Biomedical subjects

J P Benoit

Publications and source records attributed to J P Benoit.

At least 19 recordsLinked to original sources

PubMed2003

Implantable drug-releasing biodegradable microspheres for local treatment of brain glioma.

Our group have developed a new method of drug delivery into the brain using implantable biodegradable microspheres. In this mini-review, we describe the development, preclinical studies and clinical trials involving 5-fluorouracil-releasing microspheres for interstitial radiosensitization of malignant glioma. Future developments concerning these microspheres for treatment of brain tumors are presented.

Adolescent↗

PubMed2003

Biocompatibility of implantable synthetic polymeric drug carriers: focus on brain biocompatibility.

Numerous polymeric biomaterials are implanted each year in human bodies. Among them, drug delivery devices are potent novel powerful therapeutics for diseases which lack efficient treatments. Controlled release systems are in direct and sustained contact with the tissues, and some of them degrade in situ. Thus, both the material itself and its degradation products must be devoid of toxicity. The knowledge and understanding of the criteria and mechanisms determining the biocompatibility of biomaterials are therefore of great importance. The classical tissue response to a foreign material leads to the encapsulation of the implant, which may impair the drug diffusion in the surrounding tissue and/or cause implant failure. This tissue response depends on different factors, especially on the implantation site. Indeed, several organs possess a particular immunological status, which may reduce the inflammatory and immune reactions. Among them, the central nervous system is of particular interest, since many pathologies still need curative treatments. This review describes the classical foreign body reaction and exposes the particularities of the central nervous system response. The recent in vivo biocompatibility studies of implanted synthetic polymeric drug carriers are summarized in order to illustrate the behavior of different classes of polymers and the methodologies used to evaluate their tolerance.

Acute-Phase Reaction↗

PubMed2003

Mathematical modeling of drug release from bioerodible microparticles: effect of gamma-irradiation.

Bioerodible polymers used in controlled drug delivery systems, such as poly(lactic-co-glycolic acid) (PLGA) undergo radiolytic degradation during gamma-irradiation. In spite of the considerable practical importance, yet only little knowledge is available on the consequences of this sterilization method on the resulting drug release patterns in a quantitative way. The major objectives of the present study were: (i) to monitor the effects of different gamma-irradiation doses on the physicochemical properties of drug-free and drug-loaded, PLGA-based microparticles; (ii) to analyze the obtained experimental results using adequate mathematical models; (iii) to get further insight into the occurring physical and chemical phenomena; and (iv) to relate the applied gamma-irradiation dose in a quantitative way to the resulting drug release rate. 5-Fluorouracil-loaded, PLGA-based microparticles were prepared with an oil-in-water solvent extraction method and exposed to gamma-irradiation doses ranging from 0 to 33 kGy. Size exclusion chromatography, differential scanning calorimetry, scanning electron microscopy, particle size analysis, determination of the actual drug loading and in vitro drug release kinetics were used to study the effects of the gamma-irradiation dose on the physicochemical properties of the microparticles. Two mathematical models-a simplified and a more comprehensive one-were used to analyze the experimental results. The simplified model considers drug diffusion based on Fick's second law for spherical geometry and a Higuchi-like pseudo-steady-state approach. The complex model combines Monte Carlo simulations (describing polymer erosion) with partial differential equations quantifying drug diffusion with time-, position- and direction-dependent diffusivities. Interestingly, exponential relationships between the gamma-irradiation dose and the initial drug diffusivity within the microparticles could be established. Based on this knowledge both models were used to predict the resulting drug release kinetics as a function of the gamma-irradiation dose. Importantly, the theoretical predictions were confirmed by experimental results.

Dose-Response Relationship, Radiation↗

PubMed2002

Microencapsulation of protein particles within lipids using a novel supercritical fluid process.

Solvent-free microparticles, loaded with a model protein (bovine serum albumin: BSA) have been produced using a novel coating process based on supercritical (SC) fluid technology. Coating material consists of either trimyristin (Dynasan114) or Gelucire50-02, two lipidic compounds having a high melting point. Microparticles were characterized as regards their morphology, protein content and in vitro release profile. A discontinuous coating made of crystalline micro-needles was obtained using Dynasan114. It led to particles with an initial burst release of about 70% in 30 min at 37 degrees C. However, a prolonged release of the protein has been achieved over a 24 h period from particles coated with Gelucire50-02, which produces a more homogeneous, film-forming coating. Furthermore, it was shown that BSA does not undergo any degradation after SCCO2 treatment under the SC conditions used in the coating process.

Carbon Dioxide↗

PubMed2002

Development and characterization of solid lipid nanoparticles loaded with magnetite.

This paper describes the preparation of colloidal lipid particles containing magnetite from warm emulsions. A two step method was used to obtain the nanoparticles: (i) formulation of a transparent phase by heating a O/W emulsion (aqueous surfactant solution melted with a lipid phase, containing the ethyl oleate and soybean lecithin) in which modified lipophilic magnetite is incorporated, and (ii) preparation of the nanoparticles by dispersing the warm transparent phase in cold water (7 degrees C) under mechanical stirring. The latter method gives spherical nanoparticles of a mean size of 62 nm measured by Photon Correlation Spectroscopy and Transmission Electronic Microscopy. The magnetite entrapment efficiency was determined by use of a magnetophoretic sedimentation method.

Colloids↗

PubMed2002

PLGA-based microparticles: elucidation of mechanisms and a new, simple mathematical model quantifying drug release.

The two major aims of this study were: (i) to elucidate the underlying release mechanisms from drug-loaded, erodible microparticles based on poly(lactic-co-glycolic acid) (PLGA) showing biphasic drug release behavior: an initial 'burst' effect, followed by a zero order release phase; and (ii) to develop a new, simple mathematical model that allows the quantitative description of the observed in vitro drug release patterns from this type of delivery system. PLGA-based microparticles offer various advantages, such as the possibility to control the resulting drug release rate accurately over prolonged periods of time, easiness of administration (e.g., by stereotaxic injection), good biocompatibility and complete erosion (avoiding the removal of empty remnants). Consequently, the practical importance of these advanced drug delivery systems is remarkably increasing. However, only little knowledge is yet available concerning the processes controlling the release rate of the drug out of these devices. Various chemical and physical phenomena are involved, rendering the identification of the crucial mechanisms and the mathematical description of the resulting drug release kinetics difficult. In the present study, different physicochemical characterization methods (e.g., DSC, SEM, SEC, particle size analysis) were used to monitor the changes occurring within anticancer drug-loaded PLGA microparticles upon exposure to phosphate buffer pH 7.4. Based on these experimental findings, the most important underlying drug release rate controlling mechanisms were identified and a new mathematical model was developed that allows the quantitative description of the resulting release patterns.

Buffers↗

PubMed2001

Therapeutic efficacy of 5-fluorouracil-loaded microspheres on rat glioma: a magnetic resonance imaging study.

The aim of this work was to assess the therapeutic efficacy of an intratumoral bolus injection of 5-fluorouracil (FU) compared to that of drug loaded in biodegradable microspheres, for the treatment of brain tumour. Experiments were carried out using a fast-growing C6-glioma rat model. The therapeutic protocols were performed 12 days after the injection of glioma cells. At this stage, the tumours were installed and the mean volume was 13 +/- 2 microl as measured by proton magnetic resonance (MR) imaging. This technique was used for the follow-up of the tumour volume with respect to time and therapy. In terms of rat survival, both therapies induced a significant 50% increase in animal life span (p < 0.05) compared to animals receiving no drug or unloaded microspheres. Whilst no cure was observed, analysis of the MR images showed that the local and sustained delivery of FU slowed the tumour development in the vicinity of the microspheres by a factor of 3, compared with the bolus intratumoral injection.

Animals↗

PubMed2001

Analysis of brain biocompatibility of drug-releasing biodegradable microspheres by scanning and transmission electron microscopy.

OBJECT: Stereotactically guided implantation of biodegradable microspheres is a promising strategy for delivery of neurotrophic factors in a precise and spatially defined brain area. The goal in this study was to show the biocompatibility of poly(D,L,lactide-co-glycolide) microspheres with brain tissue at the ultrastructural level and to analyze the three-dimensional (3D) ultrastructure after intrastriatal implantation of these microparticles. METHODS: Scanning and transmission electron microscopy were used to study the microspheres and their environment after implantation in an inert material (gelatin) and in the rat striatum. Observations were made at different time periods, ranging from 24 hours to 2 months postimplantation. CONCLUSIONS: The progressive degradation of the microspheres, with vacuolization, deformation, and shrinkage, was well visualized. This degradation was identical in microspheres implanted in the inert material and in the rat brain tissue, independent of the presence of macrophages. The studies preformed in the striatum permitted the authors to demonstrate the structural integrity of axons in contact with microspheres, confirming the biocompatibility of the polymer. Furthermore, scanning electron microscopy showed the preservation of the 3D ultrastructure of the striatum around the microparticles. These microparticles, which can be stereotactically implanted in functional areas of the brain and can release neurotrophic factors, could represent, for some indications, an alternative to gene therapy.

Animals↗

PubMed2000

Development of microspheres for neurological disorders: from basics to clinical applications.

Drug delivery to the central nervous system remains a challenging area of investigation for both basic and clinical neuroscientists. Numerous drugs are generally excluded from blood to brain transfer due to the negligible permeability of the brain capillary endothelial wall, which makes up the blood brain barrier in vivo. For several years, we have explored the potential applications of the microencapsulation of therapeutic agents to provide local controlled drug release in the central nervous system. Due to their size, these microparticles can be easily implanted by stereotaxy in discreet, precise and functional areas of the brain without damaging the surrounding tissue. This type of implantation avoids the inconvenient insertion of large implants by open surgery and can be repeated if necessary. We have established the compatibility of poly(lactide-co-glycolide) microspheres with brain tissues. Presently, the most developed applications concern Neurology and Neuro-oncology, with local delivery of neurotrophic factors and antimitotic drugs into neurodegenerative lesions and brain tumours, respectively. The drugs that had been encapsulated by our group included nerve growth factor (NGF), 5-fluorouracil (5-FU), idoxuridine and BCNU. Preclinical studies have been performed with each drug. Studies with NGF are reported as an example. A phase I/II clinical trial has been carried out in patients with newly diagnosed glioblastomas to assess the potentialities of 5-FU-loaded microspheres when intracranially implanted.

Animals↗

PubMed2000

Intracerebral implantation of NGF-releasing biodegradable microspheres protects striatum against excitotoxic damage.

Intrastriatal implantation of genetically modified cells synthesizing nerve growth factor (NGF) constitutes one way to obtain a long-term supply of this neurotrophic factor and a neuronal protection against an excitotoxic lesion. We have investigated if NGF-loaded poly(d,l-lactide-co-glycolide) microspheres could represent an alternative to cell transplantations. These microspheres can be implanted stereotaxically and locally release the protein in a controlled and sustained way. In order to test this paradigm, the NGF release kinetics were characterized in vitro using radiolabeled NGF, immunoenzymatic assay, and PC-12 cells bioassay and then in vivo after implantation in the intact rat striatum. These microspheres were thus implanted into the rat striatum 7 days prior to infusing quinolinic acid. Control animals were either not treated or implanted with blank microspheres. The extent of the lesion and the survival of ChAT-, NADPH-d-, and DARPP-32-containing neurons were analyzed. In vitro studies showed that microspheres allowed a sustained release of bioactive NGF for at least 1 month. Microspheres implanted in the intact striatum still contained NGF after 2.5 months and they were totally degraded after 3 months. After quinolinic acid infusion, the lesion size in the group treated with NGF-releasing microspheres was reduced by 40% when compared with the control groups. A marked neuronal sparing was noted, principally concerning the cholinergic interneurons, but also neuropeptide Y/somatostatin interneurons and GABAergic striatofuge neurons. These results indicate that implantation of biodegradable NGF-releasing microspheres can be used to protect neurons from a local excitotoxic lesion and that this strategy may ultimately prove to be relevant for the treatment of various neurological diseases.

Animals↗

PubMed2000

Intraseptal implantation of NGF-releasing microspheres promote the survival of axotomized cholinergic neurons.

Neurotrophic factors therapy requires their precise delivery to the targeted neuronal population. For this purpose, a wide range of strategies have been developed, and among them the stereotaxic implantation of biodegradable microparticles. To assess the in vivo activity of NGF-releasing PLGA microspheres, unloaded and NGF-loaded microparticles were implanted in the rat brain, near the septal cholinergic neurons, axotomized by an unilateral transection of the fornix-fimbria. Histological analysis at two and six weeks after implantation revealed a non-specific astro- and micro-glial reaction around the microspheres, identical for both unloaded and NGF-loaded microspheres. No neuronal toxicity was noticed, and healthy looking neurons were observed in contact with the microspheres. In the non-treated animals, the percentage of axotomized surviving neurons, when compared to the contralateral intact side, was 31 +/- 2 and 27 +/- 1% at two and six weeks, respectively. Unloaded microspheres caused no protective nor neurotoxic effects (40 +/- 9 and 39 +/- 6% of surviving cholinergic neurons at two and six weeks, respectively). In contrast, NGF-loaded microspheres showed a significant effect on the survival of axotomized cholinergic neurons at two and six weeks after implantation (66 +/- 9 and 61 +/- 5% when compared to the contralateral intact side, respectively). These results show that PLGA microparticles present no neurotoxicity and release sufficient amounts of bioactive NGF to significantly limit the lesion-induced disappearance of cholinergic neurons in the septum during at least six weeks. PLGA microparticles can be used in the future to administer neurotrophic factors in central nervous system disorders.

Animals↗

PubMed1999

Local and sustained delivery of 5-fluorouracil from biodegradable microspheres for the radiosensitization of glioblastoma: a pilot study.

BACKGROUND: The authors have developed a new method of drug delivery into the brain using implantable biodegradable microspheres. In this study, this method was used to provide localized and sustained delivery of 5-fluorouracil (5-FU) after the surgical resection of glioblastoma. This antimetabolite and radiosensitizing drug was selected in an attempt to decrease the rate of local recurrence of the tumor. METHODS: Eight patients with newly diagnosed glioblastoma were included in the study and 2 increasing amounts of 5-FU were studied (70 mg and 132 mg). After surgical resection of the tumor, poly(D-L lactide-co-glycolide) 5-FU-loaded microspheres with an average dimension of 45 microm were implanted in the wall of the surgical bed. External beam radiation (59.4 grays) was initiated before the seventh postsurgical day. Patients were followed by clinical examination, magnetic resonance imaging, and 5-FU assays in the blood and cerebrospinal fluid (CSF). RESULTS: 5-FU assays confirmed sustained concentrations in the CSF for at least 1 month. Concentrations of 5-FU in the blood were lower and transitory. Systemic tolerance to the treatment was good; one case of recurrent brain swelling was observed at the higher dose studied. At the time of last follow-up the overall median survival time was 98 weeks from the time of implantation and 2 patients had achieved disease remission at 139 and 153 weeks, respectively. CONCLUSIONS: This study demonstrates that biodegradable microspheres are efficient systems for drug delivery into the brain and may have future application in the treatment of brain tumors. Further studies are needed to confirm the potential of 5-FU-loaded microspheres for the radiosensitization of glioblastoma. [Please see editorial on pages 197-9, this issue].

Adolescent↗

PubMed1999

Modulated release of IdUrd from poly (D,L-lactide-co-glycolide) microspheres by addition of poly (D,L-lactide) oligomers.

This paper reports the release characteristics of a radiosensitizer, 5-iodo-2'-deoxyuridine (IdUrd), from poly (D,L-lactide-co-glycolide) 50: 50 (PLGA) microparticles obtained by a phase separation technique. Poly (D,L-lactide) oligomers (D,L-PLA) were incorporated into the PLGA matrix in order to accelerate the overall drug release rate and regulate the triphasic release profile exhibited by the standard PLGA microparticles. For D,L-PLA (800), the burst effect was large and the IdUrd release was complete between 28 and 35 days. These results were attributed to rapid pore formation on the periphery of the microsphere in the early stages of incubation, due to hydrosolubility of the smallest oligomers (D,L-PLA (800)). In the case of D,L-PLA (1,100), drug release occurred over a six week period, the standard time course of conventional radiation therapy. The period during which the radiosensitizer was incorporated in human brain tumor cell nuclei after its entrapment in biodegradable microspheres was determined by using an organotypical tissue culture. The presence of radiosensitizer in the DNA of tumor cell nuclei was detected by immunohistochemical labelling of tumor fragments. IdUrd release from standard microspheres (7+/-0.5 weeks) was longer than from oligomer-containing batches. For D,L-PLA (800)-containing microspheres, the radiosensitizer was entirely released within 4. 5+/-0.5 weeks. The microspheres containing D,L-PLA (1,100) allowed an IdUrd release over a 5 to 6 week period. The ex vivo data were consistent with the in vitro findings in terms of release duration.

Biodegradation, Environmental↗

PubMed1999

Development of 5-iodo-2'-deoxyuridine milling process to reduce initial burst release from PLGA microparticles.

The aim of this study was to prepare 5-iodo-2'-deoxyuridine (IdUrd) loaded poly(d,l-lactide-co-glycolide) (PLGA) microspheres with a reduced initial burst in the in vitro release profile, by modifying the drug grinding conditions. IdUrd particle size reduction has been performed using spray-drying or ball milling. Spray-drying significantly reduced drug particle size with a change of the initial crystalline form to an amorphous one and led to a high initial burst. Conversely, ball milling did not affect the initial IdUrd crystallinity. Therefore, the grinding process was optimized to emphasize the initial burst reduction. A first step allowed us to set qualitative parameters such as ball number (7) and cooling with liquid nitrogen to obtain a mean size reduction and a narrow distribution. In a second step, three parameters including milling speed, drug amount and time were studied by a response surface analysis. The interrelationship between drug amount and milling speed was the most significant factor. To reduce particle size it should be necessary to use a moderate speed associated with a sufficient drug amount (400-500 mg). IdUrd release from microparticles prepared by the o/w emulsion/extraction solvent evaporation process with the lowest crystalline particle size (15.3 microns) was studied. Burst effect could be reduced significantly. Concerning the first phase of drug release, the burst was 8.7% for 15.3 microns compared to 19% for 19.5 microns milled drug particles.

Chemistry, Pharmaceutical↗

PubMed1999

The characterization and release kinetics evaluation of baclofen microspheres designed for intrathecal injection.

Baclofen, a water soluble drug advocated for the treatment of spinal spasticity, was microencapsulated, using the oil/water emulsion extraction process in an attempt to identify the appropriate experimental conditions capable of producing microspheres releasing baclofen over 2-4 weeks. Individual microspheres ranging in size from 15 to 30 microns were formed exhibiting smooth surfaces at low drug payload (12.8% w/w), irregular and rough surface at high drug content (33.9% w/w). The microencapsulation yield remained practically unchanged (85-90%) up to theoretical payloads of 37.5% w/w, and decreased markedly to 70% when the initial theoretical payload was 50% w/w. The in vitro release profile of baclofen from the poly(D,L-lactide-co-glycolide) microspheres was biphasic only for the high drug payload microspheres with a rapid release of 70% within 48 h, followed by a slower release rate over at least 25 days. In contrast, the microspheres containing low baclofen contents (12.8% w/w) exhibited a gradual and progressive release rate over the course of the experiment. The baclofen release data did not fit either the general equation which describes the diffusional release of dispersed tiny drug particles from spherical micromatrices, or to the kinetic equations which describe the release of dissolved drug from monolithic microspherical devices. It appears that the release of baclofen from the present microspheres is not governed by a unique mechanism. This should be attributed either to the presence of some uncoated drug particles or to the large size of the embedded drug particles compared with the relatively small size of the spherical micromatices, or to some polymeric erosion occurring after several days incubation in the release medium.

Baclofen↗

PubMed1999

Why does PEG 400 co-encapsulation improve NGF stability and release from PLGA biodegradable microspheres?

PURPOSE: The aim of this work was to understand the mechanism by which co-encapsulated PEG 400 improved the stability of NGF and allowed a continuous release from PLGA 37.5/25 microspheres. METHODS: Microparticles were prepared according to the double emulsion method. PEG 400 was added with NGF in the internal aqueous phase (PEG/PLGA ratio 1/1 and 1.8/1). Its effect was investigated through interfacial tension studies. Protein stability was assessed by ELISA. RESULTS: A novel application of PEG in protein stabilization during encapsulation was evidenced by adsorption kinetics studies. PEG 400 limited the penetration of NGF in the interfacial film of the primary emulsion. Consequently, it stabilized the NGF by reducing the contact with the organic phase. In addition, it avoided the NGF release profile to level off by limiting the irreversible NGF anchorage in the polymer layers. On the other hand, the amount of active NGF released in the early stages was increased. During microparticle preparation, NaCl could be added in the external aqueous phase to modify the structure of microparticles. This allowed to reduce the initial release rate without affecting the protein stability always encountered in the absence of PEG. CONCLUSIONS: PEG 400 appeared of major interest to achieve a continuous delivery of NGF over seven weeks from biodegradable microparticles prepared by the double emulsion technique.

Biodegradation, Environmental↗

PubMed1999

Direct qualitative and quantitative characterization of a radiosensitizer, 5-iodo-2'-deoxyuridine within biodegradable polymeric microspheres by FT-Raman spectroscopy.

Non-destructive qualitative and quantitative characterization of a radiosensitizer, 5-iodo-2'-deoxyuridine (IdUrd), incorporated within injectable microspheres of a biodegradable polymer, poly(D,L-lactide-co-glycolide) (PLGA), was performed using Fourier transform (FT) Raman spectroscopy. Raman spectra of IdUrd, free and entrapped in microspheres, were recorded under fluorescence-free conditions, described and assigned. For the Raman bands of the PLGA microspheres, assignments with preferential localization of the corresponding vibrations at lactic or glycolic units were proposed. No evidence for drug-polymer interactions in microspheres was found. This allowed the FT-Raman spectra to be used for the quantification of the IdUrd content in the samples. For the microspheres with IdUrd loadings varying from 2 to 27% of the total weight, the methodology used provided good reproducibility and precision (1%). Within the sensitivity of the technique, samples exposed to sterilization doses (27 kGy) of gamma-radiation did not exhibit marked changes in the drug structure.

Humans↗

PubMed1998

NGF release from poly(D,L-lactide-co-glycolide) microspheres. Effect of some formulation parameters on encapsulated NGF stability.

Poly(d,l-lactide-co-glycolide) (PLGA 37.5/25 and 25/50) biodegradable microparticles, which allow the locally delivery of a precise amount of a drug by stereotactic injection in the brain, were prepared by a W/O/W emulsion solvent evaporation/extraction method which had been previously optimized. The aim of this work was to study the influence of two formulation parameters (the presence of NaCl in the dispersing phase and the type of PLGA) on the NGF release profiles and NGF stability during microencapsulation. A honey-comb-like structure characterized the internal morphology of the microspheres. The initial burst was attributed to the rapid penetration of the release medium inside the matrix through a network of pores and to the desorption of weakly adsorbed protein from the surface of the internal cavities. The non-release fraction of the encapsulated protein observed after twelve weeks of incubation was accounted for firstly by the adsorption of the released protein on the degrading microparticles and secondly by the entanglement of the encapsulated protein in the polymer chains. The use of sodium chloride in the dispersing phase of the double emulsion markedly reduced the burst effect by making the microparticle morphology more compact. Unfortunately, it induced in parallel a pronounced NGF denaturation. Finally, it appeared that microparticles made from a hydrophilic uncapped PLGA 37.5/25 in the absence of salt, allowed the release of intact NGF at least during the first 24 h as determined by both ELISA and a PC12 cell-based bioassay.

Animals↗