Development and Evaluation of Novel Baricitinib Formulation for Psoriasis Treatment

Abstract

[eng] This doctoral thesis investigates the development of a lipid-based topical formulation of baricitinib for treating psoriasis, a chronic inflammatory skin condition. Psoriasis affects millions globally and presents with red, scaly patches on the skin. While oral baricitinib, a Janus kinase (JAK) inhibitor, is used for autoimmune diseases like psoriasis, it can lead to systemic side effects. To address this, the research aims to create a topical formulation that targets affected skin, reducing systemic exposure and associated risks. The main objective of the study was to develop a topical formulation of baricitinib. The first phase involved assessing the solubility of baricitinib in different solvents and excipients, identifying those that would enhance skin permeability. The second phase focused on formulating and characterizing a stable topical product, evaluating its physical and chemical properties, and testing its efficacy and tolerability in a psoriasis model. Baricitinib showed poor solubility in water, a challenge for creating an effective topical treatment. However, the permeation enhancer Transcutol proved effective, increasing baricitinib’s solubility and penetration in skin tissues. This solvent allowed the drug to remain stable for at least a week, making it suitable for further formulation development. The lipid-based formulation (BCT-OS) was developed using excipients like Transcutol P, Labrafac Lipophile, and Lauroglycol 90 / Surfadone, chosen for their solubilizing and permeation-enhancing properties. The formulation was stable, had a skin-appropriate pH, and showed favorable rheological behavior for easy application. In vitro studies revealed that 80% of the drug was released from the formulation, while ex vivo permeation studies demonstrated that most of the drug remained in the skin, indicating potential for targeted treatment. The formulation’s efficacy was tested in an imiquimod-induced psoriasis model in mice. The results showed a significant reduction in common psoriasis symptoms, such as skin thickening, erythema, and edema. These findings confirmed baricitinib’s anti-inflammatory properties, facilitated by the inhibition of the JAK-STAT pathway, were effectively delivered through the topical formulation. The treatment also helped restore skin structure, alleviating symptoms. The formulation’s tolerability was confirmed through tests showing improved skin barrier function, with reduced transepidermal water loss and increased stratum corneum hydration. Histopathological analysis indicated no irritation or inflammation after application, confirming its safety for long-term use. The success of this formulation lies in the enhanced solubility of baricitinib achieved through the use of Transcutol. The lipid-based system enabled effective drug retention in the skin, limiting systemic exposure. In vivo studies further demonstrated the formulation’s therapeutic potential, significantly reducing psoriasis markers and restoring skin health. In summary, this research successfully developed a stable, effective, and well-tolerated topical formulation of baricitinib for psoriasis. The formulation’s localized action reduces the risks of systemic side effects, making it a promising candidate for future clinical studies. This innovation offers a new approach to treating psoriasis, improving patient outcomes and quality of life.

[spa] Esta tesis doctoral aborda el desarrollo de una formulación tópica a base de lípidos de baricitinib para el tratamiento de la psoriasis, una enfermedad inflamatoria crónica de la piel. La psoriasis afecta a millones de personas, manifestándose en parches rojos y escamosos. Aunque el baricitinib oral, un inhibidor de la quinasa Janus (JAK), se utiliza para enfermedades autoinmunes, su administración sistémica puede causar efectos adversos. El objetivo de este trabajo fue desarrollar una formulación tópica que permita aplicar el tratamiento directamente sobre las zonas afectadas, reduciendo los riesgos sistémicos. El estudio se dividió en dos fases principales. En la primera, se evaluó la solubilidad del baricitinib en diferentes disolventes y excipientes, identificando aquellos que mejorarían la permeabilidad cutánea. Se encontró que Transcutol era un solvente eficaz para aumentar la solubilidad y la estabilidad del baricitinib. En la segunda fase, se formuló una crema a base de lípidos (BCT-OS) utilizando excipientes como Transcutol P, que mostró una estabilidad adecuada y un pH compatible con la piel. Los estudios in vitro revelaron que el 80% del fármaco se liberaba de la formulación, y los estudios ex vivo demostraron que la mayor parte del baricitinib se retenía en las capas cutáneas, limitando su paso al torrente sanguíneo. En un modelo de psoriasis inducida en ratones, la formulación mostró eficacia al reducir síntomas como el engrosamiento de la piel, el eritema y el edema, asociados con la inflamación en la psoriasis. Además de ser eficaz, la formulación fue bien tolerada, mejorando la función barrera de la piel, sin causar irritación ni inflamación. La reducción de la pérdida de agua transepidérmica y el aumento de la hidratación del estrato córneo respaldan su seguridad para un uso prolongado. En conclusión, esta investigación desarrolló una formulación tópica de baricitinib estable, eficaz y segura para el tratamiento de la psoriasis. Su acción localizada disminuye el riesgo de efectos adversos sistémicos, lo que la convierte en una opción prometedora para futuros estudios clínicos, mejorando potencialmente la calidad de vida de los pacientes.