JP2015523351A - 結核予防用経口使用不活化マイコバクテリア - Google Patents
結核予防用経口使用不活化マイコバクテリア Download PDFInfo
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- JP2015523351A JP2015523351A JP2015516652A JP2015516652A JP2015523351A JP 2015523351 A JP2015523351 A JP 2015523351A JP 2015516652 A JP2015516652 A JP 2015516652A JP 2015516652 A JP2015516652 A JP 2015516652A JP 2015523351 A JP2015523351 A JP 2015523351A
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Abstract
Description
(a)不活化マイコバクテリアを定期的に経口投与する;
(b)投与間隔は5日以下である;及び
(c)与薬される投与回数は5回以上である、
ことを特徴とする。
(a)不活化マイコバクテリアを定期的に経口投与する;
(b)投与間隔は5日以下である;及び
(c)与薬される投与回数は5回以上である、
ことを特徴とする。
マイコバクテリア属(genus of the mycobacteria)はマイコバクテリウム科(family of Mycobacteriaceae)に属し、好気性桿菌により生成される。
「結核の予防」という表現は、潜伏状態から活動性結核へ感染が進行することを制御することにより活動性結核の症状発現を防止することを意味する。
本発明の目的によれば、不活化マイコバクテリアは経口投与される。
(2)希釈剤(例えば、無水ラクトース、ラクトース一水和物、リン酸カルシウム、リン酸水素カルシウム無水物、リン酸水素カルシウム二水和物、硫酸カルシウム、炭酸カルシウム、カルボキシメチルセルロースカルシウム、結晶セルロース、セルロース粉末、酢酸ルロース、デキストラン、デキストリン、デキストロース、フルクトース、グリセリルパルミトステアレート、カオリン、ラクチロール、炭酸マグネシウム、酸化マグネシウム、マルチトール、マルトデキストリン、マルトース、ポリメタクリレート、α化デンプン、塩化ナトリウム、デンプン、蔗糖など)、
(3)滑沢剤(例えば、ステアリン酸マグネシウム、ステアリン酸カルシウム、グリセリンパルミトステアレート、ポロキサマ、酸化マグネシウム、安息香酸ナトリウム、コロイドシリカ、ラウリル硫酸ナトリウム、ステアリルフマル酸ナトリウム、ステアリン酸、タルク又はベヘン酸グリセリル等)、
(4)懸濁化剤(沈殿防止剤)(例えば、キサンタンガム、グアガム、アルギン酸、ベントナイト、カルボマー、カルボキシメチルセルロースナトリウム、カルボキシメチルセルロースカルシウム、ヒドロキシエチルセルロース、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、アルギン酸ヒドロキシプロピル、結晶セルロース、セルロース粉末、コロイド状無水二酸化ケイ素、デキストリン、ゼラチン、カオリン、ケイ酸マグネシウムアルミニウム、マルチトール、ポリビニルピロリドン、ソルビタンエステル又はトラガントなど)、
(5)結合剤(例えば、三ケイ酸マグネシウム、セルロース、デンプン、デキストリン、デキストロース、ポリデキストロース、マルトース、マルトデキストリン、エチルセルロース、メチルセルロース、ポリメチルアクリレート、タルク、ポリビニルピロリドン、ステアリン酸又は蔗糖など)、
(6)脱凝集剤(例えば、低置換ヒドロキシプロピルセルロース、第三リン酸カルシウム、カルボキシメチルセルロースナトリウム、カルボキシメチルセルロースカルシウム、クロスカルメロースナトリウム、クロスポリビニルピロリドン又はマチルセルロースなど)、(7)塗工剤(例えば、キトサン、フタル酸ジブチル、セバシン酸ジブチル、フタル酸ジエチル、フタル酸ジメチル、エチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒプロメロース、マルトデキストリン、ポリメタクリレート、ポリビニルアセテートフタレート(PVAP)又はクエン酸トリエチルなど)、
(8)分散剤(例えば、ポロキサマ又はソルビタンエステルなど)、
(9)甘味剤(例えば、アスパルテーム、マンニトール、ソルビトール、サッカリンナトリウム、サイクラミン酸ナトリウム、蔗糖、デキストロース、グルコース、イヌリン、イソマルトース、ラクチトール、マルトース、マルトール、スクラロース、トレハロース、キシリトール又はタウマチンなど)、
(10)矯味矯臭剤及び
(11)調味料などである。
これらは単独でも使用できるし、あるいは適宜組み合わせて併用することもできる。
Institut German Traias i PujolのUnitat de Tuberculosi Experimental菌寄託機関から入手した結核菌(M. tuberculosis)の臨床株(TOL-3)をProskauer Beck液体培地中で指数関数増殖 が起こり、1ml当たり1.7x107コロニー形成単位(CFUs)濃度に達するまで培養し、得られた培養物を用いて不活化マイコバクテリアを作成した。
1)対照群:非処置
2)グループ1(感染前処置群):ゾンデにより経口的に不活化マイコバクテリア含有生成物を強制摂取させた。感染前10日目から投与を開始し、各48時間毎に投与し、不活化マイコバクテリア含有生成物5回投与した。各投与毎に、容量0.3mlを投与した。全体で4種類の希釈度、すなわち、1:1、1:10、1:100及び1:1000(それぞれグループ1a、1b、1c及び1dに対応する)の希釈度をテストした。
3)グループ2(感染後処置群):ゾンデにより経口的に不活化マイコバクテリア含有生成物を強制摂取させた。感染後11日目から投与を開始し、各48時間毎に投与し、不活化マイコバクテリア含有生成物5回投与した。各投与毎に、容量0.3mlを投与した。全体で4種類の希釈度、すなわち、1:1、1:10、1:100及び1:1000(それぞれグループ2a、2b、2c及び2dに対応する)の希釈度をテストした。
マウスの観察 スコア
体重
正常(体重減少無し。マウスは正常通りに成長する) 0
体重減少<10% 1
体重減少10−15%(糞便の外観及び量に有り得べき変化) 2
体重減少>15%(マウスは水を飲まないか又は餌を食べない) 3
外観
正常 0
外皮が劣化した状態 1
外皮が劣化した状態又は目或いは鼻分泌物の存在 2
異常な姿勢 3
苦痛の徴候の観察
徴候無し(自傷行為又は異音が観察されない) 0
自傷行為又は異音が観察される 3
刺激に対する反応
正常(攻撃又は昏睡状態の何れも無し) 0
非常に攻撃的又は昏睡状態 3
脚注:
スコア0−2:正常
スコア3 :管理プロトコルの適用頻度を2回/日まで増大する。
2個以上のコンセプトでスコア3が得られた場合、全てのスコア3はスコア4になる。
1個以上のスコアが4の値に達した場合、マウスを屠殺する。
この実施例で使用した治療薬はM. bovis BCG(SSI)の市販菌株から作成した。この菌株をProskauer Beck液体培地中で指数関数増殖 が起こり、1ml当たり1.03x108コロニー形成単位(CFUs)濃度に達するまで培養した。得られた培養物を実施例1に述べた方法と同じ方法を用いて不活化させた。
1)対照群:非処置
2)グループ1(感染後処置群):ゾンデにより経口的に不活化マイコバクテリア含有生成物を強制摂取させた。感染後12日目から投与を開始し、各48時間毎に投与し、不活化マイコバクテリア含有生成物5回投与した。引き続き、各マウスの生存時間に応じて、実験の終了まで1週間に3回(月曜日、水曜日及び金曜日)投与した。
M. bovis BCGの不活化菌を実施例2に述べた方法と同じ方法で作成した。
1)対照群:非処置
2)グループ1(感染前処置群):ゾンデにより経口的に不活化マイコバクテリア含有生成物を13回強制摂取させた。感染前29日目から投与を開始し、1週間に3回(月曜日、水曜日及び金曜日)投与した。各投与において、1:1000希釈度に対応する容量0.3ml(2.575x103CFUsに相当)を投与した。
結核菌(TOL-3)の不活化菌を実施例1に述べた方法と同じ方法で作成した。
1)対照群:非処置
2)グループ1(感染前処置):ゾンデにより経口的に不活化マイコバクテリア含有生成物を5回強制摂取させた。感染前10日目から投与を開始し、各48時間毎に投与し、続いて、実験が終わるまで1週間に3回(月曜日、水曜日及び金曜日)投与した。各投与において、1:1000希釈度の溶液を0.3ml投与した。
3)グループ2(感染後処置群):ゾンデにより経口的に不活化マイコバクテリア含有生成物を5回強制摂取させた。感染後11日目から投与を開始し、各48時間毎に投与し、続いて、実験が終わるまで1週間に3回(月曜日、水曜日及び金曜日)投与した。各投与において、1:10希釈度の溶液を0.3ml投与した。
カンサシ菌(Mycobacteriumu kansasii)は晩生(遅生育)の非結核性抗酸菌である。Institut German Traias i PujolのUnitat de Tuberculosi Experimental菌寄託機関から入手したカンサシ菌の臨床株(TOL)をProskauer Beck液体培地中で指数関数増殖 が起こり、1ml当たり8.07x104コロニー形成単位(CFUs)濃度に達するまで培養し、得られた培養物を用いて不活化マイコバクテリアを作成した。
1)対照群:非処置
2)グループ1(感染前処置):ゾンデにより経口的に不活化マイコバクテリア含有生成物を13回強制摂取させた。1週間に3回(月曜日、水曜日及び金曜日)投与した。このグループは最後の投与後、24時間目に感染させた。
3)グループ2(感染後処置群):感染後、15日目から、ゾンデにより経口的に不活化マイコバクテリア含有生成物を13回強制摂取させた。1週間に3回(月曜日、水曜日及び金曜日)投与した。
マイコバクテリウム・フォーチュイタムは速生育非結核性抗酸菌である。Institut German Traias i PujolのUnitat de Tuberculosi Experimental菌寄託機関から入手したフォーチュイタム菌の環境株(environmental strain)(マンレサ(Manresa)株)をMiddlebrook 7H9固体培地中で、1ml当たり2x109コロニー形成単位(CFUs)濃度に達するまで培養し、得られた培養物を用いて不活化マイコバクテリアを作成した。
1)対照群:非処置
2)グループ1(感染前処置):ゾンデにより経口的に不活化マイコバクテリア含有生成物を10回強制摂取させた。1週間に5回(月曜日から金曜日)投与した。このグループは最後の投与後、24時間目に感染させた。
3)グループ2(感染後処置群):感染後、5日目から処置を開始し、ゾンデにより経口的に不活化マイコバクテリア含有生成物を10回強制摂取させた。1週間に5回(月曜日から金曜日)投与した。
マイコバクテリウム・フォーチュイタム(マンレサ株)の不活化菌を実施例6に述べた方法と同じ方法で生成した。
1)対照群:耐性構築処置無し
2)グループ1:ゾンデを用いて経口的に不活化マイコバクテリア含有生成物を14回強制摂取させることにより処置した。1週間に7回(月曜日から日曜日)投与した。RIMSTARによる活動性結核症の治療終了後(63日目)、72時間目に前記耐性構築処置を開始し、76日目に最後の投与を行った。
Claims (15)
- 結核予防用医薬品を製造するための不活化マイコバクテリアの使用であって、
(a)不活化マイコバクテリアを定期的に経口投与する;
(b)投与間隔は5日以下である;及び
(c)与薬される投与回数は5回以上である、
ことを特徴とする不活化マイコバクテリアの使用。 - 不活化マイコバクテリアは、Mycobacterium tuberculosis、Mycobacterium bovis、Mycobacterium africanum、Mycobacterium microti、Mycobacterium bovis BCG、
Mycobacterium fortuitum及びMycobacterium kansasiiからなる群から選択される、
ことを特徴とする請求項1に記載の不活化マイコバクテリアの使用。 - 不活化マイコバクテリアは、Mycobacterium tuberculosis、Mycobacterium bovis、Mycobacterium bovis BCG、Mycobacterium fortuitum及びMycobacterium kansasiiからなる群から選択される、
ことを特徴とする請求項2に記載の不活化マイコバクテリアの使用。 - マイコバクテリアは加熱プロセスにより不活化される、
ことを特徴とする請求項1−3の何れかに記載の不活化マイコバクテリアの使用。 - 投与間隔が3日以下である、
ことを特徴とする請求項1−4の何れかに記載の不活化マイコバクテリアの使用。 - 投与間隔が2日以下である、
ことを特徴とする請求項5に記載の不活化マイコバクテリアの使用。 - 与薬される投与回数が7回以上である、
ことを特徴とする請求項1−6の何れかに記載の不活化マイコバクテリアの使用。 - 与薬される投与回数が9回以上である、
ことを特徴とする請求項7に記載の不活化マイコバクテリアの使用。 - 各投与は103から109個の不活化マイコバクテリアからなる、
ことを特徴とする請求項1−8の何れかに記載の不活化マイコバクテリアの使用。 - マイコバクテリアは、不活化マイコバクテリアと、少なくとも1種類の薬剤的に使用可能な賦形剤とからなる医薬組成物の剤形で投与される、
ことを特徴とする請求項1−9の何れかに記載の不活化マイコバクテリアの使用。 - 医薬組成物の剤形はカプセル剤である、
ことを特徴とする請求項10に記載の不活化マイコバクテリアの使用。 - 医薬組成物の剤形は錠剤である、
ことを特徴とする請求項10に記載の不活化マイコバクテリアの使用。 - 不活化マイコバクテリアは、結核菌に感染しているが、その感染が潜伏状態である個体に投与される、
ことを特徴とする請求項1−12の何れかに記載の不活化マイコバクテリアの使用。 - 個体は以前に活動性結核症を発症したことがある、
ことを特徴とする請求項13に記載の不活化マイコバクテリアの使用。 - 不活化マイコバクテリアは、結核菌に感染していない個体に投与される、
ことを特徴とする請求項1−12の何れかに記載の不活化マイコバクテリアの使用。
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US9579371B2 (en) | 2017-02-28 |
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