Diclofenac Loaded Lipid Nanovesicles Prepared by Double Solvent Displacement for Skin Drug Delivery.

PURPOSE: Herein, we detail a promising strategy of nanovesicle preparation based on control of phospholipid self-assembly: the Double Solvent Displacement. A systematic study was conducted and diclofenac as drug model encapsulated. In vitro skin studies were carried out to identify better formulation for dermal/transdermal delivery. METHODS: This method consists in two solvent displacements. The first one, made in a free water environment, has allowed triggering a phospholipid pre-organization. The second one, based on the diffusion into an aqueous phase has led to liposome formation. RESULTS: Homogeneous liposomes were obtained with a size close to 100 nm and a negative zeta potential around -40 mV. After incorporation of acid diclofenac, we obtained nanoliposomes with a size between 101 ± 45 and 133 ± 66 nm, a zeta potential between 34 ± 2 and 49 ± 3 mV, and the encapsulation efficiency (EE%) was between 58 ± 3 and 87 ± 5%. In vitro permeation studies showed that formulation with higher EE% dispayed the higher transdermal passage (18,4% of the applied dose) especially targeting dermis and beyond. CONCLUSIONS: Our results suggest that our diclofenac loaded lipid vesicles have significant potential as transdermal skin drug delivery system. Here, we produced cost effective lipid nanovesicles in a merely manner according to a process easily transposable to industrial scale. Graphical Abstract ᅟ.

Preparation and characterization of amorphous solid dispersions of nimesulide in cyclodextrin copolymers.

A study to enhance the dissolution rate of nimesulide (NIM), a poorly water-soluble, non-steroidal anti-inflammatory drug, was carried out through developing new amorphous solid dispersions (ASD) based on soluble or insoluble water cyclodextrin copolymers (alpha-cyclodextrin, beta-cyclodextrin and y-cyclodextrin polymers) synthesized by direct melt polycondensation. Amorphous solid dispersions of NIM in cyclodextrin copolymers, obtained by solvent evaporation, were characterized by thermogravimetric analyzer (TGA), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and fourier transform-infrared spectroscopy (FT-IR). These analyses provided the existence of interactions between amorphous drug and its carrier. A burst release of more than 80% NIM within approximately 70 minutes was seen with soluble alpha-cyclodextrin polymers (poly-alpha-sol) and insoluble gamma-cyclodextrin polymers (poly-gamma-insol) where no significant differences were observed with the other copolymers. Mathematical kinetic models such as zero order, Higuchi and Korsmeyer-Peppas were used to evaluate the kinetic and mechanism of release of NIM from the different ASD compared to lactose reference matrix. The kinetic of release of NIM from different ASD followed a Higuchi model and the mechanism of release was explained by Korsmeyer-Peppas model in which a fickian diffusion for lactose and soluble beta-cyclodextrin polymers (poly-beta-sol) was observed. However, an anomalous non-Fickian transport was found for the other copolymers.

[Repackaging drugs in pill-box in France: an illegal activity for pharmacists?]. / Le déconditionnement/reconditionnement des spécialités pharmaceutiques en pharmacies : un acte illégal ?

Drug repackaging in pill-box by pharmacists is booming since few years. However, repackaging processes needed to open the industrially primary packaging will be found illegal in France. Thus, in this country drug repacking remains legal only by overwrapping medicines. Now, this solution is not applicable for example, with divisible or liquid forms. Therefore, packaging recommendations must be taken immediately in order to preserve the quality of drugs dispensed and to obtain a legalization of this activity.

[The radiopharmacy end?]. / La fin de la radiopharmacie ?

In France, radiopharmaceuticals preparation and dispensation are made under the responsibility of a pharmacist. This last one made a pharmaceutical over-specialization in the field of the medical use of radioelements. However, a flaw in the French law allows nuclear medicine units to avoid the presence of the radiopharmacist decreasing so the quality and the safety of the care brought to patients. This article aims at looking for legal solutions to maintain these quality and safety by the empowerment of the radiopharmacist statute while taking into account economic aspects.

rhEGF microsphere formulation and in vitro skin evaluation.

An optimized process for protein encapsulation was applied to formulate epidermal growth factor (rhEGF)-poly-epsilon-caprolactone microspheres. Microparticles mean size was 3.8 microm +/- 0.2 and the encapsulation efficiency was 41.9% +/- 2.6. rhEGF recovery after the encapsulation process was approximately 70% (41.9% inside the microspheres and 30% still active in the external phase). In vitro release experiments in McIlvaine buffered solution showed a rhEGF sustained release over 4 days. Skin absorption studies conducted on full-thickness human skin using the Franz cell method showed that 20% rhEGF was released from the microspheres after 24 h exposure. Microspheres accumulated in the stratum corneum where they may act as a rhEGF reservoir. Therefore, rhEGF-PCL microparticles seemed to be promising systems due to their ability to provide locally a sustained release of rhEGF in skin layers.

Skin absorption studies of octyl-methoxycinnamate loaded poly(D,L-lactide) nanoparticles: estimation of the UV filter distribution and release behaviour in skin layers.

New formulation strategies have to be developed to limit the skin penetration of UV-filter. Nanoparticles (NP) are very suitable for that purpose. In this study, the skin distribution, at different times (1, 2 and 3 h), of octyl-methoxycinnamate (OMC) from loaded PLA-nanoparticles was compared to a classical formulation containing non-encapsulated OMC, using the Franz cell method. The results showed that the OMC penetration was clearly impeded by stratum corneum and that the major part of the OMC-NP was accumulated at the skin surface (> 80%). A significant lower OMC amount was quantified in viable skin with NP compared to the OMC emulgel. To accurately determine the real OMC amount in close contact with viable skin layers two solvents were used to extract OMC from the skin compartments. Acetone (ACET) allowed quantifying both OMC in NP and OMC released from the particles, while isopropylmyristate (IPM), a non-solvent of the NP polymer (PLA), allowed quantifying only OMC released from the particles. Using IPM as an extraction solvent, it appeared that the OMC released from NP, in contact with viable skin, was 3-fold lower than free OMC diffused from the emulgel. Lastly, a sustained release was observed when nanoparticles were used.

Development of alpha-tocopherol acetate nanoparticles: influence of preparative processes.

We studied different methods of preparing alpha-tocopherol acetate (ATA) nanoparticles, which are to be used in targeting the lungs as aerosols in order to prevent cigarette smoke toxicity. Poly-(lactide) nanoparticles were prepared using nanoprecipitation and solvent evaporation techniques, which produced, respectively, too small and too large nanoparticles to be aerosolized. The emulsification-diffusion method produced 2 months stable nanoparticles with a size between (500-700 nm). Increasing ATA concentration (1-7 mg/mL) induced a decrease in the association rate (97-93%) and in the adsorbed ATA rate (7-4.5%), which was associated with variations of Zeta potentials (-27.5 to -24.3 mV) and decrease in polymeric wall thickness and density.

Conservative three-quarter versus subtotal seven-eighths parathyroidectomy in secondary hyperparathyroidism.

OBJECTIVE: There is at present no consensus concerning surgical techniques for secondary hyperparathyroidism (SHPT) in end-stage renal disease (ESRD). Although both subtotal and total parathyroidectomy provide low rates of recurrence, they may induce hypoparathyroidism, damaging the bone and cardiovascular systems. The aim of our study was to compare 3/4 and 7/8 parathyroidectomy in this population and to discuss the potential benefit of more conservative treatment. STUDY DESIGN: Prospective observational study in a university teaching hospital between 2010 and 2014. METHODS: The study included 34 consecutive ESRD patients with SHPT: 19 underwent 3/4 parathyroidectomy (group A*3/4) and 15 underwent 7/8 parathyroidectomy (group B*7/8). Serum intact 1-84 PTH levels (before and 6 months after surgery) and hospital stay were compared between the two groups. RESULTS: Before surgery, PTH levels were similar between the two groups. At month 6 following surgery, median PTH levels were significantly higher in group A*3/4 than in group B*7/8 (109 versus 24pg/mL, respectively; P<0.0006). Hospital stay was shorter in group A*3/4 (4.79 versus 6.80 days, respectively; P=0.008). Postoperative hypoparathyroidism requiring long-term calcium and 1alpha(OH) D3 treatment was reported in 5% of patients in group A*3/4 and 26% of patients in group B*7/8 (P=0.04). CONCLUSIONS: In this preliminary study, 3/4 conservative parathyroidectomy seemed effective and safe, with less reported morbidity than 7/8 parathyroidectomy, as assessed by lower rates of irreversible hypoparathyroidism and shorter hospital stay. LEVEL OF EVIDENCE: 3b, individual case-control study.

Fecal microbiota transplantation to eradicate vancomycin-resistant enterococci colonization in case of an outbreak.

OBJECTIVE: A rapid and worrying emergence of vancomycin-resistant enterococci (VRE) gut colonization is occurring worldwide and may be responsible for outbreaks, especially in healthcare facilities. While no efficient decolonization strategies are recommended, we assessed fecal microbiota transplantation (FMT) to eradicate VRE colonization. PATIENTS AND METHOD: Our main objective was to measure the impact of FMT on decolonization of VRE carriers, confirmed by at least two consecutive negative rectal swabs at one-week interval during a 3-month follow-up period. Patients received no antibiotic prior to the FMT. RESULTS: After a month only three patients remained colonized with VRE. Decolonization was associated with 87.5% (n=7) of success after three months as only one patient remained colonized. CONCLUSION: Our first results confirm that the FMT seems to be safe, with an impact on VRE colonization over time that may help control outbreaks.

Percutaneous release of caffeine from microemulsion, emulsion and gel dosage forms.

The transport of caffeine to the hypodermis by an alcohol-free o/w microemulsion was investigated and compared with an aqueous gel and an o/w emulsion. The microemulsion was well characterized and in vitro diffusion measurements through pig skin having the hypodermis either kept or removed were performed in static Franz cells. The microemulsion allowed delivery of a large fraction of the caffeine in the hypodermis: 23% of caffeine reached the hypodermis after 24h diffusion, 1.3-fold larger than from the emulsion and gel dosage forms. Half this amount was stored in the hypodermis, the other half continuing its diffusion to the receptor compartment of the Franz cell.

Lipid nanocarriers as skin drug delivery systems: Properties, mechanisms of skin interactions and medical applications.

During the past decades, lipid nanocarriers are gaining momentum with their multiple advantages for the management of skin diseases. Lipid nanocarriers enable to target the therapeutic payload to deep skin layers or even to reach the blood circulation making them a promising cutting-edge technology. Lipid nanocarriers refer to a large panel of drug delivery systems. Lipid vesicles are the most conventional, known to be able to carry lipophilic and hydrophilic active agents. A variety of lipid vesicles with high flexibility and deformability could be obtained by adjusting their composition; namely ethosomes, transfersomes and penetration enhancer lipid vesicles which achieve the best results in term of skin permeation. Others are designed with the objective to perform higher encapsulation rate and higher stability, such as solid lipid nanoparticles and nanostructured lipid nanocarriers. In this review, we attempted to give an overview of lipid based nanocarriers developed with the aim to enhance dermal and transdermal drug delivery. A special focus is put on the nanocarrier composition, behavior and interaction mechanisms with the skin. Recent applications of lipid-based nanocarriers for the management of skin diseases and other illnesses are highlighted as well.

Clearance of carbapenem-resistant Enterobacteriaceae vs vancomycin-resistant enterococci carriage after faecal microbiota transplant: a prospective comparative study.

BACKGROUND: Carbapenem-resistant Enterobacteriaceae (CRE) and vancomycin-resistant enterococci (VRE) carriage are increasing worldwide. Faecal microbiota transplantation (FMT) appears to be an attractive option for decolonization. This study aimed to evaluate CRE vs VRE clearance by FMT among carriers. METHODS: A multi-centre trial was undertaken on patients with CRE or VRE digestive tract colonization who received FMT between January 2015 and April 2017. Adult patients with CRE or VRE colonization, confirmed by three consecutive rectal swabs at weekly intervals, including one in the week prior to FMT, were included in the study. Patients with immunosuppression or concomitant antibiotic prescription at the time of FMT were excluded. Successful decolonization was determined by at least two consecutive negative rectal swabs [polymerase chain reaction (PCR) and culture] on Days 7, 14, 21 and 28, and monthly for three months following FMT. RESULTS: Seventeen patients were included, with a median age of 73 years [interquartile range (IQR) 64.3-79.0]. Median duration of carriage of CRE or VRE before FMT was 62.5 days (IQR 57.0-77.5). One week after FMT, three of eight patients were free of CRE colonization and three of nine patients were free of VRE colonization. After three months, four of eight patients were free of CRE colonization and seven of eight patients were free of VRE colonization. Qualitative PCR results were concordant with culture. Six patients received antibiotics during follow-up, three in each group. No adverse events were reported. CONCLUSION: CRE and VRE clearance rates were not significantly different in this study, possibly due to the small sample size, but a trend was observed. These data should be confirmed by larger cohorts and randomized trials.

The effect of monomers on the formulation of polymeric nanocapsules based on polyureas and polyamides.

Formulation of nanocapsules based on polyureas and polyamides have been tested using a patented process. This method based on polycondensation reaction of two complementary monomers and spontaneous formation of oil in water emulsion, is an alternative concept to the known technique based on the same type of reaction used for the formulation of microcapsules, and in which the lipophilic monomer was emulsified in the organic phase before the formation of the polymeric membrane. Nanocapsules can be prepared from different monomers. Wall based on cross-linked polymer contributes to the stability of nanocapsules during and after formulation. The permeability of the polymeric wall is related to its crystallinity and contributes to the growth of nanocapsule membrane by the diffusion of the hydrophilic monomers to get stable colloidal suspensions.

Degradation of paraoxon (VX chemical agent simulant) and bacteria by magnesium oxide depends on the crystalline structure of magnesium oxide.

In this work, our goal was to study the capability of a single metallic oxide to neutralize a chemical agent and to exhibit an antibacterial effect. We tested two types of magnesium oxides, MgO. The first MgO sample tested, which commercial data size characteristic was -325 mesh (MgO-1) destroyed in 3 h, 89.7% of paraoxon and 93.2% of 4-nitrophenol, the first degradation product. The second MgO sample, which commercial data size was <50 nm (MgO-2) neutralized in the same time, 19.5% of paraoxon and 10.9% of 4-nitrophenol. For MgO-1 no degradation products could be detected by GC-MS. MgO-1 had a bactericidal activity on Escherichia coli (6 log in 1 h), and showed a decrease of almost 3 log on a Staphylococcus aureus population in 3 h. MgO-2 caused a decrease of 2 log of a E.coli culture but had no activity against S. aureus. Neither of these two products had an activity on Bacillus subtilis spores. Analytical investigations showed that the real sizes of MgO nanoparticles were 11 nm for MgO-1 and 25 nm for MgO-2. Moreover, their crystalline structures were different. These results highlighted the importance of the size of the nanoparticles and their microscopic arrangements to detoxify chemical products and to inhibit or kill microbial strains.

Stability studies on colloidal suspensions of polyurethane nanocapsules.

Generally nanocapsules suspensions are a colloidal system in a metastable state, there is aggregation due to attraction and repulsion forces between particles. The objective of this work was to bring the role of the polymeric membrane in the protection of the active drug against damaging caused by external agents and to select the monomer which leads to obtain stable formulation with the highest possible payload of the active drug. The stability testing involving visual aspect, particle size measurement, transmission electron microscopy (TEM) examination, and drug loss was conduced after 6 months of storage at different temperatures (4, 25, and 45 degrees C). The colloidal suspensions of nanocapsules were obtained using the combined interfacial polycondensation and spontaneous emulsification, the technique was used to encapsulate alpha-tocopherol using polyurethanes polymers. It is a one step procedure: An organic phase composed of a water miscible solvent (acetone), lipophilic monomer (Isophorone diisocyanate IPDI), oil, and a lipophilic surfactant, is injected in an aqueous phase containing hydrophilic monomer (diol with various molecular weight: 1,2-ethanediol (ED), 1,4-butanediol (BD), and 1,6-hexanediol (HD)) and hydrophilic emulsifying agent. The water miscible solvent diffuses to the aqueous phase, the oil precipitates as nano-droplets, and the two monomers react at the interface, forming a membrane around the nanoemulsion leading to nanocapsules. A good physical stability of suspensions corresponds to absence of symptoms such as sedimentation or agglomeration, significant size change and alpha-tocopherol degradation due to external agents such as oxygen, temperature, and ultraviolet (UV) irradiation. The size of nanocapsules before storage was about 232 +/- 3, 258 +/- 29, and 312 +/- 4 nm for ED, BD, and HD, respectively. After 6 months of storage, polyurethanes nanocapsules possess good stability against aggregation at 4 and 25 degrees C. Comparing results obtained using different monomers, it reveals that the polyurethane based on HD offers good protection of alpha-tocopherol against damaging caused by the temperature and UV irradiation.

Nanoparticles for drug delivery: review of the formulation and process difficulties illustrated by the emulsion-diffusion process.

The elaboration of nanoparticles aqueous suspensions aimed at the drug delivery and related process development appear as difficult tasks, due to specificities related to the nanometric size. Such small sizes are required for specific applications in pharmacy. The switch of micrometric to nanometric field represents an actual challenge and cannot be considered as a simple scaling-down of chemical engineers. Ideas and concepts developed first in nanosciences have been adapted to the pharmaceutical application in drug delivery. In spite of drastic constraints due to pharmaceutical application, some parameters allow the control. A brief and not exhaustive review of the state-of-the-art on polymer particles used in the drug delivery field is presented. Attention was more particularly paid on preparation processes and their constraints by describing advantages and drawbacks of each process. The adaptation to the pharmaceutical field, the difficulties and pitfalls which are shared, with most research works in nanoscience, are illustrated thanks to our own results on nanocapsules obtained by "emulsion-diffusion" process presented as a case-study. Thanks to these results, we illustrate the peculiar features and difficulties encountered regarding nanocapsules preparation and characterization. Indeed, such a process allows to prepare nanocapsules of few hundreds nanometers diameter having an oil core surrounded by a polymeric membrane. The characterization of such soft particles colloidal suspensions is often difficult and involves heavy investigation techniques in order to highlight physical mechanisms leading to the nanocapsule properties. This is a key step regarding the final properties as a drug delivery system.

Preparation and characterization of spironolactone-loaded nanocapsules for paediatric use.

Spironolactone is a steroidal diuretic showing incomplete oral behaviour because of its low solubility and slow dissolution rate. In this study, we applied the nanoprecipitation method to prepare spironolactone-loaded nanocapsules, at laboratory-scale and pilot-scale. The effect of several formulation variables on the spironolactone-loaded nanocapsules properties (average size, drug release rate and drug entrapment) was investigated. The optimized formulations at laboratory-scale and pilot-scale lead to the preparation of spironolactone-loaded nanocapsules with a mean size of 320 and 400 nm, respectively, a high encapsulation efficiency (96.21% and 90.56% respectively), both stable for 6 months. The release of spironolactone from nanocapsules was rapid and complete in a simulated gastric fluid, therefore recourse to spironolactone nanoencapsulation should enhance its oral bioavailability and probably its efficiency. The optimized formulations lead to a high drug-concentration in the liquid preparation (1.5 mg/ml) allowing minimizing the preparation volume administered for children medication.

Advances in psoriasis physiopathology and treatments: Up to date of mechanistic insights and perspectives of novel therapies based on innovative skin drug delivery systems (ISDDS).

Psoriasis is a chronic inflammatory disease affecting mainly the skin but which can be complicated by psoriatic arthritis (PsA).This autoimmune skin disorder concerns 2-5% of the world population. To date, the physiopathology of psoriasis is not still completely elucidated but many researches are ongoing which have led for example to the discovery of the Th17/Th22 pathway. The conventional therapeutic approaches (local or systemic route) appeal to various classes of drugs with complex mechanisms of action and non-negligible side effects. Although there is no therapy capable to cure psoriasis, the current goal is to relieve symptoms as longer as possible with a good benefit/risk ratio. That is one of the principal limits of conventional antipsoriatic drugs. New formulations based on nanoencapsulation are a promising opportunity to answer to this limit by offering an optimization of the conventional antipsoriatic drug use (higher activity, lower side effects and frequency of application, etc.). Herein, we tried to put in perspective the mechanistic insights (histological and immunological views) proposed into scientific literature these last years in order to have a better comprehension of psoriasis physiopathology resulting in skin lesions and PsA. The therapeutic armamentarium and the different strategies in the management of psoriasis are discussed in greater details. To finish, the field of encapsulation in nanoparticles is broached in order to put forward recent advances in innovative skin drug delivery systems (ISDDSs) of antipsoriatic active agents for a better efficacy, safety and compliance.

Carbon nanotubes from synthesis to in vivo biomedical applications.

Owing to their unique and interesting properties, extensive research round the globe has been carried out on carbon nanotubes and carbon nanotubes based systems to investigate their practical usefulness in biomedical applications. The results from these studies demonstrate a great promise in their use in targeted drug delivery systems, diagnostic techniques and in bio-analytical applications. Although, carbon nanotubes possess quite interesting properties, which make them potential candidates in the biomedical science, but they also have some inherent properties which arise great concern regarding their biosafety. In this comprehensive review, we have discussed different aspects of carbon nanotubes and carbon nanotube based systems related to biomedical applications. In the beginning, a short historical account of these tiny yet powerful particles is given followed by discussion regarding their types, properties, methods of synthesis, large scale production method, purification techniques and characterization aspects of carbon nanotubes. In the second part of the review, the functionalization of carbon nanotubes is reviewed in detail, which is not only important to make them biocompatible and stable in biological systems but also render them a great property of loading various biomolecules, diagnostic and therapeutic moieties resulting in diversified applications. In the final part of the review, emphasis is given on the pharmacokinetic aspects of carbon nanotubes including administration routes, absorption mechanisms, distribution and elimination of carbon nanotubes based systems. Lastly, a comprehensive account about the potential biomedical applications has been given followed by insights into the future.