Analysis of amino acid copolymer compositions

Patent metadata

Field	Value
Publication number	US-9410964-B2
Application number	US-201514941006-A
Country	US
Kind code	B2
Filing date	Nov 13, 2015
Priority date	Apr 16, 2008
Publication date	Aug 9, 2016
Grant date	Aug 9, 2016

Abstract

Methods for analyzing, selecting, characterizing or classifying compositions of a co-polymer, e.g., glatiramer acetate are described. The methods entail analysis of pyro-glutamate in the composition, and, in some methods, comparing the amount of pyro-glutamate present in a composition to a reference standard.

First claim

What is claimed is:

1. A method for manufacturing a pharmaceutical composition comprising glatiramer acetate, the method comprising:
preparing an amino acid copolymer of L-glutamic acid, L-alanine, L-lysine, and L-tyrosine, wherein the preparing step comprises co-polymerizing N-carboxy anhydrides of L-alanine, benzyl-protected L-glutamic acid, trifluoroacetic acid (TFA)-protected L-lysine, and L-tyrosine to generate a first material; treating the first material to deprotect the benzyl-protected L-glutamic acid therein and to partially depolymerize the first material, thereby generating a second material; treating the second material to deprotect the TFA-protected L-lysine to produce a third material; and purifying the third material, to thereby produce the copolymer of L-glutamic acid, L-alanine, L-lysine, and L-tyrosine;
measuring pyro-glutamate content of the copolymer in a sample of the copolymer;
processing the copolymer to produce a pharmaceutical composition comprising glatiramer acetate only if the measured pyro-glutamate content of the copolymer in the sample is within 2000-7000 parts per million (ppm) on a dry weight/dry weight basis,
thereby producing a pharmaceutical composition comprising glatiramer acetate.

2. The method of claim 1 wherein: the step of deprotecting the TFA-protected L-lysine comprises treating the second material with aqueous piperidine.

3. The method of claim 1 , wherein co-polymerizing N-carboxy anhydrides of L-alanine, benzyl-protected L-glutamic acid, trifluoroacetic acid (TFA)-protected L-lysine, and L-tyrosine to generate a first material comprises contacting the N-carboxy anhydrides of L-alanine, benzyl-protected L-glutamic acid, trifluoroacetic acid (TFA)-protected L-lysine, and L-tyrosine with diethylamine.

4. The method of claim 2 , wherein co-polymerizing N-carboxy anhydrides of L-alanine, benzyl-protected L-glutamic acid, trifluoroacetic acid (TFA)-protected L-lysine, and L-tyrosine to generate a first material comprises contacting the N-carboxy anhydrides of L-alanine, benzyl-protected L-glutamic acid, trifluoroacetic acid (TFA)-protected L-lysine, and L-tyrosine with diethylamine.

5. The method of claim 1 , wherein treating the first material to deprotect the benzyl-protected L-glutamic acid therein and to partially depolymerize the first material comprises treating the first material with anhydrous 33% HBr in acetic acid.

6. The method of claim 2 , wherein treating the first material to deprotect the benzyl-protected L-glutamic acid therein and to partially depolymerize the first material comprises treating the first material with anhydrous 33% HBr in acetic acid.

7. The method of claim 3 , wherein treating the first material to deprotect the benzyl-protected L-glutamic acid therein and to partially depolymerize the first material comprises treating the first material with anhydrous 33% HBr in acetic acid.

8. The method of claim 1 , wherein measuring pyro-glutamate content of the copolymer in a sample of the copolymer comprises obtaining a sample of a manufacturing batch of the copolymer.

9. The method of claim 1 , wherein measuring pyro-glutamate content of the copolymer in a sample of the copolymer comprises digesting the copolymer in the sample with pyroglutamate aminopeptidase.

10. The method of claim 1 , wherein measuring pyro-glutamate content comprises determining the ppm on a dry weight/dry weight basis of pyro-Glu in the sample of the copolymer.

11. The method of claim 1 , further comprising packaging, labeling, or releasing into commerce the pharmaceutical composition comprising glatiramer acetate.

12. The method of claim 1 , further comprising offering for sale or selling the pharmaceutical composition comprising glatiramer acetate.

13. The method of claim 1 , further comprising shipping or moving to a new location the pharmaceutical composition comprising glatiramer acetate.

14. The method of claim 2 , wherein the glatiramer acetate has an Mp of 5000-9000 Da.

Assignees

• Momenta Pharmaceuticals Inc

Inventors

• Zhu Xiangping
• Shriver Zachary
• Jiang Yanjie
• Bauer Corinne
• Anderson James Eric
• Ahern Peter James

Classifications

• C08G69/10

  Alpha-amino-carboxylic acids {(polysuccinimides C08G73/1092)} · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• G01N33/6812 Primary

  Assays for specific amino acids · CPC title

• C12Q1/37 Primary

  involving peptidase or proteinase · CPC title