Interactions of hydrophilic quantum dots with defect-free and defect containing supported lipid membranes.

Quantum dots (QDs) are semiconductor nanoparticles with unique optical and electronic properties, whose interest as potential nano-theranostic platforms for imaging and sensing is increasing. The design and use of QDs requires the understanding of cell-nanoparticle interactions at a microscopic and nanoscale level. Model systems such as supported lipid bilayers (SLBs) are useful, less complex platforms mimicking physico-chemical properties of cell membranes. In this work, we investigated the effect of topographical homogeneity of SLBs bearing different surface charge in the adsorption of hydrophilic QDs. Using quartz-crystal microbalance, a label-free surface sensitive technique, we show significant differences in the interactions of QDs onto homogeneous and inhomogeneous SLBs formed following different strategies. Within short time scales, QDs adsorb onto topographically homogeneous, defect-free SLBs is driven by electrostatic interactions, leading to no layer disruption. After prolonged QD exposure, the nanomechanical stability of the SLB decreases suggesting nanoparticle insertion. In the case of inhomogeneous, defect containing layers, QDs target preferentially membrane defects, driven by a subtle interplay of electrostatic and entropic effects, inducing local vesicle rupture and QD insertion at membrane edges.

Development of mAb-loaded 3D-printed (FDM) implantable devices based on PLGA.

The main objective of this work was to explore the feasibility to print monoclonal antibody (mAb)-loaded implantable systems using fused-deposition modelling (FDM) to build complex dosage form designs. Indeed, to our knowledge, this work is the first investigation of mAb-loaded devices using FDM. To make this possible, different steps were developed and optimized. A mAb solution was stabilized using trehalose (TRE), sucrose (SUC), hydroxypropyl-ß-cyclodextrin (HP-ß-CD), sorbitol or inulin (INU) in order to be spray dried (SD). Printable filaments were then made of poly(lactide-co-glycolide) (PLGA) and mAb powder (15% w/w) using hot melt extrusion (HME). The FDM process was optimized to print these filaments without altering the mAb stability. TRE was selected and associated to L-leucine (LEU) to increase the mAb stability. The stability was then evaluated considering high and low molecular weight species levels. The mAb-based devices were well-stabilized with the selected excipients during both the HME and the FDM processes. The 3D-printed devices showed sustained-release profiles with a low burst effect. The mAb-binding capacity was preserved up to 70% following the whole fabrication process. These promising results demonstrate that FDM could be used to produce mAb-loaded devices with good stability, affinity and sustained-release profiles of the mAb.

Investigation of the parameters used in fused deposition modeling of poly(lactic acid) to optimize 3D printing sessions.

This study assesses the feasibility of printing implantable devices using 3D printing Fused deposition modeling (FDM) technology. The influence of the deposition temperature, the deposition rate and the layer thickness on the printing process and the physical properties of the devices were evaluated. The filaments were composed of neat poly(lactic acid) (PLA) and blends of different plasticizers (polyethylene glycol 400 (PEG 400), triacetine (TA), acetyltriethyl citrate (ATEC) and triethyl citrate (TEC)) at 10% (w/w). The assessment of thermomechanical characteristics and morphology of both filaments and devices (cylinders and dog bones) were performed. The influence of each parameter was evaluated using a design of experiment (DoE) and the significance of the results was discussed. A large amount of data about the evaluation of FDM process parameters are already available in the literature. However, specific insights needed to be increased into the impact of the use of PLA and plasticized PLA raw material on the feasibility of printing devices in three dimensions. To conclude, the ductility was improved with a high layer thickness, low temperature and using ATEC. Whereas, adhesion was promoted with an increase in temperature, a lower layer thickness and adding TA.

Development and evaluation of chitosan and chitosan derivative nanoparticles containing insulin for oral administration.

Chitosan and chitosan derivative-based nanoparticles loaded with insulin were prepared by self-assembly, via electrostatic interactions between the negatively charged drug and the positively charged polymers. In the investigated chitosan derivatives, the amine groups were substituted to different extents (33, 52 or 99%) by 2-hydroxypropyl-3-trimethyl ammonium groups, rendering the polymers permanently positively charged, irrespective of the pH. This is an important property for this type of advanced drug delivery system, since the pH value changes throughout the gastrointestinal tract and electrostatic interactions are of crucial importance for the stability of the nanoparticles. Permanent positive charges are also in favor of mucoadhesion. In contrast, the electric charges of chitosan molecules depend on the pH of the surrounding medium. Since the solubility of the chitosan derivatives increased due to the introduction of quaternary ammonium groups, sodium tripolyphosphate (TPP) was added to the systems to create supplementary cross-links and stabilize the nanoparticles. The presence of TPP influenced both the dissolution of the polymer matrix as well as the resulting release kinetics. The underlying drug release mechanisms were found to be more complex than simple diffusion under constant conditions, likely involving also ionic interactions and matrix dissolution. The most promising formulation was based on a chitosan derivative with 33% substitution degree and characterized by a Z-average of 142 ± 10 nm, a zeta potential of 29 ± 1 mV, an encapsulation efficacy of 52 ± 3% and, most importantly, the release of insulin was sustained for more than 210 min.

Stability study of full-length antibody (anti-TNF alpha) loaded PLGA microspheres.

Antibodies (Abs) require the development of stable formulations and specific delivery strategies given their susceptibility to a variety of physical and chemical degradation pathways. In this study, the encapsulation of an antibody into polylactide-co-glycolide (PLGA) based microspheres was explored to obtain a controlled-release of the incorporated drug. In order to avoid stability issues, a solid-in-oil-in-water (s/o/w) method was preferred. The solid phase was made of anti-TNF alpha monoclonal antibody (MAb) spray-dried microparticles, and the PLGA microspheres were produced using two different polymers (i.e., Resomer(®) RG505 and Resomer(®) RG755S). The stability of the MAb incorporated into the microspheres was investigated under three conditions (5 ± 3°C, 25 ± 2°C/60% RH and 40 ± 2°C/75% RH) for 12 weeks. During this stability study, it was demonstrated that the MAb loaded PLGA microspheres were stable when stored at 5 ± 3°C and that the Resomer(®) RG755S, composed of 75%(w/w) lactic acid as PLGA, was preferred to preserve the stability of the system. Storage at temperatures higher than 5°C led to antibody stability issues such as aggregation, fragmentation and loss of activity. The release profiles were also altered. Physical ageing of the system associated with changes in the glass transition temperature and enthalpy of relaxation was noticed during the storage of the MAb loaded PLGA microspheres.

Characterization and optimization of GMO-based gels with long term release for intraarticular administration.

Osteoarthritis is characterized by slow degenerative processes in the articular cartilage within synovial joints. It could be interesting to develop a sustained-release formulation that could be effective on both pain/inflammation and restoration of mechanical integrity of the joint. Recently, an injectable system based on glycerol monooleate (GMO), containing clonidine as a model hydrophilic analgesic/anti-inflammatory drug and hyaluronic acid as a viscoelastic scaffold, showed promising potential as a biodegradable and biocompatible preparation to sustain the drug activity. However, drug release from the system is relatively fast (complete within 1 week) and the underlying drug release mechanisms not fully understood. The aims of this study were: (i) to significantly improve this type of local controlled drug delivery system by further sustaining clonidine release, and (ii) to elucidate the underlying mass transport mechanisms. The addition of FDA-approved inactive ingredients such as sodium oleate or purified soybean oil was found to be highly effective. The release rate could be substantially reduced (e.g., 50% release after 10 days), due to the increased hydrophobicity of the systems, resulting in slower and reduced water uptake and reduced drug mobility. Interestingly, Fick's second law of diffusion could be used to quantitatively describe drug release.

Levodopa delivery systems for the treatment of Parkinson's disease: an overview.

This review describes the different drug delivery systems containing levodopa that are used in the treatment of Parkinson's disease. Their composition, process of preparation, advantages, disadvantages and limitations are discussed as well as the major objective in the management of Parkinson's disease according to the pathology of the disease.

Pharmacoscintigraphic and pharmacokinetic evaluation on healthy human volunteers of sustained-release floating minitablets containing levodopa and carbidopa.

In this study, scintigraphic and pharmacokinetic studies were conducted on 10 healthy, fed volunteers. Two concepts of sustained-release floating minitablets--Levo-Form 1 (matrix) and 2 (coated)--were evaluated and compared to the marketed product Prolopa HBS 125. All the floating forms were radiolabelled with (111)In in order to evaluate their gastric residence time using gamma-scintigraphy. It was shown that the three formulations offered almost the same mean gastric residence time, which was about 240 min. Prolopa HBS 125 and Levo-Form 2 presented intragastric disintegration, which can lead to a more pronounced "peak & valley" effect on the plasma concentration-time profile of levodopa. In contrast, the plasma concentration-time profile of levodopa following the administration of Levo-Form 1 was more evenly distributed. Moreover, Levo-Form 1 provided the lowest variations between men and women in terms of AUC and C(max) values. Finally, when the same amount of inhibitors of extracerebral dopa decarboxylase--carbidopa and benserazide--had been administrated, the mean AUC, C(max) and T(max) values obtained for benserazide were lower than those obtained for carbidopa.

Evaluation and floating enhancement of levodopa sustained release floating minitablets coated with insoluble acrylic polymer.

This article describes the in vitro evaluation and the enhancement of the floating properties of coated sustained release (SR) minitablets (MTs). The evaluated system consisted of a 3-mm drug-containing gas-generating core prepared by melt granulation and subsequent compression, which was then coated with a flexible polymeric membrane. Eudragit RL30D and acetyl triethylcitrate were used as a film former and a plasticizer, respectively. The coating level was fixed at 20% (wt/wt). The optimally coated floating MTs floated within 10 min and remained buoyant for more than 13 h, regardless of the pH of the test medium. By evaluating the dissolution profiles of levodopa at different pH, it was found that the release of levodopa was sustained for more than 12 h regardless of the pH, even if the coating did not cancel the effect of the pH-dependent solubility of the active drug. Finally, the robustness of the coated floating MTs was assessed by testing the drug release variability in function of the stirring conditions during dissolution tests.

New levodopa sustained-release floating minitablets coated with insoluble acrylic polymer.

The aim of this study was to develop a new coated multiple-unit sustained-release floating system that is able to float over an extended period of time. Levodopa was used as a model drug. The system consisted of a 3mm drug-containing gas-generating core, prepared by melt granulation and subsequent compression, and coated with a flexible polymeric membrane. Eudragit RL30D and ATEC were used as a film former and a plasticizer, respectively. The coating level was fixed at 20% (w/w). The floating lag time decreased as the proportion of effervescent agents increased. The optimized coated floating minitablets could float within 20min and remained buoyant for more than 13h. In addition, a sustained release of levodopa for more than 20h was observed.

Development and evaluation of new multiple-unit levodopa sustained-release floating dosage forms.

This work relates to the development and the in vitro evaluation of sustained-release minitablets (MT), prepared by melt granulation and subsequent compression, which are designed to float over an extended period of time. Levodopa was used as a model drug. The importance of the composition and manufacturing parameters of the MT on their floating and dissolution properties was then examined. The investigation showed that MT composition and MT diameter had the greatest influence on drug release, which was sustained for more than 8h. By using the same formulation, the best floating properties were obtained with 3mm MT prepared at low compression forces ranging between 50 and 100N. Their resultant-weight (RW) values were always higher than those obtained with a marketed HBS dosage form within 13h. When they were filled into gelatin capsules, no sticking was observed. By evaluating the dissolution profiles of levodopa at different pH values, it was found that dissolution profiles depend more on the prolonged-release ability of Methocel K15M than on the pH-dependent solubility of levodopa. Finally, the robustness of the floating MT was assessed by testing the drug release variability in function of the stirring conditions during dissolution tests.

In vitro and in vivo evaluation of floating riboflavin pellets developed using the melt pelletization process.

Floating pellets were prepared using the melt pelletization process in a Mi-Pro high shear mixer (Pro-C-epT, Belgium). Formulations were based on a mixture of Compritol and Precirol as meltable binders and on the use of sodium bicarbonate and tartaric acid as gas-generating agents. Good floating abilities were obtained by using the gas-generating agents in both the inner matrix and the outer coating layer of the pellets. In vitro evaluation of floating capability was performed both by using the resultant weight apparatus and by counting floating pellets at the surface of beakers containing 0.1N HCl solution, in vivo evaluation of floating pellets capabilities was also performed. Riboflavin-containing floating pellets (FRF) were administered orally to nine healthy volunteers versus non-floating pellets (NFRF). Volunteers were divided in two groups, fasted group (n=4) 729 kcal and fed group (n=5) 1634 kcal as the total calorie intake on the testing day. An increase of urinary excretion of riboflavin was observed when the volunteers were dosed with the floating pellets, especially after feeding. As riboflavin has a narrow window of absorption in the upper part of small intestine, this phenomenon could be attributable to the gastric retention of floating pellets.