JP2006104193A - Method for producing atomized substance and atomized substance - Google Patents
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本発明は、微粒子化された物質の製造方法および微粒子化された物質に関する。 The present invention relates to a method for producing a finely divided substance and a finely divided substance.
従来より、半導体材料を用いた発光素子や診断薬、磁性材料を用いた超高密度記録媒体、金属材料を用いた触媒、有機化合物を用いた医薬品などの生理活性物質などの各種化学品において、微粒子の応用が図られており、例えば、溶解度が約１０ｍｇ／ｍｌ未満の、水に難溶な有機化合物の微粒子は、医薬品、インク、染料、顔料、潤滑剤、殺虫剤、農薬、肥料、化粧品などの幅広い化学品に応用されている。更に、例えば医薬品等において、特に水に難溶な薬物は、溶出速度が極めて遅く、体内においてその吸収部位を過ぎてもなお十分に溶出しない場合がある。そこで、斯かる問題に対処するため、ナノサイズの粒径まで微粒子化し比表面積を増大して溶解速度を向上させることにより、その生体利用効率を高める技術が提案されている。 Conventionally, in various chemical products such as light-emitting elements and diagnostic agents using semiconductor materials, ultra-high density recording media using magnetic materials, catalysts using metal materials, bioactive substances such as pharmaceuticals using organic compounds, Application of fine particles is being made. For example, fine particles of water-insoluble organic compounds having a solubility of less than about 10 mg / ml are pharmaceuticals, inks, dyes, pigments, lubricants, insecticides, agricultural chemicals, fertilizers, cosmetics. Applied to a wide range of chemical products. Furthermore, for example, drugs that are hardly soluble in water, such as pharmaceuticals, have a very low elution rate, and may not sufficiently elute even after passing through the absorption site in the body. Therefore, in order to cope with such a problem, a technique has been proposed in which the bioavailability is increased by increasing the specific surface area by increasing the specific surface area by increasing the specific surface area to a nano-sized particle size.
一方、ナノサイズの微粒子を製造する方法は多く提案されており、その方法は、バルクを砕いてナノサイズまで小さくするブレイクダウン手法とクラスターサイズの微粒子を成長させナノサイズまで大きくするビルドアップ手法の２つの方法に大別される。例えば、ブレイクダウン手法に分類される方法として、ボールミル法（例えば特許文献１参照）が挙げられるが、この方法では、４００ｎｍより小さな医薬品微粒子を得ることが出来るものの、グラインダー材料などの異物の混入が避けられないという欠点がある。これに対して、そのような混入の惧れのないビルドアップ手法に分類される方法として、溶質の過飽和溶液から溶質微粒子を析出させる晶析を利用した技術（例えば特許文献２参照）が挙げられるが、この方法では、例えば１５６ｎｍの医薬品微粒子を得ることが出来るものの、用いる溶媒の種類や医薬品との組成比に大きく影響を受けるため、好適な条件設定が困難であるという欠点がある。 On the other hand, many methods for producing nano-sized fine particles have been proposed. The methods include a breakdown method that breaks down the bulk into nano-sized particles and a build-up method that grows cluster-sized fine particles and increases them into nano-sized particles. It is roughly divided into two methods. For example, as a method classified as a breakdown method, there is a ball mill method (see, for example, Patent Document 1). In this method, pharmaceutical fine particles smaller than 400 nm can be obtained, but foreign substances such as a grinder material are mixed. There is a disadvantage that it cannot be avoided. On the other hand, as a method classified as such a build-up method with no fear of mixing, there is a technique using crystallization (for example, see Patent Document 2) that precipitates solute fine particles from a solute supersaturated solution. However, in this method, for example, 156 nm fine drug particles can be obtained, but since it is greatly affected by the type of solvent used and the composition ratio with the drug, there is a drawback that it is difficult to set suitable conditions.
また、ブレイクダウン、ビルドアップ両手法共、得られる微粒子の粒径の制御が難しいばかりか、粒径分布が大きくなるという欠点があり、更に、ナノサイズの微粒子は凝集しやすい性質があるため、通常、ブレイクダウン、ビルドアップ両手法共、その微粒子の凝集を防止するために界面活性剤などの分散剤を用いる必要があり、医薬品などには望ましくない化合物の混入を避けられない。
本発明は、前述の従来技術に鑑みてなされたものであり、その目的は、晶析法により微粒子化された物質の製造方法であって、粒径分布の狭い微粒子を得ることが出来、しかも、分散剤を用いずとも微粒子間の凝集を抑制することが出来る、粒子化された物質の製造方法および微粒子化された物質を提供することにある。 The present invention has been made in view of the above-described prior art, and an object of the present invention is a method for producing a material finely divided by a crystallization method, which can obtain fine particles having a narrow particle size distribution. Another object of the present invention is to provide a method for producing a granulated substance and a finely divided substance that can suppress aggregation between the fine particles without using a dispersant.
本発明者らは、前記課題を解決すべく鋭意検討した結果、晶析法を行う際に、過飽和溶液を多数の微細突起を有する基板と接触させることにより、粒度分布の狭い、しかも、分散剤を含まない微粒子を凝集物なく製造することが出来ることを見出し、本発明に到達した。 As a result of intensive studies to solve the above-mentioned problems, the inventors of the present invention have a narrow particle size distribution by bringing a supersaturated solution into contact with a substrate having a large number of fine protrusions when performing a crystallization method. It has been found that fine particles containing no can be produced without agglomerates, and the present invention has been achieved.
すなわち、本発明の第１の要旨は、晶析法により微粒子化された物質の製造方法であって、微粒子化する対象物質を含む溶液を調製し、表面に微細突起を１００個／ｃｍ２以上の密度で有する基板と接触させて微粒子を析出させることを特徴とする晶析法により微粒子化された物質の製造方法に存する。そして、本発明の第２の要旨は、上記の製造方法により得られた生理活性物質の微粒子であって、分散剤を含有しないことを特徴とする生理活性物質の微粒子に存する。 That is, the first gist of the present invention is a method for producing a material that has been microparticulated by a crystallization method, in which a solution containing a target material to be microparticulated is prepared, and the surface has 100 fine projections / cm 2 or more. A method for producing a material finely divided by a crystallization method, characterized in that the fine particles are precipitated by contacting with a substrate having a density of 5%. The second gist of the present invention resides in a fine particle of a physiologically active substance obtained by the above-described production method, which is characterized by not containing a dispersant.
本発明によれば、粒径分布の狭い微粒子を得ることが出来、しかも、分散剤を用いずとも微粒子間の凝集を抑制できる。従って、例えば、水に難溶な医薬品などにおいては、微粒子化して比表面積を増大し溶解速度を向上させることによりその生体利用効率を高めることが出来、更に、粒径分布を揃えることで体内に取り込まれるタイミングを揃えることも可能であり、しかも、分散剤などの好ましくない化合物を含有しないナノ粒子の医薬品などの生理活性物質などとしてその活用が期待できる。 According to the present invention, fine particles having a narrow particle size distribution can be obtained, and aggregation between the fine particles can be suppressed without using a dispersant. Therefore, for example, in medicines that are sparingly soluble in water, the bioavailability can be increased by increasing the specific surface area by increasing the specific surface area and improving the dissolution rate. It is possible to arrange the timing of incorporation, and the utilization thereof can be expected as a physiologically active substance such as a nano-particle pharmaceutical that does not contain an undesirable compound such as a dispersant.
本発明において、晶析法により微粒子化する対象物質（原料物質）としては、溶媒に溶解するものであれば特に限定されない。原料物質の溶媒に対する溶解度は、通常１ｍｇ／ｍｌ以上、好ましくは５ｍｇ／ｍｌ以上である。特に平均粒径１μ未満の微粒子が望まれる医薬品、インク、顔料、化粧品などの構成材料が好ましい。中でも、水に難溶な医薬品（２０℃の水に対する溶解度が通常１００ｍｇ／ｍｌ以下、好ましくは１０ｍｇ／ｍｌ以下）は、微粒子化して比表面積を増大し溶解速度を向上させることにより、その生体利用効率を高めることが出来、更に、粒径分布を揃えることで体内に取り込まれるタイミングが揃うため適材適所の投与が可能となるため好ましい。 In the present invention, the target substance (raw material) to be finely divided by the crystallization method is not particularly limited as long as it is soluble in a solvent. The solubility of the raw material in the solvent is usually 1 mg / ml or more, preferably 5 mg / ml or more. In particular, constituent materials such as pharmaceuticals, inks, pigments, cosmetics, and the like for which fine particles having an average particle size of less than 1 μm are desired are preferable. Among them, pharmaceuticals that are sparingly soluble in water (the solubility in water at 20 ° C. is usually 100 mg / ml or less, preferably 10 mg / ml or less) are biodivided by increasing the specific surface area by increasing the specific surface area and improving the dissolution rate. The efficiency can be increased, and furthermore, since the timing to be taken into the body is aligned by aligning the particle size distribution, it is possible to administer the right material at the right place, which is preferable.
また、溶媒としては、原料物質の溶解度が通常１ｍｇ／ｍｌ以上、好ましくは５ｍｇ／ｍｌ以上のものの中から、原料物質の種類に応じて適宜選択することが出来る。なお、その溶媒としては、少なくとも０〜３０℃の温度において液体状態であるものが好ましく、特に２０〜３０℃において液体状態であるものが好ましい。溶媒の具体例としては、水；アルコール、アセトン、テトラヒドロフラン（ＴＨＦ）、メチルエチルケトン（ＭＥＫ）、ジメチルスルホキシド（ＤＭＳＯ）等の極性溶媒；エーテル、トルエン、クロロホルム等の非極性溶媒などが挙げられる。 The solvent can be appropriately selected from those having a solubility of the raw material of usually 1 mg / ml or more, preferably 5 mg / ml or more according to the kind of the raw material. The solvent is preferably in a liquid state at a temperature of at least 0 to 30 ° C., and particularly preferably in a liquid state at 20 to 30 ° C. Specific examples of the solvent include water; polar solvents such as alcohol, acetone, tetrahydrofuran (THF), methyl ethyl ketone (MEK), and dimethyl sulfoxide (DMSO); nonpolar solvents such as ether, toluene, and chloroform.
原料物質が水溶性である場合には、溶媒としては水が好ましく、油溶性化合物である場合には、非極性溶媒が好ましいが、例えば溶液の昇降温操作により溶解度が変化することを考慮すれば、水溶性目的物の場合であっても溶媒として非極性溶媒を用いることも出来、また、その逆の組み合わせも可能である。 When the raw material is water-soluble, water is preferred as the solvent, and when it is an oil-soluble compound, a nonpolar solvent is preferred, but considering that the solubility changes due to, for example, a temperature raising / lowering operation of the solution. Even in the case of a water-soluble target, a nonpolar solvent can be used as the solvent, and vice versa.
本発明において、原料物質を過飽和状態で含む溶液を接触させる基板は、表面に、微細突起を有するものである。そして、その微細突起の密度は、１００個／ｃｍ２以上であることを必須とするが、好ましくは１万個／ｃｍ２以上、更に好ましくは１億個／ｃｍ２以上である。微細突起の密度の上限は通常１００億個／ｃｍ２である。微細突起の密度が前記範囲未満では、目的とする微粒子を製造することが困難となる。 In the present invention, the substrate that contacts the solution containing the raw material in a supersaturated state has fine protrusions on the surface. The density of the fine protrusions is required to be 100 pieces / cm 2 or more, preferably 10,000 pieces / cm 2 or more, more preferably 100 million pieces / cm 2 or more. The upper limit of the density of the fine protrusions is usually 10 billion pieces / cm 2 . If the density of the fine protrusions is less than the above range, it is difficult to produce the intended fine particles.
また、微細突起の形状としては、円錐状、円錐台状、多角錐状、多角錐台状、円柱状、多角柱状などの各種形状のものが挙げられ、その形状は限定されるものではないが、微細突起の形状が析出する微粒子の形態に影響を与える場合があると考えられることから、狭い粒径分布の微粒子を製造するためには、前記の密度で形成されている微細突起の各々が実質的に同一形状であることが好ましい。また、微細突起を有する基板を制作することの容易さの観点からも実質的に同一形状であることが好ましい。また、微細突起の高さの下限は、通常１０ｎｍ、好ましくは５０ｎｍであり、上限は、通常５，０００ｎｍ、好ましく１，０００ｎｍである。
また、基板表面の前記微細突起の配列は、粒径分布の面から規則性を有するのが好ましく、例えば、千鳥配列、六方充填配列、立方充填配列などが挙げられる。
Examples of the shape of the fine protrusion include various shapes such as a conical shape, a truncated cone shape, a polygonal pyramid shape, a polygonal frustum shape, a columnar shape, and a polygonal columnar shape, but the shape is not limited. In order to produce fine particles having a narrow particle size distribution, it is considered that the shape of the fine protrusions may affect the form of the precipitated fine particles. It is preferable that they have substantially the same shape. Moreover, it is preferable that it is substantially the same shape also from a viewpoint of the ease of producing the board | substrate which has a microprotrusion. Further, the lower limit of the height of the fine protrusion is usually 10 nm, preferably 50 nm, and the upper limit is usually 5,000 nm, preferably 1,000 nm.
The arrangement of the fine protrusions on the substrate surface preferably has regularity in terms of particle size distribution, and examples thereof include a staggered arrangement, a hexagonal packing arrangement, and a cubic packing arrangement.
なお、微細突起を表面に有する基板の材質としては、前記の微細突起の形成が可能であり、且つ、接触せられる溶液の溶媒に対して耐溶媒性を有すると共に、溶質と化学反応を起こさないものであれば特に限定されるものではないが、吸着などの物理的現象を生じることのないものが好ましい。具体的には、例えば、鉄、ニッケル、アルミニウム等の金属、それらの合金、ガラス、プラスチック等が挙げられる。 In addition, as a material of the substrate having fine protrusions on the surface, the fine protrusions can be formed, have solvent resistance to the solvent of the solution to be contacted, and do not cause a chemical reaction with the solute. Although it will not specifically limit if it is a thing, The thing which does not produce physical phenomena, such as adsorption | suction, is preferable. Specific examples include metals such as iron, nickel, and aluminum, alloys thereof, glass, and plastics.
また、微細突起の形成方法としては、例えば、半導体リソグラフィー手法、干渉露光手法でパターンニングされた原板にニッケルを電鋳して形成する方法、基板の上に半導体を気相成長させて島状突起を自己組織化させる方法などが挙げられる。中で、突起形状のコントロール性の容易さの面から、リソグラフィー手法を用いた方法が好ましい。また、突起表面の化学的性質に基づいて微粒子析出の程度が変わるため、突起表面が疎水化処理されたり逆に親水化処理されたりしていてもよい。 In addition, as a method for forming fine protrusions, for example, a method in which nickel is electroformed on an original plate patterned by a semiconductor lithography method or an interference exposure method, and an island-like protrusion is formed by vapor-growing a semiconductor on a substrate. And a method for self-organizing. Among them, a method using a lithography method is preferable from the viewpoint of easy control of the protrusion shape. Further, since the degree of fine particle precipitation changes based on the chemical properties of the protrusion surface, the protrusion surface may be subjected to a hydrophobic treatment or conversely a hydrophilic treatment.
本発明の製造方法において、原料物質を過飽和状態で含む溶液を調製し、表面に前記微細突起を有する前記基板と接触させるには、原料物質の飽和溶解度未満の溶液を過飽和状態とした後、前記基板と接触することとしてもよいが、基板表面の微細突起の頂部、および／または、突起側面や谷部に規則的に原料物質の微粒子を析出させ得る面からは、原料物質の飽和溶解度未満の溶液を前記基板と接触させた後、当該溶液を過飽和状態とするのが好ましい。 In the production method of the present invention, in order to prepare a solution containing a raw material in a supersaturated state and contact the substrate having the fine protrusions on the surface, the solution having a saturation solubility lower than that of the raw material is supersaturated, It may be in contact with the substrate, but from the surface where fine particles of the raw material can be regularly deposited on the tops of the fine protrusions on the surface of the substrate and / or on the side surfaces and valleys of the protrusions, the lower than the saturation solubility of the raw material After bringing the solution into contact with the substrate, the solution is preferably supersaturated.
なお、飽和溶解度未満の溶液を過飽和状態とするには、溶液の温度を下げる方法や溶媒を蒸発させて溶質の濃度を低下させる方法などがあるが、操作性の容易さの面から、溶液の温度を下げる方法が好ましい。また、溶液の温度を下げるには、基板表面の微細突起に効果的に原料物質の析出を行い得る面から、基板の温度を下げて伝熱により溶液の温度を下げるのが好ましい。なお、その際、低下させる温度幅は通常１〜１００℃の範囲である。 In order to bring the solution having a saturation solubility lower than the supersaturated state, there are a method for lowering the temperature of the solution and a method for lowering the concentration of the solute by evaporating the solvent. A method of lowering the temperature is preferred. In order to lower the temperature of the solution, it is preferable that the temperature of the solution is lowered by heat transfer by lowering the temperature of the substrate in order to effectively deposit the raw material on the fine protrusions on the surface of the substrate. In this case, the temperature range to be lowered is usually in the range of 1 to 100 ° C.
本発明において、原料物質を過飽和状態で含む溶液を前記基板と接触させることにより、原料物質の微粒子が基板表面の微細突起の頂部、および／または、突起側面や谷部など、突起周辺に析出する。その際、析出する原料物質の微粒子は、結晶質であっても非晶質であってもよい。また、結晶質の場合、基板表面の微細突起表面の結晶構造等により、析出する微粒子の結晶系を制御することも出来る。 In the present invention, by bringing a solution containing a raw material in a supersaturated state into contact with the substrate, the fine particles of the raw material are precipitated around the protrusions such as the tops of the fine protrusions on the substrate surface and / or the side surfaces and valleys of the protrusions. . At this time, the deposited fine particles of the raw material may be crystalline or amorphous. In the case of a crystalline material, the crystal system of the deposited fine particles can be controlled by the crystal structure of the surface of the fine protrusions on the substrate surface.
本発明において、前述の如くして析出させた微粒子は、残余溶液を除去した後に回収する。その際、従来の方法で微粒子を製造した場合、微粒子と残余溶液を分離するためには濾過、遠心分離などの煩雑な操作が必要であるが、本発明においては、例えば、微粒子に対する貧溶媒で基板ごと洗浄する方法、空気、窒素などの不活性ガスで残余溶液を吹き飛ばす方法、それらの方法を組み合わせた方法により、容易に微粒子と残余溶液を分離することが出来る。更に、残余溶液を除去した後、貧溶媒中で超音波処理する方法、中程度の溶解度を持つ溶媒を流す方法、貧溶媒に浸し基板を加熱する方法などで微粒子をスラリー状で回収することが出来る。 In the present invention, the fine particles precipitated as described above are collected after the residual solution is removed. At that time, when the fine particles are produced by a conventional method, complicated operations such as filtration and centrifugation are required to separate the fine particles from the residual solution. In the present invention, for example, a poor solvent for the fine particles is used. The fine particles and the residual solution can be easily separated by a method of cleaning the entire substrate, a method of blowing the residual solution with an inert gas such as air or nitrogen, or a method combining these methods. Further, after removing the residual solution, the fine particles can be recovered in a slurry state by a method of ultrasonication in a poor solvent, a method of flowing a solvent having a medium solubility, a method of heating the substrate by dipping in the poor solvent, etc. I can do it.
得られた微粒子スラリーは、基板表面での析出後、基板から離脱させられるまでの間、基板表面の微細突起周辺に付着し相互の接触が回避されていることから、微粒子間の凝集が抑制されており、以後の所望の操作を速やかに行うことにより、ナノ粒子の凝集が進まない状態で用いることが出来、また、ある程度凝集が進んだとしても、超音波処理などの簡便な方法で再分散させることが容易である。 The resulting fine particle slurry adheres to the periphery of the fine protrusions on the substrate surface and is prevented from contacting each other until it is released from the substrate after being deposited on the substrate surface, so that aggregation between the fine particles is suppressed. It can be used in a state where the aggregation of nanoparticles does not progress by promptly performing the desired operation thereafter, and even if the aggregation has progressed to some extent, it is redispersed by a simple method such as ultrasonic treatment. It is easy to make.
本発明の製造方法は、微粒子の大きさや粒径分布のコントロール性に優れ、得られる微粒子の平均粒径は、通常１ｎｍ以上１ｍｍ未満の範囲、好ましくは１ｎｍ以上５００μｍ未満の範囲、更に好ましくは１ｎｍ以上５０μｍ未満の範囲、特に好ましくは１ｎｍ以上１μｍ未満の範囲でコントロール可能である。なお、本発明において、平均粒径とは重量平均粒径を意味する。重量平均粒径は動的光散乱法により測定することが出来る。 The production method of the present invention is excellent in controllability of the size and particle size distribution of fine particles, and the average particle size of the obtained fine particles is usually in the range of 1 nm to less than 1 mm, preferably in the range of 1 nm to less than 500 μm, more preferably 1 nm. It can be controlled in the range of 50 μm or less, particularly preferably in the range of 1 nm or more and less than 1 μm. In the present invention, the average particle diameter means a weight average particle diameter. The weight average particle diameter can be measured by a dynamic light scattering method.
また、本発明において、得られる微粒子は次のような狭い粒径分布を有する。すなわち、重量換算分布において、小さい粒径から積算して全体重量の５０重量％までの粒子群を与える径である篩下５０重量％粒径（Ｄ50）に対する、同じく全体重量の９０重量％までの粒子群を与える径である篩下９０重量％粒径（Ｄ90）の比（Ｄ90／Ｄ50）は、通常２以下であり、好ましくは１．８以下、特に好ましくは１．５以下、という粗大粒径粒子の少ない粒径分布である。更に、同じく全体重量の１０重量％までの粒子群を与える径である篩下１０重量％粒径（Ｄ10）に対する、同じく全体重量の５０重量％までの粒子群を与える径である篩下５０重量％粒径（Ｄ50）の比（Ｄ50／Ｄ10）は、通常２以下、好ましくは１．８以下、特に好ましくは１．５以下、という超微細粒径粒子も少ない粒径分布である。上記粒径分布は動的光散乱法により測定することが出来る。 In the present invention, the fine particles obtained have the following narrow particle size distribution. That is, in the weight conversion distribution, up to 90% by weight of the total weight with respect to the 50 % by weight particle size (D 50 ) under the sieve, which is a diameter that gives a particle group up to 50% by weight of the total weight from the small particle size. The ratio (D 90 / D 50 ) of the 90 % by weight particle size (D 90 ) under the sieve, which is the diameter that gives a particle group, is usually 2 or less, preferably 1.8 or less, particularly preferably 1.5 or less. This is a particle size distribution with a small number of coarse particles. Furthermore, for a particle size (D 10 ) of 10 % by weight under the sieve, which is the diameter that gives a particle group of up to 10% by weight of the total weight, the sieve 50 is also a diameter that gives a particle group of up to 50% by weight of the total weight. The ratio (D 50 / D 10 ) of the weight% particle size (D 50 ) is usually 2 or less, preferably 1.8 or less, particularly preferably 1.5 or less, with a very small particle size distribution with a small particle size distribution. is there. The particle size distribution can be measured by a dynamic light scattering method.
実施例１：
２０℃の室温下、Ｌ−グルタミン酸６２ｍｇを秤り取り、３０ｍｌねじ口瓶中の水１０ｍｌに投入して溶解させ、溶液を調製した。２０℃におけるＬ−グルタミン酸の水に対する溶解度は７．２ｍｇ／ｍｌであるのに対して、調製したＬ−グルタミン酸溶液の濃度は６．２ｍｇ／ｍｌであり、飽和溶解度を下回っている。
Example 1:
At room temperature of 20 ° C., 62 mg of L-glutamic acid was weighed out and poured into 10 ml of water in a 30 ml screw cap bottle to prepare a solution. The solubility of L-glutamic acid in water at 20 ° C. is 7.2 mg / ml, whereas the concentration of the prepared L-glutamic acid solution is 6.2 mg / ml, which is lower than the saturation solubility.
一方、底面に１９×２３ｍｍの平面を有するＳＵＳ製のバルブを逆さにして固定し、その上に、表面に半導体リソグラフィー手法で縦横４５０ｎｍ間隔毎に高さ４５０ｎｍの円錐状のニッケルの微細突起が５億個／ｃｍ２の密度でパターンニングされ、裏面は平面である、大きさ９×１０ｍｍ、厚さ０．３ｍｍの基板を置き、当該基板上に、室温下、前記で得られた溶液０．０５ｇをマイクロピペットで滴下して液滴を形成した後、０℃に冷却した冷媒をバルブに連続的に流し１６分間保った。０℃におけるＬ−グルタミン酸の水に対する溶解度は３．３ｍｇ／ｍｌであるので、溶液は過飽和状態を経て、Ｌ−グルタミン酸の微粒子が析出していると推察された。 On the other hand, a SUS bulb having a flat surface of 19 × 23 mm on the bottom surface is fixed upside down, and there are 5 conical nickel fine protrusions having a height of 450 nm at every 450 nm vertical and horizontal intervals on the surface by a semiconductor lithography method. A substrate having a size of 9 × 10 mm and a thickness of 0.3 mm, which is patterned with a density of 100 million pieces / cm 2 and whose back surface is flat, is placed on the substrate, and the solution obtained as described above is obtained at room temperature at a temperature of 0. 05 g was dropped with a micropipette to form droplets, and then the refrigerant cooled to 0 ° C. was continuously flowed through the valve and maintained for 16 minutes. Since the solubility of L-glutamic acid in water at 0 ° C. was 3.3 mg / ml, it was assumed that the solution passed through a supersaturated state and L-glutamic acid fine particles were precipitated.
引き続いて、直径５ｃｍのシャーレに室温の水２０ｍｌを溜めておき、 基板の両側をピンセットで掴みシャーレ中の水に全体を２回通して残余飽和溶液を洗浄除去し、直後に窒素ガンで窒素を吹き付けて乾燥させ、サンプルを得た。サンプルの表面を走査型電子顕微鏡で２万２千倍に拡大して観察したところ、一部の微細突起の頂部に、粒径１８０ｎｍのＬ−グルタミン酸のナノ粒子が付着しているのが観察された。 Subsequently, 20 ml of room temperature water was stored in a petri dish with a diameter of 5 cm, the both sides of the substrate were held with tweezers, and the remaining saturated solution was washed and removed through the water in the petri dish twice. The sample was obtained by spraying and drying. When the surface of the sample was observed with a scanning electron microscope at a magnification of 22,000 times, it was observed that nanoparticles of L-glutamic acid having a particle size of 180 nm adhered to the tops of some fine protrusions. It was.
同様に作製した別のサンプルを３０ｍｌねじ口瓶中の１０ｍｌの水中に入れ超音波をかけることにより、Ｌ−グルタミン酸ナノ粒子を基板から離脱させた後、得られるＬ−グルタミン酸ナノ粒子を含むスラリーについて、Ｍａｌｖｅｒｎ社製動的光散乱粒度分布測定装置「ＨＰＰＳ」を用いて粒度分布を測定すると、平均粒径が約１８０ｎｍのナノ粒子となる。これら粒子は、Ｄ90／Ｄ50値やＤ50／Ｄ10値が小さい、粒径分布の狭い微粒子であることがわかる。また、得られたＬ−グルタミン酸ナノ粒子は界面活性剤等の分散剤を含んでいないナノ粒子である。 Another sample prepared in the same manner is placed in 10 ml of water in a 30 ml screw mouth bottle and subjected to ultrasonic waves to release L-glutamic acid nanoparticles from the substrate, and then the resulting slurry containing L-glutamic acid nanoparticles is obtained. When the particle size distribution is measured using a dynamic light scattering particle size distribution measuring device “HPPS” manufactured by Malvern, nanoparticles having an average particle size of about 180 nm are obtained. It can be seen that these particles are fine particles having a small D 90 / D 50 value or D 50 / D 10 value and a narrow particle size distribution. The obtained L-glutamic acid nanoparticles are nanoparticles that do not contain a dispersant such as a surfactant.
比較例１
実施例１で用いたのと同じ溶液５ｍｌを１０ｍｌバイヤル瓶中に入れ、０℃の冷媒中に浸し１６分間保持したところ、白濁した微粒子スラリーが得られた。このスラリーについて、実施例１と同様の方法で粒度分布を測定したところ、平均粒径８μｍであり、Ｄ90／Ｄ50が３．０、Ｄ50／Ｄ10が２．５と粒径分布の広いものである。
Comparative Example 1
When 5 ml of the same solution used in Example 1 was placed in a 10 ml vial, immersed in a refrigerant at 0 ° C. and held for 16 minutes, a cloudy fine particle slurry was obtained. The particle size distribution of this slurry was measured in the same manner as in Example 1. As a result, the average particle size was 8 μm, D 90 / D 50 was 3.0, and D 50 / D 10 was 2.5. It is wide.
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| JP2009173655A (en) * | 2008-01-23 | 2009-08-06 | Biocodex | Method for preparing stiripentol particle with prescribed particle size distribution |
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| US8623415B2 (en) | 2007-07-06 | 2014-01-07 | M. Technique Co., Ltd. | Method for producing biologically ingestible microparticles, biologically ingestible microparticles, and dispersion and pharmaceutical composition containing the same |
| JP2009173655A (en) * | 2008-01-23 | 2009-08-06 | Biocodex | Method for preparing stiripentol particle with prescribed particle size distribution |
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