CN111436429A - Pharmaceutical composition for environmental disinfection and preparation method thereof - Google Patents
Pharmaceutical composition for environmental disinfection and preparation method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N33/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds
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- A01N33/12—Quaternary ammonium compounds
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
- A01N25/02—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing liquids as carriers, diluents or solvents
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- A—HUMAN NECESSITIES
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- A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
- A01N25/22—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing ingredients stabilising the active ingredients
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N35/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having two bonds to hetero atoms with at the most one bond to halogen, e.g. aldehyde radical
- A01N35/02—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having two bonds to hetero atoms with at the most one bond to halogen, e.g. aldehyde radical containing aliphatically bound aldehyde or keto groups, or thio analogues thereof; Derivatives thereof, e.g. acetals
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Abstract
The invention provides a pharmaceutical composition for environmental disinfection and a preparation method thereof, and relates to the field of veterinary disinfectants, wherein each 1L of the composition comprises 30-200 g of single-chain quaternary ammonium salt, 50-300 g of double-chain quaternary ammonium salt, 0.005-0.5 g of solution stabilizer, 0.5-3 g of acid-base regulator and the balance of purified water.
Description
Technical Field
The invention relates to the field of disinfectants for animals, in particular to a pharmaceutical composition containing single-chain quaternary ammonium salt and double-chain quaternary ammonium salt for environmental disinfection and a preparation method thereof.
Background
In recent years, serious animal epidemic diseases which occur successively not only cause great economic loss in the animal husbandry of China, but also directly threaten the health of people. At present, the occurrence of animal epidemic diseases is getting more and more intense.
Epidemic of infectious diseases in animals must have 3 of the most basic conditions, namely, the origin of infection, the route of transmission, and the susceptible animal, and only if these 3 conditions coexist and are linked to each other will the infectious disease become prevalent in the animal population. At present, the control of animal infectious diseases in China mainly comprises three modes of vaccine immunity, drug control and environmental disinfection. However, the ubiquitous concept of 'light-weight rearing and light-weight prevention and heavy-weight prevention' mainly depends on vaccine immunization and drug control for controlling animal infectious diseases.
Disinfection is the first measure to implement the prevention as the main policy. Generally, the disinfectant is used for disinfecting livestock and poultry (including skin mucosa and superficial body cavities on the body surface of the animal) and the surrounding environment thereof to kill pathogens, reduce the pollution of the pathogens to the feeding environment, cut off the transmission path of diseases, and achieve the purposes of preventing the occurrence and spread of the diseases and further controlling and eliminating infectious diseases. Therefore, thorough and standardized disinfection is the most effective and convenient method for preventing and controlling diseases. The disinfection of livestock and poultry and the surrounding environment by using a disinfectant to kill pathogens has become an important measure for preventing and controlling the epidemic of the infectious diseases of the livestock and poultry.
Most of the currently used chemical disinfectants are single disinfectant, such as phenol, formaldehyde, ethanol, bleaching powder, etc. However, the single-component disinfectant for animals often has the defects of narrow disinfection spectrum and application range, poor stability, strong corrosivity, irritation and toxicity, high disinfection performance easily affected by other substances, high price and the like, and has an unsatisfactory disinfection effect and certain limitation on use. Therefore, it is particularly necessary to develop a veterinary compound disinfectant to improve the sterilization effect and overcome the disadvantages of single veterinary disinfectant. Therefore, aiming at the current situation that the livestock and poultry breeding industry in China frequently outbreaks of epidemic diseases caused by poor breeding environment and the veterinary disinfectant production enterprises are poor in innovation capability, the research on the efficient, safe and broad-spectrum compound disinfectant with the effect of killing various pathogenic microorganisms such as avian influenza virus, circovirus, porcine reproductive and respiratory syndrome virus, foot and mouth disease virus, streptococcus and the like is carried out, and the compound disinfectant is an urgent demand for ensuring healthy development of the livestock and poultry industry in China and improving the living standard of people. Therefore, the development of the medicinal composition for environment disinfection, which has good disinfection effect, high stability and long sterilization and disinfection time, has great significance.
Disclosure of Invention
The invention aims to provide the medicinal composition for environmental disinfection, which has the advantages of simple process, good disinfection effect, high stability, long sterilization and disinfection action time and low cost. The invention also provides a preparation method of the pharmaceutical composition for environmental disinfection. The composition has obvious effect on RNA virus, parvovirus, adenovirus, poliovirus, avian influenza, newcastle disease, infectious bursal disease and other bacterial viruses.
It is another object of the present invention to provide a pharmaceutical composition for environmental sterilization which is superior to conventional pharmaceutical compositions for environmental sterilization. The composition is a drug composition for environmental disinfection, which is obtained by using the composition of disodium ethylenediamine tetraacetate and Provichem2203 as a solution stabilizer, and compared with the drug compositions for environmental disinfection obtained by other inventions, the composition has higher stability and better sterilization and disinfection effects. And the composition of the disodium ethylene diamine tetraacetate and the Provichem2203 is used as a solution stabilizer to obtain the environment disinfection pharmaceutical composition, and when the pH value of a composition system is 8-10, the composition has longer sterilization and disinfection action time compared with the composition of which the pH value is not in the range of 8-10.
Another object of the present invention is to provide a pharmaceutical composition for environmental disinfection.
In order to achieve the purpose of the invention, the technical scheme adopted by the invention is as follows:
the pharmaceutical composition for environmental disinfection is characterized in that each 1L of the pharmaceutical composition comprises 30-200 g of single-chain quaternary ammonium salt, 50-300 g of double-chain quaternary ammonium salt, 0.005-0.5 g of solution stabilizer, 0.5-3 g of acid-base regulator and the balance of purified water.
Wherein the single-chain quaternary ammonium salt is selected from: one or more of dodecyl dimethyl benzyl ammonium bromide, dodecyl dimethyl benzyl ammonium chloride, tetradecyl dimethyl benzyl ammonium chloride, hexadecyl dimethyl ethyl ammonium bromide, hexadecyl dimethyl benzyl ammonium chloride, miropyrammonium chloride, porilium chloride and benzethonium chloride; wherein, the dodecyl dimethyl benzyl ammonium chloride is selected from: dodecyl (60% C)14，30％C16，5％C18，5％C12) Dimethyl benzyl ammonium chloride, dodecyl (50% C)12，30％C14，17％C17，3％C18) Dimethyl benzyl ammonium chloride, dodecyl (100% C)14) Dimethyl benzyl ammonium chloride, dodecyl (50% C)14，40％C12，10％C16) Dimethyl benzyl ammonium chloride, dodecyl (58% C)14，28％C16，14％C12) One kind of dimethyl benzyl ammonium chloride.
Wherein the double-chain quaternary ammonium salt is selected from: one or more of dioctyl dimethyl ammonium chloride, octyl decyl dimethyl ammonium chloride, didecyl/dioctyl dimethyl ammonium chloride, dioctyl dimethyl ammonium chloride and didecyl dimethyl ammonium bromide.
Wherein the solution stabilizer is selected from: one or more of polyphosphate, 1, 3-diketone, hydroxycarboxylic acid, disodium ethylene diamine tetraacetate, polyamine, aminocarboxylic acid, Provichem 2202, Provichem2203, HT-944 and polyvinyl alcohol. Preferably said solution stabilizer is selected from: a combination of disodium edetate and Provichem 2203; the weight ratio of the disodium ethylene diamine tetraacetate to the Provichem2203 is 1: 1-10: 1, and the most preferable solution stabilizer is selected from the following components: a combination of disodium edetate and Provichem 2203; the weight ratio of the disodium ethylene diamine tetraacetate to the Provichem2203 composition is 3: 1.
Wherein the pH value of the composition is 8-10.
Most preferably, the composition of the present invention comprises 100g of dodecyl (50% C) per 1L14，40％C12，10％C16) Dimethyl benzyl ammonium chloride, 150g of didecyl dimethyl ammonium chloride, 0.06g of ethylene diamine tetraacetic acid disodium, 0.02g of Provichem2203, a proper amount of an acid-base regulator until the pH value is 8-10, and the balance of purified water.
The preparation method of the composition comprises the following steps:
1) mixing single-chain quaternary ammonium salt raw material medicine with a proper amount of purified water, and heating at 70 ℃ to completely melt the raw material medicine into a flowable state;
2) sequentially adding the double-chain quaternary ammonium salt and the solution stabilizer into a stirrer and uniformly stirring;
3) and (3) adjusting the pH value of the medicinal composition for environmental disinfection to 8-10 by using an acid-base regulator, and fixing the volume to obtain the medicinal composition.
Preferably, the preparation method of the composition of the present invention comprises the following steps: mixing single-chain quaternary ammonium salt raw material medicine with a proper amount of purified water, and heating at 70 ℃ to completely melt the raw material medicine into a flowable state; sequentially adding the double-chain quaternary ammonium salt and the solution stabilizer into a stirrer and uniformly stirring; and (3) adjusting the pH value of the medicinal composition for environmental disinfection to 8-10 by using an acid-base regulator, and fixing the volume to obtain the medicinal composition.
The main component of the pharmaceutical composition for environmental disinfection prepared by the invention is dodecyl (50% C)14，40％C12， 10％C16) Dimethyl benzyl ammonium chloride and didecyl dimethyl ammonium chloride. Dodecyl (50% C)14，40％C12，10％C16) The dimethyl benzyl ammonium chloride is single-chain quaternary ammonium salt, and the didecyl dimethyl ammonium chloride is double-chain quaternary ammonium salt. The biocidal effect of quaternary ammonium salts results from the interaction of the cationic head group of the quaternary ammonium nitrogen in its molecule with the negatively charged head group of the acidic phospholipid in the cell membrane, once they have combinedIn addition, the hydrophobic tail group of the quaternary ammonium salt can be embedded into the interior of the hydrophobic membrane of the microorganism, and the cell membrane and the quaternary ammonium salt can form mixed micelle aggregates at higher concentration of the quaternary ammonium salt so as to be disintegrated. The quaternary ammonium salt disinfectant has bacteriostasis function at low concentration, and can kill most kinds of bacteria propagules and partial viruses at higher concentration.
The pharmaceutical composition for environmental disinfection prepared by the invention has the advantages of simple preparation process, good disinfection effect, high stability, long sterilization and disinfection action time and low cost, is suitable for large-scale industrial production, and has great significance for sustainable development of animal husbandry.
The environment disinfection pharmaceutical composition prepared by the invention is better than the conventional environment disinfection pharmaceutical composition, the composition is obtained by using the composition of disodium ethylenediamine tetraacetic acid and Provichem2203 as a solution stabilizer, and compared with other environment disinfection pharmaceutical compositions obtained by the invention, the composition has higher stability and better sterilization and disinfection effects. And the composition of the disodium ethylene diamine tetraacetate and the Provichem2203 is used as a solution stabilizer to obtain the environment disinfection pharmaceutical composition, and when the pH value of a composition system is 8-10, the composition has longer sterilization and disinfection action time compared with the composition of which the pH value is not in the range of 8-10.
At present, the quaternary ammonium salt microbicidal medicines on the market comprise: benzalkonium bromide solution, benzalkonium chloride solution and compound glutaraldehyde solution, wherein the types of the benzalkonium bromide solution, the benzalkonium chloride solution and the compound glutaraldehyde solution are as follows: benzalkonium chloride solution and compound glutaraldehyde solution.
The components of the composition comprise: the benzalkonium chloride solution mainly comprises benzalkonium chloride, and the compound glutaraldehyde solution mainly comprises glutaraldehyde and benzalkonium chloride.
The disadvantages are that: the benzalkonium chloride solution is a single-chain quaternary ammonium salt single preparation, has a narrow disinfection range and only aims at specific bacteria; the compound glutaraldehyde solution is a preparation compounded by glutaraldehyde and single-chain quaternary ammonium salt, the disinfection range is not wide due to the compounding of the single-chain quaternary ammonium salt and the double-chain quaternary ammonium salt, the sterilization effect time of the preparation is long, generally more than 10 hours, and the glutaraldehyde has certain toxicity and can cause bronchitis and pulmonary edema.
The main differences with the present invention are: the known quaternary ammonium salt microbial killing medicine has a narrow killing range on bacteria and viruses, and the composition has an obvious effect on various bacteria and viruses such as RNA viruses, parvoviruses, adenoviruses, polioviruses, avian influenza, newcastle diseases, infectious bursal diseases and the like; the sterilization effect of the known quaternary ammonium salt microbial killing medicine is short, the sterilization effect time is long, the sterilization effect of the composition is more durable, and the sterilization rate of the composition to various bacteria and viruses can reach more than 99.9 percent in about 2.5 min.
Products containing the same ingredients as the present invention are currently reported as: veterinary disinfectant and preparation method thereof (application No. 200910087914.5, the components similar to the invention comprise benzalkonium chloride and didecyl dimethyl ammonium bromide), novel disinfectant prepared by utilizing quaternary ammonium salt and alcohol (application No. 201410807324.6, the components similar to the invention comprise at least one of benzalkonium chloride, benzalkonium bromide, hexadecyl trimethyl ammonium, bisdecyl dimethyl ammonium and alkyl trimethyl ammonium carbonate), disinfectant of quaternary ammonium salt polymer and copolymer (application No. 200680039366.3, the components similar to the invention comprise benzalkonium chloride, benzethonium chloride, dimethyl didecyl ammonium chloride or mixture thereof), disinfectant capable of being used by high dilution, preparation method and application (application No. 201010216594.1, the components similar to the invention comprise dimethyl dodecyl didodecyl ammonium chloride, benzalkonium chloride, dodecyl dimethyl ethyl phenethyl ammonium bromide, dodecyl dimethyl dodecyl benzyl chloride, benzyl benzalkonium chloride, or mixture thereof), One or a mixture of more than two of dimethyl bisdecyl ammonium chloride, dimethyl bisdecyl ammonium bromide, dimethyl bisdecyl ammonium carbonate, dimethyl bistetradecyl ammonium chloride, dimethyl bishexadecyl ammonium chloride and benzethonium chloride), a disinfectant in the food field and a preparation method (application number: 201010219496.3, ingredients similar to the present invention include one or more of benzalkonium bromide, benzalkonium chloride, dimethyl didodecyl ammonium chloride, dimethyl dihexadecyl ammonium chloride, dodecyl dimethyl ethyl benzene oxyethyl ammonium bromide, dimethyl bisdecyl ammonium chloride, dimethyl bisdecyl ammonium bromide, dimethyl bisdecyl ammonium carbonate, dimethyl bistetradecyl ammonium chloride, benzethonium chloride) and topical antimicrobial compositions (application No.: 201780025348.8, ingredients similar to the present invention include didecyl dimethyl ammonium chloride, benzethonium chloride, benzalkonium chloride, polydiallyl dimethyl ammonium chloride, or mixtures thereof).
The disinfectant for animals and the preparation method thereof (application number: 200910087914.5) only disclose the average sterilization rate of different times of dilution on escherichia coli and staphylococcus aureus within 10 min; a novel disinfectant (application No. 201410807324.6) prepared from quaternary ammonium salt and alcohol only discloses average bactericidal rate of Escherichia coli 8099, Staphylococcus aureus ATCC6538, Candida albicans ATCC10231, Pseudomonas aeruginosa ATCC15442 and Aspergillus niger within 5 min; the disinfectant of quaternary ammonium salt polymer and copolymer (application number: 200680039366.3) only discloses average bacteriostatic ability in 48h of escherichia coli, staphylococcus aureus, MSRA and vancomycin-resistant enterococcus faecalis; the disinfectant which can be diluted by high times and used, the preparation method and the application (application number: 201010216594.1) only disclose the average sterilization rate of different times of dilution on escherichia coli, candida albicans and staphylococcus aureus within 20 min; the disinfectant in the food field and the preparation method (application number: 201010219496.3) only disclose the average sterilization effect of different times of dilution on escherichia coli within 10 min; topical antimicrobial compositions (application No. 201780025348.8) only published the average bactericidal effect of different fold dilutions on e.coli over 3 h. None of the products containing the same ingredients as those of the present invention reported above exhibit their long term bactericidal efficacy.
Compared with the products containing the same components as those reported at present, the invention has the main advantages that the invention has more obvious disinfection effect on various bacteria and viruses, the sterilization and disinfection onset time is short, and particularly, the invention has better stability and more durable disinfection effect.
The following experimental data comparison shows that the technology of the invention is superior to the product technology related to the invention which is disclosed at present:
the disinfectant of the present invention and the two disinfectants and products related to the present invention are diluted with sterilized hard water to a certain concentration according to the instructions, and the test groups are set as shown in the following table 1, test results table 2 and table 3:
TABLE 1 test grouping and dilution ratio
Remarking: the D1 product is a product prepared according to the disinfectant for animals and the preparation method thereof (application number: 200910087914.5);
the D2 product is a product prepared according to a novel disinfectant (application No. 201410807324.6) prepared by using quaternary ammonium salt and alcohol;
the D3 product was a product prepared as a disinfectant based on quaternary ammonium salt polymers and copolymers (application No.: 200680039366.3);
the D4 product is a disinfectant which can be diluted and used by high times, a preparation method and application (application number: 201010216594.1);
the D5 product is prepared according to the disinfectant in the food field and the preparation method (application number: 201010219496.3);
product D6 is a product prepared in accordance with the topical antimicrobial composition (application No.: 201780025348.8);
TABLE 2 comparison of the disinfecting effects on E.coli
Note: the above results are the average of 3 tests.
TABLE 3 comparison of the disinfecting effects on Staphylococcus aureus
Note: the above results are the average of 3 tests.
Test results show that the invention has good effect of killing escherichia coli and staphylococcus aureus, the killing rate of the invention to the escherichia coli and the staphylococcus aureus reaches more than 99.7 percent in 2.5min, and the killing rate is still 99.8 percent in 120 h. The benzalkonium chloride solution and the compound glutaraldehyde solution have relatively poor killing effects on escherichia coli and staphylococcus aureus, no killing effect exists in 2.5min, the highest killing effect on the escherichia coli and the staphylococcus aureus is achieved in 60min, and the killing effects are obviously reduced along with the increase of time. The killing effect of the D1-D6 products on escherichia coli and staphylococcus aureus is obviously lower than that of the invention, and the killing effect has a descending trend along with the increase of time and is obviously lower than that of the invention.
The formula of the invention is obtained by screening, and the screening process is as follows:
1 screening of effective ingredients
1.1 formulation screening
The single-chain and double-chain quaternary ammonium salts with the best bactericidal effect are screened out by measuring the minimum inhibition and bactericidal concentration of various single-chain and double-chain quaternary ammonium salt raw materials through escherichia coli 8099 and staphylococcus aureus ATCC 6538. The specific screening results are shown in Table 4-1.
TABLE 4-1 measurement of minimum inhibitory concentration (MIC/MBC) of quaternary ammonium salt disinfectant
Note: the above results are the average of 3 tests. The experimental conditions are 20 +/-1 ℃, and the action time of the MBC group is 5 min.
The negative control group was grown aseptically.
The results show that: the minimum inhibitory concentration of benzalkonium chloride in the single-chain quaternary ammonium salt to escherichia coli is 0.004 mu g/ml, the minimum bactericidal concentration is 0.061 mu g/ml, the bacteriostatic and bactericidal effects are the best, the minimum inhibitory concentration of benzalkonium chloride to staphylococcus aureus is 0.001 mu g/ml, the minimum bactericidal concentration is 0.015 mu g/ml, and the bacteriostatic and bactericidal effects are the best; the minimum inhibitory concentration of decamethylammonium chloride in the double-chain quaternary ammonium salt to escherichia coli is 0.004 mu g/ml, the minimum bactericidal concentration is 0.030 mu g/ml, and the inhibitory and bactericidal effects are the best, the minimum inhibitory concentration of decamethylammonium chloride to staphylococcus aureus is 0.001 mu g/ml, the minimum bactericidal concentration is 0.030 mu g/ml, and the inhibitory and bactericidal effects are the best. Therefore, benzalkonium chloride and decamethyl ammonium chloride are selected as the compound components of the invention.
1.2 proportional screening
The disinfectant indicator bacteria Escherichia coli 8099 and Staphylococcus aureus ATCC6538 for animals are used as test strains to carry out combined drug susceptibility test. A chessboard method is used, a 96-hole sterile microporous plate is used, and according to the measured MIC values of the single-chain and double-chain quaternary ammonium salts, 9-time MIC, 3-time MIC, 1-time MIC, 1/3MIC and 1/9MIC of the two drugs are combined respectively. The checkerboard test was repeated 3 times per strain. The test result takes part of the index of the inhibitory concentration (FIC) as the judgment basis of the combined drug sensitivity test.
And (4) result discrimination: according to the bacteriostasis condition of the combined drug sensitivity and the single drug sensitivity, a part of bacteriostasis concentration index (FIC) is taken as a judgment basis.
Note: when FIC is less than or equal to 0.5, the synergistic effect is expressed;
when FIC is more than 0.5 and less than or equal to 1, the additive effect is shown;
when FIC is more than 1 and less than or equal to 2, the effect is irrelevant;
antagonism is indicated when FIC > 2.
TABLE 4-2 Combined susceptibility test results for benzalkonium chloride and decamethylammonium chloride to Escherichia coli (8099)
Note: the above results are the average of 3 tests. The test conditions were all 20. + -. 1 ℃. The positive control group was turbid, and the negative control group was aseptically grown.
Benzalkonium chloride-decamethylammonium chloride (1: 2): FIC 0.0004/0.004+0.001/0.004 0.35, and has synergistic effect
Benzalkonium chloride-decamethylammonium chloride (1: 1): FIC 0.001/0.004+ 0.001/0.004-0.5, and has synergistic effect
Benzalkonium chloride-decamethylammonium chloride (2: 1): FIC 0.001/0.004+0.0004/0.004 ═ 0.35, synergistic effect
TABLE 4-3 Combined susceptibility test results for benzalkonium chloride and decamethylammonium chloride to Staphylococcus aureus (ATCC 6538)
Note: the above results are the average of 3 tests. The test conditions were all 20. + -. 1 ℃. The positive control group was turbid, and the negative control group was aseptically grown.
Benzalkonium chloride-decamethylammonium chloride (1: 2): FIC 0.0004/0.004+0.001/0.004 0.35, and has synergistic effect
Benzalkonium chloride-decamethylammonium chloride (1: 1): FIC 0.001/0.004+ 0.001/0.004-0.5, and has synergistic effect
Benzalkonium chloride-decamethylammonium chloride (2: 1): FIC 0.001/0.004+0.0004/0.004 ═ 0.35, synergistic effect
The results show that: by carrying out MIC/MBC screening on a single quaternary ammonium salt medicament, benzalkonium chloride and decamethyl chloride with the best antibacterial and bactericidal effects are screened out to be used as main components of the formula. The antibacterial agent indicator bacterium Escherichia coli 8099 and the staphylococcus aureus ATCC6538 are subjected to combined drug sensitivity test to obtain that when the ratio of benzalkonium chloride to decamethylammonium chloride is 2:1-1:2, the two drugs have a synergistic effect and have the strongest antibacterial effect, and the ratio of benzalkonium chloride to decamethylammonium chloride is 1:1.5 by comprehensive consideration.
2 selection of the type and concentration of the stabilizer
Quaternary ammonium salt disinfectants are cationic surfactants and therefore cannot be used in combination with anionic surfactants, such as soap, lecithin, washing powder, tween-80, and other substances have antagonistic effects against quaternary ammonium salt disinfectants, such as metal ions of iodine, potassium iodide, silver protein, salicylic acid, mercuric chloride, peroxide, calcium, magnesium, iron, aluminum, and the like.
Sources of the stabilizer:
EDTA-2 Na: purchased from Nanjing chemical reagents GmbH, and analyzed;
polyvinyl alcohol: purchased from Jiangxi Alkagaku pharmaceutical Co., Ltd, and analyzed;
provichem 2203: the stabilizer is purchased from Prowilliam corporation, is of a pharmaceutical grade, is a novel copolymerization type stabilizer, and is not reported to be used in the disinfection field;
2.1 screening of concentrations of different types of stabilizers
Test conditions are established: selecting three common stabilizers of EDTA & 2Na, polyvinyl alcohol and Provichem2203, setting different concentrations, preparing a prescription preparation, inspecting the properties, pH value, clarity, content measurement and bacterium inhibition effect of the preparation under each concentration, and screening out the optimal type and concentration of the stabilizer. The specific screening results are shown in tables 4-6.
TABLE 4-4 characterization of EDTA-2 Na as stabilizer
Tables 4-5 characterization of polyvinyl alcohol Properties as stabilizers
Tables 4-6 characterization of Provichem2203 Properties as stabilizers
The above test results show that different kinds of stabilizersThe character, pH value, clarity and main drug component content of the invention are not obviously influenced, then the invention adopts a drug sensitive tablet method, the invention measures the diameters of inhibition zones of staphylococcus aureus, escherichia coli and candida albicans by measuring the concentrations and the types of different stabilizers, the test data is collected by Excel, the variance analysis is carried out by SPSS17.0 software, and the result is analyzed by using the software
Indicating that the difference is obvious when P is less than 0.05 marked by an alphabetic marking method; p > 0.05 means that the difference is not significant in order to select the optimal stabilizer type and concentration.
Firstly, the optimal concentration data of three stabilizers of EDTA & 2Na, polyvinyl alcohol and Provichem2203 are analyzed, and the specific results are shown in tables 4-7-4-9.
TABLE 4-7 inhibiting effect of EDTA-2 Na with different concentrations on Staphylococcus aureus, Escherichia coli and Candida albicans
Note: the same column mark shows obvious difference with different lower case letters, and P is less than 0.05; no or the same letter indicates no significant difference, P > 0.05.
From the above results, it can be seen that:
staphylococcus aureus: in the tested EDTA-2 Na concentration, when the added concentration is 0.006%, the bacteriostatic effect of the invention on staphylococcus aureus is better and is obviously better than that of other concentrations. Therefore, 0.006% of EDTA-2 Na was selected for addition to the present invention.
Coli: in the tested EDTA & 2Na concentration, when the added concentration is 0.006%, the antibacterial effect on escherichia coli is better and is obviously better than that of other concentrations. Therefore, 0.006% of EDTA-2 Na was selected for addition to the present invention.
Candida albicans: in the concentration of the EDTA & 2Na which is considered, when the added concentration is 0.002%, the bacteriostatic effect of the invention on the Candida albicans is better and is obviously better than that of other concentrations. When the added concentration is 0.006 percent, the bacteriostatic effect on the candida albicans is only inferior to that of the invention with the concentration of 0.002 percent, and the bacteriostatic effect is obviously superior to that of other concentrations.
The disinfectant mainly aims at various bacteria, but not only at a certain pathogenic bacterium. Therefore, in summary, it is tentatively selected to add 0.006% EDTA-2 Na to the present invention.
TABLE 4-8 bacteriostatic effect of polyvinyl alcohol of different concentrations on Staphylococcus aureus, Escherichia coli, Candida albicans
Note: the same column mark shows obvious difference with different lower case letters, and P is less than 0.05; no or the same letter indicates no significant difference, P > 0.05.
From the above results, it can be seen that:
staphylococcus aureus: in the concentration of the polyvinyl alcohol to be investigated, when the added concentration is 0.001%, the bacteriostatic effect of the polyvinyl alcohol bacteriostatic agent on staphylococcus aureus is better and is obviously better than that of other concentrations. Therefore, 0.001% polyvinyl alcohol was selected for addition to the present invention.
Coli: in the concentration of the polyvinyl alcohol to be investigated, when the added concentration is 0.001% and 0.002%, the antibacterial effect of the polyvinyl alcohol antibacterial agent on escherichia coli is better and is obviously better than that of other concentrations. Thus, 0.001% or 0.002% polyvinyl alcohol may be added to the present invention.
Candida albicans: in the concentration of the polyvinyl alcohol to be investigated, when the added concentration is 0.001%, 0.002%, 0.005% and 0.010%, the bacteriostatic effect of the polyvinyl alcohol bacteriostatic agent on candida albicans is equivalent and is obviously better than the bacteriostatic effect of the polyvinyl alcohol which is not added and has the concentration of 0.020%.
In conclusion, 0.001% of polyvinyl alcohol can be temporarily added into the antibacterial agent, so that the antibacterial effect of the antibacterial agent reaches a better level.
Tables 4-9 bacteriostatic effects of Provichem2203 at different concentrations on Staphylococcus aureus, Escherichia coli and Candida albicans
Note: the same column mark shows obvious difference with different lower case letters, and P is less than 0.05; no or the same letter indicates no significant difference, P > 0.05.
From the above results, it can be seen that:
staphylococcus aureus: in the tested Provichem2203 concentrations, when the added concentrations are 0.005% and 0.002%, the bacteriostatic effect of the bacteriostatic agent on staphylococcus aureus is better and is obviously better than that of other concentrations. Thus, Provichem2203 can be added to the present invention at 0.005% and 0.002% as an option.
Coli: in the observed Provichem2203 concentrations, when the added concentrations are 0.005% and 0.002%, the antibacterial effect on escherichia coli is better and is obviously better than that of other concentrations. Thus, 0.005% and 0.002% of Provichem2203 can be added to the present invention.
Candida albicans: in the studied Provichem2203 concentration, when the added concentration is 0.002%, the bacteriostatic effect of the bacteriostatic agent on Candida albicans is better and is obviously better than that of other concentrations. Thus, 0.005% of Provichem2203 can be added to the present invention.
In conclusion, 0.002% of Provichem2203 can be added into the antibacterial agent, so that the antibacterial effect of the antibacterial agent reaches a better level.
2.2 screening of stabilizer classes
The selected EDTA-2 Na, polyvinyl alcohol and Provichem2203 with the optimal concentration are combined in pairs to compare the bacteriostatic effects of staphylococcus aureus, escherichia coli and candida albicans, so as to screen out the optimal stabilizer variety.
TABLE 4-10 bacteriostatic effect of stabilizers with different proportions on Staphylococcus aureus, Escherichia coli and Candida albicans
Note: the same column mark shows obvious difference with different lower case letters, and P is less than 0.05; no or the same letter indicates no significant difference, P > 0.05.
From the above results, it is clear that EDTA.2 Na: when Provichem2203 is 3:1, the composite stabilizer has better bacteriostatic effect on staphylococcus aureus, escherichia coli and candida albicans, and is obviously superior to other composite stabilizers. Therefore, edta.2 Na was chosen in the final formulation: provichem 2203-3: 1 is the best stabilizer type and concentration of the invention, namely EDTA-2 Na concentration is 0.006%, and Provichem2203 concentration is 0.002%.
3 selection of pH value
Test conditions are established: according to the formula of the invention, 5 parts of preparation samples are prepared, and the pH is adjusted to 2, 4, 6, 8 and 10 by using sodium hydroxide or hydrochloric acid test solution respectively. And inspecting the properties, clarity, precipitation and bacteriostasis effect of the preparations with various pH values so as to screen out the optimal pH value.
Tables 4-11 examination of the Properties of the invention at different pH values
Taking 5 parts of each 50ml of completely packaged sample under each pH condition, adopting a drug sensitive strip method, measuring the sizes of the bacteriostatic circle diameters of staphylococcus aureus, escherichia coli and candida albicans by the method for measuring different pH values, collecting test data by using Excel, carrying out variance analysis by using SPSS17.0 software, and using results to carry out variance analysis by using SPSS17.0 software
Indicating that the difference is obvious when P is less than 0.05 marked by an alphabetic marking method; p > 0.05 means no significant difference, in order to select the most significantThe pH value is good. The specific results are shown in tables 4-12.
TABLE 4-12 bacteriostatic effect of different pH values on Staphylococcus aureus, Escherichia coli and Candida albicans
Note: the same column mark shows obvious difference with different lower case letters, and P is less than 0.05; no or the same letter indicates no significant difference, P > 0.05.
From the above results, it can be seen that:
staphylococcus aureus: among the pH values to be investigated, the bacteriostatic effect of the pH value groups of 8 and 10 is the best, and is obviously higher than that of the pH value groups of 2, 4 and 6. Therefore, when the pH value is 8-10, the antibacterial effect on staphylococcus aureus is better.
Coli: of the pH values examined, the group with pH value 8 has the best bacteriostatic effect, and the group with pH value 10 is next, and the pH values are obviously higher than the groups with pH values of 2, 4 and 6. Therefore, when the pH value is 8-10, the antibacterial effect on escherichia coli is good.
Candida albicans: of the pH values examined, the group pH 8 had the best bacteriostatic effect, and the group pH 10 was followed and was significantly higher than the groups pH 2, 4 and 6. Therefore, when the pH value is 8-10, the bacteriostatic effect of the invention on Candida albicans is better.
In view of the above, the pH of the present invention is set to 8 to 10, and the most preferred pH is 8, since the effect of the present invention is mainly to kill microorganisms such as bacteria and fungi.
Detailed Description
Example one
30g of dodecyl (50% C)14，40％C12，10％C16) Mixing the bulk drug of dimethyl benzyl ammonium chloride with a proper amount of purified water, and heating at 70 ℃ to completely melt the bulk drug of dimethyl benzyl ammonium chloride into a flowable state; sequentially adding 60g of didecyl dimethyl ammonium chloride, 0.006g of ethylene diamine tetraacetic acid and 0.002g of Provichem2203, and uniformly stirring on a stirrer; adjusting the pH value of the pharmaceutical composition for environmental disinfection to 8-10 by using an acid-base regulator, and purifyingThe water is added to a constant volume of 1L to obtain the medicinal composition for environmental disinfection.
Example two
50g of dodecyl (50% C)14，40％C12，10％C16) Mixing the bulk drug of dimethyl benzyl ammonium chloride with a proper amount of purified water, heating at 70 ℃ to completely melt the bulk drug of dimethyl benzyl ammonium chloride into a flowable state, sequentially adding 75g of didecyl dimethyl ammonium chloride, 0.015g of disodium ethylene diamine tetraacetate and 0.008g of Provichem2203, uniformly stirring on a stirrer, adjusting the pH value of the pharmaceutical composition for environmental disinfection to 8-10 by using an acid-base regulator, and fixing the volume of the purified water to 1L to obtain the pharmaceutical composition for environmental disinfection.
EXAMPLE III
100g of dodecyl (50% C)14，40％C12，10％C16) Mixing the bulk drug of dimethyl benzyl ammonium chloride with a proper amount of purified water, heating at 70 ℃ to completely melt the bulk drug of dimethyl benzyl ammonium chloride into a flowable state, sequentially adding 150g of didecyl dimethyl ammonium chloride, 0.06g of disodium ethylene diamine tetraacetate and 0.02g of Provichem2203, uniformly stirring on a stirrer, adjusting the pH value of the pharmaceutical composition for environmental disinfection to 8-10 by using an acid-base regulator, and fixing the volume of the purified water to 1L to obtain the pharmaceutical composition for environmental disinfection.
Example four
100g of dodecyl (50% C)14，40％C12，10％C16) Mixing the bulk drug of dimethyl benzyl ammonium chloride with a proper amount of purified water, heating at 70 ℃ to completely melt the bulk drug of dimethyl benzyl ammonium chloride into a flowable state, sequentially adding 200g of didecyl dimethyl ammonium chloride, 0.3g of disodium ethylene diamine tetraacetate and 0.2g of Provichem2203, uniformly stirring on a stirrer, adjusting the pH value of the pharmaceutical composition for environmental disinfection to 8-10 by using an acid-base regulator, and fixing the volume of the purified water to 1L to obtain the pharmaceutical composition for environmental disinfection.
EXAMPLE five
150g of dodecyl (50% C)14，40％C12，10％C16) Mixing the bulk drug of dimethyl benzyl ammonium chloride with a proper amount of purified water, and heating at 70 ℃ to completely melt the bulk drug of dimethyl benzyl ammonium chloride into a flowable state; 200g of didecyl dimethyl ammonium chloride, 0.2gAnd (2) uniformly stirring 0.08g of Provichem2203 and disodium ethylene diamine tetraacetate on a stirrer, adjusting the pH value of the pharmaceutical composition for environmental disinfection to 8-10 by using an acid-base regulator, and fixing the volume of purified water to 1L to obtain the pharmaceutical composition for environmental disinfection.
EXAMPLE six
200g of dodecyl (50% C)14，40％C12，10％C16) Mixing the bulk drug of dimethyl benzyl ammonium chloride with a proper amount of purified water, heating at 70 ℃ to completely melt the bulk drug of dimethyl benzyl ammonium chloride into a flowable state, sequentially adding 250g of didecyl dimethyl ammonium chloride, 0.006g of disodium ethylene diamine tetraacetate and 0.004g of Provichem2203, uniformly stirring on a stirrer, adjusting the pH value of the pharmaceutical composition for environmental disinfection to 8-10 by using an acid-base regulator, and fixing the volume of the purified water to 1L to obtain the pharmaceutical composition for environmental disinfection.
EXAMPLE seven
200g of dodecyl (50% C)14，40％C12，10％C16) Mixing the bulk drug of dimethyl benzyl ammonium chloride with a proper amount of purified water, heating at 70 ℃ to completely melt the bulk drug of dimethyl benzyl ammonium chloride into a flowable state, sequentially adding 300g of didecyl dimethyl ammonium chloride, 0.15g of disodium ethylene diamine tetraacetate and 0.1g of Provichem2203, uniformly stirring on a stirrer, adjusting the pH value of the pharmaceutical composition for environmental disinfection to 8-10 by using an acid-base regulator, and fixing the volume of the purified water to 1L to obtain the pharmaceutical composition for environmental disinfection.
The amounts of the components described in one of the first to seventh examples are increased or decreased according to the same proportion, and the obtained weight part relationship of the components all belongs to the protection scope of the invention.
Example eight
Stability test
The test sample is the environment disinfection pharmaceutical composition prepared in the first embodiment, the second embodiment and the third embodiment; the detection items comprise characters, pH value, clarity, microorganism killing effect and content.
Accelerated test
Three batches of samples prepared in the first, second and third examples were placed at 40 + -2 deg.C and 65 + -5% relative humidity for six months, and sampled at the end of 0, 1, 2, 3 and 6 months, and the properties, pH, clarity, microbial killing effect, content and other items were examined, and compared with the results of the 0 day test, the results are shown in Table 1 below.
Long term test
Three batches of samples prepared in the first, second and third examples are placed at 25 +/-2 ℃ and 60 +/-10% of relative humidity, sampled at 0, 3, 6, 9, 12, 18 and 24 months, and examined for properties, pH value, clarity, microbial killing effect, content and other items, and compared with the detection results of 0 day, the results are shown in the following table 2.
TABLE 1 accelerated test results for three lots of samples
Note: a represents the sterilization rate;
b represents dodecyl (50% C)14，40％C12，10％C16) Dimethyl benzyl ammonium chloride;
c represents didecyl dimethyl ammonium chloride
TABLE 2 Long-term test results for three batches of samples
Note: a represents the sterilization rate;
b represents dodecyl (50% C)14，40％C12，10％C16) Dimethyl benzyl ammonium chloride;
c represents didecyl dimethyl ammonium chloride
The results of accelerated tests and long-term tests show that when three batches of samples prepared in the first, second and third examples are placed for 6 months at 40 +/-2 ℃ and RH65 +/-5% and for 36 months at 25 +/-2 ℃ and RH60 +/-10%, the appearance and the properties of the samples are not obviously changed, the pH and the clarity are in accordance with the specification, the content change is not obvious, and the microbial killing effect is not obviously changed.
The stability tests and results obtained by increasing or decreasing the amount of each component described in one of examples one to seven and one of examples one to seven are within the scope of the present invention.
Claims (8)
1. The pharmaceutical composition for environmental disinfection is characterized in that each 1L of the pharmaceutical composition comprises 30-200 g of single-chain quaternary ammonium salt, 50-300 g of double-chain quaternary ammonium salt, 0.005-0.5 g of solution stabilizer, 0.5-3 g of acid-base regulator and the balance of purified water.
2. The composition of claim 1, wherein said single chain quaternary ammonium salt is selected from the group consisting of: one or more of dodecyl dimethyl benzyl ammonium bromide, dodecyl dimethyl benzyl ammonium chloride, tetradecyl dimethyl benzyl ammonium chloride, hexadecyl dimethyl ethyl ammonium bromide, hexadecyl dimethyl benzyl ammonium chloride, miropyram, polonium chloride and benzethonium chloride; wherein, the dodecyl dimethyl benzyl ammonium chloride is selected from: dodecyl (60% C)14，30％C16，5％C18，5％C12) Dimethyl benzyl ammonium chloride, dodecyl (50% C)12，30％C14，17％C17，3％C18) Dimethyl benzyl ammonium chloride, dodecyl (100% C)14) Dimethyl benzyl ammonium chloride, dodecyl (50% C)14，40％C12，10％C16) Dimethyl benzyl ammonium chloride, dodecyl (58% C)14，28％C16，14％C12) One kind of dimethyl benzyl ammonium chloride.
3. The composition of claim 1, wherein said double-stranded quaternary ammonium salt is selected from the group consisting of: one or more of dioctyl dimethyl ammonium chloride, octyl decyl dimethyl ammonium chloride, didecyl/dioctyl dimethyl ammonium chloride, dioctyl dimethyl ammonium chloride and didecyl dimethyl ammonium bromide.
4. The composition of claim 1, wherein the solution stabilizer is selected from the group consisting of: one or more of polyphosphate, 1, 3-diketone, hydroxycarboxylic acid, disodium ethylene diamine tetraacetate, polyamine, aminocarboxylic acid, Provichem 2202, Provichem2203, HT-944 and polyvinyl alcohol.
5. The composition of claim 1, wherein the solution stabilizer is selected from the group consisting of: a combination of disodium edetate and Provichem 2203; the weight ratio of the disodium ethylene diamine tetraacetate to the Provichem2203 is 1: 1-10: 1.
6. The composition of claim 1, wherein the solution stabilizer is selected from the group consisting of: a combination of disodium edetate and Provichem 2203; the weight ratio of the disodium ethylene diamine tetraacetate to the Provichem2203 composition is 3: 1.
7. The composition of claim 1, wherein the composition has a pH of 8 to 10.
8. The composition of claim 1, comprising 100g dodecyl (50% C) per 1L14，40％C12，10％C16) Dimethyl benzyl ammonium chloride, 150g of didecyl dimethyl ammonium chloride, 0.06g of ethylene diamine tetraacetic acid disodium, 0.02g of Provichem2203, a proper amount of an acid-base regulator until the pH value is 8-10, and the balance of purified water.
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| CN112655704A (en) * | 2020-12-23 | 2021-04-16 | 合肥天一生物技术研究所有限责任公司 | Quaternary ammonium salt composite disinfectant |
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