Salt form of a multi-arm polymer-drug conjugate

Patent metadata

Field	Value
Publication number	US-9226969-B2
Application number	US-201013510587-A
Country	US
Kind code	B2
Filing date	Nov 18, 2010
Priority date	Nov 18, 2009
Publication date	Jan 5, 2016
Grant date	Jan 5, 2016

Abstract

Among other aspects, provided herein is a hydrohalide salt of a multi-arm water-soluble polyethylene glycol-drug conjugate, along with related methods of making and using the same. The hydrohalide salt is stably formed, and appears to be more resistant to hydrolytic degradation than the corresponding free base form of the conjugate.

First claim

The invention claimed is:

1. A hydrohalide salt form of a polymer-active agent conjugate corresponding to structure (I):

wherein each n is an integer ranging from about 20 to about 500 and greater than 95 mole percent of irinotecan's basic nitrogen atoms are protonated in hydrohalide (HX) salt form, where X is selected from fluoride, chloride, bromide, and iodide.

2. The hydrohalide salt of claim 1 , wherein greater than 96 mole percent of irinotecan's basic nitrogen atoms are protonated in hydrohalide salt form.

3. The hydrohalide salt of claim 1 , wherein the hydrohalide salt is a hydrochloride salt.

4. The hydrochloride salt of claim 3 , wherein n is an integer ranging from about 80 to about 150.

5. A method for preparing a composition comprising a hydrohalide salt of a polymer-active agent conjugate corresponding to structure (I), the method comprising:

(i) treating glycine-irinotecan hydrohalide, where the amino group of glycine is in protected form, with a molar excess of hydrohalic acid to thereby remove the protecting group to form deprotected glycine-irinotecan hydrohalide,
(ii) coupling the deprotected glycine-irinotecan hydrohalide from step (i) with a polymer reagent bearing an active ester in the presence of a base to form 4-arm-pentaerythritolyl-polyethylene glycol-carboxymethyl-glycine-irinotecan hydrohalide salt, and
(iii) recovering the 4-arm-pentaerythritolyl-polyethylene glycol-carboxymethyl-glycine-irinotecan hydrohalide salt by precipitation.

6. The method of claim 5 , where the recovered 4-arm-pentaerythritolyl-polyethylene glycol-carboxymethyl-glycine-irinotecan hydrohalide possesses greater than 95 mole percent of irinotecan's basic nitrogen atoms in hydrohalide (HX) salt form.

7. The method of claim 5 , further comprising (iv) analyzing the recovered 4-arm-pentaerythritolyl-polyethylene glycol-carboxymethyl-glycine-irinotecan hydrohalide salt for halide content, and, in the event the halide content is less than 95 mole percent, (v) dissolving the recovered 4-arm-pentaerythritolyl-polyethylene glycol-carboxymethyl-glycine-irinotecan hydrohalide salt in ethyl acetate, and adding additional hydrohalic acid.

8. The method of claim 7 , wherein the hydrohalic acid is added in the form of an ethanol solution.

9. The method of claim 8 , wherein following the adding of additional hydrohalic acid in step (v), the 4-arm-pentaerythritolyl-polyethylene glycol-carboxymethyl-glycine-irinotecan hydrohalide salt is recovered by precipitation.

10. The method of claim 5 , wherein the glycine-irinotecan hydrohalide in protected form is treated with a ten-fold or greater molar excess of hydrohalic acid to thereby remove the protecting group to form glycine-irinotecan hydrohalide.

11. The method of claim 5 , wherein the glycine-irinotecan hydrohalide in protected form is ter-butyloxycarbonyl(Boc)-glycine-irinotecan hydrochloride, where the amino group of glycine is Boc-protected.

12. The method of claim 5 , wherein the glycine-irinotecan hydrohalide in step (i) is glycine-irinotecan hydrochloride in protected form, and the glycine-irinotecan hydrochloride in protected form is treated with hydrochloric acid to remove the protecting group.

13. The method of claim 5 , where step (i) further comprises isolating the glycine-irinotecan hydrohalide prior to step (ii).

14. The method of claim 13 , where the isolating of the glycine-irinotecan hydrohalide prior to step (ii) is by precipitation.

15. The method of claim 5 , where step (ii) is carried out in a chlorinated solvent.

16. A composition comprising a hydrohalide salt of 4-arm-pentaerythritolyl-polyethylene glycol-carboxymethyl-glycine-irinotecan prepared according to claim 5 .

17. A pharmaceutically acceptable composition comprising the hydrohalide salt of claim 1 and a pharmaceutically acceptable excipient.

18. The pharmaceutically acceptable composition of claim 17 comprising lactate buffer, in lyophilized form.

19. A method of treating cancer in a mammalian subject by administering a therapeutically effective amount of a pharmaceutically acceptable composition of claim 17 to a subject diagnosed as having one or more cancerous solid tumors over a duration of time effective to produce an inhibition of solid tumor growth in the subject.

20. The method of claim 19 , wherein the cancerous solid tumor is selected from the group consisting of colorectal, ovarian, cervical, breast and non-small cell lung.

21. The composition of claim 17 , wherein the polymer reagent bearing an active ester is obtainable from a method comprising: alkoxylating in a suitable solvent a previously isolated alkoxylatable oligomer to form an alkoxylated polymeric material, wherein the previously isolated alkoxylatable oligomer has a known and defined weight-average molecular weight of greater than 300 Daltons; modifying the alkoxylated polymeric material, in one or more steps, to bear an active ester, thereby forming a polymer reagent bearing an active ester.

22. The composition of claim 21 , wherein the polymer reagent bearing an active ester has the following structure:

wherein each n is from about 40 to about 500.

Assignees

• Chong Anthony O
• Lee Seoju
• Joshi Bhalchandra V
• Bray Brian
• Nie Shaoyong
• Spence Patrick L
• Kozlowski Antoni
• Mcmanus Samuel P
• Tipnis Sachin
• Swallow David
• Handley John R
• Schaefer Anthony G
• Nektar Therapeutics

Inventors

• Chong Anthony O
• Lee Seoju
• Joshi Bhalchandra V
• Bray Brian
• Nie Shaoyong
• Spence Patrick L
• Kozlowski Antoni
• Mcmanus Samuel P
• Tipnis Sachin
• Lavaty Greg
• Swallow David
• Handley John R
• Schaefer Anthony G

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P1/04

  for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants · CPC title

• A61P15/00

  Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• C07C51/412

  by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part · CPC title