Nanostructured Lipid Carriers Enhances The Safety Profile of Tretinoin: In Vitro and Healthy Human Volunteers’ Studies

Abstract

Aim: To enhance the tretinoin (TRE) safety profile through the encapsulation in nanostructured lipid carriers (NLC). Materials & methods: NLC-TRE was developed using a 2³ experimental factorial design, characterized (HPLC, dynamic light scattering, differential scanning calorimetry, x-ray diffraction analysis, transmission electron microscopy, cryo-transmission electron microscopy) and evaluated by in vitro studies and in healthy volunteers. Results: The NLC-TRE presented spherical structures, average particle size of 130 nm, zeta potential of 24 mV and encapsulation efficiency of 98%. The NLC-TRE protected TRE against oxidation (p < 0.0001) and promoted epidermal targeting (p < 0.0001) compared with the marketed product, both 0.05% TRE. The in vitro assay on reconstructed human epidermis and the measurement of transepidermal water loss in healthy volunteers demonstrated an enhanced safety profile in comparison to the marketed product (p < 0.0002). Conclusion: The NLC-TRE enhances the epidermal targeting and safety profile of TRE, representing a potential safer alternative for the topical treatment of skin disorders using TRE.

Graphical abstract

Keywords::

• nanostructured lipid carrier
• reconstructed human epidermis
• safety profile
• transepidermal water loss
• tretinoin

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/nnm-2021-0031

Author contributions

FA Lima, ECO Reis, IR Silva and LAC Carvalho conducted the experiments, analyzed the data and wrote the manuscript. RVR Vilela, SS Maria-Engler, RL Oréfice, LAM Ferreira and GAC Goulart designed the work, analyzed data and wrote the manuscript.

Financial & competing interests disclosure

This study was financially supported by FAPEMIG, FAPESP (17/04926-6 and 18/14936-1), CAPES and CNPq. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Data sharing statement

The authors certify that this manuscript reports original clinical trial data (Registro Brasileiro de Ensaios Clínicos, RBR-3t5ts4). All individual participant data that underlies the results reported in the article, after deidentification are available, along with the study protocol, statistical analysis plan and informed consent form (in Portuguese). The data will be available immediately following article publication to researchers who provide a methodologically sound proposal. Proposals to access data should be directed to GAC Goulart (Universidade Federal de Minas Gerais) and to gain access, the data requestor will need to sign a data access agreement form.

Blinded for review

Experiments were performed in the Center of Microscopy at the Universidade Federal de Minas Gerais (http://www.microscopia.ufmg.br).

The pig ears were obtained from a local slaughterhouse (Approved by the Ethics Committee on Animal Use of the Universidade Federal de Minas Gerais - Protocol CEUA: 174/2018).

The study was previously approved by the Research Ethics Committee of the Universidade Federal de Minas Gerais, under protocol number CAAE 89452318.7.0000.5149.

Normal human epidermal keratinocytes (NHEK) were isolated from donated foreskin samples obtained from the University of São Paulo Hospital (HU-USP). Cells were isolated as described previously [27] under the approval of the local Ethics Committee (HU CEP Case No. 943/09 and CEP FCF/USP 534).

Acknowledgments

The authors also like to acknowledge the Center of Microscopy (CM) at UFMG (http://www.microscopia.ufmg.br) for providing the equipment and technical support for experiments involving TEM and to A Käch (University of Zurich) and R Fleck (Kings College London) for the support in the experiments involving cryo-TEM performed in the CM-UFMG. The authors also acknowledge the Ophthalmological Center of Minas Gerais and the Faculty of Pharmacy of UFMG for allowing the use of physical facilities to conduct clinical studies and acknowledge all the human volunteers.

Additional information

Funding

This study was financially supported by FAPEMIG, FAPESP (17/04926-6 and 18/14936-1), CAPES and CNPq. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.