PARENTERAL (INJECTABLE) FORMULATION TECHNOLOGIES
According to Kalorama Information, the implantable and injectable drug delivery market had revenues of $9.8 billion worldwide
in 2006.18 The parenteral route of administration will continue to play an important role in drug delivery, particularly for proteins,
for a number of reasons. First, an obvious case is for drugs with poor oral bioavailability. While alternative routes of administration
such as pulmonary are evolving, parenteral administration has a significant history with well understood development times.
Second, injections can allow a drug to be delivered right at the site of action, as in the case of local anesthesia. Third,
most targeted delivery systems will be based on injectable formulations (e.g., immunoliposomes). Fourth, oral delivery is
limited to 24-hour durations due to the normal transit time of the GI tract. Injectable controlled-release formulations will
continue to play a major role for delivery over a period of days, weeks, or even months. Fifth, injections are often the only
practical route of delivery in many animal health applications. Finally, there are a number of conditions where oral administration
is contraindicated (e.g., presurgery, patients with nausea, unconscious patients, etc.).
Of the above factors, the need for controlled release is clearly of greatest significance when looking toward the future.
The market potential for proteins alone is exemplified by PEGylation, the covalent attachment of polyethylene glycol to a
protein drug. The worldwide sales of the top three PEGylated products (Neulasta, Pegasys, and Peg-Intron) was over $3 billion
While PEGylation and related technologies provide prolonged circulation time for a protein, there are a number of drawbacks:
Manufacturing yields can be low, affecting the cost of goods; bioactivity can be significantly reduced; distribution in the
body can be adversely affected; and of course the protein itself is modified, complicating safety and regulatory assessment.19,20 For these reasons, there is much activity in injectable controlled-release formulation technologies that deliver a protein
without covalent modification. Such controlled-release approaches include biodegradable microspheres, insitu gelling systems,
and multivesicular liposomes, all of which have been used in marketed products. An example of prolonged delivery of interferon-alpha
using DepoFoam multivesicular liposomes is shown in Figure 2.21 [Editors note: Figures for this article are not available online. To obtain a complete copy of the article with figures,
please send your mailing address to firstname.lastname@example.org
]. These technologies hold significant promise for the future.
For self-administration by patients, injections have three major drawbacks. First, many patients fear needles. Previous advances
in needle technology have produced narrow gauge needles which significantly reduce the sensation of the injection. Pens that
hide the needle, needle-less jet injectors such as the Biojector, and micro-needle systems22 that deliver solutions through a platform of miniature needles will further help address this issue. Second, patient administration
will continue to be limited to subcutaneous injections in order avoid inadvertent intravenous administration. This leads to
the third limitation, the limited volume which can be delivered by the subcutaneous route (typically 0.5–1 mL).
Horspool and Lipinski have reviewed the various routes of administration and the doses that can be delivered by each.23 Figure 3 describes some of the typical doses which can be administered by various routes of administration. [Editors note:
Figures for this article are not available online. To obtain a complete copy of the article with figures, please send your
mailing address to email@example.com
]. With the exception of intravenous and oral delivery, subcutaneous delivery has the potential to administer more drug than
nearly any other route of administration. Nonetheless, the limited volume which can be given by the subcutaneous route can
be problematic. Halozyme Therapeutics, Inc., has introduced a recombinant hyaluronidase that temporarily hydrolyzes the connective
tissue in the subcutaneous space, thereby increasing the practical subcutaneous injection volume.24 Once further established, this approach has the potential to significantly increase the number of drugs that can be self-administered
NANO AND MICRO-TECHNOLOGY
Much has been written regarding miniaturized devices that will impact the future of medicine. Smart nanotubes have been envisioned
that encapsulate drug and then open up to deliver a drug in a particular location in response to a stimulus.25 Microprocessors will be able to deliver drug at predetermined times from tiny devices with multiple reservoirs.26 The possibilities seem endless.