ORALLY DISINTEGRATING DOSAGE FORMS

• US 20070292508A1
• Filed: 05/29/2007
• Published: 12/20/2007
• Est. Priority Date: 06/05/2006
• Status: Abandoned Application

• Current Assignee: Balchem Corporation
• Original Assignee: Balchem Corporation
• Inventors: Richardson, Paul, Szamosi, Janos, Yu, Liangping
• Application Number:
  US11/754,507
• Publication Number:
  US 20070292508A1
• Time in Patent Office: Days
• US Class Current: 424/469
• CPC Class Codes: A61K 31/16 Amides, e.g. hydroxamic acids
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/5015 Organic compounds, e.g. fats, sugars
• CPC Class Codes: A61K 9/5042 Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose

Abstract

The present invention is directed to orally disintegrating dosage forms comprising lipid coated substrates and silicified excipients. The use of silicified excipients in the orally disintegrating dosage form along with lipid coating of active agents, allows for improvements in the ability to prepare these dosage forms. Further, the dosage form can prevent unpleasant taste or aftertaste and provide better chemical and mechanical stability of the coated active substrate. This present invention also provides the possibility of harder more durable tablets, along with targeted immediate or modified release profiles for the active agent.

Claims

1. An orally disintegrating dosage form comprising:

a plurality of lipid coated active substrates, and a silicified excipient.

2. The orally disintegrating dosage form of claims 1, where the dosage form disintegrates in the oral cavity leaving swallowable residuals within tow minutes, without ingestion of water.

3. The orally disintegrating dosage forms claims 1 and 2, wherein the dosage form contains at least 10% silicified excipient by weight of total excipients.

4. The orally disintegrating dosage forms of claims 1-3, wherein the silicified excipient is a cellulose derivative.

5. The orally disintegrating dosage forms of claim 1-4, wherein the silicified excipient is silicified microcrystalline cellulose.

6. The orally disintegrating dosage forms of claim 5, wherein the silicified excipient is Prosolv®

.

7. The orally disintegrating dosage form of claim 1, wherein the active concentration in the lipid coated substrate is at least 10%, preferably at least 40%, more preferably at least 65%, more preferably at least 75%, even more preferably at least 90%.

8. The orally disintegrating dosage form of claim 7, wherein the lipid is a wax or a fatty acid glycerol ester, and any combinations or mixtures thereof.

9. The orally disintegrating dosage form of claim 8, wherein the was is selected from a group consisting of paraffin wax, camauba wax, beeswax etc., and any combinations of mixtures thereof.

10. The orally disintegrating dosage form of claim 8, wherein the fatty acid glycerol ester selected from a group consisting of fully or partially hydrogenated monoglycerides, diglyceride and triglycerides, and any combinations or mixtures thereof.

11. The orally disintegrating dosage form of claim 10, wherein the fatty acid glycerol ester is a hydrogenated vegetable oil.

12. The orally disintegrating dosage form of claims 1-11, wherein the lipid coating comprises at least one additional acceptable additive selected from the group consisting of inert diluents, fillers, lubricants, binders, glidants, plasticizers, sensory masking agents, flavors, pH triggers, antioxidants, taste maskers, bitter blockers, and combinations thereof.

13. The orally disintegrating dosage form of claims 1-12, wherein the lipid coating on the substrate is at least 90% of the weight of the coated active substrate.

14. The orally disintegrating dosage form of claims 1-12, wherein the lipid coating on the substrate is at least 60% of the weight of the coated active substrate.

15. The orally disintegrating dosage form of claims 1-12, wherein the lipid coating on the substrate is at least 35% of the weight of the coated active substrate.

16. The orally disintegrating dosage form of claims 1-12, wherein the lipid coating on the substrate is at least 10% of the weight of the coated active substrate.

17. The orally disintegrating dosage form of claims 1-16, wherein the active is taste masked.

18. The orally disintegrating dosage form of claims 1-17, wherein the dosage form has an immediate release profile of the active.

19. The orally disintegrating dosage form of claims 1-17, wherein the dosage form has a modified release profile of the active.

20. The orally disintegrating dosage for of claim 19, wherein the modified release is a delayed-release.

21. The orally disintegrating dosage form of claim 19, wherein the modified release is a controlled-release.

22. The orally disintegrating dosage form of claim 19, wherein the active agent is a pulsatile release.

23. The orally disintegrating dosage form of claim 1-22, wherein the active agent is selected from the group consisting of antihistamines;

antibiotics;

antituberculosis agents;

cholinergic agents;

antimuscarinics;

sympathomimetics;

sympatholytic agents;

miscellaneous autonomic drugs;

iron preperations;

haemostatics;

cardiac drugs;

antihypertensive agents;

vasodilators;

non-steroidal anti-inflammatory agents;

opiate agonists;

anticonvulsants;

tranquilizers;

chemotherapeutic agents;

lipid lowering agents;

H₂-antagonists;

anti-coagulant and anti-platelet agents;

bronchodilators;

stimulants;

barbiturates;

sedatives;

expectorants;

antiemetics;

gastro-intestinal drugs;

antithyroid agents;

genitourinary smooth muscle relaxants;

vitamins;

unclassified agents;

steroids;

glucocorticoids, and any combinations or mixtures of the foregoing.

24. The orally disintegrating dosage form of claim 23, wherein the active agent is acetaminophen.

25. The orally disintegrating dosage form of claims 23, wherein the active agent is guaifenesin.

26. The orally disintegrating dosage form of claims 23, wherein the active agent is ibuprofen.

27. The orally disintegrating dosage form claims 23, wherein the active agent is ranitidine.

28. The orally disintegrating dosage form of claims 23, wherein the active agent is caffeine.

29. The orally disintegrating dosage form of claims 24 and 26, wherein a portion of the active agent substrates comprise an opioid analgesic.

30. The orally disintegrating dosage form of claim 29, wherein the opioid active agent comprises hydrocodone or its salts or derivatives.

31. The orally disintegrating dosage form of claims 1-22, wherein the active agent is selected from the group consisting of vitamins, minerals, amino acids, herbal agents, botanical agents, enzymes, living or attenuated organisms such as prebiotics or probiotics and mixtures of any of the foregoing.

32. A method of preparing an orally disintegrating dosage form, comprising:

a) blending a plurality of lipid coated active agent substrates with excipients that include a silicified excipient;

b) optionally adding additional excipients;

c)tableting the pre-mix to form an orally disintegrating dosage form.

33. The method of preparing an orally disintegrating dosage form of claims 32, where the dosage form disintegrates in the oral cavity of any species leaving swallowable residuals within two minutes, without ingestion of water.

34. The method of preparing an orally disintegrating dosage form of claims 32 and 33, where in the dosage form contains at least 10% silicified excipient by weight of total excipients.

35. The method of preparing and orally disintegrating dosage form of claim 32-34, where in the silicified excipient is silicified microcrystalline cellulose.

36. The method of preparing an orally disintegrating dosage form of claim 32, where in the active concentration in the lipid coated substrate is at least 10%, preferably at least 40%, more preferably at least 65%, more preferably at least 75%, even more preferably at least 90%.

37. The method of preparing an orally disintegrating dosage form of claims 32-36, wherein the lipid coated active substrate comprises a lipid.

38. The method of preparing an orally disintegrating dosage form of claim 37, wherein the lipid is a wax or a fatty acid glycerol ester, and any combinations or mixtures thereof.

39. The method of preparing an orally disintegrating dosage form of claim 38, wherein the wax is selected from a group consisting of paraffin was, carnauba wax, paraffin wax, beeswax etc., and any combinations of mixtures thereof.

40. The method of preparing an orally disintegrating dosage form of claim 39, wherein the fatty acid glycerol ester selected from a group consisting of fully or partially hydrogenated monoglycerides, diglyceride and triglycerides, and any combinations or mixtures thereof.

41. The method of preparing an orally disintegrating dosage form of claim 40, wherein the fatty acid glycerol ester is a hydrogenated vegetable oil.

42. The method of preparing an orally disintegrating dosage form of claims 32-41, wherein the lipid coating comprises at least one additional acceptable additive.

43. The method of preparing an orally disintegrating dosage form of claim 42, wherein the additive is selected from the group consisting of inert diluents, fillers, lubricant, binders, glidants, plasticizers, sensory masking agents, flavors, pH triggers, antioxidants, taste maskers, bitter blockers, cellulose derivatives and combinations thereof.

44. The method of preparing an orally disintegrating dosage form of claim 43, wherein the cellulose derivative is ethylcellulose.

45. The method of preparing an orally disintegrating dosage form of claims 32-44, wherein the lipid coating on the substrate is lead than 90% of the weight of the coated active substrate.

46. The method of preparing an orally disintegrating dosage form of claims 32-44, wherein the lipid coating on the substrate is lead than 60% of the weight of the coated active substrate.

47. The method of preparing an orally disintegrating dosage form of claims 32-46, wherein the lipid coating on the substrate is less than 35% of the weight of the coated active substrate.

48. The method of preparing an orally disintegrating dosage form of claims 32-44, wherein the lipid coating on the substrate is less than 10% of the weight of the coated active substrate.

49. The method of preparing an orally disintegrating dosage form of claims 32-48, wherein the active is taste masked.

50. The method of preparing an orally disintegrating dosage form of claims 32-48, wherein the dosage form has an immediate release profile of the active substrate.

51. The method of preparing an orally disintegrating dosage form of claims 32-48, wherein the dosage form has a modified release profile of the active substrate.

52. The method of preparing an orally disintegrating dosage form of claim 51, wherein the modified release is a delayed-release.

53. The method of preparing an orally disintegrating dosage form of claim 51, wherein the modified release is a controlled-release.

54. The method of preparing an orally disintegrating dosage form of claim 51, wherein the modified release is a pulsatiled release.

55. The method of preparing an orally disintegrating dosage form of claims 32-54, wherein the active agent is selected from the group consisting of antihistamines;

antibiotics;

antituberculosis agents;

cholinergic agents;

antimuscarinics;

sympathomimetics;

sympatholytic agents;

miscellaneous autonomic drugs;

iron preperations;

haemostatics;

cardiac drugs;

antihypertensive agents;

vasodilators;

non-steroidal anti-inflammatory agents;

opiate agonists;

anticonvulsants;

tranquilizers;

chemotherapeutic agents;

lipid lowering agents;

H₂-antagonists;

anti-coagulant and anti-platelet agents;

bronchodilators;

stimulants;

barbiturates;

sedatives;

expectorants;

antiemetics;

gastro-intestinal drugs;

antithyroid agents;

genitourinary smooth muscle relaxants;

vitamins;

unclassified agents;

steroids;

glucocorticoids, and any combinations or mixtures of the foregoing.

56. The method of preparing an orally disintegrating dosage form of claims 55, wherein the active agent is acetaminophen.

57. The method of preparing an orally disintegrating dosage form of claims 55, wherein the active agent is guaifenesin.

58. The method of preparing an orally disintegrating dosage form of claims 55, wherein the active agent is ibuprofen.

59. The method of preparing an orally disintegration dosage form of claims 55, wherein the active agent is ranitidine.

60. The method of preparing orally disintegrating dosage form of claims 55, wherein the active agent is caffeine.

61. The method of preparing an orally disintegrating dosage form of claims 56 and 58, wherein a portion of the active agent comprises an opioid analgesic.

62. The method of preparing an orally disintegrating dosage form of claim 61, wherein the opioid active agent comprises hydrocodone or its salts or derivatives.

63. The method of preparing an orally disintegrating dosage form of claims 32-54, wherein the active agent is selected from the group consisting of vitamins, minerals, amino acids, herbal agents, botanical agents, enzymes, living or attenuated organisms such as prebiotics or probiotics and mixtures of any of the foregoing.

64. An orally disintegrating dosage form, comprising

a plurality of substrates comprising an active agent microencapsulated with hydrogenated vegetable oil or an animal fat,

a particulate agglomerate of a co-processed microcrystalline cellulose and from about 0.1% to about 20% silicon dioxide, by weight of the microcrystalline cellulose, the microcrystalline cellulose and silicon dioxide being in intimate association with each other, and the silicon dioxide portion of the agglomerate being derived from a silicon dioxide having a particle size from about 1 nanometer (nm) to about 100 microns (.mu.m), based on average primary particle size,

the plurality of substrates and particulate agglomerate of coprocessed microcrystalline cellulose being directly compressed into a solid dosage form containing a therapeutically effective amount of the active agent and an effective amount of said coprocessed microcrystalline cellulose such that the dosage form disintegrates in the oral cavity of a human leaving swallowable residuals within two minutes, without ingestion of water.

65. An orally disintegrating dosage form, comprising

a compressed mixture of (1) a plurality of substrates comprising an active agent microencapsulated with hydrogenated vegetable oil or an animal fat and (2) a particulate agglomerate of coprocessed microcrystalline cellulose and from about 0.1% to about 20% silicon dioxide, by weight of the microcrystalline cellulose, the microcrystalline cellulose and silicon dioxide being in intimate association with each other, and the silicon dioxide portion of the agglomerate being derived from a silicon dioxide having a particle size from about 1 nanometer (nm) to about 100 microns (.mu.m), based on average primary particle size, the mixture of substrates and coprocessed microcrystalline cellulose being capable of being sieved through a USSS 40-mesh screen with no observable clogging on the screen.