Compositions of a polyorthoester and an aprotic solvent

Patent metadata

Field	Value
Publication number	US-9744163-B2
Application number	US-201414210263-A
Country	US
Kind code	B2
Filing date	Mar 13, 2014
Priority date	Mar 15, 2013
Publication date	Aug 29, 2017
Grant date	Aug 29, 2017

Abstract

Delivery systems and compositions comprised of a biodegradable polyorthoester polymer, an aprotic solvent, and a drug are described. The solvent is selected to modulate release of drug from the composition, where, in some embodiments, the solvent is rapidly released after administration and provides a corresponding rapid rate of drug release. Alternatively, in other embodiments, the solvent is slowly released from the composition after its administration, and provides a correspondingly slow rate of drug release.

First claim

What is claimed is:

1. A delivery system, comprising:
(i) a polyorthoester represented by Formula III,

where
A is R 1 or R 3 ,
R* is C1-4 alkyl,
n ranges from 5 to 1000,
R 1 is:

p and q are integers that vary from between about 1 to 20 and the average number of p or the average of the sum of p and q is between 1 and 7;
R 3 and R 6 are each independently:

x is an integer of 0-10;
R 5 is H or methyl, and
the fraction of A units that are of formula R 1 is between 0 and 25 mole percent;
(ii) a solvent consisting essentially of one or more aprotic solvents, wherein at least one of the one or more aprotic solvents is selected from dimethyl sulfoxide, dimethyl acetamide, and N-methyl pyrrolidone, in which the polyorthoester is miscible to form a single phase; and
(iii) a therapeutically active agent dispersed or solubilized in the single phase.

2. The delivery system of claim 1 , wherein the solvent is an organic solvent having a water solubility of greater than 25% by weight of the solvent in water at room temperature.

3. The delivery system of claim 1 , wherein the solvent is a dipolar aprotic solvent having a dipole moment greater than 2 Debye.

4. The delivery system of claim 1 , wherein the solvent is dimethyl sulfoxide.

5. The delivery system of claim 1 , wherein the solvent is N-methyl pyrrolidone.

6. The delivery system of claim 1 , wherein the therapeutically active agent is an anti-emetic, a local anesthetic or an opioid.

7. The delivery system of claim 6 , wherein the therapeutically active agent is granisetron, ropivacaine, or bupivacaine.

8. The delivery system of claim 1 , wherein A is R 1 in 0 to 10% of the monomeric units of the polyorthoester.

9. The delivery system of claim 1 , wherein the active agent is granisetron in an amount between 1-5 percent by weight of the delivery system, and the solvent is DMSO in an amount between 10-35 percent by weight of the delivery system.

10. The delivery system of claim 1 , wherein the system is flowable, and the solvent has a dipole moment greater than 2 Debye (D).

11. The delivery system of claim 10 , wherein the therapeutically active agent is an anti-emetic, a local anesthetic or an opioid.

12. The delivery system of claim 11 , wherein the therapeutically active agent is granisetron, ropivacaine, or bupivacaine.

13. The delivery system of claim 10 , wherein A is R 1 in 0 to 10% of the monomeric units of the polyorthoester.

14. The delivery system of claim 10 , wherein the active agent is granisetron in an amount between 1-5 percent by weight of the composition, and the solvent is DMSO in an amount between 10-35 percent by weight of the composition.

15. The delivery system of claim 1 , wherein R 3 and R 6 are both —(CH 2 —CH 2 —O) 2 —(CH 2 —CH 2 )—; R 5 is hydrogen; and p is 1 or 2.

16. The delivery system of claim 1 , wherein the polyorthoester comprises subunits selected from

where
x is an integer from 1-4,
the total amount of p is an integer from 1-20, and
s is an integer from 1-4.

17. The delivery system of claim 1 , wherein the polyorthoester comprises alternating residues of 3,9-diethyl-3,9-2,4,8,10-tetraoxaspiro[5.5]undecane-3,9-diyl,

and a diol-ate residue of triethylene glycol or of triethylene glycol diglycolide, and comprises from about 0 to about 25 mole percent of glycolide-containing subunits.

18. The delivery system of claim 17 , wherein the polyorthoester has a molecular weight of 1,000 Da to 10,000 Da.

19. The delivery system of claim 1 , wherein the polyorthoester is prepared by reacting diketene acetal, 3,9-di(ethylidene)-2,4,8,10-tetraoxaspiro[5.5]undecane,

with triethylene glycol and triethylene glycol diglycolide.

20. The delivery system of claim 19 , wherein the polyorthoester comprises about 20 mole percent R 1 , where R 1 is triethylene glycol diglycolide, and 80 mole percent R 3 , where R 3 is triethylene glycol.

21. The delivery system of claim 1 , wherein the aprotic solvent is dimethyl acetamide.

Assignees

• Heron Therapeutics Inc

Inventors

• Ottoboni Thomas B
• Schillinger Lee Ann Lynn
• Niemann Joseph

Classifications

• A61P1/12

  Antidiarrhoeals · CPC title

• A61P23/02

  Local anaesthetics · CPC title

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title

• A61K9/08

  Solutions {(composition of solutions A61K47/00)} · CPC title

• A61K9/0024 Primary

  Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue (compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L) · CPC title