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 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.
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:
Dose
C 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 0-t , AUC inf , or a combination of AUC 0-t and 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.
4. The method of claim 1 , wherein the dosage form is equivalent to a KEPPRA® tablet, as defined by NDA No. N021035, in terms of C max , AUC 0-t and/or AUC 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 0-t in the range of 0.89 to 0.98 and for AUC 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° 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
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° 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:
Dose
C 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 0-t , AUC inf , or a combination of AUC 0-t and 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.
18. The method of claim 15 , wherein the dosage form is equivalent to a KEPPRA® tablet, as defined by NDA No. N021035, in terms of C max , AUC 0-t , AUC 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° 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° C. for six months at 75% RH.
26. The method of claim 15 , 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.
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° 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.