Insulin prodrugs hydrolyzable in vivo to yield peglylated insulin
View Patent ↗The present invention relates generally to hydrolyzable drug-oligomer conjugates, pharmaceutical compositions comprising such conjugates, and to methods for making and using such conjugates and pharmaceutical compositions. For example, a conjugate of insulin, PEG, and oleic acid can be orally administered.
1. A drug-oligomer conjugate having the following general formula:
D—[(H—H′ q )—L o ] p (Formula 10)
wherein
D is insulin or a functional equivalent thereof;
H is a PEG polymer having from 1 to 10 PEG units;
H′ is a hydrophilic moiety;
L is a lipophilic moiety;
the H—H′ bond is 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′ q )—L o ] can form a bond with D.
2. The drug-oligomer conjugate of claim 1 , wherein H, H′ and L are selected and arranged such that the drug-oligomer conjugate is amphiphilic.
3. The drug-oligomer conjugate of claim 1 , wherein H is a PEG polymer having from 2 to 8 PEG units.
4. The drug-oligomer conjugate of claim 1 , wherein H is a PEG polymer having from 2 to 7 PEG units.
5. The drug-oligomer conjugate of claim 1 , wherein H is a PEG polymer having 3 PEG units.
6. The drug-oligomer conjugate of claim 1 , wherein H is a PEG polymer having 4 PEG units.
7. The drug-oligomer conjugate of claim 1 , wherein H is a PEG polymer having 5 PEG units.
8. The drug-oligomer conjugate of claim 1 , wherein H is a PEG polymer having 6 PEG units.
9. The drug-oligomer conjugate of claim 1 , wherein H′ is a hydrophilic moiety selected from the group consisting of straight or branched PEG polymers and sugars.
10. The drug-oligomer conjugate of claim 1 , wherein H′ is a straight PEG polymer.
11. The drug-oligomer conjugate of claim 10 , wherein the PEG polymer has from 1 to 130 PEG units.
12. The drug-oligomer conjugate of claim 10 , wherein the PEG polymer has from 1 to 100 PEG units.
13. The drug-oligomer conjugate of claim 1 , wherein L is a lipophilic moiety selected from the group consisting of alkyl moieties, cholesterol, and fatty acid moieties.
14. The drug-oligomer conjugate of claim 1 , wherein L is an alkyl moiety.
15. The drug-oligomer conjugate of claim 1 , wherein L is cholesterol.
16. The drug-oligomer conjugate of claim 1 , wherein L is a fatty acid moiety.
17. The drug-oligomer conjugate of claim 16 , wherein the fatty acid moiety has between 2 and 28 carbon atoms.
18. The drug-oligomer conjugate of claim 16 , wherein the fatty acid moiety has between 12 and 22 carbon atoms.
19. The drug-oligomer conjugate of claim 1 , wherein D is insulin or insulin lispro.
20. The drug-oligomer conjugate of claim 1 , wherein the H′—L bond is non-hydrolyzable.
21. The drug-oligomer conjugate of claim 1 , wherein H′ and L are present as a component H′—L having the formula CH 3 (CH 2 ) n (OC 2 H 4 ) m OH (Formula 3), wherein n=3 to 25 and m=1 to 7.
22. The drug-oligomer conjugate of claim 1 , wherein H′ and L are present as a component H′—L having the formula CH 3 (CH 2 ) n (OC 2 H 4 ) m OCH 2 CO 2 H (Formula 4), wherein n=3 to 25 and m=1 to 6.
23. The drug-oligomer conjugate of claim 1 , wherein H′ and L are present as a component H′—L having the formula R—(OC 2 H 4 ) m CH 2 CO 2 H (Formula 6), wherein m=0 to 5 and R=cholesterol or adamantane.
24. The drug-oligomer conjugate of claim 1 , wherein H′ and L are present as a component H′—L having the formula CH 3 (CH 2 —CH═CH) 6 (CH 2 ) 2 CH 2 (OC 2 H 4 ) m OH (Formula 8), wherein m=1 to 7.
25. The drug-oligomer conjugate of claim 1 , wherein H′ and L are present as a component H′—L having the formula CH 3 (CH 2 —CH═CH) 6 (CH 2 ) 2 CX(OC 2 H 4 ) m OH (Formula 9), wherein m=1 to 7.