Biomedical Engineering Reference
In-Depth Information
11.3.5 Surfactants
Surfactants have the ability to lower surface tension of protein solutions and to pre-
vent protein adsorption and/or aggregation at hydrophobic surfaces. Among the vari-
ous surfactants, nonionic surfactants are generally preferred possibly because of the
interaction of ionic surfactants with chemical groups in proteins, leading to protein
denaturation and reduced therapeutic efficiency. Examples of commercial aqueous
solutions of protein-containing surfactants and their concentrations are INF-1B
(polysorbate 20, 0.01%) and muromonab CD3 (polysorbate 80, 0.1%).
Polysorbate 20 when coencapsulated with insulin by the water-oil-water double
emulsion method has shown improved insulin stability within particles and has reduced
the formation of high-molecular-weight aggregates during the prolonged release period
[123]
. The gelling properties of the amphiphilic block copolymer poloxamer 407 were
successfully employed for urease encapsulation while maintaining the therapeutic
efficiency
[124]
. Poloxamer 188 was also successfully used when mixed with PLGA
for prolonged release of active INF-
[125]
. Interleukin-1 (IL-1
) was protected
by phosphatidylcholine from damage during the double emulsion process, but under-
went inactivation during microsphere incubation
[126]
. SDS was found to significantly
reduce insulin aggregation at the methylene chloride-water interface
[127]
.
11.3.6 Polyhydroxylated Alcohols
PEGs, in addition to their role as chemical modifiers, are also known for their pro-
tective capacity against aggregation and thermal denaturation during carrier manufac-
ture. PEG 400 dissolved in the inner aqueous phase provided a protective effect to
NGF, asparaginase, and -chymotrypsin as a result of protein displacement from the
interface during the double emulsion process and during lyophilization
[80,100]
. In
one study, a mixture of PEG 400 and BSA in the inner aqueous phase fully preserved
IGF-I integrity along with optimized sonication conditions but significantly decreased
the entrapment efficiency
[98]
. PEG can be added either in the aqueous or the organic
phase (with the polymer)
[111,128]
. PEG 2000 was found to more effectively stabilize
HBcAg against methylene chloride-induced degradation compared to PEG 6000
[85]
.
A major limitation of polyhydroxylated alcohols and nonionic surfactants is that
PEG and nonionic polyether surfactants like polysorbate 80 are known to produce
peroxides upon aging. These peroxides are responsible for drug degradation in poly-
ether-containing systems. Careful purification of PEG-containing adjuvant prior
to formulation may minimize this potential degradation mechanism, resulting in
improved drugs with more therapeutic activity
[129]
.
11.3.7 Antioxidants and Chelating Agents
Oxidation is one of the major causes of the chemical degradation pathways of proteins
and peptides. There are several functional groups in proteins that undergo oxidation, like
thioether in methionine, sulfhydryl in cysteine, disulfide in cystine, imidazole in histi-
dine, indole in tryptophan, and phenol in tyrosine. These groups and consequently the
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