JP5616617B2 - Eye drops for silicone hydrogel contact lenses - Google Patents
Eye drops for silicone hydrogel contact lenses Download PDFInfo
- Publication number
- JP5616617B2 JP5616617B2 JP2009274828A JP2009274828A JP5616617B2 JP 5616617 B2 JP5616617 B2 JP 5616617B2 JP 2009274828 A JP2009274828 A JP 2009274828A JP 2009274828 A JP2009274828 A JP 2009274828A JP 5616617 B2 JP5616617 B2 JP 5616617B2
- Authority
- JP
- Japan
- Prior art keywords
- shcl
- pranoprofen
- silicone hydrogel
- salt
- contact lens
- 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.)
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- 239000003889 eye drop Substances 0.000 title claims description 104
- 239000000017 hydrogel Substances 0.000 title claims description 54
- 229920001296 polysiloxane Polymers 0.000 title claims description 52
- 229940012356 eye drops Drugs 0.000 title description 45
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- 229960003101 pranoprofen Drugs 0.000 claims description 110
- 150000003839 salts Chemical class 0.000 claims description 86
- 230000035699 permeability Effects 0.000 claims description 70
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- 108090000623 proteins and genes Proteins 0.000 claims description 66
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Description
本発明は、シリコーンハイドロゲルコンタクトレンズへのプラノプロフェン及び/又はその塩の透過性を向上させることができる、シリコーンハイドロゲルコンタクトレンズ用点眼剤に関する。また、本発明は、シリコーンハイドロゲルコンタクトレンズへのプラノプロフェン及び/又はその塩の透過性を向上させる方法、並びに、シリコーンハイドロゲルコンタクトレンズへのプラノプロフェン及び/又はその塩の透過性を向上させる作用を点眼剤に付与する方法に関する。また、本発明は、シリコーンハイドロゲルコンタクトレンズへのプラノプロフェン及び/又はその塩の透過性を向上させるための剤に関する。更に、本発明は、シリコーンハイドロゲルコンタクトレンズに対するプラノプロフェン及び/又はその塩の透過性を向上させる透過性向上物質をスクリーニングする方法に関する。更に本発明は、イオン性シリコーンハイドロゲルコンタクトレンズへの花粉タンパク質の蓄積を抑制する方法等に関する。 The present invention relates to an eye drop for a silicone hydrogel contact lens that can improve the permeability of pranoprofen and / or a salt thereof to the silicone hydrogel contact lens. The present invention also provides a method for improving the permeability of pranoprofen and / or its salt to a silicone hydrogel contact lens, and the permeability of pranoprofen and / or its salt to a silicone hydrogel contact lens. The present invention relates to a method for imparting an improving action to eye drops. Moreover, this invention relates to the agent for improving the permeability | transmittance of the planoprofen and / or its salt to a silicone hydrogel contact lens. Furthermore, the present invention relates to a method for screening a substance for improving permeability that improves the permeability of pranoprofen and / or a salt thereof to a silicone hydrogel contact lens. Furthermore, the present invention relates to a method for suppressing the accumulation of pollen protein in an ionic silicone hydrogel contact lens.
近年、コンタクトレンズ(CL)の装用者が増えており、中でもソフトコンタクトレンズ(SCL)の装用者が増えている。一般的に、SCLを装用した場合には、大気からの酸素供給量が低下し、その結果として角膜上皮細胞の分裂抑制や角膜肥厚につながる場合があることが指摘されている。そのため、より高い酸素透過性を有するSCLの開発が進められてきた。 In recent years, the number of wearers of contact lenses (CL) has increased, and in particular, the number of wearers of soft contact lenses (SCL) has increased. In general, it has been pointed out that when SCL is worn, the amount of oxygen supplied from the atmosphere decreases, which may result in suppression of corneal epithelial cell division and corneal thickening. Therefore, development of SCL having higher oxygen permeability has been advanced.
シリコーンハイドロゲルコンタクトレンズは、そのような背景の下、高酸素透過性を有するSCLとして近年開発されてきたものである。シリコーンハイドロゲルコンタクトレンズは、ハイドロゲルにシリコーンを配合することにより、従来のハイドロゲルコンタクトレンズの数倍の酸素透過性を実現する。従って、SCLの弱点である酸素供給不足を改善することができ、酸素不足に伴う角膜に対する悪影響を大幅に抑制できるものとして、大きく期待されている。 Under such circumstances, silicone hydrogel contact lenses have been developed in recent years as SCL having high oxygen permeability. Silicone hydrogel contact lenses achieve oxygen permeability several times that of conventional hydrogel contact lenses by blending silicone with hydrogel. Therefore, it is highly expected that the oxygen supply deficiency, which is a weak point of SCL, can be improved and the adverse effects on the cornea due to the oxygen deficiency can be greatly suppressed.
また、SCLは一般にハードコンタクトレンズに比べて大きく、その装用中には角膜表面がほぼ全面的に覆われた状態となる。そして、SCL装用中には、SCLと角膜表面の間から涙液の流入及び流出(即ち、ポンプ作用による涙液交換)は殆ど行われず、SCL下の涙液交換はSCLを介した涙液の透過に依存していることが分かっている(非特許文献1−2参照)。このようにSCL下の涙液交換の殆どは、SCLを介した涙液の透過により行われるため、SCL装用者の眼に対して適用される点眼剤は、配合される薬理成分のSCLへの透過性を十分に高めておくことが求められる。 In addition, SCL is generally larger than a hard contact lens, and the cornea surface is almost entirely covered during wearing. And during SCL wearing, there is almost no inflow and outflow of tears between the SCL and the corneal surface (that is, tear exchange by pump action), and tear exchange under SCL is the tear fluid via SCL. It is known that it depends on transmission (see Non-Patent Document 1-2). As described above, most of the tear fluid exchange under SCL is performed by permeation of tear fluid through SCL, so the eye drops applied to the eyes of the SCL wearer are the pharmacological components to be mixed into SCL. It is required to sufficiently increase the permeability.
そのため、SCL装用者の眼に対して適用される点眼剤については、SCLの種類に応じて、安全性等の影響のみならず、薬理活性成分のSCLへの透過性をも十分に考慮して設計することが不可欠である。特に、SCLは素材によってイオン性の有無や含水率等が種々異なるため、SCL装用者の眼に適用される点眼剤は、適用されるSCLの性質に応じて製剤設計を行うことが肝要である。 Therefore, for eye drops applied to the eyes of SCL wearers, depending on the type of SCL, not only the impact on safety, but also the permeability of pharmacologically active ingredients to SCL is fully considered. It is essential to design. In particular, since the presence or absence of ionicity and the water content of SCL vary depending on the material, it is important that eye drops applied to the eyes of SCL wearers should be formulated according to the nature of the applied SCL. .
ところで、花粉症は、花粉に含まれる花粉タンパク質が抗原となって粘膜等と接触することにより引き起こされるアレルギー症状である。近年、花粉症の患者が増加しており、大きな社会問題になりつつある。眼科分野でも、花粉症の予防や悪化抑制に有用な点眼剤の開発が強く求められている。 By the way, hay fever is an allergic symptom caused by pollen protein contained in pollen becoming an antigen and contacting mucous membranes and the like. In recent years, the number of patients with hay fever is increasing, which is becoming a major social problem. In the field of ophthalmology, there is a strong demand for the development of eye drops useful for the prevention of hay fever and suppression of deterioration.
一方、プラノプロフェン及び/又はその塩は、炎症性眼疾患を治療することを目的として点眼剤に使用されており(特許文献1−3参照)、特にSCLを使用することに伴って引き起こされる角膜炎に対しても有効であることも分かっている。このようなプラノプロフェン及び/又はその塩の作用は、角膜を含む外眼部や角膜の奥に存在する前眼部に働きかけることにより発揮されることが知られている。しかしながら、これまでに、シリコーンハイドロゲルコンタクトレンズを装用中の眼に対して、プラノプロフェン及び/又はその塩を適用した場合の影響については明らかにはされていない。ましてや、プラノプロフェン及び/又はその塩と界面活性剤とを併用してシリコーンハイドロゲルコンタクトレンズに適用した場合の影響については、推認すらできないのが現状である。 On the other hand, pranoprofen and / or a salt thereof is used in eye drops for the purpose of treating inflammatory eye diseases (see Patent Documents 1-3), and particularly caused by using SCL. It has also been shown to be effective against keratitis. It is known that such action of pranoprofen and / or a salt thereof is exerted by acting on the outer eye part including the cornea or the anterior eye part existing in the back of the cornea. However, until now, the effect of applying pranoprofen and / or a salt thereof to an eye wearing a silicone hydrogel contact lens has not been clarified. Moreover, the present situation is that it is not even possible to infer the effect of applying pranoprofen and / or a salt thereof and a surfactant in combination to a silicone hydrogel contact lens.
本発明者等は、各種SCLに対してプラノプロフェン及び/又はその塩を適用した場合の影響について種々の検討を行っていたところ、全く予想していなかったことに、シリコーンハイドロゲルコンタクトレンズ(以下、SHCLと略記することもある)では、他のSCLと比較してプラノプロフェン及び/又はその塩のレンズ透過量が著しく少ないという全く新しい知見を得た。プラノプロフェン及び/又はその塩は、その作用発揮のためには角膜を含む外眼部や角膜の奥の前眼部への働きかけが重要となるが、このようにレンズ透過量が極めて少ないと、SHCL装用中の眼に対してプラノプロフェン及び/又はその塩を含有する点眼剤を適用しても十分な量が角膜に供給されず、満足な効果が得られない恐れがある。 The present inventors have conducted various studies on the effects of applying pranoprofen and / or a salt thereof to various SCLs, and have not anticipated at all that silicone hydrogel contact lenses ( Hereinafter, it may be abbreviated as SHCL), and a completely new finding was obtained that the lens permeation amount of pranoprofen and / or its salt was remarkably small compared with other SCLs. In order for pranoprofen and / or its salt to exert its action, it is important to act on the outer eye part including the cornea and the anterior eye part in the back of the cornea. Even if an ophthalmic solution containing pranoprofen and / or a salt thereof is applied to the eye wearing SHCL, a sufficient amount may not be supplied to the cornea and a satisfactory effect may not be obtained.
そこで、SHCL装用中に点眼された場合に、SHCLへのプラノプロフェン及び/又はその塩の透過性が向上しており、プラノプロフェン及び/又はその塩の角膜到達量を増加できるSHCL用点眼剤の開発が求められている。 Therefore, when instilled while wearing SHCL, the permeability of pranoprofen and / or its salt to SHCL has been improved, and the inhalation of SHCL can increase the amount of pranoprofen and / or its salt reaching the cornea Development of agents is required.
本発明者らは、前記課題を解決するために鋭意検討した結果、プラノプロフェン及び/又はその塩に加えて界面活性剤を組み合わせて用いると、プラノプロフェン及び/又はその塩のSHCLに対する透過量を著しく増加できることを見出した。更に本発明者等は検討を進め、プラノプロフェン及び/又はその塩に界面活性剤を組み合わせて用いることにより、イオン性SHCLへの花粉タンパク質の蓄積をも顕著に抑制できることを見出した。更に、本発明者らは、このイオン性SHCLに対する花粉タンパク質蓄積抑制効果は、プラノプロフェン及び/又はその塩と界面活性剤と共に、ビタミンB6類を更に組み合わせて用いることにより一層向上させることができることをも見出した。本発明は、かかる知見に基づいて、更に改良を重ねることにより完成したものである。 As a result of intensive studies to solve the above problems, the present inventors have found that when a surfactant is used in combination with pranoprofen and / or a salt thereof, peranoprofen and / or a salt thereof permeates SHCL. We have found that the amount can be significantly increased. Furthermore, the present inventors have further studied and found that accumulation of pollen protein in ionic SHCL can be remarkably suppressed by using a combination of a surfactant and pranoprofen and / or a salt thereof. Furthermore, the present inventors can further improve the pollen protein accumulation inhibitory effect on ionic SHCL by further using vitamin B6 in combination with pranoprofen and / or a salt thereof and a surfactant. I also found. The present invention has been completed by making further improvements based on such findings.
即ち、本発明は下記に掲げるSHCL用点眼剤を提供する。
項1. (A)プラノプロフェン及びその塩からなる群より選択される少なくとも1種と、(B)界面活性剤とを含有する、シリコーンハイドロゲルコンタクトレンズ用点眼剤。
項2. (B)成分として、非イオン性界面活性剤、陽イオン性界面活性剤及び両性界面活性剤からなる群より選択される少なくとも1種を含む、項1に記載のシリコーンハイドロゲルコンタクトレンズ用点眼剤。
項3. 更に(C)ビタミンB6類を含有する、項1又は2に記載のシリコーンハイドロゲルコンタクトレンズ用点眼剤。
項4. 更に(D)緩衝剤を含有する、項1乃至3のいずれかに記載のシリコーンハイドロゲルコンタクトレンズ用点眼剤。
項5. (A)成分の配合割合が0.005〜0.5w/v%である、項1乃至4のいずれかに記載のシリコーンハイドロゲルコンタクトレンズ用点眼剤。
項6. (B)成分の配合割合が0.001〜1.0w/v%である、項1乃至5のいずれかに記載のシリコーンハイドロゲルコンタクトレンズ用点眼剤。
項7. シリコーンハイドロゲルコンタクトレンズが非イオン性である、項1乃至6のいずれかに記載のシリコーンハイドロゲルコンタクトレンズ用点眼剤。
項8. シリコーンハイドロゲルコンタクトレンズがイオン性である、項1乃至6のいずれかに記載のシリコーンハイドロゲルコンタクトレンズ用点眼剤。
That is, the present invention provides the following eye drops for SHCL.
Item 1. An eye drop for a silicone hydrogel contact lens, comprising (A) at least one selected from the group consisting of pranoprofen and a salt thereof, and (B) a surfactant.
Item 2. Item 2. The eye drop for a silicone hydrogel contact lens according to Item 1, comprising at least one selected from the group consisting of a nonionic surfactant, a cationic surfactant and an amphoteric surfactant as component (B). .
Item 3. Item 3. The eye drop for a silicone hydrogel contact lens according to Item 1 or 2, further comprising (C) vitamin B6.
Item 4. Item 4. The eye drop for a silicone hydrogel contact lens according to any one of Items 1 to 3, further comprising (D) a buffer.
Item 5. Item 5. The eye drop for a silicone hydrogel contact lens according to any one of Items 1 to 4, wherein the blending ratio of the component (A) is 0.005 to 0.5 w / v%.
Item 6. Item 6. The eye drop for a silicone hydrogel contact lens according to any one of Items 1 to 5, wherein the blending ratio of the component (B) is 0.001 to 1.0 w / v%.
Item 8.
また、本発明は、下記に掲げるSHCLへのプラノプロフェン及び/又はその塩の透過性向上方法、並びにSHCLへのプラノプロフェン及び/又はその塩の透過性を向上させる作用を点眼剤に付与する方法を提供する。
項9.(A)プラノプロフェン及びその塩からなる群より選択される少なくとも1種と(B)界面活性剤とを併用することを特徴とする、シリコーンハイドロゲルコンタクトレンズへの該(A)成分の透過性を向上させる方法。
項10.(A)プラノプロフェン及びその塩からなる群より選択される少なくとも1種を含有するシリコーンハイドロゲルコンタクトレンズ用点眼剤に、(B)界面活性剤を配合することを特徴とする、シリコーンハイドロゲルコンタクトレンズへの該(A)成分の透過性を向上させる作用を該点眼剤に付与する方法。
In addition, the present invention provides eye drops with the following methods for improving the permeability of pranoprofen and / or its salt to SHCL, and improving the permeability of pranoprofen and / or its salt to SHCL. Provide a way to do it.
Item 9. (A) Permeation of the component (A) into a silicone hydrogel contact lens, comprising using at least one selected from the group consisting of pranoprofen and a salt thereof and (B) a surfactant. To improve performance.
また、本発明は、下記に掲げるSHCLへのプラノプロフェン及び/又はその塩の透過性向上剤を提供する。
項11. (B)界面活性剤を含有する、シリコーンハイドロゲルコンタクトレンズへの(A)プラノプロフェン及びその塩からなる群より選択される少なくとも1種の透過性を向上させるための剤。
Moreover, this invention provides the permeability | transmittance improvement agent of the planoprofen and / or its salt with respect to SHCL hung up below.
Item 11. (B) An agent for improving permeability of at least one selected from the group consisting of (A) pranoprofen and a salt thereof into a silicone hydrogel contact lens, containing a surfactant.
更に、本発明は、下記に掲げる透過性向上物質のスクリーニング方法を提供する。
項12. シリコーンハイドロゲルコンタクトレンズに対するプラノプロフェン及びその塩からなる群より選択される少なくとも1種のプラノプロフェン類の透過性を向上させる透過性向上物質のスクリーニング方法であって、
(a)プラノプロフェン類を含むコントロール溶液、並びにプラノプロフェン類と被験物質とを含む被験溶液を、試験溶液として各々調製する工程、
(b)上記試験溶液を各々、シリコーンハイドロゲルコンタクトレンズの片側面のみに所定時間接触させ、該レンズの上記試験溶液を接触させていない他方の片側面から滲出したプラノプロフェン類の量を測定することにより、各試験溶液のプラノプロフェン類の透過量を求める工程、並びに
(c)上記工程(b)において測定されたプラノプロフェン類の透過量が、コントロール溶液よりも多い被験溶液を選び、該被験溶液に含まれる被験物質を上記透過性向上物質として選択する工程、
を含むスクリーニング方法。
Furthermore, this invention provides the screening method of the permeability | transmittance improvement substance hung up below.
Item 12. A method for screening a permeability-improving substance for improving the permeability of at least one kind of pranoprofen selected from the group consisting of pranoprofen and a salt thereof for a silicone hydrogel contact lens,
(a) preparing a control solution containing pranoprofen and a test solution containing pranoprofen and a test substance as a test solution,
(b) Each of the test solutions is brought into contact with only one side of the silicone hydrogel contact lens for a predetermined time, and the amount of pranoprofen exuded from the other side of the lens not contacting the test solution is measured. Determining the amount of peranoprofen permeation in each test solution, and
(c) a step of selecting a test solution in which the amount of peroprofen permeation measured in the step (b) is larger than that of a control solution, and selecting a test substance contained in the test solution as the permeability improving substance,
A screening method comprising:
また、本発明は、下記に掲げるイオン性SHCLへの花粉タンパク質の蓄積を抑制する方法、並びにイオン性SHCLへの花粉タンパク質の蓄積を抑制する作用を点眼剤に付与する方法を提供する。
項13.(A)プラノプロフェン及びその塩からなる群より選択される少なくとも1種と(B)界面活性剤とを含有するシリコーンハイドロゲルコンタクトレンズ用点眼剤を、イオン性シリコーンハイドロゲルコンタクトレンズと接触させることを特徴とする、イオン性シリコーンハイドロゲルコンタクトレンズへの花粉タンパク質の蓄積を抑制する方法。
項14.シリコーンハイドロゲルコンタクトレンズ用点眼剤に、(A) プラノプロフェン及びその塩からなる群より選択される少なくとも1種と(B)界面活性剤とを配合することを特徴とする、イオン性シリコーンハイドロゲルコンタクトレンズへの花粉タンパク質の蓄積を抑制する作用を該点眼剤に付与する方法。
In addition, the present invention provides a method for suppressing the accumulation of pollen protein in ionic SHCL and a method for imparting to the eye drops the action of suppressing the accumulation of pollen protein in ionic SHCL.
Item 14. An ionic silicone hydro, characterized in that the eye drop for a silicone hydrogel contact lens contains (A) at least one selected from the group consisting of pranoprofen and a salt thereof and (B) a surfactant. A method of imparting to the eye drop an action of suppressing the accumulation of pollen protein in a gel contact lens.
本発明のSHCL用点眼剤によれば、SHCLへのプラノプロフェン及び/又はその塩の透過性を顕著に向上させることができるので、SHCL装用中に点眼しても、プラノプロフェン及び/又はその塩の角膜への到達量を増加させ、ひいては角膜における炎症性眼疾患を有効に治療乃至予防することが可能になる。 According to the eye drop for SHCL of the present invention, the permeability of pranoprofen and / or a salt thereof to SHCL can be remarkably improved. Therefore, even when instilled during SHCL wearing, pranoprofen and / or The amount of the salt reaching the cornea can be increased, and as a result, inflammatory eye diseases in the cornea can be effectively treated or prevented.
更に、本発明のスクリーニング方法は、SHCLへのプラノプロフェン及び/又はその塩の透過性を向上させ得る透過性向上物質の取得を可能にするので、SHCLへのプラノプロフェン及び/又はその塩の透過性が向上し、それによりSHCL装用中に使用しても角膜における炎症性眼疾患を有効に治療乃至予防できるSHCL用の点眼剤の開発に有用である。 Furthermore, since the screening method of the present invention makes it possible to obtain a substance that improves the permeability of pranoprofen and / or its salt to SHCL, pranoprofen and / or its salt to SHCL. Therefore, it is useful for the development of eye drops for SHCL that can effectively treat or prevent inflammatory eye diseases in the cornea even when used while wearing SHCL.
また、イオン性SHCLには花粉タンパク質が著しく吸着し易いという特有の課題があることも本発明者等の研究により明らかとなっている。一般に、タンパク質は、SHCLに対しては吸着し難いと考えられており、かかる知見は全く意外なものである。そして一般的に、コンタクトレンズ装用時には、眼が乾き易くなり、その結果、涙液による洗浄作用が低下して、花粉等の異物が眼に滞留し易くなるため、花粉症の発症リスクが高くなると考えられている。そのうえ、コンタクトレンズに花粉タンパク質が多量に吸着し蓄積していくとすれば、花粉症の発症リスクを著しく高めることになり、アレルギー症状を誘発する一因にもなりかねない。更に、コンタクトレンズに吸着した花粉タンパク質の除去が不十分になれば、コンタクトレンズの装用感が損なわれて不快感を誘発し、使用期間が短縮化されることにもなる。然るに、本発明のSHCL用点眼剤によれば、イオン性SHCLの装用中に花粉タンパク質とイオン性SHCLが接触しても、イオン性SHCLからの花粉タンパク質の除去を促進し、再付着も防止することで、イオン性SHCLへの花粉タンパク質の蓄積を抑制できる。従って、本発明のSHCL用点眼剤によれば、花粉症又は花粉症予備軍の使用者にとってアレルギー症状の発症リスクを低減させることができ、またイオン性SHCLを清潔に保持することもできる。 In addition, studies by the present inventors have revealed that ionic SHCL has a unique problem that pollen proteins are remarkably easily adsorbed. In general, proteins are thought to be difficult to adsorb to SHCL, and this finding is completely unexpected. And generally, when wearing contact lenses, the eyes are likely to dry, and as a result, the cleaning action by tears is reduced, and foreign substances such as pollen are likely to stay in the eyes, which increases the risk of developing hay fever. It is considered. Moreover, if a large amount of pollen protein is adsorbed and accumulated on the contact lens, it will significantly increase the risk of developing hay fever and may contribute to allergic symptoms. Furthermore, if the pollen protein adsorbed on the contact lens is insufficiently removed, the wearing feeling of the contact lens is impaired, causing discomfort and shortening the use period. However, according to the ophthalmic solution for SHCL of the present invention, even when pollen protein and ionic SHCL come into contact with each other during wearing of ionic SHCL, it promotes removal of pollen protein from ionic SHCL and prevents reattachment. In this way, accumulation of pollen protein in ionic SHCL can be suppressed. Therefore, according to the eye drop for SHCL of the present invention, the risk of developing allergic symptoms can be reduced for users of hay fever or the pollinosis reserve army, and ionic SHCL can be kept clean.
(I) SHCL用点眼剤
本発明のSHCL用点眼剤は、プラノプロフェン及びその塩からなる群より選択される少なくとも1種(以下、(A)成分と表記することもある)を含有する。プラノプロフェンは、α−メチル−5H−[1]ベンゾピラノ[2,3-b]ピリジン−7−酢酸とも称される公知化合物であり、公知の方法により合成してもよく市販品として入手することもできる。
(I) SHCL eye drops The SHCL eye drops of the present invention contain at least one selected from the group consisting of pranoprofen and a salt thereof (hereinafter sometimes referred to as component (A)). Planoprofen is a known compound also called α-methyl-5H- [1] benzopyrano [2,3-b] pyridine-7-acetic acid, which may be synthesized by a known method and obtained as a commercial product. You can also.
本発明で使用される上記(A)成分の内、プラノプロフェンの塩としては、医薬上、薬理学的に(製薬上)又は生理学的に許容されるものであれば、特に制限されないが、具体的には、無機塩基との塩[例えば、ナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩、アルミニウム塩等]や、有機塩基との塩[例えば、メチルアミン、トリエチルアミン、ジエチルアミン、トリエタノールアミン、モルホリン、ピペラジン、ピロリジン、トリピリジン、ピコリン等との塩]等が挙げられる。これらのプラノプロフェンの塩は、1種単独で使用してもよく、また2種以上を任意に組み合わせて使用してもよい。 Among the components (A) used in the present invention, the salt of pranoprofen is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specifically, a salt with an inorganic base [eg, sodium salt, potassium salt, calcium salt, magnesium salt, aluminum salt, etc.] or a salt with an organic base [eg, methylamine, triethylamine, diethylamine, triethanolamine, Salt with morpholine, piperazine, pyrrolidine, tripyridine, picoline, etc.]. These pranoprofen salts may be used alone or in any combination of two or more.
本発明のSHCL用点眼剤には、(A)成分として、プラノプロフェン及びその塩の中から、1種のものを選択して単独で使用してもよく、2種以上のものを任意に組み合わせて使用してもよい。界面活性剤によるSHCL透過性向上効果をより一層有効に奏させるという観点から、本発明に使用される(A)成分として、好ましくはプラノプロフェンが挙げられる。ここで例示する(A)成分は、イオン性SHCLに対する花粉タンパク質蓄積抑制効果を一層有効に奏させるという観点からも好適である。 In the eye drop for SHCL of the present invention, as the component (A), one type of pranoprofen and a salt thereof may be selected and used alone, or two or more types may be arbitrarily selected. You may use it in combination. From the viewpoint of more effectively exerting the effect of improving the SHCL permeability by the surfactant, the component (A) used in the present invention is preferably pranoprofen. The component (A) exemplified here is also suitable from the viewpoint of more effectively producing the pollen protein accumulation suppressing effect on ionic SHCL.
本発明のSHCL用点眼剤において、上記(A)成分の配合割合は、該(A)成分の種類、他の配合成分の種類等に応じて適宜設定されるが、一例として、該点眼剤の総量に対して、該(A)成分が総量で0.005〜0.5w/v%、好ましくは0.01〜0.2w/v%、更に好ましくは0.05〜0.1w/v%が例示される。 In the eye drop for SHCL of the present invention, the blending ratio of the component (A) is appropriately set according to the type of the component (A), the type of the other blended components, etc. The total amount of the component (A) is 0.005 to 0.5 w / v%, preferably 0.01 to 0.2 w / v%, more preferably 0.05 to 0.1 w / v%. Is exemplified.
更に、本発明のSHCL用点眼剤は、上記(A)成分に加えて、界面活性剤(以下、(B)成分と表記することもある)を含有する。このように界面活性剤を配合することによって、SHCLへのプラノプロフェン及び/又はその塩の透過性を向上させることが可能になり、またイオン性SHCLへの花粉タンパク質の蓄積を格段顕著に抑制することが可能になる。 Furthermore, the eye drop for SHCL of the present invention contains a surfactant (hereinafter also referred to as component (B)) in addition to the component (A). By adding a surfactant in this way, it becomes possible to improve the permeability of pranoprofen and / or its salt to SHCL, and significantly suppress the accumulation of pollen proteins in ionic SHCL. It becomes possible to do.
上記(B)成分として使用される界面活性剤としては、医薬上、薬理学的に(製薬上)又は生理学的に許容されることを限度として特に制限されず、非イオン性界面活性剤、両性界面活性剤、陰イオン性界面活性剤、陽イオン性界面活性剤等が例示される。 The surfactant used as the component (B) is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, and is a nonionic surfactant or amphoteric. Examples include surfactants, anionic surfactants, and cationic surfactants.
上記(B)成分として配合可能な非イオン性界面活性剤としては、具体的には、モノラウリン酸POE(20)ソルビタン(ポリソルベート20)、モノパルミチン酸POE(20)ソルビタン(ポリソルベート40)、モノステアリン酸POE(20)ソルビタン(ポリソルベート60)、トリステアリン酸POE(20)ソルビタン(ポリソルベート65)、モノオレイン酸POE(20)ソルビタン(ポリソルベート80)、等のPOEソルビタン脂肪酸エステル類;ポロクサマー407、ポロクサマー235、ポロクサマー188、ポロクサマー403、ポロクサマー237、ポロクサマー124等のPOE・POPブロックコポリマー類; POE(60)硬化ヒマシ油(ポリオキシエチレン硬化ヒマシ油60)等のPOE硬化ヒマシ油類;POE(9)ラウリルエーテル等のPOEアルキルエーテル類;POE(20)POP(4)セチルエーテル等のPOE-POPアルキルエーテル類;POE(10)ノニルフェニルエーテル等のPOEアルキルフェニルエーテル類等が挙げられる。なお、上記で例示する化合物において、POEはポリオキシエチレン、POPはポリオキシプロピレン、及び括弧内の数字は付加モル数を示す。 Specific examples of the nonionic surfactant that can be blended as the component (B) include monolauric acid POE (20) sorbitan (polysorbate 20), monopalmitic acid POE (20) sorbitan (polysorbate 40), and monostearin. POE sorbitan fatty acid esters such as acid POE (20) sorbitan (polysorbate 60), tristearic acid POE (20) sorbitan (polysorbate 65), monooleic acid POE (20) sorbitan (polysorbate 80); poloxamer 407, poloxamer 235 POE / POP block copolymers such as Poloxamer 188, Poloxamer 403, Poloxamer 237 and Poloxamer 124; POE hydrogenated castor oil such as POE (60) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 60); POE (9) lauryl POE alkyl ethers such as ether; POE (20) POP (4) POE-POP alkyl ethers such as cetyl ether; POE (10) POE alkylphenyl ethers such as alkenyl phenyl ether. In the compounds exemplified above, POE is polyoxyethylene, POP is polyoxypropylene, and the numbers in parentheses indicate the number of moles added.
また、上記(B)成分として配合可能な両性界面活性剤(即ち、分子内に陽イオン性部位と陰イオン性部位の両方の性質を有する界面活性剤)としては、具体的には、アルキルジアミノエチルグリシン及びその塩(塩酸アルキルジアミノエチルグリシン)等が例示される。 Further, as the amphoteric surfactant that can be blended as the component (B) (that is, a surfactant having both a cationic site and an anionic site in the molecule), specifically, an alkyldiamino Examples thereof include ethyl glycine and its salt (alkyldiaminoethyl glycine hydrochloride).
また、上記(B)成分として配合可能な陽イオン性界面活性剤としては、具体的には、塩化ベンザルコニウム、塩化ベンゼトニウム等の第4級アンモニウム塩型の陽イオン性界面活性剤;クロルヘキシジン塩(グルコン酸クロルヘキシジン、塩酸クロルヘキシジンなど)、ポリヘキサメチレンビグアニド塩(塩酸ポリヘキサメチレンビグアニドなど)等のアミン塩型の陽イオン性界面活性剤等が例示される。 Specific examples of the cationic surfactant that can be blended as the component (B) include quaternary ammonium salt type cationic surfactants such as benzalkonium chloride and benzethonium chloride; chlorhexidine salts Examples include amine salt-type cationic surfactants such as chlorhexidine gluconate and chlorhexidine hydrochloride, and polyhexamethylene biguanide salts (such as polyhexamethylene biguanide hydrochloride).
また、上記(B)成分として配合可能な陰イオン性界面活性剤としては、具体的には、アルキルベンゼンスルホン酸塩、アルキル硫酸塩、ポリオキシエチレンアルキル硫酸塩、脂肪族α−スルホメチルエステル、αオレフィンスルホン酸等が例示される。 Specific examples of the anionic surfactant that can be blended as the component (B) include alkylbenzene sulfonates, alkyl sulfates, polyoxyethylene alkyl sulfates, aliphatic α-sulfomethyl esters, α Examples include olefin sulfonic acid.
本発明のSHCL用点眼剤において、上記界面活性剤は、1種単独で使用してもよく、また2種以上を組み合わせて使用してもよい。 In the eye drop for SHCL of the present invention, the above surfactants may be used alone or in combination of two or more.
上記(B)成分の中でも、SHCLへのプラノプロフェン及び/又はその塩の透過性を向上させる作用が格段高められるという観点から、好ましくは非イオン性界面活性剤、陽イオン性界面活性剤、両性界面活性剤;より好ましくは非イオン性界面活性剤、陽イオン性界面活性剤;更に好ましくは、POEソルビタン脂肪酸エステル類、POE硬化ヒマシ油類、POE・POPブロックコポリマー類、第4級アンモニウム塩型陽イオン性界面活性剤;更に好ましくはPOEソルビタン脂肪酸エステル類、第4級アンモニウム塩型陽イオン性界面活性剤;特に好ましくはポリソルベート80、塩化ベンザルコニウムが挙げられる。ここで例示する(B)成分は、イオン性SHCLに対する花粉タンパク質蓄積抑制効果を格段顕著に高めるという観点からも好適である。
Among the above components (B), from the viewpoint that the effect of improving the permeability of pranoprofen and / or its salt to SHCL is significantly increased, preferably a nonionic surfactant, a cationic surfactant, Amphoteric surfactants; more preferably nonionic surfactants, cationic surfactants; still more preferably POE sorbitan fatty acid esters, POE hydrogenated castor oils, POE / POP block copolymers, quaternary ammonium salts Type cationic surfactants; more preferably POE sorbitan fatty acid esters, quaternary ammonium salt type cationic surfactants; particularly preferably
本発明のSHCL用点眼剤において、上記(B)成分の配合割合は、該(B)成分の種類、他の配合成分の種類等に応じて適宜設定されるが、一例として、該点眼剤の総量に対して、該(B)成分が総量で0.001〜1w/v%、好ましくは0.005〜0.5w/v%、更に好ましくは0.01〜0.3w/v%が例示される。 In the eye drop for SHCL of the present invention, the blending ratio of the component (B) is appropriately set according to the type of the component (B), the type of other blending components, etc., as an example, The total amount of the component (B) is 0.001-1 w / v%, preferably 0.005-0.5 w / v%, more preferably 0.01-0.3 w / v%. Is done.
本発明のSHCL用点眼剤において、上記(A)成分に対する上記(B)成分の比率については、前述する配合割合を満たす限り特に制限されるものではないが、SHCLへのプラノプロフェン及び/又はその塩の透過性をより効果的に向上させるという観点から、上記(A)成分の総量100重量部当たり、上記(B)成分の総量が1〜2000重量部、好ましくは5〜1000重量部、更に好ましくは10〜600重量部となる比率を充足することが望ましい。また、上記比率を充足することによって、イオン性SHCLへの花粉タンパク質の蓄積をより一層有効に抑制することも可能となる。 In the eye drop for SHCL of the present invention, the ratio of the component (B) to the component (A) is not particularly limited as long as the above-described blending ratio is satisfied, but pranoprofen and / or SHCL. From the viewpoint of more effectively improving the permeability of the salt, the total amount of the component (B) is 1 to 2000 parts by weight, preferably 5 to 1000 parts by weight per 100 parts by weight of the total amount of the component (A). More preferably, it is desirable to satisfy a ratio of 10 to 600 parts by weight. In addition, by satisfying the above ratio, it becomes possible to more effectively suppress pollen protein accumulation in ionic SHCL.
本発明のSHCL用点眼剤は、上記(A)及び(B)成分に加えて、ビタミンB6類(以下、(C)成分と表記することもある)を含有することが好ましい。このように更に(C)成分を含むことによって、イオン性SHCLへの花粉タンパク質の蓄積を抑制する作用を一層増強させることができる。 The eye drop for SHCL of the present invention preferably contains vitamin B6 (hereinafter also referred to as component (C)) in addition to the components (A) and (B). Thus, by further including the component (C), the action of suppressing the accumulation of pollen protein in ionic SHCL can be further enhanced.
本発明のSHCL用点眼剤に使用されるビタミンB6類については、医薬上、薬理学的に(製薬上)又は生理学的に許容される限り、特に制限されないが、具体的には、ピリドキシン、ピリドキサール、ピリドキサミン、及びこれらの塩が挙げられる。 The vitamin B6s used in the SHCL eye drops of the present invention are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable, and specifically include pyridoxine and pyridoxal. , Pyridoxamine, and salts thereof.
本発明で使用される上記(C)成分の内、ピリドキシン、ピリドキサール、及びピリドキサミンの塩については、医薬上、薬理学的に(製薬上)又は生理学的に許容されるものであれば、特に制限されないが、具体的には、有機酸塩[例えば、モノカルボン酸塩(酢酸塩、トリフルオロ酢酸塩、酪酸塩、パルミチン酸塩、ステアリン酸塩等)、多価カルボン酸塩(フマル酸塩、マレイン酸塩、コハク酸塩、マロン酸塩等)、オキシカルボン酸塩(乳酸塩、酒石酸塩、クエン酸塩等)、有機スルホン酸塩(メタンスルホン酸塩、トルエンスルホン酸塩、トシル酸塩等)等]、無機酸塩(例えば、塩酸塩、硫酸塩、硝酸塩、臭化水素酸塩、リン酸塩等)等が挙げられる。これらの塩の中でも、好ましくは無機酸塩、より好ましくは塩酸塩及びリン酸塩、特に好ましくは塩酸塩が挙げられる。これらのピリドキシン、ピリドキサール、及びピリドキサミンの塩は、1種単独で使用してもよく、また2種以上を任意に組み合わせて使用してもよい。 Among the components (C) used in the present invention, pyridoxine, pyridoxal and pyridoxamine salts are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specifically, organic acid salts [for example, monocarboxylate (acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.), polyvalent carboxylate (fumarate, Maleate, succinate, malonate, etc.), oxycarboxylate (lactate, tartrate, citrate, etc.), organic sulfonate (methanesulfonate, toluenesulfonate, tosylate, etc.) Etc.], inorganic acid salts (for example, hydrochloride, sulfate, nitrate, hydrobromide, phosphate, etc.). Among these salts, preferred are inorganic acid salts, more preferred are hydrochlorides and phosphates, and particularly preferred are hydrochlorides. These pyridoxine, pyridoxal, and pyridoxamine salts may be used alone or in any combination of two or more.
これらのビタミンB6類の内、イオン性SHCLへの花粉タンパク質蓄積抑制作用を一層高めるという観点から、好ましくはピリドキシン及びその塩、より好ましくはピリドキシン及びその無機酸塩、更に好ましくはピリドキシン塩酸塩及びピリドキシンリン酸塩、特に好ましくはピリドキシン塩酸塩(塩酸ピリドキシン)が挙げられる。 Of these vitamin B6s, pyridoxine and its salts, preferably pyridoxine and its inorganic acid salts, more preferably pyridoxine hydrochloride and pyridoxine, from the viewpoint of further enhancing the action of suppressing pollen protein accumulation on ionic SHCL. Phosphate, particularly preferably pyridoxine hydrochloride (pyridoxine hydrochloride) is mentioned.
本発明のSHCL用点眼剤に上記(C)成分を配合する場合、該(C)成分の配合割合については、特に制限されないが、イオン性SHCLへの花粉タンパク質の蓄積を抑制する効果を一層高めるという観点から、SHCL用点眼剤の総量に対して、該(C)成分が総量で0.001〜1.0w/v%、好ましくは0.01〜0.5w/v%、更に好ましくは0.02〜0.2w/v%が挙げられる。 When the above component (C) is added to the SHCL eye drop of the present invention, the mixing ratio of the component (C) is not particularly limited, but the effect of suppressing the accumulation of pollen protein in ionic SHCL is further enhanced. In view of the above, the total amount of the component (C) is 0.001 to 1.0 w / v%, preferably 0.01 to 0.5 w / v%, more preferably 0 with respect to the total amount of the eye drops for SHCL. 0.02 to 0.2 w / v%.
また、本発明のSHCL用点眼剤において、上記(A)成分に対する上記(C)成分の比率については、前述する配合割合を満たす限り特に制限されるものではないが、イオン性SHCLへの花粉タンパク質の蓄積を抑制する効果をより一層向上させるという観点から、上記(A)成分の総量100重量部当たり、上記(C)成分の総量が2〜4000重量部、好ましくは20〜2000重量部、更に好ましくは40〜800重量部となる比率を充足することが望ましい。 Further, in the eye drop for SHCL of the present invention, the ratio of the component (C) to the component (A) is not particularly limited as long as the above-described blending ratio is satisfied, but pollen protein to ionic SHCL From the viewpoint of further improving the effect of suppressing the accumulation of the above, the total amount of the component (C) is 2 to 4000 parts by weight, preferably 20 to 2000 parts by weight per 100 parts by weight of the total amount of the component (A). It is desirable to satisfy the ratio of preferably 40 to 800 parts by weight.
本発明のSHCL用点眼剤は、更に上記(A)及び(B)成分に加えて、緩衝剤を含有してもよい。本発明のSHCL用点眼剤に配合できる緩衝剤としては、医薬上、薬理学的に(製薬上)又は生理学的に許容されるものであれば、特に制限されない。かかる緩衝剤の一例として、ホウ酸緩衝剤、リン酸緩衝剤、炭酸緩衝剤、クエン酸緩衝剤、酢酸緩衝剤、トリス緩衝剤、イプシロン−アミノカプロン酸、アスパラギン酸、アスパラギン酸塩等が挙げられる。これらの緩衝剤は組み合わせて使用しても良い。好ましい緩衝剤は、ホウ酸緩衝剤、リン酸緩衝剤、炭酸緩衝剤、及びクエン酸緩衝剤であり、更に好ましい緩衝剤は、ホウ酸緩衝剤、及びリン酸緩衝剤であり、特に好ましい緩衝剤は、ホウ酸緩衝剤である。ホウ酸緩衝剤としては、ホウ酸、又はホウ酸アルカリ金属塩、ホウ酸アルカリ土類金属塩等のホウ酸塩が挙げられる。リン酸緩衝剤としては、リン酸、又はリン酸アルカリ金属塩、リン酸アルカリ土類金属塩等のリン酸塩が挙げられる。炭酸緩衝剤としては、炭酸、又は炭酸アルカリ金属塩、炭酸アルカリ土類金属塩等の炭酸塩が挙げられる。クエン酸緩衝剤としては、クエン酸、又はクエン酸アルカリ金属塩、クエン酸アルカリ土類金属塩等が挙げられる。また、ホウ酸緩衝剤又はリン酸緩衝剤として、ホウ酸塩又はリン酸塩の水和物を用いてもよい。より具体的な例として、ホウ酸緩衝剤として、ホウ酸又はその塩(ホウ酸ナトリウム、テトラホウ酸カリウム、メタホウ酸カリウム、ホウ酸アンモニウム、ホウ砂等);リン酸緩衝剤として、リン酸又はその塩(リン酸水素二ナトリウム、リン酸二水素ナトリウム、リン酸二水素カリウム、リン酸三ナトリウム、リン酸二カリウム、リン酸一水素カルシウム、リン酸二水素カルシウム等);炭酸緩衝剤として、炭酸又はその塩(炭酸水素ナトリウム、炭酸ナトリウム、炭酸アンモニウム、炭酸カリウム、炭酸カルシウム、炭酸水素カリウム、炭酸マグネシウム等);クエン酸緩衝剤として、クエン酸又はその塩(クエン酸ナトリウム、クエン酸カリウム、クエン酸カルシウム、クエン酸二水素ナトリウム、クエン酸二ナトリウム等);酢酸緩衝剤として、酢酸又はその塩(酢酸アンモニウム、酢酸カリウム、酢酸カルシウム、酢酸ナトリウム等);トリス緩衝剤として、トリス(ヒドロキシメチル)アミノメタン又はその塩(塩酸塩、酢酸塩、スルホン酸塩等);アスパラギン酸又はその塩(アスパラギン酸ナトリウム、アスパラギン酸マグネシウム、アスパラギン酸カリウム等)等が例示できる。これらの緩衝剤は1種単独で使用してもよく、また2種以上を任意に組み合わせて使用してもよい。 The eye drop for SHCL of the present invention may further contain a buffering agent in addition to the components (A) and (B). The buffer that can be incorporated into the eye drops for SHCL of the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of such buffers include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, tris buffer, epsilon-aminocaproic acid, aspartic acid, aspartate and the like. These buffering agents may be used in combination. Preferred buffering agents are borate buffering agents, phosphate buffering agents, carbonate buffering agents, and citrate buffering agents, and more preferred buffering agents are boric acid buffering agents and phosphate buffering agents, and particularly preferred buffering agents. Is a borate buffer. Examples of the boric acid buffer include boric acid or boric acid salts such as alkali metal borate and alkaline earth metal borate. Examples of the phosphate buffer include phosphoric acid or phosphates such as alkali metal phosphates and alkaline earth metal phosphates. Examples of the carbonate buffer include carbonates or carbonates such as alkali metal carbonates and alkaline earth metal carbonates. Examples of the citrate buffer include citric acid, alkali metal citrate, and alkaline earth metal citrate. Moreover, you may use the borate or the hydrate of a phosphate as a borate buffer or a phosphate buffer. As a more specific example, boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.); as a phosphate buffer, phosphoric acid or a salt thereof Salt (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.); Or a salt thereof (sodium bicarbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium bicarbonate, magnesium carbonate, etc.); citric acid or a salt thereof (sodium citrate, potassium citrate, citric acid, etc.) Calcium acetate, sodium dihydrogen citrate, disodium citrate, etc.); with acetate buffer Acetic acid or a salt thereof (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.); as a Tris buffer, tris (hydroxymethyl) aminomethane or a salt thereof (hydrochloride, acetate, sulfonate, etc.); Examples include aspartic acid or a salt thereof (sodium aspartate, magnesium aspartate, potassium aspartate, etc.). These buffering agents may be used alone or in any combination of two or more.
本発明のSHCL用点眼剤に緩衝剤を配合する場合、該緩衝剤の配合割合については、使用する緩衝剤の種類、他の配合成分の種類や量、該点眼剤の用途等に応じて異なり、一律に規定することはできないが、例えば、該点眼剤の総量に対して、該緩衝剤が総量で0.01〜10w/v%、好ましくは0.1〜5w/v%、更に好ましくは0.5〜2w/v%となる割合が例示される。 When a buffering agent is blended in the SHCL eyedrops of the present invention, the blending ratio of the buffering agent varies depending on the type of buffering agent used, the type and amount of other blending components, the use of the eyedrops, etc. However, for example, the total amount of the buffer is 0.01 to 10 w / v%, preferably 0.1 to 5 w / v%, more preferably, with respect to the total amount of the eye drops. A ratio of 0.5 to 2 w / v% is exemplified.
本発明のSHCL用点眼剤は、更に等張化剤を含有していてもよい。本発明のSHCL用点眼剤に配合できる等張化剤としては、医薬上、薬理学的に(製薬上)又は生理学的に許容されるものであれば、特に制限されない。かかる等張化剤の具体例として、例えば、リン酸水素二ナトリウム、リン酸二水素ナトリウム、リン酸二水素カリウム、亜硫酸水素ナトリウム、亜硫酸ナトリウム、塩化カリウム、塩化カルシウム、塩化ナトリウム、塩化マグネシウム、酢酸カリウム、酢酸ナトリウム、炭酸水素ナトリウム、炭酸ナトリウム、チオ硫酸ナトリウム、硫酸マグネシウム、グリセリン、プロピレングリコール等が挙げられる。これらの等張化剤の中でも、より確実に本発明の効果を奏させるという観点から、好ましくは、塩化ナトリウム、塩化カリウム、塩化カルシウム、塩化マグネシウム、グリセリン、及びプロピレングリコールが挙げられる。これらの等張化剤は、1種単独で使用してもよく、また2種以上を任意に組み合わせて使用してもよい。 The eye drop for SHCL of the present invention may further contain an isotonic agent. The isotonic agent that can be incorporated into the SHCL eye drops of the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of such isotonic agents include, for example, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium hydrogen sulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, acetic acid Examples include potassium, sodium acetate, sodium hydrogen carbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, glycerin, propylene glycol and the like. Among these isotonic agents, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, glycerin, and propylene glycol are preferable from the viewpoint of more reliably achieving the effects of the present invention. These isotonic agents may be used alone or in any combination of two or more.
本発明のSHCL用点眼剤に等張化剤を配合する場合、該等張化剤の配合割合については、使用する等張化剤の種類等に応じて異なり、一律に規定することはできないが、例えば、該等張化剤が総量で0.01〜10w/v%、好ましくは0.05〜5w/v%、更に好ましくは0.1〜3w/v%となる割合が例示される。 When an isotonic agent is blended in the SHCL eyedrops of the present invention, the blending ratio of the isotonic agent differs depending on the type of tonicity agent used and cannot be uniformly defined. For example, the ratio by which the total amount of the tonicity agent is 0.01 to 10 w / v%, preferably 0.05 to 5 w / v%, more preferably 0.1 to 3 w / v% is exemplified.
本発明のSHCL用点眼剤のpHについては、医薬上、薬理学的に(製薬上)又は生理学的に許容される範囲内であれば特に限定されるものではない。本発明のSHCL用点眼剤のpHの一例として、4.0〜9.5、好ましくは5.0〜8.5、より好ましくは、5.5〜8.0、更に好ましくは6.0〜8.0となる範囲が挙げられる。 The pH of the eye drops for SHCL of the present invention is not particularly limited as long as it is within a range that is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. As an example of the pH of the eye drops for SHCL of the present invention, 4.0 to 9.5, preferably 5.0 to 8.5, more preferably 5.5 to 8.0, still more preferably 6.0 to The range which becomes 8.0 is mentioned.
また、本発明のSHCL用点眼剤の浸透圧については、生体に許容される範囲内であれば、特に制限されない。本発明のSHCL用点眼剤の浸透圧比の一例として、好ましくは0.7〜5.0、更に好ましくは0.9〜3.0、特に好ましくは1.0〜2.0となる範囲が挙げられる。浸透圧の調整は無機塩、多価アルコール、糖アルコール、糖類等を用いて、当該技術分野で既知の方法で行うことができる。浸透圧比は、第十五改正日本薬局方に基づき0.9w/v%塩化ナトリウム水溶液の浸透圧に対する試料の浸透圧の比とし、浸透圧は日本薬局方記載の浸透圧測定法(氷点降下法)を参考にして測定する。浸透圧比測定用標準液は、塩化ナトリウム(日本薬局方標準試薬)を500〜650℃で40〜50分間乾燥した後、デシケーター(シリカゲル)中で放冷し、その0.900gを正確に量り、精製水に溶かし正確に100mLとして調製するか、市販の浸透圧比測定用標準液(0.9w/v%塩化ナトリウム水溶液)を用いる。 Further, the osmotic pressure of the eye drop for SHCL of the present invention is not particularly limited as long as it is within a range acceptable for a living body. As an example of the osmotic pressure ratio of the eye drops for SHCL of the present invention, a range of preferably 0.7 to 5.0, more preferably 0.9 to 3.0, and particularly preferably 1.0 to 2.0 is mentioned. It is done. The osmotic pressure can be adjusted by a method known in the art using inorganic salts, polyhydric alcohols, sugar alcohols, saccharides and the like. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to the osmotic pressure of 0.9w / v% sodium chloride aqueous solution based on the 15th revised Japanese Pharmacopoeia. The osmotic pressure is the osmotic pressure measurement method described in the Japanese Pharmacopoeia (freezing point depression method) Measure with reference to. The standard solution for measuring the osmotic pressure ratio was sodium chloride (Japanese Pharmacopoeia standard reagent) dried at 500-650 ° C for 40-50 minutes, and then allowed to cool in a desiccator (silica gel). Dissolve in water to prepare exactly 100 mL, or use a commercially available standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution).
本発明のSHCL用点眼剤は、本発明の効果を妨げない限り、上記成分の他に、種々の薬理活性成分や生理活性成分を組み合わせて適当量含有してもよい。かかる成分は特に制限されず、例えば、一般用医薬品製造(輸入)承認基準2000年版(薬事審査研究会監修)に記載された眼科用薬における有効成分が例示できる。具体的には、本発明のSHCL用点眼剤において用いられる成分としては、次のような成分が挙げられる。
抗ヒスタミン剤:例えば、イプロヘプチン、ジフェンヒドラミン、マレイン酸クロルフェニラミン等。
充血除去剤:テトラヒドロゾリン、ナファゾリン、エピネフリン、エフェドリン、メチルエフェドリン等。
殺菌剤:例えば、アクリノール、セチルピリジニウム等。
ビタミン類:フラビンアデニンジヌクレオチドナトリウム、シアノコバラミン、酢酸レチノール、パルミチン酸レチノール、塩酸ピリドキシン、パンテノール、パントテン酸カルシウム、酢酸トコフェロール等。
アミノ酸類:アスパラギン酸カリウム、アスパラギン酸マグネシウム、アミノエチルスルホン酸等。
消炎剤:例えば、グリチルレチン酸、グリチルリチン酸、サリチル酸メチル、サリチル酸グリコール、アラントイン、アズレン、アズレンスルホン酸、グアイアズレン、トラネキサム酸、ε−アミノカプロン酸、ベルベリン、リゾチーム、甘草等。
収斂剤:例えば、亜鉛華、乳酸亜鉛、硫酸亜鉛等。
その他:例えば、メチル硫酸ネオスチグミン、フマル酸ケトチフェン、クロモグリク酸ナトリウム、コンドロイチン硫酸ナトリウム、ヒアルロン酸ナトリウム、スルファメトキサゾール、インドメタシン、イブプロフェン、イブプロフェンピコノール、ブフェキサマク、フルフェナム酸ブチル、ベンダザック、ピロキシカム、ケトプロフェン、フェルビナク、紫根、セイヨウトチノキ、及びこれらの塩等。
The eye drop for SHCL of the present invention may contain an appropriate amount of various pharmacologically active components and physiologically active components in addition to the above components as long as the effects of the present invention are not hindered. Such an ingredient is not particularly limited, and examples thereof include an active ingredient in an ophthalmic drug described in the over-the-counter drug manufacturing (import) approval standard 2000 edition (supervised by the Pharmaceutical Affairs Research Committee). Specifically, examples of the components used in the SHCL eyedrops of the present invention include the following components.
Antihistamines: for example, iproheptin, diphenhydramine, chlorpheniramine maleate and the like.
Decongestant: Tetrahydrozoline, naphazoline, epinephrine, ephedrine, methylephedrine, etc.
Bactericides: for example, acrinol, cetylpyridinium, etc.
Vitamins: flavin adenine dinucleotide sodium, cyanocobalamin, retinol acetate, retinol palmitate, pyridoxine hydrochloride, panthenol, calcium pantothenate, tocopherol acetate, etc.
Amino acids: potassium aspartate, magnesium aspartate, aminoethylsulfonic acid and the like.
Anti-inflammatory agents: for example, glycyrrhetinic acid, glycyrrhizic acid, methyl salicylate, glycol salicylate, allantoin, azulene, azulenesulfonic acid, guaiazulene, tranexamic acid, ε-aminocaproic acid, berberine, lysozyme, licorice, etc.
Astringent: For example, zinc white, zinc lactate, zinc sulfate and the like.
Other: for example, neostigmine methyl sulfate, ketotifen fumarate, sodium cromoglycate, sodium chondroitin sulfate, sodium hyaluronate, sulfamethoxazole, indomethacin, ibuprofen, ibuprofen piconol, bufexamac, butyl flufenamic acid, bendazac, piroxicam, ketoprofen , Felbinac, purple root, horse chestnut, and salts thereof.
また、本発明のSHCL用点眼剤には、発明の効果を損なわない範囲であれば、その用途や形態に応じて、常法に従い、様々な添加物を適宜選択し、1種又はそれ以上を併用して適当量含有させてもよい。それらの添加物として、例えば、医薬品添加物事典2005(日本医薬品添加剤協会編集)に記載された各種添加物が例示できる。代表的な成分として次の添加物が挙げられる。
担体:例えば、水、含水エタノール等の水性担体。
増粘剤:例えば、カルボキシビニルポリマー、ヒドロキシエチルセルロース、ヒドロキシプロピルメチルセルロース、メチルセルロース、アルギン酸、ポリビニルアルコール(完全、又は部分ケン化物)、ポリビニルピロリドン、マクロゴール、コンドロイチン硫酸ナトリウム、ヒアルロン酸ナトリウム等。
糖類:例えば、グルコース、シクロデキストリン等。
糖アルコール類:例えば、キシリトール、ソルビトール、マンニトールなど。これらはd体、l体又はdl体のいずれでもよい。
防腐剤、殺菌剤又は抗菌剤:例えば、安息香酸ナトリウム、エタノール、クロロブタノール、ソルビン酸、ソルビン酸カリウム、デヒドロ酢酸ナトリウム、パラオキシ安息香酸メチル、パラオキシ安息香酸エチル、パラオキシ安息香酸プロピル、パラオキシ安息香酸ブチル、硫酸オキシキノリン、フェネチルアルコール、ベンジルアルコール、ビグアニド化合物、グローキル(ローディア社製商品名)等。
pH調節剤:例えば、塩酸、ホウ酸、アミノエチルスルホン酸、イプシロン−アミノカプロン酸、クエン酸、酢酸、水酸化ナトリウム、水酸化カリウム、水酸化カルシウム、水酸化マグネシウム、炭酸水素ナトリウム、炭酸ナトリウム、ホウ砂、トリエタノールアミン、モノエタノールアミン、ジイソプロパノールアミン、硫酸、リン酸、ポリリン酸、プロピオン酸、シュウ酸、グルコン酸、フマル酸、乳酸、酒石酸、リンゴ酸、コハク酸、グルコノラクトン、酢酸アンモニウム等。
安定化剤:ジブチルヒドロキシトルエン、トロメタモール、ナトリウムホルムアルデヒドスルホキシレート(ロンガリット)、トコフェロール、ピロ亜硫酸ナトリウム、モノエタノールアミン、モノステアリン酸アルミニウム、モノステアリン酸グリセリン等。
香料又は清涼化剤:メントール、アネトール、オイゲノール、カンフル、ゲラニオール、シネオール、ボルネオール、リモネン、リュウノウ等。これらは、d体、l体又はdl体のいずれでもよく、また精油(ハッカ油、クールミント油、スペアミント油、ペパーミント油、ウイキョウ油、ケイヒ油、ベルガモット油、ユーカリ油、ローズ油等)として配合してもよい。
In addition, in the eye drops for SHCL of the present invention, various additives are appropriately selected according to conventional methods according to the use and form as long as they do not impair the effects of the invention, and one or more of them are selected. An appropriate amount may be contained in combination. Examples of such additives include various additives described in Pharmaceutical Additives Encyclopedia 2005 (edited by Japan Pharmaceutical Additives Association). Typical additives include the following additives.
Carrier: An aqueous carrier such as water or hydrous ethanol.
Thickeners: for example, carboxyvinyl polymer, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, alginic acid, polyvinyl alcohol (completely or partially saponified), polyvinylpyrrolidone, macrogol, sodium chondroitin sulfate, sodium hyaluronate and the like.
Sugars: for example, glucose, cyclodextrin and the like.
Sugar alcohols: For example, xylitol, sorbitol, mannitol and the like. These may be d-form, l-form or dl-form.
Preservatives, bactericides or antibacterials: for example, sodium benzoate, ethanol, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, methyl parahydroxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate Oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds, glowkill (trade name, manufactured by Rhodia), etc.
pH adjuster: for example, hydrochloric acid, boric acid, aminoethylsulfonic acid, epsilon-aminocaproic acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium bicarbonate, sodium carbonate, boro Sand, triethanolamine, monoethanolamine, diisopropanolamine, sulfuric acid, phosphoric acid, polyphosphoric acid, propionic acid, oxalic acid, gluconic acid, fumaric acid, lactic acid, tartaric acid, malic acid, succinic acid, gluconolactone, ammonium acetate etc.
Stabilizer: Dibutylhydroxytoluene, trometamol, sodium formaldehyde sulfoxylate (Longalite), tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, glyceryl monostearate, etc.
Perfume or refreshing agent: menthol, anethole, eugenol, camphor, geraniol, cineol, borneol, limonene, ryuno and the like. These may be either d-form, l-form or dl-form, and are formulated as essential oils (mint oil, cool mint oil, spearmint oil, peppermint oil, fennel oil, cinnamon oil, bergamot oil, eucalyptus oil, rose oil, etc.) May be.
本発明のSHCL用点眼剤は、例えば、精製水、生理食塩水等の水性担体等に、上記(A)及び(B)成分、必要に応じて他の配合成分を所望の濃度となるように添加し、常法に準じて調製される。 The eye drop for SHCL of the present invention, for example, in the aqueous carrier such as purified water, physiological saline, etc., so that the above components (A) and (B), and other compounding components as required, at a desired concentration It is added and prepared according to a conventional method.
本発明のSHCL用点眼剤において、適用対象となるSHCLの種類については特に制限されず、現在市販されている、或いは将来市販される全てのSHCLを適用対象にできる。とりわけ、本発明のSHCL用点眼剤は、非イオン性のSHCLに対するプラノプロフェン及び/又はその塩の透過性の向上を特に有効に獲得し得るので、本発明のSHCL用点眼剤の適用対象として非イオン性のSHCLが好適である。また、イオン性SHCLは花粉タンパク質を非常に吸着し易いという特有の課題が明らかとなっており、本発明のSHCL用点眼剤によれば、このイオン性SHCLへの花粉タンパク質の蓄積を有効に抑制することができる。かかる本発明の効果に鑑みれば、本発明のSHCL用点眼剤の好適な適用対象の一例として、イオン性SHCLを挙げることもできる。ここで非イオン性とは、当業者が通常理解するように、米国FDA(米国食品医薬品局)基準に則り、コンタクトレンズ素材中のイオン性成分含有率が1mol%未満であることを言い、イオン性とは、米国FDA基準に則り、コンタクトレンズ素材中のイオン性成分含有率が1mol%以上であることを言う。また、適用対象となるSHCLの含水率についても特に制限されず、例えば、90%以下、好ましくは60%以下、更に好ましくは50%以下が挙げられる。なお、SHCLはハイドロゲル素材を含むものであるため、少なくとも0%より多い水分を含む。 In the eye drop for SHCL of the present invention, the type of SHCL to be applied is not particularly limited, and all SHCL currently marketed or marketed in the future can be applied. In particular, the ophthalmic solution for SHCL of the present invention can particularly effectively improve the permeability of pranoprofen and / or a salt thereof to nonionic SHCL, so that the ophthalmic solution for SHCL of the present invention is applied. Nonionic SHCL is preferred. In addition, the unique problem that ionic SHCL is very easy to adsorb pollen protein has been clarified, and according to the eye drops for SHCL of the present invention, the accumulation of pollen protein in ionic SHCL is effectively suppressed. can do. In view of the effects of the present invention, ionic SHCL may be mentioned as an example of a suitable application target of the eye drop for SHCL of the present invention. Non-ionic here means that the ionic component content in the contact lens material is less than 1 mol% in accordance with US FDA (Food and Drug Administration) standards, as normally understood by those skilled in the art. The property means that the content of ionic components in the contact lens material is 1 mol% or more in accordance with US FDA standards. Further, the moisture content of SHCL to be applied is not particularly limited, and examples thereof include 90% or less, preferably 60% or less, and more preferably 50% or less. Since SHCL contains a hydrogel material, it contains at least more than 0% moisture.
また、非イオン性SHCLでは、含水率が低くなるにつれて、プラノプロフェン及び/又はその塩の透過性が低くなる傾向がある。本発明のSHCL用点眼剤によれば、このように透過性が低いSHCLに対しても、プラノプロフェン及び/又はその塩の透過性を有効に改善することができる。かかる本発明のレンズ透過性向上効果に鑑みれば、本発明のSHCL用点眼剤の好適な適用対象の一例として、含水率が低く50%以下の非イオン性SHCLが挙げられる。 Moreover, in nonionic SHCL, there exists a tendency for the permeability | transmittance of a pranoprofen and / or its salt to become low as a moisture content becomes low. According to the eye drop for SHCL of the present invention, the permeability of pranoprofen and / or a salt thereof can be effectively improved even for SHCL having such a low permeability. In view of the effect of improving the lens permeability of the present invention, an example of a suitable application target of the eye drop for SHCL of the present invention is nonionic SHCL having a low moisture content of 50% or less.
ここでSHCLの含水率とは、SHCL中の水の割合を示し、具体的には以下の計算式により求められる。 Here, the moisture content of SHCL indicates the ratio of water in SHCL, and is specifically determined by the following calculation formula.
含水率(%)=(含水した水の重量/含水状態のSHCLの重量)×100
かかる含水率は、ISO18369-4:2006の記載に従って重量測定方法により測定され得る。
Moisture content (%) = (weight of hydrated water / weight of hydrated SHCL) x 100
Such moisture content can be measured by a gravimetric method according to the description of ISO18369-4: 2006.
また、一般に材質が柔らかい非シリコーンハイドロゲルコンタクトレンズに比べ、材質が硬いSHCLは、異物の吸着によるレンズの変形や濡れ性低下により、使用感の悪化を感じさせ易く、眼粘膜障害を引き起こし易い傾向にある。本発明のSHCL用点眼剤によれば、このように使用感悪化や眼粘膜障害を引き起こし易い硬い材質のイオン性SHCLへの花粉タンパク質の吸着を有効に抑制することができ、それによりレンズの変形や変質を防いで、使用感の悪化や眼粘膜障害を効果的に防止することもできる。かかる本発明の花粉タンパク質蓄積抑制効果に鑑みれば、本発明のSHCL用点眼剤の好適な適用対象として、硬度が比較的高いイオン性SHCLが挙げられる。好ましくは、適用対象となるイオン性SHCLの硬度は、下記のテクスチャーアナライザーによる測定方法により測定した場合の硬度が、3g以上、好ましくは4g以上、より好ましくは6g以上、更に好ましくは8g以上である。また、適用対象となるSHCLの硬度の上限値については、特に制限されないが、好ましくは15g以下、更に好ましくは12g以下である。 In addition, compared to non-silicone hydrogel contact lenses, which are generally soft, SHCL, which is a hard material, tends to cause deterioration of the feeling of use due to lens deformation and reduced wettability due to the adsorption of foreign substances, and tends to cause ocular mucosal damage. It is in. According to the eye drop for SHCL of the present invention, it is possible to effectively suppress the adsorption of pollen protein to the ionic SHCL, which is a hard material that easily causes deterioration in use feeling and eye mucous membrane damage, thereby deforming the lens. It is also possible to effectively prevent deterioration of the feeling of use and ocular mucosal damage by preventing or deterioration. In view of the pollen protein accumulation inhibitory effect of the present invention, ionic SHCL having a relatively high hardness can be mentioned as a suitable application target of the eye drop for SHCL of the present invention. Preferably, the hardness of the ionic SHCL to be applied is 3 g or more, preferably 4 g or more, more preferably 6 g or more, still more preferably 8 g or more when measured by the following measurement method using a texture analyzer. . Further, the upper limit value of the hardness of the SHCL to be applied is not particularly limited, but is preferably 15 g or less, more preferably 12 g or less.
コンタクトレンズの硬度は、テクスチャーアナライザー(製品名:TA.XT.plus TEXTURE ANALYSER(Stable Micro Systems Limited製))を用いて、具体的に以下のようにして測定され得る。 The hardness of the contact lens can be specifically measured as follows using a texture analyzer (product name: TA.XT.plus TEXTURE ANALYSER (manufactured by Stable Micro Systems Limited)).
まず、測定対象となるコンタクトレンズをパッケージから取り出し、余分な水分をふき取って、生理食塩水(0.9%塩化ナトリウム溶液)で濯いだ後、生理食塩水を満たしたプラスチックシャーレの底に凸面が上方になるように配置する。次いで、測定器のプローブの真下に該コンタクトレンズが来るように調節し、以下の測定条件下で測定を行う。 First, remove the contact lens to be measured from the package, wipe off excess water, rinse with physiological saline (0.9% sodium chloride solution), and then raise the convex surface on the bottom of the plastic petri dish filled with physiological saline. Arrange so that Next, the contact lens is adjusted to be directly below the probe of the measuring instrument, and measurement is performed under the following measurement conditions.
[測定条件]
測定器の設定:
テストモード 圧縮測定
プローブタイプ φ10mmシリンダープローブ
Target Mode Distance
Distance 2.5mm
Triger Type Auto
Triger Force 0.1g
Test Speed 1.0mm/sec
プローブがレンズ頂点を押し下げ始めてから2.5mm(2.5秒)レンズを押しつぶす際の応力を測定し、その最大値を硬度として記録する。
[Measurement condition]
Instrument settings:
Test mode Compression measurement Probe type φ10mm cylinder probe
Target Mode Distance
Distance 2.5mm
Triger Type Auto
Triger Force 0.1g
Test Speed 1.0mm / sec
Measure the stress when crushing the lens 2.5mm (2.5 seconds) after the probe starts to push down the lens apex, and record the maximum value as hardness.
本発明のSHCL用点眼剤は、SHCLを装着中の眼に直接点すことができる。 The eye drop for SHCL of the present invention can be applied directly to the eye wearing the SHCL.
本発明のSHCL用点眼剤は、プラノプロフェン及び/又はその塩の角膜への到達量を増加できるので、炎症性眼疾患(例えば、角膜炎、前眼部ブドウ膜炎等)の治療乃至予防に有効であり、炎症性眼疾患の治療乃至予防剤として、とりわけコンタクトレンズ装用により誘発される炎症性眼疾患の治療乃至予防剤として有用である。従って、本発明のSHCL用点眼剤は、目の炎症により生じた異物感などの症状の改善剤として有用である。また、本発明のSHCL用点眼剤は、イオン性SHCL装用中に手軽に使用できるので、イオン性SHCL装用中に花粉タンパク質が吸着し蓄積していくのを効果的に抑制でき、イオン性SHCL装用中の不快感を防止して快適にイオン性SHCLを装用することを可能にする。よって、コンタクトレンズ上に吸着された花粉タンパク質が、長時間眼に接触し続けるのを防ぎ、花粉によるアレルギーの予防や悪化の防止にも有効である。従って、花粉症又は花粉症予備軍のイオン性SHCL使用者への適用に好適である。 Since the eye drop for SHCL of the present invention can increase the amount of pranoprofen and / or its salt reaching the cornea, it can treat or prevent inflammatory eye diseases (for example, keratitis, anterior uveitis, etc.). And is useful as a therapeutic or prophylactic agent for inflammatory eye diseases, particularly as a therapeutic or prophylactic agent for inflammatory eye diseases induced by wearing contact lenses. Therefore, the eye drop for SHCL of the present invention is useful as an agent for improving symptoms such as a foreign body sensation caused by eye inflammation. In addition, since the eye drop for SHCL of the present invention can be easily used during ionic SHCL wearing, it can effectively suppress the adsorption and accumulation of pollen protein during ionic SHCL wearing, and ionic SHCL wearing It is possible to wear ionic SHCL comfortably while preventing discomfort inside. Therefore, the pollen protein adsorbed on the contact lens is prevented from being kept in contact with the eye for a long time, and it is also effective in preventing allergy and preventing deterioration due to pollen. Therefore, it is suitable for application to ionic SHCL users of hay fever or hay fever reserve.
(II) SHCLへのプラノプロフェン及び/又はその塩の透過性の向上方法、並びにSHCLへのプラノプロフェン及び/又はその塩の透過性を向上させる作用を点眼剤に付与する方法
前述するように、SHCLへの上記(A)成分の透過性を上記(B)成分によって向上させることができる。
(II) A method for improving the permeability of pranoprofen and / or a salt thereof to SHCL, and a method for imparting an action to improve the permeability of pranoprofen and / or a salt thereof to SHCL as described above Furthermore, the permeability of the component (A) to SHCL can be improved by the component (B).
従って、本発明は、更に別の観点から、(A)プラノプロフェン及びその塩からなる群より選択される少なくとも1種と(B)界面活性剤とを併用することを特徴とする、SHCLへの該(A)成分の透過性を向上させる方法を提供する。また、本発明は、(A)プラノプロフェン及びその塩からなる群より選択される少なくとも1種を含有するSHCL用点眼剤に、(B)界面活性剤を配合することを特徴とする、SHCLへの該(A)成分の透過性を向上させる作用を該点眼剤に付与する方法をも提供する。 Accordingly, the present invention, from yet another point of view, is a combination of at least one selected from the group consisting of (A) pranoprofen and a salt thereof and (B) a surfactant. A method for improving the permeability of the component (A) is provided. The present invention also provides an SHCL ophthalmic solution containing at least one selected from the group consisting of (A) pranoprofen and a salt thereof, and (B) a surfactant, There is also provided a method for imparting an action to improve the permeability of the component (A) to the eye drop.
当該方法において、使用する(A)及び(B)成分の種類や配合割合、その他に配合される成分の種類や配合割合、SHCL用点眼剤の適用対象となるSHCLの種類等については、前記「(I)SHCL用点眼剤」と同様である。 In the method, the types and blending ratios of the components (A) and (B) to be used, the types and blending ratios of other components, the types of SHCL to be applied to the eye drops for SHCL, etc. (I) SHCL eye drops ”.
(III) SHCLへのプラノプロフェン及び/又はその塩の透過性を向上させるための剤
前述するように、SHCLへの上記(A)成分の透過性を上記(B)成分によって向上せることができる。
(III) Agent for improving the permeability of pranoprofen and / or a salt thereof to SHCL As described above, the permeability of the component (A) to SHCL can be improved by the component (B). it can.
従って、本発明は、更に別の観点から、(B)界面活性剤を有効成分として含有する、SHCLへの(A)プラノプロフェン及びその塩からなる群より選択される少なくとも1種の透過性を向上させるための剤を提供する。 Accordingly, the present invention, from yet another viewpoint, comprises (B) a surfactant as an active ingredient, and at least one permeability selected from the group consisting of (A) pranoprofen and a salt thereof into SHCL. An agent for improving the resistance is provided.
該剤において、有効成分である(B)成分の種類、適用対象となるSHCL、SHCLへの透過性の対象となる(A)成分の種類等については、前記「(I)SHCL用点眼剤」と同様である。 In the agent, the type of component (B) that is an active ingredient, the target SHCL, the type of component (A) that is subject to permeability to SHCL, etc., the above ((I) SHCL eye drops) It is the same.
(IV)SHCLに対するプラノプロフェン及び/又はその塩の透過性を向上させる物質のスクリーニング方法
また、前述するように、本発明者によって、上記(A)成分がSHCLへの透過性が著しく低いという新たな知見が得られている。そこで、更に、本発明は、SHCLに対するプラノプロフェン及びその塩からなる群より選択される少なくとも1種のプラノプロフェン類の透過性を向上させる透過性向上物質をスクリーニングする方法をも提供する。具体的には、本スクリーニング方法は、下記(a)〜(c)工程を包含する方法である。
(a) プラノプロフェン及びその塩からなる群より選択される少なくとも1種のプラノプロフェン類を含むコントロール溶液、並びにプラノプロフェン類と被験物質とを含む被験溶液を、試験溶液として各々調製する工程、
(b)上記試験溶液を各々、シリコーンハイドロゲルコンタクトレンズの片側面のみに所定時間接触させ、該レンズの上記試験溶液を接触させていない他方の片側面から滲出したプラノプロフェン類の量を測定することにより、各試験溶液のプラノプロフェン類の透過量を求める工程、並びに
(c)上記工程(b)において測定されたプラノプロフェン類の透過量が、コントロール溶液よりも多い被験溶液を選び、該被験溶液に含まれる被験物質を上記透過性向上物質として選択する工程。
(IV) A screening method for a substance that improves the permeability of pranoprofen and / or a salt thereof to SHCL Further, as described above, the present inventor said that the component (A) has extremely low permeability to SHCL. New knowledge has been obtained. Therefore, the present invention further provides a method for screening a substance for improving permeability that improves the permeability of at least one kind of pranoprofen selected from the group consisting of pranoprofen and a salt thereof against SHCL. Specifically, this screening method is a method including the following steps (a) to (c).
(a) A control solution containing at least one kind of pranoprofen selected from the group consisting of pranoprofen and a salt thereof, and a test solution containing pranoprofen and a test substance are prepared as test solutions, respectively. Process,
(b) Each of the test solutions is brought into contact with only one side of the silicone hydrogel contact lens for a predetermined time, and the amount of pranoprofen exuded from the other side of the lens not contacting the test solution is measured. Determining the amount of peranoprofen permeation in each test solution, and
(c) A step of selecting a test solution in which the amount of peranoprofen permeation measured in the step (b) is larger than that of a control solution, and selecting a test substance contained in the test solution as the permeability improving substance.
本スクリーニング方法において、被験物質とは、スクリーニングに供される上記透過性向上物質の候補物質である。また、候補物質は、SHCL用点眼剤に配合できるように、医薬上、薬理学的に(製薬上)又は生理学的に許容されるものであることが望ましい。 In the present screening method, the test substance is a candidate substance for the permeability improving substance to be used for screening. Moreover, it is desirable that the candidate substance is pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable so that the candidate substance can be incorporated into the eye drops for SHCL.
上記(a)工程において、被験溶液は、水や緩衝液等の水性担体にプラノプロフェン及びその塩からなる群より選択される少なくとも1種のプラノプロフェン類を例えば0.05〜0.1w/v%となるように添加し、更に被験物質を適当量添加することにより調製される。ここで、被験物質は段階的に希釈しておき、複数の濃度の被験物質を含む被験溶液を調製しておくことが望ましい。また、プラノプロフェン類を含有するコントロール溶液は、被験物質を添加しないこと以外は、被験溶液と同組成とすることが望ましい。斯くして調製した被験溶液及びコントロール溶液を試験溶液として用いて、次の(b)工程に供する。 In the step (a), the test solution is prepared by adding 0.05 to 0.1 w of at least one kind of pranoprofen selected from the group consisting of pranoprofen and a salt thereof in an aqueous carrier such as water or a buffer. It is prepared by adding so that it becomes / v% and further adding an appropriate amount of the test substance. Here, it is desirable to dilute the test substance in stages and prepare a test solution containing a plurality of concentrations of the test substance. Further, it is desirable that the control solution containing pranoprofen has the same composition as the test solution except that the test substance is not added. Using the test solution and the control solution thus prepared as test solutions, they are subjected to the next step (b).
上記(b)工程は、溶液を収容可能な2つの区画(セル)を有し且つこれらの2つの区画はSHCLを介して隔てられている装置等を用いて実施することができる。このような装置としては、例えばビードレックス社製の膜透過実験装置が使用できる。具体的には、上記装置の一方の区画に上記試験溶液(コントロール溶液又は被験溶液)を充填し、更に他方の区画には何も充填しないか、或いは好ましくはプラノプロフェン類を含まない溶液(以下、ブランク溶液と表記する)等を充填して、所定時間(例えば4〜24時間程度)経過後に、SHCLを介して上記他方の区画(ブランク溶液を充填した場合には、該ブランク溶液)側に移行したプラノプロフェン類の量を定量する。斯くして定量されるプラノプロフェン類の量が、上記(b)工程で求められるプラノプロフェン類の透過量である。なお、上記ブランク溶液は、充填される試験溶液(コントロール溶液又は被験溶液)と浸透圧が同等であることが望ましい。 The step (b) can be performed using an apparatus or the like that has two compartments (cells) capable of containing a solution and these two compartments are separated via SHCL. As such an apparatus, for example, a membrane permeation experiment apparatus manufactured by Beadrex can be used. Specifically, the test solution (control solution or test solution) is filled in one compartment of the apparatus and nothing is filled in the other compartment, or a solution preferably containing no pranoprofen ( In the following, it is filled with a blank solution, etc., and after the passage of a predetermined time (for example, about 4 to 24 hours), the other compartment (the blank solution when filled with the blank solution) side through SHCL Quantify the amount of pranoprofen transferred to. The amount of pranoprofen thus determined is the permeation amount of pranoprofen determined in the step (b). In addition, as for the said blank solution, it is desirable that the osmotic pressure is equivalent to the test solution (control solution or test solution) with which it is filled.
また、上記透過性向上物質の選択に関する工程(c)において、SHCLへのプラノプロフェン類の透過性を向上させる作用が強い透過性向上物質を選択するには、(b)工程において求められたプラノプロフェン類の透過量がコントロール溶液よりも多い被験溶液を選べばよい。 Further, in the step (c) relating to the selection of the above-described permeability-improving substance, in order to select a permeability-improving substance having a strong effect of improving the permeability of pranoprofen to SHCL, it was required in the process (b). A test solution having a larger amount of peranoprofen permeation than the control solution may be selected.
本スクリーニング方法により得られる透過性向上物質は、SHCLへのプラノプロフェン及び/又はその塩の透過性を向上させることを目的として、プラノプロフェン及び/又はその塩を含むSHCL用点眼剤に配合することができる。 The permeability-improving substance obtained by this screening method is incorporated into SHCL eye drops containing pranoprofen and / or its salt for the purpose of improving the permeability of pranoprofen and / or its salt to SHCL. can do.
(V)イオン性SHCLへの花粉タンパク質の蓄積を抑制する方法、並びにイオン性SHCLへの花粉タンパク質の蓄積を抑制する作用を点眼剤に付与する方法
前述するように、上記(A)及び(B)成分を併用することによって、イオン性SHCL装用眼が花粉に晒されても、イオン性SHCLからの花粉タンパク質の除去を促進して再付着を防止でき、イオン性SHCLへの花粉タンパク質の蓄積を抑制することが可能になる。
(V) A method for suppressing the accumulation of pollen protein in ionic SHCL, and a method for imparting to the eye drops the effect of suppressing the accumulation of pollen protein in ionic SHCL As described above, (A) and (B In combination with ingredients, even if the ionic SHCL wearing eye is exposed to pollen, it can promote the removal of pollen protein from the ionic SHCL to prevent reattachment, and the accumulation of pollen protein in the ionic SHCL It becomes possible to suppress.
従って、本発明は、更に別の観点から、(A)プラノプロフェン及びその塩からなる群より選択される少なくとも1種と(B)界面活性剤とを含有するSHCL用点眼剤を、イオン性SHCLと接触させることを特徴とする、イオン性SHCLへの花粉タンパク質の蓄積を抑制する方法を提供する。更には、SHCL用点眼剤に、(A)プラノプロフェン及びその塩からなる群より選択される少なくとも1種と(B)界面活性剤とを配合することを特徴とする、イオン性SHCLへの花粉タンパク質の蓄積を抑制する作用を該点眼剤に付与する方法を提供する。 Therefore, the present invention, from yet another point of view, provides an eye drop for SHCL containing at least one selected from the group consisting of (A) pranoprofen and a salt thereof and (B) a surfactant. Provided is a method for suppressing the accumulation of pollen protein in ionic SHCL, which comprises contacting with SHCL. Furthermore, the eye drops for SHCL are formulated with (A) at least one selected from the group consisting of pranoprofen and a salt thereof and (B) a surfactant. Provided is a method for imparting an action of suppressing the accumulation of pollen protein to the eye drop.
当該方法において、使用する(A)及び(B)成分の種類や配合割合、その他に配合される成分の種類や配合割合、適用対象となるイオン性SHCLの種類等については、前記「(I)SHCL用点眼剤」と同様である。 In the method, the types and blending ratios of the components (A) and (B) to be used, the types and blending ratios of other components, the types of ionic SHCL to be applied, etc. It is the same as “eye drops for SHCL”.
以下に、実施例に基づいて本発明を詳細に説明するが、本発明はこれらの実施例によって限定されるものではない。
参考試験例1:プラノプロフェンのSCL透過性の比較評価
表1で示されるSCLを用いて、プラノプロフェンのレンズ透過性について評価した。
EXAMPLES The present invention will be described in detail below based on examples, but the present invention is not limited to these examples.
Reference Test Example 1: Comparative Evaluation of SCL Permeability of Planoprofen Using SCL shown in Table 1, the lens permeability of pranoprofen was evaluated.
プラノプロフェンのSCL透過性評価の測定は、膜透過実験装置(ビードレックス社製)を用いて以下の方法に従い実施した。表1に示す各ソフトコンタクトレンズを膜透過実験装置にセットし、一方のセルIには生理食塩水(0.9w/v%塩化ナトリウム)を5ml、他方のセルIIには0.05w/v%プラノプロフェン含有溶液(ホウ酸0.5w/v%、ホウ砂適量、塩化ナトリウム0.7w/v%;pH7.5)を5ml充填した。次いで、24時間後に生理食塩水側の液を1ml採取し、常法に従いHPLC法にてプラノプロフェンの濃度を測定し、セルIに移行したプラノプロフェンの量を算出した。斯くして算出されたセルIに移行したプラノプロフェンの量から、プラノプロフェンのレンズ透過率を下式に従って算出した。 The measurement of the SCL permeability evaluation of pranoprofen was performed according to the following method using a membrane permeation experiment apparatus (manufactured by Beadrex). Each soft contact lens shown in Table 1 was set in a membrane permeation experiment apparatus. One cell I had 5 ml of physiological saline (0.9 w / v% sodium chloride) and the other cell II had 0.05 w / v. 5 ml of a solution containing% pranoprofen (boric acid 0.5 w / v%, appropriate amount of borax, sodium chloride 0.7 w / v%; pH 7.5) was charged. Subsequently, 1 ml of the physiological saline solution was collected 24 hours later, and the concentration of pranoprofen was measured by an HPLC method according to a conventional method, and the amount of pranoprofen transferred to cell I was calculated. From the amount of pranoprofen transferred to cell I thus calculated, the lens transmittance of pranoprofen was calculated according to the following equation.
結果を図1に示す。図1から明らかなように、シリコーンハイドロゲルコンタクトレンズであるレンズA及びBでは、ハイドロゲルコンタクトレンズであるレンズCと比較して、著しくプラノプロフェンのレンズ透過性が悪いことが判明した。 The results are shown in FIG. As is apparent from FIG. 1, it was found that the lenses A and B, which are silicone hydrogel contact lenses, have significantly poorer lens transmission of pranoprofen than the lens C, which is a hydrogel contact lens.
試験例1:プラノプロフェンのレンズ透過試験1:
表2に示す点眼剤(実施例1及び比較例1)を用いて、プラノプロフェンのSHCL透過性について評価した。
Test Example 1: Planoprofen lens transmission test 1:
Using the eye drops shown in Table 2 (Example 1 and Comparative Example 1), pranoprofen was evaluated for SHCL permeability.
プラノプロフェンのSHCL透過性評価の測定は、膜透過実験装置(ビードレックス社製)を用いて以下の方法に従い実施した。表1に示すレンズB(SHCL)を膜透過実験装置にセットし、一方のセルIには生理食塩水(0.9w/v%塩化ナトリウム)を5mL、他方のセルIIには表2に示す各点眼剤を5mL正確に充填した。尚、各点眼剤の浸透圧はほぼ同じとなるように揃えた。次いで、24時間後に生理食塩水側の液を1mL採取し、常法に従いHPLC法によりプラノプロフェンの濃度を測定し、セルIに移行したプラノプロフェンの量を算出した。斯くして算出されたセルIに移行したプラノプロフェンの量から、参考試験例1と同様の方法でプラノプロフェンのレンズ透過率(%)を算出した。 Measurement of SHCL permeability evaluation of pranoprofen was carried out according to the following method using a membrane permeation experiment apparatus (manufactured by Beadrex). The lens B (SHCL) shown in Table 1 is set in a membrane permeation experiment apparatus. One cell I has 5 mL of physiological saline (0.9 w / v% sodium chloride), and the other cell II has Table 2 Each eye drop was accurately filled with 5 mL. Incidentally, the osmotic pressures of the respective eye drops were arranged to be substantially the same. Subsequently, 1 mL of the physiological saline solution was collected after 24 hours, and the concentration of pranoprofen was measured by an HPLC method according to a conventional method, and the amount of pranoprofen transferred to cell I was calculated. From the amount of pranoprofen transferred to cell I thus calculated, the lens transmittance (%) of pranoprofen was calculated in the same manner as in Reference Test Example 1.
結果を図2に示す。図2から明らかなように、実施例1の点眼剤ではプラノプロフェンのレンズ透過率が比較例1の点眼剤と比較して著しく増加していることが判明した。即ち、プラノプロフェンと非イオン性界面活性剤(ポリソルベート80)を併用することによって、SHCLへのプラノプロフェンの透過性が著しく向上することが確認された。 The results are shown in FIG. As apparent from FIG. 2, it was found that in the eye drop of Example 1, the lens transmittance of pranoprofen was remarkably increased as compared with the eye drop of Comparative Example 1. That is, it was confirmed that the use of pranoprofen and a nonionic surfactant (polysorbate 80) together significantly improved the permeability of pranoprofen to SHCL.
試験例2:プラノプロフェンのレンズ透過試験2:
表3に示す点眼剤(実施例2及び比較例2)を用いて、上記試験例1と同様の方法で、プラノプロフェンのSHCL透過性について評価した。
Test Example 2: Planoprofen lens transmission test 2:
Using the eye drops shown in Table 3 (Example 2 and Comparative Example 2), the SHCL permeability of pranoprofen was evaluated in the same manner as in Test Example 1 above.
結果を図3に示す。図3から分かるように、実施例2の点眼剤では、プラノプロフェンのレンズ透過率が比較例2の点眼剤と比較して著しく高い値を示した。即ち、本結果から、プラノプロフェンと陽イオン性界面活性剤(塩化ベンザルコニウム)を併用することによっても、SHCLへのプラノプロフェンの透過性が向上することが確認された。 The results are shown in FIG. As can be seen from FIG. 3, in the eye drop of Example 2, the lens transmittance of pranoprofen was significantly higher than that of the eye drop of Comparative Example 2. That is, from this result, it was confirmed that the use of pranoprofen and a cationic surfactant (benzalkonium chloride) also improves the permeability of pranoprofen to SHCL.
参考試験例2:塩酸ピリドキシンのレンズ透過性試験
塩酸ピリドキシンは、角膜細胞の新陳代謝を促進し、目の疲れを緩和させる作用を発揮することが知られている。そのため、SHCL用点眼剤に塩酸ピリドキシンを配合するにも、プラノプロフェン及び/又はその塩を配合する場合と同様に、塩酸ピリドキシンがSHCLを透過して角膜に到達できるように製剤設計することが求められる。そこで、SHCLへの塩酸ピリドキシンの透過性を評価するために、以下の試験を実施した。
Reference Test Example 2: Lens Permeability Test of Pyridoxine Hydrochloride Pyridoxine hydrochloride is known to exhibit the action of promoting metabolism of corneal cells and relieving eye fatigue. Therefore, even when pyridoxine hydrochloride is added to the eye drops for SHCL, the formulation can be designed so that pyridoxine hydrochloride can penetrate the SHCL and reach the cornea, as in the case of adding pranoprofen and / or a salt thereof. Desired. Therefore, the following tests were conducted to evaluate the permeability of pyridoxine hydrochloride to SHCL.
具体的には、表4に示す点眼剤(参考例1−2)を用いて、上記試験例1と同様の方法で試験を行い、塩酸ピリドキシンのSHCL透過性について評価した。 Specifically, using the eye drops shown in Table 4 (Reference Example 1-2), a test was performed in the same manner as in Test Example 1 above, and the SHCL permeability of pyridoxine hydrochloride was evaluated.
結果を図4に示す。この結果から、塩酸ピリドキシンは、プラノプロフェン及び/又はその塩と同様にSHCL透過性が低いものの、界面活性剤(ポリソルベート80)を併用してもSHCL透過性は向上しないことが確認された。 The results are shown in FIG. From this result, it was confirmed that pyridoxine hydrochloride has low SHCL permeability like pranoprofen and / or its salt, but SHCL permeability is not improved even when a surfactant (polysorbate 80) is used in combination.
レンズ透過性試験に関する総合考察
参考試験例1、試験例1及び2の結果に示すように、実施例1及び2の点眼剤において認められたSHCLに対する透過率は、非シリコーンハイドロゲルレンズ(表1のレンズC)に対する透過率と同程度にまで改善することができたことから、プラノプロフェンと界面活性剤との併用によって、SHCL用点眼剤に特有の課題を見事に解決できることが明らかとなった。また、かかる結果から、プラノプロフェン及び/又はその塩と界面活性剤を併用した点眼剤は、SHCL装用中の眼に適用しても有効量のプラノプロフェン及び/又はその塩が角膜に到達でき、プラノプロフェン及び/又はその塩に基づく薬理効果を有効に奏し得ることが確認された。
General Consideration Regarding Lens Permeability Test As shown in the results of Reference Test Example 1 and Test Examples 1 and 2, the transmittance for SHCL observed in the eye drops of Examples 1 and 2 is a non-silicone hydrogel lens (Table 1). As a result, it was clarified that the combination of pranoprofen and a surfactant can solve the problems specific to eye drops for SHCL. It was. In addition, based on these results, it was found that an eye drop comprising a combination of pranoprofen and / or a salt thereof and a surfactant can reach an effective amount of pranoprofen and / or a salt thereof even when applied to an eye wearing SHCL. It was confirmed that pharmacological effects based on pranoprofen and / or its salts can be effectively exhibited.
更に、このような界面活性剤との併用による有効成分のSHCL透過性の向上は、有効成分としてプラノプロフェン及び/又はその塩を選択することによって認められる特有の効果であることも確認された。 Furthermore, it was confirmed that the improvement of SHCL permeability of the active ingredient by the combined use with such a surfactant is a unique effect recognized by selecting pranoprofen and / or a salt thereof as the active ingredient. .
参考試験例3:SCLに対する花粉タンパク質吸着特性の評価
表5に示す4種のソフトコンタクトレンズを試験に用いて、ソフトコンタクトレンズに対する花粉タンパク質の吸着特性を評価した。
Reference Test Example 3: Evaluation of Pollen Protein Adsorption Characteristics to SCL Four kinds of soft contact lenses shown in Table 5 were used in the test to evaluate the pollen protein adsorption characteristics to the soft contact lenses.
まず、試験に使用するレンズを、生理食塩液4mLに1枚ずつ浸漬させ、室温にて一晩保存した(レンズの前処理)。 First, the lenses used for the test were immersed one by one in 4 mL of physiological saline and stored overnight at room temperature (lens pretreatment).
花粉タンパク質抗原((株)エル・エス・エル社製 Cedar Pollen Extract-Ja、性状:凍結乾燥粉末(Cedar Pollen粗抽出物 Mountain ceder、Juniperus Asheiiの花粉から抽出))を、生理食塩液に溶解し、5mg/30mL花粉タンパク質液を調製した。24穴プレートの各穴に、花粉タンパク質液1.0mLを入れ、前処理済みのレンズの余分な水分をふき取った後に浸漬し、34℃120rpmにて18時間振とうを行った。次いで、レンズを取り出し、生理食塩液100mLに素早く(約1秒)浸漬させて余分な液をすすいだ後、ビーカーのふちを使って軽く水分を切り、24穴プレートの各穴に入れた花粉タンパク質分離用液(1%炭酸ナトリウム及び1%SDS含有水溶液)1mLに浸漬させた。34℃120rpmで3時間振とうし、レンズに吸着した花粉タンパク質を花粉タンパク質分離用液中に分離させた。 Pollen protein antigen (Cedar Pollen Extract-Ja, manufactured by LSL, Inc., property: freeze-dried powder (Cedar Pollen crude extract Mountain ceder, extracted from pollen of Juniperus Asheii)) dissolved in physiological saline 5 mg / 30 mL pollen protein solution was prepared. In each hole of the 24-well plate, 1.0 mL of pollen protein solution was put, and after wiping off excess moisture from the pretreated lens, it was immersed and shaken at 34 ° C. and 120 rpm for 18 hours. Next, take out the lens, quickly soak (about 1 second) in 100 mL of physiological saline, rinse the excess liquid, and then lightly drain the water using the edge of a beaker, then put the pollen protein into each hole of the 24-well plate. It was immersed in 1 mL of separation liquid (aqueous solution containing 1% sodium carbonate and 1% SDS). The mixture was shaken at 34 ° C. and 120 rpm for 3 hours to separate the pollen protein adsorbed on the lens into the pollen protein separation solution.
マイクロBCAアッセイキット(Thermo SCIENTIFIC,Pierce #23235)を用いて、花粉タンパク質分離用液中の花粉タンパク質量を、アルブミン換算値として定量し、レンズに対する花粉タンパク質吸着量を求めた。 Using a micro BCA assay kit (Thermo SCIENTIFIC, Pierce # 23235), the amount of pollen protein in the pollen protein separation solution was quantified as an albumin equivalent value to determine the amount of pollen protein adsorbed to the lens.
なお、各ソフトコンタクトレンズの硬度は、上述のようにテクスチャーアナライザー(製品名:TA.XT.plus TEXTURE ANALYSER(Stable Micro Systems Limited製))を用いて測定した値である。 The hardness of each soft contact lens is a value measured using a texture analyzer (product name: TA.XT.plus TEXTURE ANALYSER (manufactured by Stable Micro Systems Limited)) as described above.
結果を図5に示す。図5に示されるように、イオン性SHCLであるレンズ1を用いた場合には、非シリコンソフトコンタクトレンズであるレンズ3及びレンズ4や、非イオン性SHCLであるレンズ2と比較すると、顕著に高い花粉タンパク質の吸着が認められた。この結果から、花粉タンパク質は、ソフトコンタクトレンズの中でもイオン性SHCLに対して極めて多量に吸着する傾向があり、イオン性SHCLには、花粉タンパク質を非常に吸着し易いという特有の課題が存在することが確認された。 The results are shown in FIG. As shown in FIG. 5, when the lens 1 that is ionic SHCL is used, the lens 3 and the lens 4 that are non-silicon soft contact lenses and the lens 2 that is non-ionic SHCL are remarkably different. High pollen protein adsorption was observed. From this result, pollen protein tends to adsorb very large amount to ionic SHCL among soft contact lenses, and ionic SHCL has a unique problem that it is very easy to adsorb pollen protein. Was confirmed.
試験例3:イオン性SHCLに対する花粉タンパク質の蓄積抑制の評価
上記参考試験例3にて花粉タンパク質の顕著な吸着が確認されたレンズ1(イオン性SHCL)を用いて、下記の試験を実施した。
Test Example 3 Evaluation of Inhibition of Pollen Protein Accumulation on Ionic SHCL The following test was carried out using the lens 1 (ionic SHCL) in which significant adsorption of pollen protein was confirmed in Reference Test Example 3 above.
先ず、レンズ1を、5mLの生理食塩液に1枚ずつ浸漬させ、5時間室温にて保存した(レンズの前処理)。花粉タンパク質抗原((株)エル・エス・エル社製 Cedar Pollen Extract-Ja、性状:凍結乾燥粉末(Cedar Pollen粗抽出物 Mountain ceder、Juniperus Asheiiの花粉から抽出))を生理食塩液に溶解し、5mg/50mL花粉タンパク質液を調製した。24穴プレートの各穴に、1.0mLの花粉タンパク質液を入れ、前処理したレンズの余分な水分をふき取った後に浸漬させ、34℃、400rpmで24時間振とうを行った。 First, the lenses 1 were immersed one by one in 5 mL of physiological saline and stored at room temperature for 5 hours (lens pretreatment). Pollen protein antigen (CEL Pollen Extract-Ja, manufactured by LSL Co., Ltd.) Properties: Lyophilized powder (Cedar Pollen crude extract Mountain ceder, extracted from pollen of Juniperus Asheii) in physiological saline, A 5 mg / 50 mL pollen protein solution was prepared. 1.0 mL of the pollen protein solution was put into each hole of the 24-well plate, the excess moisture of the pretreated lens was wiped off and immersed, and shaken at 34 ° C. and 400 rpm for 24 hours.
花粉タンパク質液に浸漬させたレンズ1を取り出し、生理食塩水100mLに素早く(約1秒)浸漬させて余分な液をすすいだ後、水分をふき取り、24穴プレートに入れた表6に記載の各試験液(実施例3−4、及びコントロール)1.0mLにそれぞれ浸漬して34℃、400rpmで18時間振とうを行った。その後、レンズ1を取り出し、生理食塩水100mLに素早く(約1秒)浸漬させて余分な液をすすいだ後、ビーカーのふちを使って、軽く水分を切り、24穴プレートに入れた花粉タンパク質分離用液(1%炭酸ナトリウム及び1%SDS含有水溶液)0.5mLに浸漬させた。34℃、400rpmで3時間振とうし、レンズに吸着していた花粉タンパク質を花粉タンパク質分離用液中に分離させた。 The lens 1 immersed in the pollen protein solution is taken out, quickly immersed (about 1 second) in 100 mL of physiological saline, rinsed with excess liquid, wiped off moisture, and placed in a 24-well plate. Each sample was immersed in 1.0 mL of the test solution (Example 3-4 and control) and shaken at 34 ° C. and 400 rpm for 18 hours. After that, take out the lens 1, soak it quickly (about 1 second) in 100 mL of physiological saline, rinse the excess liquid, and then use a beaker's edge to lightly drain the water and place it in a 24-well plate. It was immersed in 0.5 mL of the liquid for use (aqueous solution containing 1% sodium carbonate and 1% SDS). The mixture was shaken at 34 ° C. and 400 rpm for 3 hours to separate the pollen protein adsorbed on the lens into the pollen protein separation solution.
また、各試験液の影響を差し引くことによって、より正確に花粉タンパク質吸着量を算出するために、ブランク群として、花粉タンパク質液で処理する工程を生理食塩水での処理に変更した以外は、上記と同様に各試験液での処理と花粉タンパク質分離用液での処理を行ったものを用意した。 Moreover, in order to calculate the amount of pollen protein adsorption more accurately by subtracting the influence of each test solution, as a blank group, except that the step of treating with the pollen protein solution was changed to treatment with physiological saline, In the same manner as described above, a sample treated with each test solution and treated with a pollen protein separating solution was prepared.
マイクロBCAアッセイキット(Thermo SCIENTIFIC,Pierce #23235)を用いて、花粉タンパク質分離用液中に存在する花粉タンパク質の量を、アルブミン換算値として定量し、レンズ1から脱離した花粉タンパク質の量(花粉タンパク質吸着量)を求めた。なお、花粉タンパク質吸着量の算出に際して、各サンプルの吸光度から、上記ブランク群の吸光度を差し引いて、アルブミン換算値として算出することにより、花粉タンパク質吸着量を求めた。次いで、次式に従い、コントロール試験液を用いた場合の花粉タンパク質吸着量に対する、各実施例の試験液を用いた場合の花粉タンパク質吸着量の割合から、花粉タンパク質吸着改善率(%)を算出した。 Using a micro BCA assay kit (Thermo SCIENTIFIC, Pierce # 23235), the amount of pollen protein present in the pollen protein separation solution was quantified as an albumin equivalent, and the amount of pollen protein detached from lens 1 (pollen) Protein adsorption amount) was determined. In calculating the amount of pollen protein adsorbed, the amount of pollen protein adsorbed was determined by subtracting the absorbance of the blank group from the absorbance of each sample and calculating it as an albumin equivalent value. Then, according to the following formula, the pollen protein adsorption improvement rate (%) was calculated from the ratio of the pollen protein adsorption amount when using the test solution of each Example to the pollen protein adsorption amount when using the control test solution. .
結果を図6に示す。その結果、プラノプロフェンと界面活性剤とを組み合わせて用いた場合には、非常に高い花粉タンパク質吸着改善率が達成され、イオン性SHCLに対する花粉タンパク質の吸着量を効果的に低減でき、蓄積を抑制することができることが明らかとなった(実施例3)。また、このプラノプロフェンと界面活性剤に対して、塩酸ピリドキシンを更に組み合わせて用いた場合には(実施例4)、より格段顕著に高い花粉タンパク質蓄積抑制効果が得られることも明らかとなった。 The results are shown in FIG. As a result, when pranoprofen and a surfactant are used in combination, a very high pollen protein adsorption improvement rate is achieved, and the amount of pollen protein adsorbed on ionic SHCL can be effectively reduced and accumulated. It became clear that it can suppress (Example 3). It was also revealed that when this pranoprofen and surfactant were used in combination with pyridoxine hydrochloride (Example 4), a markedly higher pollen protein accumulation inhibitory effect was obtained. .
製剤例
表7に記載の処方で、SHCL用点眼剤(実施例5−23)が調製される。
Formulation Example With the formulation described in Table 7, an eye drop for SHCL (Example 5-23) is prepared.
Claims (10)
(a)プラノプロフェン類を含むコントロール溶液、並びにプラノプロフェン類と被験物質とを含む被験溶液を、試験溶液として各々調製する工程、
(b)上記試験溶液を各々、シリコーンハイドロゲルコンタクトレンズの片側面のみに所定時間接触させ、該レンズの上記試験溶液を接触させていない他方の片側面から滲出したプラノプロフェン類の量を測定することにより、各試験溶液のプラノプロフェン類の透過量を求める工程、並びに
(c)上記工程(b)において測定されたプラノプロフェン類の透過量が、コントロール溶液よりも多い被験溶液を選び、該被験溶液に含まれる被験物質を上記透過性向上物質として選択する工程、を含むスクリーニング方法。 A screening method for a permeability-improving substance for improving the permeability of at least one kind of pranoprofen selected from the group consisting of pranoprofen and a salt thereof for a silicone hydrogel contact lens,
(A) preparing a control solution containing pranoprofen and a test solution containing pranoprofen and a test substance as a test solution,
(B) Each of the test solutions is brought into contact with only one side of the silicone hydrogel contact lens for a predetermined time, and the amount of planoprofen exuded from the other side of the lens not contacting the test solution is measured. A test solution in which the amount of peranoprofen permeation of each test solution is determined, and (c) the amount of peranoprofen permeation measured in step (b) above is greater than that of the control solution. And a step of selecting a test substance contained in the test solution as the permeability improving substance.
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