PHARMACEUTICAL COMPOSITIONS

• US 20130245061A1
• Filed: 12/01/2011
• Published: 09/19/2013
• Est. Priority Date: 12/03/2010
• Status: Abandoned Application

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Li, Ping, Li, Shoufeng, Zhu, Jiahao, Cao, Yu, Hackl, Wolfgang, Mirza, Tahseen, Zehender, Hartmut
• Application Number:
  US13/989,250
• Publication Number:
  US 20130245061A1
• Time in Patent Office: Days
• US Class Current: 514/293
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1641 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

A pharmaceutical composition for the oral administration of a therapeutic compound of formula (I), comprising granules that comprise at least therapeutic compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt, or a hydrate or solvate thereof; at least one non-ionic surfactant that is Vitamin E-TPGS in an amount ranging from about 15 to about 80% by weight of the composition; and at least one a dissolution enhancing agent selected from polyethylene glycol, polyethylene oxide, and any combination of the foregoing; processes for making such pharmaceutical compositions; a kit comprising such pharmaceutical composition and the instructions for administration thereof; and related uses and methods of treatment.

Claims

1. A pharmaceutical composition comprising granules that comprise:

(a) a therapeutic compound of formula (I)

2. The pharmaceutical composition of claim 1, wherein the therapeutic compound of formula (I) is 2-Methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile or its monotosylate salt.

3. The pharmaceutical composition according to claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount ranging from about 30 to about 60% by weight based on the total weight of the composition.

4. The pharmaceutical composition according to claim 1, wherein the at least one non-ionic surfactant that is Vitamin E TPGS is present in an amount ranging from about 15 to about 45% by weight of the composition.

5. The pharmaceutical composition according to claim 1, wherein the at least one dissolution enhancing agent is present in an amount ranging from about 1 to about 15% by weight of the composition.

6. The pharmaceutical composition of claim 1, wherein the at least one dissolution enhancing agent is polyethylene glycol.

7. The pharmaceutical composition of claim 6, wherein the at least one dissolution enhancing agent is PEG3350.

8. The pharmaceutical composition according to claim 1, wherein the composition is formulated in an oral dosage form, preferably a capsule or a sachet.

9. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is a supersaturated system.

10. A process for making the pharmaceutical composition of claim 1 comprising the steps of (a) combining or mixing the therapeutic compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt, or a hydrate or solvate thereof, at least one non-ionic surfactant Vitamin E TPGS in an amount ranging from about 15 to about 80% of the composition, and at least one dissolution enhancing agent selected from the group consisting of polyethylene glycol (PEG), polyethylene oxide, and any combination of the foregoing, (b) granulating the mixture using an extruder or other suitable equipment while heating the mixture to a product temperature below the melting point of the Vitamin E TPGS;

and (c) cooling the granules to room temperature.

11. A process for making the pharmaceutical composition of claim 1 comprising the steps of:

(a) dividing the non-ionic surfactant Vitamin E TPGS into a first portion and a second portion, (b) combining or mixing the therapeutic compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt, or a hydrate or solvate thereof, the first portion of the non-ionic surfactant Vitamin E TPGS, and the dissolution enhancing agent selected from the group consisting of polyethylene glycol (PEG), polyethylene oxide, and any combination of the foregoing, (c) heating the second portion of the non-ionic surfactant Vitamin E TPGS, (d) granulating the mixture using an extruder or other suitable equipment while slowly adding the second portion of the non-ionic surfactant Vitamin E TPG to the mixture and maintaining a product temperature below about 38°

C., and (e) cooling the granules to room temperature.

16. A method of treatment of subject suffering from suffering from a proliferative disease or a mTOR kinase dependent disease comprising administering a therapeutically effective amount of a pharmaceutical composition according to claim 1 to a subject in need thereof.

17. A method according to claim 16, wherein the pharmaceutical composition is administered in an amount sufficient to provide to provide a AUC of about 200 to about 70,000 ng*h/mL of the compound of formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt, or a hydrate or solvate thereof, in the subject'"'"'s plasma.

18. A method according to claim 16, wherein the pharmaceutical composition is administered to said subject with food and wherein the administration of such pharmaceutical composition with food results in an increase in the bioavailability of the compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt, or a hydrate or solvate thereof, as compared to administration of the pharmaceutical composition to a subject without food.

12. (canceled)

13. (canceled)

14. A kit comprising (a) an oral pharmaceutical composition which comprises granules that comprise a therapeutic compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt, or a hydrate or solvate thereof, at least one non-ionic surfactant that is Vitamin E TPGS in an amount ranging from about 15 to 80% by weight of the composition and at least one dissolution enhancing agent selected from polyethylene glycol, polyethylene oxide, and any combination of the foregoing, and (b) written instructions, wherein such written instructions provide that such oral pharmaceutical composition may be taken between thirty minutes prior to the consumption of food until about two hours after the consumption of food.

15. (canceled)