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 in 2004.

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 csethi@advanstar.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 by injection.

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.