Methods and compositions for reducing toxicity of a pharmaceutical compound

• US 20060089331A1
• Filed: 10/14/2005
• Published: 04/27/2006
• Est. Priority Date: 10/15/2004
• Status: Active Grant

• Current Assignee: Seo Hong Yoo
• Original Assignee: Seo Hong Yoo
• Inventors: Yoo, Seo Hong
• Granted Patent: US 7,772,220 B2
• Time in Patent Office: Days
• US Class Current: 514/58
• 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 31/575 substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
• CPC Class Codes: A61K 31/715 Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
• CPC Class Codes: A61K 31/718 Starch or degraded starch, e.g. amylose, amylopectin
• CPC Class Codes: A61K 35/413 Gall bladder; Bile
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/554 the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid
• CPC Class Codes: A61K 9/0095 Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• 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 3/06 Antihyperlipidemics
• 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 31/14 for RNA viruses
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present disclosure is related to clear aqueous solutions of one or more bile acids and either an aqueous soluble starch conversion product or a non-starch polysaccharide. Solutions of the disclosure may be administered to a subject in conjunction with a pharmaceutical compound having one or more toxic effects. In some embodiments, solutions of the disclosure are administered to a mammal in conjunction with a pharmaceutical compound associated with a peripherial neurotoxicity (e.g., cisplatin and/or suramin) to reduce or eliminate the neuropathic effect(s).

Claims

1. A method of ameliorating or eliminating a toxic effect of a pharmaceutical compound in a subject comprising:

administering to a subject a clear aqueous solution comprising;

(a) a first material selected from the group consisting of a bile acid, an aqueous soluble derivative of a bile acid, a bile acid salt, and a bile acid conjugated with an amine by an amide linkage;

(b) a carbohydrate selected from the group consisting of an aqueous soluble starch conversion product or an aqueous soluble non-starch polysaccharide;

(c) water, wherein the first material and the carbohydrate both remain in solution for all pH values of the solution within a selected range of pH values; and

administering a pharmaceutical compound that has a toxic effect in the subject.

2. The clear aqueous solution according to claim 1, wherein the toxic effect is a p53-mediated neuropathic effect.

3. The clear aqueous solution according to claim 1, wherein the toxic effect is axonal degeneration.

4. The method of claim 1, wherein the subject is a mammal.

5. The method of claim 1, wherein the subject is a human.

6. The method of claim 1, wherein the subject receives at least one dose of a pharmaceutical compound after said aqueous solution administration.

7. The method of claim 1, wherein said subject receives said pharmaceutical compound before said aqueous solution administration.

8. The method of claim 1, wherein said subject receives said pharmaceutical compound concurrently with said aqueous solution administration.

9. The method of claim 1, wherein the first material is selected from the group consisting of chenodeoxycholic acid, cholic acid, hyodeoxycholic acid, deoxycholic acid, 7-oxolithocholic acid, lithocholic acid, iododeoxycholic acid, iocholic acid, tauroursodeoxycholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, glycoursodeoxycholic acid, taurocholic acid, glycocholic acid, their derivatives at a hydroxyl or carboxylic acid group on the steroid nucleus, their salts, or their conjugates with amines.

10. The method of claim 1, wherein the first material is ursodeoxycholic acid or a sodium salt of ursodeoxycholic acid.

11. The method of claim 1, wherein the selected pH range is between approximately 1 and approximately 10 inclusive.

12. The method of claim 1, wherein the aqueous soluble starch conversion product is selected from the group consisting of maltodextrin, dextrin, liquid glucose, corn syrup solid, and soluble starch.

13. The method of claim 12, wherein the aqueous soluble starch conversion product is maltodextrin.

14. The method of claim 1, wherein the aqueous soluble non-starch polysaccharide is selected from the group consisting of dextran, guar gum, pectin, indigestible soluble fiber.

15. The method of claim 1, wherein the pharmaceutical compound is selected from the group consisting of a chemotherapeutic compound, an antineoplastic compound, an immunoactive compound, a hydroxymethyl glutaryl coenzyme A reductase inhibitor, a proteosome inhibitor, an antiretroviral agent, and combinations thereof.

16. The method of claim 1, wherein the pharmaceutical compound is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, suramin, bleomycin sulfate, azathioprine, azacitidine, busulfan, doxorubicin hydrochloride, paclitaxel, mitomycin, epothilone, colchicine, metronidazole, sapsone, misonidazole, sulfasalazine, disulfiram, nitrofurantoin, tacrolimus, nucleoside analogs, taxanes, gangliosides, vincristine, penicillamine, thalidomide, vidarabine, isoniazid, vincaalkaloids, amiodarone, perhexiline, leflunomide, bortezomib, Didanosine, Zalcitabine, Stavudine, Lamivudine, Prevastatin, lovastatin, simvastatin, fluvastatin, and rosuvastatin.

17. The method of claim 1, wherein the pharmaceutical compound is cisplatin.

18. A clear aqueous solution comprising:

(a) a first material selected from the group consisting of a bile acid, an aqueous soluble derivative of a bile acid, a bile acid salt, and a bile acid conjugated with an amine by an amide linkage;

(b) a carbohydrate selected from the group consisting of an aqueous soluble starch conversion product or an aqueous soluble non-starch polysaccharide;

(c) a pharmaceutically effective amount of a pharmaceutical compound; and

(d) water,

wherein the first material and the carbohydrate both remain in solution for all pH values of the solution within a selected range of pH values and wherein the pharmaceutical compound has a toxic effect when administered to a mammal.

19. The clear aqueous solution according to claim 18, wherein the toxic effect is a p53-mediated neuropathic effect.

20. The clear aqueous solution according to claim 18, wherein the toxic effect is axonal degeneration.

21. The clear aqueous solution of claim 18, wherein the first material is present in a neuroprotective amount.

22. The clear aqueous solution of claim 18, wherein the pharmaceutical compound remains in solution for all pH values within the selected range.

23. The clear aqueous solution of claim 18, wherein the first material is selected from the group consisting of chenodeoxycholic acid, cholic acid, hyodeoxycholic acid, deoxycholic acid, 7-oxolithocholic acid, lithocholic acid, iododeoxycholic acid, iocholic acid, tauroursodeoxycholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, glycoursodeoxycholic acid, taurocholic acid, glycocholic acid, their derivatives at a hydroxyl or carboxylic acid group on the steroid nucleus, their salts, or their conjugates with amines.

24. The clear aqueous solution of claim 18, wherein the first material is ursodeoxycholic acid or a sodium salt of ursodeoxycholic acid.

25. The clear aqueous solution of claim 18, wherein the selected pH range is between approximately 1 and approximately 10 inclusive.

26. The clear aqueous solution of claim 18, wherein the aqueous soluble starch conversion product is selected from the group consisting of maltodextrin, dextrin, liquid glucose, corn syrup solid, and soluble starch.

27. The clear aqueous solution of claim 26, wherein the aqueous soluble starch conversion product is maltodextrin.

28. The clear aqueous solution of claim 18, wherein the aqueous soluble non-starch polysaccharide is selected from the group consisting of dextran, guar gum, pectin, indigestible soluble fiber.

29. The clear aqueous solution of claim 18, wherein the pharmaceutical compound is selected from the group consisting of a chemotherapeutic compound, an antineoplastic compound, an immunoactive compound, a hydroxymethyl glutaryl coenzyme A reductase inhibitor, a proteosome inhibitor, an antiretroviral agent, and combinations thereof.

30. The clear aqueous solution of claim 18, wherein the pharmaceutical compound is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, suramin, bleomycin sulfate, azathioprine, azacitidine, busulfan, doxorubicin hydrochloride, paclitaxel, mitomycin, epothilone, colchicine, metronidazole, sapsone, misonidazole, sulfasalazine, disulfiram, nitrofurantoin, tacrolimus, nucleoside analogs, taxanes, gangliosides, vincristine, penicillamine, thalidomide, vidarabine, isoniazid, vincaalkaloids, amiodarone, perhexiline, leflunomide, bortezomib, Didanosine, Zalcitabine, Stavudine, Lamivudine, Prevastatin, lovastatin, simvastatin, fluvastatin, and rosuvastatin.

31. The clear aqueous solution of claim 18, wherein the pharmaceutical compound is cisplatin.

32. A method of reducing or eliminating the neuropathic effect of a pharmaceutical compound in a subject that has received or is likely to receive a pharmaceutical compound that has a neuropathic effect, said method comprising:

administering to a human a clear aqueous solution comprising;

(a) a first material selected from the group consisting of a bile acid, an aqueous soluble derivative of a bile acid, a bile acid salt, and a bile acid conjugated with an amine by an amide linkage;

(b) a carbohydrate selected from the group consisting of an aqueous soluble starch conversion product or an aqueous soluble non-starch polysaccharide;

(c) water,

wherein the first material and the carbohydrate both remain in solution for all pH values of the solution within a selected range of pH values.

33. The method of claim 32, wherein the pharmaceutical compound is selected from the group consisting of cisplatin and suramin.

34. A clear aqueous solution comprising:

(a) a first material selected from the group consisting of an aqueous soluble bile acid, a bile acid salt, and a bile acid conjugated with an amine by an amide linkage;

(b) an aqueous soluble hydrolytic product of starch;

(c) a pharmaceutically effective amount of a chemotherapeutic compound selected from the group consisting of cisplatin and suramin; and

(d) water,

wherein the first material and the aqueous soluble hydrolytic product of starch both remain in solution at all pH values from about pH 1 to about pH 14.