JP2022070924A - アルギン酸をベースとする抗菌性化合物を使用して炎症と疾患を阻害するための組成物及び方法 - Google Patents
アルギン酸をベースとする抗菌性化合物を使用して炎症と疾患を阻害するための組成物及び方法 Download PDFInfo
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- JP2022070924A JP2022070924A JP2022017393A JP2022017393A JP2022070924A JP 2022070924 A JP2022070924 A JP 2022070924A JP 2022017393 A JP2022017393 A JP 2022017393A JP 2022017393 A JP2022017393 A JP 2022017393A JP 2022070924 A JP2022070924 A JP 2022070924A
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- alginic acid
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Abstract
Description
本出願は、2013年12月19日に出願された米国仮出願第61/918,445号の利益を主張するものであり、その内容は、その全体において参照により本明細書に組み込まれる。
トール様受容体(TLR)は、潜在的に有害な物質、特に微生物由来の化学物質への曝露に対する、免疫系の初期の警告兆候(warning sign)である。具体的に、TLRは、細菌、原生動物、菌類、及びウィルスに存在する、病原体に関連する分子パターン(PAMP)と呼ばれる分子構造に結合する。活性化の後、TLRは、活性化されたB細胞の核因子κ軽鎖エンハンサー(NFkB)を含む、炎症及び細胞の免疫防御を活性化する、多数の生化学的なカスケードを引き起こす。NFkBは、マスター遺伝子のレギュレータであり、その活性化は、炎症、TNFアルファ、IL-1、及び他のインターロイキンを含む、多くの炎症性メディエータ(mediatory)及び抗炎症性サイトカインの合成の増加を結果としてもたらす。多くのウィルスのために、典型的に微生物感染に対する免疫防御を支援する、炎症性の経路の活性化は、代わりに、感染性を増強する。HIV、肝炎、及びHSVを含む特定のウィルスは、NFkBの活性化が宿主細胞を感染させることを要求すると、現在知られている。例えば、活性化の後、NFkBは、統合されたHIVゲノムの転写を始めるために、HIV末端反復配列上の部位に結合する。(Pande and Ramos,Curr.Med.Chem.,vol.10,no.16,pgs.1603-15(2003)を参照)。事実上、身体自体の自然な反応は、ウィルスの感染性に起因している。
多くの性活動の結果、光顕レベルでの組織に対する身体外傷がもたらされる。解剖学的なバリアの破壊の後、例えば粘膜、好中球は、肥満細胞などの炎症細胞により放出された様々なサイトカインにより引きつけられる。好中球は食作用により損傷を受けた細胞を呑み込み、そのプロセスにおいて、健康な周囲の細胞に対して有毒な多量の活性酸素種(ROS)を生成且つ放出する。ROSは、細胞の抗酸化剤、特にグルタチオンに反応する。ROSへの曝露の後、還元グルタチオン(GSH)はその酸化した状態(GSSG)に変わる。細胞のレベルの酸化型グルタチオンの細胞レベルの増加は、NFkBの活性化を引き起こす。上述のように、NFkBの活性化はウィルス性STDの感染症を促進する。
アルギン酸塩(alginate)は、褐藻類から抽出することができる天然高分子である。該天然高分子は、二糖類、1、4-架橋β-D-マンヌロン酸(M)及びα-L-グルロン酸(G)で構成される。前記天然高分子は、連続するM残基のブロック、連続するD残基のブロック、又は代替的なD及びM残基で構成され得る。M:Gの比率はソースに依存して異なる。最も商業上利用可能なアルギン酸塩は、14-31%の間のG含量率を持つが、Laminaria hyperboreanのアルギン酸塩は60%のG含量率を持つ。より多くの定義された化学構造と物理的性質を備えたアルギン酸塩は、細菌の生合成を使用して得ることができる。しかし、細菌のアルギン酸塩は、C2及び/又はC3においてO-アセチル基を有する。アセチル基は、4-57%の間で異なるアセチル化の程度を備えたマヌロン酸残基に排他的に関連する。(Donati and Paoletti,“Material Properties of Alginates,”in Alginates:Biology and Applications:Biology and Applications, Rehm,ed.,Springer Dordrecht Heidelburg, London,UK,2009,page 10及び“The History of Aglinate Chemistry-Bacterial,”Cyber Colloids,LTD,http://www.cybercolloids.net/information/technical-articles/history-alginate-chemistry-bacterialを参照)。アセチル基は、陽イオン結合の能力と選択性を減少させ、溶液粘度を増加させ、水収容力を増強し、アルギン酸リアーゼによる分解を保護する。(Flemming and Wingender,“The Crucial Role of Extracellular Polymeric Substances in Biofilms,”in Biofilms in Wastewater Treatment:An Interdisciplinary Approach,Wuertz,Bishop,Wilderer,eds.,IWA Publishing,London,UK 2003,page 184を参照)。アルギン酸塩は典型的に、アルギン酸塩を形成するためにアルカリ溶液と塩を使用して、褐藻類から抽出される。アルギン酸塩は更に、アルギン酸を形成するために酸により処理され得る。
テノホビル(その誘導体、アナログ、プロドラッグ、及び塩を含む)は、逆転写酵素を遮断する、ヌクレオチドアナログ逆転写酵素阻害剤(NtRTI)として知られる抗レトロウィルス薬の分類に属する。テノホビルは、化学名1-(6-アミノプリン-9-イル)プロパン-2-イルオキシメチルホスホン酸[CAS登録番号:147127-20-6]を持つ。テノホビルは、Gilead Sciences,Inc.,(Foster City,CA)などから市販で入手可能である。テノホビルの構造は以下のように示される:
1つの実施形態において、上述の特異的なアルギン酸の亜群は、酸緩衝避妊薬の一部であり得る。そのような酸緩衝避妊薬の限定しない1つの例は、酸性型(Amphora(登録商標)ゲルとしても知られる(米国特許第6,706,276号、WO01/66084))であり、それは、身体の開口部(例えば膣)に配されると、射精液との接触後にマトリックスを形成し、それにより、精子、及び/又は、STD並びにSTIを引き起こす微生物を補足して不活性化する、ゲルである。1つの通常の実施形態において、酸緩衝避妊薬は、(1)マトリックスを形成する化合物、(2)生体付着性化合物、及び(3)乳酸を含む。アルギン酸、カラギーナン、又はキトサンなどの幾つかの化合物は、マトリックスを形成する化合物及び生体付着性化合物の両方として作用することができる。
1つの実施形態において、医薬担体は水である。経腟分娩に適した他の薬学的に許容可能な担体は周知であり、水の代わりに使用することができる。適切な薬学的に許容可能な担体の一例は、白色ワセリンなどのワセリンである。
付加的な随意の賦形剤は、緩衝剤、増粘剤、保水剤、及び防腐剤などの本開示の組成物の中で使用されてもよい。適切な緩衝剤は、例えば、乳酸、クエン酸、酸性酒石酸カリウム、酒石酸水素カリウム、安息香酸、ソルビン酸、フマル酸、アスコルビン酸、ステアリン酸、オレイン酸、酒石酸、エデト酸エチレンジアミン四酢酸、酢酸、リンゴ酸などを含むが、これらに限定されない。適切な増粘剤は、例えば、キサンタンガム、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、カルボキシルメチルセルロースナトリウム、キトサン、ポリカルボフィル、カルボポール、ジェランガム、ポロクサマー、カラギーナン、イオタカラギーナンなどを含むが、これらに限定されない。適切な保水剤は、例えば、グリセロール、ポリエチレングリコール、プロピレングリコール、ソルビトール、トリアセチンなどを含むが、これらに限定されない。1つの典型的な実施形態において、グリセロールは、膣の内に配された場合にゲル上での乾燥皮膜の形成を防ぐために使用される。グリセロールは、潤滑剤としても作用するかもしれない。加えて、組成物は防腐剤も含んでもよい。適切な防腐剤は、例えば、安息香酸、安息香酸ナトリウム、メチルパラベン、エチルパラベン、ブチルパラベン、プロピルパラベン、塩化ベンジルアルコニウム、硝酸フェニル水銀、クロルヘキシジンなどを含むが、これらに限定されない。1つの典型的な実施形態において、安息香酸が使用され、それは酸性型ゲルの緩衝能力にも寄与するかもしれない。
医薬組成物は、ゲル、半固体、クリーム、及び/又はローションの形態であってもよい。通常、アルギン酸をベースとする殺菌剤は、膣又は直腸の腔を洗い流すために使用されるゲル、クリーム、ローション、非水溶液又は水溶液として達成され得る、膣及び/又は子宮頚及び/又は直腸の内膜に適用される局所軟膏、及び/又は、膣又は直腸用坐剤として投与されてもよい。他の実施形態において、アルギン酸をベースとする殺微生物剤組成物は、スプレー製剤で投与されてもよい。加えて、アルギン酸をベースとする殺微生物剤組成物は、殺菌剤をしみ込ませたペッサリー、及び女性用並びに男性用コンドームを使用して送達されてもよい。
テノホビルは、287.2(無水)又は305(一水和物として)の分子量を備えたオフホワイト粉末剤である。テノホビルは、酸性のpHでは水溶性でなく、故にアルギン酸と容易に組み合わせることができない。本開示は、アルギン酸とテノホビルを組み合わせるための様々な製造法を提供する。
典型的な実施形態において、本開示は、本明細書に記載されるような、アルギン酸をベースとする抗菌性組成物の局所適用を含む。本開示の文脈において、用語「局所適用」は、皮膚と同様に体腔への適用を含むことを、理解されたい。故に、例えば、前述の組成物は、膣、肛門、直腸、又は口などの体腔に適用される。更に、局所適用は、性交の前、その間、又はその後に行なわれてもよく、性交とは別に行われてもよい。
その最も単純な形態において、アルギン酸をベースとする殺菌剤は、アルギン酸、テノホビル、及び水を含む。また別の形態において、アルギン酸、イオタカラギーナン、テノホビル、及び水を組み合わせる。本明細書に言及される製剤の何れかのために、パモ酸を随意に加えて、テノホビルの可溶性、透過性、又は吸収性を増強する。
その最も単純な形態において、アルギン酸をベースとする殺菌剤及び避妊薬は、アルギン酸、テノホビル、乳酸、及び水を含む。また別の形態において、アルギン酸、キサンタンガム、テノホビル、乳酸、及び水を組み合わせる。また別の形態において、アルギン酸、イオタカラギーナン、テノホビル、乳酸、及び水を組み合わせる。別の形態において、アルギン酸、キサンタンガム、テノホビル、乳酸、クエン酸、安息香酸、酒石酸水素カリウム、グリセリン、及び水を組み合わせる。別の形態において、アルギン酸、イオタカラギーナン、テノホビル、乳酸、クエン酸、安息香酸、酒石酸水素カリウム、グリセリン、及び水を組み合わせる。本明細書に言及される製剤の何れかのために、パモ酸を随意に加えて、テノホビルの可溶性、透過性、又は吸収性を増強する。
この実施例において、酸緩衝避妊薬、アンフォラゲルの避妊能力を評価するために、臨床試験を行った。アンフォラゲルを、非劣性研究において、Conceptrol(登録商標)膣用ゲル(Revive Personal Products Company, Madison, New Jersey)と比較した。Conceptrol(登録商標)膣用ゲルは、2.5mL容量のゲルの中に4%のノノキシノール-9を含有する、局所用ゲルである。18-35歳の間の健康な女性を臨床試験に参加させ、半数にはアンフォラゲル(1回の使用につき5mL用量)を与え、もう半数にはConceptrol(登録商標)ゲル(1回の使用につき2.5mL用量)を与えた。女性に、異性間性交をする2時間前にゲルを膣内に挿入するよう指示した。両方のゲルを7の生理周期の期間にわたり投与し、ユーザーの亜群は、更に6のサイクルの間、アンフォラゲルを使用し続けた。評価期間の終わりに、女性の亜群は、膣及び子宮頚における病変を検知するコルポスコピー、及び膣フローラにおける任意の変化を測定するための試験を受けた。
Claims (29)
- 炎症及び疾患を阻害する組成物であって、該組成物は、1-(6-アミノプリン-9-イル)プロパン-2-イルオキシメチルホスホン酸(テノホビル)又はその生理的に機能的な誘導体、アルギン酸、及び水性ベースの担体を含み;
ここで、アルギン酸は20,000乃至400,000の間の平均分子量を持ち;及び
アルギン酸は、0.25乃至2.0の間のマンヌロン酸塩残基:グルロン酸塩残基の比率を持つ
ことを特徴とする組成物。 - 酸緩衝避妊薬であって、薬学的に許容可能な担体の中に、1-(6-アミノプリン-9-イル)プロパン-2-イルオキシメチルホスホン酸(テノホビル)又はその生理的に機能的な誘導体、アルギン酸、生体付着性化合物、及び乳酸を含み;
ここで、アルギン酸は20,000乃至400,000の間の平均分子量を持ち;及び
アルギン酸は、0.25乃至2.0の間のマンヌロン酸塩残基:グルロン酸塩残基の比率を持つ
ことを特徴とする酸緩衝避妊薬。 - マンヌロン酸塩残基:グルロン酸塩残基の比率は、0.3乃至1.5の間である、ことを特徴とする請求項1又は2に記載の組成物。
- マンヌロン酸塩残基:グルロン酸塩残基の比率は、0.3乃至1の間である、ことを特徴とする請求項1又は2に記載の組成物。
- マンヌロン酸塩残基:グルロン酸塩残基の比率は、0.3乃至0.8の間である、ことを特徴とする請求項1又は2に記載の組成物。
- マンヌロン酸塩残基:グルロン酸塩残基の比率は、0.3乃至0.6の間である、ことを特徴とする請求項1又は2に記載の組成物。
- アルギン酸は、75,000乃至375,000の間の分子量を持つ、ことを特徴とする請求項1又は2に記載の組成物。
- アルギン酸は、100,000乃至300,000の間の分子量を持つ、ことを特徴とする請求項1又は2に記載の組成物。
- アルギン酸は、100,000乃至200,000の間の分子量を持つ、ことを特徴とする請求項1又は2に記載の組成物。
- 乳酸を更に含む、請求項1に記載の組成物。
- 生体付着性化合物を更に含む、請求項1に記載の組成物。
- 緩衝剤、増粘剤、保水剤、又は防腐剤を更に含む、請求項1乃至11の何れか1つに記載の組成物。
- パモ酸又はその塩を更に含む、請求項1乃至12の何れか1つに記載の組成物。
- 担体は水である、ことを特徴とする請求項1乃至13の何れか1つに記載の組成物。
- 乳酸はL-乳酸である、ことを特徴とする請求項2又は9に記載の組成物。
- 炎症及び疾患を阻害する方法であって、請求項1乃至15の何れか1つに係る組成物の有効な量を局所投与する工程を含む、方法。
- 炎症及び疾患を阻害する方法であって、薬学的に許容可能な担体の中に、アルギン酸、生体付着性化合物、及び乳酸を含む化合物を局所投与する工程を含み;
ここで、アルギン酸は20,000乃至400,000の間の平均分子量を持ち;及び
アルギン酸は、0.25乃至2.0の間のマンヌロン酸塩残基:グルロン酸塩残基の比率を持つ
ことを特徴とする方法。 - マンヌロン酸塩残基:グルロン酸塩残基の比率は、0.3乃至1.5の間である、ことを特徴とする請求項17に記載の方法。
- マンヌロン酸塩残基:グルロン酸塩残基の比率は、0.3乃至1の間である、ことを特徴とする請求項17に記載の方法。
- マンヌロン酸塩残基:グルロン酸塩残基の比率は、0.3乃至0.8の間である、ことを特徴とする請求項17に記載の方法。
- マンヌロン酸塩残基:グルロン酸塩残基の比率は、0.3乃至0.6の間である、ことを特徴とする請求項17に記載の方法。
- アルギン酸は、75,000乃至375,000の間の分子量を持つ、ことを特徴とする請求項17に記載の方法。
- アルギン酸は、100,000乃至300,000の間の分子量を持つ、ことを特徴とする請求項17に記載の方法。
- アルギン酸は、100,000乃至200,000の間の分子量を持つ、ことを特徴とする請求項17に記載の方法。
- 疾患は性行為感染症である、ことを特徴とする請求項16乃至24の何れか1つに記載の方法。
- 請求項1乃至15の何れか1つの組成物を製造する方法であって:
(a)1-(6-アミノプリン-9-イル)プロパン-2-イルオキシメチルホスホン酸(テノホビル)又はその生理学的に機能的な誘導体を塩基性溶液に溶かす工程;
(b)pHを中性より下に調整する工程、及び
(c)アルギン酸を加える工程
を含む、方法。 - pHは、乳酸を使用して工程(b)において調整される、ことを特徴とする請求項26に記載の方法。
- 請求項1乃至15の何れか1つに記載の組成物と、該組成物を分配するためのデバイスとを含む、キット。
- 請求項1乃至15の何れか1つに記載の組成物で覆われる、バリアデバイス。
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