Traditional Chinese medicine activator

Abstract

To provide an activator for Chinese herbal medicine that solves differences in medicinal effect due to the composition of intestinal bacterial flora.SOLUTION: An activator for Chinese herbal medicine contains a cellulose acetate with a total acetyl substitution of 0.4 or more and 1.0 or less. In another embodiment, the activator for Chinese herbal medicine contains an agent for growing enteric bacteria having a glycoside degrading ability.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This invention relates to an activator for Kampo medicines. More specifically, this invention relates to an activator for making Kampo medicines more likely to exhibit their medicinal effects. [Background technology]

[0002] The herbal medicines that make up traditional Chinese medicine prescriptions contain various glycosides as active ingredients. Glycosides are a general term for substances in which a sugar and a non-sugar compound are bonded together, and the non-sugar portion is called an aglycone. Examples of aglycones include various terpenoids, steroids, quinones, and lignans.

[0003] Glycosides, which are bound to sugars, are water-soluble and highly absorbable in the digestive tract, but they have the characteristic of not easily permeating hydrophobic biological membranes. On the other hand, aglycones, which are produced by the hydrolysis of glycosides, are hydrophobic and can easily permeate biological membranes. Therefore, in many traditional Chinese medicine prescriptions, the active ingredients are taken orally as glycosides, hydrolyzed in the intestinal tract, and absorbed as aglycones, thereby exerting their medicinal effects. Intestinal bacteria are deeply involved in this hydrolysis of glycosides.

[0004] Non-patent document 1 discloses a method for culturing human intestinal bacteria. Non-patent document 2 investigates the relationship between the ability to break down diol saponins, which are glycosides found in ginseng and other substances, and intestinal bacteria.

[0005] Generally, the human intestinal tract is home to over 400 diverse species of bacteria living in symbiosis, forming what is known as the gut microbiota. The composition of the gut microbiota varies from person to person and fluctuates with age, lifestyle, and other factors. If the proportion of gut bacteria that contribute to the hydrolysis of glycosides is low in the gut microbiota, the effects of orally ingested herbal medicine may not be fully obtained. This is one of the reasons why there are individual differences in the efficacy of herbal medicine.

[0006] As a means of eliminating individual differences in drug efficacy caused by differences in glycoside degradation ability, Patent Document 1 describes a method of hydrolyzing glycosides in herbal medicines by treating them with multiple enzymes and microorganisms before oral administration. However, the method disclosed in Patent Document 1 requires multi-stage processing, which is not easy to implement. Furthermore, since the water solubility of glycosides is lost through hydrolysis, absorption in the gastrointestinal tract is limited, and some of the efficacy may be inhibited. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] Patent No. 5917772 [Non-patent literature]

[0008] [Non-Patent Document 1] Martens EC, Chiang HC and Gordon JI, "Mucosal glycan foraging enhances fitness and transmission of a saccharolytic human gut bacterial symbiont.", Cell Host Microbe, 2008, vol. 4, p. 447-457 [Non-Patent Document 2] HASEGAWA et al., Journal of Traditional Medicines, 2007, Vol. 24, pp. 140-143. [Overview of the Initiative] [Problems that the invention aims to solve]

[0009] In order for herbal medicines to exert their full efficacy, it is necessary to orally ingest the active ingredients as water-soluble glycosides, and to hydrolyze the glycosides to remove the sugars in the presence of intestinal bacteria such as colonic epithelium, where the absorption of the medicinal ingredients occurs.

[0010] For example, Non-Patent Document 2 identifies Bacteroides uniformis as an intestinal bacterium involved in the hydrolysis of glycosides in a detailed study of 17 subjects. Therefore, by increasing the proportion of Bacteroides uniformis in the gut microbiota, it is possible to enhance the absorption of the active ingredients and activate the herbal medicine, even in individuals with low glycoside degradation ability who are less likely to benefit from herbal medicines. However, no method has yet been proposed for increasing the proportion of specific intestinal bacteria in the human gut microbiota in order to activate herbal medicines.

[0011] The object of the present invention is to provide a herbal medicine activator that can fully exert the efficacy of herbal medicines by increasing the occupancy rate of specific intestinal bacteria that promote the hydrolysis of glycosides, which are the active ingredients of herbal medicines, without impairing the water solubility of these glycosides. [Means for solving the problem]

[0012] As a result of diligent research, the inventors discovered that cellulose acetate with an adjusted total acetyl substitution degree selectively promotes the growth of intestinal bacteria that have the ability to hydrolyze glycosides, which are active ingredients in traditional Chinese medicine, while preventing the growth of other intestinal bacteria that are not involved in glycoside degradation. This led to the completion of the present invention.

[0013] In other words, the herbal medicine activator according to the present invention contains cellulose acetate having a total acetyl substitution degree of 0.4 or more and 1.0 or less.

[0014] Preferably, in this herbal medicine activator, the viscosity-average degree of polymerization (DPv) of cellulose acetate is 10 or more and 400 or less.

[0015] Preferably, in this herbal medicine activator, the compositional distribution index (CDI) of cellulose acetate is 2.0 or less. The definition of compositional distribution index (CDI) is as follows: CDI = (Measured value of the composition distribution's full width at half maximum) / (Theoretical value of the composition distribution's full width at half maximum) (Here, the measured value of the composition distribution half-width is the composition distribution half-width obtained by HPLC analysis of cellulose acetate propionate obtained by propionylating all the remaining hydroxyl groups of cellulose acetate (sample), and the theoretical value of the composition distribution half-width is the value obtained by the following formula.)

Number

[0016] A preferred traditional Chinese medicine composition contains any of the above-mentioned traditional Chinese medicine activators and a traditional Chinese medicine.

[0017] Preferably, the active ingredient of this traditional Chinese medicine is saponin. Preferably, this saponin is a diol-based saponin.

[0018] From another perspective, the present invention is a growth agent for intestinal bacteria having the ability to hydrolyze glycosides. This growth agent contains cellulose acetate having a total degree of acetyl substitution of 0.4 or more and 1.0 or less. Preferably, this intestinal bacterium is Bacteroides uniformis.

[0019] A preferred traditional Chinese medicine activator contains any of the above-mentioned growth agents.

Effect of the Invention

[0020] According to the traditional Chinese medicine activator of the present invention, in the human intestinal flora, the occupancy rate of intestinal bacteria having the ability to hydrolyze glycosides is improved. As a result, even in individuals with low glycoside-degrading ability, the production of highly absorbable aglycones is promoted, and the efficacy of traditional Chinese medicine is fully exerted. Thereby, the individual difference in drug efficacy is eliminated.

Mode for Carrying Out the Invention

[0021] The present invention will be described in detail below based on preferred embodiments. The scope of the present invention is not limited to these descriptions, and it is possible to implement the invention in ways other than those exemplified below, as long as the spirit of the invention is not impaired. Furthermore, the present invention is not limited to the following embodiments, and various modifications are possible within the scope of the claims. Other embodiments obtained by appropriately combining the technical means disclosed in each of the multiple embodiments are also included in the technical scope of the present invention.

[0022] In this specification, "X~Y" indicating a range means "X or more and Y or less." Also, unless otherwise noted, "ppm" means "ppm by weight" or "ppm by mass." Furthermore, "weight" and "mass," "parts by weight" and "parts by mass," and "weight%" and "mass%" are treated as synonyms.

[0023] [Traditional Chinese Medicine Activator] The herbal medicine activator relating to this disclosure includes cellulose acetate (hereinafter sometimes referred to as "low-substituted cellulose acetate") having a total acetyl substitution degree of 0.4 to 1.0. Here, "activation of herbal medicine" means improving the absorption of its active ingredients so that the efficacy of the herbal medicine can be effectively exerted.

[0024] In many traditional Chinese medicine prescriptions, the active ingredients, ingested orally as glycosides, are hydrolyzed and absorbed from the intestinal tract to obtain their medicinal effects. The human intestinal tract is home to a wide variety of bacteria that constitute the gut microbiota. Among the bacteria that make up the gut microbiota, certain intestinal bacteria are involved in the hydrolysis of glycosides.

[0025] Intestinal bacteria capable of hydrolyzing glycosides proliferate by metabolizing cellulose acetate having a total acetyl substitution degree of 0.4 to 1.0 according to this disclosure. In other words, this low-substituted cellulose acetate is a growth factor for intestinal bacteria capable of hydrolyzing glycosides. On the other hand, this low-substituted cellulose acetate does not contribute to the growth of other intestinal bacteria that do not possess the ability to hydrolyze glycosides. As a result, in the intestinal tract of humans who ingest the low-substituted cellulose according to this disclosure, an intestinal microbiota with a high proportion of intestinal bacteria capable of hydrolyzing glycosides is formed. This promotes the hydrolysis of orally ingested glycosides, allowing for efficient absorption of active ingredients, thus fully demonstrating the efficacy of the herbal medicine. Furthermore, with the herbal medicine activator according to this disclosure, the therapeutic effects of the herbal medicine can be fully obtained even in individuals who inherently have low glycoside degradation ability. By using this herbal medicine activator in combination with herbal medicine, the individual differences in therapeutic effects that have been a problem in the past can be eliminated.

[0026] [Traditional Chinese Medicine] The herbal medicines (crude drugs) activated by the herbal medicine activator described herein contain glycosides as active ingredients. There are many types of glycosides contained in herbal medicines, each with different combinations of sugars and non-sugar compounds (aglycones).

[0027] Examples of sugars that make up glycosides include aldoses such as glucose, mannose, galactose, fucose, rhamnose, arabinose, and xylose, and ketoses such as fructose. Examples of aglycones that make up glycosides include various terpenoids, steroids, quinones, and lignans.

[0028] Saponins are a representative example of glycosides that are effective components of useful herbal medicines. Saponins are known as active ingredients in medicinal ginseng and other plants. Saponins are broadly classified into triterpenoid saponins and steroid saponins depending on the type of aglycone. Triterpenoid saponins are further divided into oleanolic saponins and damaraneic saponins, and damaraneic saponins are further classified into protobanaxatriol (triolic saponins) and protopanaxadiol (diolic saponins).

[0029] Examples of crude drugs containing damaran saponins include ginseng and jujube. Examples of crude drugs containing oleanol saponins include Polygala tenuifolia, Licorice, Platycodon grandiflorus, Achyranthes bidentata, Bupleurum chinense, Senega, and Akebia quinata. Examples of crude drugs containing steroid saponins include Anemarrhena asphodeloides and Ophiopogon japonicus.

[0030] In herbal medicines containing saponins as active ingredients, the effects of the herbal medicine activator disclosed herein are easily obtained. A more preferred active ingredient is a diol-type saponin.

[0031] [Total degree of acetyl substitution in cellulose acetate] The cellulose acetate of this disclosure has a total acetyl substitution degree (substitution degree) of 0.4 to 1.0. When the total acetyl substitution degree is within this range, it exhibits excellent solubility in water, while outside this range, solubility tends to decrease. Orally ingested cellulose acetate is broken down into acetic acid and cellulose in the digestive tract by intestinal bacteria. Furthermore, cellulose is broken down into short-chain fatty acids such as acetic acid via oligosaccharides and monosaccharides. Low-substituted cellulose acetate according to this disclosure is particularly assimilated by intestinal bacteria that have the ability to hydrolyze glycosides. The breakdown of cellulose acetate into acetic acid and cellulose is thought to occur by extracellular enzymes. Therefore, cellulose acetate with high water solubility is more easily broken down, which is thought to lead to the proliferation of intestinal bacteria that have the ability to hydrolyze glycosides. From this viewpoint, a total acetyl substitution degree of 0.4 to 1.0 is preferred, and 0.5 to 0.9 is more preferred.

[0032] The total acetyl substitution degree can be determined by converting the degree of acetation, which is calculated according to the method for measuring the degree of acetation in ASTM:D-871-96 (Test methods for cellulose acetate, etc.), using the following formula. This is the most common method for determining the degree of substitution of cellulose acetate. DS=162.14×AV×0.01 / (60.052-42.037×AV×0.01) DS: Total degree of acetyl substitution AV: Degree of acetic acid (%)

[0033] The method for measuring the degree of acetic acid (AV) is as follows:

[0034] First, 500 mg of dried cellulose acetate (sample) is accurately weighed and dissolved in 50 ml of a mixed solvent of ultrapure water and acetone (volume ratio 4:1). Then, 50 ml of 0.2 N sodium hydroxide aqueous solution is added, and saponification is carried out at 25°C for 2 hours. Next, 50 ml of 0.2 N hydrochloric acid is added, and the amount of acetic acid removed is titrated with 0.2 N sodium hydroxide aqueous solution (0.2 N sodium hydroxide normal solution) using phenolphthalein as an indicator. A blank test (test without a sample) is also performed in the same manner. Finally, the AV (degree of acetic acid) (%) is calculated according to the following formula. AV(%) = (AB) × F × 1.201 / Sample mass (g) A: Titration volume (ml) of 0.2N sodium hydroxide normal solution B: Titration volume (ml) of 0.2N sodium hydroxide normal solution in the blank test. F: Factor of 0.2N sodium hydroxide normal solution

[0035] [Viscosity-average degree of polymerization (DPv) of cellulose acetate] The viscosity-average degree of polymerization (DPv) of the cellulose acetate according to this disclosure is not particularly limited, but is preferably 10 to 400. Low-substituted cellulose acetate with a viscosity-average degree of polymerization in this range is less susceptible to decomposition by digestive enzymes, etc., and therefore easily reaches the inside of the intestinal tract and is readily assimilated by the aforementioned intestinal bacteria. From this viewpoint, a viscosity-average degree of polymerization of 15 to 300 is more preferable, and 20 to 200 is even more preferable.

[0036] Viscosity-average degree of polymerization (DPv) is the intrinsic viscosity number ([η], unit: cm) of low-substituted cellulose acetate. 3 It is determined based on / g).

[0037] Intrinsic viscosity number ([η], unit: cm) 3The viscosity ( / g) is determined according to JIS-K-7367-1 and ISO1628-1. Specifically, a sample solution is prepared using dimethyl sulfoxide (DMSO) as the solvent, and the logarithmic relative viscosity at 25°C, measured using a size 1C Ubbelohde viscometer, is divided by the concentration of the sample solution.

[0038] Using the obtained intrinsic viscosity number [η], the viscosity-average molecular weight was calculated according to the following formula, following the literature by Kamide et al. (Polymer Journal, 13, 421-431 (1981)). Viscosity average molecular weight = (limiting viscosity number [η] / 0.171) (1 / 0.61)

[0039] Using the calculated viscosity-average molecular weight, the viscosity-average degree of polymerization (DPv) was determined by the following formula. Viscosity average degree of polymerization (DPv) = viscosity average molecular weight / (162.14+42.037×DS) In the formula, DS represents the total degree of acetyl substitution as described above.

[0040] [Composition Distribution Index (CDI) of Cellulose Acetate] In this disclosure, the composition distribution index (CDI) of cellulose acetate is not particularly limited. The composition distribution index (CDI) may be, for example, 1.0 or more and 3.0 or less. The composition distribution index (CDI) is more preferably 1.0 or more and 2.5 or less, even more preferably 1.0 or more and 2.0 or less, even more preferably 1.0 or more and 1.8 or less, and particularly preferably 1.0 or more and 1.6 or less.

[0041] The lower limit of the Composition Distribution Index (CDI) is 0, but this can only be achieved with special synthetic techniques, such as acetylating only the 6th position of glucose residues with 100% selectivity while leaving other positions unacetylated, and no such synthetic technique is known. In a situation where all hydroxyl groups of glucose residues are acetylated and deacetylated with equal probability, the CDI becomes 1.0, but in actual cellulose reactions, considerable ingenuity is required to approach this ideal state. The smaller the Composition Distribution Index (CDI), the more uniform the composition distribution (intermolecular substitution degree distribution). A uniform composition distribution allows for water solubility over a wider range than usual due to the total degree of acetyl substitution, resulting in uniform dissolution, no structural viscosity, making it easier to ingest or administer, easily decomposed, and thus facilitating the effects of increased intestinal bacterial occupancy and activation of herbal medicines, as mentioned above.

[0042] Here, the Compositional Distribution Index (CDI) is defined as the ratio of the measured value of the compositional distribution full width at half maximum (FWHM) to the theoretical value [(measured value of compositional distribution FWHM) / (theoretical value of compositional distribution FWHM)]. The compositional distribution FWHM is also called the "intermolecular substitution degree distribution FWHM" or simply the "substitution degree distribution FWHM".

[0043] To evaluate the uniformity of the total acetyl substitution degree of cellulose acetate, the width at half maximum (FWHM) of the maximum peak in the intermolecular substitution degree distribution curve of cellulose acetate can be used as an indicator. The FWHM is the width of the chart at half the height of the peak, when the total acetyl substitution degree is on the horizontal axis (x-axis) and the abundance at this substitution degree is on the vertical axis (y-axis), and it is an indicator that represents the variability of the distribution. The FWHM of the substitution degree distribution can be determined by high-performance liquid chromatography (HPLC) measurement. The method for converting the horizontal axis (elution time) of the elution curve of cellulose ester in HPLC to the substitution degree (0 to 3) is described in Japanese Patent Publication No. 2003-201301 (paragraphs 0037 to 0040).

[0044] (Theoretical value of the full width at half maximum of the composition distribution) The composition distribution half-width (substitution degree distribution half-width) can be calculated probabilistically. That is, the theoretical value of the composition distribution half-width can be obtained by the following equation (1).

number

[0045] Equation (1) represents the compositional distribution full width at half maximum (FWHM) that inevitably arises when all hydroxyl groups of cellulose are acetylated and deacetylated with equal probability, and is derived according to the so-called binomial theorem. Furthermore, the theoretical value of the compositional distribution FWHM can be expressed in terms of the degree of substitution and degree of polymerization as follows. Equation (2) below is the defining formula for calculating the theoretical value of the compositional distribution FWHM.

number

[0046] (Measured values ​​of the full width at half maximum of the composition distribution) In this disclosure, the measured value of the compositional distribution half width at half width is the compositional distribution half width at half width obtained by measuring cellulose acetate propionate, which is obtained by propionylating all the remaining hydroxyl groups (unsubstituted hydroxyl groups) of cellulose acetate (sample), using high-performance liquid chromatography (HPLC).

[0047] The purpose of derivatizing residual hydroxyl groups in cellulose acetate as a pretreatment before HPLC measurement is to convert low-substituted cellulose acetate (e.g., cellulose acetate with a total acetyl substitution of 1.0 or less) into a derivative that is easily soluble in organic solvents, making it suitable for HPLC measurement. That is, the residual hydroxyl groups in the molecule are completely propionized, and the fully derivatized cellulose acetate propionate (CAP) is measured by HPLC to determine the composition distribution full width at half maximum (measured value). Here, derivatization must be complete, with no residual hydroxyl groups remaining in the molecule, and only acetyl and propionyl groups present. In other words, the sum of the total acetyl substitution (DSac) and the total propionyl substitution (DSpr) is 3. This is because the relationship DSac + DSpr = 3 is used to create a calibration curve for converting the horizontal axis (elution time) of the HPLC elution curve of CAP to the total acetyl substitution (0-3).

[0048] Complete derivatization of low-substituted cellulose acetate can be carried out, for example, by reacting it with propionic anhydride using N,N-dimethylaminopyridine as a catalyst in a pyridine / N,N-dimethylacetamide mixed solvent. More specifically, 20 parts by mass of the mixed solvent [pyridine / N,N-dimethylacetamide = 1 / 1 (v / v)] per 1 part by mass of low-substituted cellulose acetate (sample) is used as the solvent, 6.0 to 7.5 equivalents of propionic anhydride relative to the hydroxyl groups of the cellulose acetate are used as the propionylating agent, and 6.5 to 8.0 mol% of N,N-dimethylaminopyridine relative to the hydroxyl groups of the cellulose acetate are used as the catalyst, and propionylation is carried out at a temperature of 100°C for a reaction time of 1.5 to 3.0 hours. Subsequently, for example, by adding 1 part by mass of the reaction mixture to 10 parts by mass of a water / methanol mixed solvent (volume ratio 1 / 1) at room temperature, the precipitate obtained is washed five times with this water / methanol mixed solvent and then vacuum-dried at 60°C for 3 hours to obtain fully derivatized cellulose acetate propionate (CAP).

[0049] In HPLC measurement, multiple cellulose acetate propionates with different degrees of total acetyl substitution are used as standard samples, and HPLC measurements are performed using a predetermined measuring instrument and conditions. A calibration curve [a curve showing the relationship between the elution time of cellulose acetate propionate and the degree of total acetyl substitution (0-3), usually a cubic curve] is then created using the analytical values ​​of these standard samples. Based on this calibration curve, the full width at half maximum (measured value) of the compositional distribution of low-substituted cellulose acetate (sample) is determined. What is determined by this HPLC analysis is the relationship between the elution time and the distribution of the degree of total acetyl substitution of cellulose acetate propionate. This is essentially no different from determining the distribution of the degree of total acetyl substitution of cellulose acetate as described in this disclosure, since it is the relationship between the elution time and the distribution of the degree of acetyl substitution of a substance in which all residual hydroxyl groups in the sample molecule have been converted to propionyloxy groups.

[0050] The measurement conditions for HPLC are as follows: Equipment: Agilent 1100 Series Column: Waters Nova-Pak phenyl 60Å 4μm (150mm × 3.9mmφ) + guard column Column temperature: 30℃ Detection: Varian 380-LC Injection volume: 5.0μL (sample concentration: 0.1% (wt / vol)) Eluent: Solution A: MeOH / H2O=8 / 1(v / v), Solution B: CHCl3 / MeOH=8 / 1(v / v) Gradient: A / B = 80 / 20 → 0 / 100 (28 min) Flow rate: 0.7mL / min

[0051] In the substitution degree distribution curve obtained from the calibration curve [the substitution degree distribution curve of cellulose acetate propionate with the abundance of cellulose acetate propionate on the vertical axis and the total degree of acetyl substitution on the horizontal axis] (also called the "intermolecular substitution degree distribution curve"), the full width at half maximum of the substitution degree distribution is determined for the maximum peak (E) corresponding to the average degree of substitution as follows: A baseline (AB) is drawn tangent to the base (A) on the low-substitution side of peak (E) and the base (B) on the high-substitution side. A perpendicular line is drawn from the maximum peak (E) to the horizontal axis to this baseline. The intersection point (C) of the perpendicular line and the baseline (AB) is determined, and the midpoint (D) between the maximum peak (E) and the intersection point (C) is found. A straight line is drawn through the midpoint (D) and parallel to the baseline (AB), and the two intersection points (A', B') with the intermolecular substitution degree distribution curve are found. Draw perpendicular lines from the two intersection points (A', B') to the horizontal axis, find the width between the two intersection points on the horizontal axis, and take this as the full width at half maximum (i.e., the full width at half maximum of the permutation distribution).

[0052] Next, the correction value Z is determined based on the correction formula shown below. This correction allows for the determination of a more accurate half-width (measured value) of the degree of substitution distribution, even if the configuration of the measuring device and the measurement conditions differ, by obtaining the same (or nearly the same) value. Z=(X 2 -Y 2 ) 1 / 2 (In the formula, X is the half-width at half maximum (uncorrected value) of the degree of substitution distribution obtained using a predetermined measuring device and measurement conditions. Y = (ab)x / 3 + b (0 ≤ x ≤ 3). Here, a is the apparent half-width at half maximum of the degree of substitution distribution of cellulose acetate with a total degree of substitution of 3 obtained using the same measuring device and measurement conditions as X, and b is the apparent half-width at half maximum of the degree of substitution distribution of cellulose propionate with a total degree of substitution of 3 obtained using the same measuring device and measurement conditions as X. x is the total degree of acetyl substitution of the sample (0 ≤ x ≤ 3).)

[0053] Furthermore, the cellulose acetate (or cellulose propionate) with a total substitution degree of 3 mentioned above refers to a cellulose ester in which all hydroxyl groups of cellulose are esterified, and in practice (ideally) it is a cellulose ester that does not have a substitution degree distribution full width at half maximum (i.e., a substitution degree distribution full width at half maximum of 0).

[0054] The degree of substitution distribution of cellulose acetate can be controlled by optimizing the post-treatment conditions after the hydrolysis of cellulose acetate, as described later. Furthermore, the degree of substitution distribution can be narrowed by hydrolysis (maturation reaction) of cellulose acetate at high temperatures of 90°C or higher (or exceeding 90°C). The inventors have found that when hydrolyzing cellulose acetate to obtain low-substituted cellulose acetate, reacting at high temperatures of 90°C or higher (or exceeding 90°C), preferably in the presence of a strong acid such as sulfuric acid, in a large amount of acetic acid, does not reduce the degree of polymerization, but rather reduces viscosity with decreasing CDI. In other words, they have clarified that the decrease in viscosity associated with high-temperature reactions is not due to a decrease in the degree of polymerization, but rather to a decrease in structural viscosity due to a narrower degree of substitution distribution. When hydrolysis of cellulose acetate is performed under the above conditions, not only the forward reaction but also the reverse reaction occurs, resulting in an extremely small CDI value for the product (low-substituted cellulose acetate) and a significant improvement in its solubility in water. In contrast, when hydrolysis of cellulose acetate is carried out under conditions where the reverse reaction is unlikely to occur, the degree of substitution distribution broadens due to various factors, increasing the content of cellulose acetate with a total acetyl substitution degree of less than 0.4 (which is poorly soluble in water) and cellulose acetate with a total acetyl substitution degree of more than 1.0 (which is poorly soluble in water), and consequently decreasing the overall solubility in water.

[0055] [Dispersity (polydispersity, Mw / Mn)] The degree of dispersion (polydispersibility, Mw / Mn) of the molecular weight distribution (degree of polymerization distribution) in this disclosure is a value obtained by GPC-light scattering using cellulose acetate propionate, which is obtained by propionizing all the remaining hydroxyl groups of cellulose acetate (sample).

[0056] The degree of dispersion (polydispersibility, Mw / Mn) of the low-substituted cellulose acetate of this disclosure is preferably in the range of 1.2 to 3.5. Low-substituted cellulose acetate with a dispersion degree (Mw / Mn) in the above range has uniform molecular size and excellent solubility in water. Orally ingested cellulose acetate is broken down into acetic acid and cellulose in the digestive tract by intestinal bacteria. Furthermore, cellulose is broken down into short-chain fatty acids such as acetic acid via oligosaccharides and monosaccharides. Low-substituted cellulose acetate according to this disclosure is particularly assimilated by intestinal bacteria that have the ability to hydrolyze glycosides. The breakdown of cellulose acetate into acetic acid and cellulose is thought to occur by extracellular enzymes. Therefore, cellulose acetate with high solubility in water is more easily broken down, which is thought to lead to the proliferation of intestinal bacteria that have the ability to hydrolyze glycosides. From this viewpoint, the degree of dispersion (polydispersibility, Mw / Mn) of the low-substituted cellulose acetate is more preferably 1.2 to 2.5, and even more preferably 1.2 to 2.0.

[0057] The degree of dispersibility (polydispersibility, Mw / Mn) of low-substituted cellulose acetate can be determined by known methods. Specifically, the degree of dispersibility (polydispersibility, Mw / Mn) of low-substituted cellulose acetate is determined by converting the cellulose acetate (sample) into fully derivatized cellulose acetate propionate (CAP) using the same method as when determining the measured value of the composition distribution half-width, in order to make the sample soluble in an organic solvent, and then performing size exclusion chromatography (GPC) measurement under the following apparatus and conditions (GPC-light scattering method). Equipment: Shodex GPC "SYSTEM-21H" Solvent: Acetone Columns: GMHxl (Tosoh) x 2, Guard column (Tosoh TSKgel guardcolumn HXL-H) Flow rate: 0.8ml / min Temperature: 29℃ Sample concentration: 0.25% (wt / vol) Injection volume: 100μl Detection: MALLS (Multi-angle light scattering detector) (Wyatt, "DAWN-EOS") MALLS correction standard material: PMMA (molecular weight 27600)

[0058] [Weight average degree of polymerization (DPw)] The weight-average degree of polymerization (DPw) in this disclosure is the value obtained by the GPC-light scattering method described above, using cellulose acetate propionate obtained by propionylating all remaining hydroxyl groups of low-substituted cellulose acetate (sample).

[0059] The weight-average degree of polymerization (DPw) of the low-substituted cellulose acetate according to this disclosure is preferably in the range of 10 to 400. If the weight-average degree of polymerization (DPw) is too high, the solubility in water tends to be poor. The weight-average degree of polymerization (DPw) is preferably 15 to 300, and more preferably 20 to 200. Cellulose acetate ingested orally is broken down into acetic acid and cellulose in the digestive tract by intestinal bacteria. Furthermore, cellulose is broken down into short-chain fatty acids such as acetic acid via oligosaccharides and monosaccharides. The low-substituted cellulose acetate according to this disclosure is particularly assimilated by intestinal bacteria that have the ability to hydrolyze glycosides. The breakdown of cellulose acetate into acetic acid and cellulose is thought to occur by extracellular enzymes. Therefore, cellulose acetate with high solubility in water is more easily broken down, which is thought to lead to the proliferation of intestinal bacteria that have the ability to hydrolyze glycosides.

[0060] The weight-average degree of polymerization (DPw) of low-substituted cellulose acetate is determined by the same method used to determine the measured full width at half maximum of the composition distribution, as described above, by converting the cellulose acetate (sample) into fully derivatized cellulose acetate propionate (CAP) and then performing size exclusion chromatography (GPC) measurement (GPC-light scattering method). The equipment and conditions for GPC measurement are as described above.

[0061] [Production of low-substituted cellulose acetate] The low-substituted cellulose acetate in this disclosure can be produced, for example, by (A) a hydrolysis step (maturation step) of medium to high-substituted cellulose acetate, (B) a precipitation step, and (C) a washing and neutralization step, if necessary. The total degree of acetyl substitution of the medium to high-substituted cellulose acetate is, for example, 1.5 to 3, preferably 2 to 3.

[0062] (A) Hydrolysis process (ripening process) The hydrolysis reaction can be carried out by reacting the raw material, medium to highly substituted cellulose acetate (hereinafter referred to as raw material cellulose acetate), with water in an organic solvent in the presence of a catalyst (aging catalyst). Examples of organic solvents include acetic acid, acetone, alcohols (such as methanol), and mixed solvents thereof. Among these, solvents containing at least acetic acid are preferred. As a catalyst, catalysts generally used as deacetylation catalysts can be used. Sulfuric acid is particularly preferred as a catalyst.

[0063] The amount of organic solvent (e.g., acetic acid) used is, for example, 0.5 to 50 parts by mass, preferably 1 to 20 parts by mass, and more preferably 3 to 10 parts by mass, per 1 part by mass of the raw material cellulose acetate.

[0064] The amount of catalyst (e.g., sulfuric acid) used is, for example, 0.005 to 1 part by mass, preferably 0.01 to 0.5 parts by mass, and more preferably 0.02 to 0.3 parts by mass, per 1 part by mass of raw material cellulose acetate. If the amount of catalyst is too small, the hydrolysis time will be too long, which may cause a decrease in the molecular weight of cellulose acetate. On the other hand, if the amount of catalyst is too large, the degree of change in the depolymerization rate with respect to the hydrolysis temperature will be large, and the depolymerization rate will be large even at a relatively low hydrolysis temperature, making it difficult to obtain cellulose acetate with a sufficiently large molecular weight.

[0065] The amount of water in the hydrolysis step is, for example, 0.5 to 20 parts by mass, preferably 1 to 10 parts by mass, and more preferably 2 to 7 parts by mass, per 1 part by mass of the raw material cellulose acetate. The amount of water is, for example, 0.1 to 5 parts by mass, preferably 0.3 to 2 parts by mass, and more preferably 0.5 to 1.5 parts by mass, per 1 part by mass of the organic solvent (e.g., acetic acid). The entire amount of water may be present in the system at the start of the reaction, but in order to prevent precipitation of cellulose acetate, some of the water to be used may be present in the system at the start of the reaction, and the remaining water may be added to the system in one to several portions.

[0066] The reaction temperature in the hydrolysis step is, for example, 40 to 130°C, preferably 50 to 120°C, and more preferably 60 to 110°C. In particular, when the reaction temperature is 90°C or higher (or above 90°C), the reaction equilibrium tends to shift in a direction in which the rate of the reverse reaction (acetylation reaction) increases relative to the forward reaction (hydrolysis reaction). As a result, the degree of substitution distribution becomes narrower, and cellulose acetate with an extremely low compositional distribution index CDI can be obtained without specially devising post-treatment conditions. In this case, it is preferable to use a strong acid such as sulfuric acid as a catalyst, and it is also preferable to use an excess of acetic acid as the reaction solvent. Furthermore, even when the reaction temperature is 90°C or lower, as will be described later, in the precipitation step, a precipitation method using a mixed solvent containing two or more solvents as the precipitation solvent, or by precipitation fractionation and / or dissolution fractionation, can be used to obtain low-substituted cellulose acetate with a very low compositional distribution index CDI.

[0067] (B) Sedimentation process In this step, after the hydrolysis reaction is complete, the reaction system is cooled to room temperature, and a precipitation solvent is added to precipitate cellulose acetate. As the precipitation solvent, an organic solvent that is miscible with water or an organic solvent with high solubility in water can be used. Examples include ketones such as acetone and methyl ethyl ketone; alcohols such as methanol, ethanol, and isopropyl alcohol; esters such as ethyl acetate; nitrogen-containing compounds such as acetonitrile; ethers such as tetrahydrofuran; and mixed solvents thereof.

[0068] By using a mixed solvent containing two or more solvents as the precipitation solvent, the same effect as the precipitation fractionation described later can be obtained, and low-substituted cellulose acetate with a narrow compositional distribution (degree of intermolecular substitution distribution) and a small compositional distribution index (CDI) can be obtained. Preferred mixed solvents include, for example, a mixed solvent of acetone and methanol, or a mixed solvent of isopropyl alcohol and methanol.

[0069] Furthermore, by further precipitation fractionation (fractional precipitation) and / or dissolution fractionation (fractional dissolution) of the precipitated cellulose acetate, it is possible to obtain low-substituted cellulose acetate with a narrow compositional distribution (degree of intermolecular substitution distribution) and a very small compositional distribution index (CDI).

[0070] Precipitation fractionation can be carried out, for example, by dissolving the precipitated cellulose acetate (solid) in water to make an aqueous solution of an appropriate concentration (e.g., 2 to 10% by mass, preferably 3 to 8% by mass), adding a poor solvent to this aqueous solution (or adding the aqueous solution to a poor solvent), maintaining it at an appropriate temperature (e.g., 30°C or lower, preferably 20°C or lower) to precipitate the cellulose acetate, and recovering the precipitate. Examples of poor solvents include alcohols such as methanol and ketones such as acetone. The amount of poor solvent used is, for example, 1 to 10 parts by mass, preferably 2 to 7 parts by mass, per 1 part by mass of the aqueous solution.

[0071] Dissolution and fractionation can be carried out, for example, by adding a mixed solvent of water and an organic solvent (e.g., a ketone such as acetone, an alcohol such as ethanol, etc.) to the cellulose acetate (solid) obtained by precipitation or the cellulose acetate (solid) obtained by precipitation fractionation, stirring at an appropriate temperature (e.g., 20 to 80°C, preferably 25 to 60°C), separating into a concentrated phase and a dilute phase by centrifugation, and then adding the precipitation solvent (e.g., a ketone such as acetone, an alcohol such as methanol, etc.) to the separated dilute phase to recover the precipitate (solid). The concentration of the organic solvent in the mixed solvent of water and the organic solvent is, for example, 5 to 50% by mass, preferably 10 to 40% by mass.

[0072] (C) Washing and neutralization process The precipitate (solid matter) obtained in the precipitation step (B) is preferably washed with an organic solvent (poor solvent) such as methanol or other alcohols, or acetone or other ketones. It is also preferable to wash and neutralize it with an organic solvent containing a basic substance (for example, methanol or other alcohols, or acetone or other ketones). The neutralization step may be provided separately immediately after the hydrolysis step, in which case it is preferable to add a basic substance or an aqueous solution thereof to the hydrolysis reaction bath.

[0073] Examples of the basic substance that can be used include alkali metal compounds (e.g., alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal bicarbonates such as sodium bicarbonate; alkali metal carboxylates such as sodium acetate and potassium acetate; sodium alkoxides such as sodium methoxide and sodium ethoxide), and alkaline earth metal compounds (e.g., alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide; alkaline earth metal carbonates such as magnesium carbonate and calcium carbonate; alkaline earth metal carboxylates such as magnesium acetate and calcium acetate; alkaline earth metal alkoxides such as magnesium ethoxide). Among these, alkali metal compounds such as potassium acetate are particularly preferred.

[0074] Washing and / or neutralization can efficiently remove impurities such as catalysts (sulfuric acid, etc.) used in the hydrolysis process.

[0075] The low-substituted cellulose acetate obtained in this way can be adjusted to a specific particle size range by crushing, sieving, or granulating as needed.

[0076] [Other optional components] The manufactured cellulose acetate with a total acetyl substitution degree of 0.4 to 1.0 can be used as is as the herbal medicine activator of this disclosure, but known additives may be added within a range that does not inhibit the effects of the present invention. Examples of such additives include excipients, fluidizers, binders, disintegrants, lubricants, dispersants, surfactants, thickeners, pH adjusters, colorants, solubilizers, fragrances, flavorings, and coatings.

[0077] [Traditional Chinese Medicine Composition] If necessary, the herbal medicine activator disclosed herein and the aforementioned herbal medicines (crude drugs) can be combined to form a herbal medicine composition. That is, the herbal medicine composition disclosed herein contains cellulose acetate with a total acetyl substitution degree of 0.4 to 1.0 and a herbal medicine. The type and amount of herbal medicine to be incorporated into this herbal medicine composition are appropriately prepared within the range in which the effects of the present invention can be obtained. Herbal medicines containing saponins as active ingredients are preferred, and herbal medicines containing diol saponins are more preferred.

[0078] [Intestinal bacteria growth agent] In other words, the herbal medicine activator relating to this disclosure includes an intestinal bacterial growth agent (hereinafter referred to as the "growth agent") which contains cellulose acetate (low-substituted cellulose acetate) with a total acetyl substitution degree of 0.4 to 1.0 that selectively promotes the growth of intestinal bacteria having the ability to hydrolyze the aforementioned glycosides. Substances that bring about beneficial effects on the host through the growth and activation of beneficial intestinal bacteria, such as the growth agent relating to this disclosure, are also called prebiotics. Details of the low-substituted cellulose acetate in the growth agent relating to this disclosure are as described above with respect to the herbal medicine activator.

[0079] For example, the genus Bacteroides is one of the major constituent groups of bacteria that make up the human gut microbiota. Examples of gut bacteria belonging to this genus Bacteroides include Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides ovatus, Bacteroides fragilis, Bacteroides destasonis, Bacteroides vulfatus, and Bacteroides meraninogenicus. Among these, Bacteroides uniformis is an example of a gut bacterium that selectively grows by utilizing low-substituted cellulose acetate. Bacteroides uniformis is an intestinal bacterium that has the ability to hydrolyze glycosides.

[0080] Here, "selective growth" by the growth agent according to this disclosure means that it promotes the growth of Bacteroides uniformis but does not promote the growth of other intestinal bacteria. Due to this selective growth effect, the proportion of intestinal bacteria with glycoside hydrolysis ability (e.g., Bacteroides uniformis) increases in the intestinal microbiota of humans who ingest the growth agent according to this disclosure. As a result, the efficacy of the herbal medicine becomes easier to obtain even in individuals with low glycoside degradation ability, and individual differences in drug efficacy are eliminated.

[0081] [How to use] The herbal medicine activator and intestinal bacterial growth agent disclosed herein can be used in various forms, including powders, granules, tablets, sugar-coated tablets, capsules, syrups, pills, suspensions, liquids, and emulsions. Since this herbal medicine activator and intestinal bacterial growth agent promote the absorption of the active ingredients of herbal medicines by increasing the proportion of intestinal bacteria that have glycoside-degrading properties, administration into the intestinal tract is preferred. Methods of administration into the intestinal tract include oral ingestion and administration by suppositories, etc. This herbal medicine activator and intestinal bacterial growth agent may be administered simultaneously with herbal medicines, or separately before or after the administration of herbal medicines. Alternatively, it may be administered as a herbal medicine composition containing herbal medicines.

[0082] The amount of the herbal medicine activator or intestinal bacterial growth agent disclosed herein to be taken or administered should be sufficient to produce the desired effect. Specifically, it can be determined empirically by considering the individual's age, weight, sex, health status, and other conditions such as the condition of the stomach, small intestine, and large intestine, as well as the method of ingestion or administration, and the form of the formulation. The amount taken or administered per dose may be, for example, 5 mg / kg body weight to 60 mg / kg body weight, or 10 mg / kg body weight to 40 mg / kg body weight. The number of times taken or administered may be once or more than once. If more than once, it may be taken or administered regularly, irregularly, or as needed. The appropriate number of times can be determined empirically by considering the individual's conditions, the method of ingestion or administration, and the form of the formulation, similar to the amount taken or administered. [Examples]

[0083] The effects of the present invention will be demonstrated below by the examples, but the present invention should not be interpreted restrictively based on the description in these examples.

[0084] (Test 1) [Example 1] [Preparation of Cellulose Acetate] To 1 part by mass of cellulose acetate (Daicel Corporation, trade name "L-70", total acetyl substitution degree 2.43, 6% viscosity: 145 mPa·s), 4.4 parts by mass of acetic acid and 1.9 parts by mass of water were added, and the mixture was stirred for 3 hours to dissolve the cellulose acetate. To this solution, 0.58 parts by mass of acetic acid and 0.13 parts by mass of sulfuric acid were added, and the resulting solution was maintained at 70°C to start hydrolysis. During hydrolysis, water was added in two stages to prevent precipitation of cellulose acetate. Specifically, 0.65 parts by mass of water was added over 5 minutes 1 hour after the start of the reaction. Two hours later, 1.29 parts by mass of water was added over 10 minutes. The reaction was then continued for another 4 hours. The total hydrolysis time was 7 hours. The first hydrolysis step (first maturation step) is from the start of the reaction until the start of the first addition of water, the second hydrolysis step (second maturation step) is from the start of the first addition of water until the start of the second addition of water, and the third hydrolysis step (third maturation step) is from the start of the second addition of water until the end of the reaction.

[0085] The hydrolysis reaction was stopped by adding a 24% magnesium acetate aqueous solution containing 1.1 equivalents of magnesium acetate relative to sulfuric acid to the obtained reaction mixture. Then, 3.6 times the mass of acetone relative to this reaction mixture was prepared. The reaction mixture was added dropwise to this acetone over 60 minutes under stirring to form a precipitate. Subsequently, the precipitate was filtered and recovered as a wet cake with a solid content of 15% by mass. 16 parts by mass of acetone / water mixed solvent (acetone concentration 20% by mass) was added to 1 part by mass of the solid content of the obtained precipitate, and the mixture was stirred at 40°C for 8 hours. After that, the mixture was filtered to obtain a wet cake with a solid content of 15% by mass. Furthermore, 16 parts by mass of methanol was added to 1 part by mass of the solid content of the obtained wet cake, and the mixture was stirred at 25°C for 1 hour, followed by filtration to obtain a wet cake with a solid content of 15% by mass. The stirring and filtration in methanol were repeated five more times, and the mixture was dried to obtain low-substituted cellulose acetate.

[0086] The total degree of acetyl substitution, viscosity-average degree of polymerization (DPv), degree of dispersion (polydispersibility, Mw / Mn), measured width at half maximum, and compositional distribution index (CDI) of the obtained low-substituted cellulose acetate were measured using the method described above. As a result, the obtained low-substituted cellulose acetate had a total degree of acetyl substitution of 0.78, a viscosity-average degree of polymerization (DPv) of 128, a weight-average molecular weight (DPw) of 124, a degree of dispersion (polydispersibility, Mw / Mn) of 2.0, a measured width at half maximum of 0.305, and a compositional distribution index (CDI) of 1.90. In the following evaluation tests, this low-substituted cellulose acetate was used as is as the herbal medicine activator in Example 1 in the following single-cell culture experiment.

[0087] [Single-bacterial culture experiment] We prepared strains ATCC 29148 as Bacteroides thetaiotaomicron, ATCC 8483 as Bacteroides ovatus, ATCC 25285 as Bacteroides fragilis, and ATCC 8492 as Bacteroides uniformis (obtained from the Microbial Materials Development Laboratory (RIKEN)).

[0088] Each bacterial strain was grown in GAM medium (Nissui) until the mid-logarithmic growth phase, and then 0.1 ml of each culture was inoculated into fresh GAM medium. This was repeated three times. The resulting cultures were then centrifuged at 4°C and 2,300 G for 10 minutes, and the precipitate was suspended in anaerobic diluents (0.4 g / L KH2PO4, 0.4 g / L NaCl, 0.4 g / L (NH4)2SO4, 0.013 g / L MnSO4·5H2O, 0.03 g / L CaCl2·2H2O, 0.045 g / L MgSO4·7H2O, 8.8 mg / L FeSO4·7H2O, 8.8 mg / L ZnSO4·7H2O, 0.82 mg / L CoCl2·6H2O, 0.59 g / L L-Cysteine, 4.7 g / L Na2CO3). The obtained suspension was centrifuged under the above conditions, and the precipitate was resuspended in the above anaerobic diluent to prepare an inoculum for each bacterial strain.

[0089] Based on Non-Patent Document 2, 13.6 g / L KH2PO4, 0.9 g / L NaCl, 1.1 g / L (NH4)2SO4, 0.5 g / L L-cysteine, 1.2 mg / L hematin, 31 mg / L L-histidine, 9.5 mg / L MgCl2, 0.4 mg / L FeSO4·7H2O, 5.5 mg / L CaCl2, 1 mg / L vitamin K1, 5 μg / L vitamin B 12 and 1 mL / L of 0.1% by mass resazurin solution were prepared to obtain a minimal medium. To this minimal medium, the traditional Chinese medicine activator of Example 1 (cellulose acetate with an overall degree of acetylation of 0.78) was added at a concentration of 0.5% by mass.

[0090] To 5 mL of the medium to which the traditional Chinese medicine activator of Example 1 was added, 0.1 mL of the inoculum prepared by the above method was added, and each strain was cultured at 37 °C for 120 hours. For each culture solution before and after culturing, the absorbance (OD 660 ) at a wavelength of 660 nm was measured using a miniphoto518R (manufactured by TAITEC). The absorbance (OD 660 120 ) after 120 hours of culturing and the absorbance (OD 660 0 ) at the start of culturing (0 hour) were used to calculate the difference ΔOD 660 (= OD 660 120 - OD 660 0 ). The average value obtained from three measurements is shown in Table 1 below. The difference ΔOD 660 is an index of bacterial growth, and a larger value means that the growth was promoted more.

[0091] [Comparative Example 1] A single-bacterium culture experiment was conducted in the same manner except that glucose was used instead of celluose acetate with an overall degree of acetylation of 0.78, and the difference ΔOD 660 was determined. The obtained results are shown in Table 1 below.

[0092] [Reference Example 1] This reference example 1 is the control group. The single-cell culture experiment was conducted similarly, except that cellulose acetate with a total acetyl substitution degree of 0.78 was not added, and the difference ΔOD was observed. 660 The following was calculated. The results are shown in Table 1 below.

[0093] [Table 1]

[0094] As shown in Table 1, with the herbal medicine activator of Example 1, Bacteroides thetaiotaomicron, Bacteroides ovatus, and Bacteroides fragilis did not proliferate, while only Bacteroides uniformis proliferated. In Reference Example 1, none of the bacteria proliferated. In Comparative Example 1, all bacteria proliferated. These results demonstrate that Example 1 selectively promotes the growth of Bacteroides uniformis.

[0095] (Exam 2) In Experiment 2, the bacterial flora of human feces was analyzed to confirm the effect of the herbal medicine activator described in Example 1.

[0096] [Analysis of bacterial flora in human feces] Fecal samples were collected from four healthy male volunteers (23 ± 0.71 years old) who had not taken antibiotics for three months. One part by mass of each collected fecal sample was mixed with four parts by mass of 0.1 M PBS buffer (8 g / L NaCl, 0.2 g / L KCl, 1.15 g / L Na2HPO3, 0.2 g / L KH2PO3) to form a slurry. This slurry was filtered through two layers of surgical gauze. These procedures were performed within 5 minutes of fecal collection.

[0097] 1 mL of the filtered slurry was transferred to a test tube containing 9 mL of intestinal environment medium (2 g / L peptone water, 2 g / L yeast extract, 0.1 g / L NaCl, 0.04 g / L K2HPO4, 0.04 g / L KH2PO4, 0.01 g / L MgSO4·7H2O, 0.01 g / L CaCl4·6H2O, 0.5 g / L bile salt, 2 mL / L Tween 80, 1 mL / L 0.05% hemin solution, 0.01 mL / L vitamin K1, 1 mL / L 0.1% resazurin solution, 0.5 g / L L-cysteine ​​HCl, 2 g / L NaHCO3) in an anaerobic chamber (Coy Laboratory Products, Glass Lake, Michigan). 0.1 g of the herbal medicine activator from Example 1 (cellulose acetate with a total acetyl substitution degree of 0.78) was added to this test tube. The headspace of the test tube was replaced with nitrogen gas, sealed with a butyl rubber stopper and a plastic cap, and then incubated at 37°C for 24 hours.

[0098] DNA was extracted from the obtained cultures according to the method described in "Improved extraction of PCR-quality community DNA from digesta and fecal samples." (Yu Z and Morrison M, Biotechniques, 36:808-812 (2004)). The extracted DNA was analyzed using a next-generation sequencer MiSeq (Illumina) under the following conditions to determine the bacterial composition. • Reagents: MiSeq Reagent Kit V3 • Operating conditions: Illumina 2 x 300-bp paired-end sequencing protocol • Data analysis: QIIME2 2018.11.28, DADA2 plugin, similarity threshold 90% The average results of the bacterial composition analysis of four volunteers are shown in Table 2 below.

[0099] [Reference example 2] Reference Example 2 is the control group. The bacterial flora analysis of human feces was performed in the same manner as above, except that cellulose acetate with a total acetyl substitution degree of 0.78 was not added. The results are shown in Table 2 below.

[0100] [Table 2]

[0101] As shown in Table 2, Bacteroides uniformis significantly proliferated when using the herbal medicine activator in Example 1 compared to Reference Example 2. This result indicates that low-substituted cellulose acetate is a growth factor for Bacteroides uniformis, and that in Example 1, this bacterium proliferated selectively, improving its occupancy rate in the gut microbiota.

[0102] As shown in Tables 1 and 2, the herbal medicine activators in the examples received higher evaluations compared to the comparative examples and reference examples. This evaluation clearly demonstrates the superiority of the present invention. [Industrial applicability]

[0103] The herbal medicine activators described above can also be applied to animals other than humans.

Claims

1. It contains a herbal medicine activator and herbal medicine. The active ingredient in the above herbal medicine is a diol saponin. A Kampo medicine composition comprising the above-mentioned Kampo medicine activator, which contains cellulose acetate having a total acetyl substitution degree of 0.4 or more and 1.0 or less.

2. The herbal medicine composition according to claim 1, wherein the viscosity-average degree of polymerization (DPv) of the cellulose acetate is 10 or more and 400 or less.

3. The herbal medicine composition according to claim 1 or 2, wherein the composition distribution index (CDI) of the cellulose acetate described above is 3.0 or less. CDI = (Measured value of the composition distribution's full width at half maximum) / (Theoretical value of the composition distribution's full width at half maximum) (Here, the measured value of the composition distribution half width is the composition distribution half width obtained by HPLC analysis of cellulose acetate propionate, which is obtained by propionizing all the remaining hydroxyl groups of cellulose acetate (sample), and the theoretical value of the composition distribution half width is the value obtained by the following formula.) [Math 1] In the above formula, DS is the total degree of acetyl substitution, and DPw is the weight-average degree of polymerization determined by GPC-light scattering using cellulose acetate propionate obtained by propionylating all remaining hydroxyl groups of cellulose acetate (sample).

4. A growth agent for intestinal bacteria having glycoside-degrading properties, comprising cellulose acetate having a total acetyl substitution degree of 0.4 or more and 1.0 or less, The above-mentioned intestinal bacteria is a growth agent for Bacteroides uniformis.

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