JP2011207851A - Swelling spherical core - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a readily producible spherical core having a swelling property without dispersion of physical properties, and to provide a membrane rupture type limited-time release formulation easily allowing drug elution control with high accuracy.SOLUTION: There are provided the spherical core including crystalline cellulose and one or more swelling agents selected from among croscarmellose sodium, pregelatinized starch, sodium carboxymethyl starch, hydroxypropyl cellulose with a low substitution degree, and crospovidone in a mass ratio of (90:10)-(30:70), and having a volume swelling degree of 100-700% by water absorption and a sphericity of ≥0.7 and ≤1; a spherical raw granule in which the surface of the spherical core is coated with a drug; and a spherical granule in which the surface of the spherical raw granule is coated with a water-insoluble substance.

Description

  The present invention relates to a spherical nucleus having swelling properties used for chronotherapy in the field of pharmaceuticals, spherical granules and spherical granules produced using the spherical nucleus. The present invention also relates to a method for producing a spherical nucleus.

It is known that periodic changes in pathology occur in many chronic diseases. This is based on the fact that many of the human physiological functions are dominated by the body clock and periodically fluctuate. Against this background, time pharmacotherapy has been studied in which the drug concentration is increased by only increasing the blood concentration of the drug only during the time when symptoms appear or when necessary for treatment. In particular, a timed-release formulation that has the function of delaying the onset of drug efficacy for a required time by releasing the drug after a predetermined time has elapsed after taking it enables real-time drug therapy to be realized by a normal dosing method. Become. By adjusting the release start time, a time-release preparation can be designed according to the purpose.
For example, if the release start time is adjusted to several hours, the drug can act on the small and large intestines, and if the release start time is adjusted to several minutes, the drug can be made to act on the stomach. Furthermore, it can also be used as a mask for drugs having an unpleasant taste.
A membrane-ruptured time-release preparation, which is one form of this time-release preparation, is a tablet or granule containing a drug and a swellable substance coated with a water-insoluble film. In this preparation, when the swellable substance in the preparation expands due to water that permeates through the water-insoluble film when administered to a living body, and the film is broken by the expansion force, the drug is eluted for the first time. ing.

Patent Document 1 discloses a film-ruptured long-lasting formulation in which a drug is attached around a core particle together with a swelling agent and coated with a mixture of a water-insoluble coating substance and an additive. As a method for producing this preparation, a swelling agent is sprayed and adhered to the surface of the core particles.
Patent Document 2 discloses a membrane-ruptured delayed-release preparation in which a disintegrating agent is attached to a core-containing drug and coated with a mixture of a permeable water-insoluble polymer and a glidant.
Patent Document 3 discloses a membrane-ruptured delayed-release preparation in which a core obtained by spheroidizing a drug and a disintegrant in a wet state is coated with a mixture of a water-soluble polymer and an insoluble polymer. .
Patent Document 4 discloses a membrane-ruptured time-release preparation in which a core obtained by spheroidizing a drug and a water-swellable substance in a wet state is coated with a film containing a water-insoluble polymer.

JP 62-30709 A Special table 2003-510346 gazette Japanese translation of PCT publication No. 2004-510812 JP 2009-191034 A

Patent Document 1 describes a method in which a swelling agent is sprayed onto the core particles, but the powdery swelling agent adheres unevenly to the core particle surfaces. Therefore, the outer coating film is not coated with a uniform thickness, and as a result, there is a problem that it is very difficult to control the film rupture of the resulting preparation.
In Patent Document 2, a liquid in which a disintegrant is suspended in an organic solvent is used to spray (spray) the medicine containing the core. However, the organic solvent has various problems such as environment, cost, and residue. is there. In addition, conversion from an organic solvent system to an aqueous solution system or an aqueous suspension system is generally attempted. However, when a disintegrant is suspended in an aqueous solution, the volume of the system expands due to water absorption and the viscosity of the system is increased. It becomes high and it becomes difficult to spray. Further, when the system is diluted to make the viscosity low, there arises a problem that the working efficiency is extremely deteriorated.
Further, as in Patent Documents 1 and 2, the method of attaching a drug, a swelling agent, or the like to the core (core) has a problem that the size of the finally obtained granules increases. In non-parrel 103 (particle size: 355-850 μm / manufactured by Freund Sangyo Co., Ltd.), which is generally used as a nucleus, the particle size of the obtained granule is at least about 500-1000 μm, and a smaller granule is obtained. I can't.

Since the cores of Patent Documents 3 and 4 contain a drug, the core has high sphericity due to the physical properties of the drug (hygroscopicity, cohesiveness, degradability, etc.), and has a uniform drug content and particle size. There has been a problem that it becomes difficult to stably manufacture. In addition, since the optimum production conditions of the nucleus are different for each type of drug, there is a problem that it is necessary to optimize the production conditions every time the type of drug is changed.
Furthermore, as in Patent Documents 3 and 4, when producing granules using extrusion granulation, it is generally difficult to obtain granules having a high sphericity and a small particle size. In particular, when a drug or swelling agent that is difficult to extrude is included, there is a problem that the amount and type of the compound are limited. In Patent Document 3, the particle size of the granule is described as 500 to 4000 μm, and in Patent Document 4, it is described as 180 to 500 μm. However, in practice, only 420 to 500 μm granules are obtained in the example of Patent Document 4.
An object of the present invention is to provide a highly accurate timed-release preparation, to provide a spherical nucleus having swelling properties as a core of the time-released preparation, and to easily obtain a time-released preparation with high accuracy. .

As a result of intensive studies on the above problems, the inventors of the present invention coat a spherical nucleus present in a state where a swelling agent and crystalline cellulose are randomly mixed with a layer containing a drug and a layer containing a water-insoluble substance. Thus, the inventors have found that the above problems can be solved and completed the present invention.
That is, the present invention is as follows.
[1] A spherical nucleus composed of a mixture containing crystalline cellulose and a swelling agent.
[2] The spherical nucleus according to [1] above, wherein the mass ratio of crystalline cellulose to swelling agent is 90:10 to 30:70.
[3] The spherical nucleus according to [1] or [2] above, wherein the mass ratio of crystalline cellulose to swelling agent is 60:40 to 40:60.
[4] The spherical nucleus according to any one of [1] to [3], wherein the volume swelling degree due to water absorption is 100% to 700%.
[5] The spherical nucleus according to any one of [1] to [4] above, wherein the sphericity is 0.7 or more and 1 or less.

[6] The spherical nucleus according to any one of [1] to [5] above, wherein the density is 0.8 g / ml or more and 1 g / ml or less.
[7] The spherical nucleus according to any one of [1] to [6] above, wherein the particle size is 200 to 500 μm.
[8] The above-mentioned [1] to [7], wherein the swelling agent is at least one selected from croscarmellose sodium, pregelatinized starch, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, and crospovidone. ] The spherical nucleus in any one of.
[9] A spherical elementary granule characterized in that the surface of the spherical nucleus according to any one of [1] to [8] is coated with a drug.
[10] A spherical granule in which the surface of the spherical elementary granule according to [9] is coated with a water-insoluble substance.
[11] The spherical granule according to [10] above, wherein the drug release start time is 15 to 30 minutes.
[12] The method for producing a spherical nucleus according to any one of [1] to [8], wherein the crystalline cellulose and the swelling agent are spheroidized in a wet state.

The present invention is a spherical nucleus in which crystalline cellulose and a swelling agent are present in a mixed state at random. Compared with the method in which the surface of the nucleus is coated with the swelling agent, there is an advantage that the labor for that amount is unnecessary, and a nucleus with a smooth surface and high sphericity is easily obtained. Furthermore, since the swelling agent having an important role in controlling film rupture is uniformly distributed in the nucleus, the degree of expansion of the nucleus can be easily controlled.
Furthermore, since the spherical nuclei of the present invention do not contain a drug, it is possible to produce spherical nuclei with high sphericity that maintain a certain quality, without being affected by the physical properties of the drug, as compared with nuclei that contain a drug in advance. In addition, since the swelling agent absorbs water and expands without being influenced by the drug, it is possible to easily obtain a highly accurate membrane-ruptured time-release preparation.

1 is a drug elution curve of spherical granules A to F obtained in Examples 1 to 5 and Comparative Example 1. FIG. FIG. 2 is a drug elution curve of spherical granules C, G, and H obtained in Examples 3, 6, and 7. FIG. 3 is a drug elution curve of spherical granules K and L obtained in Example 10.

Hereinafter, the present invention will be described in detail. In addition, this invention is not limited to the following description, It can implement by changing variously within the range of the summary.
The spherical nucleus of the present invention is composed of a composition containing crystalline cellulose and a swelling agent, and the swelling agent is not coated around the nucleus made of crystalline cellulose, and crystalline cellulose and swelling agent are randomly mixed in the nucleus. To do. Spherical nuclei coated with a swelling agent around the nuclei, when immersed in water, the swelling agent attached to the surface collapses and peels off from the nuclei, whereas in the spherical nuclei of the present invention, the swelling agent peels off from the nuclei. The feature is that the nucleus itself expands greatly.
Here, in the present invention, the “core” is for forming a layer made of a water-insoluble component or a layer made of a drug on the outer shell when used as a time-release preparation. Since this spherical nucleus does not contain a drug, the swelling agent in the nucleus absorbs water and is easily expanded without being affected by the drug. This large swelling effect is an important factor in obtaining a highly accurate time-release preparation.

In the present invention, the drug is a pharmaceutically active medicinal ingredient.
Crystalline cellulose refers to cellulosic materials such as linters, pulps, and regenerated fibers that are acid hydrolyzed, alkali oxidatively decomposed, or a combination of both, or subjected to mechanical treatment such as pulverization after the above chemical treatment. It is obtained. Crystalline cellulose here means the cellulose whose crystallinity calculated | required by a X ray diffraction method is 10% or more. Preferably it is 40% or more. The average degree of polymerization is preferably 60 to 375. When the average degree of polymerization is 60 or less, the entanglement of cellulose molecules is reduced, so that the degree of wear of the spherical nuclei is increased. More preferably, it is 60-300. The water absorption is preferably 1.0 to 2.8 ml / g, and the 200 mesh fraction is preferably 80% by mass or less. The water absorption is in accordance with the method for measuring the oil absorption described in JIS K5101, using distilled water instead of oil. The end point is the point where the water begins to drain after the whole becomes one soul. In addition, crystalline cellulose can be used in the form of powder.

  A swelling agent is a substance that absorbs moisture and expands. Here, in the present invention, the swelling agent does not contain cellulose. Specifically, the swelling agent is a substance having a sedimentation volume of 2 to 30 ml / g, which will be described later, and a disintegrant usually used in the technical field of pharmaceutical preparations can be suitably used. Here, the disintegrating agent refers to a substance listed as a disintegrating agent in, for example, the index 397 according to use in the Pharmaceutical Additives Dictionary 2007. Specific examples of the disintegrant include, for example, croscarmellose sodium, carmellose, carmellose calcium, carmellose sodium, celluloses such as low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, hydroxypropyl starch, rice starch, wheat starch , Starches such as corn starch, potato starch and partially pregelatinized starch, and synthetic polymers such as crospovidone and crospovidone copolymer. Two or more selected from the above may be used in combination. The swelling agent can be a powder.

  Particularly preferably, the following may be mentioned (described as a compound name (trade name / manufacturer)). Croscarmellose sodium (Kickolate / Asahi Kasei Chemicals Co., Ltd., Primerose / DMV, Ac-Di-Sol / Kaneda, etc.), pregelatinized starch (SWELSTAR PD-1 / Asahi Kasei Chemicals Co., Ltd.), LYCATAB PGS / Rocket Japan, Amicol / Nippon Star Chemical Co., Ltd.), carboxymethyl starch sodium (GLYCOLYS / Rocket Japan, Primojel / DMV, Exprotab / Kimura Sangyo etc.), low substituted hydroxypropylcellulose (L-HPC / Shin-Etsu Chemical Co., Ltd.), Cross Povidone (Cross Povidone / Gokyo Sangyo, Kollidon / BASF Japan, Polyplusdon / ISP Japan, etc.). More preferred is croscarmellose sodium.

Although the preferable manufacturing method of the spherical nucleus of this invention is described, it is not limited to the following method.
While mixing the powder containing crystalline cellulose and swelling agent with a high-speed stirring granulator, distilled water is added and kneaded and granulated. Instead of distilled water, an aqueous solution such as hydroxypropylcellulose, starch paste, polyvinylpyrrolidone, or an organic solvent may be used as a binding solution, but use of an aqueous solution such as hydroxypropylcellulose, starch paste, polyvinylpyrrolidone is preferable. Extrusion granulation described in Patent Documents 3 and 4 as a granulation method involves extruding a wet product obtained by adding a binder to a mixture and kneading it from a screen of a certain size, followed by drying and classification. This is a granulation method for obtaining granules. Therefore, it is generally difficult to obtain granules having a high sphericity and a small particle size. In addition, when a drug or swelling agent that is difficult to extrude is included, the amount and type of the compound are limited, which is not preferable. On the other hand, stirring granulation is a granulation method in which a binder is sprinkled and granulated while stirring the mixture with a stirring blade, and it is easy to obtain granules having a high sphericity and a small particle size.
Then, it moves to a rolling fluidized bed granulator (rolling type fluidized bed coating device), spheroidizes while spraying distilled water, and then dried and sieved as necessary to obtain spherical nuclei.

In order to uniformly attach a drug layer or a water-insoluble substance coating layer to the spherical core surface, it is preferable that the core has a uniform particle size and a high sphericity. Moreover, in order to prevent the damage at the time of coating, it is preferable that it is a hard core with a high density. In addition, if the particle size of the spherical nuclei is too small, the particles tend to aggregate at the time of coating. If the particle size is too large, the texture such as a rough surface is not good. Therefore, the particle size of the spherical nuclei is preferably in the range of 200 to 500 μm. More preferably, it is 300-500 micrometers.
In order to produce spherical nuclei satisfying the above physical properties, an appropriate amount of water and stirring speed during production are important factors. If the crystalline cellulose and the swelling agent have the same mass ratio, when the amount of water added during production is increased, both the density and sphericity of the resulting spherical nuclei increase and the particle size tends to increase. On the other hand, when the stirring speed is increased at the same mass ratio of the crystalline cellulose and the swelling agent, both the density and sphericity of the resulting spherical nuclei are lowered, and the particle size tends to be reduced. Moreover, in the prescription with a large ratio of the swelling agent, a larger amount of water is required, and the volume of the solid matter is expanded, so that the amount charged into the apparatus is reduced. In order to obtain spherical nuclei having such suitable physical properties, it is important to produce them while adjusting the amount of water and stirring conditions.

For example, in the case of producing spherical nuclei using a high-speed stirring granulator, the preferable amount of water is 6 to 20 times in terms of mass ratio with respect to the swelling agent, and the preferable stirring speed is 500 m / min or less for the main blade, Is 800 m / min or less. On the other hand, Patent Documents 3 and 4 describe that the “drug-containing core” is produced by blending water or a 10% ethanol aqueous solution having a mass ratio of 5 times or less with respect to the swelling agent. (Example). It is considered that not only the difference in the apparatus but also the presence or absence of the drug in the nucleus has a great influence on the optimum amount of water added during production and other production conditions.
When producing the spherical core of the present invention, if it is pharmaceutically inert, excipients other than crystalline cellulose (sugars such as lactose, sucrose, D-mannitol, starches such as corn starch, potato starch, or the like Inorganic substances such as calcium diphosphate and aluminum silicate) may be blended to such an extent that the effects of the present invention are not hindered.

The volume of the spherical nucleus of the present invention swells due to water absorption. This swelling effect makes it possible to reliably rupture a water-insoluble film. The volume swelling degree to explain the measurement method later is an increase rate of the volume of the spherical nucleus after swelling with respect to the spherical nucleus before swelling. For example, when the volume expansion purity is 100%, it means that the volume after swelling is increased by 100% compared to the volume before swelling, that is, doubled. In this invention, it is preferable that it is 100 to 700% with respect to the volume of the spherical nucleus before swelling, More preferably, it is 200 to 600%.
As the blending ratio of the swelling agent increases, the volume swelling degree increases. However, when the ratio of the swelling agent increases too much, the surface of the obtained spherical core becomes rough, and the sphericity and density become low. Further, when swelling due to water absorption, there arises a problem that the spherical nucleus collapses and the shape cannot be maintained. Therefore, the spherical nucleus preferably contains crystalline cellulose and a swelling agent in a mass ratio of 90:10 to 30:70. When the swelling agent is less than 10% by mass, the spherical nuclei cannot sufficiently expand due to water absorption, and it becomes difficult to rupture the membrane. When the swelling agent is more than 70% by mass, the spherical nucleus surface becomes rough, and it becomes difficult to uniformly attach the drug layer and the film layer of the water-insoluble substance. The mass ratio of crystalline cellulose and swelling agent is more preferably 60:40 to 40:60.

The absence of a drug in the spherical nucleus of the present invention is an important point for obtaining a large swelling effect. When the drug is present in the spherical nucleus, the swelling agent is sufficiently prevented from sucking water and expanding. If the drug has high hygroscopicity, the drug absorbs the water that has entered the core, and accordingly, the swelling agent is not easily absorbed or expanded. In the case of a hydrophobic drug, a hydrophobic substance is scattered in the nucleus, so that water does not easily enter the nucleus and the swelling agent is not sufficiently absorbed or expanded. Patent Document 3 describes a nucleus containing a drug, but describes that the volume when hydrated is expanded only by 20 to 100%.
The spherical nucleus of the present invention preferably has a sphericity of 0.7 or more and 1 or less. If the sphericity is low, it becomes difficult to uniformly attach a drug layer or a water-insoluble substance film layer to the surface of the spherical nucleus, and it becomes difficult to control film rupture as desired. The higher the sphericity, the better, and more preferably 0.8 or more.
The density is preferably 0.8 g / ml or more and 1 g / ml or less. When the density is low, the flow of spherical nuclei is deteriorated during coating, and uniform coating becomes difficult. Further, the spherical nuclei are agglomerated and broken, making it difficult to obtain a high-quality time-release preparation. In order to obtain the desired sphericity and density, as described above, an appropriate amount of water and stirring speed during the production of spherical nuclei are important factors.

The spherical element granule of the present invention having a drug-containing layer around the spherical nucleus is produced, for example, by the following method.
While rolling the spherical core in a centrifugal fluid type coating apparatus, a binder-containing aqueous solution is continuously sprayed, and at the same time, a powder comprising a drug and, if necessary, an excipient is supplied. Coat and dry to give spherical granules. Alternatively, while the spherical nuclei are fluidized in the fluidized bed coating apparatus, a solution in which the drug is dissolved or suspended in the aqueous binder solution is sprayed, the powder containing the drug is coated on the spherical nuclei, and dried to form spherical granules. And
The amount of the drug layer is determined depending on the dose of the drug, but is 0.1 to 300% by mass with respect to the spherical nucleus. Since the spherical elementary granule of the present invention has a drug attached to the surface of the spherical nucleus, as in Patent Documents 3 and 4, there is an advantage that the compounding amount of the drug is not limited as compared with the nucleus containing the drug in advance. is there.

Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, starch paste, pregelatinized starch, polyvinylpyrrolidone, gum arabic, sugar syrup, sodium carboxymethylcellulose, pullulan, etc. The aqueous solution itself may act as an aqueous binder solution.
Examples of excipients include lactose, corn starch, crystalline cellulose, sucrose, D-mannitol, pregelatinized starch, and partially pregelatinized starch.
In addition, after attaching the drug, a spherical elementary granule may be applied with a seal coat according to a commonly used method.

The spherical granule having a coating layer containing a water-insoluble substance around the spherical elementary granule of the present invention is produced, for example, by the following method.
An aqueous suspension containing a water-insoluble substance is sprayed and coated while the spherical granules are flowing, and dried to form a film layer to obtain spherical granules. At this time, an organic solvent is not preferable as a solvent for suspending the water-insoluble substance.
Examples of the coating apparatus to be used include ordinary coating machines such as a centrifugal fluidized coating apparatus, a fluidized bed coating apparatus, a rolling fluidized bed coating apparatus, and a pan type coating apparatus.
The amount of the water-insoluble substance used for the coating varies depending on the release start time of the drug, the size of the spherical nucleus, etc., but is 5 to 200% by mass, preferably 10 to 100% by mass, more preferably the spherical nucleus. It is 10-50 mass%.

Examples of the water-insoluble substance include ethyl cellulose, ethyl acrylate / methyl methacrylate copolymer, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, carboxymethyl ethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose acetate succinate, shellac, and the like. Two or more selected from the above may be used in combination. Preferably, it is ethyl cellulose.
In addition to the water-insoluble substance, the film layer containing the water-insoluble substance can contain additives for the purpose of plasticizer, wax, colorant, fragrance, lubricant, aggregation inhibitor and the like.

When the spherical granule of the present invention is orally administered, the swelling agent in the spherical nucleus at the center gradually swells by absorbing moisture in the digestive tract through the coating layer. After a certain period of time, the film is destroyed due to an increase in volume due to swelling of the swelling agent in the spherical nucleus, and the entire amount of drug is released instantaneously. The time until the start of drug release (release start time) and the time from the start of drug release until most of the drug is released (release time) depend on the type of water-insoluble substance and the amount of coating. , And the type and blending ratio of the swelling agent in the spherical nucleus at the center. The more the compounding ratio of the swelling agent is, the stronger the swelling effect is, and the more the coating film with less water-insoluble substance and the more easily moisture penetrates, the shorter the release start time and the release time. The release start time is preferably within 30 minutes, more preferably within 15 to 30 minutes. The release time is preferably within 90 minutes, more preferably within 60 minutes, and even more preferably within 30 minutes.
In addition, in patent document 4, although there exists description regarding the technique which controls discharge | release start time and discharge | release time, the objective is achieved by adjusting the alcohol concentration used for manufacture of a nucleus or film formation. However, the use of organic solvents has various problems such as environment, cost, and residue, and generally it is not desirable to use them if possible. In the present invention, it is possible to control the release start time and the release time without using any organic solvent.

The present invention will be described based on examples.
The physical property measuring method and conditions used in the present invention are as follows.
First, physical property measurement methods are summarized below.
<Volume swelling degree of spherical core [%]>
The sample is swollen by dropping water with a dropper and wiped off after 5 minutes. Micrographs before and after swelling are taken, the short diameter and long diameter are measured, and the volume of particles before and after swelling is calculated using the average value of these as the diameter. It implements about 20 particle | grains, calculates | requires the average value, and makes it a volume swelling degree from the following formula | equation.
Volume swelling degree [%] = (Volume after swelling−Volume before swelling) × 100 / Volume before swelling

<Sphericality of spherical nucleus>
Take a micrograph of the sample and measure the minor axis / major axis ratio. It carries out about 150 particle | grains and makes the average value the sphericity.
<Spherical nucleus density [g / ml]>
Measured using a Scott volume meter (Tsutsui Rikenki Co., Ltd.). The sample is allowed to flow down in the 25 ml measuring container over 30 to 60 seconds using a quantitative feeder. The excess sample deposited on the top of the container is then scraped off, and then the loosely filled weight of the container is weighed. The value obtained by dividing the weight loosely packed in the container by the volume of the measurement container is defined as the density. Measure three times and take the average value.

<Drug dissolution test>
Measurement is performed using a dissolution tester DT-610 (JASCO Corporation) and a spectrophotometer V-530 (JASCO Corporation). The test is carried out in accordance with the general test method “dissolution test method”, the device is “device 2” (paddle method), the paddle rotation speed is 100 rpm, and the test solution is the Japanese Pharmacopoeia “dissolution test first solution”. Measure three times and take the average value.
<Drug release start time, release time>
When the dissolution rate of the drug is less than 5%, the release of the drug is suppressed, and the time when the dissolution rate is less than 5% is defined as the release start time. The time from the release start time until the drug dissolution rate reaches 80% or more is defined as the release time.

[Example 1]
High-speed crystalline cellulose (water absorption 2.1 ml / g, 200 mesh fraction 30%, average polymerization degree 220, crystallinity 65%) 1440 g and croscarmellose sodium (Kickolate ND-2HS / Asahi Kasei Chemicals) 160 g Charged to a stirring granulator (vertical granulator FM-VG-10P / Paurec Co., Ltd.), temperature 45 ° C., main blade 264 m / min (radius 14 cm, 300 rpm), cross screw 251 m / min (radius 4 cm, 1000 rpm) While stirring, 2720 g of distilled water (a mass ratio of 17.0 times the swelling agent) was added little by little, and the mixture was stirred and granulated for 60 minutes to obtain a wet spherical granule (crystalline cellulose: swelling agent = 90:10).

Next, 1000 g of the obtained spherical granulated material was charged into a rolling fluidized bed coating apparatus (Multiplex MP-01 / Paurec Co., Ltd.) with moisture, temperature 50 ° C., speed 301 m / min (radius 8 cm, 600 rpm). ), 300 g of distilled water was added little by little over 30 minutes, and then rolled at a temperature of 25 ° C. and a speed of 301 m / min for 30 minutes to smooth the surface and make it spherical. Next, drying was performed while rolling at a temperature of 80 ° C. and a speed of 75 m / min (radius 8 cm, 150 rpm) to obtain spherical nuclei.
A spherical core A having a particle size of 300 to 500 μm was obtained with a sieve. The ratio of the particle diameter of 300 to 500 μm was 52% by mass with respect to the whole spherical nucleus before sieving. When the obtained spherical nucleus A was observed with a high-resolution scanning electron microscope (SEM), the surface was smooth. Further, the volume swelling degree, sphericity degree, and density were determined according to the above-described methods, and those values are shown in Table 1.
600 g of spherical nuclei A were charged into a rolling fluidized bed coating apparatus (Multiplex MP-01 / Paurec Co., Ltd.), and an aqueous drug dispersion (3.9% by mass riboflavin, 0.8% by mass hydroxypropylcellulose, 95.3). Sprayed and coated with (mass% distilled water) to obtain spherical granule A containing 2.0% by mass of riboflavin with respect to the spherical nucleus.

  Subsequently, 550 g of the obtained spherical elementary granules A were charged into a rolling fluidized bed coating apparatus (Multiplex MP-01 / Paurec Co., Ltd.), and 13% by weight ethyl cellulose (Celios Coat EC-30A / Asahi Kasei Chemicals Co., Ltd.) as a water-insoluble substance. )), An aqueous suspension containing 2% by mass triethyl citrate as a plasticizer and 85% by mass distilled water was sprayed and coated to 10% by mass (solid content) with respect to the spherical core and dried. Thereafter, the coating layer was formed by heating in an oven at 105 ° C. for 1 hour. Particles of 500 μm or more were removed with a sieve to obtain spherical granules A in which ethyl cellulose and triethyl citrate were coated with a solid content of 10% by mass.

[Example 2]
600 g of crystalline cellulose and 400 g of croscarmellose sodium were charged into a high-speed stirring granulator, and 3950 g of distilled water (a mass ratio of 9.9 times the swelling agent) was added little by little while stirring under the same conditions as in Example 1. Thereafter, the mixture was stirred and granulated for 60 minutes to obtain a wet spherical granulated product (crystalline cellulose: swelling agent = 60: 40).
Next, 1000 g of the obtained spherical granulated product was charged into a rolling fluidized bed coating apparatus with water, and rolled under the same conditions as in Example 1 to smooth the surface and make it spherical. Next, drying was performed while rolling at a temperature of 80 ° C. and a speed of 75 m / min (radius 8 cm, 150 rpm) to obtain spherical nuclei.
Spherical nuclei B having a particle size of 300 to 500 μm were obtained with a sieve. The ratio of the particle diameter of 300 to 500 μm was 45% by mass with respect to the whole spherical nucleus before sieving. When the obtained spherical nucleus B was observed with a high resolution scanning electron microscope (SEM), the surface was smooth. Further, the volume swelling degree, sphericity degree, and density were determined according to the above-described methods, and those values are shown in Table 1.
Using spherical nuclei B, spherical elementary granules B were obtained in the same manner as in Example 1.
Subsequently, the obtained spherical elementary granules B were used in the same manner as in Example 1 to obtain spherical granules B coated with 30% by mass of ethyl cellulose and triethyl citrate with a solid content.

[Example 3]
400 g of crystalline cellulose and 400 g of croscarmellose sodium were charged into a high-speed stirring granulator, and 3760 g of distilled water (a mass ratio of 9.4 times the swelling agent) was added little by little while stirring under the same conditions as in Example 1. Thereafter, the mixture was stirred and granulated for 60 minutes to obtain a wet spherical granulated product (crystalline cellulose: swelling agent = 50: 50).
Next, 1000 g of the obtained spherical granulated product was charged into a rolling fluidized bed coating apparatus with water, and rolled under the same conditions as in Example 1 to smooth the surface and make it spherical. Next, drying was performed while rolling at a temperature of 80 ° C. and a speed of 75 m / min (radius 8 cm, 150 rpm) to obtain spherical nuclei.
Spherical nuclei C having a particle size of 300 to 500 μm were obtained with a sieve. The ratio of the particle diameter of 300 to 500 μm was 32% by mass with respect to the whole spherical nucleus before sieving. When the obtained spherical nucleus C was observed with a high resolution scanning electron microscope (SEM), the surface was smooth. Further, the volume swelling degree, sphericity degree, and density were determined according to the above-described methods, and those values are shown in Table 1.
Using spherical nuclei C, spherical elementary granules C were obtained in the same manner as in Example 1.
Subsequently, the obtained spherical elementary granules C were used in the same manner as in Example 1 to obtain spherical granules C coated with 30% by mass of ethyl cellulose and triethyl citrate in solid content.

[Example 4]
320 g of crystalline cellulose and 480 g of croscarmellose sodium were charged into a high-speed stirring granulator, and 4400 g of distilled water (a mass ratio of 9.2 times the swelling agent) was added little by little while stirring under the same conditions as in Example 1. Thereafter, the mixture was stirred and granulated for 60 minutes to obtain a wet spherical granulated product (crystalline cellulose: swelling agent = 40: 60).
Next, 1000 g of the obtained spherical granulated product was charged into a rolling fluidized bed coating apparatus with water, and rolled under the same conditions as in Example 1 to smooth the surface and make it spherical. Next, drying was performed while rolling at a temperature of 80 ° C. and a speed of 75 m / min (radius 8 cm, 150 rpm) to obtain spherical nuclei.
Spherical nuclei D having a particle size of 300 to 500 μm were obtained with a sieve. The ratio of the particle diameter of 300 to 500 μm was 25% by mass with respect to the whole spherical nucleus before sieving. When the obtained spherical nucleus D was observed with a high-resolution scanning electron microscope (SEM), the surface was smooth. Further, the volume swelling degree, sphericity degree, and density were determined according to the above-described methods, and those values are shown in Table 1.
Using the spherical nucleus D, spherical elementary granules D were obtained in the same manner as in Example 1.
Subsequently, the obtained spherical elementary granules D were used in the same manner as in Example 1 to obtain spherical granules D in which ethyl cellulose and triethyl citrate were coated with a solid content of 30% by mass.

[Example 5]
210 g of crystalline cellulose and 490 g of croscarmellose sodium were charged into a high-speed stirring granulator, and 4340 g of distilled water (a mass ratio of 8.9 times the swelling agent) was added little by little while stirring under the same conditions as in Example 1. Thereafter, the mixture was stirred and granulated for 60 minutes to obtain a wet spherical granulated product (crystalline cellulose: swelling agent = 30: 70).
Next, 1000 g of the obtained spherical granulated product was charged into a rolling fluidized bed coating apparatus with water, and rolled under the same conditions as in Example 1 to smooth the surface and make it spherical. Next, drying was performed while rolling at a temperature of 80 ° C. and a speed of 75 m / min (radius 8 cm, 150 rpm) to obtain spherical nuclei.
A spherical nucleus E having a particle size of 300 to 500 μm was obtained with a sieve. The ratio of the particle size of 300 to 500 μm with respect to the whole spherical core before sieving was 13% by mass. When the obtained spherical nucleus E was observed with a high resolution scanning electron microscope (SEM), irregularities were observed on the surface. Further, the volume swelling degree, sphericity degree, and density were determined according to the above-described methods, and those values are shown in Table 1.
Using the spherical nucleus E, spherical elementary granules E were obtained in the same manner as in Example 1.
Subsequently, the obtained spherical elementary granules E were used in the same manner as in Example 1 to obtain spherical granules E covered with 30% by mass of ethyl cellulose and triethyl citrate in solid content.

[Comparative Example 1]
Only 1600 g of crystalline cellulose (water absorption 2.1 ml / g, 200 mesh fraction 30%, average polymerization degree 220, crystallization degree 65%) is stirred at high speed with a high-speed agitation granulator (Vertical Granulator FM-VG-10P / Co., Ltd.) Was added at a temperature of 45 ° C., main blade 264 m / min (radius 14 cm, 300 rpm) and cross screw 251 m / min (radius 4 cm, 1000 rpm), and then gradually added 1520 g of distilled water, followed by stirring for 60 minutes. Granulation was performed to obtain a wet spherical granule.
Next, 1000 g of the obtained spherical granulated material was charged into a rolling fluidized bed coating apparatus (Multiplex MP-01 / Paurec Co., Ltd.) with moisture, temperature 50 ° C., speed 301 m / min (radius 8 cm, 600 rpm). ), 300 g of distilled water was added little by little over 30 minutes, and then rolled at a temperature of 25 ° C. and a speed of 301 m / min for 30 minutes to smooth the surface and make it spherical. Next, drying was performed while rolling at a temperature of 80 ° C. and a speed of 75 m / min (radius 8 cm, 150 rpm) to obtain spherical nuclei.
Spherical nuclei F having a particle size of 300 to 500 μm were obtained with a sieve. The ratio of the particle diameter of 300 to 500 μm was 65% by mass with respect to the whole spherical nucleus before sieving. When the obtained spherical nucleus F was observed with a high-resolution scanning electron microscope (SEM), the surface was smooth. Further, the volume swelling degree, sphericity degree, and density were determined according to the above-described methods, and those values are shown in Table 1.
Using spherical nuclei F, spherical elementary granules F were obtained in the same manner as in Example 1.
Next, using the obtained spherical elementary granules F, spherical granules F in which 10% by mass of ethyl cellulose and triethyl citrate were coated with a solid content were obtained in the same manner as in Example 1.

[Comparative Example 2]
Only 600 g of croscarmellose sodium (Kickolate ND-2HS / Asahi Kasei Chemicals Co., Ltd.) was charged into a high-speed stirring granulator (Vertical Granulator FM-VG-10P / Paurec Co., Ltd.), temperature 45 ° C., main blade 264 m / 4500 g of distilled water (a mass ratio of 7.5 times the swelling agent) was added little by little while stirring with a minute (radius 14 cm, 300 rpm) and a cross screw 251 m / min (radius 4 cm, 1000 rpm), followed by stirring for 60 minutes. However, it became a lump-like lump and could not be spheroidized.

[Test Example 1]
According to the method described above, drug dissolution test on spherical granules A to F was performed. The elution amount of riboflavin was measured by the UV method (wavelength: 445 nm), and was evaluated as a percentage of the elution amount with respect to the riboflavin amount contained in the spherical granules A to F. The obtained elution curve is shown in FIG. 1, and each release start time (time when the drug dissolution rate is less than 5%) and release time (time from the release start time until the drug dissolution rate reaches 80% or more) ) Is shown in Table 1.

In Examples 1 to 5 and Comparative Examples 1 and 2, the blending ratio of the swelling agent is evaluated.
From Examples 1 to 5 (Table 1 and FIG. 1), it was confirmed that spherical nuclei having different physical properties were obtained depending on the blending ratio (90:10 to 30:70) of crystalline cellulose and swelling agent (carboxymethylcellulose sodium). . Further, it was confirmed that the release start time and the release time can be shortened as the blending ratio of the swelling agent is increased, and the drug elution can be controlled.
Spherical granules A (Example 1) in which the ratio of crystalline cellulose to swelling agent is 90:10 showed a sustained release elution pattern after a certain release start time due to the low degree of swelling of the nuclei.
Spherical granule E (Example 5) with a ratio of crystalline cellulose to swelling agent of 30:70 showed a 10 minute release onset time, during which time drug elution occurred gradually and nearly 4% elution occurred. did.

In contrast, spherical granules B to D (Examples 2 to 4) in which the ratio of crystalline cellulose and swelling agent is 60:40 to 40:60 are 80% or more within 1 hour after a certain release start time, respectively. Drug release was observed, and spherical granules with very high precision and ease of adjustment were obtained.
Further, the surface of the spherical nucleus E was uneven, and the shape was slightly distorted as compared with other spherical nuclei. On the other hand, since the spherical nuclei A to D have a smooth surface, a film of a drug or a water-insoluble substance can be formed uniformly.
From Comparative Example 1, it was found that the spherical granule F obtained by using only crystalline cellulose without containing a swelling agent hardly releases the drug even after 10 hours, and is inappropriate as a membrane rupture type time-release preparation. .
From Comparative Example 2, it was found that spherical nuclei could not be obtained only with the swelling agent.

[Example 6]
First, croscarmellose sodium (Kickolate ND-2HS / Asahi Kasei Chemicals), pregelatinized starch (SWELSTAR PD-1 / Asahi Kasei Chemicals), carboxymethyl starch sodium (Primojel) used as a preferred swelling agent in the present invention / DMV), low substituted hydroxypropylcellulose (L-HPC LH-21 / Shin-Etsu Chemical Co., Ltd.), and crospovidone (Polyplastone XL-10 / ISP) were measured by the following procedure.
75 ml of distilled water was put into a beaker, and 1.0 g of a swelling agent was added little by little while stirring with a stirrer.
After all the swelling agent was added, the mixture was stirred for 3 minutes.
The suspension was transferred to a 100 ml graduated cylinder, made up to 100 ml and placed in a settling tube.
The suspension was allowed to stand for 16 hours and the sedimentation volume was read.
As a result, carboxymethyl starch sodium: 28.8 ml / g, low-substituted hydroxypropylcellulose: 21.0 ml / g, croscarmellose sodium: 16.5 ml / g, pregelatinized starch: 12. It was 0 ml / g, crospovidone: 6.1 ml / g. Here, the sedimentation volume is considered to correlate with the swelling property of the swelling agent, that is, it is presumed that the larger the sedimentation volume, the higher the swelling property.

Since the volume swelling degree in the spherical nucleus of the present invention is considered to be affected by the swelling property of the swelling agent, two types of sodium carboxymethyl starch that showed the largest sedimentation volume and crospovidone that showed the smallest sedimentation volume were used. The spherical nuclei were produced and evaluated.
In Example 3, spherical nuclei were obtained in exactly the same manner except that carboxymethyl starch sodium (Primojel / DMV) was used instead of croscarmellose sodium (Kickolate ND-2HS / Asahi Kasei Chemicals Corporation).
A spherical nucleus G having a particle size of 300 to 500 μm was obtained with a sieve. The ratio of the particle diameter of 300 to 500 μm was 30% by mass with respect to the whole spherical nucleus before sieving. When the obtained spherical nucleus G was observed with a high-resolution scanning electron microscope (SEM), the surface was smooth. Further, the volume swelling degree, sphericity degree, and density were determined according to the above-described methods, and those values are shown in Table 2.
Using the spherical nucleus G, spherical element granules G were obtained in the same manner as in Example 1.
Subsequently, the obtained spherical elementary granules G were used in the same manner as in Example 1 to obtain spherical granules G coated with 30% by mass of ethyl cellulose and triethyl citrate in solid content.

[Example 7]
In Example 3, spherical nuclei were obtained in exactly the same manner except that crospovidone (polyplastidone XL-10 / ISP) was used instead of croscarmellose sodium (Kickolate ND-2HS / Asahi Kasei Chemicals Corporation). It was.
A spherical nucleus H having a particle size of 300 to 500 μm was obtained with a sieve. The ratio of the particle diameter of 300 to 500 μm was 39% by mass with respect to the whole spherical nucleus before sieving. When the obtained spherical nucleus H was observed with a high-resolution scanning electron microscope (SEM), the surface was smooth. Further, the volume swelling degree, sphericity degree, and density were determined according to the above-described methods, and those values are shown in Table 2.
Using spherical nuclei H, spherical elementary granules H were obtained in the same manner as in Example 1.
Next, using the obtained spherical elementary granules H, spherical granules H coated with 30% by mass of ethyl cellulose and triethyl citrate in solid content were obtained in the same manner as in Example 1.

[Test Example 2]
In accordance with the method described above, drug dissolution tests on spherical granules G and H were performed. The elution amount of riboflavin was measured by the UV method (wavelength: 445 nm) and evaluated by the percentage of the elution amount with respect to the amount of riboflavin contained in the spherical granules G and H. The obtained elution curve is shown in FIG. 2, and each release start time (time when the drug dissolution rate is less than 5%) and release time (time from the release start time until the drug dissolution rate reaches 80% or more) ) Is shown in Table 2.

In Examples 3, 6, and 7, the type of swelling agent is evaluated.
From Examples 3, 6, and 7 (Tables 1, 2 and 2), it was confirmed that spherical nuclei having substantially the same physical properties could be obtained even if the type was changed if the mixing ratio of the swelling agent was the same. Among the swelling agents listed in Example 6, carboxymethyl starch sodium having the greatest swelling property, croscarmellose sodium having the moderate swelling property, and crospovidone having the smallest swelling property were confirmed. As a result, similar results are expected to be obtained using other swelling agents. In addition, the spherical granules G and H (Examples 6 and 7) showed a release start time of 30 minutes and a release time of 30 minutes as in the case of the spherical granules C (Example 3), and the same effect could be confirmed. .

[Example 8]
In Example 3, the amount of distilled water added while stirring with a high-speed agitation granulator (vertical granulator FM-VG-10P / Paurec Co., Ltd.) was 2000 g (a mass ratio of 5.0 times the swelling agent). A spherical nucleus was obtained in exactly the same manner except that
A spherical nucleus I having a particle size of 300 to 500 μm was obtained with a sieve. The ratio of the particle diameter of 300 to 500 μm was 11% by mass with respect to the whole spherical nucleus before sieving. When the obtained spherical nucleus I was observed with a high-resolution scanning electron microscope (SEM), the surface was uneven. Further, the volume swelling degree, sphericity degree, and density were determined according to the above-described methods, and those values are shown in Table 3.

[Example 9]
In Example 3, the stirring conditions of a high-speed stirring granulator (vertical granulator FM-VG-10P / Paurec Co., Ltd.) were as follows: main blade 879 m / min (radius 14 cm, 900 rpm), cross screw 754 m / min (radius 4 cm) A spherical nucleus was obtained in exactly the same manner except that the rotation speed was 3000 rpm.
A spherical nucleus J having a particle size of 300 to 500 μm was obtained with a sieve. The ratio of the particle size of 300 to 500 μm with respect to the whole spherical core before sieving was 13% by mass. When the obtained spherical nucleus J was observed with a high-resolution scanning electron microscope (SEM), the surface was uneven. Further, the volume swelling degree, sphericity degree, and density were determined according to the above-described methods, and those values are shown in Table 3.

In Examples 8 and 9, the production conditions of spherical nuclei are evaluated.
Compared with the spherical nucleus C (Example 3), the spherical nucleus I had a distorted shape (low sphericity), a rough surface, and a low volume swelling degree. This is probably because the swelling agent could not swell sufficiently due to the small amount of water added, and the crystalline cellulose and the swelling agent were mixed non-uniformly to form spherical nuclei. It was confirmed that there was an amount of water.
Compared with the spherical nucleus C (Example 3), the spherical nucleus J had the same volume swell, but the shape was distorted (the sphericity was low) and the surface was rough. This seems to be because the spheroidization could not be appropriately made due to the high stirring speed, and it was confirmed that there were optimum stirring conditions for obtaining a preferable spherical nucleus.
The spherical nucleus C has a substantially true sphere shape, and it is highly possible that a good preparation can be obtained.

[Example 10]
Using the spherical granule C obtained in Example 3, in the same manner as in Example 1, spherical granules K coated with 40% by mass of ethyl cellulose and triethyl citrate in solid content, and spherical particles coated with 60% by mass Granule L was obtained.

[Test Example 3]
In accordance with the method described above, a drug dissolution test on the spherical granules K and L was performed. The elution amount of riboflavin was measured by the UV method (wavelength: 445 nm) and evaluated by the percentage of the elution amount with respect to the amount of riboflavin contained in the spherical granules K and L. The obtained elution curve is shown in FIG. 3, and each release start time (time when the drug elution rate is less than 5%) and release time (time from the release start time until the drug elution rate becomes 80% or more) ) Is shown in Table 4.

In Example 10, the coating amount of the water-insoluble substance is evaluated.
Compared to the elution pattern of spherical granules C (Example 3) coated with 30% by mass using the same spherical nucleus, spherical granules K and L coated up to 40% by mass and 60% by mass have the release start time, In addition, it was confirmed that the release time was long and the drug elution could be controlled by the coating amount of the water-insoluble substance. This is considered to be because when the coating amount of the water-insoluble substance increases, it becomes difficult for water to penetrate.

  The present invention can be suitably used in the pharmaceutical field, particularly in time pharmacotherapy. It can be used as a membrane-ruptured time-release preparation with high accuracy and easy drug elution control.

Claims (12)

  A spherical nucleus composed of a mixture containing crystalline cellulose and a swelling agent.   The spherical nucleus according to claim 1, wherein the mass ratio of the crystalline cellulose to the swelling agent is 90:10 to 30:70.   The spherical nucleus according to claim 1 or 2, wherein the mass ratio of the crystalline cellulose to the swelling agent is 60:40 to 40:60.   The spherical nucleus according to any one of claims 1 to 3, wherein a volume swelling degree due to water absorption is 100% to 700%.   The spherical nucleus according to any one of claims 1 to 4, wherein the sphericity is 0.7 or more and 1 or less.   The spherical nucleus according to any one of claims 1 to 5, wherein the density is 0.8 g / ml or more and 1 g / ml or less.   The spherical nucleus according to any one of claims 1 to 6, wherein the particle diameter is 200 to 500 µm.   The swelling agent is at least one selected from croscarmellose sodium, pregelatinized starch, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, and crospovidone. Spherical nucleus.   A spherical elementary granule characterized in that the surface of the spherical nucleus according to any one of claims 1 to 8 is coated with a drug.   A spherical granule characterized in that the surface of the spherical elementary granule according to claim 9 is coated with a water-insoluble substance.   The spherical granule according to claim 10, wherein the drug release start time is 15 to 30 minutes.   The method for producing a spherical nucleus according to any one of claims 1 to 8, wherein the crystalline cellulose and the swelling agent are spheroidized in a wet state.