Peptides delivery routes

Yamamoto A, Hayakawa E, Lee VH (1990) Insulin and proinsulin proteolysis in mucosal homogenates of the albino rabbit Implications in peptide delivery from nonoral routes. Life Sci 47 2465-2474... 

Wearly LL (1991) Recent progress in protein and peptide delivery by non-invasive routes. Crit. Rev. Ther. Drug Carrier 8 331-394. 

Hydrophobic polymers are often used to deliver biomacromolecules regardless of the route of administration. The rapid transit time of approximately 8 hours limits the time of a device in the gastrointestinal (GI) system, consequently the mechanisms possible for oral drug release are limited. The predominant method of release from hydrophobic polymers has been degradation, or biodegradation, of a polymeric matrix by hydrolysis (Figure 11.1). In fact, all of the hydrophobic polymers described in this chapter for use as oral protein or peptide delivery are hydrolytically unstable. 

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. 

In order to overcome these issues, various noninvasive routes are tested for the delivery of peptides. The oral mucosa due to its high vascularity, avoidance of hepatic first-pass metabolism, and the absence of degradative enzymes normally present in the GI tract has been explored as a suitable route for peptide delivery. Several studies of peptide absorption through the oral mucosa have been conducted, and the results have been impressive in some cases, and not in the others. The development of mucoadhesive systems for buccal and sublingual delivery has increased the absorption and bioavailability of peptides, and various formulations have been developed using these systems. 

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). 

No matter what degree of optimization can actually be achieved via this route, it must be remembered that vaginal delivery is only applicable to approximately 50% of the population. Thus it may be that the true potential of this route lies in the treatment of female-specific conditions, such as in the treatment of climacteric symptoms of the menopause etc., rather than more general applications such as insulin/peptide delivery. 

An important question is how to achieve the most efficient delivery of PNA. This problem does not usually have a definite answer and many different factors must be considered. Table 1 reviews the main types of PNA-peptide conjugates and indicates the most important issues in each case. The internalization routes are schematically drawn in Fig. 2. Depending on the peptide attached, the PNA oligomer is internalized via endocytosis or directly delivered across the cell membrane. For nuclear localization signals (NLS) and tetralysine (K4) the delivery route is not clear yet. The same holds true for nuclear delivery with CPPs. Some CPPs (e.g., transportan) have been shown to accumulate in the nucleus, while others have not. 

Teng, C.L.D. Groves, M.J. The effect of compactional pressure on urease activity. Pharm. Res. 1988, 5, 776-780. Alur, H.H. Paher, S.I. Mitra, A.K. Johnston, T.P. Transmucosal sustained delivery of chlorpheniramine maleate in rabbits using a novel, natural mucoadhesive gum as an excipient in buccal tablets. Int. J. Pharm. 1999,188, 1-10. Kondo, S. Sugimoto, I. Moment analysis of intravenous, intraduodenal, buccal, rectal, and percutaneous nifedipine in rats. J. Pharmacobio. Dyn. 1987, 10, 462 69. Yamamoto, A. Hayakawa, E. Lee, V.H. Insulin and proinsulin proteolysis in mucosal homogenates of the albino rabbit implications in peptide delivery from nonoral routes. Life Sci. 1990, 26, 2465-2474. 

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. 

Keywords Drug delivery systems Targeted drug delivery Nanoparticles Nanobiotechnology Personalized medicine Routes of drug administration Drug delivery devices Controlled release Protein/peptide delivery Drug formulations... 

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). 

Therapeutic proteins and peptides have gained a significant market interest owing to their increased development and applicability to multiple disease conditions (Chin et al., 2012 Park et al., 2011). For the systemic delivery of therapeutic peptides and proteins, parenteral administration is currently believed to be the most efficient route and also the delivery method of choice to achieve therapeutic activity compared with transdermal, pulmonary, nasal, oral, and buccal delivery routes (Fig. 11.4) (Muranishi, 1985 Lennemas, 1995 Ghilzai, 2004). But, for the usually faced chronic conditions, patients find the use of daily injections both unpleasant and difficult to be self-administered. 

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