CN111632033B - Medicine composition for resisting carbapenem-resistant Klebsiella pneumoniae and preparation method and application thereof - Google Patents
Medicine composition for resisting carbapenem-resistant Klebsiella pneumoniae and preparation method and application thereof Download PDFInfo
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- CN111632033B CN111632033B CN202010512570.4A CN202010512570A CN111632033B CN 111632033 B CN111632033 B CN 111632033B CN 202010512570 A CN202010512570 A CN 202010512570A CN 111632033 B CN111632033 B CN 111632033B
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- salidroside
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- pharmaceutical composition
- ciprofloxacin hydrochloride
- carbapenem
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- 241000588747 Klebsiella pneumoniae Species 0.000 title claims abstract description 38
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- 238000002360 preparation method Methods 0.000 title claims abstract description 21
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- DIOIOSKKIYDRIQ-UHFFFAOYSA-N ciprofloxacin hydrochloride Chemical compound Cl.C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 DIOIOSKKIYDRIQ-UHFFFAOYSA-N 0.000 claims abstract description 63
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- NSKGQURZWSPSBC-UHFFFAOYSA-N ribostamycin A Natural products NC1C(O)C(O)C(CN)OC1OC1C(OC2C(C(O)C(CO)O2)O)C(O)C(N)CC1N NSKGQURZWSPSBC-UHFFFAOYSA-N 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 229960000707 tobramycin Drugs 0.000 description 1
- NLVFBUXFDBBNBW-PBSUHMDJSA-N tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
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Abstract
The invention belongs to the technical field of medicinal preparations, and particularly relates to a medicine for resisting carbapenem-resistant Klebsiella pneumoniae, and a preparation method and application thereof. The invention provides a medicine for resisting carbapenem-resistant Klebsiella pneumoniae, which comprises ciprofloxacin hydrochloride and salidroside. The pharmaceutical composition for resisting the carbapenem-resistant Klebsiella pneumoniae provided by the invention has good effect.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition for resisting carbapenem-resistant Klebsiella pneumoniae, and a preparation method and an application thereof.
Background
Klebsiella Pneumoniae (KP) is one of the important opportunistic pathogens that cause hospital-acquired infections, and can cause respiratory, urinary, and bloodstream infections, as well as bacteremia, etc. Currently, carbapenem drugs are first-line drugs for treating klebsiella pneumoniae infection, but due to wide clinical use and even abuse, the number of carbapenem-resistant klebsiella pneumoniae (CRKP) is remarkably increased. CRKP has drug resistance to most beta-lactam antibacterial drugs and drug resistance to antibacterial drugs irrelevant to carbapenemase drug resistance mechanism, so that the traditional CRKP-resistant antibacterial combination drug has poor effect, and drug-resistant Klebsiella pneumoniae (XDR-KP) is widely spread, which brings great difficulty to clinical anti-infection treatment and becomes a social health problem of global common attention. Therefore, it is the research direction of our research to provide an antibacterial combination drug with good CRKP resistance.
Disclosure of Invention
The invention aims to provide a medicine composition with good effect for resisting carbapenem-resistant Klebsiella pneumoniae. The pharmaceutical composition for resisting the carbapenem-resistant Klebsiella pneumoniae provided by the invention has good effect.
In order to achieve the above object, the present invention provides the following technical solutions;
the invention provides a medicine composition for resisting carbapenem-resistant Klebsiella pneumoniae, which comprises ciprofloxacin hydrochloride and salidroside.
Preferably, the mass ratio of the ciprofloxacin hydrochloride to the salidroside is (1-12): (1-12).
Preferably, the pharmaceutical composition of the invention further comprises medically acceptable auxiliary materials; the auxiliary materials comprise freeze-dried excipients;
the mass ratio of ciprofloxacin hydrochloride, salidroside and freeze-drying excipient in the medicine is (1-12): (1-12): (0.05-12).
Preferably, the freeze-drying excipient is selected from any one or more of mannitol, glycine, lactose, sucrose, glucose and sorbitol.
Preferably, the auxiliary materials also comprise an acid-base regulator; the acid-base regulator is selected from any one or more of sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid and sulfuric acid.
The invention provides a preparation method of the pharmaceutical composition in the technical scheme, which comprises the following steps:
(1) mixing ciprofloxacin hydrochloride, salidroside and freeze-dried excipient to obtain a mixture, mixing the mixture with water for injection to obtain a mixture, and filtering the mixture to obtain a liquid medicine;
(2) the liquid medicine is made into freeze-dried powder to obtain the medicinal composition.
Preferably, the pH value of the liquid medicine in the step (1) is 5.0-7.0.
Preferably, the volume ratio of the mass of the mixture in the step (1) to the water for injection is 100-1000 g: 5000-500000 mL.
The invention also provides application of the pharmaceutical composition in the technical scheme or the pharmaceutical composition prepared by the preparation method in the technical scheme in reversing the drug resistance of the carbapenems Klebsiella pneumoniae.
Preferably, the resistance comprises resistance due to β -lactam antibiotics, carbapenem antibiotics, fluoroquinolone antibiotics, aminoglycoside antibiotics or tetracycline antibiotics.
The invention provides a pharmaceutical composition, which comprises ciprofloxacin hydrochloride and salidroside. On the basis that ciprofloxacin hydrochloride has an antibacterial effect, salidroside is added, and the two components are combined to generate a synergistic antibacterial effect, so that the drug resistance of CRKP can be reversed. The antibacterial agent provided by the invention has a good antibacterial effect, does not enhance the drug resistance of bacteria, and can reverse the drug resistance of CRKP. The embodiment result shows that the antibacterial drug provided by the invention can reduce the drug resistance of CRKP to ciprofloxacin hydrochloride.
The following examples are provided to illustrate the antibacterial agent of the present invention and its preparation and application in detail, but they should not be construed as limiting the scope of the present invention.
The invention provides a medicine composition for resisting carbapenem-resistant Klebsiella pneumoniae, which comprises ciprofloxacin and salidroside. On the basis that the ciprofloxacin hydrochloride inhibits the bacterial reproduction, the salidroside further generates synergistic antibiosis with the ciprofloxacin hydrochloride. The combined medicine for resisting the carbapenem-resistant Klebsiella pneumoniae provided by the invention has good effect. Compared with single ciprofloxacin, the medicine for resisting the carbapenem-resistant Klebsiella pneumoniae provided by the invention has obviously improved in-vitro antibacterial effect on the carbapenem-resistant Klebsiella pneumoniae. The embodiment result shows that the medicine for resisting the carbapenem-resistant Klebsiella pneumoniae provided by the invention can increase and reduce the drug resistance of CRKP bacteria to ciprofloxacin hydrochloride.
Detailed Description
The invention provides a pharmaceutical composition, which comprises ciprofloxacin hydrochloride and salidroside.
The ciprofloxacin hydrochloride preparation comprises 1-12 parts of ciprofloxacin hydrochloride by mass, and is more preferably 2-11 parts.
The traditional Chinese medicine composition preferably comprises 1-12 parts of salidroside, more preferably 2-11 parts of ciprofloxacin hydrochloride by mass. In the invention, the purity of the salidroside is more than 98 percent by mass, and the salidroside has the function of synergistically increasing the antibacterial action of ciprofloxacin hydrochloride.
The pharmaceutical composition also comprises medically acceptable auxiliary materials; the excipients include a lyophilized excipient. The mass ratio of ciprofloxacin hydrochloride, salidroside and freeze-drying excipient in the medicine is preferably (2-11): (2-11): (0.05-10). The freeze-drying excipient is preferably selected from any one or more of mannitol, glycine, lactose, sucrose, glucose and sorbitol. The auxiliary materials preferably also comprise an acid-base regulator; the acid-base regulator is preferably selected from any one or more of sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid and sulfuric acid. In the invention, the dosage form of the pharmaceutical composition is preferably freeze-dried powder injection.
The invention provides a preparation method of the pharmaceutical composition in the technical scheme, which comprises the following steps:
(1) mixing ciprofloxacin hydrochloride, salidroside and freeze-dried excipient to obtain a mixture, mixing the mixture with water for injection to obtain a mixture, and filtering the mixture to obtain a liquid medicine;
(2) the liquid medicine is made into freeze-dried powder to obtain the medicinal composition.
The method comprises the steps of mixing ciprofloxacin hydrochloride, salidroside and freeze-drying excipient to obtain a mixture, mixing the mixture with water for injection to obtain a mixture, and filtering the mixture to obtain a liquid medicine. In the invention, the volume ratio of the mass of the mixture to the water for injection is preferably 100-1000 g: 5000-100000 mL, more preferably 200-900 g: 5000-100000 mL. The method is characterized by also comprising the step of mixing the mixture with activated carbon before filtration, wherein the mass ratio of the volume of the mixture to the activated carbon is preferably 1000-100000 mL: 1-500 g, more preferably 2000-100000 mL: 1-500 g; after the filtration, preferably, the method further comprises the step of complementing the filtrate with water for injection until the volume of the water for injection is equal to the volume of the water for injection before the mixture is mixed with the water for injection; the pH value of the liquid medicine is preferably 5.0-7.0, and more preferably 5.5-6.5.
After the liquid medicine is obtained, the liquid medicine is prepared into freeze-dried powder to obtain the pharmaceutical composition. The preparation of the freeze-dried powder comprises freezing and drying. The preparation method of the freeze-dried powder adopts a pharmaceutical process known to those skilled in the art, and preferably comprises two schematic freeze-drying curves as shown in the following freeze-drying curve A and freeze-drying curve B:
in the specific examples of the preparation of the freeze-dried powder injection, the freeze-drying curve used is the freeze-drying curve A, unless otherwise specified.
In the present invention, the preparation of the lyophilized powder preferably further comprises a tamponade treatment; the press plug is preferably a vacuum press plug. Before freezing, preferably, the method also comprises the steps of performing filter membrane sterilization and filling treatment on the liquid medicine; the filter membrane pore size of the filtration is preferably 0.2 μm. The filling process preferably comprises filling the liquid medicine in a penicillin bottle.
The invention also provides application of the pharmaceutical composition in the technical scheme or the pharmaceutical composition prepared by the preparation method in the technical scheme in reversing the drug resistance of the carbapenems Klebsiella pneumoniae (CRKP). In the present invention, the resistance preferably includes resistance caused by β -lactam antibiotics, carbapenem antibiotics, fluoroquinolone antibiotics, aminoglycoside antibiotics or tetracycline antibiotics (including but not limited to methacycline, minocycline, chlortetracycline, tigecycline, etc.); the beta-lactam antibiotics preferably comprise penicillins and cephalosporins; the carbapenem antibiotics preferably include imipenem, meropenem, panipenem, ertapenem, biapenem and doripenem; the fluoroquinolone antibiotics preferably comprise ofloxacin, ciprofloxacin, norfloxacin, pefloxacin and ciprofloxacin; the aminoglycoside antibiotics preferably comprise streptomycin, kanamycin, gentamicin, tobramycin, amikacin, etimicin, ribostamycin, netilmicin, and micronomicin; the tetracycline antibiotics preferably include methacycline, minocycline, chlortetracycline, and tigecycline.
The invention preferably adjusts the antibacterial mass ratio of the ciprofloxacin hydrochloride and the salidroside according to the difference of the CRKP drug resistance degree (namely the minimum inhibitory concentration MIC) to the carbapenem drug (taking imipenem as an example), and specifically comprises the following steps:
when the MIC of CRKP to imipenem is more than or equal to 16 and less than or equal to 32, the preferred proportion of the antibacterial combination drug is that the mass ratio of ciprofloxacin hydrochloride to salidroside is 2-10: 1-3;
when the 32< MIC of CRKP to imipenem is less than or equal to 64, the preferred proportion of the antibacterial combination drug is that the mass ratio of ciprofloxacin hydrochloride to salidroside is 2-10: 2-6;
when the MIC of CRKP to imipenem is 64< MIC < 128, the preferred proportion of the antibacterial combination drug is that the mass ratio of ciprofloxacin hydrochloride to salidroside is 2-10: 4 to 8.
When the MIC of CRKP to imipenem is more than 128, the preferred proportion of the antibacterial combination drug is that the mass ratio of ciprofloxacin hydrochloride to salidroside is 2-10: 8 to 10.
The present invention provides a pharmaceutical composition against carbapenem-resistant Klebsiella pneumoniae, a method for preparing the same, and applications thereof, which are described in detail below with reference to the examples, but the scope of the present invention is not limited thereto.
Example 1
A medicine for resisting carbapenem-resistant Klebsiella pneumoniae is prepared from ciprofloxacin hydrochloride and salidroside at a mass ratio of 1: 1.
Adding 100g ciprofloxacin hydrochloride, 100g salidroside, 10g lactose and 5g potassium dihydrogen phosphate into 10000ml of water for injection, stirring uniformly, adding 10g activated carbon, stirring fully, and filtering the activated carbon. Adding water for injection to 10000ml, measuring the pH value, adding dipotassium hydrogen phosphate to adjust the pH value of the solution to 5.0-7.0, filtering the solution through two 0.2 mu m filter membranes, subpackaging the filtrate into 1000 bottles (10ml:100mg) of penicillin bottles by using an automatic filling machine, performing half stoppering, performing freeze-drying by using a freeze-drying box to obtain the ciprofloxacin hydrochloride and salidroside composition freeze-dried powder injection, performing vacuum stoppering, taking out the injection from the box, and rolling an aluminum cover to obtain 1000 antibacterial drugs.
Example 2
A medicine for resisting carbapenem-resistant Klebsiella pneumoniae is prepared from ciprofloxacin hydrochloride and salidroside at a mass ratio of 1: 3.
Adding 100g ciprofloxacin hydrochloride, 300g salidroside, 20g lactose and 5g potassium dihydrogen phosphate into 10000ml of water for injection, stirring uniformly, adding 20g activated carbon, stirring fully, and filtering the activated carbon. Adding water for injection to 10000ml, measuring the pH value, adding dipotassium hydrogen phosphate to adjust the pH value of the solution to 5.0-7.0, filtering the solution through two 0.2 mu m filter membranes, subpackaging the filtrate into 1000 bottles (10ml:100mg) of penicillin bottles by using an automatic filling machine, performing half stoppering, performing freeze-drying by using a freeze-drying box to obtain the ciprofloxacin hydrochloride and salidroside composition freeze-dried powder injection, performing vacuum stoppering, taking out the injection from the box, and rolling an aluminum cover to obtain 1000 antibacterial drugs.
Example 3
A medicine for resisting carbapenem-resistant Klebsiella pneumoniae is prepared from ciprofloxacin hydrochloride and salidroside at a mass ratio of 1: 5.
Adding 100g ciprofloxacin hydrochloride, 500g salidroside, 20g lactose and 5g potassium dihydrogen phosphate into 10000ml of water for injection, stirring uniformly, adding 20g activated carbon, stirring fully, and filtering the activated carbon. Adding water for injection to 10000ml, measuring the pH value, adding dipotassium hydrogen phosphate to adjust the pH value of the solution to 5.0-7.0, filtering the solution through two 0.2 mu m filter membranes, subpackaging the filtrate into 1000 bottles (10ml:100mg) of penicillin bottles by using an automatic filling machine, performing half stoppering, performing freeze-drying by using a freeze-drying box to obtain the ciprofloxacin hydrochloride and salidroside composition freeze-dried powder injection, performing vacuum stoppering, taking out the injection from the box, and rolling an aluminum cover to obtain 1000 antibacterial drugs.
Example 4
A medicine for resisting carbapenem-resistant Klebsiella pneumoniae is prepared from ciprofloxacin hydrochloride and salidroside at a mass ratio of 3: 1.
Adding 300g ciprofloxacin hydrochloride, 100g salidroside, 30g lactose and 5g potassium dihydrogen phosphate into 10000ml of water for injection, stirring uniformly, adding 20g activated carbon, stirring fully, and filtering the activated carbon. Adding water for injection to make up to 30000ml, measuring pH value, adding dipotassium hydrogen phosphate to adjust pH of the solution to 5.0-7.0, filtering the solution through two 0.2 mu m filter membranes, subpackaging the filtrate into 3000 bottles (10ml:100mg) of penicillin bottles by using an automatic filling machine, half plugging, freeze-drying by using a freeze-drying box to obtain the ciprofloxacin hydrochloride and salidroside composition freeze-dried powder injection, pressing the plugs in vacuum, taking out the injection box, and rolling an aluminum cover to obtain 3000 antibacterial drugs.
Example 5
A medicine for resisting carbapenem-resistant Klebsiella pneumoniae is prepared from ciprofloxacin hydrochloride and salidroside at a mass ratio of 5: 2.
500g ciprofloxacin hydrochloride, 200g salidroside, 30g lactose and 5g potassium dihydrogen phosphate are added into 50000ml water for injection, 30g activated carbon is added after even stirring, and the activated carbon is filtered after full stirring. Adding water for injection to 50000ml, measuring pH value, adding dipotassium hydrogen phosphate to adjust pH value of the solution to 5.0-7.0, filtering the solution through two 0.2 mu m filter membranes, subpackaging the filtrate into 5000 bottles (10ml:100mg) of penicillin bottles by using an automatic filling machine, performing half-stoppering, performing freeze-drying by using a freeze-drying box to obtain ciprofloxacin hydrochloride and salidroside composition freeze-dried powder injection, performing vacuum stoppering, discharging, and rolling an aluminum cover to obtain 5000 antibacterial drugs.
Test example
In order to verify the antibacterial activity of the antibacterial combination drug of the present invention, the inventors carried out an in vitro bacteriostasis test
1. Screening of test strains
The clinical separated Klebsiella pneumoniae (the strain is from subsidiary hospitals of the Jiujiang academy of academic and Japan) is collected, and the sensitivity of the Klebsiella pneumoniae to clinically 2 common carbapenem drugs, namely Imipenem (IPM) and Ertapenem (ETP), is determined by adopting a trace broth dilution method. The drug sensitivity result is judged according to the standard of the American clinical laboratory standardization research institute (CLSI)2017, and the carbapenem-resistant Klebsiella pneumoniae (CRKP) is screened. The quality control strain is Klebsiella pneumoniae ATCC 13883.
2. Preparation of bacterial suspension
3-5 colonies were picked from blood agar plates that had been purified and cultured overnight and inoculated into sterile 0.9% sodium chloride solution. The turbidity of the bacterial liquid is adjusted to 0.5 McLeod turbidity by a turbidimeter, and then the bacterial liquid is diluted by MH broth by 100 times to obtain bacterial suspension.
3. Antimicrobial drug formulation
Ciprofloxacin hydrochloride and salidroside stock solutions were formulated at a concentration of 5120 μ g/mL as required by the American society for clinical laboratory standardization standards.
4. Broth microdilution method:
ciprofloxacin hydrochloride and salidroside were diluted in MH broth to 10 dilutions. The concentration of ciprofloxacin hydrochloride is 0.5-256 mug/mL, the concentration of salidroside is 2-1024 mug/mL, 100 muL of each concentration liquid medicine is added into the 1 st to 10 th holes of each row in a sterile 96-hole plate, 100 muL of diluted liquid medicine is added into each hole, and meanwhile, a negative control and a blank control are carried out. Culturing at 37 ℃ for 16-18 h, observing the result and recording the Minimum Inhibitory Concentration (MIC) value of each drug when the drugs are used singly.
5. Micro chessboard dilution method
Both drugs were diluted in MH broth in 8 concentration gradients based on 2-fold MIC values. According to the chessboard design, 50 mu L of the mixture is added into each hole, 100 mu L of diluted bacteria liquid is added at the same time, after the mixture is cultured for 16-18 h at 37 ℃, the MIC (MIC for combination of A drugs and MIC for combination of B drugs) of each drug in the optimal combination is observed and recorded. And calculating a partial inhibitory concentration index (FIC) value. FIC is less than or equal to 0.5; 0.5-FIC not more than 1; FIC is more than 1 and less than or equal to 2, and no relevant effect exists; FIC > 2 antagonism.
6. Test results
The test results are shown in table 1, and it can be seen from table 1 that salidroside has no antibacterial effect when used alone, the MICs of ciprofloxacin to the screened CRKP strains are all more than or equal to 16 mug/ml, and are both drug-resistant to ciprofloxacin (MIC more than or equal to 4 mug/ml), but after the ciprofloxacin and the salidroside are combined, the in vitro antibacterial effect on carbon-resistant qingzyme-like Klebsiella pneumoniae (CRKP) is obviously better than the effect of ciprofloxacin glycoside alone, and the action mode between the ciprofloxacin and the CRKP is a synergistic mode.
TABLE 1 in vitro antibacterial action of Salidroside and ciprofloxacin hydrochloride on CRKP alone or in combination
Note: - - -is inactive
Example 6
A medicine for resisting carbapenem-resistant Klebsiella pneumoniae is prepared from ciprofloxacin hydrochloride and salidroside at a mass ratio of 2: 1.
Adding 200g ciprofloxacin hydrochloride, 100g salidroside, 20g lactose and 5g potassium dihydrogen phosphate into 20000ml injection water, stirring, adding 20g activated carbon, stirring, and filtering. Adding water for injection to 20000ml, measuring pH, adding dipotassium hydrogen phosphate to adjust pH to 5.5-6.5, filtering the solution through two 0.2 μm filter membranes, subpackaging the filtrate into 2000 vials (10ml:100mg) by an automatic filling machine, half plugging, freeze-drying by a freeze-drying box to obtain the ciprofloxacin hydrochloride and salidroside composition freeze-dried powder injection, vacuum-pressing the plugs, taking out the injection, and rolling an aluminum cover to obtain 2000 antibacterial drugs.
Example 7
A medicine for resisting carbapenem-resistant Klebsiella pneumoniae is prepared from ciprofloxacin hydrochloride and salidroside at a mass ratio of 3: 1.
Adding 300g ciprofloxacin hydrochloride, 100g salidroside, 30g lactose and 5g potassium dihydrogen phosphate into 30000ml of water for injection, stirring uniformly, adding 30g activated carbon, stirring fully, and filtering the activated carbon. Adding water for injection to make up to 30000ml, measuring pH value, adding dipotassium hydrogen phosphate to adjust pH of the solution to 5.5-6.5, filtering the solution through two 0.2 mu m filter membranes, subpackaging the filtrate into 3000 bottles (10ml:100mg) of penicillin bottles by using an automatic filling machine, half plugging, freeze-drying by using a freeze-drying box to obtain the ciprofloxacin hydrochloride and salidroside composition freeze-dried powder injection, pressing the plugs in vacuum, taking out the injection box, and rolling an aluminum cover to obtain 3000 antibacterial drugs.
Example 8
A medicine for resisting carbapenem-resistant Klebsiella pneumoniae is prepared from ciprofloxacin hydrochloride and salidroside at a mass ratio of 1: 3.
Adding 100g ciprofloxacin hydrochloride, 300g salidroside, 20g lactose and 5g potassium dihydrogen phosphate into 10000ml of water for injection, stirring uniformly, adding 20g activated carbon, stirring fully, and filtering the activated carbon. Adding water for injection to 10000ml, measuring the pH value, adding dipotassium hydrogen phosphate to adjust the pH value of the solution to 5.5-6.5, filtering the solution through two filter membranes with the diameter of 0.2 mu m, subpackaging the filtrate into 1000 vials (10ml:100mg) of penicillin bottles by using an automatic filling machine, performing half stoppering, performing freeze-drying by using a freeze-drying box to obtain the ciprofloxacin hydrochloride and salidroside composition freeze-dried powder injection, performing vacuum stoppering, taking out the lyophilized powder injection, and rolling an aluminum cover to obtain 1000 antibacterial drugs.
Example 9
A medicine for resisting carbapenem-resistant Klebsiella pneumoniae is prepared from ciprofloxacin hydrochloride and salidroside at a mass ratio of 1: 5.
Adding 100g ciprofloxacin hydrochloride, 500g salidroside, 40g lactose and 5g potassium dihydrogen phosphate into 10000ml of water for injection, stirring uniformly, adding 30g activated carbon, stirring fully, and filtering the activated carbon. Adding water for injection to 10000ml, measuring the pH value, adding dipotassium hydrogen phosphate to adjust the pH value of the solution to 5.5-6.5, filtering the solution through two filter membranes with the diameter of 0.2 mu m, subpackaging the filtrate into 1000 vials (10ml:100mg) of penicillin bottles by using an automatic filling machine, performing half stoppering, performing freeze-drying by using a freeze-drying box to obtain the ciprofloxacin hydrochloride and salidroside composition freeze-dried powder injection, performing vacuum stoppering, taking out the lyophilized powder injection, and rolling an aluminum cover to obtain 1000 antibacterial drugs.
Application example 1
Experimental strains: the strain is confirmed to be carbapenem-resistant Klebsiella pneumoniae (CRKP) by reference to the standard interpretation of the American society for clinical laboratory standards research (CLSI)2017 of the United states clinical laboratory, wherein the carbapenem-resistant Klebsiella pneumoniae (No. 146553, originated in the clinical laboratory of Sudoku affiliated to the Jiujiang academy of academic, and isolated from clinical patients).
Experimental animals: 18-22 g of Kunming mouse with half male and half female, and feeding the Kunming mouse in an animal house for 3-5 days before the experiment.
Mouse Minimal Lethal Dose (MLD) assay: after the experimental strain is cultured by MH culture solution, 5% high-activity dry yeast solution is used for diluting to the final concentration required by infected animals, the mice are infected by abdominal cavity, 0.5 mL/mouse is used, 10 mice are infected by each group, and the MLD of the mice with 100% mortality caused by the experimental strain is measured.
And (3) pharmacodynamic experiment: the test bacterial liquid (MLD) is subjected to intraperitoneal infection, ciprofloxacin hydrochloride is injected into the abdominal cavity, the pharmaceutical composition in example 6, the pharmaceutical composition in example 7, the pharmaceutical composition in example 8, the pharmaceutical composition in example 9 and physiological saline are injected into the abdominal cavity of the blank control group, the administration dose is calculated according to the ciprofloxacin hydrochloride, and the administration dose is converted into the administration dose of the mouse according to the body surface area. Mice were injected 2 times daily for 3 consecutive days and observed to record survival by 1-3 days of infection.
Results of the experiment
The results of the in vivo CRKP activity test of each administration group are shown in table 2, and from the experimental results, when ciprofloxacin hydrochloride is administered alone, only 1 mouse survives after 48h, the effect of the combination administration group is obviously stronger than that of ciprofloxacin hydrochloride alone, and the mice treated by the drugs prepared in example 8 and example 9 are recovered from infection after 12h, and the vital signs and the activity status are basically not different from those of the blank control group.
TABLE 2 in vivo CRKP Activity test for each administration group
The invention provides an antibacterial drug which has a good effect and can avoid enhancing the drug resistance of bacteria, and a preparation method and application thereof.
Although the present invention has been described in detail with reference to the above embodiments, it is only a part of the embodiments of the present invention, not all of the embodiments, and other embodiments can be obtained without inventive step according to the embodiments, and the embodiments are within the scope of the present invention.
Claims (8)
1. A pharmaceutical composition is characterized in that the effective components comprise ciprofloxacin hydrochloride and salidroside;
the mass ratio of the ciprofloxacin hydrochloride to the salidroside is (1-3): (1-12).
2. The pharmaceutical composition of claim 1, wherein the medicament further comprises a pharmaceutically acceptable excipient; the auxiliary materials comprise freeze-dried excipients;
the mass ratio of ciprofloxacin hydrochloride, salidroside and freeze-drying excipient in the medicine is (1-3): (1-12): (0.05-12).
3. The pharmaceutical composition of claim 2, wherein the freeze-drying excipient is selected from any one or more of mannitol, glycine, lactose, sucrose, glucose and sorbitol.
4. The pharmaceutical composition of claim 2, wherein the adjuvant further comprises an acid-base modifier;
the acid-base regulator is selected from any one or more of sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid and sulfuric acid.
5. A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 4, comprising the steps of:
(1) mixing ciprofloxacin hydrochloride, salidroside and freeze-dried excipient to obtain a mixture, mixing the mixture with water for injection to obtain a mixture, and filtering the mixture to obtain a liquid medicine;
(2) the liquid medicine is made into freeze-dried powder to obtain the medicinal composition.
6. The method according to claim 5, wherein the pH of the chemical solution in the step (1) is 5.0 to 7.0.
7. The preparation method according to claim 5, wherein the volume ratio of the mass of the mixture in the step (1) to the water for injection is 100-1000 g: 5000-500000 mL.
8. Use of the pharmaceutical composition of any one of claims 1 to 4 or the pharmaceutical composition prepared by the preparation method of any one of claims 5 to 7 in the preparation of a medicament for reversing the resistance of the carbapenem-resistant Klebsiella pneumoniae.
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| CN110251526A (en) * | 2019-07-22 | 2019-09-20 | 陕西科技大学 | Paeoniflorin is inhibiting the application in the growth of Carbapenem-resistant parapneumonia klebsiella |
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| CN110251526A (en) * | 2019-07-22 | 2019-09-20 | 陕西科技大学 | Paeoniflorin is inhibiting the application in the growth of Carbapenem-resistant parapneumonia klebsiella |
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