Stéphane Gibaud

Microemulsions for oral administration and their therapeutic applications

Introduction: The microemulsion concept was introduced in 1943 by Hoar and Schulman. Self-microemulsifying drug delivery systems (S(M)EDDS) are much more recent and can be described as isotropic solutions of oils and surfactants that form oil-in-water O/W microemulsions when they are poured into an aqueous medium. When they are presented as soft capsules for oral delivery, S(M)EDDS have the ability to considerably improve the intestinal absorption of agents that are incorporated into the S(M)EDDS. Forty percent of newly discovered drug candidates have little or no water solubility and therefore have low and/or variable bioavailability profiles. Many of these drugs are good candidates for formulation into S(M)EDDS. Areas covered: This paper describes the preparation and assessment of these formulations and their current applications. The characterisation of this type of formulation has improved, and in vitro models (Caco-2 cell cultures, Ussing chambers, the everted sac technique, etc.) can be used for screening different formulations. It describes also marketed formulations (i.e., cyclosporin and saquinavir S(M)EDDS) and some other formulations. Expert opinion: Actual applications of S(M)EDDS remain rare. The first drug marketed as a S(M)EDDS was cyclosporin, and it had significantly improved bioavailability compared with the conventional solution. In the last decade, several S(M)EDDS loaded with antiviral drugs (e.g., ritonavir, saquinavir) were tested for treatment of HIV infection, but the relative improvement in clinical benefit was not significant. The S(M)EDDS formulation of Norvir® (soft capsules) has been withdrawn in some countries.

Phthalimido–ferrocidiphenol cyclodextrin complexes: Characterization and anticancer activity

Several ferrocenyl analogues of tamoxifen have already showed strong antiproliferative activity in experimental glioma models. Nevertheless, these compounds are very poorly soluble in water and an adapted formulation is needed. In this work, we have tailored and optimized methylated cyclodextrin soluble complexes of phthalimido-ferrocidiphenol for the first time. The complexes were characterized, and the optimized formulation was tested for in vitro efficacy and cell proliferation assays on U87, human glioblastoma cancer cells. Molecular modeling can provide accurate information about the inclusion process. The inclusion of all the moieties at the same time (i.e., ferrocene, phthalimidylpropyl, 2 phenols) is not possible due to the steric hindrance of the 1:4 system. The 1:3 systems are possible but do not seem very relevant. However, various 1:2 and 1:1 complexes are mostly present in aqueous solutions. Some experiments have confirmed our hypothesis. First, interactions between the phenol, phthalimidylpropyl and ferrocenyl groups have been observed in our NMR experiments. Second, the inclusion of phthalimidylpropyl was detected by UV-vis spectrophotometry with an apparent 1:1 interaction, which was observed through the Benesi-Hildebrand method. The complex is readily soluble in water and keeps its pharmacological activity against U87 tumor cells (IC50=0.028 ± 0.007 μM vs. 0.018 ± 0.003 μM for PhtFerr).

Synthesis and characterization of S-nitrosoglutathione-oligosaccharide-chitosan as a nitric oxide donor

Objectives: The aim of this work is to synthesize a novel stable and biodegradable nitric oxide (NO) donor polymer based on a chitosan backbone. This polymer needed to be linked to glutathione (GSH), which was nitrosated in a second step. This polymer has been developed as an NO delivery platform that could be further evaluated for an oral delivery in Crohn’s disease. Methods: The new polymer (named S-nitrosoglutathione-oligosaccharide-chitosan or SNOC) was obtained using a two-step procedure involving the linkage of GSH to chitosan via an amidine reaction followed by a post-nitrosation with NaNO2. The GSH linkage was assessed using NMR, FTIR and an Ellman’s test, whereas the final NO amount was determined by the Griess and Saville method. Results: Polymers with different numbers of NO groups were obtained (159.04 ± 64.16 µmol/g of polymer for SNOC G1 and 525.08 ± 151.35 µmol/g of polymer for SNOC G2) depending on the procedure used for production. When tested in an Ussing chamber, SNOC G2 had a sustained release of NO and nitrites for at least 6 h. Conclusion: We believe that this type of polymer is adapted for the development of various formulations, including microparticles.

Synthesis of S-nitrosoglutathione-alginate for prolonged delivery of nitric oxide in intestines

Abstract S-nitrosothiols are a class of NO-donors currently under investigation for the treatment of various diseases. In this study, we developed a novel NO-donor (S-nitrosoglutathione-alginate, SNA) by cross-linking alginate with S-nitrosothiols, which can deliver NO in a sustained manner. This compound can be further evaluated for oral delivery to treat Crohn’s disease. This new compound was prepared using a two-step procedure involving (I) linkage of reduced glutathione to alginate and (II) post-nitrosation with sodium nitrite (NaNO2). The amount of linked thiol moieties for the possible nitrosation was calculated using Ellman’s method, and the amount of NO abducted on the polymer was calculated using the Griess–Saville method. An ex vivo model (i.e. Ussing chamber) was used to investigate the permeation of this new NO-donor across the rat intestinal barrier. We obtained polymers with different numbers of abducted NOs (174u2009±u200921u2009μmol/g for SNA F1 and 468u2009±u200923u2009μmol/g for SNA F2) depending on the procedure used for nitrosation. In the ex vivo studies in the Ussing chamber, SNA F2 exhibited a sustained release for at least 10u2009h. The effect of pH on the stability of the new compound was also investigated, and the new compound was more stable at a mildly basic pH of 8.4 where 73% remained after 1 week. However, only 50% remained after 1 week at an acidic pH of 1.2. In the cytotoxicity studies (Caco2), this compound was nontoxic at concentrations of less than 200u2009μM.

The antitumor effects of an arsthinol–cyclodextrin complex in a heterotopic mouse model of glioma

In this paper, we examined arsthinol-cyclodextrin complexes, which display an anticancer activity. The association constants were 17,502±522 M(-1) for hydroxypropyl-β-cyclodextrin and 12,038±10,168 M(-1) for randomized methylated β-cyclodextrin. (1)H NMR experiments in solution also confirmed the formation of these complexes and demonstrated an insertion of the arsthinol (STB) with its dithiarsolane extremity into the wide rim of the hydroxypropyl-β-cyclodextrin cavity. Complexed arsthinol was more effective than arsenic trioxide (As2O3) and melarsoprol on the U87 MG cell line. Importantly, in the in vivo study, we observed significant antitumor activity against heterotopic xenografts after i.p. administration and did not see any signs of toxicity. This remains to be verified using an orthotopic model.

Thiomers and their potential applications in drug delivery

ABSTRACT Introduction: Thiomers are the product of the immobilization of sulfhydryl-bearing ligands onto the polymer backbone of a conventional polymer, which results in a significant improvement in mucoadhesion; in situ gelation and efflux inhibition compare with unchanged polymers. Because of thiol groups, thiomers have more reactivity and enhanced protection against oxidation. Since the late 1990s, extensive work has been conducted on these promising polymeric excipients in the pharmaceutical field. Areas covered: This review covers thiomers, their classification and their different properties. Various techniques for the synthesis, purification and characterization of thiomers are described in detail. This review also encompasses their various properties such as mucoadhesion, permeation enhancement, in situ gelation and efflux inhibition, as well as different formulations based on thiomers. In addition to the use of thiomers as multifunctional excipients, this review also encompasses their use as drugs. Expert opinion: The synthesis is realized by linkage of sulfhydryl-bearing ligands but reported methods give low yields. Higher degrees of modification are not necessary and would probably lead to extreme changes in properties. Nevertheless, an accurate characterization of the final product is important. The scale-up procedure for industrial manufacturing has been adapted to produce GMP materials; Lacrimera® eye drops have already entered the European market.

Characterization of mitotane (o,p'-DDD)--cyclodextrin inclusion complexes: phase-solubility method and NMR.

Mitotane (o,p-dichlorodimethyl dichloroethane [o,p-DDD]) is used for the treatment of adrenocortical cancer and occasionally Cushings syndrome. This drug is very poorly soluble in water, and following oral administration, approximately 60% of the dose is recovered in the feces unaltered. The preparation of a soluble formulation (i.e. by complexation with cyclodextrins) with improved bioavailability is the aim of this work. The inclusion of mitotane in methyl-ß-cyclodextrins was studied using both phase-solubility methods and NMR experiments. To elucidate the inclusion mechanism, o,p-DDD was compared to its regioisomer (i.e. p,p-DDD). It was demonstrated that two dimethyl-ß-cyclodextrins (DMßCD) can complex with the aromatic rings. From the phase-solubility diagrams, we observe that both cases are very different: K(1:1) is between 37 000 and 85 000 mol.l(-1), whereas K(1:2) is between 5.3 and 32 mol.l(-1). The NMR experiments confirmed the inclusion but it also gave an insight into the kinetics of the dissociation: the ortho-chloro moiety is in slow exchange on the NMR time scale, whereas the para-chloro moiety is in fast exchange rate.

Effect of intravenous hydration in patients receiving bisphosphonate therapy.

Background Patients with advanced cancers are at high risk for bone metastases, which accelerate bone resorption and skeletal complications. Therefore, bisphosphonates, which are strong inhibitors of bone resorption, are widely used to prevent pathological fractures, pain and tumour-induced hypercalcaemia. Intravenous infusion of bisphosphonate is associated with dose- and infusion rate-dependent adverse renal effects. Objective The present study investigated the effect of hydration on bisphosphonate efficacy and safety. Settings The 600-bed CHOV Hospital (Neufchâteau, France) and the Université de Lorraine (Nancy, France). Methods Patients who received pamidronate or zoledronic acid treatments were identified: 50 patients [16 of whom were hydrated and 34 of whom were non-hydrated]. Data on serum calcium levels, creatinine clearance and clinical tolerance were collected. Main outcome measure The impact of hydration on these parameters was analysed between day 1 and day 7. Results Bisphosphonate normalized calcaemia and hydration did not induce further reduction of calcium levels. Patient kidneys were significantly preserved by hydration in both groups (median clearance: +6.2xa0%), whereas dehydrated patients had lower creatinine clearance (median clearance: −1.1xa0%). Hydration did not influence other clinical or biological parameters tested. Conclusion Hydration plays an important role in the treatment of hypercalcaemia by pamidronate and zoledronic acid: it enhances kidney protection (i.e., creatinine clearance).

Anticancer properties of lipid and poly(ε-caprolactone) nanocapsules loaded with ferrocenyl-tamoxifen derivatives

We synthesized new tamoxifen derivatives as anticancer drug candidates and elaborated on convection‐enhanced delivery (CED) as a strategy for delivery.

The effect of intravenous isosorbide dinitrate in acute decompensated heart failure in hospital

Background According to new recommendations for the management of acute decompensated heart failure (ADHF) in 2015, intravenous vasodilator therapy might be given as an early therapy when systolic blood pressure is normal to high (≥110xa0mmHg). Only 29% of patients with ADHF are treated with vasodilators without medical contraindication. Objective To evaluate the effect of the systematic use of ISDN on ADHF without contraindication especially on rehospitalization rate. Settings The 600-bed hospital (Centre Hospitalier de l’Ouest Vosgien, Neufchâteau, France). Methods This is a retrospective study with data analysed from medical records. Patients with ADHF episodes and hospitalization in the cardiology department or intensive care unit (ICU) between November 2013 and December 2015 were included resulting in 199 hospitalizations in the analysis (37 were treated by ISDN, and 162 were not). Main outcome measure Effects of ISDN on 180-day hospital readmission for ADHF or acute myocardial infarction (AMI), in-hospital mortality, length of stay, number of ICU admissions, and ICU length of stay. Results Patients who received ISDN required more ICU admissions than the other patients (54.1 vs 33.3%, pxa0=xa00.02). Nevertheless 180-day hospital readmission was lower for patients who were receiving ISDN (8.1 vs 22.8%, pxa0=xa00.04). ISDN did not influence other clinical outcomes tested. Conclusion ISDN may minimize or prevent the consequences of altered haemodynamics. Lower rehospitalization rate with ISDN was seen in this study.