A low-irritation polycresolsulfonate rinsing solution and its preparation method

Abstract

The application discloses a low-irritation policresulen flushing solution and a preparation method thereof, and relates to the technical field of pharmaceutical preparations.The preparation method comprises the following steps: S1, pouring policresulen into a container, heating to a temperature of 55-65 DEG C, and then adding karanja oil to form a mixture A; S2, rapidly stirring the mixture A for 8-15 min until it is dissolved, then adding spironolactone, uniformly stirring, and reducing the temperature to 24-27 DEG C to form a mixture B; S3, sequentially adding succinic anhydride and water to the mixture B, filtering after stirring for 10-20 min, and performing filling, sealing and terminal sterilization according to specifications, so that the policresulen flushing solution is obtained.The policresulen flushing solution prepared by the application has the advantages of good clarity, low irritation, high stability, less increase of related substances, simple operation, and low production cost.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations, in particular to a low-irritation policresulen irrigation solution and a preparation method thereof. BACKGROUND

[0002] Policresulen (C 15 H 16 O8S2(C8H8O4S) n ; n = 0-20) is a topical hemostatic and bactericidal agent, which has strong killing effect on various pathogens, including gram-negative bacteria, gram-positive bacteria, fungi, mycoplasma, chlamydia, viruses, etc., and maintains the normal vaginal acidic environment while selectively acting on the diseased tissue, promotes the recovery of the physiological internal environment of the vagina, and has the effects of astringency, hemostasis and promotion of wound healing. It is mainly used in gynecology, surgery, dermatology and otolaryngology, and has the advantage of no damage to normal tissues.

[0003] Policresulen is a red-brown liquid and a strong acidic substance, which has the following effects: ① anti-bacterial, fungal and protozoal infection; ② selective action on necrotic tissue and columnar epithelium and denaturation, but no effect on normal squamous epithelium; ③ hemostatic effect by coagulating plasma proteins and significantly stimulating vasoconstriction. Policresulen has a broad-spectrum antibacterial effect, including gram-positive bacteria, gram-negative bacteria and certain fungi, and is particularly effective against Gardnerella, anaerobes and trichomonads.

[0004] The currently commonly used policresulen preparations in clinical practice are vaginal suppositories, solutions and gels. The policresulen solution prepared by adding edetic acid in the prior art has the disadvantages of many impurities, difficult control of related substances, strong irritation and being not conducive to large-scale production. SUMMARY

[0005] In view of the above-mentioned defects of the prior art, the present application provides a low-irritation policresulen irrigation solution and a preparation method thereof to solve the problems in the background art.

[0006] To achieve the above-mentioned purpose, the present application provides the following technical solutions:

[0007] A low-irritation policresulen irrigation solution, which contains the following raw materials per mL of policresulen irrigation solution: 70-150 mg of policresulen, 10-25 mg of cananga oil, 7-12 mg of spironolactone and 1-3 mg of succinic anhydride, and the balance is water.

[0008] Preferably, a low-irritation policresulen irrigation solution, which contains the following raw materials per mL of policresulen irrigation solution: 100 mg of policresulen, 15 mg of cananga oil, 10 mg of spironolactone, 2 mg of succinic anhydride, and the balance is water.

[0009] Preferably, the preparation method of the cannanga oil comprises the following steps:

[0010] (1) Pretreatment: flowers of Cymbidium grandiflorum (C. odorata Baill. f. forma macrophylla) are placed in a container, and a solution of rosemary acid with a mass concentration of 0.1% to 0.5% is added to the container, and after being mixed uniformly, the container is sealed;

[0011] (2) High-pressure treatment: the sealed container is placed in an ultra-high pressure device for ultra-high pressure treatment, with a pressure of 200 to 450 MPa, a pressure holding time of 10 to 20 min, and a temperature of 25 to 35°C;

[0012] (3) Water vapor distillation treatment: after the ultra-high pressure treatment is completed, water vapor distillation is carried out at a temperature of 90 to 100°C for 50 to 70 min, and the upper oil phase is collected, which is the cannanga oil.

[0013] Preferably, the weight ratio of the Cymbidium grandiflorum flowers to the rosemary acid solution in step (1) is 1: (5 to 10).

[0014] Preferably, the preparation method comprises the following steps:

[0015] S1, pour the policresulen into a container, heat to a temperature of 55 to 65°C within 30 to 120 min, then add the cannanga oil to form a mixture A;

[0016] S2, quickly stir the mixture A for 8 to 15 min until it is clear, then add spironolactone, stir uniformly to a temperature of 24 to 27°C, and form a mixture B;

[0017] S3, add succinic anhydride and water to the mixture B in sequence, stir for 10 to 20 min, then filter with a filter membrane, and according to the specifications, perform filling, sealing, and terminal sterilization at 110°C for 10 min to obtain the policresulen flushing solution.

[0018] Preferably, the material of the container in step S1 is stainless steel 316.

[0019] Preferably, the stirring speed is 250 to 400 rpm.

[0020] Preferably, the material of the filter membrane in step S3 is one of polyether sulfone, nylon, or polytetrafluoroethylene.

[0021] Preferably, the precision of the filter membrane in step S3 is 0.45 μm.

[0022] Preferably, the material of the filling in step S3 is sodium-calcium glass, and the sealing is performed with an oral polyolefin safety cap.

[0023] Compared with the prior art, the beneficial effects of the present invention are:

[0024] (1) The technical solution of the present invention is different from the prior art. No chelating agent edepic acid is added during the preparation process. The present invention utilizes the reaction between cananol oil, spironolactone and succinic anhydride and polycresolsulfonaldehyde. Cananol oil can effectively reduce the irritation of polycresolsulfonaldehyde. At the same time, succinic anhydride and spironolactone can accelerate the reaction rate of polycresolsulfonaldehyde and cananol oil, increase the amount of drug grafting, not only increase the effective content of the drug, but also help reduce the amount of drug used, and also help the long-term storage of the drug.

[0025] (2) The prepared polycresolsulfonate rinsing solution has good clarity, low irritation, high stability, and low impurity increase. It is also easy to operate and has low production cost. In addition, by controlling the amount of Kanan oil added during the preparation process within a specific range and controlling the content of related substances, and by combining it with a specific preparation sequence, the prepared polycresolsulfonate rinsing solution has good stability. Detailed Implementation

[0026] The technical solution of the present invention will be further described in detail below with reference to specific embodiments.

[0027] 1. Reference formulation

[0028]

[0029]

[0030] In accordance with the "Selection and Determination Procedures for Reference Preparations of Generic Chemical Drugs" and the announcement of the list of reference preparations for generic drugs (batch 37 and batch 54), Albothyl, manufactured by Takeda GmbH and imported into China as the original drug, was selected as the reference preparation. The specification is 36% (w / w), and it should be stored away from light with a shelf life of 60 months.

[0031] Microbial limit test method: ChP 2020 edition, Part IV, General Rules 1105 and 1106, test limit: total number of molds and yeasts ≤10 1 cfu / ml; Total aerobic bacteria count ≤10 2 CFU / ml; Escherichia coli not detected / ml; Staphylococcus aureus not detected / ml; Pseudomonas aeruginosa not detected / ml; Candida albicans not detected / ml.

[0032] Content determination method: General Chapter 0701, Part IV, ChP 2020 Edition; Detection limit: 95.0%–105.0%.

[0033] Example 1

[0034] A low-irritation policresulen rinse solution, each mL of the policresulen rinse solution containing the following raw materials: policresulen 150 mg, cannanga oil 25 mg, spironolactone 12 mg, succinic anhydride 3 mg, and the balance being water.

[0035] The preparation method of the cannanga oil comprises the following steps:

[0036] (1) Pretreatment: the large-leaf ylang-ylang flowers are placed in a container, a 0.5% rosmarinic acid solution is added to the container, and the container is sealed after uniform mixing; the weight ratio of the large-leaf ylang-ylang flowers to the rosmarinic acid solution is 1:10;

[0037] (2) High-pressure treatment: the sealed container is placed in an ultrahigh-pressure device for ultrahigh-pressure treatment, the pressure is 450 MPa, the pressure holding time is 20 min, and the temperature is 35°C;

[0038] (3) Water vapor distillation treatment: after the ultrahigh-pressure treatment is completed, water vapor distillation is performed at a temperature of 100°C for 70 min, and the upper oil phase is collected, which is the cannanga oil.

[0039] A preparation method of a low-irritation policresulen rinse solution, comprising the following steps:

[0040] S1, pour the policresulen into a stainless steel 316 container, heat to a temperature of 65°C within 120 min, then add the cannanga oil to form a mixture A;

[0041] S2, quickly stir the mixture A for 15 min until it is clear, then add the spironolactone, stir uniformly to a temperature of 27°C to form a mixture B; the stirring speed is 400 rpm;

[0042] S3, add the succinic anhydride and water to the mixture B in sequence, stir for 20 min, then filter with a 0.45 μm polyether sulfone filter membrane, fill according to the specifications in a sodium-calcium glass bottle, seal and terminal sterilize to obtain the policresulen rinse solution; the stirring speed is 400 rpm.

[0043] Example 2

[0044] A low-irritation policresulen rinse solution, each mL of the policresulen rinse solution containing the following raw materials: policresulen 70 mg, cannanga oil 10 mg, spironolactone 7 mg, succinic anhydride 1 mg, and the balance being water.

[0045] The preparation method of the cannanga oil comprises the following steps:

[0046] (1) Pretreatment: the large-leaf ylang-ylang flowers are placed in a container, a 0.5% rosmarinic acid solution is added to the container, and the container is sealed after uniform mixing; the weight ratio of the large-leaf ylang-ylang flowers to the rosmarinic acid solution is 1:10;

[0047] (2) High pressure treatment: The sealed container is placed in an ultra-high pressure device for ultra-high pressure treatment, with a pressure of 200MPa, a holding time of 10min, and a temperature of 25℃.

[0048] (3) Steam distillation treatment: After the ultra-high pressure is completed, steam distillation is carried out at a temperature of 90℃ for 50 minutes, and the upper oil phase is collected, which is the Kanan oil.

[0049] A method for preparing a low-irritant polycresolsulfonate rinsing solution includes the following steps:

[0050] S1. Pour polycresolsulfonate into a stainless steel 316 container, heat it to 55°C within 30 minutes, then add Kanan oil to form mixture A.

[0051] S2. Mixture A is rapidly stirred for 8 minutes until dissolved, then spironolactone is added, stirred evenly, and cooled to 24°C to form mixture B; the stirring speed is 250 rpm.

[0052] S3. Add succinic anhydride and water to mixture B in sequence, stir for 10 min, filter with a 0.45 μm nylon filter membrane, fill into sodium calcium glass bottles according to specifications, seal and terminal sterilize to obtain polycresolsulfonate rinsing solution; the stirring speed is 250 rpm.

[0053] Example 3

[0054] A low-irritant polycresolsulfonate rinsing solution contains the following ingredients per mL: 100 mg polycresolsulfonate, 15 mg cananol oil, 10 mg spironolactone, 2 mg succinic anhydride, and the remainder is water.

[0055] The preparation method of the Kanan refueling includes the following steps:

[0056] (1) Pretreatment: Place the ylang-ylang flowers in a container, add a 0.3% rosmarinic acid solution to the container, mix well, and then seal the container; the weight ratio of the ylang-ylang flowers to the rosmarinic acid solution is 1:8.

[0057] (2) High pressure treatment: The sealed container is placed in an ultra-high pressure device for ultra-high pressure treatment, with a pressure of 300MPa, a holding time of 15min, and a temperature of 30℃.

[0058] (3) Steam distillation treatment: After the ultra-high pressure is completed, steam distillation is carried out at a temperature of 98℃ for 60 minutes, and the upper oil phase is collected, which is the Kanan oil.

[0059] A method for preparing a low-irritant polycresolsulfonate rinsing solution includes the following steps:

[0060] S1. Pour polycresolsulfonate into a stainless steel 316 container, heat it to 60°C within 100 minutes, then add Kanan oil to form mixture A.

[0061] S2. Mixture A is stirred rapidly for 10 minutes until dissolved, then spironolactone is added, stirred evenly, and cooled to 25°C to form mixture B; the stirring speed is 300 rpm.

[0062] S3. Add succinic anhydride and water to mixture B in sequence, stir for 15 min, filter with a 0.45 μm polytetrafluoroethylene filter membrane, fill into sodium-calcium glass bottles according to specifications, seal and terminal sterilize to obtain polycresolsulfonate rinsing solution; the stirring speed is 300 rpm.

[0063] Comparative Example 1

[0064] The difference between this comparative example and Example 3 is that the rosmarinic acid solution in the preparation method of Kanan oil is replaced with citric acid aqueous solution, while the other components and steps remain unchanged.

[0065] A low-irritant polycresolsulfonate rinsing solution contains the following ingredients per mL: 100 mg polycresolsulfonate, 15 mg cananol oil, 10 mg spironolactone, 2 mg succinic anhydride, and the remainder is water.

[0066] The preparation method of the Kanan refueling includes the following steps:

[0067] (1) Pretreatment: Place the large-leaf ylang-ylang flowers in a container, add a 0.3% citric acid aqueous solution to the container, mix well, and then seal the container; the weight ratio of the large-leaf ylang-ylang flowers to the citric acid aqueous solution is 1:8;

[0068] (2) High pressure treatment: The sealed container is placed in an ultra-high pressure device for ultra-high pressure treatment, with a pressure of 300MPa, a holding time of 15min, and a temperature of 30℃.

[0069] (3) Steam distillation treatment: After the ultra-high pressure is completed, steam distillation is carried out at a temperature of 98℃ for 60 minutes, and the upper oil phase is collected, which is the Kanan oil.

[0070] A method for preparing a low-irritant polycresolsulfonate rinsing solution includes the following steps:

[0071] S1. Pour polycresolsulfonate into a stainless steel 316 container, heat it to 60°C within 100 minutes, then add Kanan oil to form mixture A.

[0072] S2. Mixture A is stirred rapidly for 10 minutes until dissolved, then spironolactone is added, stirred evenly, and cooled to 25°C to form mixture B; the stirring speed is 300 rpm.

[0073] S3. Add succinic anhydride and water to mixture B in sequence, stir for 15 min, filter with a 0.45 μm polytetrafluoroethylene filter membrane, fill into sodium-calcium glass bottles according to specifications, seal and terminal sterilize to obtain polycresolsulfonate rinsing solution; the stirring speed is 300 rpm.

[0074] Comparative Example 2

[0075] The difference between this comparative example and Example 3 is that no canan oil is added to the raw materials, while the other components and steps remain the same.

[0076] A low-irritant polycresolsulfonate rinsing solution contains the following ingredients per mL: 100 mg polycresolsulfonate, 10 mg spironolactone, 2 mg succinic anhydride, and the remainder is water.

[0077] A method for preparing a low-irritant polycresolsulfonate rinsing solution includes the following steps:

[0078] S1. Pour polycresolsulfonate into a stainless steel 316 container and heat it to 60°C within 100 minutes; then add spironolactone, stir evenly and cool to 25°C to form mixture A; the stirring speed is 300 rpm.

[0079] S2. Add succinic anhydride and water to mixture A in sequence, stir for 15 min, filter with a 0.45 μm polytetrafluoroethylene filter membrane, fill into a soda-lime glass bottle according to specifications, seal and terminal sterilize to obtain polycresolsulfonate rinsing solution; the stirring speed is 300 rpm.

[0080] Comparative Example 3

[0081] The difference between this comparative example and Example 3 is that spironolactone is not added to the raw materials, while the other components and steps remain unchanged.

[0082] A low-irritant polycresolsulfonate rinsing solution contains the following ingredients per mL: 100 mg polycresolsulfonate, 15 mg cananol oil, 2 mg succinic anhydride, and the remainder is water.

[0083] The preparation method of the Kanan refueling includes the following steps:

[0084] (1) Pretreatment: Place the ylang-ylang flowers in a container, add a 0.3% rosmarinic acid solution to the container, mix well, and then seal the container; the weight ratio of the ylang-ylang flowers to the rosmarinic acid solution is 1:8.

[0085] (2) High pressure treatment: The sealed container is placed in an ultra-high pressure device for ultra-high pressure treatment, with a pressure of 300MPa, a holding time of 15min, and a temperature of 30℃.

[0086] (3) Steam distillation treatment: After the ultra-high pressure is completed, steam distillation is carried out at a temperature of 98℃ for 60 minutes, and the upper oil phase is collected, which is the Kanan oil.

[0087] A method for preparing a low-irritant polycresolsulfonate rinsing solution includes the following steps:

[0088] S1. Pour polycresolsulfonate into a stainless steel 316 container, heat it to 60°C within 100 minutes, then add Kanan oil to form mixture A.

[0089] S2. Stir mixture A rapidly for 10 minutes until dissolved, then cool to 25°C; the stirring speed is 300 rpm.

[0090] S3. Add succinic anhydride and water sequentially to the mixture A obtained in step S2, stir for 15 minutes, filter with a 0.45μm polytetrafluoroethylene filter membrane, fill into a sodium-calcium glass bottle according to specifications, seal and terminal sterilize to obtain polycresolsulfonate rinsing solution; the stirring speed is 300rpm.

[0091] Comparative Example 4

[0092] The difference between this comparative example and Example 3 is that succinic anhydride is not added to the raw materials, while the other components and steps remain unchanged.

[0093] A low-irritant polycresolsulfonate rinsing solution contains the following ingredients per mL: 100 mg polycresolsulfonate, 15 mg cananol oil, 10 mg spironolactone, and the remainder is water.

[0094] The preparation method of the Kanan refueling includes the following steps:

[0095] (1) Pretreatment: Place the ylang-ylang flowers in a container, add a 0.3% rosmarinic acid solution to the container, mix well, and then seal the container; the weight ratio of the ylang-ylang flowers to the rosmarinic acid solution is 1:8.

[0096] (2) High pressure treatment: The sealed container is placed in an ultra-high pressure device for ultra-high pressure treatment, with a pressure of 300MPa, a holding time of 15min, and a temperature of 30℃.

[0097] (3) Steam distillation treatment: After the ultra-high pressure is completed, steam distillation is carried out at a temperature of 98℃ for 60 minutes, and the upper oil phase is collected, which is the Kanan oil.

[0098] A method for preparing a low-irritant polycresolsulfonate rinsing solution includes the following steps:

[0099] S1. Pour polycresolsulfonate into a stainless steel 316 container, heat it to 60°C within 100 minutes, then add Kanan oil to form mixture A.

[0100] S2. Mixture A is stirred rapidly for 10 minutes until dissolved, then spironolactone is added, stirred evenly, and cooled to 25°C to form mixture B; the stirring speed is 300 rpm.

[0101] S3. Add water to mixture B, stir for 15 minutes, filter with a 0.45μm polytetrafluoroethylene filter membrane, fill into sodium-calcium glass bottles according to specifications, seal and terminally sterilize to obtain polycresolsulfonate rinsing solution; the stirring speed is 300 rpm.

[0102] Comparative Example 5

[0103] The difference between this comparative example and Example 3 is that the preparation method of the polycresolsulfonate rinsing solution is changed to a one-time mixing, while the other components and steps remain unchanged.

[0104] A low-irritant polycresolsulfonate rinsing solution contains the following ingredients per mL: 100 mg polycresolsulfonate, 15 mg cananol oil, 10 mg spironolactone, 2 mg succinic anhydride, and the remainder is water.

[0105] The preparation method of the Kanan refueling includes the following steps:

[0106] (1) Pretreatment: Place the ylang-ylang flowers in a container, add a 0.3% rosmarinic acid solution to the container, mix well, and then seal the container; the weight ratio of the ylang-ylang flowers to the rosmarinic acid solution is 1:8.

[0107] (2) High pressure treatment: The sealed container is placed in an ultra-high pressure device for ultra-high pressure treatment, with a pressure of 300MPa, a holding time of 15min, and a temperature of 30℃.

[0108] (3) Steam distillation treatment: After the ultra-high pressure is completed, steam distillation is carried out at a temperature of 98℃ for 60 minutes, and the upper oil phase is collected, which is the Kanan oil.

[0109] A method for preparing a low-irritant polycresolsulfonate rinsing solution includes the following steps:

[0110] Pour the prescribed amounts of polycresolsulfonate, cananol oil, spironolactone, succinic anhydride, and water into a stainless steel 316 container. Heat to 60°C within 100 minutes, stir until homogeneous, and then cool to 25°C. The stirring speed is 300 rpm. Filter the solution through a 0.45 μm polytetrafluoroethylene membrane, fill into sodium-calcium glass bottles according to specifications, seal, and perform terminal sterilization to obtain the polycresolsulfonate rinsing solution.

[0111] Experimental Example 1

[0112] 1.1 Take the polycresolsulfonate rinsing solution prepared in Examples 1 to 3, use the reference preparation as the control group, and test the relevant substance content and other indicators according to the experimental methods of influencing factors in the drug stability guidelines, referring to the "Basic Technical Guidelines for Research on Chemical Drug Preparations".

[0113] 1.2 The polycresolsulfonate rinsing solutions prepared in Example 3 and Comparative Examples 1-5 were placed under strong light (4500±500Lux) and high temperature (40℃, 60℃) conditions, respectively. Samples were taken on the 10th and 30th days, respectively, and stability indicators such as related substances and changes in physical properties were tested.

[0114] 1.3 Test Results

[0115] The sample test results at 0d are shown in Table 1, and the stability test results are shown in Tables 2-8:

[0116] Table 1 Sample Testing

[0117]

[0118] As shown in Table 1, the polycresolsulfonate rinsing solutions prepared in Examples 1-3 and the reference preparation were all within the limit range and qualified at day 0. Furthermore, the content of the polycresolsulfonate rinsing solutions prepared in Examples 1-3 was higher than that of the reference preparation.

[0119] Table 2 Stability test results of Example 3

[0120]

[0121]

[0122] Table 3. Stability test results of the reference formulation

[0123]

[0124] Table 4 shows the stability test results for Comparative Example 1.

[0125]

[0126] Table 5. Stability test results for Comparative Example 2

[0127]

[0128]

[0129] Table 6. Stability test results for Comparative Example 3

[0130]

[0131] Table 7 shows the stability test results for Comparative Example 4.

[0132]

[0133]

[0134] Table 8 shows the stability test results for Comparative Example 5.

[0135]

[0136] As shown in Tables 2-8, the polycresolsulfonate rinsing solution prepared using the components and preparation method of Example 3 has fewer impurities. This indicates that in the preparation process of the polycresolsulfonate rinsing solution, the absence of a certain component or failure to prepare the canan oil according to this technical solution can lead to a high level of impurities in the final product, which is not conducive to subsequent large-scale production. As shown in Table 3, the content of polysulfonic acid increased slightly at a high temperature of 60°C, and the content of polysulfonic acid also increased slightly after being placed under high temperature conditions for 30 days; no significant changes were observed in the content of other impurities. Table 5 shows that the detection level of m-cresol increased significantly (exceeding the limit) after 10 days of storage at high temperature compared to other conditions. The detection levels of other impurities were: 60℃ > 40℃ > light exposure. After 30 days of storage at 60℃, due to changes in properties, the polymerization of impurities changed significantly. The contents of m-cresol-4-sulfonic acid, m-cresol-4,6-disulfonic acid, and bis(cresol)sulfonic acid decreased compared to 10 days, while m-cresol-6-sulfonic acid and polysulfonic acid increased, resulting in a sharp increase in the detection level of m-cresol. Under high temperature conditions of 40℃, the related substance m-cresol-6-sulfonic acid... The levels of m-cresol and biscresol sulfonic acid increased significantly, indicating that high temperature conditions would increase their levels. Compared with the 10-day samples under the same conditions, the levels of polysulfonic acid and m-cresol in the 30-day samples at 40℃ and 60℃ were slightly higher. As shown in Table 6, the peak at 60℃ interfered with the elution of m-cresol-4-sulfonic acid, resulting in a lower detection level than at 40℃. Compared with the results at 40℃ and under light, m-cresol-4-sulfonic acid showed an increasing trend. The detection levels of m-cresol, biscresol sulfonic acid, and polysulfonic acid were 60℃ > 40℃ > under light, indicating an increase.

[0137] Experiment Example 2: Investigation of Canaan Refueling Usage

[0138] 2.1 Canan oil can effectively reduce the irritation of polycresolsulfonate. Different amounts of canan oil may affect the stability of the product. Therefore, the preparation method of Example 3 was used to prepare products with different amounts of canan oil to investigate the influencing factors.

[0139] The samples were placed at 40℃ and 60℃ under 4500Lux±500Lux of light for 10 days and 30 days, respectively, to investigate the effect of different amounts of Kanan oil added on the product. The results are as follows:

[0140] 2.2 Sample Setup

[0141] Table 9 Samples under investigation

[0142] Serial number Kananga oil amount investigation % (w / w) Sample 1 0.1％ Sample 2 1.0％ Sample 3 1.2％ Sample 4 1.5％ Sample 5 2.0％ Sample 6 2.5％ Sample 7 5.0％％

[0143] 2.3 Observation Results

[0144] The results of the dosage study are shown in Tables 10-16:

[0145] Table 10 Results of the investigation of Sample 1

[0146]

[0147] Table 11 Results of the investigation of Sample 2

[0148]

[0149]

[0150] Note: The sample stored at 60℃ for 30 days was not properly sealed, which caused solvent evaporation and affected the sample test results.

[0151] Table 12 Results of the investigation of sample 3

[0152]

[0153] Table 13 Results of the investigation of sample 4

[0154]

[0155]

[0156] Table 14 Results of the investigation of sample 5

[0157]

[0158] Table 15 Results of the investigation of sample 6

[0159]

[0160]

[0161] Table 16 Results of the investigation of sample 7

[0162]

[0163] Conclusion: Samples prepared with 1.0%, 1.2%, 1.5%, 2.0%, and 2.5% cananol oil addition all met the key quality attributes. The content of related substances in these samples did not change significantly under 40℃, 60℃, and light conditions; the properties did not change significantly under 40℃ and light conditions. Therefore, there was no significant difference in product quality and stability among samples prepared with cananol oil addition within the range of 1.0%-2.5%. However, it was found that when the cananol oil addition was 0.1% and 5.0%, the content of related substances increased, and an increase in impurities and a decrease in effective content were observed in the polycresolsulfonate rinsing solution, indicating that the optimal cananol oil addition range is 1.0%-2.5%.

[0164] Experiment Example 3: Investigation of the order of raw material addition

[0165] (1) Add the prescribed amount of canan oil to the prescribed amount of water. Stirring at 300 rpm at 60°C does not dissolve the oil. Therefore, the temperature is increased and heated to 90°C, but the oil still does not dissolve.

[0166] (2) Add the prescribed amount of canan oil to the prescribed amount of polycresolsulfonate and stir at 300 rpm for 10 minutes at 60°C until dissolved. After cooling to 24-27°C, add spironolactone, succinic anhydride and water in sequence. The test results showed that the amount of impurities increased.

[0167] (3) When the prescribed amounts of polycresolsulfonate, cananol oil, spironolactone, succinic anhydride and water were mixed at once, it was found that the amount of impurities increased and the content of the active ingredients did not meet the limit range.

[0168] (4) Add the prescribed amount of canan oil to the prescribed amount of polycresolsulfonate and stir at 300 rpm for 10 minutes at 60°C until dissolved. First add succinic anhydride and water, stir evenly and cool to 24-27°C before adding spironolactone. The test results showed that the content of the active ingredient did not meet the limit range.

[0169] (5) Add the prescribed amount of canan oil to the prescribed amount of polycresolsulfonate and stir at 300 rpm for 10 min at 60°C until dissolved. Add spironolactone and stir evenly. After cooling to 24-27°C, no solid precipitation occurs. Add succinic anhydride and water and find that the impurity content and active ingredient content are within the limit range.

[0170] Therefore, the proposed process is to add Kanan oil to polycresol sulfonate and stir at 300 rpm at 60°C until it is completely dissolved, add spironolactone, stir evenly, and cool to 24-27°C until no solid precipitation occurs. Then add succinic anhydride and water to obtain the polycresol sulfonate solution sample.

[0171] Experiment Example 4: Investigation of the Dissolution Temperature of Canaan Oil

[0172] 4.1 Dissolving Kanan oil requires heating the polycresolsulfonate raw material before dissolving it. Therefore, the heating temperature may affect the relevant substances, so the dissolution temperature of Kanan oil needs to be investigated.

[0173] 4.2 Using the raw materials and their contents as described in Example 3, the temperature settings are shown in the table below:

[0174] Table 17 Temperature Settings

[0175] Sample Kananga oil dissolution temperature (℃) Sample 8 55 Sample 9 60 Sample 10 65

[0176] Add Kanan oil to polycresolsulfonate and stir at 300 rpm at the temperature corresponding to Table 17 until dissolved. Record the dissolution time and investigate the effect of temperature on the quality of the product during the dissolution of Kanan oil.

[0177] 4.3 The results are shown in Table 18:

[0178] Table 18. Investigation of the dissolution temperature of Canaan oil.

[0179]

[0180] Conclusion: When the dissolution temperature of Kanan oil is within the range of 55℃ to 65℃, the related substances of the prepared samples show no significant differences and are no worse than the reference preparation, and are within the limit range. Therefore, the proposed dissolution temperature of Kanan oil is 60℃±5℃.

[0181] Experimental Example 5: Investigation of Heating Time for Polycresolsulfonate

[0182] 5.1 As production scales up, polycresolsulfonate may require longer heating times, which could lead to an increase in related costs. Therefore, we intend to investigate the heating time for polycresolsulfonate.

[0183] 5.2 Using the raw materials and their contents as described in Example 3, the heating time was set as shown in the table below:

[0184] Table 19 Heating Time Settings

[0185] Sample Heating time (min) Sample 11 30 Sample 12 60 Sample 13 90 Sample 14 120

[0186] Add kanan oil to polycresol sulfonate and stir at 300 rpm at 60°C until dissolved. Add spironolactone and stir until uniform. After cooling to 24-27°C, no solid precipitates. Then add succinic anhydride and water to obtain a polycresol sulfonate solution sample. Investigate the effect of different heating times on the quality of this product.

[0187] 5.3 The results of the investigation are shown in Table 20:

[0188] Table 20 Heating Time Examination

[0189]

[0190] Conclusion: The contents and related substances of the samples prepared by heating polycresolsulfonate for 30 min, 60 min, 90 min and 120 min were not significantly different, and were no worse than the reference preparation. Therefore, the heating time of polycresolsulfonate should not exceed 120 min.

[0191] Experiment Example 6: Finished Product Storage Time - An Investigation of 316 Stainless Steel

[0192] 6.1 The prepared polycresolsulfonate rinsing solution should be temporarily stored in a 316 stainless steel container, so the storage time in the 316 container needs to be investigated.

[0193] The polycresolsulfonate solution prepared in Example 3 was placed in a 316 stainless steel container and left for 0h, 4h, 8h, 12h, 48h, 72h, 96h, and 120h before being sent for content and related substance content testing. The effect of storing the solution in a 316 stainless steel container for a certain period of time on the quality of the product was investigated.

[0194] 6.2 The results are shown in Table 21:

[0195] Table 21. Investigation of Finished Product Storage Time

[0196]

[0197]

[0198] Conclusion: After the finished product was stored in a 316 stainless steel container for 4h, 8h, 12h, 48h, 72h, 96h, and 120h, there were no significant differences in the content and related substances compared with the 0h sample. Moreover, the quality of the samples at these time points was no worse than that of the reference preparation. Therefore, it is proposed that polycresolsulfonate can be stored in a 316 stainless steel container for a maximum of 120h.

[0199] Experiment 7: Investigation of Filter Membrane Adsorption and Compatibility

[0200] 7.1 This product is intended to be filtered using a filter membrane with a pore size of 0.45 μm. Therefore, the adsorption and compatibility of filter membranes made of different materials were investigated. The raw material composition, dosage, and some preparation methods of Example 3 were used (except for the filter membrane material, everything else was the same).

[0201] 7.2 Examination Methods

[0202] Membrane adsorption: The adsorption of this product was examined in the solution after filtering 2ml / 5ml / 8ml of drug solution through a 0.45μm pore size polyethersulfone / nylon / polytetrafluoroethylene membrane.

[0203] Membrane compatibility: Polyethersulfone / nylon / polytetrafluoroethylene filter membranes with a pore size of 0.45 μm were immersed in 20 ml of drug solution for 0.5 h and 1 h respectively, and then the relevant substances were tested to investigate the compatibility between the product and the filter membrane.

[0204] 7.3 The results of the investigation are shown in Tables 22 and 23:

[0205] Table 22 Results of membrane adsorption study

[0206]

[0207] Table 23 Filter Membrane Compatibility and Results

[0208]

[0209]

[0210] Conclusion: After soaking in 0.45μm pore size filter membranes made of polyethersulfone, nylon, and polytetrafluoroethylene for 1 hour, no significant change in impurity detection was observed, indicating good compatibility of the filter membranes within 1 hour. After discarding 2ml, 5ml, and 8ml of the initial filtrate from polyethersulfone, nylon, and polytetrafluoroethylene filter membranes, respectively, the active pharmaceutical ingredient content in the subsequent filtrates was basically the same as that in the unfiltered sample, indicating that the 0.45μm pore size filter membranes of polyethersulfone, nylon, and polytetrafluoroethylene did not adsorb this product. Therefore, polycresolsulfonate solution can be prepared using 0.45μm pore size polyethersulfone, nylon, and polytetrafluoroethylene filter membranes without discarding the filtrate.

[0211] Experimental Example 8: Packaging Material Investigation

[0212] 8.1 This product has low acidity. We plan to investigate different packaging materials to determine the final packaging material to be selected.

[0213] 8.2 The polycresolsulfonate rinsing solution prepared in Example 3 was tested at 40°C, 60°C, and under light conditions. The results for different packaging materials are shown in Table 24.

[0214] Table 24 Packaging Material

[0215] Sample Packaging material material Packaging material manufacturer Sample 15 Soda-lime glass Shandong Pharmaceutical Glass Sample 16 Medium borosilicate Shandong Lino Sample 17 Polyester Guizhou Qianye Sample 18 Polypropylene Shanghai Haichang

[0216] 8.3 Test Results

[0217] As shown in Tables 25 to 27:

[0218] Table 25 Test results of different packaging materials at 40℃

[0219]

[0220]

[0221] Table 26 Test results of different packaging materials at 60℃

[0222]

[0223] Table 27 Test results of different packaging materials under illumination conditions

[0224]

[0225]

[0226] Conclusion: Under 40℃ conditions, the content and related substances of self-prepared reagents packaged in different packaging materials did not change significantly; the properties of self-prepared reagents packaged in soda-lime glass packaging did not change significantly, while the self-prepared reagents packaged in borosilicate, polyester, and polypropylene packaging materials showed a darkening of color.

[0227] The content of the self-prepared reagents packaged in different packaging materials and the related substances, except for m-cresol, did not change significantly at 60℃, while m-cresol showed a slight increase with a low increase rate; the properties of the self-prepared reagents packaged in different packaging materials all changed at 60℃ (the color of the self-prepared reagents darkened).

[0228] Under light conditions, the properties, content, and related substances of the self-prepared reagent packaged in different packaging materials did not change significantly.

[0229] In summary, soda-lime glass packaging materials do not exhibit significant changes in properties under high-temperature conditions, and show less change in the properties of packaged products compared to other packaging materials. Therefore, soda-lime glass packaging materials are proposed as the choice for pharmaceutical packaging materials.

[0230] Experiment Example 9: Irritation of vaginal mucosa by polycresolsulfonate douche solution

[0231] 9.1 Experimental Objective

[0232] The study aimed to observe the local irritation of the vaginal mucosa in animals after repeated vaginal irrigation with polycresolsulfonate solution, providing experimental evidence for clinical drug use.

[0233] 9.2 Experimental Methods

[0234] Twenty-four healthy female SD rats (200-225g) were randomly divided into eight groups of three rats each, based on their body weight. The polycresolsulfonate irrigation solution group (Example 3, Comparative Examples 1-5) received the solution at a daily dose of 0.5g / kg, the reference preparation group (0.5g / kg), and the blank control group. The daily dose was administered in four divided doses, with vaginal irrigation every hour for four consecutive days to ensure sufficient contact between the drug and the vaginal mucosa. This administration was continued for seven days. The vaginal mucosa was visually inspected 24 hours after the last irrigation. The animals were sacrificed 48 hours after the last irrigation, and the vaginal mucosa was dissected for congestion and swelling, followed by histopathological examination.

[0235] The reaction of the vaginal mucosa was scored according to the irritation response evaluation criteria, and the irritation intensity of the polycresolsulfonate irritant was evaluated according to the irritation intensity grading criteria. The irritation response scoring criteria are shown in Table 28, and the irritation intensity grading criteria of the polycresolsulfonate irritant are shown in Table 29.

[0236] Table 28 Stimulus Response Scoring Criteria

[0237]

[0238] Table 29 Irritation Intensity Grading Standards for Polycresolsulfonate Rinse Solution

[0239] Integral mean Strength score 0～0.49 No irritation 0.5～1.99 Mild irritation 2.0～5.99 Moderate irritation 6.0～8.0 Strong irritation

[0240] 9.3 Stimulation Test Results

[0241] As shown in Table 30:

[0242] Table 30 Stimulation Tests

[0243]

[0244]

[0245] As shown in Table 30, the polycresolsulfonate rinsing solution of the present invention is non-irritating and safe to use when used to rinse the vaginal mucosa. Comparison of Example 3 with Comparative Examples 1-5 shows that the selection of raw materials and the preparation method are crucial to the success of this technical solution. The optimal effect can only be obtained by mixing materials in a specific order during preparation. Even if the rosmarinic acid solution is replaced with an aqueous citric acid solution, both being acidic solutions, the same technical effect cannot be achieved. Polycresolsulfonate can react with spironolactone, succinic anhydride, and canamyl, reducing the irritation to the vaginal mucosa caused by the presence of polycresolsulfonate in the rinsing solution. Comparison of Example 3 with the reference formulation group shows that the polycresolsulfonate rinsing solution prepared by the prior art has a certain degree of irritation to the vaginal mucosa, while the polycresolsulfonate rinsing solution prepared using this application is non-irritating.

[0246] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A low-irritation polyparaphenylene sulfide bisalanine (PMSB) irrigant, characterized in that, Each mL of the polyhexamethylene biguanide sulfonate flushing solution contains the following raw materials: polyhexamethylene biguanide sulfonate 70-150 mg, cananga oil 10-25 mg, spironolactone 7-12 mg, succinic anhydride 1-3 mg, and the rest is water.

2. A low-irritation polyparabenzoseptine lavage solution according to claim 1, characterized in that, Each mL of the polyhexamethylene biguanide sulfonate flushing solution contains the following raw materials: polyhexamethylene biguanide sulfonate 100 mg, cananga oil 15 mg, spironolactone 10 mg, succinic anhydride 2 mg, and the rest is water.

3. A low-irritation polyparabenzoseptine lavage solution according to claim 1, characterized in that, The preparation method of the cananga oil comprises the following steps: (1) Pretreatment: the flowers of Anoectochilus roxburghii are placed in a container, and a 0.1%-0.5% rosemary acid solution is added to the container, and the mixture is uniformly mixed, and the container is sealed; (2) High-pressure treatment: the sealed container is placed in an ultrahigh-pressure device for ultrahigh-pressure treatment, the pressure is 200-450 MPa, the pressure holding time is 10-20 min, and the temperature is 25-35 ℃; (3) Water vapor distillation treatment: after the ultrahigh-pressure treatment is completed, water vapor distillation is carried out at a temperature of 90-100 ℃ for 50-70 min, and the upper oil phase is collected, which is the cananga oil.

4. A low-irritation polyparabenzoseptine lavage solution according to claim 3, characterized in that, The weight ratio of the flowers of Anoectochilus roxburghii to the rosemary acid solution in step (1) is 1: (5-10).

5. The method of producing the low-irritation polyparaphenylene sulfide naphthalene rinse solution as claimed in any one of claims 1 to 4, characterized by, The method comprises the following steps: S1, pour the polyhexamethylene biguanide sulfonate into a container, heat to a temperature of 55-65 ℃ within 30-120 min, then add the cananga oil to form a mixture A; S2, quickly stir the mixture A for 8-15 min until it is clear, then add the spironolactone, stir uniformly to a temperature of 24-27 ℃, and form a mixture B; S3, add the succinic anhydride and water to the mixture B in sequence, stir for 10-20 min, then filter through a filter membrane, fill according to the specifications, seal, and terminal sterilization to obtain the polyhexamethylene biguanide sulfonate flushing solution.

6. The method for preparing the low-irritation polycresolsulfonate rinsing solution according to claim 5, characterized in that, The material of the container in step S1 is stainless steel 316.

7. The method of claim 5, wherein the low-irritation polyparaphenylene sulfide rinse solution is prepared by adding 0.1 to 0.3 parts by weight of sodium sulfite to 100 parts by weight of the polyparaphenylene sulfide solution. The stirring speed is 250-400 rpm.

8. The method of claim 5, wherein the low-irritation polyparaphenylene sulfide rinse solution is prepared by adding 0.1 to 0.3 parts by weight of sodium sulfite to 100 parts by weight of the polyparaphenylene sulfide solution. The material of the filter membrane in step S3 is one of polyether sulfone, nylon or polytetrafluoroethylene.

9. The method of claim 5, wherein the low-irritation polyparaphenylene sulfide rinse solution is prepared by adding 0.1 to 0.3 parts by weight of sodium sulfite to 100 parts by weight of the polyparaphenylene sulfide solution. The precision of the filter membrane in step S3 is 0.45 μm.

10. The method for preparing the low-irritation polycresolsulfonate rinsing solution according to claim 5, characterized in that, The material of the filling in step S3 is sodium-calcium glass.

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