JP7007392B2 - 唾液腺炎の治療におけるボツリヌス神経毒素の改善された使用 - Google Patents
唾液腺炎の治療におけるボツリヌス神経毒素の改善された使用 Download PDFInfo
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- JP7007392B2 JP7007392B2 JP2019544657A JP2019544657A JP7007392B2 JP 7007392 B2 JP7007392 B2 JP 7007392B2 JP 2019544657 A JP2019544657 A JP 2019544657A JP 2019544657 A JP2019544657 A JP 2019544657A JP 7007392 B2 JP7007392 B2 JP 7007392B2
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Description
本発明の目的の一つは、例えば抗菌作用、凝集、ペリクル形成、消化、味覚、排泄および/または水収支のための潤滑剤として、イオンリザーバとして、緩衝剤として、洗浄剤として被験者において通常に生理的機能を示すが流涎を示さない程度に唾液産生量を抑制し、唾液腺の活性を長期間制限する、唾液腺炎または唾液分泌亢進に関連する疾患または状態の治療のためのボツリヌス神経毒素を提供することである。本発明の別の目的は、ボツリヌス神経毒素による治療に関連した副作用を回避すること、または治療中に頻度、重症度および/または持続期間を少なくとも減少させることである。本発明のさらなる目的として、ボツリヌス神経毒素は、基礎疾患が治療によって冒されないように長期間にわたる有利な治療結果を提供する必要があり、それ故に長期持続療法は、反復注射サイクルによって有効性の減少もしくは安全性を損なうことなく効果的かつ安全に適用される必要がある。
本発明は、本発明の以下の詳細な説明およびそれに含まれる実施例を参照することによってより容易に理解され得る。
- 耳下腺:各側に0.6ml、
- 顎下腺:各側に0.4ml。
数回の連続治療サイクルが想定される場合、かりに以前の治療サイクルでは口腔乾燥症または嚥下障害が生じる場合は注入量を減らすことができる。このような副作用のさらなる発生を回避するために、注入者の裁量で減量することを勧める。減量したボツリヌス神経毒素の投与が想定される場合、耳下腺および顎下腺に投与される注入量は以下の通りである。
- 耳下腺:各側に0.45ml、
- 顎下腺:各側に0.3ml。
1 乾燥(流涎なし)
2 軽度(唇がぬれる)
3 中度(唇と下顎がぬれる)
4 重度(流涎が衣類をぬらすまで拡大)
5 重篤(手、受け皿および物体がぬれる)
流涎の頻度
1 なし
2 時折(毎日ではない)
3 頻繁(日常の一部)
4 常時
全体として、慢性の厄介な唾液腺炎を有する184人の被験者を試験のMP中に治療した。この試験は、2つの共一次有効性評価項目を有した。共一次有効性評価項目の1つは4週目のベースラインからの非刺激唾液流量(uSFR)の変化であった(経時的平均変化は表1を参照)。すべての時点で、uSFRは両方のNT201処置群で有意に減少し、その効果は図1に示すようにNT201 100U用量群でより顕著であった。4週目では、プラセボを上回る統計的に有意な優位性がNT201 100U群で示された(p=0.004)。NT201 75Uの平均uSFR値(表1)は、8週目および12週目に0.05未満のp値に達した(p値:それぞれ0.022と0.019)。NT201 100UおよびNT201 75Uの両群で観察された治療効果は臨床的関連性と見なすことができる。
他の共一次有効性評価項目は、4週目に変化スケールの全体的印象(GICS)により測定された被験者の全体的機能的スケールの改善であった。GICSは7ポイントのリッカート尺度で、「唾液腺への最後の注射の直前と比較して、治療結果として現在どのように機能しているかの全体的印象はどうですか?」の質問に被験者が答えることで完結し、どちらの用量群も改善に達した。プラセボを上回る100U処置群が有利な統計的有意差は4週目で見られた(p=0.002、表2、図2)。75U群は4週目にプラセボと比較して数値的に良好な結果を示したが、その差は統計的有意差を間もなく失った(p=0.055)。それにもかかわらず、図2に提示したように0.05未満のp値は、両群では8週目と12週目、100Uの用量群で16週目に達した。
流涎に関して臨床的に有意な改善と考えられているGICS評価項目の前定義効果基準はスルールで少なくとも1点の改善(最小改善)であった。全ての処置群についてのレスポンダー解析の結果を表3および図3に示す。
主観的評価項目のドローリング重症度および頻度スケール(DSFS)も評価した。DSFSは、2つのサブスケール、すなわちドローリング頻度の4ポイントのリッカート尺度および流唾重症度の5ポイントのリッカート尺度からなる。DSFSの記述統計は、プラセボ群では臨床的に関連した改善が見られなかったのに対し、両NT 201処置群では関連した唾液腺炎症の改善を示した。表4および図4に示したように、ベースラインからの経時の平均合計スコア変化は8週目に100U処置群で-1.89の最大改善、次が12週目に75U処置群で-1.76の改善が続いた。混合モデル反復測度解析(MMRM)による治療比較から、4、8、および12週目でプラセボと比較したときに両NT 201群の0.05未満のp値が明らかである。
最後に、パーキンソン病の修正Radboud Oral Motor Inventory(mROMP)は、5ポイントのリッカート尺度の9項目の質問表を含むドローリングサブスケールを用いて評価した。両方のNT 201処置群は、表5および図5に示したプラセボ群と比較して、mROMPドローリングで優れた有効性を示した。ベースラインからの経時的平均変化は、8週目に100U処置群で-6.58、12週目に75U処置群で-6.77の最大改善に達する。本発明者らは、両方の用量群で見られた治療効果はプラセボの効果より優れており、NT201効果は全ての測定間で一貫し、また観察全体で安定し、両用量の適切な臨床的関連性が確認されると結論した。
病因によるサブグループ解析は、NT201 100U群における脳卒中後の唾液腺炎を有する被験者がパーキンソン病または非定型パーキンソニズムに関連する唾液腺炎を有する被験者よりuSFRの平均減少がより大きいことを示した(表6)。
16週間の間隔による3回の連続治療サイクルにおける有効性は、さらに唾液腺炎改善の証拠を提供した。2回目の注射後の全観察時間点についての試験ベースラインからのuSFR変化、および各注射(1回目の注射後16、32および48週)からそれぞれの評価時点(1回目の注射後20、36および52週)までの変化、ならびに各サイクルにおけるサイクルの終了/試験の終了訪問(1回目の注射後32、48および64週)までの変化も評価した。
Claims (13)
- ボツリヌス神経毒素を含有する唾液腺炎または唾液分泌亢進の治療剤であって、前記治療剤は耳下腺および顎下腺に注射により投与され、ここで各耳下腺と各顎下腺に投与される前記ボツリヌス神経毒素の用量の間の比が1.45対1~1.7対1であり、前記治療剤は10週間~20週間の時間間隔で少なくとも2回投与され、前記ボツリヌス神経毒素はボツリヌス毒素血清型Aであり、前記ボツリヌス神経毒素の総用量は70U~110Uであり、水性組成物の形態にある、治療剤。
- 注射部位あたり0.3~0.5mLで顎下腺に投与され、注射部位あたり0.5~0.7mLで耳下腺に投与される、請求項1に記載の治療剤。
- 各顎下腺の1箇所および/または各耳下腺の1箇所に注入される、請求項1又は2に記載の治療剤。
- 超音波ガイダンスを使用してまたは超音波ガイダンスを使用せずに耳下腺および顎下腺に注入される、請求項1~3のいずれか一項に記載の治療剤。
- 少なくとも3回、または少なくとも4回の治療サイクルで耳下腺および顎下腺に投与される、請求項1~4のいずれかに一項に記載の治療剤。
- 前記時間間隔は12~20週間である、請求項1~5のいずれか一項に記載の治療剤。
- 前記時間間隔は14~18週間である、請求項6に記載の治療剤。
- 前記時間間隔は15、16又は17週間である、請求項7に記載の治療剤。
- 前記ボツリヌス神経毒素はボツリヌス神経毒素複合体である、請求項1~8のいずれかに一項に記載の治療剤。
- 前記ボツリヌス神経毒素は、ボツリヌス神経毒素複合体の神経毒素成分であり、ここで前記神経毒素成分は、ボツリヌス菌神経毒素複合体の他のいかなるタンパク質成分も含まない、請求項1~9のいずれかに一項に記載の治療剤。
- 前記唾液腺炎または唾液分泌亢進が、パーキンソン病、進行性核上性麻痺、大脳皮質基底核変性症、多系統萎縮症、筋萎縮性側索硬化症(ALS)、脳性麻痺、脳卒中、外傷性脳損傷(TBI)、クロザピン誘発性過唾液分泌、レット症候群、アンジェルマン症候群、てんかん性脳症および脳腫瘍、咽頭喉頭全摘術、喉頭亜全摘出術および声門上喉頭切除術、認知症もしくは知的障害により引き起こされる、請求項1~10のいずれかに一項に記載の治療剤。
- 前記唾液腺炎または唾液分泌亢進が脳卒中により引き起こされる、請求項11に記載の治療剤。
- 45~55U/mLの範囲のボツリヌス神経毒素濃度を有する、請求項1~12のいずれか1項に記載の治療剤。
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US11925677B2 (en) | 2021-07-12 | 2024-03-12 | Penland Foundation | Treatment of diabetes and chronic pancreatitis using botulinum toxin |
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