JPH08333238A - Enteric coated preparation coated by solventless enteric coating agent using liquid wax - Google Patents

Abstract

PURPOSE: To obtain an enteric coated preparation coated by a fine powdery enteric coating agent while sprinkling waxes of a liquid state to a solid medicine. CONSTITUTION: This enteric coated preparation is obtained by coating a granular preparation, a powdery preparation or a bulk medicine with a fine powdery enteric coating agent having <=10μm particle diameter (e.g. hydroxypropyl methyl cellulose acetate succinate) while sprinkling waxes of a liquid state at a room temperature or waxes which have <=90 deg.C melting point and are made to be a liquid state by heating and melting (e.g. lauryl alcohol). By the solventless coating not requiring the drying and completed in a short period, the enteric coated preparation having an acid resistance is obtained. Since the drying of solvent is not necessary and the coating time is short, it is possible to shorten the manufacturing process and by the solventless coating, it is possible to apply it to medicines unstable to water and organic solvents. Further, a surfactant, etc., commonly used in an aqueous enteric coating as a dispersing agent, are not necessary.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an enteric preparation.
More specifically, it relates to an enteric-coated preparation obtained by coating a solid drug with a solventless enteric-coating agent using a liquid wax.

[0002]

2. Description of the Related Art Enteric coatings are widely used for various purposes such as protecting a drug sensitive to acid from gastric acid or protecting a gastric mucosa from a drug having irritation or injury to the stomach wall.

Cellulose-based cellulose acetate phthalate (CA) is used as an enteric coating agent.
P), cellulose acetate trimellitate (CA
T), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), carboxymethylethylcellulose (CMEC), and vinyl-based polyvinyl alcohol acetate phthalate (PVC).
AP) is an acrylic type, a copolymer of methacrylic acid and ethyl acrylate is used.

These coating agents can be used for coating by dissolving the polymer in an organic solvent or as an aqueous latex or an aqueous dispersion. In either method, since an organic solvent or water is used as a solvent, it took a long time to spray these coating liquids, and also a drying time of the solvent was required.
Since some drugs dislike contact with water or an organic solvent, it has been desired to develop an enteric coating method that does not use a solvent.

Waxes are generally used for controlling the dissolution of sustained-release preparations because they are hydrophobic and do not dissolve in water. Combinations of these waxes with an enteric coating agent are disclosed, for example, in JP-A-56-1.
No. 64114 discloses a method of enteric coating granules wet-granulated with a composition containing a higher fatty acid or a metal salt thereof by a conventionally known method in JP-A-62-33128.
As an enteric-coated preparation of interferon, micelles are prepared from an unsaturated fatty acid and a surfactant in an aqueous system, and the micelles are freeze-dried, formed into granules and the like, and then enteric-coated. In 20219, undercoating of an enteric-coated preparation is coated with a composition containing a higher fatty acid. In JP-A-58-46019, a coating of the sustained-release part of a sustained-release preparation of nifedipine with an enteric-coated coating agent is used. It has been proposed to dissolve fats and oils in a common solvent (ethanol, dichloroethane, etc.) and use them for coating.

[Problems to be Solved by the Invention]

However, in all of these coating methods, waxes and enteric coating are used in combination, but the enteric coating itself is a conventionally known method using a solvent, and it takes a long time for coating and drying.

As a method of coating waxes, for example, in Japanese Patent Laid-Open No. 1-287019, a melting point of 4 is used.
Higher fatty acids, higher alcohols, higher fatty acid esters, etc., which are lipid substances at 0 ° C. or higher, are heated above their melting point or dissolved in an organic solvent, and spray-coated using a coating pan or a centrifugal fluidized coating granulator. In JP-A 1-287021, a method of applying ethyl cellulose or an enteric coating after heating is performed by heating a wax having a melting point of 40 to 90 ° C. in powder or pellet form to a temperature higher than the melting point of the wax by using a fluidized bed coating device. In JP-A-2-142735, a method of coating a lipid powder having a melting point of 40 ° C. or higher by mechanical stirring is proposed, but these are intended for the purpose of sustained-release preparation or masking of bitterness. The above formulation does not mention the combination with an enteric coating agent.

Further, in Japanese Patent Laid-Open No. 2-292229,
A sustained-release preparation may be obtained by heating a mixture of a poorly soluble drug, a higher fatty acid that is solid at room temperature, an enteric coating agent, and a surfactant, and kneading the mixture while melting the higher fatty acid to produce granules. Although disclosed, it is not related to acid-resistant enteric coated formulations. In JP-A-62-181214 also, as the low melting point substance having a melting point of 30 to 100 ° C., oils and fats, fatty acids and higher alcohols are mentioned, and a drug having a powdery low melting point substance as a core is provided around it. A method for producing sustained-release granules by melt-adhering and granulating by adhesion, and further by coating the particles obtained by stirring and rolling to obtain talc and the like is disclosed. It is said that the coating is densified by using an enteric coating agent finely pulverized to a size of 10 μm or less in the case of the above-mentioned coating, but this is not related to the enteric coated preparation having acid resistance.

The inventors of the present invention have conducted extensive studies in view of the above points, and as a result of spraying liquid waxes and coating with a fine powder enteric coating agent, drying is required in a short time. It was found that an enteric-coated preparation having acid resistance can be obtained by a non-solvent-free coating, and completed the present invention.

[0010]

That is, the present invention provides an enteric-coated preparation in which a solid drug is sprayed with a liquid wax and coated with a fine powder enteric coating agent.

The present invention also provides an enteric preparation, wherein the solid drug is a granule, a fine granule or a drug substance.

The present invention further provides an enteric preparation in which the liquid wax is a liquid at room temperature or a solid having a melting point of 90 ° C or lower.

The present invention also provides an enteric preparation, wherein the fine powdery enteric coating agent has a particle size of 10 μm or less.

The present invention will be described in detail below. The enteric-coated preparation according to the present invention is characterized in that a solid drug is coated with a finely powdered enteric coating base while spraying waxes that are liquid at room temperature or waxes that are melted by heating and made into liquids. It is what

The waxes used in the present invention are not particularly limited as long as they are hydrophobic and have a property of fusing a fine powdery enteric coating agent. For example, hydrocarbons such as paraffin, microcrystalline wax and vaseline; beeswax such as beeswax and bleaching beeswax; higher alcohols such as lauryl alcohol, cetyl alcohol and stearyl alcohol; oleic acid, linoleic acid, palmitic acid, stearic acid, etc. Higher fatty acids of carnauba wax, rice wax, etc .; glycerin fatty acid esters such as olive oil, soybean oil, beef tallow, lard, cacao butter, hydrogenated castor oil, hydrogenated castor oil, glycerin monostearate; , Lubri Wax-101 (hydrogenated vegetable oil), Pol
Examples include ishing Wax-101 (a mixture of carnauba wax and paraffin), Precirol (glycerin-mono, di, tri mixed palmitate), sorbitan monostearate, acetylated glycerin monostearate, and sucrose fatty acid esters.

It is preferable that these waxes are liquid at room temperature or have a melting point of 90.degree.
This is because a method of spraying a liquid wax at the time of coating a fine powder enteric coating agent is advantageous for improving the yield of the coating agent, and it is preferable to use a wax which is liquid at room temperature and has no volatility. Can have a melting point of 90 ° C. or lower. The volatile waxes are
There is a concern that the content may change during storage and the acid resistance may deteriorate, and waxes having a melting point of 90 ° C. or higher may be difficult to melt by heating and spray.

These waxes can be used alone or as a mixture of two or more. Further, even waxes having a melting point of 90 ° C. or higher can be used in the present invention by mixing with waxes which are liquid or have a low melting point at room temperature so that the mixture has a melting point of 90 ° C. or lower.

Among the above waxes, higher alcohols, higher fatty acids, which have a low melting point or are liquid at room temperature,
Glycerin fatty acid esters are excellent and suitable for the property of fusing the enteric coating agent.

Further, the combined use of a plasticizer usually used for enteric coating, such as triethyl citrate and triacetin, improves the film-forming property and lowers the substantial melting point of waxes. Very useful. In addition, a sustained-release preparation can be prepared by using water-soluble polyhydric alcohols such as polyethylene glycol together.

In the present invention, since the enteric coating agent on fine powder is sprayed and coated, preferable solid medicines that can be applied are granules, fine granules or drug substance, which are close to spherical. It is preferable that the amount of the enteric coating agent required to obtain the acid resistance is small as much as possible.

The enteric coating agent used in the present invention is
Preferably, it is a fine powder having a particle size of 10 μm or less. For example, in the case of cellulose, cellulose acetate phthalate (CAP) and cellulose acetate trimellitate (C
AT), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), carboxymethylethylcellulose (CMEC), but vinyl-based polyvinyl alcohol acetate phthalate (PVA).
If P) is an acrylic type, a copolymer of methacrylic acid and ethyl acrylate can be used. If the average particle size exceeds 10 μm, the coating agent may not adhere well to the granules and may not be coated.

Among these coating agents, hydroxypropylmethylcellulose acetate succinate (HPMCAS), which has a low softening temperature and excellent film forming property, is suitable.

Further, a sustained-release preparation can be prepared by using a fine powder of a polymer other than the enteric coating agent, such as ethyl cellulose or an acrylic polymer in combination.

In order to carry out the present invention, since a solvent is not used, a great drying capacity is not required, and a certain amount of heating is applied to spread and fuse the finely powdered enteric coating agent. And a stirring capability, and examples thereof include a centrifugal fluidized coating apparatus, a pan coating apparatus, and a fluidized bed coating apparatus. Among these coating apparatuses, a centrifugal fluidized coating apparatus having an appropriate stirring ability is suitable.

The coating with the enteric coating agent is performed, for example, by stirring a granular or fine-grained solid drug in the centrifugal fluidized coating device as described above while stirring it to form a liquid wax or a liquid wax heated and melted at room temperature. It is sprayed or sprayed, and at the same time, an enteric coating agent of 10 μm or less is sprayed to coat the solid drug. These series of operations can be carried out several times by changing the composition of each. If the wax used at this time has a high melting point, it is free to be heated in order to secure the spreadability. Further, for the purpose of preventing sticking of the granules during coating, talc, aerosil (SiO ₂ ), magnesium stearate, corn starch or the like may be used in combination.

The weight ratio of the waxes to the enteric coating agent and the coating amount with respect to the solid drug in the present invention are important factors for obtaining acid resistance. Agent, etc.) varies greatly depending on the composition ratio of the drug in the agent, etc., but is generally in the range of waxes: enteric coating agent = 2: 8 to 8: 2. The disintegration property in the second pharmacopoeia liquid (pH 6.8) is lost, and below this, the fusion of the enteric coating agent becomes insufficient.

The coating amount is a weight ratio of the coated enteric coating agent to the solid drug and is generally 10 to 50.
It is in the range of% by weight.

In the present invention, since the enteric coating agent is sprayed for coating, the treatment time is extremely short even if the coating amount is increased.

The enteric preparation of the present invention obtained as described above may be further coated with another polymer compound thereafter. Further, drugs and additives (plasticizers, colorants, pigments, anti-adhesives (talc), fats and oils, etc.) which are usually pharmaceutically acceptable may be added to these coatings.

Further, a curing treatment after coating
By performing (heat treatment), the coating film becomes uniform, and more excellent enteric coated granules can be obtained. The curing temperature may be higher than the melting point of the wax used.

[0031]

EXAMPLES The present invention will now be described in more detail with reference to examples, but the present invention is not limited to these examples. The parts and% in the examples are% by weight.

[Experiment 1: Preparation of VB ₂ -containing granules] Nuclear granules
(Non-parell 101 20-24 # manufactured by Freund Sangyo Co., Ltd.) 200
0 g was charged into a centrifugal fluidized coating apparatus (CF coater CF-360 manufactured by Freund Sangyo Co., Ltd.), and VB ₂ 75 was added while spraying a 5% aqueous solution of hydroxypropyl cellulose.
g, and 1175 g of corn starch were uniformly mixed to disperse the powder to prepare granules. The content of VB _{2 in} this granule was 2%.

Example 1 VB ₂ produced in Experiment 1 2%
Centrifugal fluid coating equipment (CFcoate
r CF-360 made by Freund Sangyo Co., Ltd.), intake temperature 60 ℃, product temperature 40 ℃, rotation speed 150rpm, 30 ℃
120g of lauryl alcohol heated and melted to 20g /
Hydroxypropyl methylcellulose acetate succinate (average particle size 5μ while adding at a rate of min
m: AS-MF 120 g of Shin-Etsu Chemical Co., Ltd. and 120 g of talc were uniformly mixed to add powder at a rate of 40 g / min for coating. The yield was 92%. The processing time was 6 minutes. The coated granules were treated with the 1st solution according to the Japanese Pharmacopoeia 12 dissolution test
As a result of measuring the elution rate after time, the elution rate was 1.0%
And showed excellent acid resistance. Further, according to the Japanese Pharmacopoeia 12 disintegration test method, the disintegration time of the granules in the second liquid was measured, which was 5 min, and it was found that the granules exhibited enteric properties.

[Example 2] VB ₂ produced in Experiment 1 2%
Centrifugal fluid coating equipment (CFcoate
r CF-360 manufactured by Freund Sangyo Co., Ltd.), intake temperature 80 ℃, product temperature 45 ℃, rotation speed 200rpm, 60 ℃
90 g of cetyl alcohol heated and melted to 10 g / mi
Hydroxypropylmethylcellulose acetate succinate (average particle size 5 μm: A
S-MF Shin-Etsu Chemical Co., Ltd. 90g, Talc 90
Coating was performed by adding powder in which g was uniformly mixed at a rate of 20 g / min. The yield was 93%. The processing time was 6 minutes. According to the Japanese Pharmacopoeia 12 dissolution test method, the dissolution rate of the coated granules in the first liquid after 2 hours was measured. As a result, the dissolution rate was 1.5%, indicating excellent acid resistance. Further, according to the Japanese Pharmacopoeia 12 disintegration test method, the disintegration time of the granules in the second liquid was measured, and it was 6 min.

[Example 3] VB ₂ produced in Experiment 1 2%
200 g of the contained granules were charged into a sugar-coated bread, and the intake air temperature was 80
C., product temperature 50.degree. C., hydroxypropylmethyl cellulose acetate succinate (average particle size 5 .mu.m: AS-M
50 g of Shin-Etsu Chemical Co., Ltd.) and 40 g of talc are uniformly mixed, and half of the powder is added, and 20 g of lauryl alcohol heated and melted at 30 ° C. is added to the powder. The coating was performed by adding 20 g. The yield was 90%. The processing time was 5 minutes. According to the Japanese Pharmacopoeia 12 dissolution test method, the dissolution rate of the coated granules in the first liquid after 2 hours was measured. As a result, the dissolution rate was 2.0%, indicating excellent acid resistance. Further, according to the Japanese Pharmacopoeia 12 disintegration test method, the disintegration time of the granules in the second liquid was measured, which was 5 min, and it was found that the granules exhibited enteric properties.

Example 4 VB ₂ prepared in Experiment 1 2%
Centrifugal fluid coating equipment (CFcoate
r CF-360 made by Freund Sangyo Co., Ltd.), intake temperature 80 ℃, product temperature 45 ℃, rotation speed 150rpm, 60 ℃
90 g of glycerin monostearate melted by heating to 8
Hydroxypropyl methylcellulose acetate succinate (average particle size 5
μm: AS-MF manufactured by Shin-Etsu Chemical Co., Ltd. 90 g and talc 90 g were uniformly mixed, and a powder was added at a rate of 16 g / min for coating. The yield was 93%. The processing time was 12 minutes. The coated granules were treated with the 1st solution according to the Japanese Pharmacopoeia 12 dissolution test
As a result of measuring the elution rate after time, the elution rate was 2.2%
And showed excellent acid resistance. Further, according to the Japanese Pharmacopoeia 12 disintegration test method, the disintegration time of the granules in the second liquid was measured, and it was 7 min, which showed that the granules had enteric properties.

Example 5 VB ₂ produced in Experiment 1 2%
Centrifugal fluidized coating equipment (CFcoate
r CF-360 manufactured by Freund Sangyo Co., Ltd.), 10 g / min of a mixed solution of 40 g of lauryl alcohol and 8 g of triethyl citrate, which was heated and melted at 30 ° C. at an intake temperature of 60 ° C., a product temperature of 40 ° C. and a rotation speed of 150 rpm. While adding at a rate of 40 g, hydroxypropylmethylcellulose acetate succinate (average particle diameter 5 μm: AS-MF manufactured by Shin-Etsu Chemical Co., Ltd.) 40 g, talc 40 g of a powder uniformly mixed were added at a rate of 20 g / min. Coating was performed. The yield was 97%. The processing time was 4 minutes. According to the Japanese Pharmacopoeia 12 dissolution test method, the dissolution rate of the coated granules in the first liquid after 2 hours was measured. As a result, the dissolution rate was 0.8%, indicating excellent acid resistance. Further, according to the Japanese Pharmacopoeia 12 disintegration test method, the disintegration time of the granules in the second liquid was measured, which was 5 min, and it was found that the granules exhibited enteric properties.

Example 6 VB ₂ prepared in Experiment 1 2%
Centrifugal fluidized coating equipment (CFcoate
r CF-360 made by Freund Sangyo Co., Ltd.), intake temperature 60 ℃, product temperature 40 ℃, rotation speed 150rpm, 30 ℃
60 g of lauryl alcohol heated and melted to 20 g / m
Hydroxypropylmethylcellulose phthalate (average particle size 5 μm: HP-55U while adding at a rate of in
Powder was obtained by uniformly mixing 60 g of F Shin-Etsu Chemical Co., Ltd. and 60 g of talc at a rate of 40 g / min for coating. The yield was 90%. The processing time was 3 minutes. According to the Japanese Pharmacopoeia 12 dissolution test method, the dissolution rate of the coated granules in the first liquid after 2 hours was measured. As a result, the dissolution rate was 2.0%, indicating excellent acid resistance. In addition, according to the Japanese Pharmacopoeia 12 disintegration test method,
When the disintegration time of the granules in the second liquid was measured, it was 8 mi.
It was n and it was found to show enteric properties.

Comparative Example 1 VB ₂ granules prepared in Experiment 1 were coated with hydroxypropylmethylcellulose acetate succinate (AS-MF, manufactured by Shin-Etsu Chemical Co., Ltd.) using a coating solution having the following composition in an aqueous dispersion system. did. 400 g of VB ₂ granules were charged into a fluidized bed coating device (Multiplex MP-01 manufactured by Paulec Co., Ltd.),
Intake temperature 80 ° C, exhaust temperature 35 ° C, coating liquid spray rate 25 g / min, coating amount of hydroxypropylmethylcellulose acetate succinate (AS-MF Shin-Etsu Chemical Co., Ltd.) on elementary granules (30
%) Was the same as in Example 1 until the coating was carried out. The coating yield was 92% and the coating time was 68 min. After that, as post-drying, 60 ℃, 3
Drying was performed for 0 min. The total time required for producing coated granules was 98 min. [Coating liquid composition] Hydroxypropyl methylcellulose acetate succinate (AS-MF manufactured by Shin-Etsu Chemical Co., Ltd.) 7.00% Triethyl citrate 1.96 Talc 2.10 Sodium lauryl sulfate 0.21 Water 88.73 Total 100.00

[0040]

The conventional enteric coating is carried out by using an organic solvent solution of an enteric coating agent, an aqueous latex or an aqueous dispersion. For this reason, spraying requires a long time, and also requires drying time of the solvent, and depending on the drug, there are problems such as dislike contact with water or an organic solvent or dislike heating during drying. It was

According to the present invention, an enteric coated preparation having acid resistance can be obtained by a solventless coating which does not require drying in a short time. Therefore, it is not necessary to dry the solvent (no heating at the time of drying) and the coating time is short, so that the manufacturing process can be shortened. In addition, the solvent-free coating can be applied to drugs that are unstable to water and organic solvents. Further, there is an advantage that it is not necessary to use a surfactant or the like which is commonly used as a dispersant in an aqueous enteric coating.

Claims (4)

[Claims] 1. An enteric-coated preparation in which a solid drug is sprayed with a liquid wax while being coated with a fine-powdered enteric coating agent. 2. The enteric coated preparation according to claim 1, wherein the solid drug is a granule, a fine granule or a drug substance. 3. The enteric-coated preparation according to claim 1, wherein the liquid wax is a liquid at room temperature or a solid having a melting point of 90 ° C. or lower. 4. The enteric preparation according to claim 1, wherein the fine powdery enteric coating agent has a particle size of 10 μm or less.