Vitamin E succinate stabilized pharmaceutical compositions, methods for the preparation and the use thereof

• US 8,470,873 B2
• Filed: 02/01/2007
• Issued: 06/25/2013
• Est. Priority Date: 02/01/2006
• Status: Active Grant

• Current Assignee: Latitude Pharmaceuticals Inc.
• Original Assignee: Mast Therapeutics, Inc. (Savara, Inc.)
• Inventors: Chen, Andrew Xian
• Primary Examiner(s): Boesen, Agnieszka
• Application Number:
  US11/702,014
• Publication Number:
  US 20070207173A1
• Time in Patent Office: 2,336 Days
• Field of Search: None
• US Class Current: 514/449
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/355 Tocopherols, e.g. vitamin E
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• 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 9/10 Dispersions; Emulsions A61K9/06 takes precedence; composition of dispersions, emulsions A61K47/00
• CPC Class Codes: A61K 9/107 Emulsions ; Emulsion preconcentrates; Micelles composition of emulsions 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
• CPC Class Codes: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/06 : Antiarrhythmics
• CPC Class Codes: A61P 9/12 : Antihypertensives

Abstract

The present invention provides vitamin E succinate (VES)-stabilized compositions, methods for the preparation thereof and methods useful for the in vivo delivery of substantially water insoluble and optionally chemically unstable pharmacologically active agents (such as docetaxel).

Claims

1. A vitamin E succinate (VES) stabilized oil-in-water emulsion comprising:

vitamin E succinate (VES) and

oil droplets in an aqueous medium, wherein the oil droplets comprise a substantial portion of a substantially water insoluble pharmacologically active agent, wherein the pharmacologically active agent in the emulsion consists of docetaxel;

wherein

the average diameter of the droplets being no greater than about 1 micron, wherein the emulsion is stabilized by a submicron suspension of vitamin E succinate (VES), and the emulsion has a zeta potential between −

20 mV and −

50 mV.

2. The emulsion according to claim 1, wherein the emulsion is sterilized by filtration.

3. The emulsion according to claim 1, wherein the oil droplets of the emulsion are liquid or are free of crystalline solid at ambient temperature, and wherein the pharmacologically active agent is substantially dissolved in the oil droplets.

4. The emulsion according to claim 1, prepared by a double homogenization method, comprising:

a. homogenizing VES in water to form a submicron VES suspension;

b. dissolving the substantially water insoluble pharmacologically active agent in an oil solution containing at least one injectable oil and at least one injectable phospholipid to form an oil phase;

c. combining the submicron VES suspension, the oil phase and optionally other pharmaceutically acceptable ingredients to form a mixture; and

d. homogenizing the mixture to produce the emulsion.

5. The emulsion of claim 1, comprising at least one injectable oil, injectable phospholipids and water, wherein the average diameter of the oil droplets is less than 200 nm, and the docetaxel-to-oil ratio is no less than 1:

50 by weight.

6. The emulsion according to claim 1, wherein

a. docetaxel is in a weight percentage concentration range of 0.1 to 1;

b. vitamin E succinate is in a weight percentage concentration range of 0.1 to 3;

c. the at least one injectable oil is a vegetable oil in a weight percentage concentration range of 1 to 10;

d. optionally, a medium chain triglyceride oil is in a weight percentage concentration range of 1 to 10;

e. a phospholipid is in a weight percentage concentration range of 1 to 20;

f. optionally, cholesterol is in a weight percentage concentration range of 0.01 to 5;

g. water is in a weight percentage concentration range of 40 to 90; and

h. the pH of the emulsion is about 5 to 9.

7. The emulsion according to claim 6, further comprising a bulking agent selected from dextrose, sucrose, lactose and a mixture thereof in a weight percentage concentration range of 5 to 50.

10. The emulsion according to claim 1, wherein the oil droplets comprise no less than about 70% of the substantially water insoluble pharmacologically active agent.

11. The emulsion according to claim 1, wherein the emulsion comprises VES in a weight percentage concentration range of 0.1 to 1.2.

12. The emulsion according to claim 1, comprising

a. docetaxel in a weight percentage concentration range of 0.1 to 1;

b. VES in a weight percentage concentration range of 0.2 to 1;

c. a vegetable oil in a weight percentage concentration range of 3 to 5;

d. a medium chain triglyceride oil in a weight percentage concentration range of 3 to 5;

e. a phospholipid in a weight percentage concentration range of 8 to 12;

f. cholesterol in a weight percentage concentration range of 0.4 to 0.8; and

g. water.

13. The emulsion according to claim 1, wherein the docetaxel is docetaxel trihydrate.

15. The emulsion according to claim 1, wherein:

a. docetaxel in a weight percentage concentration range of 0.1 to 1;

b. vitamin E succinate in a weight percentage concentration range of 0.1 to 3;

c. a vegetable oil in a weight percentage concentration range of 1 to 10;

d. a medium chain triglyceride oil in a weight percentage concentration range of 1 to 10;

e. a phospholipid in a weight percentage concentration range of 1 to 20;

f. cholesterol in a weight percentage concentration range of 0.01 to 5; and

g. water.

16. The stabilized emulsion according to claim 15, further comprising a bulking agent selected from the group consisting of dextrose, sucrose, lactose and a mixture thereof in a weight percentage concentration range of 5 to 50.

17. The stabilized emulsion according to claim 15, wherein the docetaxel is in a weight percentage of 0.6.

18. The stabilized emulsion according to claim 15, wherein the VES is in a weight percentage concentration range of 0.2 to 1.

19. The stabilized emulsion according to claim 15, wherein the vegetable oil is in a weight percentage concentration range of 3 to 5.

20. The stabilized emulsion according to claim 15, wherein the medium chain triglyceride oil is in a weight percentage concentration range of 3 to 5.

21. The stabilized emulsion according to claim 15, wherein the phospholipid is a weight percentage concentration range of 8 to 12.

22. The stabilized emulsion according to claim 15, wherein cholesterol in a weight percentage concentration range of 0.4 to 0.8.

23. The stabilized emulsion according to claim 15, wherein the docetaxel is docetaxel trihydrate.

24. The emulsion according to claim 1, wherein:

a. docetaxel in a weight percentage concentration range of 0.1 to 1;

b. VES in a weight percentage concentration range of 0.2 to 1;

c. a vegetable oil in a weight percentage concentration range of 3 to 5;

d. a medium chain triglyceride oil in a weight percentage concentration range of 3 to 5;

e. a phospholipid in a weight percentage concentration range of 8 to 12;

f. cholesterol in a weight percentage concentration range of 0.4 to 0.8; and

g. water.

25. The stabilized oil-in-water emulsion according to claim 24, wherein the docetaxel is docetaxel trihydrate.

26. The emulsion according to claim 1, wherein:

a. docetaxel in a weight percentage of 0.6;

b. vitamin E succinate in a weight percentage of 0.3;

c. a soybean oil in a weight percentage of 4;

d. a medium chain triglyceride oil in a weight percentage 4;

e. a phospholipid in a weight percentage of 10;

f. cholesterol in a weight percentage of 0.6; and

g. water.

27. The stabilized oil-in-water emulsion according to claim 26, wherein the docetaxel is docetaxel trihydrate.

8. A suspension, said suspension comprising:

vitamin E succinate (VES) and

submicron solid particles of an amorphous or crystalline pharmacologically active agent, wherein the pharmacologically active agent in the suspension consists of docetaxel;

wherein

the pharmacologically active agent is dispersed in an aqueous medium and stabilized by VES, wherein the solid particles are substantially free of liquid oil, have an average diameter of less than 200 nm and a zeta potential between −

20 mV and −

50 mV.

9. The suspension according to claim 8, wherein the suspension comprises:

docetaxel in a weight percentage concentration range of about 0.1 to about 1.0;

lecithin in a weight percentage concentration range of about 5 to about 15;

cholesterol in a weight percentage concentration range of about 0.5 to about 2;

VES in a weight percentage concentration range of about 0.1 to about 5;

a bulking agent selected from sucrose, dextrose, lactose, and a mixture thereof in a weight percentage concentration range of about 10 to about 20; and

water.

14. The suspension according to claim 8, wherein the docetaxel is docetaxel trihydrate.