A pharmaceutical composition for treating asthma and its application

Abstract

The present invention belongs to the field of medical technology, and specifically relates to a pharmaceutical composition for treating asthma, and a pharmaceutical preparation and application thereof, wherein the pharmaceutical composition comprises naringenin and isobergamot lactone, and the weight ratio of the naringenin and isobergamot lactone is 5:0.2-1. Pharmacological experiments show that the pharmaceutical composition of the present invention can significantly reduce the levels of TNF-α, IL-4, IL-17, and IgE in the serum of asthmatic rats, greatly improve the therapeutic effect of asthma, and the effect is significantly better than the same dose of naringenin and isobergamot lactone alone, which shows that the combination of naringenin and isobergamot lactone has a significant synergistic effect. In addition, the pharmaceutical composition of the present invention also has fewer toxic and side effects, is easy to use, improves patient acceptance, has the prospect of being developed into a drug for the treatment of asthma, and has important social and economic benefits.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to a pharmaceutical composition for treating asthma and an application thereof. Background Art

[0002] Bronchial asthma (abbreviated as asthma) is a heterogeneous disease involving multiple inflammatory cells such as eosinophils (Eos), mast cells (MCs), T lymphocytes (Tcells), polymorphonuclear neutrophils (PMN) and airway epithelial cells (ECs). It is characterized by chronic airway inflammation, airway hyperresponsiveness, airway remodeling and increased airway mucus secretion. Clinical manifestations include repeated coughing, wheezing, sputum and shortness of breath. It is currently believed that the pathogenesis of asthma is the result of the combined effects of genetics and the environment, mainly including genetic mechanisms, airway inflammation-immune mechanisms and neural regulation mechanisms. In recent years, its prevalence, especially the prevalence of childhood asthma, has been increasing year by year worldwide, bringing heavy economic and psychological burdens to patients' families.

[0003] The goal of asthma treatment is to achieve long-term good asthma control, minimize symptoms, and reduce the incidence of death, hospitalization, and emergency visits. Among them, anti-inflammatory and bronchodilator administration is the main method of asthma treatment. The more effective drugs for the treatment of asthma in Western medicine are glucocorticoids, β2-receptor agonists, leukotriene modifiers, theophylline, anticholinergic drugs, antihistamines, and some biological targeted drugs. They are characterized by strong anti-inflammatory ability, but long-term use has many side effects and can easily lead to osteoporosis, secondary infection, adrenal cortex suppression, nausea, bitter taste in the mouth, and other adverse reactions. In recent years, traditional Chinese medicine has achieved many research results in the control and treatment of asthma, including research on Chinese medicine compound prescriptions, single Chinese medicine, and Chinese medicine monomers.

[0004] The inventor has long been committed to the research and development of Chinese medicine compound, Chinese medicine monomer and other drugs, and has previously applied for a number of invention patents in the field of related drugs. For example, China's authorized patent CN114209781B discloses a Chinese medicine composition for treating asthma, which is made of the following raw materials in weight ratio: 8g of dried tangerine peel, 8g of dried pinellia tuber, 8g of bamboo shavings, 12g of Poria, 8g of bran-fried immature bitter orange, 8g of ginkgo, 4g of fried scutellaria, 6g of Belamcanda chinensis, 12g of Fritillaria thunbergii, 15g of fried perilla seeds, 12g of honey loquat leaves, 15g of duckweed, and 4g of raw licorice. The Chinese medicine composition is neither cold nor dry, and has the effects of pungent opening and bitter descending, warm and cool, supplementing and purging, dispelling evil and nourishing the body, focusing on coordination, and achieving the functions of regulating qi and resolving phlegm, clearing the gallbladder and harmonizing the stomach, and promoting the function of three burners. It is a prescription for treating both the symptoms and the root causes, and has a significant effect in clinical treatment of childhood asthma. However, due to the complex ingredients of traditional Chinese medicine, the quality is difficult to control, the patient acceptance is limited, and there may be irritation to the gastrointestinal tract, and it is inconvenient to carry, resulting in poor compliance of patients, making it difficult for patients to adhere to long-term use. At the same time, due to the high cost and safety risks of traditional Chinese medicine prescriptions, it is not conducive to effective quality control and large-scale production. In view of this, it is imperative to develop a pharmaceutical composition for the treatment of asthma that is effective, safe and easy to take by conducting in-depth research and screening of natural product active ingredient monomers in classic traditional Chinese medicine prescriptions using modern pharmacological research methods.

[0005] Naringenin is a polyhydroxyflavonoid compound, its chemical name is 4',5,7-trihydroxyflavone, and its molecular formula is C 15 H 12 O5, molecular weight is 272.25. It is mainly distributed in many herbs and fruits, such as grapefruit, bergamot, sour cherry, lime, tomato, etc. Naringenin has antibacterial, anti-inflammatory, antioxidant, free radical scavenging, antitussive and antiasthmatic, lipid-lowering, anticancer and antitumor, and immune system regulation. Studies have found that naringenin can regulate the BK of respiratory smooth muscle. ca The hyperpolarized state mediated by the channel regulates the contraction of the respiratory smooth muscle and produces a diastolic effect, thereby exerting its antitussive and antiasthmatic effects. However, the effect of using naringenin alone to treat asthma is limited. Therefore, how to further improve the effect of naringenin in treating asthma is still a technical problem that needs to be solved urgently by those skilled in the art.

[0006] Isobergamot lactone is a 7,8-furano-coumarin compound extracted from the roots of Angelica sinensis, Angelica sinensis, and Saposhnikovia divaricata of the Umbelliferae family. Its molecular formula is C 12 H8O4, molecular weight is 216.19. Isobergamote lactone mainly has antibacterial and antitumor biological activities. There is no report on the use of isobergamote lactone in the treatment of asthma, and there is no research on the combination of isobergamote lactone and naringenin in the treatment of asthma. Summary of the invention

[0007] The purpose of the present invention is to provide a pharmaceutical composition for treating asthma with a synergistic effect, so as to provide a new idea for treating asthma safely, effectively, conveniently and economically in clinical practice.

[0008] Specifically, the present invention is realized through the following technical solutions.

[0009] In a first aspect, the present invention provides a pharmaceutical composition for treating asthma, the pharmaceutical composition comprising naringenin and isobergamot lactone, the weight ratio of naringenin to isobergamot lactone being 5:0.2-1, wherein the naringenin is a main active ingredient for treating asthma, and the isobergamot lactone is an auxiliary ingredient for enhancing the efficacy of naringenin in treating asthma.

[0010] In a preferred embodiment of the present invention, the weight ratio of naringenin to isobergamot lactone is 5:0.5-1.

[0011] In a preferred embodiment of the present invention, the weight ratio of naringenin to isobergapeptide is 5:0.5-0.8.

[0012] In a preferred embodiment of the present invention, the weight ratio of naringenin to isobergapeptide is 5:0.7.

[0013] In a preferred embodiment of the present invention, the pharmaceutical composition consists of naringenin and isobergamot lactone, and the weight ratio of naringenin to isobergamot lactone is 5:0.2-1.

[0014] In a preferred embodiment of the present invention, the effect of naringenin in treating asthma can be significantly enhanced by using naringenin and isobergapten together.

[0015] In a second aspect, the present invention provides a pharmaceutical preparation, comprising the pharmaceutical composition described in the first aspect, and a pharmaceutically acceptable carrier.

[0016] In a preferred embodiment of the present invention, the dosage form of the pharmaceutical preparation is an oral dosage form or a spray.

[0017] In a preferred embodiment of the present invention, the oral dosage form is capsule, granule, tablet or syrup.

[0018] In addition, those skilled in the art will understand that the naringenin and isobergamotolide in the pharmaceutical composition of the present invention can also be administered sequentially or simultaneously in different pharmaceutical preparations.

[0019] In a third aspect, the present invention provides use of the pharmaceutical composition described in the first aspect or the pharmaceutical preparation described in the second aspect in the preparation of a drug for treating asthma.

[0020] In a preferred embodiment of the present invention, the drug is used to reduce the levels of TNF-α, IL-4, IL-17 and IgE in the serum of asthma patients.

[0021] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] The inventors unexpectedly discovered during the research process that the combination of naringenin and isobergamot lactone in a specific dosage ratio can significantly reduce the content of TNF-α, IL-4, IL-17, and IgE in the serum of asthmatic rats, greatly improve the therapeutic effect of asthma, and the effect is significantly better than the same dose of naringenin and isobergamot lactone used alone. This shows that the combination of naringenin and isobergamot lactone has a significant synergistic effect. The pharmaceutical composition of the present invention also has fewer toxic and side effects, is easy to use, improves patient acceptance, has the prospect of being developed into a drug for treating asthma, and has important social and economic benefits. DETAILED DESCRIPTION

[0024] The inventors conducted in-depth research on Chinese herbal compound and Chinese herbal monomers for the treatment of asthma and unexpectedly found through extensive screening that the combined use of naringenin and isobergamotolide can significantly improve the therapeutic effect of asthma. Based on this, the present invention was completed.

[0025] As used herein, naringenin and isobergamot lactone in the pharmaceutical composition of the present invention can be administered in the same pharmaceutical preparation or in different pharmaceutical preparations. In the case of administration in different pharmaceutical preparations, the dosage forms of naringenin and isobergamot lactone can be the same or different. Furthermore, naringenin and isobergamot lactone can be administered simultaneously or sequentially.

[0026] As used herein, "auxiliary ingredients" generally refer to substances that have no or almost no target pharmacological activity but can enhance the target pharmacological activity of the main active ingredient. The target pharmacological activity of the present invention is mainly the effect of treating asthma.

[0027] As used herein, "pharmaceutically acceptable carrier" refers to any excipient that can be prepared into a pharmaceutical preparation with naringenin and isobergamot lactone and used for clinical treatment, and is selected from one or more of fillers, binders, lubricants, disintegrants, suspending agents, solvents, wetting agents, surfactants, pigments, flavoring agents, etc.

[0028] The filler of the present invention includes but is not limited to corn starch, pregelatinized starch, maltodextrin, microcrystalline cellulose, lactose, etc.; the binder includes but is not limited to hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, syrup, starch slurry, etc.; the lubricant includes but is not limited to talc, stearic acid, sodium lauryl sulfate, sodium oleate, magnesium stearate, poloxamer, etc.; the disintegrant includes but is not limited to starch effervescent mixture, i.e. sodium bicarbonate and citric acid, low-substituted hydroxypropyl cellulose, tartaric acid, etc.; the suspending agent includes but is not limited to polysaccharides such as agar, alginic acid, acacia gum, cellulose ether and carboxymethyl chitosan, etc.

[0029] The pharmaceutical composition can be prepared into an oral dosage form or a spray. The oral dosage form is a capsule, a granule, a tablet or a syrup.

[0030] The above-mentioned various dosage forms can be prepared according to conventional processes in the field of pharmaceutical preparations.

[0031] The naringenin and isobergamot lactone used in the pharmaceutical composition of the present invention can be extracted and separated from plants containing the components by conventional biological purification methods, or can be purchased from commercial products.

[0032] In the medical uses described above, the administration time, number of administrations and frequency of administration of the pharmaceutical composition of the present invention need to be determined according to the specific diagnosis results of the disease, which is within the technical scope mastered by those skilled in the art.

[0033] The treatment plan for rats can be applied to humans, and the effective doses of all drugs for humans can be converted by the effective doses of the drugs for rats, which is also easy to achieve for ordinary technicians in this field.

[0034] The present invention will be further described with reference to specific embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the scope of the present invention.

[0035] If no specific techniques or conditions are specified in the examples, the techniques or conditions described in the literature in the field or the product instructions are used. If no manufacturer is specified for the reagents or instruments used, they are all conventional products that can be purchased through regular channels.

[0036] The experimental methods in the following examples are conventional methods unless otherwise specified. The experimental materials used in the following examples are commercially available products unless otherwise specified.

[0037] Unless otherwise specified, all percentages and parts in the present invention are percentages and parts by weight.

[0038] Example: Pharmacodynamic study of the pharmaceutical composition of the present invention in treating asthma

[0039] 1. Main experimental materials

[0040] 1.1 Experimental animals

[0041] Sixty male healthy clean-grade SD rats, weighing 180-210 g, were provided by the Animal Experiment Center of Harbin Medical University.

[0042] 1.2 Drugs and reagents

[0043] Naringin, isobergamotolide, dexamethasone acetate tablets, rat TNF-α ELISA kit, rat IL-4 ELISA kit, rat IL-17 ELISA kit and rat IgE ELISA kit were purchased from a reagent company.

[0044] 2. Experimental Methods

[0045] 2.1 Establishment of asthma animal model

[0046] After 3 days of adaptive feeding, the rats except the blank group were injected with 10% egg protein + 10% aluminum hydroxide saline solution 1ml on the 1st and 8th days of the experiment, and 0.5ml was injected subcutaneously at each point on both sides of the waist to sensitize the rats. From the 15th day, 5% egg protein saline was used for aerosol inhalation to stimulate asthma in rats, with an aerosol flow rate of 5ml / min, 20rain each time, once every other day, for a total of 4 weeks. The signs of successful stimulation were cyanosis of the lips, abdominal muscle spasms, accelerated breathing, nodding breathing, and unstable standing in rats. At the corresponding time, the blank group was injected with saline instead of egg protein for intraperitoneal injection and aerosol inhalation.

[0047] 2.2 Animal grouping and drug administration

[0048] Sixty rats were randomly divided into 6 groups, 10 rats in each group, namely blank group, model group, dexamethasone group, naringenin group, isobergamote group, and naringenin + isobergamote group. The blank group and model group were gavaged with equal amount of normal saline 0.5h before challenge; the dexamethasone group was given dexamethasone 5mg / kg 0.5h before challenge; the naringenin group was given naringenin 57mg / kg 0.5h before challenge; the isobergamote group was given isobergamote 57mg / kg 0.5h before challenge; the naringenin + isobergamote group was given naringenin 50mg / kg + isobergamote 7mg / kg 0.5h before challenge. Each treatment group was gavaged daily from the first asthma challenge until sacrifice, for 4 consecutive weeks.

[0049] 2.3 Specimen collection

[0050] Blood samples were drawn from the jugular vein 2 hours after the last administration, left to stand for 5 hours, and then centrifuged at 3500 r / min for 8 minutes. The upper layer of serum was collected and kept at low temperature for later use.

[0051] 2.4 Detection of related cytokine expression in serum

[0052] The expressions of related cytokines TNF-α, IL-4, IL-17 and IgE were detected by ELISA.

[0053] 2.5 Statistical methods

[0054] The results were analyzed using SPSS23.0 statistical software, and the data were expressed as mean ± standard deviation (x ± s). One-way analysis of variance was used for comparison among multiple groups, and t-test was used for comparison between two groups. P < 0.05 indicated that the difference was statistically significant, and P < 0.01 indicated that the difference was statistically significant.

[0055] 3. Experimental results

[0056] The expressions of relevant cytokines TNF-α, IL-4, IL-17 and IgE in serum are shown in Table 1.

[0057] As shown in Table 1, compared with the blank group, the levels of TNF-α, IL-4, IL-17, and IgE in the serum of asthmatic rats in the model group were significantly increased (P<0.01); compared with the model group, the levels of TNF-α, IL-4, IL-17, and IgE in the serum of asthmatic rats in the naringenin group (P<0.05), naringenin + isobergamot lactone group (P<0.01), and dexamethasone group (P<0.01) were statistically significantly reduced. From these results, it can be seen that when isobergamot lactone is used alone, it has only a weak improvement effect on the levels of TNF-α, IL-4, IL-17, and IgE in the serum of asthmatic rats. When naringenin and isobergamot lactone are used in combination, the combined group has a significantly better effect on reducing the levels of TNF-α, IL-4, IL-17, and IgE in the serum of asthmatic rats than the naringenin alone group, and the effect of the combined group is similar to that of the positive control drug dexamethasone. This indicates that the combination of naringenin and isobergamot lactone has a significant synergistic effect in reducing the levels of TNF-α, IL-4, IL-17, and IgE in the serum of asthmatic rats.

[0058] Table 1: Comparison of serum TNF-α, IL-4, IL-17, and IgE levels in rats of each group (x±s, n=10)

[0059]

[0060] 4. Experimental conclusion

[0061] Asthma is a heterogeneous disease involving a variety of inflammatory cells such as eosinophils (Eos), mast cells (MCs), T lymphocytes (Tcells), polymorphonuclear neutrophils (PMN) and airway epithelial cells (ECs). Therefore, the detection of inflammatory factors TNF-α, IL-4, IL-17, and IgE levels are directly related to asthma, and reducing the above indicators can reflect the therapeutic effect on asthma. The experimental results showed that when naringenin was combined with isobergamphol, the combined group had a significantly better effect on reducing the levels of TNF-α, IL-4, IL-17, and IgE in the serum of asthmatic rats than the group using naringenin and isobergamphol alone, and the effect of the combined group was similar to that of the positive control drug dexamethasone. This shows that when naringenin and isobergamot lactone are used in combination, the therapeutic effect of the combination group on asthma is significantly better than the same dose of naringenin and isobergamot lactone alone, and the therapeutic effect of the combination group on asthma is similar to that of the positive control drug dexamethasone. This shows that after naringenin and isobergamot lactone are used in combination, the therapeutic effect on asthma has a significant synergistic effect. Therefore, the pharmaceutical composition containing naringenin and isobergamot lactone of the present invention has the prospect of being developed into a drug for treating asthma, and has important social and economic benefits.

[0062] In the above animal experiments, no obvious adverse reactions were observed for the pharmaceutical composition of the present invention, and the experimental animals had good tolerance to it.

[0063] Obviously, the above embodiments are only examples for clearly explaining the present invention, and are not intended to limit the implementation methods of the present invention. Those skilled in the art may make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these modifications and variations.

Claims

1. A pharmaceutical composition for treating asthma, characterized in that: The pharmaceutical composition comprises naringenin and isobergamot lactone, and the weight ratio of naringenin to isobergamot lactone is 5: 0.2-1, wherein the naringenin is the main active ingredient for treating asthma, and the isobergamot lactone is an auxiliary ingredient for enhancing the efficacy of naringenin in treating asthma.

2. The pharmaceutical composition according to claim 1, characterized in that The weight ratio of naringenin to isobergamot lactone is 5:0.5-1.

3. The pharmaceutical composition according to claim 1, characterized in that The weight ratio of naringenin to isobergamot lactone is 5:0.5-0.

8.

4. A pharmaceutical preparation, characterized in that The pharmaceutical preparation comprises the pharmaceutical composition according to any one of claims 1 to 3, and a pharmaceutically acceptable carrier.

5. The pharmaceutical preparation according to claim 4, characterized in that The dosage form of the pharmaceutical preparation is an oral dosage form or a spray.

6. The pharmaceutical preparation according to claim 5, characterized in that The oral dosage form is capsule, granule, tablet or syrup.

7. Use of the pharmaceutical composition according to any one of claims 1 to 3 or the pharmaceutical preparation according to any one of claims 4 to 6 in the preparation of a medicament for treating asthma.

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