Peptides oral administration

SS Davis. Overcoming barriers to the oral administration of peptide drugs. J Pharm Sci 11 353-355, 1990. 

G Gwinup, AN Elias, ES Domurat. Insulin and C-peptide levels following oral administration of insulin in intestinal-enzyme protected capsules. Gen Pharmacol 22 143-246, 1991. 

The oral administration of large proteins and peptides is limited due to their low membrane permeability. These compounds are mainly restricted to the para-cellular pathway, but because of their polar characteristics and their size the pore of the tight junctional system is also highly restrictive. An additional transcellular pathway has therefore been suggested for these peptides, i.e., the transcytotic pathway, which involves a receptor-mediated endocytosis in Caco-2 cells [126],... 

The addition of PEG to the gels was critical because the PEG chains participate in the macromolecular complexes, function as a peptide stabilizer and enhance the mucoadhesive characteristics of the gels. In this work, strong dose-dependent hypoglycemic effects were observed in healthy and diabetic rats following oral administration of these gels. 

Table 1 summarizes the antihypertensive effects of ACE inhibitory small peptides. Information of dosage is also listed. It is clear that small peptides can exert an antihypertensive action following oral administration to mild hypertensive subjects, similar to therapeutic ACE inhibitory drugs, despite their poor potency on ACE inhibitory activity. It seems likely that ca. 20-fold higher doses of small peptides than drugs are required to... 

It has been clarified that absorbed VY was accumulated in the kidney and aorta in orally administrated SHR, along with the suppression of local ACE activities in both organs (Eig. 2). This finding suggested that both organs must be a targeted tissue for antihypertensive VY. The report that therapeutic ACE inhibitor captopril controlled vessel fimctions also allowed us to consider the potential role of ACE inhibitory small peptides in contracted vessels. 

Masnda O, Nakamura Y, Takano T. (1996) Anti-hypertensive peptides are present in aorta after oral administration of sour milk containing these peptides to spontaneously hypertensive rats. JNutr 126 3063-3068. 

TVpes of preparations (B). As a peptide, insulin is unsuitable for oral administration (destruction by gastrointestinal proteases) and thus needs to be given parenterally. Usually, insulin preparations are injected subcutaneously. The duration of action depends on the rate of absorption from the injection site. 

Gly-Asn-Leu-Tyr-Pro-Gly (Table 4.1). The purified peptide was evaluated for antihypertensive effects in SHRs following oral administration. 

FIGURE 4.3 Antihypertensive activities of ACE-inhibitory peptides after single oral administration in SHRs. SHRs were administered captopril (O), the ACE-inhibitory peptide from rotifer ( ) at a dose of 50mg/kg. Changes in systolic blood pressure were expressed as mean SE [n—5). Statistical analyses were done by Student t-test (P<0.05) (Skeggs et at., 1957). 

Asn-Pro, Asp-Met, Asp-Leu, Ala-Val, and Gly-Val were isolated from fermented sardine sauce further, the ACE-inhibitory peptides Ala-Pro, Arg-Pro, Gly-Pro, and Ala-Gly-Pro were isolated from fermented bonito sauce. Val-Pro was also identified in salted and fermented anchovy by Lee (1996). Among the peptides identified by Ichimura et al. (2003), Ala-Pro, Lys-Pro, and Arg-Pro showed strong and similar inhibitory activity. Ichimura et al. (2003) also isolated nine types of peptides containing Pro residues in their carboxy terminals. Due to the unique structure of Pro as an imino acid, peptide bonds containing Pro residues are often resistant to hydrolysis by common peptidases. This may be the reason why these Pro-containing dipeptides survived after long-term fermentation. Among these peptides, Lys-Pro was further evaluated in vivo in male SHRs (Charles River Japan, Yokohama) by oral administration. As shown in Fig. 5.3, orally administered Lys-Pro shows a tendency to lower the blood pressure of SHRs. 

Hideaki, K., Masayoshi, K., Shigeru, S., Chiyo, D., Kunio, D., Nobuyasu, M., and Toshio, S. (1993). Oral administration of peptides derived from bonito bowels decreases blood pressure in spontaneously hypertensive rats by inhibiting angiotensin converting enzyme. Comp. Biochem. Physiol. C 104, 351-353. 

Another subclass of proteases attacks internal peptide bonds and liberates large peptide fragments. Bromelain, a plant protease derived from the stem of the pineapple plant, can even produce detectable serum proteolysis after oral administration (180). Oral therapy with bromelain significandy reduces bruising that stems from obstetrical manipulations (181). Bromelain—pancreatin combinations have been more effective in digestive insufficiency compared to either pancreatin or placebo (182,183). Bromelain may also enhance the activity of antibiotics, especially tetracycline, when administered concurrendy (184). 

In a mouse model of aerosol sensitization to birch pollen we previously demonstrated that intranasal as well as oral administration of the major birch pollen allergen Bet v 1 prevented allergic sensitization, airway inflammation and airway hyperresponsiveness [28], Similar effects were achieved using hypoallergenic derivates of Bet v 1, containing the immunodominant T cell peptides but not the anaphylactogenic B cell epitopes, for intranasal tolerance induction [60],... 

Therapeutic peptides, proteins, and peptidomimetics are getting increasingly important. These compounds are degraded in the first instance by luminally secreted and brush border membrane-bound proteases. Because of their hydrophilic character and comparatively large size, they are usually uptaken via the paracellular route after oral administration. 

Aprotinin is a polypeptide consisting of 58 amino acid residues derived from bovine lung tissues and shows inhibitory activity toward various proteolytic enzymes including chymo-trypsin, kallikrein, plasmin, and trypsin. It was also one of the first enzyme inhibitors used as an auxiliary agent for oral (poly)peptide administration. The co-administration of aprotinin led to an increased bioavailability of peptide and protein drugs [5,44,45], The Bowman-Birk inhibitor (71 amino acids, 8 kDa) and the Kunitz trypsin inhibitor (184 amino acids, 21 kDa) belong to the soybean trypsin inhibitors. Both are known to inhibit trypsin, chymotrypsin, and elastase, whereas carboxypeptidase A and B cannot be inhibited [7,46],... 

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. 

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