Administration routes biopharmaceutics

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. 

Once the physicochemical and biopharmaceutical properties of the drug are determined and the desired plasma concentration profile is defined, the pharmaceutical scientist can select and develop an efficacious dosage form by utilizing a formulation approach, a prodrug approach, a device approach, or an alternative administration route approach. 

Since oral administration is the most common and useful, there are many opportunities in developing oral dosage forms. The oral route faces several obstacles to drug absorption, such as the first pass effect, individual variabihty of bioavailability, and drug-induced local irritation to gastric and intestinal mucosa. According to the US Food and Drug Administration (FDA) Biopharmaceutics Classification System... 

Section 16.2.6 discusses biopharmaceutics of nasal preparations fi om a general biopharmaceutics viewpoint. This subsection adds some more specific details, first on the nasal absorption and then on the many investigations on absorption enhancing substances. The interest for nasal absorption is predominantly raised by the desire to find an alternative administration route for systemically acting active substances. 

Despite tremendous innovations in the field of drug delivery technology, oral intake remains the preferred route of drug administration, for reasons of patient convenience and therapy compliance. Compounds intended for oral administration must have adequate biopharmaceutical properties in order to achieve therapeutic concentrations at the targeted site of action. 

The transformation of a drug into a medicinal product is a complex process that is controlled by a range of competing factors. The formulator must amalgamate the preformulation information and the clinical indication, which may suggest a particular route of administration (e.g. inhalation of salbutamol. Table 2.2), with toxicology and biopharmaceutical data determining... 

By this we mean interactions that occur after the medicine has been administered to the patient. For the most part, they are physical interactions. However, the major distinctions are that the interaction is between the medicine (including excipients) and the body fluids, primarily comprising aqueous solutions, and that they have the potential to influence the rate of absorption of the drug. They will vary depending on the route of administration. Because physiological and biopharmaceutical interactions are so important, and they are not specifically linked, for example, to the stability of the medicinal product, and also because they occur after the medicine has been administered to the patient, they have been included as a special category for the purposes of this discussion. The importance and potential impact of biopharmaceutical interactions of excipients has been recognized for some years (see for example Ref. 29). 

Due to the lack of activity after oral administration for most peptides and proteins, administration by injection or infusion - that is, by intravenous (IV), subcutaneous (SC), or intramuscular (IM) administration - is frequently the preferred route of delivery for these drug products. In addition, other non-oral administration pathways have been utilized, including nasal, buccal, rectal, vaginal, transder-mal, ocular, or pulmonary drug delivery. Some of these delivery pathways will be discussed in the following sections in the order of the increasing biopharmaceutic challenges to obtain adequate systemic exposure. 

Various characteristics of the molecule influence its chances of reaching its target receptor since they influence the nature and extent of the body s effect on it. A drug s pharmacokinetic profile therefore determines the extent of the drug s opportunity to exert its pharmacodynamic effect. While there are various routes for human drug administration (oral rectal intravenous, subcutaneous, intramuscular, and intra-arterial injections topical and direct inhalation into the lungs), the most common for small-molecule drugs is oral administration, and discussions in the first part of this chapter therefore focus on oral administration. (In contrast, biopharmaceuticals are typically administered by injection, often directly into the bloodstream.)... 

Despite the significant development in the biopharmaceutical area in recent years, many challenges have yet to be overcome. Among the main obstacles faced by companies are the development of improved formulations and new routes of administration, as well as the delivery of the active molecules to the site of therapeutic action. Many biopharmaceuticals present limitations of low stability in vitro (shelf-life) or in vivo (half-life after injection in the patient), and low solubility and bioavailability (Muller and Keck, 2004). 

With the advent of new biotechnological techniques endogenous compounds like insulin, buserelin or octreotide have become available at affordable prices. All of these substances still have to undergo needle application. Until today the development of alternative delivery systems for the nasal, buccal, peroral, rectal and pulmonary routes for the administration of those class III drugs according to the biopharmaceutics classification system (BCS) (Amidon et al. 1995) could not keep pace with this development of endogenous compounds or is not economic enough for the health care payers (e.g. insulin application via the pulmonary route). 

The vagina is a possible site for the systemic administration of various drugs. However, the low and erratic bioavailability of biopharmaceuticals via this route necessitates the use of absorption enhancers. Until safe, non-toxic absorption enhancers can be found, the route is of limited potential. A further major limitation of this route is the lack of reproducibility resulting from cyclic changes in the reproductive system. Finally, no matter what degree of optimization can be achieved via this route, it can only ever benefit approximately 50% of the population ... 

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