WO2013077459A1

WO2013077459A1 - Apparatus for preparing fine particles

Info

Publication number: WO2013077459A1
Application number: PCT/JP2012/080801
Authority: WO
Inventors: Toshihiko Arita; Koichi Nakahara
Original assignee: Tohoku University; Suntory Holdings Limited
Priority date: 2011-11-24
Filing date: 2012-11-21
Publication date: 2013-05-30
Also published as: JP2013107065A; JP5933234B2; KR101981348B1; KR20140095470A

Abstract

An apparatus for preparing fine particle including a feeding unit 1 for feeding fluid, a mixing unit 2 for mixing substance in the fluid, and a spraying unit 3 for spraying the fluid mixed with the substance through a nozzle 11 for its adiabatic expansion The inner face of the nozzle 11 is formed of a dielectric material.

Description

DESCRIPTION

[Title of the Invention] "APPARATUS FOR PREPARING FINE PARTICLES"

[Technical Field]

[0001]

The present invention relates to a fine particle preparing apparatus for preparing fine particles, comprising a feeding means for feeding fluid, a mixing means for mixing substance in the fluid, and a spraying means for spraying the fluid mixed with the substance through a nozzle for its adiabatic expansion.

[Background Art]

[0002]

Many of substances such as drugs, natural substances are hardly water-soluble. In particular, it is said that about 40% of drugs are hardly water-soluble. There is a need for increasing their solubility by micronizing these drugs to increase their specific surface areas.

As a conventional apparatus for preparing fine particles of substance, there are known a variety of apparatuses that implement such techniques as supercritical technique (RESS technique), micelle forming technique, micronization (pulverization) technique, etc. (see, for instance, Patent Document 1 and Non-Patent Document 1 identified below).

[Related]

[Patent Document]

[0003]

[Patent Document l] International Patent Application Publication 2006/046670 [Non-Patent Document]

[0004]

[Non-Patent Document l] Satoshi, NISHIKINO, "Drug Delivery System" 24-5, 2009, p.492-498

[Summary of the Invention]

[Object to be Achieved by Invention]

[0005]

However, with the apparatus based on any one of the above techniques, stable and reliable preparing of fine particles of a size smaller than 100 nm in diameter (fine particles of such size will be defined as "nanoparticles" hereinafter) has not yet been prepared possible, for the following reason. Even when nanoparticles have been once formed, the formed nanoparticles cannot maintain their dispersed state, so that they flocculate again. Incidentally, in order to avoid such re-flocculation, it is conceivable for example to coat the surfaces of the nanoparticles with an additive such as a surface -activating agent. However, if such additive gives certain unfavorable effect to human body, use of such nanoparticles is not feasible in production of a medical drug or food product.

[0006]

The object of the present invention is to provide an apparatus for preparing fine particles that is capable of preparing nanoparticles of a size smaller than 100 nm in diameter in a stable and reliable manner. [Means for Achieving the Object]

[0007]

According to a first characterizing feature of an apparatus for preparing fine particle relating to the present invention, the apparatus comprises^ _a feeding means for feeding fluid, a mixing means for mixing substance in the fluid, and a spraying means for spraying the fluid mixed with the substance through a nozzle for its adiabatic expansion; wherein the inner face of the nozzle is formed of a dielectric material.

[0008]

[Function and Effect]

With the above -described characterizing feature, when the substance is caused to pass a passage inside the nozzle, the substance takes an electrostatic charge due to friction thereof with the nozzle inner face, so that the nanoparticles too will take the electrostatic charge. As these nanoparticles have the electrostatic charge of a same sign (a like pole), the nanoparticles repel each other due to the electrostatic force (repelling force), thus preventing re-flocculation thereof. Therefore, prevention of re-flocculation is made possible without using any additive such as a surface-activating agent or the like in particular. Consequently, it is possible to prepare nanoparticles having an average particle size smaller than 100 nm in diameter in a stable and reliable manner.

[0009]

According to a second characterizing feature of the present invention, the nozzle has a length from 20 mm to 600 mm.

[0010]

[Function and Effect]

With the above-described feature that the nozzle has a length from 20 mm to 600 mm, the friction between the substance and the nozzle inner face is facilitated, so that the substance can be caused to take the electrostatic charge in even more reliable manner.

[0011]

According to a third characterizing feature of the present invention, the fluid comprises liquefied carbon dioxide.

[0012]

Liquefied carbon dioxide has a higher density than carbon dioxide under its gas state including the supercritical state, so that a greater amount of the substance can be dispersed, mixed or dissolved therein. Hence, efficient preparing of nanoparticles is made possible. Further, liquefied carbon dioxide is non-noxious, so even if adsorbed in human body, it will give no harmful effect thereto. Hence, it is advantageous in making a medical or food product. Moreover, since liquefied carbon dioxide can be maintained at a low temperature such as a temperature lower than the room temperature, it can be used also in using the nanoparticles in manufacture of a medical product or food product that is vulnerable to high temperatures.

[0013]

According to a fourth characterizing feature of the present invention, the apparatus further comprises a warming means for warming the nozzle.

[0014]

[Function and Effect]

When the fluid is sprayed through the nozzle for its adiabatic expansion, there occurs reduction in the temperature of the nozzle, which leads in turn to dew condensation on the nozzle. And, if this dew freezes, it may block out the passage in the nozzle. However, with the above -described characterizing feature of the invention, as the nozzle is warmed by the warming means, reduction of temperature of the nozzle is avoided, so that occurrence of such dew condensation can be restricted. As a result, the blocking-out of the nozzle passage due to dew condensation can be prevented effectively.

[Brief Description of the Drawings]

[0015]

[Fig. l] is a view showing conceptually a fine particle preparing apparatus according to the present invention,

[Fig. 2] is a view showing conceptually a fine particle preparing apparatus according to a further embodiment of the present invention,

[Fig. 3] shows an electron microscope photo (SEM: scanning electron microscopy) of nanoparticles of sesamin prepared with using the inventive fine particle preparing apparatus,

[Fig. 4] shows an electron microscope photo (SEM^ scanning electron microscopy) of sesamin raw material prior to its formation into nanoparticles,

[Fig. 5] shows an electron microscope photo (SEM) of nanoparticles of naproxen prepared with using the inventive fine particle preparing apparatus,

[Fig. 6] is a view showing analysis pattern of powder X-ray analysis (PXRD) of the nanoparticles and raw material of sesamin, and

[Fig. 7] is a view showing elution pattern of the nanoparticles and the raw material of sesamin.

[Modes of Embodying the Invention]

[0016]

Next, an embodiment of a fine particle preparing apparatus according to the present invention will be described with reference to the accompanying drawings.

[Embodiment]

As shown in Fig. 1, a fine particle preparing apparatus relating to the present invention includes a feeding means for feeding fluid, a mixing means for mixing substance in the fluid, a spraying means for spraying the fluid mixed with the substance through a nozzle for adiabatic expansion thereof, and a collecting means for collecting the prepared fine particles.

[0017]

[Feeding Means] The feeding means 1 includes a fluid reservoir container 5 for reserving an amount of fluid therein, a feeding pump 6 for feeding the fluid to the mixing means 2 and a primary valve 7 for adjusting the flow rate of the fluid. The fluid reservoir container 5 and the mixing means 2 to be detailed later are connected to each other via a piping 8. In the mid of the piping 8 extension, there are provided the feeding pump 6 and the primary valve 7. When the primary valve 7 is opened, the fluid inside the fluid reservoir container 5 is conveyed inside the piping 8 by the feeding pump 6 to be fed into a pressure-resistant vessel (not shown) of the mixing means 2.

[0018]

The fluid usable in the present invention is not particularly limited if the fluid can disperse, mix or dissolve the substance. Yet, preferably, the fluid has a high density for facilitating the dispersion, mixing or dissolution of the substance and gives almost no effect on human body. As some non-limiting examples of such fluid, a supercritical fluid of e.g. supercritical carbon dioxide, liquefied carbon dioxide, etc. can be cited; and among them, liquefied carbon dioxide is particularly preferred.

[0019]

[Mixing Means]

The mixing means 2 includes the pressure -resistant vessel (not shown) for dispersing, mixing or dissolving the substance in the fluid at a predetermined pressure and a filter (not shown) for filtering the resultant fluid containing the substance dispersed, mixed or dissolved therein. The substance will be dispersed, mixed or dissolved in the fluid in the pressure-resistant vessel. In this, even if a portion thereof remains un-dispersed, un-mixed or un- dissolved therein, such remaining substance will be removed by the filter, so that there is no risk of a piping 12 and a passage of a nozzle 11 disposed downstream to be detailed later being blocked out by the un-dispersed, uirmixed or urrdissolved substance. [0020]

[Spraying Means]

The spraying means 3 includes a secondary valve 10 for flow rate adjustment, and the nozzle 11 for spraying the filtered fluid. The mixing means 2 and the nozzle 11 are connected to each other via the piping 12, and the secondary valve 10 is incorporated in the piping 12. When the secondary valve 10 is opened, an amount of fluid filtered by the non-illustrated filter of the mixing means 2 will be conveyed inside the piping 12 to be fed to the nozzle 11.

[0021]

Inside the nozzle 11, there is formed an un-illustrated passage through which the fluid is caused to flow. The material forming the nozzle 11 per se is not particularly limited, but the essential requirement is at least the inner face (passage) of the nozzle 11 being formed of a dielectric material. As some non-limiting examples of such dielectric material usable in the inner face of the nozzle 1, glass, synthetic resin etc. can be cited. Incidentally, as to a synthetic resin, polyether ether ketone (PEEK) having high mechanical strength and superior workability is preferred in particular.

[0022]

Further, the inner diameter of the inner face of the nozzle 11 can range from 20 ji m to 100 μ m, preferably from 25 ji m to 65 μ m, more preferably from 40 m to 60 u . Also, the length of the nozzle 11 can range from 20 mm to 600mm, preferably from 30 mm to 400 mm, more preferably from 50 mm to 200 mm.

[0023]

[Collecting Means] The collecting means 4 includes a collection chamber 13 which surrounds the frontal periphery of the nozzle 11; and inside this collection chamber 13, e.g. a glass bottle 14 for containing prepared nanop articles, a substrate 15 shown in Fig. 2 and formed of mica or for X-ray diffraction etc. to which the nanoparticles are caused to adhere can be disposed. Further, the collection chamber 13 can be configured to be sealable, so that an amount of inactive gas such as nitrogen can be charged therein, if necessary. [0024]

[Warming Means]

When the fluid is sprayed from the nozzle 11 for its adiabatic expansion, this may lead to reduction of the temperature of the nozzle 11 which leads in turn to dew formation, and this dew may freeze to block out the passage eventually. In order to prevent this, a warming (or heating) means (not shown) such as a heater can be provided for warming or heating the leading end of the nozzle 11. With provision of such warming means, the fine particle preparing apparatus can be used even at a location where a great amount of water vapor is present in the atmosphere. Further, if the spraying is continued for a long period, this will lead to excessive reduction in the temperature of the nozzle 11, so that dry ice formed as a result thereof will tend to adhere to the surrounding of the nozzle 11. If this is left without any treatment, it may cause block-out of the passage. Hence, by warming the nozzle 11 with the warming means, such temperature reduction of the nozzle 11 is prevented, thus preventing adherence of dry ice, preventing eventual block-out of the passage of the nozzle 11.

Meanwhile, the warming means may be configured to warm/heat not only the nozzle 11, but also the entire spraying meant 3 or the mixing means 2. [0025]

[Method of Preparing Nanop articles]

Preparing of nanoparticles with using the apparatus configured as described above will be implemented as follows.

[0026]

First, a predetermined amount of substance will be charged into the unillustrated pressure-resistant vessel of the mixing means 2! and then the primary valve 7 will be opened to feed the fluid until a predetermined pressure (e.g. 10 MPa) is reached thereby to disperse, mix or dissolve the substance therein.

[0027]

Thereafter, the secondary valve 10 will be opened, whereby the fluid containing the substance dispersed, mixed or dissolved therein will be sprayed from the nozzle 11 into the collection chamber 13. In this, the fluid sprayed from the nozzle 11 will experience sudden and sharp volume expansion, so that there occurs sharp temperature deduction due to the joule-thomson effect. This results in sharp drop in the dissolution rate of the substance relative to the fluid, so that an amount of substance will precipitate therein. As this precipitation process occurs within a very short period of time, nanoparticles having a narrow particle size distribution range can be obtained.

[0028]

The nanoparticles thus obtained will be collected in e.g. the glass bottle 14 set in advance inside the collection chamber 13.

In the present invention, when the substance is caused to pass the passage in the nozzle 11, there is generated electrostatic charge therein due to the friction occurring between them and the nozzle inner face, so that the nanoparticles too will take this electrostatic charge. And, as these nanoparticles have the electrostatic charge of a same sign (a like pole), the nanoparticles will repel each other due to the electrostatic force (repelling force), thus effectively preventing re-flocculation thereof. Therefore, according to the present invention, re-flocculation of nanoparticles can be effectively prevented without using an additive such as a surface -activating agent or the like in particular. Consequently, nanoparticles having an average particle size smaller than 100 nm (100 nm or smaller) can be prepared in a stable manner.

[Example]

[0029]

Nanoparticles were prepared from two kinds of compounds'- sesamin and naproxen.

[0030]

6.4 mg of sesamin was measured and then charged into a sample folder having an inner capacity of 1 ml (a pressure -resistant vessel sealed with a filter having a pore diameter of 10 /u rn) ^' and as a fluid, liquefied carbon dioxide was introduced therein at the room temperature until the pressure of 10 MPa was reached, thereby to cause the sesamin to dissolve therein.

[0031]

Then, by opening the secondary valve, from a PEEK shielded glass nozzle havin an inner diameter of 50 μ m and a passage length of 100 mm (i.e. a nozzle wherein an inside portion thereof forming the passage is formed of PEEK and the outer periphery of this inner portion is coated with glass), the liquefied carbon dioxide with sesamin dissolved therein was sprayed into the collection chamber for its adiabatic expansion, thus preparing fine particles. Similarly, 6.0 mg of naproxen was measured and fine particles thereof were prepared by a process similar to the above.

[0032]

Then, the fine particles of sesamin and naproxen thus prepared were respectively caused to adhere to a substrate formed of mica and this was then coated with platinum (Pt) by the sputtering technique. Incidentally, this coating by the sputtering technique may be effected if or when necessary.

[0033]

On these respective fine particles of sesamin and naproxen coated with platinum, particle diameters thereof were checked with using a scanning electron microscopy (SEM). Further, as to the sesamin fine particles, the primary particle size and crystalline condition thereof were studied by the powder X-ray diffraction technique (PXRD)

[0034]

As shown in Fig. 3 (a), (b), as to sesamin, nanop articles having an average particle size of 50 nm or less were prepared. Further, as shown in Fig. 5 (a), (b), as to naproxen, nanoparticles having an average particle size of 50 nm approximately were prepared. And, it was seen that neither of these nanoparticles suffered flocculation, hence, nanoparticles having favorable dispersion condition were prepared.

[0035]

Next, in order to investigate the crystalline condition of the sesamin nanoparticles produced, a powder X-ray analysis (PXRD) was carried out. Incidentally, as a comparison example, a powder X-ray analysis (PXRD) was carried out also on the sesamin raw material.

[0036]

As shown in Fig. 6, in the powder X-ray analysis of the sesamin raw material (0.4 mg), a sharp peak was clearly observed in the vicinity of 15 degrees. Whereas, no such clear peak was observed in the powder X-ray analysis of the sesamin nanoparticles (0.4 mg). This suggests that many of the sesamin nanoparticles took the non- crystalline (amorphous) form, unlike the sesamin raw material.

[0037] Incidentally, calculation of the primary particle size of the sesamin raw material with using the Scherrer's formula from the obtained PXRD peak gave calculated values from 190 nm to 370 nm.

[0038]

Subsequently, elution tests were conducted on the sesamin nanoparticles and the raw material thereof.

0.5 mg respectively of the sesamin nanoparticles and raw material were charged into the glass bottle and simultaneously, 5 ml of water was added thereto respectively, and the light absorbance at 285 nm thereof were determined.

[0039]

As shown in Fig. 7, in the case of the sesamin nanoparticles, all the particles were dissolved speedily after the introduction of water. Whereas, in the case of the sesamin raw material, the dissolution of all the material required at least ten and some few hours. That is, it was confirmed that sesamin in the form of nanoparticles can be dissolved in water at a significantly higher rate than the raw material thereof.

[0040]

Therefore, it was suggested that the present invention achieves significant improvement in the dissolution rate of drug which would otherwise be hardly soluble to water, through increase in the specific surface area per unit weight of drug due to formation thereof into nanoparticles, regardless of the crystalline condition of the particles. [Industrial Applicability]

[0041]

The fine particle preparing apparatus relating to the present invention may be used for preparing nanoparticles of a variety of substance such as natural products, drugs, etc. [Description of Reference Marks/Numerals] [0042]

1. feeding means

2 mixing means

3 spraying means

4 collecting means

5 fluid reservoir container

6 feeding pump

7 primary valve

8 piping

10 secondary valve

11 nozzle

12 piping

13 collection chamber

14 glass bottle

13 substrate

Claims

[claim l] An apparatus for preparing fine particle comprising:

a feeding means for feeding fluid;

a mixing means for mixing substance in the fluid, and

a spraying means for spraying the fluid mixed with the substance through a nozzle for its adiabatic expansion!

wherein the inner face of the nozzle is formed of a dielectric material.

[claim 2] The fine particle preparing apparatus according to claim 1, wherein the nozzle has a length from 20 mm to 600 mm.

[claim 3] The fine particle preparing apparatus according to claim 1 or 2, wherein the fluid comprises liquefied carbon dioxide.

[claim 4] The fine particle preparing apparatus according to claim 1 or 2, further comprising a warming means for warming the nozzle.

[claim 5] The fine particle preparing apparatus according to claim 3, further comprising a warming means for warming the nozzle.