Tablet comprising levetiracetam

Abstract

To provide a tablet comprising levetiracetam with good dissolution property.SOLUTION: The present invention provides a tablet comprising levetiracetam, sodium croscarmellose, and one or more additives selected from the group consisting of sucrose fatty acid ester, hardened oil, magnesium stearate, and calcium stearate.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a levetiracetam-containing tablet having good dissolution properties. [Background technology]

[0002] Levetiracetam is a compound represented by the chemical name: (2S)-2-(2-Oxopyrrolidine-1-yl)butyramide. Currently, it is known that levetiracetam is used for partial seizures (including secondarily generalized seizures) in epilepsy patients, and for combination therapy with antiepileptic drugs for tonic-clonic seizures in epilepsy patients for whom other antiepileptic drugs are not sufficiently effective (Non-Patent Document 1). Patent Document 1 also describes a pharmaceutical composition containing levetiracetam, and 2.0-9.0% by weight of a disintegrant, 0.0-3.0% by weight of a lubricant, 0.5-6.0% by weight of a binder, and 0.0-1.0% by weight of a lubricant based on the total weight of the pharmaceutical composition.

[0003] Furthermore, Patent Document 2 describes a levetiracetam-containing pharmaceutical composition that contains levetiracetam and at least one of sodium stearyl fumarate and calcium stearate.

[0004] However, there is no description of a levetiracetam tablet containing levetiracetam, croscarmellose sodium, hydrogenated oil, etc. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Special Publication No. 2009-502835 [Patent Document 2] JP 2018-70534 A [Non-patent literature]

[0006] [Non-Patent Document 1] Package insert "E Keppra Tablets 250 mg / 500 mg", revised September 2018 (13th edition) Summary of the Invention [Problem to be solved by the invention]

[0007] An object of the present invention is to provide a levetiracetam tablet having good dissolution properties, and further to provide a levetiracetam tablet having good tablet hardness and disintegrability. [Means for solving the problem]

[0008] The present invention relates to a tablet comprising levetiracetam, croscarmellose sodium, and one or more additives selected from the group consisting of sucrose fatty acid esters, hydrogenated oils, magnesium stearate, and calcium stearate.

[0009] That is, the present invention provides (1) A tablet comprising levetiracetam, croscarmellose sodium, and one or more additives selected from the group consisting of sucrose fatty acid esters, hardened oils, magnesium stearate, and calcium stearate; (2) The tablet according to (1) above, wherein the additive is a sucrose fatty acid ester and / or a hardened oil. (3) The tablet according to any one of (1) to (2), wherein the sedimentation volume of croscarmellose sodium is 10 to 18 ml. (4) The tablet according to any one of (1) to (3), comprising 1 to 10% by weight of croscarmellose sodium per tablet. (5) The tablet according to any one of (1) to (4), comprising 0.1 to 3% by weight of hydrogenated oil per tablet. (6) The tablet according to any one of (1) to (4), comprising 0.1 to 3% by weight of sucrose fatty acid ester per tablet. (7) The tablet according to any one of (1) to (6), wherein each tablet contains 80 to 89% levetiracetam. Effect of the Invention

[0010] According to the present invention, by selecting a specific additive, it is possible to provide a levetiracetam tablet which exhibits a rapid dissolution behavior of levetiracetam from the tablet and further has good tablet hardness and disintegrability. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The tablet containing levetiracetam of the present invention will be described below.

[0012] Levetiracetam used in the present invention is used in combination therapy with antiepileptic drugs for partial seizures (including secondarily generalized seizures) in epilepsy patients and tonic-clonic seizures in epilepsy patients who do not respond adequately to other antiepileptic drugs.

[0013] The usual adult dosage is 1000mg of levetiracetam taken orally twice a day. The dosage can be increased or decreased depending on symptoms up to a maximum of 3000mg per day, but increases should be made at intervals of at least 2 weeks, with increments of 1000mg or less per day.

[0014] In addition, children aged 4 years or older are usually given 20mg / kg of levetiracetam per day, divided into two doses, orally. The dose can be increased or decreased depending on symptoms, up to a maximum of 60mg / kg per day, but increases should be made at intervals of at least 2 weeks, with increments of 20mg / kg or less per day. However, for children weighing 50kg or more, the same dosage and administration method as for adults should be used.

[0015] The content of levetiracetam is 80 to 92%, and in one embodiment 85 to 89%, based on the total weight of the tablet.

[0016] In this specification, the sedimentation volume refers to the sedimentation volume of the sample read from the measuring cylinder after placing 75 ml of water in a 100 ml stoppered measuring cylinder, adding 1.5 g of the sample in 0.5 g increments while shaking vigorously, adding more water to make 100 ml, shaking well until the sample is uniformly dispersed, and then leaving the cylinder to stand for 4 hours.

[0017] The croscarmellose sodium used in the present invention is not particularly limited as long as it is pharma- ceutically acceptable. In one embodiment, the croscarmellose sodium has a sedimentation volume of 10 to 18 ml, and the croscarmellose sodium having a sedimentation volume of 10 to 18 ml is defined as the croscarmellose sodium having a sedimentation volume of 10 to 18 ml when the solvent is water. Specifically, for example, in one embodiment, KICCOLATE ND-200 (Nichirin Chemical Industry Co., Ltd.) and VIVASOL SF200 (JRS PHARMA) can be mentioned. In one embodiment, KICCOLATE ND-200 (Nichirin Chemical Industry Co., Ltd.) can be mentioned.

[0018] The blending amount of croscarmellose sodium is 1 to 10% by weight, in one embodiment 2 to 8% by weight, and in one embodiment 4 to 6% by weight, based on the total weight of the tablet.

[0019] The hardened oil used in the present invention is not particularly limited as long as it is pharmaceutical acceptable.Hydrogenated oils include, for example, hydrogenated vegetable oils such as castor oil, rapeseed oil, cottonseed oil, soybean oil, coconut oil, palm kernel oil, palm oil, and hydrogenated animal oils such as beef tallow, whale oil, and fish oil.In one embodiment, hydrogenated vegetable oils such as castor oil, rapeseed oil, cottonseed oil, soybean oil, coconut oil, palm kernel oil, and palm oil are included.In one embodiment, castor oil is included.

[0020] The amount of the hardened oil is 0.1 to 3% by weight, in one embodiment 0.3 to 2% by weight, and in another embodiment 0.6 to 1.2% by weight, based on the total weight of the tablet. The hardened oil may be used in combination with the sucrose fatty acid ester.

[0021] The sucrose fatty acid ester used in the present invention is not particularly limited as long as it is pharma- ceutical acceptable. The amount of the sucrose fatty acid ester is 0.1 to 3% by weight, in one embodiment 0.3 to 2% by weight, and in another embodiment 0.6 to 1.2% by weight, based on the total weight of the tablet. The sucrose fatty acid ester may be used in combination with a hardened oil.

[0022] The tablet of the present invention may be a plain tablet, a coated tablet, or an orally disintegrating tablet.

[0023] The tablet containing levetiracetam of the present invention is formulated by further using various pharmaceutical additives as appropriate within the scope of achieving the desired effect of the present invention. Such pharmaceutical additives are not particularly limited as long as they are pharmaceutical and pharmacologically acceptable. For example, excipients, binders, disintegrants, acidulants, effervescent agents, sweeteners, flavors, colorants, buffers, antioxidants, surfactants, film coating agents, etc. may be used.

[0024] Examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, crystalline cellulose, low-substituted hydroxypropylcellulose, carmellose sodium, gum arabic, dextrin, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminometasilicate.

[0025] Examples of binders include gum arabic, hypromellose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, and the like.

[0026] Examples of disintegrants include corn starch, potato starch, carmellose calcium, carmellose sodium, low-substituted hydroxypropyl cellulose, and the like.

[0027] Examples of acidulants include citric acid, tartaric acid, malic acid, etc.

[0028] The foaming agent may, for example, be sodium bicarbonate.

[0029] Examples of sweeteners include sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia, and thaumatin.

[0030] Examples of the flavoring include lemon, lemon lime, orange, menthol, and the like.

[0031] Examples of colorants include Food Yellow No. 4, Food Yellow No. 5, Food Red No. 3, Food Red No. 102, Food Blue No. 3, Food Yellow No. 4 Aluminum Lake, Food Yellow No. 5 Aluminum Lake, Food Red No. 3 Aluminum Lake, Food Blue No. 2 Aluminum Lake, Yellow Ferric Oxide, Ferric Oxide, etc. Colorants can also be used in the coating layer.

[0032] Examples of the buffer include citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid or a salt thereof, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine or a salt thereof, magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid, boric acid or a salt thereof, and the like.

[0033] Examples of the antioxidant include ascorbic acid, dibutylhydroxytoluene, and propyl gallate.

[0034] Examples of the surfactant include polysorbate 80, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil, and the like.

[0035] Examples of film coating agents include hypromellose, hydroxypropyl cellulose, polyvinyl alcohol, titanium oxide, talc, premix coating agents, etc. Examples of premix coating agents include Opadry II, Opadry QX, and Opadry ambII, and some embodiments include Opadry II.

[0036] The tablet of the present invention can be produced by a method known per se, including steps of pulverization, mixing, granulation, drying, sieving, molding (tabletting), coating, etc. In detail, the tablet of the present invention is produced by mixing levetiracetam, light anhydrous silicic acid, and croscarmellose sodium, fluidized bed granulation using an aqueous solution of HPC-L or HPC-SSL as a binding liquid, drying, sieving, mixing with croscarmellose sodium, crystalline cellulose, and a lubricant, tableting, forming uncoated tablets, and then coating the uncoated tablets with Opadry II, a premix coating agent. More specifically, for uncoated tablets, for example, levetiracetam, excipients, light anhydrous silicic acid, and croscarmellose sodium are mixed, and the mixture is sprayed and dried with a binder solution prepared by dissolving and dispersing a binder in a pharma- ceutically acceptable solvent, to obtain granules, which are then blended with a lubricant and molded (compressed) to produce uncoated tablets; alternatively, levetiracetam, excipients, light anhydrous silicic acid, croscarmellose sodium, and a lubricant are mixed, and the mixture is sprayed and dried with a binder solution prepared by dissolving and dispersing a binder in a pharma- ceutically acceptable solvent, to obtain granules, which are then blended with croscarmellose sodium and molded (compressed) to produce uncoated tablets; alternatively, excipients are mixed, and the mixture is sprayed and dried with a binder solution prepared by dissolving and dispersing levetiracetam and a binder in a pharma- ceutically acceptable solvent, to obtain granules, which are then blended with a lubricant and molded (compressed) to produce uncoated tablets. In addition, levetiracetam, light anhydrous silicic acid, croscarmellose sodium, and a binder are dissolved and dispersed in a pharma- ceutically acceptable solvent as excipients, and the binder solution is sprayed and dried to obtain granules, which are then mixed with a lubricant and molded (compressed) to produce plain tablets.

[0037] Coated tablets are produced by applying a coating layer to a plain tablet. EXAMPLES

[0038] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to the following examples in any way.

[0039] Example 1 250.0 g of levetiracetam, 5.5 g of croscarmellose sodium (Nichirin Chemical Industry Kiccolate ND-200), and 1.0 g of light anhydrous silicic acid (Nippon Aerosil Aerosil 200) were mixed. The mixture was then crushed using a sieve with an opening of 850 μm to obtain a mixed powder. 8.2 g of hydroxypropyl cellulose (Nippon Soda HPC-SSL) was dissolved in 155.8 g of water to obtain a binding liquid. The mixed powder was placed in a fluidized bed granulator (Powrex MP-01), and the binding liquid was sprayed onto the mixture while fluidizing it to granulate it. After granulation, the mixture was dried using the fluidized bed granulator. The granulated product was sized using a power mill (Dalton P-04S, screen diameter 0.5 mm). The sized product, 5.5 g of croscarmellose sodium, 3.4 g of crystalline cellulose (Asahi Kasei Ceolas KG-1000), and 3.4 g of magnesium stearate (Taihei Chemical Industry Vegetable) were put into a bag and mixed to prepare granules for tableting. The granules for tableting were compressed using a rotary tableting machine (Kikusui Seisakusho VEL5) and an oval-shaped punch with a major axis of 16.4 mm and a minor axis of 7.7 mm at a tableting pressure of 10 or 12 kN to obtain plain tablets. 100 g of Opadry (Colorcon OPADRY2) was dissolved and dispersed in 500 g of water to prepare a coating liquid. Using a coating device (Powrex Doriacoater DRC-300), the coating liquid was sprayed onto the plain tablets until a predetermined mass was reached, followed by film coating to obtain the tablets of Example 1 (568.0 mg per tablet).

[0040] Example 2 Tablets of Example 2 (568.0 mg per tablet) were obtained in the same manner as in Example 1, except that magnesium stearate (Taihei Chemical Industry Co., Ltd., vegetable-based) was changed to calcium stearate (Taihei Chemical Industry Co., Ltd.).

[0041] Example 3 Tablets of Example 3 were obtained (568.0 mg per tablet) in the same manner as in Example 1, except that magnesium stearate (Taihei Chemical Industry Co., Ltd., vegetable-based) was replaced with hardened oil (Freund Corporation, Lubriwax 101).

[0042] Example 4 Tablets of Example 4 were obtained in the same manner as in Example 1, except that 3.4 g of magnesium stearate (Taihei Chemical Industry Co., Ltd., vegetable-based) was changed to 1.7 g of hardened oil (Freund Corporation, LUBRIWAX 101) and 1.7 g of sucrose fatty acid ester (Mitsubishi Chemical Foods Corporation, SURFHOPE SE PHARMA J-1816). (568.0 mg per tablet)

[0043] Example 5 5000g of levetiracetam, 110g of croscarmellose sodium (Nichirin Chemical Industry Kiccolate ND-200), and 20g of light anhydrous silicic acid (Nippon Aerosil Aerosil 200) were mixed. The mixture was then crushed using a power mill (Dalton P-3S, screen diameter 0.5mm) to obtain a mixed powder. 164g of hydroxypropyl cellulose (Nippon Soda HPC-SSL) was dissolved in 3116g of water to obtain a binding liquid. The mixed powder was placed in a fluidized bed granulator (Freund NFLO-5), and the binding liquid was sprayed onto the mixture while fluidizing it to obtain granulation. After completion of granulation, the mixture was dried using a fluidized bed granulator. The granulated product was sized using a power mill (Dalton P-3S, screen diameter 0.5mm). 264.7 g of the sized product, 5.5 g of croscarmellose sodium, 3.4 g of crystalline cellulose (Asahi Kasei Ceolas KG-1000), and 3.4 g of sucrose fatty acid ester (Mitsubishi Chemical Foods Surfhope SE PHARMA J-1816) were put into a bag and mixed to prepare granules for tableting. The granules for tableting were compressed using a rotary tableting machine (Kikusui Seisakusho VEL5) and an oval-shaped punch with a major axis of 16.4 mm and a minor axis of 7.7 mm at a tableting pressure of 10 kN to obtain plain tablets. 50 g of Opadry (Colorcon OPADRY2) was dissolved and dispersed in 250 g of water to prepare a coating liquid. Using a coating device (Powrex Doriacoater DRC-300), the coating liquid was sprayed onto the plain tablets until a predetermined mass was reached, and film coating was performed to obtain tablets of Example 5 (568.0 mg per tablet).

[0044] The formulation amounts of the tablets obtained in Examples 1 to 5 are shown in Table 1.

[0045] [Table 1]

[0046] Test Example 1: Dissolution test The tablets obtained in Examples 1 to 5 were tested using water as a dissolution test medium according to the dissolution test method (paddle method) of the General Tests of the Japanese Pharmacopoeia, 17th Edition. Furthermore, the tablets obtained in Examples 3, 4, and 5 were also tested using water as a dissolution test medium according to the Dissolution Test Method (paddle method) of the General Tests of the Japanese Pharmacopoeia, 17th Edition after storage for 10 days at 25°C and 75% RH without packaging.

[0047] The results of the dissolution test are shown in Table 2.

[0048] [Table 2]

[0049] As a result, Examples 1 to 5 containing croscarmellose sodium (Kiccolate ND-200 (sedimentation volume 10 to 18 ml)) showed good dissolution properties. Furthermore, Examples 3, 4, and 5 maintained good dissolution properties even after storage for 10 days at 25°C and 75% RH without packaging.

[0050] Test Example 2: Disintegration test The test was carried out using water as the test liquid and the disintegration test method of the general test method of the Japanese Pharmacopoeia, 17th Edition. The test was carried out on 6 tablets each of the tablets obtained in Examples 1 to 5, and the disintegration time was measured using a stopwatch.

[0051] Test Example 3: Tablet Hardness Measurement Ten tablets each of the tablets obtained in Examples 1 to 5 were measured using a Schleuniger tablet hardness tester.

[0052] Test Example 4: Wear test The test was carried out according to the tablet friability test method in the Reference Information of the Japanese Pharmacopoeia, 17th Edition. The test was carried out using as close as possible to 6.5 g of the tablets obtained in Examples 1 to 5 as samples.

[0053] The results of the disintegration test, tablet hardness measurement and friability test are shown in Table 3.

[0054] [Table 3]

[0055] As a result, the tablets of Examples 1 to 5, which used croscarmellose sodium (Kiccolate ND-200 (sedimentation volume 10 to 18 ml)), magnesium stearate, calcium stearate, hydrogenated oil, and sucrose fatty acid ester, had a tablet hardness of 70 N or more and a disintegration time of 6 minutes 30 seconds or less. In particular, the tablets of Examples 3, 4, and 5, which used hydrogenated oil and sucrose fatty acid ester, had a tablet hardness of 100 N or more and a disintegration time of 4 minutes 30 seconds or less.

Claims

1. A tablet comprising levetiracetam, croscarmellose sodium having a sedimentation volume of 10 to 18 ml, and one or more additives selected from the group consisting of sucrose fatty acid esters, hardened oils, magnesium stearate, and calcium stearate.

2. 2. The tablet according to claim 1, which contains 1 to 10% by weight of croscarmellose sodium per tablet.

3. The tablet according to any one of claims 1 to 2, comprising 0.1 to 3% by weight of hardened oil per tablet.

4. 3. The tablet according to claim 1, comprising 0.1 to 3% by weight of sucrose fatty acid ester per tablet.

5. The tablet according to any one of claims 1 to 4, comprising 80 to 89% by weight of levetiracetam per tablet.

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