Administration route permeability

The fate of injected liposomes is drastically altered by administration route, dose and size, lipid composition, surface modification, and encapsulated drugs. Liposomes encapsulating drugs are often administered iv, therefore, the stability of liposomes in plasma is important. When liposomes composed of PC with unsaturated fatty acyl chains are incubated in the presence of serum, an efflux of internal solute from the liposomes is observed. This increase in permeability is caused by the transfer of phospholipids to high density lipoprotein (HDL) in serum (55). To reduce the efflux of liposomal contents, cholesterol is added as a liposomal component... 

Recently, several in vitro experiments substantiated the potential of the human vaginal mucosa as a good administration route relating to the degree of permeation when compared with other mucosal surfaces. In fact, the vagina can be more permeable to some commonly used model substances, such as water, 17[3-cstradiol (Figure 3), arecoline, arecaidine, and vasopressin, than colonic or small intestinal mucosa, or at least as permeable as when compared to human buccal mucosa [46,47],... 

Absorption across biological membranes is often necessary for a chemical to manifest toxicity. In many cases several membranes need to be crossed and the structure of both the chemical and the membrane need to be evaluated in the process. The major routes of absorption are ingestion, inhalation, dermal and, in the case of exposures in aquatic systems, gills. Factors that influence absorption have been reviewed recently. Methods to assess absorption include in vivo, in vitro, various cellular cultures as well as modelling approaches. Solubility and permeability are barriers to absorption and guidelines have been developed to estimate the likelihood of candidate molecules being absorbed after oral administration. ... 

Class IV drugs have low aqueous solubility and poor membrane permeability and as such are often considered as poor drug candidates for oral administration. Other routes of administration may need to be considered. For example, neomycin falls into this category, and its oral use is to achieve sterilization of the gut. There is too little information about these compounds and the effect of food to offer general observations. 

Where an unusual excipient is chosen, or where an established excipient is chosen for a dosage form that results in its administration by a novel route of administration, then additional data will need to form part of the application. In effect, a novel excipient will need to be supported by data similar to those required for a new drug, with full supporting data including composition, function, and safety. Novel excipients include the components of the matrix in prolonged release products, new propellants, and new permeability enhancers. The exception to this need for extensive supporting data would be for a material already approved for food use and administered by the oral route or a material already approved for cosmetic use with a topical route of administration. In all cases the quality of the excipients has to be described adequately and shown to be satisfactory (which will depend on its role). 

Research studies investigating exposure to JP-8 via oral administration offers an alternative examination of the systemic effects of JP-8 on immune function. Admittedly, this does not ideally mimic occupational exposures, but it does eliminate technical limitations associated with inhalation and dermal penetration of JP-8. It has been suggested that the only route available that can assess the whole mixture (JP-8 in its entirety), without fractionation due to volatilization of components, is the oral route [1] as select components of JP-8 may have increased permeability during dermal exposure, other specific components may be enriched following inhalation exposures[71]. 

The ex vivo methods lend themselves easily for the performance of mechanistic investigations. In order to optimize selection of drug candidates prior to further clinical development, it is important to decipher the contributive roles of permeation, metabolism, efflux, and toxicity. This will then make it possible to properly channel the optimization process, for instance, by permeation enhancement, mucoadhesion, modification of the physicochemical characteristics of the drug, or even change in the route of administration in case the drug and/or formulation turns out to be too toxic. Regarding permeability studies, it is possible not only to quantify passive diffusion but also to identify and characterize (compound)-specific carrier-mediated transport routes. These tools have been used to identify and characterize the relative contribution of... 

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... 

In general, when the cells of the endothelium in the lungs are the target cells of interest (see Chapters 7 and 9 on aspects of targeting drugs to endothelium in inflammatory diseases and cancer, respectively), systemic administration seems the route of choice. Bronchial epithelium on the other hand can more easily be reached via the pulmonary route. The accessibility of other cells in the lungs is most hkely governed by disease conditions, factors that can affect epithehal permeability and vascular permeability, and others as described earher. 

Pharmacokinetics plays a very important role in the manner in which opioids are abused. Morphine and many of its derivatives are slowly and erratically absorbed after oral administration, which makes this route suitable for long-term management of pain but not for producing euphoria. In addition, opioids undergo considerable first-pass metabolism, which accounts for their low potency after oral administration. Heroin is more potent than morphine, although its effects arise primarily from metabolism to morphine. The potency difference is attributed to heroin s greater membrane permeability and resultant increased absorption into the brain. 

For liquid (e.g., solution, suspension, elixir) and semisolid (e.g., creams, ointments) dosage forms in permeable or semipermeable container closure systems, a change to an ink and/or adhesive used on the permeable or semipermeable packaging component to one that has never been used in a CDER-approved product of the same dosage form, same route of administration, and same type of permeable or semipermeable packaging component (e.g., low density polyethylene, polyvinyl chloride). 

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