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Last Updated: September 21, 2021

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Claims for Patent: 9,339,489


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Summary for Patent: 9,339,489
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 10 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:14/277,901
Patent Claims: 1. A rapidly dispersible solid dosage form comprising a three-dimensionally printed bound matrix comprising 50-80% wt of levetiracetam (LEV), 3-35% wt of disintegrant and 0.5-20% wt of binder, wherein the matrix disperses in about 15 sec or less in a volume of about 15 ml or less of water or saliva, wherein the matrix has a hardness of at least 2 kp.

2. The dosage form of claim 1, wherein the bound matrix further comprises antioxidant.

3. The dosage form of claim 2, wherein the bound matrix comprises 0.005 to about 5.0% wt of antioxidant.

4. The dosage form of claim 1, wherein the bound 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.

5. The rapidly dispersible solid dosage form of claim 1, wherein the dosage form provides a Cmax within the ranges listed below when respective doses of levetiracetam are administered to a 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.

6. The dosage form of claim 5, wherein the dosage form provides a Tmax within the range of 0.15-1.5 hours.

7. The dosage form of claim 5, wherein the dosage form provides an AUC.sub.0-t or an 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.

8. The rapidly dispersible solid dosage form of claim 1, 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-00012 Dose C.sub.max (mg) (microg/ml) 1000 14-27 750 10-19 500 5-10 250 4-7.

9. The dosage form of claim 8, wherein the dosage form provides a Tmax within the range of 2-5 hours.

10. The dosage form of claim 8, wherein the dosage form provides an AUC.sub.0-t or an AUC.sub.inf within the ranges listed below TABLE-US-00013 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.

11. The rapidly dispersible solid dosage form of claim 1, wherein the dosage form provides a fed/fasted ratio for Cmax, as measured in micrograms/ml, in the range of 0.55 to 0.74 and for Tmax, as measured in hours, in the range of 5 to 21.

12. The dosage form of claim 11, wherein the dosage form provides a fed/fasted ratio, for AUC.sub.0-t, as measured in microg-hr/ml, in the range of 0.89 to 0.98 and for AUC.sub.inf, as measured in microg-hr/ml, in the range of 0.89 to 0.99.

13. The dosage form of claim 1, wherein the dosage form is equivalent in rate and extent of absorption to a KEPPRA.RTM. tablet, as defined by NDA No. N021035, in terms of C.sub.max, AUC.sub.0-t or AUC.sub.inf.

14. The dosage form of claim 1, wherein: a) the dosage form is not compressed; b) the bound matrix is not compressed; c) the exterior of the bound matrix is harder than the interior of the bound matrix; d) the dissolution time of LEV is slower than the dispersion time of the bound matrix when placed in an aqueous fluid; e) the bound matrix disperses in about 10 seconds or less when placed in a small volume of aqueous fluid; f) at least 75% 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 bound matrix is substantially uniform; j) the dosage form comprises one or more other medicaments; k) the bound matrix further comprises glycerin; l) the bound matrix further comprises glycerin in an amount ranging from about 0.05%-3% wt; or m) at least 95% wt 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.

15. The dosage form of claim 1, wherein the bound matrix further comprises one or more surfactants, one or more antioxidants, glycerin and optionally one or more of the following: one or more glidants, one or more flavorants, one or more preservatives; the bound matrix comprises particles bound by binder and LEV; the bound matrix is porous and non-compressed; and the bound matrix disperses in less than 15 sec in a volume of 10 ml of aqueous fluid.

16. The dosage form of claim 15 wherein: a) the at least one surfactant 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 at least one antioxidant is present in an amount range from about 0.005 to about 5.0% wt based upon the final weight of the dosage form; c) the at least one glidant is present in an amount range from about 0.1 to about 2.0% wt, based upon the final weight of the dosage form; or d) the bound matrix comprises about 250 to about 1000 mg of LEV.

17. The dosage form of claim 1, wherein the dosage form has been prepared by a three-dimensional printing process.

18. The dosage form of claim 1, wherein the dosage form comprises the following ingredients TABLE-US-00014 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.

19. The dosage form according to claim 18, wherein the dosage form further comprises antioxidant.

20. The dosage form of claim 3, wherein: a) the hardness of the bound matrix ranges from about 2 to about 6 kp or about 3 to about 9 kp; b) the bound matrix disperses in 10 sec or less when placed in 15 ml of water or saliva; c) binder is introduced into the bound matrix by way of printing fluid used to form the matrix; d) binder is introduced into the bound matrix by way of bulk powder used to form the matrix; e) the bound matrix comprises about 250 mg to about 1000 mg of LEV; f) the bound matrix comprises 15 to 50 printed incremental layers; g) the bound matrix comprises 15 to 50 printed incremental layers and the thickness of an incremental layer ranges from 0.008 to 0.012 inches; or h) the bound matrix is porous and non-compressed.

21. The dosage form of claim 1, wherein the dosage form is preservative free.

22. A method of treating a disease, condition or disorder that is therapeutically responsive to levetiracetam comprising administering a dosage form of claim 1 one to three times daily to a subject in need thereof throughout a treatment period.

23. The dosage form of claim 1, wherein the hardness is about 2 to about 6 kp or about 3 to about 9 kp.

24. A rapidly dispersible solid dosage form comprising a three-dimensionally printed bound matrix comprising 50-80% wt of levetiracetam, 3-35% wt of disintegrant and 0.5-20% wt of binder, wherein the matrix disperses in about 15 sec or less in a volume of about 15 ml or less of water or saliva, wherein the matrix has a hardness of at least 2 kp, and the dosage form provides a fed/fasted ratio, for AUC.sub.0-t, as measured in microg-hr/ml, in the range of 0.89 to 0.98 and for AUC.sub.inf, as measured in microg-hr/ml, in the range of 0.89 to 0.99.

25. A rapidly dispersible solid dosage form comprising a three-dimensionally printed bound matrix comprising 50-80% wt of levetiracetam, 3-35% wt of disintegrant and 0.5-20% wt of binder, wherein the matrix disperses in about 15 sec or less in a volume of about 15 ml or less of water or saliva, wherein the matrix has a hardness of at least 2 kp, and the bound matrix is porous and non-compressed.

26. A rapidly dispersible solid dosage form comprising a three-dimensionally printed bound matrix comprising 50-80% wt of levetiracetam, 3-35% wt of disintegrant and 0.5-20% wt of binder, wherein the matrix disperses in about 15 sec or less in a volume of about 15 ml or less of water or saliva, wherein the matrix has a hardness of at least 2 kp, and the bound matrix comprises about 250 to about 1000 mg of levetiracetam.

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