JP2007291071A - Hypnotic pharmaceutical composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new pharmaceutical composition for sleep, ameliorating sleep disorders or improving sleep. <P>SOLUTION: One or more species selected from Ligusticum acutilobum, ginger, Cinnamomi cortex, casey, Cinnamomi petiole, Aurantii nobilis pericarpium, Picea jezoensis var. hondoensis, Scutellaria, Atractylodis lanceae rhizoma and leaves of ginkgo, or extracts of those enhance hypnotic action of an anti-histamine material. The composition containing the components expresses excellent hypnotic effect and is useful as the pharmaceutical composition for sleep, treating sleep disorders and improving sleep. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a novel hypnotic pharmaceutical composition.

There are various patterns of sleep disorders such as insomnia and hypersomnia, circadian rhythm disorders, and sleep-related complications. Among them, insomnia is further classified into sleep disorder, mid-wake awakening, deep sleep disorder, and early morning awakening.
Sleep disorders not only cause personal health problems such as delayed recovery of physical and mental fatigue, decreased immune and defense mechanisms, and onset and worsening of physical and mental illnesses, but also various problems in daily life (concentration difficulty, malaise, reduced motivation) , Displeased, etc.), and the ability of the person cannot be fully demonstrated, and this has a negative impact on work and schoolwork. In addition, if not properly diagnosed and treated, mistakes related to sleepiness will cause social losses due to traffic accidents and occupational accidents.
For medical use that requires a doctor's prescription for the treatment of insomnia, sleeping drugs such as barbiturates, benzodiazepines, and barbital acids are used, and over-the-counter drugs that do not require a doctor's prescription Antihistamines having hypnotic action, especially diphenhydramine hydrochloride, are used and are also available in Japan.
In addition, in order to obtain a drug with enhanced hypnotic action, for example, a combination of Western Chabo clock extract and an antihistamine substance (for example, see Patent Document 1), diphenhydramine hydrochloride, valerian or sansounin It has been attempted to use them together (for example, see Patent Document 2).
However, so far, an antihistamine-like substance and a touki or extract thereof, a show or extract thereof, a cinnamon extract or extract thereof, a cinnamon extract or extract thereof, a heiyo or extract thereof, a chimney or extract thereof, a spruce Also known are hypnotics, sleep disorders, or sleep-improving pharmaceutical compositions containing the extract, the hornon or the extract thereof, the jujube or the extract thereof, or the ginkgo or the extract thereof. Absent.

Japanese Patent No. 2943247 Japanese Patent No. 2969509

  However, there is a problem that Western Chavo clock grass has an action of lowering blood pressure, and is difficult to apply especially to patients with low blood pressure. Moreover, there is a problem that sansounin and valerian have digestive side effects and are difficult to use. Moreover, it is difficult to say that an antihistamine substance alone has a sufficiently high effect as a hypnotic action. In view of such circumstances, the present invention provides a hypnotic pharmaceutical composition with fewer side effects and higher effectiveness.

As a result of intensive studies, the present inventors have found that antihistamines having hypnotic action and originally, Toki, Ryokan, Keihi, Keishi, Keihei, Chimpi, Spruce, Ogon, which have little or no hypnotic action, The present inventors have found that the hypnotic action of an antihistaminic substance can be remarkably enhanced by using one or more selected from the group consisting of Sojutsu and Ginkgo biloba leaves or extracts thereof, thereby completing the present invention.

That is, the present invention relates to the following inventions.
(1) A hypnotic, a sleep disorder improving or a sleep improving pharmaceutical composition comprising an antihistamine and one or more selected from the following group.
Group: Spruce or its extract, Scarlet or its extract, Keihi or its extract, Keishi or its extract, Keihei or its extract, Chimpi or its extract, Spruce or its extract, Ogon or its extract (2) A pharmaceutical composition comprising an antihistamine substance and Toki or an extract thereof.
(3) A pharmaceutical composition comprising an antihistamine substance and Tokyo or an extract thereof.
(4) A pharmaceutical composition comprising an antihistaminic substance and Keihi or an extract thereof.
(5) A pharmaceutical composition comprising an antihistaminic substance and Keishi or an extract thereof.
(6) A pharmaceutical composition comprising an antihistamine substance and Keiyo Hay or an extract thereof.
(7) A pharmaceutical composition comprising an antihistaminic substance and chimpi or an extract thereof.
(8) A pharmaceutical composition comprising an antihistaminic substance and spruce or an extract thereof.
(9) A pharmaceutical composition comprising an antihistamine and ougon or an extract thereof.
(10) A pharmaceutical composition comprising an antihistaminic substance and sojutsu or an extract thereof.
(11) A pharmaceutical composition comprising an antihistamine substance and ginkgo biloba leaves or an extract thereof.
(12) The antihistamine substance is alimemazine or a salt thereof, diphenhydramine or a salt thereof, chlorpheniramine or a salt thereof, doxylamine or a salt thereof, mequitazine or a salt thereof, clemastine or a salt thereof, carbinoxamine or a salt thereof, diphenylpyraline or a salt thereof The pharmaceutical composition according to any one of (1) to (11) above, which is one or more selected from a salt and cromoglycic acid or a salt thereof.
(13) The pharmaceutical composition according to any one of the above (1) to (11), wherein the antihistamine substance is diphenhydramine or a salt thereof.
(14) The pharmaceutical composition according to the above (11) or (13), wherein the diphenhydramine or a salt thereof is diphenhydramine hydrochloride.
(15) The pharmaceutical composition according to any one of (1) to (14) above, wherein the preparation is an oral administration preparation.
(16) The pharmaceutical composition according to any one of the above (1) to (14), wherein the dosage form of the preparation is a powder, a fine granule, a granule, a tablet, a liquid, a troche, or a jelly.
(17) An action enhancer for an antihistamine substance containing one or more selected from the following group.
Group: Spruce or its extract, Scarlet or its extract, Keihi or its extract, Keishi or its extract, Keihei or its extract, Chimpi or its extract, Spruce or its extract, Ogon or its extract , Sojutsu or its extract and Ginkgo biloba or its extract

  As will be apparent from Examples below, one or more selected from the group consisting of an antihistaminic substance and Toki, Syoukyo, Keihi, Keishi, Keihei, Chimpi, Spruce, Ogon, Sowetsu and Ginkgo biloba leaves or extracts thereof A pharmaceutical composition containing two or more kinds showed an excellent hypnotic action.

  Accordingly, a pharmaceutical composition comprising an antihistamine and one or more selected from the group consisting of Toki, Showa, Keihi, Keishi, Keihei, Chimpi, Ogon, Sojutsu and Ginkgo biloba or extracts thereof Is useful for hypnosis, for treating sleep disorders, and for improving sleep.

  The antihistaminic substance according to the present invention suppresses the action of histamine in the central nervous system and has a hypnotic action. Examples of the antihistamine having such an action include diphenhydramine, diphenylpyralin, clemastine, alimemazine, chlorpheniramine, doxylamine, mequitazine, carbinoxamine and cromoglycic acid. These antihistamines may be free bases or free acids as they are, but may be pharmaceutically acceptable salts. Examples of salts of antihistamines include mineral salts such as hydrochloride, sulfate, and nitrate, organic acid salts such as fumarate, methanesulfonate, and laurate, sodium salts, potassium salts, and calcium salts. And alkali metal salts such as magnesium salts, alkaline earth metal salts and the like. These antihistamines are known compounds, and commercially available products may be used, or they can be produced based on known methods. As the antihistaminic substance according to the present invention, diphenhydramine or a salt thereof is preferable. Examples of the salt of diphenhydramine include mineral acid salts such as hydrochloride and sulfate, and organic acid salts such as salicylic acid, tannic acid, and lauryl sulfuric acid. In the present invention, diphenhydramine hydrochloride is preferred.

  Next, the component mix | blended with the antihistamine substance in this invention is demonstrated.

  The present invention relates to the action of an antihistamine substance on one or more selected from the group consisting of Tokyo, Syoukyo, Keihi, Keishi, Keihei Hei, Chimpi, Spruce, Ogon, Sojutsu and Ginkgo biloba or extracts thereof. It is characterized by blending to enhance

  Toki (Toki) is a cerebral family of Toki or Hokaitouki roots that are usually boiled, and is known to have sedation, analgesia, and smooth muscle excitability. Ginger (ginger) is a rhizome of Ginger family ginger, and is known to have a sweating action, a healthy stomach action, and the like. Keihi (cinnamon) is a dried cinnamon bark, and is known to promote intestinal peristalsis, antipyretic, sedation, and the like. Keiyo Hay (Katsura leaf pattern) is an essential oil obtained by steam-distilling bay leaves, and Keishi (Katsura branch) is a dried cinnamon thin branch of 1 cm or less, with both cinnamon hay and Keishi. Used as an analog of Keihi. Chimpi (Chest) is a dried citrus peel, and is known to have a healthy stomach, intestinal regulation, antitussive, antipruritic action, expectorant action, and the like. Spruce (orange peel) is the dried skin of the mandarin family, Daidai, and is used as an analog of chimpanzee. Ougon (yellow goose) is obtained by drying roots of the family Lamiaceae, and is known to have a sedative antihypertensive action, an antipyretic action, a diuretic action, an antibacterial action, an antiviral action, an antifungal action, and the like. Sojutsu (acupuncture) is a dried rhizome of asteraceae of Asteraceae, and is known to have a healthy stomach action, diuretic action, sweating action, sedation action, hypoglycemic action, tonic action, and the like. Ginkgo biloba is a dried ginkgo leaf of Ginkgoaceae, and is known to have an antioxidant action, a blood flow improving action, a blood flow increasing action, a PAF inhibitory action, a tranquilizing action, and the like.

In the present invention, the shape of the leaves of Tokyo, Syougyo, Keihi, Keishi, Keihei, Chimpi, Spruce, Ogon, Sojutsu and Ginkgo can be freely adjusted as necessary. For example, the medicinal part of the plant of the raw material can be dried, or subjected to simple processing and used as it is, or can be cut or crushed into small pieces or small chunks, or pulverized into powder You can also. For example, powdered powders include powdery ground powder, powdered red pepper powder, powdered cinnamon powder, powdered champagne powder, powdered spruce powder, powdered red powder, powdered ginger leaves, and ginkgo leaf powder. These dried products or those cut, crushed or pulverized may be used as they are, and extracts extracted from the leaves of Toki, Syougyo, Keihi, Chimpi, Spruce, Ogon, Sojutsu and Ginkgo are known. May be. An extract is a liquid obtained by adding a suitable leachate to a leaf of Toki, Syoukyo, Keihi, Chimpi, Spruce, Ogon, Sojutsu or Ginkgo biloba, or a liquid obtained by concentrating the leachate, or an essential oil obtained by steam distillation or the like. Specifically, “extract” and “tinc” can be mentioned. For example, “Toki extract” and “Toki tincture” can be cited as “Touki extract”, and “Keihi tincture”, “Keihi extract”, “Keihi oil” and the like can be cited as Extracts from Keihi. As the leaching agent, a suitable one for leaching by a known method may be selected, and is not particularly limited. For example, water, ethanol, alcohol such as methanol, acetone, dichloromethane, chloroform, ethylene glycol, propylene glycol, A solvent such as glycerin or a mixed solvent thereof can be exemplified.
In the pharmaceutical composition of the present invention, one or two selected from the group consisting of an antihistaminic substance and Tokyo, Tokyo, Keihi, Keishi, Keihei, Chimpi, Spruce, Ogon, Sojutsu and Ginkgo biloba leaves or extracts thereof The above blending ratio is not particularly limited, but 1 to 5000 parts by weight of Toki or an extract thereof, preferably 1 to 1000 parts by weight, or 1 Extract is 1 to 5000 parts by weight, preferably 1 to 1000 parts by weight, Keihi or its extract is 1 to 5000 parts by weight, preferably 1 to 1000 parts by weight, Keishi or its extract is 1 to 5000 parts by weight, preferably 1 to 1000 parts by weight, Keiyo Hay or its extract is 1 to 5000 parts by weight, preferably 1-1000 parts by weight. 1 to 3000 parts by weight, preferably 1 to 1000 parts by weight of chimpi or its extract, 1 to 5000 parts by weight of spruce or its extract, preferably 1 to 1000 parts by weight, 1 -1000 parts by weight, Sojitsu or its extract is 1-5000 parts by weight, preferably 1-1000 parts by weight, Ginkgo biloba or its extract is 1-5000 parts by weight, preferably 1-1000 parts by weight.
In administering the pharmaceutical composition of the present invention, the dosage of the pharmaceutical composition may be appropriately determined according to the patient's sex, weight, age, symptoms, administration method, number of administrations, administration timing, and the like. In the pharmaceutical composition of the present invention, the dose of the antihistaminic substance is usually 10 to 300 mg per day for the patient, preferably 25 to 100 mg. When the antihistaminic substance is diphenhydramine hydrochloride The diphenhydramine hydrochloride is more preferably 50 to 75 mg.
Moreover, the dosage of Toki or its extract is usually 100 to 10,000 mg per day, preferably 500 to 5000 mg, and more preferably 1000 to 5000 mg when Toki or its extract is an extract of Toki. The dosage of the pepper or the extract thereof is usually 100 to 10,000 mg per day, preferably 500 to 5000 mg, and when the pepper or the extract thereof is a pepper extract, it is 1500 to 3000 mg. More preferably. The dosage of cinnamon or its extract is usually 100 to 10000 mg per day, preferably 500 to 5000 mg, and more preferably 1000 to 5000 mg when the cinnamon or its extract is an extract of cinnamon. The dosage of Keishi or an extract thereof is usually 100 to 10,000 mg, preferably 500 to 5000 mg, and more preferably 1000 to 5000 mg when Keishi or an extract thereof is an extract of Keishi. The dosage of Keihei or its extract is usually 100 to 10000 mg, preferably 500 to 5000 mg, and more preferably 1000 to 5000 mg when Keiyo or its extract is an extract of Keihei. The dose of chimpi or an extract thereof is usually 100 to 10,000 mg, preferably 500 to 5000 mg, and more preferably 2500 to 5000 mg when the chimpi or extract thereof is an extract of chimpi. The dose of spruce or its extract is usually 100 to 10,000 mg, preferably 500 to 5000 mg, and more preferably 2500 to 5000 mg when the spruce or its extract is an extract of spruce. The dosage of ougon or an extract thereof is usually 100 to 10000 mg, preferably 500 to 6000 mg, and more preferably 3000 to 6000 mg when ougon or an extract thereof is an ougon extract. The dosage of Sojutsu or its extract is usually 100 to 10000 mg, preferably 500 to 5000 mg, and more preferably 2500 to 5000 mg when the Sojutsu or its extract is an extract of Sojutsu. The dosage of ginkgo biloba leaves or their extract is usually 100-10000 mg, preferably 500-5000 mg, and more preferably 100-300 mg when the ginkgo biloba leaves or its extract is an extract of ginkgo biloba. preferable.

  The pharmaceutical composition of the present invention includes one or more selected from the group consisting of Tokyo, Tokyo, Keihi, Keishi, Keihei, Chimpi, Spruce, Ogon, Sojutsu and Ginkgo biloba or an extract thereof, and antihistamine. In addition to the active substance, the following pharmaceutical ingredients may be further blended. Examples of ingredients that can be added include plants such as Western Chabo Clock, Sunsonin, Valerian or Extracts thereof, Aspirin, Aspirin Aluminum, Sazapyrine, Etensamide, Salicylamide, Acetaminophen, Isopropyl Antipyrine and other antipyretic analgesics, bromvalerylurea, Examples include sedatives such as allyl isopropyl acetyl urea, amino acids such as tryptophan, valine, leucine, isoleucine, alanine, arginine, glutamine, lysine, asparagine, glycine, serine, ortinin, etc. It shouldn't be. These pharmaceutical ingredients may be blended with a single ingredient or in combination of two or more.

  The pharmaceutical composition of the present invention can be administered orally or parenterally. The preparations for parenteral administration include injections, plasters, spirits, extracts, suppositories, suspensions, tinctures, ointments, poultices, nasal drops, inhalants, liniments, and lotions. And dosage forms such as aerosols. Examples of the preparation to be administered orally include dosage forms such as tablets, capsules, powders, granules, fine granules, solutions, troches, and jelly. In the present invention, oral preparations are preferred. Of these, tablets, capsules, powders, granules, fine granules, solutions, troches, and jelly preparations that can be administered orally are preferred.

  Formulation can be performed by known formulation techniques, and appropriate formulation additives can be added to the formulation. What is necessary is just to add a formulation additive suitably in the range which does not impair the effect of this invention. Formulation additives include, for example, excipients, bases, disintegrants, binders, lubricants, coating agents, fluidizers, plasticizers, surfactants, enablers, buffers, solubilizers, dissolution agents Adjuvants, solvents, stabilizers, emulsifiers, suspending agents, dispersants, antioxidants, fillers, thickeners, thickeners, pH regulators, preservatives, preservatives, sweeteners, flavoring agents, Examples thereof include a refreshing agent, a flavoring agent / fragrance, a fragrance, and a coloring agent. These formulation additives may be used alone or in combination of two or more.

  The pharmaceutical composition of the present invention may be produced as a single preparation containing a plurality of components according to the present invention and administered (taken), or each component according to the present invention may be divided into different preparations. The kit preparation may be such that these preparations can be simultaneously or sequentially administered (taken).

  The pharmaceutical composition of the present invention is preferably used for treatment of sleep disorders, hypnosis, and sleep improvement. Indications include temporary relief of symptoms of insomnia (bad sleep, light sleep, etc.), insomnia, neurosis and the like.

  Hereinafter, the present invention will be described with reference to examples. However, the present invention should not be limited to these examples.

1. For the test method test, 5 weeks old mice were used, and one group consisted of 6 mice. The samples shown in Table 1 were orally administered, and 30 mg after administration, 60 mg / kg of hexobarbital (administration liquid amount: 10 mL / kg) was intraperitoneally administered. The time (sleeping time) from the disappearance of the normal reflection of the mouse to the reappearance was measured with a stopwatch. A control was orally administered with a 0.5% methylcellulose solution containing no drug. The results are shown in Table 1.

Values indicate mean ± standard deviation.
Significant with the control group by Student's t-test or Aspin-Welch's t-test (* p <0.05, ** p <0.01).
Significant (#p <0.05, ## p <0.01) with the diphenhydramine hydrochloride alone group by Student's t-test or Aspin-Welch's t-test.

2. Test results As is clear from Table 1, diphenhydramine hydrochloride + toki group of Examples 1 to 7, diphenhydramine hydrochloride + show group, diphenhydramine hydrochloride + caihi group, diphenhydramine hydrochloride + chimpi group, diphenhydramine hydrochloride + ougon group, diphenhydramine hydrochloride + In the Sojutsu group and the diphenhydramine hydrochloride + ginkgo biloba group, both the control group of Comparative Example 1 and the diphenhydramine hydrochloride single group of Comparative Example 2 significantly increased the duration of disappearance of the right-angled reflex. Accordingly, it has been found that an antihistamine substance and one or more combinations selected from the group consisting of Toki, Showa, Keihi, Chimpi, Ogon, Sojutsu and Ginkgo biloba have excellent hypnotic effects. It was found that the hypnotic action of diphenhydramine hydrochloride was enhanced in all of Toki, Showa, Keihi, Chimpi, Ogon, Sojutsu and Ginkgo biloba.

  One or more species selected from the group consisting of Tokyo, Syoukyo, Keihi, Keishi, Keihei, Chimpi, Spruce, Ogon, Sojutsu and Ginkgo biloba or their extracts enhance the hypnotic action of antihistamines Showed that to do.

  Accordingly, it contains an antihistaminic substance and one or more selected from the group consisting of Toki, Syoukyo, Keihi, Keishi, Keiyo Hay, Chimpi, Spruce, Ogon, Sojutsu and Ginkgo biloba or extracts thereof. The pharmaceutical composition exhibits an excellent hypnotic effect, and is useful for hypnosis, prevention and / or treatment of sleep disorders, sleep improvement and the like.

Claims (17)

A pharmaceutical composition for hypnosis, treatment of sleep disorders or sleep improvement, comprising an antihistamine and one or more selected from the following group.
Group: Spruce or its extract, Scarlet or its extract, Keihi or its extract, Keishi or its extract, Keihei or its extract, Chimpi or its extract, Spruce or its extract, Ogon or its extract , Sojutsu or its extract and Ginkgo biloba or its extract A pharmaceutical composition comprising an antihistamine substance and Toki or an extract thereof. A pharmaceutical composition comprising an antihistamine and Tokyo or an extract thereof. A pharmaceutical composition comprising an antihistaminic substance and Keihi or an extract thereof. A pharmaceutical composition comprising an antihistaminic substance and Keishi or an extract thereof. A pharmaceutical composition comprising an antihistamine substance and Keiyo Hay or an extract thereof. A pharmaceutical composition comprising an antihistaminic substance and chimpi or an extract thereof. A pharmaceutical composition comprising an antihistaminic substance and spruce or an extract thereof. A pharmaceutical composition comprising an antihistamine and ougon or an extract thereof. A pharmaceutical composition comprising an antihistamine and a jujube or an extract thereof. A pharmaceutical composition comprising an antihistaminic substance and a ginkgo leaf or an extract thereof. The antihistamine consists of alimemazine or a salt thereof, diphenhydramine or a salt thereof, chlorpheniramine or a salt thereof, doxylamine or a salt thereof, mequitazine or a salt thereof, clemastine or a salt thereof, carbinoxamine or a salt thereof, and diphenylpyrine or a salt thereof The pharmaceutical composition according to any one of claims 1 to 11, which is one or more selected from the group. The pharmaceutical composition according to any one of claims 1 to 11, wherein the antihistaminic substance is diphenhydramine or a salt thereof. The pharmaceutical composition according to claim 12 or 13, wherein the diphenhydramine or a salt thereof is diphenhydramine hydrochloride. The pharmaceutical composition according to any one of claims 1 to 14, wherein the preparation is an oral administration preparation. The pharmaceutical composition according to any one of claims 1 to 14, wherein the dosage form of the preparation is a powder, a fine granule, a granule, a tablet, a liquid, a troche or a jelly. An action enhancer of an antihistamine substance containing one or more selected from the following group.
Group: Spruce or its extract, Scarlet or its extract, Keihi or its extract, Keishi or its extract, Keihei or its extract, Chimpi or its extract, Spruce or its extract, Ogon or its extract , Sojutsu or its extract and Ginkgo biloba or its extract