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WO2013100660A2 - Composition pharmaceutique pour le traitement de la douleur oculaire contenant un inhibiteur de la synthèse de la pge2 - Google Patents

Composition pharmaceutique pour le traitement de la douleur oculaire contenant un inhibiteur de la synthèse de la pge2 Download PDF

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Publication number
WO2013100660A2
WO2013100660A2 PCT/KR2012/011631 KR2012011631W WO2013100660A2 WO 2013100660 A2 WO2013100660 A2 WO 2013100660A2 KR 2012011631 W KR2012011631 W KR 2012011631W WO 2013100660 A2 WO2013100660 A2 WO 2013100660A2
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Prior art keywords
eye
pain
pge2
protein
pharmaceutical composition
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Ceased
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PCT/KR2012/011631
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English (en)
Korean (ko)
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WO2013100660A3 (fr
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이형근
심종우
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Industry Academic Cooperation Foundation of Yonsei University
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Industry Academic Cooperation Foundation of Yonsei University
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Priority claimed from KR1020120074204A external-priority patent/KR101373246B1/ko
Application filed by Industry Academic Cooperation Foundation of Yonsei University filed Critical Industry Academic Cooperation Foundation of Yonsei University
Priority to JP2014550020A priority Critical patent/JP5870211B2/ja
Priority to US14/648,970 priority patent/US9629855B2/en
Publication of WO2013100660A2 publication Critical patent/WO2013100660A2/fr
Publication of WO2013100660A3 publication Critical patent/WO2013100660A3/fr
Anticipated expiration legal-status Critical
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    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • 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 a pharmaceutical composition for treating ocular pain comprising a PGE2 synthesis inhibitor.
  • Dry eye syndrome is a very common disease with a prevalence of 5.5-15%, depending on the study population, age, and diagnostic criteria used in various epidemiologic studies worldwide.
  • the disease is characterized by eye pain, irregular corneal surfaces, blurred and fluctuating vision, and increased risk of corneal ulcers.
  • Altered corneal permeability in chronic dry eye and dry keratitis derived from an unstable tear film has been known to cause inflammation, which is due to an increase in inflammation-mediated chemokines and cytokines in the tear, immune activity by conjunctival epithelium and adhesion molecules ( Increased expression of HLA-DR and intercellular adhesion molecule [ICAM-1]), and increased T lymphocyte counts in the conjunctiva.
  • IAM-1 intercellular adhesion molecule
  • Corneal ulcers resulting from keratoconjunctivitis sicca can cause vision loss, vision loss and even eye loss.
  • the concentration and activity of matrix metalloproteinase-9 (MMP-9) has been reported to increase significantly in the corneal epithelium and tear of experimental dry eye (EDE) mice as well as in tears of dry eye patients.
  • Dry eye syndrome generally causes tears or fluctuations in the composition of the tear film, causing various uncomfortable symptoms.
  • a new form of dry eye syndrome has been developed due to diseases caused by changes in tear film composition and neurogenic factors such as dry eye syndrome after LASIK (American Journal of Ophthalmology, 140 507, 2005).
  • Dry eye syndrome is found in more than 50% of all patients who visit ophthalmologists, and the elderly population, especially more than 70 to 80% of women who pass menopause, complain of eye discomfort due to dry eye syndrome.
  • the cause of dry eye was thought to be due to the lack of aqueous layer due to decreased tear production in the tear glands, but recently, the inflammatory response or endogenous inflammatory response due to external stimulation has been found to be the primary cause.
  • Chronic ocular surface damage caused by disorder of epithelial cells and degradation of the interaction between corneal epithelial cells and corneal parenchymal cells has been a problem.
  • Dry eye may be caused by aging, hormonal changes, environmental factors (wind, heat, dust, tobacco smoke, hair dryers), reduction of eye blink frequency (VDT syndrome), contact lens wear, LASIK, cause of medication It can be caused by a variety of causes, including immune diseases (lupus, rheumatoid arthritis and Sjogren's syndrome) (American Journal of Ophthalmology, 137, 337-342, 2004).
  • NASAID a non-specific COX enzyme inhibitor used to reduce inflammation
  • the drug is known to reduce inflammation and reduce pain, but it is also known to cause additional activation to produce leukotrienes, lipoxins and hydroperoxyeicosatetraenoic acids.
  • non-specific COX enzyme inhibitors have been developed and used as eye drops, but serious side effects such as corneal perforation have been reported to the academic community by activation of the additional inflammatory products specified above.
  • the present inventors have made intensive efforts to develop a pharmaceutical composition for treating or preventing ocular diseases causing eye pain, including dry eye syndrome, and thus, expression of PGE2 (prostaglandin E2) in the tears of patients with ocular pain symptoms compared to normal people. It was confirmed that the level is high, and when the PGE2 synthesis inhibitor was applied to an animal model, it was confirmed that the eye pain treatment effect was completed and the present invention was completed.
  • PGE2 prostaglandin E2
  • An object of the present invention to provide a pharmaceutical composition for preventing or treating ocular pain comprising PGE2 synthesis inhibitor as an active ingredient, and to provide a kit for diagnosing ocular pain, which can measure the level of PGE2.
  • the present invention on the basis of a high level of PGE2 and a low level of PGD2 in tears of a patient with ocular pain symptoms, provides a pharmaceutical composition for preventing or treating ocular pain comprising PGE2 synthesis inhibitor as an active ingredient, A method of screening for reducing ocular pain relief agents is provided. Furthermore, PGE2, PGD2 and COX2 levels may be measured in the tears of patients to provide kits for diagnosing eye pain and information for diagnosing eye pain.
  • the present invention provides a pharmaceutical composition for the prevention or treatment of eye pain comprising PGE2 synthesis inhibitor as an active ingredient.
  • the present invention provides a dietary supplement for preventing or improving ocular pain, comprising as an active ingredient a PGE2 synthesis inhibitor in another embodiment.
  • the PGE2 synthesis inhibitor is 5-Deoxy-A12, 14-PGJ2, Exisulind, NS-398, Leukotnene C4, mk-886, Analogues of MK-886, MF63, Thienopyrrole, Naphthalene disulphonamide, Resveratrol and ⁇ - It may be characterized in that it is selected from the group consisting of hydroxybutenolide.
  • the pharmaceutical composition may be characterized by reducing the expression level of PGE2.
  • the eye pain may be characterized in that the eye pain due to dry eye, inflammatory eye disease or the use of contact lenses.
  • the pharmaceutical composition may be in the form of suspensions, powders, powders, granules, tablets, sustained release preparations, injections, ointments, eye drops, capsules, contact lens cleaners or contact lens lubricants,
  • the composition may be characterized as targeting humans.
  • the health functional food may be characterized in that the capsule, tablets, granules, powder or beverage form.
  • (c) providing a method of screening an ocular pain relief agent comprising determining that the sample is a substance that alleviates ocular pain when the amount or activity of the protein is determined to be modulated.
  • (c) providing a method for screening an ocular pain relief agent, comprising determining that the sample is a substance that alleviates ocular pain when the expression level of the gene is measured to be controlled to be reduced, and the gene encoding the PGE2 protein is It may be characterized by represented by SEQ ID NO: 2.
  • (c) providing a method of screening an ocular pain relief agent comprising determining that the sample is a substance that alleviates ocular pain when the amount or activity of the protein is determined to be modulated.
  • (c) providing a method of screening an ocular pain relief agent, comprising determining that the sample is a substance that alleviates ocular pain when the expression level of the gene is measured to be controlled to be reduced, and the gene encoding the COX2 protein is It may be characterized by represented by SEQ ID NO: 4.
  • the present invention provides a pharmaceutical composition for preventing or treating ocular pain, including the COX2 inhibitor as an active ingredient.
  • the present invention provides a method of preparing a biologically-modified product, comprising: (a) measuring the level of PGE2 represented by SEQ ID NO: 1 from a biological sample isolated from a patient;
  • the information providing method may further comprise the step of measuring the level of PGD2 or COX2 and comparing with the level of the normal control sample. At this time, when the PGE2 and COX2 levels are overexpressed than the normal control, and the PGD2 level is lower than the normal control, eye pain may be determined.
  • the present invention provides a kit for diagnosing or predicting eye pain, which includes an antibody that specifically binds to a protein attached to PGE2.
  • the kit for diagnosing or predicting eye pain may further include an antibody specifically binding to a protein attached to PGD2 or a protein attached to COX2.
  • the kit is characterized in that it comprises an antibody that attaches a protein for detection to PGE2, PGD2 and COX2 and specifically binds to the adhesion protein.
  • the attached protein may be horseradish peroxidase, alkaline phosphatase or ⁇ -galactosidase.
  • the levels of PGE2, PGD2 and COX2 are enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry. It may be characterized by measuring by (LC-MS) or LC-MS / MS.
  • ELISA enzyme-linked immunosorbent assay
  • RIA radioimmunoassay
  • GC-MS gas chromatography-mass spectrometry
  • LC-MS liquid chromatography-mass spectrometry
  • composition of the present invention may be prepared as a pharmaceutical composition, a neutraceutical composition or a food composition.
  • the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers included in the pharmaceutical compositions of the present invention are those commonly used in the preparation, such as lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, Calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, and the like It doesn't happen.
  • the pharmaceutical composition of the present invention may further include a lubricant, a humectant, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like.
  • a lubricant e.g., talc, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, aminol, sorbitol, sorbitol, sorbitol, talame, sorbitol, sorbitol, sorbitol, talame, fame, famb, fambambambambambambambambambambambambambambambambambambucil, a glycerin,
  • Suitable dosages of the pharmaceutical compositions of the present invention may vary depending on factors such as the formulation method, mode of administration, age, weight, sex, morbidity, condition of food, time of administration, route of administration, rate of excretion and response to response of the patient. Can be.
  • the dosage of the pharmaceutical composition of the present invention may be 0.001-100 mg / kg body weight, 0.01-80 mg / kg body weight, 0.1-60 mg / kg body weight per day on an adult basis.
  • the doctor or pharmacist may be divided administration once a day to several times.
  • the formulation of 0.001 to 3% (w / v, below), preferably about 0.01 to 1% is applied once to several times per day.
  • the pharmaceutical and health food composition of the present invention may be formulated by using a pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by those skilled in the art. It may be prepared in a dosage form or incorporated into a multi-dose container.
  • the formulation of the composition of the present invention is a solution, suspension, syrup, emulsion, liposome, extract, powder, powder, granule, tablet, sustained release eye drop, capsule, contact It is a lens cleaner and a contact lens lubricant, and may further include a dispersant or stabilizer.
  • diagnosis refers to identifying the presence or characteristics of a pathological condition, determining the susceptibility of an object to a specific disease or condition, determining whether an object currently has a particular disease or condition. And determining the prognosis of one subject with a particular disease or condition.
  • sample refers to an unknown candidate used in screening to test whether it affects the expression level of a gene or affects the amount or activity of a protein.
  • the sample includes, but is not limited to, chemicals, nucleotides, antisense-RNAs and natural extracts.
  • Measurement of the change in the expression level of the gene can be carried out through various methods known in the art. For example, RT-PCR (Sambrook et al., Molecular Cloning. A Laboratory Manual, 3rd ed. Cold Spring Harbor Press (2001)), Northern blotting (Peter B. Kaufma et al., Molecular and Cellular Methods in Biology and Medicine , 102-108, CRC press), hybridization reaction using cDNA microarray (Sambrook et al., Molecular Cloning.A Laboratory Manual, 3rd ed. Cold Spring Harbor Press (2001)) or in situ hybridization reaction (Sambrook et al. , Molecular Cloning.A Laboratory Manual, 3rd ed.Cold Spring Harbor Press (2001)).
  • RNA is isolated from cells treated with a sample, and then single-stranded cDNA is prepared using oligo dT primers and reverse transcriptase. Then, single-stranded cDNA is used as a template, and PCR reaction is performed using a gene-specific primer set. Gene-specific primer sets are listed in Table 2 below. Then, the PCR amplification product is electrophoresed, and the formed band is analyzed to measure the change in the expression level of the gene.
  • Changes in the amount of protein can be carried out through various immunoassay methods known in the art. Examples include, but are not limited to, radioimmunoassay, radioimmunoprecipitation, immunoprecipitation, enzyme-linked immunosorbentassay (ELISA), capture-ELISA, inhibition or hardwood assays, and sandwich assays.
  • the immunoassay or method of immunostaining is described in Enzyme Immunoassay, ET Maggio, ed., CRC Press, Boca Raton, Florida, 1980; Gaastra, W., Enzyme-linked immunosorbent assay (ELISA), in Methods in Molecular Biology, Vol.
  • certain embodiments of the present invention comprise the steps of: (a) coating an extract from the cells to which the sample has been treated on the surface of the solid substrate; (b) reacting the protein-specific antibody with the cell extract; (c) reacting the resultant of step (b) with a secondary antibody to which an enzyme is bound; And (d) measuring the activity of the enzyme.
  • Suitable as the solid substrate are hydrocarbon polymers (eg polystyrene and polypropylene), glass, metals or gels, most preferably microtiter plates.
  • Enzymes bound to the secondary antibody include, but are not limited to, enzymes that catalyze color reaction, fluorescence, luminescence or infrared reaction, for example, alkaline phosphatase, ⁇ -galactosidase, hose Radish peroxidase, luciferase and cytochrome P450.
  • alkaline phosphatase When alkaline phosphatase is used as the enzyme binding to the secondary antibody, bromochloroindolyl phosphate (BCIP), nitro blue tetrazolium (NBT), naphthol-ASB1-phosphate (naphthol-AS-B1) as a substrate chloronaphthol, aminoethylcarbazole, diaminobenzidine, D-luciferin, lucigenin (bis-N) when colorimetric substrates such as -phosphate) and enhanced chemifluorescence (ECF) are used, and horse radish peroxidase is used.
  • BCIP bromochloroindolyl phosphate
  • NBT nitro blue tetrazolium
  • naphthol-ASB1-phosphate naphthol-AS-B1
  • aminoethylcarbazole aminoethylcarbazole
  • diaminobenzidine diaminobenz
  • -Methylacridinium nitrate resorupin benzyl ether, luminol, amplex red reagent (10-acetyl-3,7-dihydroxyphenoxazine), TMB (3,3,5,5-tetramethylbenzidine), ABTS Substrates such as (2,2'-Azine-di [3-ethylbenzthiazoline sulfonate]) and o-phenylenediamine (OPD) can be used.
  • Measurement of the final enzyme activity or signal in the ELISA method can be carried out according to various methods known in the art. If biotin is used as a label, the signal can be easily detected with streptavidin and luciferin if luciferase is used.
  • PGE2, PGD2 and COX2 are preferably detectably labeled.
  • Various methods available for labeling biomolecules are well known to those skilled in the art and are contemplated within the scope of the present invention. Such methods include Tijssen, 'Practice and theory of enzyme immuno assays', Burden, RH and von Knippenburg (Eds), Volume 15 (1985), 'Basic methods in molecular biology'; Davis LG, Dibmer MD; Battey Elsevier (1990), Mayer et al., (Eds) 'Immunochemical methods in cell and molecular biology' Academic Press, London (1987), or in the series 'Methods in Enzymology', Academic Press, Inc.
  • marker types include enzymes, radioisotopes, colloidal metals, fluorescent compounds, chemiluminescent compounds and bioluminescent compounds.
  • markers include phosphors (eg, fluresin, rhodamine, Texas red, etc.), enzymes (eg, horseradish peroxidase, ⁇ -galactosidase, alkaline phosphatase), radioisotopes (eg, 32 P or 125I), biotin, digoxigenin, colloidal metals, chemiluminescent or bioluminescent compounds (eg, dioxetane, luminol or acridinium). Labeling methods such as covalent binding of enzymes or biotinyl groups, iodide methods, phosphorylation methods, biotinylation methods and the like are well known in the art.
  • enzymes eg, horseradish peroxidase, ⁇ -galactosidase, alkaline phosphatase
  • radioisotopes eg, 32 P or 125I
  • biotin digoxigenin
  • colloidal metals eg, chemilum
  • Detection methods include, but are not limited to, autoradiography, fluorescence microscopy, direct and indirect enzyme reactions, and the like. Commonly used detection assays include radioisotopes or non-radioisotope methods. These include Western blotting, overlay-analysis, Radioimmuno Assay (RIA) and Immune Radioimmunometric Assay (IRMA), Enzyme Immuno Assay (EIA), Enzyme Linked Immuno Sorbent Assay (ELISA), Fluorescent Immuno Assay (CIA) and Chemiluminoluminescent Immune Assay).
  • RIA Radioimmuno Assay
  • IRMA Immune Radioimmunometric Assay
  • EIA Enzyme Immuno Assay
  • ELISA Enzyme Linked Immuno Sorbent Assay
  • CIA Fluorescent Immuno Assay
  • Chemiluminoluminescent Immune Assay Chemiluminoluminescent Immune Assay
  • the ocular pain symptoms can be improved by selectively suppressing the expression level of PGE2, and furthermore, for the treatment and prevention of dry eye syndrome. It works.
  • PGD2 and COX2 can easily diagnose the symptoms of eye pain in the clinic can be widely used to determine the condition of the patient as well as dry eye patients.
  • Figure 1 is a graph showing the relationship between the degree of PGE2 / PGD2 level contained in the tears of patients with eye pain symptoms and the symptoms of patients.
  • Figure 2 is a result showing the degree of eye discomfort after instilling a COX2 inhibitor in the mouse causing the eye pain.
  • Figure 3 is a result of measuring the mRNA level of TNF-alpha after instilling a COX2 inhibitor in the eye-induced mice.
  • Figure 4 is a result of measuring the mRNA level of IL-1 after instilling a COX2 inhibitor in the eye-induced mice.
  • the degree of symptom was checked by visual analogue scale before tears were collected.
  • the visual pain scale was scaled from 0 to 10, with 0 being asymptomatic and 10 being unbearable pain or discomfort. It was statistically analyzed whether this was related to changes in prostaglandin levels.
  • each substance known as a PGE synthesis inhibitor was divided into experimental groups and control groups. 5 ⁇ g / ml celecoxib (sigma) was added twice a day to the experimental group, and 0.1% hyaluronic acid (hyaluronic acid) was added to the control group.
  • PGE2 synthesis inhibitors were administered to patients with ocular pain symptoms, and the number of eye blinks was reduced compared to the control group.
  • PGE2 synthesis inhibitors used were 15-Deoxy-A12, 14-PGJ2, Exisulind, NS-398, Leukotnene C4, mk-886, Analogues of MK-886, MF63, Thienopyrrole, Naphthalene disulphonamide, Resveratrol, ⁇ -hydroxybutenolide .
  • selective COX2 inhibitors were administered to patients with ocular pain symptoms and the number of eye blinks was reduced compared to the control group (Diclofenac) with non-selective COX2 inhibitory properties.
  • Selective COX2 inhibitors were structurally classified and used as Nimesulud, Celecoxib, Meloxicam, S-2474 (3,5-di-tert-buryl-4-hydroxybensylidene) and cis-Stilbenes as the representative substances. Ibuprofen was included as the NSAID with.
  • the ocular pain symptoms can be improved by selectively suppressing the expression level of PGE2, and furthermore, for the treatment and prevention of dry eye syndrome. It is useful because it works.
  • SEQ ID NOs: 1 and 2 represent the PGE2 protein sequence and the gene sequence encoding the protein, respectively
  • SEQ ID NOs: 3 and 4 represent the COX2 protein sequence and the gene sequence encoding the protein, respectively.

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Abstract

La présente invention concerne une composition pharmaceutique utilisée dans le traitement de la douleur oculaire, contenant un inhibiteur de la synthèse de la PGE2. L'utilisation de ladite composition pharmaceutique dans la prévention ou le traitement de la douleur oculaire, contenant l'inhibiteur de synthèse de la PGE2 en tant que principe actif, permet de soulager les symptômes de la douleur oculaire en inhibant sélectivement le niveau d'expression de la PGE2. En outre, cette composition possède les avantages de traiter et prévenir la xérophtalmie et de surmonter et prévenir l'inconfort oculaire provoqué par diverses circonstances induisant une inflammation, notamment suite à un acte chirurgical. Par ailleurs, grâce à l'utilisation d'un kit détectant la quantité de PGE2, de PGD2 et de COX2, la présente invention permet de diagnostiquer facilement les symptômes de douleur oculaire en pratique clinique, et peut être largement mise en application dans le contrôle de patients atteints de xérophtalmie, ou suite à une chirurgie oculaire.
PCT/KR2012/011631 2011-12-29 2012-12-27 Composition pharmaceutique pour le traitement de la douleur oculaire contenant un inhibiteur de la synthèse de la pge2 Ceased WO2013100660A2 (fr)

Priority Applications (2)

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JP2014550020A JP5870211B2 (ja) 2011-12-29 2012-12-27 Ｐｇｅ２合成抑制剤を含む眼球痛症治療用薬学組成物
US14/648,970 US9629855B2 (en) 2011-12-29 2012-12-27 Pharmaceutical composition for treatment of eye pain, containing PGE2 synthesis inhibitor

Applications Claiming Priority (4)

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KR20110146450 2011-12-29
KR10-2011-0146450 2011-12-29
KR10-2012-0074204 2012-07-06
KR1020120074204A KR101373246B1 (ko) 2011-12-29 2012-07-06 Ｐｇｅ2 합성 억제제를 포함하는 안구 통증 치료용 약학 조성물

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016031869A1 (fr) * 2014-08-28 2016-03-03 学校法人 慶應義塾 Composition pharmaceutique pour la prophylaxie et/ou le traitement de maladies cornéennes et conjonctivales, ou d'une presbytie, contenant un composé du stilbène en tant que principe actif

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020086070A1 (en) * 2000-03-11 2002-07-04 Kuhrts Eric Hauser Anti-inflammatory and connective tissue repair formulations
US20110281882A1 (en) * 2007-08-10 2011-11-17 Jinzhong Zhang Compositions and Methods for Treating, Controlling, Reducing, or Ameliorating Inflammatory Pain

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016031869A1 (fr) * 2014-08-28 2016-03-03 学校法人 慶應義塾 Composition pharmaceutique pour la prophylaxie et/ou le traitement de maladies cornéennes et conjonctivales, ou d'une presbytie, contenant un composé du stilbène en tant que principe actif
US9968566B2 (en) 2014-08-28 2018-05-15 Keio University Pharmaceutical composition for prophylaxis and/or treatment of corneal and conjunctival diseases or presbyopia containing stilbene compound as active ingredient

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