JP2005169259A - Production method of fine particle and apparatus therefor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a production method of fine particle which is capable of preventing the incorporation of foreign matters, reliably performing washing and sterilization, responding to CIP(cleaning in place)/SIP(sterilization in place), steadily performing a stable operation without danger of misoperation and performing high precision dispersion, crushing, emulsification and liposome formation, and to provide an apparatus therefor. <P>SOLUTION: Materials to be pulverized are introduced between at least two sheets of elastomers having a hardness higher than the hardness of the material to be pulverized, subsequently, at least one sheet of elastomers is vibrated and, thereby, the material to be pulverized is ground between the elastomers. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a method and apparatus for producing fine particles using vibration of an elastic body, and more particularly to a method and apparatus for producing fine particles suitable for producing a large amount of fine particles having a particle diameter of several nanometers to several hundred nanometers in a short time. .

  Drug development begins with basic research, and drug candidates are determined through drug screening from new compounds obtained by chemical synthesis. Next, drugs that have been proven to be effective and safe from preclinical studies such as kinetic metabolism studies and safety studies are put into three-stage clinical trials, phase I, phase II, and phase III, and finally effective. Products that are confirmed to be safe and safe are subject to manufacturing approval and marketing approval.

  As described above, many stages of selection are performed in the development of pharmaceuticals, and it is generally said that there are thousands to tens of thousands of candidate substances behind a new drug. In addition, many of the candidate substances have very low solubility in water and organic solvents that can be used as pharmaceuticals and are hardly soluble. Since this low solubility reduces bioavailability, pharmacological tests by oral administration, intramuscular administration, or intravenous administration have been difficult. This is a major drawback because it requires a longer period of research and a large amount of money, which causes many researchers to be spent. As a method for improving such a defect, there is a method in which candidate substances are fine particles in the nm range. Advantages of this method include the following (1) to (5).

(1) When the particle surface area increases according to Neues-Whiteney's law, the dissolution rate increases. Substances with particle sizes in the nanometer range and significantly increased surface area are important for all cases where dissolution rate is a determinant of bioavailability.
(2) Intravenous administration of a poorly soluble substance is possible without causing capillary blockage by using a nanosuspension.
(3) When a hardly soluble substance is administered as a solution, a relatively large amount of the preparation is required. However, a preparation containing the difficultly requested substance as ultrafine particles can reduce the dose.
(4) Drugs having ultrafine particles can be easily used for targeting (drug target transport system and the like) and controlled release (drug release control and release control).
(5) Sterilization at the time of drug design (aseptic filtration method) is facilitated, and the safety of the drug itself as a drug is significantly increased.

  Conventionally, as a method of producing fine particles of a hardly soluble substance, a mechanical method such as a method using a bead mill, a method using an ultra-high pressure homogenizer, a method using a roll mill, a physical method for generating erosion by an ultrasonic disperser, and a chemical method A typical membrane emulsification method is known. However, in the case of a bead mill, (1) impurities due to the wear powder of the beads themselves are mixed. (2) By using micro beads, it is possible to reduce the particle diameter of the obtained particles. In some cases, it is not possible to cope with the case where the viscosity becomes high, and the cases where it can be used are limited, (3) poor cleaning properties, (4) high running costs because it is necessary to replenish beads, etc. There were drawbacks.

  In addition, in the case of an ultra-high pressure homogenizer, (1) it is difficult to stably operate the machine, (2) there is a lot of wear of the orifice and the pressure booster pump seal, (3) poor cleaning and sterilization, (4) There are drawbacks such as high power, high running cost as well as equipment, and (5) inability to cope with high viscosity.

  Furthermore, in the case of a roll mill, it is not possible to cope with the case of low viscosity, (2) it cannot be made a sealed type, (3) work risk is high, and (4) it is necessary to process several tens of times In the case of an ultrasonic disperser, there are drawbacks such as insufficient pulverization capability, and in the case of milky membrane, there is a disadvantage that an expensive dedicated emulsifier or a large pump is required. .

  Accordingly, there is a need for a preparation method using a dispersion emulsification apparatus that can easily and reliably prepare nanosuspensions and nanoemulsions for drug administration and satisfy all requirements for equipment for producing pharmaceuticals. It was.

On the other hand, the inventors have studied actuators using ultrasonic vibration for many years (Patent Documents 1 and 2 and Non-Patent Documents 1 and 2).
JP-A-8-132382 No. 2001-233154 Development of spherical ultrasonic motor: Journal of Japan Society for Precision Engineering, vol66, No5, pp769-774,2000 Introduction to Ultrasonic Motor, Naoshi Mijo, Toshio Suda General Electronic Publishing Company

This is because a traveling wave is generated on the elastic body surface (opposite side to which the piezoelectric element is attached) by applying a two-phase alternating voltage having different phases to the piezoelectric element of the elastic body having the piezoelectric element attached to the back surface. It is generated and driven by pressing a non-vibrating plate (see FIG. 1).
In this case, when the pressing of the stator is increased, the amplitude is compressed to several tens nm to several hundreds nm. At this time, the stator surface is elliptically moving with the generation of traveling waves. Therefore, the rotor for one wave moves up and down so as to collide with the stator, and a shearing force is also generated in the lateral direction. When the stator is fixed in this state, the contact surface is worn, and even if the stator is made of metal, uniform wear powder of several μm to several hundred μm is generated. The present inventors have found that this phenomenon can be applied to fine particles and dispersion of drugs and the like, and have reached the present invention.

Therefore, the first object of the present invention is not only to be able to perform cleaning and sterilization reliably, but also to be compatible with CIP / SIP, there is no risk of erroneous operation, it can be stably operated stably, and highly accurate dispersion, An object of the present invention is to provide a method for producing fine particles that can be crushed, emulsified, and made into liposomes.
A second object of the present invention is to provide an apparatus for producing a large amount of fine particles having a particle diameter of several nanometers to several hundred nanometers in a short time.

  The above objects of the present invention are to introduce a material to be atomized between at least two elastic bodies having a hardness higher than that of the material to be atomized, and then vibrate at least one of the elastic bodies, The object is achieved by a method for producing fine particles characterized by pulverizing the material to be atomized between the elastic bodies, and an apparatus for carrying out the method.

  According to the present invention, since a drug suspension of nanoparticles excellent in bioavailability can be easily adjusted, it has a particularly great effect on shortening the pharmaceutical development period.

In the method for producing fine particles of the present invention, since the material to be atomized is pulverized by fine vertical vibrations on the surface of the vibrating elastic body (vibrating crusher), the hardness of the elastic body constituting the vibrating crusher is set to be atomized. It must be higher than the hardness of the material.
The material to be atomized may be compressed and filled between two vibrating crushers. One of the two vibration crushers may be an elastic body having no piezoelectric element and a base that does not vibrate independently. Further, an idler plate that can freely vibrate and can move within a certain range may be disposed between the two vibration crushers.

  The hardness of the base and the idle plate needs to be higher than the hardness of the material to be atomized, but it is preferable not to be higher than the hardness of the vibration crusher. Further, although it depends on the required degree of atomization, it can be atomized by directly pressing a block-shaped material to be atomized against a vibration crusher to wear the block surface.

As means for vibrating the vibration crusher, there are electromagnetic means, means using a capacitor, means using a piezoelectric element, etc. In the present invention, the piezoelectric element is attached to the back surface of the elastic body constituting the vibration crusher. Things are preferable. By applying a voltage to the piezoelectric element, it is possible to easily generate high-frequency and powerful ultrasonic vibrations in the vibration crusher as compared with other means (see FIG. 2 described later).
The piezoelectric element to be attached to the back surface of the elastic body of the vibration crusher can be appropriately selected from known ones.

  Next, the apparatus for producing fine particles of the present invention will be described with reference to examples. FIG. 1 is a diagram for explaining the principle of an ultrasonic motor applied to the apparatus of the present invention. FIG. 2 is a diagram for explaining the principle of the apparatus of the present invention. In FIG. 2, reference numeral 1 is an elastic body constituting the vibration crusher, 2 is a piezoelectric element, 3 is an elastic body as a base, and 10 is a vibration crusher. When a voltage is applied to the piezoelectric element 2 of the vibration crusher 10, a minute gap is formed between the vibration crusher 10 and the base 3 as shown in the figure. Since this gap repeats generation and disappearance in an ultrasonic cycle, the substance can be pulverized and atomized by introducing the substance to be atomized into this gap. That is, in the present invention, it is only necessary to be able to use the generation / extinction of the minute space as described above. Therefore, another vibration crusher may be arranged instead of the base, A floating plate made of an elastic body that does not generate ultrasonic vibrations by itself may be interposed.

  FIG. 3 is a conceptual cross-sectional view of the atomized portion of the apparatus according to the present invention, which includes the circular vibration crusher 10 and the base 3. As shown in the figure, the atomizing substance introduction port is provided in the vibration crusher 10, and a protrusion having a slope is provided in the center of the base 3, whereby the atomizing substance is supplied between the vibration crusher 10 and the base 3. I can do it. In this case, the atomized substance can be continuously produced by providing an outlet for the atomized substance. Further, it is also possible to adopt a batch type in which the material to be atomized is previously put on the atomized surface of the base 3 and then the vibration crusher 10 is disposed.

  FIG. 4 is an apparatus in which the side wall portion (which can be expressed as a side surface portion of the die) 3 ′ of the base 3 in FIG. 3 where the vibration crusher 10 is inserted is separated. Thus, by removing the said side wall part, the atomized substance can be taken out easily, without moving an apparatus.

  FIG. 5 shows an atomization apparatus in which the atomization portion including the vibration crusher 10 and the base 3 is integrated with the tray 5 via the cylinder 4 or is separably arranged in the tray. Its cross-sectional view is shown in FIG. As can be understood from the use state diagram shown in FIG. 7, the fine particles falling on the tray gather at the lower part of the cylinder 4 and enter the cylinder 4 through an opening (not shown) provided at the lower part of the cylinder. The particles that have entered the cylinder are moved upward by a suction means or a screw mechanism (not shown), and then enter the atomizing portion again to be further atomized. By repeating this appropriately, a micro-product having a desired particle size can be obtained.

  According to the present invention, fine particles having a particle size of several nm to several hundreds of nm can be produced in a large amount in a short time, and thus it is extremely useful for shortening the research period and reducing the development cost in the preparation.

FIG. 1 is a diagram for explaining the principle of an ultrasonic motor applied to the apparatus of the present invention. FIG. 2 is a diagram for explaining the principle of the apparatus of the present invention. FIG. 3 is a conceptual cross-sectional view of the atomized portion in the apparatus of the present invention, which is composed of a circular vibration crusher and a base. FIG. 4 is an apparatus in which the base in FIG. 3 is separated from the portion where the vibration crusher is inserted, particularly the side wall portion. FIG. 5 shows an atomization device in which the atomization portion composed of the vibration crusher and the base is integrated with the tray via a cylinder or is separably arranged in the tray. 6 is a cross-sectional view of the atomization apparatus of FIG. FIG. 7 is a diagram for explaining a use state of the atomization apparatus of FIG.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Elastic body 2 Piezoelectric element 3 Base 3 'Side surface part of mortar 4 Cylinder 5 Receptacle
10 Vibration crusher

Claims (9)

  Introducing a material to be atomized between at least two elastic bodies having a hardness higher than that of the material to be atomized, then vibrating at least one of the elastic bodies, and A method for producing fine particles, comprising crushing a chemical substance.   The method for producing fine particles according to claim 1, wherein the vibration of the elastic body is ultrasonic vibration.   The method for producing fine particles according to claim 1 or 2, wherein the vibrating elastic body is a vibration crusher in which vibration generating means is provided on the back surface of the elastic body.   The method for producing fine particles according to claim 3, wherein both of the two elastic bodies sandwiching the material to be atomized are vibration crushers having vibration generating means on the back surface. The method for producing fine particles according to claim 3 or 4, wherein the vibration generating means is a piezoelectric element.   An apparatus comprising at least two casings formed so as to be able to supply the material to be atomized and at least two independent elastic bodies that are housed adjacent to each other in the casing and can vibrate; At least the outermost elastic body has vibration generating means on the back surface, and means for sequentially introducing the introduced substance to be atomized between the elastic bodies is provided. manufacturing device.   The fine particle manufacturing apparatus according to claim 6, wherein the means for generating vibration is a piezoelectric element attached to the back surface of the elastic body.   The apparatus for producing fine particles according to claim 6 or 7, comprising a supply port for a material to be atomized and a discharge port for a material to be atomized. The apparatus for producing fine particles according to any one of claims 6 to 8, wherein a surface for pulverizing the material to be atomized is not a horizontal plane.