Rheological temperature sweeping in a quality by design approach for formulation development and optimization.

Many topical drug products are multi-phase systems which are prone to phase separation exhibiting a high risk for not meeting the critical quality attributes (CQAs) of a pharmaceutical product such as uniform active pharmaceutical ingredient (API) distribution and physical homogeneity. In order to investigate and control these CQAs a rheological temperature sweeping (RTS) method was implemented and refined to enable quantification of these characteristics within a quality by design (QbD) approach. For method implementation, emulsion and ointment compositions were prepared within a design of experiments (DoE) and critical responses from RTS were extracted via principal component analysis (PCA) in a multivariate data analysis (MVA) approach. The span after 3 cycles of RTS on emulsions and a combination of 5 principal components (PCs) for ointments were selected as responses from PCA. The span correlates with the droplet size of selected emulsions followed during stability whereas the combination of the PCs for ointments enables a differentiation of the compositions. Identified critical material attributes (CMAs) are the emulsifier concentration of the emulsion and the liquid paraffin (LP) content of the ointments. In conclusion, RTS enables a rapid screening of liquid and semi-solid products in a quantitative manner for pharmaceutical development and formulation optimization.

Design of lipid microparticle dispersions based on the physicochemical properties of the lipid and aqueous phase.

Lipid microparticle (LMP) dispersions may be utilized as novel pharmaceutical dosage forms for different administration routes. The particle size and particle size distribution of the LMPs can be classified to the most crucial specifications for therapeutical and research applications. The size parameters can be adjusted via the physicochemical properties of the inner lipid and the outer aqueous phase. In the present study, ten different solid lipids with incorporated lecithin and four concentrations of the surfactant poloxamer 407 (P407) were utilized for LMP dispersion preparation. Physicochemical properties of the bulk and dispersed lipid matrices as well as features of the P407 solutions were determined. Correlations between the mean particle size (mean) of the LMPs and the span as parameter for the particle size distribution as responses were identified by plotting against the measured physicochemical parameters. Most significant linear correlations were found between the mean and the micellization onset temperature (Tmicell) in the parent solution and the dynamic viscosity of the emulsifier solution at 25 °C and between the span and the Tmicell in the LMP dispersion. Consequently, P407 micelles as a reservoir for surfactant monomers and the overall viscosity as a separator between newly-formed lipid droplets are fundamental stabilizing parameters.

Applications and limitations of lipid nanoparticles in dermal and transdermal drug delivery via the follicular route.

Lipid nanoparticles (LN) such as solid lipid nanoparticles (SLN) and nanolipid carriers (NLC) feature several claimed benefits for topical drug therapy including biocompatible ingredients, drug release modification, adhesion to the skin, and film formation with subsequent hydration of the superficial skin layers. However, penetration and permeation into and across deeper skin layers are restricted due to the barrier function of the stratum corneum (SC). As different kinds of nanoparticles provide the potential for penetration into hair follicles (HF) LN are applicable drug delivery systems (DDS) for this route in order to enhance the dermal and transdermal bioavailability of active pharmaceutical ingredients (API). Therefore, this review addresses the HF as application site, published formulations of LN which showed follicular penetration (FP), and characterization methods in order to identify and quantify the accumulation of API delivered by the LN in the HF. Since LN are based on lipids that appear in human sebum which is the predominant medium in HF an increased localization of the colloidal carriers as well as a promoted drug release may be assumed. Therefore, sebum-like lipid material and a size of less or equal 640 nm are appropriate specifications for FP of particulate formulations.

Development, formulation, and characterization of an adapalene-loaded solid lipid microparticle dispersion for follicular penetration.

The model retinoid adapalene was formulated in a novel solid lipid microparticle (SLM) dispersion as a topical drug delivery system for transport of the active pharmaceutical ingredient (API) into hair follicle orifices. The aims of the investigations were the solid-state characterization of the lipid matrix (LM) with wide angle X-ray diffraction (WAXD) and hot-stage light microscopy (HS), the design space analysis of the developed SLM dispersion with a Box-Behnken design, the stability study of the manufactured formulation for particle size with laser diffraction and polarization intensity differential scattering (LD/PIDS) and thermal behavior with differential scanning calorimetry (DSC), and the structure analysis of the SLM dispersion with light microscopy, transmission electron microscopy (TEM), and scanning electron microscopy (SEM). The formulation showed a constant mean particle size (MPS) of 4.2 µm over 24 weeks with a melting point of about 56°C. The potential for dermal application was determined by a follicular penetration (FP) study with porcine ear skin and thermal analysis of the interaction with artificial human skin lipids like sebum and stratum corneum lipid mixture. The in vitro studies confirmed both the follicular penetration potential and a targeted erosion or dissolution of the particles in sebum.

Comparison of rheological properties, follicular penetration, drug release, and permeation behavior of a novel topical drug delivery system and a conventional cream.

A novel adapalene-loaded solid lipid microparticle (SLMA) dispersion as a topical drug delivery system (TDDS) for follicular penetration has been introduced. The objective of the present study was to investigate the rheological properties, the follicular penetration with differential tape stripping on porcine ear skin, the drug release in sebum and stratum corneum (SC) lipid mixtures, and the permeation behavior across human SC in comparison with a commercially available cream as standard. Physicochemical characterization reveals that adapalene is homogeneously distributed within the SLMA dispersion and chemically stable for at least 24 weeks. The SLMA dispersion shows a lower complex viscosity at 20 °C and a higher one at 32 °C than the cream, while the phase angle of the dispersion is always larger at both temperatures. Both formulations feature an equivalent potential for follicular penetration and deposition. However, the superiority of the SLMA dispersion is based on the preferential drug release in sebum while there is no or just a slight release in SC lipids and no permeation for both formulations. Due to the similarity of the glyceride matrix of the SLMA to sebum components, a targeted drug delivery into sebum and thereby an increased follicular penetration may be facilitated.

Facilitation of spinal NMDA receptor currents by spillover of synaptically released glycine.

In the mammalian CNS, N-methyl-D-aspartate (NMDA) receptors serve prominent roles in many physiological and pathophysiological processes including pain transmission. For full activation, NMDA receptors require the binding of glycine. It is not known whether the brain uses changes in extracellular glycine to modulate synaptic NMDA responses. Here, we show that synaptically released glycine facilitates NMDA receptor currents in the superficial dorsal horn, an area critically involved in pain processing. During high presynaptic activity, glycine released from inhibitory interneurons escapes the synaptic cleft and reaches nearby NMDA receptors by so-called spillover. In vivo, this process may contribute to the development of inflammatory hyperalgesia.