Sustained release drug delivery systems with reduced impurities and related methods
The present disclosure relates to sustained release drug delivery systems. In some cases, a composition comprises an active pharmaceutical agent; at least one of sucrose acetate isobutyrate and a polyorthoester; an organic solvent; and 2,6-dimethylaniline, wherein the 2,6-dimethylaniline is present at a level less than 500 ppm. In some cases, a composition comprises N-oxide of active pharmaceutical agent at a level less than 1 wt %, based on weight of the composition. In some case, a composition comprises metal present at a level less than 5 ppm. Dosage forms and methods are also provided.
1. A pharmaceutical composition comprising:
bupivacaine free base present in the pharmaceutical composition in an amount ranging from 10 wt % to 15 wt %, based on weight of the pharmaceutical composition;
sucrose acetate isobutyrate present in the pharmaceutical composition in an amount ranging from 63 wt % to 67 wt %, based on weight of the pharmaceutical composition;
benzyl alcohol present in the pharmaceutical composition in an amount ranging from 20 wt % to 25 wt %, based on weight of the pharmaceutical composition;
benzyl acetate; and
2,6-dimethylaniline,
wherein the benzyl acetate is present in the pharmaceutical composition at a level less than 30 mg/mL,
wherein the 2,6-dimethylaniline is present in the pharmaceutical composition at a level less than 12 ppm, and
wherein the pharmaceutical composition is suitable for parenteral use in humans.
2. The pharmaceutical composition of claim 1 , wherein the 2,6-dimethylaniline is present in the pharmaceutical composition at a level less than or equal to 10 ppm.
3. The pharmaceutical composition of claim 1 , wherein the 2,6-dimethylaniline is present in the pharmaceutical composition at a level ranging from 0.3 ppm to 10 ppm.
4. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition further comprises bupivacaine N-oxide.
5. The pharmaceutical composition of claim 4 , wherein the bupivacaine N-oxide is present in the pharmaceutical composition at a level less than 1 wt %, based on weight of the pharmaceutical composition.
6. The pharmaceutical composition of claim 4 , wherein the bupivacaine N-oxide is present in the pharmaceutical composition at a level ranging from 0.01 wt % to 1 wt %, based on weight of the pharmaceutical composition.
7. The pharmaceutical composition of claim 1 , wherein the benzyl acetate is present in the pharmaceutical composition at a level ranging from 0.1 mg/mL to 20 mg/mL.
8. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition further comprises benzyl isobutyrate.
9. The pharmaceutical composition of claim 8 , wherein the benzyl isobutyrate is present in the pharmaceutical composition at a level ranging from 0.1 mg/mL to 40 mg/mL.
10. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is storage stable such that when the pharmaceutical composition is stored in a sealed, upright, clear glass vial at 25° C./60% RH for 36 months, the 2,6-dimethylaniline is present at a level of less than 12 ppm.
11. The pharmaceutical composition of claim 4 , wherein the pharmaceutical composition is storage stable such that when the pharmaceutical composition is stored in a sealed, upright, clear glass vial at 25° C./60% RH for 36 months, the bupivacaine N-oxide is present at a level of less than 1 wt %, based on weight of the pharmaceutical composition.
12. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is storage stable such that when the pharmaceutical composition is stored in a sealed, upright, clear glass vial at 25° C./60% RH for 36 months, the benzyl acetate is present at a level of less than 30 mg/mL.
13. The pharmaceutical composition of claim 8 , wherein the pharmaceutical composition is storage stable such that when the pharmaceutical composition is stored in a sealed, upright, clear glass vial at 25° C./60% RH for 36 months, the benzyl isobutyrate is present at a level of less than 50 mg/mL.
14. A dosage system comprising:
a container comprising a first inert material;
a closure capable of closing the container, the closure comprising a second inert material; and
the pharmaceutical composition of claim 1 contained within the container.
15. The dosage system of claim 14 , wherein the second inert material comprises a fluorinated polymer.
16. The dosage system of claim 14 , wherein the first inert material comprises glass that does not contain iron.
17. A dosage system comprising:
a first container;
a second container within the first container, the second container comprising a first inert material and the first container reduces ambient visible light from irradiating onto the second container; and
the pharmaceutical composition of claim 1 within the second container.
18. The dosage system of claim 17 , wherein the first container comprises a box.
19. A pharmaceutical composition comprising:
bupivacaine free base present in the pharmaceutical composition in an amount ranging from 10 wt % to 15 wt %, based on weight of the pharmaceutical composition;
sucrose acetate isobutyrate present in the pharmaceutical composition in an amount ranging from 63 wt % to 67 wt %, based on weight of the pharmaceutical composition;
benzyl alcohol present in the pharmaceutical composition in an amount ranging from 20 wt % to 25 wt %, based on weight of the pharmaceutical composition;
benzyl acetate; and
2,6-dimethylaniline,
wherein the benzyl acetate is present in the pharmaceutical composition at a level less than 30 mg/mL,
wherein the 2,6-dimethylaniline is present in the pharmaceutical composition at a level less than 12 ppm, and
wherein the pharmaceutical composition is sterile.
20. The pharmaceutical composition of claim 19 , wherein the 2,6-dimethylaniline is present in the pharmaceutical composition at a level less than or equal to 10 ppm.
21. The pharmaceutical composition of claim 19 , wherein the 2,6-dimethylaniline is present in the pharmaceutical composition at a level ranging from 0.3 ppm to 10 ppm.
22. The pharmaceutical composition of claim 19 , wherein the pharmaceutical composition further comprises bupivacaine N-oxide.
23. The pharmaceutical composition of claim 19 , wherein the pharmaceutical composition further comprises benzyl isobutyrate.
24. The pharmaceutical composition of claim 19 , wherein the pharmaceutical composition is storage stable such that when the pharmaceutical composition is stored in a sealed, upright, clear glass vial at 25° C./60% RH for 36 months, the 2,6-dimethylaniline is present at a level of less than 12 ppm.
25. The pharmaceutical composition of claim 22 , wherein the pharmaceutical composition is storage stable such that when the pharmaceutical composition is stored in a sealed, upright, clear glass vial at 25° C./60% RH for 36 months, the bupivacaine N-oxide is present at a level of less than 1 wt %, based on weight of the pharmaceutical composition.
26. The pharmaceutical composition of claim 19 , wherein the pharmaceutical composition is storage stable such that when the pharmaceutical composition is stored in a sealed, upright, clear glass vial at 25° C./60% RH for 36 months, the benzyl acetate is present at a level of less than 30 mg/mL.
27. The pharmaceutical composition of claim 23 , wherein the pharmaceutical composition is storage stable such that when the pharmaceutical composition is stored in a sealed, upright, clear glass vial at 25° C./60% RH for 36 months, the benzyl isobutyrate is present at a level of less than 50 mg/mL.