PHARMACEUTICAL COMPOSITIONS AND USE THEREOF

• US 20070249632A1
• Filed: 03/28/2007
• Published: 10/25/2007
• Est. Priority Date: 06/16/2005
• Status: Abandoned Application

• Current Assignee: Myrexis, Inc.
• Original Assignee: Myriad Genetics, Inc.
• Inventors: Shih, Chung, Zentner, Gaylen, McRea, James
• Application Number:
  US11/692,655
• Publication Number:
  US 20070249632A1
• Time in Patent Office: Days
• US Class Current: 514/258.100
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• 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 47/26 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 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: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• 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 relates to pharmaceutical compositions and dosage compositions of compounds, including injectable formulations for the parenteral delivery of such compounds into patients in need of such treatment. Also featured are methods of making and using the compositions, including methods for the treatment of neoplastic diseases.

Claims

1. A pharmaceutical composition, comprising:

a therapeutically effective amount of at least one compound having Formula I;

or a salt thereof wherein;

R₁ is chosen from OCH3, OCHF2, and OCH2CH3; and

R₂ is chosen from CH3, Cl, CH2F, and SCH3;

and one or more liquid diluents.

2. The pharmaceutical composition of claim 1, wherein one or more of the liquid diluents comprise one or more aqueous diluents.

3. The pharmaceutical composition of claim 2, wherein the at least one compound is in admixture with the one or more liquid diluents at amounts of from about 0.01 μ

g/ml to about 150 mg/ml.

4. The pharmaceutical composition of claim 2, wherein said aqueous diluents are chosen from:

water, saline solutions, Ringer'"'"'s solutions, lactated Ringer'"'"'s solutions, bicarbonate solutions, and aqueous dextrose solutions.

5. The pharmaceutical composition of claim 1, wherein one or more of said liquid diluents comprise one or more non-ionic surfactants.

6. The pharmaceutical composition of claim 5, wherein the weight to weight ratio between said at least one compound and said one or more liquid diluents is from about 1:

10,000 to about 1;

1.

7. The pharmaceutical composition of claim 5, wherein said one or more non-ionic surfactants are chosen from:

a polyethoxylated castor oil,

a polysorbate,

a sorbitan ester,

a polyoxyethylene fatty acid ester,

a polyoxyethylene alkyl ether,

a polyoxyethylene fatty acid ether, and

an ethoxylated fatty acid.

8. The pharmaceutical composition of claim 5, wherein one or more of said non-ionic surfactants is a polyethoxylated castor oil.

9. The pharmaceutical composition of claim 8, wherein the polyethoxylated castor oil is polyoxyl 35 castor oil.

10. The pharmaceutical composition of claim 9, wherein the weight to weight ratio between said at least one compound and said polyoxyl 35 castor oil is from about 1:

500 to about 1;

5.

11. The pharmaceutical composition of claim 5, wherein said one or more liquid diluents further comprise at least one viscosity reducing agent.

12. The pharmaceutical composition of claim 11, wherein the at least one viscosity reducing agent is chosen from C_1-5 alkanols, benzyl alcohol, and low molecular weight aliphatic mono carboxylic acids.

13. The pharmaceutical composition of claim 11, wherein at least one of the viscosity reducing agents is ethanol.

14. The pharmaceutical composition of claim 13, wherein the ratio of the at least one non-ionic surfactant to the at least one viscosity reducing agent is about 20:

1 to about 1;

10 (w/w).

15. The pharmaceutical composition of claim 5, further comprising one or more excipients.

16. The pharmaceutical composition of claim 15, wherein the one or more excipients are chosen from preservatives, antioxidants, pH adjusting agents, osmolarity adjusting agents, and stabilizers.

17. The pharmaceutical composition of claim 16, wherein at least one of the excipients is an antioxidant.

18. The pharmaceutical composition of claim 5 further comprising at least one aqueous diluent.

19. The pharmaceutical composition of claim 18, wherein the volume to volume ratio of the one or more non-ionic surfactants to the at least one aqueous diluent is 100:

1 to 1;

20,000.

20. The pharmaceutical composition of claim 19, wherein said ratio is from about 1:

50 to about 1;

5,000.

21. The pharmaceutical composition of claim 18, wherein the at least one aqueous diluent is chosen from water, saline solutions, Ringer'"'"'s solutions, lactated Ringer'"'"'s solutions, bicarbonate solutions, and aqueous dextrose solutions.

22. The pharmaceutical composition of claim 21, further comprising at least one viscosity reducing agent.

23. The pharmaceutical composition of claim 22, wherein the at least one viscosity reducing agent is chosen from C_1-5 alkanols, benzyl alcohol, and low molecular weight aliphatic mono carboxylic acids.

24. The pharmaceutical composition of claim 23, wherein the at least one viscosity reducing agent is ethanol.

25. The pharmaceutical composition of claim 23, further comprising one or more excipients.

26. The pharmaceutical composition of claim 25, wherein the one or more excipients are chosen from preservatives, antioxidants, pH adjusting agents, osmolarity adjusting agents, and stabilizers.

27. The pharmaceutical composition of claim 26, wherein one or more of the excipients is an antioxidant.

28. The pharmaceutical composition according to claim 27, wherein the compound of Formula I is chosen from:

(2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(2-Fluoromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(4-Methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine;

(4-Difluoromethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-(4-ethoxy-phenyl)-methylamine;

(4-Ethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(2-Methylthio-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine; and

pharmaceutically acceptable salts thereof.

29. A kit comprising the pharmaceutical composition of claim 1.

30. The kit of claim 29 wherein components of the pharmaceutical composition are provided together in a single container or compartment.

31. The kit of claim 29 wherein pre-treatment medicinal agents are optionally included.

32. The kit of claim 31 wherein the pre-treatment medicinal agents are chosen from antihistamines, anti-inflammatory steroids, and/or combinations thereof.

34. A method of treating diseases and disorders chosen from neoplastic diseases, cancers, disorders of the immune system, and diseases and disorders associated with the hyperproliferation of cells in mammals, comprising administering to a mammal in need of such treatment a pharmaceutical composition according to claim 1.

35. A dosage composition comprising a pharmaceutical composition according to claim 1 diluted in one or more liquid diluents.

38. A method of preparing the dosage composition of claim 35 comprising the steps of:

a. at least partially dissolving at least one compound of Formula I in one or more liquid diluents to form a pharmaceutical composition; and

b. diluting said pharmaceutical composition in one or more liquid diluents.

40. A method of treating diseases and disorders chosen from neoplastic diseases, cancers, disorders of the immune system, and diseases and disorders associated with the hyperproliferation of cells in mammals, comprising administering to a mammal in need of such treatment a pharmaceutical composition according to claim 1.

41. The use of claim 40, wherein the dosage composition is administered parenterally to a mammal in need thereof.

42. A kit comprising the dosage composition of claim 35.

43. The kit of claim 42 wherein components of the dosage composition are provided together in a single container or compartment.

44. The kit of claim 42 wherein pre-treatment medicinal agents are optionally included.

45. The kit of claim 44 wherein the pre-treatment medicinal agents are chosen from antihistamines, anti-inflammatory steroids, and/or combinations thereof.

33. (canceled)

36. A dosage composition suitable for parenteral administration to a mammal, comprising a therapeutically effective amount of at least one compound having Formula I:

or a salt thereof wherein;

R₁ is chosen from OCH3, OCHF2, and OCH2CH3; and

R₂ is chosen from CH3, Cl, CH2F, and SCH3;

in admixture with a liquid diluent comprising

polyoxyl 35 castor oil,

ethanol,

an antioxidant, and

an aqueous diluent selected from water, saline solutions, Ringer'"'"'s solutions, lactated Ringer'"'"'s solutions, bicarbonate solutions, and aqueous dextrose solutions, wherein the weight to weight ratio between said compound and said polyoxyl 35 castor oil is from about 1;

500 to about 1;

5, the weight to weight ratio between said polyoxyl 35 castor oil and said ethanol is from about 1;

10 to about 20;

1, and the volume to volume ratio between said polyoxyl 35 castor oil and said aqueous diluent is from about 1;

50 to about 1;

5,000.

37. The dosage composition according to claim 36, wherein the compound of Formula I is chosen from:

(2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(2-Fluoromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(4-Methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine;

(4-Difluoromethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-(4-ethoxy-phenyl)-methylamine;

(4-Ethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(2-Methylthio-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine; and

pharmaceutically acceptable salts thereof.

39. (canceled)