Applications and recent advances in transdermal drug delivery systems for the treatment of rheumatoid arthritis

Abstract

Rheumatoid arthritis is a chronic, systemic autoimmune disease predominantly based on joint lesions with an extremely high disability and deformity rate. Several drugs have been used for the treatment of rheumatoid arthritis, but their use is limited by suboptimal bioavailability, serious adverse effects, and nonnegligible first-pass effects. In contrast, transdermal drug delivery systems (TDDSs) can avoid these drawbacks and improve patient compliance, making them a promising option for the treatment of rheumatoid arthritis (RA). Of course, TDDSs also face unique challenges, as the physiological barrier of the skin makes drug delivery somewhat limited. To overcome this barrier and maximize drug delivery efficiency, TDDSs have evolved in terms of the principle of transdermal facilitation and transdermal facilitation technology, and different generations of TDDSs have been derived, which have significantly improved transdermal efficiency and even achieved individualized controlled drug delivery. In this review, we summarize the different generations of transdermal drug delivery systems, the corresponding transdermal strategies, and their applications in the treatment of RA.

Keywords: Advanced devices; Different generations; Drug therapy; Enhancement strategies; Microneedles; Rheumatoid arthritis; Transdermal delivery mechanism; Transdermal drug delivery systems.

Graphical abstract

Figure 1

Pathogenesis and pathways of rheumatoid arthritis.

Figure 2

Schematic diagram of skin structure.

Figure 3

Classification of transdermal generations based on mechanism, applicable drugs, and applied technologies.

Figure 4

Summary of chemical penetration enhancers according to molecular structure. SC, stratum corneum.

Figure 5

Nanocarriers and vesicular systems for enhancing drug penetration.

Figure 6

The mechanism of different nanocarriers.

Figure 7

Drug loading methods of PELNV: passive drug loading method and active drug loading method. Reprinted with the permission from Ref. . Copyright © 2021 Elsevier.

Figure 8

Generating devices of cold atmospheric plasma generating device. Reprinted with the permission from Ref. . Copyright © 2022 Elsevier.

Figure 9

(A) Fluorescence images of different hydrogel groups containing green fluorescein at 2, 4, 6, and 8 h of in vitro skin permeation. (a1–a4) Free MTX group, (b1–b4) Free MTX + EO group, (c1–c4) MTX-NMs group, (d1–d4) MTX-NMs + EO group. (B) Histopathological images (a1–a5) and visual representation (b1–b5) of skin irritability experiments treated with (a1,b1) normal saline, (a2,b2) formalin, (a3,b3) Free MTX, (a4,b4) Free MTX + EO, (a5,b5) MTX-NMs + EO. (C) Histopathological sections (a1–a4) of the ankle joint of mice in different treatment groups. (a1) Normal saline, (a2) CFA, (a3) free MTX-based hydrogel, (a4) MTX-NMs + EO-based hydrogel. Reprinted with the permission from Ref. . Copyright © 2020 Elsevier.

Figure 10

(A) CLSM images of FLS uptake of DAPI-labeled and C6-labeled nanoparticles. DAPI stained the nucleus and C6 stained the cytoplasm. (B) SEM images of Tet-6 s-NPs (CaCO₃)/PG-MNs. (C) CLSM images of penetration of sulforhodamine B-labeled 6 s-NPs (CaCO₃)/PG-MNs into the skin. (D) Sulforhodamine B-labeled 6 s-NPs (CaCO₃)/PG-MNs-treated skin, OCT embedded and liquid nitrogen freezer, sliced horizontally with the skin surface, supporting the results of the puncture performance study. (E) The appearance of paw swelling. (F) Micrographs of H&E-stained pathological sections of ankle joints from AA-bearing rats treated with the test preparations. (G) Micrographs of immunohistochemical sections of VEGF and MVD in synovial tissues from AA-bearing rats. (H) Irritation response of the skin in AA-bearing rats before and after treatment with the test preparations. Reprinted with the permission from Ref. . Copyright © 2022 Elsevier.