Protein and Peptide Delivery through Respiratory Pathway - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 455

and corticosteroids are bioactive in the lung at 5-50 mg/dose; also many peptide and
protein drugs require deep lung doses in the 2-20 mg/dose range; traditional inhala-
tion systems have primarily been designed to deliver drugs in this range.

9.5.9.3 Stability Issues for Macromolecules
Existing aerosol systems are inappropriate for formulations of delicate macromole-

cules. Most macromolecules are unstable in the liquid state, amorphous, and highly
moisture sensitive in the dry state. There are exceptions, including Genentech's
Pulmozyme, the first FDA approved aerosol protein, a 33 kDa digestive enzyme
(DNAse) available as a stable liquid formulation for nebulization. Other proteins such
as growth hormone, G-CSF, and IFNs aggregate and are to some extent denatured by
nebulization [174] .

9.5.9.4 Variation in Delivered Dose
For systemic delivery of various macromolecule drugs, the reproducibility of deliv-
ered dose through existing systems is too variable for several reasons.

9.5.10 Intranasal Delivery of Peptides and Proteins
Oral administration of peptides is very difficult because of GI enzymatic degrada-
tion and hepatic first-pass effects. Increasing evidence suggests that the intranasal
route of administration may be an attractive and convenient option for the delivery of
certain compounds to the brain and for immunization with antibodies. In fact, several
peptides, including luteinizing hormone-releasing hormone, oxytocin, calcitonin,
and vasopressin, are routinely administered intranasally in clinical practice, and other
peptides, including insulin, glucagon, growth hormone, growth hormone-releasing
hormone, and somatostatin, are currently under investigation [174]. The efficacy of
peptides/proteins following nasal administration is highly dependent on the molecu-
lar structure and size of the drug. Research has demonstrated gene delivery in rat via
nasal instillation [45]. It was noticed that mitral cells from the olfactory bulb, locus
coeruleus, and area postrema expressed

-galactocidase for 12 days; these could be
useful for gene therapy of diseases affecting different CNS structures.

β

9.5.10.1 For Brain Targeting
Investigational studies in humans provided evidence of direct delivery of macromol-

ecules to the CNS following nasal administration. Research showed CNS effects of
intranasal corticotrophin-releasing hormone (CRH) without altering plasma cortisol or
CRH levels [175]. A further study demonstrated the effects of neuropeptides like adre-
nocorticotropin (ACTH 4-10) and melanocyte-stimulating hormone in human volun-
teers, following nasal solution of the peptides [176]. The peptides are known to be the
most potent regulators of neurobehavioral functions in animals. Intranasal delivery of
peptide T was found to be beneficial in the treatment of painful peripheral neuropathy
of AIDS, and a clinical trial was approved by the US FDA for the Phase II study [177].