JP4473539B2 - Pharmaceutical composition - Google Patents
Pharmaceutical composition Download PDFInfo
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- JP4473539B2 JP4473539B2 JP2003291957A JP2003291957A JP4473539B2 JP 4473539 B2 JP4473539 B2 JP 4473539B2 JP 2003291957 A JP2003291957 A JP 2003291957A JP 2003291957 A JP2003291957 A JP 2003291957A JP 4473539 B2 JP4473539 B2 JP 4473539B2
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- Prior art keywords
- salt
- phenylephrine
- pharmaceutical composition
- carbinoxamine
- calcium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000008194 pharmaceutical composition Substances 0.000 title description 25
- 150000003839 salts Chemical class 0.000 claims description 48
- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 claims description 28
- 229960001802 phenylephrine Drugs 0.000 claims description 27
- OJFSXZCBGQGRNV-UHFFFAOYSA-N carbinoxamine Chemical compound C=1C=CC=NC=1C(OCCN(C)C)C1=CC=C(Cl)C=C1 OJFSXZCBGQGRNV-UHFFFAOYSA-N 0.000 claims description 15
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 15
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 14
- 229960000428 carbinoxamine Drugs 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 7
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 7
- 239000001110 calcium chloride Substances 0.000 claims description 7
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 7
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 7
- 229940009662 edetate Drugs 0.000 claims description 6
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 5
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 5
- 235000011148 calcium chloride Nutrition 0.000 claims description 5
- 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 claims description 5
- 239000001354 calcium citrate Substances 0.000 claims description 5
- MKJXYGKVIBWPFZ-UHFFFAOYSA-L calcium lactate Chemical compound [Ca+2].CC(O)C([O-])=O.CC(O)C([O-])=O MKJXYGKVIBWPFZ-UHFFFAOYSA-L 0.000 claims description 5
- 239000001527 calcium lactate Substances 0.000 claims description 5
- 229960002401 calcium lactate Drugs 0.000 claims description 5
- 235000011086 calcium lactate Nutrition 0.000 claims description 5
- 235000015165 citric acid Nutrition 0.000 claims description 5
- 235000011147 magnesium chloride Nutrition 0.000 claims description 5
- 206010039083 rhinitis Diseases 0.000 claims description 5
- 230000000087 stabilizing effect Effects 0.000 claims description 5
- 239000011975 tartaric acid Substances 0.000 claims description 5
- 235000002906 tartaric acid Nutrition 0.000 claims description 5
- 235000013337 tricalcium citrate Nutrition 0.000 claims description 5
- 239000000043 antiallergic agent Substances 0.000 claims description 3
- 229960003733 phenylephrine hydrochloride Drugs 0.000 description 11
- OCYSGIYOVXAGKQ-FVGYRXGTSA-N phenylephrine hydrochloride Chemical compound [H+].[Cl-].CNC[C@H](O)C1=CC=CC(O)=C1 OCYSGIYOVXAGKQ-FVGYRXGTSA-N 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 229960000456 carbinoxamine maleate Drugs 0.000 description 6
- GVNWHCVWDRNXAZ-BTJKTKAUSA-N carbinoxamine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(OCCN(C)C)C1=CC=C(Cl)C=C1 GVNWHCVWDRNXAZ-BTJKTKAUSA-N 0.000 description 6
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 5
- 229960002713 calcium chloride Drugs 0.000 description 5
- 238000004040 coloring Methods 0.000 description 5
- 238000002845 discoloration Methods 0.000 description 5
- 229960002337 magnesium chloride Drugs 0.000 description 5
- 229930006000 Sucrose Natural products 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 206010028735 Nasal congestion Diseases 0.000 description 3
- 229960004256 calcium citrate Drugs 0.000 description 3
- 229960004106 citric acid Drugs 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 229960001367 tartaric acid Drugs 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 239000000739 antihistaminic agent Substances 0.000 description 2
- LLSDKQJKOVVTOJ-UHFFFAOYSA-L calcium chloride dihydrate Chemical compound O.O.[Cl-].[Cl-].[Ca+2] LLSDKQJKOVVTOJ-UHFFFAOYSA-L 0.000 description 2
- 229940052299 calcium chloride dihydrate Drugs 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 2
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 229940075582 sorbic acid Drugs 0.000 description 2
- 235000010199 sorbic acid Nutrition 0.000 description 2
- 239000004334 sorbic acid Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 229920002472 Starch Polymers 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
- 239000002253 acid Substances 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- -1 amino acid salts Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 229940124623 antihistamine drug Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- JHECKPXUCKQCSH-UHFFFAOYSA-J calcium;disodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate;hydrate Chemical compound O.[Na+].[Na+].[Ca+2].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O JHECKPXUCKQCSH-UHFFFAOYSA-J 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- YKZPPPNXRZHVGX-PXYKVGKMSA-L dipotassium;(2s)-2-aminobutanedioate;hydron;hydrate Chemical compound [H+].[H+].O.[K+].[K+].[O-]C(=O)[C@@H](N)CC([O-])=O.[O-]C(=O)[C@@H](N)CC([O-])=O YKZPPPNXRZHVGX-PXYKVGKMSA-L 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229940050906 magnesium chloride hexahydrate Drugs 0.000 description 1
- DHRRIBDTHFBPNG-UHFFFAOYSA-L magnesium dichloride hexahydrate Chemical compound O.O.O.O.O.O.[Mg+2].[Cl-].[Cl-] DHRRIBDTHFBPNG-UHFFFAOYSA-L 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 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
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229940068988 potassium aspartate Drugs 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 206010041232 sneezing Diseases 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000003639 vasoconstrictive effect Effects 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
Description
本発明は、フェニレフリン又はその塩が経時的に安定であるカルビノキサミン又はその塩とフェニレフリン又はその塩を含有する医薬組成物に関する。 The present invention relates to a pharmaceutical composition comprising carbinoxamine or a salt thereof and phenylephrine or a salt thereof, wherein phenylephrine or a salt thereof is stable over time.
フェニレフリン又はその塩は、強力な血管収縮作用を有し、それを有効成分とする医薬組成物は抗鼻炎薬等として使用されている。しかしながら、フェニレフリン又はその塩は、他の化合物と共存させ長時間保存すると分解して着色又は変色し、経時安定性が劣るという問題がある。例えば、塩酸フェニレフリンはアルカリ、第二鉄塩、酸化剤との配合禁忌があり（非特許文献１）、アスパラギン酸カリウム等のアミノ酸又はアミノ酸塩が共存する水溶液中では、着色又は変色劣化が著しいことが知られている（特許文献１）。
フェニレフリンの安定化方法として、ソルビン酸又はその塩を安定化剤とすることが知られている（特許文献１）が充分な安定性は得られない。
Phenylephrine or a salt thereof has a strong vasoconstrictive action, and a pharmaceutical composition containing it as an active ingredient is used as an anti-rhinitis drug or the like. However, phenylephrine or a salt thereof has a problem in that when it coexists with other compounds and stored for a long period of time, it decomposes and becomes colored or discolored, resulting in poor stability over time. For example, phenylephrine hydrochloride has contraindications with alkalis, ferric salts, and oxidizing agents (Non-patent Document 1), and in aqueous solutions in which amino acids or amino acid salts such as potassium aspartate coexist, coloring or discoloration deterioration is remarkable. Is known (Patent Document 1).
As a method for stabilizing phenylephrine, it is known that sorbic acid or a salt thereof is used as a stabilizer (Patent Document 1), but sufficient stability cannot be obtained.
一方、カルビノキサミン又はその塩は抗アレルギー作用、抗ヒスタミン作用を有し、感冒に伴う鼻炎、アレルギー性鼻炎等による鼻閉の治療改善薬として使用されている。 On the other hand, carbinoxamine or a salt thereof has an antiallergic action and an antihistamine action and is used as a therapeutic improving agent for nasal congestion due to rhinitis associated with the common cold, allergic rhinitis and the like.
フェニレフリン又はその塩とカルビノキサミン又はその塩を併用すると、種々の症状に対応できる抗鼻炎薬が得られることが期待されるが、この組成物中においてもフェニレフリン又はその塩は、同様に経時安定性が悪いという問題があった。
本発明者らは、フェニレフリン又はその塩及びカルビノキサミン又はその塩を配合した組成物中における、フェニレフリン又はその塩の安定化を検討してきたが、前記ソルビン酸の塩を添加しても、フェニレフリン又はその塩の安定性は改善されなかった。 The present inventors have studied the stabilization of phenylephrine or a salt thereof in a composition containing phenylephrine or a salt thereof and carbinoxamine or a salt thereof, but even if the salt of sorbic acid is added, the phenylephrine or the salt thereof The stability of the salt was not improved.
本発明の目的は、フェニレフリン又はその塩及びカルビノキサミン又はその塩を有効成分として含有し、フェニレフリン又はその塩が経時的に安定な医薬組成物を提供することにある。 An object of the present invention is to provide a pharmaceutical composition containing phenylephrine or a salt thereof and carbinoxamine or a salt thereof as active ingredients, and phenylephrine or a salt thereof being stable over time.
本発明者らは、フェニレフリン又はその塩をカルビノキサミン又はその塩と併用した医薬組成物中におけるフェニレフリン又はその塩の安定化法について鋭意検討を進めた結果、特定の酸又は塩を配合すると、経時安定性が著しく改善することを見出し、本発明を完成した。 As a result of intensive investigations on a method for stabilizing phenylephrine or a salt thereof in a pharmaceutical composition in which phenylephrine or a salt thereof is used in combination with carbinoxamine or a salt thereof, the present inventors have found that when a specific acid or salt is added, As a result, the present invention was completed.
すなわち、本発明は、次の成分（Ａ）、（Ｂ）及び（Ｃ）：
（Ａ）フェニレフリン又はその塩、
（Ｂ）カルビノキサミン又はその塩、
（Ｃ）クエン酸、酒石酸、塩化カルシウム、塩化マグネシウム、クエン酸カルシウム、乳酸カルシウム及びエデト酸塩から選ばれる１種又は２種以上、
を含有する医薬組成物を提供するものである。
また、本発明は、クエン酸、酒石酸、塩化カルシウム、塩化マグネシウム、クエン酸カルシウム、乳酸カルシウム及びエデト酸塩から選ばれる１種又は２種以上を添加することを特徴とするフェニレフリン又はその塩とカルビノキサミン又はその塩とを含有する医薬組成物中のフェニレフリン又はその塩の安定化方法を提供するものである。
That is, the present invention includes the following components (A), (B) and (C):
(A) phenylephrine or a salt thereof,
(B) carbinoxamine or a salt thereof,
(C) one or more selected from citric acid, tartaric acid, calcium chloride, magnesium chloride, calcium citrate, calcium lactate and edetate,
The pharmaceutical composition containing this is provided.
The present invention also provides phenylephrine or a salt thereof and carbinoxamine, characterized by adding one or more selected from citric acid, tartaric acid, calcium chloride, magnesium chloride, calcium citrate, calcium lactate and edetate. Alternatively, the present invention provides a method for stabilizing phenylephrine or a salt thereof in a pharmaceutical composition containing the salt or a salt thereof.
本発明の医薬組成物は、フェニレフリン又はその塩が経時的に分解せず、着色、変色を起こさず安定である。 In the pharmaceutical composition of the present invention, phenylephrine or a salt thereof does not decompose over time and is stable without causing coloring or discoloration.
本発明で使用するフェニレフリンの塩としては、薬学的に許容されている塩であれば特に制限されず、塩酸塩、硝酸塩、臭化水素酸塩、ｐ−トルエンスルホン酸塩、メタンスルホン酸塩、フマル酸塩、コハク酸塩、乳酸塩、マレイン酸塩等が挙げられる。フェニレフリン又はその塩（成分（Ａ））としては、塩酸フェニレフリンが特に好ましい。
フェニレフリン又はその塩は、医薬組成物中に０．０３〜９０重量％、特に０．２〜６０重量％含有するのが好ましい。
The phenylephrine salt used in the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt. Hydrochloride, nitrate, hydrobromide, p-toluenesulfonate, methanesulfonate, Examples include fumarate, succinate, lactate, maleate and the like. As phenylephrine or a salt thereof (component (A)), phenylephrine hydrochloride is particularly preferred.
Phenylephrine or a salt thereof is preferably contained in the pharmaceutical composition in an amount of 0.03 to 90% by weight, particularly 0.2 to 60% by weight.
本発明で使用するカルビノキサミンの塩としては、薬学的に許容されている塩であれば特に制限されず、マレイン酸塩、塩酸塩、硝酸塩、臭化水素酸塩、ｐ−トルエンスルホン酸塩、メタンスルホン酸塩、フマル酸塩、コハク酸塩、乳酸塩等が挙げられる。カルビノキサミン又はその塩（成分（Ｂ））としては、マレイン酸カルビノキサミンが特に好ましい。
カルビノキサミン又はその塩は、医薬組成物中に０．０２〜９０重量％、特に０．１〜４０重量％含有するのが好ましい。
The carbinoxamine salt used in the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt. Maleate, hydrochloride, nitrate, hydrobromide, p-toluenesulfonate, methane Examples include sulfonate, fumarate, succinate, and lactate. As the carbinoxamine or a salt thereof (component (B)), carbinoxamine maleate is particularly preferable.
Carbinoxamine or a salt thereof is preferably contained in the pharmaceutical composition in an amount of 0.02 to 90% by weight, particularly 0.1 to 40% by weight.
本発明で使用する成分（Ｃ）は、フェニレフリン又はその塩をカルビノキサミン又はその塩とを含有する医薬組成物中において、フェニレフリン又はその塩が経時的に分解し、着色及び変色するのを抑制する安定化剤であって、クエン酸、酒石酸、塩化カルシウム、塩化マグネシウム、クエン酸カルシウム、乳酸カルシウム及びエデト酸塩の群から選ばれ、１種又は２種以上を適宜混合して使用される。これらの安定化剤は水和物、例えば塩化カルシウムニ水和物、塩化マグネシウム六水和物等であってもよい。エデト酸塩としては、例えば、エデト酸二ナトリウム、エデト酸カルシウムニナトリウム等が挙げられる。 Ingredient (C) used in the present invention is a pharmaceutical composition containing phenylephrine or a salt thereof and carbinoxamine or a salt thereof, which suppresses the degradation or coloring and discoloration of phenylephrine or a salt thereof over time. The agent is selected from the group consisting of citric acid, tartaric acid, calcium chloride, magnesium chloride, calcium citrate, calcium lactate and edetate, and one or two or more are used as appropriate. These stabilizers may be hydrates such as calcium chloride dihydrate, magnesium chloride hexahydrate and the like. Examples of the edetate include disodium edetate and calcium disodium edetate.
成分（Ｃ）は、フェニレフリン又はその塩の安定化効果の点から医薬組成物中に０．１〜１０．０重量％、特に０．３〜５．２重量％含有するのが好ましい。 Component (C) is preferably contained in the pharmaceutical composition in an amount of 0.1 to 10.0% by weight, particularly 0.3 to 5.2% by weight, from the viewpoint of the stabilizing effect of phenylephrine or a salt thereof.
成分（Ｃ）の配合方法は、特に限定されず、例えば、粉末として配合する、溶媒に溶解後配合する方法等が挙げられる。粉末として添加する方法としては、市販の製品のまま添加するか又は粉砕して添加する。溶媒としては水、エタノール、メタノール、２−プロパノール又は水−エタノール混合物等が挙げられるが、特に水-エタノール混合物が好ましい。 The blending method of component (C) is not particularly limited, and examples thereof include a blending method as a powder and a blending method after dissolving in a solvent. As a method of adding as a powder, it is added as a commercial product or added after being pulverized. Examples of the solvent include water, ethanol, methanol, 2-propanol, and a water-ethanol mixture, and a water-ethanol mixture is particularly preferable.
本発明の医薬組成物の剤型は、錠剤、顆粒剤、散剤、カプセル剤、懸濁剤、注射剤、坐剤等の種々の剤型が挙げられる。
これらの剤型の製剤を調製するに際に使用する担体としては、乳糖、デンプン、白糖、ブドウ糖、マンニトール、結晶セルロース、植物末等の賦形剤；ヒドロキシプロピルセルロース、メチルセルロース、ポリビニルピロリドン等の結合剤；カルボキシメチルセルロースカルシウム、低置換度ヒドロキシプロピルセルロース、アルギン酸ナトリウム等の崩壊剤；ステアリン酸マグネシウム、タルク、シリコーン油等の滑沢剤；界面活性剤；着色剤；矯味剤；矯臭剤；溶解補助剤；保存剤等が挙げられる。
Examples of the dosage form of the pharmaceutical composition of the present invention include various dosage forms such as tablets, granules, powders, capsules, suspensions, injections, and suppositories.
Carriers used in preparing these dosage forms include lactose, starch, sucrose, glucose, mannitol, crystalline cellulose, plant powder and other excipients; binding of hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone, etc. Agents; disintegrating agents such as carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose and sodium alginate; lubricants such as magnesium stearate, talc and silicone oil; surfactants; coloring agents; flavoring agents; flavoring agents; A preservative and the like.
本発明の医薬組成物は、特にくしゃみ、鼻みず、鼻づまり、頭重等の鼻炎薬、抗アレルギー薬、抗ヒスタミン薬、低血圧治療薬等として有用であって、その投与量は成人１日あたり１０mg〜１０ｇ、好ましくは５０mg〜３ｇ程度であり、この１日あたりの投与量を１〜数回に分けて投与する。また、フェニレフリン又はその塩は成人１日あたり３〜６０mg、好ましくは６〜３０mg、カルビノキサミン又はその塩は１．６〜３２mg、好ましくは３．２〜１６mg量投与するのが好ましい。 The pharmaceutical composition of the present invention is particularly useful as a rhinitis drug such as sneezing, nasal congestion, nasal congestion, headache, etc., an antiallergic drug, an antihistamine drug, a hypotensive drug, etc. The dose is about 10 mg to 10 g, preferably about 50 mg to 3 g, and the daily dose is divided into 1 to several times. Further, phenylephrine or a salt thereof is preferably administered in an amount of 3 to 60 mg, preferably 6 to 30 mg per day for an adult, and carbinoxamine or a salt thereof is 1.6 to 32 mg, preferably 3.2 to 16 mg.
次に、実施例を挙げて本発明を更に詳細に説明するが、本発明はこれらの実施例に限定されるものではない。 EXAMPLES Next, although an Example is given and this invention is demonstrated further in detail, this invention is not limited to these Examples.
実施例１
下記組成の各配合成分を秤量し、４２メッシュ篩で篩過することにより混合した後、５０重量％エタノール水溶液(３mL)を滴下しながら乳鉢にて粉砕し、練合し、更にハコ型乾燥機にて乾燥して医薬組成物を得た。製造した医薬組成物をビン容器に入れて密封して、５０℃の恒温槽に１０日保存後の塩酸フェニレフリン量をＨＰＬＣにて測定し、対初期値に対する残存％を算出した。結果を表１に示す。
Example 1
Each compounding component having the following composition was weighed and mixed by sieving with a 42 mesh sieve, then pulverized and kneaded in a mortar while dropping a 50% by weight aqueous ethanol solution (3 mL), and further a box-type dryer. And dried to obtain a pharmaceutical composition. The manufactured pharmaceutical composition was put in a bottle container and sealed, and the amount of phenylephrine hydrochloride after storage for 10 days in a thermostat at 50 ° C. was measured by HPLC, and the residual% relative to the initial value was calculated. The results are shown in Table 1.
医薬組成物
組成：塩酸フェニレフリン １．００ｇ
マレイン酸カルビノキサミン １．６０
精製白糖 ２６．５４
成分（Ｃ）又は比較化合物（表１） 表１に記載する量
Pharmaceutical composition Composition: Phenylephrine hydrochloride 1.00g
Carbinoxamine maleate 1.60
Purified white sugar 26.54
Component (C) or comparative compound (Table 1) Amounts listed in Table 1
マレイン酸カルビノキサミンを含有しない医薬組成物（２）では塩酸フェニレフリンは安定であったが、マレイン酸カルビノキサミンを配合した医薬組成物（１）では塩酸フェニレフリンの経時安定性が低下した。
これに対して、本発明の成分（Ｃ）を含有する医薬組成物は、何れも長時間高温で保存しても安定であった。また、本発明の医薬組成物は、５０℃で１０日保存した後でも、着色、変色は認められなかった。
Phenylephrine hydrochloride was stable in the pharmaceutical composition (2) not containing carbinoxamine maleate, but the temporal stability of phenylephrine hydrochloride was lowered in the pharmaceutical composition (1) containing carbinoxamine maleate.
On the other hand, any pharmaceutical composition containing the component (C) of the present invention was stable even when stored at a high temperature for a long time. In addition, the pharmaceutical composition of the present invention was not colored or discolored even after being stored at 50 ° C. for 10 days.
実施例２
塩化カルシウム、塩化マグネシウムの含有量を変えて、医薬組成物中の塩酸フェニレフリンの安定性を、実施例１と同様にして測定した。
医薬組成物の組成：塩酸フェニレフリン １．００ｇ
マレイン酸カルビノキサミン １．６０
精製白糖 ２６．５４
塩化カルシウム又は塩化マグネシウム 表２に記載する量
Example 2
The stability of phenylephrine hydrochloride in the pharmaceutical composition was measured in the same manner as in Example 1 by changing the contents of calcium chloride and magnesium chloride.
Composition of the pharmaceutical composition: phenylephrine hydrochloride 1.00 g
Carbinoxamine maleate 1.60
Purified white sugar 26.54
Calcium chloride or magnesium chloride Amounts listed in Table 2
何れの医薬組成物中においても、塩酸フェニレフリンは経時安定性に優れていた。また、保存後においても着色、変色は認められなかった。 In any pharmaceutical composition, phenylephrine hydrochloride was excellent in stability over time. Moreover, coloring and discoloration were not recognized after storage.
実施例３
医薬組成物の製造：
塩酸フェニレフリン１１．０重量部、マレイン酸カルビノキサミン１６．８重量部、アビセルＰＨ−Ｆ２０ １５．０重量部及び精製白糖（ＦＳ−２）２５４．６重量部を混合し、塩化カルシウム２水和物２．０重量部、エタノール（９５）４０重量部及び精製水４０重量部を加え、混合練合（バーチカルグラニュレーターＶＧ−１０：パウレック（株）製）した後、流動層乾燥機（Parugura PDX-10：松井製作所（株）製）を使用して乾燥し、次いで、整粒（クアドロコーミルＱＣ−１９７Ｓ：パウレック（株）製）して顆粒（粒径０．７１〜１．０mm）を製造した。
Example 3
Production of pharmaceutical composition:
11.0 parts by weight of phenylephrine hydrochloride, 16.8 parts by weight of carbinoxamine maleate, 15.0 parts by weight of Avicel PH-F20 and 254.6 parts by weight of purified sucrose (FS-2) were mixed, and calcium chloride dihydrate 2 0.0 part by weight, 40 parts by weight of ethanol (95) and 40 parts by weight of purified water were added and mixed and kneaded (vertical granulator VG-10: manufactured by Pauleck Co., Ltd.), and then fluidized bed dryer (Parugura PDX-10). : Matsui Seisakusho Co., Ltd.) and then granulated (Quadrocomil QC-197S: Paulek Co., Ltd.) to produce granules (particle size 0.71-1.0 mm) .
製造した顆粒を２号カプセルに充填し、５０℃に静置保存した後の塩酸フェニレフリンの残存量は、１０日後で９７．７％、１ヵ月後で９１．９％と経時安定性に優れていた。また、保存後においても着色、変色は認められなかった。 The amount of phenylephrine hydrochloride remaining after filling the produced granules into No. 2 capsules and allowing them to stand at 50 ° C. is 97.7% after 10 days and 91.9% after 1 month. It was. Moreover, coloring and discoloration were not recognized after storage.
Claims (2)
（Ａ）フェニレフリン又はその塩、
（Ｂ）カルビノキサミン又はその塩、
（Ｃ）クエン酸、酒石酸、塩化カルシウム、塩化マグネシウム、クエン酸カルシウム、乳酸カルシウム及びエデト酸塩から選ばれる１種又は２種以上、
を含有する抗鼻炎薬または抗アレルギー薬組成物。 The following components (A), (B) and (C):
(A) phenylephrine or a salt thereof,
(B) carbinoxamine or a salt thereof,
(C) one or more selected from citric acid, tartaric acid, calcium chloride, magnesium chloride, calcium citrate, calcium lactate and edetate,
An anti-rhinitis or anti-allergic agent composition.
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