APR Nov/Dec 2022 - 62

» DRUG DELIVERY
»
biologics and biopharmaceuticals cover a broad class of molecules
that include, among others, peptides, proteins, nucleic acids as well
as blood, tissue, cell and gene products. Biologics have the potential
to change patient lives significantly. For example, in some types of
cancer, biologics constitute the first new treatments in decades. In fact,
biologics appear to show promise across almost all disease areas as
well as many diagnostic applications. The expectation is that biologics
will significantly overtake innovative small molecules sales over the
next five years. By 2027, biologics sales are forecasted to exceed small
molecules sales by $120 billion.5
Biologics are a complex class of drug. They typically have a poor
stability profile (compared to small molecules), and are often sensitive
to temperature, light and pH changes. Additionally, they have poor
permeability through the intestinal epithelium and are susceptible to
enzymatic degradation in the gastrointestinal tract.6
This means that,
historically, biologics have been administered parenterally, despite
this being invasive and inconvenient for the patient, and resource
hungry for healthcare systems.7
In recent years, inhaled formulations and DPI systems have become
widely accepted as an alternative to the SC and enteral (oral)
administration of therapeutic peptides and proteins. They avoid
the potential of poor absorption and high metabolism in the
gastrointestinal tract, and the first-pass effects in the liver. In addition,
inhalation therapy, unlike injection delivery, is pain free making it more
convenient for patients. Whilst this is a highly active area of research in
general terms, for smaller biologics, such as insulin, systemic delivery
is possible and for larger molecules, such as monoclonal antibodies
(mAbs), local treatment of the lung tissue is possible.
Traditional 'carrier-based' DPI drug delivery, however, is not always
suited to the delivery of these promising molecules, particularly those
that require additional stabilization. Stresses from size reduction,
but also during storage and handling, can reduce the activity of
biologics. Alternative processing strategies are required, and the use
of excipients to stabilize the biologic and improve powder properties
may be required.
Excipients in Spray Drying
Particle engineering offers an alternative route, which is especially
suitable for high dose and biological formulations. Spray drying is
the most commonly used technology for particle engineering in DPI,
although also other alternatives exist, like spheroid formation or freeze
drying. Spray drying can be used to modify the particle morphology of
the API, resulting in a reduced aerodynamic diameter without having
poor flow and poor aerosolization properties. The physical properties of
spray-dried particles are highly dependent on the process parameters
used and the composition of the spraying matrix. Without excipients,
material properties are highly dependent on the properties of the
drug. Unfortunately, very few molecules can be directly spray-dried
with the desired physical properties without the addition of excipients.
Excipients are added to improve the general powder handling, or they
can be added to protect the API from external stresses.
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Whilst many excipients are described for this application in literature,
three excipients in particular show great promise for use as a filler in
the spray-drying processes. These are trehalose and sucrose, which
are non-reducing crystalline disaccharides, and the sugar alcohol
mannitol. All three provide improved compatibility with biomolecules
compared to reducing sugars. They are not easily hydrolyzed by acid,
and they can help these complex molecules maintain their native
conformation. In addition, they can enable modification of the
resulting powder's physical properties. They also have an excellent
safety profile and are commonly used as lyo- and cryo- protectants in
parenteral administration of therapeutic proteins.
Trehalose and sucrose are particularly attractive due to their high
glass transition temperature. This enables the formation of a glassy
amorphous matrix, which in turn may be particularly suited to
maintaining the stability and activity of biomolecules. In addition,
when compared to other disaccharides, trehalose is highly stable
under low-pH conditions.
Because trehalose can function as a particle matrix/stabilizing agent,
it is a promising excipient for the delivery of biomolecules, such as
peptides and proteins. Sucrose could also play a role in this area, and
it has a demonstrated utility as an excipient for peptide and protein
delivery, for example it is already being utilized in many biologic
formulations, including COVID vaccines.
Mannitol has a much lower glass transition temperature, when
compared to sucrose and trehalose,
typically
reported to be
approximately 13°C. The impact of this is that it tends to crystalize
after spray drying. The transition from an amorphous material to
crystalline material may introduce stresses that can damage sensitive
molecules, such as biologics. However, many molecules can tolerate
these stresses, and in some cases, it may be preferable to have the
more thermodynamically stable crystalline form. If an amorphous
glass is required, then the crystallization of a matrix containing
mannitol can be impeded with the addition of further excipients
such as glycine and inorganic salts. Additionally, mannitol has a
proven application in pulmonary delivery due to its use in Exubera®,
the first inhaled insulin dry powder inhaler that was available in the
market between 2006 and 2008.8
Figure 2. Visual representation of a spray drying process of a
biologic with a disaccharide and leucine. Disaccharide molecules
shield the biologic to protect them against external stresses, and
leucine typically accumulates at the surface.
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