JP7449336B2 - 医薬品(2) - Google Patents
医薬品(2) Download PDFInfo
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- JP7449336B2 JP7449336B2 JP2022113726A JP2022113726A JP7449336B2 JP 7449336 B2 JP7449336 B2 JP 7449336B2 JP 2022113726 A JP2022113726 A JP 2022113726A JP 2022113726 A JP2022113726 A JP 2022113726A JP 7449336 B2 JP7449336 B2 JP 7449336B2
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- 229950002083 octabenzone Drugs 0.000 description 1
- OIPZNTLJVJGRCI-UHFFFAOYSA-M octadecanoyloxyaluminum;dihydrate Chemical compound O.O.CCCCCCCCCCCCCCCCCC(=O)O[Al] OIPZNTLJVJGRCI-UHFFFAOYSA-M 0.000 description 1
- 229960003921 octisalate Drugs 0.000 description 1
- FMJSMJQBSVNSBF-UHFFFAOYSA-N octocrylene Chemical compound C=1C=CC=CC=1C(=C(C#N)C(=O)OCC(CC)CCCC)C1=CC=CC=C1 FMJSMJQBSVNSBF-UHFFFAOYSA-N 0.000 description 1
- WCJLCOAEJIHPCW-UHFFFAOYSA-N octyl 2-hydroxybenzoate Chemical compound CCCCCCCCOC(=O)C1=CC=CC=C1O WCJLCOAEJIHPCW-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 238000012261 overproduction Methods 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229960001257 oxyquinoline sulfate Drugs 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000000734 parasympathomimetic agent Substances 0.000 description 1
- 235000019477 peppermint oil Nutrition 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 229960000969 phenyl salicylate Drugs 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- LYKRPDCJKSXAHS-UHFFFAOYSA-N phenyl-(2,3,4,5-tetrahydroxyphenyl)methanone Chemical compound OC1=C(O)C(O)=CC(C(=O)C=2C=CC=CC=2)=C1O LYKRPDCJKSXAHS-UHFFFAOYSA-N 0.000 description 1
- 229940067107 phenylethyl alcohol Drugs 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229960001697 physostigmine Drugs 0.000 description 1
- PIJVFDBKTWXHHD-HIFRSBDPSA-N physostigmine Chemical compound C12=CC(OC(=O)NC)=CC=C2N(C)[C@@H]2[C@@]1(C)CCN2C PIJVFDBKTWXHHD-HIFRSBDPSA-N 0.000 description 1
- 229960002139 pilocarpine hydrochloride Drugs 0.000 description 1
- RNAICSBVACLLGM-GNAZCLTHSA-N pilocarpine hydrochloride Chemical compound Cl.C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C RNAICSBVACLLGM-GNAZCLTHSA-N 0.000 description 1
- 229960001963 pilocarpine nitrate Drugs 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003207 poly(ethylene-2,6-naphthalate) Polymers 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 229920001281 polyalkylene Polymers 0.000 description 1
- 229920001230 polyarylate Polymers 0.000 description 1
- 229920001707 polybutylene terephthalate Polymers 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229940068886 polyethylene glycol 300 Drugs 0.000 description 1
- 239000011112 polyethylene naphthalate Substances 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229960004109 potassium acetate Drugs 0.000 description 1
- 229940068988 potassium aspartate Drugs 0.000 description 1
- 229960004839 potassium iodide Drugs 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- 201000006366 primary open angle glaucoma Diseases 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000006085 pyrrolopyridyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 239000003590 rho kinase inhibitor Substances 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 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 1
- 229950007455 ripasudil Drugs 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 229920006300 shrink film Polymers 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 229960003885 sodium benzoate Drugs 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000019259 sodium dehydroacetate Nutrition 0.000 description 1
- 229940079839 sodium dehydroacetate Drugs 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 229940037001 sodium edetate Drugs 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229940006186 sodium polystyrene sulfonate Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- DSOWAKKSGYUMTF-GZOLSCHFSA-M sodium;(1e)-1-(6-methyl-2,4-dioxopyran-3-ylidene)ethanolate Chemical compound [Na+].C\C([O-])=C1/C(=O)OC(C)=CC1=O DSOWAKKSGYUMTF-GZOLSCHFSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 229940032330 sulfuric acid Drugs 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229940127230 sympathomimetic drug Drugs 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229960004458 tafluprost Drugs 0.000 description 1
- WSNODXPBBALQOF-VEJSHDCNSA-N tafluprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\C(F)(F)COC1=CC=CC=C1 WSNODXPBBALQOF-VEJSHDCNSA-N 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000004588 thienopyridyl group Chemical group S1C(=CC2=C1C=CC=N2)* 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 235000019149 tocopherols Nutrition 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M toluenesulfonate group Chemical group C=1(C(=CC=CC1)S(=O)(=O)[O-])C LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- WYXIGTJNYDDFFH-UHFFFAOYSA-Q triazanium;borate Chemical compound [NH4+].[NH4+].[NH4+].[O-]B([O-])[O-] WYXIGTJNYDDFFH-UHFFFAOYSA-Q 0.000 description 1
- 125000001425 triazolyl group Chemical group 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
- MDYZKJNTKZIUSK-UHFFFAOYSA-N tyloxapol Chemical compound O=C.C1CO1.CC(C)(C)CC(C)(C)C1=CC=C(O)C=C1 MDYZKJNTKZIUSK-UHFFFAOYSA-N 0.000 description 1
- 229920001664 tyloxapol Polymers 0.000 description 1
- 229960004224 tyloxapol Drugs 0.000 description 1
- 239000006097 ultraviolet radiation absorber Substances 0.000 description 1
- 229950008081 unoprostone isopropyl Drugs 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- 239000004711 α-olefin Substances 0.000 description 1
- QUEDXNHFTDJVIY-UHFFFAOYSA-N γ-tocopherol Chemical class OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 QUEDXNHFTDJVIY-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
- A61J1/14—Details; Accessories therefor
- A61J1/1468—Containers characterised by specific material properties
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
Description
具体的には例えば、以下の構造式:
そのため、これらのイソキノリン-6-アミノ誘導体を、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。
そこで、本発明者は、イソキノリン-6-アミノ誘導体の、水性組成物中での熱に対する安定性を改善するため更に鋭意検討した。しかるところ、イソキノリン-6-アミノ誘導体を含有する水性組成物を、ポリエステル系樹脂製容器又はポリオレフィン系樹脂製容器という特定の容器に収容した場合に、高温保存時の含量低下が抑制され、熱安定性の改善された医薬製剤となることを見出し、本発明を完成した。
R3は水素原子又はヒドロキシ基を示し、
Aは-CH(R4)-又は-CH2-CH(R4)-(ここでR4は置換基を有してもよいC6~C10アリール基、又は置換基を有してもよい5~10員のヘテロアリール基を示す。)を示し、
さらに、式(1)には、その互変異性体も含まれる。)
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又はポリオレフィン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。
R3は水素原子又はヒドロキシ基を示し、
Aは-CH(R4)-又は-CH2-CH(R4)-(ここでR4は置換基を有してもよいC6~C10アリール基、又は置換基を有してもよい5~10員のヘテロアリール基を示す。)を示し、
さらに、式(1)には、その互変異性体も含まれる。)
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」には、一般式(1)で表される化合物そのもののほか、その塩や溶媒和物も含まれる。
また、一般式(1)で表される化合物やその塩の溶媒和物としては、水和物やアルコール和物等が挙げられる。
さらに、一般式(1)で表される化合物の化学構造中に不斉炭素が存する場合には、種々の立体異性体が存在し得るが、一般式(1)で表される化合物としてはその立体配置は特に限定されず、単一の立体異性体でも、各種立体異性体の任意の割合の混合物でもよい。
なお、本明細書において、各種の式で表される化合物がその化学構造中に不斉炭素を有する場合においては、特に立体配置を指定しない限り、斯かる式は各種立体異性体単独及びそれらの任意の割合の混合物の全てを包含する。従って、特に立体配置を指定しない式で表される化合物は、単一の立体異性体であってもよく、また、各種立体異性体の任意の割合の混合物であってもよい。
本明細書において、「C6~C10アリール基」とは、炭素数6~10のアリール基を意味する。「C6~C10アリール基」としては、具体的には例えば、フェニル基、ナフチル基等が挙げられ、フェニル基が好ましい。
本明細書において、「置換基を有してもよいC6~C10アリール基」としては、4-クロロフェニル基、4-(2,4-ジメチルフェニルカルボキシメチル)フェニル基が好ましい。
本明細書において、「置換基を有してもよい5~10員のヘテロアリール基」としては、3-チエニル基が好ましい。
R3がヒドロキシ基である場合、R3の置換位置はイソキノリン環上であれば限定されないが、イソキノリン環の1位が好ましい。
また、別の態様として、「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、下記式(5)又は(5'):
また、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市販されており、これらの市販品を用いてもよい。市販品としては、具体的には例えば、Medchemexpress社製やChemscene LLS社製のネタースジル2メシル酸塩(式(4)で表される化合物)や、Shanghai biopharmaleader社製のネタースジルの1塩酸塩(式(3)で表される化合物の1塩酸塩)、MedKoo biosciences社製のヴェロスジル(式(6)で表される化合物のフリー体)などが挙げられる。
特に、一般式(1)で表される化合物としてネタースジルを使用する場合においては、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、ネタースジルをフリー体に換算して0.0001~1w/v%含有するのが好ましく、0.001~0.5w/v%含有するのがより好ましく、0.005~0.1w/v%含有するのがさらに好ましく、0.01~0.04w/v%含有するのが特に好ましい。
また、一般式(1)で表される化合物としてヴェロスジルを使用する場合においては、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、ヴェロスジルをフリー体に換算して0.01~3.5w/v%含有するのが好ましく、0.1~2.5w/v%含有するのがより好ましく、0.2~1.5w/v%含有するのがさらに好ましく、0.3~0.8w/v%含有するのが特に好ましい。
さらに、一般式(1)で表される化合物として式(8)で表される化合物を使用する場合においては、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、式(8)で表される化合物をフリー体に換算して0.0001~3w/v%含有するのが好ましく、0.001~2w/v%含有するのがより好ましく、0.005~1w/v%含有するのがさらに好ましく、0.01~0.5w/v%含有するのが特に好ましい。
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、90~99.99質量%が特に好ましい。
他の薬効成分としては、β遮断薬が好ましく、チモロールが好ましい。
<A-1> (rac)-2-(ジメチルアミノ)-N-(1-ヒドロキシイソキノリン-6-イル)-2-(チオフェン-3-イル)アセトアミド塩酸塩、トラボプロスト、ホウ酸、D-マンニトール、塩化ベンザルコニウム、ステアリン酸ポリオキシル40、ポリエチレングリコール400、EDTA、及び精製水を含む組成物。
<A-2> (rac)-2-(ジメチルアミノ)-N-(1-ヒドロキシイソキノリン-6-イル)-2-(チオフェン-3-イル)アセトアミド塩酸塩、トラボプロスト、ホウ酸、D-マンニトール、塩化ベンザルコニウム、クレモフォールRH40、ポリエチレングリコール400、EDTA、及び精製水を含む組成物。
<A-3> (rac)-2-(ジメチルアミノ)-N-(1-ヒドロキシイソキノリン-6-イル)-2-(チオフェン-3-イル)アセトアミド塩酸塩、トラボプロスト、ホウ酸、D-マンニトール、ステアリン酸ポリオキシル40、ポリエチレングリコール400、EDTA、及び精製水を含む組成物。
<A-4> (rac)-2-(ジメチルアミノ)-N-(1-ヒドロキシイソキノリン-6-イル)-2-(チオフェン-3-イル)アセトアミド塩酸塩、ラタノプロスト、一塩基性リン酸ナトリウム、二塩基性リン酸ナトリウム、塩化ベンザルコニウム、塩化ナトリウム、EDTA、及び精製水を含む組成物。
<A-5> (rac)-2-(ジメチルアミノ)-N-(1-ヒドロキシイソキノリン-6-イル)-2-(チオフェン-3-イル)アセトアミド塩酸塩、ラタノプロスト、ホウ酸、D-マンニトール、塩化ベンザルコニウム、EDTA、及び精製水を含む組成物。
<A-6> (rac)-2-(ジメチルアミノ)-N-(1-ヒドロキシイソキノリン-6-イル)-2-(チオフェン-3-イル)アセトアミド塩酸塩、ビマトプロスト、一塩基性リン酸ナトリウム、二塩基性リン酸ナトリウム、塩化ベンザルコニウム、塩化ナトリウム、EDTA、及び精製水を含む組成物。
<A-7> (rac)-2-(ジメチルアミノ)-N-(1-ヒドロキシイソキノリン-6-イル)-2-(チオフェン-3-イル)アセトアミド塩酸塩、ビマトプロスト、一塩基性リン酸ナトリウム、二塩基性リン酸ナトリウム、塩化ベンザルコニウム、塩化ナトリウム、EDTA、及び精製水を含む組成物。
<A-8> (rac)-2-(ジメチルアミノ)-N-(1-ヒドロキシイソキノリン-6-イル)-2-(チオフェン-3-イル)アセトアミド塩酸塩、ビマトプロスト、ホウ酸、D-マンニトール、及び精製水を含む組成物。
<A-9> 2,4-ジメチル安息香酸(S)-4-(3-アミノ-1-(イソキノリン-6-イルアミノ)-1-オキソプロパン-2-イル)ベンジル、トラボプロスト、ホウ酸、D-マンニトール、塩化ベンザルコニウム、ステアリン酸ポリオキシル40、ポリエチレングリコール400、EDTA、及び精製水を含む組成物。
<A-10> 2,4-ジメチル安息香酸(S)-4-(3-アミノ-1-(イソキノリン-6-イルアミノ)-1-オキソプロパン-2-イル)ベンジル、ラタノプロスト、ホウ酸、D-マンニトール、塩化ベンザルコニウム、ステアリン酸ポリオキシル40、ポリエチレングリコール400、EDTA、及び精製水を含む組成物。
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、第十七改正日本薬局方 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。
容器としては、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、点眼剤用容器であるのが好ましい。
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、一般式(1)で表される化合物の高温保存時の含量低下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。
このようなポリオレフィン系樹脂としては、具体的には例えば、ポリエチレン(より詳細には例えば低密度ポリエチレン(直鎖状低密度ポリエチレンを含む)、高密度ポリエチレン、中密度ポリエチレンなど)、ポリプロピレン、環状ポリオレフィン、ポリ(4-メチルペンテン)、ポリテトラフルオロエチレン、エチレン・プロピレン共重合体、エチレン・α-オレフィン共重合体、エチレン・アクリル酸共重合体、エチレン・メタクリル酸共重合体、エチレン・酢酸ビニル共重合体、エチレン・アクリル酸エチル共重合体等が挙げられ、これらの1種又は2種以上を組合わせて使用できる。ポリオレフィン系樹脂としては、一般式(1)で表される化合物の高温保存時の含量低下を抑制する観点から、ポリエチレン、ポリプロピレン、環状ポリオレフィンが好ましく、低密度ポリエチレン、中密度ポリエチレン、高密度ポリエチレン、ポリプロピレンがより好ましく、低密度ポリエチレン、高密度ポリエチレン、ポリプロピレンが特に好ましい。
なお、本明細書において、「ポリオレフィン系樹脂製」とは、その材質の少なくとも一部にポリオレフィン系樹脂を含んでいることを意味し、例えば、ポリオレフィン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「ポリオレフィン系樹脂製」に含まれる。
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、ノルエピネフリントランスポーター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。
[1] 下記の一般式(1)
R3は水素原子又はヒドロキシ基を示し、
Aは-CH(R4)-又は-CH2-CH(R4)-(ここでR4は置換基を有してもよいC6~C10アリール基、又は置換基を有してもよい5~10員のヘテロアリール基を示す。)を示し、
さらに、式(1)には、その互変異性体も含まれる。)
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又はポリオレフィン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、下記式(2)、(5)、(5')又は(8):
[3] 前記一般式(1)で表される化合物が、下記式(3)又は(6):
[6] 前記ポリオレフィン系樹脂が、ポリエチレン又はポリプロピレンである、[1]~[5]のいずれか記載の医薬製剤。
[7] 前記容器が、点眼剤用容器である、[1]~[6]のいずれか記載の医薬製剤。
[9] 前記一般式(1)で表される化合物が、前記式(2)、(5)、(5')又は(8)で表される化合物である、[8]記載の方法。
[10] 前記一般式(1)で表される化合物が、前記式(3)又は(6)で表される化合物である、[8]記載の方法。
[11] 前記一般式(1)で表される化合物が、前記式(4)又は(7)で表される化合物である、[8]記載の方法。
[12] 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、[8]~[11]のいずれか記載の方法。
[13] 前記ポリオレフィン系樹脂が、ポリエチレン又はポリプロピレンである、[8]~[12]のいずれか記載の方法。
[14] 前記容器が、点眼剤用容器である、[8]~[13]のいずれか記載の方法。
また、以下の試験例において、HPLCを用いたネタースジルの測定は、カラムとしてODSカラムを、移動相として0.01モル/L リン酸緩衝液とアセトニトリルを、検出器として紫外吸光光度計(波長:254nm)をそれぞれ用いて行った。
ネタースジルの水性組成物中での熱に対する安定性を、高温条件下で一定期間保存後のネタースジルの含量低下の有無を確認することにより評価した。
すなわち、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、低密度ポリエチレン(LDPE)製、高密度ポリエチレン(HDPE)製、又はポリプロピレン(PP)製の容器に入れて、それぞれ実施例1~4の医薬製剤とした。また、別途、同一の水性組成物をガラス製の容器に入れて、比較例の医薬製剤とした。
得られた各医薬製剤を、80℃で1週間保存した。保存後のネタースジルの含量低下の有無を確認するため、各医薬製剤における、保存前後の水性組成物中のネタースジルの濃度を測定した。水性組成物中のネタースジルの濃度は、HPLCを用いて、濃度既知のネタースジル溶液のピーク面積に対する水性組成物中のピーク面積の比率を測定することにより算出した。
そして、得られた水性組成物中のネタースジルの濃度より、以下の式に従い、ネタースジルの残存率(%)を評価した。
特に、ポリエチレンテレフタレート(PET)製又はポリエチレン(LDPE、HDPE)製の容器に収容した場合、含量低下の抑制の度合いは顕著であった。
ネタースジルのポリエステル系樹脂製容器への吸着の有無を検討するため、ネタースジルを含有する水性組成物にポリエステル系樹脂製の切片を共存させて一定期間保存した後の、水性組成物中のネタースジルの含量低下の有無を確認した。
すなわち、表3に示す水性組成物を常法により調製した後、そのうち5mLをガラス容器に収容し、さらに、水性組成物にポリエチレンテレフタレート(PET)製の樹脂切片3枚(それぞれ、1cm×2cmの大きさ)を浸漬させて、例1の医薬製剤を得た。また、別途、ポリエチレンテレフタレート製の樹脂切片を浸漬させない以外は例1と同様にして、例2の医薬製剤を得た。
得られた各医薬製剤を、60℃で1週間保存した。保存後のネタースジルの含量低下の有無を確認するため、試験例1と同様の方法により、ネタースジルの残存率(%)を評価した。
結果を表3に示す。
表4~表12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1~36の医薬製剤を製造できる。
製造例1~36において、ポリエチレンテレフタレート製の代わりに高密度ポリエチレン製の点眼剤用容器を用いて、製造例37~72の医薬製剤を製造できる。
製造例1~36において、ポリエチレンテレフタレート製の代わりにポリプロピレン製の点眼剤用容器を用いて、製造例73~108の医薬製剤を製造できる。
製造例1~36において、ポリエチレンテレフタレート製の代わりに低密度ポリエチレン製の点眼剤用容器を用いて、製造例109~144の医薬製剤を製造できる。
製造例1~144において、ネタースジル2メシル酸塩の代わりに、フリー体として0.5gのヴェロスジル1塩酸塩を用いたものを、製造例145~288の医薬製剤として、常法により製造できる。
製造例1~144において、ネタースジル2メシル酸塩の代わりに、フリー体として0.7gのヴェロスジル1塩酸塩を用いたものを、製造例289~432の医薬製剤として、常法により製造できる。
製造例1~144において、ネタースジル2メシル酸塩の代わりに、0.02gの式(8)で表される化合物を用いたものを、製造例433~576の医薬製剤として、常法により製造できる。
Claims (6)
- 前記水性組成物のpH(25℃)が5~6である、請求項1記載の医薬製剤。
- 前記容器が、点眼剤用容器である、請求項1又は2記載の医薬製剤。
- 前記水性組成物のpH(25℃)が5~6である、請求項4記載の方法。
- 前記容器が、点眼剤用容器である、請求項4又は5記載の方法。
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