Neuroprotective effect of solubilized UDCA in focal ischemic model

• US 20060051319A1
• Filed: 08/30/2005
• Published: 03/09/2006
• Est. Priority Date: 08/30/2004
• Status: Active Grant

• Current Assignee: Seo Hong Yoo
• Original Assignee: Seo Hong Yoo
• Inventors: Yoo, Seo Hong
• Granted Patent: US 8,173,627 B2
• Time in Patent Office: Days
• US Class Current: 424/85.100
• 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 31/4743 condensed with ring systems having sulfur as a ring hetero atom
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 31/553 having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
• CPC Class Codes: A61K 31/554 having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• 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 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• 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 31/723 Xanthans
• CPC Class Codes: A61K 31/727 Heparin; Heparan
• CPC Class Codes: A61K 35/413 Gall bladder; Bile
• CPC Class Codes: A61K 36/16 Ginkgophyta, e.g. Ginkgoaceae (Ginkgo family)
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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

Abstract

The present disclosure provides compositions and methods for treating, ameliorating, or relieving at least one symptom associated with loss of blood flow to the brain including, without limitation, ischemic stroke. Compositions of the disclosure may comprise a bile acid compound and a carbohydrate, wherein both materials remain in solution for all pH values of the solution within a selected range of pH values. Symptoms may include infarct volume, functional recovery, apoptosis, and/or eNOS expression.

Claims

1. A method of reducing infarction volume of an ischemic stroke in a subject having or at risk of having an ischemic stroke, said method comprising:

administering to the subject a composition comprising;

(a) a bile acid 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; and

(c) water,

wherein the bile acid material and the carbohydrate both remain in solution for all pH values of the solution within a selected range of pH values and wherein infarction volume is reduced.

7. A method according to any one of claims 1-6, wherein the composition further comprises at least one pharmaceutical in a pharmaceutically effective amount.

8. A method according to claim 7, wherein the pharmaceutical is selected from the group consisting of an anticoagulant, a fibrinolytic inhibitor, an antiplatelet compound, a calcium channel blocker, a corticosteroid, a ganglionic blocking agent, a hemopoietic growth factor, a hemostatic compound, a nitric oxide donor, a thrombolytic agent, a vasoactive agent, an oriental medicine, and an Individual compound.

9. A method according to claim 7, wherein the pharmaceutical is selected from the group consisting of anisindion, dicumarol, warfarin sodium, citrate dextrose solution, danaproid sodium, heparin sodium, aminocaproic acid, tranexamic acid, ticlopidine HCl, clopidogrel bisulfate, eptifibatide, tirofiban HCL, amlodipine salts, bepridil HCL, diltiazem HCL, felodipine, Nifedipine, betamethasone, dexamethasone, fludrocortisone, flunisolide, hydrocortisone, mecamylamine HCl, trimethaphan camsylate, erythropoietin, a granulocyte colony stimulating factor, microfibrillar collagen, absorbable gelatin, thrombin, L-arginine, nitric oxide synthase inhibitors, amciximab, alteplase, streptokinase, urokinase, diazoxide, hydralazine HCl, minoxidil, dan shen, dengzhanhua, didang tang, ginkgo biloba, lubeluzole, mannitol solution, naftidrofury, pentoxifylline, propentofylline, pentifylline piracetam, prostacyclin, puerarin, sanchi, theophylline, aminophylline, tirilazad, triflusal, and vinpocetin.

10. A method according to any one of claims 1-6, wherein the composition is a clear solution.

11. A method according to any one of claims 1-6, wherein the bile acid material is selected from the group consisting of ursodeoxycholic acid, chenodeoxycholic acid, cholic acid, hyodeoxycholic acid, deoxycholic acid, 7-oxolithocholic acid, lithocholic acid, iododeoxycholic acid, iocholic acid, tauroursodeoxycholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, taurolithocholic acid, glycoursodeoxycholic acid, taurocholic acid, glycocholic acid, and their derivatives at a hydroxyl or carboxylic acid group on the steroid nucleus.

12. A method according to claim 11, wherein the bile acid material is ursodeoxycholic acid.

13. A method according to claim 12, wherein the composition is a dried solubilized ursodeoxycholic acid formulation.

14. A method according to claim 12, wherein said administering is performed such that the subject receives from about 25 mg/kg to about 400 mg/kg ursodeoxycholic acid.

15. A method according to any one of claims 1-6, wherein the administering is during or after the ischemic stroke.

16. A method according to any one of claims 1-6, wherein the subject is a non-human mammal.

17. A method according to any one of claims 1-6, wherein the subject is a human.

18. A method according to any one of claims 1-6, wherein the composition is free of cyclodextrin.

19. A method according to any one of claims 1-6, wherein the administering comprises administering by a route selected from the group consisting of orally administering, sublingually administering, parenterally administering, intradermally injecting, subcutaneously injecting, intrathyroidally injecting, intravenously injecting, intranasally administering, transdermally administering, and transconjunctivally administering.

2. A method of enhancing functional recovery in a subject having or at risk of having an ischemic stroke, said method comprising:

administering to the subject a composition comprising;

(a) a bile acid 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; and

(c) water,

wherein the bile acid material and the carbohydrate both remain in solution for all pH values of the solution within a selected range of pH values and wherein functional recovery is improved.

3. A method of increasing the expression of eNOS in a subject having or at risk of having an ischemic stroke, said method comprising:

administering to the ischemic stroke subject a composition comprising;

(a) a bile acid 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; and

(c) water,

wherein the bile acid material and the carbohydrate both remain in solution for all pH values of the solution within a selected range of pH values and wherein eNOS expression is increased.

4. A method of inhibiting apoptosis and increasing the expression of eNOS in a subject having or at risk of having an ischemic stroke, said method comprising:

administering to the ischemic stroke subject a composition comprising;

(a) a bile acid 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; and

(c) water,

wherein the bile acid material and the carbohydrate both remain in solution for all pH values of the solution within a selected range of pH values and wherein apoptosis is reduced and eNOS expression is increased.

5. A method of treating at least one symptom of ischemic stroke in a subject having or at risk of having an ischemic stroke, said method comprising:

administering to the subject a composition comprising;

(a) a bile acid 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; and

(c) water,

wherein the bile acid material and the carbohydrate both remain in solution for all pH values of the solution within a selected range of pH values and wherein at least one symptom of ischemic stroke is treated.

6. A method of delivering a bile acid material to the brain in a subject comprising:

administering to the subject a composition comprising;

(a) a bile acid 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; and

(c) water,

wherein the bile acid material and the carbohydrate both remain in solution for all pH values of the solution within a selected range of pH values and wherein a bile acid material is delivered to the brain.