Pharmaceutical biotechnology最新文献

When a therapeutic effect is optimized by precise control of specific temporal patterns of plasma levels, infusion offers distinct advantages over oral administration, bolus injection, or depot delivery of polypeptides. The limitations of oral delivery are well known, and although research is under way into development of carrier systems that prevent degradation of labile agents, it is unlikely that the variances in absorption will meet the need for precise control. Depot delivery from subcutaneous or intramuscular implants presents a difficult situation when local tissue reactions to the agent sometimes occur. Removal of a depot system in the event of adverse reactions presents additional difficulties. Bolus injections are unable to sustain constant plasma levels unless the drug half-life is long or the injections are frequently administered. Insulin injections, for example, would be required every 30-60 minutes to approximate the plasma levels provided by a continuous infusion; such frequent injections would not be practical on a 24-hour basis. For the developer of new polypeptides, parenteral administration offers the most direct route to the marketplace. The step from periodic injections to tightly controlled infusion is a logical progression as compared with modification of the molecules or vehicles to obtain equivalent profiles. In Table II several different types of devices that can be used for infusion of proteins are compared. Microelectronics have played a major role in the miniaturization of infusion devices and undoubtedly will continue to do so. Micromachining, a spin-off technology of integrated circuit manufacture, will also find application in small infusion devices. In the future, we will have cost-effective disposable devices (Saaman et al., 1994) built on this technology that are programmable and thus can be adapted to meet each individual therapeutic need (Horres, 1994). We can also expect to see more closed-loop drug delivery systems where biosensors and infusion devices are combined to optimize a particular therapy. Recent positive results obtained in diabetics by a decade on tight glucose control may forecast a resurgence of popularity of insulin pumps. At the other end of the spectrum, low-cost, small, and simple-to-use osmotically powered systems are close to being marketed; these systems will make infusion almost as convenient as transdermal patches. We will also see major advances in how drugs and devices are interfaced. Prefilled and ready-to-use drug cartridges have proven to be efficient in surgical and emergency medicine and can greatly improve most infusion applications. It is anticipated that coded, prefilled cartridges or pouches will be automatically, recognized by preprogrammed pumps to reduce operator labor and entry error.

The key components to the successful development of a biodegradable microsphere formulation for the delivery of proteins are polymer chemistry, engineering, and protein stability. These areas are intricately related and require a thorough investigation prior to embarking on the encapsulation of proteins. While each of these components is important for the development of a biodegradable microsphere formulation for protein delivery, other critical issues should also be considered. In particular, preclinical studies in the appropriate animal model are usually necessary to assess the potential feasibility of a continuous-release dosage form. These studies should be performed at the earliest possible stage of development to validate the feasibility of a controlled release formulation. After the utility of a controlled release formulation has been demonstrated, the polymer matrix should be chosen and bench-scale production of microspheres initiated. The only polymers presently approved for human use for controlled delivery are the polylactides [poly(lactic acid), poly(glycolic acid), and poly(lactic-coglycolic) acid]. These polymers require multiphase processes involving several steps to produce microspheres containing the desired protein. A thorough review of previous work on encapsulation with these polymers should provide some insight into conditions to be assessed in developing a process. Once a process is chosen, it must be optimized to provide the highest possible yield of microspheres with the desired characteristics (e.g., loading, release, size, etc.). Finally, the final aseptic process should be validated and methods generated to assess the final product. The clinical studies should then start upon approval of the IND application. In the future, the biotechnology industry, and the pharmaceutical industry in general, will be seeking new methods to improve the delivery of therapeutic agents such as proteins and peptides. Formulations like biodegradable microspheres significantly reduce health-care costs since fewer administrations are needed, and they provide a competitive advantage in markets with several competing products (e.g., LHRH agonist market). Further, many new indications such as neurological diseases may require a long-term delivery system. The future success of biodegradable microsphere formulations will primarily depend on the commitment of the pharmaceutical and biotechnology industries to the development of this technology.