Sparing methylation of β-cyclodextrin mitigates cytotoxicity and permeability induction in respiratory epithelial cell layers in vitro

in Journal of Controlled Release (2009), 136

Cyclodextrins (CDs) are promising solubility enhancers for inhaled drug delivery. However, they have dose-dependent effects on the respiratory epithelium, which may have advantages for permeability ... [more ▼]

Cyclodextrins (CDs) are promising solubility enhancers for inhaled drug delivery. However, they have dose-dependent effects on the respiratory epithelium, which may have advantages for permeability enhancement but also gives rise to safety concerns. In this study, the methyl thiazol tetrazolium (MTT) assay was used to compare a new sparingly methylated β-CD, Kleptose® Crysmeβ (Crysmeb) with the more established CD derivatives hydroxypropyl-γ-cyclodextrin (HPγCD), randomly methylated β-cyclodextrin (Rameb) and hydroxypropyl-β-cyclodextrin (HPβCD). The βCD derivatives affected cell metabolism in A549 cells in a concentration dependent manner with LDso of 56, 31 and 11 mM obtained for HPβCD, Crysmeb and Rameb, respectively. Calu-3 cells were less susceptible to βCD with an LDso of 25 mM being obtained for Rameb only. Permeability increases in Calu-3 cell layers were observed with βCD derivatives and a concentration dependency shown. The mechanism of permeability enhancement and its reversibility was investigated. Rameb produced an irreversible loss of cell layer barrier function at ≥25 mM, but perturbations of epithelial integrity were moderate and reversible in the case of HPβCD and Crysmeb (25-50 mM). Given its high solubilisation capacity, the low toxicity and transient absorption promoting properties, this study identifies Crysmeb as a promising adjuvant in formulations for inhalation. [less ▲]

Unsuccessful Induction of Endometriosis in Female Rhesus Macaques (Macaca mulatta).

in Gynecologic & Obstetric Investigation (2008), 66(2), 84-90

Background/Aims: The aim of this study was to induce endometriosis in female rhesus macaques (Macaca mulatta) for research purposes. Methods: Three female monkeys from 4 to 4.5 years of age underwent ... [more ▼]

Background/Aims: The aim of this study was to induce endometriosis in female rhesus macaques (Macaca mulatta) for research purposes. Methods: Three female monkeys from 4 to 4.5 years of age underwent three consecutive attempts at endometriosis induction over an 8-month period: (i) the first attempt involved intravaginal sampling of endometrial tissue and transplantation into the intrapelvic cavity; (ii) the second entailed surgical removal of endometrium after hysterotomy and intra-abdominal placement, and (iii) the third used endometrial mucosa obtained by scraping the uterus after hysterectomy, placed in a surgical pouch created in the retrovesical space (Retzius). In each case, the pelvic cavity was closely inspected after 7, 9, and 6 weeks respectively for the presence of endometriotic lesions, and peritoneal biopsies were performed. Results: Neither macroscopic observation nor histological analysis revealed any endometriotic lesions. Conclusion: This failure to induce endometriosis in female rhesus macaques suggests that this species is not the most efficient experimental model among primates to investigate endometriosis development or treatment. [less ▲]

Theoretical and Experimental Investigations of Organic Acids/Cyclodextrin Complexes and Their Consequences Upon the Formation of Miconazole/Cyclodextrin/Acid Ternary Inclusion Complexes

in International Journal of Pharmaceutics (2008), 347(1-2), 62-70

(1)H NMR spectrometry, FT-IR spectroscopy, as well as molecular modeling at the AM1 level and normal mode analysis were used to characterise the interactions and the formation of inclusion complexes ... [more ▼]

(1)H NMR spectrometry, FT-IR spectroscopy, as well as molecular modeling at the AM1 level and normal mode analysis were used to characterise the interactions and the formation of inclusion complexes between three organic acids: maleic, fumaric, L-tartaric acids and betaCD. In aqueous medium, the complexation was confirmed by (1)H NMR spectroscopy using two-dimensional technique. The stable geometries of the complexes were determined by molecular modeling. Experimental infrared frequencies were assigned on the base of the vibrational normal mode calculation at the fully optimized geometry for the inclusion complexes. All the results point out the presence of stable inclusion complexes between acids and betaCD at the solid state. These results show the double role of the acid. Correlated with the theoretical and experimental data previously obtained for the miconazole/CD/acids complexes, in function of both acids and CDs structures, the acids can either stabilize the complexes by formation of a multicomponent complex or form acid/CD inclusion complexes, hindering the guest inclusion. [less ▲]

Validation of manufacturing process of Diltiazem HCl tablets by NIR spectrophotometry (NIRS)

in Journal of Pharmaceutical & Biomedical Analysis (2007), 45(2), 356-361

The goal of this study was to apply the Process Analytical Technology FDA's initiative in pharmaceutical tablets manufacturing. Near Infrared Spectrophotometry (NIRS) was used as a non-destructive, very ... [more ▼]

The goal of this study was to apply the Process Analytical Technology FDA's initiative in pharmaceutical tablets manufacturing. Near Infrared Spectrophotometry (NIRS) was used as a non-destructive, very fast technique requiring no sample preparation. Direct compression powder blends containing Diltiazem HCl as a model drug were pressed into tablets for the calibration and the validation steps. First, a partial least squares model was built to calibrate the NIR spectrometer. Then, this model was validated and compared with a validated UV spectrophotometry reference method. For this comparison, the Bland and Altman's statistical method was applied. The manufacturing process was validated by producing three batches at three different concentration levels. The NIR analysis of these batches was performed during 3 days. This study shows that NIRS can be used to validate the whole manufacturing process and not only as an analytical method for tablets assay. NIRS is an interesting tool to show possible variations during the manufacturing process which could lead the finished product to fall outside of specifications. [less ▲]

Characterization of siRNA lipoplexes in terms of size and zeta potential data

Poster (2007, October)

USE OF A TRIOXOPYRIMIDINE FOR THE TREATMENT AND PREVENTION OF BRONCHIAL INFLAMMATORY DISEASES.

Patent (2007)

Solid lipid microparticles containing the sunscreen agent, octyl-dimethylaminobenzoate: Effect of the vehicle

in European Journal of Pharmaceutics & Biopharmaceutics (2007), 66(3), 483-487

Solid lipid microparticles (SLMs) loaded with the sunscreen agent, octyl-dimethyl amino benzoate (ODAB), were prepared in order to achieve enhanced sunscreen photostability. The microparticles were ... [more ▼]

Solid lipid microparticles (SLMs) loaded with the sunscreen agent, octyl-dimethyl amino benzoate (ODAB), were prepared in order to achieve enhanced sunscreen photostability. The microparticles were produced by the melt dispersion technique using glyceryl behenate as lipidic material and poloxamer 188 as the emulsifier. The obtained SLMs showed proper features in terms of morphology, size distribution (1.67-15.81 mu m) and ODAB loading (16.15 +/- 0.11%, w/w). The sunscreen release from the SLMs was slower than its dissolution rate and the photodecomposition of ODAB was markedly decreased (> 51.3%) by encapsulation into the lipid microparticles. The efficacy of the SLM carrier system was also evaluated after their introduction in model topical formulations (i.e., hydrogel and oil-in-water emulsion). Further in vitro release measurements, performed using Franz diffusion cells with polycarbonate membranes, indicated that the retention capacity of the microparticles was lost after their incorporation into the emulsion, whereas it was retained in the hydrogel. Moreover, the SLMs achieved a reduction of the sunscreen photodegradation in the hydrogel vehicle (the ODAB loss decreased from 87.4% to 59.1%), whereas no significant photoprotective effect was observed in the emulsion. Therefore, the efficacy of the ODAB-loaded SLMs was markedly affected by the vehicle. (c) 2007 Elsevier B.V. All rights reserved. [less ▲]

Evaluation of the cytotoxicity of cyclodextrins on endothelial cells using MTT assay

Poster (2007, April)

Contribution of cyclodextrins in the development of different pharmaceutical formulations of a new matrix metalloproteinase inhibitor

in Journal of Inclusion Phenomena and Macrocyclic Chemistry (2007, April), 57(1-4), 303-308

Ro 28-2653 is a new synthetic inhibitor of matrix metalloproteinases. The ability of these enzymes to degrade various components of the extracellular matrix seems to play a major role in tumors ... [more ▼]

Ro 28-2653 is a new synthetic inhibitor of matrix metalloproteinases. The ability of these enzymes to degrade various components of the extracellular matrix seems to play a major role in tumors progression and is potentially effective against bronchial remodeling in asthma and BPCO. Ro 28-2653 is very poorly soluble in water. This low solubility estimated at about 0.56 mu g/ml in water at 25 degrees C gives rise to difficulties in pharmaceutical formulation of oral, injectable or nebulizable solutions. The purpose of our study is to prepare and to characterize inclusion complexes between Ro 28-2653 and cyclodextrins and to investigate the biopharmaceutical repercussion of the inclusion of the active substance. The complex formation was investigated by phase solubility studies. H-1-NMR spectroscopy and molecular modeling studies were carried out to elucidate the structure of the inclusion complex between Ro 28-2653 and cyclodextrin. Oral, intravenous and nebulizable solutions of Ro 28-2653 were developed with cyclodextrin. The in vivo studies were performed on healthy sheep for the pharmacokinetic evaluation of the oral and intravenous formulations while the nebulization of the complex solution was studied by using an asthma model in mouse. [less ▲]

Solid lipid microparticles as a sustained release system for pulmonary drug delivery

in European Journal of Pharmaceutics & Biopharmaceutics (2007), 65(1), 47-56

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 ... [more ▼]

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. (c) 2006 Elsevier B.V. All rights reserved. [less ▲]