JP2018114267A - オキシステロールを含有する成形可能な凍結乾燥インプラント - Google Patents
オキシステロールを含有する成形可能な凍結乾燥インプラント Download PDFInfo
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- JP2018114267A JP2018114267A JP2017223344A JP2017223344A JP2018114267A JP 2018114267 A JP2018114267 A JP 2018114267A JP 2017223344 A JP2017223344 A JP 2017223344A JP 2017223344 A JP2017223344 A JP 2017223344A JP 2018114267 A JP2018114267 A JP 2018114267A
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- implant
- matrix
- bone
- lyophilized
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Abstract
Description
[0004]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。
[0031]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。
[0044]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。
[0074]以下のセクション見出しは制限されるべきでなく、他のセクション見出しと交換することもできる。
[0075]オキシステロールを含有する凍結乾燥インプラントならびにそのようなインプラントの製造法及び使用法を提供する。再水和すると、インプラントは骨欠損内に容易に適合するように成形できる。一部の態様において、凍結乾燥インプラントは、架橋していても又はしていなくてもよい生分解性ポリマー、無機粒子、及び骨原性物質、例えばその内部に組み込まれたオキシステロールを有している。さらに、これらに加えて膨張可能相材料、例えばカルボキシメチルセルロース、アルギネート、ペクチン又はキトサンも含みうる成形可能なインプラントも提供する。一側面において、本願は、生分解性ポリマー、無機粒子、及びオキシステロールを含む活性薬の組合せを含む成形可能な凍結乾燥インプラントを含む移植可能な骨原性医用材料に向けられる。
[0082]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。
[0096]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。
[00105]一部の態様において、インプラントは、オキシステロール(例えばOxy133)のほか、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に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。
[00123]乾燥粘着塊は、様々な流体で湿らせる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又はスラリーにすることができる(その後凍結乾燥できる)。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。
[00136]一部の態様において、インプラントは、生分解性ポリマー、無機粒子及びオキシステロール、例えば骨形成を促進するための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。インプラントは、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に投与でき、そしてまた脊髄障害のある対象にも投与できる。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。
[00142]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XX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。
[00155]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)、部分脱灰、完全脱灰、又はそれらの組合せを含むものであっても、本質的にそれらから成るものであっても、又はそれらから成るものであってもよい。一部の態様において、無機粒子は、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む、本質的にそれらから成る、又はそれらから成る。
[00170]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、例えば膨張可能相などの材料を含みうる。膨張可能相は、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。
[00179]一部の態様において、ステロール、例えば有効量のOxy133を含む凍結乾燥インプラントが提供される。生分解性ポリマー、無機粒子及びオキシステロールを含有するスラリーは凍結乾燥される。生分解性ポリマー、無機粒子及びオキシステロールを一緒に混合してスラリーを形成させるために、任意の適切な液体がスラリーに使用できる。適切な液体は、例えば、水、食塩溶液(例えば生理食塩水)、糖溶液、又はそれらの組合せなどの水性調製物などである。
[00186]一部の態様において、インプラントは、インプラントの全重量を基にして約20wt%〜約90wt%の量のオキシステロールを生分解性ポリマーに添加し(生分解性ポリマーは、約0.1wt%〜約20wt%の量である)、混合物を形成させることにより製造される。インプラントを形成するために多孔質セラミック粒子も混合物に添加されるが、多孔質セラミック粒子はインプラントの全重量を基にして約30wt%〜約99.5wt%の量である。一部の態様において、混合物は、スラリー、パテ、又はペーストを形成するので、これを凍結乾燥する。
[00197]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)をインプラントの表面又は内部に、手作業、混合、スプレー、含浸、注射、刷毛塗り及び/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。
[00200]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、一つ又は複数の成長因子、スタチンなどを含む一つ又は複数の追加の治療薬とを含む。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。
NFカッパB阻害薬、例えばジチオカルバメートなどの抗酸化剤、及びその他の化合物、例えばスルファサラジン、スタチンなどである。
キット
[00208]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。
[00216]表1に示す組成を有する第一の成形可能インプラント剤を製造した。
[00219]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。
[00222]上記実施例1又は2の組成明細に従って成形可能インプラントを製造した。インプラントを流体(例えば無菌水)で湿らせた。インプラントを湿らせた後、流体はインプラントに吸収された。
[00224]上記実施例1又は2の組成明細に従って成形可能インプラントを製造した。インプラントを流体(例えば血液)で湿らせた。インプラントを湿らせた後、流体はインプラントに吸収された。
[00226]上記実施例1又は2の組成明細に従って成形可能インプラントを製造した。インプラントを流体(例えば骨髄穿刺液)で湿らせた。インプラントを湿らせた後、流体はインプラントに吸収された。
[00228]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。
[00230]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。
[00232]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。
[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、記載の製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。
[00236]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、記載の製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。
[00238]以下の表3に記載のように、粉砕架橋ウシコラーゲン、セラミック及びカルボキシメチルセルロース(CMC)を含有する乾燥マトリックスを製造した。Oxy133は、凍結乾燥後に一定量の脱イオン水(同じく表3に掲載)で処理したときに凍結乾燥インプラントが約5wt%、30wt%又は41.5wt%のOxy133を含有するのに足る量で添加された。表3には、凍結乾燥前に乾燥マトリックスを混合するために必要な0.9%食塩溶液の量、ならびに凍結乾燥後に凍結乾燥インプラントに必要な脱イオン水の量も掲載されている。
[00240]以下の表4に記載のように、粉砕架橋ウシコラーゲン、セラミック及びカルボキシメチルセルロース(CMC)を含有する乾燥マトリックスを製造した。Oxy133は、凍結乾燥後に一定量の脱イオン水(表5に掲載)で処理したときに凍結乾燥インプラントが約5wt%、30wt%又は41.5wt%のOxy133を含有するのに足る量で添加された。表4には、凍結乾燥前に乾燥マトリックスを混合するために必要な0.9%食塩溶液の量も掲載されている。凍結乾燥後、インプラントを切断し、秤量して、脱イオン水で再水和する前のそれらの重量を表5に掲載する。表5には、凍結乾燥後に凍結乾燥インプラントに必要な脱イオン水の量も掲載されている。
[00243]本実施例では、より大きいバッチを製造した。表4のサンプル5を10倍にスケールアップした。さらに、凍結乾燥前の流体を0.9%の食塩水から脱イオン水に換えた。従って、本実施例のバッチは、3.6グラムのコラーゲン、0.45グラムのCMC及び凍結乾燥前の流体として100mLの脱イオン水を含んでいた。これらの成分を200mLのガラス製ビーカー中で撹拌プレートを用いて約5分間混合した。次に、得られたスラリーを、図8に示すように、長方形の金型にピペットを用いて充填した。一晩の凍結乾燥後、図9に示すように、8個の長方形の凍結乾燥ストリップを得た。各ストリップを0.9%食塩溶液で再水和した。図10に示すように、インプラントの一つから1.68gの小片を切り出し、1.3mLの食塩水で再水和した。図11及び12に示すように、インプラントは食塩水を直ちに吸収し、10秒間の混合後、使用の準備が整った。図13は、水和されたインプラントが、骨空洞への移植のために、円筒形の形状に手で成形されているところを示している。本実施例は、サンプル及び凍結乾燥インプラントの製造法がスケールアップできることを示した。本実施例はまた、凍結乾燥前及び後の水和流体として水と食塩溶液が互換的に使用できることも示した。本実施例は、より少ない再水和量を使用してサンプルをより硬くする、又はより多い再水和量を使用してサンプルをより柔らかくするといった修正も可能である。インプラントの所望の稠度は再水和量に基づいて変更することができる。
12 生分解性ポリマー
14 無機粒子
16 オキシステロール
20 インプラント
Claims (20)
- 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凍結乾燥インプラントであって、該凍結乾燥インプラントは、インプラントの約0.1wt%〜約20wt%の量の生分解性ポリマー、インプラントの約0.1wt%〜約75wt%の量の無機粒子、及びインプラントの約0.01wt%〜約90wt%の量のオキシステロールを含む凍結乾燥インプラント。
- 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)、Oxy153又はそれらの水和物、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に記載の凍結乾燥インプラント。
- (i)生分解性ポリマーが架橋され、凍結乾燥された移植可能マトリックスを形成するか、又は(ii)生分解性ポリマーが架橋されていない、請求項1に記載の凍結乾燥インプラント。
- 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、又はそれらの組合せを含む、請求項3に記載の凍結乾燥インプラント。
- 無機粒子が、(i)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;(ii)約125μm〜約750μmの粒径;(iii)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;又は(iv)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1に記載の凍結乾燥インプラント。
- 凍結乾燥インプラントが、賦形剤、希釈剤、担体、ビヒクル、可溶化剤、安定剤、増量剤、抗酸化剤又は結合剤をさらに含む、請求項1に記載の凍結乾燥インプラント。
- 賦形剤が、マンニトール、アルギネート、リン酸ナトリウム又はカリウム、クエン酸、酒石酸、ゼラチン、グリシン、ラクトース、スクロース、マルトース、グリセリン、デキストロース、デキストラン、トレハロース、ヘタスターチ、アスコルビン酸、アセチルシステイン、システイン、亜硫酸水素ナトリウム、ブチル−ヒドロキシアニソール、ブチル−ヒドロキシトルエン又はα−酢酸トコフェロール、又はキレート化剤を含む、請求項6に記載の凍結乾燥インプラント。
- 凍結乾燥インプラントの体積が、約3/4mL〜約10mLを含む、請求項1に記載の凍結乾燥インプラント。
- 約2wt%〜約4wt%の量の膨張可能相材料をさらに含む、請求項1に記載の凍結乾燥インプラント。
- 膨張可能相材料が、カルボキシメチルセルロース、アルギネート、キトサン、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、ヒドロキシエチルメチルセルロース、ヒドロキシエチルセルロース及びそれらの塩、カーボポール、ポリ(ヒドロキシエチルメタクリレート)、ポリ(メトキシエチルメタクリレート)、ポリ(メトキシエトキシ−エチルメタクリレート)、ポリメチルメタクリレート(PMMA)、メチルメタクリレート(MMA)、ゼラチン、ポリビニルアルコール、プロピレングリコール、PEG200、PEG300、PEG400、PEG500、PEG550、PEG600、PEG700、PEG800、PEG900、PEG1000、PEG1450、PEG3350、PEG4500、PEG8000又はそれらの組合せを含む、請求項9に記載の凍結乾燥インプラント。
- (i)凍結乾燥インプラントが、スポンジプラグ、ストリップ、又は円筒形の形状に成形可能であり;又は(ii)凍結乾燥インプラントが、椎体間ケージ、椎体間スペーサー、又は腰椎頸椎椎体間ケージに移植されるように設計されており;そして凍結乾燥インプラントが、自家移植片、同種移植片及び/又は異種移植片の骨粒子を含む、請求項2に記載の凍結乾燥インプラント。
- 凍結乾燥インプラントが、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流体で湿らせた後に成形可能である、請求項2に記載の凍結乾燥インプラント。
- 凍結乾燥インプラントの製造法であって、該方法は、流体をインプラントと混合し、前記インプラントはインプラントの全重量を基にして約0.01wt%〜約90wt%の量のオキシステロール、約0.1wt%〜約20wt%の量の生分解性ポリマー、及び約0.1wt%〜約75wt%の量の無機粒子を含み、そして流体と混合されたインプラントを凍結乾燥に付して、凍結乾燥インプラントを形成することを含む製造法。
- 流体が、約0.25mL〜約50mLの量の水、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ある、請求項13に記載の凍結乾燥インプラントの製造法。
- インプラントが、約2wt%〜約4wt%の量の膨張可能相材料をさらに含む、請求項13に記載の凍結乾燥インプラントの製造法。
- 膨張可能相材料が、カルボキシメチルセルロース、ペクチン又はキトサンである、請求項15に記載の凍結乾燥インプラントの製造法。
- 凍結乾燥の前にインプラントを金型に入れることをさらに含む、請求項13に記載の凍結乾燥インプラントの製造法。
- 凍結乾燥インプラントの体積が、約3/4mL〜約10mLを含む、請求項13に記載の凍結乾燥インプラントの製造法。
- 骨欠損の治療を必要としている患者における骨欠損の治療法であって、該方法は、骨欠損部又はその近傍に流体で水和された凍結乾燥インプラントを移植することを含み、前記凍結乾燥インプラントは、インプラントの約0.1wt%〜約20wt%の量の生分解性ポリマー、インプラントの約0.1wt%〜約75wt%の量の無機粒子、及びインプラントの約0.01wt%〜約90wt%の量のオキシステロールを含む治療法。
- 凍結乾燥インプラントが、約2wt%〜約4wt%の量の膨張可能相材料をさらに含む、請求項19に記載の骨欠損の治療法。
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US20210260254A1 (en) | 2021-08-26 |
US10987450B2 (en) | 2021-04-27 |
US10688222B2 (en) | 2020-06-23 |
KR20180057539A (ko) | 2018-05-30 |
CN108079374A (zh) | 2018-05-29 |
AU2017248473A1 (en) | 2018-06-07 |
US20200261625A1 (en) | 2020-08-20 |
US20180140746A1 (en) | 2018-05-24 |
CN108079374B (zh) | 2022-03-04 |
EP3323437B1 (en) | 2022-04-27 |
EP3323437A1 (en) | 2018-05-23 |
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