Sustained release drug delivery systems with reduced impurities and related methods

Patent metadata

Field	Value
Publication number	US-11400019-B2
Application number	US-202117504913-A
Country	US
Kind code	B2
Filing date	Oct 19, 2021
Priority date	Jan 13, 2020
Publication date	Aug 2, 2022
Grant date	Aug 2, 2022

Abstract

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.

First claim

What is claimed is:

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.

Assignees

• Durect Corp

Inventors

• Miksztal Andrew R
• Joice Judy
• Autio Susan
• Davis Mark P

Classifications

• A61K47/34

  Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers (A61K47/10 takes precedence) · CPC title

• A61K47/14

  Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters · CPC title

• A61K31/445 Primary

  Non condensed piperidines, e.g. piperocaine · CPC title

• A61K9/0019 Primary

  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

• A61K47/26

  Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin · CPC title