Compositions of a polyorthoester and an aprotic solvent
View Patent ↗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.
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 .