JPH04283520A - Spherical nuclei and spherical granule - Google Patents

Abstract

PURPOSE:To provide the subject specified pherical nuclei and the subject spheri cal granule obtained by using the spherical nuclei. CONSTITUTION:A pharmaceutically inactive spherical nuclei containing 10-70wt.% crtstalline cellulose having 60-375 average polymerization degree and 10-90wt.% water-soluble additive ius used and the surface thereof is coated with a drug. The above-treated nuclei is then further film coated to obtain the objective spherical granule. In comparison with the conventional spherical nuclei, the above-obtained spherical nuclei has a proper water absorption capacity and a low abrasion wear and coagulation between granules can be reduce therefor. The efficiency of coating is high and the rate of power coating is also high. In addition, the spherical granule of this invention is resistive to destruction due to intestinal motion in comparison with a phperical granule prepared by using the conventional spherical nuclei and a desired dissolution pattern, therefor, can be readily obtained.

Description

[Detailed description of the invention]

0001

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to spherical nuclei and spherical granules produced using spherical nuclei.

0002

BACKGROUND OF THE INVENTION Pharmaceuticals are often coated with a film as a means for controlling the release of long-acting pharmaceuticals, as a means for enteric coating, as a means for improving the stability of active pharmaceutical ingredients, or as a means for masking taste. When applying film coating to granules, in order to increase the coating efficiency and coat with good reproducibility, a powder consisting of drug and excipients is coated on a core that is nearly spherical in shape. Taelin granules are often used. In this case, it has been common to use Nonpareil (trade name, manufactured by Freund Sangyo Co., Ltd., ingredients: white sugar or white sugar/starch) as described in Japanese Patent Application Laid-Open No. 61-1614.

[0003] Furthermore, JP-A-61-213201 relates to crystalline cellulose spherical granules that can be used as cores for coating, and has an apparent density of 0.65 g/ml or more and a sphericity of 0.8 or more. It is stipulated that Furthermore, in JP-A-63-301816, spherical core granules made of crystalline cellulose are used in the examples, but the particle size range is 2.
There is no other description other than 0 to 32 mesh. Furthermore, these documents do not contain any description of crystalline cellulose as a raw material. In addition, the sphericity mentioned in the former only refers to the length of the minor axis/length of the major axis, and it is unclear whether it defines individual particles or the entire particle. These have no regulations regarding water absorption and abrasion degree, which are considered important for spherical nuclei, and there is no description of water absorption.

0004

However, when a core made of sucrose or sucrose/starch is used as a core, the core is coated with a drug-containing powder using a binding liquid and then coated with a film. In the formulation method used, white sugar, the main component of the core, dissolves in the binding liquid, making the surface sticky, and the core is highly abrasive. There were problems such as adhesion of granules to the wall and deterioration of yield and coating efficiency. In addition, when granules are administered into the body, white sugar, which is the main component of the nucleus, gradually elutes and the strength decreases, so when force is applied due to intestinal movement, a coating is applied to control the elution. There was a problem that the layer was broken and it was difficult to obtain the desired elution pattern.

[0005] Although the conventional spherical core made of crystalline cellulose has the advantage of reducing the degree of abrasion and improving the strength of the core, the water absorption rate of the core is too high and it is difficult to coat the powder containing the drug. However, there are disadvantages in that a large amount of binding liquid is required and the powder coating speed is slow.

[0006]

[Means and effects for solving the problem] The present inventors
As a result of intensive studies, the average degree of polymerization of the core was 60 to 375.
By using a pharmaceutically inert spherical core containing 10-70% of crystalline cellulose and 10-90% of a water-soluble additive, the above problems were solved and the present invention was completed.

That is, in the present invention, the average degree of polymerization is 60 to 37.
a pharmaceutically inert spherical core containing 10-70% of crystalline cellulose and 10-90% of a water-soluble additive;
and a spherical granule having a powder layer containing a drug around the spherical core, and a coating layer of a coating agent around the powder layer. The spherical nucleus of the present invention does not disintegrate and has high strength, so when spherical granules using this are administered into the body,
Since the granules are less likely to be destroyed by intestinal movements, there is an advantage that the coating layer for controlling elution is less likely to be destroyed, making it easier to obtain a desired elution pattern.

[0008] In the present invention, the core has an average degree of polymerization of 60 to 3.
75% crystalline cellulose (hereinafter abbreviated as crystalline cellulose) and 10% to 70% water-soluble additives.
Since we use a pharmaceutically inactive spherical core containing 0%, the spherical core has moderate water absorption, so compared to conventional sucrose and sucrose/starch cores, the aggregation of granules is 1. /10 or less, and since adhesion of granules to the machine wall can be prevented, there is an advantage that strict control of conditions such as binding liquid spray rate and powder supply rate is not necessary. Furthermore, since there is almost no wear and tear during coating, there is an advantage that coating efficiency is high. In addition, compared to conventional spherical cores made of crystalline cellulose, the spherical cores of the present invention contain water-soluble components and have appropriate water absorption properties, resulting in less consumption of binding liquid and faster powder coating speed. There are advantages.

The present invention will be explained in detail below. The spherical core in the present invention is composed of 10 to 70%, preferably 10 to 50%, of crystalline cellulose having an average degree of polymerization of 60 to 375.
, must contain 10-90% water-soluble additives and be pharmaceutically inert. The term "pharmaceutically inactive" as used herein means that it does not contain any medicinal ingredients. Further, preferably the average particle size is 100 to 1000 μm, preferably 100 μm.
~700 μm, particularly preferably 150 to 500 μm, apparent tapping density is 0.65 g/ml or more, preferably 0.75 g/ml or more, and sphericity is 0.7 or more, preferably 0.8 or more. , and its water absorption rate is 5~
15%, the degree of abrasion is 1% or less, preferably 0.8% or less, and substantially does not disintegrate in water. If the crystalline cellulose content is 70% or more, the water absorption rate of the core becomes too high, and a large amount of binding liquid is required when coating the drug-containing powder. Furthermore, the adhesion of the powder to the core becomes weaker. Furthermore, if the content of crystalline cellulose is less than 10%, the degree of abrasion of the core becomes large and the water absorption rate becomes too low, which is not preferable. Water-soluble additives are necessary to suppress the water absorption rate of the cores and increase the adhesion of the powder to the cores when the binding liquid is sprayed onto the spherical cores to coat the powder. 90% is appropriate. If the content of the water-soluble additive is 90% or more, the degree of abrasion of the core becomes large and the water absorption rate becomes too low. Further, if it is less than 10%, the water absorption rate of the core becomes large and the adhesion becomes low when the binding liquid is sprayed onto the core, which is not preferable because the adhesion of the powder becomes weak.

[0010] The average particle diameter of the spherical core is determined by the amount of drug-containing powder, the amount of coating, and the target particle size of the spherical granules, but if it is less than 100 μm, it is difficult to coat the powder and the granules are If the diameter is 1000 μm or more, the amount of drug to be coated will be limited, which is not preferable. Preferably 100 μm to 700 μm, particularly preferably 150 μm
It is μm to 500 μm. In addition, the tapping apparent density is preferably 0.65 g/ml or more; if it is less than that, the fluidity of the core will be poor during powder coating.
Uniform coating is difficult. In addition, aggregation of granules increases. Particularly preferably, it is 0.75 g/ml or more. Furthermore, if the sphericity is less than 0.7, the sphericity of the spherical granules made using it will be poor, which is not preferable in terms of product aesthetics or control of drug elution rate. Particularly preferably, it is 0.8 or more. In addition, if the water absorption rate of the spherical core is less than 5%, when the binding liquid or coating liquid is sprayed, the granules will agglomerate and adhere to the machine wall.
When the water absorption rate is greater than 15%, the amount of liquid absorbed by the core increases, resulting in a disadvantage that the coating speed of the powder becomes slow. Furthermore, if the degree of abrasion is greater than 1%, abrasion occurs during coating, resulting in poor yield and coating efficiency. In addition, it maintains its strength by not substantially disintegrating in water, and when administered into the body, it prevents the destruction of the spherical granules and maintains the desired elution pattern until drug elution is completed.

The components of the spherical nucleus of the present invention will be described.
The crystalline cellulose used can be obtained by acid hydrolysis, alkaline oxidative decomposition, or a combination of both, or by mechanical treatment such as crushing after the above chemical treatment. The average degree of polymerization must be from 60 to 375. Preferably it is 100-300. The term "crystalline cellulose" as used herein refers to cellulose having a crystallinity of 10% or more as determined by X-ray diffraction. Preferably it is 40% or more. In addition, the water absorption amount is 1.0 to 2.8ml.
/g, the 200 mesh fraction is preferably 80% or less. When the average degree of polymerization is less than 60, the degree of wear of the spherical core increases because the entanglement of cellulose molecules decreases.
On the other hand, if it is larger than 375, fibrous properties appear, making it difficult to form a sphere, which is not preferable. The water-soluble additives referred to here are pharmaceutically inert additives that can dissolve approximately 1 g or more in 100 g of water, including sugars such as lactose, sucrose, D-mannitol, and glucose, dextrin, and alpha - Processed starch products such as converted starch, polyvinylpyrrolidone,
These include synthetic polymers such as polyethylene glycol, and cellulose derivatives such as methylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose. Additives other than crystalline cellulose and water-soluble additives may be pharmaceutically inert, such as starches such as cornstarch, potato starch, dicalcium phosphate, aluminum silicate, etc. and fatty acids such as magnesium stearate.

The spherical core of the present invention is produced, for example, by the following method. A powder containing 10 to 70% crystalline cellulose and 10 to 90% water-soluble additives is placed in a mixing agitation granulator, and distilled water is added and kneaded. Instead of distilled water, an aqueous solution of hydroxypropylcellulose, starch paste, polyvinylpyrrolidone, etc. may be used as the binding liquid. Thereafter, the kneaded product is extruded and granulated using an extrusion granulator. Thereafter, the extrudate is transferred to a rolling coating device, spheroidized, dried and, if necessary, sieved to obtain spherical cores. In this method, the kneaded material is strongly consolidated during extrusion granulation, so even when the content of crystalline cellulose is small, it has the advantage that spherical nuclei with a low degree of wear can be produced. The water-soluble additive also acts as a lubricant for smooth extrusion during extrusion granulation. As described above, the spherical core of the present invention has the advantage that it can be manufactured by combining conventionally used inexpensive equipment without using expensive equipment.

The method for producing spherical granules of the present invention will be described. Conventionally, coating of powder layers containing drugs and film coating were often performed using organic solvents, but due to environmental and
Due to issues such as cost and residue, attempts are being made to gradually switch from organic solvent systems to aqueous solutions and aqueous suspension systems. Therefore, it is preferable to use an aqueous solution system or an aqueous suspension system as described below, and there is also the advantage that the effect of the spherical nuclei of the present invention is more pronounced when carried out in an aqueous system. While rolling the spherical core in a rolling coating device, an aqueous binder-containing solution is continuously sprayed, and at the same time, a powder consisting of a drug and, if necessary, an excipient is supplied to the spherical core. Coating the body to form elementary granules, or spraying a solution in which the drug is dissolved or suspended in an aqueous binder solution while fluidizing the spherical core in a fluidized bed coating machine to contain the drug in the spherical core. coated with powder,
Let it be an elementary granule. If necessary, after drying the elementary granules, an aqueous solution of a coating agent or an aqueous suspension of a coating agent is sprayed and dried to form a coating for moisture-proofing, bitterness masking, enteric properties, long-acting properties, etc. Form layers to form spherical granules. Furthermore, when coating the powder containing the drug, an aqueous solution or suspension of the coating agent may be simultaneously sprayed.

The amount of powder used for coating varies depending on the amount of drug to be administered and the size of the final granules, but is approximately 5 to 300% of the spherical core. However, it may be more if necessary. In addition, although the type of drug does not matter, water-soluble drugs dissolve in an aqueous binder solution and become sticky, making it easier for granules to adhere to each other and agglomerate, so the effect of using the spherical core of the present invention is more pronounced. Become.

As a binder, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose
cellulose derivatives such as cellulose (HPMC), methylcellulose, sodium carboxymethylcellulose, starch pastes, pregelatinized starch and other processed starch products,
Preferred are aqueous solutions of polysaccharides such as gum arabic and pullulan, synthetic polymers such as polyvinylpyrrolidone (PVP), and saccharides such as sugar syrup. When the drug is water-soluble, the aqueous drug solution itself may be used as the aqueous binder solution. Further, when using an organic solvent, PVP, HPC, etc. may be dissolved in the organic solvent.

Examples of excipients include celluloses such as crystalline cellulose and low-substituted hydroxypropyl cellulose;
Starches such as corn starch (CS), pregelatinized starch, partially pregelatinized starch, lactose, sucrose,
Examples include sugars such as D-mannitol, and inorganic substances such as talc, silicic anhydride, and aluminum silicate. As the coating machine, a conventional coating machine such as a centrifugal fluid coating machine, a fluidized bed coating machine, a rolling fluidized bed coating machine, or a pan type coating machine can be used.

[0017] As the aqueous solution of the coating agent, HPM
Examples include aqueous solutions of C, HPC, PVP, polyvinyl alcohol, polyethylene glycol, and the like. The aqueous suspension of the coating agent is a suspension of a water-insoluble coating agent, such as ethyl cellulose (E
C), hydroxypropyl methyl cellulose sphthalate, cellulose acetate phthalate, carboxymethyl ethyl cellulose, cellulose acetate, cellulose acetate butyrate, hydroxypropyl methyl cellulose acetate succinate Examples include aqueous suspensions of celluloses such as carbonate, acrylic copolymers, vinyl copolymers, shellac, silicone resins, and the like. Commercially available products include, for example, TC-5 (HPMC, manufactured by Shin-Etsu Chemical Co., Ltd.) and EC-N-10F (EC, manufactured by Shin-Etsu Chemical Co., Ltd.).
, Aquacoat (EC aqueous suspension, manufactured by FMC, USA), Eudragit L-30D-55, Eudragit NE30D
(Both are aqueous suspensions of acrylic copolymers, manufactured by Rehm Pharma, Germany). These coating agents may be used alone or in combination of two or more. Furthermore, when an organic solvent is used, a solvent system in which the above-mentioned coating agent is dissolved is used. A mixture of water and an organic solvent miscible with water such as ethanol or acetone may also be used. Further, water-soluble substances, plasticizers, stabilizers, colorants, drugs, etc. for controlling the elution rate may be added as necessary. Although the amount of the coating layer varies depending on the purpose of coating, it is about 1 to 50%, preferably about 2 to 30%, based on the elementary particles.

A powder layer and a coating layer of a coating agent may be further formed on the obtained spherical granules. The obtained spherical granules may be filled into capsules by a known method, or mixed with appropriate excipients and compressed to form tablets.

[0019]

[Examples] The present invention will be explained below with reference to Examples. The methods for evaluating the physical properties of crystalline cellulose, spherical nuclei, and spherical granules are as follows. The crystalline cellulose used here had a crystallinity of 10% or more. Crystalline Cellulose/Average Degree of Polymerization Industrial and Engineer
ing Chemistry; vol. 42, p50
2 (1950) according to the copper ammonium solution viscosity method.・Water absorption (ml/g) According to the oil absorption measurement method described in JIS K5101,
Use distilled water instead of oil. The end point is the point at which the water begins to separate from the water after the whole becomes a single lump.・200 mesh fraction (%) A mesh size of 75 was obtained using a low-tap sieve shaker made by Yanagimoto Seisakusho.
Sample 3 using a μm (200 mesh) JIS standard sieve.
This is the residue on the sieve after sieving 0g for 30 minutes.

Spherical core/average particle size (μm) Using a low-tap sieve shaker manufactured by Yanagimoto Seisakusho, 30 g of sample was sieved for 10 minutes using a JIS standard sieve, and the cumulative particle size of 50% by weight was determined as the average particle size. do.・Tapping apparent density (g/ml) Fill a 100ml measuring cylinder with 30g of sample,
Tap about a few times and ask. The number of repetitions is 3, and the average value is taken. - Take microscopic photographs of 100 particles with sphericity, determine the short axis/long axis ratio of each, and take the average value.・Water absorption rate (%) While rotating 400 g of spherical cores (solid content equivalent) in a centrifugal fluid coating device [CF-360, manufactured by Freund Sangyo Co., Ltd.], a 3% HPC (low viscosity type) aqueous solution was added. Spray at a rate of 6 g/min. The process is continued until the nuclei begin to adhere to each other, which is defined as the end point, and the required liquid weight (g) is determined. The water absorption rate is expressed by the following formula. Note that the water content in the formula is the water content originally contained in the spherical core.

[0021]

[Math 1]

・Abrasion degree (%) 10g of sample was placed in the Kayagaki type abrasion measurement machine, and the rotation speed was 25 rpm.
Rotate for 15 minutes to represent weight loss due to powdering. The number of repetitions is 3, and the average value is taken. Spherical granules/coating efficiency (%) Divide the amount of spherical granules recovered by the total amount of raw materials used.・Degree of agglomeration (%) Disperse spherical granules on paper, count the number of agglomerated granules, and divide by the total number. Performed with n=1,000.

[0023]

[Example 1] 400 g of crystalline cellulose (a) shown in Table 1
, 600 g of 200 mesh lactose (manufactured by DMV) were mixed in a plastic bag, placed in a planetary mixer 5DM-R (manufactured by Shinagawa Seisakusho), added with 0.7 kg of distilled water, and kneaded for 5 minutes. Thereafter, it is extruded using an extrusion granulator RG-5 type (manufactured by Kikusui Seisakusho, screen diameter: 0.5 mm). Take 0.6 kg of extrudate and use Marmerizer-Q-
230 (manufactured by Fuji Paudal Co., Ltd.), and rolled at 500 rpm for 20 minutes while spraying distilled water little by little to form spheres. Fluidized bed granulator UNI-GLA for wet spheres
Pour into TT (manufactured by Okawara Kakoki Co., Ltd.) at an inlet temperature of 60
It was dried at °C and sieved with 16 mesh (1 mm opening) to obtain a spherical core (A). Table 2 shows the physical properties of the obtained spherical nucleus (A).
Shown below.

[0024]

[Example 2] Using crystalline cellulose (b) shown in Table 1,
A spherical core (B) was obtained in the same manner as in Example 1 except that the amount of water added was reduced. Table 2 shows the physical properties of the obtained spherical nucleus (B).
Shown below.

[0025]

[Example 3] Using crystalline cellulose (c) shown in Table 1,
A spherical core (C) was obtained in the same manner as in Example 1 except that the amount of water added was reduced. Table 2 shows the physical properties of the obtained spherical nucleus (C).
Shown below.

[0026]

[Example 4] Using crystalline cellulose (d) shown in Table 1,
A spherical core (D) was obtained in the same manner as in Example 1 except that the amount of water added was increased. Table 2 shows the physical properties of the obtained spherical nucleus (D).
Shown below.

[0027]

[Comparative Example 1] Using crystalline cellulose (e) shown in Table 1,
A spherical core (E) was obtained in the same manner as in Example 1 except that the amount of water added was reduced. Table 2 shows the physical properties of the obtained spherical nucleus (E).
Shown below.

[0028]

[Comparative Example 2] Using crystalline cellulose (f) shown in Table 1,
A spherical core (F) was obtained in the same manner as in Example 1 except that the amount of water added was increased. Table 2 shows the physical properties of the obtained spherical nucleus (F).
Shown below.

[0029]

[Example 5] 400 g of the spherical core (A) of Example 1 was coated with a centrifugal fluid coating device [manufactured by Freund Sangyo Co., Ltd., CF
-360], air temperature 40℃, rotor rotation speed 1
60 rpm, HPC (low viscosity type) aqueous solution (3%
W/V) was sprayed at a rate of 10 ml/min, a powder having the following composition was supplied while monitoring the granulation state, and powder coating was performed. The granules are then removed and dried at 40° C. for 16 hours. Next, the fine powder was cut through a sieve with an opening of 106 μm to obtain elementary granules.

Powder composition Theophylline (manufactured by Wako Pure Chemical Industries, Ltd.) 50g white
Sugar (manufactured by Kyushu Sugar Co., Ltd.) 100gC
S (manufactured by Nippon Star Chemical Co., Ltd.) 50g, the elementary granules were placed in a CF-360 device, and the air temperature was 60°C.
The aqueous suspension having the following composition was sprayed at a rate of 20 ml/min at a rotational speed of 200 rpm to form a sustained release coating.

Aqueous suspension Aquacoat 400g (EC aqueous suspension, 30% W/V, manufactured by FMC, USA) Triethyl citrate (manufactured by Wako Pure Chemical Industries, Ltd.) 25g
After coating, put it in a dryer at 60℃ for 1 hour.
Spherical granules were obtained. Table 3 shows the measurement results of the time (T (minutes)) required from the start of supply of the binding liquid to the end of powder coating, the degree of aggregation of the obtained spherical granules, and the coating efficiency.

[0032]

Examples 6 to 8 Spherical granules were obtained in the same manner as in Example 5, except that spherical nuclei (B), (C), and (D) were used. Table 3 shows the measurement results of T (min), degree of agglomeration of spherical granules, and coating efficiency.

[0033]

Comparative Examples 3 and 4 Spherical granules were obtained in the same manner as in Example 5, except that spherical nuclei (E) and (F) were used. T (minutes)
Table 3 shows the measurement results of the degree of agglomeration and coating efficiency of the spherical granules.

[0034]

[Example 9] A spherical nucleus (G
) was obtained. Table 5 shows the physical properties of the obtained spherical nucleus (G).

[0035]

[Example 10] Spherical nuclei (
H) was obtained. Table 5 shows the physical properties of the obtained spherical nucleus (H).

[0036]

[Example 11] Spherical nuclei (
I) was obtained. Table 5 shows the physical properties of the obtained spherical core (I).

[0037]

[Comparative Example 5] Using the formulation (j) shown in Table 4, spherical nuclei (J
) was obtained. Table 5 shows the physical properties of the obtained spherical nucleus (J).

[0038]

[Comparative Example 6] Using the recipe (k) shown in Table 4, the spherical nuclei (K
) was obtained. Table 5 shows the physical properties of the obtained spherical nucleus (K).

[0039]

[Comparative Example 7] Nonpareil-101 (commercial product, manufactured by Freund Sangyo Co., Ltd., trade name) 42 mesh to 32 mesh was used as the spherical core (L). The composition of the spherical nucleus (L) is shown in Table 4 (l
), and the physical properties are shown in Table 5.

[0040]

[Comparative Example 8] Nonpareil-103 (commercial product, manufactured by Freund Sangyo Co., Ltd., trade name) 42 mesh to 32 mesh was used as the spherical core (M). The composition of the spherical nucleus (M) is shown in Table 4 (m
), and the physical properties are shown in Table 5.

[0041]

[Examples 12 to 14] Spherical nuclei (G) and (H) shown in Table 5
, (I) was used in the same manner as in Example 5 to obtain spherical granules. Table 6 shows the measurement results of T (min), degree of agglomeration of spherical granules, and coating efficiency.

[0042]

[Comparative Examples 9 to 12] Spherical nuclei (J), (K) shown in Table 5,
Spherical granules were obtained in the same manner as in Example 5 except for using (L) and (M). Table 6 shows the measurement results of T (min), degree of agglomeration of spherical granules, and coating efficiency.

[0043]

[Example 15] 500 g of the spherical cores (A) shown in Table 2 were coated in a fluidized bed coating machine (manufactured by Okawara Kakoki Co., Ltd., UNI
GLATT), and the following drug aqueous solution was sprayed at a rate of 10 ml/min to coat the drug while the inlet temperature was set to 60° C. and the solution was allowed to flow. Drug solution composition Sulpirin (manufactured by Hoei Yakuko Co., Ltd.) 100g HPC (
Low viscosity type) 5g distilled water
145g Next, for bitterness masking, add TC-5 (
Shin-Etsu Chemical Co., Ltd.) aqueous solution (10% W/V) 150ml
Spray at a rate of 10 ml/min. The granules are then removed and dried at 40° C. for 16 hours. Next, the fine powder was cut through a sieve with an opening of 106 μm to obtain spherical granules. Table 7 shows the measurement results of the degree of agglomeration and coating efficiency of the spherical granules.

[0044]

[Comparative Example 13] Example 1 except for using a spherical nucleus (L)
The procedure was repeated in the same manner as in 5 to obtain spherical granules. Table 7 shows the measurement results of the degree of agglomeration and coating efficiency of the spherical granules.

[0045]

[Example 16] 400 g of the spherical nucleus (I) shown in Table 5 was coated with a centrifugal fluid coating device [manufactured by Freund Sangyo Co., Ltd., C
F-360], the air temperature was set to 40°C, the rotor rotation speed was set to 160 rpm, and while spraying 100 ml of polyvinylpyrrolidone (manufactured by BASF, K-30) aqueous solution (6% W/V), powder having the following composition was added. powder coating. The granules are then removed and dried at 40° C. for 16 hours. Next, the fine powder was cut through a sieve with an opening of 106 μm to obtain elementary granules.

Powder composition Riboflavin (Wako Pure Chemical Industries, Ltd.)
20g Lactose (manufactured by DMV, 200 mesh) 60g C S (manufactured by Nippon Deka Chemical Co., Ltd.)
20g Next, put the elementary granules into a CF-360 device and set the air temperature to 60.
℃, the rotor rotation speed is 200 rpm, and an aqueous suspension having the following composition is sprayed at a rate of 15 ml/min to perform coating.

Aqueous suspension composition Eudragit L-30D-55 300g (3
0% W/V, manufactured by Lehm Pharma, Germany) Talc (manufactured by Wako Pure Chemical Industries, Ltd.) 15 g Triethyl citrate (manufactured by Wako Pure Chemical Industries, Ltd.) 9 g Distilled water 136
g After coating, it was dried at 40°C for 16 hours to obtain enteric coated spherical granules. Table 8 shows the measurement results of the degree of aggregation and coating efficiency of the enteric coated spherical granules obtained.

[0048]

[Comparative Example 14] Example 1 except for using a spherical nucleus (M)
The procedure was repeated in the same manner as in 6 to obtain spherical granules. Table 8 shows the measurement results of the degree of agglomeration and coating efficiency of the spherical granules.

[0049]

[Example 17] After producing elementary granules in the same manner as in Example 16,
The elementary granules are placed in a CF-360 apparatus, the air temperature is set to 60 DEG C., the rotor rotation speed is set to 200 rpm, and an aqueous suspension having the following composition is sprayed at a rate of 15 ml/min to form a sustained release coating. Aqueous suspension Aquacoat 300g (EC aqueous suspension, 30% W/V, manufactured by FMC, USA) Mybaset 9-40 25g (glycerin acetic acid fatty acid ester, manufactured by Koyo Shokai Co., Ltd.)
After coating, put it in a dryer at 60℃ for 1 hour.
Obtain spherical granules.

[0050]

[Comparative Example 15] Elementary granules were produced in the same manner as in Comparative Example 14. Thereafter, the same procedure as in Example 17 is carried out to obtain spherical granules.

[0051]

[Test Example 1] Approximately 300 sustained-release spherical granules obtained in Example 17
mg (equivalent to 10 mg of riboflavin) after a light meal,
The drug is administered with 100 ml of water, and urine is collected every hour to quantify riboflavin by high-performance liquid chromatography to determine the urinary excretion rate over time (n=5). The results are shown in Table 9.

[0052]

[Test Example 2] Similar to Test Example 1, the spherical granules obtained in Comparative Example 15 were tested and the results are shown in Table 9. Compared to Test Example 1, in Test Example 2, the peak of the discharge rate was faster and higher, and the disappearance was also faster. This means that because the granules are destroyed in the body by intestinal movements, the drug dissolves quickly, making it difficult to maintain sustained release. In contrast, Test Example 1 exhibited sustained release properties. In addition, in the dissolution test using the paddle of the Japanese Pharmacopoeia (11 stations), Example 17
There was almost no difference in the elution rate of the spherical granules of Comparative Example 15 and Comparative Example 15.

[0053]

[Table 1]

[0054]

[Table 2]

[0055]

[Table 3]

[0056]

[Table 4]

[0057]

[Table 5]

[0058]

[Table 6]

[0059]

[Table 7]

[0060]

[Table 8]

[0061]

[Table 9]

[0062]

Effects of the Invention: By using the spherical core of the present invention, which has the characteristics of moderate water absorption and high strength, the core is coated with drug-containing powder and further coated with a coating agent to form a spherical core. When making granules, the aggregation of granules is reduced to about 1/10 compared to conventional cores made mainly of white sugar, and the coating efficiency is about 5% higher, making it easy to produce spherical granules with high commercial value. Can be manufactured. In addition, since the spherical core of the present invention contains 10 to 90% of water-soluble additives, its water absorption rate is suppressed compared to conventional spherical cores mainly made of crystalline cellulose, and the powder content of the core is reduced. Because of its strong adhesion, the powder coating speed is fast and the amount of binding liquid can be small. Also,
Since the spherical core of the present invention does not disintegrate and has high strength, when the spherical granules are administered into the body, they are less likely to be destroyed by intestinal movements, making it easier to obtain the desired elution pattern.

Claims (2)

[Claims] Claim 1: 10 to 70% crystalline cellulose having an average degree of polymerization of 60 to 375 and 10 to 70% of a water-soluble additive.
Pharmaceutically inactive spherical core containing 90%. 2. A spherical granule comprising a spherical core according to claim 1, a powder layer containing a drug around the spherical core, and a coating layer around the powder layer.