JP2020079213A - Drug carrier, drug structure, use thereof, production method, and method of suppressing helicobacter pylori using the same - Google Patents
Drug carrier, drug structure, use thereof, production method, and method of suppressing helicobacter pylori using the same Download PDFInfo
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本発明は薬物担体、薬物構造体、その用途、製造方法及びそれを使用したヘリコバクターピロリの抑制方法に関し、特に外部磁場の誘導を受けることができる薬物担体及び該薬物担体を含む薬物構造体に関する。 The present invention relates to a drug carrier, a drug structure, its use, a manufacturing method and a method for suppressing Helicobacter pylori using the same, and more particularly to a drug carrier capable of receiving induction of an external magnetic field and a drug structure containing the drug carrier.
ヘリコバクターピロリは胃と十二指腸中に生存する一種の細菌であり、流行病学の研究でヘリコバクターピロリは主に汚染された飲用水または食物を通じて伝播することが実証されている。未発展または発展途上の国の二十歳以下の人口群において、ヘリコバクターピロリの感染率は８０〜９０％に達する。 Helicobacter pylori is a type of bacterium that lives in the stomach and duodenum, and epidemiologic studies have demonstrated that Helicobacter pylori is transmitted primarily through contaminated drinking water or food. In populations under the age of 20 in undeveloped or developing countries, the infection rate of Helicobacter pylori reaches 80-90%.
人体がヘリコバクターピロリに感染すると、ヘリコバクターピロリが人体の胃上皮細胞層中に付着し、ヘリコバクターピロリはその分泌するウレアーゼにより人体の胃に極少量存在する尿素をアルカリ性のアンモニアに変化させ、ヘリコバクターピロリ感染部位の中性環境を維持し、ヘリコバクターピロリが胃酸により破壊されないようにする。このほか、ヘリコバクターピロリが含有する各種毒素及び毒性作用を有する酵素は、ヘリコバクターピロリの転移繁殖に有利であるだけでなく、ヘリコバクターピロリの生存を助ける。 When the human body is infected with Helicobacter pylori, Helicobacter pylori attaches to the gastric epithelial cell layer of the human body, and the urease secreted by Helicobacter pylori changes urea, which is present in the human body in a very small amount, to alkaline ammonia, and Helicobacter pylori infection. Maintains a neutral environment at the site and prevents Helicobacter pylori from being destroyed by gastric acid. In addition, various toxins and enzymes having toxic effects contained in Helicobacter pylori are not only advantageous for the metastatic breeding of Helicobacter pylori, but also help the survival of Helicobacter pylori.
ヘリコバクターピロリは胃粘膜層を通過して胃上皮細胞表面の中性環境に到達し、胃上皮細胞を破壊する。この過程で、胃上皮細胞が酸素フリーラジカル反応物やプロテアーゼ生成物などを放出し、前述の酸素フリーラジカル反応物やプロテアーゼ生成物が胃上皮細胞に対して有毒な作用を発生するため、慢性炎症や消化性潰瘍（胃壁または十二指腸壁の破損）を引き起こすことがある。適切に治療しない場合、胃腸の出血、穿孔または胃流出路閉塞等の合併症につながり、最も重篤な場合胃がんを引き起こす可能性がある。 Helicobacter pylori passes through the gastric mucosal layer to reach the neutral environment on the surface of gastric epithelial cells and destroys gastric epithelial cells. During this process, gastric epithelial cells release oxygen free radical reactants and protease products, which cause toxic effects on gastric epithelial cells, resulting in chronic inflammation. Or it may cause peptic ulcer (damage of stomach wall or duodenal wall). If not treated properly, it can lead to complications such as gastrointestinal bleeding, perforation or gastric outflow obstruction, and in the most severe cases can cause gastric cancer.
現在ヘリコバクターピロリの根絶治療は主に、３剤併用療法または４剤併用療法を利用して治療が行われている。ヘリコバクターピロリを抑制する抗生物質には、現在クラリスロマイシン（ｃｌａｒｉｔｈｒｏｍｙｃｉｎ）、レボフロキサシン（ｌｅｖｏｆｌｏｘａｃｉｎ）、メトロニダゾール（ｍｅｔｒｏｎｉｄａｚｏｌｅ）、テトラサイクリン（ｔｅｔｒａｃｙｃｌｉｎｅ）、アモキシシリン（ａｍｏｘｉｃｉｌｌｉｎ）が含まれる。しかしながら、ヘリコバクターピロリの根絶治療のプロセスには時間がかかり、１回に服用する薬物の数量が多過ぎる（約１０個の薬物）だけでなく、ヘリコバクターピロリを根絶する薬物が患者にめまいや下痢、舌苔の発生、口内味覚障害、アレルギー等の副作用を生じ、患者の服薬コンプライアンスが低くなり、治療が失敗しやすい。 At present, the eradication treatment of Helicobacter pylori is mainly performed by using the three-drug combination therapy or the four-drug combination therapy. Antibiotics that inhibit Helicobacter pylori currently include clarithromycin, levofloxacin, metronidazole, tetracycline, and amoxicillin. However, the process of eradicating Helicobacter pylori is time-consuming, and not only is the number of drugs taken at one time too large (about 10 drugs), but the drug that eradicates Helicobacter pylori causes dizziness, diarrhea, and diarrhea in patients. It causes side effects such as tongue coating, taste disorder in the mouth, and allergies, which reduces the patient's compliance with medication and is likely to cause treatment failure.
中華民国第Ｉ５１０２５５号特許では、架橋キトサンとアモキシシリンのナノ粒子を含み、そのうち、陰イオン界面活性剤と油を添加する方式で油中水滴型エマルションを形成し、架橋キトサンでアモキシシリンをカプセル化するものが開示されている。これらの粒子の平均粒子径は１００〜６００ｎｍであり、かつ該カプセル化されたアモキシシリンはナノ粒子総重量の少なくとも５％（ｗ／ｗ）である。これらナノ粒子の経口服用時、該ナノ粒子は胃の中で自由なアモキシシリンまたはマイクロメートルサイズの微粒子より長い滞留時間を有する。 In the patent No. I510255 of the Republic of China, crosslinked chitosan and amoxicillin nanoparticles are included, of which a water-in-oil emulsion is formed by a method of adding an anionic surfactant and oil, and the amoxicillin is encapsulated with the crosslinked chitosan. Is disclosed. The average particle size of these particles is 100-600 nm and the encapsulated amoxicillin is at least 5% (w/w) of the total weight of the nanoparticles. When taken orally these nanoparticles have a longer residence time in the stomach than free amoxicillin or micrometer sized microparticles.
中華民国第２０１１３８７８８号特許では、消化器潰瘍に用いる薬物構造体が開示されており、該薬物構造体はアルギン酸を基質として薬物をカプセル化し、小球体を形成してから、キトサン外膜で該小球体をカプセル化して該薬物構造体を形成するものが開示されている。この特許の明細書７ページ１８〜２５行目によると、該薬物構造体はコロイド形態のアルギン酸を形成することで徐放効果を達成している。 Chinese Patent No. 2011138788 discloses a drug structure for use in digestive ulcer, wherein the drug structure encapsulates the drug using alginic acid as a substrate to form microspheres, and the chitosan outer membrane is used to form the microspheres. What encapsulates spheres to form the drug structure is disclosed. According to the specification, page 7, lines 18 to 25, the drug structure achieves a sustained release effect by forming alginic acid in a colloidal form.
米国特許第６２８４７４５号では、アルギン酸とキトサンを併用した薬物構造体が開示されており、該薬物構造体の製造過程ではパントテン酸カルシウム（ｃａｌｃｉｕｍ ｐａｎｔｏｔｈｅｎａｔｅ）を添加して、アルギン酸の製造に用いるアルギン酸ナトリウムにゲルビーズ（ｂｅａｄ）を形成させ、薬物をカプセル化している。該薬物構造体は２時間以内に含有薬物を放出する速放特性を備えている。 US Pat. No. 6,284,745 discloses a drug structure in which alginic acid and chitosan are used in combination, and calcium pantothenate is added to the sodium alginate used in the manufacture of alginic acid in the process of manufacturing the drug structure. The drug is encapsulated by forming gel beads. The drug structure has an immediate release property that releases the contained drug within 2 hours.
中華民国第Ｉ４８２６３２号特許では、共重合したアルギン酸塩とキトサンをヘリコバクターピロリ根絶治療の薬物担体とするものが開示されており、アルギン酸塩とキトサン分子間の相互作用を通じ、胃粘膜環境中（ｐＨ７.４）で薬物を効果的に該薬物担体中から放出させてヘリコバクターピロリの成長を抑制することができ、かつ、キトサンの粘膜付着特性により薬物担体を胃粘膜上に付着させ、薬物の胃粘膜における放出時間を延長することができる。 Taiwan Patent No. I482632 discloses a copolymer of alginate and chitosan as a drug carrier for the eradication of Helicobacter pylori, and through the interaction between alginate and chitosan molecules, in the gastric mucosal environment (pH 7. In 4), the drug can be effectively released from the drug carrier to suppress the growth of Helicobacter pylori, and the mucoadhesive property of chitosan causes the drug carrier to adhere to the gastric mucosa, thereby improving the gastric mucosa The release time can be extended.
前述の特許ですでに多くのヘリコバクターピロリの抑制に用いることができる小球体薬物担体や小球体薬物構造体が開示されているが、どのように薬物担体または薬物構造体の治療効果を向上し、患者が１回に服用する薬物の数量と、過多な薬物を服用することで患者に生じる副作用を減少するかは、未だ解決が待たれている問題である。 Although the aforementioned patents have already disclosed microsphere drug carriers and microsphere drug structures that can be used for the suppression of many Helicobacter pylori, how to improve the therapeutic effect of drug carriers or drug structures, The number of drugs taken by a patient at one time and whether side effects caused to patients by taking too many drugs are reduced are problems that have yet to be resolved.
本発明の目的は、上述の問題に対し、９０〜１１０重量部の負電荷を持つポリマーと、４００〜１２５０重量部のキトサンと、１５０〜５００重量部の磁性粒子を含む薬物担体を提供することにある。 It is an object of the present invention to provide a drug carrier containing 90 to 110 parts by weight of a negatively charged polymer, 400 to 1250 parts by weight of chitosan, and 150 to 500 parts by weight of magnetic particles, in order to solve the above problems. It is in.
上述の薬物担体は、該負電荷を持つポリマーの重量部が１００、該キトサンの重量部が６００〜８５０、該磁性粒子の重量部が２５０〜３５０である。 In the drug carrier, 100 parts by weight of the polymer having the negative charge is 600 parts by weight of the chitosan, and 250 parts by weight of the magnetic particles is 250 parts by weight.
上述の薬物担体は、その粒子径が１２０〜２００ｎｍである。 The drug carrier has a particle size of 120 to 200 nm.
上述の薬物担体は、水溶液中の表面電位が４５〜４９ｍＶである。 The drug carrier has a surface potential of 45 to 49 mV in an aqueous solution.
上述の薬物担体は、該負電荷を持つポリマーが、アルギン酸塩、ヘパリン、ポリアクリル酸、ポリメタクリル酸、カルボキシメチルセルロースで構成される群より選択される。 In the drug carrier, the polymer having the negative charge is selected from the group consisting of alginate, heparin, polyacrylic acid, polymethacrylic acid, and carboxymethylcellulose.
上述の目的及びその他目的を達するため、本発明のヘリコバクターピロリを抑制する薬物の製造のための薬物担体は、上述の薬物担体を含む。 In order to achieve the above-mentioned object and other objects, a drug carrier for producing a drug for suppressing Helicobacter pylori of the present invention includes the above-mentioned drug carrier.
上述の目的及びその他目的を達するため、本発明の薬物担体の製造方法は、（ａ）９０〜１１０重量部の負電荷を持つポリマー溶液、４００〜１２５０重量部のキトサン溶液及び１５０〜５００重量部の磁性粒子を提供する工程と、（ｂ）該負電荷を持つポリマー溶液、該キトサン溶液及び該磁性粒子を混合して初期溶液とする工程と、（ｃ）該初期溶液を撹拌し、少なくとも１０分間以上反応させて薬物担体粒子を形成する工程と、を含む。 In order to achieve the above objects and other objects, the method for producing a drug carrier according to the present invention comprises: (a) 90 to 110 parts by weight of a negatively charged polymer solution, 400 to 1250 parts by weight of a chitosan solution, and 150 to 500 parts by weight. The step of providing magnetic particles, (b) mixing the polymer solution having the negative charge, the chitosan solution, and the magnetic particles to form an initial solution, and (c) stirring the initial solution for at least 10 Reacting for more than a minute to form drug carrier particles.
上述の製造方法は、該負電荷を持つポリマーの重量部が１００、該キトサンの重量部が６００〜８５０、該磁性粒子の重量部が２５０〜３５０である。 In the above-mentioned manufacturing method, 100 parts by weight of the polymer having the negative charge is 600 to 850 parts by weight of the chitosan, and 250 to 350 parts by weight of the magnetic particles.
上述の目的及びその他目的を達するため、本発明の薬物構造体は、９０〜１１０重量部の負電荷を持つポリマーと、４００〜１２５０重量部のキトサンと、１５０〜５００重量部の磁性粒子と、ヘリコバクターピロリを抑制する活性を備えた５００〜１５００重量部の活性成分を含む。 To achieve the above and other objects, the drug structure of the present invention comprises 90 to 110 parts by weight of a negatively charged polymer, 400 to 1250 parts by weight of chitosan, and 150 to 500 parts by weight of magnetic particles. Includes 500 to 1500 parts by weight of active ingredient with Helicobacter pylori inhibiting activity.
上述の薬物構造体は、該負電荷を持つポリマーの重量部が１００、該キトサンの重量部が６００〜８５０、該磁性粒子の重量部が２５０〜３５０、該活性成分の重量部が７５０〜１０００である。 In the above drug structure, 100 parts by weight of the polymer having the negative charge, 600 to 850 parts by weight of the chitosan, 250 to 350 parts by weight of the magnetic particles, and 750 to 1000 parts by weight of the active ingredient. Is.
上述の薬物構造体は、該薬物構造体の粒子径が１３７〜２１０ｎｍである。 The drug structure described above has a particle size of the drug structure of 137 to 210 nm.
上述の薬物構造体は、該薬物構造体の活性成分カプセル化効率が７２.６〜７９.２％である。 The drug structure described above has an encapsulation efficiency of the active ingredient of the drug structure of 72.6 to 79.2%.
上述の薬物構造体は、該薬物構造体がカプセル化する活性成分が薬物構造体総重量の３０〜４５％（ｗ／ｗ）である。 In the drug structure described above, the active ingredient encapsulated by the drug structure is 30 to 45% (w/w) of the total weight of the drug structure.
上述の薬物構造体は、該薬物構造体の水溶液中の表面電位が４４〜４８ｍＶである。 The drug structure described above has a surface potential of 44 to 48 mV in an aqueous solution of the drug structure.
上述の薬物構造体は、該負電荷を持つポリマーが、アルギン酸塩、ヘパリン、ポリアクリル酸、ポリメタクリル酸、カルボキシメチルセルロースで構成される群より選択される。 In the drug structure described above, the polymer having the negative charge is selected from the group consisting of alginate, heparin, polyacrylic acid, polymethacrylic acid, and carboxymethylcellulose.
上述の薬物構造体は、該活性成分が、アモキシシリン、クラリスロマイシン、オメプラゾール、レボフロキサシン、メトロニダゾールまたはテトラサイクリンで構成される群より選択される。 In the above-mentioned drug structure, the active ingredient is selected from the group consisting of amoxicillin, clarithromycin, omeprazole, levofloxacin, metronidazole or tetracycline.
上述の目的及びその他目的を達するため、本発明の薬物構造体の製造方法は、（ａ）９０〜１１０重量部の負電荷を持つポリマー溶液、４００〜１２５０重量部のキトサン溶液、１５０〜５００重量部の磁性粒子、５００〜１５００重量部の活性成分溶液を提供する工程と、（ｂ）該負電荷を持つポリマー溶液、該キトサン溶液、該磁性粒子および該活性成分溶液を混合して初期溶液とする工程と、（ｃ）該初期溶液を撹拌し、少なくとも１０分間以上反応させて薬物担体粒子を形成する工程と、を含む。 In order to achieve the above-mentioned object and other objects, the method for producing a drug structure of the present invention comprises: (a) 90-110 parts by weight of a negatively charged polymer solution, 400-1250 parts by weight of chitosan solution, 150-500 parts by weight. Magnetic particles, 500 to 1500 parts by weight of the active ingredient solution, and (b) the negatively charged polymer solution, the chitosan solution, the magnetic particles and the active ingredient solution are mixed to form an initial solution. And (c) stirring the initial solution and reacting for at least 10 minutes to form drug carrier particles.
上述の製造方法は、該負電荷を持つポリマーの重量部が１００、該キトサンの重量部が６００〜８５０、該磁性粒子の重量部が２５０〜３５０、該活性成分の重量部が７５０〜１０００である。 In the above-mentioned production method, 100 parts by weight of the polymer having the negative charge, 600 to 850 parts by weight of the chitosan, 250 to 350 parts by weight of the magnetic particles, and 750 to 1000 parts by weight of the active ingredient are used. is there.
上述の目的及びその他目的を達するため、本発明のヘリコバクターピロリを抑制する方法は、（a）上述の薬物構造体を提供する工程と、（b）有効量の該薬物構造体をヘリコバクターピロリ群体に投与する工程を含む。 In order to achieve the above-mentioned objects and other objects, the method for suppressing Helicobacter pylori of the present invention comprises (a) a step of providing the above-mentioned drug structure, and (b) an effective amount of the drug structure to Helicobacter pylori colonies. The step of administering is included.
上述の抑制方法はさらに、（c）外部磁場を提供し、それを該薬物構造体に印加する工程を含む。 The suppression method described above further comprises the step of (c) providing an external magnetic field and applying it to the drug structure.
上述の薬物担体及び薬物構造体により、薬物担体または薬物構造体の治療効果をより高めることができ、患者が１回に服用する薬物の数量を減少し、過多な薬物を服用することで患者に生じる副作用の問題を解決することができる。 The above-mentioned drug carrier and drug structure can further enhance the therapeutic effect of the drug carrier or drug structure, reduce the number of drugs taken by the patient at one time, and increase the patient's dose by taking an excessive amount of drug. The problem of side effects that occur can be solved.
本発明の目的、特徴、効果について充分に理解できるように、以下で具体的な実施例に添付の図面を組み合わせ、本発明について詳細に説明する。 In order that the objects, features, and effects of the present invention can be fully understood, the present invention will be described in detail below by combining specific embodiments with the accompanying drawings.
本発明の薬物担体の製造方法は、薬物担体が次の方法で製造される。 In the method for producing the drug carrier of the present invention, the drug carrier is produced by the following method.
まず、９０〜１１０重量部の負電荷を持つポリマー（ｎｅｇａｔｉｖｅｌｙ ｃｈａｒｇｅｄ ｐｏｌｙｍｅｒ）、４００〜１２５０重量部のキトサン（Ｃｈｉｔｏｓａｎ）及び１５０〜５００重量部の磁性粒子を提供し、該負電荷を持つポリマーが、アルギン酸塩、ヘパリン、ポリアクリル酸、ポリメタクリル酸、カルボキシメチルセルロースで構成される群より選択され、該負電荷を持つポリマーと該キトサンがいずれも溶液形態であり、該磁性粒子は溶液中に溶解させる、または溶液中に溶解させないことを選択できる。溶液形態を形成した負電荷を持つポリマー、キトサン及び磁性粒子は、前述の各成分のｐＨ値の制御に役立ち、各成分を適した帯電状態にすることができる。 First, 90 to 110 parts by weight of a negatively charged polymer, 400 to 1250 parts by weight of chitosan and 150 to 500 parts by weight of magnetic particles are provided, and the negatively charged polymer is Selected from the group consisting of alginate, heparin, polyacrylic acid, polymethacrylic acid, carboxymethylcellulose, both the negatively charged polymer and the chitosan are in solution form, and the magnetic particles are dissolved in the solution. , Or not dissolved in solution. The polymer, chitosan, and magnetic particles having a negative charge in the form of a solution help control the pH value of each of the above-mentioned components, and can bring each component into a suitable charged state.
続いて、前述の負電荷を持つポリマー溶液、キトサン溶液及び磁性粒子を撹拌またはその他混合方式で均一に混合して初期溶液を形成し、該初期溶液の溶液形態は該薬物担体中の各成分を適した帯電状態に保持し、該薬物担体の構造を維持することができる。 Subsequently, the polymer solution having a negative charge, the chitosan solution and the magnetic particles are uniformly mixed by stirring or other mixing method to form an initial solution, and the solution form of the initial solution is such that each component in the drug carrier is It can be maintained in a suitable charged state to maintain the structure of the drug carrier.
最後に、該初期溶液を２５℃の環境下で撹拌し、１０分間または１０分間以上（例えば１５分間、２０分間）反応させ、該初期溶液中の該負電荷を持つポリマー、該キトサン及び該磁性粒子に、それぞれの帯電特性を通じて相互間で静電吸引力を生じさせ、相互に結合させて薬物担体粒子を形成し、これによりこれら薬物担体を含有する溶液を得ることができる。 Finally, the initial solution is stirred in an environment of 25° C. and reacted for 10 minutes or 10 minutes or more (for example, 15 minutes or 20 minutes), and the polymer having the negative charge in the initial solution, the chitosan and the magnetic It is possible to generate electrostatic attraction between the particles through their respective charging characteristics and to bond them to each other to form drug carrier particles, whereby a solution containing these drug carriers can be obtained.
該薬物担体は薬物または活性物質の担体とされるため、上述の薬物担体の製造過程において、該薬物担体の初期溶液中に活性物質または薬物を同時に加え、該薬物担体中の各成分に粒子形態を形成させたとき、活性物質または薬物をカプセル化している、または該薬物担体中の各成分に粒子形態を形成させるとき、別途該薬物担体粒子を含有する溶液と活性物質または薬物を含有する溶液を混合し、活性物質または薬物を該薬物担体粒子の外側表面に付着させ、これにより該薬物担体に薬物または活性物質を保持させることができる。上述の活性物質または薬物をカプセル化している該薬物担体粒子が即ち、薬物構造体であり、該薬物構造体の製造方法については後述する。 Since the drug carrier is a carrier for the drug or active substance, the active substance or drug is simultaneously added to the initial solution of the drug carrier in the above-mentioned process for producing the drug carrier, and each component in the drug carrier is in the form of particles. When the drug is formed, the active substance or drug is encapsulated, or when each component in the drug carrier is formed into a particle form, a solution containing the drug carrier particle and a solution containing the active substance or drug separately. And the active substance or drug is attached to the outer surface of the drug carrier particles, whereby the drug carrier or active substance can be retained on the drug carrier. The drug carrier particles encapsulating the above-mentioned active substance or drug are a drug structure, and a method for producing the drug structure will be described later.
該薬物担体の製造方法において、該負電荷を持つポリマーの重量部は、好ましくは９５〜１０５重量部であり、該キトサンの重量部は、好ましくは６００〜８５０重量部であり、該磁性粒子の重量部は、好ましくは２５０〜３５０重量部である。 In the method for producing the drug carrier, the weight part of the polymer having the negative charge is preferably 95 to 105 parts by weight, and the weight part of the chitosan is preferably 600 to 850 parts by weight. The weight part is preferably 250 to 350 parts by weight.
該薬物担体の製造材料は、順に混合され、まず該キトサン溶液及び該磁性粒子を混合してキトサン・磁性粒子溶液を形成し、さらに該キトサン・磁性粒子溶液と該負電荷を持つポリマー溶液を混合する。その他の実施例において、該キトサン溶液、該磁性粒子及び該負電荷を持つポリマー溶液を同時に混合するか、その他の順序で混合してもよく、これに限らない。このほか、本実施例において、該磁性粒子は酸化鉄溶液の形態に形成されるが、その他の実施例で、該磁性粒子はその他溶液形態とするか、または溶液中に溶解させないこともできる。 The materials for producing the drug carrier are mixed in order, first, the chitosan solution and the magnetic particles are mixed to form a chitosan/magnetic particle solution, and further, the chitosan/magnetic particle solution and the polymer solution having the negative charge are mixed. To do. In other embodiments, the chitosan solution, the magnetic particles, and the polymer solution having a negative charge may be mixed at the same time or in any other order, but not limited thereto. In addition, in the present embodiment, the magnetic particles are formed in the form of iron oxide solution, but in other embodiments, the magnetic particles may be in other solution form or may not be dissolved in the solution.
本実施例において、該薬物担体を含有する溶液のｐＨ値の範囲はｐＨ ３〜５.５に設定され、好ましい範囲はｐＨ４〜４.５である。但し、その他の実施例において、該薬物担体を含有する溶液のｐＨ値は、初期反応時、キトサン溶液、負電荷を持つポリマー溶液、酸化鉄溶液のｐＨ値の違いによって変動し、本実施例に限らない。 In the present example, the pH value range of the solution containing the drug carrier is set to pH 3 to 5.5, and the preferable range is pH 4 to 4.5. However, in other examples, the pH value of the solution containing the drug carrier varies depending on the difference in the pH values of the chitosan solution, the polymer solution having a negative charge, and the iron oxide solution during the initial reaction. Not exclusively.
本実施例において、該キトサン溶液のｐＨ値の範囲はｐＨ２.５〜５であり、好ましい範囲はｐＨ３.５〜４である。該酸化鉄溶液のｐＨ値の範囲はｐＨ２.５〜５であり、好ましい範囲はｐＨ３.５〜４である。該負電荷を持つポリマー溶液のｐＨ値の範囲はｐＨ６〜８であり、好ましい範囲はｐＨ７.４〜８.０である。但し、その他の実施例において、該キトサン溶液、該酸化鉄溶液及び該負電荷を持つポリマー溶液のｐＨ値は、使用ニーズに応じて調整でき、本実施例に限らない。 In this example, the pH value range of the chitosan solution is pH 2.5 to 5, and the preferred range is pH 3.5 to 4. The pH value range of the iron oxide solution is pH 2.5 to 5, and the preferred range is pH 3.5 to 4. The pH value of the polymer solution having the negative charge is pH 6 to 8, and the preferable range is pH 7.4 to 8.0. However, in other examples, the pH values of the chitosan solution, the iron oxide solution, and the negatively charged polymer solution can be adjusted according to the needs of use, and are not limited to this example.
本実施例において、該薬物担体はヘリコバクターピロリを抑制する薬物の製造に用いるか、またはヘリコバクターピロリを抑制する薬物または活性物質の担体とすることができる。但し、その他の実施例において、該薬物担体は、その他細菌を抑制またはその他疾病を治療する薬物の製造に用いるか、またはその他細菌を抑制、その他疾病を治療する薬物または活性物質の担体とすることができ、本実施例に限らない。 In the present Example, the drug carrier can be used for producing a drug that suppresses Helicobacter pylori, or can be a carrier for a drug or active substance that suppresses Helicobacter pylori. However, in other examples, the drug carrier is used for the manufacture of a drug for inhibiting other bacteria or treating other diseases, or is used as a carrier for a drug or active substance inhibiting other bacteria or treating other diseases. However, the present invention is not limited to this embodiment.
本実施例において、負電荷を持つポリマーとは、中性及び酸性環境下で負電荷を持つポリマーを指し、より具体的には、ｐＨ値が約１〜８の環境中で負電荷を持つポリマーを指すことができ、より好ましくはｐＨ値が約２〜８の環境中で負電荷を持つポリマーを指すことができる。負電荷を持つポリマーは、アルギン酸塩（ａｌｇｉｎａｔｅ）、ヘパリン（ｈｅｐａｒｉｎ）、ポリアクリル酸（ｐｏｌｙａｃｒｙｌｉｃ ａｃｉｄ）、ポリメタクリル酸（ｐｏｌｙ（ｍｅｔｈａｃｒｙｌｉｃ ａｃｉｄ））、カルボキシメチルセルロース（ｃａｒｂｏｘｙｍｅｔｈｙｌ ｃｅｌｌｕｌｏｓｅ）を含むが、これらに限らない。 In this example, the polymer having a negative charge refers to a polymer having a negative charge in a neutral and acidic environment, and more specifically, a polymer having a negative charge in an environment having a pH value of about 1 to 8. Can be referred to, and more preferably, a polymer having a negative charge in an environment having a pH value of about 2 to 8 can be referred to. Negatively charged polymers include, but are not limited to, alginate, heparin, polyacrylic acid, polymethacrylic acid, and carboxymethylcellulose. Absent.
本実施例において、キトサンは、キチン（ｃｈｉｔｉｎ）を熱濃アルカリ処理して脱アセチル化（ｄｅａｃｅｔｙｌａｔｉｏｎ）反応を発生させ、キチン中のアセチル基をアミノ基に変換させて得られる。但し、その他の実施例において、その他本分野の既知の技術を使用してキトサンを取得してもよく、本実施例に限らない。本実施例において、用いるキトサンの分子量は約１５,０００Ｄａであり、かつ脱アセチル化度は８４％である。但し、その他の実施例において、用いるキトサンの分子量は１２,０００Ｄａ〜１８,０００Ｄａまたはその他の数値範囲の分子量とし、かつ脱アセチル化度は６０〜９０％またはその他の数値範囲の脱アセチル化度としてもよく、本実施例に限らない。キトサン分子は酸性の環境下で正電荷を持ち、粘膜付着性（ｍｕｃｏａｄｓｉｖｅ）等の特性を有し、医薬の分野で広く運用されている。キトサン分子は高反応性のアミノ基とヒドロキシ基等の基を備えているため、その他の誘導体を作らせることができ、かつ弱酸性の水溶液中に溶解するため、使用者の用途の必要に応じ、キトサン分子を薄膜、ビーズ、繊維、ゲル等の形態にすることができる。キトサンはアレルギー反応や拒絶反応を生じないため、生物組織に対して生物的適合性があり、同時に、キトサンは生成される生成物を酵素作用で無毒のアミノ糖（ａｍｉｎｏ ｓｕｇａｒｓ）に分解するため、完全に生体に吸収させることができ、副作用を生じない。 In this example, chitosan is obtained by treating chitin with hot concentrated alkali to generate a deacetylation reaction and converting the acetyl group in chitin into an amino group. However, in other examples, chitosan may be obtained by using other techniques known in the art, and the present invention is not limited to this example. In this example, the molecular weight of chitosan used is about 15,000 Da and the degree of deacetylation is 84%. However, in other examples, the chitosan used has a molecular weight of 12,000 Da to 18,000 Da or other numerical range and a deacetylation degree of 60 to 90% or other numerical range. However, the present invention is not limited to this embodiment. Chitosan molecules have a positive charge in an acidic environment, have characteristics such as mucoadhesive properties, and are widely used in the field of medicine. Since the chitosan molecule has highly reactive groups such as amino and hydroxy groups, it can be used to form other derivatives and can be dissolved in a weakly acidic aqueous solution, depending on the needs of the user. Chitosan molecules can be in the form of thin films, beads, fibers, gels and the like. Since chitosan does not cause allergic reaction or rejection reaction, it is biocompatible with biological tissues, and at the same time, chitosan decomposes the produced product into non-toxic amino sugars (amino sugars) by enzymatic action. It can be completely absorbed by the living body without causing side effects.
本実施例において、磁性粒子とは、磁性を備えた物質の粒子を指し、所謂「磁性を備えた物質（ｓｕｂｓｔａｎｃｅ ｈａｖｉｎｇ ｍａｇｎｅｔｉｃ）」とは、外部磁場を通じて磁化させ、かつ外部磁場の誘導を受けることができる物質を指し、例えば、酸化鉄（磁鉄鉱）粒子（ｍａｇｎｅｔｉｔｅ ｐａｒｔｉｃｌｅｓ）、コバルト添加酸化鉄粒子（Ｃｏ−ｄｏｐｅｄ ｍａｇｎｅｔｉｔｅ ｐａｒｔｉｃｌｅｓ）、マンガン添加酸化鉄（Ｍｎ−ｄｏｐｅｄ ｍａｇｎｅｔｉｔｅ ｐａｒｔｉｃｌｅｓ）またはニッケル添加酸化鉄（Ｎｉ−ｄｏｐｅｄ ｍａｇｎｅｔｉｔｅ ｐａｒｔｉｃｌｅｓ）を含むがこれらに限らない、鉄含有物質とすることができる。 In the present embodiment, the magnetic particles refer to particles of a substance having magnetism, and the so-called “substance having magnetism” means to be magnetized through an external magnetic field and to be induced by an external magnetic field. A substance capable of being produced, for example, iron oxide (magnetite) particles, cobalt-added iron oxide particles (Co-doped magnetite particles), manganese-added iron oxide (Mn-doped magnetite particles) or nickel-added iron oxide (Ni). -Iron-containing materials, including but not limited to doped magnetite particles.
薬物担体試料の作製：
該薬物担体粒子自体の物理的及び化学的性質をより理解するため、上述の薬物担体の製造方法に従って薬物担体試料１〜５を作製した。具体的な作製過程を以下で説明する。
Preparation of drug carrier sample:
In order to better understand the physical and chemical properties of the drug carrier particles themselves, drug carrier samples 1 to 5 were prepared according to the above-mentioned drug carrier manufacturing method. A specific manufacturing process will be described below.
まず、濃度０.５ｍｇ／ｍｌのキトサン溶液（０.０１Ｍの酢酸に溶解、ｐＨ＝４.０）、濃度１.０ｍｇ／ｍｌのポリアクリル酸溶液（０.０１Ｎの水酸化ナトリウムに溶解、ｐＨ＝７.４） 及び濃度０.２ｍｇ／ｍｌの酸化鉄溶液（０.０１Ｍの酢酸に溶解、ｐＨ＝４.０）を取得する。上述の各成分溶液の溶剤、溶液濃度及び溶液ｐＨ値は好ましい実施方式に過ぎず、その他の実施例において、該キトサン溶液の濃度範囲は０.３〜０.７ｍｇ／ｍｌ、該キトサン溶液のｐＨ値範囲は約ｐＨ３〜５の間に設定することができ、該ポリアクリル酸溶液の濃度範囲は０.８〜１.２ｍｇ／ｍｌ、該ポリアクリル酸溶液のｐＨ値範囲はｐＨ７〜８.５の間に設定することができ、該酸化鉄溶液の濃度範囲は０.１〜０.４ｍｇ／ｍｌ、該酸化鉄溶液のｐＨ値範囲はｐＨ３〜５の間に設定することができる。このほか、本発明の属する技術分野において通常の知識を有する者は、本分野の既知の技術に基づき作製の必要に応じて上述の各成分溶液の溶剤、溶液濃度及び溶液ｐＨ値を調整または変更してもよく、例えば、キトサン及び酸化鉄を塩酸中に溶解させ（０.０１Ｍ；ｐＨ＝２.０）、ポリアクリル酸を水酸化カリウム中に溶解させ（０.０１Ｍ；ｐＨ＝８）、酸アルカリ滴定方式で上述の各成分溶液の濃度範囲に滴定してもよく、本実施例はこれに限らない。 First, a chitosan solution with a concentration of 0.5 mg/ml (dissolved in 0.01 M acetic acid, pH=4.0), a polyacrylic acid solution with a concentration of 1.0 mg/ml (dissolved in 0.01 N sodium hydroxide, pH =7.4) and a concentration of 0.2 mg/ml iron oxide solution (dissolved in 0.01 M acetic acid, pH=4.0). The solvent, solution concentration and solution pH value of each component solution described above are only preferred modes of implementation, and in other examples, the concentration range of the chitosan solution is 0.3 to 0.7 mg/ml, the pH of the chitosan solution is The value range can be set between about pH 3 and 5, the concentration range of the polyacrylic acid solution is 0.8 to 1.2 mg/ml, and the pH value range of the polyacrylic acid solution is pH 7 to 8.5. The iron oxide solution may have a concentration range of 0.1 to 0.4 mg/ml, and the iron oxide solution may have a pH value range of 3 to 5. In addition, a person having ordinary knowledge in the technical field to which the present invention pertains adjusts or changes the solvent, the solution concentration and the solution pH value of each of the above-mentioned component solutions as necessary according to the known technology in the field. For example, chitosan and iron oxide are dissolved in hydrochloric acid (0.01M; pH=2.0), polyacrylic acid is dissolved in potassium hydroxide (0.01M; pH=8), The acid-alkali titration method may be used for titration within the concentration range of each component solution described above, and the present embodiment is not limited to this.
続いて、下記表１に示す試料１〜５の薬物担体中の各成分の重量比に基づき、薬物担体試料１〜５のそれぞれに必要なキトサン溶液、ポリアクリル酸溶液及び酸化鉄溶液の量をそれぞれ準備する。試料１は１２５０重量部のキトサン、１００重量部のポリアクリル酸及び５００重量部の酸化鉄を含む。試料２は８３０重量部のキトサン、１００重量部のポリアクリル酸及び３３０重量部の酸化鉄を含む。試料３は６３０重量部のキトサン、１００重量部のポリアクリル酸及び２５０重量部の酸化鉄を含む。試料４は５００重量部のキトサン、１００重量部のポリアクリル酸及び２００重量部の酸化鉄を含む。試料５は４２０重量部のキトサン、１００重量部のポリアクリル酸及び１７０重量部の酸化鉄を含む。 Then, based on the weight ratio of each component in the drug carrier of Samples 1 to 5 shown in Table 1 below, the amounts of chitosan solution, polyacrylic acid solution and iron oxide solution required for each of the drug carrier samples 1 to 5 were determined. Prepare each. Sample 1 contains 1250 parts by weight chitosan, 100 parts by weight polyacrylic acid and 500 parts by weight iron oxide. Sample 2 contains 830 parts by weight chitosan, 100 parts by weight polyacrylic acid and 330 parts by weight iron oxide. Sample 3 contains 630 parts by weight chitosan, 100 parts by weight polyacrylic acid and 250 parts by weight iron oxide. Sample 4 contained 500 parts by weight chitosan, 100 parts by weight polyacrylic acid and 200 parts by weight iron oxide. Sample 5 contained 420 parts by weight chitosan, 100 parts by weight polyacrylic acid and 170 parts by weight iron oxide.
最後に、上述の薬物担体の製造方法を参照し、それぞれまず各試料中の該キトサン溶液と酸化鉄溶液を混合してキトサン・酸化鉄溶液とし、さらに各試料中のキトサン・酸化鉄溶液とポリアクリル酸溶液を混合して反応させ、薬物担体を含有する溶液を製造し、これにより薬物担体試料１〜５を取得することができる。 Finally, referring to the above-mentioned method for producing a drug carrier, first, the chitosan solution and iron oxide solution in each sample are mixed to obtain a chitosan/iron oxide solution, and further, the chitosan/iron oxide solution and polyoxide in each sample are mixed. Acrylic acid solutions are mixed and reacted to produce a solution containing a drug carrier, whereby drug carrier samples 1 to 5 can be obtained.
表２に本実施例中の薬物担体試料１〜５の平均粒子径、多分散指数（Ｐｏｌｙｄｉｓｅｐｅｒｓｅ Ｉｎｄｅｘ， ＰＤＩ）、及び表面電位を示す。 Table 2 shows the average particle size, polydispersity index (Polydise Index, PDI), and surface potential of the drug carrier samples 1 to 5 in this example.
上の表２に示すように、本実施例中の薬物担体の粒子径は約１２０〜２００ｎｍであり、１４０〜１５０ｎｍがより好ましく、該薬物担体の寸法は該薬物担体の生体内における吸収効率に有利である。該薬物担体は水溶液中での表面電位が４５〜４９ｍＶであり、４５〜４８ｍＶがより好ましく、この表面電位は本発明の薬物構造体の胃中における滞留時間に有益である。このほか、表２中の薬物担体のＰＤＩデータから分かるように、該薬物担体の粒子径は分布範囲が小さく、良好な均一性（ｈｏｍｏｇｅｎｅｉｔｙ）を備えている。 As shown in Table 2 above, the particle size of the drug carrier in this example is about 120 to 200 nm, more preferably 140 to 150 nm, and the size of the drug carrier depends on the absorption efficiency of the drug carrier in vivo. It is advantageous. The drug carrier has a surface potential of 45 to 49 mV in an aqueous solution, more preferably 45 to 48 mV, and this surface potential is beneficial to the residence time of the drug structure of the present invention in the stomach. In addition, as can be seen from the PDI data of the drug carrier shown in Table 2, the particle size of the drug carrier has a narrow distribution range and good homogeneity.
薬物構造体の製造方法：
薬物構造体は次の方法で製造される。
Method of manufacturing drug structure:
The drug structure is manufactured by the following method.
まず、９０〜１１０重量部の負電荷を持つポリマー、４００〜１２５０重量部のキトサン、１５０〜５００重量部の磁性粒子及び５００〜１５００重量部の活性成分を提供し、該負電荷を持つポリマー、該キトサン及び該活性成分がいずれも溶液形態であり、該磁性粒子は溶液中に溶解させる、または溶液中に溶解させないことを選択できる。溶液形態を形成した負電荷を持つポリマー、キトサン、磁性粒子及び活性成分は、前述の各成分のｐＨ値の制御に役立ち、各成分を適した帯電状態にすることができる。 First, 90 to 110 parts by weight of a negatively charged polymer, 400 to 1250 parts by weight of chitosan, 150 to 500 parts by weight of magnetic particles and 500 to 1500 parts by weight of an active ingredient are provided, and the negatively charged polymer is provided. Both the chitosan and the active ingredient are in solution form and the magnetic particles can be chosen to be dissolved in a solution or not. The negatively charged polymer, chitosan, magnetic particles and active ingredient in the form of a solution serve to control the pH value of each of the above-mentioned components and can bring each of the components into a suitable charged state.
続いて、前述の負電荷を持つポリマー溶液、キトサン溶液、磁性粒子及び活性成分溶液を撹拌またはその他混合方式で均一に混合して初期溶液を形成し、該初期溶液の溶液形態は該薬物構造体中の各成分を適した帯電状態に保持し、該薬物構造体の構造を維持することができる。 Subsequently, the polymer solution having a negative charge, the chitosan solution, the magnetic particles and the active ingredient solution are uniformly mixed by stirring or other mixing method to form an initial solution, and the initial solution has a solution form of the drug structure. Each of the components therein can be maintained in a suitable charged state to maintain the structure of the drug structure.
最後に、該初期溶液を２５℃の環境下で撹拌し、１０分間反応させ、該初期溶液中の該負電荷を持つポリマー、該キトサン、該磁性粒子及び該活性成分に、それぞれの帯電特性を通じて相互間で静電吸引力を生じさせ、相互に結合させて薬物構造体を形成し、これによりこれら薬物構造体を含有する溶液を得ることができる。 Finally, the initial solution is stirred in an environment of 25° C. and reacted for 10 minutes to allow the negatively charged polymer, the chitosan, the magnetic particles and the active ingredient in the initial solution to pass through their respective charging characteristics. It is possible to generate an electrostatic attraction force between each other and to bond them to each other to form a drug structure, thereby obtaining a solution containing these drug structures.
このほか、本実施例の薬物構造体の製造方法で使用する材料のうち、該負電荷を持つポリマー、該キトサン及び該磁性粒子はいずれも前述の薬物担体の製造方法で使用する材料であり、即ち、本実施例における薬物構造体は、前述の薬物担体成分と該活性成分で構成され、該薬物担体は該活性成分の担体とされる。 In addition, among the materials used in the method for producing the drug structure of the present example, the polymer having the negative charge, the chitosan and the magnetic particles are all materials used in the method for producing the drug carrier described above, That is, the drug structure in the present example is composed of the above-mentioned drug carrier component and the active ingredient, and the drug carrier serves as the carrier of the active ingredient.
本実施例における薬物担体及び薬物構造体はコアシェル構造ではなく、かつ磁性物質が薬物構造体内部に均一に分散されているため、本実施例の薬物担体及び薬物構造体の製造方法は、油中水滴型乳化法ではなく溶液式の製法を採用しており、即ち、各成分溶液を均一に混合し、本実施例の薬物担体及び薬物構造体中の各成分の帯電特性を通じて相互の静電吸引力を生じさせ、本実施例の薬物担体及び薬物構造体を得る。従来のコアシェル式薬物担体及び薬物構造体の製造方法と比較して、本実施例の薬物担体及び薬物構造体の製造方法は、界面活性剤及と油を加えて乳化剤を形成する必要がないため、本実施例の薬物担体及び薬物構造体の製造方法の製造過程は、従来のコアシェル式薬物担体及び薬物構造体の製造方法より簡易であり、同時に、本実施例の薬物構造体の製造方法で得た薬物構造体は、従来の薬物構造体と比較してより優れた活性成分カプセル化効率を備えている。 Since the drug carrier and the drug structure in the present example do not have the core-shell structure and the magnetic substance is uniformly dispersed inside the drug structure, the method for producing the drug carrier and the drug structure in the present example is A solution type manufacturing method is adopted instead of the water drop type emulsification method, that is, the respective component solutions are uniformly mixed, and mutual electrostatic attraction is achieved through the charging characteristics of the respective components in the drug carrier and the drug structure of this example. A force is generated to obtain the drug carrier and drug structure of this example. Compared to the conventional core-shell type drug carrier and the method for producing the drug structure, the method for producing the drug carrier and the drug structure of the present example does not require addition of a surfactant and oil to form an emulsifier. The manufacturing process of the method for producing the drug carrier and the drug structure of the present example is simpler than the conventional method for producing the core-shell type drug carrier and the drug structure, and at the same time, the method for producing the drug structure of the present example The obtained drug structure has superior active ingredient encapsulation efficiency as compared with the conventional drug structure.
本実施例の薬物構造体の製造方法において、該負電荷を持つポリマー、該キトサン及び該磁性粒子の重量部の好ましい範囲は、前述の薬物担体の製造方法中で述べた各成分の重量部の好ましい範囲を参照でき、該活性成分の重量部は７５０〜１０００重量部が好ましい。 In the method for producing the drug structure of the present Example, the preferable range of the weight part of the polymer having the negative charge, the chitosan and the magnetic particles is the weight part of each component described in the above-mentioned method for producing the drug carrier. With reference to the preferred range, the active ingredient is preferably 750 to 1000 parts by weight.
本実施例において、薬物構造体の製造材料は順に混合され、まず該負電荷を持つポリマー溶液と該活性成分溶液を混合して第１事前混合溶液を形成し、さらに該キトサン溶液と該磁性粒子を混合して第２事前混合溶液とした後、最後に該第１事前混合溶液と該第２事前混合溶液を混合して該初期溶液を形成する。但し、その他の実施例において、該キトサン溶液、該磁性粒子、該負電荷を持つポリマー溶液及び活性成分溶液を同時に混合するか、その他の順序で混合してもよく、本実施例に限らない。このほか、本実施例において、該磁性粒子は酸化鉄溶液の形態に形成されるが、その他の実施例で、該磁性粒子はその他溶液形態とするか、または溶液中に溶解させないこともできる。 In the present example, the materials for manufacturing the drug structure are mixed in order, first, the polymer solution having the negative charge and the active ingredient solution are mixed to form a first premixed solution, and the chitosan solution and the magnetic particles are further mixed. Are mixed to form a second premixed solution, and finally, the first premixed solution and the second premixed solution are mixed to form the initial solution. However, in other examples, the chitosan solution, the magnetic particles, the polymer solution having the negative charge, and the active ingredient solution may be mixed at the same time, or may be mixed in another order, and the present invention is not limited to this example. In addition, in the present embodiment, the magnetic particles are formed in the form of iron oxide solution, but in other embodiments, the magnetic particles may be in other solution form or may not be dissolved in the solution.
本実施例の薬物構造体の製造方法において、該キトサン溶液、該酸化鉄溶液及び該負電荷を持つポリマー溶液のｐＨ値は、前述の薬物担体の製造方法で述べた各成分のｐＨ値を参照することができ、該活性成分溶液のｐＨ値の範囲はｐＨ６.５〜８.５とすることができ、該活性成分溶液の好ましいｐＨ値の範囲はｐＨ７.４〜８.０とすることができる。但し、その他の実施例において、該キトサン溶液、該酸化鉄溶液、該負電荷を持つポリマー溶液及び該活性成分溶液のｐＨ値は、使用ニーズに応じて調整でき、本実施例に限らない。 In the method for producing the drug structure of the present example, the pH values of the chitosan solution, the iron oxide solution and the polymer solution having the negative charge are referred to the pH values of the respective components described in the method for producing the drug carrier. The pH value range of the active ingredient solution can be pH 6.5 to 8.5, and the preferable pH value range of the active ingredient solution can be pH 7.4 to 8.0. it can. However, in other examples, the pH values of the chitosan solution, the iron oxide solution, the polymer solution having the negative charge, and the active ingredient solution can be adjusted according to the needs of use, and are not limited to this example.
該活性成分の定義は、治療、予防、検査等の目的を達成するためのあらゆる化合物である。本実施例において、該活性成分はさらに、ヘリコバクターピロリを抑制する活性を備えた物質（ｓｕｂｓｔａｎｃｅ ｈａｖｉｎｇ ａｃｔｉｖｉｔｙ ｏｆ ｉｎｈｉｂｉｔｉｎｇ Ｈ．ｐｙｌｏｒｉ）と定義でき、これにはアモキシシリン、クラリスロマイシン、オメプラゾール、レボフロキサシン、メトロニダゾールまたはテトラサイクリンが含まれる。 The definition of the active ingredient is any compound for achieving the purpose of treatment, prevention, test and the like. In the present example, the active ingredient can be further defined as a substance having activity to suppress Helicobacter pylori (substance having activity of inhibiting H. pylori), which includes amoxicillin, clarithromycin, omeprazole, levofloxacin, metronidazole or Includes tetracycline.
本実施例において、「ヘリコバクターピロリを抑制する活性」とは、大きくは「ヘリコバクターピロリ群体の大きさを控制し、ヘリコバクターピロリ群体を縮小、及び（または）ヘリコバクターピロリ群体を消失させる」活性を有することを指し、小さくは、「ヘリコバクターピロリ個体の生理活性を低下させる、ヘリコバクターピロリ個体の感染力を低下させる、及び（または）ヘリコバクターピロリ個体を消滅させる」活性を有することを指す。 In the present Example, the "activity to suppress Helicobacter pylori" means that it has an activity to "maintain the size of Helicobacter pylori colonies, reduce Helicobacter pylori colonies, and/or eliminate Helicobacter pylori colonies". The term “small” means having an activity of “reducing the physiological activity of a Helicobacter pylori individual, reducing the infectivity of a Helicobacter pylori individual, and/or extinguishing an individual Helicobacter pylori”.
薬物構造体試料の作製：
本実施例において、上述の薬物構造体の製造方法に従って薬物構造体試料Ａ〜Ｅを作製した。具体的な作製過程を以下で説明する。
Preparation of drug structure sample:
In this example, drug structure samples A to E were prepared according to the method for manufacturing a drug structure described above. A specific manufacturing process will be described below.
まず、濃度０.５ｍｇ／ｍｌのキトサン溶液（０.０１Ｍの酢酸に溶解、ｐＨ＝４.０）、濃度１.０ｍｇ／ｍｌのポリアクリル酸溶液（０.０１Ｎの水酸化ナトリウムに溶解、ｐＨ＝７.４）、濃度０.２ｍｇ／ｍｌの酸化鉄溶液（０.０１Ｍの酢酸に溶解、ｐＨ＝４.０）及び活性成分とする濃度１.５ｍｇ／ｍｌのアモキシシリン溶液（０.０１Ｎの水酸化ナトリウムに溶解、ｐＨ＝７.４）を取得する。その他の実施例において、該キトサン溶液、該ポリアクリル酸溶液及び該酸化鉄溶液の濃度範囲及びｐＨ値範囲は、上述の薬物担体試料作製過程における対応成分溶液の条件を参考とすることができ、該アモキシシリン溶液の濃度範囲は１〜２ｍｇ／ｍｌの間に設定することができ、該アモキシシリン溶液のｐＨ値範囲は約ｐＨ６.５〜８.５の間とすることができる。上述の各成分溶液の溶剤、溶液濃度及び溶液ｐＨ値は、単に好ましい実施方式にすぎず、本発明の属する技術分野において通常の知識を有する者は、前述の薬物担体試料作製過程を参照し、作製の必要に応じて上述の各成分溶液の溶剤、溶液濃度及び溶液ｐＨ値を調整または変更してもよく、本実施例に限らない。 First, a chitosan solution with a concentration of 0.5 mg/ml (dissolved in 0.01 M acetic acid, pH=4.0), a polyacrylic acid solution with a concentration of 1.0 mg/ml (dissolved in 0.01 N sodium hydroxide, pH = 7.4), a concentration of 0.2 mg/ml iron oxide solution (dissolved in 0.01 M acetic acid, pH = 4.0) and a concentration of 1.5 mg/ml amoxicillin solution as an active ingredient (0.01 N). Dissolve in sodium hydroxide, get pH=7.4). In other examples, the concentration range and pH value range of the chitosan solution, the polyacrylic acid solution, and the iron oxide solution can refer to the conditions of the corresponding component solution in the above-mentioned drug carrier sample preparation process, The concentration range of the amoxicillin solution can be set between 1 and 2 mg/ml, and the pH value range of the amoxicillin solution can be between about 6.5 and 8.5. The solvent, solution concentration and solution pH value of each component solution described above are merely preferable modes of implementation, and those having ordinary knowledge in the technical field to which the present invention pertains may refer to the above-mentioned drug carrier sample preparation process, The solvent, the solution concentration and the solution pH value of each component solution described above may be adjusted or changed according to the necessity of production, and the present invention is not limited to this example.
続いて、下記表３に示す試料Ａ〜Ｅの薬物構造体中の各成分の重量比に基づき、薬物構造体試料Ａ〜Ｅのそれぞれに必要なキトサン溶液、ポリアクリル酸溶液、酸化鉄溶液及びアモキシシリン溶液の量をそれぞれ準備する。試料Ａは１２５０重量部のキトサン、１００重量部のポリアクリル酸、５００重量部の酸化鉄及び１５００重量部のアモキシシリンを含む。試料Ｂは８３０重量部のキトサン、１００重量部のポリアクリル酸、３３０重量部の酸化鉄及び１０００重量部のアモキシシリンを含む。試料Ｃは６３０重量部のキトサン、１００重量部のポリアクリル酸、２５０重量部の酸化鉄及び７５０重量部のアモキシシリンを含む。試料Ｄは５００重量部のキトサン、１００重量部のポリアクリル酸、２００重量部の酸化鉄及び６００重量部のアモキシシリンを含む。試料Ｅは４２０重量部のキトサン、１００重量部のポリアクリル酸、１７０重量部の酸化鉄及び５００重量部のアモキシシリンを含む。 Then, based on the weight ratio of each component in the drug structure of Samples A to E shown in Table 3 below, a chitosan solution, a polyacrylic acid solution, an iron oxide solution and a necessary solution for each of the drug structure samples A to E were obtained. Prepare each volume of amoxicillin solution. Sample A contains 1250 parts by weight chitosan, 100 parts by weight polyacrylic acid, 500 parts by weight iron oxide and 1500 parts by weight amoxicillin. Sample B contains 830 parts by weight chitosan, 100 parts by weight polyacrylic acid, 330 parts by weight iron oxide and 1000 parts by weight amoxicillin. Sample C contains 630 parts by weight chitosan, 100 parts by weight polyacrylic acid, 250 parts by weight iron oxide and 750 parts by weight amoxicillin. Sample D contains 500 parts by weight chitosan, 100 parts by weight polyacrylic acid, 200 parts by weight iron oxide and 600 parts by weight amoxicillin. Sample E contains 420 parts by weight chitosan, 100 parts by weight polyacrylic acid, 170 parts by weight iron oxide and 500 parts by weight amoxicillin.
最後に、上述の薬物構造体の製造方法を参照し、それぞれまず各試料中のポリアクリル酸溶液とアモキシシリン溶液を混合して第１事前混合溶液を形成し、さらに各試料中のキトサン溶液と酸化鉄溶液を混合して第２事前混合溶液を形成し、最後に各試料中の第１事前混合溶液と第２事前混合溶液を混合して該初期溶液を形成し、該初期溶液を撹拌して１０分間反応させ、薬物構造体を含有する溶液を得ることができ、即ち、薬物構造体試料Ａ〜Ｅが得られる。 Finally, referring to the above-mentioned method for producing the drug structure, first, the polyacrylic acid solution and the amoxicillin solution in each sample are mixed to form a first premixed solution, and the chitosan solution and the oxidation in each sample are further mixed. The iron solution is mixed to form a second premixed solution, and finally the first premixed solution and the second premixed solution in each sample are mixed to form the initial solution, and the initial solution is stirred. After reacting for 10 minutes, a solution containing the drug structure can be obtained, that is, drug structure samples A to E are obtained.
下記表４に本実施例中の薬物構造体試料Ａ〜Ｅの平均粒子径、ＰＤＩ、及び表面電位を示す。 Table 4 below shows the average particle size, PDI, and surface potential of the drug structure samples A to E in this example.
上の表４に示すように、本実施例中の薬物構造体の粒子径は約１３７〜２１０ｎｍであり、１５０〜１７０ｎｍがより好ましく、該薬物構造体の寸法は該薬物構造体の生体内における吸収効率に有利である。本実施例における薬物構造体の活性成分カプセル化効率は約７２.６〜７９.２％であり、７５〜７８％がより好ましい。該薬物構造体がカプセル化する活性成分は薬物構造体総重量の３０〜４５％（ｗ／ｗ）であり、３５〜４０％（ｗ／ｗ）がより好ましく、３７〜３８％（ｗ／ｗ）が最も好ましい。該薬物構造体は水溶液中での表面電位が４４〜４８ｍＶであり、４５〜４７ｍＶがより好ましく、この表面電位は本発明の薬物構造体の胃中における滞留時間に有益である。このほか、表４中の薬物構造体のＰＤＩデータから分かるように、該薬物構造体の粒子径は分布範囲が小さく、良好な均一性（ｈｏｍｏｇｅｎｅｉｔｙ）を備えている。 As shown in Table 4 above, the particle size of the drug structure in this example is about 137 to 210 nm, more preferably 150 to 170 nm, and the size of the drug structure in vivo in the drug structure. It is advantageous for absorption efficiency. The active ingredient encapsulation efficiency of the drug structure in this example is about 72.6 to 79.2%, more preferably 75 to 78%. The active ingredient encapsulated by the drug structure is 30 to 45% (w/w) of the total weight of the drug structure, more preferably 35 to 40% (w/w), and 37 to 38% (w/w). ) Is most preferred. The drug structure has a surface potential in an aqueous solution of 44 to 48 mV, more preferably 45 to 47 mV, and this surface potential is beneficial to the residence time of the drug structure of the present invention in the stomach. In addition, as can be seen from the PDI data of the drug structure in Table 4, the particle size of the drug structure has a narrow distribution range and good homogeneity.
薬物担体試料及び薬物構造体試料の表面形態分析： Surface morphology analysis of drug carrier and drug structure samples:
図１に薬物担体試料２、３及び薬物構造体試料Ｂ、Ｃの透過型電子顕微鏡（ｔｒａｎｓｍｉｓｓｉｏｎ ｅｌｅｃｔｒｏｎ ｍｉｃｒｏｓｃｏｐｅ， ＴＥＭ）による観察下の表面形態を示す。薬物担体試料２、３及び薬物構造体試料Ｂ、Ｃの粒子凝集形態はいずれも類似しており、このことから本実施例における薬物担体と薬物構造体は相似した物理的性質を有すると推測できる。このほか、図１からさらに、本実施例における薬物担体試料及び薬物構造体試料はいずれもナノレベルの粒子であることが分かる。従来のナノレベルの薬物担体粒子及び薬物構造体粒子は生体内でいずれも良好な吸収効率と良好な粘膜透過力を備えているため、本実施例における薬物担体試料及び薬物構造体試料も生体内で良好な吸収効率と良好な粘膜透過力を備えていると予想できる。 FIG. 1 shows the surface morphology of the drug carrier samples 2 and 3 and the drug structure samples B and C as observed by a transmission electron microscope (TEM). The drug carrier samples 2 and 3 and the drug structure samples B and C all have similar particle aggregation forms, which suggests that the drug carrier and the drug structure in this example have similar physical properties. . In addition, it can be further seen from FIG. 1 that both the drug carrier sample and the drug structure sample in this example are nano-level particles. Since both conventional nano-level drug carrier particles and drug structure particles have good absorption efficiency and good mucosal permeability in the living body, the drug carrier sample and the drug structure sample in this example are also in vivo. Therefore, it can be expected to have good absorption efficiency and good mucosal permeability.
薬物構造体の磁場誘導試験： Magnetic field induction test of drug structure:
まず、前述の薬物構造体試料の製造方法で薬物構造体試料Ｂ及びＣを含有する溶液を作製し、薬物構造体試料Ｂ及びＣを含有する溶液をフラスコにそれぞれ入れ、続いて磁石を前述の試料Ｂ及びＣの溶液を入れたフラスコの側壁に当て、フラスコ内の試料Ｂ及びＣが磁石の吸引を受けて生じる試料Ｂ及びＣのフラスコ内における分布位置の変化を観察した。上述の試験は薬物構造体試料Ｂ及びＣが生物体の胃にあるとき外部磁場の誘導を受ける状況を模擬したものである。 First, a solution containing the drug structure samples B and C was prepared by the above-described method for producing a drug structure sample, and the solutions containing the drug structure samples B and C were placed in a flask, respectively, and subsequently, the magnet was replaced with the above-mentioned magnet. The solutions of Samples B and C were applied to the side wall of the flask, and changes in the distribution position of Samples B and C in the flask caused by the attraction of magnets to the samples B and C were observed. The test described above simulates the situation where drug structure samples B and C are subject to the induction of an external magnetic field when in the stomach of an organism.
図２に該薬物構造体の磁場誘導による移動状況を示す。外部からの磁石の誘導下で、薬物構造体試料Ｂ及びＣが内部に磁性粒子を含有しているため、薬物構造体試料Ｂ及びＣはいずれも外部の磁石の磁力吸引を受けて磁石に近いフラスコの壁の方向に移動し、かつ図２から分かるように、薬物構造体試料Ｃがより優れた磁場誘導効果を備えている。上述の試験から、本実施例における薬物構造体は外部磁場の誘導を受けて該薬物構造体が生物体の胃の特定位置に停留する時間を延長することができ、該薬物構造体中の薬物の放出及び該薬物構造体の生物体内における停留時間延長に有利であることが推測される。同時に、該薬物構造体は外部磁場の誘導を受けて病原菌が集合している位置により近づくことができる。例えば、患者に該薬物構造体を服用させ、該薬物構造体が人体の胃の中に進入した後、外部から電磁場を加え、患者体内の薬物構造体を誘導し、患者の胃壁細胞層に一定時間停留させたり、患者体内の薬物構造体を誘導し、病原菌が集合している胃壁または胃粘膜の位置に接近させたりすることができる。 FIG. 2 shows the movement of the drug structure by magnetic field induction. Since drug structure samples B and C contain magnetic particles inside under the guidance of a magnet from the outside, both drug structure samples B and C are magnetically attracted by an external magnet and are close to the magnet. Moving in the direction of the wall of the flask, and as can be seen from FIG. 2, the drug structure sample C has a better magnetic field inducing effect. From the above-mentioned test, the drug structure in this example can be extended by the induction of an external magnetic field for a longer time for the drug structure to stay in a specific position of the stomach of an organism. It is speculated that there is an advantage in the release of the drug and extension of the residence time of the drug structure in the living body. At the same time, the drug structure can be brought closer to the position where pathogenic bacteria are gathered under the influence of an external magnetic field. For example, a patient takes the drug structure, and after the drug structure enters the stomach of the human body, an electromagnetic field is applied from the outside to induce the drug structure in the patient's body, and the drug structure in the stomach wall cell layer of the patient is kept constant. It can be retained for a period of time, or the drug structure in the patient's body can be induced to approach the position of the gastric wall or gastric mucosa where pathogenic bacteria are gathered.
本実施例の薬物に効果をより高く発揮させることができる薬物構造体は、薬物構造体の治療効果をより高めることができ、患者が１回に服用する薬物の数量を減少し、過多な薬物を服用することで患者に生じる副作用の問題を解決することができる。 The drug structure capable of exerting a higher effect on the drug of the present example can further enhance the therapeutic effect of the drug structure, reduce the number of drugs taken by a patient at one time, and increase the amount of excessive drug. Taking the drug can solve the problem of side effects that occur in patients.
異なるｐＨ値環境下における薬物構造体の粒子特性の試験： Examination of particle characteristics of drug structure under different pH value environment:
まず、前述の薬物構造体試料の製造方法で薬物構造体試料Ｂ及びＣを含有する溶液を作製し、薬物構造体試料Ｂ及びＣを含有する溶液をそれぞれ５つの容器に分割して入れる。続いて、前述の５組の薬物構造体試料Ｂを含有する分割溶液のｐＨ値をｐＨ２.５、４.０、５.０、６.０、７.４にそれぞれ調整し、同時に前述の５組の薬物構造体試料Ｃを含有する分割溶液のｐＨ値をｐＨ２.５、４.０、５.０、６.０、７.４にそれぞれ調整する。これにより、薬物構造体が胃の中で異なるｐＨ値を有する位置（胃酸環境（ｐＨ２.５）、異なる胃壁粘膜層深さの環境（ｐＨ４.０〜６.０）及び胃壁細胞層環境（ｐＨ７.４））を代表する。最後に、前述の５組の薬物構造体試料Ｂを含有する分割溶液及び前述の５組の薬物構造体試料Ｃを含有する分割溶液中からそれぞれ実験試料を取り出し、ナノ粒子径及び電位分析装置（Ｚｅｔａｓｉｚｅｒ ＮＡＮＯ−ＺＳ９０）と透過型電子顕微鏡で試料Ｂ及びＣの異なるｐＨ値環境下における平均粒子凝集体寸法、表面電位、分布形態を観察する。 First, a solution containing the drug structure samples B and C is prepared by the above-described method for producing a drug structure sample, and the solutions containing the drug structure samples B and C are divided and placed in five containers, respectively. Subsequently, the pH values of the divided solutions containing the above-mentioned 5 sets of drug structure sample B were adjusted to pH 2.5, 4.0, 5.0, 6.0 and 7.4, respectively, and at the same time, 5 The pH values of the split solutions containing the set of drug structure samples C are adjusted to pH 2.5, 4.0, 5.0, 6.0, 7.4, respectively. Accordingly, the drug structure has different pH values in the stomach (gastric acid environment (pH 2.5), different gastric wall mucosal layer depth environments (pH 4.0 to 6.0) and gastric wall cell layer environment (pH 7). .4)). Finally, an experimental sample was taken out from each of the divided solution containing the above-mentioned 5 sets of drug structure sample B and the divided solution containing the above-mentioned 5 sets of drug structure sample C, and the nanoparticle diameter and potential analyzer ( Zetasizer NANO-ZS90) and a transmission electron microscope are used to observe the average particle aggregate size, surface potential, and distribution morphology of Samples B and C under different pH environment.
まず図３及び図４を参照する。図３に試料Ｂの異なるｐＨ値環境下における平均粒子凝集体寸法及び表面電位の変化を示す。図４に試料Ｃの異なるｐＨ値環境下における平均粒子凝集体寸法及び表面電位の変化を示す。 First, refer to FIG. 3 and FIG. FIG. 3 shows changes in the average particle aggregate size and surface potential of Sample B under different pH value environments. FIG. 4 shows changes in the average particle aggregate size and surface potential of Sample C under different pH environment.
図３と図４から分かるように、ｐＨ２.５の環境下（即ち、人体内の胃酸液環境に相当）で、試料Ｂ及びＣは胃酸の侵蝕を受けて破壊されることがなく、試料Ｂ及びＣの表面はまだ約６０ｍＶの正電荷を持っている。 As can be seen from FIGS. 3 and 4, in the environment of pH 2.5 (that is, equivalent to the gastric acid solution environment in the human body), Samples B and C are not destroyed by the erosion of gastric acid, The surface of C and C still has a positive charge of about 60 mV.
また、試料Ｂ及びＣに含まれるキトサン及びポリアクリル酸自体が粘膜組織に粘着する特性を備えているため、薬物構造体が人体の胃にあるとき、胃壁粘膜層に粘着する傾向があり、胃壁粘膜層のｐＨ値はその深さにより約４.０、５.０、６.０である。図３と図４から分かるように、試料Ｂ及びＣがｐＨ４.０〜６.０の環境にあるとき、試料Ｂ及びＣの表面はまだ約３０〜５０ｍＶの正電荷を持っている。かつ、ｐＨ７.４の環境下（即ち、人体内の胃壁細胞層環境に相当）では、環境中のｐＨ値が中性に近付くため、キトサンが非帯電状態となり、試料Ｂ及びＣの表面電位が０ｍＶに近付く。 In addition, since chitosan and polyacrylic acid themselves contained in Samples B and C have the property of adhering to the mucosal tissue, when the drug structure is in the stomach of the human body, it tends to adhere to the mucosal layer of the stomach wall, The pH value of the mucosal layer is about 4.0, 5.0, 6.0 depending on its depth. As can be seen from FIGS. 3 and 4, when the samples B and C are in the environment of pH 4.0 to 6.0, the surfaces of the samples B and C still have a positive charge of about 30 to 50 mV. Moreover, under an environment of pH 7.4 (that is, equivalent to the gastric wall cell layer environment in the human body), the pH value in the environment approaches neutral, so that chitosan becomes non-charged and the surface potentials of the samples B and C are It approaches 0 mV.
同時に図５及び図６を参照する。図５に試料Ｂの異なるｐＨ値環境下における分布形態、図６に試料Ｃの異なるｐＨ値環境下における分布形態をそれぞれ示す。前述のように、環境中のｐＨ値が中性に近付くと、キトサンが非帯電状態となるため、試料Ｂ及びＣはｐＨ２.５の環境で緩い分散状態を呈し、中性に近い環境では凝集状態を呈する。同時に図３及び図４を参照する。試料Ｂ及びＣが置かれた環境のｐＨ値がｐＨ２.５からｐＨ７.４まで上昇すると、試料Ｂ及びＣの平均粒子凝集体寸法もナノ構造寸法から約２５マイクロメートルの構造粒子寸法まで大きくなる。 At the same time, please refer to FIG. 5 and FIG. FIG. 5 shows the distribution form of sample B under different pH value environments, and FIG. 6 shows the distribution form of sample C under different pH value environments. As described above, when the pH value in the environment approaches neutrality, the chitosan becomes non-charged state, so that the samples B and C exhibit a loose dispersion state in the environment of pH 2.5, and aggregate in the near neutrality environment. Exhibit a state. At the same time, please refer to FIG. 3 and FIG. As the pH value of the environment in which the samples B and C are placed rises from pH 2.5 to pH 7.4, the average particle aggregate size of the samples B and C also increases from the nanostructured size to the structural particle size of about 25 micrometers. ..
以上の試験結果から分かるように、該薬物構造体を粘膜組織に粘着させ、かつ胃壁細胞層の中性環境に近付けると、キトサンとポリアクリル酸の帯電特性の変化により、該薬物構造体を徐々に瓦解させ、該薬物構造体中の活性成分放出を促進する。上述の薬物構造体の特性は、薬物構造体中の活性成分（即ち、ヘリコバクターピロリを抑制または消滅する薬物）を病原菌が凝集している位置により近付けて放出させることができ、活性成分の治療効果向上に有益である。 As can be seen from the above test results, when the drug structure was adhered to the mucosal tissue and brought close to the neutral environment of the gastric parietal cell layer, the drug structure was gradually changed due to the change in the charging property of chitosan and polyacrylic acid. To promote the release of the active ingredient in the drug structure. The above-mentioned characteristic of the drug structure is that the active ingredient in the drug structure (that is, the drug that suppresses or eliminates Helicobacter pylori) can be released closer to the position where the pathogenic bacteria are aggregated, and the therapeutic effect of the active ingredient can be obtained. It is beneficial for improvement.
薬物構造体の薬物放出率試験： Drug structure release rate test:
本実施例における薬物構造体の放出特性をより理解するため、まず前述の薬物構造体試料の作製方法で薬物構造体試料Ｂ及びＣを含有する溶液を作製し、続いて薬物構造体試料Ｂ及びＣの溶液を遠心濃縮し、試料Ｂ及びＣの濃縮液を透析膜に入れる。さらに試料Ｂ及びＣの濃縮液を含有する透析膜をｐＨ２.５の模擬溶液中にそれぞれ入れ、濃縮液のｐＨ値を徐々にｐＨ２.５に接近させる。前述の試料Ｂ及びＣの濃縮液を含有する透析膜をｐＨ２.５の環境中に２時間置いた後、前述の試料Ｂ及びＣの濃縮液を含有する透析膜をｐＨ６.５の模擬溶液中にそれぞれ入れ、濃縮液のｐＨ値を徐々にｐＨ６.５に接近させる。前述の試料Ｂ及びＣの濃縮液を含有する透析膜をｐＨ６.５の環境中に２時間置いた後、前述の試料Ｂ及びＣの濃縮液を含有する透析膜をｐＨ７.４の模擬溶液中にそれぞれ入れ、濃縮液のｐＨ値を徐々にｐＨ７.４に接近させる。前述の試料Ｂ及びＣの濃縮液を含有する透析膜をｐＨ７.４の環境中に４４時間置く。同時に、前述の試料Ｂ及びＣの濃縮液を含有する透析膜は、前述の異なるｐＨ値の模擬溶液中で低倍回転速度（本実施例において、回転速度は１００ｒｐｍに設定されるが、低倍回転速度の設定は本実施例に限らない）で回転され、上述の操作過程により模擬試料Ｂ及びＣの胃と胃粘膜部位における薬物放出を模擬する。同時に、異なる時間点で、高速液体クロマトグラフィーにより前述の試料Ｂ及びＣを含有する透析膜が入れられた異なるｐＨ値の模擬溶液中でアモキシシリン試料を採集し、かつ波長２２９ｎｍの条件下でアモキシシリンの濃度を測定し、異なるｐＨ値環境中で測定を行い、試料Ｂ及びＣが放出する活性成分濃度を放出率に換算する。 In order to better understand the release characteristics of the drug structure in this example, first, a solution containing the drug structure samples B and C was prepared by the above-described method for preparing the drug structure sample, and subsequently, the drug structure sample B and The solution of C is concentrated by centrifugation, and the concentrated solutions of samples B and C are put into a dialysis membrane. Further, the dialysis membranes containing the concentrated solutions of Samples B and C are respectively put in the simulated solution of pH 2.5, and the pH value of the concentrated solution is gradually approached to pH 2.5. After placing the dialysis membrane containing the concentrated solutions of Samples B and C for 2 hours in an environment of pH 2.5, the dialysis membrane containing the concentrated solutions of Samples B and C in a simulated solution of pH 6.5. Respectively, and gradually adjust the pH value of the concentrated solution to pH 6.5. After placing the dialysis membrane containing the concentrated solutions of Samples B and C for 2 hours in an environment of pH 6.5, the dialysis membrane containing the concentrated solutions of Samples B and C in a simulated solution of pH 7.4. Respectively, and gradually adjust the pH value of the concentrated solution to pH 7.4. The dialysis membrane containing the concentrated solutions of Samples B and C described above is placed in an environment of pH 7.4 for 44 hours. At the same time, the dialysis membrane containing the concentrated solutions of Samples B and C described above has a low rotation speed (in the present example, the rotation speed is set to 100 rpm, but the low The setting of the rotation speed is not limited to this example), and the drug release in the stomach and the gastric mucosa site of the simulated samples B and C is simulated by the above-described operation process. Simultaneously, at different time points, amoxicillin samples were collected by high performance liquid chromatography in simulated solutions of different pH values containing dialysis membranes containing samples B and C as described above, and amoxicillin samples under the condition of wavelength 229 nm. The concentration is measured, and the measurement is performed in an environment with different pH values, and the concentration of the active ingredient released by Samples B and C is converted into the release rate.
試験結果は図７に示すとおりであり、薬物構造体試料Ｂ及びＣが放出する活性成分は中性（アルカリ性）に近い環境であるほど放出率が高くなる。この実験結果は前述の図３及び図４で観察された、キトサンの帯電特性の変化により該薬物構造体が緩む状況と一致しており、このことから、本実施例の薬物構造体は胃壁細胞層で優れた放出率を備えていることが分かる。このほか、図７では、試験時間の延長に伴って、試料Ｃの放出率が高くなる（９０％超）ことが観察できる。薬物構造体中の負電荷を持つポリマーが多いほど、活性成分とキトサン上の正電荷を争い、薬物構造体中の静電力を利用して引き付け結合する活性成分がより放出されやすくなるためである。 The test results are shown in FIG. 7, and the release rate of the active ingredient released by the drug structure samples B and C becomes higher as the environment becomes closer to neutral (alkaline). This experimental result is consistent with the situation observed in FIGS. 3 and 4 described above in which the drug structure relaxes due to the change in the charging property of chitosan. It can be seen that the layers have excellent release rates. In addition, in FIG. 7, it can be observed that the release rate of the sample C increases (more than 90%) with the extension of the test time. This is because the more negatively charged polymers in the drug structure, the more positive charges on the active ingredient and chitosan contend with each other, and the more easily the active ingredient that attracts and binds using the electrostatic force in the drug structure is released. ..
薬物構造体の粘液層通過能力試験： Test for ability of drug structure to pass through mucus layer:
まず、上層が２０ｍｇ／ｍｌのムチンを含有する溶液（ｐＨ４.５）と下層が５０ｍｇ／ｍｌのムチンを含有する溶液（ｐＨ７.４）の模擬粘液層（模擬粘液層の構造は図８を参照）を作製し、異なる深さの胃粘膜粘液層環境を模擬する。前述の模擬粘液層を４つの微量遠心管に入れ、蛍光物質を含有し、かつ濃縮を経て改質した試料Ｃの濃縮液と０.０１Ｎ塩酸溶液（ｐＨ２.５）を混合した後、前述の４つの微量遠心管中の模擬粘液層にそれぞれゆっくり加え、上述の４つの試料Ｃを含有する混合液を加えた模擬粘液層を、本試験の４つの試験試料とする。続いて、上述の４つの試験試料にそれぞれ異なる次の試験条件を適用する。（１）試料Ｃを含有する混合液を加えた後、外部磁場なしで５分間静置する；（２）試料Ｃを含有する混合液を加えた後、外部磁場を印加して５分間静置する；（３）試料Ｃを含有する混合液を加えた後、外部磁場なしで１０分間静置する；（４）試料Ｃを含有する混合液を加えた後、外部磁場を印加して１０分間静置する。本試験の４つの試験試料で上述の試験条件を完了した後、続いて該試験試料を冷凍し、冷凍した試験試料の切片を用い、蛍光顕微鏡で試料Ｃの模擬粘液層中の分布状況を観察する。上述の試験を通じ、薬物構造体試料Ｃの粘膜通過能力に対する外部磁場の影響の有無を評価することができる。上述の外部磁場を印加する方法は、該微量遠心管底部に磁石を置くことで行う（図８参照）。 First, a simulated mucus layer of a solution containing 20 mg/ml mucin (pH 4.5) in the upper layer and a solution (pH 7.4) containing mucin in the lower layer of 50 mg/ml (see FIG. 8 for the structure of the simulated mucus layer). ) Is prepared to simulate the mucosal mucus layer environment at different depths. The simulated mucus layer was placed in four microcentrifuge tubes, mixed with a concentrated solution of sample C containing a fluorescent substance and modified through concentration and a 0.01N hydrochloric acid solution (pH 2.5), and then The simulated mucus layers added slowly to the simulated mucus layers in the four microcentrifuge tubes and the mixed solution containing the above-mentioned four samples C were used as the four test samples in this test. Subsequently, the following different test conditions are applied to the above-mentioned four test samples. (1) After adding the mixed solution containing the sample C, let stand for 5 minutes without an external magnetic field; (2) After adding the mixed solution containing the sample C, leave it for 5 minutes by applying an external magnetic field (3) After adding the mixed solution containing the sample C, let stand for 10 minutes without an external magnetic field; (4) After adding the mixed solution containing the sample C, apply an external magnetic field for 10 minutes Let stand. After completing the above test conditions with the four test samples of this test, the test samples were subsequently frozen, and the distribution of the sample C in the simulated mucus layer was observed with a fluorescence microscope using sections of the frozen test samples. To do. Through the above-mentioned test, it is possible to evaluate the presence or absence of the influence of the external magnetic field on the mucosal passage ability of the drug structure sample C. The above-mentioned method of applying the external magnetic field is performed by placing a magnet at the bottom of the microcentrifuge tube (see FIG. 8).
試験結果を図９に示す。静置時間が長いほど、薬物構造体試料Ｃが粘液層中で分布する深さ位置がより底部に近くなる。外部磁場がかかると、薬物構造体試料Ｃが粘液層中で分布する深さ位置がいずれも外部磁場なしのときより底部に近くなり、かつ外部磁場を印加する時間が長いほど、薬物構造体試料Ｃが粘液層中で分布する深さ位置がより底部に近くなる。上述の試験から、本実施例における薬物構造体は外部磁場の誘導を受けて胃粘膜層を迅速に通過でき、該薬物構造体中の薬物または活性物質に粘膜層を迅速に通過させ、病原菌凝集位置近くで薬物放出と殺菌を行なわせることができると推測される。 The test results are shown in FIG. The longer the standing time, the closer the depth position where the drug structure sample C is distributed in the mucus layer becomes closer to the bottom. When an external magnetic field is applied, the depth positions where the drug structure sample C is distributed in the mucus layer are closer to the bottom than when there is no external magnetic field, and the longer the external magnetic field is applied, the longer the drug structure sample is applied. The depth position where C is distributed in the mucus layer becomes closer to the bottom. From the above-mentioned test, the drug structure in the present example can be rapidly passed through the gastric mucosal layer under the induction of the external magnetic field, and the drug or active substance in the drug structure can be rapidly passed through the mucosal layer to cause the aggregation of pathogenic bacteria. It is speculated that drug release and sterilization could occur near the location.
薬物構造体のヘリコバクターピロリに対する抑制試験： Inhibition test of drug structure against Helicobacter pylori:
まず、７種類の異なる菌株のヘリコバクターピロリ菌液を取得する。前述の７種類のヘリコバクターピロリ菌液の最小発育阻止濃度（ｍｉｎｉｍｕｍ ｉｎｈｉｂｉｔｏｒｙ ｃｏｎｃｅｎｔｒａｔｉｏｎ， ＭＩＣ）はそれぞれ、０.０１６μｇ／ｍｌ（ＮＯ. １２６-６）、０.０６２５μｇ／ｍｌ（ＮＯ.１２７-４）、０.０６２５μｇ／ｍｌ（ＮＯ. １２７-９）、０.１２５μｇ／ｍｌ（ＮＯ. １２７-１０）、０.２５μｇ／ｍｌ（ＮＯ. １２５-５６）、０.２５μｇ／ｍｌ（ＮＯ. １２５-５７）、０.５μｇ／ｍｌ（ＮＯ.１２５-５４））である。さらに、各菌株のヘリコバクターピロリ菌液を４つの１５ｍｌ遠心管に分けて入れ、各遠心管内にそれぞれ５ｍｌのヘリコバクターピロリ菌液が入れられる。前述の４つの遠心管はそれぞれ実験群１、実験群２、実験群３、対照群である。続いて、各菌株のヘリコバクターピロリの実験群１にその最小発育阻止濃度のアモキシシリンを加え、実験群２にその最小発育阻止濃度の試料３（即ち薬物担体）を加え、実験群３に最小発育阻止濃度のアモキシシリンを含有する試料Ｃ（即ち薬物構造体）を加え、対照群には何も加えない。最後に、各菌株のヘリコバクターピロリ実験群１〜３及び対照群をインキュベータ内に入れ、３７℃の嫌気性環境下で４８時間培養する。４８時間の培養後、各菌株のヘリコバクターピロリ実験群１〜３及び対照群からそれぞれ菌液を取り出し、分光光度計により波長４５０ｎｍの条件下で前述の実験群の菌液及び対照群の菌液のＯＤ値を測定し、さらに細菌抑制率に換算して、アモキシシリン、活性成分がない実験試料２、及び活性成分を有する試料Ｃのヘリコバクターピロリに対する抑制効果をそれぞれ分析した。 First, 7 kinds of Helicobacter pylori liquid of different strains are obtained. The minimum inhibitory concentration (MIC) of the above-mentioned 7 kinds of Helicobacter pylori liquid was 0.016 μg/ml (NO. 126-6), 0.0625 μg/ml (NO. 127-4), respectively. 0.0625 μg/ml (NO. 127-9), 0.125 μg/ml (NO. 127-10), 0.25 μg/ml (NO. 125-56), 0.25 μg/ml (NO. 125-57) ), 0.5 μg/ml (NO. 125-54)). Further, the Helicobacter pylori broth of each strain is put into four 15 ml centrifuge tubes separately, and 5 ml of each Helicobacter pylori broth is put in each centrifuge tube. The above-mentioned four centrifuge tubes are an experimental group 1, an experimental group 2, an experimental group 3 and a control group, respectively. Subsequently, the minimum inhibitory concentration of amoxicillin was added to the experimental group 1 of Helicobacter pylori of each strain, the sample 3 (that is, the drug carrier) of the minimum inhibitory concentration was added to the experimental group 2, and the minimum inhibitory concentration was added to the experimental group 3. Sample C containing a concentration of amoxicillin (ie drug structure) is added and nothing is added to the control group. Finally, the Helicobacter pylori experimental groups 1 to 3 and the control group of each strain are placed in an incubator and cultured in an anaerobic environment at 37°C for 48 hours. After culturing for 48 hours, the bacterial solution was taken out from each of the Helicobacter pylori experimental groups 1 to 3 and the control group of each strain, and the bacterial solution of the experimental group and the bacterial solution of the control group under the condition of a wavelength of 450 nm was measured by a spectrophotometer. The OD value was measured and further converted into a bacterial inhibition rate, and the inhibitory effects on the Helicobacter pylori of amoxicillin, the experimental sample 2 having no active ingredient, and the sample C having an active ingredient were analyzed.
試験結果を図１０に示す。異なる菌株のヘリコバクターピロリはアモキシシリンに対して異なる感受性を有するため、異なる菌株のヘリコバクターピロリ実験群１からアモキシシリンのヘリコバクターピロリに対する異なる抑制効果を観察することができる。試料Ｃに含まれる活性成分はアモキシシリンであり、図１０から分かるように、各菌株のヘリコバクターピロリには、試料Ｃの添加とアモキシシリンのみの添加が相当の抑制効果を備えている。一方で、図１０からやはり分かるように、いかなる活性成分も含まない試料３も、一部菌株のヘリコバクターピロリに対して若干の抑制効果を備えている。 The test results are shown in FIG. Since Helicobacter pylori of different strains have different sensitivities to Amoxicillin, different inhibitory effects of Amoxicillin on Helicobacter pylori can be observed from Helicobacter pylori experimental group 1 of different strains. The active ingredient contained in sample C is amoxicillin, and as can be seen from FIG. 10, the addition of sample C and the addition of amoxicillin alone have a considerable inhibitory effect on Helicobacter pylori of each strain. On the other hand, as can be seen from FIG. 10, Sample 3, which does not contain any active ingredient, also has a slight inhibitory effect on Helicobacter pylori of some strains.
上述の試験結果から分かるように、本実施例における薬物構造体は単一の活性成分を含むだけであるが、やはり効果的にヘリコバクターピロリを抑制することができる。本実施例において、該薬物構造体は前述したヘリコバクターピロリを抑制可能な活性成分のうち１種類の活性成分を含むのみであり、即ち、該薬物構造体は単一成分を含むのみで、その他活性成分またはヘリコバクターピロリの抑制を補助する補助活性成分を含んでいない。但し、その他の実施例において、該薬物構造体は２種類以上の活性成分、または補助活性成分を含んでもよく、本実施例に限らない。 As can be seen from the above-mentioned test results, the drug structure in this example only contains a single active ingredient, but it can also effectively suppress Helicobacter pylori. In this example, the drug structure contains only one kind of active ingredient among the above-mentioned active ingredients capable of suppressing Helicobacter pylori, that is, the drug structure contains only a single ingredient and other active ingredients. It does not contain any ingredients or co-active ingredients that help control Helicobacter pylori. However, in other examples, the drug structure may contain two or more kinds of active ingredients or auxiliary active ingredients, and is not limited to this example.
本実施例において、該補助活性成分とは、ヘリコバクターピロリの抑制を補助する活性を備えた物質を指し、所謂「ヘリコバクターピロリの抑制を補助する活性を備えた物質（ｓｕｂｓｔａｎｃｅ ｈａｖｉｎｇ ａｕｘｉｌｉａｒｙ ａｃｔｉｖｉｔｙ ｏｆ ｉｎｈｉｂｉｔｉｎｇ Ｈ．ｐｙｌｏｒｉ）」とは、直接的でなく前述の「ヘリコバクターピロリを抑制する」活性を備え、前述の活性成分にその効果を有利に発揮させる物質を指す。例えば、現行の胃潰瘍治療の投薬において、抗生物質を使用するほか、さらにプロトンポンプ阻害薬を併用する必要がある。該プロトンポンプ阻害薬は直接ヘリコバクターピロリを抑制する活性を備えておらず、補助的に抗生物質の効果を高めるものである。つまり、前述のプロトンポンプ阻害薬は、「ヘリコバクターピロリの抑制を補助する活性」を備えた物質の一種である。前述のプロトンポンプ阻害薬のほか、その他補助活性成分（例えばビスマス剤等の補助活性成分）を含む。 In the present Example, the auxiliary active ingredient refers to a substance having an activity of assisting the suppression of Helicobacter pylori, and is referred to as a so-called “substance having aiding activity of inhibiting H. pylori. “Pylori)” refers to a substance that has the above-mentioned “inhibit Helicobacter pylori” activity rather than direct action, and causes the above-mentioned active ingredient to exert its effect advantageously. For example, in the current medication for treating gastric ulcer, in addition to the use of antibiotics, it is necessary to use a proton pump inhibitor in combination. The proton pump inhibitor does not have the activity of directly suppressing Helicobacter pylori, but supplementally enhances the effect of antibiotics. That is, the above-mentioned proton pump inhibitor is a kind of substance having “activity that helps suppress Helicobacter pylori”. In addition to the above-mentioned proton pump inhibitor, other auxiliary active ingredients (for example, auxiliary active ingredients such as bismuth agents) are included.
しかしながら、本実施例における補助活性成分は薬理学的に薬物の投与補助、薬物の味の改善、または薬物の保存期間延長のために設計された物質を含まない点に注意すべきである。例えば、本実施例における補助活性成分は、医薬用担体、風味剤、または防腐剤等、薬物構造体中に常用される添加剤を含まない。 However, it should be noted that the auxiliary active ingredients in this example do not include substances that are pharmacologically designed to aid administration of the drug, improve the taste of the drug, or extend the shelf life of the drug. For example, the supplementary active ingredients in this example do not include additives commonly used in drug structures such as pharmaceutical carriers, flavors, or preservatives.
本実施例において、同時に生物体外でヘリコバクターピロリを抑制する方法を提供する。この方法は、前述の薬物構造体を提供する工程と、有効量の該薬物構造体をヘリコバクターピロリ群体に投与する工程を含む。本実施例において、ヘリコバクターピロリを抑制する方法はさらに、外部磁場を提供し、該薬物構造体に印加する工程を含んでもよく、該薬物構造体により的を絞ってヘリコバクターピロリを抑制、さらには消滅させることができる。但し、その他実施例において、該外部磁場を印加しないことを選択してもよく、本実施例に限らない。このほか、本実施例のヘリコバクターピロリを抑制する方法において、本実施例の薬物構造体のみを投与することを選択し、その他ヘリコバクターピロリを抑制する活性成分または補助活性成分を組み合わせて投与せず、またその他ヘリコバクターピロリを抑制する手段を組み合わせないこともできる。 In this example, at the same time, a method for suppressing Helicobacter pylori outside an organism is provided. The method comprises the steps of providing a drug structure as described above and administering an effective amount of the drug structure to a Helicobacter pylori colony. In this example, the method for suppressing Helicobacter pylori may further include the step of providing an external magnetic field and applying to the drug structure, wherein the drug structure is targeted to suppress Helicobacter pylori, and even disappear. Can be made. However, in other embodiments, it may be selected not to apply the external magnetic field, and the present invention is not limited to this embodiment. In addition, in the method of suppressing Helicobacter pylori of the present Example, it is selected to administer only the drug structure of the present Example, other active ingredients or auxiliary active ingredients that suppress Helicobacter pylori are not administered in combination, It is also possible not to combine other means for suppressing Helicobacter pylori.
本実施例において、本実施例の薬物構造体を使用してヘリコバクターピロリを抑制するとき、該薬物構造体の有効量は１〜１０ｍｇ／ｋｇ／ｄａｙとすることができ、３〜７ｍｇ／ｋｇ／ｄａｙが好ましく、５ｍｇ／ｋｇ／ｄａｙが最も好ましい。 In this Example, when Helicobacter pylori is suppressed using the drug structure of this Example, the effective amount of the drug structure can be 1 to 10 mg/kg/day, and 3 to 7 mg/kg/day. Day is preferred and 5 mg/kg/day is most preferred.
このほか、本実施例の薬物構造体はさらに、薬物服用回数及び数量の減少、薬物により引き起こされる副作用の緩和、治療を受ける個体の服薬コンプライアンス向上などを含め、その他用途に用いることができる。 In addition, the drug structure of this example can be used for other purposes, such as reducing the frequency and number of drug administrations, alleviating side effects caused by drugs, and improving compliance of the individual receiving treatment.
上述の薬物担体及び薬物構造体には磁性粒子が含有され、外部磁場の誘導を受けて該薬物構造体が生物体の胃の特定位置に停留する時間を延長することができ、該薬物構造体中の薬物の放出及び該薬物構造体の生物体内における停留時間延長に有利である。同時に、該薬物担体及び該薬物構造体は外部磁場の誘導を受けて胃粘膜層を迅速に通過し、病原菌が凝集する位置近くで薬物放出と殺菌を行うことができる。上述の薬物担体及び薬物構造体により、薬物構造体の治療効果をより高めることができ、患者が１回に服用する薬物の数量を減少し、過多な薬物を服用することで患者に生じる副作用の問題を解決することができる。 The above-mentioned drug carrier and drug structure contain magnetic particles, which can prolong the time for which the drug structure stays at a specific position in the stomach of an organism under the influence of an external magnetic field. It is advantageous for the release of the drug therein and the extension of the residence time of the drug structure in the living body. At the same time, the drug carrier and the drug structure can be rapidly passed through the gastric mucosal layer under the influence of an external magnetic field to perform drug release and sterilization near the position where pathogenic bacteria aggregate. The above-mentioned drug carrier and drug structure can further enhance the therapeutic effect of the drug structure, reduce the number of drugs taken by the patient at one time, and reduce the side effects of patients who take too much drug. Can solve the problem.
本発明は上述で最良の実施例を開示したが、当業者であれば理解できるように、この実施例は単に本発明を説明するために用いたのみであり、本発明の範囲を限定すると理解されるべきではない。注意すべきは、この実施例と同等効果を有する変化および置換はすべて、本発明の範疇内に含まれることである。このため、本発明の保護範囲は、特許請求の範囲の定義に準じる。
Although the present invention has been disclosed above with reference to the best embodiment, it will be understood by those skilled in the art that this embodiment is merely used to illustrate the present invention and limits the scope of the present invention. Should not be done. It should be noted that all changes and substitutions having the same effect as this embodiment are included in the scope of the present invention. Therefore, the protection scope of the present invention complies with the definition of the claims.
Claims (20)
（ａ）９０〜１１０重量部の負電荷を持つポリマー溶液と、４００〜１２５０重量部のキトサン溶液と、１５０〜５００重量部の磁性粒子を提供する工程と、
（ｂ）該負電荷を持つポリマー溶液と、該キトサン溶液及び該磁性粒子を混合し、初期溶液とする工程と、
（ｃ）該初期溶液を少なくとも１０分間以上撹拌し、薬物担体粒子を形成する工程と、
を含むことを特徴とする、薬物担体の製造方法。 A method for producing a drug carrier, comprising:
(A) providing 90 to 110 parts by weight of a negatively charged polymer solution, 400 to 1250 parts by weight of a chitosan solution, and 150 to 500 parts by weight of magnetic particles;
(B) a step of mixing the polymer solution having the negative charge, the chitosan solution and the magnetic particles to obtain an initial solution,
(C) stirring the initial solution for at least 10 minutes or more to form drug carrier particles;
A method for producing a drug carrier, which comprises:
（ａ）９０〜１１０重量部の負電荷を持つポリマー溶液と、４００〜１２５０重量部のキトサン溶液と、１５０〜５００重量部の磁性粒子と、５００〜１５００重量部の活性成分溶液を提供する工程と、
（ｂ）該負電荷を持つポリマー溶液と、該キトサン溶液と、該磁性粒子と、該活性成分溶液を混合し、初期溶液とする工程と、
（ｃ）該初期溶液を少なくとも１０分間以上撹拌し、薬物担体粒子を形成する工程と、
を含むことを特徴とする、薬物構造体の製造方法。 A method of manufacturing a drug structure, comprising:
(A) providing 90 to 110 parts by weight of a negatively charged polymer solution, 400 to 1250 parts by weight of chitosan solution, 150 to 500 parts by weight of magnetic particles, and 500 to 1500 parts by weight of an active ingredient solution When,
(B) a step of mixing the negatively charged polymer solution, the chitosan solution, the magnetic particles, and the active ingredient solution to obtain an initial solution,
(C) stirring the initial solution for at least 10 minutes or more to form drug carrier particles;
A method for producing a drug structure, comprising:
（ａ）請求項９乃至１６のいずれかに記載の薬物構造体を提供する工程と、
（ｂ）有効量の該薬物構造体をヘリコバクターピロリ群体に投与する工程と、
を含むことを特徴とする、ヘリコバクターピロリを抑制する方法。 A method of suppressing Helicobacter pylori,
(A) providing the drug structure according to any one of claims 9 to 16;
(B) administering an effective amount of the drug structure to a Helicobacter pylori colony,
A method for suppressing Helicobacter pylori, comprising:
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