KR102503531B1 - Composition for raising core body temperature - Google Patents

Abstract

An object of the present invention is to provide a composition for raising core body temperature, and a food-drink composition for raising core body temperature, which is safe and can obtain an effect of raising core body temperature that is not transient. A means to solve the subject is to use one or two or more compounds selected from the group consisting of lophenol compounds and cyclolanostane compounds.

Description

Composition for raising core body temperature

The present invention relates to a composition for raising core body temperature.

Body temperature can be broadly divided into outer shell temperature, such as body surface temperature, and core body temperature. The outer shell temperature is easily changed by changes in the environmental temperature, but the core body temperature is maintained within a certain range (Non-Patent Document 1). Here, a person's body temperature decreases due to lifestyle factors such as lack of exercise and lack of sleep, and external factors such as air conditioning and excessive stress. In addition, symptoms such as coldness, respiratory disease, swelling of the lower extremities and malaise of the body appear due to a decrease in body temperature (Non-Patent Documents 2 to 5).

For symptoms caused by a drop in body temperature, raising the body surface temperature is effective as a temporary countermeasure. Here, as a means of increasing the body surface temperature, methods such as taking heat into the body by using a warming agent, ingestion of warm food, etc., and means aimed at improving blood flow such as ingestion of herbal medicine are known (patented). Literature 1, 2).

However, these means for raising the body temperature for the purpose of improving blood flow cannot raise the core body temperature, and thus cannot lead to a fundamental solution to lowering the body temperature (Patent Documents 2 and 3).

As prior art related to materials having an action of normalizing the modulation of core body temperature, proanthocyanidins extracted from the bark of pine trees, extracts of Cistanche plants in the Orobanchaceae family, and quinoa extracts , black ginger extract, etc. are known (Patent Documents 1 to 4).

By the way, among plant sterols, compounds having a cyclolanostane skeleton and compounds having a lophenol skeleton have an effect of reducing the amount of lipid peroxide in the blood in arteriosclerosis model animals, thoracic aorta It has been found to have an effect of suppressing the number of plaque formation, and its use as an antioxidant has been proposed (Patent Document 5).

Japanese Unexamined Patent Publication No. 2006-143654 Japanese Unexamined Patent Publication No. 2011-157302 Japanese Unexamined Patent Publication No. 2010-260848 Japanese Unexamined Patent Publication No. 2014-15430 International Publication No. 2010/058795 Pamphlet

Biomechanism Journal 16(1), 1992 Journal of the Japan Mibyeong System Society 　13(1): 92-95, 2007 Showa Academic Journal 　75(6): 652-656, 2015 Miyazaki Prefectural College of Nursing Research Keynote 8(1): 13-27 Nose 　 Y. et 　 al. Kawasaki 　 Journal of 　 Medical 　 Welfare, 16(2), 58-63, 2011

As described above, since the core body temperature cannot be raised by means of increasing the body temperature for the purpose of improving blood flow, a fundamental solution to lowering the body temperature cannot be reached.

Then, the present invention has as a problem to provide a core body temperature raising agent capable of obtaining a core body temperature raising effect that is safe and not transient, and a food-drink composition for raising core body temperature. do.

The present inventors have discovered that one or two or more compounds selected from the group consisting of lophenol compounds and cyclolanostane compounds have a core body temperature raising action, and completed the present invention.

That is, 1st invention which solves the said subject is a core body temperature raising agent or core body temperature raising composition which contains as an active ingredient one or two or more compounds selected from the group which consists of a lophenol compound and a cyclolanostane compound. In addition, in this specification, the terms of a composition and an agent have the same meaning.

The following aspects are included in 1st invention.

In a preferred embodiment of the present invention, one or two or more compounds selected from the group consisting of the lophenol compound and the cyclolanostane compound are selected from the group consisting of 4-methylcholest-7-en-3-ol and 4-methylergost-7 -The group consisting of -en-3-ol, 4-methylstigmast-7-en-3-ol, 9,19-cyclolanostan-3-ol, 24-methylene-9,19-cyclolanostan-3-ol It is 1 or 2 or more compounds selected from.

Moreover, it is preferable to set this invention as the form containing 0.00001 mass % or more of the said compound in total amount.

In addition, the present invention is also an agent for increasing core body temperature or a composition for increasing core body temperature, which contains, as an active ingredient, a composition containing at least 0.00001% by mass of one or two or more compounds selected from the group consisting of lophenol compounds and cyclolanostane compounds. do.

Further, the agent for increasing core body temperature or the composition for raising core body temperature of the present invention is preferably in a form used for preventing and/or improving diseases caused by lowering of core body temperature.

Among them, the agent for increasing core body temperature or the composition for raising core body temperature of the present invention can be suitably used for poor circulation caused by a drop in core body temperature and/or respiratory diseases caused by a drop in core body temperature.

Moreover, this invention is also a food-drinks composition for raising core body temperature, which contains as an active ingredient 1 or 2 or more compounds selected from the group which consists of a lophenol compound and a cyclolanostane compound.

In a preferable aspect of the food-drinks composition of the present invention, one or two or more compounds selected from the group consisting of lophenol compounds and cyclolanostane compounds are 4-methylcholeth-7-en-3-ol, 4-methyl ether Ghost-7-en-3-ol, 4-methylstigmast-7-en-3-ol, 9, 19-cyclolanostane-3-ol, 24-methylene-9, 19-cyclolanostane-3- It is one or two or more compounds selected from the group consisting of ol.

Moreover, it is preferable to make the food-drinks composition of this invention into the form containing 0.00001 mass % or more of the said compound in total amount.

Moreover, this invention is also a food-drink composition for raising core body temperature, which contains as an active ingredient the composition containing 0.00001 mass % or more of 1 or 2 or more compounds selected from the group which consists of a lophenol compound and a cyclolanostane compound.

Further, the food-drink composition for raising core body temperature of the present invention is preferably in a form used for preventing and/or improving diseases caused by lowering core body temperature.

The food-drink composition for raising core body temperature of the present invention can be suitably used for poor circulation caused by a drop in core body temperature and/or respiratory diseases caused by a drop in core body temperature.

In addition, the second invention to solve the above problems is to use a compound selected from the group consisting of a lophenol compound and a cyclolanostane compound in the production of a composition for preventing or ameliorating a disease caused by a decrease in core body temperature And, the preferred form of the compound is as described above.

Moreover, the following aspects are included in 2nd invention.

Use of a composition containing 0.00001% by mass or more in total amount of a compound selected from the group consisting of lophenol compounds and cyclolanostane compounds in the production of a composition for preventing or ameliorating a disease caused by a decrease in core body temperature.

In a preferred aspect of the present invention, the preventive or ameliorative composition is a composition for increasing core body temperature.

In a preferred embodiment of the present invention, the composition for prevention or improvement is a composition for preventing or improving poor circulation caused by a decrease in core body temperature and/or respiratory diseases caused by a decrease in core body temperature.

Further, the third invention to solve the above problems is a compound selected from the group consisting of lophenol compounds and cyclolanostane compounds used for preventing or improving diseases caused by lowering of core body temperature, The form is as described above.

In a preferred embodiment of the present invention, the disease caused by a lowered core body temperature is poor circulation caused by a lowered core body temperature and/or a respiratory disease caused by a lowered core body temperature.

In a preferred embodiment of the present invention, the compound is used for preventing or ameliorating poor circulation caused by a decrease in core body temperature and/or respiratory diseases caused by a decrease in core body temperature.

In addition, the fourth invention for solving the above problems is core body temperature, which includes administering a compound selected from the group consisting of a lophenol compound and a cyclolanostane compound to a subject having a disease caused by a decrease in core body temperature. It is a method for preventing or improving a disease caused by a decrease in , and the preferred form of the compound is as described above.

Moreover, 4th invention makes the following a preferable aspect.

Administering to the subject a composition containing 0.00001% by mass or more of a compound selected from the group consisting of the lophenol compound and the cyclolanostane compound in a total amount.

In a preferred embodiment of the present invention, the disease caused by a lowered core body temperature is poor circulation caused by a lowered core body temperature and/or a respiratory disease caused by a lowered core body temperature.

In a preferred embodiment of the present invention, the disease caused by the lowering of the core body temperature is a respiratory disease.

1 is a graph showing the transition of core body temperature in each group in Example 1. FIG.

Next, a preferred embodiment of the present invention will be described in detail. However, the present invention is not limited to the following preferred forms, and can be freely changed within the scope of the present invention. In addition, in this specification, a percentage is a display by mass unless otherwise specified.

The agent for increasing core body temperature of the present invention contains a compound selected from the group consisting of a lophenol compound (Compound 1) and a cyclolanostane compound (Compound 2) as an active ingredient. Compound 1 and compound 2 are represented by the following general formula (1) and general formula (2), respectively.

[Tue 1]

compound 1

In general formula (1), R1 is a C5-C16 straight-chain or branched-chain alkyl group, or an alkenyl group containing 1 or 2 double bonds. Moreover, the said alkyl group or alkenyl group may be a substituted alkyl group or substituted alkenyl group in which 1 or 2 hydrogen atoms are substituted by the hydroxyl group and/or the carbonyl group.

Moreover, R2 and R3 are each independently a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. Here, as a C1-C3 alkyl group, a methyl group, an ethyl group, etc. are preferable, and a methyl group is especially preferable. Further, the alkyl group may be a substituted alkyl group in which at least one hydrogen atom is substituted with a hydroxyl group and/or a carbonyl group.

[Tue 2]

Moreover, R4 forms C=O together with the carbon atom which comprises a ring, or is either -OH or _-OCOCH3 .

In the said general formula (1), it is preferable that R1 is any one of the groups represented by the following formula.

[Tue 3]

(Ra and Rb are each independently a hydrogen atom, a hydroxyl group or a methyl group)

(Rc and Rd are each independently a hydrogen atom, a hydroxyl group or a methyl group)

Moreover, in the said general formula (1), it is preferable that one of R2 and R3 is a hydrogen atom and the other is a methyl group, and it is preferable that R4 is a hydrogen group.

As compound 1, preferably, 4-methylcholest-7-en-3-ol, 4-methylergost-7-en-3-ol and 4-methylstigmast-7-en-3-ol are selected. can be heard Each compound has a structure represented by the following formula, respectively.

[Tuesday 4]

4-Methylcholeth-7-en-3-ol

[Tuesday 5]

4-methylergost-7-en-3-ol

[Tue 6]

4-methylstigmast-7-en-3-ol

Compound 1 can be chemically produced based on known production methods.

For example, based on the supplement data described in Vitali "Matyash" et al., "PLOS" BIOLOGY, "Volume" 2, "Issue 10, e280, 2004, it is possible to synthesize.

In addition, it is known that Compound 1 is contained in plants, and Compound 1 can be produced based on a known method for producing lophenol (Biochemical Experimental Method 24, Lipid Metabolism Experimental Method, by Mitsuhiro Yamada, Society Press, p. 174, 1989).

For example, it is possible to extract from a plant containing Compound 1 using a method such as hot water extraction, organic solvent extraction, supercritical extraction or subcritical extraction (eg See, for example, Japanese Patent Publication No. 3905913). Compound 1 can be extracted, for example, from plants in the Liliaceae family, Legumes family, Crested family, Solanaceae family, and Basaceae family.

The molecular weight and structure of Compound 1 prepared as described above can be determined or confirmed by, for example, mass spectrometry (MS) and nuclear magnetic resonance spectrometry (NMR).

Compound 1 may also be a pharmaceutically acceptable salt. As pharmaceutically acceptable salts, both metal salts (inorganic salts) and organic salts are included, and their list is in "Remington's Pharmaceutical Sciences, 17th edition, 1985, page 1418. ” can be exemplified.

Specifically, inorganic acid salts such as hydrochlorides, sulfates, phosphates, diphosphates, and brittle hydrogenates; malates, maleates, fumarates, tartarates, succinates, citrates, acetates, lactates; Organic acid salts such as methane sulfonate, p-toluene sulfonate, pamoate, salicylate, and stearate are included without limitation.

Moreover, it can also be set as a salt with metal salts, such as sodium, potassium, calcium, magnesium, and aluminum, and amino acids, such as lysine. In addition, solvates such as hydrates of the above compounds or pharmaceutically acceptable salts thereof can also be used.

[Tue 7]

compound 2

In general formula (2), R<5> is a C6-C8 straight or branched alkyl group, and the alkenyl group containing 1 or 2 double bonds. Moreover, the said alkyl group or alkenyl group may be a substituted alkyl group or substituted alkenyl group in which 1 or 2 hydrogen atoms are substituted by the hydroxyl group and/or the carbonyl group.

Moreover, R6 and R7 are a hydrogen atom or a methyl group each independently. Moreover, R8 forms C=O together with the carbon atom which comprises a ring, or is any of the following formula.

[Tue 8]

In the above general formula (2), it is preferable that R5 is any one of the groups represented by the following formula.

[Tue 9]

(Re is a hydrogen atom, a hydroxyl group or a methyl group, and Rf is a hydrogen atom or a hydroxyl group)

(Rg is a hydrogen atom, a hydroxyl group or a methyl group)

Moreover, in the said general formula (2), it is preferable that one of R6 and R7 is a hydrogen atom and the other is a methyl group, and it is preferable that R8 is a hydroxyl group.

As compound 2, Preferably, 9,19-cyclolanostan-3-ol and 24-methylene-9,19-cyclolanostan-3-ol are mentioned. Each compound has a structure represented by the following formula, respectively.

[Tue 10]

9, 19-cyclolanostane-3-ol

[Tue 11]

24-methylene-9, 19-cyclolanostan-3-ol

Compound 2 can be chemically produced based on known production methods. For example, 24-methylene-9,19-cyclolanostan-3-ol (common name: 24-methylenecycloartanol) is disclosed in Japanese Laid-Open Patent Publication No. 57-018617 or International Publication No. 2012/023599 (γ -Method of synthesizing from oryzanol). Further, Compound 2 can be produced by using a hydrolyzate of cycloartenol ferulate as a starting material by a method disclosed in Japanese Laid-Open Patent Publication No. 2003-277269.

[Tue 12]

Cycloartenol Ferulate

In addition, it is known that compound 2 is also contained in plants such as Liliaceae, Legumes, Coriaceae, Solanaceae and Basaceae ([Phytochemistry, USA, 1977, Vol. 16, Vol. 140- Page 141], [Handbook of Phytochemical Constitution of GRAS Herbs and Other Economic Plants (Handbook of Phytochemical Constituents of GRAS Herbs and Other Economic Plants), 1992, CRC, USA Press], or [Hager's 　 Handbuch 　der 　 Pharmazeutischen 　 Praxis, Volumes 2-6, 1969-1979, Germany, Springer-Pairach Berlin] ). Therefore, compound 2 can be extracted from these plants by a known method such as organic solvent extraction or hot water extraction (see, for example, Japanese Patent Publication No. 3924310). Compound 2 is preferably extracted from a plant of the genus Liliaceae and Aloe.

The molecular weight and structure of the compound prepared as described above can be determined or confirmed by, for example, a mass spectrum (MS) method, a nuclear magnetic resonance spectrum (NMR) method, or the like.

Further, compound 2 may be a pharmaceutically acceptable salt. Such salts are as exemplified for compound 1.

The agent for increasing core body temperature or the composition for raising core body temperature (hereinafter referred to as a composition for raising core body temperature) of the present invention contains a compound selected from the group consisting of Compound 1 and Compound 2 as an active ingredient. The compound may be one type, that is, either compound 1 or compound 2 alone or a mixture of compound 1 and compound 2.

When compound 1 or compound 2 is used alone, compound 1 (mainly 4-methylcholest-7-en-3-ol, 4-methylergost-7-en-3-ol, or 4-methylstigma str-7-en-3-ol) or compound 2 (mainly 9,19-cyclolanostan-3-ol or 24-methylene-9,19-cyclolanostan-3-ol) desirable.

Among them, 4-methylcholest-7-en-3-ol is particularly preferable as compound 1 from the viewpoint of physical properties such as solubility that are considered when used as an active ingredient in a composition for increasing core body temperature, and as compound 2 9,19-cyclolanostan-3-ol is particularly preferred.

In the case of contrasting Compound 1 and Compound 2, Compound 1 (mainly 4-methylcholesterol-7-en-3-ol, 4-methylergost-7-en-3-ol or 4-methylstigma It is more preferable that it is steam-7-en-3-ol).

Moreover, also in each of compound 1 or compound 2, 1 type of compound may be used, and a some compound may be mixed and used.

The composition for increasing core body temperature of the present invention preferably contains 4-methylcholesterate-7-en-3-ol, 4-methylergost-7-en-3-ol, and 4-methylstigmast-7- A compound selected from the group consisting of en-3-ol, 9,19-cyclolanostan-3-ol, 24-methylene-9,19-cyclolanostan-3-ol is contained as an active ingredient.

In the case of combining both Compound 1 and Compound 2 (mixture of Compound 1 and Compound 2), the mass ratio range of Compound 1 and Compound 2 is, for example, as follows.

Compound 1:Compound 2 is preferably 5:1 to 1:5, more preferably 3:1 to 1:3, and particularly preferably 2:1 to 1:2.

The content of the compound in the composition for increasing core body temperature of the present invention can be appropriately selected depending on symptoms and the like, but the total amount is preferably at least 0.00001% by mass or more, more preferably at least 0.0001% by mass or more, still more preferably. is at least 0.0005% by mass or more, particularly preferably at least 0.001% by mass or more. The upper limit of the amount of the agent for increasing core body temperature of the present invention is not particularly limited, but the total amount is 90% by mass or less, preferably 70% by mass or less, and more preferably 50% by mass or less. is exemplified

Further, the composition for increasing core body temperature of the present invention may be formulated to contain, as an active ingredient, a composition containing 0.00001% by mass or more of a compound selected from the group consisting of compound 1 and compound 2.

Examples of such compositions include, for example, an extract obtained from a plant containing the above-mentioned compound 1, an extract obtained from a plant containing compound 2, and an extract obtained from a plant containing both compounds 1 and 2, and these mixtures can be mentioned.

Here, as a plant containing compound 1 and compound 2, plants, such as a Lily family, a leguminous family, a crested family, a nightshade family, and Basaceae, are mentioned, for example.

As an example of the compounds contained in natural plants, among aloe vera, compound 1 (mainly 4-methylcholes-7-en-3-ol, 4-methylergost-7-en-3-ol and 4 -Methylstigmast-7-en-3-ol), and compound 2 (mainly 9,19-cyclolanostan-3-ol and 24-methylene-9,19-cyclolanostan-3-ol) It is known that it has been

Therefore, using aloe vera as a raw material, 4-methylcholeth-7-en-3-ol, 4-methylergost-7-en-3-ol, or 4-methylstigmast-7-en- Either 3-ol (Compound 1), or 9,19-cyclolanostan-3-ol, or 24-methylene-9,19-cyclolanostan-3-ol (Compound 2) was purified, respectively. Thus, it is possible to obtain a mixture containing compound 1:compound 2 in a ratio of 5:1 to 1:5, preferably 3:1 to 1:3, and particularly preferably 2:1 to 1:2. The composition obtained in this way is suitable as an active ingredient of the composition for increasing core body temperature of the present invention.

Further, the agent for increasing core body temperature or the composition for increasing core body temperature of the present invention contains one or two or more compounds selected from the group consisting of lophenol compounds and cyclolanostane compounds in a total amount, preferably at least 0.0001% by mass or more, and further It is preferable to take the form containing a composition containing preferably at least 0.0005% by mass or more, particularly preferably at least 0.001% by mass or more as an active ingredient.

The agent for increasing core body temperature or the composition for core body temperature of the present invention can be used as a pharmaceutical or pharmaceutical composition.

When used as a pharmaceutical or pharmaceutical composition, the agent for increasing core body temperature of the present invention is preferably administered orally or parenterally to mammals including humans.

The agent for increasing core body temperature of the present invention is effective for preventing and/or improving symptoms caused by lowering of core body temperature.

In addition, in this specification, the concept of "prevention" includes reduction of the risk of disease occurrence. In addition, the concept of "improvement" includes any (both) of treatment and alleviation of symptoms.

In the present invention, as symptoms or diseases caused by a decrease in core body temperature, poor circulation, digestive diseases (vomiting, chronic diarrhea, anorexia, loose stools), hypothermia, respiratory diseases (asthma, phlegm) , dizziness, dizziness, orthostatic disorder (not feeling good when standing up from lying down), edema of the lower extremities, chronic malaise, lethargy, and decline in intellectual work ability.

In addition, the symptom due to poor circulation defined in the present invention represents a symptom caused by a decrease in core body temperature, particularly among symptoms caused by a drop in core body temperature, constriction of peripheral blood vessels, a drop in blood flow, and the like.

Further, the digestive disease defined in the present invention refers to a digestive disease caused by a decrease in core body temperature, among examples of causes of digestive disease, such as lower core body temperature, food poisoning, excessive intake of alcohol, unbalanced sex hormones, and the like. .

In addition, dizziness, dizziness, orthostatic disorder (not feeling good when standing up from lying down), edema of the lower limbs, and symptoms caused by chronic malaise, as defined in the present invention, include lowering of core body temperature, heart failure or disturbance of life rhythm, Among symptoms caused by a disorder in the balance of sex hormones, etc., symptoms caused by a decrease in core body temperature are particularly shown.

The agent for increasing core body temperature or the composition for raising core body temperature of the present invention is effective in preventing and/or improving one or more of the above symptoms.

Among them, the food-drink composition of the present invention can be suitably used for poor circulation caused by a decrease in core body temperature and respiratory diseases (asthma, phlegm) caused by a decrease in core body temperature.

The form of the agent for increasing core body temperature or the composition for core body temperature of the present invention is not particularly limited and can be appropriately selected depending on usage. Specifically, tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, syrups, suppositories, injections, ointments, patches, eye drops, nasal drops and the like can be exemplified.

The administration timing of the agent for increasing core body temperature or the composition for core body temperature of the present invention is not particularly limited, and can be appropriately selected depending on the target disease. In addition, the dosage is preferably determined depending on the type of preparation, usage, age and sex of the patient, other conditions, severity of symptoms, and the like.

The dosage of the agent for increasing core body temperature or the composition for core body temperature of the present invention is appropriately selected depending on the usage, age, sex, disease severity of the patient, and other conditions. Usually, it is based on the range of preferably 0.0001 to 100 mg/day, more preferably 0.001 to 50 mg/day, particularly preferably 0.01 to 10 mg/day, in terms of the amount of the active ingredient.

Further, the agent for increasing core body temperature or the composition for core body temperature of the present invention is preferably continuously used for 3 weeks or more, more preferably 6 weeks or more, and particularly preferably 12 weeks or more.

The agent for increasing core body temperature or the composition for core body temperature of the present invention may contain additives generally used in medicine. Examples of additives include excipients, binders, disintegrants, lubricants, stabilizers, flavoring agents, diluents, surfactants, and solvents for injections.

The agent for increasing core body temperature or the composition for core body temperature of the present invention can be produced by blending the compound as an active ingredient with a pharmaceutical carrier. The agent for increasing core body temperature of the present invention can be produced, for example, by formulating the compound together with the above additives.

Further, the agent for increasing core body temperature or the composition for core body temperature of the present invention is an extract obtained by extracting, supercritical or subcritical extraction using hot water or various solvents using a known plant or the like containing the compound as a raw material. It can also be manufactured by formulating with the above-mentioned additives.

In particular, the agent for increasing core body temperature or the composition for core body temperature of the present invention containing Compound 1 and Compound 2 in the range of the specific mass ratio can be prepared by mixing each compound in the range of the mass ratio. In addition, such an agent for increasing core body temperature or a composition for core body temperature is obtained by extraction using hot water or various solvents, supercritical extraction, subcritical extraction, etc., using known plants containing Compounds 1 and 2 as raw materials It is also possible to manufacture by using the extract prepared by the method.

Moreover, this invention is also a food-drinks composition for raising core body temperature. In the present invention, the "food and drink composition" includes food and drink consumed by humans as well as feed consumed by animals other than humans.

The food-drink composition for raising core body temperature of the present invention contains a compound selected from the group consisting of compound 1 and compound 2 as an active ingredient. The compound may be one type, that is, either compound 1 or compound 2 alone or a mixture of compound 1 and compound 2.

When compound 1 or compound 2 is used alone, compound 1 (mainly 4-methylcholest-7-en-3-ol, 4-methylergost-7-en-3-ol, or 4-methylstigma str-7-en-3-ol) or compound 2 (mainly 9,19-cyclolanostan-3-ol or 24-methylene-9,19-cyclolanostan-3-ol) desirable.

Among them, 4-methylcholester-7-en-3-ol is particularly preferred as compound 1 from the viewpoint of physical properties such as solubility that are considered when used as an active ingredient in a food-drink composition for raising core body temperature. As 2, 9, 19-cyclolanostan-3-ol is especially preferable.

In the case of contrasting Compound 1 and Compound 2, Compound 1 (mainly 4-methylcholesterol-7-en-3-ol, 4-methylergost-7-en-3-ol or 4-methylstigma It is more preferable that it is steam-7-en-3-ol).

Moreover, also in each of compound 1 or compound 2, 1 type of compound may be used, and a some compound may be mixed and used.

The food-drink composition for raising core body temperature of the present invention is preferably 4-methylcholesterol-7-en-3-ol, 4-methylergost-7-en-3-ol, 4-methylstigmast- A compound selected from the group consisting of 7-en-3-ol, 9,19-cyclolanostan-3-ol, 24-methylene-9, and 19-cyclolanostan-3-ol is contained as an active ingredient.

In the case of combining both Compound 1 and Compound 2 (mixture of Compound 1 and Compound 2), the mass ratio range of Compound 1 and Compound 2 includes, for example, the following.

Compound 1:Compound 2 is preferably 5:1 to 1:5, more preferably 3:1 to 1:3, and particularly preferably 2:1 to 1:2.

The content of the above compound in the food-drink composition for increasing core body temperature of the present invention can be appropriately selected depending on symptoms and the like, but the total amount is preferably at least 0.00001% by mass or more, more preferably at least 0.0001% by mass or more, and even more. It is preferably at least 0.0005% by mass or more, particularly preferably at least 0.001% by mass or more. In addition, the upper limit of the amount in the food-drink composition for raising core body temperature of the present invention is not particularly limited, but an example is 90% by mass or less, preferably 70% by mass or less, and more preferably 50% by mass or less as a total amount. do.

Moreover, the food-drinks composition for raising core body temperature of this invention contains the composition containing the compound selected from the group which consists of compound 1 and compound 2 as an active ingredient. The compound may be one type or multiple types.

As such a composition, for example, an extract obtained from a plant containing the above-mentioned compound 1, an extract obtained from a plant containing compound 2, and an extract obtained from a plant containing both compound 1 and compound 2, and these mixtures can be mentioned.

For example, as an example included in natural plants, among aloe vera, compound 1 (mainly 4-methylcholes-7-en-3-ol, 4-methylergost-7-en-3-ol and 4-methylstigmast-7-en-3-ol) and compound 2 (mainly 9,19-cyclolanostan-3-ol and 24-methylene-9,19-cyclolanostan-3-ol) It is known to contain

Therefore, using aloe vera as a raw material, 4-methylcholeth-7-en-3-ol, 4-methylergost-7-en-3-ol, or 4-methylstigmast-7-en- Either 3-ol (Compound 1), or 9,19-cyclolanostan-3-ol, or 24-methylene-9,19-cyclolanostan-3-ol (Compound 2) was purified, respectively. Thus, it is possible to obtain a mixture containing compound 1:compound 2 in a ratio of 5:1 to 1:5, preferably 3:1 to 1:3, and particularly preferably 2:1 to 1:2. The composition obtained in this way is suitable as an active ingredient of the food-drink composition for raising core body temperature of the present invention.

Further, the food-drink composition for increasing core body temperature of the present invention contains one or two or more compounds selected from the group consisting of lophenol compounds and cyclolanostane compounds in a total amount, preferably at least 0.00001% by mass or more, more preferably It is preferable to take a form containing as an active ingredient a composition containing at least 0.0001% by mass or more, more preferably at least 0.0005% by mass or more, particularly preferably at least 0.001% by mass or more.

The food-drink composition for raising core body temperature of the present invention is effective for preventing and/or improving symptoms or diseases caused by lowering core body temperature.

In the food-drinks composition for raising core body temperature of the present invention, the symptoms or diseases caused by the lowering of the core body temperature are the same as those to be prevented and/or improved in the pharmaceutical form described above.

The amount of the compound in the food-drink composition for raising core body temperature is, depending on the form, the total amount of the compound, preferably 0.0001 to 100 mg/day, more preferably 0.001 to 50 mg/day, Particularly preferably, it may be in an amount suitable for ingestion in the range of 0.01 to 10 mg/day. Therefore, the food-drink composition for raising core body temperature of the present invention contains the above compounds in a total amount of preferably 0.0001 to 100 mg/day, more preferably 0.001 to 50 mg/day, particularly preferably 0.01 to 10 mg. It is preferable to use / day intake.

Further, it is preferable that the food-drink composition for raising core body temperature of the present invention be used continuously for preferably 3 weeks or more, more preferably 6 weeks or more, and particularly preferably 12 weeks or more.

The food-drink composition for increasing core body temperature is preferably a health functional food. "Health functional food" refers to foods that have direct or indirect indications of disease preventive effects or disease risk reduction effects, and functionalities indicated on product packages based on scientific grounds under the responsibility of business operators, according to the Consumer Agency. Means declared food. Examples include foods currently sold in Japan in the form of foods for specified health use, foods with functional claims, and health supplements.

The form of the food-drink composition for increasing core body temperature is not particularly limited, but beverages such as soft drinks, carbonated drinks, nutritional drinks, fruit drinks, and lactic acid bacteria drinks (including concentrated stock solutions and powders for preparation of these drinks), It is particularly preferable from the viewpoint of efficiently ingesting the compound.

Moreover, as a form of a functional food or drink, a granular, tablet-like or liquid supplement is also preferable from the viewpoint that the intake amount of the active ingredient can be grasped easily by the ingester.

In addition, it is also preferable to use such a functional food or drink in a form in which indications for use such as "for preventing or improving symptoms caused by a decrease in core body temperature" or "for raising core body temperature" are added. That is, the food-drink composition for raising core body temperature of the present invention contains, as an active ingredient, a compound selected from the group consisting of compound 1 and compound 2, to which the application "for raising core body temperature" has been added, for example. It is preferably marketed as a food-drink composition for preventing and/or improving symptoms caused by a drop in body temperature.

The "indication" includes all indications having a function of informing the user of the purpose. In other words, as long as the above indications can be recalled or inferred, regardless of the purpose of the indication, the contents of the indication, the object or medium to be displayed, etc., all of them fall under the above "indications". .

In addition, the above-mentioned "mark added" means that the display behavior of trying to associate and recognize the said mark and the food-drinks composition (product) for raising core body temperature exists.

It is preferable that the act of displaying is such that a consumer can directly recognize the use. Specifically, the act of describing the use of the food-drink composition for raising core body temperature according to the present invention on the product or product packaging, advertisements related to the product, price tags, or transaction documents (including those provided by electronic methods) The act of describing the above uses can be exemplified.

On the other hand, as the content to be displayed (display content), it is preferable that it is a display authorized by the government or the like (for example, a display that has been authorized based on various systems determined by the government and is performed in a manner based on such approval).

Examples include indications of health food, functional food and drink, enteral nutrition food, food for special use, food with health function, food for specified health use, food with nutritional function, food with functional claims, quasi-pharmaceuticals, etc. can do. In particular, indications authorized by the Consumer Affairs Agency, for example, indications approved by certain health food systems and systems similar thereto, can be exemplified. Examples of the latter include labeling as food for specified health uses, labeling as conditionally specified food for health use, labeling to the effect that it affects the structure or function of the body, labeling for reducing disease risk, etc. Labeling as a food for specific health use (particularly, labeling for health use) as defined by the Enforcement Rules (Japan Ministry of Health, Labor and Welfare Ordinance No. 86 of April 30, 2003), and similar labels are listed as typical examples. It is possible.

Words indicating the above use are not limited to words such as "for the prevention and/or improvement of symptoms caused by a decrease in core body temperature" and "for an increase in core body temperature", and even if words other than that, core body temperature Needless to say, any language expressing an action or effect of preventing or ameliorating symptoms caused by a decrease in , is included in the scope of the present invention.

Further, the food or drink composition for raising core body temperature of the present invention preferably includes, in addition to the indication of the intended use, an indication of the active ingredient and an indication of the relationship between the intended use and the active ingredient.

The food-drink composition for increasing core body temperature can be produced by blending a compound selected from Compound 1 and Compound 2 as an active ingredient. The food-drink composition for raising core body temperature of the present invention can be produced, for example, by mixing the above compound with a food-drinks composition raw material and processing it.

In addition, the food-drink composition for raising core body temperature uses a known plant or the like containing the compound as a raw material, and extracts obtained by extraction using hot water or various solvents, supercritical extraction, or subcritical extraction, It can also be manufactured by processing together with a composition raw material.

Further, when the form of the food-drink composition for raising core body temperature is a granular, tablet, or liquid supplement, the compound as an active ingredient is, for example, lactulose, maltitol, lactitol, etc. Sugars and other sugars, such as dextrin and starch; Proteins such as gelatin, soybean protein and corn protein; Amino acids such as alanine, glutamine and isoleucine; Polysaccharides such as cellulose and gum arabic; Soybean oil ), it is also preferable to formulate together with fats and oils, such as a neutral fatty acid triglyceride.

[Example]

Next, the present invention will be described in more detail by showing examples, but the present invention is not limited to the following examples.

[Production Example 1]

(Preparation of lophenol compound (compound 1))

100 kg of mesophyll (transparent gel part) of aloe vera gel was liquefied using a homogenizer, and a mixture of 100 L of ethyl acetate/butanol (3:1) was added thereto and stirred. After being allowed to stand overnight, the ethyl acetate/butanol mixture and the aqueous layer were separated, and the ethyl acetate/butanol mixture was recovered. This ethyl acetate/butanol mixture was concentrated under reduced pressure. The mass of the recovered ethyl acetate/butanol mixture liquid extract was 13.5 g.

A solution in which 13 g of the extract was dissolved in 1 ml of a chloroform/methanol (1:1) mixture was passed through a column packed with 400 g of silica gel 60 (manufactured by Merck), and adsorbed onto the column, Using a chloroform/methanol mixture (chloroform: methanol = 100: 1, 25: 1, 10: 1, 5: 1, and 1: 1 mixing ratio), the stepwise gradient method of increasing the methanol concentration step by step method), and the eluate was fractionated for each mixing ratio of the mixture. Among these fractions, the presence of the lophenol compound of the present invention in the fraction eluted with chloroform: methanol = 25: 1 was determined by normal phase and reverse phase thin layer chromatography (manufactured by Merck Corporation). Silica gel 60F254 and RP-18F2543).

After removing the solvent from this fraction, it was dissolved in 1 ml of a chloroform/methanol (1:1) mixture, passed through a column packed with 100 g of silica gel 60, and adsorbed onto the column, followed by hexane/ethyl acetate (4:1). ) and eluted with 1100 ml of the mixed solution. The elution fraction was sequentially fractionated into 300 ml (fraction A), 300 ml (fraction B), and 500 ml (fraction C).

It was confirmed by normal phase and reverse phase thin layer chromatography that the lophenol compound, which is Compound 1 of the present invention, was concentrated in fraction A, and further, COSMOSIL C18 (manufactured by NACALAI TESQUE, INC) Using HPLC equipped with chloroform/hexane (85:15), it was separated into a mixed solution, and 4-methylcholester-7-en-3-ol, 4-methylergost-7-en-3-ol, and 1.3 mg, 1.2 mg, and 1 mg of 4-methylstigmast-7-en-3-ol were obtained, respectively. The structure of each compound was confirmed by mass (MS) analysis and NMR.

[Production Example 2]

(Preparation of cyclolanostane compound (Compound 2))

To 8.0 g of γ-oryzanol (manufactured by Oryza Oil & Fat Chemical Co., Ltd.), add 250 ml of distilled water, 50 g of sodium hydroxide, 150 ml of isopropanol, 150 ml of ethanol, and 150 ml of methanol, and heat to reflux for 2 hours using a mantle heater. did After the reaction, the reaction liquid was added to 1300 ml of water, and the produced white precipitate was suction filtered to obtain a solid substance. In order to wash the residual alkali, after suspending the obtained sludge in 1000 ml of water, suction filtration was performed again. This operation was repeated twice, and 5.91 g of oryzanol hydrolyzate was obtained by freezing and drying the final residue under reduced pressure. The hydrolyzate was purified by HPLC to obtain 2435 mg of cycloaltenol and 1543 mg of 24-methylene-9,19-cycloranostan-3-ol (Compound 2).

Next, 9,19-cyclolanostan-3-ol (Compound 2) was synthesized using the obtained cycloaltenol.

302 mg of cycloaltenol, 150 ml of isopropanol, and 1.0 g of powdery 5% palladium-supported carbon catalyst were placed, sealed in an autoclave, substituted with nitrogen gas, and then 3 kg/cm of hydrogen gas. was introduced under the pressure of It was heated while stirring, and when it reached 50 degreeC, the hydrogen pressure was set to 5 kg/cm<2>, and it was made to react for 6 hours maintaining pressure by replenishing absorbed hydrogen. The reaction solution was filtered to remove the catalyst, concentrated, and then purified by silica gel column chromatography (developing solvent: chloroform 100%) to obtain 9,19-cyclolanostan-3-ol 275 mg was obtained.

[Production Example 3]

(Preparation of a sample to which a mixture of a lophenol compound and a cycloranostane compound was added)

4-Methylcholest-7-en-3-ol, 4-methylergost-7-en-3-ol, and 4-methylstigmast-7-en-3-ol obtained by Production Example 1 And, using 9,19-cyclolanostane-3-ol and 24-methylene-9,19-cyclolanostane-3-ol obtained in Production Example 2, a lophenol compound and a cyclolanostane compound A mixture was obtained in which the mass ratio was a lophenol compound (Compound 1):cycloranostane compound (Compound 2) = 1:1.

A mixture of a lophenol compound and a cyclolanostane compound was dispersed using propylene glycol (manufactured by Wako Pure Chemical Industries, Ltd.) to prepare a 5000-fold diluted solution. This solution was diluted 100 times with distilled water to prepare test sample 1.

That is, test sample 1 containing 0.0002% by mass of Compound 1 (lophenol compound) and Compound 2 (cyclolanostane compound) in a total amount was prepared.

[Example 1]

In this Example, the core body temperature raising action of the composition containing Compound 1 and Compound 2 was examined.

(1) Test sample

In this example, test sample 1 obtained in Production Example 3 was used. In addition, as a control sample, a 1% propylene glycol aqueous solution was used.

(2) Test method

Six-week-old C57BL/6 mice (manufactured by Nippon SLC) were pre-fed for 1 week with animal feed D12450B (manufactured by Research Diets, Inc.), followed by animal feed D12492 (manufactured by Research Diets, Inc.). The sample was changed to , and breeding was carried out for 2 weeks. The reared C57BL/6 mice were divided into a control group and a test sample group so that there were 12 mice in each group, and continuous administration of the test sample was started. In addition, administration of the test sample was performed by administering test sample 1 to the mouse so as to achieve 200 µL/10 g body weight per day. On the other hand, the same amount of 1% propylene glycol aqueous solution was administered to the control group as a test sample.

Six weeks and 12 weeks after the start of continuous administration of test sample 1, the core body temperature was confirmed by rectal temperature measurement (data logger thermometer (TR-7wf) manufactured by T&D Corporation).

(3) Test results

The core body temperature after 6 weeks from the start of administration is shown in Table 1, the core body temperature after 12 weeks is shown in Table 2, and the transition of core body temperature in each group is shown in Fig. 1. In the table, the value is expressed as the average value ± standard deviation of 12 animals, and the p value in the table shows the probability of significance by the Student's t test.

Table 1 Results of core body temperature (rectal temperature) measurement (6 weeks of intake) test group Core body temperature (℃) p-value (vs control) control group 36.15±0.32 test sample group 36.28±0.33 0.200

Table 2 Results of core body temperature (rectal temperature) measurement (12 weeks of intake) test group Core body temperature (℃) p-value (vs control) control group 36.85±0.26 test sample group 36.09±0.26 0.046

In addition, as a result of performing the same test on the test sample containing 0.0002 mass% of the above-mentioned compound 1 alone and the test sample containing 0.0002 mass% of compound 2 alone, all test samples were similar to test sample 1, and the control group In comparison, core body temperature showed a high value.

(4) Consideration

From the results of Tables 1 and 2, compared to the control group, the test sample group ingested a test sample containing 0.0002% by mass of a cyclolanostane compound and a lophenol compound had a higher core body temperature than that of the control group.

In addition to this, comparing Tables 1 and 2, the difference in core body temperature between the test sample group and the control group was greater at the 12th week of intake than at the 6th week of intake.

From the above, it was found that the cyclolanostane compound and the lophenol compound have an effect of increasing core body temperature.

More specifically, 4-methylcholest-7-en-3-ol, 4-methylergost-7-en-3-ol, 4-methylstigmast-7-en-3-ol, 9, 19 - It was found that cyclolanostan-3-ol and 24-methylene-9,19-cyclolanostan-3-ol have a core body temperature raising action.

Further, from the graph of Fig. 1, it was found that the core body temperature of the test sample group was higher than that of the control group at both 6 weeks and 12 weeks of ingestion.

In addition, the transition of body temperature from 6 weeks of intake to 12 weeks of intake of the test sample group was -0.19 ° C, while the transition of body temperature from 6 weeks of intake to 12 weeks of intake of the control group was -0.30 ° C.

Here, in both the test sample group and the control group, a decrease in core body temperature was observed from 6 weeks of ingestion to 12 weeks of ingestion, but considering that core body temperature decreased due to external factors such as cooling and stress, the graph of FIG. 1 (test sample From the comparison of the change in body temperature between the group and the control group), it can be said that the test sample group had an effect of suppressing a decrease in core body temperature.

From the above results in Table 1, Table 2, and FIG. 1, by ingesting 0.00001% by mass or more, preferably 0.0001% by mass or more of the cyclolanostane compound and the lophenol compound, a more excellent effect of increasing core body temperature and prevention of lowering of core body temperature It was found that the action was obtained.

In addition, since the effect of increasing the core body temperature and the effect of preventing a decrease in core body temperature were recognized in the test sample group ingested with the test sample containing the cyclolanostane compound and the lophenol compound, the cyclolanostane compound and the lophenol compound were added at 0.00001 It has been found that even the composition containing at least % by mass has an effect of increasing core body temperature and a function of preventing a decrease in core body temperature.

[Example 2]

A medicament having a core body temperature raising effect comprising the following composition was manufactured by the following method.

In a mixture containing the lophenol compound prepared in Production Example 1 and the cyclolanostane compound prepared in Production Example 2 in a ratio of lophenol compound: cyclolanostane compound = 1: 1, carboxymethyl cellulose (CMC: die 2% by mass of a composition containing 0.001% by mass of the mixture prepared by adding and dispersing Ichikogyo Seiyaku Co., Ltd., medium-chain fatty acid (MCT: manufactured by Riken Vitamin Co., Ltd.) ) 2% by mass, glycerin fatty acid ester (manufactured by Riken Vitamin Co., Ltd.) 4% by mass, saponin (manufactured by Maruzen Pharmaceutical Co., Ltd.) 0.5% by mass, ethanol (manufactured by Nippon Alcohol Sangyo Co., Ltd.) ) at 0.2%, maltitol (manufactured by Hayashibara Co., Ltd.) at 1.3% by mass, glycerin (manufactured by Nichiyu Co., Ltd.) at 78%, and water were added and mixed so that the total amount was 100% by mass, and A syrup-like formulation containing a mixture of a phenolic compound (Compound 1) and a cyclolanostane compound (Compound 2) at a final concentration of 0.00002% by mass was prepared.

The drug of the present embodiment is effective in improving symptoms caused by a decrease in core body temperature.

[Example 3]

A food or drink composition comprising the following composition and having an effect of preventing and/or improving symptoms caused by a decrease in core body temperature was manufactured by the following method.

A mixture containing 4% of a lophenol compound prepared in Production Example 1 and a cyclolanostane compound prepared in Production Example 2 at a ratio of lophenol compound:cyclolanostane compound = 6.1:3.9, and other medium chain fatty acids ( MCT: Riken Vitamin Co., Ltd.) 2%, glycerin fatty acid ester (Riken Vitamin Co., Ltd.) 4%, saponin (Maruzen Pharmaceutical Co., Ltd.) 0.5%, ethanol (Nippon Alcohol Sangyo Co., Ltd.) 0.2%, maltitol (Hayashibara Co., Ltd.) ) 1.3%, 78% glycerin (manufactured by Nichiyu Co., Ltd.), and 10% water were mixed to prepare a food additive containing a mixture of a cyclolanostane compound and a lophenol compound.

A food-drinks composition containing 0.00002% by mass of a mixture of a lophenol compound (Compound 1) and a cyclolanostane compound (Compound 2) at a final concentration was prepared by adding the prepared food additive to a beverage and mixing it uniformly.

[Example 4]

Contains 0.2% of test sample 1 prepared in Production Example 3, in addition, 2% of medium-chain fatty acids (MCT: Riken Vitamin Co., Ltd.), 4% glycerin fatty acid ester (Riken Vitamin Co., Ltd.), saponin (manufactured by Maruzen Pharmaceutical Co., Ltd.) ) 0.5%, ethanol (manufactured by Nippon Alcohol Sangyo Co., Ltd.) 0.2%, maltitol (manufactured by Hayashibara Co., Ltd.) 1.3%, glycerin (manufactured by Nichiyu Co., Ltd.) 78%, and 10% water were mixed to obtain a cyclolanostane compound and a lophenol compound. A food/drink composition containing the mixture was prepared.

The food-drink composition of this embodiment is effective for preventing and/or improving symptoms caused by a decrease in core body temperature.

INDUSTRIAL APPLICABILITY The present invention can be used to prevent and/or ameliorate symptoms caused by lowering of core body temperature.

Claims (8)

One or two or more compounds selected from the group consisting of lophenol compounds and cyclolanostane compounds are 4-methylcholes-7-en-3-ol, 4-methylergost-7-en-3-ol, 4 -Methylstigmast-7-en-3-ol, 9, 19-cyclolanostan-3-ol, and 24-methylene-9, 19-cyclolanostan-3-ol 1 or 2 or more selected from the group consisting of A composition for increasing core body temperature, comprising a compound as an active ingredient. According to claim 1,
A composition for increasing core body temperature, comprising, as an active ingredient, a composition containing at least 0.00001% by mass of one or two or more compounds selected from the group consisting of lophenol compounds and cyclolanostane compounds. According to claim 1 or 2,
A composition for increasing core body temperature, which is used to prevent or improve diseases caused by lowering of core body temperature. According to claim 1 or 2,
A food or drink composition or a pharmaceutical composition, A composition for increasing core body temperature. delete delete delete delete

Images