JP2009051761A - Aqueous medicinal composition containing levocabastine and lidocaine - Google Patents
Aqueous medicinal composition containing levocabastine and lidocaine Download PDFInfo
- Publication number
- JP2009051761A JP2009051761A JP2007219084A JP2007219084A JP2009051761A JP 2009051761 A JP2009051761 A JP 2009051761A JP 2007219084 A JP2007219084 A JP 2007219084A JP 2007219084 A JP2007219084 A JP 2007219084A JP 2009051761 A JP2009051761 A JP 2009051761A
- Authority
- JP
- Japan
- Prior art keywords
- pharmaceutical composition
- aqueous pharmaceutical
- levocabastine
- salt
- salts
- 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.)
- Granted
Links
- 229960001120 levocabastine Drugs 0.000 title claims abstract description 50
- ZCGOMHNNNFPNMX-KYTRFIICSA-N levocabastine Chemical compound C1([C@@]2(C(O)=O)CCN(C[C@H]2C)[C@@H]2CC[C@@](CC2)(C#N)C=2C=CC(F)=CC=2)=CC=CC=C1 ZCGOMHNNNFPNMX-KYTRFIICSA-N 0.000 title claims abstract description 50
- 239000000203 mixture Substances 0.000 title claims abstract description 43
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 229960004194 lidocaine Drugs 0.000 title claims abstract description 21
- 150000003839 salts Chemical class 0.000 claims abstract description 82
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 claims abstract description 22
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 claims abstract description 22
- 229940041616 menthol Drugs 0.000 claims abstract description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims description 83
- 239000002562 thickening agent Substances 0.000 claims description 23
- 239000003889 eye drop Substances 0.000 claims description 14
- 239000007923 nasal drop Substances 0.000 claims description 12
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 9
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 9
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 9
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical group OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 9
- 210000004877 mucosa Anatomy 0.000 claims 1
- 239000002245 particle Substances 0.000 abstract description 42
- 235000002639 sodium chloride Nutrition 0.000 description 84
- 238000002156 mixing Methods 0.000 description 16
- 238000009472 formulation Methods 0.000 description 12
- -1 inorganic acid salts Chemical class 0.000 description 11
- 238000000034 method Methods 0.000 description 10
- PIZLBWGMERQCOC-UHFFFAOYSA-N dibenzyl carbonate Chemical compound C=1C=CC=CC=1COC(=O)OCC1=CC=CC=C1 PIZLBWGMERQCOC-UHFFFAOYSA-N 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 229940012356 eye drops Drugs 0.000 description 9
- 229960001828 levocabastine hydrochloride Drugs 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 230000003204 osmotic effect Effects 0.000 description 8
- 238000003860 storage Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000000872 buffer Substances 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 7
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
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- 239000003814 drug Substances 0.000 description 5
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
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- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 150000007529 inorganic bases Chemical class 0.000 description 4
- 150000007530 organic bases Chemical class 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
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- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 229960004393 lidocaine hydrochloride Drugs 0.000 description 3
- YECIFGHRMFEPJK-UHFFFAOYSA-N lidocaine hydrochloride monohydrate Chemical compound O.[Cl-].CC[NH+](CC)CC(=O)NC1=C(C)C=CC=C1C YECIFGHRMFEPJK-UHFFFAOYSA-N 0.000 description 3
- 239000003589 local anesthetic agent Substances 0.000 description 3
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- 238000011105 stabilization Methods 0.000 description 3
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- DRGAZIDRYFYHIJ-UHFFFAOYSA-N 2,2':6',2''-terpyridine Chemical compound N1=CC=CC=C1C1=CC=CC(C=2N=CC=CC=2)=N1 DRGAZIDRYFYHIJ-UHFFFAOYSA-N 0.000 description 2
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 2
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- GEYJUFBPCGDENK-UHFFFAOYSA-M sodium;3,8-dimethyl-5-propan-2-ylazulene-1-sulfonate Chemical compound [Na+].CC(C)C1=CC=C(C)C2=C(S([O-])(=O)=O)C=C(C)C2=C1 GEYJUFBPCGDENK-UHFFFAOYSA-M 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000019721 spearmint oil Nutrition 0.000 description 1
- 229960000654 sulfafurazole Drugs 0.000 description 1
- 229960005404 sulfamethoxazole Drugs 0.000 description 1
- YZMCKZRAOLZXAZ-UHFFFAOYSA-N sulfisomidine Chemical compound CC1=NC(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 YZMCKZRAOLZXAZ-UHFFFAOYSA-N 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- 229940021790 tetrahydrozoline hydrochloride Drugs 0.000 description 1
- 229960000337 tetryzoline Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229940042585 tocopherol acetate Drugs 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 229940050168 zinc lactate Drugs 0.000 description 1
- 239000011576 zinc lactate Substances 0.000 description 1
- 235000000193 zinc lactate Nutrition 0.000 description 1
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
- 229960001763 zinc sulfate Drugs 0.000 description 1
- 229910000368 zinc sulfate Inorganic materials 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Abstract
Description
本発明は、レボカバスチン及び／又はその塩の粒子サイズを安定に保持できる水性医薬組成物に関する。 The present invention relates to an aqueous pharmaceutical composition that can stably maintain the particle size of levocabastine and / or a salt thereof.
レボカバスチンは、ヒスタミンH1拮抗作用の他に、ケミカルメディエーター遊離抑制作用や好酸球遊走抑制作用があり、アレルギー性鼻炎やアレルギー性結膜炎等のアレルギー性疾患の治療薬として、点鼻剤や点眼剤等に配合して使用されている。レボカバスチンは、水に難溶性であるため、水性医薬組成物とする場合には懸濁状態で製剤化されている。通常、薬効成分が懸濁状態である場合、その成分の生物学的利用率は懸濁粒子のサイズに大きく依存することから、製造後、流通、販売、保管期間を経て実際に使用されるまで懸濁粒子の大きさが変化しないことが求められる。しかしながら、レボカバスチンは、溶液中で凝集、結晶成長、沈降等が生じやすく、その粒子のサイズが経時的に増大することが分かっており、レボカバスチンを水性医薬組成物に配合するには、レボカバスチンの粒子サイズの経時的な増大を防いで安定化を図ることが必要である。 In addition to histamine H1 antagonistic activity, levocabastine has chemical mediator release inhibitory activity and eosinophil migration inhibitory activity, and as a therapeutic agent for allergic diseases such as allergic rhinitis and allergic conjunctivitis, nasal drops and eye drops, etc. Used in combination. Levocabastine is sparingly soluble in water, so it is formulated in a suspended state when it is used as an aqueous pharmaceutical composition. Normally, when a medicinal ingredient is in a suspended state, the bioavailability of that ingredient depends largely on the size of the suspended particles, so after production, distribution, sales, and storage period until it is actually used It is required that the size of the suspended particles does not change. However, it is known that levocabastine is prone to agglomeration, crystal growth, sedimentation, etc. in the solution, and that the size of the particles increases with time. To formulate levocabastine into an aqueous pharmaceutical composition, It is necessary to prevent the size from increasing over time and stabilize.
これまでに、レボカバスチンと共に、多価アルコール、結晶セルロース・カルメロースナトリウム、及び清涼化剤を併用することによって、水性医薬組成物において、レボカバスチンの粒子サイズの変化を防ぎ、良好な分散性が得られることが報告されている（特許文献１参照）。しかしながら、レボカバスチンを含む水性医薬組成物の処方の多様化に対応するために、特許文献１に報告されている処方以外にも、レボカバスチンの粒子サイズを安定化させる技術の開発が望まれている。 So far, by using together with levocabastine, polyhydric alcohol, crystalline cellulose / carmellose sodium, and a refreshing agent, it is possible to prevent change in the particle size of levocabastine and obtain good dispersibility in aqueous pharmaceutical compositions. Has been reported (see Patent Document 1). However, in order to cope with the diversification of the formulation of an aqueous pharmaceutical composition containing levocabastine, development of a technique for stabilizing the particle size of levocabastine is desired in addition to the formulation reported in Patent Document 1.
一方、リドカインは、神経膜のナトリウムチャネルをブロックして活動電位の伝導を可逆的に抑制する作用があり、局所麻酔剤として、点鼻剤や点眼剤等に配合して使用されている。また、メントールは、清涼感や爽快感を付与する作用があり、清涼化剤として、点鼻剤や点眼剤等に配合して使用されている。 On the other hand, lidocaine has an action of reversibly inhibiting action potential conduction by blocking sodium channels in the nerve membrane, and is used as a local anesthetic in nasal drops and eye drops. Moreover, menthol has the effect | action which provides a refreshing feeling and a refreshing feeling, and is mix | blended and used for a nasal drop, eye drops, etc. as a refreshing agent.
しかしながら、リドカイン及びメントールは、それぞれ局所麻酔剤及び清涼化剤等として使用し得ることが知られているに止まり、水性医薬組成物において、レボカバスチンの粒子サイズに与える影響については明らかにされていない。
そこで、本発明の目的は、レボカバスチン及び／又はその塩の粒子サイズの経時的な増大を抑制し、当該粒子サイズが安定に保持される水性医薬組成物を提供することである。 Accordingly, an object of the present invention is to provide an aqueous pharmaceutical composition that suppresses an increase in the particle size of levocabastine and / or a salt thereof over time and stably maintains the particle size.
本発明者等は、上記課題を解決すべく鋭意検討した結果、レボカバスチン及び／又はその塩と共に、リドカイン及び／又はその塩、並びにメントールを水性医薬組成物に配合することによって、懸濁されたレボカバスチン及び／又はその塩の粒子サイズの経時的な増大の抑制が図られ、当該粒子サイズの安定な保持が可能になることを見出した。また、レボカバスチン及び／又はその塩の粒子サイズの増大抑制は、粘稠剤(好ましくはセルロース系増粘剤、特に好ましくはヒドロキシプロピルメチルセルロース)を更に配合した場合に、一層顕著になることを見出した。本発明は、かかる知見に基づいて、更に改良を重ねることにより完成したものである。 As a result of intensive studies to solve the above-mentioned problems, the inventors of the present invention suspended levocabastine by adding lidocaine and / or a salt thereof and menthol together with levocabastine and / or a salt thereof to an aqueous pharmaceutical composition. In addition, the inventors have found that the increase in the particle size of the salt over time can be suppressed, and the particle size can be stably maintained. Further, it was found that the increase in the particle size of levocabastine and / or a salt thereof becomes more prominent when a thickener (preferably a cellulose-based thickener, particularly preferably hydroxypropylmethylcellulose) is further added. . The present invention has been completed by making further improvements based on such findings.
即ち、本発明は、下記に掲げる水性医薬組成物及び方法である。
項１． (A)レボカバスチン及び／又はその塩、(B)リドカイン及び／又はその塩、及び(C)メントールを含有することを特徴とする水性医薬組成物。
項２． (A)成分の総量100重量部に対して、(B)成分が総量で18〜16000重量部、且つ(C)成分が総量で0.1〜3800重量部である、項１に記載の水性医薬組成物。
項３． 更に、粘稠剤を含有する、項１又は２に記載の水性医薬組成物。
項４． 粘稠剤が、セルロース系増粘剤である、項３に記載の水性医薬組成物。
項５． 粘稠剤が、ヒドロキシプロピルメチルセルロースである、項３に記載の水性医薬組成物。
項６． 粘膜適用組成物である、項１乃至５のいずれかに記載の水性医薬組成物。
項７． 眼科用組成物又は耳鼻科用組成物である、項１乃至５のいずれかに記載の水性医薬組成物。
項８． 点眼剤又は点鼻剤である、項１乃至５のいずれかに記載の水性医薬組成物。
項９． 水性医薬組成物の総量当たり、(A)成分を0.006〜0.05w/v%、(B)成分を0.05〜1w/v%、及び(C)成分を0.0002〜0.05w/v%含有する、項８に記載の水性医薬組成物。
項１０． レボカバスチン及び／又はその塩を含有する水性医薬組成物中で、(B)リドカイン及び／又はその塩、及び(C)メントールを共存させることを特徴とする、レボカバスチン及び／又はその塩の粒子サイズの安定化方法。
That is, this invention is the aqueous | water-based pharmaceutical composition and method hung up below.
Item 1. An aqueous pharmaceutical composition comprising (A) levocabastine and / or a salt thereof, (B) lidocaine and / or a salt thereof, and (C) menthol.
Item 2. Item 2. The aqueous pharmaceutical composition according to Item 1, wherein the total amount of component (A) is 18 to 16000 parts by weight and the total amount of component (C) is 0.1 to 3800 parts by weight relative to 100 parts by weight of component object.
Item 3. Item 3. The aqueous pharmaceutical composition according to Item 1 or 2, further comprising a thickening agent.
Item 4. Item 4. The aqueous pharmaceutical composition according to Item 3, wherein the thickening agent is a cellulosic thickener.
Item 5. Item 4. The aqueous pharmaceutical composition according to Item 3, wherein the thickening agent is hydroxypropylmethylcellulose.
Item 6. Item 6. The aqueous pharmaceutical composition according to any one of Items 1 to 5, which is a mucosa-applied composition.
Item 7. Item 6. The aqueous pharmaceutical composition according to any one of Items 1 to 5, which is an ophthalmic composition or an otolaryngological composition.
Item 8. Item 6. The aqueous pharmaceutical composition according to any one of Items 1 to 5, which is an eye drop or a nasal drop.
Item 9. Item (A) contains 0.006 to 0.05 w / v%, (B) component 0.05 to 1 w / v%, and (C) component 0.0002 to 0.05 w / v% per total amount of the aqueous pharmaceutical composition The aqueous pharmaceutical composition according to 8.
Item 10. In the aqueous pharmaceutical composition containing levocabastine and / or a salt thereof, (B) lidocaine and / or a salt thereof, and (C) menthol are allowed to coexist, and the particle size of levocabastine and / or a salt thereof is characterized by Stabilization method.
本発明の水性医薬組成物中ではレボカバスチン及び／又はその塩の粒子サイズの増大が抑制されているので、レボカバスチン及び／又はその塩の生物学的利用率が安定に保持され、レボカバスチン及び／又はその塩の分散安定化も期待される。 In the aqueous pharmaceutical composition of the present invention, the increase in the particle size of levocabastine and / or its salt is suppressed, so that the bioavailability of levocabastine and / or its salt is stably maintained, and levocabastine and / or its Dispersion stabilization of the salt is also expected.
また、本発明の水性医薬組成物において、リドカイン及び／又はその塩、並びにメントールは、レボカバスチン及び／又はその塩の粒子サイズの安定化に寄与するのみならず、ぞれぞれ局所麻酔作用及び清涼化作用をも発現し得る。かかる作用に基づいて、本発明の水性医薬組成物は、優れた薬理作用や使用感を呈することもでき、有用性が高い。 Further, in the aqueous pharmaceutical composition of the present invention, lidocaine and / or a salt thereof and menthol not only contribute to stabilization of the particle size of levocabastine and / or a salt thereof, but also each have a local anesthetic action and a refreshing effect. It can also exert an oxidative effect. Based on this action, the aqueous pharmaceutical composition of the present invention can also exhibit excellent pharmacological action and feeling of use, and is highly useful.
以下、本発明を詳細に説明する。本明細書において、水性医薬組成物とは、組成物中に水を少なくとも50w/v％以上、さらに好ましくは70w/v％以上含有する医薬組成物を意味する。 Hereinafter, the present invention will be described in detail. In the present specification, the aqueous pharmaceutical composition means a pharmaceutical composition containing at least 50 w / v% or more, more preferably 70 w / v% or more of water in the composition.
(I)水性医薬組成物
本発明の水性医薬組成物は、レボカバスチン及び／又はその塩（以下、単に(A)成分と表記することもある）を含有する。レボカバスチンは、(-)-(3S,4R)-1-[シス-4-シアノ-4-(4-フルオロフェニル)シクロヘキシル]-3-メチル-4-フェニルピペリジン-4-カルボン酸とも称される公知化合物である。
(I) Aqueous Pharmaceutical Composition The aqueous pharmaceutical composition of the present invention contains levocabastine and / or a salt thereof (hereinafter sometimes simply referred to as component (A)). Levocabastine is also referred to as (-)-(3S, 4R) -1- [cis-4-cyano-4- (4-fluorophenyl) cyclohexyl] -3-methyl-4-phenylpiperidine-4-carboxylic acid It is a known compound.
レボカバスチンの塩は、医薬上、薬理学的に（製薬上）又は生理学的に許容されることを限度として、特に制限されるものではない。このような塩として、具体的には、酸付加塩、有機塩基との塩、無機塩基との塩等が挙げられる。より具体的には、酸付加塩としては、例えば、塩酸塩、硫酸塩、硝酸塩、臭化水素酸塩、リン酸塩等の無機酸塩；モノカルボン酸塩（酢酸塩、トリフルオロ酢酸塩、酪酸塩、パルミチン酸塩、ステアリン酸塩等の有機酸塩；フマル酸塩、マレイン酸塩、コハク酸塩、マロン酸塩等の多価カルボン酸塩；乳酸塩、酒石酸塩、クエン酸塩等のオキシカルボン酸塩；メタンスルホン酸塩、トルエンスルホン酸塩(オルト型、メタ型、パラ型)等の有機スルホン酸塩等が例示される。また、有機塩基との塩としては、メチルアミン、トリエチルアミン、トリエタノールアミン、モルホリン、ピペラジン、ピロリジン、トリピリジン、ピコリン等の有機アミンとの塩が例示される。また、無機塩基との塩としては、アンモニウム塩；ナトリウム塩、カリウム塩等のアルカリ金属との塩；カルシウム塩、マグネシウム塩等のアルカリ土類金属との塩；アルミニウム塩等の金属との塩が例示される。これらの中でも、好ましくは酸付加塩、更に好ましくは塩酸塩が挙げられる。これらのレボカバスチンの塩は、１種単独で使用してもよく、また２種以上を任意に組み合わせて使用してもよい。 The salt of levocabastine is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of such salts include acid addition salts, salts with organic bases, salts with inorganic bases, and the like. More specifically, examples of the acid addition salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide and phosphate; monocarboxylate (acetate, trifluoroacetate, Organic acid salts such as butyrate, palmitate, stearate; polyvalent carboxylates such as fumarate, maleate, succinate, malonate; lactate, tartrate, citrate, etc. Examples thereof include organic sulfonates such as methanesulfonate, toluenesulfonate (ortho-type, meta-type, para-type), etc. Examples of salts with organic bases include methylamine and triethylamine. And salts with organic amines such as triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picoline, etc. Examples of salts with inorganic bases include ammonium salts; Examples include salts with alkali metals such as salts, salts with alkaline earth metals such as calcium salts and magnesium salts, salts with metals such as aluminum salts, etc. Among these, acid addition salts are preferable, and more preferable. These salts of levocabastine may be used alone or in any combination of two or more.
本発明の水性医薬組成物には、これらのレボカバスチン及びその塩の中から、一種を選択して単独で使用してもよく、二種以上を任意に組み合わせて使用してもよい。好ましくはレボカバスチンの塩酸塩、即ち塩酸レボカバスチンである。 In the aqueous pharmaceutical composition of the present invention, one of these levocabastine and a salt thereof may be selected and used alone, or two or more may be used in any combination. Levocabastine hydrochloride, that is, levocabastine hydrochloride is preferred.
本発明の水性医薬組成物において、レボカバスチン及び／又はその塩の配合割合は、特に制限されるものではなく、該組成物の用途や製剤形態等に応じて適宜設定できる。水性医薬組成物中のレボカバスチン及び／又はその塩の配合割合の一例として、水性医薬組成物の総量に対し、これらが総量で0.0001〜0.1w/v％、好ましくは0.0005〜0.05w/v％となる割合が例示される。レボカバスチン及び／又はその塩の配合割合として、より具体的には、水性医薬組成物が点眼剤又は点鼻剤の場合は、好ましくは0.006〜0.05w/v％、特に好ましくは0.0125〜0.027w/v％；水性医薬組成物が洗眼剤又は鼻洗浄剤の場合は、好ましくは0.0006〜0.005w/v％、特に好ましくは0.00125〜0.0027w/v％が例示される。このような割合でレボカバスチン及び／又はその塩を含むことによって、その薬理効果及び本発明の効果をより有効に奏させることが可能になる。 In the aqueous pharmaceutical composition of the present invention, the blending ratio of levocabastine and / or a salt thereof is not particularly limited, and can be appropriately set according to the use, formulation form and the like of the composition. As an example of the blending ratio of levocabastine and / or a salt thereof in the aqueous pharmaceutical composition, the total amount of the aqueous pharmaceutical composition is 0.0001 to 0.1 w / v%, preferably 0.0005 to 0.05 w / v%. The ratio is illustrated. More specifically, the blending ratio of levocabastine and / or a salt thereof is preferably 0.006 to 0.05 w / v%, particularly preferably 0.0125 to 0.027 w /% when the aqueous pharmaceutical composition is an eye drop or nasal drop. v%; When the aqueous pharmaceutical composition is an eye wash or a nasal wash, it is preferably 0.0006 to 0.005 w / v%, particularly preferably 0.00125 to 0.0027 w / v%. By including levocabastine and / or a salt thereof in such a ratio, the pharmacological effect and the effect of the present invention can be more effectively exhibited.
また、本発明の水性医薬組成物は、リドカイン及び／又はその塩（以下、単に(B)成分と表記することもある）を含有する。リドカインは、2-ジエチルアミノ-N-(2,6-ジメチルフェニル)アセタミドとも称される公知化合物である。 Further, the aqueous pharmaceutical composition of the present invention contains lidocaine and / or a salt thereof (hereinafter sometimes simply referred to as component (B)). Lidocaine is a known compound also called 2-diethylamino-N- (2,6-dimethylphenyl) acetamide.
リドカインの塩は、医薬上、薬理学的に（製薬上）又は生理学的に許容されることを限度として、特に制限されるものではない。このような塩として、具体的には、酸付加塩、有機塩基との塩、無機塩基との塩等が挙げられる。より具体的には、酸付加塩としては、例えば、塩酸塩、硫酸塩、硝酸塩、臭化水素酸塩、リン酸塩等の無機酸塩；モノカルボン酸塩（酢酸塩、トリフルオロ酢酸塩、酪酸塩、パルミチン酸塩、ステアリン酸塩等の有機酸塩；フマル酸塩、マレイン酸塩、コハク酸塩、マロン酸塩等の多価カルボン酸塩；乳酸塩、酒石酸塩、クエン酸塩等のオキシカルボン酸塩；メタンスルホン酸塩、トルエンスルホン酸塩(オルト型、メタ型、パラ型)等の有機スルホン酸塩等が例示される。また、有機塩基との塩としては、メチルアミン、トリエチルアミン、トリエタノールアミン、モルホリン、ピペラジン、ピロリジン、トリピリジン、ピコリン等の有機アミンとの塩が例示される。また、無機塩基との塩としては、アンモニウム塩；ナトリウム塩、カリウム塩等のアルカリ金属との塩；カルシウム塩、マグネシウム塩等のアルカリ土類金属との塩；アルミニウム塩等の金属との塩が例示される。これらの中でも、好ましくは酸付加塩、更に好ましくは塩酸塩が挙げられる。これらのリドカインの塩は、１種単独で使用してもよく、また２種以上を任意に組み合わせて使用してもよい。 The salt of lidocaine is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of such salts include acid addition salts, salts with organic bases, salts with inorganic bases, and the like. More specifically, examples of the acid addition salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide and phosphate; monocarboxylate (acetate, trifluoroacetate, Organic acid salts such as butyrate, palmitate, stearate; polyvalent carboxylates such as fumarate, maleate, succinate, malonate; lactate, tartrate, citrate, etc. Examples thereof include organic sulfonates such as methanesulfonate, toluenesulfonate (ortho-type, meta-type, para-type), etc. Examples of salts with organic bases include methylamine and triethylamine. And salts with organic amines such as triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picoline, etc. Examples of salts with inorganic bases include ammonium salts; Examples include salts with alkali metals such as salts, salts with alkaline earth metals such as calcium salts and magnesium salts, salts with metals such as aluminum salts, etc. Among these, acid addition salts are preferable, and more preferable. These lidocaine salts may be used alone or in any combination of two or more thereof.
本発明の水性医薬組成物には、これらのリドカイン及びその塩の中から、一種を選択して単独で使用してもよく、二種以上を任意に組み合わせて使用してもよい。好ましくは、リドカイン及びリドカインの塩酸塩（即ち、塩酸リドカイン）である。 In the aqueous pharmaceutical composition of the present invention, one of these lidocaines and salts thereof may be selected and used alone, or two or more may be used in any combination. Lidocaine and hydrochloride of lidocaine (that is, lidocaine hydrochloride) are preferable.
本発明の水性医薬組成物において、リドカイン及び／又はその塩の配合割合は、特に制限されるものではなく、該組成物の用途や製剤形態等に応じて適宜設定できる。水性医薬組成物中のリドカイン及び／又はその塩の配合割合の一例として、これらが総量で0.001〜8w/v％、好ましくは0.005〜4w/v％となる割合が例示される。リドカイン及び／又はその塩の配合割合として、より具体的には、水性医薬組成物が点眼剤又は点鼻剤の場合は、好ましくは0.05〜1w/v％、特に好ましくは0.1〜0.5w/v％；水性医薬組成物が洗眼剤又は鼻洗浄剤の場合は、好ましくは0.005〜0.1w/v％、特に好ましくは0.01〜0.05w/v％が例示される。このような割合でリドカイン及び／又はその塩を含むことによって、レボカバスチン及び／又はその塩の粒子サイズの経時的な増大の抑制効果をより有効に奏させることが可能になる。 In the aqueous pharmaceutical composition of the present invention, the blending ratio of lidocaine and / or a salt thereof is not particularly limited, and can be appropriately set according to the use or formulation form of the composition. As an example of the blending ratio of lidocaine and / or a salt thereof in the aqueous pharmaceutical composition, a ratio in which the total amount is 0.001 to 8 w / v%, preferably 0.005 to 4 w / v% is exemplified. More specifically, the blending ratio of lidocaine and / or a salt thereof is preferably 0.05 to 1 w / v%, particularly preferably 0.1 to 0.5 w / v when the aqueous pharmaceutical composition is an eye drop or nasal drop. %: When the aqueous pharmaceutical composition is an eye wash or nasal wash, it is preferably 0.005 to 0.1 w / v%, particularly preferably 0.01 to 0.05 w / v%. By including lidocaine and / or a salt thereof at such a ratio, it becomes possible to more effectively exhibit the effect of suppressing the increase in the particle size of levocabastine and / or the salt over time.
更に、本発明の水性医薬組成物は、メントール（以下、単に(C)成分と表記することもある）を含有する。本発明で使用されるメントールは、d体、l体、dl体のいずれであってもよいが、好ましくはｌ体である。また、本発明において、(C)成分として、メントールを含有する精油を使用してもよい。このような精油としては、例えば、ハッカ油、クールミント油、スペアミント油、ペパーミント油等が挙げられる。 Furthermore, the aqueous pharmaceutical composition of the present invention contains menthol (hereinafter sometimes simply referred to as component (C)). The menthol used in the present invention may be any of d-form, l-form and dl-form, but is preferably l-form. In the present invention, an essential oil containing menthol may be used as the component (C). Examples of such essential oils include mint oil, cool mint oil, spearmint oil, peppermint oil and the like.
本発明の水性医薬組成物において、メントールの配合割合は、特に制限されるものではなく、該組成物の用途や製剤形態等に応じて適宜設定できる。水性医薬組成物中のメントールの配合割合の一例として、これらが総量で0.00005〜1w/v％、好ましくは0.0001〜0.5w/v％となる割合が例示される。メントールの配合割合として、より具体的には、水性医薬組成物が点眼剤又は点鼻剤の場合は、好ましくは0.0001〜0.5w/v％、特に好ましくは0.0002〜0.05w/v％；水性医薬組成物が洗眼剤又は鼻洗浄剤の場合は、好ましくは0.0001〜0.1w/v％、特に好ましくは0.0002〜0.01w/v％が例示される。このような割合でメントールを含むことによって、レボカバスチン及び／又はその塩の粒子サイズの経時的な増大の抑制効果が一層顕著になる。なお、(C)成分として、メントールを含む精油を使用する場合は、当該精油の配合割合は、配合される精油中のメントール含有量が上記割合を満たすように設定される。 In the aqueous pharmaceutical composition of the present invention, the blending ratio of menthol is not particularly limited, and can be appropriately set according to the use or formulation form of the composition. As an example of the blending ratio of menthol in the aqueous pharmaceutical composition, a ratio in which the total amount is 0.00005 to 1 w / v%, preferably 0.0001 to 0.5 w / v% is exemplified. More specifically, the menthol content is preferably 0.0001 to 0.5 w / v%, particularly preferably 0.0002 to 0.05 w / v% when the aqueous pharmaceutical composition is eye drops or nasal drops; When the composition is an eye wash or a nasal wash, it is preferably 0.0001 to 0.1 w / v%, particularly preferably 0.0002 to 0.01 w / v%. By including menthol at such a ratio, the effect of suppressing the increase in the particle size of levocabastine and / or its salt over time becomes even more remarkable. In addition, when using the essential oil containing menthol as (C) component, the mixture ratio of the said essential oil is set so that the menthol content in the essential oil mix | blended may satisfy | fill the said ratio.
本発明の水性医薬組成物において、上記(A)〜(C)成分の比率については、特に制限されないが、以下の範囲を充足することによって、レボカバスチン及び／又はその塩の粒子サイズの経時的な増大の抑制効果をより一層顕著ならしめることができる：
(A)成分の総量100重量部に対して、(B)成分が総量で18〜16000重量部、且つ(C)成分が総量で0.1〜3800重量部；好ましくは(B)成分が総量で185〜4000重量部、且つ(C)成分が総量で0.3〜1900重量部；更に好ましくは(B)成分が総量で370〜2000重量部、且つ(C)成分が総量で0.7〜200重量部。
In the aqueous pharmaceutical composition of the present invention, the ratio of the components (A) to (C) is not particularly limited, but by satisfying the following range, the particle size of levocabastine and / or a salt thereof over time is increased. The suppression effect of the increase can be made even more pronounced:
The total amount of component (A) is 100 parts by weight, and the total amount of component (B) is 18 to 16000 parts by weight, and the total amount of component (C) is 0.1 to 3800 parts by weight; preferably the total amount of component (B) is 185 ~ 4000 parts by weight, and (C) component is 0.3 to 1900 parts by weight in total; more preferably (B) is 370 to 2000 parts by weight in total, and (C) is 0.7 to 200 parts by weight in total.
本発明の水性医薬組成物は、上記(A)〜(C)成分に加えて、粘稠剤を含むことが好ましい。本発明の水性医薬組成物に配合できる粘稠剤としては、医薬上、薬理学的に（製薬上）又は生理学的に許容されるものであれば、特に制限されない。このような粘稠剤の具体例としては、ヒドロキシプロピルメチルセルロース、エチルセルロース、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、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、カルボキシエチルセルロース、ニトロセルロース等のセルロース系増粘剤；アラビアゴム、カラヤガム、キサンタンガム、キャロブガム、グアーガム、ダルマンガム、トラガントガム、ベンゾインゴム、ローカストビーンガム、カゼイン、寒天、アルギン酸、カラギーナン、ゼラチン、ペクチン、ポリビニルアルコール(完全又は部分ケン化物)、ポリビニルピロリドン、カルボキシビニルポリマー等が例示される。これらの中でも、レボカバスチン及び／又はその塩の粒子サイズの経時的な増大の抑制をより一層有効に獲得させるという観点から、好ましくはセルロース系増粘剤、特に好ましくはヒドロキシプロピルメチルセルロースである。本発明に使用されるヒドロキシプロピルメチルセルロースについては、その種類は特に制限されないが、例えば、ヒドロキシプロピルメチルセルロース２２０８、ヒドロキシプロピルメチルセルロース２９０６、ヒドロキシプロピルメチルセルロース２９１０などが挙げられる。特に好ましくは、ヒドロキシプロピルメチルセルロース２９０６、ヒドロキシプロピルメチルセルロース２９１０等が挙げられる。上記粘稠剤は、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 The aqueous pharmaceutical composition of the present invention preferably contains a thickener in addition to the components (A) to (C). The viscous agent that can be blended in the aqueous pharmaceutical composition of the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of such thickeners include cellulose thickeners such as hydroxypropylmethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, carboxyethylcellulose, nitrocellulose, etc. Gum arabic, karaya gum, xanthan gum, carob gum, guar gum, dalman gum, tragacanth gum, benzoin gum, locust bean gum, casein, agar, alginic acid, carrageenan, gelatin, pectin, polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone, carboxyvinyl Examples thereof include polymers. Among these, a cellulosic thickener is preferable, and hydroxypropylmethylcellulose is particularly preferable from the viewpoint of more effectively obtaining suppression of increase in the particle size of levocabastine and / or a salt thereof with time. The type of hydroxypropylmethylcellulose used in the present invention is not particularly limited, and examples thereof include hydroxypropylmethylcellulose 2208, hydroxypropylmethylcellulose 2906, and hydroxypropylmethylcellulose 2910. Particularly preferred are hydroxypropylmethylcellulose 2906, hydroxypropylmethylcellulose 2910 and the like. The said thickener may be used individually by 1 type, and may be used in combination of 2 or more type.
本発明の水性医薬組成物に粘稠剤を配合する場合、該粘稠剤の配合割合については、使用する粘稠剤の種類や期待される効果等に応じて適宜設定できる。水性医薬組成物中の粘稠剤の配合割合の一例として、これらが総量で0.0001〜3w/v％、好ましくは0.0005〜1w/v％となる割合が例示される。粘稠剤の配合割合として、より具体的には、水性医薬組成物が点眼剤又は点鼻剤の場合は、好ましくは0.001〜0.35w/v％、特に好ましくは0.0025〜0.3w/v％；水性医薬組成物が洗眼剤又は鼻洗浄剤の場合は、好ましくは0.001〜0.35w/v％、特に好ましくは0.0025〜0.3w/v％が例示される。このような割合で粘稠剤（好ましくはセルロース系増粘剤、特に好ましくはヒドロキシプロピルメチルセルロース）を含むことによって、より効果的なレボカバスチン及び／又はその塩の粒子サイズの増大抑制が可能になる。 When a thickener is blended in the aqueous pharmaceutical composition of the present invention, the blending ratio of the thickener can be appropriately set according to the type of the thickener used, the expected effect, and the like. As an example of the blending ratio of the viscous agent in the aqueous pharmaceutical composition, a ratio in which the total amount is 0.0001 to 3 w / v%, preferably 0.0005 to 1 w / v% is exemplified. More specifically, when the aqueous pharmaceutical composition is an eye drop or nasal drop, the blending ratio of the viscous agent is preferably 0.001 to 0.35 w / v%, particularly preferably 0.0025 to 0.3 w / v%; When the aqueous pharmaceutical composition is an eye wash or nasal wash, it is preferably 0.001 to 0.35 w / v%, particularly preferably 0.0025 to 0.3 w / v%. By containing a thickener (preferably a cellulosic thickener, particularly preferably hydroxypropylmethylcellulose) at such a ratio, it becomes possible to more effectively suppress the increase in the particle size of levocabastine and / or a salt thereof.
また、粘稠剤を配合する場合、一層効果的にレボカバスチン及び／又はその塩の粒子サイズの増大を抑制するという観点から、上記(A)成分に対する粘稠剤の比率として以下の範囲を充足していることが望ましい：(A)成分100重量部当たり、粘稠剤が1.85〜4000重量部、好ましくは3.5〜1400重量部、更に好ましくは9〜930重量部。 In addition, when blending a thickener, the following range is satisfied as the ratio of the thickener to the component (A) from the viewpoint of more effectively suppressing the increase in the particle size of levocabastine and / or its salt. It is desirable that the thickener is 1.85 to 4000 parts by weight, preferably 3.5 to 1400 parts by weight, more preferably 9 to 930 parts by weight per 100 parts by weight of component (A).
本発明の水性医薬組成物は、上記成分に加えて、更に緩衝剤を含有することができる。本発明の水性医薬組成物に配合できる緩衝剤としては、医薬上、薬理学的に（製薬上）又は生理学的に許容されるものであれば、特に制限されない。かかる緩衝剤の一例として、ホウ酸緩衝剤、リン酸緩衝剤、炭酸緩衝剤、クエン酸緩衝剤、酢酸緩衝剤、ε−アミノカプロン酸、アスパラギン酸、アスパラギン酸塩などが挙げられる。これらの緩衝剤は１種単独で使用してもよく、また２種以上を任意に組み合わせて使用してもよい。上記緩衝剤の中でも、ホウ酸緩衝液及びリン酸緩衝液は好適である。 In addition to the above components, the aqueous pharmaceutical composition of the present invention can further contain a buffer. The buffer that can be incorporated into the aqueous pharmaceutical composition of the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of such buffers include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, ε-aminocaproic acid, aspartic acid, aspartate and the like. These buffering agents may be used alone or in any combination of two or more. Among the above buffering agents, borate buffer and phosphate buffer are suitable.
本発明の水性医薬組成物に緩衝剤を配合する場合、該緩衝剤の配合割合については、使用する緩衝剤の種類や期待される効果等に応じて異なり、一律に規定することはできないが、例えば、水性医薬組成物において、該緩衝剤が総量で0.01〜5w/v％、好ましくは0.1〜4w/v％、更に好ましくは0.3〜3w/v％となる割合が例示される。 When blending a buffering agent in the aqueous pharmaceutical composition of the present invention, the blending ratio of the buffering agent differs depending on the type of buffering agent used and expected effects, etc., and cannot be defined uniformly, For example, in the aqueous pharmaceutical composition, the ratio of the buffering agent in the total amount is 0.01 to 5 w / v%, preferably 0.1 to 4 w / v%, more preferably 0.3 to 3 w / v%.
また、本発明の水性医薬組成物は、配合成分の化学的安定性が著しく損なわれない範囲で、生体に許容される範囲内のｐＨに調節することができる。適切なｐＨは、該水性医薬組成物の適用部位、製剤形態等により異なるが、通常6〜9、好ましくは6.5〜8.5、更に好ましくは6.8〜8.2、特に好ましくは7〜8である。ｐＨの調節は、前記緩衝剤、或いは当該技術分野で通常使用されているｐＨ調整剤、等張化剤、塩類等を用いて、当該技術分野で既知の方法で行うことができる。 In addition, the aqueous pharmaceutical composition of the present invention can be adjusted to a pH within the range acceptable to the living body within the range where the chemical stability of the compounding components is not significantly impaired. The appropriate pH varies depending on the application site, formulation form and the like of the aqueous pharmaceutical composition, but is usually 6 to 9, preferably 6.5 to 8.5, more preferably 6.8 to 8.2, and particularly preferably 7 to 8. The pH can be adjusted by a method known in the art using the buffer, a pH adjuster, an isotonic agent, a salt or the like usually used in the art.
本発明の水性医薬組成物は、更に必要に応じて、生体に許容される範囲内の浸透圧比に調節することができる。適切な浸透圧比は適用部位、製剤形態等により異なるが、通常0.3〜4.2、好ましくは0.5〜4.0、更に好ましくは0.8〜3.8である。浸透圧の調整は無機塩、多価アルコール、糖アルコール、糖類などを用いて、当該技術分野で既知の方法で行うことができる。浸透圧比は、第十五改正日本薬局方を参考にして0.9w/v％塩化ナトリウム水溶液の浸透圧に対する試料の浸透圧の比とし、浸透圧は日本薬局方記載の浸透圧測定法（氷点降下法）を参考にして測定する。浸透圧比測定用標準液は、塩化ナトリウム（日本薬局方標準試薬）を500〜650℃で40〜50分間乾燥した後、デシケーター（シリカゲル）中で放冷し、その0.900ｇを正確に量り、精製水に溶かし正確に100ｍＬとして調製するか、市販の浸透圧比測定用標準液（0.9w/v％塩化ナトリウム水溶液）を用いる。 If necessary, the aqueous pharmaceutical composition of the present invention can be adjusted to an osmotic pressure ratio within a range acceptable to the living body. The appropriate osmotic pressure ratio varies depending on the application site, formulation form, etc., but is usually 0.3 to 4.2, preferably 0.5 to 4.0, and more preferably 0.8 to 3.8. The adjustment of the osmotic pressure can be performed by a method known in the art using inorganic salts, polyhydric alcohols, sugar alcohols, saccharides and the like. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to the osmotic pressure of the 0.9 w / v% sodium chloride aqueous solution with reference to the 15th revised Japanese Pharmacopoeia. Method). The standard solution for measuring the osmotic pressure ratio was sodium chloride (Japanese Pharmacopoeia standard reagent) dried at 500-650 ° C for 40-50 minutes, and then allowed to cool in a desiccator (silica gel). Dissolve in water to make exactly 100 mL, or use a commercially available standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution).
本発明の水性医薬組成物は、本発明の効果を妨げない限り、上記成分の他に、種々の薬理活性成分や生理活性成分を組み合わせて適当量含有してもよい。かかる成分は特に制限されず、例えば、一般用医薬品製造（輸入）承認基準２０００年版（薬事審査研究会監修）に記載された各種医薬における有効成分が例示できる。具体的に、眼科用薬又は耳鼻科用薬において用いられる成分としては、次のような成分が挙げられる。 The aqueous pharmaceutical composition of the present invention may contain an appropriate amount of various pharmacologically active ingredients and physiologically active ingredients in addition to the above-mentioned ingredients as long as the effects of the present invention are not hindered. Such an ingredient is not particularly limited, and examples thereof include active ingredients in various pharmaceuticals described in the over-the-counter drug manufacturing (import) approval standard 2000 edition (supervised by the Pharmaceutical Affairs Research Committee). Specifically, the following components may be mentioned as components used in ophthalmic drugs or otolaryngological drugs.
エピネフリン、塩酸エピネフリン、塩酸エフェドリン、塩酸テトラヒドロゾリン、塩酸ナファゾリン、硝酸ナファゾリン、塩酸フェニレフリン、dl-塩酸メチルエフェドリン、硝酸テトラヒドロゾリン、メチル硫酸ネオスチグミン、硫酸亜鉛、乳酸亜鉛、アラントイン、プラノプロフェン、ε−アミノカプロン酸、塩化リゾチーム、アズレンスルホン酸ナトリウム、グリチルリチン酸二カリウム、サリチル酸メチル、塩化ベルベリン、硫酸ベルベリン、塩酸イプロヘプチン、塩酸ジフェンヒドラミン、ジフェンヒドラミン、マレイン酸クロルフェニラミン、酢酸レチノール、パルミチン酸レチノール、塩酸ピリドキシン、フラビンアデニンジヌクレオチドナトリウム、シアノコバラミン、パンテノール、パントテン酸カルシウム、パントテン酸ナトリウム、酢酸トコフェロール、アミノエチルスルホン酸（タウリン）、アスパラギン酸カリウム、アスパラギン酸マグネシウム、アスパラギン酸マグネシウム・カリウム混合物、スルファメトキサゾール、スルファイソキサゾール、スルファメトキサゾールナトリウム、スルファイソミジンナトリウム、グルコース、ヒアルロン酸ナトリウム、コンドロイチン硫酸ナトリウム、アクリノール、塩化セチルピリジニウム、ポリビニルアルコール（完全又は部分ケン化物）、ポリビニルピロリドン等。 Epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline nitrate, phenylephrine hydrochloride, dl-methylephedrine hydrochloride, tetrahydrozoline nitrate, neostigmine methyl sulfate, zinc sulfate, zinc lactate, allantoin, pranoprofen, ε-aminocaproic acid, Lysozyme chloride, sodium azulenesulfonate, dipotassium glycyrrhizinate, methyl salicylate, berberine chloride, berberine sulfate, iproheptin hydrochloride, diphenhydramine hydrochloride, diphenhydramine, chlorpheniramine maleate, retinol acetate, retinol palmitate, pyridoxine hydrochloride, flavin adenine dinucleotide Sodium, cyanocobalamin, panthenol, calcium pantothenate, pantothenic acid Thorium, tocopherol acetate, aminoethylsulfonic acid (taurine), potassium aspartate, magnesium aspartate, magnesium aspartate / potassium mixture, sulfamethoxazole, sulfaisoxazole, sulfamethoxazole sodium, sulfaiso Midine sodium, glucose, sodium hyaluronate, sodium chondroitin sulfate, acrinol, cetylpyridinium chloride, polyvinyl alcohol (completely or partially saponified), polyvinylpyrrolidone and the like.
また、本発明の水性医薬組成物には、発明の効果を損なわない範囲であれば、その用途や製剤形態に応じて、常法に従い、様々な添加物を適宜選択し、一種またはそれ以上を併用して適当量含有させてもよい。それらの添加物として、例えば、医薬品添加物事典２００５（日本医薬品添加剤協会編集）に記載された各種添加物が例示できる。代表的な成分として次の添加物が挙げられる。 In addition, in the aqueous pharmaceutical composition of the present invention, various additives are appropriately selected according to conventional methods according to the use and formulation form within a range that does not impair the effects of the invention, and one or more of them are selected. An appropriate amount may be contained in combination. Examples of such additives include various additives described in Pharmaceutical Additives Encyclopedia 2005 (edited by Japan Pharmaceutical Additives Association). Typical additives include the following additives.
マクロゴール、ポロクサマー、ポロキサミン、ポリソルベート８０、ポリオキシエチレン(60)硬化ヒマシ油、アルキルジアミノエチルグリシン、塩化ベンザルコニウム、塩化ベンゼトニウム、パラベン類、ソルビン酸、ソルビン酸カリウム、ポリヘキサメチレンビグアニド、塩化カリウム、塩化ナトリウム、塩化カルシウム、硫酸マグネシウム、グリセリン、プロピレングリコール、カンフル、ゲラニオール、ボルネオール、ウイキョウ油、ベルガモット油、ユーカリ油、ローズ油、エデト酸ナトリウム、塩化ベンゼトニウム、クエン酸、トロメタモール、グルコン酸クロルヘキシジン、クロロブタノール、酢酸ナトリウム、酢酸、炭酸水素ナトリウム、炭酸ナトリウム等。 Macrogol, poloxamer, poloxamine, polysorbate 80, polyoxyethylene (60) hydrogenated castor oil, alkyldiaminoethylglycine, benzalkonium chloride, benzethonium chloride, parabens, sorbic acid, potassium sorbate, polyhexamethylene biguanide, potassium chloride , Sodium chloride, calcium chloride, magnesium sulfate, glycerin, propylene glycol, camphor, geraniol, borneol, fennel oil, bergamot oil, eucalyptus oil, rose oil, sodium edetate, benzethonium chloride, citric acid, trometamol, chlorhexidine gluconate, chloro Butanol, sodium acetate, acetic acid, sodium bicarbonate, sodium carbonate, etc.
本発明の水性医薬組成物は、液状であり、流動性があるため粘膜に適用し易くなっている。水を50w/v％以上含む従来の水性組成物では、レボカバスチン及び／又はその塩は、保存時間の経過に伴って粒子サイズが増大することによって、生物学的利用率や分散安定性等に悪影響を及ぼす可能性があるが、本発明の水性医薬組成物では、水を50w/v％以上含む液状でありながら、かかる欠点が解消されている。 The aqueous pharmaceutical composition of the present invention is liquid and has fluidity, so that it can be easily applied to mucous membranes. In conventional aqueous compositions containing 50% w / v water or more, levocabastine and / or its salt adversely affects bioavailability, dispersion stability, etc. due to increased particle size over the course of storage time. However, in the aqueous pharmaceutical composition of the present invention, such a drawback is solved while it is a liquid containing 50 w / v% or more of water.
本発明の水性医薬組成物は、上記(A)〜(C)成分に基づく有用作用を発現できるため、医薬品や医薬部外品等の製剤として使用される。本発明の水性医薬組成物の製剤形態としては、具体的には、点眼剤（但し、点眼剤にはコンタクトレンズ装用中に点眼可能な点眼剤を含む）、洗眼剤（但し、洗眼剤にはコンタクトレンズ装用中に洗眼可能な洗眼剤を含む）等の眼科用組成物；点鼻剤、鼻洗浄液、点耳剤等の耳鼻科用組成物；コンタクトレンズケア用剤（コンタクトレンズ消毒剤、コンタクトレンズ用保存剤、コンタクトレンズ用洗浄剤、コンタクトレンズ用洗浄保存剤）等のコンタクトレンズ用組成物；口腔咽頭薬、含嗽薬（含嗽用剤）等の口腔用組成物等が挙げられる。これらの製剤形態の中でも、好ましくは眼科用組成物、耳鼻科用組成物等の粘膜適用組成物であり、更に好ましくは点眼剤又は点鼻剤である。 Since the aqueous pharmaceutical composition of the present invention can exhibit useful effects based on the above components (A) to (C), it is used as a pharmaceutical or quasi-drug preparation. Specifically, the aqueous pharmaceutical composition of the present invention includes eye drops (however, eye drops include eye drops that can be applied while wearing contact lenses), eye wash (however, for eye wash) Ophthalmic compositions such as eyewashes that can be washed while wearing contact lenses; otolaryngological compositions such as nasal drops, nasal rinses, and ear drops; contact lens care agents (contact lens disinfectants, contacts) Examples include contact lens compositions such as lens preservatives, contact lens cleaners, and contact lens cleaner preservatives; and oral compositions such as oropharyngeal drugs and gargles (mouth rinses). Among these preparation forms, preferred are mucosa-applied compositions such as ophthalmic compositions and otolaryngological compositions, and more preferred are eye drops or nasal drops.
なお、上記コンタクトレンズ用組成物は、ハードコンタクトレンズ又はソフトコンタクトレンズの別を問わず、あらゆるタイプのコンタクトレンズに適用できる。 In addition, the said composition for contact lenses can be applied to all types of contact lenses, regardless of whether they are hard contact lenses or soft contact lenses.
本発明の水性医薬組成物は、レボカバスチン及び／又はその塩の作用に基づく各種医薬用途、例えばアレルギー症状の予防乃至緩和用組成物として有用である。また、本発明の水性医薬組成物は、眼のかゆみ、結膜充血、鼻づまり、鼻汁過多、くしゃみ、頭重等の症状の改善用組成物としても有用である。従って、本発明の水性医薬組成物は、鼻炎症状の治療又は緩和用組成物としても使用できる。 The aqueous pharmaceutical composition of the present invention is useful for various pharmaceutical uses based on the action of levocabastine and / or a salt thereof, for example, a composition for preventing or alleviating allergic symptoms. The aqueous pharmaceutical composition of the present invention is also useful as a composition for improving symptoms such as eye itchiness, conjunctival congestion, nasal congestion, excessive nasal discharge, sneezing, and head weight. Therefore, the aqueous pharmaceutical composition of the present invention can also be used as a composition for treating or alleviating nasal inflammation.
本発明の水性医薬組成物は、精製水を基剤として使用し、上記配合成分の所定量を添加、混合し、目的とする製剤形態に応じて製剤化することにより製造できる。 The aqueous pharmaceutical composition of the present invention can be produced by using purified water as a base, adding and mixing predetermined amounts of the above-mentioned blending components, and formulating it according to the intended formulation form.
(II) レボカバスチン及び／又はその塩の粒子サイズの安定化方法
前述するように、水性医薬組成物中で、レボカバスチン及び／又はその塩、リドカイン及び／又はその塩、並びにメントールを共存させることによって、水性医薬組成物においてレボカバスチン及び／又はその塩の粒子サイズの増大抑制を図ることができる。従って、本発明は、レボカバスチン及び／又はその塩を含有する水性医薬組成物中で、(B)リドカイン及び／又はその塩、及び(C)メントールを共存させることを特徴とする、レボカバスチン及び／又はその塩の粒子サイズの安定化方法（増大抑制方法）を提供する。
(II) Method for stabilizing particle size of levocabastine and / or salt thereof As described above, by coexisting levocabastine and / or salt thereof, lidocaine and / or salt thereof, and menthol in an aqueous pharmaceutical composition, In the aqueous pharmaceutical composition, increase in the particle size of levocabastine and / or a salt thereof can be suppressed. Therefore, the present invention provides levocabastine and / or a pharmaceutical composition comprising (B) lidocaine and / or a salt thereof and (C) menthol in an aqueous pharmaceutical composition containing levocabastine and / or a salt thereof. A method for stabilizing the particle size of the salt (a method for suppressing increase) is provided.
当該方法において、使用するレボカバスチン及び／又はその塩の種類や濃度、リドカイン及び／又はその塩の種類や濃度、メントールの種類や濃度、その他の配合成分の種類や濃度、水性医薬組成物の製剤形態や用途等については、前記「(I)水性医薬組成物」の欄に記載の通りである。 In this method, the type and concentration of levocabastine and / or its salt to be used, the type and concentration of lidocaine and / or its salt, the type and concentration of menthol, the type and concentration of other ingredients, and the formulation of the aqueous pharmaceutical composition The use and the like are as described in the column “(I) Aqueous pharmaceutical composition”.
以下に、実施例、試験例等に基づいて本発明を詳細に説明するが、本発明はこれらによって限定されるものではない。 Hereinafter, the present invention will be described in detail based on examples, test examples, and the like, but the present invention is not limited thereto.
試験例１ 塩酸レボカバスチンの粒子サイズの安定性の評価
表１に示す組成の水性医薬組成物(実施例１及び比較例１−３)を調製し、それぞれを10mL容量ガラススクリューバイアルに5mLずつ充填し、50℃で１週間保存した。
Test Example 1 Evaluation of Stability of Particle Size of Levocabastine Hydrochloride Aqueous pharmaceutical compositions (Example 1 and Comparative Example 1-3) having the composition shown in Table 1 were prepared, and 5 mL each was filled into a 10 mL glass screw vial. And stored at 50 ° C. for 1 week.
結果を図１に示す。この結果から、塩酸レボカバスチン単独（比較例１）、及び塩酸レボカバスチンとメントールの併用（比較例３）では、保存後の粒子サイズの増大が認められた。また、塩酸レボカバスチンと塩酸リドカインの併用（比較例２）では、保存後の粒子サイズの増大が顕著になる傾向が認められた。これに対して、塩酸レボカバスチン、塩酸リドカイン及びメントールを併用すると（実施例１）、驚くべきことに、保存後の粒子サイズが増大することなく、安定に保持されていることが確認された。 The results are shown in FIG. From this result, an increase in the particle size after storage was observed in the case of levocabastine hydrochloride alone (Comparative Example 1) and the combination of levocabastine hydrochloride and menthol (Comparative Example 3). In addition, in the combined use of levocabastine hydrochloride and lidocaine hydrochloride (Comparative Example 2), an increase in the particle size after storage was observed to be remarkable. On the other hand, when levocabastine hydrochloride, lidocaine hydrochloride and menthol were used in combination (Example 1), it was surprisingly confirmed that the particle size after storage was stably maintained without increasing.
なお、通常、医薬品には、25℃で3年間は安定性を保つことが必要とされており、その安定性は50℃で2ヶ月の過酷保存条件に相当すると考えられている。一方、本試験で採用した過酷保存条件は、50℃で１週間であり、通常の医薬品の安定性の評価条件よりは緩やかであるといえる。このような穏やかな条件であるにも拘わらず、実施例１と比較例１−３では粒子サイズの変化に明らかな差が認められたことから、実際に医薬品として流通させた場合、実施例１と比較例１−３では粒子サイズの変化の差は、極めて顕著になると予想される。 In general, pharmaceutical products are required to maintain stability at 25 ° C for 3 years, and the stability is considered to correspond to harsh storage conditions at 50 ° C for 2 months. On the other hand, the harsh storage conditions employed in this study are one week at 50 ° C., which can be said to be milder than the usual conditions for evaluating the stability of pharmaceutical products. In spite of such mild conditions, there was a clear difference in the change in particle size between Example 1 and Comparative Example 1-3. In Comparative Example 1-3, the difference in particle size change is expected to be extremely significant.
製剤例
表２及び３に記載の処方で、点眼剤（実施例２−１２）及び点鼻剤（実施例１３−２３）を調製した。
Formulation Examples Eye drops (Example 2-12) and nasal drops (Examples 13-23) were prepared according to the formulations shown in Tables 2 and 3.
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| JP2011093891A (en) * | 2009-09-30 | 2011-05-12 | Rohto Pharmaceutical Co Ltd | Composition for ophthalmology |
| JP2011148791A (en) * | 2009-12-25 | 2011-08-04 | Rohto Pharmaceutical Co Ltd | Ophthalmologic composition for silicone hydrogel contact lens |
| JP2014211652A (en) * | 2009-12-25 | 2014-11-13 | ロート製薬株式会社 | Ophthalmic composition for silicone hydrogel contact lens |
| JP2015107993A (en) * | 2009-12-25 | 2015-06-11 | ロート製薬株式会社 | Ophthalmic composition for silicone hydrogel contact lens |
| JP2021157197A (en) * | 2009-12-25 | 2021-10-07 | ロート製薬株式会社 | Ophthalmic compositions for silicone hydrogel contact lenses |
| JP2015508807A (en) * | 2012-02-28 | 2015-03-23 | アンテクＡｍｍｔｅｋ | Liquid preparation of hypoglycemic sulfonamide |
| US11110059B2 (en) | 2012-02-28 | 2021-09-07 | Ammtek | Liquid formulations of hypoglycaemic sulfonamides |
| US11911505B2 (en) | 2012-02-28 | 2024-02-27 | Ammtek | Liquid formulations of hypoglycaemic sulfonamides |
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