JP2020172486A - Aqueous pharmaceutical composition containing epinastine or salt thereof - Google Patents
Aqueous pharmaceutical composition containing epinastine or salt thereof Download PDFInfo
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- JP2020172486A JP2020172486A JP2020070406A JP2020070406A JP2020172486A JP 2020172486 A JP2020172486 A JP 2020172486A JP 2020070406 A JP2020070406 A JP 2020070406A JP 2020070406 A JP2020070406 A JP 2020070406A JP 2020172486 A JP2020172486 A JP 2020172486A
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- JP
- Japan
- Prior art keywords
- acid
- pharmaceutical composition
- salt
- aqueous pharmaceutical
- epinastine
- 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.)
- Pending
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 102
- 150000003839 salts Chemical class 0.000 title claims abstract description 97
- WHWZLSFABNNENI-UHFFFAOYSA-N epinastine Chemical compound C1C2=CC=CC=C2C2CN=C(N)N2C2=CC=CC=C21 WHWZLSFABNNENI-UHFFFAOYSA-N 0.000 title claims abstract description 63
- 229960003449 epinastine Drugs 0.000 title claims abstract description 49
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 claims abstract description 45
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 54
- 235000010199 sorbic acid Nutrition 0.000 claims description 24
- 239000004334 sorbic acid Substances 0.000 claims description 24
- 229940075582 sorbic acid Drugs 0.000 claims description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 23
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 claims description 23
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 claims description 22
- 229960002684 aminocaproic acid Drugs 0.000 claims description 19
- 239000003889 eye drop Substances 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 19
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- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229960002969 oleic acid Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000006353 oxyethylene group Chemical group 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229940113116 polyethylene glycol 1000 Drugs 0.000 description 1
- 239000010318 polygalacturonic acid Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 description 1
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010988 polyoxyethylene sorbitan tristearate Nutrition 0.000 description 1
- 239000001816 polyoxyethylene sorbitan tristearate Substances 0.000 description 1
- 229940099429 polyoxyl 40 stearate Drugs 0.000 description 1
- 229940101027 polysorbate 40 Drugs 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 229940099511 polysorbate 65 Drugs 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000001508 potassium citrate Substances 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
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- ANDAULZAMAPNOJ-UHFFFAOYSA-M potassium;6-aminohexanoate Chemical compound [K+].NCCCCCC([O-])=O ANDAULZAMAPNOJ-UHFFFAOYSA-M 0.000 description 1
- WKZJASQVARUVAW-UHFFFAOYSA-M potassium;hydron;2-hydroxypropane-1,2,3-tricarboxylate Chemical compound [K+].OC(=O)CC(O)(C(O)=O)CC([O-])=O WKZJASQVARUVAW-UHFFFAOYSA-M 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 235000004400 serine Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- 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 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 229940010747 sodium hyaluronate Drugs 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- LROWVYNUWKVTCU-STWYSWDKSA-M sodium sorbate Chemical compound [Na+].C\C=C\C=C\C([O-])=O LROWVYNUWKVTCU-STWYSWDKSA-M 0.000 description 1
- 235000019250 sodium sorbate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000004328 sodium tetraborate Substances 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 1
- WSWCOQWTEOXDQX-MQQKCMAXSA-N sorbic acid group Chemical group C(\C=C\C=C\C)(=O)O WSWCOQWTEOXDQX-MQQKCMAXSA-N 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 150000003900 succinic acid esters Chemical class 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 210000001138 tear Anatomy 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 235000013337 tricalcium citrate Nutrition 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- PLSARIKBYIPYPF-UHFFFAOYSA-H trimagnesium dicitrate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O PLSARIKBYIPYPF-UHFFFAOYSA-H 0.000 description 1
- WUUHFRRPHJEEKV-UHFFFAOYSA-N tripotassium borate Chemical compound [K+].[K+].[K+].[O-]B([O-])[O-] WUUHFRRPHJEEKV-UHFFFAOYSA-N 0.000 description 1
- 235000015870 tripotassium citrate Nutrition 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
- 235000019263 trisodium citrate Nutrition 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 235000014393 valine Nutrition 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Abstract
Description
本発明は、エピナスチンまたはその塩を含有する水性医薬組成物、より詳しくはエピナスチン又はその塩と、低級脂肪族カルボン酸類とを含有する水性医薬組成物（以下、「本発明の水性医薬組成物」ともいう）に関する。 The present invention is an aqueous pharmaceutical composition containing epinastine or a salt thereof, more specifically, an aqueous pharmaceutical composition containing epinastine or a salt thereof and lower aliphatic carboxylic acids (hereinafter, "the aqueous pharmaceutical composition of the present invention"). Also called).
現在、アレルギー性結膜炎治療剤として日本で上市されている、エピナスチン塩酸塩を有効成分とするアレジオン（登録商標）点眼液０．０５％は、その用法・用量が通常１回１滴、１日４回点眼することと定められている（非特許文献１）。 Currently, 0.05% of Alesion (registered trademark) ophthalmic solution containing epinastine hydrochloride as an active ingredient, which is marketed in Japan as a therapeutic agent for allergic conjunctivitis, is usually used and dosed at 1 drop per day, 4 per day. It is stipulated that the eye drops should be applied (Non-Patent Document 1).
服薬アドヒアランスの観点から、点眼剤として１日４回の点眼は、日常生活において数時間点眼できない状況もあり得るため、これより少ない点眼回数が望ましい。しかしながら、点眼回数を減らすと眼組織中の有効濃度を維持できずに薬効を低減させる可能性があり、薬効を発揮するためには眼組織中の有効濃度を維持する必要がある。眼組織中の有効濃度を維持する方法として、有効成分の配合濃度を増大する方法、吸収促進剤を用いる方法、増粘剤を配合することにより組織滞留性を向上させる方法等が知られている。
例えば、特許文献１には、β遮断薬を、アルギン酸を含有する水溶液に加えてｐＨを６〜８に調整することによって投与後の作用時間の延長効果があることが記載されている。また、特許文献２には、β遮断薬に糖アルコールを含有させることにより、薬物の眼内移行性を向上することが記載されている。しかしながら、低級脂肪族カルボン酸の添加により、エピナスチンまたはその塩の眼組織への移行を向上させて、眼組織中の有効濃度を維持させるとの報告はない。
From the viewpoint of medication adherence, it is desirable to use less than this number of eye drops because it may not be possible to apply eye drops four times a day for several hours in daily life. However, if the number of instillations is reduced, the effective concentration in the eye tissue cannot be maintained and the drug effect may be reduced, and it is necessary to maintain the effective concentration in the eye tissue in order to exert the drug effect. As a method of maintaining the effective concentration in the ocular tissue, a method of increasing the blending concentration of the active ingredient, a method of using an absorption promoter, a method of improving tissue retention by blending a thickener, and the like are known. ..
For example, Patent Document 1 describes that adding a β-blocker to an aqueous solution containing alginic acid and adjusting the pH to 6 to 8 has an effect of prolonging the action time after administration. Further, Patent Document 2 describes that by adding a sugar alcohol to a β-blocker, the transferability of the drug into the eye is improved. However, it has not been reported that the addition of a lower aliphatic carboxylic acid enhances the transfer of epinastine or a salt thereof to the ocular tissue and maintains the effective concentration in the ocular tissue.
したがって、優れた薬効をもたらすために有効成分の組織、特に眼組織への移行性を向上させることは非常に有用であり、有効成分としてエピナスチン又はその塩を含有する、組織、特に眼組織への移行性を向上させた水性医薬組成物を提供することは興味深い課題である。 Therefore, it is very useful to improve the transferability of the active ingredient to tissues, especially eye tissues, in order to bring about excellent medicinal properties, and to tissues containing epinastine or a salt thereof as active ingredients, especially to eye tissues. It is an interesting subject to provide an aqueous pharmaceutical composition with improved migration.
本発明者らは、エピナスチン又はその塩を含有する水性医薬組成物について鋭意研究を行ったところ、エピナスチン又はその塩と、低級脂肪族カルボン酸類とを含有する水性医薬組成物を、眼に点眼投与した場合にエピナスチンの眼組織への移行性が向上することを見出し、本発明の完成に至った。 As a result of diligent research on an aqueous pharmaceutical composition containing epinastine or a salt thereof, the present inventors instilled an aqueous pharmaceutical composition containing epinastine or a salt thereof and lower aliphatic carboxylic acids into the eye. In this case, it was found that the transferability of epinastine to the eye tissue was improved, and the present invention was completed.
具体的に、本発明は以下を提供する。
（１）エピナスチン又はその塩と、低級脂肪族カルボン酸類とを含有する水性医薬組成物。
（２）エピナスチン又はその塩が、エピナスチン塩酸塩である、（１）に記載の水性医薬組成物。
（３）エピナスチン又はその塩の濃度が、０．０１〜５％（ｗ／ｖ）である、（１）又は（２）に記載の水性医薬組成物。
（４）エピナスチン又はその塩の濃度が、０．０５％（ｗ／ｖ）以上である、（１）又は（２）に記載の水性医薬組成物。
（５）エピナスチン又はその塩の濃度が、０．１％（ｗ／ｖ）である、（１）〜（４）のいずれか１つに記載の水性医薬組成物。
（６）低級脂肪族カルボン酸類が、酢酸、クエン酸、エデト酸、ソルビン酸、ε−アミノカプロン酸及びそれらの塩からなる群より選択される１種以上である、（１）〜（５）のいずれか１つに記載の水性医薬組成物。
（７）低級脂肪族カルボン酸類が、ソルビン酸又はその塩である、（１）〜（６）のいずれか１つに記載の水性医薬組成物。
（８）ソルビン酸又はその塩の濃度が、０．０１〜２％（ｗ／ｖ）である、（６）又は（７）に記載の水性医薬組成物。
（９）低級脂肪族カルボン酸類が、クエン酸又はその塩である、（１）〜（６）のいずれか１つに記載の水性医薬組成物。
（１０）クエン酸又はその塩の濃度が、０．０１〜３．５％（ｗ／ｖ）である、（６）又は（９）に記載の水性医薬組成物。
（１１）低級脂肪族カルボン酸類が、ε−アミノカプロン酸又はその塩である、（１）〜（６）のいずれか１つに記載の水性医薬組成物。
（１２）ε−アミノカプロン酸又はその塩の濃度が、０．０１〜１％（ｗ／ｖ）である、（６）又は（１１）に記載の水性医薬組成物。
（１３）さらに等張化剤を含有する、（１）〜（１２）のいずれか１つに記載の水性医薬組成物。
（１４）眼科用である、（１）〜（１３）のいずれか１つに記載の水性医薬組成物。
（１５）点眼剤である、（１）〜（１４）のいずれか１つに記載の水性医薬組成物。
（１６）有効成分としてエピナスチン又はその塩を含有する水性医薬組成物に、低級脂肪族カルボン酸類を配合することによって、エピナスチン又はその塩の眼組織への移行性を向上させる方法。
（１７）低級脂肪族カルボン酸類が、酢酸、クエン酸、エデト酸、ソルビン酸、ε−アミノカプロン酸及びそれらの塩からなる群より選択される１種以上である、（１６）に記載の方法。
（１８）低級脂肪族カルボン酸類が、ソルビン酸又はその塩である、（１６）又は（１７）に記載の方法。
（１９）低級脂肪族カルボン酸類が、クエン酸又はその塩である、（１６）又は（１７）に記載の方法。
（２０）低級脂肪族カルボン酸類が、ε−アミノカプロン酸又はその塩である、（１６）又は（１７）に記載の方法。
（２１）眼組織が結膜である、（１６）〜（２０）のいずれか１つに記載の方法。
なお、前記（１）から（２１）の各構成は、任意に２以上を選択して組み合わせることができる。
Specifically, the present invention provides:
(1) An aqueous pharmaceutical composition containing epinastine or a salt thereof and lower aliphatic carboxylic acids.
(2) The aqueous pharmaceutical composition according to (1), wherein epinastine or a salt thereof is epinastine hydrochloride.
(3) The aqueous pharmaceutical composition according to (1) or (2), wherein the concentration of epinastine or a salt thereof is 0.01 to 5% (w / v).
(4) The aqueous pharmaceutical composition according to (1) or (2), wherein the concentration of epinastine or a salt thereof is 0.05% (w / v) or more.
(5) The aqueous pharmaceutical composition according to any one of (1) to (4), wherein the concentration of epinastine or a salt thereof is 0.1% (w / v).
(6) The lower aliphatic carboxylic acids are one or more selected from the group consisting of acetic acid, citric acid, edetic acid, sorbic acid, ε-aminocaproic acid and salts thereof, according to (1) to (5). The aqueous pharmaceutical composition according to any one.
(7) The aqueous pharmaceutical composition according to any one of (1) to (6), wherein the lower aliphatic carboxylic acid is sorbic acid or a salt thereof.
(8) The aqueous pharmaceutical composition according to (6) or (7), wherein the concentration of sorbic acid or a salt thereof is 0.01 to 2% (w / v).
(9) The aqueous pharmaceutical composition according to any one of (1) to (6), wherein the lower aliphatic carboxylic acid is citric acid or a salt thereof.
(10) The aqueous pharmaceutical composition according to (6) or (9), wherein the concentration of citric acid or a salt thereof is 0.01 to 3.5% (w / v).
(11) The aqueous pharmaceutical composition according to any one of (1) to (6), wherein the lower aliphatic carboxylic acid is ε-aminocaproic acid or a salt thereof.
(12) The aqueous pharmaceutical composition according to (6) or (11), wherein the concentration of ε-aminocaproic acid or a salt thereof is 0.01 to 1% (w / v).
(13) The aqueous pharmaceutical composition according to any one of (1) to (12), which further contains an isotonic agent.
(14) The aqueous pharmaceutical composition according to any one of (1) to (13), which is for ophthalmology.
(15) The aqueous pharmaceutical composition according to any one of (1) to (14), which is an eye drop.
(16) A method for improving the transferability of epinastine or a salt thereof to an ocular tissue by blending a lower aliphatic carboxylic acid with an aqueous pharmaceutical composition containing epinastine or a salt thereof as an active ingredient.
(17) The method according to (16), wherein the lower aliphatic carboxylic acids are at least one selected from the group consisting of acetic acid, citric acid, edetic acid, sorbic acid, ε-aminocaproic acid and salts thereof.
(18) The method according to (16) or (17), wherein the lower aliphatic carboxylic acid is sorbic acid or a salt thereof.
(19) The method according to (16) or (17), wherein the lower aliphatic carboxylic acid is citric acid or a salt thereof.
(20) The method according to (16) or (17), wherein the lower aliphatic carboxylic acid is ε-aminocaproic acid or a salt thereof.
(21) The method according to any one of (16) to (20), wherein the eye tissue is conjunctiva.
In addition, each configuration of (1) to (21) can be arbitrarily selected and combined with two or more.
さらに、本発明は以下も提供する。
（２２）治療が必要な患者に、治療上の有効量の（１）〜（１５）のいずれかに記載の水性医薬組成物を投与することを特徴とする、アレルギー性疾患の治療方法。
（２３）アレルギー性疾患の治療に使用する、（１）〜（１５）のいずれかに記載の水性医薬組成物。
（２４）アレルギー性疾患を治療するための医薬を製造するための、（１）〜（１５）のいずれかに記載の水性医薬組成物の使用。
Furthermore, the present invention also provides:
(22) A method for treating an allergic disease, which comprises administering a therapeutically effective amount of the aqueous pharmaceutical composition according to any one of (1) to (15) to a patient in need of treatment.
(23) The aqueous pharmaceutical composition according to any one of (1) to (15), which is used for treating allergic diseases.
(24) Use of the aqueous pharmaceutical composition according to any one of (1) to (15) for producing a drug for treating an allergic disease.
本発明は、エピナスチン又はその塩を含有する水性医薬組成物に、低級脂肪族カルボン酸類を配合することによって、エピナスチン又はその塩の眼組織への移行性を向上させて優れた薬効をもたらす、水性医薬組成物を得ることができる。 According to the present invention, by blending a lower aliphatic carboxylic acid with an aqueous pharmaceutical composition containing epinastine or a salt thereof, the transferability of epinastine or a salt thereof to an ocular tissue is improved to bring about an excellent medicinal effect. A pharmaceutical composition can be obtained.
以下に、本発明について詳細に説明する。 The present invention will be described in detail below.
本発明において、「エピナスチン」とは、化学名（±）−３−Ａｍｉｎｏ−９，１３ｂ−ｄｉｈｙｄｒｏ−１Ｈ−ｄｉｂｅｎｚ［ｃ，ｆ］ｉｍｉｄａｚｏ［１，５−ａ］ａｚｅｐｉｎｅで表される化合物であり、また下記式：
本発明の水性医薬組成物において、含有されるエピナスチンはラセミ体であってもよく、光学異性体であってもよい。 In the aqueous pharmaceutical composition of the present invention, the epinastine contained may be a racemate or an optical isomer.
本発明の水性医薬組成物において、含有されるエピナスチンは塩であってもよく、医薬として許容される塩であれば特に制限はない。塩としては例えば、無機酸との塩、有機酸との塩等が挙げられる。
無機酸との塩としては、塩酸、臭化水素酸、ヨウ化水素酸、硝酸、硫酸、リン酸等との塩が挙げられる。
有機酸との塩としては、酢酸、シュウ酸、フマル酸、マレイン酸、コハク酸、リンゴ酸、クエン酸、酒石酸、アジピン酸、グルコン酸、グルコヘプト酸、グルクロン酸、テレフタル酸、メタンスルホン酸、アラニン、乳酸、馬尿酸、１，２−エタンジスルホン酸、イセチオン酸、ラクトビオン酸、オレイン酸、没食子酸、パモ酸、ポリガラクツロン酸、ステアリン酸、タンニン酸、トリフルオロメタンスルホン酸、ベンゼンスルホン酸、ｐ−トルエンスルホン酸、硫酸ラウリル、硫酸メチル、ナフタレンスルホン酸、スルホサリチル酸等との塩が挙げられる。
エピナスチンの塩としては、一塩酸塩（エピナスチン塩酸塩）が特に好ましい。
In the aqueous pharmaceutical composition of the present invention, the epinastine contained may be a salt, and is not particularly limited as long as it is a pharmaceutically acceptable salt. Examples of the salt include a salt with an inorganic acid, a salt with an organic acid, and the like.
Examples of the salt with the inorganic acid include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
Salts with organic acids include acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptoic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, and alanine. , Lactic acid, horse uric acid, 1,2-ethanedisulfonic acid, isetioic acid, lactobionic acid, oleic acid, gallic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p- Examples thereof include salts with toluene sulfonic acid, lauryl sulfate, methyl sulfate, naphthalene sulfonic acid, sulfosalicylic acid and the like.
As the salt of epinastine, monohydrochloride (epinastine hydrochloride) is particularly preferable.
本発明の水性医薬組成物において、含有されるエピナスチン又はその塩は、水和物又は溶媒和物の形態をとってもよい。 The epinastine or a salt thereof contained in the aqueous pharmaceutical composition of the present invention may take the form of a hydrate or a solvate.
本発明の水性医薬組成物において、エピナスチン又はその塩の含有量は、０．０１％（ｗ／ｖ）以上が好ましく、０．０５％（ｗ／ｖ）以上がより好ましく、０．１％（ｗ／ｖ）以上がさらに好ましく、その上限は眼科製剤として許容される濃度であればよく、例えば５％（ｗ／ｖ）である。エピナスチン又はその塩の含有量としては、０．０１〜５％（ｗ／ｖ）が好ましく、０．０５〜１％（ｗ／ｖ）がより好ましく、０．０５〜０．２％（ｗ／ｖ）がさらに好ましく、０．０５〜０．１％（ｗ／ｖ）が特に好ましい。例えば、その含有量は０．１％（ｗ／ｖ）である。 In the aqueous pharmaceutical composition of the present invention, the content of epinastine or a salt thereof is preferably 0.01% (w / v) or more, more preferably 0.05% (w / v) or more, and 0.1% (w / v) or more. w / v) or more is more preferable, and the upper limit thereof may be any concentration acceptable for ophthalmic preparations, for example, 5% (w / v). The content of epinastine or a salt thereof is preferably 0.01 to 5% (w / v), more preferably 0.05 to 1% (w / v), and more preferably 0.05 to 0.2% (w / v). v) is more preferable, and 0.05 to 0.1% (w / v) is particularly preferable. For example, its content is 0.1% (w / v).
なお、本発明において、「％（ｗ／ｖ）」は、本発明の水性医薬組成物１００ｍＬ中に含まれる対象成分の質量（ｇ）を意味する。本発明においてエピナスチンの塩が含有される場合、その値はエピナスチンの塩の含有量である。また、本発明においてエピナスチン又はその塩が、水和物又は溶媒和物の形態をとって配合される場合、その値はエピナスチン又はその塩の、水和物又は溶媒和物の含有量である。以下、特に断りがない限り同様とする。 In the present invention, "% (w / v)" means the mass (g) of the target component contained in 100 mL of the aqueous pharmaceutical composition of the present invention. When a salt of epinastine is contained in the present invention, the value is the content of the salt of epinastine. When epinastine or a salt thereof is blended in the form of a hydrate or a solvate in the present invention, the value is the content of the hydrate or the solvate of the epinastine or a salt thereof. The same shall apply hereinafter unless otherwise specified.
本発明において、「低級脂肪族カルボン酸類」とは、炭素数１５個以下であり、１個以上のカルボキシル基を有するカルボン酸を指す。
低級脂肪族カルボン酸類のカルボキシル基の数は、特に限定されないが、１〜４個が好ましく、１〜３個がより好ましい。また、低級脂肪族カルボン酸類の炭素数は、１５個以下であればよく、好ましくは２〜１２個であり、より好ましくは４〜１０個である。
In the present invention, the "lower aliphatic carboxylic acid" refers to a carboxylic acid having 15 or less carbon atoms and having one or more carboxyl groups.
The number of carboxyl groups of the lower aliphatic carboxylic acids is not particularly limited, but is preferably 1 to 4, and more preferably 1 to 3. The carbon number of the lower aliphatic carboxylic acids may be 15 or less, preferably 2 to 12, and more preferably 4 to 10.
低級脂肪族カルボン酸類中の炭素鎖は、直鎖でも分枝でもよく、飽和でも不飽和でもよい。
また、低級脂肪族カルボン酸類は、カルボキシル基以外にも置換基を有していてもよく、置換基の数や種類は特に限定されない。置換基としては例えば、アミノ基、水酸基等が挙げられる。
The carbon chain in the lower aliphatic carboxylic acids may be linear or branched, and may be saturated or unsaturated.
Further, the lower aliphatic carboxylic acids may have a substituent other than the carboxyl group, and the number and types of the substituents are not particularly limited. Examples of the substituent include an amino group and a hydroxyl group.
本発明の水性医薬組成物において、含有される低級脂肪族カルボン酸類は塩形態であってもよく、医薬として許容される塩であれば特に制限はない。塩としては例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩、マグネシウム、カルシウム等のアルカリ土類金属塩等が挙げられる。また、含有される低級脂肪族カルボン酸類が置換基として例えば、アミノ基を有する場合には、その塩としては塩酸、臭化水素酸、ヨウ化水素酸、硝酸、硫酸、リン酸等の無機酸との塩等が挙げられる。 In the aqueous pharmaceutical composition of the present invention, the lower aliphatic carboxylic acids contained may be in the salt form, and are not particularly limited as long as they are pharmaceutically acceptable salts. Examples of the salt include alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as magnesium and calcium. When the contained lower aliphatic carboxylic acid has, for example, an amino group as a substituent, the salt thereof is an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, or phosphoric acid. And salt and the like.
本発明の水性医薬組成物において、含有される低級脂肪族カルボン酸類は、例えば、酢酸、プロピオン酸、酪酸、吉草酸、カプロン酸、乳酸、リンゴ酸、クエン酸、シュウ酸、マロン酸、コハク酸、グルタル酸、アジピン酸、フマル酸、マレイン酸、ピルビン酸、酒石酸、ソルビン酸、エデト酸、ε−アミノカプロン酸（イプシロン−アミノカプロン酸）、グリシン、アラニン、ロイシン、イソロイシン、バリン、セリン、アスパラギン酸、グルタミン酸又はこれらの塩等が挙げられ、これらの水和物又は溶媒和物であってもよい。好ましくは、酢酸、クエン酸、エデト酸、ソルビン酸、ε−アミノカプロン酸又はこれらの塩であり、より好ましくは、ソルビン酸又はその塩、クエン酸又はその塩、ε−アミノカプロン酸又はその塩であり、さらに好ましくは、ソルビン酸又はその塩である。ソルビン酸又はその塩としては例えば、ソルビン酸、ソルビン酸ナトリウム、ソルビン酸カリウムが挙げられる。クエン酸又はその塩としては例えば、クエン酸、クエン酸一ナトリウム、クエン酸二ナトリウム、クエン酸三ナトリウム、クエン酸一カリウム、クエン酸二カリウム、クエン酸三カリウム、クエン酸マグネシウム、クエン酸カルシウムが挙げられる。ε−アミノカプロン酸又はその塩としては例えば、ε−アミノカプロン酸、ε−アミノカプロン酸ナトリウム、ε−アミノカプロン酸カリウム、ε−アミノカプロン酸塩酸塩、ε−アミノカプロン酸臭化水素酸塩、ε−アミノカプロン酸ヨウ化水素酸塩、ε−アミノカプロン酸硝酸塩、ε−アミノカプロン酸硫酸塩、ε−アミノカプロン酸リン酸塩が挙げられる。 The lower aliphatic carboxylic acids contained in the aqueous pharmaceutical composition of the present invention include, for example, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, lactic acid, malic acid, citric acid, oxalic acid, malonic acid and succinic acid. , Glutalic acid, adipic acid, fumaric acid, maleic acid, pyruvate, tartrate, sorbic acid, edetonic acid, ε-aminocaproic acid (epsilon-aminocaproic acid), glycine, alanine, leucine, isoleucine, valine, serine, aspartic acid Examples thereof include glutamic acid and salts thereof, and these hydrates or solvates may be used. Preferably, it is acetic acid, citric acid, edetonic acid, sorbic acid, ε-aminocaproic acid or a salt thereof, and more preferably sorbic acid or a salt thereof, citric acid or a salt thereof, ε-aminocaproic acid or a salt thereof. , More preferably, sorbic acid or a salt thereof. Examples of sorbic acid or a salt thereof include sorbic acid, sodium sorbate, and potassium sorbate. Examples of citric acid or a salt thereof include citric acid, monosodium citrate, disodium citrate, trisodium citrate, monopotassium citrate, dipotassium citrate, tripotassium citrate, magnesium citrate, and calcium citrate. Can be mentioned. Examples of ε-aminocaproic acid or a salt thereof include ε-aminocaproic acid, sodium ε-aminocaproate, potassium ε-aminocaproate, ε-aminocapronate, ε-aminocaproic acid hydrobromide, and iodine ε-aminocaproate. Hydrochloride, ε-aminocaproic acid nitrate, ε-aminocaproic acid sulfate, ε-aminocaproic acid phosphate can be mentioned.
本発明の水性医薬組成物において、低級脂肪族カルボン酸類は、医薬品の添加剤、例えば緩衝剤、安定化剤、防腐剤、ｐＨ調節剤等としての作用も有する。そのため、低級脂肪族カルボン酸類は、医薬品の添加剤としても使用することができる。低級脂肪族カルボン酸類が、例えば、酢酸又はその塩であれば緩衝剤、ｐH調節剤等の作用を有し、クエン酸又はその塩であれば緩衝剤、ｐH調節剤等の作用を有し、エデト酸又はその塩であれば安定化剤等の作用を有し、ソルビン酸又はその塩であれば防腐剤等の作用を有し、ε−アミノカプロン酸又はその塩であれば、緩衝剤等の作用を有する。
また本発明の水性医薬組成物において、低級脂肪族カルボン酸類は、１種または２種以上一緒に用いてもよい。
In the aqueous pharmaceutical composition of the present invention, the lower aliphatic carboxylic acids also have an action as a pharmaceutical additive, for example, a buffer, a stabilizer, a preservative, a pH adjuster and the like. Therefore, lower aliphatic carboxylic acids can also be used as additives for pharmaceutical products. If the lower aliphatic carboxylic acid is, for example, acetic acid or a salt thereof, it has an action of a buffer, a pH regulator, etc., and if it is citric acid or a salt thereof, it has an action of a buffer, a pH regulator, etc. If it is edetic acid or a salt thereof, it has an action such as a stabilizer, if it is sorbic acid or a salt thereof, it has an action such as an antiseptic, and if it is ε-aminocaproic acid or a salt thereof, it has a buffering agent or the like. Has an action.
Further, in the aqueous pharmaceutical composition of the present invention, one or more lower aliphatic carboxylic acids may be used together.
本発明の水性医薬組成物において、低級脂肪族カルボン酸類の含有量は、種類によって適宜調整できるが、例えば、０．０１〜３．５％（ｗ／ｖ）である。０．０１〜２％（ｗ／ｖ）が好ましく、０．０５〜１．５％（ｗ／ｖ）がより好ましく、０．０５〜１％（ｗ／ｖ）がさらに好ましく、０．１〜１％（ｗ／ｖ）がさらにより好ましい。例えば、低級脂肪族カルボン酸類がソルビン酸又はその塩である場合、その含有量は、０．０１〜２％（ｗ／ｖ）が好ましく、０．１〜１％（ｗ／ｖ）がより好ましく、０．２〜０．８％（ｗ／ｖ）がさらに好ましい。例えば、その含有量は、０．６％（ｗ／ｖ）である。例えば、低級脂肪族カルボン酸類がクエン酸又はその塩である場合、その含有量は、０．０１〜３．５％（ｗ／ｖ）が好ましく、０．１〜２．５％（ｗ／ｖ）がより好ましく、０．５〜２％（ｗ／ｖ）がさらに好ましい。例えば、その含有量は、１．６％（ｗ／ｖ）である。例えば、低級脂肪族カルボン酸類がε−アミノカプロン酸又はその塩である場合、その含有量は、０．０１〜１％（ｗ／ｖ）が好ましく、０．１〜１％（ｗ／ｖ）がより好ましく、０．２〜０．８％（ｗ／ｖ）がさらに好ましい。例えば、その含有量は、０．５％（ｗ／ｖ）である。 In the aqueous pharmaceutical composition of the present invention, the content of the lower aliphatic carboxylic acids can be appropriately adjusted depending on the type, and is, for example, 0.01 to 3.5% (w / v). 0.01 to 2% (w / v) is preferable, 0.05 to 1.5% (w / v) is more preferable, 0.05 to 1% (w / v) is further preferable, and 0.1 to 1%. 1% (w / v) is even more preferred. For example, when the lower aliphatic carboxylic acids are sorbic acid or a salt thereof, the content thereof is preferably 0.01 to 2% (w / v), more preferably 0.1 to 1% (w / v). , 0.2-0.8% (w / v) is more preferable. For example, its content is 0.6% (w / v). For example, when the lower aliphatic carboxylic acids are citric acid or a salt thereof, the content thereof is preferably 0.01 to 3.5% (w / v), preferably 0.1 to 2.5% (w / v). ) Is more preferable, and 0.5 to 2% (w / v) is further preferable. For example, its content is 1.6% (w / v). For example, when the lower aliphatic carboxylic acids are ε-aminocaproic acid or a salt thereof, the content thereof is preferably 0.01 to 1% (w / v), preferably 0.1 to 1% (w / v). More preferably, 0.2 to 0.8% (w / v) is further preferable. For example, its content is 0.5% (w / v).
本発明において、「水性医薬組成物」とは水を含有する医薬組成物を指す。本発明の水性医薬組成物に含まれる水の含有量は、医薬組成物として使用可能な量であれば特に制限はされないが、水性医薬組成物の総重量に対して、１０％（ｗ／ｖ）以上が好ましく、３０％（ｗ／ｖ）以上がより好ましく、５０％（ｗ／ｖ）以上がさらに好ましい。特に、好ましくは７０％（ｗ／ｖ）以上であり、より好ましくは９０％（ｗ／ｖ）以上であり、さらに好ましくは９５％（ｗ／ｖ）以上である。 In the present invention, the "aqueous pharmaceutical composition" refers to a pharmaceutical composition containing water. The content of water contained in the aqueous pharmaceutical composition of the present invention is not particularly limited as long as it can be used as a pharmaceutical composition, but is 10% (w / v) with respect to the total weight of the aqueous pharmaceutical composition. ) Or more, more preferably 30% (w / v) or more, and even more preferably 50% (w / v) or more. In particular, it is preferably 70% (w / v) or more, more preferably 90% (w / v) or more, and even more preferably 95% (w / v) or more.
本発明において、眼組織とは、例えば、結膜、角膜、涙液、房水、前房等が挙げられる。本発明の水性医薬組成物を眼に投与する場合、眼組織へのエピナスチン又はその塩の移行量を増大（または向上ともいう）させることができ、特に結膜への移行量を増大させることが好ましい。 In the present invention, the eye tissue includes, for example, conjunctiva, cornea, tears, aqueous humor, anterior chamber and the like. When the aqueous pharmaceutical composition of the present invention is administered to the eye, the amount of epinastine or a salt thereof transferred to the eye tissue can be increased (also referred to as improvement), and it is particularly preferable to increase the amount transferred to the conjunctiva. ..
本発明において、「患者」とは、ヒトのみに限らずその他の動物、例えば、イヌ、ネコ、ウマなども意味する。患者は、好ましくは哺乳動物であり、より好ましくはヒトである。本発明において、「治療上の有効量」とは、未治療対象と比べて、疾患およびその症状の治療効果をもたらす量、または疾患およびその症状の進行の遅延をもたらす量などを指す。 In the present invention, the term "patient" means not only humans but also other animals such as dogs, cats and horses. The patient is preferably a mammal, more preferably a human. In the present invention, the "therapeutically effective amount" refers to an amount that brings about a therapeutic effect on a disease and its symptoms, or an amount that causes a delay in the progression of the disease and its symptoms, as compared with an untreated subject.
本発明の水性医薬組成物には、必要に応じて医薬品の添加剤を用いることができ、例えば、緩衝剤、粘稠化剤、界面活性化剤、等張化剤、安定化剤、防腐剤、抗酸化剤、ｐＨ調節剤等を加えることができる。これらは、それぞれ単独で用いてもよく、また、２種以上を適宜組み合わせて用いてもよく、適量を配合することができる。 Pharmaceutical additives can be used in the aqueous pharmaceutical composition of the present invention, if necessary, for example, buffering agents, thickening agents, surfactants, tonicity agents, stabilizers, preservatives. , Antioxidants, pH adjusters and the like can be added. Each of these may be used alone, or two or more thereof may be used in combination as appropriate, and an appropriate amount may be blended.
本発明の水性医薬組成物に緩衝剤を配合する場合の緩衝剤は、医薬品の添加剤として使用可能な緩衝剤を適宜配合することができ、例えば、リン酸又はその塩、ホウ酸又はその塩、炭酸又はその塩或いは有機アミン等が挙げられ、これらの水和物又は溶媒和物であってもよい。 When a buffering agent is blended in the aqueous pharmaceutical composition of the present invention, a buffering agent that can be used as an additive for pharmaceuticals can be appropriately blended. For example, phosphoric acid or a salt thereof, boric acid or a salt thereof can be blended appropriately. , Carbonate or salts thereof, organic amines and the like, and may be hydrates or solvates thereof.
リン酸又はその塩としては、リン酸、リン酸ナトリウム、リン酸二水素ナトリウム、リン酸水素二ナトリウム、リン酸カリウム、リン酸二水素カリウム、リン酸水素二カリウム等が挙げられ、これらの水和物であってもよい。 Examples of phosphoric acid or a salt thereof include phosphoric acid, sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate and the like, and these waters. It may be Japanese.
ホウ酸又はその塩としては、ホウ酸、ホウ酸ナトリウム（ホウ砂）、ホウ酸カリウム等が挙げられ、これらの水和物であってもよい。 Examples of boric acid or a salt thereof include boric acid, sodium borate (borax), potassium borate and the like, and hydrates thereof may be used.
炭酸又はその塩としては、炭酸ナトリウム、炭酸水素ナトリウム等が挙げられ、これらの水和物であってもよい。 Examples of carbonic acid or a salt thereof include sodium carbonate, sodium hydrogencarbonate and the like, and hydrates thereof may be used.
有機アミンとしては、トロメタモール等が挙げられ、これらの水和物であってもよい。 Examples of the organic amine include tromethamole and the like, and these hydrates may be used.
本発明の水性医薬組成物に緩衝剤を配合する場合の緩衝剤の含有量は、緩衝剤の種類などにより適宜調整することができるが、０．００１〜１０％（ｗ／ｖ）が好ましく、０．０１〜５％（ｗ／ｖ）がより好ましく、０．１〜５％（ｗ／ｖ）がさらに好ましく、０．１〜１％（ｗ／ｖ）が特に好ましい。
また本発明の水性医薬組成物に緩衝剤を配合する場合には、緩衝剤を１種または２種以上一緒に用いてもよい。
The content of the buffer when the buffer is added to the aqueous pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the buffer and the like, but is preferably 0.001 to 10% (w / v). 0.01 to 5% (w / v) is more preferable, 0.1 to 5% (w / v) is further preferable, and 0.1 to 1% (w / v) is particularly preferable.
Further, when a buffering agent is blended in the aqueous pharmaceutical composition of the present invention, one or more buffering agents may be used together.
本発明の水性医薬組成物に粘稠化剤を配合する場合の粘稠化剤は、医薬品の添加剤として使用可能な粘稠化剤を適宜配合することができ、例えば、メチルセルロース、エチルセルロース、ヒドロキシメチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシエチルメチルセルロース、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、カルボキシメチルセルロースナトリウム、ヒドロキシプロピルメチルセルロースアセテートサクシネート、ヒドロキシプロピルメチルセルロースフタレート、カルボキシメチルエチルセルロース、酢酸フタル酸セルロース、ポリビニルピロリドン、ポリビニルアルコール、カルボキシビニルポリマー、ポリエチレングリコール、ヒアルロン酸ナトリウム等が挙げられる。 When the thickening agent is blended in the aqueous pharmaceutical composition of the present invention, the thickening agent that can be used as an additive for pharmaceuticals can be appropriately blended, and for example, methyl cellulose, ethyl cellulose, and hydroxy Methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropylmethyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, carboxymethyl ethyl cellulose, cellulose acetate phthalate, polyvinylpyrrolidone, polyvinyl alcohol , Carboxyvinyl polymer, polyethylene glycol, sodium hyaluronate and the like.
本発明の水性医薬組成物に粘稠化剤を配合する場合の粘稠化剤の含有量は、粘稠化剤の種類などにより適宜調整することができるが、０．００１〜５％（ｗ／ｖ）が好ましく、０．０１〜３％（ｗ／ｖ）がより好ましく、０．１〜２％（ｗ／ｖ）がさらに好ましい。
また本発明の水性医薬組成物に粘稠化剤を配合する場合には、粘稠化剤を１種または２種以上一緒に用いてもよい。
The content of the thickening agent when the thickening agent is added to the aqueous pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the thickening agent and the like, but is 0.001 to 5% (w). / V) is preferable, 0.01 to 3% (w / v) is more preferable, and 0.1 to 2% (w / v) is further preferable.
Further, when the thickening agent is blended in the aqueous pharmaceutical composition of the present invention, one or more thickening agents may be used together.
本発明の水性医薬組成物に界面活性化剤を配合する場合の界面活性化剤は、医薬品の添加剤として使用可能な界面活性化剤を適宜配合することができ、例えば、カチオン性界面活性化剤、アニオン性界面活性化剤、非イオン性界面活性化剤等が挙げられる。 When a surfactant is blended in the aqueous pharmaceutical composition of the present invention, a surfactant that can be used as an additive for pharmaceuticals can be appropriately blended as the surfactant, for example, cationic surfactant activation. Agents, anionic surfactants, nonionic surfactants and the like can be mentioned.
カチオン性界面活性化剤としては、アルキルアミン塩、アルキルアミンポリオキシエチレン付加物、脂肪酸トリエタノールアミンモノエステル塩、アシルアミノエチルジエチルアミン塩、脂肪酸ポリアミン縮合物、アルキルイミダゾリン、１−アシルアミノエチル−２−アルキルイミダゾリン、１−ヒドロキシルエチル−２−アルキルイミダゾリン等が挙げられる。なお、塩化ベンザルコニウム等の第四級アンモニウムカチオンは、カチオン性界面活性化剤の性質を有しているが、これらは本発明におけるカチオン性界面活性化剤には含まれない。 Examples of the cationic surfactant include alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoester salts, acylaminoethyl diethylamine salts, fatty acid polyamine condensates, alkylimidazolin, and 1-acylaminoethyl-2. -Alkyl imidazoline, 1-hydroxyl ethyl-2-alkyl imidazoline and the like can be mentioned. Quaternary ammonium cations such as benzalkonium chloride have the properties of a cationic surfactant, but they are not included in the cationic surfactant in the present invention.
アニオン性界面活性化剤としては、レシチン等のリン脂質等が挙げられる。 Examples of the anionic surfactant include phospholipids such as lecithin.
非イオン性界面活性化剤としては、ステアリン酸ポリオキシル４０等のポリオキシエチレン脂肪酸エステル；ポリソルベート８０、ポリソルベート６０、ポリソルベート４０、ポリオキシエチレンソルビタンモノラウレート、ポリオキシエチレンソルビタントリオレート、ポリソルベート６５等のポリオキシエチレンソルビタン脂肪酸エステル；ポリオキシエチレン硬化ヒマシ油１０、ポリオキシエチレン硬化ヒマシ油４０、ポリオキシエチレン硬化ヒマシ油５０、ポリオキシエチレン硬化ヒマシ油６０等のポリオキシエチレン硬化ヒマシ油；ポリオキシル５ヒマシ油、ポリオキシル９ヒマシ油、ポリオキシル１５ヒマシ油、ポリオキシル３５ヒマシ油、ポリオキシル４０ヒマシ油等のポリオキシルヒマシ油；ポリオキシエチレン（１６０）ポリオキシプロピレン（３０）グリコール、ポリオキシエチレン（４２）ポリオキシプロピレン（６７）グリコール、ポリオキシエチレン（５４）ポリオキシプロピレン（３９）グリコール、ポリオキシエチレン（１９６）ポリオキシプロピレン（６７）グリコール、ポリオキシエチレン（２０）ポリオキシプロピレン（２０）グリコール等のポリオキシエチレンポリオキシプロピレングリコール；ショ糖ステアリン酸エステル等のショ糖脂肪酸エステル；トコフェロールポリエチレングリコール１０００コハク酸エステル（ビタミンＥ ＴＰＧＳ）等が挙げられる。 Examples of the nonionic surfactant include polyoxyethylene fatty acid esters such as polyoxyl 40 stearate; polysorbate 80, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan triolate, and polysorbate 65. Polyoxyethylene sorbitan fatty acid ester; polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, etc. Polyoxyethylene hydrogenated castor oil; polyoxyl 5 castor Polyoxyl castor oil such as oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, polyoxyl 40 castor oil; polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (42) polyoxy Poly such as propylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, polyoxyethylene (20) polyoxypropylene (20) glycol, etc. Oxyethylene polyoxypropylene glycol; sucrose fatty acid ester such as sucrose stearic acid ester; tocopherol polyethylene glycol 1000 succinic acid ester (vitamin E TPGS) and the like.
本発明の水性医薬組成物に界面活性化剤を配合する場合の界面活性化剤の含有量は、界面活性化剤の種類などにより適宜調整することができるが、０．０１〜１％（ｗ／ｖ）が好ましく、０．０５〜０．５％（ｗ／ｖ）がより好ましく、０．０５〜０．２％（ｗ／ｖ）がさらに好ましい。
また本発明の水性医薬組成物に界面活性剤を配合する場合には、界面活性剤を１種または２種以上一緒に用いてもよい。
The content of the surfactant when the surfactant is blended in the aqueous pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the surfactant and the like, but is 0.01 to 1% (w). / V) is preferable, 0.05 to 0.5% (w / v) is more preferable, and 0.05 to 0.2% (w / v) is even more preferable.
Further, when a surfactant is blended in the aqueous pharmaceutical composition of the present invention, one or more surfactants may be used together.
本発明の水性医薬組成物に等張化剤を配合する場合の等張化剤は、医薬品の添加剤として使用可能な等張化剤を適宜配合することができ、例えば、イオン性等張化剤、非イオン性等張化剤等が挙げられる。 When the isotonic agent is blended in the aqueous pharmaceutical composition of the present invention, the isotonic agent that can be used as an additive for pharmaceuticals can be appropriately blended, and for example, ionic isotonicization. Examples include agents and nonionic isotonic agents.
イオン性等張化剤としては、塩化ナトリウム、塩化カリウム、塩化カルシウム、塩化マグネシウム等が挙げられる。 Examples of the ionic isotonic agent include sodium chloride, potassium chloride, calcium chloride, magnesium chloride and the like.
非イオン性等張化剤としては、グリセリン、プロピレングリコール、ポリエチレングリコール、ソルビトール、マンニトール、トレハロース、マルトース、スクロース、キシリトール等が挙げられる。 Examples of the nonionic isotonic agent include glycerin, propylene glycol, polyethylene glycol, sorbitol, mannitol, trehalose, maltose, sucrose, xylitol and the like.
本発明の水性医薬組成物に等張化剤を配合する場合の等張化剤としては、イオン性等張化剤が好ましく、塩化ナトリウムが特に好ましい。 As the tonicity agent when the tonicity agent is blended in the aqueous pharmaceutical composition of the present invention, an ionic isotonicity agent is preferable, and sodium chloride is particularly preferable.
本発明の水性医薬組成物に等張化剤を配合する場合の等張化剤の含有量は、等張化剤の種類などにより適宜調整することができるが、０．００１〜１０％（ｗ／ｖ）が好ましく、０．０１〜５％（ｗ／ｖ）がより好ましく、０．１〜３％（ｗ／ｖ）がさらに好ましく、０．２〜１％（ｗ／ｖ）が特に好ましい。
また本発明の水性医薬組成物に等張化剤を配合する場合には、等張化剤を１種または２種以上一緒に用いてもよい。
The content of the tonicity agent when the tonicity agent is blended in the aqueous pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the tonicity agent, etc. / V) is preferable, 0.01 to 5% (w / v) is more preferable, 0.1 to 3% (w / v) is further preferable, and 0.2 to 1% (w / v) is particularly preferable. ..
When the isotonic agent is blended in the aqueous pharmaceutical composition of the present invention, one or two or more isotonic agents may be used together.
本発明の水性医薬組成物に安定化剤を配合する場合の安定化剤は、医薬品の添加剤として使用可能な安定化剤を適宜配合することができ、例えば、シクロデキストリン、チオ硫酸ナトリウム等が挙げられる。 When a stabilizer is added to the aqueous pharmaceutical composition of the present invention, a stabilizer that can be used as an additive for a pharmaceutical product can be appropriately added, and examples thereof include cyclodextrin and sodium thiosulfate. Can be mentioned.
本発明の水性医薬組成物に安定化剤を配合する場合の安定化剤の含有量は、安定化剤の種類などにより適宜調整することができるが、０．００１〜５％（ｗ／ｖ）が好ましく、０．０１〜３％（ｗ／ｖ）がより好ましく、０．０５〜１％（ｗ／ｖ）がさらに好ましい。
また本発明の水性医薬組成物に安定化剤を配合する場合には、安定化剤を１種または２種以上一緒に用いてもよい。
The content of the stabilizer when the stabilizer is added to the aqueous pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the stabilizer and the like, but is 0.001 to 5% (w / v). Is preferable, 0.01 to 3% (w / v) is more preferable, and 0.05 to 1% (w / v) is further preferable.
Further, when a stabilizer is blended in the aqueous pharmaceutical composition of the present invention, one or more stabilizers may be used together.
本発明の水性医薬組成物に防腐剤を配合する場合の防腐剤は、医薬品の添加剤として使用可能な防腐剤を適宜配合することができ、例えば、塩化ベンザルコニウム、臭化ベンザルコニウム、塩化ベンゼトニウム、グルコン酸クロルヘキシジン、塩酸クロルヘキシジン、パラオキシ安息香酸メチル、パラオキシ安息香酸プロピル、亜塩素酸ナトリウム又はクロロブタノール等が挙げられる。 When a preservative is blended in the aqueous pharmaceutical composition of the present invention, a preservative that can be used as an additive for pharmaceuticals can be appropriately blended. For example, benzalkonium chloride, benzalkonium bromide, etc. Benzalkonium chloride, chlorhexidine gluconate, chlorhexidine hydrochloride, methyl paraoxybenzoate, propyl paraoxybenzoate, sodium chlorate, chlorobutanol and the like can be mentioned.
本発明の水性医薬組成物に防腐剤を配合する場合の防腐剤の含有量は、防腐剤の種類などにより適宜調整することができるが、安全性に悪影響を及ぼさない程度の量がよく、例えば、０．０００１〜０．１％（ｗ／ｖ）が好ましく、０．００１〜０．０５％（ｗ／ｖ）がより好ましい。 The content of the preservative when the preservative is added to the aqueous pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the preservative and the like, but the amount should not adversely affect the safety, for example. , 0.0001 to 0.1% (w / v), more preferably 0.001 to 0.05% (w / v).
本発明の水性医薬組成物に抗酸化剤を配合する場合の抗酸化剤は、医薬品の添加剤として使用可能な抗酸化剤を適宜配合することができ、例えば、アスコルビン酸、トコフェロール、ジブチルヒドロキシトルエン、亜硫酸ナトリウム等が挙げられる。 When an antioxidant is added to the aqueous pharmaceutical composition of the present invention, an antioxidant that can be used as an additive for a pharmaceutical product can be appropriately added. For example, ascorbic acid, tocopherol, and dibutylhydroxytoluene can be added. , Sodium sulfite and the like.
本発明の水性医薬組成物に抗酸化剤を配合する場合の抗酸化剤の含有量は、抗酸化剤の種類などにより適宜調整することができるが、０．００１〜５％（ｗ／ｖ）が好ましく、０．０１〜３％（ｗ／ｖ）がより好ましく、０．１〜２％（ｗ／ｖ）がさらに好ましい。
また本発明の水性医薬組成物に抗酸化剤を配合する場合には、抗酸化剤を１種または２種以上一緒に用いてもよい。
The content of the antioxidant when the aqueous pharmaceutical composition of the present invention is blended with the antioxidant can be appropriately adjusted depending on the type of the antioxidant and the like, but is 0.001 to 5% (w / v). Is preferable, 0.01 to 3% (w / v) is more preferable, and 0.1 to 2% (w / v) is further preferable.
In addition, when an antioxidant is blended in the aqueous pharmaceutical composition of the present invention, one or more antioxidants may be used together.
本発明の水性医薬組成物にｐＨ調節剤を配合する場合のｐＨ調節剤は、医薬品の添加剤として使用可能なｐＨ調節剤を適宜配合することができるが、例えば、酸又は塩基であり、酸としては例えば、塩酸、リン酸等、塩基としては例えば、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸水素ナトリウム等が挙げられる。 When a pH adjuster is added to the aqueous pharmaceutical composition of the present invention, a pH adjuster that can be used as an additive for a pharmaceutical agent can be appropriately added, and is, for example, an acid or a base. Examples include hydrochloric acid, phosphoric acid and the like, and bases include, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate and the like.
本発明の水性医薬組成物のｐＨは、医薬品として許容される範囲内にあればよく、例えば４．０〜８．５又は４．０〜８．０の範囲内であり、６．０〜８．０が好ましく、６．５〜７．５がより好ましい。特に好ましいｐＨは、６．７〜７．３であるが、６．７、６．８、６．９、７．０、７．１、７．２、７．３もさらにより好ましい。 The pH of the aqueous pharmaceutical composition of the present invention may be in the range acceptable for pharmaceutical products, for example, in the range of 4.0 to 8.5 or 4.0 to 8.0, and 6.0 to 8 .0 is preferable, and 6.5 to 7.5 is more preferable. Particularly preferred pH is 6.7 to 7.3, but 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3 are even more preferred.
本発明の水性医薬組成物の浸透圧比は、医薬品として許容される範囲内にあればよく、例えば０．５〜２．０であり、０．７〜１．６が好ましく、０．８〜１．４がより好ましく、０．９〜１．２がさらに好ましい。 The osmotic pressure ratio of the aqueous pharmaceutical composition of the present invention may be within the range acceptable for pharmaceutical products, for example, 0.5 to 2.0, preferably 0.7 to 1.6, and 0.8 to 1 .4 is more preferable, and 0.9 to 1.2 is even more preferable.
本発明の水性医薬組成物は、非経口（例えば、局所）投与に適している。本発明の水性医薬組成物の非経口投与経路としては、医薬品として許容される局所投与経路、例えば、眼への局所投与（例えば、点眼投与）、点鼻（経鼻）投与、耳への局所投与（例えば、点耳投与）、吸入投与、噴霧投与、経皮投与、皮膚上投与、注射投与などが挙げられる。好ましくは、眼への局所投与である。また、本発明の水性医薬組成物は、経口投与することもできる。 The aqueous pharmaceutical composition of the present invention is suitable for parenteral (eg, topical) administration. The parenteral administration route of the aqueous pharmaceutical composition of the present invention includes a locally acceptable route of administration as a pharmaceutical product, for example, local administration to the eye (for example, eye drop administration), nasal drop (nasal) administration, and topical administration to the ear. Examples thereof include administration (for example, ear drop administration), inhalation administration, spray administration, transdermal administration, intradermal administration, injection administration and the like. Topical administration to the eye is preferred. The aqueous pharmaceutical composition of the present invention can also be orally administered.
本発明の水性医薬組成物は、眼科用製剤、耳鼻科用製剤、吸入用製剤、経皮吸収用製剤として用いることができ、その剤形は、医薬品として使用可能なものであれば特に制限されるものではない。剤形としては、例えば、液剤、懸濁剤等の経口投与剤、点眼剤、点鼻剤、点耳剤、吸入剤、（吸入粉末剤、吸入液剤、吸入エアゾール剤）、軟膏剤、クリーム剤、ゲル剤、経皮吸収型製剤、貼付剤（テープ剤、パップ剤）、外用液剤（ローション剤、リニメント剤）、外用固形剤（外用散剤）、スプレー剤（ポンプスプレー剤、外用エアゾール剤）、注射剤（輸液剤、埋め込み注射剤、持続性注射剤）等の局所投与剤が挙げられる。好ましくは点眼剤、眼科用経皮吸収型製剤又は眼科用注射剤であり、より好ましくは点眼剤である。これらは当該技術分野における通常の方法に従って製造することができる。 The aqueous pharmaceutical composition of the present invention can be used as an ophthalmic preparation, an otolaryngological preparation, an inhalation preparation, and a transdermal preparation, and the dosage form thereof is particularly limited as long as it can be used as a pharmaceutical product. It's not something. Dosage forms include, for example, oral administrations such as liquids and suspensions, eye drops, nasal drops, ear drops, inhalants, (inhalation powders, inhalation solutions, inhalation aerosols), ointments, creams. , Gel agent, transdermal absorption type preparation, patch (tape agent, poultice agent), external liquid agent (lotion agent, liniment agent), external solid agent (external powder), spray agent (pump spray agent, external aerosol agent), Topical administration agents such as injections (infusions, implantable injections, continuous injections) can be mentioned. It is preferably an eye drop, a transdermal preparation for ophthalmology, or an injection for ophthalmology, and more preferably an eye drop. These can be manufactured according to the usual methods in the art.
本発明の水性医薬組成物は、構成成分が全て溶解または一部懸濁していてもよく、またエマルション、半固体状の形態であってもよい。本発明の水性医薬組成物は、構成成分が全て溶解している溶液状態であることがより好ましく、水溶液であることが最も好ましい。例えば、眼科用であれば点眼剤（点眼液）が特に好ましい。 The aqueous pharmaceutical composition of the present invention may have all the constituents dissolved or partially suspended, or may be in the form of an emulsion or a semi-solid. The aqueous pharmaceutical composition of the present invention is more preferably in a solution state in which all the constituent components are dissolved, and most preferably an aqueous solution. For example, eye drops (eye drops) are particularly preferable for ophthalmology.
本発明の水性医薬組成物がエマルションである場合は、水中油型エマルション（水相を連続相として、水相と分散した油性液滴から構成されるエマルション）であっても油中水型エマルション（油相を連続相として、油と分散した水性液滴から構成されるエマルション）であってもよい。 When the aqueous pharmaceutical composition of the present invention is an emulsion, even an oil-in-water emulsion (an emulsion composed of oily droplets dispersed in an aqueous phase with the aqueous phase as a continuous phase) is an aqueous emulsion in oil (an emulsion). An emulsion composed of aqueous droplets dispersed with oil, with the oil phase as a continuous phase) may be used.
本発明の水性医薬組成物を眼科用製剤として使用する場合は、特にアレルギー性結膜炎の治療剤として有用である。また、本発明の水性医薬組成物は、特に断りのない限り、エピナスチン又はその塩以外の医薬品活性成分、例えば他の点眼剤に用いられる有効成分を含んでいてもよい。 When the aqueous pharmaceutical composition of the present invention is used as an ophthalmic preparation, it is particularly useful as a therapeutic agent for allergic conjunctivitis. Further, unless otherwise specified, the aqueous pharmaceutical composition of the present invention may contain a pharmaceutical active ingredient other than epinastine or a salt thereof, for example, an active ingredient used in other eye drops.
本発明の水性医薬組成物を点眼剤として眼に投与する場合、所望の薬効を奏するのに十分であれば用法用量に特に制限はないが、１回１滴、１日１〜１０回、好ましくは１日１〜６回、より好ましくは１日２〜４回、さらに好ましくは１日２回又は１日４回、特に好ましくは１日２回に分けて点眼することができる。また、コンタクトレンズ装用時においても使用することができる。 When the aqueous pharmaceutical composition of the present invention is administered to the eye as an eye drop, the dosage is not particularly limited as long as it is sufficient to achieve the desired medicinal effect, but one drop at a time, preferably 1 to 10 times a day. Can be instilled 1 to 6 times a day, more preferably 2 to 4 times a day, more preferably 2 times a day or 4 times a day, and particularly preferably 2 times a day. It can also be used when wearing contact lenses.
本発明の水性医薬組成物を点眼剤として使用する場合、マルチドーズ型容器、１回使い切りのユニットドーズ型容器またはＰＦＭＤ（Ｐｒｅｓｅｒｖａｔｉｖｅ Ｆｒｅｅ Ｍｕｌｔｉ Ｄｏｓｅ）容器のいずれに収容されていてもよい。なお、容器の素材に特に制限はなく、一般に汎用される点眼剤の容器であればよいが、好ましくは樹脂製容器であり、例えば、ポリエチレン（ＰＥ）製、ポリプロピレン（ＰＰ）製、ポリエチレンテレフタレート（ＰＥＴ）製、ポリブチレンテレフタレート（ＰＢＴ）製、ポリプロピレン−ポリエチレンコポリマー製、ポリ塩化ビニル製、アクリル製、ポリスチレン製、ポリ環状オレフィンコポリマー製等の容器を用いることができる。また、樹脂製容器の材質が、例えばポリエチレンであれば、ポリエチレンはその密度によって分類され、低密度ポリエチレン（ＬＤＰＥ）製、中密度ポリエチレン（ＭＤＰＥ）製、高密度ポリエチレン（ＨＤＰＥ）製等の容器を用いることができる。 When the aqueous pharmaceutical composition of the present invention is used as an eye drop, it may be contained in either a multi-dose container, a single-use unit-dose container, or a PFMD (Preservative Free Multi Dose) container. The material of the container is not particularly limited, and any container for eye drops that is generally used may be used, but a resin container is preferable, and for example, polyethylene (PE), polypropylene (PP), or polyethylene terephthalate ( Containers made of PET), polybutylene terephthalate (PBT), polypropylene-polyethylene copolymer, polyvinyl chloride, acrylic, polystyrene, polycyclic olefin copolymer and the like can be used. If the material of the resin container is, for example, polyethylene, polyethylene is classified according to its density, and containers made of low-density polyethylene (LDPE), medium-density polyethylene (MDPE), high-density polyethylene (HDPE), etc. are used. Can be used.
以下に、製剤例および試験例を示すが、これらは本発明をより良く理解するためのものであり、本発明の範囲を限定するものではない。 Examples of formulations and test examples are shown below, but these are for a better understanding of the present invention and do not limit the scope of the present invention.
製剤例
以下に本発明の代表的な製剤例を示す。なお、下記製剤例において各成分の配合量は製剤１ｍＬ中の含量である。
Examples of formulations The following are typical examples of formulations of the present invention. In the following formulation example, the blending amount of each component is the content in 1 mL of the formulation.
製剤例１
エピナスチン塩酸塩 １ｍｇ
ソルビン酸 ５ｍｇ
塩化ナトリウム ５ｍｇ
希塩酸 適量
水酸化ナトリウム 適量
精製水 適量
ｐＨ ７．０
Formulation Example 1
Epinastine hydrochloride 1 mg
Sorbic acid 5 mg
Sodium chloride 5 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 7.0
製剤例２
エピナスチン塩酸塩 ０．５ｍｇ
ソルビン酸 ５ｍｇ
塩化ナトリウム ５ｍｇ
希塩酸 適量
水酸化ナトリウム 適量
精製水 適量
ｐＨ ７．０
Preparation example 2
Epinastine hydrochloride 0.5 mg
Sorbic acid 5 mg
Sodium chloride 5 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 7.0
製剤例３
エピナスチン塩酸塩 ０．５ｍｇ
ソルビン酸 １ｍｇ
ほう酸 １ｍｇ
塩化ナトリウム ５ｍｇ
希塩酸 適量
水酸化ナトリウム 適量
精製水 適量
ｐＨ ７．０
Preparation example 3
Epinastine hydrochloride 0.5 mg
Sorbic acid 1 mg
Boric acid 1 mg
Sodium chloride 5 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 7.0
製剤例４
エピナスチン塩酸塩 １ｍｇ
エデト酸ナトリウム水和物 １ｍｇ
ほう酸 ０．５ｍｇ
クエン酸ナトリウム １ｍｇ
希塩酸 適量
水酸化ナトリウム 適量
精製水 適量
ｐＨ ７．０
Preparation example 4
Epinastine hydrochloride 1 mg
Sodium edetate hydrate 1 mg
Boric acid 0.5 mg
Sodium citrate 1 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 7.0
製剤例５
エピナスチン塩酸塩 １ｍｇ
エデト酸ナトリウム水和物 ０．５ｍｇ
ε−アミノカプロン酸 ２ｍｇ
希塩酸 適量
水酸化ナトリウム 適量
精製水 適量
ｐＨ ７．０
Formulation Example 5
Epinastine hydrochloride 1 mg
Sodium edetate hydrate 0.5 mg
ε-aminocaproic acid 2 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 7.0
製剤例６
エピナスチン塩酸塩 １ｍｇ
ε−アミノカプロン酸 ３ｍｇ
塩化ナトリウム ９ｍｇ
希塩酸 適量
水酸化ナトリウム 適量
精製水 適量
ｐＨ ７．０
Formulation Example 6
Epinastine hydrochloride 1 mg
ε-aminocaproic acid 3 mg
Sodium chloride 9 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 7.0
製剤例７
エピナスチン塩酸塩 １ｍｇ
クエン酸ナトリウム水和物 １０ｍｇ
塩化ナトリウム ５ｍｇ
希塩酸 適量
水酸化ナトリウム 適量
精製水 適量
ｐＨ ７．０
Formulation Example 7
Epinastine hydrochloride 1 mg
Sodium citrate hydrate 10 mg
Sodium chloride 5 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 7.0
製剤例８
エピナスチン塩酸塩 １ｍｇ
エデト酸ナトリウム水和物 １ｍｇ
塩化ナトリウム ８ｍｇ
希塩酸 適量
水酸化ナトリウム 適量
精製水 適量
ｐＨ ７．０
Formulation Example 8
Epinastine hydrochloride 1 mg
Sodium edetate hydrate 1 mg
Sodium chloride 8 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 7.0
試験例
１．眼内動態試験（１）
（１）被験製剤の調製
下表１の濃度になるように、エピナスチン塩酸塩、ソルビン酸、塩化ナトリウムを水に溶解し、ｐＨ調節剤（希塩酸および／または水酸化ナトリウム）と水を加えて全量を１０ｍＬとし、濾過滅菌を行うことにより、実施例１の製剤（ｐＨ７．０）を調製した。
また、実施例１の製剤の調製方法と同様の方法にて、下表１の比較例１及び比較例２の製剤を調製した。なお、比較例１及び比較例２の塩化ナトリウムの含有量は、実施例１の浸透圧に合わせるために適宜調整した。
(1) Preparation of test preparation Dissolve epinastine hydrochloride, sorbic acid, and sodium chloride in water so that the concentrations shown in Table 1 below are obtained, and add a pH adjuster (dilute hydrochloric acid and / or sodium hydroxide) and water to make the total amount. The preparation (pH 7.0) of Example 1 was prepared by sterilizing by filtration with 10 mL.
Moreover, the preparations of Comparative Example 1 and Comparative Example 2 in Table 1 below were prepared by the same method as the preparation method of the preparation of Example 1. The sodium chloride content of Comparative Example 1 and Comparative Example 2 was appropriately adjusted to match the osmotic pressure of Example 1.
（２）試験方法
各被験製剤５μＬをラットに１回点眼投与し（ｎ＝４〜６）、点眼投与後１時間および４時間の時点で屠殺処分後の眼球を摘出した。その結膜中のエピナスチン濃度を測定し、平均値を算出した。
(2) Test method 5 μL of each test preparation was administered to rats by eye drop once (n = 4 to 6), and the eyeballs after sacrifice were removed 1 hour and 4 hours after the eye drop administration. The epinastine concentration in the conjunctiva was measured and the average value was calculated.
（３）試験結果及び考察
試験結果を表２に示す。
表２に示されるように、ソルビン酸を含有する実施例１は、ソルビン酸を含有しない比較例１及び比較例２と比べて、結膜組織中のエピナスチン濃度が約３倍増大することが確認された。従って、本発明の水性医薬組成物は顕著な結膜組織への移行性を示した。 As shown in Table 2, it was confirmed that Example 1 containing sorbic acid increased the epinastine concentration in the conjunctival tissue by about 3 times as compared with Comparative Example 1 and Comparative Example 2 containing no sorbic acid. It was. Therefore, the aqueous pharmaceutical composition of the present invention showed remarkable transferability to the conjunctival tissue.
２．眼内動態試験（２）
（１）被験製剤の調製
実施例１の製剤の調製方法と同様の方法にて、下表３の実施例２及び実施例３の製剤を調製した。また、比較対象として比較例１を再度調製した。なお、実施例２及び実施例３の塩化ナトリウムの含有量は、比較例１の浸透圧に合わせるために適宜調整した。
(1) Preparation of test preparation The preparations of Example 2 and Example 3 in Table 3 below were prepared in the same manner as the preparation method of the preparation of Example 1. In addition, Comparative Example 1 was prepared again as a comparison target. The sodium chloride contents of Examples 2 and 3 were appropriately adjusted to match the osmotic pressure of Comparative Example 1.
（２）試験方法
各被験製剤５μＬをラットに１回点眼投与し（ｎ＝６）、点眼投与後１時間の時点で屠殺処分後の眼球を摘出した。その結膜中のエピナスチン濃度を測定し、平均値を算出した。
(2) Test method 5 μL of each test preparation was administered to rats by eye drop once (n = 6), and the eyeball after sacrifice was removed 1 hour after the eye drop administration. The epinastine concentration in the conjunctiva was measured and the average value was calculated.
（３）試験結果及び考察
試験結果を表４に示す。
表４に示されるように、クエン酸ナトリウム水和物を含有する実施例２、ε−アミノカプロン酸を含有する実施例３は、低級脂肪族カルボン酸類を含有しない比較例１と比べて、結膜組織中のエピナスチン濃度がそれぞれ約１．２倍、約１．３倍増大することが確認された。従って、本発明の水性医薬組成物において、エピナスチンの結膜組織への移行性が向上することが示された。 As shown in Table 4, Example 2 containing sodium citrate hydrate and Example 3 containing ε-aminocaproic acid have a conjunctival structure as compared with Comparative Example 1 containing no lower aliphatic carboxylic acid. It was confirmed that the epinastine concentration in the medium increased about 1.2 times and about 1.3 times, respectively. Therefore, it was shown that in the aqueous pharmaceutical composition of the present invention, the transferability of epinastine to the conjunctival tissue is improved.
上記試験（１）および（２）の結果から、エピナスチン又はその塩を含有する水性医薬組成物に低級脂肪族カルボン酸類を配合することによって、エピナスチンの眼組織への移行性が向上することが示された。 From the results of the above tests (1) and (2), it is shown that the transferability of epinastine to the ocular tissue is improved by adding the lower aliphatic carboxylic acids to the aqueous pharmaceutical composition containing epinastine or a salt thereof. Was done.
本発明は、エピナスチン又はその塩と、低級脂肪族カルボン酸類とを含有する水性医薬組成物を提供する。 The present invention provides an aqueous pharmaceutical composition containing epinastine or a salt thereof and lower aliphatic carboxylic acids.
Claims (21)
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| JP2022062596A (en) * | 2020-10-08 | 2022-04-20 | 参天製薬株式会社 | Pollen rupture inhibitor containing epinastine or salt thereof |
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| JP2022062596A (en) * | 2020-10-08 | 2022-04-20 | 参天製薬株式会社 | Pollen rupture inhibitor containing epinastine or salt thereof |
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