Search Results (40)

Nanocrystals, defined as crystalline particles with dimensions in the nanometer range (<1000 nm), exhibit unique properties that enhance the efficacy of poorly soluble active compounds. This review explores the fundamental aspects of nanocrystals, including their characteristics and various preparation methods, while addressing critical factors that influence their stability and incorporation into final products. A key focus of the review is the advantages offered by nanocrystals in dermal applications. It also highlights their ability to enhance passive diffusion into the skin and facilitate penetration via particle-assisted dermal penetration. Additionally, the review discusses their capacity to penetrate into hair follicles, enabling targeted drug delivery, and their synergistic potential when combined with microneedles, which further enhance the dermal absorption of active compounds. The review also addresses several commercial products that successfully employ nanocrystal technology, showcasing its practical applications. Summary: Nanocrystals with their special properties are an emerging trend for dermal applications, particularly the development of plantCrystals—natural nanocrystals sourced from plant materials—which represent a promising path for future research and formulation strategies. These advancements could lead to more sustainable and effective dermal products. Full article

Background/Objective: This study provided a comparison of the influence of each component of the microemulsion formulation and investigated the impact of varying concentrations of the microemulsion components on curcumin’s ability to penetrate the skin using an ex vivo porcine ear model. Methods: Curcumin microemulsions with different compositions were prepared and analyzed for their physicochemical properties. The dermal penetration efficacy of curcumin was evaluated from the different formulations and compared with non-microemulsion formulations. Results: Findings proved that microemulsion formulations improve the dermal penetration efficacy for curcumin when compared with non-microemulsion formulations. The composition of the microemulsion affects the penetration efficacy of curcumin and increases with decreasing oil content and increasing surfactant and water content. The best penetration for curcumin is achieved with a microemulsion that contained 7.7 g of medium-chain triglycerides as the oil phase, 6.92 g of Tween^® 80 and 62.28 g of ethanol as the surfactant mixture, and 23.1 g water. Conclusions: The present study provides a foundational basis for further development of different microemulsion formulations for enhancing the dermal penetration of poorly water-soluble active compounds. Full article

(1) Background: Ethanol is a multifunctional excipient often used as a preservative in topical formulations. Due to its known ability to impair skin barrier function, this study investigated the effect of ethanol (EtOH) as a preservative in creams on the dermal penetration of active compounds. (2) Methods: A hydrophilic and a lipophilic fluorescent dye were used as active ingredient surrogates that were incorporated into creams with and without ethanol. The dermal penetration efficacy was assessed by epifluorescence microscopy on an ex vivo porcine ear model with intact and irritated skin. (3) Results: Ethanol reduced the dermal penetration by about 40% for the hydrophilic and about 20% for the lipophilic surrogates on intact skin, but had minimal impact on irritated skin. The bio-physical skin properties were also altered by the addition of ethanol to the cream. On intact skin, it increased transepidermal water loss (TEWL) and decreased skin hydration, whereas on irritated skin, it decreased TEWL and increased skin hydration. The results indicate that skin impairment can be considered to have different stages, while in an early stage of skin impairment, the formation of a “Pudding skin” is proposed. A “Pudding skin” is the formation of a thin layer of dried skin on top of the skin that “seals” the lower parts of the skin and reduces dermal penetration and water loss from inside the skin and reduces the dermal penetration of chemical compounds from outside the skin. (4) Conclusions: Overall, the findings emphasize the need to carefully consider the use of ethanol in formulations, balancing its preservative benefits with its potential to impair the efficacy of active ingredients, particularly in varying skin conditions. Full article

Dermal drug delivery presents a significant challenge for poorly soluble active compounds like curcumin, which often struggle to penetrate the skin barrier effectively. In this study, the dermal penetration efficacy of curcumin nanocrystals and bulk suspensions when applied to skin using microneedles of varying lengths—0.25 mm, 0.5 mm, and 1.0 mm—was investigated in an ex vivo porcine ear model. The findings revealed that all formulations, in conjunction with microneedle application, facilitated transepidermal penetration; however, the combination of microneedles and curcumin nanocrystals demonstrated the highest efficacy. Notably, the 1.0 mm microneedle length provided optimal penetration, significantly enhancing curcumin delivery compared with bulk suspensions alone. Additionally, even the use of 0.25 mm microneedles resulted in a high level of efficiency, indicating that shorter microneedles can still effectively facilitate drug delivery. Overall, this study underscores the potential of microneedle technology in improving the transepidermal absorption of poorly soluble actives like curcumin, suggesting that the integration of nanocrystals with microneedles could enhance the therapeutic effects of topical curcumin applications. Full article

The limited water solubility of active compounds remains a significant challenge for efficient dermal drug delivery, particularly for BCS class IV drugs such as curcumin. This study aimed to enhance curcumin’s dermal penetration using two strategies: extracellular vesicles (EVs) and plantCrystals derived from soybeans. EVs were isolated using classical methods. However, plantCrystals containing extracellular vesicles (PCEVs) were formed during the preparation of plantCrystals through bead milling. Curcumin was either added after PCEVs were formed, resulting in curcumin-added PCEVs, or added to the soybean dispersion before bead milling, forming curcumin-loaded PCEVs. The formulations were characterized for their physicochemical properties and assessed for dermal penetration efficacy using quantitative dermatokinetic and semi-quantitative ex vivo porcine ear models. The results indicated that curcumin-loaded PCEVs achieved higher penetration efficacy compared to curcumin-added PCEVs and curcumin-loaded EVs, with approximately 1.5-fold and 2.7-fold increases in penetration efficacy, respectively. Additionally, curcumin-loaded PCEVs showed superior penetration depth, while curcumin from the curcumin-loaded EVs remained in the stratum corneum. These findings suggest that the plantCrystals strategy via bead milling offers a more effective approach than the classical EVs strategy for improving the topical delivery of class IV drugs like curcumin. Full article

Objective: This study aimed to investigate the feasibility of using the digital image processing technique, developed to semi-quantitatively study dermal penetration, to study corneal penetration in an ex vivo porcine eye model. Here, we investigated various formulation strategies intended to enhance dermal and corneal bioavailability of the model hydrophobic drug, curcumin. Methods: Several formulation principles were explored, including oily solutions, oily suspensions, aqueous nanosuspension, micelles, liposomes and cyclodextrins. The dermal penetration efficacy was tested using an ex vivo porcine ear model previously developed at Philipps-Universität Marburg with subsequent digital image processing. This image analysis method was further applied to study corneal penetration using an ex vivo porcine whole-eye model. Results: For dermal penetration, oily solutions, oily suspensions and nanosuspensions exhibited the least penetration, whereas liposomes and cyclodextrins showed enhanced penetration. Corneal curcumin penetration correlated with dermal penetration, with curcumin loaded into cyclodextrins penetrating the deepest. Conclusions: Overall, our study suggests that the image analysis method previously developed for ex vivo skin penetration can easily be repurposed to study corneal penetration of hydrophobic drugs. Full article

The influence of size, particle concentration and applied dose (finite vs. infinite dose) on the dermal penetration efficacy of curcumin was investigated in this study. For this, curcumin suspensions with different particle sizes (approx. 20 µm and approx. 250 nm) were produced in different concentrations (0.625–5% (w/w)). The dermal penetration efficacy was determined semi-quantitatively on the ex vivo porcine ear model. The results demonstrated that the presence of particles increases the dermal penetration efficacy of the active compounds being dissolved in the water phase of the formulation. The reason for this is the formation of an aqueous meniscus that develops between particles and skin due to the partial evaporation of water from the vehicle after topical application. The aqueous meniscus contains dissolved active ingredients, and therefore creates a small local spot with a locally high concentration gradient that leads to improved dermal penetration. The increase in penetration efficacy depends on the number of particles in the vehicle, i.e., higher numbers of particles and longer contact times lead to higher penetration efficacy. Therefore, nanocrystals with a high particle concentration were found to be the most suitable formulation principle for efficient and deep dermal penetration of poorly water-soluble active ingredients. Full article

(1) Background: Amorphous drug systems are an intensively studied approach to overcome the insufficient bioavailability of poorly soluble drugs. Here, paper tablets were studied, which were made from cellulose-based paper matrices loaded with norfloxacin. Moreover, wet granulation was introduced as an additional processing step for improving the flowability of the solids, which is necessary when considering production on an industrial scale. (2) Methods: The possible impact of the wet granulation on the crystallinity of norfloxacin was studied by examining granulated and non-granulated samples. Crystallinity investigations were performed using X-ray powder diffraction (XRD) and terahertz time-domain spectroscopy (THz TDS). (3) Results: THz TDS allowed for a more straightforward crystallinity assessment than XRD. Moreover, using THz TDS, it was possible to detect minor changes in the crystallinity of the API after the granulation, whereas this was not possible with the XRD analysis. (4) Conclusions: THz TDS results indicate a partial crystallization of norfloxacin due to the wet granulation. Depending on the formulation, THz TDS can serve as a beneficial and advantageous tool to determine the crystallinity of an API. Full article

Curcumin is a biopharmaceutical classification system (BCS) class IV substance with many potential therapeutic effects. However, like many other BCS IV active pharmaceutical ingredients, complex formulations are needed to guarantee a sufficiently high bioavailability. A not-so-well-known delivery system is a suspoemulsion (SE). SEs are emulsions with a crystalline API in continuous or dispersed phases. This study aimed to produce curcumin-loaded o/w suspoemulsions with the particle in the oil phase for, e.g., encapsulation or triggered release effects. The particles need to be smaller than the emulsion droplet size to attain high encapsulation efficiencies (EE) in the oil phase. Sonofragmentation and bead milling were tested for their ability to produce these nanocrystals in different dispersion media. It was discovered that production in miglyol was the best fit for the needed application of the crystals in SEs. Around 85% (by volume) of the particles produced with bead milling were smaller than the droplet size of about 5 µm. In contrast, only 23% of the sonofragmentated particles were below the diameter of those droplets. This oily suspension was then used to successfully produce hydrogel-based o/w suspoemulsions. In the second part of this study, we investigated different methods for determining encapsulation efficiency, but none of the methods accurately and satisfactorily resolved the encapsulation efficiency. Finally, the suspoemulsions could not be macroscopically distinguished from one another and were physically stable. In summary, we showed that stable hydrogel-based curcumin-loaded o/w suspoemulsions could be produced. Full article

Hair follicles constitute important drug delivery targets for skin antisepsis since they contain ≈25% of the skin microbiome. Nanoparticles are known to penetrate deeply into hair follicles. By massaging the skin, the follicular penetration process is enhanced based on a ratchet effect. Subsequently, an intrafollicular drug release can be initiated by various trigger mechanisms. Here, we present novel ultraviolet A (UVA)-responsive nanocapsules (NCs) with a size between 400 and 600 nm containing hydroxyethyl starch (HES) functionalized by an o-nitrobenzyl linker. A phase transfer into phosphate-buffered saline (PBS) and ethanol was carried out, during which an aggregation of the particles was observed by means of dynamic light scattering (DLS). The highest stabilization for the target medium ethanol as well as UVA-dependent release of ethanol from the HES-NCs was achieved by adding 0.1% betaine monohydrate. Furthermore, sufficient cytocompatibility of the HES-NCs was demonstrated. On ex vivo porcine ear skin, a strong UVA-induced release of the model drug sulforhodamine 101 (SR101) could be demonstrated after application of the NCs in cyclohexane using laser scanning microscopy. In a final experiment, a microbial reduction comparable to that of an ethanol control was demonstrated on ex vivo porcine ear skin using a novel UVA-LED lamp for triggering the release of ethanol from HES-NCs. Our study provides first indications that an advanced skin antisepsis based on the eradication of intrafollicular microorganisms could be achieved by the topical application of UVA-responsive NCs. Full article

(1) Background: Many drugs possess poor bioavailability, and many strategies are available to overcome this issue. In this study, smartFilm technology, i.e., a porous cellulose matrix (paper), in which the active compound can be loaded onto in an amorphous state was utilised for oral administration to improve the solubility and bioactivity of a poorly soluble BSC class IV antibiotic. (2) Methods: Norfloxacin was used as the model drug and loaded into commercially available paper. The resulting norfloxacin-loaded smartFilms were transformed into smartFilm granules via wet granulation and the resulting norfloxacin-loaded smartFilm granules were transformed into norfloxacin-loaded tablets made from paper, i.e., smartFilm tablets. The crystalline state of norfloxacin was investigated, as well as the pharmaceutical properties of the granules and the tablets. The bioactivity of the smartFilm tablets was assessed in vitro and ex vivo to determine the antibacterial activity of norfloxacin. The results were compared to a physical mixture tablet that contained non-loaded paper granules and equal amounts of norfloxacin as a crystalline powder. (3) Results: Norfloxacin-loaded smartFilm granules and norfloxacin-loaded smartFilm tablets contained norfloxacin in an amorphous state, which resulted in an improved and faster release of norfloxacin when compared to the physical mixture tablet. The bioactivity was up to three times higher when compared to the physical mixture tablet. The ex vivo model was demonstrated to be a useful tool that allows for a fast and cost-effective discrimination between “good” and “bad” formulations. It provides realistic physiological conditions and can therefore yield meaningful, additional biopharmaceutical information that cannot be assessed in classical in vitro experiments. (4) Conclusions: smartFilm tablets are a promising, universal, industrially feasible and cost-effective formulation strategy for improved solubility and enhanced bioactivity of poorly soluble drugs. Full article

Antioxidants can reduce free radical formation in deeper skin layers where typical sunscreen filters may no longer be effective. Here, a general method is presented to pre-select optimum combinations of antioxidants and physical filters. The radical production of selected common physical filters after UV irradiation, the capacity of different antioxidants and the interaction between these compounds was investigated in solution by optical measurement of DPPH scavenging, allowing a theoretical calculation of the antioxidant amount necessary to scavenge UV-induced radicals. Furthermore, the antioxidant capacity and the scattering properties were determined. All physical filters induced different amounts of radicals in suspensions depending on the coating. ZnO coated with polydimethylsiloxane and myristic acid (ZnOpolymyr) showed the lowest radical formation. Epigallocatechin-gallate (EGCG) provided the highest antioxidant capacity. Different formulations with different ratios of selected physical filters and antioxidants were prepared. It turned out that the high radical protection factor (RPF) of cream formulations, which originally did not contain any physical filters, was reduced when such filters were added. The data demonstrates that the addition of physical filters to antioxidant-containing formulations lowers their reduction capacity, but to varying degrees. An optimal combination of physical filters and antioxidants must be pre-selected in order to incorporate them into a formulation and verify their effect on skin. Full article

Many orally administrated drugs exhibit poor bioavailability due to their limited solubility. The smartFilm technology is an innovative approach to improve the drug aqueous solubility, where the drug is embedded within the matrix of cellulose-based paper in an amorphous state, hence increasing its solubility. Despite its proven effectiveness, smartFilms, i.e., pieces of paper, exhibit limited flowability and are not easy to swallow, and thus oral administration is not convenient. In addition, there is a lack of knowledge of their mechanical behavior under compression. This study aimed to transform unloaded smartFilms, i.e., paper, into a flowable physical form and investigated its mechanical behavior when compressed. Granules made of paper were prepared via wet granulation and were compressed into tablets. The influence of using different amounts and forms of sucrose, as a binder, on the pharmaceutical properties of the produced granules and tablets was studied and the most suitable composition was identified by using instrumented die experiments. For this, the Poisson’s ratio and Young’s modulus were determined for different compaction force levels and the deformation behavior was estimated with the Heckel mathematical model. All granule batches showed good flowability with angle of repose values between 25–35°. Granule batches with ≤30% dry sucrose content produced tablets that fulfilled the European Pharmacopeia requirements, and the compaction behavior of the granules was found to be comparable to the behavior of classical binders and compression enhancers. Paper can be transferred into granules. These granules can be used as suitable intermediate products for the production of tablets made of paper in large, industrial scale. Full article

(1) Background: Numerous oral drugs exhibit limited bioavailability due to their poor solubility and poor intestinal permeability. The smartFilm technology is an innovative approach that improves the drug aqueous solubility via incorporating the drug in an amorphous state into a cellulose-based matrix, i.e., paper. smartFilms can be transformed into a free-flowing physical form (i.e., paper granules) that can be compressed into tablets with optimum physico-chemical and pharmaceutical properties. The aim of this study was to investigate if smartFilm tablets are suitable for improved oral delivery of poorly water-soluble drugs. (2) Methods: Curcumin is a poorly soluble drug with low intestinal permeability and was used for the production of curcumin-loaded smartFilms. The curcumin-loaded smartFilms were transferred into smartFilm granules which were then compressed into curcumin-loaded smartFilm tablets. The tablets were characterized regarding their physico-chemical and pharmaceutical properties, and the intestinal permeability of curcumin was determined with the ex vivo porcine intestinal model. The ex vivo intestinal permeability of curcumin from the smartFilm tablets was compared to a physical mixture of curcumin and paper and to a classical and to an innovative commercial product, respectively. (3) Results: The produced curcumin-loaded smartFilm tablets fulfilled the European Pharmacopoeia requirements, incorporated curcumin in amorphous state within the cellulose matrix and exhibited an enhanced dissolution rate. The ex vivo intestinal permeation data were shown to correlate to the in vitro dissolution data. The ex vivo intestinal permeation of curcumin from the smartFilm tablets was about two-fold higher when compared to the physical mixture and the classical commercial product. No differences in the ex vivo bioavailability were found between the smartFilm tablets and the innovative commercial product. (4) Conclusions: smartFilm tablets are a cost-effective and industrially feasible formulation approach for the formulation of poorly water-soluble drugs, i.e., BCS class II and IV drugs. Full article

The effective dermal penetration of active ingredients (AI) is a major task in the formulation of topical products. Besides the vehicle, the mechanical skin treatments are also considered to impact the penetration efficacy of AI. In particular, professional skin treatments, i.e., professional cosmetic skin treatments, are considered to be optimal for the dermal delivery of AI. However, a systematic study that proves these theories is not yet available and was therefore performed in this study while utilizing an ex vivo porcine ear model with subsequent digital image analysis. Hydrophilic and lipophilic fluorescent dyes were used as AI surrogates and were applied onto the skin without and with professional skin treatments. The skin hydration and the penetration efficacy were determined, respectively. Results showed that professional skin treatments with massage were able to increase the skin hydration, whereas a professional skin treatment without massage could not increase the skin hydration when compared to skin without professional skin treatment. Regarding the penetration efficacy, it was found that all parameters tested, i.e., type of professional skin treatment, lipophilicity of the AI, and the time point at which the AI are applied onto the skin, can have a tremendous impact on the penetration efficacy of the AI. The most effective penetration and the most effective skin hydration is achieved with a professional skin treatment that includes a professional skin massage. This kind of skin treatment can therefore be used to improve dermal drug delivery. Full article