A new application of Thiopeptidecycline

A technology of thiopeptidecycline and antibiotics, which is applied in the direction of medical preparations of non-active ingredients, cyclic peptide components, dispersion liquid delivery, etc., can solve the problems of anti-anaerobic bacteria, Clostridium difficile and other problems that have not been seen. Achieve super antibacterial activity, strong antibacterial activity, and small safety hazards

Active Publication Date: 2019-08-30
NANJING BIOTICA PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In vitro activity studies have shown that Thiopeptidecycline can kill Gram-positive aerobic bacteria at very low concentrations (ng / mL). report

Method used

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  • A new application of Thiopeptidecycline
  • A new application of Thiopeptidecycline
  • A new application of Thiopeptidecycline

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1 In vitro anti-Clostridium difficile and its drug-resistant strain activity of thiopeptcycline

[0028] The in vitro antibacterial activity of Thiopeptidecycline was tested against Clostridium difficile ATCC 9689, a clinically isolated strain of Clostridium difficile LCN 001, and a clinically isolated drug-resistant strain, and compared with vancomycin. According to the broth dilution method recommended by CLSI M11-A7, the minimum inhibitory concentration (MIC) of Thiopeptidecycline was determined. According to the measurement needs, the Brooke's broth supplemented with Hemin (5 mg / ml), vitamin K1 (1 μg / ml), lysed horse blood (5%) and oxidase (1:25v / v) was divided into different measurement groups, and then Thiopeptidecycline or vancomycin in DMSO was added. The concentration range of the test drug was 0.025 μg / ml-128 μg / ml. Check the growth of Clostridium difficile in each culture medium, the minimum antibacterial drug concentration at which the experimental...

Embodiment 2

[0031] Example 2 Thiopeptidecycline LC-MS / MS detection method

[0032] Add 90 μl of methanol containing 5 ng / ml verapamil to 30 μl of blood or urine sample, vortex for 3 minutes, then centrifuge at 14,000 rpm for 5 minutes, take 80 μl of the supernatant, and inject it into LC-MS / MS for analysis.

[0033] High performance liquid chromatography: Chromatographic column: Waters Symmetry 300 C18 3.5μm 2.1*100mm;

[0034] Mobile phase A: 10mM ammonium acetate + 0.02% ammonia solution; mobile phase B: methanol;

[0035] Analysis time: 5.2min Injection volume: 5μL Column temperature: 25°C;

[0036] Gradient elution:

[0037] time (min) Flow rate (mL / min) B％ 0.00 0.4 67 2.40 0.4 67 2.45 0.4 90 3.80 0.4 90 3.85 0.4 67 5.20 0.4 67

[0038] Mass spectrometry: positive ion mode (Agilent6460B)

[0039] Detection ion pair: Thiopeptidecycline: 1437.3→172.0, fragmentor=135, CE=22;

[0040] Verapamil (internal standard): 455.2→165.1, frag...

Embodiment 3

[0042] Example 3 Pharmacokinetic Study of Oral Thiopeptidecycline

[0043] Preparation method of Thiopeptidecycline medicinal solution: Take a certain amount of Thiopeptidecycline and place it in a mixed solvent containing 10% PEG400, 1% Tween 80, and 5 mg / ml citric acid at pH 5.0, and shake until clear to obtain Thiopeptidecycline Gastrointestinal solution.

[0044] Male rats were divided into high, medium and low dose groups according to the purpose of the experiment. Among them, the high dose group is 50 mg / Kg, the middle dose group is 25 mg / Kg, the low 1 dose group is 5 mg / Kg, and the low 2 dose group is 1 mg / Kg. About 0.3 ml of blood samples were collected at each time point of about 15 minutes, 30 minutes, 45 minutes, 1, 2, 4, 6, 8 and 24 hours after the administration for the determination of bioavailability. See Example 2 for the method.

[0045] Table 2 Concentration-time data (ng / ml) of thiopeptcycline in plasma after oral administration of thiopeptetcycline in rat...

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Abstract

The invention discloses the application of thiopeptidecycline in the preparation of medicines for treating Clostridium difficile infectious diseases and its complications. Thiopeptidecycline has significant activity against Clostridium difficile and its drug-resistant strains, and has important clinical application value. In vivo experiments have verified that the thiopeptidecycline does not enter the blood circulation after oral administration. In view of the characteristics of intestinal administration, the present invention also provides an oral preparation of the thiopeptidecycline containing a safe and effective dose and a preparation method thereof.

Description

technical field [0001] The invention belongs to the field of novel antibiotics and applications thereof, and specifically relates to the new application of thiopeptidecycline against Clostridium difficile and drug-resistant strains thereof and oral preparations of thiopeptidecycline. Background technique [0002] Clostridium difficile (Clostridium difficile) is a Gram-positive anaerobic bacillus, about 3% of the general population have the parasitism of the intestinal tract. Clostridium difficile is an opportunistic pathogen. Under normal circumstances, it is controlled by other bacteria in the human body and will not endanger human health. Clostridium difficile infection (CDI) is usually caused by excessive or irrational use of broad-spectrum antibiotics (clindamycin, ampicillin, cephalosporins, lincomycin, etc.) With the continuous emergence of drug-resistant strains, CDI is increasing. Studies have found that CDI is mainly caused by the cytotoxic effects of toxins A and...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K38/12A61P31/04
CPCA61K9/0007A61K9/0053A61K9/0095A61K9/06A61K9/08A61K9/107A61K9/146A61K9/1641A61K9/1652A61K9/19A61K9/2018A61K9/2054A61K9/2059A61K9/2853A61K9/2866A61K9/2873A61K9/4866A61K9/5031A61K9/5078A61K38/12A61K47/10A61K47/26A61K47/40A61K47/44A61K9/00A61K47/00A61P31/04A61K9/0014A61K9/0056A61K9/2009A61K9/2013A61K9/2027A61K9/2886A61K9/485
Inventor 陈依军钱军建吴旭日
Owner NANJING BIOTICA PHARMA
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