Assessment of novel oral lipid-based formulations of amphotericin B using an in vitro lipolysis model (original) (raw)
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Journal of Antimicrobial Chemotherapy, 2009
To assess the pharmacokinetics and biodistribution of amphotericin B (AmB) following oral administration in a novel mono/diglyceride-phospholipid formulation and to compare with intravenous (iv) administrations using commercial formulations. Methods: Rats were allocated into the following treatment groups: oral gavage of AmB dispersed in mono/diglyceride-phospholipid formulation at doses of 4.5 and 10 mg/kg; iv bolus administration of 0.8 mg/kg Fungizone w ; iv bolus of 5 mg/kg Abelcet w and iv bolus of 5 mg/kg AmBisome w. Blood was sampled from jugular vein cannula at certain time points. The animals were sacrificed 72 h following administration of AmB and multiple tissues were harvested. The concentration of AmB in plasma and tissues was determined by means of HPLC. The plasma creatinine concentrations were determined using an enzymatic kit. Results: The pharmacokinetics and tissue distribution of AmB following iv administrations of the commercial formulations were found to be highly formulation dependent. The terminal half-life and biodistribution of orally administered AmB in a mono/diglyceride-phospholipid formulation resembled those of Fungizone w. The larger volume of the co-administered lipid-based formulation in the case of the higher dose of orally administered AmB resulted in flip-flop kinetics and in preferential distribution into the kidneys. No nephrotoxicity was detected for any formulation and route of administration. Conclusions: Oral administration of AmB in a mono/diglyceride-phospholipid formulation to rats resulted in significant intestinal absorption into the systemic circulation with pharmacokinetic and biodistribution properties similar to a micellar iv preparation.
Acta bio-medica : Atenei Parmensis, 2012
Amphotericin B is a polyene macrolide derived from Streptomyces nodosus. Introduced into therapy in 1957, for decades amphotericin B has been the "gold standard" for fighting systemic fungal infections. In order to facilitate its systemic use, much attention has been paid to the development of pharmaceutical forms that could reduce its toxicity, especially for the kidney. Because of its low solubility in water and excellent solubility in lipids, amphotericin B is an ideal candidate for lipid-based formulations. Three different lipid formulations for intravenous infusion are currently commercially available: liposomal amphotericin (AmBisome), Amphotericin lipid complex (Abelcet) and Amphotericin colloidal dispersion (Amphocil). The three lipid formulations of amphotericin B show significantly different structural, physical, chemical, pharmacokinetic, pharmacodynamic and toxicological characteristics. Several lines of evidence indicate that the three formulations of amphoter...
Liposomal formulations of amphotericin B: differences according to the scientific evidence
Revista española de quimioterapia : publicación oficial de la Sociedad Española de Quimioterapia, 2015
This article presents an overview of the characteristics of liposomes as drug carriers, particularly in relation to liposomal formulations of amphotericin B. General features regarding structure, liposome-cell interactions, stability, encapsulation of active substances and elimination of liposomes are described. Up to the present time extensive efforts to produce similar or bioequivalent products of amphotericin B formulations, in particular in the case of liposomal amphotericin B, have been unsuccessful in spite of having a very similar composition and even an apparently identical manufacturing process. Guidelines for the development of generic liposomal formulations developed by the FDA and EMA are also summarized. Based on the available evidence of the composition of liposomes, any differences in the manufacturing process even if the same lipid composition is used may result in different final products. Therefore, it seems unreasonable to infer that all amphotericin B liposomal f...
2016
Successful delivery of pharmaceuticals orally requires a firm understanding of how dosage forms behave during their passage through the gastrointestinal (GI) tract. In this study, the GI transit time and absorption of amphotericin B (AmB) solid lipid nanoparticles (SLN) were investigated in rats, using paracetamol (PAR) and sulphapyridine (SP) as indirect markers. A high encapsulation efficiency of 91.2% was obtained for the AmB SLNs. The SLNs were exhaustively characterised with regards to size, zeta potential (ZP), viscosity, density, migration propensity within agarose gel, in vitro drug release and morphology, to ensure similar disposition in the GI tract after simultaneous oral administration. Freeze-drying did not significantly alter the size or ZP of the AmB SLNs, and in vitro drug release from fresh and freeze-dried SLNs were identical. AmB, PAR and sulphasalazine (SSZ) (the latter being the prodrug of SP) were individually formulated into SLNs using beeswax and theobroma oi...
Overview of the lipid formulations of amphotericin B
Journal of Antimicrobial Chemotherapy, 2002
Invasive fungal infections have been increasingly recognized as a major cause of morbidity and mortality in the immunocompromised host. Amphotericin B has a broad spectrum and has remained the drug of choice for life-threatening invasive fungal infections. However, adverse events, particularly renal insufficiency, are limiting factors in achieving an effective dose: the prescription of amphotericin B is a compromise between toxicity and efficacy. Lipid formulations offer a better therapeutic index by circumscribing amphotericin B toxicity. Three lipid formulations are available in most countries: AmBisome, the only true liposome; Abelcet, with a ribbon-like structure; and Amphocil/Amphotec, composed of disc-like structures. All these formulations contain amphotericin B, but they differ in shape, size, reticuloendothelial clearance, Cmax, AUC and visceral diffusion. The impact of these differences in pharmacokinetics and pharmacodynamics on clinical efficacy is still unclear. Efficac...
AmbiOnp: Solid Lipid Nanoparticles of Amphotericin B for Oral Administration
Journal of Biomedical Nanotechnology, 2011
Amphotericin B is the most effective gold standard drug against various fungal infections, especially in second line treatment of leishmaniasis. However, its usefulness is limited due to severe nephrotoxicity, which may lead to kidney failure. Due to its poor oral bioavailability, it is often administered parenterally to patients suffering from systemic fungal infection or visceral leishmaniasis (kala azar). In this investigation, solid lipid nanoparticles were formulated for oral administration of Amphotericin B. For this purpose, novel microemulsion based nanoprecipitation technique was employed. The influence of process variables such as sonication and dialysis time was studied. The optimized formulation was characterized for parameters such as particle size, polydispersity index, zeta potential, drug content and entrapment efficiency. The pH stability of the developed Amphotericin B solid lipid nanoparticles (AmbiOnp) at pH 1.2, 4, 6.8 values demonstrated enhanced protection of entrapped Amphotericin B. Further, single dose acute toxicity study established the safety of AmbiOnp for oral administration. In vivo pharmacokinetic studies revealed increase in % relative bioavailability of AmbiOnp in comparison to the plain drug. Additionally, the t 1/2 of encapsulated Amphotericin B was significantly greater than that of plain drug, indicating the controlled release of Amphotericin B from AmbiOnp. Overall, the developed formulation; AmbiOnp was found to be successful in oral delivery of Amphotericin B.
Hemolytic and pharmacokinetic studies of liposomal and particulate amphotericin B formulations
Amphotericin B (AmB) is a very effective antifungal and antiparasitic drug with a narrow therapeutic window. To improve its efficacy/toxicity balance, new controlled release formulations have been developed based on different encapsulation systems, aggregation states and particle sizes modifications. The kinetics of the hemolytic process was studied not only to characterize the toxicity of different formulations but also as an indicator of drug release. Pharmacokinetic studies in beagle dogs were carried out with those formulations that exhibited the least hemolytic toxicity: liposomal formulation (AmBisome ® ), poly-aggregated AmB and encapsulated particulate AmB formulation. A novel poly-aggregated AmB formulation proved to be comparable in terms of low hemolytic activity with the marketed gold standard formulation: AmBisome ® . Its pharmacokinetic profile, characterized by a smaller area under the curve and larger volume of distribution, was markedly different from AmBisome ® , resulting in a cost-effective alternative for the treatment of leishmaniasis which can enhance the AmB passive target by the uptake by the cells of the reticulo-endothelial system. Effects of different variables such as type of formulation, dose, microencapsulation, anesthesia and dog's healthy state on AmB pharmacokinetics were studied.
Lipid formulations of amphotericin B: where are we today?
Journal de Mycologie Médicale / Journal of Medical Mycology, 2005
Amphotericin B deoxycholate (AmBD) was introduced 45 years ago for the treatment of invasive mycoses, on the basis of open-label non comparative data. Throughout these years of use it proved to be a life-saving drug but also a toxic compound which under current approval criteria might not meet licensing requirements. It still remains the gold standard of therapy for the broader spectrum of invasive mycoses, and exhibits the least potential for resistance. It is the drug used as comparator agent in clinical trials to test new antifungal agents. The three lipid based formulations of amphotericin B (LFABs) were created in an effort to overcome the toxicity of AmBD (nephrotoxicity and infusion related toxicity) and represent a significant advance in drug delivery technology. They have different physicochemical and pharmacokinetic properties, which have not yet found their clinical relevance. Clinically they have not proved more efficacious than the parent drug despite the advantage of administration in higher doses, but they have proved to be significantly less nephrotoxic. Few comparative studies of lipid products have been conducted. Liposomal amphotericin B (LAmB) is better tolerated with respect to infusion related events and can be infused in a shorter time. Amphotericin B colloidal dispersion (ABCD) has limited acceptance among clinicians because of the number of infusion related events. More head to head clinical trials are needed to check if one formulation is better than the others. Appropriate dosing is still open for LAmB and the role of LFABs as comparator drugs in clinical trials is emerging. The cost effectiveness of their use needs still remains to be demonstrated. In this paper, their role in combination antifungal therapy is investigated as well as new modes of administration (i.e. aerosolized).