Classifications

• • 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
  • A61K31/4704—2-Quinolinones, e.g. carbostyril
• • 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
  • A61K47/02—Inorganic compounds
• • 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
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
• • 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
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• • 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
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
  • A61K47/38—Cellulose; Derivatives thereof
• • 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
  • A61K9/10—Dispersions; Emulsions
• • 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

Definitions

• the present invention relates to an aqueous suspension containing rebamipide or a salt thereof and at least one polymer selected from the group consisting of sodium carmellose, dextran and polyvinylpyrrolidone.
• Dry eye is a disease that begins with unpleasant symptoms such as dry eyes and rumbling, and when it worsens, it causes a great deal of trouble in daily life.
• the number of dry eye patients is increasing year by year with the advent of an aging society and the increase in VDT (visual display tertiary) work such as personal computers.
• VDT visual display tertiary
• Non-Patent Document 1 objective findings of dry eye patients (corneal epithelial disorders, etc.) were obtained by instilling eye drops containing rebamipide. , It is described that the subjective symptoms have improved.
• eye drops containing rebamipide (free form) at a concentration of 2% (w / v) are used as a therapeutic agent for dry eye (product name: Mucosta (registered trademark) eye drops UD 2%).
• Mucosta (registered trademark) ophthalmic solution UD2% contains polyvinyl alcohol partially saponified as an additive.
• Patent Document 1 by blending polyvinyl alcohol (PVA) together with rebamipide in an aqueous solution, the state of fine particles is obtained without using a special dispersion / suspension device. It is described that the rebamipide of the above can be uniformly dispersed, and the suspended state can be stably maintained without causing the reaggregation of the fine particles of the rebamipide.
• Non-Patent Document 2 states that lacrimal passage obstruction and lacrimal pouchitis may appear as serious side effects of Mucosta (registered trademark) ophthalmic solution UD2%, and tears in cases in which lacrimal passage obstruction and lacrimal pouchitis are observed. It is stated that white substances may be found in Hokkaido. Furthermore, New Ophthalmology, 32 (12), 1741-1747 (2015) (Non-Patent Document 3) suggests that PVA has the property of reacting with borate ions to gel. Many of the eye drops on the market in Japan contain boric acid as an additive.
• An object of the present invention without the use of PVA as an additive is to prepare a rebamipide-containing aqueous suspension having similar properties to Mucosta ® ophthalmic solution UD2%.
• the present invention relates to the following.
• the average particle size of rebamipide is 0.1 to 3 ⁇ m
• the K value of polyvinylpyrrolidone is 30
• the kinematic viscosity is 1.8 to 3.0 mm 2 / s, and it is characterized by being administered by eye drops.
• Aqueous suspension Aqueous suspension.
• a rebamipide-containing aqueous suspension which is expected to be less likely to cause side effects such as lacrimal passage obstruction and lacrimal pouchitis observed in commercially available "Mucosta (registered trademark) ophthalmic solution UD2%".
• Mocosta registered trademark
• UD2% ophthalmic solution
• Rebamipide used in the present invention is a compound represented by the following formula.
• the chemical name of rebamipide used in the present invention is (2RS) -2- (4-Chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionic acid.
• the rebamipide used in the present invention can be produced according to a usual method in the field of synthetic organic chemistry. Further, it is commercially available from SIGMA as a rebamipide hydrate.
• the salt of levamipide used in the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt, and can be used with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitrate, sulfuric acid, and phosphoric acid.
• Salt acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptoic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, horseuric acid, 1,2-ethanedisulfonic acid, Isetioic acid, lactobionic acid, oleic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, sulfosalicylic acid Salts with organic acids such as; quaternary ammonium salts with methyl bromide, methyl iodide, etc .; salts with halogen
• a solvate of rebamipide such as rebamipide hydrate is included in "rebamipide or a salt thereof”.
• rebamipide (free form) is preferable as "rebamipide or a salt thereof”.
• rebamipide or a salt thereof when rebamipide or a salt thereof contains geometric isomers or optical isomers, the isomers or salts thereof are also included in the scope of the present invention. In addition, when rebamipide or a salt thereof has proton tautomerism, the tautomer or a salt thereof is also included in the scope of the present invention.
• crystal polymorph system means that the crystal form changes depending on the conditions and conditions such as production, crystallization, and storage of the crystals (note that this state includes the formulated state). It means the individual crystal form at each stage and the whole process.
• the concentration of rebamipide or a salt thereof contained in the present aqueous suspension is preferably 0.5 to 5% (w / v), more preferably 1 to 3% (w / v), and 2 It is more preferably% (w / v).
• This aqueous suspension contains at least one polymer selected from the group consisting of sodium carmellose, dextran and polyvinylpyrrolidone.
• sodium carmellose means a cellulose derivative also also known as sodium carboxymethyl cellulose.
• dextran means dextran having various molecular weights.
• examples of the dextran contained in the present aqueous suspension include dextran 40 and dextran 70, and dextran 70 is particularly preferable.
• polyvinylpyrrolidone means a polymer compound in which N-vinyl-2-pyrrolidone is polymerized.
• Polyvinylpyrrolidone also called povidone, is commonly used as a thickening agent.
• the K value of polyvinylpyrrolidone contained in the present aqueous suspension is preferably 17 or more, more preferably 17 to 90, further preferably 17 to 60, and most preferably 30. preferable.
• a K value of 30 is synonymous with a K value in the range of 27 to 32.4.
• polyvinylpyrrolidone K15 polyvinylpyrrolidone K15
• polyvinylpyrrolidone K17 polyvinylpyrrolidone K17
• polyvinylpyrrolidone K25 polyvinylpyrrolidone K25
• polyvinylpyrrolidone K30 polyvinylpyrrolidone K40.
• polyvinylpyrrolidone K40 Polyvinylpyrrolidone K50 (PVP K50), Polyvinylpyrrolidone K60 (PVP K60), Polyvinylpyrrolidone K70 (PVP K70), Polyvinylpyrrolidone K80 (PVP K80), Polyvinylpyrrolidone K85 (PVP K85), Polyvinylpyrrolidone K90 (PVP) K90), polyvinylpyrrolidone K120 (PVP K120) and the like, but polyvinylpyrrolidone K30 (PVP K30), polyvinylpyrrolidone K40 (PVP K40), polyvinylpyrrolidone K50 (PVP K50), polyvinylpyrrolidone K60 (PVP K60) are preferable. Polyvinylpyrrolidone K30 (PVP K30) is particularly preferable.
• the K value of polyvinylpyrrolidone is a viscosity characteristic value that correlates with the molecular weight, and is a numerical value calculated by applying the relative viscosity value (25 ° C.) measured by a capillary viscometer to the following Fikenscher equation (1). be.
• ⁇ rel is the relative viscosity of the polyvinylpyrrolidone aqueous solution with respect to water
• c is the polyvinylpyrrolidone concentration (%) in the polyvinylpyrrolidone aqueous solution.
• K30 is the above formula.
• the viscosity characteristic value (K value) calculated by applying to (1) is in the range of 27 to 32.4.
• the polyvinylpyrrolidone contained in this aqueous suspension may be used alone, or two or more kinds of polyvinylpyrrolidones having different K values may be used in any combination.
• the concentration of the polymer contained in the aqueous suspension is preferably 0.1 to 10% (w / v), more preferably 1 to 10% (w / v), and 1 to 3% (w). / V) is most preferable.
• the safety of polyvinylpyrrolidone when it is added to ophthalmic solution at a concentration of more than 2% (w / v) has not been clinically confirmed. This does not prevent the concentration of polyvinylpyrrolidone contained in the aqueous suspension from exceeding 2% (w / v), but the concentration of polyvinylpyrrolidone contained in the aqueous suspension is It can be a reason for 2% (w / v) or less. Therefore, when the polymer contained in this aqueous suspension is polyvinylpyrrolidone in particular, the blending concentration thereof is more preferably 0.1 to 2% (w / v), and 0.5 to 0.5 to 2. It is more preferably 2% (w / v), particularly preferably 1 to 2% (w / v), and most preferably 2% (w / v).
• a carboxyvinyl polymer can be added for the purpose of improving the kinematic viscosity of the aqueous suspension.
• the carboxyl vinyl polymer means a polymer of acrylic acid, which is also called carbomer.
• Carboxyvinyl polymers are commercially available.
• CARBOPOL registered trademark
• 981NF CARBOPOL (registered trademark) 981NF
• CARBOPOL registered trademark
• 974PNF CARBOPOL (registered trademark) 974PNF
• CARBOPOL registered trademark 971PNF and the like are commercially available from Lubrizol.
• the concentration of the carboxyvinyl polymer contained in the aqueous suspension is preferably 0.01 to 1% (w / v), more preferably 0.03 to 0.5% (w / v). It is preferably 0.05 to 0.3% (w / v), more preferably 0.05 to 0.2% (w / v), and most preferably 0.05 to 0.2% (w / v).
• the aqueous suspension means a suspension based on water.
• the average particle size (D50) of rebamipide or a salt thereof contained in the aqueous suspension of the present invention is preferably 0.01 to 10 ⁇ m, more preferably 0.05 to 5 ⁇ m, and 0.1 to 0.1 to 5. It is more preferably 3 ⁇ m, most preferably 0.5 to 1 ⁇ m.
• the average particle size of rebamipide contained in this aqueous suspension is calculated by a laser diffraction method. The method for measuring the average particle size of rebamipide is also disclosed in Japanese Patent Application Laid-Open No. 2010-507566 described in the section on background art.
• the aqueous suspension of the present invention preferably does not contain polyvinyl alcohol (PVA).
• PVA polyvinyl alcohol
• "does not contain polyvinyl alcohol” literally means that it does not contain polyvinyl alcohol (PVA) at all or contains substantially no polyvinyl alcohol.
• polyvinyl alcohol includes a partially saponified product of polyvinyl alcohol.
• This aqueous suspension is administered locally to the eye in several divided doses a day for the treatment or alleviation of dry eye or its associated symptoms, but is preferably administered by eye drops once a day, four times a day. Will be done.
• This aqueous suspension can be in a dosage form that is administered locally to the eye, but it is preferably an eye drop that is filled in an eye drop container.
• the kinematic viscosity of this aqueous suspension is preferably 1.0 to 10.0 mm 2 / s, more preferably 1.5 to 5.0 mm 2 / s, and 1.8 to 3.0 mm 2 It is more preferably / s, and most preferably 2.0 to 2.5 mm 2 / s.
• the kinematic viscosity is measured with an Ubbelohde viscometer (measurement temperature: 25.0 ° C.).
• This aqueous suspension can be used as a single-use unit-dose type eye drop, or can be used as a multi-dose type eye drop by adding a preservative.
• preservative examples include silver or silver salt, benzalkonium chloride, chlorobutanol, etc., but silver salt is particularly preferable.
• the silver salt is, for example, silver nitrate, silver sulfate, silver chloride, silver bromide, silver oxide, silver acetate, silver carbonate, silver citrate, silver lactate, silver phosphate, silver oxalate, silver thiosulfate. , Protein silver and the like, but preferably means silver nitrate.
• the concentration of silver or silver salt contained in the aqueous suspension is preferably more than 0.000005% (w / v), more preferably 0.000006 to 0.0002% (w / v). Preferably, it is more preferably 0.000007 to 0.00015% (w / v), particularly preferably 0.000008 to 0.00012% (w / v), and 0.000009 to 0.0001%. It is most preferably (w / v).
• the concentration of silver nitrate contained in the aqueous suspension is preferably more than 0.00001% (w / v), 0.000011 to 0. It is more preferably .0001% (w / v), further preferably 0.000015 to 0.00005% (w / v), and more preferably 0.00002 to 0.00005% (w / v). This is particularly preferable, and 0.00002 to 0.00004% (w / v) is most preferable.
• Additives other than at least one polymer and preservative selected from the group consisting of sodium carmellose, dextran and polyvinylpyrrolidone can be added to this aqueous suspension.
• the additive include buffering agents such as sodium citrate, sodium phosphate, sodium acetate and epsilon-aminocaproic acid; isotonic agents such as sodium chloride, potassium chloride and concentrated glycerin; pH such as hydrochloric acid and sodium hydroxide. Regulators and the like are exemplified.
• the pH of the aqueous suspension is preferably 4.0 to 7.0, more preferably 5.0 to 7.0, and most preferably 5.5 to 6.5.
• the osmotic pressure ratio of this aqueous suspension is preferably 0.5 to 1.5, more preferably 0.7 to 1.3, and most preferably 0.9 to 1.1.
• This aqueous suspension can also be applied to eyes wearing hard contact lenses and soft contact lenses.
• Soft contact lenses shall be in accordance with Pharmaceutical Trial No. 645, March 31, 1999, "Handling of materials to be attached when applying for manufacturing (import) approval of soft contact lenses and disinfectants for soft contact lenses.” It is classified into four. That is, Group I (water content less than 50% and non-ionic), Group II (water content 50% or more and non-ionic), Group III (water content less than 50% and ionic). It is classified into Group IV (water content of 50% or more and ionic), and among the constituent monomers of the raw material polymer, those having an anionic molar% of 1% or more are ionic. Those with less than 1% are considered nonionic.
• soft contact lenses examples include 2-hydroxyethyl methacrylate (HEMA), (polyethylene glycol) monomethacrylate (PEGMA), glycerol methacrylate (GMA), N, N-dimethylacrylamide (DMA), and vinyl alcohol (VA). , N-vinylpyrrolidone (NVP or VP), methacrylic acid (MAA), fluorine-based methacrylate-based compounds, silicon-containing methacrylate-based compounds, silicone hydrogels, soft contact lenses containing cycloalkyl methacrylate and the like as main components, and the like. ..
• HEMA 2-hydroxyethyl methacrylate
• PEGMA polyethylene glycol) monomethacrylate
• GMA glycerol methacrylate
• DMA N-dimethylacrylamide
• VA vinyl alcohol
• MAA methacrylic acid
• fluorine-based methacrylate-based compounds silicon-containing methacrylate-
• administered by eye drops to an eye wearing soft contact lenses means that the aqueous suspension can be administered by eye drops while wearing soft contact lenses. Since it is known that benzalkonium chloride adsorbs to soft contact lenses and deforms soft contact lenses, "this aqueous suspension administered by eye drops to eyes wearing soft contact lenses” is It is preferable that benzalkonium chloride is not contained as an antiseptic.
• Formulation 1-1 Sodium citrate hydrate 0.146 g, sodium chloride 0.62 g, potassium chloride 0.18 g, carboxyvinyl polymer 0.11 g, polyvinylpyrrolidone 2.0 g, silver nitrate 0.00004 g are dissolved in water and levamipide. 2.0 g was added and the mixture was stirred and suspended to adjust the pH to 6.9, and water was added to make 100 mL.
• Comparative prescription 1-1 Commercially available "Mucosta (registered trademark) ophthalmic solution UD2%" was used.
• Comparative Formula 1-2 artificial tears: 0.85 g of sodium chloride, 0.4 g of potassium chloride, and 0.022 g of calcium chloride hydrate were dissolved in water to make 100 mL.
• Boric acid-containing liquid 0.5 g of boric acid, 0.4 g of sodium chloride, and 0.1 g of potassium chloride were dissolved in water to adjust the pH to 7.0, and water was added to make 100 mL.
• Test 2 Measure the particle size (D50) of rebamipide contained in the polyvinyl alcohol partially saponified product used in Mucosta (registered trademark) ophthalmic solution UD2% and the aqueous suspension in which rebamipide is suspended in each polymer other than PVA. And compared these.
• Example preparation method Each solution was prepared by dissolving the components shown in Table 2 in water in a soluble concentration range between 0.5% (w / v) and 1% (w / v), to which the final concentration was 2%. An aqueous suspension was prepared by adding levamipide in an amount (w / v).
• Test method The particle size distribution was measured using a laser diffraction type particle size distribution measuring device, and the particle size (D50) of rebamipide was compared.
• Formulation 3-1 sodium citrate hydrate 0.15 g, sodium chloride 0.62 g, potassium chloride 0.18 g, carboxyvinyl polymers (CARBOPOL (TM) 971PNF) 0.11g, polyvinyl pyrrolidone K30 2 g, nitrate 0. 00003 g was dissolved in water, 2 g of levamipide was added, and the mixture was stirred and suspended to adjust the pH to 5.9, and water was added to make 100 mL.
• CARBOPOL (TM) 971PNF carboxyvinyl polymers
• Formulations 3-2 to 3-6 Prepared in the same manner as Formulation 3-1 according to the formulation table of Table 3. Comparative prescription: Commercially available "Mucosta (registered trademark) ophthalmic solution UD 2%" was used.
• Formulation 4-1 sodium citrate hydrate 0.146 g, sodium chloride 0.62 g, potassium chloride 0.18 g, carboxyvinyl polymers (CARBOPOL (TM) 971PNF) 0.11g, polyvinyl pyrrolidone K30 2 g, nitrate 0. 00004 g was dissolved in water, 2 g of levamipide was added, and the mixture was stirred and suspended to adjust the pH to 5.9, and water was added to make 100 mL.
• CARBOPOL (TM) 971PNF carboxyvinyl polymers
• Comparative prescription Commercially available "Mucosta (registered trademark) ophthalmic solution UD 2%" was used. (Test method) The particle size distribution was measured using a laser diffraction type particle size distribution measuring device.
• the therapeutic effect on dry eye can be evaluated by a test using a dry eye model animal or the like. It has been confirmed that this aqueous suspension has the same therapeutic effect as "Mucosta (registered trademark) ophthalmic solution UD 2%" in a general-purpose dry eye model animal.
• Formulation 5-1 sodium citrate hydrate 0.146 g, sodium chloride 0.62 g, potassium chloride 0.18 g, carboxyvinyl polymers (CARBOPOL (TM) 971PNF) 0.11g, polyvinyl pyrrolidone K30 2 g, nitrate 0. 00004 g was dissolved in water, 2 g of levamipide was added, and the mixture was stirred and suspended to adjust the pH to 5.9, and water was added to make 100 mL.
• CARBOPOL (TM) 971PNF carboxyvinyl polymers
• Comparative prescription Commercially available "Mucosta (registered trademark) ophthalmic solution UD2%" was used. (Test method) 5 mL of Formulation 5-1 and Comparative Formulation were placed in an eye drop container and stored at 60 ° C. for 2 weeks. It was also stored at 40 ° C. for 2 and 3 months. In order to evaluate the physicochemical properties before and after storage, the following test items and measurement methods were used.
• the pH, viscosity, particle size, and redispersibility were measured.
• -PH The Japanese Pharmacopoeia general test method The pH measurement method was followed.
• -Viscosity For the comparative formulation, the viscosity was measured using a cone plate type viscometer according to the "Japanese Pharmacopoeia General Test Method Viscosity Measurement Method 2nd Method".
• the kinematic viscosity was measured using an Ubbelohde viscometer according to the "Japanese Pharmacopoeia General Test Method Viscosity Measurement Method 1st Method”.
• -Particle size The particle size distribution was measured using a laser diffraction type particle size distribution measuring device.
• -Redispersibility The bottle was held sideways between the thumb and index finger, shaken left and right for 15 seconds, and if there was no visual adhesion to the bottle, the redispersibility was good.
• Comparative prescription 6-1 Commercially available "Mucosta (registered trademark) ophthalmic solution UD 2%" was used.
• Comparative prescription 6-2 was prepared according to the prescription shown in Table 6. Specifically, 0.15 g of sodium citrate hydrate, 0.72 g of sodium chloride, 0.18 g of potassium chloride, 1 g of polyvinyl alcohol partial saponified product, and 0.01 g of chlorhexizing luconate are dissolved in water, and 2 g of levamipide is added. The mixture was stirred and suspended to adjust the pH to 6.0, and water was added to make 100 mL.
• Comparative formulation 6-3 to 6-12 Prepared in the same manner as comparative formulation 6-2 according to the formulations shown in Tables 6 and 7.
• the storage efficacy test was conducted in accordance with the 17th revised Japanese Pharmacopoeia Preservation Efficacy Test Law.
• Escherichia coli E. coli
• Pseudomonas aeruginosa P. aeruginosa
• Staphylococcus aureus S. aureus
• Candida albicans Candida albicans
• Candida albicans Candida albicans
• Chlorhexidine gluconate is an excellent preservative in that it can be used for eyes wearing soft contact lenses, but it has been clarified that it is not suitable as a preservative for rebamipide-containing aqueous suspensions. This is because the amount of chlorhexidine gluconate dissolved in the suspended ophthalmic solution was only about 3% with respect to the blended amount, so that a complex with rebamipide was formed and precipitated, and the preservation effect was sufficiently exhibited. It was thought that the quantity did not exist.
• Formulation 7-1 was prepared according to the formulations shown in Table 8. Specifically, sodium citrate hydrate 0.146 g, sodium chloride 0.65 g, potassium chloride 0.18 g, polyvinyl pyrrolidone K30 2 g, carboxyvinyl polymers (CARBOPOL (TM) 971PNF) 0.11g, nitrate 0. 00004 g was dissolved in water, 2 g of levamipide was added, and the mixture was stirred and suspended to adjust the pH to 5.9, and water was added to make 100 mL.
• Formulations 7-2-7-4 Prepared in the same manner as Formulation 7-1 according to the formulations shown in Table 8. (Test method) ⁇ Preservation efficacy test> The storage efficacy test was conducted in accordance with the 17th revised Japanese Pharmacopoeia Preservation Efficacy Test Law. In this test, Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), Candida albicans (Candida albicans), and Candida albicans (Candida albicans) were used as test bacteria. ..
• Test results The test results are shown in Tables 8 and 9. It was confirmed that this aqueous suspension containing 0.00002% (w / v) or more of silver nitrate conforms to the storage efficacy test. In addition, no change in the silver nitrate concentration in this aqueous suspension was observed during the storage period.
• this aqueous eye drop can be commercialized as a multi-dose type eye drop that can be instilled multiple times.
• Prescription 8-1 was prepared according to the prescription shown in Table 10. Specifically, 0.146 g of sodium citrate hydrate, 0.65 g of sodium chloride, 0.18 g of potassium chloride, 1 g of polyvinylpyrrolidone K30, 0.5 g of methyl cellulose, and 0.0000473 g of silver nitrate are dissolved in water, and 2 g of levamipide is added. The mixture was stirred and suspended to adjust the pH to 5.9, and water was added to make 100 mL.
• Amount of change Measured value after immersion in chemical solution or re-immersion-Measured value during immersion in physiological saline ⁇ Unit of change amount> mm: Diameter, base curve (test result)
• the amount of change was equal to or less than that of the comparative formulation.
• the subsequent immersion in physiological saline returned to the standard of contact lens for visual acuity correction (Table 13), Notification No. 349 of the Ministry of Health, Labor and Welfare.
• Mucosta (R) ophthalmic solution UD2% is capable instillation into soft contact lens wear eye.

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