JPWO2020066577A1 - Periodontal disease remedy - Google Patents
Periodontal disease remedy Download PDFInfo
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- JPWO2020066577A1 JPWO2020066577A1 JP2020548356A JP2020548356A JPWO2020066577A1 JP WO2020066577 A1 JPWO2020066577 A1 JP WO2020066577A1 JP 2020548356 A JP2020548356 A JP 2020548356A JP 2020548356 A JP2020548356 A JP 2020548356A JP WO2020066577 A1 JPWO2020066577 A1 JP WO2020066577A1
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- ala
- periodontal disease
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Abstract
本発明は、従来の光線動力学的治療法(PDT)では効力示さない歯周病病原菌に対してもPDTが可能となる治療薬及び治療方法を提供することを課題とする。
下記式(I)
【化1】
(式中、R1は、水素原子又はアシル基を表し、R2は、水素原子、アルキル基、シクロアルキル基、アリール基又はアラルキル基を表す。)で表される化合物又は薬学的に許容されるその塩を含む歯周病の治療薬を、歯周病患部に投与し、その後360nm〜700nmの波長の光を照射する。An object of the present invention is to provide a therapeutic agent and a therapeutic method that enable PDT even for periodontal disease pathogens that are not effective by conventional photodynamic therapy (PDT).
The following formula (I)
[Chemical 1]
(In the formula, R 1 represents a hydrogen atom or an acyl group, and R 2 represents a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group or an aralkyl group) or a pharmaceutically acceptable compound. A therapeutic agent for periodontal disease containing a salt thereof is administered to the affected part of the periodontal disease, and then light having a wavelength of 360 nm to 700 nm is irradiated.
Description
本発明は、5−アミノレブリン酸(以下「ALA」ということがある。)若しくはその誘導体又はそれらの塩を含有し、360nm〜700nmの波長の光を照射するALA−光線力学的療法(以下「ALA−PDT」ということがある。)において用いられる歯周病の治療剤に関する。 The present invention contains 5-aminolevulinic acid (hereinafter sometimes referred to as "ALA") or a derivative thereof or a salt thereof, and irradiates light having a wavelength of 360 nm to 700 nm ALA-photodynamic therapy (hereinafter referred to as "ALA"). -PDT "), which relates to a therapeutic agent for periodontal disease.
近年、光に反応する化合物を投与し、光を照射することにより標的箇所を治療する方法である光線動力学的療法(以下PDTという。)が開発されてきた。PDTは、治療が簡便で、生体侵襲性が小さく、臓器温存が可能であること等から、クオリティ・オブ・ライフ(Quality Of Life;QOL)を考慮した新たながん治療法として注目されている。 In recent years, photodynamic therapy (hereinafter referred to as PDT), which is a method of treating a target site by administering a compound that reacts with light and irradiating with light, has been developed. PDT is attracting attention as a new cancer treatment method considering Quality Of Life (QOL) because it is easy to treat, has low bioinvasiveness, and can preserve organs. ..
PDTに用いられる薬剤の一つであるALAは、動物や植物や菌類に広く存在する色素生合成経路の中間体として知られており、通常ALAシンセターゼにより、スクシニルCoAとグリシンとから生合成される。ALA自体には光感受性はないが、細胞内でヘム生合成経路の一連の酵素群によりプロトポルフィリンIX(以下「PpIX」ともいう)に代謝活性化され、直接腫瘍組織や新生血管へ特異的に集積し、かかるPpIX集積部位にレーザー光を照射すると、光の励起により生ずる一重項酸素及び/又はヒドロキシルラジカル、スーパーオキシド等に代表される活性酸素種によりがん細胞が変性・壊死することが知られている。 ALA, one of the drugs used for PDT, is known as an intermediate in the pigment biosynthesis pathway widely present in animals, plants and fungi, and is usually biosynthesized from succinyl-CoA and glycine by ALA synthesizer. .. Although ALA itself is not photosensitive, it is metabolically activated into protoporphyrin IX (hereinafter also referred to as "PpIX") by a series of enzymes in the heme biosynthetic pathway in cells, and is directly directed to tumor tissue and new blood vessels. It is known that when the PpIX accumulation site is accumulated and the PpIX accumulation site is irradiated with laser light, cancer cells are denatured and necrotic by active oxygen species typified by singlet oxygen and / or hydroxyl radical, superoxide, etc. generated by excitation of light. Has been done.
1986年にカナダクイーンズ大ケネディー教授が、ALAを塗布し、光を照射することで皮膚がんの治療ができることを報告(例えば、非特許文献1参照)して以来、ALAを用いた様々な部位の病変部等の診断及び治療方法が報告されており、例えば、ALAを体内に投与すると、がんにALAから誘導されるPpIXが蓄積し、光照射で蛍光を発するという知見に基づいて開発された腫瘍診断剤等が提案されている(例えば、特許文献1及び2参照)。
Since Professor Kennedy of Queens University of Canada reported in 1986 that skin cancer can be treated by applying ALA and irradiating it with light (see, for example, Non-Patent Document 1), various sites using ALA have been used. Diagnosis and treatment methods for lesions of ALA have been reported. For example, it was developed based on the finding that when ALA is administered into the body, PpIX induced from ALA accumulates in cancer and emits fluorescence by light irradiation. Tumor diagnostic agents and the like have been proposed (see, for example,
一方、歯周病治療の分野においても、広義の光療法(phototherapy)として、約20年前より高出力レーザーをはじめとしたさまざまな光エネルギーを用いた治療が行われており、最近は、光と色素の併用による光化学反応を使用した抗菌的光線力学的療法(antimicrobial photodynamic therapy: a−PDT)が、新しい手段として注目を集めている。 On the other hand, in the field of periodontal disease treatment, as phototherapy in a broad sense, treatment using various light energies such as high-power laser has been performed for about 20 years, and recently, light Antimicrobial photodynamic therapy (a-PDT), which uses a photochemical reaction in combination with a dye, is attracting attention as a new means.
歯周病の原因菌の一つであるエンテロコッカス・フェカリス(E.フェカリス)を滅菌した単根歯中において培養液AC Broth(アルドリッチ社製)を用いて4週間培養し、100μmolのメチレンブルーの溶液で洗浄後、660nmの光を照射したが、E.フェカリスは死滅しないことが知られている(特許文献3参照)。 Enterococcus faecalis (E. faecalis), which is one of the causative bacteria of periodontal disease, was cultured in sterilized single root teeth using the culture solution AC Broth (manufactured by Aldrich) for 4 weeks, and in a 100 μmol methylene blue solution. After washing, it was irradiated with light of 660 nm. It is known that Fecalis does not die (see Patent Document 3).
また、よりエネルギーの高い波長405nmの半導体レーザーを、歯周病原因菌であるポルフィノモナス・ジンジバリス(P.ジンジバリス)、プレボテラ・インターメディア(P.インターメディア)、E.フェカリスに照射したところ、照射時間と照射光強度に比例して、P.ジンジバリス及びP.インターメディアは、菌体数が減少したが、E.フェカリスは、菌体数は減少しなかったことが知られている(非特許文献2)。 In addition, semiconductor lasers with a higher energy wavelength of 405 nm were used by Porphyromonas gingivalis (P. gingivalis), Prevotella intermedia (P. intermedia), which are the causative agents of periodontal disease. When Fecalis was irradiated, P.I. Gingivalis and P.I. In the intermedia, the number of cells decreased, but E. It is known that the number of cells of Fecalis did not decrease (Non-Patent Document 2).
PDTは、非侵襲性で副作用や患者への肉体的苦痛はほとんど無く、安全且つ簡単な治療法であるにも関わらず、歯周病原因菌の中に従来の方法では効力を示さない菌がいるという問題に直面した。
本発明の課題は、従来のPDTでは効力を示さない歯周病病原菌に対してもPDTが可能となる治療薬、治療方法等を提供することにある。PDT is non-invasive, has almost no side effects or physical pain to the patient, and although it is a safe and easy treatment method, some of the bacteria that cause periodontal disease are not effective by conventional methods. I faced the problem of being there.
An object of the present invention is to provide a therapeutic agent, a therapeutic method, etc. that enable PDT even for periodontal disease pathogens that are not effective with conventional PDT.
本発明者らは、E.フェカリスが光照射しても死滅しないのは、もともと菌体内で、PpIXを生合成できないためであると考え、生体内でPpIXを生成できるように、ALAを添加した培地でE.フェカリスを培養し、光を照射したが、菌は死滅しなかった。そこで、培養条件を種々検討した結果、ALAの存在下、嫌気性条件下に培養を行い、その後光照射することでE.フェカリスを死滅させることができることを見いだし、本発明を完成するに至った。 The present inventors have described E.I. It is thought that the reason why Fecalis does not die even when irradiated with light is that PpIX cannot be biosynthesized in the cells, and E.I. Fecalis was cultivated and irradiated with light, but the bacteria did not die. Therefore, as a result of various studies on the culture conditions, E.I. It was found that Fecalis could be killed, and the present invention was completed.
すなわち、本発明は以下の事項により特定される次のとおりのものである。
(1)下記式(I)
(式中、R1は、水素原子又はアシル基を表し、R2は、水素原子、アルキル基、シクロアルキル基、アリール基又はアラルキル基を表す。)で表される化合物又は薬学的に許容されるそれらの塩(以下「ALA類」ということがある。)を含み、歯周病患部に式(I)で表される化合物又は薬学的に許容されるそれらの塩を投与し、その後360nm〜700nmの波長の光を照射する5−アミノレブリン酸−光線力学的療法のための歯周病の治療薬。
(2)歯周病における歯周病原因菌が、E.フェカリスである(1)に記載の治療薬。
(3)360nm〜700nmの波長の光が、青色発光ダイオードである(1)に記載の治療薬。
また本発明の他の実施態様は以下のとおりである。
(4)上記式(I)で表される化合物又は薬学的に許容されるそれらの塩を歯周病患部に投与し、その後360nm〜700nmの波長の光を照射する歯周病の治療方法。
(5)歯周病患部に投与し、その後360nm〜700nmの波長の光を照射する歯周病の治療に用いるための上記式(I)で表される化合物又は薬学的に許容されるそれらの塩。
(6)歯周病患部に投与し、その後360nm〜700nmの波長の光を照射する歯周病の治療薬の製造に用いるための上記式(I)で表される化合物又は薬学的に許容されるそれらの塩の利用。That is, the present invention is as follows specified by the following matters.
(1) The following formula (I)
(In the formula, R 1 represents a hydrogen atom or an acyl group, and R 2 represents a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group or an aralkyl group) or a pharmaceutically acceptable compound. These salts (hereinafter sometimes referred to as "ALAs") are contained, and the compound represented by the formula (I) or pharmaceutically acceptable salts thereof is administered to the affected part of the periodontal disease, and then 360 nm. 5-Aminolevulinic acid-a therapeutic agent for periodontal disease for photodynamic therapy, which irradiates light with a wavelength of ~ 700 nm.
(2) Periodontal disease-causing bacteria in periodontal disease are E.I. The therapeutic agent according to (1), which is Fecalis.
(3) The therapeutic agent according to (1), wherein the light having a wavelength of 360 nm to 700 nm is a blue light emitting diode.
In addition, other embodiments of the present invention are as follows.
(4) A method for treating periodontal disease in which a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof is administered to the affected area of periodontal disease and then irradiated with light having a wavelength of 360 nm to 700 nm. ..
(5) Compounds represented by the above formula (I) or pharmaceutically acceptable compounds for use in the treatment of periodontal disease, which are administered to the affected area of periodontal disease and then irradiated with light having a wavelength of 360 nm to 700 nm. Salt.
(6) The compound represented by the above formula (I) or pharmaceutically acceptable for use in the production of a therapeutic agent for periodontal disease, which is administered to the affected area of periodontal disease and then irradiated with light having a wavelength of 360 nm to 700 nm. The use of those salts to be done.
本発明の歯周病の治療剤を用いて歯周病の治療を行うと、非侵襲性で副作用や患者への肉体的苦痛はほとんど無く、安全且つ簡単に、従来の方法では効力が及ばなかった歯周病原因菌が原因となる歯周病をも治療することができる。 Treatment of periodontal disease using the therapeutic agent for periodontal disease of the present invention is non-invasive, has almost no side effects or physical pain to the patient, is safe and easy, and is ineffective by conventional methods. Periodontal disease caused by bacteria that cause periodontal disease can also be treated.
本発明の歯周病の治療剤としては、ALA類を含有し、360nm〜700nmの波長の光を照射するALA−PDTにおいて用いられるALA−PDTのための治療剤であれば特に制限されず、360nm〜700nmの波長の光を照射するALA−PDTの前に、360nm〜420nmの波長の励起光を照射して、PpIX蓄積部位を検出する5−アミノレブリン酸−光線力学的診断(ALA−PDD)を行うこともできるが、かかるALA−PDDを行うことを必要としない治療剤を特に好適に例示することができる。また、本発明の歯周病の治療剤が適用される治療システムとしては、ALA−PDTデバイスを具備したシステムであればよく、ALA類の投与デバイスやALA−PDDを備えたものであってよい。 The therapeutic agent for periodontal disease of the present invention is not particularly limited as long as it is a therapeutic agent for ALA-PDT that contains ALA and is used in ALA-PDT that irradiates light having a wavelength of 360 nm to 700 nm. 5-Aminolevulinic acid-photodynamic diagnosis (ALA-PDD) to detect PpIX accumulation sites by irradiating excitation light with a wavelength of 360 nm to 420 nm before ALA-PDT irradiating light with a wavelength of 360 nm to 700 nm. However, a therapeutic agent that does not require such ALA-PDD can be particularly preferably exemplified. Further, the treatment system to which the therapeutic agent for periodontal disease of the present invention is applied may be any system provided with an ALA-PDT device, and may be provided with an ALA-class administration device or an ALA-PDD. ..
式(I)で示される化合物中、R1は、水素原子又はアシル基を表し、R2は、水素原子、直鎖若しくは分岐状アルキル基、シクロアルキル基、アリール基又はアラルキル基を表す。In the compound represented by the formula (I), R 1 represents a hydrogen atom or an acyl group, and R 2 represents a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group, an aryl group or an aralkyl group.
R1におけるアシル基としては、ホルミル基、アセチル基、プロピオニル基、ブチリル基、イソブチリル基、バレリル基、イソバレリル基、ピバロイル基、ヘキサノイル基、オクタノイル基、ベンジルカルボニル基等の直鎖又は分岐状の炭素数1〜8のアルカノイル基や、ベンゾイル基、1−ナフトイル基、2−ナフトイル基等の炭素数7〜14のアロイル基を挙げることができる。なお、本発明において、アシル基に、メトキシカルボニル基、エトキシカルボニル基、n−プロポキシカルボニル基、イソプロポキシカルボニル基等のアルコキシカルボニル基を便宜上含むものとする。Examples of the acyl group in R 1 include linear or branched carbons such as formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, hexanoyl group, octanoyl group and benzylcarbonyl group. Examples thereof include an alkanoyl group having a number of 1 to 8 and an aloyl group having 7 to 14 carbon atoms such as a benzoyl group, a 1-naphthoyl group and a 2-naphthoyl group. In the present invention, the acyl group includes an alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, or an isopropoxycarbonyl group for convenience.
R2におけるアルキル基としては、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、sec−ブチル基、tert−ブチル基、ペンチル基、イソペンチル基、ネオペンチル基、ヘキシル基、ヘプチル基、オクチル基等の直鎖又は分岐状の炭素数1〜8のアルキル基を挙げることができる。The alkyl group in R 2, a methyl group, an ethyl group, a propyl group, an isopropyl group, butyl group, isobutyl group, sec- butyl group, tert- butyl group, a pentyl group, an isopentyl group, a neopentyl group, a hexyl group, a heptyl group , A linear or branched alkyl group having 1 to 8 carbon atoms such as an octyl group can be mentioned.
R2におけるシクロアルキル基としては、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、シクロヘプチル基、シクロオクチル基、シクロドデシル基、1−シクロヘキセニル基等の飽和又は一部不飽和結合が存在する炭素数3〜8のシクロアルキル基を挙げることができる。As the cycloalkyl group in R 2, there are saturated or partially unsaturated bonds such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclododecyl group, and a 1-cyclohexenyl group. Cycloalkyl groups having 3 to 8 carbon atoms can be mentioned.
R2におけるアリール基としては、フェニル基、ナフチル基、アントリル基、フェナントリル基等の炭素数6〜14のアリール基を挙げることができる。Examples of the aryl group in R 2 include an aryl group having 6 to 14 carbon atoms such as a phenyl group, a naphthyl group, an anthryl group and a phenanthryl group.
R2におけるアラルキル基としては、アリール部分は上記アリール基と同じ例示ができ、アルキル部分は上記アルキル基と同じ例示ができ、具体的には、ベンジル基、フェネチル基、フェニルプロピル基、フェニルブチル基、ベンズヒドリル基、トリチル基、ナフチルメチル基、ナフチルエチル基等の炭素数7〜20のアラルキル基を挙げることができる。The aralkyl group in R 2, the aryl moiety can be the same example as above aryl group, the alkyl moiety can be the same example as above alkyl group, specifically, a benzyl group, phenethyl group, phenylpropyl group, phenylbutyl group , Benzhydryl group, trityl group, naphthylmethyl group, naphthylethyl group and other aralkyl groups having 7 to 20 carbon atoms can be mentioned.
上記R1及びR2は、必要に応じて化学的に許容される範囲で置換基を有していてもよく、そのような置換基として、例えば、ハロゲン原子、アルキル基、ハロアルキル基、アルコキシ基、ニトロ基、アリール基等が挙げられる。The above R 1 and R 2 may have a substituent within a chemically acceptable range, if necessary, and examples of such a substituent include a halogen atom, an alkyl group, a haloalkyl group, and an alkoxy group. , Nitro group, aryl group and the like.
式(I)で表される化合物として、生体内において、PpIXを形成することができるALAの任意のALA誘導体として作用するのが好ましく、例えば、生体内でALAを形成し得るALAプロドラッグ又は中間体としてALAを形成せずにポルフィリンに変換(例えば、酵素的に)されるALAプロドラッグが挙げられ、中でも、ALAエステルが好ましく挙げられる。 As the compound represented by the formula (I), it is preferable to act as any ALA derivative of ALA capable of forming PpIX in vivo, for example, an ALA prodrug or an intermediate capable of forming ALA in vivo. Examples of the ALA prodrug which is converted (for example, enzymatically) to porphyrin without forming ALA as a body are mentioned, and among them, ALA ester is preferably mentioned.
ALAエステルとして、例えば、ALA メチルエステル、ALA エチルエステル、ALA n−プロピルエステル、ALA n−ブチルエステル、ALA n−ペンチルエステル、ALA n−ヘキシルエステル、ALA n−オクチルエステル、ALA 2−メトキシエチルエステル、ALA 2−メチル−n−ペンチルエステル、ALA 4−メチル−n−ペンチルエステル、ALA 1−エチル−n−ブチルエステル、ALA 3,3−ジメチル−n−ブチルエステル、ALA ベンジルエステル、ALA 4−イソプロピルベンジルエステル、ALA 4−メチルベンジルエステル、ALA 2−メチルベンジルエステル、ALA 3−メチルベンジルエステル、ALA 4−(t−ブチル)ベンジルエステル、ALA 4−(トリフルオロメチル)ベンジルエステル、ALA 4−メトキシベンジルエステル、ALA 3,4−(ジクロロ)ベンジルエステル、ALA 4−クロロベンジルエステル、ALA 4−フルオロベンジルエステル、ALA 2−フルオロベンジルエステル、ALA 3−フルオロベンジルエステル、ALA 2,3,4,5,6−ペンタフルオロベンジルエステル、ALA 3−ニトロベンジルエステル、ALA 4−ニトロベンジルエステル、ALA 2−フェニルエチルエステル、ALA 4−フェニルブチルエステル、ALA 3−ピリジル−メチルエステル、ALA 4−フェニルベンジルエステル、N−[(1−アセチルオキシ)エトキシカルボニル]ALA ベンジルエステル、N−ホルミル−ALA メチルエステル、N−アセチル−ALA エチルエステル、N−プロピオニル−ALA メチルエステル、N−ブチリル−ALA メチルエステル、N−ホルミル−ALA エチルエステル、N−アセチル−ALA エチルエステル、N−プロピオニル−ALA エチルエステル、N−ブチリル−ALA エチルエステルが挙げられる。 Examples of ALA esters include ALA methyl ester, ALA ethyl ester, ALA n-propyl ester, ALA n-butyl ester, ALA n-pentyl ester, ALA n-hexyl ester, ALA n-octyl ester, and ALA 2-methoxyethyl ester. , ALA 2-methyl-n-pentyl ester, ALA 4-methyl-n-pentyl ester, ALA 1-ethyl-n-butyl ester, ALA 3,3-dimethyl-n-butyl ester, ALA benzyl ester, ALA 4- Isopropylbenzyl ester, ALA 4-methylbenzyl ester, ALA 2-methylbenzyl ester, ALA 3-methylbenzyl ester, ALA 4- (t-butyl) benzyl ester, ALA 4- (trifluoromethyl) benzyl ester, ALA 4- Methoxybenzyl ester, ALA 3,4- (dichloro) benzyl ester, ALA 4-chlorobenzyl ester, ALA 4-fluorobenzyl ester, ALA 2-fluorobenzyl ester, ALA 3-fluorobenzyl ester, ALA 2,3,4 5,6-Pentafluorobenzyl ester, ALA 3-nitrobenzyl ester, ALA 4-nitrobenzyl ester, ALA 2-phenylethyl ester, ALA 4-phenylbutyl ester, ALA 3-pyridyl-methyl ester, ALA 4-phenylbenzyl Esters, N-[(1-acetyloxy) ethoxycarbonyl] ALA benzyl ester, N-formyl-ALA methyl ester, N-acetyl-ALA ethyl ester, N-propionyl-ALA methyl ester, N-butyryl-ALA methyl ester, Examples thereof include N-formyl-ALA ethyl ester, N-acetyl-ALA ethyl ester, N-propionyl-ALA ethyl ester, and N-butyryl-ALA ethyl ester.
式(I)で表される化合物は、投与する形態に応じて、溶解性を上げるための各種の塩として投与することができる。式(I)で表される化合物の塩として、例えば、薬理学的に許容される酸付加塩、金属塩、アンモニウム塩、有機アミン付加塩等が挙げられる。酸付加塩として、例えば、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、リン酸塩、硝酸塩、硫酸塩等の各無機酸塩、ギ酸塩、酢酸塩、プロピオン酸塩、トルエンスルホン酸塩、コハク酸塩、シュウ酸塩、乳酸塩、酒石酸塩、グリコール酸塩、メタンスルホン酸塩、酪酸塩、吉草酸塩、クエン酸塩、フマル酸塩、マレイン酸塩、リンゴ酸塩等の各有機酸付加塩等を例示することができる。金属塩としては、リチウム塩、ナトリウム塩、カリウム塩等の各アルカリ金属塩、マグネシウム、カルシウム塩等の各アルカリ土類金属塩、アルミニウム、亜鉛等の各金属塩を例示することができる。アンモニウム塩としては、アンモニウム塩、テトラメチルアンモニウム塩等のアルキルアンモニウム塩等を例示することができる。有機アミン塩としては、トリエチルアミン塩、ピペリジン塩、モルホリン塩、トルイジン塩等の各塩を例示することができる。なお、これらの塩は使用時において溶液としても用いることができる。 The compound represented by the formula (I) can be administered as various salts for increasing solubility depending on the form of administration. Examples of the salt of the compound represented by the formula (I) include a pharmacologically acceptable acid addition salt, metal salt, ammonium salt, organic amine addition salt and the like. As acid addition salts, for example, each inorganic acid salt such as hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate, formate, acetate, propionate, toluenesulfonic acid Salt, succinate, oxalate, lactate, tartrate, glycolate, methanesulfonate, butyrate, valerate, citrate, fumarate, maleate, malate, etc. Examples thereof include organic acid addition salts. Examples of the metal salt include alkali metal salts such as lithium salt, sodium salt and potassium salt, alkaline earth metal salts such as magnesium and calcium salt, and metal salts such as aluminum and zinc. Examples of the ammonium salt include alkylammonium salts such as ammonium salt and tetramethylammonium salt. Examples of the organic amine salt include each salt such as triethylamine salt, piperidine salt, morpholine salt, and toluidine salt. These salts can also be used as a solution at the time of use.
ALA誘導体として、ALA又はALA メチルエステル、ALA エチルエステル、ALA プロピルエステル、ALA ブチルエステル、ALA ペンチルエステル等の各種エステル類、及びにこれらの塩酸塩、リン酸塩、硫酸塩が好ましく挙げられ、ALA塩酸塩やALAリン酸塩が特に好ましく挙げられる。 As the ALA derivative, various esters such as ALA or ALA methyl ester, ALA ethyl ester, ALA propyl ester, ALA butyl ester and ALA pentyl ester, and these hydrochlorides, phosphates and sulfates are preferably mentioned, and ALA is preferable. Hydrochlorides and ALA phosphates are particularly preferred.
ALA誘導体は、化学合成、微生物による生産、酵素による生産のいずれの公知の方法によって製造することができる。また、上記ALA誘導体は、水和物又は溶媒和物を形成していてもよく、またいずれかを単独で又は2種以上を適宜組み合わせて用いることができる。 The ALA derivative can be produced by any known method of chemical synthesis, microbial production, or enzymatic production. In addition, the ALA derivative may form a hydrate or a solvate, and either of them may be used alone or in combination of two or more.
上記ALA誘導体を水溶液として調製する場合には、ALA誘導体の分解を防ぐため、水溶液がアルカリ性とならないように留意する必要がある。アルカリ性となってしまう場合は、酸素を除去することによって分解を防ぐことができる。 When the above ALA derivative is prepared as an aqueous solution, care must be taken not to make the aqueous solution alkaline in order to prevent decomposition of the ALA derivative. If it becomes alkaline, it can be prevented from decomposing by removing oxygen.
前記ALA類に加えて、必要に応じて以下に示す光増感剤を混合して使用することも同時投与することもできる。
ヘマトポルフィリン誘導体(HpD);フォトフリン[Photofrin](登録商標)(クアドラ ロジック テクノロジーズ社,バンクーバー,カナダ)、ヘマトポルフィリンIX(HpIX)等のヘマトポルフィリン;フォトサン[Photosan]III(シーホフ ラボラトリアム社,シーホフ,ヴェッセルブレーネルコーフ,ドイツ);テトラ(m−ヒドロキシフェニル)クロリン(m−THPC)、バクテリオクロリン(スコティア製薬会社,サリー州,イギリス)、モノ−L−アスパラチルクロリンe6(NPe6)(日本石油化学会社,カリフォルニア州,アメリカ)、クロリンe6(ポルフィリン プロダクト社)、ベンゾポルフィリン(クアドラ ロジック テクノロジーズ社,バンクーバー,カナダ)(例えば、benzoporphyrin derivative monoacid ring A、BPD−MA)、プルプリン[purpurine](PDT製薬会社,カリフォルニア州,アメリカ)(例えば、スズ−エチルエチオプルプリン[tin-ethyl etiopurpurin]、SnET2)等のクロリン;フタロシアニン(例えば、亜鉛−(クアドラロジックテクノロジーズ社,バンクーバー,カナダ)、いくらかのアルミニウム−又はシリコンフタロシアニン,これらはスルホン酸化されていてもよく、特にアルミニウムフタロシアニンジスルホン酸(AlPcS2a)、アルミニウムフタロシアニンテトラスルホン酸(AlPcS4)等のスルホン酸化フタロシアニン);ポルフィセン;ヒポクレリリン[hypocrellin];プロトポルフィリンIX(PpIX);ヘマトポルフィリンジ−エステル;ウロポルフィリン;コプロポルフィリン;ジュウテロポルフィリン;ポリヘマトポルフィリン(PHP)、及びそれらの前駆体、誘導体;テトラサイクリン(例えば、トピサイクリン[Topicycline](登録商標)、シャイアー社[Shire])。
これらは、1種単独で、又は2種以上を混合して用いることができる。In addition to the ALAs, the following photosensitizers can be mixed and used or co-administered as needed.
Hematoporphyrin derivatives (HpD); Hematoporphyrins such as Photofrin (registered trademark) (Quadra Logic Technologies, Vancouver, Canada), Hematoporphyrin IX (HpIX); Siehoff, Wesselbrenerkov, Germany); Tetra (m-hydroxyphenyl) porphyrin (m-THPC), Bacterioporphyrin (Scotia Pharmaceutical Company, Sally, UK), Mono-L-Asparatyl Porphyrin e6 (NPe6) (Japan) Petrochemical Company, California, USA), Chlorin e6 (Porphyrin Products), Benzoporphyrin (Quadra Logic Technologies, Vancouver, Canada) (eg, benzoporphyrin derivative monoacid ring A, BPD-MA), Purpurine (PDT) Porphyrins such as pharmaceutical companies, California, USA (eg tin-ethyl etiopurpurin, SnET2); phthalocyanine (eg zinc- (Quadralogic Technologies, Vancouver, Canada), some aluminum -Or silicon phthalocyanine, which may be sulfonated, in particular sulfonated phthalocyanine such as aluminum phthalocyanine disulfonic acid (AlPcS 2a ), aluminum phthalocyanine tetrasulfonic acid (AlPcS 4 ); porphysen; hypocrellin; protoporphyrin. IX (PpIX); hematoporphyrin diester; uroporphyrin; coproporphyrin; juuteroporphyrin; polyhematoporphyrin (PHP) and its precursors and derivatives; tetracycline (eg, Topicycline®), Shire (Shire)).
These can be used alone or in combination of two or more.
さらに、ALA類は、光感作効果を上げ、よってPDTを促進することができる他の活性を有する化合物とともに投与することができる。そのような化合物として、例えば、キレート剤が挙げられ、より具体的には、アミノポリカルボン酸、金属解毒に関する文献又は磁気共鳴映像法に用いる造影剤中の常磁性金属イオンのキレート化に関する文献に記載されているキレート剤等が挙げられ、さらに具体的には、エチレンジアミン−N,N,N’,N’−四酢酸(EDTA)、1,2−ジアミノシクロヘキサン−N,N,N’,N’−四酢酸(CDTA)、ジエチレントリアミン−N,N,N’,N’’,N’’−五酢酸(DTPA)、1,4,7,10−テトラアザシクロドデカン−1,4,7,10−テトラ酢酸(DOTA)、デスフェリオキサミン又は周知のそれらの誘導体/類似体が挙げられ、これらは、1種単独で、又は2種以上を混合して用いることができる。
キレート剤を有する場合、該キレート剤は、標準的には0.05〜20%(w/v)の濃度で、例えば、0.1〜10%(w/v)の濃度で用いられる。In addition, ALAs can be administered with compounds having other activities that can enhance the photosensitizing effect and thus promote PDT. Examples of such compounds include chelating agents, and more specifically, in the literature on aminopolycarboxylic acid, metal detoxification, or the literature on chelation of paramagnetic metal ions in contrasting agents used in magnetic resonance imaging. Examples thereof include the listed chelating agents, and more specifically, ethylenediamine-N, N, N', N'-tetraacetic acid (EDTA), 1,2-diaminocyclohexane-N, N, N', N. '-Tetraacetic acid (CDTA), diethylenetriamine-N, N, N', N'', N'-pentetic acid (DTPA), 1,4,7,10-tetraazacyclododecane-1,4,7, Examples thereof include 10-tetraacetic acid (DOTA), desferrioxamine or well-known derivatives / analogs thereof, which can be used alone or in admixture of two or more.
When having a chelating agent, the chelating agent is typically used at a concentration of 0.05 to 20% (w / v), for example at a concentration of 0.1 to 10% (w / v).
本発明においてALA類を歯周病患部に投与するとは、歯周病患部又はその周辺へ局所投与することをいい、特に局所塗布が好ましい。歯周ポケット内への局所投与は、当該分野において公知の技術、例えば、注射器、カテーテル又は他の好適な薬物送達システムを使用することによって行うことができる。 In the present invention, administration of ALAs to a periodontal disease-affected portion means local administration to or around the periodontal disease-affected portion, and topical application is particularly preferable. Topical administration into the periodontal pocket can be performed by using techniques known in the art, such as syringes, catheters or other suitable drug delivery systems.
本発明の治療薬の剤型として、例えば、ゲル、クリーム、軟膏、スプレー、ローション、エアロゾル、外用液剤等が挙げられる。 Examples of the dosage form of the therapeutic agent of the present invention include gels, creams, ointments, sprays, lotions, aerosols, and external liquids.
本発明の治療薬において、含まれるALA類の濃度は、化合物の化学的性質、化学組成、投与方法及び治療されるべき疾患の程度を含むさまざまな要因に応じて変化するが、20%(w/v)未満の濃度範囲が好ましく、0.05〜16%(w/v)がさらに好ましく、0.5〜14%(w/v)が特に好ましく、例えば、1.5〜12.0%(w/v)又は2〜10%(w/v)の範囲を好適に例示することができる。 In the therapeutic agent of the present invention, the concentration of ALAs contained varies depending on various factors including the chemical properties, chemical composition, administration method and degree of the disease to be treated, but is 20% (w). A concentration range of less than / v) is preferred, more preferably 0.05 to 16% (w / v), particularly preferably 0.5 to 14% (w / v), for example 1.5 to 12.0%. A range of (w / v) or 2-10% (w / v) can be preferably exemplified.
本発明の歯周病の治療方法は、光に反応する化合物を歯周病原因菌に投与し、光を照射することにより歯周病を治療するPDTを行う際に、それ自身は光増感作用を有さないALA類を歯周病患部に投与し、色素生合成経路を経て誘導されたPpIXが歯周病原因菌における細胞内に集積し、歯周病原因菌細胞内に蓄積したPpIXを、光を照射して励起させることで、周囲の酸素分子を光励起し、その結果生成する光の励起により生ずる一重項酸素及び/又はヒドロキシルラジカル、スーパーオキシド等に代表される活性酸素種が、その強い酸化力による殺細胞効果を有することを利用する歯周病の治療方法である。 The method for treating periodontal disease of the present invention is itself photosensitized when a light-responsive compound is administered to a periodontal disease-causing bacterium and PDT for treating periodontal disease is performed by irradiating with light. ALAs that have no action were administered to the affected area of periodontal disease, and PpIX induced via the pigment biosynthesis pathway accumulated in the cells of the periodontal disease-causing bacteria and accumulated in the periodontal disease-causing bacteria cells. By irradiating PpIX with light to excite it, surrounding oxygen molecules are photoexcited, and the active oxygen species typified by single term oxygen and / or hydroxyl radical, superoxide, etc. generated by the excitation of the resulting light , It is a treatment method for periodontal disease utilizing the fact that it has a cell-killing effect due to its strong oxidizing power.
本発明の治療薬は、歯周病の患部及びその周辺、特に歯周ポケット内に投与され、望ましい光感作効果を得るため治療されるべき部位が露光される前に、特定の時間が経過していることが好ましい。露光前に、余剰の治療薬は除去されることが好ましい。 The therapeutic agent of the present invention is administered in and around the affected area of periodontal disease, particularly in the periodontal pocket, and a specific time elapses before the site to be treated for obtaining the desired photosensitizing effect is exposed. It is preferable to do so. Prior to exposure, excess therapeutic agent is preferably removed.
投与した後、露光が行われるまでの時間は、ALA類の種類、治療すべき条件及び投与の形態によって決まる。その時間は、例えば、約3〜6時間が挙げられ、0〜90分間、5〜90分間、30〜90分間が好ましく挙げられ、10〜50分間が特に好ましく挙げられる。 The time from administration to exposure depends on the type of ALA, the conditions to be treated and the form of administration. The time is, for example, about 3 to 6 hours, preferably 0 to 90 minutes, 5 to 90 minutes, 30 to 90 minutes, and particularly preferably 10 to 50 minutes.
本発明の治療薬が歯周ポケット等の歯周病患部に投与された後、歯周ポケット内等の歯周病患部が嫌気性条件下におかれる必要がある。本発明において歯周病患部を嫌気性条件下におくとは、歯周病患部が嫌気性条件下におかれていない場合には、歯周病患部を嫌気性条件下にすること、歯周病患部がすでに嫌気性条件下におかれている場合には、その状態を保つこと、歯周病患部がすでに嫌気性条件下におかれている場合であっても本発明の治療薬を投与するときに嫌気性条件下でなくなった場合には、元の状態に復帰させる又は嫌気性条件下にすることを意味する。歯周ポケット等の歯周病患部を嫌気性条件下におくには、例えば、歯周病患部周辺を酸素が遮断できる材質のもので覆う方法等が考えられる。また、歯周病患部はもともと歯根に近い部分であり、歯周病原因菌が繁殖している環境は、嫌気性であるので、歯周病原因菌が繁殖している部位まで本発明の治療薬が浸透できるように物理的又は化学的な手法を用いることも考えられる。 After the therapeutic agent of the present invention is administered to a periodontal disease-affected portion such as a periodontal pocket, the periodontal disease-affected portion such as in the periodontal pocket needs to be placed under anaerobic conditions. In the present invention, to put the periodontal disease-affected part under anaerobic conditions means to put the periodontal disease-affected part under anaerobic conditions when the periodontal disease-affected part is not under anaerobic conditions. If the periodontal diseased area is already under anaerobic conditions, maintain that state, and even if the periodontal diseased area is already under anaerobic conditions, the present invention When the anaerobic condition disappears when the therapeutic drug is administered, it means to return to the original state or to bring the anaerobic condition. In order to keep the periodontal disease-affected part such as the periodontal pocket under anaerobic conditions, for example, a method of covering the area around the periodontal disease-affected part with a material capable of blocking oxygen can be considered. Further, since the periodontal disease-affected portion is originally a portion close to the tooth root and the environment in which the periodontal disease-causing bacteria are propagated is anaerobic, the present invention includes the portion in which the periodontal disease-causing bacteria are propagated. It is also conceivable to use physical or chemical methods to allow the therapeutic agent to penetrate.
本発明の治療薬を投与後、光活性化は、当該分野において公知である光源を用いて行うことができ、例えば青色LED、赤色LED等の発光ダイオード、青色半導体レーザー、赤色半導体レーザー等の半導体レーザー、強い青色又は赤色発光スペクトルをもつ放電ランプ等を挙げることができるが、装置がコンパクトになり、コスト面や可搬性において有利であることから、青色LED又は赤色LEDを好適に例示することができる。照射に使用する光の波長は、より効率的な光感作効果を得るために選択することができ、360〜700nmの範囲の光が挙げられる。また、エネルギー密度は、10〜200J/cm2の範囲が好ましく、10〜100J/cm2の範囲がさらに好ましく、20〜60J/cm2の範囲が特に好ましい。After administration of the therapeutic agent of the present invention, photoactivation can be performed using a light source known in the art, for example, a light emitting diode such as a blue LED or a red LED, a semiconductor such as a blue semiconductor laser or a red semiconductor laser. A laser, a discharge lamp having a strong blue or red emission spectrum, and the like can be mentioned, but a blue LED or a red LED can be preferably exemplified because the device becomes compact and is advantageous in terms of cost and portability. can. The wavelength of the light used for irradiation can be selected in order to obtain a more efficient photosensitization effect, and examples thereof include light in the range of 360 to 700 nm. The energy density is preferably in the range of 10~200J / cm 2, more preferably in the range of 10 to 100J / cm 2, the range of 20~60J / cm 2 is particularly preferred.
また、用いる光源のパワー密度は、本発明の効果を奏する範囲であれば特に制限を受けず、例えば、15〜400mW/cm2の範囲が好ましく、15〜50mW/cm2、5〜40mW/cm2、10〜35mW/cm2の範囲がさらに好ましく、15〜35mW/cm2の範囲が特に好ましい。The power density of the light source used, if the range the effects of the present invention is not particularly restricted, for example, preferably in the range of 15~400mW / cm 2, 15~50mW / cm 2, 5~40mW / cm The range of 2 , 10 to 35 mW / cm 2 is more preferable, and the range of 15 to 35 mW / cm 2 is particularly preferable.
また、照射光は、連続光であってもよく、パルス光であってもよいが、パルス光を利用することにより、正常な皮膚表面への損傷を小さくできる点で、パルス光がより好ましい。 Further, the irradiation light may be continuous light or pulsed light, but pulsed light is more preferable in that damage to a normal skin surface can be reduced by using pulsed light.
光照射時間は、エネルギー密度及びパワー密度にもよるが、5〜30分間、好ましくは15分間行うことが望ましい。照射は1回だけであってもよく、あるいは、例えば照射の間隔を1〜10分間とし、光照射量をいくつかに分割した光照射として用いてもよい。 The light irradiation time depends on the energy density and the power density, but is preferably 5 to 30 minutes, preferably 15 minutes. The irradiation may be performed only once, or for example, the irradiation interval may be 1 to 10 minutes, and the light irradiation amount may be divided into several parts and used as light irradiation.
励起光照射デバイスとしては、光源用細径光ファイバーを挙げることができ、蓄積されたPpIXを励起させるALA−PDTステップにおいて照射する励起光の光源としては、微小な歯周病原因菌の繁殖部位についてもPpIXの励起を行うことを可能とするために放射照度が強く、正確な自動識別を可能とするために照射面積が狭い半導体レーザー又はLED光源が好ましく、励起光を導光して一端から外部へ出射する励起光導光部を有することが好ましく、励起光導光部としては、具体的には細径光ファイバーが挙げられる。 Examples of the excitation light irradiation device include a small-diameter optical fiber for a light source. A semiconductor laser or LED light source having a strong radiation illuminance to enable excitation of PpIX and a narrow irradiation area to enable accurate automatic identification is preferable, and the excitation light is guided to the outside from one end. It is preferable to have an excitation light light source unit that emits light to the light source, and specific examples of the excitation light light source unit include a small-diameter optical fiber.
前記のように、本発明の治療剤を用いる治療方法においては、ALA−PDDを行うこともできる。ALA−PDDは、本発明のALA−PDTの前に、歯周病原因菌細胞内に蓄積したPpIXに紫色の光を照射すると赤色の蛍光を発することを利用して、歯周病原因菌の付着部位を特定する判定方法である。かかるALA−PDDステップにおいて用いられるALA−PDDデバイスとしては、PpIXの励起光照射デバイスと、励起状態のPpIX特有の赤色蛍光検出デバイス、あるいは、これらが一体化されたデバイスを例示することができる。PpIXの励起光照射デバイスから照射する光としては、PpIXを励起させることで、PpIX特有の赤色蛍光が観察できる波長の光が好ましく、いわゆるソーレー帯に属するPpIXの吸収ピークに属する紫外光に近い紫色の波長の光であって、少なくとも360nm〜420nmの範囲内の波長の光であればよく、例えば、360〜420nm、403〜410nm等を挙げることができるが、中でも408nmが好ましい。 As described above, in the treatment method using the therapeutic agent of the present invention, ALA-PDD can also be performed. ALA-PDD uses the fact that PpIX accumulated in the cells of the periodontal disease-causing bacteria emits red fluorescence when the PpIX accumulated in the cells of the periodontal disease-causing bacteria is irradiated with purple light before the ALA-PDT of the present invention. This is a determination method for identifying the attachment site. Examples of the ALA-PDD device used in the ALA-PDD step include an excitation light irradiation device of PpIX, a red fluorescence detection device peculiar to PpIX in an excited state, or a device in which these are integrated. As the light emitted from the PpIX excitation light irradiation device, light having a wavelength at which red fluorescence peculiar to PpIX can be observed by exciting PpIX is preferable, and purple close to ultraviolet light belonging to the absorption peak of PpIX belonging to the so-called Soret band. The light having a wavelength in the range of at least 360 nm to 420 nm may be used, and examples thereof include 360 to 420 nm and 403 to 410 nm, with 408 nm being preferable.
上記ALA−PDDステップにおける励起光を照射する光源としては、公知のものを使用することができ、例えば紫色LED、好ましくはフラッシュライト型紫色LEDや、半導体レーザー等の光源を挙げることができるが、装置がコンパクトになり、コスト面や可搬性において有利である紫色LED、中でもフラッシュライト型紫色LEDや、紫色半導体ダイオードを好適に例示することができる。また、PpIX蓄積部位を検出し、照射すべき歯周病病原菌の繁殖範囲を判断するための、赤色の蛍光、具体的には610nm〜750nm、好ましくは625〜638nmの波長の蛍光を検出するための赤色蛍光検出デバイスとしては、肉眼による検出デバイスやCCDカメラによる検出デバイスを挙げることができる。 As the light source for irradiating the excitation light in the ALA-PDD step, a known light source can be used, and examples thereof include a purple LED, preferably a flashlight type purple LED, and a light source such as a semiconductor laser. A purple LED, which makes the device compact and is advantageous in terms of cost and portability, particularly a flashlight type purple LED and a purple semiconductor diode can be preferably exemplified. Further, in order to detect the PpIX accumulation site and to detect the fluorescence of red, specifically, the fluorescence having a wavelength of 610 nm to 750 nm, preferably 625 to 638 nm, for determining the propagation range of the periodontal disease pathogen to be irradiated. Examples of the red fluorescence detection device include a detection device with the naked eye and a detection device with a CCD camera.
励起光照射デバイスと赤色蛍光検出デバイスとが一体化されたALA−PDDデバイスとしては、光源・計測用細径光ファイバーを挙げることができ、蓄積されたPpIXを励起させるALA−PDDステップにおいて照射する励起光の光源としては、微小な歯周病原因菌の繁殖部位についてもPpIXの検出を行うことを可能とするために放射照度が強く、正確な自動識別を可能とするために照射面積が狭い半導体レーザー光源が好ましく、励起光を導光して一端から外部へ出射する励起光導光部を有することが好ましく、励起光導光部としては、具体的には細径光ファイバーを挙げることができる。光源に用いられる素子としては、InGaN等の半導体混晶を用いることができ、InGaNの配合比を変えることで、紫色光を発振することができる。具体的には直径5.6mm程度のコンパクトなレーザーダイオードを好適に例示することができる。レーザーダイオードから4レーザーアウトプットのポートと、スペクトル測定用のポートはビルトイン高感度スペクトロスコープで連結されたデスクトップPCほどのサイズである装置を例示することができる。また、前記励起光によって励起されたPpIXが発する蛍光を受光する受光工程においては計測用細径光ファイバーが用いられ、該計測用細径光ファイバーは前記光源用細径光ファイバーと一体化され、受光した蛍光を検出器に導光してPpIX蓄積部位の判定を行う。 Examples of the ALA-PDD device in which the excitation light irradiation device and the red fluorescence detection device are integrated include a light source and a small-diameter optical fiber for measurement, and the excitation to be irradiated in the ALA-PDD step for exciting the accumulated PpIX. As a light source, a semiconductor having a strong radiation illuminance to enable detection of PpIX even for a small propagation site of periodontal disease-causing bacteria and a narrow irradiation area to enable accurate automatic identification. A laser light source is preferable, and it is preferable to have an excitation light light guide unit that guides the excitation light and emits it to the outside from one end. Specific examples of the excitation light light guide unit include a small-diameter optical fiber. As an element used as a light source, a semiconductor mixed crystal such as InGaN can be used, and purple light can be oscillated by changing the blending ratio of InGaN. Specifically, a compact laser diode having a diameter of about 5.6 mm can be preferably exemplified. A device in which the port for 4 laser outputs from the laser diode and the port for spectrum measurement are about the size of a desktop PC connected by a built-in high-sensitivity spectrometer can be exemplified. Further, in the light receiving step of receiving the fluorescence emitted by PpIX excited by the excitation light, a small-diameter optical fiber for measurement is used, and the small-diameter optical fiber for measurement is integrated with the small-diameter optical fiber for a light source, and the received fluorescence is received. Is guided to the detector to determine the PpIX accumulation site.
以下に、実施例を挙げて本発明を具体的に説明するが、本発明の技術的範囲は、これら実施例により限定されるものではない。 Hereinafter, the present invention will be specifically described with reference to examples, but the technical scope of the present invention is not limited to these examples.
E.フェカリスJCM5803をブレインハートインフュージョン培地(BHI)(Difco Laboratories, Detroit, Mich, USA)にて、37℃で8時間培養し、0.8×109CFU/mlに調整した。その後、37℃で嫌気性条件下(N280%,CO210%,H210%)に6時間静置した後、1.0×109CFU/mlに調整し菌体サンプルとした。ALAはPBS(nacalai tesque、東京)1.2mlに溶解し、さらに10N NaOH溶液0.3mlを加えて、pH5.0のALA溶液を調整した。24穴プレートに上記調整したE.フェカリス菌体と上記調整したALA溶液を加え、ALAの最終濃度を0%(w/v)、0.05%(w/v)、0.5%(w/v)、5%(w/v)、10%(w/v)に調整した。37℃で嫌気条件下に暗所で静置し、2時間後に青色LED(波長397±13nm、出力35mW、照射径15.5mm、平均パワー密度19mW/cm2、G-Light Prima-II Plus, GC,東京)を光学ステージ上で1分間照射した。希釈平板法に基づき、光照射して得られた培養液を、BHIを用いてOD=0.1となるように希釈し、希釈した各培養液を寒天培地上で1日間培養した。その結果を図1に示す。なお、ALAの最終濃度0%(w/v)に調整したものに関しては前記青色LEDによる光照射を行わない群も設けた。
なお、図1の各寒天培地上のコロニーは、各行ごとに上からALAの濃度が、0%(w/v)、0.05%(w/v)、0.5%(w/v)、5%(w/v)、10%(w/v)、0%(w/v)+光非照射の培養液から形成されたコロニー(図1中の1〜6)を表す。E. Faecalis JCM5803 brain heart infusion medium (BHI) (Difco Laboratories, Detroit , Mich, USA) at, for 8 hours at 37 ° C., and adjusted to 0.8 × 10 9 CFU / ml. Then, under anaerobic conditions at 37 ℃ (N 2 80%,
The colonies on each agar medium in FIG. 1 had ALA concentrations of 0% (w / v), 0.05% (w / v), and 0.5% (w / v) from the top for each row. It represents colonies (1 to 6 in FIG. 1) formed from a culture medium of 5, 5% (w / v), 10% (w / v), 0% (w / v) + non-irradiated culture medium.
図1から明らかなように、ALAの最終濃度が5%(w/v)及び10%(w/v)の場合には、光照射することにより、E.フェカリスの生菌数が著しく減少し、本発明の治療剤を用いて人体を侵襲することなく歯周病を治療することができることが示唆された。 As is clear from FIG. 1, when the final concentration of ALA is 5% (w / v) and 10% (w / v), the E.I. It was suggested that the viable cell count of Fecalis was significantly reduced, and that the therapeutic agent of the present invention could be used to treat periodontal disease without invading the human body.
[参考例1]
E.フェカリスJCM5803をブレインハートインフュージョン培地(BHI)(Difco Laboratories, Detroit, Mich, USA)にて、37℃で8時間培養し、0.8×109CFU/mlに調整した。ALAはPBS(nacalai tesque,東京)に1.2mlに溶解し、10N NaOH溶液0.3mlを加えて、pH5.0のALA溶液を調整した。上記調整したALA溶液にEDTAを0.05%(w/v)となるように添加してALA−EDTA溶液を調製した。24穴プレートに上記調整したE.フェカリス菌体と上記調整したALA溶液又はALA+EDTA溶液を加え、それぞれALAの最終濃度0%(w/v)、0.05%(w/v)、0.5%(w/v)に調整した。37℃で好気性条件下に暗所で静置し、2時間及び4時間後に青色LED(波長397±13nm、出力35mW、照射径15.5mm、平均パワー密度19mW/cm2、G-Light Prima-II Plus、GC、東京)を光学ステージ上で1分間照射した。希釈平板法に基づき、光照射して得られた培養液を、BHIを用いて1倍、10倍、100倍、1000倍希釈し、希釈した各培養液を寒天培地上で1日間培養した。その結果を図2に示す。
なお、図2の左から培養液を1倍希釈、10倍希釈、100倍希釈、1000倍希釈した結果を表し、各寒天培地上のコロニーは、各行ごとに上からALA溶液を添加した培養液中のALA濃度が、0%(w/v)、0.05%(w/v)、0.5%(w/v)、の培養液から形成されたコロニー(図2中の1〜3)、ALA+EDTA溶液を添加した培養液中のALA濃度が、0%(w/v)、0.05%(w/v)、0.5%(w/v)、の培養液から形成されたコロニー(図2中の4〜6)を表す。[Reference example 1]
E. Faecalis JCM5803 brain heart infusion medium (BHI) (Difco Laboratories, Detroit , Mich, USA) at, for 8 hours at 37 ° C., and adjusted to 0.8 × 10 9 CFU / ml. ALA was dissolved in PBS (nacalai tesque, Tokyo) in 1.2 ml, and 0.3 ml of 10N NaOH solution was added to prepare an ALA solution having a pH of 5.0. An ALA-EDTA solution was prepared by adding EDTA to the above-prepared ALA solution so as to have a concentration of 0.05% (w / v). The above-adjusted E.I. Fecalis cells and the above-adjusted ALA solution or ALA + EDTA solution were added to adjust the final concentrations of ALA to 0% (w / v), 0.05% (w / v), and 0.5% (w / v), respectively. .. After 2 hours and 4 hours, the blue LED (wavelength 397 ± 13 nm, output 35 mW, irradiation diameter 15.5 mm, average power density 19 mW / cm 2 , G-Light Prima) was allowed to stand in a dark place at 37 ° C. under aerobic conditions. -II Plus, GC, Tokyo) was irradiated on the optical stage for 1 minute. Based on the dilution plate method, the culture solution obtained by irradiation with light was diluted 1-fold, 10-fold, 100-fold, and 1000-fold with BHI, and each diluted culture solution was cultured on an agar medium for 1 day. The result is shown in FIG.
The results of 1-fold dilution, 10-fold dilution, 100-fold dilution, and 1000-fold dilution of the culture solution are shown from the left in FIG. 2, and the colonies on each agar medium are the culture solutions to which the ALA solution is added from the top for each row. Colonies formed from cultures having ALA concentrations of 0% (w / v), 0.05% (w / v), and 0.5% (w / v) (1 to 3 in FIG. 2). ), The ALA concentration in the culture solution to which the ALA + EDTA solution was added was formed from the culture solution of 0% (w / v), 0.05% (w / v), 0.5% (w / v). Represents a colony (4-6 in FIG. 2).
図2から明らかなように、好気性条件下で培養を行って光照射した場合には、E.フェカリスの生菌数は、ALAを添加した場合でもブランクの場合と全く変わらず、ALAを添加した効果は見られなかった。 As is clear from FIG. 2, when the cells were cultured under aerobic conditions and irradiated with light, E.I. The viable cell count of Fecalis was completely the same even when ALA was added as in the case of blank, and the effect of adding ALA was not observed.
本発明の治療薬及び治療方法は、従来の方法では、効力がなかった歯周病原因菌に対しても効力を有することから、歯周病を治療する分野で有用である。
The therapeutic agent and the therapeutic method of the present invention are useful in the field of treating periodontal disease because they are effective against periodontal disease-causing bacteria that have not been effective by the conventional methods.
Claims (6)
(式中、R1は、水素原子又はアシル基を表し、R2は、水素原子、アルキル基、シクロアルキル基、アリール基又はアラルキル基を表す。)で表される化合物又は薬学的に許容されるその塩を含み、歯周病患部に式(I)で表される化合物又は薬学的に許容されるその塩を投与し、その後360nm〜700nmの波長の光を照射する5−アミノレブリン酸−光線力学的療法(ALA−PDT)のための歯周病の治療薬。The following formula (I)
(In the formula, R 1 represents a hydrogen atom or an acyl group, and R 2 represents a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group or an aralkyl group) or a pharmaceutically acceptable compound. 5-Aminolevulinic acid, which contains the salt of hydrogen, is administered to the affected area of periodontal disease with the compound represented by the formula (I) or the pharmaceutically acceptable salt thereof, and then irradiated with light having a wavelength of 360 nm to 700 nm. A therapeutic agent for periodontal disease for photodynamic therapy (ALA-PDT).
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US20110027384A1 (en) * | 2008-04-04 | 2011-02-03 | National University Of Singapore | Photosensitising composition and its uses |
KR20120065536A (en) * | 2010-12-13 | 2012-06-21 | 광주과학기술원 | Pharmaceutical compositions for preventing or treating periodontal diseases comprising photosensitizers and pine resin extracts as an active ingredient using led irradiation |
WO2013005379A1 (en) * | 2011-07-01 | 2013-01-10 | Sbiファーマ株式会社 | Photodynamic therapy using photosensitizing agent or 5-aminolevulinic acid |
JP2017006454A (en) * | 2015-06-24 | 2017-01-12 | 公立大学法人名古屋市立大学 | Light irradiation device for photodynamic treatment |
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KR20120065536A (en) * | 2010-12-13 | 2012-06-21 | 광주과학기술원 | Pharmaceutical compositions for preventing or treating periodontal diseases comprising photosensitizers and pine resin extracts as an active ingredient using led irradiation |
WO2013005379A1 (en) * | 2011-07-01 | 2013-01-10 | Sbiファーマ株式会社 | Photodynamic therapy using photosensitizing agent or 5-aminolevulinic acid |
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