Polypeptide synthesis for drug delivery

• US 8,455,619 B2
• Filed: 11/23/2009
• Issued: 06/04/2013
• Est. Priority Date: 11/25/2008
• Status: Active Grant

• Current Assignee: Keith R. Latham
• Original Assignee: Keith R. Latham
• Inventors: Latham, Keith R.
• Primary Examiner(s): Lukton, David
• Application Number:
  US12/623,584
• Publication Number:
  US 20100130723A1
• Time in Patent Office: 1,289 Days
• Field of Search: 530/333, 530/342
• US Class Current: 530/333
• CPC Class Codes: C07K 1/02 in solution C07K1/003, C07K1/006 take precedence
• CPC Class Codes: C07K 1/10 using coupling agents C07K1/006 takes precedence

Abstract

The present invention provides improved methods for the synthesis of polypeptide or peptide-linked compounds via a NCA-based polymerization reaction that produces high product yields in much less time. Such improved methods are achieved by application of a higher temperature and/or reduced pressure to the reaction such that an NCA-containing monomer melts.

Claims

1. A method comprising the following steps:

(a) combining one or more initiators and one or more NCA-containing monomers in a reaction vessel to form a reaction mixture; and

(b) heating the reaction mixture to an elevated temperature at or above the melting point of at least one of the NCA-containing monomers, wherein at least one of the NCA-containing monomers melts at the elevated temperature during step (b),

wherein the elevated temperature is in a range from about 55°

C. to about 70°

C.

2. The method of claim 1, further comprising:

(c) maintaining the temperature of the reaction mixture heated in step (b) at or above the melting point of the at least one NCA-containing monomer melted in step (b) until an NCA-based polymerization reaction involving the one or more initiators and the one or more NCA-containing monomers reaches or nears completion.

3. The method of claim 2, wherein the maintaining step (c) is carried out until evolution of CO₂ from the reaction mixture is no longer visible.

4. The method of claim 2, wherein the maintaining step (c) is carried out until a visible solid precipitate is formed in the reaction mixture.

5. The method of claim 1, wherein the one or more initiators comprises two or more different types of initiators.

6. The method of claim 1, wherein the one or more NCA-containing monomers comprises two or more different types of NCA-containing monomers.

7. A method comprising the following steps:

(a) combining one or more initiators and one or more NCA-containing monomers in a reaction vessel to form a reaction mixture; and

(b) heating the reaction mixture to an elevated temperature at or above the melting point of at least one of the NCA-containing monomers, wherein at least one of the NCA-containing monomers melts at the elevated temperature during step (b),

wherein at least one of the one or more initiators is an active agent or drug,.

wherein the active agent or drug is amphetamine, serotonin, catecholamine, L-DOPA, dopamine, 3,5,5′

,3′

-tetraiodo-L-thyronine (T4), or 3,5,3′

-triiodo-L-thyronine (T3).

8. The method of claim 7, wherein the one or more initiators and the one or more NCA-containing monomers are combined in step (a) in an aprotic solvent.

9. A method comprising the following steps:

(a) combining one or more initiators and one or more NCA-containing monomers in an aprotic solvent in a reaction vessel to form a reaction mixture; and

(b) heating the reaction mixture to an elevated temperature at or above the melting point of at least one of the NCA-containing monomers, wherein at least one of the NCA-containing monomers melts at the elevated temperature during step (b),

wherein the elevated temperature is above the boiling point of the aprotic solvent.

10. The method of claim 9, wherein the base monomer of at least one of the one or more NCA-containing monomers is an active agent or drug.

11. The method of claim 10, wherein the active agent or drug is L-DOPA, 3,5,3′

,5′

-tetraiodothyronine (T4), or 3,5,3′

-triiodo-L-thyronine (T3).

12. The method of claim 9, wherein most or all of the aprotic solvent evaporates or boils out of the reaction mixture during step (b).

13. The method of claim 9, wherein the one or more initiators and the one or more NCA-containing monomers are homogeneously mixed in the aprotic solvent in step (a).

14. The method of claim 9, wherein the aprotic solvent has a boiling point below the melting point of the at least one NCA-containing monomer melted during step (b).

15. The method of claim 9, further comprising:

(c) maintaining the temperature of the reaction mixture heated in step (b) at or above the melting point of the at least one NCA-containing monomer melted in step (b) until an NCA-based polymerization reaction involving the one or more initiators and the one or more NCA-containing monomers reaches or nears completion.

16. The method of claim 9, wherein at least one of the one or more initiators is an active agent or drug.

17. The method of claim 16, wherein the active agent or drug is amphetamine, serotonin, catecholamine, L-DOPA, dopamine, 3,5,5′

,3′

-tetraiodo-L-thyronine (T4), or 3,5,3′

triiodo-L-thyronine (T3).

18. The method of claim 17, wherein the active agent or drug is amphetamine.

19. The method of claim 9, wherein the ratio of the amount of the one or more initiators to the amount of the one or more NCA-containing monomers combined in step (a) is chosen to determine the average length of polymers produced by an NCA-based polymerization reaction involving the one or more initiators and the one or more NCA-containing monomers.

20. The method of claim 9, wherein the aprotic solvent comprises one or more of the following:

perfluorohexane, pentane, hexane, cyclohexane, carbon tetrachloride, benzene, carbon disulfide, diisopropyl ether, diethyl ether, t-butyl methyl ether (MTBE), chloroform, ethyl acetate, tetrahydrofuran (THF), methylene chloride, 2-butanone, acetone, acetonitrile, dichloromethane, or nitrobenzene.

21. The method of claim 9, wherein the elevated temperature is in a range from about 50 to about 75°

C.

22. The method of claim 9, further comprising:

(c) applying a reduced pressure to the reaction mixture.

23. The method of claim 22, wherein the reduced pressure is between zero inches of Hg to about 20 inches of Hg.

24. The method of claim 22, wherein step (c) is performed during step (b).

25. The method of claim 22, wherein step (c) is performed after step (a).