WO2017047597A1 - 角膜真菌症の予防または治療剤 - Google Patents

角膜真菌症の予防または治療剤 Download PDF

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Publication number
WO2017047597A1
WO2017047597A1 PCT/JP2016/077014 JP2016077014W WO2017047597A1 WO 2017047597 A1 WO2017047597 A1 WO 2017047597A1 JP 2016077014 W JP2016077014 W JP 2016077014W WO 2017047597 A1 WO2017047597 A1 WO 2017047597A1
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WIPO (PCT)
Prior art keywords
therapeutic agent
polyethylene glycol
rapamycin
salt
preventive
Prior art date
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Ceased
Application number
PCT/JP2016/077014
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English (en)
French (fr)
Japanese (ja)
Inventor
ジンチョン チャン
正明 景山
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Santen Pharmaceutical Co Ltd
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Santen 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
Priority to EP16846468.3A priority Critical patent/EP3351244A4/en
Priority to MX2018003381A priority patent/MX393608B/es
Priority to SG11201802091RA priority patent/SG11201802091RA/en
Priority to KR1020187010106A priority patent/KR20180053340A/ko
Priority to US15/760,210 priority patent/US10166217B2/en
Priority to MYPI2018000383A priority patent/MY183906A/en
Priority to CN201680054195.5A priority patent/CN108025000A/zh
Priority to BR112018005305-8A priority patent/BR112018005305A2/pt
Priority to HK18116109.4A priority patent/HK1256969A1/en
Application filed by Santen Pharmaceutical Co Ltd filed Critical Santen Pharmaceutical Co Ltd
Publication of WO2017047597A1 publication Critical patent/WO2017047597A1/ja
Priority to PH12018500579A priority patent/PH12018500579A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics

Definitions

  • the present invention relates to a preventive or therapeutic agent for corneal mycosis comprising rapamycin or a salt thereof as an active ingredient.
  • Keratomycosis is one of the infections in the cornea caused by fungi and is also called mycotic keratitis. Corneal mycosis is known to be caused by trauma caused by plants, continuous wear of soft contact lenses, long-term instillation of steroids, and the like. In addition, corneal mycosis is often difficult to diagnose and becomes intractable if appropriate treatment is not performed at an early stage, leaving a strong corneal scar and reducing visual acuity.
  • Natamycin ophthalmic solution is generally used as a medical drug for corneal mycosis. Natamycin ophthalmic solution usually requires one drop at a time and frequent eye drops. In addition, it is known that natamycin ophthalmic solution has a low corneal permeability of the drug and a sufficient therapeutic effect cannot be obtained (Non-patent Documents 1 and 2).
  • rapamycin also referred to as “sirolimus” is a metabolite of the actinomycete Streptomyces hygroscopicus isolated from the soil of Easter Island, and was found as a macrolide antibiotic in the 1970s.
  • Patent Document 1 discloses the effect of suppressing vascular permeability enhancement by rapamycin.
  • Patent Document 2 discloses a composition for treating age-related macular degeneration (also referred to as “AMD”).
  • the problem to be solved by the present invention is to find a drug that treats corneal mycosis, and further, to find a drug that maintains the therapeutic effect of corneal mycosis for a long period of time with fewer administrations than existing drugs. To find.
  • rapamycin or a salt thereof has an effect for preventing or treating corneal mycosis. Furthermore, administration of rapamycin or its salt, polyethylene glycol and ethanol-containing injections under the conjunctiva will maintain the therapeutic effect of corneal mycosis for a long period of time with fewer administrations than existing drugs. The present invention was completed.
  • the present invention relates to a preventive or therapeutic agent for corneal mycosis (hereinafter, also referred to as “this drug”) containing rapamycin or a salt thereof as an active ingredient.
  • this agent contains polyethylene glycol.
  • the concentration of polyethylene glycol is preferably 80 to 99% (w / w), more preferably 90 to 98% (w / w).
  • the polyethylene glycol is preferably polyethylene glycol 400.
  • this agent contains ethanol.
  • the administration form of this drug is preferably subconjunctival administration.
  • the dosage form of this drug is preferably an injection.
  • the dosage form is subconjunctival administration;
  • the dosage form is an injection;
  • the concentration of rapamycin or its salt is 1-5% (w / w); It preferably contains ethanol and polyethylene glycol 400, and the concentration of polyethylene glycol 400 is 90 to 98% (w / w).
  • the dosage form is subconjunctival administration;
  • the dosage form is an injection;
  • the concentration of rapamycin or its salt is 2-4% (w / w); It preferably contains ethanol and polyethylene glycol 400, the ethanol concentration is 4% (w / w), and the polyethylene glycol 400 concentration is 92-94% (w / w).
  • this drug is preferably used so that it is administered at intervals of at least 5 days.
  • the causative bacterium of corneal mycosis is preferably at least one selected from the group consisting of Candida, Fusarium, Saccharomyces, Penicillium, and Aspergillus.
  • Candida genus is C.I. albicans is preferred.
  • another aspect of the present invention relates to a pharmaceutical composition for preventing or treating corneal mycosis, which contains rapamycin or a salt thereof as an active ingredient.
  • Another aspect of the present invention relates to rapamycin or a salt thereof for use in the prevention or treatment of corneal mycosis.
  • Another aspect of the present invention relates to the use of rapamycin or a salt thereof for the manufacture of a medicament for preventing or treating corneal mycosis.
  • Another aspect of the invention relates to a method for treating corneal mycosis comprising administering an effective amount of rapamycin or a salt thereof.
  • a preventive or therapeutic agent for corneal mycosis comprising rapamycin or a salt thereof as an active ingredient. Furthermore, the therapeutic effect of corneal mycosis can be maintained for a long period of time with a smaller number of administrations than existing drugs by administering an injection containing rapamycin or a salt thereof, polyethylene glycol and ethanol under the conjunctiva. Can do.
  • Rapamycin is also called sirolimus and is a substance represented by the following chemical structural formula.
  • the salt of rapamycin is not particularly limited as long as it is a pharmaceutically acceptable salt; salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; acetic acid, fumaric acid , Maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, With organic acids such as oleic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate
  • rapamycin or a salt thereof has a geometric isomer or an optical isomer
  • the isomer or a salt thereof is also included in the scope of the present invention.
  • a proton tautomer exists in rapamycin or a salt thereof
  • the tautomer or a salt thereof is also included in the scope of the present invention.
  • Rapamycin or a salt thereof may take the form of a hydrate or a solvate.
  • crystal polymorph group refers to various crystal forms depending on conditions and states (including the formulated state in this state) such as production, crystallization, and storage of these crystals. It means a mixture of crystal forms at each stage and crystal forms throughout the process, when changing.
  • Rapamycin or a salt thereof can be produced according to an ordinary method in the biochemistry / organic chemistry field. Moreover, what is marketed can also be used for rapamycin or its salt.
  • the concentration of rapamycin or a salt thereof is not particularly limited as long as it is an amount sufficient to achieve a desired drug effect, but is preferably 0.01 to 20% (w / w), preferably 0.1 to 15 % (W / w) is more preferable, 0.5 to 10% (w / w) is more preferable, 1 to 5% (w / w) is still more preferable, and 2 to 4% (w / w) is particularly preferable 2% (w / w), 2.5% (w / w), 3% (w / w), 3.5% (w / w), and 4% (w / w) are most preferable.
  • the agent can contain polyethylene glycol.
  • Polyethylene glycol (hereinafter also referred to as “PEG”) is a polyether polymerized with ethylene glycol, and is represented by the chemical structural formula HO (CH 2 CH 2 O) n H, where n is the number of polymerizations.
  • the average molecular weight of polyethylene glycol is preferably from 100 to 2000, more preferably from 100 to 1000, still more preferably from 100 to 800, even more preferably from 200 to 600, even more preferably from 400 to 600, and from 400 to 600 Particularly preferred, 400 is most preferred.
  • polyethylene glycol include polyethylene glycol 100 (PEG 100), polyethylene glycol 200 (PEG 200), polyethylene glycol 300 (PEG 300), polyethylene glycol 400 (PEG 400), polyethylene glycol 600 (PEG 600), polyethylene glycol 800 (PEG 800), and the like. Can be mentioned.
  • the polyethylene glycol concentration is preferably 70 to 99.99% (w / w), more preferably 80 to 99.9% (w / w), and further 80 to 99% (w / w). 90 to 99% (w / w) is particularly preferable, and 90 to 98% (w / w) is most preferable.
  • This agent can contain ethanol.
  • the ethanol concentration is preferably 0.01 to 30% (w / w), more preferably 0.1 to 15% (w / w), and 0.5 to 10% (w / w). More preferably, 1 to 5% (w / w) is even more preferable, 2 to 4% (w / w) is particularly preferable, 2% (w / w), 2.5% (w / w), 3% (W / w), 3.5% (w / w), 4% (w / w) are most preferred.
  • the concentration of rapamycin or its salt is 1-5% (w / w);
  • examples thereof include a preventive or therapeutic agent for corneal mycosis, which contains ethanol and polyethylene glycol 400 and has a polyethylene glycol 400 concentration of 90 to 98% (w / w).
  • the concentration of rapamycin or its salt is 2-4% (w / w);
  • a prophylactic or therapeutic agent for corneal mycosis comprising ethanol and polyethylene glycol 400, wherein the ethanol concentration is 4% (w / w) and the polyethylene glycol 400 concentration is 92 to 94% (w / w).
  • the concentration of rapamycin or its salt is 2-4% (w / w);
  • a prophylactic or therapeutic agent for corneal mycosis comprising ethanol and polyethylene glycol 400, wherein the ethanol concentration is 4% (w / w) and the polyethylene glycol 400 concentration is 92 to 94% (w / w).
  • the administration form of this drug is preferably parenteral administration, more preferably ophthalmic administration, intraconjunctival sac administration, intravitreal administration, subconjunctival administration, subtenon administration, particularly preferably conjunctiva.
  • parenteral administration more preferably ophthalmic administration, intraconjunctival sac administration, intravitreal administration, subconjunctival administration, subtenon administration, particularly preferably conjunctiva.
  • the dosage form of this agent is not particularly limited as long as it can be used as a pharmaceutical product, and examples thereof include eye drops, eye ointments, injections, and insertion agents.
  • An injection is preferable, an ophthalmic injection is more preferable, and an injection for subconjunctival administration is particularly preferable.
  • the dose is not particularly limited as long as it is sufficient to achieve the desired drug effect, but preferably 1 to 100 ⁇ L, more preferably 5 to 50 ⁇ L at a time. 10 to 30 ⁇ L is more preferable, and 10 ⁇ L, 20 ⁇ L, or 30 ⁇ L is most preferable.
  • the dose of rapamycin or a salt thereof is preferably 0.001 to 30 mg / eye, more preferably 0.01 to 10 mg / eye, further preferably 0.1 to 5 mg / eye, and 0.2 to 1.6 mg / eye.
  • 0.2 mg / eye 0.3 mg / eye, 0.4 mg / eye, 0.5 mg / eye, 0.6 mg / eye, 0.7 mg / eye, 0.8 mg / eye, 0.9 mg / Most preferred are eye, 1 mg / eye, 1.2 mg / eye, 1.4 mg / eye or 1.6 mg / eye.
  • the dose interval is not particularly limited as long as it is sufficient to achieve the desired drug effect, but it is administered at least once a day to once every 6 months
  • the dose interval is administered at least once a day to once every 6 months
  • it is administered at least once every 5 days, at least once a week, at least once every 2 weeks, at least once a month, at least once every 2 months.
  • an administration interval can be changed suitably, it is preferable to administer at intervals of at least 5 days.
  • This agent can be prepared by using a widely used technique and, if necessary, a pharmaceutically acceptable additive.
  • the additive include isotonic agents, buffering agents, surfactants, thickeners and the like.
  • isotonizing agent sodium chloride etc. are mentioned, for example.
  • the buffering agent include sodium phosphate.
  • the surfactant include polyoxyethylene sorbitan monooleate.
  • the thickener include methyl cellulose.
  • examples of the causative bacteria of corneal mycosis include Candida genus, Fusarium genus, Saccharomyces genus, Penicillium genus, and Aspergillus genus.
  • Candida genus C.I. albicans.
  • 20 ⁇ L of 4% (w / w) rapamycin solution (0.88 mg rapamycin) was administered subconjunctivally on the day of induction.
  • FIG. 1 shows the results of clinical scores of each group on the 2nd day and 5th day of induction.
  • “Group 1” indicates a base administration group
  • “Group 2” indicates a rapamycin administration group.
  • the rapamycin-administered group had a lower clinical score than the base-administered group on any observation day. That is, corneal mycosis was improved by subconjunctival administration of rapamycin, and rapamycin was shown to be effective in preventing or treating corneal mycosis. In addition, it was shown that administration of an injection containing rapamycin, polyethylene glycol and ethanol once under the conjunctiva has a remarkable therapeutic effect for corneal mycosis continuously for at least 5 days.
  • formulation example The pharmaceutical agent of the present invention will be described more specifically with formulation examples, but the present invention is not limited to these formulation examples.
  • Formulation Example 1 Injection (4% (w / w)) Rapamycin in 100g: 4g Ethanol: 4g Polyethylene glycol 400: 92 g
  • Formulation Example 2 Injection (2% (w / w)) Rapamycin in 100g: 2g Ethanol: 4g Polyethylene glycol 400: 94 g
  • Formulation Example 3 Injection (0.2% (w / w)) Rapamycin in 100g: 0.2g Ethanol: 4g Polyethylene glycol 400: 95.8 g
  • the injection can be prepared by dissolving rapamycin in ethanol and polyethylene glycol 400.
  • Rapamycin or a salt thereof is useful as a preventive or therapeutic agent for corneal mycosis.

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  • Health & Medical Sciences (AREA)
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  • Animal Behavior & Ethology (AREA)
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  • Engineering & Computer Science (AREA)
  • Ophthalmology & Optometry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Inorganic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Dermatology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
PCT/JP2016/077014 2015-09-18 2016-09-13 角膜真菌症の予防または治療剤 Ceased WO2017047597A1 (ja)

Priority Applications (10)

Application Number Priority Date Filing Date Title
BR112018005305-8A BR112018005305A2 (pt) 2015-09-18 2016-09-13 agente profilático ou terapêutico da queratite fungal
MX2018003381A MX393608B (es) 2015-09-18 2016-09-13 Profilactico o agente terapeutico para queratitis fungica.
SG11201802091RA SG11201802091RA (en) 2015-09-18 2016-09-13 Fungal keratitis prophylactic or therapeutic agent
KR1020187010106A KR20180053340A (ko) 2015-09-18 2016-09-13 각막진균증의 예방 또는 치료제
US15/760,210 US10166217B2 (en) 2015-09-18 2016-09-13 Fungal keratitis prophylactic or therapeutic agent
EP16846468.3A EP3351244A4 (en) 2015-09-18 2016-09-13 PROPHYLACTIC OR THERAPEUTIC AGENT FOR PURPOSE CERATITIS
CN201680054195.5A CN108025000A (zh) 2015-09-18 2016-09-13 角膜真菌病的预防或治疗剂
MYPI2018000383A MY183906A (en) 2015-09-18 2016-09-13 Fungal keratitis prophylactic or therapeutic agent
HK18116109.4A HK1256969A1 (en) 2015-09-18 2016-09-13 Fungal keratitis prophylactic or therapeutic agent
PH12018500579A PH12018500579A1 (en) 2015-09-18 2018-03-16 Fungal keratitis prophylactic or therapeutic agent

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201562220847P 2015-09-18 2015-09-18
US62/220,847 2015-09-18

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WO2017047597A1 true WO2017047597A1 (ja) 2017-03-23

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US (1) US10166217B2 (enExample)
EP (1) EP3351244A4 (enExample)
JP (1) JP6639364B2 (enExample)
KR (1) KR20180053340A (enExample)
CN (1) CN108025000A (enExample)
BR (1) BR112018005305A2 (enExample)
HK (2) HK1253545A1 (enExample)
MX (1) MX393608B (enExample)
MY (1) MY183906A (enExample)
PH (1) PH12018500579A1 (enExample)
SG (1) SG11201802091RA (enExample)
TW (1) TWI721015B (enExample)
WO (1) WO2017047597A1 (enExample)

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CN112957321B (zh) * 2021-03-04 2022-08-05 青岛大学附属医院 一种氧化硫酸软骨素改性的那他霉素滴眼液及其制备方法
CN114568490B (zh) * 2022-04-01 2023-12-19 眉山职业技术学院(眉山技师学院) 雷帕霉素在抑制柑橘青霉菌生长中的应用

Citations (1)

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Publication number Priority date Publication date Assignee Title
JP2008530128A (ja) * 2005-02-09 2008-08-07 マクサイト， インコーポレイテッド 疾患または状態を処置するための液体処方物

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101137369A (zh) * 2005-02-09 2008-03-05 马库赛特公司 用于眼治疗的制剂
US8222271B2 (en) 2006-03-23 2012-07-17 Santen Pharmaceutical Co., Ltd. Formulations and methods for vascular permeability-related diseases or conditions
ES2507078T3 (es) * 2007-08-16 2014-10-14 Santen Pharmaceutical Co., Ltd Formulaciones de rapamicina para tratamiento de la degeneración macular relacionada con la edad

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
JP2008530128A (ja) * 2005-02-09 2008-08-07 マクサイト， インコーポレイテッド 疾患または状態を処置するための液体処方物

Non-Patent Citations (2)

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Title
KAYO UCHIYAMA: "Topical Fluconazole : High Intraocular Penetration without Corneal Toxicity", JOURNAL OF THE JUZEN MEDICAL SOCIETY, vol. 110, no. 5, 6, 2001, pages 339 - 347, XP009508975, ISSN: 0022-7226 *
VEZINA, C. ET AL.: "RAPAMYCIN (AY-22,989), A NEW ANTIFUNGAL ANTIBIOTIC I. TAXONOMY OF THE PRODUCING STREPTOMYCETE AND ISOLATION OF THE ACTIVE PRINCIPLE", THE JOURNAL OF ANTIBIOTICS, vol. 28, no. 10, 1975, pages 721 - 726, XP001161176, ISSN: 0021-8820 *

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SG11201802091RA (en) 2018-04-27
KR20180053340A (ko) 2018-05-21
MY183906A (en) 2021-03-17
TWI721015B (zh) 2021-03-11
US10166217B2 (en) 2019-01-01
US20180271841A1 (en) 2018-09-27
BR112018005305A2 (pt) 2018-10-09
PH12018500579A1 (en) 2018-09-10
MX393608B (es) 2025-03-24
JP6639364B2 (ja) 2020-02-05
EP3351244A4 (en) 2019-05-01
TW201717943A (zh) 2017-06-01
CN108025000A (zh) 2018-05-11
MX2018003381A (es) 2018-08-15
HK1256969A1 (en) 2019-10-04
HK1253545A1 (zh) 2019-06-21
EP3351244A1 (en) 2018-07-25
JP2017057199A (ja) 2017-03-23

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