Parenteral Delivery of Peptides and Proteins - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 549

alternative to the conventional formulations of proteins and peptides, in which the pro-
tein and peptide are usually either lyophilized in suspension or in an aqueous solu-
tion form [165] . However, the particulate systems suffer from the disadvantage of low
protein loading levels, a relatively faster release than the desired rate, and difficulties
in crossing the biological barriers to achieve the desired biodistribution of the nanocar-
riers encapsulating the protein [164] . However, many developments have been made
to overcome these challenges by designing targeted delivery systems in a form of a
nanocarrier, either based on polymeric, solid lipid nanoparticles (SLNs), or liposomal
technology, with defined size and surface properties for favorably altering the partic-
ulate biodistribution [164,165] . The development of delivery systems for therapeutic
proteins and their evaluation depend on biophysical, biochemical, and physiological
characteristics of protein molecules, including their molecular size, biological half-life,
immunogenicity, conformational stability, dose requirement, site and rate of adminis-
tration, and pharmacokinetic and pharmacodynamic behavior [165,166] .
A list of all P/P drugs which have been investigated for injectable particulate
delivery systems have been summarized in Table 11.2 .
11.5.1 Microspheres
The history of microspheres marketed for P/P drugs is nearly a quarter century old
when Ipsen Biotech of France released the microsphere formulation of LHRH ago-
nist [D-Trp6]-LHRH for treatment of prostate cancer [184] . At present many micro-
sphere-peptide formulations are available in the market and some of them have been
summarized in Table 11.3 [185] . The microsphere-peptide formulations are generally
marketed in vials as a sterile, preservative-free powder to be suspended in a ster-
ile diluent containing a suspending agent when needed for subcutaneous/intravenous
injection, and should be used immediately.
In addition to the above P/P drugs that have been marketed into microspheres for-
mulations, many other proteins have also been investigated for formulation into
microspheres such as TRH [185,186] , recombinant human EGF, recombinant human
granulocyte colony-stimulating factor [187,188] , recombinant human interferon-
[189] as well as neuropeptides [190] . These P/P drugs are formulated into microspheres
for slow drug release after implanting them in the body in the desired organ [188,190] .
Most commonly used techniques for microsphere preparation of proteins are spray
drying, double emulsion, phase separation-coacervation, emulsion-desolvation method,
emulsion-thermal denaturation, spray freeze drying (Nutropin Depot [191,192] ), and
use of crosslinking agents (glutaraldehyde for albumin or epichlorohydrin for starch
[144,183,191] ). To avoid agitation during preparation of microspheres, a reverse
micelle solvent evaporation technique was proposed to encapsulate model proteins like
SOD, -galactosidase, and recombinant human TNF in L-PLA microspheres in their
active form to prepare the water-oil emulsions [193,194] . Protein solution can also be
remotely loaded into presterilized porous microspheres to protect proteins from a harsh
manufacturing environment [191,194] .
The method of P/P encapsulation in polymeric microspheres should show opti-
mal protein loading, high yield of microspheres, stability of the encapsulated protein,