阅读说明：本技术 抗hpv型***用温敏凝胶、其制备方法及应用 (anti-HPV type vaginal temperature-sensitive gel, preparation method and application thereof ) 是由 刘志鹏 徐俊 于 2019-12-12 设计创作，主要内容包括：本发明提供了一种抗HPV型阴道用温敏凝胶、其制备方法及应用。该温敏凝胶包括特定配比的泊洛沙姆、壳聚糖、葡萄糖酸氯己定、大鲵低聚糖肽、重组人干扰素、细胞生长因子,在此基础上可进一步添加抗病毒药物、抗细菌药物、抗真菌药物、抗霉菌药物、抗支原体药物等功效成分；该温敏凝胶是一种缓释制剂,其pH值符合阴道环境,低于28℃时呈液体状态,可渗透到子宫、阴道深部褶皱处,杀灭病原体,接触体温3-5分钟后,形成凝胶,覆盖于病患部位,不易溢出,最大限度保证了药物与受药部位的作用时间及作用浓度。而且,本发明的凝胶能够阻逆HPV病毒E6,E7蛋白合成,抑制HPV病毒增殖；同时对革兰氏阳性菌、阴性菌及真菌均有较强的杀菌作用。(The invention provides an anti-HPV type vaginal temperature-sensitive gel, a preparation method and application thereof. The temperature-sensitive gel comprises poloxamer, chitosan, chlorhexidine gluconate, giant salamander oligosaccharide peptide, recombinant human interferon and cell growth factors in a specific ratio, and on the basis, effective components such as antiviral drugs, antibacterial drugs, antifungal drugs, mycoplasma resistant drugs and the like can be further added; the temperature-sensitive gel is a sustained-release preparation, the pH value of the temperature-sensitive gel accords with the vaginal environment, the temperature-sensitive gel is in a liquid state at the temperature of lower than 28 ℃, the temperature-sensitive gel can permeate into deep folds of uterus and vagina to kill pathogens, the gel is formed after contacting with body temperature for 3-5 minutes, the gel is covered on the affected part and is not easy to overflow, and the action time and the action concentration of a medicament and a medicament receiving part are ensured to the maximum extent. Moreover, the gel of the invention can prevent the synthesis of E6 and E7 proteins of the HPV virus and inhibit the proliferation of the HPV virus; meanwhile, the bactericidal composition has strong bactericidal effect on gram-positive bacteria, gram-negative bacteria and fungi.)

1. The vaginal temperature-sensitive gel for resisting HPV type is characterized by comprising the following components in parts by weight: 10-30 parts of poloxamer, 0.05-1 part of chitosan, 0.1-1 part of chlorhexidine gluconate and 1-5 parts of giant salamander oligosaccharide peptide; the temperature-sensitive gel for resisting HPV type vagina contains 100-1000 ten thousand IU recombinant human interferon; the temperature-sensitive gel for resisting HPV type vagina contains 1-100 mug/mL cell growth factors.

2. The vaginal temperature-sensitive gel for anti-HPV types according to claim 1, characterized in that the poloxamer is selected from one or several of the following components: poloxamer 407, poloxamer 108, poloxamer 188, poloxamer 338.

3. The vaginal temperature-sensitive gel for anti-HPV types according to claim 1, characterized in that it further comprises one or several of the following components: antiviral drugs, antibacterial drugs, antifungal drugs, anti mycoplasma drugs.

4. The vaginal temperature-sensitive gel for anti-HPV types according to claim 3, characterised in that the antiviral drug is selected from one or several of the following components: giant salamander oligosaccharide peptide, recombinant human interferon, cell growth factor and gallate.

5. The vaginal temperature-sensitive gel for anti-HPV types according to claim 3, characterized in that the antibacterial drug is selected from one of the following components: compound povidone iodine liniment, compound chlorhexidine gargle, compound neomycin, potassium permanganate, benzoyl peroxide, compound chlorhexidine, erythromycin, metronidazole chlorhexidine, a methyl violet solution, clindamycin metronidazole, lidocaine chlorhexidine, crotamiton, ftibamzone, metronidazole glucose, neomycin fluocinolone acetonide, ciprofloxacin hydrochloride, and lincomycin hydrochloride.

6. The vaginal temperature-sensitive gel for anti-HPV types according to claim 3, characterized in that the antifungal drug is selected from one of the following components: undecylenic acid, acetic acid, salicylic acid, lactic acid, griseofulvin, nystatin, candicidin, econazole, miconazole, bifonazole, clotrimazole, ketoconazole, amphotericin B, flucytosine, mepacrycin, globithromycin, fluconazole, itraconazole.

7. The vaginal temperature-sensitive gel for anti-HPV types according to claim 3, characterized in that the antimycotic drug is selected from one of the following components: nystatin, fluconazole, amphotericin B, miconazole, ketoconazole.

8. The vaginal temperature-sensitive gel for anti-HPV types according to claim 3, characterized in that the anti-mycoplasma drug is selected from one of the following components: tetracycline, doxycycline, azithromycin, methacycline, minocycline, josamycin, zedoary turmeric oil.

9. The method for preparing the anti-HPV type vaginal temperature-sensitive gel according to any one of claims 1-8, characterized by comprising the following steps:

1) adding water into poloxamer and chitosan according to the formula amount, uniformly stirring, standing for swelling, and then adjusting the pH value to 4.0-4.5 to obtain blank gel;

2) mixing the blank gel obtained in the step 1) with other components according to the formula amount, and uniformly stirring to obtain the anti-HPV type vaginal temperature-sensitive gel.

10. The use of the anti-HPV vaginal temperature-sensitive gel according to any one of claims 1-8 for the preparation of a vaginal HPV infection treatment or vaginal repair drug.

Technical Field

The invention relates to the technical field of gynecological external medicines, in particular to an anti-HPV type vaginal temperature-sensitive gel, and a preparation method and application thereof.

Background

The vagina of a woman is naturally warm and wet, has more secretion and is easy to breed microorganisms, so that the nursing of the vagina is an important means for ensuring the health of the woman. Among vaginal care products, lotions, suppositories, traditional gels are the most widely used dosage forms; wherein, the lotion is a liquid preparation, although the lotion can wash vagina, the lotion is easy to overflow out of the body, which causes too short local action time and poor local nursing and sterilizing effects; moreover, the genital tract is cleaned by a large amount of lotion, which can destroy the natural protection mechanism of the vagina and the homeostasis in the vagina, and is easy to generate negative effects. The suppository has good local retention characteristics, but the effective part of local treatment is limited to 2-4cm of the vaginal orifice, and the vagina is 10-12cm long; the suppository cannot cover the whole reproduction, so that the nursing effect is poor, the inflammation is not easy to treat, and the suppository is a source of repeated attacks of the inflammation of a plurality of women.

The gel preparation overcomes the problems to a certain extent, can be delivered to 8cm in the vagina by virtue of an administration device, and has good adhesiveness. However, the drug is not uniformly dispersed in contact with the tissues of a patient when the drug is administered in the form of solid gel, and the current gel has small gel strength, poor biological adhesion and insufficient local action time, so that the curative effect is greatly influenced.

HPV (Human papilloma virus) is currently the only virus worldwide that has been shown to be directly associated with cancer (recurrent infection with HPV can induce the development and progression of cervical cancer in women). According to epidemiological statistics, almost all cervical cancer cases are caused by HPV infection. At present, the HPV infection rate in China is very high, the one-time sexual infection rate of 40-year-old women reaches 91 percent, and the high-risk type infection rate reaches 40 percent. While most HPV infections are cleared by the body's own immune system, in some cases, HPV infection may become persistent. Thus, all women are at risk of conversion of HPV infection to persistent infection, as well as the risk of pre-cancerous lesions developing invasive cervical cancer. Therefore, the prevention and control of HPV virus has important significance on female physiological health; however, in the prior art, prevention and treatment of HPV virus are mainly realized by vaccines or interferon, no external active prevention means exists, and the commonly used vaginal external medicine has no HPV prevention and treatment effect.

Disclosure of Invention

The invention aims to provide an anti-HPV type vaginal temperature-sensitive gel, a preparation method and application thereof aiming at overcoming the technical defects in the prior art, so as to solve the technical problem that the conventional vaginal gel in the prior art does not have an anti-HPV effect.

The invention also aims to solve the technical problem that the treatment effect of the conventional vaginal gel on female vaginitis needs to be improved.

In order to achieve the technical purpose, the invention adopts the following technical scheme:

the vaginal temperature-sensitive gel for resisting HPV comprises the following components in parts by weight: 10-30 parts of poloxamer, 0.05-1 part of chitosan, 0.1-1 part of chlorhexidine gluconate and 1-5 parts of giant salamander oligosaccharide peptide; the temperature-sensitive gel for resisting HPV type vagina contains 100-1000 ten thousand IU recombinant human interferon; the temperature-sensitive gel for resisting HPV type vagina contains 1-100 mug/mL cell growth factors.

Preferably, the anti-HPV type vaginal temperature-sensitive gel comprises the following components in parts by weight: 15-25 parts of poloxamer, 0.5-1 part of chitosan, 0.1-0.5 part of chlorhexidine gluconate and 1.4-4.5 parts of giant salamander oligosaccharide peptide; the temperature-sensitive gel for resisting HPV type vagina contains 100-7000 million IU recombinant human interferon; the temperature-sensitive gel for resisting HPV type vagina contains 1-70 mu g/mL cell growth factors. Thereby obtaining the temperature-sensitive gel with higher adhesiveness.

Preferably, the poloxamer is selected from one or several of the following components: poloxamer 407, poloxamer 108, poloxamer 188, poloxamer 338.

Preferably, the temperature-sensitive gel further comprises one or more of the following components: antiviral drugs, antibacterial drugs, antifungal drugs, anti mycoplasma drugs.

Preferably, the antiviral drug is selected from one or several of the following components: giant salamander oligosaccharide peptide, recombinant human interferon, cell growth factor and gallate.

Preferably, the antibacterial drug is selected from one of the following components: compound povidone iodine liniment, compound chlorhexidine gargle, compound neomycin, potassium permanganate, benzoyl peroxide, compound chlorhexidine, erythromycin, metronidazole chlorhexidine, a methyl violet solution, clindamycin metronidazole, lidocaine chlorhexidine, crotamiton, ftibamzone, metronidazole glucose, neomycin fluocinolone acetonide, ciprofloxacin hydrochloride, and lincomycin hydrochloride.

Preferably, the antifungal drug is selected from one of the following components: undecylenic acid, acetic acid, salicylic acid, lactic acid, griseofulvin, nystatin, candicidin, econazole, miconazole, bifonazole, clotrimazole, ketoconazole, amphotericin B, flucytosine, mepacrycin, globithromycin, fluconazole, itraconazole.

Preferably, the antimycotic drug is selected from one of the following components: nystatin, fluconazole, amphotericin B, miconazole, ketoconazole.

Preferably, the anti-mycoplasma drug is selected from one of the following ingredients: tetracycline, doxycycline, azithromycin, methacycline, minocycline, josamycin, zedoary turmeric oil.

Preferably, the pH value of the temperature-sensitive gel is 4.0-4.5; the temperature of the temperature-sensitive gel is 28 ℃.

On the basis of the technical scheme, the invention further provides a preparation method of the anti-HPV type vaginal thermosensitive gel, which comprises the following steps:

1) adding water into poloxamer and chitosan according to the formula amount, uniformly stirring, standing for swelling, and then adjusting the pH value to 4.0-4.5 to obtain blank gel;

2) mixing the blank gel obtained in the step 1) with other components according to the formula amount, and uniformly stirring to obtain the anti-HPV type vaginal temperature-sensitive gel.

On the basis of the technical scheme, the invention further provides application of the HPV-resistant vaginal temperature-sensitive gel in preparation of vaginal HPV infection treatment medicines or vaginal repair medicines.

In addition, the anti-HPV type vaginal temperature-sensitive gel can also be used for treating vaginal diseases and other vaginal inflammations caused by HPV infection, including mycotic vaginitis, bacterial vaginitis, candidal vaginitis, senile vaginitis, trichomonas vaginitis, mycoplasma vaginitis and juvenile vaginitis.

Preferably, the chitosan is carboxymethyl chitosan.

The invention provides an anti-HPV type vaginal temperature-sensitive gel, a preparation method and application thereof. The technical scheme provides a temperature-sensitive blank gel which can carry out reversible sol-gel conversion along with temperature change as a matrix, and further functional components are added into the matrix. The temperature-sensitive gel comprises poloxamer, chitosan, chlorhexidine gluconate, giant salamander oligosaccharide peptide, recombinant human interferon and cell growth factors in a specific ratio, and on the basis, effective components such as antiviral drugs, antibacterial drugs, antifungal drugs, mycoplasma resistant drugs and the like can be further added; the temperature-sensitive gel is a sustained-release preparation, the pH value of the temperature-sensitive gel accords with the vaginal environment, the temperature-sensitive gel is in a liquid state at the temperature of lower than 28 ℃, the temperature-sensitive gel can permeate into deep folds of uterus and vagina to kill pathogens, the gel is formed after contacting with body temperature for 3-5 minutes, the gel is covered on the affected part and is not easy to overflow, and the action time and the action concentration of a medicament and a medicament receiving part are ensured to the maximum extent. Moreover, the gel of the invention can prevent the synthesis of E6 and E7 proteins of the HPV virus and inhibit the proliferation of the HPV virus; meanwhile, the vaginal suppository has a strong bactericidal effect on gram-positive bacteria, gram-negative bacteria and fungi, and can overcome the defects of short action time, incapability of radical treatment, easiness in relapse and the like of common vaginal medicaments at present.

The invention has stronger killing effect on HPV virus, gram-positive bacteria, gram-negative bacteria and fungi; and the use is convenient, and the effect is good. Meanwhile, the temperature-sensitive gel has good prevention and treatment effects on mycotic vaginitis, bacterial vaginitis, candida vaginitis, senile vaginitis, trichomonas vaginitis, mycoplasma vaginitis and juvenile vaginitis.

The invention can safely and effectively treat vaginal HPV infection and various bacterial vaginal diseases. The temperature-sensitive characteristic of liquid at low temperature and gel at high temperature enables the medicine to be uniformly covered on the surface of the mucosa, and the characteristic successfully solves a plurality of defects of the conventional gel in the prior art. The vaginal HPV infection treatment and vaginal care solution provided by the invention is a highly compliant and effective choice for patients.

Compared with the prior art, the technical effects of the invention are also reflected in the following aspects in a centralized way: when the temperature is lower than a certain gelling temperature, the preparation is in a liquid form, can permeate into any deep folds of the vagina and the uterus, is converted into a solid state after contacting with the body temperature for 3-5 minutes, can form a membrane with certain strength on the surface of a mucosa, greatly enhances the coverage protection and the lubricity of the vagina mucosa, and greatly improves the antibacterial capability. The problem that common gel is not uniformly dispersed at the affected part is successfully solved, the problem that the suppository cannot reach the deep part of the vagina is also avoided, the medicine concentration is maintained within a certain time, and the mucous membrane is mechanically protected. It is convenient and sanitary to use, does not pollute clothes, and has high patient compliance.

Drawings

FIG. 1 is a graph showing the amount of residual gel in the vagina of an experimental animal with time, according to an embodiment of the present invention.

FIG. 2 is a graph showing the result of the relative expression rate of mRNA of HPV in different experimental groups in accordance with the embodiment of the present invention.

Detailed Description

Hereinafter, specific embodiments of the present invention will be described in detail. Well-known structures or functions may not be described in detail in the following embodiments in order to avoid unnecessarily obscuring the details. Approximating language, as used herein in the following examples, may be applied to identify quantitative representations that could permissibly vary in number without resulting in a change in the basic function. Unless defined otherwise, technical and scientific terms used in the following examples have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.