Parenteral Delivery of Peptides and Proteins - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 561

bromide (CTAB, stabilizer), DOTAP, and DDAB (cationic surfactants), monostearin
(SLN with or without PEG 2000), sterylamine, emulsifying wax, and thiamine. These
agents are well studied in research and show little or no systemic toxicity. They are
widely used for P/P drug delivery.
The second generation of lipid nanoparticles has been introduced with the term
nanostructured lipid conjugates (NLC). These particles are prepared from a blend of
a solid lipid with a liquid lipid (oils) in such a proportion that the mixture has to be
solid at a minimum temperature of 40°C [282,283] . Another modification of SLN has
been introduced as lipid drug conjugates (LDC), which were developed especially for
the hydrophilic drug molecules [281,284] . These advanced lipid carriers have shown
advantages over the conventional SLNs in being more flexibile for modulation of drug
release, increasing the protein and peptide loading, and preventing its leakage and
degradation during release.
The main factors influencing P/P release from solid lipid particles are the physico-
chemical characteristics of the P/P drug itself: particle size, lipid matrix composition,
surfactants used, drug distribution throughout the matrix, method of preparation, and
production parameters [285-287] .
Further improvement of tissue selectivity can be achieved by engineering the surface
of lipid carriers with hydrophilic polymers or coupling targeting ligands; for example,
by modifying surface characteristics. Lipid nanoparticles coated with PEG or chitosan
have been developed and reported [288] . Some of the P/P associated with SLN, their
production procedure, and the association efficiency are tabulated in Table 11.8 .
Although future application of SLN in P/P drug delivery is inevitable, researchers
should also check the product for cytotoxicity of lipid carrier in in vivo evaluation.
However, many research articles report that cytotoxicity of the SLN can be mainly
attributed to components of the aqueous phase, especially to nonionic emulsifiers and
preservatives rather than lipid. Lipid carriers prepared with several different lipids
and emulsifying agents did not exhibit any cytotoxic effects in vitro up to concentra-
tions of 2.5% lipid [299] . In fact, it has been shown that even concentrations higher
than 10% of lipid phase led to a viability of 80% with cultured human granulocytes
in culture [299] .
More formulation aspects must be considered while formulating lipid carriers,
such as the presence of alternative colloidal structures (micelles, liposomes, mixed
micelles, drug nanocrystals) in the aqueous dispersion; the complexity of the physi-
cal state of the lipid (transformation between different modifications, possibility of
supercooled melts), which causes stability problems during storage or administration
(e.g., gelation, particle size increase, drug expulsion); and sample dilution or water
removal, which might significantly change the equilibrium between the different col-
loidal species and the physical state of the lipid [300] .
11.5.6 Hydrogels
Hydrogels ( Fig. 11.10 ), as the name suggests, are gelled networks of hydrophilic poly-
mers. They may exist as a covalently crosslinked chemical gel network or as physi-
cal gel without covalent crosslinking. Physical gels form by linking polymer chains