Periodic Reporting for period 1 - Crystals4Skin (Rational development of nanocrystalline drugs for skin administration)
Periodo di rendicontazione: 2023-06-01 al 2025-05-31
Although most of the drug products currently in the market are developed to be taken orally, other drug delivery routes appear as alternatives to address patient-specific conditions that also affect families, health care units, and public policies. For example, the management of geriatric patients is often complicated by the difficulty that patients find in swallowing medicines and by polymedication, mainly in elders living with dementia, Parkinson’s disease and sequelae of stroke. Another illustration related to the importance of alternative routes of drug administration in both curative and palliative care comes from the management of cancer patients. Chemotherapy involves the use of several medicines and therapeutic approaches that often lead to severe gastrointestinal side effects. Such situations could be relieved by the aid of integrated and people-centered health technologies, like the use of nanocrystals to treat skin diseases locally.
In comparison to other types of nanoparticulate materials, nanocrystals are considered the simplest systems because they only require the active pharmaceutical ingredient to be ‘precipitated’. In terms of crystal structure, however, the pharmaceutical ingredient can be prepared in a variety of crystal forms. Nanocrystals can stick better to the skin, enter hair follicles, and release medicine slowly over time. The motivation for this project was the idea that the effectiveness of nanocrystals depends not just on their size, but also on their crystal structure and surface features. Surprisingly, up to now, the studies in the literature have ignored these factors in dermal and transdermal delivery. The potential impact of the selection of crystal forms has been widely documented in delivery studies via the gut. Little is known, however, about the structure-to-property relationships that drive the performance of crystals delivered to the skin. The Crystals4Skin project have investigated how different crystal forms of nanocrystals behave when applied to the skin. The team has combined chemistry, nanotechnology, biology, and medicine to ensure these new treatments are safe, effective, and meet high-quality standards. This research supports better drug delivery options, especially for vulnerable patients, and aligns with EU goals for innovative, people-centred healthcare.
In comparison to other types of nanoparticulate materials, nanocrystals are considered the simplest systems because they only require the active pharmaceutical ingredient to be ‘precipitated’. In terms of crystal structure, however, the pharmaceutical ingredient can be prepared in a variety of crystal forms. Nanocrystals can stick better to the skin, enter hair follicles, and release medicine slowly over time. The motivation for this project was the idea that the effectiveness of nanocrystals depends not just on their size, but also on their crystal structure and surface features. Surprisingly, up to now, the studies in the literature have ignored these factors in dermal and transdermal delivery. The potential impact of the selection of crystal forms has been widely documented in delivery studies via the gut. Little is known, however, about the structure-to-property relationships that drive the performance of crystals delivered to the skin. The Crystals4Skin project have investigated how different crystal forms of nanocrystals behave when applied to the skin. The team has combined chemistry, nanotechnology, biology, and medicine to ensure these new treatments are safe, effective, and meet high-quality standards. This research supports better drug delivery options, especially for vulnerable patients, and aligns with EU goals for innovative, people-centred healthcare.
Crystals4Skin has brought together a multidisciplinary team of researchers. The project was hosted by Dr. Kateřina Poláková, group leader of the Nanomaterials in Biomedicine Group at RCPTM-CATRIN (Palacký University Olomouc, Czechia). Additionally, part of the research took place as a secondment stay in Prof. Thiago Caon’s group at the Federal University of Santa Catarina (Laboratory of Pharmaceutical Technology, UFSC, Brazil). The research relating the chemical synthesis, the characterisation of the particles, and the cytotoxicity studies in cell models were performed in Czechia, while the pharmaceutical delivery studies in ex-situ human tissue model was made in Brazil. This study was the first time in which the effect of crystal form diversity was addressed in follicular studies and the first time ever that human follicles were tested in delivery. The findings open a new technological opportunity that can expand the repertoire of products used in dermal/transdermal delivery – with impacts in the society’s health and with commercial benefits.
Firstly, curcumin was selected as a model of study and the chosen crystal forms were analyzed (especially the surface) with appropriate computational tools. Later, nanocrystals of curcumin Polymorph I and curcumin cocrystals with resorcinol and pyrogallol were prepared using colloidal milling and characterized using various techniques. A final stage involved the study of the fate of the NCs on the skin (delivery tests) and on skin-related cells (cytotoxicity tests). The different crystal forms have shown markedly different physicochemical but also biopharmaceutical properties. For instance, curcumin Polymorph I NCs showed a better penetration through the hair follicles than cocrystals or dissolved curcumin. This is likely due to their adhesion and lipophilic nature, which illustrates a better compatibility with the follicular environment. The cocrystals, instead, are suggested to be more suitable for delivering a drug into more hydrophilic environments.
The project also initiated valuable discussions on the societal and gender dimensions of the methods and tissue models used to study skin and follicular delivery, which may influence both scientific communities and society at large. For example, obtaining suitable skin samples was difficult due to sanitary regulations and access limitations, particularly for porcine skin. Human samples, in turn, were mostly donated from lightly pigmented male donors, raising concerns about gender, race, and socioeconomic biases. The study emphasized that underrepresentation of highly pigmented skin could limit the standardization of the findings and risk reinforcing health disparities. It also highlighted the need for more inclusive and diverse skin models in drug delivery studies and called for further research on how natural variations in follicle structure, pigmentation, and skin properties might affect drug delivery performance and clinical relevance.
Firstly, curcumin was selected as a model of study and the chosen crystal forms were analyzed (especially the surface) with appropriate computational tools. Later, nanocrystals of curcumin Polymorph I and curcumin cocrystals with resorcinol and pyrogallol were prepared using colloidal milling and characterized using various techniques. A final stage involved the study of the fate of the NCs on the skin (delivery tests) and on skin-related cells (cytotoxicity tests). The different crystal forms have shown markedly different physicochemical but also biopharmaceutical properties. For instance, curcumin Polymorph I NCs showed a better penetration through the hair follicles than cocrystals or dissolved curcumin. This is likely due to their adhesion and lipophilic nature, which illustrates a better compatibility with the follicular environment. The cocrystals, instead, are suggested to be more suitable for delivering a drug into more hydrophilic environments.
The project also initiated valuable discussions on the societal and gender dimensions of the methods and tissue models used to study skin and follicular delivery, which may influence both scientific communities and society at large. For example, obtaining suitable skin samples was difficult due to sanitary regulations and access limitations, particularly for porcine skin. Human samples, in turn, were mostly donated from lightly pigmented male donors, raising concerns about gender, race, and socioeconomic biases. The study emphasized that underrepresentation of highly pigmented skin could limit the standardization of the findings and risk reinforcing health disparities. It also highlighted the need for more inclusive and diverse skin models in drug delivery studies and called for further research on how natural variations in follicle structure, pigmentation, and skin properties might affect drug delivery performance and clinical relevance.
Current strategies for dermal and transdermal drug delivery largely rely on passive diffusion through the stratum corneum, which presents limitations in terms of permeability/permeation, dosage control, and compatibility with active pharmaceutical ingredients. While the follicular route has been recognized as a promising alternative due to its natural invagination into the skin, it remains underutilized in pharmaceutical development, primarily due to a lack of understanding of how particulate systems behave in this complex environment. The Crystals4Skin project addressed this critical knowledge gap by introducing a novel concept: that the crystal form of nanocrystals (NCs)—even when composed of the same active ingredient—can have a profound impact on drug delivery efficiency via the follicular pathway. The project demonstrated, for the first time, that crystal structure-driven differences in lipophilicity, anisotropy, and surface energy determine the ability of NCs to penetrate the hair follicle. Using curcumin as a model compound, it was shown that curcumin polymorph I—a more lipophilic and surface-compatible form—achieved deeper and more efficient follicular delivery than its cocrystals with pyrogallol or resorcinol. These findings, confirmed through fluorescence imaging in both human and porcine skin models, set a new scientific precedent for rationally designing NCs with specific physicochemical properties tailored for follicular targeting.
To fully leverage these results, the following avenues are identified as essential for further uptake and translation beyond the state-of-the-art - which have already been considered in the dissemination, communication and career development plans:
- Further research and validation in more diverse human populations, especially with highly pigmented and gender-balanced skin models, to ensure equitable clinical relevance.
- Development of standardized testing models for follicular delivery, including in vitro and ex vivo protocols that can bridge preclinical and clinical findings.
- Engagement with regulatory authorities to integrate crystal-form-dependent delivery principles into the evaluation frameworks for topical pharmaceuticals.
- Collaborations/communication with pharmaceutical companies to integrate these findings into commercial product pipelines targeting dermatological and cosmetic applications.
In summary, Crystals4Skin has advanced the state of the art by providing a fundamental mechanistic understanding of how nanocrystal engineering—at the structural level—can unlock the full potential of the follicular route. These insights pave the way for the design of next-generation dermal therapeutics that are not only more effective but also more inclusive and scientifically robust.
To fully leverage these results, the following avenues are identified as essential for further uptake and translation beyond the state-of-the-art - which have already been considered in the dissemination, communication and career development plans:
- Further research and validation in more diverse human populations, especially with highly pigmented and gender-balanced skin models, to ensure equitable clinical relevance.
- Development of standardized testing models for follicular delivery, including in vitro and ex vivo protocols that can bridge preclinical and clinical findings.
- Engagement with regulatory authorities to integrate crystal-form-dependent delivery principles into the evaluation frameworks for topical pharmaceuticals.
- Collaborations/communication with pharmaceutical companies to integrate these findings into commercial product pipelines targeting dermatological and cosmetic applications.
In summary, Crystals4Skin has advanced the state of the art by providing a fundamental mechanistic understanding of how nanocrystal engineering—at the structural level—can unlock the full potential of the follicular route. These insights pave the way for the design of next-generation dermal therapeutics that are not only more effective but also more inclusive and scientifically robust.