JP4590525B2 - Anti-leishmania - Google Patents
Anti-leishmania Download PDFInfo
- Publication number
- JP4590525B2 JP4590525B2 JP2004015622A JP2004015622A JP4590525B2 JP 4590525 B2 JP4590525 B2 JP 4590525B2 JP 2004015622 A JP2004015622 A JP 2004015622A JP 2004015622 A JP2004015622 A JP 2004015622A JP 4590525 B2 JP4590525 B2 JP 4590525B2
- Authority
- JP
- Japan
- Prior art keywords
- leishmania
- agent
- antiprotozoal
- extract
- plant
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
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Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Medicines Containing Plant Substances (AREA)
Description
本発明は、植物由来で、抗原虫活性または抗リーシュマニア活性を示す物質を有効成分として含有する抗原虫剤、特に抗リーシュマニア剤に関する。 The present invention relates to an antiprotozoal agent, particularly an anti-Leishmania agent, which contains a plant-derived substance exhibiting antiprotozoal activity or anti-Leishmania activity as an active ingredient.
従来より、リーシュマニア原虫、マラリア原虫、膣トリコモナス、トリパノソーマ、ニューモシスチス・カリニ等の様々な原虫が寄生虫病を引き起こすことが知られている。 Conventionally, various protozoa such as Leishmania protozoa, malaria protozoa, vaginal Trichomonas, trypanosoma, and Pneumocystis carini are known to cause parasitic diseases.
中でもリーシュマニア症は、リーシュマニア原虫(Leishmania原虫)により引き起こされる南米を含む熱帯地方特有の寄生虫病で、WHO指定の六大熱帯病の一つである。アフリカ、中近東、中南米およびアジアでの総患者数はおよそ1200万人であり、毎年40万人が感染している。感染経路は、吸血性昆虫であるサシチョウバエであり、このサシチョウバエの体内のリーシュマニア原虫が吸血時に傷口から侵入することにより感染が成立する。原虫は、マクロファージに寄生し、内臓型、皮膚型および粘膜皮膚型の病態を呈する。特に、内臓型は重篤な場合には死に至る危険な病態である。 In particular, leishmaniasis is a parasitic disease peculiar to the tropics including South America caused by a leishmania protozoa (Leishmania protozoa), and is one of the six major tropical diseases designated by WHO. The total number of patients in Africa, the Middle East, Latin America and Asia is approximately 12 million, with 400,000 being infected each year. The infection route is a fly sucker that is a blood-sucking insect, and infection is established when a leishmania protozoa in the body of the fly fly invades from a wound during blood sucking. Protozoa parasitize macrophages and exhibit visceral, dermal and mucocutaneous pathologies. In particular, the visceral type is a dangerous pathological condition that can lead to death in severe cases.
リーシュマニア原虫には、Leishmania donovani、L. tropica、L. mexicanaおよびL. braziliensisの4つの群(complex)があり、それぞれによって発生する病態は異なるが、基本的には原虫がそれぞれの臓器、局所のマクロファージに寄生することが原因となる。内臓リーシュマニアは、L. donovaniが肝臓、脾臓、骨髄等のマクロファージ、細網内皮系細胞に寄生することで引き起こされる。主症状は、肝臓、脾臓の肥大、貧血、白血球の減少、発熱、リンパ節腫脹である。皮膚リーシュマニアは旧世界型と新世界型に分けられる。旧世界皮膚リーシュマニアは、L. tropicaにより引き起こされるもので、新世界皮膚リーシュマニアは、L. mexicanaにより引き起こされるが、いずれも皮膚のマクロファージに寄生し皮膚潰瘍を形成する。L. braziliensisは、粘膜と皮膚に病変を作る粘膜皮膚リーシュマニアを引き起こすが、皮膚リーシュマニアを引き起こす場合もある。 There are four Leishmania protozoa, Leishmania donovani, L. tropica, L. mexicana, and L. braziliensis, and the pathology that occurs depends on each. It is caused by parasitizing the macrophages. Visceral leishmania is caused by L. donovani parasitizing macrophages such as liver, spleen and bone marrow, and reticuloendothelial cells. The main symptoms are liver and spleen enlargement, anemia, white blood cell loss, fever and lymphadenopathy. Skin leishmania can be divided into Old World and New World types. Old World Skin Leishmania is caused by L. tropica, and New World Skin Leishmania is caused by L. mexicana, both of which parasitize skin macrophages and form skin ulcers. L. braziliensis causes mucocutaneous leishmania that causes lesions in the mucosa and skin, but can also cause cutaneous leishmania.
このようにリーシュマニア原虫は多様性に富んでおり、免疫学的な見地からしても、似たような病態でも地域により抗原性に差がある。このことがワクチン開発を困難にしており、化学療法の必要性が高い。 Thus, Leishmania protozoa are rich in diversity, and there are differences in antigenicity from region to region even in similar pathological conditions from an immunological standpoint. This makes vaccine development difficult and the need for chemotherapy is high.
現在、リーシュマニア症の治療には五価のアンチモン剤(商標名ペントスタム:Pentostam、グルカンタイム:Glucantime)が第一選択薬として用いられており、それらが有効でない場合、ペンタミジン(Pentamidine)、アンフォテリシンB(Amphotericin B)等が用いられる。しかし、これらの薬剤は強い副作用を示すことがあり、使用に関しては医師の注意が必要である。また、アンチモン剤は高価なことも問題点である。 Currently, pentavalent antimony drugs (trade names: Pentostam, Glucantime) are used as first-line drugs for the treatment of leishmaniasis, and if they are not effective, pentamidine, amphotericin B (Amphotericin B) or the like is used. However, these drugs may have strong side effects and require physician attention when used. Another problem is that the antimony agent is expensive.
この他の治療薬として、特許文献1は、ゲルマクラノリド型またはグアイアノリド型セスキテルペノイド化合物およびそれを含む医薬について開示しており、特許文献2は、リーシュマニア症の治療に有効なトリアゾール誘導体を開示している。
しかし、現在でも、より安価で副作用が少ない治療薬の開発が望まれている。
As other therapeutic agents, Patent Document 1 discloses a germanacranolide-type or guaianolide-type sesquiterpenoid compound and a drug containing the same, and Patent Document 2 discloses a triazole derivative effective for the treatment of leishmaniasis. Yes.
However, even now, it is desired to develop a therapeutic agent that is less expensive and has fewer side effects.
Cedrela種の植物の心材からは、数種のトリテルペノイド類が抽出されている(非特許文献1)。C. toonaの種子からは2種類のリモノイドが単離されているが(非特許文献2)、これらのリモノイドが抗原虫活性を有することについては知られていない。また、Cedrela種の植物のその他の成分として、カジナン型セスキテルペンおよびクマリン誘導体が報告されているが(非特許文献1、非特許文献3)、これらの抗原虫活性についても知られていない。 Several types of triterpenoids have been extracted from the heartwood of Cedrela plant (Non-patent Document 1). Two types of limonoids have been isolated from C. toona seeds (Non-patent Document 2), but it is not known that these limonoids have antiprotozoal activity. Further, as other components of the plant of Cedrela species, casinane-type sesquiterpenes and coumarin derivatives have been reported (Non-patent Documents 1 and 3), but their antiprotozoan activity is not known.
いくつかのCordia種の植物から、数種のベンゾキノンおよびヒロドキノン誘導体が単離されている。これらの成分はp-ベンゾキノンまたはp-ヒドロキノン部分を有する(非特許文献4〜7)。Cordia種の植物からの成分の単離に関して多くの報告がなされているが、C. fragrantissimaから化学物質を単離したという報告はなく、該植物における抗原虫活性を有する化合物の存在についても報告されていない。 Several benzoquinone and hydrodoquinone derivatives have been isolated from several Cordia species plants. These components have a p-benzoquinone or p-hydroquinone moiety (Non-Patent Documents 4 to 7). There have been many reports on the isolation of components from plants of the Cordia species, but there have been no reports of isolation of chemicals from C. fragrantissima, and the presence of compounds with antiprotozoal activity in the plants has also been reported. Not.
Dalbergia属の植物は、通常、ネオフラボノイドを含む。この植物の心材には、4-アリールクマリン誘導体、p-ヒドロキノン誘導体及びジフェニルプロペン誘導体が含まれることが報告されている(非特許文献8)。しかし、これらの薬理学的活性については、不明瞭な点が多い。 Plants of the genus Dalbergia usually contain neoflavonoids. This plant heartwood has been reported to contain 4-arylcoumarin derivatives, p-hydroquinone derivatives and diphenylpropene derivatives (Non-patent Document 8). However, there are many unclear points regarding these pharmacological activities.
Calophyllum種の植物から単離されたCalanolide Aは、強力な抗HIVクマリンとして知られ、抗HIV剤としての有力な候補薬物である(非特許文献9)。しかし、C. Kunstleri由来の成分が抗原虫活性を有することについては知られていない。 Calanolide A isolated from a plant of the Calophyllum species is known as a powerful anti-HIV coumarin and is a promising candidate drug as an anti-HIV agent (Non-patent Document 9). However, it is not known that components derived from C. Kunstleri have antiprotozoal activity.
本発明は、安価で副作用が少ない抗原虫剤を提供することを目的とする。
本発明は、安価で副作用が少ない抗リーシュマニア剤を提供することを目的とする。
An object of the present invention is to provide an antiprotozoal agent that is inexpensive and has few side effects.
An object of the present invention is to provide an anti-Leishmania agent that is inexpensive and has few side effects.
本発明者らは、ミャンマーに生息する植物の抽出物の抗原虫活性についてスクリーニングを行った結果、特定の植物に由来する物質が抗原虫活性、特に抗リーシュマニア活性を示すことを見いだし、本発明を完成するに至った。 As a result of screening for the antiprotozoan activity of extracts of plants inhabiting Myanmar, the present inventors have found that a substance derived from a specific plant exhibits antiprotozoal activity, particularly anti-Leishmania activity, and the present invention. It came to complete.
上記課題を解決する本発明は、以下の発明を包含する。
(1)Dipterocarpus tuberculatus Roxb.;Grevillea robusta A-Cun.;Xylocarpus moluccensis(Lam.)Roem.;Tectona grandis Linn.f.;Lagerstroemia tomentosa Presl.;Terminalia chebula Retz.;Haplophragma adenophyllum (Wall.) Dep;Xylia dolabriformis Benth.;Cananga odorata Hook.f.&.T.;Michelia champaca Linn.;Cordia fragrantissima Kurz.;Acacia catechu Willd.;Albizzia procera Benth.;Dalbergia oliveri Gamble.;Terminalia tomentosa W&A.;Cedrela serrata Royle.;Calophyllum kunstleri King.;Cedrela toona Roxb.;Albizzia odoratissima Benth.;Dalbergia cultrata Grah.;Chukrasia tabularis A. Juss.;Anogeissus acuminata Wall.;Lagerstroemia villosa Wall.およびDillenia pentagyna Roxb.からなる群から選択される少なくとも1種の植物に由来し、抗原虫活性を示す物質を有効成分として含有する抗原虫剤。
(2)抗リーシュマニア剤である(1)記載の抗原虫剤。
The present invention for solving the above problems includes the following inventions.
(1) Dipterocarpus tuberculatus Roxb .; Grevillea robusta A-Cun .; Xylocarpus moluccensis (Lam.) Roem .; Tectona grandis Linn.f .; Lagerstroemia tomentosa Presl .; Terminalia chebula Retz .; Haplophragma adenophyllum (X) Dolabriformis Benth .; Cananga odorata Hook.f. &. T.; Michelia champaca Linn.; Cordia fragrantissima Kurz.; Acacia catechu Willd.; Albizzia procera Benth.; Dalbergia oliveri Gamble.; Terminalia tomentosa W &A.; Cedrelale. Calophyllum kunstleri King .; Cedrela toona Roxb .; Albizzia odoratissima Benth .; Dalbergia cultrata Grah .; Chukrasia tabularis A. Juss .; Anogeissus acuminata Wall .; Lagerstroemia villosa Wall. An antiprotozoal agent containing a substance derived from a plant of a species and exhibiting antiprotozoal activity as an active ingredient.
(2) The antiprotozoal agent according to (1), which is an anti-Leishmania agent.
(3)Dipterocarpus tuberculatus Roxb.;Grevillea robusta A-Cun.;Xylocarpus moluccensis(Lam.)Roem.;Tectona grandis Linn.f.;Lagerstroemia tomentosa Presl.;Terminalia chebula Retz.;Haplophragma adenophyllum (Wall.) Dep;Xylia dolabriformis Benth.;Cananga odorata Hook.f.&.T.;Michelia champaca Linn.;Cordia fragrantissima Kurz.;Acacia catechu Willd.;Albizzia procera Benth.;Dalbergia oliveri Gamble.;Terminalia tomentosa W&A.;Cedrela serrata Royle.;Calophyllum kunstleri King.;Cedrela toona Roxb.;Albizzia odoratissima Benth.;Dalbergia cultrata Grah.;Chukrasia tabularis A. Juss.;Anogeissus acuminata Wall.;Lagerstroemia villosa Wall.およびDillenia pentagyna Roxb.からなる群から選択される少なくとも1種の植物の抽出物またはその処理物を有効成分として含有する抗原虫剤。
(4)前記植物の心材の抽出物またはその処理物を有効成分として含有する(3)記載の抗原虫剤。
(5)抗リーシュマニア剤である(3)または(4)記載の抗原虫剤。
(3) Dipterocarpus tuberculatus Roxb .; Grevillea robusta A-Cun .; Xylocarpus moluccensis (Lam.) Roem .; Tectona grandis Linn.f .; Lagerstroemia tomentosa Presl .; Terminalia chebula Retz .; Haplophragma adenophyllum (X) Dolabriformis Benth .; Cananga odorata Hook.f. &. T.; Michelia champaca Linn.; Cordia fragrantissima Kurz.; Acacia catechu Willd.; Albizzia procera Benth.; Dalbergia oliveri Gamble.; Terminalia tomentosa W &A.; Cedrelale. Calophyllum kunstleri King .; Cedrela toona Roxb .; Albizzia odoratissima Benth .; Dalbergia cultrata Grah .; Chukrasia tabularis A. Juss .; Anogeissus acuminata Wall .; Lagerstroemia villosa Wall. An antiprotozoal agent containing an extract of a seed plant or a processed product thereof as an active ingredient.
(4) The antiprotozoal agent according to (3), which contains an extract of the plant heartwood or a processed product thereof as an active ingredient.
(5) The antiprotozoal agent according to (3) or (4), which is an anti-Leishmania agent.
(6)Dipterocarpus tuberculatus Roxb.;Grevillea robusta A-Cun.;Xylocarpus moluccensis(Lam.)Roem.;Tectona grandis Linn.f.;Lagerstroemia tomentosa Presl.;Terminalia chebula Retz.;Haplophragma adenophyllum (Wall.) Dep;Xylia dolabriformis Benth.;Cananga odorata Hook.f.&.T.;Michelia champaca Linn.;Cordia fragrantissima Kurz.;Acacia catechu Willd.;Albizzia procera Benth.;Dalbergia oliveri Gamble.;Terminalia tomentosa W&A.;Cedrela serrata Royle.;Calophyllum kunstleri King.;Cedrela toona Roxb.;Albizzia odoratissima Benth.;Dalbergia cultrata Grah.;Chukrasia tabularis A. Juss.;Anogeissus acuminata Wall.;Lagerstroemia villosa Wall.およびDillenia pentagyna Roxb.からなる群から選択される少なくとも1種の植物を粉砕する工程、得られた粉砕物を抽出する工程、および必要に応じて精製処理を行う工程を含む、抗原虫剤の製造方法。 (6) Dipterocarpus tuberculatus Roxb .; Grevillea robusta A-Cun .; Xylocarpus moluccensis (Lam.) Roem .; Tectona grandis Linn.f .; Lagerstroemia tomentosa Presl .; Terminalia chebula Retz .; Haplophragma adenophyllum (X) Dolabriformis Benth .; Cananga odorata Hook.f. &. T.; Michelia champaca Linn.; Cordia fragrantissima Kurz.; Acacia catechu Willd.; Albizzia procera Benth.; Dalbergia oliveri Gamble.; Terminalia tomentosa W &A.; Cedrelale. Calophyllum kunstleri King .; Cedrela toona Roxb .; Albizzia odoratissima Benth .; Dalbergia cultrata Grah .; Chukrasia tabularis A. Juss .; Anogeissus acuminata Wall .; Lagerstroemia villosa Wall. A method for producing an antiprotozoal agent, comprising a step of pulverizing a seed plant, a step of extracting the obtained pulverized product, and a step of performing a purification treatment as necessary.
本発明の抗原虫剤は、リーシュマニア原虫、マラリア原虫、膣トリコモナス、トリパノソーマ、ニューモシスチス・カリニ等の様々な原虫が引き起こす寄生虫病の治療に有効である。 The antiprotozoal agent of the present invention is effective in the treatment of parasitic diseases caused by various protozoa such as Leishmania protozoa, malaria protozoa, vaginal Trichomonas, trypanosoma, and Pneumocystis carini.
本発明の抗リーシュマニア剤は、リーシュマニア症の治療に有効である。
本発明の抗原虫剤は材料が安価であり、製造が容易であるため、安価である。
The anti-leishmania agent of the present invention is effective for the treatment of leishmaniasis.
The antiprotozoal agent of the present invention is inexpensive because it is inexpensive and easy to manufacture.
本発明の抗原虫剤は、天然成分由来の物質を有効成分として含有しており、副作用の問題が少ない。 The antiprotozoal agent of the present invention contains a substance derived from a natural component as an active ingredient and has few problems of side effects.
本発明の抗原虫剤は、Dipterocarpus tuberculatus Roxb.;Grevillea robusta A-Cun.;Xylocarpus moluccensis(Lam.)Roem.;Tectona grandis Linn.f.;Lagerstroemia tomentosa Presl.;Terminalia chebula Retz.;Haplophragma adenophyllum (Wall.) Dep;Xylia dolabriformis Benth.;Cananga odorata Hook.f.&.T.;Michelia champaca Linn.;Cordia fragrantissima Kurz.;Acacia catechu Willd.;Albizzia procera Benth.;Dalbergia oliveri Gamble.;Terminalia tomentosa W&A.;Cedrela serrata Royle.;Calophyllum kunstleri King.;Cedrela toona Roxb.;Albizzia odoratissima Benth.;Dalbergia cultrata Grah.;Chukrasia tabularis A. Juss.;Anogeissus acuminata Wall.;Lagerstroemia villosa Wall.およびDillenia pentagyna Roxb.からなる群から選択される少なくとも1種の植物に由来し、抗原虫活性、特に抗リーシュマニア活性を示す物質を有効成分として含有する。 The antiprotozoal agent of the present invention includes Dipterocarpus tuberculatus Roxb .; Grevillea robusta A-Cun .; Xylocarpus moluccensis (Lam.) Roem .; Tectona grandis Linn.f .; Lagerstroemia tomentosa Presl .; Terminalia chebula Retz. .) Dep; Xylia dolabriformis Benth .; Cananga odorata Hook.f. &. T .; Michelia champaca Linn .; Cordia fragrantissima Kurz .; Acacia catechu Willd .; Albizzia procera Benth .; Dalbergia oliveri Gamble .; Terminalia tomentosa W & A. Cedrela serrata Royle .; Calophyllum kunstleri King .; Cedrela toona Roxb .; Albizzia odoratissima Benth .; Dalbergia cultrata Grah .; Chukrasia tabularis A. Juss .; Anogeissus acuminata Wall .; A substance derived from at least one selected plant and having antiprotozoal activity, particularly anti-Leishmania activity, is contained as an active ingredient.
好ましくは、Cordia fragrantissima KurzおよびCedrela serrata Royle.からなる群から選択される少なくとも1種の植物に由来し、抗原虫活性、特に抗リーシュマニア活性を示す物質を有効成分として含有する。 Preferably, a substance derived from at least one plant selected from the group consisting of Cordia fragrantissima Kurz and Cedrela serrata Royle. Contains a substance exhibiting antiprotozoal activity, particularly anti-Leishmania activity, as an active ingredient.
本発明で用いる植物の生産地や品種は特に制限されない。その果実を搾汁したもの、破砕、粉砕等により粉末化処理したもの等を用いてもよいが、抽出物またはその処理物、特に、心材、樹皮および葉の抽出物またはその処理物を用いることが好ましい。 There are no particular restrictions on the production area or variety of the plant used in the present invention. The fruit may be squeezed, pulverized, pulverized, etc., but the extract or processed product thereof, in particular, the heartwood, bark and leaf extract or processed product thereof should be used. Is preferred.
上記原材料からの有効成分の抽出方法として公知の方法を使用でき、例えば溶媒による抽出法や炭酸ガスを使用する超臨界抽出法が挙げられる。超臨界抽出法と溶媒による抽出法を組み合わせて使用してもよい。 A known method can be used as a method for extracting an active ingredient from the raw material, and examples thereof include a solvent extraction method and a supercritical extraction method using carbon dioxide gas. A combination of supercritical extraction and solvent extraction may be used.
抽出物として用いる場合、用いる抽出溶媒としては、水、アセトン、ジオキサン、ヘキサン、メチルエチルケトン、アセトニトリル、酢酸エチル、ブチルメチルケトン、ジエチルエーテル、ジクロロメタン、キシレン、トリクロロエチレン、四塩化炭素、ベンゼン、クロロホルム、トルエンならびにアルコール、例えば、メタノール、エタノール、プロピルアルコール、イソプロピルアルコール、ブタノール、イソブタノール等の低級アルコールおよびプロピレングリコール、1,3-ブチレングリコール等の多価アルコール等が挙げられる。好ましくはアルコール、より好ましくは低級アルコール、特に好ましくはメタノールを使用する。上記の溶媒を単独で使用しても、2種以上を混合して使用してもよく、水と有機溶媒を併用してもよい。通常、植物1kg当り抽出溶媒3〜10Lを使用する。 When used as an extract, extraction solvents used include water, acetone, dioxane, hexane, methyl ethyl ketone, acetonitrile, ethyl acetate, butyl methyl ketone, diethyl ether, dichloromethane, xylene, trichloroethylene, carbon tetrachloride, benzene, chloroform, toluene and Examples of the alcohol include lower alcohols such as methanol, ethanol, propyl alcohol, isopropyl alcohol, butanol and isobutanol, and polyhydric alcohols such as propylene glycol and 1,3-butylene glycol. Preferably, alcohol, more preferably lower alcohol, particularly preferably methanol is used. The above solvents may be used alone, or two or more kinds may be mixed and used, or water and an organic solvent may be used in combination. Usually, 3 to 10 L of extraction solvent is used per 1 kg of plant.
抽出温度に特に制限はなく、溶媒の融点ないし溶媒の沸点の範囲内であればよく、超臨界抽出をしてもよい。超臨界抽出は、好ましくは炭酸ガスを主溶媒とし、エントレーナーとしてメタノール、エタノール等のアルコール類を添加して行われる。また、抽出は、通常常圧下で行うが、加圧下または減圧下で行ってもよい。抽出時間は、抽出温度や使用量等により異なるが、通常5分間〜1日間である。 The extraction temperature is not particularly limited, and may be within the range of the melting point of the solvent to the boiling point of the solvent, and supercritical extraction may be performed. The supercritical extraction is preferably performed by using carbon dioxide gas as a main solvent and adding an alcohol such as methanol or ethanol as an entrainer. The extraction is usually performed under normal pressure, but may be performed under pressure or under reduced pressure. The extraction time varies depending on the extraction temperature, the amount used, etc., but is usually 5 minutes to 1 day.
前記のようにして得られた抽出液を、布、ステンレスフィルター、濾紙等で濾過して不純物等を取り除くことで、目的の抽出液を得ることができる。また、濾過後の抽出液に、スプレードライ処理、フリーズドライ処理、超臨界処理等の処理を施してもよい。このようにして得られる抽出物は、そのまま本発明の抗原虫剤の有効成分として用いることができる。 The extract obtained as described above is filtered with a cloth, a stainless steel filter, a filter paper or the like to remove impurities and the like, whereby the target extract can be obtained. Moreover, you may give processes, such as a spray-dry process, a freeze-dry process, a supercritical process, to the extract after filtration. The extract thus obtained can be used as it is as an active ingredient of the antiprotozoal agent of the present invention.
また、さらに当該抽出物をイオン交換クロマトグラフィー、ゲル濾過クロマトグラフィー、透析等の各種精製手段により処理し、さらに活性を高めた処理物を用いることもできる。本発明においては、精製処理を施した処理物を用いるのが好ましい。 Furthermore, the extract can be further processed by various purification means such as ion exchange chromatography, gel filtration chromatography, dialysis, etc., and a processed product with further enhanced activity can be used. In the present invention, it is preferable to use a processed product subjected to purification treatment.
本発明の抗原虫剤は、リーシュマニア原虫、マラリア原虫、膣トリコモナス、トリパノソーマ、ニューモシスチス・カリニ等の原虫が引き起こす寄生虫病の治療に有効である。特に、リーシュマニア原虫が引き起こすリーシュマニア症の治療に有効であるため、本発明の一態様において、本発明の抗原虫剤は、抗リーシュマニア剤として好ましく使用できる。 The antiprotozoal agent of the present invention is effective for the treatment of parasitic diseases caused by protozoa such as Leishmania protozoa, malaria protozoa, vaginal Trichomonas, trypanosoma, and Pneumocystis carini. In particular, the antiprotozoal agent of the present invention can be preferably used as an anti-Leishmania agent in one embodiment of the present invention because it is effective for the treatment of leishmaniasis caused by Leishmania protozoa.
リーシュマニア症は、内臓リーシュマニア症(カラアザール)、旧世界皮膚リーシュマニア症、新世界皮膚リーシュマニア症、皮膚粘膜リーシュマニア症の4型に分類することができ、本発明の抗リーシュマニア剤は、旧世界皮膚リーシュマニア症および新世界皮膚リーシュマニア症の治療に特に有効である。 Leishmaniasis can be classified into four types: visceral leishmaniasis (Kala Azar), old world cutaneous leishmaniasis, new world cutaneous leishmaniasis, mucocutaneous leishmaniasis, and the anti-leishmania agent of the present invention is It is particularly effective in the treatment of Old World Skin Leishmaniasis and New World Skin Leishmaniasis.
また、リーシュマニア症の原因となるリーシュマニア原虫としては、Leishmania aethiopica、Leishmania braziliensis、Leishmania donovani、Leishmania furunculosa、Leishmania major、Leishmania mexicana、Leishmania peruviana、Leishmania pifanoi、Leishmania tropica等が挙げられるが、本発明の抗リーシュマニア剤は、Leishmania majorによって引き起こされるリーシュマニア症の治療に特に有効である。 Examples of Leishmania protozoa causing Leishmaniasis include Leishmania aethiopica, Leishmania braziliensis, Leishmania donovani, Leishmania furunculosa, Leishmania major, Leishmania mexicana, Leishmania peruviana, Leishmania pifanoi, Leishmania tropica, etc. Anti-Leishmania drugs are particularly effective in the treatment of leishmaniasis caused by Leishmania major.
また、本発明の抗原虫剤は、単一種の植物に由来するものでもよいし、複数種の植物に由来するものでもよい。本発明の抗原虫剤は、上記植物に由来し抗原虫活性を有する物質、または上記植物の抽出物もしくはその処理物を、公知の医薬用担体と組み合わせて製剤化することができる。 Further, the antiprotozoal agent of the present invention may be derived from a single type of plant or may be derived from a plurality of types of plants. The antiprotozoal agent of the present invention can be formulated by combining a substance derived from the above plant and having antiprotozoal activity, or an extract of the above plant or a processed product thereof with a known pharmaceutical carrier.
投与形態としては、特に制限はなく、必要に応じ適宜選択されるが、一般には錠剤、カプセル剤、顆粒剤、細粒剤、散剤、液剤、シロップ剤、懸濁剤、乳剤、エリキシル剤、エキス剤等の経口剤、または注射剤、点滴剤、坐剤、吸入剤、経皮吸収剤、経粘膜吸収剤、貼付剤、軟膏剤等の非経口剤として使用される。このうちエキス剤とは、生薬の浸出液を濃縮して得られる剤であり、軟エキス剤、乾燥エキス剤の2種類がある。エキス剤は、通常、有効成分を含有する植物を粉砕後、浸出剤を加えて一定時間冷浸または温浸させるか、あるいはパーコレーション法により浸出させ、この浸出液を濃縮することにより製造する。 The dosage form is not particularly limited and is appropriately selected as necessary. Generally, tablets, capsules, granules, fine granules, powders, solutions, syrups, suspensions, emulsions, elixirs, extracts It is used as an oral preparation such as an injection, or a parenteral preparation such as an injection, infusion, suppository, inhalation, transdermal absorption agent, transmucosal absorption agent, patch, ointment and the like. Among these, an extract is an agent obtained by concentrating a crude drug leachate, and there are two types, a soft extract and a dry extract. An extract is usually produced by pulverizing a plant containing an active ingredient, and then adding a leaching agent and cooling or digestion for a certain time, or leaching by a percolation method, and concentrating the leaching solution.
本発明の抗原虫剤または抗リーシュマニア剤の投与量は、患者の年令、体重、疾患の程度、投与経路により異なるが、例えば経口投与では、本発明の抽出物またはその処理物の抽出物乾燥粉末として、通常1日10〜3000mgであり、投与回数は、通常、経口投与では1日1〜3回である。 The dose of the antiprotozoal agent or anti-leishmania agent of the present invention varies depending on the age, body weight, degree of disease and route of administration of the patient. For example, in the case of oral administration, the extract of the present invention or an extract of the processed product thereof The dry powder is usually 10 to 3000 mg per day, and the frequency of administration is usually 1 to 3 times per day for oral administration.
経口剤は、例えばデンプン、乳糖、白糖、マンニット、カルボキシメチルセルロース、コーンスターチ、無機塩類等の賦形剤を用いて常法に従って製造される。 Oral preparations are produced according to a conventional method using excipients such as starch, lactose, sucrose, mannitol, carboxymethylcellulose, corn starch, and inorganic salts.
この種の製剤には、適宜前記賦形剤の他に、結合剤、崩壊剤、界面活性剤、滑沢剤、流動性促進剤、矯味剤、着色剤、香料等を使用することができる。 In this type of preparation, a binder, a disintegrant, a surfactant, a lubricant, a fluidity promoter, a corrigent, a colorant, a fragrance and the like can be appropriately used in addition to the above-mentioned excipients.
結合剤の具体例としては、結晶セルロース、結晶セルロース・カルメロースナトリウム、メチルセルロース、ヒドロキシプロピルセルロース、低置換度ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルメチルセルロースフタレート、ヒドロキシプロピルメチルセルロースアセテートサクシネート、カルメロースナトリウム、エチルセルロース、カルボキシメチルエチルセルロース、ヒドロキシエチルセルロース、コムギデンプン、コメデンプン、トウモロコシデンプン、バレイショデンプン、デキストリン、アルファー化デンプン、部分アルファー化デンプン、ヒドロキシプロWピルスターチ、プルラン、ポリビニルピロリドン、アミノアルキルメタクリレートコポリマーE、アミノアルキルメタクリレートコポリマーRS、メタクリル酸コポリマーL、メタクリル酸コポリマー、ポリビニルアセタールジエチルアミノアセテート、ポリビニルアルコール、アラビアゴム、アラビアゴム末、寒天、ゼラチン、白色セラック、トラガント、精製白糖、マクロゴールが挙げられる。 Specific examples of the binder include crystalline cellulose, crystalline cellulose / carmellose sodium, methylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carmellose sodium , Ethylcellulose, carboxymethylethylcellulose, hydroxyethylcellulose, wheat starch, rice starch, corn starch, potato starch, dextrin, pregelatinized starch, partially pregelatinized starch, hydroxypro W pill starch, pullulan, polyvinylpyrrolidone, aminoalkyl methacrylate copolymer E, amino Alkyl meta Relay copolymers RS, methacrylic acid copolymer L, methacrylic acid copolymer, polyvinyl acetal diethylamino acetate, polyvinyl alcohol, gum arabic, gum arabic powder, agar, gelatin, white shellac, tragacanth, purified sucrose, macrogol.
崩壊剤の具体例としては、結晶セルロース、メチルセルロース、低置換度ヒドロキシプロピルセルロース、カルメロース、カルメロースカルシウム、カルメロースナトリウム、クロスカルメロースナトリウム、コムギデンプン、コメデンプン、トウモロコシデンプン、バレイショデンプン、部分アルファー化デンプン、ヒドロキシプロピルスターチ、カルボキシメチルスターチナトリウム、トラガントが挙げられる。 Specific examples of the disintegrant include crystalline cellulose, methylcellulose, low-substituted hydroxypropylcellulose, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, wheat starch, rice starch, corn starch, potato starch, and partially pregelatinized. Starch, hydroxypropyl starch, sodium carboxymethyl starch, tragacanth can be mentioned.
界面活性剤の具体例としては、大豆レシチン、ショ糖脂肪酸エステル、ステアリン酸ポリオキシル、ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンポリオキシプロピレングリコール、セスキオレイン酸ソルビタン、トリオレイン酸ソルビタン、モノステアリン酸ソルビタン、モノパルミチン酸ソルビタン、モノラウリン酸ソルビタン、ポリソルベート、モノステアリン酸グリセリン、ラウリル硫酸ナトリウム、ラウロマクロゴールが挙げられる。 Specific examples of surfactants include soybean lecithin, sucrose fatty acid ester, polyoxyl stearate, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, sorbitan sesquioleate, sorbitan trioleate, sorbitan monostearate Sorbitan monopalmitate, sorbitan monolaurate, polysorbate, glyceryl monostearate, sodium lauryl sulfate, lauromacrogol.
滑沢剤の具体例としては、コムギデンプン、コメデンプン、トウモロコシデンプン、ステアリン酸、ステアリン酸カルシウム、ステアリン酸マグネシウム、含水二酸化ケイ素、軽質無水ケイ酸、合成ケイ酸アルミニウム、乾燥水酸化アルミニウムゲル、タルク、メタケイ酸アルミン酸マグネシウム、リン酸水素カルシウム、無水リン酸水素カルシウム、ショ糖脂肪酸エステル、ロウ類、水素添加植物油、ポリエチレングリコールが挙げられる。 Specific examples of lubricants include wheat starch, rice starch, corn starch, stearic acid, calcium stearate, magnesium stearate, hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, dry aluminum hydroxide gel, talc, Examples thereof include magnesium aluminate metasilicate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, sucrose fatty acid ester, waxes, hydrogenated vegetable oil, and polyethylene glycol.
流動性促進剤の具体例としては、含水二酸化ケイ素、軽質無水ケイ酸、乾燥水酸化アルミニウムゲル、合成ケイ酸アルミニウム、ケイ酸マグネシウムが挙げられる。 Specific examples of the fluidity promoter include hydrous silicon dioxide, light anhydrous silicic acid, dry aluminum hydroxide gel, synthetic aluminum silicate, and magnesium silicate.
また、本発明の抗原虫剤または抗リーシュマニア剤は、液剤、シロップ剤、懸濁剤、乳剤、エリキシル剤として投与する場合には、矯味矯臭剤、着色剤を含有してもよい。 In addition, the antiprotozoal agent or anti-leishmania agent of the present invention may contain a flavoring agent and a coloring agent when administered as a solution, syrup, suspension, emulsion, or elixir.
本発明の抗原虫剤または抗リューシュマニア剤は、食品、チューインガム、飲料等に添加して、いわゆる特定保健用食品(例えば、抗リューシュマニア食品)等とすることもできる。 The antiprotozoal agent or anti-Lyusmania agent of the present invention can be added to foods, chewing gums, beverages and the like to make so-called foods for specific health (for example, anti-Lyusmania foods).
以下、実施例により本発明をさらに具体的に説明するが、本発明の範囲はこれらの実施例に限定されるものではない。 EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the scope of the present invention is not limited to these examples.
リーシュマニア プロマスチゴートの培養
Medium 199培地(Life Technologies Co. Ltd.)を用いて、Leishmania major のプロマスチゴート(MHOM/SU/73/5ASKH)を培養した。プロマスチゴートは、熱不活化(56℃で30分)ウシ胎仔血清(10%)を補充した培地中、5% CO2下、27℃にて培養した。
Leishmania promastigote culture
Leishmania major promastigotes (MHOM / SU / 73 / 5ASKH) were cultured using Medium 199 medium (Life Technologies Co. Ltd.). Promastigotes were cultured at 27 ° C. under 5% CO 2 in a medium supplemented with heat inactivated (30 minutes at 56 ° C.) fetal calf serum (10%).
抽出物の調製及び抗リーシュマニア活性の測定
ミャンマー産の植物75種の材部30〜50gをメタノール100 mlずつを用いて4時間、50℃で3回抽出し、抽出液を合わせて減圧下濃縮し、メタノール抽出エキスを得た。
Preparation of extract and measurement of anti-Leishmania activity 30-50 g of 75 species of Myanmar plants were extracted 3 times at 50 ° C for 4 hours with 100 ml of methanol, combined with the extract and concentrated under reduced pressure. And a methanol extract was obtained.
メタノール抽出エキスの抗リーシュマニア活性を、WST-8(2-(2-メトキシ-4-ニトロフェニル)-3-(4-ニトロフェニル)-5-(2,4-ジスルホフェニル)-2H-テトラゾリウム モノナトリウム塩)と1-メトキシPMS(1-メトキシ-5-メチルフェナジニウムメチル硫酸塩)の混合物(テトラカラーワン試薬)を用いるMTT改良法によって、以下のようにアッセイした。 The anti-Leishmania activity of the methanol extract was measured using WST-8 (2- (2-methoxy-4-nitrophenyl) -3- (4-nitrophenyl) -5- (2,4-disulfophenyl) -2H- Tetrazolium monosodium salt) and 1-methoxy PMS (1-methoxy-5-methylphenazinium methyl sulfate) mixture (Tetracolor One reagent) was used to assay as follows.
抽出エキス40 mgをDMSO 1mlに溶解した後、Medium 199培地(Life Technologies Co. Ltd.)で希釈し、メンブレンフィルターに通した。試料溶液は9つの濃度に調製し、マイクロタイタープレートに各濃度の試料溶液50μlと、最終濃度が2×105/mlとなるように調製したリーシュマニア培養液50μlをそれぞれ接種し、培養液の全量を100μlとした。 40 mg of the extract was dissolved in 1 ml of DMSO, diluted with Medium 199 medium (Life Technologies Co. Ltd.), and passed through a membrane filter. Prepare sample solutions at 9 concentrations, inoculate a microtiter plate with 50 μl of each concentration of sample solution and 50 μl of Leishmania culture solution prepared to a final concentration of 2 × 10 5 / ml. The total volume was 100 μl.
27℃、5% CO2下で48時間インキュベートを行った後、テトラカラーワン試薬(生化学工業(株)製)を加え、27℃で6時間のインキュベートの後にマイクロプレートリーダーによりOD値(450〜630nm)を測定した。試験は、各試料及び各濃度につき3ウェルずつ行い、平均値よりMLC(minimum lethal concentration)、MIC(minimum inhibitory concentration)を求めた。結果を表1に示す。 After incubation for 48 hours at 27 ° C. and 5% CO 2 , Tetracolor One reagent (Seikagaku Corporation) was added, and after incubation for 6 hours at 27 ° C., the OD value (450 ~ 630nm) was measured. The test was carried out for 3 wells for each sample and each concentration, and MLC (minimum lethal concentration) and MIC (minimum inhibitory concentration) were determined from the average values. The results are shown in Table 1.
表1の結果から、Dipterocarpus tuberculatus Roxb.;Grevillea robusta A-Cun.;Xylocarpus moluccensis(Lam.)Roem.;Tectona grandis Linn.f.;Lagerstroemia tomentosa Presl.;Terminalia chebula Retz.;Haplophragma adenophyllum (Wall.) Dep;Xylia dolabriformis Benth.;Cananga odorata Hook.f.&.T.;Michelia champaca Linn.;Cordia fragrantissima Kurz.;Acacia catechu Willd.;Albizzia procera Benth.;Dalbergia oliveri Gamble.;Terminalia tomentosa W&A.;Cedrela serrata Royle.;Calophyllum kunstleri King.;Cedrela toona Roxb.;Albizzia odoratissima Benth.;Dalbergia cultrata Grah.;Chukrasia tabularis A. Juss.;Anogeissus acuminata Wall.;Lagerstroemia villosa Wall.およびDillenia pentagyna Roxb.は、その抽出物のMLC値及びMIC値のいずれかが400未満の値を示しており、これらの植物の抽出物およびこれらの植物に由来する成分が抗リーシュマニア活性を有することが明らかとなった。 From the results in Table 1, Dipterocarpus tuberculatus Roxb .; Grevillea robusta A-Cun .; Xylocarpus moluccensis (Lam.) Roem .; Tectona grandis Linn.f .; Lagerstroemia tomentosa Presl .; Terminalia chebula Retz .; Haplophragma adenophyllum Dep; Xylia dolabriformis Benth .; Cananga odorata Hook.f. &. T .; Michelia champaca Linn .; Cordia fragrantissima Kurz .; Acacia catechu Willd .; Albizzia procera Benth .; Dalbergia oliveri Gamble .; Terminalia tomentosa W & la. Calophyllum kunstleri King .; Cedrela toona Roxb .; Albizzia odoratissima Benth .; Dalbergia cultrata Grah .; Chukrasia tabularis A. Juss .; Anogeissus acuminata Wall .; Lagerstroemia villosa Wall. Either MLC value or MIC value was less than 400, and it was revealed that extracts of these plants and components derived from these plants have anti-Leishmania activity.
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