Juniper Publishers-Open Access Journal of Pharmacy & Pharmaceutical Sciences
Nasal Delivery of Proteins and Peptides
Authored by June Shao
Recent years have shown that nasal route can be a
potential route for the systemic delivery of protein/peptide drugs as it
has a considerably large absorption area (150cm2) which is highly
vascularized and has permeability similar to or higher than the small
intestinal mucosa. Nasal delivery of protein/peptide drugs also offers
other benefits such as ease of administration, noninvasive
administration, rapid onset of action, and the avoidance of
gastrointestinal degradation and hepatic first-pass effects [1].
Nasal route can be utilized to enhance the delivery of drugs to the
brain as nose to brain delivery bypasses the blood-brain barrier [2].
However, nasal delivery also suffers from several limitations such as
low membrane permeability to hydrophilic molecules (especially when the
molecular weight is over several thousand daltons), small applicable
volume per dose, enzymatic degradation, and mucociliary clearance [3].
Thus far, several protein/peptide drugs with largest
molecular weight being 3432 Da, have been successfully formulated into
nasal delivery products and approved by the US FDA. These commercially
available drugs include Desmopressin (1183Da), Nafarelin Acetate
(1321Da), Oxytocin (1007Da), and Salmon Calcitonin (3432Da) [4].
Nasal delivery of larger molecular weight protein/peptide drugs still
remain a challenge, mainly due to the low permeability caused by the
drugs being hydrophilic and large in size. Several drug delivery
technologies have been explored for these macromolecules but have gained
limited success.
Main limitation to nasal delivery of large molecular
weight protein/peptide drugs is the low membrane permeability. The rate
of permeation is highly sensitive to molecular size for compounds with
molecular weight (MW) ≥300 Da [5].
A large number of therapeutic agents, peptides and proteins in
particular have shown that for compounds >1k Da, bioavailability can
be directly predicted from the knowledge of MW. In general, the
bioavailability of these large molecules ranges from 0.5% to 5% [6]. Use of permeation enhancers can help in increasing the transport of proteins and peptides across the nasal membrane [7].
Absorption enhancers such as bile salts, surfactants,
fluidic acid derivatives, phosphatidylcholines, cyclodextrins and cell-
penetrating peptide (CPP) have been studied to enhance the intranasal
absorption of protein/peptide drugs [8].
Absorption enhancers are effective in improving the nasal absorption by
either increasing the fluidity of the bilayer of the epithelial cell
membrane and there by opening aqueous pores as a result of calcium ion
chelation or by increasing the intracellular delivery using functional
moieties [7,9].
Mucolytic agent along with nonionic surfactant has been shown to
enhance the nasal absorption of calcitonin in rats and achieved 3.5
times higher bioavailability as compared to the commercial calcitonin
nasal spray Miacalcin [10].
Delivery of insulin from nose to the distal regions of the brain was significantly enhanced by L- or D-penetratin as CPP [9].
However, absorption enhancers tend to cause severe nasal irritation and
damage the nasal membrane at the concentrations required to effectively
promote the nasal absorption [7].
Drug carrier systems such as liposomes, emulsions, nanoemulsions,
nano/micro particles and niosomes with permeation-enhancing function,
have been evaluated to deliver protein and peptide drugs through nasal
cavity. Intranasal delivery of human growth hormone (hGH) - 22kDa
protein, using glutathione (permeation enhancer) added microparticles as
delivery system increased the relative bioavailability approximately by
three folds as compared to the microparticles without glutathione [4].
H102, a novel β-sheet breaker peptide, was encapsulated into liposomes
to reduce its degradation and increase its brain penetration through
intranasal administration for the treatment of Alzheimer's disease [11].
The study showed 2.92 fold larger AUC in hippocampus with liposomes than a solution of H102 peptide. Mitra et al. [12]
reported enhanced absorption of insulin through rat's mucosa using
emulsion system. The AUC was observed 4 times higher when insulin was
loaded in o/w emulsion as compared to pure buffer solution of insulin.
Sintov et al. [13]
demonstrated that intranasal delivery of o/w micro emulsion system with
20% water content (insulin in aqueous phase) achieved an absolute
bioavailability of 7.5% using rabbit as an animal model. Mucociliary
clearance (MCC) is a normal defense mechanism of the nasal cavity that
clears mucus as well as substances adhering to the nasal mucosa
(bacteria, allergens etc.) and drains them into the nasopharynx for
eventual discharge into the gastrointestinal tract. Whenever a substance
is nasally administered, it is cleared from the nasal cavity in about
21 min [14]. Thus, MCC reduces the retention time of the drug at the absorption mucosa, resulting in a low bioavailability [3].
Use of mucoadhesive agents has been explored to
prolong the intimate contact time of the formulation on the nasal mucosa
by adhering to the surface of the mucus layer and thereby enhancing the
bioavailability. Nazar et al. [15]
studied the effect of insulin loaded hydrogels and observed significant
decrease in glucose levels in diabetic rats over the period of 24h.
However, it is generally difficult to achieve a satisfactory nasal
absorption of macromolecular drugs by increasing the retention time
alone because it has to simultaneously overcome the physical barrier of
the epithelium for a drug to permeate into the systemic circulation.
Also intranasal formulations with mucoadhesive agents have not gained
much of a commercial success due to the patient discomfort.
Proteolytic enzymes (amino peptidases and proteases)
present in nasal mucosa can be another barrier for intranasal delivery
of protein/peptide drugs although the enzymatic activity in nasal cavity
is relatively lower than the gastrointestinal tract [16]. Zhou et al. [17]
found that the amino peptidase activity in nasal tissue was about half
of that in the intestinal tissue. Enzyme inhibitors have been
investigated to protect the protein/peptide drugs from the enzyme
activity present in nasal mucosa [18].
Inhibitors with a trypsin-inhibiting activity have been proved to be
useful in enhancing the nasal absorption of salmon calcitonin [19].
However, proteolytic enzyme inhibitors themselves
cannot facilitate the penetration of drugs across the epithelial
membrane and therefore, are generally unable to considerably improve
bioavailability in the absence of absorption enhancers. Furthermore, the
enzyme inhibitors will affect the normal metabolism of the body,
resulting in serious side effects. Therefore, enzyme inhibitors do not
seem to be an effective and safe method of improving the nasal
absorption of proteins and peptides [20].
Another limitation to nasal delivery is the applicable volume of the
formulation which is restricted to 25- 250μL per dose. Several
approaches have been explored to use this volume effectively which
includes the use of solubilizers and gelling agents [21].
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