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lung is classically for local therapy, pulmonary delivery is a major opportunity for systemic delivery of macromolecules including proteins and approaches to gene therapy [119]. |
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Delivery of a drug to the lung is highly dependent on particle size and 12 m is appropriate [119,120]. Dry powders are particularly useful to stabilize proteins. Loss of drug in the device and in the respiratory tract complicates the determination of bioavailabilities. Intratracheal infusions in rats are a useful test of the feasibility of pulmonary absorption [121]. The long-term inflammatory and immunological response to such delivery has yet to be characterized. As with novel delivery, patient compliance, bioavailability, stability, and particularly reproducibility, depend on the device, and the device should be finalized prior to the latter stages of Phase II. |
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For life-threatening diseases or those in which the quality of life is impaired, parenteral controlled-release administration either by injection or infusion pumps may be appropriate. For diseases where patient compliance, convenience, or repetitive administration by injection is an issue, the use of an implant may be appropriate. There are numerous depot formulations where drug delivery is controlled by solubility such as insoluble salts or emulsions. Direct infusion into physiological compartments, for example, intrathecal baclofen [122], may permit therapy for debilitating diseases. Miniaturization of mechanical devices and improved biocompatibility of materials are making these devices more acceptable, but the limitation is still the size of the reservoir for the drug. Clinical development is ongoing for products for spasticity with baclofen [122,123], patient-controlled analgesia [124], and diabetes [125]. The infusion pump must be registered as a device with an IDE and 510K, and then an IND and NDA must be filed for the delivery device for that drug and indication. Stability studies in the container and for beyond the period of use in the pump are required. As with iontophoresis, Phase I and IIa studies may be conducted with devices with broader capabilities, but specialized devices with safety and ruggedness built-in are required for Phase IIb and Phase III trials. Sterility and pyrogenicity must be adequately handled and evaluated in processing. Additional microbiological stability requirements must be included. |
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Implants have potential for treating diseases where patient compliance is an issue and where the drug is potent. Examples are naltrexone for drug abuse [126] and a number of other CNS and hormonal indications. For most pharmaceutical applications, subcutaneous implants must be easily removed intact for safety reasons to terminate drug therapy and pose long-term toxicological issues. Alternatively, microsphere implants may be used where the drug has a wide therapeutic window and few drug interactions. There are two basic approaches: diffusion controlled and chemically controlled where a reaction lib- |
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