JP2018533414A - オキシステロールの薬物負荷を有するインプラント及びその使用法 - Google Patents
オキシステロールの薬物負荷を有するインプラント及びその使用法 Download PDFInfo
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- JP2018533414A JP2018533414A JP2018521850A JP2018521850A JP2018533414A JP 2018533414 A JP2018533414 A JP 2018533414A JP 2018521850 A JP2018521850 A JP 2018521850A JP 2018521850 A JP2018521850 A JP 2018521850A JP 2018533414 A JP2018533414 A JP 2018533414A
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- implant
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- bone
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- oxysterol
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Abstract
Description
[0001]本願は、2015年7月10日出願の米国特許出願第14/796,601号、発明の名称「オキシステロールの高薬物負荷を有するインプラント及びその使用法(IMPLANTS HAVING A HIGH DRUG LOAD OF AN OXYSTEROL AND METHODS OF USE)」の一部継続出願である。
[0005]骨欠損の治療に様々な材料が提案されている。従来の骨移植のほか、いくつかのマトリックス材料を含むいくつかの合成骨移植片代替物が使用又は探求されている。
[0010]一部の態様において、構造:
[0026]本明細書及び添付の特許請求の範囲で使用されている単数形の“a”、“an”、及び“the”は、一つの指示対象に明示的かつ明白に限定されていない限り、複数の指示対象も含む。従って、例えば、“あるインプラント(an implant)”と言う場合、1個、2個、3個又はそれ以上のインプラントを含む。
[0039]式中、R1は、単独の場合は水素であるか、又はR2と一緒になった場合は(C5〜C14)アリーレノであり;R2は、単独の場合は水素であるか、又はR1と一緒になった場合は(C5〜C14)アリーレノである。
[0069]本明細書中で使用されている“P−15”という用語は、I型コラーゲンの細胞結合ドメインと同一の合成15アミノ酸残基を意味する。P−15の主な作用様式は、細胞が基質に接着できるようにアンカーを提供することである。例えば、P−15は、無機ウシ骨ミネラル(anorganic bovine bone mineral,ABM)に吸着できるので、細胞接着とその後の細胞活性化を増強する。
[0071]以下のセクション見出しは限定されるべきでなく、他のセクション見出しと交換することもできる。
[0072]一部の態様において、インプラントは、高い無機物含量又は同種移植片含量を有しながら、なお結合及び凝集性でありうる堅固なインプラントでありうる。一部の態様において、骨成長を促進するために骨欠損部又はその近傍に適合するように設計された耐圧縮性インプラントを提供する。耐圧縮性インプラントは、インプラントの約0.1wt%〜約20wt%の量の生分解性ポリマー及びインプラントの約5wt%〜約90wt%の量の凍結乾燥オキシステロールを含む。
[0078]一部の態様において、Rは、アルキル、ヘテロアルキル、アルカニル、へテロアルカニル、アルケニル、ヘテロアルケニル、アルキニル、ヘテロアルキニル、アルキルジイル、ヘテロアルキルジイル、アルキレノ、ヘテロアルキレノ、アリール、アリールジイル、アリーレノ、アリールアリール、ビアリール、アリールアルキル、ヘテロアリール、ヘテロアリールジイル、ヘテロアリーレノ、ヘテロアリール−ヘテロアリール、ビヘテロアリール、ヘテロアリールアルキル又はそれらの組合せを含む。一部の態様において、R置換基は、(C1〜C20)アルキル又はヘテロアルキル、(C2〜C20)アリール又はヘテロアリール、(C6〜C26)アリールアルキル又はヘテロアルキル及び(C5〜C20) アリールアルキル又はヘテロアリール−ヘテロアルキル、(C4〜C10)アルキルジイル又はヘテロアルキルジイル、又は(C4〜C10)アルキレノ又はヘテロアルキレノを含む。R置換基は、環状でも非環状でも、分枝でも非分枝でも、置換でも非置換でも、芳香族でも、飽和でも不飽和鎖でも、又はそれらの組合せでもよい。一部の態様において、R置換基は脂肪族基である。一部の態様において、R置換基は環状基である。一部の態様において、R置換基はヘキシル基である。
[0081]又はその薬学的に許容可能な塩、溶媒和物もしくは水和物を含むインプラント又はマトリックスである。Oxy133は、Oxy133又はその薬学的に許容可能な塩、溶媒和物もしくは水和物と、薬学的に許容可能な担体を含む生物活性組成物又は医薬組成物として使用できる。Oxy133は、IUPAC名(3S,5S,6S,8R,9S,10R,13S,14S,17S)−17−((S)−2−ヒドロキシオクタン−2−イル)−10,13−ジメチルヘキサデカヒドロ−1H−シクロペンタ[a]フェナントレン−3,6−ジオールを有する。
[0093]一部の態様において、オキシステロール、例えばOxy133は高度に精製されている。一部の態様において、Oxy133は結晶化又は再結晶化されうる。一部の態様において、精製Oxy133は、以下に示すように、アセトン/水の3:1混合物からOxy133を再結晶化することにより形成される。
[00102]一部の態様において、インプラントは、細胞をインビボで3次元の組織形成過程に誘導するための組織足場を提供するマトリックスを含む。一部の態様において、インプラントは骨の内部成長を促進するための多孔質足場を提供する。マトリックスは、形態学上、細胞移動を誘導するので、細胞はマトリックスの内部又はマトリックスを覆うように移動できる。その後、細胞は増殖し、新しい組織を合成し、骨及び/又は軟骨を形成できる。一部の態様において、一つ又は複数の組織マトリックスは互いに積み重ねられる。
[00120]乾燥粘着塊は、様々な流体で湿らせるか又は水和することにより、展性及び成形可能インプラントにすることができる。一部の態様において、マトリックスは、無菌水、生理食塩水、塩化ナトリウム、デキストロース、乳酸リンゲル液、PBS、血液、骨髄穿刺液、骨髄画分又はそれらの組合せで湿らせる。マトリックスを湿らせることができる流体の量は、約0.25、0.5、1.0、1.5、2.0、2.5、3.0、3.5、4.0、4.5、5.0、5.5、6.0、6.5、7.0、7.5、8.0、8.5、9.0、9.5、10.0、10.5、11.0、11.5、12.0、12.5、13.0、13.5、14.0、14.5、15.0、15.5、16.0、16.5、17.0、17.5、18.0、18.5、19.0、19.5、20.0、20.5、21.0、21.5、22.0、22.5、23.0、23.5、24.0、24.5、25.0、25.5、26.0、26.5、27.0、27.5、28.0、28.5、29.0、29.5、30.0、30.5、31.0、31.5、32.0、32.5、33.0、33.5、34.0、34.5、35.0、35.5、36.0、36.5、37.0、37.5、38.0、38.5、39.0、39.5、40.0、40.5、41.0、41.5、42.0、42.5、43.0、43.5、44.0、44.5、45.0、45.5、46.0、46.5、47.0、47.5、48.0、48.5、49.0、49.5〜約50.0mlなどである。
[00133]一部の態様において、インプラントは、生分解性ポリマー、無機粒子及び骨形成を促進するためのオキシステロール、例えばOxy133を含む。使用中、Oxy133は骨状態に対する治療を提供する。Oxy133は、骨形成、骨芽細胞分化、骨形態形成及び/又は骨増殖を促進する。この治療薬は、開放骨折及び癒着不能のリスクの高い骨折を治療するため、及び脊髄障害のある対象に投与できる。すなわち、Oxy133は、脊椎固定を誘導でき、変性円板疾患や腰椎又は頸椎を冒す関節炎の治療に役立ちうる。
[00139]一部の態様において、マトリックスは、例えばコラーゲンなどの生分解性ポリマーを含む。一部の態様において、生分解性ポリマーは架橋されている。コラーゲンの例は、ヒト又はヒト以外(ウシ、ヒツジ、魚、及び/又はブタ)のコラーゲン、カルボキシメチルセルロース(CMC)、アルギネートのほか、組換えコラーゲン又はそれらの組合せなどである。適切なコラーゲンの例は、ヒトコラーゲンI型、ヒトコラーゲンII型、ヒトコラーゲンIII型、ヒトコラーゲンIV型、ヒトコラーゲンV型、ヒトコラーゲンVI型、ヒトコラーゲンVII型、ヒトコラーゲンVIII型、ヒトコラーゲンIX型、ヒトコラーゲンX型、ヒトコラーゲンXI型、ヒトコラーゲンXII型、ヒトコラーゲンXIII型、ヒトコラーゲンXIV型、ヒトコラーゲンXV型、ヒトコラーゲンXVI型、ヒトコラーゲンXVII型、ヒトコラーゲンXVIII型、ヒトコラーゲンXIX型、ヒトコラーゲンXXI型、ヒトコラーゲンXXII型、ヒトコラーゲンXXIII型、ヒトコラーゲンXXIV型、ヒトコラーゲンXXV型、ヒトコラーゲンXXVI型、ヒトコラーゲンXXVII型、及びヒトコラーゲンXXVIII型、又はそれらの組合せなどであるが、これらに限定されない。コラーゲンは、さらに、上記コラーゲン型のいずれかのヘテロ−及びホモ−三量体も含みうる。一部の態様において、コラーゲンは、ヒトコラーゲンI型、ヒトコラーゲンII型、ヒトコラーゲンIII型のヘテロ−又はホモ−三量体、又はそれらの組合せを含む。様々な態様において、コラーゲンは架橋されていてもよい。
[00154]一部の態様において、マトリックスは、例えばセラミックスなどの無機粒子を含む。一部の態様において、マトリックス中の粒子は、再吸収可能なセラミック、骨、合成分解性ポリマー、ヒアルロン酸、キトサン又はそれらの組合せを含む。一部の態様において、粒子は、皮質骨、海綿骨、及び/又は皮質海綿骨、同種骨、異種骨、又は遺伝子組換え骨の組織を含む。骨成分は、完全灰化(fully mineralized)でも、又は部分もしくは完全脱灰でも、又はそれらの組合せでもよい。骨成分は、完全灰化又は部分もしくは完全脱灰骨から成りうる。
[00169]一部の態様において、インプラントは、インプラントの膨潤を促進するために、例えば膨張相などの材料を含みうる。膨張相は、流体(例えば、生理食塩水、水、体液など)を取り込むと膨潤するポリマーを含むので、インプラントの体積が増大する。これによってインプラントは長期間所定の位置にさらに保持される。
[00178]一部の態様において、マトリックスは、インプラントの全重量を基にして約0.1wt%〜約20wt%の量の生分解性ポリマーを含む耐圧縮性マトリックスを形成し;そしてオキシステロールをマトリックス上にインプラントの全重量を基にして約5wt%〜約90wt%の量で添加し、その場合にオキシステロールはマトリックス上に凍結乾燥されることによって製造される。一部の態様において、オキシステロールがマトリックス上に凍結乾燥される前に、オキシステロールはエタノール中に溶解される及び/又はインプラントは架橋される。一部の態様において、オキシステロールはマトリックス上に凍結乾燥(lyophilization)によって凍結乾燥(freeze-dried)される。
[00190]一部の態様において、治療薬(オキシステロール(一つ又は複数の成長因子を含むこともある)など)は、インプラントの表面又は内部に、手作業、スプレー、含浸、注射、刷毛塗り、凍結乾燥及び/又は注入によって配置し、インプラントに染み込ませることができる。
[00196]一部の態様において、インプラントはさらに、オキシステロールと一つ又は複数の追加の治療薬、例えば一つ又は複数の成長因子、スタチンなどを含む。マトリックス内に包含される単離された骨誘導因子は典型的には無菌である。非制限的方法において、無菌性は、例えば無菌ろ過膜(例えば0.2ミクロンの膜又はフィルター)を通すろ過によって容易に達成される。一態様において、マトリックスは、骨形成タンパク質(“BMP”)のファミリーの一つ又は複数のメンバーを含む骨誘導因子を含む。BMPは、内因性骨組織に対して骨誘導又は成長促進活性を有する、又はプロコラーゲン前駆体として機能すると考えられているタンパク質のクラスである。BMPファミリーの公知メンバーは、BMP−1、BMP−2、BMP−3、BMP−4、BMP−5、BMP−6、BMP−7、BMP−8、BMP−9、BMP−10、BMP−11、BMP−12、BMP−13、BMP−14(GDF−5)、BMP−15、BMP−16、BMP−17、BMP−18、ならびにそれらのポリヌクレオチド又はポリペプチドのほか、それらをコードする成熟ポリペプチド又はポリヌクレオチドなどであるが、これらに限定されない。
キット
[00205]生分解性ポリマー、無機粒子、オキシステロール及びインプラントを投与するためのデバイスは滅菌可能でありうる。様々な態様において、マトリックスの一つ又は複数の成分、及び/又はそれを投与するための医療デバイスは、最終包装時の最終滅菌工程で放射線により滅菌できる。製品の最終滅菌は、個々の製品構成要素を別々に滅菌し、無菌環境で最終的に包装する無菌法などの方法よりも無菌性に対する一段と大きい保証を提供する。
[00214]表1に示す組成を有する第一のインプラント剤を製造した。
[00217]表2に示す組成を有する成形可能インプラント剤を製造した。
[00220]上記実施例1又は2の組成明細に従って組成物を製造した。組成物は無菌水で湿らせた。
[00222]上記実施例1又は2の組成明細に従って組成物を製造した。組成物は血液で湿らせた。
[00224]上記実施例1又は2の組成明細に従って組成物を製造した。組成物は骨髄穿刺液で湿らせた。
[00226]本明細書中に記載の、Oxy133、コラーゲン、及びセラミック粒子を含有するマトリックスの乾燥組成物を製造し、1.4ccのヘパリン化ウサギ血で湿らせた。マトリックスを丸めて球形及び円筒形に成形した。成形マトリックスにわずかな亀裂が観察されたので、追加のヘパリン化ウサギ血0.3ccをマトリックスに添加した。湿潤流体の追加により、マトリックスは亀裂なしに成形できた。
[00228]本明細書中に記載の、Oxy133、コラーゲン、セラミック粒子、及びカルボキシメチルセルロースを含有するマトリックスの乾燥組成物を製造した。乾燥マトリックスをヘパリン化ウサギ血で増分的に(少しずつ量を増やして)湿らせた。約1.3cc未満の血液量ではマトリックスを適切に湿らせるのに効果的でないことが分かった。1.43ccの血液の添加後、マトリックスを丸めて凝集性の球形及び円筒形に成形したが、亀裂は見られなかった。カルボキシメチルセルロースは、マトリックスに凝集性及び接着性を提供することが見出された。
[00230]本明細書中に記載の、Oxy133、コラーゲン、及びセラミック粒子を含有するマトリックスの乾燥組成物を製造し、1.46ccの生理的に許容可能な食塩水で湿らせた。新鮮な骨移植片をウサギの腸骨稜から得た。骨片を徐々にマトリックスに添加した。マトリックスは凝集的に丸められて球形及び円筒形に成形されたが、2.0ccの量までの骨移植片の添加では、亀裂は見られなかった。
[00232]本明細書中に記載の、Oxy133、コラーゲン及びセラミックを含有するマトリックスの乾燥組成物を製造し、無菌水で湿らせて、図6に示すようにラットの脊椎に移植した。湿らせたマトリックスをカミソリの刃で半分に切断し、2等分にした。2個のインプラントを挿入前に円筒形に成形し、各被験動物の後側方腔に両側に配置した。各インプラントは20mgのOxy133を含有していた。X線写真を、手術のおよそ10分後、4週間後、及び8週間後に撮影した。図6に示されているように、4週間及び8週間時点で、インプラントはL3(第3腰椎)〜L5の横突起間への骨の架橋を促進した。固定は8週間の犠牲時に手触診により試験した。インプラントを配置した脊椎の部分は手触診による評価で限定的な柔軟性を示しており、固定が起きたことを示していた。この研究で、記載のインプラント剤の移植を受けたラット脊椎の5/5(100%)に固定が観察された。インプラントの各側に67mgのOxy133を有するインプラントについても同様の結果が得られた。
[00234]本明細書中に記載の、Oxy133、コラーゲン及びセラミックを含有するマトリックスの乾燥組成物を製造し、無菌水で湿らせて、図6に示すようにラットの脊椎に移植した。湿らせたマトリックスをカミソリの刃で半分に切断し、2等分にした。2個のインプラントを挿入前に円筒形に成形し、各被験動物の後側方腔に両側に配置した。各インプラントは125mgのOxy133を含有していた。X線写真を、手術のおよそ10分後、4週間後、及び8週間後に撮影した。図6に示されているように、4週間及び8週間時点で、インプラントはL3〜L5の横突起間への骨の架橋を促進した。固定は8週間の犠牲時に手触診により試験した。インプラントを配置した脊椎の部分は手触診による評価で限定的な柔軟性を示しており、固定が起きたことを示していた。この研究で、記載のインプラント剤の移植を受けたラット脊椎の5/5(100%)に固定が観察された。
Claims (18)
- 骨成長を促進するために骨欠損部又はその近傍に適合するように設計された耐圧縮性インプラントであって、前記耐圧縮性インプラントは、インプラントの約0.1wt%〜約20wt%の量の生分解性ポリマー及びインプラントの約5wt%〜約90wt%の量の凍結乾燥オキシステロールを含む耐圧縮性インプラント。
- インプラントが、インビボで少なくとも30日間、任意の一方向に約10%を超えて圧縮されず、さらに、自家移植片、同種移植片及び/又は異種移植片骨粒子を含む、請求項1に記載のインプラント。
- インプラントが、BMP及びP−15をさらに含む、請求項1に記載のインプラント。
- インプラントが、インプラントの約0.1wt%〜約75wt%の量の無機粒子をさらに含み、(i)無機粒子は生分解性ポリマー全体に均一に又は不均一に分布し;及び/又は(ii)オキシステロールは生分解性ポリマー全体に均一に又は不均一に分布している、請求項1に記載のインプラント。
- 生分解性ポリマーがインプラントの約8.0wt%〜約13wt%の量であり、オキシステロールがインプラントの約5wt%〜約80wt%の量であり、そして無機粒子がインプラントの約7.0wt%〜約25wt%の量である、請求項4に記載のインプラント。
- (i)インプラントが架橋され、オキシステロールが約1mg/cc〜約1.0g/ccの量でインプラントに負荷されているか、又は(ii)インプラントは架橋されておらず、オキシステロールが約1mg/cc〜約1.0g/ccの量でインプラントに負荷されている、請求項1に記載のインプラント。
- 生分解性ポリマーが、ブタ由来コラーゲン、ヒト由来コラーゲン、ウシ由来コラーゲン、魚由来コラーゲン、ヒツジ由来コラーゲン、組換えコラーゲン、ゼラチン、CMC、アルギネート又はそれらの組合せを含む、請求項1に記載のインプラント。
- (i)無機粒子が、骨粉、脱灰骨粉、多孔質リン酸カルシウムセラミックス、ヒドロキシアパタイト、リン酸三カルシウム、生物活性ガラス又はそれらの組合せを含み;(ii)無機粒子が約125μm〜約750μmの粒径を含み;(iii)無機粒子が約70:75〜約90:10の比率のリン酸三カルシウムとヒドロキシアパタイトを含み;又は(iv)無機粒子が約85:15の比率のリン酸三カルシウムとヒドロキシアパタイトを含む、請求項4に記載のインプラント。
- オキシステロールが、(3S,5S,6S,8R,9S,10R,13S,14S,17S) 17−((S)−2−ヒドロキシオクタン−2−イル)−10,13−ジメチルヘキサデカヒドロ−lH−シクロペンタ[a]フェナントレン−3,6−ジオール(Oxy133)、又はその水和物、溶媒和物、非晶質形、もしくは薬学的に許容可能な塩を含む、請求項1に記載のインプラント。
- 流体が、水、塩化ナトリウム、デキストロース、乳酸リンゲル液、血液、骨髄穿刺液又はそれらの組合せを含む、請求項3に記載のインプラント。
- 骨成長を促進するために骨欠損部位又はその近傍に適合するように設計された移植可能マトリックスであって、マトリックスは、マトリックスの約0.1wt%〜約15wt%の量の架橋生分解性ポリマー及びマトリックスの約5wt%〜約90wt%の量の凍結乾燥オキシステロールを含み、前記オキシステロールは約1mg/cc〜約1.0g/ccの濃度を有する移植可能マトリックス。
- インプラントが、BMP及びP−15をさらに含む、請求項11に記載のマトリックス。
- マトリックスが粘着塊を形成するように設計され、流体で湿らせた後成形可能になる、請求項11に記載のマトリックス。
- マトリックスの約0.1wt%〜約75wt%の量の無機粒子をさらに含む、請求項11に記載のマトリックス。
- 架橋生分解性ポリマーがマトリックスの約8.0wt%〜約13wt%の量であり、オキシステロールがインプラントの約5wt%〜約80wt%の量であり、そして無機粒子がインプラントの約7.0wt%〜約25wt%の量である、請求項14に記載のマトリックス。
- 架橋生分解性ポリマーが、ブタ由来コラーゲン、ヒト由来コラーゲン、ウシ由来コラーゲン、魚由来コラーゲン、ヒツジ由来コラーゲン、組換えコラーゲン、ゼラチン、CMC、アルギネート又はそれらの組合せを含む、請求項11に記載のマトリックス。
- (i)無機粒子が、骨粉、脱灰骨粉、多孔質リン酸カルシウムセラミックス、ヒドロキシアパタイト、リン酸三カルシウム、生物活性ガラス又はそれらの組合せを含み;(ii)無機粒子が約125μm〜約750μmの粒径を含み;(iii)無機粒子が約70:75〜約90:10の比率のリン酸三カルシウムとヒドロキシアパタイトを含み;又は(iv)無機粒子が約85:15の比率のリン酸三カルシウムとヒドロキシアパタイトを含む、請求項14に記載のマトリックス。
- オキシステロールが、(3S,5S,6S,8R,9S,10R,13S,14S,17S) 17−((S)−2−ヒドロキシオクタン−2−イル)−10,13−ジメチルヘキサデカヒドロ−lH−シクロペンタ[a]フェナントレン−3,6−ジオール(Oxy133)、又はその水和物、溶媒和物、非晶質形、もしくは薬学的に許容可能な塩を含む、請求項11に記載のマトリックス。
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