Polymer stabilized neuropeptides
View Patent ↗A substantially hydrophilic conjugate is provided having a peptide that is capable of passing the blood-brain barrier covalently linked to a water-soluble nonpeptidic polymer such as polyethylene glycol. The conjugate exhibits improved solubility and in vivo stability and is capable of passing the blood-brain barrier of an animal.
1. A hydrophilic polymer-peptide conjugate consisting of a peptide that is either biphalin or [D-Pen 2 , D-Pen 5 ] enkephalin (DPDPE) covalently linked to one or more water-soluble polymer chains having a molecular weight from about 2,000 to about 100,000 daltons and selected from either poly(ethylene glycol) or copolymers of ethylene glycol and propylene glycol, wherein said conjugate, when administered into the blood circulation of a mammal, is capable of transport across the blood brain barrier.
2. The conjugate of claim 1 , which, when administered to the blood circulation of a mammal, has an extended duration of analgesic effect when compared to the corresponding unconjugated peptide.
3. The conjugate of claim 1 , wherein said one or more water soluble polymer chains is absent one or more lipophilic moieties.
4. The conjugate of claim 1 , wherein said peptide is covalently linked to at least one terminus of said one or more polymer chains.
5. The conjugate of claim 1 , wherein said peptide is covalently linked at an N-terminus to said one or more polymer chains.
6. The conjugate of claim 1 , wherein said water-soluble, polymer chain is a copolymer of polyethylene glycol and polypropylene glycol.
7. The conjugate of claim 1 , wherein said water-soluble polymer chain is polyethylene glycol.
8. The conjugate of claim 7 , wherein said polyethylene glycol is selected from the group consisting of monomethoxypolyethylene glycol, branched polyethylene glycol, polyethylene glycol with degradable linkages in the backbone, homobifunctional polyethylene glycol, heterobifunctional polyethylene glycol, multi-arm polyethylene glycol, pendant polyethylene glycol, and forked polyethylene glycol.
9. The conjugate of claim 1 , wherein said peptide is conjugated to a single polyethylene glycol chain.
10. The conjugate of claim 1 , comprising biphalin covalently attached to two polyethylene glycol chains.
11. The conjugate of claim 1 , wherein said polymer chain is polyethylene glycol having a nominal average molecular weight of about 2,000 daltons to about 40,000 daltons.
12. The conjugate of claim 11 , wherein said polyethylene glycol has a nominal average molecular weight selected from the group consisting of 2000 daltons, 5000 daltons, 8,000 daltons, 10,000 daltons, 12,000 daltons and 20,000 daltons.
13. The conjugate of claim 11 , wherein said polyethylene glycol has a nominal average molecular weight of 2,000 daltons.
14. A pharmaceutical composition comprising a conjugate according to claim 1 and a pharmaceutically acceptable carrier.
15. The conjugate of claim 7 , wherein said polymer chain is linear.
16. The conjugate of claim 1 , wherein said peptide is covalently linked to said one or more water soluble polymer chains at a tyrosine residue of said peptide.
17. The conjugate of claim 1 , wherein said peptide is biphalin.
18. The conjugate of claim 1 , wherein said peptide is DPDPE.
19. The conjugate of claim 1 , wherein said polymer chain is absent fatty acids and glycolipids.
20. The conjugate of claim 1 , wherein said polymer chain is monomethoxypolyethylene glycol.