A traditional Chinese medicine volatile oil composition for treating functional abdominal pain syndrome and application thereof

Abstract

The present application relates to the technical field of medicine, in particular to a traditional Chinese medicine volatile oil composition for treating functional abdominal pain syndrome and application thereof, wherein the traditional Chinese medicine volatile oil composition comprises volatile oil of raw ginger and volatile oil of turmeric, and further comprises any one of volatile oil of peppermint, volatile oil of caraway and volatile oil of cumin.The present application takes advantage of multi-component and multi-target of traditional Chinese medicine, takes volatile oil of five medicinal materials of peppermint, caraway, turmeric, cumin and raw ginger as main components, establishes a new method of designing traditional Chinese medicine compound based on target complementation and addition of main components, and develops a new compound mainly for analgesia, supplemented by anti-inflammation and not affecting gastrointestinal function, aiming at main symptoms of FAPs, in order to provide a new pharmaceutical composition for clinical treatment of FAPs.The compound designed by the present application has clear analgesic and anti-inflammatory effects and has no obvious effect on gastrointestinal function of mice.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a traditional Chinese medicine volatile oil composition for treating functional abdominal pain syndrome and its application. Background Technology

[0002] Functional abdominal pain syndrome (FAPs) is a functional disorder characterized by persistent or frequently recurring abdominal pain that is unrelated to gastrointestinal function but closely related to changes in the intrinsic pain regulation system. It is a type of functional gastrointestinal disorder. The overall incidence of FAPs is relatively high (1.3%-2.2%), affecting 10%-25% of school-aged children and causing higher rates of absenteeism, sleep problems, physical pain, depression, and anxiety, leading to a decline in overall quality of life.

[0003] The pathological mechanisms of functional gastrointestinal disorders (FAPs) are complex and not yet fully understood. Current research suggests that abnormalities in the brain-gut axis play a significant role in the pathogenesis of FAPs and other functional gastrointestinal disorders. FAPs may be a form of central pain, caused by multiple factors affecting the central nervous system's physiological regulation of normal intestinal function. This leads to amplification of normal endocrine signals in the central nervous system, producing abnormal sensations and resulting in abdominal pain. Currently, there is no effective treatment for FAPs. Clinical treatment mainly focuses on symptomatic medications, including antidepressants and analgesics, but the therapeutic effects are unsatisfactory and adverse reactions are severe. With the continuous in-depth research on drugs and diseases, summarizing the clinical efficacy and side effects of single-component, single-target drugs, it has gradually been recognized that multi-component, multi-target drugs have greater advantages. Developing multi-target, low-adverse-effect natural drugs has become an important research direction.

[0004] Volatile oils of traditional Chinese medicine are a key material basis for the efficacy of aromatic Chinese herbs, possessing strong biological activities such as relieving exterior syndromes, resolving dampness, promoting qi circulation, and opening the orifices. Classic prescriptions containing volatile oils of traditional Chinese medicine are widely used for various types of pain, regulating the gastrointestinal tract, calming the mind, and refreshing the spirit, exerting antibacterial, antiviral, and anti-inflammatory effects. Their aromatic dampness-resolving effect is mainly characterized by dispelling turbidity and invigorating the spleen, promoting spleen and stomach function, harmonizing the stomach and relieving exterior syndromes, smoothing qi flow, and dispelling dampness. Modern research shows that volatile oils of traditional Chinese medicine can regulate digestive system activity. Their aromatic odor can stimulate the sense of smell and taste, promote the secretion of digestive juices, increase gastric mucosal blood flow, alleviate gastric spasms and smooth muscle spasms, and stimulate intestinal peristalsis, eliminating flatulence and thus regulating gastrointestinal function. However, there are currently no products using volatile oils of traditional Chinese medicine to treat febrile acute pancreatitis (FAP). Summary of the Invention

[0005] The purpose of this invention is to provide a traditional Chinese medicine volatile oil composition for the treatment of functional abdominal pain syndrome (FAP) and its application. Targeting the main symptoms of FAP, a new compound formula has been developed that is primarily analgesic with secondary anti-inflammatory effects and does not affect gastrointestinal function, aiming to provide a new pharmaceutical composition for the clinical treatment of FAP.

[0006] To achieve the above objectives, the present invention provides the following solution:

[0007] This invention provides a traditional Chinese medicine volatile oil composition for treating functional abdominal pain syndrome, the traditional Chinese medicine volatile oil composition comprising ginger volatile oil and turmeric volatile oil.

[0008] Furthermore, the herbal volatile oil composition also includes a third volatile oil, which is any one of peppermint volatile oil, Tibetan fennel volatile oil, and fennel volatile oil.

[0009] Furthermore, the volume ratio of the ginger volatile oil, turmeric volatile oil, and any third volatile oil is 1:1:1.

[0010] The present invention also provides the application of the aforementioned traditional Chinese medicine volatile oil composition in the preparation of a medicament for treating functional abdominal pain syndrome.

[0011] Furthermore, the drug acts on FAPs-related genes through complementary action of the main chemical components in the traditional Chinese medicine volatile oil composition, thereby exerting analgesic and anti-inflammatory effects and treating functional abdominal pain syndrome.

[0012] The present invention discloses the following technical effects:

[0013] This invention leverages the advantages of traditional Chinese medicine (TCM) in its multi-component and multi-target effects. Using the volatile oils of five herbs—peppermint, fennel, turmeric, fennel, and ginger—as the main components, a novel method for designing TCM compound formulas based on complementary and amplifying the main component targets is established. Combined with in vivo animal experiments and mechanism-of-action studies, a new compound formula targeting the main symptoms of febrile acute exacerbations (FAPs) has been developed, primarily for analgesia with secondary anti-inflammatory effects, without affecting gastrointestinal function. This aims to provide a new pharmaceutical composition for the clinical treatment of FAPs. Furthermore, the formula designed in this invention exhibits clear analgesic and anti-inflammatory effects without significantly affecting the gastrointestinal function of mice. Attached Figure Description

[0014] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0015] Figure 1GC-MS chromatogram of peppermint volatile oil;

[0016] Figure 2 Gas chromatography-mass spectrometry (GC-MS) analysis chromatogram of volatile oil from Tibetan fennel;

[0017] Figure 3 The gas chromatography-mass spectrometry (GC-MS) chromatogram of volatile oil from turmeric;

[0018] Figure 4 The gas chromatography-mass spectrometry (GC-MS) chromatogram of volatile oil from ginger.

[0019] Figure 5 GC-MS chromatogram of volatile oil from fennel seeds;

[0020] Figure 6 This is a network of interactions between target proteins associated with FAPs. Detailed Implementation

[0021] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0022] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Every smaller range between any stated value or intermediate value within a stated range, and any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0023] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0024] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be readily apparent to those skilled in the art. This specification and embodiments are merely exemplary.

[0025] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0026] Example 1

[0027] 1. Materials and Methods

[0028] 1.1 Determination of main components by gas chromatography-mass spectrometry

[0029] Qualitative and semi-quantitative analyses of the main components of volatile oils from five medicinal herbs—peppermint, fennel, turmeric, fennel, and ginger—were performed using gas chromatography-mass spectrometry (GC-MS). A Shimadzu GCMS-QP2010 Plus instrument was used to analyze the five commercially available volatile oil samples. Components with a content greater than 1% in each volatile oil were identified as the main components, and information such as CAS spectroscopy, molecular formula, molecular weight, and chemical structural formula were collected to establish a chemical composition library.

[0030] 1.2 Identification of the target proteins of chemical components

[0031] The target sites of chemical components were predicted by searching the database of the Traditional Chinese Medicine Systems Pharmacology Analysis Platform (http: / / tcmspw.com / , TCMSP, v:2.3) and Swiss TargetPredict (http: / / tcmspw.com / ), and a target site database was established.

[0032] 1.3 Collection of FAP-related targets and analysis of protein-protein interactions

[0033] By searching for reported genes related to functional abdominal pain syndrome (FAPs) in DrugBank (https: / / go.drugbank.com / ) using the keyword "functional abdominal pain syndrome", relevant literature was reviewed, related genes were identified, duplicate genes were removed, and the obtained targets were further standardized and named in the Uniport (https: / / www.uniprot.org / ) database to obtain a database of FAP-related targets.

[0034] Protein-protein interaction data were acquired using the STRING platform and imported into Cytoscape software to obtain a protein-protein interaction network. The NetworkAnalyzer tool was used to calculate network topology parameters, including degree (degree > mean) and betweenness centrality (BC > mean), to identify key disease targets.

[0035] 1.4 Target-based formulation design

[0036] Based on the established database of FAPs and chemical component targets, different cross-analyses were conducted to determine the effects of five volatile oils on key FAPs targets. By leveraging the characteristics and advantages of multiple components and targets in traditional Chinese medicine, and based on covering as many targets as possible, a new traditional Chinese medicine compound was designed using the method of complementarity and addition of main component targets.

[0037] 1.5 Study on the analgesic effect of the formula

[0038] The analgesic effect of the designed compound was studied using acetic acid writhing and hot plate tests. Healthy Kunming mice, weighing 20–22 g, were selected. Male mice were used for the acetic acid writhing test, and female mice were used for the hot plate test. They were randomly divided into a control group, a positive control group (aspirin 200 mg / kg), and groups with different prescriptions (100 mg / kg), with 10 mice in each group. The mice were administered the medication by gavage at a volume of 0.1 ml / 10 g body weight, once daily for 5 consecutive days, or as a single dose. One hour after administration, the mice were injected intraperitoneally with 0.1 ml / 10 g body weight of 0.6% acetic acid solution. The number of writhing episodes and the time of the first writhing episode were recorded within 15 minutes, or the time of the appearance of the paw-licking response was observed one hour after administration.

[0039] 1.6 Study on the anti-inflammatory effect of the formulation

[0040] The anti-inflammatory effect of the designed compound was studied using a xylene-induced ear swelling experiment in mice. Healthy Kunming mice, weighing 20–22 g, were randomly divided into three groups (n=10 per group): a control group, a positive control group (aspirin 200 mg / kg), and a group receiving different formulations (100 mg / kg). Administered by gavage once daily for 5 consecutive days, the control group received the same volume of solvent as a control. Thirty minutes after the last administration, 0.02 ml of 100% xylene was applied to both the anterior and posterior surfaces of the right ear of each mouse, with the left ear serving as a control. Fifteen minutes later, the mice were euthanized by cervical dislocation, and circular ear pieces were punched from the same location using a 6 mm diameter punch. The ear pieces were weighed using an electronic balance. The degree of swelling (right ear weight minus left ear weight per mouse) was used as the detection index.

[0041] 1.7 Effect on intestinal propulsion in mice

[0042] Mice were administered the drug via gavage for 5 consecutive days or as a single dose. They were fasted for 12 hours before the last dose. 30 minutes after the last dose, they were administered an activated charcoal suspension (0.2 ml / 10 g of activated charcoal powder suspension prepared with 10% gum arabic). Thirty minutes later, the animals were euthanized by cervical dislocation. The abdominal cavity was opened, the mesentery was separated, and the entire small intestine from the stomach to the ileocecal junction was removed and laid flat on a glass plate. The distance from the pylorus to the ileocecal junction was measured as the total length of the small intestine, and the distance from the pylorus to the leading edge of the charcoal propulsion was measured as the charcoal propulsion distance. The percentage of charcoal propulsion in each group was calculated.

[0043] 1.8 Study on the mechanism of action

[0044] After the acetic acid writhing test in mice, brain tissue was collected and enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of 5-hydroxytryptamine (5-HT), γ-aminobutyric acid (GABA), and prostaglandin E2 (PGE2) in the brain tissue.

[0045] 2 Results

[0046] 2.1 Qualitative and quantitative analysis of samples used in pharmacological studies

[0047] Gas chromatography-mass spectrometry (chromatogram shown) Figure 1-5 Using a peak area greater than 1% as the standard, the main chemical components in the five volatile oils were screened and determined. Fourteen chemical components were screened from ginger, six from fennel, two from fennel seeds, eight from turmeric, and twelve from peppermint. Information on each chemical component is shown in Table 1.

[0048] Table 15 Information on Main Chemical Components of Volatile Oils

[0049] medicinal materials CAS# English name content medicinal materials CAS# English name content Mint 10458-14-7 menthone 18.65 turmeric 87440-60-6 Curlone 15.08 Mint 1196-31-2 isomenthone 8.17 Ginger 112-95-8 Eicosane 3.48 Mint 15932-80-6 (RS)-Pulegone 2.21 Ginger 20307-83-9 β-sesquiphellandrene 14.07 Mint 16409-45-3 1-mentyl acetate 4.91 Ginger 23513-14-6 6-Gingerol 2.25 Mint 18172-67-3 Beta-pinene 1.82 Ginger 31295-56-4 Dodecane, 2, 6, 1 l-trime 3.1 Mint 491-02-1 neoisomenthol 5.29 Ginger 39029-41-9 gamma-cadinene 2.85 Mint 589-98-0 3-Octanol 1.24 Ginger 470-82-6 Eucalyptol 2.68 Mint 5989-27-5 D-Limonene 6.13 Ginger 495-60-3 zingiberene 40.17 Mint 7786-67-6 Isoprcgol 1.34 Ginger 495-61-4 β-bisabolene 7.59 Mint 80-56-8 Alpha-pinene 1.06 Ginger 502-61-4 farnesen 4.2 Mint 89-78-1 menthol 41.61 Ginger 544-85-4 Dotriacontane 1.95 Mint 89-81-6 piperitone 1.26 Ginger 62185-53-9 5-(2-Methylpropyl)nonane 2.14 Tibetan fennel 2244-16-8 D-Carvone 61.71 Ginger 629-59-4 Tetradecane 1.24 Tibetan fennel 5989-27-5 D-Limonene 32.44 Ginger 644-30-4 α-curcumene 9.55 turmeric 108645-54-1 (-)-(E)-α-Atlantone 1.56 Ginger 79-92-5 camphene 2.1 turmeric 180315-67-7 Tumerone 31.64 Fennel 104-46-1 cis-Anethol 87.01 turmeric 20307-83-9 β-sesquiphellandrene 7.15 Fennel 123-11-5 p-Anisaldehyde 1.47 turmeric 495-60-3 zingiberene 8.13 Fennel 140-67-0 Estragole 3.56 turmeric 495-61-4 (S)-beta-bisabolene 1.24 Fennel 78259-41-3 Foeniculin 1.23 turmeric 532-65-0 ar-turmerone 25.61 Fennel 78-70-6 Linalool 1.43 turmeric 644-30-4 α-curcumene 4.39 Fennel 80-56-8 α-Pinene 1.01

[0050] 2.2 Collection of chemically related targets and analysis of protein-protein interactions

[0051] Fourteen chemical components in ginger can act on 141 targets; six chemical components in fennel can act on 145 targets; two chemical components in Tibetan fennel can act on 101 targets; eight chemical components in turmeric can act on 203 targets; and twelve chemical components in peppermint can act on 47 targets.

[0052] 2.3 Collection of FAPs-related targets

[0053] A search for "functional abdominal pain syndrome" in DrugBank yielded 262 reported genes associated with FAPs. Related literature from DrugBank, specifically the brain-gut axis, returned 332 genes, along with 198 other genes mentioned in the literature. After removing duplicate genes from these three sources, 468 FAP-related targets were identified and compiled into a database. A PPI network was then constructed (see...). Figure 6 Using BetweennessCentrality and Degree greater than the mean as indicators, 94 core targets of FAPs were screened and confirmed.

[0054] 2.4 Target-based formulation design

[0055] Table 2 shows the number of chemical components, target points, and the proportion of FAP-related targets in the five volatile oils.

[0056] Table 2 Relationship between drug targets and FAPS targets

[0057]

[0058]

[0059] As shown in Table 2, turmeric, ginger, and fennel have relatively more target sites. Through cross-analysis, turmeric and ginger affect more FAPS-related target sites, with 40 and 33 respectively. A total of 94 FAPS-related core target sites have been identified. Peppermint, Tibetan fennel, turmeric, ginger, and fennel can act on 3, 8, 20, 20, and 10 core target sites respectively. The five volatile oils can affect a total of 27 core target sites, as shown in Table 3.

[0060] Table 3. Core targets that different medicinal materials can act upon.

[0061]

[0062] Based on the distribution of the target sites of the main chemical components in the five volatile oils, the key target sites affected by ginger and turmeric are complementary. The combination of the two drugs can affect 27 core target sites. Therefore, the basic prescription was determined to consist of ginger and turmeric. By adding other medicinal materials to enhance the target effects, a total of four compound prescriptions were designed:

[0063] Formula B: Ginger + Turmeric (volume ratio 1:1)

[0064] Formula C: Ginger + Turmeric + Peppermint (volume ratio 1:1:1)

[0065] Formula D: Ginger + Turmeric + Fennel (volume ratio 1:1:1)

[0066] Formula E: Ginger + Turmeric + Fennel (volume ratio 1:1:1)

[0067] 2.5 Study on the analgesic effect of the formula

[0068] 2.5.1 Analgesic effect of single-dose acetic acid writhing in mice

[0069] Table 4. Analgesic effect of different formulations on writhing pain in mice after single administration of acetic acid.

[0070]

[0071] As shown in Table 4, each of the new formulations has a certain analgesic effect when administered once. Formulation C has the strongest activity, which is comparable to that of the positive control drug aspirin. It shows a statistically significant difference compared with the blank control group. At the same time, formulation C can significantly prolong the latency period of pain onset.

[0072] 2.5.2 Analgesic effect of a single hot plate test in mice

[0073] Table 5. Analgesic effect (s) of different formulations in mice after repeated administration of hot plate test.

[0074]

[0075] As shown in Table 5, except for the model control group, the pain threshold of each group was prolonged after the last administration, and the pain threshold at 60 min was significantly different from that at 60 min (P<0.05).

[0076] 2.5.3 Analgesic effect of repeated administration of acetic acid to mice during writhing.

[0077] Table 6. Analgesic effect of acetic acid writhing in mice after repeated administration of different formulations.

[0078]

[0079] Compared with the model control group, the latency period of each drug administration group was prolonged to varying degrees; the number of writhing movements was also reduced. Compared with the model group, the positive control drug aspirin and the C and E groups could prolong the writhing latency period and reduce the number of writhing movements in mice (P<0.05).

[0080] Formula E, when administered repeatedly, can alleviate acetic acid-induced pain in mice, exhibiting a stronger analgesic effect.

[0081] 2.6 Study on the anti-inflammatory effect of the formulation

[0082] Table 7. Effects of different formulations on the degree of swelling (mg) and inhibition rate (%) of xylene-induced ear swelling in mice.

[0083]

[0084] Note: *: P<0.05 compared to the model group.

[0085] Compared with the model group, the positive control drug aspirin significantly reduced ear swelling in xylene-induced inflammatory mice (p<0.05), with an inhibition rate of 41.6%. The inhibition rates of mouse ear swelling by formulations B, C, D, and E were 34.6%, 50.6%, 21.21%, and 29.0%, respectively. Compared with the model group, formulation C had a significant reducing effect on mouse ear swelling (p<0.05).

[0086] 2.7 Intestinal propulsion in mice

[0087] Table 8. Effects of different volatile oil formulations on intestinal propulsion in normal mice. n=10)

[0088]

[0089] Note: Compared with the blank control group, *P<0.05, **P<0.01

[0090] Compared with the blank control group, the percentage of carbon powder propulsion in mice in the Imodium positive control group decreased significantly after single or multiple administrations, and the intestinal propulsion speed slowed down significantly (P<0.01). At a dose of 200 mg / kg, different volatile oil formulations and different administration times had little effect on the percentage of carbon powder propulsion in the small intestine of mice, and no significant statistical difference was found compared with the blank control group (P>0.05). Different formulations had no effect on the intestinal propulsion function of normal mice.

[0091] 2.8 Study on the mechanism of action

[0092] Table 9. Changes in 5-HT, PGE2, and GABA levels in mouse brain tissue after repeated administration of different formulations (pg / mg.pro)

[0093]

[0094]

[0095] As shown in Table 9, significant changes occurred in the levels of 5-HT, PGE2, and GABA in mouse brain tissue, indicating that the anti-inflammatory and analgesic mechanisms of different formulations may be related to the regulation of the levels of active substances and neurotransmitters such as 5-HT, PGE2, and GABA. Formulation C reduced 5-HT levels comparable to that of the positive control drug aspirin.

[0096] In summary, the results of the above study indicate that the four formulations, formulation C (ginger + turmeric + peppermint) and formulation E (ginger + turmeric + fennel), have clear analgesic and anti-inflammatory effects. The four formulations had no significant effect on the gastrointestinal function of mice, suggesting that formulations C and E may have a good therapeutic effect on FAPs.

[0097] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.

Claims

1. A traditional Chinese medicine volatile oil composition for treating functional abdominal pain syndrome, characterized in that, The herbal volatile oil composition comprises ginger volatile oil, turmeric volatile oil, and peppermint volatile oil; The volume ratio of ginger volatile oil, turmeric volatile oil, and peppermint volatile oil is 1:1:

1.

2. The use of the traditional Chinese medicine volatile oil composition according to claim 1 in the preparation of a medicament for treating functional abdominal pain syndrome.

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