Parenteral Delivery of Peptides and Proteins - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 570

Table 11.11 Pulsatile Delivery of P/P

Proteins/Peptides Characteristics of the Pulsatile Release Reference

Insulin Pulsatile release of human insulin in 0.8 mU/kg/min,

7.5 min on/7.5 min off over 4 min in normal volunteers
has been found to be as effective as continuous
administration of 0.4 mU/kg/min in the suppression of
endogenous glucose production and the enhancement
of the metabolic clearance rate of glucose

[363]

Glucagon Weigle et al. demonstrated that over a 90-min period

hepatocyte glucose production in response to a fixed
total dose of glucagon was enhanced if that glucagon
was delivered in a series of six 3-min pulses with 15-
min interval pulses

[364]

GnRH Intravenous pulsatile GnRH confers an advantage over

the gonadotropins because of its ability to mimic
normal menstrual cycle dynamics, and thus results in a
single follicle ovulation

[365]

Pulsatile delivery systems rely on changes within the delivery system to determine
a lag time before release (open loop or external regulated) or are triggered to release
bursts of a bioactive by environmental changes in the area in which the delivery sys-
tem is placed (triggered systems/internal regulated or closed loop/self-regulated).
Single-shot delivery of vaccines is also an extracted application of the pulsatile deliv-
ery system. An accurate and precise mechanism to switch delivery on and off in an
oscillatory pattern is the crucial requirement to develop an effective pulsatile delivery
system [362] .
Different dosage forms, such as microparticles, coarse particulates, large solid
implants, hydrogels, osmotic pump, and liposomes, are being exploited for pulsatile/
time-controlled delivery system. The findings in Table 11.11 indicate the importance
of pulsatile delivery in protein and peptide delivery.

11.5.9.1 Ext��na﻽﻽y R��﻽﻽at�d/O��n Loo� Syst�ms
An open loop or externally regulated pulsatile system uses external triggers, such
as ultrasound, thermal, electric, light, chemical, or biochemical, to achieve pulsatile
delivery of drugs [360,366] . Electric current and ultrasound have been used to modu-
late transdermal drug delivery; these techniques are called iontophoresis and phono-
phoresis, respectively. BSA, insulin, and many other P/P drugs are tested for their
structural integrity after ultrasonic triggering from nonerodible polymeric systems
and were found to be intact. Magnetically modulated delivery systems incorporate
small magnetic beads within a polymer matrix that also contains the drug [367,368] .
The use of hydrogels sensitive to pH, temperature, or electric field to achieve pul-
satile drug delivery has been reviewed [360] . Polymers such as poly( N -isopropyl