JP2018536659A - 白内障および老視の抑制に用いられるpegを含有する二官能性分子 - Google Patents
白内障および老視の抑制に用いられるpegを含有する二官能性分子 Download PDFInfo
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- JP2018536659A JP2018536659A JP2018524251A JP2018524251A JP2018536659A JP 2018536659 A JP2018536659 A JP 2018536659A JP 2018524251 A JP2018524251 A JP 2018524251A JP 2018524251 A JP2018524251 A JP 2018524251A JP 2018536659 A JP2018536659 A JP 2018536659A
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- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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Abstract
Description
本明細書に開示されるのは、クリスタリン凝集体の脱凝集化/形成を防止する方法であって、クリスタリン凝集体の脱凝集化および/または形成を防止するのに十分な量の二官能性分子を含む組成物とクリスタリン凝集体とを接触させることを含む方法である。当業者であれば、本明細書に開示される二官能性分子は一般にγクリスタリン電荷マスキング剤として記載されるが、β−クリスタリンのタンパク質凝集をも脱凝集化/予防することも期待されることを認識するであろう。眼における白内障形成の進行を抑制または後退させる方法であって、本明細書に記載の二官能性分子を含む有効な白内障抑制量の眼科用組成物と眼を接触させることを含む方法がさらに開示される。眼における老視の進行を抑制または後退させる方法であって、本明細書に記載の二官能性分子を含む有効な老視抑制量の眼科用組成物と眼を接触させることを含む方法もまた開示される。
ある実施形態では、眼科用組成物は少なくとも第2の二官能性分子をさらに含み、同少なくとも第2の二官能性分子は、置換または非置換のアミン、スクシンイミド、カルボン酸、イソシアネート、イソチオシアネート、スルホニルクロリド、アルデヒド、カルボジイミド、アシルアジド、無水物、フルオロベンゼン、カーボネート、N−ヒドロキシスクシンイミドエステル、イミドエステル、エポキシドまたはフルオロフェニルエステルを含み、第2の分子毛に共有結合されており、第2の分子毛は、4〜200個のオキシエチレン基、アルコキシエチレン基またはアリールオキシエチレン基を有するポリエチレングリコール、アルコキシポリエチレングリコール、またはアルコキシポリエチレングリコール;ポリ(2−ヒドロキシプロピル)メタクリルアミド(HPMA);ポリ(2−ヒドロキシエチル)メタクリレート(HEMA)、プライ(2−オキサジリン)、ポリ(m−ホスホコリン)、ポリリジンまたはポリグルタミン酸であり、同第2の分子毛は150〜8000の分子量を有する。
一実施形態では、本明細書に記載の二官能性分子は、アルツハイマー病、パーキンソン病およびハンチントン病などのタンパク質フォールディングに関連する疾患の治療にも有用である。特定の実施形態では、二官能性分子は、タンパク質フォールディングに関連する疾患の治療において、経口用組成物として投与される。
例えば、コンタクトレンズ及び徐放性に関するそれらの教示について本明細書に組み込まれる、米国特許第5,658,592号明細書;米国特許第6,027,745号明細書;国際公開第2003/003073号パンフレット;米国特許出願公開第2005−0079197号明細書において記載されている、徐放薬物を含むコンタクトレンズを製造する公知の方法に従い、コンタクトレンズに、γ−クリスタリン電荷マスキング剤組成物を組み込むか、結合させるか、又は付着させることにより、徐放性γ−クリスタリン電荷マスキング剤組成物を製造することができる。具体的には、限定されるものではないが、γ−クリスタリン電荷マスキング剤組成物を、ポリビニルピロリドン、ヒアルロン酸ナトリウムなど、微粒子化剤、又はゲル徐放剤の一部に付着させることにより、コンタクトレンズを製造することができる。加えて、レンズの前面を形成する構成要素、及びレンズの裏面を形成する構成要素からコンタクトレンズを製造するなどによって、γ−クリスタリン電荷マスキング剤組成物のリザーバを形成することによって、徐放性を達成することもできる。
一実施形態において、γ−クリスタリン電荷マスキング剤は、涙点プラグで投与される。本明細書で使用されるように、涙点プラグなる用語は、下涙点または上涙点をそれぞれ通って眼の下涙小管または上涙小管に挿入するのに適したサイズおよび形状のデバイスを指す。
本発明は、以下の非限定的な実施例によってさらに説明される:
γD−およびγS−クリスタリンDNA配列は、マサチューセッツ工科大学(マサチューセッツ州ケンブリッジ)のキング研究所(KingLabs)によって提供されたpQe1プラスミド中にある。γ−クリスタリンタンパク質配列は、精製目的のために6xN末端ヒスチジンタグ(hisタグ)を含む。プラスミドをクローン化コンピテント細胞系に形質転換して、追加のプラスミドDNAを作製した。続いて、プラスミドを、タンパク質合成のための発現コンピテント細胞系(TAM1大腸菌細胞(カリフォルニア州、カールスバド、アクティブモティーフ(ActiveMotif)))に形質転換した。
(1)精製したタンパク質のバッチを、HiTrap(商標名)脱塩カラムを用いてPBS(pH=6.8)に緩衝液交換した。
(3)100mgのCA(PEG)nを上記タンパク質の3−5mlバッチに添加した。
実施例1:未修飾のγD−クリスタリンタンパク質の動的光散乱
最初に、0.1mg/mLの濃度で未修飾のγD−クリスタリンタンパク質の溶液をDLSによって試験した。遅れ時間(遅延時間)に対してプロットされた測定された相関関数g2−1は、図2の散乱角30°に対して与えられている。種々の緩和時間の重量のCONTIN分析を、30°〜60°の範囲にわたる散乱角について、図3に与えられている。溶液中に2つの集団が存在することは明らかであり、1つは凝集体に対応し、もう1つは解凝集化タンパク質に対応する。図4に与えられているように、動的光散乱の理論を用いたこれらのデータの分析は、対応する流体力学的旋回半径がそれぞれ64nmおよび1.2nmであることを示している。
CA(PEG)4による修飾について、実施例1と対応する結果を図5〜7に示し、その結果から、凝集体は存在せず、非凝集タンパク質のサイズは2nmである。濃度は、0.9mg/mLのタンパク質および33mg/mLのCA(PEG)4である。CA(PEG)4は
実施例3:CA(PEG)1で修飾されたγD−クリスタリンタンパク質の動的光散乱
CA(PEG)1による修飾について、実施例1と対応する結果を図8〜10に示し、その結果から、凝集物は存在せず、凝集していないタンパク質のサイズは2nmである。濃度は、0.9mg/mLのタンパク質および33mg/mLのCA(PEG)1である。CA(PEG)1は
実施例4:CA(PEG)2で修飾されたγD−クリスタリンタンパク質の動的光散乱
CA(PEG)2による修飾について、実施例1と対応する結果を図11〜13に示し、その結果から、凝集物は存在せず、凝集していないタンパク質のサイズは2nmである。濃度は、0.4mg/mLのタンパク質および15mg/mLのCA(PEG)2である。CA(PEG)2は
実施例5:CA(PEG)3で修飾されたγD−クリスタリンタンパク質の動的光散乱
CA(PEG)3による修飾について、実施例1と対応する結果を図14〜16に示し、その結果から、凝集物は存在せず、凝集していないタンパク質のサイズは2nmである。濃度は、0.3mg/mLのタンパク質および11mg/mLのCA(PEG)3である。CA(PEG)3は
結論:全てのCA(PEG)1−4は、動的光散乱によって決定されるように、γD−クリスタリンタンパク質の凝集を完全に防止する上で有効な薬剤である。
Claims (23)
- 二官能性分子を含む眼科用組成物であって、前記二官能性分子は、
分子毛に共有結合される、置換または非置換の、アミン、スクシンイミド、カルボン酸、イソシアネート、イソチオシアネート、スルホニルクロリド、アルデヒド、カルボジイミド、アシルアジド、無水物、フルオロベンゼン、カーボネート、N−ヒドロキシスクシンイミドエステル、イミドエステル、エポキシドまたはフルオロフェニルエステルと、
前記分子毛と、
を含み、前記分子毛は、1〜3個のオキシエチレン基を有するポリエチレングリコール、1〜3個のアルコキシエチレン基を有するアルコキシポリエチレングリコール、または1〜3個のアリールオキシエチレン基を有するアリールオキシポリエチレングリコールである、眼科用組成物。 - 前記二官能性分子は、NH2、N−ヒドロキシスクシンイミド又はCOOHを含む、請求項1に記載の眼科用組成物。
- 前記二官能性分子は、
である、請求項1に記載の眼科用組成物。 - 請求項1に記載の眼科用組成物は、少なくとも第2の二官能性分子を更に含み、前記少なくとも第2の二官能性分子は、
第2の分子毛に共有結合される、置換または非置換の、アミン、スクシンイミド、カルボン酸、イソシアネート、イソチオシアネート、スルホニルクロリド、アルデヒド、カルボジイミド、アシルアジド、無水物、フルオロベンゼン、カーボネート、N−ヒドロキシスクシンイミドエステル、イミドエステル、エポキシドまたはフルオロフェニルエステルと、
前記第2の分子毛と、
を含み、前記第2の分子毛は、4〜200個のオキシエチレン、アルコキシエチレン、またはアリールオキシエチレン基を有するポリエチレングリコール、アルコキシ−ポリエチレングリコールまたはアルコキシポリエチレングリコール、ポリ(2−ヒドロキシプロピル)メタクリルアミド(HPMA)、ポリ(2−ヒドロキシエチル)メタクリレート(HEMA)、プライ(2−オキサジリン)、ポリ(m−ホスホコリン)、ポリリジンまたはポリグルタミン酸であり、前記第2の分子毛は150〜8000の分子量を有する、眼科用組成物。 - 前記眼科用組成物が点眼剤である、請求項1に記載の眼科用組成物。
- 前記眼科用組成物は、眼科用液剤、眼科用懸濁剤、眼科用軟膏剤、スプレー剤または眼科用ゲル剤の形態である、請求項1に記載の眼科用組成物。
- 前記眼科用組成物は、緩衝剤、等張化剤、可溶化剤、防腐剤、増粘剤、キレート剤、抗酸化剤、抗生物質、糖およびpH調節剤またはそれらの組み合わせを含む、請求項6に記載の眼科用組成物。
- 前記眼科用組成物は眼科用デバイスである、請求項1に記載の眼科用組成物。
- 前記眼科用デバイスは、コンタクトレンズまたは涙点プラグの形態にある、請求項8に記載の眼科用組成物。
- 前記眼科用組成物は、徐放性組成物である、請求項1に記載の眼科用組成物。
- 前記眼科用組成物は、徐放性組成物である、請求項4に記載の眼科用組成物。
- 白内障形成、老視または眼の水晶体の加齢に関連する変性の進行を抑制または後退させる方法において、前記方法は、
有効な白内障抑制量の眼科用組成物を眼に接触させることを含み、
前記眼科用組成物は二官能性分子を含み、前記二官能性分子は、
分子毛に共有結合される、置換または非置換の、アミン、スクシンイミド、カルボン酸、イソシアネート、イソチオシアネート、スルホニルクロリド、アルデヒド、カルボジイミド、アシルアジド、無水物、フルオロベンゼン、カーボネート、N−ヒドロキシスクシンイミドエステル、イミドエステル、エポキシドまたはフルオロフェニルエステルと、
前記分子毛と、
を含み、前記分子毛は1〜3個のオキシエチレン基を有するポリエチレングリコール、1〜3個のアルコキシエチレン基を有するアルコキシポリエチレングリコール、又は1〜3個のアリールオキシエチレン基を有するアリールオキシポリエチレングリコールである、方法。 - 前記二官能性分子は、NH2、N−ヒドロキシスクシンイミド又はCOOHを含む、請求項12に記載の方法。
- 前記二官能性分子は、
である、請求項12に記載の方法。 - 前記眼科用組成物は、少なくとも第2の二官能性分子を更に含み、前記少なくとも第2の二官能性分子は、
第2の分子毛に共有結合される、置換または非置換の、アミン、スクシンイミド、カルボン酸、イソシアネート、イソチオシアネート、スルホニルクロリド、アルデヒド、カルボジイミド、アシルアジド、無水物、フルオロベンゼン、カーボネート、N−ヒドロキシスクシンイミドエステル、イミドエステル、エポキシドまたはフルオロフェニルエステルと、
前記第2の分子毛と、
を含み、前記第2の分子毛は、4〜200個のオキシエチレン、アルコキシエチレン、またはアリールオキシエチレン基を有するポリエチレングリコール、アルコキシ−ポリエチレングリコールまたはアルコキシポリエチレングリコール、ポリ(2−ヒドロキシプロピル)メタクリルアミド(HPMA)、ポリ(2−ヒドロキシエチル)メタクリレート(HEMA)、プライ(2−オキサジリン)、ポリ(m−ホスホコリン)、ポリリジンまたはポリグルタミン酸であり、前記第2の分子毛は150〜8000の分子量を有する、請求項12に記載の方法。 - 前記眼科用組成物が点眼剤である、請求項12に記載の方法。
- 前記眼科用組成物は、眼科用液剤、眼科用懸濁剤、眼科用軟膏剤、スプレー剤または眼科用ゲル剤の形態である、請求項12に記載の方法。
- 前記眼科用組成物は、緩衝剤、等張化剤、可溶化剤、防腐剤、増粘剤、キレート剤、抗酸化剤、抗生物質、糖およびpH調節剤またはそれらの組み合わせを含む、請求項17に記載の方法。
- 前記眼科用組成物は眼科用デバイスである、請求項12に記載の方法。
- 前記眼科用デバイスは、コンタクトレンズまたは涙点プラグの形態にある、請求項19に記載の方法。
- 前記眼科用組成物は、徐放性組成物である、請求項12に記載の方法。
- 前記眼科用組成物は、徐放性組成物である、請求項15に記載の方法。
- 前記眼科用組成物は、点眼、噴霧、注入、イオントフォレシスまたは超音波増強によって投与される、請求項12に記載の方法。
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WO2017083619A1 (en) | 2017-05-18 |
JP6794444B2 (ja) | 2020-12-02 |
ZA201802978B (en) | 2019-07-31 |
US20170135972A1 (en) | 2017-05-18 |
SG11201803606XA (en) | 2018-05-30 |
BR112018009582A2 (pt) | 2018-11-06 |
US10736863B2 (en) | 2020-08-11 |
PE20181070A1 (es) | 2018-07-04 |
AU2016354479A1 (en) | 2018-05-24 |
EP3373921B1 (en) | 2019-08-28 |
KR20180083378A (ko) | 2018-07-20 |
AU2016354479B2 (en) | 2021-10-07 |
EP3373921A1 (en) | 2018-09-19 |
EA201891161A1 (ru) | 2018-10-31 |
MX2018005903A (es) | 2019-04-04 |
CR20180294A (es) | 2018-08-10 |
IL259027A (en) | 2018-06-28 |
CA3004585A1 (en) | 2017-05-18 |
IL259027B (en) | 2021-05-31 |
ES2745291T3 (es) | 2020-02-28 |
SA518391553B1 (ar) | 2021-03-01 |
CL2018001282A1 (es) | 2018-11-16 |
EA035402B1 (ru) | 2020-06-08 |
CN108348494A (zh) | 2018-07-31 |
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