CN111249292B - 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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- CN111249292B CN111249292B CN202010137497.7A CN202010137497A CN111249292B CN 111249292 B CN111249292 B CN 111249292B CN 202010137497 A CN202010137497 A CN 202010137497A CN 111249292 B CN111249292 B CN 111249292B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
- A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—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
- A61K47/50—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
- A61K47/69—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
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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-beta-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-beta-cyclodextrin inclusion compound, the weight ratio of roxithromycin to hydroxypropyl-beta-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. The in vitro antibacterial effect of roxithromycin is about the same as that of erythromycin,but the antibacterial effect in vivo is stronger than that of 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 antimicrobial action assay for antimicrobial pharmaceutical compositionsStator
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. 0.5ml of test bacterial liquid of the culture time is sucked, and sterile water is added for dilution 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 (2)
1. The usage of cefotiam hydrochloride and roxithromycin in the combined preparation of the antibacterial pharmaceutical composition is that the weight ratio of the cefotiam hydrochloride to the roxithromycin is 2: 1; the target of action of the antibacterial drug composition is pseudomonas aeruginosa; the antibacterial medicine composition is an injection, and the preparation method comprises the following 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-beta-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.
2. The use according to claim 1, wherein the weight ratio of roxithromycin to hydroxypropyl- β -cyclodextrin in said roxithromycin-hydroxypropyl- β -cyclodextrin inclusion complex is 2: 1.
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