CN111658763B

CN111658763B - Gynecological antibacterial gel and preparation method thereof

Info

Publication number: CN111658763B
Application number: CN202010602227.9A
Authority: CN
Inventors: 艾恒玲; 苗春兴; 武晓萌; 董丽; 朱旭瑶; 苗慧
Original assignee: Mudanjiang Medical University
Current assignee: Mudanjiang Medical University
Priority date: 2020-06-29
Filing date: 2020-06-29
Publication date: 2022-07-01
Anticipated expiration: 2040-06-29
Also published as: CN111658763A

Abstract

The invention discloses a gynecological antibacterial gel and a preparation method thereof, wherein the gynecological antibacterial gel is prepared from the following components in percentage by weight: 2-6% of ciclopirox olamine, 2-6% of alkannin compounds, 1-3% of oat alkaloids, 1-3% of collagen, 5-10% of sodium carboxymethylcellulose, 2-8% of sodium alginate, 2-6% of tween-803, 2-8% of propylene glycol, 1-3% of cooling agent, a proper amount of pH regulator and the balance of purified water. The gynecological bacteriostatic gel disclosed by the invention is used by matching the antibiotic ciclopirox olamine with the natural active product alkannin compound, so that a synergistic effect can be generated in the aspect of inhibiting the growth of harmful bacteria in the gynecological vagina, and the bacteriostatic efficiency and the treatment effect are improved; drug resistance easily caused by using a single antibiotic is avoided, and the dosage of the drug can be reduced; by adding oat alkaloid and collagen in a matching way, the anti-inflammation and itching-relieving effects can be further improved, and the damaged mucous membrane of the vagina can be effectively repaired.

Description

Gynecological antibacterial gel and preparation method thereof

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a gynecological antibacterial gel and a preparation method thereof.

Background

Vaginitis is a common disease of obstetrics and gynecology, married women suffer from vaginitis for at least 1-2 times in the life, and pregnant and lying-in women suffer from vaginitis which affects the pregnancy result and the postpartum course. Generally, the vagina has some resident flora such as B-type hemolytic streptococcus, candida albicans and the like, and when the body resistance is low, the vaginal mucosa is injured or the acidity in the vagina is changed, the virulence of the bacteria is increased, and the bacteria become pathogenic bacteria to cause vaginitis to happen. For example, the glycogen content of vaginal epithelial cells of a pregnant woman is increased, the acidity of the vagina is enhanced, the renal threshold is reduced, the sugar content in urine is increased, and the growth and the reproduction of candida albicans are promoted. Clinically, vaginitis is classified into nonspecific, fungal, bacterial, viral and protozoal vaginitis according to the etiology of the vaginal inflammatory disease.

The physiological characteristics and anatomical structure of the female vagina are special. In recent years, resistance to antibiotics has exhibited explosive states in different microbial flora, largely due to the unlimited use of antibiotics. The application of antibiotics in large quantities destroys the normal bacterial colony environment of the vagina, resulting in the inhibition of normal parasitic bacteria playing a defense function or the conversion into opportunistic pathogenic bacteria. Genital tract infection presents a complex situation that various pathogenic bacteria act simultaneously, so that vaginitis is easy to relapse. Vaginitis is often accompanied by cervicitis and cervical erosion, is a common and frequently encountered gynecological disease, and causes great pain to patients due to the fact that leukorrhagia is obviously increased, or abnormal color, quality and smell are often accompanied by symptoms such as pudendum itching, lower abdomen pain, lumbago, frequent micturition, urgent micturition and the like. According to the incomplete statistics of the world health organization, the incidence rate of various gynecological diseases in women is more than 65%. The incidence rate of gynecological diseases of women of childbearing age is more than 70%, wherein, a small part of people seriously influence normal work and life due to the disease conditions, and meanwhile, the gynecological inflammation also has the characteristic of repeated attack. The method for treating the disease comprises physical therapy and drug therapy. Physical therapy is sometimes susceptible to epithelial cell destruction; the drug therapy is mainly local therapy, and because the vagina has abundant capillary vessels and lymphatic vessels, and the vagina does not have clear nerve endings, the pain stimulation of a patient is small when the drug is administered, and the drug is an effective drug release part for specific diseases and drugs, the drug can be placed in the vagina and absorbed into local or systemic blood circulation through vaginal mucosa to achieve the aim of local or systemic therapy. In recent years, the application research of the gel agent draws attention of scholars at home and abroad, because the gel material has biological adhesion and good biocompatibility, the medicine can adhere to the vaginal mucosa and slowly diffuse from the gel to the mucosa, the retention time is longer, the gel agent is favorable for thoroughly killing pathogens, and the gel agent is favored by patients due to the advantages of unique lubricity, cool feeling, convenient use and the like. Therefore, the research on the gynecological external antibacterial gel with good curative effect and small side effect has very important practical significance.

Disclosure of Invention

Aiming at the defects of the prior art, the invention provides the gynecological antibacterial gel which directly acts on an affected part, has an excellent antibacterial effect and can effectively repair the damaged mucosa of the vagina and the preparation method thereof, and has the characteristics of quick sterilization, itching relieving, inflammation diminishing, pain relieving, difficult repetition, safe use and the like.

In order to achieve the purpose of the invention, the technical scheme adopted by the invention is as follows:

the bacteriostatic gel for gynecology is prepared from the following components in percentage by weight: 2-6% of ciclopirox olamine, 2-6% of alkannin compounds, 1-3% of oat alkaloids, 1-3% of collagen, 5-10% of sodium carboxymethylcellulose, 2-8% of sodium alginate, 2-6% of tween-803, 2-8% of propylene glycol, 1-3% of cooling agent, a proper amount of pH regulator and the balance of purified water.

Preferably, the bacteriostatic gel is prepared from the following components in percentage by weight: 3-5% of ciclopirox olamine, 3-5% of alkannin compounds, 1-2% of oat alkaloids, 1-2% of collagen, 6-8% of sodium carboxymethylcellulose, 4-6% of sodium alginate, 3-5% of tween-803, 3-6% of propylene glycol, 1-2% of a cooling agent, a proper amount of a pH regulator and the balance of purified water.

Preferably, the bacteriostatic gel is prepared from the following components in percentage by weight: 4% of ciclopirox olamine, 4% of alkannin compounds, 2% of oat alkaloids, 1% of collagen, 7% of sodium carboxymethylcellulose, 5% of sodium alginate, tween-804, 5% of propylene glycol, 1% of a cooling agent, a proper amount of a pH regulator and the balance of purified water.

Preferably, the shikonins are selected from shikonin, methyl shikonin, deoxyshikonin or acetylshikonin.

Preferably, the cooling agent is selected from one or more of borneol, menthol or L-menthyl lactate.

Preferably, the pH adjusting agent is selected from acetic acid, citric acid, lactic acid, tartaric acid, disodium hydrogen phosphate or dipotassium hydrogen phosphate.

Preferably, the pH value of the bacteriostatic gel is 4-6.

Further, the invention also provides a preparation method of the gynecological antibacterial gel, which comprises the following steps:

(1) weighing Tween-80 and propylene glycol according to a weight ratio, adding a proper amount of purified water, and uniformly stirring to completely dissolve to prepare an aqueous solution;

(2) weighing sodium carboxymethylcellulose and sodium alginate according to the weight ratio, dissolving in the aqueous solution, fully swelling, and preparing into a matrix solution;

(3) weighing ciclopirox olamine and alkannin compounds according to the weight ratio, adding the rest purified water to completely dissolve, and slowly adding the mixture into the matrix solution under continuous stirring to prepare an active solution;

(4) weighing the avenanthramide, the collagen and the cool feeling agent according to the weight proportion, sequentially adding the avenanthramide, the collagen and the cool feeling agent into the active solution, uniformly stirring, then adding a proper amount of pH regulator, and regulating the pH value to 4-6 to obtain the gynecological antibacterial gel.

Further, the invention also provides application of the antibacterial gel in preparation of a medicament for treating gynecological inflammation.

Preferably, the gynecological inflammation comprises vaginitis, vulvitis, cervicitis and pelvic inflammation.

Ciclopirox olamine is a broad-spectrum antifungal pyridone, is produced by Federal Germany pharmaceutical factories firstly, and has an inhibiting effect on various dermatophytes. Substances such as amino acids, potassium ions, phosphates and the like which are necessary for preventing the survival of Candida albicans cells inhibit or kill fungal cells by causing the exhaustion of certain important substrates or ions in the cells through cell membranes. The product can inhibit various dermatophytes and yeasts at lower concentration, and also has inhibitory effect on Escherichia coli, Bacillus proteus, Pseudomonas aeruginosa, Staphylococcus aureus and hemolytic streptococcus at higher concentration. Is mainly used for superficial fungus and candida albicans infection of epidermis and mucous membrane, and has obvious curative effect and low toxic and side effect. The action mechanism of the medicine is mainly that the integrity of fungal cell membranes is changed, so that nutrients in cells are outflowed, and the uptake of protein precursor substances is blocked, so that fungal cells are killed. Has strong bacteriostatic and bactericidal effects on dermatophytes, saccharomycetes, mycete and the like, and has strong permeability. Has good inhibition effect on various actinomycetes, gram-positive bacteria, gram-negative bacteria, various mycoplasma, chlamydia, trichomonas and the like. After the vaginal cream, gel or suppository is prepared into vaginal cream, gel or suppository and administered through vagina and rectum, the curative effect can be generated locally, the local concentration of the medicine is increased, the first pass effect of the medicine in liver and gastrointestinal tract is avoided, the toxic and side effect of the medicine caused by systemic administration can be reduced, the curative effect of the medicine is better exerted, and the compliance of patients is improved. Is mainly used for treating mycotic vaginitis caused by candida albicans and is the best choice for local application.

Radix Arnebiae is dry root of arnebia euchroma (Royle) Johnst or arnebia euchroma (Royle) Johnst of Boraginaceae, and contains naphthoquinone pigment and polysaccharide compound as main ingredients. Modern pharmacological research shows that the lithospermum has better effects of resisting bacteria, tumors, viruses, inflammation, allergy, liver protection, enzyme reduction and the like, and is a plant with high medicinal value. Researches show that the lithospermum extract has obvious bacteriostatic action on staphylococcus aureus, staphylococcus albus, pseudomonas aeruginosa, escherichia coli, typhoid bacillus, streptococcus A and streptococcus B. The naphthoquinone in the lithospermum has strong antifungal effect and has obvious therapeutic effect on candidiasis. In-vitro antifungal effect research is carried out on the lithospermum naphthoquinone derivative, the lithospermum naphthoquinone derivative is found to have broad-spectrum antifungal activity, wherein the activity of shikonin for resisting saccharomycetes is stronger than that of fluconazole, the MIC for resisting Candida krusei and saccharomyces cerevisiae is 4 microgrammes/ml which are respectively 4 times and 2 times of that of the fluconazole, and the effect of resisting Candida glabrata is equivalent to that of the fluconazole; MICs of deoxyshikonin for resisting candida krusei and saccharomyces cerevisiae are respectively 4 mug/ml and 2 mug/ml which are respectively 4 times and 3 times of fluconazole; the antifungal activity of acetylshikonin and hydroxyisovalerylshikonin is lower than that of fluconazole, and the activity of candida krusei is higher than that of fluconazole.

Oats are rich in various functional components such as protein, fat, saponin alkaloid and the like, and the oats are called as 'complete nutritional food' by nutritionists. Modern pharmacological research shows that the avenanthramides have the important effects of strong oxidation resistance, lipid reduction, anti-proliferation, itching relieving, inflammation diminishing and the like, and are the raw material source of important health care products and the effective components of novel skin care medicines required by modern healthy life. The avenanthramides are alkaline organic compounds with cyclic structures, are unique nitrogen-containing phenolic acid derivatives, are also the only nitrogen-containing organic compounds found in the oats, and have remarkable biological activity and optical activity. The avenanthramides have anti-inflammatory and antipruritic effects by inhibiting histamine signal transduction.

Compared with the prior art, the invention has the beneficial effects that: the gynecological bacteriostatic gel disclosed by the invention is used by matching the antibiotic ciclopirox olamine with the natural active product alkannin compound, so that a synergistic effect can be generated in the aspect of inhibiting the growth of harmful bacteria in the gynecological vagina, and the bacteriostatic efficiency and the treatment effect are improved; drug resistance easily caused by using a single antibiotic is avoided, and the dosage of the drug can be reduced; by adding oat alkaloid and collagen in a matching way, the anti-inflammation and itching-relieving effects can be further improved, and the damaged mucous membrane of the vagina can be effectively repaired. The gynecological antibacterial gel is safe, free of stimulation and high in stability, is beneficial to quick recovery of patients with gynecological inflammation, and has good treatment effects on diseases such as vaginitis, vulvitis, cervicitis and pelvic inflammation.

Detailed Description

The terms used in the present invention have generally the meanings that are commonly understood by those of ordinary skill in the art, unless otherwise specified. The present invention will be described in further detail with reference to the following data in conjunction with specific examples. The following examples are intended to illustrate the invention and are not intended to limit the scope of the invention in any way.

Example 1

The bacteriostatic gel for gynecology is prepared from the following components in percentage by weight: 4% of ciclopirox olamine, 4% of alkannin, 2% of oat alkaloid, 1% of collagen, 7% of sodium carboxymethylcellulose, 5% of sodium alginate, tween-804, 5% of propylene glycol, 1% of borneol, a proper amount of pH regulator and the balance of purified water.

The preparation method of the antibacterial gel comprises the following steps:

(3) weighing ciclopirox olamine and shikonin according to the weight ratio, adding the rest purified water to completely dissolve, and slowly adding the mixture into the matrix solution under continuous stirring to prepare an active solution;

(4) weighing the avenanthramide, the collagen and the borneol according to the weight proportion, sequentially adding the avenanthramide, the collagen and the borneol into the active solution, uniformly stirring, then adding a proper amount of pH regulator, and regulating the pH value to be 5 to obtain the gynecological antibacterial gel.

Example 2

The bacteriostatic gel for gynecology is prepared from the following components in percentage by weight: 5% of ciclopirox olamine, 3% of methyl alkannin, 2% of oat alkaloid, 1% of collagen, 6% of sodium carboxymethylcellulose, 4% of sodium alginate, tween-805%, 3% of propylene glycol, 1% of menthol, a proper amount of pH regulator and the balance of purified water.

The preparation method of the antibacterial gel comprises the following steps:

(3) weighing ciclopirox olamine and the methyl alkannin according to the weight ratio, adding the rest purified water to completely dissolve, and slowly adding the mixture into the matrix solution under continuous stirring to prepare an active solution;

(4) weighing the avenanthramide, the collagen and the menthol according to the weight ratio, sequentially adding the avenanthramide, the collagen and the menthol into the active solution, uniformly stirring, then adding a proper amount of pH regulator, and regulating the pH value to 4.5 to obtain the gynecological antibacterial gel.

Example 3

The bacteriostatic gel for gynecology is prepared from the following components in percentage by weight: 3% of ciclopirox olamine, 5% of deoxyshikonin, 1% of oat alkaloid, 2% of collagen, 8% of sodium carboxymethylcellulose, 6% of sodium alginate, tween-803, 6% of propylene glycol, 2% of L-menthyl lactate, a proper amount of pH regulator and the balance of purified water.

The preparation method of the antibacterial gel comprises the following steps:

(1) weighing Tween-80 and propylene glycol according to weight proportion, adding appropriate amount of purified water, stirring to dissolve completely, and preparing into aqueous solution;

(3) weighing ciclopirox olamine and deoxyshikonin according to the weight ratio, adding the rest purified water to completely dissolve, and slowly adding the rest purified water into the matrix solution under continuous stirring to prepare an active solution;

(4) weighing the avenanthramide, the collagen and the L-menthyl lactate according to the weight proportion, sequentially adding the avenanthramide, the collagen and the L-menthyl lactate into the active solution, uniformly stirring, then adding a proper amount of pH regulator, and regulating the pH value to 5.5 to obtain the gynecological antibacterial gel.

Comparative example 1

The bacteriostatic gel for gynecology is prepared from the following components in percentage by weight: 8% of ciclopirox olamine, 2% of oat alkaloid, 1% of collagen, 7% of sodium carboxymethylcellulose, 5% of sodium alginate, tween-804, 5% of propylene glycol, 1% of borneol, a proper amount of pH regulator and the balance of purified water. The preparation method is the same as example 1.

Comparative example 2

The bacteriostatic gel for gynecology is prepared from the following components in percentage by weight: 8% of alkannin, 2% of oat alkaloid, 1% of collagen, 7% of sodium carboxymethylcellulose, 5% of sodium alginate, tween-804, 5% of propylene glycol, 1% of borneol, a proper amount of pH regulator and the balance of purified water. The preparation method is the same as example 1.

Experiment of bacteriostatic effect

Experimental strains:

candida albicans (ATCC10231), Escherichia coli (ATCC25922), Staphylococcus aureus (ATCC6538), Gardnerella vaginalis (Gardnerella vagiana) (ATCC14018), and 4 standard strains.

The experimental method comprises the following steps:

one loop of logarithmic phase strain was evenly spread on nutrient agar medium, 3 round holes were punched in each plate, and 30. mu.l of bacteriostatic gel was added to each round hole (examples 1-3 and comparative examples 1-2). Aerobic bacteria are placed in an electric heating constant temperature incubator and cultured for 24 hours at 37 ℃, anaerobic bacteria are placed in an anaerobic tank firstly and then placed in the same incubator and cultured for 48 hours at 37 ℃. After the culture was completed, the diameter (mm) of the zone of inhibition on the plate was measured. The experiment was repeated 5 times and the results averaged. The results of the experiment are shown in table 1.

TABLE 1 in vitro inhibitory action of the bacteriostatic gels (n ═ 5, mm)

As can be seen from the results of the bacteriostatic ring experiment in Table 1, the bacteriostatic gels of examples 1-3 have the largest average value (exceeding 20mm) of the diameters of the bacteriostatic rings of Candida albicans, and are obviously superior to the diameters of the bacteriostatic rings of comparative examples 1-2; has obvious inhibiting effect on colibacillus, staphylococcus aureus and gardnerella vaginalis. Comparing examples 1-3 with comparative examples 1-2, it can be found that when ciclopirox olamine and alkannin compounds are used together in a certain proportion range, a synergistic effect can be generated in the aspect of inhibiting the growth of harmful bacteria in the vagina of gynecology, the synergistic effect can obviously improve the bacteriostatic efficiency by using the ciclopirox olamine and the alkannin compounds in a compatible way, the treatment effect is improved, the dosage of antibiotics is reduced, and the drug resistance phenomenon is avoided.

Action of bacteriostatic gel on mycotic vaginitis of rats

After the rat is fixed, the forceps are lifted from the vaginal opening, the mixed solution of gentamicin and penicillin is injected by using an intragastric syringe needle, after 5 days of continuous decontamination, the vaginal secretion is taken to culture pathogen, and the test is negative. The false estrus was established by subcutaneous injection of estradiol and immunosuppression was induced by subcutaneous injection of hydrocortisone. In sham rats, mucosa was traumatized with a needle at 1cm from vaginal opening, and Candida albicans (3 × 10) was injected⁸CFU/ml), the injection dose was 0.6ml/kg, and the vaginal external orifice was blocked with a gel sponge. The injection was given another 1 additional time every other day. And on the 7 th day of infection, taking vaginal secretion for microscopic examination and fungus culture, and determining that the vaginal secretion is positive in microscopic examination and strain identification, namely that the vaginal secretion is successfully infected. The rats successfully infected were randomly divided into 5 groups of 10 animals per group, the bacteriostatic gels of examples 1-3 and comparative examples 1-2. Another 10 infected rats were left untreated and were set as a model group. After day 5 of inoculation, the administration was continued for 7 days. After stopping taking the drug, the vaginal secretion of the rat is taken for examination on the 1 st and 3 rd days, and the negative pathogen is determined to be negative in both examinations. The results are shown in Table 2.

TABLE 2 Effect of the bacteriostatic gel on mycotic vaginitis of rats

As is clear from the experimental results shown in Table 2, the bacteriostatic gels of examples 1-3 had excellent therapeutic effects on fungal vaginitis infected with Candida albicans, and 10 infected rats turned negative all after the treatment. In contrast, the bacteriostatic gel of comparative examples 1-2, which only contains a single bacteriostatic active ingredient, has a general therapeutic effect on fungal vaginitis in rats, and only 40-50% of infected rats can be cured after treatment. The combination of ciclopirox olamine and alkannin compounds is proved to be capable of effectively treating the mycotic vaginitis of rats, and the synergistic interaction between the ciclopirox olamine and the alkannin compounds provides a new direction and basis for clinical application and treatment of gynecological inflammation.

As will be realized, the invention is capable of other and different embodiments and its several details are capable of modifications in various obvious respects, all without departing from the spirit and scope of the present invention, and all changes that come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

Claims

1. The bacteriostatic gel for gynecology is characterized by being prepared from the following components in percentage by weight: 2-6% of ciclopirox olamine, 2-6% of alkannin compounds, 1-3% of oat alkaloids, 1-3% of collagen, 5-10% of sodium carboxymethylcellulose, 2-8% of sodium alginate, 2-6% of tween-803, 2-8% of propylene glycol, 1-3% of cooling agent, a proper amount of pH regulator and the balance of purified water.

2. Bacteriostatic gel for gynaecology according to claim 1, characterized in that it is made of the following components in percentage by weight: 3-5% of ciclopirox olamine, 3-5% of alkannin compounds, 1-2% of oat alkaloids, 1-2% of collagen, 6-8% of sodium carboxymethylcellulose, 4-6% of sodium alginate, 3-5% of tween-803, 3-6% of propylene glycol, 1-2% of a cooling agent, a proper amount of a pH regulator and the balance of purified water.

3. Bacteriostatic gel for gynaecology according to claim 2, characterized in that it is made of the following components in percentage by weight: 4% of ciclopirox olamine, 4% of alkannin compounds, 2% of oat alkaloids, 1% of collagen, 7% of sodium carboxymethylcellulose, 5% of sodium alginate, tween-804, 5% of propylene glycol, 1% of a cooling agent, a proper amount of a pH regulator and the balance of purified water.

4. Bacteriostatic gel for gynaecology according to any of claims 1-3, characterized in that the shikonin compound is selected from shikonin, methyl shikonin, deoxyshikonin or acetylshikonin.

5. A bacteriostatic gel for the gynaecology according to any one of claims 1 to 3, wherein the cooling agent is selected from one or more of borneol, menthol or L-menthyl lactate.

6. A bacteriostatic gel for use according to any one of claims 1 to 3, wherein the pH adjusting agent is selected from acetic acid, citric acid, lactic acid, tartaric acid, disodium hydrogen phosphate or dipotassium hydrogen phosphate.

7. Bacteriostatic gel for gynaecology according to any of claims 1-3, wherein the pH of the bacteriostatic gel is 4-6.

8. A preparation method of bacteriostatic gel for gynecology according to any one of claims 1 to 7, characterized by comprising the following steps:

(4) weighing the oat alkaloid, the collagen and the cool feeling agent according to the weight proportion, sequentially adding the oat alkaloid, the collagen and the cool feeling agent into the active solution, uniformly stirring, then adding a proper amount of pH regulator, and regulating the pH value to 4-6 to obtain the gynecological antibacterial gel.

9. Use of a bacteriostatic gel according to any one of claims 1 to 7 in the preparation of a medicament for the treatment of gynecological inflammation.

10. Use according to claim 9, wherein the gynaecological inflammation comprises vaginitis, vulvitis, cervicitis and pelvic inflammation.