Investigation of diclofenac release and dynamic structural behavior of non-lamellar liquid crystal formulations during in situ formation by UV-Vis imaging and SAXS.

In situ formation of high viscous inverse lyotropic non-lamellar liquid crystalline phases is a promising approach for sustained drug delivery in the joint. The in situ forming process on exposure of two diclofenac-loaded preformulations to aqueous media was characterized with respect to depot size and shape, initial release and structural transitions using UV-Vis imaging and spatially and time-resolved synchrotron small-angle X-ray scattering (SAXS). The preformulations consisted of 10 % (w/w) ethanol, 10 % (w/w) water and a binary lipid mixture of glycerol monooleate (GMO):1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DOPG) or GMO:medium chain triglycerides (MCT). Upon injection of preformulations into an employed injection-cell containing excess of bio-relevant medium, rapid generation of liquid crystalline depots was observed. UV-Vis images and constructed 2D SAXS maps of the injection-cell showed depots with different shapes and sizes, and features with high nanostructural heterogeneity. More extensive swelling of the GMO:DOPG-based preformulation was observed compared to the GMO:MCT-based preformulation. The UV image analysis found that a higher amount of diclofenac was released in the image area after 20 h from the GMO:MCT depot compared to the GMO:DOPG depot. The injection-cell setup employing UV-Vis imaging and synchrotron SAXS constitutes an attractive approach for evaluating the in situ forming processes of liquid crystalline depots.

An in vitro gel-based system for characterizing and predicting the long-term performance of PLGA in situ forming implants.

In situ forming implants are exposed to an extracellular matrix resembling a gel rather than aqueous solution upon subcutaneous administration. The aim of study was to develop a gel-based release testing system for characterizing the long-term in vitro behavior of in situ forming implants. The gel-based system consisted of an agarose gel mimicking the subcutaneous injection site and a receiver layer comprising phosphate buffer. Poly(D,L-lactide-co-glycolide) in situ forming implants containing leuprolide acetate as the model peptide and N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO) or triacetin as co-solvent were investigated. The gel-based release testing system discriminated between the formulations. Accelerated release data obtained at elevated temperatures were able to predict real-time release applying the Arrhenius equation. Monitoring of the microenvironmental pH of the implants was performed by UV-Vis imaging in the gel-based system at 50 °C. A pH drop (from pH 7.4 to 6.7 for the NMP and DMSO implants, to pH 5.5 for the triacetin implants) within the first day was observed, followed by an increase to pH âˆ¼7.4. The gel-based system coupled with UV imaging offered opportunity for detailed evaluation and prediction of the in vitro performance of long-acting injectables, facilitating future development of in situ depot forming delivery systems.

Critical factors influencing the in vivo performance of long-acting lipophilic solutions--impact on in vitro release method design.

Parenteral long-acting lipophilic solutions have been used for decades and might in the future be used in the design of depots with tailored delivery characteristics. The present review highlights major factors influencing the in vivo performance of lipophilic solutions. Furthermore, an account is given of the characteristics of employed in vitro release methods with a focus on the "state" of sink condition, the stirring conditions, and the oil-water interfacial area. Finally, the capability of in vitro release data to predict the in vivo performance of drug substances administrated in the form of lipophilic solutions is discussed. It is suggested that as long as the major rate-limiting in vivo release mechanism is governed by the drug partitioning between the oil vehicle and the tissue fluid, the use of in vitro release testing in quality control appears to be realistic. With increasing lipophilicity of the drug substances and longer duration of action, the in vivo drug release process may become more complex. As discussed, practical analytical problems together with the inability of release methods to mimic two or more concomitant in vivo events may constitute severe impediments for establishment of in vitro in vivo correlations.

Drug-liposome distribution phenomena studied by capillary electrophoresis-frontal analysis.

The potential of using CE frontal analysis (CE-FA) for the study of low-molecular-weight drug-liposome interactions was assessed. The interaction of bupivacaine, brompheniramine, chlorpromazine, imipramine, and ropivacaine with net negatively charged 80/20 mol% 1-oleoyl-2-palmitoyl-sn-glycero-3-phosphocholine/egg yolk phosphatidic acid liposome suspensions in HEPES buffer at pH 7.4 was investigated. The fraction of free drug as a function of lipid concentration was measured and apparent liposome-buffer distribution coefficients were determined for the basic drug substances. The distribution coefficients increased in the order ropivacaine, bupivacaine, brompheniramine, imipramine, and chlorpromazine. The developed CE method was relatively fast allowing estimates of drug-liposome affinity to be obtained within 15 min. CE-FA may have the potential to become a valuable tool for the characterization of drug-liposome interactions in relation to estimation of drug lipophilicity and for the evaluation of drug distribution in liposomal drug delivery systems.