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US 10,882,961 B2Granted
Method of production of graft co-polymer excipient with a superior peptide and protein binding property
AssigneePharmalN Corporation
InventorsCynthia C. Jones, Joshua F. Alfaro, Gerardo M. Castillo
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Abstract
Provided herein is a process of preparing a semi-random graft co-polymer, the product of which is difficult to fully characterize chemically. The product of the present disclosure has unique and useful properties of 1) binding to a peptide and 2) upon co-administration of the product and the peptide into animals the product prolongs the blood circulation time and elevates the level of the peptide, compared to the peptide alone without the product of the disclosure.
Claims16
A method of preparing a semi-random graft co-polymer, comprising:
- step (a):
- dissolving a linear polyamine backbone containing W moles of free primary amino groups in an aqueous solvent to provide solution A having a volume Y;
- and
- B1 or B2, wherein:
- B1 comprises steps (b), (c), (d), and (e):
- step (b):
- activating a protective chain selected from polyethylene glycol, polypropylene glycol, polyethylene-polypropylene glycol copolymer, methoxylated polyethylene glycol, methoxylated polypropylene glycol, methoxylated polyethylene-polypropylene glycol copolymer, ethoxylated polyethylene glycol, ethoxylated polypropylene glycol, and ethoxylated polyethylene-polypropylene glycol copolymer, wherein the protective chain contains 0.5-1.2×W moles of carboxyl groups with 1.7-7.0×W moles of N-hydroxysuccinimidesulfate and 1.5-3.6×W moles of 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride in an aqueous solvent, at pH 4-5.5 having a final volume of Z, such that W/(Y+Z) has a ratio of 30-55 mM, for a period of time of up to 30 minutes to provide a solution B;
- step (c):
- adding solution B to solution A with continuous mixing to provide solution C;
- step (d):
- adjusting the pH of solution C to above 6.5;
- and
- step (e):
- adding 0.5-1.5×W of additional 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride to solution C 2 to 3 hours after steps (b-d);
- and waiting until the primary amino groups are 55-40% of W moles to provide a semi-random graft co-polymer comprising a protective chain-grafted polyamine;
- and
- B2 comprises steps (b-d) and step (e):
- steps (b-d):
- adding a protective chain containing 0.5-1.2×W moles of carboxyl group, 1.7-7.0×W moles of N-hydroxysuccinimidesulfate, and 1.5-3.6×W moles of 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride to solution A to provide solution C;
- adjusting the pH of solution C to above 6.5;
- and
- step (e):
- adding 0.5-1.5×W of additional 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride to solution C 2 to 3 hours after steps (b-d);
- and waiting until the primary amino groups are 55-40% of W moles to provide a semi-random graft co-polymer comprising a protective chain-grafted polyamine.
21 more elements
Dependencies are inferred from the claim text.