Antibacterial Efficacy against an In Vivo Salmonella typhimurium Infection Model and Pharmacokinetics of a Liposomal Ciprofloxacin Formulation

Abstract

The fluoroquinolone antibiotic ciprofloxacin has been encapsulated into large unilamellar vesicles (LUV) at efficiencies approaching 100%. Drug accumulation proceeded in response to a transmembrane gradient of methylammonium sulfate and occurred concomitantly with the efflux of methylamine. A mechanism for the encapsulation process is described. LUV composed of dipalmitoylphosphatidylcholine-cholesterol (DPPC/chol), distearoylphosphatidylcholine-cholesterol (DSPC/chol), or sphingomyelin-cholesterol (SM/chol) increased the circulation lifetime of ciprofloxacin after intravenous (i.v.) administration by >15-fold. The retention of ciprofloxacin in liposomes in the circulation decreased in the sequence SM/chol > DSPC/chol > DPPC/chol. Increased circulation lifetimes were associated with enhanced delivery of the drug to the livers, spleens, kidneys, and lungs of mice. Encapsulation of ciprofloxacin also conferred significant increases in the longevity of the drug in the plasma after intraperitoneal administration and in the lungs after intratracheal administration in comparison to free ciprofloxacin. The efficacy of a single i.v. administration of an SM/chol formulation of ciprofloxacin was measured in a Salmonella typhimurium infection model. At 20 mg of ciprofloxacin per kg of body weight, the encapsulated formulation resulted in 103- to 104-fold fewer viable bacteria in the livers and spleens of infected mice than was observed for animals treated with free ciprofloxacin. These results show the utility of liposomal encapsulation of ciprofloxacin in improving the pharmacokinetics, biodistribution, and antibacterial efficacy of the antibiotic. In addition, these formulations are well suited for i.v., intraperitoneal, and intratracheal or aerosol administration.

Liposome-based antitubercular drug therapy in a guinea pig model of tuberculosis

“…We observed similar results in mice dosed with liposomal ATD [2]. The improvement in pharmacokinetic parameters following liposomal encapsulation has also been reported for other drugs such as amphotericin B [3] and ciprofloxacin [4]. The animals were sacrificed at various time points to evaluate the drug content in organ homogenates of lungs, liver and spleen.…”

The Vesosome - A Multicompartment Drug Delivery Vehicle

“…Conventional pH-loaded liposomes can retain essentially all encapsulated ciprofloxacin when stored in buffer for 12 weeks at 21° C and 8 weeks at 37° C [36,37]. Although liposomal cipro has shown increased efficacy due to a prolonged residence of cipro in the blood (free cipro is cleared in minutes), the halflife of release from the liposomes was only 1 hour, yet the liposomes themselves circulated for more than 24 hours [23,37].…”

“…A second example is vincristine, a naturally occurring dimeric catharanthus alkaloid that has been used extensively as an antitumor agent since the 1960's. The therapeutic activity of vincristine is dictated by the duration of therapeutic concentrations at the tumor site [36,38,39]. However, vincristine administered to patients by long-term infusion is associated with severe toxicities.…”

Nebulization of liposome encapsulated antitubercular drugs in guinea pigs

“…free drugs, however, were undetectable in the lungs/macrophages beyond 48 h. The data clearly shows the ability of nebulized liposomes to target the alveolar macrophages, which are the abode of tubercle bacilli. It is known that the nebulization of liposomal drug leads to sustained pulmonary drug levels [5] as observed in our study, and the safety of liposomal drugs is also well established [6].From the patient's point of view, nebulization of liposomes would be perhaps more acceptable compared with i.v. liposomes.…”