Administration, drugs pulmonary route

Parenteral administration is not perceived as a problem in the context of drugs which are administered infrequently, or as a once-off dose to a patient. However, in the case of products administered frequently/daily (e.g. insulin to diabetics), non-parenteral delivery routes would be preferred. Such routes would be more convenient, less invasive, less painful and generally would achieve better patient compliance. Alternative potential delivery routes include oral, nasal, transmucosal, transdermal or pulmonary routes. Although such routes have proven possible in the context of many drugs, routine administration of biopharmaceuticals by such means has proven to be technically challenging. Obstacles encountered include their high molecular mass, their susceptibility to enzymatic inactivation and their potential to aggregate. 

In general, when the cells of the endothelium in the lungs are the target cells of interest (see Chapters 7 and 9 on aspects of targeting drugs to endothelium in inflammatory diseases and cancer, respectively), systemic administration seems the route of choice. Bronchial epithelium on the other hand can more easily be reached via the pulmonary route. The accessibility of other cells in the lungs is most hkely governed by disease conditions, factors that can affect epithehal permeability and vascular permeability, and others as described earher. 

With regard to the systemic administration of smaller proteins (<20 kDa), the development of insulin for inhalation has shown that the pulmonary route is a feasible route of administration. However, advanced inhalation devices and formulations were required to obtain a reproducible lung deposition. It will be especially necessary to deal with the problems that occur when drugs with a small therapeutic window are administered. To enable widespread use of the lung as port of entry for these small proteins, future developments should be directed towards more simple inhalation devices which still give a high and reproducible lung deposition. The formulations that will be required for these proteins are likely to be much more complex and advanced than those that are currently used. Examples are formu-... 

The advantages of administration by intramuscular injection are that the muscle can act as a depot, and the rate of disappearance of drug from the site of injection can be calculated. Inhalational, intranasal, and intratracheal administration are normally reserved for vapors and aerosols including anesthetics. Absorption is facilitated by small-sized particles, high lipid solubility, sufficient pulmonary blood flow, and a large absorptive surface area, as it is present in healthy lungs. Administration by these routes can be very rapid when several of the factors favoring increased absorption are combined. 

With the advent of new biotechnological techniques endogenous compounds like insulin, buserelin or octreotide have become available at affordable prices. All of these substances still have to undergo needle application. Until today the development of alternative delivery systems for the nasal, buccal, peroral, rectal and pulmonary routes for the administration of those class III drugs according to the biopharmaceutics classification system (BCS) (Amidon et al. 1995) could not keep pace with this development of endogenous compounds or is not economic enough for the health care payers (e.g. insulin application via the pulmonary route). 

From pharmacology results and proposed clinical program, select route of administration (oral, pulmonary, intramuscular, subcutaneous, transdermal, ocular, vaginal, buccal, sublingual, etc.) and formulation type to be dosed (solution, suspension, tablet, capsule, granulation powder, microspheres, microemulsion, depot drug, etc.). 

Although routine oral delivery of proteins has not been realized, some protein formulations have been developed for pulmonary delivery. Pulmonary delivery can result in either parenteral or local administration of the drug and, like oral delivery, is considered non-invasive. As with other routes of delivery, the size of the protein may limit its ability to be delivered systemi-cally via the pulmonary route of administration. Pulmozyme , a DNase-based formulation approved for the treatment of cystic fibrosis (CF), is delivered to the lungs by a nebulizer to clear blockage of the airways in the CF patient.Formulations for insulin to be administered by inhalation for systemic delivery of... 

Drugs may be administered directly into the respiratory tract for activity on, or through, the pulmonary epithelium and mucous membranes. Access to the systemic circulation is relatively enhanced and rapid following administration by this route because the pulmonary surface area is large. A drug solution can be administered as an aerosol that is inhaled. The advantage of this route of administration is the almost instantaneous... 

The high solubility of respiratory gases allows the use of fluorocarbons for liquid ventilation and drug delivery by the pulmonary route [178]. For administration of drugs via the pulmonary route, reverse water in fluorocarbon emulsions... 

As pharmaceutical scientists gain experience and tackle the primary challenges of developing stable parenteral formulations of proteins, the horizons continue to expand and novel delivery systems and alternative routes of administration are being sought. The interest in protein drug delivery is reflected by the wealth of literature that covers this topic [150-154]. Typically, protein therapeutics are prepared as sterile products for parenteral administration, but in the past several years, there has been increased interest in pulmonary, oral, transdermal, and controlled-release injectable formulations and many advances have been made. Some of the more promising recent developments are summarized in this section. 

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