Showing papers in "Critical Reviews in Therapeutic Drug Carrier Systems in 1991"

Cell cultures as models for drug absorption across the intestinal mucosa

Abstract: This review deals with cell culture models for studies of drug absorption across the intestinal mucosa. The selection of appropriate cells and cell culture conditions is discussed, guidelines for the characterization of the cell models are presented, and the intestinal barriers to drug absorption are discussed and compared with those in the cell culture models. Finally, recent applications of the cell culture models in drug and peptide absorption and metabolism studies are reviewed.

Cellular and molecular basis of barrier function in oral epithelium.

Abstract: The use of the oral mucosa for drug delivery and the erroneous belief that it is a nonkeratinized tissue have given rise to the suggestion that the oral mucosa is a permeable tissue. Such an assumption is not supported by studies which indicate that permeability differs significantly in different oral regions, depending on the pattern of epithelial differentiation. Keratinized regions such as hard palate and gingiva have a permeability which is significantly less than nonkeratinized regions like buccal mucosa and floor of mouth. Nevertheless, all oral regions are more permeable than skin. Associated with these differences in permeability are differences in the type and amount of intercellular lipid; areas of keratinized tissue contain predominantly neutral lipids (ceramides) apparently derived from lamellate membrane-coating granules. In nonkeratinized areas, the lipids consist of as yet uncharacterized glycosyl ceramides that appear to be derived from membrane-coating granules that differ morphologically from those present in nonkeratinized tissue.

Developments in buccal drug delivery.

Abstract: The buccal mucosa offers excellent possibilities for the (long-term) delivery of suitable drugs, especially for metabolically unstable drugs, such as peptides. A review is given of the present knowledge about buccal drug absorption and drug delivery devices. The structure and physiology of the oral mucosae are described, as well as interspecies differences with respect to tissue permeability. Methods to determine mucosal drug absorption, either in vivo or in vitro, are discussed, as well as absorption pathways, mechanisms, and enhancement. Technological strategies to control transbuccal drug absorption comprise the design of mucoadhesive devices in order to shorten diffusion pathways and prolong administration, and structural and chemical modulation of the device with the aim of shifting the rate-limiting transport step from the tissue to the device. Finally, examples of buccally administered drugs are given and devices currently used in local therapy are described.

Hydrophilic matrix sustained release systems based on polysaccharide carriers.

Abstract: The hydrophilic matrix (HM) continues to be a popular and widely used strategy for sustained-release drug delivery, with polysaccharides and their derivatives being the polymers of choice as the rate-controlling carriers for these systems. This review provides an appraisal of the more recent developments in the design and in our understanding of the behavior of HM systems. It also focuses on areas of current interest not encompassed by previous reviews.

Recent progress in protein and peptide delivery by noninvasive routes.

Abstract: Much progress has been made in the last 5 years toward delivery of protein and peptide drugs by noninvasive routes. The obstacles of instability, poor absorption, rapid metabolism, and nonlinear pharmacokinetics are great challenges for which some solutions are now emerging. Structural modifications of the protein by chemical or recombinant means have improved stability and minimized enzymatic cleavage in some cases. Protection of the protein or peptide drug via liposomes or polymers also offers a means for increasing stability and prolonging half-life. Novel permeation enhancers, which show minimal irritation to mucosal membranes, have become available and show promise for increasing absorption of proteins delivered by a number of noninvasive routes. There are examples in which several of these methods have been used concomitantly to achieve maximum effect; for instance, a bioadhesive microsphere formulation containing a novel permeation enhancer was used to maximize nasal delivery of insulin. Therefore, general methods exist whereby delivery by any noninvasive route may be improved. In some cases, choice of the best route of delivery for a particular drug makes the difference between success and failure. A comparison of the enzyme activity at the various sites of delivery is helpful and, fortuitously, the enkephalins, model peptides whose rate of cleavage and type of degradation products offer information about the type and activity of enzymes present, have been studied extensively. This work is reviewed for each delivery site as are the effects of coadministration of enzyme inhibitors. Permeation enhancers and examples for their use at each site of delivery are presented. The use of polymers for bioadhesion and for protection from metabolism at various sites is reviewed. Since systemic delivery of proteins via the pulmonary route is now receiving more attention, special emphasis is given to that work. Generally, the focus is on work published or presented since 1988, since publications prior to that date have already been thoroughly reviewed. The studies presented indicate that the problems of delivering protein and peptide drugs by noninvasive means can be minimized; although delivery by these routes still may not be bioequivalent to invasive methods, the convenience to the patient will, in some cases, outweigh the demand for complete bioequivalence.

Gamma scintigraphy and neutron activation techniques in the in vivo assessment of orally administered dosage forms.

Abstract: Earlier applications of external scintigraphy to pharmaceutical research have been reviewed. This article will concentrate mainly on recent applications of the technique to the study of the in vivo behavior of solid oral dosage forms

The regulation of epidermal lipid synthesis by permeability barrier requirements.

Abstract: A major function of the skin is to prevent the loss of fluids. The barrier to fluid loss resides in the intercellular lipids (primarily sterols, fatty acids, and sphingolipids) of the stratum corneum. The epidermis is a very active site of lipid synthesis and when the permeability barrier is disrupted by topical solvents or detergents a marked stimulation of sterol, fatty acid, and sphingolipid synthesis occurs. Essential fatty acid deficient mice, with a chronic disturbance in barrier function, also have an increase in epidermal lipid synthesis. When the defect in barrier function is artificially corrected by occlusion with a water vapor impermeable membrane the increase in epidermal lipid synthesis is prevented, suggesting that water flux may be a regulatory factor. The activity of the key rate limiting enzyme in cholesterol synthesis, HMG CoA reductase is increased following barrier disruption due to both an increased quantity of enzyme and an increase in activation state. Similarly, the activity of serine palmitoyl transferase, the rate limiting enzyme in sphingolipid synthesis is also increased following barrier disruption. Occlusion prevents the increase in HMG CoA reductase and serine palmitoyl transferase activity. When the increase in epidermal lipid synthesis is inhibited by occlusion the characteristic rapid return of stratum corneum lipids and recovery of barrier function is prevented. Moreover, when epidermal cholesterol synthesis is inhibited by lovastatin, an inhibitor of HMG CoA reductase, the rate of recovery of barrier structure and function is delayed. Similarly, B chloroalanine, an inhibitor of serine palmitoyl transferase and sphingolipid synthesis, also impairs barrier recovery. Thus, disruption of the barrier stimulates epidermal lipid synthesis which provides the lipids necessary for the repair of the barrier. The signals that initiate and coordinate this response are yet to be defined, but the understanding of this process may allow for pharmacological interventions that will specifically disrupt the barrier and allow for the transcutaneous delivery of drugs.

Drug delivery to the brain using polymers.

Abstract: The delivery of drugs to the brain has been a major challenge to the scientist developing drugs designed for central nervous system (CNS) activity. One of the obstacles to the progress is the transport of drug through the blood brain barrier (BBB). The criteria for effective drug delivery to the CNS include the following: (a) the drug must have access to the brain, (b) the effect of the drug should be localized, (c) the drug must be stable, and (d) the effective dose should be sustained and controlled. To meet some of the above criteria, two approaches have been used: systemic administration of drugs, and direct delivery of drugs into the brain. The systemic administration of drugs relies on passive diffusion of drug through the BBB, formation of lipid soluble prodrugs and the use of monoclonal antibodies for targeting the drug to the CNS. The other approach includes the use of implantable polymer systems and infusion pumps. Both of the approaches have some advantages and disadvantages. Because of the enormous amount of literature on drug delivery to the brain, the following review focuses on the use of polymer-based implantable systems. The review includes nondegradable and biodegradable polymer implants from the conceptual phase to the clinic.

The antibody-linked chelating polymers for nuclear therapy and diagnostics.

Abstract: This review deals with the problem of protein modification with chelating polymers. The main purpose of this approach is the preparation of monoclonal antibodies labeled with heavy metal isotopes (alpha-, beta-, and delta-emitting metals and metals used for NMR-tomography). Traditional binding of metals with proteins via chelating agents directly coupled to protein molecule does not allow binding a high number of metal atoms per single protein molecule and can also alter protein specific properties. At the same time, metal-to-protein binding via intermediate chelating polymer makes possible the binding of several dozen metal atoms per single protein without affecting its specific properties. Moreover, the variations in polymer properties and molecular weight allow controlled modified antibody biodistribution and clearance rate. Modified antibodies can be used successfully for nuclear and NMR diagnostics and for nuclear therapy. The following problems are discussed: the chemistry of the coupling of chelating groups to polymer backbone; the binding of chelating polymers to proteins, including monoclonal antibodies; the ability of chelating polymer-to-protein conjugates to bind heavy metals; the influence of the modification on protein conformation and specific properties; the behavior of metal-containing conjugates in vivo; the practical use of conjugates obtained for radioimmunoimaging, radioimmunotherapy, NMR-tomography, and in vitro immunoassays. Future prospects of the approach are also discussed.

Enhanced skin permeability for transdermal drug delivery: physiopathological and physicochemical considerations.

Abstract: To deliver drugs through the skin for systemic medication, the skin permeability needs enhancing by either modifying the drug molecules, or applying skin permeation enhancers to reduce the barrier property of the skin. Traditionally, the enhancement of skin permeability is considered as the result from the improvement of the lipophilicity of drugs and the partition of drugs into the skin, or from the direct actions of skin permeation enhancers on the chemical structure and/or composition of lipids and proteins in the stratum corneum. However, on the other hand, the skin also responds to drugs and/or skin permeation enhancers physiopathologically via its inflammatory and immune reaction. The physiopathological responses of the skin can also induce the changes in the chemical structure and composition of lipids and proteins in the skin. Therefore, the possible role of physiopathological responses of the skin in the enhanced skin permeability should be concerned.

Chemoembolism in cancer chemotherapy.

Abstract: For the basis of this paper, we confine the discussion to intraarterial administration of chemotherapeutic drugs and show how efficacy may be further enhanced by formulation of the drugs in microcapsules capable of embolic entrapment within the tumor

Microencapsulation of drugs by pan and air suspension techniques.

Abstract: This review examines recent advances in the commercial production of microencapsulated drug products. Factors influencing drug selection are considered with particular reference to the design of controlled drug delivery systems. The formulation of both aqueous and nonaqueous coating materials is discussed with examples of common problems encountered in applied coatings and ways to overcome same. Methods of core production are considered with emphasis on spheronization procedures. Pan and air suspension techniques, together with modification thereof, are discussed. Certain newer in vitro procedures such as scanning electron microscopy with energy dispersive analysis or topographical plots of dissolution data for complex microencapsulated systems are presented. Finally aspects of the stability and in vivo testing of microencapsulated products are considered in the context of requirements for regulatory approval.