JP2022090090A - Pharmaceutical (4) - Google Patents
Pharmaceutical (4) Download PDFInfo
- Publication number
- JP2022090090A JP2022090090A JP2022071540A JP2022071540A JP2022090090A JP 2022090090 A JP2022090090 A JP 2022090090A JP 2022071540 A JP2022071540 A JP 2022071540A JP 2022071540 A JP2022071540 A JP 2022071540A JP 2022090090 A JP2022090090 A JP 2022090090A
- Authority
- JP
- Japan
- Prior art keywords
- salt
- aqueous composition
- container
- acid
- sodium
- 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
Links
- 150000003839 salts Chemical class 0.000 abstract description 64
- 239000000203 mixture Substances 0.000 abstract description 52
- 239000012453 solvate Substances 0.000 abstract description 27
- 229920001225 polyester resin Polymers 0.000 abstract description 25
- 150000001875 compounds Chemical class 0.000 abstract description 23
- 239000013078 crystal Substances 0.000 abstract description 18
- 238000000034 method Methods 0.000 abstract description 15
- 208000010412 Glaucoma Diseases 0.000 abstract description 12
- 201000010099 disease Diseases 0.000 abstract description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 8
- 238000003860 storage Methods 0.000 abstract description 7
- 125000005843 halogen group Chemical group 0.000 abstract description 5
- 206010030043 Ocular hypertension Diseases 0.000 abstract description 3
- 230000002401 inhibitory effect Effects 0.000 abstract description 3
- 230000008021 deposition Effects 0.000 abstract 1
- 125000002183 isoquinolinyl group Chemical class C1(=NC=CC2=CC=CC=C12)* 0.000 abstract 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- 235000002639 sodium chloride Nutrition 0.000 description 67
- -1 polyethylene terephthalate Polymers 0.000 description 32
- 239000000825 pharmaceutical preparation Substances 0.000 description 19
- 239000002904 solvent Substances 0.000 description 16
- 238000001556 precipitation Methods 0.000 description 15
- QSKQVZWVLOIIEV-NSHDSACASA-N ripasudil Chemical compound C[C@H]1CNCCCN1S(=O)(=O)C1=CC=CC2=CN=CC(F)=C12 QSKQVZWVLOIIEV-NSHDSACASA-N 0.000 description 15
- 239000004645 polyester resin Substances 0.000 description 14
- 229920000139 polyethylene terephthalate Polymers 0.000 description 13
- 239000005020 polyethylene terephthalate Substances 0.000 description 13
- 229950007455 ripasudil Drugs 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 239000000243 solution Substances 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- 239000003889 eye drop Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 239000006096 absorbing agent Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 150000002537 isoquinolines Chemical class 0.000 description 6
- 230000000938 luteal effect Effects 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000007796 conventional method Methods 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 5
- 235000019799 monosodium phosphate Nutrition 0.000 description 5
- 230000000144 pharmacologic effect Effects 0.000 description 5
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 5
- OJUADEYTZGIMIV-NSHDSACASA-N 4-bromo-5-[[(2s)-2-methyl-1,4-diazepan-1-yl]sulfonyl]isoquinoline Chemical compound C[C@H]1CNCCCN1S(=O)(=O)C1=CC=CC2=CN=CC(Br)=C12 OJUADEYTZGIMIV-NSHDSACASA-N 0.000 description 4
- FMRHJJZUHUTGKE-UHFFFAOYSA-N Ethylhexyl salicylate Chemical compound CCCCC(CC)COC(=O)C1=CC=CC=C1O FMRHJJZUHUTGKE-UHFFFAOYSA-N 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 229940012356 eye drops Drugs 0.000 description 4
- 235000011187 glycerol Nutrition 0.000 description 4
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 4
- 229920000728 polyester Polymers 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
- 239000003087 receptor blocking agent Substances 0.000 description 4
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- 239000011347 resin Substances 0.000 description 4
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 3
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 description 3
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- 229940124186 Dehydrogenase inhibitor Drugs 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- OMCPLEZZPVJJIS-UHFFFAOYSA-N Hypadil (TN) Chemical compound C1C(O[N+]([O-])=O)COC2=C1C=CC=C2OCC(O)CNC(C)C OMCPLEZZPVJJIS-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 239000003732 agents acting on the eye Substances 0.000 description 3
- 239000002876 beta blocker Substances 0.000 description 3
- 229940097320 beta blocking agent Drugs 0.000 description 3
- 229960000722 brinzolamide Drugs 0.000 description 3
- HCRKCZRJWPKOAR-JTQLQIEISA-N brinzolamide Chemical compound CCN[C@H]1CN(CCCOC)S(=O)(=O)C2=C1C=C(S(N)(=O)=O)S2 HCRKCZRJWPKOAR-JTQLQIEISA-N 0.000 description 3
- 229930016911 cinnamic acid Natural products 0.000 description 3
- 235000013985 cinnamic acid Nutrition 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
- 230000007850 degeneration Effects 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 229960003933 dorzolamide Drugs 0.000 description 3
- IAVUPMFITXYVAF-XPUUQOCRSA-N dorzolamide Chemical compound CCN[C@H]1C[C@H](C)S(=O)(=O)C2=C1C=C(S(N)(=O)=O)S2 IAVUPMFITXYVAF-XPUUQOCRSA-N 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- GGXICVAJURFBLW-CEYXHVGTSA-N latanoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@@H](O)CCC1=CC=CC=C1 GGXICVAJURFBLW-CEYXHVGTSA-N 0.000 description 3
- 229960001160 latanoprost Drugs 0.000 description 3
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 3
- 229950000754 nipradilol Drugs 0.000 description 3
- 229940125702 ophthalmic agent Drugs 0.000 description 3
- 239000000734 parasympathomimetic agent Substances 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 238000006116 polymerization reaction Methods 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 150000003169 prostaglandin F2α derivatives Chemical class 0.000 description 3
- 208000004644 retinal vein occlusion Diseases 0.000 description 3
- 229940127230 sympathomimetic drug Drugs 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- 229960004605 timolol Drugs 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 2
- WMFHUUKYIUOHRA-UHFFFAOYSA-N (3-phenoxyphenyl)methanamine;hydrochloride Chemical compound Cl.NCC1=CC=CC(OC=2C=CC=CC=2)=C1 WMFHUUKYIUOHRA-UHFFFAOYSA-N 0.000 description 2
- 229930182837 (R)-adrenaline Natural products 0.000 description 2
- ZMWRRFHBXARRRT-UHFFFAOYSA-N 2-(benzotriazol-2-yl)-4,6-bis(2-methylbutan-2-yl)phenol Chemical compound CCC(C)(C)C1=CC(C(C)(C)CC)=CC(N2N=C3C=CC=CC3=N2)=C1O ZMWRRFHBXARRRT-UHFFFAOYSA-N 0.000 description 2
- IYAZLDLPUNDVAG-UHFFFAOYSA-N 2-(benzotriazol-2-yl)-4-(2,4,4-trimethylpentan-2-yl)phenol Chemical compound CC(C)(C)CC(C)(C)C1=CC=C(O)C(N2N=C3C=CC=CC3=N2)=C1 IYAZLDLPUNDVAG-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
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- CMDJNMACGABCKQ-XVSRHIFFSA-N 4-fluoro-5-[[(2s)-2-methyl-1,4-diazepan-1-yl]sulfonyl]isoquinoline;dihydrate;hydrochloride Chemical compound O.O.Cl.C[C@H]1CNCCCN1S(=O)(=O)C1=CC=CC2=CN=CC(F)=C12 CMDJNMACGABCKQ-XVSRHIFFSA-N 0.000 description 2
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- 239000004359 castor oil Substances 0.000 description 2
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- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
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Abstract
Description
本発明は、医薬製剤等に関する。 The present invention relates to pharmaceutical preparations and the like.
以下の構造式: The following structural formula:
で表されるリパスジル(化学名:4-フルオロ-5-[[(2S)-2-メチル-1,4-ジアゼパン-1-イル]スルホニル]イソキノリン)や、以下の構造式: Ripasudil (chemical name: 4-fluoro-5-[[(2S) -2-methyl-1,4-diazepan-1-yl] sulfonyl] isoquinoline) and the following structural formula:
で表される4-ブロモ-5-[[(2S)-2-メチル-1,4-ジアゼパン-1-イル]スルホニル]イソキノリンなどのハロゲン化イソキノリン誘導体は、Rhoキナーゼ阻害作用等の薬理作用(例えば、特許文献1、2)を有し、眼疾患の予防や治療に有用であることが知られている。具体的には例えば、高眼圧症や緑内障等の予防又は治療(例えば、特許文献3)、あるいは加齢黄斑変性等の眼底疾患の予防又は治療(例えば、特許文献4)に有用であることが報告されている。 Halogenated isoquinoline derivatives such as 4-bromo-5-[[(2S) -2-methyl-1,4-diazepan-1-yl] sulfonyl] isoquinoline represented by 4 have pharmacological actions such as Rho kinase inhibitory action ( For example, it has Patent Documents 1 and 2) and is known to be useful for the prevention and treatment of eye diseases. Specifically, it may be useful for the prevention or treatment of ocular hypertension, glaucoma, etc. (for example, Patent Document 3), or the prevention or treatment of fundus diseases such as age-related macular degeneration (for example, Patent Document 4). It has been reported.
そのため、これらのハロゲン化イソキノリン誘導体を、例えば眼科用剤等として安定的に製剤化する技術を確立することは、極めて有用である。 Therefore, it is extremely useful to establish a technique for stably formulating these halogenated isoquinoline derivatives as, for example, an ophthalmic agent.
眼科用剤等は、通常、水を含有する組成物(水性組成物)であり、内容物の散逸や外気からの不純物の混入等を防ぐため、容器に収容する必要がある。そのため、本発明者は、ハロゲン化イソキノリン誘導体であるリパスジルを眼科用剤等として製剤化するに当たり、水性組成物を収容するための容器の材質を検討した。しかるところ、特定の材質の容器にリパスジルを含有する水性組成物を収容すると、低温での保存により、水性組成物中に結晶が析出するという問題が生じることが判明した。
そこで、本発明は、ハロゲン化イソキノリン誘導体含有水性組成物の、低温保存時の結晶析出を抑制する技術を提供することを目的とする。
Ophthalmic agents and the like are usually compositions containing water (aqueous compositions), and need to be contained in a container in order to prevent the contents from being dissipated and impurities from the outside air from being mixed. Therefore, the present inventor examined the material of the container for accommodating the aqueous composition when formulating ripasudil, which is a halogenated isoquinoline derivative, as an ophthalmic agent or the like. However, it has been found that when an aqueous composition containing ripasudil is contained in a container made of a specific material, there is a problem that crystals are precipitated in the aqueous composition due to storage at a low temperature.
Therefore, an object of the present invention is to provide a technique for suppressing crystal precipitation of a halogenated isoquinoline derivative-containing aqueous composition during low-temperature storage.
そこで本発明者は、前記課題を解決するため鋭意検討したところ、リパスジル等のハロゲン化イソキノリン誘導体を含有する水性組成物を容器に収容するに際し、容器の材質をポリエステル系樹脂製とした場合に特異的に低温保存後でも結晶の析出を抑制できることを見出し、本発明を完成した。 Therefore, the present inventor has made a diligent study to solve the above-mentioned problems, and found that when an aqueous composition containing a halogenated isoquinoline derivative such as ripasudil is contained in a container, it is peculiar when the material of the container is made of a polyester resin. We have found that the precipitation of crystals can be suppressed even after storage at low temperature, and completed the present invention.
すなわち、本発明は、次の一般式(1) That is, the present invention has the following general formula (1).
[式中、Xはハロゲン原子を示す。]
で表される化合物若しくはその塩又はそれらの溶媒和物を含有する水性組成物が、ポリエステル系樹脂製容器に収容されてなる、医薬製剤を提供するものである。
また、本発明は、前記一般式(1)で表される化合物若しくはその塩又はそれらの溶媒和物を含有する水性組成物を、ポリエステル系樹脂製容器に収容する工程を含む、水性組成物の結晶析出の抑制方法を提供するものである。
[In the formula, X represents a halogen atom. ]
An aqueous composition containing a compound represented by (1) or a salt thereof or a solvate thereof is provided as a pharmaceutical preparation contained in a polyester resin container.
Further, the present invention comprises a step of accommodating an aqueous composition containing the compound represented by the general formula (1), a salt thereof, or a solvate thereof in a polyester resin container. It provides a method for suppressing crystal precipitation.
本発明によれば、リパスジル等のハロゲン化イソキノリン誘導体を含有する水性組成物の低温保存時の結晶析出を抑制できる。 According to the present invention, it is possible to suppress crystal precipitation of an aqueous composition containing a halogenated isoquinoline derivative such as ripasudil during low temperature storage.
本明細書は、これらに何ら限定されるものではないが、例えば以下の態様の発明を開示する。
[1]次の一般式(1)
The present specification discloses, for example, the invention of the following aspects, without limitation to these.
[1] The following general formula (1)
[式中、Xはハロゲン原子を示す。]
で表される化合物若しくはその塩又はそれらの溶媒和物を含有する水性組成物が、ポリエステル系樹脂製容器に収容されてなる、医薬製剤。
[2]前記一般式(1)で表される化合物が、リパスジルである、[1]記載の医薬製剤。
[3]前記ポリエステル系樹脂が、ポリエチレンテレフタレートである、[1]又は[2]記載の医薬製剤。
[4]前記ポリエステル系樹脂製容器が、点眼剤用容器である、[1]~[3]のいずれか記載の医薬製剤。
[5]前記一般式(1)で表される化合物若しくはその塩又はそれらの溶媒和物を含有する水性組成物を、ポリエステル系樹脂製容器に収容する工程を含む、水性組成物の結晶析出の抑制方法。
[6]前記一般式(1)で表される化合物が、リパスジルである、[5]記載の方法。
[7]前記ポリエステル系樹脂が、ポリエチレンテレフタレートである、[5]又は[6]記載の方法。
[8]前記ポリエステル系樹脂製容器が、点眼剤用容器である、[5]~[7]のいずれか記載の方法。
[In the formula, X represents a halogen atom. ]
A pharmaceutical preparation in which an aqueous composition containing a compound represented by (1), a salt thereof, or a solvate thereof is contained in a polyester resin container.
[2] The pharmaceutical preparation according to [1], wherein the compound represented by the general formula (1) is ripasudil.
[3] The pharmaceutical preparation according to [1] or [2], wherein the polyester resin is polyethylene terephthalate.
[4] The pharmaceutical preparation according to any one of [1] to [3], wherein the polyester-based resin container is a container for eye drops.
[5] Crystal precipitation of an aqueous composition comprising a step of accommodating an aqueous composition containing the compound represented by the general formula (1), a salt thereof, or a solvate thereof in a polyester resin container. Suppression method.
[6] The method according to [5], wherein the compound represented by the general formula (1) is ripasudil.
[7] The method according to [5] or [6], wherein the polyester resin is polyethylene terephthalate.
[8] The method according to any one of [5] to [7], wherein the polyester-based resin container is a container for eye drops.
[9]前記水性組成物が、さらにα1受容体遮断薬、α2受容体作動薬、β遮断薬、炭酸脱水素酵素阻害剤、プロスタグランジンF2α誘導体、交感神経作動薬、副交感神経作動薬、カルシウム拮抗剤及びコリンエステラーゼ阻害剤よりなる群から選ばれる1種以上を含有する、[1]~[4]のいずれか記載の医薬製剤。
[10]前記水性組成物が、さらにラタノプロスト、ニプラジロール、ドルゾラミド、ブリンゾラミド及びチモロール並びにそれらの塩よりなる群から選ばれる1種以上を含有する、[1]~[4]のいずれか記載の医薬製剤。
[11]前記水性組成物が、さらにα1受容体遮断薬、α2受容体作動薬、β遮断薬、炭酸脱水素酵素阻害剤、プロスタグランジンF2α誘導体、交感神経作動薬、副交感神経作動薬、カルシウム拮抗剤及びコリンエステラーゼ阻害剤よりなる群から選ばれる1種以上を含有する、[5]~[8]のいずれか記載の方法。
[12]前記水性組成物が、さらにラタノプロスト、ニプラジロール、ドルゾラミド、ブリンゾラミド及びチモロール並びにそれらの塩よりなる群から選ばれる1種以上を含有する、[5]~[8]のいずれか記載の方法。
[9] The aqueous composition further comprises an α1 receptor blocker, an α2 receptor antagonist, a β blocker, a carbonate dehydrogenase inhibitor, a prostaglandin F2α derivative, a sympathomimetic agent, a parasympathomimetic agent, and calcium. The pharmaceutical preparation according to any one of [1] to [4], which contains at least one selected from the group consisting of an antagonist and a cholineresterase inhibitor.
[10] The pharmaceutical preparation according to any one of [1] to [4], wherein the aqueous composition further contains at least one selected from the group consisting of latanoprost, nipradilol, dorzolamide, brinzolamide and timolol, and salts thereof. ..
[11] The aqueous composition further comprises an α1 receptor blocker, an α2 receptor antagonist, a β blocker, a carbonate dehydrogenase inhibitor, a prostaglandin F2α derivative, a sympathomimetic agent, a parasympathomimetic agent, and calcium. The method according to any one of [5] to [8], which comprises at least one selected from the group consisting of an antagonist and a cholineresterase inhibitor.
[12] The method according to any one of [5] to [8], wherein the aqueous composition further contains at least one selected from the group consisting of latanoprost, nipradilol, dorzolamide, brinzolamide and timolol, and salts thereof.
前記一般式(1)において、ハロゲン原子としては、フッ素原子、塩素原子、臭素原子等が挙げられる。前記一般式(1)において、ハロゲン原子としては、フッ素原子、臭素原子が好ましく、フッ素原子が特に好ましい。
また、前記一般式(1)において、メチル基の置換したホモピペラジン環を構成する炭素原子は不斉炭素である。そのため、立体異性が生じるが、一般式(1)で表される化合物にはいずれの立体異性体も包含され、単一の立体異性体でもよく、各種立体異性体の任意の割合の混合物でもよい。前記一般式(1)で表される化合物としては、絶対配置がS配置である化合物が好ましい。
In the general formula (1), examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and the like. In the general formula (1), as the halogen atom, a fluorine atom and a bromine atom are preferable, and a fluorine atom is particularly preferable.
Further, in the general formula (1), the carbon atom constituting the methyl group-substituted homopiperazine ring is an asymmetric carbon. Therefore, steric isomers occur, but any steric isomer is included in the compound represented by the general formula (1), and a single steric isomer may be used, or a mixture of various steric isomers in any proportion may be used. .. As the compound represented by the general formula (1), a compound having an absolute configuration of S is preferable.
前記一般式(1)で表される化合物の塩としては、薬学上許容される塩であれば特に限定されず、具体的には例えば、塩酸塩、硫酸塩、硝酸塩、フッ化水素酸塩、臭化水素酸塩等の無機酸塩;酢酸塩、酒石酸塩、乳酸塩、クエン酸塩、フマル酸塩、マレイン酸塩、コハク酸塩、メタンスルホン酸塩、エタンスルホン酸塩、ベンゼンスルホン酸塩、トルエンスルホン酸塩、ナフタレンスルホン酸塩、カンファ―スルホン酸塩等の有機酸塩等が挙げられ、塩酸塩が好ましい。
さらに、前記一般式(1)で表される化合物又はその塩は、水和物やアルコール和物等の溶媒和物であってもよく、水和物であるのが好ましい。
The salt of the compound represented by the general formula (1) is not particularly limited as long as it is a pharmaceutically acceptable salt, and specifically, for example, a hydrochloride, a sulfate, a nitrate, a hydrofluoride salt, and the like. Inorganic acid salts such as hydrobromide; acetate, tartrate, lactate, citrate, fumarate, maleate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate , Toluene sulfonate, naphthalene sulfonate, organic acid salts such as camphor sulfonate and the like, and hydrochloride is preferable.
Further, the compound represented by the general formula (1) or a salt thereof may be a solvate such as a hydrate or an alcoholic mixture, and is preferably a hydrate.
前記一般式(1)で表される化合物若しくはその塩又はそれらの溶媒和物としては、具体的には例えば、
リパスジル(化学名:4-フルオロ-5-[[(2S)-2-メチル-1,4-ジアゼパン-1-イル]スルホニル]イソキノリン)若しくはその塩又はそれらの溶媒和物;
4-ブロモ-5-[[(2S)-2-メチル-1,4-ジアゼパン-1-イル]スルホニル]イソキノリン若しくはその塩又はそれらの溶媒和物;
等が挙げられる。
Specific examples of the compound represented by the general formula (1), a salt thereof, or a solvate thereof include, for example,
Ripasudil (chemical name: 4-fluoro-5-[[(2S) -2-methyl-1,4-diazepan-1-yl] sulfonyl] isoquinoline) or a salt thereof or a solvate thereof;
4-Bromo-5-[[(2S) -2-methyl-1,4-diazepan-1-yl] sulfonyl] isoquinoline or a salt thereof or a solvate thereof;
And so on.
前記一般式(1)で表される化合物若しくはその塩又はそれらの溶媒和物としては、リパスジル若しくはその塩又はそれらの溶媒和物、4-ブロモ-5-[[(2S)-2-メチル-1,4-ジアゼパン-1-イル]スルホニル]イソキノリン若しくはその塩又はそれらの溶媒和物が好ましく、リパスジル若しくはその塩又はそれらの溶媒和物がより好ましく、リパスジル若しくはその塩酸塩又はそれらの水和物がさらに好ましく、以下の構造式: Examples of the compound represented by the general formula (1) or a salt thereof or a solvate thereof include lipasyl or a salt thereof or a solvate thereof, 4-bromo-5-[[(2S) -2-methyl-. 1,4-Diazepan-1-yl] sulfonyl] isoquinoline or a salt thereof or a solvate thereof is preferable, lipasyl or a salt thereof or a solvate thereof is more preferable, and lipasyl or a hydrochloride thereof or a hydrate thereof Is more preferable, and the following structural formula:
で表されるリパスジル塩酸塩水和物(リパスジル1塩酸塩2水和物)が特に好ましい。 Ripasudil hydrochloride hydrate represented by (ripasudil monohydrochloride dihydrate) is particularly preferable.
前記一般式(1)で表される化合物若しくはその塩又はそれらの溶媒和物は公知であり、公知の方法により製造できる。具体的には例えば、リパスジル若しくはその塩又はそれらの溶媒和物は、国際公開第1999/020620号パンフレット、国際公開第2006/057397号パンフレット記載の方法等により製造することが出来る。また、4-ブロモ-5-[[(2S)-2-メチル-1,4-ジアゼパン-1-イル]スルホニル]イソキノリン若しくはその塩又はそれらの溶媒和物は、国際公開第2006/115244号パンフレット記載の方法等により製造することが出来る。 The compound represented by the general formula (1), a salt thereof, or a solvate thereof is known and can be produced by a known method. Specifically, for example, ripasudil or a salt thereof or a solvate thereof can be produced by the methods described in International Publication No. 1999/20620 Pamphlet, International Publication No. 2006/057397 Pamphlet and the like. In addition, 4-bromo-5-[[(2S) -2-methyl-1,4-diazepan-1-yl] sulfonyl] isoquinoline or a salt thereof or a solvate thereof is available in International Publication No. 2006/115244. It can be manufactured by the method described.
水性組成物中の前記一般式(1)で表される化合物若しくはその塩又はそれらの溶媒和物の含有量は特に限定されず、適用疾患や患者の性別、年齢、症状等に応じて適宜検討して決定すればよいが、優れた薬理作用を得る観点から、水性組成物全容量に対して、一般式(1)で表される化合物のフリー体に換算して0.01~10w/v%含有するのが好ましく、0.02~8w/v%含有するのがより好ましく、0.04~6w/v%含有するのが特に好ましい。中でも、一般式(1)で表される化合物としてリパスジルを用いる場合においては、優れた薬理作用を得る観点から、水性組成物全容量に対して、リパスジル若しくはその塩又はそれらの溶媒和物を、フリー体に換算して0.05~5w/v%含有するのが好ましく、0.1~3w/v%含有するのがより好ましく、0.1~2w/v%含有するのが特に好ましい。 The content of the compound represented by the general formula (1) or a salt thereof or a solvate thereof in the aqueous composition is not particularly limited, and is appropriately examined according to the applicable disease, the sex, age, symptom, etc. of the patient. However, from the viewpoint of obtaining excellent pharmacological action, 0.01 to 10 w / v in terms of the free form of the compound represented by the general formula (1) with respect to the total volume of the aqueous composition. % Is preferably contained, 0.02 to 8 w / v% is more preferable, and 0.04 to 6 w / v% is particularly preferable. Above all, when ripasudil is used as the compound represented by the general formula (1), ripasudil or a salt thereof or a solvate thereof is added to the total volume of the aqueous composition from the viewpoint of obtaining excellent pharmacological action. It is preferably contained in an amount of 0.05 to 5 w / v%, more preferably 0.1 to 3 w / v%, and particularly preferably 0.1 to 2 w / v% in terms of a free form.
本明細書において「水性組成物」とは、少なくとも水を含有する組成物を意味し、その性状としては、液状(溶液又は懸濁液)、半固形状(軟膏)が挙げられる。なお、組成物中の水としては例えば、精製水、注射用水、滅菌精製水等を用いることができる。
水性組成物に含まれる水の含有量は特に限定されないが、5質量%以上が好ましく、20質量%以上がより好ましく、50質量%以上がさらに好ましく、90質量%以上がさらにより好ましく、90~99.8質量%が特に好ましい。
As used herein, the term "aqueous composition" means a composition containing at least water, and examples thereof include liquid (solution or suspension) and semi-solid (ointment). As the water in the composition, for example, purified water, water for injection, sterile purified water and the like can be used.
The content of water contained in the aqueous composition is not particularly limited, but is preferably 5% by mass or more, more preferably 20% by mass or more, further preferably 50% by mass or more, still more preferably 90% by mass or more, and 90 to 90% by mass. 99.8% by mass is particularly preferable.
水性組成物は、例えば、第十六改正日本薬局方 製剤総則等に記載の公知の方法に従って、種々の剤形とすることができる。剤形としては、後述する容器に収容可能なものである限り特に限定されないが、例えば、注射剤、吸入液剤、点眼剤、眼軟膏剤、点耳剤、点鼻液剤、注腸剤、外用液剤、スプレー剤、軟膏剤、ゲル剤、経口液剤、シロップ剤等が挙げられる。剤形としては、一般式(1)で表される化合物の有する薬理作用を有利に利用する観点から、眼疾患用剤、具体的には点眼剤、眼軟膏剤が好ましく、点眼剤が特に好ましい。 The aqueous composition can be in various dosage forms according to, for example, a known method described in the 16th revised Japanese Pharmacopoeia General Regulations for Formulations and the like. The dosage form is not particularly limited as long as it can be accommodated in a container described later, but for example, an injection, an inhalation solution, an eye drop, an eye ointment, an ear drop, a nasal drop, an enema, and an external solution. , Sprays, ointments, gels, oral solutions, syrups and the like. As the dosage form, an agent for eye diseases, specifically an eye drop or an eye ointment, is preferable, and an eye drop is particularly preferable, from the viewpoint of advantageously utilizing the pharmacological action of the compound represented by the general formula (1). ..
水性組成物には、上記した以外に、剤形に応じて、医薬品や医薬部外品等で利用される添加物を含んでいても良い。このような添加物としては、例えば、無機塩類、等張化剤、キレート剤、安定化剤、pH調節剤、防腐剤、抗酸化剤、粘稠化剤、界面活性剤、可溶化剤、懸濁化剤、清涼化剤、分散剤、保存剤、油性基剤、乳剤性基剤、水溶性基剤等が挙げられる。
こうした添加物としては、具体的には例えば、アスコルビン酸、アスパラギン酸カリウム、亜硫酸水素ナトリウム、アルギン酸、安息香酸ナトリウム、安息香酸ベンジル、イプシロン-アミノカプロン酸、ウイキョウ油、エタノール、エチレン・酢酸ビニル共重合体、エデト酸ナトリウム、エデト酸四ナトリウム、塩化カリウム、塩化カルシウム水和物、塩化ナトリウム、塩化マグネシウム、塩酸、塩酸アルキルジアミノエチルグリシン液、カルボキシビニルポリマー、乾燥亜硫酸ナトリウム、乾燥炭酸ナトリウム、d-カンフル、dl-カンフル、キシリトール、クエン酸水和物、クエン酸ナトリウム水和物、グリセリン、グルコン酸、L-グルタミン酸、L-グルタミン酸ナトリウム、クレアチニン、クロルヘキシジングルコン酸塩液、クロロブタノール、結晶リン酸二水素ナトリウム、ゲラニオール、コンドロイチン硫酸ナトリウム、酢酸、酢酸カリウム、酢酸ナトリウム水和物、酸化チタン、ジェランガム、ジブチルヒドロキシトルエン、臭化カリウム、臭化べンゾドデシニウム、酒石酸、水酸化ナトリウム、ステアリン酸ポリオキシル45、精製ラノリン、D-ソルビトール、ソルビトール液、ソルビン酸、ソルビン酸カリウム、タウリン、炭酸水素ナトリウム、炭酸ナトリウム水和物、チオ硫酸ナトリウム水和物、チメロサール、チロキサポール、デヒドロ酢酸ナトリウム、トロメタモール、濃グリセリン、濃縮混合トコフェロール、白色ワセリン、ハッカ水、ハッカ油、濃ベンザルコニウム塩化物液50、パラオキシ安息香酸エチル、パラオキシ安息香酸ブチル、パラオキシ安息香酸プロピル、パラオキシ安息香酸メチル、ヒアルロン酸ナトリウム、人血清アルブミン、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒプロメロース、氷酢酸、ピロ亜硫酸ナトリウム、フェニルエチルアルコール、ブドウ糖、プロピレングリコール、ベルガモット油、ベンザルコニウム塩化物、ベンザルコニウム塩化物液、ベンジルアルコール、ベンゼトニウム塩化物、ベンゼトニウム塩化物液、ホウ砂、ホウ酸、ポビドン、ポリオキシエチレン(200)ポリオキシプロピレングルコール(70)、ポリスチレンスルホン酸ナトリウム、ポリソルベート80、ポリオキシエチレン硬化ヒマシ油60、ポリビニルアルコール(部分けん化物)、d-ボルネオール、マクロゴール4000、マクロゴール6000、D-マンニトール、無水クエン酸、無水リン酸一水素ナトリウム、無水リン酸二水素ナトリウム、メタンスルホン酸、メチルセルロース、l-メントール、モノエタノールアミン、モノステアリン酸アルミニウム、モノステアリン酸ポリエチレングリコール、ユーカリ油、ヨウ化カリウム、硫酸、硫酸オキシキノリン、流動パラフィン、リュウノウ、リン酸、リン酸水素ナトリウム水和物、リン酸二水素カリウム、リン酸二水素ナトリウム、リン酸二水素ナトリウム一水和物、リンゴ酸、ワセリン等が例示される。
In addition to the above, the aqueous composition may contain additives used in pharmaceuticals, quasi-drugs, etc., depending on the dosage form. Examples of such additives include inorganic salts, tonicity agents, chelating agents, stabilizers, pH adjusters, preservatives, antioxidants, thickening agents, surfactants, solubilizers, suspensions. Examples thereof include turbidizers, refreshing agents, dispersants, preservatives, oily bases, emulsion bases, water-soluble bases and the like.
Specific examples of such additives include ascorbic acid, potassium aspartate, sodium hydrogen sulfite, alginic acid, sodium benzoate, benzyl benzoate, epsilon-aminocaproic acid, uikyo oil, ethanol, and ethylene / vinyl acetate copolymers. , Sodium edetate, tetrasodium edetate, potassium chloride, calcium chloride hydrate, sodium chloride, magnesium chloride, hydrochloric acid, alkyldiaminoethylglycine hydrochloride solution, carboxyvinyl polymer, dry sodium sulfite, dry sodium carbonate, d-campul, dl-kanfur, xylitol, citrate hydrate, sodium citrate hydrate, glycerin, gluconic acid, L-glutamic acid, sodium L-glutamate, creatinine, chlorhexizing luconate solution, chlorobutanol, crystalline sodium dihydrogen phosphate , Geraniol, chondroitin sodium sulfate, acetic acid, potassium acetate, sodium acetate hydrate, titanium oxide, gellan gum, dibutyl hydroxytoluene, potassium bromide, benzododecinium bromide, tartrate acid, sodium hydroxide, polyoxyl 45 stearate, purified lanolin, D-sorbitol, sorbitol solution, sorbic acid, potassium sorbate, taurine, sodium hydrogen carbonate, sodium carbonate hydrate, sodium thiosulfate hydrate, thimerosal, tyrosapol, sodium dehydroacetate, tromethamol, concentrated glycerin, concentrated mixed tocopherol, White vaseline, peppermint water, peppermint oil, concentrated benzalconium chloride solution 50, ethyl paraoxybenzoate, butyl paraoxybenzoate, propyl paraoxybenzoate, methyl paraoxybenzoate, sodium hyaluronate, human serum albumin, hydroxyethylcellulose, hydroxy Propyl cellulose, hypromellose, glacial acetic acid, sodium pyrosulfate, phenylethyl alcohol, glucose, propylene glycol, bergamot oil, benzalconium chloride, benzalconium chloride solution, benzyl alcohol, benzethonium chloride, benzethonium chloride solution, hoe Sand, boric acid, povidone, polyoxyethylene (200) polyoxypropylene glucol (70), sodium polystyrene sulfonate, polysorbate 80, polyoxyethylene hydrogenated castor oil 60, polyvinyl alcohol (partially saponified), d-bornole, Macro Goal 4000, Macro Goal 600 0, D-mannitol, anhydrous citrate, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, methanesulfonic acid, methylcellulose, l-menthol, monoethanolamine, aluminum monostearate, polyethylene glycol monostearate, eucalyptus Oil, potassium iodide, sulfuric acid, oxyquinoline sulfate, liquid paraffin, rhyuno, phosphoric acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium dihydrogen phosphate monohydrate, Examples thereof include phosphate, vaseline and the like.
添加物としては、例えば、塩化カリウム、塩化カルシウム水和物、塩化ナトリウム、塩化マグネシウム、グリセリン、酢酸、酢酸カリウム、酢酸ナトリウム水和物、酒石酸、水酸化ナトリウム、炭酸水素ナトリウム、炭酸ナトリウム水和物、濃グリセリン、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒプロメロース、ホウ砂、ホウ酸、ポビドン、ポリソルベート80、ポリオキシエチレン硬化ヒマシ油、モノステアリン酸ポリエチレングリコール、ポリビニルアルコール(部分けん化物)、マクロゴール4000、マクロゴール6000、無水クエン酸、無水リン酸一水素ナトリウム、無水リン酸二水素ナトリウム、メチルセルロース、モノエタノールアミン、リン酸、リン酸水素ナトリウム水和物、リン酸二水素カリウム、リン酸二水素ナトリウム、リン酸二水素ナトリウム一水和物、ヒアルロン酸ナトリウム、ブドウ糖、l-メントール等が好ましい。 Additives include, for example, potassium chloride, calcium chloride hydrate, sodium chloride, magnesium chloride, glycerin, acetic acid, potassium acetate, sodium acetate hydrate, tartaric acid, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate hydrate. , Concentrated glycerin, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromerose, borosand, boric acid, povidone, polysorbate 80, polyoxyethylene hydrogenated castor oil, polyethylene glycol monostearate, polyvinyl alcohol (partially saponified), macrogol 4000, macro Goal 6000, anhydrous citric acid, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, methylcellulose, monoethanolamine, phosphoric acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, Monosodium dihydrogen phosphate monohydrate, sodium hyaluronate, glucose, l-menthol and the like are preferable.
水性組成物は、さらに、上記した以外に、適用疾患等に応じて、他の薬効成分を含んでいても良い。このような薬効成分としては、例えば、ブナゾシン塩酸塩などのブナゾシン若しくはその塩又はそれらの溶媒和物を含むα1受容体遮断薬;ブリモニジン酒石酸塩などのブリモニジン若しくはその塩又はそれらの溶媒和物、アプラクロニジン若しくはその塩又はそれらの溶媒和物を含むα2受容体遮断薬;カルテオール塩酸塩などのカルテオール若しくはその塩又はそれらの溶媒和物、ニプラジロール若しくはその塩又はそれらの溶媒和物、チモロールマレイン酸塩などのチモロール若しくはその塩又はそれらの溶媒和物、ベタキソロール塩酸塩などのベタキソロール若しくはその塩又はそれらの溶媒和物、レボブノロール塩酸塩などのレボブノロール若しくはその塩又はそれらの溶媒和物、ベフノロール若しくはその塩又はそれらの溶媒和物、メチプラノロール若しくはその塩又はそれらの溶媒和物を含むβ遮断薬;ドルゾラミド塩酸塩などのドルゾラミド若しくはその塩又はそれらの溶媒和物、ブリンゾラミド若しくはその塩又はそれらの溶媒和物、アセタゾラミド若しくはその塩又はそれらの溶媒和物、ジクロルフェナミド若しくはその塩又はそれらの溶媒和物、メタゾラミド若しくはその塩又はそれらの溶媒和物を含む炭酸脱水素酵素阻害剤;イソプロピルウノプロストン若しくはその塩又はそれらの溶媒和物、タフルプロスト若しくはその塩又はそれらの溶媒和物、トラボプロスト若しくはその塩又はそれらの溶媒和物、ビマトプロスト若しくはその塩又はそれらの溶媒和物、ラタノプロスト若しくはその塩又はそれらの溶媒和物、クロプロステノール若しくはその塩又はそれらの溶媒和物、フルプロステノール若しくはその塩又はそれらの溶媒和物を含むプロスタグランジンF2α誘導体;ジピべフリン塩酸塩などのジピべフリン若しくはその塩又はそれらの溶媒和物、エピネフリン、エピネフリンホウ酸塩、エピネフリン塩酸塩などのエピネフリン若しくはその塩又はそれらの溶媒和物を含む交感神経作動薬;ジスチグミン臭化物若しくはその塩又はそれらの溶媒和物、ピロカルピン、ピロカルピン塩酸塩、ピロカルピン硝酸塩などのピロカルピン若しくはその塩又はそれらの溶媒和物、カルバコール若しくはその塩又はそれらの溶媒和物を含む副交感神経作動薬;ロメリジン塩酸塩などのロメリジン若しくはその塩又はそれらの溶媒和物を含むカルシウム拮抗薬;デメカリウム若しくはその塩又はそれらの溶媒和物、エコチオフェート若しくはその塩又はそれらの溶媒和物、フィゾスチグミン若しくはその塩又はそれらの溶媒和物を含むコリンエステラーゼ阻害剤などが挙げられ、これらの1種又は2種以上を配合できる。
他の薬効成分としては、ラタノプロスト、ニプラジロール、ドルゾラミド、ブリンゾラミド及びチモロール並びにそれらの塩よりなる群から選ばれる1種以上が好ましい。
In addition to the above, the aqueous composition may further contain other medicinal ingredients depending on the applicable disease and the like. Such medicinal ingredients include, for example, an α1 receptor blocker containing bunazocin such as bunazosin hydrochloride or a salt thereof or a solvent thereof; brimonidine such as brimonidine tartrate or a salt thereof or a solvent thereof, appla. Α2 receptor blocker containing chronidine or a salt thereof or a solvate thereof; a quarteol such as carteol hydrochloride or a salt thereof or a solvate thereof, niprazirol or a salt thereof or a solvate thereof, thymorol maleic acid. Timorol such as a salt or a salt thereof or a solvent thereof, betaxolol such as betaxolol hydrochloride or a salt thereof or a solvent thereof, levobnorol such as levobnorol hydrochloride or a salt thereof or a solvent thereof, befnolol or a salt thereof. Or a β-blocker containing methipranolol or a salt thereof or a salt thereof; a dolzoramide such as dolzolamide hydrochloride or a salt thereof or a solvate thereof, brinzoramide or a salt thereof or a solvate thereof. A carbonate dehydrogenase inhibitor containing a substance, acetazolamide or a salt thereof or a solvent thereof, dichlorphenamide or a salt thereof or a solvent thereof, metazolamide or a salt thereof or a solvent thereof; isopropyl unoprostone. Or its salts or their salts, tafluprost or its salts or their salts, travoprost or its salts or their salts, bimatoprost or its salts or their salts, ratanoprost or its salts or theirs. Prostaglandin F2α derivative containing a solvent product of, cloprostenol or a salt thereof or a solvent product thereof, fluprostenol or a salt thereof or a salt product thereof; Or a sympathomimetic agent containing epinephrine such as a salt thereof or a solvent thereof, epinephrine, epinephrineborate, an epinephrine hydrochloride or a salt thereof or a solvent thereof; a dystigmine bromide or a salt thereof or a solvent thereof. , Pyrocarpine such as Pyrocarpine, Pyrocarpine hydrochloride, Pyrocarpine nitrate or a salt thereof or a solvent thereof, Carbacol or a salt thereof or a parasympathomimetic agent containing a solvent thereof; Lomeridine such as Lomeridine hydrochloride or a salt thereof or a salt thereof. Demepotassium or salts thereof or theirs Examples thereof include solvates, ecothiophates or salts thereof or solvates thereof, physostigmine or salts thereof or cholinesterase inhibitors containing solvates thereof, and one or more of these can be blended.
As the other medicinal ingredient, at least one selected from the group consisting of latanoprost, nipradilol, dorzolamide, brinzolamide and timolol, and salts thereof is preferable.
水性組成物のpHは特に限定されないが、4~9が好ましく、4.5~8がより好ましく、5~7が特に好ましい。また、生理食塩水に対する浸透圧比は特に限定されないが、0.6~3が好ましく、0.6~2が特に好ましい。 The pH of the aqueous composition is not particularly limited, but is preferably 4 to 9, more preferably 4.5 to 8, and particularly preferably 5 to 7. The osmotic pressure ratio with respect to the physiological saline is not particularly limited, but is preferably 0.6 to 3, and particularly preferably 0.6 to 2.
本明細書において「容器」とは、前記水性組成物を直接的に収容する包装体を意味する。容器は、第十六改正日本薬局方 通則に定義される「密閉容器」、「気密容器」、「密封容器」のいずれをも包含する概念である。 As used herein, the term "container" means a package that directly contains the aqueous composition. The container is a concept that includes any of "sealed container", "airtight container", and "sealed container" defined in the 16th revised Japanese Pharmacopoeia General Regulations.
当該容器の形態は、前記水性組成物を収容可能であることを限度として特に限定されず、剤形、医薬製剤の用途等に応じて適宜選択、設定すればよい。このような容器の形態としては、具体的には例えば、注射剤用容器、吸入剤用容器、スプレー剤用容器、ボトル状容器、チューブ状容器、点眼剤用容器、点鼻剤用容器、点耳剤用容器、バッグ容器等が挙げられる。 The form of the container is not particularly limited as long as it can accommodate the aqueous composition, and may be appropriately selected and set according to the dosage form, the use of the pharmaceutical preparation, and the like. Specific examples of such a container include a container for injection, a container for inhalant, a container for spray, a bottle-shaped container, a tubular container, a container for eye drops, a container for nasal drops, and a dot. Examples include ears containers, bag containers and the like.
本明細書において「ポリエステル系樹脂製容器」とは、容器のうち少なくとも水性組成物と接する部分が「ポリエステル系樹脂製」である容器を意味する。従って、例えば、水性組成物と接する内層にポリエステル系樹脂の層を設け、その外側に他の材質の樹脂等を積層等させてなる容器も、「ポリエステル系樹脂製容器」に該当する。ここで、ポリエステル系樹脂を構成するジカルボン酸、ジオールは特に限定されず、ジカルボン酸としては例えばフタル酸、テレフタル酸、2,6-ナフタレンジカルボン酸などが、ジオールとしては例えばエチレングリコール、1,3-プロパンジオール、1,4-ブタンジオール、1,4-シクロヘキサンジメタノール、ビスフェノールなどが挙げられる。また、単一種のポリエステル単位の重合体であっても、複数種のポリエステル単位の重合体であってもよい。また、複数種のポリエステル単位の重合体の場合には、その重合様式は特に限定されず、ランダム重合でもブロック重合でもよい。さらに、その立体規則性(タクティシティー)は特に限定されない。
このようなポリエステル系樹脂としては、具体的には例えば、ポリアルキレンテレフタレート(例えば、ポリエチレンテレフタレート、ポリブチレンテレフタレート等)、ポリアルキレンナフタレート(例えば、ポリエチレンナフタレート、ポリブチレンナフタレート等)、ポリシクロアルキレンテレフタレート(例えば、ポリ(1,4-シクロヘキシレンジメチレンテレフタレート)等)、ポリアリレート(例えば、ビスフェノールとフタル酸で構成された樹脂等)等のホモポリエステルや、これらのホモポリエステル単位を主成分として含むコポリエステル、さらには前記ホモポリエステルの共重合体などが挙げられ、これらの1種又は2種以上を組合わせて使用できる。ポリエステル系樹脂としては、結晶の析出を抑制する観点から、ポリエチレンテレフタレートが好ましい。
なお、本明細書において「ポリエステル系樹脂製」とは、その材質の少なくとも一部にポリエステル系樹脂を含んでいることを意味し、例えば、ポリエステル系樹脂と他の樹脂との2種以上の樹脂の混合体(ポリマーアロイ)も「ポリエステル系樹脂製」に含まれる。
As used herein, the term "polyester-based resin container" means a container in which at least a portion of the container in contact with the aqueous composition is "made of polyester-based resin". Therefore, for example, a container in which a polyester-based resin layer is provided on an inner layer in contact with an aqueous composition and a resin or the like of another material is laminated on the outer side thereof also falls under the category of "polyester-based resin container". Here, the dicarboxylic acid and diol constituting the polyester resin are not particularly limited, and the dicarboxylic acid is, for example, phthalic acid, terephthalic acid, 2,6-naphthalenedicarboxylic acid, and the diol is, for example, ethylene glycol, 1,3. -Propanediol, 1,4-butanediol, 1,4-cyclohexanedimethanol, bisphenol and the like can be mentioned. Further, it may be a polymer of a single type of polyester unit or a polymer of a plurality of types of polyester units. Further, in the case of a polymer of a plurality of types of polyester units, the polymerization mode is not particularly limited, and random polymerization or block polymerization may be used. Furthermore, its stereoregularity (tacticity) is not particularly limited.
Specific examples of such polyester-based resins include polyalkylene terephthalate (for example, polyethylene terephthalate, polybutylene terephthalate, etc.), polyalkylene naphthalate (for example, polyethylene naphthalate, polybutylene naphthalate, etc.), and polycyclo. The main components are homopolyesters such as alkylene terephthalates (for example, poly (for example, 1,4-cyclohexylene methylene terephthalate)) and polyarylates (for example, resins composed of bisphenol and phthalic acid), and homopolyester units thereof. Examples thereof include copolyesters contained in the above, and copolymers of the homopolyesters, and one type or a combination of two or more of these can be used. As the polyester resin, polyethylene terephthalate is preferable from the viewpoint of suppressing the precipitation of crystals.
In addition, in this specification, "made of polyester-based resin" means that at least a part of the material contains polyester-based resin, for example, two or more kinds of resins of polyester-based resin and other resins. (Polyester alloy) is also included in "made of polyester resin".
ポリエステル系樹脂製容器には、さらに紫外線吸収剤や紫外線散乱剤などの紫外線の透過を妨げる物質を練り込むのが好ましい。これにより、一般式(1)で表される化合物の光に対する安定性が改善される。こうした物質としては、具体的には例えば、紫外線散乱剤としては、酸化チタン;酸化亜鉛等が挙げられる。また、紫外線吸収剤としては、2-(2H-ベンゾトリアゾール-2-イル)-p-クレゾール(例えば、Tinuvin P:BASF社)、2-(2H-ベンゾトリアゾール-2-イル)-4,6-ビス(1-メチル-1-フェニルエチル)フェノール(例えば、Tinuvin 234:BASF社)、2-(3,5-ジ-t-ブチル-2-ヒドロキシフェニル)ベンゾトリアゾール(例えば、Tinuvin320:BASF社)、2-[5-クロロ(2H)-ベンゾトリアゾール-2-イル]-4-メチル-6-(tert-ブチル)フェノール(例えば、Tinuvin 326:BASF社)、2-(3,5-ジ-t-ブチル-2-ヒドロキシフェニル)-5-クロロベンゾトリアゾール(例えば、Tinuvin327:BASF社)、2-(2H-ベンゾトリアゾール-2-イル)-4,6-ジ-tert-ペンチルフェノール(例えば、Tinuvin PA328:BASF社)、2-(2H-ベンゾトリアゾール-2-イル)-4-(1,1,3,3-テトラメチルブチル)フェノール(例えば、Tinuvin 329:BASF社)、2,2'-メチルレンビス[6-(2H-ベンゾトリアゾール-2-イル)-4-(1,1,3,3-テトラメチルブチル)フェノール(例えば、Tinuvin 360:BASF社)、メチル3-(3-(2H-ベンゾトリアゾール-2-イル)-5-tert-ブチル-4-ヒドロキシフェニル)プロピオネートとポリエチレングリコール300の反応生成物(例えば、Tinuvin 213:BASF社)、2-(2H-ベンゾトリアゾール-2-イル)-6-ドデシル-4-メチルフェノール(例えば、Tinuvin 571:BASF社)、2-(2'-ヒドロキシ-3',5'-ジ-t-アミルフェニル)ベンゾトリアゾール、2-[2'-ヒドロキシ-3'-(3'',4'',5'',6''-テトラヒドロフタルイミドメチル)-5'-メチルフェニル]ベンゾトリアゾール、2,2'-メチレンビス[4-(1,1,3,3-テトラメチルブチル)-6-(2H-ベンゾトリアゾール-2-イル)フェノール]等のベンゾトリアゾール系紫外線吸収剤;2,2-ビス{[2-シアノ-3,3-ジフェニルアクリロイルオキシ]メチル}プロパン-1,3-ジイル=ビス(2-シアノ-3,3-ジフェニルアクリレート)(例えば、Uvinul 3030 FF:BASF社)、2-シアノ-3,3-ジフェニルアクリル酸エチル(例えば、Uvinul 3035:BASF社)、2-シアノ-3,3-ジフェニルアクリル酸2-エチルへキシル(例えば、Uvinul 3039:BASF社)等のシアノアクリレート系紫外線吸収剤;2-(4,6-ジフェニル-1,3,5-トリアジン-2-イル)-5-[(ヘキシル)オキシ]-フェノール(例えば、Tinuvin 1577 ED:BASF社)等のトリアジン系紫外線吸収剤;オクタベンゾン(例えば、Chimassorb 81:BASF社)、2,2'-ジヒドロキシ-4,4'-ジメトキシベンフェノン(例えば、Uvinul 3049:BASF社)、2,2'-4,4'-テトラヒドロベンフェノン(例えば、Uvinul 3050:BASF社)、オキシベンゾン、ヒドロキシメトキシベンゾフェノンスルホン酸、ヒドロキシメトキシベンゾフェノンスルホン酸ナトリウム、ジヒドロキシジメトキシベンゾフェノン、ジヒドロキシジメトキシベンゾフェノンジスルホン酸ナトリウム、ジヒドロキシベンゾフェノン、テトラヒドロキシベンゾフェノン等のベンゾフェノン系紫外線吸収剤;ジイソプロピルケイ皮酸メチル、シノキサート、ジパラメトキシケイ皮酸モノ-2-エチルヘキサン酸グリセリル、パラメトキシケイ皮酸イソプロピル・ジイソプロピルケイ皮酸エステル混合物、パラメトキシケイ皮酸2-エチルヘキシル、ケイ皮酸ベンジル等のケイ皮酸系紫外線吸収剤;パラアミノ安息香酸、パラアミノ安息香酸エチル、パラアミノ安息香酸グリセリル、パラジメチルアミノ安息香酸アミル、パラジメチルアミノ安息香酸2-エチルヘキシル、4-[N,N-ジ(2-ヒドロキシプロピル)アミノ]安息香酸エチル等の安息香酸エステル系紫外線吸収剤;サリチル酸エチレングリコール、サリチル酸オクチル、サリチル酸ジプロピレングリコール、サリチル酸フェニル、サリチル酸ホモメンチル、サリチル酸メチル等のサリチル酸系紫外線吸収剤;グアイアズレン;ジメトキシベンジリデンジオキソイミダゾリジンプロピオン酸2-エチルヘキシル;2,4,6-トリス[4-(2-エチルヘキシルオキシカルボニル)アニリノ]1,3,5-トリアジン;パラヒドロキシアニソール;4-tert-ブチル-4'-メトキシジベンゾイルメタン;フェニルベンズイミダゾールスルホン酸;2-(4-ジエチルアミノ-2-ヒドロキシベンゾイル)-安息香酸ヘキシルなどが挙げられる。 It is preferable to further knead a substance that obstructs the transmission of ultraviolet rays, such as an ultraviolet absorber and an ultraviolet scattering agent, into the polyester resin container. This improves the stability of the compound represented by the general formula (1) to light. Specific examples of such a substance include titanium oxide; zinc oxide and the like as an ultraviolet scattering agent. Examples of the ultraviolet absorber include 2- (2H-benzotriazole-2-yl) -p-cresol (for example, Tinuvin P: BASF), 2- (2H-benzotriazole-2-yl) -4,6. -Bis (1-methyl-1-phenylethyl) phenol (eg, Tinuvin 234: BASF), 2- (3,5-di-t-butyl-2-hydroxyphenyl) benzotriazole (eg, Tinuvin320: BASF) ), 2- [5-Chloro (2H) -benzotriazole-2-yl] -4-methyl-6- (tert-butyl) phenol (eg, Tinuvin 326: BASF), 2- (3,5-di). -T-butyl-2-hydroxyphenyl) -5-chlorobenzotriazole (eg, Tinuvin327: BASF), 2- (2H-benzotriazole-2-yl) -4,6-di-tert-pentylphenol (eg, Tinuvin327: BASF) , Tinuvin PA328: BASF), 2- (2H-benzotriazole-2-yl) -4- (1,1,3,3-tetramethylbutyl) phenol (eg, Tinuvin 329: BASF), 2,2 '-Methyllenbis [6- (2H-benzotriazole-2-yl) -4- (1,1,3,3-tetramethylbutyl) phenol (eg, Tinuvin 360: BASF), Methyl 3- (3-( Reaction product of 2H-benzotriazole-2-yl) -5-tert-butyl-4-hydroxyphenyl) propionate and polyethylene glycol 300 (eg, Tinuvin 213: BASF), 2- (2H-benzotriazole-2-). Il) -6-dodecyl-4-methylphenol (eg, Tinuvin 571: BASF), 2- (2'-hydroxy-3', 5'-di-t-amylphenyl) benzotriazole, 2- [2' -Hydroxy-3'-(3'', 4'', 5'', 6''-tetrahydrophthalimidemethyl) -5'-methylphenyl] benzotriazole, 2,2'-methylenebis [4- (1,1) , 3,3-Tetramethylbutyl) -6- (2H-benzotriazole-2-yl) phenol] and other benzotriazole-based ultraviolet absorbers; 2,2-bis {[2-cyano-3,3-diphenylacryloyl) Oxy] Methyl} Propane-1,3-diyl-bis (2-cyano-3,3-diphenylacrylate) (eg, Uvinul 3030 FF: BASF), ethyl 2-cyano-3,3-diphenylacrylate (eg Uvinul 3035: BASF), 2-ethylhexyl 2-cyano-3,3-diphenylacrylate (eg Uvinul) 3039: BASF) and other cyanoacrylate-based UV absorbers; 2- (4,6-diphenyl-1,3,5-triazine-2-yl) -5-[(hexyl) oxy] -phenol (eg, Tinuvin) Triazine-based ultraviolet absorbers such as 1577 ED: BASF); octabenzophenone (eg, Chimassorb 81: BASF), 2,2'-dihydroxy-4,4'-dimethoxybenzophenone (eg, Uvinul 3049: BASF), 2,2'-4,4'-tetrahydrobenphenone (eg, Uvinul 3050: BASF), oxybenzone, hydroxymethoxybenzophenone sulfonic acid, sodium hydroxymethoxybenzophenone sulfonate, dihydroxydimethoxybenzophenone, sodium dihydroxydimethoxybenzophenone disulfonate, dihydroxy Benzophenone-based UV absorbers such as benzophenone and tetrahydroxybenzophenone; methyl diisopropyl cinnamic acid, cinoxate, mono-2-ethylhexanate glyceryl, paramethoxycinnamic acid isopropyl-diisopropyl cinnamic acid ester mixture, Cinnamic acid-based UV absorbers such as 2-ethylhexyl paramethoxycinnamic acid and benzyl silicate; paraaminobenzoic acid, ethyl paraaminobenzoate, glyceryl paraaminobenzoate, amyl paradimethylaminobenzoate, paradimethylaminobenzoic acid 2 -Ethylhexyl, 4- [N, N-di (2-hydroxypropyl) amino] benzoate ester-based ultraviolet absorbers such as ethyl benzoate; ethylene glycol salicylate, octyl salicylate, dipropylene glycol salicylate, phenyl salicylate, homomentyl salicylate, Salicylic acid-based ultraviolet absorbers such as methyl salicylate; guaiazulene; dimethoxybenzylenedioxoimidazolidinepropionate 2-ethylhexyl; 2,4,6-tris [4- (2-ethylhexyloxycarbonyl) anilino] 1,3,5-triazine Parahydroxyanisole; 4-tert-butyl-4'-methoxydibenzoylmethane; phenylbe Nzuimidazole sulfonic acid; 2- (4-diethylamino-2-hydroxybenzoyl) -hexylbenzoate and the like can be mentioned.
なお、紫外線の透過を妨げる物質を容器に練り込む場合、その配合割合は、当該物質の種類等によって異なるが、例えば、容器中に、0.001~50質量%、好ましくは0.002~25質量%、特に好ましくは0.01~10質量%程度とすればよい。 When a substance that hinders the transmission of ultraviolet rays is kneaded into a container, the mixing ratio thereof varies depending on the type of the substance and the like, but for example, 0.001 to 50% by mass, preferably 0.002 to 25 in the container. It may be about% by mass, particularly preferably about 0.01 to 10% by mass.
容器は、その内部が肉眼で視認可能(観察可能)であるのが好ましい。内部が視認可能であれば、医薬製剤の製造工程において異物混入の有無等の検査が可能となる、医薬製剤の使用者が内容物(水性組成物)の残量を確認できる等のメリットが生ずる。ここで、視認可能性は、少なくとも容器表面の一部において確保されていればよい(例えば、点眼剤用容器の側面がシュリンクフィルム等により見通せなくなっていても、底面が視認可能であれば視認可能と言える。)。容器表面の一部において内部が視認可能であれば、これにより、容器内の水性組成物が確認可能となる。 It is preferable that the inside of the container is visible (observable) with the naked eye. If the inside is visible, there are merits such as being able to inspect for foreign substances in the manufacturing process of the pharmaceutical product and allowing the user of the pharmaceutical product to check the remaining amount of the content (aqueous composition). .. Here, the visibility may be ensured at least on a part of the surface of the container (for example, even if the side surface of the eye drop container cannot be seen due to a shrink film or the like, it is visible if the bottom surface is visible. It can be said.). If the inside is visible on a part of the surface of the container, this makes it possible to confirm the aqueous composition in the container.
容器への水性組成物の収容手段は特に限定されず、容器の形態等に従って常法により充填等すればよい。 The means for accommodating the aqueous composition in the container is not particularly limited, and the container may be filled by a conventional method according to the shape of the container or the like.
医薬製剤の適用疾患は特に限定されず、前記一般式(1)で表される化合物の有する薬理作用等に応じて適宜選択すればよい。
具体的には例えば、一般式(1)で表される化合物の有するRhoキナーゼ阻害作用や眼圧低下作用に基づき、高眼圧症や緑内障の予防又は治療剤として利用できる。ここで、緑内障としては、より詳細には例えば、原発性開放隅角緑内障、正常眼圧緑内障、房水産生過多緑内障、急性閉塞隅角緑内障、慢性閉塞隅角緑内障、plateau iris syndrome、混合型緑内障、ステロイド緑内障、水晶体の嚢性緑内障、色素緑内障、アミロイド緑内障、血管新生緑内障、悪性緑内障などが挙げられる。
The disease to which the pharmaceutical preparation is applied is not particularly limited, and may be appropriately selected depending on the pharmacological action of the compound represented by the general formula (1) and the like.
Specifically, for example, it can be used as a preventive or therapeutic agent for ocular hypertension and glaucoma based on the Rho-kinase inhibitory action and the intraocular pressure lowering action of the compound represented by the general formula (1). Here, as glaucoma, more specifically, for example, primary open-angle glaucoma, normal-tension glaucoma, tufted glaucoma, acute closed-angle glaucoma, chronic closed-angle glaucoma, plateau iris syndrome, mixed glaucoma. , Steroid glaucoma, cystic glaucoma of the crystalline body, pigmented glaucoma, amyloid glaucoma, angiogenic glaucoma, malignant glaucoma and the like.
また、日本国特許第5557408号公報に開示されるように、眼底疾患(主として網膜及び/又は脈絡膜に発現する病変。具体的には例えば、高血圧と動脈硬化による眼底変化、網膜中心動脈閉塞症、網膜中心静脈閉塞症(central retinal vein occlusion)や網膜静脈分枝閉塞症(branch retinal vein occlusion)等の網膜静脈閉塞症、糖尿病網膜症、糖尿病黄斑浮腫、糖尿病黄斑症、イールズ病(Eales disease)、コーツ病(Coats disease)等の網膜血管先天異常、ヒッペル病(von Hippel disease)、脈なし病(pulseless disease)、黄斑疾患(中心性網脈絡膜症(central serous chorioretinopathy)、嚢胞様黄斑浮腫(cystoid macular edema)、加齢黄斑変性(age-related macular degeneration)、黄斑円孔(macular hole)、近視性黄斑萎縮(myopic macular degeneration)、網膜硝子体界面黄斑変性症、薬物毒性黄斑変性症、遺伝性黄斑変性等)、(裂孔原性、牽引性、滲出性等の)網膜剥離、網膜色素変性症、未熟児網膜症等が挙げられる。)の予防又は治療剤、より好適には糖尿病網膜症、糖尿病黄斑浮腫又は加齢黄斑変性の予防又は治療剤として利用できる。 Further, as disclosed in Japanese Patent No. 5557408, fundus diseases (lesions that develop mainly in the retina and / or choroid. Specifically, for example, changes in the fundus due to hypertension and arteriosclerosis, central retinal artery occlusion, etc. Retinal vein occlusion such as central retinal vein occlusion and branch retinal vein occlusion, diabetic retinopathy, diabetic luteal edema, diabetic luteal occlusion, Eales disease, Congenital retinal vascular abnormalities such as Coats disease, von Hippel disease, pulseless disease, luteal disease (central serous chorioretinopathy), cystoid macular. edema), age-related macular degeneration, macular hole, myopic macular degeneration, retinal vitreous interface luteal degeneration, drug-toxic luteal degeneration, hereditary luteal lesions Preventive or therapeutic agents for (degeneration, etc.), retinal detachment (such as rhegmatogenous, traction, exudative, etc.), retinal pigment degeneration, premature infant retinopathy, etc.), more preferably diabetic retinopathy, diabetes. It can be used as a prophylactic or therapeutic agent for retinal edema or age-related retinal degeneration.
次に、実施例を挙げて本発明を更に説明するが、本発明はこれらに何ら限定されるものではない。
なお、以下の試験例において、リパスジル1塩酸塩2水和物は、例えば国際公開第2006/057397号パンフレット記載の方法により製造することが出来る。
Next, the present invention will be further described with reference to examples, but the present invention is not limited thereto.
In the following test examples, ripasudil monohydrochloride dihydrate can be produced, for example, by the method described in International Publication No. 2006/057397.
[試験例1]保存試験 その1
表1に示す処方の水性組成物を常法により調製した後、ポリエチレンテレフタレート(PET)製、又はポリ塩化ビニル(PVC)製の容器に入れて医薬製剤を製した。
得られた各医薬製剤を、0℃で2日間保存した後、結晶析出の有無を目視により評価した。なお、結晶析出が認められない場合を○、結晶析出が認められた場合を×とした。
結果を表2に示す。
[Test Example 1] Preservation test 1
The aqueous composition according to the formulation shown in Table 1 was prepared by a conventional method, and then placed in a container made of polyethylene terephthalate (PET) or polyvinyl chloride (PVC) to prepare a pharmaceutical preparation.
Each of the obtained pharmaceutical preparations was stored at 0 ° C. for 2 days, and then the presence or absence of crystal precipitation was visually evaluated. The case where crystal precipitation was not observed was evaluated as ◯, and the case where crystal precipitation was observed was evaluated as x.
The results are shown in Table 2.
表2記載の結果の通り、リパスジルを含有する水性組成物をポリエチレンテレフタレート(PET)製等のポリエステル系樹脂製容器に収容した場合、低温で保存した場合においても結晶析出が認められなかったのに対し、ポリ塩化ビニル(PVC)製の容器に収容した場合、結晶析出が認められた。 As shown in the results shown in Table 2, when the aqueous composition containing lipasyl was housed in a polyester resin container made of polyethylene terephthalate (PET) or the like, no crystal precipitation was observed even when stored at a low temperature. On the other hand, when it was housed in a container made of polyvinyl chloride (PVC), crystal precipitation was observed.
[試験例2]保存試験 その2
表3に示す水性組成物を常法により調製した後、ポリエチレンテレフタレート(PET)製の容器に入れて医薬製剤を製した。
得られた医薬製剤を、0℃で21日間保存した後、結晶析出の有無を目視により評価した。なお、結晶析出が認められない場合を○、結晶析出が認められた場合を×とした。
結果を表4に示す。
[Test Example 2] Preservation test 2
The aqueous composition shown in Table 3 was prepared by a conventional method, and then placed in a container made of polyethylene terephthalate (PET) to prepare a pharmaceutical preparation.
The obtained pharmaceutical preparation was stored at 0 ° C. for 21 days, and then the presence or absence of crystal precipitation was visually evaluated. The case where crystal precipitation was not observed was evaluated as ◯, and the case where crystal precipitation was observed was evaluated as x.
The results are shown in Table 4.
表4記載の結果の通り、水性組成物の処方を変更した場合であっても、ポリエチレンテレフタレート(PET)製等のポリエステル系樹脂製容器に収容した場合、低温で保存した場合においても結晶析出が認められなかった。 As shown in the results shown in Table 4, even when the formulation of the aqueous composition is changed, crystal precipitation occurs even when stored in a polyester resin container such as polyethylene terephthalate (PET) or stored at a low temperature. I was not able to admit.
以上の試験例1、2の結果から、リパスジルを含む一般式(1)で表される化合物若しくはその塩又はそれらの溶媒和物を含有する水性組成物をポリエステル系樹脂製容器に収容した場合、低温で保存した場合でも相対的に結晶が析出し難く、保存安定性に優れることが明らかとなった。 From the results of Test Examples 1 and 2 above, when an aqueous composition containing a compound represented by the general formula (1) containing ripasudil, a salt thereof, or a solvate thereof is housed in a polyester resin container. It was clarified that crystals are relatively difficult to precipitate even when stored at a low temperature, and the storage stability is excellent.
[製造例1~27]
表5~表7に記載の成分及び分量(水性組成物100mL当たりの量(g))を含有する水性組成物を常法により調製し、これをポリエチレンテレフタレート製の点眼剤用容器に収容して、製造例1~27の医薬製剤を製造できる。
[Manufacturing Examples 1-27]
An aqueous composition containing the components and amounts (amount (g) per 100 mL of the aqueous composition) shown in Tables 5 to 7 is prepared by a conventional method, and the aqueous composition is contained in a polyethylene terephthalate container for eye drops. , The pharmaceutical preparations of Production Examples 1 to 27 can be produced.
[製造例28~54]
製造例1~27において、リパスジル1塩酸塩2水和物の代わりに同量の4-ブロモ-5-[[(2S)-2-メチル-1,4-ジアゼパン-1-イル]スルホニル]イソキノリンを用いたものを、製造例28~54の医薬製剤として、常法により製造できる。
[Manufacturing Examples 28 to 54]
In Production Examples 1-27, the same amount of 4-bromo-5-[[(2S) -2-methyl-1,4-diazepan-1-yl] sulfonyl] isoquinoline is used instead of ribasudil monohydrochloride dihydrate. Can be produced by a conventional method as a pharmaceutical preparation of Production Examples 28 to 54.
本発明によれば、保存安定性に優れた医薬製剤を提供でき、医薬品産業等において好適に利用できる。 According to the present invention, it is possible to provide a pharmaceutical preparation having excellent storage stability, which can be suitably used in the pharmaceutical industry and the like.
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