APR Nov/Dec 2022 - 61

« DRUG DELIVERY
Table 1. The advantages and disadvantages of common pulmonary
delivery systems1
Delivery system
Dry powder inhaler (DPI)
* Compact/portable
* Quick and easy to use
Pressurized metered-dose
inhaler (pMDI)
* Compact/portable
* Quick and easy to use
* Can be used with
different drugs/doses
Nebulizer
* No hand-mouth
coordination required
Soft mist inhaler (SMI)
* Compact/ portable
* Low drug flow
* High fine particle fraction
* Higher inspiratory
flow required
* Requires high levels of handmouth
coordination
* Propellant required
* Bulky / not portable
* Requires a power source
* Takes longer to
deliver treatment
* Drug wastage levels
necessitate higher doses
* Requires higher level of
coordination
* Small quantities per dose
* Drug needs to be soluble
carbon footprint because, unlike pressurized metered-dose inhalers
(pMDI), they do not contain a propellant.
Trends in the Industry
In order to expand and fully utilize the inhaled route there is a
requirement to deliver high drug doses (for example in the case of
antibiotics). Additionally, with the increasing popularity of biologics
and complexity of dose adjustment, pulmonary delivery can be
an ideal platform to accommodate the formulation of this class of
complex molecules.
Delivering High Doses
The efficacy of an inhaled drug heavily relies on the deposition of
the active pharmaceutical ingredient (API) into the lungs, and it is
the aerodynamic particle size distribution (APSD) that defines how
powders behave in an airstream during inhalation.
Generally, API particles after crystallization require size reduction
to allow inhalation delivery. The optimal aerodynamic particle size
to reach the bronchial region is <5 μm, with the majority of the
particles being 2-3 μm.2
Traditionally, top-down processes, like
micronization, are used for the particle size reduction. This approach
presents flowability and dispersibility challenges. Particles with lower
particle size have high surface area and hence high adhesive forces.
Overcoming these challenges relies on the careful design of both the
powder blend and the DPI device.
The most common approach to address these challenges is to formulate
APIs with a carrier excipient, usually lactose monohydrate. The carrier
has coarser particles than the API, typically between 50 to 100 μm in
Advantages
* Requires lower levels
of patient coordination
than other methods
Disadvantages
* Drug preparation differs
between DPI devices
diameter, and form a loose bond with the drug.2
As the formulation is
inhaled, the drug detaches from the carrier particle, allowing the drug
to be delivered to lungs and the carrier to be deposited in the throat
and swallowed. Using a carrier also aids fluidization and dispersion,
improving the flow of the formulation to aid processing steps such as
device filling and dose metering.
This approach is referred to as " carrier-based " formulation and is well
established for the majority of formulations and it works very well. Both
the powder blend and the DPI device must be carefully designed to
ensure detachment of the micronized drug from the carrier excipient
on inhalation.
DPIs are typically designed to deliver API doses of microgram
quantities. For example, the Ellipta® product range contains 40 µg of
vilanterol trifenatate and 74.2 µg umeclidinium bromide with a total
powder mass of 12.5 mg (mainly lactose monohydrate).3
For some APIs
however, higher doses are required to achieve the desired therapeutic
effect. As drug loading increases, it becomes increasingly challenging
to maintain the correct adhesion-cohesion balance, whilst avoiding
powder blend challenges such as uniformity and segregation. In the
traditional carrier-based model, an increased delivered dose therefore
requires a corresponding increase in excipient, which may come with
some challenges. Large volumes of powder threaten effective drugcarrier
separation, and can be difficult to inhale, threatening dose
uniformity. Large powder volumes are also associated with side effects,
the most commonly reported being coughing. Aside from being
unpleasant, in people with pulmonary diseases, such a lung cancer or
Cystic Fibrosis (CF), coughing can irritate and damage the lung, adding
to the likelihood of adverse outcomes. In addition, introducing large
volumes of powder to the lungs increases the chances of the drug
being removed via mucociliary clearance.4
The Rise of Biologics
Biologics are a class of medications that offer unique treatment
options for many of the world's most challenging diseases. The terms
Figure 1. Key properties of some high purity, low endotoxin
grade stabilizers that are typically used in particle engineered
DPI formulations.
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APR Nov/Dec 2022

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