JPS63267731A - Tablet composition - Google Patents

Abstract

PURPOSE:To obtain a tablet composition containing beta-1,4 glucan powder having specific size and specific surface area. CONSTITUTION:A table composition containing preferably 2-20wt.% beta-1,4 glucan having 30mum at most, preferably 20mum at most average particle diameter and >=1.3ml/g specific surface area. The composition enables tableting of prescription containing a large amount of a medicinal component (main drug) which has not been attained by existing crystalline cellulose and can provide tablets high uniformity of content and low separation and segregation. The above-mentioned fine powder cellulose is obtained by hydrolyzing pulp in 10% hydrochloric acid at 105 deg.C for 20min to give an acid-insoluble residue, which is filtered, dried, pulverized by a high-speed rotary impact grinder or an air flow type grinder. In order to obtain powder having smaller average particle diameter, the ground powder may be optionally classified, if necessary.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to a one-tablet composition. More specifically, it is a tablet composition containing β-1,4 glucan powder having specified powder properties, which improves the binding property as a binder and increases the hardness of the tablet. The present invention relates to a tablet composition that enables formulations containing a large amount of medicinal ingredients (herbal medicines) to be made into tablets, which could not be achieved with the conventional methods, and also enables tablets with high content uniformity with little separation and segregation to be obtained.

(Prior Art) Tablets are composed of a main drug, an excipient, a binder, a disintegrant, and other additives. Among these ingredients other than the main drug, binders include crystalline cellulose, hydroxypropyl cellulose, calcium phosphate, etc. Among them, crystalline cellulose has the highest binding property and is widely used. The average particle size of commercially available crystalline cellulose is approximately 6 μm (Avicel PH-MO6 manufactured by Asahi Kasei Corporation), approximately 155w5 (Avicel PH-M15 manufactured by Asahi Kasei), and approximately 2 μm.
5 μm (Avicel PH-M25 manufactured by the same company), approximately 45 μm
(Avicel ■PH-101, PH-301 manufactured by the same company), approximately 120μ dew (Avicel ■PH-102, PH-3 manufactured by the same company)
02). Among these, crystalline cellulose with a diameter of approximately 45 μm and approximately 120 μm is used as a binder for tablets. Furthermore, crystalline cellulose with an average particle size of approximately 6.15.251 m1 is mainly used as a compounding agent for cosmetics.The reason why crystalline cellulose with such an average particle size has been used as a binder for tablets in the past. This is because the average particle size is determined by the overall balance between the binding property, which is the intended property of the binder, and other physical properties. Generally, it has been said that if the average particle size of crystalline cellulose is too large or too small, separation and segregation will easily occur in relation to the main drug, other excipients, or granules.

According to Avicel Jiho No. 43 (published by Asahi Kasei Kogyo), in the so-called wet tableting method, in which crystalline cellulose and other additives are added to granules and then compressed, the granules are separated from the crystalline cellulose and other additives. Segregation can be a problem, and measures to prevent it include reducing the particle size of the granules to an extent that does not impair fluidity, increasing the particle size of crystalline cellulose and other additives closer to the granules, and increasing the particle size of crystalline cellulose and other additives. Increasing the bulk density of other additives is mentioned.

Furthermore, according to Japanese Patent Publication No. 57-14651, a pharmaceutical composition comprising β-1,4 glucan powder having specified powder characteristics, a poorly water-soluble main ingredient within a limited range, a disintegrant, and a surfactant. When directly compressed into tablets, there is less variation in the active ingredient content between tablets, and single-tablet strength, degree of disintegration, and dissolution rate of herbal medicine are improved, all of the problems associated with directly compressed tablets are solved. However, according to the example, the main pot lid is only 60 pieces.

The amount of β-1,4 glucan powder added is also as large as about 37 parts. Also, reference example 2. In Table 1, β-1,4 glucan powder with an average particle size ranging from 10 μm to 300 μm was used, the amount added was 36.5% by weight, and phenacetin was tableted into 60 wt qb1 having a specific shape. However, the strength of one tablet has only reached 2,03,8 kf. In particular, the tablet strength of a formulation without β-1,4 glue flour with an average particle size of 10° and 20μ is as follows:
It is lower than my father-in-law's β-1°4 formula that does not contain glutinous flour. It is also stated that there is no significant difference in the content of the active ingredient.

Further, in Example 5 of Japanese Patent Publication No. 56-38128, Sample 0 with an average particle size of 20 μm is used, but capping occurs and it is not formed into a single tablet. Differences from the present invention will be described later.

On the other hand, as a recent trend in formulation technology, tablets are becoming smaller, and in this case, the amount of the active ingredient added remains the same in many cases. Inevitably, the proportion of herbal medicines in prescriptions will increase. Conversely, the amount of ingredients other than crude drugs added is limited, and therefore the amount of crystalline cellulose used as a binder is also limited, making it impossible for tablets to exhibit sufficient binding properties and have hardness that is suitable for practical use. However, there are many cases where this cannot be done using the direct compression method. In other words, in order to reduce the size of a single tablet, it is necessary to be able to compress tablets with as high a proportion of herbal medicine as possible in the prescription. Tokuko Sho 56-381
In Example 5 of 28, ascorbic acid was directly compressed into tablets, but the proportion of ascorbic acid in the prescription was 8.
I am in charge of 0. It is assumed that formulations with ascorbic acid exceeding 80%'i will have low tablet hardness and will lose commercial value.

(Problems to be solved by the invention) In this way, when using conventional crystalline cellulose, the amount added is limited when a large amount of herbal medicine is added, so it cannot exhibit sufficient binding properties, and tablets with hardness that is suitable for practical use cannot be obtained. There were cases where this was not possible. On the other hand, in order to increase the hardness of a tablet, it is possible to increase the compression pressure during tablet compression, but this may result in capping or lamination, which may cause the tablet to crack, or even if it does not break, the hardness of the tablet decreases. There were times when I did something like that. In addition, increasing the molding pressure resulted in an increased frequency of abrasion and breakage of the punches of the tableting machine.

Regarding separation and segregation, in particular, after preparing granules containing the active ingredient in advance using the wet tableting and bed method, binders or disintegrants,
In the tableting method in which lubricant t is added and tableted, there have been problems with separation and segregation between the granules and components added later, that is, uniformity of the crude drug content.

(Means and Effects for Solving the Problems) The object of the present invention is to solve these problems and to provide a 7-1,4-glucan that has the specified powder properties as a binder. An object of the present invention is to provide a tablet composition using powder. In other words, it was considered impossible to use according to conventional knowledge,
By using β-1,4 glucan powder, which has an average particle size of at most 30 μm and a specific surface area of 1.34 f or more as measured by the BET method, the hardness of the tablet If? This makes it possible to form tablets with high-quality pharmaceutical formulations that could not be achieved with conventional crystalline cellulose, making it possible to compress tablets with lower molding pressure than before, and also suppressing variations in the metal cap of the main drug per tablet. It became.

The various effects of the tablet composition of the present invention can be obtained only when the specified β-1,4 glucan powder gold described below is used. Specifically, the present invention provides a tablet containing β-1,4 glucan powder (hereinafter referred to as fine cellulose) having an average particle diameter of at most 30 μm and a specific surface area of 1.3 nV9 or more as measured by the BET method. It is a composition.

The present invention will be explained in detail below. The finely divided cellulose of the present invention is obtained by decomposing cellulose materials such as linters and pulps by acidic hydrolysis or alkaline oxidative decomposition, or a combination of both, followed by purification and pulverization or grinding after, during, or before drying. It is necessary that the average particle size is at most 30 μm, preferably at most 20 μm, and the specific surface area measured by the BH method is 1.3 Jf or more. The amount of finely divided cellulose added to the tablet composition is preferably 2 to 20 parts by weight.

The smaller the average particle size of finely divided cellulose, the better the hardness of tablets made using it, but when the average particle size exceeds 30 μwrf, there is no significant improvement in tablet hardness compared to when conventional crystalline cellulose is used. Unachievable. Furthermore, even if the average particle size is 30 μm or less, the specific surface area is 1.3 m! /f
If it is less than that, the desired tablet hardness cannot be obtained.

The relationship with β-1,4 glucan powder having an average particle size of 10.20 μm described in Reference Example 2 and Table 1 of Japanese Patent Publication No. 57-14651 will be mentioned. β-1,4 with various average particle sizes
The manufacturing method for glucan powder has not been disclosed. but,
For example, if you try to reduce the average particle size by pulverization,
It is considered inappropriate to use in such experiments because there is a risk of not only decreasing the particle size but also greatly changing the roughening volume and other powder physical properties.
-The manufacturing method of 1,4 glucan powder is divided into m parts.

It is assumed that this was due to wind classification. By the way, a commercially available crystalline cellulose, Avicel@PH-101'i, was air-classified to obtain crystalline cellulose with an average particle size of 20 μm (hereinafter referred to as a classified product). A tablet containing the classified product was prepared and the tablet hardness was compared with that of a tablet containing Avicel PH-101. Although the tablet hardness was slightly higher, there was no significant difference. On the other hand, the hardness of the tablet containing the finely divided cellulose of the present invention is 2
It was ~3 times higher. The specific surface area of the classified product is 1.1 rre/
? It is not much different from that of Avicel ■PH-101.

Since crystalline cellulose is originally a porous powder, it is presumed that even if the particle size changes through classification, the specific surface area will not change much. The specific surface area of the finely divided cellulose of the present invention is 1.3
tri/ or more, which is considerably higher than classified products. It is thought that the specific surface area increases due to morphological changes caused by pulverization or the like. Therefore, the present invention cannot be achieved simply by sieving and classifying commercially available crystalline cellulose. In addition, in Example 5 of Special Publication No. 56-38128,
Sample 0 with an average particle size of 20 μm is used, but when a sample was prepared according to Example 4, which describes the manufacturing method of this sample, the average particle size was 20 μm, but the specific surface area was 0.8 -/l, and unlike the finely divided cellulose of the present invention, it did not exhibit binding properties.

The finely divided cellulose of the present invention is produced, for example, by the following method, but is not limited to these methods.

The acid-insoluble residue obtained by hydrolyzing the pulp in 10% hydrochloric acid at 105°C for 20 minutes is washed with P filter, dried, and pulverized using a high-speed rotational impact crusher or an airflow crusher. obtain. Furthermore, if you want to obtain powder with a small average particle size,
If necessary, classification may be performed after the pulverization step.

There are two types of tablet-making methods: direct powder compression method (direct compression method) and granule compression method (mixed compression method).

When tablets are manufactured by the direct compression method, the tablets are composed of crude drugs, excipients, binders, disintegrants, etc., and the mutual relationships among these components cannot be ignored. When finely divided cellulose is added, the fluidity of the formulation tends to decrease, and although it depends on each component other than finely divided cellulose, in order to keep tablet weight variations within an acceptable range, the upper limit of the amount of finely divided cellulose added is 20%. There is a weight station. In addition, the lower limit of the amount of finely powdered cellulose added to significantly improve tablet hardness is 2 weight range.
In order to improve the tablet hardness of a composition containing finely divided cellulose, it is necessary that the finely divided cellulose be attached to the surface of the crude drug or other additives.

Compared to the conventional crystalline cellulose, Avicel PH-101 formulation system, which has been considered the best binder in the direct compression method,
The tablet hardness of the formulation containing finely powdered cellulose was 2 to 3 times higher. In addition, with conventional crystalline cellulose, it was possible to raise the ascorbic acid concentration in the prescription only to 80 parts by weight when ascorbic acid was applied directly, but with finely powdered cellulose, it was possible to raise the concentration of ascorbic acid in the formulation to 86 parts by weight. It was possible.

In addition, conventional crystalline cellulose has a molding pressure of 1 ton/c
From the hardness of the tablet obtained in step 11, the molding pressure was 1.5 ton/c.
The tablets obtained in Ii had low hardness and showed a tendency to cap, but no capping was observed in the formulation containing finely powdered cellulose. In terms of molding pressure, finely powdered cellulose formulations require less than half of the conventional crystalline cellulose formulations, and it is possible to compress tablets with lower molding pressure.Using finely divided cellulose reduces wear and tear on the punches of the tablet machine. It is estimated that this can be suppressed.

If finely divided cellulose is added to the granules obtained by granulation and then tableted, the upper limit of the amount of finely divided cellulose to be added should be set at #: t20 weight, since the granules themselves have a certain degree of moldability. Furthermore, in order to significantly improve tablet hardness, the lower limit of the amount of finely divided cellulose added is 2 weight range. In this method, as in the case of direct compression tablets, the surface of the granules is coated with finely divided cellulose, making it possible to obtain tablets with higher hardness than conventional crystalline cellulose. Furthermore, when conventionally adding crystalline cellulose as a powder and compressing it into tablets, separation and segregation of the granules and crystalline cellulose occurred, resulting in variations in the weight of the tablets and loss of uniformity in herbal drug content. . Since finely divided cellulose has a smaller average particle size than conventional crystalline cellulose, the gap between it and the particle size of the granules is larger than that of conventional crystalline cellulose, and from the conventional thinking, separation and segregation from the granules would be more likely to occur. However, the opposite is true,
Since the finely divided cellulose adheres uniformly to the granule surface, no one-separation segregation occurs.

The tablet composition of the present invention can be made into tablets using conventional manufacturing methods. Therefore, finely powdered cellulose is added to one or more crude drug ingredients, and other additives are added as necessary, and then shaped into one tablet by a known method such as dry or wet. Alternatively, after adding additives to 181 or more crude drug ingredients, it is made into granules using a known method.

Finely powdered cellulose and other additives are added as necessary to form the mixture into tablets. It is also free to film-coat or sugar-coat the tablet composition defined in the present invention.

Prior to Examples, methods for measuring physical properties of powder and tablets will be explained.

<Average particle size (μ,)> Sample 50F was sieved for 30 minutes using a JiS standard sieve using a rotary tube sieve shaker manufactured by Yanagimoto Seisakusho, and a cumulative particle size of 5 ([1
% particle size is taken as the average particle size. 400 mesh pass is 50
If the weight exceeds qbt, the powder that has passed through 400 meshes should be measured using a high slag sedimentation particle size distribution analyzer (CP-
Particle size distribution was determined by 50), and 400 was determined by sieving.
Cumulative 50 when combined with particle size distribution of fractions larger than mesh
Let the particle size of the heavy grain be the average particle size. Note that as the average particle size becomes smaller.

Some particles agglomerate on the sieve, making it difficult to sieve, but in that case, the particle size is small enough to be detected by a high slag sedimentation particle size distribution analyzer, so it can be directly sieved without sieving. It was measured.

<Specific surface area (Jy)> Uses 2300t flow loop made by Takasugi Seisakusho ■.

The measurement was carried out by the BET method using nitrogen gas as the adsorption gas.

<Tablet hardness (kt)> It is expressed as the load when a tablet is broken by applying a load in the radial direction using a Schroinger hardness tester manufactured by Freund Sangyo ■. The number of repetitions is 10, and the average value is taken.

<Content uniformity (%)> Accurately weigh one tablet and thoroughly crush it in a mortar. Approximately 5 pieces of crushed material
Accurately weigh 0q1 and place it in a 100-volume volumetric flask. 0.
Add about 70ml of IN hydrochloric acid, seal, and shake for 1 hour in an auto shaker. Add 061N hydrochloric acid up to the marked line and mix well. Membrane filter with 0.2μ grooves for all dispersion liquids
Dilute the p-filtered solution 15 times. The absorbance of the diluted solution was measured at wavelength 2 using a UV150-02 colorimeter manufactured by Takashi Seisakusho.
Measure at 44μ■. From the calibration curve created in advance,
The amount of zenacetin in the tablet is determined, and the zenacetin content *Xi (a) relative to the theoretical amount that should be contained in the tablet is calculated.The number of repetitions is lO, and its average value (X) and coefficient of variation (CV) are calculated.

Aobsd-: zenacetin content measurement value Acalc,
: 7 Theoretical value of enacetin content The samples used in the Examples and Comparative Examples were prepared as follows.

Sample (2), CB), (C): A commercially available DP bulb was cut into pieces and hydrolyzed in 10% hydrochloric acid at 105°C for 20 minutes. The acid-insoluble residue obtained was filtered, washed, and dried. Samples (4), [F]), and 0 having different average particle sizes were obtained by pulverizing with 5TJ-200 manufactured by Seishin Enterprise ■, which is a type of air flow pulverizer, and varying the amount of raw material supplied.

Sample 0): Crystalline cellulose manufactured by Asahi Kasei Corporation, Avicel@
PH-MO6 was used as sample (D).

Sample [F]: Crystalline cellulose manufactured by Asahi Kasei Kogyo ■, Avicel ■PH-1011 - Sample ■.

Sample P: Crystalline cellulose manufactured by Asahi Kasei Corporation, Avicel P
This was designated as the H-102i sample.

Sample port: Sample (■) was classified, and the fine powder side was designated as sample (G).

Table 1 shows the powder properties of samples (1) to (G).

Table 1 (Example) Example 1 Samples (2), (B), (Ot-30f each, lactose (rJ
Manufactured by MV.

100 mesh) 268.5ft-1.5 was mixed for 100 minutes in an S-type blender, 1.5fi of pharmacopoeial magnesium stearate (manufactured by Taihei Kagaku ■) was added, and the mixture was further mixed for 1 minute. Using an RT-89 type rotary tablet press with an 8 φ, 12R punch, the rotation speed was 25.
It was compressed into tablets at rpm to obtain tablets weighing 200 capes. The results are shown in Table 2.Comparative Examples 1 to 4 Samples [F]), (E), (rl, C)tl- were each compressed into tablets according to the method of Example 1. The results are shown in Table 2. Also.

The maximum hardness of the tablet obtained with each formulation is plotted on the vertical axis.
The results of plotting the average particle size on the horizontal axis are shown in FIG.

Table 2 From Table 2, Comparative Examples 1 to 4 had a molding pressure of 1.0 ton/c.
The tablet shows maximum hardness at lI, and the molding pressure is 1.5 ton/
aj shows a capping tendency, molding pressure 1.0 to
The hardness was lower than n/cd. In contrast, Example 1
Samples (To), (Bl, (O) finely powdered cellulose had a tablet hardness that increased as the molding pressure increased in the range of 1.5 ton/di or less. From FIG. Particle size 120μS) → Comparative example 2 (particle size 45μW &
)→Comparative Example 4 (20 μl IK), commercial products, and classified products thereof do not change the maximum tablet hardness so much even if the average particle size becomes smaller. However, in Example 1, 28μ → 12μ
As the average particle diameter decreased from 5μ to 5μ, the maximum tablet hardness significantly increased. This was applied to sample (2), (BJ) on the surface of DMV100 mesh lactose.

(O adhered well and was thought to reduce contact between lactose, which has little moldability. On the other hand, Sample E, a commercially available product) hardly adhered. Figures 2 and 3 show scanning electron micrographs of a formulation prepared by mixing sample port) and sample [F] with lactose. From the results for sample 0.0, the average particle size was 30 or less. Even though the specific surface area is 1.3 ff! When it was less than 1/2, the tablet hardness was the same or lower than that of the commercial product ■.

Example 2 Pharmacopoeia crystalline ascorbic acid (manufactured by Takeda Pharmaceutical Co., Ltd.) and sample port) were mixed in a 56-volume V-type blender in the amounts shown in Table 3.
Mix for a minute and then add magnesium stearate (Mg-8
t) After adding e and mixing for 5 minutes, the results were directly compressed using a tablet mold @250Mg according to Example 1, and the results are shown in Table 4.

Comparative example 5.6 Using sample ①, it was directly compressed into tablets according to Example 2.

The blending amounts are shown in Table 3, and the results are shown in Table 4.

Table 3 Table 4 In the formulation of ascorbic acid and commercially available crystalline cellulose, tablets with practical hardness were finally produced when the ascorbic acid content was 80 parts by weight.

Micropowdered cellulose, sample @)? , tablets with an ascorbic acid content of 86 weight range could be directly compressed. An attempt was made to prepare a tablet with an ascorbine e content of 86 using a commercially available product, but the hardness was so low that it could not be put to practical use.

Example 3 Pharmacopoeia Zenacetin [Sansui Chemical ■W] 350 f.

Pharmacopoeia lactose (manufactured by DMV, 200 Metsu-7 Yu) 79f, pharmacopoeia cornstarch [manufactured by Nippon Higaku ■ 150F, #JII fibrillar calcium glycolate [manufactured by Nichirin Kagaku@].

After mixing 25 f (product name ECG-505) in a plastic bag for 1 minute, mix it with a planetary mixer (5D
Mr) K transfer L, hydroxypropylcellulose-
Type L [manufactured by Nisso ■] 6-layer aqueous solution 83f and water 100F' (j
It was added and kneaded. The obtained mixed material was crushed and granulated using a flash mill (FL-200, manufactured by Fuji Baudal). This is 4
The mixture was dried at 0° C. for 16 hours and then sieved through a 10-mesh sieve to obtain granules. The above operation was repeated t-3 times, and the obtained granules were mixed to obtain zenacetin granules having the following particle size distribution.

The average particle size was 550 μm, and the roughening volume was 2.4 sg/r.

Zenacetin granules 450f and sample 50f'k1.5 were mixed for 100 minutes in an S-type blender, 1.5 ft of magnesium stearate was added, mixed for 1 minute, and then tableted according to Example IK. The results of the obtained tablet hardness are shown in Table 5. Also, the content of 7-enacetene in the tablets compressed at a molding pressure of 0 and 7 to It is shown in Table 6.

Comparative example 7 Using sample [F], tablets were compressed according to Example 3.

Table 5 shows the tablet hardness, and Table 6 shows the 7enacetin content and its coefficient of variation.

Table 5 Table 6 Maximum tablet hardness ti, Example 3 gave 7.2 kf, Comparative Example 7 gave 4.8 kf, and even in the wet tableting bed method, the sample
Using this method, higher tablet hardness was achieved compared to the sample. Sample (2) has barely reached the practical hardness, but since the sample (amount of sample) has sufficient hardness, it is possible to compress the tablet by lowering the molding pressure or reducing the amount of sample. Furthermore, when the zenacetin content in one tablet was examined, the coefficient of variation (CV) of Example 3 was considerably smaller. This means that the conventional problem of variation in the content of the active ingredient in tablets due to separation and segregation of commercially available crystalline cellulose can be greatly reduced by using finely divided cellulose. This effect is due to the fact that finely divided cellulose adheres to the surface of other components (granules in this case), as shown in Figures 2 and 3. The reduction was significantly greater than that of cellulose.

(Effects of the Invention) The tablet composition provided by the present invention is less likely to cause capping and provides higher tablet hardness than conventional tablet compositions containing crystalline cellulose. This shows that tablets with the same hardness can be manufactured with a lower amount of β-1,4 glucan powder added than conventional tablets, making it easier to directly compress Kooh Pharmaceutical products and manufacture small tablets. be able to.

For example, direct tableting using commercially available crystalline cellulose,
Contains ascorbic acid! Although the limit was 80% by weight, by using the finely divided cellulose of the present invention, tablets with an ascorbic acid content of 86 parts can be manufactured.

In addition, it is possible to produce tablets with the same hardness even if the tablets are compressed using a lower compression pressure than conventional tablets, which reduces the wear and tear of punches and reduces the deactivation of crude drugs caused by heat generation due to friction. .

Furthermore, in the tablet composition provided by the present invention, when micronized cellulose is added as a final powder in the granule compression method, separation and segregation of granules and crystalline cellulose, which was a problem when conventional crystalline cellulose was added as a final powder, can be avoided. Therefore, it is possible to produce tablets with extremely high uniformity of the active ingredient content.

[Brief explanation of drawings]

FIG. 1 is a graph showing the maximum hardness and average particle size of the tablets obtained in Example 1, and FIG. 2 is an electron micrograph showing the particle structure of a formulation prepared by mixing sample CB) and milk m. FIG. 3 is an electron micrograph showing the particle structure of a formulation containing sample [F] and lactose.

Claims (3)

[Claims] (1) A tablet composition characterized by containing β-1,4 glucan powder having an average particle size of at most 30 μm and a specific surface area of 1.3 ml/g or more. (2) The tablet composition according to claim 1, wherein the average particle size of the β-1,4 glucan powder is at most 20 μm. (3) The tablet composition according to claim 1 or 2, which contains 2 to 20 weight percent of β-1,4 glucan powder.