CN107875154B - Composition containing piperacillin, pharmaceutical preparation and application thereof - Google Patents
Composition containing piperacillin, pharmaceutical preparation and application thereof Download PDFInfo
- Publication number
- CN107875154B CN107875154B CN201711415490.1A CN201711415490A CN107875154B CN 107875154 B CN107875154 B CN 107875154B CN 201711415490 A CN201711415490 A CN 201711415490A CN 107875154 B CN107875154 B CN 107875154B
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- Prior art keywords
- sulbactam
- piperacillin
- ampicillin
- composition
- acinetobacter baumannii
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
Abstract
The invention provides a composition containing piperacillin, which contains piperacillin, ampicillin and sulbactam in a certain proportion. The invention also provides a pharmaceutical preparation and application thereof. The composition and the pharmaceutical preparation can obviously inhibit drug-resistant acinetobacter baumannii, can play a good role in treating carbapenem antibiotics or drug-resistant acinetobacter baumannii infection of cefoperazone and sulbactam, and have obvious clinical advantages.
Description
Technical Field
The invention relates to a composition containing piperacillin and application thereof.
Background
Acinetobacter baumannii is an important pathogenic bacterium and can cause infection of systems such as respiratory system, blood system, abdominal cavity system, central nerve system, urinary system, skin soft tissue system and the like. According to the report of 2016 (Chinese bacterial drug resistance monitor) of China, the Acinetobacter baumannii is the most abundant pathogenic bacterium in respiratory specimens, and the bacterium is suggested to have very important influence on respiratory diseases. Especially for critically ill patients who are hospitalized for a long time, pulmonary infection caused by acinetobacter baumannii has become an important cause of death. In addition, among all clinical isolates, the proportion of acinetobacter baumannii is also as high as 10.8%, second only to escherichia coli and klebsiella pneumoniae.
The carbapenem antibiotics have a good effect on acinetobacter baumannii infection all the time. However, with the widespread use, multiple drug resistance and extensive drug resistance have appeared, and many acinetobacter baumannii have lacked sensitivity to penems. Other clinical drug treatment options include polymyxin, cefoperazone sulbactam and the like. However, the strong nephrotoxicity of polymyxin limits the application of polymyxin, and the drug resistance problem of cefoperazone sulbactam to acinetobacter baumannii is increasingly highlighted.
According to the 2010 CHINET report, the drug resistance rate of Acinetobacter baumannii to cefoperazone sulbactam is 30%, while the 2016 report shows that the ratio has increased to 43%. Therefore, there is an urgent clinical need for a safer and more effective drug for the treatment of drug-resistant acinetobacter baumannii infection.
Disclosure of Invention
The invention aims to solve the problem of drug resistance of acinetobacter baumannii, in particular to the problem of drug resistance of acinetobacter baumannii to cefoperazone and sulbactam.
Drug resistance of bacteria is a complex problem, and the drug resistance mechanism comprises the production of drug-inactivating enzymes by bacteria, the change of drug action targets by bacteria, the change of cell membrane permeability of bacteria, the over-expression of intracellular efflux pumps of bacteria and the like. Piperacillin is a common penicillin antibacterial drug in clinic. However, the drug resistance rate of acinetobacter baumannii to piperacillin is reported to reach more than 70%. Surprisingly, however, the inventors have accomplished the object of the present invention by studying a composition containing piperacillin and other components, which has a very good antibacterial effect against acinetobacter baumannii.
The invention provides a composition containing piperacillin, which also contains ampicillin and sulbactam, wherein the weight ratio of piperacillin to ampicillin to sulbactam is 200-400: 0.02-6: 100.
Preferably, in the composition of the present invention, the weight ratio of piperacillin, ampicillin and sulbactam may be 200: 400.02-3: 100, more preferably 200: 0.02-3: 100, 300: 0.02-3: 100, or 400: 0.02-3: 100. Another preferred embodiment is that the weight ratio of piperacillin, ampicillin and sulbactam in the composition of the invention may be 200: 400.04-6: 100, further preferably 200: 0.04-6: 100, 300: 0.04-6: 100 or 400: 0.04-6: 100.
Preferably, the composition of the invention consists of piperacillin, ampicillin and sulbactam.
The invention also provides a pharmaceutical preparation which contains the composition.
Preferably, the pharmaceutical preparation may be an injection. Further preferably, the injection may be in the form of a dry powder or a solution prepared by dissolving the injection in a solvent. The dry powder can be in the form of sterile powder injection or freeze-dried powder injection. The solvent may be a conventional solvent suitable for clinical use, such as an aqueous glucose solution or an aqueous sodium chloride solution, and the like.
The compositions or pharmaceutical preparations of the present invention can be prepared by methods conventional in the art.
The invention also provides a method for treating bacterial infection diseases, which comprises using the composition or the pharmaceutical preparation. Alternatively, the invention also provides an application of the composition or the pharmaceutical preparation in preparing medicines for treating bacterial infection diseases.
Preferably, the bacterium is drug-resistant acinetobacter baumannii.
Further preferably, the drug resistance is cefoperazone sulbactam drug resistance.
It should be noted that the terms "piperacillin", "ampicillin" or "sulbactam" are used generically herein, i.e., piperacillin, ampicillin or sulbactam may refer to their free acids, salts, polymorphs, hydrates or solvates in different forms. For example, piperacillin acid ((2S, 5R, 6R) -3, 3-dimethyl-6- [ (R) -2- (4-ethyl-2, 3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido ] -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid), piperacillin sodium ((2S, 5R, 6R) -3, 3-dimethyl-6- [ (R) -2- (4-ethyl-2, 3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido ] -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid sodium salt), ampicillin acid ((2S, 5R, 6R) -3, 3-dimethyl-6- [ (R) -2-amino-2-phenylacetamido ] -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid), ampicillin sodium ((2S, 5R, 6R) -3, 3-dimethyl-6- [ (R) -2-amino-2-phenylacetamido ] -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid sodium salt), sulbactam acid ((2S, 5R) -3, 3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid-4), 4-dioxide), sulbactam sodium ((2S, 5R) -3, 3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid sodium-4, 4-dioxide), and the like. The pharmaceutical preparation of the present invention is prepared according to certain dosage form requirements, and can be directly provided for a subject to use. The composition of the present invention may contain a certain amount of moisture or impurities. The pharmaceutical preparation of the invention can contain a certain amount of auxiliary materials.
An amount of sulbactam and ampicillin is used in the piperacillin composition of the invention to improve the drug resistance of acinetobacter baumannii. Although the prior art formulations containing sulbactam are also used for the treatment of acinetobacter baumannii infections, it is generally believed that sulbactam itself plays a role. The invention discovers that a small amount of ampicillin in the composition plays an unusual synergistic effect on the drug-resistant acinetobacter baumannii for the first time. The mechanism may be that ampicillin molecules attack drug-resistant bacteria first, so that the permeability of cell membranes is increased, and the probability and concentration of other drugs in cells are increased.
The composition and the preparation can be used for clinically treating infectious diseases caused by drug-resistant acinetobacter baumannii, particularly can still have a treatment effect after the acinetobacter baumannii is resistant to drugs such as cefoperazone, sulbactam and the like, and have obvious technical effects and clinical advantages.
Detailed Description
The present invention is further illustrated by the following examples, which are not intended to limit the technical solutions and effects of the present invention.
Example 1 preparation of piperacillin composition
Taking piperacillin sodium (1000 g calculated by piperacillin acid), ampicillin sodium (0.1 g calculated by ampicillin acid) and sulbactam sodium (500 g calculated by sulbactam acid), and fully and uniformly mixing the three materials by using a single-cone helical belt mixer to obtain the composition. Packaging a part of the composition under aseptic condition to obtain injection (sterile powder for injection) in dry powder form. Dissolving another part of the composition with 100 times (ml/g) of 0.9% sodium chloride aqueous solution, and packaging to obtain injection in the form of solution.
Example 2 preparation of piperacillin composition
Dissolving piperacillin acid 1000g, ampicillin acid 0.3g and sulbactam acid 500g with aqueous solution containing 343g sodium bicarbonate, lyophilizing, and packaging to obtain a dry powder injection (lyophilized powder for injection) containing the composition.
Examples 3-6 preparation of piperacillin compositions
Examples 3-6 were performed similarly to example 1, with piperacillin and sulbactam in the same amounts as in example 1, except that ampicillin was used in increasing amounts of 1g, 3g, 10g and 15g in each example.
Comparative examples 1 to 2
Comparative examples 1-2 were conducted similarly to example 1, with piperacillin and sulbactam in the same amounts as in example 1, except that ampicillin was used in amounts of 60g and 200g in comparative examples 1-2, respectively.
Comparative example 3
Comparative example 3 was carried out similarly to example 1, with piperacillin and sulbactam in the same amounts as in example 1, except that ampicillin was not used.
Examples 7-8 preparation of piperacillin compositions
Examples 7-8 were carried out analogously to example 1, except that piperacillin was used in both examples in an amount of 1500g, sulbactam was used in an amount of 500g, and ampicillin was used in an amount of 5g and 15g, respectively.
Example 9 preparation of piperacillin composition
Taking piperacillin sodium (1000 g calculated by piperacillin acid), ampicillin acid 0.1g and sulbactam sodium (250 g calculated by sulbactam acid), and fully and uniformly mixing by using a multidirectional motion mixer to obtain the composition. Packaging a part of the composition under aseptic condition to obtain dry powder injection.
Examples 10-14 preparation of piperacillin compositions
Examples 10-14 were performed similarly to example 9, with the same amounts of piperacillin and sulbactam as in example 9. Except that the amount of ampicillin in each example was increased to 0.2g, 0.7g, 3g, 5g and 15g, respectively.
Comparative examples 4 to 5
Comparative examples 4-5 were performed similarly to example 9, with the same amounts of piperacillin and sulbactam as in example 9. Except that the amounts of ampicillin used in comparative examples 4 to 5 were 80g and 300g, respectively.
Experimental example 1 study of the protective action of different compositions on the infection of test animals by Acinetobacter baumannii
Test materials: the test samples were the compositions of examples 1-14 and comparative examples 1-5, meropenem, sulbactam, cefoperazone sulbactam. The test animals were ICR mice. The tested strains are ATCC19606 (Acinetobacter baumannii standard strain), CBP-R (carbapenem-resistant Acinetobacter baumannii strain), CPZ/S-R (cefoperazone-resistant sulbactam Acinetobacter baumannii strain), wherein the standard strain is from ATCC, and other strains are from clinical separation.
The dosage range of the test sample is groped: the test strains were diluted to 10 with 5% high activity dry yeast-1、10-2、10-3、10-4Diluted bacteria solutions with different concentrations were injected into the abdominal cavity of the test animals at 0.5 ml/mouse. The number of deaths of the mice was recorded after infection, and the minimum bacterial mass that caused 100% of the deaths of the mice was recorded as 1 MLD. The mice were infected with 1MLD (MLD) dose of 5% high activity dry yeast, immediately and 6 hours later, pre-tested with three test sample doses of different concentrations, high, medium and low, and the survival number of the mice after infection was recorded, based on which the dosing dose for animal protection test was designed. Suitable doses are given in which more than 70% of the infected animals survive in the highest concentration group and more than 70% of the infected animals die in the lowest concentration group.
Animal protection test: mice which are fasted for 18 hours before the experiment and have no water supply and weight of 25-30g are selected, half of the mice are male and female, and are randomly divided into a plurality of groups: (1) ATCC19606 group, (2) CBP-R group, (3) CPZ/S-R group, 5 test sample concentrations per group, 10 animals per group, and 10 animals as blank control group. 0.5ml of a 1MLD amount of the bacterial liquid is intraperitoneally injected into each mouse to form an infection model, test sample liquid with different concentrations is subcutaneously injected into each mouse 0h and 6h after infection, and the blank control group is given with the same volume of sterile injection water. The observation was continued for 7 days and the mortality of each group of animals was recorded. The 50% Effective Dose (ED) of each test sample was calculated by the Bliss method50)。ED50The smaller the size, the better the bacteriostatic effect in the test sample is, and the better the protective effect on the test animal is.
And (3) test results: s, A, B, C, D denotes different EDs50A rank. S: ED (electronic device)50≤20mg/kg；A：20mg/kg＜ED50≤50mg/kg；B：50mg/kg＜ED50≤100mg/kg；C：100mg/kg＜ED50≤200mg/kg；D：ED50> 200 mg/kg. Table 1 lists the main results of this test.
Table 1: ED of different compositions on Acinetobacter baumannii infected animals50Situation(s)
In the test, for the acinetobacter baumannii standard strain without drug resistance, each test sample can effectively inhibit bacteria. In contrast, the single drug effect of meropenem or sulbactam is more advantageous.
For drug-resistant acinetobacter baumannii, the drug effect of meropenem or sulbactam single prescription is obviously reduced, the cefoperazone sulbactam compound fails to provide better effect, and the piperacillin composition has obviously better antibacterial action and shows strong synergistic action. The amount of ampicillin influences this effect, and when a small amount of ampicillin is present, the composition has a better effect on the drug-resistant bacteria.
The invention has been described in detail with reference to the general description, specific embodiments and tests. On the basis of the present invention, reasonable modification or improvement can be made by those skilled in the art. Accordingly, it is intended that all such modifications and improvements be included within the scope of the invention without departing from the spirit thereof.
Industrial applicability
The invention provides a composition containing piperacillin. The composition contains piperacillin, ampicillin and sulbactam in a certain proportion, wherein the weight ratio of the piperacillin to the ampicillin to the sulbactam is 200-400: 0.02-6: 100. The invention also provides a pharmaceutical preparation containing the composition and application thereof. The composition and the pharmaceutical preparation can obviously inhibit drug-resistant acinetobacter baumannii, can play a good role in treating carbapenem antibiotics or drug-resistant acinetobacter baumannii infection of cefoperazone and sulbactam, have obvious clinical advantages, and have good economic value and application prospect.
Claims (9)
1. A composition containing piperacillin also contains ampicillin and sulbactam, wherein the weight ratio of piperacillin to ampicillin to sulbactam is 200-400: 0.02-6: 100.
2. The composition according to claim 1, wherein the weight ratio of piperacillin, ampicillin and sulbactam is 200-400: 0.02-3: 100, or 200-400: 0.04-6: 100.
3. A composition according to claim 1, consisting of piperacillin, ampicillin and sulbactam.
4. A pharmaceutical formulation comprising the composition of any one of claims 1-3.
5. The pharmaceutical formulation of claim 4, which is an injection.
6. The pharmaceutical formulation of claim 5, wherein the injection is in the form of a dry powder or a solution.
7. The pharmaceutical preparation of claim 6, wherein the injection in the form of dry powder is a sterile powder injection or a lyophilized powder injection.
8. Use of a composition according to any one of claims 1 to 3 or a pharmaceutical formulation according to any one of claims 4 to 7 in the manufacture of a medicament for the treatment of a bacterial infection, said bacterium being drug-resistant acinetobacter baumannii.
9. The use according to claim 8, wherein said drug resistance is cefoperazone sulbactam resistance.
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| CN201711415490.1A CN107875154B (en) | 2017-12-25 | 2017-12-25 | Composition containing piperacillin, pharmaceutical preparation and application thereof |
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| CN201711415490.1A CN107875154B (en) | 2017-12-25 | 2017-12-25 | Composition containing piperacillin, pharmaceutical preparation and application thereof |
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| CN107875154A CN107875154A (en) | 2018-04-06 |
| CN107875154B true CN107875154B (en) | 2021-05-14 |
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| CN111658642A (en) * | 2019-03-05 | 2020-09-15 | 广州新创忆药物临床研究有限公司 | Composition for treating carbapenem antibiotic-resistant acinetobacter baumannii infection |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1850046A (en) * | 2006-06-01 | 2006-10-25 | 济南帅华医药科技有限公司 | Slow-release preparation containing beta-lactamase inhibitor and its use |
| CN111511368A (en) * | 2017-12-25 | 2020-08-07 | 湘北威尔曼制药股份有限公司 | Composition containing piperacillin, pharmaceutical preparation and application thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1850046A (en) * | 2006-06-01 | 2006-10-25 | 济南帅华医药科技有限公司 | Slow-release preparation containing beta-lactamase inhibitor and its use |
| CN111511368A (en) * | 2017-12-25 | 2020-08-07 | 湘北威尔曼制药股份有限公司 | Composition containing piperacillin, pharmaceutical preparation and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 鲍曼不动杆菌耐药性分析;严汝庆;《贵阳中医学院学报》;20121231;第34卷(第6期);全文，尤其是摘要、第117页最后一段 * |
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