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Biomedical subjects

R Gurny

Publications and source records attributed to R Gurny.

At least 91 records · Page 5Linked to original sources
PubMed1995

Ocular availability of gentamicin in small animals after topical administration of a conventional eye drop solution and a novel long acting bioadhesive ophthalmic drug insert.

PURPOSE: Gentamicin eye drop solutions have a short precorneal residence time. The present study investigates the effect of gentamicin using a new long acting delivery Bioadhesive Ophthalmic Insert (BODI) in healthy dogs and rabbits and compares the results with a conventional regimen using an eye drop solution. METHODS: In vivo assays were performed on animals after deposition of one BODI and instillations of an eye drop solution. Tear samples were collected over 72 hours and 60 minutes, in the case of inserts and eye drop solution respectively. The gentamicin concentration profiles in tear fluid (determined by a fluorescent polarization immunoassay technique) was individually analyzed, in each animal, in relation with the minimum inhibitory concentration observed in vitro against some bacteria. A non classical pharmacokinetic approach was used for the analysis of the topically applied drug substance, involving two parameters: the efficacy area under the curve (AUCeff) and the efficacy time (teff). RESULTS: In the case of the eye drop solution, the AUCeff were higher in dogs (2.80 10(3) - 3.64 10(3) [micrograms ml-1 h]) than in rabbits (0.64 x 10(3) - 0.95 x 10(3) [micrograms ml-1 h]); the teff had a similar behavior: 6-15 [h] in dogs and 2-6 [h] in rabbits. In the case of BODIs, the AUCeff and the teff were quite similar between dogs and rabbits: 190 10(3) - 205 10(3) [micrograms ml-1 h] and 70-76 [h], respectively. The AUCeff and the teff were always much higher in the case of BODIs than for the eye drop solution both in dogs and rabbits. CONCLUSIONS: This study shows that topical administration of gentamicin using BODIs can improve treatment due to the decreasing number of applications while ensuring an effective level of antibiotic in tears controlled by the device.

Animals↗
PubMed1995

PEG-coated poly(lactic acid) nanoparticles for the delivery of hexadecafluoro zinc phthalocyanine to EMT-6 mouse mammary tumours.

Hexadecafluoro zinc phthalocyanine (ZnPcF16), a second generation sensitizer for the photodynamic therapy of cancer, was incorporated in three vehicles: poly(D,L-lactic acid) (PLA) nanoparticles, polyethylene glycol (PEG)-coated nanoparticles and a Cremophor EL (CRM) oil-water emulsion. Nanoparticles were prepared by the salting-out procedure. Biodistribution of the dye was assessed by fluorescence in EMT-6 mammary tumour bearing mice after intravenous injection of 1 mumol kg-1 ZnPcF16. Plain nanoparticles were rapidly retained by the reticuloendothelial system (RES) as reflected by the low area under the blood concentration-time curve (AUC0-168, 57 micrograms h g-1). Little tumour uptake of the dye was observed with this formulation. In contrast, PEG-coated nanoparticles displayed a reduced RES uptake, leading to significantly higher blood levels over an extended period (t1/2 30 h; AUC 0-168 227 micrograms h g-1) and enhanced tumour uptake. At 48 h post injection, tumour to skin and tumour to muscle concentration ratios reached 3.5 and 10.8, respectively. Blood levels of ZnPcF16 after administration as a CRM emulsion decreased faster than with PEG-coated nanoparticles (t1/2 12 h), but since no early liver uptake was observed, the AUC0-168 and the tumour uptake were only slightly lower. However, with the CRM formulation, a late liver uptake was observed, reaching 51% of the injected dose after 7 days.

Animals↗
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↗
PubMed1994

Biocompatibility of a new semisolid bioerodible poly(ortho ester) intended for the ocular delivery of 5-fluorouracil.

The biocompatibility of a new semisolid, hydrophobic poly(ortho ester) (POE) intended for controlled drug delivery to the eye was evaluated. The polymer was injected subconjunctivally in rabbits, and clinical and histologic examinations were performed 3, 10, 15, and 21 days after injection. Polymers injected as controls were an aqueous gel of sodium hyaluronate (SH), 1% in phosphate buffer, and medical grade silicone oil. After injection, the POE emulsified into small droplets and a focal eosinophilic reaction was noted at 3 days' implantation. At 10 days' implantation, the POE was not identified in the implantation site and the inflammatory reaction had resolved, with fibroblasts being the predominant cell type. At 15 and 21 days, no POE was identified and normal appearing tissue was present in the injection site. Sodium hyaluronate was not inflammatory over the period of the implantations. Silicone oil induced a slight inflammation at 3 days, with the presence of eosinophils and limited necrosis with cellular debris. Silicone oil was present in the implantation site at 3, 10, 15, and 21 days. The inflammatory response to the respective polymers was evaluated in the subconjunctival tissue. The inflammatory reaction was quantified at the implant site, adjacent subconjunctival tissues, and scleral and corneal stroma. The inflammatory cell densities in these respective tissue zones were determined, and the ratio of eosinophils over total inflammatory cells was calculated. POE did not become encapsulated with fibrous tissue, but biodegraded in a short time, indicating its potential for use after glaucoma filtration surgery.

Animals↗
PubMed1994

Gamma sterilization of a semi-solid poly(ortho ester) designed for controlled drug delivery--validation and radiation effects.

Radiation sterilization is becoming increasingly popular for the sterilization of many pharmaceutical products. Although this technique is not limited to the sterilization of polymers, it is probably the most suitable method for such materials. This method however suffers several drawbacks. The sterilization of a product must lead to a safety level of 10(-6), i.e. one chance in a million to find a contaminated sample. In many cases, this assurance of sterility can be achieved by using a uniform treatment dose of 2.5 Mrad, recommended by the pharmacopeia. We investigated the possibility of using doses of radiation inferior to 2.5 Mrad to sterilize a semi-solid poly(ortho ester) (POE) developed for use as carrier in controlled drug delivery. After determination of the initial bioburden, the polymer was intentionally contaminated with the bioindicator Bacillus pumilus E 601. Following exposure to gamma irradiation, the D10 value of the radio resistant bioindicator was determined. Using the initial contamination value, the reduction factor D10 and the safety level, it is possible to calculate an optimal sterilizing dose for POE. All polymers are affected by ionizing radiation and the amount of radiation which produces a significant change in properties may vary from one polymer to the other. A molecular weight and dynamic viscosity decrease resulting from backbone cleavage was observed for this POE at a dose lower than 2.0 Mrad. Evaluation of the structure using 1H-NMR, 13C-NMR and IR analysis shows that for doses higher than 2.0 Mrad, another degredation process takes place.(ABSTRACT TRUNCATED AT 250 WORDS)

Chemical Phenomena↗
PubMed1994

In vivo evaluation of dosage forms: application of gamma scintigraphy to non-enteral routes of administration.

The trend to deliver drugs to defined areas of the body involves sophisticated carriers systems. In addition to the in vitro drug release profile one must be aware of the in vivo behaviour of the dosage form and the drug. Gamma scintigraphy is an elegant way to gain insights of the actual in vivo distribution pattern of dosage forms. This technique relies on the use of radioactive tracers included into the medicament and selected so as to enable an optimum detection by a gamma ray camera. The choice of a convenient label enables the in vivo determination of the targeting of the formulation administered through a large number of routes. The present paper reviews applications of gamma scintigraphy for the evaluation of dosage forms administered by the parenteral, rectal, buccal, nasal, pulmonary, and ophthalmic routes.

Administration, Buccal↗
PubMed1993

Biotolerance of a semisolid hydrophobic biodegradable poly(ortho ester) for controlled drug delivery.

We evaluated the biotolerance of a new semisolid poly(ortho ester) (POE) intended for controlled drug delivery. Two different investigations were carried out in rats: subcutaneous injections and the cage-implant system. Sodium hyaluronate (SH), 1%, in phosphate buffer was used as a noninflammatory control. When injected subcutaneously in rats, the POE induced a mild and local inflammation at 3 and 7 days followed by a minimal chronic inflammation at 14 and 21 days. When using the cage-implant system, we quantified the inflammatory components of the exudate surrounding the implanted material within the cage system at 3, 7, 14, and 21 days. The total leukocyte and macrophage concentrations were higher only at 7 days for both SH and POE compared to the control (empty cage). The other parameters were not significantly different from the control. These results show that POE is well-tolerated by rats when used subcutaneously.

Animals↗
PubMed1993

Sodium hyaluronate 0.25% used as a vehicle increases the bioavailability of topically administered gentamicin.

Sodium hyaluronate (SH) solutions have a longer precorneal residence time than isotonic saline solution in rabbits and in humans. The present study investigates the effect of a 0.25% SH vehicle, compared with a phosphate buffer solution (PBS), on the tear concentration after topical administration of gentamicin sulfate (GS) in humans. Eight volunteers received 25 microliters 0.5% GS in PBS in the left eye and 25 microliters 0.5% GS in 0.25% SH in the right eye. Tear samples of 1 microliters were taken from the inferior sulcus using a capillary before instillation and 5, 10, 20, and 40 min after instillation. The tear concentration of GS was determined by radioimmunoassay. There was a statistically significantly higher concentration of GS in the inferior conjunctival sulcus of the SH-instilled eye at 5 min (P < 0.01) and at 10 min (P < 0.05) after instillation (paired t-test, n = 9). At 20 min the concentration of GS in the SH-instilled eye was only slightly higher, and at 40 min GS concentrations in left and right eyes were comparable. SH 0.25% used as a vehicle therefore increases the availability of GS at the ocular surface for at least 10 min. This effect could be due to the prolonged precorneal residence time of SH.

Administration, Topical↗
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↗
PubMed1993

Synthesis and characterization of a new biodegradable semi-solid poly(ortho ester) for drug delivery systems.

Since the late 1970s, three families of poly(ortho esters) (POE) were synthesized to provide bioerodible carriers for drug delivery devices. The most recent POE is a semi-solid polymer with a viscous behavior at room temperature. Polymer synthesis by a transesterification reaction between a triol and a trialkyl ortho ester is described. The structure of the polymer was confirmed by conventional methods such as 1H-NMR, 13C-NMR and FT-IR. Information concerning average molecular weight and intrinsic viscosity was obtained respectively by GPC and viscosimetry. Residual solvents in the polymer were determined using gas chromatography. The chromatographic conditions were optimized to enable the quantification of the solvents in concentrations of a few percent. The mechanical behavior of the semi-solid POE was determined by rheometric measurements. Hydrolysis of the polymer leads to the formation of the original triol and the carboxylic acid derived from the trialkyl ortho ester used in the transesterification step. No toxicological problems associated with these compounds are anticipated.

Biodegradation, Environmental↗
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↗
PubMed1990

Precorneal residence time in humans of sodium hyaluronate as measured by gamma scintigraphy.

The aim of the present study was to quantify in man the distribution and clearance of two aqueous sodium hyaluronate (SH) solutions of 0.125% and 0.250% after the administration of 25 microliters onto the cornea. Isotonic phosphate buffer (PB) was used as a reference instillation. No systemic or local medication was given to the seven 18- to 30-year-old, healthy male volunteers. A detailed evaluation of the anterior segment of the eye, as well as a Schirmer test and a break-up time measurement, yielded results within the normal range. The clearance of 0.125% and 0.250% SH solutions radiolabelled with sodium pertechnetate Tc-99m was measured by gamma scintigraphy and compared with that of a PB solution tagged with the same radiolabel. There was no statistically significant difference between the quantities of 0.125% SH and PB solutions remaining in the precorneal space at 20 min (paired t-test, P = 0.78, n = 7). However, in comparing the 0.250% SH with the PB solution, we observed a statistically significant difference (P = 0.01, n = 7) in the amount remaining in the precorneal space after the same interval. Actually, 53% of the radiolabelled 0.250% SH solution remained on the cornea as compared with 30% for the 0.125% SH solution and 18.3% for the PB solution. These results suggest that an SH solution of 0.250% might have a prolonged residence time on the precorneal surface, and that SH could therefore be used as an additive in various drug-release systems for the eye.

Administration, Topical↗
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

Comparison of different models for the testing of pilocarpine eyedrops using conventional eyedrops and a novel depot formulation (nanoparticles).

An objective in the development of ophthalmic formulations is the use of in vitro or animal models that closely resemble the clinical situation. For this reason, experiments with conventional pilocarpine nitrate eyedrops and a depot formulation of pilocarpine nitrate sorbed to poly (butylcyanoacrylate) nanoparticles were carried out. In vitro, the diffusion of pilocarpine through bovine cornea was measured using Edelhauser cells. In vivo, the rabbit aqueous humor concentration of pilocarpine and miosis were determined after application of the above formulations. In addition, intraocular pressure was measured. Since pilocarpine has little influence on intraocular pressure in healthy rabbits, the pressure had to be increased artificially. Three models were employed that are described in the literature, namely, the betamethasone model, the alpha-chymotrypsin model, and the water-loading model. Pilocarpine could be loaded onto nanoparticles by 15% but was rapidly released from the nanoparticles based on the bovine corneal experiment. Nanoparticles only enhanced the aqueous humor concentration at 30 min; this increase, however, led to a considerably extended period of miosis as well as a reduction in intraocular pressure. The duration of the action and the intensity of the response were different among the three models tested. According to the present results, the betamethasone model seems to represent the best correlation to the clinical situation.

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

[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↗