JP6867035B2 - Method for producing crystalline drug nanoparticles - Google Patents
Method for producing crystalline drug nanoparticles Download PDFInfo
- Publication number
- JP6867035B2 JP6867035B2 JP2017554796A JP2017554796A JP6867035B2 JP 6867035 B2 JP6867035 B2 JP 6867035B2 JP 2017554796 A JP2017554796 A JP 2017554796A JP 2017554796 A JP2017554796 A JP 2017554796A JP 6867035 B2 JP6867035 B2 JP 6867035B2
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- JP
- Japan
- Prior art keywords
- drug
- water
- mixture
- nanoparticles
- crystalline
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Images
Classifications
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- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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Description
結晶質薬物と水溶性高分子を加熱し、混練する結晶質薬物ナノ粒子の製造方法及び結晶質薬物のナノ粒子化方法に関する。 The present invention relates to a method for producing crystalline drug nanoparticles in which a crystalline drug and a water-soluble polymer are heated and kneaded, and a method for forming nanoparticles of the crystalline drug.
従来、薬物を微粒子化すると表面積が増大することにより薬物の溶解速度が増加することが知られており、薬物の微粒子化は、難水溶性薬物の溶解性及び薬物の体内への吸収割合を示すバイオアべイラビリティーを改善する手法の一つに挙げられている。従来の薬物微粒子の調製方法には、ボールミルやロッドミルを用いる乾式粉砕法、ビーズミルを用いる湿式粉砕法、高圧ホモジナイザー法、共沈法、晶析法等がある（特許文献１）。しかし、乾式粉砕法は、バッチ式であるため大量生産が困難であった。また、湿式粉砕法や高圧ホモジナイザー法は、ナノ粒子を得ることはできるが、ナノ粒子が懸濁液状態で得られるため、固形製剤とするには乾燥工程が必要であり、水に化学分解しやすい薬物には適用できないとの問題があった。薬物粒子を有機溶媒中で析出させる共沈法や晶析法では、ナノ粒子を取り出すときに有機溶媒の除去が必要であり、ナノ粒子中へ有機溶媒が残存するとの問題があった。そのため、乾燥工程や有機溶媒が不要であり、簡易に連続的に薬物のナノ粒子を製造できる方法が求められていた。 Conventionally, it has been known that when a drug is micronized, the dissolution rate of the drug increases due to an increase in the surface area, and the micronization of a drug indicates the solubility of a poorly water-soluble drug and the absorption rate of the drug into the body. It is listed as one of the methods to improve bioavailability. Conventional methods for preparing drug fine particles include a dry pulverization method using a ball mill or a rod mill, a wet pulverization method using a bead mill, a high-pressure homogenizer method, a coprecipitation method, a crystallization method, and the like (Patent Document 1). However, since the dry pulverization method is a batch method, mass production is difficult. In addition, the wet pulverization method and the high-pressure homogenizer method can obtain nanoparticles, but since the nanoparticles are obtained in a suspension state, a drying step is required to form a solid preparation, which is chemically decomposed into water. There was a problem that it could not be applied to easy drugs. In the coprecipitation method and the crystallization method in which the drug particles are precipitated in an organic solvent, it is necessary to remove the organic solvent when taking out the nanoparticles, and there is a problem that the organic solvent remains in the nanoparticles. Therefore, there has been a demand for a method that does not require a drying step or an organic solvent and can easily and continuously produce drug nanoparticles.
一方、高分子材料を混合する方法の一つとして、加熱溶融混練法が知られている。この方法は、対象物を粉砕するための方法ではなく、薬物に関する分野では、難水溶性薬物と水溶性高分子の混合物を加熱混練することにより、難水溶性薬物が非晶質状態で分散した固体分散体を得るために用いられている（特許文献２）。この固体分散体も、難水溶性薬物の溶解性を向上できるため、難水溶性薬物の溶解性及びバイオアべイラビリティーを改善するために用いられる。しかし、固体分散体自身の安定性に問題があり、非晶質状態が物理的又は化学的に不安定な薬物には用いることができない等の問題がある。また、加熱溶融混練法を、結晶質の薬物粒子を水溶性ポリマーで被覆するためや（特許文献３）、薬物を一旦溶融して賦形剤と混合した後、薬物を再結晶化させるため（特許文献４）に用いることも提案されている。しかしながら、加熱溶融混練法により結晶質薬物ナノ粒子を製造することは提案されていなかった。例えば、特許文献３に記載された方法は、薬物に対して少量の水溶性ポリマーを使用して薬物粒子を水溶性ポリマーで被覆する方法であり、特許文献４に記載された方法では、薬物を再結晶化させることにより結晶質粒子の粒子径を縮小させているが、得られる粒子の平均粒子径はミクロンサイズでありナノサイズではなかった。
On the other hand, a heat-melt kneading method is known as one of the methods for mixing polymer materials. This method is not a method for pulverizing an object, and in the field of drugs, the poorly water-soluble drug is dispersed in an amorphous state by heating and kneading a mixture of the poorly water-soluble drug and a water-soluble polymer. It is used to obtain a solid dispersion (Patent Document 2). Since this solid dispersion can also improve the solubility of the poorly water-soluble drug, it is used to improve the solubility and bioavailability of the poorly water-soluble drug. However, there is a problem in the stability of the solid dispersion itself, and there is a problem that it cannot be used for a drug whose amorphous state is physically or chemically unstable. Further, the heat-melt kneading method is used to coat crystalline drug particles with a water-soluble polymer (Patent Document 3), or to recrystallize the drug after melting the drug once and mixing it with an excipient (Patent Document 3). It has also been proposed to be used in Patent Document 4). However, it has not been proposed to produce crystalline drug nanoparticles by a heat-melt kneading method. For example, the method described in
本発明の課題は、上記問題を解決し、乾燥工程や有機溶媒が不要であり、簡易に連続的に結晶質の薬物ナノ粒子を製造できる結晶質薬物ナノ粒子の製造方法、及び乾燥工程や有機溶媒が不要であり、結晶質薬物を簡易に連続的にナノ粒子化できる結晶質薬物のナノ粒子化方法を提供することにある。 The subject of the present invention is a method for producing crystalline drug nanoparticles, which solves the above-mentioned problems, does not require a drying step or an organic solvent, and can easily and continuously produce crystalline drug nanoparticles, and a drying step or an organic substance. It is an object of the present invention to provide a method for making a crystalline drug into nanoparticles, which does not require a solvent and can easily and continuously make nanoparticles of a crystalline drug.
本発明者らは、結晶質薬物のナノ粒子化を検討するにあたり、従来は結晶質薬物ナノ粒子の製造に用いられていなかった加熱溶融混練法に着目した。そして、検討を進めたところ、結晶質の薬物と水溶性高分子を特定の割合で混合し、混合物を加熱混練するときの加熱温度を薬物の融点との関係で特定の範囲とすることにより、加熱混練によってナノサイズの結晶質薬物粒子が得られることを見いだした。具体的には、薬物の割合が薬物と水溶性高分子の合計に対して４０質量％以下となるように両者を混合し、加熱温度を薬物の融点より低くする場合には、加熱温度が薬物の融点より５０℃以上低くなるように、加熱温度を薬物の融点より高くする場合には、加熱温度が薬物の融点より１０℃以上高くなるように加熱して混練することにより、結晶質薬物ナノ粒子が得られることを見いだした。また、薬物の混合割合の下限は、加熱温度を薬物の融点より低くする場合は１５質量％であり、加熱温度を薬物の融点より高くする場合は２０質量％であった。さらに、界面活性剤を前記混合物中に添加すると、ナノ粒子化がより促進されると共に、得られたナノ粒子の使用時の分散安定性が優れることを見いだした。 In investigating the nanoparticle formation of crystalline drugs, the present inventors focused on a heat-melt kneading method that was not conventionally used for producing crystalline drug nanoparticles. Then, as a result of further examination, the crystalline drug and the water-soluble polymer were mixed at a specific ratio, and the heating temperature at the time of heating and kneading the mixture was set to a specific range in relation to the melting point of the drug. It was found that nano-sized crystalline drug particles can be obtained by heat kneading. Specifically, when the mixture is mixed so that the ratio of the drug is 40% by mass or less with respect to the total of the drug and the water-soluble polymer and the heating temperature is lower than the melting point of the drug, the heating temperature is the drug. When the heating temperature is higher than the melting point of the drug so as to be 50 ° C. or more lower than the melting point of the drug, the crystalline drug nano is kneaded by heating so that the heating temperature is 10 ° C. or more higher than the melting point of the drug. We found that particles were obtained. The lower limit of the mixing ratio of the drug was 15% by mass when the heating temperature was lower than the melting point of the drug, and 20% by mass when the heating temperature was higher than the melting point of the drug. Furthermore, it has been found that when a surfactant is added to the mixture, nanoparticle formation is further promoted and the dispersion stability of the obtained nanoparticles during use is excellent.
すなわち、本発明は以下に示す事項により特定されるものである。
（１）結晶質薬物と水溶性高分子を、前記薬物が前記薬物及び前記水溶性高分子の合計に対して１５〜４０質量％となるように混合した混合物を、前記薬物の融点より５０℃以上低い温度で加熱し、混練することを特徴とする結晶質薬物ナノ粒子の製造方法。
（２）結晶質薬物と水溶性高分子を、前記薬物が前記薬物及び前記水溶性高分子の合計に対して２０〜４０質量％となるように混合した混合物を、前記薬物の融点より１０℃以上高い温度で加熱し、混練することを特徴とする結晶質薬物ナノ粒子の製造方法。
（３）混合物が、界面活性剤をさらに含むことを特徴とする上記（１）又は（２）記載の結晶質薬物ナノ粒子の製造方法。
（４）混合物における界面活性剤の含有量が、薬物、水溶性高分子及び前記界面活性剤の合計に対して５質量％以上であることを特徴とする上記（１）〜（３）のいずれか記載の結晶質薬物ナノ粒子の製造方法。
（５）混合物を加熱し、混練した後、前記混合物を水中に投入することを特徴とする上記（１）〜（４）のいずれか記載の結晶質薬物ナノ粒子の製造方法。
（６）結晶質薬物及び水溶性高分子の混合物を加熱し、混練することにより前記結晶質薬物を結晶質ナノ粒子にする方法であって、前記混合物における前記薬物の含有量が前記薬物及び前記水溶性高分子の合計に対して１５〜４０質量％であり、加熱温度が前記薬物の融点より５０℃以上低い温度である、又は前記混合物における前記薬物の含有量が前記薬物及び前記水溶性高分子の合計に対して２０〜４０質量％であり、加熱温度が前記薬物の融点より１０℃以上高い温度であることを特徴とする結晶質薬物のナノ粒子化方法。That is, the present invention is specified by the following matters.
(1) A mixture of a crystalline drug and a water-soluble polymer so that the drug is 15 to 40% by mass based on the total of the drug and the water-soluble polymer is 50 ° C. from the melting point of the drug. A method for producing crystalline drug nanoparticles, which comprises heating at a lower temperature and kneading.
(2) A mixture of a crystalline drug and a water-soluble polymer so that the drug is 20 to 40% by mass based on the total of the drug and the water-soluble polymer is 10 ° C. from the melting point of the drug. A method for producing crystalline drug nanoparticles, which comprises heating at a higher temperature and kneading.
(3) The method for producing crystalline drug nanoparticles according to (1) or (2) above, wherein the mixture further contains a surfactant.
(4) Any of the above (1) to (3), wherein the content of the surfactant in the mixture is 5% by mass or more based on the total of the drug, the water-soluble polymer and the surfactant. The method for producing crystalline drug nanoparticles according to the above.
(5) The method for producing crystalline drug nanoparticles according to any one of (1) to (4) above, wherein the mixture is heated and kneaded, and then the mixture is put into water.
(6) A method in which a mixture of a crystalline drug and a water-soluble polymer is heated and kneaded to form the crystalline drug into crystalline nanoparticles, wherein the content of the drug in the mixture is the drug and the said. It is 15-40% by mass based on the total amount of the water-soluble polymer, the heating temperature is 50 ° C. or more lower than the melting point of the drug, or the content of the drug in the mixture is the drug and the water-soluble high. A method for producing nanoparticles of a crystalline drug, which is 20 to 40% by mass based on the total amount of molecules, and the heating temperature is 10 ° C. or higher higher than the melting point of the drug.
本発明の結晶質薬物ナノ粒子の製造方法は、乾燥工程や有機溶媒が不要で、簡易に連続的に結晶質の薬物ナノ粒子を製造できる。また、本発明の結晶質薬物のナノ粒子化方法は、乾燥工程や有機溶媒が不要で、簡易に連続的に結晶質薬物をナノ粒子化できる。 The method for producing crystalline drug nanoparticles of the present invention does not require a drying step or an organic solvent, and can easily and continuously produce crystalline drug nanoparticles. Further, the method for making a crystalline drug into nanoparticles of the present invention does not require a drying step or an organic solvent, and can easily and continuously make a crystalline drug into nanoparticles.
本発明の結晶質薬物ナノ粒子の製造方法は、結晶質薬物と水溶性高分子を、前記薬物が前記薬物及び前記水溶性高分子の合計に対して１５〜４０質量％となるように混合した混合物を、前記薬物の融点より５０℃以上低い温度で加熱し、混練することを特徴とする。また、本発明の結晶質薬物ナノ粒子の製造方法は、結晶質薬物と水溶性高分子を、前記薬物が前記薬物及び前記水溶性高分子の合計に対して２０〜４０質量％となるように混合した混合物を、前記薬物の融点より１０℃以上高い温度で加熱し、混練することを特徴とする。本発明における結晶質薬物としては、特に限定されるものではないが、例えば、難水溶性薬物を挙げることができる。難水溶性薬物とは、日本薬局方に規定される「やや溶けにくい」「溶けにくい」「極めて溶けにくい」「ほとんど溶けない」に分類される薬物をいう。結晶質薬物と水溶性高分子の混合物を混練する場合、水溶性高分子を混練可能な程度に軟化させる必要があるので、薬物の融点より５０℃以上低い温度で加熱しながら混練する場合は、水溶性高分子が軟化する温度を確保する観点から、例えば、アプレピタント、ピロキシカム、レセルピン、フェニトイン、グリセオフルビン、ニフェジピン、フロセミド、インドメタシン、グリベンクラミド、ニトラゼパム、メフェナム酸、カルバマゼピン、ヒドロコルチゾン、ヒドロクロロチアジド、プレドニゾロン、べラパミル、シロリムス、ジルチアゼム、テオフィリン、ナプロキセン等の融点が１５０℃以上である薬物を挙げることができる。また、薬物の融点より１０℃以上高い温度で加熱し、混練する場合は、高温になり過ぎないようにする観点から、例えば、イブプロフェン、ケトプロフェン、フェノフィブラート、エトフィブラート、ゲムフィブロジム、フェニルブタゾン、トルナフタート、リドカイン、ナブメトン等の融点が１１０℃以下である薬物を挙げることができる。
In the method for producing crystalline drug nanoparticles of the present invention, a crystalline drug and a water-soluble polymer are mixed so that the drug is 15 to 40% by mass based on the total of the drug and the water-soluble polymer. The mixture is heated at a
本発明における水溶性高分子としては、特に限定されるものではないが、例えば、メチルセルロース、エチルセルロース、ヒドロキシメチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロース、ポリビニルアルコール、ポリビニルピロリドン、デキストリン等を挙げることができる。これらの中でも、製剤添加剤として広く用いられており、安価であるという観点から、ヒドロキシプロピルセルロース、ポリビニルピロリドン、ヒドロキシプロピルメチルセルロースを好適に例示することができる。 The water-soluble polymer in the present invention is not particularly limited, but for example, methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, dextrin and the like. Can be mentioned. Among these, hydroxypropyl cellulose, polyvinylpyrrolidone, and hydroxypropyl methyl cellulose can be preferably exemplified from the viewpoint that they are widely used as pharmaceutical additives and are inexpensive.
本発明の製造方法では、結晶質薬物と水溶性高分子の混合物を、結晶質薬物の融点より５０℃以上低い温度で加熱し、混練する場合は、結晶質薬物が結晶質薬物と水溶性高分子の合計に対して１５〜４０質量％となるように、結晶質薬物と水溶性高分子とを混合する。得られる粒子径の観点から、結晶質薬物の混合割合は、２５〜３５質量％が好ましい。また、結晶質薬物と水溶性高分子の混合物を、結晶質薬物の融点より１０℃以上高い温度で加熱し、混練する場合は、結晶質薬物が結晶質薬物と水溶性高分子の合計に対して２０〜４０質量％となるように、結晶質薬物と水溶性高分子とを混合する。得られる粒子径の観点から、結晶質薬物の混合割合は、２５〜３５質量％が好ましい。
In the production method of the present invention, when a mixture of a crystalline drug and a water-soluble polymer is heated at a
本発明の製造方法では、結晶質薬物と水溶性高分子の混合物を、結晶質薬物の融点より低い温度で加熱し、混練する場合は、結晶質薬物の融点より５０℃以上低い温度で加熱する。加熱温度の下限は、使用する水溶性高分子が混練可能な程度に軟化する温度以上であれば特に限定されるものではない。加熱温度をかかる範囲の温度とすることにより、混練中、結晶質薬物は融解することなく結晶性を維持したまま存在し、前記混合物に加わるせん断力により結晶質薬物の粒子径が小さくなる。本発明においては、結晶質薬物と水溶性高分子を上記割合で混合することにより、混練によるせん断力が結晶質薬物に効果的に加わると考えられる。また、混練中に結晶質薬物粒子の表面部分の軟化した水溶性高分子中への溶け込みも生じていると考えられ、結晶質の薬物ナノ粒子が得られる。結晶質薬物と水溶性高分子の混合物を、結晶質薬物の融点より高い温度で加熱し、混練する場合は、結晶質薬物の融点より１０℃以上高い温度で加熱する。加熱温度の上限は、使用する薬物が分解しない温度であれば特に限定されるものではない。この場合、加熱温度より低い融点を有する薬物は、混練中に融解状態になると考えられ、せん断力により融解状態の薬物のドメインサイズが減少していき、ナノレベルまたは分子レベルで薬物と水溶性高分子が混和する。そして、加熱混練終了後、室温まで冷やされていく過程で、薬物はナノ結晶粒子として析出する。ここで、結晶質薬物と水溶性高分子の混合物を、結晶質薬物の融点より５０℃以上低い温度で加熱し、混練するとは、加熱により前記混合物を結晶質薬物の融点より５０℃以上低い温度とした状態で混練することをいい、前記混合物を前記温度となるように加熱しながら混練する場合、一旦加熱により前記温度とした混合物の温度を保温等により維持しながら混練する場合も含む。結晶質薬物と水溶性高分子の混合物を、結晶質薬物の融点より１０℃以上高い温度で加熱する場合も同様である。また、ナノ粒子とは、ミクロンサイズ未満の平均粒子径を有する粒子、すなわち平均粒子径が１μｍ未満の粒子のことをいう。
In the production method of the present invention, a mixture of a crystalline drug and a water-soluble polymer is heated at a temperature lower than the melting point of the crystalline drug, and when kneading, it is heated at a
本発明の製造方法における加熱混練は、本発明における混合物を所定の温度で加熱し、混練できれば、その具体的な方法は特に限定されるものではないが、例えば、一軸又は二軸のエクストリューダ（混練押出機）等の加熱溶融混練機を用いた方法を挙げることができる。エクストリューダは、混合物を加熱しながら混練できるため、加熱と混練を同時にでき、また混練時の温度調節が容易であるので好適である。中でも混練及び押出し能力の高い二軸のエクストリューダが好ましい。エクストリューダを用いる場合、結晶質薬物と水溶性高分子を本発明における混合比で混合した混合物をエクストリューダの原料供給口に投入し、エクストリューダに備えられたヒ―タで加熱しながらスクリューで混練する。投入された混合物は、スクリューにより混練されながら排出口に向かって押し出される。結晶質薬物と水溶性高分子は、予め混合したものをエクストリューダに投入してもよく、結晶質薬物と水溶性高分子を別々に投入し、混練中に本発明における混合割合となるようにしてもよい。前記混合物を本発明における温度で混練する時間及び混練力は、使用する結晶質薬物と水溶性高分子に応じて適宜選択できる。 The specific method of heat kneading in the production method of the present invention is not particularly limited as long as the mixture in the present invention can be heated at a predetermined temperature and kneaded, but for example, a uniaxial or biaxial extruder ( A method using a heat-melt kneader such as a kneading extruder) can be mentioned. Since the extractor can be kneaded while heating the mixture, heating and kneading can be performed at the same time, and the temperature can be easily controlled during kneading, which is suitable. Of these, a biaxial extender having high kneading and extrusion ability is preferable. When using an extruder, a mixture of a crystalline drug and a water-soluble polymer mixed at the mixing ratio in the present invention is put into the raw material supply port of the extruder, and is heated by a heater provided in the extruder with a screw. Knead. The charged mixture is extruded toward the discharge port while being kneaded by a screw. The crystalline drug and the water-soluble polymer may be mixed in advance into the extruder, or the crystalline drug and the water-soluble polymer may be added separately so as to have the mixing ratio in the present invention during kneading. You may. The time and kneading force for kneading the mixture at the temperature in the present invention can be appropriately selected depending on the crystalline drug to be used and the water-soluble polymer.
本発明の製造方法では、結晶質薬物と水溶性高分子の混合物は、さらに界面活性剤を含むことができる。本発明における界面活性剤としては、特に限定されるものではないが、例えば、ドデシル硫酸ナトリウム、デオキシコール酸ナトリウム等の陰イオン界面活性剤、臭化ヘキサデシルトリメチルアンモニウム、臭化ミリスチルトリメチルアンモニウム等の陽イオン界面活性剤、Tween、Span又はBrijの商品名で販売されている非イオン性界面活性剤、ポロキサマー等の非イオン性界面活性剤などを挙げることができる。この中でも、水分散時におけるナノ粒子の分散安定性を高める観点から、ドデシル硫酸ナトリウム、臭化ヘキサデシルトリメチルアンモニウム、ポロキサマーを好適に例示できる。結晶質薬物と水溶性高分子の混合物に、さらに界面活性剤を添加することにより、結晶質薬物のナノ粒子化をより促進することができ、また得られたナノ粒子の使用時の分散安定性を向上させることができる。界面活性剤の配合量は、使用する結晶質薬物と水溶性高分子の種類に応じて適宜選択することができ、特に限定されるものではないが、ナノ粒子化を促進し、得られたナノ粒子の使用時の分散安定性を向上させる観点から、結晶質薬物、水溶性高分子及び界面活性剤の合計に対して５質量％以上が好ましい。また、上限は特に制限されるものではないが、製剤化した際の毒性及び安全性の観点から４０質量％以下が好ましく、界面活性剤の配合量は、５〜４０質量％が好ましく、５〜１５質量％がより好ましい。例えば、エクストリューダを用いる場合、界面活性剤を、結晶質薬物及び水溶性高分子と予め混合して、エクストリューダに投入してもよく、結晶質薬物や水溶性高分子とは別々に投入し、混練中に３成分が本発明における混合割合となるようにしてもよい。 In the production method of the present invention, the mixture of the crystalline drug and the water-soluble polymer can further contain a surfactant. The surfactant in the present invention is not particularly limited, but for example, anionic surfactants such as sodium dodecyl sulfate and sodium deoxycholate, hexadecyltrimethylammonium bromide, myristyltrimethylammonium bromide and the like. Examples thereof include cationic surfactants, nonionic surfactants sold under the trade names of Tween, Span and Brij, and nonionic surfactants such as poloxamers. Among these, sodium dodecyl sulfate, hexadecyltrimethylammonium bromide, and poloxamer can be preferably exemplified from the viewpoint of enhancing the dispersion stability of nanoparticles during water dispersion. By further adding a surfactant to the mixture of the crystalline drug and the water-soluble polymer, the formation of nanoparticles of the crystalline drug can be further promoted, and the dispersion stability of the obtained nanoparticles during use can be further promoted. Can be improved. The blending amount of the surfactant can be appropriately selected depending on the type of crystalline drug and water-soluble polymer used, and is not particularly limited, but promotes nanoparticulation and obtains nano-sized nanomolecules. From the viewpoint of improving the dispersion stability of the particles during use, 5% by mass or more is preferable with respect to the total of the crystalline drug, the water-soluble polymer and the surfactant. The upper limit is not particularly limited, but 40% by mass or less is preferable from the viewpoint of toxicity and safety when formulated, and the blending amount of the surfactant is preferably 5 to 40% by mass, and 5 to 5 by mass. 15% by mass is more preferable. For example, when an extruder is used, the surfactant may be mixed with the crystalline drug and the water-soluble polymer in advance and added to the extruder, or the surfactant may be added separately from the crystalline drug and the water-soluble polymer. , The three components may be the mixing ratio in the present invention during kneading.
本発明の製造方法では、結晶質薬物と水溶性高分子の混合物を加熱し、混練することにより、前記混合物中で結晶質薬物をナノ粒子化することができる。本発明の製造方法により製造されたナノ粒子は、水溶性高分子中に分散しているため、そのまま経口剤に加工することができる。経口剤は、服用後、崩壊し、水溶性高分子が溶けて薬物ナノ粒子が体内に分散されて吸収される。本発明の製造方法では、ナノ粒子の製造にあたり、水や有機溶媒を使用する必要がないため、本発明の製造方法で得られた薬物ナノ粒子は、経口剤に加工するために水の乾燥工程や有機溶媒の除去工程は必要としない。また、本発明では、結晶質薬物と水溶性高分子の混合物をエクストリューダ等の加熱溶融混練機に投入するだけで、結晶質薬物のナノ粒子化ができるので、簡易な工程で連続生産が可能であり、結晶質薬物ナノ粒子の大量生産が可能となる。また、結晶質薬物と水溶性高分子の混合物に界面活性剤をさらに混合することにより、水溶性高分子が溶けて薬物ナノ粒子が体内に吸収されるときの薬物ナノ粒子の分散性がよくなり、体内への吸収性が向上する。さらに、本発明の製造方法では、混合物を加熱し、混練した後、前記混合物を水中に投入することにより、混合物中の水溶性高分子を水中に溶解させ、結晶質薬物ナノ粒子を混合物から分離することができる。特に、界面活性剤を混合物中に添加すると水中での結晶質薬物ナノ粒子の分散安定性が向上するため、得られたナノ粒子を凝集させることなく分離することができる。分離した結晶質薬物ナノ粒子は、濾過、乾燥等により取り出すことができる。 In the production method of the present invention, the crystalline drug can be made into nanoparticles in the mixture by heating and kneading the mixture of the crystalline drug and the water-soluble polymer. Since the nanoparticles produced by the production method of the present invention are dispersed in the water-soluble polymer, they can be processed into oral preparations as they are. After taking the oral preparation, it disintegrates, the water-soluble polymer dissolves, and the drug nanoparticles are dispersed and absorbed in the body. Since it is not necessary to use water or an organic solvent in the production of nanoparticles in the production method of the present invention, the drug nanoparticles obtained by the production method of the present invention are subjected to a water drying step for processing into an oral preparation. And no organic solvent removal step is required. Further, in the present invention, the crystalline drug can be made into nanoparticles simply by putting the mixture of the crystalline drug and the water-soluble polymer into a heat-melt kneader such as an extruder, so that continuous production is possible with a simple process. This enables mass production of crystalline drug nanoparticles. Further, by further mixing the surfactant with the mixture of the crystalline drug and the water-soluble polymer, the dispersibility of the drug nanoparticles when the water-soluble polymer is dissolved and the drug nanoparticles are absorbed into the body is improved. , Improves absorption into the body. Further, in the production method of the present invention, the mixture is heated and kneaded, and then the mixture is put into water to dissolve the water-soluble polymer in the mixture in water and separate crystalline drug nanoparticles from the mixture. can do. In particular, when a surfactant is added to the mixture, the dispersion stability of the crystalline drug nanoparticles in water is improved, so that the obtained nanoparticles can be separated without agglomeration. The separated crystalline drug nanoparticles can be taken out by filtration, drying or the like.
以下、本発明の実施例を挙げて、本発明を具体的に説明するが、本発明の技術的範囲はこれらの例示に限定されるものではない。 Hereinafter, the present invention will be specifically described with reference to examples of the present invention, but the technical scope of the present invention is not limited to these examples.
グリベンクラミド（ＧＬＢ）、ポリビニルピロリドン（ＰＶＰ）及びドデシル硫酸ナトリウム（ＳＤＳ）を、ＧＬＢ：ＰＶＰ：ＳＤＳの質量比が３：６：１となるようにボルテックスミキサーを用いて５分間混合し、物理的混合物（Physical mixture：ＰＭ）を得た。得られたＰＭを、加熱溶融混練機（HAAKE Minilab II、Thermo scientific社製）を用いて、ＰＭの温度が９０℃となるように加熱条件を調整し、スクリュー回転数１０、２００、３５０ｒｐｍ、スループット２ｇ／ｍｉｎ、処理回数１〜３回の条件で加熱混練処理を行った。また、ＰＭの温度が１１５℃となるように加熱条件を調整し、スクリュー回転数３５０ｒｐｍ、スループット２ｇ／ｍｉｎ、処理回数３回の条件で加熱混練処理を行った。使用した加熱溶融混練機の仕様は、モーター力が０．４ｋＷ、スクリューは、円錐形、スクリュー上底の直径が５ｍｍ、スクリュー下底の直径が１４ｍｍ、長さが１０９．５ｍｍであった。調製温度９０℃及び１１５℃は、ＰＭが押出し可能な温度であった。また、温度は加熱溶融混練機の出口近くで測定した。得られたペレットをボールミル(MM400、Restch社製)を用いて５分間粉砕し、１００ｍｅｓｈの篩で篩過したものを加熱溶融混練物（Hotmelt extrudate：ＨＭＥ）とした。得られたＨＭＥを薬物濃度０．５ｍｇ／ｍｌとなるように蒸留水に分散させ、１分間回転混和を行うことによりＨＭＥ懸濁液を得た。図１に実施例１の製造工程の模式図を示す。 Glibenclamide (GLB), polyvinylpyrrolidone (PVP) and sodium dodecyl sulfate (SDS) are mixed for 5 minutes using a vortex mixer so that the mass ratio of GLB: PVP: SDS is 3: 6: 1, and the physical mixture is prepared. (Physical mixture: PM) was obtained. The obtained PM was heated and melted and kneaded (HAAKE Minilab II, manufactured by Thermo scientific) to adjust the heating conditions so that the PM temperature was 90 ° C., and the screw rotation speed was 10, 200, 350 rpm, and the throughput. The heat kneading treatment was carried out under the conditions of 2 g / min and the number of treatments to 1 to 3 times. Further, the heating conditions were adjusted so that the PM temperature was 115 ° C., and the heat kneading treatment was performed under the conditions of a screw rotation speed of 350 rpm, a throughput of 2 g / min, and a number of treatments of 3 times. The specifications of the heat-melt kneader used were a motor force of 0.4 kW, a screw having a conical shape, a screw upper base diameter of 5 mm, a screw lower base diameter of 14 mm, and a length of 109.5 mm. The preparation temperatures of 90 ° C. and 115 ° C. were temperatures at which PM could be extruded. The temperature was measured near the outlet of the heat-melt kneader. The obtained pellets were pulverized using a ball mill (MM400, manufactured by Restch) for 5 minutes, and sieved through a 100 mesh sieve to obtain a hot melt extrudate (HME). The obtained HME was dispersed in distilled water so as to have a drug concentration of 0.5 mg / ml, and the mixture was rotated and mixed for 1 minute to obtain an HME suspension. FIG. 1 shows a schematic diagram of the manufacturing process of Example 1.
フェノフィブラート（ＦＦＢ）、ポリビニルピロリドン（ＰＶＰ）及びドデシル硫酸ナトリウム（ＳＤＳ）を、ＦＦＢ：ＰＶＰ：ＳＤＳの質量比が３：６：１となるようにボルテックスミキサーを用いて５分間混合し、物理的混合物（Physical mixture：ＰＭ）を得た。得られたＰＭを、加熱溶融混練機（HAAKE Minilab II、Thermo scientific社製）を用いて、ＰＭの温度が９０℃となるように加熱条件を調整し、スクリュー回転数１０、２００、３５０ｒｐｍ、スループット２ｇ／ｍｉｎ、処理回数１〜３回の条件で加熱混練処理を行った。使用した加熱溶融混練機の仕様は、モーター力が０．４ｋＷ、スクリューは、円錐形、スクリュー上底の直径が５ｍｍ、スクリュー下底の直径が１４ｍｍ、長さが１０９．５ｍｍであった。調製温度９０℃は、ＰＭが押出し可能な温度であった。また、温度は加熱溶融混練機の出口近くで測定した。得られたペレットをボールミル(MM400、Restch社製)を用いて５分間粉砕し、１００ｍｅｓｈの篩で篩過したものを加熱溶融混練物（Hot melt extrudate：ＨＭＥ）とした。得られたＨＭＥを薬物濃度０．５ｍｇ／ｍｌとなるように蒸留水に分散させ、１分間回転混和を行うことによりＨＭＥ懸濁液を得た。図１に実施例２の製造工程の模式図を示す。 Fenofibrate (FFB), polyvinylpyrrolidone (PVP) and sodium dodecyl sulfate (SDS) are physically mixed for 5 minutes using a vortex mixer so that the mass ratio of FFB: PVP: SDS is 3: 6: 1. A mixture (Physical mixture: PM) was obtained. The obtained PM was heated and melted and kneaded (HAAKE Minilab II, manufactured by Thermo scientific) to adjust the heating conditions so that the PM temperature was 90 ° C., and the screw rotation speed was 10, 200, 350 rpm, and the throughput. The heat kneading treatment was carried out under the conditions of 2 g / min and the number of treatments to 1 to 3 times. The specifications of the heat-melt kneader used were a motor force of 0.4 kW, a screw having a conical shape, a screw upper base diameter of 5 mm, a screw lower base diameter of 14 mm, and a length of 109.5 mm. The preparation temperature of 90 ° C. was a temperature at which PM could be extruded. The temperature was measured near the outlet of the heat-melt kneader. The obtained pellets were pulverized using a ball mill (MM400, manufactured by Restch) for 5 minutes, and sieved through a 100 mesh sieve to obtain a hot melt extrudate (HME). The obtained HME was dispersed in distilled water so as to have a drug concentration of 0.5 mg / ml, and the mixture was rotated and mixed for 1 minute to obtain an HME suspension. FIG. 1 shows a schematic diagram of the manufacturing process of Example 2.
［比較例１］
グリベンクラミド（ＧＬＢ）、ポリビニルピロリドン（ＰＶＰ）及びドデシル硫酸ナトリウム（ＳＤＳ）を、ＧＬＢ：ＰＶＰ：ＳＤＳの質量比が３：６：１となるようにボルテックスミキサーを用いて５分間混合し、物理的混合物（Physical mixture：ＰＭ）を得た。得られたＰＭを、ボールミル(MM400、Restch社製)を用いて５分間粉砕し、１００ｍｅｓｈの篩で篩過したものを粉砕混合物（Ground mixture：ＧＭ）とした。得られたＧＭを薬物濃度０．５ｍｇ／ｍｌとなるように蒸留水に分散させ、１分間回転混和を行うことによりＧＭ懸濁液を得た。図２に比較例１の製造工程の模式図を示す。[Comparative Example 1]
Glibenclamide (GLB), polyvinylpyrrolidone (PVP) and sodium dodecyl sulfate (SDS) are mixed for 5 minutes using a vortex mixer so that the mass ratio of GLB: PVP: SDS is 3: 6: 1, and the physical mixture is prepared. (Physical mixture: PM) was obtained. The obtained PM was pulverized using a ball mill (MM400, manufactured by Restch) for 5 minutes, and sieved through a 100 mesh sieve to obtain a pulverized mixture (GM). The obtained GM was dispersed in distilled water so as to have a drug concentration of 0.5 mg / ml, and the mixture was rotated and mixed for 1 minute to obtain a GM suspension. FIG. 2 shows a schematic diagram of the manufacturing process of Comparative Example 1.
［比較例２］
ＰＭの温度を１３０℃、１４０℃となるように加熱条件を調製し、スクリュー回転数を３５０ｒｐｍ、スループットを２ｇ／ｍｉｎ、処理回数を３回として、それ以外は実施例１と同じ条件で、加熱溶融混練物（ＨＭＥ）を得て、さらにＨＭＥ懸濁液を得た。[Comparative Example 2]
The heating conditions were adjusted so that the PM temperature was 130 ° C. and 140 ° C., the screw rotation speed was 350 rpm, the throughput was 2 g / min, the number of treatments was 3, and the heating was performed under the same conditions as in Example 1 except for the above conditions. A melt-kneaded product (HME) was obtained, and an HME suspension was further obtained.
［比較例３］
フェノフィブラート（ＦＦＢ）、ポリビニルピロリドン（ＰＶＰ）及びドデシル硫酸ナトリウム（ＳＤＳ）を、ＦＦＢ：ＰＶＰ：ＳＤＳの質量比が３：６：１となるようにボルテックスミキサーを用いて５分間混合し、物理的混合物（Physical mixture：ＰＭ）を得た。得られたＰＭを、ボールミル(MM400、Restch社製)を用いて５分間粉砕し、１００ｍｅｓｈの篩で篩過したものを粉砕混合物（Ground mixture：ＧＭ）とした。得られたＧＭを薬物濃度０．５ｍｇ／ｍｌとなるように蒸留水に分散させ、１分間回転混和を行うことによりＧＭ懸濁液を得た。図２に比較例３の製造工程の模式図を示す。[Comparative Example 3]
Fenofibrate (FFB), polyvinylpyrrolidone (PVP) and sodium dodecyl sulfate (SDS) are physically mixed for 5 minutes using a vortex mixer so that the mass ratio of FFB: PVP: SDS is 3: 6: 1. A mixture (Physical mixture: PM) was obtained. The obtained PM was pulverized using a ball mill (MM400, manufactured by Restch) for 5 minutes, and sieved through a 100 mesh sieve to obtain a pulverized mixture (GM). The obtained GM was dispersed in distilled water so as to have a drug concentration of 0.5 mg / ml, and the mixture was rotated and mixed for 1 minute to obtain a GM suspension. FIG. 2 shows a schematic diagram of the manufacturing process of Comparative Example 3.
実施例１において、スクリュー回転数３５０ｒｐｍ、処理回数３回の条件で得られた加熱溶融混練物中のグリベンクラミド粒子の粒度分布をＨＭＥ懸濁液を用いて測定した結果を図３に示す。粒度分布は、Nanotrac UPA−UT１５１（Microtrac社製）を使用して測定した。図３（ａ）は、水分散直後に測定した結果であり、実施例１で得られたグリベンクラミド粒子は、単峰性の粒度分布を有し、その平均粒子径は約１００ｎｍであった。図３（ｂ）は、水分散後２５℃の条件下で６時間静置保存後の測定結果であり、実施例１で得られたグリベンクラミド粒子は、６時間静置後も、粒子径に大きな変化は認められず、分散安定性が高いことが示された。また、図４は、使用したグリベンクラミド原料の電子顕微鏡画像である。使用したグリベンクラミド原料の粒子径は数十μｍ〜数百μｍであった。 FIG. 3 shows the results of measuring the particle size distribution of the glibenclamide particles in the heat-melt kneaded product obtained under the conditions of a screw rotation speed of 350 rpm and a number of treatments of 3 times in Example 1 using an HME suspension. The particle size distribution was measured using Nanotrac UPA-UT151 (manufactured by Microtrac). FIG. 3A shows the results measured immediately after the water dispersion, and the glibenclamide particles obtained in Example 1 had a monomodal particle size distribution, and the average particle size was about 100 nm. FIG. 3B shows the measurement results after standing and storing for 6 hours under the condition of 25 ° C. after water dispersion, and the glibenclamide particles obtained in Example 1 have a large particle size even after standing for 6 hours. No change was observed, indicating high dispersion stability. Further, FIG. 4 is an electron microscope image of the glibenclamide raw material used. The particle size of the glibenclamide raw material used was several tens of μm to several hundreds of μm.
また、実施例２において、スクリュー回転数３５０ｒｐｍ、処理回数３回の条件で得られた加熱溶融混練物中のフェノフィブラート粒子の粒度分布をＨＭＥ懸濁液を用いて測定した結果を図５に示す。図５（ａ）は、水分散直後に測定した結果であり、実施例２で得られたフェノフィブラート粒子は、単峰性の粒度分布を有し、その平均粒子径は約２２０ｎｍであった。図５（ｂ）は、水分散後２５℃の条件下で６時間静置保存後の測定結果であり、実施例２で得られたフェノフィブラート粒子は、６時間静置後も、粒子径に大きな変化は認められず、分散安定性が高いことが示された。また、図６は、使用したフェノフィブラート原料の電子顕微鏡画像である。使用したフェノフィブラート原料の粒子径は数μｍ〜数十μｍであった。 Further, in Example 2, the results of measuring the particle size distribution of the fenofibrate particles in the heat-melt kneaded product obtained under the conditions of a screw rotation speed of 350 rpm and a number of treatments of 3 times using an HME suspension are shown in FIG. .. FIG. 5A shows the results measured immediately after the water dispersion, and the fenofibrate particles obtained in Example 2 had a monomodal particle size distribution, and the average particle size was about 220 nm. FIG. 5B shows the measurement results after standing and storing for 6 hours under the condition of 25 ° C. after water dispersion, and the fenofibrate particles obtained in Example 2 have a particle size even after standing for 6 hours. No significant changes were observed, indicating high dispersion stability. Further, FIG. 6 is an electron microscope image of the fenofibrate raw material used. The particle size of the fenofibrate raw material used was several μm to several tens of μm.
表１は、実施例１において、調製温度９０℃で、スクリュー回転数１０ｒｐｍで処理回数１回、スクリュー回転数２００ｒｐｍで処理回数１回、スクリュー回転数２００ｒｐｍで処理回数２回、スクリュー回転数３５０ｒｐｍで処理回数１回、スクリュー回転数３５０ｒｐｍで処理回数２回、スクリュー回転数３５０ｒｐｍで処理回数３回の各条件で得られた加熱溶融混練物及び調製温度１１５℃で、スクリュー回転数３５０ｒｐｍで処理回数３回の条件で得られた加熱溶融混練物中のグリベンクラミド粒子、比較例１で得られた粉砕混合物中のグリベンクラミド粒子、並びに比較例２で得られた加熱溶融混練物中のグリベンクラミド粒子の水分散直後の平均粒子径と、６時間静置保存後の平均粒子径の測定結果を示したものである。表１に記載された平均粒子径は、各試料について３サンプルを測定し平均したものである。また、表２は、実施例１における調製温度９０℃にて調製した試料の各スクリュー回転数及び処理回数の組合せにおけるトルクと滞留時間を測定した結果である。トルクは、物体を回転させる力のことであり、試料にかかるせん断応力の目安となる。滞留時間とは、加熱溶融混練機に投入されたＰＭが加熱混練されている時間である。トルクは、加熱溶融混練機に付属されている測定器を用いて測定し、滞留時間は、一定時間内に加熱溶融混練機から排出されるペレットの質量を測定することで評価した。また、本願明細書及び図面において、スクリュー回転数と処理回数の組合せを、（スクリュー回転数［ｒｐｍ］，処理回数［回］）で表すことがある。例えば、ＨＭＥ（１０，１）は、加熱溶融混練物（ＨＭＥ）を得る条件がスクリュー回転数１０ｒｐｍ、処理回数１回であることを表す。 Table 1 shows, in Example 1, at a preparation temperature of 90 ° C., a screw rotation speed of 10 rpm and a processing number of 1 time, a screw rotation speed of 200 rpm and a processing number of 1 time, a screw rotation speed of 200 rpm and a processing number of 2 times, and a screw rotation speed of 350 rpm. Heat-melt kneaded product obtained under the conditions of 1 treatment, 2 treatments at a screw rotation speed of 350 rpm, and 3 treatments at a screw rotation speed of 350 rpm, and a preparation temperature of 115 ° C., a screw rotation speed of 350 rpm and a treatment count of 3 Immediately after water dispersion of the glibenclamid particles in the heat-melt kneaded product obtained under the same conditions, the gliben clamid particles in the pulverized mixture obtained in Comparative Example 1, and the gliben clamid particles in the heat-melt kneaded product obtained in Comparative Example 2. The measurement results of the average particle size of the above and the average particle size after being stored for 6 hours are shown. The average particle size shown in Table 1 is the average of 3 samples measured for each sample. Table 2 shows the results of measuring the torque and the residence time in the combination of each screw rotation speed and the number of treatments of the sample prepared at the preparation temperature of 90 ° C. in Example 1. Torque is a force that rotates an object and is a measure of shear stress applied to a sample. The residence time is the time during which the PM charged into the heat-melt kneader is heat-kneaded. The torque was measured using a measuring instrument attached to the heat-melt kneader, and the residence time was evaluated by measuring the mass of pellets discharged from the heat-melt kneader within a certain period of time. Further, in the specification and drawings of the present application, the combination of the screw rotation speed and the processing number may be represented by (screw rotation speed [rpm], processing number [times]). For example, HME (10, 1) indicates that the conditions for obtaining the heat-melt kneaded product (HME) are a screw rotation speed of 10 rpm and a number of treatments of 1.
表１の結果から、実施例１で得られた加熱溶融混練物（ＨＭＥ）中のグリベンクラミド粒子は、いずれも平均粒子径が５００ｎｍ以下であり、ナノ粒子が得られていた。また、６時間静置後も、粒子径に大きな変化は認められず、分散安定性が高いことが示された。一方、比較例１で得られた粉砕混合物（ＧＭ）は、平均粒子径が３μｍを超えていた。また、比較例２で得られたグリベンクラミド粒子は、分散直後は平均粒子径が５００ｎｍ以下であったが、６時間静置したものは沈殿が生じていた。表２の結果からは、スクリュー回転数の増加によりトルク値が増加することが認められた。また、ＨＭＥ(１０,１)、ＨＭＥ(２００,２)およびＨＭＥ(３５０,３)では、滞留時間は約５分と同等の値を示した。表１において、滞留時間が等しい、ＨＭＥ(１０,１)、ＨＭＥ(２００,２)およびＨＭＥ(３５０,３)の結果を比べると、スクリュー回転数が増加するにつれ、得られるナノ粒子の粒子径が小さくなっている。これは、スクリュー回転数の増加に伴い、加熱混練中のせん断力が増加し、薬物の粒子サイズが小さくなったと考えられる。また、表１において、スクリュー回転数が等しい、ＨＭＥ(３５０,１)、ＨＭＥ(３５０,２)およびＨＭＥ(３５０,３)の結果を比べると、滞留時間が増加するにつれ、得られるナノ粒子の粒子径が小さくなった。このことから、加熱混練中に徐々に薬物の粒子サイズが小さくなったことがわかる。 From the results in Table 1, all the glibenclamide particles in the heat-melt kneaded product (HME) obtained in Example 1 had an average particle size of 500 nm or less, and nanoparticles were obtained. In addition, no significant change was observed in the particle size even after standing for 6 hours, indicating that the dispersion stability was high. On the other hand, the pulverized mixture (GM) obtained in Comparative Example 1 had an average particle size of more than 3 μm. The glibenclamide particles obtained in Comparative Example 2 had an average particle size of 500 nm or less immediately after dispersion, but those left to stand for 6 hours had precipitation. From the results in Table 2, it was confirmed that the torque value increased as the screw rotation speed increased. Further, in HME (10,1), HME (200,2) and HME (350,3), the residence time showed a value equivalent to about 5 minutes. Comparing the results of HME (10,1), HME (200,2) and HME (350,3) with the same residence time in Table 1, the particle size of the obtained nanoparticles increases as the screw rotation speed increases. Is getting smaller. It is considered that this is because the shearing force during heat kneading increased and the particle size of the drug decreased as the screw rotation speed increased. Further, in Table 1, comparing the results of HME (350,1), HME (350,2) and HME (350,3) having the same screw rotation speed, as the residence time increases, the obtained nanoparticles The particle size has become smaller. From this, it can be seen that the particle size of the drug gradually decreased during heat kneading.
表３は、実施例２で、スクリュー回転数１０ｒｐｍで処理回数１回、スクリュー回転数２００ｒｐｍで処理回数１回、スクリュー回転数２００ｒｐｍで処理回数２回、スクリュー回転数３５０ｒｐｍで処理回数１回、スクリュー回転数３５０ｒｐｍで処理回数２回、スクリュー回転数３５０ｒｐｍで処理回数３回の各条件で得られた加熱溶融混練物中のフェノフィブラート粒子、及び比較例３で得られた粉砕混合物中のフェノフィブラート粒子の水分散直後の平均粒子径と、６時間静置保存後の平均粒子径の測定結果を示す。表３に記載された平均粒子径は、各試料について３サンプルを測定し平均したものである。また、表４は、実施例２における上記各スクリュー回転数及び処理回数の組合せにおけるトルクと滞留時間を測定した結果である。トルクと滞留時間の測定は実施例１の場合と同様に行った。 Table 3 shows Example 2, in which the screw rotation speed is 10 rpm and the processing number is 1 time, the screw rotation speed is 200 rpm and the processing number is 1 time, the screw rotation speed is 200 rpm and the processing number is 2 times, and the screw rotation speed is 350 rpm and the processing number is 1 time. Phenofibrate particles in the heat-melt kneaded product obtained under the conditions of two treatments at a rotation speed of 350 rpm and three treatments at a screw rotation speed of 350 rpm, and phenofibrate particles in the pulverized mixture obtained in Comparative Example 3. The measurement results of the average particle size immediately after the water dispersion and the average particle size after standing storage for 6 hours are shown. The average particle size shown in Table 3 is the average of 3 samples measured for each sample. Further, Table 4 shows the results of measuring the torque and the residence time in the combination of the screw rotation speed and the processing number in the second embodiment. The torque and residence time were measured in the same manner as in Example 1.
表３の結果から、実施例２で得られた加熱溶融混練物（ＨＭＥ）中のフェノフィブラート粒子は、いずれも平均粒子径が２５０ｎｍ以下であり、ナノ粒子が得られていた。また、６時間静置後も、粒子径に大きな変化は認められず、分散安定性が高いことが示された。一方、比較例３で得られた粉砕混合物（ＧＭ）は、平均粒子径が３μｍを超えていた。
表４の結果からは、スクリュー回転数の増加によりトルク値が増加することが認められた。また、ＨＭＥ(１０,１)、ＨＭＥ(２００,２)およびＨＭＥ(３５０,３)では、滞留時間は約５分と同等の値を示した。表３において、滞留時間が等しい、ＨＭＥ(１０,１)、ＨＭＥ(２００,２)およびＨＭＥ(３５０,３)の結果を比べると、得られるナノ粒子の粒子径のスクリュー回転数による変化はみられなかった。また、表１において、スクリュー回転数が等しい、ＨＭＥ(３５０,１)、ＨＭＥ(３５０,２)およびＨＭＥ(３５０,３)の結果を比べると、得られるナノ粒子の粒子径の滞留時間による変化はみられなかった。これは、実施例２の場合は、加熱混練中において、融解したフェノフィブラートはせん断力により軟化した水溶性高分子とナノサイズまたは分子レベルで混和するためと考えられる。 From the results in Table 3, the fenofibrate particles in the heat-melt kneaded product (HME) obtained in Example 2 all had an average particle size of 250 nm or less, and nanoparticles were obtained. In addition, no significant change was observed in the particle size even after standing for 6 hours, indicating that the dispersion stability was high. On the other hand, the pulverized mixture (GM) obtained in Comparative Example 3 had an average particle size of more than 3 μm.
From the results in Table 4, it was confirmed that the torque value increased as the screw rotation speed increased. Further, in HME (10,1), HME (200,2) and HME (350,3), the residence time showed a value equivalent to about 5 minutes. In Table 3, when the results of HME (10,1), HME (200,2) and HME (350,3) with the same residence time are compared, the change in the particle size of the obtained nanoparticles due to the screw rotation speed is observed. I couldn't. Further, in Table 1, when the results of HME (350,1), HME (350,2) and HME (350,3) having the same screw rotation speed are compared, the change due to the residence time of the particle size of the obtained nanoparticles is compared. It was not seen. It is considered that this is because, in the case of Example 2, the melted fenofibrate is mixed with the water-soluble polymer softened by the shearing force at the nano-sized or molecular level during the heat kneading.
図７は、実施例１に関して行ったＸ線回折測定の結果である。図中（ａ）は原料として使用したグリベンクラミド、（ｂ）はポリビニルピロリドン（ＰＶＰ）、（ｃ）はドデシル硫酸ナトリウム（ＳＤＳ）、（ｄ）は途中で得られる物理的混合物（ＰＭ）、（ｅ）は比較例１で得られた粉砕混合物（ＧＭ）、（ｆ）〜（ｋ）は、実施例１で得られたグリベンクラミド粒子を含む加熱溶融混練物（ＧＬＢ ＨＭＥ）であり、スクリュー回転数及び処理回数は、（ｆ）が（１０，１）、（ｇ）が（２００，１）、（ｈ）が（２００，２）、（ｉ）が（３５０，１）、（ｊ）が（３５０，２）、（ｋ）が（３５０，３）である。（ａ）における２θ＝１１．７２°、１９．１６°は、グリベンクラミドの結晶に特徴的なピークである。実施例１で得られた（ｆ）〜（ｋ）においても同様のピークが認められることから、実施例１で得られた加熱溶融混練物中のグリベンクラミド粒子は結晶質であることがわかる。 FIG. 7 is the result of the X-ray diffraction measurement performed for Example 1. In the figure, (a) is glibenclamide used as a raw material, (b) is polyvinylpyrrolidone (PVP), (c) is sodium dodecyl sulfate (SDS), and (d) is a physical mixture (PM) obtained on the way, (e). ) Is the pulverized mixture (GM) obtained in Comparative Example 1, and (f) to (k) are the heat-melt kneaded product (GLB HME) containing the glibenclamide particles obtained in Example 1. The number of processes is (f) for (10,1), (g) for (200,1), (h) for (200,2), (i) for (350,1), and (j) for (350). , 2), (k) is (350,3). 2θ = 11.72 ° and 19.16 ° in (a) are peaks characteristic of glibenclamide crystals. Since the same peaks are observed in (f) to (k) obtained in Example 1, it can be seen that the glibenclamide particles in the heat-melt kneaded product obtained in Example 1 are crystalline.
図８は、実施例２に関して行ったＸ線回折測定の結果である。図中（ｌ）は原料として使用したフェノフィブラート、（ｍ）はポリビニルピロリドン（ＰＶＰ）、（ｎ）はドデシル硫酸ナトリウム（ＳＤＳ）、（ｏ）は途中で得られる物理的混合物（ＰＭ）、（ｐ）は比較例３で得られた粉砕混合物（ＧＭ）、（ｑ）〜（ｖ）は、実施例２で得られたフェノフィブラート粒子を含む加熱溶融混練物（ＦＦＢ ＨＭＥ）であり、スクリュー回転数及び処理回数は、（ｑ）が（１０，１）、（ｒ）が（２００，１）、（ｓ）が（２００，２）、（ｔ）が（３５０，１）、（ｕ）が（３５０，２）、（ｖ）が（３５０，３）である。（ｌ）における２θ＝１４．４８°、１６．２４°は、フェノフィブラートの結晶に特徴的なピークである。実施例２で得られた（ｑ）〜（ｖ）においても同様のピークが認められることから、実施例２で得られた加熱溶融混練物中のフェノフィブラート粒子は結晶質であることがわかる。 FIG. 8 is the result of the X-ray diffraction measurement performed for Example 2. In the figure, (l) is fenofibrate used as a raw material, (m) is polyvinylpyrrolidone (PVP), (n) is sodium dodecyl sulfate (SDS), and (o) is a physical mixture (PM) obtained on the way. p) is the pulverized mixture (GM) obtained in Comparative Example 3, and (q) to (v) are the heat-melt kneaded product (FFB HME) containing the fenofibrate particles obtained in Example 2, and the screw rotation The number and number of processes are (q) for (10,1), (r) for (200,1), (s) for (200,2), (t) for (350,1), and (u). (350,2) and (v) are (350,3). 2θ = 14.48 ° and 16.24 ° in (l) are peaks characteristic of fenofibrate crystals. Since the same peaks are observed in (q) to (v) obtained in Example 2, it can be seen that the fenofibrate particles in the heat-melt kneaded product obtained in Example 2 are crystalline.
図１０は、実施例１で調製温度９０℃、スクリュー回転数３５０ｒｐｍ、処理回数３回で得られたグリベンクラミド（ＧＬＢ）粒子を含む加熱溶融混練物（ＧＬＢ ＨＭＥ）、及び実施例２でスクリュー回転数３５０ｒｐｍ、処理回数３回で得られたフェノフィブラート（ＦＦＢ）粒子を含む加熱溶融混練物（ＦＦＢ ＨＭＥ）のそれぞれのＨＭＥ懸濁液を凍結乾燥させた（図９）試料のＸ線回折測定の結果である。図中（ａ）は原料として使用したグリベンクラミド（ＧＬＢ）、（ｂ）はポリビニルピロリドン（ＰＶＰ）、（ｃ）はドデシル硫酸ナトリウム（ＳＤＳ）、（ｄ）は途中で得られる物理的混合物（ＰＭ）、（ｅ）はＧＬＢ ＨＭＥのＨＭＥ懸濁液を凍結乾燥させた試料、（ｆ）は原料として使用したフェノフィブラート（ＦＦＢ）、（ｇ）はポリビニルピロリドン（ＰＶＰ）、（ｈ）はドデシル硫酸ナトリウム（ＳＤＳ）、（ｉ）は途中で得られる物理的混合物（ＰＭ）、（ｊ）はＦＦＢ ＨＭＥのＨＭＥ懸濁液を凍結乾燥させた試料のＸ線回折測定の結果である。（ｅ）における２θ＝１１．７２°、１９．１６°はグリベンクラミドの結晶に特徴的なピークであり、（ｊ）における２θ＝１４．４８°、１６．２４°はフェノフィブラートの結晶に特徴的なピークである。この結果から、実施例１で得られたグリベンクラミド（ＧＬＢ）粒子及び実施例２で得られたフェノフィブラート（ＦＦＢ）粒子は、蒸留水中においても結晶質であることがわかる。 FIG. 10 shows a heat-melt kneaded product (GLB HME) containing Glybenclamid (GLB) particles obtained in Example 1 at a preparation temperature of 90 ° C., a screw rotation speed of 350 rpm, and three treatments, and a screw rotation speed in Example 2. Each HME suspension of the heat-melt kneaded product (FFB HME) containing fenofibrate (FFB) particles obtained at 350 rpm and three treatments was freeze-dried (Fig. 9). Results of X-ray diffraction measurement of the sample. Is. In the figure, (a) is glibenclamid (GLB) used as a raw material, (b) is polyvinylpyrrolidone (PVP), (c) is sodium dodecyl sulfate (SDS), and (d) is a physical mixture (PM) obtained on the way. , (E) is a sample obtained by freeze-drying an HME suspension of GLB HME, (f) is phenofibrate (FFB) used as a raw material, (g) is polyvinylpyrrolidone (PVP), and (h) is sodium dodecyl sulfate. (SDS) and (i) are the results of the physical mixture (PM) obtained on the way, and (j) are the results of X-ray diffraction measurement of the sample obtained by freeze-drying the HME suspension of FFB HME. 2θ = 11.72 ° and 19.16 ° in (e) are characteristic peaks of glibenclamide crystals, and 2θ = 14.48 ° and 16.24 ° in (j) are characteristic of fenofibrate crystals. Peak. From this result, it can be seen that the glibenclamide (GLB) particles obtained in Example 1 and the fenofibrate (FFB) particles obtained in Example 2 are crystalline even in distilled water.
図１１に、実施例１及び２で使用した各成分単独及び３成分混合物の示差走査熱量分析（ＤＳＣ）測定結果を示す。図中、（ａ）はグリベンクラミド、（ｂ）はフェノフィブラート、（ｃ）はポリビニルピロリドン、（ｄ）はドデシル硫酸ナトリウム、（ｅ）は、グリベンクラミド、ポリビニルピロリドン及びドデシル硫酸ナトリウムの物理的混合物（ＰＭ）、（ｆ）は、フェノフィブラート、ポリビニルピロリドン及びドデシル硫酸ナトリウムの物理的混合物（ＰＭ）の結果である。（ａ）の１７０℃付近のピークは、グリベンクラミドの融解に由来するピークであり、（ｂ）の７９℃付近のピークは、フェノフィブラートの融解に由来するピークである。したがって、グリベンクラミドの融点は１７０℃であり、フェノフィブラートの融点は７９℃であることがわかる。実施例１では、加熱温度がグリベンクラミドの融点より５０℃以上低いため、加熱混練中にグリベンクラミドは融解せずに結晶状態を維持していると考えられ、実施例２では、加熱温度がフェノフィブラートの融点より１０℃以上高いため、加熱混練中にフェノフィブラートは一度融解すると考えられる。 FIG. 11 shows the differential scanning calorimetry (DSC) measurement results of each component alone and a mixture of three components used in Examples 1 and 2. In the figure, (a) is glibenclamide, (b) is fenofibrate, (c) is polyvinylpyrrolidone, (d) is sodium dodecyl sulfate, and (e) is a physical mixture of glibenclamide, polyvinylpyrrolidone and sodium dodecyl sulfate (PM). ), (F) are the results of a physical mixture (PM) of fenofibrate, polyvinylpyrrolidone and sodium dodecyl sulfate. The peak near 170 ° C. in (a) is a peak derived from the melting of glibenclamide, and the peak near 79 ° C. in (b) is a peak derived from the melting of fenofibrate. Therefore, it can be seen that the melting point of glibenclamide is 170 ° C. and the melting point of fenofibrate is 79 ° C. In Example 1, since the heating temperature is 50 ° C. or more lower than the melting point of glibenclamide, it is considered that glibenclamide does not melt during heat kneading and maintains a crystalline state. In Example 2, the heating temperature is phenofibrate. Since it is more than 10 ° C. higher than the melting point, it is considered that the phenofibrate melts once during heat kneading.
以下の表５の配合、スクリュー回転数、処理回数及び処理温度で、実施例１と同様に加熱溶融混練物を作製した。得られた加熱溶融混練物中の薬物粒子の平均粒子径は、表５のとおりであった。表５において、ＭＦＡはメフェナム酸、ＩＭＣはインドメタシンを表す。メフェナム酸の融点は２３０℃であり、インドメタシンの融点は１６０℃である。また、ＨＰＣはヒドロキシプロピルセルロースを表し、Ｐｏｌｏｘａｍｅｒ（ポロキサマー）及びＣＴＡＢ（臭化ヘキサデシルトリメチルアンモニウム）は界面活性剤である。 A heat-melt kneaded product was prepared in the same manner as in Example 1 with the formulations shown in Table 5 below, the screw rotation speed, the number of treatments, and the treatment temperature. The average particle size of the drug particles in the obtained heat-melt kneaded product is as shown in Table 5. In Table 5, MFA stands for mefenamic acid and IMC stands for indomethacin. Mefenamic acid has a melting point of 230 ° C and indomethacin has a melting point of 160 ° C. In addition, HPC represents hydroxypropyl cellulose, and Poloxamer and CTAB (hexadecyltrimethylammonium bromide) are surfactants.
［比較例４］
以下の表６の配合、スクリュー回転数、処理回数及び処理温度で、実施例１と同様に加熱溶融混練物を作製した。得られた加熱溶融混練物中の薬物粒子の平均粒子径は、表６のとおりであった。[Comparative Example 4]
A heat-melt kneaded product was prepared in the same manner as in Example 1 with the formulations shown in Table 6 below, the screw rotation speed, the number of treatments, and the treatment temperature. The average particle size of the drug particles in the obtained heat-melt kneaded product is as shown in Table 6.
表５の結果から、実施例３で得られた薬物粒子の平均粒子径は２８０ｎｍ以下であり、いずれもナノ粒子であった。また、Ｘ線回折測定の結果、得られたいずれのナノ粒子も結晶質であった。比較例４のＭＦＡ／ＰＶＰ／Ｐｏｌｏｘａｍｅｒを配合した例は、加熱混練時の温度がＭＦＡの融点より低かったが、その差が４０℃しかなかったため、得られたものは非晶質であった。また、ＧＬＢ／ＰＶＰ／ＳＤＳを４：５：１で配合した例は、薬物であるＧＬＢの混合割合が、ＧＬＢとＰＶＰの合計に対して４４％であったため、得られた粒子の平均粒子径は３μｍを超え、ナノ粒子が得られなかった。ＧＬＢ／ＰＶＰ／ＳＤＳを１：８：１で配合した例は、薬物であるＧＬＢの混合割合が、ＧＬＢとＰＶＰの合計に対して１１％であったため、加熱混練時にＧＬＢが融解し非晶質となった。表１のＧＬＢ ＨＭＥ（１０，１）と表５のＧＬＢ ＨＭＥ（１０，１）とを比較すると、両者は共にＧＬＢの混合割合が、ＧＬＢとＰＶＰの合計に対して３３％であり、加熱混練時の温度が９０℃であるが、表１のＧＬＢ ＨＭＥ（１０，１）では、平均粒子径が１９８．８ｎｍであるのに対し、表５のＧＬＢ ＨＭＥ（１０，１）では、２１０ｎｍであった。これは、界面活性剤を配合したことにより、表１のＧＬＢ ＨＭＥ（１０，１）においては、ナノ粒子化がより促進されたためと考えられる。また、表５のＧＬＢ ＨＭＥ（１０，１）では、界面活性剤を用いていないため、得られた粒子を他の実施例と同様に蒸留水に分散させることはできなかった。そのため、ＳＤＳを溶解させた蒸留水中に超音波処理しながら分散させた。表５の結果はこうして分散させた粒子の平均粒子径を測定した結果である。 From the results in Table 5, the average particle size of the drug particles obtained in Example 3 was 280 nm or less, and all of them were nanoparticles. Moreover, as a result of the X-ray diffraction measurement, all the obtained nanoparticles were crystalline. In the example in which MFA / PVP / Poloxamer of Comparative Example 4 was blended, the temperature at the time of heat kneading was lower than the melting point of MFA, but the difference was only 40 ° C., so that the obtained product was amorphous. Further, in the example in which GLB / PVP / SDS was blended at a ratio of 4: 5: 1, the mixing ratio of the drug GLB was 44% with respect to the total of GLB and PVP, so that the average particle size of the obtained particles was obtained. Exceeded 3 μm, and nanoparticles were not obtained. In the example in which GLB / PVP / SDS was mixed at a ratio of 1: 8: 1, the mixing ratio of the drug GLB was 11% with respect to the total of GLB and PVP, so that GLB melted during heat kneading and was amorphous. It became. Comparing the GLB HME (10, 1) in Table 1 and the GLB HME (10, 1) in Table 5, the mixing ratio of GLB in both cases is 33% with respect to the total of GLB and PVP, and heat kneading is performed. The temperature at the time is 90 ° C., but in GLB HME (10, 1) in Table 1, the average particle size is 198.8 nm, whereas in GLB HME (10, 1) in Table 5, it is 210 nm. It was. It is considered that this is because the addition of the surfactant further promoted the nanoparticulation of GLB HME (10, 1) in Table 1. Further, in GLB HME (10, 1) in Table 5, since no surfactant was used, the obtained particles could not be dispersed in distilled water in the same manner as in other examples. Therefore, the SDS was dispersed in distilled water in which SDS was dissolved while being ultrasonically treated. The results in Table 5 are the results of measuring the average particle size of the particles dispersed in this way.
以下の表７の配合、スクリュー回転数、処理回数及び処理温度で、実施例２と同様に加熱溶融混練物を作製した。得られた加熱溶融混練物中の薬物粒子の平均粒子径は、表７のとおりであった。表７において、ＩＢＵはイブプロフェンを表し、イブプロフェンの融点は７６℃である。 A heat-melt kneaded product was prepared in the same manner as in Example 2 with the formulations shown in Table 7 below, the screw rotation speed, the number of treatments, and the treatment temperature. The average particle size of the drug particles in the obtained heat-melt kneaded product is as shown in Table 7. In Table 7, IBU represents ibuprofen, which has a melting point of 76 ° C.
［比較例５］
以下の表８の配合、スクリュー回転数、処理回数及び処理温度で、実施例２と同様に加熱溶融混練物を作製した。得られた加熱溶融混練物中の薬物粒子の平均粒子径は、表８のとおりであった。[Comparative Example 5]
A heat-melt kneaded product was prepared in the same manner as in Example 2 with the formulations shown in Table 8 below, the screw rotation speed, the number of treatments, and the treatment temperature. The average particle size of the drug particles in the obtained heat-melt kneaded product is as shown in Table 8.
表７の結果から、実施例４で得られた薬物粒子の平均粒子径は３５０ｎｍ以下であり、いずれもナノ粒子であった。また、Ｘ線回折測定の結果、得られたいずれのナノ粒子も結晶質であった。表８の結果から、比較例５のＦＦＢ／ＰＶＰ／ＳＤＳを４：５：１で配合した例は、薬物であるＦＦＢの混合割合が、ＦＦＢとＰＶＰの合計に対して４４％であったため、得られた粒子の平均粒子径は３μｍを超え、ナノ粒子が得られなかった。ＦＦＢ／ＰＶＰ／ＳＤＳを３：１５：２で配合した例は、薬物であるＦＦＢの混合割合が、ＦＦＢとＰＶＰの合計に対して１７％であったため、加熱混練時にＦＦＢが融解し非晶質となった。表３のＦＦＢＨＭＥ（１０，１）と表７のＦＦＢＨＭＥ（１０，１）とを比較すると、両者は共にＦＦＢの混合割合が、ＦＦＢとＰＶＰの合計に対して３３％であり、加熱混練時の温度が９０℃であるが、表３のＦＦＢＨＭＥ（１０，１）では、平均粒子径が２１２．５ｎｍであるのに対し、表７のＦＦＢＨＭＥ（１０，１）では、２３０ｎｍであった。これは、界面活性剤を配合したことにより、表３のＦＦＢＨＭＥ（１０，１）においては、ナノ粒子化がより促進されたためと考えられる。また、表７のＦＦＢ ＨＭＥ（１０，１）では、界面活性剤を用いていないため、得られた粒子を他の実施例と同様に蒸留水に分散させることはできなかった。そのため、ＳＤＳを溶解させた蒸留水中に超音波処理しながら分散させた。表７の結果はこうして分散させた粒子の平均粒子径を測定した結果である。 From the results in Table 7, the average particle size of the drug particles obtained in Example 4 was 350 nm or less, and all of them were nanoparticles. Moreover, as a result of the X-ray diffraction measurement, all the obtained nanoparticles were crystalline. From the results in Table 8, in the example in which FFB / PVP / SDS of Comparative Example 5 was blended at a ratio of 4: 5: 1, the mixing ratio of the drug FFB was 44% with respect to the total of FFB and PVP. The average particle size of the obtained particles exceeded 3 μm, and nanoparticles could not be obtained. In the example in which FFB / PVP / SDS was blended at a ratio of 3:15: 2, the mixing ratio of the drug FFB was 17% with respect to the total of FFB and PVP, so that the FFB melted during heat kneading and became amorphous. It became. Comparing FFBHME (10, 1) in Table 3 and FFBHME (10, 1) in Table 7, the mixing ratio of FFB in both cases was 33% of the total of FFB and PVP, and they were kneaded by heating. Although the temperature was 90 ° C., the average particle size of FFBHME (10, 1) in Table 3 was 212.5 nm, whereas that of FFBHME (10, 1) in Table 7 was 230 nm. It is considered that this is because the addition of the surfactant further promoted the nanoparticulation in FFBHME (10, 1) in Table 3. Further, in FFB HME (10, 1) in Table 7, since the surfactant was not used, the obtained particles could not be dispersed in distilled water as in the other examples. Therefore, the SDS was dispersed in distilled water in which SDS was dissolved while being ultrasonically treated. The results in Table 7 are the results of measuring the average particle size of the particles dispersed in this way.
本発明の結晶質薬物ナノ粒子の製造方法及び結晶質薬物のナノ粒子化方法は、乾燥工程や有機溶媒が不要で、簡易に連続的に結晶質薬物をナノ粒子化できるので、薬物、特に難水溶性薬物の溶解性改善技術として有用である。 The method for producing crystalline drug nanoparticles and the method for converting crystalline drugs into nanoparticles of the present invention do not require a drying step or an organic solvent, and can easily and continuously convert crystalline drugs into nanoparticles, which is particularly difficult for drugs. It is useful as a technique for improving the solubility of water-soluble drugs.
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