Can the cavi-precipitation process be exploited to generate smaller size drug nanocrystal?

OBJECTIVE: Cavi-precipitation has the potential to generate drug nanocrystals very efficiently. Achieving smaller than 100 nm particle size for organic drug substances still remained a challenge. The objective of this study was to demonstrate if cavi-precipitation technology can be used to generate smaller than 100 nm drug nanocrystal particle. SIGNIFICANCE: This study demonstrates that cavi-precipitation process can be used to generate drug nanocrystals of the model compound resveratrol (RVT) consists of crystallites of 30-50 nm size. METHOD: RVT was dissolved in different organic solvents to prepare the solvent phase (S-phase). Several stabilizers were tested for the organic phase. A combination of SDS and PVP was used stabilizer system in the aqueous anti-solvent phase (AS-phase). The S-phase was added to the AS-phase inside the Emulsiflex C5 homogenizer. Nanosuspension was characterized by laser diffractometry (LD), photon correlation spectroscopy (PCS) and scanning electron microscopy (SEM). The solid state of the suspended particles was investigated by powder X-ray diffractometry (PXRD) and differential scanning calorimetry (DSC). RESULTS: It was found that DMSO, alone or in combination with acetone in the S-Phase generated the smallest size RVT nanocrystals. The optimum solvent (S) antisolvent (AS) ratio (S:AS) was found to be 3.6:56.4 (v:v). Span 20 was identified as the best stabilizer for the organic phase at a ratio (w:w) of 1:3 (Span 20:RVT). The particles precipitated from different solvents were predominantly crystalline. CONCLUSIONS: The best sample had a mean particle size (LD) of 167 nm [d(0.5)] which was composed of smaller crystallites having 30-50 nm size (SEM).

Production of drug nanosuspensions: effect of drug physical properties on nanosizing efficiency.

OBJECTIVE: Drug nanosuspension is one of the established methods to improve the bioavailability of poorly soluble drugs. Drug physical properties aspect (morphology, solid state, starting size et al) is a critical parameter determining the production efficiency. Some drug modification approaches such as spray-drying were proved to improve the millability of drug powders. However, the mechanism behind those improved performances is unclear. This study is to systematically investigate the influence of those physical properties. METHODS: Five different APIs (active pharmaceutical ingredients) with different millabilities, i.e. resveratrol, hesperetin, glibenclamide, rutin, and quercetin, were processed by standard high pressure homogenization (HPH), wet bead milling (WBM), and a combinative method of spray-drying and HPH. RESULTS: Smaller starting sizes of certain APIs could accelerate the particle size reduction velocity during both HPH and WBM processes. Spherical particles were observed for almost all spray-dried powders (except spray-dried hesperetin) after spray-drying. The crystallinity of some spray-dried samples such as rutin and glibenclamide became much lower than their corresponding unmodified powders. Almost all spray-dried drug powders after HPH processes could lead to smaller nanocrystal particle size than unmodified APIs. CONCLUSION: The modified microstructure instead of solid state after spray-drying explained the potential reason for improved nanosizing efficiency. In addition, the contribution of starting size on the production efficiency was also critical according to both HPH and WBM results.

Solidification of hesperidin nanosuspension by spray drying optimized by design of experiment (DoE).

OBJECTIVE: To accelerate the determination of optimal spray drying parameters, a "Design of Experiment" (DoE) software was applied to produce well redispersible hesperidin nanocrystals. SIGNIFICANCE: For final solid dosage forms, aqueous liquid nanosuspensions need to be solidified, whereas spray drying is a large-scale cost-effective industrial process. METHODS: A nanosuspension with 18% (w/w) of hesperidin stabilized by 1% (w/w) of poloxamer 188 was produced by wet bead milling. The sizes of original and redispersed spray-dried nanosuspensions were determined by laser diffractometry (LD) and photon correlation spectroscopy (PCS) and used as effect parameters. In addition, light microscopy was performed to judge the redispersion quality. RESULTS: After a two-step design of MODDE 9, screening model and response surface model (RSM), the inlet temperature of spray dryer and the concentration of protectant (polyvinylpyrrolidone, PVP K25) were identified as the most important factors affecting the redispersion of nanocrystals. As predicted in the RSM modeling, when 5% (w/w) of PVP K25 was added in an 18% (w/w) of hesperidin nanosuspension, subsequently spray-dried at an inlet temperature of 100 °C, well redispersed solid nanocrystals with an average particle size of 276 nm were obtained. By the use of PVP K25, the saturation solubility of the redispersed nanocrystals in water was improved to 86.81 µg/ml, about 2.5-fold of the original nanosuspension. In addition, the dissolution velocity was accelerated. CONCLUSIONS: This was attributed to the additional effects of steric stabilization on the nanocrystals and solubilization by the PVP polymer from spray drying.

Systematical investigation of a combinative particle size reduction technology for production of resveratrol nanosuspensions.

Nanosizing is frequently used as formulation approach to increase the bioavailability of poorly water-soluble drugs. However, standard size reduction processes can be relatively time-consuming. It was found that the modification of the physical properties of a starting material by means of spray-drying can be used to improve the effectiveness of a subsequently performed high pressure homogenization. Such a process belongs to the combinative particle size reduction methods and is also referred to as H 42 process. Based on previous studies, it was hypothesized that the improved efficiency was a result of reduced crystallinity of the modified drug. The present study was conducted in order to asses this hypothesis in a systematical manner by applying design of experiment (DoE) principles. Resveratrol was selected as model compound for this study. It was processed by both standard high pressure homogenization and by a combinative particle size reduction process (the H42 process). An optimized resveratrol/surfactant ratio for the spray-dried intermediate was identified by using the response-surface methodology. The optimization led to a nanosuspension with a mean particle size of 192 nm, which is much smaller than the mean particle size of 569 nm when standard high pressure homogenization was used. Both predominately crystalline and predominately amorphous solids resulted from the spray-drying process. In contrast to the initial hypothesis, the smallest particle sizes were achieved by processing predominately crystalline intermediate with high pressure homogenization.

Effect of four different size reduction methods on the particle size, solubility enhancement and physical stability of nicergoline nanocrystals.

Nicergoline, a poorly soluble active pharmaceutical ingredient, possesses vaso-active properties which causes peripheral and central vasodilatation. In this study, nanocrystals of nicergoline were prepared in an aqueous solution of polysorbate 80 (nanosuspension) by using four different laboratory scale size reduction techniques: high pressure homogenization (HPH), bead milling (BM) and combination techniques (high pressure homogenization followed by bead milling HPH + BM, and bead milling followed by high pressure homogenization BM + HPH). Nanocrystals were investigated regarding to their mean particles size, zeta potential and particle dissolution. A short term physical stability study on nanocrystals stored at three different temperatures (4, 20 and 40 °C) was performed to evaluate the tendency to change in particle size, aggregation and zeta potential. The size reduction technique and the process parameters like milling time, number of homogenization cycles and pressure greatly affected the size of nanocrystals. Among the techniques used, the combination techniques showed superior and consistent particle size reduction compared to the other two methods, HPH + BM and BM + HPH giving nanocrystals of a mean particle size of 260 and 353 nm, respectively. The particle dissolution was increased for any nanocrystals samples, but it was particularly increased by HPH and combination techniques. Independently to the production method, nicergoline nanocrystals showed slight increase in particle size over the time, but remained below 500 nm at 20 °C and refrigeration conditions.

Trehalose is not a universal solution for solid lipid nanoparticles freeze-drying.

OBJECTIVE: To prepare stable and easy to handle formulation of solid lipid nanoparticles (SLNs) by freeze-drying with or without cryoprotectants, as appropriate. MATERIALS AND METHODS: SLNs were freeze-dried without cryoprotectants or with cryoprotectants in quantities selected by freeze-thaw test (sucrose, glucose) or literature search (trehalose, maltose). Appearance, re-dispersability and size distribution of re-dispersed samples were evaluated. RESULTS: SLN could be freeze-dried using 10% sucrose, trehalose or maltose. Trehalose was effective in protecting one of presented formulations that was already very stable on its own; its efficiency in protecting other two formulations was limited. DISCUSSION: Our results are in line with various reports of successful freeze-drying of SLN, but considering the stability of original dispersions, no improvement was achieved. CONCLUSION: We confirmed that trehalose is among the most suitable cryoprotectant for SLN, however it did not improve shelf-life of the most stable formulation.

Factors influencing the release kinetics of drug nanocrystal-loaded pellet formulations.

CONTEXT: This article discusses the downstream processing of nanosuspensions into oral solid dosage forms. OBJECTIVE: Various factors influencing the release kinetics of various pellet formulations containing drug nanocrystals have been evaluated. The effects of binder types, drug content and pellet type on the in-vitro dissolution profiles were investigated. MATERIALS AND METHODS: Hydrocortisone acetate (HCA) was nanosized by using a piston gap homogenizer Micron Lab 40. The nanosuspension was admixed to various binder solutions based on chitosan chloride, polyvinyl alcohol, hydroxypropyl methylcellulose or polyvinylpyrrolidone (PVP) and sprayed on sugar beads using fluidized bed coating. For comparison, matrix cores have also been prepared using the extrusion-spheronization process. An enteric top coating was applied onto both pellet types. All pellet formulations have been tested In in-vitro dissolution studies. RESULTS AND DISCUSSION: HCA nanosuspensions were compatible with all binders tested except for PVP. Various suspensions could be successfully transferred into spray coated pellets as well as matrix cores including a top coating. The different binder types have influenced the stability of the nanosuspensions, the zeta potential of the drug nanocrystals as well as the dissolution profiles of the final solid dosage forms. CONCLUSION: Nanosuspensions can be easily processed into various pellet formulations. Spray coating with water-soluble binders is recommended for high dose drugs. This technology is also more variable with respect to the drug load In the final dosage form. Matrix cores can be beneficial for highly water-insoluble formulations, especially when only relatively low doses are needed.

The use of hot and cold high pressure homogenization to enhance the loading capacity and encapsulation efficiency of nanostructured lipid carriers for the hydrophilic antiretroviral drug, didanosine for potential administration to paediatric patients.

A major obstacle to the application of nanostructured lipid carriers (NLCs) as carriers for hydrophilic drugs is the limited loading capacity (LC) and encapsulation efficiency (EE) of NLCs for these molecules. The purpose of this research was to design and implement a strategy to enhance the LC and EE of NLCs for the hydrophilic drug, didanosine (DDI). DDI was dispersed in Transcutol(®) HP and the particle size of DDI in the liquid lipid was reduced gradually using hot high pressure homogenization (HPH). The product obtained thereafter was added to Precirol(®) ATO 5 and the hot mixture was immediately dried using liquid nitrogen. The dried materials were then ground and passed through a 200 µm sieve and the solid lipid particles were dispersed in a surfactant solution and subsequently used to manufacture DDI-loaded NLCs using cold HPH. The LC and EE of NLCs for DDI manufactured using the new strategy were 3.39 ± 0.63% and 51.58 ± 1.31%, respectively, compared to 0.079 ± 0.001% and 32.45 ± 0.08%, respectively, obtained when DDI-loaded NLCs were produced using conventional hot HPH. The enhanced LC and EE for DDI make NLCs a potential technology for the oral administration of DDI to paediatric patients.

In vitro protein adsorption studies on nevirapine nanosuspensions for HIV/AIDS chemotherapy.

Nevirapine is a poorly water-soluble antiretroviral drug. Intravenous nevirapine nanosuspensions (NS) (457 ± 10 nm) were prepared by high-pressure homogenization. NS were surface modified by stabilizer adsorption, e.g., serum albumin, polysaccharide and polyethylene glycol (PEG) 1000. The NS were characterized for mean particle size, particle size distribution and polydispersity index. The targeting potential of the nonmodified and three surface-modified NS to the mononuclear phagocytic system (MPS) cells that serve as potent viral reservoirs was assessed by in vitro protein adsorption studies using two-dimensional polyacrylamide gel electrophoresis (2-D PAGE). The adsorption patterns were qualitatively identical, but showed quantitative differences. The relatively adsorbed high amounts of immunoglobulins indicate uptake by liver and spleen, observed quantitative differences (e.g., the amount of dysopsonin albumin and apolipoproteins) can modulate the organ distribution. Controlled in vitro optimization of the protein adsorption by surface modification of the nanocrystals can reduce the number of animals required for in vivo studies and accelerate development of targeted nanoparticles. FROM THE CLINICAL EDITOR: In this study, intravenous nevirapine (a poorly water-soluble antiretroviral drug) nanosuspensions were prepared by high-pressure homogenization and characterized.

Evaluation of the in vitro differential protein adsorption patterns of didanosine-loaded nanostructured lipid carriers (NLCs) for potential targeting to the brain.

The preferential in vitro adsorption of apolipoprotein E (Apo E) onto the surface of colloidal drug carriers may be used as a strategy to evaluate the in vivo potential for such systems to transport drugs to the brain. The aim of this research was to investigate the in vitro protein adsorption patterns of didanosine-loaded nanostructured lipid carriers (DDI-NLCs), using two-dimensional polyacrylamide gel electrophoresis (2-D PAGE), in order to establish the potential for NLCs to deliver DDI to the brain. NLC formulations were manufactured using high-pressure homogenization using a lipid matrix consisting of a mixture of Precirol(®) ATO 5 and Transcutol(®) HP. The 2-D PAGE analysis revealed that NLCs in formulations stabilized using Solutol(®) HS 15 alone or with a ternary surfactant system consisting of Solutol(®) HS 15, Tween(®) 80, and Lutrol(®) F68, preferentially adsorbed proteins, such as Apo E. Particles stabilized with Tween(®) 80 and Lutrol(®) F68 did not adsorb Apo E in these studies, which could be related to the relatively large particle size and hence small surface area observed for these NLCs. These findings have revealed that DDI-loaded NLCs may have the potential to deliver DDI to the brain in vivo and, in addition, to Tween(®) 80, which has already been shown to have the ability to facilitate the targeting of colloidal drug delivery systems to the brain. Solutol(®) HS 15-stabilized nanoparticles may also achieve a similar purpose.

Formulation development and in vitro evaluation of didanosine-loaded nanostructured lipid carriers for the potential treatment of AIDS dementia complex.

The purpose of this article was to investigate the feasibility of incorporating didanosine (DDI) into nanostructured lipid carriers (NLC) for potential treatment of AIDS dementia complex. Aqueous DDI-free and DDI-loaded NLC were manufactured using hot high-pressure homogenization. The lipid matrix contained a mixture of Precirol® ATO 5 and Transcutol® HP. Photon correlation spectroscopy revealed that the mean particle size for all formulations was below 250 nm with narrow polydispersity indices. In addition, the d99% values for all formulations determined using laser diffractometry were below 400 nm with the span values ranging from 0.84 to 1.0. The zeta potential values ranged from -18.4 to -11.4 mV and the encapsulation efficiency of NLC for DDI ranged from 33.02% to 78.34%. These parameters remained relatively constant for all formulations tested following storage for 2 months at 25°C indicating that all the formulations were relatively stable. Differential scanning calorimetry revealed a decrease in the degree of crystallinity of NLC in all formulations developed relative to the bulk lipid material. In addition, wide-angle X-ray scattering showed that NLC in all formulations tested existed in a single ß-modification form and that DDI that had been incorporated into the NLC appeared to be molecularly dispersed in the lipid matrices. Images of the NLC formulations obtained using transmission electron microscopy revealed that all formulations contained a mixture of spherical and nonspherical particles irrespective of the amount of DDI that was added during the manufacture of the formulations.

Sub-50 nm ultra-small organic drug nanosuspension prepared by cavi-precipitation and its brain targeting potential.

The purpose of this study was to show whether it is possible to prepare sub 100 nm or preferably sub-50 nm drug nanosuspension (NS) of suitable quality for intravenous administration. Furthermore, we have studied how the brain targeting potential of such small size organic NS differs from relatively bigger size NS. Two combination technologies (cavi-precipitation, H96) and a standard high-pressure homogenization (HPH) technology were used to prepare drug NS of different sizes. The cavi-precipitation process generated the smallest AmB NS, i.e., 27 nm compared to 79 nm by H96 technology and 252 nm by standard HPH technology. Dialysis of the nanosuspension in the original dispersion media was found to be the most efficient solvent removal method without negatively affecting particle size. The removal of organic solvent was found to drastically improve the stability of the formulations. The protein adsorption pattern shows that the small size NS particles obtained by the cavi-precipitation process have the potential to circulate longer in the bloodstream and have the potential to be taken up by the blood-brain barrier. The cavi-precipitation process generated ultrafine NS particles, which fulfilled the quality requirements for intravenous administration and offer a potential solution for brain targeting.

Lipid nanoparticles: effect on bioavailability and pharmacokinetic changes.

The main aim of pharmaceutical technology research is the design of successful formulations for effective therapy, taking into account several issues including therapeutic requirements and patient compliance. In this regard, several achievements have been reported with colloidal carriers, in particular with lipid nanoparticles, due to their unique physicochemical properties. For several years these carriers have been showing potential success for several administration routes, namely oral, dermal, parenteral, and, more recently, for pulmonary and brain targeting. The present chapter provides a review of the use of solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) to modify the release profile and the pharmacokinetic parameters of active pharmaceutical ingredients (APIs) incorporated in these lipid matrices, aiming to modify the API bioavailability, either upwards or downwards depending on the therapeutic requirement. Definitions of the morphological characteristics, surface properties, and polymorphic structures will also be given, emphasizing their influence on the incorporation parameters of the API, such as yield of production, loading capacity, and encapsulation efficiency.

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.

Formulation development of lipid nanoparticles: Improved lipid screening and development of tacrolimus loaded nanostructured lipid carriers (NLC).

Lipid nanoparticles are well-known nanocarriers for improved drug delivery. Their formulation development typically involves three formulations steps. In the first part a suitable lipid mixture which enables a high loading capacity and high encapsulation efficacy of the active needs to be identified (lipid screening). In the second step suitable stabilizers that enable the production of small-sized lipid nanoparticles with narrow size distribution and sufficient physical stability need to be identified (stabilizer screening, optimization of production parameters) and in the third step the biopharmaceutical efficacy needs to be evaluated. Based on the results obtained the formulations will require further optimization. The classical formulation development of lipid nanoparticles and especially the classical lipid screening is tedious. Therefore, in this study, a novel approach for the lipid screening that was based on the determination of the Hansen solubility parameters was evaluated and the results obtained were compared to the results from the classical model. Tacrolimus was used as a model drug. Results showed that both lipid screenings led to similar results, indicating that the new approach can be used for future developments. The optimized formulation was composed of a lipid matrix system that contained waxes, triglycerides and monoacylglycerols with various carbon chain lengths (C8, C10, C16, C18) and enabled an encapsulation efficiency of ~99%. The stabilizer screening showed that surfactants with high HLB values, lower molecular weight, and shorter alkyl chain length tended to form smaller particles with narrower size distribution and better physical stability. The most suitable surfactant was found to be a caprylyl/capryl glucoside (Plantacare® 810), a PEG-free stabilizer, that is extremely mild for atopic skin. It led to particle sizes of about 200 nm and a zeta potential well above |30| mV. The optimized formulation contained 0.1% tacrolimus and possessed good physical stability. In conclusion, an optimized method for the selection of lipids that results in a limited number of experiments could be established and tacrolimus loaded lipid nanoparticles with similar drug load as a marketed formulation was successfully developed in this study.

Secretory phospholipase A2 inhibitor PX-18 preserves microvascular reactivity after cerebral ischemia in piglets.

Cerebral ischemia/reperfusion (I/R) results in cellular energy failure and dysfunction of the neurovascular unit that contribute to subsequent neuronal cell death in the neonate. PX-18 is a putative neuroprotective inhibitor of secretory phospholipase A(2) (sPLA(2)) but its in vivo testing has been limited by its poor solubility. Our purpose was to assess whether PX-18 preserved neuronal-vascular reactivity to I/R-sensitive endothelium-dependent (hypercapnia, bradykinin) and/or neuron-dependent (N-methyl-D-aspartate; NMDA) stimuli. To make the drug available for in vivo studies, PX-18 was formulated as a 3% nanosuspension applying high pressure homogenization. Newborn piglets (1-day old, n=40) were anesthetized and ventilated, and cerebrovascular reactivity to the above stimuli was determined by measuring changes in pial arteriolar diameters using the closed cranial window/intravital videomicroscopy technique. Intravenous infusion of PX-18 nanosuspension (6 mg/kg, 20 min) did not affect baseline arteriolar diameters, or hypercapnia-, bradykinin-, or NMDA-induced pial arteriolar vasodilation under normoxic conditions. Global cerebral ischemia (10 min) followed by 1 h of reperfusion significantly attenuated hypercapnia-, bradykinin-, and NMDA-induced vasodilation in untreated or vehicle-treated controls. However, PX-18 resulted in nearly full preservation of cerebrovascular reactivity to all these stimuli. In conclusion, inhibition of sPLA(2) by PX-18 improves neurovascular function both at the neuronal and the microvascular level following I/R. This effect of PX-18 likely contributes to its neuroprotective effect.

Lipid nanoparticles (SLN, NLC) in cosmetic and pharmaceutical dermal products.

Solid lipid nanoparticles (SLN) are distinguishable from nanostructured lipid carriers (NLC) by the composition of the solid particle matrix. Both are an alternative carrier system to liposomes and emulsions. This review paper focuses on lipid nanoparticles for dermal application. Production of lipid nanoparticles and final products containing lipid nanoparticles is feasible by well-established production methods. SLN and NLC exhibit many features for dermal application of cosmetics and pharmaceutics, i.e. controlled release of actives, drug targeting, occlusion and associated with it penetration enhancement and increase of skin hydration. Due to the production of lipid nanoparticles from physiological and/or biodegradable lipids, this carrier system exhibits an excellent tolerability. The lipid nanoparticles are a "nanosafe" carrier. Furthermore, an overview of the cosmetic products currently on the market is given and the improvement of the benefit/risk ratio of the topical therapy is shown.

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 - 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.

Phenylethyl resorcinol smartLipids for skin brightening - Increased loading & chemical stability.

Phenylethyl resorcinol (PER, 4-(1-phenylethyl)1,3-benzenediol) is a very potent tyrosinase inhibitor with clinically proven effectiveness at already 0.5%. A major challenge of incorporating PER into dermal products is its high sensitivity against light. Previously, by incorporating PER in nanostructured lipid carriers (NLC), chemical stability and tyrosinase activity could be increased by 29% and 67%, respectively. Despite this, degradation still occurred accompanied with reddish discoloration of the formulation - not acceptable for market products. In this study PER was incorporated into smartLipids, the 3rd generation of lipid carriers. Compared to NLC, the smartLipids formulation had a higher PER loading, was PEG-free and used ECOCERT-certified Lanette N. For PER stabilization, 14 additives from three groups were investigated: UV blockers, antioxidants and chelating agents. The UV blockers Tinosorb S and Oxynex ST liquid, as well as the chelating agents ethylenediaminetetraacetic acid and phytic acid completely prevented reddish discoloration under test conditions (3 months in the dark and 7 days at light exposure). Investigating the stabilizing mechanisms, UV absorbers with high absorption in UV-A range were most effective (Tinosorb S, Oxynex liquid). They showed good stabilization in dark and at light exposure. Chelating agents had mainly an effect via pH shift to pH 2, thus are not suitable for dermal products requiring pH around 5. Antioxidants were less effective. The antioxidants propyl gallate and BHT showed best stabilization at storage in dark and slightly less at light exposure, not impairing the physical stability. Some antioxidants even accelerated discoloration (e.g. Tinogard TT). In general, low standard electrode potential (<0.4 mV) seems to be favorable for PER stabilization. In conclusion, Tinosorb S proved to be the best stabilizer; combination with an antioxidant is optional. By combination of smartPearls technology and the Tinosorb S stabilization, PER market products without discoloration are feasible.