Glass Microneedles: A Case Study for Regulatory Approval Using a Quality by Design Approach.

In this paper, a roadmap is provided for the regulatory approval of one of the exciting and dynamic drug delivery fields, microneedles, by using a Quality by Design approach to pharmaceutical product development. In this regard, a quality target product profile (QTPP) and the critical quality attributes (CQA) of microneedles are identified. A case study of the recently patented method of fabricating glass microneedles entirely from a therapeutic agent, thus eliminating the requirement for additional excipients is discussed. The glass microneedle, ArrayPatch, is a propriety wearable device with platform potential consisting of an array of sharp, but painless, dissolvable microneedles manufactured with 100% drug. The microneedles penetrate the skin on application and dissolve to deliver a locally effective dose. The in vitro characterization of the microneedle CQAs under WHO-guided stability conditions will be described to assess the manufacturing readiness of ArrayPatch.  A live technical video is also provided, presenting a unique procedure of jugular vein cannulation through the ear vein of a pig animal model to study the in vivo pharmacokinetics of ArrayPatch compared to standard-of-care marketed products.

Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS): A rapid test for enteric coating thickness and integrity of controlled release pellet formulations.

There are no rapid dissolution based tests for determining coating thickness, integrity and drug concentration in controlled release pellets either during production or post-production. The manufacture of pellets requires several coating steps depending on the formulation. The sub-coating and enteric coating steps typically take up to six hours each followed by additional drying steps. Post production regulatory dissolution testing also takes up to six hours to determine if the batch can be released for commercial sale. The thickness of the enteric coating is a key factor that determines the release rate of the drug in the gastro-intestinal tract. Also, the amount of drug per unit mass decreases with increasing thickness of the enteric coating. In this study, the coating process is tracked from start to finish on an hourly basis by taking samples of pellets during production and testing those using BARDS (Broadband Acoustic Resonance Dissolution Spectroscopy). BARDS offers a rapid approach to characterising enteric coatings with measurements based on reproducible changes in the compressibility of a solvent due to the evolution of air during dissolution. This is monitored acoustically via associated changes in the frequency of induced acoustic resonances. A steady state acoustic lag time is associated with the disintegration of the enteric coatings in basic solution. This lag time is pH dependent and is indicative of the rate at which the coating layer dissolves. BARDS represents a possible future surrogate test for conventional USP dissolution testing as its data correlates directly with the thickness of the enteric coating, its integrity and also with the drug loading as validated by HPLC.

Role of Drug Adsorption onto the Silica Surface in Drug Release from Mesoporous Silica Systems.

Factors contributing to incomplete drug release from a number of mesoporous silica formulations are not well understood. This study aims to address this gap in knowledge by exploring the role of drug adsorption onto silica substrates during the drug release process in dissolution media. Adsorption isotherms were generated to understand drug adsorption behavior onto the silica surface. Two silica materials were selected (SBA-15 (mesoporous) and Aerosil 200 (nonporous)) to investigate the influence of porous architecture on the adsorption/dissolution processes. The ability of the dissolution medium to wet the silica surface, particularly the porous network, was investigated by the addition of a surfactant to the dissolution medium. The results demonstrated that a larger amount of drug was bound/m2 to the nonporous surface than to the mesoporous material. Adsorption isotherms proved useful in understanding drug adsorption/release behavior for the nonporous silica formulation. However, the quantity of drug remaining on the mesoporous silica surface after dissolution was significantly higher than the amount predicted using adsorption isotherm data. These results suggest that a fraction of loaded drug molecules were tightly bound to the silica surface or attached to sites which are inaccessible for the dissolution media. The presence of surfactant, sodium dodecyl sulfate, in the media enhanced drug release from the silica surface. This behavior can be attributed to both the improved wetting characteristics of the media and adsorption of the surfactant to the silica surface. The findings of this study reinforce the significance of the role that silica porous architecture plays in the dissolution process and indicates that accessible surface area is an important parameter to consider for mesoporous systems in relation to drug release.

Lipidic dispersion to reduce food dependent oral bioavailability of fenofibrate: In vitro, in vivo and in silico assessments.

Novel formulations that overcome the solubility limitations of poorly water soluble drugs (PWSD) are becoming ever more critical to a drug development process inundated with these compounds. There is a clear need for developing bio-enabling formulation approaches to improve oral bioavailability for PWSD, but also to establish a range of predictive in vitro and in silico biopharmaceutics based tools for guiding formulation design and forecasting in vivo effects. The dual aim of this study was to examine the potential for a novel lipid based formulation, termed a lipidic dispersion, to enhance fasted state oral bioavailability of fenofibrate, while also assessing the predictive ability of biorelevant in vitro and in silico testing. Formulation as a lipidic dispersion improved both dissolution and solubilisation of fenofibrate through a combination of altered solid state characteristics and incorporation of solubilising lipidic excipients. These changes resulted in an increased rate of absorption and increased maximal plasma concentrations compared to a commercial, micronised product (Lipantil® Micro) in a pig model. Combination of biorelevant in vitro measurements with in silico physiologically based pharmacokinetic (PBPK) modelling resulted in an accurate prediction of formulation performance and forecasts a reduction in food effects on fenofibrate bioavailability through maximising its fasted state dissolution.

Synthesis and biological evaluation of novel isoellipticine derivatives and salts.

Synthesis of novel 7-substituted isoellipticines and isoellipticinium salts is described, with optimisation of routes, representing a new class of anti-cancer agent. Initial assessment of biological activity using a topoisomerase II decatenation assay and NCI screening highlighted strong anti-cancer activity, further developed in a panel of isoellipticinium salts. Interestingly, low correlation between results of the topoisomerase II decatenation assay and NCI screen throughout the panel suggest that topo II is not the most important biological target with respect to anti-cancer activity in this new class of compounds. Results also suggest that solubility is not the limiting factor in activity of the isoellipticinium salts. Overall, 20 novel ellipticine analogues were prepared and full anti-cancer profiling was completed for 13 isoellipticine derivatives and salts. Two compounds display significant specificity towards CNS cancer cell lines and are lead compounds for future development.

Desmethylabietospiran, a naturally occurring self-gelation agent.

A new self-gelating triterpenoid natural product has been isolated from the bark of the silver fir, Abies alba. The structure is desmethylabietospiran (3) on the basis of chemical and spectroscopic evidence. Also reported is a more efficient isolation procedure of abietospiran (1) from A. alba.