Biomedical subjects

R Gurny

Publications and source records attributed to R Gurny.

At least 55 records · Page 3Linked to original sources

PubMed2000

A poly(ortho ester) designed for combined ocular delivery of dexamethasone sodium phosphate and 5-fluorouracil: subconjunctival tolerance and in vitro release.

A viscous hydrophobic poly(ortho ester) (POE) has been developed as a biocompatible, biodegradable sustained release system for selected cases of glaucoma filtering surgery. Dexamethasone and 5-fluorouracil (5-FU) are frequently administered together post-operatively, for their anti-fibroblastic and anti-inflammatory properties, respectively. A combined sustained release of both drugs could be advantageously used. Drug release kinetics were studied using specially designed thermostated cells. Subconjunctival tolerance was evaluated on New Zealand albino rabbits by clinical evaluation. Due to its basicity, the addition of dexamethasone sodium phosphate (DEX-P) stabilized the polymer and prolonged 5-FU in vitro release from 2 to 4 days. Both therapeutic agents were released concomitantly, according to a linear profile. The presence of 5-FU only slightly affected the overall subconjunctival tolerance of POE in rabbits, whereas the addition of DEX-P markedly improved POE tolerance by reducing the hyperemia of the conjunctiva to a minimal grade.

Animals↗

PubMed2000

Salivary fluoride concentrations following applications of bioadhesive tablets and mouthrinses.

Presence of elevated fluoride concentration in saliva is important for the prevention of caries. In the present study, we developed an intra-oral bioadhesive tablet aimed at delivering F(-) in the mouth over a prolonged period of time. Various tablet formulations were tested in vivo for their tolerance and adhesiveness. Two formulations were selected for further studies on salivary fluoride clearance. For comparison, mouthrinses with increasing F(-) concentrations were also examined. Results indicate that a bioadhesive tablet located on the upper gingiva is able to sustain salivary F(-) concentrations for about 10h without major side effects. Mouthrinses with high F(-) concentration were able to prolong salivary fluoride retention for more than 6h.

Adhesives↗

PubMed2000

Formulation and technology aspects of conrolled drug delivery in animals.

In the veterinary field, the development of new routes of administration or new delivery systems capable of controlling the release of drugs are of considerable interest. Because of the large number of food-producing animals and the unique problems associated with the administration of drugs to these animals, the potential markets are huge and will only be fully realized if improvements to old dosage forms lead to practical and effective formulations. This review intends to summarize the state of the art in the field of veterinary controlled and/or prolonged release systems.

Journal Article↗

PubMed2000

Near infrared with principal component analysis as a novel analytical approach for nanoparticle technology.

PURPOSE: To progress in the characterization of a poly(MePEGcyanoacrylate-co-hexadecylcyanoacrylate) (poly(PEGCA-co-HDCA) copolymer and the nanoparticles formed from this copolymer. METHODS: Poly(PEGCA-co-HDCA) at a MePEG/hexadecyl ratio of 1:4 was investigated by 1H-NMR and near infrared spectroscopy. The nanoparticle suspensions, obtained by the methods of nanoprecipitation or emulsion--solvent evaporation, as well as the crude nanoparticles and their dispersion medium--were analyzed by MePEG measurement, 1H-NMR, and near infrared spectroscopy. RESULTS: The 1H-NMR results showed that the (poly(PEGCA-co-HDCA) copolymer obtained bore lateral hydrophilic MePEG chains and lateral hydrophobic hexadecyl chains in a final ratio of 1:4. However, this ratio, although reproducible from batch to batch, represented only a mean value for different molecular species. Indeed, our results demonstrated the formation of more hydrophobic poly(alkyl-cyanoacrylate) oligomers (with a higher content of hexadecyl chains) and other more hydrophilic oligomers (with a higher MePEG content). Only the more hydrophobic oligomers were able to form solid pegylated nanoparticles. As far as these nanoparticles were concerned, determination of their MePEG content allowed the calculation of a distance of 1.2 nm and 1.05 nm between 2 grafted MePEG chains at the nanoparticle surface, when obtained by nanoprecipitation and emulsion-solvent evaporation, respectively. Moreover, when the same copolymer batch was used, different nanoparticles were obtained according to the preparation method, as seen by near infrared spectroscopy. CONCLUSIONS: The nanoparticles obtained by nanoprecipitation or emulsion-solvent evaporation of poly(PEGCA-co-HDCA) 1:4 copolymer displayed a different supramolecular organization, as evidenced by the near infrared spectroscopy results. Moreover, these nanoparticles showed surface characteristics compatible with a long circulating carrier.

Colloids↗

PubMed2000

Freeze-drying and lyopreservation of diblock and triblock poly(lactic acid)-poly(ethylene oxide) (PLA-PEO) copolymer nanoparticles.

In this study, the formulation and process parameters that determine successful production and long-term stability of freeze-dried poly(lactic acid) (PLA) nanoparticles with "hairy-like" poly(ethylene oxide) (PEO) surfaces were investigated. Nanoparticles with grafted (covalently bound) PEO coatings were produced by the salting-out method from blends of PLA and PLA-PEO diblock or triblock copolymers. PLA nanoparticles with physically adsorbed PEO were also produced. The redispersibility of the nanoparticles after freeze-drying under various conditions was assessed. The surface of the nanoparticles was characterized and classified in terms of "brush" and "loop" conformations. Upon freeze-drying, it appeared that the presence of PEO at the nanoparticle surface could severely impair the redispersibility of the particles, especially in the PEO-grafted systems. This effect was shown to be related to the amount and molecular weight of PEO in the various formulations. In most cases, particle aggregation was prevented by use of trehalose as lyoprotective agent. Increasing the concentration of particles in the suspension to be freeze-dried was shown to induce much less damage to the nanoparticles, and freezing the suspension at a very low temperature (-196 degrees C) was found to further improve the lyoprotective effect. Most of the lyoprotected nanoparticles remained stable for at least 12 weeks at 4 and -25 degrees C. The production and preservation of freeze-dried PLA-PEO diblock and triblock copolymer nanoparticles is feasible under optimized lyoprotective conditions.

Drug Delivery Systems↗

PubMed2000

Chitosan as tear substitute: a wetting agent endowed with antimicrobial efficacy.

A cationic biopolymer, chitosan, is proposed for use in artificial tear formulations. It is endowed with good wetting properties as well as an antibacterial effect that are desirable in cases of dry eye, which is often complicated by secondary infections. Solutions containing 0.5% w/v of a low molecular weight (M(w)) chitosan (160 kDa) were assessed for antibacterial efficacy against E. coli and S. aureus by using the usual broth-dilution technique. The in vitro evaluation showed that concentrations of chitosan as low as 0.0375% still exert a bacteriostatic effect against E. coli. Minimal inhibitory concentration (MIC) values of chitosan were calculated to be as low as 0.375 mg/ml for E. coli and 0.15 mg/ml for S. aureus. Gamma scintigraphic studies demonstrated that chitosan formulations remain on the precorneal surface as long as commonly used commercial artificial tears (Protagent collyrium and Protagent-SE unit-dose) having a 5-fold higher viscosity.

Animals↗

PubMed2000

Cellular uptake of PEO surface-modified nanoparticles: evaluation of nanoparticles made of PLA:PEO diblock and triblock copolymers.

Nanoparticles with either physically adsorbed or covalently bound poly(ethylene oxide) (PEO) coatings were produced from various combinations of poly(lactic acid) (PLA) and diblock or triblock copolymers of PLA and PEO. The particles were produced by the salting-out process and purified by the cross-flow filtration technique. The amount of PEO at the nanoparticle surface, as well as the residual amount of emulsifier poly(vinyl alcohol) were assessed, with a good correlation with expected values. Stability of the nanoparticulate suspensions was studied at 4 degrees C and after freezing under various conditions for up to 6 months. The nanoparticle redispersibility after storage was related to the thermal behavior of the PEO coatings. The in vitro cellular uptake of the different types of nanoparticles was compared by flow cytometry after incubation with human monocytes in serum and in plasma. The influence of the PEO molecular weight and surface density on the particle uptake was especially marked for the diblock and triblock copolymer formulations, with a decrease in uptake of up to 65% with one of the diblock copolymer formulations. Nanoparticles made of triblock copolymer with short PEO chains at their surface in the postulated "loop conformation" proved to be as resistant to cellular uptake as nanoparticles made of diblock copolymers with PEO chains in the "brush conformation".

Cell Line↗

PubMed1999

Concomitant and controlled release of dexamethasone and 5-fluorouracil from poly(ortho ester).

A viscous bioerodible and hydrophobic poly(ortho ester) has been developed as a biocompatible, sustained drug release system for an ophthalmic application in intraocular proliferative disorders. The combination of wound healing modulators such as 5-fluorouracil and dexamethasone is a major advantage since these drugs act at different stages of these diseases. Since 5-fluorouracil is an acidic, water-soluble compound and dexamethasone exists in three chemical forms, i.e. the water-insoluble base, the highly hydrophobic acetate ester or the basic phosphate salt, it was of interest to investigate whether the physicochemical properties of the drugs have an influence on their release rates, and whether a concomitant and sustained release of both 5-fluorouracil and dexamethasone could be achieved. It has been found that lipophilicity and acidobasicity play a major role in controlling drug release rates and polymer degradation. The combination of 5-fluorouracil and dexamethasone phosphate allows a sustained and concomitant release of both drugs, due to the basic characteristics of the corticosteroid which stabilize the polymer. This system appears to be promising for concomitant and controlled drug delivery aimed at the pharmacological treatment of intraocular proliferative disorders.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1999

Topical use of chitosan in ophthalmology: tolerance assessment and evaluation of precorneal retention.

The mucoadhesive polysaccharide chitosan was evaluated as a potential component in ophthalmic gels for enabling increased precorneal drug residence times. This cationic vehicle was expected to slow down drug elimination by the lacrymal flow both by increasing solution viscosity and by interacting with the negative charges of the mucus. The molecular weight (Mw) and concentration of polysaccharide were studied in four types of chitosan as parameters that might influence ocular tolerability and precorneal residence time of formulations containing tobramycin as therapeutic agent. An ocular irritation test, using confocal laser scanning ophthalmoscopy (CLSO) combined with corneal fluorescein staining, clearly demonstrated the excellent tolerance of chitosan after topical administration onto the corneal surface. Gamma scintigraphic data showed that the clearance of the formulations labelled with 99mTc-DTPA was significantly delayed in the presence of chitosan with respect to the commercial collyrium (Tobrex(R)), regardless of the concentration and of the molecular weight of chitosan in solution. At least a 3-fold increase of the corneal residence time was achieved in the presence of chitosan when compared to Tobrex(R).

Animals↗

PubMed1999

Stability studies of a somatostatin analogue in biodegradable implants.

In recent years, peptides and proteins have received much attention as drug candidates. For many polypeptides, particularly hormones, it is desirable to release the drug continuously at a controlled rate over a period of weeks or even months, and thus a controlled release system is needed. Polylactic acid (PLA) is a biocompatible and biodegradable material with wide utility for many applications, including the design of controlled release systems for pharmaceutical agents. Pharmaceutical development of these delivery systems presents new problems in the area of stability assessment, especially for peptide drugs. In this study, we aimed to investigate the influence of different steps, during the manufacturing of an implant, on peptide stability in the polymeric matrix. Polylactic acid implants containing vapreotide, a somatostatin analogue, were prepared by extrusion. The effects of time, extrusion and temperature on the peptide stability were studied. The influence of various gamma sterilization doses, as well as the conditions under which the implants were irradiated, were also investigated. Peptide stability in the polymeric matrix was evaluated at various temperatures and at various time intervals up to 9 months.

Absorbable Implants↗

PubMed1999

Highly loaded nanoparticulate carrier using an hydrophobic antisense oligonucleotide complex.

Antisense oligonucleotides, and particularly those with phosphorothioate backbones, have emerged as potential gene specific therapeutic agents and are currently undergoing evaluation in clinical trials for a variety of diseases. In the area of HIV-1 therapeutics, targeting of oligonucleotides to infected cells, such as macrophages, would be highly desirable. The present study was designed to prepare and characterize oligonucleotide-loaded nanoparticles for this purpose. Due to their hydrophilic characteristics, oligonucleotides are difficult to entrap in polymeric particles. Here, the oligonucleotides were first complexed with cetyltrimethylammonium bromide. The oligonucleotide-loaded nanoparticles were prepared by the emulsification-diffusion method and subsequently purified. In comparison with previous studies, a high oligonucleotide-loading was achieved; 2.5, 5 and 10% oligonucleotide loading were assessed. If the initial oligonucleotide content was 4%, this method produced a final oligonucleotide loading of 1.9% with an entrapment efficiency of 47%. The integrity of the oligonucleotide and of the polymer, in the final freeze-dried product, was retained.

Cetrimonium↗

PubMed1999

Uptake of oligonucleotide-loaded nanoparticles in prostatic cancer cells and their intracellular localization.

The development of antisense biotechnology is dependent, in part, on creating improved methods for delivering oligonucleotides to cells. In this study, we investigated a colloidal system (nanoparticles (NP) of poly (D,L) lactic acid) that affects the intracellular delivery of oligonucleotides. We have examined the intracellular compartmentalization in DU145 cells of fluorescein labeled phosphorothioate oligonucleotides, both in the free state and when loaded into NP. Fluorescent oligonucleotides were incubated for 18 h with DU145 cells and the mean intracellular fluorescence was determined by flow cytometry. After the addition of monensin, an increase in signal intensity was observed, indicating that free oligonucleotides were resident in an acidic intracellular environment, whereas oligonucleotides from the NP did not reside in an acidic compartment. Free and NP loaded with oligonucleotides effluxed from DU145 cells from two intracellular compartments. This preliminary report indicates that colloidal carriers such as NP could prove to be useful in affecting intracellular trafficking of oligonucleotides in DU145 and in other cells.

Humans↗

PubMed1999

Ocular tolerance of preservatives on the murine cornea.

We investigated the effects of instilling 13 commonly used preservatives on the murine cornea in vivo. Due to the instillation of preservatives, micro-lesions are formed on the cornea and can be selectively marked by fluorescein. The sum of the resulting fluorescent areas was measured using an episcopic microscope coupled to an image processing system. All the tested preservatives proved to be well-tolerated by the eye at commonly used concentrations. However, in some cases, increased concentrations of preservatives or combinations resulted in significant increase of the amount of corneal damage. With increasing the concentration, corneal lesion increased the most in the case of cetylpyridinium. While a combination of chlorobutanol 0.5% and phenylethylalcohol 0.5% did not result in an increase in corneal damage (when compared to the use of each separately), the associations of thiomersal 0.02% and phenylethylalcohol 0.4% on one hand and of edetate disodium (EDTA) 0.1% and benzalkonium 0.01% on the other, resulted in significant increases in the amount of corneal damage. However, in none of the tested combinations, the increase in the observed damage exceed the limit of ocular intolerance we had defined beforehand: thus, they were all deemed relatively well-tolerated. In the last part of the study, we investigated the effects of combining several preservatives, at usual concentrations, with an anesthetic solution of oxybuprocaine and found no notable increase in ocular damage.

Animals↗

PubMed1999

Injection-molding versus extrusion as manufacturing technique for the preparation of biodegradable implants.

Polylactic acid (PLA) is a biocompatible and biodegradable material with wide utility for many applications, including the design of controlled-release systems for pharmaceutical agents. The factors determining the degradation kinetics of these systems include the composition and the molecular mass of the polymer, the morphology and the structure of the device, and the influence of thermal processes. The processing of the polymer determines the structure and design of the device, and influences to a high degree its morphology, namely its microporous structure, polymeric chain orientation and crystallinity.In this work, we aimed to compare the influence of two different implant manufacturing techniques, extrusion and injection-molding, on the in vitro degradation of the polymeric matrix. Both kinds of implants were loaded with a somatostatin analogue. Decrease in molecular weight, and polydispersity evolution during an accelerated in vitro degradation test were studied by size exclusion chromatography. Morphological changes in the polymeric matrix during degradation were followed after defined time intervals by means of scanning electron microscopy. Crystallinity studies were performed by differential scanning calorimetry and by X-ray analysis. Peptide stability in the polymeric matrix after both manufacturing methods was evaluated. Peptide release profiles, obtained in vitro during a week dissolution test, from both implant samples, were studied. It was shown that both molecular weight and polydispersity decreased after extrusion or injection-molding. This decrease was more pronounced with the latter technique. Crystallinity studies demonstrated that the crystalline network was not destroyed after both manufacturing methods. Peptide release profiles obtained in vitro were in good accordance with scanning electron microscopy. It was found that both manufacturing techniques had to be considered, although the extruded implants degraded more rapidly in vitro than the injection-molded ones.

Absorbable Implants↗

PubMed1999

Formulation and lyoprotection of poly(lactic acid-co-ethylene oxide) nanoparticles: influence on physical stability and in vitro cell uptake.

PURPOSE: To investigate the feasibility of producing freeze-dried poly(ethylene oxide) (PEO)-surface modified nanoparticles and to study their ability to avoid the mononuclear phagocytic system (MPS), as a function of the PEO chain length and surface density. METHODS: The nanoparticles were produced by the salting-out method using blends of poly(D,L-lactic acid) (PLA) and poly(D,L-lactic acidco-ethylene oxide) (PLA-PEO) copolymers. The nanoparticles were purified by cross-flow filtration and freeze-dried as such or with variable amounts of trehalose as a lyoprotectant. The redispersibility of the particles was determined immediately after freeze-drying and after 12 months of storage at -25 degrees C. The uptake of the nanoparticles by human monocytes was studied in vitro by flow cytometry. RESULTS: PLA-PEO nanoparticles could be produced from all the polymeric blends used. Particle aggregation after freeze-drying was shown to be directly related to the presence of PEO. Whereas this problem could be circumvented by use of trehalose, subsequent aggregation was shown to occur during storage. These phenomena were possibly related to the specific thermal behaviours of PEO and trehalose. In cell studies, a clear relationship between the PEO content and the decrease of uptake was demonstrated. CONCLUSIONS: The rational design of freeze-dried PEO-surface modified nanoparticles with potential MPS avoidance ability is feasible by using the polymer blends approach combined with appropriate lyoprotection and optimal storage conditions.

Biodegradation, Environmental↗

PubMed1999

Synthesis and characterization of self-catalyzed poly(ortho-esters) based on decanediol and decanediol-lactate.

The synthesis of poly(ortho-esters) (POEs) containing lactic acid dimers in the polymer backbone for possible use in controlled drug release applications is described. These autocatalyzed POEs are prepared by the acid catalyzed condensation of 3,9-diethylidene-2,4,8,10-tetraoxaspiro(5,5)undecane with diols to produce linear polymers. The diols used were a mixture of decanediol-lactate and decanediol in various molar ratio to produce polymers with different lactic acid contents. Polymer structures were confirmed by 13C NMR, 1H NMR, and FT-IR and physico-chemical properties, such as molecular weights, glass transition temperatures and viscoelastic behavior, were also determined.

Calorimetry, Differential Scanning↗

PubMed1998

Polymeric nano- and microparticles for the oral delivery of peptides and peptidomimetics.

Due to recent advances, numerous bioactive peptides are now available in large quantities. Administering these substances by the oral route appears as a formidable challenge due to their insufficient stability in the gastrointestinal tract and their poor absorption pattern. Several approaches have been investigated to improve their oral bioavailability. Among them, the use of polymeric particulate delivery systems (microparticles and nanoparticles) represents a promising concept. Encapsulating or incorporating peptides in particles should at least protect these substances against degradation and, in some cases, also enhance their absorption. The aim of this paper is to review the principal studies where peptide-loaded particles were administered by the oral route. The preparation methods and in vitro trials are presented and in vivo results are discussed with emphasis placed on the peptide blood levels reached or on the biological effects observed. Whether or not intact particles can be taken up and translocated to the systemic circulation is not the aim of this review.

Journal Article↗

PubMed1998

In vitro drug release from self-catalyzed poly(ortho ester): case study of 5-fluorouracil.

Self-catalyzed poly(ortho esters) are a new variation of linear poly(ortho esters) prepared by the addition of diols to the diketene acetal 3,9-diethylidene-2,4,8,10-tetraoxaspiro[5,5]undecane where dimer segments of lactic acid or glycolic acid are built into the polymer backbone. By varying the concentration of these segments, polymer erosion rate can be controlled. The present investigation describes the in vitro drug release characteristics from these new polymers. Because poly(ortho esters) have potential applications for the delivery of antifibroblastic agents for example after glaucoma-filtering surgery, the in vitro release studies were evaluated using 5-fluorouracil as the active compound. It was shown that a mole ratio of 90/10 or 80/20 diol/diol-lactate incorporated into the polymer lead to a release of 5-fluorouracil by an erosion process. Smaller amounts of diol-lactate lead to a concomitant drug release by diffusion and erosion. It was also shown that the release rate depends on the alkyl chain length of the diol in the polymer backbone but it does not depend on the drug loading.

Catalysis↗