JP2011528031A - 徐放性薬剤キャリア組成物 - Google Patents
徐放性薬剤キャリア組成物 Download PDFInfo
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- JP2011528031A JP2011528031A JP2011518059A JP2011518059A JP2011528031A JP 2011528031 A JP2011528031 A JP 2011528031A JP 2011518059 A JP2011518059 A JP 2011518059A JP 2011518059 A JP2011518059 A JP 2011518059A JP 2011528031 A JP2011528031 A JP 2011528031A
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Abstract
Description
全身性ドキシサイクリンおよびNSAIDの併用療法への使用は、慢性歯周炎患者の歯肉の組織損傷を抑制することが分かっている。組織損傷は、病原菌の活動とホストマトリックスメタロプロテアーゼ(MMP)の活性とが相俟って引き起こされる。抗炎症薬物と併用した抗生物質治療がこれらの2つの経路を抑制する。これら薬物を制御下で局所的に放出させることにより、薬効の向上および治療による副作用の軽減を達成する。
骨増生を必要とする骨疾患には、良性および悪性骨腫瘍、骨内の癌、感染性骨疾患の他、内分泌学的要因、自己免疫的要因、栄養不足、遺伝学的要因および骨の成長と吸収の不均衡に関する病因による他の骨疾患がある。例えば、骨肉腫/骨の悪性線維性組織球腫(PDQ)、骨肉腫、軟骨性肉腫、ユーイング肉腫、悪性線維性組織球腫、線維肉腫および悪性線維性組織球腫、骨巨細胞腫、脊索腫、リンパ腫、多発性骨髄腫、骨関節症、骨パジェット病、関節炎、退行性変化、骨粗鬆症、骨形成不全症、骨棘、腎性骨異栄養症、副甲状腺機能亢進症、骨髄炎、内軟骨腫、骨軟骨腫、大理石骨病、糖尿病に関連する骨および関節の異常といった疾患がある。
これまで脂質と生体ポリマーの併用法が企図されてきたが、臨床現場への導入はまだ成功していない。
「リン脂質」は、グリセロール骨格上に単一のホスファチジル結合を有し、残りの2つの位置に脂肪酸を有するホスホグリセリドである。しかしながら、炭素数が少なくとも14のアルキル鎖、アルケニル鎖または他の任意の炭化水素鎖を含む脂肪酸残基以外の炭化水素鎖を有するホスホグリセリドも本発明の範囲に含まれることを明確に理解していただきたい。結合は、リン脂質に見られるアシル結合の代わりにエーテル結合であってもよい。
本発明の方法および組成物における生分解性ポリエステルは、他の実施形態ではPLA(ポリ乳酸)である。「PLA」は、ポリ(L-ラクチド)、ポリ(D-ラクチド)およびポリ(DL-ラクチド)を指す。ポリ(DL-ラクチド)の代表的な構造を以下に示す。
本発明の方法および組成物における抗生物質は、他の実施形態ではドキシサイクリンである。他の実施形態では、抗生物質が疎水性テトラサイクリンである。疎水性テトラサイクリンの非限定的な例としては、6-デメチル-6-デオキシテトラサイクリン、6-メチレンテトラサイクリン、ミノサイクリン(7-ジメチルアミノ-6-デメチル-6-デオキシテトラサイクリンとしても既知)、および13-フェニルメルカプト-a-6-デオキシ-テトラサイクリンがある。他の実施形態では、抗生物質がドキシサイクリン、テトラサイクリンおよびミノサイクリンからなる群から選択される。他の実施形態では、抗生物質を基質組成物に組み込む。
任意の適切なNSAIDを徐放および/または制御放出のため基質組成物には組み込むことができる。本発明の方法および組成物におけるNSAIDは、一実施形態では、フルルビプロフェンである。他の実施形態では、NSAIDがイブプロフェンおよびフルルビプロフェンからなる群から選択される。他の実施形態では、NSAIDがイブプロフェン、フルルビプロフェン、アミノサリチル酸塩ナトリウム、トリサリチル酸コリンマグネシウム、サリチル酸コリン、ジクロフェナク、ジフルニサル、エトドラク、フェノプロフェン、インドメタシン、ケトプロフェン、ケトラックトロメタミン、サリチル酸マグネシウム、メクロフェナム酸、メフェナム酸、ナブメトン、ナプロキセン、オキサプロジン、オキシフェンブタゾン、ピロキシカム、サルサレート、スリンダク、トルメチンからなる群から選択される。
他の実施形態では、本発明の方法および組成物における活性物質がステロイドである。一実施形態では、ステロイドがステロイド性抗炎症薬である。本発明の製剤で使用すべきステロイド性抗炎症薬(SAID)の非限定的な例は、必ずしもそれだけに限定されるわけではないが、下記のようなコルチコステロイドを含む:ベタメタゾン、吉草酸ベタメタゾン、コーチゾン、デキサメタゾン、デキサメタゾン21-リン酸、フルドロコルチゾン、フルメタゾン、フルオシノニド、フルオシノニドデソニド、フルオシノロン、フルオシノロンアセトニド、フルオコルトロン、ハルシノニド、ハロプレドン、ヒドロコルチゾン、ヒドロコルチゾン17-吉草酸、ヒドロコルチゾン17-酪酸、ヒドロコルチゾン21-アセテートメチルプレドニゾロン、プレドニゾロン、プレドニゾロン21-リン酸、プレドニゾン、トリアムシノロン、トリアムシノロンアセトニド、コルトドキソン、フルオラセトニド、フルドロコルチゾン、ジフルオルゾンジアセテート、フルランドレノロンアセトニド、メドリゾン、アムシナフェル、アムシナフィド、ベタメタゾンおよびそのエステル類、クロロプレドニゾン、クロルコルテロン、デシノロン、デソニド、ジクロリゾン、ジフルプレドナート、フルクロロニド、フルメタゾン、フルニソリド、フルコルトロン、フルオロメサロン、フルペロロン、フルプレドニゾロン、メプレドニゾン、メチルメプレドニゾロン、パラメタゾン、酢酸コルチゾン、シクロペンチルプロピオン酸ヒドロコルチゾン、コルトドキソン、フルセトニド、酢酸フルドロコルチゾン、フルランドレノロンアセトニド、メドリゾン、アムシナファル、アムシナフィド、ベタメタゾン、安息香酸ベタメタゾン、酢酸クロロプレドニゾン、酢酸クロコルトロン、デシノロンアセトニド、デスオキシメタゾン、酢酸ジクロリゾン、ジフルプレドナート、フルクロロニド、ピバル酸フルメタゾン、酢酸フルニソリド、酢酸フルペロロン、吉草酸フルプレドニゾロン、酢酸パラメタゾン、プレドニゾラマート、プレドニバル、トリアムシノロンヘキサセトニド、コルチバゾール、ホルモコルタール、ニバゾール。
ここで使用する「抗癌剤」という用語は、癌および/または癌に関連する疾病の治療に使用可能な任意のタイプの薬物を指す。抗癌剤には、癌細胞(癌腫瘍)および癌腫瘍の成長および/または生存能力、および/または癌に関連する疾病および症状に直接または間接的に影響を及ぼす可能性がある任意の天然分子または合成生成分子が含まれる可能性がある。抗癌剤は、例えば天然のタンパクまたはペプチド、修飾タンパクまたはペプチド、組換えタンパク、化学合成したタンパクまたはペプチド、低経口生物学的利用能タンパクまたはペプチド、化学分子、合成化学分子、化学療法薬、生物学的治療薬等、またはそれらの組合せを含む可能性がある。抗癌剤は、癌細胞に対する細胞毒性(細胞にとって有毒であること)および/または細胞増殖抑制性(細胞成長を抑制すること)および/または抗増殖性を有することができ、またそれ自体の効果を癌細胞に対して直接且つ/または間接的に及ぼすことができる。いくつかの実施形態によれば、抗癌剤は単独および/または組み合わせで、および/または1つ以上の追加的な癌治療の前後に投与することができる。追加的な癌治療としては、必ずしもそれだけに限定されるわけではないが、化学療法(癌細胞に影響を及ぼす薬剤の使用)、放射線療法(癌細胞に影響を及ぼす様々なソースの高エネルギー放射線)、生物学的治療(免疫系の癌との戦いを助ける治療)、外科的処置(癌腫瘍の外科的除去)、遺伝子治療、骨髄移植、当技術分野で知られる他の任意の治療、またはそれらの任意の組合せ等を挙げることができる。
他の実施形態では、本発明の方法および組成物における活性物質が骨の形成を誘導または刺激する化合物である。他の実施形態では、活性物質が骨原性因子である。他の実施形態では、骨原性因子が骨の形成を誘導または刺激する任意のペプチド、ポリペプチド、タンパク質、または他の任意の化合物若しくは組成物を指す。他の実施形態では、骨原性因子が骨芽細胞や骨細胞のような骨の細胞への骨修復細胞の分化を誘導する。他の実施形態では、骨原性因子がTGF-β、BMPおよびFGFからなる群から選択される。他の実施形態では、骨原性因子が骨を形成する骨の細胞への骨修復細胞の分化を誘導するのに十分な濃度で本発明の基質組成物内に封入される。
他の実施形態では、本発明の方法および組成物における活性物質が骨再生を支援するのに有用な化合物である。他の実施形態では、活性物質が骨吸収抑制剤である。他の実施形態では、活性物質が骨密度維持薬品である。他の実施形態では、化合物をオステオプロテゲリン(OPG)、BMP-2、BMP-4、血管内皮細胞成長因子(VEGF)、アレンドロネート、エチドロン酸二ナトリウム、パミドロン酸、リセドロネート、チルドロネートからなる群から選択する。他の実施形態では、化合物がオステオプロテゲリン(OPG)(破骨細胞成熟および活性を阻害し、破骨細胞アポトーシスを誘導する、自然に隠れたおとり受容体)である。他の実施形態では、活性物質が骨再構築要素である。骨再構築要素の非限定的な例は、BMPペプチドである。各可能性は本発明の別々の実施形態を表す。
他の実施形態では、生物学的活性成分が例えば下記の抗真菌剤である:アンホテリシンBコレステリル硫酸錯体、ナタマイシン、アムホテリシン、クロトリマゾール、ナイスタチン、アンホテリシンB脂質錯体、フルコナゾール、フルシトシン、グリセオフルビン、イトラコナゾール、ケトコナゾール、安息香酸およびサリチル酸、ベタメタゾンおよびクロトリマゾール、ブテナフィン、石炭酸フクシン、シクロピロックス、クリオキノール、クリオキノールおよびヒドロコルチゾン、クロトリマゾール、エコナゾール、ゲンチアナバイオレット、ハロプロジン、ヨードキノールおよびヒドロコルチゾン、ケトコナゾール、ミコナゾール、ナフチフィン、ナイスタチン、ナイスタチンおよびトリアムシノロン、オキシコナゾール、チオ硫酸ナトリウム、スルコナゾール、テルビナフィン、トルナフテート、トリアセチン、ウンデシレン酸およびその誘導体、ブトコナゾール、クロトリマゾール、スルファニルアミド、テルコナゾールおよびチオコナゾール。
他の実施形態では、本発明の方法および組成物における基質組成が更に標的分子と相互に作用可能な標的部分を含む。標的分子をコラーゲン分子、フィブリン分子およびヘパリンからなる群から選択するのが好ましい。他の実施形態では、標的分子が標的細胞の細胞外基質(ECM)の一部を形成する別の表面分子である。ECMは細胞によって生成され局所的に組み立てられる。ECMの組立ておよび維持に関与する最も重要な細胞は、線維芽細胞である。ECMは、GAGs(ムコ多糖)と呼ばれる多糖鎖および様々なタンパク繊維、例えばコラーゲン、エラスチン、フィブロネクチンおよびラミニンを含む。
他の実施形態では、本発明の方法および組成物における基質組成物が更に遊離脂肪酸を含む。他の実施形態では、遊離脂肪酸がω-6脂肪酸である。他の実施形態では、遊離脂肪酸がω-9脂肪酸である。他の実施形態では、遊離脂肪酸をω-6脂肪酸およびω-9脂肪酸からなる群から選択する。他の実施形態では、遊離脂肪酸が14以上の炭素原子を有する。他の実施形態では、遊離脂肪酸が16以上の炭素原子を有する。他の実施形態では、遊離脂肪酸が16の炭素原子を有する。他の実施形態では、遊離脂肪酸が18の炭素原子を有する。他の実施形態では、遊離脂肪酸が16〜22の炭素原子を有する。他の実施形態では、遊離脂肪酸が16〜20の炭素原子を有する。他の実施形態では、遊離脂肪酸が16〜18の炭素原子を有する。他の実施形態では、遊離脂肪酸が18〜22の炭素原子を有する。他の実施形態では、遊離脂肪酸が18〜20の炭素原子を有する。他の実施形態では、遊離脂肪酸がリノール酸である。他の実施形態では、遊離脂肪酸がリノレン酸である。他の実施形態では、遊離脂肪酸がオレイン酸である。他の実施形態では、遊離脂肪酸をリノール酸、リノレン酸およびオレイン酸からなる群から選択する。他の実施形態では、遊離脂肪酸が当業界で既知の他の適当な遊離脂肪酸である。他の実施形態では、遊離脂肪酸が基質組成物に柔軟性を付加する。他の実施形態では、遊離脂肪酸が生体内放出速度をおとす。他の実施形態では、遊離脂肪酸が生体内制御放出の整合性を改善する。いくつかの実施形態において、脂肪酸は不飽和である。他の実施形態では、遊離脂肪酸が飽和する。他の実施形態では、少なくとも14の炭素原子を有する飽和脂肪酸を組み込むことにより生成する基質組成物のゲル-流体相転移温度が上昇する。
本発明の基質組成物に関する活性成分の90%の生体内放出時間は、1週間〜6ヶ月であるのが好ましい。他の実施形態では、放出時間が4日〜6ヵ月である。他の実施形態では、放出時間が1週間〜5ヵ月である。他の実施形態では、放出時間が1週間〜5ヵ月である。他の実施形態では、放出時間が1週間〜4ヵ月である。他の実施形態では、放出時間が1週間〜3ヵ月である。他の実施形態では、放出時間が1週間〜2ヵ月である。他の実施形態では、放出時間が2週間〜6ヵ月である。他の実施形態では、放出時間が2週間〜5ヵ月である。他の実施形態では、放出時間が2週間〜4ヵ月である。他の実施形態では、放出時間が2週間〜3ヵ月である。他の実施形態では、放出時間が3週間〜6ヵ月である。他の実施形態では、放出時間が3週間〜5ヵ月である。他の実施形態では、放出時間が3週間〜4ヵ月である。他の実施形態では、放出時間が3週間〜3ヵ月である。各可能性は本発明の別々の実施形態を表す。
他の実施形態では、本発明の基質組成物が有機溶媒の蒸発後のインプラントの形態である。溶媒の蒸発を通常20〜60℃の温度で行う。
本発明の他の実施形態は、抗生物質を必要とする被検体に投与する方法を提供し、該方法は被検体に本発明の基質組成物を投与することにより抗生物質を必要とする被検体に投与するステップを含む。他の実施形態では、基質組成物を含む医薬組成物を投与する。他の実施形態では、基質組成物を含むインプラントを投与する。他の実施形態では、基質組成物を含む注射可能な製剤を注射する。各可能性は本発明の別々の実施形態を表す。
本発明の組成物を得るために、任意の適切な方法を利用して耐水性基質へのポリマーおよび脂質の均一な分散をもたらすことができる。有利なことに、いくつかの実施形態に従って利用される方法は、製造プロセスのいかなる段階でも水の使用を避ける。
ここで用いる「飽和脂質」という用語は、基質中に存在する疎水性薬剤および標的部分並びに存在し得る他の脂質と結合するリン脂質による基質組成物のポリマーの飽和を指す。ここに記載するように、いくつかの実施形態では、本発明の基質組成物がホスファチジルコリン以外のリン脂質を含む。他の実施態様において、基質組成物はリン脂質以外の脂質を含む。基質組成物は、どのような脂質が存在しても飽和する。「飽和」とは、基質に組み込み得るのに用いたタイプの最大量の脂質を基質が含有している状態を指す。脂質飽和を得るためのポリマー対脂質の比を決定する方法、および基質の脂質飽和度を決定する方法をここに記載する。各可能性は本発明の別々の実施形態を表す。
使用する略語は、ホスホエタノールアミン=PE;ホスファチジルコリン=PC;1,2-ジミリストイル-sn-グリセロ-3-ホスホエタノールアミン=DMPE(14:0);1,2-ジパルミトイル-sn-グリセロ-3-ホスホエタノールアミン=DPPE(16:0);1,2-ジステアロイル-sn-グリセロ-3-ホスホコリン=DSPC(18:0);1,2-ジパルミトイル-sn-グリセロ-3-ホスホコリン=DPPC(16:0);1,2-ジオレオイル-sn-グリセロ-3-ホスホコリン=DOPC(18:1);1-パルミトイル-2-{6-[(7-ニトロ-2-1,3-ベンゾオキサジアゾール-4-イル)アミノ]ヘキサノイル}-sn-グリセロ-3-ホスホコリン=NBD-PCである。
脂質飽和ポリマー基質を生成するために2つの混合物を作成する。
1.生分解性ポリマーと、ステロールおよび/またはリン脂質構成成分とを揮発性有機溶媒と混合して、示差走査熱量測定(DSC)プロファイルによって測定される脂質飽和ポリマー基質の溶液または懸濁液を得る。
2.活性物質およびリン脂質構成成分を第2の揮発性有機溶媒と混合して第2の溶液または懸濁液を得る。
3.これら2つの溶液または懸濁液を一緒にし、平衡に達するまで混合し、その後有機溶媒を蒸発させて薬剤含有脂質飽和ポリマー基質を得る。
I.第1の溶液の調製
ポリマー(PLGA、PGA、PLAまたはそれらの組合せ)と、ステロール(例えばコレステロール)および/またはα−またはγ−トコフェロールおよび/またはホスファチジルエタノールアミンのような極性脂質とを揮発性有機溶媒(例えばクロロホルムを含む/含まない酢酸エチル)に混合する。この混合物を混合する。このプロセス全体を通常室温で行う。こうして第1脂質/ポリマー混合物が得られる。
下記の材料を揮発性有機溶媒(典型的にはN-メチルピロリドン[NMP]、メタノール、酢酸エチルまたはそれらの組合せ)と混合する。
a.活性化合物。
b.ホスホコリンまたはホスファチジルコリン誘導体、例えば基質中の全脂質の30〜90質量%として存在する1,2-ジステアロイル-sn-グリセロ-3-ホスホコリン(DSPC)またはジオレオイル-ホスファチジルコリン(DOPC)、すなわち30〜90質量%のリン脂質、ステロール、セラミド、脂肪酸等。
c.いくつかの実験では、ホスファチジルエタノールアミン、例えばジメチルジミリストイルホスファチジルエタノールアミン(DMPE)またはジパルミトイルホスファチジルエタノールアミン(DPPE)、基質中の全脂質の0.1〜50質量%として存在。
d.いくつかの実験では、標的部分、例えばフィブロネクチン-水素化ホスファチジルエタノールアミン(HPE)錯体が基質中の全脂質の0.1〜10 mol%として含れる。この錯体を形成するために、コラーゲン結合領域を含むフィブロネクチンタンパクまたはその断片をHPEのアミン頭部基とチオエーテル結合によって結合させる。
e.いくつかの実験では、0.1〜15質量%の遊離脂肪酸、例えばリノール酸(Ln)またはオレイン酸(OA)が基質中の全脂質の0.1〜10質量%として含れる。
f.いくつかの実験では、リン酸塩のような塩が含れる。
第2懸濁液(または溶液)を撹拌下で第1の溶液に添加する。撹拌を最長5時間継続する。このプロセス全体は、特定の製剤、使用する脂質の性質および特定の薬剤に応じて室温〜最高60℃で実行する。生成する混合物は均質にすべきである。
いくつかの実験では、段階IIIで得た溶液を乾燥した加熱空気中に噴霧する。
被覆粒子および被覆デバイスを貯蔵用に真空乾燥する。
酢酸エチルに下記の材料を混合する。
・50〜75kDaのPLGA(ポリ(乳酸-グリコール酸)、85:15の比率)
・コレステロール(対PLGA、50%〜100% w/w)
下記の材料を揮発性有機溶媒(メタノールおよび酢酸エチル)と混合する。
a.活性化合物:抗生物質ドキシサイクリンハイクレート
b.PLGAに対し300〜700% w/wとして存在する1,2-ジステアロイル-sn-グリセロ-3-ホスホコリン(DSPC)
第2の溶液または懸濁液を通常撹拌下で第1懸濁液に添加する。撹拌を1〜5分間継続する。このプロセス全体を使用する脂質に応じて20〜50℃の温度で実行する。
骨充填材粒子を被覆するために、段階IIIの混合物に粒子を添加し、その後揮発性有機溶媒を蒸発させた。このプロセス全体を40〜50℃の温度で実行する。
被覆骨片を貯蔵用に真空乾燥する。
a. PLGA/酢酸エチル、300mg/ml(SS1、1ml)):(i)4mlのガラスバイアルで300mgのPLGA(50:50、シグマ)を秤量し、(ii)1mlの酢酸エチルを加え、(iii)5分間渦動させ、(iv)室温(RT)で12〜18時間撹拌し、(v)ポリマー粒子が完全に溶解したことを確認し、(vi)N2下で閉じ、アルミホイルで包んでRTで維持し、(vii)この溶液は1ヶ月間有効である。
b. コレステロール/酢酸エチル、30mg/ml(SS2、1ml):(i)4mlガラスバイアルで30mgのコレステロール(シグマ99%)を秤量し、(ii)1mlの酢酸エチルを加え、(iii)RTで5分間渦動させ、(iv)コレステロールが完全に溶解したことを確認する。そうでなければ更に2分間渦動させ、(v)N2下で閉じ、アルミホイルで包んでRTで維持し、(vi)この溶液は1ヶ月間有効である。
c. 酢酸エチル:メタノール1:1(SS2.1):(i)20mlのガラスバイアル内に10mlの酢酸エチルを入れ、(ii)同バイアルに10mlのメタノールを加え、(iii)20秒間渦動させ、(iv)溶液をRTで維持し、(v)この溶液は1ヶ月間有効である。
d. チアベンダゾール(TBZ)/酢酸エチル:メタノール1:1、10mg/ml(SS3、1mI):(i)4mlガラスバイアルで10mgのTBZを秤量し、(ii)1mlのSS2.1貯蔵溶液を加え、(iii)RTで5分間渦動させ、(iv)TBZが完全に溶解したことを確認する。そうでなければ更に2分間渦動させる。溶液がある程度白濁したら、(v)N2下で閉じ、アルミホイルで包んでRTで維持し、(vi)この溶液は1ヶ月間有効である。
i. 1mlのSS2(CH-EA、30mgのCH)を0.2mlのSSl(PLGA/EA、60mgのPLGA)に添加して4mlガラスバイアルに入れる。
ii. RTで5分間渦動させる。
iii. 混合物が均一で澄んでいることを確認する。そうでなければiiに戻る。
iv. N2下で閉じ、アルミホイルで包んでRTで維持する。
v. この溶液は1ヶ月間有効である。
vi. 溶液Aの濃度:[CH]=25mg/ml;[PLGA]=50mg/ml
i. 4mlガラスバイアルで225mgのリン脂質(14:0)を秤量する。
ii. 0.75mlのSS3(TBZ/EA-MET、7.5mgのTBZ)を添加する。
iii. バイアル内に0.25mlの酢酸エチルを添加する。
iv. RTで2分間渦動させる。
v. N2下で閉じ、アルミホイルで包んでRTで維持する。
vi. この溶液は1ヶ月間有効である。
vii. 濃度:[リン脂質(14:0)]=225mg/ml、[TBZ]=7.5mg/ml
i. 0.4mlの溶液Bを4mlガラスバイアルに注入する。
ii. このバイアルに0.6mlの溶液Aを添加する。
iii. RTで2分間渦動させる。
iv. 検査:この溶液がRTで液体であり、やや濁った淡黄色である。
v. N2下で閉じ、アルミホイルで包む。
vi. 濃度:[CH]=15mg/ml;[PLGA]=30mg/ml;[14:0]=90mg/ml;[TBZ]=3mg/ml
i. 1.8mlガラスバイアルで12.5(±0.5)mgの骨片(Bio-OssまたはEndoBon(登録商標))を秤量する。
ii. 骨を浄化水(1/2mlのDDW)で洗浄する;マイクロピペットで水を吸い出した後、12〜18時間真空下に置く。
iii. 45℃に加熱した加熱ブロックを準備する。
iv. 溶液Cを30秒間45℃に加熱する。溶液が完全に融解し、均一化することを確認する。
v. 10〜100 μlマイクロピペットで骨片に50μlの溶液Cを加える。
vi. 1.8mlのバイアルを封印せずに加熱ブロック(45℃)内に30分間置く。
vii. 加熱から取り出してストッパーで閉止する。
viii. バイアル(半封止)を回転ポンプ(1×10-1 Torr(13.3 Pa))で12〜18時間減圧する。
ix. 融合骨片をスパーテルで緩やかに分離する。
x. 乾燥状態の被覆骨片を新しい4mlガラスバイアルに移す。
xi. N2下で閉じ、アルミホイルで包んでRTで維持する。
xii. 被覆骨片は1ヶ月間有効である。
A.ウサギの脛骨骨髄炎
B.バクテリア:黄色ブドウ球菌
1. 骨に外傷を負わせた(試験Aの判定どおり)(動物数:10)。
2. 空隙(骨の傷口)にリン酸三カルシウム(TCP)材料を充填し、ボーンワックスで封止した。
3. この部位に規定の量の細菌を注射によって装填した。
4. 期間:22日間。臨床徴候および体重を観察した(週3回)。
5. 培養時間終了時:動物から基本的な血液学的で生化学的な血液を採血した(試験終了前)。
6. 試験終了前(20日目まで)の脛骨のX線撮影を行った。
7. 試験を終了し、細菌学的試験のための脛骨を採取した。
8. 細菌を骨から抽出し、細菌濃度(後述)を判定した。
1. 骨に外傷を負わせた(上述の試験Aの場合と同様)(動物数:13)。
2. 空隙(骨の傷口)にTCP材料を充填し、ボーンワックスで封止した。
3. この部位に規定の量の細菌を注射によって装填した(負荷は試験Aの結果が出次第判定される)。
4. 期間:22日間。臨床徴候および体重を観察した(週3回)。
5. 培養期間中:7日目および16日目に動物から基本的な血液学的で生化学的な血液パネルを採血した(試験終了前)。
6. 試験終了前、1(または2)日目〜20日目までの脛骨のX線撮影を行った。
7. 実験を終了し、細菌学的試験のための脛骨を収集した。
8. 細菌を骨から抽出し、上述の試験Aに記載したように細菌濃度を判定した。
9. 局所的薬剤濃度を検定した。
1. 骨に外傷を負わせた(上述の試験Aの場合と同様)(動物数:24)。
2. 空隙(骨の傷口)にTCPを充填し、ボーンワックスで封止した。
3. この部位に規定の量の細菌を注射によって装填した(負荷は試験Aの結果が出次第判定される)。
4. 期間:45日。臨床徴候および体重を観察した(週3回)。終了時間は、培養時間中に得たX線撮影結果によって決定した。
5. 培養時間中:0、10、30および45日目に動物から基本的な血液学的で生化学的な血液パネルを採血した(試験終了前)。
6. 動物から1、3、10、16および30日目に血液薬剤濃度分析のために採血した。
7. 試験終了前、2、20、30および43日目の脛骨のX線撮影を行った。
8. 実験を終了し、組織学的試験のための脛骨を採取した。
9. 50%の動物(12匹)に対する負傷部位の組織学的試験。
10. 細菌を骨から抽出し、50%の動物(12匹の動物)の細菌濃度を上述のように判定した。
・フルルビプロフェンおよびドキシサイクリンの超高投与量、高投与量、中投与量または低投与量(それぞれ30、15、5、1mg/アプリケーション部位、VH、H、M、Lと表記する)を含有する基質インプラントの局所塗布。
・上述の高、中、および低投与量を含む基質分量(負対照)に対応する基質分量での活性成分を含有しない基質インプラントの局所塗布。
・遊離薬剤として投与される上述の超高、高、中および低投与量に対応する投与量でのフルルビプロフェンおよびドキシサイクリンの局所塗布。
・上述の高、中、および低投与量に対応する投与量でのフルルビプロフェンおよびドキシサイクリンの1日2回の全身投与。これ(SRPと併せて)は、この動物モデルの歯周炎治療の参照基準と考える。
・無処置(追加的な負対照群)。
・組織中のキャリアの生体内安定性を決定するためのキャリア標識レベル、
・塗布部位、周囲組織および血行におけるフルルビプロフェン、ドキシサイクリンおよびその既知の代謝物質のレベル、
・毒性試験。
これに加えて下記の有効性指標も判定する:
・探針深さ(PD)、臨床的アタッチメントレベル(CAL)、探針時の出血(BOP)のような臨床パラメータの改善、
・セメント‐エナメル接合部から歯槽骨頂までの距離のような放射線学的パラメータの改善、
・組織学的分析。
Claims (48)
- a.極性基を有する第1の脂質に関連する生分解性ポリマーと、
b.少なくとも14の炭素からなる炭化水素鎖を有する少なくとも1つのリン脂質を含む第2の脂質と、
c.薬学的活性物質とを含み、前記薬学的活性物質の徐放を付与するのに適するようにした基質組成物。 - 前記リン脂質が、少なくとも14の炭素を有する脂肪酸部分を含むホスファチジルコリンである請求項1に記載の基質組成物。
- 前記生分解性ポリマーが、PLA(ポリ乳酸)、PGA(ポリグリコール酸)、PLGA(ポリ(乳酸−グリコール酸)からなる群から選択された生分解性ポリエステルである請求項1に記載の基質組成物。
- 前記薬学的活性物質が、抗生物質、抗真菌薬、非ステロイド抗炎症薬、ステロイド、抗癌剤、骨原性因子および骨吸収抑制剤から選択される請求項1に記載の基質組成物。
- 前記極性基を有する第1の脂質がステロールを含む請求項1に記載の基質組成物。
- 前記薬学的活性物質が抗生物質、抗真菌薬から選択される請求項4に記載の基質組成物。
- 前記薬学的活性物質が抗癌剤である請求項4に記載の基質組成物。
- 前記薬学的活性物質が非ステロイド抗炎症薬(NSAID)である請求項4に記載の基質組成物。
- 前記薬学的活性物質がステロイドである請求項4に記載の基質組成物。
- 前記薬学的活性物質が骨原性因子、骨吸収抑制剤から選択される請求項4に記載の基質組成物。
- 前記生分解性ポリマーに対する全脂質の質量比が、1.5:1〜9:1である請求項1に記載の基質組成物。
- 抗生物質、抗真菌薬、非ステロイド抗炎症薬(NSAID)、ステロイド、抗癌剤、骨原性因子、骨吸収抑制剤から選択される複数の薬学的活性物質を含む請求項1に記載の基質組成物。
- 前記組成物が均質である請求項1に記載の基質組成物。
- スフィンゴ脂質を含む請求項1に記載の基質組成物。
- トコフェロールを含む請求項1に記載の基質組成物。
- 前記組成物が実質的に水の無いものである請求項1に記載の基質組成物。
- ホスファチジルセリン、ホスファチジルグリセロール、ホスファチジルイノシトールからなる群から選択される追加のリン脂質を更に含む請求項1に記載の基質組成物。
- 14以上の炭素原子を有する遊離脂肪酸を更に含む請求項1に記載の基質組成物。
- コラーゲン分子、フィブリン分子およびヘパリンからなる群から選択される標的分子と相互作用可能な標的部分を更に含む請求項1に記載の基質組成物。
- 前記標的部分がフィブロネクチンペプチドである請求項19に記載の基質組成物。
- ペギル化脂質を更に含む請求項1に記載の基質組成物。
- 前記ステロールがコレステロールである請求項5に記載の基質組成物。
- 前記コレステロールが前記基質組成物の総脂質含有量の5〜50モル%の量で存在する請求項22に記載の基質組成物。
- 前記薬学的活性物質の少なくとも50%がゼロ次速度過程で前記組成物から放出される薬学的活性物質の徐放用の請求項1に記載の基質組成物。
- 前記薬学的活性物質の少なくとも60%がゼロ次速度過程で前記組成物から放出される薬学的活性物質の徐放用の請求項24に記載の基質組成物。
- 前記薬学的活性物質の少なくとも65%がゼロ次速度過程で前記組成物から放出される薬学的活性物質の徐放用の請求項25に記載の基質組成物。
- 請求項1に記載の基質組成物を含むインプラント。
- 請求項1に記載の基質組成物を含む活性物質の徐放用の医薬組成物。
- 前記活性物質が、抗生物質、抗真菌薬、非ステロイド抗炎症薬、ステロイド、抗癌剤、骨原性因子、骨吸収抑制剤から選択される請求項28に記載の医薬組成物。
- 必要とする被検体に請求項6に記載の基質組成物を投与することにより抗生物質を該被検体に投与するステップを備える抗生物質を被検体に投与する方法。
- 必要とする被検体に請求項6に記載の基質組成物を投与することにより該被検体の歯周炎を治療するステップを備える被検体の歯周炎を治療する方法。
- 必要とする被検体に請求項8に記載の基質組成物を投与することにより非ステロイド抗炎症薬を該被検体に投与するステップを備える非ステロイド抗炎症薬(NSAID)を被検体に投与する方法。
- 必要とする被検体に請求項8に記載の基質組成物を投与することにより該被検体の歯周炎を治療するステップを備える被検体の歯周炎を治療する方法。
- 必要とする被検体に請求項10に記載の基質組成物を投与することにより該被検体に骨吸収抑制剤を投与するステップを備える骨吸収抑制剤を被検体に投与する方法。
- 必要とする被検体に請求項10に記載の基質組成物を投与することにより該被検体の骨増生を刺激するステップを備える被検体の骨増生を刺激する方法。
- 基板と、前記基板の少なくとも一画分上に堆積させた生体適合性コーティングとを備え、該生体適合性コーティングが請求項1に記載の基質組成物を含む医療装置。
- 前記生体適合性コーティングが多層を含む請求項36に記載の医療装置。
- 前記基板が、ヒドロキシアパタイト、ステンレス鋼、コバルトクロム、チタン合金、タンタル、セラミック、ゼラチンからなる群から選択される少なくとも1つの材料を含む請求項36に記載の医療装置。
- 前記基板が、整形外科用爪、整形外科用ねじ、整形外科用ステープル、整形外科用ワイヤ、整形外科用ピン、金属またはポリマーインプラント、骨充填材粒子、コラーゲンおよび非コラーゲンメンブレン、縫合材料、整形外科用セメント、スポンジから選択される請求項36に記載の医療装置。
- 前記骨充填材粒子が、同種骨片、異種骨片、人工骨片から選択される請求項39に記載の医療装置。
- 整形外科用爪、整形外科用ねじ、整形外科用ステープル、整形外科用ワイヤ、整形外科用ピン、金属またはポリマーインプラント、骨充填材粒子、コラーゲンおよび非コラーゲンメンブレン、縫合材料、整形外科用セメント、スポンジから選択される基板のコーティング用の請求項1〜22のいずれか一項に記載の組成物の使用。
- 基質組成物を製造するに当たり、
a. 第1の揮発性有機溶媒に(i)生分解性ポリマーと、(ii)極性基を有する第1の脂質とを混合するステップと、
b. 第2の揮発性有機溶媒に(i)少なくとも1つの薬学的活性物質と、(ii)少なくとも14の炭素からなる炭化水素鎖を有するリン脂質から選択した第2の脂質とを混合するステップと、
c. 前記ステップ(a)および(b)で得られた生成物を混合して均質混合物を生成するステップと、
d. 前記揮発性有機溶媒を蒸発させて均質基質組成物を生成するステップとを備える基質組成物の製造方法。 - 前記リン脂質が少なくとも14の炭素を有する脂肪酸部分を含むホスファチジルコリンである請求項39に記載の方法。
- 前記第1の脂質が少なくとも14の炭素を有する脂肪酸部分を含むホスファチジルエタノールアミンである請求項39に記載の方法。
- 前記生分解性ポリマーが、PLA(ポリ乳酸)、PGA(ポリグリコール酸)、PLGA(ポリ(乳酸-グリコール酸))からなる群から選択されるポリエステルである請求項43に記載の方法。
- 前記第1の脂質がステロールである請求項43に記載の方法。
- 前記第1の脂質がホスファチジルエタノールアミンである請求項43に記載の方法。
- 前記各ステップが実質的に水の無いものである請求項43に記載の方法。
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EP2299953B1 (en) | 2017-04-12 |
AU2009272280A1 (en) | 2010-01-21 |
CA2730340C (en) | 2017-02-07 |
DK2299953T3 (en) | 2017-06-19 |
JP5681626B2 (ja) | 2015-03-11 |
HK1205960A1 (en) | 2015-12-31 |
EP2299953A1 (en) | 2011-03-30 |
US20110117197A1 (en) | 2011-05-19 |
CN104274866B (zh) | 2016-08-24 |
CA2730340A1 (en) | 2010-01-21 |
JP2015129128A (ja) | 2015-07-16 |
US20150071981A1 (en) | 2015-03-12 |
WO2010007623A1 (en) | 2010-01-21 |
US8877242B2 (en) | 2014-11-04 |
AU2009272280B2 (en) | 2015-08-06 |
CN102159163A (zh) | 2011-08-17 |
ES2630805T3 (es) | 2017-08-24 |
US20190070298A1 (en) | 2019-03-07 |
US20200289651A1 (en) | 2020-09-17 |
CN102159163B (zh) | 2014-09-10 |
US10682412B2 (en) | 2020-06-16 |
JP6053083B2 (ja) | 2016-12-27 |
PL2299953T3 (pl) | 2017-10-31 |
US10105443B2 (en) | 2018-10-23 |
US20160354470A1 (en) | 2016-12-08 |
US9421271B2 (en) | 2016-08-23 |
US20150050340A1 (en) | 2015-02-19 |
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EP2299953A4 (en) | 2013-05-29 |
JP2016145217A (ja) | 2016-08-12 |
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