Pegylated C-peptide
The present invention relates to modified forms of C-peptide, and methods for their use. In one aspect, the modified forms of C-peptide comprise PEGylated C-peptide derivatives comprising at least one PEG group attached to the N-terminus, which exhibit superior pharmacokinetic and biological activity in vivo.
1. A polyethylene glycolated (PEGylated) C-peptide having the following structure:
wherein:
C-peptide is -EAEDLQVGQVELGGGPGAGSLQPLALEGSLQ (SEQ ID NO: 1);
each R 1 is methyl;
n1 is 200 to 800;
n2 is 200 to 800;
the linker is selected from the group consisting of: —X 1 —(CH 2 ) m4 —CO— and
—X 1 —(CH 2 ) m2 —X 2 —CO—(CH 2 ) m4 —CO—;
wherein X 1 is —O— or missing;
X 2 is —NH—;
m 2 is 1 to 5; and
m 4 is 1 to 5;
wherein the linker is attached to the N-terminal amino group of the C-peptide;
wherein the molecular weight of the PEGylated C-peptide without the C-peptide portion is about 40 kDa to about 50 kDa;
or a pharmaceutically acceptable salt thereof;
and wherein the PEGylated C-peptide is for parenteral administration.
2. The PEGylated C-peptide of claim 1 , wherein the linker is X 1 —(CH 2 ) m2 —X 2 —CO—(CH 2 ) m4 —CO—.
3. A pharmaceutical composition for parenteral administration comprising the PEGylated C-peptide of claim 1 and a pharmaceutically acceptable carrier or excipient.
4. The pharmaceutical composition of claim 3 , wherein the pharmaceutically acceptable carrier or excipient is sorbitol.
5. The pharmaceutical composition of claim 4 , wherein the sorbitol is present at a concentration of about 2% to about 8% wt/wt.
6. The pharmaceutical composition of claim 5 , wherein the sorbitol is present at a concentration of about 4.7% wt/wt.
7. The pharmaceutical composition of claim 6 , wherein the composition is buffered to a pH within the range of about pH 5.5 to about pH 6.5.
8. The pharmaceutical composition of claim 7 , wherein the composition is buffered to a pH of about 6.0.
9. The pharmaceutical composition of claim 8 , wherein the composition is buffered with a phosphate buffer at a concentration of about 5 mM to about 25 mM.
10. The pharmaceutical composition of claim 9 , wherein the composition is buffered with a phosphate buffer at a concentration of about 10 mM.
11. The pharmaceutical composition of claim 3 , further comprising insulin.
12. The PEGylated C-peptide of claim 1 , wherein n1 and n2 are each within the range of about 400 to 500.
13. The PEGylated C-peptide of claim 1 , wherein n1 and n2 are each within the range of about 400 to 650.