JP6523132B2 - 低用量デスモプレシンを含有する医薬組成物 - Google Patents
低用量デスモプレシンを含有する医薬組成物 Download PDFInfo
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- JP6523132B2 JP6523132B2 JP2015206674A JP2015206674A JP6523132B2 JP 6523132 B2 JP6523132 B2 JP 6523132B2 JP 2015206674 A JP2015206674 A JP 2015206674A JP 2015206674 A JP2015206674 A JP 2015206674A JP 6523132 B2 JP6523132 B2 JP 6523132B2
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- Prior art keywords
- desmopressin
- plasma
- dosage form
- serum
- pharmaceutical composition
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
〔1〕0.5ng〜2000ngのデスモプレシンを鼻腔内投与によって投薬する投薬単位中にデスモプレシンおよび薬学上許容される担体を含んでなる、尿失禁の治療もしくは予防における使用のための、または排尿延期を誘導するための医薬組成物、
〔2〕患者に投与されるときに、血漿/血清1mL当たりデスモプレシン0.1ピコグラムから血漿/血清1mL当たり最大でデスモプレシン10.0ピコグラムまでの範囲の定常的な血漿/血清中デスモプレシン濃度を確立して尿産生を減少させるものであり、0.5ng〜20μgのデスモプレシン及び鼻腔内、舌下、頬側、経粘膜、経皮、又は皮内投与用に構成された薬学上許容される担体を含んでなる、尿失禁の治療もしくは予防のための、または排尿延期を誘導するための医薬組成物、
〔3〕0.5ngから10μgのデスモプレシンを含む、〔2〕に記載の医薬組成物、
〔4〕0.5ng〜2000ngのデスモプレシンを含む、〔2〕に記載の医薬組成物、
〔5〕患者に投与されるときに、血漿/血清1mL当たりデスモプレシン0.5ピコグラムから血漿/血清1mL当たりデスモプレシン5.0ピコグラムまでの定常的な血漿/血清中デスモプレシン濃度を確立する、〔2〕〜〔4〕いずれかに記載の医薬組成物、
〔6〕0.5ng〜600μgのデスモプレシンを鼻腔内投与によって投薬する投薬単位中にデスモプレシンおよび薬学上許容される担体を含んでなる、尿失禁の治療もしくは予防における使用のための、または排尿延期を誘導するための医薬組成物
に関する。
(a)有効成分並びに非直接圧縮賦形剤及び滑沢剤を含むマトリックスを含む混合物を形成する段階、
(b)該混合物を圧縮して、口内で溶解可能なマトリックス中に分配された有効成分を含む、多数の硬質の圧縮された急速崩壊性剤形を形成する段階、及び場合によっては、
(c)包装の前に、剤形をバラで貯蔵する段階、
を含む方法によって製造できる。好ましい実施形態においては、次いで、剤形を、1包につき少なくとも1つ存在するように、包みの内部空間に包装する。特に好ましい実施形態においては、次いで、剤形を、1包につき少なくとも1つを超えて存在するように、包みの内部に包装する。直接圧縮は、剤形を形成する好ましい方法である。
バスケットを形成するために底部末端にNo.1.70の篩いの要件に従った防錆金網の円盤を取り付けた、長さ80〜100mm、内径約28mm、外径30〜31mmのガラス又は適切なプラスチック製の筒。
温度36℃〜38℃の深さ15cm以上の水を入れた、内径約45mmの平底ガラスシリンダー。
バスケットが一定の方式で反復的に上昇及び下降し、最高位置で網が水面からほんのわずか飛び出し、最低位置でバスケットの上縁がほんのわずか水面上に残るように、バスケットをシリンダーの中心に吊り下げる
1個の成型物をバスケットに入れ、完全な上昇及び下降運動を毎分30回に等しい速度で反復するような方式でバスケットを上昇及び下降させる。網を容易には通過しない粒子が網上に残存しない場合が、成型物の崩壊である。10秒後にこのような粒子は残存すべきでない。
上に示したように、今日推奨される投与量及び得られる血漿/血漿/血清中レベルの5〜40%であるデスモプレシンの投与量及び血漿/血漿/血清中濃度は、治療上有効であり、場合によってはCDI、PNE、及び尿の薬理学的濃度を要求するさらなる臨床的徴候など、特定の疾患状態に対してより安全である。
ガラスビーカーに噴霧乾燥した魚類ゼラチン(4g)及びマンニトール(3g)を入れる。次いで、精製水(93g)を添加し、磁気撹拌子を使用する撹拌により溶液にする。pHを調べ、必要ならクエン酸で4.8に調整する。次いで、ギルソンピペットを使用し、前以て形成した約16mmのポケット直径を有する一連のブリスターポケットのそれぞれにこの溶液500mgを送達できる。ブリスターの積層はPVdCで被覆したPVCを含んでよい。次いで、投与される投与単位を、凍結トンネル中−110℃の温度で、3.2分の滞留時間で凍結し、次いで、凍結済みの投与単位を、−25℃(±5℃)の温度で1.5時間を超える時間、縦型冷凍庫中に保持した。次いで、その投与単位を、0.5ミリバールの圧力で、棚温度を最初の10℃から+20℃まで上げながら一夜凍結乾燥する。取り出す前に、乾燥トレースによって及び加圧水分検査によって投与単位の水分を調べた。
デスモプレシン(PolyPeptide Laboratories、スウェーデン)
200μg
マンニトールEP/USP(Roquette、Mannitol 35)
15mg
魚類ゼラチンUSNF/EP 20mg
クエン酸(必要なら)(pH調整剤) pH4.8まで
精製水(処理中に除去される)
単位剤形当たりのデスモプレシン量が400μgであること以外は、本明細書の実施例1の手順に従う。
単位剤形当たりのデスモプレシン量が800μgであること以外は、本明細書の実施例1の手順に従う。
WO−A−0061117の実施例1に示された一般的手順に従って、単位剤形当たり次の成分を使用してデスモプレシン剤形、口内分散性剤形を調製した。
デスモプレシン(PolyPeptide Laboratories、スウェーデン)
200μg
マンニトールEP/USP(Roquette、Mannitol35)
6mg
魚類ゼラチンUSNF/EP 10mg
クエン酸(必要なら)(pH調整剤) pH4.8まで
精製水(処理中に除去される)
単位剤形当たりのデスモプレシン量が400μgであること以外は、本明細書の実施例4の手順に従った。
単位剤形当たりのデスモプレシン量が800μgであること以外は、本明細書の実施例4の手順に従った。
以下の成分を使用し、デスモプレシンの注射可能な製剤を通常的に調製した。
デスモプレシン(PolyPeptide Laboratories、スウェーデン)
4mg
塩化ナトリウム 9mg
(National Corporation of Swedish Pharmacies、スウェーデン)
塩酸(1N)(Merck、ドイツ) pH4まで
注射用水 全量1mlまで
通常の湿式顆粒法を使用して以下の成分を含む錠剤を調製した。
デスモプレシン(PolyPeptide Laboratories、スウェーデン)
200μg
乳糖(Pharmatose 150M、DMV、オランダ) 120mg
馬鈴薯デンプン(Lyckeby AB、スウェーデン) 77mg
PVP(Kollidon25、BASF、ドイツ) 1.8mg
ステアリン酸マグネシウム(Peter Greven、ドイツ) 1mg
顆粒化用液体(水、エタノール)(処理中に除去される)
デスモプレシンの量が錠剤当たり100μgであること以外は、本明細書の比較例2の手順に従った。
研究計画
本研究では、24名の健康な非喫煙男子志願者を登録した。本研究は、1中心、オープンラベル化、ランダム化、釣合い型、4元交差第I相研究として計画した。それぞれの対象に、ランダム化した順序で、デスモプレシンを200μg、400μ及び800μgの口内分散性剤形(それぞれ、実施例4、5及び6)として舌下で及び静脈内ボーラス投与(比較例1)として2μgを投与した(比較例1)。投与と投与の間に72時間の洗浄期間を置いた。口内分散性錠剤を投与する前に頬粘膜を標準化するため、対象には食物、チューインガムなどを避けるよう求めた。対象には、練り歯磨きを使用しない、投与前の朝の歯磨きを許可した。
デスモプレシンの血漿中濃度を調べるための血液試料は、次のスケジュールで採取した、すなわち、投与前、並びに投与後15、30、45分、1、1.5、2、3、4、6、8、10、12及び24時間。静脈内投与後、5及び10分にさらなる血液試料を採取した。
血漿中のデスモプレシン濃度は、バリデーション済みのRIA法で測定した。
血漿中のデスモプレシン濃度は、商業的に入手可能なソフトウェアーWinNonlin(商標)Pro,ver.3.2(Pharsight Corporation、米国)を使用する非コンパートメント法を利用して、各投与群の個々の志願者について分析した。定量限界(LOQ)未満の血漿中濃度値、続いて定量限界(LOQ)を超える値を、NCA解析及び濃度に関する記述統計に関して「LOQ/2」に設定した。LOQを超える値が続かないLOQ未満の値は、NCA解析から排除し、濃度に関する記述統計においてゼロに設定した。
i.v.投与後における、定常状態平均分布容積(Vss)は29.7dm3であった。平均クリアランスは8.5dm3/hrと計算され、平均消失半減期は2.8時間と決定された。デスモプレシンの経口投与後における最大血漿中濃度は、投与後0.5〜2.0時間に観察された。200、400及び800μgの経口投与後における最大血漿中濃度は、それぞれ14.25、30.21、及び65.25pg/mlであった。最大値に到達した後、デスモプレシンは、2.8〜3.0時間の範囲の平均消失半減期で除去された。生体利用度は、0.23〜0.38%の95%信頼区間で0.30%と判定された。
オープンラベル、1回投与、3元交差研究として計画されたこの研究では、36名の健康な男子志願者(白色人種、黒人及びヒスパニック)を登録した。各対象に、ランダム化した順序で、1つの200μg錠剤(比較例2)として200μgのデスモプレシンを、2つの100μg錠剤(比較例3)として200μgのデスモプレシンを、及び静脈内ボーラス投与(比較例1)として2μgを投与した。
次の実施例では、過剰水和の健康で非喫煙の男子及び女子志願者における、2時間の静脈内点滴により投与された3水準の低用量デスモプレシンの抗利尿効果を示す研究について説明する。要約的には、8名の健康で過剰水和された非喫煙の年齢18〜40歳の男子及び女子志願者でのオープンラベルでの、交差研究である。対象に、初めは0.5ng/kgの投与量で、次いで1.0ng/kgの投与量で、最後に2.0ng/kgの投与量で投与した。薬力学及び薬物動態パラメーターを各投与レベルで評価した。投与と投与の間に2日間(48時間)の洗浄期間を遵守した。
デスモプレシンの3水準の投与量(I.V.点滴)のすべてが、尿濃度(重量モル浸透圧濃度)の増加及び尿排泄量の減少に関して投与量に応答した形で測定可能な抗利尿効果をもたらした。また、抗利尿効果の薬力学的持続時間は、最低用量が最短の効果持続時間を有する用量反応曲線を示した。平均最大尿重量モル浸透圧濃度(mOsm/kg)は、各投与水準において2時間の点滴の終末点で現われた。基礎平均尿重量モル浸透圧濃度は、0.5、1.0、2.0ng/kg投与量に対して、それぞれ55.8、55.8及び55.6であった。最大尿重量モル浸透圧濃度は、0.5、1.0及び2.0ng/kgの投与量に対して、それぞれ2時間で206.0、444.7及び587.2であった。平均最低尿排泄量(mL/分)も、各投与レベルについて2時間の点滴の終末点で現われた。基礎の最低尿排泄量は、0.5、1.0及び2.0ng/kgの投与量に対して、それぞれ18.6、16.6及び16.9mL/分であった。平均最低尿排泄量は、0.5、1.0及び2.0ng/kgの投与量に対して、それぞれ7.1、1.3及び0.7mL/分であった。抗利尿効果の持続時間は、およそ、0.5ng/kgの投与量で180分、1.0ng/kgの投与量で240〜280分、2.0ng/kgの投与量で360分であった。各対象に関する尿の重量モル浸透圧濃度及び排泄量、及び各時間での平均値を表1〜6及び図1〜9に記載する。
[1]0.5ngから20μgのデスモプレシン及び薬学上許容される担体を含む医薬組成物。
[2]約0.5ngから約2000ngのデスモプレシンを含む、[1]に記載の医薬組成物。
[3]約0.05μgから約10μgのデスモプレシンを含む、[1]に記載の医薬組成物。
[4]約0.1μgから約20μgのデスモプレシンを含む、[1]に記載の医薬組成物。
[5]静脈内、皮下、経粘膜、経皮、又は皮内送達用に構成された、[1]に記載の医薬組成物。
[6]口内分散性固体の形態である、[1]に記載の医薬組成物。
[7]オープンマトリックス網状組織をさらに含み、前記オープンマトリックス網状組織が、デスモプレシンに対して不活性である水溶性又は水分散性担体材料を含む、[1]に記載の医薬組成物。
[8]デスモプレシン及び薬学上許容される担体を含む医薬組成物であって、血漿/血清1mL当たりデスモプレシン約0.1ピコグラムから血漿/血清1mL当たりデスモプレシン約10.0ピコグラムまでの範囲の、定常的な血漿/血清中デスモプレシン濃度を確立するのに有効である医薬組成物。
[9]前記定常的な血漿/血清中デスモプレシン濃度が、血漿/血清1mL当たりデスモプレシン約0.5ピコグラムから血漿/血清1mL当たりデスモプレシン約5.0ピコグラムまでの範囲である、[8]に記載の医薬組成物。
[10]約0.5ngから約2000ngのデスモプレシンを含む、[8]に記載の医薬組成物。
[11]約0.05μgから約10μgのデスモプレシンを含む、[8]に記載の医薬組成物。
[12]約0.1μgから約20μgのデスモプレシンを含む、[8]に記載の医薬組成物。
[13]静脈内、皮下、経粘膜、経皮、又は皮内送達用に構成された、[8]に記載の医薬組成物。
[14]包装材料及び前記包装材料内に包含された医薬組成物を含む製造物であって、前記医薬組成物が、血友病、フォンウィルブランド病、失禁、一次性夜間遺尿症(PNE)、夜間頻尿症、又は中枢性尿崩症を治療又は予防するのに治療上有効であり、前記包装材料が、前記医薬組成物を血友病、フォンウィルブランド病、失禁、一次性夜間遺尿症(PNE)、夜間頻尿症、又は中枢性尿崩症を治療又は予防するのに使用できることを示すラベルを含み、前記医薬組成物が0.5ngから20μgのデスモプレシン及び薬学上許容される担体を含む製造物。
[15]デスモプレシンによって治療又は予防可能である疾患又は状態を治療又は予防する方法であって、患者に対して、0.5ngから20μgのデスモプレシン及び薬学上許容される担体を含む治療有効量の医薬組成物の1日量を投与することを含む方法。
[16]前記疾患又は状態が、血友病、フォンウィルブランド病、失禁、一次性夜間遺尿症(PNE)、夜間頻尿症、又は中枢性尿崩症からなる群から選択される、[15]に記載の方法。
[17]患者に対して、0.5ngから20μgのデスモプレシン及び薬学上許容される担体を含む治療有効量の医薬組成物の1日量を投与する段階を含む、患者に抗利尿効果を誘発する方法。
[18]前記患者が、フォンウィルブランド病、失禁、一次性夜間遺尿症(PNE)、夜間頻尿症、又は中枢性尿崩症からなる群から選択される疾患に罹患している、[17]に記載の方法。
Claims (3)
- 100ng〜2000ngのデスモプレシンを鼻腔内投与によって投薬する投薬単位中にデスモプレシン及び薬学上許容される担体を含んでなる、尿失禁の治療又は予防における使用のための医薬組成物。
- 患者に投与されるときに、血漿/血清1mL当たりデスモプレシン0.1ピコグラムから血漿/血清1mL当たり最大でデスモプレシン10.0ピコグラムまでの範囲の定常的な血漿/血清中デスモプレシン濃度を確立して尿産生を減少させるものであり、100ng〜2000ngのデスモプレシン及び鼻腔内、舌下、頬側、経粘膜、経皮、又は皮内投与用に構成された薬学上許容される担体を含んでなる、尿失禁の治療又は予防のための医薬組成物。
- 患者に投与されるときに、血漿/血清1mL当たりデスモプレシン0.5ピコグラムから血漿/血清1mL当たりデスモプレシン5.0ピコグラムまでの定常的な血漿/血清中デスモプレシン濃度を確立する、請求項2記載の医薬組成物。
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