Claims for Patent: 9,669,009

Summary for Patent: 9,669,009

Title:	Rapid disperse dosage form containing levetiracetam
Abstract:	A high dose rapidly dispersing three-dimensionally printed dosage form comprising a high dose of levetiracetam in a porous matrix that disperses in water within a period of less than about 15 seconds is disclosed. Also disclosed are methods of preparing the dosage form and of treating a condition, disease or disorder that is therapeutically responsive to levetiracetam.
Inventor(s):	Jacob; Jules (Yardley, PA), Coyle; Norman (Fort Washington, PA), West; Thomas G. (Lawrenceville, NJ), Monkhouse; Donald C. (Radnor, PA), Surprenant; Henry L. (Phoenixville, PA), Jain; Nemichand B. (Princeton Junction, NJ)
Assignee:	Aprecia Pharmaceuticals Company (Langhorne, PA)
Application Number:	15/095,785
Patent Claims:	1. A method of treating a disease, condition or disorder that is therapeutically responsive to levetiracetam comprising orally administering one or more times daily to a subject in need thereof a rapidly dispersible solid dosage form comprising levetiracetam in a bound porous matrix that disperses in about 15 sec or less in a volume of about 15 ml or less of water or saliva, wherein the dosage form provides a Cmax within the ranges listed below when respective doses of levetiracetam are administered to the subject in the fasting state: TABLE-US-00010 Dose C.sub.max (mg) (micrograms/ml) 1000 13-53 750 9-37 500 5-20 250 4-7 wherein the bound porous matrix comprises 50-80% wt of levetiracetam (LEV), 3-35% wt of at least one disintegrant, and 0.5-20% wt of at least one binder wherein the matrix has a hardness of at least 2 kp. 2. The method of claim 1, wherein the dosage form provides a Tmax within the range of 0.15-1.5 hours. 3. The method of claim 1, wherein the dosage form provides an AUC.sub.0-t, AUC.sub.inf, or a combination of AUC.sub.0-t and AUC.sub.inf, within the ranges listed below: TABLE-US-00011 Dose AUC.sub.0-t AUC.sub.inf (mg) (microg-hr/ml) (microg-hr/ml) 1000 170-397 176-410 750 135-315 140-324 500 90-209 93-216 250 54-127 56-131. 4. The method of claim 1, wherein the dosage form is equivalent to a KEPPRA.RTM. tablet, as defined by NDA No. N021035, in terms of C.sub.max, AUC.sub.0-t and/or AUC.sub.inf on an equi-dose basis. 5. The method of claim 1, wherein the dosage form is administered one to three times daily, and the Cmax is determined with respect to single dose. 6. The method of claim 1, wherein the dosage form provides a fed/fasted ratio for Cmax in the range of 0.55 to 0.74 and for Tmax in the range of 5 to 21 hours. 7. The method of claim 6, wherein the dosage form provides a fed/fasted ratio, for AUC.sub.0-t in the range of 0.89 to 0.98 and for AUC.sub.inf in the range of 0.89 to 0.99. 8. The method of claim 1, wherein: a) the dosage form is not compressed; b) the matrix is not compressed; c) the exterior of the dosage form is harder than the interior; d) the dissolution time of LEV is slower than the dispersion time of the matrix when placed in an aqueous fluid; e) the matrix disperses in about 10 seconds or less when placed in a small volume of aqueous fluid; f) at least 75%, at least about 90, or at least about 95% of the LEV dissolves in about 2 minutes or less when placed in an aqueous fluid; g) LEV is present in a form selected from the group consisting of hydrate, hemi-hydrate, crystalline, amorphous, anhydrate or a combination thereof; h) the dosage form comprises not more than 10% wt and not less 0.1% moisture as determined by loss on drying at 120.degree. C.; i) the hardness of the matrix is substantially uniform; j) the dosage form comprises one or more other medicaments; k) the matrix further comprises glycerin; l) the matrix further comprises glycerin, wherein the content of glycerin ranges from about 0.05%-3%; m) at least 95% of LEV is dissolved in 5 minutes or less in 900 ml of aqueous media at pH 1.2, 4.5 or 6.8 in a USP paddle apparatus operating at 50 RPM; or n) a combination thereof. 9. The method of claim 1, wherein the matrix further comprises one or more surfactants and one or more antioxidants, and optionally comprises one or more of the following: glycerin, one or more glidants, one or more flavorants and one or more preservatives. 10. The method of claim 9 wherein: a) the one or more surfactants is present in an amount ranging from about 0.05 to about 1% wt based upon the final weight of the dosage form; b) the one or more antioxidants is present in an amount ranging from about 0.005 to about 5.0% wt based upon the final weight of the dosage form; c) the at least one binder is present in an amount ranging from about 5 to about 15% wt based upon the final weight of the dosage form; d) the at least one disintegrant is present in an amount ranging from about 10 to about 30% wt based upon the final weight of the dosage form; e) the one or more glidants is present in an amount ranging from about 0.1 to about 2.0% wt, based upon the final weight of the dosage form; f) the matrix comprises about 250 to about 1000 mg, about 250 mg, about 500 mg, about 750 mg, about 1000 mg of LEV; or g) a combination thereof. 11. The method of claim 1, wherein: a) the hardness of the matrix ranges from about 2 to about 10 kp, about 2 to about 6 kp or about 3 to about 9 kp; b) the matrix disperses in 10 sec or less when placed in 15 ml of water or saliva; c) the matrix comprises 15 to 50 or 25 to 50 of printed incremental layers, wherein the thickness of an incremental layer ranges from 0.008 to 0.012 inches; d) the matrix is porous and non-compressed or e) a combination thereof. 12. The method of claim 1, wherein the dosage form comprises the following ingredients TABLE-US-00012 Ingredient Amt (% wt) LEV 60-70 Disintegrant 20-25 Binder 10-15 Sweetener 0.5-2 Glidant 0.1-1.5 Glycerin 0.1-5 Surfactant 0.05-1.5 Flavor 0-0.5. 13. The method of claim 1, wherein the matrix comprises 0.1% or less of an oxidative degradant of LEV after being stored at 21.degree. C. for six months at 75% RH. 14. The method of claim 1, wherein the dosage form is preservative free. 15. A method of treating a disease, condition or disorder that is therapeutically responsive to levetiracetam comprising orally administering one or more times daily to a subject in need thereof a rapidly dispersible solid dosage form comprising levetiracetam in a bound porous matrix that disperses in about 15 sec or less in a volume of about 15 ml or less of water or saliva, wherein the dosage form provides a Cmax within the ranges listed below when respective doses of levetiracetam are administered to a subject in the fed state: TABLE-US-00013 Dose C.sub.max (mg) (microg/ml) 1000 14-27 750 10-19 500 5-10 250 4-73 wherein the bound porous matrix comprises 50-80% wt of levetiracetam (LEV), 3-35% wt of at least one disintegrant, and 0.5-20% wt of at least one binder wherein the matrix has a hardness of at least 2 kp. 16. The method of claim 15, wherein the dosage form provides a Tmax within the range of 2-5 hours. 17. The method of claim 15, wherein the dosage form provides an AUC.sub.0-t, AUC.sub.inf, or a combination of AUC.sub.0-t and AUC.sub.inf within the ranges listed below: TABLE-US-00014 Dose AUC.sub.0-t AUC.sub.inf (mg) (microg-hr/ml) (microg-hr/ml) 1000 183-342 190-355 750 145-271 150-282 500 96-180 100-187 250 58-109 60-113. 18. The method of claim 15, wherein the dosage form is equivalent to a KEPPRA.RTM. tablet, as defined by NDA No. N021035, in terms of C.sub.max, AUC.sub.0-t, AUC.sub.inf, or a combination thereof on an equi-dose basis. 19. The method of claim 15, wherein the dosage form is administered one to three times daily, and the Cmax is determined with respect to single dose. 20. The method of claim 15, wherein: a) the dosage form is not compressed; b) the matrix is not compressed; c) the exterior of the dosage form is harder than the interior; d) the dissolution time of LEV is slower than the dispersion time of the matrix when placed in an aqueous fluid; e)the matrix disperses in about 10 seconds or less when placed in an aqueous fluid; f) at least 75%, at least about 90, or at least about 95% of the LEV dissolves in about 2 minutes or less when placed in an aqueous fluid; g) LEV is present in a form selected from the group consisting of hydrate, hemi-hydrate, crystalline, amorphous, anhydrate or a combination thereof; h) the dosage form comprises not more than 10% wt and not less 0.1% moisture as determined by loss on drying at 120.degree. C.; i) the hardness of the matrix is substantially uniform; j) the dosage form comprises one or more other medicaments; k) the matrix further comprises glycerin; l) the matrix further comprises glycerin, wherein the content of glycerin ranges from about 0.05%-3%; m) at least 95% of LEV is dissolved in 5 minutes or less in 900 ml of aqueous media at pH 1.2, 4.5 or 6.8 in a USP paddle apparatus operating at 50 RPM; or n) a combination thereof. 21. The method of claim 15, wherein the matrix further comprises one or more surfactants and one or more antioxidants, and optionally comprises one or more of the following: glycerin, one or more glidants, one or more flavorants and one or more preservatives. 22. The method of claim 21 wherein: a) the one or more surfactants is present in an amount ranging from about 0.05 to about 1% wt based upon the final weight of the dosage form; b) the one or more antioxidants is present in an amount ranging from about 0.005 to about 5.0% wt based upon the final weight of the dosage form; c) the at least one binder is present in an amount ranging from about 5 to about 15% wt based upon the final weight of the dosage form; d) the at least one disintegrant is present in an amount ranging from about 10 to about 30% wt based upon the final weight of the dosage form; e) the one or more glidants is present in an amount ranging from about 0.1 to about 2.0% wt, based upon the final weight of the dosage form; f) the matrix comprises about 250 to about 1000 mg, about 250 mg, about 500 mg, about 750 mg, about 1000 mg of LEV; or g) a combination thereof. 23. The method of claim 15, wherein: a) the hardness of the matrix ranges from about 2 to about 10 kp, about 2 to about 6 kp or about 3 to about 9 kp; b) the matrix disperses in 10 sec or less when placed in 15 ml of water or saliva; c) the matrix comprises 15 to 50 or 25 to 50 of printed incremental layers, wherein the thickness of an incremental layer ranges from 0.008 to 0.012 inches; d) the matrix is porous and non-compressed or e) a combination thereof. 24. The method of claim 15, wherein the dosage form is preservative free. 25. The method of claim 15, wherein the matrix comprises 0.1% or less of an oxidative degradant of LEV after being stored at 21.degree. C. for six months at 75% RH. 26. The method of claim 15, wherein the dosage form comprises the following ingredients TABLE-US-00015 Ingredient Amt (% wt) LEV 60-70 Disintegrant 20-25 Binder 10-15 Sweetener 0.5-2 Glidant 0.1-1.5 Glycerin 0.1-5 Surfactant 0.05-1.5 Flavor 0-0.5. 27. The method of claim 1, wherein at least one binder is water soluble. 28. The method of claim 15, wherein at least one binder is water soluble. 29. A method of treating a disease, condition or disorder that is therapeutically responsive to levetiracetam comprising orally administering one or more times daily to a subject in need thereof a three-dimensionally printed rapidly dispersible solid bound matrix comprising 50-80% wt of levetiracetam, 3-35% wt of at least one disintegrant and 0.5-20% wt of at least one binder, wherein the matrix disperses in about 15 sec or less in a volume of about 15 ml or less of water or saliva and has a hardness of at least 2 kp. 30. The method of claim 29, wherein the three-dimensionally printed rapidly dispersible solid bound matrix is porous and non-compressed and comprises 50-80% wt of levetiracetam, 3-35% wt of at least one disintegrant, 0.5-20% wt of at least one water soluble binder, 0.005 to about 5.0% wt of one or more antioxidants, about 250 mg to about 1000 mg of levetiracetam, and not more than 10% wt and not less 0.1% moisture as determined by loss on drying at 120.degree. C., wherein the matrix disperses in about 15 sec or less in a volume of about 15 ml or less of water or saliva and has a hardness of at least 2 kp.