The major challenge in peptide delivery stems from their low physicochemical and proteolytic stability as well as poor permeation
across biological barriers in the absence of a specific transport system, which is due to their hydrophilicity, charge, and
high molecular weight (> 500 Da). Peptides routinely violate the majority or all of Lipinski's predictors for good absorption
and bioavailability (4).
Following parenteral administration, the peptide drug is subjected to extensive degradation in the bloodstream, often resulting
in a short plasma half-life. In addition, the peptide drug is also subjected to metabolism by liver enzymes and clearance
by the kidneys (5). Linear peptides possess high conformation flexibility that can result in peptide denaturation and poor
targeting to the tissue of interest, which can further result in poor shelf stability.
Traditional drug development of peptides and proteins has relied on parenteral injection of liquid formulations as the fastest
and often least expensive route to commercialization. The key drivers for selecting a peptide delivery method for commercial
development include patient convenience and compliance, requirement for local or topical delivery, systemic toxicity or other
safety issues, as well as market competition. The latter driving force, combined with research efforts, has led to the development
of controlled-release technologies for peptide delivery by parenteral routes (e.g., intramuscular or subcutaneous) and prompted
the development of technologies for noninvasive peptide delivery. The oral, nasal, and pulmonary approaches are the focus
of the pharmaceutical industry while transdermal and ocular technologies are researched because these routes are preferred
for achieving local levels able to elicit therapeutic benefit.
Factors that determine the selection and development of an appropriate delivery system and route of administration are the
therapeutic dose and release profile required, the duration of treatment, the disease conditions, and target patient population
(intravenous injections or infusions for hospitalized patients, and higher patient compliance systems for out-patients). Additional
factors include the impact of processing conditions on stability and bioactivity of peptides and proteins to avoid increase
in immunogenicity or loss of efficacy, and finally, the bioavailability by means of the particular route and delivery system
Implants, capable of releasing peptides in a controlled manner for a desired length of time, are clinically important systems
for prolonged release of proteolytic labile peptides. However, zero-order release kinetics usually achieved with these systems
(i.e., ability to deliver a drug at a rate that is independent of time with the concentration of drug within a pharmaceutical
dosage form) are not always the best delivery regimes compared with pulsatile systems because down-regulation of receptors
As an alternative to repeated injections or infusion pumps, depot-delivery systems provide continuous peptide delivery after
a single administration, usually with a frequency of once-monthly or three-monthly for chronic conditions. Depot-delivery
systems can be divided into four major groups: implants, microspheres, nano-particles, and injectable solutions such as in situ forming gels. As implants necessitate the use of large gauge needles (i.e., 16 gauge) or surgical procedures for administration,
they are less patient-preferred (6).
Microspheres followed by in situ forming gels systems have resulted in the majority of approved peptide therapeutics and are prepared from degradable polymers
such as polyanhydrides, polyesters usually from poly(lactic-co-glycolic acid), lipids such as Depofoam (Pacira) (7) and Fluid-Crystal
(Camurus) (8), or even by the self-assembly of the actual endogenous peptide (e.g., lanreotide acetate [Somatuline Autogel,
Ipsen]) (9) and their derivatives (usually with polyethylene glycol, poly(orthoesters), sucrose acetate isobutyrate), collagen,
hyaluronic acid, and chitosan (10, 11). Nanoparticulate parenteral delivery, although still in preclinical stage, is showing
promise particularly for delivery of peptides across notoriously impermeable barriers, such as the BBB (12, 13), where neuropeptides
can prove significant therapies for neurological disorders (e.g., pain, depression, and neurodegenerative disorders).
Advents in injection devices enable self-administration by patients using a small-diameter needle and syringe, such as in
the case of insulin. Prefilled syringes, auto-injectors, syringe injectors, pen devices, and needleless injectors contain
cartridges loaded with the peptide. With the exception of needleless injectors, no further pharmacokinetic studies are required
because these systems result in similar pharmacology and toxicology with equivalent bioavailability (14).