Dermal smartPearls - Optimized silica particles for commercial products & mechanistic considerations.

The amorphous state of actives can be long-term stabilized by incorporation into mesoporous particles, thus the increase in the saturation solubility by amorphicity can be exploited to improve the bioavailability. In this study 5 different silica particles were investigated regarding loading capacity and long-term stability of the amorphous form. Five different silica were used ranging in pore mean size from 3 to 25 nm, pore volume 0.4 to 1.8 mL/g, and BET surface from 740 to 320 m2/g. As model active avobenzone was used, because it is a challenging molecule by its high crystallisation tendency. To be industrially feasible, a loading capacity of about 50% pore volume was investigated. The particles were loaded by an immersion evaporation method, being able to be used in industrial production. A theory of the active precipitation in the pores was developed based on the Ostwald-Miers range. The 25 nm pore-sized particles showed a crystalline fraction directly after loading, the 3 nm and 17 nm pore-sized particles after 1 month of storage. Long-term stability of 1 year had the silica with 6 nm and 10 nm pore size, thus being ideal for products. By nitrogen sorption studies, primarily filling of the pores from bottom to top was identified as loading mechanism. HPLC analysis showed some active remaining in the pores due to strong interaction with the pore surface, which needs to be considered when developing dermal products. Interestingly, the increase in saturation solubility Cs - determined in carrageenan gels - remained also for silica particles showing a minor partial crystalline avobenzone fraction. Thus, limited crystallinity does not impair the shelf-life and performance of dermal formulations.

Nanoporous smartPearls for dermal application - Identification of optimal silica types and a scalable production process as prerequisites for marketed products.

smartPearls are a dermal delivery system for poorly soluble active agents, consisting of nanoporous silica particles loaded with a long-term stable, amorphous active agent in its mesopores (2-50 nm). The amorphous state of the active agent is known to increase dermal bioavailability. For use in marketed products, optimal silica types were identified from commercially available, regulatory accepted silica. In addition, a scalable production process was demonstrated. The loading of the particles was performed by applying the immersion-evaporation method. The antioxidant rutin was used as a model active agent and ethanol was applied as the solvent. Various silica particles (Syloid®, Davisil®) differing in particle size (7-50 µm), pore diameter (3-25 nm) and pore volume (0.4-1.75 mL/g) were investigated regarding their ease of processing. The evaporation from the silica-ethanol suspensions was performed in a rotary evaporator. The finest powders were obtained with larger-sized silica. The maximum loading staying amorphous was achieved between 10% and 25% (w/w), depending on the silica type. A loading mechanism was also proposed. The most suitable processing occurred with the large-sized Syloid® XDP 3050 silica with a 50 µm particle size and a pore diameter of 25 nm, resulting in 18% (w/w) maximum loading. Based on a 10% (w/w) loading and the amorphous solubility of the active agent, for a 100 kg dermal formulation, about 500 g of loaded particles were required. This corresponds to production of 5 kg of loaded smartPearls for a formulation batch size of a ton. The production of 5 kg (i.e., about 25 L of solvent removal) can be industrially realized in a commercial 50 L rotary evaporator.

smartPearls® for dermal bioavailability enhancement - Long-term stabilization of suspensions by viscoelasticity.

smartPearls® are a novel dermal delivery system based on mesoporous (pores 2-50 nm) particles, developed in 2014. Their pores can be loaded with active which is long-term stabilized in its amorphous state. The increased saturation solubility by the amorphous state leads to an increased dermal bioavailability of poorly soluble actives. To avoid sedimentation of the porous particles (3-50 µm) in dermal formulations, viscoelastic gels were developed using ι-carrageenan, polyacrylate and the viscoelastic Kühne salad dressing as a reference from food industry. Silica particles (company Grace/US, 50 and 150 µm) were loaded into the gels and long-term stability was assessed by a VIS sedimentation test. Furthermore, the gels were characterized by analytical centrifugation (LUMiSizer®) to assess the critical rpm/g values, allowing to order them after their absolute viscoelastic stabilizing ability. Characterization was complemented by rotation rheology, amplitude sweep and a frequency sweep analysis for the determination of elastic and viscous moduli G' and G'' at varying conditions. Based on the throughout characterization, polymers can be selected to sufficiently stabilize dermal formulations even with large sized smartPearls® - the prerequisite for using this delivery system in dermal products.

Glabridin smartPearls - Silica selection, production, amorphous stability and enhanced solubility.

Glabridin, a compound in the root extract of Glycyrrhiza glabra, has been identified as an effective tyrosinase inhibitor. Applied on skin, melanin synthesis is inhibited, making glabridin an interesting candidate for skin whitening or for the treatment of age spots. However, main obstaclefor its practical use is its low dermal bioavailability, caused by its poor water solubility. In this work smartPearls technology was used to increase the glabridins water solubility. smartPearls consist of silica particles with mesopores in which actives can be loaded. By this, actives are stabilized in amorphous state and simultaneously finely distributed in nm-range. Both amorphization and nanoization are well known approaches to increase saturation solubilities. In smartPearls these approaches are combined. In the first step, glabridin smartPearls formulation was developed, screening systematically the suitability of 4 different silicas varying in their pore sizes (3, 6, 10, 17 nm). Also, most suited filling level of glabridin was determined (25, 50, 80% referred to total pore volume of respective silica). Silica loading was performed by the immersion-evaporation method, resulting in pores filled with glabridin from bottom to top. By light microscopy, dynamic scanning calorimetry and X-ray diffraction the sample with 6 nm pore size and filling levels of 25% and 50% have been verified to be completely amorphous. Highest physical storage stability of 7 months up to now was obtained for the 25% filled sample. In the next step, concept of increased saturation solubility for smartPearls was proven. Dissolution profiles were recorded in situ for glabridin smartPearls and compared to glabridin raw drug powder. Both saturation solubility and dissolution velocity were remarkably improved. The water solubility for example increased by a factor of more than 4. This makes glabridin smartPearls promising for creating skin products with improved dermal bioavailability.

smartPearls - Novel physically stable amorphous delivery system for poorly soluble dermal actives.

Dermally applied poorly soluble actives whether in cosmetics or pharmaceuticals show insufficient skin penetration. Especially actives being insoluble in both phases of dermal vehicles, i.e. water and oil have no or less real effect. An approach to overcome this obstacle is the use of amorphous actives instead of the crystalline ones. The higher saturation solubility creates an increased concentration gradient between the formulation and skin. Thus, the diffusive flux into the skin is improved. However, the amorphous state of actives is highly labile, and the durability of such formulations would be too short for a marketable product. smartPearls is a novel technology efficiently long-term stabilize the amorphous state. They consist of µm sized particles with mesopores (e.g. silica: SYLOID®, AEROPERL®, Neusilin®), in which the active can be loaded and preserved in amorphous state. Due to the tightness of the pores, not enough space is given for re-crystallization. In this work, the skin penetration of poorly soluble actives loaded in smartPearls is compared to the present "gold standards" in dermal delivery, e.g. amorphous microparticles, amorphous nanoparticles and nanocrystals. The performance was at least similar or even better than the gold standards, explainable by the increased saturation solubility of active due to a) amorphous state and b) nanostructure inside the µm-sized particles. Sedimentation investigations showed, that the physical stabilization of very dense smartPearls in semi-solid vehicles is possible by viscoelastic repulsion. Also, the technical, regulatory and marketing aspects for the use of smartPearls technology in products are discussed, e.g. status of excipients used, and advantages of not being a nanoparticle, but being as efficient as them. Overall, smartPearls proved to be a promising dermal delivery technology for poorly soluble actives with a high market potential.

Dermal miconazole nitrate nanocrystals - formulation development, increased antifungal efficacy & skin penetration.

Miconazole nitrate nanosuspension was developed to increase its antifungal activity and dermal penetration. In addition, the nanosuspension was combined with the synergistic additive chlorhexidine digluconate. The production was performed by wet bead milling and both production and formulation parameters were optimized. A stabilizer screening revealed poloxamer 407 and Tween 80 both at 0.15% as the most effective stabilizers for miconazole nanosuspensions at 1.0%. The nanocrystals were incorporated into a hydroxypropyl cellulose gel base. Short-term stability (3months) of the nanocrystal bulk population could be shown at room temperature and fridge. Besides the stable bulk nanocrystals, some longitudinal crystal growth to needle like crystals occurred. The addition of ionic compounds as the chlorhexidine digluconate often destabilizes suspensions. Surprisingly here, the addition minimized the crystal growth. An underlying mechanism is proposed. An inhibition zone assay was performed using Candida albicans (ATCC® 10231™). When comparing the nanocrystals in suspension and in gel to µm-sized miconazole nitrate formulations and two market products, the increase in inhibition zone diameter for the nanosuspension formulations was most pronounced in the chlorhexidine digluconate free formulations. These nanocrystal formulations were closely or similarly effective as the microsuspensions and the market products containing the synergistic chlorhexidine digluconate, showing the potential of the nanosuspension formulation. Nanosuspension performance was even further increased when chlorhexidine digluconate was added. Ex-vivo skin penetration studies on porcine ears revealed distinctly less remaining miconazole nitrate on the skin surface for nanocrystals (e.g., 76-86%) compared to market products (e.g. 94%). Also, penetration was increased e.g. in skin depth of 5-10µm from <1.0/1.7% to e.g. 3.3-6.2% for nanocrystals.