JPS59167521A - Enteric coating agent composition - Google Patents

Abstract

PURPOSE:To obtain the titled composition capable of giving a dense coating film in high yield and in a short time, by dispersing particles of an enteric coating agent having specific particle diameter in an aqueous medium containing triethyl citrate. CONSTITUTION:An enteric coating agent composition is prepared by dispersing particles of enteric coating agent having an average particle diameter of <10mum, preferably <=7mum in an aqueous medium containing triethyl citrate. The content of the enteric coating particles in the dispersion is preferably 5-20wt%, and the amount of triethyl citrate used as a plasticizer is >=5wt%, preferably 5-40wt% based on the coating agent. An enteric drug with a coating film having remarkably excellent density can be obtained by using the fine coating powder having particle diameter of <10mum.

Description

[Detailed description of the invention]

The present invention relates to an improved enteric coating agent composition for obtaining an enteric-coated preparation. It is known that enteric coating base materials such as acetate phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, calfoquin methyl ethyl cellulose, and methacrylic acid-methacrylic acid ester copolymer are dissolved in a suitable organic solvent. However, since such coating liquids use large amounts of organic solvents, there is a danger of explosions and fires, safety and health problems for workers, and (- indicates that organic solvents may enter the atmosphere). In addition to the problem of environmental pollution due to the release of solid drugs, there is also the disadvantage that trace amounts of organic solvents remain in the coated solid drug.As a method to solve these problems, dispersing the enteric coated base material in an aqueous medium has been proposed. There have been trials using a coating solution containing triethyl citrate, but no satisfactory results have been proposed yet. We have proposed an enteric coating composition for solid drugs that is dispersed in an aqueous medium (Japanese Patent Application Laid-Open No. 56-127322
(see publication), but the film tightness (see
There are two disadvantages: in order to form a film having sufficient resistance to gastric juices, it is necessary to apply a large amount of enteric coating agent. Further, there were other problems such as difficulty in coating the enteric coating agent with a good yield. The present inventors have conducted extensive research to improve these problems, and as a result have succeeded in developing a highly effective enteric coating composition. That is, the present invention has an average particle diameter of 10
The present invention relates to an enteric coating composition comprising enteric coating particles of less than μm (preferably 7 μm or less) dispersed in an aqueous medium containing triethyl citrate.Enteric coating composition according to the present invention i. An enteric coating agent that can be used to coat solid preparations such as tablets, granules, fine granules, gunpowders, or capsules to obtain enteric preparations with excellent film density (C2) and remarkable C2. It is possible to coat a solid drug with a high yield, and therefore, in order to obtain sufficient performance as an enteric-coated preparation, the amount of enteric coating agent consumed is small, and the time spent on coating operations is shortened. The enteric coating has the advantage of having an average particle size of 108
If it is rougher than m, the coating formed on the surface of the solid drug will be poor in density, and in order to improve this and obtain, for example, sufficient resistance to gastric juices, it is necessary to coat a large amount. Moreover, the yield per coating C is also poor. The present invention will be explained in detail below. Enteric coating agents used in the present invention include cellulose acetate phthalate (cAP), hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), carboxymethyl ethyl cellulose (CMEC), methacrylic acid-methacrylate Conventionally known materials such as acid ester copolymers can be used. As a method for preparing an aqueous dispersion containing an enteric coating agent micronized to an average particle size of less than 10 pm in the present invention C, the enteric coating agent is milled in a pneumatic mill, a vibrating ball mill, a colloid mill, etc. The average particle diameter obtained by pulverization using a conventionally known dry pulverization method is 10βm.
A method of dispersing a fine powder of less than 100 mL into water containing a plasticizer using a stirrer such as a homomixer, or a mixture of enteric coating agent and water using a grinder capable of wet grinding such as a vibrating ball mill or colloid mill. There is a method of obtaining a dispersion by adding water containing a plasticizer to an aqueous gel containing the enteric coating agent having an average particle size of less than 10 μm at a high depth and diluting the enteric coating agent. Furthermore, a mixture of an enteric coating agent, a plasticizer, and water is pulverized using a pulverizer capable of wet pulverization, such as a vibrating ball mill or a colloid mill, and water is added to the resulting aqueous dispersion to dilute it to obtain a dispersion. Is there a way to prepare the mixture? In this case, in order to prevent the enteric coating agent particles from fusing and aggregating with each other due to the high temperature of the mixture during pulverization (2. It is necessary to cool the aqueous dispersion for 7N, S-soluble coating prepared by these methods.

[Approximately 3 to 30% by weight of the particles of the dienteric coating agent, preferably 5 to 20% by weight.
If the content is below this lower limit, the coating operation will take a long time, and if it is above the above upper limit, it will be difficult to obtain a coating film with a smooth surface. 2) The plasticizers used are those used in the coating process where the sprayed aqueous dispersion dries on the solid drug (2) and thus penetrates into the enteric coating particles and gels them to form a film. In the present invention, triethyl citrate may be used alone or together with triethyl citrate and propylene glycol, dipropylene glycol, polyethylene glycol, glycerin, glycerin fatty acid ester, sorbitan fatty acid ester, polyoxyethylene alkyl ether, It is preferable to use it in combination with polyethylene glycol fatty acid ester, polyoxyethylene sorbicun fatty acid ester, etc. Furthermore, the amount of plasticizer used is 5% by weight or more, preferably 5 to 40% by weight based on the enteric coating agent. In order to improve the dispersion stability of the aqueous dispersion during coating, a polymeric substance such as C2 high viscosity type water-soluble cellulose ether may be added to the enteric coating agent in the dispersion. 5% or less by weight may be added to the dispersion liquid C2 of the present invention, and coloring agents, side effects, and surfactants may be added as necessary. Examples of solid drugs to be coated include tablets, granules, fine granules, gunpowder, capsules, etc. In order to coat these solid drugs, conventionally known methods are used, such as pan coating equipment, aerated rotating drums, etc. Using a type coating device, fluidized bed coating device, etc., coating can be performed by a method of applying an aqueous dispersion onto a solid drug using a spray gun and drying it.
Any method such as airless spray can be used. The amount of film coated on the surface of the solid drug by such coating operation varies depending on the type, shape, and size of the solid drug, as well as the surface condition of the solid drug to be coated. It may be approximately 3 to 40% of the weight ζ2. In addition, when coating an aqueous dispersion, a protective coating may be applied in advance with a coating agent such as hydroxypropyl methylcellulose in order to protect the solid drug from moisture that comes into contact with the surface of the solid drug during coating. Next, examples of the present invention will be shown. Example 1 (1) Preparation of tablets Spray-dried lactose 70 parts by weight (hereinafter simply referred to as parts),
After mixing 25 parts of corn starch and 5 parts of low-substituted hydroxypropyl cellulose for 20 minutes in a type mixer, 0.5 part of magnesium stearate was added and mixed for another 2 minutes. 9 crows,
Tablets each having a weight of 28 Qrnf were prepared. The obtained tablet had a hardness of about 10 Ky and a disintegration time of about 5 minutes. (2) Preparation of coating liquid Hydroxypropyl methyl cellulose phthalate (HPMCPI), which is an enteric coating agent, was crushed using an air flow crusher (manufactured by Nippon Pneumatic Engineering Co., Ltd., Model I-3) at an air pressure of approximately 8.5 Kl/Cd. When pulverized under the following conditions, a fine powder with an average particle diameter of 3.8 μm (7) was obtained.
PMC, 1 part of P fine powder, 3 parts of triethyl citrate
A coating solution was prepared by dispersing 1 part in 87 parts of water and stirring the mixture in an aqueous solution using a C Yuhomo mixer. For comparison, a coating liquid having the same composition as above was obtained using HPMCP powder with an average particle diameter of 10.4 μm that was crushed under conditions of a crushing pressure of about 4.5 Kylcrd. (3) Coating operation The tablets 10 prepared in (1) above are coated with an aerated rotary drum type coating device (Axela Coater 2 manufactured by Manestee Co., Ltd.).
4") ζ2 preparation, 6 parts of hydroxypropyl methylcellulose was dissolved in 94 parts of water, and a protective coating was applied to the solution by coating 1.5 parts of water. Subsequently, the HPMCP obtained in (2) above, triethyl citrate and Enteric coating was applied to the coating liquid consisting of water under the following conditions: [Coating conditions] Spray gun: 1 air spray gun Liquid feed pump: Tube pump Drying air temperature: 80°C Tablet temperature: 38-40°C Spray Pneumatic pressure crab 5 no/d Spray air inertia: 120 rpm Coating liquid spray speed: 60?/min Coating liquid consumption: 9 Ky- In addition, the amount of coating liquid consumed during coating is 2
From the point at which the mark was reached, about 50 tablets were taken out from the coating device every time 1 Ky of the coating liquid was consumed and used as sample tablets. (4) Evaluation of coated tablets The coated tablets finally obtained and the tablets sampled midway through were subjected to a first liquid disintegration test and a second liquid disintegration test according to the Japanese Straw Pharmacopoeia 10th revised disintegration test method (YU). The results are shown in Table 1. Table 1 Note 1) During the first liquid test, the test liquid penetrated into the inside of the tablet a lot;
After the first liquid test, the shape of the tablet was deformed. Note 2) During the first liquid test, C2 tablets disintegrated and had no enteric properties at all. From Table 1, HPMC with an average particle diameter of 3.8 μm! In the present invention using P, there was no change in the appearance of the tablets in the first liquid test C2 for the tablets sampled midway through the use of the coating liquid three times, but for those with an average particle size of 10.4 μm, the coating liquid was applied to Unless it was used above, the change in appearance of the tablets caused by the first solution test did not disappear. Furthermore, when the cut surface of the coating portion of the coated tablet according to the present invention was observed with a scanning electron microscope, it was found that it was an extremely dense coating, but the coating according to the comparative object was coated with HPMC! P particles are not completely fused,
There were voids between the particles, and the film was rough. Example 2 (1) Preparation of tablets A tablet was prepared in the same manner as in (1) of [Example]. (2) Preparation of coating liquid Add 450 g of enteric coating agent HPMCP to 830 g of water.
/ and an alumina pot of a vibrating ball mill (Model B-1 manufactured by Chuo Kakoki Co., Ltd.), with a vibration frequency of approximately 1500γp.
m for 3 hours to obtain an average particle size of HPMCP of 4.3 μm.
An aqueous gel was obtained. This aqueous gel was dispersed in a solution of 60% triethyl citrate dissolved in 3160% water to prepare a coating solution. For comparison, the average particle diameter of HPMCP was 12.5 μm using the same liquid composition and method 5, but only for 1 hour during crushing.
A coating solution of m was obtained. (3) Coating operation Tablets prepared in the same manner as in (1) of Example 1 for 10 seconds were charged into an aerated rotary drum type coating device (Accela Coater 24'' manufactured by Manestee Co., Ltd.), and a 6% by weight hydroxypropyl methylcellulose aqueous solution 1. After applying a protective coating to the tablets using No. 5 K, an enteric coating was applied using the coating liquid prepared in (2). Conditions for coating C were the same as in Example 1. However, the amount of coating liquid used was 4.5
It is Nino. (4) Evaluation of coated tablets The tablets obtained after spraying all of the coating liquid were tested according to the Japanese Pharmacopoeia No. + Revised Disintegration Test Method I2, and the results shown in Table 2 were obtained. Example 3 (1) Preparation of tablet Tablets were prepared in the same manner as in Example 1 (1). (2) Preparation of coating liquid Enteric coating agent Hydroxypropyl methyl cellulose acetate succinate (FiPM□As) 600
A mixture of ff, 80 g of triethyl citrate, and 2,000 g of water was heated in a vibrating ball mill (manufactured by Chuo Kakoki, Model B-'1).
and crushed for 3 hours at a vibration frequency of about 1500 rpm.
A suspension of HPMOA, S with an average particle size of 3.7 μm was obtained. For comparison, a mixture of similar proportions was ground for 45 minutes to obtain a suspension of IPMCA8 with an average particle size of 15.3 μm. A coating liquid was obtained by adding 3,200 ml of water to each of these two parts and stirring to give a uniform -C2 content. (3) Coating operation 10 kg of tablets made by C-coating in the same manner as in Example 1 (1)
The tablets were placed in an aerated rotary drum type coating device (Axela Coater 24'' manufactured by Manestee Co., Ltd.), and a protective coating was applied to the tablets using a 1.5% aqueous solution of 6% by weight hydroxypropyl methylcellulose, and then the coating prepared in (2) Enteric coating was applied using a liquid. Coating conditions C: C2 was carried out in the same manner as in Example 1. However, the amount of coating liquid used was 588 mm. (4) Evaluation of coated tablets Coating The tablets obtained after spraying all of the liquid were tested according to the Japanese Pharmacopoeia's Revised Disintegration Test Method, and the tablets coated with HPMOA8 coating liquid with an average particle size of 3.75 μm passed the first liquid test. There was no change after 2 hours, and in the second liquid test, it completely disintegrated within 12 minutes.On the other hand, the tablets in the comparative example experiment completely disintegrated during the first liquid test, and did not have enteric properties at all. Example 4 (1) Preparation of granules Bancreatin 1 (E1 concentration 4 times) 60 parts, lactose 26
．． After mixing 3 parts of corn starch and 112 parts of corn starch in a speed mixer for 30 seconds, the mixed rice was 975. 312.5y of an IPA solution in which hydroxypropyl cellulose was dissolved at a concentration of 8.0% by weight was added to Pl2, and the mixture was kneaded for an additional 23 minutes using a speed mixer. This mixture was extruded using a cylindrical extruder (manufactured by Nippon Yakugyo Kikai) with a pore diameter of 1. Orunφ
The mixture was extruded using a spray gun to produce columnar granules, and then the granules were charged into a Marmerizer (manufactured by Fuji Paudal, model Q-230) to obtain spherical granules. After drying this in a blow drier at 60° C., it was sieved to a particle size C: 14 to 24 meshes and used as granules for the experiment. The disintegration time m1 of this granule was about 3 minutes, and the bulk density was about 0.65 no/-. (2) Preparation of coating liquid Hydroxypropyl methyl cellulose acetate succinate (HPMCAS), which is an enteric coating agent, is processed using an air flow crusher (manufactured by Nippon Pneumatic Kogyo, Model I-3).
When the mixture was pulverized with C2 at an air pressure of approximately 8.5 Ky/ant, a powder of fine particles with an average particle size of 4.2 μm was obtained. A coating solution was prepared by dispersing and stirring 10 parts of this HPMCAS fine powder in an aqueous solution prepared by dissolving 2 parts of triethyl citrate in 88 parts of water using a 1/2 inch mixer. For comparison, the crushing air pressure is approximately 4.5 Ky/
HP with an average particle size of 10.5 μm crushed under CRD conditions
A coating liquid having the same composition as above was manufactured using MOAS powder. (3) Coating procedure Bancreatin I'll grains prepared in U (1) 1.
0 Ky was placed in a fluidized bed coating device (01att WSG-1, manufactured by Dai/11 Hara Seisakusho), and enteric coating was applied using the coating solution obtained in (2) above under the following conditions. [Coating conditions] Intake air temperature: 80°C Exhaust air temperature: 36-38°C Granule temperature: 35-36°C Spray pneumatic crab 2. OK Ri/d Coating liquid spray speed: 50 Y-7 minutes When the coating liquid was sprayed with L5Kf, about 50 pieces of granules were taken out from the coating device and used as sampling granules. (4) Evaluation of coated granules The final granules and sampled granules were subjected to a first liquid test in accordance with the Japanese Pharmacopoeia No. + Revised Disintegration Test Method, and the first liquid test was conducted for 60 minutes. Later in the first liquid (
Two eluted proteins were measured using a spectrophotometer to evaluate acid resistance. Furthermore, a second liquid disintegration test was conducted using two granules C after the first liquid test. These results are shown in Table 3 (
I did two. As a result, the enteric-coated granules obtained according to the present invention have excellent enteric properties, while the comparative ones have a high protein elution rate, do not have sufficient acid resistance, and Because vancreatin was coagulated due to the acidic liquid, the disintegration time of the second liquid was also significantly extended.Example 5 (1) Preparation of tablets 740 parts of lactose, 20.0 parts of corn starch, low substitution After mixing 5.0 parts of hydroxypropyl cellulose in a speed kneader for 30 seconds, water was added and kneaded. After drying, the particles were adjusted using a Crosby mill, 1.0 part of a lubricant (a mixture of 0.5 parts of magnesium stearate and 0.5 parts of talc) was added, and the mixture was mixed using a ■-type mixer and compressed into tablet powder. This tablet powder was compressed using a rotary tablet machine with a diameter of 90 mm and a tablet weight of 260 m1 to produce tablets with a hardness of approximately 12 KF and a disintegration time of approximately 9 minutes. (2) Preparation of coating liquid A mixture of carboxymethylethylcellulose (cv, Ec > 6oo) as a soluble coating agent, triethyl citrate 81' and water 2000.P was placed in a vibrating ball mill (Chuo Kako Kido B-1 model), and the vibration frequency was approximately 150.
Grinding was carried out at 0 rpm for 2 hours, and the average particle size of cMII was 4.
A 1 μm suspension was obtained. For comparison, a mixture of similar proportions was ground for 30 minutes to obtain an average particle size of CMFC of 12
．． A suspension of 0 μm was obtained. 3200y for each of these
The coating liquid was prepared by adding water and stirring to make it homogeneous. (3) Coating operation The tablets prepared in (1) above were placed in an aerated rotary drum coating device (Axela Coater 24'' manufactured by Manestee), and the tablets were coated with 6% by weight hydroxypropyl methylcellulose water m H1.5 sand. (After applying the protective coating, an enteric coating was applied using the coating solution prepared in (2) above. The coating conditions were the same as in Example 1. However, the coating solution The amount used was 5°88 KJ. (4) Evaluation of coated tablets After spraying all of the coating liquid, the tablets obtained were tested using the Japanese Pharmacopoeia Revised Disintegration Test Method. Tablets coated with a coating liquid consisting of .1 μm CMEC passed the first liquid test ζ
There was no change in the second liquid test, and in the second liquid test, all disintegrated within 18 minutes. On the other hand, the comparative example based on Experiment C2 completely collapsed during the first liquid test. Example 6 (1) Preparation of tablets Tablets were prepared in the same manner as in Example 5 (1). (2) Preparation of coating liquid Methacrylic acid-methacrylic acid ester copolymer (MAMAE), which is an enteric coating agent, is pulverized using an air flow pulverizer (manufactured by Nippon Pneumatic Kogyo, Model I-3) at an air pressure of about 7. When pulverized under the conditions of 0 Kr/d, fine particles with an average particle diameter of 32 μm were obtained. This MAMAE fine particle 10
A coating solution was prepared by dispersing and stirring 3 parts of triethyl citrate and 87 parts of water in an aqueous solution using a homomixer. For comparison, the average particle diameter was 20.
A coating solution having the same composition as above was obtained using 0 μm MAMAE powder. (3) Coating operation Ten tablets prepared in the same manner as in (1) of Example 5 were placed in an aerated rotary drum type coating device (Accelecoater 24'' manufactured by Manestee Co., Ltd.), and a 6% by weight aqueous solution of hydroxypropyl methyl cellulose was prepared. After applying a protective coating using No. 1.5, an enteric coating was applied by coating the coating solution 6,0 KP prepared in (2) above.The coating conditions were the same as in Example 1. The same operation was carried out even if there were two comparative examples. (4) Evaluation of coated tablets MAMAE with an average particle size of 3.2 μm was used. When tested according to the method, there was no change in the first liquid test (C2), and all disintegrated within 25 minutes in the C2 second liquid test.On the other hand, the comparative example completely collapsed during the first liquid test. Patent applicant Shin-Etsu Chemical Co., Ltd.

Claims (1)

[Scope of Claims] 1. Enteric coating agent composition comprising enteric coating agent particles having an average particle diameter of less than 10 μm dispersed in an aqueous medium containing triethyl citrate.2 The amount of triethyl citrate in the composition is 5% by weight of soluble coating agent
The enteric coating agent composition 3 according to claim 1, which is the above, and the enteric coating agent composition according to claim 1, wherein the enteric coating agent has an average particle size of 7 μm or less.