Cubosome-dissolving microneedle system enhances the anti-psoriatic efficacy of a synergistic combination of methotrexate and cyclosporine

Int J Pharm. 2025 Aug 20:681:125893. doi: 10.1016/j.ijpharm.2025.125893. Epub 2025 Jun 24.

Abstract

Psoriasis is a chronic, immune-mediated skin disorder marked by hyperproliferation of keratinocytes and elevated inflammatory cytokine levels. Conventional systemic therapies, such as methotrexate (MTX) and cyclosporine (CYS), though effective, are associated with significant systemic toxicity and non-specific distribution, necessitating high doses for therapeutic effect. To address these limitations, this study developed a targeted and minimally invasive transdermal system using cubosome-embedded dissolving microneedles (DMNs) co-loaded with MTX and CYS. We initially found synergistic efficacy of MTX + CYS on the LPS induced in vitro psoriasis model. Then, the dual drugs were co-loaded into cubosomes using a top-down method and optimized for physicochemical characteristics, achieving a particle size of 121.6 nm, PDI of 0.13, and zeta potential of -21.12 mV. Small-angle X-ray scattering (SAXS) confirmed a cubic internal structure (lattice parameter: 112.73 Å), while XRD analysis indicated reduced crystallinity upon encapsulation. Entrapment efficiencies reached 95.15 % (MTX) and 92.41 % (CYS), with drug loadings of 3.76 % and 2.89 %, respectively. Sustained drug release was observed: MTX and CYS showed >94 % release over 72 h at pH 7.4 and 5.5. Ex vivo permeation studies revealed enhanced skin penetration via DMNs (up to 95 % for both drugs), while in vivo pharmacokinetics showed prolonged systemic exposure: DMNs extended MTX and CYS half-lives by 4.60- and 2.54-fold, and Tmax by 10.07- and 8.14-fold compared to oral delivery. The DMNs significantly improved Psoriasis Area and Severity Index (PASI) scores and reduced skin inflammation in an imiquimod-induced psoriasis model. Immunohistochemical and ELISA studies confirmed a significant reduction in IL-2 and TNF-α expression in animal skin upon DMNs treatment. In conclusion, the MTX + CYS-loaded Cubosome-DMNs offer a potent, synergistic, and skin-targeted therapeutic platform for psoriasis treatment, combining sustained release, improved permeation, and minimized systemic toxicity in a single, minimally invasive system.

Keywords: Cubosomes; Cyclosporine; Dissolving microneedles; Methotrexate; Psoriasis; Transdermal drug delivery.

MeSH terms

  • Administration, Cutaneous
  • Animals
  • Cyclosporine* / administration & dosage
  • Cyclosporine* / chemistry
  • Cyclosporine* / pharmacokinetics
  • Cyclosporine* / pharmacology
  • Drug Delivery Systems / methods
  • Drug Liberation
  • Drug Synergism
  • Humans
  • Male
  • Methotrexate* / administration & dosage
  • Methotrexate* / chemistry
  • Methotrexate* / pharmacokinetics
  • Mice
  • Needles
  • Particle Size
  • Psoriasis* / chemically induced
  • Psoriasis* / drug therapy
  • Skin / drug effects
  • Skin / metabolism
  • Skin Absorption

Substances

  • Methotrexate
  • Cyclosporine