Preparation of aqueous clear solution dosage forms with bile acids

• US 7,166,299 B2
• Filed: 12/04/2002
• Issued: 01/23/2007
• Est. Priority Date: 07/24/1998
• Status: Expired due to Fees

• Current Assignee: Seo Hong Yoo
• Original Assignee: Seo Hong Yoo
• Inventors: Yoo, Seo Hong
• Primary Examiner(s): KIM, VICKIE Y
• Application Number:
  US10/309,603
• Publication Number:
  US 20030186933A1
• Time in Patent Office: 1,511 Days
• Field of Search: 424/455, 424/456, 424/479
• US Class Current: 424/455
• 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 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/28 Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• 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 9/0056 Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• 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: A61K 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• 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 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

Compositions for pharmaceutical and other uses comprising clear aqueous solutions of bile acids which do not form any detectable precipitates over selected ranges of pH values of the aqueous solution and methods of making such solutions. The compositions of the invention comprise water; a bile acid in the form of a bile acid, bile acid salt, or a bile acid conjugated with an amine by an amide linkage; and either or both an aqueous soluble starch conversion product and an aqueous soluble non-starch polysaccharide. The composition remains in solution without forming a precipitate over a range of pH values and, according to one embodiment, remains in solution for all pH values obtainable in an aqueous system. The composition, according to some embodiments, may further contain a pharmaceutical compound in a pharmaceutically effective amount. Non-limiting examples of pharmaceutical compounds include insulin, heparin, bismuth compounds, amantadine and rimantadine.

Claims

1. A method for achieving a C_max (μ

g UDCA/mL) of from about 4.5 to about 20.4 with a T_max of less than about 30 minutes comprising;

(a) administration of a clear oral liquid dosage form comprising;

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

(ii) a second material selected from the group consisting of an aqueous soluble starch conversion product and/or an aqueous soluble non-starch polysaccharide; and

(iii) sodium hydroxide, and,

(iv) water,

wherein the first and second materials both remain in solution for all pH values of the solution within a selected range of pH values and wherein the molar ratio of the sodium hydroxide to the first material is from about 0.6 to about 1.2.

2. The method of claim 1 wherein the dosage form is selected from the group consisting of a syrup, a thick syrup, and a paste.

3. The method of claim 1 wherein the first material is selected from the group consisting of ursodeoxycholic acid, ursodeoxycholic acid derivatives at a hydroxyl or carboxylic acid group on the steroid nucleus, ursodeoxycholic acid salts, and ursodeoxycholic acid conjugates with amines.

4. The method of claim 1 wherein the second material is selected from the group consisting of maltodextrin, dextrin, corm syrup, corn syrup solid, soluble starch, and dextrans.

5. The method of claim 1 wherein the oral liquid dosage form comprises one or more additional bile acids, aqueous soluble derivatives of bile acid, bile acid salts, and amine-conjugated bile acids conjugated by an amide linkage.

6. The method of claim 1 wherein the oral liquid dosage form additionally comprises a least one additional agent.

7. The method of claim 1 wherein the additional agent is selected from the group consisting of guar gum, pectin, acacia, carrageenan, carboxymethyl cellulose sodium, hydroxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose, polyvinyl alcohol, povidone, tragacanth gum, xanthan gum, and sorbitan ester.

8. The method of claim 1 wherein the oral liquid dosage form additionally comprises at least one pharmaceutical in a pharmaceutically effective amount.

9. The method of claim 8 wherein the pharmaceutical compound is selected from the group consisting of octreotide, sildenafil citrate, calcitriol, dihydrotachysterol, apomorphine, yohimbine, trazadone, acyclovir, cidofovir, delavirdine-mesylate, didanosine, famciclovir, foscarmet sodium, fluorouracil, ganciclovir sodium, idoxuridine, interferon-α

, β

, γ

, lamivudine, nevirapine, penciclovir, ribavirin, stavudine, triflundine, valacyclovir-HCl, zalcitabine, zidovudine, indinavir-H₂SO₄, ritonavir, nelfinavir-CH₃SO₃H, saquinavir-CH₃SO₃H, d-penicillamine, chloroquine, hydroxychloroquine, aurothioglucose, gold sodium thiomalate, auranofin levamisole, dacarbazine, isoprinosine, methyl inosine monophosphate, muramyl dipeptide, diazoxide, hydralazine-HCl, and minoxidil.

19. The method of claim 8 wherein the pharmaceutical compound is selected from the group consisting of dipyridamole, isoxsuprine HCl, niacin, nylidrin-HCl, phentolamine, doxazosin-CH₃SO₃H, prazosin-HCl, terazocin-HCl, clonidine-HCl, nifedipine, molsidomine, amiodarone, acetylsalicylic acid, verapamil, diltiazem, nisoldipine, isradipine, bepridil, isosorbide-dinitrate, pentaerythrytol-tetranitrate, nitroglycerin, cimetidine, famotidine, nizatidine, ranitidine, lansoprazole, omeprazole, misoprostol, sucralfate, metoclopramide-HCl, erythromycin, alprostadil, albuterol, pirbuterol, terbutaline-H₂SO₄, salmetrol, aminophylline, dyphylline, ephedrine, ethylnorepinephrine, isoetharine, isoproterenol, metaproterenol, nedocromil, oxtriphylline, theophylline, bitolterol, fenoterol, budesonide, flunisolide, beclomethasone-dipropionate, fluticasone-propionate, codeine, codeine sulfate, and codeine phosphate.

20. The method of claim 8 wherein the pharmaceutical compound is selected from the group consisting of dextromethorphan HBr, triamcinolone-acetonide, montelukast sodium, zafirlukast, zileution, cromolyn sodium, ipratropium bromide, nedocromil sodium benzonate, diphenhydramine-HCl, hydrocodone-bitartarate, methadone-HCl, morphine sulfate, acetylcysteine, guaifenesin, ammonium carbonate, ammonium chloride, antimony potassium tartarate, glycerin, terpin-hydrate, colfosceril palmitate, atorvastatin-calcium, cervastatin-sodium, fluvastatin-sodium, lovastatin, pravastatin-sodium, simvastatin, picrorrhiza kurroa, andrographis paniculata, moringa oleifera, albizzia lebeck, adhatoda vasica, curcuma longa, momordica charantia, gymnema sylvestre, terminalia arjuna, azadirachta indica, tinosporia cordifolia, metronidazole, amphotericin B, clotrimazole, fluconazole, haloprogin, and ketoconazole.

21. The method of claim 8 wherein the pharmaceutical compound is selected from the group consisting of griseofulvin, itraconazole, terbinafin-HCl, econazole-HNO₃, miconazole, nystatin, oxiconazole-HNO₃, sulconazole-HNO₃, cetirizine-2HCl, dexamethasone, hydrocortisone, prednisolone, cortisone, catechin and its derivatives, glycyrrhizin, glycyrrhizic acid, betamethasone, fludrocortisone acetate, flunisolide, fluticasone-propionate, methyl prednisolone, somastostatin, lispro, glucagon, acarbose, chlorpropamide, glipizide, glyburide, metformin-HCl, repaglinide, tolbutamide, colchicine, sulfinpyrazone, allopurinol, piroxicam, tolmetin sodium, indomethacin, ibuprofen, diflunisal, mefenamic acid, naproxen, trientine, sulindac, sulindac sulfone, selenium compounds insuline, heparin, ampicillin, amantadine, rimantadine, proinsulin, celecoxib, budesonide, salicylic acid and its derivatives.

10. A method for achieving a C_max (μ

g GUDCA/mL) of from about 0.3 to about 1.6 with a T_max of less than about 3.5 hours comprising;

(a) administration of a clear oral liquid dosage form comprising;

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

(ii) a second material selected from the group consisting of an aqueous soluble starch conversion product and/or an aqueous soluble non-starch polysaccharide;

(iii) sodium hydroxide, and,

(iv) water,

wherein the first and second materials both remain in solution for all pH values of the solution within a selected range of pH values and wherein the molar ratio of the sodium hydroxide to the first material is from about 0.6 to about 1.2.

11. The method of claim 10 wherein the dosage form is selected from the group consisting of a syrup, a thick syrup, and a paste.

12. The method of claim 10 wherein the first material is selected from the group consisting of glycoursodeoxycholic acid, glycoursodeoxycholic acid derivatives at a hydroxyl or carboxylic acid group on the steroid nucleus, glycoursodeoxycholic acid salts, and glycoursodeoxycholic acid conjugates with amines.

13. The method of claim 10 wherein the second material is selected from the group consisting of maltodextrin, dextrin, com syrup, com syrup solid, soluble starch, and dextrans.

14. The method of claim 10 wherein the oral liquid dosage form comprises one or more additional bile acids, aqueous soluble derivatives of bile acid, bile acid salts, and amine-conjugated bile acids conjugated by an amide linkage.

15. The method of claim 10 wherein the oral liquid dosage form additionally comprises a least one additional agent.

16. The method of claim 15 wherein the additional agent is selected from the group consisting of guar gum, pectin, acacia, carrageenan, carboxymethyl cellulose sodium, hydroxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose, polyvinyl alcohol, povidone, tragacanth gum, xanthan gum, and sorbitan ester.

17. The method of claim 10 wherein the oral liquid dosage form additionally comprises at least one pharmaceutical in a pharmaceutically effective amount.

18. The method of claim 17 wherein the pharmaceutical compound is selected from the group consisting of octreotide, sildenafil citrate, calcitriol, dihydrotachysterol, apomorphine, yohimbine, trazadone, acyclovir, cidofovir, delavirdine-mesylate, didanosine, famciclovir, foscarmet sodium, fluorouracil, ganciclovir sodium, idoxuridine, interferon-α

, β

, γ

, lamivudine, nevirapine, penciclovir, ribavirin, stavudine, triflundine, valacyclovir-HCl, zalcitabine, zidovudine, indinavir-H₂SO₄, ritonavir, nelfinavir-CH₃SO₃H, saquinavir-CH₃SO₃H, d-penicillamine, chloroquine, hydroxychloroquine, aurothioglucose, gold sodium thiomalate, auranofin levamisole, dacarbazine, isoprinosine, methyl inosine monophosphate, muramyl dipeptide, diazoxide, hydralazine-HCl, and minoxidil.

22. The method of claim 17 wherein the pharmaceutical compound is selected from the group consisting of dipyridamole, isoxsuprine HCl, niacin, nylidrin-HCl, phentolamine, doxazosin-CH₃SO₃H, prazosin-HCl, terazocin-HCl, clonidine-HCl, nifedipine, molsidomine, amiodarone, acetylsalicylic acid, verapamil, diltiazem, nisoldipine, isradipine, bepridil, isosorbide-dinitrate, pentaerythrytol-tetranitrate nitroglycerin, cimetidine, famotidine, nizatidine, ranitidine, lansoprazole, omeprazole, misoprostol, sucralfate, metoclopramide-HCl, erythromycin, alprostadil, albuterol, pirbuterol, terbutaline-H₂SO₄, salmetrol, aminophylline, dyphylline, ephedrine, ethylnorepinephrine, isoetharine, isoproterenol, metaproterenol, nedocromil, oxtriphylline, theophylline, bitolterol, fenoterol, budesonide, flunisolide, beclomethasone-dipropionate, fluticasone-propionate, codeine, codeine sulfate, and codeine phosphate.

23. The method of claim 17 wherein the pharmaceutical compound is selected from the group consisting of dextromethorphan HBr, triamcinolone-acetonide, montelukast sodium, zafirlukast, zileution, cromolyn sodium, ipratropium bromide, nedocromil sodium benzonate, diphenhydramine-HCl, hydrocodone-bitartarate, methadone-HCl, morphine sulfate, acetylcysteine, guaifenesin, ammonium carbonate, ammonium chloride, antimony potassium tartarate, glycerin, terpin-hydrate, colfosceril palmitate, atorvastatin-calcium, cervastatin-sodium, fluvastatin-sodium, lovastatin, pravastatin-sodium, simvastatin, picrorrhiza kurroa, andrographis paniculata, moringa oleifera, albizzia lebeck, adhatoda vasica, curcuma longa, momordica charantia, gymnema sylvestre, terminalia arjuna, azadirachta indica, tinosporia cordifolia, metronidazole, amphotericin B, clotrimazole, fluconazole, haloprogin, and ketoconazole.

24. The method of claim 17 wherein the pharmaceutical compound is selected from the group consisting of griseofulvin, itraconazole, terbinafin-HCl, econazole-HNO₃, miconazole, nystatin, oxiconazole-HNO₃, sulconazole-HNO₃, cetirizine-2HCl, dexamethasone, hydrocortisone, prednisolone, cortisone, catechin and its derivatives, glycyrrhizin, glycyrrhizic acid, betamethasone, fludrocortisone acetate, flunisolide, fluticasone-propionate, methyl prednisolone, somastostatin, lispro, glucagon, acarbose, chlorpropamide, glipizide, glyburide, metformin-HCl, repaglinide, tolbutamide, colchicine, sulfinpyrazone, allopurinol, piroxicam, tolmetin sodium, indomethacin, ibuprofen, diflunisal, mefenamic acid, naproxen, trientine, sulindac, sulindac sulfone, selenium compounds insuline, heparin, ampicillin, amantadine, rimantadine, proinsulin, celecoxib, budesonide, salicylic acid and its derivatives.