JP2010132644A - Ophthalmic agent containing ketotifen fumarate - Google Patents
Ophthalmic agent containing ketotifen fumarate Download PDFInfo
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- JP2010132644A JP2010132644A JP2009243182A JP2009243182A JP2010132644A JP 2010132644 A JP2010132644 A JP 2010132644A JP 2009243182 A JP2009243182 A JP 2009243182A JP 2009243182 A JP2009243182 A JP 2009243182A JP 2010132644 A JP2010132644 A JP 2010132644A
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- Prior art keywords
- gellan gum
- ketotifen fumarate
- ophthalmic
- salt
- dipotassium glycyrrhizinate
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- 229960003630 ketotifen fumarate Drugs 0.000 title claims abstract description 40
- 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 title claims abstract description 40
- 239000003732 agents acting on the eye Substances 0.000 title claims abstract description 17
- 229940125702 ophthalmic agent Drugs 0.000 title claims abstract description 17
- 229920002148 Gellan gum Polymers 0.000 claims abstract description 61
- 239000000216 gellan gum Substances 0.000 claims abstract description 61
- 235000010492 gellan gum Nutrition 0.000 claims abstract description 61
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims abstract description 41
- 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 claims abstract description 33
- 229940101029 dipotassium glycyrrhizinate Drugs 0.000 claims abstract description 33
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 238000001556 precipitation Methods 0.000 claims abstract description 21
- 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 abstract description 11
- 238000002835 absorbance Methods 0.000 claims abstract description 11
- 229960001484 edetic acid Drugs 0.000 claims abstract description 10
- 239000002244 precipitate Substances 0.000 claims abstract description 9
- 238000002360 preparation method Methods 0.000 claims description 13
- 239000001509 sodium citrate Substances 0.000 claims description 9
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 9
- 229940037001 sodium edetate Drugs 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 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 claims 1
- 229940023490 ophthalmic product Drugs 0.000 claims 1
- 238000002845 discoloration Methods 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 54
- 239000003889 eye drop Substances 0.000 description 42
- 239000008213 purified water Substances 0.000 description 25
- 239000000243 solution Substances 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- 229940012356 eye drops Drugs 0.000 description 17
- 238000004040 coloring Methods 0.000 description 15
- 238000001914 filtration Methods 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 12
- 238000010438 heat treatment Methods 0.000 description 12
- 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 description 10
- 239000004480 active ingredient Substances 0.000 description 9
- 210000004877 mucosa Anatomy 0.000 description 9
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- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 4
- 230000003266 anti-allergic effect Effects 0.000 description 4
- 230000003042 antagnostic effect Effects 0.000 description 3
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- 235000006708 antioxidants Nutrition 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 150000002617 leukotrienes Chemical class 0.000 description 3
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- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000000043 antiallergic agent Substances 0.000 description 2
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- 230000003078 antioxidant effect Effects 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
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- 238000004519 manufacturing process Methods 0.000 description 2
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- 239000011734 sodium Substances 0.000 description 2
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- 230000001225 therapeutic effect Effects 0.000 description 2
- 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
- 206010015943 Eye inflammation Diseases 0.000 description 1
- 240000004670 Glycyrrhiza echinata Species 0.000 description 1
- 235000001453 Glycyrrhiza echinata Nutrition 0.000 description 1
- 235000006200 Glycyrrhiza glabra Nutrition 0.000 description 1
- 235000017382 Glycyrrhiza lepidota Nutrition 0.000 description 1
- 239000004378 Glycyrrhizin Substances 0.000 description 1
- 102000000543 Histamine Receptors Human genes 0.000 description 1
- 108010002059 Histamine Receptors Proteins 0.000 description 1
- 206010061218 Inflammation 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
- 108010003541 Platelet Activating Factor Proteins 0.000 description 1
- 235000002911 Salvia sclarea Nutrition 0.000 description 1
- 244000182022 Salvia sclarea Species 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- RXDLGFMMQFNVLI-UHFFFAOYSA-N [Na].[Na].[Ca] Chemical compound [Na].[Na].[Ca] RXDLGFMMQFNVLI-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229940086763 ascorbic acid 100 mg Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- FNAQSUUGMSOBHW-UHFFFAOYSA-H calcium citrate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O FNAQSUUGMSOBHW-UHFFFAOYSA-H 0.000 description 1
- 239000001354 calcium citrate Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- KCIDZIIHRGYJAE-YGFYJFDDSA-L dipotassium;[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] phosphate Chemical compound [K+].[K+].OC[C@H]1O[C@H](OP([O-])([O-])=O)[C@H](O)[C@@H](O)[C@H]1O KCIDZIIHRGYJAE-YGFYJFDDSA-L 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
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- 229940079593 drug Drugs 0.000 description 1
- 229940009662 edetate Drugs 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 description 1
- 229960004949 glycyrrhizic acid Drugs 0.000 description 1
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 description 1
- 235000019410 glycyrrhizin Nutrition 0.000 description 1
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 description 1
- 241000411851 herbal medicine Species 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
- 230000001771 impaired effect Effects 0.000 description 1
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- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 229940010454 licorice Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
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- 239000003002 pH adjusting agent Substances 0.000 description 1
- 239000001508 potassium citrate Substances 0.000 description 1
- 229960002635 potassium citrate Drugs 0.000 description 1
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 description 1
- 235000011082 potassium citrates Nutrition 0.000 description 1
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- 235000013337 tricalcium citrate Nutrition 0.000 description 1
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Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
本発明は、眼科用剤に関し、さらに詳しくは、フマル酸ケトチフェン、グリチルリチン酸二カリウム、ジェランガムを配合したときに生じる着色及び沈殿を、クエン酸若しくはその塩又はエデト酸若しくはその塩を配合することにより抑制したことを特徴とする眼科用剤に関する。 The present invention relates to an ophthalmic agent, and more specifically, coloring and precipitation that occur when ketotifen fumarate, dipotassium glycyrrhizinate, and gellan gum are mixed with citric acid or a salt thereof or edetic acid or a salt thereof. The present invention relates to an ophthalmic agent characterized by being suppressed.
フマル酸ケトチフェンは、抗ヒスタミン剤の1種であり、ヒスタミンの遊離抑制作用及びヒスタミン受容体拮抗作用を有する他、ロイコトリエンの産生・遊離抑制作用及びロイコトリエン拮抗作用を有することが知られている。また、好酸球・好中球などの炎症細胞の遊走・浸潤抑制作用、活性酸素産生抑制を有することも知られている。フマル酸ケトチフェンは、上記作用機序に基づき、アレルギー症状を改善することから、アレルギー症状の予防・改善を目的とした点眼剤や点鼻剤等の有効成分として臨床的に広く用いられている(非特許文献1参照)。 Ketotifen fumarate is a kind of antihistamine and is known to have a histamine release inhibitory action and a histamine receptor antagonistic action, as well as a leukotriene production / release inhibitory action and a leukotriene antagonistic action. It is also known to have an action of suppressing migration / invasion of inflammatory cells such as eosinophils and neutrophils, and suppression of active oxygen production. Since ketotifen fumarate improves allergic symptoms based on the above mechanism of action, it is widely used clinically as an active ingredient such as eye drops and nasal drops for the purpose of prevention and improvement of allergic symptoms ( Non-patent document 1).
アレルギー症状では、好酸球などの組織障害性炎症細胞の局所への浸潤とそれに伴う組織障害が生じ、強い炎症を伴うことが知られている。しかしながら、フマル酸ケトチフェンには、抗炎症作用がないため、他の成分によって抗炎症作用を補うことが望ましい。そのような成分の1つとして、グリチルリチン酸二カリウムが挙げられる。グリチルリチン酸二カリウムは、生薬の1種である甘草から得られる化合物であり、抗炎症作用を有することが知られている。そこで、アレルギー症状等の目の炎症を抑え、角膜上皮の組織を修復する作用を有すると考えられる。また、抗アレルギー作用を有することからアレルギー症状の改善にも有効であると考えられる(非特許文献2参照)。 It is known that allergic symptoms involve local infiltration of tissue-damaging inflammatory cells such as eosinophils and accompanying tissue damage, accompanied by strong inflammation. However, since ketotifen fumarate has no anti-inflammatory action, it is desirable to supplement the anti-inflammatory action with other components. One such component is dipotassium glycyrrhizinate. Dipotassium glycyrrhizinate is a compound obtained from licorice, a kind of herbal medicine, and is known to have an anti-inflammatory effect. Therefore, it is considered that it has an action of suppressing eye inflammation such as allergic symptoms and repairing corneal epithelial tissue. Further, since it has an antiallergic action, it is considered effective for improving allergic symptoms (see Non-Patent Document 2).
また、点眼剤を眼粘膜に適用する場合、点眼液は速やかに眼粘膜から排出されてしまうため、有効成分が必ずしも十分には薬効を発揮するとは限らない。すなわち、眼粘膜に適用される点眼剤においては、有効成分の生物学的利用能を高めるために、眼粘膜における有効成分の滞留性を向上させることが好ましい。そこで、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などのセルロース系粘稠化剤を配合して点眼液に粘性を付与することによって有効成分の眼粘膜滞留性を向上させた点眼剤が提供されている。しかしながら、有効成分の眼粘膜滞留性を付与するためにセルロース系粘稠化剤を配合して点眼液の粘度を高めると、点眼剤製造時の濾過滅菌処理が困難になるという問題があった。 In addition, when an eye drop is applied to the ocular mucosa, the ophthalmic solution is quickly discharged from the ocular mucosa, so that the active ingredient does not always exhibit a sufficient medicinal effect. That is, in the eye drop applied to the ocular mucosa, it is preferable to improve the retention of the active ingredient in the ocular mucosa in order to increase the bioavailability of the active ingredient. In view of this, eye drops having improved ocular mucosal retention of active ingredients by blending a cellulose-based thickening agent such as methyl cellulose or hydroxypropyl methyl cellulose to impart viscosity to the eye drop are provided. However, when the viscosity of the eye drop is increased by adding a cellulose-based thickening agent in order to provide the ocular mucosa retention of the active ingredient, there is a problem that the filtration sterilization process at the time of producing the eye drop becomes difficult.
かかる問題を解決するため、点眼剤投与後の眼粘膜滞留性を高める一方、点眼剤の製造時や点眼容器中での保存時には点眼液の粘性が低い、新しいタイプの点眼剤の開発が求められている。そして、このような点眼剤に配合される成分の1つとして、ジェランガムが注目される。 In order to solve such a problem, development of a new type of eye drop in which the viscosity of the eye drop is low when the eye drop is manufactured or stored in an eye drop container while increasing the ocular mucosa retention after the eye drop administration is required. ing. And gellan gum attracts attention as one of the components mix | blended with such eye drops.
ジェランガムは、遊離のNa+等の陽イオンを一定量以上共存させると、ゲル化する性質を有する。ジェランガムのこの性質を利用して、ジェランガムをゲル化剤として配合したジェランガム含有点眼剤が提供されている(特許文献1及び2参照)。ジェランガム含有点眼剤を点眼した場合、眼粘膜表面でジェランガムが涙液中のNa+等の陽イオンと反応し、ゲル化して、有効成分の眼粘膜表面における滞留性が向上し、有効成分の薬効が持続することが期待される。 Gellan gum has the property of gelling when a certain amount or more of cations such as free Na + coexist. By utilizing this property of gellan gum, a gellan gum-containing eye drop containing gellan gum as a gelling agent has been provided (see Patent Documents 1 and 2). When eye drops containing gellan gum are instilled, gellan gum reacts with cations such as Na + in tear fluid on the surface of the ocular mucosa, gels, and the retention of the active ingredient on the surface of the ocular mucosa is improved. Is expected to last.
本発明者らは、抗アレルギー成分としてフマル酸ケトチフェンを配合し、フマル酸ケトチフェンに欠如する抗炎症作用を補完する成分としてグリチルリチン酸二カリウムを配合し、さらにフマル酸ケトチフェンやグリチルリチン酸二カリウムの薬効を持続させるためのジェランガムを配合した点眼剤の開発を行っていた。 The present inventors formulated ketotifen fumarate as an antiallergic component, formulated with dipotassium glycyrrhizinate as a component supplementing the anti-inflammatory action lacking in ketotifen fumarate, and further treated with ketotifen fumarate and dipotassium glycyrrhizinate. Has been developing eye drops containing gellan gum to keep the skin going.
しかしながら、フマル酸ケトチフェンとジェランガムが共存すると点眼液に経時的に着色が生じ、さらにグリチルリチン酸二カリウムが共存すると沈殿物まで析出することが分かった。点眼剤において沈殿物の析出は重大な問題であるし、着色も被服等の汚れの原因になるので、ないにこしたことはない。 However, it has been found that when ketotifen fumarate and gellan gum coexist, the ophthalmic solution is colored over time, and further when dipotassium glycyrrhizinate coexists, a precipitate is deposited. In eye drops, precipitation of precipitates is a serious problem, and coloring also causes stains on clothes and the like.
従来、点眼剤を含め液剤一般において沈殿物が析出する場合には、界面活性剤を配合して沈殿物の生成を抑制するのが常套手段であった。しかしながら、フマル酸ケトチフェン、グリチルリチン酸二カリウム及びジェランガムを同時配合した点眼剤に界面活性剤を配合しても、点眼液の着色は抑制できないことが分かった。 Conventionally, when precipitates are generally precipitated in liquid preparations including eye drops, it has been a conventional means to suppress the formation of precipitates by adding a surfactant. However, it has been found that even when a surfactant is added to an ophthalmic solution containing ketotifen fumarate, dipotassium glycyrrhizinate and gellan gum, coloring of the ophthalmic solution cannot be suppressed.
本発明の目的は、フマル酸ケトチフェン、グリチルリチン酸二カリウム及びジェランガムを配合したときに生じる着色及び沈殿を、簡易に抑制する方法を提供することである。 An object of the present invention is to provide a method for easily suppressing coloring and precipitation that occur when ketotifen fumarate, dipotassium glycyrrhizinate and gellan gum are blended.
本発明者らは、かかる課題を解決するために鋭意検討した結果、フマル酸ケトチフェン、グリチルリチン酸二カリウム及びジェランガムを含有する点眼剤に、クエン酸若しくはその塩、又はエデト酸若しくはその塩を配合することにより、点眼剤の着色及び沈殿が効果的に抑制されることを見出した。 As a result of intensive studies to solve such problems, the present inventors formulated citric acid or a salt thereof, or edetic acid or a salt thereof into an eye drop containing ketotifen fumarate, dipotassium glycyrrhizinate and gellan gum. Thus, it has been found that coloring and precipitation of eye drops are effectively suppressed.
かかる知見により得られた本発明の態様は、(a)フマル酸ケトチフェン、(b)グリチルリチン酸二カリウム、(c)ジェランガム、並びに(d)クエン酸又はその塩、及びエデト酸又はその塩の少なくとも1種を含有することを特徴とする眼科用剤である。 The aspect of the present invention obtained based on such findings includes (a) ketotifen fumarate, (b) dipotassium glycyrrhizinate, (c) gellan gum, and (d) citric acid or a salt thereof, and at least edetic acid or a salt thereof. It is an ophthalmic agent characterized by containing 1 type.
本発明の他の態様は、(a)フマル酸ケトチフェン、(b)グリチルリチン酸二カリウム、(c)ジェランガム、並びに(d)クエン酸又はその塩、及びエデト酸又はその塩の少なくとも1種を含有し、沈殿物の析出がなく、波長400nmにおける吸光度が0.2以下であることを特徴とする眼科用剤である。 Another aspect of the present invention contains at least one of (a) ketotifen fumarate, (b) dipotassium glycyrrhizinate, (c) gellan gum, and (d) citric acid or a salt thereof, and edetic acid or a salt thereof. In addition, the ophthalmic preparation is characterized in that no precipitate is deposited and the absorbance at a wavelength of 400 nm is 0.2 or less.
本発明の他の態様は、前記(d)のクエン酸の塩が、クエン酸ナトリウムである前記各眼科用剤である。 Another embodiment of the present invention is the above ophthalmic preparation wherein the salt of citric acid (d) is sodium citrate.
本発明の他の態様は、前記(d)のエデト酸の塩が、エデト酸ナトリウムである前記各眼科用剤である。 Another aspect of the present invention is the above ophthalmic preparation wherein the edetic acid salt (d) is sodium edetate.
本発明により、フマル酸ケトチフェン、グリチルリチン酸二カリウム及びジェランガムを含有する眼科用剤に特有の着色及び沈殿を簡易に抑制し、澄明な眼科用剤を提供することが可能となった。 According to the present invention, it is possible to easily suppress coloring and precipitation peculiar to an ophthalmic agent containing ketotifen fumarate, dipotassium glycyrrhizinate and gellan gum, and to provide a clear ophthalmic agent.
「フマル酸ケトチフェン」は抗アレルギー薬の1種であり、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)の名称で点眼剤が市販されている。 “Ketotifen fumarate” is a kind of antiallergic drug, and has an antiallergic action and an antagonistic action against histamine, leukotriene, and platelet activating factor, and is classified as a basic antiallergic drug based on its structure. Also called histamine antagonist. For medical use, eye drops are commercially available under the name Zaditen (registered trademark).
「フマル酸ケトチフェン」の配合(含有)濃度は適用する疾病の症状に応じて適宜に増減することができるが、眼科用剤全体の0.005〜0.5w/v%であり、治療効果の点から0.01〜0.1w/v%が好ましい。 The compounding (contained) concentration of “ketotifen fumarate” can be appropriately increased or decreased depending on the symptom of the disease to be applied, but it is 0.005 to 0.5 w / v% of the whole ophthalmic preparation, and has a therapeutic effect. From the point, 0.01 to 0.1 w / v% is preferable.
「グリチルリチン酸二カリウム」の配合(含有)濃度は、必要に応じて適宜に選択することができるが、眼科用剤全体の0.001〜0.5w/v%であり、治療効果の点から0.01〜0.5w/v%が好ましい。 The compounding (contained) concentration of “dipotassium glycyrrhizinate” can be appropriately selected as necessary, but is 0.001 to 0.5 w / v% of the whole ophthalmic preparation, from the viewpoint of therapeutic effect 0.01 to 0.5 w / v% is preferable.
「ジェランガム」の配合(含有)濃度は、必要に応じて適宜に選択することができるが、眼科用剤全体の0.001〜1.0w/v%であり、投与(点眼)後の眼科用剤(点眼液)の眼粘膜滞留性や薬物(有効成分であるフマル酸ケトチフェンやグリチルリチン酸二カリウム)の薬効の持続性等の点から0.01〜0.6w/v%が好ましい。 The blending (contained) concentration of “gellan gum” can be appropriately selected as necessary, but is 0.001 to 1.0 w / v% of the total ophthalmic preparation, and is used for ophthalmic use after administration (instillation). 0.01-0.6 w / v% is preferable from the viewpoints of ocular mucosal retention of the agent (ophthalmic solution) and sustainability of the drug (the active ingredient ketotifen fumarate or dipotassium glycyrrhizinate).
「クエン酸又はその塩」としては、クエン酸、クエン酸ナトリウム、クエン酸カリウム、クエン酸カルシウムが挙げられるが、特に好ましいのはクエン酸ナトリウムである。 Examples of “citric acid or a salt thereof” include citric acid, sodium citrate, potassium citrate, and calcium citrate, with sodium citrate being particularly preferred.
「クエン酸又はその塩」は、点眼剤等の眼科用剤において通常緩衝剤として配合される成分であるが、その本来の用途とは別に、フマル酸ケトチフェン、グリチルリチン酸二カリウム及びジェランガムを含有する眼科用剤に特有の着色及び沈殿を効果的に抑制することを見出したものである。 “Citric acid or a salt thereof” is a component that is usually blended as a buffer in ophthalmic agents such as eye drops, but contains ketotifen fumarate, dipotassium glycyrrhizinate and gellan gum separately from its original use. The present inventors have found that coloring and precipitation peculiar to ophthalmic agents are effectively suppressed.
「エデト酸又はその塩」としては、エデト酸ナトリウム、エデト酸四ナトリウム、エデト酸カルシウム二ナトリウム、エデト酸四ナトリウム四水塩が挙げられるが、特に好ましいのはエデト酸ナトリウムである。 Examples of “edetic acid or a salt thereof” include sodium edetate, tetrasodium edetate, disodium calcium edetate, and tetrasodium edetate tetrahydrate, with sodium edetate being particularly preferred.
エデト酸又はその塩は、点眼剤等の眼科用剤において通常抗酸化剤として配合される成分であるが、その本来の用途とは別に、フマル酸ケトチフェン、グリチルリチン酸二カリウム及びジェランガムを含有する眼科用剤に特有の着色及び沈殿を効果的に抑制することを見出したものである。 Edetic acid or a salt thereof is a component that is usually blended as an antioxidant in ophthalmic preparations such as eye drops, but separately from its original use, an ophthalmic composition containing ketotifen fumarate, dipotassium glycyrrhizinate and gellan gum The present invention has been found to effectively suppress coloring and precipitation peculiar to preparations.
本発明の眼科用剤は、沈殿物の析出がなく、波長400nmにおける吸光度が0.2以下であることを特徴とする。 The ophthalmic agent of the present invention is characterized in that no precipitate is deposited and the absorbance at a wavelength of 400 nm is 0.2 or less.
沈殿物の析出がないことは、眼科用剤を調製し、65℃で1週間保存した後に目視により容易に確認できる。 The absence of precipitation can be easily confirmed visually by preparing an ophthalmic agent and storing it at 65 ° C. for 1 week.
また、波長400nmのときの吸光度は0.2以下である。波長400nmの吸光度が0.2より大きいと眼科用剤は黄色となり、誤って白色系の被服等につけたときには黄色のシミとなって目立つので好ましくない。波長400nmのときの吸光度が0.1〜0.2であれば、眼科用剤は微黄色であり、誤って被服等につけてもシミとなって目立つことはない。波長400nmのときの吸光度が0.1未満であれば、眼科用剤は無色澄明に近く、誤って白色系の被服等につけてもまったく問題はない。 Further, the absorbance at a wavelength of 400 nm is 0.2 or less. If the absorbance at a wavelength of 400 nm is larger than 0.2, the ophthalmic agent becomes yellow, and when it is accidentally put on a white-type clothing, it becomes a yellow spot and it is not preferable. If the absorbance at a wavelength of 400 nm is 0.1 to 0.2, the ophthalmic agent is slightly yellow, and even if it is mistakenly applied to clothes, it does not become noticeable as a stain. If the absorbance at a wavelength of 400 nm is less than 0.1, the ophthalmic agent is almost colorless and clear, and there is no problem even if it is mistakenly applied to white clothes.
ここで、吸光度の測定は、紫外可視分光光度計を用い、精製水でゼロ点補正した後に、波長400nmでの吸収を測定する。 Here, the absorbance is measured by using an ultraviolet-visible spectrophotometer and correcting the zero point with purified water, and then measuring the absorption at a wavelength of 400 nm.
「眼科用剤」には、点眼剤の他、所定の容器の中に本願発明にかかる洗眼液を入れ、その液に目を浸して目を洗う洗眼剤なども含まれる。そして、本発明の眼科用剤を点眼剤として提供する場合、1日あたり1回〜数回に分けて、1回あたり1滴〜数滴を投与することができる。 In addition to eye drops, the “ophthalmic agent” includes an eye wash for putting the eye wash according to the present invention into a predetermined container and immersing the eyes in the solution to wash the eyes. And when providing the ophthalmic preparation of this invention as an eye drop, it can divide into 1 time-several times per day, and can administer 1 drop-several drops per time.
本発明の眼科用剤には、本発明の効果を損なわない範囲で、クエン酸又はその塩以外の緩衝剤、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配合することができる。 In the ophthalmic preparation of the present invention, a buffer other than citric acid or a salt thereof, an isotonic agent, a solubilizing agent, a preservative, a thickener, a pH adjuster, etc., as long as the effects of the present invention are not impaired. Various additives can be blended.
以下に、実施例、比較例及び試験例を挙げ、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, Comparative Examples and Test Examples.
実施例1
フマル酸ケトチフェン 69mg
ジェランガム 50mg
グリチルリチン酸二カリウム 250mg
クエン酸ナトリウム 100mg
塩酸 適量
精製水(約80mL)にジェランガムを除いた各成分を溶解後、ジェランガムを分散させて加熱溶解した。該溶液に塩酸を適量添加してpHを5.3に調整し、精製水で全量を正確に100mLとした。ろ過滅菌を行い、無菌の点眼剤を得た。
Example 1
Ketotifen fumarate 69mg
Gellan gum 50mg
Dipotassium glycyrrhizinate 250mg
Sodium citrate 100mg
Hydrochloric acid appropriate amount After dissolving each component except gellan gum in purified water (about 80 mL), gellan gum was dispersed and dissolved by heating. An appropriate amount of hydrochloric acid was added to the solution to adjust the pH to 5.3, and the total amount was adjusted to 100 mL with purified water. The solution was sterilized by filtration to obtain a sterile eye drop.
実施例2
フマル酸ケトチフェン 69mg
ジェランガム 50mg
グリチルリチン酸二カリウム 250mg
エデト酸ナトリウム 100mg
水酸化ナトリウム 適量
精製水(約80mL)にジェランガムを除いた各成分を溶解後、ジェランガムを分散させて加熱溶解した。該溶液に水酸化ナトリウムを適量添加してpHを5.3に調整し、精製水で全量を正確に100mLとした。ろ過滅菌を行い、無菌の点眼剤を得た。
Example 2
Ketotifen fumarate 69mg
Gellan gum 50mg
Dipotassium glycyrrhizinate 250mg
Sodium edetate 100mg
Sodium hydroxide proper amount After dissolving each component except gellan gum in purified water (about 80 mL), gellan gum was dispersed and dissolved by heating. An appropriate amount of sodium hydroxide was added to the solution to adjust the pH to 5.3, and the total amount was adjusted to 100 mL with purified water. The solution was sterilized by filtration to obtain a sterile eye drop.
実施例3
フマル酸ケトチフェン 69mg
ジェランガム 600mg
グリチルリチン酸二カリウム 50mg
クエン酸ナトリウム 100mg
塩酸 適量
精製水(約80mL)にジェランガムを除いた各成分を溶解後、ジェランガムを分散させて加熱溶解した。該溶液に塩酸を適量添加してpHを5.3に調整し、精製水で全量を正確に100mLとした。ろ過滅菌を行い、無菌の点眼剤を得た。
Example 3
Ketotifen fumarate 69mg
Gellan gum 600mg
Dipotassium glycyrrhizinate 50mg
Sodium citrate 100mg
Hydrochloric acid appropriate amount After dissolving each component except gellan gum in purified water (about 80 mL), gellan gum was dispersed and dissolved by heating. An appropriate amount of hydrochloric acid was added to the solution to adjust the pH to 5.3, and the total amount was adjusted to 100 mL with purified water. The solution was sterilized by filtration to obtain a sterile eye drop.
実施例4
フマル酸ケトチフェン 69mg
ジェランガム 50mg
グリチルリチン酸二カリウム 250mg
クエン酸ナトリウム 100mg
ポリソルベート80 100mg
塩酸 適量
精製水(約80mL)にジェランガムを除いた各成分を溶解後、ジェランガムを分散させて加熱溶解した。該溶液に塩酸を適量添加してpHを5.3に調整し、精製水で全量を正確に100mLとした。ろ過滅菌を行い、無菌の点眼剤を得た。
Example 4
Ketotifen fumarate 69mg
Gellan gum 50mg
Dipotassium glycyrrhizinate 250mg
Sodium citrate 100mg
Polysorbate 80 100mg
Hydrochloric acid appropriate amount After dissolving each component except gellan gum in purified water (about 80 mL), gellan gum was dispersed and dissolved by heating. An appropriate amount of hydrochloric acid was added to the solution to adjust the pH to 5.3, and the total amount was adjusted to 100 mL with purified water. The solution was sterilized by filtration to obtain a sterile eye drop.
実施例5
フマル酸ケトチフェン 69mg
ジェランガム 50mg
グリチルリチン酸二カリウム 250mg
エデト酸ナトリウム 100mg
ポリソルベート80 100mg
水酸化ナトリウム 適量
精製水(約80mL)にジェランガムを除いた各成分を溶解後、ジェランガムを分散させて加熱溶解した。該溶液に水酸化ナトリウムを適量添加してpHを5.3に調整し、精製水で全量を正確に100mLとした。ろ過滅菌を行い、無菌の点眼剤を得た。
Example 5
Ketotifen fumarate 69mg
Gellan gum 50mg
Dipotassium glycyrrhizinate 250mg
Sodium edetate 100mg
Polysorbate 80 100mg
Sodium hydroxide proper amount After dissolving each component except gellan gum in purified water (about 80 mL), gellan gum was dispersed and dissolved by heating. An appropriate amount of sodium hydroxide was added to the solution to adjust the pH to 5.3, and the total amount was adjusted to 100 mL with purified water. The solution was sterilized by filtration to obtain a sterile eye drop.
実施例6
フマル酸ケトチフェン 69mg
ジェランガム 50mg
グリチルリチン酸二カリウム 250mg
エデト酸ナトリウム 100mg
水酸化ナトリウム 適量
精製水(約80mL)にジェランガムを除いた各成分を溶解後、ジェランガムを分散させて加熱溶解した。該溶液に水酸化ナトリウムを適量添加してpHを4.8に調整し、精製水で全量を正確に100mLとした。ろ過滅菌を行い、無菌の点眼剤を得た。
Example 6
Ketotifen fumarate 69mg
Gellan gum 50mg
Dipotassium glycyrrhizinate 250mg
Sodium edetate 100mg
Sodium hydroxide proper amount After dissolving each component except gellan gum in purified water (about 80 mL), gellan gum was dispersed and dissolved by heating. An appropriate amount of sodium hydroxide was added to the solution to adjust the pH to 4.8, and the total amount was adjusted to 100 mL with purified water. The solution was sterilized by filtration to obtain a sterile eye drop.
実施例7
フマル酸ケトチフェン 69mg
ジェランガム 50mg
グリチルリチン酸二カリウム 250mg
エデト酸ナトリウム 100mg
水酸化ナトリウム 適量
精製水(約80mL)にジェランガムを除いた各成分を溶解後、ジェランガムを分散させて加熱溶解した。該溶液に水酸化ナトリウムを適量添加してpHを6.5に調整し、精製水で全量を正確に100mLとした。ろ過滅菌を行い、無菌の点眼剤を得た。
Example 7
Ketotifen fumarate 69mg
Gellan gum 50mg
Dipotassium glycyrrhizinate 250mg
Sodium edetate 100mg
Sodium hydroxide proper amount After dissolving each component except gellan gum in purified water (about 80 mL), gellan gum was dispersed and dissolved by heating. An appropriate amount of sodium hydroxide was added to the solution to adjust the pH to 6.5, and the total amount was adjusted to 100 mL with purified water. The solution was sterilized by filtration to obtain a sterile eye drop.
比較例1
フマル酸ケトチフェン 69mg
ジェランガム 600mg
水酸化ナトリウム 適量
精製水(約80mL)にフマル酸ケトチフェンを溶解後、ジェランガムを分散させて加熱溶解した。該溶液に水酸化ナトリウムを適量添加してpHを5.3に調整し、精製水で全量を正確に100mLとした。ろ過滅菌を行い、無菌の点眼剤を得た。
Comparative Example 1
Ketotifen fumarate 69mg
Gellan gum 600mg
Sodium hydroxide appropriate amount After dissolving ketotifen fumarate in purified water (about 80 mL), gellan gum was dispersed and dissolved by heating. An appropriate amount of sodium hydroxide was added to the solution to adjust the pH to 5.3, and the total amount was adjusted to 100 mL with purified water. The solution was sterilized by filtration to obtain a sterile eye drop.
比較例2
フマル酸ケトチフェン 69mg
ジェランガム 50mg
グリチルリチン酸二カリウム 250mg
水酸化ナトリウム 適量
精製水(約80mL)にジェランガムを除いた各成分を溶解後、ジェランガムを分散させて加熱溶解した。該溶液に水酸化ナトリウムを適量添加してpHを5.3に調整し、精製水で全量を正確に100mLとした。ろ過滅菌を行い、無菌の点眼剤を得た。
Comparative Example 2
Ketotifen fumarate 69mg
Gellan gum 50mg
Dipotassium glycyrrhizinate 250mg
Sodium hydroxide proper amount After dissolving each component except gellan gum in purified water (about 80 mL), gellan gum was dispersed and dissolved by heating. An appropriate amount of sodium hydroxide was added to the solution to adjust the pH to 5.3, and the total amount was adjusted to 100 mL with purified water. The solution was sterilized by filtration to obtain a sterile eye drop.
比較例3
フマル酸ケトチフェン 69mg
ジェランガム 50mg
グリチルリチン酸二カリウム 250mg
ホウ酸 500mg
水酸化ナトリウム 適量
精製水(約80mL)にジェランガムを除いた各成分を溶解後、ジェランガムを分散させて加熱溶解した。該溶液に水酸化ナトリウムを適量添加してpHを5.3に調整し、精製水で全量を正確に100mLとした。ろ過滅菌を行い、無菌の点眼剤を得た。
Comparative Example 3
Ketotifen fumarate 69mg
Gellan gum 50mg
Dipotassium glycyrrhizinate 250mg
Boric acid 500mg
Sodium hydroxide proper amount After dissolving each component except gellan gum in purified water (about 80 mL), gellan gum was dispersed and dissolved by heating. An appropriate amount of sodium hydroxide was added to the solution to adjust the pH to 5.3, and the total amount was adjusted to 100 mL with purified water. The solution was sterilized by filtration to obtain a sterile eye drop.
比較例4
フマル酸ケトチフェン 69mg
ジェランガム 50mg
グリチルリチン酸二カリウム 250mg
アスコルビン酸 100mg
水酸化ナトリウム 適量
精製水(約80mL)にジェランガムを除いた各成分を溶解後、ジェランガムを分散させて加熱溶解した。該溶液に水酸化ナトリウムを適量添加してpHを5.3に調整し、精製水で全量を正確に100mLとした。ろ過滅菌を行い、無菌の点眼剤を得た。
Comparative Example 4
Ketotifen fumarate 69mg
Gellan gum 50mg
Dipotassium glycyrrhizinate 250mg
Ascorbic acid 100mg
Sodium hydroxide proper amount After dissolving each component except gellan gum in purified water (about 80 mL), gellan gum was dispersed and dissolved by heating. An appropriate amount of sodium hydroxide was added to the solution to adjust the pH to 5.3, and the total amount was adjusted to 100 mL with purified water. The solution was sterilized by filtration to obtain a sterile eye drop.
比較例5
フマル酸ケトチフェン 69mg
ジェランガム 50mg
グリチルリチン酸二カリウム 250mg
ポリソルベート80 100mg
水酸化ナトリウム 適量
精製水(約80mL)にジェランガムを除いた各成分を溶解後、ジェランガムを分散させて加熱溶解した。該溶液に水酸化ナトリウムを適量添加してpHを5.3に調整し、精製水で全量を正確に100mLとした。ろ過滅菌を行い、無菌の点眼剤を得た。
Comparative Example 5
Ketotifen fumarate 69mg
Gellan gum 50mg
Dipotassium glycyrrhizinate 250mg
Polysorbate 80 100mg
Sodium hydroxide proper amount After dissolving each component except gellan gum in purified water (about 80 mL), gellan gum was dispersed and dissolved by heating. An appropriate amount of sodium hydroxide was added to the solution to adjust the pH to 5.3, and the total amount was adjusted to 100 mL with purified water. The solution was sterilized by filtration to obtain a sterile eye drop.
試験例
実施例及び比較例で得られた点眼剤を65℃で一週間保存し、着色の有無を調べるため波長400nmにおける吸光度測定を行った。併せて、目視観察により着色の評価及び沈殿生成の有無を確認した。結果を表1−1から1−3に示した。
Test Example The eye drops obtained in Examples and Comparative Examples were stored at 65 ° C. for one week, and absorbance was measured at a wavelength of 400 nm in order to examine the presence of coloring. In addition, the coloration evaluation and the presence or absence of precipitation were confirmed by visual observation. The results are shown in Tables 1-1 to 1-3.
総合判定の基準は次のとおりである。 The criteria for comprehensive judgment are as follows.
「着色及び沈殿なし」:○
「着色沈殿のどちらか一方がある」:△
「着色と沈殿の両者がある」:×
“No coloring or precipitation”: ○
“There is either colored precipitation”: △
“There are both coloring and precipitation”: ×
本発明にかかる実施例1〜7の点眼剤は、比較例2〜5の点眼剤と異なり、着色及び沈殿の何れも抑制された。クエン酸ナトリウムは、緩衝剤として用いられる成分であるが、他の緩衝剤(例えば、ホウ酸;比較例3)では着色及び沈殿の抑制効果は認められず、クエン酸ナトリウムに特有の効果であることが分かった。 The eye drops of Examples 1 to 7 according to the present invention were different from the eye drops of Comparative Examples 2 to 5, and both coloring and precipitation were suppressed. Sodium citrate is a component used as a buffering agent, but other buffering agents (for example, boric acid; Comparative Example 3) have no effect of suppressing coloration and precipitation, and are unique to sodium citrate. I understood that.
エデト酸ナトリウムは、抗酸化剤として用いられる成分であるが、他の抗酸化剤(例えば、アスコルビン酸;比較例4)では着色及び沈殿の抑制効果は認められず、エデト酸ナトリウムに特有の効果であることが分かった。 Although edetate sodium is a component used as an antioxidant, other antioxidants (for example, ascorbic acid; Comparative Example 4) have no effect of suppressing coloring and precipitation, and are specific to sodium edetate. It turns out that.
また、点眼剤の沈殿を抑制する方法としては界面活性剤(例えば、ポリソルベート80)の配合が一般的であるが、ポリソルベート80を配合した比較例5では、沈殿は抑制されたが、着色は抑制できなかった。 Further, as a method for suppressing the precipitation of eye drops, a surfactant (for example, polysorbate 80) is generally blended. In Comparative Example 5 in which polysorbate 80 was blended, precipitation was suppressed, but coloring was suppressed. could not.
なお、フマル酸ケトチフェンとジェランガムを配合し、グリチルリチン酸二カリウムを配合していない比較例1では、沈殿は生ぜず、吸光度0.114の微黄色であったことから、フマル酸ケトチフェン、ジェランガム及びグリチルリチン酸二カリウムを配合したときに着色及び沈殿が著しくなることが分かる。 In Comparative Example 1 in which ketotifen fumarate and gellan gum were blended and dipotassium glycyrrhizinate was not blended, precipitation did not occur and the color was slightly yellow with an absorbance of 0.114. Therefore, ketotifen fumarate, gellan gum and glycyrrhizin It turns out that coloring and precipitation become remarkable when dipotassium acid is mix | blended.
本発明により、フマル酸ケトチフェン、グリチルリチン酸二カリウム及びジェランガムを含有し、抗アレルギー作用のみならず抗炎症作用を有し、点眼後に点眼液が眼粘膜表面に滞留するため有効成分の薬効の持続が期待される澄明な点眼剤を提供することが可能となった。 According to the present invention, it contains ketotifen fumarate, dipotassium glycyrrhizinate and gellan gum, has anti-allergic action as well as anti-inflammatory action, and the ophthalmic solution stays on the surface of the ocular mucosa after instillation, so that the efficacy of the active ingredient is sustained It became possible to provide the expected clear eye drops.
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JP2006213700A (en) * | 2005-01-05 | 2006-08-17 | Taisho Pharmaceut Co Ltd | Oxymetazoline-containing aqueous composition |
JP2007176932A (en) * | 2005-11-30 | 2007-07-12 | Taisho Pharmaceut Co Ltd | Liquid preparation applied for mucosa |
WO2008026756A1 (en) * | 2006-08-28 | 2008-03-06 | Senju Pharmaceutical Co., Ltd. | Ophthalmic percutaneous absorption type preparation |
JP2008120795A (en) * | 2006-10-18 | 2008-05-29 | Taisho Pharmaceutical Co Ltd | Liquid formulation applicable to mucosa |
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JP2007176932A (en) * | 2005-11-30 | 2007-07-12 | Taisho Pharmaceut Co Ltd | Liquid preparation applied for mucosa |
WO2008026756A1 (en) * | 2006-08-28 | 2008-03-06 | Senju Pharmaceutical Co., Ltd. | Ophthalmic percutaneous absorption type preparation |
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