Showing papers in "Critical Reviews in Therapeutic Drug Carrier Systems in 1988"

Binding of acrylic polymers to mucin/epithelial surfaces: structure - property relationships

Abstract: Bioadhesion, and more specifically mucoadhesion, is becoming an important strategy for drug delivery. As a result, it is important to understand the various mechanisms that govern attachment of polymeric substances to the glycoproteins on epithelial surfaces, along with the associated structure-activity relationships of the polymer. This article reviews fundamentals of mucoadhesion, with special emphasis on structural features of the polymer as they contribute to the process of mucoadhesion. There are four possible general interactions between mucoadhesive polymers and glycoproteins: (1) covalent attachment; (2) electrostatic interaction, which requires matching of charge groups between the polymer and mucus; (3) hydrogen bonding; and (4) hydrophobic interactions. Aside from covalent attachment, which is not presently a prominent mechanism for mucoadhesion, the remaining mechanisms require maximum contact between the polymer and mucin for optimum adhesion. With polyelectrolyte polymers, the charged groups are important in controlling the degree of hydration of both the polymer and the mucous network. The expanded nature of the swollen polymer and mucus enhances the interdiffusion process and permits both a mechanical entanglement and an increase in surface contact for hydrogen bonding and/or electrostatic interaction between the polymer and the mucous network. A number of techniques are available to study mucoadhesion. Some of these are better suited to study the kinetics of the mucoadhesion process whereas others are more useful for equilibrium studies. To date, the major deficiency in basic studies of mucoadhesion is the lack of suitable information on the organization and physicochemical properties of the mucin layer.

Enzymatic barriers to peptide and protein absorption

Abstract: Continuing advances in biotechnology promise to provide a large number of peptides and proteins that would significantly expand the range of pharmaceuticals to treat diseases now poorly controlled Even at this early stage, it is clear that the success of these entities as drugs of the future would depend, at least in part, on the success in overcoming the obstacles in their delivery Chief among these are the ubiquitous enzymatic barriers These include the site of administration, where the peptide is placed, the vascular endothelium that peptides must cross to enter the circulation, the blood that distributes the peptide to its target site, and the liver and kidneys where the peptide is metabolized and eliminated, respectively The review examines: (1) the nature and efficiency of the enzymatic barriers in degrading peptides and proteins at various absorption sites, and (2) the strategies that can be used to perturb these barriers These sites include the subcutaneous and intramuscular spaces and the intestinal, nasal, buccal, rectal, vaginal, and ocular surfaces

Polyalkylcyanoacrylates as colloidal drug carriers.

Abstract: A considerable amount of energy has been spent in creating new colloidal drug delivery systems that are acceptable for general systemic use. Among these new systems, nanoparticles made with biodegradable polymers are gaining more and more interest. The aim of this paper is to describe the preparation and characterization of these nanoparticles and their in vivo behavior and to show the possibilities of using them in various fields of human medicine. The interaction of polyalkylcyanoacrylate nanoparticles with cells in culture is also discussed, as well as the possibility of improving the specificity of the carrier by coating it with monoclonal antibodies.

Alternative delivery systems for peptides and proteins as drugs.

Abstract: The emergence of recombinant DNA technology has resulted in the large-scale production of a myriad of genetically engineered proteins and peptides, making many of them available for the first time for potential use as therapeutic entities. In addition, increased knowledge in the area of peptide/polypeptide hormones has resulted in an expansion of research efforts utilizing peptide synthetic chemistry, aimed toward developing novel therapeutic peptide drugs. Proteins and peptides cannot readily be administered by the conventional oral route, and thus alternative delivery methods to circumvent the necessity of frequent injections are being explored. This article reviews the current state-of-the-art technology of such methodologies, encompassing localized administration, administration to various body cavities (i.e., nasal, rectal, etc.), as well as controlled-release injectable or implantable systems. These different approaches result in quite different pharmacokinetics that may in part dictate which approach is best suited for a particular protein or peptide.

Intestinal absorption of proteins and macromolecules and the immunological response

Abstract: Progress in the field of biotechnology has renewed interest in the oral delivery of macromolecules, in particular, proteins and peptides. While small quantities of proteins may be absorbed from the gastrointestinal tract intact, enzymatic degradation and poor absorption have historically limited protein administration to the parenteral route. By consideration of the mechanisms of macromolecular absorption from the gut, it may be possible to exploit physiological processes to promote protein uptake. However, the response of the immune system to intestinally absorbed antigen may limit the oral delivery of proteins but could provide an attractive alternative to parenteral immunization.

Gastrointestinal dynamics and pharmacology for the optimum design of controlled-release oral dosage forms.

Abstract: This article encompasses a brief discussion of the principles of pharmacodynamics of different types of drugs and the mechanisms of absorption at different sites in the gastrointestinal tract. The importance of factors such as the pH, the unstirred layer or microclimate, gastric emptying, intestinal contact time, metabolism in the gut wall, and bacterial degradation in the colon is discussed. Methods that can be used to alter the absorption of drugs such as formulation in a viscous form, a form that floats in the stomach, position release forms, combination with other drugs that may influence absorption, etc. are examined in detail.

Drug-monoclonal antibody conjugates for cancer therapy: potentials and limitations.

Abstract: The development of monoclonal antibodies against antigens associated preferentially with human tumors has reawakened interest in the use of antibodies as site-specific targeting agents for cancer therapy. There are now many reports of the construction of conjugates of drugs and toxins with antibodies which have in vitro toxic properties directed by the antibody moiety. Only recently, however, have limitations to the in vivo therapeutic application of these conjugates become appreciated. These include limited levels of antibodies accumulating in tumor deposits in patients, sometimes marked differences in the biodistribution of antibody-drug conjugates from those seen with free antibody, limited penetration of antibody and drug-antibody conjugates into tumor tissue together with heterogeneity of antigen expression within tumor, and limitation to the cytotoxicity of conjugates caused by the low drug to antibody molar ratios possible without denaturation. It is now becoming appreciated that effective development of this approach will require more than chemical conjugation of existing or even novel drugs or toxins to antibodies so that they are cytotoxic in vitro. Additional strategies will probably have to be employed, including the use of intermediate carriers to increase drug to antibody ratios in conjugates, the production of conjugates without extreme overall charge or conformation changes, techniques to increase antibody localization into tumors by, for example, regional perfusion, blood flow enhancement, or increase in antigenic expression, or the use of conjugates containing mixtures of antibodies or fragments directed against different tumor-associated antigens.

Targeting of antiviral drugs bound to protein carriers.

Abstract: The value of antiviral drugs would be improved by their selective delivery into infected cells. This goal can be achieved by conjugating the drug to a protein which is taken up specifically by the cells where the virus grows. Conjugates will be pharmacologically effective in these cells if the bond linking the drug to the carrier does not suppress the activity of the drug or if the bond is broken down with consequent intracellular release of the drug. Experiments on this approach to antiviral chemotherapy have been directed mainly at selectively delivering antiviral agents into hepatocytes in order to increase their chemotherapeutic index in the treatment of chronic hepatitis B.

Transdermal drug delivery: a review of pharmaceutics, pharmacokinetics, and pharmacodynamics.

Abstract: This article provides a critical literature review on the recent advances in the research and development of rate-controlled transdermal therapeutical systems for systemic medication. The article focuses its discussion on the recent development in the fundamentals, developmental concepts, and biomedical assessment of the transdermal controlled drug administration. The scope of the review consists of the following areas: mechanism of percutaneous absorption; enhancement of skin permeability; in vitro and in vivo evaluations of transdermal permeation kinetics and assessment of in vitro-in vivo relationship; pharmacokinetics and pharmacodynamics of transdermal controlled drug administration and establishment of pharmacokinetic/pharmacodynamic relationship; clinical performance of rate-controlled transdermal therapeutic systems; and potential development in rate-controlled transdermal drug delivery.

Limitations of transmembrane transport in drug delivery.

Abstract: The plasma membrane of all living cells controls the flow of substances, energy as well as information, between the internal cell order and surrounding cell disorder. There are three general routes along which substances may cross this barrier; free diffusion, passive and active transport, and endocytic processes. The subject of polymer drugs where biologically inert polymers bear therapeutically active low molecular weight drugs and targeting moiety became a popular issue in last decade. This review is devoted to the question of the interaction of drugs with the plasma membrane and their transport across it. As the polymer-drug conjugates are macromolecular substances, the main emphasis is focused on the problems of phagocytosis and pinocytosis.

Materials and biological aspects of synthetic polymers in controlled drug release systems: problems and challenges.

Abstract: The physico-chemical and biological aspects of polymeric materials represent vital areas in the reliable, safe, and efficacious functioning of controlled drug-delivery devices. In the case of implantable systems, potential biological problems include incompatibility of the polymers and their degradation products with the physiological environment, adverse metabolic consequences of the degradation products, and occlusion of the drug conduits (catheters) with thrombi and/or drugs, (i.e., insulin aggregates). In the case of transcutaneous drug delivery systems, proper consideration must be given to avoid skin irritation and allergic responses as well as other toxic effects. With biodegradable systems that may follow simple hydrolysis and/or enzyme-catalyzed degradation of labile chemical side-chains that hold the drug molecule and/or the main polymer chain, increased attention must be given not only to the short-term but also the long-term metabolic consequences of the degradation products. Although the term "biodegradation" is often used for in vitro situations it should be reserved only for in vivo circumstances as, at the present time, no in vitro experiments can completely simulate the in vivo environment. The misuse of this term may lead to premature predictions as to the performance of a device in vivo, a situation that ought to be avoided. Appropriate attention must also be given to the effect of drugs on polymers as drug/polymer interactions may influence the stability of both the polymers and drugs and may result in altered therapeutic performance. Standards are needed to clearly differentiate between controlled drug delivery systems and older "sustained" and "time-release" preparations.