Stable and low-irritation benzalkonium chloride contraceptive gel and preparation method thereof

Abstract

The invention discloses stable and low-irritation benzalkonium chloride contraceptive gel and a preparation method, and belongs to the technical field of biological medicine manufacturing, and the method comprises the following steps: dissolving hydroxypropyl methylcellulose in purified water, and then adding benzalkonium chloride and chlorhexidine gluconate to obtain an antibacterial matrix phase; in addition, beta-sitosterol and hydroxypropyl-beta-cyclodextrin are premixed, aloe gel freeze-dried powder, glycerin, an adjusting auxiliary material, undecylenic acid glyceride and Ectoin are added, and the mixture is homogenized to obtain an active enhanced phase; adding the activity enhancing phase into the antibacterial matrix phase, uniformly mixing, and sterilizing by ozone. Compared with the prior art, the bactericidal effect is remarkably enhanced while the dosage of the bactericide is reduced, and mucous membrane irritation is reduced; the stability of the product is effectively improved, a suitable subacid environment is created, and the unification of sterilization, protection and stability is realized.

Description

Technical Field

[0001] This invention relates to the field of biopharmaceutical manufacturing technology, and in particular to a stable, low-irritation benzalkonium chloride contraceptive gel and its preparation method. Background Technology

[0002] This invention relates to the field of biopharmaceutical manufacturing technology, specifically to a stable, low-irritation benzalkonium chloride contraceptive gel and its preparation method. Benzalkonium chloride, as a cationic surfactant, has a definite bactericidal effect and is widely used in contraceptive and antibacterial products. However, how to reduce its irritation to mucous membranes and improve the product's storage stability while ensuring its bactericidal efficacy has always been a technical challenge of continuous concern to those skilled in the art.

[0003] In the prior art, patent application number 200410088709.8 discloses a benzalkonium chloride contraceptive gel, which uses a high content of benzalkonium chloride as a single bactericidal component. Although it can achieve rapid sterilization, the high concentration of benzalkonium chloride is highly irritating to the vaginal mucosa, and long-term use may disrupt the vaginal microecological balance. Patent publication number CN106177274A reduces irritation to some extent by adding electrolyzed water, aloe vera gel and other components, but its preparation method is only a simple physical mixing, without considering the interaction between the components and the stability during long-term storage. Moreover, its bactericidal mechanism is singular, making it difficult to effectively kill pathogens while simultaneously repairing the mucosa and regulating the microecological balance.

[0004] In summary, current technologies still lack a benzalkonium chloride contraceptive gel that can effectively kill bacteria, possess good mucosal compatibility and storage stability, and synergistically exert bactericidal and repair effects. Therefore, how to achieve synergistic effects with lower bactericide dosages, how to reduce irritation and extend product shelf life through the scientific formulation of functional excipients, and how to improve the stability of active ingredients through process optimization have become urgent technical problems to be solved in this field. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention aims to provide a stable and low-irritation benzalkonium chloride contraceptive gel and its preparation method.

[0006] To achieve the above-mentioned objectives, the present invention adopts the following technical solution: A method for preparing a stable, low-irritation benzalkonium chloride contraceptive gel is as follows: Step 1: Take purified water, heat and stir, add hydroxypropyl methylcellulose and stir; add purified water and continue stirring, then cool; add benzalkonium chloride and chlorhexidine gluconate, stir, and obtain the antibacterial matrix phase; Step 2: Mix β-sitosterol, hydroxypropyl-β-cyclodextrin, aloe vera gel lyophilized powder, glycerin, and adjusting excipients; then add undecenoic acid glyceride and ectoine, homogenize, and obtain the activity-enhancing phase; Step 3: Add the activity-enhancing phase from Step 2 to the antibacterial matrix phase from Step 1, and stir at a constant temperature; then perform ozone sterilization to obtain benzalkonium chloride contraceptive gel.

[0007] A method for preparing a stable, low-irritation benzalkonium chloride contraceptive gel is as follows, in parts by weight: Step 1: Take 20-30 parts of purified water, heat and stir, add 1-3 parts of hydroxypropyl methylcellulose, stir for 5-15 minutes; add 20-30 parts of purified water, continue stirring for 5-15 minutes, cool down to below 40℃; add 0.05-0.25 parts of benzalkonium chloride and 0.01-0.03 parts of chlorhexidine gluconate, stir at 100-500 rpm for 5-30 minutes to obtain the antibacterial matrix phase; Step 2: Take 0.3-0.8 parts of β-sitosterol, 0.3-0.8 parts of hydroxypropyl-β-cyclodextrin, 0.005-1 parts of aloe vera gel lyophilized powder, 1-3 parts of glycerin, and 0.1-0.3 parts of adjusting excipients, mix and stir for 5-30 minutes; then add 0.05-0.2 parts of undecenoic acid glyceride and 0.05-0.2 parts of ectoine, homogenize, and obtain the activity-enhancing phase; Step 3: Add the activity-enhancing phase from Step 2 to the antibacterial matrix phase from Step 1, and stir at a constant temperature; then perform ozone sterilization to obtain benzalkonium chloride contraceptive gel.

[0008] The homogenization in step 2 is to homogenize at 3000-5000 rpm for 1-5 minutes.

[0009] The regulating excipient is at least one of betaine, L-proline, sorbitol, glycerophosphate choline, trehalose, and allantoin.

[0010] Preferably, the regulating excipient is a combination of betaine and allantoin in a mass ratio of 0.5-2:0.5-2.

[0011] The ozone sterilization time in step 3 is 3-8 minutes, and the ozone concentration is 0.1-0.5 mg / L.

[0012] The constant temperature stirring in step 3 is to stir at a constant temperature of 35-40℃ and 100-500 rpm for 5-30 minutes.

[0013] The heating and stirring in step 1 involves heating to 80-100℃ and stirring at 100-500 rpm.

[0014] The stable, low-irritation benzalkonium chloride contraceptive gel can also be prepared by the following method, in parts by weight: Step 1: Take 20-30 parts of purified water, heat and stir, add 0.05-0.2 parts of lactic acid and 0.1-0.4 parts of sodium lactate, then add 1-3 parts of hydroxypropyl methylcellulose, stir for 5-15 minutes; add 20-30 parts of purified water, continue stirring for 5-15 minutes, cool to below 40℃; add 0.05-0.25 parts of benzalkonium chloride and 0.01-0.03 parts of chlorhexidine gluconate, stir at 100-500 rpm for 5-30 minutes to obtain the antibacterial matrix phase; Step 2: Take 0.3-0.8 parts of β-sitosterol, 0.3-0.8 parts of hydroxypropyl-β-cyclodextrin, 0.005-1 parts of aloe vera gel lyophilized powder, 1-3 parts of glycerin, and 0.1-0.3 parts of adjusting excipients, mix and stir for 5-30 minutes; then add 0.05-0.2 parts of undecenoic acid glyceride and 0.05-0.2 parts of ectoine, homogenize, and obtain the activity-enhancing phase; Step 3: Add the activity-enhancing phase from Step 2 to the antibacterial matrix phase from Step 1, and stir at a constant temperature; then perform ozone sterilization to obtain benzalkonium chloride contraceptive gel.

[0015] The design concept of this invention begins with an in-depth analysis of the pain points of existing benzalkonium chloride contraceptive gel technology. While benzalkonium chloride, as a broad-spectrum bactericide, has a definite bactericidal effect, its use at high concentrations often leads to significant mucosal irritation and potential disruption of the vaginal microecological balance with long-term use. Furthermore, the simple gel matrix struggles to achieve a balance between effective bactericidal action and gentle protection, and the active ingredients are prone to degradation during storage, resulting in insufficient stability. Based on this, this invention proposes a systematic design from three dimensions: optimization of the bactericidal system, synergistic effects of active ingredients, and improvement of the formulation process.

[0016] In the design process, we first introduced chlorhexidine gluconate and benzalkonium chloride to form a dual cationic antibacterial system, enabling them to produce a synergistic bactericidal effect at a low total concentration. This ensured the efficacy of killing bacteria while significantly reducing the risk of direct mucosal irritation from high concentrations of benzalkonium chloride alone. Building on this, we further designed an activity-enhancing phase: β-sitosterol was used to load anti-inflammatory and repairing components, and hydroxypropyl-β-cyclodextrin was used to protect the liposomes, preventing damage to the liposome membrane by the cationic bactericide. Simultaneously, we screened various regulatory excipients and found that when betaine and allantoin were combined in a specific ratio, betaine exerted an immediate osmotic regulation effect to alleviate cell membrane shock, while allantoin provided long-term protection by promoting the repair of damaged epithelium. The two formed a complementary synergistic mechanism, while sorbitol and glycerophosphate choline failed to produce a synergistic effect due to overlapping mechanisms of action.

[0017] To further enhance the overall performance of the product, we introduced a buffer system composed of lactic acid and sodium lactate based on the initial formula. This design is not merely a simple pH adjustment, but rather a consideration of the product's stability throughout its entire lifecycle. The weakly acidic environment can inhibit the alkaline-catalyzed degradation of benzalkonium chloride during storage. Simultaneously, lactic acid, as a vaginal microecological regulator, can synergistically enhance the mucosal barrier function, and the weakly acidic conditions can also stabilize the allantoin molecular structure and improve the hydration capacity of betaine. Through this progressive design—from bactericidal mechanism to protective mechanism, from single function to synergistic effect, and from activity maintenance to microenvironment adaptation—we have ultimately created a benzalkonium chloride contraceptive gel with reliable bactericidal efficacy, low irritation, excellent storage stability, and mucosal repair benefits.

[0018] Compared with the prior art, the present invention has the following beneficial technical effects: 1) This invention uses benzalkonium chloride and chlorhexidine gluconate to form a dual cationic antibacterial system, which significantly reduces the dosage of a single bactericide while achieving synergistic effects. This ensures efficient killing of bacteria, effectively reduces mucosal irritation, and improves the safety of product use.

[0019] 2) This invention uses betaine and allantoin in a specific ratio as a regulating excipient. The immediate penetrating regulation effect of betaine and the long-term mucosal repair function of allantoin form a complementary mechanism, which improves the stability of the gel and significantly alleviates the irritation of the bactericide to the vaginal mucosa.

[0020] 3) In the preparation process, this invention introduces lactic acid and sodium lactate to form a buffer system, which stabilizes the pH of the gel in a weakly acidic range. This not only inhibits the degradation of benzalkonium chloride during storage and extends the shelf life of the product, but also further enhances the mucosal barrier function by creating an acidic environment suitable for the vaginal microecology. Detailed Implementation

[0021] Some material sources or parameters: Hydroxypropyl methylcellulose, purity: methoxy content 22.0-24.0%, hydroxypropoxy content 7.5-9.5%, food grade, conforming to the quality standards for hydroxypropyl methylcellulose in USP, EP, and JP and the purity standards for the food additive hydroxypropyl methylcellulose (E464).

[0022] Benzalkonium chloride, CAS number 139-07-1, purity: 95-105%, pharmaceutical grade, conforming to the provisions of Part II of the Pharmacopoeia of the People's Republic of China.

[0023] Chlorhexidine gluconate, CAS number 18472-51-0, is a 20% aqueous solution, appearing as a colorless to pale yellow clear liquid. Its molecular formula is C1. 34 H 54 Cl2N10 O 14 .

[0024] β-Sitosterol, CAS: 83-46-5, Product No.: 567152, purchased from Merck, Germany.

[0025] Hydroxypropyl-β-cyclodextrin, CAS number 128446-35-5, hydroxypropoxy content 19.6%-26.3%, molar substitution degree 0.40-1.50.

[0026] Aloe vera gel freeze-dried powder, purity: 200:1, cosmetic grade, conforming to the requirements of QB / T 2488.

[0027] Ectodein, CAS No. 96702-03-3, purity ≥98%.

[0028] Betaine, CAS No. 590-47-6 (monohydrate), purity ≥98%.

[0029] L-proline, CAS number 147-85-3, is a chiral amino acid with a purity ≥99%.

[0030] Sorbitol, CAS number 50-70-4, purity ≥98%, is a white crystalline powder.

[0031] Glycerophosphate choline, CAS No. 28319-77-9, purity ≥98%.

[0032] Trehalose, CAS No. 99-20-7 (anhydrous), purity ≥98%.

[0033] Allantoin, CAS number 97-59-6, purity ≥98%.

[0034] In the embodiments and comparative examples of this invention, all raw materials are commercially available products. Example 1

[0035] A method for preparing a stable, low-irritation benzalkonium chloride contraceptive gel is as follows, in parts by weight: Step 1: Take 25 parts of purified water, heat to 85℃, stir at 400 rpm, add 2 parts of hydroxypropyl methylcellulose, stir for 10 min; add 25 parts of purified water, continue stirring for 10 min, cool to 35℃; add 0.06 parts of benzalkonium chloride and 0.02 parts of chlorhexidine gluconate, stir at 300 rpm for 15 min to obtain the antibacterial matrix phase; Step 2: Take 0.5 parts β-sitosterol, 0.5 parts hydroxypropyl-β-cyclodextrin, 0.15 parts aloe vera gel lyophilized powder, 2 parts glycerol, and 0.2 parts adjusting excipients, mix and stir for 10 min; then add 0.1 parts undecenoic acid glyceride and 0.1 parts ectoine, homogenize at 4000 rpm for 3 min to obtain the activity-enhancing phase; Step 3: Add the activity-enhancing phase from Step 2 to the antibacterial matrix phase from Step 1, and stir at 37°C and 300 rpm for 15 min; then sterilize with ozone for 5 min at an ozone concentration of 0.2 mg / L to obtain benzalkonium chloride contraceptive gel.

[0036] The regulating additive is betaine. Example 2

[0037] The preparation method of a stable and low-irritation benzalkonium chloride contraceptive gel is basically the same as that in Example 1, except that the regulating excipient is L-proline. Example 3

[0038] The preparation method of a stable and low-irritation benzalkonium chloride contraceptive gel is basically the same as that in Example 1, except that the regulating excipient is sorbitol. Example 4

[0039] The preparation method of a stable and low-irritation benzalkonium chloride contraceptive gel is basically the same as that in Example 1, except that the regulating excipient is glycerophosphate choline. Example 5

[0040] The preparation method of a stable and low-irritation benzalkonium chloride contraceptive gel is basically the same as that in Example 1, except that the regulating excipient is trehalose. Example 6

[0041] The preparation method of a stable and low-irritation benzalkonium chloride contraceptive gel is basically the same as that in Example 1, except that the regulating excipient is allantoin. Example 7

[0042] The preparation method of a stable and low-irritation benzalkonium chloride contraceptive gel is basically the same as that in Example 1, except that the regulating excipients are betaine and allantoin in a mass ratio of 1:1. Example 8

[0043] The preparation method of a stable and low-irritation benzalkonium chloride contraceptive gel is basically the same as that in Example 1, except that the regulating excipients are sorbitol and glycerophosphate choline combined in a mass ratio of 1:1. Example 9

[0044] A method for preparing a stable, low-irritation benzalkonium chloride contraceptive gel is as follows, in parts by weight: Step 1: Take 25 parts of purified water, heat to 85℃, stir at 400 rpm, add 0.12 parts of lactic acid and 0.28 parts of sodium lactate, then add 2 parts of hydroxypropyl methylcellulose, stir for 10 min; add 25 parts of purified water, continue stirring for 10 min, cool to 35℃; add 0.06 parts of benzalkonium chloride and 0.02 parts of chlorhexidine gluconate, stir at 300 rpm for 15 min to obtain the antibacterial matrix phase; Step 2: Take 0.5 parts β-sitosterol, 0.5 parts hydroxypropyl-β-cyclodextrin, 0.15 parts aloe vera gel lyophilized powder, 2 parts glycerol, and 0.2 parts adjusting excipients, mix and stir for 10 min; then add 0.1 parts undecenoic acid glyceride and 0.1 parts ectoine, homogenize at 4000 rpm for 3 min to obtain the activity-enhancing phase; Step 3: Add the activity-enhancing phase from Step 2 to the antibacterial matrix phase from Step 1, and stir at 37°C and 300 rpm for 15 min; then sterilize with ozone for 5 min at an ozone concentration of 0.2 mg / L to obtain benzalkonium chloride contraceptive gel.

[0045] The regulating excipient is composed of betaine and allantoin in a mass ratio of 1:1.

[0046] Comparative Example 1 The preparation method of a stable and low-irritation benzalkonium chloride contraceptive gel is basically the same as that in Example 1, except that the conditioning excipients are not added.

[0047] Test Example 1 Stability test: Referring to the accelerated test method specified in 2.2.3.2 of the "Disinfection Technical Specifications" (2002 edition), the samples were placed in a constant temperature chamber at 37℃ for 90 days. Samples were taken before and after storage, and the content of benzalkonium chloride was determined by high performance liquid chromatography (HPLC). The content reduction rate was calculated.

[0048] Each group was tested three times, and the average value was taken. The test results are shown in Table 1.

[0049] Table 1 Experimental protocol Benzalkonium chloride reduction rate (%) Example 1 10.8 Example 2 11.2 Example 3 10.5 Example 4 10.9 Example 5 11.5 Example 6 9.8 Example 7 7.2 Example 8 10.7 Example 9 5.3 Comparative Example 1 16.5 Test Example 2 Mucosal irritation test: Following the repeated vaginal mucosal irritation test method specified in Section 2.3.3 of the "Disinfection Technical Specifications" (2002 edition), healthy adult female rabbits were selected. Benzalkonium chloride contraceptive gel prepared in the examples or comparative examples was injected into the vagina daily at a dose of 0.2 mL / kg of body weight for 5 consecutive days. Animals were sacrificed 24 hours after the last administration, and vaginal tissue was collected for pathological histological examination. The irritation index was calculated based on a comprehensive score considering indicators such as mucosal epithelium, lamina propria, and inflammatory cell infiltration. Each group was tested in triplicate, and the average value was taken. The relevant test data are summarized in Table 2.

[0050] Table 2 Experimental protocol Stimulation Index Example 1 2.1 Example 2 2.3 Example 3 1.9 Example 4 2.0 Example 5 2.4 Example 6 1.5 Example 7 0.9 Example 8 1.9 Example 9 0.7 Comparative Example 1 3.2 Test Example 3 Sterilization rate test: Referring to the quantitative bactericidal test method for suspensions specified in Section 2.1.1.2 of the "Disinfection Technical Specifications" (2002 edition), *Candida albicans* (ATCC 10231), *Staphylococcus aureus* (ATCC 6538), and *Escherichia coli* (8099) were selected as indicator strains. The benzalkonium chloride contraceptive gel stock solution prepared in the embodiments and comparative examples of this invention was mixed with the bacterial suspension at a 1:1 ratio and incubated at 25°C for 5 minutes. After terminating the reaction, the mixture was inoculated into the corresponding culture medium, and the kill rate was calculated after incubation. Each group was measured in triplicate, and the average value was taken.

[0051] The bactericidal rate test results showed that the bactericidal rate of Candida albicans, Staphylococcus aureus and Escherichia coli in Examples 1 to 9 and Comparative Example 1 reached more than 99% after 5 minutes of action, indicating that the benzalkonium chloride contraceptive gel of the present invention maintains a broad-spectrum and highly efficient bactericidal ability.

[0052] Test Example 4 In vitro spermicide test: Healthy adult male rabbits were used as experimental animals. Fresh rabbit semen was collected and diluted with physiological saline at a volume ratio of 1:10. The benzalkonium chloride contraceptive gel stock solution prepared in the embodiments and comparative examples of this invention was mixed with the semen at a ratio of 1:1 and incubated at 37°C for 120 seconds. Sperm motility was immediately observed under a microscope, and sperm immobility rate was calculated. Each group was measured in triplicate, and the average value was taken.

[0053] In vitro spermicidal test results: Examples 1-9 and Comparative Example 1 all achieved an immobilization rate of over 98% against rabbit sperm after 120 seconds of action. All examples and comparative examples demonstrated excellent spermicidal activity.

[0054] Examples 1 to 6 respectively added betaine, L-proline, sorbitol, glycerophosphate choline, trehalose, or allantoin as regulatory excipients. Compared with Comparative Example 1 (without any regulatory excipients), the above regulatory excipients can reduce the degradation rate of benzalkonium chloride in the accelerated test by adjusting the osmotic pressure of the gel system, stabilizing the microenvironment of the cationic bactericide, and providing a certain degree of mucosal protection. They also alleviate the direct damage of the dual cationic bactericide to epithelial cells in the vaginal mucosal irritation test, showing a lower decrease rate of benzalkonium chloride content and better mucosal compatibility.

[0055] Example 7 uses a 1:1 mass ratio of betaine and allantoin as a regulating excipient. Compared with Example 1, which uses betaine alone, and Example 6, which uses allantoin alone, betaine stabilizes the gel system and reduces the direct impact of bactericides on cell membranes through osmotic pressure regulation, while allantoin exerts a synergistic protective effect by promoting the repair of damaged mucosal epithelial cells. The two form a complementary mechanism of immediate osmotic regulation and long-term repair. Therefore, its benzalkonium chloride reduction rate and irritation index are significantly better than those of the two used alone. Example 8 uses a combination of sorbitol and glycerophosphate choline. Since both mainly play the functions of moisturizing and osmotic regulation, their mechanisms of action overlap and they lack functional complementarity. Therefore, its stability and irritation are between those of Example 3, which uses sorbitol alone, and Example 4, which uses glycerophosphate choline alone, and it does not show synergistic effects.

[0056] Example 9, based on Example 7, further added lactic acid and sodium lactate to form a buffer system in step 1. This buffer system stabilizes the pH of the gel in a weakly acidic environment, which on the one hand inhibits the alkaline catalytic degradation of benzalkonium chloride during storage, and on the other hand, lactic acid itself, as a vaginal microecological regulator, can synergistically enhance the mucosal barrier function with betaine and allantoin. The weakly acidic environment can also enhance the molecular stability of allantoin and the hydration capacity of betaine. Therefore, compared with Example 7, Example 9 showed a lower benzalkonium chloride reduction rate in the accelerated test and obtained a lower irritation index in the vaginal mucosal irritation test, achieving further improvement in product stability and safety.

Claims

1. A method for preparing a stable, low-irritation benzalkonium chloride contraceptive gel, characterized in that, The method is as follows: Step 1: Take purified water, heat and stir, add hydroxypropyl methylcellulose and stir; add purified water and continue stirring, then cool; add benzalkonium chloride and chlorhexidine gluconate, stir, and obtain the antibacterial matrix phase; Step 2: Mix β-sitosterol, hydroxypropyl-β-cyclodextrin, aloe vera gel lyophilized powder, glycerin, and adjusting excipients; then add undecenoic acid glyceride and ectoine, homogenize, and obtain the activity-enhancing phase; Step 3: Add the activity-enhancing phase from Step 2 to the antibacterial matrix phase from Step 1, and stir at a constant temperature; then perform ozone sterilization to obtain benzalkonium chloride contraceptive gel.

2. The method for preparing the stable and low-irritation benzalkonium chloride contraceptive gel as described in claim 1, characterized in that, The method is as follows, by weight: Step 1: Take 20-30 parts of purified water, heat and stir, add 1-3 parts of hydroxypropyl methylcellulose, stir for 5-15 minutes; add 20-30 parts of purified water, continue stirring for 5-15 minutes, cool down to below 40℃; add 0.05-0.25 parts of benzalkonium chloride and 0.01-0.03 parts of chlorhexidine gluconate, stir at 100-500 rpm for 5-30 minutes to obtain the antibacterial matrix phase; Step 2: Take 0.3-0.8 parts of β-sitosterol, 0.3-0.8 parts of hydroxypropyl-β-cyclodextrin, 0.005-1 parts of aloe vera gel lyophilized powder, 1-3 parts of glycerin, and 0.1-0.3 parts of adjusting excipients, mix and stir for 5-30 minutes; then add 0.05-0.2 parts of undecenoic acid glyceride and 0.05-0.2 parts of ectoine, homogenize, and obtain the activity-enhancing phase; Step 3: Add the activity-enhancing phase from Step 2 to the antibacterial matrix phase from Step 1, and stir at a constant temperature; then perform ozone sterilization to obtain benzalkonium chloride contraceptive gel.

3. The method for preparing the stable, low-irritation benzalkonium chloride contraceptive gel as described in claim 1 or 2, characterized in that, The homogenization in step 2 is to homogenize at 3000-5000 rpm for 1-5 minutes.

4. The method for preparing the stable, low-irritation benzalkonium chloride contraceptive gel as described in claim 1 or 2, characterized in that, The ozone sterilization time in step 3 is 3-8 minutes, and the ozone concentration is 0.1-0.5 mg / L.

5. The method for preparing the stable, low-irritation benzalkonium chloride contraceptive gel as described in claim 1 or 2, characterized in that, The constant temperature stirring in step 3 is to stir at a constant temperature of 35-40℃ and 100-500 rpm for 5-30 minutes.

6. The method for preparing the stable, low-irritation benzalkonium chloride contraceptive gel as described in claim 1 or 2, characterized in that, The heating and stirring in step 1 involves heating to 80-100℃ and stirring at 100-500 rpm.

7. The method for preparing the stable, low-irritation benzalkonium chloride contraceptive gel as described in claim 1 or 2, characterized in that, The regulating excipient is at least one of betaine, L-proline, sorbitol, glycerophosphate choline, trehalose, and allantoin.

8. The method for preparing the stable, low-irritation benzalkonium chloride contraceptive gel as described in claim 1 or 2, characterized in that, The regulating excipient is composed of betaine and allantoin in a mass ratio of 0.5-2:0.5-2.

9. The method for preparing the stable and low-irritation benzalkonium chloride contraceptive gel as described in claim 1, characterized in that, Alternatively, the following preparation method can be used, in parts by weight: Step 1: Take 20-30 parts of purified water, heat and stir, add 0.05-0.2 parts of lactic acid and 0.1-0.4 parts of sodium lactate, then add 1-3 parts of hydroxypropyl methylcellulose, stir for 5-15 minutes; add 20-30 parts of purified water, continue stirring for 5-15 minutes, cool to below 40℃; add 0.05-0.25 parts of benzalkonium chloride and 0.01-0.03 parts of chlorhexidine gluconate, stir at 100-500 rpm for 5-30 minutes to obtain the antibacterial matrix phase; Step 2: Take 0.3-0.8 parts of β-sitosterol, 0.3-0.8 parts of hydroxypropyl-β-cyclodextrin, 0.005-1 parts of aloe vera gel lyophilized powder, 1-3 parts of glycerin, and 0.1-0.3 parts of adjusting excipients, mix and stir for 5-30 minutes; then add 0.05-0.2 parts of undecenoic acid glyceride and 0.05-0.2 parts of ectoine, homogenize, and obtain the activity-enhancing phase; Step 3: Add the activity-enhancing phase from Step 2 to the antibacterial matrix phase from Step 1, and stir at a constant temperature; then perform ozone sterilization to obtain benzalkonium chloride contraceptive gel.

10. A stable, low-irritation benzalkonium chloride contraceptive gel, characterized in that, It is prepared by the preparation method described in any one of claims 1-9.