Evaluation of amorphous and lipid-based formulation strategies to increase the in vivo cannabidiol bioavailability in piglets.

Cannabidiol (CBD) suffers from poor oral bioavailability due to poor aqueous solubility and high metabolism, and is generally administered in liquid lipid vehicles. Solid-state formulations of CBD have been developed, but their ability to increase the oral bioavailability has not yet been proven in vivo. Various approaches are investigated to increase this bioavailability. This study aimed to demonstrate the enhancement of the oral bioavailability of oral solid dosage forms of amorphous CBD and lipid-based CBD formulation compared to crystalline CBD. Six piglets received the three formulations, in a cross-over design. CBD and 7 - COOH - CBD, a secondary metabolite used as an indicator of hepatic degradation, were analyzed in plasma. A 10.9-fold and 6.8-fold increase in oral bioavailability was observed for the amorphous and lipid formulations, respectively. However, the lipid-based formulation allowed reducing the inter-variability when administered to fasted animals. An entero-hepatic cycle was confirmed for amorphous formulations. Finally, this study showed that the expected protective effect of lipids against hepatic degradation of the lipid-based formulation did not occur, since the ratio CBD/metabolite was higher than that of the amorphous one.

Interaction-Induced ac Stark Shift of Exciton-Polaron Resonances.

Laser-induced shift of atomic states due to the ac Stark effect has played a central role in cold-atom physics and facilitated their emergence as analog quantum simulators. Here, we explore this phenomenon in an atomically thin layer of semiconductor MoSe_{2}, which we embedded in a heterostructure enabling charge tunability. Shining an intense pump laser with a small detuning from the material resonances, we generate a large population of virtual collective excitations and achieve a regime where interactions with this background population are the leading contribution to the ac Stark shift. Using this technique we study how itinerant charges modify-and dramatically enhance-the interactions between optical excitations. In particular, our experiments show that the interaction between attractive polarons could be more than an order of magnitude stronger than those between bare excitons.

Expression of the endocannabinoid system and response to cannabinoid components by the human fetal testis.

BACKGROUND: Cannabis consumption by pregnant women continues to increase worldwide, raising concerns about adverse effects on fetal growth and deleterious impacts on the newborn, in connection with evidence of placental transfer of cannabis compound. Cannabis action is mediated by the endocannabinoid system (ECS), which expression is well established in the brain but unknown in the developing testis. The fetal testis, whose endocrine function orchestrates the masculinization of many distant organs, is particularly sensitive to disruption by xenobiotics. In this context, we aimed to determine whether cannabis exposure has the potential to directly impact the human fetal testis. METHODS: We determined the expression of components of the ECS in the human fetal testis from 6 to 17 developmental weeks and assessed the direct effects of phytocannabinoids Δ9-trans-tetrahydrocannabinol (THC) and cannabidiol (CBD) on the testis morphology and cell functions ex vivo. RESULTS: We demonstrate the presence in the human fetal testis of two key endocannabinoids, 2-arachidonylglycerol (2-AG) and to a lower level anandamide (AEA), as well as a range of enzymes and receptors for the ECS. Ex vivo exposure of first trimester testes to CBD, THC, or CBD/THC [ratio 1:1] at 10-7 to 10-5 M altered testosterone secretion by Leydig cells, AMH secretion by Sertoli cells, and impacted testicular cell proliferation and viability as early as 72 h post-exposure. Transcriptomic analysis on 72 h-exposed fetal testis explants revealed 187 differentially expressed genes (DEGs), including genes involved in steroid synthesis and toxic substance response. Depending on the molecules and testis age, highly deleterious effects of phytocannabinoid exposure were observed on testis tissue after 14 days, including Sertoli and germ cell death. CONCLUSIONS: Our study is the first to evidence the presence of the ECS in the human fetal testis and to highlight the potential adverse effect of cannabis consumption by pregnant women onto the development of the male gonad.

3D printed, personalized sustained release cortisol for patients with adrenal insufficiency.

The standard of care for patients with Adrenal Insufficiency (AI) is suboptimal. Administration of hydrocortisone three times a day produces plasma cortisol fluctuations associated with negative health outcomes. Furthermore, there is a high inter-individual variability in cortisol need, necessitating a personalized approach. It is hypothesized that a personalized, sustained release formulation would enhance the pharmacotherapy by mimicking the physiological cortisol plasma concentration at a higher level. Therefore, a novel 24 h sustained release 3D printed (3DP) hydrocortisone formulation has been developed (M3DICORT) by coupling hot-melt extrusion with fused deposition modeling. A uniform drug distribution in the 3DP tablets is demonstrated by a content of 101.66 ± 1.60 % with an acceptance value of 4.01. Furthermore, tablets had a stable 24 h dissolution profile where the intra-batch standard deviation was ± 2.8 % and the inter-batch standard deviation was ± 6.8 %. Tablet height and hydrocortisone content were correlated (R2 = 0.996), providing a tool for easy dose personalization. Tablets maintained critical quality attributes, such as dissolution profile (f2 > 60) and content uniformity after process transfer from a single-screw extruder to a twin-screw extruder. Impurities were observed in the final product which should be mitigated before clinical assessment. To our knowledge, M3DICORT is the first 3DP hydrocortisone formulation specifically developed for AI.

Influence of API physico-chemical properties on amorphization capacity of several mesoporous silica loading methods.

The objective of this work was to evaluate the impact of physico-chemical properties of pharmaceutical drugs on the optimal mesoporous silica loading methods. Indeed, a good combination between drug and loading process has to be studied to promote the deepest penetration of the drug inside the mesopores, allowing high drug amorphization. Six molecules, namely lidocaine and its hydrochloride, ibuprofen, ketoprofen, artemether and miconazole, with different physico-chemical properties (the ionized character, the acid-base character, the HBDA number, the solubility in sc-CO2 and the behavior under subcritical CO2) were used to produce drug-silica formulations. Different impregnation processes (physical mixing, melting, wetting, sc-CO2 and subcritical CO2 impregnations) have been compared for each drug, in terms of drug recovery and crystallinity. Formulations showed drug percentage close to 100% except for supercritical soluble drug formulations impregnated by using sc-CO2. However, the basic drug character provided less or no drug loss during impregnation. Processing insoluble sc-CO2 molecule under supercritical conditions led to less crystallinity than the correspondent physical mixture suggesting an interesting repulsive effect that forces the drug penetration within the mesopores. Besides, it has been also highlighted that the HBDA number is not sufficient to predict the final drug loading. Melting methods have high interest considering the drugs tested and subcritical CO2 could increase the loading, especially for drugs with high molten viscosity. This study showed that a plethora of loading methods can be used to provide high drug loaded MS formulations with a wide choice of equipment.

Systematic study of liposomes composition towards efficient delivery of plasmid DNA as potential application of dermal fibroblasts targeting.

The use of non-viral DNA vectors to topically treat skin diseases has demonstrated a high potential. However, vectors applied on the skin face extracellular barriers including the stratum corneum and intracellular barriers such as the endosomal escape and the nuclear targeting of the plasmid DNA. The aim of this study was to develop a formulation suitable for dermal application and effective for delivering plasmid DNA into cells. Different formulations were prepared using different cationic lipids (DOTAP, DC-Chol, DOTMA) and co-lipids (DOPE, DSPE). Lipoplexes were produced by complexing liposomes with plasmid DNA at different pDNA/CL (w/w) ratios. Our results showed that appropriate pDNA/CL ratios allowing total complexation of plasmid DNA differed depending on the structure of the lipid used. The transfection rates showed that (i) higher rates were obtained with DOTMA lipoplexes, (ii) DC-Chol lipoplexes provided a transfection twice as important as DOTAP lipoplexes and (iii) when DSPE was added, the cytotoxicity decreased while transfection rates were similar. We found that formulations composed of DC-Chol:DOPE:DSPE or DOTMA:DOPE were appropriate to complex plasmid DNA and to transfect human primary dermal fibroblasts with efficacy and limited cytotoxicity. Therefore, these formulations are highly promising in the context of gene therapy to treat skin diseases.

Impregnation of mesoporous silica with poor aqueous soluble molecule using pressurized carbon dioxide: Is the solubility in the supercritical and subcritical phase a critical parameter?

Recently, mesoporous silica (MS) has been used as a material able to maintain amorphous state of active compounds and therefore, enhance the oral bioavailability of BCSII drugs. Among impregnation methods of MS, techniques using supercritical carbon dioxide (Sc-CO2) are promising tools. Solubility of compounds in Sc-CO2 is reported as one of the most critical parameters, which usually limits its use in drug formulation. Indeed, most of compounds have poor solubility in Sc-CO2. The aim of this work is to compare different MS and to study alternative processes using pressurized CO2 for insoluble molecule in Sc-CO2. By using high pressure reactor, DSC, HPLC and in vitro dissolution tests, the crystallinity and dissolution profiles of MS with different pore size (6.6 nm, 25.0 nm and 2.5 nm) impregnated with fenofibrate (FF) under Sc-CO2 were compared to select the most appropriate carrier. Then, the selected MS has been impregnated under supercritical, subcritical and atmospheric conditions. We have shown that the MS pore size of 6.6 nm provides the higher amorphous drug loading capacity as well as the faster and higher drug dissolution. In addition, FF-MS formulations produced with pressurized CO2 as fusion medium, both in subcritical and supercritical conditions; give similar crystallinity and dissolution results compared to those produced with supercritical fluids as solvent. Through this study, we show new possibilities of using CO2 for insoluble compounds in this fluid.

In vitro skin penetration enhancement techniques: A combined approach of ethosomes and microneedles.

Dermal administration of different macromolecules, such as nucleic acids, remains a real challenge because of the difficulty of crossing the main skin barrier, the stratum corneum (SC). To overcome this barrier, the use of deformable lipid-based nanovectors were developed to increase topical penetration through the SC and to promote the intercellular delivery of drugs. The purpose of this study is to compare the skin penetration of different liposome formulations according to their composition. In vitro and ex vivo experiments using Franz diffusion cells were performed to highlight the effect of (i) lipid charge, (ii) edge activators (EA) and (iii) ethanol on the diffusion properties of nanovectors. We showed that all formulations were not able to cross the SC. However, on a tape stripped skin, we showed that cationic formulations containing an EA and ethanol improved the skin penetration. The use of microneedles was considered to bypass the SC. We have shown that sodium cholate and ethanol were necessary to ensure an appropriate diffusion of liposomes into the dermis when applied by means of microneedles. This could be a promising approach to further deliver efficiently macromolecules such as genes into the skin.

RNA profiling of human testicular cells identifies syntenic lncRNAs associated with spermatogenesis.

STUDY QUESTION: Is the noncoding transcriptional landscape during spermatogenesis conserved between human and rodents? SUMMARY ANSWER: We identified a core group of 113 long noncoding RNAs (lncRNAs) and 20 novel genes dynamically and syntenically transcribed during spermatogenesis. WHAT IS KNOWN ALREADY: Spermatogenesis is a complex differentiation process driven by a tightly regulated and highly specific gene expression program. Recently, several studies in various species have established that a large proportion of known lncRNAs are preferentially expressed during meiosis and spermiogenesis in a testis-specific manner. STUDY DESIGN, SIZE, DURATION: To further investigate lncRNA expression in human spermatogenesis, we carried out a cross-species RNA profiling study using isolated testicular cells. PARTICIPANTS/MATERIALS, SETTING, METHODS: Human testes were obtained from post-mortem donors (N = 8, 51 years old on average) or from prostate cancer patients with no hormonal treatment (N = 9, 80 years old on average) and only patients with full spermatogenesis were used to prepare enriched populations of spermatocytes, spermatids, Leydig cells, peritubular cells and Sertoli cells. To minimize potential biases linked to inter-patient variations, RNAs from two or three donors were pooled prior to RNA-sequencing (paired-end, strand-specific). Resulting reads were mapped to the human genome, allowing for assembly and quantification of corresponding transcripts. MAIN RESULTS AND THE ROLE OF CHANCE: Our RNA-sequencing analysis of pools of isolated human testicular cells enabled us to reconstruct over 25 000 transcripts. Among them we identified thousands of lncRNAs, as well as many previously unidentified genes (novel unannotated transcripts) that share many properties of lncRNAs. Of note is that although noncoding genes showed much lower synteny than protein-coding ones, a significant fraction of syntenic lncRNAs displayed conserved expression during spermatogenesis. LARGE SCALE DATA: Raw data files (fastq) and a searchable table (.xlss) containing information on genomic features and expression data for all refined transcripts have been submitted to the NCBI Gene Expression Omnibus under accession number GSE74896. LIMITATIONS, REASONS FOR CAUTION: Isolation procedures may alter the physiological state of testicular cells, especially for somatic cells, leading to substantial changes at the transcriptome level. We therefore cross-validated our findings with three previously published transcriptomic analyses of human spermatogenesis. Despite the use of stringent filtration criteria, i.e. expression cut-off of at least three fragments per kilobase of exon model per million reads mapped, fold-change of at least three and false discovery rate adjusted P-values of less than <1%, the possibility of assembly artifacts and false-positive transcripts cannot be fully ruled out. WIDER IMPLICATIONS OF THE FINDINGS: For the first time, this study has led to the identification of a large number of conserved germline-associated lncRNAs that are potentially important for spermatogenesis and sexual reproduction. In addition to further substantiating the basis of the human testicular physiology, our study provides new candidate genes for male infertility of genetic origin. This is likely to be relevant for identifying interesting diagnostic and prognostic biomarkers and also potential novel therapeutic targets for male contraception. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by l'Institut national de la santé et de la recherche médicale (Inserm); l'Université de Rennes 1; l'Ecole des hautes études en santé publique (EHESP); INERIS-STORM to B.J. [N 10028NN]; Rennes Métropole 'Défis scientifiques émergents' to F.C (2011) and A.D.R (2013). The authors have no competing financial interests.

Spontaneous formation and relaxation of spin domains in antiferromagnetic spin-1 condensates.

Many-body systems at low temperatures generally organize themselves into ordered phases, whose nature and symmetries are captured by an order parameter. This order parameter is spatially uniform in the simplest cases, for example the macroscopic magnetization of a ferromagnetic material. Non-uniform situations also exist in nature, for instance in antiferromagnetic materials, where the magnetization alternates in space, or in the so-called stripe phases emerging for itinerant electrons in strongly correlated materials. Understanding such inhomogeneously ordered states is of central importance in many-body physics. Here we study experimentally the magnetic ordering of itinerant spin-1 bosons in inhomegeneous spin domains at nano-Kelvin temperatures. We demonstrate that spin domains form spontaneously, that is purely because of the antiferromagnetic interactions between the atoms and in the absence of external magnetic forces, after a phase separation transition. Furthermore, we explore how the equilibrium domain configuration emerges from an initial state prepared far from equilibrium.

Short-term effect of outdoor mould spore exposure on prescribed allergy medication sales in Central France.

BACKGROUND: Outdoor moulds are classically associated with exacerbations of asthma. OBJECTIVE: The aim of this paper was to examine nasal allergy morbidity by studying the short-term relationship between mould spore exposure and daily sales of reimbursable anti-allergic treatment in central France. METHODS: The relationship between daily changes in mould concentrations and daily sales obtained from the national healthcare database was analysed with generalized additive models, taking into account confounding factors such as air pollution, weather conditions, pollen counts, and days of the week. RESULTS: During the study, the average total yearly number of treated people was around 10 000 over approximately 230 000 surveyed. The relative risk (95% CI confidence interval) of sales of oral antihistamines with topical treatment associated with an interquartile increase in mould concentration was significant for Cladosporium 1.079 [1.019-1.142] and Aspergillus-Penicillium (Asp-Pen) 1.051 [1.021-1.082] in the whole population. When the influence of age and sex was considered, the relationship was significant only in male children aged 0-12 years and those aged between 13 and 49 years for Cladosporium: 1.256 [1.081-1.460] and 1.151 [1.063-1.245], respectively. The relationship was also significant for Asp-Pen: 1.038 [1.003-1.075] for those aged between 13 and 49 years and 1.056 [1.007-1.108] for adults over 50 years of age. CONCLUSION: The association between prescribed daily sales of oral antihistamines with topical treatment sales is associated with temporal changes to Cladosporium and Aspergillus-Penicillium in the whole population. When the influence of age and sex was considered, these two moulds contributed to prescribed medication sales only in the male general population.

An update on molecular cat allergens: Fel d 1 and what else? Chapter 1: Fel d 1, the major cat allergen.

BACKGROUND: Cats are the major source of indoor inhalant allergens after house dust mites. The global incidence of cat allergies is rising sharply, posing a major public health problem. Ten cat allergens have been identified. The major allergen responsible for symptoms is Fel d 1, a secretoglobin and not a lipocalin, making the cat a special case among mammals. MAIN BODY: Given its clinical predominance, it is essential to have a good knowledge of this allergenic fraction, including its basic structure, to understand the new exciting diagnostic and therapeutic applications currently in development. The recent arrival of the component-resolved diagnosis, which uses molecular allergens, represents a unique opportunity to improve our understanding of the disease. Recombinant Fel d 1 is now available for in vitro diagnosis by the anti-Fel d 1 specific IgE assay. The first part of the review will seek to describe the recent advances related to Fel d 1 in terms of positive diagnosis and assessment of disease severity. In daily practice, anti-Fel d 1 IgE tend to replace those directed against the overall extract but is this attitude justified? We will look at the most recent arguments to try to answer this question. In parallel, a second revolution is taking place thanks to molecular engineering, which has allowed the development of various forms of recombinant Fel d 1 and which seeks to modify the immunomodulatory properties of the molecule and thus the clinical history of the disease via various modalities of anti-Fel d 1-specific immunotherapy. We will endeavor to give a clear and practical overview of all these trends.

Peanut gastrointestinal delivery oral immunotherapy in adolescents: Results of the build-up phase of a randomized, double-blind, placebo-controlled trial (PITA study).

BACKGROUND: Oral immunotherapy to peanut is effective in desensitizing patients but has significant side effects including anaphylaxis and gastrointestinal symptoms. In most protocols, peanut is administered in a vehicle food. OBJECTIVE: In an exclusively adolescent population, we tested a new approach using sealed capsules of peanut (gastrointestinal delivery oral immunotherapy or GIDOIT) to bypass the upper gastrointestinal tract. The primary aim was to assess the efficacy of the oral build-up phase of GIDOIT and the secondary aim to analyse its safety. METHODS: Adolescents with a history of a clinical allergic reaction after peanut ingestion were included in a 2-armed, parallel-design, individually randomized, double-blind, placebo-controlled, multicentre trial after a positive double-blind placebo-controlled oral food challenge (DBPCFC1). A central randomization centre used computer-generated tables to allocate treatments. Peanut (or placebo) capsules were ingested daily over a period of 24 weeks with increments every 2 weeks from 2 to 400 mg of peanut protein (pp). Primary outcome was tolerance of 400 mg of pp at DBPCFC2. RESULTS: Thirty patients were included between September 2013 and May 2014. At DBPCFC2, unresponsiveness to 400 mg of pp was achieved in 17/21 peanut group patients (2 withdrawn patients) and 1/9 in the placebo group (Intention-to-treat analysis, P < .001, absolute difference = 0.7, 95%IC 0.43 0.96). Oropharyngeal symptoms were equally frequent in both groups. No dysphagia or other signs of eosinophilic oesophagitis occurred. Digestive adverse events (AE) were more frequent in the treated group (P = .02), but mild and without compliance issues. Only one severe advent event led to withdrawal in a patient who ingested twice the investigated treatment. Peanut-specific humoral immune responses were modulated. CONCLUSION: The GIDOIT protocol demonstrated clinical and immunological efficacy and had an acceptable level of safety with weak oropharyngeal symptoms, no dysphagia, mild digestive events and few severe systemic AE.

Development of an analytical method for crystalline content determination in amorphous solid dispersions produced by hot-melt extrusion using transmission Raman spectroscopy: A feasibility study.

The development of a quantitative method determining the crystalline percentage in an amorphous solid dispersion is of great interest in the pharmaceutical field. Indeed, the crystalline Active Pharmaceutical Ingredient transformation into its amorphous state is increasingly used as it enhances the solubility and bioavailability of Biopharmaceutical Classification System class II drugs. One way to produce amorphous solid dispersions is the Hot-Melt Extrusion (HME) process. This study reported the development and the comparison of the analytical performances of two techniques, based on backscattering and transmission Raman spectroscopy, determining the crystalline remaining content in amorphous solid dispersions produced by HME. Principal Component Analysis (PCA) and Partial Least Squares (PLS) regression were performed on preprocessed data and tended towards the same conclusions: for the backscattering Raman results, the use of the DuoScan™ mode improved the PCA and PLS results, due to a larger analyzed sampling volume. For the transmission Raman results, the determination of low crystalline percentages was possible and the best regression model was obtained using this technique. Indeed, the latter acquired spectra through the whole sample volume, in contrast with the previous surface analyses performed using the backscattering mode. This study consequently highlighted the importance of the analyzed sampling volume.

Global approach for the validation of an in-line Raman spectroscopic method to determine the API content in real-time during a hot-melt extrusion process.

Since the Food and Drug Administration (FDA) published a guidance based on the Process Analytical Technology (PAT) approach, real-time analyses during manufacturing processes are in real expansion. In this study, in-line Raman spectroscopic analyses were performed during a Hot-Melt Extrusion (HME) process to determine the Active Pharmaceutical Ingredient (API) content in real-time. The method was validated based on a univariate and a multivariate approach and the analytical performances of the obtained models were compared. Moreover, on one hand, in-line data were correlated with the real API concentration present in the sample quantified by a previously validated off-line confocal Raman microspectroscopic method. On the other hand, in-line data were also treated in function of the concentration based on the weighing of the components in the prepared mixture. The importance of developing quantitative methods based on the use of a reference method was thus highlighted. The method was validated according to the total error approach fixing the acceptance limits at ±15% and the α risk at ±5%. This method reaches the requirements of the European Pharmacopeia norms for the uniformity of content of single-dose preparations. The validation proves that future results will be in the acceptance limits with a previously defined probability. Finally, the in-line validated method was compared with the off-line one to demonstrate its ability to be used in routine analyses.

Oral probiotic treatment of Lactobacillus rhamnosus Lcr35® prevents visceral hypersensitivity to a colonic inflammation and an acute psychological stress.

AIMS: This study evaluated the efficacy of a repeated oral treatment with two active pharmaceutical ingredients (Lcr Lenio® and Lcr Restituo® ) derivated from the probiotic bacterial strain Lactobacillus rhamnosus Lcr35® in two animal models mimicking different features of irritable bowel syndrome (IBS). IBS is characterized by visceral pain associated with alteration of bowel transit. IBS patients present visceral hypersensitivity with peripheral and central origins. METHODS AND RESULTS: The injection of 2,4,6-trinitrobenzenesulfonic acid (TNBS) into the proximal colon as well as an acute partial restraint stress (PRS) produces colonic hypersensitivity measured in conscious rats by a decrease in pain threshold in response to distal colonic distension. Visceral hypersensitivity was produced by injection of TNBS 7 days before colonic distension or by acute PRS on testing day. Treatments were performed once a day during eight consecutive days. CONCLUSIONS: This study indicates that an 8-day probiotic treatment (Lcr Lenio and Lcr Restituo) produces an antihypersensitivity activity in both TNBS and PRS visceral pain models. As this probiotic strain attenuates peripherally and centrally induced visceral hypersensitivity in rats, it may be active in treatment of IBS symptoms. An immunomodulatory effect of the probiotics was highlighted in the TNBS model on the IL-23 secretion, suggesting a mechanism of action involving a regulation of the local IL-23/Th17 immune activation. SIGNIFICANCE AND IMPACT OF THE STUDY: Two formulas of Lcr35® probiotic strain show very encouraging results for the treatment of IBS patients. Further studies are needed to better understand the role and mechanisms of probiotics on the pathogenesis of IBS.

A simple calibration approach based on film-casting for confocal Raman microscopy to support the development of a hot-melt extrusion process.

When developing a new formulation, the development, calibration and validation steps of analytical methods based on vibrational spectroscopy are time-consuming. For each new formulation, real samples must be produced and a "reference method" must be used in order to determine the Active Pharmaceutical Ingredient (API) content of each sample. To circumvent this issue, the paper presents a simple approach based on the film-casting technique used as a calibration tool in the framework of hot-melt extrusion process. Confocal Raman microscopic method was successfully validated for the determination of itraconazole content in film-casting samples. Then, hot-melt extrusion was carried out to produce real samples in order to confront the results obtained with confocal Raman microscopy and Ultra High Performance Liquid Chromatography (UHPLC). The agreement between both methods was demonstrated using a comparison study based on the Bland and Altman's plot.

Binding Potency of Heparin Immobilized on Activated Charcoal for DNA Antibodies.

In vitro experiments showed that heparin adsorbed on activated charcoal can bind antibodies raised against native and single-stranded DNA in a diluted sera pool with a high level of these DNA. Thus, heparin used as anticoagulant during hemosorption procedure can demonstrate supplementary therapeutic activity resulting from its interaction with various agents involved in acute and chronic inflammatory reactions such as DNA- and RNA-binding substances, proinflammatory cytokines, complement components, growth factors, etc. Research and development of heparin-containing carbonic adsorbents for the therapy of numerous inflammatory and autoimmune diseases seems to be a promising avenue in hematology.

Vibrational spectroscopy and microspectroscopy analyzing qualitatively and quantitatively pharmaceutical hot melt extrudates.

Since the last decade, more and more Active Pharmaceutical Ingredient (API) candidates have poor water solubility inducing low bioavailability. These molecules belong to the Biopharmaceutical Classification System (BCS) classes II and IV. Thanks to Hot-Melt Extrusion (HME), it is possible to incorporate these candidates in pharmaceutical solid forms. Indeed, HME increases the solubility and the bioavailability of these drugs by encompassing them in a polymeric carrier and by forming solid dispersions. Moreover, in 2004, the FDA's guidance initiative promoted the usefulness of Process Analytical Technology (PAT) tools when developing a manufacturing process. Indeed, the main objective when developing a new pharmaceutical process is the product quality throughout the production chain. The trend is to follow this parameter in real-time in order to react immediately when there is a bias. Vibrational spectroscopic techniques, NIR and Raman, are useful to analyze processes in-line. Moreover, off-line Raman microspectroscopy is more and more used when developing new pharmaceutical processes or when analyzing optimized ones by combining the advantages of Raman spectroscopy and imaging. It is an interesting tool for homogeneity and spatial distribution studies. This review treats about spectroscopic techniques analyzing a HME process, as well off-line as in-line, presenting their advantages and their complementarities.