WO2005032546A1

WO2005032546A1 - Hypnotic composition

Info

Publication number: WO2005032546A1
Application number: PCT/JP2004/011879
Authority: WO
Inventors: Katsuya Shimoo
Original assignee: Kobayashi Pharmaceutical Co., Ltd.
Priority date: 2003-09-30
Filing date: 2004-08-19
Publication date: 2005-04-14
Also published as: JP2005104927A; JP4780907B2

Abstract

[PROBLEMS] To provide a hypnotic composition in which side effects of an antihistaminic agent on the central nervous system (unpleasant feeling after awakening and boredom) have been reduced without adversely influencing the hypnotic activity of the antihistaminic agent. [MEANS FOR SOLVING PROBLEMS] Vitamin C or an analogue thereof is used in combination with an antihistaminic agent having hypnotic activity, in particular, at least one member selected from the group consisting of ethanolamine compounds, propylamine compounds, phenothiazine compounds, piperazine compounds, piperidine compounds, and pharmaceutically acceptable salts of these.

Description

Specification

Hypnotic composition

Technical field

The present invention relates to a hypnotic composition. More specifically, the present invention relates to a hypnotic composition containing an antihistamine component having a hypnotic effect as an active ingredient. Furthermore, the present invention relates to a method for reducing side effects such as post-wake mood discomfort (including nausea and heavy head) or malaise, which the antihistamine component has. As used herein, the term “hypnotic composition” refers to a pharmaceutical composition having an action (sleep-improving action) of smoothly hypnotic and insomnia of a human with a tendency to sleep, such as poor sleep and light sleep. means.

Background art

[0002] Conventionally known hypnotics are broadly classified into barbituric acid compounds, non-barbituric acid compounds, benzodiazepine compounds, and non-benzodiazepine compounds. Both have central inhibitory effects and may cause dependence. For this reason, drugs for treating insomnia have long been required to be less likely to cause side effects. For this purpose, for example, naturally-occurring components having a tranquilizing, sedative or anxiolytic effect, such as Chinese herbs, various plant extracts and essential oils, have been proposed as hypnotics or hypnotic aids.

[0003] On the other hand, diphenhydramine hydrochloride has been conventionally used for the purpose of soothing skin itch and suppressing allergic symptoms such as sneezing and runny nose, but has a side effect of causing drowsiness when taken. Recently, hypnotics / hypnotics that exploit this side effect have been developed in Japan and are now being marketed. However, diphenhydramine hydrochloride is an antihistamine that has the effect of suppressing the action of histamine, which excites nerve cells in the brain to maintain and regulate arousal, and at an effective dose that causes sleepiness, There are problems with side effects such as pleasure (nausea, heavy head) and malaise. Therefore, there is a need for the development of a drug that suppresses and reduces the occurrence of adverse side effects while utilizing the hypnotic action of a potent antihistamine such as diphenhydramine hydrochloride.

[0004] For this purpose, conventionally, antihistamines such as diphenhydramine hydrochloride have been added to Kanokoso Co., Ltd. A hypnotic that reduces the amount of use by enhancing the hypnotic action of the antihistamine, and consequently reducing the side effects of the antihistamine, by combining the extract of grass roots), soybean jujube, or the extract of western chamomile clock grass. Have been proposed (for example, Patent Document

See 1 and 2).

Patent Document 1: JP-A-4-36243

Patent Document 2: JP-A-10-17482

Disclosure of the invention

Problems to be solved by the invention

[0005] The present invention provides a pharmaceutical composition having a safe and desired hypnotic action in which side effects of an antihistamine such as mood discomfort (including nausea and heavy headache) or malaise after waking are significantly suppressed. The purpose is to: Further, the present invention provides a method for reducing the side effects such as mood discomfort and malaise after waking while maintaining a desired hypnotic effect with respect to antihistamines such as diphenhydramine hydrochloride and chlorpheniramine maleate. Aim.

Means for solving the problem

[0006] The inventors of the present invention have made intensive studies to solve the above-mentioned problems, and found that by using vitamin Cs in combination with an antihistamine component having a hypnotic effect, a desired hypnosis of the antihistamine component was obtained. The present invention has been completed by finding that side effects such as mood discomfort and malaise after waking can be reduced while maintaining the effect.

[0007] The present invention has been developed based on such findings, and has the following aspects:

Item 1. A hypnotic composition containing an antihistamine having a sleep effect and vitamin Cs. Item 2. Antihistamine potency At least 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 kind of drug having a sleep effect.

Item 3. Antihistamine drug power The hypnotic composition according to Item 1 or 2, which is diphenhydramine, chlorpheniramine or a pharmaceutically acceptable salt thereof. The hypnotic composition also 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 an antihistamine, which comprises using a vitamin C compound in combination with an antihistamine having a sleep effect.

The method includes the following embodiments:

(2) Antihistamine potency S, 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 for reducing side effects of an antihistamine according to Item 4, which is at least one kind of drug having a sleep effect.

(3) The method for reducing the side effects of the antihistamine according to Item 4, which is S, diphenhydramine, chlorpheniramine or a pharmaceutically acceptable salt thereof, as antihistamine drug power.

(4) The method for reducing the side effects of an antihistamine according to item 4, wherein at least one selected from the group consisting of vitamins B, vitamins E, taurine, and inositols is used in combination.

[0009] Item 5. A method of using vitamin Cs as a side effect reducer of an antihistamine having a sleep effect.

The method includes the following embodiments:

(5) Antihistamine potency: 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 at least one drug having a sleep effect.

(6) The method according to item 5, which is an antihistamine drug S, diphenhydramine, chlorpheniramine or a pharmaceutically acceptable salt thereof.

(7) Item 5 in which vitamin C is used as a vitamin C-containing composition containing vitamin C and at least one selected from the group consisting of vitamin B, vitamin E, taurine, and inositol. How to describe.

[0010] Item 6. Measures to reduce the side effects of a hypnotic containing an antihistamine as an active ingredient A method for producing a hypnotic composition, comprising using a component Min C to be added to the composition.

The method includes the following embodiments:

(8) Antihistamine potency S, 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 at least one kind of drug having a sleep effect.

(9) The method according to item 6, which is an antihistamine drug S, diphenhydramine, chlorpheniramine or a pharmaceutically acceptable salt thereof.

(10) A vitamin C-containing composition containing, in addition to vitamin C, at least one selected from the group consisting of vitamin B, vitamin E, taurine, and inositol The method described in Item 6.

Hereinafter, the present invention will be described in detail.

I. Hypnotic composition

The hypnotic composition of the present invention contains vitamin Cs in addition to the antihistamine having a hypnotic action, and has a hypnotic action based on the antihistamine action of the antihistamine, Central nervous system side effects of the antihistamines, especially mood discomfort (including nausea and heavy headache) or malaise after waking, and fatigue, and anti-histamines do not contain vitamin Cs. It is characterized by being significantly suppressed or reduced as compared to the hypnotic composition.

[0012] The antihistamines targeted by the present invention are those that suppress the action of histamine in the central nervous system and have a hypnotic effect. Specific examples of the antihistamines having a powerful effect include diphenhydramine, dimenhydrinate, dipheniravirin or clemastine, and ethanolamine-based compounds, or pharmaceutically acceptable salts thereof; Propylamine-based compounds such as triprolidine, or pharmaceutically acceptable salts thereof; phenothiazine-based compounds such as promethazine or alimemazine, or pharmaceutically acceptable salts thereof; piperazine such as hydroxyzine or homochlorcyclidine A compound, or a pharmaceutically acceptable salt thereof; and Gin and urea, piperidin-based compounds, or pharmaceutically acceptable salts thereof can be mentioned.

[0013] These pharmaceutically acceptable salts include hydrochloride salts of the above components (eg, diphenhydramine hydrochloride, diphenylpyrazine hydrochloride, promethazine hydrochloride, homochlorcyclidine hydrochloride, hydroxyzine hydrochloride, cyproheptadine hydrochloride, etc.) ), Sulfates, nitrates and other inorganic acid salts, and salicylates of the above components (eg, diphenhydramine salicylate), tannates (eg, diphenylhydramine tannate), laurates (diphenyl laurate) Hydramine), maleate (eg, chlorpheniramine d_maleate, chlorpheniramine d-maleate), teocoleate (eg, diphenylviraline teocoleate), fumarate (eg, fumarate) Clemastine acid), tartrate (eg, alimemazine tartrate), pamoate (eg Organic acid salts such as hydroxyzine pamoate).

[0014] Preferably, diphenhydramine or chlorpheniramine and a pharmaceutically acceptable salt thereof (specifically, diphenhydramine hydrochloride, diphenhydramine salicinoleate, chlorpheniramine d-maleate, or cU-chlorpheniramine maleate). And more preferably with diphenhydramine and a pharmaceutically acceptable salt thereof (specifically, diphenhydramine hydrochloride).

[0015] The content 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, it can be appropriately selected based on the daily dose of the antihistamine, taking into account the mixing ratio of vitamin C, the form of the pharmaceutical composition to be administered, the unit dose thereof, and the like. The dose of the antihistamine is usually in the range of 11 to 300 mg per adult, preferably 5 to 200 mg, more preferably 10 100 mg per day. The preferred content of the antihistamine in the hypnotic composition of the present invention is 0.150% by weight, more preferably 0.20-30% by weight, and further preferably 0.520% by weight. can do.

[0016] Vitamin Cs used in combination with the above antihistamines include ascorbic acid and pharmaceutically acceptable salts thereof (eg, sodium ascorbate and calcium ascorbate), and pharmaceutically acceptable salts thereof. Derivatives (e.g., ascorbic acid Ester derivatives of ascorbic acid such as 2-darcoside, ascorbic acid 2-phosphate, ascorbic acid 2-sulfate, and ascorbic acid fatty acid ester. Preferably, it is ascorbic acid, sodium ascorbate, and calcium ascorbate.

[0017] The ratio of the vitamin Cs contained in the hypnotic composition of the present invention is determined by the above-mentioned side effect of the antihistamine which does not adversely affect the hypnotic effect of the antihistamine contained in the hypnotic composition. There is no particular limitation as long as it can suppress or reduce (mood discomfort after awakening ゃ malaise). Specifically, the mixing ratio of vitamin Cs 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. It is preferably in the range of 25 to 40,000 parts by weight, and more preferably in the range of 500,000 parts by weight. Although not particularly limited, the ratio of vitamin C contained in 100% by weight of the hypnotic composition may be in the range of 0.001 99.99% by weight. It is preferably 90% by weight, more preferably 10-80% by weight, even more preferably 20-80% by weight.

[0018] The hypnotic composition of the present invention may contain 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. And at least one selected from the group consisting of

Vitamin Bs used in combination with the above antihistamines and vitamin Cs include vitamin B1 [thiamine and pharmaceutically acceptable salts thereof (e.g., thiamine hydrochloride, thiamine nitrate, bisthiamine nitrate, thiamine disulfide, and Thiamine dicetyl sulfate ester salt)), and vitamin B1 derivatives (for example, octiamine, sicotiamine, bisuibutiamine, bisbenthamine, funorethoretiamine, fursultiamine hydrochloride, prosultiamine, benfotiamine, disetiamine hydrochloride Vitamin B1; riboflavin and pharmaceutically acceptable salts thereof (eg, sodium riboflavin phosphate ゃ sodium flavin adenine dinucleotide), and riboflavin butyrate; and vitamin B6; Toxins, pyridoxal, pyridoxamine, their pentaphosphates, and their pharmaceutically acceptable salts (eg, pyridoxine hydrochloride, pyridoxal phosphate, etc.); vitamins B12 (cobalamin, cyanocobalamin, mecobalamin, hydroxo) Kobara And pharmaceutically acceptable salts thereof (eg, hydroxocobalamin hydrochloride and hydroxocobalamin acetate); niacin (nicotinic acid, nicotinamide, and pharmaceutically acceptable salts thereof); pantothene Acids [pantothenic acid and its pharmaceutically acceptable salts (eg, calcium pantothenate and sodium pantothenate), panthenol, etc.]; biotin; and holasin (folate or its pharmaceutically acceptable salts, etc.). it can. Preference is given to vitamin B1, vitamin B2, vitamin B6 and vitamin B12. As the 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, examples of the combination include, for example, a combination of vitamin B1, vitamin B2, and vitamin B6, a combination of vitamin B1, vitamin B2, vitamin B6, and vitamin B12, and vitamin B2. And combinations of vitamins with vitamin B6. However, the mode of the powerful combination is merely an example, and the mode of the combination is not limited at all.

When the hypnotic composition of the present invention contains vitamins B, the content of vitamin B in the hypnotic composition depends on the effect of the hypnotic composition containing the antihistamine and vitamin C (hypnosis). There is no particular limitation as long as it does not adversely affect the action and the effect of reducing side effects. Preferably, the ratio is such that the anti-histamines possessed by vitamin Cs can enhance the effect of suppressing and reducing the side effects (mood discomfort after awakening ゃ the fatigue effect).

[0020] Specifically, when vitamin B1 is used, the mixing ratio of vitamin B1 to 100 parts by weight of the antihistamine in the hypnotic composition is usually in the range of 0.1 to 10,000 parts by weight. Power S can. It is preferably in the range of 0.5 to 2000 parts by weight, and 1 to 1000 parts by weight. Although not particularly limited, the proportion of vitamin B1 in 100% by weight of the hypnotic composition may be in the range of 0.0001 to 98% by weight. Good Mashiku is 0. 01- 50 weight ^_0/0, more preferably 0.05 to 30 wt ^_0/0, more preferably from 0.05 one 20 wt%.

[0021] When vitamin B2 is used, the mixing ratio of vitamin B2 to 100 parts by weight of the antihistamine in the hypnotic composition is usually in the range of 0.5 to 5000 parts by weight. It is preferably in the range of 1 to 1,000 parts by weight and 2 to 500 parts by weight. In this case, special But are not limited to, in a ratio of vitamin B2 metals contained in the hypnotic agent composition 100 wt%, can be force S mentioned range of 0. 00005- 97 weight ^_0/0. It is preferably 0.01-150% by weight, more preferably 0.05-30% by weight, and still more preferably 0.05-20% by weight.

When vitamin B6 is used, the mixing ratio of vitamin B6 with respect to 100 parts by weight of the antihistamine in the hypnotic composition can usually be in the range of 11 to 10,000 parts by weight. It is preferably in the range of 2 to 2000 parts by weight and 5 to 1000 parts by weight. Although not particularly limited as long as this is the case, the ratio of vitamin B6 contained in 100% by weight of the hypnotic composition can be in the range of 0.0001 to 98% by weight. Preferably it is 0.0150% by weight, more preferably 0.050% by weight, even more preferably 0.1-20% by weight.

[0023] When using a vitamin B12 compound, a proportion of vitamin B12 such against 100 parts by weight of antihistamines hypnotic agent composition, it may be mentioned the range of the normal 1 X 10- ⁴ 0.99 parts by weight. Preferably 5 X 10- ⁴ 30 parts by weight, 1 X 10- ³ - 15 in the range of parts by weight. This limited Rinioite not particularly limited, the proportion of vitamin B12 metals contained in the hypnotic agent composition 100 wt%, 1 X 10- ⁸ - can be given 59% by weight range. Preferably 0. 0 001- 10 weight ^_0/0, more preferably 0.5 001 5 weight ^_0/0, more preferably 0. 001 1 by weight%.

[0024] The vitamin Es used in combination with the antihistamine and the vitamin Cs include tocopherol, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable derivative thereof. Here, the derivative may be any one belonging to vitamin Es and pharmaceutically acceptable.Specifically, C1-C30 ester of pharmaceutically acceptable tocopherol, preferably C2 of tocopherol — Contains C20 esters. Listed in the Japanese Pharmacopoeia include, for example, d-hypertocopherol succinate, dl-hyto-tocophere succinate, tocopherone succinate, tocopheronole succinate, and And tocopherol conodate calcium calcium acetate, tocoprole acetate, and tocoprole. Those not listed in the Japanese Pharmacopoeia include, for example, d-hypertocoprole acetate, d-hypertocopherol acetate, d-δ-tocopherol, d-hypertocopherol, nicotinic acid DL-hyto-tocopherol, nicotine Tocopherol acid, linoleic acid DL-hyto-tocopherol, d-hyto-tocopherol, natural vitamin E, and D-hyto-tocopheryl polyethylene glycol-1000-succina Vitamin E tocopheryl derivatives such as salts. Preferred are acetic acid monophosphate, tocopherol succinate, and d-α-tocopherolone succinate.

When the hypnotic composition of the present invention contains vitamins E, the content of vitamin E in the hypnotic composition depends on the effect of the hypnotic composition containing the antihistamine and vitamin C (hypnosis). There is no particular limitation as long as it does not adversely affect the action and the effect of reducing side effects. Preferably, it is a ratio that can enhance the effect of suppressing and reducing the side effects (mood discomfort after awakening and fatigue) of the antihistamines possessed by vitamin Cs. Specifically, the mixing ratio of vitamin Es to 100 parts by weight of the antihistamine in the hypnotic composition can be appropriately selected from the range of 3 to 60,000 parts by weight. Preferably it is in the range of 5-12000 parts by weight, more preferably 10 6000 parts by weight. Although not particularly limited, the proportion of vitamin Es contained in 100% by weight of the hypnotic composition may be in the range of 0.000398% by weight. It is preferably 0.01% by weight, more preferably 0.05% to 30% by weight, and still more preferably 0.05% to 20% by 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 effect of the hypnotic composition containing the antihistamine and vitamin C (hypnotic action). And the effect of reducing side effects is not particularly limited. Preferably, the ratio is such that the anti-histamine drug possessed by vitamin Cs can enhance the effect of suppressing or reducing the side effects (mood discomfort after waking up and fatigue effect). Specifically, the mixing ratio 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 in the range of 10-60,000 parts by weight, more preferably 20-30,000 parts by weight. Although not particularly limited, the ratio of taurine contained in 100% by weight of the hypnotic composition may be in the range of 0.0005 to 99% by weight. Preferably it is 0.160% by weight, more preferably 0.1-50% by weight, even more preferably 1-130% by weight.

[0027] The inositols used in combination with the above antihistamines and vitamin Cs include, in addition to inositol, pharmaceutically acceptable inositols such as inositol darcoside, inositol phosphoglyceride, inositol hexanicotinate and meso-inositol hexanicotinate. Acceptable derivatives can be mentioned. Preferably inositol and boar Tall hexanicotinate.

When inositols are used in combination with the above antihistamine and vitamin C, the content of the inositol in the hypnotic composition depends on the effect of the hypnotic composition containing the antihistamine and vitamin C ( There is no particular limitation as long as it does not adversely affect the hypnotic effect and the side effect reducing effect). Preferably, it is a ratio capable of enhancing the effect of suppressing or alleviating the side effects (mood discomfort after waking up and malaise effect) of the antihistamines possessed by vitamin Cs. Specifically, the mixing ratio of inositols to 100 parts by weight of the antihistamine in the hypnotic composition can be appropriately selected from the range of 11 to 180,000 parts by weight, preferably 2 to 36000 parts by weight, It is preferably in the range of 5-18000 parts by weight. Although not particularly limited, the ratio of inositols contained in 100% by weight of the hypnotic composition may be in the range of 0.000199% by weight. Preferably 0.01 to 50 wt ^_0/0, more preferably 0. 05 to 30 wt ^_0/0, more preferably from 1 20% by weight 0.1.

[0029] The above-mentioned vitamins B, vitamin Es, taurine and inositols can be used alone and in combination with an antihistamine and a vitamin C, respectively. Can also be used in combination.

[0030] The hypnotic composition of the present invention may 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 bromureyl urea peryl isopropyl acetyl urea; goo, ziako, ryuu no, d-borneo monole, ginko, antelope, animal bile (bear bile), carrot, saffron, operen, hop, Chiyo Utoukou, force Gikazura, Chiyouji, Sansounin, Kanzou, force Nokosou, west ^^ Chiyabo watch grass, pottery, Bukuriyou, Psycho, Senkiyuu, Souju', Shakuyaku, Western hawthorn, sedation the plants such as Western Yadorigi as a raw material Herbal medicines containing these can be mentioned.

[0031] The hypnotic composition of the present invention can be used as an oral preparation such as tablets, pills, powders, granules, fine granules, capsules, solutions, syrups, suspensions, emulsions, and inhalants. It can also be prepared and administered as a parenteral preparation such as a suppository. Such oral preparations and parenteral preparations (suppositories) are prepared according to the form thereof according to the production methods commonly used in the art. That can be S.

[0032] In addition to the above components, the hypnotic composition of the present invention may also contain various pharmaceutically acceptable carriers and additives depending on the form of the formulation, for formulation and stabilization. You. For example, additives for oral administration include excipients such as lactose, mannitol, corn starch, partially arsenic starch, microcrystalline cellulose, low-substituted hydroxypropylcellulose, carmellose sodium, lactose, talc, etc .; -Binders such as starch, gelatin, methylcellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, microcrystalline cellulose; disintegrants such as starch, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, carboxymethyl starch; Lubricants such as magnesium stearate, talc, and caustic anhydride; suspensions such as polysorbate 80, polyoxyethylene hydrogenated castor oil, and pull nick; lj; sucrose, tanolek, precipitated carbon dioxide Coating agents such as sodium, gelatin, gum arabic, punorelane, carnauba wax, hydroxypropyl methyl phthalate; flavoring agents such as sucrose, glucose, saccharin sodium, sorbitol, citric acid, and aspartame; Stabilizers, coloring agents and the like can be mentioned.

As an additive for parenteral preparations such as suppositories, those conventionally known as bases for suppositories can be used. For example, sodium alginate, gelatin, corn starch, tragacanth gum, methinoresenorelose, hydroxyethinoresenorelose, canoleboxy methinoresenorelose, dextrin, carboxymethyl starch, polyvinyl alcohol, sodium polyacrylate, methoxy Polymers such as ethylene-maleic anhydride copolymer, polyvinyl ether and polyvinyl pyrrolidone; beeswax, olive oil, cocoa oil, sesame oil, soybean oil, jojoba oil, avocado oil, camellia oil, peanut oil, tallow, lard, lanolin, etc. Oils and fats such as polyoxyethylene hydrogenated castor oil; white petrolatum; mineral oils such as liquid paraffin, silicone oil, volatile silicone oil, petrolatum, and the like; carbon gel ointment of Hyde mouth (for example, Plastibase (trade name; Taisho Pharmaceutical Co., Ltd.) Made)) Higher fatty acids such as lauric acid, myristic acid, stearic acid, and oleic acid; esters such as cetyl lactate, isopropyl myristate, and otatyl dodecyl myristate; Alcohol; polyethylene glycol; glycerin monostearate; Nonionic surfactants such as glyceryl monooleate, propylene glycol monostearate, and polyoxyethylene cetyl alcohol ether; anionic surfactants such as sodium cetyl sulfate, sodium stearate, and sodium N-acinoregolenate Agents; lower alcohols such as ethanol and isopropanol; and triethanolamine.

[0034] If necessary, antioxidants such as 1,3-butylene glycol, ascorbic acid, and tocopherol; preservatives such as benzoic acid and paraben; polyethylene glycol, xanthan gum, sodium carboxymethylcellulose, and carboxypropylcellulose Thickeners; acids such as citric acid, lactic acid, hydrochloric acid, and boric acid; or alkalis such as sodium dihydrogen phosphate, sodium citrate, sodium hydroxide, potassium hydroxide, and triethanolamine. Buffering agents (pH adjusting agents); inorganic fillers such as kaolin, bentonite, zinc oxide and titanium oxide can also be blended.

[0035] The dosage of the hypnotic composition of the present invention for therapeutic use depends on the age, sex, degree of insomnia and the method of administration of the patient. In terms of the dose of the drug, the ratio can be about 1 to 300 mg, preferably about 5 to 200 mg, and more preferably about 10 to 100 mg. The dose of the hypnotic composition of the present invention can be administered once or several times a day. The hypnotic composition of the present invention can be used before sleep when the patient falls asleep or sleeps poorly.

[0036] The hypnotic composition of the present invention can exert the desired hypnotic action of the present invention based on an antihistamine by using vitamin Cs in combination with the antihistamine, and also provide the subject with the antihistamine. Side effects that are inconvenient to the patient, specifically, mood discomfort after waking up, which reduce and alleviate side effects of the central nervous system such as heavy headache or malaise, and are used as preferred hypnotics in terms of efficacy and side effects be able to.

[0037] II. Methods for reducing side effects of antihistamines

The method of the present invention can be carried out by using an antihistamine having a hypnotic effect in combination with vitamin Cs. In the present invention, the side effect of the antihistamine drug of interest specifically results from suppression of the action of histamine in the brain, In particular, there may be side effects of the central nervous system such as mood discomfort (including nausea and heavy headache) or malaise after waking.

[0038] Antihistamines include those described in (I) above, which have a hypnotic effect. Preferably, diphenhydramine, chlorfeniramine and a pharmaceutically acceptable salt thereof, specifically diphenhydramine hydrochloride, diphenhydramine salicinoleate, chlorpheniramine d-maleate, d-chlorpheniramine maleate Can be mentioned. More preferred are diphenhydramine and its pharmaceutically acceptable salts, especially diphenhydramine hydrochloride.

[0039] Examples of the vitamin Cs used in combination with the antihistamine include those described in the above (I). Preferably ascorbic acid, sodium ascorbate,

[0040] The ratio of vitamin Cs used in combination with the antihistamine drug is to suppress the side effects of the antihistamine drug (mood discomfort after awakening ゃ malaise) without adversely affecting the hypnotic effect of the antihistamine drug. · There is no particular restriction as long as it can be reduced. For example, the use ratio of each vitamin C in 100 parts by weight of the antihistamine is usually in the range of 10 to 200,000 parts by weight. It is preferably in the range of 25 to 40,000 parts by weight, more preferably 50 to 20000 parts by weight.

[0041] The mode of using vitamin Cs in combination with an antihistamine having a sleep effect is not particularly limited, and an antihistamine having a sleep effect at the time of use (during use) and vitamin C may be used. Any method may be used as long as the method is used in combination. For example, a method in which vitamin Cs are blended into a sleeping pill composition containing an antihistamine drug as an active ingredient and provided as a single drug (mixture), a sleeping pill composition containing an antihistamine drug as an active ingredient, Methods provided as a combination with C or a composition containing the same can be given.

[0042] In order to achieve the object of the present invention, at least one member selected from the group consisting of vitamin B, vitamin E, taurine, and inositol is added to the antihistamine, together with vitamin C. Can also be used in combination. The types of vitamins 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. And more preferably fursultiamine hydrochloride, benfotiamine and thiamine nitrate (these are vitamin B1s), riboflavin butyrate (vitamin B2s), pyridoxine hydrochloride (vitamin B6s), and cyanocobalamin (vitamin B12s) ). As powerful vitamin Bs, 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, the combination may be, for example, a combination of vitamin B1 and vitamin B2 and vitamin B6, a combination of vitamin B1 and vitamin B2 and vitamin B6 and vitamin B12, and a combination of vitamin B2 and vitamin B12. Combinations with B6 can be exemplified. However, the modes of the power and the combination are merely examples, and are not limited to these combinations.

[0043] Further, as the vitamin E, preferably, tocopherol acetate, tocopherol succinate and d-hyto-tocopherol succinate can be mentioned, and as the inositols, preferably, inositol and inositol hexanicotinate can be mentioned.

[0044] 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 100 parts by weight for vitamin B1. 2000 parts by weight, more preferably 1 to 1000 parts by weight; in the case of vitamin B2, usually in the range of 0.5 to 5000 parts by weight, preferably 1 to 1000 parts by weight, more preferably 2 to 500 parts by weight; vitamin B6s for the range of usually 1 one 10000 parts by weight, preferably 2 2000 parts by weight, more preferably 5 1000 parts by weight; in the case of vitamin B12 such normally IX 10- ⁴ - 150 parts by weight, preferably in the range of 5 X 10- ⁴ - 30 parts by weight, more preferably 1 X 10- ³ - 15 parts by weight can and Ageruko.

[0045] When vitamin Es are used in combination, the proportion of vitamin Es used per 100 parts by weight of the antihistamine can usually be appropriately selected from the range of 360000 parts by weight. Preferably it is in the range of 5 12,000 parts by weight, more preferably 10 6000 parts by weight. When taurine is used in combination, the ratio of taurine to 100 parts by weight of the antihistamine can be appropriately selected usually from the range of 5300,000 parts by weight. It is preferably in the range of 10 to 60,000 parts by weight, and more preferably in the range of 203,000 parts by weight. When inositols are used in combination, the proportion of the inositols used per 100 parts by weight of the antihistamine can be appropriately selected from the range of 11 to 180,000 parts by weight. Preferably 2 to 36000 parts by weight, more preferably 5 to 18000 It is in the range of parts by weight.

[0046] The above-mentioned vitamins B, vitamin Es, taurine and inositols can be used alone and in combination with vitamin Cs and in combination with an antihistamine, but any combination of two or more vitamins can be used. It can be used together with antihistamines together with Class C.

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, the undesirable side effects of the central nervous system, Ability to reduce post-wake mood discomfort (including nausea and heaviness) or fatigue. Therefore, the method of the present invention can be effectively used to prepare and provide a hypnotic composition which exhibits a desired hypnotic action with few side effects.

[0048] III. How to use vitamin Cs

Furthermore, the present invention provides a new use for vitamin Cs.

[0049] Specifically, the present invention first provides a method (first method) of using vitamin Cs as a side effect reducing agent for an antihistamine having a sleep effect.

[0050] Secondly, the present invention relates to a method for producing a hypnotic composition formulated to reduce side effects of a hypnotic composition containing an antihistamine as an active ingredient, To provide a method (second method) using vitamin Cs as a component to be added.

[0051] Here, as the side effect of the antihistamine drug having a sleep effect of interest, as described in the above (II), the histamine action in the brain is suppressed, and particularly, the feeling of discomfort after awakening ( They can include side effects of the central nervous system, including nausea and headaches) and malaise.

[0052] In addition, the types of antihistamines to be used, the dosages to be used, and the types and use ratios of vitamin Cs used in combination with the antihistamines are the same as those in (I) and (II) above. )).

As the antihistamine having a sleep effect, diphenhydramine or chlorpheniramine and pharmaceutically acceptable salts thereof (specifically, diphenhydramine hydrochloride, diphenhydramine salicylate, d_ Chlorpheniramine maleate or d-chlorperilamine maleate), more preferably, diphenhydramine and a pharmaceutically acceptable salt thereof (specifically, diphenhydramine hydrochloride). [0054] Examples of the vitamin Cs include those described in the above (I). Preferred are ascorbic acid, sodium ascorbate and calcium ascorbate. Vitamin C should be used in a proportion that can reduce or alleviate the adverse effects of antihistamines (ie, discomfort after waking up ゃ fatigue) without adversely affecting the hypnotic effects of the antihistamines. There is no particular limitation. Specifically, the amount of each vitamin C used per 100 parts by weight of the subject antihistamine (in the case of the second method, the antihistamine contained in the hypnotic composition) is usually 10 to 200,000 weight%. Parts, preferably 25 40000 parts by weight, more preferably 50 to 20000 parts by weight.

[0055] The first method can be carried out by adding a vitamin C compound alone or a composition containing vitamin C compounds as a side effect reducing agent to a hypnotic composition containing an antihistamine drug as an active ingredient. In addition, a vitamin C alone or a composition containing vitamin C is used as a side effect reducing agent for a hypnotic composition containing an antihistamine as an active ingredient, and as a concomitant agent (or adjuvant) of the hypnotic composition. It can also be implemented by use.

[0056] In this case, the composition containing vitamin Cs includes, in addition to vitamin Cs, a composition containing at least one selected from the group consisting of vitamins B, vitamin Es, taurine, and inositols. Lifting power S can. The types of vitamins B, vitamin Es, taurine, and inositols that can be used in this case are as described above in (I) or (Π). As the 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, the combination may be in the form of a combination of vitamin B1, vitamin B2, and vitamin B6, a combination of vitamin B1, vitamin B2, vitamin B6, and vitamin B12, and a combination of vitamin B2. And vitamin B6.組み合わせ These combinations are only examples and are not intended to be limiting.

[0057] The mixing ratio of vitamins B, vitamin Es, taurine or inositols is within a range that does not impair the effect of vitamin Cs as a side effect reducing agent for a hypnotic composition containing an antihistamine as an active ingredient. However, it is preferable to select a range that can be enhanced. For example, if vitamin B1 is used, the range should be such that vitamin B1 is usually 0.1 to 10,000 parts by weight per 100 parts by weight of the antihistamine in the target hypnotic composition. Can be selected as appropriate. It is preferably in the range of 0.5-2000 parts by weight, more preferably in the range of 1.1-1000 parts by weight. When vitamin B2 is used, it should be appropriately selected from the range where vitamin B2 is usually 0.5 to 5000 parts by weight per 100 parts by weight of the antihistamine in the target hypnotic composition. Can be. Preferably it is in the range of 1 to 1000 parts by weight, more preferably 2500 parts by weight. When vitamin B6 is used, it is appropriately selected from the range where vitamin B6 is usually in a ratio of 11 to 10,000 parts by weight with respect to 100 parts by weight of the antihistamine in the hypnotic composition used in combination with the side effect reducing agent. can do. Preferably it is in the range of 22000 parts by weight, more preferably 51000 parts by weight. When using a vitamin B12 compound, selected from a range, such as vitamin B12 such for antihistamines 100 parts by weight of the hypnotic agent composition of interest is usually in a proportion of 1 X 10- ⁴ 0.99 parts by weight can do. Preferably 5 X 10- ⁴ - 30 parts by weight, more preferably from IX 10- ³ 15 parts by weight.

[0058] When vitamin Es are used, the range is such that vitamin Es usually has a ratio of 3 to 60,000 parts by weight to 100 parts by weight of the antihistamine in the target hypnotic composition. You can choose. Preferably it is in the range of 5-12000 parts by weight, more preferably 10-6000 parts by weight. When taurine is used, it can be appropriately selected from a range in which taurine is usually in a ratio of 5 to 300,000 parts by weight with respect to 100 parts by weight of the antihistamine in the target hypnotic composition. It is preferably in the range of 10 to 60,000 parts by weight, more preferably 20 to 30,000 parts by weight. When inositols are used, they can be appropriately selected from a range in which the inositols are usually in a ratio of 11 to 180,000 parts by weight to 100 parts by weight of the antihistamine in the target hypnotic composition. It is preferably in the range of 2 to 36000 parts by weight, more preferably 5 to 18000 parts by weight.

[0059] The above-mentioned vitamins B, vitamin Es, taurine and inositols can be used alone and in combination with vitamin Cs. Any combination of two or more may be used in combination with vitamin Cs. You can also.

[0060] 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. In particular, side effects of the central nervous system (including mood discomfort after waking (including nausea and ) Or malaise) can be reduced. Therefore, the present invention provides a new use of vitamin Cs as an agent for reducing the side effects of antihistamines.

[0061] Secondly, the present invention relates to a method for producing a hypnotic composition formulated to reduce side effects of a hypnotic composition containing an antihistamine as an active ingredient, wherein the composition is added to the composition. To provide a method (second method) using vitamin Cs as a component to be added.

[0062] In the second method, the hypnotic composition containing an antihistamine as an active ingredient may be a tablet, a pill, a powder, a granule, a fine granule, a capsule as described in (I) above. Preparations, liquid preparations, syrups, suspensions, emulsions, inhalants, and other forms of oral preparations, or suppositories and other forms of parenteral preparations. The carrier can be prepared according to a conventional manufacturing method using a carrier or an additive (for example, see (I) above). The second method of the present invention is carried out in the production of a hypnotic composition by using vitamin C as an ingredient in addition to an antihistamine which is an active ingredient, a pharmaceutically acceptable carrier and additives. be able to. 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 be blended. The types of vitamins B, vitamin Es, taurine, and inositols that can be used in this case are as described above in (I) or (II). The mixing ratio of vitamins B, vitamins E, taurine or inositol may be within a range that does not interfere with the effect of vitamin Cs 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, the composition ratio of each component (vitamin Bs, vitamin Es, taurine or inositols) to 100 parts by weight of the antihistamine contained in the finally prepared hypnotic composition is determined. As the blending ratio of each component contained in 100% by weight of the hypnotic composition, the ratio described in the above (I) can be similarly mentioned.

[0063] In the second method of the present invention, when a hypnotic composition containing an antihistamine drug as an active ingredient is produced, a vitamin C compound is used as a component of the hypnotic composition to obtain a desired product obtained based on the antihistamine drug. It can reduce the unwanted side effects of the central nervous system (mood discomfort after awakening (nausea and heavy head) or malaise) while maintaining the hypnotic effect. Therefore, the present invention is a hypnotic composition containing an antihistamine as an active ingredient, and An object of the present invention is to provide a method for producing a composition which does not cause undesired side effects of the central nervous system, using a vitamin C as a prescription component.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described with reference to examples and test examples, but the present invention is not limited to these examples and the like.

[0065] Test example 1

(1) Healthy adults (subjects) were asked to take a hypnotic composition having the formulation shown in Table 1 (Comparative Examples, Examples 18 to 18). The side effects were evaluated. Each hypnotic composition was prepared as a powder in accordance with the method prescribed in the Japanese Pharmacopoeia General Rules for Preparations (powder) based on the following amounts of each component.

[0066] The dose was to be taken once every 30 minutes to 1 hour before bedtime, and alcohol and other drugs for psychiatric nerves were not used in combination. In addition, each subject (one group: 6 subjects) was asked to take any of the hypnotic compositions of the comparative example or each example, and the hypnotic action and side effects of these hypnotic compositions were evaluated. I got it.

[0067] [Table 1]

(2) The hypnotic effects of each of the hypnotic compositions (Comparative Examples, Examples 1 to 8) were evaluated for each subject in terms of three points: falling asleep, depth of sleep, and arousal when awakened the next morning. — They were evaluated by the SD method according to the five criteria described in 4. The results are shown in Table 2-4. Note that the numbers in each table indicate the number of relevant subjects.

[0068] [Table 2] (a) Sleeping: compared to usual

[Table 3]

(b) Depth of sleep: compared to usual

[Table 4]

(c) Awakening at waking

(3) For each of the hypnotic compositions (Comparative Examples, Examples 1 to 8), a table showing the presence or absence of mood discomfort (including nausea and heavy head), dizziness, and malaise up to 6 hours after waking up 1879

They were evaluated by the SD method according to the four criteria described in 5-7.

[Table 5]

(d) Mood discomfort after awakening (including nausea and heavy head)

[Table 6]

(e) dizziness after waking up

[0073] [Table 7]

(f) Fatigue after waking; presence or absence of ft feeling

Fatigue Slightly tired, Slightly tired, but not tired

I don't mind

1 1 1 3

Example 1 0 0 0 6 Example 2 0 0 2 4 Example 3 0 0 1 5 Example 4 0 0 0 6 Example 5 0 0 0 6 Example 6 0 0 0 6 Example 7 0 0 0 6 Example Example 8 0 0 1 5 As described above, by using vitamin Cs in combination with an antihistamine, the desired hypnotic action of the antihistamine is maintained, but unpleasant feelings of discomfort after awakening (nausea and heavy head) and malaise It was found that the feeling was significantly reduced, and that good awakening could be obtained. It was also found that the effect was further improved by using a combination of vitamin C and vitamin B2, and vitamin C and vitamin E.

[0074] Formulation Example 1 Tablet

A hypnotic composition (tablet) having the following compositional power was prepared according to a conventional method.

<Prescription> Single dose: 2 tablets (once before bed)

Diphenhydramine hydrochloride 50 (mg)

Asnic acid 200

Lactose 30

Ten

Crystalline cellulose 200

Five

White ^ ¾ se hook 5

500mg in total,

[0075] Formulation Example 2 Tablet

<Prescription> Single dose: 2 tablets

Diphenhydramine hydrochloride 50 (mg)

Sodium asconolevate 700

Hydroxypropinoresenololose 10

Crystal Senorelose 200

Cros Canole Melose 30

'Sonic acid Gnesium 10

Total 1000mg / 2 tablets.

Formulation Example 3 Granules

A hypnotic composition (granule) having the following compositional power was prepared according to a conventional method. <Prescription> One dose: 1 packet (1 time before bedtime)

Diphenhydramine hydrochloride 50 (mg)

Calcium ascorbate 400

Starch 300

White sugar 80

Sucrose fatty acid ester 100

D—sorbitol 10

'-S 60

Total lOOOOmgZl package.

[0077] Formulation Example 4 Powder

A hypnotic composition (powder) having the following compositional power was prepared according to a conventional method.

<Prescription> One dose: 1 packet (1 time before bedtime)

Diphenhydramine hydrochloride 50 (mg)

Asconolevic acid 50

Lactose 640

Starch 200

Hydroxypropyl cellulose 10

Cros Canole Melose 50

Total lOOOmg / 1 packet.

Industrial applicability

[0078] According to the present invention, by using vitamin Cs in combination with an antihistamine, side effects of the central nervous system of the antihistamine, which do not adversely affect the hypnotic effect of the antihistamine, (feeling sick after awakening) Pleasure (malaise) can be reduced. Therefore, according to the present invention, a hypnotic that is safe and has a high hypnotic effect can be provided.

Claims

The scope of the claims

[1] A hypnotic composition comprising an antihistamine having a sleep effect and vitamin Cs.

[2] Antihistamine potency At least selected from the group consisting of ethanolamine compounds, propylamine compounds, phenothiazine compounds, piperazine compounds, piperidine compounds, and pharmaceutically acceptable salts thereof. The hypnotic composition according to claim 1, which is one kind of drug having a sleep effect.

[3] The hypnotic composition according to claim 1 or 2, which is diphenhydramine, chlorpheniramine or a pharmaceutically acceptable salt thereof.

[4] A method for reducing side effects of an antihistamine, which comprises using a vitamin C compound in combination with an antihistamine having a sleep effect.

[5] Method of using vitamin Cs as a side effect reducer of antihistamines having sleep action

[6] A method for producing a hypnotic composition prescribed to reduce the side effects of a hypnotic containing an antihistamine as an active ingredient, wherein vitamin C is used as a component to be added to the composition.