JP2008509727A - 二段押出法によって製造される眼インプラント - Google Patents
二段押出法によって製造される眼インプラント Download PDFInfo
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- JP2008509727A JP2008509727A JP2007525641A JP2007525641A JP2008509727A JP 2008509727 A JP2008509727 A JP 2008509727A JP 2007525641 A JP2007525641 A JP 2007525641A JP 2007525641 A JP2007525641 A JP 2007525641A JP 2008509727 A JP2008509727 A JP 2008509727A
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- dexamethasone
- active agent
- implant
- release
- bioerodible implant
- Prior art date
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Abstract
Description
本明細書に使用される下記の用語は、下記の意味を有する。
用語 意味
1H-NMR 陽子核磁気共鳴
ABS ポリアクリロニトリルブタジエンスチレン
ACC 前房細胞
ALT アラニンアミノトランスフェラーゼ
API 活性薬剤成分
AVC 前部硝子体細胞
BCVA 最適矯正(best-corrected)視力
BI ベーリンガー・インゲルハイム
BRVO 網膜分枝静脈閉塞症
BSE ウシ海綿状脳症
BVOS 分枝静脈閉塞試験
B/N バッチ番号
℃ 摂氏温度
CA カリフォルニア
CAS ケミカルアブストラクトサービス
CF 指数弁別(count fingers)
CFU コロニー形成単位
cGMP 現行適正製造基準
CI 信頼区間
CIB 治験薬概要書
CO2 二酸化炭素
COEX 共押出
CRVO 中心網膜静脈閉塞症
CVOS 中心静脈閉塞試験
DDS 薬剤送達システム
DEX デキサメタゾン
DEX PS DDS デキサメタゾン後区薬剤送達システム(インプラント)
DEX PS DDS Applicator デキサメタゾン後区薬剤送達
system システム(医薬品)
DME 糖尿病性黄斑浮腫
EMEA ヨーロッパ医薬品評価機関
ETDRS 糖尿病性網膜症早期治療試験
EU 内毒素単位
°F 華氏温度
G グラム
GLP 適正ラボラトリー基準
GRB 地理的BSE(ウシ海綿状脳症)リスク
H2O 水
HDPE 高密度ポリエチレン
HPLC 高性能液体クロマトグラフィー
IEC 独立倫理委員会
IMPD 治験薬資料
INN 国際一般的名称
IOP 眼内圧
IPC 工程間管理
IR 赤外線
IRB 治験審査委員会
ISO 国際標準化機構
Kg キログラム
kGy キログレー(Kilo Grey)
LAF 層状気流
LAL リムラスアメーバ細胞溶解物
LC ラベルクレーム(Label Claim)
LOCF 繰越最終観測(Last observation carried forward)
LS ラベル強度(Label strength)
ME 黄斑浮腫
μg マイクログラム
Mg ミリグラム
μJ マイクロジュール
mL ミリリットル
Mm ミリメートル
mmHg ミリメートル水銀柱
mol モル
nまたはN 数
n/a 適用されない
ND 検出せず
Ng ナノグラム
NSAID 非ステロイド性抗炎症薬
NT 未検
OCT 光コヒーレンス断層撮影法
PDE 許容1日暴露(Permitted daily exposure)
PET ポリエチレンテレフタレート
pH 水素電位(Hydrogen potential)
Ph.Eur. ヨーロッパ薬局方
PK 薬物動態
pKa 酸の解離定数
PLGA、PLG ポリ(D,L-ラクチド-コ-グリコリド)
PME 持続性黄斑浮腫
ppm 百万分の一
PS 後区
PVR 増殖性硝子体網膜症
RH 相対湿度
SAE 重篤有害事象
SD 標準偏差
SEM 走査電子顕微鏡
TSE 伝播性海綿状脳症
USA アメリカ合衆国
USP 米国薬局方
UV 紫外線
VEGF 血管内皮成長因子
WPE 超高分子量ポリエチレン
本発明のインプラントは、生分解性ポリマーに分散された活性剤を含有する。インプラント組成は、選択された薬剤放出プロフィール、使用される特定の活性剤、治療される症状、および患者の病歴によって一般に変化する。使用しうる活性剤は下記物質を包含するがそれらに限定されない:ACE阻害薬、内因性サイトカイン、基底膜に影響を与える物質、内皮細胞の増殖に影響を与える物質、アドレナリン作用薬または遮断薬、コリン作用薬または遮断薬、アルドースレダクターゼ阻害薬、鎮痛薬、麻酔薬、抗アレルギー薬、抗炎症薬、抗高血圧薬、昇圧薬、抗細菌薬、抗ウイルス薬、抗真菌薬、抗原虫薬、抗感染薬、抗腫瘍薬、代謝拮抗薬および抗血管新生薬。
眼インプラントに使用しうるステロイド性抗炎症薬は、下記の物質を包含するが、それらに限定されない:21-アセトキシプレグネノロン、アルクロメタゾン、アルゲストン、アムシノニド、ベクロメタゾン、ベタメタゾン、ブデソニド、クロロプレドニゾン、クロベタゾール、クロベタゾン、クロコルトロン、クロプレドノール、コルチコステロン、コルチゾン、コルチバゾール、デフラザコート、デソニド、デスオキシメタゾン、デキサメタゾン、ジフロラゾン、ジフルコルトロン、ジフルプレドネート、エノキソロン、フルアザコート、フルクロロニド、フルメタゾン、フルニソリド、フルオシノロンアセトニド、フルオシノニド、フルオコルチンブチル、フルオコルトロン、フルオロメトロン、フルペロロンアセテート、フルプレドニデンアセテート、フルプレドニソロン、フルランドレノリド、フルチカソンプロピオネート、ホルモコルタール、ハルシノリド、ハロベタソールプロピオネート、ハロメタゾン、ハロプレドンアセテート、ヒドロコルタメート、ヒドロコルチゾン、ロテプレドノールエタボネート、マジプレドン、メドリゾン、メプレドニゾン、メチルプレドニゾロン、モメタゾンフロエート、パラメタゾン、プレドニカルベート、プレドニゾロン、プレドニゾロン25-ジエチルアミノ-アセテート、燐酸プレドニゾロンナトリウム、プレドニゾン、プレドニバル、プレドニリデン、リメキソロン、チキソコルトール、トリアムシノロン、トリアムシノロンアセトニド、トリアムシノロンベネトニド、トリアムシノロンヘキサアセトニド、およびそれらの誘導体。
1つの態様において、活性剤を、インプラントの生分解性ポリマーに均一に分散しうる。使用される生分解性ポリマーマトリックスの選択は、所望の放出動態、患者の耐容能(tolerance)、治療される疾患の種類等によって変化しうる。考慮されるポリマー特性は、埋め込み部位における生物適合性および生分解性、関心対象の活性剤との適合性、および加工温度を包含するが、それらに限定されない。生分解性ポリマーマトリックスは、インプラントの少なくとも約10wt%、少なくとも約20wt%、少なくとも約30wt%、少なくとも約40wt%、少なくとも約50wt%、少なくとも約60wt%、少なくとも約70wt%、少なくとも約80wt%、または少なくとも約90wt%を一般に占める。1つの態様において、生分解性ポリマーマトリックスが、インプラントの約40wt%を占める。
種々の目的のために、他の物質を配合物に使用しうる。例えば、緩衝剤および防腐剤を使用してよい。使用しうる防腐剤は、亜硫酸水素ナトリウム、硫酸水素ナトリウム、チオ硫酸ナトリウム、塩化ベンザルコニウム、クロロブタノール、チメロサール、酢酸フェニル水銀、硝酸フェニル水銀、メチルパラベン、ポリビニルアルコールおよびフェニルエチルアルコールを包含するが、それらに限定されない。使用しうる緩衝剤の例は、所望の投与経路に関してFDAで認可されている炭酸ナトリウム、硼酸ナトリウム、燐酸ナトリウム、酢酸ナトリウム、炭酸水素ナトリウム等を包含するが、それらに限定されない。塩化ナトリウムおよび塩化カリウムのような電解質も配合物に含有させてよい。
本発明のインプラントは、生分解性ポリマーマトリックスに分散した活性剤の粒子を用いて配合されると考えられる。理論に縛られるものではないが、活性剤の放出は、生分解性ポリマーマトリックスの侵食、かつ、眼液、例えば硝子体液への粒状剤の拡散、次に、ポリマーマトリックスの溶解および活性剤の放出によって達成できると考えられる。放出動態に影響を与える要因は、活性剤粒子の大きさ、活性剤の溶解性、活性剤/ポリマーの比率、製造方法、露出される表面積、およびポリマーの侵食速度のような特性を包含すると考えられる。この活性剤放出形態によって得られる放出動態は、架橋ヒドロゲルの場合のような、ポリマー膨潤によって活性剤を放出する配合物によって得られる放出動態とは異なる。その場合、活性剤は、ポリマー侵食によってではなくポリマー膨潤によって放出され、該膨潤は、露出された経路を通って液体が拡散すると共に活性剤を放出する。
本発明のインプラントおよび方法によって治療しうる眼の医学的症状の例は、ブドウ膜炎、黄斑浮腫、黄斑変性、網膜剥離、眼腫瘍、真菌またはウイルス感染症、多病巣性脈絡膜炎、糖尿病性網膜症、増殖性硝子体網膜症(PVR)、交感性眼炎、フォークト-コヤナギ-ハラダ(VKH)症候群、ヒストプラスマ症、ブドウ膜拡散および血管閉塞であるが、それらに限定されない。1つの態様において、インプラントは、ブドウ膜炎、黄斑浮腫、血管閉塞性疾患、増殖性硝子体網膜症(PVR)および種々の他の網膜症のような医学的症状を治療するのに特に有効である。
生分解性インプラントは、強膜における切開後に、ピンセット、トロカール、または他の種類のアプリケータによる配置を包含する種々の方法によって、眼に挿入しうる。ある場合には、切開せずにトロカールまたはアプリケータを使用しうる。好ましい態様において、手持形アプリケータを使用して、1つまたはそれ以上の生分解性インプラントを眼に挿入する。手持形アプリケータは一般に、18〜30GAステンレス鋼針、レバー、アクチュエーターおよびプランジャーを有して成る。
押出法の使用は、インプラントの大量製造を可能にし、ポリマーマトリックスに薬剤が均一に分散したインプラントが得られる。押出法を使用する場合、選択されるポリマーおよび活性剤は、製造に必要とされる温度、一般に少なくとも約50℃において安定である。押出法は、約25℃〜約150℃、より好ましくは約60℃〜約130℃の温度を使用する。
本発明は、後区炎症のような眼症状の治療のための一般的療法に関連した多くの問題(変動する薬物濃度、短い眼内半減期、および高レベルのコルチコステロイドへの長時間の全身的暴露を包含する)に対処することができる眼内薬剤送達システムを見出したことにに基づいている。本発明の眼内薬剤送達システムは、活性医薬としてのデキサメタゾンの使用を含み、その場合、本発明の眼内薬剤放出システムは、デキサメタゾン後区薬剤送達システム(DEX PS DDS)と称することができる。DEX PS DDSは、毛様体輪注射(眼科医に周知の投与法)による後区への配置を意図している。DEX PS DDSは、微粉化デキサメタゾンを含有する生分解性コポリマー、ポリ(乳酸グリコール酸)(PLGA)から構成することができる。DEX PS DDSは、デキサメタゾンを放出することができ、ほぼ35日間にわたって、約350〜700μgの総投与量を与える。これと比較して、他の投与経路(局所、眼周囲、全身的および標準硝子体内注射)は、等レベルのデキサメタゾンを後区に送達するのにより高い1日用量を必要とし、しかも非標的器官がコルチコステロイドに暴露される。2滴のデキサメタゾン眼科用懸濁剤0.1%を1日に4回、両眼に局所投与することは、500μg/日にほぼ相当する。全身的用量は、1,000μg/kg/日もの量になりうる(Pinar V. Intermediate uveitis. Massachusetts Eye & Ear Infirmary Immunology Service. http://www.immunology.meei.harvard.edu/imed.htm.1998; Weisbecker CA, Fraunfelder FT, Naidoff M, Tippermann R,編, 1999 Physician's Desk Reference for Ophthalmology, 第27版, Montvale, NJ:Medical Economics Company, 1998:7-8, 278-279)。DEX PS DDSを使用することによって、従来の局所的、全身的または硝子体内療法に必要とされる用量と比較して、実質的により低い1日用量のデキサメタゾンを、後区に直接的に投与することができ、それによって、潜在的副作用を最小限にしうる。デキサメタンゾンを放出する間に、ポリマーが時間の経過と共に徐々に完全に分解し、従って、患者の眼の後区に配置した後にDEX PS DDSを除去する必要がない。
分子式: C22H29FO5
分子量: 392.47
キラリティー/立体化学 デキサメタゾンは8個のキラル中心を有し、光学活性である。
性状: 白色またはほぼ白色、結晶性粉末
pHおよびpKa: デキサメタゾンはイオン化基を有していない。
融点: 253℃〜255℃
溶解性: 水: 実質的に不溶
エタノール: やや不溶
塩化メチレン: 僅かに可溶
圧縮タブレットインプラントの作製
微粉化デキサメタゾン(Pharmacia, Peapack, NJ)および微粉化疎水性末端50/50PLGA(Birmingham Polymers, Inc., Birmingham AL)を、正確に秤量し、ステンレス鋼混合容器に入れた。容器を密閉し、Turbulaミキサーに載せ、所定の強度、例えば96rpm、および所定の時間、例えば15分間で混合した。得られた粉末ブレンドを、一時に1単位の用量で(one unit dose at a time)、1個取り(single-cavity)タブレットプレスに装填した。プレスを事前設定した圧力、例えば25psi、および時間、例えば6秒間で作動させ、タブレットを形成し、室温でプレスから取り出した。デキサメタゾン/PLGA比は、全ての圧縮タブレットインプラントについて70/30 w/wであった。
押出インプラントの作製
微粉化デキサメタゾン(Pharmacia, Peapack, NJ)および非微粉化PLGAを、正確に秤量し、ステンレス鋼混合容器に入れた。容器を密閉し、Turbulaミキサーに載せ、所定の強度、例えば96rpm、および所定の時間、例えば10〜15分間で混合した。非微粉化PLGA組成物は、親水性末端PLGA(Boehringer Ingelheim, Wallingford, CT)および疎水性末端PLGA(Boehringer Ingelheim, Wallingford, CT)の30/10 w/w混合物を含んでいた。得られた粉末ブレンドを、DACA Microcompounder-Extruder(DACA, Goleta, CA)に装填し、事前設定した温度、例えば115℃、およびスクリュー速度、例えば12rpmに付した。フィラメントを誘導装置に押し出し、所定インプラント重量に対応する正確な長さにカットした。デキサメタゾン/全PLGA(親水性末端および疎水性末端)の比は、全ての押出インプラントについて60/40 w/wであった。
インプラントを硝子体に配置する方法
20ゲージ微小硝子体網膜(MVR)ナイフを使用して10〜12時の間の位置で結膜および強膜を切開することによって、ニュージーランド白ウサギの右眼の後区にインプラントを配置した。27ゲージ針を取り付けた1cc注射器を使用して、硝子体液50〜100μLを除去した。適切なインプラント(薬剤送達システム、DDS)を事前装填した滅菌トロカールを、強膜切開部から5mm挿入し、次に、プッシュワイヤ(push wire)で所定位置に引き込み、後区にインプラントを配置した。次に、強膜および結膜を、7-0 Vicryl縫合糸で閉じた。
350μgデキサメタゾン圧縮タブレットインプラントからのデキサメタゾンの生体内放出
実施例4は、押出インプラントと比較して、圧縮タブレットインプラントからの、デキサメタゾンの高い初期放出、および一般により低い硝子体内濃度を示す。350μg圧縮タブレットインプラント(350T)を、実施例3に記載したようにニュージーランド白ウサギの右眼に配置した。硝子体試料を定期的に採取し、LC/MS/MSによって分析して、生体内デキサメタゾン送達性能を測定した。図1に示すように、デキサメタゾンは、第1日(142.20ng/mL)〜第35日(2.72ng/mL)において、検出可能な平均硝子体内濃度に達し、デキサメタゾンの硝子体内濃度は、時間の経過に伴って徐々に減少した。
350μgデキサメタゾン押出インプラントからのデキサメタゾンの生体内放出
実施例5は、押出インプラントからのデキサメタゾンの、より低い初期放出、および一般により持続性の硝子体内濃度を示す。350μg押出インプラント(350E)を、実施例3に記載したようにニュージーランド白ウサギの右眼に配置した。硝子体試料を定期的に採取し、LC/MS/MSによって分析して、生体内デキサメタゾン送達性能を測定した。図1に関して、350Eは、第1日(10.66ng/mL)〜第28日(6.99ng/mL)において、検出可能な平均硝子体液濃度を示した。350Tインプラントは、第1日(p=0.037)において統計的に有意なより高いデキサメタゾン濃度を示し、一方、350Eは、第21日(p=0.041)において統計的に有意なより高いデキサメタゾンレベルを示した。
700μgデキサメタゾン圧縮タブレットインプラントからのデキサメタゾンの生体内放出
実施例6も、圧縮タブレットインプラントからの、デキサメタゾンの高い初期放出、および一般により低い硝子体内濃度を示す。700μg圧縮タブレット投与形態(700T)を、実施例3に記載したようにニュージーランド白ウサギの右眼に配置した。硝子体試料を定期的に採取し、LC/MS/MSによって分析して、生体内デキサメタゾン送達性能を測定した。図5に示すように、700Tは、第1日(198.56ng/mL)〜第42日(2.89ng/mL)において、検出可能な平均デキサメタゾン硝子体液濃度に達し、時間の経過に伴って硝子体内デキサメタゾン濃度の漸減を示した。
700μgデキサメタゾン押出インプラントからのデキサメタゾンの生体内放出
実施例7は、押出インプラントからのデキサメタゾンの、より低い初期放出、および一般により高い硝子体内濃度を示す。700μg押出インプラント(700E)を、実施例3に記載したようにニュージーランド白ウサギの右眼に配置した。硝子体試料を定期的に採取し、LC/MS/MSによって分析して、生体内デキサメタゾン送達性能を測定した。図5に示すように、700Eは、第1日(52.63ng/mL)〜第28日(119.70ng/mL)において、検出可能な平均デキサメタゾン硝子体液濃度を示した。
インプラントを作製するための押出法
1. DEX PS DDSインプラントを、タブレット成形法、一段押出法および二段押出法によって作製した。
ポリマー組成: ラクチド/グリコリドの比率は、ポリマーの分解動態、従って、インプラントのデキサメタゾン放出プロフィールに、極めて重要であることが確認された。活性剤放出の一貫性を確実にするために、該比率を48%〜52%(wt%)の範囲に調節した。
- アセトンは0.1wt%未満に調節した。
- トルエンは0.0890wt%未満を維持するように調節した。
デキサメタゾンの粒度および粒度分布は、DEX PS DDSの均質性の重要なパラメータであると考えられる。好ましいデキサメタゾン粒度分布は、少なくとも75%の、10μmより小さい(即ち、10μm未満の直径の)デキサメタゾン粒子を有する。より好ましいデキサメタゾン粒度分布は、少なくとも99%の、20μmより小さい(即ち、20μm未満の直径の)デキサメタゾン粒子を有する。インプラントにおける、そのような小さいデキサメタゾン粒子の使用は、インプラントにおける活性剤のより均一な分布(即ち、無集塊)を与え、それによって、インプラントを埋め込んだ際に、活性剤のより均一な放出が得られることを我々は見出した。
(a) PLGA(レゾマーRG502およびRG502H)の微粉砕
ジェットミル(振動供給装置)を使用して、プッシャーノズル、粉砕ノズルおよび粉砕ノズルに関してそれぞれ粉砕圧力60psi、80psiおよび80psiにおいて、30gのRG502(50:50PLGAエステル)を微粉砕した。次に、ジェットミルを使用して、プッシャーノズル、粉砕ノズルおよび粉砕ノズルに関してそれぞれ粉砕圧力20psi、40psiおよび40psiにおいて、60gのRG502Hを微粉砕した。RG502およびRG502Hの両方の平均粒度を、TSI 3225 Aerosizer DSP粒度分析器によって測定した。好ましくは、両方の粉砕ポリマーは20μm以下の平均粒度を有すべきである。
48gのデキサメタゾン、24gの微粉砕RG502Hおよび8gの微粉砕RG502を、96RPMに設定したTurbula振とう機で60分間ブレンドした。
(1) 合計80gのブレンドしたデキサメタゾン/RG502H/RG502混合物を、Haake二軸押出機のホッパーに添加した。Haake押出機を作動させ、下記のパラメータに設定した:
バレル温度: 105℃
ノズル温度: 102℃
スクリュー速度: 120RPM
供給速度設定: 250
案内板温度: 50〜55℃
循環水浴: 10℃
(2) フィラメントを収集した。第一フィラメントは、粉末ブレンドの添加から約15〜25分後に得られた。最初の5分間の押出フィラメントを廃棄した。押出物がなくなるまで、残りのフィラメントを収集した;これは一般に3〜5時間を要する。
96RPMに設定したTurbula振とう機および1つの19mmステンレス鋼球を使用して、前記工程3からのフィラメントを5分間ペレット化した。
(1) 全てのペレットを、同じホッパーに添加し、Haake押出機を作動させた。Haake押出機を下記のパラメータに設定した:
バレル温度: 107℃
ノズル温度: 90℃
スクリュー速度: 100RPM
案内板温度: 60〜65℃
循環水浴: 10℃
(2) 押出物がなくなるまで、全ての押出フィラメントを収集した。これは一般に約3時間を要する。
フィラメントを適切な長さにカットすることによって、DEX PS DDSを350μgまたは700μg投与形態として調製した。
アプリケータ組立て工程の際に、DEX PS DDSを、アプリケータシステムに挿入した。全ての操作をクラス10000クリーンルームで行った。
組立てたDEX PS DDSアプリケータシステムを、乾燥剤の小さい袋を含有するフォイルパウチに入れ、ヒートシールした。滅菌前生物汚染試験のために、工程9の前に、試料を採取した。
完成DEX PS DDSアプリケータシステムおよび乾燥剤の小さい袋を含有するヒートシールしたフォイルパウチを、ボール箱に入れ、その箱を密閉した。これらの製品含有ボール箱の最終滅菌を、25〜40kGyの範囲内のγ線の線量に暴露することによって行った。各バッチからの試料を、Ph. Eur.およびUSP基準に従って、無菌性について試験した。
一段および二段押出インプラントは、それぞれ表DおよびEに示される好ましい特性を有していた。
Claims (21)
- 眼疾患の治療用の生侵食性インプラントであって、生分解性ポリマーマトリックスに分散した活性剤を含んで成り、活性剤粒子の少なくとも約75%が約10μm未満の直径を有するインプラント。
- 活性剤粒子の少なくとも約99%が、約20μm未満の直径を有する請求項1に記載のインプラント。
- 活性剤が、ace-阻害薬、内因性サイトカイン、基底膜に影響を与える物質、内皮細胞の増殖に影響を与える物質、アドレナリン作用薬または遮断薬、コリン作用薬または遮断薬、アルドースレダクターゼ阻害薬、鎮痛薬、麻酔薬、抗アレルギー薬、抗炎症薬、ステロイド、抗高血圧薬、昇圧薬、抗細菌薬、抗ウイルス薬、抗真菌薬、抗原虫薬、抗感染薬、抗腫瘍薬、代謝拮抗薬および抗血管新生薬から成る群から選択される請求項1に記載の生侵食性インプラント。
- 活性剤が、抗炎症薬またはその誘導体を含んで成る請求項1に記載の生侵食性インプラント。
- 活性剤が、ステロイド性抗炎症薬またはその誘導体を含んで成る請求項1に記載の生侵食性インプラント。
- 活性剤が、コルチゾン、デキサメタゾン、フルオシノロン、ヒドロコルチゾン、メチルプレドニゾロン、プレドニゾロン、プレドニゾン、トリアムシノロンおよびそれらの誘導体から成る群から選択される請求項4に記載の生侵食性インプラント。
- 活性剤が、デキサメタゾンを含んで成る請求項1に記載の生侵食性インプラント。
- 眼領域に埋め込む大きさである請求項1に記載の生侵食性インプラント。
- 眼領域が、前眼房、後眼房、硝子体腔、脈絡膜、脈絡膜上腔、結膜、結膜下腔、強膜外隙、角膜内腔、角膜上腔、強膜、毛様体輪、外科的誘導無血管領域、網膜黄斑および網膜から成る群から選択される請求項8に記載の生侵食性インプラント。
- 眼領域が硝子体腔である請求項9に記載の生侵食性インプラント。
- 眼疾患の治療用の生侵食性インプラントであって、生分解性ポリマーマトリックスに分散したステロイド活性剤を含んで成り、ステロイド活性剤粒子の少なくとも約75%が約20μm未満の直径を有するインプラント。
- ステロイド活性剤が、コルチゾン、デキサメタゾン、フルオシノロン、ヒドロコルチゾン、メチルプレドニゾロン、プレドニゾロン、プレドニゾン、トリアムシノロンおよびそれらの誘導体から成る群から選択される請求項11に記載の生侵食性インプラント。
- ステロイド活性剤が、デキサメタゾンを含んで成る請求項12に記載の生侵食性インプラント。
- 眼疾患の治療用の生侵食性インプラントの製造法であって、生分解性ポリマーの複数の押出工程を含んで成る方法。
- 押出工程の前に、生分解性ポリマーを微粉砕する工程をさらに含んで成る請求項14に記載の方法。
- 生分解性ポリマーが、ポリ(乳酸-コ-グリコール酸)(PLGA)コポリマーを含んで成る請求項14に記載の方法。
- 乳酸モノマー/グリコール酸モノマーの比が、約50/50wt%である請求項16に記載の方法。
- PLGAコポリマーが、生侵食性インプラントの約20〜約90wt%である請求項16に記載の生侵食性インプラント。
- PLGAコポリマーが、生侵食性インプラントの約40wt%である請求項18に記載の方法。
- 下記の工程を含んで成る眼疾患治療用生侵食性インプラントの製造法:
(a) 生分解性ポリマーを微粉砕する工程;
(b) 微粉砕生分解性ポリマーおよび活性剤粒子をブレンドし、それによって微粉砕生分解性ポリマーと活性剤粒子とのブレンド混合物を得る工程(活性剤粒子の少なくとも約75%は、約20μm未満の直径を有する);
(c) ブレンド混合物の第一押出を行い、それによって第一押出生成物を得る工程;
(d) 第一押出生成物をペレット化する工程;
(e) ペレット化した第一押出生成物の第二押出を行い、それによって、眼疾患用の生侵食性インプラントを得る工程。 - 請求項14の方法によって製造した眼疾患治療用の生侵食性インプラント。
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US10/918,597 US20050048099A1 (en) | 2003-01-09 | 2004-08-13 | Ocular implant made by a double extrusion process |
PCT/US2005/026500 WO2006036280A1 (en) | 2004-08-13 | 2005-07-25 | Ocular implant made by a double extrusion process |
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JP2020055862A (ja) * | 2013-11-15 | 2020-04-09 | アラーガン、インコーポレイテッドAllergan,Incorporated | 持続的薬物送達インプラントによる眼の状態の治療の方法 |
JP2017528525A (ja) * | 2014-09-19 | 2017-09-28 | オクラー リミテッド | 眼科用医薬組成物 |
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