JP2017057150A - Silymarin-containing tablet - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide sugar-coated R tablets and two-stage R tablets having high content of silymarin, free from sticking and capping or tablet cracking when making tablets.SOLUTION: The present invention provides a tablet having high content of silymarin, the tablet containing the silymarin of 8 mass% or more, and hydroxypropyl cellulose, with the tablet diameter of 8 mm or more.SELECTED DRAWING: None

Description

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

  The tablet form is determined by the shape of the mortar and the punch when tableting. This tablet form is defined as (1) standard R tablet, (2) Sumikaku flat tablet, (3) Sumimaru flat tablet, (4) sugar-coated R tablet, (5 ) Classified into two-stage R tablets. Of these, the shape of (1) to (3) stands out from the angle (edge) formed by the side and top / bottom, and it is said that it has a strong resistance to throat at the time of quoting and is difficult to swallow in the case of large tablets. Yes. In the case of a general tablet that is not a chewable tablet or an intraoral quick-disintegrating tablet, it is desirable to use it for a small tablet (diameter of 8 mm or less). In addition, since the tablets (4) and (5) have a large angle (edge) formed by the side surface and the top / bottom surface of the tablet, they are easy to swallow with little resistance and irritation to the throat during drinking. Further, when comparing tablets having the same weight, tablets having smaller diameters and curvature radii are easier to swallow. For example, in a tablet having a weight of 300 mg, a sugar coated R tablet having a diameter of 8.5 mm is easier to swallow than a standard R tablet having a diameter of 9 mm. Similarly, a two-stage R tablet with a diameter of 8.5 mm is also easier to swallow than a standard R tablet with a diameter of 9 mm. Therefore, it is well understood by those skilled in the art that the tablets of (4) and (5) are suitable as the shape of a large tablet.

Meanwhile Silymarin, Asteraceae Milk thistle (scientific name Shiribamu-Marianamu Silybum marianum Gaertn, also known milk thistle, Oohireazami, milk thistle; CAS No.84604-20-6) is a general term for flavonolignan extracted from the molecular formula _C 25 _{H 22} O ₁₀ represented by Silybin (CAS No. 22888-70-6), Silydianin (CAS No. 297826-6-1), Silychristin (CAS No. 33889-69-9), It is a composition containing isosiribin (CAS No. 72581-71-6) and the like (see Non-Patent Document 1).
Patent Document 1 describes a method in which silymarin is extracted from canopy peas with a solvent such as ethyl acetate, degreased after removing the solvent, and further purified using a mixed solution of water and alcohol, and then pulverized.

Silymarin is also a therapeutic agent for liver diseases (Patent Document 2), a whitening agent (Patent Document 3), a collagen gel contractor (Patent Document 4), and an inhibitor of the production of abnormal proteins that occur with aging of the living body (Patent Document). Orally-administered drugs for uses such as 3) have been proposed. It is also added to supplements for health maintenance purposes.
In the case of tablets containing silymarin, in the case of high-content tablets, only small-shaped tablets (1) to (3) are provided, and an effective effective amount for drinking the effects of silymarin is intended to be taken. , The number of grains to be taken increased, and the feeling of being caught in the throat was strong, and it was difficult to swallow.

Japanese Patent Publication No. 63-41396 Japanese Patent Publication No.6-21075 JP 2002-220333 A Japanese Patent No. 5572406

Natural Drug Encyclopedia, edited by Takuo Okuda, Yodogawa Shoten, March 3, 1986

  The present inventor studied the production of a tablet containing high silymarin content. When producing a tablet containing silymarin at a high concentration of 8% by mass or more, when tableting is performed, the upper part of the tablet called capping becomes a dish shape. It was confirmed that a peeling phenomenon occurred. Further, when the obtained tablets were observed, many cracks were generated particularly in the vicinity of the edge of the boundary between the top surface and the side surface in the sugar-coated R tablets having a low feeling of swallowing resistance. This phenomenon varied depending on the shape of the preparation, and occurred frequently in the “sugar-coated R tablet” shape and the “two-stage R tablet” shape. However, such a capping phenomenon did not occur in the so-called (1) standard R tablet, (2) Sumikaku flat tablet, and (3) Sumimal flat tablet used for small tablets. It was speculated that this is the reason why only conventional R tablets or flat tablets that are difficult to swallow are provided in conventional silymarin tablets.

  An object of the present invention is to provide a sugar-coated R tablet and a two-stage R tablet having a high content of silymarin without capping phenomenon during tableting and cracking of the tablet. Another object of the present invention is to provide a method for producing a sugar-coated R tablet and a two-stage R tablet containing a high amount of silymarin.

  The present inventor has found a production method that suppresses capping phenomenon and cracks that occur specifically during the manufacture of sugar-coated R tablets and two-stage R tablets in the process of studying tablets containing a high amount of silymarin, and contains a high content of silymarin. Large tablets were obtained.

The main configuration of the present invention is as follows.
(1) A silymarin-rich tablet containing 8% by mass or more of silymarin and hydroxypropylcellulose and having a tablet diameter of 8 mm or more.
(2) The tablet according to (1), wherein the tablet has a sugar-coated R tablet or a two-stage R tablet.
(3) The tablet according to (1) or (2), further comprising erythritol and scallop powder.
(4) The tablet according to (3), containing 8% by mass or more of silymarin, 4% by mass or more of erythritol, 5% by mass or more of scallop powder, and 1% by mass or more of hydroxypropylcellulose.
(5) The tablet according to (4), containing 15-25% by mass of silymarin.
(6) The tablet according to any one of (3) to (5), which has a disintegration time of 45 minutes or less as measured by the method defined in the Japanese Pharmacopoeia.
(7) containing 8% by mass or more of silymarin characterized by tableting a powder obtained by granulating a powder containing silymarin, erythritol and scallop powder as an aqueous solution in which hydroxypropylcellulose is dissolved; A process for producing tablets containing a high amount of silymarin in the form of sugar-coated R tablets or double-stage R tablets having a tablet diameter of 8 mm or more.

According to the present invention, a silymarin-rich tablet containing 8% by mass or more of silymarin and having a tablet diameter of 8 mm or more is provided. The tablet of this invention turns into a tablet which is easy to drink without a crack. Moreover, the tablet of this invention has a disintegration time of 45 minutes or less, and has an immediate effect.
Furthermore, the present invention provides a method for producing a silymarin-rich tablet containing 8% by mass or more of silymarin, having a tablet diameter of 8 mm or more, and having a sugar-coated R tablet or a two-stage R tablet.

The present invention relates to a highly silymarin-containing tablet containing 8% by mass or more of silymarin and hydroxypropylcellulose, and having a tablet diameter of 8 mm or more. In addition, the present invention contains 8% by mass or more of silymarin, characterized by tableting a powder obtained by granulating a powder containing silymarin, erythritol, and scallop powder using an aqueous solution in which hydroxypropylcellulose is dissolved as a binder. The invention relates to a method for producing a tablet containing a high content of silymarin in the form of a sugar-coated R tablet or a two-stage R tablet having a tablet diameter of 8 mm or more.
The shape of the tablet of the present invention will be described.
The tablet of the present invention has a sugar-coated R tablet and a two-stage R tablet. Sugar-coated R tablets are generally used in uncoated tablets for sugar coating, but there are many cases where sugar coating is not performed. The standard R tablet has a radius of curvature of about 1.2 to 1.5 with respect to the tablet diameter φ1, whereas the sugar-coated R tablet has a radius of 0.7 to 0.7 with respect to the tablet diameter φ1. It has an upper surface and a bottom surface with a radius of curvature of about 1.0. For example, in a tablet having a diameter of 8 mm, the radius of curvature R is 6.5 mm, and the height H from the edge of the tablet is 1.3 mm. R and H increase in proportion to the diameter of the tablet.
Two-stage R tablets generally chipping during coating to improve the rolling of the tablets, a shape to be used in order to reduce the unevenness, the curvature of the R ₁ to the rising portion of the top-bottom portion radius, followed by It is formed by an arc having a radius of curvature R ₂ on the upper surface. The radius of curvature of each is R ₁ <R ₂ and the angle (edge) formed by the side surface of the tablet and the top / bottom surface is increased by the smaller curvature radius of the rising portion. It is easy to swallow with less resistance and irritation. In the case of a two-stage R tablet having a diameter of 8 mm, the radius of curvature R ₂ is typically 9.5 mm, R ₁ is 3.2 mm, and the height H from the edge of the tablet is 1.3 mm. is there. R ₁ , R ₂ and H increase in proportion to the tablet diameter.

  The tablet of the present invention contains 8% by mass or more of silymarin. In the case of containing 8% by mass or more of silymarin, an uncoated tablet or a two-stage R having a sugar-coated R-tablet shape having a diameter of 8 mm or more, which has heretofore been difficult by adopting the configuration and production method of the present invention at the time of tableting. Mold tablets can be obtained.

The tablet of the present invention contains 8% by mass or more of silymarin, 4% by mass or more of erythritol, 5% by mass or more of scallop powder, and 1% by mass or more of hydroxypropylcellulose in a tablet having a diameter of 8 mm or more.
The amount of silymarin is 8% by mass or more in anticipation of the therapeutic effect, but silymarin needs to contain erythritol, scallop powder, and hydroxypropylcellulose, so the upper limit is 40%.
Erythritol is blended for the purpose of tablet disintegration. The blending amount of erythritol is about 4 to 15% by mass, preferably 4 to 10% by mass. If the amount of erythritol is small, the disintegration property of the tablet is not improved, and if it exceeds 15% by mass, the moldability of the tablet is deteriorated.
Scallop powder is also called scallop calcium. A general method for producing scallop powder is produced by selecting, coarsely crushing, and sieving scallop shells, followed by dry heat sterilization at, for example, 200 ° C. and pulverizing to a predetermined particle size. By containing 3 to 10% by mass, preferably 4 to 8% by mass of the scallop powder, tableting can be easily performed, and preferable disintegration characteristics can be imparted to the tablet. When the scallop powder contains more than 10%, when fluidized bed granulation is performed, it is difficult for the granules to grow and the tableting property is deteriorated.
Moreover, it is necessary to mix | blend erythritol and a scallop powder simultaneously for the disintegration improvement of a tablet. When only erythritol is blended, disintegration is not improved. When only scallop powder is blended, the disintegration time is shortened under acidic conditions such as disintegration test 1 solution (pH 1.2), but the disintegration time in water is not shortened.

The tablet of the present invention may be provided with an aqueous coating layer such as sugar coating and a water-insoluble coating layer such as shellac on the surface.
For the water-soluble coating layer other than sugar coating, water-soluble polymeric polysaccharides and cellulose derivatives can be used. Examples of the polymer polysaccharide include alginic acid, alginate, mannan and chitosan. Examples of the cellulose derivative include hydroxypropylmethylcellulose (HPMC) and carboxymethylcellulose (CMC).
An example of the water-insoluble coating layer other than shellac is corn protein.

The water-soluble coating layer is 0.5 to 30% by mass, preferably 1.0 to 20.0% by mass, based on the tablet weight. The water-insoluble coating layer is 0.5 to 10% by mass, preferably 0.5 to 5.0% by mass, based on the tablet weight.
For the coating operation, a method used for coating sugar-coated tablets can be used.

Examples of the present invention, comparative examples, and test examples using the same will be described below to explain the present invention in detail.
[Preliminary test]
1. Tablet crack confirmation test with silymarin formulation Silymarin (Silymarin ETG, Indena), a commercially available raw material for supplement production, starch (PCS FC-30, Asahi Kasei Chemicals), cellulose, lubricant ( Calcium stearate, Sakai Chemical Industry Co., Ltd.) was blended with the compositions shown in Tables 1 and 2 below, and then mixed with a V-type mixer to prepare tableted powders of 500 g each.
The tablet production conditions were as follows: continuous tableting using a rotary tableting machine (VEL2, manufactured by Kikusui Seisakusho) (rotation speed 30 rpm, preload 300 kgf, main pressure 1000 kgf), weight 280 mg, standard R (φ8 mm, R10 mm), sugar coating Two types of tablets were prepared as R (φ8 mm, R6.5 mm).

2. Results The presence or absence of capping during tableting and tablet breakage during tableting were observed. Further, 20 tablets were randomly selected from the obtained tablets, placed in a small bottle, and tested for the occurrence of tablet cracking when vigorously shaken up and down 10 times. In addition, the determination of tablet cracking was determined as tablet cracking in which one of the 20 tablets was cracked or cracked, including cracks.
As shown in Table 1, in the standard R tablet, no tablet cracking occurred regardless of the silymarin content. On the other hand, as shown in Table 2, in the sugar-coated R tablet, tablet breakage occurred when silymarin was added in an amount of 8.0% by mass or more. Moreover, the frequency of tablet cracking increased as the silymarin content increased, and the sugar-coated R tablets frequently capped during tableting as the silymarin content increased.
From this preliminary test, it was judged that it was difficult to form a sugar-coated R tablet when silymarin was blended in an amount of 8.0% by mass or more.

[Confirmation of inhibitory effect on tablet breakage by granulation before tableting]
In general, it is said that a capping phenomenon and tablet breakage can be suppressed by performing a granulation operation before tableting. The effect of granulation was tested on silymarin-rich sugar-coated R tablets.
1. Test Method The effect of granulation operation before tableting on tablet cracking was confirmed.
Silymarin (Silymarin ETG, Indena), a commercially available raw material for manufacturing supplements, starch (PCS FC-30, Asahi Kasei Chemicals), cellulose, lubricant (calcium stearate, Sakai Chemical Industry), and more Hydroxypropyl cellulose (HPC: Cerney SSL, Nippon Soda Co., Ltd.) was used as a binder during granulation. Further, as Comparative Example 1, a composition using trehalose (Hayashibara) as a binder, and Comparative Examples 2 and 3 as Comparative Examples 3 and 3 without using a binder and granulating were tested.
The composition shown in Table 3 below was blended, and the concentration of silymarin was divided into two levels of 35% and 15%. Note that silymarin was previously pulverized using a sample mill (Nara Machinery Co., Ltd.) before granulating.
A fluidized bed granulator (MP-01, Paulek) was used for granulation, and HPC and trehalose were each prepared as an aqueous solution having a concentration of 5% by mass and used as a binding solution during granulation. In Comparative Example 2 and Comparative Example 3, granulation was not performed, and the raw materials were mixed to produce a tableting powder.
The tablet production conditions were as follows: continuous tableting using a rotary tableting machine (VEL2, manufactured by Kikusui Seisakusho) (rotation speed 30 rpm, preload 300 kgf, main pressure 1000 kgf), weight 280 mg, sugar coating R (φ8 mm, R6.5 mm) It was.

2. Results The presence or absence of capping phenomenon during tableting and tablet cracking during tableting were observed. Further, 20 tablets were randomly selected from the obtained tablets, placed in a small bottle, and tested for the occurrence of tablet cracking when vigorously shaken up and down 10 times. In addition, the determination of tablet cracking was determined as tablet cracking in which one of the 20 tablets was cracked or cracked, including cracks.
As shown in Table 3, in the sugar-coated R tablets, tablet breakage did not occur when HPC was added. Moreover, when trehalose was used as a binder during granulation, cracking occurred (Comparative Example 1).
As shown in Comparative Examples 2 and 3, tablet breakage occurred when tableting was performed without granulation. Since there was no big difference in the cracks of Comparative Examples 2 and 3 and Comparative Example 1, it was determined that tablet cracking was suppressed by blending of HPC, not the effect of suppressing cracking by granulation.

[Disintegration test]
The disintegration properties of the tablets of Example 1, Example 2, and Comparative Examples 1 to 3 were tested.
1. Test method The disintegration time was measured according to the disintegration test method of the Japanese Pharmacopoeia. In the measurement, a disintegration tester (Toyama Sangyo) was used, and a disintegration auxiliary plate was used. The disintegrating solution used was 37 ° C. water and 37 ° C. disintegrating test solution 1 (pH 1.2).

2. Results The disintegration time of each tablet is shown in Table 4 below.

  From the above results, it was found that the tablet disintegration time is prolonged when granulation is performed. Trehalose is highly soluble and generally does not extend the disintegration time of tablets when used as a binding solution during granulation. However, from the comparison between Comparative Example 1 and Comparative Example 2, it was found that silymarin pulverization and granulation operation itself lead to the tablet disintegration time extension. It was thought that the cause of the disintegration delay was that the poorly water-soluble silymarin was uniformly coordinated in the tablet by silymarin pulverization and granulation.

[Disintegration control test]
As described above, when HPC was blended and granulated, a tendency for the disintegration time to be delayed was confirmed, so a test for examining additives for adjusting the disintegration time was conducted.
1. Test method As shown in Table 5, tablets containing erythritol and / or scallop powder were prepared in the same manner for the purpose of adjusting disintegration (Examples 3 to 8). As a comparative example, a tablet containing no erythritol and / or scallop powder without HPC was prepared.
The shape of the tablet is sugar-coated R tablets (φ8.5 mm R7 mm: Examples 3, 5 to 8, Comparative Examples 4, 5, 7), two-stage R tablets (φ8.5 mm R ₁ 3.4 mm R ₂ 10 mm: Examples 4 and Comparative Example 6). The tableting conditions were as described above, using a rotary tableting machine (VEL2, Kikusui Seisakusho) for continuous tableting (rotation speed 30 rpm, preload 300 kgf, main pressure 1000 kgf).

2. Results Similarly, the presence or absence of capping during tableting and tablet breakage during tableting were observed. In addition, 20 tablets were randomly selected from the obtained tablets, which were also placed in a small bottle and tested for tablet breakage when vigorously shaken up and down 10 times. In addition, the determination of tablet cracking was determined as tablet cracking in which one of the 20 tablets was cracked or cracked, including cracks. Similarly, the disintegration time was measured according to the disintegration test method of the Japanese Pharmacopoeia.
As shown in Table 5, it was found that the cracking of the sugar-coated R tablet and the two-stage R tablet can be suppressed by blending HPC, and further adjusted to the desired disintegration time by blending scallop powder and erythritol.

  From the above test results, sugar-coated R or two-stage R tablets containing a high amount of silymarin can prevent cracking of the tablet and capping at the time of tableting by using HPC as a binder. Further, scallop powder and erythritol It has been found that a tablet containing a high amount of silymarin having a desired disintegration time can be obtained by blending.

Claims (7)

  A silymarin-rich tablet containing 8% by mass or more of silymarin and hydroxypropylcellulose and having a tablet diameter of 8 mm or more.   The tablet according to claim 1, wherein the tablet has a sugar-coated R tablet or a two-stage R tablet.   The tablet according to claim 1 or 2, further comprising erythritol and scallop powder.   The tablet according to claim 3, comprising 8% by mass or more of silymarin, 4% by mass or more of erythritol, 5% by mass or more of scallop powder, and 1% by mass or more of hydroxypropylcellulose.   The tablet according to claim 4 containing 15 to 25% by mass of silymarin.   The tablet according to any one of claims 3 to 5, having a disintegration time of 45 minutes or less as measured by the method defined in the Japanese Pharmacopoeia.   Contains 8% by mass or more of silymarin, characterized by tableting a powder obtained by granulating a powder containing silymarin, erythritol, and scallop powder with an aqueous solution in which hydroxypropylcellulose is dissolved as a binder, and the diameter of the tablet A method for producing tablets containing a high amount of silymarin in the form of sugar-coated R tablets or two-stage R tablets of 8 mm or more.