Application of vitamin B6 in preparation of medicine for treating allergic rhinitis

Abstract

The invention belongs to the technical field of medicines, and particularly relates to application of vitamin B6 in preparation of a medicine for treating allergic rhinitis. Animal model experiments of allergic rhinitis prove that the vitamin B6 can significantly reduce the proportion of eosinophilic granulocytes in alveolar lavage fluid of model mice and effectively reduce typical allergic behaviors. Preliminary clinical research also shows that the medicine can significantly improve rhinitis symptoms and life quality of patients, and proves that the medicine has an exact treatment effect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to the application of vitamin B6 in the preparation of a drug for treating allergic rhinitis. Background Technology

[0002] Allergic rhinitis (AR) is an inflammatory disease of the nasal cavity characterized by Th2-type cellular immunity and eosinophil activation, mediated by immunoglobulin E (IgE) in atopic individuals after exposure to allergens. Its main clinical symptoms are nasal itching, sneezing, and runny nose. The most common allergens for allergic rhinitis are pollen and dust mites. House dust mites and flour mites are the main allergens causing dust mite allergic rhinitis, while tree pollen and weed pollen are the main allergens causing pollen allergic rhinitis, including pollen from cypress, poplar, willow, elm, birch, sycamore, ash, ailanthus, wormwood, hops, lambsquarters, and ragweed. According to the World Allergy Organization (WAO), 10% to 30% of the global population suffers from allergic rhinitis. In my country, there are over 50 million people suffering from allergic rhinitis, with an incidence rate of approximately 20%, reaching as high as 10.8% in children. Allergic rhinitis often severely impacts patients' quality of life, manifesting as reduced learning and work efficiency, and even sleep and psychological disorders. Furthermore, the substantial medical expenses incurred by patients in treating respiratory allergies place a heavy burden on society and their families.

[0003] Treatment for allergic rhinitis often involves oral or topical antihistamines, oral leukotriene receptor antagonists, nasal corticosteroids, and inhaled corticosteroids. However, these medications are expensive, have limited duration of effectiveness, and symptoms often recur after discontinuation. Long-term use also carries significant side effects. Some patients opt for desensitization therapy, which involves inducing immune tolerance through gradually increasing doses of allergen extracts. However, this therapy is often inconvenient, time-consuming, and painful for patients. Furthermore, new allergens may emerge during allergen immunotherapy, posing a potential risk of severe systemic adverse reactions. Therefore, there is an urgent need to develop a new, highly effective, and safe immunotherapy strategy for allergic rhinitis. Summary of the Invention

[0004] The purpose of this invention is to provide the application of vitamin B6 in the preparation of a medicament for treating allergic rhinitis, thereby addressing the problems mentioned in the background section.

[0005] The objective of this invention is achieved through the following technical solution: This invention provides the use of vitamin B6 in the preparation of a medicament for treating allergic rhinitis.

[0006] In a preferred embodiment of the present invention, the allergic rhinitis is caused by pollen or dust mites.

[0007] The present invention also provides a pharmaceutical preparation for treating allergic rhinitis, wherein the vitamin B6 is the sole active ingredient.

[0008] In a preferred embodiment of the present invention, the drug further includes pharmaceutically acceptable excipients or carriers.

[0009] More preferably, the pharmaceutical preparation is a solution, injection, spray, nasal drops, aerosol, powder spray, tablet, capsule, or granule.

[0010] More preferably, the mass concentration of vitamin B6 in the nasal drops is 10-50 mg / ml, based on the content of pyridoxine.

[0011] More preferably, the nasal drops are prepared according to the following steps: The vitamin B6 is dissolved in physiological saline and then the pH is adjusted to 2.5-7 using a buffer solution.

[0012] More preferably, the buffer solution is a phosphate buffer solution with pH=7.4 and a concentration of 0.0001 mol / L to 0.002 mol / L.

[0013] Compared with the prior art, the beneficial effects of the present invention are as follows: (1) This invention is the first to discover and verify that vitamin B6 has a significant therapeutic effect on allergic rhinitis. Through animal model experiments of allergic rhinitis, this invention confirms that vitamin B6 can significantly reduce the proportion of eosinophils in the bronchoalveolar lavage fluid of model mice and effectively reduce typical allergic behaviors. Preliminary clinical studies also show that this drug can significantly improve patients' rhinitis symptoms and quality of life, proving its definite therapeutic effect.

[0014] (2) Vitamin B6 is an essential nutrient for the human body and has good biocompatibility and safety. No adverse reactions were observed in patients during the preliminary clinical studies of this invention. Compared with the potential side effects such as local irritation and dryness from long-term use of nasal spray hormones, or drowsiness caused by oral antihistamines, this invention provides a safer treatment approach, especially suitable for long-term management and preventive treatment.

[0015] (3) As a basic vitamin, vitamin B6 has a wide range of raw material sources and low production costs, which can significantly reduce the economic burden on patients. At the same time, its good safety and convenient administration methods (such as nasal drops and sprays) help improve patients' treatment compliance. Attached Figure Description

[0016] Figure 1 It refers to the change of PN at different buffer concentrations and pH levels; Figure 2 This study involves the detection of serum antibodies in a mouse model of allergic rhinitis treated with VB6; A) total IgE, B) Artemisia pollen-specific IgE. Figure 3 This is a behavioral monitoring study of a mouse model of allergic rhinitis treated with VB6 drug; A. nose scratching behavior, B. sneezing behavior; Figure 4 It is a drug delivery device for clinical trials of VB6 drugs; Figure 5 These are the rhinitis symptom scores before and after VB6 drug treatment in a clinical study of allergic rhinitis patients; A. Total rhinitis symptom score, B. Treatment improvement rate; Figure 6 It is a questionnaire score related to nasal conjunctivitis in patients with allergic rhinitis, used in clinical research. Detailed Implementation

[0017] In the following description, only certain exemplary embodiments are briefly described. As those skilled in the art will recognize, the described embodiments can be modified in various ways without departing from the spirit or scope of the invention. Therefore, the description of embodiments is to be considered exemplary in nature and not restrictive.

[0018] Vitamin B6 (pyridoxine) is a nutrient in the human body that has effective anti-inflammatory and antioxidant properties. It exists primarily in the forms of pyridoxine (PN), pyridoxal (PL), and pyridoxamine (PM), and can be converted into active coenzyme forms in the body. These coenzyme forms are essential for several enzymatic reactions involved in metabolism. Pyridoxal 5'-phosphate plays a crucial role in amino acid metabolism and participates in the synthesis of neurotransmitters (serotonin, dopamine, and γ-aminobutyric acid) and non-protein compounds (sphingolipids and nucleotides) in the brain. Vitamin B6 is also essential for the normal functioning of the immune system, contributing to the production of antibodies and cytokines. Vitamin B6 deficiency can lead to inflammation and inflammatory diseases such as asthma and rheumatoid arthritis. Supplementation with vitamin B6 in deficient states can reverse these effects. It has been reported that vitamin B6 exerts its anti-inflammatory effect by reducing the accumulation of sphingosine-1-phosphate cleavage product-dependent sphingosine-1-phosphate. However, whether vitamin B6 can alleviate nasal inflammatory diseases such as allergic rhinitis has not been reported.

[0019] Based on this, the present invention provides the application of vitamin B6 in the preparation of a drug for treating allergic rhinitis. Animal model experiments of allergic rhinitis have confirmed that vitamin B6 can significantly reduce the proportion of eosinophils in the bronchoalveolar lavage fluid of model mice and effectively reduce typical allergic behaviors. Preliminary clinical studies also show that this drug can significantly improve patients' rhinitis symptoms and quality of life, proving its definite therapeutic effect.

[0020] Example 1 Vitamin B6 pharmaceutical preparations and their preparation methods A method for preparing a vitamin B6 pharmaceutical preparation for treating allergic rhinitis includes the following steps: 1) Prepare raw materials: 0.1g / 2ml*10 vials of Shandong Fangming Pharmaceutical Group Co., Ltd. brand vitamin B6 injection, disodium hydrogen phosphate (Na2HPO4), sodium dihydrogen phosphate (NaH2PO4), sodium chloride (NaCl); 2) Preparation of the buffer stock solution: Weigh 2.28 g of NaH₂PO₄ and use 11.50 g of Na₂HPO₄. If physiological saline (PBS) is required, add 8.5 g of NaCl. Add to approximately 800 mL of distilled water and stir to dissolve. Measure and fine-tune the pH to 7.4 using a pH meter (if necessary, fine-tune with dilute HCl or NaOH solution). Transfer the entire solution to a 1 L volumetric flask and dilute to the mark. Serially dilute the stock solution with pure water to prepare 0.002 mol / L, 0.001 mol / L, 0.0002 mol / L, and 0.0001 mol / L phosphate buffer (PBS) solutions at pH 7.4.

[0021] 3) Take 10 vials of 0.1g / 2ml vitamin B6 injection stock solution produced by Shandong Fangming Pharmaceutical Group Co., Ltd., dilute 2 times and 5 times respectively, and dissolve them in 1mL of 0.002 mol / L, 0.001 mol / L, 0.0002 mol / L, and 0.0001 mol / L phosphate buffer solution at pH 7.4 to prepare drug solutions with concentrations of 50mg / ml, 25mg / ml, and 10mg / ml (calculated as pyridoxine). Measure the pH value to determine the optimal buffer concentration for the vitamin B6 drug preparation mixture.

[0022] The pH values ​​were measured as shown in Table 1 and Figure 1 From Table 1 and Figure 1 It can be seen that when the phosphate concentration is 0.0001 mol / L at pH 7.4, a high concentration of PN can still maintain a neutral pH, thus determining this concentration as the optimal buffer concentration for the vitamin B6 drug preparation mixture.

[0023] Table 1. Preparation of drug solutions of different concentrations and pH values Experimental Example 1 Validation of the efficacy of vitamin B6 in a mouse model of allergic rhinitis This invention also provides efficacy verification of a vitamin B6 drug preparation mixture in treating a mouse model of allergic rhinitis.

[0024] Healthy female C57 mice (purchased from Xi'an Jiaotong University) aged 5-8 weeks were selected and acclimatized for one week. They were divided into a blank control group, a VB6 drug treatment group (0.1g / 2ml*10 vials, produced by Shandong Fangming Pharmaceutical Group Co., Ltd., prepared to a concentration of 10mg / ml using 0.0001 mol / L phosphate buffer at pH 7.4), and a phosphate buffer treatment group. As shown in Table 2, on days 0 and 14, Artemisia annua pollen allergen was mixed with aluminum hydroxide PBS and injected intraperitoneally. From day 18, the drug was administered via nebulization twice daily (morning and evening) for 11 consecutive days. From day 21, the mice underwent nasal instillation for 8 consecutive days at noon to establish a mouse model of allergic rhinitis. One hour after the last nasal instillation, the mice in each group were recorded for 5 minutes of nose scratching and sneezing.

[0025] Table 2 Administration methods for each group Mice were sacrificed on day 29. Peripheral blood was collected and centrifuged at 12,000 rpm to obtain serum. Total IgE and Artemisia pollen-specific IgE were detected by ELISA (antibodies are shown in the table below). The results are as follows: Figure 2 As shown in Figure A.

[0026] The results showed that the total IgE in peripheral blood serum of mice treated with phosphate buffer reached approximately 100 ng / ml, and the OD of Artemisia pollen-specific IgE reached approximately 1 ( Figure 2 In the middle B group, the mice scratched their noses approximately 7 times and sneezed approximately 6 times. Figure 3 The total IgE level in peripheral blood serum was approximately 60 ng / ml after treatment with a vitamin B6 drug mixture. Figure 2 The specific IgEOD of Artemisia pollen (A) reached approximately 0.1 ( Figure 2 In the middle B group, the mice exhibited sneezing behavior after scratching their noses approximately 3 times. Figure 3 It significantly alleviated the symptoms of allergic diseases in mice and had a significant therapeutic effect on the disease.

[0027] Table 3 Total IgE and Artemisia pollen-specific IgE Experiment Example 2 Clinical study on the therapeutic effect of the composition on allergic rhinitis 1. Research Subjects This study screened 13 patients with allergic rhinitis who met the inclusion and exclusion criteria of this project.

[0028] 1.2 Discharge Standards 1.2.1 Inclusion Criteria (1) Patients with allergic rhinitis diagnosed according to the "Guidelines for the Diagnosis and Treatment of Allergic Rhinitis in China (2022, Revised Edition)". The diagnostic criteria are as follows:

[0029] ① Symptoms: Two or more symptoms such as paroxysmal sneezing, clear nasal discharge, nasal itching and nasal congestion occur, and the symptoms last or accumulate for more than 1 hour per day. They may be accompanied by eye symptoms such as tearing, itchy eyes and red eyes. ② Physical signs: Common signs include pale and edematous nasal mucosa and watery nasal discharge; ③ Allergen testing: Positive SPT and / or serum-specific IgE for at least one allergen, or a positive nasal provocation test.

[0030] (2) Age 14-65 years old, gender not limited; (3) No glucocorticoids, antihistamines or other medications that treat allergic rhinitis were used within two weeks of this onset of illness; (4) Voluntarily accept this plan and sign the informed consent form.

[0031] 1.2.2 Exclusion Criteria (1) Patients with concurrent sinusitis or upper respiratory tract infection; (2) Acute exacerbation of bronchial asthma and cardiovascular and cerebrovascular diseases, immunodeficiency diseases, tumors, or post-organ transplantation; (3) Those currently using oral or topical glucocorticoids; (4) Patients with known or suspected allergy to the study drug or those with contraindications to the drug; (5) Individuals who have undergone other clinical trials within the past 30 days; (6) The researcher determines that the subject has any disease or other condition that may jeopardize their safety or affect their adherence to the protocol, or that makes them unsuitable to participate in this study.

[0032] 1.2.3 Exit Criteria (1) The subject withdrew informed consent / voluntarily requested to withdraw; (2) Loss to follow-up is defined as the researcher being unable to contact the subject three times on different dates, with the last contact date being the withdrawal date.

[0033] 1.2.4 Criteria for Termination of Investigational Drug Use by Subjects (1) Those who do not meet the selection criteria / meet the exclusion criteria but are mistakenly included; (2) Subjects who experience severe adverse events that are intolerable and cannot be relieved; (3) The researchers believed that continuing treatment would be detrimental to the subjects; (4) Other circumstances where the investigator determines that it is necessary to terminate the use of the investigational drug; (5) Participate in other clinical trials during the research process.

[0034] 1.2.5 Criteria for Suspension / Termination of Subject Trials (1) The test shall be suspended under any of the following circumstances: 1) The subject is facing or will face a significant risk of physical harm related to the trial that is not reasonably risk-benefiting; 2) The clinical trial protocol, investigator's manual, informed consent form, and other related technical documents have significant flaws that are insufficient to guarantee the safety of the subjects; 3) Insufficient training or experience of relevant personnel in clinical trials leads to significant risks faced by subjects during the trial; 4) Researchers have engaged in misconduct (misconduct) that puts subjects at risk of undue harm.

[0035] (2) The experiment shall be terminated under any of the following circumstances: 1) The subject is at risk or will be at risk of significant physical harm related to the trial that is not reasonably risk-benefit in proportion to the risk; 2) There is sufficient evidence to suggest that the investigational drug is ineffective for the investigated indication; 3) The implemented clinical trial protocol differs fundamentally from the approved protocol; 4) The regulatory agency believes that continuing the clinical trial would pose a significant risk to the health of the participants or be contrary to the public interest; 5) The applicant decides to terminate the application.

[0036] 1.3 Research Content This study planned to include 13 patients with allergic rhinitis, with a 14-day intervention period. Changes in rhinitis symptoms, physical examination findings, and biochemical tests before and after the intervention were recorded and analyzed. Patients were followed up 4 weeks after the intervention ended.

[0037] 1.4 Research Process This trial was divided into two phases: the baseline phase and the treatment phase.

[0038] Baseline period: Authorized investigators will contact participants in advance to conduct outpatient assessments. Participants who meet all inclusion criteria and no exclusion criteria will be included in the baseline period. Participants will be fully informed of the program details, sign informed consent forms, and all necessary tests and data collection will be completed within the specified timeframe. Authorized personnel will then randomly assign participants to groups.

[0039] Treatment period: Once in the treatment period, subjects should take the medication as required and promptly report their experience to the researchers. If a subject experiences a serious adverse reaction or other intolerable event, the trial should be terminated, and the medication regimen should be adjusted for the patient after a comprehensive evaluation.

[0040] 1.4.1 Clinical Research Process (1) Establish a personal file for each patient, register the patient's consultation number, name, gender and other basic personal information, and inquire about the patient's past medical history, family history, medication history and lifestyle. At the initial enrollment (day 1) and the exit visit (day 14), assess the clinical symptoms and signs of the subjects, conduct the corresponding clinical laboratory examinations according to the routine diagnostic procedures, and guide the patients to fill in the questionnaire. Follow up on the patients' condition 4 weeks after the end of treatment.

[0041] (2) Instruct and supervise the patient to take the medication for 14 consecutive days.

[0042] (3) Based on a comprehensive follow-up on the patient's condition and adjustments to the treatment plan, and in accordance with the needs of the research, remind the patient to take medication and complete symptom records daily. At the same time, collect blood samples from the patient at the initial enrollment (day 1) and the exit visit (day 14) for subsequent scientific research.

[0043] The patient biological specimen collection, aliquoting, and preservation protocols are shown in Table 4.

[0044] Table 4. Patient biological specimen collection, aliquoting, and preservation protocol 1.4.2 Follow-up Patients are followed up daily via WeChat or telephone to determine any adverse reactions and patient compliance.

[0045] (1) Study withdrawal visit: For subjects who withdraw their informed consent, the reason for withdrawal should be recorded in detail. Except for subjects who refuse to participate in the study termination visit, the subject should be arranged to withdraw from the visit after the medication is discontinued. The examinations that the subject should complete during the withdrawal visit are the same as those in the last visit in the original protocol.

[0046] (2) All unplanned visits during and after the study must be recorded in the original data. During unplanned visits, the researcher should record vital signs, physical examination, adverse events, concomitant medications and treatments and their changes, as well as other information deemed necessary by the researcher, according to the purpose of the visit. If a subject withdraws from an unplanned visit, the above information should be recorded in the original data.

[0047] 1.4.3 Researcher Compliance Assessment At each follow-up visit, participants should be reminded to adhere to the protocol and medication requirements. At the final follow-up visit, participants must return all used, partially used, and unused investigational medications, including empty packaging materials. The pharmacist will assess and compare the actual number of medications taken by the patient and inquire whether the participant used the investigational medication as prescribed. Medication adherence is calculated using the formula: Adherence (%) = (Actual dosage / Theoretical dosage) × 100%. For participants with poor adherence, researchers should inform them of the importance of taking medication as prescribed. For participants who withdraw early, the withdrawal visit protocol should be followed as closely as possible.

[0048] 2 Evaluation Indicators 2.1 Main Evaluation Indicators Rhinitis symptom scoring: Before and after treatment, patients in each group were scored on their rhinitis symptoms according to the "Chinese Guidelines for the Diagnosis and Treatment of Allergic Rhinitis (2022, Revised Edition)". The main evaluation indicators included four nasal symptoms: sneezing, runny nose, nasal itching, and nasal congestion. Patients self-assessed their symptoms, rating the severity of symptoms on a scale of 0 to 3: 0 for no symptoms, 1 for mild symptoms (mild and tolerable), 2 for moderate symptoms (obvious and bothersome but tolerable), and 3 for severe symptoms (unbearable symptoms that affect daily life and / or sleep).

[0049] 2.2 Secondary evaluation indicators Quality of life assessment: The Chinese version of the Rhinoconjunctivitis Related Quality of Life Questionnaire (RQLQ) was used to assess the quality of life of each group of patients before and after treatment. The assessment items included daily life, sleep, mood, non-nasal or ocular symptoms, nasal symptoms, ocular symptoms, and overall quality of life. The assessment was divided into 7 levels according to the degree of distress, and the evaluators assessed the patients from 0 to 6 based on the severity of the distress.

[0050] Nasal turbinate swelling: 0 points, inferior turbinate not swollen, nasal cavity unobstructed; 1 point, mild swelling of inferior turbinate, middle turbinate still visible; 2 points, inferior turbinate close to nasal septum, but still with gap; 3 points, inferior turbinate close to nasal septum, middle turbinate not visible, or accompanied by polypoid changes or polyp formation of middle turbinate.

[0051] Laboratory test indicators: Fasting venous blood was drawn from each group of patients before and after treatment to measure serum total IgE.

[0052] 2.3 Safety Evaluation Indicators Fasting venous blood was drawn before and after treatment to monitor liver function, kidney function, complete blood count, and urinalysis.

[0053] 2.4 Criteria for Evaluating Therapeutic Effect The efficacy of treatment for rhinitis symptoms was assessed in accordance with the "Principles and Recommendations for the Diagnosis and Treatment of Allergic Rhinitis (2004, Lanzhou)". Assessment method: Symptom improvement rate = (Total rhinitis symptom score before treatment ~ Total rhinitis symptom score after treatment) / Total rhinitis symptom score before treatment * 100%.

[0054] Efficacy evaluation criteria: Clinical control, with an improvement rate of ≥80% in rhinitis symptoms; Significant improvement, with a 66%–79% improvement rate in rhinitis symptoms; Improvement was observed, with a symptom improvement rate of 26% to 65%. Ineffective; improvement rate of rhinitis symptoms ≤25%.

[0055] Overall effective rate = clinical control rate + significant improvement rate + improvement rate; Overall significant improvement rate = clinical control rate + significant improvement rate.

[0056] 3. Investigational Drug 3.1 Drugs in the experimental group A mixture of vitamin B6 drug compositions.

[0057] (1) Source of the drug: 0.1g / 2ml*10 vials, Shandong Fangming Pharmaceutical Group Co., Ltd. (2) Nasal spray device: like Figure 4 .

[0058] (3) Administration method: Using a nasal spray device, the patient should spray once in the morning, once in the afternoon, and once in the evening, spraying into each nostril once. The daily nasal spray dosage is approximately 24 mg, and the treatment should continue for 14 days.

[0059] During medication, avoid spicy, fishy, ​​and raw or cold foods; avoid taking other medications or treatments related to this disease.

[0060] The results are shown in Table 5 and Figure 5 As shown, after treatment with vitamin B6, the patients' sneezing symptoms tended to decrease (P=0.068), and nasal congestion symptoms and total score significantly decreased (P<0.01). Figure 5 (In the middle A group), the average symptom improvement rate per person exceeded 40%.

[0061] Table 5. Improvement of patients' sneezing, nasal congestion, and rhinitis symptoms. As shown in Table 6 and Figure 6As shown, after treatment with vitamin B6, patients experienced significant reductions in activity difficulties, sleep difficulties, ocular symptoms, non-ocular symptoms, social impairment, nasal symptoms, mood disorders, and total scores, resulting in a significant improvement in quality of life. Furthermore, no adverse reactions were observed during the trial, indicating good drug safety.

[0062] Table 6. Improvement in patients' quality of life before and after treatment The preferred embodiments of the present invention have been described in detail above; however, the present invention is not limited thereto. Within the scope of the inventive concept, various simple modifications can be made to the technical solutions of the present invention, including combinations of various technical features in any other suitable manner. These simple modifications and combinations should also be considered as the content disclosed in the present invention and are all within the protection scope of the present invention.

Claims

1. Use of vitamin B6 in the preparation of a medicament for treating allergic rhinitis.

2. Use according to claim 1, characterized in that, The allergic rhinitis is caused by pollen or dust mites.

3. A medicament for treating allergic rhinitis, characterized by comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof. It is vitamin B6 as claimed in claim 1 as the only active ingredient.

4. The medicament according to claim 3, characterized in that, The medicament further comprises a pharmaceutically acceptable adjuvant or carrier.

5. The medicament according to claim 4, characterized in that, The medicament is a solution, injection, spray, nose drop, aerosol, powder spray, tablet, capsule or granule.

6. The medicament according to claim 5, characterized in that, The mass concentration of vitamin B6 in the nose drop is 10-50 mg / ml in terms of the content of pyridoxine.

7. The medicament according to claim 6, characterized in that, The nose drop is prepared by the following steps: After the vitamin B6 is dissolved in normal saline, a buffer is used to adjust the pH to 2.5-7, and the nose drop is obtained.

8. The medicament according to claim 7, characterized in that, The buffer is a phosphate buffer with pH=7.4 and concentration of 0.0001 mol / L-0.002 mol / L.

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