Proteins delivery routes

Many therapeutic proteins must be delivered by injection as alternative delivery routes (e.g., oral) result in low bioavailability. This can be difficult,... 

Virtually all therapeutic proteins must enter the blood in order to promote a therapeutic effect. Such products must usually be administered parenterally. However, research continues on the development of non-parenteral routes which may prove more convenient, less costly and obtain improved patient compliance. Alternative potential delivery routes include transdermal, nasal, oral and bucal approaches, although most progress to date has been recorded with pulmonary-based delivery systems (Chapter 4). An inhaled insulin product ( Exubera , Chapters 4 and 11) was approved in 2006 for the treatment of type I and II diabetes. 

Disease Delivery route Treatment Vector or protein Investigator company Location... 

Many drugs can now be delivered rectally instead of by parenteral injection (intravenous route) or oral administration. Generally, the rectal delivery route is particularly suitable for pediatric and elderly patients who experience difficulty ingesting medication or who are unconscious. However, rectal bioavailabilities tend to be lower than the corresponding values of oral administration. The nature of the drug formulation has been shown to be an essential determinant of the rectal absorption profiles. The development of novel absorption enhancers with potential efficacy without mucosal irritation (low toxicity) is very important. The delivery of peptide and protein drugs by the rectal route is currently being explored and seems to be feasible. 

By considering these features, the enormous difficulties associated with overcoming the enzymatic barrier to peptide and protein delivery should be apparent. Degradation usually occurs at the site of administration and is possible in every anatomical site en route to the target receptor. Furthermore, protecting a single bond on a peptide or protein drag from a particular type of enzyme is insufficient to confer protection on the entire dmg from enzymatic hydrolysis—other enzymes may attack the protected bond and the other unprotected bonds on the dmg are still vulnerable. 

The use of penetration enhancers to improve drag absorption by variety of delivery routes is presently under investigation for example, various studies have recently been carried out to identify penetration enhancers to facilitate the absorption of peptides and proteins by various routes (Table 3.3). 

Proteins and peptides are accessible to enzymatic action due to the susceptibility of specific amino acid sequences, and such proteolysis is a naturally occurring metabolic process in vivo. Degradation pathways generally involve hydrolysis of peptide bonds by a variety of exopeptidases and endopeptidases, and the specific proteolytic enzymes associated with non-invasive routes of administration have been identified in some detail. Enzymatic activity varies depending on the delivery route and a qualitative rank ordering is shown in Table 1. Since a significant portion of dietary protein consumed by humans is assimilated by means... 

Considerations of commercial viability have likely influenced the extent of exploratory research activity on the various non-invasive delivery options available for protein and peptide delivery. Currently, the buccal/ sublingual, nasal, transdermal, pulmonary, and oral routes of administration are receiving the most attention in the scientific and patent literature with some technologies showing promise as potentially feasible commercial products. The following sections examine each of these non-invasive delivery routes in greater detail. 

The relatively non-invasive nature of transdermal drug delivery, and the fact that this route can simultaneously avoid problems associated with presystemic metabolism and mimic (at least, to some extent) parenteral input profiles, are significant advantages. There have been, therefore, diverse attempts to exploit the skin for peptide and protein delivery. As we have noted before, transdermal administration, with or without one or more enhancement technologies, will always be limited to potent drugs and this accounts, once more, for the effort devoted to peptide and protein (i.e., typically very active substances) administration via this route. 

Implantable delivery systems offer a number of advantages over more traditional delivery routes, particularly for biological macromolecules (including peptides, proteins, and oligonucleotides). Some specific delivery mechanisms to date include polymer depots (e.g., Gliadel Wafer, prolifeprosan 20 with carmustine implant) and osmotic pumps (e.g., Viadur leuprolide acetate implant). 

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