JP2008100957A - Eye drop - Google Patents
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- JP2008100957A JP2008100957A JP2006285969A JP2006285969A JP2008100957A JP 2008100957 A JP2008100957 A JP 2008100957A JP 2006285969 A JP2006285969 A JP 2006285969A JP 2006285969 A JP2006285969 A JP 2006285969A JP 2008100957 A JP2008100957 A JP 2008100957A
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- 239000003889 eye drop Substances 0.000 title claims abstract description 38
- 238000002834 transmittance Methods 0.000 claims abstract description 22
- 239000002997 ophthalmic solution Substances 0.000 claims abstract description 18
- 229940054534 ophthalmic solution Drugs 0.000 claims abstract description 18
- ZCVMWBYGMWKGHF-UHFFFAOYSA-N Ketotifene Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2CC(=O)C2=C1C=CS2 ZCVMWBYGMWKGHF-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229960004958 ketotifen Drugs 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- -1 polyethylene terephthalate Polymers 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 5
- 239000000975 dye Substances 0.000 claims description 4
- 239000000049 pigment Substances 0.000 claims description 4
- 229920000139 polyethylene terephthalate Polymers 0.000 claims description 4
- 239000005020 polyethylene terephthalate Substances 0.000 claims description 4
- 239000004698 Polyethylene Substances 0.000 claims description 3
- 239000004743 Polypropylene Substances 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 229920003207 poly(ethylene-2,6-naphthalate) Polymers 0.000 claims description 3
- 229920001230 polyarylate Polymers 0.000 claims description 3
- 229920000573 polyethylene Polymers 0.000 claims description 3
- 239000011112 polyethylene naphthalate Substances 0.000 claims description 3
- 229920001155 polypropylene Polymers 0.000 claims description 3
- 239000003086 colorant Substances 0.000 claims description 2
- 229920001577 copolymer Polymers 0.000 claims description 2
- 229920000728 polyester Polymers 0.000 claims description 2
- 239000000243 solution Substances 0.000 abstract description 12
- 230000000172 allergic effect Effects 0.000 abstract description 2
- 208000010668 atopic eczema Diseases 0.000 abstract description 2
- 239000007923 nasal drop Substances 0.000 abstract description 2
- 239000002244 precipitate Substances 0.000 abstract description 2
- 208000024891 symptom Diseases 0.000 abstract description 2
- 239000004615 ingredient Substances 0.000 abstract 1
- 238000006303 photolysis reaction Methods 0.000 abstract 1
- 230000015843 photosynthesis, light reaction Effects 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 45
- 239000008213 purified water Substances 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 18
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 14
- 229960003630 ketotifen fumarate Drugs 0.000 description 11
- YNQQEYBLVYAWNX-WLHGVMLRSA-N ketotifen fumarate Chemical compound OC(=O)\C=C\C(O)=O.C1CN(C)CCC1=C1C2=CC=CC=C2CC(=O)C2=C1C=CS2 YNQQEYBLVYAWNX-WLHGVMLRSA-N 0.000 description 11
- 229960000686 benzalkonium chloride Drugs 0.000 description 10
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- 235000011187 glycerol Nutrition 0.000 description 9
- 230000003204 osmotic effect Effects 0.000 description 9
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 9
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 9
- 229920000053 polysorbate 80 Polymers 0.000 description 9
- 229940068968 polysorbate 80 Drugs 0.000 description 9
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 9
- 229960004926 chlorobutanol Drugs 0.000 description 7
- 229940021790 tetrahydrozoline hydrochloride Drugs 0.000 description 7
- BJORNXNYWNIWEY-UHFFFAOYSA-N tetrahydrozoline hydrochloride Chemical compound Cl.N1CCN=C1C1C2=CC=CC=C2CCC1 BJORNXNYWNIWEY-UHFFFAOYSA-N 0.000 description 7
- RMRCNWBMXRMIRW-BYFNXCQMSA-M cyanocobalamin Chemical compound N#C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O RMRCNWBMXRMIRW-BYFNXCQMSA-M 0.000 description 6
- 229940065427 vitamin b6 100 mg Drugs 0.000 description 6
- 238000004040 coloring Methods 0.000 description 5
- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 description 4
- BIVBRWYINDPWKA-VLQRKCJKSA-L Glycyrrhizinate dipotassium Chemical compound [K+].[K+].O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C([O-])=O)[C@@H]1O[C@H](C([O-])=O)[C@@H](O)[C@H](O)[C@H]1O BIVBRWYINDPWKA-VLQRKCJKSA-L 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 229940046978 chlorpheniramine maleate Drugs 0.000 description 4
- 229940101029 dipotassium glycyrrhizinate Drugs 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 3
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 3
- 229960002104 cyanocobalamin Drugs 0.000 description 3
- 235000000639 cyanocobalamin Nutrition 0.000 description 3
- 239000011666 cyanocobalamin Substances 0.000 description 3
- 229940012356 eye drops Drugs 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 229940096517 menthol 5 mg Drugs 0.000 description 3
- 229940104757 vitamin E 50 mg Drugs 0.000 description 3
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 229960002684 aminocaproic acid Drugs 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 229940006423 chondroitin sulfate sodium Drugs 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- YKZPPPNXRZHVGX-PXYKVGKMSA-L dipotassium;(2s)-2-aminobutanedioate;hydron;hydrate Chemical compound [H+].[H+].O.[K+].[K+].[O-]C(=O)[C@@H](N)CC([O-])=O.[O-]C(=O)[C@@H](N)CC([O-])=O YKZPPPNXRZHVGX-PXYKVGKMSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229940041616 menthol Drugs 0.000 description 2
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
- 229920001634 Copolyester Polymers 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- XLRHXNIVIZZOON-WFUPGROFSA-L Flavin adenine dinucleotide disodium Chemical compound [Na+].[Na+].C1=NC2=C(N)N=CN=C2N1[C@@H]([C@H](O)[C@@H]1O)O[C@@H]1COP([O-])(=O)OP([O-])(=O)OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C2=NC(=O)NC(=O)C2=NC2=C1C=C(C)C(C)=C2 XLRHXNIVIZZOON-WFUPGROFSA-L 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- KXKPYJOVDUMHGS-OSRGNVMNSA-N chondroitin sulfate Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](OS(O)(=O)=O)[C@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](C(O)=O)O1 KXKPYJOVDUMHGS-OSRGNVMNSA-N 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229940051814 glycerin 2100 mg Drugs 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 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 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 238000004898 kneading Methods 0.000 description 1
- 150000002617 leukotrienes Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 1
- 229940080927 menthol 10 mg Drugs 0.000 description 1
- 229940015700 menthol 15 mg Drugs 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 235000019477 peppermint oil Nutrition 0.000 description 1
- 229940068988 potassium aspartate Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229940021651 pyridoxine hydrochloride 100 mg Drugs 0.000 description 1
- 229940037001 sodium edetate Drugs 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
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- Medical Preparation Storing Or Oral Administration Devices (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
本発明は、ケトチフェン又はその塩を含有する点眼液を、安定な状態で提供することを可能にした点眼剤に関する。 The present invention relates to an ophthalmic solution that can provide an ophthalmic solution containing ketotifen or a salt thereof in a stable state.
ケトチフェン又はその塩は、アレルギー反応の際、ヒスタミンなどの遊離抑制作用・直接拮抗作用を有し、ロイコトリエンの産生と遊離抑制・拮抗作用を有しており、また好中球・抗酸球などの炎症細胞の遊走・浸潤抑制作用、活性酸素生産抑制作用を示すことが知られており、アレルギー症状の予防のため、点眼剤や点鼻剤などとして臨床的に広く用いられている。しかし、ケトチフェン又はその塩は光に対して不安定であることが知られている（特許文献１、２参照）。 Ketotifen or a salt thereof has a release inhibitory action / direct antagonism such as histamine in the case of allergic reaction, and has a production and release inhibitory / antagonism of leukotriene. It is known to have an inhibitory effect on migration / infiltration of inflammatory cells and an active oxygen production, and is widely used clinically as an eye drop or nasal drop for the prevention of allergic symptoms. However, it is known that ketotifen or a salt thereof is unstable to light (see Patent Documents 1 and 2).
製品として点眼剤を提供する場合、その容器は内容液の異物が観察できる程度の透明性が必要である。従来、光に対して不安定なサルファ剤を茶褐色に着色した容器に充填する技術（特許文献３参照）、光に対して不安定なビタミンＡ類を３８０nm以下の波長を遮断する容器に充填する技術（特許文献４参照）、フラビンアデニンジヌクレオチドナトリウムとシアノコバラミンを同時配合した点眼液を４５０nm付近の波長の光を遮断する容器に封入する技術（特許文献５参照）などがしられているが、ケトチフェンの安定化については開示されていない。 When an eye drop is provided as a product, the container needs to be transparent enough to observe foreign matter in the liquid content. Conventionally, a technique for filling a light brown sulfa drug into a brown-brown colored container (see Patent Document 3), a technique for filling a light-unstable vitamin A into a container that blocks wavelengths of 380 nm or less (See Patent Document 4), a technique (see Patent Document 5) in which an ophthalmic solution in which flavin adenine dinucleotide sodium and cyanocobalamin are simultaneously blended is sealed in a container that blocks light having a wavelength of around 450 nm is used. No stabilization is disclosed.
本発明は、ケトチフェン又はその塩の光による分解を抑制し、長期間保存しても沈殿物や不溶化物が生じることなく透明性を保持できる点眼剤の提供を目的とする。 An object of the present invention is to provide an ophthalmic solution that suppresses the degradation of ketotifen or a salt thereof by light and can maintain transparency without producing a precipitate or an insolubilized substance even when stored for a long time.
本発明者らは課題を解決するために種々検討した結果、ケトチフェン配合点眼液をある種の容器に封入することにより、光に対して不安定なケトチフェンを透明容器に安定に配合することができることを見出し本発明を完成した。 As a result of various studies to solve the problems, the present inventors have been able to stably mix ketotifen, which is unstable to light, into a transparent container by enclosing the ketotifen-containing ophthalmic solution in a certain container. The present invention has been completed.
すなわち本発明は
（１）ケトチフェン又はその塩を含有する点眼液を、４００nm以下の波長の最大光透過率が１６％以下である着色容器に充填したことを特徴とする点眼剤、
（２）４００nm以下の波長の最大光透過率が１６％以下である容器が、顔料および染料から選ばれる少なくとも１種の着色料により着色された容器である（１）記載の点眼剤、
（３）４００nm以下の波長の最大光透過率が１６％以下である容器が、紫外線カット剤を練合した容器である（１）又は（２）に記載の点眼剤、
（４）４００nm以下の波長の最大光透過率が１６％以下である容器が、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、ポリプレピレン、ポリエチレンのいずれか１種、又はこれらの共重合ポリエステル、或いはこれらの２種以上の混合体で構成された容器であることを特徴とする（１）〜（３）のいずれかに記載の点眼剤、
である。
That is, the present invention is (1) an ophthalmic solution characterized in that an ophthalmic solution containing ketotifen or a salt thereof is filled in a colored container having a maximum light transmittance of 16% or less at a wavelength of 400 nm or less,
(2) The eye drop according to (1), wherein the container having a maximum light transmittance of 16% or less at a wavelength of 400 nm or less is a container colored with at least one colorant selected from pigments and dyes,
(3) The ophthalmic solution according to (1) or (2), wherein the container having a maximum light transmittance of 16% or less at a wavelength of 400 nm or less is a container kneaded with an ultraviolet cut agent,
(4) A container having a maximum light transmittance of 16% or less at a wavelength of 400 nm or less is any one of polyethylene terephthalate, polyarylate, polyethylene naphthalate, polypropylene, polyethylene, or a copolyester thereof, or these The ophthalmic solution according to any one of (1) to (3), which is a container composed of two or more kinds of mixtures,
It is.
本願発明の点眼剤は光暴露後であっても、不溶物が見られない安定な点眼剤であった。 The eye drop of the present invention was a stable eye drop with no insoluble matter even after exposure to light.
本発明でケトチフェンの塩は、フマル酸などの酸との塩を使用することができる。 In the present invention, the salt of ketotifen can be a salt with an acid such as fumaric acid.
本発明で４００nm以下の波長の最大光透過率が１６％以下である着色容器は、４００nm以下の波長の光を透過しにくい色に着色するのが最も簡便である。着色する際には、染料又は顔料あるいはそれらを合わせて用いることができる。着色する際は、茶色、赤色、緑色又は黄緑色にすると、４００nm以下の波長の光を吸収するものを作りやすいことから好ましい。本願発明の着色容器は染料、顔料の種類、濃度などを適宜調製することにより実験的に調節することができる。 In the present invention, the coloring container having a maximum light transmittance of 16% or less at a wavelength of 400 nm or less is most easily colored in a color that hardly transmits light of a wavelength of 400 nm or less. When coloring, dyes or pigments or a combination thereof can be used. When coloring, it is preferable to use brown, red, green or yellowish green because it is easy to make one that absorbs light having a wavelength of 400 nm or less. The colored container of the present invention can be experimentally adjusted by appropriately adjusting the type and concentration of the dye and pigment.
また、容器を着色するほか４００nm以下の波長の光を吸収するフイルムなどで被覆することも可能である。また、容器に４００nm以下の波長を吸収する紫外線カット剤などを練合する事によっても本発明の目的を達成することができる。 In addition to coloring the container, it is also possible to coat it with a film that absorbs light having a wavelength of 400 nm or less. Further, the object of the present invention can also be achieved by kneading the container with an ultraviolet cut agent that absorbs a wavelength of 400 nm or less.
なお、最大光透過率は分光光度計により通常の方法で測定することができる。 The maximum light transmittance can be measured by a spectrophotometer by a normal method.
本発明で用いる容器の素材は、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、ポリプレピレン、ポリエチレンのいずれか１種、又はこれらの共重合ポリエステル、或いはこれらの２種以上の混合体などを用いることができるが、ポリエチレンテレフタレートが最も好ましい。 As the material of the container used in the present invention, any one of polyethylene terephthalate, polyarylate, polyethylene naphthalate, polypropylene, polyethylene, or a copolymer polyester thereof, or a mixture of two or more thereof can be used. However, polyethylene terephthalate is most preferred.
本発明で点眼液はケトチフェンを配合する他は、通常の点眼剤と同様にして製造することができ、得られた点眼液を４００nm以下の波長の最大光透過率が１６％以下である容器に封入することにより製造することができる。 In the present invention, the ophthalmic solution can be produced in the same manner as normal eye drops except that ketotifen is blended, and the obtained ophthalmic solution is put into a container having a maximum light transmittance of 16% or less at a wavelength of 400 nm or less. It can be manufactured by encapsulating.
以下、実施例及び試験例により本発明をさらに詳細に説明する。 Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples.
点眼液の調製
フマル酸ケトチフェン６９mg、塩化ベンザルコニウム５mgを精製水に溶解し、これにグリセリン、水酸化ナトリウムを適量溶解し、ｐＨ５．３に調整後、全量１００mLとした。その後、ろ過滅菌を行い、無菌の点眼液とした。調整後の浸透圧を測定したところ２８６mOsmであった。
Preparation of ophthalmic solution 69 mg of ketotifen fumarate and 5 mg of benzalkonium chloride were dissolved in purified water, and appropriate amounts of glycerin and sodium hydroxide were dissolved in the solution to adjust the pH to 5.3. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop. When the osmotic pressure after adjustment was measured, it was 286 mOsm.
得られた点眼液を種々の容器に充填し、実施例１〜５、比較例１〜５の点眼剤を得た。このときの点眼容器の光線透過率は、分光光度計を用いて点眼容器の平坦な部分で測定した。使用した容器を表１に示した。 The obtained ophthalmic solution was filled in various containers to obtain eye drops of Examples 1 to 5 and Comparative Examples 1 to 5. The light transmittance of the eye drop container at this time was measured at a flat portion of the eye drop container using a spectrophotometer. The containers used are shown in Table 1.
試験例１
実施例１〜５、比較例１〜５の各点眼剤に３０００Luxの光を照射し、積算照射量約３０万Lux・hrの光に暴露した。
Test example 1
The eye drops of Examples 1 to 5 and Comparative Examples 1 to 5 were irradiated with 3000 Lux of light, and exposed to light having an integrated irradiation amount of about 300,000 Lux · hr.
試験の評価
フマル酸ケトチフェンは光によって分解し、点眼液が着色するため、光照射前後の点眼液の４００nmの吸光度を分光光度計を用いて測定し、着色度合いを評価した。
Evaluation of test Since ketotifen fumarate is decomposed by light and the ophthalmic solution is colored, the absorbance at 400 nm of the ophthalmic solution before and after the light irradiation was measured using a spectrophotometer to evaluate the degree of coloring.
光照射後の異物生成の有無を目視観察により調べた。異物生成がある場合「×」を、無い場合「○」として記した。結果を表１に示した。 The presence or absence of foreign matter generation after light irradiation was examined by visual observation. “X” is indicated when foreign matter is generated, and “◯” is indicated when there is no foreign matter. The results are shown in Table 1.
フマル酸ケトチフェン 13.8mg
塩酸テトラヒドロゾリン 50mg
グリチルリチン酸二カリウム 250mg
マレイン酸クロルフェニラミン 30mg
アミノエチルスルホン酸 1000mg
ビタミンＢ６ 100mg
ビタミンＥ 50mg
メントール 10mg
クロロブタノール 100mg
グリセリン 1650mg
ポリソルベート８０ 100mg
塩化ベンザルコニウム 10mg
水酸化ナトリウム 適量
滅菌精製水 全100mL
滅菌精製水（約８０mL）に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．３に調整後、全量を正確に１００mLとした。その後ろ過滅菌を行い、波長４００nm以下の最大光線透過率が１６％以下である緑系の着色点眼容器に充填し、施栓して無菌の点眼剤とした。浸透圧を測定したところ290mOsmであった。
Ketotifen fumarate 13.8mg
Tetrahydrozoline hydrochloride 50mg
Dipotassium glycyrrhizinate 250mg
Chlorpheniramine maleate 30mg
Aminoethylsulfonic acid 1000mg
Vitamin B6 100mg
Vitamin E 50mg
Menthol 10mg
Chlorobutanol 100mg
Glycerin 1650mg
Polysorbate 80 100mg
Benzalkonium chloride 10mg
Sodium hydroxide appropriate amount sterilized purified water 100mL
After dissolving each component in sterilized purified water (about 80 mL), an appropriate amount of sodium hydroxide was added to adjust the pH to 5.3, and the total amount was accurately adjusted to 100 mL. Thereafter, the solution was sterilized by filtration, filled into a green colored eye drop container having a maximum light transmittance of 16% or less at a wavelength of 400 nm or less, and sealed to obtain a sterile eye drop. The osmotic pressure was measured and found to be 290 mOsm.
実施例７
フマル酸ケトチフェン 69mg
塩酸テトラヒドロゾリン 50mg
グリチルリチン酸二カリウム 250mg
マレイン酸クロルフェニラミン 30mg
アミノエチルスルホン酸 1000mg
ビタミンＢ６ 100mg
ビタミンＥ 50mg
メントール 25mg
クロロブタノール 100mg
グリセリン 1630mg
ポリソルベート８０ 100mg
塩化ベンザルコニウム 10mg
水酸化ナトリウム 適量
滅菌精製水 全100mL
滅菌精製水（約８０mL）に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．３に調整後、全量を正確に１００mLとした。その後ろ過滅菌を行い、波長４００nm以下の最大光線透過率が１６％以下である緑系の着色点眼容器に充填し、施栓して無菌の点眼剤とした。浸透圧を測定したところ290mOsmであった。
Example 7
Ketotifen fumarate 69mg
Tetrahydrozoline hydrochloride 50mg
Dipotassium glycyrrhizinate 250mg
Chlorpheniramine maleate 30mg
Aminoethylsulfonic acid 1000mg
Vitamin B6 100mg
Vitamin E 50mg
Menthol 25mg
Chlorobutanol 100mg
Glycerin 1630mg
Polysorbate 80 100mg
Benzalkonium chloride 10mg
Sodium hydroxide appropriate amount sterilized purified water 100mL
After dissolving each component in sterilized purified water (about 80 mL), an appropriate amount of sodium hydroxide was added to adjust the pH to 5.3, and the total amount was accurately adjusted to 100 mL. Thereafter, the solution was sterilized by filtration, filled into a green colored eye drop container having a maximum light transmittance of 16% or less at a wavelength of 400 nm or less, and sealed to obtain a sterile eye drop. The osmotic pressure was measured and found to be 290 mOsm.
実施例８
フマル酸ケトチフェン 103.5mg
塩酸テトラヒドロゾリン 50mg
グリチルリチン酸二カリウム 250mg
マレイン酸クロルフェニラミン 30mg
アミノエチルスルホン酸 1000mg
ビタミンＢ６ 100mg
ビタミンＥ 50mg
メントール 20mg
クロロブタノール 300mg
グリセリン 1515mg
ポリソルベート８０ 100mg
塩化ベンザルコニウム 10mg
水酸化ナトリウム 適量
滅菌精製水 全100mL
滅菌精製水（約８０mL）に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．３に調整後、全量を正確に１００mLとした。その後ろ過滅菌を行い、波長４００nm以下の最大光線透過率が１６％以下である緑系の着色点眼容器に充填し、施栓して無菌の点眼剤とした。浸透圧を測定したところ289mOsmであった。
Example 8
Ketotifen fumarate 103.5mg
Tetrahydrozoline hydrochloride 50mg
Dipotassium glycyrrhizinate 250mg
Chlorpheniramine maleate 30mg
Aminoethylsulfonic acid 1000mg
Vitamin B6 100mg
Vitamin E 50mg
Menthol 20mg
Chlorobutanol 300mg
Glycerin 1515mg
Polysorbate 80 100mg
Benzalkonium chloride 10mg
Sodium hydroxide appropriate amount sterilized purified water 100mL
After dissolving each component in sterilized purified water (about 80 mL), an appropriate amount of sodium hydroxide was added to adjust the pH to 5.3, and the total amount was accurately adjusted to 100 mL. Thereafter, the solution was sterilized by filtration, filled into a green colored eye drop container having a maximum light transmittance of 16% or less at a wavelength of 400 nm or less, and sealed to obtain a sterile eye drop. When the osmotic pressure was measured, it was 289 mOsm.
実施例９
フマル酸ケトチフェン 69mg
塩酸テトラヒドロゾリン 50mg
グリチルリチン酸二カリウム 250mg
Ｌ−アスパラギン酸カリウム 1000mg
アミノエチルスルホン酸 1000mg
ビタミンＢ６ 100mg
メントール 15mg
クロロブタノール 150mg
グリセリン 790mg
ポリソルベート８０ 100mg
塩化ベンザルコニウム 10mg
ヒドロキシプロピルメチルセルロース 50mg
水酸化ナトリウム 適量
滅菌精製水 全100mL
滅菌精製水（約８０mL）に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．３に調整後、全量を正確に１００mLとした。その後ろ過滅菌を行い、波長４００nm以下の最大光線透過率が１６％以下である緑系の着色点眼容器に充填し、施栓して無菌の点眼剤とした。
Example 9
Ketotifen fumarate 69mg
Tetrahydrozoline hydrochloride 50mg
Dipotassium glycyrrhizinate 250mg
L-aspartate potassium 1000mg
Aminoethylsulfonic acid 1000mg
Vitamin B6 100mg
Menthol 15mg
Chlorobutanol 150mg
Glycerin 790mg
Polysorbate 80 100mg
Benzalkonium chloride 10mg
Hydroxypropyl methylcellulose 50mg
Sodium hydroxide appropriate amount sterilized purified water 100mL
After dissolving each component in sterilized purified water (about 80 mL), an appropriate amount of sodium hydroxide was added to adjust the pH to 5.3, and the total amount was accurately adjusted to 100 mL. Thereafter, the solution was sterilized by filtration, filled into a green colored eye drop container having a maximum light transmittance of 16% or less at a wavelength of 400 nm or less, and sealed to obtain a sterile eye drop.
実施例１０
フマル酸ケトチフェン 13.8mg
塩酸テトラヒドロゾリン 50mg
ε−アミノカプロン酸 1000mg
アミノエチルスルホン酸 1000mg
ビタミンＢ６ 100mg
シアノコバラミン 10mg
クロロブタノール 100mg
グリセリン 1020mg
ポリソルベート８０ 100mg
塩化ベンザルコニウム 10mg
希塩酸 適量
滅菌精製水 全100mL
滅菌精製水（約８０mL）に各成分を溶解後、希塩酸を適量添加しｐＨを５．３に調整後、全量を正確に１００mLとした。その後ろ過滅菌を行い、波長４００nm以下の最大光線透過率が１６％以下である緑系の着色点眼容器充填し、施栓して無菌の点眼剤とした。浸透圧を測定したところ290mOsmであった。
Example 10
Ketotifen fumarate 13.8mg
Tetrahydrozoline hydrochloride 50mg
ε-aminocaproic acid 1000mg
Aminoethylsulfonic acid 1000mg
Vitamin B6 100mg
Cyanocobalamin 10mg
Chlorobutanol 100mg
Glycerin 1020mg
Polysorbate 80 100mg
Benzalkonium chloride 10mg
Dilute hydrochloric acid appropriate amount sterilized purified water 100mL
After dissolving each component in sterilized purified water (about 80 mL), an appropriate amount of dilute hydrochloric acid was added to adjust the pH to 5.3, and the total amount was accurately adjusted to 100 mL. Thereafter, the solution was sterilized by filtration, filled with a green colored eye drop container having a maximum light transmittance of 16% or less at a wavelength of 400 nm or less, and sealed to obtain a sterile eye drop. The osmotic pressure was measured and found to be 290 mOsm.
実施例１１
フマル酸ケトチフェン 69mg
塩酸テトラヒドロゾリン 50mg
ε−アミノカプロン酸 1000mg
マレイン酸クロルフェニラミン 30mg
アミノエチルスルホン酸 1000mg
ビタミンＢ６ 100mg
シアノコバラミン 10mg
クロロブタノール 300mg
グリセリン 910mg
ポリソルベート８０ 100mg
塩化ベンザルコニウム 10mg
希塩酸 適量
滅菌精製水 全100mL
滅菌精製水（約８０mL）に各成分を溶解後、希塩酸を適量添加しｐＨを５．３に調整後、全量を正確に１００mLとした。その後ろ過滅菌を行い、波長４００nm以下の最大光線透過率が１６％以下である緑系の着色点眼容器に充填し、施栓して無菌の点眼剤とした。浸透圧を測定したところ292mOsmであった。
Example 11
Ketotifen fumarate 69mg
Tetrahydrozoline hydrochloride 50mg
ε-aminocaproic acid 1000mg
Chlorpheniramine maleate 30mg
Aminoethylsulfonic acid 1000mg
Vitamin B6 100mg
Cyanocobalamin 10mg
Chlorobutanol 300mg
Glycerin 910mg
Polysorbate 80 100mg
Benzalkonium chloride 10mg
Dilute hydrochloric acid appropriate amount sterilized purified water 100mL
After dissolving each component in sterilized purified water (about 80 mL), an appropriate amount of dilute hydrochloric acid was added to adjust the pH to 5.3, and the total amount was accurately adjusted to 100 mL. Thereafter, the solution was sterilized by filtration, filled into a green colored eye drop container having a maximum light transmittance of 16% or less at a wavelength of 400 nm or less, and sealed to obtain a sterile eye drop. When the osmotic pressure was measured, it was 292 mOsm.
実施例１２
フマル酸ケトチフェン 69mg
コンドロイチン硫酸ナトリウム 250mg
アミノエチルスルホン酸 1000mg
ｌ−メントール 5mg
ｄｌ−カンフル 5mg
ハッカ油 10mg
クロロブタノール 150mg
ホウ酸 500mg
グリセリン 1150mg
エデト酸ナトリウム 5mg
ポリソルベート８０ 100mg
塩化ベンザルコニウム 5mg
水酸化ナトリウム 適量
滅菌精製水 全100mL
滅菌精製水（８５mL）に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．６に調整後、全量を正確に１００mLとした。その後ろ過滅菌を行い、波長４００nm以下の最大光線透過率が１６％以下である緑系の着色点眼容器に充填し、施栓して無菌の点眼剤とした。浸透圧を測定したところ288mOsmであった。
Example 12
Ketotifen fumarate 69mg
Sodium chondroitin sulfate 250mg
Aminoethylsulfonic acid 1000mg
l-Menthol 5mg
dl-Camphor 5mg
Peppermint oil 10mg
Chlorobutanol 150mg
Boric acid 500mg
Glycerin 1150mg
Sodium edetate 5mg
Polysorbate 80 100mg
Benzalkonium chloride 5mg
Sodium hydroxide appropriate amount sterilized purified water 100mL
After dissolving each component in sterilized purified water (85 mL), an appropriate amount of sodium hydroxide was added to adjust the pH to 5.6, and the total amount was accurately adjusted to 100 mL. Thereafter, the solution was sterilized by filtration, filled into a green colored eye drop container having a maximum light transmittance of 16% or less at a wavelength of 400 nm or less, and sealed to obtain a sterile eye drop. When the osmotic pressure was measured, it was 288 mOsm.
実施例１３
フマル酸ケトチフェン 69mg
コンドロイチン硫酸ナトリウム 500mg
アミノエチルスルホン酸 1000mg
グリセリン 2200mg
アスパラギン酸カリウム 1000mg
メントール 5mg
ポリソルベート８０ 100mg
塩化ベンザルコニウム 5mg
水酸化ナトリウム 適量
滅菌精製水 全100mL
滅菌精製水（８５mL）に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．３に調整後、全量を正確に１００mLとした。その後ろ過滅菌を行い、波長４００nm以下の最大光線透過率が１６％以下である緑系の着色点眼容器に充填し、施栓して無菌の点眼剤とした。浸透圧を測定したところ282mOsmであった。
Example 13
Ketotifen fumarate 69mg
Chondroitin sulfate sodium 500mg
Aminoethylsulfonic acid 1000mg
Glycerin 2200mg
Potassium aspartate 1000mg
Menthol 5mg
Polysorbate 80 100mg
Benzalkonium chloride 5mg
Sodium hydroxide appropriate amount sterilized purified water 100mL
After dissolving each component in sterilized purified water (85 mL), an appropriate amount of sodium hydroxide was added to adjust the pH to 5.3, and the total amount was accurately adjusted to 100 mL. Thereafter, the solution was sterilized by filtration, filled into a green colored eye drop container having a maximum light transmittance of 16% or less at a wavelength of 400 nm or less, and sealed to obtain a sterile eye drop. When the osmotic pressure was measured, it was 282 mOsm.
実施例１４
フマル酸ケトチフェン 69mg
プラノプロフェン 50mg
塩酸テトラヒドロゾリン 50mg
塩酸ピリドキシン 100mg
アミノエチルスルホン酸 1000mg
コンドロイチン硫酸ナトリウム 500mg
グリセリン 2100mg
メントール 5mg
ポリソルベート８０ 100mg
塩化ベンザルコニウム 10mg
水酸化ナトリウム 適量
滅菌精製水 全100mL
滅菌精製水（８５mL）に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．８に調整後、全量を正確に１００mLとした。その後ろ過滅菌を行い、波長４００nm以下の最大光線透過率が１６％以下である緑系の着色点眼容器に充填し、施栓して無菌の点眼剤とした。浸透圧を測定したところ286mOsmであった。
Example 14
Ketotifen fumarate 69mg
Planoprofen 50mg
Tetrahydrozoline hydrochloride 50mg
Pyridoxine hydrochloride 100mg
Aminoethylsulfonic acid 1000mg
Chondroitin sulfate sodium 500mg
Glycerin 2100mg
Menthol 5mg
Polysorbate 80 100mg
Benzalkonium chloride 10mg
Sodium hydroxide appropriate amount sterilized purified water 100mL
After dissolving each component in sterilized purified water (85 mL), an appropriate amount of sodium hydroxide was added to adjust the pH to 5.8, and the total amount was accurately adjusted to 100 mL. Thereafter, the solution was sterilized by filtration, filled into a green colored eye drop container having a maximum light transmittance of 16% or less at a wavelength of 400 nm or less, and sealed to obtain a sterile eye drop. When the osmotic pressure was measured, it was 286 mOsm.
本発明によりケトチフェンを安定に配合することが可能になったので、医薬品の点眼剤などとして利用可能である。 Since it became possible to mix | blend ketotifen stably by this invention, it can utilize as an eye drop etc. of a pharmaceutical.
Claims (4)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2006285969A JP2008100957A (en) | 2006-10-20 | 2006-10-20 | Eye drop |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2006285969A JP2008100957A (en) | 2006-10-20 | 2006-10-20 | Eye drop |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP2008100957A true JP2008100957A (en) | 2008-05-01 |
Family
ID=39435570
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2006285969A Pending JP2008100957A (en) | 2006-10-20 | 2006-10-20 | Eye drop |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2011105707A (en) * | 2009-10-21 | 2011-06-02 | Taisho Pharmaceutical Co Ltd | Ophthalmic agent |
| JP2011219371A (en) * | 2010-04-05 | 2011-11-04 | Toyo Capsule Kk | Capsule containing ketotifen fumarate |
| WO2020241374A1 (en) * | 2019-05-31 | 2020-12-03 | 小林製薬株式会社 | Vitamin b12 compound-containing composition |
-
2006
- 2006-10-20 JP JP2006285969A patent/JP2008100957A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2011105707A (en) * | 2009-10-21 | 2011-06-02 | Taisho Pharmaceutical Co Ltd | Ophthalmic agent |
| JP2011219371A (en) * | 2010-04-05 | 2011-11-04 | Toyo Capsule Kk | Capsule containing ketotifen fumarate |
| WO2020241374A1 (en) * | 2019-05-31 | 2020-12-03 | 小林製薬株式会社 | Vitamin b12 compound-containing composition |
| JP2020196672A (en) * | 2019-05-31 | 2020-12-10 | 小林製薬株式会社 | Vitamin B12-containing composition |
| CN113811314A (en) * | 2019-05-31 | 2021-12-17 | 小林制药株式会社 | Composition containing vitamin B12 |
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