JPH02174727A - Enteric coating film - Google Patents

Abstract

PURPOSE:To obtain an enteric coating film having excellent strength of coating film and acid resistance by blending a hydroxypropylmethyl cellulose phthalate(HPMCP) having specific viscosity with specific amounts of polyethylene glycol(PEG) and shellac. CONSTITUTION:An enteric coating film comprising (A) HPMCP having 18.0-22.0% methoxyl group content, 5.0-9.0% hydroxypropoxyl group content, 27.0-35.0% carboxybenzoyl group content, about 240 average polymerization degree and 136-204 centistokes viscosity in 10% solution at 20 deg.C, (B) 0.1-20wt.%, preferably 2-10wt.% based on the component A of a PEG having 1,200-25,000 average molecular weight solid at normal temperature and (C) 5-40wt.%, preferably 15-35wt.% based on the component A of shellac. A solution of the component A in acetone is mixed with an ethanol solution having dissolved the PEG and shellac to prepare a coating solution, which is sprayed upon preparation to give an enteric preparation.

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to an enteric coating with excellent strength in the fields of food, medicine, etc.

(Prior Art) In general, enteric coating of pharmaceutical preparations is performed for the purpose of protecting acid-sensitive main drugs from gastric acid and for drug release control systems (drug delivery systems). Conventionally, in enteric-coated preparations, the tablet surface was covered with a coating to achieve the purpose. However, in recent years, from a biopharmaceutical perspective, it has been reported that enteric-coated granules show no individual differences in gastric emptying rate and absorption compared to enteric-coated tablets, and are hardly affected by meals. As an example, aspirin preparations (C, Bogentoft et al., European Journal of Clinical Pharmacology,
J, Cl1n, Pharmacol,) 14,
351355 (1978) and 1. A.Anslow
Current Therapeutic Research (C
currentTherapeutic Re5ear
ch) 36(5), 81 1-818 (1984)
).

(Problem to be solved by the invention) However, the strength of the conventional enteric coating itself is weak, and when enteric coated granules are added to tablets or capsules and processed in a pharmaceutical manner, the enteric coating is It is often destroyed by the mechanical impact of time and no longer functions as an enteric coating.

To prevent this, it is necessary to add a plasticizer, but the addition of a plasticizer often reduces the enteric properties.For example, it is known that the addition of polyethylene glycols to hydroxypropyl methyl cellulose phthalate reduces the enteric property. (For example, Shin-Etsu Chemical Co., Ltd. catalog,
1985 edition HPMCP). Therefore, there has been a demand for an enteric coating that has strong coating strength and can sufficiently guarantee enteric properties.

(Means for Solving the Problems) In consideration of these circumstances, the present inventors have conducted extensive studies on coating bases used in preparations such as enteric-coated granules and enteric-coated fine granules with strong coating strength. By combining hydroxypropyl methylcellulose phthalate, shellac, and polyethylene glycol with specific properties in a specific ratio and applying an enteric coating, an enteric coating with unexpectedly strong coating strength can be obtained. The present invention was completed by confirming that it can withstand mechanical impact even when processed into other formulations.

That is, the present invention consists of (a) hydroxypropyl methyl cellulose phthalate having a viscosity of about 136 to 204 centistokes, (b) polyethylene glycol that is solid at room temperature, and (C) shellac, and (a)
The ratio of b) and (C) is 0.1 to 20% by weight, respectively.
and 5 to 40% by weight of the enteric coating.

The methoxyl group content of the hydroxypropyl methyl cellulose phthalate (hereinafter sometimes referred to as HPMCP) of the present invention is 18.0 to 220%, the hydroxypropoxyl group content is 5.0 to 9.0%, and The content of carboxybenzoyl group is 27.0 to 35.0%,
Its average degree of polymerization is about 240, and it is a 10% solution (methanol/dichloromethane).

The viscosity at 20'C at a weight ratio of 1:1 is approximately 136-2
04 centistokes (11th Amendment Japanese Pharmacopoeia Law Hydroxypropyl Methyl Cellulose Phthalate 2007
31), and a specific example is) IP-5
58 (manufactured by Shin-Etsu Chemical Co., Ltd.).

The polyethylene glycol (hereinafter sometimes referred to as PEG) of the present invention is solid at room temperature (15 to 25°C) and has an average molecular weight of usually 1,200 to 25,000. Preferably it is 2,000 to 10,000, more preferably 7,000 to 9,500.

Specific examples include PEGI 500, PEG400
0, PEG6000 and PEG20000.

The shellac of the present invention is a resinous substance obtained by purifying and/or bleaching secretions of rank scale insects.

Next, a method for producing the enteric coating of the present invention will be described. That is, the enteric coating of the present invention is H1'MOP.

It can be obtained by coating a preparation to which it is desired to impart enteric properties with an enteric coating agent containing PE () and shellac in the ratios described above.

The preparations coated with the enteric coating include powders, fine granules, granules, gunpowder tablets, capsules, and pharmaceutically processed products thereof (for example, enteric-coated granules made into tablets or capsules, ), there are no particular limitations. moreover,
The herbal medicines to be added to these preparations are not particularly limited as long as they are enteric-coated drugs; for example, central nervous system drugs include diazepam, idebenone,
Aspirin, ibuprofen, valacetamol, naproxen, piroxicam, diclofenac, indomethacin, sulindac, lorazepam, nitrazepam, phenytoin, acetaminophen, ethenzamide, ketoprofen, etc. Cardiovascular drugs include molsidomine,
Vinpocetine, propranolol, methyldopa, dipyridamole, furosemide, triamterene, nifedipine, atenolol, spironolactone, metoprolol,
Pindolol, captopril, isosorbide nitrate, etc.
Amlexanox is a respiratory drug.

Examples of gastrointestinal drugs include dextromethorphan, theophylline, pseudoephedrine, salbutamol, and guaifenesin.
2,2-trifluoroethoxy)-2-pyridylcomethylsulfinyl)benzimidazole (hereinafter, compound A
It may also be written as ) and 5-methoxy-2-((
4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl] Benzimidazole drugs with anti-ulcer effects such as penzimitazole, cimetidine, ranitidine, pancreatin, bisacodyl, 5-aminosalicylic acid, etc. are used as antibiotics. Substances and chemotherapeutic agents include cephalexin, cefaclor, cefrazine, amoxicillin,
pipampicillin, bacampicillin, dicloxacillin,
Erythromycin, erythromycin stearate, lincomycin, doxycycline, trimethoprim/sulfamethoxazole, etc. Metabolic drugs include serrapeptase, lysozyme chloride, adenosine triphosphate, glibenclamide, potassium chloride, etc. Vitamin drugs include: Examples include vitamin B1, vitamin B2, vitamin Bs, vitamin C1, fursultiamine, and the like. Furthermore, when preparing the formulation, additives commonly used in formulation may be added, or only the additives may be coated with the enteric coating of the present invention without incorporating these active ingredients. . Examples of such additives include excipients (e.g., lactose, corn starch, sucrose, talc, crystalline cellulose, mannitol, light anhydrous silicic acid, magnesium carbonate, calcium carbonate, L-cysteine, etc.), binders (e.g., alpha modified starch, methylcellulose, carboxymethylcellulose, hydroxypropylcellulose,
Hydroxypropyl methylcellulose, polyvinylpyrrolidone, pullulan, dextrin, gum arabic, low-substituted hydroxypropylcellulose (hereinafter referred to as L-II
It is sometimes written as PC. ), etc.], disintegrants [e.g., carboxymethylcellulose calcium, starches, cross-linked carboxymethylcellulose sodium (
Hereinafter, it may also be referred to as acridyl. ), cross-linked insoluble polyvinylpyrrolidone, etc.], colorants (
Examples include titanium oxide, red iron oxide, tar pigment, etc., and two or more of these may be used.

In the present invention, solvents for dissolving I(PMCP, PEG, and shellac) include, for example, a mixture of acetone and ethanol, and a mixture of ethanol and water. May be added.

HPMCP is preferably dissolved in acetone,
The blending ratio of HPMCP to acetone is usually 3 to 1.
5 weight preload or more, or 6 to 10 weight weight. A blending ratio of 3% or less is not very preferable because the concentration in the liquid is low and the coating time is long when attempting to coat the solution in an amount sufficient to ensure enteric properties. Moreover, if it is more than 20%, the viscosity of the liquid increases, which may cause trouble during coating.

PEG and shellac are preferably soluble in ethanol, and if necessary, heating will speed up dissolution. In the case of PEG, the blending ratio of both to ethanol is usually 0.1 to 5% by weight, preferably 0.5 to 1.5% by weight,
In the case of rank 7, it is usually 1 to 10% by weight, preferably 3 to 10% by weight.
It is 6% by weight.

The enteric coating liquid is preferably obtained by mixing an acetone solution in which HPMCP is dissolved and an ethanol solution in which PEG and shellac are dissolved.

When the mixing ratio of the acetone solution and the ethanol solution is 10 to 100% by weight, particularly 10 to 70% by weight relative to the acetone solution, a mixed solution free of insoluble matter can be obtained. The mixed enteric coating agent is sprayed onto the desired formulation to obtain an enteric formulation. The composition of the three components in the enteric coat in the obtained enteric-coated preparation is HPM.
For CP, in the case of PEG, it is usually 0.1 to 20% by weight or more, or 2 to 10% by weight, and in the case of shellac, it is usually 5% by weight.
-40% by weight, preferably 15-35% by weight. Furthermore, the composition of these three is soluble in a mixture of 75 to 85% alcohol and 15 to 25% water, especially 78 to 82% alcohol and water; HPMCP is usually 1-1
A good enteric coating solution can be obtained at a starting weight ratio of 0 and also at the above ratio of PEG and shellac.

To explain in more detail the coating method with the enteric coating agent described above, there are no restrictions on the preparation before coating, but for example, in the case of tablets, the uncoated tablet is placed in a vented coating machine and the coating agent is sprayed.

At this time, there is no need to particularly adjust the temperature of the liquid during production.
Generally, room temperature (1-30°C) is sufficient. Furthermore, in the case of granules, for example, the granules before coating are placed in a fluidized coating machine and the coating agent is sprayed without controlling the liquid temperature, as in the case of tablets. The enteric preparation thus obtained may be further processed by methods known per se for printing purposes or to impart gloss. For example, in the case of enteric-coated granules or powders, they may be made into tablets or capsules (hard capsules, soft capsules) through pharmaceutical processing. Furthermore, it may be mixed with other preparations obtained by methods known per se, such as coated granules having different dissolution pH, to form a preparation for sustained use or targeting the gastrointestinal tract.

EXAMPLES The present invention will be explained in more detail with reference to Examples, Reference Examples, and Experimental Examples below, but the present invention is not limited by these.

Example 1 2100 g of non-barrel (20-28 mesh) was placed in a CF device (CF-360, manufactured by Freund, Japan), the rotor rotation speed was set to 20 Orpm, and a hydroxypropyl cellulose solution (3% (W/V)) was added at room temperature. ) 200
0ml was mixed in advance while spraying at 25ygl/min, and 20.97ml of the spraying agent had the following composition.
The granules were spray-coated at 40° C. for 916 hours under vacuum, and 12 to 32 mesh spherical nucleated granules were obtained using a round section.

[Spreading agent]

Compound A 400g Magnesium carbonate 400g00g Granules 400g Cornstarch 400gL-HPo
60! /(Hydroxypropoxyl group substitution degree: 10.0 to 13.0% (W/W), average particle size B
Below Opm, particles having the same degree of substitution and average particle diameter were used hereinafter. ) from the obtained spherical nucleated granules
A sample of 0.9 was placed in a fluidized bed coating machine (manufactured by Okawara Co., Ltd.), and the blowing temperature was controlled at 60°C and product temperature was controlled at 45°C, and the following enteric coating solution was sprayed at 50 ml/min to form enteric granules. Obtained. The obtained granules were uniformly coated with an enteric coating with almost no particle breakage or adhesion between particles during coating, and the particle size (particle size as a granule prescribed in the 11th revised Japanese Pharmacopoeia, the same test method thereafter) ), it passed the acid resistance (1st liquid) and disintegration (2nd liquid) tests in the disintegration test method prescribed in the 11th edition of the Japanese Pharmacopoeia (the same test method hereafter).

[Enteric coating agent]

HP-558780 & polyethylene glycol 5ooo sg cellar
120g aceton
13000. iF ethanol 2400. @240m9 of the enteric-coated granules obtained above were packed into No. 2 hard capsules (heavy ffi: 65
In9) was filled to obtain capsules.

The obtained capsule was disassembled, the enteric granules contained therein were taken out, and the acid resistance was examined, and it was confirmed that there were no problems.

Example 2 Non-barrel (24~s2 mesh) 42 is connected to OF device (
CF-I S 001 (manufactured by Freund), the rotor rotation speed was set to 6 Orpm, and a coating solution prepared in advance with the following composition was sprayed with 200 m/min x 2 guns to granulate. After vacuum drying the granules at 40'C for 16 hours, spherical nucleated granules with 12 to 32 meshes were obtained using a round section.

[Coating liquid J Serrapeptase 3000gL-HPo
1800g lactose
160g60g granula
1g00.9 tal
1600 f? Ethanol 1
1500g water 9700g Sample 48 to 9 from the obtained spherical nucleated granules, put them into a fluid coating machine (PLO-60, Freund/manufactured by Okawara Corporation), and control the air blowing temperature to 60°C and the exhaust temperature to about 40°C. 170g of enteric coating agent with the following composition
Enteric-coated nucleated granules were obtained by spraying with 3 guns per minute. The obtained granules were uniformly coated with an enteric coating without granule breakage during coating, and passed pharmacopoeial tests for particle size, acid resistance, and disintegration.

(Enteric coating agent) HP-55811600,9
2800 g polyethylene glycol 6000
G60g ethanol
56300 g
131500.9 420 g of enteric coated cored granules obtained above, 210 g of heptaaluminum hydroxide sodium bicarbonate coprecipitate, crystalline cellulose 5
80g, cross-linked carboxymethyl cellulose sodium 15G, 9, magnesium stearate 20g
and tableting granules 14401 prepared in advance by the following method were mixed for 3 minutes in a tumble mixer (TM-15, manufactured by Showa Kagaku Kikai Seisakusho) (mixing conditions: 10r
p.m.

3 minutes). Pure Press Collect 1
9K (manufactured by Kikusui Seisakusho) and an Oblong type punch were used to compress the tablets at a compression pressure of 1 ton/mm. The weight of each tablet is 480q, the major axis is 15", the minor axis is 6.5jIj+
A white plain tablet with a thickness of 8.411 M and a disintegration time of 1.2 minutes was obtained.

[Granules for tableting]

Crystalline cellulose was added to acetaminophen 900 P, chlorpheniramine maleate 7.5f, noskabin 48y1 anhydrous caffeine γ5y1 dihydrocodeine phosphate 24g, dl-methylephedrine hydrochloride 60g, acridyl 729 and cornstarch 72g to make 1389.
6g, and thoroughly mixed with a vertical granulator (FM-025 type, manufactured by Fuji Sangyo Co., Ltd.) (mixing conditions: 400 rpm).
m, 10 minutes), hydroxypropylcellulose 504y
was mixed with a water bath solution. The white mixture was dried with a fluidized fluid dryer (FD-38, manufactured by Fuji Sangyo Co., Ltd.) at a blowing temperature of 60°C, and then passed through a 1.5 aunφ punching screen using a power mill (Model P-3, manufactured by Showa Kagaku Kikai Seisakusho). The mixture was sieved to obtain granules for tabletting.

Example 3 Serrapeptase 500g, lactose 300091g crystalline cellulose tso y, cornstarch 1050g, acridyl 150g, hydroxypropyl cellulose 150g
F as multiplex granulator (MP-25
1450 g of water was added and granulated (granulation conditions: 400 rpm, 15 minutes). The granulated product was fluidized and dried using a multiprocessor (model FD-MX-1, manufactured by Fuji Sangyo Aeromatic Co., Ltd.) at a blowing temperature of 55°C, and then sieved on a round surface to sample the dried product of 32 to 60 grains. Take 2000f of the dried material and put it in the multiprocessor mentioned above (however, use the two-row coater type).
While controlling the air blowing temperature to about 43°C and the product temperature to about 20°C, an enteric coating agent having the following composition was sprayed at 50 da/min to obtain enteric granules. The obtained granules were uniformly coated with the enteric coating without granule breakage during coating. In addition, the enteric-coated granules were sieved through 24 to 32 meshes to examine acid resistance, and as a result, they passed the pharmacopoeia test.

[Enteric coating agent J IIP-568720,? Sera ri
240 g polyethylene glycol 6000
40g
3000fj aceton 7000
g Example 4 3300 g of the spherical nucleated granules used in Example 2 were placed in a fluidized bed coating machine Glatt WSG-15 (manufactured by Blatt, West Germany), and the air blowing temperature was approximately 55°C and the temperature of each product was approximately 43°C.
55g of the enteric coating agent below
/min to obtain enteric granules. The obtained enteric-coated granules were uniformly coated with an enteric coating without particle breakage during coating or adhesion of particles to each other, and passed pharmacopoeial tests for particle size, acid resistance, and disintegration.

[Enteric coating agent]

HP-568770g Sera Ri
187 g polyethylene glycol 6000
44g ethanol
376057A7
8770. ! i' Example 5 550 g of the spherical nucleated granules used in Example 2 were placed in a fluidized bed coating machine (FD-38, Takashi Sangyo '8), and
Enteric coated granules were obtained by spraying the following enteric coating agent at 12 I/min while fluidizing the granules at a blowing temperature of 0.00. The obtained granules were uniformly coated with the enteric coating without any granule breakage during coating. In addition, the enteric-coated granules were sieved through 24 to 32 meshes to examine acid resistance, and as a result, they passed the pharmacopoeia test.

[Enteric coating agent]

HP-558140, f Sera Ri
34.9 polyethylene glycol 5oo
o syethanol 556
0g Water 8409 Reference Example 1 In the method of Example 4, f(P-558 was
or HP-60 (manufactured by Shin-Etsu Chemical Co., Ltd., the viscosity of HP-55 and HP-50 (in 1 methanol/dichloromethane solution) is approximately 32 to 48 centistokes and approximately 44 to 66 centistokes, respectively). The enteric coated granules were sprayed with a soluble coating agent to obtain enteric coated granules (control groups 1 and 2).The enteric coated granules obtained were uniformly coated with the enteric coating without particle breakage or adhesion between particles during coating. Passed pharmacopeia tests for particle size, acid resistance, and disintegration.

Reference Example 2 In the method of Example 4, enteric coated granules were obtained by spraying the following enteric coating agent in which shellac and polyethylene glycol 6GGG were replaced with mustard oil (Control Group 3).
. The obtained enteric-coated granules are uniformly coated with an enteric coating without particle breakage or adhesion between particles during coating.
Passed pharmacopeia tests for particle size, acid resistance, and disintegration.

[Enteric coating agent J HP-558770 & castor oil
soyeta) - Le 1
980g acetone
78809 Reference Example 3 In the method of Example 5, polyethylene glycol 60
00 is polyethylene glycol 40, which is a liquid plasticizer.
Enteric coated granules were obtained by spraying the enteric coating agent modified to 0 or acetylated monoglyceride (Myverset 9-40T).

The obtained coated granules were uniformly coated without peeling of the film or roughening of the surface.

Experimental Example 1 The enteric granules obtained in Example 4, Reference Example 1 and Reference Example 2 were
Mix with crystalline cellulose at a blending ratio (enteric coated coarse particles: crystalline cellulose =) of 1:2 and 1:5, and autograph (I8
-5000. Using a small amount of magnesium stearate as an external lubricant, the tablets were compressed at a compression pressure of 1 ton/cm" to a weight of 200 # and an external diameter of 8 mm.
It was made into tablets. The obtained tablets were placed in an auxiliary cylinder used for the disintegration test of enteric-coated fine granules as defined in the 11th edition of the Japanese Pharmacopoeia, and after shaking in the first liquid for 60 minutes according to the enteric-coated disintegration test method, the remaining tablets in the auxiliary cylinder were shaken for 60 minutes. The content in the enteric-coated granules was determined by enzyme titer. All of the granules other than the granules coated with the enteric coating of the present invention showed a large decrease in content, and the strength of the enteric coating was inferior to that of the enteric coating of the present invention.

Table 1 Content in enteric-coated granules Experimental example 2 The enteric-coated granules obtained in Reference Examples 1 and 2 were made into tablets in the same manner as in Example 2. The obtained tablets were placed in an auxiliary cylinder in the same manner as in Experimental Example 1, and the tablets were placed in the first liquid at 60°C according to the enteric-coated disintegration test method.
Shake for a minute. In the beaker in which the tablets containing the enteric-coated granules obtained in Example 2 were investigated, there were no particles falling from the auxiliary tube of the enteric-coated granules, but in the case of tablets containing other enteric-coated granules, the enteric-coated granules were at the bottom of the beaker. More than 15 grains fell from the auxiliary cylinder. As is clear from the above, the granules coated with the enteric coating of the present invention had better acid resistance and the strength of the enteric coating was stronger.

Experimental Example 3 In the method of Example 4, 15 g of shellac alone and 3
Enteric-coated granules were obtained by spraying 85g of the enteric coating agent and three types of enteric coating agents in which only polyethylene glycol 5ooo was changed to 251g (control groups 4, 5 and 6). The enteric-coated granules obtained and the enteric-coated granules obtained in Example 4 (
As a result of investigating the disintegrability and acid resistance of the present invention, enteric-coated granules other than the enteric-coated granules of the present invention failed the pharmacopoeia test for disintegration or acid resistance, and could not be used as enteric-coated granules. Ta.

Table 2 Pharmacopoeia test results of enteric-coated granules Experimental example 4 The enteric-coated granules obtained in Example 5 and Reference Example 3 (control groups 7 and 8) were made into tablets in the same manner as in Example 2.

(However, the compression pressure was 2 tons/cm2.) All of the obtained tablets had a weight of 480 mm, a long axis of 151 m, a short axis of 651 m+, a thickness of 6 mm, and a disintegration time of about 3 minutes. It was a plain tablet. The resulting tablets were subjected to a disintegration test in the same manner as in Experimental Example 1, and the content of enteric-coated granules remaining in the auxiliary cylinder was measured by enzyme titer method. All of the granules other than the granules coated with the enteric coating of the present invention showed a large decrease in content, and the strength of the enteric coating was inferior to that of the enteric coating of the present invention as shown in the table below.

Table 3 Content in enteric-coated granules (voluntary) Procedural amendment 1, Indication of the case 1999 Patent Application No. 251438 2, Title of the invention Enteric-coated coating 3, Person making the amendment Relationship with the case Patent applicant ( Effects of the Invention) The enteric coating of the present invention has excellent coating strength and acid resistance, so by coating preparations such as granules and fine 9 tablets with the enteric coating, enteric preparations with strong coating strength can be obtained. It will be done.

4. Address of agent: 3-1-12 Kitahama, Chuo-ku, Osaka 541 Telephone: Osaka (06) 202-5858 (Representative) (Delivered on May 6, 1998; Number of claims increased due to amendment: Date 0) 8. Contents of amendment (1) rHP-558J on page 4, line 17 of the specification has been changed to rH
Corrected to P-55SJ.

(2) "Propranolol J" on page 6, lines 8-9 is corrected to "propranolol."

(3) "Amoxicillin" on page 7, line 7 is corrected to "amoxicillin."

(4) Insert the following statement between the bottom line (row of subject area 8) and the line of (effects of the invention) of the display in Table 3 on page 25.

``Reference Example 4 After thoroughly mixing substances with the following composition ratio, adding water and kneading, extrusion granulation machine (manufactured by Kikusui Seisakusho, screen diameter l)
, Q mmφ) and immediately granulated using a marmerizer (
The mixture was made into spherical granules using Fuji Paradal Co., Ltd. (1000 rI) m), vacuum dried for 40'0.16 hours, and sieved through a round section to obtain 12 to 42 mesh granules.

Compound A 600F magnesium carbonate 600g lactose
380 crystalline cellulose lfiOg carboxymethyl cellulose calcium 00y Hydroxypropyl cellulose 120 g Pluronic 40 g Example 6 1500 g of the granules obtained in Reference Example 4 were placed in a fluidized bed coating machine (manufactured by Okawara Co., Ltd.), and the air blowing temperature was 60°C and the product temperature was 45°.
C, and the following enteric coating solution was sprayed to obtain enteric granules. To prevent static electricity, Talc 3I/and Aerosil 3y were added and mixed.

Enteric coating liquid III'-558310! ? Cerac 62g polyethylene glycol 6QO0 Talc 38g titanium oxide
18F Reference Example 5 Lactose granules having the following composition obtained by granulating a mixed powder of lactose, corn starch and low-substituted hydroxypropylcellulose with a 10% hydroxypropylcellulose aqueous solution in a conventional manner, enteric-coated granules obtained in Example 6 The granules, crystalline cellulose, Acdisol and magnesium stearate were thoroughly mixed in the proportions shown below and tableted using a rotary tablet machine (manufactured by Kikusui Seisakusho) to produce tablets of 450 m'I per tablet. One tablet contains 5 am of compound A! include.

Lactose granules 1435f lactose
1056F cornstarch
264y Low 1 degree hydroxypropylcellulose 1F Hydroxypropylcellulose 451 Highly soluble granules (obtained in Example 6) 300f Crystalline cellulose 1500f Acudisol
250 Dust Magnesium Stearate
15g” or more

Claims (1)

Scope of Claims: Consisting of (a) hydroxypropyl methylcellulose phthalate having a viscosity of about 136 to 204 centistokes, (b) polyethylene glycol that is solid at room temperature, and (c) shellac, and (b) and The ratio of (c) is 0.1 to 20% by weight and 5 to 20% by weight, respectively.
Enteric coating that is 40% by weight.