Composite polymer bacteriostatic agent, preparation method and application

Abstract

This invention specifically relates to a composite polymer antibacterial agent, its preparation method, and its application, belonging to the field of antibacterial materials technology. The antibacterial agent, by weight percentage, comprises a core component PQ-1 (0.01%~0.1%), a synergistic component polyhexamethylene biguanide (PHMB) (0.005%~0.05%), a synergistic component polyaminopropyl biguanide (PAPB) (0.005%~0.05%), and the balance being solvent. This invention, through the synergistic combination of PQ-1 and the two synergistic components, can reduce the minimum inhibitory concentration (MIC) against typical microorganisms by more than 75% while reducing the amount of PQ-1 by 50%~80%, achieving optimized protection of the antibacterial efficacy concentration of PQ-1, while also possessing the advantages of broad spectrum, stability, mildness, and low toxicity. Its preparation process is simple and can be widely applied in ophthalmic preparations, cosmetics, and other fields, demonstrating extremely high practical value.

Description

Technical Field

[0001] This invention belongs to the field of antibacterial materials technology, specifically relating to a composite antibacterial agent with polyquaternium-1 (PQ-1) as the main component, combined with polyaminopropyl biguanide (PAPB) and polyhexamethylene biguanide (PHMB). It also relates to the preparation method of the antibacterial agent and its application in ophthalmic preparations, cosmetics, medical dressings and other fields related to optimizing the antibacterial efficacy concentration and ensuring antibacterial stability. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Polymer antibacterial agents are widely used in pharmaceuticals, daily chemicals, and food processing due to their advantages such as broad-spectrum antibacterial activity, low toxicity, and low likelihood of inducing drug resistance. Among them, polyquaternium-1 (PQ-1) has an irreplaceable advantage in mucosal contact scenarios such as ophthalmic preparations due to its excellent mildness. However, when used alone, it has the problem of weak antibacterial activity against some Gram-negative bacteria and requires a higher concentration to achieve ideal antibacterial efficacy. Polyhexamethylene biguanide (PHMB) has a broad antibacterial spectrum, inhibiting both bacteria and fungi, which can compensate for the shortcomings of PQ-1's antibacterial spectrum. However, it has poor compatibility with anionic components. Polyaminopropyl biguanide (PAPB) has high bactericidal efficiency and is effective at low concentrations. It can help improve the antibacterial efficiency of PQ-1 and reduce its usage concentration. However, when used alone, its duration of antibacterial activity is relatively short, and its stability at high temperatures needs to be improved.

[0004] To address the shortcomings of single antibacterial agents, binary composite antibacterial systems have emerged in existing technologies. However, most of these systems do not utilize PQ-1 as the core in their formulation design, failing to fully leverage PQ-1's mildness and optimize its antibacterial efficacy concentration. For example, CN104248776A discloses an antibacterial solution for dressings containing biguanide and quaternary ammonium salt antibacterial agents, but it does not address the combination of PQ-1 as the main component with PAPB, nor does it optimize the antibacterial efficacy concentration of PQ-1 for low-irritation applications such as ophthalmic and cosmetic use. Therefore, developing a composite antibacterial agent with PQ-1 as the main component, combined with PAPB and PHMB to achieve synergistic effects, significantly optimizes the antibacterial efficacy concentration, and ensures antibacterial stability has become a current research hotspot in this field. Summary of the Invention

[0005] To address the technical problems of existing technologies, such as the high concentration of PQ-1 when used alone, the narrow antibacterial spectrum, and the lack of efficient compound systems based on PQ-1, this invention provides a compound antibacterial agent based on PQ-1. Through the synergistic combination of PQ-1 with PAPB and PHMB, the technical effects of optimizing the concentration of PQ-1's antibacterial efficacy (reducing its usage concentration), broadening the bactericidal spectrum, and improving antibacterial stability are achieved, while retaining the advantages of PQ-1's mildness and low toxicity, making it suitable for various mucosal contact and daily chemical applications.

[0006] Based on the above-mentioned technical effects, the present invention provides the following technical solution: In a first aspect, a composite polymer antibacterial agent is provided, the antibacterial agent comprising a main component and a synergistic component; wherein the main component is polyquaternary ammonium salt-1 (PQ-1), with a mass fraction of 0.01% to 0.1%; the auxiliary component is a combination of polyaminopropyl biguanide (PAPB) and polyhexamethylene biguanide (PHMB), wherein the mass fraction of PAPB is 0.005% to 0.05%, the mass fraction of PHMB is 0.005% to 0.05%, and the balance is solvent; in this antibacterial agent, the content of the main component is greater than the content of any one of the synergistic components.

[0007] The composite polymer antibacterial agent of this invention uses PQ-1 as the main component. It achieves high-efficiency antibacterial activity and optimizes the antibacterial efficacy concentration through the synergistic effect of the main component and the synergistic component. Its mechanism of action is as follows: PQ-1, as the main cationic polymer, plays a basic antibacterial role by electrostatically adsorbing and binding to the negatively charged cell membrane surface of microorganisms; PHMB, as a synergistic component, can broaden the bactericidal spectrum and make up for the deficiency of PQ-1 in antibacterial activity against some Gram-negative bacteria; PAPB, as a synergistic component, can enhance the cell membrane disruption ability and improve the antibacterial efficiency, thereby reducing the required concentration of PQ-1 and optimizing the overall antibacterial efficacy concentration. The synergistic effect formed by the combination of the three components significantly reduces the effective antibacterial concentration of PQ-1, reducing the potential irritation risk caused by high concentration use, and prolongs the duration of antibacterial action and improves the antibacterial stability.

[0008] Among the above-mentioned antibacterial agents, the polyquaternium-1 has a CAS registry number of 75345-27-6, a molecular weight of 6500~57000 Da, and a weight-average molecular weight of 3~4×10⁻⁶. 4 Da.

[0009] The polyaminopropyl biguanide has a CAS registration number of 133029-32-0, a molecular weight of 1000~10000 Da, and a weight-average molecular weight of 1000~1500 Da.

[0010] The polyhexamethylene biguanide has a CAS registration number of 32289-58-0, a molecular weight of 1000-10000 Da, and a degree of polymerization of 6-30.

[0011] The solvent is designed to dissolve the main and synergistic components and meet the requirements of the test environment. Those skilled in the art can routinely select a suitable solvent based on the target application of the antibacterial agent; feasible solvents include water, physiological saline, and ethanol solutions (5-20 wt.%).

[0012] Furthermore, in the above-mentioned antibacterial agent, PQ-1 is 0.02~0.08 wt.%, PHMB is 0.01~0.03 wt.%, PAPB is 0.01~0.03 wt.%, and the balance is solvent; in this embodiment, the weight percentage of PQ-1 is 1~4 times the sum of the weight percentages of the synergistic components PHMB and PAPB, ensuring the core antibacterial effect of the main components and the synergistic effect on the optimization of the antibacterial efficacy concentration.

[0013] Secondly, a method for preparing the composite polymer antibacterial agent described in the first aspect is provided: Solvent is measured according to the specified ratio and placed in a stirring container, with the temperature controlled at 20-30℃; PQ-1, PHMB, and PAPB are added to the solvent sequentially, stirring at 180-400 r / min for 5-10 min after each addition to ensure complete dissolution of the previous component before adding the next; after all components are dissolved, stirring continues for 10-15 min to obtain a uniform and transparent composite polymer antibacterial agent. Optionally, the above antibacterial agent is subjected to filtration (filtration accuracy 0.22 μm) and sterilization (autoclave at 121℃ for 20 min) for use in pharmaceutical applications.

[0014] Thirdly, the application of the composite polymer antibacterial agent described in the first aspect is provided.

[0015] The above applications include, but are not limited to, the preparation of ophthalmic preparations, skin or mucous membrane care, medical consumables, or personal care products.

[0016] Examples of the above-mentioned ophthalmic preparations include care solutions, eye drops, or eye washes.

[0017] The aforementioned skin or mucous membrane care products include care solutions used for wound sterilization, oral care solutions, or intimate area care solutions.

[0018] The aforementioned medical consumables may be used for surface disinfection or sterilization of interventional devices, masks, and medical dressings.

[0019] The aforementioned personal care products include skin care products, hand sanitizers, hand gels, fabric softeners, and laundry detergents.

[0020] Compared with the prior art, the beneficial effects of the present invention are: The composite antibacterial agent provided by this invention, with PQ-1 as the main component and two synergistic components, reduces the effective antibacterial concentration of PQ-1 by 40% to 60% compared to its single use. The overall composite antibacterial agent reduces the minimum inhibitory concentration (MIC) of various microorganisms by 40% to 60% and the minimum bactericidal concentration (MBC) by 30% to 50% compared to its single use, achieving highly efficient antibacterial activity at low concentrations while retaining the mildness of PQ-1. 1. Broad spectrum of bactericidal activity: It can effectively inhibit a variety of microorganisms such as Gram-positive bacteria (e.g. Staphylococcus aureus), Gram-negative bacteria (e.g. Escherichia coli, Pseudomonas aeruginosa), and fungi (e.g. Candida albicans, Aspergillus niger), and also has an inhibitory effect on some viruses (e.g. adenovirus); 2. High stability: Stable antibacterial activity within the pH range of 4~9; activity retention rate ≥90% after 3 months of storage at 60℃; compatible with most nonionic and cationic surfactants; suitable for complex formulation systems. 3. Mild and low toxicity: At low concentrations, it has extremely low irritation to the skin and mucous membranes, and at ophthalmic concentrations, its cytotoxicity is significantly lower than that of a single antibacterial agent, meeting the safety requirements of pharmaceuticals and daily chemical products; 4. Wide range of applications: The solvent and ratio can be adjusted according to different scenarios, making it suitable for multiple fields such as ophthalmic preparations, contact lens care solutions, cosmetics, medical dressings, and food contact materials. Detailed Implementation

[0021] It should be noted that the following detailed description is illustrative and intended to provide further explanation of the invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0022] It should be noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of exemplary embodiments according to the invention. As used herein, the singular form is intended to include the plural form as well, unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof.

[0023] In the context of this specification, the word "comprising" is considered to mean "especially including". It should not be interpreted as "consisting of only".

[0024] In the description of the embodiments in this application, the words "exemplary" or "for example" are used to indicate that they are examples, illustrations, or descriptions. Any embodiment or design that is described as "exemplary" or "for example" in the embodiments of this application should not be construed as being more preferred or advantageous than other embodiments or design options. Specifically, the use of the words "exemplary" or "for example" is intended to present the relevant concepts in a specific manner.

[0025] In the description of the embodiments in this application, unless otherwise stated, "multiple" means two or more.

[0026] To enable those skilled in the art to better understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments and comparative examples.

[0027] The raw materials and specifications involved in the following examples are as follows: PQ-1 (weight-average molecular weight 5×10) 4 The microbial strains used were: Staphylococcus aureus (ATCC 6538), Escherichia coli (ATCC 8739), Pseudomonas aeruginosa (ATCC 9027), and Candida albicans (ATCC 10231), all purchased from the China General Microbiological Culture Collection Center.

[0028] Antibacterial performance test methods: MIC was determined by the nutrient broth test tube double dilution method according to GB / T 2099.4-2017, and MBC and bactericidal rate were determined by the plate count method; Antibacterial time test: Samples were taken at 5 min, 15 min, 30 min and 60 min after contact between the antibacterial agent and microorganisms, the viable bacteria count was determined and the bactericidal rate was calculated; Stability test: The antibacterial agent was stored in environments with pH 4, 7 and 9 and in an oven at 60℃ for 3 months, and the activity retention rate was determined.

[0029] Example 1 In this embodiment, a composite polymer antibacterial agent is provided, comprising the following components in the indicated mass fractions: PQ-1 0.02%, PHMB 0.01%, PAPB 0.01%, with the remainder being deionized water.

[0030] The preparation method of the above-mentioned composite polymer antibacterial agent is as follows: 99.96g of deionized water is placed in a beaker and stirred at 300r / min at 25℃. First, 0.02g of PQ-1 is added and stirred for 5min until completely dissolved. Then, 0.01g of PHMB is added and stirred for 5min until dissolved. Finally, 0.01g of PAPB is added and stirred for 10min until the solution is uniform and transparent. The solution is then filtered through a 0.22μm filter membrane to obtain the composite polymer antibacterial agent. This composite polymer antibacterial agent can be applied in multiple fields such as ophthalmic preparations and care solutions. The appropriate dosage of antibacterial agent can be selected according to the application requirements of each field.

[0031] Performance test results: For Staphylococcus aureus, MIC=1μg / mL, MBC=2μg / mL; for Escherichia coli, MIC=4μg / mL, MBC=8μg / mL; for Pseudomonas aeruginosa, MIC=4μg / mL, MBC=8μg / mL; and for Candida albicans, MIC=2μg / mL, MBC=4μg / mL; the bactericidal rate is ≥99% after 5 min of contact and ≥99.99% after 30 min of contact; the activity retention rate is ≥92% after 3 months of storage at pH 4-9 and 60℃.

[0032] Example 2 In this embodiment, another composite polymer antibacterial agent is provided, comprising the following components in the following mass fractions: PQ-1 0.05%, PHMB 0.02%, PAPB 0.02%, with the balance being a 10% volume fraction of ethanol aqueous solution.

[0033] The preparation method is as follows: 99.91g of 10% ethanol aqueous solution is placed in a beaker and stirred at 300r / min at 28℃. 0.05g of PQ-1, 0.02g of PHMB, and 0.02g of PAPB are added in sequence, with stirring for 8min after each addition. Finally, stirring is continued for 15min. The mixture is then sterilized by high-pressure steam at 121℃ for 20min to obtain a composite polymer antibacterial agent.

[0034] Performance test results: MIC=0.5μg / mL, MBC=1μg / mL for Staphylococcus aureus; MIC=2μg / mL, MBC=4μg / mL for Escherichia coli; MIC=2μg / mL, MBC=4μg / mL for Pseudomonas aeruginosa; MIC=1μg / mL, MBC=2μg / mL for Candida albicans; bactericidal rate ≥99.9% after 5 min of contact, bactericidal rate ≥99.999% after 30 min of contact; activity retention rate ≥95% after 3 months of storage at pH 4~9 and 60℃.

[0035] Example 3 In this embodiment, another composite polymer antibacterial agent is provided, comprising the following components in the indicated mass fractions: PQ-1 0.08%, PHMB 0.03%, PAPB 0.03%, with the remainder being physiological saline.

[0036] The preparation method is as follows: 99.86g of physiological saline is placed in a beaker and stirred at 300r / min at 22℃. 0.08g of PQ-1, 0.03g of PHMB, and 0.03g of PAPB are added in sequence, and stirred for 10min after each addition. Finally, stirring is continued for 12min. The mixture is then filtered and sterilized to obtain a composite polymer antibacterial agent.

[0037] Performance test results: MIC=0.5μg / mL, MBC=1μg / mL for Staphylococcus aureus; MIC=2μg / mL, MBC=4μg / mL for Escherichia coli; MIC=2μg / mL, MBC=4μg / mL for Pseudomonas aeruginosa; MIC=1μg / mL, MBC=2μg / mL for Candida albicans; bactericidal rate ≥99.9% after 5 min of contact, bactericidal rate ≥99.999% after 30 min of contact; activity retention rate ≥94% after 3 months of storage at pH 4~9 and 60℃.

[0038] Comparative Example 1 In this embodiment, a single-component antibacterial agent is provided, comprising the following components by mass fraction: PQ-1 0.1%, with the balance being deionized water.

[0039] Performance test results: MIC=4μg / mL, MBC=8μg / mL for Staphylococcus aureus; MIC=16μg / mL, MBC=16μg / mL for Escherichia coli; MIC=16μg / mL, MBC=32μg / mL for Pseudomonas aeruginosa; MIC=8μg / mL, MBC=8μg / mL for Candida albicans; bactericidal rate after 30 min of contact = 98%; activity retention rate after 3 months of storage at 60℃ = 85%.

[0040] Comparative Example 2 In this embodiment, a binary antibacterial agent is provided, comprising the following components by mass fraction: PHMB 0.05%, PAPB 0.05%, and the balance being deionized water.

[0041] Performance test results: MIC=2μg / mL, MBC=4μg / mL for Staphylococcus aureus; MIC=8μg / mL, MBC=16μg / mL for Escherichia coli; MIC=8μg / mL, MBC=16μg / mL for Pseudomonas aeruginosa; MIC=4μg / mL, MBC=8μg / mL for Candida albicans; bactericidal rate after 30 min of contact = 99.5%; activity retention rate after 3 months of storage at 60℃ = 88%.

[0042] The comparison results between Comparative Examples 1-2 and Examples 1-3 are shown in Table 1 below: Table 1. Antibacterial effects of the antibacterial agents in Examples 1-3 and Comparative Examples 1-2 In Comparative Example 1, the dosage of PQ-1 was 0.1%, in Examples 1-3 it was 0.02-0.08%, and in the antibacterial agent provided in this application, the dosage of PO-1 was reduced by 20-80%, while the MIC values ​​against various microorganisms were reduced by 75%-87.5%, significantly optimizing the antibacterial efficacy concentration of PQ-1. This demonstrates that the combination of PQ-1 with PAPB and PHMB achieves highly efficient antibacterial activity at low concentrations of PQ-1 while retaining its advantages of being mild and low in toxicity.

[0043] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A composite polymer antibacterial agent, characterized in that, The antibacterial agent comprises a main component and a synergistic component; wherein the main component is PQ-1, with a mass fraction of 0.01% to 0.1%; the auxiliary component is a combination of PAPB and PHMB, wherein the mass fraction of PAPB is 0.005% to 0.05%, the mass fraction of PHMB is 0.005% to 0.05%, and the balance is solvent; in this antibacterial agent, the content of the main component is greater than the content of any one of the synergistic components.

2. The composite polymer antibacterial agent as described in claim 1, characterized in that, The polyquaternium-1 has CAS registration number 75345-27-6, a molecular weight of 6500~57000 Da, and a weight-average molecular weight of 3~4×10⁻⁴. 4 Da.

3. The composite polymer antibacterial agent as described in claim 1, characterized in that, The polyaminopropyl biguanide has a CAS registration number of 133029-32-0, a molecular weight of 1000~10000 Da, and a weight-average molecular weight of 1000~1500 Da.

4. The composite polymer antibacterial agent as described in claim 1, characterized in that, The polyhexamethylene biguanide has a CAS registration number of 32289-58-0, a molecular weight of 1000-10000 Da, and a degree of polymerization of 6-30.

5. The composite polymer antibacterial agent as described in claim 1, characterized in that, The solvent is selected from water, physiological saline, or 5-20 wt.% ethanol solution.

6. The antibacterial agent according to any one of claims 1-5, characterized in that, PQ-1 is 0.02~0.08 wt.%, PHMB is 0.01~0.03 wt.%, PAPB is 0.01~0.03 wt.%, and the balance is solvent.

7. A method for preparing the antibacterial agent according to any one of claims 1-6, characterized in that, The steps include: measuring the solvent according to the ratio, placing it in a stirring container, and controlling the temperature at 20~30℃; adding PQ-1, PHMB, and PAPB to the solvent in sequence, stirring at a speed of 180~400r / min for 5~10min after each addition, ensuring that the previous component is completely dissolved before adding the next component; After all components have dissolved, continue stirring for 10-15 minutes to obtain a uniform and transparent composite polymer antibacterial agent.

8. The method for preparing the antibacterial agent as described in claim 7, characterized in that, When used in pharmaceutical settings, the antibacterial agent also needs to be filtered and sterilized.

9. The application of the composite polymer antibacterial agent according to any one of claims 1-6.

10. The application as described in claim 9, characterized in that, The applications include, but are not limited to, the preparation of ophthalmic preparations, skin or mucous membrane care, medical consumables, or personal care products.

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