**2.3. PIT method**

sion. Consequently, in order to improve drug loading within nanoparticles and to prevent drug leakage during storage, a new generation of lipid nanoparticles has been prepared [5,6]. NLC (nanostructured lipid carriers) are characterised by a solid lipid core consisting of a mixture of solid and liquid lipids: the resulting matrix of the lipid particles shows a melting point depression compared to the original solid lipid, but the matrix is still solid at body temperature. Depending on the method of production and on the lipid blend composition, different types of NLC are obtained: imperfect, amorphous and multiple type. In the imperfect type, lipid crystallisation is altered by small amounts of oils. In the amorphous type, the lipid matrix is solid but not crystalline (amorphous state): this can be achieved by mixing special lipids, e.g. hydroxyoctacosanyl hydroxystearate with isopropyl myristate. In the multiple type the solid lipid matrix contains tiny oil compartments: they are obtained by mixing a solid lipid with a higher amount of oil. The basic idea is that by giving a certain nanostructure to the lipid matrix, the payload for active compounds is increased and expulsion of the compound during

SLN prepared through hot homogenisation are not suitable for the encapsulation of hydro‐ philic drugs, since they would partition preferentially to the external aqueous phase of the hot nanoemulsion: to overcome this limitation lipid drug conjugate (LDC) nanoparticles were developed. In a typical process, an insoluble drug-lipid conjugate bulk is first prepared either by salt formation (e.g. with a fatty acid) or by covalent linking (e.g. esters or ethers). The

However, besides all its advantages and its versatility, HPH involves some critical process parameters like high temperatures, high pressures (cavitation forces), that may cause signifi‐ cant thermodynamic and mechanical stress for the resulting product: in particular this method is not suitable for thermo-sensitive drugs. Moreover, melted lipids are not good solvents for many drugs and this can cause a low drug loading in the SLN. For these reasons suitable alternative and easy handling production methods for lipid nanoparticles preparation have

High shear homogenisation and ultrasound homogenisation [10,11] are dispersing techniques which were initially used for the production of solid lipid nanodispersions. Both methods are widespread and easy to handle. However, dispersion quality is often compromised by the presence of microparticles. Furthermore metal contamination has to be considered if ultra‐ sounds are used [2]. In the case of high shear homogenisation, SLN can be obtained owing to the use of proper emulsifying agent, which allow the formation of the hot nanoemulsion under

In the melt dispersion technique, SLM can be obtained either from O/W or multiple W/O/W emulsions, according respectively to the lipophilic or hydrophilic character of the drug.

obtained LDC is then processed as the lipid for nanoparticles preparation [7,8].

storage is avoided [5,6].

54 Application of Nanotechnology in Drug Delivery

been widely investigated in last years [9].

simple high shear mixing [10].

**2.2. Melt dispersion technique**

*2.1.2. High shear homogenisation and ultrasound homogenisation*

The PIT (phase inversion temperature) method is commonly used for the preparation of nanoemulsions. The PIT concept uses the specific ability of some polyethoxylated surfactants to modify their affinities for water and oil as a function of the temperature. In the PIT nanoe‐ mulsion preparation method, the use of such surfactant type leads to an emulsion inversion from O/W macroemulsion to a W/O emulsion when temperature is increased above the PIT, and to the formation of a O/W nanoemulsion when the temperature is next lowered below the PIT [14].

The PIT method has been used also for the preparation of LNC (lipid nanocapsules), nano‐ particles organised in an internal liquid or semiliquid oil core and an external lipid layer solid at room temperature [15].

Recently it has been adapted for the preparation of SLN. In this case two main components are used: an oil phase, constituted by solid lipids and non-ionic surfactants and an aqueous phase containing NaCl. The aqueous phase and the oil phase are separately heated at ~90° C (above the PIT); then the aqueous phase is added dropwise, at constant temperature and under agitation, to the oil phase, in order to obtain a W/O emulsion. The mixture is then cooled to room temperature under slow and continuous stirring. At the PIT, the turbid mixture becomes clear, then below the PIT an O/W nanoemulsion is formed, which turns in SLN below the lipid melting point [16].
