Ear canal disinfectant containing isopropanol and preparation method thereof

Abstract

The invention discloses an ear canal disinfectant containing isopropanol and a preparation method of the ear canal disinfectant. The ear canal disinfectant comprises isopropanol, octenidine and a guanidyl-containing antibacterial polymer. The auditory meatus disinfectant disclosed by the invention has a good inhibition effect on Gram negative and positive bacteria such as candida albicans, staphylococcus aureus, escherichia coli and the like, and can effectively relieve and treat diseases such as auditory meatus itching and the like.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations or disinfectants, and particularly relates to an ear canal disinfectant containing isopropyl alcohol and a preparation method thereof. Background Art

[0002] Common pathogens of otitis externa include bacteria and fungi. Bacterial infections are mainly Gram-positive (such as Staphylococcus aureus) or Gram-negative (such as Escherichia coli), while fungal infections are more common with Aspergillus or Candida.

[0003] Otitis externa clinically presents with itching, pain, and exudate when accompanied by inflammation and infection. This not only reduces the patient's quality of life but also poses a health threat. However, there are currently few treatments for bacterial and fungal otitis externa. Therefore, there is a need to provide patients with more drug treatment options. Summary of the Invention

[0004] The present invention discloses an ear canal disinfectant with isopropyl alcohol as the main active ingredient. The synergistic effect of octenidine, a guanidine-containing antibacterial polymer and isopropyl alcohol improves the ability to inhibit bacteria and fungi, and can effectively relieve and treat symptoms such as ear canal itching.

[0005] The following embodiments are provided to achieve the objects of the present invention.

[0006] In one embodiment, the present invention provides an ear canal disinfectant containing isopropyl alcohol, comprising isopropyl alcohol, octenidine, a guanidine-containing antibacterial polymer, and pharmaceutical excipients.

[0007] Preferably, in the above-mentioned ear canal disinfectant of the present invention, the pharmaceutical excipients include preservatives and sterilizing water.

[0008] In some embodiments, the present invention provides an ear canal disinfectant containing isopropyl alcohol, comprising 45-55% by weight of isopropyl alcohol, 0.2-1% of octenidine, 0.2-1% of a guanidine-containing antibacterial polymer, 0.2-1% of a preservative, and an optional pH adjuster, with the balance being sterile water.

[0009] Preferably, in the above-mentioned ear canal disinfectant of the present invention, the guanidine-containing antibacterial polymer is polyhexamethylene biguanide hydrochloride, and the preservative is phenoxyethanol.

[0010] In a specific embodiment, the present invention provides an ear canal disinfectant containing isopropyl alcohol, comprising 45-55% isopropyl alcohol, 0.2-1% octenidine, 0.2-1% polyhexamethylene biguanide hydrochloride, 0.2-1% preservative phenoxyethanol, and an optional pH adjuster, with the balance being sterile water.

[0011] Preferably, in the above-mentioned ear canal disinfectant of the present invention, the pH adjuster is citric acid or baking soda.

[0012] In some embodiments, the present invention provides a method for preparing the ear canal disinfectant of the present invention, comprising the following steps:

[0013] 1) Dissolve octenidine and preservative in isopropyl alcohol;

[0014] 2) dissolving the guanidine-based antibacterial polymer in sterile water;

[0015] 3) Mix the two solutions evenly;

[0016] 4) Optionally, adjust the pH with citric acid or baking soda.

[0017] Preferably, in the preparation method of the present invention, the pH value range is 6-8, preferably 6-7.

[0018] Technical effect:

[0019] The ear canal disinfectant of the present invention has a good inhibitory effect on fungi represented by Candida albicans, Gram-positive bacteria represented by Staphylococcus aureus, and Gram-negative bacteria represented by Escherichia coli, and can effectively relieve and treat symptoms such as ear canal itching. DETAILED DESCRIPTION

[0020] The following examples are provided to describe the present invention in more detail. However, the following examples are provided only to help further understand the present invention and are not intended to limit the present invention. Those skilled in the art will appreciate that any equivalent substitutions made to the present invention, or corresponding improvements, still fall within the scope of protection of the present invention.

[0021] Example 1 Ear Canal Disinfectant

[0022] 1. Formula composition: 50g isopropyl alcohol (50% by mass), 0.5g octenidine (0.5% by mass), 0.5g polyhexamethylene biguanide hydrochloride (0.5% by mass), 0.5g phenoxyethanol (0.5% by mass), and 48.5g sterile water.

[0023] 2. Preparation process:

[0024] 1) Add 0.5 g of octenidine and 0.5 g of phenoxyethanol to 50 g of isopropyl alcohol and stir at room temperature until the octenidine and phenoxyethanol are completely dissolved in the isopropyl alcohol to form a uniform solution A;

[0025] 2) 0.5 g of polyhexamethylene biguanide hydrochloride was added to 48 g of sterilized water and stirred thoroughly to completely dissolve the polyhexamethylene biguanide hydrochloride to obtain solution B;

[0026] 3) Slowly pour solution A into solution B while stirring continuously to ensure that the two solutions are thoroughly mixed;

[0027] 4) After testing, the pH value of the mixed solution was 6.41, which met the requirements. There was no need to adjust the pH value with citric acid or baking soda, and an ear canal disinfectant with isopropyl alcohol as the main active ingredient was obtained.

[0028] 3. Antibacterial effect detection

[0029] The WS / T650-2019 "Antibacterial and Antibacterial Effect Evaluation Method" test was repeated three times (test temperature 20±1°C, exposure time 2 minutes). Antibacterial tests were conducted on Candida albicans, Staphylococcus aureus, and Escherichia coli, with an average inhibition rate of 100%, demonstrating excellent antibacterial efficacy.

[0030] 4. Clinical application

[0031] Thirty patients with external otitis and ear canal itching were treated with the ear canal disinfectant prepared in this example. The method of use was to apply an appropriate amount of disinfectant to the external auditory canal with a cotton swab, three times daily for seven consecutive days. After treatment, ear canal itching symptoms completely disappeared in 25 patients, significantly alleviated in four patients, and somewhat alleviated in one patient, for an overall effective rate of 96.7%, with no significant adverse reactions.

[0032] Example 2 Ear Canal Disinfectant

[0033] 1. Formula composition: Weigh 45 g of isopropyl alcohol (45% by mass), 0.2 g of octenidine (0.2% by mass), 0.2 g of polyhexamethylene biguanide hydrochloride (0.2% by mass), 0.2 g of phenoxyethanol (0.2% by mass), and 54.4 g of sterile water.

[0034] 2. Preparation process:

[0035] 1) Add 0.2 g of octenidine and 0.2 g of phenoxyethanol to 45 g of isopropyl alcohol and stir until completely dissolved to obtain solution C;

[0036] 2) Dissolve 0.2 g of polyhexamethylene biguanide hydrochloride in 54.4 g of sterile water and stir to prepare solution D;

[0037] 3) Pour solution C into solution D and stir thoroughly to mix;

[0038] 4) After testing, the pH value of the solution was slightly high, and citric acid was used to adjust the pH value until it reached 6.98 to obtain an ear canal disinfectant solution.

[0039] 3. Antibacterial effect detection

[0040] The WS / T650-2019 "Antibacterial and Antibacterial Effect Evaluation Method" test was repeated three times (test temperature 20±1°C, exposure time 2 minutes). Antibacterial tests were conducted on Candida albicans, Staphylococcus aureus, and Escherichia coli, with an average inhibition rate of 95%, demonstrating good antibacterial ability.

[0041] 4. Clinical application

[0042] Twenty-five patients with otitis externa were treated with the ear canal disinfectant prepared in this example, using the same method as in Example 1, three times a day for seven consecutive days. After treatment, symptoms such as ear canal itching disappeared in 18 patients, symptoms were significantly relieved in 3 patients, and symptoms were somewhat relieved in 4 patients. The total effective rate was 84%, and no serious adverse reactions were found.

[0043] Example 3 Ear Canal Disinfectant

[0044] 1. Formula composition: prepare 55g isopropyl alcohol (55% by mass), 1g octenidine (1% by mass), 1g polyhexamethylene biguanide hydrochloride (1% by mass), 1g phenoxyethanol (1% by mass), and 42g sterilized water.

[0045] 2. Preparation process

[0046] 1) Dissolve 1 g of octenidine and 1 g of phenoxyethanol in 55 g of isopropyl alcohol and stir until completely dissolved to obtain solution E;

[0047] 2) Dissolve 1 g of polyhexamethylene biguanide hydrochloride in 42 g of sterile water and stir to obtain solution F;

[0048] 3) Mix solution E and solution F and stir thoroughly;

[0049] 4) After testing, the pH value of the solution was slightly low, and baking soda was used to adjust the pH value to 6.12 to prepare an ear canal disinfectant.

[0050] 3. Antibacterial effect detection

[0051] The WS / T650-2019 "Antibacterial and Antibacterial Effect Evaluation Method" was used, and the test was repeated three times (test temperature 20±1°C, exposure time 2 minutes). Antibacterial tests were conducted on Candida albicans, Staphylococcus aureus, and Escherichia coli, with an average inhibition rate of 90%, demonstrating a moderate antibacterial effect.

[0052] 4. Clinical application

[0053] 35 patients with otitis externa were treated with the ear canal disinfectant prepared in this example, three times a day for seven consecutive days. After treatment, symptoms such as ear canal itching completely disappeared in 20 patients, significantly alleviated in 5 patients, and somewhat alleviated in 10 patients, with an overall effective rate of 71.4%. No serious adverse reactions were observed.

[0054] Example 4 In vitro antibacterial experiment comparison

[0055] 1. Prepare a YAGB solution, which is a mixed aqueous solution containing isopropyl alcohol (50% by mass), octenidine (0.5% by mass), polyhexamethylene biguanide hydrochloride (0.5% by mass), and phenoxyethanol (0.5% by mass), and detect its pH in the range of 6.0-8.0.

[0056] 2. Prepare YG solution, which is a mixed aqueous solution containing isopropyl alcohol (50% by mass) and polyhexamethylene biguanide hydrochloride (0.5% by mass), without octenidine and phenoxyethanol, and detect its pH in the range of 6.0-8.0.

[0057] 3. Prepare a GA solution, which is a mixed aqueous solution containing octenidine (0.5% by mass) and polyhexamethylene biguanide hydrochloride (0.5% by mass), without isopropyl alcohol and phenoxyethanol, and detect its pH in the range of 6.0-8.0.

[0058] The antibacterial effects of YAGB solution, YG solution, and GA solution were tested using the WS / T650-2019 "Antibacterial and Antibacterial Effect Evaluation Methods" and repeated three times (test temperature: 20±1°C, exposure time: 2 minutes). Antibacterial tests were conducted on Candida albicans, Staphylococcus aureus, and Escherichia coli. The results showed that the average inhibition rates of YAGB solution against Candida albicans, Staphylococcus aureus, and Escherichia coli were 100%, 99%, and 100%, respectively, surpassing those of YG and GA solutions, demonstrating excellent antibacterial efficacy (see Table 1).

[0059] Table 1. Average antibacterial rates of YAGB solution, YG solution, and GA solution

[0060] Average antibacterial rate% YAGB solution YG solution GA solution Escherichia coli 100.00±0.00 75.00±2.00* 3.33±2.52* Staphylococcus aureus 99.00±1.00 90.00±1.00* 0.00±5.00* Candida albicans 100.00±0.00 76.00±1.00* 0.50±4.50*

[0061] *P<0.01 compared with YAGB solution.

[0062] Example 5 Stability Study

[0063] The stability of the ear canal disinfectant of the present invention was investigated with reference to Appendix B.1 of GB / T26367-2020 "Hygiene Requirements for Guanidine Disinfectants" and GB / T38499-2020 "Method for Evaluating the Stability of Disinfectants." The ear canal disinfectant of Example 1 was left for 3 months, and the content of polyhexamethylene biguanidine hydrochloride therein was detected (twice, with the average value taken). The detection method used was a dual-beam UV-visible spectrophotometer / TU-1900 / L-453. The test results are shown in Table 2.

[0064] Table 2. Detection results of polyhexamethylene biguanide hydrochloride in ear canal disinfectant

[0065]

[0066] Conclusion: Before being placed at 37°C, the polyhexamethylene biguanide content of the disinfectant of the present invention was 0.48%. After being placed for 3 months, the polyhexamethylene biguanide content was 0.44%, with a decrease rate of 8.3%, which meets the requirements of GB / T38499-2020 "Stability Evaluation Method of Disinfectants", indicating that the product can be stored for two years.

[0067] In addition, referring to Appendix A.2 of GB / T26373-2020 "Hygiene Requirements for Alcohol Disinfectants" and Section 2.2.3 of the "Technical Specifications for Disinfection" in 2002, the stability of the ear canal disinfectant of the present invention was investigated. The ear canal disinfectant was placed for 3 months and the isopropyl alcohol content was detected (twice, with the average value taken). The detection method used was high-performance gas chromatography (Agilent 7890 / L-311). The test results are shown in Table 3.

[0068] Table 3. Test results of isopropyl alcohol content in ear canal disinfectant

[0069]

[0070] The results show that the isopropyl alcohol content of the disinfectant of the present invention is 50.8% before being placed at 37°C. After being placed for 3 months, the isopropyl alcohol content is 49.9%, with a decrease rate of 1.8%, which meets the requirements of 2.2.3 of the "Disinfection Technical Specifications" in 2002. The product can be stored at room temperature for two years.

[0071] Example 6 Skin irritation test

[0072] 1. Test basis: Technical Specifications for Disinfection (2002 edition) 2.3.3.

[0073] 2. Sample preparation: the ear canal disinfectant stock solution of Example 1.

[0074] 3. Test methods

[0075] (1) Skin: 24 hours before exposure, use shaving scissors to remove the hair on both sides of the rabbit's spine. Do not damage the skin. The hair removal area is approximately 3cm x 3cm on the left and right sides.

[0076] (2) Exposure: Using the left and right side self-comparison method, 0.5 mL of ear canal disinfectant solution was directly dropped onto an area of ​​2.5 cm x 2.5 cm of intact, hairless skin on the left side. The right side served as a blank control. 4 hours after application, the area was rinsed with purified water to remove any residue. Application was continued once daily for 14 days.

[0077] (3) Symptom Observation and Evaluation: Observe the results 24 hours after each application and score according to Table 2-11 in 2.3.3.4.2 of the Technical Specifications for Disinfection (2002 Edition). To facilitate application of the test substance and observation of the results, hair should be clipped if necessary. The control area should be treated in the same manner as the test area. The skin irritation scoring criteria and skin irritation intensity classification are shown in Tables 4 and 5, respectively.

[0078] Table 4. Skin irritation rating criteria

[0079] skin irritation Scoring Criteria Erythema formation none 0 Barely visible 1 obvious 2 serious 3 Purple-red erythema with eschar 4 Edema formation none 0 Barely visible 1 Raised skin with clear contours 2 Edema bulge of about 1mm 3 Edema swelling greater than 1 mm 4

[0080] Table 5. Skin irritation intensity classification

[0081] Skin irritation index Stimulation intensity level 0-<0.5 Non-irritating 0.5-<2.0 Mild irritation 2.0-<6.0 Moderate irritation 6.0-8.0 Strong irritation

[0082] The evaluation results are shown in Table 6.

[0083] Table 6. Skin irritation test results of ear canal disinfectant

[0084]

[0085] in conclusion:

[0086] The test substance is non-irritating to the intact skin of rabbits after multiple stimulations, which meets the requirements of 2.3.3.4.2 of the Technical Specifications for Disinfection (2002 edition).

[0087] Example 7 Antibacterial Experiment

[0088] Test sample: ear canal disinfectant of Example 1

[0089] Production specifications: 30mL. Batch number 20230425.1

[0090] Detection of microbial contamination indicators (total bacterial colony count, total fungal colony count, coliform group, Staphylococcus aureus, detection items: Pseudomonas aeruginosa, hemolytic Streptococcus); antibacterial test (Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans).

[0091] 1. Testing basis:

[0092] 1. Microbial contamination indicators: Appendix B of GB15979-2002 "Hygiene Standards for Disposable Sanitary Products".

[0093] 2. Antibacterial test: WS / T650-2019 "Evaluation Methods for Antibacterial and Antibacterial Effects" 5.1.1.

[0094] 2. Evaluation basis:

[0095] 1. Microbial contamination index: GB15979-2002 "Hygienic Standard for Disposable Sanitary Products" 4.3.

[0096] 2. Antibacterial test: WS / T650-2019 "Evaluation Methods for Antibacterial and Antibacterial Effects" 5.1.1.

[0097] 3. Test conclusion:

[0098] 1. Microbial contamination indicators

[0099] The microbial contamination index of the ear canal disinfectant was in compliance with the requirements of Section 4.3 of GB15979-2002, Hygienic Standard for Disposable Sanitary Products. The results are shown in Table 7.

[0100] Table 7. Microbiological test results

[0101] Detection indicators Standard value Measured value Total bacterial colony count (cfu / mL) ≤200 <1 Total fungal colonies (cfu / mL) ≤100 <1 coliform group Not to be detected Not detected Staphylococcus aureus Not to be detected Not detected Pseudomonas aeruginosa Not to be detected Not detected Hemolytic Streptococci Not to be detected Not detected

[0102] Note: Negative control: growth of Fusarium

[0103] 2. Escherichia coli antibacterial test (suspension method)

[0104] The test was repeated three times at a temperature of 20°C ± 1°C. Using the original ear canal disinfectant solution for 2 minutes, the average inhibition rate against Escherichia coli was 100.00%, meeting the requirements of 5.1.1 of WS / T 650-2019, "Methods for the Evaluation of Antimicrobial and Antibacterial Effects," indicating that the product exhibits strong antibacterial activity. The results are shown in Table 8.

[0105] Table 8. Antibacterial test results of ear canal disinfectant against Escherichia coli

[0106]

[0107] Note: No bacteria grew in the negative control group.

[0108] 3. Staphylococcus aureus antibacterial test (suspension method)

[0109] The test was repeated three times at a temperature of 20°C ± 1°C. The ear canal disinfectant concentrate, with an exposure time of 2 minutes, showed an average inhibition rate of 100.00% against Staphylococcus aureus, meeting the requirements of 5.1.1 of WS / T650-2019, "Methods for the Evaluation of Antimicrobial and Antibacterial Effects," indicating that the product exhibited strong antibacterial activity. The results are shown in Table 9.

[0110] Table 9. Results of antibacterial test on Staphylococcus aureus with ear canal disinfectant

[0111]

[0112] Note: No bacteria grew in the negative control group.

[0113] 4. Pseudomonas aeruginosa antibacterial test (suspension method)

[0114] The test was repeated three times at a temperature of 20°C ± 1°C. Using the original ear canal disinfectant solution for 2 minutes, the average inhibition rate against Pseudomonas aeruginosa was 100.00%, meeting the requirements of 5.1.1 of WS / T650-2019, "Methods for the Evaluation of Antimicrobial and Antibacterial Effects," indicating that the product exhibited strong antibacterial activity. The results are shown in Table 10.

[0115] Table 10. Antibacterial test results of ear canal disinfectant against Pseudomonas aeruginosa

[0116]

[0117] 5. Candida albicans antibacterial test (suspension method)

[0118] The test was repeated three times at a temperature of 20°C ± 1°C. Using the original ear canal disinfectant solution for 2 minutes, the average inhibition rate against Candida albicans was 100.00%, meeting the requirements of 5.1.1 of WS / T650-2019, "Methods for the Evaluation of Antimicrobial and Antibacterial Effects," indicating that the product exhibited strong antibacterial activity. The results are shown in Table 11.

[0119] Table 11. Antibacterial test results of ear canal disinfectant against Candida albicans

[0120]

Claims

1. An ear canal disinfectant containing isopropyl alcohol, characterized in that: The invention comprises isopropyl alcohol, octenidine, a guanidine-containing antibacterial polymer and pharmaceutical excipients.

2. The ear canal disinfectant according to claim 1, wherein the pharmaceutical excipients comprise a preservative and sterilizing water.

3. The ear canal disinfectant according to claim 1, comprising 45-55% by weight of isopropyl alcohol, 0.2-1% by weight of octenidine, 0.2-1% by weight of a guanidine-containing antibacterial polymer, and 0.2-1% by weight of a preservative, with the remainder being sterilizing water.

4. The ear canal disinfectant according to claim 1, wherein the guanidine-containing antibacterial polymer is polyhexamethylene biguanide hydrochloride. The ear canal disinfectant according to claim 2 , wherein the preservative is phenoxyethanol.

6. The ear canal disinfectant according to claim 1, comprising 45-55% by weight of isopropyl alcohol, 0.2-1% of octenidine, 0.2-1% of polyhexamethylene biguanide hydrochloride, 0.2-1% of preservative phenoxyethanol, and an optional pH adjuster, with the balance being sterile water. The ear canal disinfectant according to claim 6 , wherein the pH adjuster is citric acid or baking soda.

8. A method for preparing the ear canal disinfectant according to any one of claims 1 to 7, comprising the following steps: 1) Dissolve octenidine and preservative in isopropyl alcohol; 2) dissolving the guanidine-based antibacterial polymer in sterile water; 3) Mix the two solutions evenly; 4) Optionally, adjust the pH with citric acid or baking soda.

9. The method of claim 8, wherein the pH value is 6-8.

10. The method of claim 9, wherein the pH value is 6-7.

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