CN111249292A - Antibacterial pharmaceutical composition and preparation method and application thereof - Google Patents
Antibacterial pharmaceutical composition and preparation method and application thereof Download PDFInfo
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- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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Abstract
The invention relates to the technical field of medicines, in particular to an antibacterial pharmaceutical composition and a preparation method and application thereof. The antibacterial pharmaceutical composition contains antibacterial active ingredients consisting of cefotiam hydrochloride and roxithromycin, and the weight ratio of the cefotiam hydrochloride to the roxithromycin is 1-8: 1. The cefotiam hydrochloride and the roxithromycin are used together, so that the bactericidal effect of synergy is achieved. The composition can effectively enhance the permeability to a pseudomonas aeruginosa biomembrane to achieve the aim of enhancing the sterilization effect, and simultaneously has obvious inhibition effect on various pathogenic bacteria of escherichia coli, staphylococcus aureus, salmonella and bacillus subtilis, thereby laying a foundation for the research of novel drug-resistant bacteria drugs.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to an antibacterial pharmaceutical composition and a preparation method and application thereof.
Background
Pseudomonas Aeruginosa (also known as Pseudomonas Aeruginosa) belongs to Pseudomonas, is one of the most common non-fermented gram-negative bacteria, and is widely distributed in various water and air in the nature and normal human skin, intestinal tracts, respiratory tracts and the like. Pseudomonas aeruginosa is a common nosocomial infectious pathogen, and is generally susceptible to patients who have low immune functions such as long-term application of hormones, immunosuppressants, tumor chemoradiotherapy and the like and invasive diagnosis and treatment operations such as operations, tracheotomy or catheter indwelling and the like. Can cause serious infections such as wound infection, lower respiratory tract infection, urinary tract infection, bacteremia and the like, and is one of main conditional pathogenic bacteria for infection in respiratory medicine and Intensive Care Unit (ICU) hospitals. Because many critically ill patients in the ICU require the establishment of artificial airways and mechanical ventilation, the chances of concurrent respiratory Pseudomonas aeruginosa infection are greatly increased. In recent years, high isolation rate, high drug resistance and high fatality rate pose serious threats to clinical infection control.
The drug resistance mechanism of pseudomonas aeruginosa is very complex and mainly comprises: producing antibacterial drug inactivating enzyme or inactivating enzyme, changing the action target position of the drug, reducing the permeability of the outer membrane, over-expressing the active efflux system, and forming the biomembrane and obtaining the exogenous drug resistance gene. Therefore, clinical treatment of P.aeruginosa is extremely troublesome, for example, the mortality rate after infection in critically ill patients is increasing. The key to the pathogenesis of pseudomonas aeruginosa is the conversion of non-mucus to mucus. Many pathogenic bacteria, including pseudomonas aeruginosa, adhere to biological materials or body lumen surfaces in order to adapt to the environment, surrounding themselves by secreting glycocalyx complexes, forming a large bacterial polymer film, i.e., a bacterial biofilm. The membrane is used as a biological barrier, which can prevent and inhibit the invasion of leucocyte, macrophage, antibody, etc., prevent bacteria from being eliminated by the immune system of the organism, and reduce the sensitivity of the medicine, thereby causing the multi-drug resistance of the bacteria, and the infection is recurrent and can not be cured for a long time. Therefore, how to make the drug effectively break through the barrier of the biological membrane and kill the bacteria is the hot spot of the current research. At present, no research report and clinical application of combining cefotiam hydrochloride and roxithromycin for treating pseudomonas aeruginosa infection are found.
Disclosure of Invention
The invention aims to solve the technical problem of the prior art and provides an antibacterial pharmaceutical composition, a preparation method and application thereof.
In order to achieve the purpose, the technical scheme of the invention is as follows:
an antibacterial pharmaceutical composition comprises 2-5% of antibacterial active ingredients and 95-98% of pharmaceutically acceptable auxiliary materials in percentage by weight, wherein the antibacterial active ingredients are cefotiam hydrochloride and roxithromycin, and the weight ratio of the cefotiam hydrochloride to the roxithromycin is 1-8: 1.
Preferably, the weight ratio of the cefotiam hydrochloride to the roxithromycin is 1-4: 1.
Preferably, the weight ratio of the cefotiam hydrochloride to the roxithromycin is 2: 1.
Preferably, the cefotiam hydrochloride is prepared by taking 7-amino cephalosporanic acid as a raw material, preparing a cefotiam three-position intermediate by a boron trifluoride catalysis method, and reacting with aminothiazole acetyl chloride.
Preferably, the roxithromycin is prepared by taking thiocyanic acid and erythromycin as raw materials, oximating the raw materials into erythromycin oxime, and then reacting the erythromycin oxime with methoxyethoxy chloromethyl ether.
Further, the invention also provides a preparation method of the antibacterial medicine composition, the antibacterial medicine composition is an injection, and the preparation method comprises the following preparation steps:
(1) mixing 2g of cefotiam hydrochloride and 0.4g of anhydrous sodium carbonate, dissolving in 0.9% sodium chloride solution, and diluting to 100ml to obtain solution A for later use;
(2) dissolving 3g of roxithromycin-hydroxypropyl- β -cyclodextrin inclusion compound in 0.9% sodium chloride solution, and fixing the volume to 100ml to obtain solution B for later use;
(3) according to the weight proportion requirement of cefotiam hydrochloride and roxithromycin in the antibacterial medicine composition, the solution A and the solution B with certain volume are mixed and stirred uniformly to obtain the antibacterial medicine composition in the form of injection.
Preferably, in the roxithromycin-hydroxypropyl- β -cyclodextrin inclusion compound, the weight ratio of roxithromycin to hydroxypropyl- β -cyclodextrin is 2: 1.
Furthermore, the invention also provides application of the cefotiam hydrochloride and the roxithromycin in the combined preparation of the antibacterial pharmaceutical composition, wherein the weight ratio of the cefotiam hydrochloride to the roxithromycin is 1-8: 1.
Preferably, the weight ratio of the cefotiam hydrochloride to the roxithromycin is 2: 1.
Preferably, the antibacterial pharmaceutical composition is an injection.
Cefotiam hydrochloride is the second-generation semi-synthetic cephalosporin which is firstly marketed in Japan in 1981 and developed by Japan Wutian corporation, and the antibacterial principle of the medicament is that the antibacterial activity of the medicament is exerted by preventing the cell wall synthesis of bacteria. The action of cefotiam hydrochloride on gram-positive bacteria is close to that of cefazolin, the action on gram-negative bacteria such as haemophilus, Escherichia coli, Klebsiella and Proteus mirabilis is better, and the action on enterobacter, Citrobacter and indole-positive proteus is also antibacterial. The traditional Chinese medicine composition is clinically used for infection caused by sensitive bacteria, such as pneumonia, bronchitis, biliary tract infection, peritonitis, urinary tract infection, postoperative or trauma-caused infection and septicemia and the like.
Roxithromycin is a new generation macrolide antibiotic with strong antibacterial property, broad antibacterial spectrum and t1/2Long, etc. Roxithromycin has about the same in vitro antibacterial effect as erythromycin, but has a stronger in vivo antibacterial effect than erythromycin. In macrolide drugs, the peak concentration of roxithromycin in blood is highest, and after 150mg or 300mg of roxithromycin is taken immediately, the peak concentration in blood can be reached within 2 hours, namely 6.6-7.9mg/L and 9.1-10.8mg/L respectively, and the bioavailability is not influenced by food intake. If the medicine is continuously taken for 11 days and 300mg/d, the medicine is not accumulated in the body. The action mechanism of roxithromycin is as follows: the antibacterial peptide inhibitor has the function of inhibiting the synthesis of bacterial protein by blocking a bacterial transpeptidation way, has stronger antibacterial and bactericidal effects, and is particularly prominent in the aspect of killing mycoplasma and chlamydia.
Compared with the prior art, the invention has the beneficial effects that: the cefotiam hydrochloride can prevent the cell wall synthesis of bacteria, thereby exerting the antibacterial activity of the medicine. The roxithromycin belongs to macrolide antibiotics, and although the roxithromycin does not have the function of resisting pseudomonas aeruginosa, the roxithromycin can effectively inhibit bacterial biofilms from generating exopolysaccharides and alginate, and can also damage the surface structures of pseudomonas aeruginosa to thin and break the biofilms, thereby effectively inhibiting the adhesion of the roxithromycin to hosts. The cefotiam hydrochloride and the roxithromycin are used together, so that the bactericidal effect of synergy is achieved. The composition can effectively enhance the permeability to a pseudomonas aeruginosa biomembrane to achieve the aim of enhancing the sterilization effect, and simultaneously has obvious inhibition effect on various pathogenic bacteria of escherichia coli, staphylococcus aureus, salmonella and bacillus subtilis, thereby laying a foundation for the research of novel drug-resistant bacteria drugs.
Detailed Description
The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention. The materials, reagents and the like used are, unless otherwise specified, commercially available reagents and materials.
In vitro antibacterial effect determination of antibacterial pharmaceutical composition
1. Laboratory strains and materials
Pseudomonas aeruginosa quality control strain ATCC27853, supplied by Togaku Biotech Co., Ltd. 3 strains of multidrug-resistant pseudomonas aeruginosa separated from sputum, blood, urine and other specimens of clinical infected patients in hospitals are respectively named as PA1, PA2 and PA 3.
Culture medium: LB bacterial medium (Sigma), Nutrition agar (Qingdao Haibo Biotech, Inc.).
Medicine preparation: cefotiam hydrochloride (langen biotechnology ltd, suzhou); roxithromycin (Azta technologies, Inc.).
2. Preparation of bacterial suspension of pseudomonas aeruginosa
A ring of thalli is selected from the activated thalli inclined plane and inoculated in an LB liquid bacterial culture medium, and the liquid bacterial culture medium is put into a constant temperature shaking incubator at 37 ℃ to be cultured to logarithmic phase. According to the growth curve, the time of the bacteria culture to the logarithmic growth phase is about 8-10 h. When the above culture is performed0.5ml of the test bacterial liquid is added with sterile water and diluted to 10 times5-106CFU/ml, spare.
3. Preparation of pharmaceutical solutions
Accurately weighing a certain amount of cefotiam hydrochloride and roxithromycin to prepare a medicament solution with the concentration of 1024 mu g/ml, filtering by a 0.22 mu m filter membrane, and subpackaging for later use.
4. Determination of Minimum Inhibitory Concentration (MIC)
The raw liquid of the drug is diluted into solutions with drug concentration of 512, 256, 128, 64, 32, 16, 8, 4, 2, 1, 0.5 and 0.25 mu g/ml by using sterile LB bacterial culture medium. 1ml of the above bacterial suspension was added to a test tube containing a drug-containing medium. At this time, the drug concentration in each test tube was 256, 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125. mu.g/ml, respectively. Culturing in 37 deg.C incubator for 18h, observing antibacterial effect and recording MIC value. The results of the experiment are shown in table 1.
TABLE 1 determination of Minimum Inhibitory Concentration (MIC) for single and combined drugs
As can be seen from the experimental results in Table 1, both for the quality control strain ATCC27853 of Pseudomonas aeruginosa and for the multi-drug-resistant Pseudomonas aeruginosa PA1, PA2 and PA3 which are clinically separated, cefotiam hydrochloride alone shows stronger drug resistance, and roxithromycin alone has weak inhibition effect on Pseudomonas aeruginosa. However, when the cefotiam hydrochloride and the roxithromycin are used in a matching way, the MIC values of the two antibacterial active ingredients can be obviously reduced, which shows that the cefotiam hydrochloride and the roxithromycin can generate obvious synergistic antibacterial effect, thereby achieving the purpose of enhancing the bactericidal capacity.
5. Research on weight ratio of cefotiam hydrochloride to roxithromycin
The raw liquid of the drug is diluted into solution with drug concentration of 1024, 512, 256, 128, 64, 32, 16, 8, 4 and 2 mug/ml by using sterile LB bacterial culture medium. According to the determined MIC value, cefotiam hydrochloride and roxithromycin are sequentially designed from low to high according to a chessboard dilution method, every two combined medicaments are added into a 96-well plate according to different weight proportions, 50 mu l of each medicament is added, then 100 mu l of prepared ATCC27853 bacterial liquid is added into the well, and the well is placed into an incubator at 37 ℃ for culture for 18 hours. The bacteriostatic effect was observed and the MIC values were recorded. The chessboard dilution method results are evaluated by using component bacteriostatic concentration index FICI, and the FICI can be calculated according to the following formula:
criterion for FICI: the FICI is less than or equal to 0.5, the FICI is more than 0.5 and less than or equal to 1, the additive effect is realized, the FICI is more than 1 and less than or equal to 2, the irrelevant effect is realized, and the FICI is more than 2, and the antagonistic effect is realized. The results of the experiment are shown in table 2.
TABLE 2 dilution test results of the checkerboard method
As can be seen from the experimental results in Table 2, when cefotiam hydrochloride and roxithromycin are used together, the different weight ratios of the cefotiam hydrochloride and the roxithromycin have obvious influence on the bacteriostatic activity of pseudomonas aeruginosa. Wherein, when the weight ratio of the cefotiam hydrochloride to the roxithromycin is 1-8:1, the cefotiam hydrochloride and the roxithromycin have synergistic effect on bacteriostasis; when the weight ratio of the cefotiam hydrochloride to the roxithromycin is 2:1, the synergistic interaction between the cefotiam hydrochloride and the roxithromycin is strongest, and the FICI index can be as low as 0.25; when the weight ratio of the cefotiam hydrochloride to the roxithromycin is beyond 1-8:1 (the weight ratio is not an endpoint value), no synergistic effect can be formed between the cefotiam hydrochloride and the roxithromycin. In conclusion, the cefotiam hydrochloride and the roxithromycin in a specific weight ratio are used together, so that the bactericidal effect of synergy is achieved, the permeability of the pseudomonas aeruginosa biomembrane can be effectively enhanced, and the purpose of enhancing the bactericidal effect is achieved.
6. Inhibitory effect of combined use of cefotiam hydrochloride and roxithromycin on other strains
The strain types are as follows: escherichia coli, Staphylococcus aureus, Salmonella, and Bacillus subtilis. Accurately weighing cefotiam hydrochloride and roxithromycin according to the weight ratio of 1:1, 2:1 and 4:1, respectively preparing into medicament solutions with the concentration of 1024 mu g/ml, filtering by a 0.22 mu m filter membrane, and subpackaging for later use. The raw liquid of the drug is diluted into solutions with drug concentration of 512, 256, 128, 64, 32, 16, 8, 4, 2, 1, 0.5 and 0.25 mu g/ml by using sterile LB bacterial culture medium. 1ml of the bacterial suspension growing to logarithmic phase is added into a test tube filled with a drug-containing culture medium. At this time, the drug concentration in each test tube was 256, 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125. mu.g/ml, respectively. Culturing in 37 deg.C incubator for 18h, observing antibacterial effect and recording MIC value. The results of the experiment are shown in table 3.
TABLE 3 MIC (μ g/ml) for a combination of cefotiam hydrochloride and roxithromycin
The experimental results in table 3 show that when cefotiam hydrochloride and roxithromycin are used together according to a certain proportion, the cefotiam hydrochloride and roxithromycin also have good inhibition effect on escherichia coli, staphylococcus aureus, salmonella and bacillus subtilis. Wherein, when the weight ratio of the cefotiam hydrochloride to the roxithromycin is 2:1, the MIC values of the four strains are the lowest, and the antibacterial effect of the composition in the weight ratio is proved to be the strongest. The experimental results prove that the antibacterial pharmaceutical composition has obvious inhibition effect on various pathogenic bacteria, which lays a foundation for the research of novel anti-drug-resistant bacteria medicines.
The foregoing describes preferred embodiments of the present invention, but is not intended to limit the invention thereto. Modifications and variations of the embodiments disclosed herein may be made by those skilled in the art without departing from the scope and spirit of the invention.
Claims (10)
1. An antibacterial pharmaceutical composition comprises 2-5% of antibacterial active ingredients and 95-98% of pharmaceutically acceptable auxiliary materials in percentage by weight, and is characterized in that the antibacterial active ingredients are cefotiam hydrochloride and roxithromycin, and the weight ratio of the cefotiam hydrochloride to the roxithromycin is 1-8: 1.
2. The antibacterial pharmaceutical composition according to claim 1, wherein the weight ratio of cefotiam hydrochloride to roxithromycin is 1-4: 1.
3. The antibacterial pharmaceutical composition according to claim 2, wherein the weight ratio of cefotiam hydrochloride to roxithromycin is 2: 1.
4. The antibacterial pharmaceutical composition according to any one of claims 1 to 3, wherein cefotiam hydrochloride is prepared by reacting cefotiam 7-aminocephalosporanic acid as a raw material with aminothiazole acetyl chloride to obtain a cefotiam three-position intermediate by a boron trifluoride catalytic method.
5. The antibacterial pharmaceutical composition according to any one of claims 1 to 3, wherein the roxithromycin is prepared from thiocyanic acid and erythromycin by oximation to erythromycin oxime and reaction with methoxyethoxy chloromethyl ether.
6. The method for preparing the antibacterial pharmaceutical composition according to any one of claims 1 to 5, wherein the antibacterial pharmaceutical composition is an injection, and comprises the following preparation steps:
(1) mixing 2g of cefotiam hydrochloride and 0.4g of anhydrous sodium carbonate, dissolving in 0.9% sodium chloride solution, and diluting to 100ml to obtain solution A for later use;
(2) dissolving 3g of roxithromycin-hydroxypropyl- β -cyclodextrin inclusion compound in 0.9% sodium chloride solution, and fixing the volume to 100ml to obtain solution B for later use;
(3) according to the weight proportion requirement of cefotiam hydrochloride and roxithromycin in the antibacterial medicine composition, the solution A and the solution B with certain volume are mixed and stirred uniformly to obtain the antibacterial medicine composition in the form of injection.
7. The method of claim 6, wherein the weight ratio of roxithromycin to hydroxypropyl- β -cyclodextrin in said roxithromycin-hydroxypropyl- β -cyclodextrin inclusion compound is 2: 1.
8. The usage of the cefotiam hydrochloride and the roxithromycin in the combined preparation of the antibacterial pharmaceutical composition is that the weight ratio of the cefotiam hydrochloride to the roxithromycin is 1-8: 1.
9. The use according to claim 8, wherein the weight ratio of cefotiam hydrochloride to roxithromycin is 2: 1.
10. Use according to claim 8 or 9, wherein the antibacterial pharmaceutical composition is an injection.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101045063A (en) * | 2006-03-28 | 2007-10-03 | 广州朗圣药业有限公司 | Clarithromycin water soluber preparation for injection use |
| CN104337826A (en) * | 2013-07-30 | 2015-02-11 | 上海医药工业研究院 | Application of macrolide compound or salt thereof and pharmaceutical composition containing macrolide compound or salt |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101045063A (en) * | 2006-03-28 | 2007-10-03 | 广州朗圣药业有限公司 | Clarithromycin water soluber preparation for injection use |
| CN104337826A (en) * | 2013-07-30 | 2015-02-11 | 上海医药工业研究院 | Application of macrolide compound or salt thereof and pharmaceutical composition containing macrolide compound or salt |
Non-Patent Citations (3)
| Title |
|---|
| 孟玲: "《实用临床呼吸病诊疗精要》", 30 June 2018 * |
| 徐浩锋等: "我院住院患者抗菌药物调查分析", 《海峡药学》 * |
| 茹仁萍: "《抗感染药物临床合理应用手册》", 30 November 2016 * |
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