Controlled delivery. Both the drug's duration (for sustained delivery) and its site (targeted delivery) of action and bioavailability can be controlled.
Targeted delivery has been practiced for some time using monoclonal antibodies and surgical implantation, among other methods
(see the "Blood-Brain Barrier" box on Page 22). Sustained delivery is gaining much interest in the biopharmaceutical arena.
According to Nandini Katre of SkyePharma, "The major challenges in formulating therapeutic proteins and peptides for sustained
delivery are as follows: maintaining the structural integrity of the therapeutic molecule to preserve its bioactivity and
stability; obtaining high loading in the delivery vehicle to ensure sufficient bioavailability for the duration of therapy;
providing sustained therapeutic levels for the desired duration without a 'burst' effect, controlling the duration of drug
release to accommodate a range of dosing regimens that match therapeutic needs; and providing in vivo biological effects that
can be sustained over the required period of time."
For sustained delivery, a depot (reservoir) of drug is created in the body (at the injection site, for example), from which
the drug is released over a specified time. Biodegradable polymers open the possibility of implants that deliver a drug over
days or months. Like any other method, sustained delivery presents certain challenges. In time, a protein may interact with
its surrounding matrix, or the implant could be attacked by the immune system. If proteins stick (adsorb) to the delivery
matrix, they may not be released at all. Even before implantation, creation of a delivery matrix often involves steps that
can harm proteins. Four methods of creating a delivery matrix for sustained delivery can be used with biopharmaceuticals:
emulsification, coacervation, extrusion, and polymerization.
Emulsification. When the drug is water-soluble but the delivery matrix is not, they are dissolved into two different media and then mixed
to create a water-in-oil emulsion. Usually, for better protein distribution, that emulsion is dispersed and mixed with a second
aqueous solution to create a water-in-oil-in-water emulsion. The interfaces created by the droplets can denature proteins,
especially when a series of emulsions are used to create the delivery matrix. Additionally, energy is required to combine
the two (mechanical or ultrasonic mixing), which also can denature proteins.
Coacervation. In coacervation, formulators add a competing molecule that is more soluble to a solution of the protein in liquid. The resulting
chemical reactions create microspheres of the drug. This method is gentler than emulsification, but some loss of bioactivity
can happen through pH changes and chemical reactions.
Extrusion. A solution or particulate formulation is forced through holes to form microdroplets. High shear forces may damage proteins.
Combining this technique with lyophilization may be a better choice because the cold, dry form is more stable, and the protein
receives some protection from shear forces.
Polymerization. Hydrogels, polymers that swell when they come into contact with water or an aqueous solvent, are mixed with the drug. Electromagnetic
radiation forces chemical reactions that create a gel matrix to carry the drug.
Inhaled Biopharmaceuticals
Offering an almost direct line to the circulatory system, alveoli in the lungs would be a good place to deliver proteins.
However, because the lungs are a pathway for infections, the body's defense mechanisms make the alveoli hard to reach. Pulmonary
delivery of polypeptides requires a device such as a nebulizer that makes an aerosol of the formulation (a liquid or a lyophilized
powder) for inhalation. Only very tiny particles can reach far enough into the lungs for efficient drug delivery. The portion
of the particle size spectrum generally considered able to penetrate farthest and deposit well into the lungs (<2-3 µm) is
called the fine particle fraction (FPF). For biopharmaceutical drugs, a large portion of the device output should be 1-6 µm.
Particle size distribution and weight determine how far into the progressively smaller lung pathways the drug will go. Heavier
particles are deposited sooner, sometimes just at the back of the throat. If swallowed, the drug is wasted (see "The Oral
Route" on Page 29).
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