Showing papers in "Critical Reviews in Therapeutic Drug Carrier Systems in 1998"

Gastric Retentive Drug-Delivery Systems

Abstract: The development of a long-term oral controlled-release dosage form has been difficult mainly because of the transit of the dosage form through the gastrointestinal (GI) tract. Several approaches to extend gastric residence time have been tried. The most commonly used systems are (1) intragastric floating systems, (2) high-density systems, (3) mucoadhesive systems, (4) magnetic systems, (5) unfoldable, extendible, or swellable systems, and (6) superporous hydrogel systems. The concept of each approach is examined, and improvements that are needed for further development are discussed. Background materials in the GI physiology that are necessary for understanding the concept and usefulness of each approach are also provided.

Folate-mediated targeting of therapeutic and imaging agents to cancers

Abstract: The vitamin folic acid (FA) enters cells either through a carrier protein, termed the reduced folate carrier, or via receptor-mediated endocytosis facilitated by the folate receptor (FR). Because folate-drug conjugates are not substrates of the former, they penetrate cells exclusively via FR-mediated endocytosis. When FA is covalently linked via its gamma-carboxyl to a drug or imaging agent, FR binding affinity (KD approximately 10(-10)M) is not measurably compromised, and endocytosis proceeds relatively unhindered, promoting uptake of the attached drug/imaging agent by the FR-expressing cell. Because FRs are significantly overexpressed on a large fraction of human cancer cells (e.g., ovarian, lung, breast, endometrial, renal, colon, and cancers of myeloid hematopoietic cells), this methodology may allow for the selective delivery of a wide range of imaging and therapeutic agents to tumor tissue. Folate-mediated tumor targeting has been exploited to date for delivery of the following molecules and molecular complexes: (i) protein toxins, (ii) low-molecular-weight chemotherapeutic agents, (iii) radioimaging agents, (iv) MRI contrast agents, (v) radiotherapeutic agents, (vi) liposomes with entrapped drugs, (vii) genes, (viii) antisense oligonucleotides, (ix) ribozymes, and (x) immunotherapeutic agents. In virtually all cases, in vitro studies demonstrate a significant improvement in potency and/or cancer-cell specificity over the nontargeted form of the same pharmaceutical agent. Where live animal studies have been conducted, they also reveal significant promise.

From genes to gene medicines: recent advances in nonviral gene delivery.

Abstract: Over the last decade, research in somatic gene therapy has focused on selected approaches to deliver therapeutic genes to cells both ex vivo and in vivo. While most current gene therapy clinical trials are based on cell- and viral-mediated approaches, nonviral gene medicines are emerging as potentially safe and effective in the treatment of a wide variety of genetic and acquired diseases. Nonviral technologies consist of plasmid-based expression systems containing a gene encoding a therapeutic protein and synthetic gene delivery systems. In addition to the therapeutic gene, plasmid-based expression systems contain other genetic sequences to control the in vivo production and secretion of a protein. They may include elements that prolong extrachromosomal gene expression, cell-specific promoters and, optionally, gene switches for enabling drug-regulated gene therapy. Unique gene delivery systems will be required depending upon the biology and (patho)physiology of the target tissue. This review provides a critical view of gene therapy with a major focus on advanced nonviral technologies to control the in vivo location and function of administered genes.

Bloodless glucose measurements.

Abstract: Self-measurement of blood glucose is part of the daily routine for patients with diabetes, and healthcare professionals use these values for therapy and treatment. Healthcare providers are encouraging patients with insulin-dependent diabetes to test their blood glucose level four to six times a day to effectively manage their disease and significantly reduce the incidence of serious and costly complications. Unfortunately, people with diabetes test less than once a day on average, associating this noncompliance with pain associated with drawing blood from the finger. Glucose-monitoring techniques are under study that would allow body fluids other than blood to be used in a painless or almost painless manner. These new technologies could lead to a revolutionary advance in the treatment of diabetes, and the current research and development can now be reviewed.

Hyaluronate derivatives in drug delivery.

Abstract: Hyaluronan (HA), an abundant nonsulfated glycosaminoglycan component of synovial fluid and the extracellular matrix, is an attractive building block for new biocompatible and biodegradable polymers that have applications in drug delivery, tissue engineering, and viscosupplementation. This review consists of three subtopics: (i) chemical modification of HA; (ii) physicochemical and biochemical characterization of HA derivatives; and (iii) in vitro and in vivo bioevaluation studies. Important new products have already reached the marketplace, and the approval and introduction of a variety of new medical applications of HA-based biomaterials can be anticipated in the next decade.

The interaction of liposomes with the complement system.

Abstract: Activation of complement (C) by haptenized liposomes has been utilized for a long time to study the interaction of biological membranes with C proteins, or as a sensitive immunoassay for the measurement of specific antigens, antibodies, or serum hemolytic C levels. However, it has been increasingly recognized that regardless of antigenicity, C activation is an intrinsic property of all charged phospholipid/cholesterol bilayers. Liposome-induced C activation and its biological consequences show significant interspecies and interindividual variation, and critically depend on the properties of vesicles as well. Activation can proceed through both the classical and the alternative pathways, with or without the involvement of antibodies. The practical significance of the phenomenon is twofold: 1) opsonization of the vesicles promotes their clearance from the circulation and 2) the liberation of C3a and C5a can cause numerous, potentially adverse, biological reactions. In fact, many cardiovascular and hematological changes observed following administration of liposomes in vivo can be explained by C activation; a fact that has not yet gained wide recognition in the field of drug-carrier liposomes.

Diblock copolymer nanoparticles for drug delivery

Abstract: Diblock copolymers can form nanoparticles, that is, micelles and nanospheres, that are being studied as carriers for hydrophobic drugs and genes. The synthetic carriers mimic the spherical, supramolecular core/shell structure of lipoproteins and viruses. Hence, diblock copolymer nanoparticles may be functional, having the ability to solubilize, protect, and release drugs at sustained rates. Several studies have illustrated prolonged residence times in blood for diblock copolymer nanoparticles. They have also enhanced drug effects in animals. Diblock copolymer nanoparticles are potentially useful carriers for site-specific drug delivery.

The potential of liposomes in oral drug delivery.

Abstract: Oral liposome drug delivery has been the subject of much cynicism. Results have been quite variable and, for the most part, have not been predicated on specific objectives that would lead to success. Prerequisites are stability in the gastrointestinal environment and binding to specific sites. Transport via paracellular and transcellular routes from normal epithelial tissue or Peyer's patches leads to different outcomes of drug delivery and immunization, respectively. Polymerized, microencapsulated, and polymer-coated liposomes have all increased the potential of oral liposomes. Using targeted liposomes and a greater understanding of their cellular processing will ultimately lead to effective therapies from oral liposomes.

Novel methods of insulin delivery: an update.

Abstract: Conventional insulin therapies involve multiple daily subcutaneous injections. However, the resultant disposition of insulin and blood glucose differs considerably from that following the physiological secretion of pancreatic insulin. A variety of alternative routes/methods have been investigated to improve systemic insulin delivery. Peroral and nasal insulin administration have demonstrated good potential for the treatment of diabetes. Facilitated transdermal delivery has also enjoyed success in promoting the systemic delivery of insulin. In addition, pulmonary, buccal, and ocular insulin administration have been shown to decrease serum glucose concentrations. Other methods that have been investigated for their potential in systemic insulin delivery include rectal, vaginal, and uterine routes.

Use of nonionic block copolymers in vaccines and therapeutics.

Abstract: Nonionic block copolymers synthesized from ethylene oxide and propylene oxide were developed specifically for use as surfactants. Because the sizes and relative positions of the hydrophobic polyoxypropylene (POP) and hydrophilic polyoxyethylene (POE) blocks can be altered during synthesis, copolymers with significantly different surfactant characteristics can be produced. Copolymers of this type are currently used as excipients in a wide variety of pharmaceutical products where they act as emulsifying, wetting, thickening, stabilizing, and dispersing agents. Copolymers with unique physicochemical properties have recently been developed through the use of new manufacturing and purification techniques, and these copolymers are being used as drug-active and drug-delivery components. In this review, we summarize the current status of these new copolymers in terms of research and product development. This includes the use of new, high molecular weight copolymers as vaccine adjuvants and as vaccine-delivery vehicles. The use of purified, pharmaceutical-grade copolymers as anti-infectives and as antibiotic-delivery systems for the treatment of established bacterial and viral infections is also reviewed. These novel uses for copolymers are significantly different from the excipient uses common to this type of product and demonstrate the widespread utility of synthetic surfactant polymers.

Use of vitamin B12 conjugates to deliver protein drugs by the oral route

Abstract: The treatment of patients with most peptide and protein pharmaceuticals must currently be performed by injection, with the accompanying disadvantages of patient discomfort, increased medical costs, and reduced patient compliance. It would be much easier and more acceptable if these drugs could be given by the oral route. Unfortunately, this route cannot be used with most proteins and with peptides due to both the degradation of these molecules within the intestine and their poor uptake across the intestinal wall. In this review, an uptake system is described that potentially overcomes both these problems. This system relies upon the natural uptake mechanism for vitamin B12 to cotransport peptides and proteins linked to the vitamin B12 from the intestine to the circulation. In an exciting extension to this technology, it has been found that it is also possible to transport nanoparticles, linked to the vitamin B12, into the circulation. Such nanoparticles can potentially be loaded with peptides or proteins of choice, and so protect these molecules from degradation in the intestine, while simultaneously transporting them into the circulation. These findings are an important step in realizing the possibility of delivering almost all peptides and proteins via the oral route.

Bioerodible polymers for ocular drug delivery.

Abstract: Development of ophthalmic drug-delivery systems has always been challenging The commonly used route for drug delivery to the anterior segment of the eye has been the conjunctival cul-de-sac Because of drawbacks associated with this route, new approaches have been investigated for delivery of drugs to the eye by means of polymeric delivery systems Development of controlled drug-release devices has been a major step forward in this respect Bioerodible polymers have been at the forefront of such systems They are very important because they eliminate the need for removing the implant after complete drug release Bioerodible polymers have been divided into three classes based on their mechanism of hydrolysis: Type I--hydrolysis of crosslinked hydrogels; Type II--solubilization by ionization or hydrolysis of linear polymers; and Type III--biodegradation by backbone cleavage Polymers from all three classes are discussed in detail in this review

Ceramic drug-delivery devices.

Abstract: A variety of ceramics and delivery systems have been used to deliver chemicals, biologicals, and drugs at various rates for desired periods of time from different sites of implantation. In vitro and in vivo studies have shown that ceramics can successfully be used as drug-delivery devices. Matrices, inserts, reservoirs, cements, and particles have been used to deliver a large variety of therapeutic agents such as antibiotics, anticancer drugs, anticoagulants, analgesics, growth factors, hormones, steroids, and vaccines. In this article, the advantages and disadvantages of conventional drug-delivery systems and the different approaches used to deliver chemical and biological agents by means of ceramic systems will be reviewed.

Controlled-release products for the control of the estrus cycle in cattle, sheep, goats, deer, pigs, and horses.

Abstract: This paper describes the estrus cycles of a number of livestock breeds and reviews the controlled-release drug delivery systems that are currently available for the purpose of controlled breeding. The bovine estrus cycle is reviewed in detail, and the estrus cycles of other species are described in a manner that highlights similarities and differences between species. Pertinent formulation and pharmacokinetic information about current drug delivery systems is presented and discussed, and recent advances in this area are also described.