JP2008507590A - 免疫活性剤を経皮送達するための方法及び配合物 - Google Patents
免疫活性剤を経皮送達するための方法及び配合物 Download PDFInfo
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- JP2008507590A JP2008507590A JP2007527244A JP2007527244A JP2008507590A JP 2008507590 A JP2008507590 A JP 2008507590A JP 2007527244 A JP2007527244 A JP 2007527244A JP 2007527244 A JP2007527244 A JP 2007527244A JP 2008507590 A JP2008507590 A JP 2008507590A
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- A61K39/12—Viral antigens
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- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral antigens
- A61K39/145—Orthomyxoviridae, e.g. influenza virus
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- A—HUMAN NECESSITIES
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Abstract
Description
本明細書中で使用する用語「経皮」とは、局所治療又は全身治療のための、皮膚内へ且つ/又は皮膚を通った薬剤の送達を意味する。
当分野で知られているように、接線流入濾過(TFF)によりダイアフィルトレーション及び濃縮を同時に行うことが可能である。したがって、Pellicon XL、再生セルロース膜(Millipore、50cm2、30kD分子量カットオフ)を備えたTFFシステム(Millipore、Labscale)をワクチン原材料のダイアフィルトレーション及び濃縮に用いた。ワクチン溶液の体積は最初の体積の1/20〜1/50まで減少し、HA濃度が5〜10mgのHA/mLまで増加した。緩衝液の交換及び濃縮のために緩衝溶液も加えた。
さらなる研究では、赤血球凝集素の一価のB/Victoria株を用いて2つの配合物を調製した。配合物Cは抗原及びスクロースを1:4の重量比で含んでいた。配合物Dは抗原、トレハロース及びマンニトールを1:2:2の重量比で含んでいた。どちらの配合物も噴霧乾燥し(SD)、凍結乾燥し(FD)、その後、BCAタンパク質分析及びSRID(一元放射性免疫拡散)力価分析に供した。
Claims (32)
- バルク免疫活性剤を提供するステップと、
前記バルク免疫活性剤を接線流入濾過に供して免疫活性剤溶液を提供するステップと、
少なくとも1つの賦形剤を前記免疫活性剤溶液に加えるステップと、
前記免疫活性剤溶液を噴霧乾燥して免疫活性剤生成物を形成するステップと
を含む、免疫活性剤の配合方法。 - 前記免疫活性剤溶液を噴霧乾燥するステップを約60℃〜約250℃の範囲の入口温度で実施する、請求項1に記載の方法。
- 前記免疫活性剤溶液を噴霧乾燥するステップを約100℃〜約200℃の範囲の入口温度で実施する、請求項2に記載の方法。
- 前記免疫活性剤溶液を噴霧乾燥するステップを約0.5mL/分〜30mL/分の範囲の供給速度で実施する、請求項1に記載の方法。
- 前記免疫活性剤溶液を噴霧乾燥するステップを約2mL/分〜10mL/分の範囲の供給速度で実施する、請求項4に記載の方法。
- 前記免疫活性剤が少なくとも12カ月の室温安定性を保つ、請求項1に記載の方法。
- 前記免疫活性剤が少なくとも約70%の力価を保持する、請求項1に記載の方法。
- 前記免疫活性剤が少なくとも約80%の力価を保持する、請求項9に記載の方法。
- 前記免疫活性剤がインフルエンザワクチンを含む、請求項1に記載の方法。
- 前記免疫活性剤がスプリットバリオンインフルエンザワクチンを含む、請求項9に記載の方法。
- 前記免疫活性剤が赤血球凝集素を含む、請求項9に記載の方法。
- 前記免疫活性剤がウイルス、細菌、タンパク質系ワクチン、多糖系ワクチン、及び核酸系ワクチンからなる群から選択された抗原を含む、請求項1に記載の方法。
- 前記免疫活性剤がタンパク質、複合多糖、オリゴ糖、及びリポタンパク質からなる群から選択された抗原を含む、請求項1に記載の方法。
- 前記免疫活性剤が、百日咳菌(Bordetella pertussis)(組換えPTワクチン−無細胞性)、破傷風菌(Clostridium tetani)(精製、組換え)、ジフテリア菌(Corynebacterium diptheriae)(精製、組換え)、サイトメガロウイルス(糖タンパク質サブユニット)、A群連鎖球菌(Group A streptococcus)(糖タンパク質サブユニット、破傷風トキソイドを有する複合糖質A群多糖、毒素サブユニット担体に連結したMタンパク質/ペプチド、Mタンパク質、多価型特異的エピトープ、システインプロテアーゼ、C5aペプチダーゼ)、B型肝炎ウイルス(組換えPre−bS1、Pre−S2、S、組換えコアタンパク質)、C型肝炎ウイルス(組換え発現させた表面タンパク質及びエピトープ)、ヒトパピローマウイルス(カプシドタンパク質、TA−GN組換えタンパク質L2及びE7[HPV−6由来]、HPV−11由来のMEDI−501組換えVLP L1、4価の組換えBLP L1[HPV−6由来]、HPV−11、HPV−16、及びHPV−18、LAMP−E7[HPV−16由来])、在郷軍人病菌(Legionella pneumophila)(精製細菌表面タンパク質)、髄膜炎菌(Neisseria meningitides)(破傷風トキソイドを有する複合糖質)、緑膿菌(Pseudomonas aeruginosa)(合成ペプチド)、風疹ウイルス(合成ペプチド)、B髄膜炎菌OMPと複合した肺炎連鎖球菌(Streptococcus pneumoniae)(複合糖質[1、4、5、6B、9N、14、18C、19V、23F]、CRM197と複合した複合糖質[4、6B、9V、14、18C、19F、23F]、CRM1970と複合した複合糖質[1、4、5、6B、9V、14、18C、19F、23F]、梅毒トレポネーマ(Treponema pallidum)(表面リポタンパク質)、水痘帯状疱疹(Varicella zoster)ウイルス(サブユニット、糖タンパク質)、並びにコレラ菌(Vibrio cholerae)(複合リポ多糖)からなる群から選択される、請求項1に記載の方法。
- 免疫活性剤が、インフルエンザワクチン、ライム病ワクチン、狂犬病ワクチン、麻疹ワクチン、流行性耳下腺炎ワクチン、水痘ワクチン、天然痘ワクチン、肝炎ワクチン、百日咳ワクチン、及びジフテリアワクチンからなる群から選択される、請求項1に記載の方法。
- 免疫応答賦活アジュバントを前記免疫活性剤溶液に加えるステップをさらに含む、請求項1に記載の方法。
- 前記免疫応答賦活アジュバントが、リン酸アルミニウムゲル、水酸化アルミニウム、藻類グルカン:β−グルカン、コレラ毒素Bサブユニット、CRL1005:平均値x=8及びy=205を有するABAブロックポリマー、γインスリン:直鎖状(枝分かれしていない)β−D(2−>1)ポリフルクトフラノキシル−α−D−グルコース、ゲルブ(Gerbu)アジュバント:N−アセチルグルコサミン−(β1−4)−N−アセチルムラミル−L−アラニル−D−グルタミン(GMDP)、ジメチルジオクタデシルアンモニウムクロライド(DDA)、亜鉛L−プロリン塩錯体(Zn−Pro−8)、イミキモド(1−(2−メチルプロピル)−1H−イミダゾ[4,5−c]キノリン−4−アミン、ImmTher(商標):N−アセチルグルコアミニル−N−アセチルムラミル−L−Ala−D−isoGlu−L−Ala−グリセロールジパルミテート、MTP−PEリポソーム:C59H108N6O19PNa−3H2O(MTP)、ムラメチド(Murametide):Nac−Mur−L−Ala−D−Gln−OCH3、プルラン:β−グルカン、QS−21、S−28463:4−アミノ−a,a−ジメチル−1H−イミダゾ[4,5−c]キノリン−1−エタノール、サルボ(salvo)ペプチド:VQGEESNDK・HCl(IL−1βのペプチド163〜171)、及びスレオニル−MDP(Termurtide(商標)):N−アセチルムラミル−L−スレオニル−D−イソグルタミン、インターロイキン−18、インターロイキン−2、インターロイキン−12、インターロイキン−15、DNAオリゴヌクレオチド、CpG含有オリゴヌクレオチド、免疫調節性リンホカインをコードしている核酸配列、γインターフェロン、並びにNFκB調節シグナル伝達タンパク質からなる群から選択される、請求項16に記載の方法。
- 前記賦形剤が炭水化物、単糖、二糖、シクロデキストリン、多糖類、デンプン、セルロース、塩、リン酸ナトリウム、リン酸カルシウム、硫酸カルシウム、硫酸マグネシウム、クエン酸、酒石酸、グリシン、ポリエチレングリコール(PEG)、プルロニック、及び界面活性剤からなる群から選択される、請求項1に記載の方法。
- 前記免疫活性剤溶液が、非還元糖、多糖類、還元糖、及びシクロデキストリンからなる群から選択された安定化剤をさらに含む、請求項1に記載の方法。
- 複数の角質層穿孔微小突起を有する微小突起メンバーであって、その上に噴霧乾燥した免疫活性剤を含む生体適合性被覆膜が配置された微小突起メンバーを含む、免疫活性剤を経皮送達する装置。
- 前記免疫活性剤がインフルエンザワクチンを含む、請求項20に記載の装置。
- 前記免疫活性剤がスプリットバリオンインフルエンザワクチンを含む、請求項13に記載の装置。
- 複数の角質層穿孔微小突起を有する微小突起メンバー、及び噴霧乾燥した免疫活性剤を含む薬剤配合物を受け入れるように適応させたリザバーを含む、免疫活性剤を経皮送達する装置。
- 前記免疫活性剤がインフルエンザワクチンを含む、請求項23に記載の装置。
- 前記免疫活性剤がスプリットバリオンインフルエンザワクチンを含む、請求項23に記載の装置。
- 複数の微小突起を有する微小突起メンバーを提供するステップと、
バルク免疫活性剤を提供するステップと、
前記バルク免疫活性剤を接線流入濾過に供して第1の免疫活性剤溶液を提供するステップと、
少なくとも1つの賦形剤を前記第1の免疫活性剤溶液に加えるステップと、
前記第1の免疫活性剤溶液を噴霧乾燥してワクチン生成物を形成するステップと、
前記ワクチン生成物を第1の溶液で再構成して第2の免疫活性剤溶液を形成するステップと、
前記第2の免疫活性剤溶液を前記微小突起メンバーに適用するステップと、
前記被覆微小突起メンバーを対象の皮膚に適用するステップと
を含む、免疫活性剤の送達方法。 - 前記第2の免疫活性剤溶液を含む生体適合性被覆膜を形成するステップをさらに含み、前記第2の免疫活性剤溶液を前記微小突起メンバーに適用するステップが前記微小突起メンバーに前記生体適合性被覆膜を被覆することを含む、請求項26に記載の方法。
- 前記微小突起メンバーがリザバーをさらに含み、前記第2の免疫活性剤溶液を含む薬剤配合物を形成するステップをさらに含み、前記第2の免疫活性剤溶液を前記微小突起メンバーに適用するステップが、前記リザバーに前記薬剤配合物を装填するステップを含む、請求項26に記載の方法。
- 前記免疫活性剤がインフルエンザワクチンを含む、請求項26に記載の方法。
- 前記免疫活性剤がスプリットバリオンインフルエンザワクチンを含む、請求項29に記載の方法。
- 前記被覆微小突起メンバーを対象の皮膚に適用するステップにより約45μgの前記免疫活性剤を送達する、請求項29に記載の方法。
- 前記被覆微小突起メンバーを対象の皮膚に適用するステップにより前記免疫活性剤の少なくとも約50%をAPCが豊富な表皮層に送達する、請求項26に記載の方法。
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