JP2023172959A - Aqueous composition, method for improving antibacterial properties of aqueous composition, and method for producing aqueous composition - Google Patents
Aqueous composition, method for improving antibacterial properties of aqueous composition, and method for producing aqueous composition Download PDFInfo
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- JP2023172959A JP2023172959A JP2023085282A JP2023085282A JP2023172959A JP 2023172959 A JP2023172959 A JP 2023172959A JP 2023085282 A JP2023085282 A JP 2023085282A JP 2023085282 A JP2023085282 A JP 2023085282A JP 2023172959 A JP2023172959 A JP 2023172959A
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- aqueous composition
- epinastine
- aqueous
- concentration
- compound
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- 230000000844 anti-bacterial effect Effects 0.000 title claims abstract description 35
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- -1 biguanide compound Chemical class 0.000 claims abstract description 59
- WHWZLSFABNNENI-UHFFFAOYSA-N epinastine Chemical compound C1C2=CC=CC=C2C2CN=C(N)N2C2=CC=CC=C21 WHWZLSFABNNENI-UHFFFAOYSA-N 0.000 claims abstract description 56
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Abstract
Description
本発明は、水性組成物、水性組成物の抗菌性を高める方法、及び水性組成物の製造方法、に関する。 The present invention relates to an aqueous composition, a method for enhancing antibacterial properties of an aqueous composition, and a method for producing an aqueous composition.
エピナスチン又はその塩は、アレルギー性結膜炎の治療などの用途で、水性組成物（点眼液）として用いられている。点眼液には一般に防腐性が求められ、エピナスチン又はその塩を含有する点眼液についても防腐効力を付与する方法が検討されていた。例えば特許文献１は、０．１ｗ／ｖ％のエピナスチン又はその塩を含有し、防腐剤を含有しない点眼液が、日本薬局方に規定されている、Escherichia coli、Pseudomonas aeruginosa、Staphylococcus aureus、Candida albicans、及びAspergillus brasiliensisを用いた保存効力試験に適合することを開示している。また、特許文献２には、エピナスチン又はその塩と、エピナスチン又はその塩の含有量１重量部に対して０．１重量部以下の第四級アンモニウム化合物とを含有する水性組成物が記載されている。 Epinastine or a salt thereof is used as an aqueous composition (ophthalmic solution) for purposes such as the treatment of allergic conjunctivitis. Eye drops are generally required to have preservative properties, and methods for imparting preservative properties to eye drops containing epinastine or its salts have been studied. For example, Patent Document 1 discloses that an ophthalmic solution containing 0.1 w/v% epinastine or a salt thereof and containing no preservative is prescribed in the Japanese Pharmacopoeia for the treatment of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Candida albicans. , and Aspergillus brasiliensis. Further, Patent Document 2 describes an aqueous composition containing epinastine or a salt thereof and a quaternary ammonium compound of 0.1 part by weight or less per 1 part by weight of epinastine or a salt thereof. There is.
しかしながら、水性組成物の変質を防止するためには、水性組成物がより高い抗菌性を有することが望ましい。一方で、防腐剤は細胞傷害作用を有することが多いため、例えば眼に対する傷害を防ぐためには、防腐剤の使用量を抑えることが望ましい。 However, in order to prevent deterioration of the aqueous composition, it is desirable that the aqueous composition has higher antibacterial properties. On the other hand, since preservatives often have a cytotoxic effect, it is desirable to reduce the amount of preservatives used, for example in order to prevent damage to the eyes.
本発明は、細胞傷害作用を抑えながら、水性組成物の抗菌性を向上させることを目的とする。 The present invention aims to improve the antibacterial properties of aqueous compositions while suppressing cytotoxic effects.
本発明者らは、水性組成物を所定の組成にすることにより、防腐剤による細胞傷害作用を抑えながら、水性組成物の抗菌性を向上させることができることを見出した。さらに、本発明者らは、本発明の水性組成物においては、エピナスチン又はその塩の熱安定性が向上し、類縁物質の生成が抑制されることを見出した。すなわち本発明は以下に関する。
［１］エピナスチン又はその塩と、ビグアナイド系化合物と、を含む水性組成物であって、
組成物中のビグアナイド系化合物の濃度が、０．０５ｍｇ／ｍＬ以下である、水性組成物。
［２］前記ビグアナイド系化合物が、ポリヘキサメチレンビグアナイド、クロルヘキシジン及びこれらの塩から選択される一種以上である、［１］に記載の水性組成物。
［３］第四級アンモニウム化合物を含む、［１］又は［２］に記載の水性組成物。
［４］前記第四級アンモニウム化合物が、ベンザルコニウム塩及びベンゼトニウム塩から選択される一種以上である、［１］～［３］のいずれか１項に記載の水性組成物。
［５］組成物中の前記第四級アンモニウム化合物の濃度が、０．００００５～０．０５ｍｇ／ｍＬである、［３］又は［４］のいずれか１項に記載の水性組成物。
［６］Brevundimonas diminutaに対する抗菌性を有する、［１］～［５］のいずれか１項に記載の水性組成物。
［７］組成物中のエピナスチン又はその塩の濃度が０．７５ｍｇ／ｍＬ以上である、［１］～［６］のいずれか１項に記載の水性組成物。
［８］ｐＨが６以上８以下である、［１］～［７］のいずれか１項に記載の水性組成物。
［９］日本薬局方（第１８改正）に従う保存効力試験に適合する、［１］～［８］のいずれか１項に記載の水性組成物。
［１０］点眼液である、［１］～［９］のいずれか１項に記載の水性組成物。
［１１］エピナスチン又はその塩を含む水性組成物の抗菌性を高める方法であって、組成物中のビグアナイド系化合物の濃度が０．０５ｍｇ／ｍＬ以下となるように、前記水性組成物にビグアナイド系化合物を含有させることを含む、方法。
［１２］エピナスチン又はその塩を含む水性組成物の製造方法であって、
組成物中のビグアナイド系化合物の濃度が０．０５ｍｇ／ｍＬ以下となるように、前記水性組成物にビグアナイド系化合物を含有させることを含む、製造方法。
The present inventors have discovered that by making the aqueous composition into a predetermined composition, it is possible to improve the antibacterial properties of the aqueous composition while suppressing the cytotoxic effect of the preservative. Furthermore, the present inventors have found that in the aqueous composition of the present invention, the thermal stability of epinastine or its salt is improved, and the generation of related substances is suppressed. That is, the present invention relates to the following.
[1] An aqueous composition comprising epinastine or a salt thereof and a biguanide compound,
An aqueous composition in which the concentration of a biguanide compound is 0.05 mg/mL or less.
[2] The aqueous composition according to [1], wherein the biguanide compound is one or more selected from polyhexamethylene biguanide, chlorhexidine, and salts thereof.
[3] The aqueous composition according to [1] or [2], which contains a quaternary ammonium compound.
[4] The aqueous composition according to any one of [1] to [3], wherein the quaternary ammonium compound is one or more selected from benzalkonium salts and benzethonium salts.
[5] The aqueous composition according to any one of [3] or [4], wherein the concentration of the quaternary ammonium compound in the composition is 0.00005 to 0.05 mg/mL.
[6] The aqueous composition according to any one of [1] to [5], which has antibacterial properties against Brevundimonas diminuta.
[7] The aqueous composition according to any one of [1] to [6], wherein the concentration of epinastine or a salt thereof in the composition is 0.75 mg/mL or more.
[8] The aqueous composition according to any one of [1] to [7], which has a pH of 6 or more and 8 or less.
[9] The aqueous composition according to any one of [1] to [8], which complies with the preservative efficacy test according to the Japanese Pharmacopoeia (18th revision).
[10] The aqueous composition according to any one of [1] to [9], which is an eye drop.
[11] A method for increasing the antibacterial properties of an aqueous composition containing epinastine or a salt thereof, the method comprising adding a biguanide compound to the aqueous composition such that the concentration of the biguanide compound in the composition is 0.05 mg/mL or less. A method comprising incorporating a compound.
[12] A method for producing an aqueous composition containing epinastine or a salt thereof, comprising:
A manufacturing method comprising incorporating a biguanide compound into the aqueous composition so that the concentration of the biguanide compound in the composition is 0.05 mg/mL or less.
本発明によれば、細胞傷害作用を抑えながら、水性組成物の抗菌性を向上させることができる。 According to the present invention, the antibacterial properties of an aqueous composition can be improved while suppressing cytotoxic effects.
以下、実施形態を詳しく説明する。なお、以下の実施形態は特許請求の範囲に係る発明を限定するものではなく、また実施形態で説明されている特徴の組み合わせの全てが発明に必須のものとは限らない。実施形態で説明されている複数の特徴のうち二つ以上の特徴は任意に組み合わされてもよい。 Hereinafter, embodiments will be described in detail. Note that the following embodiments do not limit the claimed invention, and not all combinations of features described in the embodiments are essential to the invention. Two or more features among the plurality of features described in the embodiments may be arbitrarily combined.
（水性組成物）
本発明の一実施形態に係る水性組成物は、エピナスチン又はその塩と、ビグアナイド系化合物と、を含み、組成物中のビグアナイド系化合物の濃度が０．０５ｍｇ／ｍＬ以下である水性組成物である。この水性組成物は、防腐剤を含まない場合と比較して抗菌性が向上しており、一方で防腐剤を含まない場合と比較して、細胞傷害作用が実質的に増加していない。本発明において、水性組成物とは、少なくとも水を含有する組成物をいい、その性状は特に限定されない。水性組成物は、例えば、水を基剤とする、水溶液、水性懸濁液、エマルション等であってよい。このような水性組成物は点眼のために用いることができ、以下では水性組成物のことを点眼液と呼ぶことがある。
(Aqueous composition)
An aqueous composition according to an embodiment of the present invention contains epinastine or a salt thereof and a biguanide compound, and the concentration of the biguanide compound in the composition is 0.05 mg/mL or less. . This aqueous composition has improved antibacterial properties compared to the case without a preservative, while the cytotoxic effect is not substantially increased compared to the case without a preservative. In the present invention, the aqueous composition refers to a composition containing at least water, and its properties are not particularly limited. Aqueous compositions may be, for example, water-based aqueous solutions, suspensions, emulsions, and the like. Such aqueous compositions can be used for eye drops, and hereinafter the aqueous compositions may be referred to as eye drops.
エピナスチン(Epinastine)は、９，１３ｂ－ジヒドロ－１Ｈ－ジベンゾ［ｃ，ｆ］イミダゾ［１，５－ａ］アゼピン－３－アミンである。水性組成物が含んでいてもよいエピナスチンの塩の種類は特に限定されないが、例えばエピナスチン塩酸塩であってもよい。 Epinastine is 9,13b-dihydro-1H-dibenzo[c,f]imidazo[1,5-a]azepin-3-amine. The type of epinastine salt that may be contained in the aqueous composition is not particularly limited, and may be epinastine hydrochloride, for example.
水性組成物が含有するエピナスチン又はその塩の濃度は特に限定されない。例えば、エピナスチン又はその塩の濃度は、０．１ｍｇ／ｍＬ（０．０１ｗ／ｖ％）以上であってもよく、０．５ｍｇ／ｍＬ（０．０５ｗ／ｖ％）以上であってもよく、０．７５ｍｇ／ｍＬ（０．０７５ｗ／ｖ％）以上であってもよく、１ｍｇ／ｍＬ（０．１ｗ／ｖ％）以上であってもよい。また、エピナスチン又はその塩の濃度は、２ｍｇ／ｍＬ（０．２ｗ／ｖ％）以下であってもよい。 The concentration of epinastine or its salt contained in the aqueous composition is not particularly limited. For example, the concentration of epinastine or its salt may be 0.1 mg/mL (0.01 w/v%) or more, or 0.5 mg/mL (0.05 w/v%) or more, It may be 0.75 mg/mL (0.075 w/v%) or more, or it may be 1 mg/mL (0.1 w/v%) or more. Moreover, the concentration of epinastine or its salt may be 2 mg/mL (0.2 w/v%) or less.
ビグアナイド系化合物は、ビグアナイド骨格（Ｎ－Ｃ（＝Ｎ）－Ｎ－Ｃ（＝Ｎ）－Ｎ）を有する化合物である。ビグアナイド系化合物は、例えば、ポリヘキサニド（ポリヘキサメチレンビグアナイド）、クロルヘキシジン又はこれらの塩等であってよい。これらの１種又は２種以上を配合できる。 A biguanide compound is a compound having a biguanide skeleton (NC(=N)-NC(=N)-N). The biguanide compound may be, for example, polyhexanide (polyhexamethylene biguanide), chlorhexidine, or a salt thereof. One or more of these can be blended.
水性組成物中のビグアナイド系化合物の濃度は、例えば０．１ｍｇ／ｍＬ（０．０１ｗ／ｖ％）未満であってよく、好ましくは０．０５ｍｇ／ｍＬ（０．００５ｗ／ｖ％）以下であり、より好ましくは０．０３ｍｇ／ｍＬ（０．００３ｗ／ｖ％）以下であり、さらに好ましくは０．０１ｍｇ／ｍＬ（０．００１ｗ／ｖ％）以下であり、０．００５ｍｇ／ｍＬ（０．０００５ｗ／ｖ％）であってもよい。これらの濃度においては、細胞傷害作用及び類縁物質の増加が抑えられる。 The concentration of the biguanide compound in the aqueous composition may be, for example, less than 0.1 mg/mL (0.01 w/v%), preferably less than 0.05 mg/mL (0.005 w/v%). , more preferably 0.03 mg/mL (0.003 w/v%) or less, further preferably 0.01 mg/mL (0.001 w/v%) or less, 0.005 mg/mL (0.0005 w /v%). At these concentrations, cytotoxic effects and increases in related substances are suppressed.
また、水性組成物中のビグアナイド系化合物の濃度は、例えば０．０００１ｍｇ／ｍＬ以上であってよく、好ましくは０．００１ｍｇ／ｍＬ（０．０００１ｗ／ｖ％）以上であり、より好ましくは０．００１５ｍｇ／ｍＬ（０．０００１５ｗ／ｖ％）以上であり、さらに好ましくは０．００２ｍｇ／ｍＬ（０．０００２ｗ／ｖ％）である。水性組成物がこれらの濃度のビグアナイド系化合物を含有する場合、その抗菌性が向上され得る。
なお、前記した水性組成物中のビグアナイド系化合物の濃度の下限のいずれかと、前段落に記載した水性組成物中のビグアナイド系化合物の濃度の上限のいずれかとを組み合わせて、水性組成物中のビグアナイド系化合物の濃度範囲として表してもよい。
Further, the concentration of the biguanide compound in the aqueous composition may be, for example, 0.0001 mg/mL or more, preferably 0.001 mg/mL (0.0001 w/v%) or more, and more preferably 0.0001 mg/mL or more. 0015 mg/mL (0.00015 w/v%) or more, more preferably 0.002 mg/mL (0.0002 w/v%). When an aqueous composition contains these concentrations of biguanide compounds, its antibacterial properties may be improved.
In addition, by combining any of the lower limits of the concentration of the biguanide compound in the aqueous composition described above and any of the upper limits of the concentration of the biguanide compound in the aqueous composition described in the previous paragraph, It may also be expressed as a concentration range of the system compound.
水性組成物は、第四級アンモニウム化合物をさらに含有していてもよい。第四級アンモニウム化合物としては、ベンザルコニウム塩及びベンゼトニウム塩等が挙げられる。なお、これらの第四級アンモニウム化合物に結合する陰イオンの種類は特に限定されず、例えば第四級アンモニウム化合物として塩化ベンザルコニウム又は塩化ベンゼトニウム等を用いることができる。これらの１種又は２種以上を配合できる。 The aqueous composition may further contain a quaternary ammonium compound. Examples of the quaternary ammonium compound include benzalkonium salts and benzethonium salts. The type of anion that binds to these quaternary ammonium compounds is not particularly limited, and for example, benzalkonium chloride or benzethonium chloride can be used as the quaternary ammonium compound. One or more of these can be blended.
水性組成物中の第四級アンモニウム化合物の濃度は、例えば０．１ｍｇ／ｍＬ（０．０１ｗ／ｖ％）未満であってよく、好ましくは０．０５ｍｇ／ｍＬ（０．００５ｗ／ｖ％）以下であり、より好ましくは０．０３ｍｇ／ｍＬ（０．００３ｗ／ｖ％）以下であり、さらに好ましくは０．０１ｍｇ／ｍＬ（０．００１ｗ／ｖ％）以下であり、特に好ましくは０．００２ｍｇ／ｍＬ（０．０００２ｗ／ｖ％）以下である。これらの濃度においては、細胞傷害作用及び類縁物質の増加が抑えられる。 The concentration of the quaternary ammonium compound in the aqueous composition may be, for example, less than 0.1 mg/mL (0.01 w/v%), preferably 0.05 mg/mL (0.005 w/v%) or less. , more preferably 0.03 mg/mL (0.003 w/v%) or less, further preferably 0.01 mg/mL (0.001 w/v%) or less, particularly preferably 0.002 mg/mL mL (0.0002 w/v%) or less. At these concentrations, cytotoxic effects and increases in related substances are suppressed.
また、水性組成物中の第四級アンモニウム化合物の濃度は、例えば０．００００５ｍｇ／ｍＬ（０．０００００５ｗ／ｖ％）以上であってよく、好ましくは０．０００１ｍｇ／ｍＬ（０．００００１ｗ／ｖ％）以上であり、より好ましくは０．００２５ｍｇ／ｍＬ（０．０００２５ｗ／ｖ％）以上であり、さらに好ましくは０．００５ｍｇ／ｍＬ（０．０００５ｗ／ｖ％）以上である。水性組成物がこれらの濃度の第四級アンモニウム化合物を含有する場合、その抗菌性が向上され得る。
なお、前記した水性組成物中の第四級アンモニウム化合物の濃度の下限のいずれかと、前段落に記載した水性組成物中の第四級アンモニウム化合物の濃度の上限のいずれかとを組み合わせて、水性組成物中の第四級アンモニウム化合物の濃度範囲として表してもよい。
Further, the concentration of the quaternary ammonium compound in the aqueous composition may be, for example, 0.00005 mg/mL (0.000005 w/v%) or more, preferably 0.0001 mg/mL (0.00001 w/v%) or more. ) or more, more preferably 0.0025 mg/mL (0.00025 w/v%) or more, still more preferably 0.005 mg/mL (0.0005 w/v%) or more. When an aqueous composition contains these concentrations of quaternary ammonium compounds, its antibacterial properties may be improved.
In addition, by combining any of the lower limits of the concentration of the quaternary ammonium compound in the aqueous composition described above and any of the upper limits of the concentration of the quaternary ammonium compound in the aqueous composition described in the previous paragraph, the aqueous composition It may also be expressed as a concentration range of quaternary ammonium compounds in a substance.
一実施形態に係る水性組成物は、防腐剤を含まない場合と比較して、細胞傷害作用が実質的に増加していない。防腐剤とは、例えば、ビグアナイド系化合物や第四級アンモニウム化合物の他、クロロブタノール又はパラオキシ安息香酸エステル（例えば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又はパラオキシ安息香酸ブチル）のような、水酸基を有するアルコール系の防腐剤、亜塩素酸塩（例えば亜塩素酸ナトリウム）のような塩素系の防腐剤、ポリドロニウムのような陽イオンポリマー系の防腐剤等であり得る。例えば、水性組成物が、エピナスチン又はその塩と、防腐剤と、その他の成分と、のみからなる場合に、この水性組成物は、エピナスチン又はその塩と、その他の成分と、のみからなる水性組成物と比較して、細胞傷害作用が実質的に増加していない。本明細書において、「防腐剤」とは、水性組成物の抗菌性を高めることを目的に配合させる成分のことを指す。以下では、「防腐剤を含まない場合」とは、防腐剤を含まないことを除き同一組成を有することをいう。 The aqueous composition according to one embodiment does not have a substantially increased cytotoxic effect compared to a preservative-free composition. Preservatives include, for example, biguanide compounds and quaternary ammonium compounds, as well as chlorobutanol or paraoxybenzoic acid esters (for example, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, or butyl paraoxybenzoate). Examples include alcohol-based preservatives having a hydroxyl group, chlorine-based preservatives such as chlorite (eg, sodium chlorite), and cationic polymer-based preservatives such as polydronium. For example, when an aqueous composition consists only of epinastine or its salt, a preservative, and other ingredients, this aqueous composition consists only of epinastine or its salt and other ingredients. There is no substantial increase in cytotoxic effect compared to As used herein, the term "preservative" refers to a component that is added for the purpose of increasing the antibacterial properties of an aqueous composition. Hereinafter, the expression "not containing a preservative" refers to having the same composition except that it does not contain a preservative.
好ましくは、一実施形態に係る水性組成物は、防腐剤を含まない場合と比較して、角膜細胞傷害作用が実質的に増加していない。このような細胞傷害作用又は角膜細胞傷害作用は、角膜上皮細胞を水性組成物に所定の時間接触させた後に細胞生存率を測定するin vitro試験に基づいて評価することができる。角膜上皮細胞としては、例えば、ＳＩＲＣ（ウサギ角膜上皮細胞）を用いることができる。所定の時間は、特に限定されないが、例えば１０分間とすることができる。細胞生存率の測定は、当業者に公知の方法により実施することができ、その例としては、市販されている発色試薬を用いて、水性組成物との接触後の生細胞からの発色を吸光光度法により測定する方法が挙げられる。吸光光度法において、吸光度は、使用する発色試薬により適宜決めることができる。本明細書において、「細胞傷害作用が実質的に増加しない」とは、このような評価系において防腐剤を含まない水性組成物を用いて測定された細胞生存率の値に対する、各実施形態に係る水性組成物を用いて測定された細胞生存率の値の比率（各実施形態に係る水性組成物を用いて測定された細胞生存率（％）／防腐剤を含まない水性組成物を用いて測定された細胞生存率（％）×１００（％））が、７５％以上であることを意味する。好ましくは、防腐剤を含まない水性組成物を用いて測定された細胞生存率の値に対する、一実施形態に係る水性組成物を用いて測定された細胞生存率の値の比率は、８０％以上、８５％以上、９０％以上、９５％以上、又は９８％以上である。 Preferably, the aqueous composition according to one embodiment does not have a substantially increased corneal cytotoxic effect compared to a preservative-free composition. Such cytotoxic effect or corneal cytotoxic effect can be evaluated based on an in vitro test in which cell viability is measured after contacting corneal epithelial cells with an aqueous composition for a predetermined period of time. As the corneal epithelial cells, for example, SIRC (rabbit corneal epithelial cells) can be used. The predetermined time is not particularly limited, but may be, for example, 10 minutes. Measurement of cell viability can be carried out by methods known to those skilled in the art, such as using commercially available coloring reagents to absorb the color developed from living cells after contact with an aqueous composition. A method of measuring by photometry is mentioned. In the spectrophotometric method, the absorbance can be appropriately determined depending on the coloring reagent used. As used herein, "the cytotoxic effect does not substantially increase" refers to the cell viability value measured in each embodiment using an aqueous composition that does not contain a preservative in such an evaluation system. The ratio of the cell viability values measured using such aqueous compositions (cell viability (%) measured using the aqueous compositions according to each embodiment/the cell viability values measured using the aqueous compositions containing no preservatives) This means that the measured cell viability (%) x 100 (%)) is 75% or more. Preferably, the ratio of the cell viability value measured using the aqueous composition according to one embodiment to the cell viability value measured using the preservative-free aqueous composition is 80% or more. , 85% or more, 90% or more, 95% or more, or 98% or more.
本発明の水性組成物は、日本薬局方（第１８改正）に規定されている保存効力試験に適合する。「保存効力試験に適合する」とは、日本薬局方（第１８改正）に規定されている保存効力試験に従い、Escherichia coli、Pseudomonas aeruginosa、Staphylococcus aureus、Candida albicans、及びAspergillus brasiliensisを水性組成物に接種、混合し、経時的な試験菌の消長を追跡した場合において、同試験に規定されるカテゴリーＩＡの判定基準を満たすことをいう。カテゴリーＩＡの判定基準は、細菌については接種７日後に接種菌数に比べて１．０ｌｏｇ以上の減少があり、接種１４日後に接種菌数に比べて３．０ｌｏｇ以上の減少があり、接種２８日後には１４日後の菌数から増加していないこと、真菌については接種７日後、１４日後及び２８日後に接種菌数が増加していないこと、である。 The aqueous composition of the present invention complies with the preservative efficacy test prescribed in the Japanese Pharmacopoeia (18th revision). "Compatible with the preservative efficacy test" means that the aqueous composition is inoculated with Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans, and Aspergillus brasiliensis according to the preservative efficacy test specified in the Japanese Pharmacopoeia (18th revision). This means that when the test bacteria are mixed and the evolution of the test bacteria is tracked over time, they meet the criteria for Category IA specified in the test. The criteria for Category IA are that for bacteria, there is a decrease of 1.0 log or more compared to the number of inoculated bacteria 7 days after vaccination, a decrease of 3.0 log or more compared to the number of inoculated bacteria 14 days after vaccination, and 28 days after vaccination. The number of inoculated bacteria did not increase after 14 days, and the number of fungi did not increase after 7, 14, and 28 days after inoculation.
一実施形態に係る水性組成物は、防腐剤を含まない場合と比較して、水性組成物の抗菌性が向上している。一実施形態に係る水性組成物は、防腐剤を含まない場合と比較して、日本薬局方（第１８改正）に規定されている保存効力試験で用いられる、Escherichia coli、Pseudomonas aeruginosa、Staphylococcus aureus、Candida albicans、及びAspergillus brasiliensis以外の菌種のうちの少なくとも１つに対して、抗菌性を有する。このような菌種としては、水性組成物のろ過滅菌に使用されるフィルターを用いたろ過滅菌能力試験（チャレンジ試験）で用いられる代表的な指標菌であるBrevundimonas diminuta、細菌性角膜炎・結膜炎の主要起炎菌である肺炎球菌（Streptococcus pneumoniae）等が挙げられる。本明細書において、「水性組成物が抗菌性を有する」、又は「抗菌性を示す」等という場合、対象の菌種を水性組成物に接種し、所定の時間が経過した時点において、生菌数が菌接種時よりも、例えば１．０ｌｏｇ以上減少することをいう。所定の時間は、菌種に応じて適宜決めることができるが、Brevundimonas diminutaを用いる場合には、例えば、５分、３０分、１時間、３時間、６時間、２４時間又は３６時間、Streptococcus pneumoniaeを用いる場合には、例えば、５分、１０分、２０分、３０分又は１時間とすることができる。一実施形態において、水性組成物は、防腐剤を含まない場合には、このような菌種に対する抗菌性は示さないが、抗菌性を示すようになる。また、本明細書において、「水性組成物の抗菌性が向上する」とは、防腐剤を含まない場合と比較して、保存効力試験で用いられる、Escherichia coli、Pseudomonas aeruginosa、Staphylococcus aureus、Candida albicans、及びAspergillus brasiliensis以外の菌種のうちの少なくとも１つに対して抗菌性を有することのほか、防腐剤を含まない場合と比較して、菌数の減少速度が速くなることを意味する。 The aqueous composition according to one embodiment has improved antibacterial properties compared to a case where the aqueous composition does not contain a preservative. The aqueous composition according to one embodiment has Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, It has antibacterial properties against at least one species of bacteria other than Candida albicans and Aspergillus brasiliensis. Examples of such bacterial species include Brevundimonas diminuta, which is a typical indicator bacterium used in filtration sterilization ability tests (challenge tests) using filters used for filtration sterilization of aqueous compositions, and Brevundimonas diminuta, which is a typical indicator bacteria used in filtration sterilization ability tests (challenge tests) using filters used for filtration sterilization of aqueous compositions. Examples include Streptococcus pneumoniae, which is a major pathogen. In this specification, when we say that the aqueous composition has antibacterial properties or that it exhibits antibacterial properties, we inoculate the aqueous composition with the target bacterial species, and when a predetermined period of time has elapsed, viable bacteria This means that the number is reduced by, for example, 1.0 log or more compared to the time of bacterial inoculation. The predetermined time can be appropriately determined depending on the bacterial species, but when using Brevundimonas diminuta, for example, 5 minutes, 30 minutes, 1 hour, 3 hours, 6 hours, 24 hours or 36 hours, Streptococcus pneumoniae When using, for example, it can be 5 minutes, 10 minutes, 20 minutes, 30 minutes or 1 hour. In one embodiment, the aqueous composition does not exhibit antimicrobial properties against such bacterial species in the absence of preservatives, but becomes antimicrobial. In addition, in this specification, "the antibacterial properties of the aqueous composition are improved" means that Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Candida albicans, which are used in the preservative efficacy test, are In addition to having antibacterial properties against at least one of bacterial species other than Aspergillus brasiliensis and Aspergillus brasiliensis, this means that the bacterial count decreases faster than when no preservative is included.
本発明の水性組成物においては、エピナスチン又はその塩の熱安定性が向上し、類縁物質の生成が抑制され得る。エピナスチン又はその塩は長期の保存や高温、多湿での保存により類縁物質が生じることが知られる。エピナスチン又はその塩の類縁物質は、当業者に公知の方法により測定することができ、例えば、所定の温度や湿度の条件下で、所定の期間保存した後に、高速液体クロマトグラフ（ＨＰＬＣ）法により、水性組成物中の類縁物質を分析することにより評価することができる。所定の温度は、例えば、２５℃、３０℃、４０℃、５０℃、６０℃、７０℃等であってよく、限定されない。所定の湿度は、例えば、５０％ＲＨ、５５％ＲＨ、６０％ＲＨ、６５％ＲＨ、７０％ＲＨ、７５％ＲＨ、８０％ＲＨ等の相対湿度の範囲であってよく、限定されない。所定の期間は、例えば、１週間、２週間、３週間、４週間、５週間、６週間又は１か月、２か月、３か月、４か月、５か月、６か月等であってよく、限定されない。エピナスチン又はその塩の類縁物質としては、例えば、3-Amino-1,13b-dihydro-9H-dibenz [c,f] imidazo [1,5-a] azepin-9-one hydrochloride（本明細書では分解物Ａという場合もある。）、3-Amino-9H-dibenz [c,f] imidazo [1,5-a] azepine hydrochloride（本明細書では分解物Ｂという場合もある。）、6-Aminomethyl-6,11-dihydro-5H-dibenz [b,e] azepine fumarate、3-Amino-7-chloro-9,13b-dihydro-1H-dibenz [c,f] imidazo [1,5-a] azepine hydrochloride、3-Amino-7-bromo-9,13b-dihydro-1H-dibenz [c,f] imidazo [1,5-a] azepine hydrobromide等が知られる。本明細書において、「熱安定性が向上する（した）」、あるいは「類縁物質の生成が抑制される」という場合、これらの類縁物質のうちの１以上の生成、又はこれらの類縁物質を含む類縁物質量の合計が対照と比較して少なくなることをいう。 In the aqueous composition of the present invention, the thermal stability of epinastine or its salt can be improved, and the generation of related substances can be suppressed. Epinastine or its salts are known to produce related substances when stored for long periods of time, at high temperatures, and at high humidity. Epinastine or analogues of its salts can be measured by methods known to those skilled in the art, for example, after storage for a predetermined period under predetermined temperature and humidity conditions, by high performance liquid chromatography (HPLC) method. can be evaluated by analyzing related substances in the aqueous composition. The predetermined temperature may be, for example, 25°C, 30°C, 40°C, 50°C, 60°C, 70°C, etc., and is not limited. The predetermined humidity may be, for example, a range of relative humidity such as 50% RH, 55% RH, 60% RH, 65% RH, 70% RH, 75% RH, 80% RH, etc., and is not limited. The predetermined period is, for example, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, etc. Possible, not limited. Examples of analogues of epinastine or its salts include 3-Amino-1,13b-dihydro-9H-dibenz [c,f] imidazo [1,5-a] azepin-9-one hydrochloride (herein referred to as decomposition). ), 3-Amino-9H-dibenz [c,f] imidazo [1,5-a] azepine hydrochloride (herein sometimes referred to as decomposition product B), 6-Aminomethyl- 6,11-dihydro-5H-dibenz [b,e] azepine fumarate, 3-Amino-7-chloro-9,13b-dihydro-1H-dibenz [c,f] imidazo [1,5-a] azepine hydrochloride, Known examples include 3-Amino-7-bromo-9,13b-dihydro-1H-dibenz [c,f] imidazo [1,5-a] azepine hydrobromide. In this specification, when "thermal stability is improved" or "the production of related substances is suppressed", it refers to the production of one or more of these related substances, or includes the production of one or more of these related substances. This means that the total amount of related substances is lower than that of the control.
水性組成物は第四級アンモニウム化合物及びビグアナイド系化合物以外の１種以上の防腐剤を含んでいてもよいが、水性組成物中のそれらの濃度は、細胞傷害作用が実質的に増加しない範囲である。すなわち、水性組成物は、細胞傷害作用が実質的に増加する濃度の、第四級アンモニウム化合物及びビグアナイド系化合物以外の防腐剤を含有しない。本明細書において、「細胞傷障害作用が実質的に増加する」とは、細胞生存率を一定以上低下させることであり、本明細書の段落［００２０］に記載したin vitro試験において、防腐剤を含まない水性組成物を用いて測定された細胞生存率の値に対する、防腐剤を含む水性組成物を用いて測定された細胞生存率の値の比率（防腐剤を含む水性組成物を用いて測定された細胞生存率（％）／防腐剤を含まない水性組成物を用いて測定された細胞生存率（％）×１００（％））が、例えば、７５％未満、５０％未満、４０％未満、３０％未満、又は２０％未満となることをいう。水性組成物が含有する防腐剤の種類は、第四級アンモニウム化合物及びビグアナイド系化合物以外には、例えば、パラオキシ安息香酸エステル及びクロロブタノールのようなアルコール系化合物、並びに亜塩素酸塩のような塩素酸化物系化合物等であり得る。 The aqueous composition may contain one or more preservatives other than quaternary ammonium compounds and biguanides, but the concentration thereof in the aqueous composition may be such that the cytotoxic effect is not substantially increased. be. That is, the aqueous composition does not contain preservatives other than quaternary ammonium compounds and biguanide compounds at concentrations that substantially increase cytotoxic effects. As used herein, "the cell injury-damaging effect substantially increases" means that the cell survival rate decreases beyond a certain level, and in the in vitro test described in paragraph [0020] of the present specification, the preservative The ratio of cell viability values measured using an aqueous composition containing a preservative to values of cell viability measured using an aqueous composition containing no preservative. Measured cell viability (%)/cell viability measured using an aqueous composition that does not contain preservatives x 100 (%)) is, for example, less than 75%, less than 50%, 40% less than 30%, or less than 20%. In addition to quaternary ammonium compounds and biguanide compounds, the types of preservatives contained in the aqueous composition include, for example, alcohol compounds such as paraoxybenzoic acid ester and chlorobutanol, and chlorine compounds such as chlorite. It may be an oxide compound or the like.
水性組成物は、好ましくは、ビグアナイド系化合物及び第四級アンモニウム化合物以外の防腐剤を含有しない。 The aqueous composition preferably does not contain preservatives other than biguanide compounds and quaternary ammonium compounds.
上記の各実施形態に係る水性組成物が含む水は、特に限定されないが、好ましくは精製水、滅菌精製水、注射用水等である。
水性組成物のｐＨは、点眼可能であれば特に制限されないが、眼への刺激を低減する観点から、例えば６以上又は６．５以上であってもよく、８以下又は７．５以下であってもよい。
The water contained in the aqueous composition according to each of the above embodiments is not particularly limited, but preferably purified water, sterile purified water, water for injection, etc.
The pH of the aqueous composition is not particularly limited as long as it can be instilled into the eyes, but from the viewpoint of reducing eye irritation, it may be, for example, 6 or more or 6.5 or more, or 8 or less or 7.5 or less. It's okay.
水性組成物は、その他の添加剤を含んでいてもよい。添加剤の例としては、安定化剤、等張化剤、緩衝剤、ｐＨ調節剤、粘稠化剤、界面活性剤等が挙げられる。 The aqueous composition may also contain other additives. Examples of additives include stabilizers, tonicity agents, buffers, pH adjusters, thickeners, surfactants, and the like.
安定化剤の例としては、アスコルビン酸、トコフェロール、ジブチルヒドロキシトルエン、及びポピドン等が挙げられる。 Examples of stabilizers include ascorbic acid, tocopherol, dibutylhydroxytoluene, povidone, and the like.
等張化剤の例としては、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、プロピレングリコール、ポリエチレングリコール、グルコース、ソルビトール、マンニトール、トレハロース、マルトース、及びスクロース等が挙げられる。 Examples of tonicity agents include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, glycerin, propylene glycol, polyethylene glycol, glucose, sorbitol, mannitol, trehalose, maltose, and sucrose.
緩衝剤の例としては、リン酸又はその塩、クエン酸又はその塩、酢酸又はその塩、炭酸又はその塩、酒石酸又はその塩、ホウ酸又はその塩、及びトロメタモール等が挙げられる。 Examples of buffering agents include phosphoric acid or its salts, citric acid or its salts, acetic acid or its salts, carbonic acid or its salts, tartaric acid or its salts, boric acid or its salts, and trometamol.
ｐＨ調節剤の例としては、塩酸、リン酸、クエン酸、酢酸、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、及び炭酸水素ナトリウム等が挙げられる。 Examples of pH adjusters include hydrochloric acid, phosphoric acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydrogen carbonate.
粘稠化剤の例としては、カルボキシビニルポリマー、ポリビニルアルコール、ヒドロキシエチルセルロース、ヒプロメロース、メチルセルロース、及びグリセリン等が挙げられる。 Examples of thickening agents include carboxyvinyl polymers, polyvinyl alcohol, hydroxyethylcellulose, hypromellose, methylcellulose, glycerin, and the like.
界面活性剤の例としては、ポリオキシエチレン硬化ヒマシ油、モノステアリン酸ポリオキシエチレングリコール、ポリソルベート、ポリオキシエチレンポリオキシプロピレングリコール、及びショ糖脂肪酸エステル等が挙げられる。 Examples of surfactants include polyoxyethylene hydrogenated castor oil, polyoxyethylene glycol monostearate, polysorbate, polyoxyethylene polyoxypropylene glycol, and sucrose fatty acid ester.
一実施形態に係る水性組成物の浸透圧比は、特に限定されないが、眼への刺激を低減する観点から、０．６０以上、又は０．８０以上であってもよく、０．９０以上であることが好ましい。一方で、１．４０以下、又は１．２０以下であってもよく、１．１０以下であることが好ましい。浸透圧比とは、生理食塩水に対する浸透圧比である。 The osmotic pressure ratio of the aqueous composition according to one embodiment is not particularly limited, but from the viewpoint of reducing eye irritation, it may be 0.60 or more, or 0.80 or more, and is 0.90 or more. It is preferable. On the other hand, it may be 1.40 or less, or 1.20 or less, and is preferably 1.10 or less. The osmotic pressure ratio is the osmotic pressure ratio to physiological saline.
（容器等）
一実施形態に係る水性組成物は、患者への点眼用に用いることができる。また、一実施形態に係る水性組成物は、保存安定性及び携帯性等の観点から、容器に収容することができる。容器は、水性組成物を直接的に収容する包装体のことである。容器は、第十八改正日本薬局方通則に定義される「密閉容器」、「気密容器」、及び「密封容器」のいずれかである。
(containers, etc.)
The aqueous composition according to one embodiment can be used for eye drops to a patient. Moreover, the aqueous composition according to one embodiment can be stored in a container from the viewpoints of storage stability, portability, and the like. A container refers to a package that directly contains an aqueous composition. The container is one of "airtight container", "airtight container", and "sealed container" defined in the 18th revised Japanese Pharmacopoeia General Rules.
また、水性組成物は、エチレンオキサイドガスや過酸化水素等のガスで滅菌処理された容器に収容されてもよい。ガス滅菌処理で使用されるガスの種類については、特に制限されないが、例えば、エチレンオキサイドガス、過酸化水素ガス、これらと二酸化炭素等との混合ガス等が挙げられる。水性組成物は、ガンマ線照射及び電子線照射等の放射線で滅菌処理された容器に収容されていてもよい。 Further, the aqueous composition may be stored in a container sterilized with a gas such as ethylene oxide gas or hydrogen peroxide. The type of gas used in the gas sterilization process is not particularly limited, and examples thereof include ethylene oxide gas, hydrogen peroxide gas, and a mixed gas of these and carbon dioxide and the like. The aqueous composition may be housed in a container that has been sterilized with radiation such as gamma irradiation and electron beam irradiation.
容器の形態は、水性組成物を収容可能である容器であれば良く、剤形等に応じて適宜選択されても良い。容器の形態は、例えば、注射剤用容器、吸入剤用容器、スプレー剤用容器、ボトル状容器、チューブ状容器、点眼剤用容器、点鼻剤用容器、点耳剤用容器、及びバッグ容器等を含む。また、水性組成物を収容した容器は、箱及び袋等によって更に包装されていても良い。 The shape of the container may be any container that can accommodate the aqueous composition, and may be appropriately selected depending on the dosage form and the like. Container forms include, for example, injection containers, inhalant containers, spray containers, bottle-shaped containers, tube-shaped containers, eye drops containers, nasal drops containers, ear drops containers, and bag containers. Including etc. Further, the container containing the aqueous composition may be further packaged in a box, bag, or the like.
容器の材質は、容器の形態に応じて適宜選択され得る材料であって良い。容器の材質は、例えば、ガラス、プラスチック、セルロース、パルプ、ゴム、及び金属等を含む。容器の材質は、加工性、スクイズ性及び耐久性の観点から、プラスチックであって良い。 The material of the container may be appropriately selected depending on the form of the container. The material of the container includes, for example, glass, plastic, cellulose, pulp, rubber, and metal. The material of the container may be plastic from the viewpoints of processability, squeezeability, and durability.
プラスチック製容器に用いる樹脂は、熱可塑性樹脂である。熱可塑性樹脂は、例えば、ポリオレフィン系樹脂、ポリエステル系樹脂、ポリフェニレンエーテル系樹脂、ポリカーボネート系樹脂、ポリスルホン系樹脂、ポリアミド系樹脂、ポリ塩化ビニル樹脂、及びスチレン系樹脂を含む。 The resin used for the plastic container is a thermoplastic resin. Thermoplastic resins include, for example, polyolefin resins, polyester resins, polyphenylene ether resins, polycarbonate resins, polysulfone resins, polyamide resins, polyvinyl chloride resins, and styrene resins.
ポリオレフィン系樹脂は、例えば、低密度ポリエチレン（直鎖状低密度ポリエチレンを含む）、高密度ポリエチレン、中密度ポリエチレン、ポリプロピレン、環状ポリオレフィン等を含む樹脂である。 Polyolefin resins include, for example, low density polyethylene (including linear low density polyethylene), high density polyethylene, medium density polyethylene, polypropylene, cyclic polyolefin, and the like.
ポリエステル系樹脂は、例えば、ポリエチレンテレフタレート、ポリブチレンテレフタレート、ポリエチレンナフタレート、ポリブチレンナフタレート、ポリ（１，４－シクロヘキシレンジメチレンテレナフタレート）等を含む樹脂である。 The polyester resin includes, for example, polyethylene terephthalate, polybutylene terephthalate, polyethylene naphthalate, polybutylene naphthalate, poly(1,4-cyclohexylene dimethylene telenaphthalate), and the like.
なお、プラスチック製容器に用いる樹脂は、上記の２以上の樹脂を組み合わせた混合体（ポリマーアロイ）であっても良い。 Note that the resin used for the plastic container may be a mixture (polymer alloy) of two or more of the above resins.
一実施形態において、水性組成物は、変色抑制作用の観点から、ポリオレフィン系樹脂製容器に収容される。本明細書において「ポリオレフィン系樹脂製容器」とは、容器のうち少なくとも水性組成物と接する部分が「ポリオレフィン系樹脂製」である容器を意味する。したがって、例えば、水性組成物と接する内層にポリオレフィン層を設け、その外側に他の材質の樹脂等を積層等させてなる容器も、「ポリオレフィン系樹脂製容器」に該当する。ポリオレフィン系樹脂は特に限定されず、単一種のモノマーの重合体（ホモポリマー）であっても、複数種のモノマーの共重合体（コポリマー）であってもよい。また、コポリマーである場合においては、その重合様式は特に限定されず、ランダム重合でもブロック重合でもよい、さらにその立体規則性（タクティシティー）は特に限定されない。 In one embodiment, the aqueous composition is housed in a polyolefin resin container from the viewpoint of inhibiting discoloration. As used herein, the term "container made of polyolefin resin" means a container in which at least a portion of the container that comes into contact with the aqueous composition is "made of polyolefin resin." Therefore, for example, a container in which a polyolefin layer is provided on the inner layer in contact with the aqueous composition and a resin of another material is laminated on the outside also falls under the category of "polyolefin resin container." The polyolefin resin is not particularly limited, and may be a polymer of a single type of monomer (homopolymer) or a copolymer of multiple types of monomers (copolymer). Further, in the case of a copolymer, its polymerization mode is not particularly limited, and may be random polymerization or block polymerization, and its stereoregularity (tacticity) is not particularly limited.
ポリオレフィン系樹脂は、ポリプロピレンであって良い。ポリオレフィン系樹脂製容器は、紫外線吸収剤及び紫外線散乱剤等の紫外線の透過を妨げる物質を有していても良い。 The polyolefin resin may be polypropylene. The polyolefin resin container may contain a substance that prevents the transmission of ultraviolet rays, such as an ultraviolet absorber and an ultraviolet scattering agent.
一実施形態において、紫外線吸収剤は、例えば、２－（２Ｈ－ベンゾトリアゾール－２－イル）－ｐ－クレゾール（例えば、Ｔｉｎｕｖｉｎ Ｐ：ＢＡＳＦ社）、２－（２Ｈ－ベンゾトリアゾール－２－イル）－４，６－ビス（１－メチル－１－フェニルエチル）フェノール（例えば、Ｔｉｎｕｖｉｎ ２３４：ＢＡＳＦ社）である。 In one embodiment, the UV absorber is, for example, 2-(2H-benzotriazol-2-yl)-p-cresol (e.g. Tinuvin P: BASF), 2-(2H-benzotriazol-2-yl) -4,6-bis(1-methyl-1-phenylethyl)phenol (eg, Tinuvin 234: BASF).
一実施形態において、紫外線散乱剤は、例えば、酸化チタン及び酸化亜鉛等である。 In one embodiment, the UV scattering agent is, for example, titanium oxide and zinc oxide.
一実施形態において、水性組成物はマルチドーズ型容器に収容される。マルチドーズ型容器は、複数回分の使用量の水性組成物を保持し、繰返し使用可能な容器のことをいう。例えば、マルチドーズ型容器は、マルチドーズ型保存剤フリー容器と通常のマルチドーズ型容器とを含む。 In one embodiment, the aqueous composition is contained in a multi-dose container. A multi-dose container is a container that can hold multiple doses of an aqueous composition and can be used repeatedly. For example, multi-dose containers include multi-dose preservative-free containers and conventional multi-dose containers.
マルチドーズ型保存剤フリー容器は、マルチドーズ型容器の外側に浸出した水性組成物がマルチドーズ型容器内へ逆流することを防止する機構、及び、異物がマルチドーズ型容器内へ混入することを防止する機構を有する。マルチドーズ型保存剤フリー容器は、逆流防止弁、マイクロフィルター、及び特殊な二重構造容器等の構造を有する。 The multi-dose preservative-free container has a mechanism that prevents the aqueous composition that has leaked out of the multi-dose container from flowing back into the multi-dose container, and a mechanism that prevents foreign matter from entering the multi-dose container. It has a mechanism to prevent this. The multi-dose preservative-free container has structures such as a backflow prevention valve, a microfilter, and a special double-walled container.
通常のマルチドーズ型容器は、上記の機構を有していないマルチドーズ型容器のことである。なお、通常のマルチドーズ型容器において水性組成物が収容される場合、水性組成物の製造時のろ過滅菌工程にて、水性組成物をフィルターに通過させる必要がある。 A normal multi-dose container is a multi-dose container that does not have the above mechanism. In addition, when an aqueous composition is accommodated in a normal multi-dose type container, it is necessary to pass the aqueous composition through a filter in the filtration sterilization step during production of the aqueous composition.
なお、本実施形態における水性組成物は、ユニットドーズ型容器に収容されても良い。ユニットドーズ型容器は、単回分の使用量の水性組成物を保持し、１回の点眼で使用済みとなる容器のことをいう。 In addition, the aqueous composition in this embodiment may be accommodated in a unit dose type container. A unit dose type container is a container that holds a single dose of an aqueous composition and is used after one eye drop.
本発明の水性組成物は、フィルターを通過させる工程を経て患部へ提供される。ここで、「フィルター」とは、水性組成物を通過させるが、細菌及び真菌を通過させない多孔性膜を指す。フィルターの細孔径としては、通常５μｍ以下であればよいが、好ましくは０．１～２．５μｍ、更に好ましくは０．２～１μｍが挙げられる。本発明の水性組成物は、フィルター付き容器に収容され、使用時に容器のフィルターを通過させて容器外に注出されてもよい。また、本発明の水性組成物は、水性組成物の製造時のろ過滅菌工程でフィルターを通過させた水性組成物であってもよい。フィルターの素材については、特に制限されないが、例えば、ポリエーテルスルホン、ポリフッ化ビニリデン、ポリカーボネート、ポリテトラフルオロエチレン、セルロース混合エステル、ナイロン、ポリアミド等が挙げられる。 The aqueous composition of the present invention is provided to the affected area after passing through a filter. Here, "filter" refers to a porous membrane that allows aqueous compositions to pass through, but not bacteria and fungi. The pore diameter of the filter is usually 5 μm or less, preferably 0.1 to 2.5 μm, more preferably 0.2 to 1 μm. The aqueous composition of the present invention may be stored in a container with a filter, and when used, may be poured out of the container through the filter of the container. Further, the aqueous composition of the present invention may be an aqueous composition passed through a filter in a filtration sterilization step during production of the aqueous composition. The material of the filter is not particularly limited, and examples thereof include polyether sulfone, polyvinylidene fluoride, polycarbonate, polytetrafluoroethylene, cellulose mixed ester, nylon, and polyamide.
（水性組成物の製造方法及び抗菌性を高める方法）
水性組成物の製造方法は特に限定されない。エピナスチン又はその塩と、ビグアナイド系化合物と、必要に応じてその他の添加剤とを、水に溶解することにより、水性組成物を製造することができる。
(Method for producing aqueous composition and method for enhancing antibacterial properties)
The method for producing the aqueous composition is not particularly limited. An aqueous composition can be produced by dissolving epinastine or a salt thereof, a biguanide compound, and other additives as necessary in water.
本発明の一実施形態は、エピナスチン又はその塩を含む水性組成物の抗菌性を高める方法に関する。この方法は、水性組成物中のビグアナイド系化合物の濃度が０．０５ｍｇ／ｍＬ以下となるように、前記水性組成物にビグアナイド系化合物を含有させることを含む。 One embodiment of the present invention relates to a method of increasing the antibacterial properties of an aqueous composition comprising epinastine or a salt thereof. This method includes incorporating a biguanide compound into the aqueous composition such that the concentration of the biguanide compound in the aqueous composition is 0.05 mg/mL or less.
また、本発明の一実施形態は、エピナスチン又はその塩を含む水性組成物の製造方法に関する。この方法は、水性組成物中のビグアナイド系化合物の濃度が０．０５ｍｇ／ｍＬ以下となるように、前記水性組成物にビグアナイド系化合物を含有させることを含む。 Further, one embodiment of the present invention relates to a method for producing an aqueous composition containing epinastine or a salt thereof. This method includes incorporating a biguanide compound into the aqueous composition such that the concentration of the biguanide compound in the aqueous composition is 0.05 mg/mL or less.
また、本発明のエピナスチン又はその塩を含む水性組成物の抗菌性を高める方法及び製造方法の一実施形態は、第四級アンモニウム化合物を含有させる工程をさらに含んでいてもよい。 Further, an embodiment of the method for increasing the antibacterial properties of an aqueous composition containing epinastine or a salt thereof of the present invention and the manufacturing method may further include a step of containing a quaternary ammonium compound.
これらの実施形態におけるエピナスチン又はその塩の量、ビグアナイド系化合物の種類及びその量、並びにその他の成分の種類及び量等は、既に説明したように選択することができる。 In these embodiments, the amount of epinastine or its salt, the type and amount of the biguanide compound, the type and amount of other components, etc. can be selected as described above.
（実施例１）
ビグアナイド系化合物、第四級アンモニウム化合物の細胞傷害作用を評価した。評価には、均一な密度でＳＩＲＣ（ウサギ角膜上皮細胞）が播種された９６ウェルプレートを用いた。まず、試験溶液を各ウェルに添加し、１０分間静置した後、試験溶液を除去して各ウェルをＰＢＳで洗浄した。試験溶液としては、それぞれ０、０．００１、０．００２、０．０１、０．０３、０．０５、０．１、及び０．２ｍｇ／ｍＬの、塩酸ポリヘキサニド又は塩化ベンザルコニウムのＭＥＭ溶液を用いた。また、対照群として、試験溶液を添加せずに同様の評価を実施した。
(Example 1)
The cytotoxic effects of biguanide compounds and quaternary ammonium compounds were evaluated. For the evaluation, a 96-well plate in which SIRC (rabbit corneal epithelial cells) were seeded at a uniform density was used. First, a test solution was added to each well and left to stand for 10 minutes, then the test solution was removed and each well was washed with PBS. The test solutions were MEM solutions of polyhexanide hydrochloride or benzalkonium chloride at 0, 0.001, 0.002, 0.01, 0.03, 0.05, 0.1, and 0.2 mg/mL, respectively. was used. Furthermore, as a control group, similar evaluations were conducted without adding the test solution.
その後、各ウェルに発色試薬を添加し、２時間培養した。培養後、マイクロプレートリーダーで４９２ｎｍにおける吸光度を測定した。また、ＳＩＲＣを播種していないウェルにも発色試薬を添加し、同様に吸光度を測定することにより、バックグラウンドの吸光度を得た。試験溶液群について測定された吸光度から、バックグラウンドの吸光度を差し引いた値（補正値）を、データ解析に使用した。 Thereafter, a coloring reagent was added to each well and cultured for 2 hours. After culturing, absorbance at 492 nm was measured using a microplate reader. In addition, a coloring reagent was added to wells in which SIRC was not seeded, and the absorbance was measured in the same manner to obtain the background absorbance. The value obtained by subtracting the background absorbance from the absorbance measured for the test solution group (corrected value) was used for data analysis.
上記の測定を各試験溶液について５回ずつ行ったところ、以下の解析結果が得られた。下表において、細胞生存率（％）＝各試験溶液についての平均吸光度（補正値）／対照群の平均吸光度（補正値）×１００である。また、下表において、「ＢＡＣ」は塩化ベンザルコニウムを含む試験溶液を用いた場合の生存率を、「ＰＨＭＢ」は塩酸ポリヘキサニドを含む試験溶液を用いた場合の生存率を、それぞれ示す。 When the above measurements were performed five times for each test solution, the following analytical results were obtained. In the table below, cell viability (%) = average absorbance (corrected value) for each test solution/average absorbance (corrected value) of control group x 100. In the table below, "BAC" indicates the survival rate when using a test solution containing benzalkonium chloride, and "PHMB" indicates the survival rate when using a test solution containing polyhexanide hydrochloride.
上記の結果より、ビグアナイド系化合物又は第四級アンモニウム化合物の濃度が０．０５ｍｇ／ｍＬ以下である場合に、細胞生存率は防腐剤の濃度が０ｍｇ／ｍＬである場合に対して７５％以上を維持しており、ビグアナイド系化合物又は第四級アンモニウム化合物の添加により細胞傷害作用が実質的に増加しないことが確認された。特に、ビグアナイド系化合物又は第四級アンモニウム化合物の濃度が０．０３ｍｇ／ｍＬ以下である場合には、細胞生存率は防腐剤を含まない場合に対して９０％以上を維持していた。さらに、ビグアナイド系化合物又は第四級アンモニウム化合物の濃度が０．０１ｍｇ／ｍＬ以下である場合には、細胞生存率は防腐剤を含まない場合に対して９８％以上を維持していた。 From the above results, when the concentration of biguanide compounds or quaternary ammonium compounds is 0.05 mg/mL or less, the cell survival rate is 75% or more compared to when the concentration of preservatives is 0 mg/mL. It was confirmed that the addition of the biguanide compound or the quaternary ammonium compound did not substantially increase the cytotoxic effect. In particular, when the concentration of the biguanide compound or the quaternary ammonium compound was 0.03 mg/mL or less, the cell survival rate was maintained at 90% or more compared to when no preservative was included. Furthermore, when the concentration of the biguanide compound or the quaternary ammonium compound was 0.01 mg/mL or less, the cell survival rate was maintained at 98% or more compared to the case where no preservative was included.
（実施例２）
精製水、塩化ベンザルコニウム水溶液（０．０１５ｍｇ／ｍＬ）、及び塩酸ポリヘキサニド水溶液（０．００１ｍｇ／ｍＬ及び０．００２ｍｇ／ｍＬ）のそれぞれについて、保存効力試験を行った。保存効力試験は、日本薬局方（第１８改正）に従って行った。具体的には、Escherichia coli、Pseudomonas aeruginosa、Staphylococcus aureus、Candida albicans、及びAspergillus brasiliensisの各菌種を用いて、点眼液に求められるカテゴリーＩＡの判定基準を満たすかどうかを確認した。具体的な判定基準は、細菌については接種７日後に接種菌数に比べて１．０ｌｏｇ以上の減少があり、接種１４日後に接種菌数に比べて３．０ｌｏｇ以上の減少があり、接種２８日後には１４日後の菌数から増加していないこと、真菌については接種７日後、１４日後及び２８日後に接種菌数が増加していないこと、である。
(Example 2)
A preservative efficacy test was conducted on each of purified water, benzalkonium chloride aqueous solution (0.015 mg/mL), and polyhexanide hydrochloride aqueous solution (0.001 mg/mL and 0.002 mg/mL). The preservative efficacy test was conducted according to the Japanese Pharmacopoeia (18th revision). Specifically, each species of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans, and Aspergillus brasiliensis was used to confirm whether they met the Category IA criteria required for eye drops. The specific criteria for bacteria are that 7 days after vaccination there is a decrease of 1.0 log or more compared to the number of inoculated bacteria, 14 days after vaccination there is a decrease of 3.0 log or more compared to the number of inoculated bacteria, and 28 days after vaccination The number of inoculated bacteria did not increase after 14 days, and the number of fungi did not increase after 7, 14, and 28 days after inoculation.
その結果、塩化ベンザルコニウム水溶液（０．０１５ｍｇ／ｍＬ）及び塩酸ポリヘキサニド水溶液（０．００２ｍｇ／ｍＬ）は保存効力試験に適合していることが確認された。一方で、精製水（保存剤濃度０ｍｇ／ｍＬ）及び塩酸ポリヘキサニド水溶液（０．００１ｍｇ／ｍＬ）は保存効力試験に適合しないことが確認された。 As a result, it was confirmed that the benzalkonium chloride aqueous solution (0.015 mg/mL) and the polyhexanide hydrochloride aqueous solution (0.002 mg/mL) met the preservative efficacy test. On the other hand, it was confirmed that purified water (preservative concentration 0 mg/mL) and polyhexanide hydrochloride aqueous solution (0.001 mg/mL) did not meet the preservative efficacy test.
上記の結果は、点眼液に求められる抗菌性を得るために十分な最低濃度は、塩化ベンザルコニウムについては０．０１５ｍｇ／ｍＬ以下である一方で、塩酸ポリヘキサニドについてはその７．５分の１である０．００２ｍｇ／ｍＬ程度であることがわかった。実施例１の結果から、保存効力試験に適合させることに加えて、細胞障害性を実質的に増加させることなく追加的な効果を点眼液に付与するために、０．０１５ｍｇ／ｍＬ～０．０５ｍｇ／ｍＬ程度の塩化ベンザルコニウム、又は０．００２ｍｇ／ｍＬ～０．０５ｍｇ／ｍＬ程度の塩酸ポリヘキサニドを含有させてよいことがわかった。このような用途で用いる場合、濃度範囲は塩酸ポリヘキサニドの方が塩化ベンザルコニウムの方が広いと考えられる。 The above results indicate that the minimum concentration sufficient to obtain the antibacterial properties required for eye drops is 0.015 mg/mL or less for benzalkonium chloride, while for polyhexanide hydrochloride, it is 1/7.5 of that concentration. It was found that it was about 0.002 mg/mL. From the results of Example 1, in addition to meeting the preservative efficacy test, in order to impart additional efficacy to the ophthalmic solution without substantially increasing cytotoxicity, it was found that between 0.015 mg/mL and 0.5 mg/mL. It was found that benzalkonium chloride of about 0.05 mg/mL or polyhexanide hydrochloride of about 0.002 mg/mL to 0.05 mg/mL may be contained. When used in such applications, polyhexanide hydrochloride is considered to have a wider concentration range than benzalkonium chloride.
（実施例３－１（参考例））
点眼液に防腐剤を添加することにより、細胞傷害性を実質的に増加させることなく、Escherichia coli、Pseudomonas aeruginosa、Staphylococcus aureus、Candida albicans、及びAspergillus brasiliensis以外の菌種に対する抗菌性を向上させるかについて検討した。
(Example 3-1 (reference example))
Whether adding preservatives to ophthalmic solutions improves antibacterial activity against bacterial species other than Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans, and Aspergillus brasiliensis without substantially increasing cytotoxicity. investigated.
エピナスチン塩酸塩（０．１ｇ）、リン酸二水素ナトリウム水和物（０．２５２ｇ）、リン酸水素ナトリウム水和物（１．２２ｇ）、塩化ベンザルコニウム（２．５ｍｇ）、及び塩化ナトリウム（０．５１ｇ）を、精製水に溶解させ、必要に応じて塩酸（又は水酸化ナトリウム）を添加してｐＨを７．０に調整し、精製水を加えて全量を１００ｍＬとし、フィルターでろ過することにより点眼液を調製した。 Epinastine hydrochloride (0.1 g), sodium dihydrogen phosphate hydrate (0.252 g), sodium hydrogen phosphate hydrate (1.22 g), benzalkonium chloride (2.5 mg), and sodium chloride ( 0.51g) in purified water, add hydrochloric acid (or sodium hydroxide) as necessary to adjust the pH to 7.0, add purified water to make a total volume of 100mL, and filter with a filter. An eye drop was prepared by this method.
次に、得られた点眼液の抗菌性を評価した。具体的には、点眼液にBrevundimonas diminutaを添加し、５分、３０分、１時間、３時間、６時間、２４時間、又は３６時間保存した。その後、フィルターを用いて試験菌を回収し、培養後のコロニーの形成を観察得ることにより、生菌数を評価した。その結果、すべての測定時点において生菌数が１ｌｏｇ以上減少したことが確認された。 Next, the antibacterial properties of the obtained eye drops were evaluated. Specifically, Brevundimonas diminuta was added to the eye drops and stored for 5 minutes, 30 minutes, 1 hour, 3 hours, 6 hours, 24 hours, or 36 hours. Thereafter, the test bacteria were collected using a filter, and the number of viable bacteria was evaluated by observing the formation of colonies after culturing. As a result, it was confirmed that the number of viable bacteria decreased by 1 log or more at all measurement points.
（実施例３－２）
塩化ベンザルコニウムの代わりに塩酸ポリヘキサニド（０．２ｍｇ）を用いたことを除き、実施例３－１と同様に点眼液を調製し、抗菌性を評価した。その結果、生菌数が１ｌｏｇ以上減少したことが確認された。
(Example 3-2)
An eye drop was prepared in the same manner as in Example 3-1, except that polyhexanide hydrochloride (0.2 mg) was used instead of benzalkonium chloride, and its antibacterial properties were evaluated. As a result, it was confirmed that the number of viable bacteria decreased by 1 log or more.
（比較例３－１）
塩化ベンザルコニウムを添加しなかったことを除き、実施例３－１と同様に点眼液を調製し、抗菌性を評価した。その結果、生菌数の減少は見られず、生理食塩水（０．９％塩化ナトリウム水溶液）（比較例３－２）に菌を添加した場合と同様の結果が得られた。
(Comparative example 3-1)
An eye drop was prepared in the same manner as in Example 3-1, except that benzalkonium chloride was not added, and its antibacterial properties were evaluated. As a result, no decrease in the number of viable bacteria was observed, and results similar to those obtained when bacteria were added to physiological saline (0.9% sodium chloride aqueous solution) (Comparative Example 3-2) were obtained.
なお、実施例３－１及び３－２、並びに比較例３－１のそれぞれの点眼液が、第１８改正日本薬局方に規定されている、Escherichia coli、Pseudomonas aeruginosa、Staphylococcus aureus、Candida albicans、及びAspergillus brasiliensisを用いる保存効力試験法に適合していることも確認した。 In addition, each of the eye drops of Examples 3-1 and 3-2 and Comparative Example 3-1 contained Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans, and It was also confirmed that the product complied with the preservative efficacy test method using Aspergillus brasiliensis.
防腐剤を配合しなくても保存効力試験に適合することが知られている比較例３－１のエピナスチン塩酸塩点眼液は、特定の菌種に対しては抗菌性を示さなかった。一方で、実施例３－１及び３－２の結果から、ビグアナイド系化合物又は第四級アンモニウム化合物を添加することにより抗菌性が向上することが確認された。特に、保存効力試験に適合する点眼液に対して、ビグアナイド系化合物又は第四級アンモニウム化合物を含有させなかった比較例３－１の点眼液ではBrevundimonas diminutaの生菌数の減少は認められなかったのに対し、細胞傷害性を実質的に増加させない量のビグアナイド系化合物又は第四級アンモニウム化合物を含有させた実施例３－１及び３－２ではBrevundimonas diminutaの生菌数の減少が認められた。 The epinastine hydrochloride ophthalmic solution of Comparative Example 3-1, which is known to pass the preservative efficacy test even without the addition of preservatives, did not exhibit antibacterial properties against specific bacterial species. On the other hand, from the results of Examples 3-1 and 3-2, it was confirmed that antibacterial properties were improved by adding a biguanide compound or a quaternary ammonium compound. In particular, for the ophthalmic solution that complied with the preservative efficacy test, no decrease in the number of viable bacteria of Brevundimonas diminuta was observed in the ophthalmic solution of Comparative Example 3-1, which did not contain a biguanide compound or a quaternary ammonium compound. On the other hand, in Examples 3-1 and 3-2, which contained an amount of a biguanide compound or a quaternary ammonium compound that did not substantially increase cytotoxicity, a decrease in the number of viable bacteria of Brevundimonas diminuta was observed. .
（実施例４－１）
点眼液については、使用中に微生物による二次汚染の可能性があり、汚染微生物に起因する感染症を引き起こす危険性があることから防腐剤を添加する必要がある。そこで、様々な防腐剤の組成を有する水性組成物の抗菌性を、細菌性角膜炎・結膜炎の主要起炎菌である肺炎球菌（Streptococcus pneumoniae（以下、S. pneumoniaeという場合もある。））を指標菌として評価した。具体的には、実施例４－１Ａ、４－１Ｂ、４－１Ｃ及び比較例４－１の水性組成物に、Streptococcus pneumoniaeを接種菌数が1×105～1×106CFU/mLとなるように接種し、接種後5分、10分、20分、30分、及び60分の5時点で生菌数を測定した。実施例４－１Ａ、４－１Ｂ、４－１Ｃ及び比較例４－１の水性組成物の調製方法は以下の通りである。
(Example 4-1)
For eye drops, there is a possibility of secondary contamination by microorganisms during use, and there is a risk of infection caused by the contaminating microorganisms, so it is necessary to add a preservative. Therefore, we have investigated the antibacterial properties of aqueous compositions containing various preservatives to treat Streptococcus pneumoniae (hereinafter sometimes referred to as S. pneumoniae), which is the main causative agent of bacterial keratitis and conjunctivitis. It was evaluated as an indicator bacterium. Specifically, the aqueous compositions of Examples 4-1A, 4-1B, 4-1C and Comparative Example 4-1 were inoculated with Streptococcus pneumoniae at a bacterial count of 1×10 5 to 1×10 6 CFU/mL. The number of viable bacteria was measured at 5 minutes, 10 minutes, 20 minutes, 30 minutes, and 60 minutes after inoculation. The methods for preparing the aqueous compositions of Examples 4-1A, 4-1B, 4-1C and Comparative Example 4-1 are as follows.
（実施例４－１Ａ）
エピナスチン塩酸塩（0.1 g）、リン酸二水素ナトリウム水和物（0.252 g）、リン酸水素ナトリウム水和物（1.22 g）、塩酸ポリヘキサニド（0.2 mg）、塩化ベンザルコニウム（0.005 mg）、及び塩化ナトリウム（0.51 g）を、精製水に溶解させ、必要に応じて塩酸（又は水酸化ナトリウム）を添加してpHを7.0に調整し、精製水を加えて全量を100 mLとし、フィルターでろ過することで水性組成物を調製した。
(Example 4-1A)
Epinastine hydrochloride (0.1 g), sodium dihydrogen phosphate hydrate (0.252 g), sodium hydrogen phosphate hydrate (1.22 g), polyhexanide hydrochloride (0.2 mg), benzalkonium chloride (0.005 mg), and Dissolve sodium chloride (0.51 g) in purified water, add hydrochloric acid (or sodium hydroxide) as necessary to adjust the pH to 7.0, add purified water to make a total volume of 100 mL, and filter with a filter. An aqueous composition was prepared.
（実施例４－１Ｂ）
エピナスチン塩酸塩（0.1 g）、リン酸二水素ナトリウム水和物（0.252 g）、リン酸水素ナトリウム水和物（1.22 g）、塩酸ポリヘキサニド（0.2 mg）、及び塩化ナトリウム（0.51 g）を、精製水に溶解させ、必要に応じて塩酸（又は水酸化ナトリウム）を添加してpHを7.0に調整し、精製水を加えて全量を100 mLとし、フィルターでろ過することで水性組成物を調製した。
(Example 4-1B)
Purified epinastine hydrochloride (0.1 g), sodium dihydrogen phosphate hydrate (0.252 g), sodium hydrogen phosphate hydrate (1.22 g), polyhexanide hydrochloride (0.2 mg), and sodium chloride (0.51 g) An aqueous composition was prepared by dissolving it in water, adjusting the pH to 7.0 by adding hydrochloric acid (or sodium hydroxide) as necessary, adding purified water to make a total volume of 100 mL, and filtering it with a filter. .
（実施例４－１Ｃ（参考例））
エピナスチン塩酸塩（0.1 g）、リン酸二水素ナトリウム水和物（0.252 g）、リン酸水素ナトリウム水和物（1.22 g）、塩化ベンザルコニウム（0.005 mg）、及び塩化ナトリウム（0.51 g）を、精製水に溶解させ、必要に応じて塩酸（又は水酸化ナトリウム）を添加してpHを7.0に調整し、精製水を加えて全量を100 mLとし、フィルターでろ過することで水性組成物を調製した。
(Example 4-1C (reference example))
Epinastine hydrochloride (0.1 g), sodium dihydrogen phosphate hydrate (0.252 g), sodium hydrogen phosphate hydrate (1.22 g), benzalkonium chloride (0.005 mg), and sodium chloride (0.51 g). , dissolve in purified water, adjust the pH to 7.0 by adding hydrochloric acid (or sodium hydroxide) as necessary, add purified water to make a total volume of 100 mL, and filter the aqueous composition using a filter. Prepared.
（比較例４－１）
エピナスチン塩酸塩（0.1 g）、リン酸二水素ナトリウム水和物（0.252 g）、リン酸水素ナトリウム水和物（1.22 g）、及び塩化ナトリウム（0.51 g）を、精製水に溶解させ、必要に応じて塩酸（又は水酸化ナトリウム）を添加してpHを7.0に調整し、精製水を加えて全量を100 mLとし、フィルターでろ過することで水性組成物を調製した。
(Comparative example 4-1)
Epinastine hydrochloride (0.1 g), sodium dihydrogen phosphate hydrate (0.252 g), sodium hydrogen phosphate hydrate (1.22 g), and sodium chloride (0.51 g) were dissolved in purified water and added as needed. Accordingly, hydrochloric acid (or sodium hydroxide) was added to adjust the pH to 7.0, purified water was added to make the total volume 100 mL, and the mixture was filtered to prepare an aqueous composition.
実施例４－１Ａ、４－１Ｂ、４－１Ｃ及び比較例４－１の水性組成物の組成の一覧を表２に示す。 Table 2 shows a list of the compositions of the aqueous compositions of Examples 4-1A, 4-1B, 4-1C and Comparative Example 4-1.
生菌数の測定結果を表３及び図１に示す。実施例４－１Ａについては、生菌数は接種後5分で接種菌数から3.32 log減少、接種後10分で接種菌数から4.83 log減少、接種後20分以降で接種菌数から5.83 log減少となる推移を示した。なお、実施例４－１Ａは、ビグアナイド系化合物又は第四級アンモニウム化合物を単独で含有する水性組成物（実施例４－１Ｂ、４－１Ｃ）と比較して菌数減少が速くなる効果が確認された。 The measurement results of the number of viable bacteria are shown in Table 3 and FIG. 1. For Example 4-1A, the number of viable bacteria decreased by 3.32 log from the number of inoculated bacteria 5 minutes after inoculation, by 4.83 log from the number of inoculated bacteria at 10 minutes after inoculation, and by 5.83 log from the number of inoculated bacteria after 20 minutes after inoculation. It showed a decreasing trend. In addition, Example 4-1A was confirmed to have the effect of reducing the number of bacteria faster than the aqueous compositions containing a biguanide compound or a quaternary ammonium compound alone (Examples 4-1B and 4-1C). It was done.
したがって、エピナスチン又はその塩を含有する水性組成物について、ビグアナイド系化合物（塩酸ポリヘキサニド：0.002 mg/mL）と第四級アンモニウム化合物（塩化ベンザルコニウム：0.00005 mg/mL以上）を組み合わせることで、単独で含有する場合と比較して抗菌性が向上することが確認された。 Therefore, for an aqueous composition containing epinastine or a salt thereof, by combining a biguanide compound (polyhexanide hydrochloride: 0.002 mg/mL) and a quaternary ammonium compound (benzalkonium chloride: 0.00005 mg/mL or more), it is possible to It was confirmed that the antibacterial properties were improved compared to the case where it was contained.
接種後１０分以内の結果に着目すると、ビグアナイド系化合物を単独で含有する実施例４－１Ｂでは、接種後５分及び１０分において、第四級アンモニウム化合物を単独で含有する実施例４－１Ｃと比較して、生菌数がより減少した（図２－１、２－２）。さらに、接種後１０分以内においては生菌数の減少が認められなかった実施例４－１Ｃ（第四級アンモニウム化合物を単独で含有）に対し、ビグアナイド系化合物及び第四級アンモニウム化合物を組み合わせた実施例４－１Ａでは、接種後５分及び１０分において、顕著な生菌数の減少が認められ、この効果はビグアナイド系化合物を単独で含有する実施例４－１Ｂと比較しても顕著であった（図２－１、２－２）。 Focusing on the results within 10 minutes after inoculation, in Example 4-1B containing a biguanide compound alone, 5 minutes and 10 minutes after inoculation, Example 4-1C containing only a quaternary ammonium compound In comparison, the number of viable bacteria decreased more (Figures 2-1 and 2-2). Furthermore, for Example 4-1C (containing a quaternary ammonium compound alone) in which no decrease in the number of viable bacteria was observed within 10 minutes after inoculation, a biguanide compound and a quaternary ammonium compound were combined. In Example 4-1A, a significant decrease in the number of viable bacteria was observed at 5 and 10 minutes after inoculation, and this effect was remarkable even compared to Example 4-1B, which contained only a biguanide compound. (Figures 2-1 and 2-2).
（実施例４－２）
塩化ベンザルコニウムの濃度を変化させて実施例４－１と同様の試験を行った。塩酸ポリヘキサニド及び塩化ベンザルコニウムの組成を変えたこと以外は実施例４－１と同様の方法にて、実施例４－２Ａ～Ｃ及び比較例４－２の水性組成物を調製した。実施例４－２Ａ～Ｃ及び比較例４－２の水性組成物に含まれる塩酸ポリヘキサニド及び塩化ベンザルコニウムの組成は表４に示す通りである。実施例４－２Ａ、４－２Ｂ、４－２Ｃ及び比較例４－２の水性組成物に、Streptococcus pneumoniaeを接種菌数が1×105～1×106CFU/mLとなるように接種し、接種後5分、10分、20分、30分、及び60分の5時点で生菌数を測定した。結果を表４及び図３に示す。
(Example 4-2)
A test similar to Example 4-1 was conducted by changing the concentration of benzalkonium chloride. Aqueous compositions of Examples 4-2A to 4-2C and Comparative Example 4-2 were prepared in the same manner as in Example 4-1 except that the compositions of polyhexanide hydrochloride and benzalkonium chloride were changed. The compositions of polyhexanide hydrochloride and benzalkonium chloride contained in the aqueous compositions of Examples 4-2A to C and Comparative Example 4-2 are shown in Table 4. Streptococcus pneumoniae was inoculated into the aqueous compositions of Examples 4-2A, 4-2B, 4-2C and Comparative Example 4-2 so that the number of inoculated bacteria was 1×10 5 to 1×10 6 CFU/mL. The number of viable bacteria was measured at 5 minutes, 10 minutes, 20 minutes, 30 minutes, and 60 minutes after inoculation. The results are shown in Table 4 and Figure 3.
その結果、実施例４－１と同様に、ビグアナイド系化合物と第四級アンモニウム化合物を組み合わせた実施例４－２Ａ及び４－２Ｂでは、顕著な生菌数の減少が確認され、抗菌性の向上が認められた。さらに、この効果は第四級アンモニウム化合物の濃度に依存することが分かった。 As a result, similar to Example 4-1, in Examples 4-2A and 4-2B in which a biguanide compound and a quaternary ammonium compound were combined, a significant decrease in the number of viable bacteria was confirmed, and the antibacterial property was improved. was recognized. Furthermore, this effect was found to be dependent on the concentration of the quaternary ammonium compound.
（実施例５）
エピナスチン又はその塩は長期の保存や高温での保存により類縁物質が生じてしまうことが知られている。細胞傷害性が低い濃度の第四級アンモニウム化合物、ビグアナイド系化合物を点眼液に含有させた場合に、エピナスチン又はその塩の熱安定性が変わり、類縁物質の生成が変化するかを検討した。
(Example 5)
It is known that epinastine or its salts generate related substances when stored for long periods of time or at high temperatures. We investigated whether the thermal stability of epinastine or its salts would change and the production of related substances would change when ophthalmic solutions contained quaternary ammonium compounds or biguanide compounds with low cytotoxicity.
表５に示す組成となるように、実施例４－１と同様の方法により、水性組成物を調製し、ポリエチレン製の５ｍL点眼容器に５ｍL充填することで実施例５－１～５－３及び比較例５－１の点眼液を各３サンプルずつ調製した。 An aqueous composition was prepared in the same manner as in Example 4-1 so as to have the composition shown in Table 5, and 5 mL was filled into a 5 mL polyethylene eye drop container. Three samples each of the eye drops of Comparative Example 5-1 were prepared.
エピナスチン塩酸塩の分解物は高速液体クロマトグラフ（ＨＰＬＣ）法により分析した。
（エピナスチン塩酸塩の分解物測定のＨＰＬＣ条件）
検出器：紫外吸光光度計
カラム：内径4.6 mm、長さ25 cmのステンレス管に5 μmの液体クロマトグラフィー用オクタデシルシリル化シリカゲルを充填する。
The decomposition products of epinastine hydrochloride were analyzed by high performance liquid chromatography (HPLC).
(HPLC conditions for measuring decomposed products of epinastine hydrochloride)
Detector: Ultraviolet spectrophotometer Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 25 cm is packed with 5 μm octadecylsilylated silica gel for liquid chromatography.
５０℃にて６０日保存後における類縁物質の測定結果を表６に示す。 Table 6 shows the measurement results of related substances after storage at 50°C for 60 days.
塩化ベンザルコニウムを単独で配合した実施例５－３（参考例）と比較して、塩酸ポリヘキサニドを単独で配合した実施例５－２においては、分解物Ａ～Ｄの生成及び総類縁物質量が少なくなる傾向が示唆された。さらに、塩化ベンザルコニウムと塩酸ポリヘキサニドを組み合わせた実施例５－１においては、実施例５－２よりも、分解物Ａ～Ｄの生成及び総類縁物質量が抑えられることが確認された。さらに、実施例５－１は、塩化ベンザルコニウムと塩酸ポリヘキサニドを含まない比較例５－１と比較して、分解物Ａ～Ｄの生成及び総類縁物質量が顕著に抑えられていることが確認された。 Compared to Example 5-3 (reference example) in which benzalkonium chloride was blended alone, in Example 5-2 in which polyhexanide hydrochloride was blended alone, the production of decomposition products A to D and the total amount of related substances were It was suggested that there was a tendency for the number to decrease. Furthermore, it was confirmed that in Example 5-1 in which benzalkonium chloride and polyhexanide hydrochloride were combined, the production of decomposition products A to D and the total amount of related substances were suppressed compared to Example 5-2. Furthermore, in Example 5-1, the production of decomposition products A to D and the total amount of related substances were significantly suppressed compared to Comparative Example 5-1, which did not contain benzalkonium chloride and polyhexanide hydrochloride. confirmed.
実施例５－１～５－３について、６０℃にて２週間保存後、３週間保存後、６週間保存後における類縁物質を測定した結果を表７、並びに図４（分解物Ａ）、図５（分解物Ｂ）、図６（分解物Ｃ）、図７（分解物Ｄ）、図８（分解物Ｅ）及び図９（総類縁物質量）に示す。 Regarding Examples 5-1 to 5-3, the results of measuring related substances after storage at 60°C for 2 weeks, 3 weeks, and 6 weeks are shown in Table 7, as well as in Figure 4 (degraded product A) and Figure 4. 5 (degradation product B), FIG. 6 (degradation product C), FIG. 7 (degradation product D), FIG. 8 (degradation product E), and FIG. 9 (total amount of related substances).
塩化ベンザルコニウムを単独で配合した実施例５－３（参考例）と比較して、塩酸ポリヘキサニドを単独で配合した実施例５－２においては、分解物Ａ～Ｅの生成及び総類縁物質量が少なかった。さらに、塩酸ポリヘキサニドと塩化ベンザルコニウムを組み合わせた実施例５－１においては、実施例５－２よりも、分解物Ａ～Ｄの生成及び総類縁物質量が抑えられることが確認された。 Compared to Example 5-3 (reference example) in which benzalkonium chloride was blended alone, in Example 5-2 in which polyhexanide hydrochloride was blended alone, the production of decomposition products A to E and the total amount of related substances were lower. There were few. Furthermore, it was confirmed that in Example 5-1 in which polyhexanide hydrochloride and benzalkonium chloride were combined, the production of decomposition products A to D and the total amount of related substances were suppressed compared to Example 5-2.
以上より、細胞傷害性が低い濃度の第四級アンモニウム化合物、ビグアナイド系化合物及びエピナスチン又はその塩を含む点眼液は、エピナスチン又はその塩の熱安定性が向上し、類縁物質の生成が抑えられることが確認された。 From the above, the ophthalmic solution containing a quaternary ammonium compound, a biguanide compound, and epinastine or its salt at a low concentration of cytotoxicity improves the thermal stability of epinastine or its salt, and suppresses the formation of related substances. was confirmed.
（製剤例１）
エピナスチン塩酸塩（０．１ｇ）、リン酸二水素ナトリウム水和物（０．２５２ｇ）、リン酸水素ナトリウム水和物（１．２２ｇ）、塩酸ポリヘキサニド（０．１ｍｇ）、塩化ナトリウム（０．５１ｇ）を、精製水に溶解させ、必要に応じて塩酸（又は水酸化ナトリウム）を添加してｐＨを７．０に調整し、精製水を加えて全量を１００ｍＬとし、フィルターでろ過することで水性組成物を調製する。
(Formulation example 1)
Epinastine hydrochloride (0.1g), sodium dihydrogen phosphate hydrate (0.252g), sodium hydrogenphosphate hydrate (1.22g), polyhexanide hydrochloride (0.1mg), sodium chloride (0.51g) ) in purified water, add hydrochloric acid (or sodium hydroxide) as necessary to adjust the pH to 7.0, add purified water to make a total volume of 100 mL, and filter through a filter to obtain an aqueous solution. Prepare the composition.
（製剤例２～１１）
さらに、塩化ベンザルコニウムを、それぞれ０．００１５ｍｇ、０．００５ｍｇ、０．０１ｍｇ、０．０２５ｍｇ、０．０５ｍｇ、０．１ｍｇ、０．２５ｍｇ、０．５ｍｇ、１．０ｍｇ及び４．９ｍｇとしたことを除き、製剤例１と同様に水性組成物を調製する。
(Formulation examples 2 to 11)
Furthermore, benzalkonium chloride was set to 0.0015 mg, 0.005 mg, 0.01 mg, 0.025 mg, 0.05 mg, 0.1 mg, 0.25 mg, 0.5 mg, 1.0 mg and 4.9 mg, respectively. An aqueous composition is prepared in the same manner as in Formulation Example 1, except for the following.
（製剤例１２～２１）
塩酸ポリヘキサニドの量を０．２ｍｇに変更したことを除き、製剤例１～１０と同様に水性組成物を調製する。
(Formulation examples 12 to 21)
Aqueous compositions are prepared in the same manner as in Formulation Examples 1 to 10, except that the amount of polyhexanide hydrochloride was changed to 0.2 mg.
（製剤例２２）
塩化ベンザルコニウムの量を４．８ｍｇに変更したことを除き、製剤例１２と同様に水性組成物を調製する。
(Formulation example 22)
An aqueous composition is prepared in the same manner as in Formulation Example 12, except that the amount of benzalkonium chloride was changed to 4.8 mg.
これらの製剤例によっても、細胞障害作用を実質的に増加させずに、水性組成物の抗菌性を向上や、類縁物質の生成を抑制させることができる。 These formulation examples can also improve the antibacterial properties of the aqueous composition and suppress the production of related substances without substantially increasing the cytotoxic effect.
発明は上記の実施形態に制限されるものではなく、発明の要旨の範囲内で、種々の変形・変更が可能である。 The invention is not limited to the above-described embodiments, and various modifications and changes can be made within the scope of the invention.
Claims (12)
組成物中のビグアナイド系化合物の濃度が、０．０５ｍｇ／ｍＬ以下である、水性組成物。 An aqueous composition comprising epinastine or a salt thereof and a biguanide compound,
An aqueous composition in which the concentration of a biguanide compound is 0.05 mg/mL or less.
組成物中のビグアナイド系化合物の濃度が０．０５ｍｇ／ｍＬ以下となるように、前記水性組成物にビグアナイド系化合物を含有させることを含む、製造方法。 A method for producing an aqueous composition containing epinastine or a salt thereof, comprising:
A manufacturing method comprising incorporating a biguanide compound into the aqueous composition so that the concentration of the biguanide compound in the composition is 0.05 mg/mL or less.
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