WO2016047721A1 - 医薬製剤 - Google Patents
医薬製剤 Download PDFInfo
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- WO2016047721A1 WO2016047721A1 PCT/JP2015/077015 JP2015077015W WO2016047721A1 WO 2016047721 A1 WO2016047721 A1 WO 2016047721A1 JP 2015077015 W JP2015077015 W JP 2015077015W WO 2016047721 A1 WO2016047721 A1 WO 2016047721A1
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- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 229960003885 sodium benzoate Drugs 0.000 description 1
- 229940001607 sodium bisulfite Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 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
- 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
- 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
- 238000003892 spreading Methods 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
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229940032330 sulfuric acid Drugs 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000001975 sympathomimetic effect Effects 0.000 description 1
- 229940064707 sympathomimetics Drugs 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- 239000000057 synthetic resin Substances 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
- 229940095064 tartrate Drugs 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 1
- 229920005992 thermoplastic resin Polymers 0.000 description 1
- 239000002562 thickening agent Substances 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
- 235000010384 tocopherol Nutrition 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- MKPLKVHSHYCHOC-AHTXBMBWSA-N travoprost 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@@H](O)COC1=CC=CC(C(F)(F)F)=C1 MKPLKVHSHYCHOC-AHTXBMBWSA-N 0.000 description 1
- 229960002368 travoprost Drugs 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 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
- 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
- 239000004711 α-olefin Substances 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
-
- 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
-
- 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
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
-
- 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
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
- B65D81/00—Containers, packaging elements, or packages, for contents presenting particular transport or storage problems, or adapted to be used for non-packaging purposes after removal of contents
- B65D81/24—Adaptations for preventing deterioration or decay of contents; Applications to the container or packaging material of food preservatives, fungicides, pesticides or animal repellants
- B65D81/30—Adaptations for preventing deterioration or decay of contents; Applications to the container or packaging material of food preservatives, fungicides, pesticides or animal repellants by excluding light or other outside radiation
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
- C08K3/00—Use of inorganic substances as compounding ingredients
- C08K3/18—Oxygen-containing compounds, e.g. metal carbonyls
- C08K3/20—Oxides; Hydroxides
- C08K3/22—Oxides; Hydroxides of metals
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
- C08K5/00—Use of organic ingredients
- C08K5/16—Nitrogen-containing compounds
- C08K5/34—Heterocyclic compounds having nitrogen in the ring
- C08K5/3467—Heterocyclic compounds having nitrogen in the ring having more than two nitrogen atoms in the ring
- C08K5/3472—Five-membered rings
- C08K5/3475—Five-membered rings condensed with carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
- C08K3/00—Use of inorganic substances as compounding ingredients
- C08K3/18—Oxygen-containing compounds, e.g. metal carbonyls
- C08K3/20—Oxides; Hydroxides
- C08K3/22—Oxides; Hydroxides of metals
- C08K2003/2237—Oxides; Hydroxides of metals of titanium
- C08K2003/2241—Titanium dioxide
Definitions
- the present invention relates to pharmaceutical preparations and the like.
- Ripasudil (chemical name: 4-fluoro-5-[[(2S) -2-methyl-1,4-diazepan-1-yl] sulfonyl] isoquinoline) and the following structural formula:
- Halogenated isoquinoline derivatives such as 4-bromo-5-[[(2S) -2-methyl-1,4-diazepan-1-yl] sulfonyl] isoquinoline represented by the formula:
- it has patent documents 1 and 2) and is known to be useful for prevention and treatment of eye diseases.
- it is useful for prevention or treatment of ocular hypertension, glaucoma, etc. (for example, Patent Document 3), or prevention or treatment of fundus diseases such as age-related macular degeneration (for example, Patent Document 4). It has been reported.
- the present inventors first evaluated the photostability of ripaspil when formulating ripaspil, which is a halogenated isoquinoline derivative, as an ophthalmic preparation or the like.
- Ripasudil itself is extremely stable against light. It is considered that the light stability of an organic compound depends on its structure and does not depend on the state (solid, liquid, etc.).
- Ophthalmic preparations and the like are usually water-containing compositions (aqueous compositions). However, it was expected that Ripasudil would not cause a problem in light stability even when blended with an aqueous composition.
- an object of this invention is to provide the technique which improves the stability with respect to the light in the aqueous composition of halogenated isoquinoline derivatives, such as a ripaspil.
- the inventors of the present invention have made further studies in order to solve the above problems.
- the photodecomposition of Ripasudil in the aqueous composition is caused by irradiation with light having a wavelength near 300 nm. It has been found that a pharmaceutical preparation with improved light stability can be obtained by containing it in a package that blocks light, and the present invention has been completed.
- a pharmaceutical preparation comprising an aqueous composition containing a compound represented by the formula: or a salt thereof, or a solvate thereof, contained in a package that blocks light having a wavelength of 300 to 335 nm.
- ⁇ 2> including a step of containing an aqueous composition containing the compound represented by the general formula (1) or a salt thereof or a solvate thereof in a package that blocks light having a wavelength of 300 to 335 nm.
- the stability of a halogenated isoquinoline derivative such as ripaspil to light in an aqueous composition can be improved.
- a pharmaceutical preparation comprising an aqueous composition containing a compound represented by the formula: or a salt thereof, or a solvate thereof, contained in a package that blocks light having a wavelength of 300 to 335 nm.
- the primary package is Substances that block the transmission of ultraviolet rays (preferably one or more selected from ultraviolet scattering agents and ultraviolet absorbers; more preferably, one or more selected from zinc oxide, titanium oxide and benzotriazole-based ultraviolet absorbers)
- a package (preferably the interior is visually recognized) which is a container (preferably made of plastic; more preferably, a container made of polyolefin resin or polyester resin (preferably a container for eye drops)) Possible packaging); or Substances that block the transmission of ultraviolet rays (preferably one or more selected from ultraviolet scattering agents and ultraviolet absorbers; more preferably, one or more selected from zinc oxide, titanium oxide and benzotriazole-based ultraviolet absorbers)
- Container preferably made of plastic; more preferably made of polyolefin-based resin or polyester-based resin
- a packaging body (preferably a packaging body whose inside is visible); The pharmaceutical preparation according to any one of [1] to [8].
- a package preferably, an inner bag made of plastic; more preferably, a polyolefin resin or a polyester resin, preferably a bag (preferably an eye drop medication bag)
- [13] including a step of containing an aqueous composition containing the compound represented by the general formula (1) or a salt thereof or a solvate thereof in a package that blocks light having a wavelength of 300 to 335 nm.
- [14] The method according to [13], wherein the compound represented by the general formula (1) is ripaspil.
- the package blocks light rays having a wavelength of 300 to 370 nm.
- [16] The method according to [13] or [14], wherein the package blocks light rays having a wavelength of 300 to 395 nm.
- the primary package is Substances that block the transmission of ultraviolet rays (preferably one or more selected from ultraviolet scattering agents and ultraviolet absorbers; more preferably, one or more selected from zinc oxide, titanium oxide and benzotriazole-based ultraviolet absorbers)
- a package (preferably the interior is visually recognized) which is a container (preferably made of plastic; more preferably, a container made of polyolefin resin or polyester resin (preferably a container for eye drops)) Possible packaging); or Substances that block the transmission of ultraviolet rays (preferably one or more selected from ultraviolet scattering agents and ultraviolet absorbers; more preferably, one or more selected from zinc oxide, titanium oxide and benzotriazole-based ultraviolet absorbers)
- Container preferably made of plastic; more preferably made of polyolefin-based resin or polyester-based resin
- a packaging body (preferably a packaging body whose inside is visible); The method according to any one of [13] to [20], wherein [
- the aqueous composition further comprises an ⁇ 1 receptor blocker, an ⁇ 2 receptor agonist, a ⁇ blocker, a carbonic anhydrase inhibitor, a prostaglandin F2 ⁇ derivative, a sympathomimetic agent, a parasympathomimetic agent, and a calcium antagonist.
- the aqueous composition further comprises an ⁇ 1 receptor blocker, an ⁇ 2 receptor agonist, a ⁇ blocker, a carbonic anhydrase inhibitor, a prostaglandin F2 ⁇ derivative, a sympathomimetic agent, a parasympathomimetic agent, and a calcium antagonist.
- aqueous composition further contains one or more selected from the group consisting of latanoprost, nipradilol, dorzolamide, brinzolamide, timolol and salts thereof.
- examples of the halogen atom include a fluorine atom, a chlorine atom, and a bromine atom.
- the halogen atom is preferably a fluorine atom or a bromine atom, particularly preferably a fluorine atom.
- the carbon atom constituting the homopiperazine ring substituted with a methyl group is an asymmetric carbon. Therefore, although stereoisomerism occurs, the compound represented by the general formula (1) includes any stereoisomer, and may be a single stereoisomer or a mixture of various stereoisomers in any ratio. .
- the compound whose absolute configuration is S configuration is preferable.
- the salt of the compound represented by the general formula (1) is not particularly limited as long as it is a pharmaceutically acceptable salt.
- the compound represented by the general formula (1) or a salt thereof may be a solvate such as a hydrate or an alcohol solvate, and is preferably a hydrate.
- 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; Etc.
- Examples of the compound represented by the general formula (1) or a salt thereof or a solvate thereof include Ripasudil 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, ripaspil or a salt thereof or a solvate thereof is more preferable, and ripaspil or a hydrochloride thereof or a hydrate thereof. Is more preferred and has the following structural formula:
- Ripasudil hydrochloride hydrate represented by the formula (Ripazil monohydrochloride dihydrate) is particularly preferred.
- the compound represented by the general formula (1) or a salt thereof or a solvate thereof is known and can be produced by a known method.
- Ripasudil or a salt thereof or a solvate thereof can be produced by a method described in International Publication No. 1999/020620 Pamphlet, International Publication No. 2006/057397 Pamphlet or the like.
- 4-bromo-5-[[(2S) -2-methyl-1,4-diazepan-1-yl] sulfonyl] isoquinoline or a salt thereof or a solvate thereof is disclosed in International Publication No. 2006/115244 pamphlet. It can be produced by the method described.
- 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 determined according to the disease applied, the sex, age, symptoms, etc. of the patient.
- 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 % More preferably 0.02 to 8 w / v%, and particularly preferably 0.04 to 6 w / v%.
- ripaspil as the compound represented by the general formula (1)
- ripaspil or a salt thereof or a solvate thereof is used with respect to the total volume of the aqueous composition. It is preferably contained in a free form 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%.
- the “aqueous composition” means a composition containing at least water, and its properties include liquid (solution or suspension) and semi-solid (ointment).
- water in a composition purified water, water for injection, sterilized purified water, etc. can be used, for example.
- 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 more preferably 90 to 99.8% by mass is particularly preferred.
- the aqueous composition can be made into various dosage forms according to known methods described in, for example, the 16th revised Japanese Pharmacopoeia, General Rules for Preparations.
- the dosage form is not particularly limited as long as it can be accommodated in a package to be described later.
- injection, inhalation solution, eye drops, eye ointment, ear drops, nasal solution, enema, external use Liquids, sprays, ointments, gels, oral liquids, syrups and the like can be mentioned.
- an ophthalmic agent specifically an eye drop and an eye ointment are preferable, and an eye drop is particularly preferable. .
- the aqueous composition may contain additives used in pharmaceuticals, quasi drugs, etc., depending on the dosage form.
- additives include, for example, inorganic salts, isotonic agents, chelating agents, stabilizers, pH adjusters, preservatives, antioxidants, thickeners, surfactants, solubilizers, suspensions.
- examples include turbidizers, cooling agents, dispersants, preservatives, oily bases, emulsion bases, water-soluble bases, and the like.
- additives include ascorbic acid, potassium aspartate, sodium bisulfite, alginic acid, sodium benzoate, benzyl benzoate, epsilon-aminocaproic acid, fennel oil, ethanol, and ethylene / vinyl acetate copolymer.
- additives include potassium chloride, calcium chloride hydrate, sodium chloride, magnesium chloride, glycerin, acetic acid, potassium acetate, sodium acetate hydrate, tartaric acid, sodium hydroxide, sodium bicarbonate, sodium carbonate hydrate.
- the aqueous composition may further contain other medicinal ingredients depending on the disease to be applied.
- medicinal ingredients include ⁇ 1 receptor blockers including bunazosin such as bunazosin hydrochloride or a salt thereof or a solvate thereof; brimonidine or a salt thereof such as brimonidine tartrate or an solvate thereof; ⁇ 2 receptor agonist containing clonidine or a salt thereof or a solvate thereof; carteolol or a salt thereof such as carteolol hydrochloride or a solvate thereof, nipradilol or a salt thereof or a solvate thereof, timolol maleic acid Timolol such as a salt or a salt thereof or a solvate thereof, betaxolol or a salt thereof such as betaxolol hydrochloride or a solvate thereof, levobunolol or a salt thereof such as levobanolol hydrochloride or a salt thereof, levobun
- 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. Further, the osmotic pressure ratio with respect to physiological saline is not particularly limited, but is preferably 0.6 to 3, particularly preferably 0.6 to 2.
- the “packaging body” means a packaging body that directly or indirectly contains the aqueous composition.
- a container directly containing the aqueous composition for example, an eye drop container directly filled with the aqueous composition
- a package that indirectly contains the aqueous composition that is, a package that further contains the primary package: for example, an eye drop medication bag (a bag that contains an eye drop container)).
- secondary package the packaging body only needs to be able to block light in the wavelength range to be described later in the storage state normally assumed for the pharmaceutical preparation, and it does not matter whether or not it has hermeticity.
- the package is a concept including any of “sealed container”, “airtight container”, and “sealed container” defined in the 16th revised Japanese Pharmacopoeia.
- At least one of the primary package and the secondary package may block light in the wavelength range described below.
- at least the primary package has a wavelength range described later. It is preferable to block the light beam.
- the form of the package is not particularly limited as long as it can contain the aqueous composition, and is appropriately selected according to the dosage form, the use of the pharmaceutical preparation, the primary package or the secondary package, etc. You only have to set it.
- Specific examples of such a package include, for example, an injection container, an inhaler container, a spray container, a bottle container, a tube container, an eye drop container, an nasal drop as a primary package.
- Examples include a container for ear drops, a container for ear drops, and a bag container.
- examples of the secondary package include a packaging bag (for example, an eye drop medication bag), a box (for example, a paper box), a bottle (for example, a glass bottle), a can (for example, an aluminum can), and the like.
- the packaging body is an embodiment having both the primary packaging body and the secondary packaging body
- the primary packaging body is an eye drop from the viewpoint of advantageously utilizing the pharmacological action of the compound represented by the general formula (1).
- the secondary package is preferably an eye drop packaging bag.
- the material (material) of the package is not particularly limited, and may be appropriately selected according to the form of the package. Specific examples include glass, plastic, cellulose, pulp, rubber, metal and the like.
- the material of the primary package directly containing the aqueous composition is preferably made of plastic or the like from the viewpoints of processability, squeeze property, durability, and the like.
- the material of the secondary package is preferably made of plastic, cellulose, pulp, paper, etc. from the viewpoint of processability and the like.
- the resin in the case of a plastic package is preferably a thermoplastic resin regardless of whether it is a synthetic resin or a natural resin.
- a polyolefin resin a polyester resin, a polyphenylene ether resin , Polycarbonate resins, polysulfone resins, polyamide resins, polyvinyl chloride resins, styrene resins, etc., and it is preferable to use one or two or more of these in combination. Alloy).
- the primary packaging material is preferably a polyolefin resin.
- the material of the primary package is a polyolefin resin. In this case, ⁇ YI was relatively suppressed, and it was found that the storage stability was excellent.
- at least a portion of the primary package that contacts the aqueous composition only needs to be made of a polyolefin-based resin, and another material is laminated on the outside or the like.
- the “primary package is made of polyolefin resin”.
- made of polyolefin resin means that at least a part of the material contains a polyolefin resin, for example, two or more resins of a polyolefin resin and another resin. (Polyolefin alloy) is also included in the “made of polyolefin resin”.
- the polyolefin-based resin is not particularly limited, and may be a polymer (homopolymer) of a single type of monomer or a copolymer (copolymer) of a plurality of types of monomers.
- the polymerization mode is not particularly limited, and may be random polymerization or block polymerization.
- the stereoregularity (tacticity) is not particularly limited.
- Specific examples of such polyolefin resins include polyethylene (more specifically, for example, low density polyethylene (including linear low density polyethylene), high density polyethylene, medium density polyethylene, etc.), polypropylene, and cyclic polyolefin.
- Poly (4-methylpentene), polytetrafluoroethylene, ethylene / propylene copolymer, ethylene / ⁇ -olefin copolymer, ethylene / acrylic acid copolymer, ethylene / methacrylic acid copolymer, ethylene / vinyl acetate Copolymers, ethylene / ethyl acrylate copolymers and the like can be mentioned, and one or more of these can be used in combination.
- polyolefin-based resin polyethylene and polypropylene are preferable, and polypropylene is particularly preferable from the viewpoint of keeping the ⁇ YI value low.
- a polyester-type resin as a material of a primary package.
- Test Examples 9 and 10 below when the aqueous composition contained in the primary package is stored at a low temperature, crystals can precipitate, but the primary package is made of a polyester resin. Thus, it was found that such crystal precipitation is relatively difficult to occur and the storage stability is excellent.
- at least the portion of the primary package that contacts the aqueous composition only needs to be made of a polyester-based resin, and another material is laminated on the outside or the like.
- the “primary package is made of polyester resin”.
- polyester resin means that at least a part of the material contains a polyester resin, for example, two or more resins of a polyester resin and another resin.
- the mixture (polymer alloy) is also included in “made of polyester resin”.
- the dicarboxylic acid and diol constituting the polyester resin are not particularly limited.
- the dicarboxylic acid include phthalic acid, terephthalic acid, and 2,6-naphthalenedicarboxylic acid.
- the diol include ethylene glycol and 1,3. -Propanediol, 1,4-butanediol, 1,4-cyclohexanedimethanol, bisphenol and the like. Further, it may be a polymer of a single type of polyester unit or a polymer of a plurality of types of polyester units. In the case of a polymer of a plurality of types of polyester units, the polymerization mode is not particularly limited, and may be random polymerization or block polymerization.
- stereoregularity is not particularly limited.
- polyester resins include polyalkylene terephthalate (eg, polyethylene terephthalate, polybutylene terephthalate, etc.), polyalkylene naphthalate (eg, polyethylene naphthalate, polybutylene naphthalate, etc.), polycyclohexane, and the like.
- Homopolyesters such as alkylene terephthalate (for example, poly (1,4-cyclohexylenedimethylene terephthalate)), polyarylate (for example, resin composed of bisphenol and phthalic acid), and the main component of these homopolyester units And a copolymer of the above-mentioned homopolyester. These may be used alone or in combination of two or more.
- polyethylene terephthalate is preferable from the viewpoint of suppressing crystal precipitation.
- the wavelength range of light blocked by the package is sufficient in the range of 300 to 335 nm considering the normal storage environment of the pharmaceutical preparation, but from the viewpoint of further improving the stability to light, 300 to 370 nm is preferable. 300 to 395 nm is more preferable. Further, considering use under storage conditions where there is a high risk of exposure to a wavelength of less than 300 nm, 270 to 335 nm is preferable, 270 to 370 nm is more preferable, and 270 to 395 nm is particularly preferable.
- blocking light in the wavelength range means that the average value of the transmittance of light in the wavelength range is 40% or less. Therefore, for example, “a package that blocks light having a wavelength of 300 to 335 nm” means a package having an average value of light transmittance of a wavelength of 300 to 335 nm of 40% or less.
- the average value of the transmittance of light in the wavelength range of the package is preferably 30% or less, more preferably 25% or less, from the viewpoint of further improving the stability to light. % Or less, more preferably 15% or less, even more preferably 10% or less, and particularly preferably 5% or less.
- the average value of the light transmittance in a specific wavelength range is measured by measuring the light transmittance of the package in the air every 0.5 nm within the range using a spectrophotometer. Then, it can be measured by calculating the average value.
- a spectrophotometer is U-3900 (Hitachi High-Technologies Corporation).
- the specific means for blocking the light beam in the wavelength range is not particularly limited, for example, a method using a substance that blocks the light beam in the wavelength range, and more specifically, for example, A method of containing a substance that blocks light in the wavelength range in the package (for example, a method of adding a substance that blocks light in the wavelength range to glass or resin, and molding this into a container shape); A method of providing a member (for example, a film or the like) containing a substance that blocks light in the wavelength range on the surface of the package (at least one of the inside and outside of the package) (for example, a resin having the wavelength range) Add a substance that blocks the light of the film to make a heat-shrinkable film and wrap this around the outer surface of the container etc.); A method of coating a surface of the package (at least one of the inside and outside of the package) with a substance that blocks light in the wavelength range; A method of using a substance that blocks light in the above wavelength range as a main material of the package (for example,
- the substance that blocks light in the wavelength range is not particularly limited, but is preferably a substance that blocks the transmission of ultraviolet rays, such as an ultraviolet absorber and an ultraviolet scattering agent, from the viewpoint that the inside of the package can be made visible.
- examples of the ultraviolet light scattering agent include titanium oxide; zinc oxide and the like.
- ultraviolet absorbers examples include 2- (2H-benzotriazol-2-yl) -p-cresol (for example, Tinuvin P: BASF), 2- (2H-benzotriazol-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) -benzotriazol-2-yl] -4-methyl-6- (tert-butyl) phenol (for example, Tinuvin 326: BASF), 2- (3,5-di -T-butyl-2-hydroxyphenyl) -5-chlorobenzotriazole (eg, Tinuvin327: BASF), 2- (2H-benzotriazol-2-yl) -4,6-di-tert Pentylphenol (for example, Tinu
- the substance that blocks light in the wavelength range is preferably titanium oxide; a benzotriazole ultraviolet absorber.
- the blending ratio varies depending on the type of the substance, the packaging, the material of the separate member, etc.
- 0.001 to 50% by mass preferably 0.002 to 25% by mass, particularly preferably about 0.01 to 10% by mass.
- the “package that blocks light” includes a case where only a part of the package blocks light.
- the inside of the package is preferably visible (observable) with the naked eye. If the inside is visible, there will be merits such that it is possible to inspect the presence or absence of foreign matter in the manufacturing process of the pharmaceutical preparation, and the user of the pharmaceutical preparation can check the remaining amount of the content (aqueous composition). .
- “internally visible” means a state in which the inside can be visually recognized from at least a part of the outer surface of the package (for example, the side of the eye drop container that is generally columnar can be seen through a shrink film or the like). Even if it disappears, if the bottom is visible, it can be said that “the inside is visible”). Note that the visibility may be as long as the package has a certain level of transparency. Specifically, for example, the average value of the light transmittance in the visible light region (450 to 750 nm) is about 30% or more ( More preferably, it should be about 40% or more; particularly preferably, about 50% or more), but is not limited thereto.
- a material in which the primary package obstructs transmission of ultraviolet rays (more preferably, one or more selected from ultraviolet scattering agents and ultraviolet absorbers; particularly preferably zinc oxide, titanium oxide and benzotriazole-based ultraviolet absorbers).
- a package (more preferably, a container made of a polyolefin resin or a polyester resin (preferably a container for eye drops)) kneaded with one or more selected from Preferably, a package whose inside is visible) 2)
- the primary package is a substance that blocks the transmission of ultraviolet rays (more preferably, one or more selected from ultraviolet scattering agents and ultraviolet absorbers; particularly preferably zinc oxide, titanium oxide, and benzotriazole-based ultraviolet absorbers).
- a container (preferably made of plastic; more preferably made of a polyolefin resin or polyester) in which a member (preferably a heat-shrinkable film (shrink film)) kneaded on one side is kneaded.
- a package (more preferably, a package in which the inside can be visually recognized), which is a container (preferably a container for eye drops)) made of a resin based resin; 3)
- the secondary package is a substance that prevents the transmission of ultraviolet rays (preferably one or more selected from ultraviolet scatterers and ultraviolet absorbers; more preferably zinc oxide, titanium oxide, and benzotriazole-based ultraviolet absorbers).
- a bag (preferably made of plastic; more preferably, a bag made of polyolefin resin or polyester resin (preferably an eye drop medication bag)).
- a package (preferably, a package whose inside is visible); 4)
- a package in which the secondary package is a paper box that accommodates a container (preferably an eye drop container).
- the means for containing the aqueous composition in the package is not particularly limited, and it may be filled by a conventional method according to the form of the package.
- the applicable disease of the pharmaceutical preparation is not particularly limited, and may be appropriately selected according to the pharmacological action and the like of the compound represented by the general formula (1). Specifically, for example, it can be used as a prophylactic or therapeutic agent for ocular hypertension and glaucoma based on the Rho kinase inhibitory action and intraocular pressure-reducing action of the compound represented by the general formula (1).
- glaucoma more specifically, for example, primary open-angle glaucoma, normal-tension glaucoma, aqueous humor production hyperglaucoma, acute closed-angle glaucoma, chronic closed-angle glaucoma, plateau iris syndrome, mixed glaucoma Steroid glaucoma, capsular glaucoma, pigment glaucoma, amyloid glaucoma, neovascular glaucoma, malignant glaucoma and the like.
- fundus diseases (lesions that mainly appear in the retina and / or choroid.
- Ripasudil monohydrochloride dihydrate can be produced, for example, by the method described in International Publication No. 2006/057397.
- the measurement of ripaspil and its related substances using HPLC was carried out by using an ODS column as a column, 0.01 mol / L phosphate buffer and acetonitrile as a mobile phase, and ultraviolet absorption photometry as a detector. A total (wavelength: 280 nm) was used.
- Test Example 2 Evaluation of the photostability of Ripasudil in an aqueous composition As in Test Example 1, the stability to light when Ripasudil was blended in an aqueous composition was determined whether or not a decomposition product was generated by exposure. It was evaluated by checking.
- Ripasudil monohydrochloride dihydrate 0.4 g as a free form of Ripasudil
- anhydrous sodium dihydrogen phosphate 2.136 g of glycerin
- benzalkonium chloride An aqueous composition containing an appropriate amount of sodium hydroxide (pH 6.0) and sterilized purified water (residue) was prepared and placed in a transparent polypropylene container.
- Test Example 3 Confirmation of wavelength of light that causes decomposition of ripaspil in an aqueous composition 1
- the wavelength of the light beam causing the photodecomposition of Ripasudil in the aqueous composition confirmed in Test Example 2 is irradiated with a light beam having a wavelength in a specific range, and the presence or absence of a decomposition product due to exposure is confirmed.
- a spectral irradiation device (spectral unit: HSU-100S, light source: MAX-302FBD, all Asahi Spectroscopy Co., Ltd.) equipped with an optical filter, approximately 270-335 nm, 320-395 nm, 370-435 nm, 430 Light having a wavelength in the range of ⁇ 470 nm, 470 to 530 nm, 525 to 575 nm, 570 to 630 nm, 625 to 675 nm, or 660 to 740 nm was irradiated at 25 ° C. In addition, the irradiation energy was set to about 15 W ⁇ h / m 2 for light of any wavelength.
- Test Example 4 Confirmation of wavelength of light that causes decomposition of ripaspil in an aqueous composition, part 2 The test was carried out in the same manner as in Test Example 3 except that the aqueous composition was changed to the following two types and the wavelength of the irradiated light was changed to 270 to 335 nm, 320 to 395 nm, or 370 to 435 nm.
- ⁇ Aqueous composition B Per 100 mL, 0.0612 g of Ripasudil monohydrochloride dihydrate (0.05 g as a free form of Ripasudil), 0.98 g of potassium chloride, 0.002 g of benzalkonium chloride, appropriate amount of sodium hydroxide (pH 6.7) And an aqueous composition containing sterilized purified water (residue) was prepared as aqueous composition B. The results are shown in Table 4.
- Ripasudil monohydrochloride dihydrate 0.4 g as a free form of Ripasudil
- anhydrous sodium dihydrogen phosphate 2.136 g of glycerin
- benzalkonium chloride An aqueous composition containing an appropriate amount of sodium hydroxide (pH 6.0) and sterilized purified water (residue) was prepared, and this was placed in a polypropylene eye drop container containing the following ultraviolet absorber.
- a stability tester (LT-120A: Nagano Science Co., Ltd.), a D65 fluorescent lamp was used as a light source, and light of 4000 lux was irradiated under the condition of 25 ° C. so that the integrated irradiation amount became 1.2 million lux ⁇ hr. .
- ⁇ Plastic container with UV absorber> A polypropylene eye drop container containing a benzotriazole UV absorber was used.
- the average value of the light transmittance of the container is 7.2% on average at 300 to 335 nm (note that the average is 6.7% at 300 to 370 nm; the average is 11.7% at 270 to 335 nm; the average is 9.8 at 270 to 370 nm. %; Average of 10.2% at 300 to 395 nm; average of 11.8% at 270 to 395 nm).
- the container was almost transparent in appearance, and the contents were visible (for example, the light transmittance in the visible light region (450 to 750 nm) exceeded 65% at all wavelengths, and the average was 76. 2%).
- the light transmittance was measured by using a spectrophotometer (U-3900: Hitachi High-Technologies), cutting the container into a plate-shaped piece, and then setting it on the optical path so that light was incident substantially vertically. Measurements were taken every 0.5 nm. The average value of the light transmittance was calculated as the average value of the light transmittance every 0.5 nm within a predetermined wavelength range.
- the average value of the light transmittance at 300 to 335 nm of the aqueous composition containing ripaspil was 7.2% (note that the average was 6.7% at 300 to 370 nm; the average was 11 at 270 to 335 nm. 7%; average 9.8% at 270 to 370 nm; average 10.2% at 300 to 395 nm; average 11.8% at 270 to 395 nm). It became clear that stability was improved.
- Test Example 6 Confirmation of Stabilization of Ripasudil in Aqueous Composition Contained in Container (Primary Package) with Shrink Film Blended with Ultraviolet Light Scattering Agent Similar to Test Example 5, an aqueous composition containing ripaspil Attempts were made to stabilize by containing them in a container containing an ultraviolet scattering agent. That is, instead of a container containing an ultraviolet absorber, a container having a shrink film containing the following ultraviolet scattering agent is used, and a white fluorescent lamp (in a hospital dispensing room or the like) is used instead of a D65 fluorescent lamp as a light source. The test was carried out in the same manner as in Test Example 5 except that was used. The results are shown in Table 6.
- ⁇ Container with shrink film containing UV scattering agent> A white shrink film (heat-shrinkable film) (Iwata Label Co., Ltd.) kneaded with 40 to 45% by mass of titanium oxide as an ultraviolet scattering agent, and an ordinary polypropylene eye drop containing no ultraviolet absorber or ultraviolet scattering agent What was wound around the side of the container according to the conventional method was used.
- the average value of the light transmittance of the shrink film containing titanium oxide is an average of 0.3% at 300 to 335 nm (an average of 0.4% at 300 to 370 nm; an average of 0.1% at 270 to 335 nm; 270 to The average was 0.3% at 370 nm; the average was 0.4% at 300 to 395 nm; the average was 0.3% at 270 to 395 nm).
- the shrink film Since the shrink film is not transparent, the contents cannot be seen from the side of the container as it is (for example, the light transmittance in the visible light region (450 to 750 nm) was 1.1% on average) Therefore, a slit having a width of about 5 mm was provided in the lower half of the side surface of the container so that the amount of contents could be visually recognized (in this portion, the light beam could not be blocked). Moreover, since the shrink film was not wound around the container bottom face, it was in the state which can visually recognize the contents from the bottom face. The light transmittance was measured every 0.5 nm using a spectrophotometer (U-3900: Hitachi High-Technologies). The average value of the light transmittance was calculated as the average value of the light transmittance every 0.5 nm within a predetermined wavelength range.
- the average value of the light transmittance at 300 to 335 nm of the aqueous composition containing ripaspil is 0.3% (note that the average is 0.4% at 300 to 370 nm; the average is 0 at 270 to 335 nm). 1%; average 0.3% at 270 to 370 nm; average 0.4% at 300 to 395 nm; average 0.3% at 270 to 395 nm). It became clear that stability was improved.
- the aqueous composition containing the compound represented by the general formula (1) represented by Ripasudil or a salt thereof, or a solvate thereof blocks light having a wavelength of 300 to 335 nm. It was confirmed that the photostability of the compound represented by the general formula (1) in the aqueous composition was improved by being contained in the package.
- the average value of the light transmittance of the eye drop medication bag is as follows: average 0.4% at 300-335 nm; average 1.4% at 300-370 nm; average 0.2% at 270-335 nm; 270-370 nm The average was 0.9%; the average was 3.6% at 300 to 395 nm; and the average was 2.7% at 270 to 395 nm. Further, the container was white translucent in appearance, and the contents were visible (for example, the light transmittance in the visible light region (450 to 750 nm) exceeded 45% at all wavelengths, The average was 70.6%.)
- ⁇ YI As shown in Table 8, when the aqueous composition containing Ripasudil is contained in a polyolefin resin container such as polyethylene (PE) or polypropylene (PP), ⁇ YI even when stored at a high temperature for a long period of time. While the value was kept low, when it was accommodated in a polyvinyl chloride (PVC) container, the value of ⁇ YI was high.
- PE polyethylene
- PP polypropylene
- Production Examples 28 to 54 In Production Examples 1 to 27, the pharmaceutical preparations of Production Examples 28 to 54 can be produced using the same containers as used in Test Example 5 except that the material of the container is made of polyethylene instead of polypropylene.
- Production Examples 55 to 81 In Production Examples 1 to 27, instead of the polypropylene eye drop container containing a benzotriazole-based UV absorber as a container, the polypropylene eye drop wound around the side with the titanium oxide-containing shrink film used in Test Example 6 Using the container (primary package), the pharmaceutical preparations of Production Examples 55 to 81 can be produced.
- Production Examples 82 to 108 In Production Examples 1 to 27, instead of a polypropylene eye drop container containing a benzotriazole UV absorber as a container, a polyethylene eye drop container (that does not block light in the wavelength range of 300 to 335 nm) is used. Furthermore, the pharmaceutical preparations of Production Examples 82 to 108 can be produced by placing them in a transparent eye drop medication bag made of polyethylene (produced by Nippon Shokubai Co., Ltd.) (secondary package) containing the above-mentioned ultraviolet absorber. .
- Production Examples 109 to 135 In Production Examples 1 to 27, instead of polypropylene eye drop containers kneaded with benzotriazole-based UV absorbers as containers, polyethylene terephthalate eye drop containers (those that do not block light in the wavelength range of 300 to 335 nm) Can be further placed in a paper box (secondary package) to produce the pharmaceutical preparations of Production Examples 109 to 135.
- a pharmaceutical preparation excellent in stability can be provided and can be suitably used in the pharmaceutical industry and the like.
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Abstract
Description
そこで、本発明は、リパスジル等のハロゲン化イソキノリン誘導体の、水性組成物中での光に対する安定性を改善する技術を提供することを目的とする。
<1> 次の一般式(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が、波長300~335nmの光線を遮断する包装体に収容されてなる、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、波長300~335nmの光線を遮断する包装体に収容する工程を含む、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水性組成物中での光安定性を向上させる方法。
<3> 波長300~335nmの光線を遮断する包装体に収容されることを特徴とする、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。
<4> 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、波長300~335nmの光線を遮断する包装体に収容する工程を含む、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保存方法。
[1]次の一般式(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が、波長300~335nmの光線を遮断する包装体に収容されてなる、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]前記包装体が、波長300~370nmの光線を遮断するものである、[1]又は[2]記載の医薬製剤。
[4]前記包装体が、波長300~395nmの光線を遮断するものである、[1]又は[2]記載の医薬製剤。
[5]前記包装体が、波長270~335nmの光線を遮断するものである、[1]又は[2]記載の医薬製剤。
[6]前記包装体が、波長270~370nmの光線を遮断するものである、[1]又は[2]記載の医薬製剤。
[7]前記包装体が、波長270~395nmの光線を遮断するものである、[1]又は[2]記載の医薬製剤。
[8]前記包装体の内部が視認可能である、[1]~[7]のいずれか記載の医薬製剤。
[9]一次包装体が、
紫外線の透過を妨げる物質(好適には、紫外線散乱剤及び紫外線吸収剤から選ばれる1種以上;より好適には、酸化亜鉛、酸化チタン及びベンゾトリアゾール系紫外線吸収剤から選ばれる1種以上)を含有する容器(好適には、プラスチック製;より好適には、ポリオレフィン系樹脂製又はポリエステル系樹脂製の容器(好適には、点眼剤用容器))である包装体(好適には、内部が視認可能な包装体);又は、
紫外線の透過を妨げる物質(好適には、紫外線散乱剤及び紫外線吸収剤から選ばれる1種以上;より好適には、酸化亜鉛、酸化チタン及びベンゾトリアゾール系紫外線吸収剤から選ばれる1種以上)を含有する部材(好適には、熱収縮フィルム(シュリンクフィルム))を備えた容器(好適にはプラスチック製;より好適には、ポリオレフィン系樹脂製又はポリエステル系樹脂製の、容器(好適には、点眼剤用容器))である包装体(好適には、内部が視認可能な包装体);
である、[1]~[8]のいずれか記載の医薬製剤。
[10]二次包装体として、
紫外線の透過を妨げる物質(好適には、紫外線散乱剤及び紫外線吸収剤から選ばれる1種以上;より好適には、酸化亜鉛、酸化チタン及びベンゾトリアゾール系紫外線吸収剤から選ばれる1種以上)を含有する袋(好適には、プラスチック製;より好適には、ポリオレフィン系樹脂製又はポリエステル系樹脂製の、袋(好適には、点眼剤投薬袋))である包装体(好適には、内部が視認可能な包装体);及び
紙製の箱
から選ばれる1種以上を備える、[1]~[9]のいずれか記載の医薬製剤。
[11]一次包装体が、ポリオレフィン系樹脂製容器である、[1]~[10]のいずれか記載の医薬製剤。
[12]一次包装体が、ポリエステル系樹脂製容器である、[1]~[10]のいずれか記載の医薬製剤。
[14]前記一般式(1)で表される化合物が、リパスジルである、[13]記載の方法。
[15]前記包装体が、波長300~370nmの光線を遮断するものである、[13]又は[14]記載の方法。
[16]前記包装体が、波長300~395nmの光線を遮断するものである、[13]又は[14]記載の方法。
[17]前記包装体が、波長270~335nmの光線を遮断するものである、[13]又は[14]記載の方法。
[18]前記包装体が、波長270~370nmの光線を遮断するものである、[13]又は[14]記載の方法。
[19]前記包装体が、波長270~395nmの光線を遮断するものである、[13]又は[14]記載の方法。
[20]前記包装体の内部が視認可能である、[13]~[19]のいずれか記載の方法。
[21]一次包装体が、
紫外線の透過を妨げる物質(好適には、紫外線散乱剤及び紫外線吸収剤から選ばれる1種以上;より好適には、酸化亜鉛、酸化チタン及びベンゾトリアゾール系紫外線吸収剤から選ばれる1種以上)を含有する容器(好適には、プラスチック製;より好適には、ポリオレフィン系樹脂製又はポリエステル系樹脂製の容器(好適には、点眼剤用容器))である包装体(好適には、内部が視認可能な包装体);又は、
紫外線の透過を妨げる物質(好適には、紫外線散乱剤及び紫外線吸収剤から選ばれる1種以上;より好適には、酸化亜鉛、酸化チタン及びベンゾトリアゾール系紫外線吸収剤から選ばれる1種以上)を含有する部材(好適には、熱収縮フィルム(シュリンクフィルム))を備えた容器(好適にはプラスチック製;より好適には、ポリオレフィン系樹脂製又はポリエステル系樹脂製の、容器(好適には、点眼剤用容器))である包装体(好適には、内部が視認可能な包装体);
である、[13]~[20]のいずれか記載の方法。
[22]二次包装体として、
紫外線の透過を妨げる物質(好適には、紫外線散乱剤及び紫外線吸収剤から選ばれる1種以上;より好適には、酸化亜鉛、酸化チタン及びベンゾトリアゾール系紫外線吸収剤から選ばれる1種以上)を含有する袋(好適には、プラスチック製;より好適には、ポリオレフィン系樹脂製又はポリエステル系樹脂製の、袋(好適には、点眼剤投薬袋))である包装体(好適には、内部が視認可能な包装体);及び
紙製の箱
から選ばれる1種以上を備える、[13]~[21]のいずれか記載の方法。
[23]一次包装体が、ポリオレフィン系樹脂製容器である、[13]~[22]のいずれか記載の方法。
[24]一次包装体が、ポリエステル系樹脂製容器である、[13]~[22]のいずれか記載の方法。
[26]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]~[12]のいずれか記載の医薬製剤。
[27]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、[13]~[24]のいずれか記載の方法。
[28]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、[13]~[24]のいずれか記載の方法。
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。
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。
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。
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。
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。
なお、包装体は、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。
包装体として、一次包装体と二次包装体の両者を備える態様である場合は、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、一次包装体が点眼剤用容器であり、二次包装体が点眼剤包装袋である態様が好ましい。
水性組成物を直接収容する一次包装体の材質としては、加工性、スクイズ性や耐久性等の観点から、プラスチック製等であるのが好ましい。
二次包装体の材質としては、加工性等の観点から、プラスチック製、セルロース製、パルプ製、紙製等であるのが好ましい。
なお、斯かる態様においては、少なくとも一次包装体のうち水性組成物と接する部分がポリオレフィン系樹脂で構成されていればよく、さらにその外側等に別の材質が積層等されている場合であっても、「一次包装体が、ポリオレフィン系樹脂製」である場合に該当する。また、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。
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、ΔYI値を低く抑える観点から、ポリエチレン、ポリプロピレンが好ましく、ポリプロピレンが特に好ましい。
なお、斯かる態様においては、少なくとも一次包装体のうち水性組成物と接する部分がポリエステル系樹脂で構成されていればよく、さらにその外側等に別の材質が積層等されている場合であっても、「一次包装体が、ポリエステル系樹脂製」である場合に該当する。また、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、包装体の、前記波長範囲の光線の透過率の平均値は、光に対する安定性をより向上させる観点から、30%以下であるのが好ましく、25%以下であるのがより好ましく、20%以下であるのがさらに好ましく、15%以下であるのがさらにより好ましく、10%以下であるのがさらにより好ましく、5%以下であるのが特に好ましい。
なお、本明細書において、特定の波長範囲の光透過率の平均値の測定は、分光光度計を用いて当該範囲内において0.5nm毎に、空気中での包装体の光透過率を測定した後、その平均値を算出することにより測定することができる。分光光度計としては例えば、U-3900(日立ハイテクノロジーズ(株))が挙げられる。
包装体中に、前記波長範囲の光線を遮断する物質を含有せしめる方法(例えば、ガラスや樹脂に前記波長範囲の光線を遮断する物質を添加し、これを容器形状に成形する方法等);
包装体の表面(包装体の内側、外側のうち少なくとも一方の面)に前記波長範囲の光線を遮断する物質を含有する部材(例えば、フィルム等)を備えさせる方法(例えば、樹脂に前記波長範囲の光線を遮断する物質を添加して熱収縮フィルムとし、これを容器外側面に巻き付ける方法等);
包装体の表面(包装体の内側、外側のうち少なくとも一方の面)に前記波長範囲の光線を遮断する物質を塗布する方法;
前記波長範囲の光線を遮断する物質を包装体の主な材料とする方法(例えば、容器を主に金属、厚紙で構成する方法等)
等が挙げられる。
本明細書において「内部が視認可能」とは、少なくとも包装体外表面の一部分から内部が視認可能な状態を言う(例えば、通常、略円柱状である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「内部が視認可能」と言える。)。
なお、視認可能性は、包装体が一定以上の透明性を有しておればよく、具体的には例えば、可視光領域(450~750nm)の光透過率の平均値が30%程度以上(より好適には、40%程度以上;特に好適には、50%程度以上)確保されていればよいが、これに限定されるものではない。
1)一次包装体が、紫外線の透過を妨げる物質(より好適には、紫外線散乱剤及び紫外線吸収剤から選ばれる1種以上;特に好適には、酸化亜鉛、酸化チタン及びベンゾトリアゾール系紫外線吸収剤から選ばれる1種以上)を練り込んだ容器(プラスチック製、より好適には、ポリオレフィン系樹脂製又はポリエステル系樹脂製の、容器(好適には、点眼剤用容器))である包装体(より好適には、内部が視認可能な包装体);
2)一次包装体が、紫外線の透過を妨げる物質(より好適には、紫外線散乱剤及び紫外線吸収剤から選ばれる1種以上;特に好適には、酸化亜鉛、酸化チタン及びベンゾトリアゾール系紫外線吸収剤から選ばれる1種以上)を練り込んだ部材(好適には、熱収縮フィルム(シュリンクフィルム))を側面に巻き付けた容器(好適には、プラスチック製;より好適には、ポリオレフィン系樹脂製又はポリエステル系樹脂製の、容器(好適には、点眼剤用容器))である包装体(より好適には、内部が視認可能な包装体);
3)二次包装体が、紫外線の透過を妨げる物質(好適には、紫外線散乱剤及び紫外線吸収剤から選ばれる1種以上;より好適には、酸化亜鉛、酸化チタン及びベンゾトリアゾール系紫外線吸収剤から選ばれる1種以上)を練り込んだ袋(好適には、プラスチック製;より好適には、ポリオレフィン系樹脂製又はポリエステル系樹脂製の、袋(好適には、点眼剤投薬袋))である包装体(好適には、内部が視認可能な包装体);
4)二次包装体が、容器(好適には、点眼剤用容器)を収容する紙製の箱である包装体。
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。
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。
また、以下の試験例において、HPLCを用いたリパスジル及びその類縁物質の測定は、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:280nm)をそれぞれ用いて行った。
リパスジルの光に対する安定性を、曝光による分解物の生成の有無を確認することにより評価した。
すなわち、粉末状のリパスジル1塩酸塩2水和物をガラスシャーレに3mm以下の厚さになるように広げた後、光安定性試験装置(LT-120A:ナガノサイエンス(株))を用いて、D65蛍光ランプを光源として、25℃の条件下、4000luxの光を、積算照射量が40万、80万又は120万lux・hrとなるように照射した。
結果を表1に示す。
以上の試験結果から、リパスジルに代表される一般式(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、光に対して極めて安定であることが明らかとなった。
リパスジルを水性組成物中に配合した場合の光に対する安定性を、試験例1と同様、曝光による分解物の生成の有無を確認することにより評価した。
すなわち、100mL当たり、リパスジル1塩酸塩2水和物 0.4896g(リパスジルのフリー体として0.4g)、無水リン酸二水素ナトリウム 0.4g、グリセリン 2.136g、ベンザルコニウム塩化物 0.002g、水酸化ナトリウム 適量(pH 6.0)及び滅菌精製水(残余)を含有する水性組成物を調製し、これをポリプロピレン製の透明の容器に収容した。その後、光安定性試験装置(LT-120A:ナガノサイエンス(株))を用いて、D65蛍光ランプを光源として、25℃の条件下、4000luxの光を、積算照射量が30万、60万又は120万lux・hrとなるように照射した。
結果を表2に示す。
有機化合物の光分解反応は化合物中の特定の結合の強度に依存し、ひいては化合物の構造に依存する。そのため、光に対する安定性(光分解のされ易さ)は、通常は有機化合物の状態(固体、液体等)によらず同様の傾向を示すはずである。しかしながら、試験例1及び2の結果から、意外なことにリパスジルに代表される一般式(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、そのもの自体は光に対して安定であるが、水性組成物中に配合することによってはじめて光に対して不安定化する性質を有することが明らかとなった。
試験例2で確認された水性組成物中でのリパスジルの光分解につきその原因となる光線の波長を、特定の範囲の波長を有する光線を照射し、曝光による分解物の生成の有無を確認することにより確認した。
すなわち、100mL当たり、リパスジル1塩酸塩2水和物 0.0612g(リパスジルのフリー体として0.05g)、ホウ酸 1.19g、塩化カリウム 0.42g、ベンザルコニウム塩化物 0.002g、水酸化ナトリウム 適量(pH 6.7)及び滅菌精製水(残余)を含有する水性組成物を調製し、これをポリプロピレン製の透明の容器に収容した。その後、光学フィルターを備えた分光照射装置(分光ユニット:HSU-100S、光源:MAX-302FBD、いずれも朝日分光(株))を用いて、概ね270~335nm、320~395nm、370~435nm、430~470nm、470~530nm、525~575nm、570~630nm、625~675nm又は660~740nmの範囲の波長を有する光線を、25℃の条件下で照射した。なお、いずれの波長の光線も、照射エネルギーを約15W・h/m2とした。
結果を表3に示す。
なお、医薬品の保存安定性を確認する試験の一つに光安定性試験があるが、当該試験のガイドラインでは光源としてD65光源を用いることが定められている。D65光源は、ISO10977(1993)に規定されている屋外の昼光の標準として国際的に認められたものであり、300~830nmの波長域の分光分布の値で規定されている。これらのことから、医薬品について通常想定される保存条件下においては、300nm以上の波長の光を考慮すれば十分であると考えられる。
以上の点から、リパスジルに代表される、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の光安定性を確保するうえでは、特に300~335nmの波長の光線を遮断することが重要であると結論付けられた。
水性組成物を以下の2種のものに変更し、照射した光線の波長を270~335nm、320~395nm又は370~435nmとしたほかは試験例3と同様の方法により試験を実施した。
<水性組成物A>
100mL当たり、リパスジル1塩酸塩2水和物 0.0612g(リパスジルのフリー体として0.05g)、無水リン酸二水素ナトリウム 0.4g、塩化カリウム 0.78g、ベンザルコニウム塩化物 0.002g、水酸化ナトリウム 適量(pH 6.7)及び滅菌精製水(残余)を含有する水性組成物を調製し、水性組成物Aとした。
<水性組成物B>
100mL当たり、リパスジル1塩酸塩2水和物 0.0612g(リパスジルのフリー体として0.05g)、塩化カリウム 0.98g、ベンザルコニウム塩化物 0.002g、水酸化ナトリウム 適量(pH 6.7)及び滅菌精製水(残余)を含有する水性組成物を調製し、水性組成物Bとした。
結果を表4に示す。
以上の試験例3及び4の試験結果から、リパスジルに代表される、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の光安定性を確保するうえでは、その組成に拘わらず、特に300~335nmの波長の光線を遮断することが重要であると結論付けられた。
試験例3及び4で得られた結果を基に、リパスジルを含有する水性組成物を、紫外線吸収剤を配合した容器に収容することにより安定化することを試みた。
すなわち、100mL当たり、リパスジル1塩酸塩2水和物 0.4896g(リパスジルのフリー体として0.4g)、無水リン酸二水素ナトリウム 0.4g、グリセリン 2.136g、ベンザルコニウム塩化物 0.002g、水酸化ナトリウム 適量(pH 6.0)及び滅菌精製水(残余)を含有する水性組成物を調製し、これを下記の紫外線吸収剤を配合したポリプロピレン製の点眼剤用容器に収容し、光安定性試験装置(LT-120A:ナガノサイエンス社)を用いて、D65蛍光ランプを光源として、25℃の条件下、4000luxの光を、積算照射量が120万lux・hrとなるように照射した。
結果を表5に示す。
ベンゾトリアゾール系紫外線吸収剤を練り込んだポリプロピレン製の点眼剤用容器を用いた。容器の光透過率の平均値は、300~335nmで平均7.2%(なお、300~370nmで平均6.7%;270~335nmで平均11.7%;270~370nmで平均9.8%;300~395nmで平均10.2%;270~395nmで平均11.8%)であった。
当該容器は外見上ほぼ透明であり、内容物を視認できる状態であった(例えば、可視光領域(450~750nm)での光透過率は全ての波長において65%を超えており、平均76.2%であった。)。
なお、光透過率は、分光光度計(U-3900:日立ハイテクノロジーズ)を用い、容器を切断して板状片とした後、光が略垂直に入射するよう光路上にセットしたうえで、0.5nm毎に測定した。光透過率の平均値は、所定の波長範囲内の0.5nm毎の光透過率の平均値として算出した。
試験例5と同様、リパスジルを含有する水性組成物を、紫外線散乱剤を配合した容器に収容することにより安定化することを試みた。
すなわち、紫外線吸収剤を配合した容器の代わりに下記の紫外線散乱剤を配合したシュリンクフィルムを備えた容器を使用し、また、光源としてD65蛍光ランプの代わりに白色蛍光灯(病院の調剤室等で利用されている。)を用いたほかは、試験例5と同様の方法により、試験を実施した。
結果を表6に示す。
紫外線散乱剤として酸化チタン40~45質量%を練り込んだ白色のシュリンクフィルム(熱収縮フィルム)((株)岩田レーベル)を、紫外線吸収剤や紫外線散乱剤等を含有しない通常のポリプロピレン製点眼剤用容器の側面に、常法に従って巻きつけたものを用いた。酸化チタンを含有するシュリンクフィルムの光透過率の平均値は、300~335nmで平均0.3%(なお、300~370nmで平均0.4%;270~335nmで平均0.1%;270~370nmで平均0.3%;300~395nmで平均0.4%;270~395nmで平均0.3%)であった。
当該シュリンクフィルムは透明では無いため、そのままでは容器側面からは内容物を視認できる状態でなかった(例えば、可視光領域(450~750nm)での光透過率は、平均1.1%であった。)ため、容器側面の下半分に、幅5mm程のスリットを設け、内容物量を視認できるようにした(この部分では光線を遮断できない状態であった。)。また、容器底面にはシュリンクフィルムが巻きつけられていないため、底面からは内容物を視認できる状態にあった。
なお、光透過率は、分光光度計(U-3900:日立ハイテクノロジーズ)を用い、0.5nm毎に測定した。光透過率の平均値は、所定の波長範囲内の0.5nm毎の光透過率の平均値として算出した。
なお、当該点眼剤投薬袋の光透過率の平均値は、300~335nmで平均0.4%;300~370nmで平均1.4%;270~335nmで平均0.2%;270~370nmで平均0.9%;300~395nmで平均3.6%;270~395nmで平均2.7%であった。
また、当該容器は外見上白色半透明であり、内容物を視認できる状態であった(例えば、可視光領域(450~750nm)での光透過率は全ての波長において45%を超えており、平均70.6%であった。)。
表7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(PE)製、ポリプロピレン(PP)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、60℃で3ヶ月間保存し、保存前後での色差(ΔYI)を色差計(分光測色計CM-700d:コニカミノルタセンシング(株))を用いて測定し、ΔYIの値が5以上のものを×、5未満のものを○と評価した。
結果を表8に示す。
表9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(PE)製又はポリプロピレン(PP)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、60℃で3ヶ月間保存し、保存前後での色差(ΔYI)を色差計(分光測色計CM-700d:コニカミノルタセンシング(株))を用いて測定し、ΔYIの値が5以上のものを×、5未満のものを○と評価した。
結果を表10に示す。
表11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12に示す。
表13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14に示す。
表15~表17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、これを試験例5で用いたベンゾトリアゾール系紫外線吸収剤を練り込んだポリプロピレン製点眼剤用容器(一次包装体)に収容して、製造例1~27の医薬製剤を製造できる。
製造例1~27において、容器の材質をポリプロピレン製の代わりにポリエチレン製としたほかは試験例5で使用したのと同様の容器を用いて、製造例28~54の医薬製剤を製造できる。
製造例1~27において、容器としてベンゾトリアゾール系紫外線吸収剤を練り込んだポリプロピレン製点眼剤用容器の代わりに、試験例6で用いた酸化チタン含有シュリンクフィルムを側面に巻き付けたポリプロピレン製点眼剤用容器(一次包装体)を用いて、製造例55~81の医薬製剤を製造できる。
製造例1~27において、容器としてベンゾトリアゾール系紫外線吸収剤を練り込んだポリプロピレン製点眼剤用容器の代わりに、ポリエチレン製点眼剤用容器(波長300~335nmの範囲の光線を遮断しないもの)を用い、さらに、前記した紫外線吸収剤を配合したポリエチレン製の透明の点眼剤投薬袋((株)生産日本社)(二次包装体)に入れて、製造例82~108の医薬製剤を製造できる。
製造例1~27において、容器としてベンゾトリアゾール系紫外線吸収剤を練り込んだポリプロピレン製点眼剤用容器の代わりに、ポリエチレンテレフタレート製点眼剤用容器(波長300~335nmの範囲の光線を遮断しないもの)を用い、さらに、紙製の箱(二次包装体)に入れて、製造例109~135の医薬製剤を製造できる。
製造例1~135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136~270の医薬製剤として、常法により製造できる。
Claims (20)
- 前記一般式(1)で表される化合物が、リパスジルである、請求項1記載の医薬製剤。
- 包装体の内部が視認可能である、請求項1又は2記載の医薬製剤。
- 一次包装体が、紫外線の透過を妨げる物質を含有する容器である、請求項1~3のいずれか1項記載の医薬製剤。
- 一次包装体が、紫外線の透過を妨げる物質を含有する部材を備える容器である、請求項1~4のいずれか1項記載の医薬製剤。
- 一次包装体が、ポリオレフィン系樹脂製容器である、請求項1~5のいずれか1項記載の医薬製剤。
- 一次包装体が、ポリエステル系樹脂製容器である、請求項1~5のいずれか1項記載の医薬製剤。
- 二次包装体として、紫外線の透過を妨げる物質を含有する袋を備える、請求項1~7のいずれか1項記載の医薬製剤。
- 前記一般式(1)で表される化合物が、リパスジルである、請求項9記載の水性組成物。
- 包装体の内部が視認可能である、請求項9又は10記載の水性組成物。
- 一次包装体が、紫外線の透過を妨げる物質を含有する容器である、請求項9~11のいずれか1項記載の水性組成物。
- 一次包装体が、紫外線の透過を妨げる物質を含有する部材を備える容器である、請求項9~12のいずれか1項記載の水性組成物。
- 一次包装体が、ポリオレフィン系樹脂製容器である、請求項9~13のいずれか1項記載の水性組成物。
- 一次包装体が、ポリエステル系樹脂製容器である、請求項9~13のいずれか1項記載の水性組成物。
- 二次包装体として、紫外線の透過を妨げる物質を含有する袋を備える、請求項9~15のいずれか1項記載の水性組成物。
- 前記一般式(1)で表される化合物が、リパスジルである、請求項17記載の方法。
- 前記一般式(1)で表される化合物が、リパスジルである、請求項19記載の方法。
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CA2962628C (en) | 2023-01-10 |
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BR112017006149A2 (pt) | 2017-12-26 |
ES2901997T3 (es) | 2022-03-24 |
JPWO2016047721A1 (ja) | 2017-06-22 |
TW201613603A (en) | 2016-04-16 |
KR20170058367A (ko) | 2017-05-26 |
JP2023052792A (ja) | 2023-04-12 |
PT3199161T (pt) | 2022-02-08 |
MX2017003945A (es) | 2017-06-30 |
DK3199161T3 (da) | 2022-01-03 |
HUE057834T2 (hu) | 2022-06-28 |
CN106794186B (zh) | 2020-06-05 |
JP2021176842A (ja) | 2021-11-11 |
JP6244038B2 (ja) | 2017-12-06 |
US20240216272A1 (en) | 2024-07-04 |
SG11201702298VA (en) | 2017-04-27 |
JP2020002151A (ja) | 2020-01-09 |
EP3199161A4 (en) | 2018-04-11 |
CN106794186A (zh) | 2017-05-31 |
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