Composition containing piperacillin, pharmaceutical formulation thereof and use thereof

Abstract

The present disclosure provides a piperacillin-containing composition, which further containing a certain proportion of ampicillin and sulbactam. The present disclosure further provides a pharmaceutical formulation thereof and the use thereof. The composition and pharmaceutical formulation of the present disclosure can inhibit the drug-resistant Acinetobacter baumannii, and particularly have therapeutic effects on the infection caused by Acinetobacter baumannii which is resistant to carbapenem or cefoperazone-sulbactam.

Claims

1. A piperacillin-containing composition, comprising ampicillin and sulbactam, wherein the composition comprises piperacillin, ampicillin and sulbactam in a weight ratio of 200-400:0.02-6:100.

2. The composition according to claim 1, wherein the composition comprises piperacillin, ampicillin and sulbactam in a weight ratio of 200-400:0.02-3:100, or in a weight ratio of 200-400:0.04-6:100.

3. The composition according to claim 1, the composition consists of piperacillin, ampicillin and sulbactam.

4. A pharmaceutical formulation comprising the composition according claim 1.

5. The pharmaceutical formulation according to claim 4, wherein the pharmaceutical formulation is an injection.

6. The pharmaceutical formulation according to claim 5, wherein the injection is a powder for injection or a solution for injection.

7. The pharmaceutical formulation according to claim 6, wherein the powder for injection is a sterile powder for injection or lyophilized powder for injection.

8. A method for treating a bacterial infection disease, comprising administering the composition according to wherein the bacteria is drug-resistant Acinetobacter baumannii claim 1.

9. The method according to claim 8, wherein the drug-resistant Acinetobacter baumannii is resistant to cefoperazone-sulbactam.

10. The method according to claim 8, wherein the composition is formulated to a pharmaceutical formulation.

11. The method according to claim 10, wherein the pharmaceutical formulation is an injection.

12. The method according to claim 11, wherein the injection is a powder for injection or a solution for injection.

Description

DETAILED DESCRIPTION

(1) Hereinafter the present disclosure will be illustrated in details with reference to examples, but they are not intended to limit the technical solution and technical effect of the present disclosure.

Example 1: Preparation of a Piperacillin-Containing Composition

(2) 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) were taken and mixed well in a mono-cone ribbon mixer, to obtain a composition. One part of the composition was subpackaged under sterile condition to obtain a powder for injection (sterile powder for injection). The other part of the composition was dissolved by 100× (ml/g) of 0.9% aqueous sodium chloride solution, and then subpackaged to obtain solutions for injection.

Example 2: Preparation of a Piperacillin-Containing Composition

(3) 1000 g of piperacillin acid, 0.3 g of ampicillin acid and 500 g of sulbactam acid were dissolved in an aqueous solution containing 343 g sodium bicarbonate, and then lyophilized and subpackaged to obtain powder for injection (lyophilized powder for injection) containing the composition.

Examples 3-6: Preparation of a Piperacillin-Containing Composition

(4) The preparation processes of examples 3-6 were similar to that of example 1. The amounts of piperacillin and sulbactam were the same as those of example 1. While, the amounts of ampicillin gradually increased in examples 3-6, and were 1 g, 3 g, 10 g and 15 g, respectively.

Comparative Examples 1-2

(5) The preparation processes of comparative examples 1-2 were similar to that of example 1. The amounts of piperacillin and sulbactam were the same as those of example 1. While, in comparative examples 1-2, the amounts of ampicillin were 60 g and 200 g, respectively.

Comparative Example 3

(6) The preparation process of comparative example 3 was similar to that of example 1. The amounts of piperacillin and sulbactam were the same as those of example 1. While no ampicillin was included in comparative example 3.

Examples 7-8: Preparation of a Piperacillin-Containing Composition

(7) The preparation processes of examples 7-8 were similar to that of example 1. In both examples 7 and 8, the amounts of piperacillin and sulbactam were 1500 g and 500 g, respectively. While, the amounts of ampicillin were 5 g and 15 g, respectively, in examples 7 and 8.

Example 9: Preparation of a Piperacillin-Containing Composition

(8) Piperacillin sodium (1000 g calculated by piperacillin acid), 0.1 g of ampicillin acid and sulbactam sodium (250 g calculated by sulbactam acid) were mixed well in a multi-direction movement mixer, to obtain a composition. A part of the resulted composition was subpackaged under a sterile condition to obtain powder for injection.

Examples 10-14: Preparation of a Piperacillin-Containing Composition

(9) The preparation processes of examples 10-14 were similar to that of example 9. The amounts of piperacillin and sulbactam were the same as that of example 9. While, the amounts of ampicillin gradually increased in examples 10-14, and were 0.2 g, 0.7 g, 3 g, 5 g and 15 g, respectively.

Comparative Examples 4-5

(10) The preparation processes of comparative examples 4-5 were similar to that of example 9. The amounts of piperacillin and sulbactam were the same as that of example 9. While the amounts of ampicillin were 80 g and 300 g, respectively, in comparative examples 4 and 5.

Experimental Example 1: Study of Protective Effect of Different Compositions on Acinetobacter Baumannii Infection in Experimental Animals

(11) Experimental materials: Tested samples were the compositions obtained in examples 1-14 and comparative examples 1-5, as well as meropenem, sulbactam and cefoperazone-sulbactam. Tested animals were ICR mice. Tested bacterial strains were ATCC19606 (a standard strain of A. baumannii), CBP-R (a carbapenem-resistant strain of A. baumannii), and CPZ/S-R (a cefoperazone-sulbactam-resistant strain of A. baumannii). Among them, the standard strain was obtained from ATCC, and the other strains were clinically isolated.

(12) Determining the dose ranges of the tested samples: The tested strains were diluted with 5% high active dry yeast to obtain bacterial dilutions of different concentrations (10.sup.−1, 10.sup.−2, 10.sup.−3, and 10.sup.−4), and then intraperitoneally injected into the tested animals in 0.5 ml/mice. The number of dead mice after infection was recorded. The minimum bacterial dose, which kills 100% members of the mice, was recorded as 1 MLD. The mice were infected with 1 MLD of bacteria which was formulated with 5% high active dry yeast Immediately and 6 hours after the infection, a preliminary experiment was carried out with high, median and low dosages of the tested samples, and the survival numbers of the mice after infection were recorded. Based on the results of the preliminary experiment, the administration dosages of the tested samples were designed for the animal protection experiment. The appropriate administration dosage was one that resulted in more than 70% of the infected animals survived in the group administered with the highest dosage, and more than 70% of the infected animals died in the group administered with the lowest dosage.

(13) Animal protection experiment: After fasting with water only for 18 h, the mice (half male and female, 25-30 g body weight) were randomly divided into: (1) ATCC19606 group, (2) CBP-R group, and (3) CPZ/S-R group. Each group was treated with five concentrations of the samples, and included 10 animals. In addition, 10 animals were incorporated as a control group. Each mouse was intraperitoneally injected with 0.5 ml of 1 MLD bacterial solution to establish an infection model. At 0 h and 6 h after infection, the mice were subcutaneously injected with different concentrations of the tested samples, 0.2 ml/mice, and the mice of the control group were injected with the same volume of sterilized water. The animals were observed continuously for 7 days, and the death of animals in each group was recorded. The 50% effective dose (ED.sub.50) of each tested sample was calculated by the Bliss method. Smaller ED.sub.50 means that the tested sample has better anti-bacterial effect in vivo, and better protective effect on the experimental animals.

(14) Test results: S, A, B, C, D represented the different grades of ED.sub.50. S: ED.sub.5020 mg/kg; A: 20 mg/kg<ED.sub.5050 mg/kg; B: 50 mg/kg<ED.sub.50100 mg/kg; C: 100 mg/kg<ED.sub.50200 mg/kg; D: ED.sub.50>200 mg/kg. Table 1 shows the main results of this experiment.

(15) TABLE-US-00001 TABLE 1 ED.sub.50 of different compositions for animals infected with A. baumannii Strains CPZ/S-R ATCC19606 CBP-R a cefoperazone- a standard a carbapenem- sulbactam Tested strain of resistant resistant samples A. baumannii A. baumannii A. baumannii Meropenem S D C Sulbactam S C D Cefoperazone-sulbactam A C D Example 1 A B B Example 2 A A B Example 3 A B B Example 4 A B B Example 5 A B B Example 6 A B B Comparative Example 1 A C C Comparative Example 2 A C D Comparative Example 3 A C C Example 7 A B B Example 8 A B B Example 9 A A B Example 10 A B B Example 11 A A B Example 12 A B B Example 13 A B B Example 14 A B B Comparative Example 4 A C D Comparative Example 5 A D D

(16) In the above-mentioned experiments, each tested samples showed efficient inhibitory effect on the standard strain of A. baumannii without drug resistance, in which single meropenem or sulbactam was more advantageous in pharmaceutical efficacy.

(17) Regarding drug-resistant strains of A. baumannii, single meropenem or sulbactam had significantly decreased inhibitory effect, and cefoperazone-sulbactam also failed to provide satisfactory effect. In contrast, the piperacillin-containing composition of the present disclosure had significantly improved anti-bacterial effect, and showed strong synergistic effect. The amount of ampicillin in the composition affects the anti-bacterial effect thereof. The composition having a small amount of ampicillin had better anti-bacterial effect on the drug-resistant A. baumannii.

(18) The present disclosure has been described in details with general description, specific examples and experiments. On this basis, those skilled in the art can make reasonable modifications or improvements to the present disclosure. These modifications or improvements without departing from the principle and scope of the present disclosure further belong to the scope of the present disclosure.

INDUSTRIAL APPLICABILITY

(19) The present disclosure provides a piperacillin-containing composition. The composition of the present disclosure comprises piperacillin and further comprises a certain proportion of ampicillin and sulbactam, wherein the weight ratio of piperacillin, ampicillin and sulbactam is 200-400:0.02-6:100. The present disclosure further provides a pharmaceutical formulation thereof and the use thereof. The composition and pharmaceutical formulation of the present disclosure can significantly inhibit drug-resistant A. baumannii, particularly have therapeutic effects on the infection caused by A. baumannii, which is resistant to carbapenem or cefoperazone-sulbactam. The composition and pharmaceutical formulation of the present disclosure has significant clinical advantages, and good economic value and application prospect.