Protein and Peptide Delivery through Respiratory Pathway - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 435

9.3.6.3 Pharmacokinetic Evaluation of Lung Drug Uptake
The in vivo disposition of pulmonarily absorbed drugs are characterized using the
pharmacokinetic relationships generally used for intravenous and orally administered
drugs, that is, by monitoring the blood or urine drug concentration data over time after
dose administration by applying model-dependent or model-independent methods
and comparing peak drug concentration ( C max ), time for peak drug concentration to
occur ( t max ), and the extent of absorption (area under the plasma-time profile AUC).
Pharmacokinetic evaluation provides information complementary to other techniques
like suitable biochemical evaluation and radiolabeled deposition.
9.4 Pharmaceutical Issues in Peptide Drug Delivery
In pulmonary delivery of peptides and proteins, the particle deposition and absorp-
tion are influenced by the aerodynamic size of inhaled particles, resistance to air-
flow, dissolution, partition and diffusion of drug particles in respiratory tract fluids,
and stability of particles in the presence of enzymes and mucociliary clearance. In
aerosolization, a more uniform distribution with greater extent of penetration into the
peripheral or the alveolar region of the lung is achieved, but it is more costly and it is
difficult to measure the exact dose deposited in the lungs. In contrast, the instillation
process is much simpler and less expensive but results in nonuniform distribution of
drugs. The devices used to produce aerosolization are called inhalers and are classi-
fied as nebulizers (solutions), metered-dose inhalers (MDIs), and dry powder inhalers
(DPIs). Inhalers are handheld devices used to deliver medications through the pulmo-
nary route. Nebulizers convert into a fine mist and deliver the medication, which may
contain nanostructures such as liposomes, micelles, nanoparticles, and dendrimers.
However, proteinaceous drugs are often very unstable in aqueous solutions, and are
easily hydrolyzed and denatured due to high shear stress [30] . Furthermore, the drop-
lets produced by nebulizers are heterogeneous, resulting in poor drug delivery to the
lower respiratory tract. MDIs use chemical propellants to expel the medication from
the inhaler device. Recently, spacers have been added to MDIs that remove some of
the nonrespirable particles by impaction on their walls and valves. However, proteins
and peptides are susceptible to denaturation when in contact with these propellants or
with the large air-liquid interfaces that are constantly being generated during aero-
solization [31] . A number of different DPIs are designed to deliver the drug or excip-
ients powder to the lungs. These devices differ not only in their forms of particle
generation and delivery but also with regard to design differences, such as a discrete
or reservoir drug container, number of doses, and the presence of a dose counter.
Furthermore, dose emission is dependent on inhalation flow rates [32] .
9.4.1 Drug Delivery Systems
The human lung has efficient mechanisms to remove deposited particles by muco-
ciliary clearance and phagocytosis. When peptide and protein drugs are formulated