COMPOSITIONS OF A POLYORTHOESTER AND AN APROTIC SOLVENT

• US 20140296282A1
• Filed: 03/14/2014
• Published: 10/02/2014
• Est. Priority Date: 03/15/2013
• Status: Active Grant

• Current Assignee: Heron Therapeutics Inc.
• Original Assignee: Heron Therapeutics Inc.
• Inventors: Ottoboni, Thomas B., Niemann, Joseph, Schillinger, Lee Ann Lynn
• Granted Patent: US 9,446,036 B2
• Time in Patent Office: Days
• US Class Current: 514/299
• CPC Class Codes: A61K 31/439 the ring forming part of a bridged ring system, e.g. quinuclidine 8-azabicyclo [3.2.1] octanes A61K31/46
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/4458 only substituted in position 2, e.g. methylphenidate
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• CPC Class Codes: A61K 47/20 containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 9/0019 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 Class Codes: A61K 9/0024 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 Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 23/02 Local anaesthetics

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.

Claims

1. A delivery system, comprising:

a polyorthoester;

an aprotic solvent in which the polyorthoester is miscible to form a single phase; and

a therapeutically active agent dispersed or solubilized in the single phase;

wherein the active agent is released from the system over a period of between approximately 1 day and approximately 8 weeks.

2. The delivery system of claim 1, wherein the delivery system has a viscosity of less than about 10,000 cP at 37°

C.

3. 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.

4. The delivery system of claim 1, wherein the solvent is a dipolar aprotic solvent.

5. The delivery system of claim 1, wherein the solvent is in a class selected from the group consisting of an amide, a biocompatible oil, an ester of an acid, an ester of an alcohol, an ether, a ketone, a sulfoxide, a triglyceride, and an ester of a triglyceride.

6. The delivery system of claim 5, wherein the solvent is an amide selected from the group consisting of 2-pyrrolidone, dimethyl formamide, n-methyl-2-pyrrolidone, n-ethyl-2-pyrrolidone, dimethyl acetamide, n-cyclohexyl-2-pyrrolidone and caprolactam.

7. The delivery system of claim 5, wherein the solvent is a biocompatible oil, excluding non-hydrogenated vegetable oils, partially-hydrogenated vegetable oils, peanut oil, sesame oil or sunflower oil.

8. The delivery system of claim 5, wherein the solvent is an ester of an acid selected from the group consisting of carboxylic acid esters and fatty acid esters, excluding propylene glycol dicaprate and propylene glycol dicaprylate.

9. The delivery system of claim 8, wherein the solvent is selected from the group consisting of ethyl acetate, benzyl benzoate, methyl acetate, isopropyl myristate, ethyl oleate, methyl lactate and ethyl lactate.

10. The delivery system of claim 5, wherein the solvent is an ester of an alcohol, propylene carbonate (4-methyl-1,3-diololan-2-one).

11. The delivery system of claim 5, wherein the solvent is an ether selected from dimethyl ether, dimethyl isosorbide and tetrahydrofuran.

12. The delivery system of claim 5, wherein the solvent is a ketone selected from the group consisting of acetone and methyl ethyl ketone.

13. The delivery system of claim 5, wherein the solvent is a lactone selected from the group consisting of ester-caprolactone and butyrolactone.

14. The delivery system of claim 5, wherein the solvent is a sulfoxide selected from the group consisting of dimethyl sulfoxide and decylmethylsulfoxide.

15. The delivery system of claim 5, wherein the solvent is 1-dodecylazacycloheptan-2-one.

16. The delivery system of claim 1, wherein the solvent is not propylene glycol dicaprate, propylene glycol dicaprylate, glycofurol, a non- or partially-hydrogenated vegetable oil, glyceryl caprylate, glyceryl captate, glyceryl caprylate/caprate, glyceryl 10 caprylate/caprate/laurate, poly(ethylene glycol-copolypropylene glycol, poly(ethylene glycol)monomethyl ether 550, poly(ethylene glycol)dimethyl ether 250, glycerine triacetate, or a triglyceride.

17. The delivery system of claim 1, wherein the therapeutically active agent is an anti-emetic.

18. The delivery system of claim 1, wherein the polyorthoester is represented by the structure shown as Formula III.

19. The delivery system of claim 1, wherein the polyorthoester is represented by the structure shown as Formula III, 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.

30. A method of administering a therapeutically active agent, comprising:

dispensing from a needle a delivery system according to claim 1 or a composition according to claim 20.

20. A flowable composition, comprising:

a polyorthoester;

a solvent in which the polyorthoester is miscible to form a single phase; and

a therapeutically active agent dispersed or solubilized in the single phase;

wherein the solvent is an aprotic solvent with a dipole moment greater than about 2 Debye (D).

21. The composition of claim 20, wherein the solvent is an ester of an alcohol, propylene carbonate (4-methyl-1,3-diololan-2-one).

22. The composition of claim 20, wherein the solvent is a ketone selected from the group consisting of acetone and methyl ethyl ketone.

23. The composition of claim 20, wherein the solvent an amide selected from the group consisting of 2-pyrrolidone, dimethyl formamide, n-methyl-2-pyrrolidone, and dimethyl acetamide.

24. The composition of claim 20, wherein the solvent is a sulfoxide selected from the group consisting of dimethyl sulfoxide and decylmethylsulfoxide.

25. The composition of claim 20, wherein the solvent is a lactone selected from the group consisting of ester-caprolactone and butyrolactone.

26. The composition of claim 20, wherein the therapeutically active agent is an anti-emetic.

27. The composition of claim 20, wherein the polyorthoester is represented by the structure shown as Formula III.

28. The composition of claim 20, wherein the composition has a viscosity of less than about 10,000 cP at 37°

C.

29. The composition of claim 20, wherein the polyorthoester is represented by the structure shown as Formula III, 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.

31. A method of treatment, comprising:

dispensing from a needle a composition comprised of a polyorthoester, an aprotic solvent in which the polyorthoester is miscible to form a single phase; and

a therapeutically active agent dispersed or solubilized in the single phase;

wherein the solvent is selected to achieve a controlled release of the active agent from the composition according to a predetermined release profile, and wherein the release of the active agent is for a period of between approximately 1 day and approximately 8 weeks.

32. The method of claim 31, wherein the solvent is selected to have a dipole moment greater than about 2 Debye (D).

33. The method of claim 31, wherein the composition has a viscosity of less than about 10,000 cP at 37°

C.

34. A delivery system, comprising:

a polyorthoester represented by the structure shown as Formula III;

an aprotic solvent in which the polyorthoester is miscible to form a single phase, wherein aprotic solvent is DMSO in an amount between 10-35 percent by weight of the delivery system; and

a therapeutically active agent dispersed or solubilized in the single phase, wherein the therapeutically active agent is granisetron in an amount between 1-5 percent by weight of the delivery system;

wherein the active agent is released from the delivery system over a period of between approximately 1 day and approximately 8 weeks.