METHODS FOR ENHANCING STABILITY OF POLYORTHOESTERS AND THEIR FORMULATIONS
Disclosed herein are methods of enhancing the stability of a sustained pharmaceutical composition comprising an active agent and a polymer and methods of preparing such pharmaceutical compositions with enhanced stability.
1 . A method of enhancing the stability of a sustained release pharmaceutical composition comprising an active agent and a polymer, wherein the method comprises heating the pharmaceutical composition at an elevated temperature for a sufficient period of time to provide a more stable pharmaceutical composition than that of the unheated pharmaceutical composition, when stored at room temperature.
2 . The method of claim 1 , wherein the heating of the pharmaceutical composition is performed under an inert gas.
3 . The method of claim 1 , wherein the heating of the pharmaceutical composition results in the reduction of water content from the composition.
4 . The method of claim 1 , wherein the heating of the pharmaceutical composition is performed above 50° C. for at least one hour.
5 . The method of claim 1 , wherein the heating of the pharmaceutical composition is performed above 50° C. for at least 3 hours.
6 . The method of claim 1 , wherein the heating of the pharmaceutical composition is performed at about 90° C. for at least 3 hours.
7 . The method of claim 1 , wherein the heating of the pharmaceutical composition is performed at 90° C. for 24 hours.
8 . The method of claim 1 , wherein the polymer is a bioerodible polymer, or a polymer that is susceptible to hydrolysis.
9 . The method of claim 1 , wherein the polymer is a polyorthoester.
10 . A method of enhancing the stability of a sustained release pharmaceutical composition comprising a polymer, wherein the method comprises heating the pharmaceutical composition at an elevated temperature for a sufficient period of time to provide a more stable pharmaceutical composition than that of the unheated pharmaceutical composition, when stored at room temperature.
11 . The method of claim 10 , wherein the polymer is a polyorthoester polymer, and the heating of the pharmaceutical composition is performed above 50° C. for at least 3 hours.
12 . A method of enhancing the stability of a sustained release pharmaceutical composition comprising an active agent and a polyorthoester polymer, wherein the method comprises treating the pharmaceutical composition under one or more of the following conditions: an elevated temperature, a sufficient period of time, an inert gas, and a reduced pressure.
13 . A method of preparing a sustained release pharmaceutical composition with enhanced stability wherein the method comprises treating the pharmaceutical composition under one or more of the following conditions: an elevated temperature, a sufficient period of time, an inert gas, and a reduced pressure, and wherein the pharmaceutical composition comprises an active agent and a polyorthoester polymer.
14 . The method of claim 1 , wherein the temperature is at least about 80° C.
15 . The method of claim 14 , wherein the elevated temperature is maintained for a period of time of at least 24 hours.
16 . The method of claim 15 , wherein after the treatment, the average molecular weight of the polymer is reduced.
17 . The method of claim 1 , wherein the polymer is selected from the group consisting of:
where:
R is a bond, —(CH 2 )a-, or —(CH 2 )b-O—(CH2)c-; where a is an integer of 1 to 10, and b and c are independently integers of 1 to 5;
R* is a C 1-4 alkyl;
R o , R″ and R′″ are each independently H or C 1-4 alkyl;
n is an integer of at least 5; and
A is R 1 , R 2 , R 3 , or R, where
R 1 is:
where:
p is an integer of 1 to 20;
R 5 is hydrogen or C 1-4 alkyl; and
R 6 is:
where:
s is an integer of 0 to 30;
t is an integer of 2 to 200; and
R 7 is hydrogen or C 1-4 alkyl;
R 2 is:
R 3 is:
where:
x is an integer of 0 to 100;
y is an integer of 2 to 200;
q is an integer of 2 to 20;
r is an integer of 1 to 20;
R 8 is hydrogen or C 1-4 alkyl;
R 9 and R 10 are independently C 1-12 alkylene;
R 11 is hydrogen or C 1-6 alkyl and R 12 is C 1-6 alkyl; or R 11 and R 12 together are C 3-10 alkylene; and
R 4 is the residue of a diol containing at least one functional group independently selected from amide, imide, urea, and urethane groups;
in which at least 0.01 mol percent of the A units are of the formula R 1 .
18 . The method of claim 1 , wherein the composition comprises granisetron, a semi-solid delivery vehicle and a pharmaceutically acceptable liquid excipient; wherein:
(A) the semi-solid delivery vehicle, comprises:
(i) a polyorthoester of formula I
where:
R* is a C 1-4 alkyl;
n is an integer of at least 5; and
A is R 1 , R 2 , R 3 , or R 4 , where
where:
p is an integer of 1 to 20;
R 5 is hydrogen or C 1-4 alkyl; and
R 6 is:
where:
or s is an integer of 0 to 30;
t is an integer of 2 to 200; and
R 7 is hydrogen or C 1-4 alkyl;
R 2 is:
R 3 is:
where:
x is an integer of 0 to 30;
y is an integer of 2 to 200;
R 8 is hydrogen or C 1-4 alkyl;
R 9 and R 10 are independently C 1-12 alkylene;
R 11 is hydrogen or C 1-6 alkyl and R 12 is alkyl; or R 11 and R 12 together are C 3-10 alkylene; and
R 4 is the residue of a diol containing at least one functional group independently selected from amide, imide, urea, and urethane groups;
in which at least 0.01 mol percent of the A units are of the formula R 1 ; and
(ii) a pharmaceutically acceptable, polyorthoester-compatible liquid excipient selected from polyethylene glycol ether derivatives having a molecular weight between 200 and 4000, polyethylene glycol copolymers having a molecular weight between 400 and 4000, mono-, di-, or tri-glycerides of a C 2-19 aliphatic carboxylic acid or a mixture of such acids, alkoxylated tetrahydrofurfuryl alcohols and their C 1-4 alkyl ethers and C 2-19 aliphatic carboxylic acid esters, and biocompatible oils.
19 . The method of claim 17 , wherein the pharmaceutical composition comprises:
(i) 2% granisetron;
(ii) 78.4 weight % of the polyorthoester of formula 1:
where:
R* is a C 2 alkyl;
n is an integer of at least 5; and
A is R 1 or R 3 where R 1 is:
where:
p is 2;
R 5 is hydrogen; and
R 6 is:
where:
s is 3; and
R 3 is:
where x is 3;
where the polyorthoester comprises 47.4 mole % DETOSU, 42.1 mole % TEG, and 10.5 mole % of the A units are of the formula R 1 and
(iii) a pharmaceutically acceptable, polyorthoester-compatible liquid excipient that is 19.6 weight % MPEG 550 (methoxy-polyethylene glycol, Mn 550).
20 . A stabilized pharmaceutical composition prepared by the method of claim 1 .