JP4780907B2 - Hypnotic composition - Google Patents

Description

  The present invention relates to a hypnotic composition. More specifically, the present invention relates to a hypnotic composition comprising an antihistamine component having a hypnotic action as an active ingredient. Furthermore, the present invention relates to a method for reducing side effects such as mood discomfort (including nausea and head sensation) or malaise after waking that the antihistamine component has. In the present specification, the term “hypnotic composition” refers to a pharmaceutical composition having an action (sleep improvement action) for smoothly performing hypnosis and sleeping of a human who has an insomnia tendency such as poor sleep and light sleep. means.

  Conventionally known hypnotics are roughly classified into barbituric acid compounds, non-barbituric acid compounds, benzodiazepine compounds, and nonbenzodiazepine compounds, all of which have a central inhibitory action. , May cause dependency. For this reason, for the treatment of insomnia, there has been a need for a drug that has long been free from side effects. For this purpose, for example, natural ingredients having tranquility, sedation, or anxiolytic action such as traditional Chinese medicine, various plant extracts and essential oils have been proposed as hypnotics or hypnotic aids.

  On the other hand, diphenhydramine hydrochloride is a drug that has been used for the purpose of calming itching of the skin and suppressing allergic symptoms such as sneezing and runny nose, but has side effects that cause drowsiness when taken. Recently, in Japan, hypnotics and hypnotics that take advantage of this side effect have been developed and marketed. However, diphenhydramine hydrochloride is an antihistamine that suppresses the action of histamine that excites brain neurons and maintains and regulates arousal, and effective doses that cause sleepiness can cause mood discomfort during waking ( There are problems with side effects such as nausea and head feeling) and fatigue. Accordingly, there is a need to develop a drug that suppresses / reduces the occurrence of adverse side effects while utilizing the hypnotic action of such antihistamines such as diphenhydramine hydrochloride.

For these purposes, the amount of antihistamines used has been reduced by increasing the hypnotic action of antihistamines such as diphenhydramine hydrochloride and other antihistamines by combining valerian (Valgara radix), acid soy sauce, or Western Chabo clock extract. As a result, hypnotics that reduce the side effects of antihistamines have been proposed (see, for example, Patent Documents 1 and 2).
JP-A-4-36243 Japanese Patent Laid-Open No. 10-17482

  An object of the present invention is to provide a pharmaceutical composition having a safe and desired hypnotic action, in which side effects of antihistamines such as mood discomfort (including nausea and head sensation) or malaise after waking are significantly suppressed. And Furthermore, the present invention provides an antihistamine such as diphenhydramine hydrochloride and chlorpheniramine maleate while providing a method for reducing side effects such as mood discomfort and malaise after waking while maintaining a desired hypnotic effect. Objective.

  The present inventors have intensively studied to solve the above-mentioned problems. By using vitamin Cs in combination with an antihistamine component having a hypnotic action, the desired hypnotic effect of the antihistamine component is maintained. However, the present invention was completed by finding that side effects such as mood discomfort and fatigue after waking up can be reduced.

The present invention has been developed based on such findings, and has the following aspects:
Item 1. A hypnotic composition comprising an antihistamine having a sleep action and vitamin Cs.
Item 2. The antihistamine has at least one sleep action selected from the group consisting of ethanolamine compounds, propylamine compounds, phenothiazine compounds, piperazine compounds, piperidine compounds, and pharmaceutically acceptable salts thereof. Item 2. The hypnotic composition according to Item 1, which is a drug having.
Item 3. Item 3. The hypnotic composition according to Item 1 or 2, wherein the antihistamine is diphenhydramine, chlorpheniramine, or a pharmaceutically acceptable salt thereof.
The hypnotic composition includes the following embodiments:
(1) The hypnotic composition according to any one of Items 1 to 3, further comprising at least one selected from the group consisting of vitamins B, vitamins E, taurine, and inositols.

Item 4. A method for reducing side effects of the antihistamine, which comprises using a vitamin C in combination with an antihistamine having a sleep action.
The method also includes the following embodiments:
(2) The antihistamine is at least one selected from the group consisting of ethanolamine compounds, propylamine compounds, phenothiazine compounds, piperazine compounds, piperidine compounds, and pharmaceutically acceptable salts thereof. Item 5. A method for reducing side effects of an antihistamine according to Item 4, which is a drug having a sleep action.
(3) The method for reducing side effects of the antihistamine according to Item 4, wherein the antihistamine is diphenhydramine, chlorpheniramine, or a pharmaceutically acceptable salt thereof.
(4) The method for reducing side effects of the antihistamine according to Item 4, further using at least one selected from the group consisting of vitamin B, vitamin E, taurine, and inositol.

Item 5. A method of using vitamin C as a side effect reducing agent of an antihistamine having a sleeping action.
The method also includes the following embodiments:
(5) The antihistamine is at least one selected from the group consisting of ethanolamine compounds, propylamine compounds, phenothiazine compounds, piperazine compounds, piperidine compounds and pharmaceutically acceptable salts thereof. Item 6. The method according to Item 5, which is a drug having a sleep action.
(6) The method according to item 5, wherein the antihistamine is diphenhydramine, chlorpheniramine or a pharmaceutically acceptable salt thereof.
(7) Item 5. Use of vitamin C as a vitamin C-containing composition comprising vitamin C and at least one selected from the group consisting of vitamin B, vitamin E, taurine, and inositols. how to.

Item 6. A method of using a vitamin C as a component to be blended in a hypnotic composition formulated to reduce side effects of a hypnotic having an antihistamine as an active ingredient.
The method also includes the following embodiments:
(8) The antihistamine is at least one selected from the group consisting of ethanolamine compounds, propylamine compounds, phenothiazine compounds, piperazine compounds, piperidine compounds, and pharmaceutically acceptable salts thereof, Item 7. The method according to Item 6, which is a drug having a sleep action.
(9) The method according to item 6, wherein the antihistamine is diphenhydramine, chlorpheniramine or a pharmaceutically acceptable salt thereof.
(10) Item 6 used as a vitamin C-containing composition containing vitamin C in addition to vitamin C, and at least one selected from the group consisting of vitamin B, vitamin E, taurine, and inositol The method described in.

The present invention is described in detail below.
I. Hypnotic composition The hypnotic composition of the present invention contains vitamin C in addition to an antihistamine having a hypnotic action, and has a hypnotic action based on the antihistamine action of the antihistamine. However, the side effect of the central nervous system of the antihistamine, particularly mood discomfort (including nausea and headache) or malaise after waking up, is an antihistamine containing no vitamin C. It is characterized by being significantly suppressed / reduced compared to the hypnotic composition.

  The antihistamine targeted by the present invention suppresses the action of histamine in the central nervous system and has a hypnotic effect. Specific examples of the antihistamine having such an action include ethanolamine compounds such as diphenhydramine, dimenhydrinate, diphenylpyraline or clemastine, or pharmaceutically acceptable salts thereof; propylamine such as chlorpheniramine or triprolidine. Compounds, or pharmaceutically acceptable salts thereof; phenothiazine compounds, such as promethazine or alimemazine, or pharmaceutically acceptable salts thereof; piperazine compounds, such as hydroxyzine or homochlorocyclidine; or pharmaceutically acceptable salts thereof As well as piperidine compounds such as cyproheptadine, or pharmaceutically acceptable salts thereof.

  These pharmaceutically acceptable salts include hydrochlorides of the above components (for example, diphenhydramine hydrochloride, diphenylpyralin hydrochloride, promethazine hydrochloride, homochlorcyclidine hydrochloride, hydroxyzine hydrochloride, cyproheptadine hydrochloride, etc.), sulfates, nitrates, etc. As well as salicylates (eg, diphenhydramine salicylate), tannates (eg, diphenhydramine tannate), laurates (diphenhydramine laurate), and maleates (eg, chlorinated d-maleate) Pheniramine, dl-chlorpheniramine maleate), teolate (eg, diphenylpyraline teolate), fumarate (eg, clemastine fumarate), tartrate (eg, alimemazine tartrate), pamoate (example , And organic acid salts such as hydroxyzine pamoate and the like).

  Preferred are diphenhydramine or chlorpheniramine and pharmaceutically acceptable salts thereof (specifically, diphenhydramine hydrochloride, diphenhydramine salicylate, chlorpheniramine maleate, dl-chlorpheniramine maleate, etc.). Is diphenhydramine and pharmaceutically acceptable salts thereof (specifically diphenhydramine hydrochloride).

  The content ratio of these antihistamines in the hypnotic composition of the present invention is not particularly limited, and can be appropriately selected from the range of 0.01 to 99.9% by weight. Specifically, based on the daily dose of the antihistamine, it can be appropriately selected in consideration of the blending ratio of vitamin C, the form of the pharmaceutical composition to be administered, the unit dose, and the like. The dose of the antihistamine is usually in the range of 1 to 300 mg per day for an adult, preferably 5 to 200 mg, more preferably 10 to 100 mg. As a suitable content rate of the antihistamine in the hypnotic composition of this invention, 0.1-50 weight%, More preferably, it is 0.2-30 weight%, More preferably, 0.5-20 weight% is illustrated. be able to.

  Examples of vitamin C used in combination with the antihistamine include ascorbic acid and pharmaceutically acceptable salts thereof (for example, sodium ascorbate and calcium ascorbate), and pharmaceutically acceptable derivatives thereof ( For example, ascorbic acid 2-glucoside, ascorbic acid 2-phosphoric acid, ascorbic acid 2-sulfuric acid, ester derivatives of ascorbic acid such as fatty acid esters of ascorbic acid) can be mentioned. Preferred are ascorbic acid, sodium ascorbate, and calcium ascorbate.

  The ratio of vitamin C contained in the hypnotic composition of the present invention is such that the anti-histamine has the above side effects (after waking up) without adversely affecting the hypnotic action of the antihistamine contained in the hypnotic composition. There is no particular limitation as long as it is within a range that can suppress and reduce mood discomfort and fatigue. Specifically, the compounding ratio of vitamin C to 100 parts by weight of the antihistamine in the hypnotic composition can be appropriately selected from the range of 10 to 200,000 parts by weight. The range is preferably 25 to 40,000 parts by weight, more preferably 50 to 20000 parts by weight. Although it does not restrict | limit especially in this limit, As a ratio of vitamin C contained in 100 weight% of hypnotic compositions, the range of 0.001 to 99.99 weight% can be mentioned. Preferably it is 1-90 weight%, More preferably, it is 10-80 weight%, More preferably, it is 20-80 weight%.

The hypnotic composition of the present invention, from the group consisting of vitamin B, vitamin E, taurine, and inositol, in addition to the antihistamine and vitamin C, as long as the effects of the present invention are not impaired. Vitamin B used in combination with the above antihistamine and vitamin C, which can contain at least one selected from the above, includes vitamin B1 [thiamine and pharmaceutically acceptable salts thereof (for example, thiamine hydrochloride, nitric acid). Thiamine, bistiamine nitrate, thiamine disulfide, and thiamine dicetyl sulfate, etc.), and vitamin B1 derivatives (eg, octothiamine, chicotiamine, bisbutiamine, bisbenchamine, fursultiamine, fursultiamine hydrochloride, Sultiamine, benfotiamine, dice hydrochloride Vitamin B1 such as amine); vitamin B2 [riboflavin and pharmaceutically acceptable salts thereof (for example, riboflavin sodium phosphate and flavin adenine dinucleotide sodium) and riboflavin butyrate]; vitamin B6 [pyridoxine, Pyridoxal, pyridoxamine, and their 5′-phosphate esters, and pharmaceutically acceptable salts thereof (eg, pyridoxine hydrochloride, pyridoxal phosphate, etc.); vitamin B12 (cobalamin, cyanocobalamin, mecobalamin, hydroxocobalamin, and Pharmaceutically acceptable salts thereof (such as hydroxocobalamin hydrochloride and hydroxocobalamin acetate); niacin (such as nicotinic acid, nicotinamide, and pharmaceutically acceptable salts thereof); pantothene S [pantothenic acid and its pharmaceutically acceptable salts (e.g. calcium and sodium pantothenate pantothenic acid), such as panthenol]; biotin; and Horashin (such as folic acid or a pharmaceutically acceptable salt thereof) can be exemplified. Vitamin B1, vitamin B2, vitamin B6 and vitamin B12 are preferred. In addition, as for vitamin B, one or more vitamins belonging to the same group may be used, or vitamins belonging to two or more different groups may be used in combination. In the latter case, for example, combinations of vitamin B1, vitamin B2, and vitamin B6, vitamin B1, vitamin B2, vitamin B6, vitamin B12, and vitamin B2 The combination with vitamin B6 class etc. can be mentioned. However, such a combination mode is merely an example, and the combination mode is not limited at all.

  When the hypnotic composition of the present invention contains vitamin Bs, the content of vitamin B in the hypnotic composition is such that the action of the hypnotic composition containing an antihistamine and vitamin C (hypnotic action and side effect reduction). There is no particular limitation as long as it does not adversely affect (action). Preferably, the ratio is such that the inhibitory / reducing action to the side effects (feeling discomfort and worried after waking up) of vitamin Cs can be enhanced.

  Specifically, when vitamin B1 is used, the blending ratio of vitamin B1 to 100 parts by weight of the antihistamine in the hypnotic composition can usually range from 0.1 to 10,000 parts by weight. Preferably it is the range of 0.5-2000 weight part and 1-1000 weight part. Although it does not restrict | limit especially in this limit, As a ratio of vitamin B1 contained in 100 weight% of hypnotic compositions, the range of 0.00001 to 98 weight% can be mentioned. Preferably it is 0.01-50 weight%, More preferably, it is 0.05-30 weight%, More preferably, it is 0.05-20 weight%.

  When using vitamin B2 type, the range of 0.5-5000 weight part can be normally mentioned as a compounding ratio of vitamin B2 with respect to 100 weight part of antihistamines in a hypnotic composition. Preferably it is the range of 1-1000 weight part and 2-500 weight part. Although it does not restrict | limit especially in this limit, As a ratio of vitamin B2 contained in 100 weight% of hypnotic compositions, the range of 0.00005-97 weight% can be mentioned. Preferably it is 0.01-50 weight%, More preferably, it is 0.05-30 weight%, More preferably, it is 0.05-20 weight%.

  When using vitamin B6, the range of 1 to 10000 parts by weight can usually be mentioned as the blending ratio of vitamin B6 to 100 parts by weight of the antihistamine in the hypnotic composition. Preferably it is the range of 2-2000 weight part and 5-1000 weight part. Although it does not restrict | limit in particular in this limit, As a ratio of vitamin B6 contained in 100 weight% of hypnotic compositions, the range of 0.0001-98 weight% can be mentioned. Preferably it is 0.01 to 50 weight%, More preferably, it is 0.05 to 30 weight%, More preferably, it is 0.1 to 20 weight%.

When vitamin B12 is used, the blending ratio of vitamin B12 to 100 parts by weight of the antihistamine in the hypnotic composition can usually range from 1 × 10 ^{−4 to} 150 parts by weight. Preferably, it is in the range of 5 × 10 ⁻⁴ to 30 parts by weight and 1 × 10 ⁻³ to 15 parts by weight. Although it does not restrict | limit in particular in this limit, As a ratio of vitamin B12 contained in 100 weight% of hypnotic compositions, the range of 1 * 10 < ^-8 > -59 weight% can be mentioned. Preferably it is 0.0001 to 10 weight%, More preferably, it is 0.001 to 5 weight%, More preferably, it is 0.001 to 1 weight%.

  Vitamin E used in combination with the antihistamine and vitamin C is tocopherol, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable derivative thereof. Here, the derivative may be any one that belongs to vitamin E and is pharmaceutically acceptable, and specifically, a pharmaceutically acceptable C1 to C30 ester of tocopherol, preferably C2 to C of tocopherol. C20 ester is included. Examples of substances listed in the Japanese Pharmacopoeia include d-α-tocopherol succinate, dl-α-tocopherol succinate, tocopherol succinate, dl-α-tocopherol calcium succinate, tocopherol calcium succinate, tocopherol acetate , And tocopherol. Non-Japanese Pharmacopoeia includes, for example, d-α-tocopherol acetate, dl-α-tocopherol acetate, d-δ-tocopherol, dl-α-tocopherol, DL-α-tocopherol nicotinate, tocopherol nicotinate, linol Mention may be made of vitamin E tocopheryl derivatives such as acid DL-α-tocopherol, d-α-tocopherol, natural vitamin E, and D-α-tocopheryl polyethylene glycol-1000-succinate. Preferred are tocopherol acetate, tocopherol succinate, and d-α-tocopherol succinate.

  When the hypnotic composition of the present invention contains vitamin E, the content of vitamin E in the hypnotic composition is determined by the action of the hypnotic composition containing an antihistamine and vitamin C (reducing hypnotic and side effects). There is no particular limitation as long as it does not adversely affect (action). Preferably, it is a ratio that can enhance the inhibitory / reducing action to the side effects (feeling discomfort and worries after waking up) of antihistamines possessed by vitamin Cs. Specifically, the blending ratio of vitamin E to 100 parts by weight of the antihistamine in the hypnotic composition can be appropriately selected from the range of 3 to 60000 parts by weight. The range is preferably 5 to 12000 parts by weight, more preferably 10 to 6000 parts by weight. Although it does not restrict | limit especially in this limit, As a ratio of vitamin E contained in 100 weight% of hypnotic compositions, the range of 0.0003-98 weight% can be mentioned. Preferably it is 0.01-50 weight%, More preferably, it is 0.05-30 weight%, More preferably, it is 0.05-20 weight%.

  When taurine is used in combination with the above antihistamine and vitamin C, the content of taurine in the hypnotic composition depends on the action of the hypnotic composition containing the antihistamine and vitamin C (hypnotic action and side effect reduction). There is no particular limitation as long as it does not adversely affect (action). Preferably, it is a ratio that can enhance the inhibitory / reducing action to the side effects (feeling discomfort and worries after waking up) of antihistamines possessed by vitamin Cs. Specifically, the proportion of taurine to 100 parts by weight of the antihistamine in the hypnotic composition can be appropriately selected from the range of 5 to 300,000 parts by weight. Preferably it is 10-60,000 weight part, More preferably, it is the range of 20-30000 weight part. Although it does not restrict | limit especially in this limit, As a ratio of the taurine contained in 100 weight% of hypnotic compositions, the range of 0.0005 to 99 weight% can be mentioned. Preferably it is 0.1 to 60 weight%, More preferably, it is 0.1 to 50 weight%, More preferably, it is 1 to 30 weight%.

  Inositols used in combination with the above antihistamines and vitamin C include inositol, pharmaceutically acceptable derivatives of inositol such as inositol glucoside, inositol phosphoglyceride, inositol hexanicotinate and mezoinositol hexanicotinate Can be mentioned. Inositol and inositol hexanicotinate are preferable.

  When inositols are used in combination with the antihistamine and vitamin C, the content of inositols in the hypnotic composition depends on the action of the hypnotic composition containing the antihistamine and vitamin C (hypnotic action and There is no particular limitation as long as it does not adversely affect the side effect reducing action. Preferably, it is a ratio that can enhance the inhibitory / reducing action to the side effects (feeling discomfort and worries after waking up) of antihistamines possessed by vitamin Cs. Specifically, the blending ratio of the inositols with respect to 100 parts by weight of the antihistamine in the hypnotic composition can be appropriately selected from the range of 1-18000 parts by weight. Preferably it is 2-36000 weight part, More preferably, it is the range of 5-18000 weight part. Although it does not restrict | limit especially in this limit, As a ratio of inositol contained in 100 weight% of hypnotic compositions, the range of 0.0001-99 weight% can be mentioned. Preferably it is 0.01 to 50 weight%, More preferably, it is 0.05 to 30 weight%, More preferably, it is 0.1 to 20 weight%.

  The vitamin Bs, vitamin Es, taurine and inositols can be used alone with antihistamines and vitamins C, respectively, but two or more can be used in combination with antihistamines. it can.

  The hypnotic composition of the present invention can also contain other medicinal ingredients as long as the effects of the present invention are not impaired. These medicinal ingredients include hypnotic sedatives such as bromvaleryl urea and allyl isopropyl acetylurea; beetle, musk, rhubarb, d-borneol, ginkgo, antelope, animal gall (bear gall), carrot, saffron, auren, hop, butterfly Herbal medicines with sedative effects from plants such as pearl millet, scorpionfish, clove, licorice, licorice, valerian, western tea clock, cypress, bukkuri, psycho, senkyu, sardine, peonies, hawthorn and mistletoe. Can be mentioned.

  The hypnotic composition of the present invention can be used as oral preparations such as tablets, pills, powders, granules, fine granules, capsules, solutions, syrups, suspensions, emulsions, and inhalants, and suppositories. It can be prepared and administered as a parenteral agent. Such oral preparations and parenteral preparations (suppositories) can be prepared according to production methods conventionally used in the art depending on the form.

  In addition to the above components, the hypnotic composition of the present invention may be formulated with various pharmaceutically acceptable carriers and additives depending on the form of the preparation for formulation and stabilization. For example, excipients for oral administration include lactose, mannitol, corn starch, partially pregelatinized starch, crystalline cellulose, low-substituted hydroxypropylcellulose, carmellose sodium, lactose, talc and other excipients; starch, α -Binders such as starch, gelatin, methylcellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, crystalline cellulose; disintegrants such as starch, carboxymethylcellulose calcium, low substituted hydroxypropylcellulose, carboxymethylstarch; magnesium stearate, talc , Lubricants such as silicic acid anhydride; Suspending agents such as polysorbate 80, polyoxyethylene hydrogenated castor oil, and pluronic; sucrose, talc, precipitated calcium carbonate, zera Coating agents such as chin, gum arabic, pullulan, carnauba wax, hydroxypropylmethyl phthalate; corrigents such as sucrose, glucose, sodium saccharin, sorbitol, citric acid, and aspartame; and various brighteners, stabilizers, colorants, etc. Can be mentioned.

  Moreover, as an additive for parenteral preparations such as suppositories, conventionally known ones can be used as a suppository base. For example, sodium alginate, gelatin, corn starch, tragacanth gum, methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, dextrin, carboxymethyl starch, polyvinyl alcohol, sodium polyacrylate, methoxyethylene-maleic anhydride copolymer, polyvinyl ether, polyvinyl pyrrolidone, etc. Polymers; beeswax, olive oil, cacao oil, sesame oil, soybean oil, jojoba oil, avocado oil, coconut oil, peanut oil, beef tallow, lard, lanolin, etc., oils such as polyoxyethylene hydrogenated castor oil; white petrolatum; liquid paraffin, Mineral oils such as silicone oil, volatile silicone oil, petrolatum; hydrocarbon gel ointment (for example, plastibase (trade name; manufactured by Taisho Pharmaceutical Co., Ltd.)); lauric acid, Higher fatty acids such as stinic acid, stearic acid, oleic acid; esters such as cetyl lactate, isopropyl myristate, octyldodecyl myristate; higher alcohols such as cetyl alcohol, octyldodecanol, lauryl alcohol, stearyl alcohol; polyethylene glycol; mono Nonionic surfactants such as glyceryl stearate, glyceryl monooleate, propylene glycol monostearate, polyoxyethylene cetyl alcohol ether; anionic interfaces such as sodium cetyl sulfate, sodium stearate, sodium N-acyl glutamate Activators; lower alcohols such as ethanol and isopropanol; triethanolamine and the like.

  Further, if necessary, antioxidants such as 1,3-butylene glycol, ascorbic acid and tocopherol; preservatives such as benzoic acid and parabens; thickeners such as polyethylene glycol, xanthan gum, sodium carboxymethylcellulose, and carboxypropylcellulose Buffers such as citric acid, lactic acid, hydrochloric acid and boric acid, or alkali such as sodium dihydrogen phosphate, sodium citrate, sodium hydroxide, potassium hydroxide, and triethanolamine (pH adjusters) Inorganic fillers such as kaolin, bentonite, zinc oxide and titanium oxide can also be blended.

  The dosage when the hypnotic composition of the present invention is used therapeutically depends on the patient's age, sex, degree of insomnia, and administration method, but depends on the dosage of the antihistamine per day for an adult. In terms of conversion, the ratio is about 1 to 300 mg, preferably about 5 to 200 mg, and more preferably about 10 to 100 mg. In addition, the hypnotic composition of the present invention can be administered once a day or several times a day. The hypnotic composition of the present invention can be usually used before sleeping, when sleep is poor or when sleep is shallow.

  The hypnotic composition of the present invention can exhibit the desired hypnotic action of the present invention based on the antihistamine by using a combination of vitamin C and an antihistamine, and is inconvenient for the subject possessed by the antihistamine. Side effects, specifically, central nervous system side effects such as mood discomfort, headache, and fatigue after waking up are alleviated and can be used as a preferred hypnotic agent in terms of efficacy and side effects .

II. Method for Reducing Side Effects of Antihistamine Drug The method of the present invention can be carried out by using a combination of vitamin C and an antihistamine drug having a hypnotic action. In the present invention, the side effect of the antihistamine targeted is specifically caused by suppression of the action of histamine in the brain, particularly mood discomfort (including nausea and head sensation) after waking or fatigue Listed are side effects of the central nervous system.

  Examples of the antihistamine include those described in the above (I) having a hypnotic action. Preferably, diphenhydramine, chlorpheniramine and pharmaceutically acceptable salts thereof, specifically, diphenhydramine hydrochloride, diphenhydramine salicylate, d-chlorpheniramine maleate, and dl-chlorpheniramine maleate can be mentioned. More preferred are diphenhydramine and pharmaceutically acceptable salts thereof, particularly diphenhydramine hydrochloride.

  Examples of vitamin C used in combination with the antihistamine include those described in (I) above. Ascorbic acid, sodium ascorbate, and calcium ascorbate are preferable.

  The proportion of vitamin C used in combination with antihistamines suppresses or reduces the side effects of antihistamines (feeling of discomfort and fatigue after waking) without adversely affecting the hypnotic action of antihistamines There is no particular limitation as long as it can be performed. For example, the use ratio of each vitamin C relative to 100 parts by weight of the antihistamine can usually range from 10 to 200,000 parts by weight. The range is preferably 25 to 40,000 parts by weight, more preferably 50 to 20000 parts by weight.

  The aspect of using vitamin C in combination with the antihistamine having a sleeping action is not particularly limited, and the antihistamine having a sleeping action and vitamin C are used in combination during use (during administration). Any method can be used. For example, a method of providing vitamin Cs as a single agent (mixture) by blending vitamin Cs with a sleeping agent composition containing an antihistamine as an active ingredient, a sleeping agent composition containing an antihistamine as an active ingredient, and vitamin Cs Or the method of providing as a combination agent with the composition containing it can be mentioned.

  In order to achieve the object of the present invention, the antihistamine may be used in combination with vitamin C and at least one selected from the group consisting of vitamin B, vitamin E, taurine, and inositol. it can. The types of vitamin B, vitamin E, taurine, and inositol that can be used in this case are as described in (I) above. Vitamin B is preferably vitamin B1, vitamin B2, vitamin B6, and vitamin B12, more preferably fursultiamine hydrochloride, benfotiamine and thiamine nitrate (above, vitamin B1), riboflavin butyrate ( Vitamin B2), pyridoxine hydrochloride (vitamin B6), and cyanocobalamin (vitamin B12). Such vitamin Bs may use a single vitamin or a plurality of vitamins belonging to the same group, or a combination of two or more vitamins belonging to different groups. In the latter case, combinations of vitamin B1, vitamin B2, and vitamin B6, vitamin B1, vitamin B2, vitamin B6, and vitamin B12, and vitamin B2 and vitamin A combination with B6 class can be illustrated. However, the mode of such a combination is merely an example, and is not limited to these combinations.

  Further, as vitamin E, preferably tocopherol acetate, tocopherol succinate and d-α-tocopherol succinate, and as inositol, preferably inositol and inositol hexanicotinate can be mentioned.

For example, when vitamin B is used, the use ratio of each vitamin B to 100 parts by weight of the antihistamine is usually in the range of 0.1 to 10,000 parts by weight, preferably 0.5 to 2000 parts by weight in the case of vitamin B1. More preferably 1-1000 parts by weight; in the case of vitamins B2, usually in the range of 0.5-5000 parts by weight, preferably 1-1000 parts by weight, more preferably 2-500 parts by weight; Usually in the range of 1 to 10,000 parts by weight, preferably in the range of 2 to 2000 parts by weight, more preferably in the range of 5 to 1000 parts by weight; in the case of vitamin B12, it is usually in the range of 1 × 10 ^{−4 to} 150 parts by weight, preferably 5 × 10 ^-4 to 30 parts by weight, more preferably 1 × 10 ^-3 to 15 parts by weight.

  When vitamin E is used in combination, the use ratio of vitamin E to 100 parts by weight of the antihistamine can be appropriately selected from the range of usually 3 to 60000 parts by weight. The range is preferably 5 to 12000 parts by weight, more preferably 10 to 6000 parts by weight. When taurine is used in combination, the use ratio of taurine with respect to 100 parts by weight of the antihistamine can be appropriately selected from the range of usually 5 to 300,000 parts by weight. Preferably it is 10-60,000 weight part, More preferably, it is the range of 20-30000 weight part. When inositols are used in combination, the use ratio of inositols with respect to 100 parts by weight of the antihistamine can be appropriately selected from the range of 1-18000 parts by weight. Preferably it is 2-36000 weight part, More preferably, it is the range of 5-18000 weight part.

  The above vitamin B, vitamin E, taurine and inositol can be combined with vitamin C alone and in combination with an antihistamine, but any combination of two or more can be combined with vitamin C. It can also be used in combination with histamine drugs.

  According to the method of the present invention, by using vitamin Cs in combination with an antihistamine, while maintaining the desired hypnotic action of the antihistamine, its undesirable side effects (especially after awakening) Pleasant feeling (including nausea and head feeling) or fatigue) can be reduced. Therefore, the method of the present invention can be effectively used to prepare and provide a hypnotic composition that exhibits a desired hypnotic effect with few side effects.

III. Method for Using Vitamin Cs Further, the present invention provides new uses for vitamin Cs.

  Specifically, the present invention firstly provides a method (first method) in which vitamin C is used as a side effect reducing agent of an antihistamine having a sleeping action.

  In addition, the present invention secondly relates to a method for producing a hypnotic composition formulated to reduce the side effects of a hypnotic composition containing an antihistamine as an active ingredient, and vitamin C as a component to be blended in the composition. A method using a class (second method) is provided.

  Here, as described in (II) above, side effects of antihistamines that have a sleep action as a target include mood discomfort (such as nausea and head weight) that occurs as a result of suppression of the action of histamine in the brain. And other side effects of the central nervous system such as malaise).

  In addition, as the types of antihistamines to be used here and their dosages, and the types of vitamin C used in combination therewith and the proportions thereof, those described in the above (I) and (II) are mentioned. be able to.

  Antihistamines having a sleeping action are preferably diphenhydramine or chlorpheniramine and pharmaceutically acceptable salts thereof (specifically diphenhydramine hydrochloride, diphenhydramine salicylate, chlorpheniramine d-maleate, or dl-malein). More preferred examples include diphenhydramine and pharmaceutically acceptable salts thereof (specifically diphenhydramine hydrochloride).

  Examples of vitamin C include those described in (I) above. Ascorbic acid, sodium ascorbate, and calcium ascorbate are preferable. The use ratio of vitamin C is within the range that can suppress / reduce the side effects (feeling discomfort and malaise after waking) of antihistamines without adversely affecting the hypnotic action of antihistamines. There is no particular restriction. Specifically, as a use ratio of each vitamin C to 100 parts by weight of the target antihistamine (in the case of the second method, an antihistamine contained in the hypnotic composition), usually 10 to 200,000 parts by weight The range is preferably 25 to 40,000 parts by weight, more preferably 50 to 20000 parts by weight.

  Said 1st method can also be implemented by mix | blending the composition containing vitamin C single or vitamin C as a side effect reducing agent with the hypnotic composition which uses an antihistamine as an active ingredient, By using vitamin C alone or a composition containing vitamin C as a side effect reducing agent for a hypnotic composition containing an antihistamine as an active ingredient, as a concomitant (or adjuvant) of the hypnotic composition It can also be implemented.

  In this case, examples of the composition containing vitamin C include those containing at least one selected from the group consisting of vitamin B, vitamin E, taurine, and inositol in addition to vitamin C. it can. The types of vitamin B, vitamin E, taurine, and inositol that can be used in this case are as described above in (I) or (II). In addition, as for vitamin B, vitamins belonging to the same group may be used alone or in combination, or vitamins belonging to two or more different groups may be used in combination. In the latter case, combinations of vitamin B1, vitamin B2, and vitamin B6, vitamin B1, vitamin B2, vitamin B6, and vitamin B12, and vitamin B2 and vitamin A combination with B6 class can be illustrated. However, these combinations are examples and are not limited at all.

The blending ratio of vitamin B, vitamin E, taurine or inositol may be within a range that does not interfere with the effect of vitamin C as a side effect reducing agent for a hypnotic composition containing an antihistamine as an active ingredient, It is preferable to select a range that can be enhanced. For example, when vitamin B1 is used, it is appropriately selected from a range in which vitamin B1 is usually 0.1 to 10,000 parts by weight with respect to 100 parts by weight of the antihistamine in the hypnotic composition of interest. can do. Preferably it is 0.5-2000 weight part, More preferably, it is the range of 1-1000 weight part. When using vitamin B2s, select appropriately from the range in which vitamin B2s are usually in a proportion of 0.5 to 5000 parts by weight with respect to 100 parts by weight of the antihistamine in the hypnotic composition of interest. Can do. Preferably it is 1-1000 weight part, More preferably, it is the range of 2-500 weight part. When vitamin B6 is used, it is appropriately selected from a range in which vitamin B6 is usually 1 to 10,000 parts by weight per 100 parts by weight of the antihistamine in the hypnotic composition used in combination with a side effect reducing agent. can do. Preferably it is 2-2000 weight part, More preferably, it is the range of 5-1000 weight part. When vitamin B12 is used, it is appropriately selected from a range in which vitamin B12 is usually in a ratio of 1 × 10 ^{−4 to} 150 parts by weight with respect to 100 parts by weight of the antihistamine in the target hypnotic composition. can do. Preferably it is 5 * 10 < ^-4 > -30 weight part, More preferably, it is the range of 1 * 10 < ^-3 > -15 weight part.

  When vitamin E is used, it may be appropriately selected from the range in which vitamin E is usually in a ratio of 3 to 60000 parts by weight with respect to 100 parts by weight of the antihistamine in the hypnotic composition of interest. it can. The range is preferably 5 to 12000 parts by weight, more preferably 10 to 6000 parts by weight. When taurine is used, it can be appropriately selected from a range in which taurine is usually 5 to 300,000 parts by weight with respect to 100 parts by weight of the antihistamine in the hypnotic composition of interest. Preferably it is 10-60,000 weight part, More preferably, it is the range of 20-30000 weight part. When using inositol, it can select suitably from the range in which inositol usually becomes a ratio of 1-18000 weight part with respect to 100 weight part of antihistamines in the hypnotic composition made into object. Preferably it is 2-36000 weight part, More preferably, it is the range of 5-18000 weight part.

  The vitamin Bs, vitamin Es, taurine and inositols can be used alone and in combination with vitamins C, but two or more can be arbitrarily combined and used in combination with vitamins C.

  In the first method of the present invention, by using vitamin Cs or a composition containing the same as an antihistamine, while maintaining the desired hypnotic action of the antihistamine, it is not preferable, particularly in the central nervous system. Side effects (feeling discomfort after waking up (including nausea and headache) or malaise) can be reduced. Therefore, the present invention provides a new use as a side effect reducing agent of vitamin C class antihistamines.

  In addition, the present invention secondly relates to a method for producing a hypnotic composition formulated to reduce the side effects of a hypnotic composition containing an antihistamine as an active ingredient, and vitamin C as a component to be blended in the composition. A method using a class (second method) is provided.

  In the second method, the hypnotic composition containing an antihistamine as an active ingredient is a tablet, pill, powder, granule, fine granule, capsule, liquid as described in (I) above. , Syrups, suspensions, emulsions or inhalation forms such as oral preparations, or parenteral forms such as suppositories, and carriers commonly used depending on the form Using additives (see, for example, (I) above), they can be prepared according to conventional manufacturing methods. The second method of the present invention is carried out by using vitamin C as a component in addition to an antihistamine, which is an active ingredient, and a pharmaceutically acceptable carrier or additive, in the production of a hypnotic composition. Can do. In this case, in combination with vitamin C, at least one selected from the group consisting of vitamin B, vitamin E, taurine, and inositol can also be blended. The types of vitamin B, vitamin E, taurine, and inositol that can be used in this case are as described above in (I) or (II). The blending ratio of vitamin B, vitamin E, taurine or inositol may be within a range that does not interfere with the effect of vitamin C as a side effect reducing agent for a hypnotic composition containing an antihistamine as an active ingredient, It is preferable to select a range that can be enhanced. Specifically, as a blending ratio of each component (vitamin B, vitamin E, taurine or inositol) with respect to 100 parts by weight of the antihistamine contained in the finally prepared hypnotic composition, and final hypnosis As a blending ratio of each component contained in 100% by weight of the agent composition, the ratio described in the above (I) can be similarly exemplified.

  In the second method of the present invention, when producing a hypnotic composition containing an antihistamine as an active ingredient, the desired hypnotic action obtained based on the antihistamine is obtained by using vitamin C as a composition component. While maintaining it, the undesirable central nervous system side effects (feeling discomfort after waking up (nausea or head feeling) or fatigue) can be reduced. Therefore, the present invention uses vitamin C as a prescription ingredient in a method for producing a hypnotic composition containing an antihistamine as an active ingredient and causing no undesirable side effects of the central nervous system. A method is provided.

  EXAMPLES Hereinafter, although an Example and a test example are given and this invention is demonstrated, this invention is not limited to these Examples.

Test example 1
(1) For healthy adults (subjects), a hypnotic composition (comparative example, Examples 1 to 8) comprising the prescriptions listed in Table 1 is taken, and the hypnotic action of each hypnotic composition and its Side effects were evaluated. Each hypnotic composition was prepared as a powder according to the method prescribed in the Japanese Pharmacopoeia General Formulation (powder) based on the following blending amounts of each component.

  In addition, the dose was taken once every 30 minutes to 1 hour before going to bed, and no alcohol or other neuropsychiatric drugs were used in combination. In addition, each subject (1 group: 6 persons) was given either the comparative example or the hypnotic composition of each example, and the hypnotic action and side effects of these hypnotic compositions were evaluated. I got it.

（２）各催眠剤組成物（比較例、実施例１〜８）の催眠作用を、各被験者に、寝付き、眠りの深さ、及び翌朝の目覚め時の覚醒感、の３点について、表２〜４に記載する５つの基準に従ってＳＤ法により評価してもらった。結果を表２〜４に併せて記載する。なお、各表中の数字は、該当する被験者の人数を意味する。

(2) The hypnotic action of each hypnotic composition (comparative example, Examples 1 to 8) is shown in Table 2 with respect to three subjects: sleep, depth of sleep, and arousal feeling when waking up the next morning. They were evaluated by the SD method according to the five criteria described in -4. The results are listed in Tables 2 to 4. In addition, the number in each table | surface means the number of applicable test subjects.

（３）各催眠剤組成物（比較例、実施例１〜８）について、目覚め後６時間までの間における気分不快感（悪心や頭重感を含む）、めまい、及び倦怠感の有無について表５〜７に記載する４つの基準に従ってＳＤ法により評価してもらった。

(3) About each hypnotic composition (comparative example, Examples 1-8) about the presence or absence of mood discomfort (including nausea and head sensation), dizziness, and malaise until 6 hours after waking up Table 5 They were evaluated by the SD method according to the four criteria described in -7.

上記に示すように、ビタミンＣ類を、抗ヒスタミン薬と併用して用いることによって、抗ヒスタミン薬の所望の催眠作用はそのままに、好ましくない目覚め後の気分不快感（悪心や頭重感）や倦怠感が有意に軽減されており、良好な目覚めが得られることがわかった。またその効果は、ビタミンＣ類とビタミンＢ２類、ビタミンＣ類とビタミンＥ類を組み合わせて用いることによって、なおよくなることがわかった。

As shown above, when vitamin C is used in combination with an antihistamine, the desired hypnotic effect of the antihistamine remains unchanged, and unpleasant awakening discomfort (nausea or head feeling) or malaise It was found that the feeling was significantly reduced and good awakening was obtained. In addition, it has been found that the effect is further improved by using a combination of vitamins C and B2, and vitamins C and E.

Formulation Example 1 Tablet A hypnotic composition (tablet) having the following composition was prepared according to a conventional method.
<Prescription> Single dose: 2 tablets (once before going to bed)
Diphenhydramine hydrochloride 50 (mg)
Ascorbic acid 200
Lactose 30
Starch 10
Crystalline cellulose 200
Magnesium stearate 5
White shellac 5
Total 500mg / 2 tablets.

Formulation Example 2 Tablet A hypnotic composition (tablet) having the following composition was prepared according to a conventional method.
<Prescription> Single dose: 2 tablets Diphenhydramine hydrochloride 50 (mg)
Sodium ascorbate 700
Hydroxypropyl cellulose 10
Crystalline cellulose 200
Croscarmellose 30
Magnesium stearate 10
Total 1000mg / 2 tablets.

Formulation Example 3 Granule A hypnotic composition (granule) having the following composition was prepared according to a conventional method.
<Prescription> Single dose: 1 pack (once before going to bed)
Diphenhydramine hydrochloride 50 (mg)
Calcium ascorbate 400
Starch 300
Sucrose 80
Sucrose fatty acid ester 100
D-sorbitol 10
Hydroxypropylcellulose 60
Total 1000mg / pack.

Formulation Example 4 Powder A hypnotic composition (powder) having the following composition was prepared according to a conventional method.
<Prescription> Single dose: 1 pack (once before going to bed)
Diphenhydramine hydrochloride 50 (mg)
Ascorbic acid 50
Lactose 640
Starch 200
Hydroxypropyl cellulose 10
Croscarmellose 50
Total 1000mg / pack.

  According to the present invention, by using vitamin C in combination with an antihistamine, the side effects of the central nervous system of the antihistamine, such as mood discomfort and malaise after waking, are observed without adversely affecting the hypnotic action of the antihistamine. Feeling) can be reduced. Therefore, according to the present invention, a hypnotic agent that is safe and has a high hypnotic effect can be provided.

Claims (4)

A hypnotic composition comprising diphenhydramine having a sleeping action or a pharmaceutically acceptable salt thereof and ascorbic acid or a pharmaceutically acceptable salt thereof. The hypnotic composition according to claim 1, further comprising inositols. A method for producing a hypnotic composition comprising diphenhydramine having a sleeping action or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the composition comprises ascorbic acid or a pharmaceutically acceptable salt thereof . Furthermore, the method of Claim 3 which mix | blends inositol.