+

WO1998030221A1 - Composition de type emulsion huile/eau a usage ophtalmique et contenant du difluprednate - Google Patents

Composition de type emulsion huile/eau a usage ophtalmique et contenant du difluprednate Download PDF

Info

Publication number
WO1998030221A1
WO1998030221A1 PCT/JP1998/000048 JP9800048W WO9830221A1 WO 1998030221 A1 WO1998030221 A1 WO 1998030221A1 JP 9800048 W JP9800048 W JP 9800048W WO 9830221 A1 WO9830221 A1 WO 9830221A1
Authority
WO
WIPO (PCT)
Prior art keywords
difluprednate
emulsion
oil
weight
present
Prior art date
Application number
PCT/JP1998/000048
Other languages
English (en)
Japanese (ja)
Inventor
Hidekazu Suzuki
Satoshi Yamazaki
Yoshikazu Naito
Masanobu Takeuchi
Yoshiaki Saito
Original Assignee
Wakamoto Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Wakamoto Pharmaceutical Co., Ltd. filed Critical Wakamoto Pharmaceutical Co., Ltd.
Priority to AU53424/98A priority Critical patent/AU5342498A/en
Publication of WO1998030221A1 publication Critical patent/WO1998030221A1/fr

Links

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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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

Definitions

  • the present invention relates to a 0 / W emulsion composition containing difluprednate for eye drops. More specifically, the present invention relates to an ophthalmic 0 / W emulsion composition containing difluprednate, a phospholipid, an oil, and water, which is excellent in the solubility of difluprednate in tears.
  • Conventional technology relates to a 0 / W emulsion composition containing difluprednate for eye drops. More specifically, the present invention relates to an ophthalmic 0 / W emulsion composition containing difluprednate, a phospholipid, an oil, and water, which is excellent in the solubility of difluprednate in tears.
  • difluprednate used in the present invention is a synthetic corticosteroid exhibiting an excellent anti-inflammatory effect by transdermal administration.
  • JP-A-8-217678 discloses that difluprednate is effective for treating ocular inflammation and allergic diseases.
  • difluprednate is hardly soluble in water, it cannot be dispensed as with ordinary aqueous eye drops.
  • a water-soluble polymer is used as an ophthalmic solution. Discloses a difluprednate suspension having improved dispersibility.
  • an aqueous suspension generally has a disadvantage that the feeling of use is poor and that the crystal particles precipitate at the bottom of the container during long-term storage and solidify, and are not evenly dispersed even when shaken vigorously.
  • the crystal particles have low solubility in tears, so there is a problem in bioavailability.
  • Japanese Patent Application Laid-Open No. 5-186333 and W094 / 05298 disclose 0 / W emulsion composed of drugs, oils, phospholipids and surfactants as a prior art relating to ophthalmic excipients for poorly water-soluble drugs. A composition is disclosed. However, these prior arts do not describe improving the solubility of a poorly water-soluble drug in tears. Disclosure of the invention
  • the present invention has been made in view of the problem of a conventional technology for solubilizing a poorly water-soluble drug in water, and an object of the present invention is to provide an ophthalmic composition excellent in the solubility of difluprednate in tears. Is to provide.
  • the present inventors have conducted intensive studies to achieve the above-mentioned object, and found that the 0 / W emulsion composition containing difluprednate, phospholipid, oil and water has a solubility of difluprednate in tears. And found that the present invention was significantly improved, and completed the present invention.
  • the present invention is a 0 / W emulsion composition containing difluprednate, a phospholipid, an oil, and water (hereinafter sometimes simply referred to as “emulsion”).
  • emulsion a 0 / W emulsion composition containing difluprednate, a phospholipid, an oil, and water
  • solubility of difluprednate in tears can be adjusted by appropriately changing the mixing ratio of these components.
  • the difluprednaton-containing 0 / W emulsion composition of the present invention may be used as an eye drop, as an eye drop, for inflammatory diseases of the external and anterior eye parts, for example, blepharitis, blepharitis, conjunctivitis, keratitis, scleritis, episcleritis It can be effectively applied to the treatment of meningitis, ulceris, iridocyclitis, uveitis, postoperative inflammation, allergic conjunctivitis, catarrh conjunctivitis, spring catarrhal and allergic eye diseases.
  • the difluprednate concentration of the ophthalmic difluprednate-containing 0 / W emulsion composition of the present invention is not particularly limited, but is usually 0.002 to 0.5 w / v, preferably 0.002 to 0.6 w / v. / v%.
  • concentration of difluprednate is lower than 0.002 w / v%, the concentration of difluprednate dissolved in tears decreases.
  • diflup Increasing the concentration of redonate above 0.5 w / v! 3 ⁇ 4 does not improve the dissolution concentration of difluprednate in the tears of the resulting emulsion.
  • concentration of difluprednate in the composition is in the range of 0.002 to 0.06 w / v%, the concentration of difluprednate dissolving in tears, particularly a high emulsion can be obtained.
  • the "phospholipid” used in the present invention is not particularly limited. Examples include glycerol, dicetyl phosphate, sphingomyelin, synthetic phospholipids such as dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine or distearoyl phosphatidylcholine, and mixtures of these phospholipids.
  • These phospholipids include, for example, Coatsome (registered trademark) NC-10S (high-purity egg yolk lecithin, Nippon Oil & Fats Co., Ltd.), purified egg yolk lecithin (Asahi Kasei Corporation), egg yolk lecithin PL-100H, and PL-100E.
  • NC-21 hydrogenated soybean lecithin, Nippon Oil & Fats Co., Ltd.
  • egg yolk lecithin LPL-20 egg yolk lecithin LPL-20
  • sphingolipid CB-1 sphingolipid, Cupi Co., Ltd.
  • coatsome
  • MC-6060 L- ⁇ -dipalmitoylphosphatidylcholine, Nippon Oil & Fats Co., Ltd.
  • Coatsom II-6060 L-palpaltoyltoylphosphatidic acid, Nippon Oil & Fats Co., Ltd.
  • Coatso IMU registered trademark
  • MGLS-6060 L- ⁇ -dipalmitoyl phosphatidyl DL-glycerol Na salt, Nippon Oil & Fats Co., Ltd.
  • Coatsome registered trademark
  • GLA-6060 Li Ichiichi dipalmitoyl phosphatidyl-1 DL —excellent sold under trade names such as glycerol NH 4 salt and NOF Corporation Available at
  • the amount of the phospholipid used in the emulsion of the present invention is not particularly limited, but is usually 5 to 80 parts by weight, preferably 5 to 15 parts by weight, per 1 part by weight of difluprednate.
  • the amount of the phospholipid used is in the range of 5 to 15 parts by weight per 1 part by weight of difluprednate, an emulsion having a particularly high concentration of difluprednate dissolved in tears can be obtained.
  • the amount of the phospholipid used is less than 5 parts by weight per 1 part by weight of difluprednate, crystals of difluprednate are easily precipitated in the emulsion, and it is necessary to prepare an emulsion having a desired difluprednate concentration. It becomes difficult. If the amount of the phospholipid used exceeds 80 parts by weight per 1 part by weight of difluprednate, the dissolution concentration of difluprednate in tears decreases.
  • an emulsifying aid may be added to these phospholipids.
  • the emulsification aid include sterols such as cholesterol, aliphatic amines such as stearylamine, saturated fatty acids such as stearic acid, palmitic acid, myristic acid, linoleic acid, and oleic acid; And the like, for example, salts that are chemically acceptable (eg, sodium salt ⁇ potassium salt).
  • sterols such as cholesterol
  • aliphatic amines such as stearylamine
  • saturated fatty acids such as stearic acid, palmitic acid, myristic acid, linoleic acid, and oleic acid
  • salts that are chemically acceptable eg, sodium salt ⁇ potassium salt
  • oil used in the present invention there is no particular limitation on the oil used in the present invention.
  • vegetable oils such as soybean oil, sesame oil, corn oil, peanut oil, olive oil, safflower oil, jojoba oil, cottonseed oil, rapeseed oil, etc.
  • Mono-, di-, or triglycerides of fatty acids having 6 to 18 carbon atoms such as oil derived from fats and oils, glycerin tricaprylate, tricabrylin, etc. (for example, cabronic acid, stearic acid, panolemitic acid, myristic acid, linoleic acid, etc.)
  • mineral oils such as liquid paraffin and light liquid paraffin, silicone oil, fatty acid esters and the like.
  • the viscosity and specific gravity of these oils are not particularly limited, and any viscosity and specific gravity can be used in the present invention.
  • the composition of the present invention contains at least one selected from these oils. These oils are refined soybean oil (Showa Sangyo Co., Ltd.), refined olive oil (Showa Sangyo Co., Ltd.), NIKK0L safflower oil (Nikko Chemicals Co., Ltd.), NIKK0L jojoba oil E (Nikko Chemicals Co., Ltd.) )), NIKK0L Triesta F-810 (medium chain fatty acid triglyceride, Nikko Chemicals Co., Ltd.), Panassate 810 (medium chain fatty acid tridaliceride, Nippon Yushi Co., Ltd.), NIKKOL TrifatP-52 (hydrogenated palm oil fatty acid) Triglyceride, Nikko Chemicals Co., Ltd.), NIKKOL MGS-A (glycer
  • liquid paraffin is suitable for the present invention.
  • the amount of the oil used in the emulsion of the present invention is not particularly limited, but is usually 0.5 to 80 parts by weight per 1 part by weight of the phospholipid, and the concentration in the emulsion is 25 w / v or less. It is preferred that When the amount of the oil is 0.5 parts by weight or more based on 1 part by weight of the phospholipid, an emulsion having a particularly high concentration of difluprednate dissolved in tears can be obtained.
  • the amount of the oil used is less than 0.5 part by weight per 1 part by weight of the phospholipid, the phospholipid in the emulsion is easily oxidized and the stability of the emulsion is low.
  • the amount of oil used exceeds 80 parts by weight per 1 part by weight of the phospholipid, the emulsified system tends to collapse and the emulsion becomes unstable.
  • the concentration of the oil in the emulsion exceeds 25 w / v%, the emulsion becomes creamy, and the feeling of use during instillation deteriorates.
  • xylitol xylitol, mannitol, Tonicity agents such as polyhydric alcohols such as propylene glycol and glycerin, pH adjusters such as sodium hydroxide and hydrochloric acid, methyl parahydroxybenzoate, parahydroxybenzoate Parabens such as propyl acid, sorbic acid and their pharmaceutically acceptable salts, benzyl alcohol, phenyl alcohol, benzethonium chloride, benzalkonium chloride, chlorhexidine dalconate, oxyquinoline sulfate, chlorobutanol, thimerosal, etc.
  • Preservatives synthetic polymers such as methylcellulose, hydroxypropylmethylcellulose, hydroxyethyl cellulose, polyvinylpyrrolidone, polyvinylalcohol, sodium polyacrylate, proteinaceous polymers such as gelatin, dextran, carrageenan Thickeners such as polysaccharides such as chondroitin sodium sulfate, xanthan gum, gum arabic, gum arabic, mouth-casta bean gum, antioxidants such as ascorbic acid, sodium bisulfite, sodium thioglycolate and ⁇ -thioglycerin Agent, acetic acid, phosphoric acid and their pharmaceutically acceptable salts, monoethanolamine, triethano-lamine, boric acid, borax, sodium carbonate, sodium bicarbonate, aminoethylsulfonic acid, £ -aminocaproic acid, sodium chloride
  • a buffer such as potassium chloride may be added to water, oil or phospholipid, which is an essential component of the present invention, as long as the
  • At least one selected from stabilizing agents such as amino acids, chelating agents, polycarboxylic acid compounds and their pharmaceutically acceptable salts, nonionic water-soluble cellulose derivatives, tocoprole and derivatives thereof, is used.
  • stabilizing agents such as amino acids, chelating agents, polycarboxylic acid compounds and their pharmaceutically acceptable salts, nonionic water-soluble cellulose derivatives, tocoprole and derivatives thereof.
  • the amino acids used in the present invention include cysteine, histidine and their pharmaceutically acceptable salts (eg, hydrochloride), methionine, phenylalanine, serine and the like.
  • Chelating agent used in the present invention polycarboxylic acid compound and their pharmaceutically
  • the acceptable salts for example, eel, ethylenediaminetetraacetic acid (hereinafter abbreviated as EDTA), cunic acid, thiomalic acid, L-glutamic acid, succinic acid, malonic acid, maleic acid, dl-malic acid, Adipic acid, tartaric acid, D-tartaric acid, fumaric acid, L-aspartic acid, glycyrrhizic acid, hydroxyethylethylenediamine triacetic acid, diethylenetriaminepentaacetic acid and their pharmaceutically acceptable salts, and L-cystine Is mentioned.
  • the composition of the present invention desirably contains at least one selected from these chelating agents, polycarbonate compounds and pharmaceutically acceptable salts thereof.
  • Pharmaceutically acceptable salts of EDTA used in the present invention include, for example, sodium edetate, tetrasodium edetate, tetrasodium edetate tetrahydrate, calcium sodium edetate, and the like.
  • the pharmaceutically acceptable salts of citrate used in the present invention include, for example, sodium citrate, disodium citrate, trisodium citrate, sodium dihydrogen citrate, calcium citrate, and dihydrogen citrate. Examples thereof include potassium, potassium dihydrogen citrate, and tripotassium citrate monohydrate.
  • polycarboxylic acid compounds and their pharmaceutically acceptable salts EDTA, cunic acid and their pharmaceutically acceptable salts, which are widely used as ophthalmic agents, are preferred.
  • the amount of the chelating agent, the polycarboxylic acid compound and the pharmaceutically acceptable salt thereof is usually 0.0001 to 0.2 w / v, preferably 0.002 to 0.05 w / v%.
  • the non-ionic water-soluble cellulose derivative used in the emulsion of the present invention is not particularly limited.
  • composition of the present invention contains at least one selected from these nonionic water-soluble cellulose derivatives.
  • methylcellulose and hydroxypropylmethylcellulose are preferred, with methylcellulose being the most preferred.
  • the amount of the nonionic water-soluble cellulose derivative to be used is usually 0.0005 to 5 w / v%, preferably 0.02 to 0.5 w / v%.
  • Examples of the tocopherol derivative used in the composition of the present invention include tocopheryl acetate, tocoprole nicotinate, and tocoprole succinate.
  • the emulsion of the present invention can be sterilized by a filtration sterilization method using a membrane, a heat sterilization method, or the like.
  • the emulsion is filled into an ophthalmic bottle, and this is mixed with a polyethylene film together with an oxygen scavenger (eg, Ageless (registered trademark), Mitsubishi Gas Chemical Co., Ltd.). It may be packaged in an aluminum foil laminate bag.
  • an oxygen scavenger eg, Ageless (registered trademark), Mitsubishi Gas Chemical Co., Ltd.
  • the emulsion of the present invention is usually prepared at pH 4 to 9, but pH 5.5 to 8.0 is preferable from the viewpoint of eye irritation.
  • a method for producing the emulsion of the present invention will be described.
  • Various known methods are available, for example, egg yolk lecithin and, if desired, a phospholipid such as phosphatidylethanolamine and an emulsifying aid such as oleic acid, and difluprednate in an appropriate form such as hexane, ethanol, etc.
  • the solvent is distilled off under reduced pressure to prepare a lipid thin film. Add oil and water, shake vigorously and pre-emulsify. This liquid is emulsified by a commonly used emulsifying machine.
  • the pH is adjusted to a target pH with HC1 or NaOH or the like, whereby the 0 / W emulsion containing difluprednate of the present invention can be obtained. Further, after filling this emulsion into an eye drop bottle, it is sterilized to obtain an eye drop of the present invention.
  • the present invention will be described in more detail with reference to Examples.
  • the instilled drug disappears quickly from the eye surface, which is the main absorption site, due to the turnover of tears. Therefore, the following method was employed for evaluating the solubility of difluprednate in tears of the emulsion of the present invention in order to measure the amount of difluprednate immediately dissolved in tears.
  • the artificial tears used in place of the tears were PBSs commonly used for biochemical tests (composition: NaCl 0.8 w / v K, KC 1.02 w / v%, Na 2 HP0 40 . 115w / v 3 ⁇ 4, KH 2 P0 4 0. 02w / v 3 ⁇ 4, PH7. 4) was used. Place this PBS in a 15 mL test tube with a lid. C was kept at a constant temperature in a constant temperature bath. Next, a predetermined amount of emulsion was added to the above PBS, and the mixture was gently inverted at room temperature for 30 seconds. The addition amounts of emulsion and PBS are as follows.
  • EPC Egg yolk lecithin
  • PYL purified egg yolk lecithin
  • difluprednate was dissolved in ethanol, mixed with the above phospholipid solution, and then the solvent was distilled off using an evaporator and then a vacuum pump to form a phospholipid thin film containing difluprednate.
  • Liquid paraffin No. 200-S, Sanko Chemical Industry Co., Ltd.
  • an aqueous glycerin solution were added to this phospholipid thin film, and vigorously shaken and stirred to perform preliminary emulsification.
  • the pre-emulsion was further added with 2! 3 ⁇ 4 glycerin aqueous solution to make up to 100 mL, and passed through 30 times under pressure of 750 kg / cm 2 using a Microfreezer (M-110EH).
  • Emulsified 1N NaOH was added to the liquid after the emulsification, and the pH was adjusted to 6.5 to 7.5 to obtain an emulsion of the present invention containing difluprednate.
  • To a predetermined amount of difluprednate was added 50 mL of an aqueous solution of glycerin (pH 7.0), dispersed and suspended by stirring and sonication (using BRANS0NIC 12 (manufactured by Branson)). The pH was adjusted to 7.0 with NaOH to prepare a difluprednate suspension.
  • Table 1 shows the formulations of the emulsions of the present invention containing difluprednate, and the dissolution concentrations of difluprednate when these difluprednate suspensions were diluted with PBS, or as a comparative example.
  • the emulsion of the present invention showed a very high difluprednate dissolution concentration regardless of the dilution ratio of PBS. From these results, the 0 / W emulsion for ophthalmic use of the present invention comprising difluprednate, phospholipid, liquid paraffin and water is excellent in difluprednate solubility in artificial tears.
  • Formulation Phospholipid Liquid paraffin difluprednate-diflu dissolved concentration (g / niL) w / v% w / v 3 ⁇ 4 w / v% 21-fold dilution 51-fold dilution
  • Emulsion of the present invention is diluted 21, 51-fold with PBS.
  • Phospholipid EPC: PYL-7: 3 (weight ratio)
  • Dissolution concentration of diflu Dissolution concentration of di 7 leprednate
  • the concentration of difluprednate was varied from 0.002 to 0.5 w / v%, and the emulsion of the present invention was obtained in the same manner as in Example 1 below.
  • Table 12 shows the formulation of the emulsion of the present invention and the dissolution concentration of difluprednate when these or the difluprednate suspension were diluted 51-fold with PBS as a comparative example.
  • Dissolution test The emulsion of the present invention is diluted 51 times with PBS.
  • Dissolution concentration of diflu Dissolution concentration of difluprednate
  • the emulsion of the present invention was obtained in the same manner as in Example 1 except that the concentrations of difluprednate, phospholipid and liquid paraffin were variously changed. Table 1 shows that And the dissolution concentration of difluprednate when these were diluted 51-fold with PBS.
  • difluprednate solubility of difluprednate depends on the concentration of difluprednate in emulsion, the weight ratio of phospholipid to difluprednate, and the weight ratio of oil to phospholipid.
  • Dissolution concentration of diflu Dissolution concentration of diflubrednate Formulation Example 1
  • Methylcellulose (Metrose (registered trademark) S-100, Shin-Etsu Chemical Co., Ltd.) was dispersed in hot water (70 ° C. or higher) to form a uniform hot water slurry, which was then cooled and dissolved while stirring. Glycerin, chlorobutanol and EDTA disodium are stirred into this. The mixture was dissolved by stirring to prepare a solution of a water-soluble component. To 500 ml of this solution, 500 ml of the emulsion 22 of Formulation 22, prepared in a total volume of 100 mL, was added and mixed well.
  • This mixture was adjusted to pH 6.0 with IN HC1, and then filtered through a membrane having a pore size of 0.8 to prepare an emulsion containing the above additives.
  • This emulsion was filled into an eye drop bottle and heat sterilized by an intermittent sterilization method to obtain an eye drop of the present invention containing difluprednate. Further, the obtained eye drop of the present invention and Ageless (registered trademark) Z (Mitsubishi Gas Chemical Co., Ltd.) were packaged in a polyethylene film and aluminum foil laminated bag. The procedure is shown below.
  • EPC and PYL were dissolved in a mixture of hexanenoethanol (10-1 (v / v)) with stirring.
  • difluprednate was dissolved in ethanol, mixed with the above phospholipid solution with stirring, and then the solvent was distilled off using an evaporator followed by a vacuum pump to form a phospholipid thin film containing difluprednate.
  • methyl cellulose Metalroz (registered trademark) SM-100, Shin-Etsu Chemical Co., Ltd.
  • Glycerin, potassium sorbate and disodium EDTA were dissolved in the solution by stirring to prepare a solution of a water-soluble component.
  • This emulsion was filled into an eye drop bottle, and heat sterilized by an intermittent sterilization method to obtain an eye drop of the present invention containing difluprednate. Further, the obtained ophthalmic solution of the present invention and Ageless (registered trademark) Z (Mitsubishi Gas Chemical Co., Ltd.) were packaged in a polyethylene bag and aluminum foil laminated bag. The prescription is shown below.
  • the ophthalmic solution of the present invention containing difluprednate was obtained by preparing the emulsion described in Formulation Example 4 by replacing sodium disodium EDTA with sodium citrate and potassium sorbate with benzyl alcohol.
  • package the same as Formulation Example 1. went. The prescription is shown below c
  • the oil was prepared in place of refined soybean oil (Showa Sangyo Co., Ltd.) to obtain an eye drop of the present invention containing difluprednate. Further, packaging was performed in the same manner as in Preparation Example 1. The prescription is shown below.
  • the ophthalmic difluprednate-containing 0 / W emulsion composition of the present invention is excellent in the solubility of difluprednate in tears. Therefore, a sufficient anti-inflammatory effect can be expected at a low dose, and it is economical, and further, it can be expected to reduce systemic side effects that are a concern when instilling difluprednate.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Ophthalmology & Optometry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne une composition de type émulsion huile/eau à usage ophtalmique, laquelle contient du difluprednate, un phospholipide, une huile et de l'eau. Cette composition possède d'excellentes qualités en ce qui concerne la solubilité du difluprednate dans le fluide lacrymal, et possède ainsi un effet anti-inflammatoire satisfaisant même en faible dose. Il est ainsi possible d'améliorer l'efficacité sur le plan économique ou, encore, de réduire les effets adverses systémiques auxquels on peut s'attendre lorsque l'on met des gouttes de difluprednate dans les yeux.
PCT/JP1998/000048 1997-01-10 1998-01-09 Composition de type emulsion huile/eau a usage ophtalmique et contenant du difluprednate WO1998030221A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU53424/98A AU5342498A (en) 1997-01-10 1998-01-09 Difluprednate-containing ophthalmic o/w emulsion composition

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP9/13196 1997-01-10
JP1319697 1997-01-10

Publications (1)

Publication Number Publication Date
WO1998030221A1 true WO1998030221A1 (fr) 1998-07-16

Family

ID=11826413

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1998/000048 WO1998030221A1 (fr) 1997-01-10 1998-01-09 Composition de type emulsion huile/eau a usage ophtalmique et contenant du difluprednate

Country Status (2)

Country Link
AU (1) AU5342498A (fr)
WO (1) WO1998030221A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0878197A1 (fr) * 1997-05-14 1998-11-18 Senju Pharmaceutical Co., Ltd. Compositions à base de difluprednate
WO2002011734A1 (fr) * 2000-08-08 2002-02-14 Wakamoto Pharmaceutical Co., Ltd. Compositions pharmaceutiques aqueuses
JP3410364B2 (ja) 1997-05-14 2003-05-26 千寿製薬株式会社 ジフルプレドナート含有組成物
WO2005082335A1 (fr) * 2004-02-26 2005-09-09 Kowa Company., Ltd. Préparation ophtalmique
JP5138128B2 (ja) * 1998-08-21 2013-02-06 千寿製薬株式会社 水性液剤
WO2014126266A1 (fr) * 2013-02-15 2014-08-21 Senju Pharmaceutical Co., Ltd. Composition d'émulsion à base de difluprédnate contenant du zinc
WO2014126267A1 (fr) 2013-02-15 2014-08-21 Senju Pharmaceutical Co., Ltd. Composition d'émulsion de difluprednate contenant un métal antimicrobien

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61249918A (ja) * 1985-04-26 1986-11-07 Yutaka Mizushima 点眼剤
JPS62270521A (ja) * 1986-05-16 1987-11-24 Green Cross Corp:The フルルビプロフエン眼投与製剤
JPH05170643A (ja) * 1991-10-21 1993-07-09 Pola Chem Ind Inc 水性目薬及びその製造法
JPH05186333A (ja) * 1991-07-05 1993-07-27 Yissum Res Dev Co Of Hebrew Univ Of Jerusalem 眼用組成物
JPH08217678A (ja) * 1993-12-27 1996-08-27 Senju Pharmaceut Co Ltd ジフルプレドナート含有点眼用懸濁液剤

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61249918A (ja) * 1985-04-26 1986-11-07 Yutaka Mizushima 点眼剤
JPS62270521A (ja) * 1986-05-16 1987-11-24 Green Cross Corp:The フルルビプロフエン眼投与製剤
JPH05186333A (ja) * 1991-07-05 1993-07-27 Yissum Res Dev Co Of Hebrew Univ Of Jerusalem 眼用組成物
JPH05170643A (ja) * 1991-10-21 1993-07-09 Pola Chem Ind Inc 水性目薬及びその製造法
JPH08217678A (ja) * 1993-12-27 1996-08-27 Senju Pharmaceut Co Ltd ジフルプレドナート含有点眼用懸濁液剤

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3410364B2 (ja) 1997-05-14 2003-05-26 千寿製薬株式会社 ジフルプレドナート含有組成物
US6114319A (en) * 1997-05-14 2000-09-05 Senju Pharmaceutical Co., Ltd. Compositions containing difluprednate
EP0878197A1 (fr) * 1997-05-14 1998-11-18 Senju Pharmaceutical Co., Ltd. Compositions à base de difluprednate
JP5138128B2 (ja) * 1998-08-21 2013-02-06 千寿製薬株式会社 水性液剤
US7612115B2 (en) 2000-08-08 2009-11-03 Wakamoto Pharmaceutical Co., Ltd. Aqueous pharmaceutical compositions
WO2002011734A1 (fr) * 2000-08-08 2002-02-14 Wakamoto Pharmaceutical Co., Ltd. Compositions pharmaceutiques aqueuses
WO2005082335A1 (fr) * 2004-02-26 2005-09-09 Kowa Company., Ltd. Préparation ophtalmique
WO2014126266A1 (fr) * 2013-02-15 2014-08-21 Senju Pharmaceutical Co., Ltd. Composition d'émulsion à base de difluprédnate contenant du zinc
WO2014126267A1 (fr) 2013-02-15 2014-08-21 Senju Pharmaceutical Co., Ltd. Composition d'émulsion de difluprednate contenant un métal antimicrobien
US20150374820A1 (en) * 2013-02-15 2015-12-31 Senju Pharmaceutical Co., Ltd. Difluprednate emulsion composition containing zinc
JP2016507468A (ja) * 2013-02-15 2016-03-10 千寿製薬株式会社 亜鉛を含有するジフルプレドナートエマルション組成物
JP2016507469A (ja) * 2013-02-15 2016-03-10 千寿製薬株式会社 抗菌性金属を含有するジフルプレドナートエマルション組成物
RU2666961C2 (ru) * 2013-02-15 2018-09-13 Сэндзю Фармацевтикал Ко., Лтд. Эмульсионная композиция дифлюпредната, содержащая антимикробный металл

Also Published As

Publication number Publication date
AU5342498A (en) 1998-08-03

Similar Documents

Publication Publication Date Title
US8697751B2 (en) Pharmaceutical composition containing prostaglandin
JP5452472B2 (ja) プロスタグランジン類を含有する眼科用水中油型エマルジョン
US6432439B1 (en) O/W emulsion composition
JP2009533462A (ja) ブリモニジンおよびチモロールの組成物
WO1997005882A1 (fr) Composition d'emulsion aqueuse pour collyres
JP5021887B2 (ja) アゼチジン誘導体に基づく医薬組成物
JP4933897B2 (ja) 眼内移行性促進水性点眼剤
JP5593345B2 (ja) イソプロピルウノプロストンの分解抑制方法
NZ539046A (en) Chemotherapeutic self-emulsifying microemulsion compositions of paclitaxel with improved oral bioavailability
WO1998030221A1 (fr) Composition de type emulsion huile/eau a usage ophtalmique et contenant du difluprednate
RU2348615C2 (ru) Эмульгирующие системы, содержащие производные азетидина
JP6934581B2 (ja) エピナスチン又はその塩を含有する水性医薬組成物
WO2006004085A1 (fr) Composition médicinale à base d'eau contenant de l'azithromycine et procédé servant à préparer celle-ci
JP2000143542A (ja) 難溶性免疫抑制剤含有ｏ／ｗエマルジョン製剤
TW202320774A (zh) 用於口服之舒緩肽ｂ２受體拮抗劑之基於脂質之組成物
JP2003055201A (ja) ビタミンａ類含有可溶化組成物及びビタミンａ類の安定化方法
JP4221073B2 (ja) 乳剤用保存剤および乳剤
JP2001172183A (ja) 眼科用医薬組成物
EP2827838A1 (fr) Composition pharmaceutique ophtalmique contenant un inhibiteur d'anhydrase carbonique et procédé pour sa préparation
US20250032412A1 (en) Self-emulsifying oil-in-water microemulsion or nanoemulsion, and emulsifying composition
JP2003286163A (ja) ジクロフェナクナトリウム経口製剤
GR1009616B (el) Οφθαλμικο φαρμακευτικο σκευασμα που περιεχει βρινζολαμιδη και τιμολολη και μεθοδος παρασκευης αυτου

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA CN JP US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载