JP2024087332A - Composition for application to nasal mucosa - Google Patents

Abstract

[Problem] The object of the present invention is to provide a new non-pharmacological therapeutic means capable of improving sleep disorders. [Solution] A composition for application to the nasal mucosa, which is adjusted to a temperature of 35 to 43°C when used, is effective in preventing and/or improving sleep disorders. [Selected Figure] None

Description

The present invention relates to a composition for application to the nasal mucosa for use in preventing and/or improving sleep disorders.

In recent years, it is said that one in five Japanese people suffer from some kind of sleep disorder, and the number is about one in three people over the age of 60, so sleep disorders have become a problem that can be considered a national disease.

Drug therapy is generally the treatment of choice for sleep disorders. However, drug therapy is difficult to administer as it must be administered carefully under a doctor's prescription, and there is also a tendency to avoid long-term use due to concerns about side effects.

Therefore, the use of natural product-derived ingredients to improve sleep disorders has been studied. In particular, there have been many reports on the use of lavender, which contains linalyl acetate as its main ingredient, to improve sleep (e.g., Non-Patent Document 1, Patent Document 1, etc.).

Effects of aromatic bathing on cardiac autonomic nervous activity during sleep, Journal of the Japanese Society of Balneology, Climatology, and Physical Medicine, 64 (2), 87-92 (2001)

JP 2011-051970 A

The effectiveness of lavender fragrance components in improving sleep is widely accepted. However, the fragrance alone may not be sufficient to effectively improve sleep. For this reason, further options are desirable as non-pharmacological treatments for improving sleep disorders.

Therefore, the present invention aims to provide a new non-pharmacological therapeutic means for improving sleep disorders.

After extensive research, the inventors have unexpectedly found that applying a liquid preparation adjusted to a temperature of 35-43°C to the nasal mucosa has the effect of improving sleep disorders. The present invention was completed through further research based on this finding.

That is, the present invention provides the following aspects.
Item 1. A composition for application to the nasal mucosa, which is adjusted to a temperature of 35 to 43° C. when used, and is used for preventing and/or improving sleep disorders.
Item 2. The composition for application to nasal mucosa according to Item 1, which is diluted or dissolved with heated water when used.
Item 3. The composition for application to the nasal mucosa according to Item 1 or 2, comprising a plant extract selected from the group consisting of extracts of plants of the genus Mint, extracts of plants of the genus Lavandula, and extracts of plants of the genus Citrus.
Item 4. The composition for application to nasal mucosa according to Item 3, wherein the Mint plant is selected from the group consisting of peppermint, spearmint, lavender mint, bergamot mint, and peppermint.
Item 5. The composition for application to nasal mucosa according to Item 3 or 4, wherein the Lavandula plant is lavender.
Item 6. The composition for application to nasal mucosa according to any one of Items 3 to 5, wherein the Citrus plant is selected from the group consisting of orange, grapefruit, mandarin orange, lemon, yuzu, lime, and bergamot.
Item 7. The composition for application to the nasal mucosa according to any one of Items 1 to 6, comprising an ingredient selected from the group consisting of menthol, menthone, menthofuran, limonene, pinene, carvone, dihydrocarvone, terpinyl acetate, cineole, linalyl acetate, linalool, camphor, fenchone, carene, bergapten, and bergamotene.
Item 8. The composition for application to nasal mucosa according to any one of Items 1 to 7, further comprising a nonionic surfactant.
Item 9. The nasal mucosa composition according to any one of Items 1 to 8, which is used to improve wakefulness.

The present invention provides a new non-pharmacological therapeutic method for improving sleep disorders.

The composition for application to nasal mucosa of the present disclosure is characterized in that it is adjusted to a temperature of 35 to 43°C during use and is used to prevent and/or improve sleep disorders. The composition for application to nasal mucosa of the present invention is described in detail below. In this specification, a numerical range indicated by two numerical values and "to" includes the two numerical values as the lower and upper limits. For example, the expression 2 to 15% by weight means 2% by weight or more and 15% by weight or less.

Basic Composition The basic composition of the composition for application to nasal mucosa of the present disclosure is not particularly limited, as long as it can be applied to the nasal cavity as is, or after dilution or dissolution. Usually, the composition for application to nasal mucosa of the present disclosure is designed so as to be substantially isotonic with physiological saline when in use, specifically, so that the osmotic pressure ratio (i.e., the relative value of the osmotic pressure when the osmotic pressure of physiological saline is taken as 1) of the composition for application to nasal mucosa of the present disclosure when in use is 1 or thereabout, more specifically, 0.7 to 1.3.

In order to adjust the osmotic pressure ratio during use to fall within the above-mentioned predetermined range, the composition for application to the nasal mucosa of the present disclosure includes, as a specific osmotic pressure regulator, which is not particularly limited as long as it is water-soluble, examples of which include sugars (glucose, fructose, maltose, etc.), polyhydric alcohols (glycerin, propylene glycol, ethylene glycol, etc.), sugar alcohols (sorbitol, mannitol, xylitol, etc.), inorganic salts (sodium chloride, potassium chloride, sodium bicarbonate, etc.). These osmotic pressure regulators may be used alone or in combination. Among these, preferred osmotic pressure regulators include polyhydric alcohols and inorganic salts, and more preferred examples include glycerin, propylene glycol, and sodium chloride.

The amount of these osmotic pressure regulators is appropriately set according to the osmotic pressure ratio during use of the composition for nasal mucosa of the present disclosure. For example, the content of polyhydric alcohol may be 0.1 to 0.6% by weight, preferably 0.18 to 0.58% by weight, more preferably 0.3 to 0.56% by weight, 0.4 to 0.54% by weight, or 0.45 to 0.52% by weight. The content of inorganic salt may be 0.5 to 0.9% by weight, preferably 0.55 to 0.8% by weight, more preferably 0.58 to 0.8% by weight, or 0.58 to 0.7% by weight.

The composition for application to nasal mucosa of the present disclosure preferably contains a specified plant extract from the viewpoint of improving the effect of preventing and/or improving sleep disorders. In addition, when the composition for application to nasal mucosa of the present disclosure contains a nonionic surfactant, it is preferable to incorporate a specified plant extract from the viewpoint of reducing irritation to the nasal mucosa.

The specified plant extract is selected from the group consisting of extracts of plants of the genus Mint, extracts of plants of the genus Lavandula, and extracts of plants of the genus Citrus.

Examples of mint plants include peppermint, spearmint, lavender mint, bergamot mint, and peppermint. These mint plants may be used alone or in combination of two or more species. Among these mint plants, peppermint is preferred from the viewpoint of improving the effect of preventing and/or improving sleep disorders.

Examples of Lavandula plants include lavender. Examples of Citrus plants include oranges, grapefruits, mandarins, lemons, yuzu, limes, and bergamot. These Citrus plants may be used alone or in combination. Among these Citrus plants, bergamot is preferred from the viewpoint of improving the effect of preventing and/or improving sleep disorders.

The specified plant extract can be obtained by steam distillation or solvent extraction using the above-mentioned plants as raw materials. In the case of an extract by steam distillation, there is an extract (essential oil) obtained by applying high-temperature steam (gas) generated by heating to the raw material to lower the boiling point of the required high-boiling point substance and distilling it. In the case of an extract by solvent extraction, there is an extract obtained by performing an extraction process using an extraction solvent such as hydrocarbon solvents such as n-pentane, isopentane, n-hexane, cyclohexane, petroleum ether, ligroin, methylene chloride, ethylene dichloride, carbon tetrachloride, benzene, toluene, etc.; lower monohydric alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, etc.; ketone solvents such as acetone; ether solvents such as diethyl ether; ester solvents such as methyl acetate and ethyl acetate, etc., and then removing the solvent. Among these extracts, from the viewpoint of improving the effect of preventing and/or improving sleep disorders, it is preferable that the specified plant extract is an extract (essential oil) obtained by steam distillation.

The specified plant extract may contain components derived from the above plants without any particular limitation. Specific examples of such components include fragrance components such as menthol, menthone, menthofuran, limonene, pinene, carvone, dihydrocarvone, terpinyl acetate, cineole, linalyl acetate, linalool, camphor, fenchone, carene, bergapten, and bergamotene. These components may be used alone or in combination.

When the composition for application to the nasal mucosa of the present disclosure contains a specified plant extract, the content of the specified plant extract at the time of use is not particularly limited, but may be, for example, 0.0005 to 0.3% by weight, preferably 0.001 to 0.1% by weight, more preferably 0.003 to 0.05% by weight, and even more preferably 0.003 to 0.04% by weight, 0.004 to 0.03% by weight, or 0.004 to 0.025% by weight.

The contents of various plant extracts include the following:
Extract of a mint plant: for example, 0.0005 to 0.1% by weight, preferably 0.001 to 0.05% by weight, more preferably 0.002 to 0.03% by weight, and even more preferably 0.0035 to 0.012% by weight
Extract of a plant of the genus Lavandula: for example, 0.0005 to 0.05% by weight, preferably 0.001 to 0.03% by weight, more preferably 0.002 to 0.015% by weight, and even more preferably 0.003 to 0.008% by weight
Citrus plant extract: for example, 0.0003 to 0.08% by weight, preferably 0.0005 to 0.05% by weight, more preferably 0.0008 to 0.03% by weight, and even more preferably 0.001 to 0.025% by weight

The content of a specified plant extract means the content of only the components derived from the specified plant. If the extract contains components other than the components derived from the specified plant, such as the solvent used in the extraction operation, the content of the other components is excluded.

When the composition for application to mucosa of the present disclosure contains a nonionic surfactant, the content of the specified plant extract per 1 part by weight of the nonionic surfactant is, for example, 0.005 to 3 parts by weight, preferably 0.005 to 2.5 parts by weight, more preferably 0.01 to 2 parts by weight, and even more preferably 0.05 to 1 part by weight, 0.08 to 0.5 parts by weight, or 0.1 to 0.45 parts by weight.

The contents of various plant extracts per part by weight of the nonionic surfactant are as follows:
Extract of a plant of the genus Mint: for example, 0.01 to 2 parts by weight, preferably 0.02 to 1 parts by weight, more preferably 0.04 to 0.6 parts by weight, and even more preferably 0.07 to 0.24 parts by weight Extract of a plant of the genus Lavandula: for example, 0.01 to 1 part by weight, preferably 0.02 to 0.6 parts by weight, more preferably 0.04 to 0.3 parts by weight, and even more preferably 0.06 to 0.16 parts by weight Extract of a plant of the genus Citrus: for example, 0.006 to 0.4 parts by weight, preferably 0.01 to 0.2 parts by weight, more preferably 0.016 to 0.8 parts by weight, and even more preferably 0.02 to 0.5 parts by weight

Nonionic surfactant The composition for application to the nasal mucosa of the present disclosure may contain a nonionic surfactant. The nonionic surfactant is not particularly limited, but may be, for example, polyoxyethylene hydrogenated castor oil, sorbitan fatty acid ester, glycerin fatty acid ester, propylene glycol fatty acid ester, glycerin alkyl ether, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbit fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene alkyl or arachidyl ether, polyoxyethylene polyoxypropylene alkyl ether, etc. These nonionic surfactants may be used alone or in combination of multiple types. Among these nonionic surfactants, polyoxyethylene sorbitan fatty acid ester is preferably used.

Examples of polyoxyethylene sorbitan fatty acid esters include polyoxyethylene sorbitan trioleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan tristearate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitate, and polyoxyethylene sorbitan monolaurate. The average number of moles of ethylene oxide (EO) added in these polyoxyethylene sorbitan fatty acid esters is not particularly limited, but may be, for example, 5 to 40 moles, preferably 10 to 30 moles, more preferably 15 to 25 moles, and even more preferably 18 to 22 moles. These polyoxyethylene sorbitan fatty acid esters may be used alone or in combination of two or more kinds. Among these polyoxyethylene sorbitan fatty acid esters, polyoxyethylene sorbitan monooleate (polyoxyethylene (18-22) sorbitan monooleate) having an average number of moles of ethylene oxide (EO) added of 18 to 22 moles is preferable.

When the composition for application to the nasal mucosa of the present disclosure contains a nonionic surfactant, the content of the nonionic surfactant when used is, for example, 0.02 to 0.12% by weight, preferably 0.03 to 0.09% by weight, and more preferably 0.04 to 0.07% by weight.

Other Components In addition to the above-mentioned components, the composition for application to the nasal mucosa of the present disclosure may contain other bases and/or additives required for formulation, etc., within the scope of not impairing the effects of the present invention. Such bases and additives are not particularly limited as long as they are pharma- ceutically acceptable, and examples thereof include water, monohydric lower alcohols having 1 to 5 carbon atoms, preservatives, colorants, thickeners, pH adjusters, wetting agents, preservatives, stabilizers, antioxidants, chelating agents, adhesives, buffers, solubilizers, solubilizers, preservatives, etc.

These bases and/or additives may be used alone or in combination of two or more. The content of these bases and/or additives may be appropriately set depending on the formulation form, etc.

In addition to the above-mentioned components, the composition for application to the nasal mucosa of the present invention may contain other pharmacological components as necessary, provided that the effects of the present invention are not impaired. Examples of such pharmacological components include vitamins, antihistamines, local anesthetics, anti-inflammatory agents, mucosal protective agents, blood circulation promoting components, cooling agents, mucopolysaccharides, and the like. These pharmacological components may be used alone or in combination of two or more. When these pharmacological components are contained, the content thereof may be appropriately set depending on the type of pharmacological component used, the expected effect, and the like.

Formulation Form and Product Classification The composition for application to the nasal mucosa of the present disclosure may be in a non-concentrated formulation form that does not require dilution with water when used, or in a concentrated formulation form that requires dilution with water when used.

A non-concentrated formulation is specifically a liquid that is substantially isotonic with physiological saline. Concentrated formulations include, for example, liquids or semi-solids (gels, pastes) that have an osmotic pressure ratio that exceeds that of substantially isotonic with physiological saline, and solids. In the case of solids, it is preferable that they are powders or granules that can be easily dissolved in water when used.

When the composition for application to the nasal mucosa of the present disclosure is a concentrated liquid or semi-solid formulation, the concentration ratio is not particularly limited, but may be, for example, 3 to 50 times, preferably 5 to 30 times, and more preferably 6 to 15 times.

Product categories for the compositions disclosed herein for application to the nasal mucosa include nasal washes and nasal gargles.

Uses The composition for application to the nasal mucosa of the present disclosure is used for the prevention and/or improvement of sleep disorders. In the present invention, "sleep disorder" refers to a condition in which the Pittsburgh Sleep Quality Index (PSQIG) total score is 5.5 or more. Preferably, in the present disclosure, the sleep disorder is a sleep disorder not caused by a respiratory disease and/or a sleep disorder not caused by an otolaryngological disease.

The composition for application to the nasal mucosa of the present disclosure has an excellent effect of improving sleep disorders, and therefore effective improvement can be expected even if the degree of sleep disorder is severe. From this perspective, the suitable degree of sleep disorder in the present disclosure is a PSQIG of 7 or more, preferably 8 or more, more preferably 8.5 or more, and even more preferably 8.8 or more.

More specifically, the composition for application to the nasal mucosa of the present disclosure can be used to improve sleep quality, shorten the time it takes to fall asleep (i.e., the time it takes to fall asleep), and/or improve awakening (i.e., to wake up smoothly in the morning and to enhance the feeling of refreshment upon waking), and is particularly preferably used to improve awakening.

The composition for application to the nasal mucosa of the present disclosure is in the form of a liquid formulation that is substantially isotonic with physiological saline when in use. The temperature of the liquid formulation when in use is 35°C to 43°C, and from the viewpoint of further improving the effect of preventing and/or improving sleep disorders, the temperature is preferably 37°C to 43°C, and more preferably 39°C to 43°C or 39°C to 41°C.

When the composition for application to nasal mucosa of the present disclosure is of a non-concentrated type, it can be used without dilution after heating, and when the composition for application to nasal mucosa of the present disclosure is of a concentrated type, it can be used after dilution with heated water or after dissolving in heated water. The temperature of the heated water used for dilution or dissolution can be easily set taking into consideration the formulation form and dilution ratio of the composition for application to nasal mucosa of the present disclosure.

Dosage and method of use The composition for application to nasal mucosa of the present disclosure is applied to the inside of the nasal cavity.Specific method of use of the composition for application to nasal mucosa of the present disclosure can be used as a method of nasal washing, specifically, a method of directly pouring into the nasal cavity to wash it, more specifically, a method of pouring the composition for application to nasal mucosa into the nasal cavity and expelling it from the mouth, a method of pouring the composition for application to nasal mucosa into one nasal cavity and expelling it from the other nasal cavity, etc.

The amount of the composition for application to the nasal mucosa of the present disclosure used in one application is appropriately set depending on the degree of the effect of preventing and/or improving sleep disorders to be imparted, the age, etc., but the amount in the form at the time of use (i.e., the amount of a liquid at 35°C to 43°C that is substantially isotonic with physiological saline) may be, for example, 20 to 300 mL, preferably 50 to 300 mL, more preferably 100 to 300 mL, even more preferably 200 to 300 mL, and even more preferably 230 to 300 mL, 230 to 280 mL, or 230 to 250 mL.

There are no particular limitations on the timing or number of times per day that the composition for application to the nasal mucosa of the present disclosure is applied to the nasal mucosa, and examples of such applications include application upon waking up, before going out, upon returning home, before bathing, before going to bed, etc., 1 to 3 times per day, preferably 1 to 2 times, and more preferably 2 times.

The composition for application to nasal mucosa of the present disclosure is preferably applied continuously in order to effectively prevent and/or improve sleep disorders. Specific application periods for the composition for application to nasal mucosa of the present disclosure include, for example, 3 days or more, preferably 4 days or more, and more preferably 5 days or more. In addition, since the composition for application to nasal mucosa of the present disclosure provides an effect of preventing and/or improving sleep disorders early, specific upper limits for the application period include, for example, 4 weeks or less, 3 weeks or less, 2 weeks or less, or 1 week or less.

The present invention will be explained in more detail below with reference to examples, but the present invention is not limited to these.

Test Example An 8-fold concentrate of the composition for application to nasal mucosa having the composition shown in Tables 1 and 2 (i.e., a concentrated type composition for application to nasal mucosa in which the concentration of each component other than water is 8 times the concentration shown in Tables 1 and 2) was prepared as a stock solution, and heated water was added to each volume of the stock solution to dilute it to 8 times the volume, thereby finally preparing a liquid formulation (in the form at the time of use) of the composition for application to nasal mucosa having the composition and temperature shown in Tables 1 and 2 as a nasal wash. The details of each component in Tables 1 and 2 are as follows. In addition, in Tables 1 and 2, the osmotic pressure ratio is the relative value of the osmotic pressure when the osmotic pressure of physiological saline is set to 1.0.
Polysorbate: Polysorbate 80 (Polyoxyethylene (20) sorbitan monooleate)
Peppermint fragrance: peppermint essential oil containing menthol, menthone, 1,8-cineole, menthofuran, l-carvone, dihydrocarvone, and α-terpinyl acetate. Lavender fragrance: lavender essential oil containing linalyl acetate, linalool, 1,8-cineole, camphor, pinene, limonene, fenchone, and δ-3-carene. Bergamot fragrance: bergamot essential oil containing linalyl acetate, bergaptene, bergamotene, linalool, and limonene.

Fourteen subjects (mean Pittsburgh Sleep Quality Index (PSQIG) score: 9.1) who were aware of symptoms of sleep disorders, did not regularly use nasal irrigation, and did not suffer from respiratory or otorhinolaryngological diseases were given nasal irrigation of both nostrils twice a day for five days, after waking up and before going to bed, using the liquid formulation (nasal irrigation solution) of the composition for application to the nasal mucosa shown in Tables 1 and 2. The amount of nasal irrigation solution used per time was 250 ml after dilution with purified water. At the end of the five-day test, all subjects rated the quality of sleep (overall evaluation), time to fall asleep (i.e., the time it takes to fall asleep; the shorter the time, the higher the satisfaction), and awakening (i.e., the smoother the awakening in the morning and the stronger the feeling of refreshment when waking up, the higher the satisfaction), as well as the stimulation of the nasal mucosa during nasal irrigation (the weaker the stimulation, the higher the satisfaction). The five-point scale was "satisfied," "rather satisfied," "neither satisfied nor unsatisfied," and "dissatisfied." The total number of subjects who answered "Satisfied" and "Rather Satisfied" was obtained as the effective score. The effective score when the nasal wash of Comparative Example 1 was used was set at 100, and the relative effective scores when the nasal wash of the other Comparative Examples and Examples were used were derived as the evaluation value for each item. The results are shown in Tables 1 and 2.

As shown in Tables 1 and 2, compared to nasal washes prepared at 25°C (Comparative Examples 1 to 4), nasal washes prepared at 37°C or 40°C (Examples 1 to 8) improved sleep quality, shortened time to fall asleep, and improved awakening, and improved sleep disorder symptoms in subjects with high PSQIG. In addition, when lavender or bergamot fragrance ingredients, which are recognized to have a sleep-inducing effect, were used, nasal washes prepared at 25°C (Comparative Examples 3 and 4) contributed to shortening time to fall asleep, but did not effectively improve awakening and overall sleep quality, while nasal washes prepared at 40°C (Examples 5 and 6) significantly improved awakening and sleep quality, despite having the same composition as Comparative Examples 3 and 4. Furthermore, the average PSQIG value after use for Example 7 was 5.4, and excellent effects were observed despite the continuous use period of the nasal wash being only 5 days.

In addition, when comparing compositions with the same composition, the compositions for nasal mucosa application prepared at 37°C or 40°C (Examples 2, 3, 5, and 6) reduced irritation to the nasal mucosa compared to the compositions for nasal mucosa application prepared at 25°C (Comparative Examples 1 to 4), despite the same osmotic pressure ratio. The effect of reducing irritation observed in Examples 2, 3, 5, and 6 was also observed in the other Examples 1, 4, 7, and 8.

For the above Comparative Examples 1 to 4 and Examples 1 to 8, concentrated compositions for application to nasal mucosa were prepared by changing the concentration ratio to 5 times or 20 times, and the temperature and amount of heated water added were appropriately changed to perform follow-up tests using compositions for application to nasal mucosa with the same composition and temperature as those in Tables 1 and 2. As a result, it was found that Examples 1 to 8 similarly achieved the effect of improving sleep disorder symptoms and reducing irritation to the nasal mucosa.

Furthermore, the above Example 1 was tested in the same manner, except that the temperature after dilution was changed to 35°C. As a result, the same effect of improving sleep disorder symptoms and reducing irritation to the nasal mucosa as in Example 1 was obtained.

Claims (9)

A composition for application to the nasal mucosa that is adjusted to a temperature of 35-43°C when in use and is used to prevent and/or improve sleep disorders. The composition for application to the nasal mucosa according to claim 1, which is diluted or dissolved with warmed water at the time of use. The composition for application to the nasal mucosa according to claim 1, comprising an extract of a plant selected from the group consisting of extracts of plants of the genus Mint, extracts of plants of the genus Lavandula, and extracts of plants of the genus Citrus. The composition for application to the nasal mucosa according to claim 3, wherein the Mint plant is selected from the group consisting of peppermint, spearmint, lavender mint, bergamot mint, and peppermint. The composition for application to the nasal mucosa according to claim 3, wherein the Lavandula plant is lavender. The composition for application to the nasal mucosa according to claim 3, wherein the Citrus plant is selected from the group consisting of orange, grapefruit, mandarin orange, lemon, yuzu, lime, and bergamot. The composition for application to the nasal mucosa according to claim 1, comprising a component selected from the group consisting of menthol, menthone, menthofuran, limonene, pinene, carvone, dihydrocarvone, terpinyl acetate, cineole, linalyl acetate, linalool, camphor, fenchone, carene, bergapten, and bergamotene. The composition for application to the nasal mucosa according to claim 1, further comprising a nonionic surfactant. The nasal mucosa composition according to claim 1, which is used to improve wakefulness.