Delivery, oral routes

Drug Delivery Oral Route, p. 1242. Gelatin-Containing Formulations Changes in Dissolution Characteristics, p. 1861. 

Delivery of peptides and proteins via the gastrointestinal tract has not been successful because of poor penetration through the intestinal epithelium and high levels of proteolytic activity in the gastrointestinal tract. Liposomal encapsulation of proteins and peptides will not improve the efficiency and capacity of this absorption pathway considerably (e.g., Ryman et al., 1982 Machy and Leserman, 1987 Weiner and Chia-Ming Chiang, 1988). These difficulties in delivery via the oral route caused the parenteral route to remain the preferred route for the administration of therapeutic peptides... 

Historically, the oral route of administration has been used the most for both conventional and novel drug-delivery systems. There are many obvious reasons for this, not the least of which would include acceptance by the patient and ease of administration. The types of sustained- and controlled-release systems employed for oral administration include virtually every currently known theoretical mechanism for such application. This is because there is more flexibility in dosage design, since constraints, such as sterility and potential damage at the site of administration, axe minimized. Because of this, it is convenient to discuss the different types of dosage forms by using those developed for oral administration as initial examples. 

A prodrug approach may be used to obtain maximum systemic concentration in the body by the oral route. The prodrug optimization of drug delivery may overcome several limiting factors such as... 

Most drugs are delivered at sites that are remote from their sites of action. Although the most convenient route of administration is the oral route, this presents significant challenges to the delivery of a drug molecule. Clearly, in order to be effective, an orally delivered drug must avoid several potential barriers. For example, it must ... 

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. 

Lead optimization of new chemical entities (NCEs) based on pharmacokinetic behavior plays a major role in modern drug discovery. Despite advancement of drug delivery methods, the oral route remains the most frequent route of administration for approved new drugs. Therefore, during lead optimization it is essential to identify NCEs with sufficient oral absorption predicted using a variety of in vitro and in vivo assays. It is well recognized that in order for a NCE to achieve reasonable oral absorption, it will need to have adequate aqueous solubility, as well as intestinal permeability [1], Recent advancements in chemistry, such as parallel and combinatorial synthesis, have resulted in a multifold increase in the number of compounds that are available for evaluation in new drug discovery. Furthermore, a variety of improved structural chemistry... 

Unfortunately, the referenced tables were not included with the report. Dr. Abramson told us that he had concluded that the inhalation route was approximately one-third as effective as the oral route. Abramson s ability to arrive at the same conclusion as we did almost ten years later is remarkable, considering that he did not have the benefit of the sophisticated delivery system, including controlled breathing, as we did in our later studies at Edgewood Arsenal. 

Testosterone (T.) derivatives for clinical use. T. esters for im. depot injection are T. propionate and T. heptanoate (or enanthate). These are given in oily solution by deep intramuscular injection. Upon diffusion of the ester from the depot, esterases quickly split off the acyl residue, to yield free T. With increasing lipophilicity, esters will tend to remain in the depot, and the duration of action therefore lengthens. A T. ester for oral use is the undecanoate. Owing to the fatty acid nature of undecanoic acid, this ester is absorbed into the lymph, enabling it to bypass the liver and enter, via the thoracic duct, the general circulation. 17-0 Methyltestosterone is effective by the oral route due to its increased metabolic stability, but because of the hepatotoxicity of Cl 7-alkylated androgens (cholestasis, tumors) its use should be avoided. Orally active mesterolone is 1 a-methyl-dihydrotestosterone. Trans-dermal delivery systems for T. are also available. 

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