JP6709693B2 - Silymarin granules - Google Patents

Description

The present invention relates to silymarin granules.

In recent years, much attention has been paid to the functionality of polyphenol compounds such as flavonoids, catechins, and plant pigments, and many compositions containing these have been developed.
Silymarin is one of the natural extracts containing such a polyphenol compound, and is an extract extracted from the seed of a plant called Silybum marianum (scientific name: Silybum marianum (L.) Gaerth). Silymarin is known to contain, as its constituent components, silybin, isosilybin, silydianin, and silychristin classified into flavonolignans.

Silymarin is useful for enhancing liver function and preventing aging, and also promotes healing in the treatment of erythema, burns, dystrophic condition of skin or mucous membrane, dermatitis, etc., and irritation from the external environment (radiation, wind, sun, etc.) It is known to be useful in protecting the skin from the skin (Patent Document 1). Further, silymarin suppresses sebum secretion (Patent Document 2), enhances epidermal permeation barrier (Patent Document 3), treats psoriasis and atopic dermatitis (Patent Document 4), and improves flattening of the epidermis (Patent Document 5). )It has been known. On the other hand, it is known that when 10% or more of silymarin is blended in the composition, capping frequently occurs during tableting, which deteriorates the production efficiency of the target tablet. Therefore, in the case of producing an oral preparation containing a high content of silymarin, it is general practice to granulate the composition and prepare a hard capsule by filling the capsule. However, even if such a granulated composition is used as a raw material for tablets, setting the content of silymarin in the tablet to 40% by mass or more causes frequent tableting troubles such as capping or causes an appropriate tablet. Since physical properties (hardness and disintegration time) were not obtained, production was practically difficult.

The frequency of capping increases as the tableting pressure during tablet molding increases. From the viewpoint of ease of drinking, tablets used for health foods often have a diameter of 8 to 9 mm, and in actual production of such tablets, it is common to form tablets at a tableting pressure of 1000 kgf to 1500 kgf. It is said that capping is likely to occur at these pressures unless a suitable tableting powder is used. On the other hand, capping is less likely to occur at a low pressing pressure of 1000 kgf or less, but the tablet hardness obtained is low and problems such as tablet breakage during product distribution occur. Due to these problems, tablets containing 40% by mass or more of silymarin have not been provided.

JP, 1-100132, A JP, 2000-169332, A JP-A-2000-169328 JP-A-5-286864 JP, 2004-91397, A

An object of the present invention is to provide silymarin granules having a novel structure and tablets containing a high concentration of silymarin containing the silymarin granules for facilitating tablet-molding of tablets containing high concentration of silymarin.

The main configuration of the present invention is as follows.
1. A granule formed of only silymarin, wherein the silymarin microparticles constituting the granule have an oriented maximum diameter of 0.3 to 4 μm .
2. 2. The granule according to 1, wherein the bulk density of the granule is 0.3 to 0.5 g/mL and the angle of repose is 40 to 50 degrees.
3. The granule according to 1 or 2, wherein the silymarin contains 80% by mass or more of flavonolignan in terms of silybin.
4.1 A tablet containing the granules according to any one of 1 to 3 and containing 80 mass% or more of silymarin .

The present invention provides a granule formed only of silymarin. These granules have the same powder characteristics as ordinary granules, but they are suitable for tableting, and can be tableted with almost no excipients added, such as capping and sticking. It has the property of being less likely to cause tableting problems. In addition, the tablet using this granule can be reduced in the addition of the excipient as much as possible, and thus has a very high content of silymarin of 40 to 99% by mass. Therefore, the tablet shape of one tablet for administering the required amount can be extremely miniaturized.
In addition, even if it is manufactured by low pressing pressure, it can be molded easily and it becomes a hard tablet, so even if coating is performed, the tablet will not be damaged during the coating process and the tablet should be film-coated or sugar-coated. Is easy.

5 is an image showing the appearance of the powder of Comparative Example 1. 5 is an image showing the appearance of the powder of Comparative Example 2. It is an image which shows the external appearance of the granule of an example. 4 is a scanning electron microscope observation image of Comparative Example 1. 9 is a scanning electron microscope observation image of Comparative Example 2. It is a scanning electron microscope observation image of the silymarin granules of an example. It is the image which further expanded the scanning electron microscope image of a silymarin granule. It is observed that the granules are composed of fine particles.

The present invention relates to granules formed only of silymarin, the granules being aggregates of fine particles.
Silymarin (CAS No. 65666-07-1) is a flavonogranum extracted from the Asteraceae maria thistle (scientific name Silybum marianam Silybum marianum Gaertn, which is also known as Milk thistle, Greater thistle, Milk thistle; CAS No. 84604-20-6). And is represented by the molecular formula C ₂₅ H ₂₂ O ₁₀ , silybin (Silybin; CAS No. 22888-70-6), silydianin (Silydianin; CAS No. 29782-68-1), silychristin (Sily christin; CAS No. 33889-69-9), isosilibin (CAS No. 72581-71-6) and the like (Natural Drug Encyclopedia, edited by Takuo Okuda, Hirokawa Shoten, published March 3, 1986). ).

In the present invention, a composition containing these flavonolignans contained in an extract extracted from a plant containing silymarin is referred to as silymarin as in the prior art. For example, as an extract extracted from a plant body containing silymarin, there is a thistle extract. In the present invention, components such as silybin, isosilibin, silydianin, and silyristin are collectively referred to as silymarins.
Silymarin is a mixture of flavonolignans as described above, and the content of silymarin in a plant extract or plant is determined by a spectrophotometer-based method (Wagner, H., et al., Arznein. Forsch, 18). , 696, 1968.), a method by thin layer chromatography (Wagner, H., et al., Arznein. Forsch, 24, 466, 1974.), a method by high performance liquid chromatography (Titel, G., et al., J. Chromatogr., 135, 499, 1977., Titter, G., et al., J. Chromatogr., 153, 227, 1978., Quercia, V., et al. (Ed)., Elsevier Scientific Publishing Company, Amsterdam, 1983, p1.). Among these measurement methods, 2,4-dinitrohydrazine analysis, which is one of the methods based on the measurement by a spectrophotometer, has been reported in the German Pharmacopoeia (monograph on fruits of Silybum marianum) and widely used. Has been.

As a method for isolating silymarin from fruit of Silybum marianum with high purity, there are a method of isolating at a purity of 70 to 80% and a method of isolating at a purity of 90 to 96% (Japanese Patent Publication No. 63-41396). It has already been reported. Silymarin is usually commercially available, which can be obtained from dried thistle seeds by extraction with ethanol, ethyl acetate, acetone, etc., and obtained as a dry powder by spray drying. The silymarin used in the present invention can be the commercially available silymarin prepared as described above. Further, it can be used as a compound by further isolating and purifying from extracts and extracts obtained by concentrating constituent components of silymarin such as silybin, isosiribin, silydianin, and silyristin from thistle.
As the plant body containing silymarin in the present invention, all parts such as leaves, stems, buds, flowers, above-ground parts such as woody parts and bark, underground parts such as roots and tubers, seeds, and resins can be used.
The silymarin and the plant containing the same in the present invention are obtained by extracting the dried product obtained by drying the plant itself and the plant using various solvents. For example, water or alcohols such as ethanol and methanol, polyhydric alcohols such as propylene glycol and 1,3-butylene glycol, and extraction using organic solvents such as ether, acetone, and ethyl acetate, the solvent is extracted by various methods. After removal, the dried powder can be used as a raw material for the silymarin of the present invention.

The plant body of the silymarin raw material in the present invention is extracted by a conventional method from natural dried, hot air dried, freeze-dried or fermented plants. In addition, the plant extract can be obtained as a powder by further performing processes such as re-extraction, concentration, and pulverization according to a conventional method. These powders can be used in the present invention. Examples of commercially available silymarin powder include "Silymarin ET" and "Silymarin ETG" (all manufactured by Indena). Silymarin preferably contains 50% by mass or more of silymarins such as the above-mentioned silybin, and particularly preferably contains 80% by mass or more of flavonolignan in terms of silybin.
The granules formed by only the silymarin of the present invention can be blended in the tablet in an amount of 10 to 99% by mass, preferably 40 to 80% by mass.
Hereinafter, in the present specification, granules formed by only silymarin are referred to as “silymarin granules”.

The silymarin granules of the present invention are subjected to impact, compression, and shearing forces repeatedly on the above-mentioned dried extract to make the silymarin fine, and by repeating this operation, the silymarin is made into fine particles, and the fine particles are compounded. Then, the complex of silymarin particles shaped in this way is further pulverized to prepare the complex. Silymarin granules can be sieved as necessary to make the size of the particles uniform. A device for simultaneously forming fine particles by repeating compression, shearing, and impact while simultaneously forming a composite is commercially available under the name of a dry-type composite device, and this device can be used. An example of the dry compounding device is "Nobilta NOB (product name)" manufactured by Hosokawa Micron Corporation. In Nobilta NOB, while the rotor rotates at high speed in the mixing container, the raw materials are subjected to impact, compression, and shearing forces to make them finer, and the composite particles are automatically processed while processing the surface shape of the finely divided particles. This is a device to be manufactured (see JP 2010-180099 A).
In addition, by using individual devices that individually have the functions of fine crushing, impact, compression, and shear, the finely pulverized silymarin is repeatedly subjected to repeated impact, compression, and shearing operations to form silymarin particles, which are then crushed and sieved. It can be divided into the silymarin granules of the present invention.

Silymarin granules are granules formed only of silymarin and have a structure in which the granules are aggregates of fine particles. In the aggregate, particles having a maximum unidirectional diameter of 0.3 to 4 μm are strongly bonded. This structure can be well understood by observing the surface of the aggregate with a scanning electron microscope. The particles are micronized particles of silymarin.
Silymarin granules are a mixture (composite product) of various particle sizes adjusted by the above-described dry compounding device, and further crushed by a commonly used crushing device and sieved to obtain a desired particle size. It can be obtained as a granule having. In order to use the granules as a raw material by the tableting method, the granules are sieved and classified to have a particle size of 10 to 400 μm. The granules classified in this way have a bulk density of 0.3 to 0.5 g/mL, an angle of repose of 40 to 50 degrees, and behave as a fluid powder. It is also suitable for tableting properties.

The silymarin granules can be tablet-molded as they are, or can be tablet-molded by adding an excipient to obtain tablets containing a high concentration of silymarin. If necessary, excipients such as cellulose and calcium stearate, lubricants, and other active ingredients (physiologically active ingredients) can be added to the tablet containing the silymarin granules of the present invention. Alternatively, a commercially available composite excipient, for example, “F-melt” manufactured by Fuji Chemical Industry Co., Ltd. can be blended.
The tableting may be a general molding tableting device such as a rotary tableting machine used for manufacturing tablets. In the case of tablets having a diameter of 8 to 9 mm, the tableting pressure for tableting is preferably 1000 kgf or less.

Hereinafter, the present invention will be described more specifically with reference to Examples and Comparative Examples.
<Production example of silymarin granules>
Silymarin granules were prepared using "Silymarin ETG" (manufactured by Indena, containing 65% by mass of flavonolignans) which is a commercially available bulk silymarin as silymarin.
Further, a dry compounding device "Nobilta NOB-MINI" manufactured by Hosokawa Micron Co., Ltd. was used as a manufacturing device for silymarin granules. "Nobilta NOB-MINI" is a horizontal cylindrical mixing container in which a rotor with blades rotates at a high peripheral speed of 40 m/s or more, and impact, compression, and shearing forces act uniformly on each particle. Is designed to be. It is a device that can simultaneously advance fine particle formation and composite formation by adjusting the rotation speed and the operating time. The body casing has a water-cooled jacket structure, which can suppress an increase in product temperature even if high energy is applied. 20 g of "Silymarin ETG" was put into this apparatus, and the apparatus was operated at 20° C. for 0.2 minutes under the condition of 0.2 kW according to the instruction manual of the apparatus, and shock, compression and shear were repeated to collect 19 g of silymarin granules.

<Comparative example>
The above "Silymarin ETG" as Comparative Example 1 and "Silymarin ETG" as Comparative Example 2 were finely pulverized using a crusher "Super Clean Mill" manufactured by Nara Machinery Co., Ltd., and then classified using a 16 mesh sieve. Powder was used.

<Powder characteristics>
The appearance, bulk density, and angle of repose of the silymarin granules of the present invention, the powder of Comparative Example 1 and the powder of Comparative Example 2 were measured. The particle size distribution of each particle is measured by a laser diffraction type particle size distribution device (Malvern Co., Mastersizer 2000), and the particle size distribution [volume %] and frequency particle size (10% frequency particle size D10, 50% frequency particle size D50, The 90% frequency particle size D90) was measured.

1. Macroscopic observation results Images of macroscopic observation of each powder are shown in FIGS. 1, 2 and 3. In Comparative Example 1, particles of various sizes are mixed, and in Comparative Example 2, the particle size is made fine by pulverization and is made uniform. In the example, the yellow color of silymarin was lightened by forming composite particles.

2. Powder Properties The results of measuring the bulk density and angle of repose of each powder are shown in Table 1 below.

The bulk density of Comparative Example 1 was high, and that of Comparative Example 2 was substantially the same as that of the example. In addition, the angle of repose was low in the example, and the liquidity was slightly improved.

3. Particle size distribution 10% frequency particle size D10, 50% frequency particle size D50, 90% frequency particle size D90 of each powder are shown in Table 2 below.

<Particle structure observation (scanning electron microscope observation)>
The observed image of Comparative Example 1 is shown in FIG. 4, the observed image of Comparative Example 2 is shown in FIG. 5, and the observed image of Example is shown in FIG. The fine structure of each particle was confirmed by observation with a scanning electron microscope.
It was confirmed that in Comparative Examples 1 and 2, the particle surface had a smooth structure, whereas in the Example, extremely fine particles were attached to the particle surface.

<Observation of fine structure of granules of Examples>
An image obtained by further enlarging the observed image of the silymarin granules of the example based on the above observation results is shown in FIG. 7. From this image, it can be seen that the silymarin granules of the examples have a structure in which extremely fine particles are aggregated. The size of the particles forming this aggregate was measured as the maximum diameter in the fixed direction. The measurement was performed on 200 particles in an image obtained by a scanning electron microscope (S-3400, manufactured by Hitachi High-Technologies Corporation) with image analysis/measurement software (Win ROOF, manufactured by Mitani Corporation). .. The measurement results are shown in Table 3.

It was found that the silymarin granules of the examples are aggregates of fine particles having an average maximum unidirectional diameter of 1 μm.

<Example of production of tablets containing silymarin>
1. Tableting Moldability Evaluation Tablets were tabletted using the silymarin granules or powders of Comparative Examples 1 and 2 and Examples, and the tableting suitability of each was evaluated. The mixed powder containing 40% by mass of each silymarin granule or powder, 59% by mass of F-melt, and 1% by mass of calcium stearate was molded into tablets (9φ, 340 mg) (direct mixing), and the hardness of the obtained tablets was measured. A single-shot tableting machine (made by Okada Seiko Co., Ltd.) was used for tableting at a tableting pressure of 400, 600, and 1000 kgf. The hardness of the obtained tablets was measured using a hardness measuring machine (made by Okada Seiko Co., Ltd.). The measurement results are shown in Table 4 below.

The silymarin granules of Examples satisfied the hardness of 7 kgf or more required by the tablets at any pressing pressure. Further, Comparative Examples 1 and 2 (crushed powder of silymarin bulk powder) satisfied the hardness required by the tablets only when the tableting pressure was 1000 kgf. From this test, it was found that the silymarin granules of the examples showed excellent tableting suitability and that they could be molded at a low tableting pressure, which is considered to cause less capping.

2. Production Example and Evaluation Based on Formulation Design Composition of silymarin granules 40% by mass of Example, 59% by mass of F-melt, 1% by mass of calcium stearate (formulation 1), 80% by mass of silymarin granules of Example, 19% by mass of F-melt, calcium stearate A 1% by mass composition (formulation 2) was formed into tablets under the tableting conditions shown in Table 5 below. The hardness and disintegration time of the obtained tablets were measured. The measurement results are shown in Table 5. The tablets were tablets of 9φ and 340 mg, and were manufactured using a single-shot tableting machine (made by Okada Seiko Co., Ltd.). The tablet hardness was measured using a hardness meter (made by Okada Seiko Co., Ltd.), and the disintegration time was measured according to the Japanese Pharmacopoeia.

As shown in Table 5, both Formulation 1 and Formulation 2 had appropriate physical properties as tablets.
From the above test, it became clear that a tablet containing 40% by mass or 80% by mass of silymarin can be molded by tableting by using the silymarin granules of the present invention.

Claims (4)

A granule formed of only silymarin, wherein the silymarin microparticles constituting the granule have an oriented maximum diameter of 0.3 to 4 μm . The granule according to claim 1, wherein the bulk density of the granule is 0.3 to 0.5 g/mL and the angle of repose is 40 to 50 degrees. The granule according to claim 1 or 2, wherein the silymarin contains 80% by mass or more of flavonolignan in terms of silybin. A tablet containing the granule according to any one of claims 1 to 3 and containing 80 mass% or more of silymarin .