WO2004098592A1 - Composition contenant un derive d'oxazolidinone - Google Patents

Composition contenant un derive d'oxazolidinone Download PDF

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Publication number
WO2004098592A1
WO2004098592A1 PCT/JP2004/006425 JP2004006425W WO2004098592A1 WO 2004098592 A1 WO2004098592 A1 WO 2004098592A1 JP 2004006425 W JP2004006425 W JP 2004006425W WO 2004098592 A1 WO2004098592 A1 WO 2004098592A1
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WIPO (PCT)
Prior art keywords
propoxyphenyl
methoxy
methyl
year
composition
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PCT/JP2004/006425
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English (en)
Japanese (ja)
Inventor
Kazuhisa Tsujimoto
Osamu Sakai
Yoshikuni Nakamura
Katsuhiro Inada
Kayoko Ueda
Original Assignee
Senju Pharmaceutical Co. Ltd.
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Priority claimed from JP2003128355A external-priority patent/JP2006199588A/ja
Priority claimed from JP2004000178A external-priority patent/JP2006169112A/ja
Application filed by Senju Pharmaceutical Co. Ltd. filed Critical Senju Pharmaceutical Co. Ltd.
Publication of WO2004098592A1 publication Critical patent/WO2004098592A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • A61P27/14—Decongestants or antiallergics

Definitions

  • the present invention relates to a composition containing 5- (4-methoxy-3-propoxyphenyl) -1-methyl-21-year-old xazolidinone or a pharmaceutically acceptable salt thereof. Ming background technology
  • the drug In order for topical ocular administration to be effective against allergic or inflammatory eye diseases, the drug must reach the affected area and stay there for the required time at the required concentration. Also, since it is administered topically to the eye, it is necessary that there be no eye irritation or that the eye irritation be minimal enough to withstand use.
  • 5- (4-methoxy-3-propoxyphenyl) -1-methyl-2-year-old xazolidinone is a compound that is hardly soluble in water and unstable in water. Conventionally, it is necessary to produce poorly water-soluble drugs as aqueous solutions such as eye drops and nasal drops. In such a case, a surfactant or the like is added.
  • Japanese Patent Publication No. Hei 5-770612 discloses non-steroidal antirheumatic drugs, steroids, cardiac glycosides, benzodiazepine derivatives, benzimidazole derivatives, piperidine derivatives, piperazine derivatives, imidazole derivatives.
  • a method for solubilization of a poorly soluble conjugate such as a triazole derivative using a cyclodextrin for example, hydroxyethyl-1-i8-cyclodextrin ⁇ hydroxypropyl-1; 8-cyclodextrin.
  • the solubilization of a poorly soluble drug depends on the shape, size, physical and chemical properties of the poorly soluble drug, and the physical and chemical properties of the solubilizer used. At present, it is not easy to produce a stable aqueous solution of a poorly soluble drug because the combination and the mixing ratio are different. As far as the present inventors know, 5- (4-methoxy-3-propoxyphenyl) -5-methyl-2-year-old xazolidinone is described in terms of its stable aqueous solution and its solubilization method. There is no document that describes this method or suggests such a method.
  • corneal ulcers involve the activity of inflammatory cells such as corneal stromal cells and neutrophils, and complex interactions are induced through cytokins and proteases secreted by them. It is thought to form a pathological condition.
  • steroids are used for corneal ulcers, but there are various problems such as susceptibility to infection and increased intraocular pressure. Therefore, development of a useful and safe drug for corneal ulcer is desired.
  • PDE-IV inhibitors are known to have an inhibitory effect on cytoplasmic in production (inflammatory cells), neutrophil migration and MMP production (HLF-1 human lung-derived fibroblasts). ing.
  • JP-T-2003-520825 discloses the treatment of a corneal ulcer with an ⁇ -sulfonylhydroxamic acid derivative which is a phosphodiesterase inhibitor.
  • Japanese Patent Application Publication No. 2002-53373883 discloses that the level of cyclic adenosine monophosphate (3 ', 5'-monophosphate (cAM ⁇ )) is increased by inhibiting PDE-IV.
  • cAM ⁇ cyclic adenosine monophosphate
  • a compound and a pharmaceutical composition for treating a disease are disclosed, and corneal ulcer is exemplified as one of the target diseases.
  • An object of the present invention is to provide a stable composition containing 5- (4-methoxy-3-propoxyphenyl) -5-methyl-2-year-old xazolidinone or a pharmaceutically acceptable salt thereof. It is in.
  • a further object of the present invention is to provide 5- (4-methoxy-13-propoxyphenyl) -1-methyl-2-year-old xazolidinone or a pharmaceutically acceptable salt thereof.
  • An object of the present invention is to provide a composition for topical administration to the eye for treating allergic eye diseases, for treating eye inflammation, and for treating corneal ulcer.
  • a further object of the present invention is to provide a stable aqueous solution containing an effective concentration of 5- (4-methoxy-3-propoxyphenyl) -5-methyl-2-agexazolidinone or a pharmaceutically acceptable salt thereof. It is to provide a liquid agent.
  • a further object of the present invention is to solubilize sparingly soluble 5- (4-methoxy-13-propoxyphenyl) -5-methyl-12-year-old xazolidinone or a pharmacologically acceptable salt thereof, And to provide a method for stabilization.
  • a further object of the present invention is to provide (R)-(-)-5- (4-methoxy-13-propoxyphenyl) -5-methyl-12-year-old xazolidinone or a pharmaceutically acceptable salt thereof. It is an object of the present invention to provide a composition for topical administration, which contains the compound in a form where its racemization is prevented.
  • a still further object of the present invention is to provide a poorly soluble (R)-(-)-5- (4—methoxy-13-propoxyphenyl) -1-methyl-12-year-old xazolidinone or
  • An object of the present invention is to provide a method for preventing racemization of a pharmacologically acceptable salt.
  • the present invention provides the following. -1.5-(4-Methoxy-3-propoxyphenyl)-5-Methyl-
  • composition for topical ocular administration for treating allergic eye diseases comprising one-year-old xazolidinone or a pharmaceutically acceptable salt thereof.
  • composition for topical administration to the eye for the treatment of ocular inflammation comprising 5- (4-methoxy-3-propoxyphenyl) -5-methyl-2-oxazolidinone or a pharmaceutically acceptable salt thereof.
  • composition for topical administration to the eye for treating ocular inflammation which comprises 5-methyl-2-year-old xazolidinone or a pharmaceutically acceptable salt thereof.
  • composition for topical ocular administration according to any one of the above 1 to 6, which is in the form of an aqueous solution.
  • composition for topical ocular administration according to any one of the above 1 to 6, which is in the form of a suspension.
  • composition for ocular topical administration according to any one of the above 1 to 6, which is in the form of an oily ophthalmic solution.
  • composition for topical administration to the eye according to any one of the above 1 to 6, which is in the form of an emulsion.
  • composition for topical ocular administration according to any one of the above items 1 to 10, which is in the range defined by OwZv ⁇ .
  • composition for topical ocular administration according to any one of the above 1 to 6, which is in the form of an ointment.
  • Hydroxypropyl 1) 8-cyclodextrin The lower limit of the concentration is 0.5 wZv% and the upper limit is selected from the range of 25 wZv%.
  • aqueous liquid preparation according to any one of the above items 14 to 16 wherein the pH of the aqueous liquid preparation is in the range of 3 to 9. 1 8.
  • the oily liquid composition for topical administration according to the above item 23 or 24, which is a nasal solution.
  • a method comprising blending an oil and / or a medium-chain fatty acid triglyceride into an oily liquid preparation.
  • a stabilized composition for treating allergic diseases and inflammatory diseases such as allergic eye disease treatment, inflammatory eye disease treatment and corneal ulcer treatment
  • the composition can be used in various applications including injections, and is particularly suitable for use as a composition for topical administration to the eye and other compositions for topical administration.
  • the composition for topical administration to the eye of the present invention can be used as an aqueous solution such as ophthalmic solution, suspension ophthalmic solution, emulsion or the like, an oily solution or an ointment, allergic conjunctivitis, allergic eye diseases such as spring catarrh, grape It is advantageously used for the treatment of ocular inflammation such as meningitis, blepharitis, lacrimal canalitis, oculophthalmitis, and postoperative endophthalmitis.
  • the composition for topical administration to the eye of the present invention is also useful as a therapeutic agent for corneal ulcer.
  • the aqueous solution and the composition for topical administration of the present invention are advantageously used for allergic diseases such as atopic dermatitis, asthma and chronic obstructive pulmonary disease.
  • FIG. 1 is a graph showing the inhibitory effects of the suspension of the present application, rolipram and full-year rometron on the LTD 4 and PAF-induced conjunctival eosinophil models in Experimental Example 1.
  • the vertical axis represents the absorbance (490 nm).
  • RP indicates rolipram.
  • FM indicates full-length Rometron.
  • Each column shows the average soil standard error.
  • ** indicates a significant difference (P ⁇ 0.01) from the control (Dumiett's test).
  • FIG. 2 is a diagram showing the inhibitory effects of the suspension of the present application, betamethosone and full-year rometron on antigen-induced conjunctivitis in Experimental Example 1.
  • the vertical axis represents the score or absorbance (490 nm).
  • BM indicates a solid evening zone.
  • FM indicates full-length rometron.
  • Each column shows the average soil standard error.
  • ** indicates a significant difference (P ⁇ 0.01) from the control (Dunnett's test).
  • ⁇ 7-8.
  • FIG. 3 is a diagram showing the inhibitory effects of the aqueous solution of the present application and betamethasone on antigen-induced conjunctivitis in Experimental Example 1.
  • the vertical axis represents the score or absorbance (490 nm).
  • BM indicates solid zoning.
  • Each column shows the mean standard error.
  • ** indicates a significant difference (P 0.01) from the control (Dunnett's test).
  • n 9-10.
  • Figure 4 is a graph showing the effect of (R)-(-)-15- (4-methoxy-3-propoxyphenyl) -15-methyl-2-year-old xazolidinone on endotoxin-induced corneal opacity by eye drops. is there.
  • FIG. 5 is a graph showing the effect of (R)-(—)-15- (4-methoxy-13-propoxyphenyl) -15-methyl-2-year-old xazolidinone on endotoxin-induced corneal neovascularization. It is. BEST MODE FOR CARRYING OUT THE INVENTION
  • the compounds of the present invention contained in the composition for topical administration to the eye of the present invention include racemic forms, (R) forms and (S) forms.
  • racemic form, the (R) form, and a mixture of the (R) form and the (S) form, which are located between the two and contain the (R) form in a ratio of 1 Z2 or more are preferable.
  • 5-(4-Methoxy-3-propoxyphenyl)-5-methyl-2-year-old oxazolidinone is a pharmacologically acceptable salt of sodium salt such as sodium salt and potassium salt.
  • Metal salts may be mentioned, but any other salts may be used as appropriate for the purpose of the present invention, as long as they are pharmacologically acceptable salts.
  • 5- (4-Methoxy-3-propoxyphenyl) 15-methyl-12-oxazolidinone is described in, for example, the above-mentioned Japanese Patent Application Laid-Open No. Hei 7-6-1978 and Japanese Patent Laid-Open Publication No. Hei 11-113. It can be produced by the method described in JP-A-693.
  • composition for topical administration to the eye of the present invention is in the form of an aqueous solution such as an ophthalmic solution, a suspended ophthalmic solution or an emulsion, for example, (R)-(1-)-5- (4-methoxy-13-) Propoxyphenyl)-5-Methyl-12-year-old xazolidinone or its pharmacologically acceptable salt content usually has a lower limit of about 0.001 w / v%, preferably about 0.005 w / v%.
  • the content of hydroxypropyl 1 / 5-cyclodextrin is lower limit of about 0.5 w / v%, preferably about 3. Ow / v%, more preferably 5. Ow / v%. %,
  • the upper limit is about 25 w / v%, preferably about 12.5 w / v%, more preferably about 8. Ow / v%, and the particularly preferable content is about 6.5 w / v%.
  • composition for topical administration to the eye of the present invention is in the form of an ophthalmic ointment, for example, (R) 1 (-)-5- (4-methoxy-3-propoxyphenyl) 15-methyl-1-2 —
  • the content of oxazolidinone or a pharmacologically acceptable salt thereof is generally lower limit of about 0.001 w / w%, preferably about 0.005 w / w%, more preferably about 0.01 w / w%. / w%, upper limit: 10 Ow / w%, preferably about 2.0 w / w%, more preferably about 0.1 w / w%, depending on the intended use and the degree of indication May be appropriately increased or decreased.
  • composition for topical administration to the eye of the present invention is in the form of an aqueous solution such as an ophthalmic solution, a suspension ophthalmic solution or an emulsion, it does not contradict the purpose of the present invention.
  • aqueous solution such as an ophthalmic solution, a suspension ophthalmic solution or an emulsion
  • additives such as a buffer, a thickening agent, a chelating agent, a preservative, a pH adjuster, and a fragrance may be appropriately added.
  • Examples of the tonicity agent include sodium chloride, potassium chloride, glycerin, mannitol, sorbitol, boric acid, glucose, propylene glycol and the like.
  • Examples of the buffer include phosphate buffer, borate buffer, citrate buffer, tartrate buffer, acetate buffer, sodium dihydrogen phosphate, sodium hydrogen phosphate, sodium citrate, boric acid , Sodium borate, sodium acetate, amino acids and the like.
  • Polyvinyl pyrrolidone, cal Examples include boxymethylcellulose, carboxypropylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, and sodium polyacrylate.
  • Examples of the chelating agent include sodium edetate, sodium citrate, and condensed sodium phosphate.
  • preservatives include quaternary ammonium salts such as benzalkonium chloride and benzonium chloride, para-hydroxybenzoic esters such as methyl paraoxybenzoate and propyl parahydroxybenzoate, chlorhexidine dalconate, Sorbic acid and its salts, thimerosal and the like.
  • Examples of the pH adjuster include hydrochloric acid, sodium hydroxide, phosphoric acid, and acetic acid.
  • Examples of the fragrance include 1-men I-one, borneol, camphor, and eucalyptus oil.
  • the concentration of each of the above-mentioned additives blended in the composition for topical administration to the eye of the present invention is, for example, the isotonic agent is blended to a concentration such that the osmotic pressure ratio becomes about 0.8 to 1.2, and the buffer is 0.8.
  • the content of the thickener is about 0.1 to 1 OwZv%.
  • the composition of the present invention comprises (R)-(-)-5- (4-methoxy-3-propoxyphenyl) -1-methyl-2-year-old xazolidinone or a pharmaceutically acceptable salt or oil thereof.
  • Liquid (oil-based liquid) using an oil as a medium for example, a solution in which the present compound is dissolved or suspended in an oil as a base
  • alcohol such as ethanol, water
  • It may be an oil-based liquid (oil-based liquid) further containing an emulsifier.
  • oils that can be used in the present invention, those that can be applied to eyes with low toxicity and low irritation are used.
  • oils examples include those containing fatty acid esters of glycerin, such as soybean oil, sesame oil, camellia oil, rapeseed oil, corn oil, etc., and particularly suitable are castor oil and medium-chain fatty acid esters.
  • Liglycerides for example, Miglyol (trade name, Mitsuba trade)] can be mentioned.
  • the quantitative ratio between the two may be arbitrary.
  • an alcohol that is miscible with oil the amount thereof may be appropriately determined.
  • water and an emulsifier those components can be added in appropriate amounts as long as the medium is maintained as an oil. The same applies when other oils are used.
  • the content of the pharmacologically acceptable salt thereof is usually lower limit of about 0.001 w / v%, preferably about 0.005 w / v%, more preferably about 0.01 w / v%, Upper limit: about 2.0 w / v%, preferably about 0.5 w / v%, more preferably about 0.25 w / v%, still more preferably 0.1 w / v%
  • the dose may be adjusted according to the purpose of use and the severity of the indication.
  • the composition of the present invention can also be provided as an aqueous preparation such as an oil-in-water (OZW) emulsion or microemulsion.
  • OZW oil-in-water
  • a surfactant for example, a nonionic surfactant having a surface activity can be blended as an emulsifier.
  • nonionic surfactants include polyoxyethylene hydrogenated castor oil or polyoxyethylene sorbitan fatty acid ester, preferably polyoxyethylene sorbitan monolate and polyoxyethylene sorbitan monolaurate. Polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, and the like.
  • composition for topical administration to the eye of the present invention is used in the form of an aqueous solution as an ophthalmic solution, a suspension ophthalmic solution or an emulsion
  • the pH is adjusted to about 3 to 9, preferably about 6 to 8.
  • composition for topical administration to the eye of the present invention is used as an ophthalmic ointment
  • purified lanolin, vaseline, plastibase, liquid paraffin and the like are appropriately used as the ointment base.
  • composition for topical administration to the eye of the present invention may appropriately contain other same or different kinds of pharmaceutically active ingredients as long as the object of the present invention is not adversely affected.
  • composition for topical administration to the eye of the present invention can be produced by a method known per se, for example, a method described in a liquid preparation such as an eye drop in the Japanese Pharmacopoeia, the 14th Revised Japanese Pharmacopoeia, general rules for preparations, or an ointment. it can.
  • composition for topical administration to the eye of the present invention can be used in warm-blooded animals (for example, humans, rats, mice, rabbits, rabbits, dogs, cats, etc.).
  • composition for topical administration to the eye of the present invention is, for example, (R)-(1-)-5- (4-methoxy-13-propoxyphenyl) -5-methyl-2-year-old xazolidinone 0.1 w / v %
  • the number of administrations can be increased or decreased as appropriate depending on the degree of the indication.
  • composition for topical administration of the present invention is used as an ointment in the form of an ophthalmic ointment.
  • the present invention contains 0.1 w / w% of (R)-(—)-5- (4-methoxy-3-propoxyphenyl) -15-methyl-2 one-year-old xazolidinone.
  • Ophthalmic ointment may be given to adults 3 to 6 times daily.
  • the number of administrations can be increased or decreased as appropriate depending on the degree of the adaptation symptom.
  • the present invention will be described in more detail with reference to experimental examples and examples. The light is not limited by these.
  • Table 2 shows the results. Table 2 Solubility of (R) (—)-5- (4-Methoxy-3-propoxyphenyl) —5-Methyl-2-year-old xazolidinone with various additives
  • (R)-(-)-5- (4-methoxy-13-propoxyphenyl) -15-methyl-2-oxazolidinone is a compound that is hardly soluble in water and can be used in aqueous solutions at pH 5-8. Although unstable, it was solubilized by the addition of hydroxypropyl-1-cyclodextrin, and was stable as at least 5- (4-methoxy-13-propoxyphenyl) -5-methyl-21-year-old xazolidinone. It has been found that conversion can be achieved simultaneously.
  • Experimental Example 5 0.05% and 0.25% (R)-(I)-5-(4-Methoxy-3-propoxyphenyl) -5-Methyl-2-year-old Stability of aqueous solution of xazolidinone
  • Table 6 shows the results. Table 6 0.05% and 0.25% containing (hydroxypropyl-1) 8-cyclodextrin (R)-(-1) -1 5- (4-methoxy-3-propoxyphenyl) -1-5-methyl-21 Stability of aqueous oxazolidinone solutions
  • An oily solution was prepared by dissolving the present compound in oil according to the formulation shown in Table 7 below, and the presence or absence of a change in the content of the present compound under constant temperature conditions.
  • the residual ratio of this compound (however, the (R) -form and (S) -form cannot be distinguished) was measured by HPLC, and the change in optical activity was measured to determine the optical activity.
  • the presence of an increase in the isomer (S) -form was examined.
  • an aqueous solution containing hydroxypropyl mono-S-cyclodextrin (formulation No.
  • test substance The test substances used in each experiment are as follows.
  • Mouth lipram was suspended in the above vehicle at 1.0%.
  • Eosinophil infiltration into the conjunctiva was determined as follows. 5 mL of 0.5% a-hexadecyltrimethylammonium bromide (HTAB) in 0.1 M phosphate buffered saline was added to the corneal sample. After homogenization, freezing and thawing were repeated twice, and the sample was centrifuged at 3000Xg for 10 minutes. 20 L of the supernatant was distributed to each well of a 96-well tissue culture plate.
  • HTAB a-hexadecyltrimethylammonium bromide
  • Guinea pigs were sensitized by intraperitoneal injection of 10 Atg ovalbumin. (OA; Sigma) together with 30 mg of aluminum hydroxide. Allergic conjunctivitis was induced 14 days (first) and 15 days (second) after sensitization by instilling 10 L of 1.5% 0A. The test substance was administered by instillation at 6, 4, 1, 1 and 0.5 hours before the first and second allergic conjunctivitis induction. The control group received saline in the same manner as the drug-treated group.
  • OA ovalbumin.
  • Eosinophil infiltration into the conjunctiva was assessed by measuring the activity of Eosinophi I peroxidase (EPo), a cytotoxic protein in eosinophils. That is, 1 mL of HTAB buffer (0.5% HTBA, 10 mM phosphate buffered saline ( ⁇ 7.4)) was added to the extracted conjunctiva, and the conjunctiva was minced with scissors. Further, 4 mL of HTAB buffer was added and stirred.
  • Eosinophi I peroxidase Eosinophi I peroxidase
  • EP0 activity in the conjunctiva of the control group increased by LTD 4 and PAF.
  • the 0.5% suspension of the present invention significantly suppressed the increase in EP0 activity of the conjunctiva.
  • the effect of the 0.5% suspension of the present application was higher than that of the 0.1% oral lipram and the 0.1% full-length liposome.
  • FIG. 2 shows the results of a comparative test of the suspension of the present application with betamethasone and full-length lometron.
  • the conjunctival edema of the control group was measured.
  • the 0.5% suspension of the present invention significantly suppressed conjunctival edema.
  • the 0.1% betamethasone solution showed the same inhibitory effect as the suspension of the present application, but was not statistically significant.
  • 0.1% Fluorometron did not significantly suppress conjunctival edema.
  • the 0.5% suspension of the present invention showed an effect superior to that of 0.1% betazone and 0.1% fluorometron, and significantly suppressed the increase in EP0 activity.
  • Fig. 3 shows the results of a comparison test between the aqueous solution of the present application and betamethasone. 21 Japanese Patent Office] 4, 6.200
  • Conjunctival edema was suppressed by instillation of the aqueous solution of the present application.
  • the inhibitory effects of the aqueous solutions of 0.05%, 0.1% and 0.25% of the present application were also found to be strong for 0.1% betamethasone.
  • test drug was 0.1% (R) — (1) -15- (4-methoxy-3-propoxyphenyl) -15-methyl-2-oxazolidinone in the following base at 0.1 wZ
  • a mixture of equal volumes of 5% ketamine and 2% xylazine was administered intramuscularly (1 mIg) to the muscles of 12 birds and subjected to general anesthesia, and then 1% endotoxin derived from Pseudomonas aeruginosa dissolved in physiological saline
  • the (lipopolysaccharide, LPS) solution was injected into the corneal stratum corneum of one eye of the egret at a rate of 0.1 i.
  • scoring evaluation was performed on corneal opacity and corneal neovascularization according to the criteria shown in Table 11.
  • the test drug was administered to the endotoxin-injected eyes of six egrets four times a day at a dose of 50 ⁇ I each time.
  • the base was similarly administered to the endotoxin-injected eyes of the egret.
  • Example 2 Ophthalmic solution (R)-(-) — 5— (4-Methoxy-1-3-propoxyphenyl) -1-5-Methyl-1-2-year-old oxazolidinone 0.01 g
  • Example 3 Ophthalmic solution using the above ingredients to form an ophthalmic solution in a conventional manner
  • Example 5 Suspended ophthalmic solution
  • Example 9 Ear drops
  • Example 1 Oily ophthalmic solution
  • the present compound is added to castor oil and dissolved with stirring. If necessary, dissolve by heating and sterilize by filtration to produce eye drops.
  • Example 13 Oily eye drops
  • Miglyol 8 1 2 N (medium chain fatty acid triglyceride) 100 mL
  • Miglyol 8 1 2 N (medium chain fatty acid triglyceride) 50 mL
  • Miglyol 812N and castor oil are mixed, and this compound is added to this solution and dissolved with stirring. Heat if necessary to dissolve. After that, make up with castor oil and sterilize by filtration to produce eye drops.
  • Example 15 Oily eye drops
  • the present compound is added to sesame oil and dissolved with stirring. If necessary, dissolve by heating and sterilize by filtration to produce eye drops.
  • Example 16 Oily eye drops
  • Miglioyl 8 1 2 N (medium chain fatty acid triglyceride)
  • Miglyol 812N and ethanol are mixed according to the above formula, and this compound is added to this solution and dissolved with stirring. Heat if necessary to dissolve. Then, make up with Miglyol 81211 and sterilize by filtration to produce eye drops.
  • Example 18 Oily eye drops
  • Miglyol 8 1 2 N (medium chain fatty acid triglyceride) 46 mL
  • concentrated glycerin and polysorbate 80 are added to purified water and dissolved with stirring with a homomixer. Then, the present compound dissolved in castor oil is added dropwise and emulsified with a homomixer. After micronization with a microfluidizer, adjust the pH, remove the solution, sterilize by filtration to produce eye drops.
  • Emulsion ophthalmic solution
  • concentrated glycerin and polysorbate 80 are added to purified water, dissolved with stirring with a wood mixer, the compound dissolved in castor oil is added dropwise, and emulsified with a homomixer. Micronization is performed with a microfluidizer. Hydroxypropyl 1) 8-cyclodextrin is dissolved in purified water, and this solution and an equal amount of the above emulsified solution are stirred at 10 ° C for 1 hour, adjusted to pH, and sterilized by filtration to produce eye drops. .
  • Example 21 Emulsion ophthalmic solution
  • concentrated glycerin and polysorbate 80 are added to purified water and dissolved with stirring with a homomixer. Then, the present compound dissolved in castor oil is added dropwise and emulsified with a homomixer. Immediately after emulsification, dissolve sodium chloride and micronize with a microfluidizer. Then adjust the pH and sterilize by filtration to produce eye drops.
  • concentrated glycerin, polysorbate 80 and sodium chloride are added to purified water, and the mixture is dissolved with stirring with a homomixer.
  • the compound dissolved in castor oil is added dropwise and emulsified with a homomixer.
  • Example 24 Emulsion ophthalmic solution
  • Miglyol 8 1 2 N (medium chain fatty acid triglyceride) 1.0 g
  • concentrated glycerin and polyvinyl alcohol are added to purified water, dissolved with stirring using a wood mixer, and the compound dissolved in Miglyol 812N is added dropwise and emulsified with a homomixer. Micronization is performed with a microfluidizer. Then adjust the pH and sterilize by filtration to produce eye drops.
  • composition for topical administration to the eye of the present invention may be, for example, an ophthalmic solution, a suspended ophthalmic solution, an emulsion or an ointment, allergic conjunctivitis, allergic eye diseases such as spring catarrh, uveitis, blepharitis, lacrimal canalicular It is advantageously used for the treatment of ophthalmic diseases such as inflammation, panophthalmitis and postoperative endophthalmitis. While several embodiments of the present invention have been described in detail, those skilled in the art will recognize that certain embodiments illustrated and modified in various ways without departing substantially from the novel teachings and advantages of the present invention. It is possible to make changes, so such modifications and changes Furthermore, all of them are included in the spirit and scope of the present invention defined in the following claims.

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  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Ophthalmology & Optometry (AREA)
  • Epidemiology (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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Abstract

La présente invention concerne une composition stabilisée destinée au traitement de maladies oculaires allergiques et d'ophtalmie. Cette composition contient 5-(4-méthoxy-3-propoxyphényle)-5-méthyle-2-oxazolidinone ou un sel de ce composé répondant aux normes pharmaceutiques. Cette composition est, en particulier, prévue pour une administration topique, et est plus particulièrement destinée aux yeux.
PCT/JP2004/006425 2003-05-06 2004-05-06 Composition contenant un derive d'oxazolidinone WO2004098592A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP2003-128355 2003-05-06
JP2003128355A JP2006199588A (ja) 2003-05-06 2003-05-06 オキサゾリジノン誘導体含有水性液剤
JP2004-000178 2004-01-05
JP2004000178A JP2006169112A (ja) 2004-01-05 2004-01-05 オキサゾリジノン誘導体含有眼局所投与用組成物

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WO2004098592A1 true WO2004098592A1 (fr) 2004-11-18

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3266446A1 (fr) * 2016-07-07 2018-01-10 Laboratorios SALVAT, S.A. Composition ophtalmique comprenant de l'huile de ricin et d'un triglyceride a chaine moyenne

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JPS62501289A (ja) * 1984-10-19 1987-05-21 シエ−リング　アクチエンゲゼルシヤフト 炎症の局所治療剤
JPH0867674A (ja) * 1993-07-02 1996-03-12 Senju Pharmaceut Co Ltd 眼圧降下剤
JPH11513693A (ja) * 1995-10-20 1999-11-24 シエーリング アクチエンゲゼルシヤフト キラールなメチルフェニルオキサゾリジノン
JP3094233B2 (ja) * 1992-07-08 2000-10-03 サンテン オイ （ｓ）−チモロール半水和物を含有する局所眼科治療用組成物及びその製造方法
WO2002015940A2 (fr) * 2000-08-22 2002-02-28 Pharmacia Corporation Composition de solution d'un medicament antibiotique a base d'oxazolidinone presentant une charge de medicament amelioree

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JPS62501289A (ja) * 1984-10-19 1987-05-21 シエ−リング　アクチエンゲゼルシヤフト 炎症の局所治療剤
JP3094233B2 (ja) * 1992-07-08 2000-10-03 サンテン オイ （ｓ）−チモロール半水和物を含有する局所眼科治療用組成物及びその製造方法
JPH0867674A (ja) * 1993-07-02 1996-03-12 Senju Pharmaceut Co Ltd 眼圧降下剤
JPH11513693A (ja) * 1995-10-20 1999-11-24 シエーリング アクチエンゲゼルシヤフト キラールなメチルフェニルオキサゾリジノン
WO2002015940A2 (fr) * 2000-08-22 2002-02-28 Pharmacia Corporation Composition de solution d'un medicament antibiotique a base d'oxazolidinone presentant une charge de medicament amelioree

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DINTER H. ET AL: "The type IV phosphodiesterase specific inhibitor mesopram inhibits experimental autoimmune encephalomyelitis in rodents", J. OF NEUROIMMUNOLOGY, vol. 108, no. 1-2, 2000, pages 136 - 146, XP001004891 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3266446A1 (fr) * 2016-07-07 2018-01-10 Laboratorios SALVAT, S.A. Composition ophtalmique comprenant de l'huile de ricin et d'un triglyceride a chaine moyenne
CN107582605A (zh) * 2016-07-07 2018-01-16 萨尔瓦特实验室股份有限公司 眼用组合物
US10660848B2 (en) 2016-07-07 2020-05-26 Laboratorios Salvat, S.A. Ophthalmic compositions

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