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WO2018143685A1 - Composition de timbre transdermique pour faire baisser la tension artérielle - Google Patents

Composition de timbre transdermique pour faire baisser la tension artérielle Download PDF

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Publication number
WO2018143685A1
WO2018143685A1 PCT/KR2018/001371 KR2018001371W WO2018143685A1 WO 2018143685 A1 WO2018143685 A1 WO 2018143685A1 KR 2018001371 W KR2018001371 W KR 2018001371W WO 2018143685 A1 WO2018143685 A1 WO 2018143685A1
Authority
WO
WIPO (PCT)
Prior art keywords
patch
agonist
blood pressure
trpa1
composition
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/KR2018/001371
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English (en)
Korean (ko)
Inventor
김희영
양채하
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.)
Industry Academic Coorperation Foundation of Daegu Haany University
Original Assignee
Industry Academic Coorperation Foundation of Daegu Haany University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Industry Academic Coorperation Foundation of Daegu Haany University filed Critical Industry Academic Coorperation Foundation of Daegu Haany University
Publication of WO2018143685A1 publication Critical patent/WO2018143685A1/fr
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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/31—Brassicaceae or Cruciferae (Mustard family), e.g. broccoli, cabbage or kohlrabi

Definitions

  • the present invention relates to a patch composition for lowering blood pressure, and specifically, among a group consisting of an agonist of TRPV1 (agonist) and agonists of transient receptor potential cation channel subfamily A member 1 (TRPA1).
  • the present invention relates to a patch composition for lowering blood pressure, which contains a selected agonist as an active ingredient, a patch to which the patch composition is applied, and a method of using the patch.
  • Hypertension is one of the most common diseases in the world, and in Korea, it is a very common disease found in more than 30% of adults. Hypertension causes a variety of complications throughout the body, including coronary artery disease, stroke, and kidney failure, many of which cause serious and life-threatening problems.
  • Risk factors associated with hypertension include environmental and psychological factors such as family history, drinking, smoking, aging, lack of exercise, obesity, salty eating and stress.
  • TRPV transient receptor potential cation channel subfamily V
  • TRPV transient receptor potential cation channel subfamily V
  • TRPV1 reacts to a temperature of 43 ° C or higher
  • TRPV3 reacts to a temperature of 35 ° C or higher
  • TRPV4 reacts to a temperature of 33 ° C or higher.
  • TRPV1 reacts to a temperature of 43 ° C or higher
  • TRPV3 reacts to a temperature of 35 ° C or higher
  • TRPV4 reacts to a temperature of 33 ° C or higher.
  • the corresponding TRPV receptor is activated to feel the temperature.
  • TRPA1 Transient receptor potential cation channel subfamily A member 1
  • SP substance P
  • CGRP calcitonin gene related peptide
  • TRPA1 plays an important role in the conduction of pain caused by various stimuli.
  • TRPA1 is activated by mustards such as allyl isothiocyanate, cinnamaldehyde, allicin, cinnamon and garlic, and environmental hazards such as acrolein.
  • TRPA1 is known to contribute to the pain induced by high threshold mechanical stimulation (Kwan et al., 2006) and cold stimulation below 17 ° C.
  • TRPA1 is reported to be expressed in sensory neurons containing TRPV1 and neuropeptides, suggesting that TRPA1 will most likely be expressed in C-fibers.
  • the present inventors unlike the existing techniques related to hypertension, can be more easily used in real life, and studied a method of reducing the blood pressure effectively in the state of Korean medicine in a hypertension state.
  • it was intended to develop a method of contacting the skin more easily without ingesting it in the form of food or injecting the drug in the form of an injection, etc., and aimed at the development of a suitable patch formulation.
  • the blood pressure can be effectively lowered by stimulating C-fiber of medial nerve of medial cuff using agonists of TRPV1 or TRPA1.
  • the patch composition containing the agonist of or TRPA1 and the patch coated with the patch composition it was confirmed that the blood pressure can be effectively lowered through a simple and safe method of attaching the patch to the skin, thereby completing the present invention.
  • the main object of the present invention is to provide a patch composition that can effectively lower blood pressure in a high blood pressure state more simply and safely in real life.
  • Another object of the present invention to provide a patch for lowering blood pressure to which the patch composition is applied.
  • Another object of the present invention is to provide a method of effectively using the patch.
  • the present invention provides an agonist selected from the group consisting of agonists of TRPV1 (agonist) and agonists of transient receptor potential cation channel subfamily A member 1 (TRPA1).
  • agonist selected from the group consisting of agonists of TRPV1 (agonist) and agonists of transient receptor potential cation channel subfamily A member 1 (TRPA1).
  • TRPA1 transient receptor potential cation channel subfamily A member 1
  • a blood pressure lowering patch composition containing the active ingredient.
  • the agonist of TRPV1 is capsaicin
  • the agonist of TRPA1 is a mustard oil.
  • the patch composition of the present invention it is preferable to contain the agonist of TRPV1 at 0.001 to 20% by weight.
  • the agonist of TRPA1 is preferably contained in an amount of 0.001 to 20% by weight.
  • the present invention provides a patch for lowering blood pressure, wherein the patch composition is applied to a support.
  • the present invention is a method for effectively using the patch, characterized in that by attaching the patch to the skin of the inner bleeding site so that the agonist included in the patch stimulates the internal vascular blood Provides a way to use the patch.
  • the patch composition of the present invention contains an agonist selected from the group consisting of agonists of TRPV1 and agonists of TRPA1, thereby stimulating C-fiber nerves (C-fiber) of the medial median nerve of the cuff to effectively lower the blood pressure in the hypertensive state. Since the patch composition may have the same effect as the method of contacting the skin, the patch composition or the patch of the present invention has an advantage of lowering blood pressure very easily and safely compared to conventional oral drugs. In addition, it is possible to use capsaicin or mustard oil, rather than an expensive compound, as an agonist.
  • TRPV1 capsaicin
  • TRPA1 mustard oil
  • Figure 2 shows the internal vascular site located inside the wrist of a person.
  • Figure 3 is a graph showing the results of experiments on the blood pressure lowering effect of the agonist (capsaicin) of TRPV1 through clinical trials.
  • the present invention uses C-fiber of medial nerve of medial cuff using agonists of TRPV1 (transient receptor potential cation channel subfamily V member 1) or TRPA1 (transient receptor potential cation channel subfamily A member 1) of neurons. Stimulation was based on a new discovery that blood pressure drops.
  • TRPV1 is a protein that acts as a receptor for neurons to receive thermal stimuli. It is registered in Genbank as Accession number NP_061197, and consists of the amino acid sequence shown in SEQ ID NO: 1.
  • TRPA1 is a non-selective cation pathway protein expressed in pain sensory nerves and is registered in Genbank as Accession number NP_015628 and consists of an amino acid sequence as shown in SEQ ID NO: 2.
  • Stimulating the C-fiber nerves of the medial median nerve of the cuff using such agonists of TRPV1 or TRPA1 can be achieved by contacting these agonists to the skin.
  • Capsaicin or resiniferatoxin may be used as an agonist of TRPV1, and a compound known as an agonist of TRPV1 may be used, and a mustard oil or 4-oxo may be used as an agonist of TRPA1.
  • 2-nonoral (4-oxo-2-nonenal), icilin, polygodial, hepoxilin can be used, and other compounds known as agonists of TRPA-1 can be used.
  • capsaicin is used as the agonist of TRPV1
  • mustard oil is used as the agonist of TRPA1 which is preferable in view of blood pressure lowering effect, side effects, easy availability of materials, and economical efficiency.
  • a patch may be used.
  • the present invention provides a patch composition for applying to such a patch.
  • the patch composition of the present invention is characterized by containing an agonist selected from the group consisting of agonists of TRPV1 and agonists of TRPA1 as an active ingredient.
  • the patch composition of the present invention may be made of only one agonist selected from agonists of TRPV1 and agonists of TRPA1 as an active ingredient, may comprise both agonists of TRPV1 and agonists of TRPA1. Since two types of agonists stimulate different receptor proteins, it may be desirable to include all of them for a more effective blood pressure drop.
  • the agonist of TRPV1 in the patch composition of the present invention may be contained in 0.001 to 20% by weight of the total weight of the composition. This is a content that can expect a blood pressure lowering effect through sufficient stimulation of the patch composition during skin contact, more preferably 0.01 to 10% by weight in terms of sufficient stimulation of the receptor protein, reduced discomfort due to skin contact, economics, etc. It is good that it is good, More preferably, it is 0.1-2 weight%.
  • the agonist of TRPA1 may also be contained in 0.001 to 20% by weight of the total weight of the composition for the same reason, more preferably 0.01 to 10% by weight, more preferably 0.1 to 2% by weight.
  • the patch composition of the present invention may comprise a diluent or excipient for formulation in addition to the agonist.
  • the diluent may be a solvent capable of dissolving or dispersing the agonist, and water, a buffer, oil, and the like may be used.
  • a polymer capable of increasing the skin adhesion of the patch composition may be used.
  • a polymer forming a hydrophilic gel, a tape, or a film may be used as the polymer.
  • Such polymers include polyalkylvinylether-maleic acid copolymers, poloxamers, polyvinylpyrrolidones, vinylpyrrolidone-vinylacetate copolymers, polyethylene glycols, polypropylene glycols, polyacrylic acids, sodium polyacrylates or copolymers thereof, poly Synthetic polymers such as vinyl alcohol, polyacrylate, polymethacrylate, polyquaternium, and carboxypolymethylene series; Collagen, galactomannan; Starch, starch derivatives and hydrolysates; Cellulose derivatives such as methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and hydroxypropylmethyl cellulose; Colloidal silicic acid; And sugars such as natural compounds such as lactose, saccharose, fructose and glucose or derivatives thereof.
  • solvent of these polymers water or ethanol alone or a mixture thereof is mainly used, and other solvents, for example, ethyl acetate, methylene chloride, isopropyl alcohol, acetonitrile alone, or a mixture thereof may be controlled. It may be.
  • the patch composition of the present invention may further include a filler, an anticoagulant, a lubricant, a humectant, a fragrance, an emulsifier, a preservative, and the like in addition to the agonist, diluent, and excipient as described above, to provide rapid, sustained or delayed release of the active ingredient.
  • the patch composition of the present invention can be used as a patch itself in the form of a film, a tape or a gel (gel), but preferably applied to a support to be used in the form of a patch.
  • a support may be a nonwoven fabric made of polyester, polyvinylchloride, polyethylene, polypropylene, rayon or cotton, or a water-insoluble polymer, or a polymer partially soluble in water.
  • Polymers that can be used include cellulose acetate phthalate, cellac, polyvinylacetate, ethyl cellulose, polymethyl methacrylate, methacryloylethyl betaine / methacrylate copolymer, methacrylic acid copolymer, aminoalkyl methacrylate airborne Coalescence alone or mixtures thereof.
  • the patch may be prepared by applying the patch composition of the present invention to the upper surface of the support to form a formulation layer, and it is preferable to further form a release layer on the upper surface of the formulation layer so that the formulation layer is protected before use.
  • a peeling layer the film by which silicone mold release processes, such as polyester and a polypropylene, were used can be used.
  • the agonist of TRPV1 or the agonist of TRPA1 contained in the patch stimulates the C fiber nerve (C-fiber) of the median nerve to effectively increase blood pressure. You can descend. More preferably, it is preferable to use the method of contacting each agonist to the skin of the inner vascular site located in the median nerve for more effective blood pressure drop. Internal bleeding is anatomically 5-6 cm away from the wrist in the median nerve of the arm, and according to Bone Medicine, it corresponds to 2/12 villages from the wrist when the total length between the wrist and elbow joint is 1 Say where you are.
  • mice were used as animal models and their effects on blood pressure were investigated when capsaicin or TRPA1 agonist was used as a TRPV1 agonist and mustard oil was stimulated.
  • Sprague-Dawley rats weighing about 300 g were divided into three groups and physiological saline (control), capsaicin 0.5% (w / v) solution (experimental group 1) or mustard oil 0.5% (w / v) 50 ⁇ l of solution (Experimental Group 2) was injected into a stress bag to induce stress hypertension, and blood pressure was measured every 10 minutes for 120 minutes.
  • Intravascular percutaneous nerve stimulation was performed for 30 minutes to observe the change of blood pressure in hypertensive patients (control group), and 1% capsaicin was applied to the median nerve area including intravascular blood (experimental group).
  • the experimental group to which capsaicin was applied showed a similar pattern to that of the control group subjected to endothelial percutaneous neural stimulation (TENS) and showed a superior blood pressure lowering effect. .
  • the patch composition of the present invention can effectively lower the blood pressure in the hypertensive state by skin contact of the internal acupuncture points, the patch composition can be used for the manufacture of a patch product for use in lowering blood pressure by attaching to the skin of the internal acupoints.

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  • Health & Medical Sciences (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Mycology (AREA)
  • Microbiology (AREA)
  • Medical Informatics (AREA)
  • Botany (AREA)
  • Biotechnology (AREA)
  • Dermatology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne une composition de timbre transdermique qui permet de faire baisser la pression artérielle et, plus particulièrement, une composition de timbre transdermique comprenant comme principe actif un agoniste sélectionné dans le groupe constitué par un agoniste du récepteur TRPV1 (membre 1 de la sous-famille V du canal cationique à potentiel de récepteur transitoire) et un agoniste du récepteur TRPA1 (membre 1 de la sous-famille A du canal cationique à potentiel de récepteur transitoire) en tant que principe actif pour faire baisser la tension artérielle, un timbre transdermique recouvert de la composition dudit timbre, ainsi qu'une méthode d'utilisation de celui-ci. Selon la présente invention, la composition de timbre transdermique, contenant un agoniste sélectionné dans le groupe constitué par un agoniste de TRPV1 et un agoniste de TRPA1, est capable de stimuler les fibres C du nerf médian à l'intérieur du poignet afin de faire efficacement baisser la tension artérielle provoquée par l'hypertension. Étant donné que l'effet susmentionné peut être provoqué par la mise en contact d'une composition de timbre transdermique avec la peau, l'utilisation de la composition de timbre ou du timbre selon la présente invention présente l'avantage de faire facilement baisser la tension artérielle sans danger, par comparaison avec les médicaments par voie orale existants. De plus, il est possible d'utiliser comme agoniste de la capsaïcine ou de l'huile de moutarde plutôt que des composés coûteux, ce qui offre l'avantage de fournir le timbre transdermique à un coût très peu élevé.
PCT/KR2018/001371 2017-02-02 2018-02-01 Composition de timbre transdermique pour faire baisser la tension artérielle Ceased WO2018143685A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2017-0014800 2017-02-02
KR1020170014800A KR101880442B1 (ko) 2017-02-02 2017-02-02 혈압 강하용 패치 조성물

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WO2018143685A1 true WO2018143685A1 (fr) 2018-08-09

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040202707A1 (en) * 2003-04-14 2004-10-14 Walter Muller Therapeutic patch
US20060165764A1 (en) * 2005-01-26 2006-07-27 Akinori Hanatani Tape preparation
US20100172946A1 (en) * 2007-06-08 2010-07-08 Samyang Corporation Matrix-type transdermal drug delivery system and preparation method thereof

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100815610B1 (ko) 2006-11-23 2008-03-21 동국대학교 산학협력단 제조 추출물을 함유하는 고혈압의 예방 및 치료용약학조성물
WO2008133982A2 (fr) * 2007-04-27 2008-11-06 Lectec Corporation Timbre adhésif contenant un agent aversif
KR101084529B1 (ko) 2009-02-24 2011-11-18 전남대학교산학협력단 인터루킨-24 또는 그를 암호화하는 유전자를 포함하는 고혈압 예방 또는 치료용 의약조성물
KR101328137B1 (ko) 2011-12-23 2013-11-11 건국대학교 산학협력단 포스포리파제 ｃ감마 또는 표피성장인자 수용체 저해제를 유효성분으로 포함하는 고혈압 치료 또는 예방용 조성물

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040202707A1 (en) * 2003-04-14 2004-10-14 Walter Muller Therapeutic patch
US20060165764A1 (en) * 2005-01-26 2006-07-27 Akinori Hanatani Tape preparation
US20100172946A1 (en) * 2007-06-08 2010-07-08 Samyang Corporation Matrix-type transdermal drug delivery system and preparation method thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
EARLEY, SCOTT: "TRPA1 Channels in the Vasculature", BRITISH JOURNAL OF PHARMACOLOGY, vol. 167, no. 1, 2012, pages 13 - 22, XP055532172 *
YANG, DACHUN ET AL.: "Activation of TRPV1 by Dietary Capsaicin Improves Endothelium-dependent Vasorelaxation and Prevents Hypertension", CELL METABOLISM, vol. 12, no. 2, 2010, pages 130 - 141, XP055532169 *

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