Biodegradable controlled release flash flow melt-spun delivery system

• US 5,518,730 A
• Filed: 06/03/1992
• Issued: 05/21/1996
• Est. Priority Date: 06/03/1992
• Status: Expired due to Term

• Current Assignee: Chantilly Biopharma, LLC
• Original Assignee: Fuisz Technologies Limited (Bausch Health Cos., Inc.)
• Inventors: Fuisz, Richard C.
• Primary Examiner(s): Webman, Edward J.
• Application Number:
  US07/893,238
• Time in Patent Office: 1,448 Days
• Field of Search: 424/426, 424/444, 424/452, 424/468, 425/9
• US Class Current: 424/426
• CPC Class Codes: A61K 9/70 Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug hollow drug-filled fibres A61K9/0092
• CPC Class Codes: A61L 17/005 containing a biologically active substance, e.g. a medicament or a biocide
• CPC Class Codes: A61L 2300/406 Antibiotics
• CPC Class Codes: A61L 2300/43 Hormones, e.g. dexamethasone
• CPC Class Codes: A61L 2300/604 Biodegradation
• CPC Class Codes: Y10S 424/13 Burn treatment
• CPC Class Codes: Y10S 424/15 Suppositories

Abstract

Biodegradable controlled release delivery systems using melt-spun biodegradable polymers as carriers for bio-effecting agents such as pharmaceutical actives are disclosed. Oral dosage forms as well as implants are described.

Claims

1. A biodegradable controlled release composition comprising a non-saccharide biodegradable polymer united with a bio-effecting agent formed by flash-flow melt-spin processing said polymer and said bio-effecting agent.

2. The composition of claim 1, wherein the polymer is selected from the group consisting of:

poly(glycolic acid), poly(lactic acid), polydioxanes, polyoxalates, poly(α

-esters), polycarbonates, polyanhydrides, polyacetals, polycaprolactones, poly(orthoesters), polyamino acids, polyurethanes, polyiminocarbonates, polyamides, poly(alkyl cyanoacrylates), sebacic acid, polyethylene glycol, polyphosphazene, bis(p-carboxyphenoxy)propane, bis(p-carboxyphenoxy)methane copolymers thereof and mixtures thereof.

3. The composition of claim 2, wherein the bio-effecting agent is useful in the prophylactic or therapeutic treatment of an animal.

4. The composition of claim 3, wherein the bio-effecting agent is selected from the group consisting of angiotensin converting enzyme inhibitors, anti-asthmatics, anti-cholesterolemics, anti-convulsants, anti-depressants, anti-diarrhea preparations, anti-infectives, anti-inflammatory agents, anti-nauseants, anti-stroke agents, anti-tumor drugs, anti-tussives, anti-uricemic drugs, amino-acid preparations, antiemetics, antiobesity drugs, antiparasitics, antipyretics, appetite stimulants, cerebral dilators, chelating agents, cholecystokinin antagonists, cognition activators, deodorants, dermatological agents, diabetes agents, diuretics, erythropoietic drugs, fertility agents, synthetic hormones, laxatives, mineral supplements, neuroleptics, neuromuscular agents, peripheral vaso-dilators, prostaglandins, vaginal preparations, vaso-constrictors and vertigo agents.

5. The composition of claim 4, wherein the bio-effecting agent is selected from the group consisting of acetaminophen, acetic acid, acetylsalicylic acid, buffered acetylsalicylic acid, albuterol, albuterol sulfate, ethanol isopropanol, allantoin, aloe, aluminum acetate, aluminum carbonate, aluminum chlorohydrate, aluminum hydroxide, alprozolam, amino acids, aminobenzoic acid, amoxicillin, ampicillin, amsacrine, amsalog, anethole, aspartame, atenolol, bacitracin, balsam peru, beclomethasone dipropionate, benzocaine, benzoic acid, benzophenones, benzoyl peroxide, biotin, bisacodyl, bornyl acetate, bromopheniramine maleate, buspirone, caffeine, calamine, calcium, calcium carbonate, calcium casinate, calcium hydroxide, camphor, captopril, cascara sagrada, castor oil, cefaclor, cefadroxil, cephalexin, cetylalcohol, cetylpyridinium chloride, chelated minerals, chloramphenicol, chlorcyclizine hydrochloride, chlorhexidine gluconate, chloroxylenol, chloropentostatin, chlorpheniramine maleate, cholestyramine resin, choline bitartrate, cimetidine hydrochloride, cinnamedrine hydrochloride, citalopram, citric acid, cocoa butter, cod liver oil, codeine and codeine phosphate, clonidine, clonidine hydrochloride, clorfibrate, ciprofloxacin HCl, cyanocobalamin, cyclizine hydrochloride, danthron, dexbrompheniranime maleate, dextromethorphan hydrobromide, diazapam, dibucaine, diclofenac sodium, digoxin, diltiazem, dimethicone, dioxybenzone, diphenhydramine citrate, diphenhydramine hydrochloride, docusate calicum, docusate potassium, docusate sodium, doxycycline hyclate, doxylamine succinate, efaroxan, enalapril, enoxacin, erythromycin, estropipate, ethinyl estradiol, ephedrine, epinephrine bitartrate, erythropoietin, eucalyptol, ferrous fumarate, ferrous gluconate, ferrous sulfate, folic acid, fosphenytoin, fluoxetine HCl, furosemide, gabapentan, gentamicin, gemfibrozil, glipizide, glycerin, glyceryl stearate, griseofulvin, guaifenesin, hexylresorcinol, hydrochlorothiaxide, hydrocodone bitartrate, hydrocortisone, hydrocortisone acetate, 8-hydroxyquinoline sulfate, ibuprofen, indomethacin, inositol, insulin, iodine, ipecac, iron, isoxicam, ketamine, koalin, lactic acid, lanolin, lecithin, lidocaine, lidocaine hydrochloride, lifinopril, liotrix, lovastatin, magnesium carbonate, magnesium hydroxide, magnesium salicylate, magnesium trisilocate, mefenamic acid, meclofenanic acid, meclofenamate sodium, medroxyprogesterone acetate, methenamine mandelate, menthol, meperidine hydrochloride, metaproterenol sulfate, methyl nicotinate, methyl salicylate, methylcellulose, methsuximide, metromidazole, metromidazole hydrochloride, metoprolol tartrate, miconazole nitrate, mineral oil, minoxidil, morphine, naproxen, naproxen sodium, nifedipine, neomycin sulfate, niacin, niacinamide, nicotine, nicotinamide, nitroglycerin, nonoxynol-9, norethindone, norethindone acetate, nystatin, octoxynol, octyl dimethyl PABA, octyl methoxycinnamate, omega-3 polyunsaturated fatty acids, omeprazole, oxolinic acid, oxybenzone, oxtriphylline, para-aminobenzoic acid (PABA), padimate O, paramethadione, pentastatin, peppermint oil, pentaerythriol tetranitrate, pentobarbital sodium, pheniramine maleate, phenobarbital, phenol, phenolphthalein, phenylephrine hydrochloride, phenylpropanolamine, phenylpropanolamine hydrochloride, phenytoin, phenelzine sulfate, pirmenol, piroxicam, polymycin B sulfate, potassium chloride, potassium nitrate, prazepam, procainamide hydrochloride, procaterol, propoxyphene, propoxyphene HCl, propoxyphene napsylate, pramiracetin, pramoxine, pramoxine hydrochloride, propronolol HCl, pseudoephedrine hydrochloride, pseudoephedrine sulfate, pyridoxine, quinapril, quinidine gluconate, quinestrol, ralitoline, ranitadine, resorcinol, riboflavin, salicylic acid, sesame oil, shark liver oil, simethicone, sodium bicarbonate, sodium citrate, sodium fluoride, sodium monofluorophosphate, sulfanethoxazole, sulfur, tacrine, tacrine HCl, theophylline, terfenidine, thioperidone, trimetrexate, triazolam, timolol maleate, tretinoin, tetracycline hydrochloride, tolmetin, tolnaftate, triclosan, triprolidine hydrochloride, undecylenic acid, vancomycin, verapamil HCl, vidaribine phosphate, vitamin A, vitamin B, vitamin C, vitamin D, vitamin E, vitamin K, witch hazel, xylometazoline hydrochloride, zinc, zinc sulfate, and zinc undecylenate.

6. The composition of claim 3 wherein the bioeffecting agent is selected from the group consisting of ache drugs, alkaloids, anti-spasmodics, anticoagulants, contraceptives and hyperglycemic agents.

7. The composition of claim 3 in an oral dosage form.

8. The composition of claim 3 in an implantable dosage form.

9. The composition of claim 3 in a wound treatment dosage form.

26. The composition of claim 3, wherein the bio-effecting agent is selected from the group consisting of anti-histamines, anti-manics, anti-viral agents, anesthetics, antacids, anti-arthritics, anti-biotics, anti-psychotics, anti-spasmodics, anxiolytic agents, appetite suppressants, cardiovascular agents, cough suppressants, emollients, gastro-intestinal agents, growth regulators, hypoglycemic agents, respiratory stimulants, and vitamins.

10. A controlled release flash-flow melt-spun composition comprising:

(a) a non-saccharide biodegradable polymer for physically protecting an active agent past the stomach and releasing the active agent in the small intestine; and

(b) a bio-effecting agent united with said polymer.

11. The composition of claim 10, wherein the polymer is selected from the group consisting of:

poly(glycolic acid), poly(lactic acid), polydioxanes, polyoxalates, poly(α

-esters), polycarbonates, polyanhydrides, polyacetals, polycaprolactones, poly(orthoesters), polyamino acids, polyurethanes, polyiminocarbonates, polyamide, poly(alkyl cyanoacrylates), sebacic acid, polyethylene glycol, polyphosphazene, bis(p-carboxyphenoxy)propane, bis(p-carboxyphenoxy)methane, copolymers thereof and mixtures thereof.

12. The composition of claim 10, wherein the bio-effecting agent is selected from the group consisting of peptides, antibiotics and mixtures thereof.

13. The composition of claim 12, wherein the bio-effecting agent is insulin.

14. A controlled release flash flow melt-spun composition for treatment of ruminants comprising:

a) a non-saccharide biodegradable polymer which is protective of an active in the environment of the rumen at pH of about 5 or more but which releases the active in environment of the abomasum at pH of about 3.5 or less; and

b) a bio-effecting active united with said polymer.

15. The composition of claim 14, wherein the active is a therapeutic, prophylactic or nutritive agent.

16. The composition of claim 14, wherein the active is selected from the group consisting of antibiotics, amino-acids, hormones and mixtures thereof.

17. A method of treating an animal comprising administering to said animal a flash flow melt-spun controlled release composition comprising a non-saccharide biodegradable polymer and a bio-effecting therapeutic or prophylactic active.

18. The method of claim 17, wherein the polymer is selected from the group consisting of:

poly(glycolic acid), poly(lactic acid), polydioxanes, polyoxalates, poly(α

-esters), polycarbonates, polyanhydrides, polyacetals, polycaprolactones, poly(orthoesters), polyamino acids, polyurethanes, polyiminocarbonates, polyamides, poly(alkyl cyanoscrylates), sebacic acid, polyethylene glycol, polyphosphazene, bis(p-carboxyphenoxy)propane, bis(p-carboxyphenoxy)methane copolymers thereof and mixtures thereof.

19. The composition of claim 17, wherein the bio-effecting agent is selected from the group consisting of acetaminophen, acetic acid, acetylsalicylic acid and its buffered form, albuterol, and albuterol sulfate, ethanol isopropanol, allantoin, aloe, aluminum acetate, aluminum carbonate, chlorohydrate, hydroxide, alprozolam, amino acids, aminobenzoic acid, amoxicillin, ampicillin, amsacrine, amsalog, anethole, aspartame, atenolol, bacitracin, balsam peru, beclomethasone dipropionate, benzocaine, benzoic acid, benzophenones, benzoyl peroxide, biotin, bisacodyl, bornyl acetate, bromopheniramine maleate, buspirone, caffeine, calamine, calcium, calcium carbonate, calcium casinate, calcium hydroxide, camphor, captopril, cascara sagrada, castor oil, cefaclor, cefadroxil, cephalexin, cetylalcohol, cetylpyridinium chloride, chelated minerals, chloramphenicol, chlorcyclizine hydrochloride, chlorhexidine gluconate, chloroxylenol, chloropentostatin, chlorpheniramine maleate, cholestyramine resin, choline bitartrate, cimetidine hydrochloride, cinnamedrine hydrochloride, citalopram, citric acid, cocoa butter, cod liver oil, codeine and codeine phosphate, clonidine, clonidine hydrochloride, clorfibrate, ciprofloxacin HCl, cyanocobalamin, cyclizine hydrochloride, danthron, dexbrompheniranime maleate, dextromethorphan hydrobromide, diazapam, dibucaine, diclofenac sodium, digoxin, diltiazem, dimethicone, dioxybenzone, diphenhydramine citrate, diphenhydramine hydrochloride, docusate calicum, docusate potassium, docusate sodium, doxycycline hyclate, doxylamine succinate, efaroxan, enalapril, enoxacin, erythromycin, estropipate, ethinyl estradiol, ephedrine, epinephrine bitartrate, erythropoietin, eucalyptol, ferrous fumarate, ferrous gluconate, ferrous sulfate, folic acid, fosphenytoin, fluoxetine HCl, furosemide, gabapentan, gentamicin, gemfibrozil, glipizide, glycerin, glyceryl stearate, griseofulvin, guaifenesin, hexylresorcinol, hydrochlorothiaxide, hydrocodone bitartrate, hydrocortisone, hydrocortisone acetate, 8-hydroxyquinoline sulfate, ibuprofen, indomethacin, inositol, insulin, iodine, ipecac, iron, isoxicam, ketamine, koalin, lactic acid, lanolin, lecithin, lidocaine, lidocaine hydrochloride, lifinopril, liotrix, lovastatin, magnesium carbonate, magnesium hydroxide, salicylate, magnesium trisilocate, mefenamic acid, meclofenanic acid, meclofenamate sodium, medroxyprogesterone acetate, methenamine mandelate, menthol, meperidine hydrochloride, metaproterenol sulfate, methyl nicotinate, methyl salicylate, methylcellulose, methsuximide, metromidazole, metromidazole hydrochloride, metoprolol tartrate, miconazole nitrate, mineral oil, minoxidil, morphine, naproxen, naproxen sodium, nifedipine, neomycin sulfate, niacin, niacinamide, nicotine, nicotinamide, nitroglycerin, nonoxynol-9, norethindone, norethindone acetate, nystatin, octoxynol, octyl dimethyl PABA, octyl methoxycinnamate, omega-3 polyunsaturated fatty acids, omeprazole, oxolinic acid, oxybenzone, oxtriphylline, para-aminobenzoic acid (PABA), padimate O, paramethadione, pentastatin, peppermint oil, pentaerythriol tetranitrate, pentobarbital sodium, pheniramine maleate, phenobarbital, phenol, phenolphthalein, phenylephrine hydrochloride, phenylpropanolamine, phenylpropanolamine hydrochloride, phenytoin, phenelzine sulfate, pirmenol, piroxicam, polymycin B sulfate, potassium chloride, potassium nitrate, prazepam, procainamide hydrochloride, procaterol, propoxyphene, propoxyphene HCl, propoxyphene napsylate, pramiracetin, pramoxine, pramoxine hydrochloride, propronolol HCl, pseudoephedrine hydrochloride, pseudoephedrine sulfate, pyridoxine, quinapril, quinidine gluconate, quinestrol, ralitoline, ranitadine, resorcinol, riboflavin, salicylic acid, sesame oil, shark liver oil, simethicone, sodium bicarbonate, sodium citrate, sodium fluoride, sodium monofluorophosphate, sulfanethoxazole, sulfur, tacrine, tacrine HCl, theophylline, terfenidine, thioperidone, trimetrexate, triazolam, timolol maleate, tretinoin, tetracycline hydrochloride, tolmetin, tolnaftate, triclosan, triprolidine hydrochloride, undecylenic acid, vancomycin, verapamil HCl, vidaribine phosphate, vitamin A, vitamin B, vitamin C, vitamin D, vitamin E, vitamin K, witch hazel, xylometazoline hydrochloride, zinc, zinc sulfate, and zinc undecylenate.

20. The method of claim 17, wherein the polymer is erodible in the presence of animal body fluids.

27. The method of claim 17, wherein the bioeffecting agent is selected from the group consisting of anti-histamines, anti-manics, anti-viral agents, anesthetics, antacids, anti-arthritics, anti-biotics, anti-psychotics, anti-spasmodics, anxiolytic agents, appetite suppressants, cardiovascular agents, cough suppressants, emollients, gastro-intestinal agents, growth regulators, hypoglycemic agents, respiratory stimulants, and vitamins.

21. A flash-flow melt-spun drug delivery system capable of controllably releasing a pharmaceutically active agent in an animal comprising a non-saccharide biodegradable polymer and a pharmaceutically active agent wherein the polymer is in predominantly amorphous form and is united with said active agent.

22. A method of preparing a controlled release pharmaceutical composition comprising subjecting a mixture of a biodegradable non-saccharide polymer and a pharmaceutically active agent to flash-flow melt-spinning to unite said polymer and active under conditions which produce a solid capable of releasing said active in an animal.

23. A device for promoting the growth of living tissue comprising a biocompatable or implantable support structure impregnated or coated with a biodegradable controlled release flash-flow melt-spun composition comprising a non-saccharide biodegradable polymer united with a growth regulator.

24. The device of claim 23, wherein the growth regulator is selected from the group consisting of human growth hormone, bovine growth hormone and porcine growth hormone.

25. A method of making a device for promoting the growth of living tissue comprising (i) flash-flow melt-spinning a composition comprising a non-saccharide biodegradable polymer and a growth regulator and (ii) collecting said composition on a support structure.

28. A sustained release solid composition formed by flash-flow melt-spin processing a solid non-saccharide biodegradable polymer and a solid bio-effecting agent.