Amphiphilic drug-oligomer conjugates with hydroyzable lipophile components and methods for making and using the same

• US 6,309,633 B1
• Filed: 06/19/1999
• Issued: 10/30/2001
• Est. Priority Date: 06/19/1999
• Status: Expired due to Term

• Current Assignee: Biocon Limited (Biocon Incorporated)
• Original Assignee: Nobex Corporation (Biocon Incorporated)
• Inventors: Rajagopalan, Jayanthi Sethuraman, Ramaswamy, Muthukumar, Ekwuribe, Nnochiri
• Primary Examiner(s): Russel, Jeffrey E.
• Application Number:
  US09/336,548
• Time in Patent Office: 864 Days
• Field of Search: 424/85.1, 424/85.2, 424/85.4, 424/85.5, 424/85.6, 424/85.7, 424/94.3, 424/178.1, 424/179.1, 424/193.1, 424/194.1, 435/188, 514/2, 514/3, 514/8, 514/12, 514/21, 514/476, 514/506, 514/579, 514/613, 514/715, 530/300, 530/303, 530/322, 530/345, 530/350, 530/351, 530/403, 530/405, 530/406, 530/409, 530/410, 530/411
• US Class Current: 424/85.1
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• 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: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention provides a drug-oligomer conjugate having the following general formula:

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.

Claims

1. A drug-oligomer conjugate having the following general formula:

2. The drug-oligomer conjugate of claim 1 wherein L is selected so as to render the D—

[(H—

S_n)—

L_o]_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_n)—

L_o]_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:

6. The drug oligomer conjugate of claim 5 wherein L is selected so as to render the D—

[(H—

S_n—

H′

_q)—

L_o]_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_n—

H′

_q)—

L_o]_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_n—

H′

_q)—

L_o]_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_n—

H′

_q)—

L_o oligomer comprises an H′

—

L subunit selected from the group consisting of;

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′

_q—

S_n)—

L_o]_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′

_q—

S_n)—

L_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_2-7.

14. The drug-oligomer conjugate of claim 11 wherein D is insulin or a functional equivalent thereof and H is PEG₃.

15. A drug-oligomer conjugate having the following general formula:

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_2-7.

18. The drug-oligomer conjugate of claim 15 wherein D is insulin or a functional equivalent thereof and H is PEG₃.

19. The drug-oligomer conjugate of claim 16 wherein D is insulin or a functional equivalent thereof and H is PEG_2-7.

20. The drug-oligomer conjugate of claim 16 wherein D is insulin or a functional equivalent thereof and H is PEG₃.

21. A drug-oligomer conjugate having the following general formula:

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_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:

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:

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:

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 β

-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:

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:

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;

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;

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:

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:

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.