WO2008001591A1

WO2008001591A1 - Nucleus particle for layering and method for producing the same

Info

Publication number: WO2008001591A1
Application number: PCT/JP2007/061541
Authority: WO
Inventors: Narimichi Takei; Takeshi Honma; Ikuo Tanai; Terumi Takahashi
Original assignee: Freund Corporation
Priority date: 2006-06-29
Filing date: 2007-06-07
Publication date: 2008-01-03
Also published as: JP2008007458A

Abstract

Disclosed is a nucleus particle for layering which is composed of a non-active component. The surface of the nucleus particle for layering is covered with an active component. The nucleus particle for layering has a core particle mainly composed of a sugar and a covering layer formed on the surface of the core particle. In particular, a high effect can be achieved by having the covering layer mainly composed of a polymer compound such as a cellulose derivative.

Description

Specification

Core particle for layering and manufacturing method thereof

Technical field

[0001] The present invention relates to a core particle for layering for coating an active ingredient (drug) on its surface and a method for producing the same.

This application claims priority based on Japanese Patent Application No. 2006-179684 filed in Japan on June 29, 2006, the contents of which are incorporated herein by reference.

Background art

[0002] In DDS (Drug Delivery System), there is a technique called Controlled Release (release control) as one of the techniques for optimally maintaining the active ingredient concentration hourly pattern at the site of action of the active ingredient.

As a sustained-release preparation (Controlled Release preparation) for realizing such a method, the active ingredient is coated on the surface of core particles for layering (for example, “Nonparel (registered trademark)” manufactured by Freund Sangyo Co., Ltd.). (Layered), a film base material that has been further coated according to the purpose (see, for example, Patent Document 1) or a hard capsule filled is known.

[0003] Here, the core particle for layering is usually composed of a component that does not contain an active component, that is, a component that is an inactive component, and serves as a central core (hereinafter referred to as a central core particle). Is rolled in various granulators, and the powder that is the main component of the core particles for layering is supplied thereto, and the granulation is performed by spraying a liquid for wetting the central core particles and the powder. Then, it is manufactured by a method of drying the granulated particles.

As the main component of the core particle for layering, sugars such as sucrose and lactose; sugar alcohols such as xylitol and mannitol; crystalline cellulose and z or powdered cellulose; starches such as corn starch are often used.

Patent Document 1: Japanese Patent Laid-Open No. 2002-284674

Disclosure of the invention

Problems to be solved by the invention [0004] However, some sugars have reactivity (for example, Maillard reaction) with some of the active ingredients. There is a problem that the type of active ingredient layered on the surface is limited. In addition, sugar has a relatively low mechanical strength (hardness). When a strong shearing force is applied to particles during granulation, wear or breakage occurs at the time of layering. There was also a problem that it was inferior and layering was inferior. In addition, the blocking particles thus generated are removed by sieving or the like, and as a result, the recovery rate of the drug particles having a target particle size is lowered. Furthermore, if wear or damage occurs during layering, losses due to the loss occur, which is disadvantageous in terms of workability and cost during layering.

On the other hand, layering core particles mainly composed of crystalline cellulose are preferable in that they have little reactivity with active ingredients having high hardness. However, such layering core particles are water-insoluble and have high moisture absorption, so that the active ingredient is layered on the surface of the layering core particle while keeping the surface of the core layer wet with water. It was difficult to do, but there was also a problem with layering. If layering is difficult, it will not be possible to efficiently layer to the target active ingredient content, and in this case also, the recovery rate of drug particles with the target particle size will decrease.

[0005] The present invention has been made in view of the above circumstances, and it is possible to satisfactorily layer a wide variety of active ingredients on the surface, and to obtain layered drug particles having a desired particle size at a high recovery rate. It is an object to provide a nuclear particle for layering that can be performed.

Means for solving the problem

[0006] As a result of intensive studies, the present inventors have found that the above problem can be solved by forming a coating layer on the surface of the layering core particles, and have completed the present invention. The layering core particle according to the first aspect of the present invention is a layering core particle composed of a non-active component and having an active component coated on the surface thereof, the saccharide being a main component. Core particles, and a coating layer formed on the surface of the core particles.

The saccharide is preferably at least one selected from the group consisting of sugar, sugar alcohol, starches, powdered cellulose, and crystalline cellulose. The coating layer preferably contains a polymer compound as a main component.

A cellulose derivative is suitable as the polymer compound.

The method for producing core particles for layering according to the second aspect of the present invention is a method for producing core particles for layering in which the active ingredient is coated on the surface, and the main component is sugar. A core particle production process for producing core particles as components; and a coating layer forming process for forming a coating layer on the surface of the core particles.

In the coating layer forming step, the coating layer is preferably formed by spraying a coating layer forming component-containing liquid.

The invention's effect

[0007] According to the present invention, it is possible to provide core particles for layering that can satisfactorily layer a wide variety of active ingredients on the surface and obtain layered drug particles with a high recovery rate.

Brief Description of Drawings

FIG. 1 is a cross-sectional view showing an example of a layering core particle of the present invention.

FIG. 2 is a cross-sectional view showing the main part of an example of a centrifugal tumbling granulator used in the production method of the present invention.

Explanation of symbols

[0009] 10 Core particles for layering

11 core particles

12 Coating layer

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail.

The layering core particle of the present invention is for coating the surface with an active ingredient, and is suitably used, for example, in the field of sustained-release preparations. The core particle for layering itself is a component that does not contain an active ingredient, that is, an inactive ingredient, and is formed on the core particle 11 having a saccharide as a main component and the surface of the core particle 11 as shown in FIG. It has a coating layer 12. In FIG. 1, reference numeral 10 denotes a nuclear particle for layering. [0011] Here, the saccharides that are the main components of the core particles 11 include sugars, sugar alcohols, starches, powdered cellulose, crystalline cellulose, and the like that are commonly used as pharmaceutical or food additives. One or more of these can be used.

In the present specification, the main component refers to a component that occupies 50% by mass or more of the whole.

Sugars include sugars such as sucrose, sucrose, lactose, glucose, fructose and maltose; sugar alcohols such as xylitol, sorbitol, mannitol, maltitol, ratitol and erythritol; starches such as corn starch, rice starch and dextrin; powder Examples include cellulose and crystalline cellulose. Among these, cores are sugars that are reactive with some of the active ingredients and do not exhibit sufficient hardness, and crystalline cellulose that has high moisture absorption and insufficient active ingredient layering. In the case where it is the main component of the particle 11, as will be described in detail later, the effect of forming the coating layer 12 is particularly effective.

The particle size of the core particle 11 is not particularly limited, but it is preferable that the particle size (sieving method) is:! To 2000 / im.

[0012] The coating layer 12 formed on the surface of the core particle 11 is preferably formed mainly of a high molecular compound that is usually used as an additive for pharmaceuticals or foods.

The polymer compound may be either a natural polymer compound or a synthetic polymer compound. Specifically, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succin Preferred examples include cellulose derivatives such as nate, ethylcellulose, methinorescenellose, canoleboxi chinenorescenellose, hydroxyethinorescenellose, and cellulose acetate phthalate. Other examples include acrylic polymers such as amino alkyl methacrylate copolymers and methacrylic acid copolymers, corn starch, alpha starch, partially alpha starch, starch such as hydroxypropyl starch, dextrin and pullulan, polyvinyl alcohol, poly Butyl acetate phthalate, polybutyl pyrrolidone, gum arabic powder, sodium alginate, agar, gelatin, xanthan gum, hemicellulose, shellac, zein, polyoxyethylene polyoxypropylene glycol, carboxybutyl polymer, acetoacetate Examples include roulose and yeast extract.

By providing such a coating layer 12, the active ingredient layered on the surface of the layering core particle 10 and the core particle 11 do not come into direct contact with each other. Therefore, even when there is reactivity between the core particle 11 and the active ingredient to be layered, the reaction is suppressed. Even when it is a main component, a wide variety of active ingredients can be layered without restriction.

Further, when such a coating layer 12 is provided, the core particle 10 for layering with higher hardness can be obtained in addition to the above-described effects. The core particle 10 for layering with high hardness is also suitable from the viewpoint of a modification with less damage and wear.

In addition, when such a coating layer 12 is provided, when the main component of the core particle 11 is moistened with moisture and is blocking sucrose, the penetration of moisture into the core particle 11 can be reduced, and blocking during layering can be achieved. Can be suppressed. Since the blocking particles generated by blocking are removed by sieving or the like, if blocking occurs, the recovery rate of drug particles having the intended particle size will eventually decrease. Such problems can also be avoided. On the other hand, even when the main component of the core particle 11 is crystalline cellulose having a high water absorbability, by providing the coating layer 12 in this manner, the water absorbability is reduced and an appropriate wettability can be maintained, thereby improving efficiency. Layering progresses. When the layering progresses efficiently, the drug particles with a small particle size due to the difficulty of the layering decrease, and the recovery rate of the drug particle with the target particle size is improved.

[0014] Among these, it is preferable to select the above-described polymer compound as the main component of the coating layer 12 in terms of obtaining such an effect, and cellulose derivatives are preferable. When the main component of the coating layer 12 is a cellulose derivative, it is easy to obtain layering core particles 10 with higher hardness, which is also preferable. More preferably, the ratio of the cellulose derivative in the coating layer 12 is 80% by mass or more, and more preferably 90% by mass or more. The upper limit of the ratio of the cellulose derivative in the coating layer 12 is preferably 100% by mass or less.

The coating layer 12 may contain an additive such as a colorant such as a pigment or a plasticizer for enhancing the film forming property. However, some additives have reactivity with active ingredients. Care must be taken when using plasticizers in particular. It is preferable to use a plasticizer as much as possible.

[0015] In addition, examples of sugar alcohols that may be formed of the sugar alcohol as the main component of the coating layer 12 include xylitol, erythritol, and mannitol. Among these, D-mannitol having no Maillard reaction with an active ingredient having an amino group is particularly suitable.

The thickness of the coating layer 12 is not particularly limited. However, when the mass of the core particle 11 is 100%, the thickness of the coating layer 12 is preferably in the range of 0.5 to 200%. Masle.

[0016] The layering core particle 10 as described above includes a core particle manufacturing process for manufacturing a core particle 11 mainly composed of a saccharide, and a coating layer for forming a coating layer 12 on the surface of the manufactured core particle 11. The core particle manufacturing process can be performed by a centrifugal tumbling granulator 20 as shown in FIG. 2, for example.

The centrifugal rolling granulator 20 of FIG. 2 includes a centrifugal rolling chamber 21 that granulates while rolling powder. The centrifugal rolling chamber 21 has a cylindrical fixed wall 22 disposed so that its axis is in the vertical direction, and is disposed inside the fixed wall 22 and is spaced from the inner wall of the fixed wall 22 with a predetermined tarance. And a circular rotating plate 23 that rotates in the horizontal direction about the central axis 24, and by rolling the powder on the rotating plate 23, this powder is formed into spherical core particles 11. It is something to granulate. In this example, the rotating dish 23 has a shape in which the peripheral edge is gradually inclined upward, and the powder can be uniformly rolled thereon.

In the centrifugal rolling chamber 21, a thermometer such as a thermocouple (not shown) is installed so that the particle temperature can be measured.

[0017] The centrifugal rolling chamber 21 is provided with a powder supply pipe (powder supply device) 25 so that the raw material powder of the core particles 11 can be dispersed. In addition, the centrifugal rolling chamber 21 is also provided with a spray device 26, and a liquid for promoting the aggregation of the powder or a liquid containing a component that acts as a binder is contained in the centrifugal rolling chamber 21 as necessary. Can spray. Further, in this example, an air chamber 27 is formed below the rotating dish 23, and a compressed air supply pipe 28 is connected to the air chamber 27, and compressed air is supplied into the air chamber 27 from the compressed air supply pipe 28. By feeding in, between the inner wall of the fixed wall 22 and the rotating plate 23 High-pressure air (hereinafter referred to as “slit air”) is introduced from the clearance into the centrifugal rolling chamber 21 to further improve the mixing and circulation of the powder. Reference numeral 29 in the figure denotes an exhaust port.

[0018] In order to produce the core particles 11 using this centrifugal rolling granulator 20, first, powder is introduced from the powder supply pipe 25, and the rotating dish 23 is about 360mm in diameter. For example, rotate at 40-400 rpm. Then, while introducing the slit air into the centrifugal rolling chamber 21, the liquid is sprayed from the spray device 26 and granulated while moistening the powder.

The size of the powder to be introduced is not particularly limited, but those having an average particle size of:! To 100 zm are preferred, and more preferably 10 to 50 zm.

[0019] Examples of the liquid to be sprayed (hereinafter sometimes referred to as a spraying liquid) include water, alcohol, and the like, and the granulated powders agglomerate with each other when they come into contact with the liquid and become wet. In the case of a product, such spraying of the liquid for spraying is effective.

As the spray liquid, a solution in which a component that acts as a binder between powders is dissolved or dispersed in water can be suitably used. Such components include sugar derivatives such as sugar, sugar alcohol, crystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate succinate, starches, polyvinylpyrrolidone, poly (meth) acrylic acid and Examples thereof include esters, polyvinyl alcohol and derivatives thereof, and polyoxyethylene hydrogenated castor oil. These components may be used alone or in combination of two or more, but are particularly selected from the group consisting of sugar, sugar alcohol, starches, crystalline cellulose, hydroxypropyl cellulose, and polyvinylpyrrolidone. When one or more types are used, a stronger binder force is exhibited when the powder is mainly composed of saccharides, and core particles 11 with higher hardness are easily obtained, which is preferable. The concentration of these components in the spray liquid may be set as appropriate according to the type of the component. In the present specification, “(meth) attalinoleic acid” means one or both of acrylic acid in which a hydrogen atom is bonded to the primary position and methacrylic acid in which a methyl group is bonded to the primary position. Unless otherwise specified, the asterisk (the carbon atom at the arbor) is a carbon atom to which a carbonyl group is bonded.

[0020] Further, in the core particle manufacturing process, the powder can be granulated in the presence of the central core particle. In that case, first, the central core particles are charged into the centrifugal rolling chamber 21, and then the rotating dish 23 is rotated while introducing the slit chamber into the centrifugal rolling chamber 21. Next, while introducing the raw material powder into the centrifugal rolling chamber 21 from the powder supply pipe 25, the spraying liquid is sprayed from the spray device 16, and the powder and / or the core particles are granulated while being wetted. . By using the central core particles in this way, the powder tends to aggregate around the central core particles, and granulation can be performed more efficiently.

Preferable central core particles include granulated sugar and secondary particles in which saccharide powder is associated. The secondary particles associated with the saccharide powder are those obtained by previously moistening the primary particles of the saccharide powder and mixing and associating with some pressure. The size and shape of the central core particles can be selected as appropriate, but those having a particle diameter measured by a sieving method in the range of 50 to 1000 μm are preferred.

The amount of the central core particles to be used can be appropriately set, but is usually in the range of 50 to 1000 parts by mass with respect to 100 parts by mass of the powder supplied from the powder supply pipe 25.

[0021] After the granulation in this way, the undried wet particles are taken out from the centrifugal tumbling granulator 20, and a fluidized bed apparatus (for example, a fluidized bed granulated coating apparatus "Flow coater" manufactured by Freund Sangyo Co., Ltd.) The core particles 11 can be obtained by transferring to the apparatus and drying.

Next, the obtained core particles 11 are made to flow with heated air in the fluidized bed apparatus, and the coating layer forming component-containing liquid is sprayed into the fluidized bed apparatus (coating layer forming step), whereby the core It is possible to obtain the layering core particle 10 in which the coating layer 12 is formed on the surface of the particle 11. Thus, the method of performing the coating layer forming step in the fluidized bed apparatus is particularly preferable when forming the coating layer 12 mainly composed of a polymer compound, and in such a case, the coating layer forming component-containing liquid is used. As a coating solution, the coating layer forming component mainly composed of a polymer compound is dissolved and Z or dispersed in water and Z or alcohol. The concentration of the coating layer forming component in the coating layer forming component-containing liquid is not particularly limited, but the coating layer 12 can be formed more satisfactorily when it is:! To 30% by mass.

On the other hand, a coating layer 12 mainly composed of powdered sugar alcohol such as D_mannitol is applied. In the case of formation, first, the obtained core particles 11 are again put into a centrifugal rolling granulation apparatus 20 as shown in FIG. The sugar alcohol is supplied from and sprayed with a spraying liquid selected from the examples exemplified above. Then, unwet wet particles are taken out from the centrifugal tumbling granulator 20, transferred to another drying device such as a fluidized bed device, and dried, whereby sugar alcohol is mainly contained on the surface of the core particles 11. The core particle 10 for layering in which the coating layer 12 is formed can be obtained.

In addition to the fluidized bed apparatus such as a fluidized bed granulation coating apparatus, the coating layer 12 can be formed by a centrifugal rolling granulation coating apparatus (for example, “CF Durayuratori”, “Daranyu” manufactured by Freund Sangyo Co., Ltd.). Rex "etc.) and a composite granulation coating apparatus (for example," Spiraflow "manufactured by Freund Sangyo Co., Ltd.) can be used.

[0023] As another method for producing layering core particles, a method of using a device equipped with a microwave introduction means in the centrifugal tumbling granulator 20 can be exemplified.

As such an apparatus, one having a configuration in which one end of a microwave waveguide is connected as a microwave introduction means to the lid 20a in FIG. According to such a device, the microwave oscillated from the microwave oscillating device is transmitted and introduced into the centrifugal rolling chamber 21 by connecting the microwave oscillating device to the other end of the microwave waveguide. , Centrifugal rolling chamber 2

The particles in 1 can be irradiated with microwaves.

[0024] When such an apparatus is used, the core particle manufacturing process and the coating layer forming process can be performed continuously in one apparatus, and no transfer work is required. Produces core particles 10 for layering.

Specifically, the core particles 11 are produced in a centrifugal tumbling granulator equipped with microwave introduction means, and then the granulated core particles 11 are dried while being irradiated with microwaves. A coating layer 12 is formed on the core particle 11.

[0025] The layering core particle 10 thus produced has an active component coated on its surface.

, Become drug particles. Further, coating of a film base according to the purpose, filling into a hard capsule, etc. is carried out as necessary to make a drug such as a sustained-release preparation. The active ingredient coating is applied by centrifugal rolling granulation coating equipment (for example, “Freund Sangyo Co., Ltd.”

“CF Daranayureta”, “Daranurex”, etc. ), Fluidized bed granulation coating equipment (example: For example, “Flow Coater” manufactured by Freund Corporation. ), A composite granulation coating apparatus (for example, “Spiraflow” manufactured by Freund Corporation) or the like.

[0026] Such layering core particle 10 is obtained by forming a covering layer 12 on the surface of a core particle 11 containing saccharides as a main component, and includes a core particle 11 and an active ingredient to be coated. A covering layer 12 is interposed between them. Therefore, a wide variety of active ingredients can be satisfactorily layered on the surface without being limited by the reactivity with the core particle 11.

Active ingredients include, for example, hypnosis, sedative, antipyretic analgesic / anti-inflammatory agent, neuropsychiatric agent, autonomic nerve agent, anti-parkinsonian agent, antihistamine, cardiotonic agent, diuretic agent, antihypertensive agent, vasoconstrictor, arteriosclerotic agent Antitussive expectorant, vitamins, nourishing tonics, antibiotics, gastrointestinal drugs, etc.

In addition, since the core particle 10 for layering is also excellent in layering properties (blocking suppression, layering efficiency), it is possible to obtain drug particles having a target particle size with a high recovery rate.

Furthermore, when the main component of the coating layer 12 is a polymer compound such as a cellulose derivative, the core particle 10 for layering can be provided with high hardness and low damage and wear during layering.

Example

[0027] [Core particle production example 1]

In the centrifugal rolling chamber 21 of the centrifugal rolling granulator 20 shown in Fig. 2, 1.5 kg of granulated sugar with a particle size (sieving method) of 20 0 to 300 111 is charged as the core particle, and slit air is supplied. The rotating pan 23 was rotated at 160 rpm. Next, 3 kg of a mixed powder composed of 60% by mass of refined sucrose powder having an average particle size of 10 μm and 40% by mass of corn starch is supplied from the powder supply tube 25 into the centrifugal rolling chamber 21, and a 5% by mass hydroxypropylmethyl cell. An aqueous solution of sucrose (HPMC) is sprayed from the spray device 26 into the centrifugal rolling chamber 21 and granulated, and then the wet particles obtained are mixed with a fluidized bed granulation coating device (“flow coater type 5”, “ (Freund Sangyo Co., Ltd.) and set in this fluidized bed equipment at 90 ° C. The specified heated air was introduced and dried until the temperature of the particles reached 60 ° C. The granulated product was sieved to 355-500 μm to make the core particle (1).

[0028] [Core particle production example 2]

Granulation was performed in the same manner as in Core Particle Production Example 1 except that 3 kg of purified sucrose powder having an average particle size of 10 zm was used as the powder supplied from the powder supply pipe 25 instead of the mixed powder. Next, the resulting undried wet particles were transferred into a fluidized bed granulation coating device (“Flow Coater Type 1-5”, manufactured by Freund Corporation) and installed in this fluidized bed device at 80 ° C. Introduced heated air was introduced and dried until the particle temperature reached 50 ° C. The granulated product obtained by further IJing to 355 to 500 μm was used as the core particle (2).

[0029] [Core particle production example 3]

2 kg of crystalline cellulose powder with an average particle size of 50 zm is placed in the centrifugal rolling chamber 21 of the centrifugal rolling granulator 20 shown in Fig. 2, and the rotating dish 23 is rotated by 200ι · ρπι while supplying slit air. It was. In this state, purified water was sprayed from the spray device 26 into the centrifugal rolling chamber 21 and granulated until the particle diameter grew to about 355 to 500 μm.

Next, the resulting undried wet particles were transferred into a fluidized bed granulation coating device (“Flow coater 1-5”, manufactured by Freund Sangyo Co., Ltd.) and dried in the same manner as in Core Particle Production Example 2. did. The granulated product was sieved to 355 to 500 μm to obtain core particles (3).

[0030] [Example 1]

Put 3 kg of core particles (1) into a fluidized bed granulation coating device (“Flow Coater Type 1-5”, manufactured by Freund Sangyo Co., Ltd.), and introduce heated air set at 80 ° C. A 5 mass% ^ 1 PMC aqueous solution was sprayed to form a coating layer on the surface of the core particles (1). Here, the amount of spray spraying was set so that the mass of HPMC was 3Z100 of the mass of the core particles (1). After spraying the HPMC aqueous solution, the particles were dried until the temperature of the particles reached 50 ° C to obtain layering core particles (1), and the following evaluation was performed.

[0031] (Evaluation) (1) Degree of wear

The obtained core particles for layering (1) are sieved to a particle size of 355-500 xm, and about 10 g is precisely weighed (Wt) and placed in a stainless steel cylindrical container with an inner diameter of 32 mm and a depth of 65 mm. The mixture was shaken with a mixer mill (SPEX) for 10 minutes. After shaking, mesh opening 300 μ The fine powder was removed by transferring to a sieve of m (No. 50), and the residue (Ws) on the sieve was precisely weighed, and the friability was obtained by the following formula (i).

Note that the friability of the core particles for normal layering is preferably 1.0% or less, more preferably 0.3% or less. Therefore, in this evaluation, the friability is less than 0.3% as A, 0.3 or more and less than 1.0% as B, and 1.0% or more as C, and the results are shown in Table 1.

Friction (%) = (Wt-Ws) / Wt X 100 · · · (i)

[0032] (2) Recovery rate of drug particles after layering

The obtained core particles for layering (1) are sieved to a particle size of 355 to 500 xm, and 1 kg is weighed and charged into the centrifugal rolling chamber 21 of the centrifugal rolling granulator 20 shown in FIG. Then, the rotating plate 23 was rotated at 160 rpm while supplying slits. Next, lkg of aminophylline with an average particle size of 15 zm is supplied as an active ingredient from the powder supply pipe 25 into the centrifugal rolling chamber 21 and a 2% by mass 1!? 1 ^ 〇 aqueous solution is supplied from the spray device 26 to the centrifugal rolling chamber 21. Sprayed inside to obtain undried drug particles layered with the active ingredient.

Next, the undried drug particles are transferred into a fluidized bed granulation coating device (“Flow Coater Type 5”, manufactured by Freund Corporation) and heated to 50 ° C. in the fluidized bed device. Air was introduced and dried until the particle temperature reached 40 ° C.

From the thus obtained dried drug particles, those having a particle size of 425 to 600 μm were sieved, and the mass ratio with respect to the total amount of the drug particles after drying was determined to obtain the recovery rate (%). The results are shown in Table 1.

[0033] (3) Rate of color difference change of drug particles after layering

About 100 g of the dried drug particles obtained in (2) above were placed in a Sampnole bottle, sealed, and stored in a 60 ° C incubator for 7 days. The color difference before and after storage was measured and the rate of change ΔΕ was determined. The results are shown in Table 1, where 8 is less than 0 to less than 0, B is 10 or more and less than 20, and C is 20 or more. For color difference meter, Nippon Denshoku Industries Co., Ltd .: SZ_∑90 is used, and color difference Δ 基づき is measured based on L * a * b * color system in accordance with JIS Z-8729, 8730. did.

[0034] [Example 2]

A core particle for layering (2) was obtained and evaluated in the same manner as in Example 1 except that the core particle (2) was used instead of the core particle (1). The results are shown in Table 1. [0035] [Example 3]

A core particle for layering (3) was obtained and evaluated in the same manner as in Example 1 except that the core particle (3) was used instead of the core particle (1). The results are shown in Table 1.

[Example 4]

2 kg of core particles (1) were charged into the centrifugal rolling chamber 21 of the centrifugal rolling granulator 20 shown in FIG. 2, and the rotating dish 23 was rotated at 160 rpm while supplying slit air. Next, 1 kg of D-mannitol having an average particle size of 13 zm is supplied from the powder supply pipe 25 into the centrifugal rolling chamber 21 and a 5 mass% 1!? 1 ^ 〇 aqueous solution is supplied from the spray device 26 to the centrifugal rolling chamber 21. Sprayed on.

Next, the contents were transferred into a fluidized bed granulation coating device (“Flow Coater Ichiichi Type 5”, manufactured by Freund Sangyo Co., Ltd.), and heated air set at 80 ° C in this fluidized bed device. It was introduced and dried until the temperature of the particles reached 50 ° C to obtain core particles for layering (4). Then, in the same manner as in Example 1, the recovery rate and color difference change rate of drug particles after layering were evaluated. The results are shown in Table 1.

[0037] [Example 5]

A core particle for layering (5) was obtained and evaluated in the same manner as in Example 4 except that the core particle (2) was used instead of the core particle (1). The results are shown in Table 1.

[0038] [Example 6]

A core particle for layering (6) was obtained and evaluated in the same manner as in Example 4 except that the core particle (3) was used instead of the core particle (1). The results are shown in Table 1.

[Comparative Example 1]

For the core particles (1) obtained in Core Particle Production Example 1, the friability of the core particles 1, the recovery rate of drug particles after layering, and the color difference change rate were evaluated in the same manner as in Example 1. The results are shown in Table 1.

[Comparative Example 2]

For the core particles (2) obtained in the core particle production example 2, the friability of the core particles 2, the recovery rate of the drug particles after layering, and the color difference change rate were evaluated in the same manner as in Example 1. The results are shown in Table 1. [Comparative Example 3]

For the core particles (3) obtained in Core Particle Production Example 3, the friability of the core particles 3, the recovery rate of drug particles after layering, and the color difference change rate were evaluated in the same manner as in Example 1. The results are shown in Table 1.

[table 1]

As shown in Table 1, the core particles for layering in each Example in which a coating layer was formed on the surface of the core particles were excellent in layering properties, and drug particles with the desired particle size were obtained with a high recovery rate. It was. In addition, even when layering core particles using sugar as a core particle are layered with an aminophylline reactive with sugar as an active ingredient (Examples 1, 2, 4, and 5), a coating layer is formed. Therefore, it was shown that discoloration due to a reaction with a small color difference change rate was suppressed. In particular, when the coating layer was formed from HPMC, a cellulose derivative, layering core particles with high hardness and low friability were obtained.

[Example 7]

Granulate in the same manner as in core particle production example (1) except that a centrifugal tumbling granulator equipped with microwave irradiation means was used. Without being transferred to, microwaves were irradiated in a centrifugal tumbling granulator equipped with microwave irradiation means and dried to obtain core particles.

Then, a 5 mass% HPMC aqueous solution was sprayed from the spray device 26 while continuously irradiating microwaves to form a coating layer. Here, the amount of spraying was set so that the amount of HPMC was 3/100 of the mass of the core particles.

According to such Example 7, the core particles and the coating layer could be dried in a shorter time than Example 1, which was efficient.

Moreover, when each evaluation similar to Example 1 was performed, the equivalent result was obtained. Industrial applicability

INDUSTRIAL APPLICABILITY The present invention is extremely useful industrially because it can provide layered core particles that can satisfactorily layer a wide variety of active ingredients on the surface and obtain layered drug particles with a high recovery rate.

Claims

The scope of the claims

[1] Non-active component power A layering core particle for coating an active component on its surface, comprising a core particle mainly composed of a saccharide and a coating layer formed on the surface of the core particle. Core particles for layering.

2. The core particle for layering according to claim 1, wherein the saccharide is at least one selected from the group consisting of sugar, sugar alcohol, starches, powdered cellulose, and crystalline cellulose.

[3] The core particle for layering according to claim 1, wherein the coating layer contains a polymer compound as a main component.

[4] The core particle for layering according to claim 3, wherein the polymer compound is a cellulose derivative.

[5] A method for producing layering core particles comprising a non-active component and having a surface coated with the active component,

A core particle production process for producing core particles mainly composed of sugars;

The manufacturing method of the core particle for layering which has the coating layer formation process which forms a coating layer on the surface of the said core particle.

6. The method for producing layering core particles according to claim 5, wherein in the coating layer forming step, the coating layer is formed by spraying a coating layer forming component-containing liquid.