JP2005325070A - Sleep improver - Google Patents

Abstract

PROBLEM TO BE SOLVED: To secure a comfortable sleep by relieving temporary insomnia that many modern people have such as "bad sleep" and "slow sleep" using the hypnotic action of antihistamines To provide an excellent sleep improving agent.
A sleep-improving agent comprising an antihistamine and one or more compounds selected from the group consisting of vitamins and / or minerals.
[Selection figure] None

Description

  The present invention relates to a sleep improving agent, and more particularly, to a novel sleep improving agent containing an antihistamine and vitamins and / or minerals.

  Many people are suffering from insomnia due to stress society and poor environment. According to a survey result that 80% of modern people have insomnia, it is said that more than 1 out of 5 Japanese people suffer from insomnia.

  For such insomnia, sleep-improving agents containing antihistamines as an active ingredient are temporarily insomnia, not only in the US, UK, Germany, Canada, etc. Provided to relieve symptoms.

  By the way, even if you say insomnia, depending on the state, you may have trouble falling asleep (even if you go to bed and go into a futon, you will not sleep well), a deep sleep disorder (even if you intend to have plenty of sleep time, you feel a good sleep) Do not wake up), awakening in the middle (awake many times in the night, then it is difficult to fall asleep again), early awakening (wakes up early in the morning and still wants to sleep, but cannot sleep) There are various types. For such various types of insomnia patients, an antihistamine alone may not provide a sufficient effect as a sleep improving agent.

  In addition, in order to enhance the hypnotic action of antihistamines, combined use with extract of Western chrysanthemum (Patent Document 1), combined use with valerian (Valgara radix) and / or acid soy sauce (Patent Document 2), etc. is attempted. However, the combined use of these hypnotic herbal medicines and antihistamines is expected to increase the effect, but there are safety issues, and is provided to many patients as a sleep improvement agent for over-the-counter medicines. It was difficult.

JP-A-4-36243 Japanese Patent Laid-Open No. 10-17482

  Therefore, the problem of the present invention is that more patients can use the hypnotic action of antihistamines, and the temporary insomnia symptoms of many modern people such as “bad sleep” and “slow sleep” are present. The object is to provide a safe sleep-improving agent that can relieve and ensure a comfortable sleep.

  As a result of intensive studies in view of these circumstances, the present inventors have formulated vitamins and / or minerals commonly used in the amount of antihistamine necessary for obtaining a sleep effect, The present inventors have found that the hypnotic action of antihistamines is enhanced and thus completed the present invention.

  That is, the present invention is a sleep improving agent comprising an antihistamine and one or more compounds selected from the group consisting of vitamins and / or minerals.

By adding vitamins and / or minerals to the antihistamine, it is possible to obtain a better sleep improvement effect than the antihistamine-only sleep-improving agent.
And since the vitamins and minerals used in the sleep improving agent of the present invention are generally highly safe and widely used, the high safety of the sleep improving agent of the present invention itself can be guaranteed. It is.

  The sleep-improving agent of the present invention is prepared by further blending vitamins and / or minerals with an antihistamine in an amount necessary for obtaining a sleep effect.

  The antihistamine used in the sleep-improving agent of the present invention is not particularly limited as long as it has an anti-H1 histamine action, but anti-H1 histamine such as ethanolamine, phenothiazine, piperazine, piperidine, propylamine and the like. Medication can be used.

  Preferable specific examples of the anti-H1 histamine used in the present invention include diphenhydramine, doxylamine, clemastine, diphenylpyraline, carbinoxamine, etc. for ethanolamine, promethazine, mequitazine, alimemazine, isothipentil, etc. for phenothiazine, piperazine , Hydroxyzine, homochlorocyclidine, etc., piperidine series, hydroxyzine, cyproheptadine, etc., and propylamine series, chlorpheniramine, triprolidine, brompheniramine and the like. More preferable specific examples include ethanolamine anti-H1 histamine drugs such as diphenhydramine, doxylamine, clemastine, diphenylpyralin and carbinoxamine. Among these ethanolamine anti-H1 histamine drugs, it is particularly preferable to use diphenhydramine or doxylamine. These anti-H1 histamine drugs may be used alone or in combination of two or more.

  These antihistamines may be used as they are as the free base, but hydrochloric acid, citric acid, succinic acid, salicylic acid, diphenyldisulfonic acid, tartaric acid, tannic acid, theocric acid, lauryl sulfuric acid, sulfuric acid, pamoic acid, hibenzic acid, It may be used in the form of an acid addition salt such as maleic acid.

  The preferred acid addition salts of these antihistamines vary depending on the type of antihistamine, but examples of preferred acid addition salts in the case of diphenhydramine include diphenhydramine hydrochloride, diphenhydramine citrate, and diphenhydramine tannate. A preferred acid addition salt is diphenhydramine hydrochloride. Further, doxylamine succinate as a preferred acid addition salt of doxylamine, clemastine fumarate as a preferred acid addition salt of clemastine, diphenylpyraline teocrate, diphenylpyraline hydrochloride, and carbinoxamine Preferred acid addition salts include carbinoxamine maleate.

  In the sleep improving agent of this invention, it is necessary to mix | blend the quantity of antihistamine required in order to acquire a sleep effect. The compounding amount of this antihistamine varies depending on each antihistamine, and also varies depending on the type of free base or acid addition salt thereof. Although it cannot be generally stated, the dose per adult is approximately 1 It is preferable to be set to ˜200 mg.

  For example, when diphenhydramine hydrochloride or diphenhydramine citrate is used as an anti-H1 histamine drug, the dose per adult is preferably 25 to 75 mg, and particularly preferably 50 mg. It is preferable to mix | blend with a sleep improving agent so that an amount may become an amount corresponding to this. In addition, when doxylamine succinate is used, the dose per adult is preferably 12.5-50 mg, particularly preferably 25 mg. It is preferable to mix. Furthermore, when clemastine is used, the dose per adult is preferably 1-2 mg, and when diphenylpyralin is used, the dose per adult should be 1-12 mg. When carbinoxamine maleate is used, the dose per adult is preferably 4 to 12 mg. Therefore, it is preferable to prepare a sleep improving agent with a blending amount corresponding to these doses.

  On the other hand, preferable vitamins and minerals used in the sleep-improving agent of the present invention include vitamin C, vitamin B group, calcium and magnesium, and these vitamins and minerals are one or two kinds. The above can be mixed and used.

  Among these, examples of vitamin C include ascorbic acid such as ascorbic acid, sodium ascorbate, calcium ascorbate, and metal salts thereof.

In addition, as vitamin B group, thiamine, thiamine hydrochloride, thiamine nitrate, thiamine nitrate disulfide (bisthiamine nitrate), thiamine disulfide, thiamine dicetyl sulfate ester salt, dicetiamine hydrochloride, fursultiamine hydrochloride, fursultiamine, octothiamine, chicotiamine Vitamin B ₁ and its salts such as bisivebutamine, bisbenchamine, prosultiamine, benfotiamine, cocarboxylase, dibenzoylthiamine and their derivatives, riboflavin, riboflavin butyrate, sodium riboflavin phosphate, flavin adenine dinucleotide, etc. vitamin B ₂ and its salts and its derivatives, pyridoxine, pyridoxal, pyridoxamine, pyridoxine phosphate, pyridoxal phosphate, phosphate pyridoxamine Vitamins of B ₆ and its salts and derivatives, cobalamin, cyanocobalamin, hydroxocobalamin acetate hydroxocobalamin, vitamin B ₁₂ and its salts and its derivatives such as mecobalamin, nicotinic acid, nicotinamide, inositol hexanicotinate, such Hepuronikato Niacin and its salts and derivatives thereof, pantothenic acid and its salts such as calcium pantothenate, sodium pantothenate, panthenol and panthetin and derivatives thereof, biotin, folic acid, orotic acid, potassium orotate, magnesium orotate, choline orotate, etc. Orotic acid and its salts and derivatives thereof, pangamic acid and its salts and derivatives thereof such as pangamic acid and calcium pangamate, thioctic acid (lipoic acid) Thioctic acid such as thioctic acid amide and salts thereof and derivatives thereof, paraaminobenzoic acid (PABA) and salts thereof and derivatives thereof, inositol and salts thereof such as inositol and inositol hexanicotinate and derivatives thereof, choline, choline orotate, tartaric acid Mention may be made of vitamins and vitamin-like substances such as choline such as choline hydrogen and its salts and derivatives thereof. Among these vitamin B groups, one or more selected from the group consisting of vitamin B ₁ , vitamin B ₆ , vitamin B ₁₂ and salts thereof and derivatives thereof are preferable.

  Furthermore, as calcium, calcium gluconate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, calcium glycerophosphate, calcium lactate, precipitated calcium carbonate, calcium chloride, calcium carbonate, calcium hydroxide, calcium lactate, calcium gluconate, citric acid Calcium, calcium L-aspartate, calcium L-glutamate, calcium glycerophosphate, 5'-ribonucleotide calcium, calcium sulfate, tricalcium phosphate, calcium propionate, calcium dihydrogen phosphate, calcium dihydrogen phosphate, carboxymethylcellulose calcium , Stearoyl calcium lactate, calcium oxide and the like.

  Further, as magnesium, magnesium silicate, magnesium oxide, magnesium carbonate, magnesium hydroxide, magnesium silicate aluminate, magnesium hydroxide aluminate, magnesium metasilicate aluminate, aluminum hydroxide / magnesium carbonate mixed dry gel, hydroxide Examples thereof include coprecipitation products of magnesium and potassium aluminum sulfate, and coprecipitation products of aluminum hydroxide, calcium carbonate, and magnesium carbonate.

  The compounding amount of vitamins and / or minerals in the sleep-improving agent of the present invention varies depending on the type, and thus cannot be generally stated. However, the dose per adult for enhancing the hypnotic effect of the anti-H1 histamine drug Is approximately in the range of 0.1 μg to 3.0 g, and therefore, an amount corresponding to this may be used.

  Specifically, for example, the dose of vitamin C per adult is usually in the range of 5 to 3000 mg, preferably 25 to 2000 mg, and more preferably 50 to 500 mg. May be added to the sleep improving agent.

Moreover, although the compounding quantity of a vitamin B group changes with kinds of vitamin B group, since the dosage per time exists in the range of about 0.1 micrograms-1.5 g, what is necessary is just to set it as the quantity corresponding to this. . More specifically, the dose of vitamin B ₁ per adult is usually in the range of 0.1 to 500 mg, preferably 0.5 to 200 mg, and more preferably 1 to 100 mg. What is necessary is just to determine the quantity which was done as a compounding quantity in a sleep improving agent. The dose per adult dose of vitamin _{B 2} is in the range of usually 0.5～180Mg, preferably 1～90Mg, more preferably from 2～45Mg. The dose per adult dose of vitamin _{B 6} is in the range of usually 0.1 to 500 mg, preferably 1 to 200 mg, more preferably from 5 to 100 mg. The dose per adult dose of vitamin _{B 12} is in the range of usually 0.0001～15Mg, preferably 0.0005～3Mg, more preferably from 0.001～1.5Mg. The dose of niacin per adult is usually in the range of 0.1 to 1000 mg, preferably 1 to 800 mg, more preferably 12 to 400 mg. The dose of pantothenic acid per adult is usually in the range of 0.1 to 120 mg, preferably 1 to 60 mg, and more preferably 5 to 30 mg. The dose of biotin per adult is usually in the range of 0.001 to 10 mg, preferably 0.001 to 1 mg, and more preferably 0.01 to 0.5 mg. The dose of folic acid per adult is usually in the range of 0.01 to 100 mg, preferably 0.05 to 20 mg, and more preferably 0.1 to 10 mg. The dose of orotic acid per adult is usually in the range of 1 to 500 mg, preferably 5 to 200 mg, more preferably 10 to 100 mg. The dose of pangamic acid per adult is usually in the range of 0.0001 to 1 mg, preferably 0.0005 to 0.5 mg, and more preferably 0.001 to 0.1 mg. The dose of thioctic acid (lipoic acid) per adult is usually in the range of 0.1 to 500 mg, preferably 1 to 200 mg, more preferably 2 to 100 mg. The dose of paraaminobenzoic acid per adult is usually in the range of 1-1500 mg, preferably 2-1000 mg, more preferably 10-500 mg. The dose of inositol per adult is usually in the range of 1 to 800 mg, preferably 5 to 400 mg, more preferably 10 to 200 mg. The dose of choline per adult is usually in the range of 1-1500 mg, preferably 2-1000 mg, more preferably 10-500 mg. Therefore, when using the vitamins listed above, the amount corresponding to this should be the blending amount in the sleep improving agent.

  On the other hand, when calcium is used as a mineral, the dose per adult for enhancing the hypnotic effect of anti-H1 histamine is usually 2500 mg or less, preferably 2 to 600 mg, more preferably as calcium. Since it is 5 to 300 mg, the amount corresponding to this may be the blending amount in the sleep improving agent.

  Moreover, when using magnesium as a mineral, the dosage per adult for enhancing the sleep effect of the anti-H1 histamine drug is usually 700 mg or less, preferably 1 to 320 mg, more preferably magnesium. Is 2 to 160 mg, so the amount corresponding to this may be the blending amount in the sleep improving agent.

  The sleep-improving agent of the present invention can be produced by a conventional formulation method using anti-H1 histamine drug and vitamins and / or minerals as well as known formulation additives as necessary. it can. The proportion of the anti-H1 histamine drug and vitamins and / or minerals used in this case varies depending on the type of the substance used, but generally, the vitamins and / or the anti-H1 histamine drug is 100 parts by weight. The mineral is preferably about 0.0002 to 6000 parts by weight, and more preferably 0.002 to 1000 parts by weight.

  The formulation additives used in the above formulation include excipients, bases, binders, disintegrants, disintegration aids, lubricants, fluidizing agents, coating agents, plasticizers, antifoaming agents, sugar coatings Agent, skin, brightener, foaming agent, moisture proofing agent, surfactant, solubilizer, buffer, solubilizer, solubilizer, solvent, stabilizer, emulsifier, suspending agent, dispersant, antioxidant Agents, fillers, thickeners, thickeners, pH adjusters, preservatives, preservatives, sweeteners, flavoring agents, cooling agents, flavoring agents / fragrances, fragrances, colorants, and the like.

  The dosage form of the sleep-improving agent of the present invention includes tablets, caplets, hard capsules, soft capsules, orally disintegrating tablets, chewable tablets, granules, fine granules, dry syrups, syrups, liquids for internal use, etc. It can be used as a preparation, and it is particularly preferable to use it as an internal solid preparation.

  Moreover, it is preferable that the sleep improving agent of this invention is a form taken once a day before going to bed.

  In the sleep-improving agent of the present invention, there are unclear parts of the mechanism of action by which vitamins and / or minerals enhance the hypnotic effect of anti-H1 histamine drugs. For example, vitamin B group has an action to stabilize the mind and nerves. Yes, this is thought to be related to the enhancement of the hypnotic effect. In addition, vitamin C promotes hormone secretion, calcium works on the parasympathetic nerve and relaxes it, and magnesium suppresses nerve excitement in response to stimulating hypnotic effects. It is thought that.

  Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

Example 1
Tablets:
Granules for tableting in a conventional manner using 200 g of diphenhydramine hydrochloride, 20 g of bisbenchamine, 40 g of pyridoxine hydrochloride, 2 g of cyanocobalamin, 304 g of lactose, 100 g of corn starch, 310 g of crystalline cellulose, 20 g of croscarmellose sodium, 24 g of polyvinylpyrrolidone Got. 9g of talc and 9g of magnesium stearate were mixed with 918 g of the granules for tableting, and then tableted to obtain 3300 uncoated tablets having a diameter of 9 mm, a thickness of 4.2 mm, and a tablet weight of 260 mg.

Example 2
Tablets:
Diphenhydramine hydrochloride 100 g, thiamine hydrochloride 2 g, cyanocobalamin 1 g, nicotinamide 30 g, calcium pantothenate 20 g, riboflavin butyrate 10 g, ascorbic acid 100 g, calcium gluconate 30 g, lactose 317 g, crystalline cellulose 318 g, croscarmellose sodium 20 g, light anhydrous silica Granulation was carried out by a conventional method using 48 g of acid and 24 g of hydroxypropylose to obtain granules for tableting. 918 g of this granule was mixed with 9 g of magnesium stearate and 9 g of talc, and then tableted to obtain 3300 uncoated tablets with a diameter of 9 mm, a thickness of 4.2 mm, and a tablet weight of 260 mg.

Example 3
Granules:
Diphenhydramine hydrochloride 50 g, calcium ascorbate 500 g, thiamine hydrochloride 20 g, riboflavin 2 g, pidoxine hydrochloride 20 g, cyanocobalamin 0.5 g, folic acid 0.4 g, biotin 0.5 g, orotic acid 60 g, calcium pangamate 0.2 g, thioctic acid 5 g, Inositol 50g, Choline hydrogen tartrate 25g, Calcium gluconate 200g, Mannitol 501.4g, Potato starch 520g, Hydroxypropylcellulose 5g, Light anhydrous silicic acid 20g, Fragrance 20g In this way, 900 sachet granules were obtained.

Example 4
Capsule:
200 g of diphenhydramine hydrochloride, 100 g of thiamine hydrochloride, 200 g of pyridoxine hydrochloride, 0.5 g of cyanocobalamin, 120 g of crystalline cellulose, 109.5 g of lactose, and 70 g of corn starch are mixed to make a mixed powder, which is hard so that it becomes 200 mg per capsule. Capsules (size 2) were filled to obtain 3800 capsules.

Example 5
Coated tablets:
Diphenhydramine hydrochloride 200 g, Benfotiamine 80 g, Ribiflavin sodium phosphate 32 g, Pyridoxal phosphate 80 g, Calcium hydrogen phosphate 240 g, Calcium lactate 240 g, Crystalline cellulose 360 g, Low-substituted hydroxypropylcellulose 200 g, Crosscamellose sodium 40 g, Lactose 424 g, light anhydrous silicic acid 96 g, and hydroxypropylcellulose 48 g were granulated by a conventional method to obtain granules for tableting. After mixing 1836 g of this granule for tableting with 18 g of talc and 18 g of magnesium stearate, tableting was performed to obtain 7000 uncoated tablets having a diameter of 9 mm, a thickness of 4.2 mm, and a tablet weight of 260 mg. Using this uncoated tablet of 6000 tablets, a 10% aqueous coating solution containing 150 g of hydroxypropylmethylcellulose 2910, 10 g of macrogol 6000, 22 g of titanium oxide and 18 g of talc was applied to the uncoated tablet using a high coater (Freund Sangyo). In the dry state, spray coating was performed at 5 mg / tablet to obtain a coated tablet.

Example 6
Coated tablets:
200 g of diphenhydramine hydrochloride, 200 g of ascorbic acid, 40 g of calcium pantothenate, 310 g of crystalline cellulose, 240 g of lactose, 10 g of crospopidone, 20 g of light anhydrous silicic acid, 10 g of talc, and 10 g of magnesium stearate were obtained to obtain granules for tableting. The granules for tableting were tableted to obtain 3600 uncoated tablets having a diameter of 9 mm, a thickness of 4.2 mm, and a tablet weight of 260 mg. Using these 3000 uncoated tablets, a 10% aqueous coating solution containing 150 g of hydroxypropylmethylcellulose 2910, 10 g of macrogol 6000, 16 g of titanium oxide and 24 g of talc was applied to the uncoated tablets using a high coater (Freund Sangyo). In the dry state, it was spray coated with 10 mg / tablet to obtain a coated tablet.

Example 7
Granules:
Diphenhydramine hydrochloride 100 g, ascorbic acid 200 g, calcium ascorbate 200 g, thiamine nitrate 6 g, riboflavin 4 g, pyridoxine hydrochloride 6 g, cyanocobalamin 1 g, panthenol 10 g, inositol hexanicotinate 160 g, mannitol 940 g, low-substituted hydroxypropyl cellulose 200 g, Starch 87g, Hydroxypropylcellulose 6g, Light anhydrous silicic acid 20g, Aspartame 20g, Acesulfame potassium 20g, Fragrance 20g, granulated in a conventional manner and sealed to give 1g per package. Obtained.

Example 8
Granules:
Diphenhydramine hydrochloride 100 g, Ascorbic acid 200 g, Ascorbic acid calcium 200 g, Fursultiamine hydrochloride 40 g, Riboflavin 4 g, Pyridoxine hydrochloride 6 g, Cyanocobalamin 1 g, Glycerophosphate calcium 200 g, Magnesium aluminate metasilicate 120 g, Mannitol 1100 g, Low substituted hydroxypropyl cellulose 240 g , 86 g of Tomokoshi starch, 7 g of hydroxypropylcellulose, 24 g of light anhydrous silicic acid, 24 g of aspartame, 24 g of acesulfame potassium, 24 g of fragrance, and then granulated by a conventional method and packaged to give 1.2 g per package. 1800 granules of granules were obtained.

Comparative Example 1
Capsule:
200 g of diphenhydramine hydrochloride, 220 g of crystalline cellulose, 260 g of lactose and 120 g of corn starch are uniformly mixed to produce a mixed powder, which is filled into hard capsules (size No. 2) to 200 mg per capsule, and 3800 comparative capsules Got.

Comparative Example 2
Capsule:
100 g of thiamine hydrochloride, 200 g of pyridoxine hydrochloride, 0.5 g of cyanocobalamin, 220 g of crystalline cellulose, 209.5 g of lactose and 70 g of corn starch are mixed to make a mixed powder, and hard capsules (size 2) No.) to obtain 3800 comparative capsules.

Test example 1
Hypnosis test:
The capsules obtained in Example 4 and Comparative Examples 1 and 2 were administered to 12 adults with mild insomnia for 7 days, about 30 minutes before going to bed, and sleeping disorder (sleeping: sleeping) Bad, hard to sleep), deep sleep disorder (even if I intended to have plenty of sleep time, I don't feel a good sleep), awakening midway (I wake up many times in the night and then it is difficult to sleep again), The effect of the drug on early arousal (wakes up early in the morning and still wants to sleep but cannot sleep) was tested. The evaluation of the test was performed in five stages: good, slightly good, unchanged, slightly bad, and bad. The results of improvement of sleep deprivation disorder, deep sleep disorder, midway awakening and early awakening are shown in Table 1 as the improvement rate (%).

As is apparent from the above results, the hypnosis improving agent of the present invention was superior to the comparative preparations in improving sleep, deep sleep disorder, mid-term awakening and early awakening.
that's all

Claims (10)

  A sleep improving agent comprising a combination of an antihistamine and one or more compounds selected from the group consisting of vitamins and / or minerals.   The sleep improving agent according to claim 1, wherein the antihistamine is an ethanolamine anti-H1 histamine.   The sleep improving agent according to claim 2, wherein the ethanolamine anti-H1 histamine is diphenhydramine or an acid addition salt thereof.   The sleep-improving agent according to claim 3, wherein diphenhydramine or an acid addition salt thereof is used in an amount of 25 to 75 mg per adult.   The sleep improving agent according to claim 2, wherein the ethanolamine anti-H1 histamine is doxylamine or an acid addition salt thereof.   The sleep improving agent according to claim 5, wherein doxylamine or an acid addition salt thereof is used in the range of 12.5 to 50 mg as an adult dose.   The sleep improving agent according to claim 1, wherein the vitamins are one or more selected from vitamin C and vitamin B groups. The sleep improving agent according to claim 7, wherein the vitamin B group is one or more selected from vitamin B ₁ , vitamin B ₆ , vitamin B ₁₂ and salts thereof and derivatives thereof.   The sleep improving agent according to claim 1, wherein the mineral is calcium and / or magnesium. The sleep improving agent according to any one of claims 1 to 9, wherein the amount of vitamins and / or minerals is 0.0002 to 6000 parts by weight with respect to 100 parts by weight of the anti-H1 histamine drug.