Highly plastic granules for making fast melting tablets

• US 20050013857A1
• Filed: 05/07/2004
• Published: 01/20/2005
• Est. Priority Date: 05/07/2003
• Status: Active Grant

• Current Assignee: Akina Inc.
• Original Assignee: Akina Inc.
• Inventors: Park, Sang Yeob, Pai, Chaul Min, Seomoon, Gun, Park, Kinam, Fu, Yourong
• Granted Patent: US 7,749,533 B2
• Time in Patent Office: Days
• US Class Current: 424/464
• 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

Abstract

A fast-melting pharmaceutical tablet comprises a porous, plastic substance, a water penetration enhancer and a binder. One or more drugs can be incorporated into the formulation at different stages of the process so as to afford a pharmaceutically active tablet. Methods of making the pharmaceutical tablet entail combining the porous, plastic material, the water penetration enhancing agent, and the binder so as to form highly plastic granules, which are compressed into tablets. The resulting tablets dissolve rapidly in the mouth and have good hardness with low brittleness. The tablets are particularly valuable to those who have difficulty swallowing conventional pills.

Claims

1. A tablet capable of melting rapidly in the buccal cavity, which tablet comprises a plurality of highly plastic granules, said granules comprising a porous, plastic substance, a water penetration enhancer, and a binder.

2. The tablet of claim 1, further comprising an active pharmaceutical ingredient or dietary supplement.

3. The tablet of claim 1, wherein the porous, plastic substance is characterized by exhibiting plastic deformation when 500 mg of the substance is compressed in a 0.5-inch diameter die at a pressure less than about 1,500 pounds.

4. The tablet of claim 1, wherein the porous, plastic substance comprises from about 1% to about 95% of the tablet by weight.

5. The tablet of claim 1, wherein the water penetration enhancer is characterized by exhibiting complete wetting of a 200 mg tablet comprised thereof within 60 seconds after contacting a 0.5 ml water drop provided on a flat surface on which the water drop does not spread, which tablet is formed at 300 pounds in a 0.5 inch diameter die.

6. The tablet of claim 1, wherein the water penetration enhancer comprises from about 1% to about 95% of the tablet by weight.

7. The tablet of claim 1, wherein the binder permits particles of the porous, plastic substance and the water penetration enhancer to adhere to each other sufficiently to prevent particle segregation and to increase granule adherence at the low pressure used to form the tablet.

8. The tablet of claim 1, wherein the binder comprises from about 1% to about 90% of the tablet by weight.

9. The tablet of claim 1, wherein the porous, plastic substance and the water penetration enhancer are the same material.

10. The tablet of claim 2, wherein the active pharmaceutical ingredient is crystalline, microcrystalline or amorphous.

11. The tablet of claim 2, wherein the active pharmaceutical ingredient is coated with one or more excipients.

12. The tablet of claim 1, wherein the porous, plastic substance is selected from the group consisting of maltodextrin, dextrin, ethylcellulose, gum arabic, xanthan gum and its derivatives, guar gum and its derivatives, seaweed gums, carrageenan, dextran, gelatin, alginates, pectins, starch and starch derivatives (e.g., hydroxypropyl starch or carboxymethyl starch), cellulose esters (e.g., carboxymethylcellulose or cellulose ethers hydroxyethylmethylcelluloses), homo- or co-polymers of an unsaturated acid (e.g., acrylic acid or a salt thereof), homo- or co-polymers of an unsaturated amide (e.g., acrylamide), homo- or co-polymers of ethylene imine, a vinyl polymer (e.g., poly(vinyl alcohol)), homo- or co-polymers of a vinyl ester (e.g., vinylpyrrolidone, vinyloxazolidone, vinylmethyloxazolidone, vinylamine, and vinylpyrridine), alkylglycol, and polyalkylene oxide (e.g., polyethylene oxide), oxyethylene alkylether, dextrates, dextrose, fructose, lactitol, lactose, maltitol, maltose, mannitol, sorbitol, sucrose, erythritol, and xylitol, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, cellulose acetate, calcium sulfate, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, and carboxymethylcellulose-calcium salt.

13. The tablet of claim 1, wherein the water penetration enhancer is selected from the group consisting of dextrates, dextrin, dextrose, fructose, lactitol, lactose, maltitol, maltose, mannitol, mannose, sorbitol, sucrose, erythritol, xylitol, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, cellulose acetate, calcium sulfate, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, carboxymethylcellulose-calcium salt, and combinations thereof.

14. The tablet of claim 1, wherein the binder is selected from the group consisting of dextrates, dextrin, dextrose, fructose, lactitol, lactose, maltitol, maltose, mannitol, mannose, sorbitol, sucrose, erythritol, xylitol, starch, gelatin, acacia, alginic acid, sodium alginate, cellulose, carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, methylcellulose, polydextrose, poly(acrylic acid), CARBOMER, poly(ethylene oxide), and povidone.

15. The tablet of claim 2, wherein the active pharmaceutical ingredient belongs to a class of drugs selected from the group consisting of anti-migraines, anti-rheumatics, nonsteroidal anti-inflammatories, opioids, anti-mycobacterials, anti-parasites, anti-virals, beta-lactams, macrolide antibiotics, fluoroquinolones, tetracyclines, alkylating agents, anti-metabolites, hormonal drugs and antagonists, mitotic inhibitors, immunosuppressants, anti-arrhythmics, anti-hypertensives, beta-adrenergic blockers, calcium channel blockers, hypolipidemics, nitrates, anti-convulsants, anti-depressants, anxiolytics, sedatives, hypnotics, neurodegenerative disease drugs, ophthalmic drugs, anti-peptics, bismuth salts, anti-emetics, laxatives, coagulants, anti-coagulants, hemotopoietics, anti-diabetics, contraceptives, thyroid and anti-thyroid drugs, diuretics, electrolytes, gout therapy drugs, anti-asthmatics, antihistamines, cough, cold and flu drugs, and nutritional supplements.

16. The tablet of claim 2, wherein the active ingredient is a drug selected from the group consisting of loratadine, desloratadine, cetirizine, chlorpheniramine, diphenhydramine, fexofenadine, dextromethorphan, guaifensin, pseudoephedrine, acetaminophen, aspirin, ibuprofen, ketoprofen, indomethacin, piroxicam, celecoxib, fentanyl, hydrocodone, oxycodone, cyclosporine, methotrexate, valacyclovir, amoxicillin, cefixime, azithromycin, methotrexate, tamoxifen, sirolimus, tacrolimus, digoxin, captopril, clonidine hydrochloride, minoxidil, reserpine, metoprolol, propranolol, diltiazem, felodipine, nifedipine, fenofibrate, atorvastatin, lovastatin, pravastatin, simvastatin, nitroglycerin, phenobarbital, phenytoin, mirtazapine, bupropion, fluoxetine, paroxetine, sertraline, venlafaxine, chlorpromazine, risperidone, chlordiazepoxide, diazepam, carbidopa and levodopa, sodium biocarbonate, calcium carbonate, cimetidine, famotidine, ranitidine, lansoprazole, omeprazole, diphenhydramine, ondansetron, dexamethasone, bisacodyl, loperamide, phytonadione, ticlopidine, warfarin, ferrous salts, methylprednisolone, prednisone, metformin, nateglinide, repaglinide, tolbutamide, glipizide, iodides, amiloride, furosemide, theophylline, folic acid, vitamins, and caffeine.

17. The tablet of claim 1, which has a weight in the range of about 5 mg to about 5,000 mg.

18. The tablet of claim 17, which has a weight in the range of 50 mg to 500 mg.

19. The tablet of claim 1, which melts in the mouth in less than about 90 seconds.

20. The tablet of claim 19, which melts in the mouth in less than about 60 seconds.

21. The tablet of claim 1, which further comprises at least one additional ingredient selected from the group consisting of surfactants, superdisintegrants, superporous hydrogel particles, effervescent agents, lubricants, flavoring agents, and coloring agents.

22. A method of making a fast-melting pharmaceutical tablet, comprising:

combining a porous, plastic substance, and a water penetration enhancer to form an admixture thereof;

treating the admixture with an amount of a binder effective to form a mass of agglomerated particles thereof;

sieving and/or drying the agglomerated particles so as to isolate a plurality of highly plastic granules; and

compressing the highly plastic granules under low pressure to afford the fast melting pharmaceutical tablet.

23. The method of claim 22, further comprising intimately combining an active pharmaceutical ingredient with the porous, plastic substance, the water penetration enhancer, and/or the binder prior to admixing the porous, plastic substance and the water penetration enhancer.

24. The method of claim 22, wherein the porous, plastic substance is water soluble or water dispersible.

25. The method of claim 22, wherein the porous, plastic substance is a powder having a porous structure that exhibits plastic deformation whenever 500 mg of the powder is compressed into a 0.5-inch diameter die at a pressure less than about 1,500 pounds.

26. The method of claim 22, wherein the water penetration enhancer is characterized by exhibiting complete wetting of a 200 mg tablet comprised thereof within 60 seconds after contacting a 0.5 ml water drop provided on a flat surface on which the water drop does not spread, which tablet is formed at 300 pounds in a 0.5 inch diameter die.

27. The method of claim 22, wherein the binder is provided in liquid or semi-solid form.

28. The method of claim 22, wherein the binder is dissolved in aqueous solution or a mixture of water and an organic solvent prior to said treating.

29. The method of claim 22, wherein compressing is performed with a tablet press under a compression pressure less than about 150 MPa.

30. The method of claim 29, wherein the compression pressure is less than about 35 MPa.

31. The method of claim 30, wherein the compression pressure is less than about 10 MPa.

32. The method of claim 22, further comprising combining the highly plastic granules with at least one additional ingredient prior to compressing.

33. The method of claim 32, wherein the at least one additional ingredient is selected from the group consisting of surfactants, superdisintegrants, superporous hydrogel particles, effervescent agents, lubricants, flavoring agents, and coloring agents.

34. The method of claim 22, wherein the porous, plastic substance and the water penetration enhancer are identical substances.

35. The method of claim 22, wherein the agglomerated particles are subjected to mixing with a high shear mixer, low shear mixer, or fluid bed mixer.

36. The method of claim 22, wherein the drying entails air drying, vacuum drying, oven drying, fluidized bed drying, or microwave drying.

37. A pharmaceutical tablet having fast dissolving properties made by the method of claim 22.

38. The method of claim 22, further comprising intimately combining an active pharmaceutical ingredient with the highly plastic granules prior to compressing.

39. A pharmaceutical tablet having fast dissolving properties made by the method of claim 38.

40. A method of making a fast-melting pharmaceutical tablet, comprising:

treating a porous, plastic substance with an amount of a binder effective to form a first mass of agglomerated particles thereof;

treating a water penetration enhancer with an amount of a binder effective to form a second mass of agglomerated particles thereof;

sieving, admixing and drying said masses of agglomerated particles together so as to isolate a plurality of highly plastic granules; and

compressing the highly plastic granules under low pressure to afford the fast melting pharmaceutical tablet.

41. The method of claim 40, further comprising intimately combining an active pharmaceutical ingredient with the porous, plastic substance, the water penetration enhancer, and/or the binder prior to admixing the masses of agglomerated particles together.

42. The method of claim 40, wherein the porous, plastic substance is water soluble or water dispersible.

43. The method of claim 40, wherein the porous, plastic substance is a powder having a porous structure that exhibits plastic deformation whenever 500 mg of the powder is compressed into a 0.5-inch diameter die at a pressure less than about 1,500 pounds.

44. The method of claim 40, wherein the water penetration enhancer is characterized by exhibiting complete wetting of a 200 mg tablet comprised thereof within 60 seconds after contacting a 0.5 ml water drop provided on a flat surface on which the water drop does not spread, which tablet is formed at 300 pounds in a 0.5 inch diameter die.

45. The method of claim 40, wherein the binder is provided in liquid or semi-solid form.

46. The method of claim 40, wherein the binder is dissolved in aqueous solution or a mixture of water and an organic solvent prior to said treating.

47. The method of claim 40, wherein compressing is performed with a tablet press under a compression pressure less than about 150 MPa.

48. The method of claim 47, wherein the compression pressure is less than about 35 MPa.

49. The method of claim 48, wherein the compression pressure is less than about 10 MPa.

50. The method of claim 40, further comprising combining the highly plastic granules with at least one additional ingredient prior to compressing.

51. The method of claim 50, wherein the at least one additional ingredient is selected from the group consisting of surfactants, superdisintegrants, superporous hydrogel particles, effervescent agents, lubricants, flavoring agents, and coloring agents.

52. The method of claim 40, wherein the porous, plastic substance and the water penetration enhancer are identical substances.

53. The method of claim 40, wherein the agglomerated particles are subjected to mixing with a high shear mixer, low shear mixer, or fluid bed mixer.

54. The method of claim 40, wherein the drying entails air drying, vacuum drying, oven drying, fluidized bed drying, or microwave drying.

55. A pharmaceutical tablet having fast dissolving properties made by the method of claim 40.

56. The method of claim 40, further comprising intimately combining an active pharmaceutical ingredient with the highly plastic granules prior to compressing.

57. A pharmaceutical tablet having fast dissolving properties made by the method of claim 56.