Oral delivery of peptides

Leuprolide acetate, a synthetic nonapeptide, is prescribed for the treatment of metastatic prostate cancer and endometriosis. Leuprolide acetate is presented in a number of injectable dosage forms including Lupron sterile solution for subcutaneous administration (1 and 5 mg mL 1) and Lupron depot controlled release formulation for intramuscular injection (3.75 and 7.5 mg). Zheng and Fulu [106] have evaluated the in vivo effect of leuprolide loaded micro emulsions on the genital organs of the male and female rats. In the preliminary pharmacokinetic studies, oral microemulsions of leuprolide administration resulted in 10-fold higher plasma levels of leuprolide as compared to that of saline solution (Fig. 9.4). 

---

Jung, T., Kamm, W., Breitenbach, A., Kaiserling, E., Xiao, J.X., Kissel, T., Biodegradable nanoparticles for oral delivery of peptides Is there a role for polymers to affect mucosal uptake Eur J Pharm Biopharm 50, 147-160 (2000). 

Saffran, M., Kumar, G.S., Neckers, D.C., Pena, J., Jones, R.H., and Field, B., Biodegradable azopolymer coating for oral delivery of peptide drugs, Biochem. Soc. Trans., 18 752-754 (1990). 

Besides parenteral application of microspheres and nanoparticles for cell selective delivery of drugs, they have more recently been studied for their application in oral delivery of peptides and peptidomimetics [30]. Immunological tolerance induction against beta-lac-toglobulin could be achieved by application of this protein in a poly-lactic-glycolide microsphere formulation [31]. 

Despite the fact that these polymers show delivery patterns comparable to gastric transit, there have not been any substantial reports of oral delivery of peptides or proteins based on this type of polymer. Further investigations into this polymer may... 

Bemkop-Schntirch, A. and Scerbe-Saiko, A. (1998). Synthesis and in vitro evaluation of chitosan/EDTA/protease inhibitor conjugates which might be useful in oral delivery of peptides and proteins. Pharmaceut. Res., 15, 263-369. 

Geary, R.S., and H.W. Schlameus. 1993. Vancomycin and insulin used as models for oral delivery of peptides. J Control Release 23 65. 

Mahato RI, Narang AS, Thoma L, Miller DD. Emerging trends in oral delivery of peptide and protein drugs. Crit Rev Ther Drue Carrier Syst. 2003 20 153-214. 

Iwanaga, K., Ono, S., Narioka, K., et al. Application of surface-coated liposomes for oral delivery of peptide effects of coating the liposome s surface on the GI transit of insulin. -/. Pharm. Sci. 88 248—252, 1999. 

Most peptides and proteins are currently formulated as parenteral formulations because of their poor oral bioavailability. Nevertheless, oral delivery of peptides and proteins would be the preferred route of administration if bioavailability issues could be overcome, as it offers the advantages of convenient, pain-free administration. Although various factors such as permeability, chemical and metabolic stability and gastrointestinal transit time can affect the rate and extent of absorption of orally administered peptides and proteins, molecular size is generally considered the ultimate obstacle [36]. 

Several promising strategies have emerged from the intensive recent research efforts into the oral delivery of peptides and proteins [6, 36, 37]. Absorption enhancers may be used either to temporarily disrupt the intestinal barrier so that drug... 

Bayat, A., Sadeghi, M.M., Avadi, M.R., Amini, M, Rafiee-Tehrani, M., Shafiee, A. and Junginger, H.E. (2006) Synthesis of A-A dimethyl A-ethyl chitosan as carrier for oral delivery of peptide drugs. J. Bioact. Compat Polym. 21 433-444. 

Mi, F. L., Y. Y. Wu, et al. (2008). Oral delivery of peptide drugs using nanoparticles self-assembled by poly(gamma-glutamic acid) and a chitosan derivative functionalized by trimethylation. Bioconjug Chem 19(6) 1248-55. 

Liposomal formulations are one of the most promising particulate carriers and have been used for several years for oral delivery of peptide drugs such as... 

These polymer-coated liposomes showed high potency in oral delivery of peptide drugs such as insulin and calcitonin, mainly because of the mucoadhe-sion of the chitosan-coated liposomes to the intestinal tract (Takeuchi et al. 1996, 2001,2003,2005a). Similar trials have been reported by Guo et al. (2003), who investigated the effect of chitosan concentration and lipid type on the characteristics of chitosan-coated liposomes and their interactions with leupro-lide. They found that a thicker adsorptive layer could be realized by using low... 

In the gastrointestinal tract, the enzymatic barrier is probably the most significant obstacle to the successful oral delivery of peptides and proteins, as demonstrated by the following observations ... 

Ability to maintain a constant drug input in the colon for up to 24 h or to deliver drug over an interval as short as 4 h Oral delivery of peptides and proteins. The system can be used to study colonic absorption in humans prior to development of colon-specific delivery systems. 

In the past 2 decades, significant progress has been made in the oral delivery of peptides and proteins that... 

While injection has served as the primary means of delivering macromolecules produced by biotechnology, many non-invasive routes have been explored as alternatives. Oral delivery remains the most common method of delivery for most small molecule drugs. However, oral delivery most often does not work for macromolecules because proteins are digested before they have an opportunity to reach the bloodstream. Commercially successful oral delivery of peptides and proteins has not been achievable with the exception of DDAVP (9 amino acids) and cyclosporin (11 amino acids), two digestion resistant small peptides. 

Allemann, E. Leroux, J. Gurny, R. Polymeric nano- and microparticles for the oral delivery of peptides and peptidomimetics. Adv. Drug Deliv. Rev. 1W8, 34 (2-3),... 

In conclusion, although oral delivery is the preferred route for peptide and protein drugs, there are many drawbacks, as addressed previously. Successful oral delivery of peptide and protein drugs is likely to remain a formidable challenge for some time. 

Sawada, T, Sako, K., Nakashina, H., Fukui, M., and Ohmura, T. Exploitation of novel time-release dosage forms for oral delivery of peptide drugs. AAPS PharmSci 1(1 Suppl.), 1998. 

Thus far, the universal application of this transport system for the oral delivery of peptides and proteins seems to be hampered only by its limited uptake capacity 1 nmol per dose. Even though this amount of uptake may be adequate for molecules such as LHRH or... 

---