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In this work, poly(N-isopropylacrylamide) (PNIPAM) based chemically cross-linked hydrogels are used as novel precipitation and stabilization media for solid lipid nanoparticles (SLNs) for the first time. The hydrogels and the hybrid thermoresponsive composite hydrogels with SLNs were characterized by SEM, DSC, DLS and rheometric analysis. The results showed that the SLNs obtained directly in the gel matrix by the newly devised method were well-dispersed and remained stable for one month. A remarkable advantage of this approach is that it yields the thermoresponsive nanocomposite hydrogels in a single step. This approach is a significant advancement in the preparation of hybrid thermoresponsive nanocomposite systems based on smart gels and SLNs for their use in biomedical applications.

Some approaches to enhance the entrapment efficiency within nanoparticulate systems, chiefly of hydrophilic molecules, developed mainly by the Turin University Pharmaceutical Technology group, are discussed. Several approaches have been developed: the first entails associating anticancer hydrophilic molecules to liposomes, developing lipophilic prodrugs of these molecules, and encapsulating them in liposomes. The transformation of hydrophilic drugs into lipophilic prodrugs can also overcome problems of poor entrapment efficiency and rapid release from polymer nanocarriers. Examples are nanospheres and nanocapsules produced from various PEGylated poly(alkylcyanoacrylate) copolymers. Strategies have also been developed to enhance hydrophilic drug entrapment in solid lipid nanoparticles (SLN). Hydrophobic ion pairing was designed to enable various antitumor drugs to be entrapped in SLN, produced by the coacervation method. Another technique comprises the covalent linkage of antitumoral or antiviral drugs to a squalenoyl-derived chain, affording bioconjugates that self-assemble as stable nanoparticles. A further development comprises mesoporous silica nanoparticles with immobilized hydrophilic antioxidants, for topical applications: they were complexed with hydrophilic antioxidants (Trolox ® or rutin). Polymer-shelled and perfluoropentane-cored nanobubbles have also been designed, as versatile multifunctional carriers for the delivery of gases, drugs, and genes; the size range is below 500 nm, with shell thickness in the 30–50 nm range.

Central nervous system disorders are already prevalent and steadily increasing among populations worldwide. However, most of the pharmaceuticals present on world markets are ineffective in treating cerebral diseases, because they cannot effectively cross the blood brain barrier (BBB). Solid lipid nanoparticles (SLN) are nanospheres made from biocompatible solid lipids, with unique advantages among drug carriers: they can be used as vehicles to cross the BBB. This review examines the main aspects surrounding brain delivery with SLN, and illustrates the principal mechanisms used to enhance brain uptake of the delivered drug.

Cyclosporine-loaded solid lipid nanoparticles were prepared according to the coacervation method: various stabilizers were used in order to obtain nanoparticles with different surface charge. These formulations were tested on rabbit corneas. Corneal irritation was measured according to opacity and permeability test; the interaction of labeled solid lipid nanoparticles with the cornea was studied by fluorescence microscopy; drug accumulation and permeation through the cornea were studied after labeling cyclosporine with a fluorescent probe. Nanoparticles were not irritant to the cornea, according to the opacity and permeability test. Cationic (chitosan coated) solid lipid nanoparticles enhanced drug accumulation and permeation through rabbit cornea, compared to anionic and non-ionic solid lipid nanoparticles and other reference formulations, probably due to the interaction of chitosan coated nanoparticles with corneal epithelial cells.

Stearic acid solid lipid nanoparticles (SLN) were prepared according to the coacervation technique, consisting in fatty acid precipitation of alkaline salt from a solution. SLN can encapsulate Amphotericin B with high efficiency in its monomeric form. SLN markedly increase in vitro drug toxicity towards Saccharomyces cerevisiae (taken as model yeast), expressed as potassium leakage. Yeast susceptibility towards Amphotericin B is increased when the drug is loaded in nanoparticles compared to the free drug, even if inhibition is limited by drug encapsulation within lipid matrix.

Coacervation technique, a solvent-free, feasible and versatile method, based on a phase transformation from soap micellar solution into fatty acid solid particles by acid addition, was used to prepare cisplatin loaded solid lipid nanoparticles (SLN) of stearic acid. Different polymers were tested to stabilise SLN suspensions. Solubilisation of cisplatin, a hydrophilic antitumor agent, within sodium stearate micelles was possible by the formation of a hydrophobic ion-pair with sodium dioctylsulfosuccinate. Several SLN were produced, whose particle size were in the 275–525 nm range. Cisplatin encapsulation efficiency up to 90 % was obtained, depending on both stearic acid concentration and stabilisers type and concentration. The in vitro cisplatin release showed a burst effect of about 10–20 %, corresponding to the non-encapsulated drug, and then a complete drug release was reached after 24 h.

Elastic positively-charged liposomes of soya lecithin were prepared using sucrose monopalmitate as deforming agent, and l-alanine benzyl ester or stearylamine as cationic charge-inducing agent. The positive charge of the liposomes was confirmed by zeta potential measurements and their elasticity by filtration through microporous filter. Positively-charged liposomes had a higher acyclovir entrapment efficiency than negatively-charged liposomes. Elastic positively-charged liposomes containing acyclovir, applied non-occlusively to pig-ear skin, determined a skin flux similar to that of non-elastic positively-charged liposomes, prepared using soya lecithin, cholesterol and stearylamine, but higher than that of non-elastic negatively-charged liposomes or control suspension. Skin deposition of acyclovir from elastic positively-charged liposomes was higher (up to 600 nmol/cm 2 ) than that from non-elastic positively- or negatively-charged liposomes (respectively 344 nmol/cm 2 , 237 nmol/cm 2 ) and than that from elastic negatively-charged liposomes (435 nmol/cm 2 ). The enhanced ACV accumulation within the skin obtained with elastic positively-charged liposomes might help to optimize drug targeting, creating new opportunities for well-controlled, modern, topical application of ACV in the treatment of Herpes simplex.

Several liposome dispersions, gel-emulsions and o/w microemulsions were developed using soy lecithin and non-ionic, non-ethoxylated, glucose-and sucrose-derived, well-tolerated and skin compatible emulsifiers. The systems prepared were characterised by determining their mean sizes, which in the case of liposomes markedly decreased in the presence of sucrose esters (from 450 to 350 nm) and, in the case of microemulsion were about 30 nm. α-tocopherol (vitamin E) was then added to the formulations and its stability against photodegradation under UVB light was studied. The best protective effect was noted when α-tocopherol was dissolved in the inner phase of o/w microemulsion in the presence of ascorbic acid in the outer phase, as no decrease in vitamin E content occurred after 9 h of irradiation. Liposome dispersions, particularly when formulated with sucrose monoesters as auxiliary surfactants, and gel emulsions also significantly increased α-tocopherol photostability compared to ethanol or surfactant solutions. Skin deposition of α-tocopherol within intact pig ear skin from liposomes, gel emulsions and microemulsions were assessed and compared with values for ethanol solutions. Only gel emulsions and microemulsions gave rise to significant skin depositions of α-tocopherol.

o/w emulsions with zinc oxide and salicylic acid were prepared at a pH between 4.0 and 5.2 in order to determine the best pH at which both molecules are simultaneously present in the system. The emulsion's structure and the presence of zinc oxide crystals were investigated by optical microscopy. Zinc oxide caused a slight increase in pH of the emulsions over time. The emulsion that had the most stable pH was that at pH 4.6. Salicylic acid diffusion from these systems, studied as a function of pH and the amount of zinc oxide crystals, was maximal at pH 4.6 and was found to be unrelated to the apparent partition coefficient or to the un-dissociated molar fraction of salicylic acid. Zinc oxide decreased the diffusion of salicylic acid from all emulsions.

The aim of this study was to evaluate the possibility of using liposomes for skin delivery of dipotassium glycyrrhizinate (KG), an anti-inflammatory agent employed in treating acute and chronic dermatitis, and of formulating such liposomes in an oil-in-water emulsion (O/W). KG had emulsifying properties and the possibility of producing elastic liposomes was verified. Liposomes containing soya lecithin (PC) or hydrogenated soya lecithin (HPC) mixed with KG in w/w ratios of 2:1, 4:1 or 8:1 were prepared by the solvent evaporation method and then passed through a high pressure homogeniser. Liposome size and entrapment efficiency were determined and the interaction between KG and HPC was investigated using differential scanning calorimetry (DSC). Transepidermal permeation through intact pig skin and skin deposition of KG from liposomes and O/W emulsion containing liposomes were assessed and compared with values for aqueous control solutions. No marked differences were observed between PC and HPC liposomes. Liposome sizes ranged from 90 to 120 nm. Entrapment efficiency depended on the lipid:KG ratio; the maximum efficiency was obtained at 4:1 w/w. KG interacted with liposomes disrupting and fluidising the lipid bilayer, forming elastic liposomes able to penetrate through membrane pores of diameter much smaller than their own diameter. The liposome structure was maintained when dispersed in an O/W emulsion. The skin fluxes were less than the HPLC detection limit for all systems, while skin deposition increased 4.5-fold compared with aqueous solutions when KG was formulated in liposomes.

Vitamin A and vitamin A palmitate photostability were tested in different media. Ethanol and octyl octanoate solutions of these two vitamins, as such and with the addition of sunscreens (3,4 methylbenzilidencanfora, butyl methoxy dibenzoylmethane and octyl methoxycinnamate) or beta-carotene and butylated hydroxy toluene, were analysed spectrophotometrically after UVB or UVA irradiation. An O/W fluid emulsion with 0.5% w/w of retinyl palmitate, with and without butylated hydroxy toluene, was prepared. The oil containing the vitamin was extracted with HCl and aluminium sulfate and analysed spectrophotometrically after UVB or UVA irradiation. The fluid emulsion containing retinyl palmitate with and without butylated hydroxy toluene was stored at different temperatures and analysed every week spectrophotometrically for a month. Of the sunscreens tested butyl methoxy dibenzoylmethane showed the strongest protective action towards vitamin A and vitamin A palmitate, whereas beta-carotene did not protect either vitamin. Butylated hydroxy toluene inhibited the photodegradation of both vitamins dissolved in octyl octanoate, suggesting that oxygen may be involved in their degradation. O/W emulsion promoted slightly the degradation of vitamin A ester. Butylated hydroxy toluene protected retinyl palmitate from degradation induced by light and heat.

Two oil-in-water microemulsions with the same oil/water/co-surfactant (isopropylmyristate, water, 1-butanol), but differing in the surfactant (Aerosol OT or egg lecithin) were studied. The additions of butanolic solutions of two drugs at different lipophilicity (menadione and prednisone) to the same mixture of water/oil/surfactant were examined. The ΔH values were substantially similar to those obtained in the absence of any drug, except in the case of menadione which gave less endothermic values in the microemulsion containing lecithin as a surfactant.

The topical administration of timolol as an ion-pair with octanoate was achieved by use of an oil-in-water microemulsion containing lecithin as a surfactant. The microemulsion, a solution of the ion-pair and a solution of timolol alone were instilled in the conjunctival sac of rabbits. A rapid method for the separation and determination of timolol in aqueous humour by HPTLC was used. The bioavailability of timolol from the microemulsion and the ion-pair solution was higher than that obtained from timolol alone. The areas under the curve for timolol in aqueous humour after administration of the microemulsion and the ion-pair solution were 3.5 and 4.2 times higher, respectively, than that observed after the administration of timolol alone.