Compositions comprising a polymeric reagent and a pharmacologically active agent

Patent metadata

Field	Value
Publication number	US-9399070-B2
Application number	US-201514720213-A
Country	US
Kind code	B2
Filing date	May 22, 2015
Priority date	May 23, 2003
Publication date	Jul 26, 2016
Grant date	Jul 26, 2016

Abstract

Pharmaceutical compositions of conjugates are provided. The conjugates can be prepared by (among other ways) conjugating a pharmacologically active agent with a polymeric reagent that has a particular arrangement of atoms. Related methods, preparations, and so forth are also provided.

First claim

What is claimed is:

1. A composition comprising
(i) a polymeric reagent of the following structure,

wherein:
POLY 1 is a poly(alkylene glycol);
POLY 2 is a poly(alkylene glycol);
(a) is 0, 1, 2 or 3;
(b) is 0, 1, 2 or 3;
(e) is 0, 1, 2 or 3;
(f′) is 0, 1, 2 or 3;
(g′) is 0, 1, 2 or 3;
(h) is 0, 1, 2 or 3;
(j) is 0 to 20;
each R 1 is independently H or an organic radical selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl and substituted aryl;
X 1 , when present, is a first spacer moiety;
X 2 , when present, is a second spacer moiety;
X 5 , when present, is a fifth spacer moiety;
X 6 , when present, is a sixth spacer moiety;
X 7 , when present, is a seventh spacer moiety;
X 8 , when present, is an eighth spacer moiety;
R 5 is a branching moiety selected from the group consisting of

 wherein (p) is 1-10 and (q) is 1-10; and
Z is a reactive group suitable for reaction with an electrophile or nucleophile of a biologically active agent; and
(ii) a pharmacologically active agent,

wherein there is an excess of the polymeric reagent relative to the pharmacologically active agent in the composition.

2. The composition of claim 1 , wherein each R 1 is H.

3. The composition of claim 1 , wherein each poly(alkylene glycol) is a poly(ethylene glycol).

4. The composition of claim 3 , wherein each poly(ethylene glycol) is terminally capped with methoxy.

5. The composition of claim 4 , wherein each poly(ethylene glycol) has a molecular weight of from about 100 Daltons to about 100,000 Daltons.

6. The composition of claim 5 , wherein each poly(ethylene glycol) has a molecular weight of from about 1,000 Daltons to about 60,000 Daltons.

7. The composition of claim 6 , wherein each poly(ethylene glycol) has a molecular weight of from about 2,000 Daltons to about 50,000 Daltons.

8. The composition of claim 1 , wherein the polymeric reagent has the following structure:

when the branching moiety R 5 is

 and,
wherein:
(n) is 2 to 4000;
(g′) is 0, 1, 2 or 3;
(h) is 0, 1, 2 or 3;
(j) is 0 to 20
(p) is 1;
(q) is 1; and
Z is a reactive group suitable for reaction with an electrophile or nucleophile of a biologically active agent.

9. The composition of claim 1 , wherein the pharmacologically active agent is selected from the group consisting of erythropoietin, granulocyte-colony stimulating factor, interferon-α, human growth hormone, interferon-β, follicle stimulating hormone, Factor VIII, B-domain delated Factor VIII, desmopressin and amdoxivir.

10. The composition of claim 1 , wherein each R 1 is an organic radical and is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl and substituted aryl.

11. The composition of claim 1 , wherein the polymeric reagent has as structure selected from the group consisting of

wherein each (m) is 2 to 4000.

12. The composition of claim 1 , wherein the polymeric reagent has a structure selected from the group consisting of

13. The composition of claim 1 , wherein the polymeric reagent has a structure selected from the group consisting of

wherein each (m) is 2 to 4000 and each (n) 0 to 20.

14. The composition of claim 1 , wherein the polymeric reagent has the following structure:

15. The composition of claim 1 , wherein the polymeric reagent has the following structure:

Assignees

• Nektar Therapeutics

Inventors

• Harris J Milton
• Kozlowski Antoni
• Mcmanus Samuel P
• Bentley Michael D
• Charles Stephen A

Classifications

• A61K31/4025

  not condensed and containing further heterocyclic rings, e.g. cromakalim · CPC title

• A61K31/357

  having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel · CPC title

• A61K38/212

  IFN-alpha · CPC title

• A61K38/24

  Follicle-stimulating hormone [FSH]; Chorionic gonadotropins, e.g. HCG; Luteinising hormone [LH]; Thyroid-stimulating hormone [TSH] · CPC title

• A61K47/60 Primary

  the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol · CPC title