JP6647925B2 - Silymarin-rich tablets - Google Patents

Description

  The present invention relates to a tablet containing a high concentration of silymarin.

In recent years, paying attention to the functionality of polyphenol compounds such as flavonoids, catechins, and vegetable pigments, 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 Maria Thistle (scientific name: Silybum marianum (L) Gaertn). Silymarin is known to contain silybin, isosilybin, silydinine, and silychristin classified as flavonolignans as its constituent components.

  Silymarin is useful for enhancing liver function and preventing aging, and further promotes healing in the treatment of erythema, burns, dystrophic conditions of the skin or mucous membranes, dermatitis, etc., and stimuli from the external environment (radiation, wind, sun, etc.) It is known that it is useful for protecting the skin from the skin (Patent Document 1). In addition, the effect of silymarin on suppressing sebum secretion (Patent Document 2), the effect of enhancing epidermal penetration barrier (Patent Document 3), the therapeutic effect of psoriasis and atopic dermatitis (Patent Document 4), and the effect of improving epidermal flattening are known. I have. On the other hand, it is known that when silymarin is incorporated in the composition in an amount of 10% or more, capping frequently occurs at the time of tableting, and the production efficiency of a target tablet is deteriorated. For this reason, when producing an oral preparation containing a high content of silymarin, it is generally practiced to granulate the composition to form a hard capsule preparation filled in a capsule.

  Capping occurs more frequently as the tableting pressure during tablet formation increases. Tablets used in health foods often have a diameter of 8 to 9 mm from the viewpoint of ease of drinking, and during the actual production of such tablets, it is common to form tablets at a tableting pressure of about 1000 kgf to about 1500 kgf, Unless the powder is suitable, capping is likely to occur at these compression forces. On the other hand, if the compression pressure is 1000 kgf or less, capping is unlikely to occur, but the obtained tablet hardness is low, and problems such as breakage of the tablet during distribution of the product occur. In order to solve this problem, it is desirable to obtain a tablet having a hardness that can withstand distribution at a low compression pressure. However, in the case of using a tableting powder containing 10% or more of silymarin, it has been difficult to form a tablet at the time. Since a compression pressure of about 1500 kgf was required, it was impossible to perform tablet molding at a low compression pressure that hardly caused capping.

JP-A-01-100132 JP 2000-169332 A JP 2000-169328 A JP 05-286864 A

  An object of the present invention is to provide a tablet containing 10% by mass or more of silymarin and a method for continuously producing the tablet at a compression pressure of 1000 kgf or less.

The main configuration of the present invention is as follows.
1. Silymarin 10% by mass or more, the collagen powder 15 to 50 wt%, 3-10 wt% calcium carbonate powder, containing 0.5 to 3 wt% hydroxypropyl cellulose, tablet hardness Ru least 7kgf der tablets.
2. 2. The tablet according to 1, wherein the silymarin is an extract derived from Maria Thistle (Silybum marianum).
3. 3. The tablet according to 1 or 2 , wherein the calcium carbonate powder is scallop shell powder.
4. Silymarin 10% by mass or more, the collagen powder 15 to 50 wt%, 3 to 10 wt% calcium carbonate powder, tableting to Rukoto granules of the powder mixture containing 0.5 to 3 wt% hydroxypropyl cellulose The method for producing a tablet according to any one of claims 1 to 3 , characterized in that:

  According to the present invention, a tablet containing 10% by mass or more of silymarin and a method for producing the tablet are provided. Since the tablet of the present invention has sufficient hardness as a tablet, it is advantageous in distribution. Further, in the method of the present invention, capping hardly occurs because the method is manufactured at a low pressing pressure. Therefore, the tablet is not damaged during the coating process, and the tablet can be coated with a film or sugar coating.

It is a graph which shows the tableting pressure at the time of manufacturing the tablet of a test example, and the result of having measured the hardness change of the obtained tablet.

The present invention relates to a tablet containing 10% by mass or more of silymarin, wherein the tablet contains collagen powder, calcium carbonate powder, and hydroxypropylcellulose.
Silymarin (CAS No. 65666-07-1) is a general term for flavonolignans extracted from the Asteraceae Maria Thistle (scientific name: Silybum marianum, also known as Milk Thistle, Gibium oleracea, Thistle Thistle; CAS No. 84604-20-6). Silybin (CAS No. 22888-70-6), Silydianin (CAS No. 29782-68-1), Silychristin (Silychristin; CAS No. 33889-69-9) represented by the molecular formula C25H22O10; It is a composition containing Isosilybin (CAS No. 72581-71-6) (Natural Drug Dictionary, edited by Takuo Okuda, Hirokawa Shoten, Showa 61) March 3 issue reference).

In the present invention, these flavonolignan-containing compositions contained in an extract extracted from a plant body containing silymarin are referred to as silymarin as in the prior art. For example, as an extract extracted from a plant body containing silymarin, there is a Maria Thistle extract. In the present invention, components such as silybin, isosilybin, silidianin, and silychristin are collectively referred to as silymarins.
Silymarin is a mixture of flavonolignans as described above, and the content of plant extracts and plants in the form of silymarin is determined by a method based on measurement by a spectrophotometer (Wagner, H., et al., Arzneim. Forsch, 18). , 696, 1968.), a method by thin-layer chromatography (Wagner, H., et al., Arzneim. Forsch, 24, 466, 1974.), a method by high-performance liquid chromatography (Tittel, G., et al., J. Chromatogr., 135, 499, 1977., Title, G., et al., J. Chromatogr., 153, 227, 1978., Quercia, V., et al., Chromatography in Biochemistry, M. dicine and Enviromental Research, Frigerio, A. (Ed)., can be measured Elsevier Scientific Publishing Company, Amsterdam, 1983, by p1.). Among these measuring methods, 2,4-dinitrohydrazine analysis, which is one of the methods based on the measurement by a spectrophotometer, is reported in the German Pharmacopoeia (monograph on the fruit of Silybum marianum) and is widely used. Have been.

As a method for isolating silymarin from the fruit of Maria thistle with high purity, a method of isolating with a purity of 70 to 80% and a method of isolating with a purity of 90 to 96% (JP-B-63-41396) have already been known. It has been reported. Silymarin is usually commercially available as an extract raw material obtained by extracting from a thistle seed with ethanol, ethyl acetate, acetone, or the like, and obtaining a dry powder by spray drying. The silymarin used in the present invention is thus prepared, and commercially available silymarin can be used as it is. An extract obtained by concentrating silymarin constituents such as silybin, isosilybin, silidianin, and silychristin from Maria thistle, and an extract obtained by isolating and purifying the extract can be used as a compound.
Plants containing silymarin in the present invention can be used in all parts such as above-ground parts such as leaves, stems, buds, flowers, woody parts, bark (bark), underground parts such as roots and tubers, seeds and resins. is there.
The silymarin and the plant body containing the silymarin in the present invention are dried by themselves and are extracted using various solvents. For example, water or alcohols such as ethanol and methanol, polyhydric alcohols such as propylene glycol and 1,3-butylene glycol, ethers, acetone, and organic solvents such as ethyl acetate are extracted, and 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 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. Further, the plant extract can be obtained as a powder by subjecting it to a process such as re-extraction, concentration, and powdering according to a conventional method. In the present invention, these powders can be used. Examples of commercially available silymarin powder include “Silymarin ET” and “Silymarin ETG” (all manufactured by Indena).
Silymarin can be blended in the tablet in an amount of 10 to 50% by mass. If the content exceeds 50% by mass, the compounding amounts of the collagen powder, calcium carbonate powder, and hydroxypropylcellulose described below decrease, so that tableting aptitude decreases and the occurrence of capping increases.

Collagen has a structure in which three polypeptide chains are spirally wound, and a plurality of collagen molecules of about 300 nm associate with each other with a shift of 67 nm to form long collagen fibers. Collagen is a main protein that forms raw hides, tendons, bones, and the like of fish, pigs, cows, and the like, but most of them are insoluble in water. Collagen is insoluble but is a biological component and has excellent safety, and has advantages such as being less likely to cause an immune reaction because of high homology between animals.
On the other hand, since water-soluble collagen has a high moisture content and a low heat denaturation temperature in a transparent solution state, some collagens have an improved heat denaturation temperature. In the present invention, either water-insoluble collagen or water-soluble collagen can be used. As the collagen, those extracted from the skin and bones of livestock such as cattle and pigs can be generally used, but collagen derived from fish may be used.
The tablet of the present invention preferably contains 15 to 50% by mass of collagen powder. Examples of the collagen used in the present invention include HACP-01 (manufactured by ZELICE).

In the tablet of the present invention, it is necessary to mix calcium carbonate powder in an amount of 3 to 10% by mass. As the calcium carbonate powder, at least one substance selected from scallop shell powder, eggshell calcium powder, and coral calcium powder is preferable. Scallop shell powder is particularly preferred. The scallop shell powder is commercially available as a powdered scallop shell that has been fired and then powdered. However, once calcined, calcium carbonate (CaCO ₃₎ changes to calcium oxide (CaO), which is not preferable.
As the scallop shell powder, a powder that is finely pulverized by a pulverizing device such as a roller mill, classified, and has a uniform particle size is commercially available, and can be used. Examples of the scallop shell powder used in the present invention include "scallop powder" and "scallop powder S" (both manufactured by NC Corporation).

It is necessary that the tablet of the present invention contains 0.5 to 3% by mass of hydroxypropylcellulose. Hydroxypropylcellulose (hereinafter "HPC") is obtained by etherifying hydroxyl groups of cellulose with propylene oxide. HPC has a number of hydroxypropyl groups _{(-OCH 2 CH (OH) CH} 3). The average number of substituted hydroxyl groups per glucose is expressed as degree of substitution (DS), which is up to three. However, since the hydroxypropyl group also contains a hydroxyl group, it is also etherified during the reaction. Therefore, the molar substitution degree (MS), which is the number of hydroxypropyl groups per glucose, is larger than 3.
Since cellulose has high crystallinity, MS must be 4 or more to make HPC water-soluble. Since it has a hydrophobic group and a hydrophilic group, the lower critical solution temperature (LCST) is about 45 ° C., and becomes insoluble at a temperature higher than 45 ° C. In the present invention, it is preferably water-soluble.
HPC is widely used as a food additive, and its safety is well known. The molecular weight of HPC, which is commercially available as a food additive, is in the range of 40,000 to 910000, but the molecular weight can be selected as needed. In the present invention, those having a small molecular weight are preferable, and those having a mass average molecular weight of 40,000 to 140,000 are particularly preferable. The molecular weight of HPC can be easily measured by gel permeation chromatography (GPC method).
Examples of HPC commercially available as a food additive include, for example, Cerny SSL (molecular weight: 40,000), Cerny SL (molecular weight: 100,000), Cerny L (molecular weight: 140,000), Cerny M (molecular weight: 620000), and Celney H (molecular weight: manufactured by Nippon Soda Co., Ltd.). 910000).

The tablet of the present invention can be easily produced by mixing and granulating silymarin, collagen powder, calcium carbonate, and HPC, and compressing the mixture. The granulation is preferably performed using a fluidized bed granulator. For mixing, a general mixer such as a V-type mixer or a rocking mixer can be used. Excipients such as cellulose and calcium stearate, lubricants, and other active ingredients (bioactive ingredients) can also be added to the tablet of the present invention.
Tableting may be performed by a general molding tableting device such as a rotary tableting machine used for tablet production. In the case of a tablet having a diameter of 8 to 9 mm, the tableting pressure at the time of tableting is 1000 kgf or less.

Hereinafter, the present invention will be described more specifically with reference to Test Examples, Examples, and Comparative Examples.
Test example: Tableting test of silymarin-containing powder <Test method>
Tablets were prepared from powders having the compositions shown in Table 1 below, the state of tableting was observed, and a tablet hardness test was performed.
As silymarin, commercially available silymarin bulk powder "Silymarin ETG" (manufactured by Indena), calcium carbonate powder "scallop powder" (manufactured by NC Corporation), and HPC Cerny SSL (manufactured by Nippon Soda Co., Ltd.) Was. Also, 1% by mass of calcium stearate was added as a lubricant. The silymarin ETG was pulverized in advance into a fine powder using a pulverizer.

Tablets that are health foods are often sold in aluminum bags or bottles, but tablets with a diameter of 8 to 9 mm must have a hardness of 7 kgf or more so that tablets do not crack during the distribution process. Is desirable. In actual production, a rotary tableting machine is used, but it is desirable that the tableting machine can be produced at a tableting rotation speed of 30 rpm or more from the viewpoint of productivity. In order to prevent capping in actual production using a rotary tableting machine, it is desirable that the composition be such that a tablet having a compression pressure of 1000 kgf or less and a hardness of 7 kgf or more can be obtained. Therefore, a pressing pressure of 500 kgf was set as a manufacturing condition in the case of using a single-shot tableting machine capable of obtaining the same hardness as that of a rotary tableting machine at a tablet rotation speed of 30 rpm and a pressing pressure of 1000 kgf. That is, the conditions of the compounding to achieve a hardness of 7 kgf or more at a pressing pressure of 500 kgf of a single-shot tableting machine were examined.
Each component was weighed, granulated by a fluid bed granulator, and then mixed with a lubricant by a V-type mixer. Using a single-shot tableting machine (manufactured by Okada Seiko Co., Ltd.), tableting was performed at a tableting pressure of 300, 400, 500, 600, and 1000 kgf. The tablets were 200 mg tablets (using a punch having a diameter of 8 mm and an R of 10 mm). The occurrence of capping at the time of tableting was visually confirmed, and the hardness of the obtained tablet was measured using a hardness meter (manufactured by Okada Seiko Co., Ltd.).

<Result>
FIG. 1 shows the relationship between the hardness of each tablet and the compression pressure. In any of the test examples, a tablet having a hardness of 7 kgf or more can be obtained by increasing the compression pressure. However, only a test example 4 can obtain a hardness of 7 kgf or more at a compression pressure of 500 kgf. Test Example 5 was a composition obtained by removing silymarin from Test Example 4. However, since the hardness was the same as Test Example 4, the increase in tablet hardness under low compression conditions was due to collagen powder, scallop powder, HPC Was found to be due to the composition of Further, a tableting test was conducted by separately mixing cellulose powder and silymarin as excipients, but the capping was severe and tablets could not be obtained.
From the above test, it was considered that the blending of Test Example 4 was necessary to obtain a tablet having a compression pressure of 1000 kgf or less and a hardness of 7 kgf or more and a diameter of 8 to 9 mm using a rotary tableting machine of an actual production machine. .

Examples and Comparative Examples Using a rotary tableting device (AP-38, 38 columns, 30 rpm, manufactured by Hata Iron Works, 30 rpm) used in actual production, tablets of the compositions of Examples and Comparative Examples in Table 2 below were tableted. Molded. The tableting pressure was set in the range of 300 kgf to 1500 kgf. In Example 1 and Comparative Example 1, a punch having a diameter of 8.5 mm and an R of 7 mm was used. In Comparative Example 2, a punch having a diameter of 8 mm and an R of 6.5 mm was used.

After each component was weighed, it was granulated by a fluid bed granulator (FLO-200 manufactured by Freund), and a lubricant was mixed using a V-type mixer, followed by continuous tableting. As shown in Table 3 below, in the composition of Example 1, a tablet having a compression pressure of 300 kgf and a hardness of 15.2 kgf was obtained. Tableting was performed at a compression pressure in the range of 300 kgf to 900 kgf, and the target tablets could be produced continuously without capping. In Comparative Example 1, capping occurred at a compression pressure of 700 kgf or more, and tablet making could not be performed. At a compression pressure of 500 kgf at which capping does not occur, the tablet hardness was 3.5 kgf, and tablets having sufficient hardness could not be obtained. In Comparative Example 2, capping occurred at a compression pressure of 900 kgf or more, and at a compression pressure of 700 kgf, the tablet hardness was 5.5 kgf, which was still an insufficient hardness.
From the above description, only Example 1 was a tablet containing a high content of silymarin, but could be produced at a low compression pressure without capping.

Claims (4)

Silymarin 10% by mass or more, the collagen powder 15 to 50 wt%, 3-10 wt% calcium carbonate powder, containing 0.5 to 3 wt% hydroxypropyl cellulose, tablet hardness Ru least 7kgf der tablets. The tablet according to claim 1, wherein the silymarin is an extract derived from Maria Thistle (Silybum marianum). 3. The tablet according to claim 1, wherein the calcium carbonate powder is scallop shell powder. Silymarin 10% by mass or more, the collagen powder 15 to 50 wt%, 3 to 10 wt% calcium carbonate powder, tableting to Rukoto granules of the powder mixture containing 0.5 to 3 wt% hydroxypropyl cellulose The method for producing a tablet according to any one of claims 1 to 3 , characterized in that:

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