JPH0592918A - Nucleated powder and its production - Google Patents

Abstract

PURPOSE:To control elution properties of a medicine in powder having a small particle diameter. CONSTITUTION:A nucleated powder is obtained by spraying and coating a fine granular nucleus with a mixture solution containing a water-soluble polymer, e.g. hydroxypropyl cellulose or hydroxypropyl methyl cellulose and at least one medicine. The particle diameter of the resultant nucleated powder is substantially <=500mum. The fine granular nucleus is preferably spherical. The nucleated powder is obtained by sprinkling a powdery sprinkling agent while spraying the mixture solution thereon. The dry coated powder is directly used or as a granule, a tablet or a capsule.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a dry powdered drug which can appropriately control the elution of a physiologically active substance in the fields of food, pharmaceuticals, agricultural chemicals and the like, and a method for producing the same.

[0002]

2. Description of the Related Art Generally, many studies have been conducted on drug release control systems (drug delivery systems) for foods, pharmaceuticals, agricultural chemicals and the like. Particularly in the oral dosage form, the granules show no difference in gastric emptying rate and absorbability than the tablets, and are hardly affected by diet. Therefore, oral preparations can be made into granules, or tablets can be blended with granules [Drug Development and
Industrial Pharmacy (Drug Development a
nd Industrial Pharmacy), 9 (7), 1379-1396 (1983)], and capsules filled with granules.

Regarding the granules, JP-A-63-222121
The publication discloses a method for producing granules by extrusion molding a drug, hydroxypropyl cellulose and an ethanol-soluble plasticizer. In this method, a large amount of plasticizer is used to give flexibility.
Japanese Patent Laid-Open No. 63-99009 discloses a method of spraying an aqueous solution of a binder or an alcohol solution while rolling solid particles containing a drug and spraying hydrophobic solid fine particles which are not easily dissolved in the stomach and intestines. It is disclosed. In this way, long-lasting granules are obtained.

JP-A-63-222112 discloses a preparation of sustained-release granules containing a drug, an ethanol-insoluble water-soluble polymer substance and an ethanol-soluble water-soluble polymer substance. This method requires a large amount of ethanol-insoluble water-soluble polymer, and for example, 55% or more of ethanol-insoluble water-soluble polymer is used in the examples.

Japanese Unexamined Patent Publication (Kokai) No. 63-243036 discloses gastric retention type sustained release granules of calcium silicate and hydroxypropylmethyl cellulose. According to this method, calcium silicate which is powder is formulated by a dry method so that the apparent specific gravity becomes 1.0 or less.

Further, the applicant of the present invention has filed Japanese Patent Application Laid-Open No. 2-1749.
In Japanese Patent No. 31, a method was proposed in which a dispersion of low-substituted hydroxypropylcellulose is sprayed on core granules to obtain core-containing granules. The granules obtained by this method have high strength and excellent disintegration.

European Patent Publication 0452286A
2 consists of at least 50% by weight of microcrystalline cellulose and has an average particle diameter of 100 to 1000 μm.
Disclosed are spherical granules obtained by coating an inert spherical core of m with a powder containing an active ingredient using an aqueous solution of a binder and spraying an aqueous solution or dispersion of a coating agent. There is.

The granules obtained by these methods are characterized in that most of their particle diameters are 500 μm or more.
Further, the granules have large and uniform particle diameters. Therefore, in the case of coating the dissolution control base to control the dissolution of the drug, the coating variation is small and advantageous. However, because of the large particle size, not only is the dispensability poor, but when added to tablets and capsules, the amount of added granules varies greatly. Furthermore, regarding the dosage form of granules, a particle size test and a disintegration test are required in the section of “11th Amended Japanese Pharmacopoeia (hereinafter sometimes referred to as the Japanese Pharmacopoeia) / General Rules for Formulation 5 Granules”. However, it is difficult to formulate the drug in order to control the drug release satisfying those regulations.

On the other hand, the powder has no regulation of the Japanese Pharmacopoeia disintegration test and its particle size is as small as 500 μm or less, so that it has excellent dispensability as compared with granules, and when it is blended in tablets or capsules, The variation in the added amount becomes small. In addition, powders generally have higher gastric emptying rate and absorbability than granules. However, due to the high gastric emptying rate of the powder,
Depending on the drug, the blood concentration may be increased early and side effects may occur. Moreover, among the prior art relating to the above-mentioned granules, when a drug is blended in the core and the drug elution is controlled by coating a polymer base, for example, when it is directly applied to the powder, the coating has a large variation and the coating accuracy is poor. And the coating amount also increases. Therefore,
It is difficult to accurately control the release of a drug in a powder having a smaller particle size than a granule.

[0010]

SUMMARY OF THE INVENTION An object of the present invention is to provide a powder and a method for producing the same, which can control the dissolution of a drug with high accuracy even if the particle size is small.

Another object of the present invention is to provide granules, tablets and capsules containing the above powder.

[0012]

The present inventors have conducted extensive studies in order to control the dissolution of a drug in a powder, and as a result, have found that a core having a small particle size contains (1) a water-soluble polymer and (2) a drug. The present invention has been completed by discovering that (3) the coating layer contains a drug by spraying the liquid, the dispersion of the coating is small, the coating amount can be increased, and the elution of the drug can be appropriately controlled.

That is, according to the present invention, at least one physiologically active substance (hereinafter,
(Referred to as drug) and has a particle size of substantially 50
Provided is a dry powder having a particle size of 0 μm or less and a method for producing the same.

The present invention also provides granules, tablets or capsules containing the dry powder.

In the present specification, "substantially" means that a small amount of particles having a particle diameter outside the above range may be included as long as the particles are inevitably mixed.

The term "coating" is used not only to cover the entire surface of the nucleus, but also to cover a part of the surface of the nucleus and a case where it is adsorbed or absorbed.

Further, the term "spherical" is not limited to a true sphere,
It is used to mean a shape having a curved surface such as an elliptical cross section, an eggplant shape, or a droplet shape.

The particle size of the fine-grained core is substantially 500 μm.
m or less, 50 to 500 μm, preferably 1
It is about 100 to 400 μm. As the core having such a particle diameter, for example, 200 to 30 of crystalline cellulose is used.
0 μm spherical granulation product (Asahi Kasei Co., Ltd., Avicel SP,
Hereinafter, described as Avicel SP), crystalline cellulose (3
Part) and lactose (7 parts), a spherical granulated product of 200 to 350 μm (manufactured by Freund, non-pareil, NP-7:
3), crystalline cellulose (5 parts) and lactose (5 parts)
Part) a spherical granulated product of 200 to 350 μm (manufactured by Freund, non-pareil, hereinafter referred to as NP-5: 5), lactose (9 parts) and pregelatinized starch (1 part) with stirring of 50 to 250 μm. Granular product, JP-A-61-21
Microcrystalline cellulose spherical granules described in JP 3201 A, fine particles of 500 μm or less, processed products such as wax formed into a spherical shape by spray chilling or melt granulation,
Processed products such as gelatin beads products of oil component, porous particles such as calcium silicate, starch, chitin, cellulose, chitosan, bulk products such as granulated sugar, crystalline lactose, crystalline cellulose, sodium chloride and processed products thereof. Is mentioned.

The core may contain the drug described below, but the core may not contain the drug because the release property of the drug can be controlled by the coating layer containing the drug.

Even if the core is in the form of fine particles, it is preferable that the core has a spherical shape in order to reduce the dispersion of the coating and increase the coating amount.

Examples of the water-soluble polymer include, for example, hydroxypropyl cellulose (hereinafter sometimes referred to as HPC), polyvinylpyrrolidone, and other ethanol-soluble water-soluble polymers; hydroxypropyl methyl cellulose (hereinafter referred to as HPMC). )), Ethanol-insoluble water-soluble polymers such as methyl cellulose, sodium carboxymethyl cellulose, sodium polyacrylate, polyvinyl alcohol, sodium alginate, and guar gum. The dissolution of the drug can be controlled by using the ethanol-soluble water-soluble polymer and the ethanol-insoluble water-soluble polymer in combination, or by using the water-soluble polymers having different viscosities together.

Preferred water-soluble polymers include HPC and HP
MC, cellulose derivatives such as methyl cellulose, and polyvinyl alcohol are included. Particularly preferred water-soluble polymers are cellulose derivatives such as HPC and HPMC.

HPC has a hydroxypropoxyl group,
For example, 53.4 to 77.5% by weight, preferably 60 to
Contains about 70% by weight. The viscosity of a 2 wt% aqueous solution of HPC at 20 ° C. is usually about 1 to 150,000 cps. As such HPC, Japanese Pharmacopoeia hydroxypropyl cellulose or the like is used (hereinafter, the viscosity of HPC is the value of a 2 wt% aqueous solution at 20 ° C.).

The HPC used in the present invention has a different degree of substitution of hydroxypropoxyl groups from the low-substituted hydroxypropyl cellulose disclosed in Japanese Patent Application Laid-Open No. 2-174931.

HPMC is a mixed ether in which a methoxyl group and a hydroxypropoxyl group are bonded. HPMC
The content of the methoxyl group is, for example, 19 to 30% by weight, and the content of the hydroxypropoxyl group is, for example, 4
It is about 12% by weight. HPMC 2 at 20 ℃
The viscosity of the weight% aqueous solution is usually about 1 to 40,000 centistokes. As such HPMC, Japanese Pharmacopoeia Hydroxypropyl Methyl Cellulose 2208, Japanese Pharmacopoeia Hydroxypropyl Methyl Cellulose 2906, Japanese Pharmacopoeia Hydroxypropyl Methyl Cellulose 2910 and the like are used. Hydroxypropylmethyl cellulose may be used alone or in combination of two or more.

The drug is not particularly limited as long as it is administered as a powder. As the drug, for example, as a central nervous system drug, diazepam, idebenone, aspirin, ibuprofen, paracetamol, naproxen, piroxicam,
Diclofenac, indomethacin, sulindac, lorazepam, nitrazepam, phenytoin, acetaminophen, etenzamid, ketoprofen, etc .; as cardiovascular drugs molsidomine, vinpocetine, delapril hydrochloride, propranolol, methyldopa, dipyridamole, furosemide, triamterene, nofedipine, nifedipine, nifedipine. Metoprolol, pindolol, captopril, isosorbide dinitrate, etc .; As a respiratory drug, amlexanox, dextromethorphan, theophylline, pseudoephedrine, salbutamol, guaifenicin, etc .; Digestive drug:
Benzimidazoles such as lansoprazole and omeprazole, cimetidine, ranitidine, pancreatin, bisacodyl, 5-aminosalicylic acid, etc .; antibiotics and chemotherapeutic agents cephalexin, cefaclor, cefradine, amoxicillin, pivampicillin, bacampicillin, dicloxacillin, erythromycin, erythromycin, erythromycin, erythromycin.
Erythromycin stearate, lincomycin, doxycycline, trimethoprim / sulfamethoxazole, etc .; as metabolic drugs, serrapeptase, lysozyme chloride, adenosine triphosphate, glypenclamide, potassium chloride, etc .; as vitamin drugs, vitamin B ₁ , Vitamin B ₂ , vitamin B ₆ , vitamin C, fursultiamine, vitamin A, vitamin E, vitamin D, vitamin K and the like; antacids and the like. These drugs may be used alone or in combination of two or more.

The coating layer containing the drug increases the strength of the dry powder, and therefore, the low-substituted hydroxypropyl cellulose (hereinafter referred to as L-H) described in, for example, JP-A-2-174931.
(Described as PC) and other additives may be included.

As the additive, an additive which is generally added when producing a powder can be used. As an additive,
For example, excipients such as lactose, corn starch, sucrose, talc, crystalline cellulose, mannitol, light anhydrous silicic acid, magnesium carbonate, calcium carbonate, L-cystine; pregelatinized starch, partially pregelatinized starch, methyl cellulose, carboxymethyl cellulose,
Binders such as polyvinylpyrrolidone, pullulan, dextrin and gum arabic; disintegrators such as carboxymethylcellulose calcium, starches, crosslinked sodium carboxymethylcellulose, crosslinked insoluble polyvinylpyrrolidone; coloring of titanium oxide, red iron oxide, tar pigments, etc. Agents and the like. You may use 2 or more types of these additives.

The content of the water-soluble polymer such as HPC and / or HPMC may be in the range that can control the dissolution of the drug in the dry powder, for example, 0.1 weight to 50.
%, Preferably about 1 to 30% by weight. When the proportion of the water-soluble polymer is less than 0.1% by weight, it is difficult to control the elution of the drug, and when it exceeds 50% by weight, the drug content decreases.

The ratio of the coating layer to the core can be selected within a range in which the drug dissolution property can be controlled, and is, for example, about 50 to 400 parts by weight with respect to 100 parts by weight of the core. Cover amount is 5
If it is less than 0 part by weight, it is difficult to control the elution of the drug, and if it exceeds 400 parts by weight, the particles grow large and it becomes difficult to fall within the particle size specification of the powder.

The coating layer may be formed of a plurality of layers, as long as at least one of the plurality of coating layers contains a drug.

The particle size of the dry-coated powder of the present invention is substantially 5
The thickness is 00 μm or less, preferably 50 to 500 μm, and more preferably 100 to 400 μm. Particle size is 500μ
If it exceeds m, the dispensability tends to deteriorate as described above. If the particle size is smaller than 50 μm, problems such as the powder adhering to the walls of the manufacturing equipment due to static electricity during manufacturing are likely to occur.

The dry-coated powder of the present invention is used for forming a core having an appropriate particle size,
Selecting the viscosity grade and content of the water-soluble polymer, eg HPC and / or HPMC, and the ratio of the ethanol-soluble water-soluble polymer (eg HPC) to the ethanol-insoluble water-soluble polymer (eg HPMC). By this, the drug dissolution property can be controlled. Further, the dissolution property of the drug is not so much affected, and the dissolution property can be appropriately controlled.

In the production method of the present invention, the fine granular core is coated with a mixed solution containing a water-soluble polymer and at least one physiologically active substance.

The mixed solution may be a solution or a dispersion. The mixed liquid can be prepared using water, an organic solvent such as ethanol, or a mixed liquid thereof.

The concentration of the water-soluble polymer in the mixed solution varies depending on the ratio of the drug and the additive, but is usually 0.1 to 50% by weight, preferably about 0.5 to 10% by weight. If the concentration is less than 0.1% by weight, the binding force of the drug to the nucleus is small, and if it exceeds 50% by weight, the viscosity of the mixed solution is increased and the workability is likely to be deteriorated.

The coating layer is not limited to one layer and may be formed of a plurality of layers. In this case, select the compounding ratio of water-soluble polymer and the grade of viscosity, or use the mixed liquid with the ratio of the drug and other additives changed, and coat them sequentially to determine the drug concentration of each layer continuously or stepwise. It may be changed to. In that case, as long as the entire coating layer contains the water-soluble polymer in an amount of 0.1 to 50% by weight, it may be coated with a mixed solution having a mixing ratio outside the range of 0.1 to 50% by weight. Furthermore, an inactive film may be formed between a plurality of layers by a known method to block each layer containing the drug.

When two or more drugs having poor compounding properties are compounded, the mixture may be used simultaneously or separately to coat the core.

In another method of the present invention, a powder-dispersing agent mixed with a drug and / or an additive may be sprayed while spraying the mixed solution on the core. In this method, the coating layer can be formed by a simple operation of spraying the powdery spraying agent. The particle size of the dusting agent is generally about 100 μm or less, preferably about 50 μm or less.

Granulation is performed by coating the core with the mixed solution or the like by the above-mentioned method. The granulation temperature is set within a range that does not impair the stability of the drug. If the drug is highly stable, the temperature of the mixture does not need to be adjusted,
Generally, it can be performed at room temperature of about 1 to 30 ° C. The method of coating the core is not particularly limited, for example, centrifugal fluidized coating granulator, fluidized coating granulator,
Conventional equipment such as agitation granulator can be used. Specific examples of the centrifugal fluidized coating granulator include a CF device and Spiral Flow manufactured by Freund, a multiplex manufactured by Paulec, and a new malmock manufactured by Fuji Paudal.

After drying the granulated product, a dry powder having a uniform particle size is obtained by a sieve. Since the shape of the powder usually corresponds to the nucleus, it is possible to obtain a substantially spherical nucleated powder.
As the sieve, for example, a 32 mesh (500 μm) round sieve can be used, and a powdered material with a nucleus can be obtained by selecting a powder that passes through the 32 mesh.

The dry coated powder thus obtained may be coated by a conventional method in order to impart taste masking, enteric properties, gastric properties and the like.

As the coating agent, for example, hydroxypropylmethyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyoxyethylene glycol, Tween 80,
Pluronic F68, castor oil, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate (hereinafter referred to as HP-55), hydroxymethylcellulose acetate succinate, acrylic acid copolymer, carboxymethylethylcellulose, polyvinyl acetal diethylaminoacetate, shellac, waxes, And pigments such as talc, titanium oxide and red iron oxide.

The dry powder can be directly used as a powder. Furthermore, the dry-coated powder may be added to granules or tablets in the form of granules or tablets according to a conventional method, or may be capsules filled in capsules.

[0045]

The dry-coated powder of the present invention and the dry-coated powder contained in the granules, tablets and capsules have excellent dispensability, small variation in the addition amount, and small particle size,
The release of the drug can be controlled accurately.

According to the production method of the present invention, the dry powder having the above-mentioned excellent properties can be easily and easily obtained.

[0047]

The present invention will be described in more detail based on the following examples, comparative examples and experimental examples, but the present invention is not limited thereto.

Example 1Manufacture of dry powder  Avicel SP (200-300μm) 700g fluid type
For coating granulator (made by Paulec: FD-3S)
Put, control the air temperature to 70 ℃ and the product temperature to about 40 ℃.
While using the bottom spray method, the following composition prepared in advance
Of the bulk liquid was sprayed and coated. Specified amount of bulk
When the liquid is sprayed, stop spraying and continue drying for 1 minute
After that, pass through a 32 mesh round sieve and
A nuclear powder was obtained.

[Bulk Liquid] Vinpocetine 10 g Lactose 50 g Talc 40 g L-HPC 40 g HPC (type M, viscosity 300 cps) 12 g HPC (type L, viscosity 8 cps) 88 g water 2160 gManufacture of film-coated dry powder  470 g of the obtained dry-coated powder was applied to the above fluid-type coating
Put in a granulator and control the blast temperature to 65 ℃ and the product temperature to 38 ℃.
Bottom spray method,
A film solution having the above composition was sprayed at a liquid speed of 10 g / min,
I started Sprays when a specified amount of film liquid is sprayed
After stopping the fog and letting it dry for 1 minute, 32 Messi
Sieving with a round sieve of 480g and film coating of 480g
A nuclear powder was obtained.

[Film Liquid] HPMC (Type 2910, viscosity 6 centistokes) 22.4 g Macrogol 6000 4.6 g Titanium oxide 2.6 g Yellow ferric sesquioxide 0.4 g Water 370.0 g Obtained film-coated nucleated powder When the particle size was evaluated according to "General Rules for Formulation of Japanese Pharmacopoeia 11-Powder Item / Particle Size Test", the powder was a fine-grained powder conforming to the regulations of the Japanese Pharmacopoeia as follows.

[0051]Example 2Manufacture of dry powder and film-coated dry powder  Instead of the Avicel SP of Example 1, NP-7: 3 (200
~ 350 μm) Same as Example 1 except using 700 g
And 925 g of dry powder and 480 g of film
A coating dry powder was obtained.

The particle size test result of the film-coated dry powder was also a fine-grained powder that complies with the regulations of the Japanese Pharmacopoeia.

[0053]

[0044]Example 3Manufacture of dry powder  NP-5: 5 (200-350μm) 70g mini CF
Put in a machine (made by Freund) and the rotor speed is 400
1% by weight of HPMC (type 2910) melted at rpm
Dissolved water / ethanol mixed solution under the condition of 2 g / min.
Lansoprazole 10g, Magnesium carbonate while spraying
Um 10g, Graniu sugar 10g, corn starch
A spraying agent prepared by uniformly mixing 20 g was sprayed at 4 g / min.
The coating liquid was sprayed even after the end of the spraying to obtain a granulated product.
Vacuum dry the granules at 40 ° C for 16 hours to obtain a 32 mesh circle.
After sieving with a sieve, the obtained granules are as follows.
It was a powdered nuclear material that passed the Japanese particle size test.

[0054] Manufacturing of capsules  240 mg of the obtained dry-coated powder was filled in a capsule filling machine (Park
No. 2 hard capsule (weight: 65m) using Davis
g) was filled to prepare a capsule.

Example 4Manufacture of dry powder  Birch with 900g lactose and 100g pregelatinized starch
Cal granulator (manufactured by Paulec: FM-VG-
10), stir at 400 rpm for 1 minute, then add water
It was added and granulated. Vacuum dry the granulate at 40 ° C. for 16 hours
And then 60 mesh (250 μm) and 200 mesh
(74 μm) sieve to obtain 74-250 μm nuclei
It was 760 g of the obtained core was prepared in advance and
Coating with Luk solution in the same manner as in Example 1.
Then, 970 g of a dry powder was obtained.

[Bulk Liquid] Vinpocetine 100 g Lactose 10 g Talc 10 g L-HPC 20 g HPC (Type M) 20 g HPC (Type SSL, viscosity 2 cps) 80 g Water 2160 g The obtained nucleated powder has a particle size of Japanese Pharmacopoeia as follows. The test was met.

[0057] Tablet manufacturing  500 g of the obtained dry-coated powder, 200 g of crystalline cellulose,
49 g corn starch and magne stearate
11 g of sium was mixed with a tumble type mixer (Showa Kagaku Kikai Seisakusho)
Manufactured; TM-15) was rotated 10 times and mixed. The mixture
Pure Press Collect 12HUK (Kikusui Seisakusho)
Using a 9.5 mmφ flat punch, compressing pressure of 1 ton / punch
It was compressed with. Each tablet weighs 380 mg and has a thickness of 4 m.
m, and the disintegration time was 2 minutes.

Example 5Manufacture of dry powder  Granuose sugar was sieved to obtain a core of 300 to 400 μm. Nuclear
2670g CF machine (made by Freund: CF-360)
And prepared in advance with the rotor rotating at 100 rpm.
A bulk liquid having the following composition was sprayed at 10 ml / min for granulation.
Vacuum dry the granules at 40 ° C for 16 hours to obtain a 32 mesh circle.
It was passed through a sieve.

[Bulk Liquid] Serapeptase 10 g Lactose 3 g Talc 5 g L-HPC 10 g HPMC (Type 2208, viscosity 4000 centistokes) 2 g Water 270 g The obtained nucleated powder complies with the particle size test of the Japanese Pharmacopoeia as follows. Was there.

[0060] Manufacture of enteric coated dry powder  480 g of the above-mentioned dry powder was put into FD-3S, and the blowing temperature was 6
Prepared in advance by controlling at 0 ℃ and exhaust temperature of about 40 ℃
The enteric film solution of the following composition was applied by the top spray method.
It was sprayed at 15 g / min to obtain an enteric coated dry powder.

HP-55 116 g Shellac 28 g Macrogol 6000 6 g Ethanol 563 g Acetone 1315 g The obtained enteric coated dry powder was suitable for the particle size test of the Japanese Pharmacopoeia as follows.

[0062] Furthermore, enteric coated dry powder is 60 mesh (250 μm)
And classified with a sieve of No. 1 and subjected to an acid resistance test with respect to the residual product of 60 mesh. The test method was in accordance with the first method of Japanese Pharmacopoeia General Test Method 46 Dissolution Test Method. Since the particle size of the enteric coated dry powder was small, the mesh of the rotating basket was 80 mesh.

As a result of using the 1st solution of the Japanese Pharmacopoeia-General Test Method 38 disintegration test method as a test solution, the serrapeptase content after operation for 1 hour was 93%, and acid resistance was ensured.

Example 6Manufacture of dry powder  Lactose 800g and Avicel RC (manufactured by Asahi Kasei Corporation) 2
00g to Vertical Granulator (FM-VG-1
0), 350 ml of water while stirring at 250 rpm
Was added and kneaded. Punching the kneaded product with 0.4 mmφ
Sand machine with screen that opens (Kikusui Seisakusho: RG
-C125) and granulated by extrusion.

The granulated product was vacuum dried at 40 ° C. for 16 hours, and the dried product was sized by a power mill with a screen (Showa Kagaku Kikai Seisakusho: P-3) having a 1 mmφ punching opening,
A cylindrical core was used.

Using 700 g of the obtained core, 900 g of a dry powder was obtained in the same manner as in Example 1. The dry coated powder thus obtained complied with the particle size test of the Japanese Pharmacopoeia as described below.

[0067] Examples 7 to 9 In the same manner as in the production of the dry-coated powder of Example 1, except that the HPC grade of the bulk liquid and the amount thereof were changed as follows,
A dry powder was produced.

Example 7 Example 8 Example 9 HPC (Type M) -12 g-HPC (Type L) 100 g --- HPC (Type SSL) -88 100 g The obtained dry powders were all as follows. It conformed to the Japanese particle size test.

Sieve Example 7 Example 8 Example 9 No. 18 (850 μm) residual 0% 0% 0% No. 30 (500 μm) residual 1% 1% 0% 200 (75 μm) residual 99% 99% 100% 200 No. (75 μm) passage 0% 0% 0% Examples 10 to 12 Example 1 except that the HPC of the bulk liquid was replaced with HPMC and the amounts of HPMC and lactose used were varied as follows.
A dry powder was produced in the same manner as the dry powder of the above.

Example 10 Example 11 Example 12 HPMC (Type 2910) 100 g 120 g 50 g Lactose 50 g 30 g 100 g The obtained dry-coated powders were all suitable for the particle size test of the Japanese Pharmacopoeia as follows.

Sieve Example 10 Example 11 Example 12 No. 18 (850 μm) residual 0% 0% 0% No. 30 (500 μm) residual 2% 3% 1% No. 200 (75 μm) residual 98% 97% 99% 200 No. (75 μm) passage 0% 0% 0% Comparative Example 1 Lactose of Example 6 was reduced by 10 g and vinpocetine was added by 10 g.
A powder was obtained in the same manner as in the production of the dry powdered product of Example 6, except that the amount was increased. The powder thus obtained complied with the particle size test of the Japanese Pharmacopoeia as described below.

[0072] Comparative Example 2 Vinpocetin 10 g, lactose 740 g, crystalline cellulose 2
00g, HPC (type L) 50g are put in a vertical granulator (FM-VG-10), and 400 rpm.
150 ml of water was added with stirring at and kneaded. The kneaded product was vacuum dried at 40 ° C. for 16 hours, and the dried product was passed through a 32 mesh round sieve to obtain a powder. The powder thus obtained complied with the particle size test of the Japanese Pharmacopoeia as described below.

[0073] Experimental Example 1 The dissolution properties of the dry powdered powder obtained in Examples 1 to 3 and the powdered powders obtained in Comparative Examples 1 and 2 were measured by the Japanese Pharmacopoeia Dissolution Test Method 2 (100).
rpm). As a test solution, the Japanese Pharmacopoeia Solution No. 1 having good solubility of pinpocetine was used. The test results are shown in Table 1.

[0074]

[Table 1] As is clear from Table 1, in the dry powder of each example, the rise of the dissolution rate due to the liquidity of the test solution is not as sharp as that of the powder of the comparative example, and therefore, the blood concentration of the drug during administration is It is suggested that there is no sudden rise.

Experimental Example 2 The dissolution properties of the dry-coated powders obtained in Example 1 and Examples 7 to 9 were examined in the same manner as in Experimental Example 1. The results are shown in Table 2.

[0076]

[Table 2] From Table 2, it was confirmed that the elution property could be controlled by the grade (viscosity) of HPC.

Experimental Example 3 The dissolution properties of the dry-coated powders obtained in Example 1 and Examples 10 to 12 were examined in the same manner as in Experimental Example 1. The results are shown in Table 3.

[0078]

[Table 3] From Table 3, it was confirmed that the elution property can be controlled by the amount of HPMC added.

Example 13 In the same manner as in Example 1, vinpocetine in the bulk liquid was changed to idebenone to obtain 925 g of a dry powder. The obtained powders passed the Japanese particle size test as described below.

[0080] Example 14 400 g of calcium silicate (porous powder, manufactured by Tokuyama Soda Co., Ltd.) was put in the fluidized-type coating granulator of Example 1, and the blast temperature was controlled at 80 ° C and the product temperature at about 35 ° C. An HPMC aqueous solution having a concentration of 5% was sprayed by a top spray method at a liquid speed of 20 g / min to granulate. When 250 g of HPMC was sprayed, the granulation was stopped, and after drying for 5 minutes, 42 mesh (350 μm)
And 80 mesh (177μm) round sieve using 177μm
˜350 μm nuclei were obtained.

130 g of the obtained core was put in the above fluidized coating granulator, and the air temperature was controlled at 60 ° C. and the product temperature at about 35 ° C., and 5% concentration of ethyl cellulose (viscosity grade: 7 cp) was applied by the bottom spray method. Was sprayed at a liquid velocity of 8 g / min for coating. When 39 g of ethyl cellulose was sprayed, the coating was stopped, and the coating was dried for 3 minutes as it was, and then a coated mesh was obtained using a 32 mesh (500 μm) round sieve.

60 g of the obtained coated core was coated in the same manner as in Example 1 using a previously prepared bulk liquid having the following composition to obtain 80 g of a dry powder.

[Bulk Liquid] Delapril Hydrochloride 3 g Lactose 3 g Talc 4 g L-HPC 4 g HPC (type M) 2 g HPC (type L) 8 g Water 216 g Adapted.

[0084]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display area A61K 47/38 C 7329-4C D 7329-4C

Claims (7)

[Claims] 1. A dry-coated powder having a fine-grained core coated with a water-soluble polymer and at least one physiologically active substance, and having a particle size of substantially 500 μm or less. 2. The dry-coated powder according to claim 1, wherein the fine granular core is spherical. 3. The dry-coated powder according to claim 1, wherein the water-soluble polymer is a cellulose derivative. 4. The dry powder according to claim 1, wherein the content of the water-soluble polymer is 0.1 to 50% by weight. 5. A method for producing a dry-coated powder, which comprises coating a fine granular core with a mixed solution containing a water-soluble polymer and at least one physiologically active substance. 6. The method for producing a dry-coated powder according to claim 5, wherein the powder-like powder is sprayed while spraying the mixed liquid. 7. A granule, tablet or capsule containing the dry coated powder according to claim 1.