JP2010265234A - Agent for improving oral cavity bacterial flora - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an agent for improving oral cavity bacterial flora, inhibiting the proliferation of the bacteria in an oral cavity in order to make a hygienic condition in the oral cavity good, also enabling to keep the dominance of indigenous bacteria by making the proliferation of the indigenous bacteria more predominant in the oral cavity than that of causing bacteria of aspiration pneumonia, and also in considering that it acts in a human oral cavity and in the point of safety, comprising a food component or food raw material. <P>SOLUTION: This agent for improving the oral cavity bacterial flora is provided by containing caffeine or theophylline as an active ingredient, capable of making the hygienic condition in the oral cavity as good by inhibiting the proliferation of the bacteria, and keeping the dominance of the indigenous bacteria by making the proliferation of the indigenous bacteria more predominant than that of the causing bacteria of the aspiration pneumonia. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to an oral microbiota-improving agent, mainly for the purpose of preventing aspiration pneumonia, making the oral cavity a good sanitary state by inhibiting bacterial growth, and reducing the growth of normal bacteria to aspiration pneumonia The present invention relates to a device devised so that the predominance of resident bacteria can be maintained by making the state superior to the growth of the resulting bacteria.

Aged pneumonia is often aspiration pneumonia caused by aspiration of food, saliva, etc., and is said to account for about 30 to 70%. The effectiveness of quality oral care by professionals such as dental hygienists has been shown to prevent aspiration pneumonia (Non-Patent Documents 1 to 3), but there is a limit to the provision of oral care by specialists. There is. There is a need for a device that can maintain the oral hygiene of the elderly well even with ordinary oral cleaning performed by the person, family, nursing staff, and the like.

  To prevent oral aspiration pneumonia, in order to maintain good oral hygiene, suppress bacterial growth in the oral cavity and prevent bacteria such as periodontal disease and opportunistic bacteria that cause aspiration pneumonia. It is important to reduce, increase the proportion of resident bacteria, and improve the oral flora (Non-Patent Document 4). In particular, “Storeptococcus mitis” is the most prevalent resident bacterium. (Non-Patent Document 5)

  For the prevention of aspiration pneumonia, a composition (Patent Document 1) having a strong growth inhibitory activity against periodontal disease bacteria, an agent for reducing the number of “Candida albicans” (Patent Document 2), a bactericidal agent (Patent Document 3) has been proposed, but effects on bacterial flora improvement and resident bacteria have not been studied.

  Probiotics such as gums containing butyric acid bacteria (Patent Document 4), lactic acid bacteria (Patent Documents 5 to 8), and “Streptococcus salivarius” (Patent Document 9) have been proposed as methods for improving oral bacterial flora. However, the idea that prevention with only probiotics in humans is actually difficult (Non-Patent Document 6) is shown.

  Many other methods and methods for improving bacterial flora are provided for the purpose of preventing and treating caries and periodontal disease, and few have studied the effects on normal bacteria (Patent Literature). 10-15). For example, Patent Document 16 is examining only the bacteria of “Streptococcus mitis” and other “Streptococcus genus”, and the effects on opportunistic infections and periodontal pathogens are as follows. It is unknown. For example, Patent Document 17 is effective only for obligate anaerobic bacteria. For example, in Patent Document 18, the influence on opportunistic bacteria is unknown. The effectiveness of the improvement of the bacterial flora in these examples cannot be judged from the viewpoint of prevention of aspiration pneumonia.

  In order to maintain good oral hygiene, the use of existing antibacterial agents may be considered, but antibacterial agents may also act on normal bacteria and destroy normal bacterial flora. It is not appropriate from the viewpoint of prevention of aspiration pneumonia.

  On the other hand, caffeine and theophylline are components contained in tea, coffee, black tea, etc., and no effect on oral bacteria when used as a beverage has been observed (Non-patent Document 7). The antibacterial properties of caffeine and theophylline have been clarified in Patent Document 19, but in the explanation of the term “hygienic treatment”, “to remove as much as possible all bacteria including bacteria that are normally harmful to humans. ”And does not feature improved bacterial flora. Patent Document 19 is a cleaning composition, which is intended for hygienic treatment of “hard surfaces, particularly glass surfaces”.

JP 2007-210922 A JP 2008-44186 A Patent 4203120 JP 2004-189709 A Special table 2003-534362 gazette JP 05-004927 A US Extract 2003/0170184 US Sho 2002/0012637 JP 2005-517439 Gazette JP 2000-344642 A JP-A-10-291920 JP 08-175947 A Japanese Patent Laid-Open No. 08-175946 Japanese Patent Laid-Open No. 07-206621 JP 2007-509927 A JP 2007-509927 A JP 2007-509927 A JP 2007-509927 A Japanese translation of PCT publication No. 2003-510411

Okuda et al., Dentistry Bulletin, 105 (2), 129-137, 2005 Yoneyama et al., Journal of Japanese Dental Society, 20, 2001 Hirota et al., Journal of the Japan Geriatrics Society, 34 (2), 1997 Hanada, oral bacteria and aspiration pneumonia. Seminar! Eating / swallowing rehabilitation, medical and dental publishing, pp. 14-25, 2005 Smith et al., Oral. Microbiol. Immunol. 8, 1-4, 1993 Maeda et al., Dental therapy, 25 (3), 61-68, 2006 Cogo et al., Can. J. et al. Microbiol. , 54 (6), 501-508, 2008

  As described above, according to the above-described conventional configuration, it is repeated, but the oral hygiene condition is improved, the bacterial growth in the oral cavity is suppressed, and the bacterial growth in the oral cavity is inhibited by aspiration pneumonia There has been a problem that sufficient studies have not been made on making it superior to the growth of bacteria caused by.

  The present invention has been made based on such points, and the object of the present invention is to suppress the growth of bacteria in the oral cavity and improve the oral hygiene in order to improve the oral hygiene. From the viewpoint of safety, it is possible to maintain the dominance of resident bacteria by making the growth superior to the growth of bacteria due to aspiration pneumonia, and to act in the human oral cavity. An object of the present invention is to provide an oral flora improving agent comprising food ingredients and food materials.

In order to solve the above-mentioned problems, the present inventors have conducted a search for finding effective food ingredients and food materials that are considered to be highly safe. As a result, caffeine and theophylline inhibit the growth of all the resident bacteria used in the experiment and the bacteria caused by aspiration pneumonia, and the inhibition of this growth is less aspiration than the resident bacteria. The present invention was found out by working strongly against bacteria caused by pneumonia.
In addition, we found the concentration of food ingredients that suppress the growth of resident bacteria rather than the growth of bacteria caused by aspiration pneumonia. By not including these component concentrations, the effectiveness of caffeine and theophylline can be further exhibited.
That is, the oral flora improving agent according to claim 1 is characterized by containing caffeine or theophylline as an active ingredient.
An oral flora improving agent according to claim 2 is characterized in that, in the oral flora improving agent according to claim 1, the caffeine or theophylline is contained in a concentration of 0.1 wt% or more.
The oral flora improving agent according to claim 3 is characterized in that in the oral flora improving agent according to claim 2, the caffeine or theophylline is lower than a concentration of 0.6 wt% as a liquid component. It is.
Further, the oral flora improving agent according to claim 4 is the compounding component according to claim 2, wherein sodium citrate, epigallocatechin gallate, and xylitol are 0.1 wt% or more and 0, respectively, as liquid components. It is characterized by not containing a concentration of 0.001 wt% or more and 0.05 wt% or more.

  As described above, the invention described in claim 1 of the present application contains caffeine or theophylline as an active ingredient, thereby making the oral cavity a good sanitary state by suppressing the growth of bacteria, and the growth of resident bacteria. It is an oral flora improving agent that retains the dominance of resident bacteria in the oral cavity by maintaining the dominance of resident bacteria by making it superior to the growth of bacteria caused by aspiration pneumonia.

  Further, the invention according to claim 2 is to increase the effectiveness of caffeine or theophylline by containing caffeine or theophylline of the oral flora improving agent according to claim 1 at a concentration of 0.1 wt% or more. It is a characteristic oral bacterial flora improving agent.

The invention according to claim 3 is characterized in that caffeine or theophylline does not excessively suppress the growth of normal bacteria in the oral cavity by being lower than 0.6 wt% as a liquid component. The oral microbiota improving agent described.

The invention according to claim 4 is the compounding ingredient according to claim 2, wherein sodium citrate salt, epigallocatechin gallate and xylitol as liquid components are 0.1 wt% or more and 0.001 wt%, respectively. As described above, it is an oral flora improving agent characterized by not excessively suppressing the growth of normal bacteria in the oral cavity by not containing 0.05 wt% or more.

It is a figure which shows one embodiment of this invention, and is a graph for showing evaluation of Example 2. FIG. It is a figure which shows one embodiment of this invention, and is a graph for showing evaluation of Example 3 and Example 4. FIG. It is a figure which shows one embodiment of this invention, and is a graph for showing evaluation of Example 42. It is a figure which shows one embodiment of this invention, and is a graph for showing evaluation of Example 55. It is a figure which shows one embodiment of this invention, and is a graph for showing evaluation of Example 56, Example 57, and Example 58. It is a figure which shows one embodiment of this invention, and is a graph for showing evaluation of Example 59, Example 60, and Example 61. FIG. It is a figure which shows one embodiment of this invention, and is a graph for showing evaluation of Example 62, Example 63, and Example 64. FIG. It is a figure which shows one embodiment of this invention, and is a graph for showing evaluation of Example 65, Example 66, and Example 67.

Hereinafter, an embodiment of the present invention will be described with reference to FIGS.
First, it is said that caffeine is produced in the world as natural caffeine at 3000 to 4000 tons per year, and theophylline is produced at 1000 to 5000 tons per year. In Japan, it is extracted and purified from tea.

  Caffeine or theophylline is blended in oral creams, gels, mouthwashes, oral spray solutions, gums and the like. Caffeine or theophylline is blended in oral creams, gels, mouthwashes, oral spray solutions, gums, and the like, and contains 0.1 wt% or more.

  The formulation of caffeine or theophylline into a cream or gel for the oral cavity is dissolved in the liquid part of the cream or gel, or dispersed in the form of crystals or capsules in the cream or gel. The concentration of caffeine in the cream or gel for the oral cavity when it is dissolved in the liquid part of the cream or gel is within 2.0 wt%. The concentration of theophylline in a cream or gel for the oral cavity is dissolved within 0.8 wt% when dissolved in a liquid part such as cream or gel. When the composition of caffeine or theophylline in a cream or gel for the oral cavity is dispersed in the form of crystals, capsules or the like, it is desired that it is not excessively dissolved in the oral cavity.

Formulation of caffeine or theophylline into a mouthwash or an oral spray solution is dissolved in the solution. The concentration of caffeine in the mouthwash or oral spray is within 2.0 wt%. The concentration of theophylline in the mouthwash and spray is within 0.8 wt%. It is desirable that the amount of caffeine or theophylline in the mouth wash solution or oral spray solution is preferably within 0.6 wt%.

  Formulation of caffeine or theophylline into a gum is dissolved in the gum, dispersed in the form of crystals, capsules, and the like. When the blend of caffeine or theophylline into a gum is dispersed in the form of crystals, capsules, etc., it is desirable that it is not excessively dissolved in the oral cavity.

  Ingredients in oral creams, gels, mouthwashes, oral sprays, gums, and other ingredients increase the osmotic pressure of the ingredients and increase the growth of dominant, normal bacteria in the oral cavity. It is desirable not to suppress it. For example, it is desirable that the composition of the mouthwash does not contain sodium chloride having a concentration of 1 wt% or more. It is desired that the blended component does not strongly suppress the growth of dominant bacteria in the oral cavity by reducing the pH of the blended component concentration. For example, it is desirable that the blending component of the mouthwash does not contain ascorbic acid having a concentration of 0.2 wt% or more in an unbuffered state. For example, it is desirable that the composition of the mouthwash does not contain succinic acid at a concentration of 0.05 wt% or more in an unbuffered state. For example, it is desirable that the composition of the mouthwash does not contain citric acid at a concentration of 0.05 wt% or more in an unbuffered state. Moreover, in the compounding component of the mouthwash, it is desirable that citric acid does not contain a concentration of 0.1 wt% or more as a sodium salt. In addition to the above, it is desirable that the blended component concentration does not strongly suppress the growth of the dominant bacteria in the oral cavity. For example, it is desirable that the composition of the mouthwash does not contain epigallocatechin gallate having a concentration of 0.001 wt% or more. For example, it is desirable that the ingredients contained in the mouthwash do not contain xylitol at a concentration of 0.05 wt% or more.

  EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited by these.

The bacteria used were sold by RIKEN. The distributed bacteria were reconstituted according to the procedure of “Opening method of lyophilized and L-dried ampules” enclosed at the time of distribution and the medium and conditions described in the JCM Catalogue of each bacteria. Bacteria not immediately subjected to experiments were stored in liquid nitrogen in a microbank (PRO-LAB DIAGNOSTICS) or a sterilized skim milk solution. As resident bacteria dominant in the oral cavity (Non-patent Document 5), Streptococcus mitis (JCM12971 ^T ) (hereinafter referred to as “S. mitis”), Streptococcus oralis (JCM12997 ^T ) (hereinafter referred to as “S. Oralis”). And Streptococcus sarivarius (JCM5705 ^T ) (hereinafter referred to as “S. salivarius”). As a causative bacterium of aspiration pneumonia, Streptococcus anginosus (JCM12993 ^T ) (hereinafter referred to as “S. anginosus”), Streptococcus sanguinis (JCM5708 ^T ) (hereinafter referred to as “S. sanguinisto stocosto stocus stocosto stocus stocostos custoc stocosto stocus stocosto stocus stocostois stocostois stocostos custocosto stocostois stocostois stocosto stocostois stocostois stocostos custocostostocostocostoscus JCM12994 ^T ) (hereinafter referred to as “S. constellatus”), Streptococcus intermediaus (JCM12996 ^T ) (hereinafter referred to as “S. intermediaus”), Streptococcus mutans (JCM5705 ^T ). , Staphylococcus aureus ( CM20624 ^T) (hereinafter referred to as "Stap. ^{Aureus".), Enterococcus faecalis (JCM5803 T} ) ( hereinafter referred to as "E. ^{Faecalis".), Enterococcus faecium (JCM5804 T} ) ( hereinafter referred to as "E. Faecium".) , Bacteroides fragilis (JCM11019 ^T) (hereinafter, referred to as "B. ^{fragilis".), Capnocytophaga ochracea (JCM12966 T} ) ( hereinafter, "C. ochracea" ^{hereinafter.), Eikenella corrodens (JCM12952 T} ) ( hereinafter, "E. corrodens "), Fusobacterium nucleatum (JCM8532). ^T ) (hereinafter referred to as “F. nucleatum”), Escherichia coli (JCM1649 ^T ) (hereinafter referred to as “E. coli”), Prevotella melaninogenica (JCM6325 ^T ) (hereinafter referred to as “P. melanoid”). Prevotella oralis (JCM12251 ^T ) (hereinafter referred to as “P. oralis”) was used.

For each bacterium, an approximate expression was obtained for the relationship between the turbidity OD ₆₆₀ and the viable cell count (CFU / ml) in Mueller Hinton Broth (Difco) (hereinafter referred to as “MHB”). S. mitis and S.M. anginosus determined an approximate expression for the relationship between the turbidity OD ₆₃₀ in MHB and the viable cell count (CFU / ml). Each approximate expression was used to prepare a growth curve and to estimate the number of viable cells before and after the test culture.

In Examples 1 to 10, caffeine was blended in concentrations of 1 wt% to 1/2 each as a mouthwash or a spray for mouth. However, the evaluation was made into MHB for comparison of bacterial growth. The resident and most prevalent bacteria S. mitius and a bacterial cause of aspiration pneumonia Anginosus was used for evaluation. In a 96-well flat-bottomed microplate, a solution containing approximately 5 × 10 ⁵ CFU / ml of the bacterium was added to 100 μl per well of Example 1 to Example 10, and 5 wells per bacterium were prepared. Similarly, a bacterial solution not containing caffeine was prepared and used as a control. The microplate was placed in a jar containing an O ₂ absorption / CO ₂ generator (Aneropack) for drug sensitivity test and placed at 35 ° C. for 8 hours. Thereafter, the microplate was measured for OD ₆₃₀ using a microplate reader, and the viable cell count was estimated. The obtained data were averaged and evaluated on the order of 10% when the control was taken as 100%.

The evaluation results of Examples 1 to 10 are shown in Table 1. Evaluation is based on S.E. angiosus growth inhibitory action The concentration when it became larger than mitis was determined to be appropriate (◯), and other than that, it was determined to be inappropriate (x). In Examples 2 and 3, good evaluation was obtained.

In Examples 11 to 20, theophylline was blended so as to have a concentration of 0.5 wt% to 1/2 as a mouthwash or a spray for mouth. Evaluation was performed in the same manner as in Example 1 to Example 10.

The results of the evaluation of Examples 11 to 20 are shown in Table 2. Good evaluation was obtained from Example 11 to Example 14.

In Example 2, S.I. mitis, S.M. oralis, S .; salivarius, S.M. sanguinis, S .; constellatus, S .; intermedius, S.M. mutans, Snap. Aureus, E.M. faecalis, E .; faecium, B.M. fragilis, C.I. ochracea, E .; corrodens, F.M. nucleatum, E.I. coli, P.M. melaninogenica, P.M. Evaluation using oraris was performed. In a 24-well flat-bottom microplate, the liquid containing approximately 5 × 10 ⁵ CFU / ml of the bacterium was prepared in an amount of 1.5 ml per well and 3 wells per bacterium for the formulation of Example 2. However, Snap. aureus is approximately 7 × 10 ⁴ CFU / ml, P. aureus. melaninogenica and P. a. The oralis was approximately 5 × 10 ⁶ CFU / ml. Similarly, a bacterial solution not containing caffeine was prepared and controlled. The microplate was placed under conditions set for each bacterium from a growth curve and the like, and then OD ₆₆₀ was measured to estimate the viable cell count. The obtained data were averaged and evaluated on the order of 10% when the control was 100%.

The results of the evaluation of Example 2 are shown in FIG.
In the graph of FIG. 1, the vertical axis indicates the type of bacteria, and the horizontal axis indicates the growth rate of bacteria when the control is 100%. The white bar graph in FIG. 1 shows the growth rate when the normal bacteria control in the oral cavity is taken as 100%, and the solid bar graph in FIG. The growth rate is shown as%. In Example 2, the oral bacteria S. mitis, S.M. oralis, S .; Sarivarius was inhibited from proliferation by around 40% to 50%. On the other hand, the bacterium S. intermedius, Snap. Aureus, B.M. fragilis, C.I. ochracea, E .; corrodens, F.M. nucleatum, P.M. melaninogenica, P.M. Oralis was almost completely inhibited from growing. S. sanguinis, S .; constellatus, E .; The growth of E. coli was about 10%, which was suppressed more than that of resident bacteria. S. The reason why% of mitis differs from Table 1 is considered to be because the conditions such as the evaluation amount are different. As a result of evaluation of Example 2, S.I. In a concentration that suppresses the growth of resident bacteria such as mitis, bacteria caused by aspiration pneumonia are further suppressed, and Example 2 is excellent in solving the problem to be solved by the present invention. Showed the effect.

From the results of evaluation of Example 1 and Example 2, as a mouthwash or a spray for mouth, Example 21 was 0.8 wt%, Example 22 was 0.7 wt%, and Example 23 was 0.6 wt%. Of caffeine. Evaluation is based on S.E. mitis, S.M. oralis, S .; salivarius, S.M. mutans, E.M. The same method as in Example 2 was used using faecalis.

The evaluation results of Example 21 to Example 23 are shown in Table 3. However, the result of evaluation of Example 2 is also attached for reference. In Examples 21 to 23, S. cerevisiae, which is a resident and most prevalent bacterial species, is used. Most of mitis was suppressed. According to the evaluation results of Example 11 and Example 23, the concentrations of caffeine and theophylline are preferably lower than 0.6 wt%.

In Examples 24 to 33, sodium citrate was blended so as to have a concentration from 0.1 wt% to ½ each as a mouthwash or oral spray. The evaluation was performed in the same manner as in Examples 1 to 10 in terms of S.P. Observe the growth of M. Mitis growth of 60% or less may be inappropriate (x), and other than this was determined as appropriate (◯).

Table 4 shows the evaluation results of Examples 24 to 33. Example 24 could be unsuitable.

In Example 34, 0.2 wt% of sodium citrate was blended with reference to Example 24. Example 34 is similar to Example 2 in S.I. mitis, S.M. oralis, S .; salivarius, S.M. sanguinis, S .; constellatus, S .; intermedius, S.M. mutans, Snap. aureus, E .; faecalis, E .; faecium, B.M. fragilis, C.I. ochracea, E .; corrodens, F.M. nucleatum, E.I. coli, P.M. melaninogenica, P.M. Evaluation was carried out by the method using oralis.

The results of evaluation of Example 34 are shown in FIG.
The graph in FIG. 2 is expressed in the same manner as in FIG. In Example 34, the growth of resident bacteria was suppressed from 10% to 40%. At this sodium citrate concentration, S. sanguinis, C.I. ochracea, E .; corrodens, F.M. nucleatum, P.M. Suppression of the growth of the causative bacteria excluding melaninogenica was less than that of resident bacteria. Therefore, in Example 34, S.I. There are bacteria that cause aspiration pneumonia that cannot still inhibit growth at concentrations that inhibit the growth of resident bacteria such as mitis. Therefore, in blending sodium citrate, it is desirable that the concentration be in the range of Example 25 to Example 33, or a concentration lower than those of these Examples.

In Examples 35 to 44, epigallocatechin gallate was blended so as to have a concentration from 0.1 wt% to ½ each as a mouthwash or an oral spray. Evaluation was performed in the same manner as in Example 24 to Example 33.

The results of evaluation of Example 35 to Example 44 are shown in Table 5. Epigallocatechin gallate may be unsuitable in Example 35 to Example 41.

Example 42 was also evaluated in the same manner as in Example 34.

The results of the evaluation of Example 42 are shown in FIG.
The graph in FIG. 3 is expressed in the same manner as in FIG. In Example 42, the growth of resident bacteria was suppressed by around 50%. In comparison to this, the bacterial S. sanguinis, S .; mutans, E.M. faecium, E.M. In E. coli, proliferation is not suppressed, and E. coli Faecalis also hardly inhibited growth. Therefore, in Example 42, there are bacteria due to aspiration pneumonia that cannot still inhibit growth at a concentration that inhibits the growth of resident bacteria. In formulating epigallocatechin gallate, Example 43 To a concentration in the range of Example 44, or a concentration lower than those in Examples.

In Examples 45 to 54, xylitol was blended so as to have a concentration from 5 wt% to ½ each as a mouthwash or an oral spray. Evaluation was performed in the same manner as in Example 24 to Example 33.

Table 6 shows the results of the evaluation of Examples 45 to 54. Xylitol may be unsuitable in Example 45 to Example 51.

In Example 55, 0.1 wt% of xylitol was blended with reference to Example 51 and Example 52. Evaluation was performed in the same manner as in Example 34.

The results of the evaluation of Example 55 are shown in FIG.
The graph in FIG. 4 is expressed in the same manner as in FIG. In Example 55, the growth of resident bacteria was suppressed by around 40%. Compared with this, the growth suppression to the bacteria of the cause of evaluation was all equal to or less than that of the resident bacteria. Therefore, in Example 55, S.I. There were many bacteria caused by aspiration pneumonia that could not inhibit the growth at concentrations that inhibit the growth of resident bacteria such as mitis. In formulating xylitol, it is desirable that the concentration be in the range of Example 52 to Example 54, or a concentration lower than these Examples.

In Example 56, 10 ml of a 2 wt% caffeine solution was placed in a glass container containing a stirring bar and heated on a hot plate, and 10 g of inulin (trade name of Fuji Nippon Seika Co., Ltd.) was gradually added, and the liquid was transparent. Stir until. This solution is gently put into a 24-well flat-bottomed microplate at 500 μl per well and allowed to stand overnight to form a cream. In Example 57 and Example 58, creams were prepared in the same manner as in Example 56 using 10 ml of 1.5 wt% caffeine solution and 10 ml of 1 wt% caffeine solution, respectively.

In Example 59, agar is added and dissolved in 10 ml of 1 wt% caffeine solution heated on a hot plate in the same manner as in Example 56 so as to be 1 wt%. Gently place 500 μl of this solution into a 24-well flat-bottomed microplate per well and let stand overnight for a gel. In Example 60 and Example 61, gels were prepared in the same manner as in Example 59 using 10 ml of a 0.75 wt% caffeine solution and 10 ml of a 0.5 wt% caffeine solution, respectively.

In Examples 56 to 61, elution of caffeine was observed. The microplate was placed in an incubator at 35 ° C. for 1 hour, and 500 μl of ultrapure water heated to 35 ° C. was added to each well and placed in an incubator at 35 ° C. After a certain time, 200 μl was gently taken from each well. The collected water was diluted sequentially, the absorbance was measured at a wavelength of 274 nm, and the caffeine concentration was determined from a calibration curve prepared in advance.

The results of Example 56 to Example 58 are shown in FIG. 5, and the results of Example 59 to Example 61 are shown in FIG.
In the graphs of FIGS. 5 and 6, the horizontal axis represents the elapsed time after the incubator was added, and the vertical axis represents the amount of caffeine in ultrapure water at that time. In any of Examples 56 to 61, it was estimated that the concentration shown in claim 2 had been reached 30 minutes after the incubator was charged. It was estimated that the concentration was lower than that shown in claim 3 until 4 hours later. A cream using inulin and a gel using agar can be expected to have good effects by blending caffeine or theophylline at an appropriate concentration in carrying out the present invention.

Examples 62 to 67 are blended as shown in Table 7.

In Examples 62 to 67, caffeine elution was observed in the same manner as in Example 56.

The results of Examples 62 to 64 are shown in FIG. 7, and the results of Examples 65 to 67 are shown in FIG.
In the graphs of FIG. 7 and FIG. 8, the horizontal axis indicates the elapsed time after the incubator is inserted, and the vertical axis indicates the amount of caffeine of ultrapure water at that time, similarly to the graph of FIG. In Example 63 and Example 66, caffeine elution was suppressed by adding glycerin to agar based gel. Example 64 and Example 67 differed from the elution state of caffeine compared with other examples by using the material which mixed inulin and caffeine. From the above, when caffeine and theophylline are blended in cream or gel and the present invention is carried out, the effect of elution suppression by glycerin and the elution state adjustment by inulin and caffeine mixture can be expected.

Examples 68 to 73 are blended as shown in Table 8.

The oral flora improving agent of the present invention is to make the oral cavity in a good hygiene state by suppressing the growth of bacteria, and to make the growth of normal bacteria superior to the growth of bacteria caused by aspiration pneumonia Can maintain the predominance of resident bacteria, and can prevent the onset of pneumonia due to aspiration of the elderly.

The oral bacterial flora improving agent of the present invention can maintain hygiene in the oral cavity of the elderly well by blending with oral cream, gel, mouthwash, oral spray, etc., and aspiration pneumonia Can be prevented.

In addition, the oral flora improving agent of the present invention can be applied to the prevention of periodontal disease and the like by blending it into a mouthwash, a liquid for oral spray, a gum and the like.

Claims (4)

An oral flora improving agent comprising caffeine or theophylline as an active ingredient. In the oral flora improving agent according to claim 1,
The above-mentioned caffeine or theophylline contains 0.1 wt% or more of an oral bacterial flora improving agent. In the oral flora improving agent according to claim 2,
An oral flora improving agent, wherein the caffeine or theophylline is lower than a concentration of 0.6 wt% as a liquid component. The compounding component according to claim 2,
Oral bacteria characterized by not containing sodium citrate salt, epigallocatechin gallate and xylitol as liquid components in concentrations of 0.1 wt% or more, 0.001 wt% or more, 0.05 wt% or more, respectively Plexus improving agent.

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