Strategies for the nanoencapsulation of hydrophilic molecules in polymer-based nanoparticles

Hydrophilic drug delivery still remains a challenge; this either being attributed to the fragility and poor cellular penetration of macromolecules, or to the unsuitable pharmacokinetics and toxicity of small drugs, for instance anticancer agents. By offering more favourable pharmacokinetics and protection of the drug, encapsulation in polymer nanoparticles constitutes an attractive possibility to overcome these problems. This review provides an overview of the strategies that have been developed for encapsulating hydrophilic molecules in polymer-containing nanoparticles, e.g. nanospheres and nanocapsules. Polymer nanospheres are loaded either by drug entrapment (by pH modification, use of reverse micelles or the addition of a polyanion) and generally produce a poor level of entrapment efficiency, or molecule sorption onto the nanosphere surface (by pH modification, use of high drug concentration, or ion-pair formation) with the drawbacks of a less-well protected drug from degradation and a faster drug release. Another strategy consists of the use of aqueous-core nanocapsules, generally surrounded by a thin polymer layer, in which hydrophilic molecules are directly solubilised in internal water, and are thus entrapped within the nanocapsule core, assuring drug protection and sustained release. Nanocapsules require less polymer compared to nanospheres; on the other hand, when the drug is entrapped, it has to be added before or during the formulation process, and is thus likely to be degraded. Overall, drug encapsulation in polymer nanoparticles provides a better pharmacokinetic profile and bioavailability, enhanced anticancer activity, reduced drug toxicity and modified drug distribution as compared to free drugs

Design and stability study of a paediatric oral solution of methotrexate 2mg/ml

Oral paediatric forms development by pharmaceutical industry is still insufficient. The present study was performed to propose an adapted and pleasant formulation of liquid oral formulation of MTX. The solution is composed of injectable methotrexate, water, Ora Sweet(®) and sodium bicarbonate. After 120 days storage, pH remained stable at about 8 in all formulations, insuring no risk of MTX precipitation. MTX content in solution formulation, determined by high performance liquid chromatography measurements, remained in the specifications of >90% of the initial concentration when stored at 4 and 25°C. Forced degradation of MTX by heat and acidic conditions allowed formation and detection of degradation products by the analytical method. Microbial study of the preparation shows that the solution remains in the specifications during all the storage, or after one sample each week during one month, eventually indicating the microbial properties are not affected by patient use. To conclude, we here propose a new MTX liquid formulation stable for at least 120 days

Stability of micafungin sodium solutions at different concentrations in glass bottles and syringes

Micafungin is a costly treatment and packaging of 50mg or 100mg bottles only are available, while doses lower than 5mg and 20mg are often necessary in neonates and paediatrics patients, respectively. The stability of micafungin sodium in polypropylene syringes and glass bottles was studied at different concentrations. Solutions of micafungin diluted with NaCl 0.9% were prepared in glass bottles (20 and 10mg/mL) or syringes (1 and 0.5mg/mL) and stored at 25°C, 60% humidity (RH), in the dark (ICH conditions). Solutions were also exposed to heat (70°C) or alkaline solution (NaOH) in order to force degradation. Samples were analysed at days 1, 5, 8 (for bottles) and also 15 (for syringes) after the preparation and assayed in triplicate. Stability was studied using a stability-indicating high-performance liquid chromatographic method. Syringes stored at 25°C retained over 90% of their initial concentration over the study period. Temperature and alkaline conditions had significant effect on the stability of micafungin, leading to apparition of degradation products. Moreover, sub visible particles were in the specification of the European Pharmacopeia along 15 days. To conclude, micafungin diluted in NaCl 0.9% and stored in polypropylene syringes was chemically stable for at least 15 days at 25°C in the dark

Successful treatment of a recurrent Aspergillus niger otomycosis with local application of voriconazole

Fungal otitis (otomycosis) is a common infection encountered by otolaryngologists. Nevertheless, its management can be challenging because of its high recurrence rate and of the limited therapeutic options. A 45-year-old woman suffered from recurrent otomycosis. The ineffectiveness of successive antibiotic cures and repeated topical treatments with nystatin and then with econazole cream led to perform microbiological analyses. Culture of ear swab grew Aspergillus niger. The use of a 1% voriconazole sterile solution previously validated for treatment of eye infections was considered after ensuring the absence of known ototoxic effects of the antifungal and of the excipients. The patient was advised to apply locally this voriconazole solution daily for 14 days (3 drops, 3-4 times a day). Full recovery was obtained at the end of the treatment, and no relevant side effects were noticed. More than one year after completion of therapy, there was no recurrence. Our observation shows that voriconazole 1% solution is an interesting option for treating otomycosis which failed to respond to usual therapeutic options. Further prospective studies are now warranted to confirm these findings

Traitement des angiofibromes de la sclérose tubéreuse de Bourneville par des préparations topiques à base de sirolimus : état des lieux de la préparation en France et revue de la littérature

Introduction Parmi les différentes affections dermatologiques associées à la sclérose tubéreuse de Bourneville (STB), les angiofibromes faciaux sont les plus défigurants. Présents chez 85 % des patients, leurs répercussions sont autant physiques que psychologiques. Les moyens utilisés pour les traiter tels la chirurgie, la cryothérapie, l’électrocoagulation, la dermabrasion ou le laser ont montré leur efficacité dans certains cas. Mais ils présentent des aspects contraignants pour leur mise en œuvre, notamment chez les plus jeunes, et peuvent se compliquer ou engendrer des séquelles permanentes. Depuis la démonstration de l’efficacité du sirolimus par voie systémique sur les angiofibromes, des formes topiques de ce médicament ont été développées. Le but de l’étude qui a été menée est de faire le point sur l’état de la préparation topique de sirolimus en France et de comparer ces données à celles trouvées dans la littérature. Matériel et méthodes Un questionnaire en ligne a été envoyé aux pharmaciens de 31 centres hospitaliers universitaires (CHU) de France et de 40 centres hospitaliers membres de l’Assistance publique–Hôpitaux de Paris (AP–HP), les interrogeant sur la réalisation de la forme topique, les modalités de préparation, de délivrance au patient, les études menées ainsi que celles à venir. Une revue de la littérature scientifique et médicale, des essais cliniques ainsi que des brevets déposés ont été menés. Résultats Onze CHU réalisent fréquemment cette préparation en France (taux de réponse de 55 %) ; la majorité depuis un an en moyenne. Les formes galéniques utilisées sont des pommades ou des crèmes et les dosages varient de 0,1 % à 1 %. Elles sont délivrées aux patients ambulatoires par le biais de la rétrocession hospitalière. Selon nos calculs, le coût d’un pot de 25 g de sirolimus à 0,1 % est de 110 €. Les principales causes de non réalisation sont le coût élevé de la préparation, le manque de données de sécurité et d’efficacité à long terme ou l’absence de demande de la part des services dermatologiques. À ce jour, plus d’une vingtaine d’articles ont été publiés sur le sujet. Cette forme topique a montré son efficacité uniquement dans des petites séries de cas où très peu d’effets indésirables ont été observés. Quatre essais cliniques ont été menés ou sont en cours et deux formules de sirolimus en topique ont été brevetées. Discussion Les formes galéniques, les dosages et modalités de préparation varient d’un établissement à l’autre. Cette diversité est expliquée par le fait qu’à ce jour, très peu de données croisant doses/degrés d’étendue des lésions/formes galéniques utilisées et efficacité du traitement sont disponibles. Conclusion L’émergence d’un consensus en ce qui concerne la formulation (crème ou pommade, concentration en sirolimus…) serait une avancée pour la prise en charge des patients atteints de STB. Mots clés Sclérose tubéreuse de Bourneville; Sirolimus; Topiqu

Reverse micelle-loaded lipid nanocarriers: A novel drug delivery system for the sustained release of doxorubicin hydrochloride

In this study, we are pioneering new nanotechnology for the encapsulation of anticancer drugs (doxorubicin (DOX) and/or docetaxel (DOCE)), whatever their solubility and water affinity. The purpose of this study is to highlight the potential of this recently patented technology, by carrying out a thorough physicochemical characterisation of these multiscaled nanocarriers, followed by the study of an encapsulation and release model of hydrophilic anticancer drug. The formulation process is based on a low-energy nano-emulsification method and allows the generation of a structure composed of oil-based nanocarriers loaded with reverse micelles. Thanks to this, hydrophilic contents can be solubilised in the oily core of this kind of nano-emulsion along with lipophilic content. The results emphasise some original structure particularities due to the multistep formulation process, and the diffusion-based behaviour revealed for the DOX release profile that is shown to be intimately linked to the morphology of the particles

Différences de connectivité effective entre des enfants dyslexiques et des enfants lecteurs normaux pendant une tâche de lecture de pseudomots : une étude par IRMf

International audiencePurpose.—This fMRI study investigated phonological and lexicosemantic processing in dyslexic and in chronological age- and reading level-matched children in a pseudoword reading task.Materials and methods.—The effective connectivity network was compared between the three groups using a structural model including the supramarginal cortex (BA 40; BA: Brodmann area), fusiform cortex (BA 37) and inferior frontal cortex (BA 44/45) areas of the left hemisphere.Results.—The results revealed differences in connectivity patterns. In dyslexic patients, in contrast with chronological age- and reading level-matched groups, no causal relationship was demonstrated between BA 40 and BA 44/45. However, a significant causal relationship was demonstrated between BA 37 and BA 44/45 both in dyslexic children and in the reading levelmatchedgroup.Conclusions.—These findings were interpreted as evidence for a phonological deficit in developmental dyslexiaBut.—Explorer par imagerie fonctionnelle d’activation cérébrale chez l’enfant les aires corticales et les circuits cérébraux impliqués dans le traitement phonologique et lexico sémantique d’une tâche de lecture.Matériel et methods.—Un réseau d’aires cérébrales interconnectées est examiné sur la base d’un modèle structural incluant les cortex supramarginal (aire 40 de Brodmann), fusiforme (aire 37de Brodmann) et frontal inférieur (aires 44/45 de Brodmann) de l’hémisphère gauche. La méthode de modélisation proposée permet d’évaluer une différence de connectivité effective des circuits engagés au cours d’une tâche de lecture de pseudomots entre des enfants dyslexiques et des enfants normaux lecteurs appariés en âge chronologique et lexical.Résultats.—Chez les patients dyslexiques, contrairement aux groupes témoins appariés par l’âge ou le niveau de lecture, aucune interaction causale n’a été démontrée entre les aires 40 et 44/45 de Brodmann qui constituent les noeuds du circuit d’assemblage phonologique. En revanche, une interaction significative a été retrouvée au niveau du circuit d’adressage lexico sémantique, entre les aires 37 et 44/45 de Brodmann, chez les enfants dyslexiques et les enfants appariés par le niveau de lecture.Conclusions.—Ces résultats confirment l’existence d’un déficit des processus phonologiques dans la dyslexie développementale

Anxiety, emotional processing and depression in people with multiple sclerosis.

BACKGROUND: Despite the high comorbidity of anxiety and depression in people with multiple sclerosis (MS), little is known about their inter-relationships. Both involve emotional perturbations and the way in which emotions are processed is likely central to both. The aim of the current study was to explore relationships between the domains of mood, emotional processing and coping and to analyse how anxiety affects coping, emotional processing, emotional balance and depression in people with MS. METHODS: A cross-sectional questionnaire study involving 189 people with MS with a confirmed diagnosis of MS recruited from three French hospitals. Study participants completed a battery of questionnaires encompassing the following domains: i. anxiety and depression (Hospital Anxiety and Depression Scale (HADS)); ii. emotional processing (Emotional Processing Scale (EPS-25)); iii. positive and negative emotions (Positive and Negative Emotionality Scale (EPN-31)); iv. alexithymia (Bermond-Vorst Alexithymia Questionnaire) and v. coping (Coping with Health Injuries and Problems-Neuro (CHIP-Neuro) questionnaire. Relationships between these domains were explored using path analysis. RESULTS: Anxiety was a strong predictor of depression, in both a direct and indirect way, and our model explained 48% of the variance of depression. Gender and functional status (measured by the Expanded Disability Status Scale) played a modest role. Non-depressed people with MS reported high levels of negative emotions and low levels of positive emotions. Anxiety also had an indirect impact on depression via one of the subscales of the Emotional Processing Scale ("Unregulated Emotion") and via negative emotions (EPN-31). CONCLUSIONS: This research confirms that anxiety is a vulnerability factor for depression via both direct and indirect pathways. Anxiety symptoms should therefore be assessed systematically and treated in order to lessen the likelihood of depression symptoms