JPH0532373B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing a solid drug with improved disintegrability, and more particularly, to a method for producing a solid drug with improved performance by selectively using a disintegrant with a specific particle size. Solid drugs are tablets, pills, granules, etc. that are mixed and molded with excipients, binders, disintegrants, lubricants, etc. added to the medicinal ingredients for convenient distribution, storage, handling, and administration. It is in the form of Among the above compounded ingredients, disintegrants are used to give solid drugs the ability to easily disintegrate in the human body's digestive fluids, and after oral ingestion, the medicinal ingredients are quickly released in the fire extinguishing organs. It is intended to do so. The disintegrants mentioned above include starch, formalized gelatin, alginic acid, cellulose glycolic acid (free acid),
Cellulose calcium glycolate, low-substituted alkyl cellulose, low-substituted hydroxyalkyl cellulose, and the like have been proposed, and several types are in practical use. Among them, cellulose calcium glycolate is recognized as having the best performance such as being tasteless, odorless, and white, having good disintegration properties, high swelling ratio, and compression moldability, and is used in the largest quantities. It is used. However, calcium fibrin glycolate also has poor binding properties, so if used in large quantities, the hardness of the molding agent will be insufficient, and even though it disintegrates quickly in water, the rate of disintegration in gastric fluid is not necessarily that high. has been pointed out. The cellulose calcium glycolate that is currently commercially available and used industrially is only a single grade manufactured and sold under the trademark ECG-505, and its standard physical properties and analytical values are based on anhydroglucose units. The polymerization degree is about 300, the carboxymethyl group substitution degree is 0.6, the pH of the medium when 1% by weight is dispersed and suspended in water is about 5, and the particle size is such that 95 parts by weight or more can pass through 200 meshes. In contrast, the inventors believe that, when used in actual solid drugs, a product that eliminates the fine powder fraction of cellulose calcium glycolate and is limited to a specific particle size or more is superior to products currently on the market. It was found that the material had a disintegrating property. When producing a solid drug, it is desirable that the ingredients are mixed as uniformly as possible, and for this purpose it has generally been thought that the finer the particle size of the ingredients, the better. Especially in the case of cellulose calcium glycolate,
Since the blending amount is at most about 2 to 10% by weight of the total, it has generally been used with fine particle size. That is, in various standards, only the upper limit of particles was determined, and no consideration was given to the existence of fine powder fractions. For example, in the specification of Japanese Patent Publication No. 43-7960, which is a manufacturing patent for cellulose calcium glycolate, Example 1
In Example 2, it was ground into 200 mesh pieces.
Each product is made by crushing it into 150 pieces. The upper limit particle size of these products is 200 mesh and 150 mesh, respectively, and all particles that can pass through a sieve corresponding to these sizes are included. This is because when particles are obtained by grinding, a fine powder fraction is always accompanied. The inventors neutralized cellulose glycolic acid using calcium carbonate, sieved the obtained cellulose glycolic acid calcium by pulverization, prepared particles with different particle sizes, and molded the solid drug by blending the same. As a result of investigating their disintegration properties, it was found that those using cellulose calcium glycolate that did not contain fine powder fractions had superior disintegration properties compared to those containing fine powder fractions. . According to the inventors' considerations, the characteristic of cellulose calcium glycolate as a disintegrant is that it has a large swelling ratio in an aqueous medium, and the disintegrant first absorbs the medium and swells, forming a solid This applies stress to the inside of the drug, leading to its collapse. If disintegration occurs through such a mechanism, stress can be applied more effectively if the individual disintegrant particles are gathered to a certain size. It is thought that even if the fine powder fraction swells, the pressure will be absorbed by the surrounding particles of other components and the effect will not be sufficiently exerted. This must be taken into account that the amount of the disintegrant is as small as 5% by weight at most. Containing a fine powder fraction means containing a fraction that is less effective as a disintegrant. According to studies conducted by the inventors of the present invention, it has been found that when the particle size is 80 mesh or less, the larger the particle size of cellulose calcium glycolate, the better a solid drug can be obtained with excellent disintegration properties. However, it was also found that the hardness of the preparation tends to be relatively lower when the particle size is large. This is explained by the poor binding function of fibrin calcium glycolate. That is, the present invention relates to a method for producing a solid drug characterized by using cellulose calcium glycolate containing no fine powder fraction as a disintegrant. Specifically, if a disintegrant that does not contain a fine powder fraction and does not contain a fraction passing through 300 meshes is used, a solid drug with excellent disintegration properties can be obtained. However, as the particle size of the disintegrant increases, the hardness of the solid drug tends to decrease, so as a disintegrant that satisfies both hardness and disintegration properties, use cellulose calcium glycolate that passes 145 mesh but does not pass 300 mesh. It is preferable to use The cellulose calcium glycolate used in the present invention has a degree of carboxymethyl substitution per anhydroglucose unit, that is, a degree of etherification of 0.30 or more.
0.80 or less is appropriate. If the degree of etherification is less than 0.3, the disintegrability and swelling ratio will not be sufficient, and if the degree of etherification is greater than 0.85, the hardness of the solid drug will tend to decrease although the disintegrability will not be particularly good. The present invention will be explained below with reference to Examples. Examples 1 to 2 and Comparative Examples 1 to 3 Cellulose calcium glycolate having a degree of carboxymethyl group substitution per anhydroglucose unit of 0.53 and a degree of neutralization of PH 5.2 was sieved as follows. Disintegrant particle size 145 mesh - 200 mesh does not pass b 200 mesh - 300 mesh c 80 mesh - 145 mesh d 200 mesh (contains fine powder) Standard product e 300 mesh (contains fine powder) Above cellulose glycolic acid A tablet containing calcium as a disintegrant, ascorbic acid as a medicinal ingredient, microcrystalline cellulose (Avicel PH101 manufactured by Asahi Kasei) and lactose as excipients, and talc and magnesium stearate as a lubricant is made by direct compression. I made it using the same method. The tablet composition and formulation conditions are as follows. Tablet composition: Ascorbic acid 50.0% by weight Avicel PH101 28.0 〃 Lactose 14.0 〃 Disintegrant 5.0 〃 Talc 2.5 〃 Magnesium stearate 0.5 〃 100.0% by weight Manufacturing conditions: Tablet press Kikusui Seisakusho Clean Press Collect 24 Molding conditions Tablet diameter 8 mmφ, Tablet thickness: 4mm, weight: 200
mg, tableting pressure 1t Tablet physical properties were measured in the following directions. Disintegration Disintegration tester according to the Japanese Pharmacopoeia (Toyama Sangyo Co., Ltd.) Measurement temperature 37±2℃ Test liquid Pharmacopoeia 1st fluid (artificial gastric fluid) n=10, expressed as the average value (seconds) of the time required for disintegration Hardness tester Tensilon UTM-1 (Toyo Seiki) Compression load cell 100Kg/cm ² Compression loader diameter 2.0mm Compression speed 0.4mm/min n=8, expressed as the average value of the pressure just before fracture starts (Kg/cm ² ) Abrasion degree 100 tablets were processed using a Kayadan type abrasion tester for 25 rotations for 3 minutes, and the weight of the powdered portion is shown in percentage (%). The particle size of the disintegrant used and the physical properties of the tablets are shown in Table 1. show

[Table] Examples using a disintegrant not containing a fine powder fraction showed superior disintegration properties compared to comparative examples (including pharmacopeia standard products) using a disintegrant containing a fine powder fraction. Furthermore, the hardness tended to be higher in those using disintegrants with smaller particle sizes. Incidentally, capping occurred during tablet compression: 4 cappings occurred in Comparative Example 2 and 1 capping occurred in Comparative Example 3 per 100 tablets, but in Examples 1-
In Comparative Example 2 and Comparative Example 1, it did not occur at all. Examples 3 to 6 and Comparative Examples 4 to 9 Using the same disintegrant as that used in Examples 1 to 2 and Comparative Examples 1 to 3, and changing the tableting conditions, tablets containing ascorbic acid as the main drug and lactose as the main drug were prepared. A simulated tablet was prepared using a direct compression method, and the physical properties of the resulting tablet were measured. Tablet composition: Vitamin C tablet: Same composition as Examples 1 and 2 Simulated tablet: Lactose 93.5% by weight Disintegrant 5.0 Talc 1.0 Magnesium stearate 0.5% by weight 100.0% by weight Tableting conditions: 0.70 g of tablet composition was compressed into 12 mmφ Molding into tablets with a thickness of 4 mm using a rod of Measure the time required for dispersion into the hardness, n=5 Hardness: Measure using a Monsanto hardness tester, n=5
The measurement results are shown in Tables 2 and 3.

【table】

[Table] In all cases, the tablets using a disintegrant that did not contain a fine powder fraction showed excellent disintegration properties.

Claims (1)

[Claims] 1 Calcium glycolate, which has a degree of carboxymethyl group substitution per anhydroglucose unit of 0.30 to 0.80 and has a particle size that does not pass through 145 meshes but does not pass through 300 meshes, is added to the main drug as a disintegrant and mixed with other excipients. 1. A method for producing a solid drug with improved disintegrability, characterized by forming it into a solid drug.