Drug Targeting Organ-Specific Strategies

70 3 Pulmonary Drug Delivery: Delivery To and Through the Lung
Table 3.5. Different issues to consider for peptide or protein inhalation formulations.
• Particle size morphology and surface characteristics
• Moisture sorption behaviour
• Stability in dry state and dissolved
• Tendency to form aggregates
• Charge of the molecule, isoelectric point
• Solubility and dissolution behaviour
• Crystallinity and crystal form
the formulation of peptide and protein powders for inhalation requires more advanced techniques
and a wide variety of excipients and production processes [16,65,74]. The reason for
this difference is found in the more complex nature of the problems and requirements related
to peptide and protein formulations.Table 3.5 summarizes a number of issues that need to
be considered when peptide or protein formulations for inhalation therapy are developed.
Many of the characteristics mentioned in Table 3.5 can be affected by the processes used to
prepare the protein or by the composition of the formulation used. Major formulation problems
connected to peptides and proteins are their low stability, hygroscopic nature, and tendency
to form aggregates, which are too large to cross the alveolar membrane.
If possible, adhesive mixtures or spherical pellets, prepared using simple excipients such as
sugars are also preferred for protein formulations. For the preparation of dry peptide-containing
formulations the most important techniques are lyophilization, spray freeze-drying,
spray-drying, co-precipitation and super critical fluid extraction. When lyophilization is used
as the drying method, milling to obtain the desired particle size can be used. For spray-drying
or supercritical fluid extraction the desired particle size can be obtained immediately from
the drying process. Lucas et al. [75] investigated different micronized bovine serum albumin–maltodextrin
(50 : 50) mixtures. Improved aerosolization behaviour was found for adhesive
mixtures based on carrier lactoses with surfaces that were modified by micronized lactose
or micronized polyethylene glycol 6000. Maa et al. [76] compared particles prepared by
spray freeze-drying with particles prepared by spray-drying. The particles contained recombinant
human deoxyribonuclease-1, or anti-IgE monoclonal antibody and different sugars as
excipient. The large size of the spray freeze-dried particles (about 8–10 µm) in combination
with their high porosity, turned out to result in improved aerosol performance compared to
the denser and smaller spray-dried particles. The lyophilization of proteins was recently reviewed
by Wang [77].
Protein instability can either be of a physical or chemical nature. The major mechanisms
underlying the degradation of proteins were recently extensively reviewed [78] Unfolding of
the protein is the main cause of physical instability and may lead to denaturation, aggregation
or surface adsorption. Excipients that preserve the protein in its preferred state of hydration
may be used to stabilize the protein. Several studies described the role of different
excipients (often in combination with production processes) in the stabilization of proteins
[65,79–82]. The major excipients used for stabilization of proteins are classified in Table 3.6.
The incorporation of the proteins in amorphous solid matrices of sugar (often referred to as
sugar glasses), seems an effective method to stabilize the solid protein [83–85]. The stabiliza-