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Biomedical subjects

E Doelker

Publications and source records attributed to E Doelker.

At least 19 recordsLinked to original sources
PubMed1997

Applications of the ion-pair concept to hydrophilic substances with special emphasis on peptides.

Previous investigations have shown that ionic drugs with high aqueous solubilities can be lipophilized by ion-pair formation, with appropriate counter-ions. This type of association may prove promising for several biopharmaceutical, analytical and technological applications. This review examines the ion-pair concept with special emphasis on its application to peptides. The conditions for ion-pair formation of different molecules, as well as their transfer to organic solvents, are described. The use of ion-pairs to increase the permeation of various therapeutic agents, including peptidic drugs, is also discussed. Recent uses of ion-pairs in micro- and nanoencapsulation of peptides are also commented upon.

Absorption↗
PubMed1996

Influence of surface free energies and cohesion parameters on pharmaceutical material interaction parameters-theoretical simulations.

PURPOSE: The aim of this study was to perform simulations of the influence of surface free energies and cohesion parameters on various interaction parameters within binary systems. METHODS: Using predictive equations derived from surface free energies and cohesion parameters originally proposed by Wu (2, 3) and by Rowe (4), values of interfacial tension, spreading and reduced spreading coefficients, interaction parameter and strength of interaction were simulated by means of a data processor. The influence of polar and disperse fractions of the two interacting materials was also examined. RESULTS: From the simulations, boundary conditions could be drawn: minimum interfacial tension, positive spreading coefficient, reduced spreading coefficient superior to unity, maximum value of the interaction parameter or of the strength of interaction. CONCLUSIONS: Simulations of the various parameters will help the formulator to select proper materials, eg. an agent that will efficiently bind some powdered substrate, a film-forming agent that will properly coat given cores or a material that will enhibit high interaction with a substrate.

Biocompatible Materials↗
PubMed1995

Pharmacokinetics of a novel HIV-1 protease inhibitor incorporated into biodegradable or enteric nanoparticles following intravenous and oral administration to mice.

CGP 57813 is a peptidomimetic inhibitor of human immunodeficiency virus type 1 (HIV-1) protease. This lipophilic compound was successfully entrapped into poly(D,L-lactic acid) (PLA) and pH sensitive methacrylic acid copolymers nanoparticle. The intravenous administration to mice of PLA nanoparticles loaded with CGP 57813 resulted in a 2-fold increase of the area under the plasma concentration-time curve, compared to a control solution. An increase in the elimination half-life (from 13 to 61 min) and in the apparent volume of distribution (1.7-3.6 L/kg) was observed for the nanoparticle incorporated compound vs control solution. Following oral administration, only nanoparticles made of the methacrylic acid copolymer soluble at low pH provided sufficient plasma levels of CGP 57813. In vitro, these nanoparticles dissolved completely within 5 min at pH 5.8. PLA nanoparticles, which are insoluble in the gastrointestinal tract, did not provide significant plasma concentrations of CGP 57813. From these observations, one can conclude that the passage of intact PLA nanoparticles across the gastrointestinal mucosa appears to be very low.

Acrylic Resins↗
PubMed1995

An investigation on the role of plasma and serum opsonins on the internalization of biodegradable poly(D,L-lactic acid) nanoparticles by human monocytes.

We demonstrate here that polyethylene glycol (PEG) 6,000 protects biodegradable poly(D,L-lactic acid) nanoparticles (PLA NP) from extensive uptake by monocytes in plasma. These results are in agreement with those previously obtained with PEG 20,000 which reduced the uptake of PLA NP by human monocytes in phosphate buffered saline and plasma, and prolonged the NP circulation time in vivo. The coating efficiency of PEG 6,000 and 20,000 was substantially decreased in serum. The difference between the uptake of plain and coated NP clearly reappeared for PEG 20,000-coated NP in heat inactivated serum and in IgG-depleted serum. We suggest that typical plasma proteins, heat labile serum proteins (e.g. complement components) and IgG are involved in the opsonization of plain and coated PLA NP. Other proteins previously found to adsorb onto these NP, namely albumin and apolipoprotein E, did not appear to directly influence the uptake process.

Biodegradation, Environmental↗
PubMed1995

In vivo evaluation of an indomethacin monolithic, extended zero-order release hard-gelatin capsule formulation based on saturated polyglycolysed glycerides.

The sustained release properties of an indomethacin hard-gelatin capsule formulated with saturated polyglycolysed glycerides (Gelucire) were demonstrated in vivo. Indomethacin was selected as a model drug with very poor solubility in water and acidic media. It is known to exhibit high intersubject variability because of enterohepatic circulation. The formulation, which in vitro showed an erosion-controlled release, was compared in six human volunteers in the fed state by using a randomized cross-over design, to a standard multiple-unit diffusion-controlled pellet capsule. Close action period values (time duration with plasma levels higher than 0.5 micrograms/ml) were found for the test and the reference formulation (5.2 and 5.7 h). The time to reach peak t(max) appeared slightly shorter for the test preparation (1.75 h) than for the reference formulation (2.67 h), but the difference was not statistically significant because of the high intersubject variability (non-parametric Wilcoxon matched pair test). Again, due to the small number of subjects entered in the study (insufficient for a real bioequivalence study) equivalence could not be accepted in terms of extent and rate of absorption based on the decision procedures involving the 90% confidence interval and the two one-sided t-tests. The mean maximum plasma concentrations Cmax were 3.35 and 2.82 micrograms/ml for the test and the reference formulation respectively, with the corresponding values of the area under the plasma concentration-time curve AUC amounting to 10.14 and 11.38 micrograms h/ml. However, a simulation on 24 subjects (3 repetitions of the same data) would lead to bioequivalence of the two preparations. As for other corrosion-controlled forms, drug release from the proposed Gelucire formulation was very sensitive to hydrodynamic conditions, leading to poor in vitro-in vivo correlation, when comparison is made with a reference formulation characterized by a diffusion-controlled release. Finally, it was concluded that erosion-controlled release formulations are especially suitable for drugs, such as indomethacin, that have low solubility in water or acidic media. More generally, sustained release hard gelatin capsules with thermosetting excipients is very versatile and their preparation is very straightforward.

Adult↗
PubMed1995

In vitro and in vivo evaluation of progesterone implants based on new biodegradable poly(glutamic and glutamate esters) copolymers.

New biodegradable polypeptidic copolymers of glutamic acid and tert-butyloxycarbonylmethyl glutamate were evaluated as implantable drug delivery systems. Three copolymers varying in degrees of esterification, which is inversely proportional to the number of glutamic residues, were selected for their range of hydrophilicity and biodegradation rates. Progesterone-containing implants were then prepared by means of an extrusion process and both in vitro and in vivo evaluations were performed. The effects of drug loading, nature, and pH of release medium were investigated. In vitro/in vivo correlations were established for some types of implants. Finally, mathematical fitting of the data, using published models, helped to better understand the mechanisms governing release.

Animals↗
PubMed1994

Internalization of poly(D,L-lactic acid) nanoparticles by isolated human leukocytes and analysis of plasma proteins adsorbed onto the particles.

The objective of this work was to investigate the interactions of poly(D,L-lactic acid) nanoparticles prepared by a recently developed salting-out process, with lymphocytes and monocytes isolated from healthy human donors. Nanoparticles were labeled with a hydrophobic fluorescent dye and incubated with lymphocytes and monocytes, and their uptake was followed by flow cytometry in the presence and absence of plasma. Plasma protein adsorption increased nanoparticle uptake by monocytes, whereas a decrease of cellular binding of the nanoparticles to lymphocytes was noted. The cellular uptake for both cell types consisted in a passive adsorption and in an energy-requiring process, because the cells became 2-3 times more fluorescent when the incubation temperature was increased from 4 to 37 degrees C. When nanoparticles were coated with polyethylene glycol 20,000, uptake by monocytes decreased by 43 and 78% in phosphate-buffered saline and plasma, respectively; a similar decrease in nanoparticle uptake was observed for lymphocytes. Two-dimensional gel electrophoresis was performed to identify the plasma opsonins adsorbed onto the nanoparticle surface. Protein mappings for uncoated and polyethylene glycol-coated nanoparticles differed for two spot series. These spots, not yet clearly identified, may represent specific apolipoproteins involved in the metabolism of human lipoproteins, indicating the possible involvement of specific receptors in the uptake of the nanoparticles.

Adsorption↗
PubMed1993

In vitro extended-release properties of drug-loaded poly(DL-lactic acid) nanoparticles produced by a salting-out procedure.

Savoxepine-loaded poly(DL-lactic acid) (PLA) nanoparticles were prepared using an emulsion technique involving a salting-out process which avoids surfactants and chlorinated solvents. After their formation, the nanoparticles were purified by cross-flow microfiltration and subsequently freeze-dried. The drug loading and the drug entrapment efficacy were improved by using savoxepine base rather than the methanesulfonate salt and by modifying the pH of the aqueous phase. A drug entrapment efficacy as high as 95% was obtained with a 9% drug loading. The overall yield of the procedure can rise up to 93%. In vitro release studies have demonstrated that by varying the mean size of the nanoparticles and their drug loading, the release of the drug from the nanoparticles can be modulated to last from several hours to more than 30 days, thus allowing the preparation of an injectable extended-release dosage form.

Antipsychotic Agents↗
PubMed1992

Long-term histopathological study of new polypeptidic biomaterials.

The long-term histopathological evaluation of a new class of synthetic polypeptides, the poly(tert-butyloxycarbonylmethyl glutamates), as implantable drug delivery systems is addressed. This evaluation was performed in rat muscles over one year. The histological analysis included the measurement of many parameters, such as the type and thickness of the collagen capsule. The influence of the presence of progesterone, the selected active drug, could also be monitored over time.

Animals↗
PubMed1989

Acute histopathological response to a new biodegradable polypeptidic polymer for implantable drug delivery system.

This article deals with the in vivo evaluation of a new class of synthetic polypeptides, the poly[(tert-butyloxycarbonylmethyl) glutamates], POMEG, as an injectable or implantable drug delivery system. Three different polymers, varying in their degree of esterification, were extruded either with or without progesterone, and finally implanted in rats up to 14 days. Histologic evaluation of the implant sites show evidence of the good biocompatibility of these polymers. In addition, the description of their in vivo behavior, based on microscopic observation of the implanted POMEG rods, enables one to appreciate their potential as a drug delivery system for short- or long-term therapy.

Animals↗
PubMed1989

Effect of polymeric network structure on drug release from cross-linked poly(vinyl alcohol) micromatrices.

Three types of poly(vinyl alcohol) were cross-linked by glutaraldehyde to form water-swellable materials possessing a three-dimensional, molecular network. Proxyphylline and theophylline were incorporated into the polymer networks during the cross-linking reaction. The firm hydrogels formed were dried and reduced to a particle size of 400-630 microns. The molecular structure of the gels was characterized by equilibrium swelling measurements which allowed the determination of the average distance between two cross-links and, hence, the macromolecular mesh size. The sulfate and glutaraldehyde residues contained in the purified and nonpurified cross-linked polymers were analyzed, and methods for their elimination and inactivation were developed. Drug release from the highly cross-linked gels could be controlled over more than 12 hr, as the diffusion process in these very dense macromolecular networks is rather slow. The extent of branching and entanglement of the polymeric chains appeared to have an important effect. In addition, the release rate was influenced greatly by the amount and, to a lesser extent, by the type of drug in the network.

Aminophylline↗
PubMed1989

Methodology for a better evaluation of the relation between mechanical strength of solids and polymorphic form.

In order to evaluate the role played by polymorphism in the mechanical strength of solid dosage forms (e.g. compressed tablets) and minimize the influence of other factors (such as compaction force, porosity, particle size, and possibly crystal habit), a melted disc technology was developed. With this technique, tablet-shaped discs of zero porosity were prepared by melting powder and subsequent crystallization in the desired modifications. Taking phenobarbitone as a model drug, different methods were used to get discs of forms I, II and III and the amorphous form. Mechanical properties of the discs were assessed, primarily through their bending strength. The Vickers hardness number was also determined for some specimen discs and monocrystals. Results showed that the amorphous form and form III of phenobarbitone gave the toughest discs and would therefore the most suitable materials to manufacture coherent tablets. Moreover, the various preparation methods used resulted in discs of different internal structures. Both crystal size and crystal habit significantly affected the physical properties of the tested materials.

Chemistry, Pharmaceutical↗
PubMed1989

[Use of principles of iontophoresis and electrophoresis for controlled release of medical substances].

The present review describes work done over the past twenty years on the controlled release of drugs using iontophoresis or electrophoresis techniques. Following a description of therapeutic applications, in vivo and in vitro studies have been discussed with emphasis on the potentials of such techniques to control drug release. Different mathematical models have been reviewed and an attempt has been made to combine them to explain the various configurations of systems currently used.

Chemistry, Pharmaceutical↗
PubMed1987

Osmotic water transport through cellulose acetate membranes produced from a latex system.

The advisability of a progressive curtailment of organic solvent film coating offers an incentive to develop latex systems. Here, the use of aqueous colloidal dispersions of cellulose acetate, plasticized with water-soluble additives, is proposed as an alternative way to obtain cellulose acetate membranes either by casting or spraying. The osmotic water permeability of both kinds of films was measured, as well as their loss of leachable materials and degree of swelling in a saturated solution of potassium chloride. The permeabilities varied over a wide range depending on the physicochemical properties of the plasticizer and its initial concentration in the latex, and on the conditions for coating (temperature, rate of spraying, and drying duration). High boiling point plasticizers gave more permeable films. Films prepared by casting were found to be sensitive to their sodium dodecyl sulfate content.

Cellulose↗
PubMed1987

Mechanically strong films produced from cellulose acetate latexes.

Mechanically strong films, comparable with those obtained from organic solutions, can be produced from cellulose acetate latexes, a new type of dispersion, both by casting and spraying. The prerequisite conditions for high strength, which include choice of water-soluble plasticizers possessing some degree of volatility, are discussed.

Cellulose↗