Excipients or auxiliary materials are used to formulate a delivery system for a drug to achieve optimal therapeutic effects. They should be able to deliver the drug at the right place at the right time and with the right dose with the optimal delivery characteristics. Basically, an excipient has to fulfill the same safety profile as a drug with the exception that it should not exert a therapeutic effect. Most excipients do comply with these requirements and do have the GRAS (generally regarded as safe, a system used by the US FDA) status when used in those amounts which are normally used to fabricate a drug delivery system.
However, various substances that are commonly used as excipients do not show complete inertness, but may have additional effects on the tissues of the absorption sites which are not intended, because the excipients are primarily used for another purpose. Many surfactants are used in a drug delivery system either as a wetting agent or as a lubricant. Others are used as a solubilizer for poorly soluble drugs. Depending on their unique structure as amphiphilic compound combining hydrophilic and lipophilic characteristics those compounds also may interact with the tissue of the mucosal surfaces and change (transiently) their structure allowing for improved absorption of especially hydrophilic and high molecular weight drugs. In order to improve the bioavailability of poorly absorbable drugs the nuisance of these surfactant compounds has turned into their primary intended action as absorption enhancers.
However, in many cases there is a direct relationship between absorption enhancing effect and toxicity of the used low molecular weight surfactants as transmucosal absorption enhancers, which excludes them for therapeutic use and hampers their commercialization especially if the poorly absorbable drug is meant for chronic use.
According to Barry (1983), an ideal absorption enhancer should have the following desirable attributes:
• The absorbing enhancing action should be immediate and unidirectional, and the duration of the effect should be specific, predictable, and suitable.
• After removal of the material from the applied membrane, the tissue should immediately fully recover its normal barrier property.
• The enhancer should show no systemic and toxic effects.
• The enhancer should not irritate or damage the applied membrane surface.
• The enhancer should be physically compatible with a wide range of drugs and pharmaceutical excipients.
• The enhancer should be applicable for chronic use.
As evident from the above points, we are currently far from having an absorption enhancer available that fulfills all the requirements. Furthermore, no knowledge is available about the long-term application of such low molecular weight absorption enhancers.
Although a lot of information is available in the literature about the efficacy and safety profile of most of the surfactants to be used as absorption enhancers, little knowledge is still available about the possible interference of these compounds with the inherent transporter systems of the cells. Such effects may become crucial when a biowaiver is granted for a drug substance that is predominantly actively absorbed via transporter systems and when the innovator product may use excipients that do not interfere with these transporter systems. When an excipient used in the multi source (generic) product does or when a different excipient used in the other formulation, these may account for strong differences in drug absorption.
There have been many attempts to search for new and safer absorption enhancers especially with respect to improving absorption of hydrophilic compounds with high molecular weight such as peptides, insulin, calcitonin, etc. These have become available in the last two decades in sufficient and affordable amounts due to the progress in biotechnology and which are used for chronic therapy mostly by injection. The development of suitable alternative delivery systems (for the nasal, buccal, rectal, vaginal, ocular, and peroral route) (yet) have not kept pace with the availability of endogenous peptides because of the lack of suitable absorption enhancers for this class of substances. However, it turned out rather surprisingly that special polymers, which show mucoadhesive properties, also are able to act as safe penetration enhancers for improved drug absorption of especially hydrophilic (peptide) drug substances.
This chapter aims to classify the existing types of absorption enhancers according to their mode of action, and to introduce the new categories of polymeric absorption enhancers for hydrophilic compounds.
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