A phenolic acid composition and its use in promoting digestion

Abstract

The present application belongs to the field of biopharmacy, and particularly relates to a phenolic acid composition and application thereof in promoting digestion. The present application firstly finds a single phenolic acid for improving dyspepsia through single-component phenolic acid experiments, then attempts to find a phenolic acid compound with a synergistic effect through compounding, and surprisingly, the combination of two phenolic acids with the best effect on promoting digestion cannot achieve the best effect optimization, but eugenol with the worst effect on promoting digestion achieves a synergistic effect on promoting digestion through compounding with other phenolic acids, and can achieve the effect of a positive drug, which provides a potential alternative drug for improving dyspepsia.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of biopharmaceuticals, and particularly relates to a phenolic acid composition and its application in promoting digestion. BACKGROUND

[0002] Dyspepsia is a group of common clinical syndromes, patients have no organic lesions, accompanied by upper abdominal pain, postprandial fullness or early satiety and other symptoms. Because the medical equipment cannot detect organic lesions, patients often do not get proper treatment, and most dyspeptic patients suffer from dyspepsia. Epidemiological surveys show that the incidence of dyspepsia in developed countries is 12% to 41%, and the reported incidence of dyspepsia in China is as high as 18% to 32%.

[0003] At present, the main ways to improve dyspepsia include acid suppression therapy, prokinetic drug therapy, psychological and behavioral therapy, etc. However, acid suppression therapy can only improve the dyspepsia caused by excessive gastric acid secretion, and the application scenario is limited; while the common prokinetic drugs can achieve certain effect in the early stage, but the long-term effect is poor, and has the disadvantages of high recurrence rate and many side effects; the psychological and behavioral therapy has limited implementability, and cannot achieve ideal effect.

[0004] In recent years, searching for new drugs for improving dyspepsia from natural plants or traditional Chinese medicines is a hot spot of related research. Studies have shown that flavonoids in polyphenols have the effect of promoting gastrointestinal peristalsis, and can improve dyspepsia to a certain extent, while the functional effect of phenolic acids in polyphenols on dyspepsia has not been reported in detail. Phenolic acids in polyphenols include caffeic acid, ferulic acid, p-coumaric acid, gallic acid, syringic acid, etc., which are widely distributed in fruits, vegetables and cereals, and have been proved to have multiple biological activities such as antioxidant, anti-inflammatory, immune regulation, anticancer, etc., and have the potential to improve dyspepsia. SUMMARY

[0005] In order to increase the selection range of existing dyspepsia improving preparations, the present application provides the following technical solutions:

[0006] The first aspect of the present application provides a phenolic acid complex preparation for improving dyspepsia, characterized in that the phenolic acid complex comprises syringic acid and one or both of p-coumaric acid and gallic acid, wherein the weight ratio of syringic acid to the other phenolic acid is 1:0.5-1.5.

[0007] Further, the phenolic acid complex preparation consists of syringic acid and p-coumaric acid; preferably, the mass ratio is 1:1.

[0008] Further, the phenolic acid complex preparation consists of syringic acid and gallic acid, preferably, the mass ratio is 1:1.

[0009] Further, the dosage form of the phenolic acid complex preparation includes at least one of the following: suspension, granules, capsules, powders, tablets, drop pills, injections, suppositories, drops.

[0010] Further, the administration route of the phenolic acid complex preparation includes at least one of the following: intravenous injection, intraperitoneal injection, intramuscular injection, subcutaneous injection, oral administration, perfusion administration.

[0011] Further, the phenolic acid complex preparation further includes at least one of the following pharmaceutically acceptable adjuvants: diluent, binder, wetting agent, lubricant, disintegrant, solvent, emulsifier, cosolvent, preservative, pH adjuster, osmotic pressure adjuster, surfactant, coating material, antioxidant or buffer.

[0012] Further, the administration dose of the phenolic acid complex preparation is 150-250 mg / Kg body weight, preferably 200 mg / Kg body weight.

[0013] The second aspect of the present application provides the use of syringic acid in the preparation of a phenolic acid complex preparation for improving indigestion, characterized in that the phenolic acid complex further includes one or both of p-coumaric acid and gallic acid, and the weight ratio of syringic acid to the other phenolic acid is 1:0.5-1.5.

[0014] Further, the phenolic acid complex preparation consists of syringic acid and p-coumaric acid, and preferably the mass ratio is 1:1.

[0015] Further, the phenolic acid complex preparation consists of syringic acid and gallic acid, and preferably the mass ratio is 1:1.

[0016] Further, the administration dose of the phenolic acid complex preparation is 150-250 mg / Kg body weight, preferably 200 mg / Kg body weight.

[0017] The beneficial effects of the present application include:

[0018] The present application first discovers a single phenolic acid for improving indigestion through single-component phenolic acid experiments, then attempts to find a phenolic acid complex with synergistic effect through compounding, and surprisingly, the combination of the two phenolic acids with the best effect on promoting digestion cannot achieve the best effect optimization, but syringic acid with the worst effect on promoting digestion can achieve synergistic effect on promoting digestion through compounding with other phenolic acids, which can achieve the effect of positive drugs, thereby providing a potential alternative drug for improving indigestion. BRIEF DESCRIPTION OF DRAWINGS

[0019] Figure 1 Single phenolic acid intervention on body weight and body weight gain rate of mice.

[0020] Figure 2 Monophenolic acid intervention mouse defecation time and rate of gastrointestinal propulsion.

[0021] Figure 3 Monophenolic acid intervention in vivo changes in digestive enzymes in mice.

[0022] Figure 4 Compound phenolic acid combination intervention mouse defecation time and rate of gastrointestinal propulsion.

[0023] Figure 5 Compound combination of syringic acid and p-coumaric acid intervention mouse defecation time and rate of gastrointestinal propulsion.

[0024] Figure 6 Compound combination of syringic acid and gallic acid intervention mouse defecation time and rate of gastrointestinal propulsion. DETAILED DESCRIPTION

[0025] The concept and technical effects of the present application will be further described below in conjunction with specific embodiments, so as to fully understand the purpose, features and effects of the present application. The methods are conventional methods unless otherwise specified. The materials can be obtained from public commercial channels unless otherwise specified. The illustrative embodiments of the present application and their descriptions are used to explain the present application and do not constitute undue limitations on the present application. It should be noted that the embodiments in the present application and the features in the embodiments can be combined with each other without conflict.

[0026] Example 1: Screening of monophenolic acid compounds

[0027] 1. Animal test grouping and dose design

[0028] 64 healthy SPF C57BL / 6J level 6-week-old male mice were provided by Beijing Vito Lihua Experimental Animal Technology Co., Ltd. and randomly divided into 9 groups, including a blank control group, a model group, a caffeic acid group, a p-coumaric acid group, a gallic acid group, a syringic acid group, a ferulic acid group, a resveratrol group, and a positive drug group.

[0029] Each example group was administered 200 mg / kg of phenolic acid dissolved in 0.5% carboxymethylcellulose sodium per day. The blank control group and the model group of mice were administered with the same volume of 0.5% carboxymethylcellulose sodium solution, and the positive control group of mice was administered with a solution of Jianweixiaoshipi. The administration was performed once a day for 40 consecutive days.

[0030] 2. Detection index

[0031] (1) Monitor the body weight and body weight gain of mice

[0032] (2) After 40 days of gavage, perform charcoal propulsion experiment and record the defecation time of the first black stool of mice

[0033] (3) Gastrointestinal propulsion rate determination: Before the test, the mice were deprived of food but not water for 16 h, and on the test day, each example group was administered a test sample by gavage once, 30 min later, each example group, the positive control group and the model group were administered loperamide hydrochloride (2-4 mg / kg BW) by gavage for modeling, the blank group was administered 0.3 mL of distilled water by gavage, 30 min later, each group was administered 0.4 mL of carbon indicator by gavage, 30 min later, the mice were sacrificed, and the gastrointestinal propulsion rate of the mice was determined.

[0034] Gastrointestinal propulsion rate = carbon indicator propulsion length (cm) / total length of small intestine (cm) x 100%

[0035] (4) The pancreas of the mice was taken, and the activities of trypsin, pancreatic amylase, and pancreatic lipase were determined. The relevant kit was provided by Solabio Company.

[0036] 3. Results

[0037] (1) As shown in Table 1, there was no difference in the body weight and body weight gain of the mice among the groups. Figure 1

[0038] (2) As shown in Table 2, compared with the blank control group, coffee acid, p-coumaric acid, syringic acid, and resveratrol could shorten the defecation time of the mice. Figure 2 (3) As shown in Table 3, compared with the blank control group, the gastrointestinal propulsion rate of the model group was significantly decreased, indicating that drug treatment impaired the gastrointestinal motility of the mice. After the intervention of coffee acid, p-coumaric acid, ferulic acid, and resveratrol, the gastrointestinal propulsion rate of the mice was significantly improved and could be restored to normal levels. Among them, coffee acid and p-coumaric acid had the best improvement effect and could reach the level of the positive drug, but syringic acid and gallic acid did not significantly improve the gastrointestinal propulsion rate of the mice.

[0039] Figure 3 (4) As shown in Table 4, compared with the blank control group, resveratrol intervention could significantly improve the trypsin activity of the mice. Coffee acid intervention could significantly improve the lipase activity of the mice. P-coumaric acid intervention could significantly improve the amylase activity of the mice.

[0040] (4) As shown in Table 4, compared with the blank control group, resveratrol intervention could significantly improve the trypsin activity of the mice. Coffee acid intervention could significantly improve the lipase activity of the mice. P-coumaric acid intervention could significantly improve the amylase activity of the mice. Figure 4 Example 2 Phenolic acid compounding experiment

[0041] 1. Animal test grouping and dose design

[0042] According to the experimental results of the single phenolic acid in Example 1, the two phenolic acids with the best effect (coffee acid and p-coumaric acid) and the two phenolic acids with the worst effect (syringic acid and gallic acid) were selected for compounding.

[0043] The mouse grouping and modeling treatment method is as described in Example 1, and the specific compounding grouping is as follows:

[0044] ​​​

[0045] Blank control group, model group, syringic acid + caffeic acid group, syringic acid + p-coumaric acid group, syringic acid + gallic acid group, caffeic acid + p-coumaric acid group, positive control group (digestive tablets).

[0046] Each example group received a daily gavage dose of 200 mg / kg (prepared according to a 1:1 ratio of phenolic acid, with 100 mg / kg of phenolic acid added alone) once a day for 40 consecutive days.

[0047] 2. Detection indicators

[0048] (1) After 40 days of gavage, a charcoal propulsion experiment was conducted to record the time of the first black stool in mice.

[0049] (2) Determination of gastrointestinal propulsion rate: Before the experiment, mice were fed but not fed water for 16 hours. On the day of the experiment, each group of the example was gavaged once. 30 minutes later, each group of the example, the positive control group and the model group were gavaged with loperamide hydrochloride (2-4 mg / kg BW) to establish the model. The blank group was gavaged with 0.3 mL of distilled water. 30 minutes later, each group was gavaged with 0.4 mL of carbon powder indicator. The mice were sacrificed 30 minutes later and the gastrointestinal propulsion rate of the mice was measured.

[0050] Gastrointestinal propulsion rate = (Length of carbon powder indicator propelled (cm) / Total length of small intestine (cm)) × 100%

[0051] 3. Results

[0052] (1) As Figure 5 As shown, compared with the blank control group, the eugenol + caffeic acid group, the eugenol + p-coumaric acid group, and the eugenol + gallic acid group all shortened the defecation time of mice. Compared with the blank control group, the gastrointestinal propulsion rate of the model group was significantly decreased. The gastrointestinal propulsion rate of mice after intervention with eugenol + p-coumaric acid and eugenol + gallic acid was significantly improved, which could significantly improve the gastrointestinal propulsion rate of mice with indigestion and reach the positive drug level. Considering the results of defecation time and gastrointestinal propulsion rate, the eugenol + p-coumaric acid group and the eugenol + gallic acid group had the best digestive promotion effect.

[0053] (2) Figure 6 As shown, the results of the two phenolic acid complex groups with the best digestive effects, eugenol + p-coumaric acid and eugenol + gallic acid, were combined and analyzed with those of monophenolic acids. It was found that after eugenol, which had the worst digestive effect, was combined with p-coumaric acid, which had the best digestive effect, and gallic acid, which had the worst digestive effect, the intervention effect of the complex phenolic acid groups was better than that of the monophenolic acid groups, and better than the combination of the two phenolic acids with the best digestive effects, namely p-coumaric acid + caffeic acid.

[0054] (3) The synergistic effect of the two combined drug combinations was calculated using the Loewe equivalent line method. The calculation method is as follows: Plot the single drug doses DA and DB at any effect point on the X and Y axes of the coordinate system, and connect the two points to obtain the linear equation: x / DA + x / DB = 1. When the two doses dA and dB are used together, the combined effect is achieved when DA or DB is used alone. The combined effect index CI = dA / DA + dB / DB. When CI < 1, it is a synergistic effect; CI = 1, it is an additive effect; and CI > 1, it is an antagonistic effect.

[0055] The calculation results are shown in the table below. The CI values ​​of the compound combinations of syringic acid + p-coumaric acid (Tables 1 and 3) and syringic acid + gallic acid (Tables 2 and 4) are all less than 1, indicating that they are synergistic.

[0056] Table 1. Calculation of the synergistic effect of eugenol and p-coumaric acid on defecation time.

[0057]

[0058] Table 2. Calculation of the synergistic effect of eugenol and gallic acid on defecation time.

[0059]

[0060] Table 3. Calculation of the synergistic effect of eugenol and p-coumaric acid on gastrointestinal propulsion rate.

[0061]

[0062] Table 4. Calculation of the synergistic effect of eugenol and gallic acid on gastrointestinal propulsion rate.

[0063]

[0064] The analysis results show that the combination of the two phenolic acids with the best digestive effects does not achieve the optimal effect. On the contrary, eugenol, which has the worst digestive effect, achieves a synergistic digestive effect when combined with other phenolic acids.

[0065] The embodiments described above are only some embodiments of the present invention, not all embodiments. Other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are all within the scope of protection of the present invention.

Claims

1. Use of Syringic acid for the preparation of a phenolic acid complex preparation for improving dyspepsia, characterized in that, The phenolic acid complex further includes one of p-coumaric acid and gallic acid, wherein the weight ratio of syringic acid to the other phenolic acid is 1:0.5-1.

5.

2. Use according to claim 1, characterized in that, The phenolic acid complex preparation consists of syringic acid and p-coumaric acid.

3. Use according to claim 1, characterized in that, The phenolic acid complex preparation consists of syringic acid and gallic acid.

4. The use according to any one of claims 1 to 3, characterized in that, The dosage form of the phenolic acid complex preparation includes at least one of suspensions, granules, capsules, powders, tablets, dripping pills, injections, suppositories, drops.

5. The use according to any one of claims 1 to 3, characterized in that, The administration route of the phenolic acid complex preparation includes at least one of intravenous injection, intraperitoneal injection, intramuscular injection, subcutaneous injection, oral administration, perfusion administration.

6. The use according to any one of claims 1 to 3, characterized in that, The phenolic acid complex preparation further includes at least one of pharmaceutically acceptable adjuvants including diluents, binding agents, wetting agents, lubricating agents, disintegrating agents, solvents, emulsifying agents, co-solvents, preservatives, pH adjusting agents, osmotic pressure adjusting agents, surfactants, coating materials, antioxidants or buffers.

7. The use according to any one of claims 1 to 3, characterized in that, The administration dose of the phenolic acid complex preparation is 150-250 mg / Kg body weight.

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