Compositions of a polyorthoester and an aprotic solvent

• US 9,446,036 B2
• Filed: 03/14/2014
• Issued: 09/20/2016
• 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): BERRIOS, JENNIFER A
• Application Number:
  US14/213,658
• Publication Number:
  US 20140296282A1
• Time in Patent Office: 921 Days
• Field of Search: None
• US Class Current: 1/1
• 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 represented by Formula III,

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, comprising from about 20-30 percent by weight dimethyl sulfoxide.

4. The delivery system of claim 1, wherein the polyorthoester has a weight average molecular weight between 3,000 and 10,000.

5. The delivery system of claim 1, comprising from 2-5 percent by weight granisetron.

6. The delivery system of claim 5, comprising about 2 weight percent granisetron.

7. The delivery system of claim 1, wherein the fraction of A units in the polyorthoester that are of formula R¹ is about 20 mole percent.

9. 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.

10. The delivery system of claim 9, wherein the polyorthoester comprises 20 mole percent triethylene glycol diglycolide and 80 mole percent triethylene glycol.

11. The delivery system of claim 9, wherein the polyorthoester is prepared by reacting DETOSU, triethylene glycol, and triethylene glycol diglycolide in a 90:

80;

20 molar ratio.

12. The delivery system of claim 1, effective to provide measurable plasma concentrations of granisetron for at least about 5 days post-administration.

13. The delivery system of claim 1, effective to release granisetron over a period of about 7 days when measured in an in-vitro dissolution test at 37°

C.

14. A method of administering granisetron, comprising:

dispensing from a needle a delivery system according to claim 1.

8. A delivery system, comprising,

a polyorthoester in an amount ranging from about 60 weight percent to about 80 weight percent, the polyorthoester having a molecular weight in a range of about 1,000 Da to 10,000 Da and comprising subunits selected from: