Process of making stable abuse-deterrent oral formulations
The present disclosure relates to cured pharmaceutical compositions designed to reduce the potential for improper administration of drugs that are subject to abuse, the process of curing such composition in order to improve the dissolution stability, method of using the same for treatment of pain.
1. A process comprising:
a. Preparing a mixture comprising:
(i) one or more drugs, one or more pharmaceutically acceptable waxes, and one or more pharmaceutically acceptable fatty acids, or
(ii) one or more drugs in the form of a fatty acid salt and one or more pharmaceutically acceptable waxes,
at a temperature sufficient to form a substantially homogeneous melt;
b. forming solid microparticles from the substantially homogeneous melt;
c. optionally further formulating the solid microparticles with additional pharmaceutically acceptable excipients, and
d. curing the solid microparticles or formulated microparticles at a temperature within the range of 25° C. up to and including the inversion temperature, for a minimum of about 48 hours.
2. The process of claim 1 , wherein the cured formulated microparticles exhibit less change in the dissolution profile after storage for 6 months at 25° C. and 60% RH than otherwise identical uncured formulated microparticles after storage for 6 months at 25° C. and 60% RH,
wherein dissolution is conducted at 100 RPM using USP Apparatus I in 900 mL of pH 4.5 sodium acetate buffer supplemented with 0.03% Tween 20 at 37° C.
3. The process of claim 1 , wherein the cured microparticles or cured formulated microparticles exhibit less than a 15% change in the mean percent drug released at the 4 hour dissolution time point after storage for 6 months at 25° C. and 60% RH, and
wherein dissolution is conducted using USP Apparatus I in pH 4.5 sodium acetate buffer supplemented with 0.03% Tween 20.
4. The process of claim 1 , wherein the cured microparticles or cured formulated microparticles exhibit less than a 10% change in the mean percent drug released at the 4 hour dissolution time point after storage for 6 months at 25° C. and 60% RH, and
wherein dissolution is conducted using USP Apparatus I in pH 4.5 sodium acetate buffer supplemented with 0.03% Tween 20.
5. The process of claim 1 , wherein the cured microparticles or cured formulated microparticles exhibit less than a 5% change in the mean percent drug released at the 4 hour dissolution time point after storage for 6 months at 25° C. and 60% RH, and
wherein dissolution is conducted using USP Apparatus I in pH 4.5 sodium acetate buffer supplemented with 0.03% Tween 20.
6. The process of claim 1 , wherein the cured microparticles or cured formulated microparticles exhibit less than a 2.5% change in the mean percent drug released at the 4 hour dissolution time point after storage for 6 months at 25° C. and 60% RH, and
wherein dissolution is conducted using USP Apparatus I in pH 4.5 sodium acetate buffer supplemented with 0.03% Tween 20.
7. The process of claim 1 , wherein the fatty acid is myristic acid, the drug is oxycodone, and the inversion temperature is approximately 36° C.
8. The process of claim 1 , wherein the fatty acid is stearic acid, the drug is oxycodone, and the inversion temperature is approximately 53° C.
9. The process of claim 1 , wherein the microparticles or formulated microparticles are cured at a first temperature above the inversion temperature and subsequently a second temperature below the inversion temperature.
10. A pharmaceutical composition prepared by the process of claim 1 .
11. A capsule comprising the pharmaceutical composition of claim 10 .
12. A pharmaceutical composition prepared by the process of claim 7 .
13. A capsule comprising the pharmaceutical composition of claim 12 .
14. Pharmaceutically acceptable solid microparticles or formulated microparticles comprising: a mixture prepared from a melt of one or more pharmaceutically acceptable waxes, one or more drugs or salts thereof with one or more fatty acids thereof, and a sufficient amount of the one or more fatty acids to provide said microparticles in substantially homogenous form, wherein said microparticles or formulated microparticles are cured at one or more temperatures within the range of 25° C. up to and including the inversion temperature, for a minimum of about 48 hour.
15. The pharmaceutically acceptable solid microparticles or formulated microparticles of claim 14 , wherein the fatty acid is myristic acid, and the drug is oxycodone.
16. A method of treating pain comprising administering the pharmaceutical composition of claim 12 to a patient in need thereof.
17. A method of treating pain comprising administering the capsule of claim 13 to a patient in need thereof.
18. A method of treating pain comprising administering the pharmaceutically acceptable microparticles or formulated microparticles of claim 14 to a patient in need thereof.
19. A method of treating pain comprising administering the pharmaceutically acceptable microparticles or formulated microparticles of claim 15 to a patient in need thereof.