JP2016519073A - プロスタミド含有眼内インプラント - Google Patents
プロスタミド含有眼内インプラント Download PDFInfo
- Publication number
- JP2016519073A JP2016519073A JP2016502643A JP2016502643A JP2016519073A JP 2016519073 A JP2016519073 A JP 2016519073A JP 2016502643 A JP2016502643 A JP 2016502643A JP 2016502643 A JP2016502643 A JP 2016502643A JP 2016519073 A JP2016519073 A JP 2016519073A
- Authority
- JP
- Japan
- Prior art keywords
- implant
- eye
- compound
- biodegradable
- intraocular
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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- 229960002470 bimatoprost Drugs 0.000 title abstract description 14
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Abstract
Description
本出願は、米国特許法大119条(e)の定めにより、2013年3月15日に登録された仮出願番号61/798,291、2013年9月13日に登録された仮出願番号61/877,573、及び2013年10月31日に登録された仮出願番号61/898,210に基づく優先権を主張し、これらの全てを参照として本明細書に組み入れる。
定義
局所的適用(例えば、点眼薬の形状)として、医薬的組成物は、活性薬剤として、治療的に効果的な量の本発明による少なくとも一つの化合物あるいは医薬的に許容されたその塩を一つあるいはそれ以上の医薬的に許容された賦形剤と組み合わせ、局所的眼用途に適した単位投与形状で調製することで調製できる。治療的に効率的な量は液体調剤において、0.0001〜10%(W/V)の間又は0.001〜5.0%(W/V)である。
患者の目に配置(眼内インプラント)用の大きさにされ調剤化され、及び、生分解性ポリマー材料(あるいは、マトリックス)中に分散された式I〜IVのいずれかの化合物を含む生分解性インプラントは眼内圧を降下させまた緑内障を治療するために有用である。我々は化合物1が、目の前眼房に直接投与された場合、目の眼内圧を下げるために特に効果的であることを発見した。生分解性インプラントは、それによりこの化合物を前眼房に投与することができる安全で、非毒性、かつ効果的手段である。
R202H、酸末端基と0.1%クロロフォルム溶液で、25℃で測定した場合0.16〜0.24dl/gの固有粘度をもつポリ(D,L−ラクチド);
R203H、酸末端基と0.1%クロロフォルム溶液で、25℃で測定した場合0.25〜0.35dl/gの固有粘度をもつポリ(D,L−ラクチド);
R202S、エステル末端基と0.1%クロロフォルム溶液で、25℃で測定した場合0.16〜0.24dl/gの固有粘度をもつポリ(D,L−ラクチド);
R203S、エステル末端基と0.1%クロロフォルム溶液で、25℃で測定した場合0.25〜0.35dl/gの固有粘度をもつポリ(D,L−ラクチド);と
RG752S,エステル末端基と固有粘度が0.16〜0.24dl/g(0.1%クロロフォルム溶液で、25℃で測定)、ポリ(D,L−ラクチド):グリコライド比がおよそ75:25であるポリ(D,L−ラクチド−コ−グリコライド)。
いくつかの実施形態において、該インプラントは押し出し成形されたインプラントである。一つの実施形態において、該インプラントは更に抗酸化剤、キレート剤、又は抗酸化剤とキレート剤の両方を含んでいてもよい。特定の形状において、該抗酸化剤はブチルヒドロキシアニソールまたはアスコルビン酸であり、該キレート剤はEDTAである。眼内インプラントは目の前眼房に配置するための大きさにしてされている。
本発明は、少なくとも1カ月、1〜3カ月間、少なくとも3カ月、3〜6カ月、あるいは6カ月以上、患者の眼の眼内圧を下げるために効果的である押し出し成形された生分解性眼内インプラントを含んでいる。一般的に、インプラントは生分解性ポリマー材料と該生分解性ポリマー材料と組み合わされた治療薬を含んでいか、からなる。該治療薬は式I、II、III、またはIVを持つ化合物である。好ましい実施形態において、該治療薬は化合物1を含んでおり、該眼内インプラントは目の前眼房への配置に適している。該眼内インプラントは1日におよそ10〜50ngの治療薬を少なくとも1カ月間生体外で放出する。
ここで述べられている眼内インプラントを作成するために種々の技術が採用される。有用な技術は、ロッド形のインプラント(あるいは、繊維)を製造するための押し出し方法(たとえば、加熱溶融押し出し法)、錠剤、ウエファー、またはペレットを製造するための圧縮方法、や生分解性シート、フィルムや、乾燥粉末を製造するための溶液成膜方法が含まれる。複数のマイクロ球体を製造するための乳化方法もまた、患者の目の中に式I〜IVのいずれかを持つ化合物を持続的に放出するための生分解性眼内薬剤配送システムの調製において役立つ。このように、一つの実施形態は、目の眼領域に配置するのに適している化合物1をカプセル化する複数の生分解性ミクロ球体を含んでいる医薬的組成物を提供することである。
緑内障を患っている者も含んでいる患者、における意図している治療効果(例えば、長期の眼内圧の減少)を提供するために、本発明によるインプラントは好ましくは目の前眼房に配置される。前眼房は虹彩と最も内側の角膜表面(内皮)の空間内を言う。しかし、幾人かの患者では、インプラントを目のガラス体に配置する必要がある。後眼房は虹彩の後ろとガラス体の表側の間の目の内側空間を言う。後眼房は、レンズと毛様体突起の間の空間、ここは角膜、虹彩およびレンズに栄養を与える房水を作り眼内圧を保つところであるが、を含む。図1に、これらとその他の目(100)の眼領域はその断面が示されている。目(100)の特定の領域は角膜(102)と虹彩(104)を含んでいるが、これらは前眼房(106)を取り囲んでいる。虹彩(104)の後ろは後眼房(108)とレンズ(110)である。前眼房の中に、前眼房隅角(112)と線維柱帯網(114)がある。更に示されているのは、角膜上皮(118)、強膜(116)、ガラス体(119)、毛様小体(120)と毛様体突起(121)である。目の後眼房部分は眼球(レンズの後ろ)の後ろ3分の2の部分であり、ガラス体、網膜と視神経を含んでいる。
a)化合物1の油形を酢酸エチル(EtOAc)におよそ50℃で加え混合物を形成し、
b)工程a)の混合物を50℃で攪拌して澄んだ溶液を形成し、
c)工程b)の澄んだ溶液を1〜3時間でおよそ30℃に冷却し、
d)化合物1の種結晶を工程c)の冷却された溶液にくわえ、
e)工程d)の種付された溶液を約30℃で1〜3時間保ち
f)工程e)の種付された溶液を約0から5℃の温度で約1〜5時間の間じゅう冷却し、
g)工程f)の溶液を約0から5℃の温度で約1〜3時間攪拌して懸濁液を作成し、
h)およそ20℃から25℃の間の温度で懸濁液を濾過しそれによって化合物1の固体形を製造する工程を含み、
ここで化合物1の種結晶は、
i)化合物1の油形をEtOAcにおよそ35から40℃の温度で溶解して混合物を形成し、
ii)工程i)の混合物をおよそ35から40℃の温度で攪拌して澄んだ溶液を形成し、
iii)工程ii)の澄んだ溶液をおよそ1〜5時間の間じゅう0から5℃の温度で冷却し、
iv)工程iii)の冷却された溶液を1〜3時間およそ0から5℃の温度で攪拌して白色の懸濁液を形成し、
v)工程iv)の白色の懸濁液をおよそ20℃と25℃の間の温度で濾過してそれによって化合物1の種結晶を製造する工程を含む方法で得る。
16.他の実施形態は、上記工程i〜vによって化合物1の結晶形を調製する方法である。
生体内におけるプロスタミドのIOP引下げ活性の比較
化合物1は集合的にプロスタミドとして知られている化合物クラス内に属する。(Woodward et al. (2007) British Journal of Pharmacology 150:342−352)
一連のプロスタミドは前房内生分解性薬剤配送システム(例えばインプラント)用に可能性のある候補として選び、房水への直接投与(それ故、前房内投与)によってIOPを降下させる能力を試験した。表1は猫(cat)虹彩分析から得られたEC50値(nM)、計算されたlogP値(clogP)、及び異なるプロスタミドを局所的または前房内に投与した後で得られたIOP降下値を載せている。前房内薬剤投与は、犬の首にある皮下ポケットに薬物注入ポンプを配置し、カニューレが目の前眼房に走りこんで、に実施した。試験は、投与レベルを確かめるために存在する溶液中の化合物濃度を測定し初期にポンプに加えられたポンプ中のそれと比較するために行われた。表1に示されているように、正常血圧の犬の目の前房内的に(直接前眼房に)投与した場合、化合物1は効果的にかつビマトプロストよりかなりより効率的にIOPを降下させる。
化合物3〜5の分子構造は以下に示されている。U.S. Patents 6,602,900, 6,124,344, 5,834,498,および/または5,688,819に、場合によって合成方法を含む化合物3〜5に関する開示がある。WO95/18102、WO96/36599、WO99/25358、US2007/0099984、US Patent5,741,810、およびSchuster et al. (2000) Mol. Pharmacol. 58:1511−1516も参照されたい。
符号「〜」は「およそ」を意味する。
符号「<」は未満を意味する。
cLogP(計算されたlogP)は化合物の親油性の度量法。各化合物の分配係数(P)はn−オクタノールと水からなる2相系のそれぞれの相中の非イオン化された化合物の平衡濃度の比を計算して測定される。
*試験化合物は、動物の皮下に埋め込まれた薬物注入ポンプを用いて前眼房(前房内的に)へ直接15ng/日〜108ng/日の投与量で投与した。左目は処置せず対照とする一方、右目だけを手術し投与した。処置した動物の数は3〜5の範囲であった。試験化合物の右目への注入は2〜3週間継続され、一方IOPはTonoVetのトノメータを用いて、両目を週3回測定した。IOP引下げ百分率は、注入開始に先立つ基準と比べて、注入の開始後、測定時に観測されたIOPの違いを百分率として計算した。15ng/日の投与レベルは、IC DDSにおける薬剤負荷を仮定し意図する投与の場所による大きさの制限に基づいて、興味対象の化合物に向け選択された。
**局所的に目へ投与された場合の、犬の眼内圧への化合物の効果が測定された。化合物は、0.1%ポリソルベート80と10mMトリス塩基を含むビヒクル中に示されている濃度に調製された。正常血圧の犬が、一つの目の眼表面に25μL投与することで処理され、対側の目は対照としてビヒクルを受けた。眼内圧は圧平空気眼圧測定法により測定した。犬の眼内圧は薬剤投与直後と6時間後に測定された。
***各化合物のプロスタミド/FP受容体活性は分離された猫虹彩括約筋の収縮として測定された。
生体内での化合物1の持続的配送のための生分解性前房内インプラント
目の前眼房への配置に適する押し出し成形されたインプラントの形で製造でき、かつ目の前眼房に配置後少なくとも3カ月、好ましくは少なくとも6カ月間、化合物1のほぼゼロ次放出を提供することが可能な生分解性調剤を見極めるため追加的な研究がなされた。インプラントが目にとって耐えうることや、もしあるとすれば、例えば痛み、赤目、炎症などの悪い反応をほとんど引き起こさないことが更に求められている。これらの目標を考慮し、一連の押し出し成形されたインプラント(例えば、インプラント1〜9を含む)が調製され、以下に述べるように生体外、生体内で試験された。インプラント1〜9の組成物、寸法、および重量は表2に示されている。インプラントを調製するために用いられた生分解性ポリマーはエボニックインダストリーズ、AGから手に入れられるRESOMER(登録商標)ポリマーの中から選ばれ、表2にそれらのポリマー識別番号で表されている。
押し出しに先立って、化合物1の純粋固体形が、粗製化合物1を酢酸エチル(EtOAc)におよそ50℃で溶解し、その温度で澄んだ溶液が得られるまで攪拌することで調製された。この澄んだ溶液は、その後およそ30℃になるまで化合物1の種結晶を種つける前に一定時間ゆっくり冷却された。この溶液は、数時間以上、0〜5℃にまで冷却される前に一定の間およそ30℃に保たれ、その間連続してその温度で攪拌された。懸濁液は続いて周囲温度で濾過され純粋な化合物1を得た。
化合物1の種結晶形は、純粋な化合物1(クロマトグラフィーによる精製後の油)をEtOAcにおよそ35〜40℃で溶解し、澄んだ溶液になるまでその温度で攪拌して得た。この澄んだ溶液はその後、およそ0〜5℃の温度まで数時間ゆっくり冷却され、続いてその温度で一定時間攪拌された。白色の懸濁液が形成され、周囲温度で濾過されて化合物1の種結晶を得た。
RESOMER(登録商標)RG755Sはエステル末端基とおよそ0.50〜0.70dl/gの固有粘度(0.1%w/vクロロフォルム溶液で、25℃で測定)とおよそ75:25のDL−ラクチド:グリコライド比をもつポリ(D,L−ラクチド−コ−グリコライド。
PEG3350=平均分子量3,350のポリエチレングリコール
ヘキサデカノール=ヘキサデカン−1−オール(セチルアルコール)
BHA=ブチルヒドロキシアニソール
EDTA=エチレンジアミン四酢酸
化合物1は次の構造を持つプロスタミド:
Claims (15)
- 請求項3に記載の生分解性眼内インプラントであって、該生分解性ポリマー材料はポリ(D,L−ラクチド)、ポリ(D,L−ラクチド−コ−グリコライド)、またはそれらの組み合わせである前記生分解性眼内インプラント。
- 請求項4に記載の生分解性眼内インプラントであって、該インプラントが該インプラントを受ける前の目のIOPと比べて、5カ月以上の間IOPを20〜30%降下させるのに効果的である前記生分解性眼内インプラント。
- 請求項5に記載のインプラントであって、該治療薬はインプラントの重量の少なくともおよそ1%でかつおよそ8%を超えない、前記インプラント。
- 請求項6に記載の生分解性眼内インプラントであって、該インプラントは押し出し工程で製造され、該インプラントは0.5〜2mmの長さ、100〜300μmの直径、総重量10〜200μgを持つ、前記生分解性眼内インプラント。
- 生分解性ポリマー材料、ヘキサデカン−1−オール、と8重量%の次の式を持つ化合物を含む生分解性眼内インプラントであって、
- 抗酸化剤又はキレート剤又は抗酸化剤とキレート剤の両方を更に含んでいる請求項8に記載のインプラント。
- 患者の目に、請求項3又は8に記載の生分解性眼内インプラントを配置し、それによって目の眼内圧を5カ月以上の間下げることを含む患者の眼内圧を下げるための方法。
- 該患者は上昇した眼内圧、高眼圧、または緑内症を持っている請求項11に記載の方法。
- 該眼内インプラントは患者の目の前眼房に配置される請求項12に記載の方法。
- 該眼内インプラントは、該インプラントを受ける前の目の眼内圧と比べて、目に設置後3〜5カ月またはそれ以上の間目の眼内圧を少なくとも30%降下させる請求項13に記載の方法。
- 生分解性ポリマー材料と該生分解性ポリマー材料と組み合わされた治療薬を含むか又はからなるインプラントである、患者の眼内圧を下げるために効果的な生分解性眼内インプラントを作製する方法であって、ここで治療薬は次の式(化合物1)を持ち、
I)化合物1を固体の形で得て、
II)該化合物1の固体を一つの生分解性ポリマーあるいは2つ以上の生分解性ポリマーとブレンドして混合物を作り、
III)該混合物を押し出してフィラメントを作り、
IV)該フィラメントを目の眼領域に配置するために適した長さに切断し、それによって眼内インプラント形成することを含む方法であり、
ここで固体の形で化合物1を得るのは、
a)化合物1の油形を酢酸エチル(EtOAc)におよそ50℃で加え混合物を形成し、
b)工程a)の混合物を50℃で攪拌して澄んだ溶液を形成し、
c)工程b)の澄んだ溶液を1〜3時間でおよそ30℃に冷却し、
d)化合物1の種結晶を工程c)の冷却された溶液に加え、
e)工程d)の種付された溶液を約30℃で1〜3時間保ち
f)工程e)からの種付された溶液を約0から5℃の温度で約1〜5時間の間冷却し、
g)工程f)からの溶液を約0から5℃の温度で約1〜3時間攪拌して懸濁液を作成し、
h)およそ20℃から25℃の間の温度で工程g)から、懸濁液を濾過しそれによって化合物1の固体形を製造する工程を含み、
ここで化合物1の種結晶は、
i)化合物1の油形をEtOAcにおよそ35から40℃の温度で溶解して混合物を形成し、
ii)工程i)の混合物をおよそ35から40℃の温度で攪拌して澄んだ溶液を形成し、
iii)工程ii)の澄んだ溶液をおよそ1〜5時間の間0から5℃の温度で冷却し、
iv)工程iii)からの冷却された溶液を1〜3時間およそ0から5℃の温度で攪拌して白色の懸濁液を形成し、
v)工程iv)からの白色の懸濁液をおよそ20℃と25℃の間の温度で濾過してそれによって化合物1の種結晶を製造する工程を含む方法で得ることを特徴とする生分解性眼内インプラントを作成する方法。
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