JPH10182438A - Powdery preparation having nucleus - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a powdery preparation having nucleus small in powder particle diameter and capable of controlling the dissolution of medicine. SOLUTION: This powdery preparation having nucleus is prepared by spray- coating a fine particulate nucleus with a mixture solution containing a water-soluble polymer, such as hydroxypropylcellulose or hydroxypropylmethylcellulose and at least one kind of medicine. The prepared powdery preparation having the nucleus has a particle diameter of substantially <=500μm. The fine particulate nucleus may be spherical and contain crystalline cellulose and a disintegrating agent. The employment of a nucleus containing crystalline cellulose and a saccharide component in the powdery preparation having the nucleus enables to control the dissolution of the medicine. The powdery preparation having the nucleus is used as such or after processed into a granule, tablet or capsule.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a nucleated powder capable of appropriately controlling the dissolution of a physiologically active substance in the fields of foods, pharmaceuticals, agricultural chemicals and the like, a method for producing the same, and a method for controlling the dissolution of a physiologically active substance. .

[0002]

2. Description of the Related Art In general, many studies have been made on drug release control systems (drug delivery systems) for foods, pharmaceuticals, agricultural chemicals, and the like. In particular, in oral dosage forms, granules have less solid differences in gastric emptying rate and absorbability than tablets, and are hardly affected by meals. For this reason, granules are used for oral administration or granules are mixed with tablets [Drug Development and
Industrial Pharmacy (Drug Development a
nd Industrial Pharmacy), 9 (7), 1379-1396 (1983)].

[0003] With regard to granules, JP-A-63-222121
Japanese Patent Application Publication No. JP-A-2005-64139 discloses a method of extruding a drug, hydroxypropylcellulose, and an ethanol-soluble plasticizer to form granules. In this method, a large amount of plasticizer is used to provide flexibility.
Japanese Patent Application Laid-Open No. 63-99009 discloses a method of spraying an aqueous solution or an alcohol solution of a binder while rolling drug-containing solid particles, and spraying hydrophobic solid fine particles which are not easily dissolved in the stomach and intestine. It has been disclosed. In this way, long-lasting granules are obtained.

Japanese Patent Application Laid-Open No. 63-222112 discloses a preparation of a sustained granule containing a drug, an ethanol-insoluble water-soluble polymer, and an ethanol-soluble water-soluble polymer. In this method, a large amount of an ethanol-insoluble water-soluble polymer is required. For example, in this example, 55% or more ethanol-insoluble water-soluble polymer is used. JP-A-63-243036 discloses sustained-release stomach-type granules of calcium silicate and hydroxypropylmethylcellulose. In this method, calcium silicate as a powder is formulated in a dry manner so that the apparent specific gravity is 1.0 or less.

[0005] Further, the present applicant has disclosed in
In Japanese Patent Publication No. 31, a method of obtaining a nucleated granule by spraying a dispersion of a low-substituted hydroxypropylcellulose on a core granule was proposed. The granules obtained by this method have high strength and excellent disintegration. European Patent Publication No. 0452562A2 discloses that at least 50% by weight of microcrystalline cellulose has an average particle size of 1%.
Coating an inert spherical core of 00-1000 μm with a powder containing the active ingredient using an aqueous solution of a binder,
Spherical granules obtained by spraying an aqueous solution or dispersion of a coating agent are disclosed.

[0006] Granules obtained by these methods are characterized in that most of the particle diameter is 500 µm or more.
Further, the granules have a large and uniform particle diameter. Therefore, when coating with an elution control base to control the elution of a drug, coating variation is small and advantageous. However, since the particle size is large, not only is the dispensing property inferior, but also when added to tablets and capsules, the amount of granules to be added varies widely. Furthermore, for the dosage form of granules, a particle size test and a disintegration test are required in the section of “11th Revised Japanese Pharmacopoeia (hereinafter sometimes referred to as JP), General Rules for Preparation 5 Granules”. However, it is difficult to formulate a drug release control that satisfies these requirements.

On the other hand, powders are not regulated by the disintegration test of the Japanese Pharmacopoeia and have a small particle size of 500 μm or less, so that they have excellent dispensing properties as compared with granules, and when mixed with tablets and capsules, Variations in the amount added are reduced. Powders generally have higher gastric emptying speed and absorbability than granules. However, due to the high gastric emptying rate of powder,
Depending on the drug, the blood concentration may increase early and side effects may occur. In addition, among the prior arts related to the granules, a method in which a drug is blended into a core and a drug elution is controlled by, for example, coating with a polymer base is applied to the powder as it is, resulting in large variations in coating and poor coating accuracy. And the amount of coating also increases. Therefore,
It is difficult to precisely control the release of a drug in a powder having a smaller particle size than a granule.

[0008]

SUMMARY OF THE INVENTION An object of the present invention is to provide a powder capable of controlling the dissolution of a drug with high precision even if the particle size is small, and a method for producing the same. It is another object of the present invention to provide granules, tablets and capsules containing the powder.

[0009]

Means for Solving the Problems The present inventors have conducted intensive studies to control the dissolution of drugs in powders.
Spraying a mixed solution containing (1) a water-soluble polymer and (2) a drug on a core with a small particle diameter, and (3) containing a drug in the coating layer, the dispersion of the coating is small and the coating amount is large. And found that the elution of the drug could be controlled appropriately, and completed the present invention.

[0010] That is, the present invention provides a nucleated nucleus in which a fine-grained nucleus is coated with at least one physiologically active substance (hereinafter referred to as a drug) together with a water-soluble polymer, and the particle diameter is substantially 500 µm or less. Provide powder. The fine-grained core may be spherical, and the water-soluble polymer may be a cellulose derivative. Further, the fine-grained core may be a core containing crystalline cellulose and a disintegrant. The present invention also includes a method using the nucleated powder, wherein the method uses a fine-grained nucleus containing crystalline cellulose and a sugar component to control the elution of a physiologically active substance. Further, the present invention provides a granule, tablet or capsule containing the nucleated powder.

In the present specification, “substantially” means that a small amount of particles having a particle diameter outside the above range may be contained as long as the particles are unavoidably mixed. The term “coating” is used to mean not only the case where the entire surface of the nucleus is covered, but also the case where the nucleus is partially covered or the case where it is adsorbed or absorbed. Further, the term “spherical” is not limited to a true spherical shape, but also includes a shape having a curved surface such as an elliptical cross section, an oval shape, and a droplet shape.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION The particle diameter of fine-grained nuclei may be substantially 500 μm or less, and is about 50 to 500 μm, preferably about 100 to 400 μm. As a nucleus having such a particle diameter, for example, 20% of crystalline cellulose
Spherical granulated product of 0 to 300 μm (Abicel SP, manufactured by Asahi Kasei Corporation), 200 to 350 μm of crystalline cellulose (3 parts) and lactose (7 parts)
Spherical granulated product (Non-pareil, manufactured by Freund)
P-7: 3), spherical granules of 200 to 350 μm made of crystalline cellulose (5 parts) and lactose (5 parts) (Freund, non-parrel, hereinafter referred to as NP-5: 5), Lactose (9 parts) and pregelatinized starch (1 part)
50-250 μm agitated granules according to JP-A-61-2
No. 13201, fine particles of 500 μm or less obtained by classifying microcrystalline cellulose spherical granules, processed products such as waxes formed into a spherical shape by spray chilling or melt granulation, processed products such as gelatin bead products of oil components, silica Examples include porous particles such as calcium acid, starch, chitin, cellulose, and chitosan; bulk products such as granulated sugar (sucrose), crystalline lactose, crystalline cellulose, and sodium chloride; and processed products thereof. The nucleus is
It may contain crystalline cellulose and a disintegrant such as Avicel RC (produced by Asahi Kasei Corporation).

The core may contain a drug described later, but the core may not contain the drug because the release of the drug can be controlled by the coating layer containing the drug. Even if the core is fine, it is preferable that the core is spherical in order to reduce the variation in coating and increase the coating amount.

Examples of the water-soluble polymer include ethanol-soluble water-soluble polymers such as hydroxypropylcellulose (hereinafter sometimes referred to as HPC) and polyvinylpyrrolidone; and hydroxypropylmethylcellulose (hereinafter referred to as HPMC). Water-soluble polymers such as methylcellulose, sodium carboxymethylcellulose, sodium polyacrylate, polyvinyl alcohol, sodium alginate, and guar gum. The dissolution of the drug can be controlled by using a water-soluble polymer that is soluble in ethanol and a water-soluble polymer that is insoluble in ethanol, or a water-soluble polymer having a different viscosity.

Preferred water-soluble polymers include HPC, HP
MC, cellulose derivatives such as methylcellulose, 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, 53.4-77.5% by weight, preferably 60-75% by weight.
It contains about 70% by weight. The viscosity of a 2% by weight aqueous solution of HPC at 20 ° C. is usually about 1 to 150,000 cps. As such HPC, Japanese Pharmacopoeia hydroxypropylcellulose is used (hereinafter, the viscosity of HPC is the value of a 2% by weight aqueous solution at 20 ° C.). The HPC used in the present invention differs from the low-substituted hydroxypropylcellulose disclosed in JP-A-2-174931 in the degree of substitution of hydroxypropoxyl groups.

HPMC is a mixed ether in which a methoxyl group and a hydroxypropoxyl group are bonded. HPMC
The methoxyl group content is, for example, 19 to 30% by weight, and the hydroxypropoxyl group content is, for example, 4% by weight.
About 12% by weight. HPMC 2 at 20 ° C
The viscosity of a weight percent aqueous solution is typically on the order of 1 to 40,000 centistokes. As such HPMC, Japanese Pharmacopoeia hydroxypropylmethylcellulose 2208, Japanese Pharmacopoeia hydroxypropylmethylcellulose 2906, Japanese Pharmacopoeia hydroxypropylmethylcellulose 2910 and the like are used. Hydroxypropyl methylcellulose can be used alone or in combination of two or more.

The drug is particularly limited as long as it is administered as a powder.
Not determined. Drugs such as central nervous system drugs
Diazepam, idebenone, aspirin, ibuprof
, Paracetamol, naproxen, piroxicam,
Diclofenac, indomethacin, sulindac, b
Lazepam, nitrazepam, phenytoin, acetamino
Fen, etenzamid, ketoprofen, etc .; cardiovascular system
Drugs include molsidomine, vinpocetine, derap hydrochloride
Lil, propranolol, methyldopa, dipyridamo
Le, furosemide, triamterene, nifedipine, ate
Nolol, spironolactone, metoprolol, pindo
Rolls, captopril, isosorbide dinitrate, etc .; respiratory
Amlexanox, dextromethorph
Fan, theophylline, pseudoephedrine, salbuta
Moles, guaifenicin, etc .; as digestive system drugs,
Benzimidas such as lansoprazole and omeprazole
Zole drugs, cimetidine, ranitidine, pancreatic
, Bisacodyl, 5-aminosalicylic acid, etc .; antibiotics
And cephalexin, cefaclo as chemotherapeutic agents
, Cefradine, amoxicillin, pivapicillin, ba
Campicillin, dicloxacillin, erythromycin,
Erythromycin stearate, lincomycin, doki
Cyclin, trimethoprim / sulfamethoxazo
Metabolic drugs such as serrapeptase and lysochloride
Team, adenosine triphosphate, grippenkura
Amide, potassium chloride, etc .;
Tamin B ₁, Vitamin B_Two, Vitamin B₆,vitamin
C, fursultiamine, vitamin A, vitamin E, Vita
Min D, vitamin K and the like; antacids and the like. this
One or more of these drugs can be used.

In order to increase the strength of the nucleated powder, the coating layer containing the drug may be, for example, a low-substituted hydroxypropylcellulose (hereinafter referred to as LH) described in JP-A-2-174931.
PC) and other additives. As the additive, an additive generally blended 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-cysteine; pregelatinized starch, partially pregelatinized starch, methylcellulose, carboxymethylcellulose, polyvinylpyrrolidone , Pullulan, dextrin, gum arabic, etc .; disintegrators such as carboxymethylcellulose calcium, starches, crosslinked sodium carboxymethylcellulose, crosslinked insolvable polyvinylpyrrolidone; titanium oxide, red iron oxide,
And coloring agents such as tar dyes. Two or more of these additives may be used.

The content of the water-soluble polymer such as HPC and / or HPMC may be within a range in which the dissolution property of the drug in the nucleated powder can be controlled.
%, 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 dissolution property of the drug can be controlled, and is, for example, about 50 to 400 parts by weight based on 100 parts by weight of the core. Coverage is 5
If the amount is less than 0 parts by weight, it is difficult to control the elution of the drug, and if it exceeds 400 parts by weight, the grains grow large and it is difficult to fall within the particle size standard of the powder. The coating layer may be formed of a plurality of layers, and it is sufficient that at least one of the plurality of coating layers contains a drug.

The particle size of the nucleated powder of the present invention is substantially 5
The thickness is not more than 00 μm, preferably 50 to 500 μm, and more preferably 100 to 400 μm. Particle size 500μ
If it exceeds m, the dispensing property tends to decrease as described above. If the particle diameter is smaller than 50 μm, problems such as the powder adhering to the walls of the manufacturing equipment due to static electricity during the manufacturing are likely to occur.

The nucleated powder of the present invention has a core having an appropriate particle size,
Selecting the viscosity grade and content of the water-soluble polymer, for example HPC and / or HPMC, and the ratio of ethanol-soluble water-soluble polymer (for example, HPC) to ethanol-insoluble water-soluble polymer (for example, HPMC) With this, the dissolution property of the drug can be controlled. Further, the dissolution property can be appropriately controlled without much influence of the liquid property in which the drug is dissolved. Further, in the method using a nucleated powder, the elution of a physiologically active substance can be controlled by using a fine-grained nucleus containing crystalline cellulose and a sugar component.

In the method of the present invention, a nucleated powder can be produced by coating the fine granular core with a mixed solution containing a water-soluble polymer and at least one physiologically active substance. The mixture may be a solution or a dispersion. The mixed solution can be prepared using an organic solvent such as water or ethanol, or a mixed solution 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 about 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 increases, and the workability tends to decrease.

The coating layer is not limited to one layer and may be formed of a plurality of layers. In this case, select the blending ratio of the water-soluble polymer and the grade of the viscosity, or sequentially coat using a mixed solution in which the ratio of the drug and other additives is changed, and continuously or stepwise adjust the drug concentration of each layer. May be varied. In that case, as long as the entire coating layer contains 0.1 to 50% by weight of the water-soluble polymer, it may be coated with a mixed solution outside the mixing ratio of 0.1 to 50% by weight. Further, an inactive film may be formed between a plurality of layers by a known method to block each layer containing a drug. When two or more drugs having poor compoundability are compounded, the nuclei may be coated by using the respective liquid mixtures simultaneously or separately.

In another method of the present invention, a powder spray mixed with a drug and / or an additive may be sprayed while spraying the mixture onto the core. In this method, the coating layer can be formed by a simple operation of spraying the powdery spray. The particle size of the dispersion is generally less than or equal to about 100 μm, preferably less than or equal to about 50 μm.

Granulation is performed by coating the nucleus with a mixed solution or the like according to the method described above. The granulation temperature is set within a range that does not impair the stability of the drug. If the stability of the drug is high, there is no need to adjust the temperature of the mixture,
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, a centrifugal flow type coating granulator, a fluid type coating granulator,
Conventional equipment such as a stirring granulator can be used. Specific examples of the centrifugal flow type coating granulation apparatus include, for example, a CF apparatus and Spiral Flow manufactured by Freund, a multiplex manufactured by Powrex, and a new malmé manufactured by Fuji Paudal.

After drying the granulated product, a nucleated powder having a uniform particle size can be obtained through a sieve. Since the shape of the powder generally corresponds to the nucleus, a substantially spherical nucleated powder can be obtained.
As the sieve, for example, a 32 mesh (500 μm) round sieve can be used, and a nucleated powder can be obtained by selecting powders passing through the 32 mesh.

The nucleated powder thus obtained may be coated by a conventional method in order to impart taste masking, enteric solubility, gastric solubility and the like. Examples of the coating agent include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F68,
Castor oil, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate (hereinafter HP-
55), hydroxymethylcellulose acetate succinate, acrylic acid copolymer, carboxymethylethylcellulose, polyvinylacetal diethylaminoacetate, shellac, waxes, and dyes such as talc, titanium oxide, and red iron oxide.

The nucleated powder can be used as a powder as it is. Further, the nucleated powder may be added to granules or tablets in the form of granules or tablets according to a conventional method, or may be a capsule filled in capsules.

[0031]

The nucleated powder of the present invention and the nucleated powder contained in granules, tablets and capsules are excellent in dispensing properties, have a small variation in the amount added, and have a small particle size.
The release property of the drug can be accurately controlled.

[0032]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples, Reference Examples, Comparative Examples, and Experimental Examples, but the present invention is not limited thereto. Example 1 Production of Nucleated Powder 700 g of Avicel SP (200 to 300 μm) was placed in a fluidized coating granulator (FD-3S, manufactured by Powrex Co.), and while controlling the blowing temperature to 70 ° C. and the product temperature to about 40 ° C., By a bottom spray method, a previously prepared bulk liquid having the following composition was sprayed and coated. The spraying was stopped at the time of spraying the specified amount of the bulk liquid, and drying was carried out for 1 minute, and then sieved with a 32 mesh round sieve to obtain 920 g of a nucleated powder. [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 g.

Preparation of nucleated powder for film coating 470 g of the obtained nucleated powder was put into the above-mentioned fluidized coating granulator, and was previously prepared by a bottom spray method while controlling the air blowing temperature at 65 ° C. and the product temperature at about 38 ° C. The obtained film liquid having the following composition was sprayed at a liquid speed of 10 g / min and coated. The spraying was stopped at the time when the prescribed amount of the film liquid was sprayed, and drying was performed for 1 minute, followed by sieving through a 32 mesh round sieve to obtain 480 g of a film-coated nucleated powder. [Film liquid] HPMC (Type 2910, viscosity 6 centistokes) 22.4 g Macrogol 6000 4.6 g Titanium oxide 2.6 g Yellow iron sesquioxide 0.4 g Water 370.0 g.

The particle size of the obtained film-coated nucleated powder was evaluated in accordance with “Japanese Pharmacopoeia General Regulations 11: Examination of powder term / granule size”. Met.

Example 2 Preparation of nucleated powder and film-coated nucleated powder In place of Avicel SP of Example 1, NP-7: 3 (200
(-350 μm) Except for using 700 g, 925 g of a nucleated powder and 480 g of a film-coated nucleated powder were obtained in the same manner as in Example 1. The test result of the particle size of the film-coated nucleated powder was also a fine powder complying with the regulations of the Japanese Pharmacopoeia.

Example 3 Preparation of nucleated powder 70 g of NP-5: 5 (200-350 μm) was added to Mini CF
Machine (manufactured by Freund) and set the rotor speed to 400
rpm, 10 g of lansoprazole, 10 g of magnesium carbonate, 10 g of granulose, and 20 g of corn starch are homogeneously mixed while spraying a mixed solution of water / ethanol in which 1% by weight of HPMC (type 2910) is dissolved at 2 g / min. The spraying agent was sprayed at 4 g / min.
After the spraying was completed, the coating liquid was sprayed to obtain granules.
The granulated product was vacuum-dried at 40 ° C. for 16 hours and sieved using a 32 mesh round sieve. The obtained granulated product was a nucleated powder that passed the particle size test of the Japanese Pharmacopoeia as follows. .

Production of capsule No. 2 hard capsule (weight: 65 m) using 240 mg of the obtained nucleated powder in a capsule filling machine (manufactured by Park Davis).
g) to prepare a capsule.

Example 4 Production of nucleated powder 900 g of lactose and 100 g of pregelatinized starch were mixed with a vertical granulator (FM-VG-, manufactured by Powrex).
After stirring for 1 minute at 400 rpm, water was added and granulated. The granulated product was vacuum-dried at 40 ° C. for 16 hours, and then classified with a sieve of 60 mesh (250 μm) and 200 mesh (74 μm) to obtain a core of 74 to 250 μm. The obtained core (760 g) was coated in the same manner as in Example 1 using a previously prepared bulk liquid having the following composition to obtain 970 g of a nucleated powder. [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 conformed to the particle size test of the Japanese Pharmacopoeia as follows.

Preparation of tablets 500 g of the obtained nucleated powder, 200 g of crystalline cellulose,
49 g of corn starch and 11 g of magnesium stearate were mixed by rotating 10 times with a tumble mixer (manufactured by Showa Chemical Machinery Co., Ltd .; TM-15). Pure Press Collect 12HUK (Kikusui Seisakusho)
And a tablet having a compression pressure of 1 ton / punch using a 9.5 mmφ flat punch. The weight of the tablet is 380mg per tablet and the thickness is 4m
m and a disintegration time of 2 minutes was obtained.

Example 5 Preparation of nucleated powder Granulose was sieved to obtain a core of 300 to 400 μm. 2670 g of the nucleus is CF machine (Freund: CF-360)
And the prepared bulk liquid having the following composition was sprayed at 10 ml / min and granulated at a rotor rotation speed of 100 rpm.
The granulated product was vacuum-dried at 40 ° C. for 16 hours and sieved with a 32-mesh round sieve. [Bulk liquid] Serrapeptase 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 conformed to the particle size test of the Japanese Pharmacopoeia as follows.

Preparation of Enteric-coated Nucleated Powder 480 g of the above-mentioned nucleated powder was placed in FD-3S, and the blast temperature was 6
The temperature was controlled at 0 ° C. and the exhaust temperature was about 40 ° C., and an enteric film liquid prepared in advance and having the following composition was sprayed at 15 g / min by a top spray method to obtain an enteric nucleated powder. HP-55 116 g Shellac 28 g Macrogol 6000 6 g Ethanol 563 g Acetone 1315 g.

The obtained enteric coated nucleated powder is as follows:
It conformed to the Japanese particle size test.

Further, the enteric nucleated powder was classified with a sieve of 60 mesh (250 μm), and an acid resistance test was performed on the residual product of 60 mesh. The test method conformed to the first method of the Japanese Pharmacopoeia General Test Method 46 Dissolution Test Method. Since the particle size of the enteric nucleated powder was small, the mesh of the rotating basket used was 80 mesh. JP / General Test Method 38 First of Collapse Test Methods
As a result of using the solution as a test solution, the serrapeptase content after one hour of operation was 93%, and acid resistance was ensured.

Example 6 Production of nucleated powder 800 g of lactose and Avicel RC (manufactured by Asahi Kasei Corporation) 2
00 g of a vertical granulator (FM-VG-1).
0), 350 ml of water with stirring at 250 rpm
Was added and kneaded. A sanding machine with a screen in which the kneaded material is opened by punching of 0.4 mmφ (Kikusui Seisakusho: RG
-C125) for extrusion granulation.

The granulated product was vacuum-dried at 40 ° C. for 16 hours, and the dried product was sized using a power mill (P-3, manufactured by Showa Kagaku Kikai Seisakusho, Ltd.) equipped with a screen having a 1 mmφ punch.
It was a cylindrical core.

Using 700 g of the obtained core, 900 g of a nucleated powder was obtained in the same manner as in Example 1. The obtained nucleated powder conformed to the particle size test of the Japanese Pharmacopoeia as described below.

Examples 7 to 9 In the same manner as in the preparation of the nucleated powder of Example 1, except that the grade and amount of HPC in the bulk liquid were changed as follows:
A nucleated 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.

All of the obtained nucleated powders conformed to the particle size test of the Japanese Pharmacopoeia as follows. Sieve Example 7 Example 8 Example 9 No. 18 (850 μm) residue 0% 0% 0% No. 30 (500 μm) residue 1% 1% 0% No. 200 (75 μm) residue 99% 99% 100% No. 200 (75 μm) ) Passing 0% 0% 0%.

Examples 10 to 12 Example 1 was repeated except that HPC in the bulk liquid was replaced with HPMC and the amounts of HPMC and lactose used were varied as follows.
A nucleated powder was produced in the same manner as in the production of a nucleated powder of No. Example 10 Example 11 Example 12 HPMC (Type 2910) 100 g 120 g 50 g Lactose 50 g 30 g 100 g.

All of the obtained nucleated powders were suitable for the particle size test of the Japanese Pharmacopoeia as follows. Sieve Example 10 Example 11 Example 12 No. 18 (850 μm) residue 0% 0% 0% No. 30 (500 μm) residue 2% 3% 1% No. 200 (75 μm) residue 98% 97% 99% No. 200 (75 μm) ) Passing 0% 0% 0%.

Comparative Example 1 Lactose of Example 6 was reduced by 10 g, and vinpocetine was reduced to 10 g.
Except for increasing the amount, a powder was obtained in the same manner as in the production of the nucleated powder of Example 6. The obtained powder conformed to the particle size test of the Japanese Pharmacopoeia as described below.

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

Experimental Example 1 The dissolution properties of the nucleated powders obtained in Examples 1 to 3 and the powders obtained in Comparative Examples 1 and 2 were measured by the Japanese Pharmacopoeia, Dissolution Test Method 2 (100
rpm). The test solution used was JP 1st solution having good pinpocetine solubility. Table 1 shows the test results.

[0056]

[Table 1] As is clear from Table 1, the rise of the dissolution rate of the nucleated powder of each example due to the liquid property of the test solution is not as sharp as that of the powder of the comparative example. It is suggested that there is no sharp rise.

Experimental Example 2 The dissolution property of the nucleated powder obtained in Example 1 and Examples 7 to 9 was examined in the same manner as in Experimental Example 1. Table 2 shows the results.

[0058]

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

Experimental Example 3 The dissolution property of the nucleated powder obtained in Example 1 and Examples 10 to 12 was examined in the same manner as in Experimental Example 1. Table 3 shows the results.

[0060]

[Table 3] From Table 3, it was confirmed that the dissolution property could 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 nucleated powder. The obtained powder passed the particle size test of the Japanese Pharmacopoeia as follows.

Example 14 400 g of calcium silicate (porous powder, manufactured by Tokuyama Soda Co., Ltd.) was put into the fluidized coating granulator of Example 1, and the air temperature was controlled at 80 ° C. and the product temperature was controlled at about 35 ° C. Meanwhile, a 5% concentration aqueous HPMC solution was sprayed at a liquid speed of 20 g / min by a top spray method to granulate. When 250 g of HPMC was sprayed, granulation was stopped, and drying was performed for 5 minutes, and then 42 mesh (350 μm)
And 177 μm using a 80 mesh (177 μm) round sieve
３５０350 μm nuclei were obtained.

130 g of the obtained core was put into the above-mentioned fluidized coating granulator, and while controlling the air blowing temperature to 60 ° C. and the product temperature to about 35 ° C., 5% ethyl cellulose (viscosity grade: 7 cp) by a bottom spray method. Was sprayed at a liquid speed of 8 g / min and coated. The coating was stopped when 39 g of ethyl cellulose was sprayed, and the coating was dried as it was for 3 minutes, and then a coated core was obtained using a 32 mesh (500 μm) round sieve.

Using the previously prepared bulk liquid having the following composition, 60 g of the obtained coated core was coated in the same manner as in Example 1 to obtain 80 g of a nucleated 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

The obtained nucleated powder conformed to the particle size test of the Japanese Pharmacopoeia as follows.

Claims (6)

[Claims] 1. A nucleated powder having a fine-grained core coated with at least one physiologically active substance together with a water-soluble polymer, and having a particle diameter of substantially 500 μm or less. 2. The nucleated powder according to claim 1, wherein the fine-grained core is spherical. 3. The nucleated powder according to claim 1, wherein the water-soluble polymer is a cellulose derivative. 4. The nucleated powder according to claim 1, wherein the fine-grained core is a core containing crystalline cellulose and a disintegrant. 5. A method using the nucleated powder according to claim 1, wherein the elution of a physiologically active substance is controlled by using fine-grained nuclei containing crystalline cellulose and a sugar component. 6. A granule, tablet or capsule containing the nucleated powder according to claim 1.