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Dislocations and tilt grain boundaries in colloidal polycrystalline hexosomes of amphiphilic β-cyclodextrins acylated on their secondary face with C14 chains were described using the concepts of coincidence site lattice and structural units.

International audience; Rectangular V-amylose single crystals were prepared by adding racemic ibuprofen to hot dilute aqueous solutions of native and enzymatically-synthesized amylose. The lamellar thickness increased with increasing degree of polymerization of amylose and reached a plateau at about 7 nm, consistent with a chain-folding mechanism. The CP/MAS NMR spectrum as well as base-plane electron and powder X-ray diffraction patterns recorded from hydrated specimens were similar to those of V-amylose complexed with propan-2-ol. Amylose was crystallized in an orthorhombic unit cell with parameters a = 2.824 ± 0.001 nm, b = 2.966 ± 0.001 nm, and c = 0.800 ± 0.001 nm. A molecular model was proposed based on structural analogies with the Vpropan-2-ol complex and on assumptions on the stoichiometry of ibuprofen. The unit cell would contain four antiparallel 7-fold amylose single helices with ibuprofen molecules distributed inside and between the helices.

International audience; Chain-folded lamellar crystalline complexes of amylose with aliphatic diols were prepared and characterized by transmission electron microscopy as well as electron and X-ray diffraction. Four allomorphs were identified, depending on the complexing diol and crystallization conditions, that consisted of orthorhombic lattices of antiparallel 6- or 7-fold amylose single helices. Straight-chain n-diols (ethane-1,2-diol, butane-1,4-diol, hexane-1,6-diol) yielded 6-fold helical complexes regardless the length of the linear chain, whereas a bulkier branched diol (2-methylpentane-2,4-diol) induced the formation of 7-fold helices. Butane-1,3-diol, that contains a straight carbon chain with one end and one side hydroxyl group, induced both 6- and 7-fold helical conformations depending on the crystallization conditions. When a diol induced more than one allomorph, an adequate control of its concentration and crystallization temperature allowed targeting a specific crystalline form. Upon drying, all allomorphs were converted into more compact pseudo-hexagonal structures. The dried form of a given complex generally retained the same helical conformation as the hydrated one.

Ocular inflammation is one of the most common symptom of eye disorders and diseases. The therapeutic management of this inflammation must be rapid and effective in order to avoid deleterious effects for the eye and the vision. Steroidal (SAID) and non-steroidal (NSAID) anti-inflammatory drugs and immunosuppressive agents have been shown to be effective in treating inflammation of the ocular surface of the eye by topical administration. However, it is well established that the anatomical and physiological ocular barriers are limiting factors for drug penetration. In addition, such drugs are generally characterized by a very low aqueous solubility, resulting in low bioavailability as only 1% to 5% of the applied drug permeates the cornea. The present review gives an updated insight on the conventional formulations used in the treatment of ocular inflammation, i.e., ointments, eye drops, solutions, suspensions, gels, and emulsions, based on the commercial products available on the US, European, and French markets. Additionally, sophisticated formulations and innovative ocular drug delivery systems will be discussed. Promising results are presented with micro- and nanoparticulated systems, or combined strategies with polymers and colloidal systems, which offer a synergy in bioavailability and sustained release. Finally, different tools allowing the physical characterization of all these delivery systems, as well as in vitro, ex vivo, and in vivo evaluations, will be considered with regards to the safety, the tolerance, and the efficiency of the drug products.

Artemisinin and its derivatives are currently recommended by World Health Organization for the treatment of malaria. Severe malaria requires a parenteral administration of artemisinin-based formulations. However, the effective use of artemisinin is limited by the pharmacokinetic characteristics of the drug (low water solubility, poor bioavailability and short half-life). To overcome some of these drawbacks, artemisinin-loaded surface-decorated nanoparticles were prepared by co-nanoprecipitation of γ-cyclodextrin bioesterified with C10 alkyl chains and polyethylene glycol (PEG) derivatives (polysorbate 80 and DMPE-mPEG2000). Using a single dose (1.5 mg kg−1 or 2 mg kg−1) by intravenous administration, we investigated the in vivo pharmacokinetic properties in healthy rats of two types of artemisinin-loaded nanoparticle formulations, namely, nanosphere and nanoreservoir systems versus an ethanolic-aqueous solution of artemisinin as reference. Significantly enhanced pharmacokinetic parameters were obtained with artemisinin-loaded nanoparticles. In comparison to reference formulation, the geometric mean exposures in plasma (AUC0-t) exhibited 2.35 and 3.26-fold increases when artemisinin was loaded in nanoreservoir and nanosphere systems, respectively. Its plasma half-life increased 4.00 and 6.25-fold and its clearance decreased up to 2.5 and 4.72-fold. Artemisinin was successfully administered intravenously by means of surface-decorated amphiphilic γ-cyclodextrin nanostructures and showed a longer elimination half-life with respect to an artemisinin solution in ethanol. Therefore, these systems are likely to provide significant advantages for the intravenous treatment of severe malaria.

A biocompatible hydrogel with a double-membrane structure is developed from cationic cellulose nanocrystals (CNC) and anionic alginate. The architecture of the double-membrane hydrogel involves an external membrane composed of neat alginate, and an internal composite hydrogel consolidates by electrostatic interactions between cationic CNC and anionic alginate. The thickness of the outer layer can be regulated by the adsorption duration of neat alginate, and the shape of the inner layer can directly determine the morphology and dimensions of the double-membrane hydrogel (microsphere, capsule, and filmlike shapes). Two drugs are introduced into the different membranes of the hydrogel, which will ensure the complexing drugs codelivery and the varied drugs release behaviors from two membranes (rapid drug release of the outer hydrogel, and prolonged drug release of the inner hydrogel). The double-membrane hydrogel containing the chemically modified cellulose nanocrystals (CCNC) in the inner membrane hydrogel can provide the sustained drug release ascribed to the "nano-obstruction effect" and "nanolocking effect" induced by the presence of CCNC components in the hydrogels. Derived from natural polysaccharides (cellulose and alginate), the novel double-membrane structure hydrogel material developed in this study is biocompatible and can realize the complexing drugs release with the first quick release of one drug and the successively slow release of another drug, which is expected to achieve the synergistic release effects or potentially provide the solution to drug resistance in biomedical application.

International audience; Soft mesoporous hierarchically structured particles were created by the self-assembly of an amphiphilic deep cavitand cyclodextrin βCD-nC10 (degree of substitution n = 7.3), with a nanocavity grafted by multiple alkyl (C10) chains on the secondary face of the βCD macrocycle through enzymatic biotransesterification, and the nonlamellar lipid monoolein (MO). The effect of the non-ionic dispersing agent polysorbate 80 (P80) on the liquid crystalline organization of the nanocarriers and their stability was studied in the context of vesicle-to-cubosome transition. The coexistence of small vesicular and nanosponge membrane objects with bigger nanoparticles with inner multicompartment cubic lattice structures was established as a typical feature of the employed dispersion process. The cryogenic transmission electron microscopy (cryo-TEM) images and small-angle X-ray scattering (SAXS) structural analyses revealed the dependence of the internal organization of the self-assembled nanoparticles on the presence of embedded βCD-nC10 deep cavitands in the lipid bilayers. The obtained results indicated that the incorporated amphiphilic βCD-nC10 building blocks stabilize the cubic lattice packing in the lipid membrane particles, which displayed structural features beyond the traditional CD nanosponges. UV-Vis spectroscopy was employed to characterize the nanoencapsulation of a model hydrophobic dimethylphenylazo-naphthol guest compound (Oil red) in the created nanocarriers. In perspective, these dual porosity carriers should be suitable for co-encapsulation and sustained delivery of peptide, protein or siRNA biopharmaceuticals together with small molecular weight drug compounds or imaging agents. © 2016 The Royal Society of Chemistry.

We previously developed two optimized formulations of dexamethasone acetate (DXMa) hydrogels by means of special cubic mixture designs for topical ocular administration. These gels were elaborated with hydroxypropyl-&beta, CD (HP&beta, CD) and hydroxypropyl-&gamma, CD (HP&gamma, CD) and commercial hydrogels in order to enhance DXMa water solubility and finally DXMa&rsquo, s ocular bioavailability and transcorneal penetration. The main objective of this study was to characterize them and to evaluate in vitro, ex vivo, and in vivo their safety, biopermanence, and transcorneal permeation. Gels A and B are Newtonian fluids and display a viscosity of 13.2 mPa.s and 18.6 mPa.s, respectively, which increases their ocular retention, according to the in vivo biopermanence study by PET/CT. These hydrogels could act as corneal absorption promoters as they allow a higher transcorneal permeation of DXMa through porcine excised cornea, compared to DEXAFREE&reg, and MAXIDEX&reg, Cytotoxicity assays showed no cytotoxic effects on human primary corneal epithelial cells (HCE). Furthermore, Gel B is clearly safe for the eye, but the effect of Gel A on the human eye cannot be predicted. Both gels were also stable 12 months at 25 &deg, C after sterilization by filtration. These results demonstrate that the developed formulations present a high potential for the topical ocular administration of dexamethasone acetate.

Dexamethasone acetate (DXMa) has proven its efficiency to treat corneal inflammation, without a great propensity to increase intraocular pressure. Unfortunately, its poor aqueous solubility, associated with a rapid precorneal elimination, results in a low drug bioavailability and a low penetration after topical ocular administration. The main objective of this study was to improve the apparent aqueous solubility of DXMa using cyclodextrins. First, hydroxypropyl-&beta, CD (HP&beta, CD) and hydroxypropyl-&gamma, CD (HP&gamma, CD) were used to enhance DXMa concentration in aqueous solution. The &beta, and &gamma, HPCD derivatives allowed the increase of the DXMa amount in solution at 25 &deg, C by a factor of 500 and 1500, respectively. Second, with the aim of improving the persistence of the complex solution after instillation in the eye, the formulations of DXMa-based CD solutions with marketed ophthalmic gels (CELLUVISC&reg, GEL-LARMES&reg, and VISMED&reg, ) were investigated and optimized by means of special cubic mixture designs, allowing the defining of mixed gels loaded with 0.7% (HP&beta, CD) and 2% (HP&gamma, CD) DXMa with osmolality within acceptable physiological range. Finally, in vitro drug release assays from the mixed gels were performed and compared with reference eye drops. Similarly to MAXIDEX&reg, and DEXAFREE&reg, in the case of mixed gel containing HP&beta, CD, more than 90% of the drug was released within 2 h, while in mixed gel containing HP&gamma, CD, the release of DXMa was partial, reaching &asymp, 60% in 2 h. This difference will have to be further addressed with ex vivo and in vivo ocular delivery experiments.

International audience; The crystallization of amylose from dilute solutions in the presence of a series of linear saturated fatty acids (C3 to C20) was investigated by varying the fatty acid concentration, crystallization temperature and solvent composition (DMSO:water in various ratios). The morphology and structure of the resulting model lamellar crystals were characterized by transmission electron microscopy as well as electron and X-ray diffraction. By adequately controlling the crystallization parameters, all fatty acids could induce the formation of both 6- and 7-fold V-amylose single helices, indicating that the amylose conformation was independent of the chain length of the complexing molecule. Three allomorphs (V6I, V6II and V7) were identified individually or in mixtures. Higher concentrations of fatty acid and DMSO and a higher temperature promoted the formation of the more compact V6I structure. V6II and V7 preferentially formed with lower concentrations of fatty acids and DMSO and at lower temperatures. In the case of C5–C20 fatty acids, V7 was only obtained in the presence of DMSO. The polymorphism of V-amylose complexes with linear saturated fatty acids thus appears to be a more general phenomenon than previously reported in the literature.

Background The modification of β-cyclodextrins (βCDs) by grafting alkyl chains on the primary and/or secondary face yields derivatives (βCD-C10) able to self-organize under nanoprecipitating conditions into nanoparticles (βCD-C10-NP) potentially useful for drug delivery. The co-nanoprecipitation of βCD-C10 with polyethylene glycol (PEG) chains yields PEGylated NPs (βCD-C10-PEG-NP) with potentially improved stealthiness. The objectives of the present study were to characterize the in vivo biodistribution of βCD-C10-PEG-NP with PEG chain length of 2000 and 5000 Da using nuclear imaging, and to preliminarily evaluate the in vivo acute and extended acute toxicity of the most suitable system. Research design and methods The in vivo and ex vivo biodistribution features of naked and decorated nanoparticles were investigated over time following intravenous injection of 125I-radiolabeled nanoparticles to mice. The potential toxicity of PEGylated βCD-C10 nanosuspensions was evaluated in a preliminary in vivo toxicity study involving blood assays and tissue histology following repeated intraperitoneal injections of nanoparticles to healthy mice. Results The results indicated that βCD-C10-PEG5000-NP presented increased stealthiness with decreased in vivo elimination and increased blood kinetics without inducing blood, kidney, spleen, and liver acute and extended acute toxicity. Conclusions βCD-C10-PEG5000-NPs are stealth and safe systems with potential for drug delivery.

This work aimed at preparing new nanoscale assemblies based on an amphiphilic bio-esterified β-cyclodextrin (β-CD), substituted at the secondary face with n-decanoic fatty acid chains (β-CD-C10), and monoolein (MO) as new carriers for parenteral drug delivery. Stable binary (β-CD-C10/MO) and ternary (β-CD-C10/MO/stabilizer) nanoscale assemblies close to 100nm in size were successfully prepared in water by the solvent displacement method. The generated nanoparticles were fully characterized by dynamic light scattering, transmission electron microscopy, small-angle X-ray scattering, residual solvent analysis, complement activation and the contribution of each formulation parameter was determined by principal component analysis. The β-CD-C10 units were shown to self-organize into nanoparticles with a hexagonal supramolecular packing that was significantly modulated by the molar ratio of the constituents and the presence of a steric or electrostatic stabilizer (DOPE-PEG2000 or DOPA/POPA, respectively). Indeed, nanoparticles differing in morphology and in hexagonal lattice parameters were obtained while the co-existence of multiple mesophases was observed in some formulations, in particular for the β-CD-C10/MO/DOPA and β-CD-C10/MO/POPA systems. The mixed β-CD-C10/MO/DOPE-PEG2000 nanoparticles (49:49:2 in mol%) appeared to be the most suitable for use as a drug delivery system since they contained a very low amount of residual solvent and showed a low level of complement C3 activation.

Selective chemical functionalization of cyclodextrins (CDs) is a readily amenable methodology to produce amphiphilic macromolecules endowed with modulable self-organizing capabilities. Herein, the synthesis of well-defined amphiphilic CD derivatives, with a "skirt-type" architecture, that incorporate long-chain fatty esters at the secondary hydroxyl rim and a variety of chemical functionalities (e. g. iodo, bromo, azido, cysteaminyl or isothiocyanato) at the primary hydroxyls rim is reported. Nanoprecipitation of the new CD facial amphiphiles, or binary mixtures of them, resulted in nanoparticles with average hydrodynamic diameters ranging from 100 to 240 nm that were stable in suspension for several months. The precise size, zeta potential and topology of the nanoparticles are intimately dependent on the functionalization pattern at the CD scaffold. Highly efficient molecular encapsulation capabilities of poorly bioavailable drugs such as diazepam (DZ) were demonstrated for certain derivatives, the drug release profile being dependent on the type of formulation (nanospheres or nanocapsules). The efficiency and versatility of the synthetic strategy, together with the possibility of exploiting the reactivity of the functional groups at the nanoparticle surface, offer excellent opportunities to further manipulate the carrier capabilities of this series of amphiphilic CDs from a bottom-up approach.

L’arsenal therapeutique conventionnel de l’amibiase comprend essentiellement des molecules imidazolees presentant beaucoup d’effets secondaires pourtant la medecine traditionnelle africaine dispose de nombreuses recettes efficaces dans la prise en charge de ce fleau. L’objectif de cette etude etait de realiser un medicament traditionnel ameliore a visee antiamibienne a base de Euphorbia hirta Linn. La plante a ete recoltee a Bangangte (Ouest-Cameroun) puis identifiee a l’Herbier National du Cameroun. Avant utilisation, elle a ete nettoyee a l’eau potable, sechee a l’ombre pendant 3 jours, puis a l’etuve a 50 °C pendant 48 heures. Les differentes formes galeniques antiamibiennes a base de Euphorbia hirta Linn ont ete repertoriees, ce qui a mis en evidence l’interet d’une forme gelule. Le screening chimique de la plante a revele la presence de flavonoides, de tannins, de sterols, de mucilages et l’absence de certains groupes tels que les alcaloides, les triterpenes, les anthocyanes et les leucoanthocyanes. Un dosage des flavonoides totaux a ete realise par spectrophotometrie a 420 nm en presence du trichlorure d’aluminium. La dose journaliere a ete exprimee en masse de flavonoides en equivalent quercetine. Des lots de gelules ont ete realises d’apres les bonnes pratiques de fabrication officinale. La dose journaliere determinee etait de 1g de plante sechee et contenait 3,44 mg equivalents quercetine. Les gelules dosees a 0,86 mg de flavonoides totaux en equivalents quercetine ont ete soumises aux controles pharmaco techniques reglementaires. Les gelules obtenues ayant passe favorablement les tests chimiques et pharmacotechniques etaient aptes a etre soumises a des etudes approfondies en vue d’une AMM qui leur donnerait une position d’alternative aux imidazoles dans la prise en charge de l’amibiase intestinale. Mots cle : Euphorbia hirta , antiamibien, medicament traditionnel ameliore.

Introduction : the present study conducted in Cameroon from June 2013 to February 2014 aimed to estimating the level of pharmacovigilance knowledge and practice of health professionals in Cameroon. Methods : we conducted a descriptive cross-sectional survey on 149 health professionals in Cameroon from June to September 2013. Data were analyzed using software IBM SPSS 20.0. We calculated proportions and odd ratio, and confident interval of their values, keeping a threshold of p of 0.05 to determine the level of significance. Results : ninety percent (90%) of declaration of side effects were made to the medical representatives and 4% to the National Pharmacovigilance Centre. Fifty four percent (54%) of physicians were not aware of the existence of a National Pharmacovigilance system. Ten (10%) of prescribers had never heard of pharmacovigilance, however respondents answered unanimously that they need training on pharmacovigilance. A wrong definition was given by most of the nurses and dentists (61,1% and 58,3% respectively) as compared to physicians and pharmacists (respectively 15.2% and 26,5%). Given the results of this study, the establishment of a National Pharmacovigilance system based on a solid legal foundation is necessary in Cameroon. This implementation must go through the involvement of all stakeholders and their awareness raising on the importance of this activity and its positive impact on the health of populations. Conclusion : pharmacovigilance is a public health problem in Cameroon, with due to lack of good knowledge and practice of prescribers, precisely physicians, pharmacists, nurses, and dentists who are not always aware of an existing pharmacovigilance system in Cameroon.

The interaction of γ-cyclodextrin with a series of six polycyclic aromatic hydrocarbons (PAHs) (naphthalene, fluorene, anthracene, phenanthrene, fluoranthene, and pyrene) was studied by high performance liquid chromatography (HPLC), using a cyano bond silica column. In order to assess the retention mechanism, two models were tested. In the first one, the interaction of the CD-PAH complex with the column was neglected, while in the second one the adsorption of this complex was taken into account. For all the PAHs, the stoichiometry of the inclusion complexes between each molecule and the γ-cyclodextrin was found to be 1 : 1 and the formation constants were calculated from the retention data. As well, the thermodynamic parameter variations were obtained using the van't Hoff plots. The enthalpy–entropy compensation was analysed in order to provide further information about the interaction mechanism between the PAHs and the macrocycle.

In a previous study, we reported on the formulation of Artemisinin-loaded surface-decorated nanoparticles (nanospheres and nanoreservoirs) by co-nanoprecipitation of PEG derivatives (PEG1500 and PEG4000-stearate, polysorbate 80) and biosynthesized γ-CD fatty esters. In the present study, the co-nanoprecipitation was extended to the use of a PEGylated phospholipid, namely DMPE-PEG2000. As our goal was to prepare long-circulating nanocarriers for further systemic delivery of Artemisinin (ART), here, we have investigated, on the one hand, the in vitro behavior of these surface-modified γ-CD-C10 particles toward the immune system (complement activation and macrophage uptake assays) and, on the other hand, their biodistribution features in mice. These experiments showed that the in vitro plasma protein adsorption and phagocytosis by macrophage cells triggered by γ-CD-C10 nanoparticles were significantly reduced when their surface was decorated with amphiphilic PEGylated molecules, in particular PEG1500-stearate, DMPE-mPEG2000 or polysorbate 80. The prolonged blood circulation time assessed by fluorescence imaging was demonstrated for unloaded γ-CD-C10-based nanospheres and nanoreservoir particles containing DMPE-PEG2000 and polysorbate80, respectively. These nanoparticles also proved to be non-hemolytic at the concentration range used in vivo. Within the limits of the conducted experiments, the co-nanoprecipitation technique may be considered as an alternative for surface modification of amphiphilic CD-based drug delivery systems and may be applied to the systemic delivery of ART.

With the aim of exploring relationships between the chemical structure and the physico-chemical properties of amphiphilic beta-cyclodextrin, a reappraisal of the obtaining of pure heptakis (2,3-di-O-hexanoyl)-beta-cyclodextrin (beta-CDC(6)) was undertaken. In this paper the chemical characterization of the newly synthesized beta-CDC(6) and its ability to form mixed structures with dimyristoylphosphatidylcholine (DMPC) are reported. Miscibility of the two amphiphiles is examined: (i) in monolayers formed at the air-water interface by analyzing the surface pressure-area isotherms; and (ii) in fully hydrated mixtures by differential scanning calorimetry (DSC) and X-ray diffraction at small and wide angles. Results demonstrate that the beta-cyclodextrin derivative is partially miscible to the phospholipid: intimate mixing occurs at beta-CDC(6) molar ratios smaller than 7-15 mol%, depending on the dimensional scale considered, while beyond these compositions phase separation is observed. At the air-water interface, the miscibility region of the two compounds shows non-ideal behavior characterized by the non-additivity of the molecular areas in the mixed monolayers. At the three-dimension level, the formation of a beta-CDC(6)/DMPC mixed lamellar phase occurs except at beta-CDC(6) molar ratios close to 5 mol% at which a highly ordered structure is depicted below the solid-to-liquid state transition of the DMPC hydrocarbon chains. At beta-CDC(6) contents higher than 7 mol%, the mixed assemblies coexist with excess amphiphilic cyclodextrin which then forms a separated hexagonal structure.

This paper describes two new possibilities of using cyclodextrins to increase water solubility and bioavailability of poorly water-soluble drugs intended for targeting delivery by the oral or the parenteral route. They use either amphiphilic cyclodextrin nanoparticles or polymeric nanoparticles containing cyclodextrins. Amphiphilic skirt-shaped cyclodextrins, resulting from the esterification of primary hydroxyl groups by hydrocarbon chains varying from C6 to C14, are capable of forming spontaneously nanoparticles which have been loaded with a series of steroid drugs. The drug in the amphiphilic cyclodextrin nanoparticles is molecularly dispersed and can be released very rapidly. Poly(isobutylcyanoacrylate) nanoparticles can be loaded with natural or hydroxypropyl cyclodextrins. This technique results in a significant increase in the loading capacity of nanoparticles with a series of steroids and in a very rapid release of the drug. Both methods are described as well as their potential interest for water-insoluble drugs.

In this study we verified the feasibility of preparing nanospheres from an amphiphilic 2,3-di- O -hexanoyl- γ -cyclodextrin ( γ CDC 6 ) using the emulsification solvent evaporation method. This preparation method consists in emulsifying an organic phase containing the cyclodextrin in an aqueous phase containing Pluronic F68 as surfactant. The influence of the process parameters, i.e. surfactant concentration and initial γ CDC 6 content, on the characteristics of nanosphere preparation, as well as on the nanosphere loading of a hydrophobic drug, progesterone, was evaluated. Cyclodextrin nanospheres presenting a mean diameter varying from 50 to 200 nm were obtained, even in the presence of low surfactant concentration. The formation of colloidal particles in these conditions was associated with the amphiphilic properties of the cyclodextrin derivative. However the partitioning of the γ CDC 6 molecule between the organic and aqueous phases was observed as being a function of surfactant concentration in the continuous phase. This partitioning was related to the formation of very small aggregates of the order 10 to 20 nm, probably Pluronic F68/ γ CDC 6 mixed micelles as evidenced by the micrographs obtained by TEM. In the case of the nanospheres loaded with progesterone, the partitioning of the drug between the dispersed phase containing the cyclodextrin and the continuous aqueous phase containing Pluronic F68/ γ CDC 6 aggregates was also demonstrated. The drug content found in the final nanospheres ranged from 4 to 5% (w/w) of the carrier. Finally, dilution experiments were carried out to evaluate the stability of the drug particle association.

Cyclodextrin nanospheres are a new type of colloidal carrier system that has been intensively studied in the area of pharmacotechnical aspects of drug association. However, the physical stability of this carrier has rarely been investigated, mainly towards the presence of another amphiphilic molecule in its environment. In this work, the first results relating to the action of solubilizing surfactants on nanospheres prepared from the amphiphilic 2,3-di-O-hexanoyl cyclomaltooctaose [γCDC6, average molar degree of substitution (MDS)=6.25] are described using n-octyl-β-d-glucopyranoside (OG) as the model. Solubilization experiments were performed by continuous addition of OG into nanosphere suspensions and it was demonstrated that, at a given critical ratio, this non-ionic detergent disrupts the spherical structure of the initial particles. The evidence of the γCDC6–OG mixed micelle formation was provided by changes in the turbidity of suspensions with OG addition and by TEM micrographs. Reconstitution of the particles was performed by two detergent removal procedures: water dilution of micellar solutions and detergent dialysis. In both cases, the formation of new aggregates was demonstrated by changes in the turbitity of the initial mixed micelles. TEM micrographs revealed reconstituted nanoparticles. The QELS size and shape of the particles was dependent on the rate of detergent removal, but not on the initial γCDC6 and OG concentrations: fast OG elimination led to the most regular spherical shapes. Finally, the entrapment upon detergent removal of the hydrophobic drug progesterone previously dissolved in the mixed micelles was investigated. In conclusion, all the results demonstrated that detergents can interact with nanospheres in a reversible process. These results will be very useful in stability studies, and also in the pharmacotechnical development of nanospheres constituted by amphiphilic cyclodextrins.

Amphiphilic cyclodextrins bearing fatty acyl chains covalently linked to their secondary hydroxyl groups are able to form nanospheres with an internal organization. The structure of several cyclodextrins with different acyl chain lengths (CD-Cn) was investigated using X-ray scattering and freeze fracture electron microscopy. From the experimental data and using physicochemical arguments, we propose structure models. βCD-C6, βCD-C8, βCD-C10, βCD-C12, and γCD-C14 form polar columns, surrounded by the paraffin chains, and associated in a 2-D hexagonal lattice. The structure of αCD-C14 and βCD-C14 is body-centered cubic; it comprises one lattice of dimers aligned along the edges of the cubic cell and a second identical lattice with a translation of the half in the three directions. This results in the formation of two globules, one at the apex and one at the center of the cell. The structures are unusual for cyclodextrin molecules; they result from the presence of the numerous paraffin chains linked to each molecule. Indeed, the structures are reminiscent of those found in lipid systems.

The influence of the water structure promoters, mannitol and sucrose, on the indomethacin/β-cyclodextrin inclusion process at different pH values was evaluated using the phase solubility method and circular dichroism spectroscopy. The effect of mannitol and sucrose on the total solubilizing activity of β-cyclodextrin as well as on the stabilization of the complex was moderate, and depended strongly on the pH value of the medium. The most pronounced effect on the association constant of the indomethacin inclusion compound was observed in KCl/HCl buffer of pH 1.6, because mannitol and sucrose, in the absence of β-cyclodextrin, approximately double the indomethacin solubility so that the constant value decreases. On the other hand, a very strong complex formation between indomethacin and β-cyclodextrin was observed in acid medium (KCl/HCl buffer, pH = 1.6), a fact not much discussed in the literature. The apparent association constant of the inclusion compound formed in the absence of mannitol or sucrose was found to be of the same order of magnitude as for the complex formed at pH 6.8. Changes in the optical activity of the indomethacin/β-cyclodextrin inclusion complex were registered in the presence of sucrose, which interacts more strongly than mannitol with water molecules, and could probably adhere to the surface of the inclusion complex, thus changing its configuration and environment.

The aim of this work was to evaluate the loading capacity and the association characteristics of the hydrophobic drug progesterone on amphiphilic cyclodextrin nanospheres prepared by the nanoprecipitation method. The colloidal suspensions were prepared in the presence or absence of two different surfactants, Pluronic F68 and Tween 80. The physicochemical characteristics of the nanospheres were assessed using a nanosizer, zetameter, and transmission electron microscope. The physical state of the drug was verified using differential scanning calorimetry (DSC) and x-ray diffraction (XRD) methods. The in vitro progesterone release was investigated at 37 degrees C after dilution of the suspensions in sink conditions. Nanospheres with a mean diameter from 100 to 300 nm and a low degree of polydispersity were prepared from amphiphilic hexanoyl-gamma-cyclodextrin. The progesterone loading capacity was not affected by the formulation parameters tested. The DSC and XRD studies demonstrated the absence of the crystalline domains of progesterone in loaded nanospheres. The DSC studies also demonstrated the presence of interactions between the drug and carrier. The release of the drug from the carrier was extremely rapid and was governed by a partition phenomenon that depends only on the solubility of the drug in the release medium. From these results, we concluded that with this method, the progesterone is molecularly associated at the surface of the cyclodextrin nanospheres, probably through hydrophobic interactions in specific sites. The release profiles obtained can be of value when an improvement in the bioavailability of the drug is desired.

Different ethylated beta-cyclodextrin (Et-beta-CD) derivatives were obtained by various synthetic routes and their chemical structures and physical properties were elucidated. The aqueous solubility studies were carried out at 25 and 37 degrees C. A gas phase chromatography analysis, with head space extraction, was developed to detect the presence of residual solvents in the dry preparations. Electrospray ionization mass spectrometry allowed the determination of the average degree of substitution and the molecular mass of the Et-beta-CDs. Nuclear magnetic resonance analysis was used to elucidate the relationship between the solubility behavior and substituted positions of ethyl groups on the CD glucopyranose units. Finally, this paper deals with different physico-chemical methods used to fully characterize the different batches of Et-beta-CD to correlate the data obtained with the pharmacotechnical behavior of these cyclodextrins.

Nowadays, colloidal drug carriers represent an alternative to solve drug bioavailabily problems. During the past two decades, colloidal drug carriers have proved to improve the therapeutic index of drugs and thus increase their efficacy and/or reduce their toxicity. However, the major challenge in the development of these drug carriers remains the search for materials able to self-organize into stable nanoscale systems. In particular, amphiphilic α-, β - and γ -cyclodextrins (CDs), grafted on their secondary or primary side with different aliphatic chains, have been investigated as drug delivery vehicles due to their ability to self-assemble and form various stable colloidal systems such as micellar aggregates, nanoreservoirs or nanoparticles exhibiting a matricial, multilamellar or hexagonal supramolecular organization. These self-assembled CD-based nanodevices show some advantages in terms of stability, good ability to associate lipophilic drugs and good in vivo tolerance. This review focuses on the potential of the structured nanoparticles obtained from nonionic amphiphilic CDs in drug delivery and targeting. We discuss the synthesis and characterization of the building blocks as well as the preparation and characterization of colloidal particles made from these materials. We also considered some pharmaceutical applications and identified opportunities for an optimum use of this CD-based nanotechnology approach in addressing worldwide priority health problems.

A new colloidal carrier system, nanocapsules, using 2,3-diacyl- O - β -cyclodextrins is described. The nanocapsules were prepared by adding a mixture of an organic solution of 2,3-diacyl- O - β -cyclodextrins (with or without a lipophilic surfactant) and an oily phase to an aqueous solution (with or without a hydrophilic surfactant) whilst stirring. Nanocapsules with a mean size of 200 nm are formed progressively. Direct microscopic observation of the particles was carried out using transmission electron microscopy (TEM) combined with the freeze-fracture method. The influence of different constituents on the preparation process was studied: type of 2,3-diacyl- O - β -cyclodextrins (β-CD-C 6 , β-CD-C 12 and β-CD-C 14 ), nature of the oily phase (benzyl benzoate, Miglyol 812®), and the surfactants used (Pluronic PEF68®, Span 85®). An investigation of lipophilic drug encapsulation was also carried out. The results of this study suggest that nanocapsules of 2,3-diacyl- O - β -cyclodextrins could be considered as a potential colloidal drug carrier system.

Solid complexes of salbutamol with β-cyclodextrin (β-CD) and different batches of ethylated β-cyctodextrin (Et-β-CD) in a 1 : 1 molar ratio were prepared by the freeze-drying method. Inclusion complexation of salbutamol with all the CD used was confirmed in the solid state by differential scanning calorimetry (DSC), and in aqueous solution by circular dichroism analysis and electrospray mass spectrometry (ES-MS). The dissolution rate of salbutamol from the inclusion complexes was determined in water. We discuss the behaviour of the dissolution profiles obtained, since the Et-β-CD complexes displayed a slower release of salbutamol compared with the β-CD complex.

A new nanosphere carrier system was obtained from amphiphilic β-cyclodextrins bearing fatty acids (with a chain length of either 6 or 12 or 14 carbon atoms) grafted at the O2 and O3 position of the β-cyclodextrin molecule. Nanospheres, with a mean diameter of several hundred nm, were prepared by progressive dispersion. The nanospheres were characterized by their density, surface charge, size and morphology, using several techniques, namely centrifugation, zeta potential determination, quasi-elastic light scattering and freeze-fracture electron microscopy.

A new nanosphere carrier system has been obtained from amphiphilic β-cyclodextrin (fatty acid chains varying from 2 to 14 carbons grafted at the O 2 and O 3 positions of β-cyclodextrin). The nanospheres, with a mean diameter varying between 90 and 150 nm, are prepared by progressive dispersion of an organic solution of modified β-cyclodextrin in an aqueous phase with or without surfactant. Various physicochemical parameters have been studied: the effect of the chain length of acyl groups (βCD with 6, 12 and 14 fatty acid carbons), and type of surfactant on the size and physicochemical properties and stability of the nanospheres. A preliminary investigation of water-soluble and insoluble drug entrapment by nanospheres was carried out.

With a view to investigating the role of encapsulation of indomethacin within modified β-cyclodextrin (βCD-C6) nanocapsules, we prepared nanocapsules with indomethacin as a model drug. These particles had an average size of 194 nm and encapsulated approximately 99% of indomethacin. The encapsulation of indomethacin within orally administered βCD-C6 nanocapsules protected against both gastric and intestinal ulceration is compared with an oral administration of an aqueous solution of Indocid®. The relative bioavailability was also increased by this encapsulation.

The morphological and topographical properties of nanospheres are of major importance for characterizing these systems. The quality, and consequently the applications, of such dispersions are determined by the mean particle size, their distribution by size and the topography of the nanospheres. This work is devoted to the application of contemporary analytical techniques: photon scanning tunnelling microscopy (PSTM), scanning force microscopy (SFM) and no-contact scanning force microscopy (NC-SFM) to image nanospheres prepared from chemically modified β-cyclodextrins (βCD-C 6 ) without any sample preparation which could introduce artefacts. We have shown that the spherical geometry and high degree of monodispersity of nanospheres from βCD-C 6 were confirmed by PSTM, but that NC-SFM was an excellent technique for the imaging of nanospheres prepared from βCD-C 6.

Kalanchoe crenata est une plante de la famille des Crassulaceae tres utilisee en medecine traditionnelle africaine. Dans la region Ouest du Cameroun, Kalanchoe crenata est tres utilisee avec satisfaction dans le traitement des otites et comme cicatrisant du nombril des nouveaux nes. Compte tenu des difficultes d’approvisionnement de la plante en saison seche et dans les zones arides, ce travail s’est donne pour objectif de mettre au point un medicament traditionnel ameliore afin de rationaliser l’utilisation de Kalanchoe crenata sous une forme galenique a biodisponibilite amelioree et disponible en toute saison. La plante, qui pousse facilement autour des habitations (plante sauvage) a ete recoltee a Bangangte durant les mois d’aout et septembre 2012 puis identifiee a l’Herbier National du Cameroun. Les feuilles ont ensuite ete nettoyees, lavees, ramollies a la flamme et broyees. Le jus brut obtenu a ete filtre sur papier Whatman n° 3 puis lyophilise, donnant une poudre a reconstituer dans de l’eau purifiee au moment de l’utilisation.Le dosage des polyphenols totaux par spectrophotometrie, methode de Folin-Ciocalteu a revele que le lyophilisat titrait 6,33 μg equivalent acide gallique (EAG) par mg.La concentration minimale inhibitrice (CMI) a ete determinee pour quelques germes habituellement mis en cause dans les otites : 50 μg EAG par ml pour Citrobacter fruendi, 100 μg EAG par ml pour Staphylococcus aureus, 200 μg EAG par ml pour Klessiella pneumoniae, Proteus mirabilis et Escherichia coli. Pour Pseudomonas aeruginosa la CMI de la poudre etait de 400 μg EAG par ml.La poudre a donc ete conditionnee pour qu’apres reconstitution, la solution puisse titrer 400 μg EAG par ml en reference a la CMI de Pseudomonas aeruginosa.La solution reconstituee s’est revelee chimiquement stable et active sur les germes plus de 20 jours apres reconstitution.La poudre soumise a une temperature de 40 °C et a la lumiere pendant un mois, s’est revelee stable.

Inclusion complexes of indomethacin in β-cyclodextrin and hydroxypropyl-β-cyclodextrin were prepared and evaluated in vivo. With respect to the gastrointestinal tolerance assessed in the rat, it appears that the inclusion of indomethacin in these cyclodextrins results in a decrease in its irritation power, confirming that this undesirable effect has at least a local origin. With respect to the dermal anti-inflammatory activity assessed on healthy volunteers by the methyl nicotinate test, the results seem to demonstrate that inclusions in either of the cyclodextrins investigated have a higher activity than free indomethacin.

The haemolytic effect toward human erythrocytes and the cytotoxicity toward P388 cells of the three natural cyclodextrins and their hydroxypropylated derivatives have been compared. The cytotoxicity of the six cyclodextrins toward these two cell types follows a similar pattern, and the curve parameters are generally of the same order of magnitude for both cell types in spite of the biological differences. The in vitro cytotoxic effect decreases in the order βCD > αCD > γCD and HPβCD > HPγCD > = HPαCD. These results showed that phenomena involved in cyclodextrin cytotoxicity are not specific to the cell type, and bore out the hypothesis of destruction of membranes by the removal of basic membrane components. Moreover, they demonstrated the influence of parameters other than CD concentration, i.e., the presence of serum components, or the density of the cells, which can dramatically influence the cytotoxic effect of CDs. In fact, the cytotoxicity of a cyclodextrin is determined by the relative proportion of cellular and extracellular molecules likely to be included and cyclodextrins.

We recently reported a one-step transesterification of cyclodextrins (CDs) by vinyl-acyl fatty esters catalyzed by thermolysin. By using the solvent displacement method and depending on the experimental conditions, the CD derivatives grafted with decanoic alkyl chains (CD-C 10 ) yielded either nanosphere or nanoreservoir-type systems with a size ranging from 70 to 220 nm. Both types of nanostructures were able to associate artemisinin (ART), a well-known antimalarial lipophilic drug. The formulation parameters were optimized to reach stable and high ART dosage corresponding to drug levels of 0.3 and 1.6 mg mL −1 in the colloidal suspension, for the spherical and reservoir-type nanosystems, respectively. PEG surface-decorated nanoparticles were also prepared by co-nanoprecipitation of PEG fatty acid esters and CD-C 10 molecules. The integration of the PEGylated amphiphiles within the CD-C 10 nanostructures did not influence the ART lyoavailability. Both types of ART-loaded nanosystems showed a sustained in vitro release profile over 96 (nanoreservoirs) and 240 h (nanospheres). Finally, the in vitro antimalarial activity was evaluated using the lactate dehydrogenase assay. ART-containing colloidal suspensions inhibited the growth of cultured Plasmodium falciparum , both multi-resistant K1 and susceptible 3D7 strains with IC 50 values (2.8 and 7.0 ng mL −1 ) close to those of reference ART solution. These colloidal nanosystems based on CD derivatives and containing ART may provide a promising alternative formulation for injectable use of ART.