Protein and Peptide Delivery through Respiratory Pathway - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 461

acetate by intratracheal instillation. Group 1 was administered a sterile formulation
consisting of 1 mg/ml leuprolide acetate IV, at a dosage of 10 g/kg. Groups 2 - 5 were

administered with a similar dose each of the formulation, but at fixed distances distal
to the epiglottis. Results of this study revealed that the extent of absorption of leupro-
lide was dependent on the distance beyond the epiglottis at which the drug was depos-
ited. Lung bioavailability ranged from about 5% to 95%, with essentially quantitative
absorption when the drug was instilled as a fine spray at the bifurcation.
Inhalation aerosol formulations of LH-RH analogs, exemplified by leuprolide
acetate, were prepared and evaluated as potential alternatives to parenteral adminis-
tration. Multiple-dose studies over a 12-week period gave measurable blood levels of
leuprolide, and the results demonstrated dose linearity in the dose range of 1.5-9 mg
daily. Formulation and device studies demonstrated that MDI formulations of peptide
and protein drugs, using leuprolide as a model drug, are feasible.

μ

9.6.2.3 Growth Hormone
Growth hormone is an approximately 22 kDa protein that is secreted in a pulsatile

manner from the pituitary throughout the day and night by the combined activities of
somatostatin and growth hormone-releasing hormone [212]. Growth hormone plays
an important role in growth and well-being, and a deficiency in infants and children
leads to impaired skeletal growth, low bone density, reduction in lean body mass,
and extracellular fluid volume and increased risk of cardiovascular diseases. Therapy
with recombinant hGH requires repeated subcutaneous injections at regular intervals
[213]. Approaches to deliver growth hormone via the respiratory tract have also been
reported [214,215]. As an alternative to delivery of hGH, a number of laboratories
have synthesized small molecules (peptides and peptidomimetics) that enhance the
release of growth hormone [216,217] . One of the studied growth hormone - releasing
peptides, SK&F 110679, has been shown to be a potent and selective stimulant of the
release of growth hormone when administered orally, intravenously, and intranasally
in humans [217 - 219] . Studies designed to evaluate absorption of SK & F 110679 fol-
lowing intranasal and oral administration in dogs provided evidence that this peptide is
well absorbed from these sites. When SK&F 110679 was administered either nasally
or orally in humans, 30-300 times greater quantities were required to elicit a growth
hormone response similar to that seen following intravenous administration [220,221].
These results suggest that the permeability of SK&F 110679 across the nasal and oral
mucosa must be low despite its smaller size and improved resistance to metabolic
degradation, which is imparted by the presence of D -amino acids in the molecule. Due
to the lack of activity following oral and nasal administration, absorption of SK&F
110679 following intratracheal administration of a single dose of SK&F 110679 at
0.1 or 0.3 mg/kg to the rat lung was evaluated, and the results showed that increments
in plasma growth hormone concentrations were maximal at 15-30 min and returned to
predose values between 45 and 60 min [221]. These findings provided the impetus for
further studies to examine the feasibility of aerosol administration of SK&F 110679.
Absorption of SK&F 110679 was further evaluated for its pharmacokinetic param-
eters following intratracheal administration in the dog, using a sensitive and specific