JP2003277295A - Method for producing drug-containing composite particle - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing drug-containing composite particles whereby the surface of a drug powder can be modified well with nano particles; the surface modification can be controlled well; and a surface-modified drug powder can be produced in a high productivity. <P>SOLUTION: A mixture of nano particles having an average particle size less than 1,000 nm and a drug powder having an average particle size larger than that of the nano particles is composited by a fluidized-bed dry granulating method or a dry mechanical particle compositing method, thus modifying the surface of the drug powder. The surface modification of the drug powder can be controlling well, and the productivity of the surface-modified powder can be enhanced. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention has an average particle size of 100.
The present invention relates to a method for producing drug-containing composite particles containing nano-order particles (nanoparticles) having a size of less than 0 nm, and in particular, it can be suitably used for a drug delivery system by satisfactorily modifying the surface of drug powder. The present invention relates to a method for producing drug-containing composite particles.

[0002]

2. Description of the Related Art Pharmaceutical preparations include, for example, ease of handling (handling) during manufacturing, masking of bitterness, control of solubility, drug delivery system (Drug Delivery System).
Since various characteristics such as Delivery System, drug delivery system, and abbreviated as DDS hereinafter) characteristics are required,
In order to impart necessary properties, a plurality of raw materials including a drug are compounded.

Examples of a composite of a plurality of raw materials include, for example, a composite of an excipient and a drug, and a drug whose surface is covered with a lubricant or a coating agent. Here, the above-mentioned excipient improves the handling of the drug,
Plays a role of facilitating formulation into a desired form,
The lubricant plays a role of making the surface of the drug smooth and glossy, and the coating agent covers the surface of the drug,
For example, it plays a role of masking the bitterness of drugs.

In particular, the technique of covering the surface of a drug with various surface modifiers such as a lubricant and a coating agent is very important in the development of a drug delivery system (Drug Delivery System, drug delivery system, hereinafter abbreviated as DDS). Attention has been paid.

For example, transpulmonary administration has been attracting attention as a drug administration method in recent years. The lung has a large absorption area comparable to the digestive tract, the alveolar epithelium is thin, and the vascular system is developed underneath it, which is advantageous for permeation and absorption of substances, enzymatic activity Is relatively low and has the advantage of being able to directly insert the drug into the systemic circulation system, and is particularly effective as a systemic administration route.

Here, as a method for delivering a drug into the lung, a method in which a drug prepared by dissolving or suspending a drug in a volatile propellant such as CFC is aerosolized and inhaled has been conventionally used. Due to restrictions on the use of the drug, the development of a method for making a drug into a dry powder and inhaling the drug has recently been advanced. In such a technique, a drug is pulverized in the order of micron and then the surface of the drug powder is modified with a lubricant such as colloidal silica to improve its fluidity. This improves the fluidity and dispersibility of the drug powder and promotes the absorption of the drug.

[0007]

However, although the conventional technique for modifying the surface of the drug powder allows the surface modification to some extent, the control of the surface modification and the productivity of the surface-modified drug powder are possible. There is a problem that there are insufficient points.

Specifically, since a lubricant such as colloidal silica is a nano-order fine powder, that is, nanoparticles, surface modification by the lubricant is not easy, and therefore,
Appropriate surface modification depending on the type and use of the drug tends to be difficult. In addition, a rotor type powder compounding device is often used for surface modification.
Not only is the control of surface modification liable to become insufficient, but it is not suitable for mass production of surface-modified drug powder.

The present invention has been made in view of the above problems, and an object thereof is to enable good surface modification of the surface of a drug powder with nanoparticles and also to achieve good control of the surface modification. And to provide a method for producing drug-containing composite particles capable of improving the productivity of a surface-modified drug powder.

[0010]

Means for Solving the Problems As a result of intensive studies in view of the above-mentioned problems, the present inventors have used a fluidized bed dry granulation method or a dry mechanical particle composite method to combine nanoparticles and drug particles. Therefore, it was found that the surface modification can be well controlled, and the productivity of the surface-modified drug powder can be improved, and the present invention has been completed.

That is, in order to solve the above-mentioned problems, the method for producing drug-containing composite particles according to the present invention comprises nanoparticles having an average particle size of less than 1000 nm and drug powder having an average particle size larger than the nanoparticles. It is characterized in that the surface of the drug powder is modified by compounding the mixture containing the compound by a fluidized bed dry granulation method or a dry mechanical particle compounding method.

According to the above method, the nanoparticles and the drug powder larger than the nanoparticles are compounded by the fluidized bed dry granulation method or the dry mechanical particle compounding method. Therefore, it becomes possible to effectively use the nanoparticles as a surface modifier of the drug powder, and the surface of the drug powder can be satisfactorily modified as compared with the conventional surface modification using micron particles. The surface modification level can be well controlled. In addition, since the fluidized bed dry granulation method and the dry mechanical particle composite method are suitable for a large amount of composite processing,
The productivity of the surface-modified drug powder can be further improved.

In the method for producing drug-containing composite particles according to the present invention, it is preferable to use a lubricant powder as the nanoparticles. As the lubricant, a colloidal inorganic compound powder or a surfactant powder is preferably used. Specifically, the colloidal inorganic compound powder is preferably colloidal silica, and the interface It is preferred that the activator is magnesium stearate or sugar ester. By using these lubricant powders, the surface of the drug powder can be satisfactorily modified.

Alternatively, in the method for producing drug-containing composite particles according to the present invention, polymer nanoparticles obtained by a spherical crystallization method may be used as the lubricant. As the polymer nanoparticles, particles made of a lactic acid / glycolic acid copolymer or hydroxymethyl cellulose phthalate are particularly preferable. This makes it possible not only to favorably modify the surface of the drug powder with the polymer, but also to favorably control the level of the surface modification with the polymer.

In the method for producing drug-containing composite particles according to the present invention, the average particle size of the drug powder is 0.01 μm or more and 5 or more.
It is preferably within the range of 00 μm or less. As a result, the drug powder whose surface is modified by nanoparticles, that is, the drug-containing composite particles according to the present invention can be efficiently and reliably manufactured.

The use of the method for producing drug-containing composite particles according to the present invention is not particularly limited, and it is preferably used for pharmaceutical / medical product-related applications where it is desired to fully utilize the characteristics of nanoparticles during use. For example, it is very suitably used for producing a transpulmonary preparation for delivering a drug in powder form to the lung and absorbing the drug from the lung. In the present invention, since the shape and density of the composite particles can be controlled well, a predetermined aerodynamic diameter can be designed and the inhalation characteristics of the drug powder can be optimized in the production of a transpulmonary preparation.

[0017]

BEST MODE FOR CARRYING OUT THE INVENTION An embodiment of the present invention will be described below with reference to FIGS.
The present invention is not limited to this.

In the method for producing drug-containing composite particles in the present embodiment, a mixture containing nanoparticles having an average particle size of less than 1000 nm and drug powder having an average particle size larger than the nanoparticles is fluidized bed dry granulated. Method or a dry mechanical particle compounding method is used to modify the surface of the drug powder.

The method for producing drug-containing composite particles according to the present invention is suitably used in a wide range of fields such as the development of various medicines and medical products. Among them, as shown in this embodiment by way of example, transpulmonary preparation It can be preferably used for the purpose of producing such a powdered medicine, the application of a drug containing a powder component to DDS, and the like.

The nanoparticles in the present invention refer to particles having an average particle size of less than 1000 nm, that is, nano-order fine particles, and are also expressed as nanospheres or nanoparticles. The average particle size is 1000 nm
The above, that is, particles having an average particle diameter of 1 μm or more are expressed as micron particles.

The material of the nanoparticles in the present invention is not particularly limited as long as it is a substance that can be made into nanoparticles, but it is particularly preferably a substance that does not adversely affect the living body when used together with a drug. preferable. Of course, the nanoparticles themselves may be the drug.

The specific type of drug used in the present invention is not particularly limited. For example, antipyretic analgesic anti-inflammatory agent, steroidal anti-inflammatory agent, antitumor agent, coronary vasodilator, peripheral vasodilator, antibiotic, synthetic antibacterial agent, antiviral agent, anticonvulsant, antitussive agent, expectorant, bronchodilator , Cardiotonic agent, diuretic, muscle relaxant, brain metabolism improving agent, minor tranquilizer, major tranquilizer, β-blocker, antiarrhythmic agent, gout treatment agent, anticoagulant, thrombolytic agent, liver disease agent, antiepileptic agent , Antihistamines, antiemetics, antihypertensives, hyperlipidemias, sympathomimetics,
Oral antidiabetic agent, oral anticancer agent, alkaloid narcotics,
Vitamin preparations, treatment agents for frequent urination, angiotensin converting enzyme inhibitors and the like can be mentioned.

In the method for producing drug-containing composite particles according to the present invention, for example, as shown in FIG. 2, nanoparticles 60 formed of a biocompatible substance and drug powder (eg, micron particles) 71 are used. By compounding, the drug-containing compound particles 70 are manufactured. This makes it possible to further improve the drug absorbability.

For example, the present invention can be used for producing a dry powder type transpulmonary preparation. Specifically, in a transpulmonary preparation, a drug powder is filled and supplied to an inhaler (dry powder injection device) and then injected into the oral cavity. The sprayed drug powder reaches the lungs from the oral cavity.

In most cases, the drug powder is micron particles, and the drug powder of micron particles is used as the drug-containing composite particles 70 surface-modified with nanoparticles, as shown in FIG. This is filled and supplied to the inhaler 40 and then injected into the oral cavity. As a result, the drug-containing composite particles 70 can be favorably deposited in the lung after being delivered from the oral cavity to the lung, and the drug absorbability can be further improved. Therefore, using the present invention,
It is also possible to use a drug that has been conventionally considered to be difficult to use as a transpulmonary preparation, for example, a peptide drug such as insulin or calcitonin.

Further, since the micron particles are finer than the nanoparticles, the micron particles have a low fluidity, which leads to deterioration in handling. Therefore, it is impossible to easily and simply fill and supply the drug powder to the inhaler. Moreover, when the composite particles collapse in the oral cavity to directly generate nanoparticles, the nanoparticles re-aggregate and cannot be dispersed well in air. Therefore, by using the production method of the present invention, the fluidity of the drug powder in the inhaler and the dispersibility in air can be improved.

Therefore, in the present embodiment, the surface of the drug is modified by forming nanoparticles from the biocompatible polymer and further compounding the nanoparticles with the drug powder. That is, in the present invention, a mixture containing nanoparticles having an average particle size of less than 1000 nm and a drug powder having an average particle size larger than the nanoparticles is prepared by a fluidized bed dry granulation method or a dry mechanical particle composite method. It includes a compounding step.

According to the above method, the nanoparticles and the drug powder are compounded by the fluidized bed dry granulation method or the dry mechanical particle compounding method, so that the nanoparticles are used as a surface modifier of the drug powder. It can be effectively used, and the surface of drug powder can be satisfactorily modified, and the modification level of the surface can be satisfactorily controlled, as compared with the conventional surface modification using micron particles. . Further, since the fluidized bed dry granulation method and the dry mechanical particle composite method are suitable for a large amount of composite processing, the productivity of the surface-modified drug powder can be further improved.

The nanoparticles used in the present invention may be made of any material capable of modifying the surface of the drug of interest and improving the absorbability and fixing property in the living body, but it is preferable. Uses various lubricant powders.

As the above-mentioned lubricant, for example, various oligosaccharides generally used as lubricants and compounds used as coating agents in the field of drugs can be preferably used.

More specifically, for example, oligosaccharides such as lactose, sucrose, mannitol, sorbitol; hydroxypropylmethylcellulose phthalate, hydroxypurpyrucellulose, carboxymethylethylcellulose,
Crystalline cellulose, gum arabic, gelatin, chitosan,
Biocompatible polymers such as polyethylene glycol, lactic acid / glycolic acid copolymers; inorganic compounds such as calcium carbonate, talc, titania (titanium oxide), silica (silicon oxide); interfaces of sugar ester, magnesium stearate, etc. Activator; and the like.

Each of the above compounds may be formed into nanoparticles. For example, in the case of an inorganic compound, it may be colloidal. Specifically, in the case of silica, commercially available colloidal silica can be preferably used.

On the other hand, the biocompatible polymer is preferably made into nanoparticles by the spherical crystallization method. That is, in the present invention, it is preferable to include a nanoparticle forming step of forming the nanoparticles used as the surface modifier by using the spherical crystallization method. In the spherical crystallization method, crystallization and granulation can be performed simultaneously, so that not only high-quality nanoparticles can be formed, but also the designability of nanoparticles can be improved.

The spherical crystallization method controls the crystal production / growth process in the final process of compound synthesis.
This is a method in which spherical crystal particles can be designed and processed by directly controlling their physical properties. In the spherical crystallization method, the spherical granulation method (S
Method A) and emulsion solvent diffusion method (ESD method).

The SA method is a method of precipitating crystals of a target substance using two kinds of solvents to form spherical granulated crystals. Specifically, first, a poor solvent in which the target substance is difficult to dissolve and a good solvent in which the target substance can be dissolved well and which can be mixed and diffused in the poor solvent are prepared. Then, a solution prepared by dissolving the target substance in a good solvent is added dropwise to the poor solvent while stirring. At this time, crystals of the target substance are deposited in the system by utilizing the decrease in solubility due to the transfer of the good solvent to the poor solvent and the temperature effect.

Furthermore, when a small amount of liquid (liquid crosslinking agent) which has an affinity for the target substance and is immiscible with the poor solvent is added to the system, the liquid crosslinking agent is liberated. Then, crosslinks are formed between the crystals, and the crystals start to agglomerate non-randomly due to the interfacial tension and the capillary force (the funicular state). When mechanical shearing force is further applied to this system, the agglomerated crystals are consolidated and become granules having a substantially spherical shape (capillary state). Furthermore, the final spherical granulated crystals are formed by randomly coalescing the granulated products.

The types of the good solvent and the poor solvent and the type of the liquid crosslinking agent are determined according to the type of the target substance and are not particularly limited. Further, the conditions at the time of crystal precipitation and the method of applying mechanical shearing force are not particularly limited, and may be appropriately selected depending on the kind of the target substance, the particle size of spherical granulated crystals (nano-order in the case of the present invention), etc. Just decide.

In the present invention, it is more preferable to use the ESD method particularly when the biocompatible polymer is made into nanoparticles. This ESD method also uses two kinds of solvents, but unlike the SA method, after forming an emulsion, the polymer is crystallized into a spherical shape by utilizing the mutual diffusion of a good solvent and a poor solvent. Is the way. Specifically, first, FIG.
As shown in the upper left of the figure, polymer solution 4 dissolved in a good solvent
1 is added dropwise to the poor solvent 42 with stirring. At this time,
As shown in the upper right of FIG. 4, the polymer solution 41 rapidly diffuses into the poor solvent, and as shown in the lower left of FIG. 4, emulsion droplets 55 are formed by self-emulsification (Marangoni effect).

Then, as shown in the lower left of FIG. 4, the emulsion droplets 55 are cooled, and the mutual diffusion of the good solvent and the poor solvent (the white arrow in the figure indicates the diffusion of the good solvent, and the black arrow indicates the diffusion of the poor solvent). ), The solubility of the drug decreases in the emulsion droplet 55, and spherical crystal particles 56 of the drug precipitate and grow while maintaining the shape of the emulsion droplet 55, as shown in the lower right of FIG.

The types of the good solvent and the poor solvent are also determined according to the type of the target polymer and the like as in the SA method, and are not particularly limited. Also,
Emulsion formation conditions, cooling conditions during crystal precipitation, etc. are not particularly limited, depending on the kind of the target polymer drug, the particle size of spherical crystal particles 55 (nano-order in the case of the present invention), etc. It may be determined appropriately.

In the above spherical crystallization method, nanoparticles can be formed by a physicochemical method, and the obtained nanoparticles are substantially spherical. Therefore, the problem of homogeneous nanoparticles being left behind such as catalyst and raw material compounds is taken into consideration. It can be easily formed without the need for Further, the spherical crystallization method is very preferable because complexed nanoparticles can be formed simply by dissolving the drug and the polymer in a good solvent.

In the present embodiment, the polymer nanoparticles (polymer nanospheres) obtained by the spherical crystallization method are:
Particles composed of a lactic acid / glycolic acid copolymer or hydroxymethyl cellulose phthalate are particularly preferred. This makes it possible not only to favorably modify the surface of the drug powder with the polymer, but also to favorably control the level of the surface modification with the polymer. Further, the polymer nanoparticles may contain not only the biocompatible polymer but also various drugs. This has the advantage that both the surface nanoparticle drug and the internal drug particle can be administered simultaneously.

Next, the flow of the production method of the present invention including the above steps will be described by taking the case of using nanoparticles (polymer nanospheres) containing a biocompatible polymer as an example.

First, as shown in the upper left of FIG. 5, nanoparticles are formed as described above in the nanoparticle forming step (see FIG. 4). As a result, a dispersion liquid 43 in which the nanoparticles 60 are dispersed is prepared as shown in the center of the upper part of the drawing.
Furthermore, as shown in the upper right of the same, this nanoparticle dispersion liquid 4
To 3, the drug powder 71 is further added and sufficiently stirred. As a result, the nanoparticle / drug dispersion liquid 44 of the drug powder 71 and the nanoparticles 60 is prepared as shown in the lower left of FIG.

In the present invention, the above-mentioned nanoparticle / drug dispersion 4 is used.
4 is used to manufacture the composite particle 70.
For production of 0, as shown in the lower left of FIG. 5, compounding is carried out using the fluidized bed dry granulation method or the dry mechanical particle compounding method (compositing step). In FIG. 5, the fluidized bed dry granulation method is abbreviated as SD, and the dry mechanical particle composite method is abbreviated as FD.

Next, the fluidized bed dry granulation method and the dry mechanical particle composite method used in the above composite step will be specifically described.

In the fluidized bed dry granulation method, specifically, FIG.
A fluidized bed dry granulation / coating type powder processing apparatus 11 as shown in FIG.

As shown in FIG. 6, the powder processing apparatus 11 generally has an upper part which is a substantially cylindrical space, and a lower part which is also substantially cylindrical and has an inner diameter smaller than that of the upper part. A casing 12 having therein a fluidized bed space 13 in which an upper portion and a lower portion are connected to each other, an inner diameter is continuously changed, and three spaces, which are a middle portion having a substantially trapezoidal cross section, are integrated, Is provided at the bottom of
A spray nozzle 14 capable of injecting a liquid raw material into the upper fluidized bed space 13, and two bag filters 15a protruding downward in an upper portion of the fluidized bed space 13.
15b, a liquid raw material supply unit (not shown), and an air supply unit (not shown) for supplying drying / fluidizing air to the fluidized bed space 13.

In the powder processing apparatus 11, by initially spraying the liquid raw material into the empty fluidized-bed space 13, the agglomeration and layering of the particles are repeated to form a granular powder. Can be formed. therefore,
It has an advantage that the apparatus configuration is simple and the manufacturing process can be simplified, high quality granules can be manufactured, and seed particles are not required to be supplied when manufacturing the granules.

In the present invention, the above-mentioned agglomerated granulation and layering granulation are utilized to make the nanoparticle / drug dispersion 44.
Is injected into the fluidized-bed space 13 as a liquid raw material to use the nanoparticles 60 and the drug powder 71 as seed particles.

Specifically, first, as shown in the left diagram of FIG. 6, the liquid raw material (arrow S in the figure) supplied from the liquid raw material supply section is injected into the fluidized bed space 13. Since the sprayed mist diameter of the liquid raw material sprayed and supplied is about 10 μm, which is an extremely minute droplet, the liquid raw material is instantaneously solidified in the process of rising in the fluidized bed space 13 to become fine particles 65, Bag filter 15a-1 above the fluidized bed space 13
Collected in 5b.

In the bag filters 15a and 15b,
The particles 65 are intermittently blown off to the spray zone 14a below the casing 12 by the pulse jet backwashing method. This spray zone 14a has a spray nozzle 1
Since it is a region where the liquid raw material is ejected from No. 4, the liquid raw material adheres to the surface of the fine particles 65 and grows while aggregating into the granules 66. This process is agglomeration granulation.

At the same time as the above-mentioned agglomerated granulation, for the granules 66 that have grown larger, the liquid raw material is the granules 66.
Is directly attached to the surface of, and further dried and solidified. This causes the granules 66 to grow further. This process is layering granulation.

By continuing such agglomeration granulation and layering granulation, as shown in the middle diagram of FIG.
A fluidized bed 6 (arrow F in the figure) is formed in the fluidized bed space 13. Although the fluidized bed is formed from the bag filter 15a to the bag filter 15b in FIG. 6, the present invention is not limited to this.

Almost all of the liquid raw material supplied thereafter adheres to and spreads on the surface of the granules 66, and is further deposited and dried. That is, layering granulation proceeds after the fluidized bed is formed. Therefore, by adjusting the period of this layering granulation, it becomes possible to control the spheroidization and increase in weight of the granules 66, and finally, as shown in the right diagram of FIG. Granules 66 having a particle size, that is, drug-containing composite particles 70 are obtained.

In the powder processing apparatus 11, the inside of the casing 12, that is, the atmosphere of the fluidized bed space 13 can be appropriately changed according to the type of the liquid raw material or the nanoparticles 60. May be. For example, various gases such as an inert gas and a heating gas may be flown into the casing 12 from the air supply unit.

As described above, in the fluidized bed dry granulation method, the nanoparticle-drug dispersion liquid 44 containing the nanoparticles 60 and the drug powder 71 is added to the flowing nanoparticles 60 and the drug powder 71. The drug-containing composite particles 70 are manufactured by drying while spraying. Therefore, the drug-containing composite particles 70 as the surface-modified drug powder 71
Can be manufactured efficiently and with high quality.

The average particle size of the drug powder 71 used in the fluidized bed dry granulation method is 0.01 μm or more and 500 μm or more.
It is preferably within the following range. Thereby, the drug-containing composite particles 70 according to the present invention can be manufactured efficiently and reliably.

Next, in the dry mechanical particle composite method, specifically, the powder processing apparatus 21 as shown in FIG. 1 and FIG.
To use.

As shown in FIG. 1, the powder processing apparatus 21 has a casing 22 that forms a closed space having a substantially cylindrical shape, and a substantially cylindrical shape with a bottom provided inside the casing 22. The cylindrical rotating body 23 and a press head 24 disposed inside the cylindrical rotating body 23 for processing an object by generating a pressing force and a shearing force on the inner peripheral surface of the cylindrical rotating body 23. Consists of.

By rotating the cylindrical rotary member 23,
The receiving surface 25 formed on the inner peripheral surface of the cylindrical rotating body 23 and the press head 24 are relatively rotated to form a gap between the receiving surface 25 and the press head 24 as shown in FIG. The compounding process is performed by applying a pressing force and a shearing force to the object to be processed 27 existing in the formed pressing portion 26.

As shown in FIG. 1, inside the casing 22, there is provided a cylindrical rotary member 23 which is substantially cylindrical and rotatable about a vertical rotation axis X. The cylindrical rotating body 23 is composed of a rotating shaft portion 32, a bottom portion 34 connected to the rotating shaft portion 32, and a cylindrical wall portion 35 connected to the bottom portion 34.

In the powder processing apparatus 21 used in this embodiment, the object 2 to be processed is pressed against the pressing portion 26.
Slits 28 penetrating the cylindrical wall portion 35 of the cylindrical rotary body 23 are formed at a plurality of locations near the bottom portion 34 of the cylindrical rotary body 23 as means for removing the object to be processed for positively circulating 7. . The slit 28 removes a part of the object to be processed 27 held by the pressing portion 26 to the outside of the processing space 29 while the cylindrical rotating body 23 is being driven and rotated, and will be described later. As described above, all the objects to be processed 27 are sequentially circulated and supplied to the pressing portion 26.

Casing 2 constituting powder processing apparatus 21
2 is supported by a support member (not shown), and is mounted and fixed on a base (not shown). The casing 22
A sealed processing space 29 for processing the object to be processed 27 is formed inside. The casing 22 has an object inlet 30. An object-to-be-processed outlet 31 for taking out the object to be processed 27 that has been processed is provided in a part of the peripheral edge of the bottom of the casing 22. With the above configuration, the object to be processed 27 can be continuously processed.

The rotary shaft portion 32 is rotatably attached to a base (not shown) via a bearing (not shown). Then, by a motor attached to this base and a drive belt (not shown) connected to the motor,
The driving force is transmitted to the pulley (not shown) of the rotary shaft portion 32, and the cylindrical rotary body 23 is rotationally driven. By rotating the cylindrical rotating body 23, a centrifugal force acts on the object to be processed 27, and the object 27 to be processed receives the receiving surface 25 of the cylindrical rotating body 23.
Will be pressed against.

The bottom portion 34 of the cylindrical rotary member 23 has a function of connecting the rotary shaft portion 22 and the cylindrical wall portion 35 of the cylindrical rotary member 23, and a holding means for holding the object to be processed 27. Have a function. That is, the bottom portion 34 has a relationship in which the surfaces thereof are bent in relation to the cylindrical wall portion 35, which will be described later, and when the cylindrical rotary body 23 rotates, the workpiece 27 is pressed without being sufficiently processed. It is prevented from escaping downward from the portion 26.

The inner peripheral surface of the cylindrical wall portion 35 is a receiving surface 2 for the object 27 to be processed which is going outward due to centrifugal force.
It becomes 5. That is, the object to be processed 27 is retained on the pressing portion 26, and the powder is processed by applying a pressing force and a shearing force to the object to be processed 27 by the cooperation of the receiving surface 25 and the press head 24.

A plurality of slits 28 are formed near the bottom of the cylindrical wall 35 as shown in FIG. The slits 28 penetrate the receiving surface 25, that is, the cylindrical wall portion 35, and are provided at, for example, a total of two positions symmetrically with respect to the rotation axis X of the cylindrical wall portion 35. The slit 28 is the object to be processed 2 held by the pressing portion 26.
A part of 7 is discharged to the outside of the pressing part 26, and functions as a means for discharging the processing object 27. The slit 28 is formed such that the ratio of the opening area on the lower side is larger than that on the upper side so that the processed object 27 held on the lower side of the receiving surface 25 is discharged more.

In the present embodiment, for example, the slits 28 are formed in the shape of a semi-circular cross section. Object to be processed 2
7 is pressed against the receiving surface 25 by the centrifugal force, and at the same time, is influenced by gravity. Therefore, in the case of the cylindrical wall portion 35 shown in FIG. 1, the object to be processed 27 tends to move vertically downward and accumulate near the boundary between the receiving surface 25 and the bottom portion 34. The object to be processed 27 deposited on this portion is
It increases the rotational load of the cylindrical rotating body 23 and inhibits the circulation of the object to be processed 27 to the pressing portion 26. Therefore, the object to be processed 27 deposited on the portion is not covered with the slit 28.
The above inconvenience is solved by positively discharging via
Improve the efficiency of powder processing.

According to the above construction, most of the object to be processed 27 existing in the pressing portion 26 is discharged to the outside of the pressing portion 26 through the slit 28. Therefore, the object to be processed 27 is held by the pressing portion 26 for a certain period of time, a pressing force and a shearing force are applied thereto, and the powder processing is reliably performed.

Inside the cylindrical rotary member 23, a press head 24 is arranged on the receiving surface 25 with a predetermined space.
Is provided. The press head 24 cooperates with the receiving surface 25 to apply a pressing force and a shearing force to the object to be processed 27. Therefore, the horizontal cross-sectional shape of the press head 24 is, for example, a semicircular shape as shown in FIG. 7. With the above-described structure, the object 27 to be processed, which is about to enter between the press head 24 and the receiving surface 25, is compacted, and an advantageous effect can be obtained for complexing and spheroidizing the powder particles.

When the horizontal cross-sectional shape of the press head 24 is semi-circular, the curvature is made larger than the curvature of the receiving surface 25. As a result, the object to be processed 27 fixed to the receiving surface 25 of the cylindrical rotating body 23 has a strong compressive force when passing through the pressing portion 26 due to the rotation of the cylindrical rotating body 23.
It receives shearing force. Here, when a mixture of a plurality of types is used as the object to be treated 27, it is subjected to a strong compressive force and a shearing force, whereby the particles are compounded, the surface of the particles is modified, the shape of the particles is controlled, and the particles are finely and precisely dispersed. As a result of mixing (powder fusion), etc., the particle characteristics can be controlled.

The press head 24 may be fixed in the same manner as the casing 22, or may be rotationally driven by using some driving means and positively rotated relative to the receiving surface 25. Good. That is, by appropriately setting the rotation direction or the rotation speed of the press head 24, the relative rotation speed between the press head 24 and the receiving surface 25 can be set more finely, and the workpiece 27 can be processed.
It is possible to set the optimum processing conditions according to the above.
The temperature of the press head 24 may be controlled. For example, although not shown, the press head 24 is not shown.
If the heat medium passage is secured in the inside of the container, it becomes easy to set the optimum processing conditions according to the thermal characteristics of the object to be processed 27.

A circulating blade 36 is provided on the lower portion of the outer periphery of the casing 22. The circulation blade 3
A plurality of 6 are provided along the circumferential direction of the cylindrical rotary body 23, but the number is arbitrary. The circulation blade 36
Is for circulating the object to be processed 27 discharged from the slit 28 to the outside of the cylindrical rotary member 23 to the pressing portion 26 again. The circulation blade 36 raises the object 27 to be processed along the outer peripheral surface of the cylindrical wall portion 35, exceeds the upper end of the cylindrical wall portion 35, and the processing space 29 of the cylindrical rotating body 23.
It is formed in conformity with the shape of the inner surface of the casing 22 in order to smoothly and surely carry it back to the pressing portion 26 and to circulate it.

By treating the object to be treated 27 by using the powder processing apparatus 21 having the above-mentioned structure, the object to be treated 27 is pressed against the receiving surface 25 of the cylindrical rotary member 23 by centrifugal force,
In response to the gathering action, a layer of the object to be treated 27 in a consolidated state is formed on the receiving surface 25. On the other hand, a part of the compacted target object 27 is discharged to the outside of the cylindrical rotary member 23 through the slit 28, and the target object 27 present inside the cylindrical rotary member 23 is The press head 24 receives a certain amount of stirring action. Therefore, the object to be processed 2
The composite processing of No. 7 can be rapidly advanced.

As described above, according to the powder processing apparatus 21, the object to be processed 27 is the object to be processed inlet 3 of the casing 22.
From 0, it is put into the processing space 29 and subjected to a strong compressive force / shearing force by the cylindrical rotating body 23 and the press head 24 to be subjected to a composite treatment. In addition, the cylindrical rotating body 23
Since the slit 28 is formed on the wall surface of the cylindrical rotary body 23, the mixture is sent to the outside of the processing space 29 of the cylindrical rotary body 23 through the slit 28 of the cylindrical rotary body 23. Then, as shown in FIG. 1, the object to be processed 27 sent to the outside is conveyed to the upper part of the cylindrical rotating body 23 by the circulation blade 36 and returned to the inside of the cylindrical rotating body 23 again. It will be subjected to compressive and shearing forces again. In this way, the object to be processed 2
7 is repeatedly subjected to a strong compressive force / shearing force by the cylindrical rotating body 23 and the press head 24, so that the compounding treatment 7 is effectively performed.

The powder processing apparatus 21 may be capable of appropriately changing the inside of the casing 22, that is, the atmosphere of the processing space 29 according to the type of the object 27 to be processed. . For example, various gases such as an inert gas and a heating gas are introduced into the inside of the casing 22 through the above-mentioned object inlet 30 or the inside of the casing 22 is pressurized or depressurized by using a pressurizing / vacuum pump or the like. It may be configured. In this case, for example, by providing a seal member (not shown) between the casing 22 and the rotary shaft portion 32 of the cylindrical rotary body 23, the atmosphere inside the processing space 29 can be adjusted reliably.

A jacket 33 for mainly adjusting the temperature of the processing space 29 is provided around the casing 22. A heating medium or a cooling medium from a separately provided tank (not shown) is circulated and supplied to the jacket 33 as needed. As a result, the casing 2
The internal temperature of 2 can be adjusted. For example, in the case of treating a drug which may be deteriorated due to temperature change as the object to be treated 7, the temperature of the object to be treated 27 during treatment is desired by circulating the heating medium or the cooling medium to the jacket 33. It can prevent the deterioration of the drug as the temperature of.

In the dry mechanical particle composite method, a particle mixture obtained by drying the nanoparticle-drug dispersion 44 is used as the object to be processed 27, and the object 27 to be processed is compressed and compressed. A plurality of nanoparticles 60 are attached to the surfaces of the drug particles 71 by applying a shearing force. Therefore, even by using this method, the drug-containing composite particles 70 can be manufactured efficiently and with high quality.

The average particle size of the drug powder 71 used in the dry mechanical particle composite method may be in the range of 0.01 μm to 500 μm, as in the fluidized bed dry granulation method. Thereby, the drug-containing composite particles 70 according to the present invention can be manufactured efficiently and reliably.

Here, in the production method according to the present invention, the surface-modified drug powder may be further agglomerated and secondary granulated to obtain drug-containing composite particles. That is, the present invention may include a secondary granulation step of secondary granulating the surface-modified drug powder.

The structure of the secondary granulation is not particularly limited, and a binder-aggregating drug powder aggregate (drug-containing composite particles) obtained by aggregating drug powder through a binder.
Or a carrier-type drug powder aggregate (drug-containing composite particles) obtained by agglomerating drug powder through carrier particles.

In the present invention, in the above secondary granulation step, it is very preferable to use the fluidized bed dry granulation method or the dry mechanical particle composite method, as in the above composite step. As a result, the surface-modified drug powder can be aggregated without impairing the structure of the drug powder, and the secondary granulated drug-containing composite particles can be obtained. The fluidized bed dry granulation method gives a binder-aggregated drug powder aggregate, and the dry mechanical particle composite method gives a carrier-type drug powder aggregate.

The drug powder aggregates (drug-containing composite particles) obtained in the above secondary granulation step are capable of dispersing and assembling surface-modified drug powders, which are primary particles containing nanoparticles. It is compounded like this. Therefore, for example, in the case of use in a transpulmonary preparation, when the drug powder aggregate is injected into the oral cavity after the drug powder aggregate is charged into the inhaler, the drug powder aggregate is well disintegrated at the time of injection. The surface-modified drug powder is dispersed and inhaled from the oral cavity to the lungs. Thereby, the drug-containing composite particles can be suitably used as an inhalation preparation.

The material used as the carrier particles is specifically, for example, polysaccharides such as microcrystalline cellulose, methyl cellulose, carmellose sodium, carmellose calcium, and low-substituted hydroxypropyl cellulose. And wheat starch,
Examples thereof include starches such as rice starch, corn starch, potato starch, hydroxypropyl starch, sodium carboxymethyl starch, α-cyclodextrin and β-cyclodextrin. Examples of hydrophilic polymers include polymers such as polymethylmethacrylate (PMMA). Among them, the polysaccharide powder is preferably microcrystalline cellulose, corn starch, potato starch or the like, and the hydrophilic polymer powder is preferably polymethylmethacrylate.

As described above, as a typical use of the present invention, use of pharmaceuticals, particularly production of highly dispersible powder inhalation preparations (transpulmonary preparations) of anti-asthma drugs and anti-allergic agents is very preferable. However, it goes without saying that the present invention is not limited to this, and can be favorably used for manufacturing and developing other pharmaceuticals and medical products.

For example, in addition to the above-mentioned transpulmonary preparations, compounding antidiabetic agents such as insulin can be used for the development of oral or transpulmonary administration type DDS preparations instead of injections. Further, by using the adhesive and adhesive nanoparticles, the drug for treating osteoporosis, such as calcitonin, can be used for the development of an oral / pulmonary administration type DDS preparation.

Furthermore, by using a hydrophilic polymer such as hydroxypropylmethylcellulose phthalate as the DDS, it can be used for the development of an aqueous enteric coating base, and can be directly biodegradable for tableting. It can also be used as an implant base or for improving absorption of other poorly absorbable orally administered drugs such as peptide drugs.

[0089]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

Example 1 35 g of pranlukast hydrate, which is an anti-asthma drug (average particle size 3 μm) having poor wettability, fluidity, dispersibility, etc., and powder treatment by a fluidized bed dry granulation method in advance Device (See Fig. 6, Agromaster AGM-made by Hosokawa Micron
2SD) dried polymer nanospheres HP-55
(Hydroxypropyl methylcellulose phthalate, average particle size 52 nm) 3.5 g, and a powder processing apparatus of a dry mechanical particle composite method (see FIGS. 1 and 7, AM-MINI (mechanofusion mini) manufactured by Hosokawa Micron, processing capacity) 100 ml / batch, casing inner diameter φ = 80 m
m, with cold water jacket, rotor speed up to 3500r
pm) and the rotor speed is 1500 rpm for 15
Processed for a minute. In addition, water is circulated through the water cooling jacket,
The powder temperature was kept below 30 ° C. This is because the powder temperature rises with time without water cooling, and a fusion phenomenon occurs around 80 ° C.

The obtained drug-containing composite particles were filled and supplied in an inhaler manufactured by Unisia Jex Co., Ltd.
The dispersed state in the air was confirmed. Moreover, the obtained drug-containing composite particles were dispersed in water to confirm wettability. Filling and feeding were easy, and the dispersed state in air and the wettability were good.

Example 2 The same process as in Example 1 was carried out except that 3.5 g of colloidal silica was used as the nanoparticles and the rotor rotation speed was 2250 rpm. The obtained drug-containing composite particles were filled and supplied to an inhaler and injected, and then the dispersion state in the air was confirmed. Moreover, the obtained drug-containing composite particles were dispersed in water to confirm wettability. Filling and feeding were easy, and the dispersed state in air and the wettability were good.

As described above, by using the method for producing drug-containing composite particles according to the present invention, the surface of pranlukast hydrate was satisfactorily modified and the dispersibility and wettability were greatly improved.

Example 3 HP-55 (hydroxypropyl methylcellulose phthalate) ethanol / water =
The 8/2 solution was dropped into water with stirring to form polymer nanospheres, and immediately pranlukast hydrate (anti-asthma drug, hydrophobic) with an average particle size of 2 μm was added to the system to prepare nanoparticles- A drug dispersion was prepared. This nanoparticle-drug dispersion was treated with a powder treatment apparatus AGM-2SD of a fluidized bed dry granulation method to obtain drug-containing composite particles whose surface was modified with HP-55.

The obtained drug-containing composite particles were filled and supplied in an inhaler and sprayed, and then the dispersion state in the air was confirmed.
Moreover, the obtained drug-containing composite particles were dispersed in water to confirm wettability. Filling and feeding were easy, and the dispersed state in air and the wettability were good.

Example 4 In Example 3, carrier particles (for example, 30 to 50 μm in average particle diameter) were charged in advance in a powder processing apparatus AGM-2SD of the fluidized bed dry granulation method, and the carrier particles were prepared. By spraying and supplying the above-mentioned nanoparticle-drug dispersion liquid onto the surface of, drug-containing composite particles were obtained. The obtained drug-containing composite particles were agglomerated on the surface of the carrier particles and became a surface-modified drug powder.

The obtained drug-containing composite particles were filled and supplied in an inhaler and sprayed, and then the dispersion state in the air was confirmed.
Moreover, the obtained drug-containing composite particles were dispersed in water to confirm wettability. Filling and feeding were easy, and the dispersed state in air and the wettability were good. This allows the drug-containing composite particles to be used as an inhalation preparation.

[0098]

INDUSTRIAL APPLICABILITY As described above, the method for producing drug-containing composite particles according to the present invention provides a mixture containing nanoparticles having an average particle size of less than 1000 nm and drug powder having an average particle size larger than the nanoparticles. , A fluidized bed dry granulation method or a dry mechanical particle compositing method for compounding to modify the surface of the drug powder.

In the above method, it is preferable to use a lubricant powder as the nanoparticles. Colloidal inorganic compound powder or surfactant powder may be used as the lubricant, and polymer nanoparticles obtained by the spherical crystallization method may be used as the lubricant.
Furthermore, it is preferable that the average particle diameter of the drug powder be within a range of 0.01 μm or more and 500 μm or less.

According to the above method, the nanoparticles and the drug powder are compounded using the fluidized bed dry granulation method or the dry mechanical particle compounding method. Therefore, it becomes possible to effectively use the nanoparticles as a surface modifier of the drug powder, and it is possible to satisfactorily modify the surface of the drug powder and to control the surface modification level satisfactorily. Play.

Further, since the fluidized bed dry granulation method and the dry mechanical particle composite method are suitable for a large amount of composite processing,
There is also an effect that the productivity of the surface-modified drug powder can be further improved.

As described above, the present invention can be applied to the development of the next-generation DDS corresponding to the aging society by, for example, an environmentally friendly mechanical process. Therefore, it is possible to establish an application technology for pharmaceuticals and medical products based on nanotechnology.

[Brief description of drawings]

FIG. 1 is a cross-sectional view showing one structural example of a powder processing apparatus used in a method for producing drug-containing composite particles according to an embodiment of the present invention.

FIG. 2 is a schematic view showing an example of a manufacturing process of drug-containing composite particles according to an embodiment of the present invention.

FIG. 3 is a schematic diagram showing an example of use of a transpulmonary preparation which is one mode of use of the present invention.

FIG. 4 is a schematic diagram illustrating an example of a spherical crystallization method used in the method for producing drug-containing composite particles according to one embodiment of the present invention, specifically, a granulation process of an emulsion solvent diffusion method. Show.

FIG. 5 is a schematic diagram showing an example of preparation of a dispersion liquid that is performed before the complexing step of the method for producing drug-containing composite particles according to the embodiment of the present invention.

FIG. 6 is a schematic diagram showing another example of the configuration of the powder processing apparatus and an example of compounding, which is used in the method for producing composite particles according to the embodiment of the present invention.

FIG. 7 is a cross-sectional view illustrating an operation when a compressive force and a shearing force are applied to an object to be processed by the powder processing apparatus shown in FIG.

[Explanation of symbols]

60 nanoparticles (lubricant powder / polymer nanoparticles) 70 Drug-containing composite particles 71 Drug powder

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 47/38 A61K 47/38 (72) Inventor Hisato Eitoku 66-12 Kusunaka-cho, Hirakata-shi, Osaka (72) Inventor Naotoshi Kinoshita 65-606 F-term, Mukojimahonmarucho, Fushimi-ku, Kyoto-shi, Kyoto (reference) 4C076 AA31 AA95 BB27 CC15 DD29 DD41 DD68 EE24 EE33 EE48

Claims (9)

[Claims] 1. A mixture containing nanoparticles having an average particle size of less than 1000 nm and a drug powder having an average particle size larger than the nanoparticles is compounded by a fluidized bed dry granulation method or a dry mechanical particle compounding method. By modifying the surface of the drug powder, the method for producing drug-containing composite particles, comprising: 2. The method for producing drug-containing composite particles according to claim 1, wherein a lubricant powder is used as the nanoparticles. 3. The method for producing drug-containing composite particles according to claim 2, wherein colloidal inorganic compound powder or surfactant powder is used as the lubricant. 4. The method for producing drug-containing composite particles according to claim 3, wherein the colloidal inorganic compound powder is colloidal silica. 5. The method for producing drug-containing composite particles according to claim 3, wherein the surfactant is magnesium stearate or sugar ester. 6. The method for producing drug-containing composite particles according to claim 2, wherein polymer nanoparticles obtained by a spherical crystallization method are used as the lubricant. 7. The method for producing drug-containing composite particles according to claim 6, wherein the polymer nanoparticles are composed of a lactic acid / glycolic acid copolymer or hydroxymethyl cellulose phthalate. 8. The average particle size of the drug powder is 0.01 μm.
The method for producing drug-containing composite particles according to any one of claims 1 to 7, wherein the method is within the range of 500 μm or less. 9. The drug-containing complex according to claim 1, which is used for producing a transpulmonary preparation for delivering a drug in powder form to the lung and absorbing the drug from the lung. Method for producing particles.