JP2007246428A - Percutaneous absorption type antihypnotic composition containing plant essential oil component as active ingredient, percutaneous absorption type antihypnotic pharmaceutical formulation and method for producing the composition and formulation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a percutaneous absorption type antihypnotic composition having higher safety and containing a plant essential oil as an active ingredient, to provide a pharmaceutical formulation, and to provide methods for producing the composition and formulation. <P>SOLUTION: A sheet-like antihypnotic composition is produced by covering a water-absorptive resin with neroli oil to obtain an essential oil-covered resin, covering the essential oil-covered resin with an essential oil desorption regulator carbon fine particles to obtain carbon-covered particles, mixing with an absorption promotor, a heat conduction preventive and the like, and hot forming the obtained. The percutaneous absorption type antihypnotic pharmaceutical formulation using neroli oil as an active ingredient is produced by using the antihypnotic composition. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  TECHNICAL FIELD The present invention relates to a composition having a sleep-wake action comprising an essential oil component obtained from a plant as an active ingredient, a pharmaceutical preparation for sleep-wake containing the composition, and methods for producing them. More specifically, the present invention relates to a percutaneous absorption-type composition having a sleep-wakefulness action, a percutaneous absorption-type pharmaceutical preparation for sleep-wakefulness containing the composition, and a production method thereof.

  Plant essential oils generally have aromaticity, but they contain many compounds such as terpenes and alcohols. The scent components of plant essential oils combined with such compounds are known to have effects of reducing tension and calming, and have been used for various rituals and treatments since ancient times.

  A large number of plants are used as raw materials for plant essential oils. Among them, Daidai (Citrus aurantium L. subsp. Amara Engel) belonging to the citrus family has long been used as a raw material for fragrances because of its fragrance. In Europe, plant essential oils have long been used for treatment, and since the 1930s, aromatherapy by internal application and application to the skin has been established as one therapy. Essential oils that are also widely used in such aromatherapy It is one of.

  In modern times, the number of patients causing sleep disorders such as insomnia and hypersomnia due to emotional loads such as stress, physical distress such as cough and pain, luxury goods or drugs that exhibit central stimulating effects, and drugs is there. It may take time to go to sleep, the circadian rhythm will go crazy, and there will be a gap between the life rhythm and the sleep time zone, causing sleep-wake rhythm disorder. In recent years, the number of depressed patients is increasing, but it is known that not only the endocrine system functions are confused, but insomnia is often accompanied (see Non-Patent Document 1).

  In other words, sleep disorders are thought to be a result of pathologically rising sleep state (sleep threshold) when humans fall asleep and fall asleep (latency to sleep) or deep sleep (number of awakenings per night and total sleep). Time) is disturbed. And when such a sleep disorder develops, there is often a phenomenon in which awakening in the morning is not good enough to make you sleepless indefinitely, motivation, behavior and concentration decline, and work and study efficiency decrease (non- Patent Document 2).

Treatment of such sleep disorders includes causal therapy and drug therapy, and drug therapy is employed when the causal therapy does not work. In pharmacotherapy, triazolam, a barbituric acid derivative with a short-acting action (blood half-life t _1/2 = about 4 to 6 hours), temazepam, a benzodiazepine, moderate action (t _1/2 = about Benzodiazepines such as nitrazepam, lormetazepam, and temazepam are used for 10-15 hours.

  D-amphetamine, an indirect acting sympathomimetic drug, is used for narcolepsy (sleep attack), which is a type of sleep disorder (hereinafter referred to as Conventional Example 1; see Non-Patent Document 3).

  On the other hand, although all of the above sleeping drugs are oral preparations, the administration of the drug can be interrupted quickly, and in order to reduce the dose compared to oral preparations, the plant essential oil is confined in carbon capsules. There has been proposed a skin absorption preparation (hereinafter referred to as Conventional Example 2; see Patent Document 1).

Pharmacology Atlas (3rd printing), p. 206 Pharmacology Atlas (3rd edition), p. 208 Bunkodo Pharmacology at a glance (1st edition, 5th edition) 19 pages Medical Science International Co., Ltd. JP-A-8-109137

When moderately acting benzodiazepines such as those described above are used for sleep disorders, the blood concentration of the drug is high even after the end of 6-8 hours of night rest, drowsiness, lack of concentration, and rapid response disorder, etc. It is known that a side effect called drunkenness appears. In addition, when a short-acting barbiturate derivative or benzodiazepine is used, although the above drunken effect does not appear, the improvement of insomnia symptoms is insufficient and sleepiness may not disappear the next day.
In such a case, it is necessary to wake up sufficiently by some means.

  Furthermore, even benzodiazepines that are used as highly safe drugs may develop resistance, and may become addicted if used continuously for 2 months or more. It is said that it cannot be applied for more than 4 weeks. For this reason, a means for awakening consciousness is required even when the symptoms are not completely relieved after the applicable period has elapsed.

  In such a case, it is conceivable to use D-amphetamine of Conventional Example 1, but D-amphetamine has a problem of high dependency and high risk of abuse.

  In addition, xanthine derivatives such as caffeine, theophylline, and theobromine may not fully exert their arousal effects when the dose is small, and conversely, if they are too large, they may cause gastric acid secretion to be too strong and cause gastric ulcers. .

  On the other hand, Conventional Example 2 is excellent in that the administration of the drug can be interrupted quickly and the dose can be reduced as compared with the oral preparation. However, in the conventional example 2, since the main purpose is to obtain an antibacterial effect and an anti-inflammatory effect, L-menthol, thymol, hinokitiol, citral and lavender are used in combination. I can't get it.

  Therefore, development of a safer therapeutic drug that does not cause drug resistance and has no side effects is desired, including examination of dosage forms.

  Under the circumstances as described above, the inventors of the present invention have found that when neroli oil is used as a transdermally absorbable preparation, a sleep / wakefulness effect is exhibited even at a very low concentration, and the present invention has been completed. Is.

  That is, this invention is a pharmaceutical composition for percutaneous absorption type sleep / wakefuling which uses neroli oil as an active ingredient. Since this percutaneous absorption type pharmaceutical composition for sleep / wakefulness contains plant-derived essential oil as an active ingredient, side effects that are problematic in conventional sleep / wakefulness pharmaceutical preparations as described above may also occur. And there are no dependency issues.

  From a die die described later, a highly aromatic essential oil (neroli oil) can be obtained by steam-distilling the flowers of the die die. Here, it is preferable that the composition contains carbon-coated particles in which a hydrophilic resin is coated with the neroli oil to form an essential oil-coated resin, and the essential oil-coated resin is coated with fine carbon powder.

  The present invention also includes neroli oil, essential oil adsorbent, free water removal agent, essential oil desorption regulator, exothermic agent, heat conduction inhibitor, absorption promoter, sheet forming base, and pressure bonding. A medicinal preparation for sleep-wakefulness comprising a medical sheet. By using a percutaneous absorption preparation having such a configuration, it is possible to release the neroli oil containing the medicinal component gradually.

  In addition, by adopting such a configuration, it is possible to obtain a sheet-like transdermal absorption-type sleep-wake medicinal composition in which medicinal ingredients are uniformly distributed, and by cutting this into a desired size, It becomes possible to easily produce a pharmaceutical composition containing a medicinal component in an amount corresponding to the physical condition of a patient.

  Here, the essential oil adsorbent is preferably a polyvinyl alcohol-based hydrophilic resin having a saponification value of 98.0 to 98.5, and the free moisture removing agent is preferably an acrylic hydrophilic resin. . The acrylic water-absorbing resin preferably has a water absorption capacity in the range of 400 to 800 times the dry resin volume.

Further, the essential oil desorption regulator is preferably a porous carbon material having a surface area of 200 to 800 m ² / g, and the exothermic agent is preferably an artificial zeolite having a pore size of 0.1 to 0.8 nm. . Moreover, it is preferable that the said heat conduction inhibitor is a polysaccharide compound.

  Furthermore, the absorption accelerator is preferably a monoterpene compound, and the monoterpene compound is preferably L-menthol or limonene. In addition, the sheet-forming base is preferably a thermoplastic resin having a saponification value of about 88.0.

  The present invention also includes an essential oil film forming step in which a predetermined amount of neroli oil is weighed and mixed with an essential oil adsorbent to form a surface film on the surface of the essential oil adsorbent with the neroli oil; A carbon-coated particle forming step of adding carbonaceous material to cover the surface of the essential oil film to form carbon-coated particles; a predetermined amount of carbon-coated particles, a heat generating agent, and a heat conduction inhibitor are uniformly mixed to form a sheet A step of forming a pharmaceutical composition for sleep / wakefulness by forming a layer of uniform thickness on the base for formation and heating to form a pharmaceutical composition for sleep / wakefulness; And a thermocompression bonding step in which the four sides of the sheet material are thermocompression-bonded. Is the method.

  Also, by using this method, a pharmaceutical preparation containing a sheet-shaped percutaneously absorbable sleep-wake medicinal composition having a desired size and containing a desired amount of a medicinal component can be obtained.

  Furthermore, by using this method, the neroli oil adsorbed on the surface of the essential oil adsorbent to form a surface film is covered with carbon particles, and these carbon-coated particles are further covered with a sheet-like material. By adopting such a configuration, it is possible to produce a transdermally absorbable preparation in which the neroli oil containing the medicinal component is not in direct contact with the skin and the neroli oil is continuously released over a long period of time. .

  This percutaneously absorbable sleep / wake drug formulation does not cause tolerance and does not become addictive as in the case of the xanthine derivatives and D-amphetamine as conventionally used. Furthermore, there is also an advantage that administration can be easily stopped by removing from the application site.

  As described above, the percutaneously absorbable sleep-wake medicinal preparation of the present invention has high safety and can be used without manifesting addiction and other special side effects. Moreover, there exists an advantage that an application site | part is also wide.

  In addition, according to the method for producing a percutaneous absorption type sleep / wakefulness pharmaceutical composition of the present invention, a percutaneous absorption type pharmaceutical composition for sleep / wakefulness can be easily produced. In particular, by using an essential oil desorbing agent as the carbon-coated particles, a sustained release effect is high.

  The percutaneously absorbable sleep / wakefulness pharmaceutical composition produced by the production method of the present invention is cut into a suitable size, and the percutaneous absorbable sleep / wakefulness pharmaceutical formulation is administered to each patient to be administered. Can be manufactured.

  Furthermore, according to the method for producing a percutaneously absorbable sleep / wakefulness pharmaceutical composition of the present invention, a percutaneous absorbable sleep / wakefulness drug containing a desired amount of a medicinal component by changing the content of carbon-coated particles. A composition can be produced, and a pharmaceutical composition for percutaneous absorption type sleep / wakefulness containing a desired amount of a medicinal ingredient can be produced using the thus produced pharmaceutical composition.

The present invention is described in further detail below.
The neroli oil used in the present invention can be obtained by steam distillation of Daidai (Citrus aurantiam L. subsp. Amara Engel) flowers mainly produced in France, Italy, Spain, Morocco and Algeria. The oil yield from Daidai flowers is about 0.1%. In addition, orange concrete can be obtained by solvent extraction, and when this is treated with alcohol, about 50% absolute is obtained. Ingredients include about 35 to 40% of 1-linalool and linalyl acetate combined, α-terpineol, geraniol, geranyl acetate, nerolidol (several percent), other terpenes such as α-pinene, dipentene, camphene, ocimene, And nitrogen-containing compounds such as methyl anthranilate and indole. In concrete, there are essential oils, jasmon, benzaldehyde, and the like.

  The neroli oil used in the present invention is composed of l-linalool and linalyl acetate (total of about 35 to 40%), α-terpineol, geraniol, geranyl acetate and nerolidol (several percent each), α-pinene, dipentene, camphene, osymene. And other terpenes, methyl anthranilate, indole and other nitrogen-containing compounds.

  As said neroli oil, what is marketed from fragrance | flavor manufacturers, such as Ogawa fragrance | flavor, can also be used.

  For comparison with the sleep-wake medicinal pharmaceutical preparation of the present invention, transdermal absorption preparations using lemon oil, orange oil, rosemary oil, and cineole eucalyptus oil were prepared.

  Lemon oil is obtained by pressing the skin of lemon (Citrus limone (L.)), which is mainly produced in California, Sicily, Calabria, Spain, and Brazil, and is also cultivated in Japan. The oil yield is 0.2 to 0.3% based on the weight of the fruit. Components include d-limonene, citral, octyl aldehyde, nonyl aldehyde, linalool, geraniol, and various other terpenoids.

  Orange oil squeezes the fruit of sweet orange (Citrus sinensis Osbeck var. Brasiliensis Tanaka) that is widely cultivated in various parts of the world such as California, Florida, Spain, Brazil, Italy, and Japan, and separates fruit juice from essential oil. Can be obtained. It can also be obtained by pressing the pericarp. The oil yield is 0.1 to 0.25% based on the fruit weight. As components, d-limonene, citral, n-decylaldehyde, d-linalool, d-terpineol, n-nonyl alcohol, and the like are included, and d-limonene accounts for 90% or more.

Cineol-based eucalyptus oil is native to Tasmania and can be obtained by steam distillation of leaves of cineole-based eucalyptus (Eucalyptus globulus Labill.), Which is mainly produced in North America, Mexico, Africa, southern Spain and the like. The oil yield is 0.75 to 1.25%. Ingredients include cineol (70-80%), α-pinene, camphene, pinocarbeveol, pinocarvone, myrtenol, berbenone, carvone, eudesmol, and C ₄ -C ₆ aliphatic aldehydes.

  Rosemary oil is obtained by steam distillation of flowers, leaves or whole plants of Mannen wax (Rosmarinus officinalis L.) originating from Spain, Yugoslavia, Tunisia, France, Italy and the like. The oil yield is 0.4 to 0.8%. Ingredients include borneol, bornyl acetate, camphor, cineol, and other terpene compounds.

  Essential oils such as lemon oil, orange oil, cineole eucalyptus oil, and rosemary oil described above may be those commercially available from fragrance manufacturers including Ogawa Fragrance Co., Ltd.

  l-Menthol (5-methyl-2- (1-methylethyl) cyclohexanol) is usually referred to as menthol. Chemically, there are 12 isomers, but those that have a cool flavor peculiar to mint are natural and synthetic l-menthol. l-Menthol is a colorless columnar or needle-like crystal that is soluble in ethanol but hardly soluble in water. It gradually sublimes at room temperature.

  In order to obtain a natural product, mint oil is cooled, and the precipitated crystals are centrifuged to obtain mint brain. The synthetic product can be obtained by hydrogenating d-citronellal obtained by fractionating citronella oil into l-isopulegol. In addition, using myrcene obtained from pinene as a raw material, specially producing a citronellal with optical activity by a catalyst, a method of asymmetric synthesis of menthol without optical resolution, and a menthol mixture obtained by hydrogenating thymol, It can also be obtained by optical resolution.

  Limonene (p-menta-1,8-diene) is a monoterpene derived from menthane and has a lemon-like aroma. d-Limonene can be obtained by steam distillation of fruit skins such as Daidai, Lemon and Orange. l-limonene can be obtained by fractionating mint oil, and dl-limonene can be obtained by fractionating camphor oil.

  The essential oil adsorbent used in the percutaneously absorbable sleep / wakefulness pharmaceutical composition of the present invention refers to an adsorbent for the above-described neroli oil, and is a polyvinyl alcohol having a saponification value of 98.0 to 98.5 ( PVA) based hydrophilic resin is preferable. If the saponification value is less than 98.0, the surface of the carrier is gelled and loses the function as an adsorption carrier. If the saponification value is 98.0 to 98.5, the function as a stable adsorption carrier without gelation. Can be maintained.

  Specific examples include Shin-Etsu Poval C-17GP and Poval (A) (manufactured by Shin-Etsu Chemical Co., Ltd.). Shin-Etsu Poval C-17GP or Poval (A) is preferably used.

  The free water removing agent used in the percutaneous absorption-type sleep / wakefulness pharmaceutical composition of the present invention refers to one that removes the water present on the skin surface of the applied site, and is preferably an acrylic hydrophilic resin. . Many of these acrylic hydrophilic resins have a high water absorption ability, and also have good adhesiveness when heated during the production of the composition described below.

  Such an acrylic water-absorbing resin only needs to be capable of sufficiently absorbing moisture generated on the skin surface of the application site while the preparation is applied to the application site, and the water absorption capacity is 400 to 800 of the dry resin volume. Those that are doubled are preferred. If it is less than 400 times, it may not be able to absorb the water, and the water absorption capacity exceeding 800 times is not necessary. Specific examples include Sun Fresh (Sanyo Chemical Industries, Ltd.) and Aqua Keep (registered trademark, manufactured by Sumitomo Seika Co., Ltd.). It is preferable to use sunfresh because crushed sunfresh has better adhesiveness than aqua keep, which is a spherical particle.

The essential oil desorption regulator used in the pharmaceutical composition for percutaneous absorption type sleep / wakefulness of the present invention covers the surface of the essential oil adsorbent having a film formed on the surface by adsorbing each essential oil described above, and the adsorbed essential oil A porous carbon material that controls the desorption of the composition. Specific examples include various activated carbons that adsorb various molecules. Use of activated carbon having a surface area of 200 to 1,000 m ² / g is preferred because the amount of essential oil adsorbed on the activated carbon is reduced and is easily desorbed, and more preferably 400 to 800 m ² / g.

  As long as the activated carbon has a surface area in this range, various commercially available products can be used. Specific examples thereof include Shirasagi P (Takeda Pharmaceutical Co., Ltd.). From the viewpoint of a small adsorption area and cost, it is preferable to use white cocoon P.

  The exothermic agent used in the pharmaceutical composition for percutaneous absorption type sleep / wakefulness of the present invention refers to a substance that adsorbs moisture in the air and generates heat of adsorption. The essential oil composition adsorbed on the adsorption carrier is desorbed using the thermal energy generated at this time. Specifically, a zeolite can be mentioned.

  As such a zeolite, it is preferable to use an artificial zeolite containing no metal and having a pore diameter of 0.1 to 0.8 nm in order to supply energy for desorption ability of the essential oil, and 0.3 to 0 It is more preferable to use one having a thickness of 4 nm. Commercially available products can be used as long as the zeolite has such a pore size, and specific examples include Zeolum (Tosoh Corporation).

  The heat conduction inhibitor used in the pharmaceutical composition for percutaneous absorption type sleep / wakefulness of the present invention can prevent conduction of heat generated suddenly by the free water adsorbed on the free water adsorbent. Refers to a compound. Specific examples include chitosan, cellulose and other polysaccharide compounds.

  When chitosan is used, there is an advantage that chitosan can be used as a carrier of such a dye when the preparation contains a dye. In place of chitosan, cellulose or the like can be used to prevent heat conduction as described above.

  The absorption enhancer used in the percutaneous absorption-type sleep / wakefulness pharmaceutical composition of the present invention refers to a monoterpene compound that acts to promote the absorption of essential oil in the preparation. Specific examples include L-menthol, and commercially available products may be used. Among these, when L-menthol is used, there is an advantage that residual free water present on the skin surface is vaporized and removed, and the skin is dried to create an environment in which essential oil is easily absorbed.

  The sheet-forming base used in the percutaneous absorption-type sleep / wakefulness pharmaceutical composition of the present invention refers to a base that forms the above-mentioned sleep / wakefulness pharmaceutical composition into a sheet, and has a saponification value of about A thermoplastic resin of 88.0 is preferred. The pharmaceutical preparation for percutaneous absorption type sleep / wakefulness of the present invention needs to be formed into a sheet by applying heat. At this time, it is preferable to use what can form the sheet | seat which adhere | attaches without closing the clearance gap between resin at the low temperature of about 180 degreeC, without disperse | distributing neroli oil from the carbon covering particle | grains mentioned above more than necessary.

  Specifically, it is preferable to use Gocelan L-0301 (registered trademark, Nippon Synthetic Chemical Co., Ltd.) or the like because of its good adhesiveness at a low temperature of about 180 ° C.

  The pharmaceutical composition for percutaneous absorption type sleep / wakefulness of the present invention comprises the above essential oil, the above essential oil adsorbent, the free water removing agent, the essential oil desorption regulator, the exothermic agent, the heat conduction inhibitor, and the absorption. The accelerator and the sheet-forming base can be mixed and manufactured as follows. Below, a manufacturing method is demonstrated.

  First, each essential oil is weighed in a predetermined amount. Next, each weighed essential oil is mixed with PVA, and a surface film is formed on each surface of the PVA by each essential oil. A predetermined amount of the above-mentioned activated carbon is added to cover the surface of the essential oil film. Therefore, when three types of essential oils are used, three types of carbon-coated particles A to C are formed. The menthol is then weighed.

  These carbon-coated particles and menthol are mixed, and further mixed and stirred with the above-described heat conduction inhibitor, sheet-forming base, and the like to obtain a uniform mixture. Next, this mixture is placed on the pressure-bonding sheet, and another pressure-bonding sheet is placed thereon, and heated to produce a sheet-like pharmaceutical composition for percutaneous absorption sleep / wakefulness of the present invention.

  Next, the mixture is sandwiched between crimping sheets and crimped by applying heat. The pressure bonding is preferably performed at about 160 to 200 ° C, more preferably at about 180 ° C. When thermocompression bonding is performed at a temperature within this range, a gap between the resin as the base for sheet formation remains, so that the essential oil molecules released from the carbon-coated particles pass through the gap from the application site. Skin is absorbed. On the other hand, if bonding is performed at a high temperature of about 230 ° C. or higher, the resin melts and the gaps between the resins are closed, and thus the above essential oil molecules are not released out of the composition.

  As the pressure-bonding sheet, it is preferable to use synthetic fiber (basis weight: 18 to 20 g), and when synthetic paper is used, there is an advantage that the pressure-bonding rate of the carbon-coated particles is good.

  This sheet is sandwiched between, for example, two sheet-like materials such as a nonwoven fabric cut into an appropriate size, and four sides of these sheet-like materials are heat-sealed, and the percutaneously absorbable sleep-wake medicinal preparation 1 of the present invention. Prepare pieces.

The sheet-like material is preferably selected from the group consisting of paper, woven fabric and non-woven fabric, and the essential oil component contained in the transdermal absorption-type sleep / wakefulness pharmaceutical composition is diffused as a gas molecule. Further, it is more preferable that it is a non-woven fabric in that these are easy to permeate through the gaps between the sheet-forming base particles.
As described above, the percutaneous absorption type pharmaceutical composition for sleep / wakefulness and the pharmaceutical preparation for sleep / wakefulness of the present invention can be produced.

  Hereinafter, the present invention will be described in detail according to examples, but the present invention is not limited to these examples.

Example 1
(1) Reagents The following reagents were used for the production of the percutaneous absorption type sleep wakefulness pharmaceutical composition, the percutaneous absorption type sleep wakefulness pharmaceutical preparation, the control preparation, and the placebo of the present invention.
(1-1) Essential oil Neroli oil, L-menthol, lemon oil, orange oil, cineole eucalyptus oil, and rosemary oil were purchased from Ogawa Fragrance Co., Ltd.

(1-2) Others As PVA, Shin-Etsu Poval C-17GP was purchased from Shin-Etsu Chemical Co., Ltd., and Goceran L-3031 was purchased from Nippon Synthetic Chemical Co., Ltd. Sunfresh (registered trademark) was purchased from Sanyo Chemical Industries as an acrylic water-absorbing resin. Shirakaba P as activated carbon was purchased from Takeda Pharmaceutical Co., Ltd., and Zeorum (registered trademark) as zeolite was purchased from Tosoh Corporation. As chitosan, Koyo Chitosan was purchased from Koyo Chemical Co., Ltd.

  Chemical fiber paper was purchased from Nippon Paperboard Daishowa Co., Ltd., and non-woven fabric was purchased from Nisshinbo Co., Ltd.

(Example 2) Manufacture of percutaneous absorption-type sleep-wake pharmaceutical composition and pharmaceutical preparation (2-1) Manufacture of carbon-coated particles Carbon-coated particles were prepared according to the formulation shown in Table 1 below. In the production of the pharmaceutical combination preparation (formulation names: SD-E, SD-F, SD-G, SD-H, and SD-J) of the present invention, each carbon adjusted with the use amount shown in Table 1 was used. It was prepared so that 1.1 g of the coated particles were contained per piece.

  Taking the case of SD-G as an example, neroli oil is weighed in the amount shown in Table 1 above, and mixed with PVA (Shin-Etsu Poval C-17GP) at room temperature in a 500 mL transparent glass sealed container. Were coated with neroli oil to form essential oil-coated particles. Next, activated carbon in the amount shown in Table 1 was added to the container and mixed to form carbon-coated particles. The prepared carbon-coated particles were stored at room temperature in a highly airtight container, for example, a glass container with a lid with a lid.

(2-2) Manufacture of a pharmaceutical composition for percutaneous absorption type anti-sleep / wakefulness The five types of carbon-coated particles prepared in the above (2-1) are mixed with the amount of the base shown in Table 2 to absorb percutaneously. A type anti-sleep awakening composition was produced.

These base components and the above carbon-coated particles were mixed as follows.
First, Sun Fresh (manufactured by Sanyo Chemical Industries), Zeolum (zeolite, manufactured by Tosoh Corporation), L-Menthol (manufactured by Ogawa Fragrance Co., Ltd.), Koyo Chitosan (manufactured by Koyo Chemical Co., Ltd.) in this order And mixed one by one to prepare a base.
Next, the carbon-coated particles 1 to 5 prepared in the above (2-1) are weighed in the amounts shown in Table 2, mixed with the above base, and further mixed with Koyo chitosan, birch P and gooselan shown in Table 2. did. In addition, the loss rate of the essential oil at the time of the thermocompression bonding mentioned later is calculated as 15%.

  Here, the mixture of the above-mentioned base and carbon-coated particles as the main agent was spread on the pressure-bonding sheet so as to have a uniform thickness, and another pressure-bonding sheet was placed thereon. This was thermocompression bonded to obtain a sheet-like pharmaceutical composition for anti-sleep awakening. This sheet-shaped anti-sleep / wakefulness pharmaceutical composition is cut into, for example, an appropriate size, and sandwiched with a sheet-like material such as a non-woven fabric cut into an appropriate size, and the four sides of the sheet-like material are heated. Sealed, and the percutaneous absorption type anti-sleep wake medicinal preparation of the present invention was prepared. Each formulation was named SD-E, SD-F, SD-G, SD-H and SD-J in numerical order.

  The placebo was produced in the same manner as described above except that black fine paper was used instead of the pharmaceutical composition containing the carbon-coated particles.

(Example 3) Evaluation of sleep-wakefulness by each essential oil component-containing percutaneous absorption preparation Evaluation of sleep-wakefulness action by each essential oil component-containing percutaneous absorption preparation was examined using the duration of pentobarbital-induced direct reflex disappearance as an index. did.
(3-1) Test animals etc. As test animals, 5-week-old ICR mice were purchased from Tokyo Experimental Animals. After acclimatization for 1 week, 10 animals per group were used. Pentobarbital was purchased from Dainippon Pharmaceutical Co., Ltd.

(3-2) Test method and effect The duration of the direct reflex disappearance (LORR) induced when pentobarbital was administered to mice was measured and evaluated as sleep time.
On the day before the test, the mouse was anesthetized with pentobarbital (70 mg / kg, ip), and the back was shaved to secure the site of application of the test drug produced in Example 2 above.
The test was carried out between 9 o'clock and 15 o'clock in a private room where the room temperature was maintained at 24 ° C.
On the day of the test, each formulation was affixed, and 3 hours later, pentobarbital (50 mg / kg, iv) was administered to the mouse, and the mouse in which the normal reflex disappeared was placed on its back on a V-shaped platform.
The evaluation of the specular reflex was that the specular reflex was restored when the mouse woke up three times within 30 seconds on the V-shaped platform. After anesthesia of the mouse, the time from the disappearance of the direct reflex to the recovery was defined as the duration of the disappearance of the direct reflex.

  SD-E, SD-F, SD-G, SD-H, SD-JK, and placebo shown in the above-mentioned table were applied to the shaved back of the mouse, and the effect of disappearing the direct reflex was examined. The placebo was produced in the same manner as the above preparation, except that black fine paper was used instead of each of the above essential oil-containing compositions.

  The results of pasting each of the above preparations and placebo are shown in FIG. As shown in FIG. 1, a significant sleep prolongation effect was observed with SD-B (using neroli oil) (indicated by * in FIG. 1, p <0.05). This showed that neroli oil had a sleep-wake effect.

(3-3) Relationship Between SD-G Dose and Sleep Awakening Effect As shown in the above (3-2), in the preparation using neroli oil, a significant sleep awakening action was observed. For this reason, the amount of neroli oil used was changed to 1/2, equal, and double, respectively, and the relationship with sleep prolongation was examined. Formulations containing these amounts of neroli oil were named SD-G1 / 2, SD-G1 and SD-G2, respectively.

The sizes of the SD-B1 / 2, SD-B1, and SD-B2 sheets were 2 cm × 2 cm, respectively. The amount of neroli oil per piece was 0.55 mg for SD-B1 / 2, 1.1 mg for SD-B1, and 2.2 mg for SD-B2.
For the mouse test, each 2 cm × 2 cm was divided into two equal parts, 0.275 mg, 0.55 mg, and 1.1 mg.

  As in (3-2) above, SD-G1 / 2, SD-G1 and SD-G2 were affixed to the shaved back of a mouse administered with pentobarbital to extend the loss of the right-handed reflex of the mouse. Observed.

  In SD-B1 / 2, no significant prolongation of the direct reflex was observed with respect to the placebo group, but in SD-B1 and SD-B2, there was a significant prolongation of the direct reflex disappearance in a dose-dependent manner. Admitted.

  As described above, the pharmaceutical preparation for sleep / wakefulness of the present invention exhibits a sleep / wakefulness action when the loss of the direct reflex of the mouse is used as an index, and is used for pharmaceuticals such as alleviation of daytime sleepiness including treatment of sleep disorders. Useful in the field.

FIG. 1 is a diagram showing the presence or absence of a sleep prolonging action when a patch containing various essential oils is used.

Claims (15)

  A pharmaceutical composition for percutaneous absorption sleep awakening comprising neroli oil as an active ingredient.   The percutaneous absorption type sleep according to claim 1, comprising carbon-coated particles in which a water-absorbing resin is coated with the neroli oil to form an essential oil-coated resin, and the essential oil-coated resin is coated with fine carbon powder. Awakening pharmaceutical composition.   A neroli oil, an essential oil adsorbent, a free moisture remover, an essential oil desorption regulator, an exothermic agent, a heat conduction inhibitor, an absorption accelerator, a sheet-forming base, and a pressure-bonding sheet. A pharmaceutical composition for skin-absorbing sleep / wakefulness.   The said essential oil adsorbent is a pharmaceutical composition for percutaneous absorption type sleep / wakefulness according to claim 3, wherein the saponification value is a polyvinyl alcohol water-absorbing resin having a saponification value of 98.0 to 98.5.   The percutaneous absorption type medical composition for sleep / wakefulness according to claim 3 or 4, wherein the free water removing agent is an acrylic water-absorbing resin.   6. The percutaneous absorption-type sleep-wake pharmaceutical composition according to claim 5, wherein the acrylic water-absorbing resin has a water absorption capacity in the range of 400 to 800 times the dry resin volume. The said essential oil desorption regulator is a porous carbon substance whose surface area is 200-800 m < ² > / g, The pharmaceutical composition for percutaneous absorption type sleep awakening in any one of Claims 3-6 characterized by the above-mentioned.   The said exothermic agent is a zeolite with a pore diameter of 0.1-0.8 nm, The pharmaceutical composition for percutaneous absorption type sleep awakening in any one of Claims 3-7 characterized by the above-mentioned.   The said thermal conduction inhibitor is a polysaccharide compound, The pharmaceutical composition for percutaneous absorption type sleep awakening according to any one of claims 3 to 8.   The said absorption enhancer is a monoterpene compound, The pharmaceutical composition for percutaneous absorption type sleep awakening in any one of Claims 3-9 characterized by the above-mentioned.   The percutaneous absorption type sleep-wake pharmaceutical composition according to claim 10, wherein the monoterpene compound is L-menthol or limonene.   The percutaneously absorbable sleep-wake medicinal composition according to any one of claims 3 to 11, wherein the sheet-forming base is a thermoplastic resin having a saponification value of about 88.0. .   The pharmaceutical formulation for percutaneous absorption type sleep awakening containing the pharmaceutical composition for percutaneous absorption type sleep awakening in any one of Claims 1-12.   An essential oil film forming step in which neroli oil is weighed and mixed with the essential oil adsorbent to form a surface film on the surface of the essential oil adsorbent with the neroli oil; after the essential oil film is formed, a porous carbon substance is added to the essential oil film A carbon-coated particle forming step of covering the surface of the substrate to form carbon-coated particles; a predetermined amount of carbon-coated particles, a heat generating agent, and a heat conduction inhibitor are uniformly mixed to form a uniform thickness on a sheet-forming substrate A method for producing a pharmaceutical composition for sleep / wakefulness comprising the steps of: forming a pharmaceutical composition for sleep / wakefulness by heating to form a pharmaceutical composition for sleep / wakefulness.   An essential oil film forming step in which a predetermined amount of neroli oil is weighed and mixed with an essential oil adsorbent to form a surface film on the surface of the essential oil adsorbent with the neroli oil; after the essential oil film is formed, a porous carbon substance is added A carbon-coated particle forming step for covering the surface of the essential oil film and forming carbon-coated particles; a predetermined amount of carbon-coated particles, a heat generating agent, and a heat conduction inhibitor are uniformly mixed to form a uniform sheet on a substrate for sheet formation Forming a layer of an appropriate thickness and heating to form a sleep-wake medicinal pharmaceutical composition; and cutting the percutaneously absorbable sleep-wake medicinal composition into a predetermined size; A method for producing a percutaneously absorbable sleep / wakefulness pharmaceutical preparation, comprising: a thermocompression bonding step in which two sheets of material are sandwiched and the four sides of the sheet material are thermocompression bonded.

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