Showing papers on "Drug carrier published in 1987"

Cyclodextrins in drug carrier systems.

Abstract: One of the important characteristics of cyclodextrins is the formation of an inclusion complex with a variety of drug molecules in solution and in the solid state. As a consequence of intensive basic research, exhaustive toxic studies, and realization of industrial production during the past decade, there seem to be no more barriers for the practical application of natural cyclodextrins in the biomedical field. Recently, a number of cyclodextrin derivatives and cyclodextrin polymers have been prepared to obtain better inclusion abilities than parent cyclodextrins. The natural cyclodextrins and their synthetic derivatives have been successfully utilized to improve various drug properties, such as solubility, dissolution and release rates, stability, or bioavailability. In addition, the enhancement of drug activity, selective transfer, or the reduction of side effects has been achieved by means of inclusion complexation. The drug-cyclodextrin complex is generally formed outside of the body and, after administration, it dissociates, releasing the drug into the organism in a fast and nearly uniform manner. In the biomedical application of cyclodextrins, therefore, particular attention should be directed to the magnitude of the stability constant of the inclusion complex. In the case of parenteral application, a rather limited amount of work has been done because the cyclodextrins in the drug carrier systems have to be more effectively designed to compete with various biological components in the circulatory system. However, the works published thus far apparently indicate that the inclusion phenomena of cyclodextrin analogs may allow the rational design of drug formulation and that the combination of molecular encapsulation with other carrier systems will become a very effective and valuable method for the development of a new drug delivery system in the near future.

The Preparation and Evaluation of Drug-Containing Poly( dl -lactide) Microspheres Formed by the Solvent Evaporation Method

Abstract: Several compounds such as caffeine, diazepam, hydrocortisone, progesterone, quinidine, quinidine hydrochloride, quinidine sulfate, and theophylline were evaluated for incorporation into poly(dl-lactide) (PLA) microspheres using the solvent evaporation technique. The process is generally limited to the entrapment of water-insoluble drugs. Adjustment of the pH of the aqueous phase to minimize drug solubility resulted in increased drug contents within the microspheres in the case of ionizable drugs. The release profile of quinidine from the microspheres was characterized by three different release phases, a lag time with no drug release, a burst effect of rapid drug release within a short period of time, and a slow release phase, respectively. The structure of the microsphere surface layer, which was a function of the pH of the aqueous phase at preparation, strongly influenced the rate and amount of drug released. Thermal analysis of quinidine-loaded microspheres revealed three thermal events, corresponding to the glass transition temperature of the polymer and to the recrystallization and melting of quinidine.

Anticancer agents coupled to N-(2-hydroxypropyl)methacrylamide copolymers. I. Evaluation of daunomycin and puromycin conjugates in vitro

Abstract: During recent years N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers have been developed as targetable drug carriers. These soluble synthetic polymers are internalized by cells by pinocytosis and they can be tailor-made to include peptidyl side-chains degradable intracellularly by specific lysosomal enzymes. Thus they provide the opportunity fo achieve controlled intracellular delivery of anticancer agents. The anthracycline antibiotic daunomycin, and protein synthesis inhibitor puromycin, were bound to HPMA copolymers via several different peptide side-chains, including Gly-Gly, Gly-Phe-Leu-Gly and Gly-Phe-Phe-Leu. Incubation of polymer-drug conjugates with isolated lysosomal enzymes (either a mixture of rat liver lysosomal enzymes or purified thiol-dependent lysosomal proteinases, cathepsins L and B) showed that significant release of drug occurred over 20 h, more than 20% of daunomycin and more than 80% of puromycin being liberated. To test their pharmacological activity conjugates were incubated with either the mouse leukaemia L1210, or the human lymphoblastoid leukaemia CCRF in vitro. The conjugates tested were all less effective than free daunomycin, but they showed differential toxicity against L1210 depending on the aminoacid sequence of their drug-polymer linkage. Inclusion of fucosylamine-terminating side-chains into the HPMA copolymer structure increased the affinity of conjugates for the L1210 cell membrane and resulted in increased toxicity. In contrast HPMA-daunomycin conjugates with or without fucosylamine affected CCRF cells equally, but this cell line was more sensitive than the mouse leukaemia to both free and polymer-bound daunomycin. Incubation of L1210 cells in polymer-bound daunomycin for 72 h, followed by plating cells out in low density in drug-free medium, showed that a concentration of polymer-bound drug (184 micrograms ml-1) could be selected to achieve a cytotoxic effect.

Lipid emulsions as drug delivery systems.

Abstract: Colloidal carriers used for the delivery of drugs take a variety of forms to include those that are solid-like in nature, such as microspheres and nanoparticles, and liquids in the form of emulsions, or vesicles (better known as liposomes). Natural colloidal particles (lipoproteins and chylomicrons present in circulating blood, for example) have also been investigated as potential carrier systems. The recent literature covering these different systems can be found in various detailed papers, review articles, and monographs.’4 This article will consider recent studies on the use of lipid emulsions as drug delivery systems and will concentrate on the intravenous route of administration. The earlier literature has been reviewed by Davis and others2

Endothelial envelopment drug carriers

Abstract: This application describes the preparation and in vivo testing of surface coatings and matrix materials, which when applied to or caused to comprise the carriers for drugs and diagnostic agents, and administered in a fashion that allows efficient vascular access, causes the carriers to recognize determinants present or normal or focally diseased endothelium, and induces the following in vivo effects: (1) rapid, partial or total endothelial envelopment of the drug (diagnostic) carrier; (2) sequestration of the carrier and protecting entrapped agent from blood vascular clearance at an early time (2 minutes) when the endothelial pocket which envelops the carrier still invaginates into the vascular compartment; (3) acceleration of the carrier's transport across or through the vascular endothelium and/or subendothelial structures into the tissue compartment (interstitium); and (4) improvement of the efficiency with which the drug (or diagnostic) carrier migrates across the endothelium, or epi-endothelial or subendothelial barriers, such that a lower total drug dose is required to obtain the desired effect relative to that required for standard agents.

Solution properties of drug carriers based on poly[N‐(2‐hydroxypropyl)methacrylamide] containing biodegradable bonds

Abstract: The solution properties of water-soluble drug carriers based on copolymers of N-(2-hydroxypropyl)methacrylamide containing p-nitroaniline (drug model) attached to the copolymer by enzymatically degradable oligopeptide chains, were studied using light scattering, GPC and sedimentation methods. It was found that these polymers associate in water forming micelles with p-nitroaniline being inside and hydrophilic polymer chains outside. The association number and compactness of micelles both depend on the content of hydrophobic side chains, polymer concentration and temperature. Micellar shells hinder the penetration of enzymes into the micellar core, thus reducing the rate of enzyme-catalyzed release of p-nitroaniline.

Redox drug delivery systems for targeting drugs to the brain.

Abstract: Drug targeting to specific receptors or specific organs has been one of the main objectives of the medicinal and pharmaceutical chemists from the beginning of the century. However, only in the past 15 years or so have there been any promising developments in achieving this goal. The term “site-specific drug delivery” covers targeting to receptors or organs or any other specific part of the body to which we wish to deliver the drug exclusively. The site-specific delivery of drugs is indeed a very attractive goal because this provides one of the most significant potential ways to improve the therapeutic index (TI) of the drugs.’ When a drug is delivered preferentially to the site of the action by virtue of this desired differential distribution, it will spare the rest of the body; thus, it will significantly reduce the overall toxicity while maintaining its therapeutic benefits. At the present time, there are three basically different approaches for site-specific drug delivery. The first, the physical or mechanical approach, is based on effectively formulating a drug in a delivery device, which by virtue of its physical localization will allow differential release of the drug. The site specificity thus is due to exclusively producing higher drug concentrations wherever the device is localized, while the drug concentration in the rest of the body is very much diminished due to the simple dilution factor. The limitations of this approach are clearly due to the fact that many desired target sites are simply not available for the physical approach. In addition, often the distributional differences due to the dilution effect may not be sufficient to produce significant improvement in the TI. The second basic approach is the biological one, according to which a drug is potentially targeted by a biological carrier that would have specific affinity for certain receptor sites, organs or other biological targets. This kind of approach, such as using monoclonal antibodydrug conjugates, erythrocyte carriers, or macromolecular product carriers (such as liposomes) has been the subject of many investigations. The limitations of this approach are primarily problems presented by stoichiometry, controlling the processes related to releasing the drugs from the biological carriers, as well as biological incompatibility of the carriers. The third approach is the chemical approach, the use of the site-specific chemical delivery systems (CDSs),’.’ which provide a wide variety of possibilities for siteenhanced or site-specific delivery. The CDS is produced by chemical reactions (at least

Bioadhesive polymers for controlled drug delivery.

Abstract: Bioadhesion may be defined' as the state in which two materials, a t least one of which is of a biological nature, are held together for an extended period of time by interfacial forces. Thus, attachment of a biological object to another biological object, e.g., cell attachment, or a synthetic polymer to a biological substrate, e.g., denture fixative, are examples of bioadhesion. For drug delivery purposes the term bioadhesion infers attachment of a drug carrier system to a specific biological location. The biological surface can be epithelial tissue or it can be the mucous coat on the surface of the tissue. If adhesive attachment is to the mucin coat the phenomena is referred to as mucoadhesion. Bioadhesion can be modeled after bacterial attachment to tissue surfaces and mucoadhesion can be modeled after much organization on epithelial tissue. Earlier work by Nagai2 has shown that mucoadhesion can be used as a platform for delivery of drugs locally to the mouth or to the cervix with concomitant improvement in therapy or, alternatively, a decrease in body load of the drug. A number of workers3-' have been exploring both the mechanism(s) of adhesion as well as ways to utilize mucoadhesion as a platform for both local and systemic delivery of drugs. This presentation will review the concept of mucoadhesion with emphasis on attachment of polyanionic swelling hydrogels. In addition, it will review some of the recent applications of mucoadhesion with particular emphasis on buccal delivery.

Drug delivery systems : fundamentals and techniques

Abstract: Drug Delivery - Where Now? Biological Opportunities for Site-Specific Drug Delivery Using Particulate Carriers Therapeutic Utility of Liposomes Monoclonal Antibodies as Carriers for Drug Delivery Soluble Polymers as Targetable Drug Carriers Design of Biodegradable Polymers for Controlled Release Implantable Osmotically Powered Drug Delivery Systems Implantable Pumps for Insulin Delivery: Current Clinical Status Technological Advances in Oral Drug Delivery Physiological and Physicochemical Factors in Drug Release in the Gastrointestinal Tract Evaluation of the Gastrointestinal Transit and Release Characteristics of Drugs Mucoadhesive Polymers in Drug Delivery Systems Use of Hydrogels Transdermal Drug Delivery Recent Advances in Intranasal Drug Delivery Systems New Systems for the Ocular Delivery of Drugs Overview.

Biopharmaceutics of Microparticulate Drug Carriers

Abstract: The concept of site-specific drug delivery is an old one, but it is only recently that full consideration has been given to the ways in which this might be achieved in practice, due largely to the advent of the new biosciences.' Clearly, a drug's therapeutic index, as measured by its pharmacological response and safety, relies on the access and specific interaction of the drug with its candidate receptor. whilst minimizing its interactions with non-target tissues. Peptide drugs illustrate the case where failure in the clinic may not be due to a poor intrinsic activity, but rather to transport factors including widespread disposition, rapid catabolism and excretion, variable or inefficient extravasation, and the subsequent high dosing levels required to obtain a therapeutic effect.' Site-specific drug delivery may be achieved by using carrier systems, where reliance is placed on exploiting both the innate pathway(s) that these carriers have, and the protection that they can afford to drugs during transit through the body. The use of a carrier opens up a range of opportunities for adjusting both drug access to its site of action and its pharmacological response that are not necessarily available by simple chemical modification of the drug alone. Such carriers can be broadly categorized as soluble (macro)molecular drug conjugates and drug-bearing particulates. In this present paper, we shall consider some of the key pharmaceutical and biopharmaceutical aspects of microparticulate carriers ranging in size from 20 nm to 20 pm diameter. Such particles can be monolithic or capsular in construction; they have been proposed as drug carriers largely due to the features given in TABLE I . These properties will be examined in some detail later. although we note here that carriers differ widely in these features. For example, small, unilamellar vesicles have a low drug-bearing capacity in relation to the composite mass of the carrier, whereas it is theoretically possible to synthesize a monolithic particulate carrier from bioactive peptides such that the carrier is composed entirely of this material. We have argued that the strategy for site-specific drug delivery should be based on consideration of the disease and drug access, retention, and timing in its interaction with the target (DART).3 Thus, in the treatment of a disease with a carrier system we need to have a clear understanding of the inherent anatomical and (patho)physiological opportunities (and constraints) for site-specific drug delivery, the intravascular or extravascular location of the target, the chronopharmacology of the drug, and the

A new drug-delivery-system of anticancer agents: activated carbon particles adsorbing anticancer agents.

Abstract: A new drug delivery system comprizing activated carbon particles adsorbing anticancer agents has been developed in order to enhance anticancer efficacy on local lesions and to reduce systemic toxicity. The system is designed to release the adsorbed anticancer agent slowly at a designated concentration level at the local site, and to allow the agent to remain for a long time at the local site, with affinity for the lymphatic system and the surface of cancer cells. Through this process, anticancer efficacy is enhanced at the local lesion and systemic toxicity decreases. Because the size of the particles influences the distribution of the agent, size is selected according to both targeted organs, i.e. lymphatic metastases, carcinomatous peritonitis, and administration methods, i.e. intramural, intracavitary, intrabronchial, or intratumoral administration.

Theoretical considerations of drug release from submicron oil in water emulsions.

Abstract: Submicron sized emulsion droplets possess a significantly greater interfacial area per unit volume than a corresponding coarse emulsion Therefore, processes such as drug binding to surfactants at the O/W interface and interfacial activity of the drug may be operative to a greater extent in submicron systems This may allow more drug mass to be associated with the nondiffusible droplet than partitioning processes alone would predict Thus, in order to evaluate and predict drug release from submicron emulsion systems in a nonempirical manner these processes must be considered Several interfacial and partitioning processes are incorporated into a mathematical model describing the in vitro diffusion of drug from a submicron emulsion across a semipermeable membrane Drug ionization and its effect on charge dependent interfacial, partitioning, and mass transport processes are considered Independent kinetic and thermodynamic evaluations of interfacial adsorption processes are experimentally accessible Initial drug release studies using sulfathiazole as a weakly acidic model compound are consistent with the model

Drug delivery to macrophages for the therapy of cancer and infectious diseases.

Abstract: The mechanisms by which mononuclear phagocytes discriminate between self and nonself, recognize foreign materials, senescent, damaged, old, or effete cells, and tumor cells are unknown. However, regardless of the mechanism(s) involved, once activated by the appropriate signal(s), macrophages are able to selectively recognize and destroy neoplastic cells in vitro and in vivo. Liposomes injected intravenously, in common with other particulate or polymeric matrices, localize preferentially in organs with high mononuclear phagocyte activity and in circulating blood monocytes. This behavior allows microparticulates to serve as a convenient system for the selective delivery of encapsulated drugs to cells of the mononuclear phagocyte series in vivo. Liposomes are a particularly attractive experimental system because of their capacity to incorporate a wide variety of water-soluble and lipid-soluble drugs. At this time, however, there is no reason to assume that a liposome-based drug delivery system will offer any significant therapeutic advantage compared to other microparticulate drug delivery systems. As in commercial development of any pharmaceutical preparation, considerations of cost-of-goods, shelf life, and acceptance of the formulation and dosing regimen by both physicians and patients will be of major importance in determining success and widespread clinical use. Liposomes containing macrophage-activating agents are highly effective at augmenting macrophage-mediated tumoricidal activity in vitro eradicating tumor metastasis in vivo, as well as protecting animals from a wide variety of microbial and viral infections. Although the demands of solving the scientific and technical problems associated with liposome development are substantial, the rapid rate of progress in biology and in pharmaceutical sciences enhances the prospect of success for at least several aspects of liposome-mediated drug delivery. The next few years will be crucial in determining whether the commercial development of liposomes is feasible or whether they will join the ranks of other drug carrier designs that have failed to fulfill their initial promise.

Temperature- and pH-sensitive liposomes for drug targeting.

Abstract: Publisher Summary This chapter discusses the temperature and pH sensitive liposomes for drug targeting. The use of hyperthermic for the purpose of drug targeting is discussed. Possible advantages of hypothermic targeting include (1) less damage to normal tissues by cooling than the damage seen with heating and (2) greater retention time of drug at the release site as a consequence of reduced blood flow. In vivo , such liposomes preferentially release encapsulated drug in a locally heated target area. When liposomes containing either tritiated methotrexate or cis-dichlorodiammineplafinum (II) (PDD) were administered to tumor-beating mice and the tumor locally heated, greater uptake of radioactive drug and greater local tumor control were observed compared to mice treated with systemic free drug and local heat. Based on the results with temperature-sensitive liposomes, containing PDD, especially the augmented drug uptake in tumors, the delay in tumor growth, and the potential decrease in nephrotoxicity, one considered the future of such targeting to be promising. Membrane fusion under moderately acidic conditions is responsible for the infection caused by a number of enveloped viruses and for the fusion that occurs when the virions are exposed to acidic pH in endosomes.

Magnetic microspheres for the targeted controlled release of drugs and diagnostic agents.

Abstract: Pharmaceutical agents with very high toxicities or production costs, short circulation times, and low plasma stabilities may require special methods of delivery in order to limit systemic side effects, deposit acceptable fractions of the injected dose in target tissues, and control local bioavailability in a manner that treats target cells or microorganisms but not bystander cells.’ Criteria for drug targeting vary, but, the most standard one in the pharmaceutical industry is that the therapeutic index should increase by at least one-half to one order of magnitude. Hence, true targeting causes drug levels in liver, bone marrow, kidney, and other major sites of toxicity to rise by less than one-third to one-tenth of the increment achieved in the selected target organ (tissue). There are two exceptions to this. The first is “site-avoidance targeting,” in which drug is allowed to reach therapeutic levels in multiple nontarget as well as target sites, provided it avoids major organfs) of toxicity. A second exception occurs when the objective is to localize a relatively nontoxic drug for reasons of rapid plasma clearance, biodegradation, high production costs, or limited commercial availability. The difficulty of targeting drugs in vivo using high-molecular-weight and supramolecular carriers (e.g., monoclonal antibodies and drug-receptor conjugates, polymeric drugs, liposomes, and standard microspheres) is that the body contains not one, but three major test tubes: the blood-vascular, extracellular, and intracellular compartments. Except for reticuloendothelial organs, which have highly porous sinusoidal endothelium, the remaining organs exhibit microvascular barriers that severely restrict the extravasation of drug carriers above ca. 3-5 nm in molecular diameter.2.3 This means that many potential carriers of sufficient molecular size to encode receptorbinding information are excluded from the extravascular compartment of normal target organs other than liver, spleen, bone marrow, and (variably) kidney. Diseased regions of organs (e.g., infarcts, infections, and tumors) exhibit variable breakdown of microvascular barriers. For example, in experimental tumors whose vascular filtration properties have been sized using fluoresceinated dextrans, moderate permeabilities are reported for 150,000-dalton species and lower permeabilities for up to 3,000,000dalton species! Even with partial breakdown, the largest soluble molecules (e.g., drug-DNA complexes), molecular microaggregates (of 3-1 00 nm) and the smallest

Particles as drug delivery systems

Abstract: Advances in genetically engineered products present an entirely new spectrum of drugs to the medical community. With these exciting new drugs come complex challenges for their delivery. The compounds are often high molecular weight proteins, many with extremely short in vivo half lives. The challenge is to deliver these new drugs to the body at a controlled rate. The rate can be uniform or programmed to a specific regimen, with time frames from hours to months. An additional challenge is posed by drugs that are highly toxic. If the drug were to home in directly on the site of action, systemic damage could be minimized. Drug loaded particles, (emulsions, liposomes or microcapsules), are being developed for both controlled and targeted drug delivery.

Viruses as tools in drug delivery.

Abstract: The hydrophobic character of the lipid bilayer provides an effective barrier for polar macromolecules. Only in exceptional cases can proteins and nucleic acids pass across cellular membranes. Direct bilayer translocation of macromolecules is, in fact, not needed for most types of exchanges between membrane-bounded compartments. Incoming nutrients and signals are usually channeled into the cells as low molecular weight substances, through the mediation of ions, or by other mechanisms that do not involve translocation of macromolecules across the lipid bilayer. In cases where macromolecular translocation is unavoidable, such as during segregation of secretory proteins into the endoplasmic reticulum or transfer of cytoplasmically translated mitochondria1 proteins into mitochondria, complex mechanisms appear to be involved.’-3 The details of these mechanisms are not yet fully understood, but it seems that the proteins are transported across the bilayers in partially unfolded form at the expense of energy (FIGURE 1 A). Paradoxically, it appears easier for the cell to carry macromolecules and other membrane-impermeable substances over a barrier made up of two membranes than of one. If the donor and the acceptor compartments each have their own limiting membranes, the preferred mode of transport of macromolecules is either direct fusion of the two membranes with each other or vesicle transport from one to the other (FIGURE 1 B).4 Neither of these mechanisms requires translocation of the macromolecules across a lipid bilayer membrane. Whenever fusion and vesicle transport occurs in the cell, it can be assumed, however, that specific mechanisms regulate the movement of the vesicles, mediate the specific recognition between the membranes, and induce membrane perturbations that lead to fission and fusion reactions. Although thousands of fusion and fission reactions take place every minute in a normal eukaryotic cell, little is known about the specific mechanisms involved.