Mose Santaniello

Novel camptothecin analogue (gimatecan)-containing liposomes prepared by the ethanol injection method.

Small‐sized liposomes have several advantages as drug delivery systems, and the ethanol injection method is a suitable technique to obtain the spontaneous formation of liposomes having a small average radius. In this paper, we show that liposomal drug formulations can be prepared in situ, by simply injecting a drug‐containing lipid(s) organic solution into an aqueous solution. Several parameters should be optimized in order to obtain a final suitable formulation, and this paper is devoted to such an investigation. Firstly, we study the liposome size distributions determined by dynamic light scattering (DLS), as function of the lipid concentration and composition, as well as the organic and aqueous phases content. This was carried out, firstly, by focusing on POPC (1‐palmitoyl‐2‐oleoyl‐sn‐glycero‐3‐phosphocholine) then on the novel L‐carnitine derivative PUCE (palmitoyl‐(R)‐carnitine undecyl ester chloride), showing that it is possible to obtain monomodal size distributions of rather small vesicles. In particular, depending on the conditions, it was possible to achieve a population of liposomes with a mean size of 100 nm, when a 50 mM POPC ethanol solution was injected in pure water; in the case of 50 mM PUCE the mean size was around 30 nm, when injected in saline (0.9% NaCl). The novel anticancer drug Gimatecan, a camptothecin derivative, was used as an example of lipophilic drug loading by the injection method. Conditions could be found, under which the resultant liposome size distributions were not affected by the presence of Gimatecan, in the case of POPC as well as in the case of PUCE. To increase the overall camptothecin concentration in the final liposomal dispersion, the novel technique of “multiple injection method” was used, and up to a final 5 times larger amount of liposomal drug could be reached by maintaining approximately the same size distribution. Once prepared, the physical and chemical stability of the liposome formulations was satisfactory within 24, as judged by DLS analysis and HPLC quantitation of lipids and drug. The Gimatecan‐containing liposomes formulations were also tested for in vitro and in vivo activity, against the human nonsmall cell lung carcinoma NCI‐H460 and a murine Lewis lung carcinoma 3 LL cell lines. In the in vitro tests, we did not observe any improvement or reduction of the Gimatecan pharmacological effect by the liposomal delivery system. More interestingly, in the in vivo Lewis lung carcinoma model, the intravenously administration of liposomal Gimatecan formulation showed a mild but significant increase of Tumor Volume Inhibition with respect to the oral no‐liposomal formulation (92% vs. 86 %, respectively; p < 0.05). Finally, our study showed that the liposomal formulation was able to realize a delivery system of a water‐insoluble drug, providing a Gimatecan formulation for intravenous administration with a preserved antitumoral activity.

Statins Solubilized in Fish Oil: Versatile and Simple Combinations by Innovative Formulations

Dyslipidemia or hyperlipidemia comprised mainly hypertriglyceridemia and/or hypercholesterolemia; it is now well established as their control is considered to have an impact on public health. Therefore, in an overcrowded field to find appropriate answers to lower blood levels of cholesterol and triglycerides, here we report findings of formulation studies, aimed to combine statins and n-3 PUFA, overcoming drawbacks related to solubility and stability. A new formulation has been made creating a solvent system that allows for a complete solubilization of statin drugs such as atorvastatin, rosuvastatin, and pitavastatin. With simvastatin, a preliminary dehydration with molecular sieves was also needed for stability purpose. These findings are of great importance and could be applied widely in all cases where a co-administration of the two active therapeutic ingredients are routinely required.

QSAR of a Series of Carnitine Acetyl Transferase (CAT) Substrates

Carnitine acyl transferases are a family of enzymes that differ with respect to subcellular localization and substrate specificity. Carnitine acetyl transferase (CAT) is mainly found in the mitochondrial matrix where it is postulated to play a key role in stabilizing the CoA-SH/CoA-SAc ratio.1 CAT catalyses the reversible reaction:

l-Carnitine Esters as “Soft”, Broad-Spectrum Antimicrobial Amphiphiles

Acetyl - L - carnitine + Coa - SH \leftrightarrow L - carnitine + acetyl - Coa

Solid compositions suitable for oral administration comprising l-carnitine or alkanoyl-l-carnitine magnesium fumarate

that has an equilibrium constant equal to 0.6. The kinetic enzymatic mechanism for CAT follows a random-order equilibrium reaction where Michaelis constant (K m ) approximates true dissociation constant (K s ) and binding of one substrate has little or no effect on binding of the second.2 The aim of this work is to study a set of acyl-CoA derivatives that includes linear, branched and cycloalkyl, and unsaturated substituents 2,3,4 A QSAR approach is used to investigate the influence of such substituents on kinetic parameters, K m and V’max.