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`commercializing new delivery modalities. It is therefore reasonable to expect that incremental
`improvements in existing technologies will continue to dominate the near—term future of depot
`delivery. These improvements may include new manufacturing process techniques, new
`approaches to sterilization, novel packaging technologies, and novel combinations of existing
`technologies. Recent examples of these include the emerging use of supercritical fluid
`technologies to make polymeric microspheres (169), evaluation of electron—beam and ethylene
`oxide as methods of sterilization (170), increasing use of delivery devices, such as the Lupron
`Depot~PED"" dual—chamber syringe, to enhance convenience during administration, and the
`integration of acid—neutralizing excipien ts in PLGA formulations to counteract acidification by
`hydrolysis products (44). Further value may be extracted from these technologies if leads are
`optimized during discovery specifically for sustained release, emphasizing potency and
`stability as key criteria.
`
`Introduction of New Excipients
`The acceptability of materials for parenteral use, from both the safety and regulatory points of
`view, continues to be a major constraint
`in the development of new depot delivery
`technolOgies. The hurdles to introduction of new excipients are significant, and few companies
`are willing to invest the significant time and money required to bring new or novel—use
`excipients through development to the market. PLGA enjoys the status of being a proven and
`well—accepted excipient, and continues to be the most common polymer used in parenteral
`sustained—release systems, further entrenching it
`in this application. Although PLGA is
`attractive in many respects, new polymeric materials are needed to provide a wider range of
`properties and potential release profiles, and to enhance the range of actives compatible with
`sustained—release approaches. In the short term,
`the most promising new candidates for
`approval are likely to be copolymers of currently-approved materials, such as copolymers of
`PLA and PEG, which can be expected to degrade to known materials. Longer-term, one
`approach to speed the introduction of new excipients could be the formation of jointly—funded
`industrial consortia, to advance the preclinical evaluation of novel ma terials.
`
`Enhanced Control over Drug Release
`Despite their many advances over the years, marketed depot delivery systems continue to offer
`a relatively limited ability to control release rate, relying on the intrinsic properties of the
`formulation (e.g., matrix degradation, API dissolution or partition, osmotic pressure, etc.) to
`govern drug release. The ability to rationally change drug release during dosing would
`represent a major step forward, and continues to cornprise an active area of scientific inquiry.
`The ultimate goal is responsive systems, or smart delivery systems, which incorporate the
`ability to sense their surroundings and alter their function in response to specific signals
`generated in the body {171). Such systems will be particularly valuable in the treatment of
`diabetes and other metabolic disorders, and may also be useful in chronotherapy (172,173).
`Several approaches have been evaluated in the pursuit of
`this goal,
`including
`environmentally responsive polymers and microprocessor—based devices. Novel polymers
`have been synthesized, which are capable of changing their properties in response to changes
`in their environment,
`including pH,
`temperature,
`ionic strength, solvent composition or
`electromagnetic radiation (174 178). These include the pH~sensitive methacrylates, which
`change in their degree of swelling as pH changes, and temperature—sensitive systems such as
`poly (Nisopropylacrylamide) (174). Microelectromechanical solutions include an electro—
`lhermally activated implantable silicon chip, under development by MicroCHlPS (179}. The
`device is segmented into multiple wells, which can be sealed prior to implantation and
`then Opened on demand. Depot delivery systems of the Future will likely include integrated
`sensing of biomarkers, metabolites, or actives, feedback—control over drug release, and real—
`time output of information relating to the underlying pathology and treatment (168).
`
`New Applications
`A number of new applications for depot delivery are emerging, including targeted delivery,
`gene delivery, and tissue engineering. Fabrication of nanoparticles from PLGA offers a new
`platform for targeted delivery, amenable to 1V administration (180}. These systems are being
`
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`13?
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`developed and studied for the targeted delivery of a range of therapeutics, from small
`molecules to nucleic acids. Nucleic acid delivery via sustained—release systems is an
`increasingly active field of research given the recent advent of RNAi technology and continued
`interest in local gene delivery (181,182). Tissue engineering and regenerative medicine strategies
`often require controlled delivery of bioactive molecules, with particular sensitivity to spatial and
`temporal control of release (183), to a particular cell type or in a particular region of the body
`(184). There are many potent growth factors including nerve growth factor, bone morphogenic
`protein and vascular endothelial growth factor, which are under investigation (185). Approaches
`for regenerating nerve tissues, repairing bone defects from fractures, infections and cancers, and
`the ability to accelerate blood vessel formation are all areas of active research. The field of
`parenteral sustained release promises to be an exciting and active area of research for many years
`to come, offering the potential to significantly increase the value of both existing and new
`therapeutics and address important unmet medical needs.
`
`wees
`
`.5‘
`
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