JP5902766B2 - 眼球インプラントに治療薬を注入するためのシステム - Google Patents
眼球インプラントに治療薬を注入するためのシステム Download PDFInfo
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- JP5902766B2 JP5902766B2 JP2014140048A JP2014140048A JP5902766B2 JP 5902766 B2 JP5902766 B2 JP 5902766B2 JP 2014140048 A JP2014140048 A JP 2014140048A JP 2014140048 A JP2014140048 A JP 2014140048A JP 5902766 B2 JP5902766 B2 JP 5902766B2
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Classifications
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Description
また、公知の半透膜の少なくとも幾つかは時間とともに変化し得る高分子の透過性を有し、更には公知の半透膜の少なくとも幾つかは幾分脆弱であり得るため、長期間の薬物放出が少なくとも幾つかの例では理想を下回る場合があることも本発明の実施形態に係る研究は示唆している。毛細管が薬物放出用として提案されてきているが、本発明の実施形態に係る研究は、例えば場合によって気泡形成や部分的な目詰まりにより、毛細管を通る流れが少なくとも幾つかの例では理想を下回り得ることも示唆している。
たとえば、市販治療薬の容積は治療期間、例えば1カ月を有するボーラス注入に対応し得、組成容量を受容するように調整された貯蔵部の容積及び放出速度は、少なくとも約2の倍数で、注入容積の治療持続期間を例えば1か月から2カ月以上まで延ばすことができる。
注入ポート部は、結膜下に配置されるようにされた滑らかな上面を有していてもよい。
容器は貫通可能な障壁を有していてもよく、貫通可能な障壁及び保持構造部の各々は、これらが眼内に位置決めされるときに周囲の組織のびらんを最小にするよう構成されている。保持構造部は、装置が補充間に眼内へ移動することを抑制又は防止できる。保持構造部は、容器から外側に延びていてもよく、かつ、標準的な縫合糸によって強膜に取り付けるための少なくとも1つの縫合穴を有していてもよい。
治療するための網膜の標的位置が同定される。治療薬の治療量を有する容器が位置決めされる。容器は長期間に少なくとも1つの治療薬の治療量を放出する多孔質構造体を有する。硝子体液の対流により標的位置に治療薬を送達するように、多孔質構造体は網膜から離れた位置の硝子体液中に位置決めされる。
保持構造部が、長期間に患者の眼の強膜に連結するように容器に取り付けられている。
保持構造部が、長期間に患者の眼の強膜に連結するように容器に取り付けられている。
容器は、貯蔵部に連結された障壁であって、貯蔵部内に治療薬を収容するように貯蔵部の少なくとも一部に沿って配置された障壁を有する。多孔質構造体が、貯蔵部に連結された第1の側と、硝子体液に連結するための第2の側とを有する。多孔質構造体は、第1の側と第2の側との間を延びる厚みと、第1の側の領域及び第2の側の領域に対応する断面寸法とを有する。多孔質構造体の断面寸法は、長期間に治療薬を放出する容器の断面寸法の少なくとも約10パーセントを有する。保持構造部が、長期間に患者の眼の強膜に連結するように容器に取り付けられている。
れている。
治療装置が、患者の眼の硝子体液中へ少なくとも1つの治療薬を放出するように供給される。治療装置は、容器と容器に取り付けられた保持構造部とを有する。保持構造部は、第1の方向に延びる第1の長い距離幅と第2の方向に延びる第2の短い距離幅とを有する狭部を有する。第1の長い距離幅は第2の短い距離幅よりも広い。細長い切開部が強膜内に形成され、切開部は眼の扁平部に沿って延びる長さと幅とを有し、長さは幅よりも大きい。治療薬を放出するように眼内に容器が位置決めされる。第1の長い距離幅の部分が実質的に細長い切開部に沿って延びるように、かつ第2の短い距離幅の部分が実質的に切開部の幅の部分を横切って延びるように保持構造部の狭部が細長い切開部と並べられる。
治療装置内へ組成の容積を注入することで眼を治療するよう治療装置が供給され、装置は、治療薬の容積を収容するチャンバーを有する容器と、チャンバーから硝子体液に治療薬を放出するメカニズムとを有する。容器の容積及び放出メカニズムは、組成の容積の各注入にて範囲内の治療薬の治療濃度を用いて眼を長期間治療するように調整され、長期間は期間の少なくとも約2倍を成す。
治療装置。
長期間は少なくとも90日以上、例えば少なくとも180日、又は少なくとも1年、少なくとも2年若しくは少なくとも3年以上を有していてもよい。硝子体内のルセンティス(商標)などの治療薬の治療濃度の目標閾値は、少なくとも0.1μg/mLの治療濃度を有していてもよい。たとえば、目標閾値濃度は、長期間に約0.1μg/mLから約5μg/mLの濃度を有していてもよく、その上限値は刊行されたデータを用いた実施例9に示す計算に基づいている。目標閾値濃度は薬物に依存するため、他の治療薬では変化可能である。
注入器187の注射器188に連結された注射針189は、容器110Cから治療薬110を引き込むために用いることができる。容器110Cは、隔膜を有するボトル、単回送達分の容器、又は組成を混合するに適した容器などの市販容器を有していてもよい。治療薬110の容量110Vが、眼内に位置決めされた治療装置100内へ注入するための注入器187内へ引き込むことができる。容量110Vは、所定の量、例えば治療装置110の容器の容積や硝子体液中への意図された注入量に基づいた容量を有していてもよい。
容量110Vの実施例は、治療装置を介して硝子体液中へ容量110Vの第1部分を注入するように、かつ治療装置110の容器内の容量110Vの第2部分を含むように容器の容積を超えていてもよい。容器110Cは治療薬110の組成110Fを有していてもよい。組成110Fは治療薬の市販組成、例えば表1Aを参照して本明細書で述べるような治療薬を有していてもよい。本明細書で述べる実施形態に係り使用するに適合可能な市販組成の非限定的な実施例は、例えばルセンティス(商標)及びトリアムシノロンを含む。
組成110Fは市販治療薬、例えばアバスチン(商標)の濃縮又は希釈組成であってもよい。硝子体液のオスモル濃度及び緊張性は約290から約320の範囲内にすることができる。たとえば、硝子体液のオスモル濃度及び緊張性と実質的に類似するオスモル濃度及び緊張性、例えば約280から約340、例えば約300mOsmの組成を有するように、アバスチン(商標)の市販組成を希釈できる。治療薬110は硝子体液と実質的に類似するオスモル濃度及び緊張性を有することができる一方で、治療薬110は、硝子体液に対して高い浸透圧の溶液又は硝子体液に対して低い浸透圧の溶液を有することができる。
長期間に治療薬を放出するための治療薬の組成及びオスモル濃度を実験して求めるように、当業者は本明細書で述べる教示に基づき実験を実施できる。
(a)免疫グロブリンG 150キロダルトン 10.5nm(b)ウシ血清アルブミン 69キロダルトン 7.2nm(c)免疫グロブリンGのFab片 49キロダルトン 流体力学的直径について報告なし
多孔質構造体は、厚さ105Tを備えていてもよい。多孔質構造体は、直径150Dを備えていてもよい。
放出速度 = (D P / F)A(cR − cV)/L
但し、
cR = 貯蔵部内の濃度
cV = 貯蔵部外、すなわち硝子体内の濃度
D = 貯蔵部溶液における治療薬の拡散係数
P = 多孔質構造体の多孔率
F = 多孔質構造体のチャネルのねじれパラメータに対応し得るチャネル・パラメータ
A = 多孔質構造体の面積
L = 多孔質構造体の厚さ(長さ)
蓄積放出 = 1−cR/cR0=1−exp((−D PA/FL VR)t)
但し、
t = 時間、
Vr = 貯蔵部容積
DTA,37℃ = DBSA,20C = (η20C/η37℃)(MWBSA/MWTA)1/3
但し、MWは、BSAまたはテスト化合物の分子量を指し、ηは水の粘性である。以下は、関心タンパク質の拡散係数を表にしたものである。
cR = cR0 exp ((−D PA/FL VR)t)
および
累積放出 = 1−cR/cRO
この状況では、装置からの放出速度(上記の方程式によって説明されている)を眼からの排出速度とする質量バランスk cV VVから、モデルを導くことができる。再配列によって、硝子体の濃度に対して以下の方程式を得る。すなわち、
cV =装置からの放出速度/k VV.
非線形部材は、貯蔵部622を備えるために、治療薬で充填される管腔621を含んでいてもよい。多孔質構造体623は、非線形部材の遠位端624に配置され、治療薬を放出することが可能である。多孔質構造体は、非線形部材のさらなる位置または代替の位置に設置されてもよい。たとえば、キャップが強膜に対して配置される場合に硝子体液に治療薬を放出するように、複数の多孔質構造体が、非線形部材に沿って、キャップと遠位端との間に配置される位置に配置されてもよい。
浸透性障壁は、浸透性障壁がアクセスポート180に挿入可能なようにサイズ設定された弾性体を含んでいてもよい。浸透性障壁は、たとえば、シロキサンまたはゴムなど1つ以上の弾性体を含んでいてもよい。浸透性障壁は、浸透性障壁をアクセスポートに保持するタブ184Tを含んでいてもよい。浸透性障壁184は、アクセスポート180を封止するようサイズ設定された、面取りされた上側リム184Rを含んでいてもよい。貯蔵部容器130のアクセスポート180は、タブ184Tがアクセスポートの環状または細長い内側チャネルを係合する場合に、面取りされたリムを係合し、浸透性障壁をアクセスポート180に封止する面取りされた上表面を含んでいてもよい。浸透性障壁が患者および治療医によって明視化されるように、浸透性障壁184は、不透明材料、たとえば灰色の材料、たとえばシリコーンを含んでいてもよい。
貯蔵部容器は、たとえばアクリル酸塩、ポリメチルメタクリレート、シロキサン、金属、チタン、ステンレス鋼、ポリカーボネート、ポリエーテルエーテルケトン(PEEK)、ポリエチレン、ポリエチレンテレフタレート(PET)、ポリイミド、ポリアミドイミド、ポリプロピレン、ポリスルホン、ポリウレタン、ポリフッ化ビニリデン、またはポリテトラフルオルエチレン(PTFE)など、多くの生体適合性材料のうちの1つ以上を含んでいてもよい。貯蔵部容器の生体適合性材料は、たとえばアクリル酸塩、ポリアクリレート、メタアクリル酸メチル、ポリメタクリル酸メチル(PMMA)、ポリカーボネートまたはシロキサンのうちの1つ以上など、光透過性材料を含んでいてもよい。貯蔵部容器130は、フランジ122および細長い狭部120NEを含む保持構造部120を形成するように、1片の材料から機械加工されることができるか、または射出成形されることができる。フランジ122は、半透明材料を含んでいてもよいので、医師がフランジの下にある組織を明視化して患者を判断し、移植時に装置100が見えるのを減少させることができる。貯蔵部容器130は、軸100Aに沿ってアクセスポート180から多孔質構造体150まで延在するチャネルを含んでいてもよく、本願明細書に記載されているように、貯蔵部の容積および多孔質構造体150の放出速度に従って、装置100に注入される製剤を放出することができる。多孔質構造体150は、たとえば接着剤で、治療装置100の遠位端に固定されることができる。代わりに、または組み合わせて、貯蔵部容器130の遠位端は、多孔質構造体150を受けるようにサイズ設定された内径を含んでいてもよく、貯蔵部容器130は、貯蔵部140の所定サイズを規定するために、遠位端の所定位置に多孔質構造体150を配置するストッパを含んでもよい。
代替として、拡張式支持部は拡張時に湾曲してもよい。拡張式装置は、遠位端に配置され、拡張式支持部に固定されている多孔質構造体150を含む。拡張式装置は、たとえば浸透性障壁184を備えたアクセスポート180を含んでいてもよい。拡張式構成では、患者の光路OPの大部分から装置が実質的にはっきり見える。
率 = Vr(dCr/dt)=−D(PA/TL)Cr
但し、率 = 装置からの治療薬放出速度
Cr =貯蔵部における治療薬濃度
Vr =貯蔵部容積
D =拡散定数
PA/TL =RRI
P =多孔率
A=面積
T =ねじれ= F =チャネル・パラメータ
実質的に一定の容積注入では、
Cr0 =(注入容積)(製剤濃度)/Vr
但し、Cr0 =製剤の注入に伴う貯蔵部内の初期濃度
注入容積=50μLでは、
Cr0 = (0.05 mL)(10 mg/mL)/Vr (1000 μg/ 1mg) = 500 μg/Vr
速度 = x(500 μg)exp(−xt)
但し、t =時間
x = (D/Vr)(PA/TL)
硝子体の質量バランスに関しては、
Vv(dCv/dt) =装置からの率= kVvCv
但し、Vv =硝子体容積(約4.5ml)
Cv =硝子体における治療薬濃度
k =硝子体からの薬の率(1/硝子体内の薬の半減期に比例する)
本願明細書において記載されている、Cvが実質的に一定のままであり、時間とともにゆっくりと変化する(すなわち、dCv/dtが約0である)実施形態に適切な条件では、
Cv=(装置からの率)/(kVv)
kVvが実質的に一定であるので、Cvの最大値は、装置からの率を最大化する条件に対応することとなる。装置への注入から所与の時間(たとえば180日)で、最大値Cvは、最大率をもたらすxの値であることがわかる。xの最適値は、所与の時間で、
d(率)/dx= 0を満たす。
率= 500(x)exp(−xt) = f(x)g(x)
但し、f(x)=500x、およびg(x)=exp(−xt)
d(率)/dx = f’(x)g(x)+ f(x)g’(x)= 500(1−xt)exp(−xt)
所与の時間では、1−xt = 0かつxt = 1の場合、t,d(率)/dx = 0
(D/Vr)(P A/TL)t = 1の場合、率は最大となる。
所与の容積では、最適PA/TL =最適RRI= Vr/(Dt)
それゆえに、所与の時間tでの最も高いCvは、
所与のVrでは、最適RRI =(PA/FL)として生じる。
また、率(Vr)/(RRI) = (Vr)/(PA/TL) = Dtは、その時の最適率を決定することになる。
たとえば、多孔質構造体の最適放出速度指数および最適貯蔵部容積は、所定の長期間、たとえば90日間、最小阻止濃度を超える治療濃度を達成するために、治療薬の所定量、たとえば50μLを受容するようにサイズ設定されている。貯蔵部の最大容積は、最適容積の約2倍以下に制限されることができる。貯蔵部容積および多孔質構造体を市販の製剤の注入容積に合わせることによって、同じ容積の市販の注入可能な製剤を受けるより大きな貯蔵部容積と比較して、装置からの治療量の放出時間を増加させることができる。本願明細書において記載されている多数の例は、製剤量を受容し長期間放出するように共に調整されている多孔質フリット構造体および貯蔵部容積を示しているが、貯蔵部に合わせられる多孔質構造体は、多孔質フリット、透過性膜、半透過性膜、毛細管または蛇行チャネル、ナノ構造体、ナノチャネル、または焼結ナノ粒子のうちの1つ以上を含んでもよく、そして、当業者は、製剤量を受容し、治療量を連続した期間放出するように1つ以上の多孔質構造体および容積を調整するために、放出速度の特徴、たとえば放出速度指数を決定することができる。
実施例1
図8は、Luer−Lok(登録商標)の先端および様々な直径の針を有する1mlの注射器から製造される規定された直径の出口ポートを備えた貯蔵部を示す。針は、全長8mmに調整したが、ここでは2mmが針ハブを越えて延在している。金属性のバリを顕微鏡下で除去した。図8−1は、注射器に取り付けられる針を示し、ついで、リン酸緩衝液(Spectrum Chemicals, B−210)における、フルオレセインナトリウムの溶液2.4mg/mL、分子量376Daで注射器を充填した。気泡を除去し、0.05mlを計量分配することができるように注射器を調整した。結果として生じた貯蔵部の形状を図8−1に示す。第1の拡張領域は、針ハブの内側と注射器の先端とによって画定されている。第2の拡張領域は、注射器内部である。貯蔵部の全容積は、0.14mlである。
実施例1
表1C 出口ポートを通るフルオレセインの放出
図11は、1mLの注射器にあるLuer−Lokの先端を切断することによって製造した多孔質膜を備えた貯蔵部を示す。注射器の端部を平滑化し、面取りした。0.2μmの孔径を備えたナイロン膜を注射器の端部を覆って配置し、1片のシリコーン管で固定した。注射器の内径は4.54mmであり、露出した膜面積16mm2を得た。PBSにおけるウシ血清アルブミン(Sigma A7906−100G)約300mg/mlのうち約100mlを添加できるように、ピストンを除去した。ピストンを交換して、空気を除去し膜を通るわずかな量の液体を押すように動かした。短時間水に浸すことによって、膜および注射器の外側を洗浄した。ついで、PBS 5mLを含む15mLバイアルに貯蔵部を配置した。蒸発を回避するために、バイアルの頂部をパラフィルムで封止した。0.5から1日の周期的な間隔で、PBSを含む新規のバイアルに貯蔵部を移動した。バイアルに蓄積したBSA量を可視光(280nm)の吸収を介して測定することによって、膜を通る拡散を測定した。2つの複製からの送達速度を図11−1に示す。このデータは、次数100kDaの分子量を備えた関心の治療薬が、孔径0.2μmの多孔質膜を通って容易に移送するであろうことを示唆している。
視野に対する干渉を最小限に抑えるために、少なくともいくつかの装置設計は、約6mmを超えて硝子体内に延びることはない。さらに、装置を硝子体内に延在させることは有益であり得る。というのは、ついで、眼球の壁からの距離だけ、薬を放出することができるからである。抗体などの高分子は、拡散プロセスではなく対流プロセスによって、硝子体から主に除去される(Computer SimμLation of Convective and Diffusive Transport of Controlled−Release Drμgs in the vitreous Hμmor, by Stay, MS; Xu, J, Randolph, TW; and VH Barocas, Pharm Res 2003, 20(1), pp. 96−102を参照)。毛様体による眼房水の分泌によって生じる圧力によって、対流を駆動することができ、硝子体中の流れは網膜に向かっている。周縁網膜に対してより多くの治療薬を送達すると考えられる、眼球と平坦なポートを有する装置とは対照的に、硝子体に延びている出口ポートでは、眼の後ろで網膜の中心に向かって薬が対流によって移動するとより考えられ得る。
23本および30本のゲージ針を使用している実施例1に記載の放出の研究を10週にわたり続けた。結果を、フィックの拡散法則に基づいて、貯蔵部内の濃度の貯蔵部からの放出速度への変化と関連するモデルと比較する。この単純なモデルは、貯蔵部の濃度が均一であり、受容液体、すなわち硝子体の濃度が無視できると想定している。微分方程式を解くことによって、1つのオリフィスを備えた貯蔵部からの以下の治療薬の累積放出を得る。すなわち、
累積放出 = 1−cR/cRO = 1−exp ((−DA/L VR)t)
但し、
cR = 貯蔵部濃度
VR = 貯蔵部容積
D = 拡散係数
A = オリフィスの面積
L = オリフィスの厚さ
t = 時間
注射器および焼結多孔質のチタン・シリンダ(Applied Porous Technologies, Inc., Mott CorporationまたはChand Eisenmann Metallurgicalから入手可能)から、貯蔵部を製造した。これらは、チタン粒子から加工された、直径が0.062インチ、厚さが0.039インチの焼結多孔質シリンダであった。多孔率は0.17であり、約3から5マイクロメートルの平均孔径を備えている。多孔質シリンダは、気泡位置の測定に従って媒質グレード0.2と特徴づけられる。多孔質シリンダを、デルリン(Delrin)(登録商標)から機械加工されたスリーブに圧入した。スリーブは、1つの平坦面全体を貯蔵部の溶液に、他の平坦面全体を面積1.9平方ミリメートルに対応するバイアルの受容溶液に露出させた。1mLのポリプロピレン注射器の先端を切断し、注射器の内径よりもわずかに大きな外径を備えたポリマースリーブを受けるように機械加工した。多孔質シリンダ/スリーブを、改変した注射器に圧入した。
多孔質シリンダは、貯蔵部と受容溶液とに露出する面積が等しいので、チャネル・パラメータは、効果的経路長のチャネル・パラメータ1.6に対応し、媒質グレード0.2から調製された多孔質のチタン・シリンダに対して1.6のねじれを示唆する。
貯蔵部を、実施例5に記載したのと同様に注射器および多孔質の焼結チタン・シリンダから製造した。多孔質の焼結チタン・シリンダ(Applied Porous Technologies, Inc., Mott CorporationまたはChand Eisenmann Metallurgicalから入手可能)は、直径が0.082インチ、厚さが0.039インチ、媒質グレードが0.2であり、チタン粒子から加工された。多孔率は0.17であり、約3から5マイクロメートルの平均孔径を備えている。多孔質シリンダは、気泡位置の測定に従って媒質グレード0.2と特徴づけられる。
多孔質シリンダを、デルリンから機械加工されたスリーブに圧入した。スリーブは、1つの平坦面全体を貯蔵部の溶液に、他の平坦面全体を面積3.4平方ミリメートルに対応するバイアルの受容溶液に露出させた。1mLのポリプロピレン注射器の先端を切断し、注射器の内径よりもわずかに大きな外径を備えたポリマースリーブを受けるように機械加工した。多孔質シリンダ/スリーブを、改変した注射器に圧入した。接着剤を備えたカプトン膜を、受容溶液に露出する表面に貼付けて、マスクを作製し、被露出領域を減少させた。第1の場合では、マスクの直径は0.062インチであり、面積1.9平方ミリメートルが受容溶液に露出していた。第2の場合では、マスクの直径は0.027インチであり、面積0.37平方ミリメートルが受容溶液に露出していた。
プロトタイプ装置を、316Lのステンレス鋼粒子から加工された、直径が0.155インチ直径、厚さが0.188インチの円筒形の、管状にした焼結多孔質ステンレス鋼シリンダ(Applied Porous Technologies, Inc., Mott CorporationまたはChand Eisenmann Metallurgicalから入手可能)から製造した。多孔質シリンダは、気泡位置の測定による0.1の媒質グレードとして特徴づけられる。媒質グレード0.1のステンレス鋼の抵抗特性を特徴づけるために、面積が12mm2のこれらの大きな既製の多孔質シリンダで、この研究を行った。
プロトタイプ装置を、316Lのステンレス鋼粒子から加工された、直径が0.031インチ直径、厚さが0.049インチの円筒形の、管状にした焼結多孔質ステンレス鋼シリンダ(Applied Porous Technologies, Inc., Mott CorporationまたはChand Eisenmann Metallurgicalから入手可能)から製造した。多孔質シリンダは、気泡位置の測定により0.2の媒質グレードとして特徴づけられる。この多孔質シリンダを特注として得た。大径で媒質グレード0.2の多孔質ステンレス鋼のシリンダを用いた(データを示さず)先の研究と、本願明細書において記載されているモデルに基づく予測とから、特性を決定した。この多孔質体シリンダの各表面積は、0.5mm2である。
本願明細書に記載されている方程式に基づいて、治療薬の硝子体濃度を予測することができる。表4は、各々のシミュレーション1、シミュレーション2、シミュレーション3、シミュレーション4およびシミュレーション5のそれぞれに適用されるパラメータ値を示す。半減期および硝子体容積は、サルのモデルに対応する(J. GaudreauLt et al.., Preclinical Pharmacokinetics of Ranibizumab (rhuFabV2) after a Single Intravitreal Administration, Invest Ophthalmol Vis Sci 2005; 46: 726−733) (Z. Yao et al., Prevention of Laser PhotocoaguLation Induced Choroidal NeovascuLarization Lesions by Intravitreal Doses of Ranibizumab in Cynomolgus Monkeys, ARVO 2009 abstract D906)。放出速度プロファイルを決定するために、パラメータPA/FLを変更することができる。たとえば、Aの値が約1mm2とすることができ、多孔率が約0.1(PA=0.1mm2)とすることができ、長さが約1mmであってもよく、ねじれに対応し得るチャネルフィットパラメータが約2(FL=2 mm)であってもよいので、PA/TLは、約0.05mmとなる。当業者は、本願明細書に記載されている教示に基づいて、長期間治療薬を延長して放出するための面積、多孔率、長さ、およびチャネルフィットパラメータを経験的に決定することができる。
500μgの単回注射は、毎月の間隔で与えることのできるLucentis(商標)の50μLボーラス注射に対応し、硝子体のLucentis(商標)(ラニビズマブ)の治療濃度の範囲は、たとえば約1ヵ月で約100μg/mLから約0.1μg/mLの最小抑制(治療)濃度に及ぶ。硝子体の治療濃度の範囲の下位に対応する最小阻止濃度は、本願明細書に記載されている実施例に従って、当業者によって経験的に決定されることができる。たとえば、硝子体の濃度を少なくとも約1μg/mLにするように、一連の6つのLucentis(商標)のそれぞれ5μgの低用量の研究を行うことができ、注入の治療上の利益は本願明細書において記載されていると判断される。
所定量は、毎月のボーラス注射量、たとえば50μLに相当する。治療装置は、容積が25μLの実質的に一定の容積の容器貯蔵部を含んでもよいので、継続および/または制御して放出するために、50μL注入のうちの最初の25μLの部分が貯蔵部に含まれ、50μLの注入のうちの第2の25μLの部分が多孔質構造体を通過して、25μLのボーラスで硝子体内に放出される。装置に注入する充填効率は、100%未満を含んでいてもよく、その充填効率に基づいて、本願明細書において記載されている教示に従って貯蔵部容積および注入容積を調整することができる。たとえば、充填効率は約90%を含んでいてもよいので、治療装置に注入される50μLに対して、第1の部分は、容器貯蔵部のチャンバに含有されている約22.5μLを含み、第2の部分は、装置を通過する約27.5μLを含む。硝子体液のLucentis(商標)の初期濃度は、貯蔵部装置に注入後すぐの約60μg/mLに相当する。硝子体液のLucentis(商標)濃度は、90日で約3.2μg/mLまで減少する。第1の注入から約90日後のLucentis(商標)の第2の50μLの注入によって、濃度が約63μg/mLまで増加する。硝子体液のLucentis(商標)濃度は、第1の注入後180日、および第2の注入後90日で約3.2μg/mLまで減少する。これらの計算値が示すのは、50μLを装置に注入した状態で、Lucentis(商標)濃度を、1mlにつき約3μgの最小阻止濃度を超えて連続的に維持することができることである。患者を治療するために、たとえば数年間で90日ごとに追加的に注入して、治療薬を送達することができる。
濃度は、360日で約0.6μg/mLとなり、最小阻止濃度約0.5に基づいて、1年に及んで単回注射での治療に適することができる。本願明細書において記載されている教示に基づいて、最小阻止濃度を当業者によって経験的に決定することができる。
硝子体内の180日のラニビズマブ濃度は、約3.128μg/mLである。
硝子体内の180日のラニビズマブ濃度は、約3.174μg/mLである。
硝子体内の180日のラニビズマブ濃度は、約3.185μg/mLである。
硝子体内の180日のラニビズマブ濃度は、約3.152μg/mLである。
硝子体内の180日のラニビズマブ濃度は、約3.065μg/mLである。
図20は、実施例10のように貯蔵部内における治療薬懸濁液の算出された時間放出プロファイルを示す。RRIが1.2mmである10μLの装置として、ヒトの硝子体中のトリアムシノロンアセトニド濃度を測定し、示した。計算は、懸濁液に対する上記の方程式に基づくものであった。プロファイルを数値シミュレーションによって作成した。T=0から即座に始まる一定の送達速度1μg/日を想定すると、ヒトの眼の硝子体中の濃度は、1日で定常状態の値の99%以内に到達することができる。薬物放出プロファイルの反対側の末端では、シミュレーションは、固体薬物すべてが実質的に無くなった場合の硝子体濃度を示す。すなわち、溶解薬物の99%以上が1日以内に送達される。
図21は、実質的に同様の多孔質フリット構造体および16μLの貯蔵部および33μLの貯蔵部を含む治療装置の放出速度プロファイルを示す。各フリットの放出速度指数は、約0.02であった。16μL貯蔵部をそれぞれ含む2つの治療装置と、33μLの貯蔵部をそれぞれ含む2つの治療装置とに対する放出速度が示されている。33μLの貯蔵部を含む装置が、16μLの貯蔵部を含む装置の約2倍の速度で、Avastin(商標)を放出した。これらの測定データが示すのは、放出速度指数および貯蔵部のサイズが、放出速度プロファイルを決定することができるので、連続した時間治療薬を放出するように放出速度指数および貯蔵部を構成することができることである。
25mg/mLのAvastin(商標);
フリット#2(0.031x 0.049”、媒質グレード0.2μm、316L SS, Mott Corporation);
上の実施例8と実質的に同様の材料(テフロン熱収縮チュービングおよびシリコーン隔壁);
37℃;
2つの複製のうちの1つが気泡を形成した場合、データを切り捨てる。下記の表5Aのデータを参照。
25mg/mLのAvastin(商標);
フリット#2(0.031x 0.049”、媒質グレード0.2μm、316L SS, Mott Corporation);
固体ビーズから機械加工され、金属棒によって閉止された;
37℃;
2つの複製のうちの1つが気泡を形成した場合、データを切り捨てる。
表5A.測定されたAvastin(商標)の放出およびRRI
図22Aは、厚さが0.049”の多孔質フリット構造体を備えたAvastin(商標)に対する累積放出を示す。実験が使用したのは、
25mg/mLのAvastin(商標);
フリット#2(0.031x 0.049”、媒質グレード0.2μm、316L SS,Mott Corporation);
ネジを有する機械加工されたポリカーボネート代用薬;
貯蔵部容積37μL;
37℃。
装置番号およびそれぞれに対応するRRIの検査済みの装置が、下の表5Bにおいて一覧を示す。計測に基づく測定RRIは0.02であり、本願明細書において記載されている治療薬の放出のモデルと一致している。各試験装置の測定RRIに関するいくつかの可変性が記されているが、各装置のRRIは、治療薬の放出を測定するのに使用されることができ、多孔質構造体は、本願明細書において記載されている気体流によってさらに特徴づけられて、患者に装着する前にRRIを測定することができる。
25mg/mLのAvastin(商標);
フリット#3(0.038x 0.029”、媒質グレード0.2μm、316L SS, Mott Corporation);
ネジを有する機械加工されたポリカーボネート代用薬;
貯蔵部容積37μL;
37℃。
装置番号およびそれぞれに対応するRRIの検査済みの装置が、下の表5Cにおいて一覧を示す。計測に基づく測定RRIは、0.034であり、本願明細書において記載されている治療薬の放出のモデルと一致している。各試験装置の測定RRIに関するいくつかの可変性が記されているが、各装置のRRIは、治療薬の放出を測定するのに使用されることができ、多孔質構造体は、本願明細書において記載されているように、気体流によってさらに特徴づけられて、患者に装着する前にRRIを測定することができる。
25mg/mLのAvastin(商標);
フリット#6(0.038x 0.029”、媒質グレード0.2μm、316L SS,Mott Corporation);
ネジを有する機械加工されたポリカーボネート代用薬;
37℃。
計測に基づく測定RRIは、0.05mmであり、本願明細書において記載されている治療薬の放出のモデルと一致している。
25mg/mLのAvastin(商標);
フリット#5(0.038x 0.029”、媒質グレード0.1μm、316L SS,Mott Corporation);
ネジを有する機械加工されたポリカーボネート代用薬;
貯蔵部容積20μL;
37℃。
計測に基づく測定RRIは、0.03であり、本願明細書において記載されている治療薬の放出のモデルと一致している。
これらの数値データはまた、現在の臨床ボーラス注射の範囲内で装置から放出される治療薬の濃度を示す。たとえば、Lucentis(商標)のような治療薬の最大の放出が患者にとって安全な範囲内にあるように、Cmaxは、0.01から0.1までのRRIに基づいて、それぞれ2.1から11.9まで変化する。
表6A.MICを超える時間(日)の計算(20μLの貯蔵部容積、T 1/2=9日、貯蔵部内の薬物濃度=10mg/ml)
表6B.MICを超える時間(日)の計算(20μLの貯蔵部容積、T 1/2=9日、貯蔵部内の薬物濃度=40mg/ml)
表6C.MICを超える時間(日)の計算(50μLの貯蔵部容積、T 1/2 = 9日、貯蔵部内の薬物濃度 = 40mg/ml)
所望の連続した期間放出するよう、貯蔵部および/または治療薬の量を調整することができる。
多孔質フリット構造体を通る小分子薬物の放出を測定するために、多孔質フリット構造体を通る貯蔵部からのフルオレセインの放出の研究を行った。フルオレセイン・モデルが示しているのは、本願明細書において記載されている多孔質フリット構造体および貯蔵部が、小分子薬物を送達する用途に適していることである。フルオレセイン・データと関連してAvastin(商標)、Lucentis(商標)およびBSAの放出プロファイルが示しているのは、多孔質フリット構造体および貯蔵部が、多くの薬物、分子、ならびに多くの分子量および分子サイズの治療薬の徐放性のために使用されることができることである。
2mg/mlのフルオレセインナトリウム;
フリット#2(0.031x0.049”、媒質グレード0.2μm、316L ss、Mott Corporation);
ネジを有する機械加工されたポリカーボネート代用薬;
37℃。
プレートリーダを用いてフルオレセインのサンプルを492nmでUV吸光度によって分析した。計測に基づく測定RRIは0.02であり、本願明細書において記載されている治療薬の放出モデルと一致している。
実験が使用したのは:
10mg/mlのLucentis(商標);
ネジを有する機械加工されたポリ(メタクリル酸メチル)代用薬;および、
貯蔵部容積30μL;
37℃。
あらゆる多孔質フリット構造体は、316L SS, Mott Corporationである。示されるデータは、気泡の成長または少ない容器容積を示した少しのサンプルを除いて、あらゆる装置からの測定データである。
図26Aおよび図26Bは、それぞれ、0.2の媒質グレードおよび0.5の媒質グレードの多孔質材料の多孔質フリット構造体の破断縁部からの走査型電子顕微鏡画像を示す。市販のサンプルは、Mott Corporationから入手し、316Lステンレス鋼を含んでいた。治療薬を放出するために材料内の多孔質構造体および相互接続チャネルを示すように、サンプルを機械的に破断した。顕微鏡写真画像は、第1の表面の開口部と第2の表面の開口部との間に配置されている複数の相互接続チャネルを示している。
圧力減衰および流れを含むがこれに限定されない多くの機械試験をフリットに受けさせることによって、サンプル要素の相対的特徴を測定することができる。これらの試験は、装置の放出プロファイルを測定するために、たとえばRRIなどの薬物放出速度の情報と組み合わせ可能である。これらの試験は、装置の多孔質構造体を通る流れを定量化し、多孔質構造体の適合性を判定するために、治療装置に配置されている多孔質構造体で使用されることができる。同様の試験を使用して、治療装置への取付け前に多孔質構造体を定量化することができる。少なくともいくつかの治療装置は、部分的に組み立てられた治療装置に装着した多孔質構造体の気体流によって、たとえば品質管理チェックとして評価されることができる。いくつかの実施形態では、多孔質構造体が治療薬を放出するのに適しており、たとえば治療装置の支持など装置に固定されることを保証するために、貯蔵部に治療薬を挿入する前に、かつ患者に挿入する前に、部分的に組み立てられているか、または実質的に組立てられた治療装置に、流れ試験を行うことができる。
上記の試験方法はそれぞれ、試験片の試験ハードウェアへの機械的接続を使用してもよく、多くの技術が探究されて利用されてきた。これらの取付け具は、確実に試験片を固定する手段(たとえば熱回収管、弾性管、比較的硬質の構成要素へのプレス嵌めなど)と、結合手段(たとえばルアー、蛇腹式取付け具、クイック連結カップリングなど)との両方を含み、試験ハードウェアに便利よく反復可能に取付けることができる。
市販の溶液を使用し、あるいは容易に入手できる機器を組み立ててカスタマイズした試験装置を作製することによって、各々の所望の試験を開発することができる。ここでも、これらの方法の両方が評価されている。作動システムは、試験片を接続する手段と、制御可能な供給源(通常は圧力であるが、これに限定されない)と、マノメータ(または他の圧力計測装置)と、試験条件を判定し、かつ/またはさらなる分析のデータを集めるのに使用される1つ以上のトランスデューサ(圧力、流れなど)から成る。
治療薬送達装置の用途に適した多孔質構造体を特定するための、圧力減衰試験 図28は、本願明細書において記載されている実施形態に従って治療装置の用途に適した多孔質フリット構造体を特定するための、多孔質構造体に使用する圧力減衰試験および試験装置を示す。
治療薬送達装置の用途に適した多孔質構造体を特定するための、圧力減衰試験 図29は、本願明細書において記載されている実施形態に従って、治療装置の用途に適した多孔質フリット構造体を特定するための、多孔質構造体に使用する圧流試験および試験装置を示す。
表7は、多孔質構造体を通る酸素または窒素などの気体の流れに基づいて、たとえばRRIなどの治療薬の放出を測定するのに使用可能な表を示す。本願明細書に記載されているように、多孔質フリット構造体にわたる圧力が低下した多孔質構造体全体の流量で、多孔質構造体を通る流れを気体の圧力の減衰時間で測定することができる。たとえばMott Corp.から入手可能な市販の媒質グレード材料のような材料の媒質グレードに基づいて、流量およびRRIを測定することができる。治療薬は、多孔質構造体または同様の試験分子を通って測定されることができる。初期の測定値は、示されている多孔質フリット構造体を備えた、Avastin(商標)に対するRRIを測定した。本願明細書において記載されている教示に基づいて、当業者は実験を行って、気体を備えた流量と治療薬の放出速度との対応を経験的に決定することができる。
直接的な硝子体内注入を介するLucentis(商標)(500μg)の標準量の投与が、滲出性加齢黄班変性(wet AMD)を患う患者の症状を減少させるのに有効であるということが証明されているが、下記の臨床研究は、滲出性加齢黄班変性を治療するためにより低濃度を使用することができることを示している。本願明細書において記載されている装置は、毎月のボーラス注射500μgに対応するより少ない量でのヒト患者のin vivoの最小阻止濃度(以下「MIC」)で、AMDを治療するために使用することができる。たとえば、表4Dおよび上の図19Aに従って、ヒトのin situの濃度プロファイルを得るために、Lucentis(商標)注入5μgを投与されることができる。
Claims (18)
- 少なくとも部分的に眼内に埋め込まれている眼球インプラントに治療薬を注入するためのシステムであって、前記システムは、
注入管腔及び出口管腔を備えた注射針を有し、前記注入管腔は、前記注入管腔からの開口部が前記出口管腔への開口部の遠位に配置されているように、前記出口管腔よりも長く、及び
前記注射針と連結し、かつ第1の流れ抵抗を有するベントを経由して前記出口管腔とに流体連結される容器を含み、
前記眼球インプラントは、前記治療薬のための単一のチャンバの貯蔵部と、前記貯蔵部から前記治療薬を放出するよう構成された多孔質構造体を備え、
注入する治療薬は、前記注入管腔を通して、前記出口管腔を通って容器内に前記眼球インプラントの貯蔵部内で処理された既存の物質の量を排出すると同時に、前記貯蔵部内に前記治療薬の量を置くことを特徴とするシステム。 - 前記多孔質構造体は第2の流れ抵抗を備えることを特徴とする請求項1に記載のシステム。
- 前記ベントの前記第1の流れ抵抗は、前記置かれた治療薬の量から、前記変位した既存の物質の前記量を少なくとも部分的に分離するため、前記多孔質構造体の第2の流れ抵抗以下であることを特徴とする請求項2に記載のシステム。
- 前記第2の流れ抵抗によって、前記既存の物質の前記多孔質構造体を通しての前記眼内への放出を阻止することを特徴とする請求項3に記載のシステム。
- 前記ベントは選択的に閉じられるよう構成されたバルブであることを特徴とする請求項2に記載のシステム。
- 前記バルブが開かれ、前記治療薬が注入されるとき、前記第1の流れ抵抗が前記第2の流れ抵抗以下であることによって、前記貯蔵部に注入した前記治療薬の量で、前記貯蔵部内に置かれた前記既存の物質の量を交換することを特徴とする請求項5に記載のシステム。
- 前記バルブが閉じられ、前記治療薬が注入されるとき、前記貯蔵部に注入された前記治療薬の前記量の一部が前記多孔質構造体を前記眼内に通過するように、前記第1の流れ抵抗は前記第2の流れ抵抗以上であることを特徴とすることを特徴とする請求項6に記載のシステム。
- 前記眼球インプラントへの前記注入管腔の挿入の深さを限定するよう構成された前記注射針に連結された停止部をさらに備えることを特徴とする請求項1に記載のシステム。
- 前記注射針は前記眼球インプラントの貫通可能な障壁と連結するよう構成されたことを特徴とする請求項1に記載のシステム。
- 前記注射針は前記眼球インプラントのアクセスポートを貫通するよう構成されたことを特徴とする請求項1に記載のシステム。
- 前記出口管腔及び前記注入管腔は同心性であることを特徴とする請求項1に記載のシステム。
- 少なくとも前記注入管腔の一部は前記出口管腔の内部に位置することを特徴とする請求項11に記載のシステム。
- 前記注入管腔は直径において前記出口管腔よりも小さいことを特徴とする請求項1に記載のシステム。
- 前記ベントは前記注入管腔の前記開口部に近接することを特徴とする請求項1に記載のシステム。
- 前記出口管腔に流体連結された前記容器は、前記既存の物質の量の変位を促進するため真空下に置かれるよう構成されたことを特徴とする請求項1に記載のシステム。
- 前記注射針と連結し、かつ前記注入管腔とに流体連結される第2の容器をさらに含むことを特徴とする請求項1に記載のシステム。
- 前記第2の容器は、前記注入管腔を経由して前記眼球インプラントへ注入するための前記治療薬のソースを供給するソース・チャンバーを有する注射器を含むことを特徴とする請求項16に記載のシステム。
- 前記注射器を前記注入管腔へ流体連結するため、前記注射器を着脱可能に受けるよう構成されたハブをさらに含むことを特徴とする請求項17に記載のシステム。
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