JP2006193462A - Percutaneous agent and oral agent using silica porous material of nanostructure as carrier - Google Patents
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本発明は、ナノ構造体シリカ多孔質材料を担体として、薬物を吸着させたことを特徴とする経皮剤及び経口剤に関し、担体への薬物の吸着性を制御できる経皮剤及び経口剤、担体からの薬物の放出性を制御できる経皮剤及び経口剤又は担体へ吸着させる薬物の選択性を制御できる経皮剤及び経口剤に関するものである。 The present invention relates to a transdermal agent and an oral preparation characterized by adsorbing a drug using a nanostructured silica porous material as a carrier, and a transdermal agent and an oral preparation capable of controlling the adsorptivity of the drug to the carrier, The present invention relates to a transdermal agent capable of controlling the release of a drug from a carrier and an oral agent or a transdermal agent capable of controlling the selectivity of a drug adsorbed on a carrier.
薬物を有効に作用させるためには、適切な量を適切な時間作用させるのが望ましい。このため、薬物の放出性を制御できる担体は好ましい。薬物を徐放性の担体に吸着させた薬剤は、一定量の薬剤を連続的に放出できる性質を有している。このような性質を持った薬剤は、皮膚を通じて薬物を伝達する経皮吸収局所作用を有する経皮剤として用いることができる。経皮剤の型としては、例えば、テープ剤、パッチ剤、貼付剤、軟膏剤が知られている。経皮剤の長所として、薬物の放出が持続的であるので、短時間に大量の薬物が皮膚に吸収されることによる副作用を軽減できることが挙げられる。Ｆｉｃｋの法則より多くの量の薬物を持続的に皮膚に透過させるためには、経皮剤内の薬物の濃度を高める必要がある。現在、さまざまな経皮剤が市販されているが、経皮剤を貼付することによる皮膚刺激の問題がある。また、それらの有効薬物の経皮吸収性及び薬効持続性は十分満足できるものではなく、放出性を改善した経皮剤の開発が期待されている。 In order for the drug to act effectively, it is desirable to act at an appropriate amount for an appropriate time. For this reason, a carrier capable of controlling the drug release is preferred. A drug in which a drug is adsorbed on a sustained-release carrier has a property that a certain amount of drug can be continuously released. The drug having such properties can be used as a transdermal agent having a transdermal absorption local action for transmitting a drug through the skin. Known types of transdermal agents include, for example, tapes, patches, patches, and ointments. As an advantage of the transdermal agent, since the release of the drug is continuous, it is possible to reduce the side effects caused by the absorption of a large amount of the drug in a short time. In order to allow a larger amount of drug to penetrate the skin continuously than Fick's law, it is necessary to increase the concentration of the drug in the transdermal agent. At present, various transdermal agents are commercially available, but there is a problem of skin irritation caused by applying the transdermal agent. In addition, the transdermal absorbability and sustained efficacy of these active drugs are not fully satisfactory, and development of transdermal agents with improved release properties is expected.
一方、経口投与したとき、薬物の即効性又は持続性に欠けるために、所望の治療効果を奏し得ない薬剤もあることから、放出性を改善した薬剤は、経皮剤だけでなく、経口剤としての用途も期待される。また、経口投与した場合には、薬物が胃内で分解するために生じる、非ステロイド系薬物をはじめとする薬物の強い副作用の問題がある。このため、胃内における薬物溶出特性が改善され、薬物の放出が制御された経口剤が望まれている。 On the other hand, when administered orally, there are some drugs that do not have the desired therapeutic effect due to lack of immediate effect or persistence of the drug. The use as is expected. In addition, when administered orally, there is a problem of strong side effects of drugs such as non-steroidal drugs, which are generated due to degradation of drugs in the stomach. Therefore, an oral preparation with improved drug dissolution characteristics in the stomach and controlled drug release is desired.
これらの理由から、有効薬物の薬効持続性などで十分な効果が期待できる放出性が改善された経皮剤及び経口剤が望まれている。また。薬物の副作用の問題が生じない経皮剤及び経口剤が望まれている。薬物を含有した粉末状担体からなるシートなどが以下に開示されている。 For these reasons, a transdermal agent and an oral preparation with improved release properties that can be expected to have a sufficient effect in maintaining the efficacy of an active drug are desired. Also. There is a demand for transdermal agents and oral agents that do not cause the problem of side effects of drugs. A sheet made of a powder carrier containing a drug is disclosed below.
特許文献１には、二酸化ケイ素からなる多孔質を充填剤とした医療用シートが開示されている。しかし、シリカ微粒子同士が不規則的に集まった多孔質シリカであるため、孔同士の連結性が少なく、孔全体を有効に利用した薬物の担持および放出が困難である。 Patent Document 1 discloses a medical sheet using a porous material made of silicon dioxide as a filler. However, since it is porous silica in which silica fine particles are irregularly gathered, there is little connectivity between pores, and it is difficult to carry and release a drug that effectively uses the whole pores.
特許文献２、３、４には、規則性を有する層状シリカやゼオライトからなる化粧料シートなどが開示されている。しかし、これらの孔径は小さいため、担持させる薬物に制限が生じる。また、担体の層状型の構造特性から薬物の効果的な放出が望めない。 Patent Documents 2, 3, and 4 disclose cosmetic sheet made of regular layered silica or zeolite. However, since these pore sizes are small, there are limitations on the drug to be carried. In addition, effective release of the drug cannot be expected due to the structural characteristics of the layered type of the carrier.
1988年に黒田らが、1990年にモービル社の研究グループが界面活性剤を鋳型とし、均一な孔径を有するナノ構造体シリカ多孔質材料の合成に成功して以来、ナノ構造体シリカ多孔質材料が次々と開発された。ナノ構造体シリカ多孔質材料は、界面活性剤などを鋳型として形成した多孔質材料であって、巨大比表面積を有し、孔径がnmオーダーで均一、かつ規則的な孔構造を有することを特徴とする。 Kuroda et al. In 1988, and in 1990, a research group at Mobil succeeded in synthesizing a nanostructured silica porous material with a uniform pore size using a surfactant as a template. Were developed one after another. Nanostructured silica porous material is a porous material formed using a surfactant or the like as a template, and has a huge specific surface area, a uniform pore size in the order of nm, and a regular pore structure. And
特許文献５には、薬理活性化合物が細孔内に充填されていて、均一な孔径から構成されるメソポーラスシリカ無機材料（ナノ構造体シリカ多孔質材料）が開示されている。巨大比表面積を有するナノ構造体シリカ多孔質材料の薬理活性化合物の吸着容量は大きいと考えられるが、孔が一次元細孔に限定されていて、薬物の担体への吸着性の制御及び薬物の担体からの放出性の制御について、高い効果を望めない。 Patent Document 5 discloses a mesoporous silica inorganic material (nanostructured silica porous material) in which a pharmacologically active compound is filled in pores and has a uniform pore diameter. The adsorption capacity of the pharmacologically active compound of the nanostructured silica porous material having a huge specific surface area is considered to be large, but the pores are limited to one-dimensional pores, and control of the adsorptivity of the drug to the carrier and the drug A high effect cannot be expected for controlling the release from the carrier.
非特許文献１、２、３では、ナノ構造体シリカ多孔質材料への薬効成分の吸着性及びナノ構造体シリカ多孔質材料からの薬物の放出性について報告されているが、経皮剤及び経口剤の担体としてナノ構造体シリカ多孔質材料の有効性について検討された例はまだない。
本発明は前記従来技術の課題に鑑みなされたものであり、その目的は有効薬物の放出性を改善した経皮剤及び経口剤を提供することである。より具体的には、薬物の担体への吸着の制御が可能な経皮剤及び経口剤を提供すること、薬物の担体からの放出の制御が可能な経皮剤及び経口剤を提供することである。また、担体へ吸着した薬物の選択が可能な経皮剤及び経口剤を提供することである。より具体的には、分子径の大きな分子や難溶性薬物など幅広い薬物の担体への吸着が可能な経皮剤及び経口剤を提供することである。さらに、胃内における薬物溶出特性を改善し、所望の部位における薬物の放出を調節できる経口剤を提供することである。 The present invention has been made in view of the above-described problems of the prior art, and an object thereof is to provide a transdermal preparation and an oral preparation with improved release of an effective drug. More specifically, by providing a transdermal agent and an oral agent capable of controlling the adsorption of the drug to the carrier, and providing a transdermal agent and an oral agent capable of controlling the release of the drug from the carrier. is there. Another object is to provide a transdermal agent and an oral agent capable of selecting a drug adsorbed on a carrier. More specifically, it is to provide a transdermal agent and an oral agent capable of adsorbing a wide range of drugs such as molecules having a large molecular diameter and poorly soluble drugs on a carrier. Furthermore, it is to provide an oral preparation capable of improving the drug dissolution characteristics in the stomach and controlling the release of the drug at a desired site.
前記目的を達成するために本発明者が鋭意検討を行った結果、ナノ構造体シリカ多孔質材料の孔径、孔の構造、粒径、粒子の形状のうち少なくともいずれか１つを調節することにより、ナノ構造体シリカ多孔質材料に吸着される薬物の放出性を制御できる経皮剤及び経口剤を得られることを見出し、本発明に想到した。また、ナノ構造体シリカ多孔質材料の内外表面の化学的性質を制御することにより、薬物の吸着性を改善した経皮剤及び経口剤を得られることを見出し、本発明に想到した。さらに、必要に応じてナノ構造体シリカ多孔質材料をｐＨなどの周辺環境に応答性を有する高分子膜や大豆油などでコーティングした経口剤を用いることにより、胃内における薬物溶出特性を改善し、所望の部位における薬物の放出性を調節できる経口剤を得られることを見出し、本発明に想到した。 As a result of intensive studies by the present inventors in order to achieve the above object, by adjusting at least one of the pore size, pore structure, particle size, and particle shape of the nanostructured silica porous material The inventors have found that a transdermal agent and an oral agent capable of controlling the release of a drug adsorbed on the nanostructured silica porous material can be obtained, and the present invention has been conceived. In addition, the inventors have found that a transdermal agent and an oral agent with improved drug adsorption can be obtained by controlling the chemical properties of the inner and outer surfaces of the nanostructured silica porous material, and have arrived at the present invention. Furthermore, the drug dissolution characteristics in the stomach are improved by using an oral preparation coated with a polymer membrane that is responsive to the surrounding environment such as pH or soybean oil, if necessary. The present inventors have found that an oral preparation capable of adjusting the drug release at a desired site can be obtained, and have arrived at the present invention.
本発明の請求項１記載の経皮剤は、高分子テンプレート法で合成したナノ構造体シリカ多孔質材料を担体として、薬物を吸着させたことを特徴とする。 The transdermal agent according to claim 1 of the present invention is characterized in that a drug is adsorbed using a nanostructured silica porous material synthesized by a polymer template method as a carrier.
本発明の請求項２記載の経皮剤は、前記請求項１記載の経皮剤で、ナノ構造体シリカ多孔質材料の孔の構造を虫食い型、六方型、立方型、層状型のいずれか１つとしたことを特徴とする。 The transdermal agent according to claim 2 of the present invention is the transdermal agent according to claim 1, wherein the pore structure of the nanostructured silica porous material is any of worm-eaten type, hexagonal type, cubic type and layered type. The number is one.
本発明の請求項３記載の経皮剤は、前記請求項１又は２記載の経皮剤で、ナノ構造体シリカ多孔質材料の孔径を１ｎｍから１００ｎｍの範囲内の任意の孔径としたことを特徴とする。 The transdermal agent according to claim 3 of the present invention is the transdermal agent according to claim 1 or 2, wherein the pore size of the nanostructured silica porous material is an arbitrary pore size within a range of 1 nm to 100 nm. Features.
本発明の請求項４記載の経皮剤は、前記請求項１〜３のいずれか１項記載の経皮剤で、ナノ構造体シリカ多孔質材料の粒子の形状を球状、針状、板状、多角体状のいずれか１つとしたことを特徴とする。 The transdermal agent according to claim 4 of the present invention is the transdermal agent according to any one of claims 1 to 3, wherein the shape of the nanostructured silica porous material particles is spherical, needle-like, or plate-like. Any one of the polygonal shapes is used.
本発明の請求項５記載の経皮剤は、前記請求項１〜４のいずれか１項記載の経皮剤で、ナノ構造体シリカ多孔質材料の粒径を、その最小径が１０ｎｍ以上であり、その最大径が１ｍｍ以下である任意の粒径としたことを特徴とする。 The transdermal agent according to claim 5 of the present invention is the transdermal agent according to any one of claims 1 to 4, wherein the nanostructured silica porous material has a minimum particle size of 10 nm or more. There is a feature that the maximum diameter is an arbitrary particle diameter of 1 mm or less.
本発明の請求項６記載の経皮剤は、前記請求項１〜５のいずれか１項記載の経皮剤で、ナノ構造体シリカ多孔質材料の内外表面を疎水性分子基で修飾したことを特徴とする。 The transdermal agent according to claim 6 of the present invention is the transdermal agent according to any one of claims 1 to 5, wherein the inner and outer surfaces of the nanostructured silica porous material are modified with hydrophobic molecular groups. It is characterized by.
本発明の請求項７記載の経皮剤は、請求項６記載の経皮剤で、疎水性分子基がチオール基であることを特徴とする。 The transdermal agent according to claim 7 of the present invention is the transdermal agent according to claim 6, characterized in that the hydrophobic molecular group is a thiol group.
本発明の請求項８記載の経皮剤は、前記請求項１〜５のいずれか１項記載の経皮剤で、ナノ構造体シリカ多孔質材料の内外表面がフリーシラノール基を有することを特徴とする。 The transdermal agent according to claim 8 of the present invention is the transdermal agent according to any one of claims 1 to 5, wherein the inner and outer surfaces of the nanostructured silica porous material have a free silanol group. And
本発明の請求項９記載の経皮剤は、前記請求項１〜８のいずれか１項記載の経皮剤で、鎮痛剤、消炎剤、解熱剤、抗腫瘍剤、抗リウマチ剤、抗関節炎剤、抗炎症剤、血液循環改善剤、抗細菌剤、精神安定剤、避妊剤又は禁煙剤のいずれか１つであることを特徴とする。 The transdermal agent according to claim 9 of the present invention is the transdermal agent according to any one of claims 1 to 8, and is an analgesic agent, anti-inflammatory agent, antipyretic agent, antitumor agent, anti-rheumatic agent, anti-arthritic agent. , An anti-inflammatory agent, a blood circulation improving agent, an antibacterial agent, a tranquilizer, a contraceptive agent or a smoking cessation agent.
本発明の請求項１０記載の経皮剤は、前記請求項１〜８のいずれか１項記載の経皮剤で、前記薬物がペプチドホルモンを含む糖尿病治療薬剤であることを特徴とする。 A transdermal agent according to claim 10 of the present invention is the transdermal agent according to any one of claims 1 to 8, wherein the drug is a therapeutic agent for diabetes including peptide hormones.
本発明の請求項１１記載の経口剤は、高分子テンプレート法で合成したナノ構造体シリカ多孔質材料を担体として、薬物を吸着させたことを特徴とする。 The oral preparation according to claim 11 of the present invention is characterized in that a drug is adsorbed using a nanostructured silica porous material synthesized by a polymer template method as a carrier.
本発明の請求項１２記載の経口剤は、前記請求項１１記載の経口剤で、ナノ構造体シリカ多孔質材料の孔の構造を虫食い型、六方型、立方型、層状型のいずれか１つとしたことを特徴とする。 The oral preparation according to claim 12 of the present invention is the oral preparation according to claim 11, wherein the pore structure of the nanostructured silica porous material is any one of worm-eaten type, hexagonal type, cubic type and layered type. It is characterized by that.
本発明の請求項１３記載の経口剤は、前記請求項１１又は１２記載の経口剤で、ナノ構造体シリカ多孔質材料の孔径を１ｎｍから１００ｎｍの範囲内の任意の孔径としたことを特徴とする。 The oral preparation according to claim 13 of the present invention is the oral preparation according to claim 11 or 12, characterized in that the pore size of the nanostructured silica porous material is an arbitrary pore size within the range of 1 nm to 100 nm. To do.
本発明の請求項１４記載の経口剤は、前記請求項１１〜１３のいずれか１項記載の経口剤で、ナノ構造体シリカ多孔質材料の粒子の形状を球状、針状、板状、多角体状のいずれか１つとしたことを特徴とする。 An oral preparation according to a fourteenth aspect of the present invention is the oral preparation according to any one of the first to eleventh aspects, wherein the shape of the nanostructured silica porous material particles is spherical, needle-like, plate-like, or polygonal. One of the body shapes is characterized.
本発明の請求項１５記載の経口剤は、前記請求項１１〜１４のいずれか１項記載の経皮剤で、ナノ構造体シリカ多孔質材料の粒径を、その最小径が１０ｎｍ以上であり、その最大径が１ｍｍ以下である任意の粒径としたことを特徴とする。
本発明の請求項１６記載の経口剤は、前記請求項１１〜１５のいずれか１項記載の経口剤で、ナノ構造体シリカ多孔質材料の内外表面を疎水性分子基で修飾したことを特徴とする。
本発明の請求項１７記載の経口剤は、請求項１６記載の経口剤で、疎水性分子基がチオール基であることを特徴とする。
The oral preparation according to claim 15 of the present invention is the transdermal preparation according to any one of claims 11 to 14, wherein the nanostructure silica porous material has a particle diameter of 10 nm or more. The maximum diameter is an arbitrary particle size of 1 mm or less.
The oral preparation according to claim 16 of the present invention is the oral preparation according to any one of claims 11 to 15, wherein the inner and outer surfaces of the nanostructured silica porous material are modified with hydrophobic molecular groups. And
The oral preparation according to claim 17 of the present invention is the oral preparation according to claim 16, characterized in that the hydrophobic molecular group is a thiol group.
本発明の請求項１８記載の経口剤は、前記請求項１１〜１５のいずれか１項記載の経口剤で、ナノ構造体シリカ多孔質材料の内外表面がフリーシラノール基を有することを特徴とする。 The oral preparation according to claim 18 of the present invention is the oral preparation according to any one of claims 11 to 15, wherein the inner and outer surfaces of the nanostructured silica porous material have a free silanol group. .
本発明の請求項１９記載の経口剤は、前記請求項１１〜１８のいずれか１項記載の経口剤で、ナノ構造体シリカ多孔質材料を大豆油でコーティングしたことを特徴とする。 The oral preparation according to claim 19 of the present invention is the oral preparation according to any one of claims 11 to 18, wherein the nanostructured silica porous material is coated with soybean oil.
本発明の請求項２０記載の経口剤は、前記請求項１１〜１８のいずれか１項記載の経口剤で、ナノ構造体シリカ多孔質材料を、疎水性を有する高分子膜でコーティングしたことを特徴とする。 The oral preparation according to claim 20 of the present invention is the oral preparation according to any one of claims 11 to 18, wherein the nanostructured silica porous material is coated with a hydrophobic polymer film. Features.
本発明の請求項２１記載の経口剤は、前記請求項１１〜１８のいずれか１項記載の経口剤で、ナノ構造体シリカ多孔質材料を、グルコース応答性を有する高分子膜でコーティングしたことを特徴とする。
本発明の請求項２２記載の経口剤は、前記請求項１１〜１８のいずれか1項記載の経口剤で、ナノ構造体シリカ多孔質材料を、ｐＨ応答性を有する高分子膜でコーティングしたことを特徴とする。
The oral preparation according to claim 21 of the present invention is the oral preparation according to any one of claims 11 to 18, wherein the nanostructured silica porous material is coated with a polymer film having glucose responsiveness. It is characterized by.
The oral preparation according to claim 22 of the present invention is the oral preparation according to any one of claims 11 to 18, wherein the nanostructured silica porous material is coated with a polymer film having pH responsiveness. It is characterized by.
本発明の請求項２３記載の経口剤は、前記請求項１１〜２２のいずれか１項記載の経口剤で、薬物が鎮痛剤、消炎剤、解熱剤、抗腫瘍剤、抗リウマチ剤、抗関節炎剤、抗炎症剤、血液循環改善剤、抗細菌剤、精神安定剤、避妊剤又は禁煙剤のいずれか１つであることを特徴とする。 The oral preparation according to claim 23 of the present invention is the oral preparation according to any one of claims 11 to 22, wherein the drug is an analgesic agent, anti-inflammatory agent, antipyretic agent, antitumor agent, antirheumatic agent, antiarthritic agent. , An anti-inflammatory agent, a blood circulation improving agent, an antibacterial agent, a tranquilizer, a contraceptive agent or a smoking cessation agent.
本発明の請求項２４記載の経口剤は、前記請求項１１〜２２のいずれか１項記載の経口剤で、薬物がペプチドホルモンを含む糖尿病治療薬剤であることを特徴とする。 An oral preparation according to claim 24 of the present invention is the oral preparation according to any one of claims 11 to 22, characterized in that the drug is an antidiabetic agent containing a peptide hormone.
本発明の請求項１記載の経皮剤によれば、高分子テンプレート法で合成したナノ構造体シリカ多孔質材料は、大きな比表面積を有するため、少量のナノ構造体シリカ多孔質材料で多量の有効薬物を吸着させることができる。これにより、経皮剤中の薬物の濃度を高めて、小さい面積の貼付で有効な薬物の放出を長く持続でき、経皮剤による皮膚刺激を最小限にできる。また、高分子テンプレート法で合成したナノ構造体シリカ多孔質材料の孔は均一な孔径でかつ、連続的に繋がっているため、幅広い薬物の選択及び有効な放出性の制御が可能である。さらに、強い副作用を持つなどの理由から通常の投与が難しい薬物をナノ構造体シリカ多孔質材料へ吸着させて、必要な作用部位で放出させることにより、薬物の副作用を最小限に抑えた投与が可能である。 According to the transdermal agent according to claim 1 of the present invention, since the nanostructured silica porous material synthesized by the polymer template method has a large specific surface area, a large amount of nanostructured silica porous material is used in a small amount. Effective drugs can be adsorbed. Accordingly, the concentration of the drug in the transdermal agent can be increased, and effective release of the drug can be sustained for a long time by applying a small area, and skin irritation by the transdermal agent can be minimized. Moreover, since the pores of the nanostructured silica porous material synthesized by the polymer template method have a uniform pore diameter and are continuously connected, it is possible to select a wide range of drugs and to control the effective release properties. In addition, drugs that are difficult to administer for reasons such as having strong side effects are adsorbed to the nanostructured silica porous material and released at the required site of action, thereby minimizing drug side effects. Is possible.
本発明の請求項２記載の経皮剤によれば、薬物によって、ナノ構造体シリカ多孔質材料の孔の構造を虫食い型、六方型、立方型、層状型のいずれか１つに制御することにより、薬物がアプローチ可能な表面積を変化させて、薬物のナノ構造体シリカ多孔質材料への吸着性及び薬物のナノ構造体シリカ多孔質材料からの放出性を制御できる。また、孔が一次元又は多次元に配列するように制御することにより、薬物がアプローチ可能な表面積を変化させて、薬物のナノ構造体シリカ多孔質材料への吸着性及び薬物のナノ構造体シリカ多孔質材料からの放出性の制御が可能である。アプローチ可能な表面積を増加させることにより、薬物の担体への吸着量を増加させ、時間当たりの担体からの薬物の放出量及び放出時間を増加させることができる。 According to the transdermal agent according to claim 2 of the present invention, the structure of the pores of the nanostructured silica porous material is controlled to any one of worm-eaten type, hexagonal type, cubic type and layered type by the drug. By changing the surface area that the drug can approach, it is possible to control the adsorptivity of the drug to the nanostructured silica porous material and the release property of the drug from the nanostructured silica porous material. In addition, by controlling the pores to be arranged in one or more dimensions, the surface area that the drug can approach is changed, so that the drug adsorbs on the nanostructured silica porous material and the drug nanostructured silica. The release from the porous material can be controlled. By increasing the approachable surface area, the amount of drug adsorbed onto the carrier can be increased, and the amount of drug released from the carrier per hour and the time of release can be increased.
本発明の請求項３記載の経皮剤によれば、薬物によって、ナノ構造体シリカ多孔質材料の孔径を１ｎｍから１００ｎｍまでの範囲内の任意の孔径に制御することにより、薬物のナノ構造体シリカ多孔質材料への吸着性及び薬物のナノ構造体シリカ多孔質材料からの放出性の制御が可能である。また、ナノ構造体シリカ多孔質材料へ吸着させる薬物の選択が可能である。細孔容積を大きくすることにより、薬物の担体への吸着量を増加させ、時間当たりの担体からの放出量を増加させることができる。また、分子径の大きな薬物を吸着させるときには、薬物が孔内で適切に担体へ吸着し放出できるようにナノ構造体シリカ多孔質材料の孔径を大きくすることができる。 According to the transdermal agent according to claim 3 of the present invention, by controlling the pore diameter of the nanostructured silica porous material to an arbitrary pore diameter within a range of 1 nm to 100 nm by the drug, the drug nanostructure It is possible to control the adsorptivity to the porous silica material and the release of the drug from the nanostructured silica porous material. It is also possible to select a drug to be adsorbed on the nanostructured silica porous material. By increasing the pore volume, the amount of drug adsorbed on the carrier can be increased, and the amount of release from the carrier per hour can be increased. When adsorbing a drug having a large molecular diameter, the pore diameter of the nanostructured silica porous material can be increased so that the drug can be appropriately adsorbed and released from the carrier within the pore.
本発明の請求項４記載の経皮剤によれば、薬物によって、ナノ構造体シリカ多孔質材料の粒子の形状を球状、針状、板状、多角体状のいずれか１つに制御することにより、薬物がアプローチ可能な表面積を変化させて、薬物のナノ構造体シリカ多孔質材料への吸着性及び薬物のナノ構造体シリカ多孔質材料からの放出性を制御できる。アプローチ可能な表面積を増加させることにより、薬物の担体への吸着量を増加させ、時間当たりの担体からの薬物の放出量及び放出時間を増加させることができる。 According to the transdermal agent of claim 4 of the present invention, the shape of the nanostructured silica porous material particles is controlled to any one of a spherical shape, a needle shape, a plate shape, and a polygon shape by a drug. By changing the surface area that the drug can approach, it is possible to control the adsorptivity of the drug to the nanostructured silica porous material and the release property of the drug from the nanostructured silica porous material. By increasing the approachable surface area, the amount of drug adsorbed onto the carrier can be increased, and the amount of drug released from the carrier per hour and the time of release can be increased.
本発明の請求項５記載の経皮剤によれば、薬物によって、ナノ構造体シリカ多孔質材料の粒径を、その最小径が１０ｎｍ以上であり、その最大径が１ｍｍ以下である任意の粒径に制御することにより、薬物がアプローチ可能な表面積を変化させて、薬物のナノ構造体シリカ多孔質材料への吸着性及び薬物のナノ構造体シリカ多孔質材料からの放出性を制御できる。粒径を小さくし、薬物がアプローチ可能な表面積を増加させるとき、薬物のナノ構造体シリカ多孔質材料への吸着効率が高く、吸着量が多い。 According to the transdermal agent of claim 5 of the present invention, the particle size of the nanostructured silica porous material may be any particle having a minimum diameter of 10 nm or more and a maximum diameter of 1 mm or less depending on the drug. By controlling the diameter, the surface area that the drug can approach can be changed to control the adsorptivity of the drug to the nanostructured silica porous material and the release property of the drug from the nanostructured silica porous material. When the particle size is reduced and the surface area that the drug can approach is increased, the adsorption efficiency of the drug to the nanostructured silica porous material is high and the adsorption amount is large.
本発明の請求項２〜５記載の経皮剤によれば、薬物によって、ナノ構造体シリカ多孔質材料の孔径、孔の構造、粒径、粒子の形状のうち少なくともいずれか１つを調節することにより、薬物のナノ構造体シリカ多孔質材料への吸着性及び薬物のナノ構造体シリカ多孔質材料からの放出性を制御できる。このため、持続的に薬物を放出することが可能となり、短時間に大量の薬物が放出されることによる副作用を軽減できる。薬物の長時間にわたる作用が可能となり、一日当たりの投与回数を減らすことができる。また、短時間で薬物を放出したい場合には、放出量を制御することができる。さらに、例えば、孔径を大きくし、粒径を小さく制御することにより分子径の大きな分子を含めた幅広い薬物の効果的な吸着が可能となる。 According to the transdermal agent according to claims 2 to 5 of the present invention, at least one of the pore size, pore structure, particle size, and particle shape of the nanostructured silica porous material is adjusted by the drug. Thus, the adsorptivity of the drug to the nanostructured silica porous material and the release property of the drug from the nanostructured silica porous material can be controlled. For this reason, it becomes possible to release a drug continuously, and the side effect by releasing a large amount of drug in a short time can be reduced. The drug can act for a long time, and the number of administrations per day can be reduced. Further, when it is desired to release the drug in a short time, the release amount can be controlled. Furthermore, for example, by increasing the pore diameter and controlling the particle diameter to be small, it is possible to effectively adsorb a wide range of drugs including molecules having a large molecular diameter.
本発明の請求項６記載の経皮剤によれば、ナノ構造体シリカ多孔質材料の内外表面を疎水性分子基で修飾することにより、単純拡散による薬物の担体への吸着だけでなく、疎水性作用による薬物の担体への吸着が可能となる。これにより、難溶性薬物の吸着性を改善できる。 According to the transdermal agent described in claim 6 of the present invention, by modifying the inner and outer surfaces of the nanostructured porous silica material with hydrophobic molecular groups, not only adsorption of the drug to the carrier by simple diffusion but also hydrophobicity The drug can be adsorbed to the carrier by sexual action. Thereby, the adsorptivity of a poorly soluble drug can be improved.
本発明の請求項７記載の経皮剤によれば、ナノ構造体シリカ多孔質材料の内外表面を疎水性分子基であるチオール基で修飾することにより、単純拡散による薬物の担体への吸着だけでなく、疎水性作用による薬物の担体への吸着が可能となる。これにより、難溶性薬物の吸着性を改善できる。 According to the transdermal agent described in claim 7 of the present invention, by simply modifying the inner and outer surfaces of the nanostructured silica porous material with a thiol group that is a hydrophobic molecular group, only adsorption of the drug to the carrier by simple diffusion is performed. In addition, the drug can be adsorbed to the carrier by a hydrophobic action. Thereby, the adsorptivity of a poorly soluble drug can be improved.
本発明の請求項８記載の経皮剤によれば、ナノ構造体シリカ多孔質材料の内外表面にフリーシラノール基を新しく作り出すことにより、薬物の吸着能を上昇させることができる。これにより、薬物の吸着性を改善できる。 According to the transdermal agent described in claim 8 of the present invention, the ability to adsorb drugs can be increased by newly creating free silanol groups on the inner and outer surfaces of the nanostructured silica porous material. Thereby, the adsorptivity of the drug can be improved.
本発明の請求項９記載の経皮剤によれば、経皮剤に吸着させる薬物として、鎮痛剤、消炎剤、解熱剤、抗腫瘍剤、抗リウマチ剤、抗関節炎剤、抗炎症剤、血液循環改善剤、抗細菌剤、精神安定剤、避妊剤又は禁煙剤のいずれか１つを選択できる。 According to the transdermal agent according to claim 9 of the present invention, the analgesic agent, anti-inflammatory agent, antipyretic agent, antitumor agent, anti-rheumatic agent, anti-arthritic agent, anti-inflammatory agent, blood circulation as the drug adsorbed on the transdermal agent Any one of an improving agent, an antibacterial agent, a tranquilizer, a contraceptive agent or a smoking cessation agent can be selected.
本発明の請求項１０記載の経皮剤によれば、経皮剤に吸着させる薬物として、ペプチドホルモンを含む糖尿病治療薬剤を選択できる。 According to the transdermal agent described in claim 10 of the present invention, a drug for treating diabetes including a peptide hormone can be selected as a drug adsorbed on the transdermal agent.
本発明の請求項１１記載の経口剤によれば、高分子テンプレート法で合成したナノ構造体シリカ多孔質材料は、大きな比表面積を有するため、少量のナノ構造体シリカ多孔質材料で多量の有効薬物を吸着させることができる。また、高分子テンプレート法で合成したナノ構造体シリカ多孔質材料の孔は均一な孔径でかつ、連続的に繋がっているため、幅広い薬物の選択及び有効な放出性の制御が可能である。さらに、ナノ構造体シリカ多孔質材料は酸に強い性質を有するため、ナノ構造体シリカ多孔質材料へ吸着された薬物の胃酸での分解を防ぐことができ、薬物が効果的に腸内へ到達できる。 According to the oral preparation of claim 11 of the present invention, since the nanostructured silica porous material synthesized by the polymer template method has a large specific surface area, a small amount of nanostructured silica porous material is effective in a large amount. Drugs can be adsorbed. Moreover, since the pores of the nanostructured silica porous material synthesized by the polymer template method have a uniform pore diameter and are continuously connected, it is possible to select a wide range of drugs and to control the effective release properties. Furthermore, since the nanostructured silica porous material has acid-resistant properties, it can prevent decomposition of the drug adsorbed on the nanostructured silica porous material with gastric acid, and the drug effectively reaches the intestines. it can.
本発明の請求項１２記載の経口剤によれば、薬物によって、ナノ構造体シリカ多孔質材料の孔の構造を虫食い型、六方型、立方型、層状型のいずれか１つに制御することにより、薬物がアプローチ可能な表面積を変化させて、薬物のナノ構造体シリカ多孔質材料への吸着性及び薬物のナノ構造体シリカ多孔質材料からの放出性を制御できる。また、孔が一次元又は多次元に配列するように制御することにより、薬物がアプローチ可能な表面積を変化させて、薬物のナノ構造体シリカ多孔質材料への吸着性及び薬物のナノ構造体シリカ多孔質材料からの放出性の制御が可能である。アプローチ可能な表面積を増加させることにより、薬物の担体への吸着量を増加させ、時間当たりの担体からの薬物の放出量及び放出時間を増加させることができる。 According to the oral preparation of the twelfth aspect of the present invention, by controlling the pore structure of the nanostructured silica porous material to any one of a worm-eaten type, a hexagonal type, a cubic type, and a layered type by a drug. The surface area that the drug can approach can be changed to control the adsorption of the drug to the nanostructured silica porous material and the release of the drug from the nanostructured silica porous material. In addition, by controlling the pores to be arranged in one or more dimensions, the surface area that the drug can approach is changed, so that the drug adsorbs on the nanostructured silica porous material and the drug nanostructured silica. The release from the porous material can be controlled. By increasing the approachable surface area, the amount of drug adsorbed onto the carrier can be increased, and the amount of drug released from the carrier per hour and the time of release can be increased.
本発明の請求項１３記載の経口剤によれば、薬物によって、ナノ構造体シリカ多孔質材料の孔径を１ｎｍから１００ｎｍまでの範囲内の任意の孔径に制御することにより、薬物のナノ構造体シリカ多孔質材料への吸着性及び薬物のナノ構造体シリカ多孔質材料からの放出性の制御が可能である。また、ナノ構造体シリカ多孔質材料へ吸着させる薬物の選択が可能である。細孔容積を大きくすることにより、薬物の担体への吸着量を増加させ、時間当たりの担体からの放出量を増加させることができる。また、分子径の大きな薬物を吸着させるときには、薬物が孔内で適切に吸着し放出できるようにナノ構造体シリカ多孔質の孔径を大きくすることができる。 According to the oral preparation of claim 13 of the present invention, the nanostructure silica of the drug is controlled by controlling the pore size of the nanostructured silica porous material to an arbitrary pore size within the range of 1 nm to 100 nm. It is possible to control the adsorptivity to the porous material and the release property of the drug from the nanostructured silica porous material. It is also possible to select a drug to be adsorbed on the nanostructured silica porous material. By increasing the pore volume, the amount of drug adsorbed on the carrier can be increased, and the amount of release from the carrier per hour can be increased. In addition, when adsorbing a drug having a large molecular diameter, the pore diameter of the nanostructured silica porous material can be increased so that the drug can be appropriately adsorbed and released in the pores.
本発明の請求項１４記載の経口剤によれば、薬物によって、ナノ構造体シリカ多孔質材料の粒子の形状を球状、針状、板状、多角体状のいずれか１つに制御することにより、薬物がアプローチ可能な表面積を変化させて、薬物のナノ構造体シリカ多孔質材料への吸着性及び薬物のナノ構造体シリカ多孔質材料からの放出性を制御できる。アプローチ可能な表面積を増加させることにより、薬物の担体への吸着量を増加させ、時間当たりの担体からの薬物の放出量及び放出時間を増加させることができる。 According to the oral preparation of claim 14 of the present invention, by controlling the shape of the particles of the nanostructured silica porous material to any one of a spherical shape, a needle shape, a plate shape, and a polygon shape by a drug. The surface area that the drug can approach can be changed to control the adsorption of the drug to the nanostructured silica porous material and the release of the drug from the nanostructured silica porous material. By increasing the approachable surface area, the amount of drug adsorbed onto the carrier can be increased, and the amount of drug released from the carrier per hour and the time of release can be increased.
本発明の請求項１５記載の経口剤によれば、薬物によって、ナノ構造体シリカ多孔質材料の粒径を、その最小径が１０ｎｍ以上であり、その最大径が１ｍｍ以下である任意の粒径に制御することにより、薬物がアプローチ可能な表面積を変化させて、薬物のナノ構造体シリカ多孔質材料への吸着性及び薬物のナノ構造体シリカ多孔質材料からの放出性を制御できる。粒径を小さくし、薬物がアプローチ可能な表面積を増加させるとき、薬物のナノ構造体シリカ多孔質材料への吸着効率が高く、吸着量が多い。なお、粒径を小さくすることにより、腸内で留まる時間を伸ばすことができ、より持続的な薬物の吸収・投与が可能である。 According to the oral preparation of claim 15 of the present invention, depending on the drug, the particle diameter of the nanostructured silica porous material may be any particle diameter having a minimum diameter of 10 nm or more and a maximum diameter of 1 mm or less. Thus, the surface area that the drug can approach can be changed to control the adsorptivity of the drug to the nanostructured silica porous material and the release property of the drug from the nanostructured silica porous material. When the particle size is reduced and the surface area that the drug can approach is increased, the adsorption efficiency of the drug to the nanostructured silica porous material is high and the adsorption amount is large. In addition, by reducing the particle size, it is possible to extend the time spent in the intestine, and it is possible to absorb and administer the drug more continuously.
本発明の請求項１２〜１５記載の経口剤によれば、薬物によって、ナノ構造体シリカ多孔質材料の孔径、孔の構造、粒径、粒子の形状のうち少なくともいずれか１つを調節することにより、薬物のナノ構造体シリカ多孔質材料への吸着性及び薬物のナノ構造体シリカ多孔質材料からの放出性を制御できる。このため、持続的に薬物を放出することが可能となり、短時間に大量の薬物が放出されることによる副作用を軽減できる。薬物の長時間にわたる作用が可能となり、一日当たりの投与回数を減らすことができる。また、短時間で薬物を放出したい場合には、放出量を制御することができる。さらに、例えば、孔径を大きくし、粒径を小さく制御することにより、分子径の大きな分子を含めた幅広い薬物の効果的吸着が可能である。 According to the oral preparation of claims 12 to 15 of the present invention, the drug adjusts at least one of the pore size, pore structure, particle size, and particle shape of the nanostructured silica porous material. Thus, it is possible to control the adsorptivity of the drug to the nanostructured silica porous material and the release property of the drug from the nanostructured silica porous material. For this reason, it becomes possible to release a drug continuously, and the side effect by releasing a large amount of drug in a short time can be reduced. The drug can act for a long time, and the number of administrations per day can be reduced. Further, when it is desired to release the drug in a short time, the release amount can be controlled. Furthermore, for example, by increasing the pore diameter and controlling the particle diameter to be small, effective adsorption of a wide range of drugs including molecules having a large molecular diameter is possible.
本発明の請求項１６記載の経口剤によれば、ナノ構造体シリカ多孔質材料の内外表面を疎水性分子基で修飾することにより、単純拡散による吸着だけでなく、疎水性作用による吸着が可能となる。これにより、難溶性薬物の吸着性を改善できる。 According to the oral preparation of the sixteenth aspect of the present invention, not only adsorption by simple diffusion but also adsorption by hydrophobic action is possible by modifying the inner and outer surfaces of the nanostructured silica porous material with hydrophobic molecular groups. It becomes. Thereby, the adsorptivity of a poorly soluble drug can be improved.
本発明の請求項１７記載の経口剤によれば、ナノ構造体シリカ多孔質材料の内外表面を疎水性分子基であるチオール基で修飾することにより、単純拡散による吸着だけでなく、疎水性作用による吸着が可能となる。これにより、難溶性薬物の吸着性を改善できる。 According to the oral preparation of claim 17 of the present invention, by modifying the inner and outer surfaces of the nanostructured silica porous material with a thiol group which is a hydrophobic molecular group, not only adsorption by simple diffusion but also hydrophobic action Adsorption by is possible. Thereby, the adsorptivity of a poorly soluble drug can be improved.
本発明の請求項１８記載の経口剤によれば、ナノ構造体シリカ多孔質材料の内外表面にフリーシラノール基を新しく作り出すことにより、薬物の吸着能を上昇させることができる。これにより、薬物の吸着性を改善できる。 According to the oral preparation of claim 18 of the present invention, the ability to adsorb drugs can be increased by newly creating free silanol groups on the inner and outer surfaces of the nanostructured silica porous material. Thereby, the adsorptivity of the drug can be improved.
本発明の請求項１９記載の経口剤によれば、大豆油でコーティングすることにより、胃内での分解を防ぎ、所望の部位における薬物の放出を調節できる。 According to the oral preparation of claim 19 of the present invention, by coating with soybean oil, it is possible to prevent degradation in the stomach and regulate the release of the drug at a desired site.
本発明の請求項２０記載の経口剤によれば、疎水性を有する高分子膜でコーティングすることにより、胃内での分解を防ぎ、所望の部位における薬物の放出を調節できる。 According to the oral preparation of claim 20 of the present invention, coating with a hydrophobic polymer membrane prevents degradation in the stomach and can regulate the release of the drug at a desired site.
本発明の請求項２１記載の経口剤によれば、グルコース応答性を有する高分子膜でコーティングすることにより、インスリンなどの糖尿病治療薬剤の投与の際、糖に反応し薬剤が放出するような自発的な血糖値の制御ができ、糖尿病治療のために有効に薬物を作用させることが可能である。 According to the oral preparation of claim 21 of the present invention, by coating with a polymer film having glucose responsiveness, spontaneous administration such that the drug is released in response to sugar upon administration of a diabetes therapeutic drug such as insulin. The blood sugar level can be controlled effectively, and the drug can be effectively acted for the treatment of diabetes.
本発明の請求項２２記載の経口剤によれば、ｐＨ応答性を有する膜でコーティングすることにより、強酸性の胃内での薬物の放出を防ぎ、胃内での副作用を低減するとともに、ｐＨが塩基性や中性の部位で薬物を放出できるように調節し薬物の利用効率を上げることができる。 According to the oral preparation of claim 22 of the present invention, coating with a membrane having pH responsiveness prevents the release of a drug in a strongly acidic stomach, reduces side effects in the stomach, and reduces the pH. Can be adjusted so that the drug can be released at a basic or neutral site, and the utilization efficiency of the drug can be increased.
本発明の請求項２３記載の経口剤によれば、経口剤に吸着させる薬物として、鎮痛剤、消炎剤、解熱剤、抗腫瘍剤、抗リウマチ剤、抗関節炎剤、抗炎症剤、血液循環改善剤、抗細菌剤、精神安定剤、避妊剤又は禁煙剤のいずれか１つを選択できる。 According to the oral preparation according to claim 23 of the present invention, as a drug adsorbed on the oral preparation, an analgesic agent, an anti-inflammatory agent, an antipyretic agent, an antitumor agent, an anti-rheumatic agent, an anti-arthritic agent, an anti-inflammatory agent, a blood circulation improving agent Any one of an antibacterial agent, a tranquilizer, a contraceptive agent or a smoking cessation agent can be selected.
本発明の請求項２４記載の経口剤によれば、経口剤に吸着させる薬物として、ペプチドホルモンを含む糖尿病治療薬剤を選択できる。 According to the oral preparation of claim 24 of the present invention, as a drug adsorbed on the oral preparation, a therapeutic drug for diabetes including peptide hormone can be selected.
以下、本発明について詳細に説明する。 Hereinafter, the present invention will be described in detail.
本発明は、高分子テンプレート法で合成したナノ構造体シリカ多孔質材料を担体として、薬物を吸着させたことを特徴とする経皮剤及び経口剤に関する。高分子テンプレート法で合成したナノ構造体シリカ多孔質材料を担体として、薬物を吸着させた経皮剤及び経口剤を用いて、その孔径、孔の構造、粒径、粒子の形状、内外表面の化学的性質のうち少なくともいずれか一つを制御する。これにより、薬物の担体への吸着性、薬物の担体からの放出性及び担体へ吸着される薬物の選択性を制御できる。 The present invention relates to a transdermal agent and an oral agent characterized in that a drug is adsorbed using a nanostructured silica porous material synthesized by a polymer template method as a carrier. Using nanostructured silica porous material synthesized by polymer template method as a carrier, and using transdermal and oral preparations adsorbing drugs, its pore size, pore structure, particle size, particle shape, inner and outer surface Control at least one of the chemical properties. Thereby, the adsorptivity of the drug to the carrier, the release property of the drug from the carrier, and the selectivity of the drug adsorbed to the carrier can be controlled.
本発明でいう高分子テンプレート法は、ブロックコポリマーなどの高分子の自己組織化により形成された規則的な液晶構造を鋳型として無機物質を転写させる方法をいう。ナノ構造体シリカ多孔質材料は、高分子テンプレート法で合成したシリカ多孔質材料であり、ナノメートルオーダーの均一な孔径、巨大な比表面積、規則的な孔構造を特徴とする。ナノ構造体シリカ多孔質材料は、粒子から構成され、その粒子に多数の孔を有する。 The polymer template method in the present invention refers to a method of transferring an inorganic substance using a regular liquid crystal structure formed by self-organization of a polymer such as a block copolymer as a template. The nanostructured silica porous material is a silica porous material synthesized by a polymer template method, and is characterized by a uniform pore size of nanometer order, a huge specific surface area, and a regular pore structure. The nanostructured silica porous material is composed of particles, and the particles have a large number of pores.
本発明でいう吸着は、薬物のナノ構造体シリカ多孔質材料を担体とし、この担体への吸着をいう。本発明でいう吸収は、薬物の皮膚への吸収をいう。本発明でいう放出は、薬物を吸着したナノ構造体シリカ多孔質材料からの薬物の放出をいう。本発明でいう薬物がアプローチ可能な表面積とは、ナノ構造体シリカ多孔質材料中で、薬物が到達できる部位の表面積である。 The adsorption referred to in the present invention refers to adsorption of a drug nanostructured silica porous material on a carrier. In the present invention, absorption refers to absorption of a drug into the skin. Release according to the present invention refers to release of a drug from the nanostructured silica porous material adsorbed with the drug. The surface area that can be approached by the drug in the present invention is the surface area of the site where the drug can reach in the nanostructured silica porous material.
ナノ構造体シリカ多孔質材料の孔の構造としては、孔が規則的な配列をした六方型（Ｈｅｘａｇｏｎａｌ）、立方型（Ｃｕｂｉｃ）、層状型（Ｌａｍｅｌｌａｒ）の構造が従来から知られている。また、孔が不規則に配列し、孔が虫食い穴のようになっている虫食い型（ｗｏｒｍ ｈｏｌｅ−ｌｉｋｅ）が従来から知られている。ナノ構造体シリカ多孔質材料の孔の構造は虫食い型、六方型、立方型、層状型のいずれか１つとする。また、孔は一次元又は多次元に配列している。これらの孔の構造に関しては、例えば、「すぐに役立つ 粒子設計・加工技術」（粉体工学会 製剤と粒子設計部会）ｐ．４３７〜を参照することができる。孔の構造は、Ｘ線回折装置（ＸＲＤ）及び透過型電子顕微鏡（ＴＥＭ）で確認する。 As the pore structure of the nanostructured silica porous material, hexagonal, cubic, and lamellar structures in which the pores are regularly arranged are conventionally known. In addition, a worm-like type in which the holes are irregularly arranged and the holes are like worm-eating holes is conventionally known. The pore structure of the nanostructured silica porous material is any one of a worm-eaten type, a hexagonal type, a cubic type, and a layered type. Moreover, the holes are arranged one-dimensionally or multidimensionally. Regarding the structure of these pores, for example, “Immediately useful particle design and processing technology” (Formulation and Particle Design Subcommittee of Powder Engineering Society) p. 437- can be referred to. The structure of the hole is confirmed with an X-ray diffractometer (XRD) and a transmission electron microscope (TEM).
ナノ構造体シリカ多孔質材料の孔径は１ｎｍから１００ｎｍまでの範囲内の任意の孔径とする。ナノ構造体シリカ多孔質材料の孔径は均一な大きさを有する。孔径は、窒素吸着測定及び透過型電子顕微鏡（ＴＥＭ）で確認する。 The pore diameter of the nanostructured silica porous material is an arbitrary pore diameter within a range from 1 nm to 100 nm. The pore size of the nanostructured silica porous material has a uniform size. The pore diameter is confirmed by nitrogen adsorption measurement and a transmission electron microscope (TEM).
ナノ構造体シリカ多孔質材料の粒子の形状は球状、針状、板状、多角体状のいずれか１つとする。粒子の形状は、電界放射型走査電子顕微鏡（ＦＥ―ＳＥＭ）で確認する。 The shape of the nanostructured silica porous material particles is any one of a spherical shape, a needle shape, a plate shape, and a polygonal shape. The shape of the particles is confirmed with a field emission scanning electron microscope (FE-SEM).
ナノ構造体シリカ多孔質材料の粒径は、その最小径が１０ｎｍ以上であり、その最大径が１ｍｍ以下である任意の粒径とする。粒径は、粒子の大きさを直径であらわしたものであるが、板状などの形状は粒径が位置により異なるので、最小径と最大径を用いて表す。最小径はナノ構造体シリカ多孔質材料の粒径の最小値、最大径はナノ構造体シリカ多孔質材料の粒径の最大値を表す。粒径は電界放射型走査電子顕微鏡（ＦＥ―ＳＥＭ）で確認する。 The particle diameter of the nanostructured silica porous material is an arbitrary particle diameter having a minimum diameter of 10 nm or more and a maximum diameter of 1 mm or less. The particle size represents the size of the particle by the diameter, but the shape such as a plate shape is expressed by using the minimum diameter and the maximum diameter because the particle size varies depending on the position. The minimum diameter represents the minimum value of the particle diameter of the nanostructured silica porous material, and the maximum diameter represents the maximum value of the particle diameter of the nanostructured silica porous material. The particle size is confirmed with a field emission scanning electron microscope (FE-SEM).
「本発明のナノ構造体シリカ多孔質材料の代表的な製法」
本発明のナノ構造体シリカ多孔質材料の代表的な製法を以下に述べる。
“Representative process for producing nanostructured silica porous material of the present invention”
A typical method for producing the nanostructured silica porous material of the present invention will be described below.
高分子テンプレートとしてブロックコポリマーを用いる。本発明のナノ構造体シリカ多孔質材料の製法に用いるブロックコポリマーとしては、P１２３、F１２７、F１０８（Ａｌｄｒｉｃｈ社製品）などが挙げられる。 A block copolymer is used as the polymer template. P123, F127, F108 (Aldrich product) etc. are mentioned as a block copolymer used for the manufacturing method of the nanostructure silica porous material of this invention.
２ｇのブロックコポリマーを、ブロックポリマーの５０〜１００ｗｔ％の１、３、５−トリメチルベンゼン（ＴＭＢ）と１２０ｍｌの２M ＨＣｌを混合した溶液に８．３ｇのテトラエトキシシラン（Ｔｅｔｒａｅｔｈｏｘｙｓｉｌａｎｅ）（ＴＥＯＳ）と５ｇのＫＣｌを加え、反応液Ａとする。前記反応液Ａを４０℃で一日間強く攪拌しながら反応させる。シリカ表面にチオール基を修飾し、表面の疎水性をあげる場合には、ＴＥＯＳの代わりに、ＴＥＯＳとＭＰＴＭＳ（メルカプトプロピルトリエトキシシラン）（Ｍｅｒｃａｐｔｏｐｒｏｐｙｌｔｒｉｅｔｈｏｘｙｓｉｌａｎｅ）をＴＥＯＳ：ＭＰＴＭＳ＝１９：１（モル比）の割合で混合したものを加える。オートクレーブに一日間攪拌した前記反応液Ａを移し、１００〜１４０℃で１〜３日間熱処理を行う。ろ過又は遠心分離により沈殿を採集し、乾燥させた後、５５０℃〜６５０℃で焼成させることにより、高分子テンプレートを除去し、これをナノ構造体シリカ多孔質材料とする。 2 g of the block copolymer was mixed with 8.3 g of tetraethoxysilane (TEOS) and 5 g of a mixed solution of 50 to 100 wt% of 1,3,5-trimethylbenzene (TMB) and 120 ml of 2M HCl. To prepare a reaction solution A. The reaction solution A is reacted at 40 ° C. with vigorous stirring for one day. When thiol groups are modified on the silica surface to increase the hydrophobicity of the surface, TEOS and MPTMS (mercaptopropyltriethoxysilane) (Mercaptopropyltriethoxysilane) of TEOS: MPTMS = 19: 1 (molar ratio) are used instead of TEOS. Add the mixture in proportion. The said reaction liquid A stirred for 1 day is moved to an autoclave, and heat processing is performed at 100-140 degreeC for 1-3 days. The precipitate is collected by filtration or centrifugation, dried, and then baked at 550 ° C. to 650 ° C. to remove the polymer template, which is used as a nanostructured silica porous material.
ナノ構造体シリカ多孔質材料の孔内に吸着させる薬物の分子サイズおよび薬物の放出速度によって孔径を制御する必要がある場合は、孔径の制御は高分子テンプレートの選択及び膨張剤の投与により行う。孔経を大きくしたい場合はブロックコポリマーを、小さくしたい場合は界面活性剤を高分子テンプレートとして選択する。 When the pore size needs to be controlled by the molecular size of the drug adsorbed in the pores of the nanostructured silica porous material and the drug release rate, the pore size is controlled by selecting a polymer template and administering an expanding agent. When it is desired to increase the pore size, a block copolymer is selected as the polymer template.
ナノ構造体シリカ多孔質材料の孔の構造、粒子の形状及び粒径の制御は、前記反応液Ａについて、無機塩の添加、攪拌速度又は反応液のｐＨを制御することにより行う。例えば、無機塩の添加を制御することにより針状で１〜２μmの粒子を得ることができる。ナノ構造体シリカ多孔質材料の孔の構造、粒子の形状及び粒径の制御については、従来から知られていて、例えば、Ｃｈｅｍ．Ｍａｔｅｒ．２００４、１６、８８９−８９８又はＣｈｅｍ．Ｒｅｖ．２００２、１０２、４０９３−などを参照することができる。 The pore structure, particle shape, and particle size of the nanostructured silica porous material are controlled by controlling the addition of an inorganic salt, the stirring speed, or the pH of the reaction solution for the reaction solution A. For example, by controlling the addition of the inorganic salt, needle-like particles having a size of 1 to 2 μm can be obtained. Control of the pore structure, particle shape and particle size of the nanostructured silica porous material has been known in the art, for example, see Chem. Mater. 2004, 16, 889-898 or Chem. Rev. Reference can be made to 2002, 102, 4093- and the like.
「薬物のナノ構造体シリカ多孔質材料への吸着」
薬物のナノ構造体シリカ多孔質材料への吸着について、以下に例を述べる。薬物とシリカ表面の等電点を考慮し緩衝液を選択する。このとき、薬物とシリカ表面の電荷が反対になるように緩衝液を選択するのが好ましい。この緩衝液に薬物（０．００４〜１ｍｇ／ｍｌ）を溶解した後、ナノ構造体シリカ多孔質材料（薬物の１〜１０倍の重量）を分散させ、密閉容器で一日間攪拌する。遠心分離で薬物含有ナノ構造体シリカ多孔質を沈殿させて、それを真空乾燥させる。遠心分離の上澄み液を採集して分光光度計にて上澄み液中の薬物の吸光度を測定し、緩衝液中の薬物の除去率からナノ構造体シリカ多孔質材料内の薬物の含有率を求める。また、液体クロマトグラフィーによって、上澄み液中の薬物濃度測定も同時に行う。また、時間経過ごとに上澄み液を採集し薬物の吸着を測定することもできる。
"Adsorption of drugs on nanostructured silica porous materials"
An example of the adsorption of the drug on the nanostructured silica porous material is described below. The buffer solution is selected in consideration of the isoelectric point between the drug and the silica surface. At this time, it is preferable to select a buffer so that the charges on the surface of the drug and silica are opposite. After the drug (0.004 to 1 mg / ml) is dissolved in this buffer solution, the nanostructured silica porous material (1 to 10 times the weight of the drug) is dispersed and stirred for one day in a sealed container. Centrifugation precipitates the drug-containing nanostructured silica porous and vacuum-dryes it. The supernatant of the centrifugal separation is collected, the absorbance of the drug in the supernatant is measured with a spectrophotometer, and the content of the drug in the nanostructured silica porous material is determined from the removal rate of the drug in the buffer. The drug concentration in the supernatant is also measured simultaneously by liquid chromatography. In addition, the supernatant can be collected at each elapse of time to measure the adsorption of the drug.
「薬物の放出速度の測定」
薬物の放出速度の測定について以下に例を述べる。リン酸塩緩衝液（ｐＨ７．４）に薬物含有物を分散させる。時間毎に緩衝液を採集し、採集した緩衝液を遠心分離し、上澄み液を得る。このとき、採取した緩衝液の量だけ新しい緩衝液を補充する。分光光度計及び液体クロマトグラフィーを用いて、前記上澄み液中の薬物の濃度を測定する。
"Measurement of drug release rate"
An example is described below for the measurement of drug release rate. Disperse the drug content in phosphate buffer (pH 7.4). A buffer solution is collected every hour, and the collected buffer solution is centrifuged to obtain a supernatant. At this time, a new buffer solution is replenished by the amount of the collected buffer solution. The concentration of the drug in the supernatant is measured using a spectrophotometer and liquid chromatography.
「ナノ構造体シリカ多孔質材料を用いた経皮剤及び経口剤」
薬物を吸着させた本発明のナノ構造体シリカ多孔質材料を用いて、従来知られている方法で、テープ剤、パッチ剤、パップ剤、軟膏剤、クリーム剤、ローション剤、液剤、ゲル製剤などの医薬上許容される任意の単位剤形で経皮剤として提供することができる。
"Transdermal and oral preparations using nanostructured silica porous material"
Using the nanostructured silica porous material of the present invention to which a drug is adsorbed, tape, patch, poultice, ointment, cream, lotion, liquid, gel preparation, etc., by a conventionally known method Any of the pharmaceutically acceptable unit dosage forms can be provided as a transdermal agent.
薬物を吸着させた本発明のナノ構造体シリカ多孔質材料を用いて、従来知られている方法で、錠剤、顆粒剤、散剤、カプセル剤、シロップ剤などの医薬上許容される任意の単位剤形で経口剤として提供することができる。胃内での分解を防ぐために又は薬物を適切な部位で作用させるために、必要に応じて、本発明による経口剤を大豆油でコーティングすること、疎水性を有する高分子膜でコーティングすること、又はグルコース応答性を有する高分子膜でコーティングすることができる。さらに、温度、湿度、ｐＨなど外部要因に対する応答性を有する物質でコーティングしてもよい。 Using the nanostructured silica porous material of the present invention to which a drug is adsorbed, any pharmaceutically acceptable unit such as a tablet, granule, powder, capsule, syrup and the like by a conventionally known method It can be provided as an oral dosage form. In order to prevent degradation in the stomach or to allow the drug to act at an appropriate site, the oral preparation according to the present invention may be coated with soybean oil, coated with a hydrophobic polymer film, if necessary. Alternatively, it can be coated with a polymer film having glucose responsiveness. Furthermore, it may be coated with a substance having responsiveness to external factors such as temperature, humidity, and pH.
なお、本発明は、上記実施形態に限定されるものではない。上記実施形態は、例示であり、本発明の特許請求の範囲に記載された技術的思想と実質的に同一な構成を有し、同様な作用効果を奏するものは、いかなるものであっても本発明の技術的範囲に包含される。 The present invention is not limited to the above embodiment. The above-described embodiment is an exemplification, and the present invention has substantially the same configuration as the technical idea described in the claims of the present invention, and any device that exhibits the same function and effect is the present invention. It is included in the technical scope of the invention.
「インスリンの吸着と放出」
粒径が異なる2種類のナノ構造体シリカ多孔質材料を用いた錠剤の吸着と放出特性を比較した。吸着させる薬物としてインスリンを用いた。上記「本発明のナノ構造体シリカ多孔質材料の代表的な製法」に従い、粒経が０．５μｍまでの範囲であるナノ構造体シリカ多孔質材料（シリカA)と、粒経が５μｍまでの範囲であるナノ構造体シリカ多孔質材料（シリカB)の２種類を作成した。このとき、シリカAとシリカBは、粒経以外の孔の構造、孔経、および粒子の形状が同じ特徴を持つように作成された。また、その重量を等しくした。そして、上記「薬物のナノ構造体シリカ多孔質材料への吸着」に従い、同一濃度のインスリン溶液中でインスリンを吸着させた後、それぞれのシリカへの吸着量を測定した。インスリンの最大吸着量を比較すると、シリカAが約１００ｍｇ/ｇ、シリカBが約５２mg/ｇとシリカAがシリカBの約2倍多かった。また、インスリンの吸着速度を比較すると、シリカAが1時間以内に全インスリン量の５０％を吸着し、２４時間でほとんど１００％のインスリンを吸着し平衡に達するのに対して、シリカBは平衡に達するのに約3日間かかった。インスリンを吸着させ平衡に達した後、それぞれを錠剤の形とした（シリカAは錠剤A、シリカBは錠剤B）。錠剤Aと錠剤Bの薬物放出速度を上記「薬物の放出速度の測定」に従い、測定した。放出速度においては錠剤Aの場合は放出実施後１６０時間まで最初の2時間（１．１ｍｇ/ｈ）を除いては一定の放出速度（０．６１ｍｇ/ｈ）でほとんどすべてのインスリンの放出が認められた反面、錠剤Bの場合は、最初の１．５時間は錠剤Aと類似な挙動を示すが、それ以降は放出速度の時間経過によるバラつきが見られ、錠剤Aと同じ時間内では吸着したインスリンの６０％の放出しか認められず、すべてのインスリンを放出するのに約３００時間がかかった。この結果により、ナノ構造体シリカ多孔質材料の粒径の差により、薬物の吸着性と放出性が異なることが明らかになった。ナノ構造体シリカ多孔質材料の粒経が小さいほど、薬物のナノ構造体シリカ多孔質材料へのアクセス経路が短く、ナノ構造体シリカ多孔質材料全体を担体として利用することが可能であることから、錠剤中のインスリンの吸着と放出効率が増加することがわかった。
"Adsorption and release of insulin"
The adsorption and release characteristics of tablets using two types of nanostructured silica porous materials with different particle sizes were compared. Insulin was used as the drug to be adsorbed. In accordance with the above “representative manufacturing method of the nanostructured silica porous material of the present invention”, the nanostructured silica porous material (silica A) having a particle size of up to 0.5 μm and the particle size of up to 5 μm Two types of nanostructured silica porous material (silica B) in the range were prepared. At this time, silica A and silica B were prepared so that the structure of the pores other than the particle diameter, the hole diameter, and the shape of the particles had the same characteristics. Moreover, the weight was made equal. Then, in accordance with the above “adsorption of drug to nanostructured silica porous material”, insulin was adsorbed in an insulin solution having the same concentration, and then the amount adsorbed on each silica was measured. Comparing the maximum amount of insulin adsorbed, silica A was about 100 mg / g, silica B was about 52 mg / g, and silica A was about twice as much as silica B. Moreover, when comparing the adsorption rate of insulin, silica A adsorbs 50% of the total amount of insulin within 1 hour, and almost 100% of insulin is adsorbed within 24 hours to reach equilibrium, whereas silica B is in equilibrium. It took about 3 days to reach. After the insulin was adsorbed and reached equilibrium, each was shaped into a tablet (silica A for tablet A and silica B for tablet B). The drug release rates of tablet A and tablet B were measured according to the above-mentioned “Measurement of drug release rate”. With regard to the release rate, in the case of tablet A, almost all insulin release was observed at a constant release rate (0.61 mg / h) except for the first 2 hours (1.1 mg / h) up to 160 hours after release. On the other hand, in the case of tablet B, the behavior was similar to that of tablet A for the first 1.5 hours, but after that, there was a variation due to the time lapse of the release rate, and it was adsorbed within the same time as tablet A. Only 60% release of insulin was observed, and it took about 300 hours to release all insulin. From this result, it became clear that the adsorptivity and release of the drug differ depending on the particle size difference of the nanostructured silica porous material. The smaller the particle size of the nanostructured silica porous material, the shorter the access path of the drug to the nanostructured silica porous material, and the entire nanostructured silica porous material can be used as a carrier. It was found that the adsorption and release efficiency of insulin in the tablet increased.
Claims (24)
The oral preparation according to any one of claims 11 to 22, wherein the drug is a therapeutic drug for diabetes containing a peptide hormone.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100845519B1 (en) * | 2007-01-31 | 2008-07-10 | 연세대학교 산학협력단 | Multifunctional silica sphere for drug delivery system and preparation method |
| KR101091770B1 (en) * | 2008-06-03 | 2011-12-12 | 한국외국어대학교 연구산학협력단 | Mesoporous silica materials and method for preparing the same |
| WO2015182866A1 (en) * | 2014-05-27 | 2015-12-03 | 서울대학교 산학협력단 | Interface between organism and wearable device |
| WO2018207744A1 (en) * | 2017-05-08 | 2018-11-15 | 富士シリシア化学株式会社 | In vivo transportation carrier, complex using same, and in vivo transportation method |
| CN115571884A (en) * | 2021-06-21 | 2023-01-06 | 复旦大学 | Silicon nano-carrier for promoting oral absorption of medicine and medicine carrying system thereof |
-
2005
- 2005-01-13 JP JP2005005832A patent/JP2006193462A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100845519B1 (en) * | 2007-01-31 | 2008-07-10 | 연세대학교 산학협력단 | Multifunctional silica sphere for drug delivery system and preparation method |
| KR101091770B1 (en) * | 2008-06-03 | 2011-12-12 | 한국외국어대학교 연구산학협력단 | Mesoporous silica materials and method for preparing the same |
| WO2015182866A1 (en) * | 2014-05-27 | 2015-12-03 | 서울대학교 산학협력단 | Interface between organism and wearable device |
| WO2018207744A1 (en) * | 2017-05-08 | 2018-11-15 | 富士シリシア化学株式会社 | In vivo transportation carrier, complex using same, and in vivo transportation method |
| CN115571884A (en) * | 2021-06-21 | 2023-01-06 | 复旦大学 | Silicon nano-carrier for promoting oral absorption of medicine and medicine carrying system thereof |
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