JPH059407B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an improved method of making enteric coated formulations.

Conventionally, a known method for producing enteric coated preparations is a method in which tablets, granules, or capsules are coated with a coating liquid in which an enteric coating base is dissolved 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, and from this perspective, the present inventors have first developed a technology with an average particle diameter of
A method for producing an enteric coated drug by coating a solid drug with a coating solution prepared by dispersing hydroxypropyl methylcellulose phthalate powder of 100 μm or less in water containing triacetin at a temperature of 25°C or less (see JP-A-55-98120) Continuing on from this, we have proposed an enteric coating agent composition for solid drugs, which is made by dispersing a powdered enteric coating base with an average particle size of 100 μm or less in an aqueous medium containing triethyl citrate.

If a coating operation is carried out using these methods and compositions, it is true that an enteric coated preparation having almost the same performance as a conventional method using an organic solvent can be obtained, but on the other hand, during the coating operation, the temperature of the coating liquid Due to its tendency to aggregate as it rises, troubles such as clogging in piping or spray guns where the coating liquid is supplied may be experienced. Therefore, there is a problem in that it is necessary to store the coating liquid at a temperature as low as possible (for example, below 25° C.), and to take measures to prevent the temperature of the path through which the coating liquid is supplied from rising as much as possible.

The inventors of the present invention have conducted repeated research in order to improve this problem, and as a result, have found a method that is extremely effective.

That is, the present invention applies to a solid dosage form an aqueous dispersion of enteric coating base powder from one spray gun and an aqueous solution or aqueous dispersion of a plasticizer from the other spray gun, respectively, simultaneously or alternately. The present invention relates to a method for producing an enteric coated preparation, which is characterized by spraying.

According to the method of the present invention, an enteric coating layer can be deposited on a solid drug without any trouble, without special precautions such as cooling the spraying liquid, even at high temperatures during normal coating operations. The coating formulation has sufficient performance as an enteric-coated formulation,
That is, it has excellent resistance to gastric juices and has the property of quickly disintegrating in intestinal fluids. Further, in preparing the coating liquid, it is possible to obtain a coating liquid with excellent uniformity without paying much special attention.

Conventionally known enteric coating bases can be used as the enteric coating base used in the present invention, such as hydroxypropyl methylcellulose phthalate (HPMCP), succinyl and acetyl mixed ester of hydroxypropyl methylcellulose (HPMCAS), cellulose acetate phthalate (CAP ),
carboxymethylethylcellulose (CMEC),
Examples include methacrylic acid-methacrylic acid ester copolymers, which are made into powder by sieving or pulverizing by a known method, if necessary. It is desirable that the average particle size is 100 μm or less, and if a coarse powder with a large average particle size is used, a dispersion using it is generally used for coating solid drugs. This may cause the nozzle of the spray gun to be clogged, and 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.

In the present invention, among the above-mentioned enteric coating bases, HPMCP, HPMCAS or
CMEC is preferred.

Plasticizers used in the present invention include triethyl citrate, tributyl citrate, acetyl tributyl citrate, acetyl triethyl citrate, propylene glycol, dipropylene glycol,
Examples include triacetylene, diacetin, monoacetin, benzyl alcohol, diethyl phthalate, dibutyl phthalate, glycerin phthalate, polyethylene glycol, polyoxyethylene alkyl ethers, polyethylene glycol fatty acid esters, and propylene glycol fatty acid esters. These may be used alone or as a mixture of two or more.

In the present invention, as a method for preparing an aqueous dispersion of fine powder of an enteric coating base, a dispersion of a predetermined composition is prepared by adding a predetermined amount of the enteric coating agent powder as described above to a predetermined amount of water while stirring. This method may be used. The amount of enteric coating base powder used is suitably such that its concentration in the aqueous dispersion ranges from 5 to 30% by weight.

In the present invention, an aqueous solution or dispersion of a plasticizer may be prepared by adding a predetermined amount of the various plasticizers described above to a predetermined amount of water to form an aqueous solution or aqueous dispersion having a predetermined composition.
In particular, when preparing an aqueous dispersion, glycerin fatty acid esters, sorbitan fatty acid esters, propylene glycol fatty acid esters, and polyoxyethylene fatty acid esters can be freely used as dispersion aids. The finely powdered aqueous dispersion of the enteric coating base or the aqueous solution or aqueous dispersion of the plasticizer contains polyvinyl alcohol, polyvinylpyrrolidone, gelatin, sodium alginate, gum arabic; methylcellulose, hydroxypropylmethylcellulose, or both. , water-soluble cellulose derivatives such as hydroxypropyl cellulose, film forming aids such as synthetic resin emulsions, antifoaming agents such as silicone resins, coloring agents such as food coloring, food lake coloring, natural coloring, and titanium oxide. Be free.

In the present invention, the plasticizer is applied on the surface of the solid drug,
As the water evaporates under the action of the heat of the drying air, it penetrates into the enteric coating base particles and gels them to form a film. This has conventionally been achieved using a coating solution in which a plasticizer and enteric coating base particles are present, but the method of the present invention also satisfies this film formation. In order to fully expect such effects in the method of the present invention,
It is desirable to use the plasticizer 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 used, the film obtained by the plasticizing effect will be more uniform and more flexible, so a large amount of plasticizer is used for coating solid drugs with complex shapes. It is advantageous to use 100% by weight or more based on the amount of enteric coating base used, but it is usually 10% to 10% by weight based on the amount of enteric coating base used. It is desirable to use it in a range of 50% by weight.

The target enteric coated preparations are tablets,
Solid drugs such as granules or capsules may be coated using conventionally known equipment, such as a pan coating equipment, a coating equipment incorporating an aeration drying mechanism, or a fluid coating equipment. The spray gun described above may be operated in a conventionally known manner, except that two different liquids are supplied to each spray gun. At this time, it is not necessary that the two liquids are supplied to the same number of spray guns, and the two liquids may be supplied to different numbers of spray guns. Moreover, it is preferable that two types of sprayed mist are concentrated in the same circular or oval shape. The two types of liquids may be sprayed simultaneously or alternately, for example, both may be sprayed continuously or one of them may be sprayed intermittently.

The amount of coating varies depending on the type of solid drug, but may be approximately 3 to 50% by weight of the solid drug. When coating a solid drug, the solid drug may be coated with another coating base, for example, a solution of a gastric soluble coating base such as hydroxypropyl methyl cellulose.
According to this, even solid drugs that are easily abraded by impact can be easily coated by the method 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 by a known method, sugar coating, coating using another coating base, etc. may be carried out as appropriate.

Next, specific examples will be given, and in the following description, "parts" simply refer to parts by weight.

Example 1 Diameter based on lactose and cornstarch
Tablets of 9.0 mm and 270 mg in weight per tablet were coated under the following conditions to obtain enteric coated tablets. As an enteric coating base
HPMCP fine powder (HP-55F, manufactured by Shin-Etsu Chemical,
The average particle size was 5.6 μm, the maximum particle size was about 15 μm). Triethyl citrate was used as a plasticizer.

Coating liquid A (enteric coating base dispersion): HPMCP fine powder...10 parts Hydroxypropylcellulose...0.05 parts Water...89.95 parts Coating liquid B (plasticizer dispersion): Triethyl citrate...15 parts Japan Pharmacopoeia polysorbate 80...0.04 parts Water...84.96 parts Using the above two types of coating liquids, coating operations were performed according to the following operating conditions.

Coating operating conditions: Coating equipment: Manufactured by Manestee, UK, 24
Inch Axela Coater Spray Gun: Two air spray type units with a nozzle diameter of 1.2 mm were installed. One gun was supplied with coating solution A and the other with coating solution B.

Liquid feed pump: Tube pump Tablet loading amount: 10Kg Temperature of coating liquids A and B: 30℃ Drying air temperature: 70~75℃ Spray air amount: 90/min to each gun Coating liquid A supply rate: 45g/min (Continuous spray) Coating liquid B supply rate: 9 g/min (Continuous spray) (Amounts of HPMCP and triethyl citrate used are
Equivalent to 100:30. ) Coating time: 160 minutes Amount of HPMCP used: 700 g (7% of the tablet) The appearance of the coated product was smooth and beautiful. Furthermore, when we applied the Japanese Pharmacopoeia's disintegration test for enteric-coated preparations, there was no change in the test with the first liquid, and it completely disintegrated in 9 to 12 minutes in the test with the second liquid, demonstrating the performance as an enteric-coated preparation. Satisfied.

Example 2 HPMCAS (hydroxypropoxyl group MS, 0.26, methoxyl group) was added to the enteric coating base.
DS, 1.87, acetyl group DS, 0.45, succinyl group
DS, 0.32) to an average particle size of 5.7 μm (maximum particle size of about 16 μm) and triethyl citrate as a plasticizer, the following coating solution was prepared.

Coating liquid A (enteric coating base dispersion): HPMCAS...10 parts Hydroxypropylcellulose...0.05 parts Water...89.95 parts Coating liquid B (plasticizer dispersion): Triethyl citrate...15 parts Japanese Pharmacopoeia Polysorbate 80...0.04 parts Water...84.96 parts For coating, 12 to 32 mesh portions of spherical granules containing pancreatin as the main ingredient are used, and 5 kg of these granules are transferred to a fluid coating device.
The mixture was loaded into WSG-5 (manufactured by Okawara Seisakusho), and a coating operation was performed according to the following operating conditions.

Coating operation conditions: Spray guns: Two air spray type units with a nozzle diameter of 1.2 mm were installed, and coating liquid A was supplied to one gun and coating liquid B was supplied to the other gun.

Liquid feed pump: Tube pump Flowing air temperature: 70°C Temperature of coating liquids A and B: 27°C Spray air amount: 100/min for each gun Coating liquid A supply rate: 65g/min Coating liquid B supply rate: 8.7 g/min (the amount of HPMCAS and triethyl citrate used is
(equivalent to 100:20) Coating time: 160 minutes Amount of HPMCAS used: 1000g (20% of granules) The appearance of the coated product was beautiful, and there was no difference from that coated with a conventional organic solvent system. Furthermore, when we applied the Japanese Pharmacopoeia's disintegration test for enteric-coated preparations, there was no change in the test with the first liquid, and it completely disintegrated in 5 to 6 minutes in the test with the second liquid, indicating its performance as an enteric-coated preparation. Satisfied.

Example 3 As a comparative example of the coating liquid of Example 1, the following coating liquid C was prepared.

Coating liquid C: HPMCP fine powder...10 parts Hydroxypropyl cellulose...0.05 parts Triethyl citrate...3 parts Japanese Pharmacopoeia polysorbate 80...0.008 parts Add water...100 parts Coating liquid A of Example 1, B and the control coating solution C of this section were each left at 30° C. for 5 hours while being stirred. Coating liquids A and B were then treated in the same manner as in Example 1, and coating liquid C was operated in the same manner as in Example 1 except that it was supplied to one spray gun. As a result, no problems occurred with coating liquids A and B, but coating liquid C
Agglomeration was observed in some parts of the spray gun, which immediately caused a blockage in the spray gun, making it impossible to spray.

Claims (1)

[Claims] 1. To a solid agent, an aqueous dispersion of enteric coating base powder is applied from one spray gun, and an aqueous solution or dispersion of a plasticizer is applied from the other spray gun, respectively, simultaneously or A method for producing an enteric coated preparation, characterized by alternating spraying. 2. Claim 1, wherein the enteric coating base powder has an average particle size of 100 μm or less.
A method for producing an enteric coated preparation as described in Section 1. 3. The method for producing an enteric coated preparation according to claim 1, wherein the enteric coating base is hydroxypropyl methyl cellulose phthalate, succinyl and acetyl mixed ester of hydroxypropyl methyl cellulose, or carboxymethyl ethyl cellulose.