JP7362302B2 - Tablets containing levetiracetam and their manufacturing method - Google Patents

Description

The present invention relates to high-content levetiracetam tablets with good manufacturability and tablet strength, and a method for manufacturing the same.

Levetiracetam (chemical name: (2S)-2-(2-Oxopyrrolidine-1-yl)butyramide) is a pyrrolidone derivative antiepileptic drug that has a specific affinity for synaptic vesicle protein 2A (SV2A) in the brain. It binds to and exhibits antiepileptic effects. Because existing anti-epileptic drugs had no known binding affinity with SV2A, levetiracetam was developed as an anti-epileptic drug with a new mechanism of action different from the known mechanisms of action, and in 1999 It was first approved in the United States and in Japan in 2010.

Commercially available levetiracetam tablets contain 250 mg or 500 mg of levetiracetam. Such tablets containing a large amount of active ingredients are large and difficult for patients to take. Therefore, miniaturization of tablets is desired.

On the other hand, the manufacture of tablets requires many additives such as excipients, binders, disintegrants, flow agents, and lubricants. In order to make tablets smaller, it is necessary to reduce the amount of each additive in the tablet, which increases the content ratio of active ingredients. Therefore, unless the active ingredient has properties suitable for tabletting, it is difficult to make tablets smaller.

Levetiracetam does not have good compression moldability and tableting problems such as capping or lamination occur during the tableting process, making it difficult to obtain levetiracetam tablets with a high content. Therefore, there is a need for a method that can successfully produce high-content levetiracetam tablets.

Tablets with a high content of levetiracetam are already known. In Patent Document 1, based on the total weight of the tablet composition, 2.0 to 9.0% by weight of a disintegrant, 0.0 to 3.0% by weight of a lubricant, 0.5 to 6.0% by weight of a binder, and 0.0-1.0% by weight of a lubricant, tablets containing 90% or more of levetiracetam are disclosed. However, Patent Document 1 is a technique for suppressing the delay in drug release over time in tablets with a high content of levetiracetam, and does not provide data regarding the strength or manufacturability of the tablets. Furthermore, it is not indicated what kind of properties the levetiracetam contained in the tablets has.

Patent Document 2 also discloses a tablet with a high content of levetiracetam. The levetiracetam contained in this tablet is characterized by an average particle size of 50 μm or less, and by controlling the particle size to this particle size, a high-content levetiracetam tablet has good disintegration properties and a tablet suitable for film coating. It has been shown that strength can be obtained.
However, the tablet manufacturing process in Patent Document 2 includes a step of adjusting the average particle size of levetiracetam to 50 μm or less, preparing a mixed powder of levetiracetam and additives, preparing a binding liquid, stirring granulation, crushing, and drying. Many steps are required, including crushing, sizing, preparation of granules for tabletting, and tableting.
Furthermore, no data regarding manufacturability during tableting is shown.

Although miniaturized high-content levetiracetam tablets are known, we have developed a high-content levetiracetam tablet that not only has good tablet strength, disintegration, and dissolution properties, but also has excellent manufacturability and manufacturing cost, and its manufacturing method. was required.

Special Publication No. 2009-502835 Special table 2017-206454 publication

Powder Diffraction, Vol. 29, No. 1, March 2014, X-ray powder diffraction data for levetiracetam, (Kai Lin Xu, Bing Liang, Xiao Qing Wu, Li Li Zhang, Pei Xiao T Ang, and Hui Lia)

An object of the present invention is to realize levetiracetam-containing tablets having good manufacturability and tablet strength using a simple and inexpensive manufacturing method.

As a result of intensive studies to solve the above problems, the present inventors have found that the characteristics of the levetiracetam crystals contained in the composition significantly affect not only tablet strength but also tablet manufacturability and manufacturing cost. I found out. That is, when a composition containing levetiracetam is measured using a powder X-ray diffractometer using CuKα as a radiation source, the integrated intensity of the diffraction peak appearing at a diffraction angle (2θ) = 15.0° ± 0.2° is When the sum is defined as integrated intensity A (cps/deg), and the sum of the integrated intensities of the diffraction peaks appearing at the diffraction angle (2θ) = 18.5 ± 0.2° is defined as integrated intensity B (cps/deg), Both diffraction peaks are based on the crystal structure of levetiracetam), and when a composition containing levetiracetam with a ratio of integrated intensity B/integrated intensity A of less than 0.45 is used, it is difficult to perform compression such as capping or lamination during the tableting process. We have found that tablet failure occurs and compression molding is not possible, or even if compression molding is possible, sufficient tablet strength cannot be obtained.
On the other hand, when a composition containing levetiracetam with a ratio of integral strength B/integral strength A of 0.45 or more is compression molded, tableting failure does not occur and tablets with excellent tablet strength and other tablet properties are obtained. The present invention was completed based on the discovery that the following can be obtained.

That is, the present invention includes the following inventions.
(1) When measured with a powder X-ray diffractometer using CuKα as a radiation source, the sum of the integrated intensities of the diffraction peaks detected at a diffraction angle (2θ) = 15.0 ± 0.2° is defined as the integrated intensity A, When the sum of integrated intensities of diffraction peaks detected at diffraction angle (2θ) = 18.5 ± 0.2° is defined as integrated intensity B, levetiracetam has a ratio of integrated intensity B/integrated intensity A of 0.45 or more. A levetiracetam-containing tablet, characterized in that it has a composition comprising:
(2) The levetiracetam-containing tablet according to (1), wherein the levetiracetam is monoclinic.
(3) The levetiracetam-containing tablet according to (1) or (2), wherein the tablet contains the levetiracetam and a pharmaceutically acceptable additive, and the levetiracetam content is 90% by weight or more. Tablet.
(4) The pharmaceutically acceptable additive is one or more components selected from the group consisting of macrogol 6000, low-substituted hydroxypropyl cellulose, light anhydrous silicic acid, and magnesium stearate. , the levetiracetam-containing tablet according to (3).
(5) Contains 0 to 1% by weight of macrogol 6000, 4 to 6% by weight of low-substituted hydroxypropyl cellulose, 1 to 3% by weight of light anhydrous silicic acid, and 0.1 to 2% by weight of magnesium stearate. The levetiracetam-containing tablet according to (4), characterized in that:
(6) By granulating levetiracetam whose integral strength B/integral strength A ratio is less than 0.45 and a pharmaceutically acceptable additive by dry granulation or fluidized bed granulation, Any one of (1) to (5), characterized in that a composition containing levetiracetam having a ratio of strength B/integrated strength A of 0.45 or more is produced and tableted by compression molding. A method for producing a levetiracetam-containing tablet as described in .

According to the present invention, high-content levetiracetam tablets with good manufacturability and tablet strength can be stably manufactured using a simple and inexpensive manufacturing method, making it possible to provide medical institutions and patients with easy-to-take tablets. became.

Levetiracetam in this specification is monoclinic as described in Non-Patent Document 1, has a space group of P21, has lattice constants of a=9.197 Å, b=8.006 Å, c=6.289 Å, α=90°, and β. = 108.457° and γ = 90°.

The measurement conditions for powder X-ray diffraction in this specification are not particularly limited, but levetiracetam related to the present invention was measured using a powder X-ray diffractometer using CuKα as a radiation source at a diffraction angle (2θ) in the range of 10 to 20°. When this happens, characteristic diffraction peaks appear around 2θ=15° and around 2θ=18.5°.

The diffraction peaks detected at 2θ=15°±0.2° in this specification correspond to the (001) plane, (110) plane, and (10-1) plane of the crystal lattice of levetiracetam in Non-Patent Document 1. This is the diffraction peak, and the value obtained by summing up the respective integrated intensities is defined as the integrated intensity A.

The diffraction peaks detected at 2θ=18.5°±0.2° in this specification are the diffraction peaks corresponding to the (011) plane and (11-1) plane of the crystal lattice of levetiracetam in Non-Patent Document 1. The integrated intensity B is the sum of the respective integrated intensities.

In this specification, capping, which is a tablet failure, refers to a phenomenon in which a portion of the upper or lower surface of a tablet peels off or is missing, and occurs during tablet compression, occurs some time after tablet compression, or occurs when a tablet is compressed. It may occur when receiving some kind of shock. Capping deteriorates the appearance of the tablet and significantly reduces its commercial value.

In this specification, lamination, which is a tableting failure, refers to a phenomenon in which layers peel or split in the horizontal direction of the side surface of a tablet. This may occur due to impact. Since the lamination loses its tablet shape, it has no commercial value.

The pharmaceutically acceptable additives herein are not particularly limited, but include components that can be mixed with levetiracetam, such as excipients, binders, disintegrants, flow agents, lubricants, etc. Can be done.

Examples of "excipients" in this specification include lactose (lactose hydrate, anhydrous lactose), sucrose, sucrose, fructose, fructooligo, etc., glucose, maltose, reduced maltose, powdered sugar, powdered candy, reduced lactose, etc. sugar alcohols such as erythritol, sorbitol, maltitol, xylitol, and D-mannitol, kaolin, calcium hydrogen phosphate, calcium sulfate, calcium carbonate, starch (e.g., corn starch, potato starch, rice starch, wheat starch, etc.) natural starch), crystalline cellulose, etc.

Examples of the "disintegrant" herein include croscarmellose sodium, carmellose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone, carmellose, and the like. Preferred is low-substituted hydroxypropyl cellulose. The content of the disintegrant relative to the tablet weight is preferably 1 to 10% by weight, more preferably 2 to 8% by weight, and particularly preferably 4 to 6% by weight.

Examples of the "binder" herein include hypromellose, corn starch, pregelatinized starch, partially pregelatinized starch, gum arabic, gum arabic powder, gelatin, agar, dextrin, pullulan, polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose, ethylcellulose. , carboxymethylethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, macrogol 6000, etc., with macrogol 6000 being preferred. The content of the binder relative to the tablet weight is preferably 6% by weight or less, more preferably 0 to 5% by weight, and particularly preferably 0 to 1% by weight.

Examples of the "plasticizing agent" in this specification include talc, hydrated silicon dioxide, light anhydrous silicic acid, etc., and preferably light anhydrous silicic acid. The content of the fluidizing agent relative to the tablet weight is preferably 0.5 to 5% by weight, more preferably 1 to 3% by weight.

Examples of the "lubricating agent" in this specification include stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated oil, sodium stearyl fumarate, sucrose fatty acid ester, and the like. Preferably it is magnesium stearate. The content of the lubricant relative to the tablet weight is preferably 0.1 to 3% by weight, more preferably 0.1 to 2% by weight.

This preparation may contain a coating agent, and any coating agent that can be used for pharmaceutical purposes may be used. For example, hypromellose, polyvinyl alcohol, ethyl cellulose, carboxymethyl ethyl cellulose, carmellose, carmellose sodium, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, PVA copolymer, ethyl acrylate/methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer, Opadry , carnauba wax, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer, and the like.

Next, the present invention will be explained in detail with reference to Examples, but the present invention is not limited to these.

Levetiracetam drug substance I was measured in the range of diffraction angle (2θ) = 5° to 20° using a powder X-ray diffractometer (MiniFlex, manufactured by Rigaku Denki) using CuKα as a radiation source, and 2θ = 15.0° ± As a result of determining the integrated intensity A of the diffraction peak at 0.2° and the integrated intensity B of the diffraction peak at 2θ=18.5°±0.2°, B/A=0.150.
It consists of 300 g of this levetiracetam drug substance I, 13.8 g of low-substituted hydroxypropyl cellulose (L-HPC LH11, manufactured by Shin-Etsu Chemical), 3.2 g of Macrogol 6000, 6.5 g of light silicic anhydride, and 0.5 g of magnesium stearate. The mixture was compressed using a dry granulator (roller compactor TF-Labo, manufactured by Freund Sangyo), and the compressed product was sized using a sizing device (oscillator TF-Labo, manufactured by Freund Sangyo) equipped with an 18 mesh screen. This process of compression and sizing using the dry granulator and sizing device was repeated once more to obtain a levetiracem composition. This levetiracetam composition was compression molded (tablet pressure 16.2 kN) using a rotary tablet press (HT-EX18SSII, manufactured by Hata Iron Works), and each tablet contained 250 mg of levetiracetam. A .0 mm oval tablet was manufactured.

A mixture consisting of 300 g of levetiracetam drug substance I, 13.8 g of low-substituted hydroxypropylcellulose (L-HPC LH11, manufactured by Shin-Etsu Chemical), 3.2 g of Macrogol 6000, 6.5 g of light anhydrous silicic acid, and 0.5 g of magnesium stearate. was compressed using a dry granulator (Roller Compactor TF-Labo, manufactured by Freund Sangyo), and this compressed product was sized using a sizing device (Oscillator TF-Labo, manufactured by Freund Sangyo) equipped with an 18 mesh screen. This process of compression and sizing using the dry granulator and sizing device was repeated two more times to obtain a levetiracetam composition. This levetiracetam composition was compression molded (tablet pressure 16.2 kN) using a rotary tablet press (HT-EX18SSII, manufactured by Hata Iron Works), and each tablet contained 250 mg of levetiracetam, with a diameter of 12.8 mm and a short axis of 6. A circular tablet of .0 mm was manufactured.

[Comparative example 1]
A mixture consisting of 300 g of levetiracetam drug substance I, 13.8 g of low-substituted hydroxypropylcellulose (L-HPC LH11, manufactured by Shin-Etsu Chemical), 3.2 g of Macrogol 6000, 6.5 g of light anhydrous silicic acid, and 0.5 g of magnesium stearate. is compressed using a dry granulation device (Roller Compactor TF-Labo, manufactured by Freund Sangyo), and this compressed product is sized using a sizing device (Oscillator TF-Labo, manufactured by Freund Sangyo) equipped with an 18-mesh screen. It was made into a composition. This levetiracetam composition was compression molded (tablet pressure 16.2 kN) using a rotary tablet press (HT-EX18SSII, manufactured by Hata Iron Works), and each tablet contained 250 mg of levetiracetam. A .0 mm oval tablet was manufactured.

[Comparative example 2]
Mix 300 g of levetiracetam drug substance I, 13.8 g of low-substituted hydroxypropylcellulose (L-HPC LH11, manufactured by Shin-Etsu Chemical), 3.2 g of Macrogol 6000, 6.5 g of light silicic anhydride, and 0.5 g of magnesium stearate. , a levetiracetam composition. This levetiracetam composition is compression molded using a rotary tablet press (HT-EX18SSII, Hata Iron Works) to produce oval tablets each containing 250 mg of levetiracetam and having a diameter of 12.8 mm and a minor axis of 6.0 mm. However, it was not possible to form tablets.

Experimental example 1
The levetiracetam compositions of Example 1, Example 2, Comparative Example 1, and Comparative Example 2 were measured from 2θ=5° to 20 Measured in the range of °. As shown in Table 1, compared to Comparative Example 2 using the direct compression method, in Comparative Example 1, Example 1, and Example 2 using the dry granulation method, by repeating dry granulation compression and sizing, It was confirmed that the ratio of integral strength B/integral strength A increases, and tableting properties and tablet strength improve accordingly.

The levetiracetam composition obtained in Example 1 was compression molded (tablet pressure 20.4 kN) using a rotary tablet press (HT-EX18SSII, Hata Iron Works) to form tablets with a diameter of 16.5 kN each containing 500 mg of levetiracetam. An oval tablet having a width of 4 mm and a short diameter of 7.7 mm was manufactured.

Levetiracetam drug substance II was measured in the range of 2θ = 5° to 20° using a powder X-ray diffractometer (MiniFlex, manufactured by Rigaku) using CuKα as a radiation source, and 2θ = 15.0° ± 0.2°. The integrated intensity A of the diffraction peak at 2θ=18.5°±0.2° and the integrated intensity B of the diffraction peak at 2θ=18.5°±0.2° were determined, and as a result, B/A=0.312.
It consists of 500 g of this levetiracetam drug substance II, 23.0 g of low-substituted hydroxypropyl cellulose (L-HPC LH11, manufactured by Shin-Etsu Chemical), 5.4 g of Macrogol 6000, 10.8 g of light silicic anhydride, and 0.8 g of magnesium stearate. The mixture was compressed using a dry granulator (Roller Compactor TF-Labo, manufactured by Freund Sangyo), and the compressed product was sized using a sizing device (Oscillator TF-Labo, manufactured by Freund Sangyo) equipped with an 18 mesh screen. This process of compression and granulation using the dry granulation device and granulation device was repeated once more to obtain a levetiracetam composition. This levetiracetam composition was compression-molded (tablet pressure 19.5 kN) using a rotary tablet machine (HT-EX18SSII, manufactured by Hata Iron Works), and each tablet contained 500 mg of levetiracetam with a diameter of 16.4 mm and a width of 7. A 7 mm oval tablet was made.

While fluidizing 250 g of levetiracetam drug substance I and 10.8 g of low-substituted hydroxypropyl cellulose (L-HPC LH11, manufactured by Shin-Etsu Chemical) in a fluidized bed granulator (Multiplex MP01, manufactured by Powrex), povidone (PVP A 3% aqueous solution mixture of K-30 (manufactured by BASF) was sprayed to obtain granules. 1.3 g of magnesium stearate was added to 268.7 g of this granulated material and mixed to obtain a levetiracetam composition. This levetiracetam composition was compression molded (tablet pressure 21.6 kN) using a rotary tablet press (HT-EX18SSII, Hata Iron Works), and each tablet contained 500 mg of levetiracetam, with a diameter of 16.4 mm and a minor axis of 7.7 mm. An oval lock was made.

[Comparative example 3]
The levetiracetam composition obtained in Comparative Example 1 was compression molded (tablet pressure 18.5 kN) using a rotary tablet press (HT-EX18SSII, Hata Iron Works) to form tablets with a diameter of 16.5 kN containing 500 mg of levetiracetam in one tablet. An oval tablet having a width of 4 mm and a short diameter of 7.7 mm was manufactured.

Experimental example 2
The levetiracetam compositions of Example 3, Example 4, Example 5, and Comparative Example 3 were measured from 2θ=5° to 20 Measured in the range of °. As shown in Table 2, regardless of the B/A ratio of the levetiracetam drug substance or the granulation method, as the B/A ratio after granulation increases, the tableting properties become better and the tablet strength increases. was confirmed.

According to the present invention, high-content tablets of levetiracetam, which have no problems in manufacturability and have good tablet strength, disintegration properties, and dissolution properties, can be realized at low cost.

Claims (4)

When measured with a powder X-ray diffractometer using CuKα as a radiation source, the sum of the integrated intensities of the diffraction peaks detected at the diffraction angle (2θ) = 15.0 ± 0.2° is defined as the integrated intensity A and the diffraction angle ( When the sum of the integrated intensities of the diffraction peaks detected at 2θ) = 18.5 ± 0.2° is defined as integrated intensity B, levetiracetam whose ratio of integrated intensity B/integrated intensity A is less than 0.45 and macro By repeating dry granulation compression and sizing, Gol 6000, low-substituted hydroxypropyl cellulose, light anhydrous silicic acid, and one or more components selected from the group consisting of magnesium stearate are combined to achieve an integral strength of B. A method for producing a levetiracetam-containing tablet , which comprises producing a granulated product containing levetiracetam with a ratio of levetiracetam/integral strength A of 0.45 or more, and forming a tablet by compression molding . The method for producing a levetiracetam-containing tablet according to claim 1, wherein the levetiracetam is monoclinic. The method for producing a levetiracetam-containing tablet according to claim 1 or 2, wherein the content of levetiracetam in the tablet is 90% by weight or more. It is characterized by containing 0-1% by weight of macrogol 6000, 4-6% by weight of low-substituted hydroxypropyl cellulose, 1-3% by weight of light silicic anhydride, and 0.1-2% by weight of magnesium stearate. The method for producing a levetiracetam-containing tablet according to claim 3 .