JP6304474B2 - Eye drops - Google Patents
Eye drops Download PDFInfo
- Publication number
- JP6304474B2 JP6304474B2 JP2013126107A JP2013126107A JP6304474B2 JP 6304474 B2 JP6304474 B2 JP 6304474B2 JP 2013126107 A JP2013126107 A JP 2013126107A JP 2013126107 A JP2013126107 A JP 2013126107A JP 6304474 B2 JP6304474 B2 JP 6304474B2
- Authority
- JP
- Japan
- Prior art keywords
- drop
- eye drop
- container
- eye
- component
- 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 138
- 229940012356 eye drops Drugs 0.000 title claims description 35
- -1 terpenoid compound Chemical class 0.000 claims description 71
- 239000006196 drop Substances 0.000 claims description 70
- 239000002562 thickening agent Substances 0.000 claims description 39
- 238000000034 method Methods 0.000 claims description 36
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- 239000004327 boric acid Substances 0.000 claims description 16
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- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 16
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 15
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 claims description 14
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- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 13
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- OSZNNLWOYWAHSS-UHFFFAOYSA-M neostigmine methyl sulfate Chemical compound COS([O-])(=O)=O.CN(C)C(=O)OC1=CC=CC([N+](C)(C)C)=C1 OSZNNLWOYWAHSS-UHFFFAOYSA-M 0.000 description 1
- 229960002253 neostigmine methylsulfate Drugs 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 229960001257 oxyquinoline sulfate Drugs 0.000 description 1
- 229940101267 panthenol Drugs 0.000 description 1
- 235000020957 pantothenol Nutrition 0.000 description 1
- 239000011619 pantothenol Substances 0.000 description 1
- RUVINXPYWBROJD-UHFFFAOYSA-N para-methoxyphenyl Natural products COC1=CC=C(C=CC)C=C1 RUVINXPYWBROJD-UHFFFAOYSA-N 0.000 description 1
- 229960004811 pemirolast potassium Drugs 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229920001992 poloxamer 407 Polymers 0.000 description 1
- 229940044476 poloxamer 407 Drugs 0.000 description 1
- 229920001987 poloxamine Polymers 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920001721 polyimide Polymers 0.000 description 1
- 229940099429 polyoxyl 40 stearate Drugs 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- NMMVKSMGBDRONO-UHFFFAOYSA-N potassium;9-methyl-3-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)pyrido[1,2-a]pyrimidin-4-one Chemical compound [K+].CC1=CC=CN(C2=O)C1=NC=C2C1=NN=N[N-]1 NMMVKSMGBDRONO-UHFFFAOYSA-N 0.000 description 1
- JVUYWILPYBCNNG-UHFFFAOYSA-N potassium;oxido(oxo)borane Chemical compound [K+].[O-]B=O JVUYWILPYBCNNG-UHFFFAOYSA-N 0.000 description 1
- 229960003101 pranoprofen Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229960000342 retinol acetate Drugs 0.000 description 1
- QGNJRVVDBSJHIZ-QHLGVNSISA-N retinyl acetate Chemical compound CC(=O)OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C QGNJRVVDBSJHIZ-QHLGVNSISA-N 0.000 description 1
- 235000019173 retinyl acetate Nutrition 0.000 description 1
- 239000011770 retinyl acetate Substances 0.000 description 1
- 229940108325 retinyl palmitate Drugs 0.000 description 1
- 235000019172 retinyl palmitate Nutrition 0.000 description 1
- 239000011769 retinyl palmitate Substances 0.000 description 1
- 239000010666 rose oil Substances 0.000 description 1
- 235000019719 rose oil Nutrition 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 229920006300 shrink film Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- GQTHJBOWLPZUOI-FJXQXJEOSA-M sodium D-pantothenate Chemical compound [Na+].OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O GQTHJBOWLPZUOI-FJXQXJEOSA-M 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 229960003885 sodium benzoate Drugs 0.000 description 1
- 235000019259 sodium dehydroacetate Nutrition 0.000 description 1
- 229940079839 sodium dehydroacetate Drugs 0.000 description 1
- 229940037001 sodium edetate Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 229940068459 sodium pantothenate Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- DSOWAKKSGYUMTF-GZOLSCHFSA-M sodium;(1e)-1-(6-methyl-2,4-dioxopyran-3-ylidene)ethanolate Chemical compound [Na+].C\C([O-])=C1/C(=O)OC(C)=CC1=O DSOWAKKSGYUMTF-GZOLSCHFSA-M 0.000 description 1
- XTXYCJOBMKKQOW-UHFFFAOYSA-N sodium;(4-aminophenyl)sulfonyl-(2,6-dimethylpyrimidin-4-yl)azanide Chemical compound [Na+].CC1=NC(C)=CC([N-]S(=O)(=O)C=2C=CC(N)=CC=2)=N1 XTXYCJOBMKKQOW-UHFFFAOYSA-N 0.000 description 1
- GEYJUFBPCGDENK-UHFFFAOYSA-M sodium;3,8-dimethyl-5-propan-2-ylazulene-1-sulfonate Chemical compound [Na+].CC(C)C1=CC=C(C)C2=C(S([O-])(=O)=O)C=C(C)C2=C1 GEYJUFBPCGDENK-UHFFFAOYSA-M 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000019721 spearmint oil Nutrition 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229960000654 sulfafurazole Drugs 0.000 description 1
- 229960005404 sulfamethoxazole Drugs 0.000 description 1
- JLKIGFTWXXRPMT-UHFFFAOYSA-N sulphamethoxazole Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 JLKIGFTWXXRPMT-UHFFFAOYSA-N 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- 229960000337 tetryzoline Drugs 0.000 description 1
- 229940042585 tocopherol acetate Drugs 0.000 description 1
- NZHGWWWHIYHZNX-CSKARUKUSA-N tranilast Chemical compound C1=C(OC)C(OC)=CC=C1\C=C\C(=O)NC1=CC=CC=C1C(O)=O NZHGWWWHIYHZNX-CSKARUKUSA-N 0.000 description 1
- 229960005342 tranilast Drugs 0.000 description 1
- WYXIGTJNYDDFFH-UHFFFAOYSA-Q triazanium;borate Chemical compound [NH4+].[NH4+].[NH4+].[O-]B([O-])[O-] WYXIGTJNYDDFFH-UHFFFAOYSA-Q 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229960004791 tropicamide Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000011576 zinc lactate Substances 0.000 description 1
- 229940050168 zinc lactate Drugs 0.000 description 1
- 235000000193 zinc lactate Nutrition 0.000 description 1
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
- 229960001763 zinc sulfate Drugs 0.000 description 1
- 229910000368 zinc sulfate Inorganic materials 0.000 description 1
Images
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medical Preparation Storing Or Oral Administration Devices (AREA)
Description
本発明は、点眼剤に関する。 The present invention relates to eye drops.
点眼剤は、目の疾患を治療する為の医薬品として多くの種類が販売されており、使用方法としては１日数回、１回１〜３滴を点眼して用いる方法が一般的である。
点眼剤の１回の使用量は、通常２９．５〜５３μＬであることが知られており（非特許文献１)、眼内から溢れだした薬液による眼周囲皮膚炎等の発生を回避する事を目的として、点眼容器のノズルにアダプタを装着したり、ノズルの撥水性を上げたりすることにより、点眼剤の１滴量を少量とする技術が知られているが（特許文献１〜２）、そのような技術と点眼液に実際に配合される成分との関係については十分に研究されていないのが現状である。
Many types of eye drops are sold as pharmaceuticals for treating eye diseases. As a method of use, a method of using 1 to 3 drops once a day is generally used.
It is known that the amount of eye drops used at one time is usually 29.5 to 53 μL (Non-patent Document 1), and avoiding the occurrence of periocular dermatitis or the like due to a chemical overflowing from the eye. For this purpose, a technique is known in which the amount of one drop of eyedrop is reduced by attaching an adapter to the nozzle of an eye drop container or increasing the water repellency of the nozzle (Patent Documents 1 and 2). However, the current situation is that the relationship between such a technique and the components actually blended into the ophthalmic solution has not been sufficiently studied.
一方、増粘剤、テルペノイド化合物、ホウ酸緩衝剤は、それぞれ点眼剤の配合成分として公知であるが、１滴量が少ない点眼剤における挙動についてはよく知られていない。 On the other hand, thickeners, terpenoid compounds, and boric acid buffers are each known as a component of eye drops, but their behavior in eye drops with a small amount of one drop is not well known.
本発明者らは、増粘剤或いはテルペノイド化合物のいずれか一方を含有する点眼剤において１滴量を少量とした場合、滴下量がばらつくという新たな課題を見出した。本発明は、増粘剤又はテルペノイド化合物を含有する点眼剤において１滴量を少なくしても、滴下量のばらつきが抑制された点眼剤を提供することを目的とする。 The present inventors have found a new problem that when the amount of one drop is made small in an eye drop containing either a thickener or a terpenoid compound, the drop amount varies. An object of the present invention is to provide an eye drop in which variation in the drop amount is suppressed even when the drop amount is reduced in an eye drop containing a thickener or a terpenoid compound.
本発明者らは上記の課題を解決するため、鋭意研究を行った結果、所定の成分を含有し、かつ、所定の１滴量で点眼できるように設計された点眼剤により課題を解決できることを見出した。即ち、本発明は、下記（１）〜（７）を提供するものである。
（１）本発明の点眼剤は、(Ａ)増粘剤又はテルペノイド化合物、及び、(Ｂ)ホウ酸緩衝剤を含有する点眼剤であって、１滴あたりの滴下量が５〜２５μＬであることを特徴とする。
（２）本発明の点眼剤は、内容積が４〜３０ｍＬである容器に充填されたことが好ましい。
（３）本発明の点眼剤は、滴下口における内径が１．５ｍｍ未満であるノズルを有する容器に充填されたことが好ましい。
（４）本発明の点眼剤は、前記増粘剤が、カルボキシビニルポリマー、ヒドロキシプロピルメチルセルロース、ヒドロキシエチルセルロース、ポリビニルピロリドン、ポリビニルアルコール、アルギン酸、及びヒアルロン酸ナトリウムからなる群より選択される少なくとも１種であることが好ましい。
（５）本発明の点眼剤は、前記テルペノイド化合物が、ｄｌ−メントール、ｌ−メントール、ｄｌ−カンフル、ｄ−カンフル、ｄ−ボルネオール、及びゲラニオールからなる群より選択される少なくとも１種であることが好ましい。
In order to solve the above-mentioned problems, the present inventors have conducted intensive research. As a result, the present invention can solve the problems by using eye drops that contain a predetermined component and can be instilled with a predetermined amount of one drop. I found it. That is, the present invention provides the following (1) to (7).
(1) The eye drop of the present invention is an eye drop containing (A) a thickener or a terpenoid compound and (B) a boric acid buffer, and the drop amount per drop is 5 to 25 μL. It is characterized by that.
(2) The eye drop of the present invention is preferably filled in a container having an internal volume of 4 to 30 mL.
(3) The eye drop of the present invention is preferably filled in a container having a nozzle having an inner diameter of less than 1.5 mm at the dropping port.
(4) In the eye drop of the present invention, the thickener is at least one selected from the group consisting of carboxyvinyl polymer, hydroxypropylmethylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, alginic acid, and sodium hyaluronate. Preferably there is.
(5) In the eye drop of the present invention, the terpenoid compound is at least one selected from the group consisting of dl-menthol, l-menthol, dl-camphor, d-camphor, d-borneol, and geraniol. Is preferred.
（６）本発明の点眼剤の１滴量のばらつき抑制方法は、点眼剤に(Ａ)増粘剤又はテルペノイド化合物、及び、(Ｂ)ホウ酸緩衝剤を含有させ、かつ該点眼剤の１滴あたりの滴下量が５〜２５μＬとなるように設計することを特徴とする。
（７）本発明の容器入り点眼剤の製造方法は、(Ａ)増粘剤又はテルペノイド化合物、及び、(Ｂ)ホウ酸緩衝剤を含有する点眼剤を、１滴あたりの滴下量が５〜２５μＬとなるように設計された容器に充填することを特徴とする。
(6) The method for suppressing variation in the amount of one drop of the eye drop of the present invention comprises (A) a thickener or a terpenoid compound and (B) a borate buffer, and It is designed so that the dropping amount per drop is 5 to 25 μL.
(7) The method for producing an eye drop in a container according to the present invention comprises (A) a thickener or a terpenoid compound, and (B) an eye drop containing a borate buffer. It is characterized by filling a container designed to be 25 μL.
本発明によれば、点眼剤の１滴量を少量とした場合でも、滴下量のばらつきを抑制できる。 According to the present invention, even when the amount of one drop of eye drops is made small, variation in the amount of drops can be suppressed.
１．点眼剤及び容器入り点眼剤
本発明は、(Ａ)成分として増粘剤又はテルペノイド化合物、及び、(Ｂ)成分としてホウ酸緩衝剤を含有し、１滴あたりの滴下量が５〜２５μＬとなるように設計された点眼剤であることを特徴とする。
1. Eye drops and eye drops in containers The present invention contains a thickener or terpenoid compound as component (A) and a borate buffer as component (B), and the amount per drop is 5 to 25 μL. It is characterized by being an eye drop designed as described above.
本明細書において含有量の単位「％」は「ｗ／ｖ％」を意味し、「ｇ／１００ｍＬ」
と同義である。
In the present specification, the unit of content “%” means “w / v%” and “g / 100 mL”.
It is synonymous with.
本明細書中、特に記載の無い限り、略号「ＰＯＥ」はポリオキシエチレンを、略号「Ｐ
ＯＰ」はポリオキシプロピレンを、それぞれ意味する。
In this specification, unless otherwise specified, the abbreviation “POE” represents polyoxyethylene, and the abbreviation “P
“OP” means polyoxypropylene, respectively.
（１）増粘剤、テルペノイド化合物［(Ａ) 成分］
本発明の点眼剤は、（Ａ）増粘剤又はテルペノイド化合物（以下、単に「（Ａ）成分」と記載することもある。）を含有する。
（Ａ）成分として使用される増粘剤については、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。このような増粘剤として、具体的には、ビニル系増粘剤[例えば、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（Ｋ２５，Ｋ３０，Ｋ９０など）、カルボキシビニルポリマーなど]、セルロース系増粘剤［例えば、メチルセルロース、エチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース（２２０８，２９０６，２９１０など）、カルボキシメチルセルロース、カルボキシエチルセルロース、ニトロセルロース又はそれらの塩など］、ポリエチレングリコール（マクロゴール３００，マクロゴール４００，マクロゴール１５００，マクロゴール４０００など）又はムコ多糖[例えば、コンドロイチン硫酸、アルギン酸、ヒアルロン酸又はそれらの塩など]などが挙げられる。これらの増粘剤は、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。尚、上記増粘剤の塩としては、例えば無機塩基との塩が挙げられ、好ましくはアルカリ金属塩又はアルカリ土類金属塩が挙げられ、さらに好ましくはナトリウム塩、カリウム塩、カルシウム塩又はマグネシウム塩であり、特にナトリウム塩が好ましい。
(1) Thickener, terpenoid compound [component (A)]
The eye drop of the present invention contains (A) a thickener or a terpenoid compound (hereinafter sometimes simply referred to as “component (A)”).
The thickener used as the component (A) is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of such thickeners include vinyl-based thickeners [eg, polyvinyl alcohol (completely or partially saponified), polyvinylpyrrolidone (K25, K30, K90, etc.), carboxyvinyl polymer, etc.], cellulose-based Thickeners [for example, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (2208, 2906, 2910, etc.), carboxymethylcellulose, carboxyethylcellulose, nitrocellulose or salts thereof], polyethylene glycol (Macrogol 300 , Macrogol 400, Macrogol 1500, Macrogol 4000, etc.) or mucopolysaccharide [eg chondroitin sulfate, alginic acid, hyaluronic acid or salts thereof Etc.] and the like. These thickeners may be used alone or in any combination of two or more. Examples of the salt of the thickener include a salt with an inorganic base, preferably an alkali metal salt or an alkaline earth metal salt, and more preferably a sodium salt, potassium salt, calcium salt or magnesium salt. In particular, a sodium salt is preferable.
これらの中で、滴下量ばらつき抑制作用を一層高めるという観点から、好ましくはビニル系増粘剤、セルロース系増粘剤、ポリエチレングリコール又はムコ多糖である。より好ましくは、ビニル系増粘剤としては、ポリビニルアルコール、ポリビニルピロリドン、カルボキシビニルポリマーであり、セルロース系増粘剤としてはメチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロース又はその塩であり、ポリエチレングリコールとしてはマクロゴール３００，マクロゴール４００であり、ムコ多糖としてはコンドロイチン硫酸又はその塩、アルギン酸またはその塩、ヒアルロン酸又はその塩である。さらに好ましくは、カルボキシビニルポリマー、ヒドロキシプロピルメチルセルロース、ヒドロキシエチルセルロース、ポリビニルピロリドン、ポリビニルアルコール、アルギン酸、ヒアルロン酸ナトリウムであり、特に好ましくはポリビニルピロリドン(Ｋ２５、Ｋ９０)、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(２２０８，２９０６，２９１０)であり、最も好ましくはポリビニルピロリドンＫ２５、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２９０６である。
さらに、これらの増粘剤の中でも１．０ｗ／ｖ％となるように精製水に溶解した場合の２５℃における粘度が以下の値を示すものが好ましい。尚、粘度の測定は、実施例に記載の方法に従う。
ポリビニルピロリドン ：好ましくは０．１〜５．０ｍＰａ・ｓ、さらに好ましくは０．３〜３．５ｍＰａ・ｓ、特に好ましくは０．５〜２．０ｍＰａ・ｓ。
カルボキシビニルポリマー ：好ましくは１〜３００００ｍＰａ・ｓ、さらに好ましくは２００〜５０００ｍＰａ・ｓ、特に好ましくは４００〜３０００ｍＰａ・ｓ。
ヒドロキシエチルセルロース ：好ましくは１〜５０００ｍＰａ・ｓ、さらに好ましくは５〜１０００ｍＰａ・ｓ、特に好ましくは１５〜６００ｍＰａ・ｓ。
ヒドロキシプロピルメチルセルロース ：好ましくは１〜３０００ｍＰａ・ｓ、さらに好ましくは５０〜８００ｍＰａ・ｓ、特に好ましくは１００〜４００ｍＰａ・ｓ。
Among these, vinyl-based thickeners, cellulose-based thickeners, polyethylene glycols, or mucopolysaccharides are preferred from the viewpoint of further enhancing the effect of suppressing the variation in dripping amount. More preferably, the vinyl thickener is polyvinyl alcohol, polyvinylpyrrolidone or carboxyvinyl polymer, and the cellulose thickener is methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose or a salt thereof. The polyethylene glycol is Macrogol 300 and Macrogol 400, and the mucopolysaccharide is chondroitin sulfate or a salt thereof, alginic acid or a salt thereof, hyaluronic acid or a salt thereof. More preferred are carboxyvinyl polymer, hydroxypropylmethylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, polyvinylalcohol, alginic acid, sodium hyaluronate, particularly preferred polyvinylpyrrolidone (K25, K90), carboxyvinyl polymer, hydroxyethylcellulose, hydroxypropylmethylcellulose. (2208, 2906, 2910), and most preferred are polyvinylpyrrolidone K25, carboxyvinyl polymer, hydroxyethylcellulose, and hydroxypropylmethylcellulose 2906.
Further, among these thickeners, those having a viscosity at 25 ° C. of the following values when dissolved in purified water so as to be 1.0 w / v% are preferable. In addition, the measurement of a viscosity follows the method as described in an Example.
Polyvinylpyrrolidone: preferably 0.1 to 5.0 mPa · s, more preferably 0.3 to 3.5 mPa · s, particularly preferably 0.5 to 2.0 mPa · s.
Carboxyvinyl polymer: preferably 1 to 30000 mPa · s, more preferably 200 to 5000 mPa · s, particularly preferably 400 to 3000 mPa · s.
Hydroxyethyl cellulose: preferably 1 to 5000 mPa · s, more preferably 5 to 1000 mPa · s, and particularly preferably 15 to 600 mPa · s.
Hydroxypropyl methylcellulose: preferably 1 to 3000 mPa · s, more preferably 50 to 800 mPa · s, particularly preferably 100 to 400 mPa · s.
（Ａ）成分として使用されるテルペノイド化合物については、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。このようなテルペノイド化合物として、具体的には、メントール、カンフル、ボルネオール、ゲラニオール、シネオール、シトロネロール、メントン、カルボン、アネトール、オイゲノール、リモネン、リナロール、酢酸リナリル、これらの誘導体等が挙げられる。これらの化合物はｄ体、ｌ体又はｄｌ体のいずれでもよい。また、本発明において、テルペノイド化合物として、上記化合物を含有する精油を使用してもよい。このような精油としては、例えば、ユーカリ油、ベルガモット油、ペパーミント油、クールミント油、スペアミント油、ハッカ油、ウイキョウ油、ケイヒ油、ローズ油等が挙げられる。これらのテルペノイド化合物は、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。
これらの中で、滴下量ばらつき抑制作用を一層高めるという観点から、好ましくは、ｄｌ−メントール、ｌ−メントール、ｄｌ−カンフル、ｄ−カンフル、ｄ−ボルネオール、ゲラニオールからなる群より選択される少なくとも１種が挙げられ、これらを含有する好ましい精油としてクールミント油、ペパーミント油、ハッカ油、樟脳油等が例示される。さらに好ましくは、ｄｌ−メントール、ｌ−メントール、ｄｌ−カンフル、ｄ−カンフル、ｄ−ボルネオールゲラニオールが挙げられ、特に好ましくは、ｌ−メントール、ｄ−カンフル、ｄｌ−カンフル、最も好ましくはｌ−メントールが挙げられる。
The terpenoid compound used as the component (A) is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of such terpenoid compounds include menthol, camphor, borneol, geraniol, cineole, citronellol, menthone, carvone, anethole, eugenol, limonene, linalool, linalyl acetate, and derivatives thereof. These compounds may be d-form, l-form or dl-form. In the present invention, an essential oil containing the above compound may be used as the terpenoid compound. Examples of such essential oils include eucalyptus oil, bergamot oil, peppermint oil, cool mint oil, spearmint oil, peppermint oil, fennel oil, cinnamon oil, and rose oil. These terpenoid compounds may be used alone or in any combination of two or more.
Among these, from the viewpoint of further enhancing the effect of suppressing the variation in the amount of dripping, at least one selected from the group consisting of dl-menthol, l-menthol, dl-camphor, d-camphor, d-borneol and geraniol is preferable. Examples of the essential oil containing these include cool mint oil, peppermint oil, mint oil, camphor oil and the like. More preferred examples include dl-menthol, l-menthol, dl-camphor, d-camphor, d-borneol geraniol, particularly preferably l-menthol, d-camphor, dl-camphor, most preferably l-menthol. Is mentioned.
本発明の点眼剤において、（Ａ）成分の含有量は特に限定されず、（Ａ）成分の種類、該点眼剤の用途、製剤形態、使用方法等に応じて適宜設定される。（Ａ）成分の含有量として、例えば、本発明の点眼剤の総量を基準に、（Ａ）成分の総含有量が、０．０００１〜１０ｗ／ｖ％であることが好ましく、０．０００５〜５ｗ／ｖ％であることがさらに好ましく、０．００１〜３ｗ／ｖ％であることが特に好ましく０．００１〜１ｗ／ｖ％であることが最も好ましい。 In the eye drop of the present invention, the content of the component (A) is not particularly limited, and is appropriately set according to the type of the component (A), the use of the eye drop, the preparation form, the usage method, and the like. As content of (A) component, it is preferable that the total content of (A) component is 0.0001-10 w / v% on the basis of the total amount of the eye drop of the present invention, for example, 0.0005 It is more preferably 5 w / v%, particularly preferably 0.001 to 3 w / v%, and most preferably 0.001 to 1 w / v%.
（Ａ）成分が増粘剤の場合、本発明の点眼剤の総量を基準に、増粘剤の含有量が、総量で、０．０１〜１０ｗ／ｖ％であることが好ましく、０．０１〜５ｗ／ｖ％であることがさらに好ましく、０．１〜３%が特に好ましく、０．１〜１%であることが最も好ましい。 When the component (A) is a thickener, the content of the thickener is preferably 0.01 to 10 w / v% in terms of the total amount based on the total amount of the eye drop of the present invention. It is more preferably ˜5 w / v%, particularly preferably 0.1 to 3%, and most preferably 0.1 to 1%.
（Ａ）成分がテルペノイド化合物の場合、本発明の点眼剤の総量を基準に、テルペノイド化合物の含有量が、総量で、０．０００１〜０．２ｗ／ｖ％であることが好ましく、０．０００５〜０．１ｗ／ｖ％であることがより好ましく、０．００１〜０．０８ｗ／ｖ％であることがさらに好ましい。なお、テルペノイド化合物を含む精油を使用する場合は、点眼剤中に含有される精油中のテルペノイド化合物が上記含有量を満たすように設定することができる。上記テルペノイド化合物の含有量は、滴下量ばらつき抑制作用を向上させるという観点から好適である。 When the component (A) is a terpenoid compound, the total content of the terpenoid compound is preferably 0.0001 to 0.2 w / v% based on the total amount of the eye drop of the present invention, and 0.0005 More preferably, it is -0.1 w / v%, and it is further more preferable that it is 0.001-0.08 w / v%. In addition, when using the essential oil containing a terpenoid compound, it can set so that the terpenoid compound in the essential oil contained in an eye drop may satisfy | fill the said content. The content of the terpenoid compound is suitable from the viewpoint of improving the dripping amount variation suppressing effect.
（２）ホウ酸緩衝剤［(Ｂ) 成分］
本発明の点眼剤は、（Ｂ）ホウ酸緩衝剤（以下、単に「（Ｂ）成分」と記載することもある。）を含有する。
(2) Borate buffer [component (B)]
The eye drop of the present invention contains (B) a borate buffer (hereinafter sometimes simply referred to as “component (B)”).
（Ｂ）成分として使用されるホウ酸緩衝剤については、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。このようなホウ酸緩衝剤として、具体的には、ホウ酸又はその塩が挙げられる。ホウ酸の塩としては、例えばホウ酸の無機酸塩、好ましくはホウ酸のアルカリ金属塩及び／又はアルカリ土類金属塩、更に好ましくはホウ酸のアルカリ金属塩の組み合わせが挙げられる。ホウ酸塩の具体例として、好ましくは、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、ホウ砂等が挙げられ、特に好ましくはホウ砂である。
これらのホウ酸又はその塩は、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。好ましくは、ホウ酸とホウ酸のアルカリ金属塩との組み合わせ、さらに好ましくはホウ酸とホウ砂との組み合わせである。
The borate buffer used as the component (B) is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of such a boric acid buffer include boric acid or a salt thereof. Examples of the salt of boric acid include a combination of an inorganic acid salt of boric acid, preferably an alkali metal salt and / or alkaline earth metal salt of boric acid, and more preferably an alkali metal salt of boric acid. Specific examples of the borate include sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, and borax, and borax is particularly preferable.
These boric acids or salts thereof may be used alone or in any combination of two or more. A combination of boric acid and an alkali metal salt of boric acid is preferable, and a combination of boric acid and borax is more preferable.
本発明の点眼剤において、（Ｂ）成分の含有量は特に限定されず、（Ｂ）成分の種類、併用する（Ａ）成分の種類及び含有量、該点眼剤の用途、製剤形態、使用方法等に応じて、適宜設定される。（Ｂ）成分の含有量としては、例えば、本発明の点眼剤の総量を基準として、（Ｂ）成分の総含有量が、０．０１〜１０ｗ／ｖ％が好ましく、０．０５〜５ｗ／ｖ％がより好ましく、０．１〜２ｗ／ｖ％であることがさらに好ましい。上記（Ｂ）成分の含有量は、滴下量ばらつき抑制作用を向上させるという観点から好適である。
また、本発明の点眼剤において、（Ｂ）成分の含有比率は特に限定されず、（Ｂ）成分の種類、併用する（Ａ）成分の種類及び含有量、該点眼剤の用途、製剤形態、使用方法等に応じて、適宜設定される。（Ａ）成分に対する（Ｂ）成分の含有比率としては、例えば、本発明の点眼剤に含まれる（Ａ）成分の総含有量１質量部に対して、（Ｂ）成分の総含有量が、０．０１〜１００００質量部であることが好ましく、０．０５〜５０００質量部であることがより好ましく、０．１〜２０００質量部であることがさらに好ましい。前記（Ａ）成分又は前記（Ｂ）成分の一方を含有しつつ１滴あたりの滴下量が少量となるように設計された点眼剤においては、滴下量のばらつきが生じ易いと言う新たな課題に対し、(Ｂ) 成分の含有比率が上記範囲内にある場合、前記（Ａ）成分の有する上述した効果を損なうことなく、滴下量のばらつきを効果的に抑制できる。
In the eye drop of the present invention, the content of the component (B) is not particularly limited, and the type of the component (B), the type and content of the component (A) to be used together, the use of the eye drop, the preparation form, and the method of use It sets suitably according to etc. As content of (B) component, 0.01 to 10 w / v% of total content of (B) component is preferable on the basis of the total amount of the eye drop of this invention, for example, 0.05 to 5 w / v% is more preferable, and 0.1 to 2 w / v% is more preferable. The content of the component (B) is suitable from the viewpoint of improving the dripping amount variation suppressing effect.
In the eye drop of the present invention, the content ratio of the component (B) is not particularly limited, and the type of the component (B), the type and content of the component (A) to be used together, the use of the eye drop, the formulation form, It is set as appropriate according to the method of use. As the content ratio of the component (B) to the component (A), for example, the total content of the component (B) is 1 part by mass of the total content of the component (A) contained in the eye drop of the present invention. It is preferably 0.01 to 10000 parts by mass, more preferably 0.05 to 5000 parts by mass, and still more preferably 0.1 to 2000 parts by mass. In eye drops that contain one of the component (A) or the component (B) and are designed to have a small drop amount per drop, a new problem is that the drop amount is likely to vary. On the other hand, when the content ratio of the component (B) is within the above range, the variation in the drop amount can be effectively suppressed without impairing the above-described effect of the component (A).
（Ａ）成分が増粘剤の場合、例えば、本発明の点眼剤に含まれる（Ａ）成分の総含有量１質量部に対して、（Ｂ）成分の総含有量が、０．０１〜５００質量部であることが好ましく、０．０５〜５０質量部であることがさらに好ましく、０．１〜２０重量部であることが特に好ましい。
（Ａ）成分がテルペノイド化合物の場合、例えば、本発明の点眼剤に含まれる（Ａ）成分の総含有量１質量部に対して、（Ｂ）成分の総含有量が、０.５〜１００００質量部であることが好ましく、０．６２５〜５０００質量部であることがさらに好ましく、１．２５〜２０００重量部であることが特に好ましい。
When the component (A) is a thickener, for example, the total content of the component (B) is 0.01 to 1 part by mass of the total content of the component (A) contained in the eye drop of the present invention. The amount is preferably 500 parts by weight, more preferably 0.05 to 50 parts by weight, and particularly preferably 0.1 to 20 parts by weight.
When the component (A) is a terpenoid compound, for example, the total content of the component (B) is 0.5 to 10,000 with respect to 1 part by mass of the total content of the component (A) contained in the eye drop of the present invention. It is preferable that it is a mass part, It is more preferable that it is 0.625-5000 mass part, It is especially preferable that it is 1.25-2000 weight part.
（３）その他の成分［任意成分］
本発明の点眼剤は、（Ａ）成分及び（Ｂ）成分に加えて、さらに点眼剤において汎用される有効成分（薬理活性成分や生理活性成分等）を配合することができる。このような成分の種類は特に制限されず、例えば、抗炎症薬成分又は収斂薬成分、抗アレルギー薬成分、ビタミン類、アミノ酸類、抗菌薬成分又は殺菌薬成分、局所麻酔薬成分、緑内障治療成分、白内障治療成分等が例示できる。本発明において好適な薬理活性成分及び生理活性成分としては、例えば、次のような成分が挙げられる。
(3) Other ingredients [arbitrary ingredients]
In addition to the component (A) and the component (B), the eye drop of the present invention can further contain an active ingredient (pharmacologically active ingredient, physiologically active ingredient, etc.) widely used in eye drops. The type of such components is not particularly limited, and examples thereof include anti-inflammatory components or astringent components, anti-allergic components, vitamins, amino acids, antibacterial components or bactericidal components, local anesthetic components, glaucoma treatment components The cataract treatment component can be exemplified. Examples of the pharmacologically active component and physiologically active component suitable in the present invention include the following components.
充血除去成分：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。
眼筋調節薬成分：例えば、アセチルコリンと類似した活性中心を有するコリンエステラーゼ阻害剤、具体的にはメチル硫酸ネオスチグミン、トロピカミド、ヘレニエン硫酸アトロピン等。
抗炎症薬成分又は収斂薬成分：硫酸亜鉛、乳酸亜鉛、アラントイン、イプシロン−アミノカプロン酸、塩化リゾチーム、プラノプロフェン、アズレンスルホン酸ナトリウム、グリチルリチン酸二カリウム、ブロムフェナクナトリウム、塩化ベルベリン、硫酸ベルベリンなど。
Decongestant: Tetrahydrozoline, naphazoline, epinephrine, ephedrine, methylephedrine, etc.
Eye muscle modulator component: For example, cholinesterase inhibitor having an active center similar to acetylcholine, specifically, neostigmine methyl sulfate, tropicamide, atropine sulfate helenien, and the like.
Anti-inflammatory component or astringent component: zinc sulfate, zinc lactate, allantoin, epsilon-aminocaproic acid, lysozyme chloride, pranoprofen, sodium azulenesulfonate, dipotassium glycyrrhizinate, bromfenac sodium, berberine chloride, berberine sulfate, etc. .
抗ヒスタミン薬成分又は抗アレルギー薬成分：アシタザノラスト、塩酸ジフェンヒドラミン、マレイン酸クロルフェニラミン、トラニラスト、クロモグリク酸ナトリウム、ペミロラストカリウムなど。 Antihistamine component or antiallergic agent component: acitazanolast, diphenhydramine hydrochloride, chlorpheniramine maleate, tranilast, sodium cromoglycate, pemirolast potassium and the like.
ビタミン：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、フラビンアデニンジヌクレオチドナトリウム、塩酸ピリドキシン、シアノコバラミン、パンテノール、パントテン酸カルシウム、パントテン酸ナトリウム、酢酸トコフェロール、など。 Vitamins: retinol acetate, retinol palmitate, pyridoxine hydrochloride, flavin adenine dinucleotide sodium, pyridoxine hydrochloride, cyanocobalamin, panthenol, calcium pantothenate, sodium pantothenate, tocopherol acetate, etc.
アミノ酸：アミノエチルスルホン酸（タウリン）、アスパラギン酸カリウム、アスパラギン酸マグネシウム、アスパラギン酸マグネシウム・カリウム混合物、イプシロン−アミノカプロン酸など。これらはｄ体、ｌ体又はｄｌ体のいずれでもよい。 Amino acids: aminoethylsulfonic acid (taurine), potassium aspartate, magnesium aspartate, magnesium and potassium aspartate mixture, epsilon-aminocaproic acid and the like. These may be d-form, l-form or dl-form.
抗菌薬成分又は殺菌薬成分：アルキルポリアミノエチルグリシン、スルファメトキサゾール、スルフイソキサゾール、スルファメトキサゾールナトリウム、スルフイソミジンナトリウムなど。 Antibacterial component or bactericidal component: alkylpolyaminoethylglycine, sulfamethoxazole, sulfisoxazole, sulfamethoxazole sodium, sulfisomidine sodium and the like.
また、本発明の点眼剤は、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、様々な成分や添加物を適宜選択し、一種またはそれ以上を併用して含有させることができる。それらの成分または添加物として、例えば、液剤の調製に一般的に使用される担体（水性溶媒、水性又は油性基剤など）、界面活性剤、防腐剤、殺菌剤又は抗菌剤、ｐＨ調節剤、等張化剤、キレート剤、緩衝剤、安定化剤等の各種添加剤が挙げられる。 In addition, the eye drop of the present invention is appropriately selected from various components and additives according to a conventional method according to its use and form as long as the effects of the invention are not impaired, and one or more of them are used in combination. Can be contained. As those components or additives, for example, carriers (aqueous solvent, aqueous or oily base, etc.) commonly used in the preparation of solutions, surfactants, preservatives, bactericides or antibacterial agents, pH adjusters, Various additives such as an isotonizing agent, a chelating agent, a buffering agent, and a stabilizing agent are included.
担体：水、含水エタノールなどの水性溶媒など。 Carrier: water, aqueous solvent such as water-containing ethanol.
界面活性剤：ＰＯＥ-ＰＯＰブロックコポリマー (具体的には、ポロクサマー４０７など)、エチレンジアミンのＰＯＥ-ＰＯＰブロックコポリマー付加物（具体的には、ポロキサミンなど）、ＰＯＥソルビタン（具体的には、ポリソルベート８０など）、ＰＯＥ硬化ヒマシ油（具体的には、ＰＯＥ(６０)硬化ヒマシ油、ＰＯＥ(４０)硬化ヒマシ油など）、ＰＯＥヒマシ油（具体的には、ＰＯＥ(１０)ヒマシ油、ＰＯＥ(３５)ヒマシ油など）、モノステアリン酸ポリエチレングリコール（具体的には、ステアリン酸ポリオキシル４０など）の非イオン性界面活性剤；アルキルジアミノエチルグリシンなどのグリシン型両性界面活性剤；アルキル４級アンモニウム塩（具体的には、塩化ベンザルコニウム、塩化ベンゼトニウムなど）などの陽イオン界面活性剤など。なお、括弧内の数字は付加モル数を示す。 Surfactant: POE-POP block copolymer (specifically, poloxamer 407, etc.), POE-POP block copolymer adduct of ethylenediamine (specifically, poloxamine, etc.), POE sorbitan (specifically, polysorbate 80, etc.) ), POE hydrogenated castor oil (specifically, POE (60) hydrogenated castor oil, POE (40) hydrogenated castor oil, etc.), POE castor oil (specifically, POE (10) castor oil, POE (35)) Castor oil), polyethylene glycol monostearate (specifically polyoxyl 40 stearate), nonionic surfactants; glycine-type amphoteric surfactants such as alkyldiaminoethylglycine; alkyl quaternary ammonium salts (specific Cation interfaces such as benzalkonium chloride and benzethonium chloride) Activators etc. The numbers in parentheses indicate the number of added moles.
防腐剤、殺菌剤又は抗菌剤：塩化ポリドロニウム、塩酸アルキルジアミノエチルグリシン、安息香酸ナトリウム、エタノール、塩化ベンザルコニウム、塩化ベンゼトニウム、グルコン酸クロルヘキシジン、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（具体的には、ポリヘキサメチレンビグアニド又はその塩酸塩など）など。 Preservatives, bactericides or antibacterial agents: polydronium chloride, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, Methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexamethylene biguanide or its hydrochloride, etc.).
ｐＨ調節剤：塩酸、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、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、ジエタノールアミンなど。 pH adjusting agent: hydrochloric acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, monoethanolamine, diisopropanolamine, sulfuric acid, phosphoric acid, diethanolamine and the like.
等張化剤：塩化カリウム、塩化ナトリウム、グリセリン、プロピレングリコールなど。 Isotonizing agents: potassium chloride, sodium chloride, glycerin, propylene glycol and the like.
キレート剤：エデト酸ナトリウム、クエン酸、又はこれらの水和物など。 Chelating agent: sodium edetate, citric acid, or hydrates thereof.
安定化剤：ジブチルヒドロキシトルエン、トロメタモール、亜硫酸水素ナトリウム、亜硫酸ナトリウムなど。
植物油 ：ゴマ油、ヒマシ油など。
Stabilizer: Dibutylhydroxytoluene, trometamol, sodium bisulfite, sodium sulfite and the like.
Vegetable oil: Sesame oil, castor oil, etc.
（４）点眼剤の物性
本発明の点眼剤の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ない。点眼剤のｐＨとしては、例えば、４．０〜９．５であることが好ましく、５．０〜９．０であることがより好ましく、５．５〜８．５であることが更に好ましい。
また、本発明の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。点眼剤の浸透圧比としては、例えば、０．５〜５．０であることが好ましく、０．６〜３．０であることがより好ましく、０．７〜２．０であることが更に好ましく、０．９〜１．５５であることが特に好ましい。浸透圧の調整は、無機塩、多価アルコール、糖アルコール、又は糖等を用いて、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、第十六改正日本薬局方に基づき、２８６ｍＯｓｍ（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。なお、浸透圧比測定用標準液（０．９ｗ／ｖ％塩化ナトリウム水溶液）については、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）を用いることができる。
上述した成分を含有する本発明の点眼剤の粘度は、１．１〜９０００ｍＰａ・ｓであることが好ましい。
本発明において、粘度の測定は、第１６改正日本薬局方の一般試験法に記載の粘度測定法に準拠し、２５℃における粘度が１００ｍＰａ・ｓ以上である場合は（２）単一円筒形回転粘度計（ブルックフィールド型粘度計）、２５℃における粘度が１００ｍＰａ・ｓ未満である場合は(３)円すい−平板形回転粘度計（コーンプレート型粘度計）にて行う。本発明においては、ロータや回転速度等の条件の選定は、装置の取扱説明書に準拠し、２５℃における粘度を測定する。
(4) Physical Properties of Eye Drops The pH of the eye drop of the present invention is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable range. As pH of eyedrops, it is preferable that it is 4.0-9.5, for example, it is more preferable that it is 5.0-9.0, and it is still more preferable that it is 5.5-8.5.
Further, the osmotic pressure of the eye drop of the present invention is not particularly limited as long as it is within the range allowed by the living body. The osmotic pressure ratio of the eye drop is, for example, preferably 0.5 to 5.0, more preferably 0.6 to 3.0, and still more preferably 0.7 to 2.0. 0.9 to 1.55 is particularly preferable. The osmotic pressure can be adjusted by a method known in the art using an inorganic salt, a polyhydric alcohol, a sugar alcohol, a sugar, or the like. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to 286 mOsm (0.9 w / v% sodium chloride aqueous solution) based on the 16th revised Japanese Pharmacopoeia. Measure with reference to (freezing point depression method). In addition, about the standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution), after drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500-650 degreeC for 40-50 minutes, it is in a desiccator (silica gel). It is allowed to cool, and 0.900 g is accurately weighed and dissolved in purified water to prepare exactly 100 mL, or a commercially available standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution) can be used. .
The viscosity of the eye drop of the present invention containing the components described above is preferably 1.1 to 9000 mPa · s.
In the present invention, the viscosity is measured in accordance with the viscosity measuring method described in the 16th revised Japanese Pharmacopoeia general test method. When the viscosity at 25 ° C. is 100 mPa · s or more, (2) single cylindrical rotation When the viscosity at 25 ° C. is less than 100 mPa · s, (3) a cone-plate rotational viscometer (cone plate viscometer) is used. In the present invention, selection of conditions such as rotor and rotation speed is based on the instruction manual of the apparatus, and the viscosity at 25 ° C. is measured.
（５）点眼剤の１滴量
本発明の点眼剤は、１滴あたりの滴下量が５〜２５μＬとなるように設計されている。点眼剤の１滴あたりの滴下量が、結膜嚢の容量内である５〜２５μＬとなるように設計されていることによって、溢れ出た点眼剤が眼の周りに付着し、使用者が不快感を生じるといったおそれがない。
また、本発明の点眼剤は、１滴あたりの滴下量が７〜２０μＬとなるように設計されていることが好ましく、９〜１５μＬとなるように設計されていることがより好ましい。
(5) One drop volume of eye drops The eye drop of the present invention is designed so that the drop volume per drop is 5 to 25 μL. It is designed so that the amount of the eye drop per drop is 5 to 25 μL, which is within the capacity of the conjunctival sac, so that the overflow eye drops adhere to the eyes and the user feels uncomfortable. There is no fear of generating.
In addition, the eye drop of the present invention is preferably designed so that the drop amount per drop is 7 to 20 μL, and more preferably 9 to 15 μL.
（６）点眼剤の容器等
本発明の点眼剤は、内容積が４〜３０ｍＬである容器に充填されてなることが好ましく、５〜２０ｍＬである容器に充填されてなることがより好ましく、６．０〜１０ｍＬである容器に充填されてなることが特に好ましい。
本発明の点眼剤を充填する容器の内容積が上記範囲内にある場合、１滴量が少量であっても点眼しやすく、本発明の効果をより一層顕著に奏することができる。また、後述するように、小さい径の点眼ノズルを用いて点眼する場合にも、滴下量のばらつきを抑制するという観点から特に好ましい。尚、このような点眼剤として、マルチドーズ型の点眼剤、即ち製品を一旦開封した後、数回以上に亘り使用される点眼剤であることが好ましい。
(6) Eye Drop Container, etc. The eye drop of the present invention is preferably filled in a container having an internal volume of 4 to 30 mL, more preferably 5 to 20 mL. It is particularly preferable that the container is filled with 0.0 to 10 mL.
When the internal volume of the container filled with the eye drop of the present invention is within the above range, even if the amount of one drop is small, it is easy to instill and the effect of the present invention can be exhibited more remarkably. Further, as will be described later, it is particularly preferable from the viewpoint of suppressing variation in the amount of dripping even when instillation is performed using an instillation nozzle having a small diameter. As such an eye drop, a multi-dose type eye drop, that is, an eye drop that is used several times or more after the product is once opened is preferable.
本発明の点眼剤は、少量を滴下するために滴下口を以下のような値にすることが好ましい。
本発明の点眼剤が充填された容器に装着される滴下ノズルの一例としては、図１、図２に示す形状のものが挙げられる。本発明の点眼剤が充填された容器に装着される滴下ノズルとしては、滴下口における内径Ｄ１が、１．５ｍｍ未満であることが好ましく、０．０１〜１．０ｍｍであることがさらに好ましく、０．０５〜０．８ｍｍであることが特に好ましく、０．１〜０．５ｍｍであることが更に特に好ましく、０．１〜０．４ｍｍであることが最も好ましい。滴下口とは、点眼剤を該容器に充填し、該ノズルを装着した後に、開口した状態で倒立状態にしたときに液滴が形成される出口部を指す。
また、本発明の点眼剤が充填された容器に装着される滴下ノズルの外径としては、ノズルの形状、材質、目的等に応じて適宜設定され、一概に規定することはできないが、例えば８ｍｍ以下が好ましく、０．１〜５ｍｍであることが更に好ましく、０．３〜３ｍｍであることが特に好ましく、０．５〜２ｍｍであることが更に特に好ましく、０．５〜１．５ｍｍであることが最も好ましい。本発明における滴下ノズルの外径とは、滴下口付近の注出管胴部における外径を示し、ノズルの先端(滴下口)部を丸める加工が施してあってもよい。
In order to drop a small amount of the eye drop of the present invention, it is preferable to set the dropping port to the following value.
As an example of the dropping nozzle attached to the container filled with the eye drop of the present invention, those having the shape shown in FIGS. As a dropping nozzle attached to a container filled with the eye drop of the present invention, the inner diameter D1 at the dropping port is preferably less than 1.5 mm, more preferably 0.01 to 1.0 mm, It is particularly preferably 0.05 to 0.8 mm, further particularly preferably 0.1 to 0.5 mm, and most preferably 0.1 to 0.4 mm. The dropping port refers to an outlet portion where droplets are formed when the eye drop is filled in the container and the nozzle is attached and then in an open state.
Further, the outer diameter of the dropping nozzle attached to the container filled with the eye drop of the present invention is appropriately set according to the shape, material, purpose, etc. of the nozzle, and cannot be generally defined, for example, 8 mm The following is preferable, more preferably 0.1 to 5 mm, particularly preferably 0.3 to 3 mm, still more preferably 0.5 to 2 mm, and more preferably 0.5 to 1.5 mm. Most preferred. The outer diameter of the dropping nozzle in the present invention indicates the outer diameter of the pouring tube body near the dropping port, and the tip (dropping port) of the nozzle may be rounded.
本発明の点眼剤を充填する容器のノズル口径における上記範囲は、１滴あたりの滴下量を５〜２５μＬとするために適している。
かかるノズルの形状とすることにより、点眼剤の１滴あたりの滴下量を５〜２５μＬとする事が容易となり、例えば、１滴あたりの滴下量が１５μＬとなるように点眼剤を効率よく用いることができる。
ノズルは、容器本体とは別成形された構造のものでも、ノズルと容器本体とが一体成型された構造のもの（例えば、１回使い切りタイプの点眼剤など）のいずれであってもよい。
The said range in the nozzle aperture of the container filled with the eyedrops of this invention is suitable in order to make the dripping amount per drop into 5-25 microliters.
By adopting such a nozzle shape, it becomes easy to set the drop amount per one drop of the eye drop to 5 to 25 μL. For example, the eye drop is efficiently used so that the drop amount per drop is 15 μL. Can do.
The nozzle may have either a structure formed separately from the container body or a structure in which the nozzle and the container body are integrally formed (for example, a one-time-use type eye drop).
本発明の点眼剤を充填する容器は、プラスチック製が好ましい。該プラスチック容器の構成材質については、特に制限されないが、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などのポリエステル、ポリアリレート、ポリカーボネート、ポリエチレン、ポリプロピレン、ポリイミド、エラストマーの何れか１種、これらの共重合体、又はこれらの２種以上の混合体が挙げられる。特に押出の加減等で本願発明の効果を発揮し易い点から、ポリエチレンテレフタレート、ポリアリレート、ポリエチレンナフタレート若しくはこれらの共重合体、又はこれらの２種以上の混合体が好ましく、特にポリエチレンテレフタレート製容器が好ましい。
なお、本発明において例えばポリエチレンテレフタレート製容器と記載する場合は、容器の構成材質中にポリエチレンテレフタレートが含有されているものであれば特に限定されないが、容器の構成材質全体の重量に対し、ポリエチレンテレフタレートが５０ｗ／ｗ％以上であるものが好ましい。
本発明の点眼剤は、このような材料を主材料とする透明容器（異物を観察するのに差し支えない程度の透明性を備えた容器）に充填されてもよいし、遮光された容器に充填されてもよい。遮光は、例えば上記した透明容器材料に着色剤を添加することにより行ってもよいし、容器をシュリンクフィルムや外箱などで覆うことにより、遮光してもよい。
またノズルの構成素材については、例えば、プラスチック製が好ましい。本発明の点眼剤の液切れを一層良好にさせ、滴下量のばらつきも抑制するという観点からは、ポリエチレン、ポリプロピレン、ポリブチレンテレフタレート又はエラストマーを構成素材として含むノズルが好ましい。ポリエチレンの種類としては、高密度ポリエチレン、低密度ポリエチレン等が挙げられ、中でも低密度ポリエチレンを構成素材として含むノズルが好ましい。
The container filled with the eye drop of the present invention is preferably made of plastic. The constituent material of the plastic container is not particularly limited. For example, any one of polyesters such as polyethylene terephthalate, polybutylene terephthalate, and polyethylene naphthalate, polyarylate, polycarbonate, polyethylene, polypropylene, polyimide, and elastomer, A copolymer or a mixture of two or more of these may be mentioned. In particular, polyethylene terephthalate, polyarylate, polyethylene naphthalate, a copolymer thereof, or a mixture of two or more of these is preferable from the viewpoint of easily exerting the effect of the present invention by adjusting the extrusion and the like. Particularly, a container made of polyethylene terephthalate. Is preferred.
In the present invention, for example, a container made of polyethylene terephthalate is not particularly limited as long as polyethylene terephthalate is contained in the constituent material of the container, but the polyethylene terephthalate is based on the total weight of the constituent material of the container. Is preferably 50 w / w% or more.
The eye drop of the present invention may be filled in a transparent container (a container having transparency that does not interfere with the observation of foreign matter) containing such a material as a main material, or in a light-shielded container. May be. The light shielding may be performed, for example, by adding a colorant to the transparent container material described above, or may be shielded by covering the container with a shrink film or an outer box.
The constituent material of the nozzle is preferably made of plastic, for example. From the viewpoint of further improving the liquid drop of the eye drop of the present invention and suppressing variation in the dripping amount, a nozzle including polyethylene, polypropylene, polybutylene terephthalate or elastomer as a constituent material is preferable. Examples of the type of polyethylene include high-density polyethylene and low-density polyethylene, and among them, a nozzle including low-density polyethylene as a constituent material is preferable.
（７）容器入り点眼剤の物性
本発明の点眼剤は、所定の１滴量を滴下するのに適した容器入りであることが好ましい。係る容器入り点眼剤のスクイズ力は、０．５〜１２Ｎであることが好ましく、１〜１０Ｎであることがさらに好ましく、１．５〜８Ｎであることが特に好ましい。スクイズ力とは、点眼剤を1滴滴下する際に必要な容器を押す力を示す。本発明の容器入り点眼剤のスクイズ力が上記範囲内にある場合、滴下量のばらつき抑制効果をより一層顕著に奏することができる。
スクイズ力の測定は、実施例に記載の方法に従って行う。
また、本発明の容器入り点眼剤の滴下時における容器の変位は、０．０１〜２．０ｍｍであることが好ましく、０．０５〜１．０ｍｍであることが更に好ましく、０．０５〜０．５ｍｍであることが特に好ましく、０．０７〜０．３ｍｍであることが最も好ましい。
容器入り点眼剤の滴下時における容器の変位とは、点眼剤を1滴滴下する際に必要な容器の変位である。本発明の容器入り点眼剤の滴下時における容器の変位が上記範囲内にある場合、滴下量のばらつき抑制効果をより一層顕著に奏することができる。
滴下時における容器の変位の測定は、実施例に記載の方法に従って行う。
(7) Physical properties of eye drop in container It is preferable that the eye drop of the present invention is in a container suitable for dropping a predetermined amount of one drop. The squeeze force of the ophthalmic solution in a container is preferably 0.5 to 12N, more preferably 1 to 10N, and particularly preferably 1.5 to 8N. The squeeze force indicates a force that pushes a container necessary for dropping one drop of eye drops. When the squeeze force of the eye drop in a container of the present invention is within the above range, the effect of suppressing variation in the amount of dripping can be more remarkably exhibited.
The squeeze force is measured according to the method described in the examples.
Further, the displacement of the container when the eye drop in the container of the present invention is dropped is preferably 0.01 to 2.0 mm, more preferably 0.05 to 1.0 mm, and 0.05 to 0. 0.5 mm is particularly preferable, and 0.07 to 0.3 mm is most preferable.
The displacement of the container when the eye drop in the container is dropped is the displacement of the container necessary for dropping one drop of the eye drop. When the displacement of the container at the time of dropping of the eye drop containing the container of the present invention is within the above range, the effect of suppressing variation in the amount of dripping can be more remarkably exhibited.
The measurement of the displacement of the container at the time of dripping is performed according to the method as described in an Example.
（８）点眼剤の用途
本発明に係る点眼薬は、一般点眼薬のほか、抗菌性点眼薬、人工涙液及びコンタクトレンズ装用中に点眼可能な点眼剤を含む。
なお、上記コンタクトレンズ装用中に点眼可能な点眼剤は、ハードコンタクトレンズ、ソフトコンタクトレンズを含むあらゆるコンタクトレンズに適用可能である。また、ソフトコンタクトレンズとは、イオン性及び非イオン性の双方を包含し、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。）及び非シリコーンハイドロゲルコンタクトレンズ（シリコーンハイドロゲルレンズでは無いソフトコンタクトレンズ）の双方を包含する。
(8) Use of eye drops In addition to general eye drops, the eye drops according to the present invention include antibacterial eye drops, artificial tears, and eye drops that can be applied while wearing contact lenses.
The eye drops that can be instilled while wearing the contact lens can be applied to all contact lenses including hard contact lenses and soft contact lenses. Soft contact lenses include both ionic and non-ionic, and include silicone hydrogel contact lenses (hereinafter abbreviated as SHCL) and non-silicone hydrogel contact lenses (silicone hydrogel lenses). Including both soft contact lenses).
（９）点眼方法
本発明の点眼剤の滴下方法は特に限定されず、点眼容器、ノズルの形状、使用目的等に応じて、あらゆる角度から点眼することが可能である。本発明の滴下量のばらつき抑制効果を一層顕著に奏するという観点から、滴下口を真下に向けて滴下するのが好ましい。
(9) Eye drop method The drop method of the eye drop of the present invention is not particularly limited, and it can be instilled from any angle depending on the eye drop container, the shape of the nozzle, the purpose of use, and the like. It is preferable that the dropping port is dropped directly below from the viewpoint of achieving the effect of suppressing variation in the dropping amount of the present invention more remarkably.
２．１滴量のばらつき抑制方法
また、前述したように、本発明の点眼剤は、(Ａ)増粘剤又はテルペノイド化合物、及び、（Ｂ）ホウ酸緩衝剤を含有し、１滴あたりの滴下量が５〜２５μＬとなるように設計されることによって、１滴量のばらつきを抑制することができる。
従って、本発明は、さらに別の観点から、点眼剤に(Ａ)成分として増粘剤又はテルペノイド化合物、及び、(Ｂ)成分としてホウ酸緩衝剤を含有させ、かつ該点眼剤の１滴あたりの滴下量が５〜２５μＬとなるように該点眼剤を設計する、１滴量のばらつきを抑制する方法をも提供する。
上記方法において、（Ａ）成分、（Ｂ）成分が共存するのであれば、それらの添加は同時であっても、別々であってもよく、その順序も特に限定されない。使用する（Ａ）成分、（Ｂ）成分の種類、それらの含有量（または配合量）、それらの含有比率、１滴あたりの滴下量、その他に配合する成分の種類、含有量（または配合量）、点眼剤の製剤形態、容器の種類、ノズルの種類、その組み合わせ、実施方法等については、前記「１．点眼剤」と同様である。
なお、本明細書において、点眼剤の１滴量のばらつきが抑制されているか否かは、後述の実施例に記載の方法によって判定することが可能である。
2.1 Droplet Variation Control Method As described above, the eye drop of the present invention contains (A) a thickener or a terpenoid compound, and (B) a borate buffer, By designing the drop amount to be 5 to 25 μL, variations in the drop amount can be suppressed.
Therefore, the present invention, from yet another point of view, contains a thickener or a terpenoid compound as the component (A) and a borate buffer as the component (B) in the eye drop, and per drop of the eye drop There is also provided a method of designing the ophthalmic solution so that the drop amount of the solution is 5 to 25 μL, and suppressing variations in the drop amount.
In the above method, as long as the component (A) and the component (B) coexist, they may be added simultaneously or separately, and the order thereof is not particularly limited. Component (A) to be used, type of component (B), their content (or blending amount), their content ratio, drop amount per drop, other types of component to be blended, content (or blending amount) ), The preparation form of the eye drop, the type of container, the type of nozzle, the combination thereof, the method of implementation, and the like are the same as those in “1. Eye drop”.
In addition, in this specification, it can be determined by the method as described in the below-mentioned Example whether the dispersion | variation in the amount of 1 drop of eyedrops is suppressed.
以下に、実施例及び試験例を挙げて本発明を詳細に説明するが、本発明はこれらの実施例等によって限定されるものではない。
また、平均滴下量(μＬ)は、各容器入り点眼剤における平均滴下量（ｍｇ）を求め、比重を１として算出した。平均滴下量（ｍｇ）の測定方法としては、容器入り点眼剤のノズルの滴下口をほぼ垂直に下に向けて滴下し、１滴滴下毎に滴下重量を測定し、この操作を２０回繰り返した値から算出した。
また、各表における組成の単位は、ｗ／ｖ％である。
Hereinafter, the present invention will be described in detail with reference to Examples and Test Examples, but the present invention is not limited to these Examples and the like.
Moreover, the average dripping amount (μL) was calculated by calculating the average dripping amount (mg) in each eye drop in each container and setting the specific gravity as 1. As a method for measuring the average drop amount (mg), the drop port of the ophthalmic nozzle in the container was dropped almost vertically downward, the drop weight was measured for each drop, and this operation was repeated 20 times. Calculated from the values.
The unit of composition in each table is w / v%.
（１）試料の調製
表１〜２に示す組成を有する各点眼剤を以下の方法で調製した。即ち、攪拌下に、精製水にヒドロキシエチルセルロース等の増粘剤を添加し分散させ、次いで、ｐＨ調整剤（水酸化ナトリウム又は塩酸）以外の成分を添加して攪拌溶解した。更に、水酸化ナトリウム又は塩酸を用いてｐＨを調整した後、精製水を適量加えて所定の濃度となるよう調製した。
調製した各点眼剤に関して、粘度の測定を行い、また、点眼剤を所定の容器に充填した容器入り点眼剤に関して、スクイズ力の測定、滴下時における容器の変位の測定、及び滴下量のばらつき試験を行った。
(1) Preparation of sample Each eye drop having the composition shown in Tables 1-2 was prepared by the following method. That is, under stirring, a thickener such as hydroxyethylcellulose was added and dispersed in purified water, and then components other than the pH adjuster (sodium hydroxide or hydrochloric acid) were added and dissolved by stirring. Furthermore, after adjusting pH using sodium hydroxide or hydrochloric acid, an appropriate amount of purified water was added to prepare a predetermined concentration.
Viscosity is measured for each of the prepared eye drops, and squeeze force measurement, measurement of container displacement at the time of dropping, and dispersion amount variation test for eye drops in containers filled with eye drops in a predetermined container. Went.
（２）物性測定方法
（２−１）粘度測定
各点眼剤の粘度を以下の方法で測定した。
２５℃における粘度が１００ｍＰａ・ｓ以上のものは、第１６改正日本薬局方 一般試験法 粘度測定法 第２法回転粘度計法に記載されている「（２）単一円筒形回転粘度計（ブルックフィールド型粘度計）」の試験法に準拠して、以下の条件で２５℃における粘度を測定した。
測定装置、回転数、ローターＮｏ．設定時間
・以下の増粘剤の１ｗ／ｖ％水溶液−カルボキシビニルポリマー、ヒドロキシプロピルメチルセルロース２９０６：
測定装置_ＴＶ−１０Ｍ、回転数_１２ｒｐｍ、ローターＮｏ．_Ｍ２、測定時間１分後の粘度
２５℃における粘度が１００ｍＰａ・ｓ未満のものは第１６改正日本薬局方 一般試験法 粘度測定法 第２法回転粘度計法に記載されている「（３）円すい−平板形回転粘度計（コーンプレート型粘度計）」の試験法に準拠して、以下の条件で２５℃における粘度を測定した。
測定装置、回転数、ローターＮｏ．及び設定時間
・実施例２−１、ヒドロキシエチルセルロースの１ｗ／ｖ％水溶液：
測定装置_ＲＣ−５５０、回転数_２０ｒｐｍ、ローター_標準コーンローター(１°３４’ ×Ｒ２４) 、設定時間_３分後の粘度
・実施例２−１以外：
測定装置_ＲＣ−５５０、回転数_５０ｒｐｍ、ローター_標準コーンローター(１°３４’ ×Ｒ２４)、設定時間_１分後の粘度
・ポリビニルピロリドンＫ２５の１ｗ／ｖ％水溶液：
測定装置_ＲＣ−５５０、回転数_１００ｒｐｍ、ローター_標準コーンローター(１°３４’ ×Ｒ２４)、設定時間_３分後の粘度
(2) Physical property measurement method (2-1) Viscosity measurement The viscosity of each eye drop was measured by the following method.
Those having a viscosity at 25 ° C. of 100 mPa · s or more are described in “16th revised Japanese Pharmacopoeia General Test Method Viscosity Measurement Method 2 Method Rotary Viscometer Method” (2) Single Cylindrical Rotational Viscometer (Brook Based on the test method of “field type viscometer”, the viscosity at 25 ° C. was measured under the following conditions.
Measuring device, rotation speed, rotor No. Setting time-1 w / v% aqueous solution of the following thickeners-carboxyvinyl polymer, hydroxypropyl methylcellulose 2906:
Measuring device_TV-10M, rotation speed_12 rpm, rotor No. _M2, Viscosity after 1 minute of measurement time Viscosity at 25 ° C. is less than 100 mPa · s is described in the 16th revised Japanese Pharmacopoeia General Test Method Viscosity Measurement Method 2 Method Viscometer “(3) Cone -The viscosity at 25 ° C was measured under the following conditions in accordance with the test method of "flat plate viscometer (cone plate viscometer)".
Measuring device, rotation speed, rotor No. And set time-Example 2-1, 1 w / v% aqueous solution of hydroxyethyl cellulose:
Measuring device_RC-550, rotation speed_20 rpm, rotor_standard cone rotor (1 ° 34 ′ × R24), set time_viscosity after 3 minutes / other than Example 2-1.
Measuring apparatus_RC-550, rotation speed_50 rpm, rotor_standard cone rotor (1 ° 34 ′ × R24), set time_viscosity after 1 minute, 1 w / v% aqueous solution of polyvinylpyrrolidone K25:
Measuring device_RC-550, rotation speed_100rpm, rotor_standard cone rotor (1 ° 34 'x R24), set time_viscosity after 3 minutes
（２−２）スクイズ力測定
各容器入り点眼剤のスクイズ力を以下の方法で測定した。
試験対象の容器入り点眼剤を、充填後未使用の状態で、滴下口を真下に向けて、２滴滴下した。次に、該容器入り点眼剤を滴下口を真下に向けて垂直な壁面に指で押さえ固定した。次いで、デジタルプッシュプルゲージ（ＣＰＵ ＧＡＵＧＥ ９５２０Ａ ，アイコーエンジニアリング（株）製）の先端に直径５ｍｍの平板型の治具を取り付けた状態で、容器の側面に圧力を加え、１滴滴下するときのスクイズ力（ Ｎ ） を測定した。測定は１０回（１０滴分）実施し、その平均を求めた。
(2-2) Squeeze force measurement The squeeze force of each eye drop in each container was measured by the following method.
Two drops of the eye drop in a container to be tested were dropped with the dropping port directed directly below in an unused state after filling. Next, the ophthalmic solution in a container was fixed by pressing with a finger on a vertical wall surface with the dripping port directed directly below. Next, squeeze when dropping one drop by applying pressure to the side of the container with a 5 mm diameter flat jig attached to the tip of a digital push-pull gauge (CPU GAUGE 9520A, manufactured by Aiko Engineering Co., Ltd.) The force (N) was measured. The measurement was carried out 10 times (for 10 drops), and the average was obtained.
(２−３)滴下時における容器の変位測定
各容器入り点眼剤の滴下時における容器の変位を、以下の方法で測定した。
試験対象の容器入り点眼剤について、充填後未使用の状態で、オートグラフ(製品名：ＡＵＴＯ ＧＲＡＰＨ ＡＧＳ−Ｘ ５ｋＮ ＴＲＡＰＥＺＩＵＭ （ＳＨＩＭＡＤＺＵ製))を用いて変位とスクイズ力の関係を求めた。その後、予め上記（２−２）の方法に従って求めておいたスクイズ力に相当する容器の変位の値を求めた。
尚、オートグラフの測定条件は以下の通りである。
・クロスヘッドスピード ：１００ｍｍ／ｍｉｎ
・治具 ：Φ５ｍｍ
(2-3) Measurement of container displacement at the time of dropping The container displacement at the time of dropping each container-containing eye drop was measured by the following method.
The relationship between displacement and squeeze force of the eye drop in a container to be tested was determined using an autograph (product name: AUTO GRAPH AGS-X 5kN TRAPEZIUM (manufactured by SHIMADZU)) in an unused state after filling. Thereafter, the displacement value of the container corresponding to the squeeze force determined in advance according to the method (2-2) was determined.
The autograph measurement conditions are as follows.
・ Cross head speed: 100mm / min
・ Jig: Φ5mm
（３）試薬
増粘剤は、１．０ｗ／ｖ％となるように精製水に溶解した場合の２５℃における粘度が以下の値を示すものを使用した (測定条件は（２）物性測定方法（２−１）粘度測定に記載の方法に準じた。) 。
カルボキシビニルポリマー ：１９１１ｍＰａ・ｓ
ヒドロキシエチルセルロース ：１８．６ｍＰａ・ｓ
ヒドロキシプロピルメチルセルロース２９０６ ：２５８．５ｍＰａ・ｓ
ポリビニルピロリドンＫ２５ ：１．２ｍＰａ・ｓ
(3) Reagent The thickener used was one having a viscosity at 25 ° C. of the following value when dissolved in purified water so as to be 1.0 w / v% (measurement conditions are (2) physical property measurement method (2-1) According to the method described in the viscosity measurement).
Carboxyvinyl polymer: 1911 mPa · s
Hydroxyethyl cellulose: 18.6 mPa · s
Hydroxypropyl methylcellulose 2906: 258.5 mPa · s
Polyvinylpyrrolidone K25: 1.2 mPa · s
［試験１］滴下量のばらつき評価１
常法により、表１に示す組成に従って各処方例（点眼剤）を調製し、内容積７．７ｍＬのポリエチレンテレフタレート製点眼容器に６ｍＬ充填し、この容器にポリエチレン製ノズルを装着した。ポリエチレン製ノズルとしては、（ｉ）５〜１５μＬの滴下に適したノズル（滴下口の内径０．３ｍｍ、外径０．９ｍｍ、ノズル以下ノズル(ｉ) と表記することもある）、及び（ｉｉ）３０〜５０μＬの滴下に適したノズル（内径２ｍｍ、外径６ｍｍ、以下ノズル(ｉｉ)と表記することもある）の２種類のノズルを使用した。この容器入り点眼剤をノズルの滴下口をほぼ垂直に下を向けて滴下し、１滴滴下毎に滴下重量を測定した。この操作を２０回繰り返すことによって求めた平均滴下量（ＡＶＧ：ｍｇ）、標準偏差（ＳＤ：ｍｇ）から、下記式（Ｉ)によって滴下量のばらつき（変動係数ＣＶ：％）を算出した。結果を表１に併せて示す。
[Test 1] Evaluation of variation in dripping amount 1
Each formulation example (eye drops) was prepared by a conventional method according to the composition shown in Table 1, and 6 mL of a polyethylene terephthalate eye drop container having an internal volume of 7.7 mL was filled, and a polyethylene nozzle was attached to the container. As the polyethylene nozzle, (i) a nozzle suitable for dropping 5 to 15 μL (the inner diameter of the dropping port is 0.3 mm, the outer diameter is 0.9 mm, and sometimes referred to as nozzle (i) below the nozzle), and (ii) 2) Nozzles suitable for dropping 30 to 50 μL (inner diameter 2 mm, outer diameter 6 mm, hereinafter sometimes referred to as nozzle (ii)) were used. The ophthalmic solution in a container was dropped with the nozzle drop opening facing substantially vertically downward, and the drop weight was measured for each drop. From the average drop amount (AVG: mg) and standard deviation (SD: mg) determined by repeating this operation 20 times, the drop amount variation (variation coefficient CV:%) was calculated by the following formula (I). The results are also shown in Table 1.
＊実施例１−１のスクイズ力は２．０Ｎであり、滴下時の容器の変位は０．０８ｍｍであった。 * The squeeze force of Example 1-1 was 2.0 N, and the displacement of the container at the time of dripping was 0.08 mm.
表１に示すとおり、増粘剤としてヒドロキシエチルセルロース(以下、ＨＥＣと表記することもある)を含有する処方例１−Ａを点眼容器に充填後、ノズル（ｉｉ）を装着し滴下した場合（参考例１−１)に比較して、ノズル（ｉ）を装着した場合には、滴下量のばらつきが格段に増大することが確認された（比較例１−１)。一方、リン酸緩衝剤、ホウ酸緩衝剤をそれぞれ含有させた処方例(比較例１−２、比較例１−３)、及び、ヒドロキシエチルセルロースとリン酸緩衝剤を共に含有させた処方例（比較例１−４)においても、ノズル(ｉ）を装着した場合には、ほぼ一定して、滴下量がばらつくことが確認された。
一方、全く意外なことに、ヒドロキシエチルセルロースとホウ酸緩衝剤を共に含有させた場合（実施例１−１)においては、変動計数が顕著に改善され、参考例１−１とほぼ同程度まで滴下量のばらつきを抑制できることが確認された。
また、健常人２名が実施例１−１を片眼に１滴ずつ両眼に点眼したところ、刺激が無く、非常に良好な使用感であった。
As shown in Table 1, when prescription example 1-A containing hydroxyethyl cellulose (hereinafter sometimes referred to as HEC) as a thickener is filled in an eye dropper container and then dropped with a nozzle (ii) (reference) In comparison with Example 1-1), it was confirmed that when the nozzle (i) was mounted, the variation in the dripping amount was remarkably increased (Comparative Example 1-1). On the other hand, a formulation example (Comparative Example 1-2, Comparative Example 1-3) containing a phosphate buffer and a borate buffer respectively, and a formulation example (Comparative Example) containing both hydroxyethyl cellulose and a phosphate buffer Also in Example 1-4), when the nozzle (i) was mounted, it was confirmed that the dripping amount was almost constant and varied.
On the other hand, surprisingly, in the case where both hydroxyethyl cellulose and borate buffer were contained (Example 1-1), the variation count was remarkably improved and dropped to almost the same level as in Reference Example 1-1. It was confirmed that variation in the amount could be suppressed.
In addition, when two healthy subjects instilled Example 1-1 into both eyes, one drop per eye, there was no irritation and the feeling was very good.
［試験２］滴下量のばらつき評価２
表２に示す組成に従って各処方例(点眼剤)を調製し、内容積７．７ｍＬのポリエチレンテレフタレート製点眼容器に６ｍＬ充填し、この容器にポリエチレン製ノズルを装着した。処方例を表２に記載のものに変更し、ポリエチレン製ノズルとして、全てノズル（ｉ）を用いたこと以外は、試験１と同様の方法でばらつき評価試験を実施し、上記式（Ｉ)によって滴下量のばらつき（変動係数ＣＶ：％）を算出した。さらに、下記式(ＩＩ)を用いて、対応する比較例に対するばらつき改善率(％)を求めた。結果を表２に示す。
尚、対応する比較例は、実施例２-１、実施例２−２、実施例２−３、実施例２−４についてはそれぞれ、比較例２-１、比較例２−２、比較例２−３、比較例２−４である。
[Test 2] Drip amount variation evaluation 2
Each formulation example (eye drops) was prepared according to the composition shown in Table 2, and 6 mL of a polyethylene terephthalate eye drop container having an internal volume of 7.7 mL was filled, and a polyethylene nozzle was attached to the container. The prescription example was changed to the one shown in Table 2, and a variation evaluation test was performed in the same manner as in Test 1 except that all the nozzles (i) were used as polyethylene nozzles, and according to the above formula (I) The variation of the dripping amount (coefficient of variation CV:%) was calculated. Furthermore, using the following formula (II), the variation improvement rate (%) for the corresponding comparative example was determined. The results are shown in Table 2.
The corresponding comparative examples are Comparative Example 2-1, Comparative Example 2-2, and Comparative Example 2 for Example 2-1, Example 2-2, Example 2-3, and Example 2-4, respectively. -3, Comparative Example 2-4.
＊各容器入り点眼剤におけるスクイズ力(Ｎ)は下記の通りであった。
実施例２−１ ４．６
実施例２−２ ２．３
実施例２−３ ２．２
実施例２−４ ２．５
＊各容器入り点眼剤における滴下時の容器の変位(ｍｍ)は下記の通りであった。
実施例２−１ ０．２０
実施例２−２ ０．１０
実施例２−３ ０．１０
実施例２−４ ０．１２
* The squeeze force (N) in each container eye drop was as follows.
Example 2-1 4.6
Example 2-2 2.3
Example 2-3 2.2
Example 2-4 2.5
* Displacement (mm) of the container at the time of dropping in each container-containing eye drop was as follows.
Example 2-1 0.20
Example 2-2 0.10
Example 2-3 0.10
Example 2-4 0.12
増粘剤としてカルボキシビニルポリマー、ヒドロキシプロピルメチルセルロース２９０６を用いた場合において、共にリン酸緩衝剤を含有させた比較例(比較例２−１、比較例２−２)に対して、ホウ酸緩衝剤を含有させた実施例(実施例２−１、実施例２−２)は、滴下時のばらつきが顕著に改善されることがわかった。
さらに、ｌ−メントール、ｄ−カンフルを含有させた場合においても、共にリン酸緩衝剤を含有させた比較例(比較例２−３、２−４)に対して、ホウ酸緩衝剤を配合した実施例(実施例２−３、実施例２−４)は、滴下時のばらつきが顕著に改善されることが確認された。
また、健常人２名が実施例２−２を片眼に１滴ずつ両眼に点眼したところ、刺激が無く、非常に良好な使用感であった。
In the case where carboxyvinyl polymer and hydroxypropylmethylcellulose 2906 are used as thickeners, the boric acid buffering agent compared to the comparative examples (Comparative Example 2-1 and Comparative Example 2-2) both containing a phosphate buffering agent. It was found that the examples (Example 2-1 and Example 2-2) containing the phenotype significantly improved the dispersion at the time of dropping.
Furthermore, even when 1-menthol and d-camphor were contained, a borate buffer was added to the comparative examples (Comparative Examples 2-3 and 2-4) both containing a phosphate buffer. In the examples (Example 2-3 and Example 2-4), it was confirmed that the dispersion at the time of dropping was remarkably improved.
Moreover, when 2 healthy persons instilled Example 2-2 drop by drop into one eye to one eye, there was no irritation | stimulation and it was a very favorable usability | use_condition.
［試験３］滴下量のばらつき評価３
表３に示す組成に従って各処方例(点眼剤)を調製し、内容積７．７ｍＬのポリエチレンテレフタレート製点眼容器に６ｍＬ充填し、この容器にポリエチレン製ノズルを装着した。処方例を表３に記載のものに変更し、ポリエチレン製ノズルとして、全てノズル（ｉ）を用いたこと以外は、試験１と同様の方法でばらつき評価試験を実施し、上記式（Ｉ)によって滴下量のばらつき（変動係数ＣＶ：％）を算出した。さらに、式(ＩＩ)を用いて、対応する比較例に対するばらつき改善率(％)を求めた。結果を表３に併せて示す。
尚、対応する比較例は、実施例３−１については比較例３−１、実施例３−２については比較例３−２、実施例３−３については比較例３−３である。
[Test 3] Evaluation of variation in dripping amount 3
Each formulation example (eye drops) was prepared according to the composition shown in Table 3, and 6 mL of a polyethylene terephthalate eye drop container having an internal volume of 7.7 mL was filled, and a polyethylene nozzle was attached to the container. The prescription example was changed to the one described in Table 3, and a variation evaluation test was performed in the same manner as in Test 1 except that all the nozzles (i) were used as polyethylene nozzles, and according to the above formula (I) The variation of the dripping amount (coefficient of variation CV:%) was calculated. Furthermore, using the formula (II), the variation improvement rate (%) for the corresponding comparative example was obtained. The results are also shown in Table 3.
The corresponding comparative examples are Comparative Example 3-1 for Example 3-1, Comparative Example 3-2 for Example 3-2, and Comparative Example 3-3 for Example 3-3.
＊各容器入り点眼剤におけるスクイズ力(Ｎ)は下記の通りであった。
実施例３−１ ２．１
実施例３−２ １．８
実施例３−３ ７．０
＊各容器入り点眼剤における滴下時の容器の変位(ｍｍ)は下記の通りであった。
実施例３−１ ０．０９
実施例３−２ ０．０７
実施例３−３ ０．３１
* The squeeze force (N) in each container eye drop was as follows.
Example 3-1 2.1
Example 3-2 1.8
Example 3-3 7.0
* Displacement (mm) of the container at the time of dropping in each container-containing eye drop was as follows.
Example 3-1 0.09
Example 3-2 0.07
Example 3-3 0.31
ポリビニルピロリドンK25等の増粘剤、又は、ｌ−メントール、ｄｌ−カンフル、ベルガモット油等のテルペノイド化合物と、ホウ酸緩衝剤を含有させた場合（実施例３−１、実施例３−２、実施例３−３)には、意外なことに滴下量のばらつきが改善されることが確認された。 When a thickener such as polyvinylpyrrolidone K25 or a terpenoid compound such as l-menthol, dl-camphor and bergamot oil and a borate buffer are contained (Example 3-1 and Example 3-2) In Example 3-3), it was surprisingly confirmed that the variation in the dripping amount was improved.
［製剤例］
表４及び表５、並びに、表６及び表７に示す製剤処方例(点眼剤)を調製し、所定の容器に充填した後所定のノズルを装着したものを製剤例(容器入り点眼剤)とした。
・製剤例１〜１３：製剤処方例１〜１３を内容積６ｍＬの容器に充填した後、滴下口における内径が０．１ｍｍであり、外径が０．４ｍｍであるノズルを装着したもの(滴下量：９μＬ)
・製剤例１４〜２６：製剤処方例１〜１３を内容積８ｍＬの容器に充填した後、滴下口における内径が０．３ｍｍであり、外径が１．０ｍｍであるノズルを装着したもの(滴下量：１５μＬ)
・製剤例２７〜３９：製剤処方例１〜１３を内容積１０ｍＬの容器に充填した後、滴下口における内径が０．５ｍｍであり、外径が１．２ｍｍであるノズルを装着したもの(滴下量：１８μＬ)
[Formulation example]
Formulation formulation examples (eye drops) shown in Tables 4 and 5, and Tables 6 and 7 were prepared. did.
Formulation Examples 1 to 13: After filling Formulation Formulation Examples 1 to 13 in a container with an internal volume of 6 mL, a nozzle having an inner diameter of 0.1 mm and an outer diameter of 0.4 mm attached to the dripping port (dropping) (Amount: 9μL)
Formulation Examples 14 to 26: After filling Formulation Formulation Examples 1 to 13 in a container with an internal volume of 8 mL, a nozzle having an inner diameter of 0.3 mm and an outer diameter of 1.0 mm attached to the dropping port (dropping) (Amount: 15 μL)
Formulation Examples 27 to 39: After filling Formulation Formulation Examples 1 to 13 in a container having an internal volume of 10 mL, a nozzle having an inner diameter of 0.5 mm and an outer diameter of 1.2 mm attached to the dropping port (dropping) (Amount: 18 μL)
本発明の点眼剤の滴下量のばらつき改善方法は、増粘剤又はテルペノイド化合物を含有する点眼剤において、１滴量を少なくして点眼する場合に、滴下量のばらつきを抑制できる。従って、本発明の点眼剤は、実用性に富み、使用感が良好である。
The method for improving the variation in the drop amount of the eye drop of the present invention can suppress the variation in the drop amount when the eye drop containing a thickener or a terpenoid compound is instilled with a small drop amount. Therefore, the eye drop of the present invention is highly practical and has a good feeling of use.
Claims (10)
(A) a thickener or terpenoid compound, and (B) a borate buffer, wherein the thickener is at least one selected from the group consisting of hydroxyethylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone The terpenoid compound is filled with an eye drop that is at least one selected from the group consisting of menthol, camphor, and bergamot oil in a container designed so that the drop amount per drop is 5 to 25 μL. A method for producing an eye drop in a container. (Except when the eye drop contains diclofenac sodium 0.1 w / v%, boric acid, borax, chlorobutanol, povidone, and polysorbate 80)
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