Compositions of a polyorthoester and an aprotic solvent

• US 9,744,163 B2
• Filed: 03/13/2014
• Issued: 08/29/2017
• Est. Priority Date: 03/15/2013
• Status: Active Grant

• Current Assignee: Heron Therapeutics Inc.
• Original Assignee: Heron Therapeutics Inc.
• Inventors: Ottoboni, Thomas B., Schillinger, Lee Ann Lynn, Niemann, Joseph
• Primary Examiner(s): Sims, Jason
• Assistant Examiner(s): Bori, Ibrahim D
• Application Number:
  US14/210,263
• Publication Number:
  US 20140275046A1
• Time in Patent Office: 1,265 Days
• Field of Search: 514282, 514330, 5142265, 514279, 514299
• 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:

(i) a polyorthoester represented by Formula III,

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 R¹ 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 R¹ 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 R³ and R⁶ are both —

(CH₂—

CH₂—

O)₂—

(CH₂—

CH₂)—

;

R⁵ is hydrogen; and

p is 1 or 2.

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

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,

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,

20. The delivery system of claim 19, wherein the polyorthoester comprises about 20 mole percent R¹, where R¹ is triethylene glycol diglycolide, and 80 mole percent R³, where R³ is triethylene glycol.

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