Nebulised antibiotherapy: conventional versus nanotechnology-based approaches, is targeting at a nano scale a difficult subject?

Nebulised antibiotics offer great advantages over intravenously administered antibiotics and other conventional antibiotic formulations. However, their use is not widely standardized in the current clinical practice. This is the consequence of large variability in the performance of nebulisers, patient compliance and a deficiency of robust preclinical and clinical data. Nebulised antibiotherapy may play a significant role in future pulmonary drug delivery treatments as it offers the potential to achieve both a high local drug concentration and a lower systemic toxicity. In this review, the physicochemical parameters required for optimal deposition to the lung in addition to the main characteristics of currently available formulations and nebuliser types are discussed. Particular attention will be focused on emerging nanotechnology based approaches which are revolutionizing inhaled therapies used to treat both infections and lung cancer. Promising carriers such as Trojan-Horse microparticles, liposomes, polymeric and lipid nanoparticulate systems have been investigated and proposed as viable options. In order to achieve site-specific targeting and to optimize the PK/PD balance critical nanoscale design parameters such as particle size, morphology, composition, rigidity and surface chemistry architecture must be controlled. Development of novel excipients to manufacture these nanomedicines and assessment of their toxicity is also a keystone and will be discussed in this review.

Unmet clinical needs in the treatment of systemic fungal infections: The role of amphotericin B and drug targeting.

Recently an increase in both the prevalence and incidence of invasive fungal infections have been reported. The number of fungal species that can cause systemic mycoses are higher and current antifungal therapies are still far from ideal. The emergence of antifungal resistances has a major clinical impact when using azoles and echinocandins leading to possible treatment failure and ultimately putting the patient's life at risk. Amphotericin B can play a key role in treating severe invasive mycoses as the incidence of antifungal resistance is very low combined with a high efficacy against a wide range of fungi. However, the use of this drug is limited due to its high toxicity and the infusion-related side effects often necessitating patient hospitalisation. New medicines based on lipid-based systems have been commercialised in the last decade, these treatments are able to reduce the toxicity of the drug but intravenous administration is still required. An oral or topically self-administered amphotericin B formulation can overcome these challenges, however such a product is not yet available. Several drug delivery systems such as cochleates, nanoparticulate and self-emulsifying systems are under development in order to enhance the solubility of the drug in aqueous media and promote oral absorption and cutaneous permeation across the skin. In this review, the type of drug delivery system and the effect of particle size on efficacy, toxicity and biodistribution will be discussed.

Engineering Oral and Parenteral Amorphous Amphotericin B Formulations against Experimental Trypanosoma cruzi Infections.

Chagas disease (CD) is a parasitic zoonosis endemic in most mainland countries of Central and South America affecting nearly 10 million people, with 100 million people at high risk of contracting the disease. Treatment is only effective if received at the early stages of the disease. Only two drugs (benznidazole and nifurtimox) have so far been marketed, and both share various limitations such as variable efficacy, many side effects, and long duration of treatment, thus reducing compliance. The in vitro and in vivo efficacy of poly-aggregated amphotericin B (AmB), encapsulated poly-aggregated AmB in albumin microspheres (AmB-AME), and dimeric AmB-sodium deoxycholate micelles (AmB-NaDC) was evaluated. Dimeric AmB-NaDC exhibited a promising selectivity index (SI = 3164) against amastigotes, which was much higher than those obtained for licensed drugs (benznidazole and nifurtimox). AmB-AME, but not AmB-NaDC, significantly reduced the parasitemia levels (3.6-fold) in comparison to the control group after parenteral administration at day 7 postinfection. However, the oral administration of AmB-NaDC (10-15 mg/kg/day for 10 days) resulted in a 75% reduction of parasitemia levels and prolonged the survival rate in 100% of the tested animals. Thus, the results presented here illustrate for the first time the oral efficacy of AmB in the treatment of trypanosomiasis. AmB-NaDC is an easily scalable, affordable formulation prepared from GRAS excipients, enabling treatment access worldwide, and therefore it can be regarded as a promising therapy for trypanosomiasis.

Analgesic and anti-inflammatory controlled-released injectable microemulsion: Pseudo-ternary phase diagrams, in vitro, ex vivo and in vivo evaluation.

PURPOSE: Development of analgesic and anti-inflammatory controlled-released injectable microemulsions utilising lysine clonixinate (LC) as model drug and generally regarded as safe (GRAS) excipients. METHODS: Different microemulsions were optimised through pseudo-ternary phase diagrams and characterised measuring droplet size, viscosity, ex vivo haemolytic activity and in vitro drug release. The anti-inflammatory and analgesic activity was tested in mice (Hot plate test) and rats (Carrageenan-induced paw edema test) respectively and their activity was compared to an aqueous solution of LC salt. RESULTS: The aqueous solution showed a faster and shorter response whereas the optimised microemulsion increased significantly (p<0.01) the potency and duration of the analgesic and anti-inflammatory activity after deep intramuscular injection. The droplet size and the viscosity were key factors to control the drug release from the systems and enhance the effect of the formulations. CONCLUSIONS: The microemulsion consisting of Labrafil®/Lauroglycol®/Polysorbate 80/water with LC (56.25/18.75/15/10, w/w) could be a promising formulation after buccal surgery due to its ability to control the drug release and significantly achieve greater analgesic and anti-inflammatory effect over 24h.