Use of beta-caryophyllene in the preparation of a medicament for the treatment of constipation-predominant irritable bowel syndrome

Abstract

This invention discloses the application of β-caryophyllene in the preparation of drugs for treating constipation-predominant irritable bowel syndrome (IBS). This invention is the first to discover the application of β-caryophyllene in the preparation of drugs for treating IBS. Studies have confirmed that β-caryophyllene can effectively improve fecal particle count, fecal water content, visceral hypersensitivity, and gastrointestinal propulsion rate in rats with a constipation-predominant IBS model, demonstrating a clear therapeutic effect on IBS. Furthermore, this invention also proposes drugs with β-caryophyllene as an active ingredient, possessing good market potential and value.

Description

Technical Field

[0001] This invention belongs to the field of new uses of pharmaceuticals, and specifically relates to the application of β-caryophyllene in the preparation of drugs for treating constipation-predominant irritable bowel syndrome. Background Technology

[0002] Constipation-predominant irritable bowel syndrome (IBS-C) is a common functional gastrointestinal disorder characterized by abdominal discomfort, abdominal pain, and changes in bowel habits. In addition to symptoms such as bloating, abdominal discomfort, and abdominal pain, IBS-C patients often experience significant constipation, including difficulty defecating, reduced frequency of bowel movements, and hard, dry stools. However, these symptoms usually lessen with bowel movements. IBS-C patients also experience heightened visceral sensations, increased sensitivity, and abnormal gastrointestinal motility. Currently, various medications are available for treating IBS-C, including polyethylene glycol, lubiprostone, linaclotide, pricanatide, tecapranolol, and tegaserod. Despite these treatment options, the abdominal discomfort symptoms often remain unrelieved. Constipation refers to reduced bowel movements, difficulty in defecation, and hard, dry stools. Common causes include insufficient fiber and water intake, as well as weakened intestinal muscle tone or slowed peristalsis due to various reasons, leading to retention of intestinal contents. Besides poor diet and lifestyle habits, the causes may be related to rectal and anal lesions, colonic obstruction, and other diseases. Treatment for constipation may include medications that promote gastrointestinal motility, probiotics, laxatives, osmotic laxatives, and stimulant laxatives, depending on the patient's condition. Ulcerative colitis is a chronic, nonspecific inflammatory disease of the colon and rectum with an unclear etiology. The lesions are limited to the large intestine mucosa and submucosa. The main symptoms are chronic, recurrent mucus-containing bloody stools and diarrhea, which may be accompanied by pain, fever, and weight loss. Colonoscopy reveals that most patients have a continuous inflammatory lesion of the intestinal mucosa progressing from the rectum to the colon, which may manifest as congestion, erosion, and ulceration. Drug treatment for ulcerative colitis mainly includes controlling the inflammatory response and symptomatic treatment. Commonly used drugs for controlling inflammatory responses include aminosalicylic acid preparations, glucocorticoids, immunosuppressants, and biological agents.

[0003] β-Caryophyllene, also known as β-eugenol, is a class of bicyclic sesquiterpenoid compounds. It is volatile and a colorless to slightly yellow oily liquid. β-Caryophyllene belongs to both natural and synthetic fragrance compounds and can be isolated from clove leaf oil, clove stem oil, cinnamon leaf oil, etc. Pharmacological studies have shown that β-caryophyllene possesses anti-inflammatory, analgesic, anti-anxiety, antidepressant, and anticonvulsant activities. β-Caryophyllene can be used to relieve ulcerative colitis and provide pain relief. However, there are currently no studies demonstrating the use of β-caryophyllene in the treatment of constipation-predominant irritable bowel syndrome (IBS). Summary of the Invention

[0004] Purpose of the invention: In order to overcome the shortcomings of the prior art, the present invention provides the application of β-caryophyllene in the preparation of drugs for treating constipation-predominant irritable bowel syndrome.

[0005] Technical solution: To achieve the above-mentioned objectives, the present invention adopts the following technical solution:

[0006] Application of β-caryophyllene in the preparation of drugs for treating constipation-predominant irritable bowel syndrome.

[0007] The present invention also provides the use of compositions containing β-caryophyllene in the preparation of medicaments for constipation-predominant irritable bowel syndrome.

[0008] The composition includes β-caryophyllene and pharmaceutically acceptable excipients.

[0009] Beneficial Effects: This invention is the first to discover the application of β-caryophyllene in the preparation of drugs for treating constipation-predominant irritable bowel syndrome (IBS). Studies have confirmed that β-caryophyllene can effectively improve fecal particle count, fecal water content, visceral hypersensitivity, and gastrointestinal propulsion rate in rats with a constipation-predominant IBS model, demonstrating a clear therapeutic effect on IBS. Furthermore, this invention also proposes drugs with β-caryophyllene as an active ingredient, possessing significant market potential and value. Attached Figure Description

[0010] Figure 1 Effects of β-caryophyllene on fecal particle number and fecal water content in IBS-C rats. (A) Fecal particle number; (B) Fecal water content. Compared with the blank control group, ** P < 0.01; compared with the IBS-C model group, # P < 0.05 ## P < 0.01; compared with the positive drug control group, & P < 0.05.

[0011] Figure 2 Effects of β-caryophyllene on visceral hypersensitivity and gastrointestinal propulsion rate in IBS-C rats. (A) Water injection volume; (B) Percentage of charcoal powder propulsion distance. Compared with the blank control group, ** P < 0.01; compared with the IBS-C model group, # P < 0.05 ## P < 0.01; compared with the positive drug control group, & P < 0.05 && P < 0.01. Detailed Implementation

[0012] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.

[0013] Example 1

[0014] A rat model of constipation-predominant irritable bowel syndrome (IBS) was established using the ice water gavage method. Following the calculation method for "equivalent dose" in animal experimental studies, rats were randomly divided into a blank control group, a model group, a positive drug control group, and an experimental group. The efficacy of β-caryophyllene in treating constipation-predominant IBS was evaluated based on indicators such as fecal particle count, fecal water content, visceral hypersensitivity, and gastrointestinal propulsion rate. The mechanism of action of β-caryophyllene in treating constipation-predominant IBS was explored.

[0015] 1. Experimental Materials

[0016] 1.1 Test Drug

[0017] The test drug was β-caryophyllene, and the positive control drug was linaclotide.

[0018] 1.2 Laboratory Animals

[0019] Female SD rats, weighing 200±20g, were purchased from Nantong University. All experimental procedures complied with the requirements of the "Guidelines for the Management and Use of Laboratory Animals".

[0020] 1.3 Statistical Methods

[0021] Experimental data were analyzed using SPSS 26.0 statistical software. All results are expressed as mean ± standard deviation (x±s). One-way ANOVA was used, and differences between groups were compared using t-tests. P < 0.05 was considered statistically significant.

[0022] 2 Experimental Methods

[0023] 2.1 Animal modeling, grouping, and drug administration

[0024] Thirty-six IBS-C model rats were randomly divided into six groups (n=6 per group): blank control group, IBS-C model group, positive drug control group (linaclotide, 3 μg / kg), low-dose β-caryophyllene group (50 mg / kg), medium-dose β-caryophyllene group (100 mg / kg), and high-dose β-caryophyllene group (200 mg / kg). Rats were administered 2 mL of ice water (0–4℃) by gavage once daily for 14 days to establish the IBS-C model. The blank control group was administered an equal volume of physiological saline instead of ice water. Gavage was scheduled at 09:00 h to avoid interference with circadian rhythms. Starting from day 15, each group received the corresponding drug via gavage, while the blank control group and model group received an equal volume of physiological saline once daily for 14 days.

[0025] 2.2 Observation Indicators

[0026] After the last administration, record the number of stool particles and the weight of dry / wet stool.

[0027] Visceral sensitivity assessment: The AWR score of rats was assessed using the colonic dilatation method to evaluate visceral hypersensitivity. Two members, unaware of the group assignments, were responsible for the procedure. Rats were fasted for 12 hours prior to the test, but water was allowed. After mild anesthesia with sevoflurane, a glycerol-lubricated 6F catheter was slowly inserted 7 cm into the anus and secured to the base of the tail with tape. The rat was placed in a transparent glass box. Once the rat was awake and stable, physiological saline (27±1℃) was injected via a balloon. The volume of saline injected to elicit an AWR score of 3 was recorded. This test was repeated three times, and the average of the three injection volumes was taken as the minimum volume threshold for AWR in that rat. The lower the threshold, the higher the visceral sensitivity. AWR scoring criteria: 0 points, no behavioral response; 1 point, slight head movement, no body movement; 2 points, abdominal muscle contraction, but the abdomen does not leave the plateau surface; 3 points, abdominal muscle contraction, the abdomen leaves the plateau surface; 4 points, the body arches, the pelvis rises, and the perineum rises away from the plateau surface.

[0028] Gastrointestinal propulsion rate assessment: The charcoal propulsion method was used to assess gastrointestinal propulsion rate. One hour after the last administration, rats were administered 2 mL of a suspension of 10% activated charcoal and 5% gum arabic by gavage. 0.5 hours later, the rats were euthanized by cervical dislocation, and the gastrointestinal tract was dissected and placed on a glass plate. The total length from the pylorus to the ileocecal junction and the distance from the pylorus to the leading edge of the charcoal were measured. The percentage of charcoal propulsion distance was calculated using the formula: Charcoal propulsion distance percentage % = Distance between the leading edge of the charcoal and the pylorus / Total length of the small intestine × 100%.

[0029] 3 Results

[0030] 3.1 Effects of β-caryophyllene on fecal particle number and fecal water content in IBS-C rats

[0031] like Figure 1As shown in Table 1, compared with the blank control group, the number of fecal particles and the fecal water content of rats in the IBS-C model group were significantly reduced (P < 0.01). However, the positive drug control group and the low, medium, and high dose β-caryophyllene groups significantly increased the number of fecal particles in the IBS-C model group (P < 0.05, P < 0.01). Compared with the positive drug control group, the number of fecal particles in the low and medium dose β-caryophyllene groups was significantly reduced (P < 0.05). However, there was no significant difference in the number of fecal particles in the high dose β-caryophyllene group compared with the positive drug control group. The positive drug control group and the medium and high dose β-caryophyllene groups significantly increased the fecal water content of rats in the IBS-C model group (P < 0.05, P < 0.01). Compared with the positive drug control group, the fecal water content in the low and medium dose β-caryophyllene groups was significantly reduced (P < 0.05, P < 0.01). However, there was no significant difference in fecal water content between the high-dose β-caryophyllene group and the positive drug control group.

[0032] Table 1. Effects of β-caryophyllene on fecal particle number and fecal moisture content of IBS-C (x±s, n=6)

[0033]

[0034] Note: Compared with the blank control group ** P < 0.01; compared with the model group, # P < 0.05 ## P < 0.01; compared with the positive drug control group, & P < 0.05 && P < 0.01.

[0035] 3.2 Effects of β-caryophyllene on visceral hypersensitivity and gastrointestinal propulsion rate in IBS-C rats

[0036] like Figure 2As shown in Table 2, the water injection volume and charcoal propulsion distance percentage at which the AWR score reached 3 in the IBS-C model group were significantly lower than those in the blank control group (P < 0.01). The positive drug control group and the medium and high dose β-caryophyllene groups significantly increased the water injection volume at which the AWR score reached 3 in rats compared to the IBS-C model group (P < 0.05, P < 0.01). Compared to the positive drug control group, the low and medium dose β-caryophyllene groups significantly decreased the water injection volume at which the AWR score reached 3 in rats (P < 0.05, P < 0.01). However, there was no significant difference in the water injection volume at which the AWR score reached 3 in the high dose β-caryophyllene group compared to the positive drug control group. The positive drug control group and the medium and high dose β-caryophyllene groups significantly increased the charcoal propulsion distance percentage compared to the IBS-C model group (P < 0.01). Compared to the positive drug control group, the low dose β-caryophyllene group significantly decreased the charcoal propulsion distance percentage (P < 0.05). However, the percentage of carbon powder propagation distance in the medium and high dose groups of β-caryophyllene was not significantly different from that in the positive drug control group.

[0037] Table 2. Effects of β-caryophyllene on visceral hypersensitivity and gastrointestinal propulsion rate in IBS-C (x±s, n=6)

[0038]

[0039] Note: Compared with the blank control group ** P < 0.01; compared with the model group, # P < 0.05 ## P < 0.01; compared with the positive drug control group, & P < 0.05 && P < 0.01.

[0040] The above results indicate that the rat model of constipation-predominant irritable bowel syndrome (IBS) established using the ice water gavage method is stable and highly reproducible, effectively mimicking the clinical state of IBS patients. After treatment with β-caryophyllene, the number of fecal particles, fecal water content, and gastrointestinal propulsion rate significantly increased, while visceral hypersensitivity significantly decreased. This demonstrates that β-caryophyllene can effectively improve relevant indicators in the rat model of constipation-predominant IBS and has a significant therapeutic effect on IBS.

[0041] The above-described embodiments are merely one implementation of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the scope of protection of the present invention. Therefore, the scope of protection of this invention should be determined by the appended claims.

Claims

1. Use of beta-caryophyllene for the manufacture of a medicament for the treatment of constipation-predominant irritable bowel syndrome.

2. Use of a composition consisting of beta-caryophyllene and pharmaceutically acceptable excipients for the manufacture of a medicament for the treatment of constipation-predominant irritable bowel syndrome.

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