Overview of research and development of new formulations of antibiotics such as liposomes, nanospheres and microspheres

In recent years, emerge in an endless stream of new forms of antibacterial agents, such as liposomes, nanospheres, microspheres, micronization, and gels Agents, gastric retention sustained-release tablets, controlled-release film agents, etc., can enhance the drug targeting, selectively distribute in the infection focus, reduce the systemic toxicity and side effects of drugs, such as liposomes, nanospheres; or make the infection site or blood obtain sustained high concentration drugs and produce multiple impact doses, such as sustained-release tablets (particles), controlled-release film agents, etc In this paper, the research on the dynamic process of cells and tissues of several new dosage forms of antibacterial drugs is summarized The therapeutic effect of kanamycin (km) liposome on Mycobacterium infection in mice was studied Compared with the mixture of free km or km and liposome empty capsule, the new formulation obviously increased the accumulation in reticuloendothelial tissues and organs, prolonged the retention time in serum and lung, and increased the amount of drug entering host macrophage Aminoglycoside antibiotics have lower permeability to cells and lower activity in the intracellular environment with pH < 7 When amikacin was entrapped into the liposome, the effect of human macrophages infected with Mycobacterium avidiae and mice infected with Mycobacterium avidiae was significantly increased; after administration, the bacterial count in the liver, spleen and kidney of mice infected with amikacin was 1 / 1000 of that of free amikacin; when the liposome with particle size of 2-3 μ m was replaced by the liposome with particle size of 0.2-0.3 μ m, the bacterial count in the lung decreased More significant The concentration of gentamicin liposome in cornea was measured 24 hours later The concentration of liposome was 20 times higher than that of free drug The concentrations of liposomes in heart, liver, spleen, lung, brain and serum were significantly higher than those of free drugs after a single dose of intravenous injection of 52mg / kg of free or liposome sulfated amikacin, which were 6.2, 9.5284.0, 3.0, 14.7 and 3 times higher, respectively, and the concentration of blood drug could be maintained for more than 24 hours, while the concentration of free amikacin was below the detection limit after 7 hours: the concentration of renal tissue decreased to 1 / 2 of free drugs This is because the content of monocyte macrophages such as spleen, liver and lung is rich and easy to absorb liposomes, while liposomes can not pass through the glomerular ultrafiltration membrane, and can not reach the renal tubules, collecting ducts and other parts 1.2 β - lactam, cloxacillin, was ineffective in the treatment of Staphylococcus aureus with intracellular infection, but the efficacy was significantly increased after inclusion of liposomes Under the electron microscope, liposomes and cells co existed in neutrophils Free ampicillin and penicillin G had no effect on Listeria monocytogenes infected by peritoneal macrophages in mice, but their liposomes had a significant inhibitory effect, killing 90% in vitro test; the therapeutic effect on C57BL / ka nude mice infected with this bacteria could be increased by 90 times When ampicillin liposomes were injected intravenously into rabbits, there was a significant difference in the disposition of male and female rabbits The mean retention time (MRT) of female rabbits was shorter than that of male rabbits, the apparent distribution volume (VT) of female rabbits was smaller when they reached steady state and the apparent distribution volume (vt) of time t was smaller, and the clearance rate (CL) was faster There was no significant difference in the pharmacokinetics of free ampicillin between male and female rabbits Free ampicillin was not found in the spleen, liver, kidney, heart and lung, but its liposomes were highly distributed in these tissues, and the concentration in the spleen and lung of female rabbits was higher than that of male rabbits 1.3 the liposomes of ofloxacin and clarithromycin developed by fluoroquinolones such as onyeji Co, Nightingale c h, Nicolau D P, etc can effectively kill the Mycobacterium avium complex (MAC) in phagocytes compared with the free drugs of the same concentration (P Ciprofloxacin liposome 0.1ml (including 273.6 μ g ciprofloxacin) was injected into the eyes of rabbits The concentration in the glass was 18.0 μ g / ml after 24 hours, 6.9 μ g / ml (> MIC90) after 3 days Ciprofloxacin was not detected at 14 days The serum concentration was 0.04-0.07 μ g / ml within 24 hours, but it was not detected again after 3-14 days 1.4 amphotericin B liposome, an antifungal drug, was given to mice and rabbits at a dose of 5mg / kg, with a plasma half-life of 3.36 and 7.56h, respectively Its concentration in kidney and lung was equivalent to that of free drug at a dose of 1mg / kg Compared with free drug at a dose of 1mg / kg, the concentration of liposome in liver and spleen was higher, while that in kidney and lung was lower The Zui concentration (Cmax) and area under the concentration time curve (AUC) of amphotericin B liposome were 8-10 times of those of the control group, and the Cmax was 14.4g/ml, which was Cmax of the free drug At 8.4 times of 1.7g/ml, the VC of the central chamber was 5.7 times lower than that of the free drugs, and T1 / 2 was 2 times higher than that of the free drugs (P = 0.03) 2 nanospheres 2.1 aminoglycosides The uptake of macrophages (MPM) and hepatocytes (RH) in vitro was observed with gm-np The results showed that the uptake of MPM was significantly higher than that of GM (P Times Different surfactants could affect the uptake of MPM and Rh, while hydrophilic surfactants tween and poloxamer 188 decreased the uptake, while dextran 70 was beneficial to the uptake of NP by hepatocytes Amikacin nanospheres were used in the eyes of New Zealand white rabbits Compared with the control group, the drug concentration in the cornea was significantly increased, and the concentration in the anterior chamber fluid was more than three times of the control group 2.2 amphotericin B was injected into Kunming mice with amphotericin B nanospheres (AMB NP) at 1 mg / kg and amphotericin B (AMB) at 1 mg / kg by tail vein respectively for 5-30 minutes The concentration of AMB NP in plasma and heart was 8 and 7 times higher than that of AMB, 3 times higher than AMB at 10h, and the same at 72h; the concentration of AMB NP reached its peak at 30min in liver, 70% higher than AMB at 10h; it reached its peak at 4H in kidney, 2 times higher than AMB at 10h, and the same at 24h-72h: 6% of AMB at 5min lung, 4.9 times lower than AMB at 30min, and slightly higher than AMB at 10h AmB-NP 1 When mg / kg was used in mice, the plasma concentration of AMB NP was significantly higher than that of AMB before 48h, which indicated that the circulation time of AMB NP in blood was prolonged; but after 48h, the plasma concentration of AMB NP group decreased rapidly, its T1 / 2 was 20.07h, while the T1 / 2 of AMB group was 50.68h; the VC of the two groups were 1.92 and 23.82ml respectively, indicating that AMB tissue distribution was more extensive; but the concentration of AMB NP in main organs did not decrease significantly, suggesting that AMB NP was more widely distributed Its AUC was higher than that of AMB, and the drug retention in blood circulation was longer When the dose of AMB NP increased from 1mg / kg to 5mg / kg, T1 / 2 increased, but AUC did not increase proportionally The results showed that the treatment of AMB nm in mice was related to the dose, and VC and Cl increased with the increase of the dose 3 microsphere 3.1 streptomycin microsphere (MS) was given to Kunming mice The radioactivity of the microsphere was measured by γ scintillation counter The results showed that the concentration of Zui in lung tissue was high, accounting for 81.39% of the tissue distribution percentage in vivo, while the concentration of heart, spleen, liver and kidney was low, which was significantly different from that of streptomycin sulfate, indicating that the pulmonary targeting of the microsphere was very good This is because the particles with a particle size of 7-12 μ M can be mechanically blocked in the lung, so as to achieve local targeting The results showed that there was a first-order dynamic process in the lung tissue, T1 / 2 was 12.48h, Tmax was 0.515h, Cmax was 4080.183ng/100mg, but the serum dynamic process could not reflect the pharmacokinetics of the lung tissue The concentration of Streptomycin Solution in blood and kidney is higher than that in other tissues, and it is easy to produce toxic reaction 3.2 rifampin Rifampicin 5mg / kg was injected into New Zealand rabbits via ear vein The blood concentration of rifampicin polylactide microspheres group was 0.72 μ g / ml 24 hours after administration, and 0.27 μ g / ml 72 hours after administration, which was still higher than rifampicin effective bacteriostatic concentration (0.02-0.05 μ g / ml) Its T1 / 2 β was 35.27 hours, and the drug was mainly concentrated in the lung, liver and spleen without retention However, the blood concentration of rifampicin solution group decreased rapidly, 24 hours after administration, the blood concentration was still higher than rifampicin effective bacteriostatic concentration (0.02-0.05 μ g / ml) It was 0.7 μ g / ml, 0.2 μ g / ml lower than the detection limit at 48h, and its T1 / 2 β was 9.07h 3.3 erythromycin Compared with enteric coated tablets, the peak time of erythromycin microcapsules in human body was (3.25 ± 0.32) and (3.36 ± 0.21) h, the peak concentration was (1.04 ± 0.09) and (1.24 ± 0.15) mg / L, respectively (P > 0.05), AUC was (5.62 ± 0.53) and (6.58 ± 0.75) mg / L · h, respectively (P < 0.05); the lag time of microcapsules was significantly shorter than that of enteric coated tablets, respectively (1.24 ± 0.21) and (1.42 ± 0.09) ）H (P < 0.05), indicating that the absorption of erythromycin microcapsules is better than that of enteric coated tablets, which is conducive to the early exertion of the antibacterial effect of erythromycin 4 Chen Qingcai, Shao Zhigao and Yu Meiyi of other dosage forms were given metronidazole buccal adhesive tablets and metronidazole tablets respectively in a single dose for periodontitis subjects, and the drug concentration in gingival crevicular fluid was (5.52 ± 5.65) and (0.64 ± 0.44) μ g / ml respectively after one week of continuous administration Buccal adhesive tablets can keep a high concentration in the oral environment The concentration of saliva and gingival crevicular fluid is more than 2 μ g / ml, which can inhibit the sensitive anaerobic bacteria The plasma concentration of isoniazid sustained-release capsule was 2-5 μ g / ml in 36 hours at a single dose of 400mg, while that of the ordinary tablet was (0.20 ± 0.45) μ g / ml in 12 hours, which was lower than the treatment concentration of 0.5 μ g / ml The pharmacokinetic study of long-acting Cefalexin granules showed that there were two peaks in the blood concentration time curve of long-acting preparation 1G in 12h Compared with the regular release preparation 0.5g × 2 (interval 5H), the first peak time was close, the second peak time was significantly delayed and the peak concentration was close The blood concentration of long-acting preparation was 4-6mg / L 3-5h after administration, which was 0.84-2.69 compared with the regular release preparation Mg/L high Therefore, the long-acting Cefalexin granules is a kind of controlled-release preparation with the peak phenomenon of the regular release preparation There is no significant difference in AUC 0-12h and MRT, which can be used for the treatment of sensitive bacterial infection and reduce the frequency of administration.