JPH0529204B2 - - Google Patents

Description

[Detailed description of the invention]

<Industrial Application Field> The present invention relates to a granular material in which a finely powdered enteric coating base is adhered to a granular material granulated using a powdery low melting point substance as a core. <Prior art> Enteric coating for pharmaceuticals is used to protect drugs that are degraded by gastric juices from gastric juices, or to efficiently exert their medicinal effects for drugs that are better absorbed in the intestine than in the stomach. It is often used for pharmaceutical purposes, and in some cases as a pharmaceutical technique, such as to prolong the duration of drugs. Generally, the coating method for obtaining enteric-coated preparations involves dissolving an enteric coating base in an organic solvent or decomposing it in water and spray coating the surface of the granular material to form an enteric coating. However, the use of organic solvents has many problems, such as adverse health effects on workers, environmental pollution, and residues in formulations, and even when using solvents that are not harmful to the human body, such as ethanol, there are concerns from the perspective of disaster prevention. Explosion-proof equipment is required, which requires a large amount of equipment cost. For this reason, a method has recently been discovered in which a coating is applied by dispersing an enteric substance together with a plasticizer in water, and this method has become widely used. However, even this method is unsuitable for drugs that are unstable in water, and furthermore, when applied to easily water-soluble drugs, the drug easily dissolves in the coating liquid, resulting in poor film formation due to adhesion of particulates during coating. It has the following disadvantages. On the other hand, enteric-coated preparations require a large amount of coating agent to ensure gastric juice resistance, which is important for quality, and also require the ability to form a dense coating without pinholes or cracks. Therefore, a large amount of coating time must be spent.
When this becomes a particulate material such as granules, the amount of coating increases further, and a precise coating operation is required. In addition, since the surface roughness of granular materials has a great effect on coating properties, it is desirable to have a spherical shape suitable for coating with a smooth surface, but complicated operations are required to make the granular material spherical. <Problems to be Solved by the Invention> The present inventor has completed the present invention as a result of intensive studies to solve the above problems. <Structure of the Invention> The present invention relates to a granular material in which a finely powdered enteric coating base is adhered to a granular material granulated using a powdery low melting point substance as a core. In the present invention, the granules granulated using a powder-like low melting point substance as cores (hereinafter referred to as coated granules) refer to the granules disclosed in JP-A-58-214333 (hereinafter referred to as the reference). The product is obtained by heating a mixture of a target drug powder, usually less than 100 μm, and a granular low-melting substance under flowing conditions so that the drug powder adheres to the low-melting substance during the process of melting the low-melting substance. refers to granular matter that is generally sized 20 to 40
Methushi's is used. It is desirable that the granules be spherical in order to efficiently apply the coating, but according to the cited granulation method, spherical particles can be produced by making the core low-melting substance spherical in advance. As a low melting point substance, its melting point is 30~100℃,
Suitably, any material may be used as long as the temperature is 50 to 80°C, such as paraffin, microcrystalline wax, hydrocarbons such as ceresin, hydrogenated oil, wood wax, fats and oils such as cacao butter, myristic acid, palmitic acid, and stearin. Fatty acids such as acids, higher alcohols such as cetanol and stearyl alcohol, polyhydric alcohols such as macrogol 6000, macrogol 4000, and batyl alcohol, waxes such as carnauba wax and beeswax, hexadecyl palmitate, octadecyl stearate, etc. Examples include esters, surfactants such as sorbitan monostearate, glycerin monostearate, acetylated glycerin monostearate, Pluronic F68, and mixtures thereof, and even substances with a relatively high melting point may contain two or more types. Substances that have an apparent melting point drop of 30 to 100°C by mixing, or drugs that themselves are low melting point substances, such as ibuprofen and trimethadione, are considered low melting point substances. It can be used as the core of the granular material to be coated without using. Next, examples of enteric coating bases include acrylic acid polymers such as methacrylic acid ethyl acrylate copolymer, methyl acrylate methacrylic acid copolymer, cellulose polymers such as cellulose acetate phthalate, and carboxymethyl ethyl cellulose. can. The size of the base is generally 0.5 to 20 μm, preferably 1 to 20 μm.
5 μm is used, and the amount used is usually 0.05 to 0.3 parts by weight per 1 part by weight of the granules to be coated. The granules of the present invention can be produced by the following method. First, a granular low melting point substance (preferably spherical or spherical) is used to mix the target drug powder and, if necessary, with an appropriate excipient under flowing conditions at a temperature higher than the melting point of the low melting point substance. Granules to be coated can be obtained by granulation while heating to a certain temperature. The obtained granules to be coated and the finely powdered enteric coating base are placed in a rotary mixer or a sugar-coating pan together with a plasticizer as the case may be, and rolled while maintaining the temperature at a temperature higher than the melting point of the low-melting substance used. After the finely powdered enteric coating base is adhered to the granular material to be coated during the melting process of the low melting point substance by moving the granular material, the target granular material can be produced by cooling it. The rolling speed is generally 30 per minute.
~40 revolutions, and rolling time is typically 10-20 minutes. When attaching the finely divided enteric coating base to the granules to be coated, water-insoluble finely divided substances such as calcium stearate, magnesium stearate, talc, light anhydrous silicic acid, magnesium aluminate metasilicate, calcium lactate, etc. When added, heated and rolled, the fine powder enteric coating base can be applied even more smoothly, and the resulting granular coating becomes dense without pinholes or cracks. . The size of the added fine powder substance is generally 0.05 to 10 μm. Further, the fine powder substance is usually used in an amount of 0.01 part by weight per part by weight of the fine powder enteric coating base.
~10 parts by weight are used. In the enteric coated granules of the present invention, the enteric coating base is usually blended in an amount of 5 to 30% (w/w), and
If a finely divided substance is added, the substance will usually be 1
It is desirable that the content is ~50% (w/w). <Effects of the Invention> The granular material of the present invention has excellent qualities as an enteric-coated preparation, such as gastric juice resistance, appearance, strength, and stability. In addition, it has the following extremely useful advantages. (1) Compared to general enteric coating, there is no need to adjust the coating solution, the coating time can be significantly shortened, and there is no need to set complicated conditions, and it can be manufactured with high yield using simple equipment. Because of this, it is low cost and extremely efficient. (2) Since there is no need to use a solvent, there is no risk of safety, hygiene, pollution, or residue in the formulation, and the stability of the active ingredient can also be improved. (3) By using water-insoluble stearic acid, cetanol, or the like as a low-melting substance used in the production of coated granules, it is possible to obtain enteric-coated granules with a controlled release rate. In addition, the elution rate can be reduced by selecting the fine powder enteric substance.
A granular material with PH control can be obtained. (4) The granules of the present invention may be made into granules as they are, or may be made into tablets by adding appropriate excipients, lubricants, disintegrating agents, etc. Furthermore, if necessary, a lubricant may be added and the mixture may be filled into hard capsules to form capsules. Next, the present invention will be specifically explained with reference to Examples. Example 1 1.0 kg of adenosine triphosphate disodium sieved through a 100 mesh sieve, 2.75 kg of lactose, and 1.25 kg of spherical stearic acid (20 to 40 mesh) were placed in a fluidized bed granulator (Grad WSG-5 type). After granulation while heating and fluidizing at 90°C, the particles were sized using 12 and 40 mesh sieves to obtain coated granules (hereinafter referred to as elementary granules). Next, 2 kg of the elementary granules and finely ground Eudragit L100 (Po¨hm of 20 μm or less) were placed in a double conical mixer with a jacket.
Pharm) and 0.3Kg of talc below,
The jacket was rotated while circulating hot water at 75°C inside the jacket, and after 10 minutes, the circulating water was switched to cold water to cool the jacket to a temperature below the melting point of stearic acid to obtain granules. Example 2 2 kg of elementary granules containing disodium adenosine triphosphate produced in the same manner as in Example 1, 0.15 kg of finely ground cellulose acetate phthalate, and talc.
0.4 kg was placed in a self-made double cone mixer with a jacket and operated in the same manner as in Example 1 to obtain granules. Example 3 Food coloring blue No. 1 0.05Kg and lactose were added to a fluidized bed granulator.
3.0Kg, corn starch 0.7Kg and spherical macrogol 6000 (20-40 mesh) 1.25Kg,
12 and 40 after granulation while heating and fluidizing at 80℃
The particles were sized using a mesh sieve to obtain elementary granules. Next, put 3 kg of the raw granules, 0.5 kg of finely ground Eudragit L100, and 0.25 kg of talc into a sugar-coated bread, and heat the sample by blowing hot air at 80°C on the side of the pan.
It was rotated at 30 rpm, and after 20 minutes, the hot air was replaced with cold air to cool it to a temperature below the melting point of Makkorogol 6000 to obtain granules. Test Example The gastric fluid resistance and dissolution properties of the granules obtained in Examples 1, 2, and 3 were examined. The measurement is carried out using a dissolution tester specified in the Dissolution Test Method 1 of the Japanese Pharmacopoeia General Testing Method, and a 2-hour test is carried out using the first solution.After 1 hour and 2 hours, the test solution is sampled to determine the dissolution. The absorbance of disodium adenosine triphosphate or food coloring blue No. 1 was measured, and the dissolution rate was calculated (gastric juice resistance test). Next, the test solution was replaced with a second solution and a test was conducted on the same sample for up to 2 hours, and the test solution was sampled at regular intervals and the absorbance of each sample was measured to calculate the dissolution rate (dissolution test). The results are shown in Table-1.

[Table] As is clear from Table 1, the granules of the present invention had sufficient gastric juice resistance and also exhibited excellent dissolution properties in the second liquid.

[Claims]

1 a rapidly dispersible core containing an active substance susceptible to sublimation and/or recrystallization, which is also rapidly dispersible, and a crosslinked polyvinylpyrrolidone b crosslinked sodium carboxymethyl cellulose c sodium starch glycolate d ion exchange resin e microcrystalline cellulose f compressible starch g starch and modified starch h alginic acid and its derivatives i formaldehyde-casein is coated with a compression coating layer containing one or more disintegrants selected from A tablet characterized in that it is capable of disintegrating in water at 20° C. within 3 minutes into a homogeneous drinkable dispersion with a particle size of 0.71 mm or less. 2 The disintegrant is cross-linked polyvinylpyrrolidone.