Delivery of biopharmaceuticals

Parenteral administration is not perceived as a problem in the context of drugs which are administered infrequently, or as a once-off dose to a patient. However, in the case of products administered frequently/daily (e.g. insulin to diabetics), non-parenteral delivery routes would be preferred. Such routes would be more convenient, less invasive, less painful and generally would achieve better patient compliance. Alternative potential delivery routes include oral, nasal, transmucosal, transdermal or pulmonary routes. Although such routes have proven possible in the context of many drugs, routine administration of biopharmaceuticals by such means has proven to be technically challenging. Obstacles encountered include their high molecular mass, their susceptibility to enzymatic inactivation and their potential to aggregate. 

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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. 

The progress in recombinant technology and molecular design and has allowed development of molecular instead of chemical modification to improve delivery of biopharmaceuticals. Chemical modifications require less effort and time than molecular approaches, which require sequence... 

The site of administration also influences their pharmacokinetic behavior. Following SC or IM administration, the bioavailability of biopharmaceuticals is often lower than with small molecules due to proteolysis during interstitial and lymphatic transit. Oral delivery of biopharmaceuticals is limited by barriers such as enzymatic and pH-dependent degradation in the gastrointestinal tract, low epithelial permeability, and instability under formulation conditions. Therefore biopharmaceuticals have an extremely low (<1%) and erratic bioavailability after oral administration [3]. 

Movement of penetrants across the mucous membranes is by diffusion. At steady state, the amount of a substance crossing the tissue per unit of time is constant and the permeability coefficients are not influenced by the concentration of the solutions or the direction of nonelectrolyte transfer. As in the epidermis of the skin, the pathways of permeation through the epithelial barriers are intercellular rather than intracellular. The permeability can be enhanced by the use surfactants such as sodium lauryl sulfate (a cationic surfactant). An unsaturated fatty acid, oleic acid, in a propylene glycol vehicle can act as a penetration enhancer for diffusion of propranolol through the porcine buccal mucosa in vitro. Delivery of biopharmaceuticals across mucosal surfaces may offer several advantages over injection techniqnes, which include the following ... 

Hamidi M, Zarrin A, Foroozesh M, et al. Applications of carrier erythrocytes in delivery of biopharmaceuticals. J Control Release 2007 118 145-160. 

In summary, it was demonstrated that chitosan capsules are stable in the stomach and the small intestine. However, in rats they were specifically degraded by microorganisms in the cecal contents on reaching the colon. Furthermore, it was shown that insulin absorption from the large intestine was improved by the co-ad-ministration of a variety of additives. Thus, these capsules may be useful carriers for the colon-specific delivery of biopharmaceuticals, including insulin. 

The delivery of biopharmaceuticals will also be the topic of the next section, which will present different drug delivery approaches, achievements as well as, limitations and future trends. 

Lee Y, Kataoka K (2009) Biosignal-sensitive polyion complex micelles for the delivery of biopharmaceuticals. Soft Matter 5 3810-3817. doi 10.1039/b909934d... 

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