Compositions of a polyorthoester and an aprotic solvent

Patent metadata

Field	Value
Publication number	US-9446036-B2
Application number	US-201414213658-A
Country	US
Kind code	B2
Filing date	Mar 14, 2014
Priority date	Mar 15, 2013
Publication date	Sep 20, 2016
Grant date	Sep 20, 2016

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:
a polyorthoester represented by Formula III,

 in an amount ranging from about 60 weight percent to about 80 weight percent, where
A is R 1 or R 3 , and the fraction of A units that are of formula R 1 is between 10 and 25 mole percent,
R* is C2 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 2;
R 5 is H;
a solvent consisting essentially of one or more aprotic solvents in an amount between about 20-35 percent by weight of the delivery system and in which the polyorthoester is miscible to form a single liquid phase, wherein at least one of the one or more aprotic solvents is dimethyl sulfoxide, and
1-5 percent by weight granisetron dispersed or solubilized in the single liquid phase.

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 R 1 is about 20 mole percent.

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:

where
x is 2,
the total amount of p is an integer from 1-20, and the average number of the sum of both p repeat units is between 1 and 7,
s is 3,
and the fraction of α-hydroxy acid containing subunits in the polyorthoester is from about 10 to about 25 mole percent,
a solvent consisting essentially of one or more aprotic solvents in an amount between about 20-35 percent by weight of the delivery system and in which the polyorthoester is miscible to form a single liquid phase, wherein at least one of the one or more aprotic solvents is dimethyl sulfoxide, and
1-5 percent by weight granisetron dispersed or solubilized in the single liquid phase.

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 .

Assignees

• Heron Therapeutics Inc

Inventors

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

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

• A61K47/10

  Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers · CPC title