Salivary secretion improving composition

Abstract

To provide a composition which can provide an improved salivary secretion amount effective for improvement in oral environment.SOLUTION: A salivary secretion improving composition contains cannabidiol (CBD) as an active ingredient. The cannabidiol, in a preferred embodiment, is contained therein in an ingestible amount of 5 to 500 mg per day. The salivary secretion improving composition is preferably a salivary secretion improving food composition containing CBD as the active ingredient, a salivary secretion improving intraoral cosmetic composition containing CBD as the active ingredient, or a salivary secretion improving pharmaceutical composition containing CBD as the active ingredient.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention relates to the improvement of the oral environment, and particularly to a cannabidiol product for contributing to the improvement of saliva secretion.

Background Art

[0002] In an aging society where countermeasures against oral frailty are highly regarded, issues and countermeasures related to saliva secretion, including dry mouth (xerostomia), are important themes. Dry mouth causes the lips and oral cavity to become dry due to a decrease in saliva secretion for some reason, leading to various disorders such as thirst, dryness of the oral mucosa, a burning sensation, chewing disorders, and swallowing disorders. In addition, food residues are likely to remain in the oral cavity, which also has drawbacks such as promoting tooth decay. Since saliva has the function of eliminating bacteria in the oral cavity and making it easier to chew food, saliva secretion is important for maintaining a healthy oral environment. As methods for promoting saliva secretion, there are only measures such as replenishing water, chewing chewing gum, ingesting foods containing sweeteners, oral exercises, salivary gland massage, and using artificial saliva. There is an urgent need to establish a radical treatment for improving the decrease in saliva secretion.

[0003] Cannabidiol (hereinafter referred to as "CBD") is a type of cannabinoid contained in the leaves and seed coats of hemp. It has attracted attention in recent years because it has no psychoactive effects and no risk of abuse. CBD has the following effects and is widely applied in the food field, cosmetics field, and medical fields such as pharmaceuticals, so it is a component with high utilization value.

[0004] For example, CBD is considered to act not only on CB1 and CB2, which are G protein-coupled receptors, but also through GPR55, TRP, 5-HT, PPAR receptors, and GABAA receptors, and anti-inflammatory, analgesic, and anxiolytic effects have been reported. (Non-Patent Document 1) In the field of dentistry, in preliminary studies, the inhibitory effect of cannabinoids on bacterial colonies in dental plaque (Non-Patent Document 2), the improvement of tooth polishing treatment by adding cannabidiol to polishing powder, the removal and bactericidal effect of dental plaque bacteria (Non-Patent Document 3) have been reported. In addition, mouse wash products containing cannabinoids, together with other natural main components, showed promising antibacterial activity against total aerobic bacteria in vitro and showed efficiency equal to or higher than that of the gold standard (chlorhexidine 0.2%), so it is reported to be effective in suppressing the amount of bacteria (Non-Patent Document 4). Furthermore, in a report on the examination of the expression of the cannabinoid receptor GPR55 in human gingival fibroblasts and the anti-inflammatory effect of cannabidiol mediated by it, there is a possibility that GPR55 may be a therapeutic target for periodontitis, suggesting that CBD may be an effective therapeutic agent (Non-Patent Document 5).

[0005] As described above, the health of teeth and the oral cavity contributes not only to physical health but also to mental and social health. In recent years, the effects of cannabinoids and CBD on the oral environment have begun to be reported.

Prior Art Documents

Non-Patent Documents

[0006]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Summary of the Invention

Problems to be Solved by the Invention

[0007] As described above, cannabinoids containing CBD have been reported to be effective in improving the oral environment, such as having anti-inflammatory, bactericidal, and bacteriostatic effects. However, there are no past inventions reporting an improvement in salivary secretion volume by cannabinoids, which is important in countermeasures against oral frailty. An object of the present invention is to provide a composition capable of improving salivary secretion volume, which is effective in countermeasures against oral frailty and aging.

Means for Solving the Problems

[0008] As a result of examining the improvement of salivary secretion volume and oral environment by ingestion of test foods containing CBD, the present inventor has first found that CBD is effective in improving the oral environment through the improvement of salivary secretion volume, and has completed the present invention. The present invention provides a composition for improving salivary secretion containing CBD as an active ingredient.

Effects of the Invention

[0009] The composition for improving salivary secretion containing CBD as an active ingredient improves the salivary secretion volume, leading to an improvement in the oral environment. Therefore, by providing foods, oral cosmetics, pharmaceuticals, etc. containing CBD as an active ingredient, oral frailty and aging can be prevented.

Brief Description of the Drawings

[0010]

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Embodiments for Carrying Out the Invention

[0011] Cannabidiol (CBD) is commercially available and can be chemically synthesized or extracted from plants. Cannabis contains more than 120 components called cannabinoids. Representative cannabinoids include CBD, tetrahydrocannabinol (THC), cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN), cannabicitran (CBT), and cannabicyclol (CBL). THC has psychoactive effects and is subject to regulation, while CBD has no psychoactive effects and no risk of abuse. CBD is commercially available, and the Narcotics Control Division of the Local Health Bureau of the Ministry of Health, Labour and Welfare requires that products containing CBD be THC-free for import.

[0012] The method of administering (ingesting) CBD is not particularly limited, and preferably includes sublingual administration (sublingual ingestion) and oral administration (oral ingestion). From the point of view of obtaining the effect of ingestion in a short time, sublingual administration (sublingual ingestion), preferably by administering (ingesting) to the lower part of the tongue while lifting the tongue upward, is preferred. Since CBD is a solid with a melting point of 62 - 63°C, it may be administered as it is, or it may be dissolved in a solvent such as oil and administered as a solution. The solvent also depends on the solubility of additives other than CBD. For example, medium chain triglycerides (MCT oil), hemp oil derived from hemp, oils such as olive oil and sesame oil, vegetable glycerin, propylene glycol, etc., which are known as components contained in the seeds of palm family plants such as coconut and palm fruit. In particular, for sublingual administration, it is preferable to drop and ingest a solution in which CBD is dissolved in MCT oil, coconut oil, olive oil, etc. under the tongue.

[0013] The amount of CBD intake varies from person to person. In clinical trials and research studies, it may be dissolved in capsules or oils (such as olive oil or sesame oil) and taken orally or sublingually. The reported range of intake is wide, from 5 to 1500 mg / day, preferably 5 to 500 mg / day, more preferably 5 to 300 mg / day, and even more preferably 5 to 220 mg / day. From the perspective that the UK Food Standards Agency (FSA) stipulates the maximum daily intake as 70 mg / day, it is preferably 5 to 70 mg / day, but there is no scientific basis for 70 mg / day. Setting the range of CBD intake at 5 to 1500 mg / day does not mean restricting the amount of CBD contained as an active ingredient in the composition for improving saliva secretion, such as the food composition for improving saliva secretion, the oral cosmetic composition for improving saliva secretion, and the pharmaceutical composition for improving saliva secretion described below, to 5 to 1500 mg. It may contain more than 1500 mg of CBD for intake over several days or long-term use. For example, a major cup or a container with a predetermined amount can be attached, and the intake amount per day or per time can be adjusted.

[0014] As shown in the clinical study described as Example 1 below, it was shown that CBD intake can reduce the discomfort in the oral cavity by increasing the saliva during stimulation. The present invention provides a composition for improving saliva secretion containing CBD as an active ingredient, utilizing the increase in saliva during stimulation by CBD intake.

[0015] The composition for improving saliva secretion can be applied to various uses for the purpose of improving saliva secretion. Specifically, the composition for improving saliva secretion can be applied to food compositions, oral cosmetic compositions, and pharmaceutical compositions. The food composition for improving saliva secretion widely includes beverages for improving saliva secretion, supplements, health foods, functional foods, beauty foods for beauty purposes, etc. In this specification, "for pharmaceutical use" includes pharmaceuticals for administration or ingestion to humans. When the composition of the present invention is applied for food use, oral cosmetic use, or pharmaceutical use, it includes those for beauty purposes in any use.

[0016] The supplement preferably contains CBD at a concentration of 0.5 to 5% by mass, and may contain one or more components selected from the group consisting of, for example, excipients, diluents, encapsulating agents, disintegrants, bulking agents, and stabilizers. The beverage preferably contains CBD at a concentration of 0.01 to 0.5%, and may contain one or more components selected from the group consisting of, for example, emulsifiers, sweeteners, flavors, antioxidants, plant extracts, preservatives, and alcohol.

[0017] Examples of the composition for improving saliva secretion include CBD oil, CBD-containing powder, CBD gummies, and CBD tablets. The composition for improving saliva secretion can contain CBD such that the daily CBD intake is preferably 5 to 500 mg, more preferably 5 to 300 mg. The CBD oil preferably contains CBD at a concentration of 1 to 40% by mass, and may contain one or more components selected from the group consisting of, for example, cannabinoids other than CBD such as CBG, CBN, and CBC, oils such as MCT oil, hemp oil, and olive oil, terpenes, and flavors.

[0018] Examples of the CBD-containing powder include a powder obtained by mixing CBD powder with a protein powder for drinking such as soy protein, and if an appropriate amount of protein is ingested per day, a CBD-containing powder that can simultaneously ingest a preferable daily CBD intake of 5 to 500 mg, more preferably 5 to 300 mg can be obtained. The CBD gummies preferably contain CBD at a concentration of 0.3 to 2% by mass, and may contain one or more components selected from the group consisting of, for example, starch syrup, fruit juice, saccharides, gelatin, flavors, antioxidants, preservatives, vegetable oils, and oblate. The CBD tablets preferably contain CBD at a concentration of 0.1 to 2% by mass, and may contain one or more components selected from the group consisting of, for example, excipients, bulking agents, saccharides, sweeteners, flavors, and antioxidants.

[0019] The oral cosmetic composition for improving saliva secretion broadly includes dental care products for improving saliva secretion (which may or may not contain toothpaste components), mouth gels (oral care gels), oral sprays, oral film agents, mouth washes (oral care liquids), etc. Stomatitis may be worsened by irritation from some components contained in toothpaste. However, if the composition for improving saliva secretion is used as a dental care product without toothpaste components and brushing is done to secrete more saliva, the mouth will become clean, and the blood circulation of the gums and mucous membranes will improve, thus accelerating the healing of stomatitis. When the composition for improving saliva secretion is used as a dental care product containing toothpaste components, the effects of normal toothbrushing can also be obtained. The oral cosmetic composition for improving saliva secretion can contain CBD such that the daily CBD intake is preferably 5 - 500 mg, more preferably 5 - 300 mg. The content concentration of CBD depends on the form of the cosmetic, but is preferably 0.01 - 3 mass%.

[0020] Examples of the pharmaceutical composition for improving saliva secretion include sublingual tablets, troches, chewing gums, sprays, ointments, powders, granules, tablets, capsules, disintegrating films, injections, etc. The pharmaceutical composition for improving saliva secretion can contain CBD such that the daily CBD intake is preferably 5 - 500 mg, more preferably 5 - 300 mg.

[0021] The pharmaceutical composition for improving saliva secretion may contain one or more pharmaceutically acceptable additives in addition to the active ingredient, depending on the administration route and dosage form. Examples of the additives include excipients, diluents, extenders, solvents, lubricants, adjuvants, binders, disintegrants, coating agents, encapsulating agents, ointment bases, suppository bases, aerosol agents, emulsifiers, dispersants, suspending agents, thickeners, isotonic agents, preservatives, antioxidants, colorants, fragrances, coating agents, stabilizers, and functional preparations. These additives can be appropriately selected from known materials according to the dosage form, etc.

[0022] The pharmaceutical composition for improving saliva secretion can be used for the treatment of salivary secretion disorders caused by Oral Frailty (weakness or decline of oral functions), dry mouth (xerostomia), etc. "Treatment" includes controlling symptoms in all aspects, specifically including prevention, treatment, alleviation of symptoms, remission of symptoms, arrest of progression, etc.

Examples

[0023] The present invention will be described in detail below based on examples, but the present invention is not limited to the examples. Example 1 In order to show the improvement of the oral environment by the improvement of the saliva secretion amount by CBD, a clinical trial was conducted. A "placebo-controlled double-blind inter-group comparison test" was carried out on healthy subjects aged 30 to 60 who are prone to dry mouth in the oral cavity, are conscious of bad breath, and feel stress in daily life, with 100 mg of CBD taken sublingually twice a day for 2 weeks.

[0024] <Test subjects> For 76 applicants who understood the content of the test and obtained consent in writing, a pre-examination was conducted, and 75 completed it. Among them, from those who were judged to have no clinical abnormalities as a result of the pre-examination and had no problems participating in the test, considering the results of bad breath measurement and stress questionnaire at the time of pre-examination, 30 test subjects aged 30 to 60 were selected by preferentially including those with a stimulated saliva volume of 2 to 6 g. Note that "stimulated saliva" is saliva secreted in response to stimuli such as imagination, vision, smell, taste, chewing, etc., and "unstimulated saliva" refers to saliva continuously secreted when there is no external stimulus such as during sleep.

[0025] As the background of the test subjects, "background investigation at pre-examination [gender, smoking habit, eating habit, exercise habit, presence or absence of menopause (for women only)]", "background investigation at pre-examination [age, number of toothbrushing times, sleep duration]", "physical measurement and physiological examination at pre-examination", "halitosis at pre-examination", "saliva volume at pre-examination", and "simple stress questionnaire (abbreviated version of 23 items) at pre-examination". As a result of performing inter-group comparison using response values, measured values, scores, calculated values, or judgment values, no significant differences were observed in all items.

[0026] <The CBD and MCT oil used> CBD provided by a US hemp company that has obtained the US Hemp Authority certification was used. This CBD has a purity of 99%, and tetrahydrocannabinol (THC) was not detected at the limit of detection (LOD: limit of detection) of 0.0001% (1 ppm). To dissolve CBD, MCT oil (MCT oil manufactured by Katsuyama Nextage Co., Ltd. (derived from coconut)) was used.

[0027] <Test method> As test foods, the test food was a food containing CBD (MCT oil, CBD), and the control food was a food not containing CBD (MCT oil only). A "placebo-controlled double-blind parallel inter-group comparison test" was conducted. The number of subjects was 30 (15 per group), and they were assigned to two groups so that there was no bias in each group considering the results of age, gender, and saliva volume at pre-examination (resting saliva, stimulated saliva). The control food intake group consisted of 5 males and 10 females, and the test food intake group consisted of 6 males and 9 females.

[0028] The subjects ingested the test food twice a day for two weeks, about 0.5 mL each time (the test food contained 100 mg of CBD), by dripping it under the tongue with reference to the scale (0.5 mL) on the dropper cap of the test food container after breakfast and after dinner. On the first day, they ingested it only once at the designated timing when they came to the hospital, and the remaining once at the timing after dinner. CBD has been reported to have a first-pass effect, and for oral ingestion, the bioavailability (an index indicating how much of the drug administered to the human body circulates throughout the body) has been reported to be 6%. However, in this example, due to sublingual administration, it is considered less likely to have a first-pass effect compared to oral ingestion. Also, since CBD binds to several receptors, it is considered more likely to feel the effect, so a two-week period was set. In this specification, before the first ingestion of the test food when coming to the hospital on the first day, which is the first day, is described as "0W time (before ingestion)", and after the first ingestion of the test food is described as "0W time (after single ingestion)", and after the ingestion of the test food at the timing after dinner on the 14th day, which is the last day, is described as "2W time".

[0029] The examinations were conducted twice before the pre-examination and before and after ingestion at 0W time, and once at 2W time, and the evaluations of each evaluation item were performed using the obtained data. As the primary evaluation items, the salivary volume (unstimulated saliva, stimulated saliva) was compared (i) before and after single ingestion [comparison between 0W time (before ingestion) and 0W time (after single ingestion)] and (ii) before and after continuous ingestion [comparison between 0W time (before ingestion) and 2W time]. As secondary evaluation items, an oral questionnaire and an analysis of safety evaluation items were performed. All of them were evaluated by unpaired t - test for the comparison between the test food intake groups using the measured values and the change rates from 0 W (before intake). Also, the time - course comparison before and after intake using the measured values was evaluated by paired t - test. In addition, for further verification of the effects of test food intake, stratified analysis was performed on the effectiveness evaluation items. Gender (male and female) was used as the stratification factor. There were 11 male - layer test subjects (5 in the control food intake group and 6 in the test food intake group), and 19 female - layer test subjects (10 in the control food intake group and 9 in the test food intake group). In this specification, for the t - test, Student's t - test was used in the case of equal variance, and Welch's t - test was used in the case of unequal variance.

[0030] In this test, 30 test subjects (15 in the control food intake group and 15 in the test food intake group) started test food intake, and all of them completed the test. After the end of the test and the acquisition of all data, compliance violations during the test period were confirmed based on the presence or absence of adverse events, cases of discontinuation / dropout, and records of daily life logs. In combination with the results of various tests and questionnaires, the test responsible institution and the test institution consulted on the handling of cases and the acceptance or rejection of data for all cases, fixed the cases, and determined the cases to be analyzed.

[0031] As a result of discussing the handling of data for each test subject in the case review meeting, the ITT (Intension To Treat) analysis target population was 30 (15 in the control food intake group and 15 in the test food intake group) at the time of allocation. Since no test subject who had never taken the test food was found in the test institution for the FAS (Full Analysis Set) analysis target population, it was also 30 (15 in the control food intake group and 15 in the test food intake group). Also, since no test subject was judged to meet the PPS (Per Protocol Set) analysis exclusion criteria, the PPS analysis target population was also 30 (15 in the control food intake group and 15 in the test food intake group). Since all analysis target populations were judged to be analysis target populations composed of the same test subjects, in this test, in principle, all analyses were performed using the ITT analysis target population.

[0032] <Result 1: Two-week continuous intake of the test food (CBD) increases the salivary volume during stimulation> Figure 1 is a graph showing the change rate of the salivary volume during stimulation before and after two-week continuous intake in the test food (CBD) intake group and the control food intake group. When comparing the salivary volume during stimulation before and after continuous intake, the test food (CBD) intake group showed a significantly higher value (p = 0.0238, d = 0.87 [large]) compared to the control food intake group. p is the p-value in statistics. In this specification, the significance level is generally set to 0.05, and when the p-value is less than 0.05, it is described as "significant". d is the effect size d called "Cohen's d". In this specification, when the absolute value of the effect size d is 0.2 or more and less than 0.5, it is "small", 0.5 or more and less than 0.8 is "medium", and 0.8 or more is "large". Figure 2 is a graph showing the salivary volume during stimulation (measured values) at 0W (before intake) and 2W for the test food (CBD) intake group and the control food intake group. A significant increase (p = 0.003) was observed at 2W only in the test food (CBD) intake group compared to 0W (before intake). From these results, it is clear that continuously ingesting the test food (CBD) increases the salivary volume during stimulation.

[0033] <Result 2: Continuous intake of the test food (CBD) increases the salivary volume during stimulation at 2W in both male and female groups> For further verification of the effect of the test food (CBD) intake, a stratified analysis with gender as a stratifying factor was performed. Figure 3 is a graph showing the change rate of the salivary volume during stimulation in the female group at 2W in the inter-group comparison using measured values in the stratified analysis. Figure 4 is a graph showing the measured values of the salivary volume during stimulation in the female group over time comparing 0W (before intake) and 2W. Figure 5 is a graph showing the change rate of the salivary volume during stimulation in the male group over time comparing 0W (before intake) and 2W using measured values in the stratified analysis. In the male and female groups, the salivary volume during stimulation at 2 weeks was significantly improved (increased: p = 0.0091 for the male group, p = 0.0100 for the female group) compared to that at 0 weeks (before ingestion) in the test food (CBD) ingestion group only. Also, in the female group, the change rate of the "salivary volume during stimulation" in the comparison before and after continuous ingestion showed a significantly higher value (p = 0.0099, d = 1.33 [large]) in the test food (CBD) ingestion group compared to the control food ingestion group. From these results, it was confirmed that continuous ingestion of the test food (CBD) increases the salivary volume during stimulation.

[0034] <Result 3: Single and continuous ingestion of the test food (CBD) reduces dissatisfaction with the mouth and teeth at 0 weeks (after single ingestion) and 2 weeks> Regarding the item "feeling dissatisfied with the mouth or teeth" in the oral questionnaire, a significant distribution difference (after ingestion: p = 0.0336, r = -0.39 [medium]) was observed between the control food ingestion group and the test food (CBD) ingestion group at 0 weeks (after single ingestion) (not shown in the figure). Figure 6 is a graph showing the comparison between the control food ingestion group and the test food (CBD) ingestion group at 2 weeks using the response values of the item "feeling dissatisfied with the mouth or teeth" in the oral questionnaire. A significant distribution difference (at 2 weeks: p = 0.0470, r = -0.36 [medium]) was observed between the control food ingestion group and the test food (CBD) ingestion group at 2 weeks. When checking the frequency distribution, at both 0 weeks (after single ingestion) and 2 weeks of continuous ingestion, the weight of the response values indicating that the test food (CBD) ingestion group felt less dissatisfaction was higher compared to the control food ingestion group. These results indicate that single and continuous ingestion of the test food (CBD) reduces dissatisfaction with the mouth and teeth.

[0035] <Result 4: Continuous ingestion of the test food (CBD) improves bad breath at 2 weeks> Figure 7 is a graph comparing the control food intake group and the test food (CBD) intake group at 2W using the response values of the item "concerned about bad breath" in the oral questionnaire. A significant distribution difference (p = 0.227, r = -0.42 [medium]) was observed between the control food intake group and the test food (CBD) intake group at 2W for "concerned about bad breath". When checking the frequency distribution, more respondents with response values indicating less dissatisfaction were observed in the test food (CBD) intake group compared to the control food intake group. Figure 8 is a graph comparing the test food (CBD) intake group at 0W (before intake) and 2W using the response values of the item "concerned about bad breath" in the oral questionnaire. A significant distribution difference (p = 0.0143) was observed between 0W (before intake) and 2W. These results indicate that continuous intake of the test food (CBD) reduces the bad breath that concerns people.

[0036] <Result 5: No side effects or safety problems were observed in the test food (CBD) intake group> In Example 1, no manifestation of side effects due to the intake of the test food was observed. When comparing between groups regarding the manifestation of adverse events, no significant difference was observed between the presence or absence of test food intake and the manifestation of events, and there was no problem with the safety of test food intake. Also, when evaluating body measurements and physiological tests as safety supplementary analyses, no significant difference was observed between the test food intake groups, and from the results of Example 1, no change in clinical test values negating the safety of the test food was observed.

[0037] From the results of Example 1, since it was observed that continuous intake of CBD increases the salivary volume during stimulation, it was suggested that continuous intake of CBD contributes to the improvement of dry mouth and the oral environment. Also, continuous intake of the test food (CBD) increases the salivary volume during stimulation in both men and women, especially in women. In the oral questionnaire, it became clear that continuous intake of the test food (CBD) improves bad breath and reduces dissatisfaction with the mouth and teeth.

Claims

1. A composition for improving saliva secretion, containing cannabidiol (CBD) as an active ingredient.

2. The composition for improving saliva secretion according to Claim 1, wherein the cannabidiol is contained in an amount that can be ingested in an amount of 5 to 500 mg per day.

3. The composition for improving saliva secretion according to Claim 1 or Claim 2, which is a food composition.

4. The composition for improving saliva secretion according to Claim 3, wherein the food composition is a beverage, a supplement, a health food, a functional food or a beauty food.

5. The composition for improving saliva secretion according to Claim 3, wherein the food composition is CBD oil, CBD-containing powder, CBD gummy or CBD tablet.

6. The composition for improving saliva secretion according to Claim 1 or Claim 2, which is an oral cosmetic composition.

7. The composition for improving saliva secretion according to Claim 6, wherein the oral cosmetic composition is a dental care product, a mouth gel, an oral spray, an oral film agent or a mouthwash.

8. The composition for improving saliva secretion according to Claim 1 or Claim 2, which is a pharmaceutical composition.

9. The composition for improving saliva secretion according to Claim 8, wherein the pharmaceutical composition is used for the treatment of salivary secretion disorders or dry mouth.

10. The composition for improving saliva secretion according to Claim 8, wherein the pharmaceutical composition is a sublingual preparation, a troche, a chewing gum preparation, a spray preparation, an ointment, a powder, a granule, a tablet, a capsule, a disintegrating film agent or an injection.

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