Application of qinlingzi vaginal preparation in preparation of medicine for resisting HPV virus infection

Abstract

The application relates to the technical field of traditional Chinese medicine, in particular to application of a qinlingzi vaginal preparation in preparation of an anti-HPV virus infection medicine, wherein the qinlingzi vaginal preparation is made of raw medicine and auxiliary materials; the raw medicine is in a proportion of 490-510 parts of Huangqin, 240-260 parts of Baijianpi, 130-150 parts of Tufuling, 240-260 parts of Shechuangzi and 50-70 parts of Wuhezi by weight; the application firstly finds the application of the qinlingzi vaginal perfusion liquid in preparation of the anti-HPV virus infection medicine, widens the application range of the qinlingzi vaginal perfusion liquid, improves the clinical application value, meets the clinical demand and fills the clinical blank; the medicine has been on the market for many years, is high in safety and accurate in curative effect.

Description

TECHNICAL FIELD

[0001] The application relates to the technical field of traditional Chinese medicine, in particular to application of a vaginal preparation of Qinziling in preparation of an anti-HPV virus infection drug. BACKGROUND

[0002] Human papilloma virus (HPV) infection is a common female lower genital tract infection and belongs to sexually transmitted infection. HPV infection can cause a series of diseases in human and even induce malignant tumors. HPV infection is mainly transmitted through sexual behavior, and its infection rate mainly depends on the age and sexual behavior habit of the population. The HPV infection rate of the uterine cervix of young and sexually active women is the highest, and the peak age of infection is about 20 years old. There is a second HPV infection peak in Chinese women, which is about 40-45 years old. Persistent infection of high-risk HPV is a necessary factor for high-grade squamous intraepithelial lesions and cancer of the lower genital tract. More than 80% of women have had HPV infection at least once in their lifetime, which has become a serious public health problem threatening women's health.

[0003] High-risk human papilloma virus (HR-HPV) is a major risk factor for the incidence of cervical cancer. Cervical cancer is the fourth most common malignant tumor in women, and its incidence rate ranks second in countries with low human development index, only next to breast cancer, and its mortality rate ranks first. It takes decades from HR-HPV infection to natural progression to cervical cancer. CIN (cervical squamous intraepithelial neoplasia) is found through cervical cancer screening, and treatment is performed on high-grade squamous intraepithelial lesions (HSIL), which can significantly reduce the incidence of cervical cancer.

[0004] At present, the main treatment method for HR-HPV in western medicine is a preventive vaccine, that is, a vaccine is inoculated before HR-HPV virus infection, but it is only for people who have not been infected. For patients who have been infected with HR-HPV, especially HSIL patients, the treatment methods include drug therapy, ablation therapy and surgical treatment.

[0005] Drug therapy currently only has recombinant human interferon alpha 2b, and has the disadvantages of low cure rate and high recurrence rate; ablation therapy must be performed on patients who meet the ablation therapy conditions, and cannot obtain further analysis of living tissues; surgical treatment includes cold knife conization and cervical loop electrosurgical excision procedure. Surgical treatment is not only expensive but also has the disadvantages of postoperative HPV persistent positivity and high recurrence rate, and is accompanied by complications such as bleeding, infection, damage, cervical stenosis adhesion, cervical endometriosis, and impact on pregnancy outcome. In summary, the existing treatment methods in western medicine do not have a special effective solution to resist HR-HPV virus.

[0006] Traditional Chinese medicine is significantly better than the above-mentioned treatment methods in the prevention stage of cervical cancer, that is, clearing HR-HPV infection, reversing or preventing cell malignant transformation, and reducing the risk of cervical cancer from the source. At present, there is no traditional Chinese medicine with definite effect for anti- HR-HPV virus for clinicians to use. According to the TCM syndrome differentiation, the main symptoms of most positive patients are a large amount of leucorrhea, yellow or purulent color, foul odor, pruritus of vulva or burning in the vagina, accompanied by whole body heavy fatigue, chest tightness, poor appetite, small abdominal pain, dry mouth, yellowish urine or sticky and indigestible stool and other symptoms, so it is of great significance to develop a traditional Chinese medicine with definite effect and high safety for anti- HR-HPV virus in order to fully exert the advantages of TCM in the aspect of "preventing disease before it occurs and preventing disease before it occurs". SUMMARY

[0007] The application provides an application of a qinlingzi vaginal preparation in preparation of an anti-HPV virus infection medicine.

[0008] Specifically, the application is implemented by the following technical scheme.

[0009] The application provides an application of a qinlingzi vaginal preparation in preparation of an anti-HPV virus infection medicine.

[0010] The qinlingzi vaginal preparation is prepared from raw medicine and excipients; the raw medicine is composed of Huangqi, Baixianpi, Tufuling, Shechuangzi and WuBeiZi.

[0011] Further, the raw medicine is mixed according to the following ratio by weight: 490-510 parts of Huangqi, 240-260 parts of Baixianpi, 130-150 parts of Tufuling, 240-260 parts of Shechuangzi and 50-70 parts of WuBeiZi.

[0012] The HPV virus infection is HPV16 infection or HPV18 infection.

[0013] The HPV virus infection is cervical HPV virus infection or vaginal HPV virus infection.

[0014] The qinlingzi vaginal preparation is any one of a tablet, a powder, a pill, a granule, an infusion, an injection, and a capsule.

[0015] Further preferably, the qinlingzi vaginal preparation is a qinlingzi vaginal infusion.

[0016] Although traditional Chinese medicine has no corresponding disease name for HPV infection, most HPV infection patients are accompanied by increased leucorrhea, yellow or yellowish green color, thick quality, pruritus of vulva, and occasionally fatigue and weakness, and the tongue and pulse are mostly red tongue, yellow and greasy fur and the like. According to the clinical manifestations, it is summarized as "excessive leucorrhea", "five-color band", "red and white band", "yin itching", "itching", "asthenia" and the like.

[0017] The traditional Chinese medicine believes that the leucorrhoea disease is caused by damp-heat and blood stasis, the Huangqin is used as the monarch in the Qinqingsu vaginal preparation formula, the Huangqin is bitter and cold, the bitterness can dry dampness, the cold can clear heat, enters the lower energizer, is good at clearing the lower energizer damp-heat, purging fire and detoxifying, the damp-heat is removed, and then the blood and qi are balanced, and the five zang organs are self-protected, the Baixianpi and the Shechuangzi are used as ministers, the Baixianpi is used for clearing heat and drying dampness, the Shechuangzi is warm, enters the spleen and kidney channels, is good at warming the kidney and assisting yang, killing insects and stopping itching, the two drugs are combined, the wind is dispelled and the itching is stopped, the yang deficiency of the lower energizer is supplemented, then the kidney yang is steamed and the gasification function is normal, so that the damp evil can be removed, the Tufuling and the Wuweizi are used as assistants, the Tufuling enters the liver and stomach channels, is used for clearing heat and detoxifying, drying dampness and stopping leucorrhoea, the Tufuling can also invigorate the spleen and stomach, then the damp evil is not generated, enters the liver channel and can also soothe the liver, the five zang organs are self-protected, the Wuweizi is sour and astringent, is cold, enters the lung, kidney and large intestine channels, the sourness can converge, the cold can clear heat, is good at astringing essence and stopping leakage, stopping leucorrhoea, and detoxifying and astringing sore. The whole formula is used in combination and is good at clearing and draining damp-heat, drying dampness and detoxifying, killing insects and stopping itching.

[0018] The Qinqingsu vaginal preparation accords with the understanding of treating the HPV infection according to the leucorrhoea disease, in addition, the modern pharmacological research proves that part of the traditional Chinese medicine ingredients in the Qinqingsu vaginal preparation has the effect of killing the HPV virus, can interfere with and block the HPV DNA synthesis, contains a large amount of alcohol, tannin, saponin and other substances with strong antibacterial and antiviral effects, can inhibit the virus replication, improve and stimulate the skin immunity, and clear the HPV infection in the female lower genital tract.

[0019] Beneficial effects:

[0020] 1. The application of the Qinqingsu vaginal preparation in preparing the HPV virus infection resisting medicine is found for the first time, the application range of the Qinqingsu vaginal preparation is widened, the clinical value is improved, and the application effect is remarkable; the marketed medicine is adopted, and the safety of the medicine is ensured.

[0021] 2. The Qinqingsu vaginal preparation is the first Chinese medicine resisting the HPV, and a new idea and a new selection are provided for the HPV treatment.

[0022] 3. The prescription composition of the Qinqingsu vaginal preparation in the application is simple and excellent, the raw medicine market supply is sufficient and the price is low. Specific embodiments

[0023] The specific embodiments of the application are further described in detail below, but the application is not limited to these embodiments, any improvement or replacement in the basic spirit of the embodiments still belongs to the scope of protection required by the claims of the application.

[0024] Example 1

[0025] The application of Qinqi Zi vaginal perfusion liquid in the preparation of an anti-HPV virus infection drug, in the following clinical trial, Qinqi Zi vaginal perfusion liquid uses the product of example 1 in the patent technology with the application number 200810121360.1 and the patent name of a traditional Chinese medicine composition for treating gynecological diseases and its production method.

[0026] Specifically, the clinical trial of Qinqi Zi vaginal perfusion liquid in treating high-risk human papilloma virus 16 / 18 (HR-HPV 16 / 18) infection in the present application

[0027] 1. Case selection

[0028] 1.1 Diagnostic criteria

[0029] 1.1.1 Western medicine diagnosis

[0030] HPV virus genome DNA detection results are HPV16 / 18 positive.

[0031] 1.1.2 TCM syndrome differentiation criteria

[0032] Refer to the 2013 edition of "Design and Practice of Traditional Chinese Medicine Clinical Trials" and the tenth edition of "Gynecology"

[0033] Main symptoms: ① Large amount of leukorrhea, yellow or purulent. ② Odor is foul. ③ Pruritus of the vulva or burning sensation in the vagina.

[0034] Secondary symptoms: ① General malaise and fatigue. ② Chest tightness and poor appetite. ③ Lower abdominal pain. ④ Dry mouth and sticky tongue. ⑤ Yellow and less urine. ⑥ Sticky and difficult to defecate.

[0035] Tongue and pulse: red tongue, yellow and greasy tongue fur, slippery and rapid pulse

[0036] The main symptoms must have at least 2 items, and the secondary symptoms must have at least 3 or more items, combined with tongue and pulse.

[0037] 1.2 Inclusion criteria

[0038] (1) The patient is 18-50 years old, including the boundary value, has a sexual history, and is a postmenopausal woman.

[0039] (2) The HPV detection result is HPV16 or HPV18 infection positive.

[0040] (3) Regular menstruation, 21 days ≤ menstrual cycle ≤ 35 days, 2 days ≤ menstrual period ≤ 8 days.

[0041] (4) No pregnancy plan within 6 months during the trial period (from the start of administration to the end of follow-up), and at the same time, the trial period voluntarily complies with the requirement of complete abstinence and can only use complete abstinence for contraception.

[0042] (5) The patient consents and signs the informed consent form.

[0043] 1.3 Exclusion Criteria

[0044] (1) Abnormal development of the reproductive system (such as imperforate hymen, vaginal atresia, etc.), or those who have received total cervical resection;

[0045] (2) Those who have received HPV vaccination in the past;

[0046] (3) Those with vaginal epithelial intraepithelial neoplasia (VaIN) in the vaginal wall or fornix;

[0047] (4) Those with a history of malignant tumors of the reproductive system (such as cervical cancer or endometrial cancer, vaginal cancer, vulvar cancer, etc.);

[0048] (5) Those with cervical histopathology results of CINIII and above;

[0049] (6) Those with severe upper and lower genital tract infections; or those with gonococcal, mycoplasma, or chlamydia infections in the cervix;

[0050] (7) Those with severe primary diseases of the heart, brain, liver, kidney, hematopoietic system, etc. (such as malignant tumors), or those with known severe immune dysfunction (such as AIDS, systemic lupus erythematosus, etc.), or those with mental illness, or those with liver and kidney function damage (ALT, AST ≥ 1.5 times the upper limit of normal, creatinine exceeding the upper limit of normal);

[0051] (8) Those who have used drugs to treat cervical HR-HPV (including traditional Chinese medicine, chemical drugs, biological products, etc.) or Class II and Class III products within 4 weeks before participating in the trial;

[0052] (9) Those who have used oral contraceptives, or glucocorticoids, or immunosuppressants within the three months before using the trial drug;

[0053] (10) Those who are pregnant or lactating;

[0054] (11) Those who are allergic to the components of Qinziling vaginal infusion or human interferon a2b vaginal effervescent tablets;

[0055] (12) Those with a history of alcohol abuse, long-term smoking, or drug abuse, or those who cannot stop alcohol abuse, smoking, or drug abuse during the trial period;

[0056] (13) Those who have participated in other clinical trials within the past 3 months;

[0057] (14) Those who are not suitable for participating in the trial according to the judgment of the researchers.

[0058] 1.4 Termination Criteria

[0059] (1) Serious safety events occur in the trial, the trial should be terminated in time;

[0060] (2) The clinical trial protocol is found to have major errors in the trial, or the protocol has serious deviations in the implementation, which makes it difficult to evaluate the efficacy of the drug, the trial should be terminated

[0061] (3) The drug treatment is found to be poor in the trial, which does not have clinical value, the trial should be terminated

[0062] (4) The sponsor requires termination of the trial;

[0063] (5) The ethics committee requires suspension or termination of the trial;

[0064] 2. Trial design

[0065] The trial cases are qualified HPV16 / 18 infected patients recruited from the gynecological clinic of Suzhou Hospital of Traditional Chinese Medicine. SAS statistical software is used to simulate the generation of 30 cases of subjects receiving treatment (trial drug and control drug) random arrangement, that is, the treatment allocation corresponding to the serial number 01-30 (i.e. random coding table) is listed. The trial group (Qinlingzi vaginal perfusion) and the control group (human interferon alpha 2b vaginal effervescent tablets) are allocated in a ratio of 2:1, that is, 20 cases in the trial group (Qinlingzi vaginal perfusion) and 10 cases in the control group (human interferon alpha 2b vaginal effervescent tablets), with a total sample size of 30 cases.

[0066] 3. Treatment method

[0067] 3.1 Trial group (Qinlingzi vaginal perfusion): vaginal medication. The medication is started on the 3rd day after menstruation, and the method is to insert the flushing head into the vagina 6-8 cm, squeeze the container with your hand, and send the liquid into the vagina. Morning and evening each once, each 1 branch (4 ml), lie in bed for 5-10 minutes after medication, use for 3 menstrual cycles.

[0068] 3.2 Control group (human interferon alpha 2b vaginal effervescent tablets): start medication on the 3rd day after menstruation, place in the posterior fornix of the vagina, once every other day, each 1 piece (500,000 IU / piece), before sleep, the method is as follows:

[0069] (1) Wash your hands and perineum, take out the drug piece from the packaging box, pull out the pull rod of the drug delivery device, and put half of the vaginal piece into the drug delivery device.

[0070] (2) When administering the drug, it is best to adopt a supine position, lie on your back, bend your knees, so that the drug delivery device can be easily inserted.

[0071] (3) Carefully place the drug delivery device in the posterior fornix of the vagina, press the pull rod, and push the drug piece into the deep part of the vagina. (See instructions for details)

[0072] (4) After use, the applicator is removed and discarded.

[0073] 3 menstrual cycles as a course of treatment.

[0074] 4. Observation items

[0075] (1) The HPV negative conversion rate after 3 menstrual cycles of medication.

[0076] (2) TCM syndrome score / efficacy evaluation, evaluated before treatment and after 3 weeks of medication, see Table 1 for specific scoring criteria.

[0077] Table 1 TCM syndrome score / efficacy evaluation criteria

[0078]

[0079] 5. Efficacy evaluation criteria

[0080] No effect: HPV remains positive; Effective: HPV16 or HPV18 negative; Marked effect: both HPV16 and HPV18 negative.

[0081] Total effective rate = (effective cases + marked effective cases) / total cases x 100%.

[0082] 6. Statistical methods

[0083] For the HPV negative conversion rate after 3 menstrual cycles of medication, the number of cases and percentage of each level of efficacy were calculated, and one-way ordered CMH-χ2 test was used for comparison between groups; the lesion reversal rate was compared between groups, and the chi-square test was used to calculate the 95% confidence interval of the rate difference between the two comparisons, and combined with the main hypothesis test for non-inferiority judgment.

[0084] 7. Test procedure

[0085] The detailed procedure of the entire clinical trial is shown in Table 2.

[0086] Table 2 Clinical trial procedure

[0087]

[0088] Note: ECG examination: the investigator selects whether to perform an ECG examination based on the subject's symptoms and signs.

[0089] 8. Results

[0090] 8.1 HPV negative conversion rate after 3 menstrual cycles of medication:

[0091] 2. Comparison of negative conversion rates between groups: There was a statistically significant difference in the negative conversion rate between the test group (Qinlingzi vaginal infusion) and the control group (human interferon alpha 2b) (P<0.05), as shown in Table 3

[0092] Table 3 Comparison of curative effects of two groups of subjects

[0093]

[0094] Note: compared with the control group, *P<0.05

[0095] 8.2 Comparison of total TCM syndrome scores before and after treatment (X±s)

[0096] The TCM syndrome scores of the two groups of subjects before and after treatment were statistically significant (P<0.01), and the TCM syndrome scores of the test group (Qinlingzi vaginal perfusion liquid) and the control group (human interferon alpha 2b) were statistically significant (P<0.05), as shown in Table 4.

[0097] Table 4 Comparison of TCM syndrome scores of two groups of subjects before and after treatment

[0098]

[0099] Note: compared with the treatment group, *P<0.01; compared with the control group, #P<0.05

[0100] 8.3 Adverse reactions

[0101] The total incidence of adverse reactions of the test group (Qinlingzi vaginal perfusion liquid) and the control group (human interferon alpha 2b) was 5.00% and 20.00%, respectively, and the difference between the groups was not statistically significant (P>0.05), as shown in Table 5.

[0102] Table 5 Comparison of adverse reactions of two groups of subjects

[0103]

[0104] In summary, the components of the present application are reasonable, the compatibility is scientific, the preparation method is simple and easy to operate, the cost is low, the effect is good, and the use is convenient. Compared with the commonly used recombinant human interferon alpha 2b, the advantages mainly lie in the following two aspects:

[0105] 1. Curative effect: Qinlingzi vaginal perfusion liquid has obvious curative effect on high-risk HPV infection, and compared with the commonly used recombinant human interferon alpha 2b, the Qinlingzi vaginal perfusion liquid has higher high-risk HPV negative conversion rate, and in terms of reducing the total TCM syndrome score, the Qinlingzi vaginal perfusion liquid still has obvious advantages compared with the recombinant human interferon alpha 2b,

[0106] 2. Drug safety: recombinant human interferon alpha 2b has adverse reactions of vaginal burning and vaginal itching, and Qinlingzi vaginal perfusion liquid has 1 case of vaginal burning. Compared with recombinant human interferon alpha 2b, the adverse reactions are fewer, and in clinical application, Qinlingzi vaginal perfusion liquid will be safer.

[0107] The components of the present application are compatible, the medicinal materials are genuine, and the raw materials are abundant. Compared with the existing clinical commonly used drugs, the present application has definite curative effect, high safety, and low drug cost, and is convenient for clinical popularization. The traditional Chinese medicine composition or traditional Chinese medicine preparation can provide a new and better choice for HPV infected patients, and has great clinical application value.

Claims

1. A use of a Qingsuling vaginal preparation in the preparation of a medicine for resisting HPV virus infection; the HPV virus infection is HPV16 infection or HPV18 infection; the HPV virus infection is cervical HPV virus infection or vaginal HPV virus infection; the Qingsuling vaginal preparation is made of raw medicine and auxiliary materials; the raw medicine is composed of Huangqi, Baixianpi, Tufuling, Shechuangzi and WuBeiZi; the raw medicine is mixed according to the following ratio by weight: Huangqi 490-510 parts, Baixianpi 240-260 parts, Tufuling 130-150 parts, Shechuangzi 240-260 parts and WuBeiZi 50-70 parts.

2. The use of the vaginal preparation of Qinyinzi according to claim 1 for preparing a medicine for resisting HPV virus infection, characterized in that, the Qingsuling vaginal preparation is any one of tablet, powder, pill, granule, perfusion liquid, injection liquid and capsule.

3. The use of the vaginal preparation of Qinyinzi according to claim 1 or 2 for the preparation of a medicine for resisting HPV virus infection, characterized in that, the Qingsuling vaginal preparation is Qingsuling vaginal perfusion liquid.

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