JP2024180618A - Tablets containing levetiracetam - Google Patents

Abstract

[Problem] The present invention aims to provide a levetiracetam-containing tablet with good dissolution. [Solution] The present invention provides a tablet containing 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. [Selected Figures] None

Description

The present invention relates to a tablet containing levetiracetam that has good dissolution properties.

Levetiracetam is a compound with the chemical name (2S)-2-(2-Oxopyrrolidine-1-yl)butyramide. Currently, levetiracetam is known to be used for partial seizures (including secondarily generalized seizures) in epilepsy patients, and as a combination therapy with antiepileptic drugs for tonic-clonic seizures in epilepsy patients who do not respond adequately to other antiepileptic drugs (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.

Patent Document 2 describes a pharmaceutical composition containing levetiracetam, which is characterized by containing levetiracetam and at least one of sodium stearyl fumarate and calcium stearate.

However, there is no description of levetiracetam tablets containing levetiracetam, croscarmellose sodium, hydrogenated oil, etc.

Special Publication No. 2009-502835 JP 2018-70534 A

Package insert "E Keppra Tablets 250 mg/500 mg", revised September 2018 (13th edition)

The object of the present invention is to provide a levetiracetam tablet having good dissolution characteristics, and further, to provide a levetiracetam tablet having good tablet hardness and disintegrability.

The present invention relates to a tablet containing 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.

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 the above (1), 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 hardened 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) above, wherein each tablet contains 80 to 89% levetiracetam.

According to the present invention, by selecting a specific additive, it is possible to provide a levetiracetam tablet that exhibits rapid dissolution behavior from the tablet and further has good tablet hardness and disintegrability.

The following describes the tablets containing levetiracetam of the present invention.

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.

Adults are usually orally administered 1,000 mg of levetiracetam per day, divided into two doses. The dosage may be increased or decreased as needed depending on symptoms, up to a maximum of 3,000 mg per day, but increases should be made at intervals of at least two weeks, with increments of 1,000 mg or less per day.

In addition, children aged 4 years or older are usually orally administered 20 mg/kg of levetiracetam per day in two divided doses. The dose can be increased or decreased as appropriate, depending on symptoms, so long as it does not exceed 60 mg/kg per day, but increases should be made in increments of 20 mg/kg or less per day, with an interval of at least two weeks. However, for children weighing 50 kg or more, the same dosage and administration method as for adults should be used.

The amount of levetiracetam in the tablet is 80-92%, and in some embodiments, 85-89%.

In this specification, the sedimentation volume refers to the sedimentation volume of the sample measured from a 100-ml stoppered measuring cylinder after adding 75 ml of water, 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 for 4 hours.

The croscarmellose sodium used in the present invention is not particularly limited as long as it is pharma- ceutical acceptable. In one embodiment, the croscarmellose sodium has a sedimentation volume of 10 to 18 ml, which is defined as croscarmellose sodium having a sedimentation volume of 10 to 18 ml when the solvent is water. Specific examples of the croscarmellose sodium include KICCOLATE ND-200 (Nichirin Chemical Industry Co., Ltd.) and VIVASOL SF200 (JRS PHARMA). In one embodiment, KICCOLATE ND-200 (Nichirin Chemical Industry Co., Ltd.) is used.

The amount of croscarmellose sodium is 1-10% by weight, in one embodiment 2-8% by weight, and in another embodiment 4-6% by weight, based on the total weight of the tablet.

The hydrogenated oil used in the present invention is not particularly limited as long as it is pharma- ceutical acceptable. Examples of hydrogenated oils include hydrogenated vegetable oils such as castor oil, rapeseed oil, cottonseed oil, soybean oil, coconut oil, palm kernel oil, and 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.

The amount of hydrogenated oil is 0.1 to 3% by weight, in some embodiments 0.3 to 2% by weight, and in some embodiments 0.6 to 1.2% by weight, based on the total weight of the tablet. It may also be used in combination with sucrose fatty acid ester.

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. It may also be used in combination with a hardened oil.

The tablets in the present invention may be plain tablets, coated tablets, or orally disintegrating tablets.

The tablets containing levetiracetam of the present invention are formulated by further using various pharmaceutical additives as appropriate within the scope of achieving the desired effects of the present invention. There are no particular limitations on such pharmaceutical additives as long as they are pharma- ceutical and pharmacologically acceptable. For example, excipients, binders, disintegrants, acidulants, effervescent agents, sweeteners, flavorings, colorants, buffers, antioxidants, surfactants, film coating agents, etc. may be used.

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, magnesium aluminometasilicate, etc.

Examples of binders include gum arabic, hypromellose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, etc.

Examples of disintegrants include corn starch, potato starch, carmellose calcium, carmellose sodium, low-substituted hydroxypropyl cellulose, etc.

Examples of acidulants include citric acid, tartaric acid, malic acid, etc.

Examples of foaming agents include baking soda.

Examples of sweeteners include sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia, thaumatin, etc.

Fragrances include, for example, lemon, lemon lime, orange, menthol, etc.

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.

Buffering agents include citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid or its salts, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine or its salts, magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid, boric acid or its salts, etc.

Examples of antioxidants include ascorbic acid, dibutylhydroxytoluene, and propyl gallate.

Examples of surfactants include polysorbate 80, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil, etc.

Examples of film coating agents include hypromellose, hydroxypropyl cellulose, polyvinyl alcohol, titanium oxide, talc, premix coating agents, etc. Premix coating agents include, in some embodiments, Opadry II, Opadry QX, and Opadry amb II, and in some embodiments, Opadry II.

The tablet of the present invention can be manufactured 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 manufactured 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, preparing 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; or 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; or an excipient is 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, the excipients, levetiracetam, light anhydrous silicic acid, croscarmellose sodium, and a binder are dissolved and dispersed in a pharma- ceutically acceptable solvent, sprayed and dried to obtain a binder solution, which is then mixed with a lubricant and molded (compressed) to produce plain tablets.

Coated tablets are produced by applying a coating layer to plain tablets.

The present invention will be explained in more detail below with reference to examples, but the present invention is not limited to the following examples.

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 charged into a fluidized bed granulator (Powrex MP-01), and the binding liquid was sprayed onto the mixture while fluidizing it, to thereby granulate it. After completion of granulation, the mixture was dried using a 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 solution. Using a coating device (Powrex Doriacoater DRC-300), the coating solution 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).

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.).

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).

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 origin) 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)

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 thereby 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 tableted using a rotary tablet press (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 weight was reached, followed by film coating to obtain tablets of Example 5 (568.0 mg per tablet).

The compounding amounts of the tablets obtained in Examples 1 to 5 are shown in Table 1.

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 after storage for 10 days at 25°C and 75% RH without packaging, 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.

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

As a result, Examples 1 to 5, which contain 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.

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 six tablets each of the tablets obtained in Examples 1 to 5, and the disintegration time was measured using a stopwatch.

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.

Test Example 4: Friability Test
The test was carried out according to the tablet friability test method in the Reference Information of the 17th Edition of the Japanese Pharmacopoeia. 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.

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

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 (5)

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, hydrogenated oils, magnesium stearate, and calcium stearate. The tablet according to claim 1, which contains 1 to 10% by weight of croscarmellose sodium per tablet. The tablet according to any one of claims 1 to 2, containing 0.1 to 3% by weight of hydrogenated oil per tablet. The tablet according to any one of claims 1 to 2, containing 0.1 to 3% by weight of sucrose fatty acid ester per tablet. The tablet according to any one of claims 1 to 4, containing 80 to 89% by weight of levetiracetam per tablet.