JP6440240B2 - External preparations to improve peripheral neuropathy-induced sensory abnormalities - Google Patents
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Description
本発明は、薬物の末梢神経障害で誘発される感覚異常の改善するためのアデノシンＡ１受容体アゴニストの外用剤、詳しくは、アデノシンＡ１受容体活性化作用を有する生薬または生薬成分を含有する外用剤に関するものである。 The present invention relates to an external preparation of an adenosine A1 receptor agonist for improving sensory abnormalities induced by peripheral neuropathy of a drug, and more specifically, an external preparation containing a crude drug or a crude drug component having an adenosine A1 receptor activation action. It is about.
医薬品の成分である薬物より生じる副作用の１つに神経障害がある。神経障害には中枢神経系、自律神経系、末梢神経系及び感覚器等の障害がある。これらの神経障害を引き起こす恐れがある医薬品として高脂血症治療薬、抗悪性腫瘍薬（抗がん剤）、抗ウィルス薬及び抗結核薬等が知られている。
このうち、末梢神経障害で誘発される感覚異常は、薬物を使用してしばらく経過した後に手・足先の痺れ感、ほてり、感覚が鈍くなる等の症状を呈する。症状は、次第に上方の腕や脚に広がる。感覚異常の多くは両足・両手で起こるが、片足・片手だけのこともある。
One of the side effects caused by drugs that are components of pharmaceuticals is neuropathy. Neurological disorders include disorders of the central nervous system, autonomic nervous system, peripheral nervous system and sensory organs. As drugs that may cause these neurological disorders, antihyperlipidemic drugs, anticancer drugs (anticancer drugs), antiviral drugs, antituberculosis drugs, and the like are known.
Among these, sensory abnormalities induced by peripheral neuropathy present symptoms such as numbness of hands and feet, hot flashes and dull sensations after a while using drugs. Symptoms gradually spread to the upper arms and legs. Most sensory abnormalities occur with both feet and hands, but sometimes with only one foot or one hand.
抗がん剤の末梢神経障害による感覚異常は、がん化学療法において問題となっている。抗がん剤の末梢神経障害の原因として、微小管の障害や血流の障害（非特許文献１）などが挙げられている。血流の障害に関しては血流改善が末梢神経障害を緩和することが知られている（非特許文献２）。 Sensory abnormalities due to peripheral neuropathy of anticancer agents are a problem in cancer chemotherapy. As a cause of peripheral neuropathy of anticancer agents, microtubule damage, blood flow disorder (Non-patent Document 1) and the like are mentioned. Regarding blood flow disorders, it is known that improving blood flow alleviates peripheral nerve disorders (Non-Patent Document 2).
一方、アデノシン受容体のサブタイプであるＡ１受容体のアゴニストは、血流を促進することに加え、疼痛抑制作用を有することが知られている（非特許文献３）。また、生薬として多用される芍薬の主要成分であるぺオニフロリンが、アデノシンＡ１受容体アゴニストとして機能することが知られている（非特許文献４）。 On the other hand, A1 receptor agonists, which are subtypes of adenosine receptors, are known to have a pain-inhibiting action in addition to promoting blood flow (Non-patent Document 3). In addition, it is known that paeoniflorin, which is a major component of glazes frequently used as crude drugs, functions as an adenosine A1 receptor agonist (Non-patent Document 4).
抗がん剤のパクタキセル誘発疼痛マウスモデルでの異痛、痛覚過敏に芍薬の経口投与が有効であることが報告されている (非特許文献５)。しかし、生薬を処方成分とする和漢薬は、通常、経口投与されるが、紫雲膏など一部を除き、外用されることは少なく、芍薬（シャクヤク）、牡丹皮（ボタンピ）などは単味で外用には用いられていない。 It has been reported that oral administration of a glaze is effective for allodynia and hyperalgesia in a mouse model of anti-cancer drug pactaxel-induced pain (Non-patent Document 5). However, Japanese herbal medicine with herbal medicine as a prescription ingredient is usually administered orally, but it is rarely used externally except for a part of Shiunko, and peony and peony are simple. It is not used for external use.
抗がん薬投与患者などで誘発される四肢末端の末梢神経障害による感覚異常の改善方法や予防方法は確立されてない。また、芍薬は単味で漢方薬として使用されておらず、また、芍薬を処方成分とする芍薬甘草湯など漢方薬は、経口投与が基本であり、感覚異常を生じている局所での治療に用いる外用剤が求められている。 There is no established method for improving or preventing sensory abnormalities caused by peripheral neuropathy at the extremities induced in patients treated with anticancer drugs. In addition, glazes are not used as traditional Chinese medicines. Also, traditional Chinese medicines such as Shakuyakukanzoto, which uses glaze as a prescription ingredient, are basically administered orally and are used for local treatments that cause sensory abnormalities. There is a need for agents.
本発明者らは、マウスにおいて、アデノシンＡ１受容体アゴニストを皮膚に塗布することで、抗がん薬投与による末梢神経障害から生じる感覚異常が改善されることを見出した。さらに、アデノシンＡ１受容体アゴニストを含有する生薬エキスを皮膚に塗布した場合においても、四肢末端の末梢神経障害を誘発する抗がん薬投与による末梢神経障害から生じる感覚異常が改善されることを見出し、本発明を完成させるに至った。
以下に本発明を詳細に説明する。
The present inventors have found that, in mice, by applying an adenosine A1 receptor agonist to the skin, sensory abnormalities resulting from peripheral neuropathy caused by anticancer drug administration are improved. Furthermore, even when a crude drug extract containing an adenosine A1 receptor agonist is applied to the skin, sensory abnormalities resulting from peripheral neuropathy caused by administration of anticancer drugs that induce peripheral neuropathy at the extremities are improved. The present invention has been completed.
The present invention is described in detail below.
末梢神経障害による感覚異常が問題となる薬物としては、例えば、微小管重合阻害薬（ビンカアルカロイド系薬剤、ハリコンドリンＢ類縁体）、微小管脱重合阻害薬（タキサン系薬剤）、白金製剤、プロテアソーム阻害剤、抗結核薬、抗原虫薬、逆転写酵素阻害薬、ＨＭＧ−ＣｏＡ還元酵素阻害薬、痛風治療薬、抗不整脈薬、インターフェロン製剤などが挙げられる。 Examples of drugs that cause sensory abnormalities due to peripheral neuropathy include microtubule polymerization inhibitors (vinca alkaloids, halichondrin B analogs), microtubule depolymerization inhibitors (taxanes), platinum preparations, proteasomes Inhibitors, antituberculosis drugs, antiprotozoal drugs, reverse transcriptase inhibitors, HMG-CoA reductase inhibitors, gout treatment drugs, antiarrhythmic drugs, interferon preparations and the like.
末梢神経障害で誘発される感覚異常としては、手先・足先の痺れ感、ほてり、痛み、痛覚過敏、異痛（アロディニア）、感覚が鈍くなるなどが挙げられる。 Examples of sensory abnormalities induced by peripheral neuropathy include numbness in the hands and toes, hot flashes, pain, hyperalgesia, allodynia, and dull sensations.
アデノシンＡ１受容体アゴニストとして、Ｎ６−シクロプロピルアデノシン(N6-Cyclopentyladnosine)など合成アデノシン誘導体；ペオニフロリンおよびペオニフロリン関連化合物（アルビフロリン、オキシペオニフロリンなどの生薬成分が挙げられる。 Examples of the adenosine A1 receptor agonist include synthetic adenosine derivatives such as N6-cyclopropyladenosine (N6-Cyclopentyladnosine); paeoniflorin and paeoniflorin-related compounds (albiflorin, oxypeoniflorin and other herbal medicine components).
本発明の外用剤は、有効成分として、アデノシンＡ１受容体アゴニスト作用を有する生薬また前記した生薬成分を用いるものである。
生薬として芍薬（シャクヤク）および／または牡丹皮（ボタンピ）、それらのエキスが挙げられるが、芍薬または芍薬エキスが好ましい。
The external preparation of the present invention uses a crude drug having an adenosine A1 receptor agonist action or the aforementioned crude drug component as an active ingredient.
Herbal medicines include glaze (peony) and / or peonies (button pi), and extracts thereof, but glaze or glaze extract is preferred.
生薬エキスは、上記生薬から水もしくはメタノール、エタノールなどのアルコール類またはそれらの混合液を使用して煎じ、加熱還流など公知の方法またはそれに準じて製造されたものであればよい。 The crude drug extract may be any of those produced from the above crude drugs by using a known method such as decoction or heating reflux using water, alcohols such as methanol and ethanol, or a mixture thereof.
本発明の外用剤は、通常外用剤に用いられる剤型を使用することができるが、好ましいものとして液剤、クリーム剤、軟膏剤、ゲル剤、貼付剤、エアゾール剤などが挙げられ、常法により製造することができる。 As the external preparation of the present invention, a dosage form usually used for external preparations can be used, and preferable examples include liquids, creams, ointments, gels, patches, aerosols and the like. Can be manufactured.
また、本発明の外用剤には必要に応じ水、低級アルコール、溶解補助剤、界面活性剤、乳化安定剤、ゲル化剤、粘着剤、その他、所望する剤型を得るための通常使用される基剤成分などを配合でき、必要に応じて血管拡張剤、副腎皮質ホルモン、角質溶解剤、保湿剤、殺菌剤、抗酸化剤、清涼化剤、香料、色素などを本発明の効果が損なわれない範囲で配合することができる。 The external preparation of the present invention is usually used to obtain a desired dosage form, if necessary, water, lower alcohol, solubilizer, surfactant, emulsion stabilizer, gelling agent, adhesive, etc. Base ingredients can be blended, and the effects of the present invention are impaired as needed, such as vasodilators, corticosteroids, keratolytic agents, moisturizers, bactericides, antioxidants, cooling agents, fragrances, pigments It can mix | blend in the range which is not.
合成アデノシンＡ１受容体作用薬やアデノシンＡ１受容体への作用を持つペオニフロリンなどの生薬成分およびそれを含有する生薬エキスを外用することで末梢神経障害による感覚異常を改善することができる。外用により経口投与より薬物の副作用などのリスクを減らすことができ、臨床への応用が容易となる。 Sensory abnormalities due to peripheral neuropathy can be improved by externally applying a crude drug component such as a synthetic adenosine A1 receptor agonist or paeoniflorin having an action on adenosine A1 receptor and a crude drug extract containing the same. External application can reduce the risk of side effects of drugs compared to oral administration, and clinical application becomes easier.
以下、本発明を実施例で説明するが、本発明はこれらに限定されるものではない。
なお、感覚異常の指標としてvon Freyフィラメントを用いた感覚の過過敏症（アロディニア）の評価を用い、また、一部の実験では、電気生理学的に、末梢神経の神経活動評価を用いた。
EXAMPLES Hereinafter, although an Example demonstrates this invention, this invention is not limited to these.
In addition, evaluation of sensory hypersensitivity (allodynia) using von Frey filament as an index of sensory abnormality was used, and in some experiments, evaluation of peripheral nerve activity was used electrophysiologically.
製造例１
＜芍薬エキス１＞
芍薬50g と純水400mLを煎じ器加え，とろ火で50分間煎じる。煎じ液を濾紙で濾過し、濾液を凍結乾燥する。得られた粉末状のエキス（13.4g、収率：26.8％）はサンプル瓶に入れ、冷蔵保管する。
Production Example 1
<Glue extract 1>
Add 50g of glaze and 400mL of pure water and brew for 50 minutes. The decoction is filtered through filter paper and the filtrate is lyophilized. The obtained powdery extract (13.4 g, yield: 26.8%) is put in a sample bottle and stored refrigerated.
製造例２
＜芍薬エキス２＞
芍薬1kgと99.5%エタノール2Lをガラス容器（ナス型フラスコの上部に摺合ジムロート冷器を装着したガラス容器）に投入し、90分間加熱還流する。冷却後、上清を分取する。残渣に99.5%エタノール2Lを加え、90分間加熱還流する。冷却後、上清を分取する。この抽出操作を再度繰り返す。分取した上清を合わせ、減圧下に濃縮する。残渣を凍結乾燥し、得られた粉末状のエキス（112.4g）はサンプル瓶に入れ、冷蔵保管する。
Production Example 2
<Glue extract 2>
Put 1 kg of glaze and 2 L of 99.5% ethanol into a glass container (glass container with a sliding Jimroth cooler on top of eggplant-shaped flask) and heat to reflux for 90 minutes. After cooling, collect the supernatant. Add 2 L of 99.5% ethanol to the residue and heat to reflux for 90 minutes. After cooling, collect the supernatant. This extraction operation is repeated again. The collected supernatants are combined and concentrated under reduced pressure. The residue is freeze-dried, and the resulting powdery extract (112.4 g) is placed in a sample bottle and stored refrigerated.
実施例１
マウス（ICR,5〜7週齢, 雄性）に、パクリタキセル（PTX、5mg/kg）単回腹腔内注射し、翌日よりA1アデノシン受容体作動薬（CPA：N6-Cyclopentyladenosine）およびその溶媒（VH2：エタノール）を20μLの容量で1日2回両足（足首から指先まで全体的に）に塗布した。アロディニアは、von Freyフィラメント（0.69 mN）を用いてスコア化（0 : 反応なし又は後肢を横にずらす行動、1 : 後肢の引き上げ行動 (lifting)、2 : 後肢の振り行動 (flinching) 又は刺激部位への舐め行動 (licking)）して評価した。
Example 1
A single intraperitoneal injection of paclitaxel (PTX, 5 mg / kg) into mice (ICR, 5-7 weeks old, male), and A1 adenosine receptor agonist (CPA: N6-Cyclopentyladenosine) and its solvent (VH2: Ethanol) was applied to both feet (totally from ankle to fingertip) twice a day in a volume of 20 μL. Allodynia is scored using von Frey filament (0.69 mN) (0: no response or hind limb lateral movement, 1: hind limb lifting (flinching), 2: hind limb swinging (flinching) or stimulation site Licking) and evaluated.
実施例２
マウス（ICR,5〜7週齢, 雄性）に、パクリタキセル（PTX、5mg/kg）単回腹腔内注射し、翌日よりペオニフロリンまたはその溶媒（VH2：エタノール）を20μLの容量で1日2回両足（足首から指先まで全体的に）に塗布した。アロディニアは、von Freyフィラメント（0.69 mN）を用いてスコア化（0 : 反応なし又は後肢を横にずらす行動、1 : 後肢の引き上げ行動 (lifting)、2 : 後肢の振り行動 (flinching) 又は刺激部位への舐め行動 (licking)）して評価した。
Example 2
Mice (ICR, 5-7 weeks old, male) were given a single intraperitoneal injection of paclitaxel (PTX, 5 mg / kg), and paeoniflorin or its solvent (VH2: ethanol) from the next day in a volume of 20 μL twice a day It was applied to the whole (from the ankle to the fingertip). Allodynia is scored using von Frey filament (0.69 mN) (0: no response or hind limb lateral movement, 1: hind limb lifting (flinching), 2: hind limb swinging (flinching) or stimulation site Licking) and evaluated.
実施例３
マウス（ICR,5〜7週齢, 雄性）に、パクリタキセル（PTX、5mg/kg）単回腹腔内注射し、翌日より芍薬エキス１またはその溶媒（VH2：エタノール）を20μLの容量で1日2回両足（足首から指先まで全体的に）に塗布した。アロディニアは、von Freyフィラメント（0.69 mN）を用いてスコア化（0 : 反応なし又は後肢を横にずらす行動、1 : 後肢の引き上げ行動 (lifting)、2 : 後肢の振り行動 (flinching) 又は刺激部位への舐め行動 (licking)）して評価した。
Example 3
Mice (ICR, 5-7 weeks old, male) were given a single intraperitoneal injection of paclitaxel (PTX, 5 mg / kg), and the following day, glaze extract 1 or its solvent (VH2: ethanol) was administered in a volume of 20 μL It was applied to both legs (overall from ankle to fingertips). Allodynia is scored using von Frey filament (0.69 mN) (0: no response or hind limb lateral movement, 1: hind limb lifting (flinching), 2: hind limb swinging (flinching) or stimulation site Licking) and evaluated.
実施例４
マウス（ICR,5〜7週齢, 雄性）に、パクリタキセル（PTX、5mg/kg）単回腹腔内注射し、翌日より芍薬エキス２またはその溶媒（VH2：エタノール）を20μLの容量で1日2回両足（足首から指先まで全体的に）に塗布した。アロディニアは、von Freyフィラメント（0.69 mN）を用いてスコア化（0 : 反応なし又は後肢を横にずらす行動、1 : 後肢の引き上げ行動 (lifting)、2 : 後肢の振り行動 (flinching) 又は刺激部位への舐め行動 (licking)）して評価した。図の値は、平均±標準誤差示した（n = 6）。* p<0.05 vs. PTX+VH2 (Holm-Sidak テスト)。
Example 4
Mice (ICR, 5-7 weeks old, male) were given a single intraperitoneal injection of paclitaxel (PTX, 5 mg / kg), and the following day, glaze extract 2 or its solvent (VH2: ethanol) was administered in a volume of 20 μL It was applied to both legs (overall from ankle to fingertips). Allodynia is scored using von Frey filament (0.69 mN) (0: no response or hind limb lateral movement, 1: hind limb lifting (flinching), 2: hind limb swinging (flinching) or stimulation site Licking) and evaluated. The values in the figure are shown as mean ± standard error (n = 6). * p <0.05 vs. PTX + VH2 (Holm-Sidak test).
実施例５
マウス（ICR,5〜7週齢, 雄性）に、パクリタキセル（PTX、5mg/kg）単回腹腔内注射し、翌日よりペオニフロリン（PNF、1%）またはその溶媒（VH2：エタノール）を20μLの容量で1日2回両足（足首から指先まで全体的に）に塗布した。PTX投与後14日目に伏在神経における神経活動を電気生理学的に評価した。自発的発火及びvon Freyフィラメント（0.69 mN）による刺激による発火を記録した。
Example 5
A single intraperitoneal injection of paclitaxel (PTX, 5 mg / kg) into a mouse (ICR, 5-7 weeks old, male), and 20 μL of paeoniflorin (PNF, 1%) or its solvent (VH2: ethanol) from the next day Applied to both feet twice a day (overall from ankle to fingertips). On day 14 after PTX administration, the neuronal activity in the saphenous nerve was evaluated electrophysiologically. Spontaneous firing and firing by stimulation with von Frey filament (0.69 mN) were recorded.
本発明の外用剤は、薬物の末梢神経障害による感覚異常を改善することができる。外用により経口投与より薬物の副作用などのリスクを減らすことができ、臨床への応用が容易となる。また、本発明の外用剤は、肌荒れなど環境要因による末梢神経障害による感覚異常にも有用である。 The external preparation of the present invention can improve sensory abnormalities caused by peripheral neuropathy of drugs. External application can reduce the risk of side effects of drugs compared to oral administration, and clinical application becomes easier. The external preparation of the present invention is also useful for sensory abnormalities due to peripheral neuropathy due to environmental factors such as rough skin.
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