WO2019045215A1 - Composition pour prévenir ou traiter les troubles du sommeil - Google Patents

Composition pour prévenir ou traiter les troubles du sommeil Download PDF

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Publication number
WO2019045215A1
WO2019045215A1 PCT/KR2018/004330 KR2018004330W WO2019045215A1 WO 2019045215 A1 WO2019045215 A1 WO 2019045215A1 KR 2018004330 W KR2018004330 W KR 2018004330W WO 2019045215 A1 WO2019045215 A1 WO 2019045215A1
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WO
WIPO (PCT)
Prior art keywords
composition
compound
preventing
sleep disorders
atopic dermatitis
Prior art date
Application number
PCT/KR2018/004330
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English (en)
Korean (ko)
Inventor
최계영
남현진
박미영
정경미
이지해
최창순
박영호
노종화
박은실
박제홍
신광현
우병영
이기화
조원경
최준호
Original Assignee
(주)아모레퍼시픽
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 claimed from KR1020180042811A external-priority patent/KR102587297B1/ko
Application filed by (주)아모레퍼시픽 filed Critical (주)아모레퍼시픽
Priority to EP18852284.1A priority Critical patent/EP3677265A4/fr
Priority to CN201880056479.7A priority patent/CN111050767A/zh
Publication of WO2019045215A1 publication Critical patent/WO2019045215A1/fr
Priority to US16/805,202 priority patent/US11382900B2/en

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    • 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
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels

Definitions

  • the present invention relates to the efficacy of preventing or treating sleep disorders of compositions containing TRPV1 antagonists.
  • Sleep disorders are commonly seen in patients with atopic dermatitis (AD), especially children. Sleep disturbances occur in about 47 to 60% of patients with atopic dermatitis and are a major factor in reducing the quality of life of the family as well as the patient. Sleep disturbances are known to affect unstable nervous function, attention deficit, emotional and behavioral disorders, and even key growth, especially in children. The pathophysiological mechanism of sleep disturbance in atopic dermatitis patients has not yet been clarified, and most of the treatment strategies are based on individual opinions of experts.
  • First-generation antihistamines are most often used to control sleep disorders. However, after 4 to 7 days of administration, most of them are resistant, so that they are not effective and their use is limited.
  • Benzodiazepines, chlorhydrates, and clonidine have been proposed as other therapies, but their therapeutic action has not been well proven. In particular, benzodiazepines may cause more severe sleep disturbances when resistance is expressed and discontinued. Side effects, including muscle relaxation and memory impairment, are particularly burdensome for children.
  • Melatonin has been proposed as a promising therapeutic agent for stimulating sleep and having immunomodulatory and antioxidant properties. However, there is still a need for a safe and effective way to control sleep disorders in patients with atopic dermatitis.
  • the inventors of the present invention have been studying a method of effectively treating sleep disorders accompanied by sleeping disorders, particularly atopic dermatitis, and unexpectedly found that certain vanilloid receptor antagonists (transient receptor potential vanilloid subfamily, member 1 antagonists, TRPV1 antagonists)
  • the present inventors completed the present invention by confirming clinically that it is possible to treat the accompanying sleeping disorder effectively and safely.
  • the present invention provides a pharmaceutical composition for preventing or treating sleep disorder comprising a compound represented by the following formula (1) as an active ingredient.
  • the present invention also provides a method for preventing or treating sleep disorders, which comprises applying the pharmaceutical composition to skin of a mammal including a human being.
  • the present invention also provides the use of the pharmaceutical composition for the manufacture of a medicament for the prevention or treatment of sleep disorders.
  • composition for preventing or treating sleep disorders according to the present invention can be particularly effectively and safely prevented or treated against sleeping disorders accompanied by atopic dermatitis.
  • FIG. 1 is a graph showing the average amount of change in sleep disorder evaluation scores before and after application of the composition of Example 1 and Comparative Example 1.
  • FIG. 1 is a graph showing the average amount of change in sleep disorder evaluation scores before and after application of the composition of Example 1 and Comparative Example 1.
  • FIG. 1A shows a result of body temperature change during transdermal administration of an AMG 517 compound (Amgen) as a TRPV1 antagonist, Of the present invention.
  • FIG. 3A and 3B show the results of pre-clinical tests on changes in body temperature at the time of oral administration according to Experimental Example 1.
  • Fig. 3A shows the results of body temperature change of AMG 517 compound (Amgen) as a TRPV1 antagonist and Fig. Of the present invention.
  • FIGS. 4A and 4B are graphs showing the results of experiments on the change of symptoms of atopic dermatitis when the dosage form of the composition for preventing or treating atopic dermatitis according to the present invention is changed.
  • FIG. 4A is a graph showing the degree of atopic symptoms
  • 4b is a graph showing the degree of atopic symptoms when the composition is applied in the form of a cream vehicle.
  • FIG. 5a and 5b are graphs showing changes in the amount of IgE antibody expressed when the form of the composition for prevention or treatment of atopic dermatitis according to the present invention is changed.
  • FIG. 5a shows that when the composition is applied in the form of an ethanol vehicle
  • FIG. 5B is a graph showing the amount of IgE antibody expression when the composition is applied in the form of a cream vehicle.
  • FIG. 5a shows that when the composition is applied in the form of an ethanol vehicle
  • FIG. 5B is a graph showing the amount of IgE antibody expression when the composition is applied in the form of a cream vehicle.
  • the present invention provides a composition capable of preventing or treating a sleep disorder by administering to a patient suffering from a sleep disorder, a life-threatening disorder accompanied by a general skin disorder, specifically, a sleep disorder accompanied by atopic dermatitis.
  • the present invention provides a method for preventing or treating a sleep disorder safely and effectively by controlling the number of times of administration of the composition of the present invention and the dose of the composition for a patient with sleep disorder.
  • composition for preventing or treating sleep disorder according to the present invention contains a compound represented by the following formula (1) as an active ingredient.
  • the compound represented by the formula (1) is a TRPV1 antagonist and is useful for diseases that can be treated therewith, for example, pain, itching, chronic inflammatory skin diseases and the like.
  • the compound of formula (I) of the present invention, its preparation method and vanilloid receptor antagonistic activity are described in detail in International Publication WO 2008/013414, the entire contents of which are incorporated herein by reference.
  • the compound of formula (I) includes both the parent compound as well as the pharmaceutically acceptable salts.
  • Examples include (1) formed with inorganic acids; Acid addition salts formed with organic acids; Or (2) salts formed when the acidic proton present in the parent compound is substituted.
  • the compound of Formula 1 as an active ingredient of the composition for preventing or treating sleep disorders, particularly atopic dermatitis accompanying sleeping disorders according to the present invention may be contained in an amount of 0.1 to 1.5% by weight based on the total composition.
  • the content of the compound represented by the general formula (1) is within the above range, the maximum efficacy for prevention and / or treatment of atopic dermatitis can be secured.
  • a preferable administration subject of the composition for preventing or treating sleep disorder of the present invention is a patient suffering from atopic dermatitis and having a sleep disorder.
  • the sleeping disorder patient of the present invention may be a patient having a Visual Analogue Scale (VAS) score of 3 to 10.
  • VAS Visual Analogue Scale
  • VAS is a continuum scale that patients can classify their discomfort for symptoms such as sleep disorders.
  • the degree of sleep disturbance can be quantified to a value between 0 and 10 when the symptom is considered, a VAS score of 0 means no sleep disorder, 10 means no worse Sleep disorder.
  • composition for preventing or treating sleep disorder, particularly atopic dermatitis accompanying sleeping disorder of the present invention can be administered orally or transdermally, but can be preferably administered transdermally.
  • composition of the present invention is merely applied to the skin (transdermal administration) to exhibit excellent sleep disorder therapeutic effect.
  • the compound of formula (I) of the present invention can be applied to the skin and exhibit excellent therapeutic effect and relief against sleeping disorder accompanying atopic dermatitis.
  • composition of the present invention shows excellent sleeping disorder treatment effect even when applied to the skin twice a day, and is excellent when used continuously for 2 weeks or more, especially 3 weeks or more, preferably 3 to 8 weeks. It exhibits the therapeutic effect of disorder.
  • the single dose of the composition for external use for skin varies depending on the condition of the patient, the body weight, the degree of disease, the composition type, the administration route and the period of time
  • (FTU) (0.5 g) corresponds to a single dose to be applied to an area twice the size of the palm of the patient ( ⁇ 2% of BSA).
  • it may be preferably 25 mg to 150 mg in case of patients with 5% to 30% BSA lesion.
  • BSA Body Surface Area
  • composition for preventing or treating sleep disorder according to the present invention can be formulated especially as an external preparation for skin and is preferably used as a cream, gel, patch, spray, ointment, warning agent, lotion, liniment, pasta, cataplasma, essence , Pack, powder, oil, wax, spray, paste, solution, suspension, emulsion, or soap.
  • the carrier the emulsifier, the moisturizer, the skin conditioner, the surfactant , Chelating agents, antioxidants, bactericides, stabilizers, and any combination thereof.
  • the carrier examples include an animal fiber, a plant fiber, a wax, a paraffin, a starch, a tragacanth, a cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc, zinc oxide, lactose, silica, aluminum hydroxide, calcium silicate, poly Amide powder, water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylglycol oil, glycerol aliphatic ester, polyethylene glycol, liquid diluent, ethoxylated isostearyl alcohol, Polyoxyethylene sorbitol esters and polyoxyethylene sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar or tragacanth, aliphatic alcohol sulfates, aliphatic alcohol ether sulf
  • moisturizing agent examples include, but are not limited to, glycerin, glyceryl stearate and the like.
  • the skin conditioning agent includes, but is not limited to, cyclomethicone, dimethicone, and the like.
  • surfactant examples include polyoxyethylene-sorbitan-fatty acid esters, polyoxyethylene fatty acid esters, sorbitan fatty acid esters, polyoxyethylene-polyoxypropylene copolymer, cetearyl glucoside and mono / diglyceride But is not limited thereto.
  • chelating agent examples include sodium ethylenediaminetetraacetate (EDTA), alpha -hydroxy fatty acid, lactoferrin, alpha -hydroxy acid, citric acid, lactic acid, malic acid, bilirubin, biliverdin, no.
  • EDTA sodium ethylenediaminetetraacetate
  • lactoferrin alpha -hydroxy acid
  • citric acid lactic acid
  • malic acid bilirubin
  • biliverdin no.
  • antioxidants examples include butylhydroxyanisole, dibutylhydroxytoluene, and propyl gallate, but are not limited thereto.
  • composition for external use for the skin may further contain, as a possible component, a pH adjusting agent, a plasticizer, a solubilizing agent, a gelling agent, a binder, an isotonizing agent, an anhydrous agent, a preservative, a dispersant, an opacifying agent, an antioxidant, Emulsifiers, organic and inorganic pigments, organic powders, ultraviolet absorbers, alcohols, blood circulation promoters, coolants, restraint agents, and the like may be added to the composition of the present invention. have.
  • the dermatological composition of the present invention is preferably a dermatological composition
  • At least one solvent selected from the group consisting of diethylene glycol monoethyl ether, polyethylene glycol, pyrrolidone-2, and dimethyl sulfoxide;
  • polyoxyethylene-sorbitan-fatty acid esters polyoxyethylene fatty acid esters, sorbitan fatty acid esters, polyoxyethylene-polyoxypropylene copolymer, cetearyl glucoside and mono / At least one component selected from the group consisting of rides;
  • the thickening agent may be in the form of an oil-in-water (O / W) emulsion, comprising at least one component selected from the group consisting of xanthan gum, gelatin, gellan gum, carrageenan and carbomer.
  • O / W oil-in-water
  • the content of the compound of Formula 1 as a drug in the composition of the present invention may be 0.1 to 1.5% by weight based on the total weight of the composition.
  • the content of the cellulose-based polymer or vinylpyrrolidone-based polymer as the stabilizer may be 1 to 5% by weight of the total composition.
  • the solvent content may be from 5 to 20% by weight of the total composition weight.
  • the content of the water phase may be 45 to 90% by weight of the total composition.
  • the content of the oil phase may be 5 to 30% by weight.
  • the surfactant content may be from 1 to 10% by weight.
  • the thickening agent may be 0.01 to 5% by weight.
  • the composition of the present invention is a mild to moderate atopic dermatitis patient.
  • 97 patients who exhibit sleeping disorder transdermally administered twice a day for 8 weeks, 1 in the test group showed statistically significant improvement in the sleeping disorder (see Experimental Example 1). From this, it was confirmed that the composition containing the compound of formula (I) of the present invention as an active ingredient can effectively and safely effectively treat sleep disorder, especially sleeping disorder accompanying atopic dermatitis, only by transdermal administration.
  • Example 1 Preparation of a pharmaceutical composition comprising the compound of formula (I) of the present invention
  • a cream form external skin composition containing the compound of formula (I) in the composition as shown in the following Table 1 was prepared. Specifically, the oil phase and water phase of the composition shown in the following Table 1 were first emulsified at 65 DEG C, and then a solution of the compound of the formula (1) dissolved in polyethylene glycol (PEG400, Merck) was added thereto. Then, the thickening agent and additives were added, homogenized, and then cooled to 35 ⁇ to prepare a cream-type external-skin composition.
  • PEG400 polyethylene glycol
  • An external preparation for external use for a cream formulation was prepared in the same manner as described in Example 1, except that the compound of Formula 1 was not used.
  • a gel containing the compound of formula (I) of the present invention was prepared by a conventional method according to the composition shown in Table 2 below.
  • An ointment containing the compound of formula (I) of the present invention was prepared by a conventional method according to the composition shown in Table 3 below.
  • Lotion preparations containing the compound of formula (I) of the present invention were prepared by a conventional method according to the composition shown in Table 4 below.
  • BSA body surface area
  • IGA Investigator's Global Assessment
  • the daily dose was applied to the skin to 25 to 150 mg / day.
  • doses 1, 3, 6, and 8 the degree of sleep disturbance felt by each patient was assessed and the change in score was calculated.
  • the sleep disorder evaluation score is a result of evaluating the degree of sleep disorder from 0 to 10 in order to recall the symptom during the last 3 days before the evaluation date, 0 means "no sleep disorder", 10 means " Severe sleep disorder ".
  • FIG. 1 is a graph showing mean changes from baseline in sleep-disturbance score before and after application of the composition of Example 1 (Compound of Formula 1 1.0%) and Comparative Example 1 (Vehicle).
  • FIG. 1 is a graph showing mean changes from baseline in sleep-disturbance score before and after application of the composition of Example 1 (Compound of Formula 1 1.0%) and Comparative Example 1 (Vehicle).
  • the composition of the present invention started to improve sleeping disturbance statistically significantly compared to the placebo group administered with the composition of Comparative Example 1 from the 3rd week of transdermal administration, And more than two times.
  • composition containing the compound of Formula 1 of the present invention effectively treats the sleep disorder that occurs in atopic dermatitis patients by transdermal administration.
  • the AMG 517 compound represented by the following formula (2) was stopped due to the side effects of body temperature during the clinical trial for treating toothache in a multinational pharmaceutical company, Amgen.
  • the body temperature of the rat increased by about 1.3 ° C at 3 mg / kg, and the effective concentration to maximize analgesic efficacy was less than 0.3 mg / kg in the rat Therefore, we believe that clinical trials have been conducted.
  • body temperature has been reported to rise to about 40 ° C and hyperthermia side effects have been observed in a concentration-dependent manner (Gavva et al ., 2008. Pain 136, 202- 210):
  • AMG 517 which is a representative reference drug, as a TRPV1 antagonist and the compound of formula 1 of the present invention
  • C57BL / 6 mice were sacrificed by tape stripping in the back skin of the experimental animals (C57BL / 6 mice) in consideration of differences in drug absorption patterns due to damage to the skin barrier in the case of skin diseases such as atopic dermatitis. %, 0.3%, and 1.0%, respectively, and body temperature changes were observed at 0, 1, 2, 4, and 6 hours before and after percutaneous application.
  • body temperature was increased ( ⁇ 0.84 °C) in the 1.0% dose group only for 2 hours, but no concentration dependence was observed.
  • transdermal drug group of the formula (1) In general, in patients with skin diseases such as atopic dermatitis, when the body temperature is increased, they cause itching and thus cause sleeping disorder. Therefore, it is known that the transdermal drug group of the formula (1) .
  • Toxic dermatitis induced by oxazolone (Ox) was applied to the neck of the rats. Ethanol vehicle was applied once a day, cream medicine twice a day for 14 days, and the degree of atopic dermatitis symptoms and IgE antibody expression . The atopic dermatitis symptoms measured at this time are excoriation, scaling, edema, and erythema.
  • FIG. 4B shows the measurement results of atopic dermatitis symptoms after ethanol vehicle was applied to hairless mice induced with oxazolone atopic dermatitis. Specifically, as a result of applying ethanol (Ox + EtOH) and ethanol containing 1 weight% of compound 1 (Ox + compound 1), in the case of an ethanol vehicle, The symptoms of atopic dermatitis are not alleviated.
  • FIG. 4B shows the measurement results of atopic dermatitis symptoms after application of a cream vehicle to hairless mice induced with oxazolone atopic dermatitis.
  • the composition of the cream 1 (Ox + Compound 1) containing 1% by weight of the composition of the Comparative Example 1 (Ox + Veh) 1 compound), in the case of a cream vehicle the symptoms of atopic dermatitis are remarkably alleviated when the compound of the formula (1) is applied to the composition of the example 1.
  • FIG. 5B shows the results of measurement of the serum IgE antibody expression level (Serum IgE) after applying an ethanol vehicle to hairless mice induced with atopic dermatitis with oxazolone. Specifically, as a result of applying ethanol (Ox + EtOH) and ethanol containing 1 weight% of compound 1 (Ox + compound 1), in the case of an ethanol vehicle, , The expression level of serum IgE antibody is increased.
  • FIG. 5B shows the results of measurement of the serum IgE antibody expression level (Serum IgE) after applying a cream vehicle to hairless mice induced with atopic dermatitis with oxazolone.
  • the composition of the cream 1 (Ox + Compound 1) containing 1% by weight of the composition of the Comparative Example 1 (Ox + Veh) 1 compound) it can be seen that in the case of a cream vehicle, the amount of the serum IgE antibody is decreased when the compound of the formula 1 is applied to the composition of Example 1.
  • the cream formulation containing 1% by weight of the compound of the formula (1) is also effective in reducing the symptoms of atopic dermatitis and the amount of IgE expression as described above to improve the sleeping disorder phenomenon.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Dermatology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition pour prévenir ou traiter les troubles du sommeil, contenant un (R)-N-[1-(3,5-difluoro-4-méthanesulfonylamino-phényl)-éthyl]-3-(2-propyl-6-trifluorométhyl-pyridine-3-yl)-acrylamide à titre de principe actif. La composition selon la présente invention peut prévenir ou traiter de manière efficace et sûre les troubles du sommeil accompagnant la dermatite atopique.
PCT/KR2018/004330 2017-08-31 2018-04-13 Composition pour prévenir ou traiter les troubles du sommeil WO2019045215A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP18852284.1A EP3677265A4 (fr) 2017-08-31 2018-04-13 Composition pour prévenir ou traiter les troubles du sommeil
CN201880056479.7A CN111050767A (zh) 2017-08-31 2018-04-13 预防或治疗睡眠障碍的组合物
US16/805,202 US11382900B2 (en) 2017-08-31 2020-02-28 Composition for preventing or treating sleep disorders

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR20170110629 2017-08-31
KR10-2017-0110629 2017-08-31
KR10-2018-0042811 2018-04-12
KR1020180042811A KR102587297B1 (ko) 2017-08-31 2018-04-12 수면장애 예방 또는 치료용 조성물

Related Child Applications (1)

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US16/805,202 Continuation-In-Part US11382900B2 (en) 2017-08-31 2020-02-28 Composition for preventing or treating sleep disorders

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WO2019045215A1 true WO2019045215A1 (fr) 2019-03-07

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008013414A1 (fr) 2006-07-27 2008-01-31 Amorepacific Corporation Nouveaux composés, isomères de ceux-ci, ou sels acceptables sur le plan pharmaceutique de ceux-ci utilisés en tant qu'antagonistes du récepteur vanilloïde, et compositions pharmaceutiques les contenant
KR20170110629A (ko) 2015-01-30 2017-10-11 브라스켐 아메리카, 인크. 변형된 폴리프로필렌 및 이의 중합체 블렌드
KR20180042811A (ko) 2016-10-18 2018-04-26 윌리 에이. 바호펜 아게 교반기 볼 밀

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008013414A1 (fr) 2006-07-27 2008-01-31 Amorepacific Corporation Nouveaux composés, isomères de ceux-ci, ou sels acceptables sur le plan pharmaceutique de ceux-ci utilisés en tant qu'antagonistes du récepteur vanilloïde, et compositions pharmaceutiques les contenant
KR101410318B1 (ko) * 2006-07-27 2014-06-27 (주)아모레퍼시픽 바닐로이드 수용체 길항제로서의 신규 화합물, 그의 이성질체, 또는 약제학적으로 허용가능한 그의 염, 및 이를함유하는 약제학적 조성물
KR20170110629A (ko) 2015-01-30 2017-10-11 브라스켐 아메리카, 인크. 변형된 폴리프로필렌 및 이의 중합체 블렌드
KR20180042811A (ko) 2016-10-18 2018-04-26 윌리 에이. 바호펜 아게 교반기 볼 밀

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
CHANG, YUNG-SEN: "Atopic dermatitis, melatonin, and sleep disturbance", PEDIATRICS, vol. 34, no. 2, 2014, pages e397 - e405, XP055581049 *
GAVVA ET AL., PAIN, vol. 136, 2008, pages 202 - 210
LIM, KYUNG-MIN: "Development of PAC-14028, a novel transient receptor potential vanilloid type 1 (TRPV1) channel antagonist as a new drug for refractory skin diseases", ARCHIVES OF PHARMACAL RESEARCH, 2012, pages 393 - 396, XP035040204, DOI: doi:10.1007/s12272-012-0321-6 *
PARK, YANG-HUI: "Oral and topical pharmacokinetic studies of a novel TRPV1 antagonist, PAC-14028 in rats and minipigs using liquid chromatography/tandem mass spectrometric method", JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, vol. 61, no. 8-14, 14 August 2012 (2012-08-14), XP028886699 *
See also references of EP3677265A4 *
YUN, JUN-WON: "TRPV1 antagonist can suppress the atopic dermatitis-like symptoms by accelerating skin barrier recovery", JOURNAL OF DERMATOLOGICAL SCIENCE, vol. 62, no. 1, 2011, pages 8 - 15, XP028166554 *

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