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ABSTRACT: For the treatment of glioblastoma multiforme, an "anticancer drug cocktail" delivered by biodegradable poly-lactide-co-glycolide (PLGA)-microspheres is proposed. Celecoxib, etoposide, and elacridar were encapsulated by an oil/water emulsification solvent evaporation method. Drug-loaded microspheres were analyzed for their physicochemical properties and evaluated in a rat glioblastoma model. Microspheres had a mean diameter 10-20 µm, and encapsulation rates varied upon lipophilicity of the drug (celecoxib: 97.4 ± 0.4%; elacridar: 98.1 ± 0.3%; and etoposide: 38.7 ± 8.3%). Drug release of celecoxib and elacridar resulted in a burst (t50: 3.1 h and 1.0 h, respectively) while etoposide release was slower (t50: 45.3 h). The comparison of celecoxib (p = 0.021) and etoposide microspheres (p = 0.002) as well as their combination (p = 0.011) led to a significant increase in the probability of survival compared to blank microspheres. Local delivery of celecoxib and etoposide microspheres was found to be suitable for the treatment of glioblastoma in rats although simultaneous drug administration did not improve the therapeutic outcome.
Journal of Microencapsulation 03/2013; · 1.55 Impact Factor
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ABSTRACT: Nanoparticles (NPs) have shown a certain potential to overcome the drawbacks of oral peptide delivery in the gastrointestinal tract such as low peptide stability and permeability. The preparation of insulin loaded NPs was carried out with Eudragit® RL or RS dissolved in different non-toxic polyethylene glycol (PEG) derivatives. The use of these non-toxic solvents allowed the design of an one step NP preparation method where insulin retained its full biological activity as it was proven in vitro and in vivo. The insulin trapping NPs were in a size range of around 150 to 250nm and exhibited a pH-dependent release. The type of solvent did not distinctly influence the particle properties or insulin stability but modified significantly the performance in vivo in rats, NPs prepared with glycofurol led to a bioavailability of F=1.4±1.0% after oral administration while NPs prepared with PEG 300 were hardly efficient (F=0.3± 0.5%). In all cases t(max) was shifted to 2h compared to 1h after subcutaneous insulin solution. In general, we believe that the method presented here is a promising way to encapsulate sensitive drugs, especially for the production of peptide loaded NPs.
International journal of pharmaceutics 01/2013; · 2.96 Impact Factor
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ABSTRACT: As a result of its broad substrate specificity and critical localization in excretory and barrier function tissues, P-glycoprotein (P-gp) plays major roles in the pharmacokinetics, safety and efficacy profiles of numerous drugs. P-gp is often responsible for the failure of many chemical treatments against cancer, immunosuppressive, infectious and neurodegenerative diseases. Among the therapeutic approaches to circumvent P-gp function, advances in the design of new chemical P-gp modulators to interact specifically with P-gp have yielded few clinical successful reports. Members of a class of components that were initially developed as surface active agents showed promising results with regard to the modulation of P-gp. These components include surfactants and amphiphilic co-polymers. Alternatively, colloidal systems were developed to facilitate drug uptake in resistant cells. This approach is based on the encapsulation of drugs, which masks them from the biological environment and prevents their transport by P-gp using the surfactants released from the nanocarrier. Likewise, a novel and synergistic strategy is currently being explored and involves nanocarrier-mediated transport and controlled release of both P-gp substrates and P-gp modulators. In this review, we discuss recent results obtained by direct modulation with chemosensitizers and the available nanotechnology to modulate P-gp function. In this manuscript, we also discuss unexplored pathways for future therapies.
Journal of Controlled Release 04/2012; 161(1):50-61. · 5.73 Impact Factor
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ABSTRACT: In inflammatory bowel disease (IBD) the disruption of the intestinal barrier function and the strong presence of immune-related cells like macrophages in inflamed tissue allow the selective accumulation of particulate carrier systems at the site of action. We developed clodronate loaded nanoparticles (ClNP) based on a cationic polymethacrylate (Eudragit RL) using a modified solvent displacement method. Particle diameter of ClNP was around 120nm and dissolution experiments showed that ionic interactions with either the dissolution medium or mucin have to take place to enable complete drug release. In murine experimental colitis in-vivo, myeloperoxidase activity decreased significantly in 2,4,6-trinitrobenzenesulfonic acid (TNBS)-colitis and oxazolone (OXA)-colitis models after treatment with ClNP while free clodronate did not show a mitigating effect. Similarly, alkaline phosphatase could be lowered significantly from 12.5±1.9 to 6.8±2.2ng/mg tissue in TNBS-colitis and from 16.6±6.2 to 11.8±2.7ng/mg tissue in OXA-colitis. In cultured RAW 264.7 cells, only ClNP but not clodronate alone led to a decrease in tumor necrosis factor-alpha and interleukin-6 secretion of the activated macrophages. The therapeutic benefit of ClNP was confirmed in-vivo although it is limited compared to data with other drugs. Cell culture experiments indicated that intracellular delivery of clodronate was necessary to obtain an anti-inflammatory effect.
Journal of Controlled Release 03/2012; 160(3):659-65. · 5.73 Impact Factor
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ABSTRACT: Topical delivery of 5-aminosalicylic acid (5-ASA) to the colonic mucosa is important in order to achieve effective drug concentration in the site of inflammation and to minimize its systemic availability. 5-ASA loaded pellets were prepared by an extrusion/spheronization method. Mucoadhesive biopolymer chitosan was incorporated into the pellets, and drug delivery to the colon was controlled by the pH-sensitive polymer Eudragit® FS. Dissolution profiles of coated pellets revealed no drug release at pH 1.2 within 2h and release as intended in the simulated distal ileum and colon. In vivo, chitosan-core drug loaded pellets (AMCh) showed 2.5-fold higher drug metabolite concentration than after chitosan free pellets (AM) administration in the inflamed colonic tissue. Additionally, AMCh demonstrated decreased in AUC in colitis group (1507 ± 400 ng h/ml) compared with AM (1907 ± 122 ng h/ml). In terms of therapeutic efficiency, administration of pellets markedly decreased the colon/body weight ratio (colitis: 0.0355 ± 0.0028; AM 0.0092 ± 0.0033; AMCh 0.0086 ± 0.0022) and myeloperoxidase activity (colitis: 3212 ± 294 U/g tissue; AM 796 ± 211 U/g; AMCh 552 ± 319 U/g). Bioadhesive chitosan pellets showed additional beneficial properties for colonic 5-ASA delivery in the treatment of inflammatory bowel disease by increasing the drug concentration locally.
European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 02/2012; 81(2):379-85. · 3.15 Impact Factor
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ABSTRACT: Lipid nanocapsules (LNC) have been suggested for a variety of pharmaceutical applications. Among them approaches for drug delivery to the skin appear particularly interesting. The current standard composition has been modified to better understand their properties by selecting a variety of different surfactants. LNC have been prepared using different non-ionic surfactants (Solutol(®) HS15: Polyoxyl 15 Hydroxystearate; Cremophor(®) EL: Polyoxyl 35 Castor Oil; Simulsol(®) 4000: Polyoxyl 40 Hydrogenated Castor Oil; Vitamin E TPGS(®): alpha-tocopheryl poly(ethylene glycol) succinate; Polysorbate 20 and 80) and analysed for their size, stability, drug release and toxicity on keratinocytes in cell culture. The feasibility of LNC using different surfactant was surprisingly easy and led to a variety of stable formulations that were selected for further investigations. Surfactants led to a variability of the release kinetics (t50% release varied from Polysorbate 20: 2.5h to Simulsol(®) 4000: 5.0h), however different formulations from the same surfactant did not differ significantly. In vitro toxicity of LNC was surfactant type dependent and a correlation between LNC and the pure respective surfactant was found. This toxicity was found to be mainly independent from the surface active properties. The surfactant type in LNC is easily interchangeable from formulation point of view. LNC appear to be appropriate as carrier for cutaneous delivery however toxicity can vary distinctly depending on the surfactant used for the preparation.
International journal of pharmaceutics 04/2011; 411(1-2):136-41. · 2.96 Impact Factor
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ABSTRACT: The colonic drug delivery in inflammatory bowel disease (IBD) by microcarriers has been suggested over the past decade; however, pharmacokinetic and biopharmaceutical details are hardly known. A model colitis was induced to male Wistar rats by trinitrobenzenesulfonic acid. Carboxyfluorescein (CF) was entrapped into microspheres (MS) prepared with the pH-sensitive polymer Eudragit® S100, in order to simulate drug delivery to the colon. Pharmacokinetic behaviour of CF-MS was compared to oral or rectal administration of CF as solution in healthy or colitis group. Colitis lowered the oral bioavailability of CF solution, compared to healthy controls (healthy: 8.4±1.5; colitis: 3.0±0.9; all μg/mlh), and similar results were obtained after rectal administration of CF solution (healthy: 5.6±2.1; colitis: 1.8±0.8). Surprisingly, CF-MS showed only minor differences between colitis and healthy controls (healthy: 1.9±0.8; colitis: 2.3±0.4). In contrary, the intra-tissue concentrations of CF of the various formulations in colitis showed lower levels than the comparable healthy group after oral drug administration. Pharmacokinetic outcome was largely disease-dependent, while CF-MS confirmed their ability to local drug delivery.
European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 10/2010; 76(2):290-5. · 3.15 Impact Factor
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ABSTRACT: Commonly, the microencapsulation of a lipophilic drug in pH-sensitive polymeric matrix via an ordinary oil/oil emulsification allows for entrapping limited drug amounts due to its loss into the external phase. Here, we propose a microencapsulation method on the basis of an oil/water emulsification method using n-butanol. Eudragit S100 microspheres were prepared by an oil/water emulsification solvent extraction method trapping ibuprofen as lipophilic model drug. Morphological analyses of the obtained particles showed a spherical shape and a sponge-like internal structure. In order to increase the entrapment efficacy several preparation parameters were optimized, such as theoretical drug load and surfactant concentration in the external phase. The particle size varied slightly around 170 microm, barely influenced by the modified process parameters. Drug leakage at pHs below the polymer dissolution pH was highest with microspheres prepared at low theoretical drug loading and low surfactant concentrations. In vitro drug release was found to be strongly pH-dependent; ibuprofen was retained in microspheres at pH 2.0 (<20% release within 4 h) whereas a higher leakage was observed at pH 5.5 and a nearly immediate drug release was obtained at pH 7.4. The use of n-butanol was found to be a new promising alternative for the preparation of pH-sensitive microspheres by an oil/water emulsification.
International journal of pharmaceutics 06/2009; 375(1-2):61-6. · 2.96 Impact Factor
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ABSTRACT: The present study shows the potential of novel nanovectors for the delivery of lipophilic radionuclides and therapeutic molecules to the brain. Lipid nanocapsules (LNC) inhibiting the P-gp pump efflux, were conjugated to OX26 monoclonal antibodies (OX26 MAb) and Fab' fragments. The OX26 MAb is directed against the transferrin receptor (TfR) highly expressed on the cerebral endothelium. The specific association of immunonanocapsules to rat brain capillary endothelial cells was demonstrated. Biodistribution of immunonanocapsules, labeled with a (188)Re lipophilic complex, was determined in healthy rats. At 24 h post-injection, the brain concentrations of Fab'-immunonanocapsules and OX26-immunonanocapsules were, respectively, 1.5 and 2-fold higher than non-targeted nanocapsules. In addition, Fab' fragments helped prolong the vascular residence time of the nanovectors but their affinity to TfR was lower than whole antibodies. The ability of immunonanocapsules to specifically target cerebral tissues in addition to the promising features of LNC is of importance to the field of nanomedicine.
Journal of Controlled Release 03/2008; 126(1):44-9. · 5.73 Impact Factor
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ABSTRACT: Immunonanocapsules were synthesized by conjugation to lipid nanocapsules (LNC) of whole OX26 monoclonal antibodies (OX26 MAb) directed against the transferrin receptor (TfR). The TfR is overexpressed on the cerebral endothelium and mediates the transcytosis mechanism. Fab' fragments, known for their reduced interaction with the reticuloendothelial system, were also conjugated to LNC. This coupling was facilitated by the incorporation of lipid PEG(2000) functionalized with reactive-sulfhydryl maleimide groups (DSPE-PEG(2000)-maleimide) into LNC shells by a post-insertion procedure, developed initially for liposome pegylation. An interfacial model using the dynamic rising drop technique helped determine the parameters influencing the DSPE-PEG(2000)-maleimide insertion and the quality of the anchorage. Heat was essential to promote both an important and stable adsorption of DSPE-PEG(2000)-maleimide onto LNC. OX26 MAb were thiolated to react with maleimide functions whereas thiol residues on Fab' fragments were used directly. The number of ligands per nanocapsule was adjusted according to their initial quantity in the coupling reaction mixture, with densities from 16 to183 whole antibodies and between 42 and 173 Fab' fragments per LNC. The specific association of immunonanocapsules to cells overexpressing TfR was thus demonstrated, suggesting their ability to deliver drugs to the brain.
Biomaterials 12/2007; 28(33):4978-90. · 7.40 Impact Factor
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ABSTRACT: The delivery of drugs to brain tumors is limited by the presence of the blood-brain barrier (BBB) separating the blood from the cerebral parenchyma. An understanding of the specific mechanisms of the brain capillary endothelium has led to the development of various strategies to enhance the penetration of drugs into the brain tissue. Active targeting is a non-invasive approach, which consists in transporting drugs to target organs using site-specific ligands. Drug-loaded nanocarriers capable of recognizing brain capillary endothelial cells and cerebral tumoral cells have shown promising potential in oncology. Endogenous and chimeric ligands binding to carriers or receptors of the BBB have been directly or indirectly conjugated to nanocarriers. This review indexes the main targeted colloidal systems used for drug delivery to the brain. Their pharmacological behavior and their therapeutic effect are discussed.
Biomaterials 12/2007; 28(33):4947-67. · 7.40 Impact Factor
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ABSTRACT: This paper presents original effects induced by temperature cycling on the transitional phase inversion of emulsions, stabilized by a nonionic polyethoxylated C18E6 surfactant model. The phase inversion follow-up is performed by electrical conductivity measurements, which involves focusing the study on the shape and location of the emulsion inversion region. In that way, new observations are brought out as a gradual evolution of the emulsion inversion along the cycling process. Two alternative approaches are considered for tackling these results: (i) first, a molecular approach regarding the particular organization and rearrangement of water clusters surrounding the surfactant polymer polar head, and (ii) second, a thermodynamic approach only considering the whole Gibbs free energy of the system. The volumic approaches are transposed, here, to the water/oil interface, and disclose that the phase inversion zone is included in a metastable region, able to stabilize for a given temperature, either metastable O/W emulsions or stable W/O ones. In that way, this study proposes novel and complementary insights into the phenomena governing the emulsion phase inversion.
The Journal of Physical Chemistry B 05/2007; 111(14):3651-7. · 3.70 Impact Factor
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ABSTRACT: To develop from an original process, a novel generation of stealth lipidic nanocapsules in order to improve the lipophilic drug delivery in accessible sites.
Nanocapsules covered by PEG1500 stearate were obtained by a low energy emulsification method. Conductivity measurements and ternary diagram were performed to describe the formulation mechanism. Hemolytic dosage CH50 and pharmacokinetic study in rats have been achieved in order to study the stealth properties of nanocapsules.
Transition from an O/W emulsion to a w/O/W emulsion was necessary to produce PEG1500 stearate nanocapsules. Interestingly nanocapsules with a size around 26 nm and a polydispersity index inferior to 0.1 were obtained. The CH50 test has revealed a very weak complement consumption in the presence of such nanocapsules. Moreover, after intravenous injection into rats, PEG1500 stearate nanocapsules exhibited long circulating properties. The experimental data support the concept of steric repulsion of the surface towards proteins, displayed by nanocapsules covered with PEG1500 stearate. These in vivo results were in agreement with the PEG1500 density calculated at the nanocarrier surface.
Injectable drug carriers have been developed. Their long-circulating properties could confer them a strong potential for lipophilic drug targeting.
Pharmaceutical Research 10/2006; 23(9):2190-9. · 4.09 Impact Factor
