Rapid disperse dosage form containing levetiracetam
View Patent ↗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.
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° 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
Dose
C 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 0-t or an AUC inf within the ranges listed below
Dose
AUC 0-t
AUC 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
Dose
C 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 0-t or an AUC inf within the ranges listed below
Dose
AUC 0-t
AUC 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 0-t , as measured in microg-hr/ml, in the range of 0.89 to 0.98 and for AUC 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® tablet, as defined by NDA No. N021035, in terms of C max , AUC 0-t or AUC 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° 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
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 0-t , as measured in microg-hr/ml, in the range of 0.89 to 0.98 and for AUC 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.