Parenterally active peptides

The first significant advances towards parenterally-active opioid peptides were made by a Sandoz group (Roemer et al., 1977 Pless et al., 1979). Within the pentapeptide [D-Ala2,MePhe4,Met(0)-ol5]enkephalin (FK 33-824, DAMME) several approaches towards a stable enkephalin analog have been combined. FK 33-824 has been reported to be several orders of magnitude more potent than morphine when applied i.c.v. and to be orally active. 

The oral mucosal route offers a number of advantages over parenteral and other non-invasive routes for the systemic delivery of biologically active peptides and proteins as well as conventional dmgs [78]. However, most drugs absorbed via the... 

Delivery of peptides and proteins via the gastrointestinal tract has not been successful because of poor penetration through the intestinal epithelium and high levels of proteolytic activity in the gastrointestinal tract. Liposomal encapsulation of proteins and peptides will not improve the efficiency and capacity of this absorption pathway considerably (e.g., Ryman et al., 1982 Machy and Leserman, 1987 Weiner and Chia-Ming Chiang, 1988). These difficulties in delivery via the oral route caused the parenteral route to remain the preferred route for the administration of therapeutic peptides... 

AstraZeneca is developing a series of selective non-peptidic 5 opioid receptor agonists for the treatment of neuropathic pain. The compounds (e.g. cpd., 1) are in preclinical studies. In vivo, they are effective analgesics with negligible tolerance and dependence. They have parenteral and oral activity with suitable pharmacokinetics and pharmacodynamics. 

One major disadvantage of peptide active substances is their denaturation and enzymatic degradation in the gastrointestinal tract, which mean that at present only parenteral, sublingual, or intranasal administration is possible. 

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. 

Of the thymic hormones currently undergoing clinical evaluation, the most detailed pharmacokinetic studies have been performed with TF5 and Tuj. The parenteral administration of TF5 has been associated with the generation of detectable serum thymic hormone bioactivity as detected in the Bach-Dardenne assay (Iwata et ah, 1981). A 10-year-old child with chronic mucocutaneous candidiasis treated with TF5 showed a prompt rise of serum FTS-like bioactivity that persisted within the normal range for several weeks following the discontinuation of treatment, but which eventually returned to low levels (Iwata et ah, 1981). These studies have clearly demonstrated that the parenteral administration of TF5 generates detectable serum bioactivity. However, it cannot be determined which of the peptides present in TF5 gave rise to the serum activity. 

---