JP2001151671A - Particle formulation with protrusion - Google Patents

Abstract

(57) [Summary] [Problem] To provide a particle preparation with projections having extremely excellent properties of being hard to roll while maintaining appropriate fluidity, and excellent in dispensing operability. SOLUTION: The present invention has a circularity coefficient of 0.85 to 1.
A protrusion-formed particle preparation in which protrusions are formed on spherical particles in the range of 00, wherein the degree of the protrusions is represented by the following formula B = (r ₂ −r ₁ ) / r ₂ , wherein r ₁ is a protrusion. Represents a radius of a circle inscribed in the particle projection image, and r ₂ represents a radius of a circle circumscribed in the particle projection image with projections.
A particle preparation having protrusions, which is in the range of 0.50.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a particle preparation with projections having excellent dispensing operability and a method for producing the same. The particle preparation with projections of the present invention has an extremely excellent property that it is difficult to roll while maintaining an appropriate fluidity, and is extremely useful as a particle preparation having excellent dispensing operability.

[0002]

2. Description of the Related Art In the case of oral solid pharmaceutical preparations, most of them are formed into particles by adding various additives to a powder of a medicinal ingredient and granulating the powder, and the particles are further processed as required. It is manufactured by doing.
For this reason, various studies have been made on the granulation technology as the most important technology among the formulation processing technologies, and various improvements have been made on a production granulation device and the like.

At present, among production granulators, agitated mixing granulators and tumbling granulators aiming at forming spherical particles having a sharp particle size distribution have been developed. It has become possible to produce fine granules and granules having a smooth surface. Further, it is possible to produce a particle preparation having a high degree of circularity by using a tumbling granulator also in a coating step for the purpose of masking bitterness, sustained release, entericization, and the like.

[0004] By the way, in the case of fine particles and granules, which require an adjustment of the amount of preparation, it is generally required that "dispensing operation is easy (excellent dispensing operability)". Fluidity is the most basic physical property for a prepared particle formulation, and spherical particles with a smooth surface meet that requirement.

[0005] However, as one of the phenomena obstructing the dispensing operation, there is a problem of run-off property often seen in a particle preparation having excellent fluidity. In other words, if the fluidity of the particle preparation is too good, the particle preparation may roll and escape from a predetermined place during dispensing operations such as weighing and division into medicine packaging paper, so that a part of the particle preparation is dissipated. There are many situations that make it unusable.

Aoki et al. Studied the escape property of the particle preparation as a measure for expressing the difficulty of handling the powder, and as a result, as a characteristic suitable for the preparation granule, the shape of the particle was examined. Reported that the surface was preferably irregular and rough (Pharmaceutics, 27, 103-106, 19
67 years).

Also, Sakashita et al. Describe a preferred particle preparation
He pointed out that it is a powder that does not adhere and has good fluidity but is hard to roll except for spherical shapes (Recent formulation technology and its applications I,
23-28, 1984 (published by Pharmaceutical Journal Co., Ltd.).

[0008] However, regarding a particle preparation having an appropriate flowability but a shape that does not easily roll, it is necessary to specifically describe what form the particles are and how to prepare the particle preparation. Is not described or suggested at all.

[0009] On the other hand, in the process of producing a particle preparation by fluidized bed granulation or crushing granulation, there may be cases where only irregular particles can be produced by chance, but only as a result, irregular particles are produced. However, this does not mean that it is possible to produce particles having a controlled shape and hard to roll as in the present invention.

As described above, although the production of true spherical particles has become relatively easy due to the advance of granulation technology,
There is still no known particle preparation which solves the problem of dispensing operation resulting from the escape property of spherical particles having a smooth surface.

[0011]

SUMMARY OF THE INVENTION An object of the present invention is to provide a particle preparation excellent in dispensing operability, which has an extremely excellent property that it is difficult to roll while maintaining an appropriate fluidity.

[0012]

Means for Solving the Problems The present inventors have found that a particle preparation with projections, in which projections having a certain degree of projection are formed on spherical particles, is difficult to roll while maintaining appropriate fluidity. It has been found that it has very good properties.

Thus, according to the present invention, there is provided a particle preparation having projections, wherein projections are formed on the surface of spherical particles having a circularity coefficient in the range of 0.85 to 1.00. The degree is expressed by the following equation: B = (r ₂ −r ₁ ) / r _{2 In the} equation, r ₁ represents the radius of a circle inscribed in the projected image of the projected particle, and r ₂ is the radius of a circle circumscribed in the projected image of the projected particle. Represents a value of the degree of protrusion B defined by 0.05 to
Provided is a particle formulation with protrusions, wherein the formulation is in the range of 0.50.

Further, according to the present invention, there is provided a method for producing a particle preparation having projections, wherein a projection-forming agent is sprayed on spherical particles under spraying of a binder solution to form projections on the surface of the particles. Is done.

Further, according to the present invention, there is provided a particle preparation with projections having a coating layer exhibiting a dissolution controlling effect on an inner layer portion and / or an outer layer portion of a projection layer formed by coating with a projection forming agent. .

In the present invention, the spherical particle is a spherical particle having a circularity coefficient in the range of 0.85 to 1.00, particularly 0.90 to 1.00. It is used as a nucleus when coating a projection-forming agent to be formed. The spherical particles generally contain active ingredients and excipients used in usual solid preparations, such as lactose, sucrose,
It contains saccharides such as D-mannitol; starches such as potato starch; cellulose derivatives such as crystalline cellulose; and inorganic salts such as calcium hydrogen phosphate and calcium sulfate.

Here, the circularity coefficient α is a value calculated according to the following equation, where F is the area of the portion surrounded by the curve having the length L.

Α = 4πF / L ² The circularity coefficient in the present invention is obtained by calculating the perimeter (L) and the projected area (F) of a particle projection image magnified by a microscope.
It can be calculated by applying the above equation.

The medicinal component contained in the spherical particles may be present in the spherical particle in a state of being mixed with the above-mentioned excipient, or the medicinal component may be coated on spherical core particles containing no medicinal component. It may exist in a state where it is not.

The size of the spherical particles used in the present invention is not particularly limited, but generally, the average particle size is 2000 μm.
m or less, especially in the range of 100-1000 μm.

For the production of these spherical particles, for example, a medicinal ingredient and the above-mentioned excipients are added, if necessary, to sugars such as sucrose; starches such as corn and potato; cellulose such as methylcellulose and hydroxypropylcellulose. Derivatives; vinyl polymers such as polyvinyl alcohol and polyvinyl pyrrolidone; acrylic polymers such as sodium polyacrylate and methacrylic acid copolymer; polyhydric alcohols such as polyethylene glycol;
Water; ethanol; granulation using a centrifugal tumbling granulator while adding a binder or a binder solution such as a water-ethanol mixture, and drying the resulting granules, or sizing the medicinal ingredients. The spherical core particles not containing, for example, sugars such as sucrose; starches such as corn and potato; cellulose derivatives such as methylcellulose and hydroxypropylcellulose; vinyl polymers such as polyvinyl alcohol and polyvinylpyrrolidone; sodium polyacrylate; While spraying a binder solution obtained by dissolving a binder such as an acrylic polymer such as a methacrylic acid copolymer or a polyhydric alcohol such as polyethylene glycol in water, ethanol, or a water-ethanol mixture, By spraying a medicinal component in the form of a sphere and coating the spherical core particles with the medicinal component Door can be.

Spherical core particles which can be used in the production of the above-mentioned spherical particles are also commercially available, for example, nonpareil (made by Freund Corporation, white spherical granules comprising purified sucrose or purified sucrose and starch) and Selfia (Asahi Kasei) Industrial, white or yellowish white spherical granules composed of crystalline cellulose). When using these commercially available spherical core particles, generally, those having an average particle size of 1000 μm or less, preferably 150 to 850 μm are suitably used, and the angle of repose of those spherical core particles is generally about 25 to
It shows a value of about 35 degrees and their escape rate is generally about 50
A value of about 70% is shown. Any spherical core particle having such values of the angle of repose and the escape rate can be used.

In the present invention, the "angle of repose" is defined as "Hidaka Shigesuke", Journal of the Society of Powder Technology, Vol. 24, pp. 664-669, 1
The values measured by the “injection method” described in 987, and the “escape rate” are shown in Aoki University: Pharmaceutical Sciences, Vol. 27,
It is a value measured by the method described in pages 103 to 106, 1967 (see Example 3 described later).

The projection-forming agent used in the present invention includes excipients in the form of powder that can form projections on the surface of spherical particles by coating and granulating the spherical particles. Examples of such powdered excipients include fine powdered substances having an average particle size of 10 μm or less, such as titanium oxide, synthetic aluminum silicate, dried aluminum hydroxide gel, magnesium stearate, calcium silicate, purified sucrose, and the like. At least one compound selected is mentioned, and preferably, titanium oxide, synthetic aluminum silicate or dried aluminum hydroxide gel can be used.

The granulation of the spherical particles with the projection-forming agent of the present invention can be carried out, for example, by spraying a powder of the projection-forming agent while spraying a binder solution on the spherical particles.

Examples of the binder solution used in the coating granulation step include purified sucrose, hydroxypropylcellulose, hydroxypropylmethylcellulose,
Methyl cellulose, ethyl cellulose and other binders with water,
Examples thereof include those dissolved in ethanol, a mixed solution of water and ethanol, and the solution is generally 0.1 to 70% (W / W);
Preferably, it can be used as a solution having a concentration of about 0.5 to 50% (W / W).

As the granulating apparatus used in the coating granulation step, any conventional granulating apparatus can be used, and particularly, a centrifugal tumbling granulator can be advantageously used.

For example, when using a centrifugal rolling granulator,
A rotating disk having a smooth surface is provided at the bottom of a cylindrical can, such as a centrifugal flow type coating granulator manufactured by Freund Corporation, and air is sent from the gap between the edge of the rotating disk and the can to powder. It is preferable to use an apparatus having a structure in which the granules are prevented from falling, fluidized, mixed and dried, and a spray device is provided above the rotating disk.
However, the centrifugal tumbling granulator is not particularly limited as long as it has the same function as the centrifugal flow type coating granulator. The rotation speed of the rotating disk in the centrifugal rolling granulator is generally in the range of 20 to 400 RPM, preferably 50 to 300 RPM, and the temperature of air sent from the gap between the edge of the rotating disk and the can body is generally 10
A temperature of 80 ° C, preferably about 20 to 60 ° C can be mentioned. As for the spraying device for spraying the binder solution, a pressurizing nozzle, a rotating disk, a two-fluid nozzle and the like which are used for spraying the solution in a normal preparation process can be used. Preferably, a two-fluid spray gun can be used.

The ratio of the binder solution to the spherical particles is not particularly limited, but generally the binder solution can be used in an amount of 0.3 to 3 g, preferably 0.5 to 2 g per 1 g of the spherical particles. In addition, the proportion of the protrusion forming agent used is generally 0.1 to 4 per g of the spherical particles.
g, preferably in the range of 0.3 to 3 g.

The projections are formed on the particle surfaces of the spherical particles by the coating granulation of the projection forming agent. In the present invention, the degree of the formed protrusion can be represented by the value of the protrusion degree (B) in the following equation.

B = (r ₂ −r ₁ ) / r _{2 In the} formula, B represents the degree of protrusion, r ₁ represents the radius of a circle inscribed in the projected particle projected image, and r ₂ represents the projected particle projected image. Represents the radius of a circle circumscribing.

According to the present invention, the particle preparation with protrusions of the present invention has a degree of protrusion (B) generally in the range of 0.05 to 0.50, preferably in the range of 0.10 to 0.35. And the standard deviation is usually 0.05 or less.

The measurement of the degree of protrusion can be usually performed by calculating the inscribed circle radius and the circumscribed circle radius with respect to the particle projection image enlarged by a microscope and applying the above formula.

As a result of the formation of the projections on the spherical particles, the circularity coefficient of the particle preparation with projections of the present invention is generally 0.60 to 0.60.
It shows a value in the range of 0.90 and its standard deviation is preferably less than 0.05.

Further, as a result of the formation of such projections,
This results in an increase in the angle of repose and a decrease in the escape rate in the protruding particle preparation of the present invention.

In the present invention, the material has a repose angle of about 2
When spherical particles having a diameter of 5 to 35 degrees are used, the particle preparation with projections on which a projection layer is formed increases spherical particles having a repose angle of at least 5 degrees or more and an escape rate of about 50 to 70%. When used, the reduction in the escape rate due to the formation of the projection layer is at least 10% or more. As a result, the particle preparation with protrusions of the present invention exhibits extremely excellent properties in dispensing operation such that it is difficult to roll while maintaining appropriate fluidity.

The thus-obtained particle preparation with projections of the present invention may further contain, for example, easily soluble, gastric, enteric or sustained-release compounds in the inner layer and / or outer layer of the projecting layer, depending on the intended use. Can be applied.

The granular preparation of the present invention having a coating layer on the inner layer portion of the protruding layer is usually prepared by applying a general coating apparatus such as a centrifugal rolling granulator or a fluidized bed granulator to spherical particles containing a medicinal ingredient. It can be produced by coating a film-forming component exhibiting a dissolution controlling effect by using the composition and then coating and granulating a projection-forming agent.

The granular preparation of the present invention having a coating layer on the outer layer portion of the projection layer is usually prepared by coating the above-mentioned coating apparatus on a particle preparation with projections obtained by coating and granulating spherical particles with a projection-forming agent. It can be manufactured by coating the film-forming component with the use.

In such a film-forming component, examples of the easily soluble or gastric-soluble film-forming component include hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, polyvinyl acetal diethylaminoacetate and the like. Examples of the enteric film-forming component include cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, and acrylic copolymers (Eudragit, manufactured by Rohm, West Germany). As the release film forming component, for example, ethyl cellulose,
Examples include aminoalkyl methacrylate copolymers and waxes.

After the completion of granulation, the thus-obtained particle preparation with protrusions is subjected to a drying step using a drying apparatus such as a fluidized-bed granulator and a tray dryer. The final product can be obtained by sieving.

Hereinafter, the present invention will be described more specifically with reference to examples.

[0043]

EXAMPLE 1 Commercially available nonpareil 103 (particle size: 24-32 (710-
500 μm)) 1000 g was put into a centrifugal flow type coating granulator, and the rotor rotation speed was 130-160 RP.
M, an aqueous solution of hydroxypropylcellulose (HPC-L) (2% (W / W))
While spraying at 10 mL / min, titanium oxide was sprayed at 15 g / min for 20 minutes, and then dried at 60 ° C for 6 hours. The angle of repose of the granules with protrusions was 39 degrees, and an increase of 10 degrees from the angle of repose of 29 degrees of the nonpareil 103 before coating granulation was recognized.

Example 2 Commercially available nonpareil 101 (particle size: 32-42 (500-
355 μm), circularity coefficient: 0.91 ± 0.01) 20
00 g was placed in a centrifugal fluidized-type coating granulator, and acetaminophen was sprayed at 12 g / min while spraying a binder solution having the following composition at a rotor rotation speed of 150 RPM and a slit air temperature of 20 ° C. at 5-37.5 mL / min. And then dried at 60 ° C. for 6 hours. [Binder solution] Ethyl cellulose 11 g 520 g of anhydrous ethanol 3 g of purified water 780 g of the obtained granules were put into a centrifugal flow type coating granulator, and the rotor rotation speed was 140-160 RP.
M, an aqueous solution of hydroxypropylcellulose (HPC-M) (2% (W / W)) at a slit air temperature of 50 ° C.
While spraying at 5 mL / min, titanium oxide was sprayed at 8 g / min at 6 g / min.
After spraying for 8 minutes, it was dried at 40 ° C. for 12 hours. The angle of repose of the granules with protrusions was 39 degrees, and an increase of 11 degrees from the angle of repose of 28 degrees of the nonpareil 101 before coating granulation was recognized.

Example 3 Commercially available nonpareil 101 (particle size: 32-42 (500-
355 μm), circularity coefficient: 0.91 ± 0.01) 60
0 g was placed in a centrifugal flow type coating granulator, the rotor rotation speed was 130-150 RPM, and the slit air temperature was 2
Acetaminophen was sprayed at 8 g / min for 26 minutes while spraying a binder solution having the following composition at 0 ° C at 5 to 20 mL / min, and then dried at 60 ° C for 6 hours. [Binder solution] 7 g of ethyl cellulose 332 g of anhydrous ethanol 2 g of purified water 714 g of the obtained granules were put into a fluidized bed granulator,
At an intake temperature of 20 to 40 ° C., a sustained-release film-forming component having the following composition was sprayed at 9 mL / min to obtain sustained-release granules. [Slow release film-forming component] 40 g of ethyl cellulose 4 g of glycerin fatty acid ester 1215 g of anhydrous ethanol 625 g of purified water 725 g of the obtained granules 646 g of the obtained granules were put into a centrifugal flow type coating granulator, and the rotor rotation speed was 130-140 RP.
M, an aqueous solution of hydroxypropylcellulose (HPC-M) (2% (W / W)) at a slit air temperature of 50 ° C.
While spraying at 5 mL / min, the titanium oxide was added at 8 g / min at 1 g / min.
After spraying for 20 minutes, it was dried at 60 ° C. for 12 hours to obtain granules with sustained release projections (see FIG. 1). The degree of protrusion of the granules with sustained release protrusion was 0.25 ± 0.04, and the circularity coefficient was 0.72 ± 0.04. In addition, the angle of repose of the granules with sustained release projections is 37 degrees,
The angle of repose of 01 increased from 28 degrees to 9 degrees. Further, the transfer rate of the granules was 46%, and the transfer rate of the non-pareil 101 before coated granulation was reduced from 65% to 19%.

Incidentally, the measurement of the slippage rate was performed by the following method. That is, a metal cylinder was filled with 2 g of the sample, the lid at the bottom of the cylinder was quickly opened, and the diameter of the cylinder was set at 15 cm below.
cm of a metal disk, the weight of the sample remaining on the disk was measured, and the slippage rate was calculated from the following equation.

Overturning rate (%) = (ab) / a × 100 a: Weight of sample (2.00 g) b: Weight of sample remaining on disk Example 4 Commercially available Selfia CP-203 (particle size : 300-150
μm, circularity coefficient: 0.96 ± 0.01) 2400 g was put into a centrifugal flow type coating granulator, the rotor solution was rotated at 150 RPM, the slit air temperature was 30 ° C., and the binder solution having the following composition was 15 to 25 mL / min. After spraying with roxatidine acetate hydrochloride at 9.5 g / min for 54 minutes, the mixture was dried at 40 ° C. for 6 hours. [Binder solution] ethyl cellulose 10 g anhydrous ethanol 1008 g purified water 5 g 500 g of the obtained fine granules was put into a fluidized bed granulator,
At an intake air temperature of 20 to 25 ° C., a sustained release film forming component having the following composition was sprayed at 9 mL / min to obtain sustained release fine granules. [Slow release film forming component] Ethyl cellulose 15 g Glycerin fatty acid ester 2 g Absolute ethanol 926 g Purified water 5 g Dichloromethane 552 g Repeated the above operation, 98 of the sustained release fine particles obtained
4 g was put into a centrifugal flow type coating granulator, the rotor rotation speed was 160 RPM, and the slit air temperature was 50-60.
Aqueous solution of hydroxypropylcellulose (HPC-
M) (2% (W / W)) while spraying titanium oxide at 10 g / min for 126 minutes while spraying at 5-10 mL / min, followed by drying at 40 ° C. for 8 hours. The degree of projection of the fine particles with sustained release projections was 0.25 ± 0.02, and the circularity coefficient was 0.82 ± 0.03. In addition, the angle of repose of the fine particles with sustained release projections was 40 degrees, and an increase of 6 degrees from the angle of repose of Selfia CP-203 before coating granulation of 34 degrees was observed. Further, the sliding rate of the fine granules was 41%, and the sliding rate of Selfia CP-203 before coating granulation was 52% to 11%.
% Decrease was observed.

[Brief description of the drawings]

FIG. 1 is a micrograph (magnification: 100 ×) of a granule with protrusions obtained in Example 3.

Claims (12)

[Claims] 1. A particle preparation with projections, wherein projections are formed on the surface of spherical particles having a circularity coefficient in the range of 0.85 to 1.00, wherein the degree of the projections is represented by the following formula B = ( r ₂ −r ₁ ) / r _{2 In the} formula, r ₁ represents the radius of a circle inscribed in the projected particle projected image, and r ₂ represents the radius of a circle circumscribed in the projected particle projected image. The value of the degree of protrusion B is 0.05 to
A particle preparation with projections, which is in the range of 0.50. 2. The particle preparation with projections according to claim 1, wherein the circularity coefficient is in the range of 0.60 to 0.90 and the standard deviation thereof is 0.05 or less. 3. The particle preparation with protrusions according to claim 1, wherein the value of the degree of protrusion B is in the range of 0.10 to 0.35 and the standard deviation thereof is 0.05 or less. 4. The particle preparation with projections according to claim 1, wherein the projections are formed on the surface of the spherical particles by coating and granulating the particle with a projection forming agent. 5. The spherical particle according to claim 1, wherein the spherical core particle containing no medicinal component is coated with the medicinal component.
4. The particle preparation with projections according to any one of 4. 6. The particle preparation with projections according to claim 1, wherein the projections cause an increase in the angle of repose and a decrease in the escape rate in the particle preparation. 7. The projection-formed particle preparation according to claim 6, wherein the increase in the angle of repose is at least 5 degrees or more. 8. The particle preparation with protrusions according to claim 6, wherein the decrease in the rolling rate is at least 10% or more. 9. The preparation according to claim 4, wherein the projection-forming agent is a fine powdery substance having a particle diameter of 10 μm or less. 10. The particle preparation with protrusions according to claim 9, wherein the fine powdery substance is titanium oxide, synthetic aluminum silicate or dried aluminum hydroxide gel. 11. The projection-formed particle preparation further comprises a coating layer exhibiting a dissolution controlling effect on an inner layer portion and / or an outer layer portion of the projection layer formed by coating the projection forming agent.
The particle preparation with protrusions according to any one of claims 10 to 10. 12. A method for producing a particle preparation having projections, wherein a powder of a projection-forming agent is sprayed onto spherical particles under spraying of a binder solution to form projections on the surface of the particles.