JPH0524139B2 - - Google Patents

Description

[Detailed description of the invention]

This invention relates to a method for producing solid drugs with improved disintegration and hardness, and more specifically, tablets and pills formed by blending with a disintegrant of cellulose calcium glycolate having improved physical properties. , relates to a method for producing solid drugs such as granules. After solid drugs are ingested, they disintegrate in the digestive juices of the stomach and intestines, releasing their medicinal ingredients and allowing them to be absorbed into the human body through the walls of the stomach and intestines, but their shape remains stable during handling. In many cases, a disintegrant is used in combination to ensure sufficient disintegration in digestive fluids while retaining water. Calcium glycolate is most commonly used as a pharmaceutical disintegrant because it has advantages such as being tasteless, odorless, white, and having good disintegration properties, swelling ratio, compression moldability, etc. It is listed in the Japanese Pharmacopoeia as methylcellulose calcium and is commercially available under the trade name ECG-505 (manufactured by Nichirin Chemical Industry Co., Ltd.). However, depending on the type of medicinal ingredient, it may not be possible to use it if it is reactive with calcium.
Problems have been pointed out, such as the use of large amounts of disintegrants may result in insufficient strength of the solid drug. Therefore, as other disintegrants, starch, formalized gelatin, alginic acid, cellulose glycolic acid (free acid type), low-substituted hydroxyalkyl cellulose, low-substituted alkyl cellulose, etc. have been proposed, and some are still used. However, they each have their own problems, such as those that are colored, have a bad taste, and do not disintegrate sufficiently unless used in large quantities. Overall, no one has been found to be better than calcium cellulose glycolate. It has not been. Incidentally, calcium cellulose glycolate is commercially available only as a single grade product, ECG-505, and its general properties are that the pH of the medium of a 1% by weight dispersion in water is 5 to 5.5, the particle size is 200 mesh passable, and it is anhydrous. The degree of substitution of carboxymethyl groups per glucose unit is 0.55-0.6. This underwater 1
% of the dispersion liquid is hereinafter referred to as the degree of neutralization. As a result of various studies, the inventors of the present invention changed the degree of substitution and neutralization of cellulose calcium glycolate, so that the degree of substitution per anhydroglucose unit was 0.30 or more and 0.55 or less, and the degree of neutralization was adjusted to a pH of approximately 4 to 4. The present invention was achieved by discovering that a disintegrating agent adjusted to 9 was superior to conventional disintegrants. The advantages of this cellulose calcium glycolate having a lower degree of substitution than conventional commercially available products are as follows. (1) Although the degree of swelling is lower than that of conventional commercially available products, the disintegration time is shorter. (2) The hardness of the molded tablet is greater than that of conventionally commercially available tablets. Therefore, when used in the same amount as conventional commercially available cellulose calcium glycolate, a solid drug with good disintegration properties and high hardness can be obtained. Alternatively, a solid drug with further improved hardness can be obtained even if the amount is reduced to such an extent that disintegration properties equivalent to those of conventional products can be obtained. In addition, conventional commercially available cellulose calcium glycolate products have a high degree of swelling and exhibit rapid dissolution by causing the tablet to disintegrate explosively in the stomach. In contrast, the cellulose calcium glycolate with a low degree of substitution used in this invention is not so large in terms of swelling degree and gradually disintegrates from the periphery, but the time required for the entire disintegration to finish is longer than that of the conventional one. shorter than For this reason, formulations suitable for drugs that require fast-acting effects and that require uniform dissolution as they irritate the gastric wall if released into the gastric fluid all at once, such as antipyretics and analgesics, are recommended. enable. Furthermore, the inventors of this invention have experimentally found that when the degree of neutralization of cellulose calcium glycolate with the same degree of substitution is changed, the disintegration properties tend to improve as the pH increases. . However, according to Japanese Patent Publication No. 7960/1989, which is a patent related to the method for producing cellulose calcium glycolate, it is stated that the neutralization conditions must be kept at a weakly acidic or neutral pH of 4 to 7. . The reason for this is that when the degree of neutralization is set to an alkaline range of PH7 or higher,
It is cited that some coagulation occurs and the swelling property is rather reduced. The inventors of this invention conducted various studies and found that in products with a degree of substitution in the range of 0.3 to 0.55, no coagulation phenomenon occurred even when the degree of neutralization was made weakly alkaline to about PH8, and the disintegration property was further improved. was found to be obtained. Regarding the degree of substitution of cellulose calcium glycolate, it is recognized that if the degree of substitution per anhydrous glycose unit is 0.3 or less, the disintegration property decreases.
On the other hand, if it is 0.55 or higher, it will not be much different from what is currently on the market. The amount of the above-mentioned disintegrant in the drug composition depends on the physical properties of the drug composition itself, but is generally about 3 to 10% by weight. That is, this invention uses calcium fibrous glycolate, which has a degree of substitution of carboxymethyl groups per anhydroglucose unit of 0.30 to 0.55 and a neutralization degree of PH of about 4 to 9, as a disintegrant and is added to the main drug together with other excipients. The present invention relates to a method for producing a solid drug with improved disintegrability, which involves mixing and shaping. This invention will be explained below with reference to Examples. Examples 1 to 2 and Comparative Example 1 Using purified wood pulp as a starting material, cellulose calcium glycolate having different degrees of carboxymethyl substitution and neutralization was produced. This cellulose calcium glycolate is used as a disintegrant, aspirin is used as a medicinal ingredient, microcrystalline cellulose (Avicel PH101, manufactured by Asahi Kasei) is used as an excipient, lactose is used, talc is used as a lubricant, and wax (Lovely Wax) is used as a lubricant.
101 (manufactured by Freund Sangyo) and sodium cellulose glycolate (JP-120, manufactured by Nichirin Kagaku Kogyo) as a binder were prepared by a direct compression method. No capping was observed during tableting, and moldability was good. The tablet composition and formulation conditions are as follows. Tablet composition Aspirin (powder) 55.0 Azecel PH101 23.0 Lactose 12.0 Disintegrant 5.0 Talc 2.5 Wax 0.5 Binder 2.0 100.0% by weight Tableting conditions Tablet machine: Kikusui Seisakusho, Clean Press Cork
24 Molding conditions: Tablet diameter 8mmφ, tablet thickness 4mm, weight 200
mg, tablet thickness 1 ton Tablet physical properties were measured by the following method. Disintegration tester based on the Japanese Pharmacopoeia (Toyama Sangyo Co., Ltd.) Measurement temperature: 37±2℃ Test liquid: Water and Pharmacopoeia No. 1 liquid (artificial gastric juice) n=10: Shown as the average value of the time required for disintegration . Hardness Testing machine: Tensilon UTM-1 (Toyo Seiki) Compression load cell: 100Kg/cm ² Crushing load rod diameter: 2.0mm Compression speed: 0.4mm/min n=7: Shown as the average value of the pressure just before collapse starts. Friability: 100 tablets were treated with a Kayagaki friability tester for 25 rotations for 3 minutes, and the weight of the powdered product is expressed as a percentage. Table 1 shows the physical properties of the tablets used and the properties of the cellulose calcium glycolate used as the disintegrant. (*However, the degree of neutralization is expressed as the pH of the medium when the sample is dispersed in 100 times the volume of distilled water.)

[Table] The tablets of Examples 1 and 2 had approximately the same hardness and friability as the comparative example (the cellulose calcium glycolate used was equivalent to the ECG-505 standard), but had excellent disintegration. It is. Examples 3 to 7 and Comparative Example 2 Using cellulose calcium glycolate with different degrees of carboxymethyl group substitution and neutralization as a disintegrant, simulated tablets mainly containing lactose were produced by a direct compression method, Physical properties of the obtained tablets were measured. Tablet composition Lactose 93.5 Disintegrant 5.0 Talc 1.0 Magnesium stearate 0.5 100.0% by weight Tableting conditions 0.75 g of the tablet composition was compressed using a 15 mm diameter rod to a thickness of 4
Molded into mm tablets. Disintegratability Fill a 25mmφ x 2m tube with water or the first liquid (artificial gastric juice), drop the tablet from the water surface into the liquid, and measure the time required for complete dispersion (water: 15℃) , 1st liquid station: 37°C) Shown as the average value of n = 12. Separately, the swelling volume of cellulose calcium glycolate in water was measured. Swelling Volume Take 3g of sample in a beaker and add 80ml of water to disperse. Pour this into a 100ml graduated cylinder. Pour off the material stuck to the vessel wall with 20ml of water and add to the graduated cylinder. Leave to stand overnight, subtract the volume of the top light solution from the total volume, and convert the obtained value to 1 g. The measurement results are shown in Table 2.

[Table] Compared to the disintegrant used in Comparative Example 2 (equivalent to ECG-505 standard), the disintegrant used in the example had a smaller swelling volume, but when made into a vague tablet, it had better disintegration in artificial gastric fluid. It was warm.

Claims (1)

[Scope of Claims] 1 Disintegration of cellulose calcium glycolate having a degree of cariboxymethyl group substitution per anhydroglucose unit of 0.30 to 0.55 and a pH of the medium after standing of a 1% distilled water dispersion of about 4 to 9. 1. A method for producing a solid drug with improved disintegration, which comprises adding and mixing a main drug with other excipients to form a solid drug. 2 The pH of the medium after the 1% distilled water dispersion is allowed to stand is approximately 7.
9. The manufacturing method according to claim 1, which uses cellulose calcium glycolate having an amount of 9 to 9. 3. Claim 1, wherein the amount of calcium glycolate added is 3 to 10% by weight of the solid drug.
The manufacturing method according to item 1 or 2.