JP2006321728A - New anti-leishmania pharmaceutical composition - Google Patents
New anti-leishmania pharmaceutical composition Download PDFInfo
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- JP2006321728A JP2006321728A JP2005144428A JP2005144428A JP2006321728A JP 2006321728 A JP2006321728 A JP 2006321728A JP 2005144428 A JP2005144428 A JP 2005144428A JP 2005144428 A JP2005144428 A JP 2005144428A JP 2006321728 A JP2006321728 A JP 2006321728A
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- leishmania
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Classifications
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- 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
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
Description
本発明は、新規な抗リーシュマニア医薬組成物に関する。 The present invention relates to a novel anti-Leishmania pharmaceutical composition.
リーシュマニア症は、熱帯地方を中心として88ヶ国にわたり流行しているWHO指定熱帯病の一つである。現在、世界中で約1200万人が感染し、毎年150万人が新たに感染しており、過去10年間でその数は急増している。リーシュマニア原虫は2宿性でヒトやげっ歯類の細網内皮系細胞内、特にマクロファージ内でアマスチゴート(無鞭毛期)型として増殖し、感染を媒介する吸血性昆虫であるサンショウバエの中腸内ではプロマスチゴート(前鞭毛期)型で増殖する。原虫の種または亜種によって病巣の位置が異なり、病態によって皮膚型、粘膜型、内臓型の3つの型に分けられるが、中でも内臓型の症状は重く、肝・脾腫大、白血球減少、発熱、リンパ節腫脹などがみられ、死に至るケースが多い。また最近では、この内臓型がHIV(ヒト免疫不全ウイルス)感染の経路中に頻繁に認められており、新たな問題となっている。このため、リーシュマニアの新規化学療法剤の開発は人類にとって緊急を要する重要な課題であると考えられる。 Leishmaniasis is one of the WHO-designated tropical diseases that is prevalent in 88 countries mainly in the tropics. Currently, about 12 million people are infected worldwide, and 1.5 million people are newly infected every year, and the number has increased rapidly over the past decade. Leishmania protozoa are biphasic and proliferate in the reticuloendothelial cells of human rodents, particularly macrophages, as amastigotes (non-flagellate), and enter the midgut of the salamander, a blood-sucking insect that mediates infection. Then it grows in a promastigote (pre-flagellar stage) type. The location of the lesion differs depending on the species or subspecies of the protozoa, and it can be divided into three types, skin type, mucosal type, and visceral type, depending on the pathological condition. There are many cases of lymphadenopathy and death. Recently, this visceral type is frequently recognized in the route of HIV (human immunodeficiency virus) infection, which is a new problem. For this reason, the development of a new chemotherapeutic agent for Leishmania is considered to be an important issue that urgently requires humankind.
従来よりリーシュマニア症の治療に用いられている薬物は、(1)第一選択薬としてペントスタムやグルカンタイムに代表される5価のアンチモン剤である。しかし、病型によって感受性に差があることや、肝機能障害や腎障害などの副作用があることや高価格であること、また安定性の面でも問題が多い。(2)ペンタミジンを代表とするジアミジン誘導体は、前述のアンチモン剤による治療が十分でない場合に第二選択薬として用いられる。(3)その他に、イミダゾール、トリアゾール系化合物やアムホテリシンBなどの抗菌剤も用いられるが、通常は効力の点でアンチモン剤に及ばない。
このように、従来の抗リーシュマニア薬とは異なる構造を有する新規な抗リーシュマニア活性成分の発見、並びに新規抗リーシュマニア治療薬の開発が急務とされている。
Drugs conventionally used for the treatment of leishmaniasis are (1) pentavalent antimony agents typified by pentostam and glucan time as first-line drugs. However, there are many problems in terms of stability due to differences in susceptibility, side effects such as liver dysfunction and kidney damage, high price, and stability. (2) A diamidine derivative typified by pentamidine is used as a second-line drug when treatment with the antimony agent is not sufficient. (3) In addition, although antibacterial agents such as imidazole, triazole compounds and amphotericin B are also used, they are usually not as effective as antimony agents in terms of efficacy.
Thus, there is an urgent need to discover a novel anti-Leishmania active ingredient having a structure different from that of conventional anti-Leishmania drugs and to develop a novel anti-Leishmania drug.
こうした目的から、従来より多くの薬用植物の中から抗リーシュマニア活性成分を探索する試みが広く行われている。例えば、非特許文献1には、ミャンマーのマメ科植物である Millettia pendula から得られるキノン化合物を含有する抽出物に優れた抗リーシュマニア活性があること、非特許文献2には、シダ植物から得られるプテロシン及びアチセン化合物、およびカバノキ科植物から得られるジアリルヘプタン化合物が抗リーシュマニア活性成分として有効であること、非特許文献3には、天然または合成によって得られるリコカルコンAが抗リーシュマニア薬の有効性分として有効であること、非特許文献4には、パラグアイのミカン科植物である Zanthoxylum chiloperone var. angustifolium に含まれる canthinone 系のインドールアルカロイドに抗リーシュマニア活性があること、非特許文献5には、ブラジルの薬用植物である Elephantopus mollis に含まれるセスキテルペン化合物に抗リーシュマニア活性があることが記載されている。 For these purposes, attempts have been widely made to search for anti-Leishmania active ingredients from among many medicinal plants. For example, Non-Patent Document 1 has excellent anti-Leishmania activity in an extract containing a quinone compound obtained from Millettia pendula, a leguminous plant in Myanmar, and Non-Patent Document 2 has an anti-Leishmania activity. Pterocin and athycene compounds, and diallyl heptane compounds obtained from birch plants are effective as an anti-Leishmania active ingredient. Non-patent document 3 describes that natural or synthetically obtained lycochalcone A is an effective anti-Leishmania drug. Non-patent document 4 shows that the canthinone-based indole alkaloids contained in Zanthoxylum chiloperone var. Angustifolium, an anti-Leishmania activity, have anti-leishmania activity. Of sesquiterpenes in Elephantopus mollis, a medicinal plant in Brazil It is described that the compound has anti-Leishmania activity.
また、本発明で用いるキノン型ジテルペンであるコマロビキノン(Komaroviquinone)は、中南米で流行している熱帯病であるシャーガス病の病原寄生虫であるトリパノソーマ・クルーズに対して、抗トリパノソーマ活性成分として有効であることが非特許文献6に記載されている。
本発明は、新規な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 a novel anti-Leishmania agent.
本発明者らは、上記目的を達成するために鋭意検討していたところ、キノン型ジテルペンであるコマロビキノン(Komaroviquinone)に抗リーシュマニア活性があることを見出し、かかる知見に基づいて、本発明を完成させたものである。
即ち、本発明は、式I:
That is, the present invention provides compounds of formula I:
本発明の抗リーシュマニア医薬組成物を用いれば、ヒト、イヌを含む哺乳動物のリーシュマニア症を効果的に治療できる。 By using the anti-Leishmania pharmaceutical composition of the present invention, leishmaniasis in mammals including humans and dogs can be effectively treated.
以下に、本発明を具体的に説明するため、本発明の抗リーシュマニア医薬組成物の有効成分であるコマロビキノンの製造例、本発明の抗リーシュマニア医薬組成物の効果を明確にするために実施例および比較例、並びに本発明の医薬組成物の製剤例を記載する。但し、本発明は、これらの実施例等により何ら限定されるものではない。 Hereinafter, in order to explain the present invention specifically, an example of producing komabiquinone, which is an active ingredient of the anti-Leishmania pharmaceutical composition of the present invention, is carried out to clarify the effect of the anti-Leishmania pharmaceutical composition of the present invention. Examples and comparative examples, and formulation examples of the pharmaceutical composition of the present invention will be described. However, the present invention is not limited to these examples.
製造例1
コマロビキノンの製造方法
当該コマロビキノンは、植物、具体的にはウズベキスタンの薬用植物であるDracocephalum komarovi を原料として抽出単離することによって調製することができる。D. komaroviは、現地では“buzbosh”と呼ばれ、血液降下、抗炎症作用があるとして煎じて服用されている(非特許文献6参照)。
D. komaroviからコマロビキノンを単離調製する場合、原料として使用するD. komaroviは、全草であってもまたその一部であってもよい。当該コマロビキノンの調製は、制限はされないが、例えばD. komaroviの全草またはその一部を、有機溶媒を含む溶媒で抽出および分画する工程を経て行うことができる (非特許文献6参照)。
Production Example 1
Production Method of Comalobiquinone The comalobiquinone can be prepared by extracting and isolating a plant, specifically, Drakocephalum komarovi, which is a medicinal plant of Uzbekistan, as a raw material. D. komarovi is called “buzbosh” in the field, and it is decocted and used as a blood lowering and anti-inflammatory action (see Non-Patent Document 6).
When isolating and preparing komabiquinone from D. komarovi, D. komarovi used as a raw material may be whole plant or a part thereof. The preparation of the comalobiquinone is not limited. For example, the whole plant of D. komarovi or a part thereof can be extracted and fractionated with a solvent containing an organic solvent (see Non-Patent Document 6).
乾燥したD. komaroviの全草1.6kgを細かくし、ヘキサン、酢酸エチルの順に各溶媒について3回ずつ、室温で一晩抽出した。その後、これらを濾過して濾液を濃縮し、22.2gの固体(以下「ヘキサン抽出物」と呼ぶ)、67.3gの固体(以下「酢酸エチル抽出物」と呼ぶ)を得た。さらに、ヘキサン抽出物、酢酸エチル抽出物それぞれをシリカゲルカラムクロマトグラフィーに付し、ヘキサン−アセトン(10:1、8:1、6:1、4:1、0:1)、メタノールの順に溶出し、各抽出物から各々6画分を得た。このうち、ヘキサン抽出物のヘキサン−アセトン(8:1および6:1)溶出画分(5.6g)と酢酸エチル抽出物のヘキサン−アセトン(6:1)溶出画分(4.6g)を合わせ、再度シリカゲルカラムクロマトグラフィーに付し、ヘキサン−酢酸エチル(6:1)溶出画分を得た。さらに、分画を繰り返し(クロロホルム−アセトン(100:1)、ベンゼン−酢酸エチル(30:1)、HPLC(YMC Pack SIL−06)を用いて、ヘキサン−酢酸エチル(5:1)にて溶出)、オレンジ色油状のコマロビキノン(124mg)を得た。
得られたコマロビキノンについて得られたデータ結果は以下の通りである。
[α]25 D +34.2゜(c 1.86, CHCl3); UV (MeOH) λmax (log ε) 366 (2.89), 272 (3.84) nm; IR (KBr) vmax 3410, 2947, 1651, 1600, 1458 cm-1.
・EIMS: m/z 360 [M+] (23), 342 (8), 316 (100), 301 (30), 273 (11), 247 (20), 221 (19).
・HREIMS: m/z 360.1934 (calcd for C21H28O5, 360.1929).
・ 1 H NMR (CDCl 3 , 500 MHz) δ:5.99 (1H, s, OH), 3.98 (1H, s, OMe), 3.23 (1H, sep, J = 7.0 Hz, 15), 2.55 (1H, d, J = 19.6 Hz, 20b), 2.30 (1H, dd, J = 12.8, 7.76 Hz, 6a), 2.26 (1H, d, J = 19.6 Hz, 20a), 2.04 (1H, dd, J = 12.8, 7.8 Hz, 6b), 2.03 (1H, overlap, 2b), 1.73 (1H, overlap, 2a), 1.71 (1H, t, J = 8.2 Hz, 5), 1.60 (1H, m, 1), 1.59 (1H, overlap, 3b), 1.18 (1H, d, J = 7.3 Hz, 16), 1.18 (1H, d, J = 7.0 Hz, 17), 1.15 (1H, dd, J = 11.3, 5.8 Hz, 3a), 0.95 (1H, s, 18), 0.86 (1H, s, 19).
・ 13 C NMR (CDCl 3 , 125 MHz)δc:189.1 (14), 183.6 (11), 156.1 (12), 142.1 (8), 138.9 (9), 137.0 (13), 100.9 (7), 79.3 (10), 61.1 (OMe), 51.4 (5), 45.7 (6), 39.0 (20), 32.0 (4), 31.2 (3), 30.3 (18), 29.8 (2), 27.0 (19), 24.3 (15), 20.4 (16), 20.4 (17), 15.6 (1).
1.6 kg of dried D. komarovi whole plant was finely divided and extracted three times for each solvent in the order of hexane and ethyl acetate overnight at room temperature. Thereafter, these were filtered and the filtrate was concentrated to obtain 22.2 g of a solid (hereinafter referred to as “hexane extract”) and 67.3 g of a solid (hereinafter referred to as “ethyl acetate extract”). Further, each of the hexane extract and the ethyl acetate extract was subjected to silica gel column chromatography, and eluted in the order of hexane-acetone (10: 1, 8: 1, 6: 1, 4: 1, 0: 1) and methanol. Six fractions were obtained from each extract. Among these, hexane-acetone (8: 1 and 6: 1) elution fraction (5.6 g) of hexane extract and hexane-acetone (6: 1) elution fraction (4.6 g) of ethyl acetate extract were used. These were combined and subjected to silica gel column chromatography again to obtain a fraction eluted with hexane-ethyl acetate (6: 1). Further, fractionation was repeated (chloroform-acetone (100: 1), benzene-ethyl acetate (30: 1), and HPLC (YMC Pack SIL-06)) and eluted with hexane-ethyl acetate (5: 1). ), An orange oily comalobiquinone (124 mg) was obtained.
The data results obtained for the obtained comalobiquinone are as follows.
[α] 25 D + 34.2 ° (c 1.86, CHCl 3 ); UV (MeOH) λ max (log ε) 366 (2.89), 272 (3.84) nm; IR (KBr) v max 3410, 2947, 1651, 1600 , 1458 cm -1 .
・ EIMS : m / z 360 [M + ] (23), 342 (8), 316 (100), 301 (30), 273 (11), 247 (20), 221 (19).
・ HREIMS : m / z 360.1934 (calcd for C 21 H 28 O 5 , 360.1929).
・ 1 H NMR (CDCl 3 , 500 MHz) δ: 5.99 (1H, s, O H ), 3.98 (1H, s, O Me ), 3.23 (1H, sep, J = 7.0 Hz, 15), 2.55 (1H , d, J = 19.6 Hz, 20b), 2.30 (1H, dd, J = 12.8, 7.76 Hz, 6a), 2.26 (1H, d, J = 19.6 Hz, 20a), 2.04 (1H, dd, J = 12.8 , 7.8 Hz, 6b), 2.03 (1H, overlap, 2b), 1.73 (1H, overlap, 2a), 1.71 (1H, t, J = 8.2 Hz, 5), 1.60 (1H, m, 1), 1.59 ( 1H, overlap, 3b), 1.18 (1H, d, J = 7.3 Hz, 16), 1.18 (1H, d, J = 7.0 Hz, 17), 1.15 (1H, dd, J = 11.3, 5.8 Hz, 3a) , 0.95 (1H, s, 18), 0.86 (1H, s, 19).
・ 13 C NMR (CDCl 3 , 125 MHz) δc: 189.1 (14), 183.6 (11), 156.1 (12), 142.1 (8), 138.9 (9), 137.0 (13), 100.9 (7), 79.3 ( 10), 61.1 (OMe), 51.4 (5), 45.7 (6), 39.0 (20), 32.0 (4), 31.2 (3), 30.3 (18), 29.8 (2), 27.0 (19), 24.3 ( 15), 20.4 (16), 20.4 (17), 15.6 (1).
実施例1
In vitro抗リーシュマニア活性の測定
検体の抗リーシュマニア活性を評価するために、リーシュマニア原虫(Leishmania major)ATCC 50122株のプロマスチゴート(前鞭毛期)およびアマスチゴート(無鞭毛期)を用いて、In vitroにおけるリーシュマニア原虫の生育阻害率を測定した。
リーシュマニア原虫のプロマスチゴート(前鞭毛期)型については、培地はSchneiders培地に20%ウシ胎児血清を加えて作成した。原虫は26℃のインキュベーター内で培養した。アマスチゴート(無鞭毛期)型については、先にマウス腹腔内マクロファージを24穴プレートに添加し、二酸化炭素5%の雰囲気下、37℃のインキュベーター内で4日間培養した。その後、マクロファージをプロマスチゴート(前鞭毛期)に感染させ、さらに同条件で培養することでアマスチゴート(無鞭毛期)に形態を変化させた後、3回洗浄した。さらに培地を加え、再培養した後、測定に用いた。
Example 1
Measurement of anti-Leishmania activity in vitro In order to evaluate the anti-Leishmania activity of a specimen, the promastigote (preflagellar stage) and amastigote (non-flagellar stage) of Leishmania major ATCC 50122 strain were used in vitro. The growth inhibition rate of Leishmania parasites was measured.
For the Promastigote (preflagellate stage) type of Leishmania parasite, the medium was prepared by adding 20% fetal bovine serum to Schneiders medium. The protozoa were cultured in an incubator at 26 ° C. For the amastigote (flagellar stage) type, mouse intraperitoneal macrophages were first added to a 24-well plate and cultured in an incubator at 37 ° C. for 4 days in an atmosphere of 5% carbon dioxide. Thereafter, macrophages were infected with promastigotes (pre-flagellar phase), and further cultured under the same conditions to change the morphology to amastigote (non-flagellar phase), and then washed three times. Furthermore, after adding a culture medium and recultivating, it used for the measurement.
リーシュマニア原虫の生育阻害率の測定は、具体的には以下のようにして行った。
検体をMeOHに溶解し、各種濃度に希釈して被検試料とした。この被検試料を、先にリーシュマニア原虫の培養液を添加しておいた24穴プレートに添加し、最終濃度を2.0、1.0、0.5、0.25、0.1、0.05μMとした。プロマスチゴート(前鞭毛期)は26℃で培養し、2時間ごとに顕微鏡下で原虫の生細胞数を求め、対照と比較した。アマスチゴート(無鞭毛期)は二酸化炭素5%の雰囲気下、37℃のインキュベーター内で24時間培養した後、顕微鏡下で観察し、対照と比較した。
この結果、コマロビキノンは、濃度2.0μMで4時間後にプロマスチゴート(前鞭毛期)の成長を阻害し始め、8時間後に50%、24時間後には95%原虫の成長を阻害した。
アマスチゴート(無鞭毛期)については、濃度1.0−2.0μMで完全に原虫は消失したが、同時にマクロファージにも影響を与えていた。濃度0.5μM、0.25μMでは、完全に原虫は消失し、マクロファージの細胞質には何ら影響を与えなかった。一方、濃度0.1μMでは、マクロファージ中の原虫数が減少するだけに留まった。濃度0.05μMでは原虫に全く効果を示さなかった(図1)。
Specifically, the growth inhibition rate of Leishmania parasites was measured as follows.
The specimen was dissolved in MeOH and diluted to various concentrations to prepare test samples. This test sample was added to a 24-well plate to which the culture medium of Leishmania parasite had been added, and the final concentration was 2.0, 1.0, 0.5, 0.25, 0.1, 0.05 μM. Promastigotes (pre-flagellar stage) were cultured at 26 ° C., and the number of viable protozoa was determined under a microscope every 2 hours and compared with a control. The amastigote (non-flagellar stage) was cultured in an incubator at 37 ° C. for 24 hours in an atmosphere of 5% carbon dioxide, then observed under a microscope and compared with a control.
As a result, comarobiquinone began to inhibit the growth of promastigote (preflagellate stage) after 4 hours at a concentration of 2.0 μM, and inhibited growth of protozoa by 50% after 8 hours and 95% after 24 hours.
In the case of amastigote (flagellar stage), the protozoa completely disappeared at a concentration of 1.0 to 2.0 μM, but at the same time, it also affected macrophages. At concentrations of 0.5 μM and 0.25 μM, the protozoa completely disappeared and had no effect on the cytoplasm of macrophages. On the other hand, at a concentration of 0.1 μM, the number of protozoa in macrophages was only reduced. At a concentration of 0.05 μM, there was no effect on the protozoa (FIG. 1).
実施例2
検体のIn vivo抗リーシュマニア活性の測定
検体のIn vivoでの抗リーシュマニア活性を評価するために、皮膚リーシュマニア症マウスモデルを用いて治療効果を調べた。
検体であるコマロビキノンとの比較として、陽性対照であるペントスタムを用いた。
コマロビキノン、ペントスタムはそれぞれDMSO、滅菌精製水に溶解した。
第8週目のマウス(Balb/C, female, 20匹)の右足蹠(footpad)に、リーシュマニア原虫(Leishmani major)ATCC 50122株のプロマスチゴート(前鞭毛期)を感染させ、感染していない正常な左足蹠のサイズをコントロールとした。感染から3週間後、マウスの右足蹠感染部位が肥大していることを確認し、各検体200μlずつ(コマロビキノン:4.0 mg/kg, ペントスタム:ヒトに対するWHO推奨濃度である20mg/kg)を投与した。腹腔内投与には26ゲージの皮下注射針と1mlのシリンジを用い、経口投与には丸型の注射針を用いた。
Example 2
Measurement of in vivo anti-leishmania activity of specimens In order to evaluate the in vivo anti-leishmania activity of specimens, the therapeutic effect was examined using a mouse model of cutaneous leishmaniasis.
As a comparison with the sample, komabiquinone, a positive control, pentostam, was used.
Comalobiquinone and pentostam were dissolved in DMSO and sterilized purified water, respectively.
Infected the right footpad of the 8th week mouse (Balb / C, female, 20 mice) with the promastigote (preflagellar stage) of Leishmani major ATCC 50122 strain. The size of the left footpad was used as a control. Three weeks after the infection, it was confirmed that the site of infection of the right footpad of the mouse was enlarged, and 200 μl of each specimen was administered (comarobiquinone: 4.0 mg / kg, pentostam: 20 mg / kg, the recommended concentration for WHO for humans). . A 26 gauge hypodermic needle and a 1 ml syringe were used for intraperitoneal administration, and a round injection needle was used for oral administration.
投与スケジュールは、4日間連続投与後、3日間投与をやめ、その後3日間連続投与した。投与開始14日後の右足蹠のサイズから非投与群のサイズを差し引き、その差異を比較し、下式に従って検体存在下での成長阻害率%を求め、各検体の抗リーシュマニア活性を評価した。
成長阻害率(%)={1−(薬物投与後の足蹠サイズの差/薬物投与前の足蹠サイ ズの差)}×100
結果を表1および図2に示す。
Growth inhibition rate (%) = {1− (difference in footpad size after drug administration / difference in footpad size before drug administration)} × 100
The results are shown in Table 1 and FIG.
コマロビキノンは、経口投与で約60%、腹腔内投与でも30−60%の成長阻害作用を示した。陽性対照試験として行ったペントスタムは、コマロビキノンの4倍量を投与したが、経口、腹腔内両投与において、6匹中4匹に潰瘍がみられた上、残りの2匹もコマロビキノンと比較して、成長阻害率は低かった。
この結果から、コマロビキノンにはIn vitro、In vivo両試験において、抗リーシュマニア活性が認められた。すなわち、コマロビキノンは、新たな抗リーシュマニア薬の有効性分となりえることがわかる。
Comalobiquinone showed growth inhibitory action of about 60% by oral administration and 30-60% by intraperitoneal administration. Pentostam, which was used as a positive control test, was administered 4 times the amount of comarobiquinone. In both oral and intraperitoneal administrations, 4 out of 6 animals showed ulcers, and the remaining 2 animals compared to comarobiquinone. The growth inhibition rate was low.
From this result, anti-leishmania activity was observed for comalobiquinone in both in vitro and in vivo tests. That is, it can be seen that comalobiquinone can be an effective component of a new anti-Leishmania drug.
式Iで表されるコマロビキノンは、その薬理作用に鑑みて、投与目的に対する各種製剤形態で使用可能である。本発明の製薬組成物は活性成分として遊離または酸付加塩の形態にある有効な量の特定化合物を、薬理的に受容しうる担体と均一に混合して製造できる。この担体は投与に対して望ましい製剤の形態に応じて、広い範囲の形態を取ることができる。これらの製薬組成物は、経口的または注射による投与に対して適する単位服用形態にあることが望ましい。経口服用形態にある組成物の調製においては、何らかの有用な薬理的に受容しうる担体が使用できる。例えば、懸濁液及びシロップ剤の如き経口液体調製物は水、シュークロース、ソルビトール、フラクトース等の糖類、ポリエチレングリコール、プロピレングリコール等のグリコール類、ゴマ油、オリーブ油、大豆油等の油類、アルキルパラヒドロキシベンゾエート等の防腐剤、ストロベリー・フレーバー、ペパーミント等のフレーバー類を使用して製造できる。 Comarobiquinone represented by Formula I can be used in various dosage forms for administration purposes in view of its pharmacological action. The pharmaceutical composition of the present invention can be produced by uniformly mixing an effective amount of a specific compound in the form of a free or acid addition salt as an active ingredient with a pharmacologically acceptable carrier. The carrier can take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are preferably in unit dosage forms suitable for oral or injection administration. Any useful pharmaceutically acceptable carrier can be used in preparing the compositions in oral dosage form. For example, oral liquid preparations such as suspensions and syrups include sugars such as water, sucrose, sorbitol and fructose, glycols such as polyethylene glycol and propylene glycol, oils such as sesame oil, olive oil and soybean oil, and alkyl paraffin. It can be produced using a preservative such as hydroxybenzoate, and flavors such as strawberry flavor and peppermint.
散剤、丸薬、カプセルおよび錠剤はラクトース、グルコース、シュークロース、マニトール等の賦形剤、デンプン、アルギン酸ソーダ等の崩壊剤、ステアリン酸マグネシウム、タルク等の滑沢剤、ポリビニルアルコール、ヒドロキシプロピルセルロース、ゼラチン等の結合剤、脂肪酸エステル等の表面活性剤、グリセリン等の可塑剤を用いて製造できる。錠剤およびカプセルが、投与が容易であるという理由で最も有用な単位経口投与剤である。錠剤やカプセルを製造する際には、固体の製薬担体が用いられる。 Powders, pills, capsules and tablets are excipients such as lactose, glucose, sucrose, mannitol, disintegrants such as starch and sodium alginate, lubricants such as magnesium stearate and talc, polyvinyl alcohol, hydroxypropylcellulose, gelatin Etc., a surface active agent such as a fatty acid ester, and a plasticizer such as glycerin. Tablets and capsules are the most useful unit oral dosages because they are easy to administer. When manufacturing tablets and capsules, solid pharmaceutical carriers are used.
また、注射用の溶液は、塩溶液、グルコース溶液または塩水とグルコース溶液の混合物
からなる担体を用いて調製することができる。
本発明の医薬は、経口的投与または注射投与され、その有効投与量は、4〜8mg/kg/日であり、その投与回数は1日約3回が好ましい。
Moreover, the solution for injection can be prepared using a carrier comprising a salt solution, a glucose solution or a mixture of salt water and a glucose solution.
The medicament of the present invention is administered orally or by injection, and its effective dose is 4-8 mg / kg / day, and the frequency of administration is preferably about 3 times a day.
製剤例1:錠剤
常法により、次の組成により錠剤を調製する。
コマロビキノン 80mg
乳糖 60mg
バレイショデンプン 30mg
ポリビニルアルコール 2mg
ステアリン酸マグネシウム 1mg
タール色素 微量
Formulation Example 1: Tablets Tablets are prepared according to the following composition by a conventional method.
Comalobiquinone 80 mg
Lactose 60mg
Potato starch 30mg
Polyvinyl alcohol 2mg
Magnesium stearate 1mg
Tar pigment Trace amount
製剤例2:散剤
常法により次の組成により散剤を作成する
コマロビキノン 80mg
乳糖 275mg
Formulation example 2: Powder Powder comarobiquinone which is prepared by the usual method and having the following composition 80 mg
Lactose 275mg
製剤例3:シロップ剤
常法により次の組成によりシロップ剤を作成する
活性成分 300mg
精製白糖 40g
パラオキシ安息香酸メチル 40mg
パラオキシ安息香酸プロピル 10mg
ストロベリー・フレーバー 0.1ml
これに水を加えて全量1000mlとする。
Formulation example 3: syrup formulation 300 mg of active ingredient for preparing a syrup formulation with the following composition by a conventional method
40g refined white sugar
Methyl paraoxybenzoate 40mg
Propyl paraoxybenzoate 10mg
Strawberry flavor 0.1ml
Water is added to make a total volume of 1000 ml.
本発明の抗リーシュマニア医薬組成物は医薬品として用いることができる。 The anti-Leishmania pharmaceutical composition of the present invention can be used as a pharmaceutical product.
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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US8373006B2 (en) | 2010-10-19 | 2013-02-12 | Aoyama Gakuin Educational Foundation | Anti-leishmanial compound and anti-leishmanial drug |
US8809555B2 (en) | 2010-10-19 | 2014-08-19 | Aoyama Gakuin Educational Foundation | Anti-leishmanial compound and anti-leishmanial drug |
-
2005
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8373006B2 (en) | 2010-10-19 | 2013-02-12 | Aoyama Gakuin Educational Foundation | Anti-leishmanial compound and anti-leishmanial drug |
US8809555B2 (en) | 2010-10-19 | 2014-08-19 | Aoyama Gakuin Educational Foundation | Anti-leishmanial compound and anti-leishmanial drug |
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