JP4305145B2 - Particle production method using micro flow channel - Google Patents

Particle production method using micro flow channel Download PDF

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JP4305145B2
JP4305145B2 JP2003394373A JP2003394373A JP4305145B2 JP 4305145 B2 JP4305145 B2 JP 4305145B2 JP 2003394373 A JP2003394373 A JP 2003394373A JP 2003394373 A JP2003394373 A JP 2003394373A JP 4305145 B2 JP4305145 B2 JP 4305145B2
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dispersed phase
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英昭 桐谷
晃治 片山
明 川井
朋裕 大川
裕樹 高宮
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Tosoh Corp
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本発明は、分取、分離用カラム充填剤、圧力測定フィルム、ノーカーボン（感圧複写）紙、トナー、シールロック剤などの接着剤、金属粒子の絶縁粒子、熱膨張剤、熱媒体、調光ガラス、ギャップ剤（スペーサ）、サーモクロミック（感温液晶、感温染料）、磁気泳動カプセル、農薬、人工飼料、人工種子、芳香剤、マッサージクリーム、口紅、ビタミン類カプセル、活性炭、含酵素カプセル、ＤＤＳ（ドラッグデリバリーシステム）等に用いられる微小なゲル粒子や、カプセルなどの製造用として好適に用いられる粒子製造方法に関する。   The present invention includes preparative, separation column fillers, pressure measuring films, carbonless (pressure-sensitive copying) paper, adhesives such as toner and seal lock agents, insulating particles of metal particles, thermal expansion agents, thermal media, preparations. Light glass, gap agent (spacer), thermochromic (thermosensitive liquid crystal, thermosensitive dye), magnetophoresis capsule, pesticide, artificial feed, artificial seed, fragrance, massage cream, lipstick, vitamins capsule, activated carbon, enzyme-containing capsule The present invention relates to a method for producing fine gel particles used for DDS (drug delivery system) and the like, and a particle production method suitably used for producing capsules and the like.

近年、数ｃｍ角のガラス基板あるいは樹脂製基板上に長さが数ｃｍ程度で、幅及び深さがサブμｍから数百μｍの微小流路を有する微小流路構造体を用いて、液体の送液による微小液滴の生成を行う研究が注目されている（例えば、非特許文献１及び非特許文献２参照）。微小流路内における粒子生成技術に関しては、図１に示すように、微小流路基板１の上に、連続相導入口２、連続相導入流路３、分散相導入口４、分散相導入流路５、排出流路７及び排出口８を有したＴ字型の構造体であり、導入された連続相と分散相とが合流する部分に合流部６が存在する。各流路の深さは１００μｍであり、図１におけるＢ−Ｂ’断面を示す図３に認められるように、分散相を導入する導入流路幅が１００μｍ、図１におけるＡ−Ａ’断面を示す図２に認められるように、連続相を導入する導入流路幅は３００〜５００μｍのＴ字型微小流路を用いて、分散相と連続相の流れの速さを制御（コントロール）して送液を行うと、分散相と連続相が流路を通じて合流する地点（合流部）において主に生成する粒子を均一にする事が可能となる。しかしながらこの方法においては、分散相が連続相内で***するとき、微小粒子の後方に線状の尾を引き、その尾が粒子から独立してさらに微小な液滴（以後、「サテライト」と呼ぶ）となり、主に生成する微小粒子と副生成するサテライトが混合した状態になり、サテライト粒子の混入によって製品の規格を満たさない場合には、均一な粒子のみを得る為に分級する必要があった。   In recent years, by using a microchannel structure having a microchannel having a length of about several centimeters on a glass substrate or a resin substrate of several centimeters square and having a width and a depth of sub μm to several hundred μm, Research that generates fine droplets by liquid feeding has attracted attention (for example, see Non-Patent Document 1 and Non-Patent Document 2). Regarding the particle generation technique in the microchannel, as shown in FIG. 1, the continuous phase inlet 2, the continuous phase inlet channel 3, the dispersed phase inlet 4, and the dispersed phase inlet flow on the microchannel substrate 1. It is a T-shaped structure having a path 5, a discharge flow path 7, and a discharge port 8, and a merging portion 6 exists at a portion where the introduced continuous phase and the dispersed phase merge. The depth of each flow path is 100 μm, and as shown in FIG. 3 showing the BB ′ cross section in FIG. 1, the width of the introduction flow path for introducing the dispersed phase is 100 μm, and the cross section AA ′ in FIG. As shown in FIG. 2, the introduction channel width for introducing the continuous phase is 300 to 500 μm, and the flow speed of the dispersed phase and the continuous phase is controlled by using a T-shaped microchannel. When the liquid feeding is performed, it is possible to make the particles generated mainly uniform at the point where the dispersed phase and the continuous phase merge through the flow path (merging portion). However, in this method, when the dispersed phase splits in the continuous phase, a linear tail is drawn behind the microparticle, and the tail is independent of the particle, and further smaller droplets (hereinafter referred to as “satellite”). In the case where the microparticles that are mainly generated and the satellites that are by-produced are mixed and the product standards are not satisfied due to the mixture of the satellite particles, it is necessary to classify in order to obtain only uniform particles. .

西迫貴志ら、「マイクロチャネルにおける液中微小液滴生成」，第４回 化学とマイクロシステム研究会 講演予稿集，５９頁，２００１年発行Takashi Nishisako et al., “Liquid microdroplet generation in microchannels”, 4th Chemistry and Microsystems Research Meeting Proceedings, 59 pages, 2001

ＴＡＫＡＳＩ ＮＩＳＩＳＡＫＯら著、「ＤＲＯＰＬＥＴ ＦＯＲＭＡＴＩＯＮ ＩＮ Ａ ＭＩＣＲＯＣＨＡＮＮＥＬ ＯＮ ＰＭＭＡ ＰＬＡＴＥ」，Ｍｉｃｒｏ Ｔｏｔａｌ Ａｎａｌｙｓｉｓ Ｓｙｓｔｅｍ，１３７〜１３８頁，２００１年発行TAKASI NISISAKO et al., “DROPLET FORMATION IN A MICROCHANNEL ON PMMA PLATE”, Micro Total Analysis System, 137-138, 2001

以上のように従来の微小流路内における粒子製造技術は、Ｔ字型微小流路において連続相と分散相の合流部で主に生成する粒子を均一とすることが可能となるが、分散相が連続相内で***するとき、微小粒子の後方に線状の尾を引き、その尾が粒子から独立してサテライトとなり、主に生成する微小粒子と副生成するサテライトが混合した状態になり、場合によっては均一な粒子のみを得る為に分級する必要があり、サテライトを実質的になくす粒子の製造方法が求められていた。   As described above, the conventional particle manufacturing technology in the microchannel allows the particles generated mainly at the joining portion of the continuous phase and the dispersed phase to be uniform in the T-shaped microchannel. When it breaks up in the continuous phase, it draws a linear tail behind the microparticles, the tail becomes a satellite independent of the particles, it is in a state where the microparticles mainly generated and the satellites by-produced are mixed, In some cases, it is necessary to classify in order to obtain only uniform particles, and there has been a demand for a method for producing particles that substantially eliminates satellites.

本発明は、上記課題に鑑みてなされたもので、微小流路内で主に生成する微小粒子の径を制御し、さらには、サテライトの発生を実質的になくす粒子の製造方法を提供することにある。   The present invention has been made in view of the above problems, and provides a method for producing particles that controls the diameter of microparticles that are mainly generated in a microchannel and that substantially eliminates the generation of satellites. It is in.

本発明は上記課題を解決するものとして、分散相を導入するための２以上の導入口及びそれに連通する分散相導入流路と、連続相を導入するための導入口及びそれに連通する連続相導入流路と、導入された分散相と連続相とを合流させる合流部を含みかつ合流により粒子を生成させた後に排出させる排出流路と、を有した微小流路構造体を用いて粒子を製造する方法であって、前記２以上の分散相導入流路は連続相導入流路に実質的に別々に連通して分散相を導入し、かつ、連続相と１つの分散相との合流により生成する液滴により連続相と別の分散相との合流により生成する液滴の生成タイミングを制御することによって、サテライトの発生要因である、主生成粒子の尾引きが短くなり、副次的に生成するサテライトを減少もしくは、さらに微小化させることができることを見いだした。さらに、２つの分散相導入流路を、連続相導入流路の同一位置の両側から合流させ、かつ、液滴を交互に生成させることによってお互いの粒子の尾引きを短くすることができ、実質的にサテライトの生成がなくなる、すなわち、生成した粒子を含む連続相中に、実質的に微小な粒子を含まないことを見いだした。また、２つの分散相導入流路が一つの分散相導入流路から分割されており、かつ、連続相導入流路の同一位置の両側から合流させることによっても同様の効果を相することも見いだした。以下、本発明を詳細に説明する。   In order to solve the above-described problems, the present invention provides two or more inlets for introducing a dispersed phase, a dispersed phase introduction channel communicating with the inlet, an inlet for introducing a continuous phase, and continuous phase introduction communicating therewith. Producing particles using a microchannel structure including a flow path and a discharge flow path that includes a merging portion for merging the introduced dispersed phase and the continuous phase and that discharges the particles after the particles are generated by merging. The two or more dispersed phase introduction flow paths are substantially separately connected to the continuous phase introduction flow path to introduce the dispersed phase, and are generated by merging the continuous phase and one dispersed phase. By controlling the generation timing of droplets generated by confluence of a continuous phase and another dispersed phase by droplets that generate, the tailing of main generated particles, which is a cause of satellites, is shortened and generated secondaryly Reduce satellites Found that it is possible to miniaturization. Furthermore, the two dispersed phase introduction channels can be merged from both sides of the same position of the continuous phase introduction channel, and the droplets can be alternately generated to shorten each other's particle tailing. Thus, it was found that the formation of satellites was eliminated, that is, the continuous phase containing the generated particles was substantially free of fine particles. It has also been found that two dispersed phase introduction channels are divided from one dispersed phase introduction channel, and that the same effect can be obtained by merging from both sides of the same position of the continuous phase introduction channel. It was. Hereinafter, the present invention will be described in detail.

粒子を製造する際、分散相が***する様子は、分散相や連続相流体の粘度、密度、送液する速度、流路幅、界面張力などによって左右される。***する際には、主に生成する粒子に加え、サテライトが副生成する。上記したように、本発明の粒子製造方法は、送液する流体の特性を変えること無しに、２以上の分散相を、連続相の導入流路に実質的に別々に導入する微小流路構造体において、ある１つの分散相流路と連続相流路の合流部で生成する液滴によって、その他の各流路で生成する液滴生成のタイミングが制御されることによって、サテライトの発生要因である主生成粒子の尾引きが短くなり、副生成するサテライトを減少、微小化、もしくは実質的になくするものである。   When the particles are produced, how the disperse phase breaks depends on the viscosity and density of the disperse phase and continuous phase fluid, the feeding speed, the channel width, the interfacial tension, and the like. When splitting, satellites are by-produced in addition to the mainly generated particles. As described above, the particle production method of the present invention has a microchannel structure in which two or more dispersed phases are introduced substantially separately into a continuous phase introduction channel without changing the characteristics of the fluid to be fed. In the body, the droplets generated at the confluence of one disperse phase channel and the continuous phase channel control the timing of the droplet generation generated in each of the other channels. The tailing of certain main product particles is shortened, and satellites generated as by-products are reduced, miniaturized, or substantially eliminated.

ここで、本発明において用いられる分散相とは、微小流路構造体により粒子を生成させるための液状物であり、例えば、スチレンなどの重合用のモノマー、ジビニルベンゼンなどの架橋剤、重合開始剤等のゲル製造用原料を適当な溶媒に溶解した媒体を指す。ここで分散相としては、本発明が微小な粒子を効率的に生成させることを目的としており、この目的を達成させるためであれば微小流路構造体中の流路を送液できるものであれば特に制限されず、さらに粒子を形成させることができればその成分も特に制限されない。また、分散相中に一部固体状物が混在したスラリー状のものであっても差し支えない。   Here, the dispersed phase used in the present invention is a liquid material for generating particles by a microchannel structure, and examples thereof include a monomer for polymerization such as styrene, a crosslinking agent such as divinylbenzene, and a polymerization initiator. The medium which melt | dissolved the raw material for gel manufactures, such as in a suitable solvent, is pointed out. Here, as the dispersed phase, the purpose of the present invention is to generate fine particles efficiently, and if it is possible to achieve this purpose, the flow path in the fine flow path structure can be fed. The component is not particularly limited as long as particles can be further formed. Moreover, it may be a slurry in which a solid phase is partially mixed in the dispersed phase.

本発明において用いられる連続相とは、微小流路構造体により分散相より粒子を生成させるために用いられる液状物であり、例えば、ポリビニルアルコールといったゲル製造用分散剤を適当な溶媒に溶解した媒体を指す。ここで連続相としては分散相と同様に、微小流路構造体中の流路を送液できるものであれば特に制限されず、さらに粒子を形成させることができればその成分は特に制限されない。また、連続相中に一部固体状物が混在したスラリー状のものであっても差し支えない。   The continuous phase used in the present invention is a liquid material used for generating particles from a dispersed phase by a microchannel structure, for example, a medium in which a dispersant for gel production such as polyvinyl alcohol is dissolved in an appropriate solvent. Point to. Here, as in the case of the dispersed phase, the continuous phase is not particularly limited as long as it can feed the flow path in the micro flow path structure, and the component is not particularly limited as long as particles can be further formed. Further, it may be a slurry in which a solid substance is partially mixed in the continuous phase.

さらに、分散相と連続相とは粒子を生成させるために、実質的に交じり合わないあるいは相溶性がない流体であり、連続相として水相を用いた場合には分散相には有機相、連続相に有機相を用いた液状物であり、その逆の形態も可能である。   Furthermore, the dispersed phase and the continuous phase are fluids that do not substantially intermix or have no compatibility in order to generate particles. When an aqueous phase is used as the continuous phase, the dispersed phase is an organic phase, a continuous phase. It is a liquid material using an organic phase as a phase, and vice versa.

本発明は、上記の分散相及び連続相を用いて特定の構造を有した微小流路構造体により、実質的に均一の粒径を有した液滴を生成させ、必要に応じてゲル化処理等を行うことで、液体クロマトグラフ等に有用なゲル等の粒子を製造できるものであり、本発明において用いられる微小流路構造体は、分散相を導入するための２以上の導入口及びそれに連通する分散相導入流路と、連続相を導入するための導入口及びそれに連通する連続相導入流路と、導入された分散相と連続相とを合流させる合流部を含みかつ合流により粒子を生成させた後に排出させる排出流路と、を有する。   According to the present invention, droplets having a substantially uniform particle diameter are generated by a microchannel structure having a specific structure using the above-described dispersed phase and continuous phase, and gelation treatment is performed as necessary. Etc. can produce particles such as gel useful for liquid chromatographs, etc., and the microchannel structure used in the present invention comprises two or more inlets for introducing a dispersed phase, and A dispersed phase introduction flow path that communicates; an inlet for introducing a continuous phase; a continuous phase introduction flow path that communicates with the inlet; and a merge portion that merges the introduced dispersed phase and the continuous phase; And a discharge channel that is discharged after being generated.

そして、このような微小流路構造体の構成とし、この微小流路構造体を用いて粒子を製造する際、２以上の分散相導入流路は連続相導入流路に実質的に別々に連通して分散相を導入し、かつ、連続相と１つの分散相との合流により生成する液滴により連続相と別の分散相との合流により生成する液滴の生成タイミングを制御するものである。生成した液滴は、連通する共通の排出流路を通って排出されるが、その際、下流の他分散相流路の合流部付近を通過する時に、その分散相流路からの液滴生成を制限する。また、通過直後には分散相流路より分散相が、連続相中に進入し始めて液滴が生成する。お互いの液滴は、後方の別の分散相流路から液滴の生成を促すと共に、自信の液滴からの尾引きが制限されることとなる。   And when it is set as the structure of such a microchannel structure, and manufacturing particle | grains using this microchannel structure, two or more disperse | distributed-phase introduction flow paths are connected to a continuous phase introduction flow path substantially separately. Then, the dispersed phase is introduced, and the generation timing of the droplets generated by the merge of the continuous phase and another dispersed phase is controlled by the droplets generated by the merge of the continuous phase and one dispersed phase. . The generated droplets are discharged through a common discharge flow channel that communicates with each other. At this time, when the droplets pass near the junction of the other dispersed phase flow channel downstream, the droplets are generated from the dispersed phase flow channel. Limit. Further, immediately after passing, the dispersed phase starts to enter the continuous phase from the dispersed phase flow path, and droplets are generated. Each droplet will encourage droplet formation from another dispersed phase flow path behind and limit tailing from the confident droplet.

さらに、２つの分散相導入流路を、連続相導入流路の同一位置の両側から合流させ、かつ、液滴を交互に生成させるとよい。こうすることにより、もう一方の他分散相流路の液滴生成をお互いに制限しあうこととなり、同一の粒子径を生成する場合に効果的な合流部配置となる。   Further, the two dispersed phase introduction channels may be joined from both sides of the same position of the continuous phase introduction channel, and droplets may be alternately generated. By doing so, droplet generation in the other other dispersed phase flow channel is mutually restricted, and an effective joining portion arrangement is obtained when the same particle diameter is generated.

また、２つの分散相導入流路が一つの分散相導入流路から分割されており、かつ、連続相導入流路の同一位置の両側から合流させるとよい。一つの分散相流路から分割されて合流することにより、分散相の送液速度を個別に制御することなく流路構造による一定の流速を得ることが出来、液滴生成のタイミングを制御しやすくなる。   Further, the two dispersed phase introduction flow paths may be divided from one dispersed phase introduction flow path, and may be merged from both sides of the same position of the continuous phase introduction flow path. By dividing and joining from one dispersed phase channel, it is possible to obtain a constant flow rate by the channel structure without individually controlling the liquid feeding speed of the dispersed phase, and it is easy to control the timing of droplet generation Become.

このような処理を施すことで、生成した粒子を含む連続相中に、実質的に微小な粒子を含まないものとなり、本発明に特有の効果を奏することとなる。   By performing such treatment, the continuous phase containing the generated particles is substantially free of fine particles, and the effects specific to the present invention are exhibited.

また、本発明により、生成した粒子の径を制御することができる。   Moreover, the diameter of the produced | generated particle | grains is controllable by this invention.

この液滴を送液するため微小流路は、ウエットエッチングや、ドライエッチング、機械加工やレーザー加工等の作製方法や、その素材として、例えば、ガラス、石英、セラミック、シリコン、あるいは金属や樹脂等または、それらの組み合わせ等には特に制限されず、連続相の導入流路に実質的に別々に連通する微小流路構造体とする事が出来れば良い。また、分散相流路と連続相流路が合流部でなす角度、幅、深さは、特に限定されないが、９０°より小さい方が良く、分散相の幅は、連続相の幅より狭い方が好ましいが、目的とする粒子の粒子径に応じて適宜決めれば良い。また、同時に２つの分散相流路が連続相流路の左右から合流することにより、その生成する液滴が交互に生成することによってお互いの尾引きの長さが抑制される。結果的にサテライトの発生を実質的になくすることができる。さらに、前記２つの分散相流路が、連続相流路の左右に合流する前の上流部分において、共通の流路から分割することによって、個別に流量を調整することなしに左右の流量を制御し、粒子の径を制御することができる。   In order to send this droplet, the micro flow path is prepared by wet etching, dry etching, machining, laser processing, or the like, and as a material thereof, for example, glass, quartz, ceramic, silicon, metal, resin, etc. Alternatively, the combination thereof is not particularly limited as long as it can be a micro flow channel structure that communicates with the continuous phase flow channel substantially separately. In addition, the angle, width, and depth that the dispersed phase flow path and the continuous phase flow path form at the junction are not particularly limited, but are preferably smaller than 90 °, and the width of the dispersed phase is narrower than the width of the continuous phase. However, it may be appropriately determined according to the particle size of the target particles. In addition, when two dispersed phase channels are joined from the left and right of the continuous phase channel at the same time, the generated droplets are alternately generated, thereby suppressing the length of each other's tailing. As a result, the generation of satellites can be substantially eliminated. Furthermore, the left and right flow rates can be controlled without adjusting the flow rates individually by dividing the two disperse phase flow channels from the common flow channel in the upstream portion before joining the left and right of the continuous phase flow channel. In addition, the particle diameter can be controlled.

なお、本発明の方法により分散相と連続相とから得られる粒子は、当初は液滴のような液体状のものであるが、例えば、ゲル製造用の原料及び重合開始剤等を含んでおれば、これに光照射処理や加熱処理することで硬化させて固体状のゲルとすることができ、このような手法は公知の光照射手段や加熱手段を微小流路構造体の内に組み入れたり、その外部に配置して処理すれば良い。また、ゲルを製造するにあたっては、微小流路構造体中で得ることもできるが、微小流路構造体からと出した後に処理をしてゲルを得てもよい。   The particles obtained from the dispersed phase and the continuous phase by the method of the present invention are initially liquid like droplets, but include, for example, a raw material for gel production and a polymerization initiator. For example, it can be cured by light irradiation treatment or heat treatment to form a solid gel. Such a method can incorporate known light irradiation means or heating means into the microchannel structure. It can be arranged outside and processed. Moreover, when manufacturing a gel, although it can also obtain in a microchannel structure, you may process after taking out from a microchannel structure, and may obtain a gel.

本発明は以下の効果を奏する。
（１）２以上の分散相の粒子を生成する時に、ある１つの分散相流路と連続相流路の合流部で生成する液滴によって、その他の各流路で生成する液滴の生成タイミングが制御されることによって、サテライトの発生要因である、主生成粒子の尾引きが短くなり、副生成するサテライトを減少させることができる。
（２）２つの分散相流路が連続相流路の左右から合流し、その生成する液滴が交互に生成することによってお互いの粒子の尾引きを短くすることができ、実質的にサテライトの生成をなくなることができる。
（３）流路幅、流路深さを粒子製造装置の製作時に規定することにより生成する粒子径制御も可能で、工業的な量産にも対応可能な方法である。 The present invention has the following effects.
(1) When generating particles of two or more dispersed phases, the generation timing of the droplets generated in each of the other channels by the droplets generated at the junction of one certain dispersed phase channel and the continuous phase channel Is controlled, the tailing of the main generation particles, which is a cause of generation of satellites, is shortened, and the satellites generated as by-products can be reduced.
(2) The two dispersed phase channels merge from the left and right of the continuous phase channel, and the generated droplets are alternately generated, so that the tailing of each particle can be shortened. Generation can be eliminated.
(3) The particle diameter can be controlled by defining the channel width and channel depth at the time of production of the particle manufacturing apparatus, and this method can be applied to industrial mass production.

以下では、本発明の実施例を示し、更に詳しく発明の実施の形態について説明する。なお、本発明は以下の実施例に限定されるものではなく、本発明の要旨を逸脱しない範囲で、任意に変更可能であることは言うまでもない。   Hereinafter, examples of the present invention will be described, and the embodiments of the invention will be described in more detail. It is needless to say that the present invention is not limited to the following examples and can be arbitrarily changed without departing from the gist of the present invention.

また、実施例においては１枚の基板上に１本の微小流路を形成したが、工業的に量産する場合は、１枚の基板上に多数の微小流路を形成する、あるいは多数形成した１枚の基板を積層することで可能となる。
（実施例１）
本発明の第１の実施例における粒子製造用微小流路を図４に示す。微小流路は７０ｍｍ×２０ｍｍ×１ｔ（厚さ）のパイレックス（登録商標）ガラス上に、微小流路に相当する連続相導入流路３、排出流路７の幅がいずれも１５０μｍ、深さ５０μｍ（図４におけるＣ−Ｃ’断面を示す図５に認められる）、分散相導入流路５の幅が１２０μｍ、深さ５０μｍである微細流路形状とし、連続相導入流路３と分散相導入流路５とが合流部がそれぞれ５０°の角度にて交わる形状の流路を１本形成した。この形状の粒子製造用微小流路構造体は図６に示す製作手順に従って以下のように作製した。厚さ１ｍｍで７０ｍｍ×２０ｍｍのガラス基板９の一方の面に、金などの金属膜１０を後述する露光光が透過しない程度の厚さに成膜し（図６（ａ）金属の成膜工程）、その金属膜上にフォトレジスト１１をコートした（図６（ｂ）フォトレジストの塗布工程）。更にフォトレジスト上に前記微小流路の形状を描いたパターンを有するフォトマスク１２を置き、そのフォトマスク上から露光し現像を行なった（図６（ｃ）露光〜現像工程）。次に、酸などで金属膜１０をエッチングした（図６（ｄ）金属膜のエッチング工程）後、レジストとガラスをフッ酸などでエッチィングし（図６（ｅ）レジスト、ガラスのエッチング工程）、さらに残った金属膜１０を酸などで溶かして（図６（ｆ）金属膜の除去工程）、微小流路が形成された基板１３を得た。実施例においては、微小流路の製作をガラス基板のエッチィングにより微小流路を形成したが、製作方法はこれに限定するものではない。 In the embodiment, one micro flow channel is formed on one substrate. However, in the case of mass production industrially, a large number of micro flow channels are formed on a single substrate or a large number of micro flow channels are formed. This is possible by stacking one substrate.
Example 1
FIG. 4 shows a microchannel for producing particles in the first embodiment of the present invention. The microchannels are on Pyrex (registered trademark) glass of 70 mm × 20 mm × 1 t (thickness). The widths of the continuous phase introduction channel 3 and the discharge channel 7 corresponding to the microchannels are both 150 μm and the depth is 50 μm. (As can be seen in FIG. 5 showing a cross section CC ′ in FIG. 4), the dispersed phase introduction channel 5 has a fine channel shape with a width of 120 μm and a depth of 50 μm, and the continuous phase introduction channel 3 and the dispersed phase introduction One channel having a shape in which the merged portion and the channel 5 intersect each other at an angle of 50 ° was formed. The microchannel structure for producing particles having this shape was produced as follows according to the production procedure shown in FIG. A metal film 10 such as gold is formed on one surface of a glass substrate 9 having a thickness of 1 mm and a size of 70 mm × 20 mm so that exposure light, which will be described later, is not transmitted (FIG. 6A, metal film forming step). ) A photoresist 11 was coated on the metal film (FIG. 6B, a photoresist coating process). Further, a photomask 12 having a pattern depicting the shape of the microchannel was placed on the photoresist, and exposure was performed from the photomask for development (FIG. 6 (c) exposure to development process). Next, after etching the metal film 10 with acid or the like (FIG. 6D, etching process of the metal film), the resist and glass are etched with hydrofluoric acid or the like (FIG. 6E, etching process of the resist and glass). Further, the remaining metal film 10 was dissolved with an acid or the like (FIG. 6 (f) metal film removal step) to obtain a substrate 13 on which a microchannel was formed. In the embodiment, the micro flow channel is formed by etching the glass substrate, but the manufacturing method is not limited to this.

この微小流路が形成された基板１３の微小流路を有する面に、微小流路の流体導入口（連続相導入口２、分散相導入口４）と流体排出口８にあたる位置に予め直径１．２ｍｍの***を、機械的加工手段を用いて設けた厚さ１ｍｍで７０ｍｍ×２０ｍｍのガラスカバー体１４を熱接合し、図７に示すように微小流路を備えた粒子製造用微小流路構造体を製作した。実施例においては、微小流路を形成する基板及びカバー体にガラス基板を用いたが、これに限定するものではない。   On the surface of the substrate 13 on which the microchannels are formed having the microchannels, a diameter 1 is previously set at a position corresponding to the fluid inlet (continuous phase inlet 2 and dispersed phase inlet 4) and the fluid outlet 8 of the microchannel. A micro-channel for particle production provided with a micro-channel as shown in FIG. 7 by thermally joining a 1 mm-thick 70 mm × 20 mm glass cover body 14 provided with a 2 mm small hole using mechanical processing means A structure was made. In the embodiment, the glass substrate is used for the substrate for forming the microchannel and the cover body, but the present invention is not limited to this.

次に本発明の粒子製造方法について説明する。図８に示すように粒子製造用微小流路構造体１５に液体が送液可能なようにホルダー１６などで保持すると共に、テフロン（登録商標）チューブ１８及びフィレットジョイント１９をホルダー１６に固定する。テフロン（登録商標）チューブ１８のもう一方はマイクロシリンジ２１、２２に接続する。これで粒子製造用微小流路構造体１５に液体の送液が可能となる。次に液滴を生成するための分散相にモノマー（スチレン）、ジビニルベンゼン、酢酸ブチル及び過酸化ベンゾイルの混合溶液をマイクロシリンジ２１に注入、連続相にポリビニルアルコール３％水溶液をマイクロシリンジ２２に注入し、マイクロシリンジポンプ２０で送液を行った。送液流速は分散相及び連続相は共に６μｌ／ｍｉｎである。送液流速が共に安定した状態で、粒子製造用微小流路構造体１５の分散相及び連続相が交わる合流部にて粒子生成が観察される。合流部の観察を図９〜図１３に示す。図中、図１１は２００倍で顕微鏡観察したもの、ホールスライドガラス上に採取した液滴にカバーグラスで蓋をし、そのカバーグラス付近に顕微鏡焦を合わせて撮影した。輝度の高い周囲の黒色部まで、主液滴である。また、図１３は１０００倍で顕微鏡観察したものであり、ホールスライドガラス上に採取した液滴にカバーグラスで蓋をし、そのカバーグラス付近に顕微鏡焦を合わせて撮影した。輝度の高い部分は２００倍での観察の輝度の高い部分である。   Next, the particle manufacturing method of the present invention will be described. As shown in FIG. 8, the microfluidic structure 15 for particle production is held by a holder 16 or the like so that liquid can be fed, and a Teflon (registered trademark) tube 18 and a fillet joint 19 are fixed to the holder 16. The other end of the Teflon (registered trademark) tube 18 is connected to the microsyringes 21 and 22. As a result, liquid can be fed to the micro-channel structure 15 for particle production. Next, a mixed solution of monomer (styrene), divinylbenzene, butyl acetate and benzoyl peroxide is injected into the microsyringe 21 as a dispersed phase for generating droplets, and a 3% aqueous solution of polyvinyl alcohol is injected into the microsyringe 22 as a continuous phase. Then, the liquid was fed by the microsyringe pump 20. The liquid feeding flow rate is 6 μl / min for both the dispersed phase and the continuous phase. Particle generation is observed at the junction where the dispersed phase and continuous phase of the micro-flow channel structure 15 for particle production intersect in a state where both the liquid feeding flow rates are stable. Observation of the junction is shown in FIGS. In the figure, FIG. 11 is a microscopic observation at 200 ×, and a droplet collected on a hole slide glass was covered with a cover glass, and the microscope was focused in the vicinity of the cover glass. It is a main droplet up to the surrounding black part with high brightness. Further, FIG. 13 was observed with a microscope at a magnification of 1000 times. The droplets collected on the hole slide glass were covered with a cover glass, and the microscopic focus was set near the cover glass and photographed. The portion with high luminance is the portion with high luminance observed at 200 times.

図から、左右の液滴の***タイミングが制御され、交互に生成していることわかる。生成された粒子２３を観察すると主に生成する液滴の径は、平均粒子径８８μｍの均一な粒子であった。また、副生成したサテライトは０．５μｍ以下で実質的に問題にならない個数であった。
（比較例１）
本発明の比較例として粒子製造用微小流路を図１４に示す。微小流路は７０ｍｍ×２０ｍｍ×１ｔ（厚さ）のパイレックス（登録商標）ガラス上に、微小流路に相当する連続相導入流路３、排出流路７の幅がいずれも１４０μｍ、深さ４６μｍ（図１４におけるＤ−Ｄ’断面を示す図１５に認められる）、分散相導入流路５の幅が１４０μｍ、深さ４６μｍである微細流路形状とし、連続相導入流路３と分散相導入流路５とが合流部がそれぞれ９０°の角度にて交わる形状の流路を１本形成した。この形状の粒子製造用微小流路構造体は実施例１に示すものと同じ手法を用いて作製、送液した。送液流速は分散相及び連続相は共に６μｌ／ｍｉｎである。送液流速が共に安定した状態で、分散相及び連続相が交わる合流部にて粒子生成が観察される。合流部の観察を図１６〜図２０に示す。図中、図１８は２００倍で顕微鏡観察したもの、ホールスライドガラス上に採取した液滴にカバーグラスで蓋をし、そのカバーグラス付近に顕微鏡焦を合わせて撮影した。輝度の高い周囲の黒色部まで、主液滴である。また、図２０は１０００倍で顕微鏡観察したものであり、ホールスライドガラス上に採取した液滴にカバーグラスで蓋をし、そのカバーグラス付近に顕微鏡焦を合わせて撮影した。輝度の高い部分は２００倍での観察の輝度の高い部分である。図２０では、比較的大きなサテライトが、多数観察される。 From the figure, it can be seen that the division timing of the left and right droplets is controlled and alternately generated. When the generated particles 23 were observed, the diameters of the generated droplets were uniform particles having an average particle diameter of 88 μm. In addition, the number of satellites by-produced was 0.5 μm or less, and the number was not substantially problematic.
(Comparative Example 1)
As a comparative example of the present invention, a fine channel for particle production is shown in FIG. The microchannels are on a 70 mm × 20 mm × 1 t (thickness) Pyrex (registered trademark) glass, and the widths of the continuous phase introduction channel 3 and the discharge channel 7 corresponding to the microchannels are both 140 μm and the depth is 46 μm. (It can be seen in FIG. 15 showing the DD ′ cross section in FIG. 14), the dispersed phase introduction channel 5 has a fine channel shape with a width of 140 μm and a depth of 46 μm, and the continuous phase introduction channel 3 and the dispersed phase introduction One flow path having a shape in which the merging portion and the flow path 5 intersect each other at an angle of 90 ° was formed. A micro-channel structure for producing particles having this shape was prepared and fed using the same technique as that shown in Example 1. The liquid feeding flow rate is 6 μl / min for both the dispersed phase and the continuous phase. Particle formation is observed at the junction where the dispersed phase and the continuous phase intersect in a state where both the liquid feeding flow rates are stable. Observation of the junction is shown in FIGS. In the figure, FIG. 18 was observed with a microscope at a magnification of 200 times, and a droplet collected on a hole slide glass was covered with a cover glass, and the microscope was focused on the vicinity of the cover glass. It is a main droplet up to the surrounding black part with high brightness. Further, FIG. 20 was observed with a microscope at a magnification of 1000 times. The droplets collected on the hole slide glass were covered with a cover glass, and the microscope was focused on the vicinity of the cover glass. The portion with high luminance is the portion with high luminance observed at 200 times. In FIG. 20, a large number of relatively large satellites are observed.

図から、液滴が***した時に長い尾を引いていることがわかる。生成された粒子２３を観察すると主に生成する液滴の径は、平均粒子径９１μｍの均一な粒子であった。また、副生成したサテライトは数μｍあり、また多数存在した。   From the figure, it can be seen that the droplet has a long tail when it breaks up. When the generated particles 23 were observed, the diameters of the generated droplets were uniform particles having an average particle diameter of 91 μm. Further, by-produced satellites were several μm and many existed.

一般的な粒子製造用微小流路を示す概略図である。It is the schematic which shows the microchannel for common particle manufacture. 図１の微小流路構造体中のＡ−Ａ’断面図（拡大）である。It is A-A 'sectional drawing (enlargement) in the microchannel structure of FIG. 図１の微小流路構造体中のＢ−Ｂ’断面図（拡大）である。It is B-B 'sectional drawing (enlargement) in the microchannel structure of FIG. 実施例１に用いた粒子製造用微小流路構造体を示す概略図である。1 is a schematic view showing a fine channel structure for particle production used in Example 1. FIG. 図４の微小流路構造体中のＣ−Ｃ’断面図（拡大）である。It is C-C 'sectional drawing (enlargement) in the microchannel structure of FIG. 実施例１における粒子製造用微小流路の形成方法を示すフロー図である。FIG. 3 is a flowchart showing a method for forming a fine channel for particle production in Example 1. 実施例１に用いた粒子製造用微小流路構造体を示す概略図である。1 is a schematic view showing a fine channel structure for particle production used in Example 1. FIG. 実施例１及び実施例２に用いた粒子製造用微小流路構造体及びポンプ接続を示す概略図である。It is the schematic which shows the microchannel structure for particle manufacture used for Example 1 and Example 2, and a pump connection. 実施例１における粒子が交互に粒子が生成している様子を示す図である。It is a figure which shows a mode that the particle | grains in Example 1 are alternately producing | generating the particle | grains. 実施例１における粒子が交互に粒子が生成している様子を示す模式図である。It is a schematic diagram which shows a mode that the particle | grains in Example 1 are producing | generating the particle | grains alternately. 実施例１における生成粒子を示す図である。FIG. 3 is a diagram showing generated particles in Example 1. 実施例１における生成粒子を示す模式図である。FIG. 3 is a schematic diagram showing generated particles in Example 1. 図１１における一部を拡大した図である。It is the figure which expanded a part in FIG. 比較例１に用いた粒子製造用微小流路構造体を示す概略図である。FIG. 3 is a schematic view showing a fine channel structure for particle production used in Comparative Example 1. 図１４の微小流路構造体中のＤ−Ｄ’断面図（拡大）である。It is D-D 'sectional drawing (enlargement) in the microchannel structure of FIG. 比較例１における流路内で粒子が尾を引いている様子を示す図である。It is a figure which shows a mode that the particle | grain has pulled the tail in the flow path in the comparative example 1. FIG. 比較例１における流路内で粒子が尾を引いている様子を示す模式図である。6 is a schematic diagram showing a state in which particles are trailing in a flow channel in Comparative Example 1. FIG. 比較例１における生成粒子を示す図である。FIG. 4 is a diagram showing generated particles in Comparative Example 1. 比較例１における生成粒子を示す模式図である。6 is a schematic diagram showing generated particles in Comparative Example 1. FIG. 図１８における一部を拡大した図である。It is the figure which expanded a part in FIG.

符号の説明Explanation of symbols

１：微小流路基板
２：連続相導入口
３：連続相導入流路
４：分散相導入口
５：分散相導入流路
６：合流部
７：排出流路
８：排出口
９：ガラス基板
１０：金属膜
１１：フォトレジスト
１２：フォトマスク
１３：微小流路が形成された基板
１４：カバー体
１５：微小流路構造体
１６：ホルダー
１７：ビーカー
１８：テフロン（登録商標）チューブ
１９：フィレットジョイント
２０：マイクロシリンジポンプ
２１：マイクロシリンジ（分散相）
２２：マイクロシリンジ（連続相）
２３：生成粒子
２４：生成する粒子
２５：生成した粒子
２６：主液滴
２７：尾引き
２８：サテライト
1: Micro-channel substrate 2: Continuous phase inlet port 3: Continuous phase inlet channel 4: Dispersed phase inlet port 5: Dispersed phase inlet channel 6: Junction portion 7: Discharge channel 8: Discharge port 9: Glass substrate 10 : Metal film 11: Photoresist 12: Photomask 13: Substrate 14 on which a microchannel is formed 14: Cover body 15: Microchannel structure 16: Holder 17: Beaker 18: Teflon (registered trademark) tube 19: Fillet joint 20: Micro syringe pump 21: Micro syringe (dispersed phase)
22: Micro syringe (continuous phase)
23: Generated particles 24: Generated particles 25: Generated particles 26: Main droplets 27: Tail 28: Satellites

Claims (1)

分散相を導入するための導入口及びそれに連通する２つの分散相導入流路と、連続相を導入するための導入口及びそれに連通する連続相導入流路と、前記２つの分散相導入流路を連続相導入流路の同一位置の両側から合流させ、導入された分散相と連続相とを合流させる合流部を含みかつ合流により粒子を生成させた後に排出させる排出流路と、を有した微小流路構造体を用いて粒子を製造する方法であって、微小流路構造体の外部に備えた分散相及び連続相を送液するポンプの送液量を調整し、一方の分散相導入流路からの分散相と連続相との合流ともう一方の分散相導入流路からの分散相と連続相との合流とのタイミングを制御して、交互に液滴を生成させることを特徴とする粒子製造方法。 An introduction port for introducing a dispersed phase and two dispersed phase introduction channels communicating therewith, an introduction port for introducing a continuous phase and a continuous phase introduction channel communicating therewith, and the two dispersed phase introduction channels And a discharge flow path that includes a merging portion for merging the introduced dispersed phase and the continuous phase from both sides at the same position of the continuous phase introduction flow path, and that discharges the particles after generating particles by the merge. This is a method for producing particles using a microchannel structure, and adjusts the amount of the pump that delivers the dispersed phase and continuous phase provided outside the microchannel structure, and introduces one of the dispersed phases. Controlling the timing of the merging of the dispersed phase and the continuous phase from the flow path and the merging of the dispersed phase and the continuous phase from the other dispersed phase introduction flow path, and generating droplets alternately Particle manufacturing method.
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