Propofol formulation containing TRIS

• US 6,177,477 B1
• Filed: 03/24/1999
• Issued: 01/23/2001
• Est. Priority Date: 03/24/1999
• Status: Expired due to Fees

• Current Assignee: Faulding Pharmaceuticals Company
• Original Assignee: American Home Products Corporation (Pfizer Inc.)
• Inventors: Joyce, Martin A., George, Mary Mathew, Yuen, Pui-Ho
• Primary Examiner(s): Harrison, Robert H.
• Application Number:
  US09/275,145
• Time in Patent Office: 671 Days
• Field of Search: 514/731, 514/740, 514/762, 514/788, 514/816, 514/937, 514/938, 514/975
• US Class Current: 514/731
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/05 Phenols cannabinoids A61K31/658
• CPC Class Codes: A61K 31/13 Amines A61K31/04 takes precedence
• CPC Class Codes: A61K 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• CPC Class Codes: A61K 9/0019 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 Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence

Abstract

Sterile pharmaceutical compositions parenteral administration containing propofol in an oil-in-water emulsion additionally containing an amount of the preservative tromethamine sufficient to prevent signficant growth of microorganisms for at least 24 hours after extrinsic contamination.

Claims

1. A sterile pharmaceutical composition for parenteral administration which comprises an oil-in-water emulsion comprising propofol in a water immiscible solvent and an amount of tromethamine, said amounts being sufficient to prevent a no more than ten-fold increase in the growth of microorganisms for at least twenty-four hours after adventitious extrinsic contamination.

2. The sterile pharmaceutical composition of claim 1 comprising not more than about 0.25% by emulsion weight tromethamine.

3. The sterile pharmaceutical composition of claim 1 comprising from about 0.15 to about 0.25% by emulsion weight tromethamine.

4. The sterile pharmaceutical composition of claim 1 comprising not more than about 30% by emulsion weight of a water immiscible solvent.

5. The sterile pharmaceutical composition of claim 1 comprising from about 10% to about 20% by emulsion weight a water immiscible solvent.

6. The sterile pharmaceutical composition of claim 5 where the water immiscible solvent is vegetable oil or ester of a fatty acid.

7. The sterile pharmaceutical composition of claim 6 where the water immiscible solvent is soy bean oil.

8. The sterile pharmaceutical composition of claim 1 wherein the pH is about 8.5 to about 10.0.

9. The sterile pharmaceutical composition of claim 1 comprising about 1% to about 2% propofol.

10. The sterile pharmaceutical composition of claim 1 comprising about 1% propofol.

11. The sterile pharmaceutical composition of claim 1 comprising about 2% propofol.

12. The sterile pharmaceutical composition of claim 1 further comprising a surfactant.

13. The sterile pharmaceutical composition of claim 12 wherein the surfactant is a naturally occuring phosphatide.

14. The sterile pharmaceutical composition of claim 13 wherein the naturally occuring phosphatide is egg lecithin.

15. The sterile pharmaceutical composition of claim 12 wherein the surfactant is a non-naturally occuring phosphatide.

16. The sterile pharmaceutical composition of claim 1 which is isotonic with blood.

17. The sterile pharmaceutical composition of claim 16 which is isotonic with blood by incorporation of glycerin.

18. The sterile pharmaceutical composition of claim 1 wherein the microorganisms include at least Staphylococcus aureus ATCC 6538, Pseudomonas aeruginosa ATCC9027 and Candida albicans ATCC 10231.

19. A sterile pharmaceutical composition in the form of an oil-in-water emulsion comprising:

a) about 2% by weight of propofol;

b) about 10% by weight of soy bean oil;

c) about 1.2% by weight of egg lecithin;

d) about 2.25% by weight of glycerin;

e) about 0.2% by weight tromethamine;

f) sodium hydroxide qs;

g) water to 100%.

20. A sterile pharmaceutical composition in the form of an oil-in-water emulsion comprising:

a) about 1% by weight of propofol;

b) about 10% by weight of soy bean oil;

c) about 1.2% by weight of egg lecithin;

d) about 2.25% by weight of glycerin;

e) about 0.2% by weight tromethamine;

f) sodium hydroxide qs;

g) water to 100%.

21. A sterile intravenous fat emulsion comprising an amount of tromethamine sufficient to prevent an at least ten fold increase in growth of microorganisms for at least 24 hours after extrinsic contamination.

22. A method of preparing a sterile pharmaceutical composition for parenteral administration comprising the steps of:

a) providing an oil phase comprising a pharmaceutical and a water-immiscible solvent;

b) providing an aqueous phase comprising a surfactant;

c) homogenizing the oil phase and aqueous phases to provide a concentrated emulsion;

d) providing preservative in water;

e) homogenizing the concentrated emulsion with preservative in water to provide a final emulsion; and

f) sterilizing the final emulsion.

23. A method of limiting microbial growth in a sterile oil-in-water emulsion pharmaceutical composition following extrinsic contamination of said sterile composition comprising incorporating into said oil-in-water emulsion an amount of tromethamine sufficient to prevent an at least ten fold increase in the growth of microorganisms for at least twenty-four hours after extrinsic contamination.