Transdermal delivery from liposomal formulations - evolution of the technology over the last three decades

Strong barrier properties of stratum corneum often limits the efficiency of drug delivery through skin. Several strategies were tried to improve permeation of drug through skin for local as well as systemic drug delivery. Incorporation of the drug within flexible liposomal vesicles has been one of the popular and well-studied approaches for delivering drug to deeper layers of the skin or even systemic circulation. Flexible/deformable/elastic liposomal systems such as invasomes, Transfersomes®, ethosomes, niosomes, etc. have demonstrated encouraging results in delivering small molecules and large proteins to the skin. It is necessary to recognize the promising concepts and analyze their potential, since a clear understanding of the drawbacks and advantages of these approaches will lead towards future development. In the current review we have attempted to give an overview of different liposomal drug carriers for transdermal drug delivery and their efficiency as drug delivery system through different in vivo and in vitro studies. Also, an overview of the studies which investigated the interactions between skin and vesicles, which have lead us to our current understanding of the skin penetration mechanisms of liposomal formulations is presented

Stability of Biorelevant Media Under Various Storage Conditions

The physical and chemical stability of various biorelevant media (FaSSGF, FaSSIF V1, FaSSIF V2, FaSSIF V3, and FeSSIF) were investigated over periods after preparation of up to 120 h at room temperature (RT) (22 degrees C) and 37 degrees C. It was shown that biorelevant instant powders are not a source of microbiological contamination. It was also established that the physical characteristics of FaSSGF and FeSSIF are invariant with time, so they can be used immediately after preparation, i.e., without any equilibration time. Alternatively, they can be stored for up to 96 h at RT before use. By contrast, FaSSIF V1 requires an equilibration time of 2 h, and FaSSIF V2 requires an equilibration time of 24 h to enable the media characteristics to stabilize. After this equilibration time, both FaSSIF V1 and V2 can also be stored for at least up to 96 h at RT prior to use; longer storage times have not yet been tested. The particle size of FaSSIF V3 appears to continually evolve over time. For FaSSIF V3, it is thus recommended that the waiting period between preparation and use be standardized among experiments. Additionally, the colloidal particle structures present in the various FaSSIF versions were analyzed by cryogenic transmission electron microscopy (Cryo-TEM). Various kinds of micelles (globular, disc, multilayer disc, and thread-like micelles) were observed in all samples, and some samples also contained unilamellar vesicles. Differences in solubility of drugs among the various FaSSIF versions can be partly explained by the results from Cryo-TEM

Nanomedicines - Tiny particles and big challenges

After decades of research, nanotechnology has been used in a broad array of biomedical products including medical devices, drug products, drug substances, and pharmaceutical-grade excipients. But like many great achievements in science, there is a fine balance between the risks and opportunities of this new technology. Some materials and surface structures in the nanosize range can exert unexpected toxicities and merit a more detailed safety assessment. Regulatory agencies such as the United States Food and Drug Administration or the European Medicines Agency have started dealing with the potential risks posed by nanomaterials. Considering that a thorough characterization is one of the key aspects of controlling such risks this review presents the regulatory background of nanosafety assessment and provides some practical advice on how to characterize nanomaterials and drug formulations. Further, the challenges of how to maintain and monitor pharmaceutical quality through a highly complex production processes will be discussed

Predictive PBPK modeling as a tool in the formulation of the drug candidate TMP-001

Since many drugs in the therapy scheme of multiple sclerosis (MS) are applied parenterally with significant side effects, oral treatment is the most accepted therapy option for chronic diseases like MS. The drug candidate TMP-001, which has disease-modifying properties, can be applied orally. Beside other symptoms, swallowing disorders have a major impact not only on the health status and quality of life of MS patients, but also impede reliable drug therapy. Consequently, the development of an easy-to-swallow liquid oral dosage form supported by a combined PBPK-IVIVC model was approached. In this context, the impact of formulation parameters was studied. Biorelevant in vitro drug release studies resulted in an almost complete release of 96.91% ± 1.00% in the intestine which was translated to rapidly increasing in silico plasma profiles. The predictions were compared to the outcome of a phase I clinical trial. A partial parameter sensitivity analysis of the in silico model deepened our understanding of the physiological processes underlying human pharmacokinetics

Advanced in silico modeling explains pharmacokinetics and biodistribution of temoporfin nanocrystals in humans

Foscan®, a formulation comprising temoporfin dissolved in a mixture of ethanol and propylene glycol, has been approved in Europe for palliative photodynamic therapy of squamous cell carcinoma of the head and neck. During clinical and preclinical studies it was observed that considering the administration route, the drug presents a rather atypical plasma profile as plasma concentration peaks delayed. Possible explanations, as for example the formation of a drug depot or aggregation after intravenous administration, are discussed in current literature. In the present study an advanced in silico model was developed and evaluated for the detailed description of Foscan® pharmacokinetics. Therefore, in vitro release data obtained from experiments with the dispersion releaser technology investigating dissolution pressures of various release media on the drug as well as in vivo data obtained from a clinical study were included into the in silico models. Furthermore, precipitation experiments were performed in presence of biorelevant media and precipitates were analyzed by nanoparticle tracking analysis. Size analysis and particle fraction were also incorporated in this model and a sensitivity analysis was performed. An optimal description of the in vivo situation based on in vitro release and particle characterization data was achieved, as demonstrated by an absolute average fold error of 1.21. This in vitro-in vivo correlation provides an explanation for the pharmacokinetics of Foscan® in humans