Application of phencyqualinium bromide as bacteriostatic active component and preparation of phencyqualinium bromide

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to application of phencycloqualinium bromide as an antibacterial active component and a preparation of the phencycloqualinium bromide. It is found that benzene ring quinaldinium bromide can be used as an antibacterial active component and has an inhibiting effect on various common bacteria and fungi (including but not limited to staphylococcus aureus, pseudomonas aeruginosa, escherichia coli, aspergillus niger, candida albicans and the like); triethanolamine or other bacteriostatic activity enhancers are mixed with the phencycloqualinium bromide, so that the bacteriostatic activity of the phencycloqualinium bromide can be remarkably improved; when a benzene ring quinaldinium bromide related preparation is prepared, other bacteriostatic agent components are not added, a good bacteriostatic effect can still be achieved, and the safety is higher.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and in particular to the application of benzyl quinoline bromide as an antibacterial active ingredient and its formulation. Background Technology

[0002] To ensure the efficacy and safety of pharmaceutical preparations, antibacterial measures are necessary. There are three main existing antibacterial measures: one is the use of sterile-resistant bottles for packaging; another is sterilization or disinfection during the production process, mostly used for injectables; and the third is the addition of antibacterial agents during the formulation process. While sterile-resistant bottles do not pose a safety risk, multi-dose bottles are expensive and have long lead times, while single-dose bottles also present problems such as high cost and potential waste. Although antibacterial agents are less expensive, overuse or misuse can have negative health effects. Studies have shown that excessive exposure to antibacterial agents may lead to decreased immunity, skin allergies, and increased bacterial and fungal resistance. Benzalkonium chloride, for example, has a significant antibacterial effect and is a widely used antibacterial agent in this field. However, numerous studies have shown that these agents can damage or irritate the skin, blood vessel walls, and respiratory tract, both internally and externally (see references: "Preliminary Evaluation of the Irritation and Safety of Benzalkonium Chloride and Decylammonium Bromide Fume Disinfection on the Respiratory Tract of Rats," Li Nanxin et al.; "Experimental Study on the Irritation of Blood Vessel Walls by Benzalkonium Chloride Solution," Yang Yimin et al.; "Comparative Study on the Skin Irritation of Benzalkonium Chloride-Containing Disinfectant Liquids," Wu Yanhong et al.; "Topical Application of Benzalkonium Chloride Induces CD4+ T Cell-Mediated Inflammatory Response in the Ocular Surface of Mice," Ouyang Weijie). Furthermore, all antibacterial agents possess a certain degree of toxicity, and data on safe exposure levels of antibacterial agents in children of different age groups remain limited, especially regarding acceptability and safety information for newborns and infants. Because the physiology and metabolism of newborns and infants are still immature, antibacterial agents considered safe in adults or older children may not be suitable for newborns and infants. Therefore, the use of antibacterial agents should be avoided as much as possible in the medication use of children in these age groups. With increasing public awareness of health and hygiene, the demand for highly effective and safe antibacterial agents is also growing. There are many types of antibacterial agents on the market, but in certain specific fields, it is still necessary to find new, more effective, and safer antibacterial ingredients.

[0003] Benzyl quinacrine bromide exhibits highly selective antagonistic effects on M1 and M3 receptors, effectively reducing their density and exerting an anti-allergic effect. It is effective in treating allergic rhinitis and chronic obstructive pulmonary disease, with few side effects and adverse reactions, and high safety. As a selective M-cholinergic receptor antagonist, Benzyl quinacrine bromide is currently used in nasal sprays to improve symptoms such as runny nose, nasal congestion, nasal itching, and sneezing caused by allergic rhinitis. No research reports on the antibacterial activity of Benzyl quinacrine bromide have been found to date.

[0004] In view of this, the present invention is hereby proposed. Summary of the Invention

[0005] To address the aforementioned technical problems, this invention provides the application of benzyl quinalmonium as an antibacterial active ingredient and its formulation.

[0006] Specifically, the technical solution of the present invention is as follows:

[0007] In a first aspect, the present invention provides the application of benzyl quinoline bromide as an antibacterial active ingredient.

[0008] Benzyl quinacrine is a known compound that is a selective M-cholinergic receptor antagonist. It is highly selective for M3 and M1 receptors, but less selective for M2 receptors, and is less likely to cause adverse reactions such as tachycardia or urinary retention. Benzyl quinacrine can competitively inhibit the binding of acetylcholine to M-cholinergic receptors on respiratory smooth muscle, thereby dilating the bronchi. Its half-life is similar to that of ipratropium bromide. Benzyl quinacrine may alleviate the symptoms of allergic rhinitis by inhibiting cholinergic nerve-mediated glandular secretion and inflammatory responses.

[0009] This invention unexpectedly discovered that benzyl quinalmonium can be used as an antibacterial active ingredient (e.g., an antibacterial agent or an active ingredient with antibacterial properties), exhibiting inhibitory effects on a variety of common bacteria and fungi (including but not limited to Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Aspergillus niger, Candida albicans, etc.); and at a certain concentration, benzyl quinalmonium can significantly reduce the number of bacteria and fungi in a short period of time, inhibiting their growth and reproduction, demonstrating good antibacterial effects.

[0010] When benzyl quinoline bromide is used as an antibacterial active ingredient, its content can be adjusted according to specific application requirements, and this invention does not impose any special restrictions.

[0011] Secondly, the present invention provides a benzyl quinoline bromide formulation, the components of which include benzyl quinoline bromide and an antibacterial activity enhancer, wherein the antibacterial activity enhancer is selected from at least one of triethanolamine, triisopropanolamine, and sorbitol.

[0012] This invention has found that triethanolamine or other antibacterial activity enhancers can be used as antibacterial activity enhancers for benzyl quinalbromide. Mixing triethanolamine or other antibacterial activity enhancers with benzyl quinalbromide can significantly improve the antibacterial activity of benzyl quinalbromide.

[0013] Preferably, the mass ratio of benzyl quinoline bromide to antibacterial activity enhancer is 2-220:3-80, more preferably 10:(3-80); and even more preferably 10:4.

[0014] In this invention, the mass ratio of benzyl quinalbromide to the antibacterial activity enhancer can be any ratio among 10:3, 10:5, 10:10, 10:15, 10:20, 10:25, 10:30, 10:35, 10:40, 10:45, 10:50, 10:55, 10:60, 10:65, 10:70, 10:75, and 10:80, or a range of ratios with any two of the above ratios as endpoints.

[0015] Preferably, the components of the benzyl quinolone bromide formulation do not include other antibacterial active ingredients besides benzyl quinolone bromide, thereby helping to better ensure or improve the safety of the formulation.

[0016] Given the antibacterial activity of phenylcycloquinoline bromide, the phenylcycloquinoline bromide formulation provided by this invention can be considered a novel antibacterial agent. As a novel antibacterial component, phenylcycloquinoline bromide can exert its antibacterial effect as the sole active ingredient or in combination with other antibacterial active ingredients. The antibacterial activity of phenylcycloquinoline bromide is positively correlated with its concentration to a certain extent. As a novel antibacterial agent, the phenylcycloquinoline bromide formulation provided by this invention must meet various pharmaceutical formulation specifications, including safety requirements.

[0017] Given the inherent medicinal functions of phenylcycloquinoline (such as selective M-cholinergic receptor antagonist), and its antibacterial efficacy while being a pharmaceutically active functional component, it is possible to maintain good efficacy and stability without adding other antibacterial agents to formulations containing phenylcycloquinoline. Therefore, the phenylcycloquinoline formulation provided by this invention, without the addition of other antibacterial active ingredients besides phenylcycloquinoline, can also be considered a phenylcycloquinoline pharmaceutical formulation with a simpler formulation and better safety.

[0018] In this invention, the benzyl quinoline bromide preparation can be a preparation containing only the single active ingredient benzyl quinoline bromide, or it can be a compound preparation containing other active ingredients.

[0019] Preferably, the benzyl quinolone bromide preparation further includes other active ingredients, that is, the benzyl quinolone bromide preparation is a compound preparation, and the other active ingredients include one or more of antihistamines, glucocorticoids, decongestants, and β2 receptor agonists.

[0020] Preferably, the antihistamine includes one or more of desloratadine, cetirizine, and fexofenadine; the glucocorticoid includes one or more of budesonide and mometasone furoate; the decongestant includes one or more of pseudoephedrine and oxymetazoline; and the β2 receptor agonist includes one or more of salbutamol and formoterol.

[0021] Those skilled in the art can use benzyl quinolone bromide as a pharmaceutically active ingredient and prepare it into various drug formulations with different targets that can be used clinically using conventional formulation processes in the art.

[0022] Preferably, the dosage forms of the benzyl quinolone bromide preparation include: nasal spray, eye drops, inhalation solution, inhalation aerosol, external solution, lotion, cream or oral liquid; more preferably, nasal spray.

[0023] The phenylcycloquinoline bromide nasal spray provided by this invention is suitable for improving symptoms such as runny nose, nasal congestion, nasal itching, and sneezing caused by allergic rhinitis; phenylcycloquinoline bromide eye drops are intended to regulate the effects of paralysis and mydriasis, mainly used for mydriasis and examination of fundus conditions; compound phenylcycloquinoline bromide and salbutamol inhalation solution is intended to be suitable for symptoms such as asthma-COPD overlap syndrome (ACOS), mucopolyseminal severe asthma, and AECOPD (acute exacerbation) requiring rapid symptom control; phenylcycloquinoline bromide inhalation aerosol is intended to be suitable for treating symptoms such as asthma and chronic obstructive pulmonary disease; phenylcycloquinoline bromide topical solution is intended to be applied to cholinergic nerve-mediated skin / mucous membrane diseases; phenylcycloquinoline bromide lotion is intended to be applied to the skin surface, for symptoms such as skin inflammation or irritation-related secretions; phenylcycloquinoline bromide cream is intended to be suitable for symptoms such as atopic dermatitis (AD), localized hyperhidrosis, and psoriatic pruritus; phenylcycloquinoline bromide oral solution is intended to be suitable for refractory irritable bowel syndrome, etc. Benzyl quinoline bromide oral solution is intended for use in refractory irritable bowel syndrome, etc.

[0024] Thirdly, the present invention provides a nasal spray whose components do not include any antibacterial active ingredients other than benzyl quinalbromide; the content of benzyl quinalbromide in the nasal spray is 0.02wt%-2.20wt%. In specific implementation, the content of benzyl quinalmonium in the nasal spray can be any value among 0.02wt%, 0.05wt%, 0.10wt%, 0.20wt%, 0.30wt%, 0.40wt%, 0.50wt%, 0.60wt%, 0.70wt%, 0.80wt%, 0.90wt%, 1.00wt%, 1.10wt%, 1.20wt%, 1.30wt%, 1.40wt%, 1.50wt%, 1.60wt%, 1.70wt%, 1.80wt%, 1.90wt%, 2.00wt%, 2.10wt%, and 2.20wt%, or a range of values ​​with any two of the above values ​​as endpoints.

[0025] Preferably, the components further contain an antibacterial activity enhancer; the antibacterial activity enhancer is selected from at least one of triethanolamine, triisopropanolamine, and sorbitol; more preferably, the antibacterial activity enhancer is triethanolamine.

[0026] Preferably, the nasal spray also includes at least one functional excipient selected from pH adjusters and osmotic pressure adjusters.

[0027] Preferably, the pH adjuster is selected from at least one of hydroxyethylpiperazine ethanesulfonic acid-sodium hydroxide buffer solution, citric acid-disodium hydrogen phosphate buffer solution, and boric acid-sodium hydroxide buffer solution; the osmotic pressure adjuster is selected from at least one of sodium chloride and mannitol.

[0028] Preferably, based on a total volume of 1000 ml, the nasal spray uses water for injection as a dispersant and contains 0.2-22 g of benzylquinoline bromide and 0.3-8 g of triethanolamine; the nasal spray has a pH of 6.5-8.0 and an osmotic pressure of 290-310 mOsm / L. Using the nasal spray provided by this invention, clinical application can achieve therapeutic effects comparable to commercially available benzylquinoline bromide nasal spray.

[0029] Fourthly, the present invention provides an oral liquid whose components do not include any antibacterial active ingredients other than benzyl quinalbromide; the content of benzyl quinalbromide in the oral liquid is 1wt%-2.20wt%.

[0030] Preferably, the oral liquid contains an antibacterial activity enhancer; the antibacterial activity enhancer is selected from at least one of triethanolamine, triisopropanolamine, and sorbitol; more preferably, the antibacterial activity enhancer is triethanolamine.

[0031] Preferably, the oral liquid also contains a flavoring agent, such as one or more of sweeteners, flavoring agents, gelling agents, and effervescent agents. More preferably, the flavoring agent is stevia.

[0032] Preferably, the flavoring agent is present in the oral liquid at a concentration of 0.01 wt% to 0.5 wt%.

[0033] Fifthly, the present invention provides a method for preparing the benzyl quinoline bromide preparation, the nasal spray, or the oral liquid, comprising: dissolving each raw material and excipient in water for injection and then sterilizing by filtration membrane.

[0034] Preferably, the pore size of the filter membrane is 0.22±0.02μm.

[0035] Beneficial effects:

[0036] This invention provides the application of benzyl quinalmonium as an antibacterial active ingredient and its formulations. This invention discovers that benzyl quinalmonium itself can be used as an antibacterial active ingredient, exhibiting inhibitory effects against a variety of common bacteria and fungi (including but not limited to Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Aspergillus niger, and Candida albicans). Mixing benzyl quinalmonium with triethanolamine or other antibacterial activity enhancers can significantly improve its antibacterial activity. In the preparation of benzyl quinalmonium-related formulations, good antibacterial effects can still be achieved without adding other antibacterial agents, and with higher safety. Detailed Implementation

[0037] Benzyl quinacrine is a novel anticholinergic drug. During the research process, this invention unexpectedly discovered its significant antibacterial activity, exhibiting good inhibitory effects against a variety of common and drug-resistant bacteria and fungi. In vitro antibacterial experiments confirmed that Benzyl quinacrine has inhibitory effects on various bacteria, including Staphylococcus aureus and Escherichia coli, with particularly significant effects against Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli, and it is also effective against some drug-resistant strains. Its antibacterial mechanism mainly involves adsorption to the bacterial surface, insertion of hydrophobic groups into the lipid layer, altering cell membrane permeability, disrupting membrane structure, causing intracellular leakage, denaturation or inhibition of enzyme or protein activity, affecting cellular metabolic processes, and ultimately leading to bacterial death. Given the inherent medicinal functions of Benzyl quinacrine (such as a selective M-cholinergic receptor antagonist), and its dual function as a pharmaceutically active functional component and antibacterial efficacy, it is possible to maintain good efficacy and stability in formulations containing Benzyl quinacrine without adding other antibacterial agents. Therefore, the phenylcycloquinoline bromide formulation provided by this invention, without the addition of other antibacterial active ingredients besides phenylcycloquinoline bromide, can also be considered a phenylcycloquinoline bromide pharmaceutical formulation with a simpler formulation and better safety. Benzylcycloquinoline bromide itself, as an active ingredient, also possesses antibacterial efficacy; therefore, in pharmaceutical formulations with phenylcycloquinoline bromide as the active ingredient, there is no need to add additional antibacterial agents, thus avoiding the risk of side effects caused by antibacterial agents. The antibacterial effect is optimal when used in combination with triethanolamine.

[0038] In some preferred and specific embodiments, the present invention provides a nasal spray drug with benzyl quinalbromide as the active ingredient for improving symptoms of runny nose, nasal congestion, nasal itching and sneezing caused by allergic rhinitis. The preparation method is as follows: accurately weigh 0.2-22g of benzyl quinalbromide and 0.3-8g of triethanolamine, add them to 1000ml of a hydroxyethylpiperazine ethanesulfonic acid-sodium hydroxide buffer solution with an endpoint of 6.5-8.0 (using water for injection as solvent, the pH of the water for injection is adjusted to 6.5-8.0 using hydroxyethylpiperazine ethanesulfonic acid-sodium hydroxide to obtain the hydroxyethylpiperazine ethanesulfonic acid-sodium hydroxide buffer solution with an endpoint of 6.5-8.0), after dissolution, measure the pH and osmotic pressure, and add an appropriate amount of sodium chloride to adjust the osmotic pressure to 260-330mOsm / L, and filter through a 0.22μm filter membrane for sterilization.

[0039] The application of antimicrobial agents in pharmaceutical preparations presents several challenges. First, while they prevent microbial contamination of drugs, their components may cause adverse reactions in certain populations, particularly children, especially around the eyes and injection sites. For instance, antimicrobial agents in ophthalmic preparations may be toxic to ocular surface cells, potentially leading to safety issues with long-term use. Furthermore, adding antimicrobial agents to high-dose infusions may react with the medication, causing adverse effects. Second, omitting antimicrobial agents can improve drug safety. For infusions administered directly into the bloodstream, the high volume and direct entry into the bloodstream necessitate extremely high quality standards. Modern infusion production achieves sterile manufacturing environments, eliminating the need for antimicrobial agents. Similarly, multi-dose ophthalmic preparations and nasal sprays are susceptible to microbial contamination after opening and during use and storage, but adding antimicrobial agents could exacerbate these problems. In recent years, some multi-dose ophthalmic preparations on the market have begun to omit antimicrobial agents to reduce potential eye hazards. Additionally, avoiding drug reactions is another advantage of not adding antimicrobial agents. Adding antibacterial agents to high-dose intravenous infusions may react with the medication, affecting its efficacy and even causing adverse effects on the human body. While antibacterial agents are not always necessary in biological products such as growth hormones, they should be used under the guidance of a doctor to avoid unnecessary health risks. The phenylcycloquinolone bromide nasal spray provided by this invention does not contain any additional antibacterial agents. This reduces the risk of allergic reactions to antibacterial ingredients in some individuals, preventing discomfort such as nasal mucosal edema and itching caused by allergies. It also reduces the irritation of antibacterial agents on sensitive nasal mucosa, alleviating burning sensations and other unpleasant experiences. Furthermore, it avoids the accumulation of toxic substances and side effects in the body caused by long-term or excessive use of products containing certain antibacterial agents.

[0040] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be clearly and completely described below. Obviously, the described embodiments are only some, not all, of the embodiments of this invention. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0041] The endpoints and any values ​​of the ranges disclosed in this specification are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0042] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "specific implementation," or "some specific implementations," etc., refer to specific features, structures, materials, or characteristics described in connection with that embodiment or example, which are included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0043] In the embodiments provided in this specification, unless specific techniques or conditions are specified, the techniques or conditions described in the literature in this field, or the product instructions, shall be followed. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased from legitimate channels.

[0044] In the following examples, the degree of reduction in bacterial count Ig values ​​at each time interval relative to the initial value (bacterial count Ig value at inoculation) was examined according to the antibacterial efficacy test method in General Chapter 1121 of Part IV of the 2020 edition of the Chinese Pharmacopoeia. The inhibition rate was calculated based on the viable bacterial count results using the following formula:

[0045] Y = (Nc - Ns) / Nc × 100%, where Y represents the inhibition rate, Nc represents the average colony count of the control sample, and Ns represents the average colony count of the test sample.

[0046] Example 1

[0047] This embodiment provides a phenylcycloquinoline bromide nasal spray: the content of phenylcycloquinoline bromide is 0.01wt%, the pH value is 6.5, and the osmotic pressure is 310mOsm / L; the pH value adjuster is hydroxyethylpiperazine ethanesulfonic acid-sodium hydroxide buffer solution, and the osmotic pressure adjuster is sodium chloride; no other antibacterial active ingredients other than phenylcycloquinoline bromide are added.

[0048] This embodiment provides a method for preparing the above-mentioned benzyl quinalbromide nasal spray. The steps are as follows: accurately weigh 0.1g of benzyl quinalbromide, add it to 1000ml of a hydroxyethylpiperazine ethanesulfonic acid-sodium hydroxide buffer solution with an endpoint of 6.5, dissolve it, measure the pH and osmotic pressure, add an appropriate amount of sodium chloride to adjust the osmotic pressure to 310mOsm / L, and filter it through a 0.22μm filter membrane for sterilization.

[0049] Example 2

[0050] This embodiment provides a phenylcycloquinoline bromide nasal spray: the content of phenylcycloquinoline bromide is 0.1 wt%, the pH value is 6.5, and the osmotic pressure is 310 mOsm / L; the pH value adjuster is hydroxyethylpiperazine ethanesulfonic acid-sodium hydroxide buffer solution, and the osmotic pressure adjuster is sodium chloride; no other antibacterial active ingredients other than phenylcycloquinoline bromide are added.

[0051] This embodiment provides a method for preparing the above-mentioned benzyl quinalbromide nasal spray. The steps are as follows: accurately weigh 1g of benzyl quinalbromide, add 1000ml of a hydroxyethylpiperazine ethanesulfonic acid-sodium hydroxide buffer solution with an endpoint of 6.5, dissolve, measure the pH and osmotic pressure, add an appropriate amount of sodium chloride to adjust the osmotic pressure to 310mOsm / L, and filter through a 0.22μm filter membrane for sterilization.

[0052] Example 3

[0053] This embodiment provides a phenylcycloquinoline bromide nasal spray: the content of phenylcycloquinoline bromide is 0.02wt%, the content of triethanolamine is 0.04wt%, the pH value is 6.5, and the osmotic pressure is 310mOsm / L; the pH value adjustment agent is hydroxyethylpiperazine ethanesulfonic acid-sodium hydroxide buffer solution, and the osmotic pressure adjustment agent is sodium chloride; no other antibacterial active ingredients other than phenylcycloquinoline bromide are added.

[0054] This embodiment provides a method for preparing the above-mentioned benzyl quinalbromide nasal spray. The steps are as follows: accurately weigh 0.2g of benzyl quinalbromide and 0.4g of triethanolamine, add 1000ml of a hydroxyethylpiperazine ethanesulfonic acid-sodium hydroxide buffer solution with an endpoint of 6.5, dissolve, measure the pH and osmotic pressure, add an appropriate amount of sodium chloride to adjust the osmotic pressure to 310mOsm / L, and filter through a 0.22μm filter membrane for sterilization.

[0055] Example 4

[0056] This embodiment provides a phenylcycloquinoline bromide nasal spray: the content of phenylcycloquinoline bromide is 0.1 wt%, the content of triethanolamine is 0.04 wt%, the pH value is 6.5, and the osmotic pressure is 310 mOsm / L; the pH value adjustment agent is hydroxyethylpiperazine ethanesulfonic acid-sodium hydroxide buffer solution, and the osmotic pressure adjustment agent is sodium chloride; no other antibacterial active ingredients other than phenylcycloquinoline bromide are added.

[0057] This embodiment provides a method for preparing the above-mentioned benzyl quinalbromide nasal spray. The steps are as follows: accurately weigh 1g of benzyl quinalbromide and 0.4g of triethanolamine, add 1000ml of a hydroxyethylpiperazine ethanesulfonic acid-sodium hydroxide buffer solution with an endpoint of 6.5, dissolve, measure the pH and osmotic pressure, add an appropriate amount of sodium chloride to adjust the osmotic pressure to 310mOsm / L, and filter through a 0.22μm filter membrane for sterilization.

[0058] Example 5

[0059] This embodiment provides a phenylcycloquinoline bromide nasal spray: the content of phenylcycloquinoline bromide is 0.1 wt%, the content of triethanolamine is 0.03 wt%, the pH value is 6.5, and the osmotic pressure is 310 mOsm / L; the pH value adjustment agent is hydroxyethylpiperazine ethanesulfonic acid-sodium hydroxide buffer solution, and the osmotic pressure adjustment agent is sodium chloride; no other antibacterial active ingredients other than phenylcycloquinoline bromide are added.

[0060] This embodiment provides a method for preparing the above-mentioned benzyl quinalbromide nasal spray. The steps are as follows: accurately weigh 1g of benzyl quinalbromide and 0.3g of triethanolamine, add 1000ml of a hydroxyethylpiperazine ethanesulfonic acid-sodium hydroxide buffer solution with an endpoint of 6.5, dissolve, measure the pH and osmotic pressure, add an appropriate amount of sodium chloride to adjust the osmotic pressure to 310mOsm / L, and filter through a 0.22μm filter membrane for sterilization.

[0061] Example 6

[0062] This embodiment provides a phenylcycloquinoline bromide nasal spray: the content of phenylcycloquinoline bromide is 0.1 wt%, the content of triethanolamine is 0.8 wt%, the pH value is 6.5, and the osmotic pressure is 310 mOsm / L; the pH value adjustment agent is hydroxyethylpiperazine ethanesulfonic acid-sodium hydroxide buffer solution, and the osmotic pressure adjustment agent is sodium chloride; no other antibacterial active ingredients other than phenylcycloquinoline bromide are added.

[0063] This embodiment provides a method for preparing the above-mentioned benzyl quinalbromide nasal spray. The steps are as follows: accurately weigh 1g of benzyl quinalbromide and 8g of triethanolamine, add 1000ml of a hydroxyethylpiperazine ethanesulfonic acid-sodium hydroxide buffer solution with an endpoint of 6.5, dissolve, measure the pH and osmotic pressure, add an appropriate amount of sodium chloride to adjust the osmotic pressure to 310mOsm / L, and filter through a 0.22μm filter membrane for sterilization.

[0064] Example 7

[0065] This embodiment provides a phenylcycloquinoline bromide nasal spray: the content of phenylcycloquinoline bromide is 0.1 wt%, the content of triisopropanolamine is 0.04 wt%, the pH value is 6.5, and the osmotic pressure is 310 mOsm / L; the pH value adjustment agent is hydroxyethylpiperazine ethanesulfonic acid-sodium hydroxide buffer solution, and the osmotic pressure adjustment agent is sodium chloride; no other antibacterial active ingredients other than phenylcycloquinoline bromide are added.

[0066] This embodiment provides a method for preparing the above-mentioned benzyl quinalbromide nasal spray. The steps are as follows: accurately weigh 1g of benzyl quinalbromide and 0.4g of triisopropanolamine excipient, add 1000ml of a hydroxyethylpiperazine ethanesulfonic acid-sodium hydroxide buffer solution with an endpoint of 6.5, dissolve, measure the pH and osmotic pressure, add an appropriate amount of sodium chloride to adjust the osmotic pressure to 310mOsm / L, and filter through a 0.22μm filter membrane for sterilization.

[0067] Example 8

[0068] This embodiment provides a benzyl quinalbromide eye drop solution: the content of benzyl quinalbromide is 0.02 wt%, the content of triethanolamine is 0.04 wt%, the pH value is 6.5, and the osmotic pressure is 310 mOsm / L; the pH value adjustment agent is hydroxyethylpiperazine ethanesulfonic acid-sodium hydroxide buffer solution, and the osmotic pressure adjustment agent is sodium chloride; no other antibacterial active ingredients other than benzyl quinalbromide are added.

[0069] This embodiment provides a method for preparing the above-mentioned benzylquinoline bromide eye drops. The steps are as follows: accurately weigh 0.2g of benzylquinoline bromide and 0.4g of triethanolamine, add them to 1000ml of a hydroxyethylpiperazine ethanesulfonic acid-sodium hydroxide buffer solution with an endpoint of 6.5, dissolve, measure the pH and osmotic pressure, and add an appropriate amount of sodium chloride to adjust the osmotic pressure to 310mOsm / L. Filter the solution sterilely through a 0.22μm filter membrane. Test the sample according to the microbial limit test for non-sterile products in the Chinese Pharmacopoeia: Microbial Count Method (General Rule 1105) and Control Bacteria Test Method (General Rule 1106) and the Microbial Limit Standard for Non-sterile Drugs (General Rule 1107), and it meets the requirements.

[0070] Example 9

[0071] This embodiment provides an inhalational compound phenylcycloquinoline bromide and salbutamol solution: the content of phenylcycloquinoline bromide is 0.02 wt%, the content of salbutamol is 0.2 wt%, the content of triethanolamine is 0.04 wt%, the pH value is 6.5, and the osmotic pressure is 310 mOsm / L; the pH value is adjusted by hydroxyethylpiperazine ethanesulfonic acid-sodium hydroxide buffer solution, and the osmotic pressure is adjusted by sodium chloride; no other antibacterial active ingredients other than phenylcycloquinoline bromide are added.

[0072] This embodiment provides a method for preparing the above-mentioned inhalation compound phenylcycloquinoline bromide and salbutamol solution. The steps are as follows: accurately weigh 0.2g of phenylcycloquinoline bromide, 2g of salbutamol, and 0.4g of triethanolamine, add them to 1000ml of a hydroxyethylpiperazine ethanesulfonic acid-sodium hydroxide buffer solution with an endpoint of 6.5, dissolve, measure the pH and osmotic pressure, and add an appropriate amount of sodium chloride to adjust the osmotic pressure to 310mOsm / L. Filter the solution sterilely through a 0.22μm filter membrane. Test the sample according to the microbial limit test for non-sterile products in the Chinese Pharmacopoeia: Microbial Count Method (General Rule 1105) and Control Bacteria Test Method (General Rule 1106) and the Microbial Limit Standard for Non-sterile Drugs (General Rule 1107), and it meets the requirements.

[0073] Example 10

[0074] This embodiment provides a benzyl quinalbromide inhalation aerosol: the content of benzyl quinalbromide is 0.1wt%, the content of triethanolamine is 0.04wt%, the content of oleic acid is 0.01wt%, the content of anhydrous ethanol is 0.8wt%, the pH adjuster is hydroxyethylpiperazine ethanesulfonic acid-sodium hydroxide buffer solution, and HFA134a is added to make up to 1000g. No other antibacterial active ingredients other than benzyl quinalbromide are added.

[0075] This embodiment provides a method for preparing the above-mentioned benzyl quinalbromide inhalation aerosol. The steps are as follows: accurately weigh 1g of benzyl quinalbromide, 0.4g of triethanolamine, 0.1g of oleic acid, and 8g of anhydrous ethanol. Add 100ml of hydroxyethylpiperazine ethanesulfonic acid-sodium hydroxide buffer solution with a final concentration of 6.5 to dissolve the mixture. Fill the aerosol can with the solution, seal the valve, and then add HFA134a to make up the volume. Shake well, dissolve the solution, and then filter it through a 0.22μm filter membrane for sterilization. The test sample was tested according to the microbial limit test for non-sterile products in the Chinese Pharmacopoeia: Microbial Count Method (General Rule 1105) and Control Bacteria Test Method (General Rule 1106) and the Microbial Limit Standard for Non-sterile Drugs (General Rule 1107), and it met the requirements.

[0076] Example 11

[0077] This embodiment provides a topical solution of benzyl quinalmonium: the content of benzyl quinalmonium is 0.1 wt%, the content of triethanolamine is 0.04 wt%, the pH value is 6.5, and the osmotic pressure is 310 mOsm / L; the pH value is adjusted by hydroxyethylpiperazine ethanesulfonic acid-sodium hydroxide buffer solution, and the osmotic pressure is adjusted by sodium chloride; no other antibacterial active ingredients other than benzyl quinalmonium are added.

[0078] This embodiment provides a method for preparing the above-mentioned benzyl quinalbromide external solution. The steps are as follows: accurately weigh 1g of benzyl quinalbromide and 0.4g of triethanolamine, add them to 1000ml of a hydroxyethylpiperazine ethanesulfonic acid-sodium hydroxide buffer solution with an endpoint of 6.5, dissolve, measure the pH and osmotic pressure, and add an appropriate amount of sodium chloride to adjust the osmotic pressure to 310mOsm / L. Filter the solution sterilely through a 0.22μm filter membrane. Test the sample according to the microbial limit test for non-sterile products in the Chinese Pharmacopoeia: Microbial Count Method (General Rule 1105) and Control Bacteria Test Method (General Rule 1106) and the Microbial Limit Standard for Non-sterile Drugs (General Rule 1107), and it meets the requirements.

[0079] Example 12

[0080] This embodiment provides a benzyl quinalmonium bromide detergent: the content of benzyl quinalmonium bromide is 0.1 wt%, the content of triethanolamine is 0.04 wt%, the content of propylene glycol is 2 wt%, the content of polysorbate 80 is 0.5 wt%, and the pH value is 6.5; the pH value adjuster is hydroxyethylpiperazine ethanesulfonic acid-sodium hydroxide buffer solution, and the osmotic pressure adjuster is sodium chloride; no other antibacterial active ingredients other than benzyl quinalmonium bromide are added.

[0081] This embodiment provides a method for preparing the above-mentioned benzyl quinalmonium bromide lotion. The steps are as follows: accurately weigh 1g of benzyl quinalmonium bromide, 0.4g of triethanolamine, 20g of propylene glycol, and 5g of polysorbate 80. Add them to 1000ml of a hydroxyethylpiperazine ethanesulfonic acid-sodium hydroxide buffer solution with an endpoint of 6.5, and add an appropriate amount of sodium chloride to adjust the osmotic pressure to 310mOsm / L. Filter the solution sterilely through a 0.22μm filter membrane. Test the sample according to the microbial limit test for non-sterile products in the Chinese Pharmacopoeia: Microbial Count Method (General Rule 1105) and Control Bacteria Test Method (General Rule 1106), and the Microbial Limit Standard for Non-sterile Drugs (General Rule 1107). The sample meets the requirements.

[0082] Example 13

[0083] This embodiment provides a benzyl quinalmonium bromide cream: the content of benzyl quinalmonium bromide is 0.1 wt%, the content of triethanolamine is 0.04 wt%, the content of white petrolatum is 10.0 wt%, the content of liquid paraffin is 5.0 wt%, the content of glyceryl monostearate is 3.0 wt%, the content of cetyl alcohol is 2 wt%, the content of glycerin is 5.0 wt%, and the pH value is 6.5; the pH value is adjusted by using hydroxyethylpiperazine ethanesulfonic acid-sodium hydroxide buffer solution; no other antibacterial active ingredients other than benzyl quinalmonium bromide are added.

[0084] This embodiment provides a method for preparing the above-mentioned benzyl quinalmonium bromide cream. The steps are as follows: accurately weigh 1g of benzyl quinalmonium bromide, 0.4g of triethanolamine, and 50g of glycerin, add them to 1000ml of a hydroxyethylpiperazine ethanesulfonic acid-sodium hydroxide buffer solution with a final concentration of 6.5, dissolve them, and then slowly add 100g of white petrolatum, 50g of liquid paraffin, 30g of glyceryl monostearate, and 20g of cetyl alcohol to the aqueous phase solution while stirring at high speed to emulsify. The test sample was tested according to the microbial limit test for non-sterile products in the Chinese Pharmacopoeia: Microbial Count Method (General Rule 1105) and Control Bacteria Test Method (General Rule 1106), and the Microbial Limit Standard for Non-sterile Drugs (General Rule 1107), and it met the requirements.

[0085] Example 14

[0086] This embodiment provides a benzyl quinalbromide oral solution: the content of benzyl quinalbromide is 1.10 wt%, the content of triethanolamine is 0.04 wt%, the content of stevia is 0.05 wt%, and the pH value is 6.5; the pH value adjuster is hydroxyethylpiperazine ethanesulfonic acid-sodium hydroxide buffer solution; no other antibacterial active ingredients other than benzyl quinalbromide are added.

[0087] This embodiment provides a method for preparing the above-mentioned benzylquinoline bromide oral solution. The steps are as follows: accurately weigh 11g of benzylquinoline bromide, 0.4g of triethanolamine, and 0.5g of stevia, add 1000ml of hydroxyethylpiperazine ethanesulfonic acid-sodium hydroxide buffer solution with a final concentration of 6.5 to dissolve, and filter sterilely through a 0.22μm filter membrane. The test sample was tested according to the microbial limit test for non-sterile products in the Chinese Pharmacopoeia: Microbial Count Method (General Rule 1105) and Control Bacteria Test Method (General Rule 1106), and the Microbial Limit Standard for Non-sterile Drugs (General Rule 1107), and met the requirements.

[0088] Example 15

[0089] This embodiment provides a benzyl quinalbromide oral solution: the content of benzyl quinalbromide is 2.20 wt%, the content of triethanolamine is 0.04 wt%, the content of stevia is 0.05 wt%, and the pH value is 6.5; the pH value adjuster is hydroxyethylpiperazine ethanesulfonic acid-sodium hydroxide buffer solution; no other antibacterial active ingredients other than benzyl quinalbromide are added.

[0090] This embodiment provides a method for preparing the above-mentioned benzylquinoline bromide oral solution. The steps are as follows: accurately weigh 22g of benzylquinoline bromide, 0.4g of triethanolamine, and 0.5g of stevia, add 1000ml of hydroxyethylpiperazine ethanesulfonic acid-sodium hydroxide buffer solution with a final concentration of 6.5 to dissolve, and filter sterilely through a 0.22μm filter membrane. The test sample was tested according to the microbial limit test for non-sterile products in the Chinese Pharmacopoeia: Microbial Count Method (General Rule 1105) and Control Bacteria Test Method (General Rule 1106), and the Microbial Limit Standard for Non-sterile Drugs (General Rule 1107), and met the requirements.

[0091] Comparative Example 1

[0092] This comparative example provides a control nasal spray: 0.4 g of triethanolamine is accurately weighed and added to 1000 ml of a hydroxyethylpiperazine ethanesulfonic acid-sodium hydroxide buffer solution with an endpoint of 6.5. After dissolution, the pH and osmotic pressure are measured, and an appropriate amount of sodium chloride is added to adjust the osmotic pressure to 310 mOsm / L. The solution is then filtered through a 0.22 μm filter membrane for sterilization.

[0093] Comparative Example 2

[0094] This comparative example provides a control nasal spray: 1g of benzyl quinalmonium bromide is accurately weighed and added to 1000ml of a hydroxyethylpiperazine ethanesulfonic acid-sodium hydroxide buffer solution with an endpoint of 8.2. After dissolution, the pH and osmotic pressure are measured, and an appropriate amount of sodium chloride is added to adjust the osmotic pressure to 310mOsm / L. The solution is then filtered through a 0.22μm filter membrane for sterilization.

[0095] Comparative Example 3

[0096] This comparative example provides a control nasal spray: accurately weigh 1g of benzyl quinalmonium bromide, 8g of sodium chloride, and 0.06g of benzalkonium chloride, dissolve them in 1000ml of water for injection, measure the pH and osmotic pressure, add 0.1mol hydrochloric acid to adjust the pH to 6.5, and filter through a 0.22μm filter membrane for sterilization.

[0097] Experimental Example 1

[0098] This experimental example uses the formulations provided in Examples 1-15 and Comparative Examples 1-3 as samples to determine the antibacterial ability of each sample.

[0099] The method is as follows:

[0100] In a clean bench, one porcelain bead each of Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli was inoculated into 10 ml of tryptic soy broth and incubated at 33°C for 18-24 hours. One porcelain bead inoculated with Candida albicans was placed into 10 ml of Sabouraud dextrose broth and incubated at 23°C for 48 hours. The fresh cultures were then diluted with 0.9% sterile sodium chloride solution to a concentration of 10⁻⁶ bacteria per ml. 7 -108 CFU / ml bacterial suspension. Take a concentrated spore suspension of Aspergillus niger and prepare a pH 7.0 sterile sodium chloride-peptone buffer containing 0.05% polysorbate 80 to a concentration of 10 CFU / ml. 7 CFU bacterial suspension.

[0101] Test sample group: Take 18 sterile brown-blue capped bottles, add 50 ml of each sample to each bottle, then add Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Aspergillus niger, and Candida albicans respectively, mix thoroughly to achieve a final concentration of 10. 5 -10 6 CFU / ml, store at 23°C, protected from light.

[0102] Bacterial suspension group: Take 5 sterile brown-blue capped bottles, add 50 ml of 0.9% sterile sodium chloride solution to each, then add Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Aspergillus niger, and Candida albicans respectively, mix thoroughly to achieve a final concentration of 10. 5 -10 6 The cfu / ml count was determined using a membrane filtration method to measure the number of viable bacteria per milliliter in the prepared bacterial solution.

[0103] After inoculation, take 10 ml of the test sample from the above sample bottle and dilute it 10-fold with tryptic soy peptone broth (TSB) at 10-fold serial dilutions. -1 10 -2 10 -3 10 -4 10 -5 10 -6 The test solution was prepared. Colony counting of the test sample group was performed according to the pharmacopoeia method. For bacterial counting, first take 10 of the above-mentioned samples... -1 10 ml of the diluted test solution was placed in 100 ml of sterile pH 7.0 sodium chloride-peptone buffer. The solution was filtered through a membrane, rinsing twice with 100 ml of pH 7.0 sterile sodium chloride-peptone buffer each time. The filtered membrane was then affixed to a tryptic soy agar (TSA) plate. 1 ml of each diluted test solution was then placed in 100 ml of sterile pH 7.0 sodium chloride-peptone buffer. The solution was filtered through a membrane, rinsing twice with 100 ml of pH 7.0 sterile sodium chloride-peptone buffer each time. The filtered membrane was then affixed to a tryptic soy agar (TSA) plate and incubated at 33°C for 5 days. The results were then observed. For fungal counting, 10 ml of the above diluted test solution was first taken... -110 ml of the diluted test solution was placed in 100 ml of sterile sodium chloride-peptone buffer (pH 7.0). The membrane was filtered twice using a 100 ml buffer solution each time. The filtered membrane was then placed on a Sabouraud dextrose agar (SDA) plate. 1 ml of each diluted test solution was then placed in 100 ml of sterile sodium chloride-peptone buffer (pH 7.0). The membrane was filtered twice using a 100 ml buffer solution (pH 7.0). The filtered membrane was then placed on a Sabouraud dextrose agar (SDA) plate and incubated at 23°C for 7 days.

[0104] Observe the results and calculate the antibacterial rate according to the following formula: where Y represents the antibacterial rate, Nc represents the average number of colonies in the control sample, and Ns represents the average number of colonies in the test sample.

[0105] Y = (Nc - Ns) / Nc × 100%.

[0106] The results of the antibacterial rate experiment are shown in Table 1.

[0107] Table 1. Results of antibacterial rate experiment (unit: %)

[0108]

[0109] As shown in Table 1, the antibacterial efficacy of benzyl quinalbromide is significantly enhanced under the influence of triethanolamine, and is comparable to the antibacterial efficacy of the formulation with added benzalkonium chloride.

[0110] Experiment Example 2

[0111] This experimental example tests the stability of the formulations provided in Examples 1-15. The testing methods followed the quality standards and operating procedures for marketed pharmaceutical products. The results are shown in Table 2.

[0112] Table 2. Accelerated stability test results (40℃±2℃, RH 75%±5%)

[0113]

[0114]

[0115]

[0116] As shown in Table 2, the accelerated test results indicate that the formulations provided in Examples 1-15, when placed at a temperature of 40℃±2℃ and a relative humidity of 75%±5% for 6 months, showed no significant changes in appearance, pH value, related substances, content, and antibacterial rate.

[0117] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. Application of benzyl quinoline bromide as an antibacterial active ingredient.

2. A benzyl quinalbromide preparation, comprising benzyl quinalbromide and an antibacterial activity enhancer, characterized in that, The antibacterial activity enhancer is selected from at least one of triethanolamine, triisopropanolamine, and sorbitol.

3. The benzyl quinoline bromide formulation according to claim 2, characterized in that, The mass ratio of benzyl quinoline bromide to antibacterial activity enhancer is 2-220:3-80, preferably 10:

4.

4. The benzyl quinoline bromide formulation according to claim 2 or 3, characterized in that, Its composition does not include any antibacterial active ingredients other than benzyl quinoline bromide.

5. The benzyl quinoline bromide formulation according to any one of claims 2-4, characterized in that, Its dosage forms include: nasal spray, eye drops, inhalation solution, inhalation aerosol, external solution, lotion, cream or oral liquid; preferably nasal spray.

6. The benzyl quinoline bromide formulation according to any one of claims 2-5, characterized in that, The benzyl quinolone bromide preparation is a preparation containing only the single active ingredient benzyl quinolone bromide, or a compound preparation containing other active ingredients, wherein the other active ingredients include one or more of antihistamines, glucocorticoids, decongestants, and β2 receptor agonists. Preferably, the antihistamine includes one or more of desloratadine, cetirizine, and fexofenadine; the glucocorticoid includes one or more of budesonide and mometasone furoate; the decongestant includes one or more of pseudoephedrine and oxymetazoline; and the β2 receptor agonist includes one or more of salbutamol and formoterol.

7. A nasal spray containing benzyl quinalbromide, characterized in that, Its components do not include other antibacterial active ingredients besides benzyl quinalbromide; the content of benzyl quinalbromide in the nasal spray is 0.02wt%-2.20wt%; preferably, the components also contain an antibacterial activity enhancer; the antibacterial activity enhancer is selected from at least one of triethanolamine, triisopropanolamine, and sorbitol.

8. The nasal spray according to claim 7, characterized in that, Its components also include at least one functional excipient among pH adjusters and osmotic pressure adjusters; Preferably, the pH adjuster is selected from at least one of hydroxyethylpiperazine ethanesulfonic acid-sodium hydroxide buffer solution, citric acid-disodium hydrogen phosphate buffer solution, and boric acid-sodium hydroxide buffer solution; the osmotic pressure adjuster is selected from at least one of sodium chloride and mannitol.

9. The nasal spray according to claim 7 or 8, characterized in that, Based on a total volume of 1000 ml, the nasal spray uses water for injection as a dispersant and contains 0.2-22 g of benzyl quinalmonium bromide and 0.3-8 g of triethanolamine; the pH value of the nasal spray is 6.5-8.0, and the osmotic pressure is 290-310 mOsm / L.

10. A method for preparing the benzyl quinoline bromide formulation according to any one of claims 2-6 or the nasal spray according to any one of claims 7-9, characterized in that, include: The raw materials and excipients are dissolved in water for injection and then sterilized by filtration membrane; the preferred pore size of the filter membrane is 0.22±0.02μm.

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