The serious issues of energy shortage and greenhouse gas emission have led to the development of coalbed methane (CBM) with new commercial ramifications. A hydrate-based gas separation technology is introduced to recover methane from CBM. However, the mechanism of hydrate nucleation needs to be clear for enhancing the hydrate formation rate and gas recovery efficiency. In this work, we studied, by means of in-situ Raman spectroscopy, the microscopic characterizations of hydrates forming in/around the initial gas-liquid interface in the case of CBM and tetrahydrofuran (THF). It is found that the hydrates accumulate as a film with horizontal crevices in the initial gas-liquid interface. These crevices prevent the hydrate film from hindering gas-liquid contact and limiting hydrate formation. Raman spectroscopy results illustrate that the initial gas-liquid interface shows a positive impact on water aggregation, and that the holding gas molecules stay stably with the water molecules. Nitrogen molecules encage into the cavities of THF hydrates along with methane molecules. For the interface and hydrate layer, water aggregation is evaluated by the Raman intensity ratio of hydrogen-bonded water (BW) and free water (FW) without any hydrogen bonds, abbreviated as I-BW/I-FW. A value of I-BW/I-FW higher than 0.85 can symbolize the occurrence of hydrate nucleation in the interface and help assess the hydrate formation.

Background: In this study, we assess the effectiveness of inhaled doxycycline, a tetracycline antibiotic displaying matrix metalloproteinases (MMP) inhibitory effects to prevent allergen-induced inflammation, hyperresponsiveness and remodeling. MMPs play key roles in the complex cascade of events leading to asthmatic phenotype.Methods: Doxycycline was administered by aerosols by the mean of a novel formulation as a complex with hydroxypropyl-gamma-cyclodextrin (HP-gamma-CD) used as an excipient. BALB/c mice (n = 16-24 in each group) were sensitized and exposed to aerosolized ovalbumin (OVA) from day 21 to 27 (short-term exposure protocol) or 5 days/odd weeks from day 22 to 96 long-term exposure protocol).Results: In the short-term exposure model, inhaled doxycycline decreased allergen-induced eosinophilic inflammation in bronchoalveolar lavage (BAL) and in peribronchial areas, as well as airway hyperresponsiveness. In lung tissue, exposure to doxycycline via inhaled route induced a fourfold increase in IL-10 levels, a twofold decrease in IL-5, IL-13 levels and diminished MMP-related proteolysis and the proportion of activated MMP-9 as compared to placebo.In the long-term exposure model, inhaled doxycycline significantly decreased the extent of glandular hyperplasia, airway wall thickening, smooth muscle hyperplasia and subepithelial Collagen deposition which are well recognized features of airway remodeling.Conclusion: Doxycycline administered by aerosols decreases the allergen-induced airway inflammation and hyperresponsiveness and inhibits the development of bronchial remodeling in a mouse model of asthma by modulation of cytokines production and MMP activity. (c) 2007 Elsevier Inc. All rights reserved.

The geometry, frequency and intensity of the vibrational bands of miconazole were derived from the density functional theory (DFT) calculations with the hybrid functional B3LYP and the 6-31G(d) basis set. Starting from the fully AM1 optimized geometries of miconazole/betaCD/acids complexes, the miconazole/acid dimers were reoptimized at the B3LYP/6-31G(d) level. Three acids were studied: maleic, fumaric and l-tartaric acids. To begin with the vibrational spectral data obtained from solid phase in mid FT-IR spectrum of miconazole and its dimers are assigned based on the results of the normal modes calculations. All the observed spectra and the calculated ones are found to be in good agreement. In a second step, theoretical results allowed the assignment of FT-IR spectrum for the miconazole/HPgammaCD inclusion complex produced by supercritical carbon dioxide treatment and confirmed the inclusion of miconazole. The experimental spectra for the miconazole/HPgammaCD/acids complexes prepared by supercritical carbon dioxide processing were also assigned using theoretical results. The results confirmed the presence of a genuine inclusion complex and also the interaction between miconazole and the acid.

The controlled release of drugs for pulmonary delivery is a research field which has been so far rather unexploited but is currently becoming increasingly attractive. The introduction part of this research article first details the potential advantages of solid lipid microparticles (SLMs) as drug carrier compared to liposomes and polymeric microspheres. The aim of this work is to use SLMs to impart a sustained release profile to a model drug, salbutamol acetonide (SA). SA was synthesized from salbutamol in order to increase the lipophilicity of this molecule and thereby to increase its incorporation efficiency into SLMs. SA-loaded SLMs were then produced by a hot emulsion technique followed by high-shear homogenisation and the manufacturing parameters were optimized using the experimental design methodology in order to reach a suitable particle size for pulmonary administration. Scanning electron micrographs showed that SLMs are spherical, have a smooth surface and that SA crystallises outside of the particles when the drug loading is higher than 20%. This was confirmed by X-ray diffraction. SA in vitro release study from SLMs showed that the release rate increased with SA loading but remained in every case lower than the dissolution rate of pure SA.

The inclusion of miconazole into cyclodextrin cavity has been demonstrated by different authors. Preliminary studies have shown which fragment of the molecule is involved in the inclusion. In the present study, AM1 approximate molecular orbital calculations have been performed on several cyclodextrins complexes (βCD, HPβCD and HPγCD) with miconazole and acidic compounds (maleic, fumaric and L-tartaric acids) as partners. For all the binary complexes, the inclusion of the dichlorobenzene–CH2–O-group leads to the most stable complex. For the ternary complexes, depending on their conformation and/or their structures, the acids can either stabilize or destabilize the complex. All the theoretical results were in good agreement with experimental data of miconazole inclusion yields into cyclodextrins. This work clearly demonstrates that the structure of both cyclodextrin and acid plays a key-role in the formation of inclusion complexes.

Ro 28-2653 (5-biphenyl-4-yl-5-[4-(4-nitro-phenyl)-piperazin-1-yl]-pyrimidine-2,4,6-trione) is a new synthetic inhibitor of matrix metalloproteinases (MMPs) with a high selectivity towards MMP2, MMP9 and membrane type 1-MMP. It has been shown that cyclodextrins (CDs) are able to form inclusion complexes with Ro 28-2653 and to increase its aqueous solubility. The aim of this study is to demonstrate that an increase in Ro 28-2653 solubility, via ternary complex formation, can lead to an increase in the oral bioavailability of this drug. This study shows that a synergistic effect exists between hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and l-lysine. The use of this multicomponent system enabled the preparation of oral and intravenous solutions of Ro 28-2653. In vivo evaluation of the oral solution of the inclusion complex of Ro 28-2653 in comparison with a suspension of the same uncomplexed drug showed a significant (p<0.05) increase in absolute bioavailability. The area under curve (AUC) and the peak serum concentration (Cmax) were approximately 10 times higher than those obtained with the suspension, while the time (Tmax) to reach Cmax was reduced. Moreover, in vivo administration of Ro 28-2653 solutions highlighted some information about the pharmacokinetic behavior of Ro 28-2653: a long biologic half-life (about 15.5h) and a small overall volume of distribution (8l).

PURPOSE Ro 28-2653 (RO) is a synthetic inhibitor of matrix metalloproteinases (MMPs), which is potentially effective against bronchial remodeling. Given that this molecule has very poor aqueous solubility, different cyclodextrins (CDs) have been tested to increase its solubility. The aim of this study was to prepare and to characterize inclusion complexes between RO and CDs, in order to develop nebulizable solutions. METHODS The complex formation was investigated by phase solubility studies. (1)H-NMR spectroscopy and molecular modeling studies were carried out to elucidate the structure of the inclusion complex between RO and dimethyl-beta-CD (DIMEB). Nebulizable solutions of RO were developed with CDs and a stability study was performed over 9 months. RESULTS The phase solubility studies showed that beta-CD and its derivatives form a 1:2 complex with RO, whereas gamma-CD includes RO with a 1:1 stoichiometry and a weak stability constant. T-ROESY spectra showed that DIMEB is able to complex two RO substituents (nitrophenyl and biphenyl groups) with preferential orientations, while molecular modeling demonstrated that the configurations observed with (1)H-NMR are energetically favorable, especially owing to H-bond formation between RO and DIMEB. Two CDs were selected to develop nebulizable solutions of RO and the stability study demonstrated that RO degradation in solution is strongly dependent on the concentration of the 1:2 inclusion complex. CONCLUSIONS CDs are able to include RO and to improve its aqueous solubility. The beta-CD derivatives can be used to formulate nebulizable solutions of RO, the stability of which depends on the concentration of the 1:2 complex.

Up to now sustained release formulations for pulmonary delivery have still not been marketed in spite of the increasing interest in this research field. The control of the drug delivery in the respiratory tract may be achievable by employing suitable carriers, possessing appropriate drug release characteristics. In this purpose liposomes have been the most studied carriers. They proved to be able to provide a sustained release to the incorporated active substances but they present some disadvantages, i.e a high production cost, a relative unstability during storage and during nebulisation that can lead to disruption and loss of entrapped substance (1). Polymeric microspheres have also been successfully tested as sustained release drug delivery system (2) but their safety still remains uncertain (3). That is the reason why we decided to focus on Solid Lipid Microparticles (SLMs), a carrier that has not been up to now much studied especially for pulmonary administration. However SLMs present several advantages: they can be considered as physiologically compatible, physicochemically stable and allowing a large-scale production at a relative low production cost. The aim of this work was to produce a drug carrier able to provide a sustained release to a s2mimetic agent and thereby to prolong its duration of action. The active substance we chose to work with is salbutamol acetonide (SA), a derivative of salbutamol that have been synthetised in order to get a more lipophilic substance and thereby to allow a more effective incorporation of this drug into SLMs. This paper describes SLMs production technique, SLMs optimisation and an in vitro drug release study.