JP5460996B2 - Ophthalmic agent - Google Patents
Ophthalmic agent Download PDFInfo
- Publication number
- JP5460996B2 JP5460996B2 JP2008268062A JP2008268062A JP5460996B2 JP 5460996 B2 JP5460996 B2 JP 5460996B2 JP 2008268062 A JP2008268062 A JP 2008268062A JP 2008268062 A JP2008268062 A JP 2008268062A JP 5460996 B2 JP5460996 B2 JP 5460996B2
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- JP
- Japan
- Prior art keywords
- pranoprofen
- ketotifen fumarate
- ophthalmic
- present
- ophthalmic agent
- 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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- 239000003732 agents acting on the eye Substances 0.000 title claims description 17
- 229940125702 ophthalmic agent Drugs 0.000 title claims description 17
- 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 claims description 31
- 229960003630 ketotifen fumarate Drugs 0.000 claims description 31
- TVQZAMVBTVNYLA-UHFFFAOYSA-N Pranoprofen Chemical compound C1=CC=C2CC3=CC(C(C(O)=O)C)=CC=C3OC2=N1 TVQZAMVBTVNYLA-UHFFFAOYSA-N 0.000 claims description 29
- 229960003101 pranoprofen Drugs 0.000 claims description 28
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 10
- 229940009662 edetate Drugs 0.000 claims description 8
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 claims description 3
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 claims description 2
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical group [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 2
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 claims description 2
- 239000003889 eye drop Substances 0.000 description 24
- 230000007794 irritation Effects 0.000 description 8
- 229940012356 eye drops Drugs 0.000 description 7
- 208000024891 symptom Diseases 0.000 description 6
- 238000000034 method Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 235000002639 sodium chloride Nutrition 0.000 description 5
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 4
- -1 aryl carboxylic acid Chemical class 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000000172 allergic effect Effects 0.000 description 3
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
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- 239000004359 castor oil Substances 0.000 description 2
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- 229960004926 chlorobutanol Drugs 0.000 description 2
- 238000004040 coloring Methods 0.000 description 2
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- 230000001687 destabilization Effects 0.000 description 2
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 2
- 229960001340 histamine Drugs 0.000 description 2
- 239000007951 isotonicity adjuster Substances 0.000 description 2
- 230000007803 itching Effects 0.000 description 2
- 150000002617 leukotrienes Chemical class 0.000 description 2
- 239000002997 ophthalmic solution Substances 0.000 description 2
- 229940054534 ophthalmic solution Drugs 0.000 description 2
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 2
- 239000003002 pH adjusting agent Substances 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
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- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- HVAUUPRFYPCOCA-AREMUKBSSA-N 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C HVAUUPRFYPCOCA-AREMUKBSSA-N 0.000 description 1
- BDOYKFSQFYNPKF-UHFFFAOYSA-N 2-[2-[bis(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetic acid;sodium Chemical compound [Na].[Na].OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O BDOYKFSQFYNPKF-UHFFFAOYSA-N 0.000 description 1
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 206010010741 Conjunctivitis Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
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- 206010020565 Hyperaemia Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010022941 Iridocyclitis Diseases 0.000 description 1
- ZCVMWBYGMWKGHF-UHFFFAOYSA-N Ketotifene Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2CC(=O)C2=C1C=CS2 ZCVMWBYGMWKGHF-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 1
- 108010003541 Platelet Activating Factor Proteins 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- 206010039705 Scleritis Diseases 0.000 description 1
- 239000004288 Sodium dehydroacetate Substances 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- GZLGNNHEHXBCBI-UHFFFAOYSA-L [Na+].[Na+].OC(=O)C(O)C(O)C(O)=O.[O-]C(=O)C(O)C(O)C([O-])=O Chemical compound [Na+].[Na+].OC(=O)C(O)C(O)C(O)=O.[O-]C(=O)C(O)C(O)C([O-])=O GZLGNNHEHXBCBI-UHFFFAOYSA-L 0.000 description 1
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- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229960002684 aminocaproic acid Drugs 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 201000004612 anterior uveitis Diseases 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- 229960001950 benzethonium chloride Drugs 0.000 description 1
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- KFGJICJPSZZEEP-UHFFFAOYSA-L dipotassium;hydrogen phosphate;hydrate Chemical compound O.[K+].[K+].OP([O-])([O-])=O KFGJICJPSZZEEP-UHFFFAOYSA-L 0.000 description 1
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Description
本発明は、プラノプロフェン及びフマル酸ケトチフェンを含有する、ｐＨが６．５を超える眼科用剤に関する。 The present invention relates to an ophthalmic agent containing pranoprofen and ketotifen fumarate having a pH of more than 6.5.
プラノプロフェン（化学名：α−メチル−５Ｈ−［１］ベンゾピラノ［２，３−ｂ］ピリジン−７−酢酸）は、炎症の原因物質プロスタグランジンの生成を抑制し、かゆみ、充血等の症状を緩和し、外眼部及び前眼部の炎症性疾患（眼瞼炎、結膜炎、角膜炎、強膜炎、上強膜炎、前眼部ブドウ膜炎、術後炎症）の治療のため、点眼剤として臨床的に広く用いられている。プラノプロフェンは、分子内にカルボキシル基を持つアリールカルボン酸であり、カルボキシル基の解離の程度により、水への溶解性が大幅に変化する。カルボキシル基が解離しやすいｐＨ７．１以上では溶解性が非常に高いが、ｐＨ５．２以下ではほとんど溶解しないことが報告されており（非特許文献１参照）、ｐＨが低いほど溶解しにくくなる性質がある。通常、プラノプロフェンは、溶解度の点からｐＨ７〜８で点眼剤として使用されている。 Planoprofen (chemical name: α-methyl-5H- [1] benzopyrano [2,3-b] pyridine-7-acetic acid) suppresses the production of prostaglandins that cause inflammation, itching, hyperemia, etc. To relieve symptoms and treat inflammatory diseases of the external and anterior eyes (blurritis, conjunctivitis, keratitis, scleritis, suprasclerosis, anterior uveitis, postoperative inflammation) Widely used clinically as eye drops. Planoprofen is an aryl carboxylic acid having a carboxyl group in the molecule, and its solubility in water varies greatly depending on the degree of dissociation of the carboxyl group. It has been reported that the solubility is very high at pH 7.1 or higher where the carboxyl group is easily dissociated, but hardly dissolves at pH 5.2 or lower (see Non-Patent Document 1). There is. Usually, pranoprofen is used as an eye drop at pH 7-8 from the viewpoint of solubility.
フマル酸ケトチフェンは、アレルギー反応の際、ヒスタミン等の遊離抑制作用・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・好酸球等の炎症細胞の遊走・浸潤抑制作用、活性酸素産生抑制作用を示すことが知られ、アレルギー症状の予防・改善のため、点眼剤や点鼻剤等として臨床的に広く用いられている。フマル酸ケトチフェンは、水溶液中での安定性の点からｐＨ５．８以下が好ましいとされており（特許文献１及び２参照）、現在発売されているフマル酸ケトチフェンを配合した点眼剤はｐＨ６未満で販売されている。 Ketotifen fumarate has a release inhibitory action / direct antagonism such as histamine during allergic reactions, and has a production and release inhibitory / antagonism action of leukotrienes. 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 and improvement of allergic symptoms. It is said that ketotifen fumarate has a pH of 5.8 or less from the viewpoint of stability in an aqueous solution (see Patent Documents 1 and 2), and an eye drop containing ketotifen fumarate currently incorporated has a pH of less than 6 Sold.
プラノプロフェンとフマル酸ケトチフェンはその薬効から同時投与するとアレルギー症状の改善に有効と考えられるが、プラノプロフェンの溶解性が高いｐＨ領域と、フマル酸ケトチフェンの水溶液中での安定性が確保できるｐＨ領域とが異なるため、プラノプロフェンとフマル酸ケトチフェンを同時に配合することが困難であり、これまでにプラノプロフェンとフマル酸ケトチフェンを同時に配合した点眼剤は上市されていない。 Planoprofen and ketotifen fumarate are considered to be effective in improving allergic symptoms when coadministered due to their medicinal properties, but the pH range where pranoprofen is highly soluble and the stability of ketotifen fumarate in aqueous solution can be ensured Since it is different from the pH range, it is difficult to mix pranoprofen and ketotifen fumarate at the same time, and no ophthalmic solution containing pranoprofen and ketotifen fumarate at the same time has been put on the market.
従来、プラノプロフェンとフマル酸ケトチフェンを同時に配合した点眼剤を提供するために、ｐＨが高い領域でプラノプロフェン及びフマル酸ケトチフェンを溶解し、その後ｐＨを低い領域に調節することにより、プラノプロフェンの溶解性とフマル酸ケトチフェンの安定性を両立させた点眼剤用組成物が開示されている（特許文献３参照）。しかし、低いｐＨでプラノプロフェンを点眼すると刺激が生じる事が知られていることから（非特許文献２参照）、この技術をそのまま点眼剤に使用するのは困難である。 Conventionally, in order to provide an ophthalmic solution containing pranoprofen and ketotifen fumarate at the same time, pranoprofen and ketotifen fumarate are dissolved in a high pH region, and then the pH is adjusted to a low region. An ophthalmic composition having both solubility of phen and stability of ketotifen fumarate is disclosed (see Patent Document 3). However, since it is known that irritation occurs when pranoprofen is instilled at a low pH (see Non-Patent Document 2), it is difficult to use this technique as it is for eye drops.
従来、プラノプロフェンの刺激を改善する方法として、プラノプロフェンとクロロブタノールを配合した点眼剤（特許文献４参照）、プラノプロフェンとコンドロイチン硫酸ナトリウムを配合した点眼剤（特許文献５参照）等が知られている。 Conventionally, as a method for improving the stimulation of pranoprofen, an eye drop containing pranoprofen and chlorobutanol (see Patent Document 4), an eye drop containing pranoprofen and sodium chondroitin sulfate (see Patent Document 5), etc. It has been known.
しかしながら、フマル酸ケトチフェン、プラノプロフェン、及びエデト酸塩を配合し、６．５を超えるｐＨに調整した点眼剤は知られていない。
本発明は、プラノプロフェンの刺激が生じにくい高いｐＨ領域においてもフマル酸ケトチフェンの安定化をはかることにより、プラノプロフェンとフマル酸ケトチフェンを同時に配合した眼科用剤を提供することを目的とする。 An object of the present invention is to provide an ophthalmic agent containing pranoprofen and ketotifen fumarate at the same time by stabilizing ketotifen fumarate even in a high pH range where the stimulation of pranoprofen is unlikely to occur. .
本発明者らは前記課題を解決するために種々検討した結果、プラノプロフェン及びフマル酸ケトチフェンを含むｐＨが６．５を超える点眼剤に、さらにエデト酸塩を配合することにより、プラノプロフェンが十分な溶解度で溶解し、かつ、刺激が生じにくく、さらにフマル酸ケトチフェンの安定性が確保できることを見出し、本発明を完成した。 The present inventors have results of various studies in order to solve the above problems, by pH containing pranoprofen and ketotifen fumarate eye drops more than 6.5, further compounding edetate, pranoprofen Was dissolved with sufficient solubility, irritation was less likely to occur, and the stability of ketotifen fumarate could be secured, and the present invention was completed.
すなわち本発明は、
（１）プラノプロフェン及びフマル酸ケトチフェンを含有し、ｐＨが６．５を超える眼科用剤において、エデト酸塩を配合したことを特徴とする眼科用剤、
（２）前記エデト酸塩が、エチレンジアミン四酢酸二ナトリウム又はエチレンジアミン四酢酸四ナトリウムである（１）に記載の眼科用剤、
（３）プラノプロフェンの含有量が眼科用剤全体の０．００５ｗ／ｖ％〜０．２ｗ／ｖ％であり、かつ、フマル酸ケトチフェンの含有量が眼科用剤全体の０．００５ｗ／ｖ％〜０．５ｗ／ｖ％である（１）又は（２）に記載の眼科用剤、である。
That is, the present invention
(1) An ophthalmic agent comprising pranoprofen and ketotifen fumarate and having an edetate salt in an ophthalmic agent having a pH of more than 6.5,
(2) The ophthalmic agent according to (1), wherein the edetate is disodium ethylenediaminetetraacetate or tetrasodium ethylenediaminetetraacetate,
(3) The content of pranoprofen is 0.005 w / v% to 0.2 w / v% of the whole ophthalmic agent, and the content of ketotifen fumarate is 0.005 w / v of the whole ophthalmic agent. The ophthalmic preparation according to (1) or (2), which is% to 0.5 w / v%.
本発明で用いるエデト酸塩は、種々の成分の安定化剤としても用いられる成分であるが、プラノプロフェンとフマル酸ケトチフェンを同時配合した系における安定化効果は、他の安定化剤では得ることができず、エデト酸塩に特異的な効果である。 The edetate used in the present invention is a component that is also used as a stabilizer for various components, but the stabilizing effect in a system in which pranoprofen and ketotifen fumarate are blended simultaneously is obtained with other stabilizers. This is an effect specific to edetate.
本発明の眼科用剤によれば、プラノプロフェン、フマル酸ケトチフェン、及びエデト酸塩を含み、６．５を超えるｐＨに調整することによって、プラノプロフェンの刺激を抑え、かつフマル酸ケトチフェンの不安定化を抑制することが可能となった。これによって長期保存においても一定の品質を保つ眼科用剤を提供することが可能となった。 According to the ophthalmic preparation of the present invention, pranoprofen, comprising ketotifen fumarate, and edetate salts, by adjusting the pH above 6.5, suppress stimulation of pranoprofen, and of ketotifen fumarate It became possible to suppress destabilization. This makes it possible to provide an ophthalmic agent that maintains a certain quality even during long-term storage.
本発明のプラノプロフェンは、非ステロイド性消炎鎮痛剤の１つであり、シクロオキシゲナーゼを阻害し、炎症の原因物質プロスタグランジンの生成を抑制することで炎症部位の消炎鎮痛作用を示す物質である。医療用の点眼剤として、ニフラン（登録商標）の販売名で市販されている他、医薬品の点眼剤として複数の製品が市販されている。 The planoprofen of the present invention is one of non-steroidal anti-inflammatory analgesics, and is a substance that exhibits anti-inflammatory analgesic action at the inflammatory site by inhibiting cyclooxygenase and suppressing the production of prostaglandins that cause inflammation. . In addition to being marketed under the trade name Niflan (registered trademark) as a medical eye drop, a plurality of products are marketed as pharmaceutical eye drops.
本発明のプラノプロフェンの配合濃度は、適用する疾病の症状に応じて適宜増減することができるが、眼科用剤全体の０．００５ｗ／ｖ％〜０．２ｗ／ｖ％であることが好ましく、０．０２５ｗ／ｖ％〜０．１ｗ／ｖ％であることがさらに好ましい。０．００５ｗ／ｖ％未満であると治療効果の点から不十分になる恐れがあり、０．２ｗ／ｖ％を超えて配合すると、溶解度が不十分になる恐れがあるからである。 The compounding concentration of pranoprofen of the present invention can be appropriately increased or decreased depending on the disease symptoms to be applied, but is preferably 0.005 w / v% to 0.2 w / v% of the whole ophthalmic preparation. 0.025 w / v% to 0.1 w / v% is more preferable. It is because there exists a possibility that it may become inadequate from the point of a therapeutic effect as it is less than 0.005 w / v%, and there exists a possibility that solubility may become inadequate when it mixes exceeding 0.2 w / v%.
また、本発明のフマル酸ケトチフェンは抗アレルギー薬の１つであり、抗アレルギー作用と共にヒスタミン、ロイコトリエン、血小板活性化因子に対する拮抗作用を有することを特徴とし、その構造から塩基性抗アレルギー薬に分類される。また、ヒスタミン拮抗薬とも呼ばれる。医療用としては、ザジテン（登録商標）の販売名で市販されている。 In addition, ketotifen fumarate of the present invention is one of antiallergic drugs, and has an antiallergic action and an antagonistic action against histamine, leukotriene, and platelet activating factor, and is classified as a basic antiallergic drug from its structure. Is done. Also called histamine antagonist. For medical use, it is marketed under the trade name of Zaditen (registered trademark).
本発明のフマル酸ケトチフェンの配合濃度は、適用する疾病の症状に応じて適宜増減することができるが、眼科用剤全体の０．００５ｗ／ｖ％〜０．５ｗ／ｖ％であることが好ましく、０．０１ｗ／ｖ％〜０．１ｗ／ｖ％であることがさらに好ましい。０．００５ｗ／ｖ％未満であると治療効果の点から不十分になる恐れがあり、０．５ｗ／ｖ％を超えて配合すると、刺激が生じる恐れがあるからである。 The compounding concentration of ketotifen fumarate of the present invention can be appropriately increased or decreased depending on the disease symptoms to be applied, but is preferably 0.005 w / v% to 0.5 w / v% of the whole ophthalmic preparation. More preferably, it is 0.01 w / v% to 0.1 w / v%. It is because there exists a possibility that it may become inadequate from the point of a therapeutic effect as it is less than 0.005 w / v%, and when it exceeds 0.5 w / v%, there exists a possibility that irritation may arise.
さらに、本発明のエデト酸塩とは、エチレンジアミン四酢酸の塩であり、本発明においてはエチレンジアミン四酢酸二ナトリウム又はエチレンジアミン四酢酸四ナトリウムを用いることもできる。 Furthermore, the edetate salt of the present invention are salts of ethylenediaminetetraacetic acid, in the present invention can also be used ethylenediaminetetraacetic acid disodium or tetrasodium ethylenediamine tetraacetate.
本発明のエデト酸塩の配合濃度は、必要に応じて適宜選択することができるが、眼科用剤製剤全体の０．０００１ｗ／ｖ％〜０．１５ｗ／ｖ％であることが好ましく、０．００１ｗ／ｖ％〜０．１ｗ／ｖ％であることがさらに好ましい。０．０００１ｗ／ｖ％未満であるとフマル酸ケトチフェンの安定性が不十分になる恐れがあり、０．１５ｗ／ｖ％を超えて配合すると使用感が悪くなる恐れがあるからである。 Blending concentration of edetate salts of the present invention can be suitably selected as needed is preferably 0.0001w / v% ~0.15w / v% of the total ophthalmic agent formulations, 0. More preferably, it is 001 w / v% to 0.1 w / v%. If it is less than 0.0001 w / v%, the stability of ketotifen fumarate may be insufficient, and if it exceeds 0.15 w / v%, the feeling of use may be deteriorated.
本発明に係る眼科用剤には、さらに緩衝剤、等張化剤、溶解補助剤、保存剤、粘稠剤、ｐＨ調整剤のような各種の添加剤を適宜添加してもよい。 Various additives such as a buffer, an isotonic agent, a solubilizing agent, a preservative, a thickener, and a pH adjuster may be appropriately added to the ophthalmic agent according to the present invention.
緩衝剤としては、例えばリン酸塩緩衝剤（リン酸二水素ナトリウム−リン酸水素二ナトリウム、リン酸二水素カリウム−水酸化カリウム）、ホウ酸緩衝剤（ホウ酸−ホウ砂）、酒石酸塩緩衝剤（酒石酸−酒石酸ナトリウム）、アミノ酸（グルタミン酸ナトリウム、イプシロンアミノカプロン酸）等が挙げられる。 Examples of the buffer include phosphate buffer (sodium dihydrogen phosphate-disodium hydrogen phosphate, potassium dihydrogen phosphate-potassium hydroxide), borate buffer (borate-borax), and tartrate buffer. Agents (tartaric acid-sodium tartrate), amino acids (sodium glutamate, epsilon aminocaproic acid) and the like.
等張化剤としては、ソルビトール、グルコース、マンニトール等の糖類、グリセリン、プロピレングリコール等の多価アルコール類、塩化ナトリウム、ホウ砂等の塩類、ホウ酸等が挙げられる。 Examples of the isotonic agent include saccharides such as sorbitol, glucose and mannitol, polyhydric alcohols such as glycerin and propylene glycol, salts such as sodium chloride and borax, and boric acid.
溶解補助剤としては、ポリオキシエチレンソルビタンモノオレート（ポリソルベート８０）、ポリオキシエチレンモノステアレート、ポリオキシエチレンヒマシ油、ポリオキシエチレン硬化ヒマシ油等の非イオン界面活性剤、ポリエチレングリコール等が挙げられる。 Examples of solubilizers include nonionic surfactants such as polyoxyethylene sorbitan monooleate (polysorbate 80), polyoxyethylene monostearate, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, and polyethylene glycol. .
保存剤としては、塩化ベンザルコニウム、塩化ベンゼトニウム、塩化セチルピリジニウム等の第四級アンモニウム塩、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等のパラオキシ安息香酸エステル類、ベンジルアルコール、フェネチルアルコール、ソルビン酸及びそれらの塩、チメロサール、クロロブタノール、デヒドロ酢酸ナトリウム等が挙げられる。 Preservatives include quaternary ammonium salts such as benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, paraoxybenzoates such as methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, and butyl paraoxybenzoate. Benzyl alcohol, phenethyl alcohol, sorbic acid and salts thereof, thimerosal, chlorobutanol, sodium dehydroacetate and the like.
粘稠剤としては、ポリビニルピロリドン、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、メチルセルロース、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及びそれらの塩等が挙げられる。 Examples of the thickener include polyvinyl pyrrolidone, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, and salts thereof.
ｐＨ調整剤としては、塩酸、リン酸、酢酸、酒石酸、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム及び炭酸水素ナトリウム等が挙げられる。 Examples of the pH adjuster include hydrochloric acid, phosphoric acid, acetic acid, tartaric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate.
本発明に係る眼科用剤は、主に点眼剤として提供される。本発明の眼科用剤は、刺激の点から６．５を超えるｐＨである必要があるが、６．６〜８．０の範囲が好ましく、６．７〜８．０の範囲がさらに好ましい。 The ophthalmic preparation according to the present invention is mainly provided as an eye drop. The ophthalmic agent of the present invention needs to have a pH exceeding 6.5 from the viewpoint of irritation, but is preferably in the range of 6.6 to 8.0, and more preferably in the range of 6.7 to 8.0.
本発明に係る眼科用剤を点眼剤とした場合、１日１回〜数回、１回１滴〜数滴を投与することができる。 When the ophthalmic preparation according to the present invention is used as an eye drop, 1 to several drops can be administered once to several times a day.
以下に、実施例及び試験例を示し、本発明を詳細に説明する。 Hereinafter, the present invention will be described in detail with reference to examples and test examples.
［実施例１］
表１に示す配合に従って、精製水（約８０ｍＬ）に各成分を溶解後、希塩酸を適量添加してｐＨを６．７に調整後、精製水で全量を正確に１００ｍＬとした。その後、ろ過滅菌を行い、無菌の点眼剤とした。
[Example 1]
According to the formulation shown in Table 1, each component was dissolved in purified water (about 80 mL), an appropriate amount of dilute hydrochloric acid was added to adjust the pH to 6.7, and the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
［比較例１〜４］
表１に示す配合に従って、実施例１と同様の手順により、無菌の点眼剤を得た。
[Comparative Examples 1-4]
According to the formulation shown in Table 1, a sterile eye drop was obtained by the same procedure as in Example 1.
［試験例１］
実施例及び比較例で得た点眼剤の調製直後の外観を観察した。また、これらをプラスチック製の点眼剤容器に充填し、５０℃で保存した時のフマル酸ケトチフェン残存量を、特開平１０−１３９６６６号公報記載の方法に基づき、高速液体クロマトグラフ法で測定した。結果を表１に示した。表１中、「実」は実施例、「比」は比較例を示し、処方の数値は「ｍｇ／１００ｍＬ」で示した。
[Test Example 1]
The appearance immediately after the preparation of eye drops obtained in Examples and Comparative Examples was observed. Further, when these were filled in a plastic eye drop container and stored at 50 ° C., the residual amount of ketotifen fumarate was measured by a high performance liquid chromatograph method based on the method described in JP-A-10-139666. The results are shown in Table 1. In Table 1, “Actual” indicates an example, “Ratio” indicates a comparative example, and the numerical value of the formulation is “mg / 100 mL”.
本発明にかかる実施例１の点眼剤は、フマル酸ケトチフェンの残存量が低下せず、着色も認められなかった。本発明の点眼剤は、比較例の点眼剤に比べて、フマル酸ケトチフェンの不安定化を抑制し、着色を抑制することから、点眼剤として有用であることがわかった。 In the eye drop of Example 1 according to the present invention, the residual amount of ketotifen fumarate did not decrease, and coloring was not recognized. The eye drop of the present invention was found to be useful as an eye drop because it suppresses the destabilization of ketotifen fumarate and suppresses coloration compared to the eye drop of the comparative example.
［参考試験例１］
プラノプロフェンを０．０５％含有するｐＨが異なる点眼剤を調製した。健常者５名が点眼し、下記評価基準により刺激感を評価した。結果を表２に示した。
○・・・刺激感がない、
△・・・刺激感がややある、
×・・・刺激感がある。
[Reference Test Example 1]
Eye drops with different pH containing 0.05% pranoprofen were prepared. Five healthy subjects instilled and evaluated the feeling of irritation according to the following evaluation criteria. The results are shown in Table 2.
○ ・ ・ ・ No irritation,
△ ... Slightly irritating,
X: There is a sense of irritation.
表２から明らかなように、６．５を超えるｐＨに調製すると、プラノプロフェンによる点眼時の刺激が抑制できることがわかった。 As is apparent from Table 2, it was found that when the pH was adjusted to more than 6.5, irritation caused by pranoprofen could be suppressed.
本発明の眼科用剤は、プラノプロフェン、フマル酸ケトチフェン、及びエデト酸塩を配合し、かつｐＨが６．５を超えることを特徴とする点眼剤であり、フマル酸ケトチフェンの経時的な残存量の低下と製剤の着色を抑制し、アレルギー症状等での眼のかゆみを長時間抑える極めて有用な点眼剤である。 Ophthalmic agents of the present invention, pranoprofen, ketotifen fumarate, and blended edetate, and a eye drops pH is equal to or more than 6.5, over time residual ketotifen fumarate It is an extremely useful eye drop that suppresses the reduction of the amount and coloring of the preparation, and suppresses itching of the eye due to allergic symptoms for a long time.
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