JPH0380767B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to improved enteric coating compositions for solid pharmaceuticals. Conventionally, a known method for producing enteric-coated preparations is to coat tablets, granules, or capsules with a coating solution prepared by dissolving an enteric coating base in an organic solvent. However, since a large amount of organic solvent is used in this case, there are risks of fire and explosion, health and safety issues for workers, and environmental pollution due to the organic solvent escaping into the atmosphere. It has the disadvantage of being disadvantageous in terms of cost. For this reason, it is desired to develop a technology for producing enteric coated preparations without using organic solvents.
Hydroxypropyl methyl cellulose phthalate powder of 100 μm or less was heated at a temperature of 25% containing triacetin.
We have proposed a method for producing enteric-coated drugs by coating solid drugs with a coating solution dispersed in water at temperatures below 0.degree. C. (see JP-A-55-98120). However, it was discovered that coated preparations made by this method had a problem in which triacetin decomposed during long-term storage and a small amount of acetic acid was released. We proposed an enteric coating agent composition for solid drugs, which is made by dispersing a coating group in an aqueous medium containing triethyl citrate (Japanese Patent Application Laid-Open No.
56-104823). If a coating operation is performed using these methods or compositions, it is true that enteric coated preparations with almost the same performance as those obtained by methods using conventional organic solvents can be obtained, but on the other hand, the conditions during the coating operation must be adjusted accordingly. It must be strictly controlled within a certain range. For example, if the spray speed during coating is too low or the temperature of the formulation is too high, the yield of the base material (adhesion rate to the formulation) will decrease, but at first glance, a coated formulation with no problems in appearance may be obtained. However, there is a problem in that gastric juice resistance, which is an important performance characteristic of enteric-coated preparations, is insufficient. Therefore, there is a problem in that a high level of skill is required of the operator in the coating operation. The inventors of the present invention have conducted extensive research in order to improve this problem, and as a result, have found a method that is extremely effective. That is, the present invention uses fine powder of hydroxypropyl methylcellulose phthalate or succinyl and acetyl mixed ester of hydroxypropyl methylcellulose, which contains triethyl citrate as a plasticizer, and contains hydroxypropylcellulose and/or hydroxypropyl as a water-soluble polymeric substance. The present invention relates to an enteric coating agent composition for solid drugs, which is prepared by dispersing methylcellulose in an aqueous medium. The composition of the present invention is a kind of suspended aqueous liquid with viscosity, and by performing a coating operation on a solid drug using this, even if the operating conditions vary to some extent, it can be coated on the solid drug with a good yield. An enteric coating layer can be formed, and the coated preparation has sufficient performance as an enteric preparation, that is, it has excellent resistance to gastric juices and has the property of being quickly disintegrated by intestinal fluids. The present invention will be explained in detail below. The hydroxypropyl methylcellulose phthalate (HPMCP) or the succinyl and acetyl mixed ester of hydroxypropyl methylcellulose (HPMCAS) used in the present invention is a known enteric coating base, and if necessary, it can be sieved or processed by a known method. It is desirable that the powder be made into a fine powder by pulverization, etc., with an average particle size of 100 μm or less.
If a coarse powder with a large average particle size is used, the resulting dispersion may clog the nozzle of a commonly used spray gun when applied to solid drug coatings. It becomes difficult to form the desired coating film. Therefore, it is particularly desirable that the powder be a fine powder of 50 μm or less. Triethyl citrate used in the present invention is used as a plasticizer and as an enteric coating base when the composition of the present invention evaporates due to drying.
It has the function of forming HPMCP or HPMCAS into a continuous film. Hydroxypropylcellulose (HPC) or hydroxypropylmethylcellulose (HPMC) as a water-soluble polymeric substance used in the present invention
has excellent compatibility with the above-mentioned triethyl citrate,
Possibly for this reason, it becomes uniformly fused with HPMCP or HPMCAS as the enteric coating base, resulting in excellent gastric fluid resistance in the coated preparation. As a means of preparing the enteric coating base composition of the present invention, HPC and/or HPMC as a water-soluble polymer substance is first dissolved in water, and the required amount of triethyl citrate as a plasticizer is added thereto. , add HPMCP or HPMCAS as the enteric coating base to this while stirring.
A dispersion of a predetermined composition may be prepared by adding the fine powder as it is or by adding a highly concentrated dispersion (aqueous medium) in advance, but there is no particular restriction on the order in which each component is added. The amount of enteric coating base fine powder used is such that the concentration in the coating liquid is 3 to 20% by weight.
Desirably, the content should be in the range of 5 to 15% by weight; below this lower limit, the coating operation will take a long time, which is economically undesirable, and above the upper limit, the coating layer will not have a smooth surface. It becomes difficult to obtain. Triethyl citrate as a plasticizer penetrates into the enteric coating base particles and gels them as water evaporates under the action of heat from dry air on the surface of the solid drug. At the same time, it also acts on the existing water-soluble polymeric substances, giving the effect of forming a uniform mixed film of both. In order to fully expect such effects, it is desirable to use this in an amount of 5% by weight or more based on the enteric coating base. In other words, if a large amount of plasticizer is added, the film obtained by this plasticizing effect will be more uniform and more flexible, so plasticizers are used for coating solid drugs with complex shapes. Although it is advantageous to add a large amount of plasticizer, and in some cases it is permissible to add more than 50% by weight of plasticizer to the amount of enteric coating base used, it is usually It is desirable to keep the amount within the range of 10 to 40% by weight based on the agent. The amount of water-soluble polymeric substance used is generally 0.5 to 20% by weight based on the enteric coating base.
Preferably it is 1 to 10% by weight. Additions above this upper limit tend to reduce the gastric juice resistance of the coated preparation, while additions below this lower limit tend not to fully exhibit the effects of the present invention. In the enteric coating agent composition (coating liquid) prepared in this way, particles of the enteric coating base tend to aggregate when the temperature is high, and the coating liquid is kept at 30°C in a storage tank during preparation or coating operation. It is desirable to maintain the following for the purpose of keeping the dispersion uniform.
Furthermore, during coating operations, care must be taken as excessive heating in the route for supplying the coating liquid to the spray gun may promote agglomeration and may clog the piping or the nozzle of the spray gun. A coloring agent, a flavoring agent, and a surfactant may be added to the coating liquid thus obtained, if necessary. The desired enteric-coated preparation can be obtained by coating solid drugs such as tablets, granules, or capsules using the above-mentioned coating liquid, and this coating operation can be carried out by conventionally known means such as pan coating equipment, air drying, etc. A method using a coating device incorporating a mechanism, a fluid coating device, etc. may be used. Further, as the spray device attached to the coating device, either an air spray or an airless spray can be used. The amount of coating varies depending on the type of solid drug, but it may be approximately 3 to 30% by weight of the solid drug. When coating a solid drug, the solid drug may be coated with another coating base, for example, an aqueous solution of a gastrically soluble coating base such as hydroxypropyl methyl cellulose, in order to prevent shock. Even solid drugs that are easily abraded can be easily coated using the coating agent composition of the present invention, and an enteric coated preparation that satisfies gastric juice resistance can be obtained with a smaller amount of coating. . Further, after the coating operation is completed, drying by a conventional method, heat treatment by simply applying heat, polishing operation by a known method, sugar coating, coating using another coating base, etc. may be carried out as appropriate. Next, specific examples will be given, but in the following description, "parts" simply refer to parts by weight. Example 1 Tablets containing lactose and corn starch as main ingredients and having a diameter of 9.0 mm and a weight of 270 mg per tablet were each coated under the following conditions to obtain enteric coated tablets. As the enteric coating base, HPMCP fine powder (HP-55F, manufactured by Shin-Etsu Chemical Co., Ltd., average particle size of about 10 μm, maximum particle size of about 30 μm) was used. Coating liquid formulation A (invention): HPMCP fine powder...10 parts Triethyl citrate...3.18 Hydroxypropylcellulose (manufactured by Nippon Soda)
HPC-H) ...0.6〃 Add water and total ...100〃 Coating liquid formulation B (control example): HPMCP fine powder ...10 parts Triethyl citrate ...3〃 Add water and total ...100 〃 Using each of the above two types of coating liquid,
The coating operation was performed according to the following operating conditions. Common operating conditions for coating: Coating equipment: 24-inch Axela coater manufactured by Manestee, UK Spray gun: Air spray type with nozzle diameter 1.2 mm Liquid feed pump: Tube type pump Tablet loading: 10 kg Coating liquid temperature: 25°C Drying air temperature: 70-75℃ Spray air amount: 120/min Coating base (HPMCP) usage amount: 800g
(8% for tablets) Operating conditions and coating results for each experiment: As shown in Table 1 However, in the same table, experiments Nos. 1 to 3 used formulation A liquid, and experiments Nos. 4 to 6 used formulation B liquid. The results are shown below.

[Table] When the coating agent composition of the present invention (formulation A) is used, there is no problem in the performance as an enteric-coated preparation that has almost the same performance despite variations in coating operating conditions. is obtained,
In addition, the yield of the coating base was over 90% in all cases, but in the control example (prescription B), although the variation was similar to that in formulation A, the yield of HPMCP was lower when the coating liquid supply rate was lowered. It was found that some products showed a decrease in the amount of water, and some even disintegrated in the test using the first solution. In addition, in Formulation A, triethyl citrate is added at 30% based on the total amount of HPMCP of the enteric coating base and HPC of the water-soluble polymer substance.
Films containing 30% triethyl citrate were added to each of HPMCP and HPC by casting from an organic solvent solution.
Both were found to have good compatibility. Example 2 HPMCAS (hydroxypropoxyl group MS0.27, methoxyl group
DS1.85, acetyl group DS0.51, succinyl group
DS0.28) was pulverized to an average particle size of 10 μm (maximum particle size of 30 μm) to prepare various coating solutions. Various types of plasticizers and water-soluble polymer substances were used in the coating liquid, and their effects on the performance of the coating formulation were compared. For coating, 12 to 32 mesh portions of spherical granules containing pancreatin as the main ingredient were used.
1 kg of each of these granules was charged into a fluidized fluid coating machine WSG-1 (manufactured by Okawara Seisakusho), and a coating operation was performed under exactly the same conditions. The results are shown in Table 2, and the products using the composition of the present invention were superior in yield and gastric fluid resistance compared to the control example. Basic formulation of coating liquid: HPMCAS 10 parts Plasticizer 3 parts Water-soluble polymer substance 0.5 parts Add water for a total of 100 parts Coating conditions: Coating liquid temperature 26℃ Coating liquid supply rate 40g/min Fluidizing air temperature 70℃ Exhaust temperature 34-39℃ Amount of coating base (HPMCAS) used: 300g (30% of granules)

[Table] Degree of coloration and degree of disintegration resulting from immersion in test liquid
compared from. Smaller numbers indicate better results.

Claims (1)

[Claims] 1 Fine powder of hydroxypropyl methylcellulose phthalate or succinyl and acetyl mixed ester of hydroxypropyl methylcellulose containing triethyl citrate as a plasticizer and dissolving hydroxypropylcellulose and/or hydroxypropylmethylcellulose as a water-soluble polymer substance. An enteric coating agent composition for a solid drug, which is dispersed in an aqueous medium.