JPH10218763A - Transpulmonary inhalation preparation and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a transpulmonary inhalation preparation by using fine granulating particles that have sharp particle size distribution and excellent handleability and is excellent in disintegration to primary particles and dispersibility. SOLUTION: This preparation is produced by using particles containing main medicine and having particle sizes of <=10μm as primary particles, spraying the particles with a spraying liquid containing a binder in a complicated type fluid bed apparatus that can effect one or more kinds of motions, for example, rolling, centrifugation, agitation, spraying and the like to prepare fine granulated particles with an average particle size of <=50μm. These particles are charged in a transpulmonary inhalation device. The binder preferably has low viscosity, low binding properties, good extensibility and penetrability, has <=3.0cps in 2wt.% aqueous solution at 20 deg.C and the content of the binder is <=5wt.% in the resultant granulated particles. The binder is, for example, hydroxypropylcellulose or polyvinyl pyrrolidone.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a preparation for pulmonary inhalation and a method for producing the same, and more particularly, to a fine particle having a sharp particle size distribution, excellent handling properties, and good disintegration and dispersibility into primary particles. The present invention relates to a preparation for pulmonary inhalation comprising fine granulated particles and a method for producing the same.

[0002]

2. Description of the Related Art In recent years, drug delivery systems (D
Under the concept of DS), a wide range of formulation studies has been conducted in conjunction with advances in equipment and the like, and the possibility of the development of new administration routes other than oral is expected. In particular, the administration method of transpulmonary inhalation is known to be an advantageous administration route because the surface area of the lung absorption site is extremely large.

[0003] For example, an inhalation preparation of a spray solution or a scattered powder (powder particles of the drug itself) by an aerosol spray generator (eg, a nebulizer or a spin heller) of a drug solution or powder such as an antiallergic agent is effective. Is known. Among them, the powder preparation is more convenient in terms of its usability. In particular, in inhalation therapy for bronchial asthma and the like, development of a dry powder inhalation formulation for inhaling a drug by a patient's own inhalation without using Freon gas has attracted attention. The condition required for a dry powder inhalation formulation is that when a patient inhales a drug, the drug must be scattered in the inhalation process with an aerodynamic diameter of 1 to 7 μm, which is considered to have a high rate of reaching the lungs. In recent years, the particle size is 1 to 10 μm
Research on particle design related to powder (dry powder) has been progressing.

However, in the case of fine particles having a small particle size,
Not only is it easy to scatter, it is also easy to adhere and aggregate, and due to poor fluidity, etc., there are difficulties in formulation and usability such as the drug adheres and remains inside the device or capsule during administration. . At present, measures have been taken to improve the surface treatment by attaching finer particles with good fluidity to the particle surface, or to adsorb it to a carrier, etc. There is a high demand for particle design for powders.

In order to prepare fine granules having a particle size of 0.2 mm or less, the present inventors have already conducted high-viscosity, low-viscosity A study was conducted using a binder as the spray liquid composition, and it was found that the operation of granulating while coating the particle surface as easily as possible was possible by using a low-viscosity binder with a weak binding force. An application has been filed as a method for producing a granulated product (WO94 / 08709).

When a binder having high viscosity (high binding force) is used, there is an advantage that the required amount of spray liquid is small and the time required for granulation is short. Since particles or aggregates having a large particle diameter are produced, there is room for improvement in the sharpness of the particle diameter distribution and the yield of particles having a target particle diameter. On the other hand, a low-viscosity (low-binding-force) binder requires a large amount of spray liquid to be used, and the required time for granulation is long. Operability is good in the sense of minimizing grains. Furthermore, if the spreadability and permeability of the binder are good, it is found that granulation proceeds while effectively coating the particle surface, and that it has desirable fine particle characteristics (1994). Proceedings of the 11th Symposium on Formulation and Particle Design, p165-170, Proceedings of the 11th Annual Meeting of the Japanese Pharmaceutical Society of Japan, p94-
95).

[0007] However, the granulated particles obtained in these reports do not satisfy the disintegration and dispersibility of the granulated particles in the inhalation process required in the preparation for pulmonary inhalation.

[0008]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a pulmonary lung comprising fine granulated particles having a sharp particle size distribution, excellent handling properties, and good disintegration and dispersibility into primary particles. An inhalation formulation is provided. Another object of the present invention is to provide a method for producing the pulmonary inhalation preparation of the present invention.

[0009]

Means for Solving the Problems The present inventors have developed a fine 1
The granulated particles are used for transpulmonary inhalation if it is possible to break down and disperse the granulated particles into primary particles in the inhalation process while overcoming the handling problems by granulating the secondary particles into secondary particles. It was considered to be useful as a powder. In this case, it is desirable from the viewpoints of inhalability and handleability that the secondary particles are as fine as possible and granulated particles having a sharp particle size distribution, but conventionally, highly accurate transpulmonary inhalation having such characteristics is desirable. No granulated product has been obtained. The present inventors have conducted intensive studies on the design of granulated particles for pulmonary inhalation from such a viewpoint, and unexpectedly found a binder having low viscosity, low binding property, good spreadability, and permeability. The inventors have found that fine granulated particles having an average particle diameter of 50 μm or less, which has a binder content of 5% by weight or less, are excellent in disintegration into primary particles and dispersibility, and the present invention. Was.

That is, the gist of the present invention is to (1) obtain particles obtained by forming particles containing a main drug into primary particles having a particle diameter of 10 μm or less and coating them with a binder while granulating them.
Transpulmonary inhalation preparation characterized by containing fine granulated particles having an average particle diameter of 50 μm or less, which show disintegration into primary particles and dispersibility in the inhalation process, (2) rolling and centrifugation in the granulation step The preparation for transpulmonary inhalation according to the above (1), which is obtained by using a multifunctional device including any of a dispersion mechanism such as stirring, jetting, and pulse jet air.
(3) The binder is a 2% by weight aqueous solution having a viscosity of not more than 3.0 centipoise at 20 ° C. and the binder content in the obtained granulated particles is not more than 5% by weight. The preparation for pulmonary inhalation according to the above (1) or (2), (4) the preparation for pulmonary inhalation according to any of the above (1) to (3), wherein the binder is hydroxypropylcellulose or polyvinylpyrrolidone, (5) ) (1)-
(4) a preparation for transpulmonary inhalation, wherein the granulated particles according to any of the above are loaded in a transpulmonary inhalation device, (6) tumbling, centrifugation, stirring, and jetting (including a Wurster type)
Using a composite fluidized bed apparatus with at least one of the following, a spray liquid containing a binder is sprayed onto primary particles having a particle diameter of 10 μm or less containing the main agent to perform granulation while coating the primary particles. A method for producing a preparation for transpulmonary inhalation containing the granulated particles, characterized in that the granulated particles exhibit an average particle size of 50 μm or less which exhibits disintegration and disintegration into primary particles during the inhalation process. (7) The production method according to (6), wherein a multifunctional device including any of a dispersion mechanism such as rolling, centrifuging, stirring, jetting, and pulse jet air is used in the granulation step. The above-mentioned (2), wherein the binder is a 2% by weight aqueous solution having a viscosity of not more than 3.0 centipoise at 20 ° C. and the binder content in the obtained granulated particles is not more than 5% by weight. 6) or the production method according to (7), wherein (9) the binder is (6) to (8), which are hydroxypropylcellulose or polyvinylpyrrolidone
(10) The method according to any one of (6) to (9), further including a step of loading the granulated particles into a transpulmonary inhalation device.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION The pulmonary inhalation preparation of the present invention is obtained by forming particles containing a main drug into primary particles having a particle size of 10 μm or less, and granulating the particles while coating them with a binder. It is characterized by containing fine granulated particles having an average particle diameter of 50 μm or less, which show good disintegration into primary particles and dispersibility in the inhalation process. The granulated particles used in the preparation for transpulmonary inhalation of the present invention use a composite fluidized bed apparatus involving at least one of tumbling, centrifugation, stirring, and jetting (including a Wurster type), and the particle diameter including the principal drug is used. It is manufactured by spraying a spray liquid containing a binder onto primary particles of 10 μm or less and performing granulation while coating the primary particles. The average particle size is 50 μm or less and the particle size is Is substantially 10
It is less than 0 μm.

Here, the particle size of the granulated particles is substantially 10
0 μm or less means that particles having a particle diameter of 100 μm or less account for at least 97% by weight or more. The presence of a large number of particles having an average particle diameter of more than 50 μm and exceeding 100 μm means that the binder content in the granulated particles is high and that particles having a strong bond are growing, and the useful rate (use rate) is only that much. It is not preferable because it becomes low.
Further, in the present specification, the particle size refers to a value measured by a sieve, and the average particle size refers to a particle size showing a weight percentage of 50%.

The average particle size of the granulated particles used in the preparation for pulmonary inhalation of the present invention should be 50 μm or less from the viewpoint of good disintegration into primary particles and good balance of the binder content in view of dispersibility. More preferably, it is 40 μm or less.

[0014] The preparation for transpulmonary inhalation of the present invention uses a composite fluidized bed apparatus involving at least one of rolling, centrifuging, stirring, and jetting (including a Wurster type) as described above, and comprises a particle containing a main drug. While forming a fluidized bed of particles having a diameter of 10 μm or less (hereinafter sometimes referred to as raw material particles), while spraying a spray liquid containing a binder having low viscosity, low binding property, good spreadability, and permeability. The binder content obtained by advancing granulation while coating is 5% by weight or less and the average particle size is 50%.
It contains fine granulated particles of μm or less. In the production of the granulated particles, coarse droplets having a particle diameter of 30 μm or more are controlled so as to be 10% by volume or less among the droplets of the spray liquid to be sprayed, and the exhaust temperature is further reduced by the heat insulation under the installation environment of the apparatus. The spray amount of the spray liquid is preferably controlled so as to be higher than the saturation temperature, preferably higher than 3 ° C.

The composite fluidized bed apparatus used in the present invention is not particularly limited as long as it is a composite fluidized bed apparatus involving at least one of rolling, centrifuging, stirring, and jetting (including a Wurster type). However, a known device can be used.

More specifically, for example, Worster (manufactured by Glatt), Spiral Flow (Freund Sangyo Co., Ltd.)
), A multiplex (manufactured by Powrex Co., Ltd.), a spira coater (manufactured by Okada Seiko Co., Ltd.), an agromaster (manufactured by Hosokawa Micron Co., Ltd.), and a new marmalizer (manufactured by Fuji Paudal Co., Ltd.). .

In the specific granulation operation in the present invention, for example, particles containing a main agent having a particle diameter of 10 μm or less, which has been prepared in advance by pulverization or the like, that is, particles containing the main agent or the main agent and various desired additives (1) The raw material particles as the secondary particles) are charged into the above-mentioned composite fluidized bed granulator, and if necessary for the purpose of ensuring fluidity in the device, a small amount of water is first sprayed or sprayed. After appropriately adding an improving agent such as Aerosil (manufactured by Nippon Aerosil Industry Co., Ltd.),
A required amount of a spray liquid containing a binder at an appropriate concentration may be sprayed while forming a fluidized bed of the raw material particles.

As the binder used in the present invention, it is preferable to use a binder having characteristics such as low viscosity, low binding, good spreadability, and permeability. For example, SSL grade of hydroxypropylcellulose (HPC-SSL) (Nippon Soda Co., Ltd.
Kollidon of polyvinylpyrrolidone (PVP)
A binder such as 12PF, Kollidon 17PF, Kollidon 25, Kollidon DA64 grade (manufactured by BASF), hydroxypropyl methylcellulose, etc., having a 2% by weight aqueous solution at 20 ° C and having a viscosity of 3.0 centipoise or less is used. .

In the present invention, various granulated particles are prepared, and their disintegration into primary particles and easiness of dispersibility are evaluated to determine the suitability as a powder for transpulmonary inhalation. 5
It was observed that the smaller the particle size was 0 μm or less and the smaller the content of the binder in the granulated particles was 5% by weight or less, the larger the degree of disintegration into primary particles and the degree of dispersibility increased. That is, the required amount of the low-binding binder hydroxypropylcellulose or polyvinylpyrrolidone is such that the binder content in the granulated particles is 5% by weight or less, more preferably 4% by weight or less. Although the strength and the particle size shift in the direction of being small, if the content of the binder is too small, it is fragile and the handling property becomes difficult. Therefore, at least 2% by weight or more is necessary. If the binder content exceeds 5% by weight, the average particle diameter tends to increase and the particle strength tends to increase, so that the desired disintegration and dispersion effects cannot be expected.
It is also possible to add additives such as surfactants and magnesium stearate during granulation to promote the disintegration of granulated particles, to add and granulate for the purpose of improving fluidization, and to use these additives. It can also be added after granulation.

In the present invention, the method of spraying the binder may be a top spray from a position slightly above the bottom of the apparatus to the bottom, a bottom spray from the bottom to the top, or a bottom spray from the bottom. A tangential (side) spray in the tangential direction may be used. For example, when it is desired to obtain granulated particles having a sharp particle size distribution with smaller granulated particles having a particle size of several tens of μm, a bottom or tangential spray is required. It is only necessary to select the spray style of the tangential (side). It is also possible to spray by combining various modes.

Further, the smaller the droplet diameter of the spray liquid is,
Further, the sharper the droplet diameter distribution, the more advantageous it is in preparing granulated particles having a sharp particle diameter distribution by gradually granulating while coating. Therefore, in the present invention, an appropriate spray liquid composition, concentration, and spray air volume may be appropriately selected. The performance of the spray nozzle affects the droplet diameter of the spray liquid, but the one used in a usual apparatus may be appropriately selected.

In order to form a fluidized bed of these particles, including raw material particles, coated particles, and particles undergoing granulation, heated air or the like is usually used.

It is important that the binder in the present invention has characteristics such as low viscosity, low bonding strength, good spreadability, and permeability. Polyvinylpyrrolidone,
Hydroxypropyl methylcellulose and the like can be appropriately prepared by adding a suitable diluent (for example, sugars such as lactose and glucose, and infusions such as amino acids) and additives, and used. In this case, it is possible to use the binder by dissolving it in a solvent such as ethanol, but it is preferable to use the binder in an aqueous system from the viewpoint of operability and the like. Further, an additive such as a surfactant may be added to the spray liquid within a range not impairing the above-mentioned functional properties such as the droplet diameter, viscosity, bonding strength, and good spreadability of the spray liquid. It is also possible to appropriately use a low-binding binder aqueous solution and a low-binding binder containing additives (bases) for various purposes for reasons such as purpose and operability. Further, the components and compositions of the spray liquid can be changed continuously or stepwise. Of course, it is desirable that these additions be as small as possible.

The viscosity of the spray liquid at 20 ° C. is desirably 20 centipoise or less, and more desirably 15 centipoise or less, from the viewpoint of the above-mentioned functions and operability. The concentration of the binder in the spray liquid is
5 in consideration of coating efficiency and required time for granulation
A binder aqueous solution of about 20% by weight is preferably used. For example, when the binder is HPC-SSL, the viscosity at 20 ° C. becomes 6 to 15 centipoise at 5 to 8% by weight. In the case of PVP, the viscosity at 20 ° C. at 5 to 20% by weight is 1 to 10 centipoise.

In the present invention, the droplet diameter distribution of the spray droplets is as follows.
It is preferable that the above coarse droplets are controlled to be 10% by volume or less, and the coarse droplets of 30 μm or more are controlled to 8% by volume.
More preferably, it is controlled as follows. By reducing the proportion of the coarse droplets in the spray droplets to make the droplets as sharp as possible in this manner,
Granulation can be advanced while performing coating, and the particle size distribution of the obtained granulated particles can be sharpened. In order to control the droplet diameter of the spray liquid in this manner, as described above, the viscosity of the spray liquid is adjusted according to the type and concentration of the binder, or the flow rate of the spray liquid and the air volume of the spray air are adjusted. Can be performed.

As a spray liquid, for example, HPC-SSL
When an aqueous solution is used, the ratio of coarse droplets is not so high, and even if coarse droplets of about several volume% are present, the binding force is not so strong, so that it does not become a controlling factor for granulation. For example, in a 5% by weight aqueous solution of HPC-SSL, the average particle diameter (d ₅₀ ) of the droplet diameter is about 10 μm by adjusting the liquid sending speed of the spray liquid under the condition that the spray air flow rate is 30 to 35 L / min. The coarse droplets having a particle size of 30 μm or more before and after can be reduced to 5 to 6% by volume or less. The droplet diameter of the spray liquid mentioned here can be measured by a laser light scattering type particle size distribution measuring device (for example, LSDA-2400A, manufactured by Tonichi Computer Applications).

The feed rate of the spray liquid is closely related to the temperature control in the fluidized bed and is a factor that affects granulation. In other words, when examining and considering cooling from the blast heating air temperature at the device inlet to the product temperature and exhaust temperature along the adiabatic cooling curve to the adiabatic saturation temperature determined by the environment (temperature, humidity) during the granulation operation, It was understood that as the exhaust temperature became higher than the adiabatic saturation temperature, the spray liquid at that time was sent while increasing the degree of addition of the coating property to the particles, and the granulation proceeded. In order for the granulation to proceed while sufficient coating proceeds, it is necessary to supply the spray liquid so that the exhaust temperature is at least 3 ° C. higher than the adiabatic saturation temperature. More preferably, the exhaust temperature is 3 to 7 ° C. higher than the adiabatic saturation temperature. If the exhaust gas temperature is higher than the adiabatic saturation temperature by more than 7 ° C., the delivery of the spray liquid will be slow and inefficient, and the spray liquid droplets will dry more and the spraying and adhesion to the particles will not be uniform. Brings inconvenience. If the exhaust temperature is lower than the adiabatic saturation temperature, the supply of the spray liquid becomes excessive, and the particles in the fluidized bed become too wet and the fluidity is reduced, and agglomerates and the like are generated to cause trouble.

That is, the sharpness of the particle size distribution as the granulated particles is determined by using an appropriate binder having the above-mentioned low viscosity, low binding force, good spreadability, and permeability under the above operating conditions. By granulating while coating at a temperature higher than the adiabatic saturation temperature, primary particles based on the main drug are used as raw material particles, and the particle surfaces with sharp particle size distribution have high smoothness and collapse into primary particles, Granulated particles having good dispersibility can be provided.
Preferably, the temperature is controlled to be 7 ° C. higher.

As described above, although there is a balance between the rolling of the powder by the agitation of the bottom disk rotor and the granulation and the pulverization by the agitation, the control of the exhaust temperature in consideration of the adiabatic saturation temperature is an important factor. . If such smooth exhaust temperature control is not performed, agglomeration may occur and uneven granulation will proceed, and the operation must be stopped.

The particle size distribution of the granulated particles can be adjusted by appropriately adjusting the stirring speed of the rotor. Generally, when the stirring speed is high, the particle size can be shifted in a finer direction.However, at this time, the generation of fine powder can be prevented by considering the spray conditions from the viewpoint of the binder concentration and the spray amount. The particle size distribution can be kept sharp.

The spraying rate of the spray liquid is naturally governed by the above factors, and coarse particles grow by spraying a spray solution of a binder having low viscosity, low binding property, good spreadability and permeability. Is suppressed, but rather there is a balance with stirring by the rotor at the bottom, pulverization due to rolling action or flow action, but it results in the direction of granulation while coating fine powder, and in sharpening the particle size distribution It will give good results.

In the case of a device in which the raw material particles and the particles in the granulation process are stirred and rolled by rotating the disk rotor at the bottom, stirring, rolling and flowing toward the upper portion and descending to the lower portion are performed at the bottom portion. Spraying and fluid drying are repeated while moving, but by increasing the rotation speed of the disk rotor at the bottom and increasing the amount of air in the fluidized bed, the particle movement becomes more active and powdering to finer particles Get offended. In addition, it is possible to easily control such complicated phenomena by giving the air flow in the countercurrent direction to the particles by operating the dispersion mechanism by pulse jet air, and it is possible to control fine particles with a sharp particle size distribution. The granulated particles can also be designed and provided as particles for pulmonary inhalation (dry powder). That is, in the present invention, it is preferable to use a multifunctional device including any of a dispersion mechanism such as rolling, centrifugation, stirring, jet flow, and pulse jet air in the granulation step.

The preparation for pulmonary inhalation according to the present invention is based on the granulated particles obtained by the above-mentioned production method, and the granulated particles are loaded into a device for pulmonary inhalation by a conventional method. It may be a formulation. The device for transpulmonary inhalation in the present invention is not particularly limited, and includes, for example, a nebulizer and a spinner. In such a preparation of the present invention, the primary particles based on the main drug reach the lungs very well because they rapidly disintegrate and disperse into fine primary particles in the inhalation process, and are extremely good. A good transpulmonary absorption is achieved. The target drug in the pulmonary inhalation preparation of the present invention is not particularly limited as long as it is a pulmonary absorbable drug. For example, drugs that act on the respiratory system found in antiallergic agents (therapeutic agents for bronchial asthma) such as sodium cromoglycate, salbutamol sulfate, and ketotifen fumarate, as well as insulin, C
It is also applicable to peptide drugs such as SF (granular colony stimulating factor). In the examples described later, diclofenac sodium as an anti-inflammatory agent is examined as a model.

[0034]

The present invention will be described in more detail with reference to the following Examples, Comparative Examples and Test Examples, but the present invention is not limited to these Examples.

Example 1 Finely pulverized diclofenac sodium particles (average particle size: 5
Aerosil # 200 (manufactured by Nippon Aerosil Industry Co., Ltd.) equivalent to 2% by weight based on 470 g) was added to 470 g, and the mixture was introduced into a tumbling fluidized bed granulator Agromaster (manufactured by Hosokawa Micron Corp.). 12 ~ heated to 60 ° C
While blowing an air amount of 15 m ³ / hr into the fluidized bed, the disk rotor was rotated at a rotation speed of 300 rpm at the bottom to roll and flow the powder. The composition of the spray liquid is HP
C-SSL 5% by weight aqueous solution, 4.5 to 3.5 g / m
At the time when 470 g of the tangential (side) spray was sprayed at a spray rate of "in", the granulation was terminated, and a granulated product I of the present invention was obtained. The spray air amount at this time is 30 to 26 L / min, and the outlet air temperature is 27 to 26.L / min.
5 ° C., which was 4 ° C. higher than the adiabatic saturation temperature. The average particle size (d ₅₀ ) of the granulated product I of the present invention is 45 μm,
The content of the binder in the granulated product was about 4.6% by weight. Further, about 97% of the granulated particles had a size of 100 μm or less.

Example 2 Finely pulverized diclofenac sodium particles (average particle size: 5
Aerosil # 200 (Nippon Aerosil Industry Co., Ltd.), equivalent to 0.62% by weight based on 500 g
Manufactured by Hosokawa Micron Co., Ltd.), and an air volume of 12 to 17 m ³ / hr heated to 60 ° C. is blown into the fluidized bed, and the bottom portion is formed. The powder was rolled and flowed by rotating the disk rotor at a rotation speed of 300 rpm. In the granulation process, pulse jet air was sent in a counter-current system (intermittent ejection of 0.3 seconds for an interval time of 2 seconds) to exert a dispersion effect. The composition of the spray liquid is a 5% by weight aqueous solution of HPC-SSL, and is 50 in a tangential (side) spray mode at a spray rate of 3.5 to 6.5 g / min.
When the spraying of 0 g is performed, the granulation is finished, and the granulated product of the present invention is obtained.
I got II. The spray air volume at this time is 27 L / mi
n, the outlet air temperature was 32 to 28 ° C., which was 4 to 7 ° C. higher than the adiabatic saturation temperature. The average particle diameter (d ₅₀ ) of the granulated product II of the present invention was 34 μm, and the content of the binder in the granulated product was about 4.7% by weight. Further, about 99% of granulated particles having a size of 100 μm or less were used.

Example 3 Finely pulverized diclofenac sodium particles (average particle size: 5
Aerosil # 200 (manufactured by Nippon Aerosil Co., Ltd.) corresponding to an amount of 2% by weight based on 500 g) was added to a tumbling fluidized bed granulator Agromaster (manufactured by Hosokawa Micron Corporation). 12 ~ heated to 60 ° C
While blowing an air amount of 15 m ³ / hr into the fluidized bed, the disk rotor was rotated at a rotation speed of 300 rpm at the bottom to roll and flow the powder. The composition of the spray liquid is Koll
A 5% by weight aqueous solution of idon 25, 4.5 to 3.5 g / m
The granulation was completed at the point of time when 500 g of the tangential (side) spray was sprayed at a spray rate of "in" to obtain a granulated product III of the present invention. The spray air amount at this time is 30 to 26 L / min, and the outlet air temperature is 27 to 26 L / min.
° C and 4 ° C higher than the adiabatic saturation temperature. The average particle size (d ₅₀ ) of the granulated product III of the present invention was 40 μm, and the content of the binder in the granulated product was about 4.5% by weight.
Further, about 97% of the granulated particles had a size of 100 μm or less.

Comparative Example 1 Finely pulverized diclofenac sodium particles (average particle size: 5)
Aerosil # 200 (Nippon Aerosil Industry Co., Ltd.), equivalent to 0.62% by weight based on 500 g
Manufactured by Hosokawa Micron Co., Ltd.), and an air volume of 12 to 17 m ³ / hr heated to 60 ° C. is blown into the fluidized bed, and the bottom portion is formed. Then, the disk rotor was rotated at a rotation speed of 300 rpm to roll and flow the powder. The composition of the spray liquid is an 8% by weight aqueous solution of HPC-SSL and a 5% by weight aqueous solution.
At the time when the spraying of 00 g and 1000 g was performed in the tangential (side) spray mode, the granulation was completed and a comparative granulated product I was obtained. The spray air volume at this time is 35 L / m
In, the outlet air temperature was 32 to 28 ° C., which was 4 to 7 ° C. higher than the adiabatic saturation temperature. The average particle size (d ₅₀ ) of the comparative granulated product I was 54 μm, and the content of the binder in the granulated product was about 10% by weight. Further, about 95% of the granulated particles had a size of 100 μm or less.

Comparative Example 2 Finely pulverized diclofenac sodium particles (average particle size: 5)
Aerosil # 200 (manufactured by Nippon Aerosil Co., Ltd.) equivalent to 2% by weight based on 500 g) was added to a tumbling fluidized bed granulator Spirocoater (manufactured by Okada Seiko Co., Ltd.). 12m ³ / hr heated to 60 ° C
While blowing the amount of air into the fluidized bed, the disk rotor was rotated at a rotation speed of 150 rpm to roll and flow the powder. The composition of the spray liquid was a 5% by weight aqueous solution of HPC-SSL, and 1100 g of the liquid was sprayed in a top spray mode at a spray rate of 5 g / min to obtain a comparative granulated product II. The spray air amount at this time is 30 to 35 L / mi.
n, the outlet air temperature was 36 to 37 ° C., which was 4 to 5 ° C. higher than the adiabatic saturation temperature. The average particle size of the comparative granulated product II was 100 μm, and the content of the binder in the granulated product was about 1
It was 0% by weight.

Each of the granulated products I to III of the present invention is a fine granulated product in which the content of the low binding binder (HPC-SSL, PVP Kollidon 25) in the granulated product is 5% by weight or less and the average particle size is 50 μm or less. In particular, in the granulated product II of the present invention, a scanning electron microscope (manufactured by Nireco Corp.) electron microscopic image suggests that it is a fine aggregate of primary particles. It was expected that physical factors could easily cause the primary particles to collapse and disperse. That is, due to the dispersion mechanism by pulse jet air at the time of granulation, the fine primary particles are aggregates formed by a weak binding force without receiving much rolling consolidation action, and are disintegrated and dispersed into primary particles. Was suggested to be effective.

Test Example 1 For the granulated products I to III of the present invention and the comparative granulated products I to II, a laser type particle size distribution analyzer (LMS-30 / dry unit) was used in a dry manner (inlet) at an air volume of 30 L / min. ,
The ease of disintegration and dispersibility of the granulated product into primary particles was evaluated by measuring the particle size of the disintegrated and dispersed particles using a Seishin Enterprise Co., Ltd.). Table 1 shows the results.

[0042]

[Table 1]

As is evident from the results in Table 1, the granules I to III of the present invention are excellent in the degree of disintegration and dispersion into primary particles, and the primary granules of the present invention exhibit a primary degree of 30% or more under the conditions of this test. Particles (10
(μm or less) and dispersibility, indicating the usefulness of the granulated product of the present invention. On the other hand, the comparative granulated products I to II are inferior in the degree of disintegration and dispersion into primary particles, and the comparative granulated products disintegrate and disperse in the inhalation process, are inhaled and reach the lungs. It was suggested that it would be difficult to do so.

Test Example 2 Using a rat (SD male rat, about 250 g, manufactured by Charles River Co., Ltd.), 1 mg of each of the granules I and II of the present invention was administered to the upper respiratory tract, and the blood concentration was determined by HPLC. As a result, as shown in FIG. 1, a high level of drug could be detected in the blood. Thus, the granulated product of the present invention was considered to be useful as a preparation for transpulmonary inhalation.
HPLC conditions were column Chemcosorb 5-ODS-H (4.6 ×
250mm, manufactured by Chemco Co., Ltd.), acetonitrile-0.1M
Sodium acetate (35/65, V / V) pH 6.3 Elution solvent, 2.8 ml / min flow rate, 280 nm UV detection wavelength.

[0045]

Industrial Applicability According to the present invention, there is provided a preparation for transpulmonary inhalation containing fine granulated particles having a sharp particle size distribution, excellent handling properties, and good disintegration and dispersibility into primary particles.

[Brief description of the drawings]

FIG. 1 shows changes in blood concentration when the granulated product of the present invention is inhaled into the upper respiratory tract of rats.

Claims (10)

[Claims] Claims: 1. Particles containing an active ingredient are made into primary particles having a particle size of 10 μm or less, and are granulated while being coated with a binder.
A preparation for transpulmonary inhalation, comprising fine granulated particles having an average particle diameter of 50 μm or less exhibiting dispersibility. 2. The method according to claim 1, wherein the granulation step is performed by using a multifunctional apparatus including any of a dispersing mechanism such as rolling, centrifuging, stirring, jetting, and pulse jet air. The preparation for pulmonary inhalation according to claim 1. 3. The method according to claim 1, wherein the binder has a viscosity of 2% by weight in an aqueous solution.
3. The preparation for transpulmonary inhalation according to claim 1 or 2, wherein the preparation has a viscosity of not more than 3.0 centipoise at 0 ° C and the binder content in the obtained granulated particles is not more than 5% by weight. 4. The preparation for pulmonary inhalation according to claim 1, wherein the binder is hydroxypropylcellulose or polyvinylpyrrolidone. 5. A transpulmonary inhalation preparation comprising the granulated particles according to claim 1 loaded in a pulmonary inhalation device. 6. Use of a composite fluidized bed apparatus involving at least one of rolling, centrifuging, stirring, and jetting (including a Wurster type) to form primary particles having a particle diameter of 10 μm or less containing a main ingredient,
Spraying a spray liquid containing a binder, granulating while coating the primary particles, disintegrating into primary particles in the inhalation process, fine granulated particles having an average particle size of 50 μm or less showing dispersibility. A method for producing a transpulmonary inhalation preparation containing the granulated particles. 7. The method according to claim 6, wherein in the granulation step, a multifunctional device including any of a dispersing mechanism such as rolling, centrifuging, stirring, jetting, and pulse jet air is used. 8. The composition according to claim 1, wherein the binder is a 2% by weight aqueous solution.
8. The method according to claim 6, wherein the granulated particles have a binder content of not more than 3.0 centipoise at 0 ° C. and not more than 5% by weight. 9. The method according to claim 6, wherein the binder is hydroxypropylcellulose or polyvinylpyrrolidone. 10. The method according to claim 6, further comprising a step of loading the granulated particles into a device for transpulmonary inhalation.