Oral delivery systems

Oral delivery is usually the preferred system for drug delivery, owing to its convenience and the high level of associated patient compliance generally attained. Biopharmaceutical delivery via this route has proven problematic for a number of reasons  

Given such difficulties, it is not unsurprising that bioavailabilities below 1 per cent are often recorded in the context of oral biopharmaceutical drug delivery. Strategies pursued to improve bioavailability include physically protecting the drug via encapsulation and formulation as microemulsions/microparticulates, as well as inclusion of protease inhibitors and permeability 

Encapsulation within an enteric coat (resistant to low pH values) protects the product during stomach transit. Microcapsules/spheres utilized have been made from various polymeric substances, including cellulose, polyvinyl alcohol, polymethylacrylates and polystyrene. Delivery systems based upon the use of liposomes and cyclodextrin-protective coats have also been developed. Included in some such systems also are protease inhibitors, such as aprotinin and ovomucoids. Permeation enhancers employed are usually detergent-based substances, which can enhance absorption through the gastrointestinal lining. 

More recently, increasing research attention has focused upon the use of mucoadhe-sive delivery systems in which the biopharmaceutical is formulated with/encapsulated in molecules that interact with the intestinal mucosa membranes. The strategy is obviously to retain the drug at the absorbing surface for a prolonged period. Non-specific (charge-based) interactions can be achieved by the use of polyacrylic acid, whereas more biospecihc interactions are achieved by using selected lectins or bacterial adhesion proteins. Despite intensive efforts, however, the successful delivery of biopharmaceuticals via the oral route remains some way off. 

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Edwards-Levy, F., Andry, M. C. Levy, M. C. (1994). Determination of free amino group content of serum-albumin microcapsules. II. Effect of variations in reaction-time and terephthaloyl chloride concentration. International Journal of Pharmaceutics, Vol. 103, 3, (March 1994), pp. (253-257), ISSN 0378-5173 Friend, D. R. (2005). New oral delivery systems for treatment of inflammatory bowel disease. Advanced Drug Delivery Reviews, Vol. 57, 2, (January 2005), pp. (247-265), ISSN 0169-409X... 

The promise of the isolation and production of therapeutic polypeptides and proteins demands that for treatment of a chronic disease state an oral delivery system be developed which will protect these valuable agents from the hostile gastric environment. Subsequently, the drugs will have to be completely released in the intestine, preferably in a state that will enhance their rapid dissolution and transport across the gut wall minimizing interaction with intestinal proteases. 

Gazzaniga, A., Bussetti, C., Moro, L., Sangali, M.E., and Giordano, F., Time dependent oral delivery systems for colon targeting, STP Pharma. Sci., 5 83-88 (1995). 

Modi NB, Wang B, Noveck RJ, et al Dose-proportional and stereospecific pharmacokinetics of methylphenidate delivered using an osmotic, controlled-release oral delivery system. J Clin Pharmacol 40 1141-1149, 2000h... 

Constant release is not always the desired solution for controlled drug administration some therapeutic situations require consecutive pulses. A biphasic oral delivery system able to release an immediate dose of therapeutic agent as well as a further pulse of drug after some hours would, useful. In order to obtain such a desired release performance, a new system (three-layer tablet) has been designed with the following characteristics ... 

Leone, M.M., Nankervis, R., Smith, A., and Ilium, L. (2004). Use of the ninhydrin assay to measure the release of chitosan from oral delivery systems. Int. J. Pharmaceut., 271, 241-243. 

Kast, C.E., et al., Development aimdvivo evaluation of an oral delivery system for low molecular weight heparin based on thiolated polycarbopffihprm. Res., 20, 931,2003. 

Baluom, M., M. Friedman, and A. Rubinstein. 2001. Improved intestinal absorption of sulpiride in rats with synchronized oral delivery systems. J Contr Rel 70 139. 

Morcol, T., et al. 2004. Calcium phosphate-PEG-insulin-casein (CAPIC) particles as oral delivery systems for insulin. Int J Pharm 277 91. 

Al-Achi, A., and R. Greenwood. 1998. Erythrocytes as oral delivery systems for human insulin. Drug Dev Ind Pharm 24 67. 

Friend, D.R. 2005. New oral delivery systems for treatment of inflammatory bowel disease. Adv... 

Foger, F., T. Schmitz, and A. Bernkop-Schniirch. 2006. In vivo evaluation of an oral delivery system for P-gp substrates based on thiolated chitosan. Biomaterials 27 4250. 

H. G. Zerbe and M. Krumme. Smartrix system Design characteristics and release properties of a novel erosion-controlled oral delivery system, in Michael J. Rathbone, Jonathan Hadgraft, and Machael S. Roberts (eds.), Drugs and the Pharmaceutical Sciences, vol. 126 Modified-Release Drug Delivery Technology. New York Marcel Dekker, 2003, pp. 59-76. 

A. Gazzaniga, M. E. Sangalli, G. Maffione, and P. Iamartino, Time-dependent oral delivery system for colon-specific release, Proceed. Intern. Symp. Control. Rel. Bioact. Mater. 20 318-319 (1993). 

Oral Delivery Systems. The oral route of drug administration has been the most popular one, however, it is not without problems and constrains. First of all, the total gastrointestinal residence time limits the time frame or "window" for oral absorption. The... 

Precise information on the enzyme specificities, and particularly the quantity of enzyme activity present in the normal human colon is not easy to find, and underlines the principal that in the development of oral delivery systems either for therapeutic macromolecules or using macromolecules as part of pharmaceutical formulations, then in vitro testing is an essential and valuable tool as described in the next section. 

The human intestine has evolved as a highly efficient organ to digest (i.e. hydrolyse) practically all the macromolecules in the human diet (albeit with the help of a few trillion bacteria ) with the exception of some plant fibres. To do this it possesses a formidable array of enzymes. This is particularly true for the digestion of proteins and peptides where peptidases are found in the stomach, are secreted by the pancreas in considerable quantities and are found on the surface of and inside intestinal epithelial cells. These enzymes work in a co-ordinated fashion to rapidly hydrolyse proteins. They present the major difficulty for designing oral delivery systems for therapeutic peptides, which may explain why 86 years after the first attempt to orally administer insulin (Bliss 1982), there is still not an oral insulin product available for diabetics. 

Palmberger T.F., Hombach J., Bemkop-Schniirch A. (2008) Thiolated chitosan Development and in vitro evaluation of an oral delivery system for acyclovir. Int J Pharm, 348(l-2) 79-85. 

Lavelle EC, Charif S, Thomas NW, Holland J, Davis SS (1995) The importance of gastrointestinal uptake of particles in the design of oral delivery systems. Adv Drug Del Revs 18 5-22... 

Cationic thiomers are obtained from chitosan by reaction of thioglycolic acid with the primary amino groups in chitosan mediated by EDCCl. Thiomers are useful to formulate oral delivery systems for insulin, calcitonin and heparin. However, carbodiimide treated heparin may lose some of its anticoagulant properties. The potential of chitosan for the oral administration of peptides is also under consideration. ... 

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