Targeted Drug Delivery - Nanomaterials for Medical Applications - page 187

is proportional to the temperature of the aqueous phase. This is also affected by
the amount of surfactant present. Thus, the higher the temperature and surfac-
tant concentration, the greater is the saturation solubility of the drug in the water
phase. In the process of cooling down the oil/water nanoemulsion temperature,
the solubility of the drug in the water phase decreases as the temperature of the
water phase decreases which leads to repartitioning of the drug into the lipid
phase. At the lipid recrystallization temperature, a solid lipid core containing
the drug forms.
In the formation of an emulsion with a lipid that is solid at room temperature
(RT), the emulsion needs to be produced at a temperature above the melting
point of the lipid. The lipid must be melted and its mixture with water, cosurfac-
tants, and the surfactant (lecithin, biliary salts, and alcohols such as butanol 68 ).
It is heated with mild stirring until the lipid melt forms a transparent, thermody-
namically stable system where the compounds are mixed in the correct ratio for
the emulsion formation. The emulsion is dispersed in a cold aqueous medium
(2-38 °C) with gentle mechanical mixing so that the small size of the resulting
particles is caused by precipitation and not mechanically induced by the stirring
process. 69,70 As high as 30% lipid solid content may be used for transfer of the
dispersion to a dry product in the form of a tablet or pellet through a granulation
process. To scale-up the process, the percentage composition, NP size, tempera-
tures of the emulsion and the water, and the hydrodynamics of mixing should be
maintained to keep the same product properties. 67
In lipid NPs, the factors that determine the loading capacity of drug are: (1)
solubility of drug in melted lipid, (2) miscibility of drug melt and lipid melt,
(3) chemical and physical structure of solid lipid matrix, and (4) polymorphic
state of lipid material. The prerequisite to obtain a substantial loading capac-
ity in a solid lipid NP is a high solubility of the drug in the lipid melt. To be
highly effective, the solubility of the drug should be higher than the dose needed
because solubility decreases with the cooling down of the lipid melt and might
be lowest in the solid lipid. At the same time, the drug should be miscible in
the lipid. Solubilizers may be added to the lipid melt-drug mixture to enhance
the drug solubility. Polydisperse lipids such those used in cosmetics showed
very good drug incorporation capacities. However, crystalline structure that is
related to the chemical nature of the lipid is a key factor to decide in determin-
ing whether a drug will be expelled or firmly incorporated in the long term.
Therefore, for a controlled optimization of drug incorporation and drug loading,
intensive characterization of the physical state of the lipid particles by NMR,
X-ray, and other new techniques are highly essential.
5.4.1 Encapsulation of the Drug
Encapsulation is the general method used for solid lipid NM drug loading
( Figure 5.1 A). There are two basic drug encapsulation methods, the hot
homogenization technique and the cold homogenization technique. 71 In both