Future Perspectives

While this chapter focuses on the significant potential of inflammatory responses, foreign body reaction, and fibrous encapsulation as being principal barriers to the bioavailability, pharmacokinetics, pharmacodynamics, and metabolism of proteins and peptides released from implanted controlled-release systems, it must be clearly noted that these barriers have been overcome for a few systems and clinically successful implants have been achieved for the release of proteins and peptides. The most obvious example is the clinical use of leuprolide acetate sustained-release systems for treatment of prostate cancer and endometriosis. The clinical success of these systems clearly demonstrates that efficacious bioavailability, pharmacokinetics, pharmacodynamics, and metabolism can be achieved with implantable controlled-release systems.

Even though the effect of acid, enzymes, and oxygen radicals generated in the inflammatory and foreign body reactions and the effect of the fibrous capsule on the diffusion and transport of proteins and peptides are generally unknown and considered to be specific to the chemistry of a given therapeutic agent, it is clear that these interactions may be minimal and may not significantly affect the achievement of clinically relevant therapeutic levels of proteins and peptides. Tissue responses to implantable peptide and protein delivery systems must be considered in the overall design, research, and development of these systems, especially in regard to the potential for protein and peptide biodegradation as well as modulation of mass transport and diffusion; they need not be a significant barrier to the development of clinically useful devices. Biodegradable polymer depots, that is, microcapsules and microspheres, pumps, and multireservoir microchip array devices, would all be expected to demonstrate the in vivo tissue responses described in this chapter (103-106). However, they do not necessarily lead to failure of the device. Therapeutic polypeptides with high potency and clinical efficacy can be delivered in spite of these tissue responses.

The clinical success as well as in vivo research studies of protein and peptide controlled-release systems of various types demonstrate that the inflammatory responses, foreign body reactions, and fibrous capsule formation do not present insurmountable barriers to the achievement of therapeutic levels of the respective protein or peptide. These observations indicate that the future development of these systems for clinical application is very promising. While the chemical and physical characteristics of each protein or peptide will ultimately determine its fate following release from a controlled-release system, attention can now be turned toward other variables unique to each controlled-release system that will determine the efficacy and appropriate and adequate function of each respective system. Thus, the future appears bright and positive for the development of protein and peptide controlled-release systems that can produce appropriate and adequate bioavailability, pharmacokinetics, and pharmacodynamics for therapeutic application.

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