JPS6141325B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a coating composition and a coating method for drugs, and more specifically, a coating composition obtained by adding a water-insoluble fine powder coating agent to an aqueous solution in which a film-forming aid is dissolved, and the use of the coating composition. This invention relates to a drug coating method. Film coating agents are frequently used as a dosage form for solid pharmaceuticals, and their use is expected to increase in the future as research on the effectiveness of drug absorption and excretion mechanisms progresses. Conventionally, when manufacturing film coating agents, a suitable coating agent is dissolved in one or more organic solvents, a plasticizer, a coloring agent, a powder agent, etc. are added to this to form a coating liquid, and this is mixed by spraying or the like. The conventional method was to coat a solid drug to produce a film coating agent. That is, since most coating agents are insoluble or sparingly soluble in water, a suitable organic solvent such as methanol, ethanol, acetone, methyl ethyl ketone, ethyl acetate, or other low boiling point organic solvent is used to dissolve the coating agent. I had no choice but to use a coating method. However, in conventional methods using such flammable organic solvents, the organic solvents are released into the atmosphere after the coating operation, causing air pollution, and if they are to be collected, expensive recovery equipment is required. There are various concerns regarding pollution, disaster prevention, safety and health, such as the risk of ignition and explosion, the need for special structural equipment in the workplace from legal requirements, and the effects on workers' bodies due to inhalation of organic solvent vapor. There was a problem. Therefore, it is most preferable to use water as a solvent, but as mentioned earlier, most coating agents are insoluble in water, making uniform coating impossible. There are very few examples of using water in this process, especially in the case of coatings using water-insoluble coating agents. It is already known that water can be used as a solvent when using water-soluble coating agents such as hydroxypropyl methylcellulose and hydroxypropylcellulose. However, since the coating agent coated with a water-soluble film agent easily dissolves in the oral cavity, one of the purposes of film coating is to prevent the unpleasant taste, odor, and irritation to the oral cavity of drugs. In addition, it is almost impossible to manufacture preparations in which the drug is expected to be released at specific sites in the body, such as enteric-coated preparations. Since the deficiencies of water-soluble coating agents can be overcome by using water-insoluble coating agents, it is strongly desired to develop a technique that uses water-insoluble coating agents and water as a method for film coating drugs. The present inventors have completed the present invention as a result of intensive study on this technical problem. That is, in the present invention, a water-insoluble coating agent is made into a fine powder, and this is mixed into a solution in which a film-forming aid is dissolved to prepare a coating composition, and a coloring agent and a powder are added to the composition as necessary. A uniform film is formed on the surface of the drug by coating the solid drug such as a tablet or granule with a conventional coating device and then drying the drug. When a drug is coated with the coating composition of the present invention, although the water-insoluble coating agent is used in suspension, it is similar to the case where a water-insoluble coating agent is dissolved in an organic solvent and coated.
It is possible to produce a uniform film coating agent, but this is because the film agent suspended in water is uniformly fused to the film adjuvant during the water evaporation process in the drying process after the coating operation, and the film is coated on the surface of the drug. This is due to the discovery that uniform film coating can be achieved. The coating agent used in the present invention is a film-forming substance commonly used for film coating of drugs, i.e., dimethylaminoethyl methacrylate, which is an acid-soluble forming agent that dissolves in the stomach.
Methyl methacrylate copolymers, polyvinyl acetal diethylamino acetate, etc. are used as gastrointestinal ampholytic film forming agents, and 2-methyl-5-vinylpyridine-methyl acrylate-methacrylic acid copolymers are used as enteric film forming agents, i.e. Cellulose acetate phthalate, silica, methyl methacrylate-methacrylic acid copolymer, methyl acrylate-methacrylic acid copolymer, hydroxypropyl methyl cellulose phthalate, and the like can be mentioned as alkaline-soluble ones. When using these coating agents for the purpose of the present invention, it is necessary to make the coating agent into fine powder in advance, and in this case, the particle size is 100 μm or less, preferably 50 μm or less.
It needs to be less than μm. In addition, if the particle size of the coating agent is large, it may be difficult for the particles of the coating agent sprayed onto the surface of the material to be uniformly fused with the film forming aid to occur quickly, or if there is a problem in the coating equipment. Due to friction, it becomes difficult to achieve a uniform coating due to peeling. Examples of means for finely pulverizing the coating agent include the use of a vibration mill, a jet mill, a low-temperature pulverizer using liquid nitrogen, and the like. On the other hand, the film forming auxiliary agent used in the present invention plays an important role in producing a uniform film coating agent, but the properties required of the auxiliary agent include the drying process after coating. It is desirable to have a substance that uniformly dissolves in the coating agent, imparts appropriate plasticity to the resulting film, and forms a moisture-proof and air-proof film without losing the inherent properties of the coating agent.
Moreover, it is particularly desirable that the adjuvant be a substance that dissolves in water. In the case of auxiliary agents that do not dissolve in water, the auxiliary agent itself becomes suspended in water, and the suspended auxiliary agent often dissolves a portion of the coating agent, which causes the coating agent to aggregate in water. However, it becomes difficult to prepare a uniformly suspended coating composition and therefore precludes spraying with the spray guns normally used in coating operations. For this reason, a method of fusing the coating agent and the auxiliary agent and then dispersing them in water has been considered, but this method requires a large amount of the auxiliary agent, making it impossible to obtain a good film coating agent. In addition, in this method, the coating agent precipitates when suspended in water,
As in the case described above, aggregation occurs and a uniform suspension cannot be maintained, making coating operations impossible. Therefore, as mentioned above, the film forming aid is preferably one that can dissolve the film agent in the drying process after coating without losing the properties of the film agent, and can also be dissolved in water. Examples of such adjuvants include polyethylene glycol of various degrees of polymerization, propylene glycol, ethyl cellosolve, dimethyl phthalate, polyoxyethylene sorbitan fatty acid ester such as Tween 80, glycerin fatty acid ester such as glycerin triacetate,
Examples include citric acid alkyl esters such as citric acid triethyl ester. When using film-forming aids, one or more of them are used depending on their compatibility with the film agent, and the amount used is 0.2 to 5 times, preferably 1 to 3 times, the amount of the film agent. This will be explained below with reference to examples. Example 1 A Granules for tableting were produced using the following ingredients by a wet granulation method, and were made into tablets with a diameter of 9 mm and a weight of 300 mm using a tablet machine.
Prepare mg convex tablets. Tablet composition (per tablet) Nicotinamide 15 mg Lactose 245 Corn starch 33 Hydroxypropylcellulose 5 Magnesium stearate 2 B The following coating compositions are prepared. Composition 2-Methyl-5-vinylpyridine-methyl acrylate-methacrylic acid copolymer (average particle size 5.5 μm) 10 g Propylene glycol 20〃 Talc 5〃 Water Total 100〃 Composition Dimethylaminoethyl methacrylate-methyl methacrylate copolymer (average Particle size 7.6
μm) 7 g Propylene glycol 14 Ethyl cellosolve 3 Talc 3.5 Titanium oxide 0.3 Water Total 100 Composition Polyvinyl acetal diethylamino acetate (average particle size 4.4 μm) 4 g Propylene glycol 10 Talc 3 Blue No. 1 dye 5 mg Water Total 100g Composition Polyvinyl acetal diethylaminoacetate (average particle size 4.4μm) 10g Ethyl cellosolve 25〃 Polyethylene glycol 400 5〃 Talc 15〃 Water Total 100〃 Preparation method of Γ coating composition A film obtained by dissolving a film forming aid in water and pulverizing it. Add the agent, then add the additive and shake. Coating method for Γ tablets 1 kg of the tablets prepared in A above were placed in an automatic pan coating device (Model FM-2 manufactured by Freund Sangyo), and the above coating composition was sprayed to increase the amount by 10 to 15 mg per tablet (composition: 10 mg). ,
Composition: 13mg, composition: 15mg).
seconds). The properties of the coated tablet thus produced are as follows. Changes over time in Γ-coated tablets Table 1 shows the results of examining changes over time for the coating agent composition.

【table】 Dissolution test of Γ coated tablets The results are shown in Table 2 below.

【table】

[Table] Example 2 Composition of granules (per 100g) Quinine sulfate 1g Lactose 75〃 Corn starch 22.5〃 Hydroxypropylcellulose 1.5〃 Wet granulation using the above ingredients (diameter of cylindrical granulator)
1.0 mm) to prepare granules. Using the coating liquid described in the composition of Example 1 and using 2 kg of the above granules, 1 kg was prepared using an automatic coating pan device (Freund Sangyo FM2 model).
Coat until the weight increases by 65 mg per gram (spray time 3 seconds, dry time 30 seconds). The results of the dissolution test are listed in Table 3 (the test method is the same as in Example 1).

[Table] Example 3 Composition of coating liquid Finely ground vinyl acetate/maleic anhydride copolymer partially methyl esterified product (average particle size 5.4 μm)
m) 4 g Benzyl alcohol 2.5〃 Propylene glycol 3.5〃 Talc 1.5〃 Water Total 100〃 Dissolve benzyl alcohol and propylene glycol in water. Talc and pulverized partial methyl ester of vinyl acetate/maleic anhydride copolymer are mixed to form a uniform suspension and used as a coating liquid. Using 1 kg of the tablets described in Example 1, a coating operation was performed using an automatic pan coating device (Freund Sangyo Model FM2) until the amount increased by 22 mg per tablet (spraying for 5 seconds, drying for 25 seconds). The obtained enteric film-coated tablets were subjected to a disintegration test for enteric-coated preparations as specified by the Japanese Pharmacopoeia.

[Table] Example 4 The samples shown in the table below were prepared from 2-methyl-5-vinylpyridine-methyl acrylate-methacrylic acid copolymer using a Fitz mill, a vibration mill, and a diet mill.

【table】

[Table] * Particle size distribution was measured using Luzetx, manufactured by Toyo Ink.
A coating liquid was prepared using Samples A to D in the above table according to the composition and preparation method described in the composition of Example 1. Using the prepared film coating solution and the tablets and apparatus described in Example 1, coating was carried out under the same conditions until the amount increased by 12 mg per tablet. The test results for the obtained film tablets were as shown in Table 5.

[Table] That is, when the pulverized product of Sample A containing 60% of particles of 100 μm or more was used, the appearance of the obtained film tablet was observed to be dull and have a rough surface. In addition, the bitter taste of nicotinamide, which is one of the tablet ingredients, is immediately felt in the oral cavity, and the dissolution test results also show that nicotinamide dissolves significantly in water. This indicates that no layer is formed. However, as the coating agent was further finely pulverized, the defects observed in Sample A disappeared, and the resulting tablets had a smooth, glossy surface, and the oral and dissolution of nicotinamide No dissolution was observed in the test, and a uniform film layer was formed on the tablet surface, proving that it was functioning as a water-insoluble coating agent. Example 5 Composition of coating liquid Finely ground methyl methacrylate/methacrylic acid copolymer (average particle size 5.0 μm) 5.0 g Propylene glycol 8.0〃 Ethyl cellosolve 4.0〃 Talc 2.5〃 Water Total 100〃 Propylene glycol and ethyl cellosolve in water dissolve in Talc and pulverized methyl methacrylate/methacrylic acid copolymer are mixed to form a uniform suspension and used as a coating liquid. Using 1 kg of the tablets described in Example 1, a coating operation was performed using an automatic pan coating device (Freund Sangyo Model FM2) until the amount increased by 30 mg per tablet (10 seconds of spraying, 20 seconds of drying). The obtained enteric film-coated tablets were subjected to a disintegration test for enteric-coated preparations as specified by the Japanese Pharmacopoeia. Test conditions Results Test with the first liquid (120 minutes) No change in appearance Test with the second liquid Collapsed after 12 minutes Example 6 Composition of coating liquid Finely ground hydroxypropyl methylcellulose phthalate (average particle size 5.5 μm) ) 5.0g Propylene glycol 10.0〃 Ethyl cellosolve 3.0〃 Talc 2.5〃 Water Total 100〃 Dissolve propylene glycol and ethyl cellosolve in water. Talc and pulverized hydroxypropyl methylcellulose phthalate are mixed to form a uniform suspension and used as a coating liquid. Using 1 kg of the tablets described in Example 1, a coating operation was performed using an automatic pan coating device (Freund Sangyo Model FM2) until the amount increased by 40 mg per tablet (10 seconds of spraying, 25 seconds of drying). The obtained enteric film-coated tablets were subjected to a disintegration test for enteric-coated preparations as specified by the Japanese Pharmacopoeia. Test conditions Results Test with 1st liquid (120 minutes) No change in appearance Test with 2nd liquid Disintegration complete after 10 minutes Example 7 Composition of coating liquid Finely pulverized cellulose acetate phthalate (average particle size 5.3 μm) 7.0g Propylene glycol 10.0 Ethyl cellosolve 3.0 Twin 80 0.5 Talc 4.0 Water Total 100 Dissolve propylene glycol, ethyl cellosolve and Twin 80 in water. Mix talc and micronized cellulose acetate phthalate,
Make a uniform suspension and use it as a coating liquid. Using 1 kg of the tablets described in Example 1, a coating operation was performed using an automatic pan coating device (Freund Sangyo Model FM2) until the amount increased by 40 mg per tablet (spraying for 15 seconds, drying for 30 seconds). The obtained enteric film-coated tablets were subjected to a disintegration test for enteric-coated preparations as specified by the Japanese Pharmacopoeia. Test conditions Results Test with 1st liquid (120 minutes) No change in appearance Test with 2nd liquid Disintegration complete after 15 minutes

Claims (1)

[Scope of Claims] 1. One or more coatings selected from the group consisting of polyethylene glycol, propylene glycol, ethyl cellosolve, dimethyl phthalate, polyoxyethylene sorbitan fatty acid ester, glycerin fatty acid ester, and citric acid alkyl ester. Formation aid, water insoluble and particle size
A chemical coating agent made by mixing a fine powder coating agent with a particle diameter of 100 μm or less and water. 2. The drug coating agent according to claim 1, wherein the water-insoluble fine powder coating agent has a particle size of 50 μm or less.