; renin; secretin; serum thymic factor; somatomedins; somatostatins; substance P; superoxide; superoxide dismutase; taftsin; tetragastrin; thrombopoietin; thymic humoral factor; thymopoietin; thymosin; thymostimulin; thyroid hormone releasing hormone; thyroid-stimulating hormone; thyrotropin releasing hormone TRH; trypsin; tuftsin; tumor growth factor; tumor necrosis factor; tyrocidin; urogastrone; urokinase; vasoactive intestinal polypeptide; vasopressins; and functional equivalents of such polypeptides. 35. The drug-oligomer conjugate of claim 32 wherein D is an antigen from an organism or associated with a disease state, selected from the group consisting of adenoviruses; anthrax; Bordetella pertussus; Botulism; bovine rhinotracheitis; Branhamella catarrhalis; canine hepatitis; canine distemper; Chlamydiae; Cholera; coccidiomycosis; cowpox; cytomegalovirus; Dengue fever; dengue toxoplasmosis; Diphtheria; encephalitis; Enterotoxigenic E. coli; Epstein Barr virus; equine encephalitis; equine infectious anemia; equine influenza; equine pneumonia; equine rhinovirus; Escherichia coli; feline leukemia; flavivirus; Globulin; haemophilus influenza type b; Haemophilus influenzae; Haemophilus pertussis; Helicobacter pylon; Hemophilus; hepatitis; hepatitis A; hepatitis B; Hepatitis C; herpes viruses; HIV; HIV- 1 viruses; HIV-2 viruses; HTLV; Influenza; Japanese encephalitis; Klebsiellae species; Legionella pneumophila; leishmania; leprosy; lyme disease; malaria immunogen; measles; meningitis; meningococcal; Meningococcal Polysaccharide Group A; Meningococcal Polysaccharide Group C; mumps; Mumps Virus; mycobacteria; Mycobacterium tuberculosis; Neisseria; Neisseria gonorrhoeae; Neisseria meningitidis; ovine blue tongue; ovine encephalitis; papilloma; parainfluenza; paramyxoviruses; Pertussis; Plague; Pneumococcus; Pneumocystis carinii; Pneumonia; Poliovirus; Proteus species; Pseudomonas aeruginosa; rabies; respiratory syncytial virus; rotavirus; Rubella; Salmonellae; schistosomiasis; Shigellae; simian immunodeficiency virus; Smallpox; Staphylococcus aureus; Staphylococcus species; Streptococcus pneumoniae; Streptococcus pyogenes; Streptococcus species; swine influenza; tetanus; Treponema pallidum; Typhoid; Vaccinia; varicella-zoster virus; and Vibrio cholerae. 36. The drug-oligomer conjugate of claim 32 wherein D is insulin or a functional equivalent thereof. 37. The drug-oligomer conjugate of claim 32 wherein H and/or H' is a sugar, independently selected from the group consisting of amino sugars, glycerol and natural monosaccharides. 38. A drug-oligomer conjugate having the following general formula: ##STR18## wherein D is a therapeutic drug moiety; H and H' are each a hydrophilic moiety, independently selected from the group consisting of straight or branched PEG polymers having from 2 to 130 PEG subunits, and sugars; the H--L bond(s) are hydrolyzable and the D--L' bond(s), when present, are hydrolysable; L and L' are each a lipophilic moiety, independently selected from the group consisting of alkyl groups having 2-24 carbon atoms, cholesterol, adamantane and fatty acids having 4-26 carbon atoms; o is a number from 1 to the maximum number of covalent bonding sites on H; and m+n+p together have a value of at least one and not exceeding the total number of covalent bonding sites on D for the --H', --L' and --H--L substituents, and wherein m and n are each at least 1. 39. The drug-oligomer conjugate of claim 38 wherein m and n are each at least 1 and p=0. 40. A drug-oligomer conjugate having the following general formula: ##STR19## wherein D is a therapeutic drug moiety; H and H' are each a hydrophilic moiety, independently selected from the group consisting of straight or branched PEG polymers having from 2 to 130 PEG subunits, and sugars; the H--L bond(s) are hydrolyzable and the D--L' bond(s), when present, are hydrolysable; L and L' are each a lipophilic moiety, independently selected from the group consisting of alkyl groups having 2-24 carbon atoms, cholesterol, adamantane and fatty acids; o is a number from 1 to the maximum number of covalent bonding sites on H; m+n+p together have a value of at least one and not exceeding the total number of covalent bonding sites on D for the --H', --L' and --H--L substituents, and wherein m and n are each at least 1; and wherein H--L is selected from the group consisting of: wherein n=3 to 25, m=1 and X.dbd.O; wherein m=0 to 5 and R=cholesterol or adamantane; and wherein m=1 to 7 and X=O. 41. The drug-oligomer conjugate of claim 40 wherein m and n are each at least 1 and p=0. 42. A pharmaceutical composition comprising the drug-oligomer conjugate of claim 40 in association with a pharmaceutical carrier. 43. A pharmaceutical composition comprising the drug-oligomer conjugate of claim 40 in association with an emulsion. 44. A pharmaceutical composition comprising the drug-oligomer conjugate of claim 40 in association with a microemulsion. 45. A method for solubilizing a drug in an oil containing pharmaceutical formulation comprising: a) providing a drug-oligomer conjugate having a formula: ##STR20## where D is a therapeutic drug moiety; H and H' are each a hydrophilic moiety, independently selected from the group consisting of straight or branched PEG polymers having from 2 to 130 PEG subunits, and sugars; the H--L bond(s) are hydrolyzable and the D--L' bond(s), when present, are hydrolysable; L and L' are each a lipophilic moiety, independently selected from the group consisting of alkyl groups having 2-24 carbon atoms, cholesterol, adamantane and fatty acids; o is a number from 1 to the maximum number of covalent bonding sites on H, m+n+p together have a value of at least one and not exceeding the total number of covalent bonding sites on D for the --H', --L' and --H--L substituents, and wherein m and n are each at least 1; b) bringing the drug-oligomer conjugate of a) into association with an oil containing pharmaceutical formulation. 46. The method of claim 45 wherein the oil containing pharmaceutical formulation is a microemulsion. 47. The method of claim 45 wherein the oil containing pharmaceutical formulation is an emulsion. 48. The method of claim 45 wherein D is insulin or a functional equivalent thereof. 49. A method for providing a drug-hydrophile conjugate to a situs of a subject, the method comprising administering to the subject a drug-oligomer conjugate having the formula: ##STR21## wherein D is a therapeutic drug moiety; H and H' are each a hydrophilic moiety, independently selected from the group consisting of straight or branched PEG polymers having from 2 to 130 PEG subunits, and sugars; L and L' are each a lipophilic moiety, independently selected from the group consisting of alkyl groups having 2-24 carbon atoms, cholesterol, adamantane and fatty acids, o is a number from 1 to the maximum number of covalent bonding sites on H; m+n+p together have a value of at least one and not exceeding the total number of covalent bonding sites on D for the --H', --L' and --H--L substituents, and wherein m and n are each at least 1; and the H--L bond(s) and/or the D--L' bonds are hydrolyzable in the subject to provide the drug-hydrophile conjugate. 50. The method of claim 49 wherein m and n are each at least 1 and p=0. 51. The method of claim 49 wherein D is insulin or a functional equivalent thereof. 52. The method of claim 49 wherein H is a straight or branched PEG polymer having from 2 to 7 PEG subunits. 53. The method of claim 49 wherein H is a straight or branched PEG polymer having from 3 to 6 subunits. 54. The method of claim 51 wherein H is a straight or branched PEG polymer having from 2 to 7 PEG subunits. 55. The method of claim 51 wherein H is a straight or branched PEG polymer having from 3 to 6 PEG subunits. 56. A method for providing a drug-PEG conjugate to a situs of a subject, wherein the drug component of the drug-PEG conjugate is selected from the group consisting of insulin and functional equivalents of insulin, and wherein the drug-PEG conjugate has enhanced activity in comparison with a corresponding unconjugated insulin molecule, the method comprising administering to the subject a drug-PEG-lipophile conjugate having a formula: wherein D is selected from the group consisting of insulin and functional equivalents of insulin; H is a straight or branched PEG polymer having from 2 to 7 PEG subunits; H' is a straight or branched PEG polymer having from 0 to 130 PEG subunits; L is a lipophilic moiety selected from the group consisting of alkyl groups having 2-24 carbon atoms, cholesterol, and fatty acids; q is a number from 1 to the maximum number of covalent bonding sites at which H' can form a bond with H; o is a number from 1 to the maximum number of covalent bonding sites at which L can form a bond with H'; p is a number from 1 to the maximum number of covalent bonding sites at which --[(H--H'.sub.q)--L.sub.o ] can form a bond with D; and the H--H' bond is hydrolyzed in the subject to provide the drug-PEG conjugate. 57. The method of claim 56 wherein H is a straight or branched PEG polymer having 2, 3, 4, 5 or 6 PEG subunits. 58. The method of claim 56 wherein the drug-PEG conjugate is administered in association with a pharmaceutically acceptable carrier as a pharmaceutical composition. 59. The method of claim 56 wherein the drug-PEG conjugate is administered in association with an emulsion as a pharmaceutical composition. 60. The method of claim 56 wherein the drug-PEG conjugate is administered in association with a microemulsion as a pharmaceutical composition.

Details for Patent 6,309,633

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Microbix Biosystems Inc.	KINLYTIC	urokinase	For Injection	021846	01/16/1978		2039-02-26
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	01/10/1978		2039-02-26
Nps Pharmaceuticals, Inc.	NATPARA	parathyroid hormone	For Injection	125511	01/23/2015		2039-02-26