Compositions of a polyorthoester and an aprotic solvent

Patent metadata

Field	Value
Publication number	US-9592227-B2
Application number	US-201414210318-A
Country	US
Kind code	B2
Filing date	Mar 13, 2014
Priority date	Mar 15, 2013
Publication date	Mar 14, 2017
Grant date	Mar 14, 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 the structure shown as 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 liquid single phase; and
(iii) about 1-20 weight percent of a local anesthetic selected from the group consisting of bupivacaine, levobupivacaine, dibucaine, mepivacaine, procaine, lidocaine, tetracaine, and ropivacaine, and their pharmaceutically acceptable salts, dispersed or solubilized in the single phase.

2. The delivery system of claim 1 , wherein the anesthetic is dispersed in the single phase.

3. The delivery system of claim 1 , wherein the anesthetic is solubilized in the single phase.

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

5. The delivery system of claim 1 , wherein the aprotic solvent is selected from either dimethyl sulfoxide or N-methyl pyrrolidone.

6. The delivery system of claim 1 , wherein the local anesthetic is bupivacaine or ropivacaine.

7. The delivery system of claim 6 , wherein the local anesthetic is bupivacaine.

8. The delivery system of claim 6 , wherein the local anesthetic is ropivacaine.

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

10. The delivery system of claim 1 , where the polyorthoester has a molecular weight between about 1,000 and 10,000 daltons.

11. The delivery system of claim 1 , wherein the aprotic solvent is present in an amount between 10-60 percent by weight of the delivery system; and the local anesthetic is present in an amount between 2 and 5 percent by weight of the delivery system.

12. A method of administering a local anesthetic, comprising dispensing from a needle a delivery system of claim 1 .

13. A method of providing local anesthesia to a patient, comprising administering to a patient a delivery system of claim 1 , in an amount effective to prevent or reduce pain.

14. The method of claim 13 , wherein the administering comprises dispensing the delivery system from a needle.

15. The method of claim 13 , wherein the administering comprises injecting the delivery system in a region of tissue near a nerve, into an epidural space, as an intrathecal injection, around the periphery of a surgical site or wound or dispensing directly into a surgical site or wound.

16. The method of claim 13 , wherein the aprotic solvent comprised in the delivery system is N-methyl pyrrolidone.

17. The delivery system of claim 1 , wherein the aprotic solvent is present in an amount between 10-20 percent by weight of the delivery system.

18. The delivery system of claim 1 , having a viscosity suitable for delivery using an 18-26 gauge needle.

19. The delivery system of claim 1 , wherein the fraction of A units that are of formula R 1 is between 10 and 25 mole percent.

20. The delivery system of claim 19 , wherein the fraction of A units that are of formula R 1 is about 20 mole percent.

21. 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 or methyl; and p is 1 or 2.

22. 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.

23. The delivery system of claim 6 , effective to provide measurable plasma concentrations of the anesthetic for up to 6 days post-administration.

24. The delivery system of claim 1 , where the rate of solvent release from the system correlates with the rate of release of the local anesthetic.

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

Assignees

• Heron Therapeutics Inc

Inventors

• Ottoboni Thomas B
• Schillinger Lee Ann Lynn

Classifications

• A61P23/02

  Local anaesthetics · CPC title

• A61P1/12

  Antidiarrhoeals · 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

• A61K47/22

  Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones · CPC title