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Biomedical subjects

C M Lehr

Publications and source records attributed to C M Lehr.

44 records · Page 3Linked to original sources
PubMed1994

Improved ocular penetration of gentamicin by mucoadhesive polymer polycarbophil in the pigmented rabbit.

PURPOSE: To investigate whether polycarbophil, a mucoadhesive polymer of the poly(acrylic acid) type, would improve the ocular delivery of topically applied gentamicin. METHODS: Two gentamicin formulations of this polymer (neutralized versus non-neutralized) and an aqueous control formulation in saline were administered to the pigmented rabbit eye. Drug concentrations in plasma, as well as in cornea, bulbar conjunctiva, anterior sclera, iris-ciliary body, aqueous humor, and vitreous humor, were measured by fluorescence polarization immunoassay. RESULTS: Both polymeric formulations increased the uptake of gentamicin by the bulbar conjunctiva two times. Drug penetration into the aqueous humor was observed with only the non-neutralized polymer, probably occurring via the conjunctival-scleral pathway facilitated by intensified contact between the mucoadhesive polymer and the underlying bulbar conjunctiva. CONCLUSION: Polymers of the poly(acrylic acid) type are potentially useful for improving topical antibiotic drug delivery, particularly when irritancy potential due to low pH can be overcome.

Absorption↗
PubMed1992

Bioadhesion by means of specific binding of tomato lectin.

The possibility of developing bioadhesive drug delivery systems on the basis of molecules which selectively bind to the small intestinal epithelium by specific, receptor-mediated mechanisms was investigated using a lectin isolated from tomato fruits (Lycopersicum esculentum). The tomato lectin (TL) was found to bind specifically onto both isolated, fixed pig enterocytes and monolayers of human Caco-2 cell cultures with a similar affinity. TL-coated polystyrene microspheres (0.98 micron) also showed specific binding to enterocytes in vitro. Lectin binding was found to be favored at neutral pH and to be reduced in an acidic environment. Crude pig gastric mucin, however showed a marked cross-reactivity in vitro, indicating that lectin binding to the cell surface in vivo might be inhibited by mucus.

Adhesiveness↗
PubMed1992

A surface energy analysis of mucoadhesion: contact angle measurements on polycarbophil and pig intestinal mucosa in physiologically relevant fluids.

The possible role of surface energy thermodynamics in mucoadhesion was investigated with Polycarbophil and pig intestinal mucosa. In separate experiments, the surface energy parameters of the substrate (mucosa) and the adhesive (polymer film) were determined by contact angle measurements on captive air/octane bubbles in three physiologically relevant test fluids (isotonic saline, artificial gastric fluid, and artificial intestinal fluid). Whereas the swollen Polycarbophil films were relatively hydrophilic as indicated by small water contact angles (22, 23, and 16 degrees), the water contact angles measured on mucosal tissue were significantly larger (61, 48, and 57 degrees). Hence, mucus was found to possess an appreciable hydrophobicity. The measured adhesive performance (force of detachment) between Polycarbophil and pig small intestinal mucosa was highest in nonbuffered saline medium, intermediate in gastric fluid, and minimal in intestinal fluid. In agreement with this trend, the mismatch in surface polarities between substrate and adhesive, calculated from the contact angle data, increased in the same order.

Acrylic Resins↗
PubMed1992

Effects of the mucoadhesive polymer polycarbophil on the intestinal absorption of a peptide drug in the rat.

The absorption across rat intestinal tissue of the model peptide drug 9-desglycinamide, 8-arginine vasopressin from bioadhesive formulations was studied in-vitro, in a chronically isolated internal loop in-situ and after intraduodenal administration in-vivo. A controlled-release bioadhesive drug delivery system was tested, consisting of microspheres of poly(2-hydroxyethyl methacrylate) with a mucoadhesive Polycarbophil-coating, as well as fast-release formulation consisting of an aqueous solution of the peptide in a suspension of Polycarbophil particles. Using the controlled-release system, a slight improvement of peptide absorption was found in-vitro in comparison with a non-adhesive control system, but not in-situ or in-vivo. In contrast, bioavailability was significantly increased in all three models from the Polycarbophil suspension in comparison with a solution of the drug in saline. The effect appeared to be dose-dependent, indicative of intrinsic penetration-enhancing properties of the mucoadhesive polymer. A prolongation of the absorption phase in-vitro and in the chronically isolated loop in-situ suggested that the polymer was able to protect the peptide from proteolytic degradation. This could be confirmed by degradation studies in-vitro. The duration of the penetration enhancing/enzyme inhibiting effect was diminished with increasing complexity of the test model, in the same way as was previously found for the bioadhesive effect. This interrelationship suggests that the observed improvement in peptide absorption and the mucoadhesive properties of this polymer are associated. The development of a fast-release oral dosage form for peptide drugs on the basis of Polycarbophil appears to be possible.

Acrylic Resins↗
PubMedDate not supplied

From sticky stuff to sweet receptors--achievements, limits and novel approaches to bioadhesion.

About 10 years ago, the concept of bioadhesion was introduced into the pharmaceutical literature and has since stimulated much research and development both in academia and in industry. The first generation of bioadhesive drug delivery systems (BBDS) were based on so-called mucoadhesive polymers, i.e. natural or synthetic macromolecules, often already well accepted and used as pharmaceutical excipients for other purposes, which show the remarkable ability to 'stick' to humid or wet mucosal tissue surfaces. While these novel dosage forms were mainly expected to allow for a possible prolongation, better localization or intensified contact to mucosal tissue surfaces, it had to be realized that these goals were often not so easily accomplished, at least not by means of such relatively straightforward technology. However, although not always convincing as a 'pharmaceutical glue', some of the mucoadhesive polymers were found to display other, possibly even more important biological activities, namely to inhibit proteolytic enzymes and/or to modulate the permeability of usually tight epithelial tissue barriers. Such features were found to be particularly useful in the context of peptide and protein drug delivery. But still, the interest in realizing 'true' bioadhesion continues: instead of mucoadhesive polymers, plant or bacterial lectins, i.e. adhesion molecules which specifically bind to sugar moieties of the epithelial cell membrane, are now widely being investigated as drug delivery adjuvants. These second-generation bioadhesives not only provide for cellular binding, but also for subsequent endo- and transcytosis. This makes the novel, specifically bioadhesive molecules particularly interesting for the controlled delivery of DNA/RNA molecules in the context of antisense or gene therapy.

Animals↗
PubMedDate not supplied

A nonviral DNA delivery system based on surface modified silica-nanoparticles can efficiently transfect cells in vitro.

Diverse polycationic polymers have been used as nonviral transfection agents. Here we report the ability of colloidal silica particles with covalently attached cationic surface modifications to transfect plasmid DNA in vitro and make an attempt to describe the structure of the resulting transfection complexes. In analogy to the terms lipoplex and polyplex, we propose to describe the nanoparticle-DNA complexes by the term "nanoplex". Three batches, Si10E, Si100E, and Si26H, sized between 10 and 100 nm and with zeta potentials ranging from +7 to +31 mV at pH 7.4 were evaluated. The galactosidase expression plasmid DNA pCMVbeta was immobilized on the particle surface and efficiently transfected Cos-1 cells. The transfection activity was accompanied by very low cytotoxicity, with LD(50) values in the milligrams per milliliter range. The most active batch, Si26H, was produced by modification of commercially available silica particles with N-(6-aminohexyl)-3-aminopropyltrimethoxysilane, yielding spherical nanoparticles with a mean diameter of 26 nm and a zeta potential of +31 mV at pH 7.4. Complexes of Si26H and pCMVbeta plasmid DNA formed at w/w ratios of 10 were most effective in promoting transfection of Cos-1 cells in the absence of serum. At this ratio, >90% of the DNA was associated with the particles, yielding nanoplexes with a net negative surface charge. When the transfection medium was supplemented with 10% serum, maximum gene expression was observed at a w/w ratio of 30, at which the resulting particle-DNA complexes possessed a positive surface charge. Transfection was strongly increased in the presence of 100 microM chloroquine in the incubation medium and reached approximately 30% of the efficiency of a 60 kDa polyethylenimine. In contrast to polyethylenimine, no toxicity was observed at the concentrations required. Atomic force microscopy of Si26H-DNA complexes revealed a spaghetti-meatball-like structure. The surface of complexes prepared at a w/w ratio of 30 was dominated by particles half-spheres. Complex sizes correlated well with those determined previously by dynamic light scattering.

Animals↗
PubMedDate not supplied

Influences of process parameters on preparation of microparticle used as a carrier system for omega - 3 unsaturated fatty acid ethyl esters used in supplementary nutrition.

Microparticles were prepared by complex coacervation to encapsulate eicosapentaenoic acid ethyl ester (EPA-EE) for incorporation into foods as a nutrition supplement. Gelatin and acacia were used in the coacervation process. With an increasing oil/polymer ratio, both yield and encapsulation rate decreased; with an increasing homogenization time, the yield remained constant while the encapsulation rate slightly increased. Several particle hardening techniques were examined and their influence on particle structure, yield and encapsulation rate were examined. Ethanol hardening was compared to cross-linking with dehydroascrobic acid with respect to both yield and encapsulation rate. The particle diameters for both formulations were similar (ethanol: 38.4 +/- 4.1 microm; cross-linking: 41.8 +/- 3.0 microm). Spray-drying of the coacervates led to the smallest particles (5.2 +/- 1.1 microm), lowest yield and encapsulation rate. All microencapsulation products were assayed for their storage stability over 4 weeks with respect to the oxidation of the encapsulated omega - 3 unsaturated fatty acid ester inside the particles. Hardening with ethanol showed the lowest amount of peroxides: particle wall cross-linking by dehydroascorbic acid and spray-drying were observed to be less protective. All microparticles were characterized for their internal structure with confocal laser scanning microscopy (CLSM) after fluorescence labelling of the polymers, in order to localize the oil phase and visualize the distribution of the polymers in the coacervates. With increasing homogenization time, the internal structure changed stepwise from a capsule structure (core/wall) towards a matrix structure. For all experiments, a homogeneous distribution for both polymers, gelatin and acacia was observed inside the particle wall. No influence of the different particle hardening procedures on the polymer distribution was found.

Dehydroascorbic Acid↗