NOVEL PHARMACEUTICAL COMPOSITIONS COMPRISING LEVETIRACETAM

Abstract

The present invention relates to a pharmaceutical composition comprising levetiracetam as active ingredient, the invention relates specifically to a prolonged release formulation.

Description

EXAMPLES

Example 1

Formulations with a 24 h In Vivo Release of Levetiracetam

Tablets A, B, and C are prepared by direct compression process according to the invention with the following core compositions (Table 1). The cores are coated by an aqueous dispersion of polyvinyl alcohol cellulose.

TABLE 1
Core compositions of tablets A, B and C.
	Tablet A	Tablet B	Tablet C
Components	mg	%	mg	%	mg	%
Levetiracetam	500.00	71.4	500.00	71.4	500.00	71.4
Methocel K 15 MCR	193.00	27.6	96.50	13.8	158.00	22.6
Kollidon SR	—	—	96.50	13.8	—	—
Carbopol 71 G	—	—	—	—	35.00	5.0
Aerosil 200	3.50	0.5	3.50	0.5	3.50	0.5
Magnesium stearate	3.50	0.5	3.50	0.5	3.50	0.5

Hydropropyl methylcellulose sold under the trademark Methocel® is used as a hydrophilic matrix agent. The compound Methocel K15 M™ is also known as hypromellose which is a hydrophilic polymer. The viscosity of an aqueous solution in water for 2% (w/w) of the compound Methocel K15M is about 15000 mPa·s, the grade K (methoxy and hydroxypropy content) is preferred for a better hydratation rate of the polymer.

Polymers sold under the trademark Carbopol are crosslinked acrylic acid-based polymers and are used as a hydrophilic matrix agent. The compound Carbopol 71 G is polyacrylic acid polymers crosslinked, also known as Carbomer (Ph.Eur.), and Carbomer 941 (USP).

Compound sold under the trademark Kollidon is polyvinylpyrrolidone or povidone. The compound Kollidon SR comprises polyvinyl acetate (80% w/w=hydrophilic polymer), povidone (19% w/w=hydrophilic polymer) and about 0.8% sodium laurylsulfate and about 0.6% of silica.

Anhydrous colloidal silica is sold under the trademark Aerosil 200.

Tablets A, B and C release the active over a period of 24 hours and are bioequivalent (Table 2).

TABLE 2
Main pharmacokinetic parameters for tablets A, B, C and for the immediate release
	tmax	Cmax	AUC(0-t)	AUC	t½		C12	C24
Treatment	(h)	(μg/mL)	(μg * h/mL)	(μg * h/mL)	(h)	Fre1	(μg/mL)	(μg/mL)
Immediate	0.75	12.6	112	117	7.6	—	3.35	1.30
release
Tablet A	4.00	5.7	106	114	8.2	0.98	3.98	2.08
Tablet B	4.00	6.4	107	114	7.7	0.97	4.13	1.82
Tablet C	4.00	5.7	102	110	8.1	0.94	4.00	1.91
Immediate release tablet = tablet which does not content specific excipients used to obtain a sustained or controlled release of the drug
tmax = the time necessary to obtain the plasma maximum concentration after administration of the drug
Cmax = the plasma maximum concentration observed after administration of the drug
AUC(0-t) = area under the curve (drug concentration vs time) from time 0 to time t
AUC = total area under the curve
t½ = biological half-life: the time required for half the quantity of drug deposited in a living organism to be metabolized or eliminated by normal biological process
Fre1 = relative bioavailability: measure of the bioavailability of the drug when compared with the immediate release formulation
C12 = plasma concentration 12 hours after the administration of the drug
C24 = plasma concentration 24 hours after the administration of the drug
* = multiplication sign

The in vitro dissolution profiles in water of tablets A, B and C were determined according to the USP 24 (apparatus n^o 2, 100 rpm, aqueous medium 900 mL) over an interval of time of 12 h.

The percentages of dissolution were in the following ranges (Table 3).

TABLE 3
Percentages of dissolution of levetiracetam obtained from tablets
A, B and C.
Time Percentages
(h)  of dissolution
0.5  19 ± 4
1    27 ± 7
2    42 ± 8
4    64 ± 10
8    85 ± 10
12   98 ± 9

Consequently, all the formulations owing dissolution profile similar to the results shown in Table 3 should be bioequivalent to tablets A, B and C.

Example 2

Formulations with a 12 h In Vitro Release of Levetiracetam in the Ranges of Tablets A, B and C as Described in Example 1

Tablets D₁ to D₁₃ are prepared by direct compression process with the following core compositions (Table 4).

TABLE 4
Core compositions of tablets D1 to D13
Components	mg	%	mg	%	mg	%
	Tablet D1	Tablet D2	Tablet D3
Levetiracetam	500.00	62.5	500.00	50.0	500.00	71.4
Methocel K 100 MCR	292.00	36.5	492.00	49.2	193.00	27.6
Aerosil 200	4.00	0.5	4.00	0.4	3.50	0.5
Magnesium stearate	4.00	0.5	4.00	0.4	3.50	0.5
	Tablet D4	Tablet D5	Tablet D6
Levetiracetam	500.00	62.5	500.00	71.4	500.00	62.4
Methocel K15 MCR	288.00	36.0	—	—	—	—
Methocel K100 MCR	—	—	96.50	13.8	146.00	18.3
Kollidon SR	—	—	96.50	13.8	146.00	18.3
Aerosil 200	4.00	0.5	3.50	0.5	4.00	0.5
Magnesium stearate	8.00	1.0	3.50	0.5	4.00	0.5
	Tablet D7	Tablet D8	Tablet D9
Levetiracetam	500.00	71.4	500.00	71.4	500.00	71.4
Methocel K15 MCR-	—	—	96.50	13.8	193.00	27.6
Methocel K 100 MCR	57.90	8.3	—	—	—	—
Kollidon SR	135.10	19.3	96.50	13.8	—	—
Aerosil 200	3.50	0.5	3.50	0.5	3.50	0.5
Magnesium stearate	3.50	0.5	3.50	0.5	3.50	0.5
	Tablet D10	Tablet D11	Tablet D12
Levetiracetam	500.00	71.4	500.00	49.0	500.00	71.4
Methocel K15 MCR	158.00	22.6	510.20	50.0	144.75	20.7
Methocel K 100 MCR	—	—	—	—	—	—
Precirol ATO 5	35.00	5.0-	—	—	48.25	6.9
Aerosil 200	3.50	0.5	5.10	0.50	3.50	0.5
Magnesium stearate	3.50	0.5	5.10	0.50	3.50	0.5
	Tablet D13
Levetiracetam	500.00	71.4
Methocel K15 MCR	96.50	13.8
Methocel K 100 MCR	—	—
Precirol ATO 5	96.50	13.8
Aerosil 200	3.50	0.5
Magnesium stearate	3.50	0.5

The compound sold under the trademark Precirol® is glyceryl palmitostearate (1,2,3-propanetriol hexadecanoate octadecanoate) and is used as lipohilic and hydrophobic matrice.

The in vitro dissolution profiles in water of tablets D₁ to D₁₃ were determined according to the USP 24 (apparatus n^o 2, 100 rpm, aqueous medium 900 mL) over an interval of time of 12 h.

All the percentages of dissolution were in the ranges of the Table 3 (example 1).

Example 3

Coated Tablet with a 24 h In Vivo Release of Levetiracetam

Table 6 shows a pharmaceutical composition F which was manufactured by dry granulation process.

TABLE 6
Composition of the coated tablet F
Components                   quantities in mg
Levetiracetam                500.00
Hydroxypropylmethylcellulose 187.75
Macrogol 6000                7.00
Anhydrous colloidal silica   3.50
Magnesium stearate           1.75
Opadry ® 85F18422 white      21.00

The in vitro dissolution profiles in water of tablet F was determined according to the USP 24 (apparatus n^o 2, 100 rpm, aqueous medium 900 mL) over an interval of time of 12 h (Table 6).

TABLE 6
Percentages of dissolution of levetiracetam from tablet F.
Time Percentages
(h)  of dissolution
0.5  21
1    33
2    50
4    72
8    94
12   100

All the percentages of dissolution were in the ranges of the Table 3 (example 1).

Example 4

Table 7 shows two pharmaceutical compositions G and H which were manufactured by dry granulation process.

TABLE 7
Composition of the coated tablets G and H
	Tablet G	Tablet H
	Components	quantities in mg
	Levetiracetam	1000.00	750.00
	Hydroxypropylmethhylcellulose	375.50	281.60
	Macrogol 6000	14.00	10.50
	Anhydrous colloidal silica	7.00	5.25
	Magnesium stearate	3.50	2.65
	Opadry ® 85F18422 white	42.00	31.50

The in vitro dissolution profiles in water of tablets G and H was determined according to the USP 24 (apparatus n^o 2, 100 rpm, aqueous medium 900 mL) over an interval of time of 12 h. All the percentages of dissolution were in the ranges of the Table 3.

Example 5

Tablet I was prepared by direct compression process according to the invention with the following core compositions (Table 7).

TABLE 7
Composition of the tablet I
Components                 quantities in mg
Levetiracetam              500.00
Methocel K15M CR           369.38
Kollidon SR                123.13
Anhydrous colloidal silica 5.00
Magnesium stearate         2.50

All the percentages of dissolution were in the ranges of the Table 3.

Example 6

Tablets J and K were prepared by direct compression process according to the invention with the following core compositions (Table 8).

TABLE 8
Composition of the tablets J and K
	Tablet J	Tablet K
	Components	quantities in mg
	Levetiracetam	500.00	500.00
	Methocel K15M CR	186.00	158.00
	Anhydrous colloidal silica	3.50	3.50
	Magnesium stearate	3.50	3.50
	PEG 6000	7.00	35.00

All the percentages of dissolution were in the ranges of the Table 3.

Example 7

Tablet L was prepared by direct compression process with the following core composition (Table 9)

		Tablet L
	Components	Quantities in mg	%
	Levetiracetam	500.00	50.0
	Methocel K 15 MCR	369.40	36.9
	Pevikon P737P	123.10	12.3
	Aerosil 200	5.00	0.5
	Magnesium stearate	2.50	0.3

Compound sold under the trademark Pevikon is a PVC resin.

All the percentages of dissolution were in the ranges of the Table 3. So the formulation owing dissolution profile similar to the results shown in Table 3 is bioequivalent to tablets A, B and C.

Claims

1. A pharmaceutical composition in the form of a tablet comprising, as active ingredient, levetiracetam and, as excipient within the core of the tablet, 5.0 to 59.0% per weight of at least one hydrophilic matrix agent, with respect to the total weight of the core of the tablet.

2. The pharmaceutical composition according to claim 1, comprising levetiracetam and a water dispersible, rate controlling polymer as hydrophilic matrix agent.

3. The pharmaceutical composition according to claim 1 or 2, wherein the composition is coated.

4. The pharmaceutical composition according to claim 1, further coated with a hydrophillic polymer to improve its appearance, wherein said polymer is Opadry™.

5. The pharmaceutical composition according to claim 1, comprising 20.0 to 30.0% per weight of hydrophilic matrix agent.

6. The pharmaceutical composition according to claim 5, wherein the hydrophilic matrix agent is hydropropyl methylcellulose.

7. The pharmaceutical composition according to claim 1, comprising levetiracetam, hydroxypropyl methylcellulose and Povidone.

8. The pharmaceutical composition according to claim 1, comprising at least one gliding agent as excipient within the core of the tablet.

9. The pharmaceutical composition according to claim 8, comprising 0.3 to 3.0% per weight of gliding agent.

10. The pharmaceutical composition according to claim 8 or 9, wherein the gliding agent is anhydrous colloidal silica.

11. The pharmaceutical composition according to claim 1, comprising at least one lubricant as excipient within the core of the tablet.

12. The pharmaceutical composition according to claim 11, comprising 0.0 to 5.50% per weight of lubricant.

13. The pharmaceutical composition according to claim 11 or 12, wherein the lubricant is magnesium stearate.

14. The pharmaceutical composition according to claim 11 or 12, wherein the lubricant is macrogol 6000.

15. The pharmaceutical composition according to claim 1, comprising at least two lubricants as excipient within the core of the tablet.

16. The pharmaceutical composition according to claim 15, wherein the lubricants are magnesium stearate and macrogol 6000.

17. A pharmaceutical composition according to claim 1, comprising levetiracetam as active ingredient and 5.0 to 59.0% per weight of hydrophilic matrix agent,0.3 to 3.0% per weight of gliding agent, andup to 5.50% per weight of lubricant,

18. A pharmaceutical composition according to claim 1, comprising levetiracetam as active ingredient and 5.0 to 59.0% per weight of hydroxypropylmethylcellulose,to 3.0% per weight of anhydrous colloidal silica,to 5.0% per weight of polyethylene glycol 6000, andup to 1.0% per weight of magnesium stearate,

18. A pharmaceutical composition according to claim 1, comprising levetiracetam as active ingredient and 8.0 to 50.0% per weight of hydrophilic matrix agent,0.3 to 2.5% per weight of gliding agent, andup to 3.5% per weight of lubricant,

19. A pharmaceutical composition according to claim 1, comprising levetiracetam as active ingredient and 15.0 to 40.0% per weight of hydrophilic matrix agent,0.4 to 2.0% per weight of gliding agent, and0.4 to 1.30% per weight of lubricant,

20. A pharmaceutical composition according to claim 1, comprising levetiracetam as active ingredient and 20.0 to 30.0% per weight of hydrophilic matrix agent,0.5% per weight of gliding agent and0.4 to 1.30% per weight of lubricant

21. A pharmaceutical composition according to claim 1, comprising levetiracetam as active ingredient and 5.0 to 59.0% per weight of hydroxypropylmethylcellulose,0.3 to 2.5% per weight of anhydrous colloidal silica,0.5 to 5.0% per weight of polyethylene glycol 6000, andup to 1.0% per weight of magnesium stearate,

22. A pharmaceutical composition according to claim 1 comprising levetiracetam as active ingredient and 8.0 to 50.0% per weight of hydroxypropylmethylcellulose,0.3 to 2.5% per weight of anhydrous colloidal silica,0.5 to 1.5% per weight of polyethylene glycol 6000, andup to 0.5% per weight of magnesium stearate,

23. A pharmaceutical composition according to claim 1, comprising levetiracetam as active ingredient and 15.0 to 40.0% per weight of hydroxypropylmethylcellulose,0.4 to 2.0% per weight of anhydrous colloidal silica,0.7 to 1.5% per weight of polyethylene glycol 6000, and0.1 to 0.3% per weight of magnesium stearate,

24. A pharmaceutical composition according to claim 1, comprising levetiracetam as active ingredient and 20.0 to 30.0% per weight of hydroxypropylmethylcellulose,0 to 25% per weight of inert or lipophilic matrix agent,0.5% per weight of anhydrous colloidal silica,1.0% per weight of polyethylene glycol 6000, and0.25% per weight of magnesium stearate,

25. A pharmaceutical composition according to claim 1, comprising levetiracetam as active ingredient and 20.0 to 30.0% per weight of hydroxypropylmethylcellulose,0.5% per weight of anhydrous colloidal silica,1.0% per weight of polyethylene glycol 6000, and0.25% per weight of magnesium stearate,

26. A pharmaceutical formulation in tablet form comprising levetiracetam having the following dissolution profile in water according to the USP 24 (apparatus no 2, 100 rpm, aqueous medium 900 mL):

27. The formulation of claim 26 having the dissolution profile:

28. The formulation according to claim 26 comprising as a percentage by weight of the table core about 70% levetiracetam, about 19-28% hydroxypropyl methylcellulose, and, optionally, about 2-14% Povidone.

29. The formulation of claim 1 comprising 30.0 to 85.0% per weight of levetiracetam with respect to the total weight of the core of the tablet.

30. The formulation of claim 29 wherein the hydrophilic matrix agent is hydroxypropyl methylcellulose and further optionally comprising about 2-14% Povidone.