JP2003275281A - Production method for composite particle containing drug - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a production method for composite particles containing drugs which is applicable ideally for various pharmaceutical fields such as DDS (drug delivery system) by improving handleability without impairing the advantage of nano-size particles. <P>SOLUTION: At least one of drugs and biocompatible polymers undergoes a nano-size granulation with an average grain size of below 1,000 nm and then, a composite processing using a fluidized bed dry peletization method or a dry type mechanical particle composite processing to form polymer nano-size composite particles. This can improve handleability without impairing the advance of nano-size particles and for example, enables an application ideal for DDS such as powder transpulmonary preparations. <P>COPYRIGHT: (C)2003,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, drug-containing composite particles applicable to drug delivery systems and the like and capable of suitably producing drug-containing composite particles The present invention relates to a method for producing composite particles.

[0002]

2. Description of the Related Art Nano-order fine powders having an average particle size of less than 1000 nm, that is, an average particle size of less than 1 μm, that is, nanoparticles have extremely large specific surface area and activity as compared with conventional micron-sized fine powders. , Various physical properties will change dramatically, and it is highly likely that it will bring breakthrough improvements in product performance characteristics in all fields. Particularly, in the field of formulation technology in the fields of pharmaceuticals and medical products, the application range of nanoparticles is extremely wide.

Specifically, first, nanoparticles have a very small particle size. Therefore, for example, in the case of an injection, the diameter of the terminal capillaries is about 4 μm. Therefore, if the solid drug is made into nanoparticles, it is possible to avoid the generation of a thrombus even if intravenous injection is performed. In addition, inflammation or tumor formation can be reduced by intramuscular injection or subcutaneous injection.

Further, since the nanoparticles have a large specific surface area, the surface energy is increased, and as a result, the nanoparticles exhibit high reactivity. Therefore, in oral or pulmonary administration of a drug, it becomes
The permeability of the drug in the living body and the accessibility to the absorption site can be improved, and because the nanoparticles easily adhere strongly to the surface of the biological membrane, the retention property of the absorption site of the drug, etc. increases, and as a result, the drug absorption Can be increased.

Therefore, nanoparticles have received a great deal of attention in the development of drug delivery systems (Drug Delivery Systems, hereinafter abbreviated as DDS).

However, while the high reactivity of the nanoparticles is an advantage of the nanoparticles, it also leads to destabilization of the nanoparticles. Therefore, problems such as a decrease in stability of the nanoparticle drug before and after administration occur.

Therefore, conventionally, a technique has been developed for improving the stability of a nanoparticle drug by complexing nanoparticles using a chemical method or a physicochemical method. Specifically, for example, a polymer nanoparticle is formed by forming a composite of a drug and a polymer by using a spherical crystallization method. As the polymer, a polymer having excellent biodegradability and biocompatibility is preferably used.

[0008]

The high reactivity of nanoparticles contributes to the strong surface adhesion of nanoparticles,
This strong surface adhesion also leads to adhesion and aggregation of nanoparticles. Therefore, the fluidity of nanoparticles is very low. Moreover, since nanoparticles are ultrafine particles, they are bulkier than conventional micro-order fine particles. therefore,
There is a problem that the handling property of the nanoparticles is lowered.

The nanoparticle composite technique such as the spherical crystallization method sufficiently enhances the stability of the nanoparticles themselves, but is not the technique of sufficiently enhancing the handleability of the stabilized nanoparticles.

For example, when a drug is administered, it is natural that the behavior of the drug after administration is important, but if the drug itself is difficult to handle before administration, no matter how excellent drug delivery is. Even if it can perform its function, it will be less complete as a drug. For example, in the case of a transpulmonary preparation, a drug powder is filled and supplied to an inhaler, but if the drug powder is nanoparticles, it cannot be easily and simply filled because the fluidity is low.

Further, the high reactivity of nanoparticles can exhibit characteristics such as excellent film formation / fusion property due to heating and mechanical stress (pressurization, shearing). Material development is also possible. However, if the handling property of nanoparticles is low, it will also affect the development of the above new materials.

[0012] Generally, it is known that it is difficult to granulate a hydrophobic powder having an electrostatic property, but a nanoparticle is a very fine particle. It is very difficult to granulate such fine particles so that they can be well dispersed during or after use.

The present invention has been made in view of the above problems, and an object of the present invention is to improve the handling property without impairing the advantages of nanoparticles, and to provide a composite particle which can be suitably applied to various pharmaceutical fields such as DDS. It is to provide a manufacturing method.

[0014]

Means for Solving the Problems As a result of intensive studies in view of the above-mentioned problems, the present inventors have taken advantage of the problem of nanoparticles that tend to agglomerate naturally, and conversely, dispersed nanoparticles when used. It was found that it is possible to improve the handleability of the nanoparticles without impairing the advantages of the nanoparticles by artificially aggregating the nanoparticles as much as possible, and completed the present invention.

That is, a method for producing drug-containing composite particles according to the present invention is a method for producing composite particles containing a drug and a biocompatible polymer in order to solve the above-mentioned problems. By converting at least one of the water-soluble polymers into nanoparticles having an average particle size of less than 1000 nm and compounding a mixture containing the nanoparticles by a fluidized bed dry granulation method or a dry mechanical particle compounding method, It is characterized by forming polymer nanocomposite particles.

According to the above method, a particle mixture containing at least one of drug nanoparticles and biocompatible polymer nanoparticles is compounded using a fluidized bed dry granulation method or a dry mechanical particle composite method. I am letting you. Therefore, functional micron particles having a nanostructure can be obtained. Therefore, for example, drug-containing composite particles capable of sufficiently dispersing drug nanoparticles at the time of use, and drug particles whose surface has been modified with biocompatible polymer nanoparticles to improve drug delivery characteristics Composite particles containing can be produced. As a result, the nanoparticle can be used for the production of a drug having improved handling properties without impairing the advantages thereof.

The method for producing drug-containing composite particles according to the present invention has an average particle size of 100 in order to solve the above problems.
It is characterized by including a primary particle forming step of forming primary particles containing nanoparticles having a size of less than 0 nm and a compounding step of compounding the primary particles so that the primary particles are reversibly aggregated.

According to the above method, the primary particles containing nanoparticles are compounded so that they can be dispersed and aggregated, so that the aggregation state of the primary particles can be controlled.
Therefore, it becomes possible to design the drug-containing composite particles (nanocomposite particles) such that the obtained drug-containing composite particles (nanocomposite particles) can be disintegrated / dispersed into primary particles containing the nanoparticles at the time of use.

Therefore, since the average particle size of the drug-containing composite particles is larger than the nano-order before use, it can be made in a state of not being bulky and excellent in fluidity, and at the time of use (after use), the nanoparticles can be used. It becomes possible to disintegrate the drug-containing composite particles into primary particles and use them so as to exert the function of. Therefore, the handling property of the nanoparticles can be improved without impairing the advantages of the nanoparticles.

In the method for producing drug-containing composite particles according to the present invention, the primary particles are preferably nanoparticle aggregates formed by aggregating a plurality of nanoparticles. By appropriately controlling the aggregation state of the nanoparticle aggregates, the drug-containing composite particles can be further disintegrated into nanoparticles after the nanoparticle aggregates that are the primary particles are disintegrated. Therefore, it becomes possible to use the drug-containing composite particles having a large particle size as the nanoparticles themselves at the time of use. As a result, the handleability can be improved while fully utilizing the advantages of the nanoparticles.

In the method for producing drug-containing composite particles according to the present invention, drug powder is preferably used as the nanoparticles. As a result, the manufacturing method according to the present invention can be preferably used for manufacturing a drug for DDS and the like.

The method for producing drug-containing composite particles according to the present invention preferably further comprises a nanoparticle forming step of forming the nanoparticles by a 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 method for producing drug-containing composite particles according to the present invention comprises:
Secondary granulation of the nanoparticle aggregates is preferred.

In the fluidized bed dry granulation method, the primary particles are secondary aggregated through the binder by drying while spraying a liquid containing the binder onto the flowing primary particles. Therefore, not only can the drug-containing composite particles be produced efficiently and with high quality, but also the aggregation state of the nanoparticles can be controlled. As a result, the handling property can be further improved without impairing the advantages of the nanoparticles.

In the fluidized bed dry granulation method, the average particle diameter of the primary particles used is 0.01 μm or more and 500 μm or more.
It is preferably within the following range. Thereby, the drug-containing composite particles in which the primary particles are secondary granulated can be efficiently and reliably produced. When used as a transpulmonary preparation described below, the average particle size of the primary particles is 0.
It is preferably in the range of 01 μm or more and 15 μm or less.

In the fluidized bed dry granulation method, it is preferable to use a binder that binds the primary particles together. The binder may be an aqueous solution of biocompatible polymer. Thereby, the secondary granulation state of the drug-containing composite particles in which the primary particles are secondary granulated can be controlled.
In particular, when a drug is used as nanoparticles, it is preferable to use a biocompatible polymer.

In the method for producing drug-containing composite particles according to the present invention, the nanoparticle aggregate is formed on the surface of carrier particles having an outer diameter larger than that of the primary particles by the dry mechanical particle composite method in the composite step. May be attached.

In the dry mechanical particle composite method, a compressive force and a shearing force are applied to a particle mixture obtained by mixing the above-mentioned primary particles and carrier particles, whereby a plurality of nanoparticle coagulates on the surface of the carrier particles. Attach the assembly. Therefore, using this method, not only can the drug-containing composite particles be produced efficiently and with high quality, but also the aggregation state of the nanoparticles can be controlled. As a result, the handling property can be further improved without impairing the advantages of the nanoparticles.

In the dry mechanical particle composite method, the average particle diameter of the primary particles used is 0.01 μm or more and 50 μm or more.
It is preferable that the particle diameter is within a range of 0 μm or less, and the average particle diameter of the carrier particles is within a range of 1 μm or more and 500 μm or less. As a result, drug-containing composite particles of carrier particles and primary particles can be efficiently and reliably produced. When used as a transpulmonary preparation described below, the average particle size of the primary particles is 0.01 μm or more and 15 μm or more.
The following range is preferable, and the average particle size of carrier particles is 1
It is preferably in the range of 0 μm or more and 100 μm or less.

In the dry mechanical particle composite method, it is preferable to use a polysaccharide powder or a hydrophilic polymer powder as the carrier particles. Thereby, the composite state of the drug-containing composite particles of carrier particles and nanoparticle aggregates,
That is, it is possible to favorably control the state in which the nanoparticle aggregates are attached to the surface of the carrier particles. In particular, when a drug is used as nanoparticles, it is preferable to use a polysaccharide powder made of the above-mentioned celluloses or starches, or a hydrophilic polymer powder made of polymethylmethacrylate.

In the method for producing drug-containing composite particles according to the present invention, the surface of the carrier particles is further modified by a fluidized bed dry granulation method or a dry mechanical particle composite method before the above-mentioned composite step. It is preferable to include a carrier particle surface modification step. The surface modification of the carrier particles in this carrier particle surface modification step may be modification for smoothing the surface of the carrier particles by each of the above methods, or the carrier particles and the lubricant particles may be modified as described above. The modification may be a compounding method.

By the above-mentioned carrier particle surface modification step, the adhered state of the primary particles on the surface of the carrier particles can be controlled. Therefore, the separability between the primary particles and the carrier particles can be controlled, and the drug-containing composite particles can be satisfactorily disintegrated and dispersed in the primary particles.

The application of the method for producing drug-containing composite particles according to the present invention is not particularly limited, and it is preferably used for applications where it is desired to make full use of the characteristics of nanoparticles at the time of use. It is very suitably used for the production of a transpulmonary preparation in which is administered to the lung to absorb the drug from the lung. In the present invention, since the shape and density of the drug-containing composite particles can be well controlled, it is possible to design a predetermined aerodynamic diameter and optimize the inhalation characteristics of the drug powder in the production of transpulmonary preparations. it can.

[0034]

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 according to the present embodiment, primary particles containing nanoparticles are formed, and the primary particles are compounded so that the primary particles are reversibly assembled. Is the way. As a method for compositing such that the primary particles are reversibly aggregated, it is very preferable to use a fluidized bed dry granulation method or a dry mechanical particle compositing method.

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 new materials. Above all, especially for pharmaceutical applications, for example, as shown in the present embodiment, It can be preferably used for the purpose of producing a powdered drug such as a transpulmonary preparation. In the following description, the drug-containing composite particles are appropriately abbreviated as composite particles for convenience of description.

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.
In the present embodiment, as one field of application of the present invention, nanoparticles of a drug will be described as an example, but it goes without saying that nanoparticles of another substance may be used. That is, in the present embodiment, drug powder is used as the nanoparticles. By using drug nanoparticles, the production method according to the present invention can be suitably used for production of a drug for DDS and the like, as described below.

The method for producing nanoparticles in the present invention is not particularly limited as long as it is a method capable of processing the target substance into particles having an average particle size of less than 1000 nm, but in the present invention. Especially, when the drug is made into nanoparticles, it is very preferable to use the spherical crystallization method.

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 drug crystals using two kinds of solvents to form spherical granulated crystals. Specifically, first, a poor solvent in which the target drug is difficult to dissolve and a good solvent in which the drug is well dissolved and which can be mixed and diffused in the poor solvent are prepared. Then, the drug solution dissolved in a good solvent is dropped into the poor solvent while stirring. At this time, the drug crystals 51 are precipitated in the system as shown in the leftmost diagram of FIG. 2A 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 cross-linking agent) which has an affinity for the drug and is immiscible with the poor solvent is added to the system, as shown in the leftmost diagram of FIG. Agent 52
Is released. Then, a bridge is formed between the crystals 51,
2 from the left in FIG. 2 (a) due to interfacial tension and capillary force.
As shown in the second figure, the crystals 51 start to aggregate non-randomly. Note that this state is called a funicular state.

When mechanical shearing force is further applied to the system in the funicular state, the agglomerated crystals 51 are consolidated, and as shown in the third diagram from the left in FIG. It becomes grain 53. This state is called a capillary state. By randomly coalescing the granulated material 53 in the capillary state, as shown in the rightmost diagram of FIG.
The final spherical granulated crystals 54 are formed.

The types of the good solvent and poor solvent and the type of the liquid cross-linking agent 52 are determined according to the type of the target drug and are not particularly limited.
In addition, the conditions for crystal precipitation and the method of applying mechanical shearing force are not particularly limited, and may depend on the target drug type, the particle size of the spherical granulated crystal 54 (nano-order in the case of the present invention), and the like. It may be appropriately determined depending on the situation.

The ESD method is also a method of using two kinds of solvents, but unlike the SA method, after forming an emulsion, the drug is crystallized into a spherical shape by utilizing the mutual diffusion of a good solvent and a poor solvent. It is a method to let. Specifically, first, a drug solution dissolved in a good solvent is dropped into a poor solvent with stirring.
At this time, since the drug and the good solvent have an affinity, the transfer of the good solvent to the poor solvent is delayed, and emulsion droplets 55 are formed as shown in the left diagram of FIG. 2B.

Then, as shown in the middle diagram of FIG.
By cooling the emulsion droplet 55 and mutual diffusion of the good solvent and the poor solvent (the black arrow in the figure indicates the diffusion of the good solvent, the white arrow indicates the diffusion of the poor solvent),
The solubility of the drug decreases, and as shown in the right diagram of FIG. 2 (b), the spherical crystal particles 56 of the drug become the emulsion droplets 5.
It precipitates and grows while maintaining the shape of 5.

The types of the above-mentioned good solvent and poor solvent are also determined according to the type of the target drug and the like, as in the SA method, and are not particularly limited. Further, the conditions for forming the emulsion, the cooling conditions for crystal precipitation, etc. are not particularly limited, and may depend on the type of the target drug, the particle size of the 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 In addition, in DDS applications, the drug may be modified with a biocompatible polymer, but in the spherical crystallization method,
It is very preferable because the complexed nanoparticles can be formed only by dissolving the drug and the polymer in a good solvent.

There are no particular restrictions on the specific type of drug that is made into nanoparticles by the spherical crystallization method. 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 , Cardiotonics, diuretics, muscle relaxants, brain metabolism improvers, minor tranquilizers, major tranquilizers, β-blockers, antiarrhythmic agents, gout remedies,
Anticoagulant, thrombolytic agent, liver disease agent, antiepileptic agent, antihistamine agent, antiemetic agent, antihypertensive agent, hyperlipidemia agent, sympathomimetic agent, oral diabetes treatment agent, oral anticancer agent,
Examples include alkaloid narcotics, vitamins, treatments for frequent urination, angiotensin converting enzyme inhibitors and the like.

In the method for producing drug-containing composite particles according to the present invention, for example, the nanoparticles formed as described above are used, and the nanoparticles are further granulated. Here, in the present invention, the above nanoparticles may be used as they are, but it is more preferable that secondary particles are further granulated after forming primary particles containing the nanoparticles.

For example, the present invention can be used for producing a dry powder type transpulmonary preparation. Here, in the transpulmonary preparation, the drug powder is first filled and supplied in an inhaler (dry powder injection device) and then injected into the oral cavity.

However, since the nanoparticles are extremely fine,
This leads to poor handling such as low fluidity. Therefore, if the drug powder is nanoparticles, it is not possible to easily and simply fill and supply the drug powder to the inhaler. Moreover,
Even if the composite particles are designed to disintegrate in the oral cavity to directly generate nanoparticles, in reality, the nanoparticles cannot be well dispersed, and some may remain aggregated. Therefore, there may be cases where the drug cannot be successfully delivered to the lungs.

Therefore, for example, if the particles are made into micron particles until they reach the lungs from the oral cavity and they are made into nanoparticles only after they reach the lungs, homogeneous micron particles can be well dispersed in the air at the time of jetting. This is preferable because it is possible to increase the delivery rate of the drug to the lungs and to form nanoparticles at the time of deposition in the lungs, which can improve the absorbability of the drug from the lungs. Therefore, in transpulmonary preparations, not only drugs such as anti-asthma drugs such as pranlukast hydrate and antiallergic drugs such as steroids that are preferably administered directly to the lung, but also peptide-based drugs such as insulin and calcitonin Drugs are also available.

Moreover, the composite particles (polymer nanocomposite particles) obtained by further compositing the nanoparticles modified with various biocompatible polymers using the spherical crystallization method
Can be used as a drug for DDS, for example, because it can improve deposition in the lungs.

Therefore, in the present embodiment, it is preferable to go through the steps of granulating the primary particles containing nanoparticles and further secondary granulating the primary particles. That is, in the present invention, a nanoparticle aggregate forming step of forming primary particles containing nanoparticles having an average particle size of less than 1000 nm, and combining the primary particles so that the primary particles are reversibly aggregated. It is preferable to include a complexing step of

If the above two steps are included, the primary particles containing nanoparticles are compounded so that they can be dispersed and aggregated, so that the aggregation state of the primary particles is controlled. Therefore, it becomes possible to design the composite particles such that the obtained composite particles can be disintegrated into primary particles containing nanoparticles when used.

As a result, since the average particle size of the composite particles is larger than nano-order before use, it can be in a state of not being bulky and excellent in fluidity, and at the time of use (after use), It is possible to disintegrate the composite particles into primary particles so that the composite particles can be used before they are used. Therefore, the handling property of the nanoparticles can be improved without impairing the advantages of the nanoparticles.

For example, as shown in FIG. 3, in a transpulmonary preparation, primary particles 61 containing drug nanoparticles are compounded to form composite particles 62, and the composite particles 62 are filled and supplied to the inhaler 40. Since the composite particles 62 can have an average particle size of about several tens of μm, their fluidity and handleability are improved, and the inhaler 4
0 can be easily and simply filled and supplied. Also,
Since it easily disintegrates and disperses in the primary particles 61 during injection,
The fine primary particles 61 pass through the airways and reliably reach the lungs.

Here, as described above, the primary particles are preferably nanoparticle aggregates formed by aggregating a plurality of nanoparticles. By appropriately controlling the aggregation state of the nanoparticle aggregates, the composite particles can be disintegrated into nanoparticles after the nanoparticle aggregates that are the primary particles are disintegrated. Therefore, it becomes possible to use composite particles having a large particle size as the nanoparticles themselves at the time of use. As a result, the handleability can be improved while fully utilizing the advantages of the nanoparticles.

Furthermore, as described above, since it is preferable to use the spherical crystallization method particularly when the drug is made into nanoparticles, the method for producing drug-containing composite particles according to the present invention is
It is preferable to include a nanoparticle forming step of forming the nanoparticles by a 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 flow of the production method of the present invention including the above steps will be described by taking the production and use of a transpulmonary preparation as an example.

First, in the nanoparticle forming step, nanoparticles are formed by the spherical crystallization method as described above (FIG. 2 (a).
(See (b)). Next, as shown in FIG. 4, in the primary particle forming step, nanoparticles are aggregated to form nanoparticle aggregates 61 as primary particles. The primary granulation method carried out in the primary particle forming step is not particularly limited, but the fluidized bed dry granulation method described below is preferably used.

As shown in FIG. 4, the nanoparticle aggregate 61 may be a non-carrier type nanoparticle aggregate 61a obtained by aggregating only the nanoparticles 60, or the nanoparticle aggregate 61 via the primary carrier 59. It may be a carrier type nanoparticle aggregate 61b formed by aggregating the particles 60.

The primary carrier 59 is not particularly limited as long as it is a material which has an affinity for a living body or which can agglomerate the nanoparticles 60 without particularly adversely affecting the living body. However, it is preferable to use a water-soluble compound especially when used in vivo. As a result, the nanoparticle aggregates 61b absorb moisture (absorb water) from the humidity constantly maintained in the living body, and the nanoparticles 60 are easily disintegrated.

In the present invention, since the carrier type nanoparticle aggregates 61b can be formed by, for example, the fluidized bed dry granulation method described in the complexing step described later, various binders described below are preferably used. You can Of course, the carrier-type nanoparticle aggregate 61b may be formed by another method.

The primary particles are nanoparticle aggregates 6
The number is not limited to 1, and may be an aggregate of nanoparticles 60 and micron particles. Alternatively, the drug powder may be surface-modified with the nanoparticles 60 containing the drug.
That is, the primary particles used in the present invention are nanoparticles 60.
Is included, and the nanoparticles 60 need to be formed in the final dispersion.

Next, in the compounding step, the nanoparticle aggregates 61 are secondary granulated, that is, compounded to produce the compound particles 62. Here, as the above-mentioned compounding step, in the present invention, it is very preferable to use a fluidized bed dry granulation method or a dry mechanical particle compounding method. This makes it possible to obtain micron particles (composite particles 62) obtained by aggregating the nanoparticles 60 without damaging the structure of the nanoparticles 60.

In the fluidized bed dry granulation method, the binder 64
Binder-aggregated composite particles 62a secondary-granulated using
In the dry mechanical particle composite method, carrier-type composite particles 62b secondary-granulated using carrier particles 63 (apart from the primary carrier 59 at the time of primary granulation) are obtained.

Composite particles 62 obtained in the above composite step
Is a composite of primary particles including nanoparticles 60, preferably nanoparticle aggregates 61, which can be dispersed and aggregated. Therefore, for example, in the case of using it in the transpulmonary preparation, when the composite particles 62 containing the drug nanoparticles 60 are charged in an inhaler and then the composite particles 62 are injected into the oral cavity, as shown in FIG. As the composite particles 62 satisfactorily disintegrate during ejection, the nanoparticle aggregates 61 are dispersed and inhaled from the oral cavity to the lungs, as shown in FIG.

More specifically, in the case of the binder aggregation type composite particles 62a obtained by the fluidized bed dry granulation method, the binder 6
In the case of the carrier type composite particles 62b obtained by the dry mechanical particle composite method, the aggregated state of No. 4 is satisfactorily collapsed at the time of jetting to produce nanoparticle aggregates 61,
The aggregated state due to the adhesion to the surface of No. 3 satisfactorily collapses at the time of jetting, and nanoparticle aggregates 61 are generated.

The average particle size of the composite particles 62 is sufficiently larger than the order of nanometers. For example, if the average particle size is several tens to several hundreds of μm, the composite particles 62 are not bulky and can have excellent fluidity. As a transpulmonary preparation, the handling property when charging an inhaler is improved. Moreover, at the time of use, it disintegrates and disperses into nanoparticle aggregates 61 (primary particles) having a size of about a dozen μm or less, preferably 0.01 μm to 15 μm, and is inhaled well into the lungs.

Further, once deposited in the lungs as nanoparticle aggregates 61 which are micron particles, the nanoparticle aggregates 61 absorb water or the primary carrier 5 due to the humidity in the lungs.
When 9 is dissolved, the nanoparticle aggregates 61 easily disintegrate and redisperse up to the nanoparticles 60. Therefore, the high reactivity of the nanoparticles 60 improves the permeability of the drug in the lung, the reachability to the absorption site, the retention property of the absorption site, and the like, and as a result, the absorbability of the drug can be increased.

As described above, by using the manufacturing method according to the present invention, the handling property of the nanoparticles 60 can be improved without impairing the advantages of the nanoparticles 60.

Next, it is preferably used in the above-mentioned compounding step and can be used in the primary particle forming step.
The fluidized bed dry granulation method and the dry mechanical particle composite method will be specifically described.

In the fluidized bed dry granulation method, specifically, FIG.
By using the fluidized bed dry granulation / coating type powder processing apparatus 11 as shown in FIG. 5, the binder aggregation type composite particles 62a are obtained.

As shown in FIG. 1, the powder processing apparatus 11 generally has an upper portion which is a substantially cylindrical space and a lower portion which is also substantially cylindrical and has an inner diameter smaller than that of the upper portion. 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 above-mentioned powder processing apparatus 11, by initially spraying the liquid raw material into the empty fluidized-bed space 13, the agglomeration of the particles and the layering granulation are repeated, whereby a granular powder is obtained. 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, by utilizing the above-mentioned agglomeration granulation and layering granulation, a liquid raw material in which nanoparticles or nanoparticle agglomerates are dispersed / suspended is jetted into the fluidized-bed space 13 to produce these nano-particles. The particles 60 or the nanoparticle aggregates 61 are used as seed particles. Further, by using the binder 64 as the liquid raw material, the nanoparticles 60 are aggregated to form the nanoparticle aggregates 61, or the nanoparticle aggregates 61 are aggregated to produce the composite particles 62 according to the present invention. can do.

Specifically, first, as shown in the left diagram of FIG. 1, 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.

Here, in the case where the seed particles are the nanoparticles 60, the fine particles 65 are bound to the binder 6 around the nanoparticles 60.
4 (that is, the primary carrier 59) is attached. When the seed particles are the nanoparticle aggregates 61,
A binder 64 is attached to the periphery of the nanoparticle aggregate 61.

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 from which the liquid raw material is jetted from 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.

When the seed particles are the nanoparticles 60, the granules 66 become the nanoparticle aggregates 61 in which the nanoparticles 60 are aggregated via the binder 64 (that is, the primary carrier 59). In addition, the seed particles are nanoparticle aggregates 61.
In this case, the nanoparticle aggregate 61 is secondarily aggregated via the binder 64 to form the composite particle 62 according to the present invention.

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 agglomerated 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. 1, 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 with a particle size are obtained, ie nanoparticle aggregates 61 or composite particles 62.

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 liquid binder 64 is added to the flowing nanoparticle aggregates 61.
The nanoparticle aggregates 61 are secondarily aggregated through the binder 64 by drying while being sprayed. therefore,
The binder aggregation type composite particles 62a can be manufactured efficiently and with high quality. Further, similarly, the nanoparticles 60 obtained by the spherical crystallization method can be used as seed particles to produce the nanoparticle aggregate 61.

Therefore, in the fluidized bed dry granulation method, starting from nanoparticles 60, formation of nanoparticle aggregates 61 to formation of composite particles 62 can be continuously carried out.
Therefore, the aggregation state of the nanoparticles 60 can be controlled well, and as a result, the handleability can be further improved without impairing the advantages of the nanoparticles 60.

The average particle size of the nanoparticle aggregates 61 used in the fluidized bed dry granulation method is 0.01 μm or more and 50 or more.
It is preferably within the range of 0 μm or less. As a result, the composite particles 62 in which the nanoparticle aggregates 61 are secondarily granulated
Can be manufactured efficiently and reliably. The present invention can be suitably used for the production of transpulmonary preparations, but in the case of transpulmonary preparations, primary particles, that is, nanoparticle aggregates 6
The average particle size of 1 is preferably in the range of 0.01 μm or more and 15 μm or less.

The binder 64 used in the fluidized bed dry granulation method may be an aqueous solution of a biocompatible polymer. Thereby, the secondary granulation state of the composite particles 62 in which the nanoparticle aggregates 61 are secondary granulated can be controlled. In particular, when a drug is used as the nanoparticles 60, it is preferable to use a biocompatible polymer.

The above-mentioned biocompatible polymer is appropriately selected according to the use of the drug and is not particularly limited. For example, hydroxypropylmethylcellulose phthalate, chitosan, lactic acid / glycolic acid copolymer Examples include coalescing. The liquid raw material used in the fluidized bed dry granulation method includes water and seed particles (nanoparticles 6).
0 or nanoparticle aggregates 61), various saccharides may be added in addition to the above various biocompatible polymers. Specific examples of this saccharide include oligosaccharides such as lactose, sucrose, mannitol, and sorbitol.

Next, in the dry mechanical particle composite method, specifically, the powder processing apparatus 21 as shown in FIG. 5 and FIG.
To use.

As shown in FIG. 5, the powder processing apparatus 21 has a casing 22 which forms a closed space having a substantially cylindrical shape, and a substantially cylindrical shape having a bottom and 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. 5, 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 the present 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 receives the centrifugal force, and receives the surface 2 of the object 27 to be processed.
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 slit 28 is formed in the shape of a semi-circular ridge. 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. 5, 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 7 to be processed deposited on the portion is positively discharged through the slit 28 to eliminate the above-mentioned inconvenience and improve the efficiency of the powder processing.

According to the above structure, 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. 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 similarly to the casing 22, or may be rotationally driven by 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 configuration, the object to be treated 27 is pressed against the receiving surface 25 of the cylindrical rotary member 23 by the 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 7
The complexing process can be rapidly advanced.

As described above, according to the powder processing apparatus 21, the object 27 to be processed is the object input port 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, the processing object 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 as shown in FIG. 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, depending on 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 that may be deteriorated due to a temperature change as the object to be treated 27, the heating medium or the cooling medium is circulated and supplied to the jacket 33 so that the temperature of the object to be treated 27 during the treatment is desired. It can prevent the deterioration of the drug as the temperature of.

In the dry mechanical particle composite method, as the object to be treated 27, primary particles, that is, nanoparticle aggregates 61 are used.
A plurality of nanoparticle aggregates 61 are attached to the surface of the carrier particles 63 by applying a compressive force and a shearing force to the object to be processed 27 by using a particle mixture in which the carrier particles 63 are mixed with each other. be able to. Therefore, using this method, not only can the composite particles 62 be manufactured efficiently and with high quality, but also the aggregation state of the nanoparticles 60 can be controlled. As a result, the handling property can be further improved without impairing the advantages of the nanoparticles 60.

The average particle size of the nanoparticle aggregates 61 (primary particles) used in the dry mechanical particle composite method is
It is in the range of 0.01 μm or more and 500 μm or less, and the average particle diameter of the carrier particles 63 is 1 μm or more and 500 μm or less.
It is preferably within the following range. Thereby, the composite particles 62 of the carrier particles 63 and the nanoparticle aggregates 61 (primary particles) can be efficiently and reliably manufactured. The present invention can be suitably used for the production of transpulmonary preparations, but in the case of transpulmonary preparations, the average particle size of primary particles, that is, nanoparticle aggregates 61 is 0.01 μm or more and 15 μm or more.
The average particle diameter of the carrier particles 63 is preferably 10 μm or more and 100 μm or less.

The carrier particles 63 used in the dry mechanical particle composite method are appropriately selected depending on the application of the drug and the like, and are not particularly limited, but in general, a living body is used. Compatible polymers are preferably used, especially polysaccharide powders or hydrophilic polymer powders.
Thereby, the carrier particles 63 and the nanoparticle aggregates 61
The composite state of the composite particles 62 with the (primary particles), that is, the state in which the nanoparticle aggregates 61 are attached to the surfaces of the carrier particles 63 can be well controlled.

As the carrier particles 63, specifically, as the polysaccharide, for example, microcrystalline cellulose, methyl cellulose, carmellose sodium, carmellose calcium, low-substituted hydroxypropyl cellulose, and other celluloses, and wheat starch. , Starch starch such as rice starch, corn starch, potato starch, hydroxypropyl starch, sodium carboxymethyl starch, α-cyclodextrin, β-cyclodextrin and the like. Further, as the hydrophilic polymer, for example, polymethylmethacrylate (PMMA)
And the like.

Especially when a drug is used as the nanoparticles 60, the polysaccharide powder is preferably microcrystalline cellulose, corn starch, potato starch or the like, and the hydrophilic polymer powder is polymethylmethacrylate. preferable.

Here, in the production method according to the present invention, further, before the above-mentioned complexing step, the surface of the carrier particles 63 is modified by a fluidized bed dry granulation method or a dry mechanical particle composite method. It is more preferable to include a particle surface modification step. By carrying out the carrier particle surface modification step, it is possible to control the attachment state of the primary particles (such as the nanoparticle aggregates 61) on the surface of the carrier particles 63. Therefore, the separability between the primary particles and the carrier particles 63 can be controlled, and the composite particles 62 can be satisfactorily disintegrated and dispersed into the primary particles.

In the surface modification of the carrier particles 63, the particles are macroscopically spherical, and microscopically projecting undulations (≦
By setting the surface having 0.1 μm), the adhesiveness / separability between the carrier particles 63 and the primary particles can be controlled. This increases the number of contact points with primary particles,
This is because the adhesion is facilitated while the contact area between the particles is reduced and the van der Waals force is reduced, so that when used as, for example, a transpulmonary preparation, the primary particles are easily separated in the air stream.

Therefore, the surface modification carried out in the carrier particle surface modification step may be any modification that satisfies the above macro and micro conditions. Specifically, by the above fluidized bed dry granulation method or dry mechanical particle composite method,
The modification may be a modification for smoothing the surface of the carrier particles 63, or a modification for compounding the carrier particles 63 and the lubricant particles by each of the above methods.

The smoothing of the surface of the carrier particles 63 can be easily carried out by using the powder processing apparatus 11 or 21 described in the fluidized bed dry granulation method or the dry mechanical particle composite method. it can. Similarly, carrier particles 63
Regarding the compounding of a lubricant and a lubricant, the above powder processing apparatus 1
It can be easily carried out by using 1 or 21.

The lubricant particles are not particularly limited as long as they are made of a material capable of controlling the adhered state (separability) between the carrier particles 63 and the primary particles by adhering to the surface of the carrier particles 63. However, for example, various oligosaccharides generally used as lubricants, compounds used as coating agents in the field of drugs, and the like can be preferably used.

Specifically, for example, oligosaccharides such as lactose, sucrose, mannitol, sorbitol; hydroxypropylmethyl cellulose phthalate, hydroxypropyl cellulose, carboxymethyl ethyl cellulose, crystalline cellulose, gum arabic, gelatin, chitosan, polyethylene glycol, lactic acid. Biocompatible polymers such as glycolic acid copolymers; inorganic compounds such as calcium carbonate, talc, titania (titanium oxide) and silica (silicon oxide); surfactants such as sugar ester and magnesium stearate; Is mentioned.

It is more preferable that the lubricant powder is made into nanoparticles. Thereby, the compounding by the fluidized bed dry granulation method or the dry mechanical particle compounding method can be favorably promoted. For example, the silica is preferably used as colloidal silica, and the biocompatible polymers are preferably polymer nanoparticles (polymer nanospheres) formed by a spherical crystallization method.

As described above, the present invention is a method of secondary granulation so that nanoparticles can be disintegrated / dispersed during use or after use, and in particular, nanoparticles or secondary particles for secondary granulation are used. It is highly preferable to use a biocompatible polymer for the granulation (aggregation) of.

In other words, the present invention is a method for producing drug-containing composite particles containing a drug and a biocompatible polymer, wherein at least one of the drug and the biocompatible polymer has an average particle size of less than 1000 nm. It can also be described as a method of forming polymer nanocomposite particles by forming a mixture of the nanoparticles and the mixture containing the nanoparticles by a fluidized bed dry granulation method or a dry mechanical particle composite method. .

As a result, functional micron particles having a nanostructure can be obtained. Therefore, for example, drug-containing composite particles capable of sufficiently dispersing drug nanoparticles at the time of use and drug particle surfaces can be biocompatible. A drug-containing composite particle having improved drug delivery characteristics can be produced by modifying with polymer nanoparticles. As a result, the nanoparticle can be used for the production of a drug having improved handling properties without impairing the advantages thereof.

As a typical use of the present invention, the use for producing pharmaceuticals, particularly the production of the above-mentioned transpulmonary preparation can be mentioned very preferably. In the present invention, since the shape and density of the drug-containing composite particles can be well controlled,
Designing a predetermined aerodynamic diameter in the manufacture of transpulmonary preparations,
The inhalation properties of the drug powder can be optimized.

Needless to say, the present invention is not limited to this, and may be suitably used for applications in which the characteristics of nanoparticles are desired to be fully utilized at the time of use. In addition to the production of pharmaceuticals, various nanotechnology can be applied. Needless to say, it can be preferably used for the development of new materials.

For example, the use of the method for producing drug-containing composite particles according to the present invention only in the development of pharmaceutical production, as described above, results in a highly dispersed powder inhalation preparation (transpulmonary preparation) containing an anti-asthma drug or an anti-allergic agent. Besides, it can be used for the development of an oral or pulmonary administration type DDS preparation which replaces an injectable drug by forming a composite particle of a therapeutic drug for diabetes such as insulin. In addition, by using adhesive and adhesive nanoparticles, oral and pulmonary administration type DD of calcitonin, etc., a therapeutic drug for osteoporosis
It can also be used to develop S formulations.

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 is also biodegradable long-term information-type embedding for direct compression. It can also be used as an implant base or for improving absorption of other poorly absorbable orally administered drugs such as peptide drugs.

[0131]

EXAMPLES The present invention will be described in more detail with reference to Examples and FIG. 7, but the present invention is not limited thereto.

Example 1 Particles of pranlukast hydrate having an average particle diameter of 1 to 2 μm were used as a model of primary particles containing nanoparticles, and a powder processing apparatus of a fluidized bed dry granulation method (see FIG. 1). Reference, Hosokawa Micron Agromaster AGM-2S
1 kg was charged in D) and fluidized while operating a swirl type pulse jet disperser. Fluidization (drying) at this time
The amount of air was 0.8 m ³ / min and the inlet air temperature was 80 ° C. Further, as a binder, an HPC (hydroxypropyl cellulose) aqueous solution at about 5 ° C. or lower is spray-supplied from the bottom spray nozzle (about 300 g in the case of a 5% aqueous solution), and granules having an average particle size of about 30 to 40 μm ( Composite particles).

The obtained granules were filled and supplied in an inhaler made by Unisia Jecks Co., Ltd. and injected, and the state of the granules before and after the injection was observed. The filling and feeding were simple, and the dispersion of the granules into the primary particles was good.

Since the obtained granules were formed through the dispersion / aggregation process by the fluidized bed dry granulation method, the dispersibility / disintegration from the granules into the primary particles was very excellent. Therefore, while supplying / filling the drug to the inhaler, it behaves as granules having good fluidity, while the dispersing action at the time of inhalation allows the granules to be well dispersed / disintegrated. Therefore, it can be seen that fine primary particles pass through the respiratory tract and reach the lungs.

Example 2 As carrier particles, lactose having an average particle size of 40 μm was used. 50 g of this lactose was treated with a powder by a dry mechanical particle composite method (see FIGS. 5 and 6, AM-MINI (mechanofusion mini) manufactured by Hosokawa Micron, processing capacity 100 ml / batch, casing inner diameter φ = 80 mm, with cold water jacket). , Rotor speed up to 3500 rpm), rotor speed 2500
Processed at rpm for 15 minutes. Water was passed through the water cooling jacket to keep the powder temperature at 40 ° C or lower. This is because the powder temperature rises with time without water cooling, and a fusion phenomenon occurs around 80 ° C.

Thus, surface modification was carried out to smooth the surface of the carrier particles by the compressive force / shearing force of the rotor. No amorphization occurred in the surface-treated lactose carrier particles.

Then, Nauta mixer (inverse cone mixer)
Pranlukast hydrate particles having an average particle size of 1 to 2 μm (model of primary particles) are attached to the surface of carrier particles by using to form granules, and the granules are filled and supplied to an inhaler, and then injected. The state of granules before and after was observed. The filling and feeding were simple, and the dispersion of the granules into the primary particles was good.

Example 3 As in Example 2, lactose having an average particle size of 40 μm was used as the carrier particles. Amount of 40 g of this lactose and 5 g of sugar ester as a lubricant
Charged in M-MINI, rotor speed 3500 rpm
For 20 minutes. As in Example 2, a water cooling jacket was used and the powder temperature was suppressed to 40 ° C or lower. Amorphization of lactose was suppressed.

After that, granules were formed in the same manner as in Example 2, filled and supplied in an inhaler and injected, and the state of granules before and after injection was observed. The filling and feeding were simple, and the dispersion of the granules into the primary particles was good. In addition, before and after surface modification with sugar ester, the results of observing the surface of carrier particles by electron micrographs are shown in FIG. 7 (500 times before surface modification on the left side of the figure, 300 times after surface modification on the upper right side of the figure). ).

Example 4 Example 3 except that 5 g of magnesium stearate (St-Mg) was used as a lubricant.
In the same manner as above, after forming granules, filling and supplying to an inhaler and injecting, the state of granules before and after injection was observed. The filling and feeding were simple, and the dispersion of the granules into the primary particles was good.
In addition, before and after surface modification with St-Mg, the results of observing the surface of the carrier particles by electron micrographs are shown in FIG. 7 (500 times before surface modification on the left side of the figure, and after surface modification on the lower right side of the figure). 300 times).

As is clear from FIG. 7, the carrier particles (crushed lactose) surface-modified with the lubricant were able to make the surface of the carrier particles smoother and more glossy than before the modification. Therefore, the adhesion / separation of the primary particles to the carrier could be greatly improved (controlled).

[Example 5] Granules were formed in the same manner as in Example 3 except that 5 g of colloidal silica was used as a lubricant. I observed. The filling and feeding were simple, and the dispersion of the granules into the primary particles was good.

As is clear from the results of FIG. 7, the sugar ester (upper right of FIG. 7) and magnesium stearate (lower right of FIG. 7) were formed on the surface of lactose by surface modification by the dry mechanical particle composite method. It can be seen that is uniformly dispersed and bonded. Therefore, it was confirmed that the fluidity of the granules (composite particles) and the dispersibility in the primary particles were significantly improved compared to the untreated product (left in Fig. 7), and the adhesion and separation of the primary particles to the carrier were greatly improved. I was able to (control) it.

Example 6 Granules were formed in the same manner as in Example 2 except that starch was used as the carrier particles, and the granules before and after injection were observed after filling and injecting into an inhaler and injecting. did. The filling and feeding were simple, and the dispersion of the granules into the primary particles was good.

[Embodiment 7] Agromaster AGM-2SD
Then, a lactose solution prepared in a 20% aqueous solution was spray-dried and granulated to obtain spherical fine particles (carrier particles) having an average particle diameter of 35 μm. During operation, the swirl flow type pulse jet disperser is operated appropriately (injection ON, time 0.3 seconds, OFF time 5 seconds, air jet pressure 5 kgf / cm ² ) and the resulting fine particles are guided along the inner wall surface of the fluidized bed. Turning dispersion (action of rolling on the wall)
By doing so, the spheroidizing and smoothing of the carrier particles were promoted. The fluidizing (drying) air amount was 0.8 m ³ / min,
Inlet air temperature 80 ℃, exhaust temperature 45 ℃, lactose solution supply rate 10g / min, lactose solution supply amount 1000g
And

Thereafter, in the same manner as in Example 2, after forming granules, filling and supplying them to the inhaler and injecting them, the state of granules before and after the injection was observed. The filling and feeding were simple, and the dispersion of the granules into the primary particles was good.

Example 8 Using the carrier particles obtained in Example 7, magnesium stearate dispersion liquid (alcohol-based, 5% dispersion liquid, 200 g) was continuously prepared.
Was supplied into the AGM-2SD to coat the surface of the fine particles prepared previously.

Thereafter, in the same manner as in Example 7, after forming granules, filling and injecting them into the inhaler and injecting them, the state of granules before and after the injection was observed. The filling and feeding were simple, and the dispersion of the granules into the primary particles was good.

In particular, when magnesium stearate was bonded to the surface of the smoothed carrier particles and then the surface was smoothed, the dispersibility / disintegration from the granules into the primary particles was extremely excellent.

[0150]

As described above, the method for producing drug-containing composite particles according to the present invention comprises a primary particle forming step of forming primary particles containing nanoparticles having an average particle diameter of less than 1000 nm, and the above primary particles So as to be reversibly assembled, a compounding step of compounding the primary particles,
The complexing step is preferably carried out by a fluidized bed dry granulation method or a dry mechanical particle complexing method, and a biocompatible polymer is preferably used for the complexing.

Further preferably, the primary particles are nanoparticle aggregates formed by aggregating a plurality of nanoparticles,
Preferably, the method includes a nanoparticle forming step of forming the nanoparticles by a spherical crystallization method, and when carrier particles are used for compounding, the surface of the carrier particles is subjected to a fluidized bed drying process before the compounding step. It includes a carrier particle surface modification step of modifying by a particle method or a dry mechanical particle composite method.

According to the above method, the primary particles containing nanoparticles are compounded so that they can be dispersed and aggregated, so that the aggregation state of the primary particles can be controlled.
Therefore, it becomes possible to design the drug-containing composite particles (nanocomposite particles) such that the obtained drug-containing composite particles (nanocomposite particles) can be disintegrated / dispersed into primary particles containing the nanoparticles at the time of use.

Therefore, before use, since the average particle size of the drug-containing composite particles is larger than nano-order, it can be in a state of not being bulky and excellent in fluidity, and at the time of use (after use), the nanoparticles can be used. It becomes possible to disintegrate the drug-containing composite particles into primary particles and use them so as to exert the function of. Therefore, the handling property can be improved without impairing the advantage of the nanoparticles.

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 the purpose of making full use of the characteristics of nanoparticles at the time of use. For example, powdery drug It is very suitably used for the production of a transpulmonary preparation in which is administered to the lung to absorb the drug from the lung. In the present invention, since the shape and density of the drug-containing composite particles can be well controlled, it is possible to design a predetermined aerodynamic diameter and optimize the inhalation characteristics of the drug powder in the production of a transpulmonary preparation. It has the effect of being able to.

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 schematic diagram showing a configuration example of a powder processing apparatus and an example of compounding used in a method for producing drug-containing composite particles according to an embodiment of the present invention.

2 (a) and (b) are schematic diagrams illustrating a spherical crystallization method used in the method for producing drug-containing composite particles according to one embodiment of the present invention, and (a) is a spherical structure. The granulation process of the granulation method is shown, and (b) shows the granulation process of the emulsion solvent diffusion method.

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 a process of aggregation, granulation, disintegration, and dispersion of drug-containing composite particles obtained by the method for producing drug-containing composite particles according to the embodiment of the present invention.

FIG. 5 is a cross-sectional view showing another configuration example of the powder processing apparatus used in the method for producing drug-containing composite particles according to the embodiment of the present invention.

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

FIG. 7 is a drawing-substituting photograph showing a specific example of surface modification of carrier particles, which is one example of the present invention, and the left is a drawing-substituting electron micrograph (500 times) of the lactose particles before complexing. Yes, the upper right is a drawing-substitute electron micrograph of the lactose particles after being complexed with sugar ester (300 times), and the lower right is a drawing-substitute electron micrograph of the lactose particles after being complexed with magnesium stearate ( 300 times).

[Explanation of symbols]

60 Nanoparticles 61 Nanoparticle aggregates (primary particles) 62 Drug-containing composite particles (polymer nanocomposite particles) 63 Carrier particles 64 Binder

Continued front page    (72) Inventor Toyokazu Yokoyama             2-29 Sayama Kitayo, Kumiyama-cho, Kuse-gun, Kyoto Prefecture (72) Inventor Hiroyuki Tsujimoto             4-8 Kamijimacho, Hirakata City, Osaka Prefecture Grand Patty             O Hirakata 11-8 (72) Inventor Masaru Iwato             21-3 Daigo Kaminoyamacho, Fushimi-ku, Kyoto-shi, Kyoto Prefecture             B3-103 F-term (reference) 4C076 AA32 BB27 CC03 CC15 CC21                       EE01 EE30 EE32 FF68

Claims (14)

[Claims] 1. A method for producing drug-containing composite particles containing a drug and a biocompatible polymer, comprising at least one of the drug and the biocompatible polymer,
Polymer nanocomposite particles are formed by forming nanoparticles having an average particle diameter of less than 1000 nm and compounding a mixture containing the nanoparticles by a fluidized bed dry granulation method or a dry mechanical particle compounding method. A method for producing a drug-containing composite particle, comprising: 2. A primary particle forming step of forming primary particles containing nanoparticles having an average particle diameter of less than 1000 nm, and a composite step of compounding the primary particles so that the primary particles are reversibly aggregated. And a drug powder is used as the nanoparticles or primary particles, the method for producing drug-containing composite particles. 3. The method for producing drug-containing composite particles according to claim 2, wherein the primary particles are nanoparticle aggregates formed by aggregating a plurality of nanoparticles. 4. The method for producing drug-containing composite particles according to claim 2 or 3, further comprising a nanoparticle forming step of forming the nanoparticles by a spherical crystallization method. 5. The method for producing drug-containing composite particles according to claim 2, 3 or 4, wherein, in the composite step, the primary particles are secondary granulated by a fluidized bed dry granulation method. 6. The average particle diameter of the primary particles is 0.01 μm.
The method for producing drug-containing composite particles according to claim 5, wherein the particle size is in the range of 500 μm or less. 7. The method for producing drug-containing composite particles according to claim 5, wherein in the fluidized bed dry granulation method, a binder that bonds primary particles to each other is used. 8. The method for producing drug-containing composite particles according to claim 7, wherein the binder is an aqueous solution of a biocompatible polymer. 9. The compounding step, wherein the primary particles are adhered to the surface of carrier particles having an outer diameter larger than that of the primary particles by a dry mechanical particle compounding method. Alternatively, the method for producing the drug-containing composite particles according to item 4. 10. The average particle diameter of the primary particles is 0.01 μm.
The method for producing drug-containing composite particles according to claim 9, wherein the carrier particles have an average particle size of 1 m or more and 500 m or less, and the average particle size of the carrier particles is 1 m or more and 500 m or less. 11. The method for producing drug-containing composite particles according to claim 9, wherein a polysaccharide powder or a hydrophilic polymer powder is used as the carrier particles. 12. A carrier particle surface modification step of modifying the surface of carrier particles by a fluidized bed dry granulation method or a dry mechanical particle composite method before the composite step. The method for producing the drug-containing composite particles according to claim 9, 10 or 11. 13. In the carrier particle surface modification step, the surface of carrier particles is smoothed by a fluidized bed dry granulation method or a dry mechanical particle compounding method, or carrier particles and lubricant particles are compounded. 13. The method for producing drug-containing composite particles according to claim 12, wherein the surface of the carrier particles is modified by changing the surface of the carrier particles. 14. The drug-containing complex according to any one of claims 1 to 13, 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.