Showing papers on "Drug carrier published in 1992"

Hydrogels: swelling, drug loading, and release.

Abstract: Hydrogels have been used by many investigators in controlled-release drug delivery systems because of their good tissue compatibility and easy manipulation of swelling level and, thereby, solute permeability The desired kinetics, duration, and rate of solute release from hydrogels are limited to specific conditions, such as hydrogel properties, amount of incorporated drug, drug solubility, and drug-polymer interactions This review summarizes the compositional and structural effects of polymers on swelling, loading, and release and approaches to characterize solute release behavior in a dynamic state A new approach is introduced to compensate drug effects (solubility and loading) with the release kinetics by varying the structure of heterogeneous polymers Modulated or pulsatile drug delivery using functional hydrogels is a recent trend in hydrogel drug delivery

Selective tumor localization and improved therapeutic index of anthracyclines encapsulated in long-circulating liposomes

Abstract: We have investigated the tissue distribution, toxicity, and antitumor activity of anthracyclines encapsulated in hydrogenated phosphatidylinositol (HPI)-containing liposomes which show a characteristic long circulation time in plasma (J. Natl. Cancer Inst., 81: 1484-1488, 1989). Phosphatidylglycerol (PG)-containing liposomes were used for comparison. Doxorubicin (DOX) or epirubicin (EPI) was encapsulated in the aqueous interior of small (65-100 nm mean diameter) HPI or PG liposomes. The DOX and EPI levels in i.m. tumor implants of the J6456 lymphoma were significantly raised by delivery in HPI liposomes but not by delivery in PG liposomes. No such increase was observed in normal muscle tissue. When DOX encapsulated in HPI liposomes was injected i.v. into BALB/c mice bearing an ascitic form of the J6456 lymphoma, more than 10% of the injected dose was recovered in the ascitic fluid in liposome-associated form. No significant accumulation of liposomal drug was observed in peritoneal washes from tumor-free mice. DOX encapsulation in either PG- or HPI-containing liposomes reduced the lethal toxicity of the drug in mice. However, only the HPI-DOX formulation was significantly more active than free DOX in the treatment of the ascitic J6456 tumor at all dose levels tested. Therapeutic results with EPI encapsulated in HPI liposomes also showed an efficacy superior to that of free EPI. These studies provide evidence that anthracyclines delivered in long-circulating liposomes extravasate with relative selectivity in tumor areas, improving the overall therapeutic index.

Drug-polymer conjugates: potential for improved chemotherapy.

Abstract: Use of polymeric drug delivery systems is rapidly becoming an established approach for improvement of cancer chemotherapy. Zoladex, a poly lactide-co-glycolide subcutaneous implant that delivers a luteinizing hormone releasing hormone analog over 28 days, is now the treatment of choice for prostate cancer, and a polyanhydride matrix containing BCNU is currently in phase III evaluation for treatment of glioma multiforme. Soluble polymers were first proposed as targetable drug carriers in the mid-1970s, and although the first conjugates are still at an early stage of development some, e.g. SMANCS (styrene maleic acid-neocarzinostatin) and monomethoxypolyethyleneglycolasparaginase, are now undergoing clinical evaluation and show considerable promise. Polymeric drug delivery systems are usually designed to produce an improved pharmacokinetic profile of an antitumor agent (controlled release) and in addition soluble carriers can achieve either first-order (organ specific) or second-order (tumor specific) drug targeting by virtue of the fact that they are usually administered intravenously and should theoretically access primary and secondary disease. Soluble polymeric carriers have the potential to improve the activity of conventional antitumor agents, peptide and protein drugs, and have recently been used in constructs for delivery of oligonucleotides. With increased awareness that the successful design of a polymeric drug delivery systems can only be achieved with prior consideration of the pathology and stage of the disease, tumor accessibility, biochemistry and cell biology of the target site, choice of appropriate therapeutic agent(s) and understanding of their fundamental mode of action, we have seen the emergence of a number of exciting and potentially more selective antitumor therapies based on polymer technologies. Here, the basic principles for design of soluble polymeric drug delivery systems are explained and illustrated using examples drawn from our studies on the development of N-(2-hydroxypropyl)methacrylamide copolymer conjugates for use in cancer chemotherapy. Those soluble polymeric carriers that are undergoing clinical evaluation are briefly reviewed.

Use of combinations gelling polysaccharides and finely divided drug carrier substrates in topical ophthalmic compositions

Abstract: Ophthalmic compositions comprising combinations of gelling polysaccharides and finely-divided drug carrier substrates which become relatively more viscous on contact with the eye are disclosed. These ophthalmic compositions are both comfortable and long-lasting Ophthalmic compositions further comprising a pharmaceutically active drug are also disclosed, as are methods of use.

Mixed micelles in drug delivery.

Abstract: Large disk-like mixed micelles composed of a drug and biological lipid are thermodynamically stable and represent a novel drug delivery system. Their unique physical properties are reflected in a significantly improved therapeutic index.

Optimized Formulation of Magnetic Chitosan Microspheres Containing the Anticancer Agent, Oxantrazole

Abstract: A combined emulsion/polymer cross-linking/solvent evaporation technique was used to prepare magnetic chitosan microspheres (MCM) containing the anticancer drug, oxantrazole. A central composite experimental design was used to simultaneously evaluate a variety of formulation factors on a number of response variables, such as the percentage of oxantrazole entrapped in the MCM. In association with the study design, statistical optimization procedures indicated the factors that significantly influence MCM preparation and what levels of the factors are needed to produce optimum MCM. Entrapment of anticancer agents into biodegradable microspheres is difficult because of low aqueous drug solubility and porosity of the particles. The latter effect was circumvented by a chitosan cross-linking step that resulted in approximately 3% (w/w) oxantrazole entrapment in the MCM via the optimization procedures. The combined formulation and statistical optimization strategy provide a basis to develop other microparticulate systems and led to a dosage form that can be used for future in vivo investigations.

Block copolymers as drug carriers.

Abstract: The main subject of this review is to describe the concept and strategy of utilizing block copolymers as drug carriers and to present a perspective for this utilization. The first section points out preferable properties of block copolymers as drug carriers with a brief survey on classifications and synthesis of block copolymers and specifies the merits of block copolymers for this purpose in the historical background of polymeric drug carriers. The second section introduces several studies using block copolymers as drug carriers. These studies contain surface modification of microspheres with block copolymers, polymeric micelles, and a conjugate of an antibody and block copolymer. In conclusion, it is determined that block copolymers possess a high potential for use as drug carriers irrespective of some difficulties in their synthesis.

Calcium alginate beads as core carriers of 5-aminosalicylic acid.

Abstract: The utilization of calcium alginate beads as core carriers for delayed dissolution followed by burst release as a potential method of intestinal site specific drug delivery was investigated. 5-Aminosalicylic acid was spray-coated on dried calcium alginate beads and then coated with different percentages of enteric coating polymer and/or sustained-release polymer. Beads coated with more than 6% (w/w) methacrylic copolymer plastisized with dibutyl sebacate and triethyl citrate resisted release in 2-hr acid fluid challenge and allowed immediate dissolution upon transfer to simulated intestinal fluid. With 6% (w/w) methacrylic copolymer on top of 4% (w/w) ethylcellulose polymer, the major portion of drug did not release in 2 hr of acid treatment or the next 3 hr of simulated intestinal fluid treatment. This dosage form provides the possibility to deliver drug to the lower intestinal tract with minimal early release, followed by sustained release in the colon.

New macromolecular carriers for drugs. I. Preparation and characterization of poly(oxyethylene‐b‐isoprene‐b‐oxyethylene) block copolymer aggregates

Abstract: This work describes the formation of discrete micelles (⋍ 0.1 μm) from ABA poly(oxyethylene-b-isoprene-b-oxyethylene) block copolymers in water. An efficient labeling of the micelles by polymerization of [14C]-styrene within the hydrophobic core is also described. These micellar nanoparticles are being considered as promising materials for controlled release and/or site-specific drug delivery systems. In experimental animals the micelles remained in circulation with a half-life in excess of 50 h. Our results demonstrate the advantages of using block copolymers for the preparation of “perfect” biocompatible surfaces such as are required for well-tolerated, long-circulating particulate drug carriers.

Low molecular weight proteins as carriers for renal drug targeting. Preparation of drug-protein conjugates and drug-spacer derivatives and their catabolism in renal cortex homogenates and lysosomal lysates.

Abstract: Low molecular weight proteins (LMWPs) are known to be reabsorbed and catabolized primarily by the proximal tubular cells of the kidneys. As such, LMWPs might serve as drug carriers that release drugs site-specifically in the kidney. We tested this concept in vitro by coupling different drugs to the LMWP lysozyme both directly (amide bond) and via different spacers: oligopeptides (amide bond), (poly-)alpha-hydroxy acids (ester bond), and a pH sensitive cis-aconityl spacer (amide bond). The capability of the kidney to release the parent drug from such drug-spacer derivatives and drug-LMWP conjugates by enzymatic or chemical hydrolysis of the bond was tested by incubation experiments in renal cortex homogenates and lysosomal lysates. Directly coupled conjugates of terminal carboxyl group containing drugs and lysozyme were catabolized to single amino acids, but did not result in release of the parent drug. The amide bond between the drug and the final amino acid (lysine) appeared to be stable in the incubation milieu. Different oligopeptide spacers coupled to the drugs showed similar results: the oligopeptide itself was cleaved but the amide bond between the drug and different single amino acids remained untouched. Only amide bonds of derivatives of carboxylic drugs with peptide structures themselves were cleaved. Some of the directly coupled conjugates of terminal amino drugs and oligopeptides showed clear release of the parent drug whereas others were stable. Terminal amino drugs were rapidly released from an acid-sensitive cis-aconityl spacer. Terminal carboxyl group containing drugs were enzymatically released from their glycolic and lactic ester spacers at different rates. These kinds of drugs were also released as parent drug from LMWP conjugates with ester spacers like L-lactic acid. Increasing spacer length by intercalating a tetra(L-lactic acid) molecular between the drug and the protein further increased the extent and rate of drug release, indicating increased accessibility of the bond to the enzymes. Terminal amino group containing drugs were rapidly generated as parent drug from LMWP conjugates using an acid-sensitive spacer. In addition the conjugates were found to be adequately stable in plasma, considering their rapid clearance from the bloodstream. It is concluded that LMWPs may indeed be of use as carriers for specific renal delivery of drugs, since renal cortex homogenates and lysosomal lysates are able to catabolize the protein and generate the parent drug from drug-LMWP conjugates bearing suitable spacers. The option of enzymatic release is limited by the narrow specificity of the lysosomal enzymes.(ABSTRACT TRUNCATED AT 400 WORDS)

Concepts on the Use of Liposomal Antimicrobial Agents: Applications for Aminoglycosides

Abstract: Liposomes are microscopic lipid vesicles consisting of one or more concentric phospholipid bilayers enclosing discrete aqueous spaces. Liposomes provide an apparently nontoxic biological delivery system for hydrophobic and hydrophilic drugs. With few exceptions liposomal antimicrobial drugs are administered intravenously, although other routes have been investigated. Intravenously administered, conventionally prepared vesicles are rapidly cleared from the blood principally by phagocytic cells of the mononuclear phagocyte system (MPS), in particular by macrophages located in the liver (Kupffer's cells) and spleen. The expectation that liposomes would provide a new form of drug carrier capable of diverse physiological selectivity has not been realized. The low endocytotic capacity of many cell types and the inability of liposomes to transverse continuous vascular endothelia have prevented the active targeting of non-MPS tissues with liposomes. Despite their well-documented toxicity and the development of new antimicrobial classes, aminoglycosides continue to have an important antimicrobial role. The encapsulation of aminoglycosides into liposomes may reduce the toxicity associated with the multiple daily administration often required for patients with normal renal function. In addition, the encapsulation of aminoglycosides alters their pharmacokinetics, increases t1/2 and area under the curve, decreases Vd and Cpmax, and causes a shift in drug accumulation from the kidney to other organs, thus potentially reducing nephrotoxicity. Studies demonstrate improved outcome for intracellular infections treated with liposomal aminoglycosides vs. free aminoglycosides. Unresolved questions include what role liposomal aminoglycosides have in the treatment of extracellular infection and whether their sustained release action will promote resistance.

Recent developments in peptide drug delivery to the brain.

Abstract: Peptide-based therapeutics are highly water-soluble compounds that do not readily enter brain from blood owing to poor transport through the brain capillary endothelial wall, i.e., the blood-brain barrier (BBB). Strategies available for peptide drug delivery to brain include: (a) neurosurgical-based (intraventricular drug infusion, hyperosmotic opening of the BBB); (b) pharmacological-based (peptide lipidization, liposomes); and (c) physiological-based (biochemical opening of the BBB, chimeric peptides). Chimeric peptides are formed by the covalent coupling of a pharmaceutical peptide (that is normally not transported through the BBB) to a brain transport vector that undergoes absorptive-mediated or receptor-mediated transcytosis through the BBB. The most efficient brain transport vector known to date is a monoclonal antibody to the transferrin receptor, and this vector achieves a brain volume of distribution approximately 18-fold greater than the plasma space by 5 hr after a single intravenous injection of antibody. The chimeric peptides are formed generally with chemical-based linkers. However, avidin/biotin-based linkers allow for high yield coupling of drug to vector, and for the release of biologically-active peptide following cleavage of the chimeric peptide linker. These strategies may also be used for the delivery of antisense oligonucleotide-based therapeutics to brain. In conclusion, the development of efficacious neuropharmaceuticals in the future will require the development of both drug delivery and drug discovery strategies that operate in parallel.

Medication vehicles made of solid lipid particles (solid lipid nanospheres sln)

Abstract: The present invention relates to a drug carrier comprising particles of lipid or lipoid material or mixtures thereof, having a diameter of 10 nm to 10 μm and solid at room temperature. The drug carrier can control the release of the active substance over a longer period of time due to the solid core, and also incorporate the hydrophilic agent into the solid core. Moreover, drug carriers degrade relatively quickly and do not produce toxic byproducts.

Synthesis and drug-release characteristics of the conjugates of mitomycin C with N-succinyl-chitosan and carboxymethyl-chitin.

Abstract: By condensation of mitomycin C (MMC) with N-succinyl-chitosan (Suc-chitosan) and carboxymethyl-chitin (CM-chitin) using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, Suc-chitosan-MMC conjugate (Suc-chitosan-MMC) and CM-chitin-MMC conjugate (CM-chitin-MMC) were prepared, respectively. The reaction conditions for 45 min at pH 5 and for 2 h at pH 5 were selected as the most appropriate for the preparations of Suc-chitosan-MMC and CM-chitin-MMC, respectively. Suc-chitosan-MMC was obtained as a water-insoluble product, while CM-chitin-MMC was partially water-soluble. When the ratio of MMC to the polymer supports changed in the conjugation reaction, the conjugates with 33% (w/w) and 23% (w/w) MMC contents were obtained as those most highly drug-loaded for Suc-chitosan-MMC and CM-chitin-MMC, respectively. At pH 7.4 at 37 degrees C, Suc-chitosan-MMC regenerated MMC very slowly, while the release of MMC from CM-chitin-MMC was relatively fast. Each drug release followed very nearly pseudo-first order kinetics, in which the apparent drug release rate constants (k(apps)) of Suc-chitosan-MMC and CM-chitin-MMC were 3.9 x 10(-3) and 1.1 x 10(-1) (h-1), respectively.

Degradable polymers for site-specific drug delivery

Abstract: The present article was aimed to review the properties and applications of the actually available biodegradable polymers that have been used as targetable drug carriers and site-specific delivery systems. We have mainly focused on microparticulate or carrier-based drug delivery systems with little emphasis on implants as site-specific delivery systems. The review was divided into two major sections. The first section includes a brief description of the properties and applications of the existing biodegradable polymers for site-specific drug delivery classified in two main categories: synthetic biopolymers (as polyesters, polyanhydrides, polyorthoesters, polyphosphazenes, polycaprolactones), and natural biomaterials (as collagen, albumin and gelatin), which still remains an active area of research in spite of the extensive development of new biodegradable polymers. The second section discusses the mechanistic approaches for the selection of polymeric carriers. General guidelines for the ideal drug carrier complex were summarized. The importance of knowing and understanding the physicochemical properties of the polymer for the optimization of the final formulation and its eventual application were emphasized. The factors governing the effective drug concentration at the specific target site were reviewed. Some of the equations describing the release kinetics of a drug from a polymeric matrix were also examined. The last section of the review describes the preparation and use of polymeric macromolecular prodrugs. A diagrammatic representation of possible polymeric prodrug systems for use in site-specific delivery was described. The basic requirements from a polymeric prodrug system were also discussed. Finally, clinical applications of polymeric prodrugs as for cancer therapy and colonic delivery were considered.

Antileishmanial drug targeting through glycosylated polymers specifically internalized by macrophage membrane lectins.

Abstract: Antileishmanial chemotherapy is hampered by the location of the parasite within the phagolysosome of the macrophage, which restricts the bioavailability of many potentially useful antileishmanial drugs. In this study, the possibility of using antileishmanial drugs targeted to the infected macrophages by means of a chemical linkage to a neutral mannose-substituted poly-L-lysine carrier molecule was explored. The study was performed in an in vitro model with Leishmania donovani-infected murine macrophages. The antileishmanial activities of various synthetic constructs were compared with those of the free drugs and the pentavalent antimonial Pentostam, which was used as the positive control. The 50% effective dose of allopurinol riboside linked to the mannosylated poly-L-lysine was below 7.5 x 10(-6) M, while it was up to 3 x 10(-4) M for the free drug, indicating that the drug bound to the polymer was 50 times more active than the free drug. Control experiments with other constructs (e.g., allopurinol riboside linked to the mannose-free polymer) confirmed that the enhancement of activity was indeed achieved by means of the mannose homing device.

Phagocytosis of liposomes by human platelets.

Abstract: We have shown that platelets are capable of phagocytosing liposomes rather than simply sequestering particles as previously postulated. Incubation of human platelets with small neutral unilamellar liposomes (approximately 74 nm) resulted in uptake of the liposomes and retention of the lipid with rapid release of the aqueous-phase components. The lipid label [3H]-cholesterylhexadecyl ether and water-soluble [3H]inulin were used to study the fate of the liposome components. Uptake of liposomes was proportional to the number of liposomes added and to the incubation time. Approximately 250 liposomes per platelet were taken up within a 5-hr incubation period. Uptake of the liposomes occurred through the open-channel system, as evidenced by thin-section electron microscopy, and was followed by accumulation and degradation in acid- and esterase-containing vesicles, as determined by changes in fluorescence of the pH-sensitive probe, pyranine (1-hydroxypyrene-3,6,8-trisulfonic acid), and hydrolysis of the cholesteryl [14C]oleate membrane marker. Uptake was inhibited by the addition of EDTA, cytochalasin B, or 2,4-dinitrophenol and iodoacetate to the medium. Results from the serotonin release assay, micro-aggregation assay, fluorescein diacetate membrane integrity assay, and electron microscopy indicate that neither the conditions for loading nor phagocytosis of liposomes significantly alter platelet function or morphology.

The use of liposomes as drug carriers in ophthalmology.

Abstract: Extensive investigations examining the use of liposomes as drug carriers have been carried out over the past 25 years. The concept of employing liposomes as drug carriers in ophthalmology is more recent. A major advantage of employing liposomes in the eye is their ability to evade initially the mononuclear phagocytes that make the intravenous use of liposomes so challenging. Recent work suggests that there are several applications in which use of liposome-entrapped drugs may prove superior to other methods for the diagnosis and treatment of ocular disease. One promising strategy that bears further investigation is ligand-mediated targeting of liposome-entrapped drugs. In order for these types of vesicles to become commercially available, they will have to be proven to be more effective than other targeted drug delivery modalities. In the final analysis, a more complete understanding of the biological changes that occur in various pathological conditions in the eye is needed in order to design the most effective drug carriers for use in ophthalmology.