JP5380930B2 - Sleep improver - Google Patents

Description

  The present invention relates to a sleep-improving agent containing peanut and an antihistamine.

  Many people suffer from insomnia due to changes in the working environment and social environment or daily stress. There are various subjective symptoms of insomnia, such as “bad sleep”, “slow sleep”, “bad awakening”, “no feeling of deep sleep”, and “drowsiness in the daytime”. In particular, there is a high desire for improvement for insomnia symptoms such as “bad sleep”, “slow sleep”, or “bad awakening”.

  To reduce insomnia, insomnia patients take hypnotics and pharmacologics as prescription drugs, hypnosis containing hypnotics such as diphenhydramine hydrochloride, hypnotic sedatives, and herbal medicines such as passiflora They are taking sedatives, taking foods that contain glycine and GABA, which are amino acids, or improving the bedding and sleeping environment.

  The ethical drugs are prescribed mainly for patients diagnosed with chronic insomnia and have a relatively strong central depressing action. For this reason, a doctor's diagnosis is necessary, and it is difficult to be prescribed for patients complaining of mild insomnia. On the other hand, sleep improvers and hypnotic sedatives, which are over-the-counter medicines, are commercially available to improve mild insomnia and temporary insomnia. In particular, an over-the-counter drug mainly composed of diphenhydramine hydrochloride is taken by many people who suffer from insomnia in order to relieve symptoms such as temporary insomnia and poor sleep. Sleep improvers with antihistamines have the effect of alleviating symptoms such as temporary insomnia and poor sleep, but adding enough antihistamines to alleviate these symptoms The sleep effect persists, and due to excessive sleepiness, a sufficient effect cannot be expected for poor awakening when waking up. On the other hand, if the amount of the antihistamine is reduced in order to attenuate sleepiness (carry-over effect) when waking up, the awakening becomes worse because the poor sleep and the shallow sleep cannot be sufficiently improved. For this reason, a sleep-improving agent that has a sufficient improvement effect against the insomnia and shallow sleep of temporary insomnia, and that has no sleepiness when waking up and has a good awakening is desired.

  So far, it has been reported that hypnotic action is enhanced by using anti-histamines together with herbal medicines such as hops, butterfly, carrots, nematodes, valerian, sansounin, and chabotoiso, but poor awakening when waking up There is no report of an improvement effect on (see Patent Documents 1, 2, and 3).

  On the other hand, the duckweed is one obtained by drying the roots of the Apiaceae, Ezoyorogusa, Ezonoyorogusa, Karabija, Kobakushi or their varieties. The sandalwood has analgesic action, respiratory center excitatory action, antibacterial action, and antiallergic action, and is used for the purpose of sedation and analgesia of headache, dizziness, sinusitis (see Non-Patent Document 1). As for internal use in humans, about 5 g of peony is decocted and drunk for the purpose of sedation of headache, and about 20 g of peony is decocted and drunk for the purpose of sedation of sinusitis (non-patent document) 1). However, no improvement effect on sleep enhancement and awakening of antihistamines by juniper has been reported.

General crude drug handbook, June 2000, P770-778 JP 2005-281201 JP Japanese Patent Laid-Open No. 10-17482 Japanese Patent Laid-Open No. 4-36243

  An object of the present invention is to provide a sleep improving agent that contains an antihistamine, effectively relieves symptoms of insomnia such as “bad sleep”, “slow sleep”, and “bad awakening” and has few side effects. is there.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have been able to effectively enhance the hypnotic effect of antihistamines and reduce drowsiness when waking up. As a result, the present inventors have found that the awakening is improved and the present invention has been completed.

That is, the present invention
(1) It is a sleep improving agent characterized by containing a juniper and an antihistamine,
(2) Antihistamines are isothipentil, iproheptin, dipheterol, diphenylpyralin, diphenhydramine, triprolidine, tripelenamine, tondilamine, promethazine, methodirazine, carbinoxamine, alimemazine, chlorpheniramine, azelastine, phenatadine, mebhydroline, olotazine, The sleep improving agent according to (1) above, which is one or more selected from the group consisting of salts,
(3) The antihistamine is the sleep improving agent according to the above (1), wherein diphenhydramine, chlorpheniramine or a salt thereof.
(4) The sleep improving agent according to any one of (1) to (3) above, for improving poor sleep, shallow sleep, and poor awakening,
(5) The sleep improving agent according to any one of claims 1 to 3, wherein the sleep duration is short,
(6) The sleep improving agent according to any one of claims 1 to 3, wherein sleepiness upon waking up is attenuated.

  According to the present invention, it has become possible to provide a sleep-improving agent in which hypnotic action of an antihistamine is enhanced and sleepiness (carry-over effect) at the time of waking is attenuated by using a crude drug juniper together with an antihistamine.

  As for the peony used in the present invention, the dry powder may be used as it is, but it is preferable to use the peanut extract because an effective amount can be obtained with a smaller intake. The extract can be easily produced by water, a lower aliphatic alcohol (methanol, ethanol, isopropyl alcohol, etc.), a lower aliphatic ketone (acetone, etc.), or a solvent containing these, by an extraction process usually performed by those skilled in the art. The produced extract can be made into a concentrated extract, a dried extract and a soft extract by a treatment such as heat treatment, freeze-drying or reduced-pressure drying.

  If necessary, the sleep-improving agent of the present invention may contain vitamins, minerals, herbal medicines, herbal extracts, organic acids, coenzymes and the like as long as the effects of the invention are not impaired.

  Examples of the antihistamine used in the present invention include istipendil, iproheptin, dipheterol, diphenylpyralin, diphenhydramine, triprolidine, tripelenamine, tondilamine, promethazine, methodirazine, carbinoxamine, alimemazine, chlorpheniramine, azelastine, phentazine, fentamethodine, methotahydrozine, Is mentioned.

  The antihistamine used in the present invention can be used as a pharmaceutically acceptable salt. Preferred pharmaceutically acceptable salts are acid addition salts such as hydrochloride, salicylate, diphenyldisulfonate, tartrate, tannate, teocrate, maleate, methylene disartylate and fumaric acid. Examples include salts.

  The present invention, if necessary, for example, excipients, binders, coating agents, lubricants, dragees, disintegrants, extenders, flavoring agents, emulsifiers, solubilizers, dispersants, stabilizers, tablets, isotonic agents, solubilizers, buffering agents, cooling agents, antifoaming agents, thickeners, water-soluble bases, suspending agents, etc. Oral preparations such as granules, powders, capsules, dry syrups, and liquids can be prepared.

  In the present invention, the doses of the antihistamine and the beak are different depending on age, sex, body weight and the like. The dose of juniper is about 0.05 to 20 g, preferably 0.1 to 3 g per adult, in terms of raw drug. The dosage of the antihistamine is generally 0.15 to 150 mg, preferably 0.5 to 100 mg. When the antihistamine is diphenhydramine hydrochloride or chlorpheniramine maleate, the dosage is preferably 1 to 75 mg.

  In the present invention, the compounding amount of juniper (in terms of drug substance) is 0.1 to 150,000 parts by mass, preferably 1 to 15000 parts by mass, and more preferably 10 to 1500 parts by mass with respect to 1 part by mass of the antihistamine. .

  Sleeping drugs (sleep-inducing agents) are classified into ultra-short-time type, short-time type, intermediate type, long-time type, and the like according to the action time. The sleep-improving agent of the present invention is preferably short in duration of action, classified into an ultra-short-time type or a short-time type, has no sleepiness when waking up, has good awakening, and has a sleep duration of 8 hours or less.

  Hereinafter, the present invention will be specifically described with reference to production examples, examples, test examples, and comparative examples.

(Production Example 1)
10 g of 50% ethanol solution was added to 100 g of dried beaklet and extracted by heating, and then ethanol was distilled off from the resulting extract. Further, a soft extract was obtained by concentration under reduced pressure.
(Production Example 2)
A 10-fold amount of 50% ethanol solution was added to 100 g of dried hops, followed by heat extraction, and a soft extract was obtained by the same extraction treatment as described above.
(Production Example 3)
Extraction and concentration were performed in the same manner as in Production Example 1 using water as the solvent to obtain a soft extract.
(Production Example 4)
Extraction was performed in the same manner as in Production Example 1 using water as a solvent, and then dried to obtain a dry extract.

Example 1
Powder 1
The peanut soft extract 4.3 g (2.9% compared to the drug substance) obtained in Production Example 1 was dried to obtain 2.7 g peanut dry extract (4. 4 drug substance comparison). By using conventional methods, 1.08 g of dried beak extract (5.0 g in terms of active ingredient), 0.125 g of diphenhydramine hydrochloride, 1.14 g of corn starch and 2.66 g of lactose were used to obtain 5.0 g of powder of diphenhydramine hydrochloride and dried beak extract. This was packaged to obtain four powders of 1.0 g per dose.

(Example 2)
The extract obtained in Production Example 4 was weighed 5.4 g (3.5% compared to the drug substance), and a total of 189 mL of solution was obtained using filtered sterilized water. Diphenhydramine hydrochloride was added to 60 mL of this solution to obtain a total of 120 mL of a solution having a final concentration of 500 mg / mL of juniper 500 (converted to the drug substance) and 12.5 mg / 10 mL of diphenhydramine hydrochloride.

(Example 3)
The extract obtained in Production Example 4 was weighed 5.4 g (3.5% compared to the drug substance), and a total of 189 mL of solution was obtained using filtered sterilized water. Chlorpheniramine d-maleate was added to 60 mL of this solution to obtain a total amount of 120 mL of solution with a final concentration of peanut 500 (raw drug substance equivalent) mg / 10 mL and d-chlorpheniramine maleate 1.5 mg / 10 mL. .

Example 4
The extract obtained in Production Example 3 was weighed 5.0 g (compared to the drug substance 1.2), and a solution of 60 mL in total was obtained using filtered sterilized water. Diphenhydramine hydrochloride was added to 60 mL of this solution to obtain a total of 120 mL of a solution having a final concentration of 500 mg / mL of juniper 500 (converted to the drug substance) and 12.5 mg / 10 mL of diphenhydramine hydrochloride.

(Test Example 1)
The effect of the peony extract obtained in Production Example 1 on the hypnotic action of diphenhydramine hydrochloride was evaluated by the following hexobarbital sleep extension test widely used for the evaluation of hypnotic sedatives and the like.
ddY male mice were used as 9-10 mice per group.
The treatment group consisted of 5 groups, the solvent group, diphenhydramine hydrochloride 10 mg / kg group (diphenhydramine hydrochloride single administration group), diphenhydramine hydrochloride 20 mg / kg group (diphenhydramine hydrochloride single administration group), juniper 400 mg / kg (raw drug equivalent) group ( Bikaku extract alone administration group), diphenhydramine hydrochloride 10 mg / kg and juniper 400 mg / kg group (diphenhydramine hydrochloride and juniper extract combined administration group).
Juniper and diphenhydramine hydrochloride were prepared using sterile filtered water. The final concentration of the adjustment solution was diphenhydramine hydrochloride 10 or 20 mg / 10 mL, juniper 400 mg (concentration of drug substance) / 10 mL, diphenhydramine hydrochloride 10 mg and juniper 400 mg (concentration of drug substance) / 10 mL.
Hexobarbital was dissolved using a 5% ethanol aqueous solution to which a small amount of 0.1N sodium hydroxide aqueous solution was added, and the hexobarbital solution was adjusted to a concentration of 50 mg / 10 mL.
Each group of mice was orally administered with a solvent or each adjustment solution, and 60 minutes later, a hexobarbital solution was intraperitoneally administered. The administration volume was 10 mL per kg body weight.
The hypnotic effect was evaluated by measuring the sleep induction time (time until disappearance of the right-angle reflex) and the sleep duration (time until recovery of the right-angle reflex—time until disappearance of the right-angle reflex) from the administration of hexobarbital.
Statistical analysis of sleep induction time and sleep duration was performed by Student's t-test (two-sided), and there was a significant difference when the risk rate (P) was less than 5% (p <0.05).
The results for sleep induction time are shown in Table 1, and the results for sleep duration are shown in Table 2.

  From the results of the test, the sleep induction time was shortened by the combined use of diphenhydramine and peony extract, and was further shortened compared to the sleep induction time by 10 mg / kg diphenhydramine hydrochloride. In addition, the sleep duration was significantly prolonged by the combination with the peony extract, and was also significantly prolonged compared with the sleep duration by 10 mg / kg diphenhydramine hydrochloride.

(Test Example 2)
The hypnotic effect 30 minutes after administration of the antihistamine was evaluated by the hexobarbital sleep extension test.
The SD male rats were orally administered with a solvent, diphenhydramine hydrochloride 12.5 mg / kg and diphenhydramine hydrochloride 25 mg / kg. The specimen was prepared using filtered sterilized water.
30 minutes after administration of each sample, a hexobarbital solution (100 mg / 5 mL) was intraperitoneally administered at a dose of 5 mL / kg.
The hypnotic action was calculated by measuring the sleep duration from the time of hexobarbital administration (time to recovery of righting reflex-time to disappearance of righting reflex).
The results are shown in Table 3.

  From the results of the test, in the group to which the antihistamine was orally administered, a significant prolongation effect on sleep duration was observed, and a hypnotic effect associated with an increase in dose was observed.

(Test Example 3)
Example 2 and Example 3 The hypnotic action 30 minutes after administration was evaluated by the hexobarbital sleep extension test.
The SD male rats were orally administered with a solvent, diphenhydramine hydrochloride 12.5 mg / kg, Example 2 at 10 mL / kg, d-chlorpheniramine maleate at 1.5 mg / kg, and Example 3 at 10 mL / kg. The specimen was prepared using filtered sterilized water.
30 minutes after administration of each sample, a hexobarbital solution (100 mg / 5 mL) was intraperitoneally administered at a dose of 5 mL / kg.
The hypnotic action was calculated by measuring the sleep duration from the time of hexobarbital administration (time to recovery of righting reflex-time to disappearance of righting reflex).
The results are shown in Table 4.

  From the results of the test, the group administered with Example 2 and Example 3 had a strong hypnotic action because the prolongation effect on sleep duration was observed 30 minutes after administration compared with the group administered with antihistamine alone. It became clear.

(Test Example 4)
The sleepiness (carry-over effect) 8 hours after administration of the antihistamine was evaluated by the following hexobarbital sleep extension test.
The SD male rats were orally administered with a solvent, diphenhydramine hydrochloride 12.5 mg / kg and diphenhydramine hydrochloride 25 mg / kg. The specimen was prepared using filtered sterilized water.
8 hours after administration of each sample, a hexobarbital solution (100 mg / 5 mL) was intraperitoneally administered at a dose of 5 mL / kg.
The sleepiness 8 hours after administration was calculated by measuring the sleep duration from the time of hexobarbital administration (time to recovery of direct reflex-time to disappear of reflex of direct reflex).
The results are shown in Table 5.

  From the results of the test, in the group that was orally administered antihistamine, a significant prolongation of sleep duration was observed even after 8 hours of oral administration, the duration of hypnotic action was long, and sleepiness at sleep (carry-over effect) It was suggested to be strong.

(Test Example 5)
Example 4 Drowsiness (carry-over effect) 8 hours after administration was evaluated by the following hexobarbital sleep extension test.
The SD male rats were orally administered with a solvent, diphenhydramine hydrochloride at a dose of 25 mg / kg, and Example 4 at a dose of 10 mL / kg. The specimen was prepared using filtered sterilized water.
8 hours after administration of each sample, a hexobarbital solution (100 mg / 5 mL) was intraperitoneally administered at a dose of 5 mL / kg.
The sleepiness 8 hours after administration was calculated by measuring the sleep duration from the time of hexobarbital administration (time to recovery of direct reflex-time to disappear of reflex of direct reflex).
The results are shown in Table 6.

  From the results of the study, in the diphenhydramine hydrochloride 25 mg / kg single administration group, a significant prolongation effect on sleep duration was observed even after 8 hours of oral administration, suggesting strong sleepiness (carry-over effect) when waking up However, no significant prolongation effect was observed in the Example 4 administration group, and it became clear that drowsiness (carry-over effect) when waking up was attenuated.

(Comparative Example 1)
The combined effect on the hypnotic action of diphenhydramine hydrochloride was evaluated for the soft hop extract obtained in Production Example 2 by the same method as in Test Example 1.
ddY male mice were used as 10 mice per group.
The treatment group consists of 5 groups, solvent group, diphenhydramine hydrochloride 10 mg / kg group (diphenhydramine hydrochloride alone administration group), diphenhydramine hydrochloride 20 mg / kg group (diphenhydramine hydrochloride alone administration group), diphenhydramine hydrochloride 10 mg / kg and hop 400 mg / kg group (Diphenhydramine hydrochloride and hop extract combined administration group), diphenhydramine hydrochloride 10 mg / kg and hop 800 mg / kg group (diphenhydramine hydrochloride and hop extract combined administration group).
Hops and diphenhydramine hydrochloride were prepared using filter sterilized water. The final concentration of the adjustment solution was 10 or 20 mg / 10 mL of diphenhydramine hydrochloride, 10 mg of diphenhydramine hydrochloride and 400 or 800 mg of hops (concentration of drug substance) / 10 mL.
The hypnotic effect was evaluated by measuring the sleep duration from the time of hexobarbital administration (time to recovery of the positive reflex—time to disappear of the positive reflex).
The results are shown in Table 7.

  From the results of the study, hop soft extract, which is a crude drug that has been reported to have a central inhibitory action such as sedation and sleep prolongation, is a high-dose single dose of 800 mg / kg in terms of the active ingredient compared to juniper soft extract. Even with multiple doses, sleep duration was not significantly prolonged. In this way, in hops known to have a hypnotic sedative effect, no prolongation effect on sleep duration was observed even when a considerably higher dose was used in combination with juniper.

  From the above results, it is possible to obtain a strong hypnotic effect by combining juniper with an antihistamine, relieving symptoms such as “bad sleep” and “slow sleep” at the time of insomnia, and “awakening” It has become possible to provide a sleep-improving agent that attenuates drowsiness, that is, sleepiness (carry-over effect) when waking up.

  According to the present invention, a highly safe and highly effective sleep-improving agent can be obtained, so that it is possible to provide a medicinal product that can be taken with peace of mind, which is useful for the prevention, alleviation, and treatment of medical conditions of people who suffer from insomnia. I can expect.

Claims (4)

A sleep-improving agent comprising at least one selected from juniper and diphenhydramine, chlorpheniramine or a salt thereof . The sleep improving agent according to claim 1 for improving poor sleep, shallow sleep, and poor awakening. The sleep improving agent according to claim 1 , wherein the sleep duration is short. The sleep improving agent according to claim 1 , wherein sleepiness when waking up is attenuated.