JP6479485B2 - Nanoparticle preparation for treatment of eye diseases - Google Patents
Nanoparticle preparation for treatment of eye diseases Download PDFInfo
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- JP6479485B2 JP6479485B2 JP2015006212A JP2015006212A JP6479485B2 JP 6479485 B2 JP6479485 B2 JP 6479485B2 JP 2015006212 A JP2015006212 A JP 2015006212A JP 2015006212 A JP2015006212 A JP 2015006212A JP 6479485 B2 JP6479485 B2 JP 6479485B2
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Description
本発明は、新規な薬物複合体およびそれを用いた眼疾患治療用ナノ粒子製剤に関する。 The present invention relates to a novel drug complex and a nanoparticle preparation for treatment of eye disease using the same.
現在、緑内障および高眼圧症等の眼疾患の治療には、眼圧降下効果のある薬物としてブリンゾラミド等の炭酸脱水素酵素阻害薬が点眼や内服液として眼科分野で使用されている。しかしながら、これらの薬物は腎臓などに蓄積し易いことから眼局所的な投与が望ましく、更に、薬物（薬効成分）量を抑える努力が必要である。一方、眼表面には角膜上皮のバリアが存在し、薬物の浸入を妨げており、結果的にこれらの薬物の有効濃度を上げている。 At present, for the treatment of eye diseases such as glaucoma and ocular hypertension, a carbonic anhydrase inhibitor such as brinzolamide is used as a drug having an intraocular pressure-lowering effect in the ophthalmological field as an eye drop and an internal solution. However, since these drugs are easily accumulated in the kidney and the like, topical administration to the eye is desirable, and further, an effort is required to suppress the amount of drug (active ingredient). On the other hand, a corneal epithelial barrier is present on the ocular surface, which prevents the entry of drugs, and as a result, the effective concentrations of these drugs are increased.
その結果、例えば、薬物としてブリンゾラミドを用いた場合、ブリンゾラミド市販薬には有効成分であるブリンゾラミドが極めて高濃度で懸濁しており、点眼後に視界を失うという問題点が指摘されている。 As a result, for example, when brinzolamide is used as a drug, brinzolamide, which is an active ingredient, is suspended at a very high concentration in commercial brinzolamide drugs, and it has been pointed out that visual loss is lost after instillation.
特許文献１では、親水性の蛍光イメージング剤であるフルオロセインをアセチル化することで疎水性プロドラッグとし、更に、ナノ粒子化することで眼内移行性の高い点眼薬とする方法が示されている。
このときプロドラッグをナノ粒子化する方法として再沈法が用いられる。プロドラッグが溶解する溶媒に溶解し、得られた溶液を、プロドラッグが溶解しない溶媒と混合し、プロドラッグがナノ粒子として存在する溶液を得て、これを点眼基材と混合することにより製造することができる。
Patent Document 1 shows a method of converting a hydrophilic fluorescence imaging agent, fluorescein, into a hydrophobic prodrug by acetylating it, and further, forming it into nanoparticles to obtain an eye drop with high transferability into the eye. There is.
At this time, a reprecipitation method is used as a method of making the prodrug into nanoparticles. The solution is dissolved in a solvent in which the prodrug is dissolved, and the resulting solution is mixed with a solvent in which the prodrug is not dissolved to obtain a solution in which the prodrug is present as nanoparticles, which is then mixed with an eye drop substrate can do.
特許文献２では、ＧＡＢＡ類似体であるバクロフェンをアシルオキシアルキルオキシカルボニル化することにより体内に吸収され易いプロドラッグとする方法を提供している。しかしながらアセタール部分の不斉誘導は高度な技術を要し、キラルなブリンゾラミドに、ラセミ体のプロドラッグ化試薬を用いるとジアステレオマー混合物を与え、ナノ粒子化が困難となることが予想される。また、眼内でプロドラッグが加水分解されて生じるアルデヒド類は、毒性および臭気が強く患者に不快感を与える可能性があり、眼疾患治療薬プロドラッグの構成成分として適当でない。 Patent Document 2 provides a method of converting baclofen, which is a GABA analog, into a prodrug which is easily absorbed in the body by acyloxyalkyloxycarbonylation. However, asymmetric induction of the acetal moiety requires a high level of technology, and it is expected that the chiral brinzolamide will give a diastereomeric mixture when a racemic prodrug forming reagent is used, making nanoparticle formation difficult. In addition, aldehydes generated by hydrolysis of prodrugs in the eye have strong toxicity and odor, which may cause discomfort to patients, and are not suitable as components of eye disease drug prodrugs.
特許文献３では、ニューロキノン系抗菌剤ノルフロキサシンをジオキソレニルメチル化することにより体内に吸収され易いプロドラッグとする方法を提供している。しかしながら、本プロドラッグ化法を薬物に適用した場合、ジオキソレニル基自体が疎水性を低下させるため、目的とするナノ粒子製剤の製造が困難となる。また、眼内でプロドラッグが加水分解されて生じる１，２−ジケトン類は、臭気が強く患者に不快感を与える可能性があり、眼疾患治療薬プロドラッグの構成成分として適当でない。 Patent Document 3 provides a method for making a neuroquinone antibiotic, norfloxacin, a prodrug which is easily absorbed into the body by dioxolenyl methylation. However, when the prodrug formation method is applied to a drug, the dioxolenyl group itself reduces the hydrophobicity, which makes it difficult to produce the target nanoparticle preparation. In addition, 1,2-diketones produced by hydrolysis of the prodrug in the eye have a strong odor and may cause discomfort to the patient, and are not suitable as a component of the eye disease drug prodrug.
通常酸アミド構造の生体内での加水分解速度は遅いことが知られている。一方、例えば、非特許文献１に記載されているように、いわゆるトリメチルロックと呼ばれる構造を有するカルボン酸由来の酸アミドの加水分解速度が通常の酸アミドと比較して約１０１１倍であることが知られている。 It is known that the in vivo hydrolysis rate of the acid amide structure is usually slow. On the other hand, as described in, for example, Non-Patent Document 1, the hydrolysis rate of an acid amide derived from a carboxylic acid having a so-called trimethyl lock structure is about 10 11 times compared to that of a normal acid amide It has been known.
また、非特許文献２では、上述のトリメチルロックとアミノ基を有する蛍光イメージング剤を複合体化させ、細胞内における複合体の加水分解により発色試薬を放出させることに成功している。しかしながら、非特許文献２には、薬物を用いること、および眼内移行性を向上させることについては何ら記載されていない。 In Non-Patent Document 2, a fluorescent imaging agent having the above-mentioned trimethyl lock and an amino group is complexed, and hydrolysis of the complex in cells is successful in releasing the color developing reagent. However, Non-Patent Document 2 does not describe at all about using a drug and improving intraocular transferability.
特許文献４では、薬物内包リポソームナノ粒子の作成技術が示されている。リポソームは細胞毒性を示さないものの、リポソームの作成に必要なリン脂質の量は原薬の数百倍と多くその安全性は十分立証されていない。 Patent Document 4 discloses a technique for producing drug-incorporated liposome nanoparticles. Liposomes do not exhibit cytotoxicity, but the amount of phospholipid required for preparation of liposomes is hundreds of times higher than that of the drug substance, and its safety has not been sufficiently proven.
特許文献５では、水に難溶なシロスタゾールをシクロデキストリンに包接させることで水に可溶とし、緑内障治療薬としての効果が期待される点眼薬の製造法が示されている。この技術はシクロデキストリンの疎水性キャビティーとの親和性が高い部位を有する原薬に適用可能であるが必ずしも一般的ではない。 Patent Document 5 discloses a method for producing an eye drop, which is rendered soluble in water by including cilostazol which is poorly soluble in water, in cyclodextrin and is expected to be effective as a glaucoma therapeutic agent. This technique is applicable, but not necessarily universally, to drug substances that have sites with high affinity for the hydrophobic cavity of cyclodextrin.
非特許文献３では、緑内障治療薬メタゾシンをリン酸カルシウムナノ粒子に内包させることで眼内移行性が向上することが示されている。リン酸カルシウムは生体適合性の高い物質であるが、点眼時の刺激性や眼内に取り込まれた際の安全性は十分立証されていない。 In Non-Patent Document 3, it is shown that ocular transferability is improved by encapsulating the glaucoma therapeutic drug metazocin in calcium phosphate nanoparticles. Calcium phosphate is a highly biocompatible substance, but its irritability when instilled and its safety when taken into the eye have not been sufficiently proven.
本発明者らは、薬物と脂溶性高分子とからなる新規な薬物複合体を眼疾患治療に用いると、持続的に著しい眼疾患治療効果が得られることを見出した。本発明はかかる知見に基づくものである。 The present inventors have found that when a novel drug complex comprising a drug and a lipid-soluble polymer is used for the treatment of eye disease, the eye disease treatment effect can be sustained continuously. The present invention is based on such findings.
したがって、本発明は、新規な薬物複合体およびそれを用いた眼疾患治療用製剤を提供することをその目的としている。 Therefore, an object of the present invention is to provide a novel drug complex and a preparation for treating ocular diseases using the same.
本発明には以下の発明が包含される。
［１］薬物と脂溶性分子とからなる薬物複合体を含んでなる、眼疾患治療用ナノ粒子製剤であって、
上記薬物と上記脂溶性分子とが、眼内ｐHにて加水分解しうる酸アミド結合を介して連結している、眼疾患治療用製剤。
［２］上記脂溶性分子が以下の一般式（I）で表されるものである、［１］に記載の製剤：
R1、R2、R3およびR4は、互いに独立して、水素、置換されていてもよいC1-18アルキル、置換されていてもよいC1-18アルコキシ、置換されていてもよいC7-18アラルコキシまたは置換されていてもよいフェノキシを表し、
あるいは、R1、R2、R3およびR4のいずれかの隣り合う基が一緒になって、置換されてもよい環を形成し、
Y は、置換されていてもよいC1-18アルキル、置換されていてもよいC1-18アルコキシ、置換されていてもよいC7-18アラルコキシおよび置換されていてもよいフェノキシからなる群から選択される基を表す）。
［３］上記薬物がブリンゾラミド、ドルゾラミド、メタゾラミド、ジピベフリン、カルテオロール、チモロール、ベタキソロール、ニプラジノール、レボブノロール、ブリモニジンおよびブナゾシンから選択されるものである、［１］または［２］に記載の製剤。
［４］上記複合体が、一般式(II)に記載の複合体である、［１］〜［３］のいずれかに記載製剤：
Ａ は水素またはＸであり、
Ｂ は水素またはＸであり、
ＡおよびＢ は同時に水素でなく、
Ｘが、以下の一般式(I)で表される基である：
R1、R2、R3およびR4は、互いに独立して、水素、置換されていてもよいC1-18アルキル、置換されていてもよいC1-18アルコキシ、置換されていてもよいC7-18アラルコキシまたは置換されていてもよいフェノキシを表し、
あるいは、R1、R2、R3およびR4のいずれかの隣り合う基が一緒になって、置換されてもよい環を形成し、
Y は置換されていてもよいC1-18アルキル、置換されていてもよいC1-18アルコキシ、置換されていてもよいC7-18アラルコキシおよび置換されていてもよいフェノキシからなる群から選択される基である））。
［５］上記複合体が以下のいずれかの式で表されるものである［１］〜［４］のいずれかに記載の製剤：
［６］上記眼疾患が緑内障、糖尿病網膜症、加齢黄班変性症、網膜色素変性症または高度近視である、［１］〜［５］のいずれかに記載の眼疾患治療用ナノ粒子製剤。
［７］上記ナノ粒子の平均粒径が１０〜１，０００ｎｍである、［１］〜［６］のいずれかに記載の製剤。
［８］一般式(II)で表される複合体：
Ａ は水素またはＸであり、
Ｂ は水素またはＸであり、
ＡおよびＢ は同時に水素でなく、
Ｘは以下の一般式(I)で表される基である：
R1、R2、R3およびR4は、互いに独立して、水素、置換されていてもよいC1-18アルキル、置換されていてもよいC1-18アルコキシ、置換されていてもよいC7-18アラルコキシまたは置換されていてもよいフェノキシを表し、
あるいは、R1、R2、R3およびR4のいずれかの隣り合う基が一緒になって、置換されてもよい環を形成し、
Yは、置換されていてもよいC1-18アルキル、置換されていてもよいC1-18アルコキシ、置換されていてもよいC7-18アラルコキシおよび置換されていてもよいフェノキシからなる群から選択される基である））。
［９］以下の化合物からなる群から選択される、［８］に記載の複合体：
［１０］［１］〜［７］のいずれかに記載の複合体の製造方法であって、上記薬物と脂溶性分子を酸アミド結合を介して連結させることを含んでなる、製造方法。
［１１］上記複合体を再沈法で処理することにより上記ナノ粒子を得ることを含んでなる、［１］〜［７］のいずれかに記載のナノ粒子製剤の製造方法。
The present invention includes the following inventions.
[1] A nanoparticle preparation for treating an eye disease, which comprises a drug complex comprising a drug and a lipid soluble molecule,
A preparation for treating an eye disease, wherein the drug and the fat-soluble molecule are linked via an acid amide bond that can be hydrolyzed at intraocular pH.
[2] The preparation according to [1], wherein the fat-soluble molecule is represented by the following general formula (I):
R 1 , R 2 , R 3 and R 4 are, independently of one another, hydrogen, optionally substituted C 1-18 alkyl, optionally substituted C 1-18 alkoxy, optionally substituted C 7- 18 represents aralkoxy or phenoxy which may be substituted,
Alternatively, any adjacent groups of R 1 , R 2 , R 3 and R 4 are taken together to form a ring which may be substituted,
Y is selected from the group consisting of optionally substituted C1-18 alkyl, optionally substituted C1-18 alkoxy, optionally substituted C7-18 aralkoxy and optionally substituted phenoxy Represents a group).
[3] The preparation according to [1] or [2], wherein the drug is selected from brinzolamide, dorzolamide, metazolamide, dipivephrin, carteolol, timolol, betaxolol, bedipazolol, niprazinol, levobnolol, brimonidine and bunazosin.
[4] The preparation according to any one of [1] to [3], wherein the complex is a complex described in the general formula (II):
A is hydrogen or X,
B is hydrogen or X,
A and B are not hydrogen at the same time,
X is a group represented by the following general formula (I):
R 1 , R 2 , R 3 and R 4 are, independently of one another, hydrogen, optionally substituted C 1-18 alkyl, optionally substituted C 1-18 alkoxy, optionally substituted C 7- 18 represents aralkoxy or phenoxy which may be substituted,
Alternatively, any adjacent groups of R 1 , R 2 , R 3 and R 4 are taken together to form a ring which may be substituted,
Y is a group selected from the group consisting of optionally substituted C1-18 alkyl, optionally substituted C1-18 alkoxy, optionally substituted C7-18 aralkoxy and optionally substituted phenoxy Is)).
[5] The preparation according to any one of [1] to [4], wherein the complex is represented by any one of the following formulas:
[6] The nanoparticle preparation for treating an eye disease according to any one of [1] to [5], wherein the eye disease is glaucoma, diabetic retinopathy, age-related macular degeneration, retinitis pigmentosa or high myopia .
[7] The preparation according to any one of [1] to [6], wherein the average particle size of the nanoparticles is 10 to 1,000 nm.
[8] Complex represented by the general formula (II):
A is hydrogen or X,
B is hydrogen or X,
A and B are not hydrogen at the same time,
X is a group represented by the following general formula (I):
R 1 , R 2 , R 3 and R 4 are, independently of one another, hydrogen, optionally substituted C 1-18 alkyl, optionally substituted C 1-18 alkoxy, optionally substituted C 7- 18 represents aralkoxy or phenoxy which may be substituted,
Alternatively, any adjacent groups of R 1 , R 2 , R 3 and R 4 are taken together to form a ring which may be substituted,
Y is selected from the group consisting of C1-18 alkyl which may be substituted, C1-18 alkoxy which may be substituted, C7-18 aralkoxy which may be substituted and phenoxy which may be substituted Groups)).
[9] The complex according to [8], which is selected from the group consisting of the following compounds:
[10] A method for producing the complex according to any one of [1] to [7], which comprises linking the drug and a lipid-soluble molecule via an acid amide bond.
[11] The method for producing a nanoparticle preparation according to any one of [1] to [7], which comprises obtaining the nanoparticles by treating the complex by a reprecipitation method.
本発明によれば、上記薬物複合体をプロドラッグとして眼疾患治療に用いることにより、顕著な眼疾患治療効果を持続的に奏することができる。本発明の薬物複合体によれば、薬物自体が難吸収性であっても、薬物の眼表面バリア透過性や眼内移行性を著しく向上させることができる。かかる本発明によれば、眼疾患治療製剤における薬物濃度を著しく低下させることもでき、眼疾患治療上有利である。 According to the present invention, by using the above drug complex as a prodrug for treating an eye disease, a remarkable eye disease therapeutic effect can be sustained. According to the drug complex of the present invention, even if the drug itself is poorly absorbed, the ocular surface barrier permeability and intraocular transferability of the drug can be remarkably improved. According to the present invention, the drug concentration in the preparation for treating an eye disease can be significantly reduced, which is advantageous for treating the eye disease.
定義
本発明において、一般式(I)のR1、R2 、R3 、R4 またはYにおける「C1-18アルキル」とは、基が直鎖状、分岐鎖状、環状あるいはそれらの組み合わせの炭素数１〜１８個のアルキルを意味する。「C1-18アルキル」としては、「C1-18直鎖アルキル」、「C3-18分岐アルキル」、または「C3-8シクロアルキル」が挙げられる。
Definitions In the present invention, “C1-18 alkyl” in R 1 , R 2 , R 3 , R 4 or Y in the general formula (I) is a linear, branched or cyclic group or a combination thereof It means alkyl having 1 to 18 carbons. Examples of "C1-18 alkyl" include "C1-18 straight chain alkyl", "C3-18 branched alkyl", or "C3-8 cycloalkyl".
本発明において、一般式(I)のR1、R2 、R3 、R4 またはYにおける「C1-18アルコキシ」とは、基が直鎖状、分岐鎖状、環状あるいはそれらの組み合わせの炭素数１〜１８個のアルコキシを意味する。「C1-18アルコキシ」としては、「C1-18直鎖アルコキシ」、「C3-18分岐アルコキシ」、または「C3-8シクロアルコキシ」が挙げられる。 In the present invention, “C1-18 alkoxy” in R 1 , R 2 , R 3 , R 4 or Y in the general formula (I) is a carbon having a linear, branched, cyclic or combination thereof. It means several 1 to 18 alkoxy. Examples of "C1-18 alkoxy" include "C1-18 straight chain alkoxy", "C3-18 branched alkoxy", or "C3-8 cycloalkoxy".
本発明において、一般式(I)のR1、R2 、R3 、R4 またはYにおける「C7-18アラルコキシ」とは、脂肪族部分が直鎖状、分岐鎖状、環状あるいはそれらの組み合わせを有する炭素数７〜１８個のアラルコキシを意味する。「C7-18アラルコキシ」とは、脂肪族部分に１〜６個の炭素原子を有し芳香族部分に６〜１２個の炭素原子を有するものが挙げられる。「C7-18アラルコキシ」としては、「C7-18直鎖アラルコキシ」、「C8-18分岐アラルコキシ」、または「C9-18シクロアラルコキシ」が挙げられる。 In the present invention, “C7-18 aralkoxy” in R 1 , R 2 , R 3 , R 4 or Y in the general formula (I) means that the aliphatic moiety is linear, branched, cyclic or a combination thereof It means that the carbon number is 7 to 18 carbons. Examples of the "C7-18 aralkoxy" include those having 1 to 6 carbon atoms in the aliphatic portion and 6 to 12 carbon atoms in the aromatic portion. Examples of the "C7-18 aralkoxy" include "C7-18 linear aralkoxy", "C8-18 branched aralkoxy", or "C9-18 cycloalralkoxy".
本発明において、一般式(I)の「C1-18アルキル」、「C1-18アルコキシ」、「C7-18アラルコキシ」および「フェノキシ」は置換されていてよく、かかる置換基としては、ジアルキルアミノ基、モノアルキルアミノ基、アルコキシ基、アルコキシカルボニル基、アルコキシカルボニルオキシ基、またはハロゲン基が挙げられる。 In the present invention, "C1-18 alkyl", "C1-18 alkoxy", "C7-18 aralkoxy" and "phenoxy" of the general formula (I) may be substituted, and such a substituent may be a dialkylamino group. And a monoalkylamino group, an alkoxy group, an alkoxycarbonyl group, an alkoxycarbonyloxy group or a halogen group.
本発明において、一般式(I)の「R1、R2、R3およびR4のいずれかの隣り合う基が一緒になって、置換されてもよい環を形成し」とは、置換基R1、R2、R3およびR4のうち互いに隣接する置換基が連結して炭素環を形成することを意味する。かかる環は一般式(I)におけるベンゼン環の炭素原子と共に、好ましくは５〜７員環を形成する。
また、かかる環は置換されてよく、かかる置換基としては、アルキル基、ジアルキルアミノ基、モノアルキルアミノ基、アルコキシ基、アルコキシカルボニル基、アルコキシカルボニルオキシ基、またはハロゲン基が挙げられる。
In the present invention, “the adjacent group of any of R 1 , R 2 , R 3 and R 4 together form a ring which may be substituted” in the general formula (I) is a substituent Substituents adjacent to each other among R 1 , R 2 , R 3 and R 4 are linked to form a carbocycle. Such a ring preferably forms a 5- to 7-membered ring with the carbon atom of the benzene ring in the general formula (I).
Also, such a ring may be substituted, and such a substituent includes an alkyl group, a dialkylamino group, a monoalkylamino group, an alkoxy group, an alkoxycarbonyl group, an alkoxycarbonyloxy group or a halogen group.
本発明において、「水難溶性」とは、２５℃で水に対する溶解度が１０ｍｇ／ｍＬ未満、好ましくは０．１ｍｇ／ｍＬ未満などであることを示し、日本薬局方の溶解性の記載における「溶けにくい」、「極めて溶けにくい」、「ほとんど溶けない」に相当する。 In the present invention, “poorly soluble in water” indicates that the solubility in water at 25 ° C. is less than 10 mg / mL, preferably less than 0.1 mg / mL, etc., and “poorly soluble” in the solubility description of the Japanese Pharmacopoeia , "Very poorly soluble", "mostly insoluble" corresponds to.
本発明は、薬物と脂溶性分子とからなる薬物複合体を含んでなる、眼疾患治療用ナノ粒子製剤であって、薬物と脂溶性分子とが眼内ｐＨにて加水分解しうる酸アミド結合を介して連結されたことを特徴としている。 The present invention relates to a nanoparticle preparation for treating an eye disease, comprising a drug complex comprising a drug and a lipid soluble molecule, wherein the acid amide bond capable of hydrolyzing the drug and the lipid soluble molecule at an intraocular pH It is characterized by being connected through.
薬物
本発明における薬物とは、特に限定されないが、眼疾患治療に用いられる薬物が挙げられ、特に、水難溶性で難吸収性である薬物にも適用可能である。上記薬物としては、特に限定されるものではないが、ブリンゾラミド、ドルゾラミド、メタゾラミド等のスルホンアミド系化合物を含んでなる炭酸脱水素酵素阻害薬、ジピベフリン等のアドレナリン誘導体を含んでなる交感神経刺激薬、カルテオロール等のカルボスチリル誘導体、チモロール等のβ-ヒドロキシルアミン系化合物を含んでなるβ遮断薬、ベタキソロール等のβ-ヒドロキシルアミン系化合物を含んでなるβ1遮断薬、ニプラジノール、レボブノロール等のβ-ヒドロキシルアミン系化合物を含んでなるα1・β遮断薬、ブリモニジン等のキノキサリン系化合物等を含んでなるα2遮断薬、ブナゾシン等のキナゾリン系化合物等を含んでなるα1遮断薬、ラタノプロスト等のプロスタグランジン関連薬、およびバルサルタン等のアンジオテンシンII受容体拮抗薬等が挙げられる。なお、ジピベフリン、カルテオロールはβ-ヒドロキシルアミン系化合物でもある。具体的には、本発明における薬物としては、好ましくはアミノ基を有する化合物であり、より好ましくは、ブリンゾラミド、ドルゾラミド等のスルホンアミド系化合物を含んでなる炭酸脱水素酵素阻害薬、ブナゾシン等のキナゾリン系化合物等のα1遮断薬が挙げられ、さらに好ましくはブリンゾラミドである。
Drug The drug in the present invention is not particularly limited, and includes a drug used for treating an eye disease, and in particular, it is also applicable to a poorly water-soluble and poorly-absorbable drug. The above drug is not particularly limited, but a carbonic anhydrase inhibitor comprising a sulfonamide type compound such as brinzolamide, dorzolamide, methazolamide or the like, a sympathomimetic drug comprising an adrenaline derivative such as dipivefrine, Carbostyl derivatives such as carteolol, β-blockers comprising β-hydroxylamine compounds such as timolol, β 1- blockers comprising β-hydroxylamine compounds such as betaxolol, β- such as niprazinol, levobanolol Α 1 · β blocker comprising hydroxylamine compound, α 2 blocker comprising quinoxaline compound such as brimonidine, etc. α 1 blocker comprising quinazoline compound such as bunazosin etc., latanoprost etc. Prostaglandin related drugs, and angiothes such as valsartan Singh II receptor antagonists, and the like. In addition, dipivefephrine and carteolol are also β-hydroxylamine compounds. Specifically, the drug in the present invention is preferably a compound having an amino group, more preferably a carbonic anhydrase inhibitor comprising a sulfonamide type compound such as brinzolamide or dorzolamide, or quinazoline such as bunazosin Examples thereof include α 1 blockers such as compounds of the present invention, and more preferred is brinzolamide.
脂溶性分子
本発明における脂溶性分子は、例えば、眼表面に存在する角膜バリア等の脂質性（疎水性）の層との相溶性が高く、その結果、該脂溶性分子と薬物複合体を形成する薬物が難吸収性の化合物であっても、該化合物の上記の眼表面バリアの透過性を向上させることができる物質が好ましい。
本発明における上記脂溶性分子の好適な実施態様としては、トリメチルロックを挙げることができる。
Lipid- soluble molecule The lipid-soluble molecule in the present invention is, for example, highly compatible with a lipidic (hydrophobic) layer such as a corneal barrier present on the ocular surface, and as a result, forms a drug complex with the lipid-soluble molecule. Preferred are substances that can improve the permeability of the above-mentioned ocular surface barrier of the compound even if the drug is a poorly absorbed compound.
As a preferred embodiment of the above-mentioned fat-soluble molecule in the present invention, trimethyl lock can be mentioned.
また、本発明の上記脂溶性分子の別の好適な実施態様としては、以下の一般式（I）で表されるものである：
R1、R2、R3およびR4は、互いに独立して、水素、置換されていてもよいC1-18アルキル、置換されていてもよいC1-18アルコキシ、置換されていてもよいC7-18アラルコキシまたは置換されていてもよいフェノキシを表し、
あるいは、R1、R2、R3およびR4のいずれかの隣り合う基が一緒になって、置換されてもよい環を形成し、
Y は、置換されていてもよいC1-18アルキル、置換されていてもよいC1-18アルコキシ、置換されていてもよいC7-18アラルコキシおよび置換されていてもよいフェノキシからなる群から選択される基を表す）。
In addition, another preferable embodiment of the above-mentioned fat-soluble molecule of the present invention is one represented by the following general formula (I):
R 1 , R 2 , R 3 and R 4 are, independently of one another, hydrogen, optionally substituted C 1-18 alkyl, optionally substituted C 1-18 alkoxy, optionally substituted C 7- 18 represents aralkoxy or phenoxy which may be substituted,
Alternatively, any adjacent groups of R 1 , R 2 , R 3 and R 4 are taken together to form a ring which may be substituted,
Y is selected from the group consisting of optionally substituted C1-18 alkyl, optionally substituted C1-18 alkoxy, optionally substituted C7-18 aralkoxy and optionally substituted phenoxy Represents a group).
R1、R2 、R3 またはR4 は、好ましくは、互いに独立して、水素、C1-10アルキル、C1-5アルコキシまたはC7-15アラルコキシであり、より好ましくは水素、メチル基、メトキシ基またはベンジルオキシ基である。
あるいは、R1、R2 、R3 またはR4 は、互いに隣接する置換基が連結して、好ましくは５〜７員環、さらに好ましくは２，５−ジメチル−２，５−ヘキサンジイル基を形成する。
R 1 , R 2 , R 3 or R 4 is preferably, independently of one another, hydrogen, C 1-10 alkyl, C 1-5 alkoxy or C 7-15 aralkoxy, more preferably hydrogen, a methyl group, a methoxy group Or benzyloxy group.
Alternatively, R 1 , R 2 , R 3 or R 4 is preferably a 5- to 7-membered ring, more preferably a 2,5-dimethyl-2,5-hexanediyl group, in which substituents adjacent to each other are linked. Form.
Yは、好ましくはC1-12アルキル、C1-12アルコキシ、C7-15アラルコキシまたはフェノキシであり、より好ましくはメチル基、i-ブトキシ基、t-ブトキシ基、オクチルオキシ基またはドデシルオキシ基である。 Y is preferably C1-12 alkyl, C1-12 alkoxy, C7-15 aralkoxy or phenoxy, more preferably a methyl group, i-butoxy group, t-butoxy group, octyloxy group or dodecyloxy group.
本発明の好ましい実施態様によれば、R1、R2 、R3 またはR4 は、互いに独立して、水素、C1-5アルキル、C1-5アルコキシまたはC7-10フェニルアルコキシであり、あるいは、R1、R2 、R3 またはR4 は、互いに隣接する置換基が連結してC1-5アルキルで置換されてよい５〜７員環を形成し、Yは、C1-5アルキルまたはC1-12アルコキシである。 According to a preferred embodiment of the invention, R 1 , R 2 , R 3 or R 4 independently of one another are hydrogen, C1-5 alkyl, C1-5 alkoxy or C7-10 phenylalkoxy, or R 1 , R 2 , R 3 or R 4 are linked together to form a 5- to 7-membered ring which may be substituted by C1-5 alkyl, and Y is C1-5 alkyl or C1−. 12 alkoxy.
本発明の別の好ましい実施態様によれば、R1、R2 、R3 またはR4 のいずれか一つがC7-10フェニルアルコキシであり、その他の置換基が互いに独立して、水素またはC1-5アルキルであり、Yは、C1-5アルキルまたはC1-12アルコキシである。 According to another preferred embodiment of the present invention, any one of R 1 , R 2 , R 3 or R 4 is C 7-10 phenylalkoxy and the other substituents independently of one another are hydrogen or C 1-. 5 alkyl and Y is C1-5 alkyl or C1-12 alkoxy.
本発明の別の好ましい実施態様によれば、R3 がC7-10フェニルアルコキシであり、R1、R2 またはR4は互いに独立して、水素またはC1-5アルキルであり、Yは、C1-5アルキルまたはC1-12アルコキシである。 According to another preferred embodiment of the present invention, R 3 is C 7-10 phenylalkoxy, R 1 , R 2 or R 4 independently of one another are hydrogen or C1-5 alkyl, Y is C1. -5 alkyl or C1-12 alkoxy.
本発明の別の好ましい実施態様によれば、R1、R2 、R3 またはR4 は、互いに独立して、水素、メチル基、メトキシ基またはベンジルオキシ基であり、あるいは、R1、R2 、R3 またはR4 は、互いに隣接する置換基が連結して、２，５−ジメチル−２，５−ヘキサンジイル基を形成し、Yは、メチル基、i-ブトキシ基、t-ブトキシ基、オクチルオキシ基またはドデシルオキシ基である。 According to another preferred embodiment of the present invention, R 1 , R 2 , R 3 or R 4 are, independently of one another, hydrogen, methyl, methoxy or benzyloxy, or alternatively R 1 , R 2 , R 3 or R 4 is such that adjacent substituents mutually combine to form a 2,5-dimethyl-2,5-hexanediyl group, Y is a methyl group, an i-butoxy group, t-butoxy group A octyloxy or dodecyloxy group.
薬物と脂溶性分子との薬物複合体
本発明における薬物と脂溶性分子との薬物複合体は、薬物と脂溶性分子とが眼内ｐＨで加水分解しうる酸アミド結合を介して連結された構造を有する。かかる複合体はプロドラッグとして用いることもできる。本発明によれば、薬物を脂溶性分子と化学結合させることにより、疎水性を向上させ、該薬物の細胞膜親和性、吸収性、または薬効の持続性を著しく向上することができる。
Drug complex of drug and lipid soluble molecule The drug complex of drug and lipid soluble molecule in the present invention is a structure in which the drug and lipid soluble molecule are linked via an acid amide bond that can be hydrolyzed at intraocular pH. Have. Such complexes can also be used as prodrugs. According to the present invention, by chemically bonding a drug to a lipid-soluble molecule, it is possible to improve the hydrophobicity and to remarkably improve the cell membrane affinity, absorption, or sustainability of the drug efficacy of the drug.
本発明の薬物複合体は、眼内ｐＨにおいて加水分解することができる。また、本発明の薬学複合体を加水分解するｐＨの好適な例としては７．０〜８．０であり、より好適な例は７．３〜７．６である。 The drug complex of the present invention can be hydrolyzed at intraocular pH. Moreover, as a suitable example of pH which hydrolyzes the pharmaceutical complex of this invention, it is 7.0-8.0, and a more preferable example is 7.3-7.6.
また、上記複合体の構造として、例えば、一般式(II)が挙げられる：
Ａ は水素またはＸであり、
Ｂ は水素またはＸであり、
ＡおよびＢ は同時に水素でなく、
Ｘが、以下の一般式(I)で表される基である：
R1、R2 、R3 またはR4 は、互いに独立して、水素、置換されていてもよいC1-18アルキル、置換されていてもよいC1-18アルコキシ、置換されていてもよいC7-18アラルコキシまたは置換されていてもよいフェノキシを表し、
あるいは、R1、R2、R3およびR4のいずれかの隣り合う基が一緒になって、置換されてもよい環を形成し、
Y は、置換されていてもよいC1-18アルキル、置換されていてもよいC1-18アルコキシ、置換されていてもよいC7-18アラルコキシおよび置換されていてもよいフェノキシからなる群から選択される基を表す）。
In addition, as a structure of the above complex, for example, general formula (II) can be mentioned:
A is hydrogen or X,
B is hydrogen or X,
A and B are not hydrogen at the same time,
X is a group represented by the following general formula (I):
R 1 , R 2 , R 3 or R 4 is, independently of one another, hydrogen, optionally substituted C 1-18 alkyl, optionally substituted C 1-18 alkoxy, optionally substituted C 7- 18 represents aralkoxy or phenoxy which may be substituted,
Alternatively, any adjacent groups of R 1 , R 2 , R 3 and R 4 are taken together to form a ring which may be substituted,
Y is selected from the group consisting of optionally substituted C1-18 alkyl, optionally substituted C1-18 alkoxy, optionally substituted C7-18 aralkoxy and optionally substituted phenoxy Represents a group).
本発明の薬物複合体における一般式(I)の好ましい態様は、上述の脂溶性分子における一般式(I)と同様であってよい。 Preferred embodiments of the general formula (I) in the drug complex of the present invention may be the same as the general formula (I) in the above-mentioned fat-soluble molecule.
本発明の薬物複合体として、好ましくは複合体が以下の化合物からなる群から選択される化合物である。
なお、以下の式において、「Me」はメチル基を表し、「i-BuO」はイソ−ブトキシ基を表す。
In the following formulas, "Me" represents a methyl group, and "i-BuO" represents an iso-butoxy group.
ナノ粒子製剤
本発明の眼疾患治療用ナノ粒子製剤は、上記薬物と脂溶性分子との薬物複合体を有効成分として含有してなる。かかる本発明の製剤は、ナノ結晶性を向上させ、眼内移行性を向上し、薬物の薬効の持続を向上する上で有利である。したがって、本発明の製剤は、好ましくは持続性製剤である。
Nanoparticle Preparation The nanoparticle preparation for treating an eye disease of the present invention comprises a drug complex of the above drug and a lipid soluble molecule as an active ingredient. Such a preparation of the present invention is advantageous in improving nanocrystalline properties, improving intraocular transferability, and improving the duration of drug efficacy. Thus, the formulation of the present invention is preferably a sustained release formulation.
本発明の製剤におけるナノ粒子は薬物と脂溶性分子との薬物複合体が集合して形成されるものが好ましい。上記複合体の大きさは、特に限定されないが、例えば、平均粒径が、１０〜１，０００ｎｍ、好ましくは１０〜２００ｎｍである。さらに、上記複合体の形状は、特に限定しないが、球体、長楕円体、略真球体、多面体、ロッド状等が挙げられ、好ましくは球体である。 Preferably, the nanoparticles in the preparation of the present invention are formed by aggregating a drug complex of a drug and a lipophilic molecule. The size of the complex is not particularly limited, and for example, the average particle size is 10 to 1,000 nm, preferably 10 to 200 nm. Further, the shape of the complex is not particularly limited, and spheres, long ellipsoids, nearly perfect spheres, polyhedrons, rod shapes and the like can be mentioned, with preference given to spheres.
なお、ナノ粒子の平均粒径は、再沈法で作成した懸濁液をフィルターで濾過し、走査型電子顕微鏡溶試料台の上に滴下して乾燥させた後Ｐｔスパッタリングして、走査型電子顕微鏡観察して求めることができる。 The average particle diameter of the nanoparticles can be determined by filtering the suspension prepared by the reprecipitation method with a filter, dropping it on a scanning electron microscope solution sample table, drying it, and then performing Pt sputtering to scan it. It can be determined by microscopic observation.
ナノ粒子製剤の製造方法
このような本発明のナノ粒子製剤は、当業者に公知の任意の手段、方法で製造することができる。その代表的な方法として、例えば、薬物である有機化合物と脂溶性分子を化学的に結合させ薬物複合体を製造する工程、および、該複合体をナノ粒子化する工程を含む製造方法を挙げることができる。
Method of Producing Nanoparticle Formulations Such nanoparticle formulations of the present invention can be produced by any means, method known to those skilled in the art. As a typical method thereof, for example, a process of chemically bonding an organic compound which is a drug and a lipid-soluble molecule to produce a drug complex, and a process of forming the complex into nanoparticles can be mentioned. Can.
本発明の製造方法において、薬物および脂溶性分子の複合体化は当業者に公知の任意の方法で行うことができる。例えば、ジクロロメタンおよびエチレンジクロリド等の適当な有機溶媒中にＮ、Ｎ−ジイソプロピルエチルアミン（ＤＩＥＰＡ）のような塩基およびＥＤＣのような縮合剤を共存させた系における酸アミド化反応（１〜２４時間、０℃〜室温）によって、該薬物と脂溶性分子とを共有結合することにより薬物複合体とすることができる。 In the production method of the present invention, conjugation of the drug and the lipid soluble molecule can be performed by any method known to those skilled in the art. For example, acid amidification reaction in a system in which a base such as N, N-diisopropylethylamine (DIEPA) and a condensing agent such as EDC coexist in a suitable organic solvent such as dichloromethane and ethylene dichloride (1 to 24 hours) The drug complex can be formed by covalently bonding the drug and a lipophilic molecule at 0 ° C. to room temperature).
上記の反応系において、薬物と脂溶性分子の溶媒中における濃度、それらのお互いの割合、およびその他の反応条件は当業者が適宜設定することができる。 In the above reaction system, the concentration of the drug and the lipid soluble molecule in the solvent, their ratio to each other, and other reaction conditions can be appropriately set by those skilled in the art.
なお、本発明のナノ粒子製剤が所望の作用・効果を発揮できる限り、薬物と脂溶性分子との薬物複合体は共有結合以外の任意の様式で複合化していてもよい。さらに、この際に、該薬物と脂溶性分子とを、例えば、飽和炭化水素基、ペプチド基等の適当なリンカ―分子を介して結合させることも可能である。 The drug complex of the drug and the lipid-soluble molecule may be complexed in any manner other than covalent bonding, as long as the nanoparticulate preparation of the present invention can exert the desired action and effect. Furthermore, at this time, it is also possible to link the drug and the lipophilic molecule via a suitable linker molecule such as, for example, a saturated hydrocarbon group or a peptide group.
このようにして得られた薬物複合体は、例えば、再沈法等の当業者に公知の任意の方法で結晶化させることによって、ナノ粒子化することができる。このようなナノ粒子化における様々な具体的な条件は当業者が適宜設定することができる。 The drug complex thus obtained can be made into nanoparticles by crystallization, for example, by any method known to those skilled in the art such as reprecipitation method. Those skilled in the art can appropriately set various specific conditions for such nanoparticle formation.
本発明では、例えば、撹拌した貧溶媒（蒸留水、超純水または適当な中性塩溶液）に、薬物である化合物と脂溶性分子を含んでなる薬物複合体および適宜ポリソルベート等の界面活性剤を含むＴＨＦおよびアセトン等の適当な良溶媒（有機溶媒）の溶液を添加して分散液を調製した後、マイクロ波照射および透析、限外濾過等の当業者公知の任意の手段を用いて有機溶媒を除去することによって、当該複合体を含んでなるナノ粒子製剤を製造することができる。 In the present invention, for example, a drug complex comprising a compound which is a drug and a lipid-soluble molecule in a stirred poor solvent (distilled water, ultrapure water or a suitable neutral salt solution) and a surfactant such as polysorbate as appropriate The dispersion is prepared by adding a solution of THF and a suitable good solvent (organic solvent) such as acetone, and then using any means known to those skilled in the art such as microwave irradiation and dialysis, ultrafiltration, etc. By removing the solvent, a nanoparticle formulation comprising the complex can be produced.
なお、上記の好適な粒径を有するナノ粒子製剤を製造するには、貧溶媒と良溶媒との容量比は１０００：１〜３：１程度の範囲が好ましく、さらに、有機溶液中の薬物複合体の濃度は、例えば、０．１〜５００ｍｇ／ｍｌの範囲であることが好ましい。 The volume ratio of the poor solvent to the good solvent is preferably in the range of about 1000: 1 to 3: 1 to produce the nanoparticle formulation having the above-described suitable particle diameter, and further, the drug complex in the organic solution The body concentration is preferably, for example, in the range of 0.1 to 500 mg / ml.
剤形
本発明の眼疾患治療用ナノ粒子製剤は、上記薬物と脂溶性分子とからなる薬物複合体をそのまま用いてもよく、薬学的に許容可能な添加剤とともに医薬組成物として用いることもできる。
本発明の眼疾患治療用ナノ粒子製剤を組成物として提供する場合、上記薬物と脂溶性分子からなる薬物複合体の含有量は、本願発明の効果を妨げない限り特に限定されない。上記薬物と脂溶性分子からなる薬物複合体の含有量は、例えば、眼疾患治療用ナノ粒子製剤全量に対して、０．００１〜１０質量％、好ましくは０．０１〜１質量％、さらに好ましくは０．１〜１質量％とすることができる。
Dosage Form The nanoparticle preparation for treating an eye disease of the present invention may use a drug complex comprising the above drug and a lipid-soluble molecule as it is, and can also be used as a pharmaceutical composition together with pharmaceutically acceptable additives. .
When providing the nanoparticle preparation for treating an eye disease of the present invention as a composition, the content of the drug complex consisting of the above drug and a lipid-soluble molecule is not particularly limited as long as the effects of the present invention are not impaired. The content of the drug complex comprising the above drug and a lipid-soluble molecule is, for example, 0.001 to 10% by mass, preferably 0.01 to 1% by mass, more preferably, relative to the total amount of the nanoparticle preparation for treating ocular diseases. Can be 0.1 to 1% by mass.
また、上記眼疾患治療用ナノ粒子製剤における薬学的に許容可能な添加剤としては、特に限定されないが、溶剤、溶解補助剤、保存剤、防腐剤、安定化剤、乳化剤、懸濁剤、ｐＨ調整剤、無痛化剤、等張化剤、緩衝剤、界面活性剤、賦形剤、増粘剤、粘稠剤、着色剤、公知のキャリア（ポリアミノ酸キャリア、合成高分子、天然高分子等）等が挙げられる。上記添加剤としては、塩化ナトリウム、濃グリセリン、ソルビトール、ブドウ糖等の等張化剤；リン酸水素ナトリウム、酢酸ナトリウム、ホウ酸、クエン酸等の緩衝化剤；ポリソルベート８０、ステアリン酸ポリオキシル４０、ポリオキシエチレン硬化ヒマシ油60等の界面活性剤；クエン酸ナトリウム、エデト酸ナトリウム等の安定化剤；塩化ベンザルコニウム、塩化ベンゼトニウム、パラオキシ安息香酸メチル、グルコン酸クロルヘキシジン液等の防腐剤；ポリビニルピロリドンＫ３０、ヒドロキシエチルセルロース、プロピレングリコール、メチルセルロース、マクロゴール４０００等の粘稠剤；カルボキシビニルポリマー、マクロゴール６０００、ポリビニルピロリドンＫ２５、ポリビニルピロリドンＫ３０等の懸濁化剤；塩酸、氷酢酸、水酸化ナトリウム等のｐＨ調整剤；塩化マグネシウム、エタノール、プロピレングリコール等の溶解補助剤を挙げることができる。 Further, the pharmaceutically acceptable additive in the above-mentioned nanoparticle preparation for treating ocular diseases is not particularly limited, but it is possible to use a solvent, a solubilizer, a preservative, a preservative, a stabilizer, an emulsifier, a suspension, pH, Modifier, soothing agent, tonicity agent, buffer, surfactant, excipient, excipient, thickener, thickener, colorant, known carrier (polyamino acid carrier, synthetic polymer, natural polymer, etc. Etc.). Examples of the additive include tonicity agents such as sodium chloride, concentrated glycerin, sorbitol and glucose; buffering agents such as sodium hydrogen phosphate, sodium acetate, boric acid and citric acid; polysorbate 80, polyoxyl stearate, poly Surfactants such as oxyethylene hydrogenated castor oil 60; Stabilizers such as sodium citrate and sodium edetate; Preservatives such as benzalkonium chloride, benzethonium chloride, methyl parahydroxybenzoate and chlorhexidine gluconate; polyvinylpyrrolidone K30 , Thickeners such as hydroxyethyl cellulose, propylene glycol, methyl cellulose and macrogol 4000; suspending agents such as carboxyvinyl polymer, macrogol 6000, polyvinyl pyrrolidone K25, polyvinyl pyrrolidone K30 etc; hydrochloric acid, ice vinegar , PH modifiers such as sodium hydroxide; can be mentioned magnesium chloride, ethanol, a solubilizing agent such as propylene glycol.
また、本発明の眼疾患治療用ナノ粒子製剤は、眼疾患に適用できるものであれば、剤形は特に限定されず、点眼剤（水溶性製剤、懸濁製剤、ゲル化製剤等）、眼軟膏、内服薬（経口薬）、点滴薬（静注薬）、コンタクトレンズ付加型薬剤等として提供することができる。 In addition, the dosage form is not particularly limited as long as the nanoparticle preparation for treating an eye disease of the present invention is applicable to an eye disease, and eye drops (water-soluble preparation, suspension preparation, gelled preparation, etc.), eye It can be provided as an ointment, internal medicine (oral medicine), drip medicine (intravenous medicine), contact lens addition type medicine and the like.
本発明の薬物と脂溶性分子からなる薬物複合体は、眼疾患に対する優れた治療または予防効果を有している。したがって、本発明の別の態様によれば、上記薬物と脂溶性分子からなる薬物複合体を有効成分として含有する、眼疾患の治療または予防剤が提供される。ここで、「治療」とは、確立された病態を改善することを意味し、「予防」とは、想定される悪化に対して事前に備えておくことであって、疾患の発生を未然に防ぐことを意味する。 The drug complex comprising the drug of the present invention and a lipid soluble molecule has an excellent therapeutic or preventive effect on eye diseases. Therefore, according to another aspect of the present invention, there is provided an agent for treating or preventing eye disease, which comprises as an active ingredient a drug complex comprising the above-mentioned drug and a lipid-soluble molecule. Here, "treatment" means to improve the established pathological condition, and "prevention" means to prepare in advance for possible deterioration and to prevent occurrence of the disease. Means to prevent.
本発明のナノ粒子製剤の適用対象となる眼疾患に特に制限はないが、例えば、視神経細胞が関与する眼疾患が挙げられ、好ましくは、緑内障、糖尿病網膜症、加齢黄班変性症、網膜色素変性症、または、高度近視である。 The eye disease to which the nanoparticle preparation of the present invention is applied is not particularly limited, and examples thereof include eye diseases involving optic nerve cells, preferably glaucoma, diabetic retinopathy, age-related macular degeneration, retina Pigmentary degeneration or high myopia.
なお、緑内障とは、視神経細胞が障害され萎縮し、視野が損なわれ、視力も低下していく眼疾患である。一般に、緑内障には、正常眼圧緑内障、色素緑内障、偽離脱緑内障、急性隅角閉塞緑内障、絶対緑内障、単性緑内障、および、満性解放隅角緑内障といった各疾患が含まれるが、これらに限定されるものではない。 Glaucoma is an eye disease in which the optic nerve cells are damaged and atrophy, visual field is impaired, and visual acuity is also reduced. In general, glaucoma includes, but is not limited to, normal-tension glaucoma, pigment glaucoma, pseudo-displacement glaucoma, acute angle closure glaucoma, absolute glaucoma, simple glaucoma, and full open angle glaucoma It is not something to be done.
また、本発明の別の態様によれば、有効量の本発明の薬物と脂溶性分子からなる薬物複合体を被験体に投与することを含んでなる、眼疾患の治療または予防方法が提供される。また、本発明の別の態様によれば、有効量の本発明の薬物と脂溶性分子からなる薬物複合体を被験体に投与することを含んでなる、被験体の眼疾患の発生リスクを軽減する方法が提供される。 In addition, according to another aspect of the present invention, there is provided a method of treating or preventing an ocular disease, comprising administering to a subject a drug complex comprising an effective amount of the drug of the present invention and a lipid soluble molecule. Ru. Also, according to another aspect of the present invention, there is provided a method of reducing the risk of developing eye disease in a subject comprising administering to the subject a drug complex comprising an effective amount of a drug of the present invention and a lipid soluble molecule. Methods are provided.
上記被験体としては、好ましくは哺乳動物であり、より好ましくはヒトである。 The subject is preferably a mammal, more preferably a human.
また、本発明の薬物と脂溶性分子からなる薬物複合体は、眼疾患に用いられる他の薬剤と組み合わせて同時または逐次に哺乳動物に投与してもよい。 In addition, a drug complex comprising a drug of the present invention and a lipid-soluble molecule may be simultaneously or sequentially administered to a mammal in combination with other drugs used for ocular diseases.
また、本発明の別の態様によれば、眼疾患治療用ナノ粒子製剤の製造における、本発明の薬物と脂溶性分子とからなる複合体の使用が提供される。また、本発明の別の態様によれば、眼疾患を治療するための、本発明の薬物と脂溶性分子とからなる薬物複合体が提供される。
上記別の態様はいずれも、本発明の眼疾患治療用ナノ粒子製剤の記載に準じて実施することができる。
In addition, according to another aspect of the present invention, there is provided the use of a complex comprising a drug of the present invention and a lipid-soluble molecule in the preparation of a nanoparticle preparation for treating ocular diseases. Also, according to another aspect of the present invention, there is provided a drug complex comprising a drug of the present invention and a lipid-soluble molecule, for treating an ocular disease.
Any of the other aspects described above can be practiced according to the description of the nanoparticle preparation for treating an eye disease of the present invention.
以下、実施例に即して本発明を具体的に説明するが、本発明の技術的範囲はこれらの記載によって何等制限されるものではない。 Hereinafter, the present invention will be specifically described based on examples, but the technical scope of the present invention is not limited by these descriptions.
実施例１
［薬物複合体の製造］
本発明の眼疾患治療用ナノ粒子製剤に用いる薬物複合体の製造工程の反応式の一例として、反応式（I）を示す。
化合物４は、例えば、Ｊ．Ｏｒｇ． Ｃｈｅｍ．，（１９８９），５４，ｐ．３３０３およびＣｈｅｍ．Ｐｈａｒｍ．Ｂｕｌｌ．，（２０００），４８，ｐ．２３８等に記載の当該分野の公知技術にしたがい市販の２，６−ジメチルヒドロキノンより合成した。
Example 1
[Manufacture of drug complex]
Reaction formula (I) is shown as an example of reaction formula of the manufacturing process of the drug complex used for the nanoparticle formulation for eye disease treatment of this invention.
Compound 4 is described, for example, in J. Org. Chem. , (1989), 54 , p. 3303 and Chem. Pharm. Bull. , (2000), 48 , p. The compound was synthesized from commercially available 2,6-dimethylhydroquinone according to a known technique in the art described in H. 238 et al.
化合物５の合成
反応式(I)において、化合物４（１６．９ｇ、５３．７ｍｍｏｌ）およびＮ、Ｎ―ジメチルアミノピリジン（９．８４ｇ、８０．５ｍｍｏｌ）のＴＨＦ溶液を０〜５℃に冷却し、ｔ−ブチルジメチルクロロシラン（９．７５ｇ、６４．７ｍｍｏｌ）を加え、室温で２０時間撹拌した。水を加えて反応を終了した後、酢酸エチルで抽出し、水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤をろ過で除去し、ロータリーエバポレータ―を用いてろ液を濃縮すると化合物５（２３．０ｇ）が得られた。
1 H NMR (400 MHz, CDCl 3 ) δ 0.02 (s, 6H), 0.87 (s, 9H), 1.58 (s, 6H), 2.09 (t, 2H, J = 6.6 Hz, ), 2.22 (s, 3H), 2.42 (s, 3H), 3.63 (t, 2H, J = 6.6 Hz), 4.70 (s, 2H), 5.84 (s, 1H), 6.46 (s, 1H), 7.33 (t, 1H, J = 7.2 Hz), 7.39 (t, 2H, J = 7.2 Hz), 7.47 (d, 2H, J = 7.2 Hz); 13 C NMR (101 MHz, CDCl 3 ) δ -5.13, 16.3, 16.5, 18.4, 26.1, 32.5, 40.0, 44.9, 62.0, 74.1, 117.8, 127.55, 127.64, 128.3, 128.8, 131.0, 131.1, 137.7, 149.8, 151.6.
Synthesis of Compound 5 In the reaction formula (I), the THF solution of compound 4 (16.9 g, 53.7 mmol) and N, N-dimethylaminopyridine (9.84 g, 80.5 mmol) was cooled to 0 to 5 ° C. T-Butyldimethylchlorosilane (9.75 g, 64.7 mmol) was added and stirred at room temperature for 20 hours. The reaction was terminated by adding water, extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the filtrate was concentrated using a rotary evaporator to give compound 5 (23.0 g).
1 H NMR (400 MHz, CDCl 3 ) δ 0.02 (s, 6 H), 0.87 (s, 9 H), 1.58 (s, 6 H), 2.09 (t, 2 H, J = 6.6 Hz,), 2.22 (s, 3 H ), 2.42 (s, 3H), 3.63 (t, 2H, J = 6.6 Hz), 4.70 (s, 2H), 5. 84 (s, 1H), 6.46 (s, 1H), 7.33 (t, 1H, J = 7.2 Hz), 7.39 (t, 2 H, J = 7.2 Hz), 7. 47 (d, 2 H, J = 7.2 Hz); 13 C NMR (101 MHz, CDCl 3 ) δ -5.13, 16.3, 16.5, 18.4, 26.1, 32.5, 40.0, 44.9, 62.0, 74.1, 117.8, 127.55, 127.64, 128.3, 128.8, 131.0, 131.1, 137.7, 149.8, 151.6.
化合物６の合成
反応式(I)において、化合物５（２３．０ｇ、５３．７ｍｍｏｌ）およびトリエチルアミン（１０．９ｇ、１０７ｍｍｏｌ）、Ｎ、Ｎ―ジメチルアミノピリジン（１．３１ｇ、１０．７ｍｍｏｌ）のＴＨＦ溶液を０〜５℃に冷却し、クロロギ酸イソブチル（９．８６ｇ、８０．５ｍｍｏｌ）を加え、室温で３時間撹拌した。水を加えて反応を終了した後、酢酸エチルで抽出し、水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤をろ過で除去し、ロータリーエバポレータ―を用いてろ液を濃縮すると化合物６（２８．４ｇ）が得られた。
1 H NMR (400 MHz, CDCl 3 ) δ 0.02 (s, 6H), 0.85 (s, 9H), 1.00 (d, 6H, J = 6.6 Hz), 1.51 (s, 6H), 2.00-2.09 (m, 1H), 2.07 (t, 2H, J = 7.6 Hz), 2.26 (s, 3H), 2.49 (s, 3H), 3.52 (t, 2H, J = 7.6 Hz), 4.02 (d, 2H, J = 6.6 Hz), 4.74 (s, 2H), 6.70 (s, 1H), 7.34 (t, 1H, J = 7.2 Hz), 7.40 (t, 2H, J = 7.2 Hz), 7.47 (d, 2H, J = 7.2 Hz); 13 C NMR (101 MHz, CDCl 3 ) δ -5.12, 16.3, 16.6, 18.3, 19.0, 26.0, 27.9, 31.8, 40.0, 45.8, 60.8, 73.7, 74.5, 123.7, 127.5, 127.8, 128.3, 129.5, 131.9, 136.0, 137.3, 145.8, 154.21, 154.27.
Synthesis of Compound 6 In the reaction formula (I), THF of compound 5 (23.0 g, 53.7 mmol), triethylamine (10.9 g, 107 mmol), N, N-dimethylaminopyridine (1.31 g, 10.7 mmol) The solution was cooled to 0-5 ° C., isobutyl chloroformate (9.86 g, 80.5 mmol) was added and stirred at room temperature for 3 hours. The reaction was terminated by adding water, extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the filtrate was concentrated using a rotary evaporator to give compound 6 (28.4 g).
1 H NMR (400 MHz, CDCl 3 ) δ 0.02 (s, 6 H), 0.85 (s, 9 H), 1.00 (d, 6 H, J = 6.6 Hz), 1.51 (s, 6 H), 2.00-2.09 (m, 1H), 2.07 (t, 2H, J = 7.6 Hz), 2.26 (s, 3H), 2.49 (s, 3H), 3.52 (t, 2H, J = 7.6 Hz), 4.02 (d, 2H, J = 6.6) Hz), 4.74 (s, 2 H), 6.70 (s, 1 H), 7.34 (t, 1 H, J = 7.2 Hz), 7. 40 (t, 2 H, J = 7.2 Hz), 7. 47 (d, 2 H, J = 7.2 Hz); 13 C NMR (101 MHz, CDCl 3 ) δ -5.12, 16.3, 16.6, 18.3, 19.9, 26.0, 27.9, 40.0, 45.8, 60.8, 73.7, 74.5, 123.7, 127.5, 127.8, 128.3, 129.5 , 131.9, 136.0, 137.3, 145.8, 154.21, 154.27.
化合物７の合成
反応式(I)において、化合物６（２８．４ｇ、５３．７ｍｍｏｌ）のＴＨＦ溶液に酢酸（６４．５ｇ、１．０７ｍｏｌ）および水（４０ｍｌ）を加え４０℃で４時間加熱した。酢酸エチルで抽出し、水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤をろ過で除去し、ロータリーエバポレータ―を用いてろ液を濃縮すると化合物７（２２．３ｇ）が得られた。
1 H NMR (400 MHz, CDCl 3 ) δ 1.00 (d, 6H, J = 6.6 Hz), 1.52 (s, 6H), 2.00-2.07 (m, 1H), 2.10 (t, 2H, J = 7.2 Hz), 2.26 (s, 3H), 2.48 (s, 3H), 3.57 (t, 2H, J = 7.6 Hz), 4.03 (d, 2H, J = 6.6 Hz), 4.75 (s, 2H), 6.71 (s, 1H), 7.35 (t, 1H, J = 7.2 Hz), 7.40 (t, 2H, J = 7.2 Hz), 7.46 (d, 2H, J = 7.2 Hz); 13 C NMR (101 MHz, CDCl 3 ) δ 16.3, 16.6, 19.0, 27.9, 31.9, 39.6, 45.7, 60.5, 73.7, 74.7, 123.9, 127.5, 127.8, 128.3, 129.8, 132.1, 135.6, 137.2, 145.7, 154.38, 154.47.
Synthesis of Compound 7 In Reaction Formula (I), acetic acid (64.5 g, 1.07 mol) and water (40 ml) were added to a THF solution of Compound 6 (28.4 g, 53.7 mmol) and heated at 40 ° C. for 4 hours . The mixture was extracted with ethyl acetate, washed with water and brine, and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the filtrate was concentrated using a rotary evaporator to give compound 7 (22.3 g).
1 H NMR (400 MHz, CDCl 3 ) δ 1.00 (d, 6 H, J = 6.6 Hz), 1.52 (s, 6 H), 2.00-2.07 (m, 1 H), 2. 10 (t, 2 H, J = 7.2 Hz) , 2.26 (s, 3H), 2.48 (s, 3H), 3.57 (t, 2H, J = 7.6 Hz), 4.03 (d, 2H, J = 6.6 Hz), 4.75 (s, 2H), 6.71 (s, 1 H), 7. 35 (t, 1 H, J = 7.2 Hz), 7. 40 (t, 2 H, J = 7.2 Hz), 7.46 (d, 2 H, J = 7.2 Hz); 13 C NMR (101 MHz, CDCl 3 ) δ 16.3, 16.6, 19.0, 27.9, 31.9, 45.7, 60.5, 73.7, 123.9, 127.5, 128.3, 129.8, 132.1, 135.6, 137.2, 145.7, 154.38, 154.47.
化合物８の合成
反応式(I)において、化合物７（２２．３ｇ、５３．７ｍｍｏｌ）のジクロロメタン溶液を０〜５℃に冷却し、クロロクロム酸ピリジニウム（１７．４ｇ、８０．７ｍｍｏｌ）を加え、室温で２時間撹拌した。反応溶液にカラムクロマトグラフィー用シリカゲルを加え、ロータリーエバポレータ―を用いて濃縮した。桐山ロートにセライトおよびカラムクロマトグラフィー用シリカゲルを順に敷き、この上に反応混合物を吸着させたシリカゲルを載せた。ろ過びんを吸引しながら、混合溶媒（ヘキサン：酢酸エチル＝４：１（ｖ：ｖ））を流した。ロータリーエバポレータ―を用いてろ液を濃縮すると化合物８（１７．８ｇ）が得られた。
1 H NMR (400 MHz, CDCl 3 ) δ 1.00 (d, 6H, J = 6.4 Hz), 1.51 (s, 6H), 2.01-2.08 (m, 1H), 2.26 (s, 3H), 2.47 (s, 3H), 2.87 (s, 2H), 4.04 (d, 2H, J = 6.4 Hz), 4.74 (s, 2H), 6.76 (s, 1H), 7.34 (t, 1H, J = 7.2 Hz), 7.40 (t, 2H, J = 7.2 Hz), 7.46 (d, 2H, J = 7.2 Hz), 9.55 (t, 1H, J = 2.6 Hz); 13 C NMR (101 MHz, CDCl 3 ) δ 16.3, 16.7, 19.0, 27.9, 31.5, 38.6, 56.7, 73.8, 74.7, 123.9, 127.5, 127.8, 128.3, 130.4, 131.5 , 134.4, 137.1, 145.3, 153.9, 154.5, 202.2 .
Synthesis of Compound 8 In Reaction Formula (I), a solution of Compound 7 (22.3 g, 53.7 mmol) in dichloromethane was cooled to 0-5 ° C., and pyridinium chlorochromate (17.4 g, 80.7 mmol) was added, Stir at room temperature for 2 hours. Silica gel for column chromatography was added to the reaction solution, and concentrated using a rotary evaporator. Celite and silica gel for column chromatography were placed in order on a Kiriyama funnel, and the silica gel to which the reaction mixture was adsorbed was loaded thereon. The mixed solvent (hexane: ethyl acetate = 4: 1 (v: v)) was flushed while suctioning the filtration bottle. The filtrate was concentrated using a rotary evaporator to give compound 8 (17.8 g).
1 H NMR (400 MHz, CDCl 3 ) δ 1.00 (d, 6 H, J = 6.4 Hz), 1.51 (s, 6 H), 2.01-2.08 (m, 1 H), 2.26 (s, 3 H), 2.47 (s, 2) 3H), 2.87 (s, 2H), 4.04 (d, 2H, J = 6.4 Hz), 4.74 (s, 2H), 6.76 (s, 1H), 7.34 (t, 1H, J = 7.2 Hz), 7.40 ( t, 2H, J = 7.2 Hz), 7.46 (d, 2H, J = 7.2 Hz), 9.55 (t, 1 H, J = 2.6 Hz); 13 C NMR (101 MHz, CDCl 3 ) δ 16.3, 16.7, 19.0 , 27.9, 31.5, 38.6, 56.7, 73.8, 74.7, 123.9, 127.8, 128.3, 130.4, 134.4, 137.1, 147.1, 145.3, 153.9, 154.5, 202.2.
化合物９の合成
過マンガン酸カリウム（６．８２ｇ、４３．１ｍｍｏｌ）に水を加えて溶解した。反応式(I)において、化合物８（１７．８ｇ、４３．１ｍｍｏｌ）にアセトンおよび水を加えて溶液とし、０〜５℃に冷却し、上記過マンガン酸カリウム水溶液を加え、室温で１７時間撹拌した。ろ過により固形物を除去した後、エバポレータ―を用いてろ液を濃縮する。塩酸を加えて酸性とした後、酢酸エチルで抽出し、水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤をろ過で除去し、ロータリーエバポレータ―を用いてろ液を濃縮した。得られた反応混合物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２：３（ｖ：ｖ））で精製すると化合物９（１２．０ｇ）が得られた。
1 H NMR (400 MHz, CDCl 3 ) δ 0.99 (d, 6H, J = 6.8 Hz), 1.60 (s, 6H,), 2.04 (sep, 1H, J = 6.8 Hz), 2.23 (s, 3H), 2.48 (s, 3H), 2.89 (s, 2H), 4.02 (d, 2H, J = 6.8 Hz), 4.73 (s, 2H), 6.72 (s, 1H), 7.33 (t, 1H, J = 7.2 Hz), 7.38 (t, 2H, J = 7.2 Hz), 7.45 (d, 2H, J = 7.2 Hz); 13 C NMR (101 MHz, CDCl 3 ) δ 16.3, 16.5, 19.0, 27.9, 31.3, 39.2, 47.4, 73.8, 74.6, 123.6, 127.5, 127.7, 128.3, 129.8, 131.6, 135.2, 137.2, 145.5, 154.0, 154.2, 177.2.
Synthesis of Compound 9 Water was added to dissolve in potassium permanganate (6.82 g, 43.1 mmol). In Reaction formula (I), acetone and water are added to compound 8 (17.8 g, 43.1 mmol) to make a solution, cooled to 0-5 ° C., the above aqueous potassium permanganate solution is added, and stirring is carried out at room temperature for 17 hours did. After removing the solids by filtration, the filtrate is concentrated using an evaporator. The reaction solution was acidified with hydrochloric acid, extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the filtrate was concentrated using a rotary evaporator. The resulting reaction mixture was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 3 (v: v)) to give compound 9 (12.0 g).
1 H NMR (400 MHz, CDCl 3 ) δ 0.99 (d, 6 H, J = 6.8 Hz), 1.60 (s, 6 H,), 2.04 (sep, 1 H, J = 6.8 Hz), 2.23 (s, 3 H), 2.48 (s, 3 H), 2. 89 (s, 2 H), 4.02 (d, 2 H, J = 6.8 Hz), 4.73 (s, 2 H), 6.72 (s, 1 H), 7.33 (t, 1 H, J = 7.2 Hz ), 7.38 (t, 2 H, J = 7.2 Hz), 7. 45 (d, 2 H, J = 7.2 Hz); 13 C NMR (101 MHz, CDCl 3 ) δ 16.3, 16.5, 19.0, 27.9, 31.3, 39.2, 47.4 , 73.8, 74.6, 123.6, 127.5, 127.7, 128.3, 129.8, 131.6, 135.2, 137.2, 145.5, 154.0, 154.2, 177.2.
ブリンゾラミド・脂溶性分子−薬物複合体（１０）の合成
ブリンゾラミド（２．００ｇ、５．２２ｍｍｏｌ）および化合物９（３．３６ｇ、７．８３ｍｍｏｌ）のジクロロメタン溶液を０〜５℃に冷却し、ＥＤＣ（２．００ｇ、１０．４ｍｍｏｌ）およびＮ、Ｎ―ジメチルアミノピリジン（６３．８ｍｇ、０．５２ｍｍｏｌ）を加え、室温で１８時間撹拌した。酢酸エチルで抽出し、水および飽和食塩水、飽和炭酸水素ナトリウム水溶液、飽和塩化アンモニウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤をろ過で除去し、ロータリーエバポレータ―を用いてろ液を濃縮した。得られた組成生物をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝５０：１（ｖ：ｖ））で精製するとブリンゾラミド・脂溶性分子−薬物複合体１０（２．５５ｇ、３．４６ｍｍｏｌ、６６％）が得られた。
1 H NMR (400 MHz, CDCl 3 ) δ 1.03 (d, 6H, J = 6.6 Hz), 1.06 (t, 3H, J = 7.0 Hz), 1.668 (s, 3H), 1.672 (s, 3H), 1.85 (quin, 2H, J = 7.0 Hz), 2.10 (sep, 1H, J = 6.6 Hz), 2.22 (s, 3H), 2.30 (s, 3H), 2.45 (d, 1H, J = 13.0 Hz), 2.49 (d, 1H, J = 13.0 Hz), 2.55 (dq, 1H, J = 11.2, 7.2 Hz), 2.61 (dq, 1H, J = 11.2, 7.2 Hz), 3.15 (quin, 1H, J = 6.8 Hz), 3.33 (s, 3H), 3.42-3.53 (m, 5H), 3.82 (t, 1H), 4.14 (d, 2H, J = 6.6 Hz), 4.61 (d, 1H, J = 10.6 Hz), 4.65 (d, 1H, J = 10.6 Hz), 6.74 (s, 1H), 7.37 (t, 1H, J = 7.0 Hz), 7.42 (t, 2H, J = 7.0 Hz), 7.48 (d, 2H, J = 7.0 Hz), 7.52 (s, 1H); 13 C NMR (101 MHz, CDCl 3 ) δ 15.70, 15.78, 16.5, 18.9, 27.9, 29.6, 32.4, 32.5, 41.1, 41.3, 46.3, 49.98, 50.03, 51.4, 58.7, 69.2, 74.7, 75.8, 123.9, 128.2, 128.49, 128.51, 131.3, 132.5, 132.8, 133.9, 136.6, 140.4, 142.1, 143.9, 146.0, 154.6, 156.0, 170.9.
Synthesis of Brinzolamide-Lipid- soluble Molecule-Drug Complex (10) A solution of Brinzolamide (2.00 g, 5.22 mmol) and Compound 9 (3.36 g, 7.83 mmol) in dichloromethane was cooled to 0-5 ° C. 2.00 g, 10.4 mmol) and N, N-dimethylaminopyridine (63.8 mg, 0.52 mmol) were added and stirred at room temperature for 18 hours. The mixture was extracted with ethyl acetate, washed with water and saturated brine, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous ammonium chloride solution, and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the filtrate was concentrated using a rotary evaporator. The resulting composition is purified by silica gel column chromatography (ethyl acetate: methanol = 50: 1 (v: v)) to give brinzolamide / lipid-soluble molecule-drug complex 10 (2.55 g, 3.46 mmol, 66%) was gotten.
1 H NMR (400 MHz, CDCl 3 ) δ 1.03 (d, 6 H, J = 6.6 Hz), 1.06 (t, 3 H, J = 7.0 Hz), 1.668 (s, 3 H), 1.672 (s, 3 H), 1. 85 (quin, 2H, J = 7.0 Hz), 2.10 (sep, 1 H, J = 6.6 Hz), 2.22 (s, 3 H), 2.30 (s, 3 H), 2.45 (d, 1 H, J = 13.0 Hz), 2.49 (d, 1H, J = 13.0 Hz), 2.55 (dq, 1 H, J = 11.2, 7.2 Hz), 2.61 (dq, 1 H, J = 11.2, 7.2 Hz), 3.15 (quin, 1 H, J = 6.8 Hz) , 3.33 (s, 3H), 3.42-3.53 (m, 5H), 3.82 (t, 1H), 4.14 (d, 2H, J = 6.6 Hz), 4.61 (d, 1 H, J = 10.6 Hz), 4.65 ( d, 1 H, J = 10.6 Hz), 6. 74 (s, 1 H), 7.43 (t, 1 H, J = 7.0 Hz), 7.42 (t, 2 H, J = 7.0 Hz), 7. 48 (d, 2 H, J = 7.0) Hz), 7.52 (s, 1 H); 13 C NMR (101 MHz, CDCl 3 ) δ 15.70, 15.78, 16.5, 18.9, 27.9, 29.6, 32.4, 31.4, 41.3, 46.3, 49.98, 50.03, 51.4, 58.7 , 69.2, 74.7, 75.8, 123.9, 128.2, 128.49, 128.51, 131.3, 132.5, 133.9, 136.6, 140.4, 142.1, 143.9, 146.0, 154.6, 156.0, 170.9.
実施例２
［再沈法によるナノ結晶化］
ブリンゾラミド・脂溶性分子−薬物複合体の濃度が２５ｍｇ／ｍＬ、ポリソルベート８０の濃度が５０ｍｇ／ｍＬとなるように調製したアセトン溶液２００μＬを、激しく撹拌した８００μＬの超純水に一気に加えて０．５％ナノ粒子分散液を調製した。これを透析膜に入れ撹拌した１％ポリソルベート８０水溶液中で透析を２回行い分散液中のアセトンを除去した。アセトン除去後に得られたナノ粒子分散液を濾過した。その概略の一例を図１に示す。
Example 2
[Nano crystallization by reprecipitation method]
200 μL of an acetone solution prepared so that the concentration of brinzolamide / lipophilic molecule-drug complex is 25 mg / mL and the concentration of polysorbate 80 is 50 mg / mL is added in a burst to 800 μL of vigorously stirred ultrapure water to 0.5 % Nanoparticle dispersion was prepared. This was placed in a dialysis membrane and dialyzed twice in a stirred 1% polysorbate 80 aqueous solution to remove acetone in the dispersion. The nanoparticle dispersion obtained after acetone removal was filtered. An example of the outline is shown in FIG.
試験例１
［電子顕微鏡による撮影］
実施例２で記載の濾過後のナノ粒子分散液をフィルターで濾過し、走査型電子顕微鏡用試料台の上に滴下して乾燥させた後Ｐｔスパッタリングして観測用サンプルにした後、走査型電子顕微鏡（JEOL製、JCM-6700F）を用いて、加速電圧２５ｋＶおよび５万倍という観測条件下、粒径を測定したところ３０〜３００ｎｍであった（図２（Ｂ））。一方、従来の市販品ブリンゾラミド点眼剤（製品名「エイゾプト」（登録商標）、販売元 日本アルコン株式会社）（以下、参考例１ともいう）に関しても走査型電子顕微鏡により、３千倍という観測条件下、写真撮影を行った（図２（Ａ））。
Test Example 1
[Shooting with an electron microscope]
The filtered nanoparticle dispersion described in Example 2 is filtered with a filter, dropped onto a scanning electron microscope sample stage, dried, and then Pt sputtering is performed to obtain a sample for observation, and then a scanning electron is obtained. The particle diameter was measured using a microscope (manufactured by JEOL, JCM-6700F) under the observation conditions of an acceleration voltage of 25 kV and 50,000 times that the particle diameter was 30 to 300 nm (FIG. 2 (B)). On the other hand, the observation condition of 3,000 times by a scanning electron microscope also with respect to a conventional commercially available brinzolamide eye drop (product name “Ayopto” (registered trademark), marketer: Nippon Alcon Co., Ltd.) (hereinafter also referred to as reference example 1). Bottom, I took a picture (Figure 2 (A)).
実施例３
［ナノ粒子製剤の調製］
実施例２で得られた濾過後のナノ粒子分散液を用いてブリンゾラミド・脂溶性分子−薬物複合体含有ナノ粒子製剤を調製した。
具体的には、０．５％ナノ粒子分散液９０μＬに、９％食塩水１０μＬを添加し０．４５％ブリンゾラミド・脂溶性分子−薬物複合体含有ナノ粒子製剤を調製した。
Example 3
[Preparation of nanoparticle formulation]
Brinzolamide / lipid-soluble molecule-drug complex-containing nanoparticle formulation was prepared using the filtered nanoparticle dispersion obtained in Example 2.
Specifically, 10 μL of 9% saline solution was added to 90 μL of 0.5% nanoparticle dispersion, to prepare a 0.45% brinzolamide / lipid-soluble molecule-drug complex-containing nanoparticle formulation.
試験例２
［ラットに対する眼圧測定実験］
ラット（１１〜１２週齢、ＳＤ、オス）をイソフルランで麻酔した後、点眼実験開始前に両目の眼圧を接触型眼圧測定機（トノラボ手持ち眼圧計、エムイーテクニカ）を用いて計測した。眼圧は一匹あたり一度の測定で６回計測し、その平均を測定値とした。
試験薬として、実施例３で製造した０．４５％ブリンゾラミド・脂溶性分子−薬物複合体含有ナノ粒子製剤（本発明の製剤）、または市販品ブリンゾラミド点眼剤（製品名「エイゾプト」（登録商標）、販売元 日本アルコン株式会社）１０μｌを右目に点眼し、生理食塩水１０μｌを左目に点眼した。各試験薬を用いた実験において、ラット６匹を用いた。点眼から１時間後に眼球を生理食塩水で洗浄し、両目の眼圧を測定した。その後、眼圧測定前に適宜麻酔を追加し、点眼から２，３，４，５，６時間後に同様に眼圧（ＩＯＰ／ｍｍＨg）を測定した。その結果を図３に示す。データのプロットは６匹の測定値の平均値であり、これに標準誤差を示す誤差バーを付した。この結果から、市販品ブリンゾラミド点眼剤では生理食塩水と比較して１時間程度の有意な眼圧降下が認められた（図３（Ａ））のに対して、ブリンゾラミド・脂溶性分子−薬物複合体含有ナノ粒子製剤では、ブリンゾラミド市販薬の５分の１程度の低い薬物濃度（モル濃度換算：5.7 mＭ）であるにもかかわらず、ブリンゾラミド市販薬と比較して、数時間程度持続的に有意な眼圧降下作用が認められた（図３（Ｂ））。
Test example 2
[Intraocular pressure measurement experiment on rats]
After anesthetizing rats (11 to 12 weeks old, SD, male) with isoflurane, the intraocular pressure of both eyes was measured using a contact-type tonometer (Tonolabo hand-held tonometer, Mie Technica) before the start of the eye drop experiment. The intraocular pressure was measured six times in one measurement per animal, and the average was taken as the measurement value.
As a test drug, the 0.45% brinzolamide-soluble lipid-molecule-drug complex-containing nanoparticle preparation (formulation of the present invention) prepared in Example 3 or a commercially available brinzolamide eye drop (product name "Aizopt" (registered trademark)) 10 μl was dispensed on the right eye, and 10 μl of physiological saline was applied on the left eye. Six rats were used in the experiment using each test drug. One hour after instillation, the eyeballs were washed with saline, and the intraocular pressure of both eyes was measured. Thereafter, anesthesia was appropriately added before measurement of intraocular pressure, and the intraocular pressure (IOP / mmHg) was similarly measured after 2, 3, 4, 5, 6 hours after instillation. The results are shown in FIG. The data plot is an average of six measurements, to which is attached an error bar indicating the standard error. From this result, a significant intraocular pressure drop of about 1 hour was recognized in the commercially available product brinzolamide eye drop as compared with physiological saline (FIG. 3 (A)), while brinzolamide / lipid-soluble molecule-drug complex Despite the low drug concentration (molar equivalent: 5.7 mM) that is about one-fifth that of brinzolamide marketed drugs, body-containing nanoparticle formulations are persistently significant for several hours compared to brinzolamide marketed drugs Good intraocular pressure reduction was observed (Fig. 3 (B)).
Claims (11)
前記薬物と前記脂溶性分子とが、眼内ｐＨにて加水分解しうる酸アミド結合を介して連結しており、
前記脂溶性分子が以下の一般式（I）で表されるものである、製剤：
R 1 、R 2 、R 3 およびR 4 は、互いに独立して、水素、置換されていてもよいC1-18アルキル、置換されていてもよいC1-18アルコキシ、置換されていてもよいC7-18アラルコキシまたは置換されていてもよいフェノキシを表し、
あるいは、R 1 、R 2 、R 3 およびR 4 のいずれかの隣り合う基が一緒になって、置換されてもよい環を形成し、
Y は、置換されていてもよいC1-18アルキル、置換されていてもよいC1-18アルコキシ、置換されていてもよいC7-18アラルコキシおよび置換されていてもよいフェノキシからなる群から選択される基を表す）。 A nanoparticle preparation for treating an eye disease, comprising a drug complex comprising a drug and a lipid-soluble molecule,
It said lipophilic molecule and said drug has linked via acid amide bond that can be hydrolyzed in intraocular pH,
The preparation , wherein the fat-soluble molecule is represented by the following general formula (I) :
R 1 , R 2 , R 3 and R 4 are, independently of one another, hydrogen, optionally substituted C 1-18 alkyl, optionally substituted C 1-18 alkoxy, optionally substituted C 7- 18 represents aralkoxy or phenoxy which may be substituted,
Alternatively, any adjacent groups of R 1 , R 2 , R 3 and R 4 are taken together to form a ring which may be substituted,
Y is selected from the group consisting of optionally substituted C1-18 alkyl, optionally substituted C1-18 alkoxy, optionally substituted C7-18 aralkoxy and optionally substituted phenoxy Represents a group).
Ａ は水素またはＸであり、
Ｂ は水素またはＸであり、
ＡおよびＢ が同時に水素でなく、
Ｘが、以下の一般式(I)で表される基である：
R1、R2、R3およびR4は、互いに独立して、水素、置換されていてもよいC1-18アルキル、置換されていてもよいC1-18アルコキシ、置換されていてもよいC7-18アラルコキシまたは置換されていてもよいフェノキシを表し、
あるいは、R1、R2、R3およびR4のいずれかの隣り合う基が一緒になって、置換されてもよい環を形成し、
Y は置換されていてもよいC1-18アルキル、置換されていてもよいC1-18アルコキシ、置換されていてもよいC7-18アラルコキシおよび置換されていてもよいフェノキシからなる群から選択される基である））。 The preparation according to any one of claims 1 to 3, wherein the complex is a complex according to the general formula (II):
A is hydrogen or X,
B is hydrogen or X,
A and B are not simultaneously hydrogen,
X is a group represented by the following general formula (I):
R 1 , R 2 , R 3 and R 4 are, independently of one another, hydrogen, optionally substituted C 1-18 alkyl, optionally substituted C 1-18 alkoxy, optionally substituted C 7- 18 represents aralkoxy or phenoxy which may be substituted,
Alternatively, any adjacent groups of R 1 , R 2 , R 3 and R 4 are taken together to form a ring which may be substituted,
Y is a group selected from the group consisting of optionally substituted C1-18 alkyl, optionally substituted C1-18 alkoxy, optionally substituted C7-18 aralkoxy and optionally substituted phenoxy Is)).
Ａ は水素またはＸであり、
Ｂ は水素またはＸであり、
ＡおよびＢ が同時に水素でなく、
Ｘは以下の一般式(I)で表される基である：
R1、R2、R3およびR4は、互いに独立して、水素、置換されていてもよいC1-18アルキル、置換されていてもよいC1-18アルコキシ、置換されていてもよいC7-18アラルコキシまたは置換されていてもよいフェノキシを表し、
あるいは、R1、R2、R3およびR4のいずれかの隣り合う基が一緒になって、置換されてもよい環を形成し、
Yは、置換されていてもよいC1-18アルキル、置換されていてもよいC1-18アルコキシ、置換されていてもよいC7-18アラルコキシおよび置換されていてもよいフェノキシからなる群から選択される基である））。 The complex represented by the general formula (II):
A is hydrogen or X,
B is hydrogen or X,
A and B are not simultaneously hydrogen,
X is a group represented by the following general formula (I):
R 1 , R 2 , R 3 and R 4 are, independently of one another, hydrogen, optionally substituted C 1-18 alkyl, optionally substituted C 1-18 alkoxy, optionally substituted C 7- 18 represents aralkoxy or phenoxy which may be substituted,
Alternatively, any adjacent groups of R 1 , R 2 , R 3 and R 4 are taken together to form a ring which may be substituted,
Y is selected from the group consisting of C1-18 alkyl which may be substituted, C1-18 alkoxy which may be substituted, C7-18 aralkoxy which may be substituted and phenoxy which may be substituted Groups)).
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