Low-irritation policresulen flushing fluid and preparation method thereof

Abstract

The invention discloses a low-irritation policresulen flushing fluid 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 the policresulen to 55-65 DEG C, and then adding Kinan oil to form a mixture A; s2, quickly stirring the mixture A for 8-15 minutes until the mixture A is dissolved and clarified, then adding spironolactone, uniformly stirring, and cooling to 24-27 DEG C to form a mixture B; and S3, sequentially adding succinic anhydride and water into the mixture B, stirring for 10-20 minutes, filtering with a filter membrane, filling according to specifications, sealing, and carrying out terminal sterilization to obtain the policresulen flushing fluid. The prepared policresulen flushing fluid is good in clarity, low in irritation, high in stability, small in related substance increment, easy and convenient to operate and low in production cost.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical preparations, and in particular to a low-irritation polycresol sulfonaldehyde flushing solution and a preparation method thereof. Background Art

[0002] Polycresol sulfonate (C 15 H 16 O 8 S 2 (C 8 H 8 O 4 S) n ; n = 0-20) is a local hemostatic and antiseptic agent, which has a strong killing effect on a variety of pathogens, including Gram-negative bacteria, Gram-positive bacteria, fungi, mycoplasma, chlamydia, viruses, etc., and it selectively acts on the diseased tissue while maintaining the normal vaginal acid environment, promoting the recovery of the vaginal physiological internal environment, and has the effects of astringency, hemostasis and promotion of wound healing. It is mainly used in gynecology, surgery, dermatology, and otolaryngology clinically, and its advantage is that it does not damage normal tissues.

[0003] Polyphenol sulfonaldehyde is a reddish brown liquid, a strong acidic substance, and its functions are: ① Anti-bacterial, fungal and protozoan infection; ② Selectively act on necrotic tissue and columnar epithelium and denature them, but have no effect on normal squamous epithelium; ③ Play a hemostatic role by coagulating plasma proteins and significantly stimulating vasoconstriction. Polyphenol sulfonaldehyde has a broad spectrum of antibacterial effects, including Gram-positive bacteria, Gram-negative bacteria and certain fungi, and is particularly effective against Ghana, anaerobic bacteria and Trichomonas.

[0004] Currently, the commonly used polycresol sulfonaldehyde preparations in clinical practice are vaginal suppositories, solutions, and gels. The disadvantages of the polycresol sulfonaldehyde solution prepared by adding edetic acid in the prior art are that it has many impurities, is difficult to control related substances, has strong irritation, and is not conducive to large-scale production. Summary of the invention

[0005] In view of the above-mentioned defects of the prior art, the present invention provides a low-irritation polycresol sulfonaldehyde flushing solution and a preparation method thereof to solve the problems raised by the above-mentioned background technology.

[0006] In order to achieve the above object, the present invention provides the following technical solutions:

[0007] A low-irritation polycresol sulfonaldehyde flushing solution, each mL of the polycresol sulfonaldehyde flushing solution contains the following raw materials: 70-150 mg of polycresol sulfonaldehyde, 10-25 mg of canangaol, 7-12 mg of spironolactone, 1-3 mg of succinic anhydride, and the balance is water.

[0008] Preferably, a low-irritation policresulen irrigation solution contains the following raw materials per mL of the 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 cananga oil includes the following steps:

[0010] (1) Pretreatment: Load the flowers of Cananga odorata var. genuina (flowers of Cananga odorata Baill. f. forma macrophylla under the genus Cananga of the Annonaceae family) into a container, add a rosmarinic acid solution with a mass concentration of 0.1% - 0.5% to the container, mix evenly, and then seal the container;

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

[0012] (3) Steam distillation treatment: After the ultra-high pressure treatment, perform steam distillation at a temperature of 90 - 100 °C for 50 - 70 min, and collect the upper oil phase, which is the cananga oil.

[0013] Preferably, in step (1), the weight ratio of the flowers of Cananga odorata var. genuina to the rosmarinic acid solution is 1:(5 - 10).

[0014] Preferably, it includes the following steps:

[0015] S1. Pour policresulen into a container, heat it to a temperature of 55 - 65 °C within 30 - 120 min, and then add cananga oil to form mixture A;

[0016] S2. Rapidly stir mixture A for 8 - 15 min until it becomes clear, then add spironolactone, stir evenly, and cool down to a temperature of 24 - 27 °C to form mixture B;

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

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

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

[0020] Preferably, the material of the membrane filter in step S3 is one of polyethersulfone, 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 soda-lime glass, and the oral pharmaceutical polyolefin safety cap is used for sealing.

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

[0024] (1) The technical solution of the present invention is different from the prior art. Chelating agent edetic acid is not added during the preparation process. The present invention uses cananga oil, spironolactone and succinic anhydride to react with policresulen. Cananga oil can effectively reduce the irritation of policresulen. At the same time, succinic anhydride and spironolactone can accelerate the reaction rate of policresulen and cananga oil, improve the drug grafting amount, not only increase the effective drug content, but also help reduce the drug usage amount, and is also beneficial to the long-term storage of the drug.

[0025] (2) The prepared policresulen irrigation solution has good clarity, low irritation, high stability, less impurity increment, and is easy to operate with low production cost. And during the preparation process, the addition amount of cananga oil is controlled within a specific range, the content of related substances is controlled, and combined with a specific preparation sequence, the prepared policresulen irrigation solution has good stability. Specific Embodiments

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

[0027] 1. Reference Preparation

[0028]

[0029]

[0030] According to the "Procedures for the Selection and Determination of Reference Preparations for Chemical Generic Drugs" and the announcements of the reference preparation catalog for generic drugs (the 37th and 54th batches), Albothyl (Aibao Liao) produced by Takeda GmbH and originally imported into China is selected as the reference preparation, with a specification of 36% (w / w), stored in the dark, and the validity period is 60 months.

[0031] Microbial Limit Test Method: General Rules 1105 and 1106 in the Fourth Part of ChP 2020 Edition, Test Limit: Total number of molds and yeasts ≤ 10 1 cfu / ml; Total number of aerobic bacteria ≤ 10 2 cfu / ml; Escherichia coli shall not be detected / ml; Staphylococcus aureus shall not be detected / ml; Pseudomonas aeruginosa shall not be detected / ml; Candida albicans shall not be detected / ml.

[0032] Assay method: General Chapter 0701, Volume IV, Chinese Pharmacopoeia 2020 Edition; Assay limit: 95.0% - 105.0%.

[0033] Example 1

[0034] A low - irritation policresulen irrigation solution, each mL of which contains the following raw materials: 150 mg of policresulen, 25 mg of cananga oil, 12 mg of spironolactone, 3 mg of succinic anhydride, and the balance is water.

[0035] The preparation method of the cananga oil includes the following steps:

[0036] (1) Pretreatment: Load the large - leaf ylang - ylang flower into a container, add a 0.5% rosmarinic acid solution by mass concentration to the container, mix evenly, and then seal the container; the weight ratio of the large - leaf ylang - ylang flower to the rosmarinic acid solution is 1:10;

[0037] (2) High - pressure treatment: Place the sealed container in a high - pressure equipment for ultra - high - pressure treatment, with a pressure of 450 MPa, a pressure - holding time of 20 min, and a temperature of 35 °C;

[0038] (3) Steam distillation treatment: After the ultra - high - pressure treatment, carry out steam distillation at a temperature of 100 °C for 70 min, and collect the upper - layer oil phase, which is the cananga oil.

[0039] A preparation method of a low - irritation policresulen irrigation solution includes the following steps:

[0040] S1. Pour policresulen into a 316 stainless - steel container, heat it to a temperature of 65 °C within 120 min, and then add cananga oil to form mixture A;

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

[0042] S3. Add succinic anhydride and water to mixture B in sequence, stir for 20 min, then filter with a 0.45 - μm polyethersulfone membrane filter, fill it into soda - lime glass bottles according to specifications, seal and perform terminal sterilization to obtain the policresulen irrigation solution; the stirring speed is 400 rpm.

[0043] Example 2

[0044] A low - irritation policresulen irrigation solution, each mL of which contains the following raw materials: 70 mg of policresulen, 10 mg of cananga oil, 7 mg of spironolactone, 1 mg of succinic anhydride, and the balance is water.

[0045] The preparation method of the cananga oil includes the following steps:

[0046] (1) Pretreatment: Place the large-leafed ylang-ylang flowers in a container, add a rosmarinic acid solution with a mass concentration of 0.1% to the container, mix evenly, and then seal the container; the weight ratio of the large-leafed ylang-ylang flowers to the rosmarinic acid solution is 1:5.

[0047] (2) High-pressure treatment: Place the sealed container in a high-pressure equipment for ultra-high pressure treatment, with a pressure of 200 MPa, a pressure-holding time of 10 min, and a temperature of 25 °C.

[0048] (3) Steam distillation treatment: After the ultra-high pressure treatment, perform steam distillation at a temperature of 90 °C for 50 min, and collect the upper oil phase, which is cananga oil.

[0049] A preparation method of a low-irritation policresulen irrigation solution, comprising the following steps:

[0050] S1. Pour policresulen into a 316 stainless steel container, heat it to a temperature of 55 °C within 30 min, and then add cananga oil to form a mixture A.

[0051] S2. Rapidly stir the mixture A for 8 min until it becomes clear, then add spironolactone, stir evenly, and cool down to a temperature of 24 °C to form a mixture B; the stirring speed is 250 rpm.

[0052] S3. Sequentially add succinic anhydride and water to the mixture B, stir for 10 min, filter with a 0.45 μm nylon filter membrane, fill it into a soda-lime glass bottle according to the specification, seal it, and perform terminal sterilization to obtain the policresulen irrigation solution; the stirring speed is 250 rpm.

[0053] Example 3

[0054] A low-irritation policresulen irrigation solution, each mL of which contains the following raw materials: 100 mg of policresulen, 15 mg of cananga oil, 10 mg of spironolactone, 2 mg of succinic anhydride, and the balance is water.

[0055] The preparation method of the cananga oil comprises the following steps:

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

[0057] (2) High-pressure treatment: Place the sealed container in a high-pressure equipment for ultra-high pressure treatment, with a pressure of 300 MPa, a pressure-holding time of 15 min, and a temperature of 30 °C.

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

[0059] A preparation method of a low-irritation policresulen irrigation solution, comprising the following steps:

[0060] S1. Pour policresulen into a 316 stainless steel container, heat it to a temperature of 60 °C within 100 min, and then add cananga oil to form a mixture A;

[0061] S2. Rapidly stir the mixture A for 10 min until it becomes clear, then add spironolactone, stir evenly and cool down to a temperature of 25 °C to form a mixture B; the stirring speed is 300 rpm;

[0062] S3. Sequentially add succinic anhydride and water to the mixture B, stir for 15 min, then filter with a 0.45 μm polytetrafluoroethylene filter membrane, fill it into soda-lime glass bottles according to specifications, seal and perform terminal sterilization to obtain the policresulen irrigation solution; the stirring speed is 300 rpm.

[0063] Comparative Example 1

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

[0065] A low-irritation policresulen irrigation solution, each mL of the policresulen irrigation solution contains the following raw materials: 100 mg of policresulen, 15 mg of cananga oil, 10 mg of spironolactone, 2 mg of succinic anhydride, and the balance is water.

[0066] The preparation method of the cananga oil comprises the following steps:

[0067] (1) Pretreatment: Load the cananga odorata flowers into a container, add a citric acid aqueous solution with a mass concentration of 0.3% to the container, mix evenly, and then seal the container; the weight ratio of the cananga odorata flowers to the citric acid aqueous solution is 1:8;

[0068] (2) High-pressure treatment: Place the sealed container in an ultra-high pressure device for ultra-high pressure treatment, with a pressure of 300 MPa, a pressure holding time of 15 min, and a temperature of 30 °C;

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

[0070] A preparation method of a low-irritation policresulen irrigation solution, comprising the following steps:

[0071] S1. Pour policresulen into a 316 stainless steel container, heat it to 60°C within 100 min, and then add cananga oil to form mixture A;

[0072] S2. Stir mixture A rapidly for 10 min until it becomes clear, then add spironolactone, stir evenly and cool down 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 and then filter with a 0.45 μm polytetrafluoroethylene filter membrane, fill it into soda-lime glass bottles according to specifications, seal and perform terminal sterilization to obtain the policresulen irrigation solution; the stirring speed is 300 rpm.

[0074] Comparative Example 2

[0075] The difference between this comparative example and Example 3 is that: cananga oil is not added in the raw materials, and the other components and steps remain unchanged.

[0076] A low-irritation policresulen irrigation solution, each mL of which contains the following raw materials: 100 mg of policresulen, 10 mg of spironolactone, 2 mg of succinic anhydride, and the balance is water.

[0077] A preparation method of a low-irritation policresulen irrigation solution, comprising the following steps:

[0078] S1. Pour policresulen into a 316 stainless steel container, heat it to 60°C within 100 min; then add spironolactone, stir evenly and cool down 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 and then filter with a 0.45 μm polytetrafluoroethylene filter membrane, fill it into soda-lime glass bottles according to specifications, seal and perform terminal sterilization to obtain the policresulen irrigation 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 in the raw materials, and the other components and steps remain unchanged.

[0082] A low-irritation policresulen irrigation solution, each mL of which contains the following raw materials: 100 mg of policresulen, 15 mg of cananga oil, 2 mg of succinic anhydride, and the balance is water.

[0083] The preparation method of the cananga oil comprises the following steps:

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

[0085] (2) High-pressure treatment: Place the sealed container in a high-pressure device for ultra-high pressure treatment, with a pressure of 300 MPa, a pressure-holding time of 15 min, and a temperature of 30 °C;

[0086] (3) Steam distillation treatment: After the ultra-high pressure treatment, perform steam distillation at a temperature of 98 °C for 60 min, and collect the upper oil phase, which is cananga oil.

[0087] A preparation method of a low-irritation policresulen irrigation solution, comprising the following steps:

[0088] S1. Pour policresulen into a 316 stainless steel container, heat it to a temperature of 60 °C within 100 min, and then add cananga oil to form mixture A;

[0089] S2. Rapidly stir mixture A for 10 min until it becomes clear, and then cool it to a temperature of 25 °C; the stirring speed is 300 rpm;

[0090] S3. Sequentially add succinic anhydride and water to mixture A obtained in step S2, stir for 15 min, filter with a 0.45 μm polytetrafluoroethylene filter membrane, fill it into soda-lime glass bottles according to specifications, seal, and perform terminal sterilization to obtain the policresulen irrigation solution; the stirring speed is 300 rpm.

[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, and the other components and steps remain unchanged.

[0093] A low-irritation policresulen irrigation solution, wherein each mL of the policresulen irrigation solution contains the following raw materials: 100 mg of policresulen, 15 mg of cananga oil, 10 mg of spironolactone, and the balance is water.

[0094] The preparation method of the cananga oil comprises the following steps:

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

[0096] (2) High-pressure treatment: Place the sealed container in a high-pressure device for ultra-high pressure treatment, with a pressure of 300 MPa, a pressure-holding time of 15 min, and a temperature of 30 °C;

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

[0098] A preparation method of a low-irritation policresulen irrigation solution, comprising the following steps:

[0099] S1. Pour policresulen into a 316 stainless steel container, heat it to a temperature of 60 °C within 100 min, and then add cananga oil to form mixture A;

[0100] S2. Rapidly stir mixture A for 10 min until it becomes clear, then add spironolactone, stir evenly and cool down to a temperature of 25 °C to form mixture B; the stirring speed is 300 rpm;

[0101] S3. Add water to mixture B, stir for 15 min, then filter with a 0.45 μm polytetrafluoroethylene filter membrane, fill it into soda-lime glass bottles according to specifications, seal and perform terminal sterilization to obtain the policresulen irrigation 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 policresulen irrigation solution becomes one-time mixing, and the other components and steps remain unchanged.

[0104] A low-irritation policresulen irrigation solution, each mL of the policresulen irrigation solution contains the following raw materials: 100 mg of policresulen, 15 mg of cananga oil, 10 mg of spironolactone, 2 mg of succinic anhydride, and the balance is water.

[0105] The preparation method of the cananga oil comprises the following steps:

[0106] (1) Pretreatment: Load large-leaf ylang-ylang flowers into a container, add a 0.3% rosmarinic acid solution by mass concentration to the container, mix evenly, and then seal the container; the weight ratio of the large-leaf ylang-ylang flowers to the rosmarinic acid solution is 1:8;

[0107] (2) High-pressure treatment: Place the sealed container in an ultra-high pressure device for ultra-high pressure treatment, with a pressure of 300 MPa, a pressure holding time of 15 min, and a temperature of 30 °C;

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

[0109] A preparation method of a low-irritation policresulen irrigation solution, comprising the following steps:

[0110] Pour the prescribed amounts of policresulen, cananga oil, spironolactone, succinic anhydride and water into a 316 stainless steel container, heat to a temperature of 60 °C within 100 min, stir evenly and then cool to a temperature of 25 °C. The stirring speed is 300 rpm. Then filter with a 0.45 μm polytetrafluoroethylene filter membrane, fill into soda-lime glass bottles according to specifications, seal and perform terminal sterilization to obtain policresulen irrigation solution.

[0111] Experimental Example 1

[0112] 1.1 Take the policresulen irrigation solutions prepared in Examples 1 to 3, use the reference preparation as the control group, refer to the "Basic Technical Guidelines for the Research of Chemical Pharmaceutical Preparations", and test indexes such as the content of related substances according to the experimental methods of influencing factors in the drug stability guidelines.

[0113] 1.2 Take the policresulen irrigation solutions prepared in Example 3 and Comparative Examples 1 to 5, place them respectively under the conditions of strong light (4500 ± 500 Lux) and high temperature (40 °C, 60 °C), sample on the 10th day and the 30th day respectively, and detect related substances and investigate stability indexes such as changes in properties.

[0114] 1.3 Test results

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

[0116] Table 1 Sample test

[0117]

[0118] As can be seen from Table 1, the policresulen irrigation solutions prepared in Examples 1 to 3 and the reference preparation are all within the limit range in the sample test at 0 d, all are qualified, and the content of the policresulen irrigation solutions prepared in Examples 1 to 3 is 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 preparation

[0123]

[0124] Table 4 Stability test results of Comparative Example 1

[0125]

[0126] Table 5 Stability test results of Comparative Example 2

[0127]

[0128]

[0129] Table 6 Stability test results of Comparative Example 3

[0130]

[0131] Table 7 Stability test results of Comparative Example 4

[0132]

[0133]

[0134] Table 8 Stability test results of Comparative Example 5

[0135]

[0136] As can be seen from Tables 2 to 8, the policresulen irrigation solution prepared by using the components and preparation method of Example 3 has few impurities, indicating that in the preparation process of the policresulen irrigation solution, if a certain component is missing or the cananga oil is not prepared according to this technical solution, it will cause a high impurity content in the finally prepared product, which is not conducive to large-scale production in the future. As can be seen from Table 3, the polysulfonic acid slightly increases at 60°C, and the content slightly increases after being placed at high temperature for 30 days; no obvious changes are seen in the results of the remaining relevant impurities and content. As can be seen from Table 5, the detected amount of m-cresol increases significantly (exceeding the limit) after being placed at high temperature for 10 days compared with other conditions, and the detected amounts of the remaining impurities are 60°C > 40°C > light; after being placed at 60°C for 30 days, due to the change in properties, the impurity polymerization situation changes significantly, the contents of m-cresol-4-sulfonic acid, m-cresol-4,6-disulfonic acid, and dimesulfenic acid decrease compared with those after 10 days, the contents of m-cresol-6-sulfonic acid and polysulfonic acid increase, and the detected amount of m-cresol increases sharply; under the high temperature condition of 40°C, the relevant substances m-cresol-6-sulfonic acid, m-cresol, and dimesulfenic acid increase significantly, indicating that the high temperature condition will increase it. Compared with the 10-day samples under the same conditions, the polysulfonic acid and m-cresol in the 40°C and 60°C 30-day samples both increase slightly. As can be seen from Table 6, there is a peak interference at 60°C that affects the peak emergence of m-cresol-4-sulfonic acid, resulting in a lower detected amount compared with 40°C. Compared with the results of 40°C and light, the m-cresol-4-sulfonic acid shows an increasing trend, and the detected amounts of m-cresol, dimesulfenic acid, and polysulfonic acid are 60°C > 40°C > light, showing an increase.

[0137] Experimental Example 2 Investigation of the dosage of cananga oil

[0138] 2.1 Cananga oil can effectively reduce the irritation of policresulen, and its different addition amounts may affect the stability of the product. Therefore, the products with different cananga oil dosages were prepared by using the preparation method of Example 3 for the investigation of influencing factors.

[0139] The samples were placed at 40°C, 60°C, and under light of 4500 Lux ± 500 Lux for 10 days and 30 days to investigate the effects of different addition amounts of cananga oil on this product. The results are as follows:

[0140] 2.2 Investigation sample settings

[0141] Table 9 Investigation samples

[0142] Serial number Investigation of the dosage of cananga oil % (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 Investigation results

[0144] The investigation results of the dosages are shown in Tables 10 - 16 as follows:

[0145] Table 10 Investigation results of Sample 1

[0146]

[0147] Table 11 Investigation results of Sample 2

[0148]

[0149]

[0150] Note * The samples at 60°C for 30 days were not tightly covered, resulting in solvent evaporation of the corresponding samples and affecting the sample test results

[0151] Table 12 Investigation results of Sample 3

[0152]

[0153] Table 13 Investigation results of Sample 4

[0154]

[0155]

[0156] Table 14 Investigation results of Sample 5

[0157]

[0158] Table 15 Investigation results of Sample 6

[0159]

[0160]

[0161] Table 16 Investigation results of Sample 7

[0162]

[0163] Conclusion: The key quality attributes of the samples prepared with 1.0%, 1.2%, 1.5%, 2.0% and 2.5% of cananga oil addition are all qualified. For the samples prepared, the related substances in content do not show significant changes under the conditions of 40°C and 60°C and light; there are no obvious changes in appearance under the conditions of 40°C and light. Therefore, there are no obvious differences in the product quality and stability of the samples prepared with cananga oil addition in the range of 1.0% - 2.5%. However, it is found that when the cananga oil addition is 0.1% and 5.0%, the content of related substances increases, impurities are found to increase in the polymetacresolsulfonic acid irrigation solution, and the effective content decreases, indicating that the most suitable range of cananga oil addition is 1.0% - 2.5%.

[0164] Experimental Example 3 Investigation on the Order of Raw Material Addition

[0165] (1) Adding the prescribed amount of cananga oil to the prescribed amount of water and stirring at 300 rpm at 60°C could not achieve a clear solution, so the temperature was increased, and heating to 90°C still could not achieve a clear solution.

[0166] (2) Adding the prescribed amount of cananga oil to the prescribed amount of polymetacresolsulfonic acid and stirring at 300 rpm at 60°C for 10 min to achieve a clear solution. After cooling to 24 - 27°C, spironolactone, succinic anhydride and water were added in sequence, and it was found through detection that the impurities increased.

[0167] (3) Mixing the prescribed amount of polymetacresolsulfonic acid, cananga oil, spironolactone, succinic anhydride and water at one time, and it was found through detection that the impurities increased and the content of the active ingredient did not meet the limit range.

[0168] (4) Adding the prescribed amount of cananga oil to the prescribed amount of polymetacresolsulfonic acid and stirring at 300 rpm at 60°C for 10 min to achieve a clear solution. First, succinic anhydride and water were added and stirred evenly. After cooling to 24 - 27°C, spironolactone was added, and it was found through detection that the content of the active ingredient did not meet the limit range.

[0169] (5) Adding the prescribed amount of cananga oil to the prescribed amount of polymetacresolsulfonic acid and stirring at 300 rpm at 60°C for 10 min to achieve a clear solution. Spironolactone was added and stirred evenly. After cooling to 24 - 27°C, no solid was precipitated. Then, succinic anhydride and water were added, and it was found that both the impurity content and the active ingredient content were within the limit range.

[0170] Therefore, the proposed process is to add cananga oil to polymetacresolsulfonic acid, stir at 300 rpm at 60°C until a clear solution is achieved, add spironolactone, stir evenly, and after cooling to 24 - 27°C with no solid precipitated, then add succinic anhydride and water to obtain the sample of polymetacresolsulfonic acid solution.

[0171] Experimental Example 4 Investigation on the Dissolution Temperature of Cananga Oil

[0172] 4.1 The dissolution of Cananjiayou requires heating the polymetacresolsulfonic acid raw material before dissolution. Therefore, the heating temperature may affect the related substances. Thus, it is necessary to investigate the dissolution temperature of Cananjiayou.

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

[0174] Table 17 Temperature Settings

[0175] Sample Dissolution temperature of cananga oil (℃) Sample 8 55 Sample 9 60 Sample 10 65

[0176] Add Cananjiayou to polymetacresolsulfonic acid, stir at 300 rpm at the corresponding temperature in Table 17 until it is completely dissolved and clear, record the dissolution time, and investigate the effect of temperature during the dissolution of Cananjiayou on the quality of this product.

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

[0178] Table 18 Investigation of the Dissolution Temperature of Cananjiayou

[0179]

[0180] Conclusion: When the dissolution temperature of Cananjiayou is within the range of 55°C to 65°C, the related substances of the prepared samples have no obvious differences and are not worse than the reference preparation, and are within the limit range. Therefore, the dissolution temperature of Cananjiayou is determined to be 60°C ± 5°C.

[0181] Experimental Example 5 Investigation of the Heating Time of Polymetacresolsulfonic Acid

[0182] 5.1 As the production batch size increases, polymetacresolsulfonic acid may require a longer heating time, and a longer heating time may lead to an increase in related substances. Therefore, it is proposed to investigate the heating time of polymetacresolsulfonic acid.

[0183] 5.2 Using the raw materials and their contents in Example 3, the heating time settings are as shown in the following table:

[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 Cananjiayou to polymetacresolsulfonic acid, stir at 300 rpm at 60°C until it is completely dissolved and clear, add spironolactone, stir evenly, cool to 24 - 27°C without solid precipitation, and then add succinic anhydride and water to obtain a sample of polymetacresolsulfonic acid solution, and investigate the effect of different heating durations on the quality of this product.

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

[0188] Table 20 Investigation of Heating Time

[0189]

[0190] Conclusion: There were no significant differences in the content and related substances of the samples prepared with policresulen heated for 30 min, 60 min, 90 min, and 120 min respectively, and they were not inferior to the reference preparation. Therefore, it was proposed that the heating time of policresulen should not exceed 120 min.

[0191] Experimental Example 6 Investigation of the storage time of the finished product in 316 stainless steel

[0192] 6.1 After the finished product of the policresulen irrigation solution was prepared, it needed to be temporarily stored in a 316 stainless steel container. Therefore, it was necessary to investigate the storage time limit in a 316 stainless steel container.

[0193] The policresulen solution prepared in Example 3 was placed in a 316 stainless steel container and sent for inspection of the content and related substance content after being stored for 0 h, 4 h, 8 h, 12 h, 48 h, 72 h, 96 h, and 120 h. The influence of storing the medicinal liquid of this product in a 316 stainless steel container for a certain period of time on the quality of this product was investigated.

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

[0195] Table 21 Investigation of the storage time of the finished product

[0196]

[0197]

[0198] Conclusion: After the finished product was stored in a 316 stainless steel container for 4 h, 8 h, 12 h, 48 h, 72 h, 96 h, and 120 h, there were no significant differences in the content and related substances compared with the sample at 0 h, and the quality of the samples at these time points was not inferior to the reference preparation. Therefore, it was proposed that policresulen could be stored in a 316 stainless steel container for up to 120 h.

[0199] Experimental Example 7 Investigation of filter membrane adsorption and compatibility

[0200] 7.1 This product was intended to be filtered using a filter membrane with a pore size of 0.45 μm. Therefore, the filter membrane adsorption and filter membrane compatibility of filter membranes made of different materials were investigated. The raw material components, dosages, and partial preparation methods of Example 3 were used (except that the filter membrane materials were different and others were the same).

[0201] 7.2 Investigation method

[0202] Filter membrane adsorption: The adsorption of the medicinal liquid on the content of this product was investigated after filtering 2 ml / 5 ml / 8 ml of the medicinal liquid through a polyethersulfone / nylon / polytetrafluoroethylene filter membrane with a pore size of 0.45 μm.

[0203] Membrane Compatibility: Polyethersulfone / nylon / polytetrafluoroethylene membranes with a pore size of 0.45 μm were placed in 20 ml of the medicinal solution and soaked for 0.5 h and 1 h respectively, and then the related substances were detected to investigate the compatibility of this product with the membranes.

[0204] 7.3 The investigation results are shown in Tables 22 - 23:

[0205] Table 22 Investigation Results of Membrane Adsorption

[0206]

[0207] Table 23 Investigation Results of Membrane Compatibility

[0208]

[0209]

[0210] Conclusion: When the 0.45 μm pore size membranes made of polyethersulfone, nylon, and polytetrafluoroethylene are soaked for 1 h, there is no obvious change in the detection of impurities, indicating that the compatibility of the membranes is good within 1 h. After discarding 2 ml, 5 ml, and 8 ml of the initial filtrate through the polyethersulfone, nylon, and polytetrafluoroethylene membranes respectively, the main drug content of the subsequent filtrate is basically the same as that of the unfiltered sample, indicating that the 0.45 μm pore size membranes made of polyethersulfone, nylon, and polytetrafluoroethylene have no adsorption on this product. Therefore, the policresulen solution can use polyethersulfone, nylon, and polytetrafluoroethylene materials with a pore size of 0.45 μm without discarding the filtrate.

[0211] Experimental Example 8 Investigation of Packaging Materials

[0212] 8.1 Since this product has a relatively low acidity, different packaging materials will be investigated to determine the final selected packaging material.

[0213] 8.2 Using the policresulen flushing solution prepared in Example 3, tests were carried out respectively under the conditions of 40 °C, 60 °C, and light, and different packaging materials are shown in Table 24:

[0214] Table 24 Packaging Materials

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

[0216] 8.3 Test Results

[0217] As shown in Tables 25 - 27:

[0218] Table 25 Test Results of Different Packaging Materials at 40 °C

[0219]

[0220]

[0221] Table 26 Test Results of Different Packaging Materials at 60°C

[0222]

[0223] Table 27 Test Results of Different Packaging Materials under Light Conditions

[0224]

[0225]

[0226] Conclusion: Under the condition of 40°C, the content and related substances of the self-developed preparation packaged in different packaging materials did not change significantly; the appearance of the self-developed preparation packaged in soda-lime glass packaging material did not change significantly, while the self-developed preparation packaged in medium-borosilicate, polyester, and polypropylene packaging materials showed a darker color.

[0227] For the self-developed preparation packaged in different packaging materials under the condition of 60°C, the content and related substances except m-cresol did not change significantly, and m-cresol increased slightly with a low growth rate; under the condition of 60°C, the appearance of the self-developed preparation packaged in different packaging materials changed (the color of the self-developed preparation became darker).

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

[0229] In summary, the properties of soda-lime glass packaging material did not change significantly under high-temperature conditions, and the appearance change of the packaged product was smaller compared with other packaging materials. Therefore, soda-lime glass packaging material is proposed to be selected as the packaging material for the preparation.

[0230] Experimental Example 9 Irritation Test of Povidone-Iodine Gargle on Vaginal Mucosa

[0231] 9.1 Experimental Purpose

[0232] To observe the local irritant reaction of povidone-iodine gargle on the vaginal mucosa of animals after multiple vaginal douches, and to provide experimental basis for clinical medication.

[0233] 9.2 Experimental Method

[0234] Take 24 healthy female SD rats (200 - 225 g), randomly divide them into 8 groups according to body weight, with 3 rats in each group. The daily dosage of the povidone-iodine gargle group (Example 3, Comparative Examples 1 - 5) is 0.5 g / kg, the reference preparation group (0.5 g / kg), and the blank control group. The daily dosage is evenly divided into 4 times and given once every 1 h by vaginal douche for 4 consecutive times to ensure sufficient contact between the drug and the vaginal mucosa. Administer the drug continuously for 7 days in this way. Observe the vaginal mucosa visually 24 h after the last vaginal douche, sacrifice the animals 48 h after the last vaginal douche, dissect the vaginal mucosa, observe for congestion and swelling, and conduct histological examination.

[0235] The reaction at the vaginal mucosa site was scored with reference to the stimulus-response evaluation criteria, and the irritation intensity of the policresulen irrigation solution was evaluated with reference to the stimulus intensity grading criteria. The stimulus-response scoring criteria are shown in Table 28, and the stimulus intensity grading criteria for the policresulen irrigation solution are shown in Table 29;

[0236] Table 28 Stimulus-response scoring criteria

[0237]

[0238] Table 29 Stimulus intensity grading criteria for the policresulen irrigation solution

[0239] Integral mean value Strength score 0～0.49 Non-irritating 0.5～1.99 Mildly irritating 2.0～5.99 Moderately irritating 6.0～8.0 Strongly irritating

[0240] 9.3 Results of irritation test

[0241] As shown in Table 30:

[0242] Table 30 Irritation test

[0243]

[0244]

[0245] As can be seen from Table 30, the policresulen irrigation solution of the present invention is non-irritating when used to irrigate the vaginal mucosa and is safe to use. By comparing Example 3 with Comparative Examples 1-5, it can be seen that the selection of raw and auxiliary materials and the preparation method of the present technical solution are very important. The best effect can be obtained only by mixing in a certain order during preparation. Even if the rosmarinic acid solution is replaced with a citric acid aqueous solution, which is also an acidic solution, the same technical effect cannot be achieved. Policresulen can react with spironolactone, succinic anhydride and cananga oil, reducing the irritation of the policresulen irrigation solution to the vaginal mucosa due to the presence of policresulen. By comparing Example 3 with the reference preparation group, it can be seen that the policresulen irrigation solution prepared by the prior art has certain irritation to the vaginal mucosa, while the policresulen irrigation solution prepared by the present application is non-irritating.

[0246] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A low-irritation polycresol sulfonate flushing solution, characterized in that: Each mL of polycresol sulfonaldehyde flushing solution contains the following raw materials: polycresol sulfonaldehyde 70-150 mg, canangaol 10-25 mg, spironolactone 7-12 mg, succinic anhydride 1-3 mg, and the balance is water.

2. A low-irritation polycresol sulfonate flushing solution according to claim 1, characterized in that: Each mL of polycresol sulfonaldehyde flushing solution contains the following raw materials: polycresol sulfonaldehyde 100 mg, canangaol 15 mg, spironolactone 10 mg, succinic anhydride 2 mg, and the balance is water.

3. A low-irritation polycresol sulfonate flushing solution according to claim 1, characterized in that: The preparation method of the cananga oil comprises the following steps: (1) Pretreatment: Place the large-leaf ylang-ylang flowers in a container, add a 0.1% to 0.5% rosmarinic acid solution into the container, mix well, and seal the container; (2) High-pressure treatment: Place the sealed container in an ultra-high-pressure device for ultra-high-pressure treatment at a pressure of 200 to 450 MPa, a holding time of 10 to 20 minutes, and a temperature of 25 to 35°C; (3) Steam distillation: After the ultrahigh pressure treatment, steam distillation is performed at a temperature of 90-100°C for 50-70 minutes, and the upper oil phase is collected, which is cananga oil.

4. A low-irritation polycresol sulfonate flushing solution according to claim 3, characterized in that: In step (1), the weight ratio of the Cananga ylang-ylang flower to the rosmarinic acid solution is 1:(5-10).

5. The method for preparing the low-irritation polycresol sulfonaldehyde flushing solution according to any one of claims 1 to 4, characterized in that: The following steps are involved: S1. Pour polycresol sulfonaldehyde into a container, heat it to a temperature of 55-65° C. within 30-120 min, and then add cananga oil to form a mixture A; S2, rapidly stirring mixture A for 8 to 15 minutes until dissolved, then adding spironolactone, stirring evenly and cooling the temperature to 24 to 27° C., to form mixture B; S3. Add succinic anhydride and water to mixture B in sequence, stir for 10 to 20 minutes, filter through a membrane, fill, seal and terminally sterilize according to specifications to obtain the polycresol sulfonaldehyde flushing solution.

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

7. The method for preparing the low-irritation polycresol sulfonaldehyde flushing solution according to claim 5, characterized in that: The stirring speed is 250-400 rpm.

8. The method for preparing the low-irritation polycresol sulfonaldehyde flushing solution according to claim 5, characterized in that: The material of the filter membrane in step S3 is one of polyethersulfone, nylon or polytetrafluoroethylene.

9. The method for preparing the low-irritation polycresol sulfonaldehyde flushing solution according to claim 5, characterized in that: The accuracy of the filter membrane in step S3 is 0.45 μm.

10. The method for preparing the low-irritation polycresol sulfonaldehyde flushing solution according to claim 5, characterized in that: The filling material in step S3 is soda-lime glass.

Images