JP3989188B2 - Bee venom therapy without a bee needle - Google Patents

Description

【００２１】
乾いた蜂毒の最も重要な成分は、メリチン（Ｍｅｌｉｔｔｉｎ）として知られたペプチドであり、脳下垂体と副腎を刺激してコルチゾン（ｃｏｒｔｉｓｏｎｅ）を生産する。これはハイドロコルチゾン（ｈｙｄｒｏｃｏｒｔｉｓｏｎｅ）よりさらに１００倍活性が強い。メリチンはまた、炎症に対抗して保護する細胞膜リソソーム（ｌｙｓｏｓｏｍｅ）を安定させる作用がある。他の主な薬理学的成分は、アパミン（ａｐａｍｉｎ）、ＭＣＤペプチド（ＭＣＤ−ｐｅｐｐｉｄｅ：ペプチド４０１として知られる）、アドラピン（ａｄｏｌａｐｉｎ）などいろいろな種類の蛋白分解酵素抑制剤などである。アパミンはメリチンのように作用する。これはまた、補体システム（ｔｈｅ ｃｏｍｐｌｅｍｅｎｔ ｓｙｓｔｅｍ）、炎症に関与するＣ_３を抑制する。ＭＣＤペプチドは、アラキドニック（ａｒａｃｈｉｄｏｎｉｃ）を抑制してプロスタグランディン（ｐｒｏｓｔａｇｌａｎｄｉｎ）合成を防止する。アドラピンは、マイクロソム（ｍｉｃｒｏｓｏｍ）のシクロオキシゲナーゼ（Ｃｙｃｌｏｏｘｙｇｅｎａｓｅ）を抑制する。これはまたリポオキシゲナーゼ（Ｌｉｐｏｘｙｇｅｎａｓｅ）とトロンボキサン（ｔｒｏｍｂｏｘａｎ）を遮断する。蛋白分解酵素抑制剤は、カラギニン（ｃａｒｒａｇｅｅｎｉｎ）、プロスタグランディンＥ_ｌ、ブラジキニン（ｂｒａｄｙｋｉｎｉｎ）及びヒスタミンにより生じる炎症を抑制する。したがって、ここに記述した用語“蜂毒”は、さらに蜂毒の薬理学的に活性な成分であるメリチンまたはメリチンとペプチド４０１を組み合わせたものなどの投与にも言及するものである。用語“蜂毒”は、また、もちろん全体蜂毒液も称することであり、同様に全体蜂毒やその構成成分を本発明に合わせて純粋に精製して調整した製剤である。
【００２２】
従来の蜂毒療法では、生きた蜂を利用してきたが、本発明の望ましい標準蜂毒製剤は液体担体と混ぜ合わせたものである。どのような液体であっても乾いた蜂毒をよく溶解することができて、皮内注射、皮下注射、筋肉注射用として医薬上適切であれば本発明で使用することができる。最も好ましい担体は、殺菌されたイオンが除去された水、または塩化ナトリウムが０．９％入っている生理的食塩水である。一般的に、本発明による液体担体は、１ｍＬごとに蜂毒を約０．１ないし約１０ｍｇ含有しているのであれば充分である。より好ましいものは、１ｍＬごとに約０．５ないし約５ｍｇの蜂毒が入っているものである。最も好ましいものは液体担体の１ｍＬごとに蜂毒約１ｍｇが入っているようにする量である。例えば、乾いた蜂毒１ｇを通常の注射用生理的食塩水（０．９％塩化ナトリウム）の１Ｌ（１，０００ｍＬ）に混ぜることである。望ましくは常温２０度の殺菌された部屋で調製する。その結果、標準蜂毒注射剤１ｍＬごとに蜂毒１ｍｇが入っている。
【００２３】
２５μｍフィルターを通過させた後、標準蜂毒注射剤には、好ましくは１ｍＬにメリチン約０．０１ないし約１．０ｍｇと蛋白質総量が約８０ないし約９，５００μｇ含まれている。より好ましくは、得られた医薬組成物が、１ｍＬごとにメリチン約０．０１ないし約０．１ｍｇと蛋白質総量が約４００ないし約４，５００μｇを含んでおり、最も好ましい標準液は、１ｍＬごとにメリチンが約０．０４ないし約０．０５ｍｇと蛋白質総量が約８００ないし約９５０μｇ含んでいるものである。最も好ましい標準液は１ｍＬごとにヒアルロニダーゼ（Ｈｙａｌｕｒｏｎｉｄａｓｅ）活性が４０〜１００ＨＨＵ／ｍＬ（１００μｇ／ｍＬ希薄）でゼラチン誘導赤血球凝集が３〜５ｍｍ／Ｈで現れるものである。
【００２４】
２５μｍフィルターにより得られたと同様の純度の蜂毒を提供するのに実用的などのような精製方法もその価値を認められてよいであろう。このような方法には、順相及び逆相クロマトグラフィー、アフィニティクロマトグラフィー、再結晶、免疫学的沈殿、膜透過方法及び他のろ過方法が網羅されている。
【００２５】
液性担体に加えて、本発明による蜂毒製剤は他の従来の賦形剤である粘度変性剤（ｖｉｓｃｏｓｉｔｙ ｍｏｄｉｆｉｅｒ）、防腐剤及び塩化ナトリウム、糖類とその類似物質などのような添加剤も含むことができる。これらのような賦形剤は、なんの制限もなしにベンジルアルコール、メチルパラバン、リンゲル及び注射用治療薬に通常使用される他の生物学的に許容し得る物質を含む。
【００２６】
本発明による液状担体には、生理的食塩水だけでなく燐酸塩緩衝液（ｐＨ．４．０）等人体に使われることができる液状担体をすべて含む。また、注射剤の可溶化剤でしばしば使われるプロピレングリコール、エチルダイゴール（Ｅｔｈｙｌ Ｄｉｇｏｌ）などのように生物学的、製剤学的に許容し得るあらゆる物質を含む。
【００２７】
本発明による代表的な製剤は、水１ｍＬごとにイタリアン蜜蜂の純粋で乾いた毒１．０ｍｇと塩化ナトリウム９．０ｍｇが入っている。また他の望ましい処方は、純粋で乾いた蜂毒１．０ｍｇ、塩化ナトリウム９．０ｍｇ、ベンジルアルコール０．００９ｍＬと水０．９９１ｍＬで構成されている。再び言及するが、これらのような処方は濾過器具を通じてどのような物質でも２５μｍより大きい物質は除去させたものである。これよりもさらに細いフィルターを使用することも意図されている。
【００２８】
蜂毒だけでいろいろな疾患、例えば、関節炎、多発性硬化症、関節や腰痛の緩和などを治療する時には、通常、複数回の注射をすることになる。一般的に蜂毒療法は、６週から１２週程度にわたって治療することが普通であり、１週に１度またはそれ以上治療し、注射数は１または２回から始まって増加させていき、後には一度の治療に２０回から５０回までも注射をするようになる。こちらに記述する蜂毒の容量は注射１回ごとに約０．０１から約１．０ｍｇまで投与する。望ましくは、蜂毒の容量は注射ごとに約０．０５から約０．５ｍｇが良いし、最も良い容量は注射ごとに約０．１ｍｇが入っているものである。したがって上述した二つの処方の１ｍＬは蜂毒０．１ｍｇが入っている０．１ｍＬずつの分割薬容量１０回分を供給するようになる。
【００２９】
本発明による蜂毒注射剤は、通常、０．１ｍＬずつ目盛りのある２５ないし２７ゲージの針がついた注射器で皮内注射する。針は、一般的に約１／４ないし約５／８インチ長の範囲のものを使用する。患者を治療する前にアレルギー反応の可能性を調べるために皮膚試験をすることが適切である。皮膚反応試験の好ましい部位として前腕の屈筋表面などに正常投与量の約１／２または０．０５ｍＬを、ゆっくりと皮内に注入して半球的水泡（ｈｅｍｉｓｐｈｅｒｉｃａｌ ｂｌｅｂ）を作る。皮膚反応の検討は腫れ跡（ｗｈｅａｌ）の大きさ、紅はん（ｅｒｙｔｈｅｍａ）の大きさ、不規則的な広がりの現れ方、試験部位から見た目に膨らんだ突起状態（ｐｓｅｕｄｏ−ｐｏｄ ｐｒｏｊｅｃｔｉｏｎｓ）に基づいて行う。正常反応は、針が入っていった所に針の末ほどの血点が見られて、腫れ跡は約０．５ないし約１．０ｃｍ、紅はんは注射部位から丸く約１ないし約２インチ広がって現れる。注射後１５分ないし３０分間に全身反応が現れないならば、陰性と見なす。
【００３０】
皮内に投与を行う際、注入に先がけて、注射プランジャをすこし引き抜き、静脈内注射を防止するために、注射器内に血が流れ込むのを観察することを薦める。注射は患者の患部に応じていろいろな異なる部位にされることになる。しかし、関節炎患者の痛みを和らげる、及び、治療をするために、例えば、痛い部位からまず注射が行われる。最も好ましくは、注射は圧痛点（ｔｅｎｄｅｒ ｐｏｉｎｔ）や引き金点（ｔｒｉｇｇｅｒ ｐｏｉｎｔ）に注射することが良い。その後、治療効果を最大にするために、皮膚の発疹状況（ｄｅｒｍａｔｏｍｅ ｃｈａｒｔ）により突起部位（ｓｐｉｎａｌ ａｒｅａ）に注射していくようにする。一般的に、治療を受ける間に、酒類の摂取は慎むようにする。局所反応が激しい場合には冷湿布（ｉｃｅ ｐａｃｋｓ）やメントール軟膏を塗るようにし、仮りにかゆみがとても激しい場合には眠る時にベナドリル（Ｂｅｎａｄｒｙｌ）７５ｍｇを服用し、昼には５０ｍｇを服用しても良い。微熱や他の悪寒が生じる場合には、アセトアミノフェンや他の解熱剤を服用してもかまわない。
【００３１】
本発明は、また、低ボルト電気ショック法を使用した精製法で蜜蜂から毒を採集する装置も含む。この抽出器は、ひとつがもうひとつの内側となっている二つの木枠で構成されている。複数の電線が外側の枠の前面に取り付けられており、これらは交互にアースしたり充電したりする。蜜蜂が近づいて二つの電線に接触するようになれば回路が完成されて結果的に衝撃を与えるようになる。
【００３２】
抽出器を蜂の巣の前に置いて、９ボルトバッテリーに電気タイマーとともに連結する。バッテリーを連結させれば電流が反復的に５秒間流れて３秒間止まるように流れる。この器具の電源をオンにすると同時に蜂らは興奮して蜂の巣から出て抽出器に向かい攻撃するようになる。同時に蜂らはフェロモンを空気中に散布して他の蜂らも興奮して攻撃するようにする。蜂らが電気ショックを受けるようになれば下腹が曲がるようになり内側木枠の上面に覆われているシリコンゴムシートに針を刺すようになる。電流が３秒間停止すれば蜂らは蜂針を取り出して死ぬことはない。シリコンゴムシートの下には純粋な液体蜂毒がたまっているようになる。内側木枠を外側の枠から取り出し滅菌された箱中に保管する。
【００３３】
この箱は滅菌された冷蔵庫（摂氏４度）に４時間ないし６時間入れて乾かす。内側の木枠を箱から取り出して大きな滅菌かごに入れて、滅菌された医薬用かみそりで乾いた蜂毒結晶体を削って取り出す。収集された蜂毒結晶体は滅菌瓶に入れて封をしておく。蜂毒は米国特許番号第４，７３９，５３１号及び同第３，１６３，８７１号に記載の方法でも生産することができる。
【００３４】
いろいろな疾患を治療することにおいて、本発明による標準蜂毒注射製剤の使用は、詳細にここに記載されて、従来技術より著しい利点を提供している。しかしながら、生きた蜂に刺されるという経験は、快いものでは決してない。３０余回刺されるという経験は、当然に不快感の程度を高めることである。蜂毒により経験する焼けつくような痛みは、他の痛みや刺激とは似つかない独特のものである。好ましくは本発明による標準製剤を、皮内に注入することは、実際、蜂針よりはるかに快いものではあるが、蜂毒の注入により発生するひりひりした痛みは、蜂毒療法で治療を受けることを躊躇させている。したがって、本発明の好ましい態様は蜂毒注射により発生する不快な刺激を和らげたり、減少させたり、時には失くしてくれるような組成物とその方法を提供している。この発見は驚くべきものであって、麻酔剤、特に局所麻酔剤を局部に適用しても蜂毒を皮内に注入した時発生する焼けつくような痛み、鋭く刺すような痛み及び他のひりひりした痛みをなくすことができなかったのが、局所麻酔剤を蜂毒と共にまたは同時に同一点に注入すれば痛みを軽減ないし除去してくれるというものである。
【００３５】
不幸にも、局所麻酔剤をこのような方法で導入することにより予想できなかった問題が発見された。例えば、リドカイン（ｌｉｄｏｃａｉｎｅ）が２％入っている蜂毒注射剤を使用すれば（リドカイン２０ｍｇ／ｍＬ：１ｍｇ／ｍＬ蜂毒）、皮内に注入する時生じる鋭く刺すような痛み、ひりつく痛み及び他のひりひりした刺激などは軽減される。しかし、リドカイン自体が蜂毒の刺激とは関係なくひりひりした刺激を誘発する。結果として蜂毒のみを使用した時よりは、はるかに改善された。しかし、ここで例にした容量の局所麻酔剤を蜂毒と共に局部及び局所に注入した時また別のひりひりした痛みが生じるようになる。
【００３６】
普通局部または局所に適用する局所麻酔剤の容量よりはるかに少ない容量（すなわち、１％未満）を注入した時蜂毒による刺激をかなり減少させると同時に局所麻酔剤の皮内注射時に発生するひりひりした刺激もなくしてくれることは予想できなかった発見であった。
【００３７】
本発明で蜂毒を使用したものは上に記述したものであるか、または、フィルターをしたものかあるいはしないものか、精製をしたものかあるいはしないものか、さらにまた他の蜂毒製剤も使用することができる。問題にする薬理学的組成物は局所麻酔剤を混ぜて単一液として単一注射器に注入することもできる。しかし、蜂毒液と局所麻酔剤を単一液に作って注射するか、あるいは同時に注射することは必ずしも必要なことではない。局所麻酔剤を別に作って蜂毒注射後同一点に注入することもでき、直ちに直前に注入することもできる局所麻酔剤を連続的に注入する場合には蜂毒注射前１時間内と注射後１０分内にすることが良い。望ましくは蜂毒と局所麻酔剤を連続的に注入する場合には蜂毒注射前１０分内や注射後数分内が良い。最も望ましい方法としては局所麻酔剤を蜂毒注射直前または直後に注入することが良い。
【００３８】
仮りに蜂毒を筋肉に注射する場合には局所麻酔剤も同一点の筋肉に注射するようになる。皮下に与える時も同一で、最も良い方法である皮内に注入する時も同一である。
【００３９】
蜂毒注射に伴うひりひりした刺激の軽減はいくらか主観的である。これはいろいろな要因、すなわち患者個人の痛みに対する苦痛域；注射数；注射毎に注入された蜂毒の容量；注射部位；皮内、皮下、筋肉注射にともなう注射の深さ等によって違う。しかし、一般的にいえるのは、ここに記述した局所麻酔剤の適正量は同一患者に同一プロトコルを適用して同一容量で注入した場合に局所麻酔剤なしに同一容量を注入した時より、現れるひりひりした刺激がはるかに軽減されることである。
【００４０】
本発明による局所麻酔剤は蜂毒注射によるひりひりした刺激を減少できるどのような組成物もすべて含む。麻酔剤は局部及び局所麻酔剤にだけ限定しない。しかし、局所麻酔剤が好ましい。本発明の麻酔剤は次の通りである。
【００４１】
アンブカイン（Ａｍｂｕｃａｉｎｅ）、アモラノン（Ａｍｏｌａｎｏｎｅ）、塩酸アミロカイン（Ａｍｙｌｏｃａｉｎｅ Ｈｙｄｒｏｃｈｌｏｒｉｄｅ）、ベノキシネート（Ｂｅｎｏｘｉｎａｔｅ）、ベンゾカイン（Ｂｅｎｚｏｃａｉｎｅ）、ベトキシカイン（Ｂｅｔｏｘｙｃａｉｎｅ）、ビフェンアミン（Ｂｉｐｈｅｎ ａｍｉｎｅ）、ブピバカイン（Ｂｕｐｉｖａｃａｉｎｅ）、ブタカイン（Ｂｕｔａｃａｉｎｅ）、ブタンベン（Ｂｕｔａｍｂｅｎ）、ブタニリカイン（Ｂｕｔａｎｉｌｉｃａｉｎｅ）、ブテスアミン（Ｂｕｔｅｔｈ ａｍｉｎｅ）、ブトキシカイン（Ｂｕｔｏｘｙｃａｉｎｅ）、カルチカイン（Ｃａｒｔｉｃａｉｎｅ）、塩酸クロロプロカイン（Ｃｈｌｏｒｏｐｒｏｃａｉｎｅ Ｈｙｄｒｏｃｈｌｏｒｉｄｅ）、コカエチレン（Ｃｏｃａｅｔｈｙｌｅｎｅ）、コカイン（Ｃｏｃａｉｎｅ）、シクロメチカイン（Ｃｙｃｌｏｍｅｔｈｙｃａｉｎｅ）、塩酸ジブカイン（Ｄｉｂｕｃａｉｎｅ Ｈｙｄｒｏｃｈｌｏｒｉｄｅ）、ジメチソクイン（Ｄｉｍｅｔｈｉｓｏｑｕｉｎ）、ジメソカイン（Ｄｉｍｅｔｈｏｃａｉｎｅ）、塩酸ジペロドン（Ｄｉｐｅｒｏｄｏｎ Ｈｙｄｒｏｃｈｌｏｒｉｄｅ）、ジクロニン（Ｄｙｃｌｏｎｉｎｅ）、エコニジン（Ｅｃｇｏｎｉｄｉｎｅ）、エクゴニン（Ｅｃｇｏｎｉｎｅ）、塩化エチル（Ｅｔｈｙｌ Ｃｈｌｏｒｉｄｅ）、エチドカイン（Ｅｔｉｄｏｃａｉｎｅ）、ｂ−エウカイン（ｂ−Ｅｕｃａｉｎｅ）、ユープロシン（Ｅｕｐｒｏｃｉｎ）、フェナルコミン（Ｆｅｎａｌｃｏｍｉｎｅ）、フォモカイン（Ｆｏｍｏｃａｉｎｅ）、塩酸ヘキシルカイン（Ｈｅｘｙｌｃａｉｎｅ Ｈｙｄｒｏｃｈｌｏｒｉｄｅ）、ヒドロキシテトラカイン（Ｈｙｄｒｏｘｙｔｅｔｒａｃａｉｎｅ）、Ｐ−アミノ安息香酸イソブチル（Ｉｓｏｂｕｔｙｌ ｐ−Ａｍｉｎｏｂｅｎｚｏａｔｅ）、ロシノカインメシレート（Ｌｅｕｃｉｎｏｃａｉｎｅ Ｍｅｓｙｌａｔｅ）、レボキサドロール（Ｌｅｖｏｘａｄｒｏｌ）、リドカイン（Ｌｌｄｏｃａｉｎｅ）、メピバカイン（Ｍｅｐｉｖａｃａｉｎｅ）、メプリルカイン（Ｍｅｐｒｙｌｃａｉｎｅ）、メタブトキシカイン（Ｍｅｔａｂｕｔｏｘｙｃａｉｎｅ）、塩化メチル（Ｍｅｔｈｙｌ Ｃｈｌｏｒｉｄｅ）、ミルテカイン（Ｍｙｒｔｅｃａｉｎｅ）、ナエパイン（Ｎａｅｐａｉｎｅ）、オクタカイン（Ｏｃｔａｃａｉｎｅ）、オルトカイン（Ｏｒｔｈｏｃａｉｎｅ）、オキセタザイン（Ｏｘｅｔｈａｚａｉｎｅ）、パレトキシカイン（Ｐａｒｅｔｈｏｘｙｃａｉｎｅ）、塩酸フェナカイン（Ｐｈｅｎａｃａｉｎｅ Ｈｙｄｒｏｃｈｌｏｒｉｄｅ）、フェノール（Ｐｈｅｎｏｌ）、ピペロカイン（Ｐｉｐｅｒｏｃａｉｎｅ）、ピリドカイン（Ｐｉｒｉｄｏｃａｉｎｅ）、ポリドカノール（Ｐｏｌｉｄｏｃａｎｏｌ）、プリドカノール（Ｐｌｉｄｏｃａｎｏｌ）、プラモキシン（Ｐｒａｍｏｘｉｎｅ）、プリコカイン（Ｐｒｉ ｃｏｃａｉｎｅ）、プロカイン（Ｐｒｏｃａｉｎｅ）、プロパノカイン（Ｐｒｏｐａｎｏｃａｉｎｅ）、プロパラカイン（Ｐｒｏｐａｒａｃａｉｎｅ）、プロピポカイン（Ｐｒｏｐｉｐｏｃａｉｎｅ）、塩酸プロポキシカイン（ＰｒｏｐｏｘｙｃａｉｎｅＨｙｄｒｏｃｈｌｏｒｉｄｅ）、擬似コカイン（Ｐｓｅｕｄｏｃｏｃａｉｎｅ）、ピロカイン（Ｐｙｒｒｏｃａｉｎｅ）、ロピバカイン（Ｒｏｐｉｖａｃａｉｎｅ）、サリチルアルコール（Ｓａｌｉｃｙｌ Ａｌｃｏｈｏｌ）、塩酸テトラカイン（Ｔｅｔｒａｃａｉｎｅ Ｈｙｄｒｏｃｈｌｏｒｉｄｅ）、トリカイン（Ｔｏｌｙｃａｉｎｅ）、トリメカイン（Ｔｒｉｍｅｃａｉｎｅ）、ゾーラミン（Ｚｏｌａｍｉｎｅ）などである。これらの中から本発明にあう最も望ましい局所麻酔体はリドカインである。
【００４２】
理解できるように、局所麻酔剤の容量は使われる蜂毒剤の量により調節される。しかし、その容量は患者の特定の状態と痛みの激しさの程度及び治療の過程等によって調節することができる。一般的に、局所麻酔剤の容量は乾いた蜂毒重量に比べて約２０：１ないし約１：１０の割合で使う。望ましい比率としては約１０：１ないし約１：５が良く、最も望ましい比率としては約３：１ないし約１：１が良い。
【００４３】
本発明にあう局所麻酔剤の製剤化に使われる液状担体や賦形剤は蜂毒製剤を作る時使用するものと同一であるか、あるいは違うこともあり得る。また、局所麻酔剤は液体であり、また、ひとつまたはそれ以上の液状担体と賦形剤があらかじめ混ざった処方薬を買うこともできる。このような場合には、また他の液状担体や賦形剤を必要としない。さらに、局所麻酔剤処方薬のこれらのような種類は蜂毒剤の担体で使用されることもあり得るし、既に前記したように標準蜂毒注射剤に混ぜて使用することもできる。
【００４４】
局所麻酔剤の注入量は注射ごとに約０．０１ないし約２．０ｍｇであり、望ましくは約０．０５ないし約１．０ｍｇである。最も望ましい容量は注射ごとに約０．１ｍｇである。
【００４５】
代表的な処方製剤は次の通りである。（１）注射用蒸溜水１．０ｍＬごとに蜜蜂の乾いた蜂毒１．０ｍｇ、塩化ナトリウム９．０ｍｇ、塩酸リドカイン１．０ｍｇが入っている。（２）注射用蒸溜水１．０ｍＬに蜜蜂の乾いた蜂毒１．０ｍｇ、塩化ナトリウム９．０ｍｇ、塩酸リドカイン１．０ｍｇ、ベンジルアルコール０．００９ｍＬ、水０．９９１ｍＬ入っている。（３）注射用水１．０ｍＬに蜜蜂の乾いた蜂毒１．０ｍｇ、塩化ナトリウム９．０ｍｇ、塩酸リドカイン１．０ｍｇ、メチルパラベン０．１ｍｇが入っている。
【００４６】
また、本発明は注射剤以外に蜂毒液が入っているクリーム、軟膏及びパッチも含む。
蜂毒クリーム製剤
乾いた蜂毒５％（１〜２５％）；
メチルサリチルレイト４％（１〜２０％）；
精製されたカプサイシン０．０３％（０．０１〜０．０５％）；
アロエ抽出液；
メントール；
カボマ９４０；
セチルアルコール；
メチルパラベン；
香料；
蝋；
精製水。
＊用法：ティースプーン１／１６ないし１／８の分量を患部にこすって塗る。
１日１〜２回使用する。
【００４７】
蜂毒パッチ製剤
乾いた蜂毒１０ｍｇ；
メチルサリチルレイト１５０ｍｇ；
精製したカプサイシン１ｍｇ；
アロエ抽出液；
メントール；
ウィット点グリセイド；
メチルパラベン。
＊性状：パッチの大きさは１００ｍｍ×１．４０ｍｍであり、上の製剤を不織布に塗布して固体面に剥離紙を覆ったものである。
＊用法：１日１〜２回、１回１枚ずつ患部に付着させる。
【００４８】
実施例
次の実施例に記述した患者らは従来の現代医学で治療を受けた患者らとして、いまだに相当な痛みが持続して苦痛を受けている。鎮痛剤、筋肉弛緩剤及び消炎剤等数多くの薬を服用して、多様な注射も行われ、脊椎矯正術、物理治療及び時には手術まで受けたにもかかわらず彼らの病的状態が良くならなかったし、特に痛みは激しかった。
【００４９】
次に記録した実施例は６番目の治療から蜂毒注射剤毎に注射０．１ｍＬごとに蜂毒とリドカインが１：１割合で入っている溶液を使用した。１番目から５番目までは純粋な蜂毒液だけを使用した。注射液は注射用生理的食塩水で混合して作られ、２５μｍフィルターを通じ精製したものである。それぞれの患者には注射１回分が０．１ｍＬずつになるように注入した。全体注射数は患者の状態と治療回数によって変わった。
【００５０】
それぞれの実施例で、患者らは本発明にあう処方製剤によって皮内注射で注入され、一週間に２回治療し、平均１２回から２０回治療をした。次の症例で、“ＲＡ Ｔｉｔｅｒ”はリューマチ様関節炎の診断にしばしば使用する血液数値である。
【００５１】
適正量数値が２０未満である場合は陰性であり、このような患者に強く望まれる結果である。“ＥＳＲ”は“赤血球沈殿率”を示し一般的に炎症を診るのに使われる。正常数値は１〜１０である。これより高い数値は全身的炎症を表す。
【００５２】
“ＲＯＭ”は運動の範囲を意味する。運動の範囲の規格値は問題がある関節によって違う。しかし、二つの端の距離が遠いほど運動の範囲は大きくなる。圧痛と膨れ（ｓｗｅｌｌｉｎｇ）は標準尺度でプラス（＋）サインで表示する。各プラス（＋）サインはおよそ２０％を意味する。
【００５３】
最も大きい数字の５プラス（＋）は最も大きい圧痛と膨潤（膨れ）を意味する“ＶＡＳ”との視覚類似比率を意味する。最もしばしば使用するバス（ＶＡＳ）は１００ｍｍの平行線の左側端は痛みが全く無いものであり、右側端はいままでの最も激しい痛みを意味する。患者は自分が現在感じる痛みの強度がどの程度であるか１００ｍｍ線上に表示するようにする。左側端で患者が表示した地点までの数値で痛みの強度を測定する。このような方法はチャーチルリビングストーンで発行した「痛みの教科書」（ニューヨーク、３次発行、１９９４年３３８〜３３９ページ）とリーアンドフェビガで発行した「痛みの管理」（フィラデルフィア、２次発行１９９０年５８１〜５８２ページ）に記述されている。
【００５４】
実施例１：リューマチ様関節炎（Ｒｈｅｕｍａｔｏｉｄ Ａｒｔｈｒｉｔｉｓ（ＲＡ））
ＮＧは３９才の女子患者でリューマチ様関節炎を１９年患っていた。彼女は抗ガン剤を含むあらゆる治療をしてみたが効果がなかった。彼女の手首と手の痛みと膨れはあまりにも深刻で耐えることができない程度であり、結果的に彼女は障害を負った。この患者は、本発明による治療を受けて９５％程度好転した。患者の状態は安定であり、痛みと膨れはそれ以上現れなかった。
【００５５】

【００５６】
実施例２：骨関節炎
ＨＲは７５才の女性で、去る２５年間退行性関節炎を患っていた。彼女の膝と脊椎は他の関節よりさらに悪化した。この患者は本発明による治療法で１８回の治療後に状態がとても良くなった。現在、他の薬物は服用せずに良好に過ごしている。
【００５７】

【００５８】
実施例３：強直性脊椎炎
ＭＯは５３才の女子患者で、腰を永らく痛めており腰推関節癒合術等の手術を何度も受けた。この患者は１８ケ月間引続きリハビリ治療を受けたにもかかわらず特別な効果がなかった。この患者は本発明による治療法で総計２６回の治療を受けてだいぶ好転した。現在薬物は服用していないが、少なくとも一ケ月に一度再診療が必要である。
【００５９】

【００６０】
実施例４：筋肉痛
ＰＡは３２才の女子で筋肉痛を患っていた。以前にはあらゆる身体的及び精神的療法が成功することができなかった。引き金誘発点注射（ｔｒｉｇｇｅｒ ｐｏｉｎｔ ｉｎｊｅｃｔｉｏｎｓ）をいくつかの部位に注射して治療した。総計１６回の治療で完全に回復された。“引き金点（ｔｒｉｇｇｅｒ ｐｏｉｎｔ）”は筋肉の特殊な部位を刺激すれば痛みを起こす点である。
【００６１】

【００６２】
実施例５：テニス肘（ｔｅｎｎｉｓ Ｅｌｂｏｗ）
ＪＫは４３才の男子で“テニス肘”を４年間患っていた。従来の現代的治療はうまくいかなかった。本発明の治療法で総計１２回の治療で完全に回復した。
【００６３】

【００６４】
実施例６：癒着性嚢炎
ＢＯは５６才の男子患者で、五十肩（ｆｒｏｚｅｎ ｓｈｏｕｌｄｅｒ）を患っている。薬物等の服用、多様な注射治療、手術も成功しなかった。この患者の運動範囲は２０％に制限されて持続的な痛みを訴えた。本発明の治療法で総計１４回の治療で完全回復した。
【００６５】

【００６６】
実施例７：慢性外科的炎症
ＢＣは４９才の男子で出血性胃潰瘍、アルコール性肝硬変、腸閉塞等で腹部手術を１０回以上受けた。外科的痛みと血胆嚢痛により、彼は重篤な薬物中毒となってしまった。本発明の治療法で総計２８回の外科的傷痕への重点的治療でほとんど１００％完治した。
【００６７】

【００６８】
実施例８：帯状疱疹性神経痛
ＪＰは７８才の女子患者で帯状疱疹を患っていた。内科的及び外科的治療は失敗した。この患者は本発明の治療法で１６回の治療後、９０％以上好転した。“水泡”は疱疹を意味する。
【００６９】

【００７０】
実施例９：乾癬
ＴＨは２８才の男子患者で、乾癬皮膚病を７年間患っていた。現代医療の薬物は一時的にしか助けにならなかった。彼の状態が益々酷くなり、蒸し暑い夏にも短いズボンを履けない程度であった。総計２４回の治療でとても好転した。この患者は少なくとも一ケ月に一度の再診療が必要である。
【００７１】
実施例１０：多発性硬化症
ＳＲは４７才の女子患者で、１５年間多発性硬化症を病んできた。あらゆる現代的治療を動員してもこの疾患が益々悪くなることを防止できなかった。彼女は引続き下肢が痺れて無感覚になり、排尿調節機能も４０％程度失って、四肢の力が益々弱くなり身体の均衡も悪くなってツエや四足歩行器に依存しなければならなかった。総計２８回の治療でこの患者の状態は非常に好転した。現在では排尿は１００％調節できるようになり、ツエや歩行器を使用しなくてもよくなった。この患者は今後も相当期間少なくとも３〜４週に一度は再診療が要求される。
【００７２】

【００７３】
実施例１１：痛み
上の実施例に列挙した１０名の患者を合わせ、合計３０名の患者に、初めの５回の治療まで適切な容量の蜂毒のみで治療した。以後、すなわち６回目からは上に記述した各頭書きに沿ってまとめた“実施例”に記述したように、蜂毒とリドカインを１：１の割合で混ぜた注射液を注入した。患者らにはどのような処方の注射を注入したかを知らせずに、毎回治療後に痛みの類型及びその強度、不快感等について質問して調べた。また、患者の蜂毒注射に対する身体言語、顔をしかめる程度、治療を受けることへの気乗りしない程度などを観察した。
【００７４】
９７％の患者らは蜂毒とリドカインを混ぜた注射剤に対して注射時に痛みと不快感が非常に減少することを客観的に報告した。次回に注射されることに対する恐怖もかなり減少し、この治療の途中脱落者は劇的に落ちた。痛みの弛緩は相当の間持続され、非常に少ない量の局所麻酔剤は単に瞬間的にだけ痛みの弛緩を与えるだけで、少し経つと痛みが突然に増加するが、このような突然の痛みの増加も経験しなかった。
【００７５】
【発明の効果】
前記の実施例を通じて分かるように、本発明は蜂毒と局所麻酔剤が混合された蜂毒注射剤を注入すれば蜂毒治療を受けている患者等の痛みと不快感を劇的に緩和させる効果がある。
【００７６】
以上では本発明を実施例によって詳細に説明したが、本発明は実施例によって限定されず、本発明が属する技術分野において通常の知識を有するものであれば本発明の思想と精神を離れることなく、本発明を修正または変更できるであろう。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to bee venom therapy, and also relates to formulation of bee venom, a method for producing bee venom, and uses thereof.
[0002]
[Prior art]
A bee product treatment refers to the medical use of various substances produced by bees, such as honey, pollen, propolis, beeswax, royal milk, and bee venom. Various studies have shown that honey has had antibacterial, antifungal, anti-inflammatory, antiproliferative and anticancer uses. For example, China has used honey as an analgesic and disinfectant for burns. Recently, it has been found that caffeic acid contained in propolis plays a role in preventing precancerous changes when carcinogens are injected into the large intestine of mice. A product made from a piece of honeycomb with a lot of pollen has not only succeeded in treating allergies, but is also used as an excellent food. The main focus here is on research to treat painful diseases caused by chronic inflammation using bee venom.
[0003]
In fact, various forms of bee treatment have been used since ancient times. Ancient authors, such as Hesiodos (800 BC), Aristophanes (450-388 BC), Baro (166-27 BC), Colmera (1st century BC) Described for culture. Hippocrates (460-377 BC), also known as the father of medicine, was also used for treatment and was named "A very mysterious remedy (Arcanum)". Garan, the father of experimental physiology (131-201 BC), made a note in his medical papers. Emperor Sharmagne (742-814 BC) said he had treated with bees. Quran 16:71 describes the bee venom as follows: “The liquid in the contents generated from these abdomen is a medicine for humans. ]
[0004]
The scientific understanding of bee products therapy and bees is about 100 years ago, a research paper by Phillip Turc, an Austrian doctor, on the unique correlation between bee needles and rheumatism. It began in earnest since the “Report” was announced.
[0005]
Today's proponents of bee remedies say that bee venom and other bee products cause chronic pain and many other diseases, including connective tissue regression and inflammation (all types of arthritis), neurological Claims to be effective for diseases such as diseases (migraine, peripheral neuritis, chronic low back pain), autoimmune diseases (multiple sclerosis, lupus), skin diseases (eczema, psoriasis, herpes inflammation) . In contrast, traditional medicine is rarely concerned with bee products, and can occur when stabbed by the following two areas that are not related to the above effects: (i) Risk of hypersensitivity reactions including anaphylactic shock, (ii) allergic reactions that appear when stabbing into bees, especially bee venom as immunotherapy for life-threatening anaphylactic reactions in adults To use.
[0006]
Despite the promise of bee product treatment in the alternative medicine community, the above reasons are also the lack of standardized bee venom preparations, limitations on the effective use of bee venom It is true that the clinical application of bee venom has been pushed from the mainstream of medicine and weakened due to processing procedures and the like. Beyond the risks described above, bee venom therapy is often painful. The method of stinging live bees and injecting bee venom is dangerous and difficult to adjust. This method is also not easy for patients to overcome the aversion of insects and bites. Even with the use of less painful techniques such as acupuncture, bee venom itself causes several unique pains, burning and stimulating pain. With such a treatment, you have to question whether the treatment itself is worse than the disease. From the viewpoint described above, there is a need for a standardized bee venom formulation and a method for injecting it into patients in need of such treatment. There is a need for a method that reduces pain during treatment, especially with bee venom, without using live bees. The present invention solves such problems in earnest.
[0007]
[Problems to be solved by the invention]
The present invention has been made to solve the above-mentioned problems, and an object of the present invention is to provide a standardized bee venom preparation suitable for injection by injection. This bee venom preparation is composed of an injection solution in which about 0.1 to about 10 mg of dried bee venom is mixed with 1 mL of the injection solution. The formulation can also include excipients such as dilute solutions, preservatives, buffers, viscosity modifiers, co-solvents and the like. Preferably, the bee venom formulation provides 0.5 ml to 5 mg of bee venom in 1 mL of injection solution.
[0008]
[Means for Solving the Problems]
Preferably, the bee venom injection contains about 0.01 to about 1 mg of melittin and about 80 to about 9500 μg of total protein. Most preferably, the bee venom injection contains about 0.04 to about 0.05 mg of melittin in 1 mL of the injection solution, and the total amount of protein is about 800 to about 950 μg.
[0009]
Preferably, the standardized bee venom injection of the present invention is filtered for bacteria, bacterial debris, viruses and other contaminants through a 25 μm filter. The formulations of the present invention are standard injections such as intradermal, subcutaneous and intramuscular and are sufficiently pure to provide safe and appropriate treatment. This is the purest injection than any other bee venom formulation known to date. Still, it retains all the most active components of bee venom and can be obtained by industrially available technology. Therefore, this standard injection exhibits a unique compromise between safety, effectiveness, convenience, cost, and the like.
[0010]
Yet another aspect of the present invention is that it significantly reduces the pain often associated with bee venom therapy. Usually, bee venom therapy is a treatment in which a small amount of bee venom is injected into several locations. For example, a bee venom solution containing 1 mg of dried bee venom in 1 mL of an injection can be injected about 50 times around inflammation and its surroundings. Therefore, 0.1 mL injection solution containing about 0.1 mg of dry bee venom will be injected for each injection. Each of the 50 injections will be accompanied by swelling and inflammation that normally appears when stabbed by a bee needle, as well as pain, burning pain, itching and irritating pain. From these, these symptoms are collectively described as “stimulated irritation”. Applying an anesthetic agent that has been used in the past does not have the effect of reducing or losing such unfortunate side effects. They can slightly reduce the discomfort when piercing the needle, but they cannot prevent the spreading irritation caused by the injected bee venom.
[0011]
Therefore, it is totally unpredictable to find anesthetics, especially local and local anesthetics, that can be injected with bee venom or injected immediately before or immediately after the injection of bee venom. . When applied in this manner, local and local anesthetics, usually 2% or less, are used to treat bee venom-like pain, but much lower concentrations and volumes are applied. It has also been found to significantly reduce the tingling irritation associated with bee venom injection. In practice, 1% to 2% local anesthetics are often applied locally in the clinic, but higher concentrations and volumes are often required during medical procedures where very severe pain is induced. From this point of view, it is surprising that an unpleasant symptom associated with bee venom injection is relieved even if a dose of 2 mg or less per injection is contained. Furthermore, it was a particularly surprising finding that such an advantage was observed when applied only 10 times the amount of bee venom.
[0012]
Not only is it surprising that the amount of local anesthetic used in applying such a method is small, it is also surprising that it works. Applying such a volume and concentration of a local anesthetic locally or topically only provides an analgesic effect for only a short time. They can alleviate some of the immediate pain at the time of injection. However, bee venom injection becomes very painful about 10-15 minutes after injection, and this time is much longer considering the relief of pain caused by small amounts of local anesthetics. Again, it was a surprising discovery that the application of the local anesthetic described here alleviates pain for a considerable time after injection. In fact, pain relief was consistent throughout. In other words, patients do not feel at all that sudden pain becomes even more serious even if the local anesthetic disappears gradually after 5-10 minutes of injection.
[0013]
Accordingly, the compounds of the present invention comprise at least one anesthetic agent in a volume effective for treating bee venom and in a volume that reduces the tingling pain associated with bee venom injection. In a preferred embodiment of the present invention, bee venom and anesthetic are mixed and administered as a single preparation. However, the compounds according to the invention can also be produced as they are, with the appropriate amount of anesthetic being first injected at the injection site of the patient, followed by the appropriate amount of bee venom or in reverse order. You can also
[0014]
Generally, the anesthetic is provided in a ratio of approximately 20: 1 to 10: 1 based on the weight of bee venom. A preferred ratio is 10: 1 to 1:10 by weight. However, a more preferred anesthetic to bee venom ratio is from 3: 1 to about 1: 1 by weight. Both bee venom and anesthetic contain at least one excipient and at least one liquid carrier. 1 mL of the compound of the present invention contains about 0.1 to about 10 mg of bee venom, and preferred standard bee venom injections are as described above.
[0015]
The present invention also provides a method for administering bee venom. To reduce patient discomfort during treatment, the therapeutic amount of bee venom and at least one anesthetic are administered simultaneously or sequentially, as described above. Both are injected into the same site, intradermal, subcutaneous, or muscle (ie, if anesthetic is injected intradermally at a specific point on the patient's left knee, bee venom is also injected intradermally at the same point) .
[0016]
The volume of anesthetics tailored to these methods is the smallest volume sufficient to reduce the soreness associated with injection of a bee venom therapeutic effect volume. Generally, about 0.01 to about 1.0 mg of bee venom is infused with each injection tailored to these methods, with a preferred volume of about 0.05 to about 0.5 mg. The most preferred volume is to administer about 0.1 mg per injection. The total dose of bee venom per treatment depends on the number of injections. Similarly, the volume of anesthetic administered is about 0.01 to about 10 mg per injection, with the desired volume being about 0.1 to about 1.0 mg. The most preferred anesthetic volume is about 0.1 to about 0.3 mg administered per injection.
[0017]
Still other aspects of the invention include rheumatoid arthritis, osteoarthritis, gout, psoriatic arthritis, ankylosing spondylitis, myalgia, myofibritis, fasciopathic pain syndrome, tennis elbow, golf elbow, fifty shoulder, slippery Bursitis, tendinitis, chronic surgical inflammation of soft and bone tissue, peripheral neuritis, neuralgia, migraine, eczema, psoriasis, multiple sclerosis, lupus as well as autoimmunity, This is a method of treating neurological, dermatological, degenerative chronic diseases and the like with an injectable bee venom preparation using the above-described pharmaceutical composition.
[0018]
The above-described objects and other features and advantages of the present invention will become apparent from the following description of the preferred embodiments of the present invention.
[0019]
BEST MODE FOR CARRYING OUT THE INVENTION
The bee venom in the present invention means a toxin obtained from bees (Apis mellifera). The general composition of bee venom is shown in Table 1 below.
[0020]
[Table 1]

[0021]
The most important component of dry bee venom is a peptide known as melittin, which stimulates the pituitary and adrenal glands to produce cortisone. This is 100 times more active than hydrocortisone. Melittin also has the effect of stabilizing the cell membrane lysosome that protects against inflammation. Other main pharmacological components are various types of protease inhibitors such as apamin, MCD peptide (MCD-peptide: known as peptide 401), adrapine and the like. Apamin acts like melittin. This is also due to the complement system, C involved in inflammation.₃Suppress. The MCD peptide inhibits arachidonic and prevents prostaglandin synthesis. Adrapine inhibits microsomal cyclooxygenase. This also blocks lipoxygenase and thromboxane. Proteolytic enzyme inhibitors include carrageenin, prostaglandin E_lInhibits inflammation caused by bradykinin and histamine. Accordingly, the term “bee venom” described herein also refers to administration of melittin, a pharmacologically active component of bee venom, or a combination of melittin and peptide 401. The term “bee venom” also refers to the whole bee venom, of course, and is a preparation prepared by purifying the whole bee venom and its components purely according to the present invention.
[0022]
While conventional bee venom therapy has utilized live bees, the preferred standard bee venom formulation of the present invention is combined with a liquid carrier. Any liquid can dissolve dry bee venom well and can be used in the present invention as long as it is pharmaceutically suitable for intradermal injection, subcutaneous injection, and intramuscular injection. The most preferred carrier is water from which sterilized ions have been removed, or physiological saline containing 0.9% sodium chloride. In general, a liquid carrier according to the present invention is sufficient if it contains about 0.1 to about 10 mg of bee venom per mL. More preferred is about 0.5 to about 5 mg of bee venom per mL. Most preferred is an amount such that about 1 mg of bee venom is contained in each mL of liquid carrier. For example, 1 g of dried bee venom is mixed with 1 L (1,000 mL) of normal saline for injection (0.9% sodium chloride). Desirably, it is prepared in a sterilized room at room temperature of 20 degrees. As a result, 1 mg of bee venom is contained in 1 mL of standard bee venom injection.
[0023]
After passing through the 25 μm filter, the standard bee venom injection preferably contains about 0.01 to about 1.0 mg of melittin and about 80 to about 9,500 μg of total protein in 1 mL. More preferably, the resulting pharmaceutical composition contains about 0.01 to about 0.1 mg of melittin and about 400 to about 4,500 μg of protein per mL, and the most preferred standard solution is about 1 mL. It contains about 0.04 to about 0.05 mg of melittin and about 800 to about 950 μg of total protein. The most preferred standard solution is one in which hyaluronidase activity is 40 to 100 HHU / mL (100 μg / mL diluted) every 1 mL and gelatin-induced hemagglutination appears at 3 to 5 mm / H.
[0024]
Any purification method that is practical to provide a bee venom of the same purity as obtained with a 25 μm filter could be appreciated. Such methods include normal and reverse phase chromatography, affinity chromatography, recrystallization, immunological precipitation, membrane permeation methods and other filtration methods.
[0025]
In addition to the liquid carrier, the bee venom formulation according to the present invention also includes other conventional excipients such as viscosity modifiers, preservatives and sodium chloride, sugars and the like, and the like. be able to. Excipients such as these include, without limitation, benzyl alcohol, methyl paraban, Ringer and other biologically acceptable substances commonly used in injectable therapeutics.
[0026]
The liquid carrier according to the present invention includes not only physiological saline but also all liquid carriers that can be used in the human body, such as phosphate buffer (pH 4.0). Also included are all biologically and pharmaceutically acceptable substances such as propylene glycol and ethyl digor which are often used as solubilizers for injections.
[0027]
A typical formulation according to the invention contains 1.0 mg of Italian bee pure and dry venom and 9.0 mg of sodium chloride per mL of water. Another desirable formulation consists of 1.0 mg pure and dry bee venom, 9.0 mg sodium chloride, 0.009 mL benzyl alcohol and 0.991 mL water. Again, formulations such as these remove any material greater than 25 μm through the filtration device. It is also contemplated to use thinner filters than this.
[0028]
When treating various diseases with bee venom alone, such as arthritis, multiple sclerosis, relief of joints and low back pain, multiple injections are usually given. In general, bee venom therapy is usually treated for about 6 to 12 weeks, and is treated once or more a week, and the number of injections is increased starting from 1 or 2 times. Will inject 20 to 50 injections in one treatment. The volume of bee venom described here is administered from about 0.01 to about 1.0 mg per injection. Desirably, the volume of bee venom should be about 0.05 to about 0.5 mg per injection, with the best volume being about 0.1 mg per injection. Therefore, 1 mL of the above-mentioned two formulas will supply 10 divided drug volumes of 0.1 mL each containing 0.1 mg of bee venom.
[0029]
The bee venom injection according to the present invention is usually injected intradermally with a syringe with a 25-27 gauge needle graduated in 0.1 mL increments. The needle is generally in the range of about 1/4 to about 5/8 inch long. It is appropriate to do a skin test to check for possible allergic reactions before treating the patient. As a preferred site for the skin reaction test, about 1/2 or 0.05 mL of a normal dose is slowly injected into the skin on the flexor surface of the forearm, etc., to make a hemispherical blister. Examination of skin reaction is based on the size of the swelling, the size of the erythema, the appearance of irregular spread, and the state of protrusions swelled from the test site (pseudo-pod projections) Do it. In normal reaction, a blood spot at the end of the needle was seen where the needle was in, the swollen trace was about 0.5 to about 1.0 cm, and the erythema was round from the injection site to about 1 to about 2 Appears in inches. If no systemic reaction appears within 15 to 30 minutes after injection, it is considered negative.
[0030]
When administering intradermally, it is recommended to slightly pull the injection plunger prior to injection and observe blood flowing into the syringe to prevent intravenous injection. Injections are made at a variety of different sites depending on the affected area of the patient. However, in order to relieve and treat pain in arthritic patients, for example, an injection is first made from the painful site. Most preferably, the injection is at a tender point or a trigger point. Thereafter, in order to maximize the therapeutic effect, injection is made into the spinal area according to the dermatome chart of the skin. In general, avoid drinking alcohol during treatment. If local reactions are severe, apply cold packs or menthol ointment. If itching is very severe, take 75 mg of Benadryl when you sleep and take 50 mg in the daytime. good. If mild fever or other chills occur, acetaminophen or other antipyretic may be taken.
[0031]
The present invention also includes an apparatus for collecting poison from bees in a purification process using a low volt electric shock technique. This extractor consists of two wooden frames, one inside the other. A plurality of electric wires are attached to the front surface of the outer frame, and these are alternately grounded and charged. When the bees approach and come into contact with the two wires, the circuit is completed and eventually impacts.
[0032]
The extractor is placed in front of the honeycomb and connected to a 9 volt battery with an electric timer. If the battery is connected, the current flows repeatedly for 5 seconds and then stops for 3 seconds. As soon as this instrument is turned on, the bees get excited and come out of the beehive and attack the extractor. At the same time, the bees sprinkle pheromones in the air so that other bees are excited and attack. When the bees receive an electric shock, the lower abdomen bends and the needle is inserted into the silicone rubber sheet covered on the upper surface of the inner wooden frame. If the current stops for 3 seconds, the bees will not take out the bees and die. A pure liquid bee venom appears under the silicon rubber sheet. Remove the inner wooden frame from the outer frame and store in a sterilized box.
[0033]
The box is dried in a sterilized refrigerator (4 degrees Celsius) for 4-6 hours. Remove the inner wooden frame from the box and place it in a large sterilized basket, and remove the dried bee venom crystals with a sterilized pharmaceutical razor. The collected bee venom crystals are placed in a sterile bottle and sealed. Bee venom can also be produced by the methods described in U.S. Pat. Nos. 4,739,531 and 3,163,871.
[0034]
In treating various diseases, the use of the standard bee venom injection formulation according to the present invention is described in detail herein and offers significant advantages over the prior art. However, the experience of being bitten by a living bee is by no means pleasant. The experience of thirty or more stings is of course increasing the degree of discomfort. The burning pain experienced by bee venom is unique because it does not resemble other pain or irritation. Preferably, the standard formulation according to the invention is injected much more comfortably than the bee needle, but the tingling pain caused by the injection of bee venom is treated with bee venom therapy. Is reminiscent of Accordingly, preferred embodiments of the present invention provide compositions and methods that alleviate, reduce or even eliminate the unpleasant irritation caused by bee venom injection. This discovery is surprising, with burning, sharp stinging and other irritation occurring when bee venom is injected into the skin even when anesthetics, especially local anesthetics, are applied locally. The pain that I could not get rid of is that if local anesthetic is injected at the same point with bee venom or at the same time, the pain can be reduced or eliminated.
[0035]
Unfortunately, problems have been discovered that could not be anticipated by introducing local anesthetics in this manner. For example, if a bee venom injection containing 2% lidocaine (lidocaine 20 mg / mL: 1 mg / mL bee venom), sharp stinging pain, cramping pain and Other irritating stimuli are reduced. However, lidocaine itself induces a irritating stimulus independent of the bee venom stimulus. As a result, it was much better than when only bee venom was used. However, when the local anesthetic of the volume exemplified here is injected locally and locally with bee venom, another soreness will be caused.
[0036]
Stimulation caused by bee venom when injected with a volume much smaller than the volume of local anesthetic applied locally or topically (ie less than 1%) and at the same time irritated during intradermal injection of local anesthetic It was a discovery that couldn't be expected to make me feel no stimulation.
[0037]
Those using bee venom in the present invention are those described above, or whether they are filtered or not, purified or not, and other bee venom preparations are also used. can do. The pharmacological composition in question can also be mixed with a local anesthetic and injected as a single solution into a single syringe. However, it is not always necessary to make bee venom and local anesthetic in a single solution or inject them at the same time. A local anesthetic can be made separately and injected at the same point after bee venom injection. Immediately before and after the injection of bee venom, the local anesthetic can be injected immediately before and after the injection. It should be within 10 minutes. Desirably, when injecting bee venom and a local anesthetic continuously, it may be within 10 minutes before bee venom injection or within several minutes after injection. The most desirable method is to inject the local anesthetic immediately before or after the bee venom injection.
[0038]
If bee venom is injected into a muscle, a local anesthetic is also injected into the same muscle. It is the same when given subcutaneously and the same when injected into the skin, which is the best method.
[0039]
The relief of the irritating irritation associated with bee venom injection is somewhat subjective. This depends on various factors: pain area for individual patient pain; number of injections; volume of bee venom injected with each injection; injection site; depth of injection with intradermal, subcutaneous and intramuscular injection. However, generally speaking, the appropriate amount of local anesthetic described here appears more than when the same volume is injected without local anesthetic when the same protocol is applied to the same patient and the same volume is injected. The irritating irritation is much reduced.
[0040]
Local anesthetics according to the present invention include any composition that can reduce the irritating irritation caused by bee venom injection. Anesthetics are not limited to local and local anesthetics. However, local anesthetics are preferred. The anesthetic agent of the present invention is as follows.
[0041]
Ambucaine, Amoranone, Amilocaine Hydrochloride, Benoxynate, Benoxynate, Bencaine, Benecaine, Benecaine, Benecaine, Benecaine Butamben, Butanilicaine, Butethamine, Butoxycaine, Carticaine, Chloroprocaine Hydrochloride, Chloroprocaine Hydrochloride Down (Cocaethylene), cocaine (Cocaine), cyclomethycaine (Cyclomethycaine), dibucaine hydrochloride (Dibucaine Hydrochloride), Jimechisokuin (dimethisoquin), Jimesokain (Dimethocaine), hydrochloric diperodon (Diperodon Hydrochloride), dyclonine (Dyclonine), Ekonijin (Ecgonidine) , Ecgonine, ethyl chloride, etidocaine, b-eucaine, euprocin, phenalkine, fomocaine, fomocaine Acid hexylcaine (Hexylcaine Hydrochloride), Hydroxytetracaine (Isobutyl p-Aminobenzoate), Rosinocaine Mesilate (Leucinocaine L) Mepivacaine, Meprilcaine, Metabutoxycaine, Methyl Chloride, Myrtecaine, Naepine, Otacine, Octaine ocaine), Okisetazain (Oxethazaine), Paretokishikain (Parethoxycaine), hydrochloric acid phenacaine (Phenacaine Hydrochloride), phenol (Phenol), piperocaine (Piperocaine), Piridokain (Piridocaine), polidocanol (Polidocanol), Puridokanoru (Plidocanol), pramoxine (Pramoxine), Pricocaine, Procaine, Propanocaine, Proparacaine, Propipocaine, Propoxycaine Hydrochloride (Propoxycaine Hydroc) loride), pseudo-cocaine (Pseudococaine), pirocaine (Pyrrocaine), ropivacaine (Ropivacaine), salicyl alcohol (Salicyl Alcohol), tetracaine hydrochloride (Tetracaine Hydrochlorine) is there. Of these, the most desirable local anesthetic body according to the present invention is lidocaine.
[0042]
As can be appreciated, the local anesthetic volume is adjusted by the amount of bee venom used. However, the volume can be adjusted according to the specific condition of the patient, the severity of the pain and the course of treatment. Generally, the local anesthetic volume is used in a ratio of about 20: 1 to about 1:10 compared to the dry bee venom weight. A desirable ratio is about 10: 1 to about 1: 5, and a most desirable ratio is about 3: 1 to about 1: 1.
[0043]
The liquid carriers and excipients used in formulating the local anesthetic according to the present invention may be the same as or different from those used when making the bee venom formulation. Also, the local anesthetic is a liquid, and prescription drugs premixed with one or more liquid carriers and excipients can be purchased. In such a case, another liquid carrier or excipient is not required. In addition, these types of local anesthetic prescriptions can be used in bee venom carriers or can be used mixed with standard bee venom injections as described above.
[0044]
The amount of local anesthetic infused is about 0.01 to about 2.0 mg, preferably about 0.05 to about 1.0 mg per injection. The most desirable volume is about 0.1 mg per injection.
[0045]
A typical prescription preparation is as follows. (1) For every 1.0 mL of distilled water for injection, 1.0 mg of dried bee venom of bees, 9.0 mg of sodium chloride, and 1.0 mg of lidocaine hydrochloride are contained. (2) 1.0 mL distilled bee water for injection contains 1.0 mg of bee venom with dry bees, 9.0 mg of sodium chloride, 1.0 mg of lidocaine hydrochloride, 0.009 mL of benzyl alcohol, and 0.991 mL of water. (3) 1.0 mL of water for injection contains 1.0 mg of dried bee venom of bees, 9.0 mg of sodium chloride, 1.0 mg of lidocaine hydrochloride, and 0.1 mg of methylparaben.
[0046]
The present invention also includes creams, ointments and patches containing bee venom in addition to injections.
Bee venom cream formulation
5% (1-25%) dry bee venom;
Methyl salicylate 4% (1-20%);
Purified capsaicin 0.03% (0.01-0.05%);
Aloe extract;
menthol;
Caboma 940;
Cetyl alcohol;
Methylparaben;
Perfume;
wax;
purified water.
* Usage: Rub 1/16 to 1/8 teaspoon on the affected area.
Use once or twice a day.
[0047]
Bee venom patch formulation
10 mg of dried bee venom;
Methyl salicylate 150 mg;
1 mg of purified capsaicin;
Aloe extract;
menthol;
Wit point glycade;
Methyl paraben.
* Property: The size of the patch is 100 mm x 1.40 mm, and the above preparation was applied to a non-woven fabric and the release paper was covered on the solid surface.
* Usage: Attach to the affected area once or twice a day.
[0048]
Example
The patients described in the following examples continue to suffer significant pain as patients treated in conventional modern medicine. Many drugs such as analgesics, muscle relaxants and anti-inflammatories have been taken and various injections have been made, and their morbidity has not improved even though they have undergone spinal correction, physical therapy and sometimes even surgery. However, the pain was particularly severe.
[0049]
The following recorded example used a solution containing a 1: 1 ratio of bee venom and lidocaine for every 0.1 mL of injection per bee venom injection from the sixth treatment. From the first to the fifth, only pure bee venom was used. The injection solution was prepared by mixing with physiological saline for injection and purified through a 25 μm filter. Each patient was infused so that a single injection would be 0.1 mL. The total number of injections varied with the patient's condition and the number of treatments.
[0050]
In each example, the patients were infused by intradermal injection with the formulation according to the invention, treated twice a week and treated on average 12 to 20 times. In the following cases, “RA Titer” is a blood value often used in the diagnosis of rheumatoid arthritis.
[0051]
If the appropriate amount is less than 20, the result is negative, which is a highly desirable result for such patients. “ESR” indicates “erythrocyte sedimentation rate” and is generally used to diagnose inflammation. A normal numerical value is 1-10. Higher numbers represent systemic inflammation.
[0052]
“ROM” means the range of motion. The standard value of the range of movement varies depending on the problem joint. However, the greater the distance between the two ends, the greater the range of motion. Tenderness and swelling are displayed with a plus (+) sign on a standard scale. Each plus (+) sign means approximately 20%.
[0053]
The largest number 5 plus (+) means the visual similarity ratio of “VAS” which means the greatest tenderness and swelling (bulge). The most frequently used bath (VAS) has 100 mm parallel lines with no pain at the left end and the right end means the most severe pain so far. The patient displays on the 100 mm line how much pain he / she currently feels. Pain intensity is measured by the numerical value up to the point indicated by the patient on the left end. Such methods include “Pain Textbooks” issued by Churchill Livingstone (New York, 3rd issue, pp. 338-339, 1994) and “Pain Management” issued by Lee and Febiga (Philadelphia, 2nd issue). 1990, pages 581-582).
[0054]
Example 1 Rheumatoid Arthritis (RA)
NG was a 39-year-old female patient who had rheumatoid arthritis for 19 years. She tried all kinds of treatments including anticancer drugs, but it didn't work. Her wrist and hand pain and blisters were so severe and unbearable that she was impaired. This patient improved about 95% after receiving treatment according to the present invention. The patient's condition was stable and no more pain and swelling.
[0055]

[0056]
Example 2: Osteoarthritis
HR is a 75-year-old woman who has suffered from degenerative arthritis for the last 25 years. Her knee and spine were worse than the other joints. This patient was in excellent condition after 18 treatments with the treatment according to the invention. Currently, other drugs are well spent without taking.
[0057]

[0058]
Example 3: Ankylosing spondylitis
MO is a 53-year-old female patient who has been hurting her back for a long time and has undergone many operations such as hip joint fusion. This patient had no special effect despite continued rehabilitation treatment for 18 months. The patient improved considerably after a total of 26 treatments with the treatment according to the invention. Currently not taking medication, but needs to be revisited at least once a month.
[0059]

[0060]
Example 4: Myalgia
PA is a 32-year-old girl with muscle pain. Previously, no physical or psychological therapy was successful. Trigger point injections were injected at several sites for treatment. A total of 16 treatments fully recovered. A “trigger point” is a point that causes pain if it stimulates a specific part of the muscle.
[0061]

[0062]
Example 5: Tennis Elbow
JK is a 43-year-old boy who suffered from “tennis elbow” for four years. Traditional modern treatments have failed. The treatment method of the present invention completely recovered after 12 treatments in total.
[0063]

[0064]
Example 6: Adhesive cystitis
BO is a 56-year-old male patient suffering from a frozen shoulder. Drugs, various injection treatments, and surgery were not successful. The patient's range of motion was limited to 20% and complained of persistent pain. The treatment method of the present invention completely recovered after 14 treatments in total.
[0065]

[0066]
Example 7: Chronic surgical inflammation
BC is a 49-year-old boy who has undergone abdominal surgery more than 10 times for hemorrhagic gastric ulcer, alcoholic cirrhosis, intestinal obstruction and the like. Surgical pain and gallbladder pain made him a serious drug addiction. With the treatment method of the present invention, a total of 28 intensive treatments for surgical scars were almost completely cured.
[0067]

[0068]
Example 8: Herpes zoster
JP was a 78-year-old female patient with shingles. Medical and surgical treatment has failed. This patient improved by more than 90% after 16 treatments with the treatment of the present invention. “Bubble” means herpes.
[0069]

[0070]
Example 9: Psoriasis
TH is a 28-year-old male patient who had been suffering from psoriasis skin disease for 7 years. Modern medical drugs only helped temporarily. His condition was getting worse and he could not wear short pants even in hot and humid summers. A total of 24 treatments improved very well. This patient needs to be revisited at least once a month.
[0071]
Example 10: Multiple sclerosis
SR is a 47-year-old female patient who has suffered from multiple sclerosis for 15 years. Mobilizing all modern treatments did not prevent the disease from getting worse. She continued to have numbness in the lower limbs, became numb, lost about 40% of urinary regulation, became weaker in limbs and worsened in balance, and had to rely on shoes and quadrupeds. . A total of 28 treatments greatly improved the patient's condition. At present, urination can be adjusted 100%, and it is no longer necessary to use shoes or walker. The patient will continue to be revisited at least once every 3-4 weeks for a considerable period of time.
[0072]

[0073]
Example 11: Pain
The 10 patients listed in the above example were combined and a total of 30 patients were treated with only the appropriate volume of bee venom until the first 5 treatments. Thereafter, that is, from the sixth time, as described in the “Examples” summarized along the respective headings described above, an injection solution in which bee venom and lidocaine were mixed at a ratio of 1: 1 was injected. Without informing the patient what kind of prescription was injected, each patient was asked and asked about the type of pain, its intensity, discomfort, etc. after each treatment. We also observed the patient's body language for bee venom injection, the degree of frowning, and the unawareness of receiving treatment.
[0074]
97% of patients objectively reported that pain and discomfort at injection were greatly reduced for injections containing bee venom and lidocaine. The fear of the next injection was also significantly reduced, and those who dropped out during this treatment dropped dramatically. Pain relaxation lasts for a considerable amount of time, and a very small amount of local anesthetic gives the pain relaxation only momentarily, and after a while the pain suddenly increases. There was no increase.
[0075]
【The invention's effect】
As can be seen from the above embodiments, the present invention dramatically reduces pain and discomfort in patients undergoing bee venom treatment by injecting a bee venom injection mixed with bee venom and a local anesthetic. effective.
[0076]
Although the present invention has been described in detail with reference to the embodiments, the present invention is not limited to the embodiments. The present invention does not depart from the spirit and spirit of the present invention as long as it has ordinary knowledge in the technical field to which the present invention belongs. The present invention may be modified or changed.

Claims (6)

An injection comprising whole bee venom as an active ingredient , 0.1 to 10 mg of total bee venom as a dry weight in 1 ml of injection solution at the time of injection, and 0.1 to 5 times the weight of the whole bee venom The said injection containing the amount of lidocaine hydrochloride and the pain accompanying the injection | pouring of whole bee venom is reduced . Whole bee venom, rheumatoid (Rheumatoid) Osteoarthritis, osteoarthritis, ankylosing spondylitis, muscle pain, tennis elbow (tennis elbow) The injection according to claim 1, which is used for treatment of golf elbow, fifty shoulders, chronic surgical inflammation of soft tissue and bone tissue, herpes zoster, psoriasis, or multiple sclerosis. The injectable preparation according to claim 1 or 2, wherein the whole bee venom is a passage product filtered through a 25 µm filter. The injection according to claim 1, wherein the amount of lidocaine hydrochloride is 1/3 to 1 times the amount of the total bee venom.   The injection according to claim 1, comprising 0.5 to 5 mg of whole bee venom as a dry weight in 1 ml of an injection solution at the time of injection.   The injection according to claim 1, comprising 1 mg of whole bee venom as a dry weight in 1 ml of injection solution at the time of injection.