JP6110367B2 - ナロキソンを含む鼻腔内医薬剤形 - Google Patents
ナロキソンを含む鼻腔内医薬剤形 Download PDFInfo
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- JP6110367B2 JP6110367B2 JP2014509762A JP2014509762A JP6110367B2 JP 6110367 B2 JP6110367 B2 JP 6110367B2 JP 2014509762 A JP2014509762 A JP 2014509762A JP 2014509762 A JP2014509762 A JP 2014509762A JP 6110367 B2 JP6110367 B2 JP 6110367B2
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
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- A61K9/0012—Galenical forms characterised by the site of application
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Description
(実施例)
目的:健常な被験者に対して、1mgの静脈内投与したナロキソンと比較して、8mgおよび16mgの鼻腔内投与したナロキソンおよび16mgの舌下投与したナロキソンの絶対バイオアベイラビリティを評価する。
1:ナロキソン8mgおよび16mgを、400μlとして鼻腔内投与した(1つの鼻孔当たり200μl)。これはほぼ0.11mg/kg体重(8mgについて)および0.22mg/kg体重(16mgについて)に相当する。
解析対象集団:登録集団を、インフォームドコンセントの書式に署名した任意の被験者と定義した。安全性解析対象集団を、いずれかの試験治療を受け、これに続く少なくとも1つの安全性評価を受けた任意の被験者と定義した。薬物動態測定のための完全解析対象集団を、試験治療を受け、これに続く少なくとも1つの有効なPK測定を受けた被験者と定義した。
試験デザイン:試験は、単一用量、非盲検、4治療、4期、無作為化クロスオーバー試験とし、健常な成人男性および女性被験者において、2種の用量の経鼻投与したナロキソンおよび1種の用量の舌下投与したナロキソンの薬物動態を、静脈内投与したナロキソンと比較して評価するためのものとした。被験者に、無作為のコードによって4治療の各々を施し、各投薬間に少なくとも14日のウォッシュアウト期間を置いた。被験者を最初の投薬日前14日以内にスクリーニングした。その後、適格の被験者に、各試験期間の投薬の前夜に試験単位に入院してもらった。被験者に、終夜絶食の後の翌朝、試験薬を投与した。各試験期間の試験薬の投与後36時間にわたって薬物動態用の血液試料を採取したが、被験者を24時間時点の血液試料の採取後に退院させた。被験者は、試験単位に再来して36時間後のPK血液試料を提供した。試験期間中、バイタルサインをモニターし、有害事象(AE)を記録した。被験者は、スクリーニング時に手続きをしたように、最後の外来通院時または試験の早期終了/中止時に試験終了手続きをした。
− 任意の人種群の男性および女性。
− ナロキソンまたは関連する化合物に対していずれかの過敏性の既往歴がある。
萎縮性粘膜、穿孔、多発性ポリープ、いずれかの側の鼻道の完全閉塞、血管腫。
萎縮性粘膜、悪性腫瘍もしくは良性腫瘍(線維腫および血管腫を含む)または嚢胞、水疱性病変(たとえば天疱瘡または多形紅斑)、舌炎、アフタ性潰瘍、扁平苔癬、白板症、感染症[細菌性、真菌性、ウイルス性(たとえばヘルペス)]。鼻腔内用製品(処方、非処方または鼻腔内投与される他のいずれかのもの)の、投薬前4週間以内の任意の使用。
安全性:治療により発現した有害事象(TEAE)の発生率は、すべての治療群にわたって類似していた。すなわち、8mg鼻腔内用ナロキソン[3件のTEAE]、16mg鼻腔内用ナロキソン[5件のTEAE]、16mg舌下用ナロキソン[1件のTEAE]、1mg静脈内用ナロキソン[4件のTEAE]であった。最も多く見られたTEAEは、SOC(器官別大分類)の胃腸障害および神経系障害において発現した。胃腸障害のTEAEは16mg鼻腔内群、1mg静脈内群および16mg舌下群のみに観察され、神経系TEAEは8mgおよび16mg鼻腔内群および1mg静脈内群のみに観察された。
Claims (15)
- オピオイド過量投与および/または少なくとも1つのその症状の治療のための、ナロキソンまたは薬学的に許容されるその塩を適用流体中に溶解して含む鼻腔内医薬剤形であって、1.3mgナロキソンHClと1.6mgナロキソンHClとの間に相当する量が鼻腔内投与され、前記量が1つの鼻孔への投与によって供給されるか、または前記量が2つの鼻孔への投与によって供給されるかであり、1つの鼻孔当たりの前記適用流体の体積が250μl以下である、前記鼻腔内医薬剤形。
- 1.3mgナロキソンHClもしくは1.4mgナロキソンHClもしくは1.5mgナロキソンHClまたは1.6mgナロキソンHClに相当する量のナロキソンまたは薬学的に許容されるその塩が鼻腔内投与される、請求項1に記載の剤形。
- 1つの鼻孔当たりの前記適用流体の体積が、200μl〜35μlの範囲内である、請求項1または2に記載の剤形。
- 1つの鼻孔当たりの前記適用流体の体積が、150μl〜100μlの範囲内である、請求項1から3のいずれかに記載の剤形。
- 前記量が1つの鼻孔への投与によって供給される、請求項1から4のいずれかに記載の剤形。
- 前記適用流体が、水および水性食塩溶液からなる群から選択される、請求項1から5のいずれかに記載の剤形。
- 前記量または前記量の半分を適用流体中に溶解して投薬単位中に含み、該含む量は、前記量が1つの鼻孔への投与によって供給されるか、または2つの鼻孔への投与によって供給されるかに依拠する、請求項1から6のいずれかに記載の剤形。
- 前記量が1つの鼻孔への投与によって供給されるか、または2つの鼻孔への投与によって供給されるかによって、単一の投薬単位または2つの投薬単位を含み、単回使用用である、請求項7に記載の剤形。
- 少なくとも2つの投薬単位を含み、複数回使用用である、請求項7に記載の剤形。
- 鼻内噴霧剤、鼻粘膜付着剤形および粘膜用霧状化器具を含む剤形の群から選択される、請求項1から9のいずれかに記載の剤形。
- ナロキソンを唯一の医薬活性化合物として含む、請求項1から10のいずれかに記載の剤形。
- オピオイド過量投与が、オピオイドの不正使用によって、または医療としてのオピオイド療法中のオピオイドの誤用事故によって生じる、請求項1から11のいずれかに記載の剤形。
- オピオイド過量投与の症状が、呼吸抑制、意識レベルの変化、縮瞳、低酸素血症、急性肺損傷および誤嚥性肺炎を含む群から選択される、請求項1から12のいずれかに記載の剤形。
- 前記量が、有効量のナロキソンを供給するために初期力価測定時間中に再投与される、請求項1から13のいずれかに記載の剤形。
- ナロキソンまたは薬学的に許容されるその塩を含む筋肉内用剤形および/または静脈内用剤形と組み合わされる、請求項1から14のいずれかに記載の剤形。
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