TOLL-LIKE RECEPTOR AGONIST FORMULATIONS AND THEIR USE

• US 20100029585A1
• Filed: 07/31/2009
• Published: 02/04/2010
• Est. Priority Date: 08/01/2008
• Status: Active Grant

• Current Assignee: VentiRx Pharmaceuticals, Inc. (Bristol-Myers Squibb Company)
• Original Assignee: VentiRx Pharmaceuticals, Inc. (Bristol-Myers Squibb Company)
• Inventors: Duvvuri, Muralikrishna, Dietsch, Gregory, Hershberg, Robert, Howbert, J. Jeffry
• Granted Patent: US 8,242,106 B2
• Time in Patent Office: Days
• US Class Current: 514/58
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/724 Cyclodextrins
• CPC Class Codes: A61K 47/40 Cyclodextrins; Derivatives thereof
• CPC Class Codes: A61K 47/6951 using cyclodextrin cyclodextrins used as simple excipients A61K47/40
• 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 9/08 Solutions composition of solutions A61K47/00
• 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 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C07D 223/16 Benzazepines; Hydrogenated benzazepines
• CPC Class Codes: C08B 37/0012 Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention is directed generally to stable formulations of a TLR agonist preferably a TLR7 or a TLR8 agonist, for use in the treatment of cancer, preferably solid tumors and lymphomas. Specifically, the present invention is directed to stable formulations of up to 50 mg/ml of a TLR agonist which comprise a cyclodextrin.

Claims

1. A solid or liquid formulation of a Toll-like receptor (TLR) agonist comprising a cyclodextrin, wherein said agonist is a benzo[b]azepine compound that is an agonist of TLR7, TLR8, or both.

2. The formulation of claim 1, wherein the TLR agonist is selected from the group consisting of (1E, 4E)-ethyl 2-amino-8-(perfluoroethyl)-3H-benzo[b]azepine-4-carboxylate;

(1E, 4E)-2-amino-N,N-bis(2-methoxyethyl)-8-(perfluoroethyl)-3H-benzo[b]azepine-4-carboxamide;

(1E, 4E)-2-amino-N,N-diethyl-8-(perfluoroethyl)-3H-benzo[b]azepine-4-carboxamide;

(1E, 4E)-2-amino-8-(perfluoroethyl)-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide;

(1E, 4E)-2-amino-N-ethyl-8-(perfluoroethyl)-3H-benzo[b]azepine-4-carboxamide;

(1E, 4E)-2-amino-8-(perfluoroethyl)-N-propyl-3H-benzo[b]azepine-4-carboxamide;

(1E, 4E)-ethyl 2-amino-8-(pyrrolidine-1-carbonyl)-3H-benzo[b]azepine-4-carboxylate;

(1E, 4E)-ethyl 2-amino-8-(4-(methoxycarbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylate;

(1E, 4E)-ethyl 2-amino-8-(4-(methylcarbamoyl)phenyl)-3H-benzo[b]azepine-4-carboxylate;

(1E, 4E)-2-amino-N,N-dipropyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamide; and

pharmaceutically acceptable salts thereof.

3. The formulation of claim 2, wherein the TLR agonist is (1E, 4E)-2-amino-N,N-dipropyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamide, and pharmaceutically acceptable salts thereof.

4. The formulation of claim 1, wherein the cyclodextrin is a β

-cyclodextrin.

5. The formulation of claim 4, wherein the β

-cyclodextrin is sulfobutyl ether β

-cyclodextrin.

6. The formulation of claim 4, wherein the formulation comprises from about 1%-30% weight/volume of the β

-cyclodextrin.

7. The formulation of claim 6, wherein the formulation comprises from about 5%-15% weight/volume of the β

-cyclodextrin.

8. The formulation of claim 1, wherein the formulation is a liquid formulation and the TLR agonist is formulated at a concentration of from about 0.5 mg/ml to about 50 mg/ml.

9. The formulation of claim 8, wherein the agonist is formulated at a concentration of from about 1 mg/ml to about 40 mg/ml.

10. The formulation of claim 9, wherein the agonist is formulated at a concentration of from about 2 mg/ml to about 15 mg/ml.

11. The formulation of claim 1, wherein the pH of the formulation is acidic.

12. The formulation of claim 11, wherein the pH is about 6.5

13. The formulation of claim 1, wherein the formulation is a lyophilized formulation.

14. The formulation of claim 1, wherein the cyclodextrin is a β

-cyclodextrin.

15. The formulation of claim 14, wherein the β

-cyclodextrin is sulfobutyl ether β

-cyclodextrin.

16. A method for treating cancer in a subject comprising administering to the subject a TLR agonist formulation solubilized in a cyclodextrin, wherein the TLR agonist is selected from the group consisting of (1E, 4E)-ethyl 2-amino-8-(perfluoroethyl)-3H-benzo[b]azepine-4-carboxylate;

(1E, 4E)-2-amino-N,N-bis(2-methoxyethyl)-8-(perfluoroethyl)-3H-benzo[b]azepine-4-carboxamide;

(1E, 4E)-2-amino-N,N-diethyl-8-(perfluoroethyl)-3H-benzo[b]azepine-4-carboxamide;

(1E, 4E)-2-amino-8-(perfluoroethyl)-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide;

(1E, 4E)-2-amino-N-ethyl-8-(perfluoroethyl)-3H-benzo[b]azepine-4-carboxamide;

(1E, 4E)-2-amino-8-(perfluoroethyl)-N-propyl-3H-benzo[b]azepine-4-carboxamide;

(1E, 4E)-ethyl 2-amino-8-(pyrrolidine-1-carbonyl)-3H-benzo[b]azepine-4-carboxylate;

(1E, 4E)-ethyl 2-amino-8-(4-(methoxycarbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylate;

(1E, 4E)-ethyl 2-amino-8-(4-(methylcarbamoyl)phenyl)-3H-benzo[b]azepine-4-carboxylate;

(1E, 4E)-2-amino-N,N-dipropyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamide; and

pharmaceutically acceptable salts thereof.

17. The method of claim 16, wherein the TLR agonist is (1E, 4E)-2-amino-N,N-dipropyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamide, or a pharmaceutically acceptable salt thereof.

18. The method of claim 16, wherein the TLR agonist is formulated at a concentration of at least 2 mg/ml.

19. The method of claim 16, wherein the formulation is suitable for administration to the subject by injection.

20. The method of claim 16, wherein the TLR agonist is administered to the subject at weekly or biweekly intervals.

21. A method for treating an infectious disease in a subject comprising administering to the subject a TLR agonist formulation which contains a cyclodextrin.

22. A method for treating atopic dermatitis in a subject comprising administering to the subject a TLR agonist formulation which contains a cyclodextrin.

23. A pharmaceutical pack or kit comprising one or more containers filled with a liquid or lyophilized TLR agonist formulation, wherein the formulation comprises a cyclodextrin.

24. The pharmaceutical pack or kit of claim 23, wherein the TLR agonist is selected from the group consisting of (1E, 4E)-ethyl 2-amino-8-(perfluoroethyl)-3H-benzo[b]azepine-4-carboxylate;

(1E, 4E)-2-amino-N,N-bis(2-methoxyethyl)-8-(perfluoroethyl)-3H-benzo[b]azepine-4-carboxamide;

(1E, 4E)-2-amino-N,N-diethyl-8-(perfluoroethyl)-3H-benzo[b]azepine-4-carboxamide;

(1E, 4E)-2-amino-8-(perfluoroethyl)-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide;

(1E, 4E)-2-amino-N-ethyl-8-(perfluoroethyl)-3H-benzo[b]azepine-4-carboxamide;

(1E, 4E)-2-amino-8-(perfluoroethyl)-N-propyl-3H-benzo[b]azepine-4-carboxamide;

(1E, 4E)-ethyl 2-amino-8-(pyrrolidine-1-carbonyl)-3H-benzo[b]azepine-4-carboxylate;

(1E, 4E)-ethyl 2-amino-8-(4-(methoxycarbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylate;

(1E, 4E)-ethyl 2-amino-8-(4-(methylcarbamoyl)phenyl)-3H-benzo[b]azepine-4-carboxylate;

(1E, 4E)-2-amino-N,N-dipropyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamide; and

pharmaceutically acceptable salts thereof.

25. The pharmaceutical pack or kit of claim 23, wherein the TLR agonist is formulated at a concentration of at least 2 mg/ml and is suitable for administration by subcutaneous injection to a human subject.