WO2019093359A1 - Agent for increasing blood flow volume in peripheral capillary - Google Patents

Agent for increasing blood flow volume in peripheral capillary Download PDF

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Publication number
WO2019093359A1
WO2019093359A1 PCT/JP2018/041298 JP2018041298W WO2019093359A1 WO 2019093359 A1 WO2019093359 A1 WO 2019093359A1 JP 2018041298 W JP2018041298 W JP 2018041298W WO 2019093359 A1 WO2019093359 A1 WO 2019093359A1
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Prior art keywords
blood flow
agent
receptor blocker
peripheral
increasing
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PCT/JP2018/041298
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French (fr)
Japanese (ja)
Inventor
隆明 稲葉
祐史 三枝
智文 景山
雅智 加藤
毅 伊藤
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参天製薬株式会社
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Publication of WO2019093359A1 publication Critical patent/WO2019093359A1/en

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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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • 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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • 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
    • A61K9/08—Solutions
    • 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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to an agent for increasing blood flow in peripheral capillaries, which contains an ⁇ 1 receptor blocker as an active ingredient, and a treatment of a bear using the same.
  • blue bears are highly visible and prompt treatment or improvement is desired
  • the treatment of blue bears is to promote blood flow improvement by, for example, massaging or warming the surroundings of the eye.
  • Most physical treatments such as making a bear unnoticeable using cosmetics etc.
  • As treatment of bears with drugs use of phytantriol and farnesol (patent documents 2 and 3) and use by off-labeling of the moisturizer hirudoid (registered trademark) are known, but most other measures are taken. Absent.
  • ⁇ 1 receptor which is one of the adrenergic receptors, is mainly distributed in vascular smooth muscle, prostate and bladder sphincter muscle.
  • the ⁇ 1 receptor blocker is used as a therapeutic agent for hypertension since it has a blood pressure lowering action by vasodilation, and it is also used as a therapeutic agent for urination disorder because it has a urinary tract smooth muscle relaxation action.
  • ACE therapy / ARB Ca antagonist
  • thiazide type diuretic / thiazide analogue diuretic is the first choice as a basic idea of hypertension treatment
  • ⁇ 1 receptor blocker is the first choice. It is not a choice.
  • nothing is known about locally administering an alpha 1 receptor blocker to increase peripheral capillary blood flow and for use in the treatment of blue bears.
  • the present inventors conducted intensive studies to find an agent for increasing blood flow in peripheral capillaries, and the site applied by applying a composition containing an ⁇ 1 receptor blocker as an active ingredient to the skin It has been found that the blood flow of the peripheral capillary blood vessels increases rapidly after application and the increase in blood flow disappears in a short time, and it has been found that the blue bear can be treated, resulting in the present invention. Specifically, the present invention provides the following.
  • An agent for increasing blood flow in peripheral capillaries which comprises an ⁇ 1 receptor blocker as an active ingredient.
  • the agent for increasing blood flow according to (6) which is administered to eyelid skin.
  • the dosage form is selected from the group consisting of an ointment, a cream, a lotion, a gel, a liniment, a transdermal preparation, a patch, a spray and an injection, (6) to (8) The blood flow increaser according to any one of the above.
  • the agent for increasing blood flow according to any one of (6) to (9), wherein the administration to the vicinity of the eye is application to eyelid skin.
  • a blood flow increase agent for peripheral capillaries which comprises bunazosin or a salt thereof as an active ingredient and is administered to eyelid skin.
  • the invention further relates to the following.
  • a composition for increasing blood flow in peripheral capillaries which comprises an ⁇ 1 receptor blocker as an active ingredient.
  • a composition for treating blue bear which comprises an ⁇ 1 receptor blocker as an active ingredient.
  • a method for increasing blood flow in peripheral capillaries comprising administering an effective amount of an ⁇ 1 receptor blocker to a subject in need thereof.
  • a method of treating a blue bear which comprises administering an effective amount of an ⁇ 1 receptor blocker to a subject in need thereof.
  • each structure of said (1) to (23) can select 2 or more arbitrarily, and can combine them.
  • an agent for increasing blood flow in peripheral capillaries which contains an ⁇ 1 receptor blocker as an active ingredient.
  • the ⁇ 1 receptor blocker is not particularly limited as long as it is a compound or a salt thereof that blocks the action of the ⁇ 1 receptor, for example, bunazosin, prazosin, terazosin, doxazosin, naphthopidil, trimazocin, dapiprasol and salts thereof And the like, and particularly preferred is bunazosin or a salt thereof.
  • bunazosin is a compound represented by the chemical name 4-Amino-2- (4-butanol-1,4-diazepan-1-yl) -6,7-dimethoxyquinazoline, and also represented by the following formula : It is a compound represented by
  • the ⁇ 1 receptor blocker may be a salt, and is not particularly limited as long as it is a pharmaceutically acceptable salt.
  • the salt include salts with inorganic acids and salts with organic acids.
  • salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • salts with organic acids include acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, tartaric acid, adipic acid, gluconic acid, glucoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid Alanine, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, oleic acid, gallic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, Examples thereof include salts with p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, sulfosalicylic acid and the like.
  • a monohydrochloride (bunazosin hydrochloride) is particularly preferable as a salt of bunazosin.
  • the ⁇ 1 receptor blocker when an optical isomer is present in the ⁇ 1 receptor blocker, the ⁇ 1 receptor blocker may be a racemate, or may be an enantiomer, a diastereomer or a mixture thereof.
  • the alpha 1 receptor blocker may be in the form of a hydrate or a solvate.
  • the agent for increasing blood flow of peripheral capillaries of the present invention can be used, for example, as cosmetics, medicines, quasi-drugs.
  • the dosage form of the peripheral capillary blood flow-increasing agent of the present invention is not particularly limited as long as it is a preparation containing an ⁇ 1 receptor blocker and delivering the ⁇ 1 receptor blocker through the skin.
  • ointments, creams, lotions, gels, liniments, transdermal preparations, patches, tapes, patches, solutions for external use, powders for external use, solid agents for external use, sprays, pump sprays, external use Aerosols, injections and the like can be mentioned, preferably ointments, creams, lotions, gels, liniments, transdermal preparations, patches, sprays and injections, more preferably ointments, Creams, lotions and gels.
  • these can be prepared using the common technique generally used in the said field.
  • the dosage form when the dosage form is an ointment, for example, a mineral oil-based oily ointment such as white petrolatum, liquid paraffin, animal and vegetable or the like can be prepared. Also, a water-soluble ointment based on macrogol etc. can be prepared.
  • a mineral oil-based oily ointment such as white petrolatum, liquid paraffin, animal and vegetable or the like
  • a water-soluble ointment based on macrogol etc. can be prepared.
  • the dosage form when the dosage form is a cream, for example, animal type, plant type, petroleum type, synthetic type hydrocarbon, oil and fat, wax ester, oil such as higher alcohol, polyhydric alcohol fatty acid ester, oxidation It can be prepared by using ethylene addition type nonionic surfactant, anionic surfactant, cationic surfactant, amphoteric surfactant, surfactant such as lecithin derivative, thickener such as polycarbophil, carboxyvinyl polymer and the like.
  • ethylene addition type nonionic surfactant anionic surfactant, cationic surfactant, amphoteric surfactant, surfactant such as lecithin derivative, thickener such as polycarbophil, carboxyvinyl polymer and the like.
  • the dosage form when the dosage form is a lotion, liquid for external use, etc., for example, water such as purified water or distilled water, lower alcohol such as ethanol, polyhydric alcohol such as glycerin, polyoxyethylene (60) cured It can be prepared using a base such as a surfactant such as castor oil.
  • a surfactant such as castor oil.
  • the dosage form when the dosage form is a gel, for example, water such as purified water and distilled water, higher alcohol, lower alcohol such as ethanol and propylene glycol, thickener such as hydroxyethyl cellulose and carboxyvinyl polymer, etc.
  • water such as purified water and distilled water
  • higher alcohol lower alcohol
  • lower alcohol such as ethanol and propylene glycol
  • thickener such as hydroxyethyl cellulose and carboxyvinyl polymer, etc.
  • the dosage form is a patch, a tape or the like, for example, acrylic, silicone, rubber, etc. pressure-sensitive adhesives (as an additive, tackifying resin, crosslinking agent, plasticizer, surfactant) , And may contain an antioxidant, etc. and supports such as non-woven fabric, film, sheet and the like.
  • pressure-sensitive adhesives as an additive, tackifying resin, crosslinking agent, plasticizer, surfactant
  • supports such as non-woven fabric, film, sheet and the like.
  • the preparation of the peripheral capillary blood flow-increasing agent of the present invention can be appropriately blended with additives usable as additives for cosmetics and medicines, as needed, regardless of its dosage form, for example, Preservatives, absorption accelerators, thickeners, stabilizers, surfactants, buffering agents, tonicity agents, pH adjusters and the like can be blended in appropriate amounts.
  • additives usable as additives for cosmetics and medicines for example, Preservatives, absorption accelerators, thickeners, stabilizers, surfactants, buffering agents, tonicity agents, pH adjusters and the like can be blended in appropriate amounts.
  • an appropriate amount of an active ingredient that can be added to cosmetics or medicines can be blended in the preparation of the present invention.
  • the single dose of the ⁇ 1 receptor blocker varies depending on the administration form and dosage form, but, for example, 0.0005 to 25 mg, preferably 0.0025 for ointments, creams, etc.
  • the amount is preferably 20 to 20 mg, more preferably 0.005 to 15 mg, still more preferably 0.025 to 10 mg, and particularly preferably 0.05 to 5 mg.
  • it is 0.005 to 10 mg, more preferably 0.1 to 3 mg.
  • the concentration of the ⁇ 1 receptor blocker varies depending on the administration form and administration form, but it is, for example, 0.001 to 50% (w / w), preferably 0 in the case of ointment, cream etc. .005 to 40% (w / w), more preferably 0.01 to 30% (w / w), still more preferably 0.05 to 20% (w / w), particularly preferably 0.1 to 10% (W / w).
  • “% (w / w)” means the mass (g) of the object component (alpha 1 receptor blocker) contained in 100 g of blood flow rate increasing agents of this invention.
  • in the vicinity of the eye refers to the eyelid and its vicinity, and includes the eyelid skin and the skin in the vicinity thereof.
  • the agent for improving blood flow in peripheral capillaries of the present invention can be used as an agent for improving blood flow disorders, to improve blood flow disorders in the vicinity of the eye by administering it in the vicinity of the eye.
  • the circulatory disorder occurring in the vicinity of the eye is, for example, eye fatigue, a bear formed under the eye, and the like, and the bear formed under the eye includes, for example, a blue bear, a tea bear, a black bear, and the like.
  • the agent for increasing blood flow in peripheral capillaries of the present invention can be used as a treatment for treating a blue bear, in particular for the prevention, treatment or amelioration of a blue bear.
  • treatment, improvement and treatment of blue bear include alleviation of symptoms of blue bear, thinning of blue bear, disappearance of blue bear and the like.
  • the agent for increasing blood flow of peripheral capillaries according to the present invention when administered in the vicinity of a thin eye of the skin, rapidly increases the blood flow of peripheral capillaries at the administration site to improve the circulatory disorder, and a short time after administration The effect disappears.
  • the agent for increasing blood flow in peripheral capillaries according to the present invention can reduce the dose of the drug by topical administration to a thin part of the skin, and can also expand peripheral capillaries to increase blood flow. Because the blood flow in the main blood vessel does not change much, and the effect of peripheral capillary dilation also disappears in a short time, side effects such as rapid blood pressure drop due to vasodilation are less likely to occur and it is used safely be able to.
  • the peripheral capillary is, for example, a blood vessel having a diameter of 10 ⁇ m or less, and the main blood vessel is a blood vessel thicker than the peripheral capillary.
  • the agent for increasing blood flow of peripheral capillaries of the present invention can be rapidly distributed, diffused and penetrated into the contacted epidermis by administering it in the vicinity of the thin eye of the skin.
  • the structure of the skin is a three-layer structure consisting of the epidermis, the dermis and the subcutaneous tissue, and the skin in the vicinity of the eyes is the thinnest in the face, the epidermis is about 0.1 mm, and the dermis is about 0.5 mm .
  • peripheral capillary blood flow-increasing agent of the present invention is particularly preferably on the skin or percutaneously.
  • the administration method and frequency of administration of the peripheral capillary blood flow increase agent of the present invention can be appropriately changed according to the dosage form, the severity of the condition to be administered, the age, the body weight, the judgment of the doctor, and the like.
  • an ointment cream, etc. it can be applied to the vicinity of the eye once to ten times a day, preferably once to six times a day, more preferably once to three times a day
  • a patch or the like it can be applied to the vicinity of the eye once to twice a day.
  • peripheral capillary blood flow increaser of the present invention also applies to the following aspects of the present invention.
  • One aspect of the present invention is a composition for increasing blood flow in peripheral capillaries, which comprises an ⁇ 1 receptor blocker as an active ingredient.
  • One aspect of the present invention is a composition for treating blue bear, which comprises an ⁇ 1 receptor blocker as an active ingredient.
  • One aspect of the invention is a method of increasing blood flow in peripheral capillaries comprising administering an effective amount of an alpha 1 receptor blocker to a subject in need thereof.
  • One aspect of the invention is a method of treating a blue bear comprising administering an effective amount of an alpha 1 receptor blocker to a subject in need thereof.
  • One aspect of the invention is the use of an alpha 1 receptor blocker for the manufacture of a medicament for increasing blood flow in peripheral capillaries.
  • One aspect of the present invention is the use of an alpha 1 receptor blocker for the manufacture of a medicament for treating a blue bear.
  • One aspect of the invention is an alpha 1 receptor blocker for use in increasing blood flow in peripheral capillaries.
  • One aspect of the invention is an alpha 1 receptor blocker for use in the treatment of blue bears.
  • Formulation Examples Representative formulation examples of the present invention are shown below.
  • the compounding quantity of each component in the following formulation example is a content in 10 g of formulation.
  • Formulation example 2 Bunazosin hydrochloride 100 mg White petrolatum suitable amount Liquid paraffin suitable amount
  • Formulation example 3 Bunazosin hydrochloride 300 mg Carboxy vinyl polymer 100 mg Bee wax 500 mg Liquid paraffin 1g White vaseline qs dilute hydrochloric acid / sodium hydroxide qs water qs pH 4.0
  • Example 1 Bunazosin hydrochloride 150 mg 0.8% hydroxyethyl cellulose qs Diluted hydrochloric acid / sodium hydroxide qs pH 4.0
  • Comparative Example 1 The preparation of Comparative Example 1 was prepared in the same manner as the preparation method of Example 1, except that bunazosin hydrochloride was not added.
  • “Hildoid (registered trademark) cream 0.3%” marketed in Japan as a reference is referred to as Comparative Example 2.
  • Blood flow variation rate (%) 100 ⁇ [(blood flow after administration of preparation) / (blood flow before administration of preparation)]
  • Table 1 shows the mean values of the blood flow rate variation rates of peripheral capillaries, and Table 2 shows the mean values of the blood flow rate variation rates of the main blood vessels.
  • Example 1 As shown in Tables 1 and 2, in Example 1, it was found that the blood flow of capillaries was significantly increased at 1 hour after administration, and the blood flow became closer to normalization with the lapse of time thereafter. On the other hand, no change in blood flow was shown in the blood flow in the main blood vessel. Further, in Comparative Example 1 which does not contain the ⁇ 1 receptor blocker, no change in the blood flow of the main blood vessel and capillary blood vessels is shown, and in Comparative Example 2, the blood flow increases with time after administration of both the main blood vessels and capillaries. Showed a tendency to
  • the agent for increasing blood flow of peripheral capillaries according to the present invention can be used for the improvement of blood circulation disorders in the vicinity of the eye by administering it as a blood circulation disorder improving agent in the vicinity of the eyes. It is expected that it can be used as a treatment for bears and the like (blue bears and the like) formed under the eyes and eyes.
  • the present invention provides an agent for increasing blood flow in peripheral capillaries, which contains an ⁇ 1 receptor blocker as an active ingredient.

Abstract

The present invention addresses the problem of providing an agent for increasing the blood flow volume in a peripheral capillary, which enables the treatment of bluish shadows under eyes. The present invention is an agent for increasing the blood flow volume in a peripheral capillary, which contains an α1 receptor blocker as an active ingredient.

Description

末梢毛細血管の血流量増加剤Peripheral capillary blood flow increaser
　本発明は、α１受容体遮断薬を有効成分として含有する、末梢毛細血管の血流量増加剤、及びそれを使用するクマの処置に関する。 The present invention relates to an agent for increasing blood flow in peripheral capillaries, which contains an α1 receptor blocker as an active ingredient, and a treatment of a bear using the same.
　眼の周りには多くの毛細血管が通っている一方で、眼の周りの皮膚は薄く、血液が滞ることにより毛細血管が透けて青っぽく見えることがあり、これは青クマと呼ばれている。青クマができる原因は、睡眠不足、疲労やストレス、冷え、生活習慣やホルモンバランスの乱れ、等が挙げられる。眼の下にできるクマには、上記の青クマ以外にも、色素沈着等による茶クマ、皮膚のたるみやへこみ等の骨格に依存する黒クマ、等が知られている。色素過剰症に起因するクマの変色に対して血管収縮薬を使用することが報告されている（特許文献１）。青クマは非常に目立つために速効性のある治療や改善が望まれているにも関わらず、青クマの対処法は、例えばマッサージや眼の周囲を温めることによって血流の改善を促すことや、化粧料等を用いてクマを目立たなくさせること、等の物理的な処置がほとんどである。薬物によるクマの治療としては、フィタントリオールやファルネソールの使用（特許文献２及び３）、保湿剤であるヒルドイド（登録商標）のオフラベルによる使用が知られているが、その他の対処はほとんどなされていない。 While there are many capillaries around the eye, the skin around the eye is thin, and when the blood stagnates, the capillaries may show through and look bluish, which is called a blue bear. The causes of blue bears include lack of sleep, fatigue and stress, chills, lifestyle and hormonal imbalance, etc. In addition to the above-mentioned blue bears, brown bears due to pigmentation and the like, black bears that rely on skeletons such as skin slack and dents, and the like are known as bears that can be produced under the eyes. It has been reported that a vasoconstrictor is used for discoloration of a bear caused by hyperpigmentation (Patent Document 1). Even though blue bears are highly visible and prompt treatment or improvement is desired, the treatment of blue bears is to promote blood flow improvement by, for example, massaging or warming the surroundings of the eye. Most physical treatments, such as making a bear unnoticeable using cosmetics etc. As treatment of bears with drugs, use of phytantriol and farnesol (patent documents 2 and 3) and use by off-labeling of the moisturizer hirudoid (registered trademark) are known, but most other measures are taken. Absent.
　一方、アドレナリン受容体の１つであるα１受容体は血管平滑筋、前立腺や膀胱括約筋などに主に分布している。α１受容体遮断薬は、血管拡張による血圧降下作用を有しているため高血圧治療剤として用いられ、また尿路平滑筋弛緩作用を有しているため排尿障害治療剤として用いられている。しかしながら、近年では、高血圧治療の基本的な考えとして、ＡＣＥ阻害薬／ＡＲＢ、Ｃａ拮抗薬、サイアザイド系利尿薬／サイアザイド類似利尿薬のいずれかを第１選択とし、α１受容体遮断薬は第１選択ではなくなっている。更に、α１受容体遮断薬を局所投与して、末梢毛細血管の血流量を増加させること、及び青クマの治療に用いることについては一切知られていない。 On the other hand, α1 receptor, which is one of the adrenergic receptors, is mainly distributed in vascular smooth muscle, prostate and bladder sphincter muscle. The α1 receptor blocker is used as a therapeutic agent for hypertension since it has a blood pressure lowering action by vasodilation, and it is also used as a therapeutic agent for urination disorder because it has a urinary tract smooth muscle relaxation action. However, in recent years, ACE therapy / ARB, Ca antagonist, thiazide type diuretic / thiazide analogue diuretic is the first choice as a basic idea of hypertension treatment, and α1 receptor blocker is the first choice. It is not a choice. Furthermore, nothing is known about locally administering an alpha 1 receptor blocker to increase peripheral capillary blood flow and for use in the treatment of blue bears.
特表２００８－５１２４６９Special Table 2008-512469 特表２００４－５０６６１３Special table 2004-506613 特表２００２－５４２１７７Special feature 2002-542177
　青クマの治療を可能とする、末梢毛細血管の血流量増加剤を提供することは興味深い課題である。 It is an interesting issue to provide peripheral capillary blood flow enhancers that allow treatment of blue bears.
　本発明者らは、末梢毛細血管の血流量増加剤を見出すために鋭意研究を行ったところ、有効成分としてα１受容体遮断薬を含有する組成物を皮膚に塗布することによって、塗布された部位の末梢毛細血管の血流量が塗布後速やかに増加し、さらに血流量の増加作用が短時間で消失することを見出し、青クマを治療可能であることを突き止めて、本発明に至った。具体的に、本発明は以下を提供する。 The present inventors conducted intensive studies to find an agent for increasing blood flow in peripheral capillaries, and the site applied by applying a composition containing an α1 receptor blocker as an active ingredient to the skin It has been found that the blood flow of the peripheral capillary blood vessels increases rapidly after application and the increase in blood flow disappears in a short time, and it has been found that the blue bear can be treated, resulting in the present invention. Specifically, the present invention provides the following.
（１）α１受容体遮断薬を有効成分として含有する、末梢毛細血管の血流量増加剤。
（２）末梢毛細血管が眼の近傍の末梢毛細血管である、（１）に記載の血流量増加剤。
（３）末梢毛細血管が眼瞼皮膚の末梢毛細血管である、（２）に記載の血流量増加剤。
（４）血流量増加剤が血行障害改善剤である、（１）～（３）のいずれか一項に記載の血流量増加剤。
（５）血流量増加剤が青クマ処置剤である、（１）～（４）のいずれか一項に記載の血流量増加剤。
（６）眼の近傍へ投与されることを特徴とする、（１）～（５）のいずれか一項に記載の血流量増加剤。
（７）眼瞼皮膚へ投与されることを特徴とする、（６）に記載の血流量増加剤。
（８）投与経路が皮膚上投与又は経皮投与である、（６）又は（７）に記載の血流量増加剤。
（９）投与剤形が軟膏剤、クリーム剤、ローション剤、ゲル剤、リニメント剤、経皮吸収型製剤、貼付剤、スプレー剤および注射剤よりなる群から選択される、（６）～（８）のいずれか一項に記載の血流量増加剤。
（１０）眼の近傍への投与が眼瞼皮膚への塗布である、（６）～（９）のいずれか一項に記載の血流量増加剤。
（１１）α１受容体遮断薬がブナゾシン又はその塩である、（１）～（１０）に記載の血流量増加剤。
（１２）ブナゾシン又はその塩を有効成分として含有し、眼瞼皮膚に投与される、末梢毛細血管の血流量増加剤。
（１３）α１受容体遮断薬を眼の近傍に投与することによる、眼の近傍の末梢毛細血管の血流量を増加させる方法。
（１４）α１受容体遮断薬を有効成分として含有する、青クマ処置剤。
（１５）α１受容体遮断薬がブナゾシン又はその塩である、（１４）に記載の処置剤。 (1) An agent for increasing blood flow in peripheral capillaries, which comprises an α1 receptor blocker as an active ingredient.
(2) The agent for increasing blood flow according to (1), wherein the peripheral capillary is a peripheral capillary near the eye.
(3) The agent for increasing blood flow according to (2), wherein the peripheral capillary is a peripheral capillary of eyelid skin.
(4) The blood flow increase agent according to any one of (1) to (3), wherein the blood flow increase agent is a blood circulation disorder improving agent.
(5) The blood flow increase agent according to any one of (1) to (4), wherein the blood flow increase agent is a blue bear treatment agent.
(6) The agent for increasing blood flow according to any one of (1) to (5), which is administered near the eye.
(7) The agent for increasing blood flow according to (6), which is administered to eyelid skin.
(8) The agent for increasing blood flow according to (6) or (7), wherein the administration route is dermal administration or transdermal administration.
(9) The dosage form is selected from the group consisting of an ointment, a cream, a lotion, a gel, a liniment, a transdermal preparation, a patch, a spray and an injection, (6) to (8) The blood flow increaser according to any one of the above.
(10) The agent for increasing blood flow according to any one of (6) to (9), wherein the administration to the vicinity of the eye is application to eyelid skin.
(11) The agent for increasing blood flow according to (1) to (10), wherein the α1 receptor blocker is bunazosin or a salt thereof.
(12) A blood flow increase agent for peripheral capillaries, which comprises bunazosin or a salt thereof as an active ingredient and is administered to eyelid skin.
(13) A method of increasing the blood flow of peripheral capillaries in the vicinity of the eye by administering an α1 receptor blocker in the vicinity of the eye.
(14) A blue bear treatment containing the α1 receptor blocker as an active ingredient.
(15) The therapeutic agent according to (14), wherein the α1 receptor blocker is bunazosin or a salt thereof.
　本発明は、更に以下にも関する。
（１６）α１受容体遮断薬を有効成分として含有する、末梢毛細血管の血流量増加用組成物。
（１７）α１受容体遮断薬を有効成分として含有する、青クマ処置用組成物。
（１８）α１受容体遮断薬を、それを必要とする対象に有効量投与することを含む、末梢毛細血管の血流量増加方法。
（１９）α１受容体遮断薬を、それを必要とする対象に有効量投与することを含む、青クマを処置する方法。
（２０）末梢毛細血管の血流量を増加させるための医薬の製造のための、α１受容体遮断薬の使用。
（２１）青クマを処置するための医薬の製造のための、α１受容体遮断薬の使用。
（２２）末梢毛細血管の血流量の増加に使用するための、α１受容体遮断薬。
（２３）青クマの処置に使用するための、α１受容体遮断薬。 The invention further relates to the following.
(16) A composition for increasing blood flow in peripheral capillaries, which comprises an α1 receptor blocker as an active ingredient.
(17) A composition for treating blue bear, which comprises an α1 receptor blocker as an active ingredient.
(18) A method for increasing blood flow in peripheral capillaries, comprising administering an effective amount of an α1 receptor blocker to a subject in need thereof.
(19) A method of treating a blue bear, which comprises administering an effective amount of an α1 receptor blocker to a subject in need thereof.
(20) Use of an α1 receptor blocker for the manufacture of a medicament for increasing blood flow in peripheral capillaries.
(21) Use of an α1 receptor blocker for the manufacture of a medicament for treating a blue bear.
(22) An α1 receptor blocker for use in increasing blood flow in peripheral capillaries.
(23) An alpha 1 receptor blocker for use in the treatment of blue bears.
　なお、前記（１）から（２３）の各構成は、任意に２以上を選択して組み合わせることができる。 In addition, each structure of said (1) to (23) can select 2 or more arbitrarily, and can combine them.
　本発明により、α１受容体遮断薬を有効成分として含有する、末梢毛細血管の血流量増加剤を提供することができる。 According to the present invention, it is possible to provide an agent for increasing blood flow in peripheral capillaries, which contains an α1 receptor blocker as an active ingredient.
　以下に、本発明について詳細に説明する。 Hereinafter, the present invention will be described in detail.
　本発明において、α１受容体遮断薬は、α１受容体の作用を遮断する化合物又はその塩であれば特に制限はなく、例えば、ブナゾシン、プラゾシン、テラゾシン、ドキサゾシン、ナフトピジル、トリマゾシン、ダピプラゾル及びそれらの塩等が挙げられ、特に好ましくはブナゾシン又はその塩である。 In the present invention, the α1 receptor blocker is not particularly limited as long as it is a compound or a salt thereof that blocks the action of the α1 receptor, for example, bunazosin, prazosin, terazosin, doxazosin, naphthopidil, trimazocin, dapiprasol and salts thereof And the like, and particularly preferred is bunazosin or a salt thereof.
　本発明において、「ブナゾシン」とは、化学名４－Ａｍｉｎｏ－２－（４－ｂｕｔａｎｏｙｌ－１，４－ｄｉａｚｅｐａｎ－１－ｙｌ）－６，７－ｄｉｍｅｔｈｏｘｙｑｕｉｎａｚｏｌｉｎｅで表される化合物であり、また下記式：
Figure JPOXMLDOC01-appb-C000001
で表される化合物である。 In the present invention, “bunazosin” is a compound represented by the chemical name 4-Amino-2- (4-butanol-1,4-diazepan-1-yl) -6,7-dimethoxyquinazoline, and also represented by the following formula :
Figure JPOXMLDOC01-appb-C000001
It is a compound represented by
　本発明において、α１受容体遮断薬は塩であってもよく、医薬として許容される塩であれば特に制限はない。塩として例えば、無機酸との塩、有機酸との塩等が挙げられる。 In the present invention, the α1 receptor blocker may be a salt, and is not particularly limited as long as it is a pharmaceutically acceptable salt. Examples of the salt include salts with inorganic acids and salts with organic acids.
　無機酸との塩としては、例えば、塩酸、臭化水素酸、ヨウ化水素酸、硝酸、硫酸、リン酸等との塩が挙げられる。 Examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
　有機酸との塩としては、例えば、酢酸、シュウ酸、フマル酸、マレイン酸、コハク酸、リンゴ酸、クエン酸、酒石酸、アジピン酸、グルコン酸、グルコヘプト酸、グルクロン酸、テレフタル酸、メタンスルホン酸、アラニン、乳酸、馬尿酸、１，２－エタンジスルホン酸、イセチオン酸、ラクトビオン酸、オレイン酸、没食子酸、パモ酸、ポリガラクツロン酸、ステアリン酸、タンニン酸、トリフルオロメタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸、硫酸ラウリル、硫酸メチル、ナフタレンスルホン酸、スルホサリチル酸等との塩が挙げられる。 Examples of salts with organic acids include acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, tartaric acid, adipic acid, gluconic acid, glucoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid Alanine, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, oleic acid, gallic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, Examples thereof include salts with p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, sulfosalicylic acid and the like.
　本発明において、α１受容体遮断薬がブナゾシンである場合には、ブナゾシンの塩としては、一塩酸塩（ブナゾシン塩酸塩）が特に好ましい。 In the present invention, when the α1 receptor blocker is bunazosin, a monohydrochloride (bunazosin hydrochloride) is particularly preferable as a salt of bunazosin.
　本発明において、α１受容体遮断薬に光学異性体が存在する場合には、α１受容体遮断薬はラセミ体であってもよく、或いはエナンチオマー、ジアステレオマー又はそれらの混合物であってもよい。 In the present invention, when an optical isomer is present in the α1 receptor blocker, the α1 receptor blocker may be a racemate, or may be an enantiomer, a diastereomer or a mixture thereof.
　本発明において、α１受容体遮断薬は、水和物又は溶媒和物の形態をとってもよい。 In the present invention, the alpha 1 receptor blocker may be in the form of a hydrate or a solvate.
　本発明の末梢毛細血管の血流量増加剤は、例えば、化粧料、医薬品、医薬部外品として使用することできる。本発明の末梢毛細血管の血流量増加剤の剤形は、α１受容体遮断薬を含有し、皮膚を通してα１受容体遮断薬を送達する製剤であれば特に限定されない。例えば、軟膏剤、クリーム剤、ローション剤、ゲル剤、リニメント剤、経皮吸収型製剤、貼付剤、テープ剤、パップ剤、外用液剤、外用散剤、外用固形剤、スプレー剤、ポンプスプレー剤、外用エアゾール剤、注射剤等が挙げられ、好ましくは軟膏剤、クリーム剤、ローション剤、ゲル剤、リニメント剤、経皮吸収型製剤、貼付剤、スプレー剤及び注射剤であり、より好ましくは軟膏剤、クリーム剤、ローション剤及びゲル剤である。なお、これらは当該分野で汎用される通常の技術を用いて調製できる。 The agent for increasing blood flow of peripheral capillaries of the present invention can be used, for example, as cosmetics, medicines, quasi-drugs. The dosage form of the peripheral capillary blood flow-increasing agent of the present invention is not particularly limited as long as it is a preparation containing an α1 receptor blocker and delivering the α1 receptor blocker through the skin. For example, ointments, creams, lotions, gels, liniments, transdermal preparations, patches, tapes, patches, solutions for external use, powders for external use, solid agents for external use, sprays, pump sprays, external use Aerosols, injections and the like can be mentioned, preferably ointments, creams, lotions, gels, liniments, transdermal preparations, patches, sprays and injections, more preferably ointments, Creams, lotions and gels. In addition, these can be prepared using the common technique generally used in the said field.
　本発明において、剤形が軟膏剤である場合には、例えば、鉱物性の白色ワセリン、流動パラフィン、動植物性等の油を基剤とする油脂性軟膏を調製できる。また、マクロゴール等を基剤とする水溶性軟膏を調製することもできる。 In the present invention, when the dosage form is an ointment, for example, a mineral oil-based oily ointment such as white petrolatum, liquid paraffin, animal and vegetable or the like can be prepared. Also, a water-soluble ointment based on macrogol etc. can be prepared.
　本発明において、剤形がクリーム剤である場合には、例えば、動物系、植物系、石油系、合成系の炭化水素、油脂、ロウエステル、高級アルコール等の油分、多価アルコール脂肪酸エステル、酸化エチレン付加型非イオン界面活性剤、アニオン界面活性剤、カチオン界面活性剤、両性界面活性剤、レシチン誘導体等の界面活性剤、ポリカーボフィル、カルボキシビニルポリマー等の増粘剤を使用し、調製できる。 In the present invention, when the dosage form is a cream, for example, animal type, plant type, petroleum type, synthetic type hydrocarbon, oil and fat, wax ester, oil such as higher alcohol, polyhydric alcohol fatty acid ester, oxidation It can be prepared by using ethylene addition type nonionic surfactant, anionic surfactant, cationic surfactant, amphoteric surfactant, surfactant such as lecithin derivative, thickener such as polycarbophil, carboxyvinyl polymer and the like.
　本発明において、剤形がローション剤や外用液剤等である場合には、例えば、精製水、蒸留水等の水、エタノール等の低級アルコール、グリセリン等の多価アルコール、ポリオキシエチレン（６０）硬化ヒマシ油等の界面活性剤等の基剤を使用し、調製できる。 In the present invention, when the dosage form is a lotion, liquid for external use, etc., for example, water such as purified water or distilled water, lower alcohol such as ethanol, polyhydric alcohol such as glycerin, polyoxyethylene (60) cured It can be prepared using a base such as a surfactant such as castor oil.
　本発明において、剤形がゲル剤である場合には、例えば、精製水、蒸留水等の水、高級アルコール、エタノール、プロピレングリコール等の低級アルコール、ヒドロキシエチルセルロース、カルボキシビニルポリマー等の増粘剤等の基剤を使用し、調製できる。 In the present invention, when the dosage form is a gel, for example, water such as purified water and distilled water, higher alcohol, lower alcohol such as ethanol and propylene glycol, thickener such as hydroxyethyl cellulose and carboxyvinyl polymer, etc. Can be prepared using
　本発明において、剤形が貼付剤やテープ剤等である場合には、例えば、アクリル系、シリコン系、ゴム系等の粘着剤（添加物として粘着付与樹脂、架橋剤、可塑剤、界面活性剤、酸化防止剤等を含んでもよい）及び不織布、フィルム、シートな等の支持体を使用し、調製できる。 In the present invention, in the case where the dosage form is a patch, a tape or the like, for example, acrylic, silicone, rubber, etc. pressure-sensitive adhesives (as an additive, tackifying resin, crosslinking agent, plasticizer, surfactant) , And may contain an antioxidant, etc. and supports such as non-woven fabric, film, sheet and the like.
　本発明の末梢毛細血管の血流量増加剤の製剤は、その剤形に関わらず、必要に応じて、化粧料や医薬品の添加剤として使用可能な添加剤を適宜配合することができ、例えば、防腐剤、吸収促進剤、増粘剤、安定化剤、界面活性化剤、緩衝化剤、等張化剤、ｐＨ調製剤等を適量配合することができる。また、本発明の製剤には、化粧料や医薬品に添加することができる有効成分を適量配合することができる。 The preparation of the peripheral capillary blood flow-increasing agent of the present invention can be appropriately blended with additives usable as additives for cosmetics and medicines, as needed, regardless of its dosage form, for example, Preservatives, absorption accelerators, thickeners, stabilizers, surfactants, buffering agents, tonicity agents, pH adjusters and the like can be blended in appropriate amounts. In addition, an appropriate amount of an active ingredient that can be added to cosmetics or medicines can be blended in the preparation of the present invention.
　本発明において、α１受容体遮断薬の１回の投与量は、その投与形態及び投与剤形によって異なるが、例えば、軟膏剤、クリーム剤等の場合、０．０００５～２５ｍｇ、好ましくは０．００２５～２０ｍｇ、より好ましくは０．００５～１５ｍｇ、さらに好ましくは０．０２５～１０ｍｇ、特に好ましくは０．０５～５ｍｇである。また、例えば、貼付剤等の場合、０．００５～１０ｍｇ、より好ましくは０．１～３ｍｇである。 In the present invention, the single dose of the α1 receptor blocker varies depending on the administration form and dosage form, but, for example, 0.0005 to 25 mg, preferably 0.0025 for ointments, creams, etc. The amount is preferably 20 to 20 mg, more preferably 0.005 to 15 mg, still more preferably 0.025 to 10 mg, and particularly preferably 0.05 to 5 mg. Also, for example, in the case of a patch etc., it is 0.005 to 10 mg, more preferably 0.1 to 3 mg.
　本発明において、α１受容体遮断薬の濃度は、その投与形態及び投与剤形によって異なるが、例えば、軟膏剤、クリーム剤等の場合、０．００１～５０％（ｗ／ｗ）、好ましくは０．００５～４０％（ｗ／ｗ）、より好ましくは０．０１～３０％（ｗ／ｗ）、さらに好ましくは０．０５～２０％（ｗ／ｗ）、特に好ましくは０．１～１０％（ｗ／ｗ）である。なお、「％（ｗ／ｗ）」は、本発明の血流量増加剤１００ｇ中に含まれる対象成分（α１受容体遮断薬）の質量（ｇ）を意味する。以下、特に断りがない限り同様とする。 In the present invention, the concentration of the α1 receptor blocker varies depending on the administration form and administration form, but it is, for example, 0.001 to 50% (w / w), preferably 0 in the case of ointment, cream etc. .005 to 40% (w / w), more preferably 0.01 to 30% (w / w), still more preferably 0.05 to 20% (w / w), particularly preferably 0.1 to 10% (W / w). In addition, "% (w / w)" means the mass (g) of the object component (alpha 1 receptor blocker) contained in 100 g of blood flow rate increasing agents of this invention. Hereinafter, the same applies unless otherwise noted.
　本発明において、「眼の近傍」とは、眼瞼及びその近傍であり、眼瞼皮膚及びその近傍の皮膚も含まれる。 In the present invention, "in the vicinity of the eye" refers to the eyelid and its vicinity, and includes the eyelid skin and the skin in the vicinity thereof.
　本発明の末梢毛細血管の血流量増加剤は、血行障害改善剤として、眼の近傍に投与することによって、眼の近傍の血行障害の改善に使用することができる。眼の近傍に生じる血行障害とは、例えば眼精疲労や眼の下にできるクマ等であり、眼の下にできるクマには、例えば青クマ、茶クマ、黒クマ等が挙げられる。本発明の末梢毛細血管の血流量増加剤は、青クマ処置剤として、特に青クマの予防、治療または改善に使用することができる。本発明において、青クマの治療、改善、処置には、青クマの症状の緩和、青クマが薄まること、青クマが消失すること等も含まれる。 The agent for improving blood flow in peripheral capillaries of the present invention can be used as an agent for improving blood flow disorders, to improve blood flow disorders in the vicinity of the eye by administering it in the vicinity of the eye. The circulatory disorder occurring in the vicinity of the eye is, for example, eye fatigue, a bear formed under the eye, and the like, and the bear formed under the eye includes, for example, a blue bear, a tea bear, a black bear, and the like. The agent for increasing blood flow in peripheral capillaries of the present invention can be used as a treatment for treating a blue bear, in particular for the prevention, treatment or amelioration of a blue bear. In the present invention, treatment, improvement and treatment of blue bear include alleviation of symptoms of blue bear, thinning of blue bear, disappearance of blue bear and the like.
　本発明の末梢毛細血管の血流量増加剤は、皮膚の薄い眼の近傍に投与することによって、投与部位の末梢毛細血管の血流量が速やかに増加して血行障害を改善し、投与後短時間で効果が消失する。また、本発明の末梢毛細血管の血流量増加剤は、皮膚の薄い部分に局所投与することによって薬物の投与量を少なくすることができ、また末梢毛細血管を拡張して血流量を増加させるものの、主血管の血流量にはあまり変化を与えず、さらに末梢毛細血管拡張作用も短時間で効果が消失するために、血管拡張作用による急激な血圧降下等の副作用も起きにくく、安全に使用することができる。なお、前記の短時間とは、投与量や投与部位によっても異なるが、例えば、８時間以下であり、６時間以下、５時間以下、４時間以下、３時間以下、２時間以下、１時間以下であってもよい。本発明において、末梢毛細血管とは、例えば直径が１０μｍ以下の血管であり、主血管とは末梢毛細血管よりも太い血管を指す。 The agent for increasing blood flow of peripheral capillaries according to the present invention, when administered in the vicinity of a thin eye of the skin, rapidly increases the blood flow of peripheral capillaries at the administration site to improve the circulatory disorder, and a short time after administration The effect disappears. In addition, the agent for increasing blood flow in peripheral capillaries according to the present invention can reduce the dose of the drug by topical administration to a thin part of the skin, and can also expand peripheral capillaries to increase blood flow. Because the blood flow in the main blood vessel does not change much, and the effect of peripheral capillary dilation also disappears in a short time, side effects such as rapid blood pressure drop due to vasodilation are less likely to occur and it is used safely be able to. In addition, although said short time changes with dosages or an administration site, it is 8 hours or less, for example, 6 hours or less, 5 hours or less, 4 hours or less, 3 hours or less, 3 hours or less, 2 hours or less, 1 hour or less It may be In the present invention, the peripheral capillary is, for example, a blood vessel having a diameter of 10 μm or less, and the main blood vessel is a blood vessel thicker than the peripheral capillary.
　本発明の末梢毛細血管の血流量増加剤は、皮膚の薄い眼の近傍に投与することによって、薬物は接触した表皮中に速やかに分布、拡散、浸透することができる。皮膚の構造は、表皮、真皮、皮下組織の３層構造を成しており、顔の中でも眼の近傍の皮膚は最も薄く、表皮は０．１ｍｍ程度、真皮は０．５ｍｍ程度とされている。 The agent for increasing blood flow of peripheral capillaries of the present invention can be rapidly distributed, diffused and penetrated into the contacted epidermis by administering it in the vicinity of the thin eye of the skin. The structure of the skin is a three-layer structure consisting of the epidermis, the dermis and the subcutaneous tissue, and the skin in the vicinity of the eyes is the thinnest in the face, the epidermis is about 0.1 mm, and the dermis is about 0.5 mm .
　本発明の末梢毛細血管の血流量増加剤の投与は、特に皮膚上投与又は経皮投与が好ましい。 The administration of the peripheral capillary blood flow-increasing agent of the present invention is particularly preferably on the skin or percutaneously.
　本発明の末梢毛細血管の血流量増加剤の投与方法及び投与回数は、剤形、投与すべき症状の軽重、年齢、体重、医師の判断等に応じて適宜変えることができる。例えば、軟膏剤クリーム剤等の場合は、１日１回～１０回、好ましくは１日１回～６回、より好ましくは１日１回～３回を眼の近傍に塗布することができ、貼付剤等の場合は、１日１回～２回を眼の近傍に貼付することができる。 The administration method and frequency of administration of the peripheral capillary blood flow increase agent of the present invention can be appropriately changed according to the dosage form, the severity of the condition to be administered, the age, the body weight, the judgment of the doctor, and the like. For example, in the case of an ointment cream, etc., it can be applied to the vicinity of the eye once to ten times a day, preferably once to six times a day, more preferably once to three times a day In the case of a patch or the like, it can be applied to the vicinity of the eye once to twice a day.
　上記の本発明の末梢毛細血管の血流量増加剤の詳細な説明は、本発明の以下に示す態様にも適用される。 The above detailed description of the peripheral capillary blood flow increaser of the present invention also applies to the following aspects of the present invention.
　本発明の一態様は、α１受容体遮断薬を有効成分として含有する、末梢毛細血管の血流量増加用組成物である。 One aspect of the present invention is a composition for increasing blood flow in peripheral capillaries, which comprises an α1 receptor blocker as an active ingredient.
　本発明の一態様は、α１受容体遮断薬を有効成分として含有する、青クマ処置用組成物である。 One aspect of the present invention is a composition for treating blue bear, which comprises an α1 receptor blocker as an active ingredient.
　本発明の一態様は、α１受容体遮断薬を、それを必要とする対象に有効量投与することを含む、末梢毛細血管の血流量増加方法である。 One aspect of the invention is a method of increasing blood flow in peripheral capillaries comprising administering an effective amount of an alpha 1 receptor blocker to a subject in need thereof.
　本発明の一態様は、α１受容体遮断薬を、それを必要とする対象に有効量投与することを含む、青クマを処置する方法である。 One aspect of the invention is a method of treating a blue bear comprising administering an effective amount of an alpha 1 receptor blocker to a subject in need thereof.
　本発明の一態様は、末梢毛細血管の血流量を増加させるための医薬の製造のための、α１受容体遮断薬の使用である。 One aspect of the invention is the use of an alpha 1 receptor blocker for the manufacture of a medicament for increasing blood flow in peripheral capillaries.
　本発明の一態様は、青クマを処置するための医薬の製造のための、α１受容体遮断薬の使用である。 One aspect of the present invention is the use of an alpha 1 receptor blocker for the manufacture of a medicament for treating a blue bear.
　本発明の一態様は、末梢毛細血管の血流量の増加に使用するための、α１受容体遮断薬である。 One aspect of the invention is an alpha 1 receptor blocker for use in increasing blood flow in peripheral capillaries.
　本発明の一態様は、青クマの処置に使用するための、α１受容体遮断薬である。 One aspect of the invention is an alpha 1 receptor blocker for use in the treatment of blue bears.
　以下に、製剤例および血流量測定試験の結果を示すが、これらは本発明をより良く理解するためのものであり、本発明の範囲を限定するものではない。 The following shows formulation examples and results of blood flow measurement tests, but these are for the purpose of better understanding the present invention and do not limit the scope of the present invention.
製剤例
　以下に本発明の代表的な製剤例を示す。なお、下記製剤例において各成分の配合量は製剤１０ｇ中の含量である。 Formulation Examples Representative formulation examples of the present invention are shown below. In addition, the compounding quantity of each component in the following formulation example is a content in 10 g of formulation.
製剤例１
　ブナゾシン塩酸塩　　　　　　　１５０ｍｇ
　ヒドロキシエチルセルロース　　　８０ｍｇ
　希塩酸／水酸化ナトリウム　　　　　　適量
　水　　　　　　　　　　　　　　　　　適量
　ｐＨ　　　　　　　　　　　　　　　４．０ Formulation example 1
Bunazosin hydrochloride 150 mg
Hydroxyethyl cellulose 80 mg
Diluted hydrochloric acid / sodium hydroxide appropriate amount water appropriate amount pH 4.0
製剤例２
　ブナゾシン塩酸塩　　　　　　　１００ｍｇ
　白色ワセリン　　　　　　　　　　　　適量
　流動パラフィン　　　　　　　　　　　適量 Formulation example 2
Bunazosin hydrochloride 100 mg
White petrolatum suitable amount Liquid paraffin suitable amount
製剤例３
　ブナゾシン塩酸塩　　　　　　　３００ｍｇ
　カルボキシビニルポリマー　　　１００ｍｇ
　ミツロウ　　　　　　　　　　　５００ｍｇ
　流動パラフィン　　　　　　　　　　　１ｇ
　白色ワセリン　　　　　　　　　　　　適量
　希塩酸／水酸化ナトリウム　　　　　　適量
　水　　　　　　　　　　　　　　　　　適量
　ｐＨ　　　　　　　　　　　　　　　４．０ Formulation example 3
Bunazosin hydrochloride 300 mg
Carboxy vinyl polymer 100 mg
Bee wax 500 mg
Liquid paraffin 1g
White vaseline qs dilute hydrochloric acid / sodium hydroxide qs water qs pH 4.0
血流量測定試験
（１）被験製剤の調製
　注射用水にヒドロキシエチルセルロースを０．８％（ｗ／ｖ）となるように加えて、１２１℃、２０分間オートクレーブしたものを、０．８％ヒドロキシエチルセルロース溶液とした。０．８％ヒドロキシエチルセルロース溶液９ｇに、ブナゾシン塩酸塩１５０ｍｇを加え、ｐＨ調整剤（希塩酸および／または水酸化ナトリウム）を加えてｐＨ４．０とし、撹拌、溶解させたのち、０．８％ヒドロキシエチルセルロース溶液を加えて全量を１０ｇとして、実施例１の製剤を調製した。なお、「％（ｗ／ｖ）」は、溶液１００ｍＬ中に含まれる対象成分（ここでは、ヒドロキシエチルセルロース）の質量（ｇ）を意味する。 Blood flow measurement test (1) Preparation of test preparation Hydroxyethylcellulose was added to water for injection to 0.8% (w / v) and autoclaved at 121 ° C. for 20 minutes, 0.8% hydroxyethylcellulose solution And 150 mg of benzazocine hydrochloride is added to 9 g of 0.8% hydroxyethyl cellulose solution, and a pH adjuster (diluted hydrochloric acid and / or sodium hydroxide) is added to adjust to pH 4.0, and after being dissolved by stirring, 0.8% hydroxyethyl cellulose The formulation of Example 1 was prepared by adding the solution to a total weight of 10 g. In addition, "% (w / v)" means the mass (g) of the object component (here, hydroxyethyl cellulose) contained in 100 mL of solutions.
実施例１
　ブナゾシン塩酸塩　　　　　　　　　　１５０ｍｇ
　０．８％ヒドロキシエチルセルロース　　　　適量
　希塩酸／水酸化ナトリウム　　　　　　　　　適量
　ｐＨ　　　　　　　　　　　　　　　　　　４．０ Example 1
Bunazosin hydrochloride 150 mg
0.8% hydroxyethyl cellulose qs Diluted hydrochloric acid / sodium hydroxide qs pH 4.0
　ブナゾシン塩酸塩を加えず調製した以外は実施例１の調製方法と同様の方法にて、比較例１の製剤を調製した。なお、参考として日本で上市されている「ヒルドイド（登録商標）クリーム０．３％」を比較例２とした。 The preparation of Comparative Example 1 was prepared in the same manner as the preparation method of Example 1, except that bunazosin hydrochloride was not added. In addition, "Hildoid (registered trademark) cream 0.3%" marketed in Japan as a reference is referred to as Comparative Example 2.
比較例１（α１受容体遮断薬を含まない）
　０．８％ヒドロキシエチルセルロース　　　　適量
　希塩酸／水酸化ナトリウム　　　　　　　　　適量
　ｐＨ　　　　　　　　　　　　　　　　　　４．０ Comparative Example 1 (not including α1 receptor blocker)
0.8% hydroxyethyl cellulose qs Diluted hydrochloric acid / sodium hydroxide qs pH 4.0
（２）試験方法
　ウサギの耳介部は皮膚が薄いことから、体重３．０～４．０ｋｇの雄ウサギ（Ｋｂｓ：ＪＷ、１群８羽）を実験に使用して、ウサギ耳介部の血流量測定を以下の方法で実施した。ウサギを保定器で保定し、ウサギが落ち着いた時点でまず右耳介部皮下の主血管及び毛細血管の各血流量をレーザー血流計（ＯＭＥＧＡＦＬＯ；オメガウェーブ社製）で３０秒間測定した。次に、被験製剤を右耳介部の皮膚に１ｇ相当量塗布し、塗布後１時間、３時間、６時間の計３ポイントにおける各血流量を同様に３０秒間測定した。 (2) Test method Since the auricle of the rabbit has thin skin, a male rabbit (Kbs: JW, 8 animals per group) with a weight of 3.0 to 4.0 kg is used for the experiment. Blood flow measurement was performed in the following manner. The rabbit was held with a retainer, and when the rabbit settled down, the blood flow of the main blood vessel and capillary blood vessels in the right auricle was first measured for 30 seconds with a laser blood flow meter (OMEGAFLO; manufactured by Omega Wave). Next, a test preparation was applied to the skin of the right auricle portion in an equivalent amount of 1 g, and each blood flow at a total of 3 points of 1 hour, 3 hours and 6 hours after application was similarly measured for 30 seconds.
　血流量は個体差が大きいため、個体ごとに、被験製剤投与前の血流量を基準として以下の式に従って各ポイントにおける血流量変動率（％）を算出し、さらに算出した個体ごとの血流量変動率の平均値を算出した。
　血流量変動率（％）＝１００×［（製剤投与後の血流量）／（製剤投与前の血流量）］ Because blood flow is large individual differences, blood flow volume fluctuation rate (%) at each point is calculated according to the following formula based on blood flow volume before administration of test preparation for each individual, and blood flow volume fluctuation calculated for each individual The average value of the rate was calculated.
Blood flow variation rate (%) = 100 × [(blood flow after administration of preparation) / (blood flow before administration of preparation)]
（３）試験結果及び考察
　末梢毛細血管の血流量変動率の平均値を表１、主血管の血流量変動率の平均値を表２に示す。
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000003
 (3) Test Results and Discussion Table 1 shows the mean values of the blood flow rate variation rates of peripheral capillaries, and Table 2 shows the mean values of the blood flow rate variation rates of the main blood vessels.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000003
　表１、表２に示されるように、実施例１では投与後１時間において毛細血管の血流量を著しく増加させ、その後時間経過と共に血流量が正常化に近づくことが認められた。一方で、主血管の血流量においては血流量の変化を示さなかった。また、α１受容体遮断薬を含まない比較例１では、主血管及び毛細血管の血流量の変化を示さず、比較例２では主血管及び毛細血管のどちらも投与後時間経過と共に血流量が増加する傾向を示した。 As shown in Tables 1 and 2, in Example 1, it was found that the blood flow of capillaries was significantly increased at 1 hour after administration, and the blood flow became closer to normalization with the lapse of time thereafter. On the other hand, no change in blood flow was shown in the blood flow in the main blood vessel. Further, in Comparative Example 1 which does not contain the α1 receptor blocker, no change in the blood flow of the main blood vessel and capillary blood vessels is shown, and in Comparative Example 2, the blood flow increases with time after administration of both the main blood vessels and capillaries. Showed a tendency to
　これにより、α１受容体遮断薬を皮膚に投与することにより、塗布された部位の末梢毛細血管の血流量が塗布後速やかに増加し、血流量の増加作用が短時間で消失する特徴があることが示唆された。以上より、本発明の末梢毛細血管の血流量増加剤は、血行障害改善剤として、眼の近傍に投与することによって、眼の近傍の血行障害の改善に使用できることが期待され、例えば眼精疲労や眼の下にできるクマ等（青クマ等）の処置剤として使用できることが期待される。 Thus, by administering the α1 receptor blocker to the skin, the blood flow of the peripheral capillary blood at the applied site is rapidly increased after application, and the blood flow increase action disappears in a short time. Was suggested. From the above, it is expected that the agent for increasing blood flow of peripheral capillaries according to the present invention can be used for the improvement of blood circulation disorders in the vicinity of the eye by administering it as a blood circulation disorder improving agent in the vicinity of the eyes. It is expected that it can be used as a treatment for bears and the like (blue bears and the like) formed under the eyes and eyes.
　本発明は、α１受容体遮断薬を有効成分として含有する、末梢毛細血管の血流量増加剤を提供する。 The present invention provides an agent for increasing blood flow in peripheral capillaries, which contains an α1 receptor blocker as an active ingredient.

Claims (15)

  1. 　α１受容体遮断薬を有効成分として含有する、末梢毛細血管の血流量増加剤。 An agent for increasing blood flow in peripheral capillaries, which comprises an α1 receptor blocker as an active ingredient.
  2. 　末梢毛細血管が眼の近傍の末梢毛細血管である、請求項１記載の血流量増加剤。 The blood flow increaser according to claim 1, wherein the peripheral capillary is a peripheral capillary near the eye.
  3. 　末梢毛細血管が眼瞼皮膚の末梢毛細血管である、請求項２記載の血流量増加剤。 The blood flow increaser according to claim 2, wherein the peripheral capillary is a peripheral capillary of eyelid skin.
  4. 　血流量増加剤が血行障害改善剤である、請求項１～３のいずれか一項記載の血流量増加剤。 The blood flow increase agent according to any one of claims 1 to 3, wherein the blood flow increase agent is a blood circulation disorder improving agent.
  5. 　血流量増加剤が青クマ処置剤である、請求項１～４のいずれか一項記載の血流量増加剤。 The blood flow increase agent according to any one of claims 1 to 4, wherein the blood flow increase agent is a blue bear treatment agent.
  6. 　眼の近傍へ投与されることを特徴とする、請求項１～５のいずれか一項記載の血流量増加剤。 The agent for increasing blood flow according to any one of claims 1 to 5, which is administered near the eye.
  7. 　眼瞼皮膚へ投与されることを特徴とする、請求項６記載の血流量増加剤。 7. The agent for increasing blood flow according to claim 6, which is administered to eyelid skin.
  8. 　投与経路が皮膚上投与又は経皮投与である、請求項６又は７記載の血流量増加剤。 The blood flow enhancer according to claim 6 or 7, wherein the administration route is on the skin or transdermally.
  9. 　投与剤形が軟膏剤、クリーム剤、ローション剤、ゲル剤、リニメント剤、経皮吸収型製剤、貼付剤、スプレー剤および注射剤よりなる群から選択される、請求項６～８のいずれか一項記載の血流量増加剤。 The dosage form is selected from the group consisting of an ointment, a cream, a lotion, a gel, a liniment, a transdermal preparation, a patch, a spray and an injection. The blood flow increaser according to the item.
  10. 　眼の近傍への投与が眼瞼皮膚への塗布である、請求項６～９のいずれか一項記載の血流量増加剤。 The agent for increasing blood flow according to any one of claims 6 to 9, wherein the administration in the vicinity of the eye is application to eyelid skin.
  11. 　α１受容体遮断薬がブナゾシン又はその塩である、請求項１～１０のいずれか一項記載の血流量増加剤。 The agent for increasing blood flow according to any one of claims 1 to 10, wherein the α1 receptor blocker is bunazosin or a salt thereof.
  12. 　ブナゾシン又はその塩を有効成分として含有し、眼瞼皮膚に投与される、末梢毛細血管の血流量増加剤。 An agent for increasing blood flow of peripheral capillaries, which comprises bunazosin or a salt thereof as an active ingredient and is administered to eyelid skin.
  13. 　α１受容体遮断薬を眼の近傍に投与することによる、眼の近傍の末梢毛細血管の血流量を増加させる方法。 A method of increasing the blood flow of peripheral capillaries in the vicinity of the eye by administering an alpha 1 receptor blocker in the vicinity of the eye.
  14. 　α１受容体遮断薬を有効成分として含有する、青クマ処置剤。 A blue bear treatment agent containing an α1 receptor blocker as an active ingredient.
  15. 　α１受容体遮断薬がブナゾシン又はその塩である、請求項１４に記載の処置剤。 The therapeutic agent according to claim 14, wherein the α1 receptor blocker is bunazosin or a salt thereof.
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