Drücken Sie „Enter“, um den Inhalte zu überspringen

Layered dissolving microneedles as a need-based delivery system to simultaneously alleviate skin and joint lesions in psoriatic arthritis

. 2021 Feb;11(2):505-519.


doi: 10.1016/j.apsb.2020.08.008.


Epub 2020 Aug 28.

Affiliations

Item in Clipboard

Kaiyue Yu et al.


Acta Pharm Sin B.


2021 Feb.

Abstract

Psoriatic arthritis (PsA) is a complicated psoriasis comorbidity with manifestations of psoriatic skin and arthritic joints, and tailoring specific treatment strategies for simultaneously delivering different drugs to different action sites in PsA remains challenging. We developed a need-based layered dissolving microneedle (MN) system loading immunosuppressant tacrolimus (TAC) and anti-inflammatory diclofenac (DIC) in different layers of MNs, i.e., TD-MN, which aims to specifically deliver TAC and DIC to skin and articular cavity, achieving simultaneous alleviation of psoriatic skin and arthritic joint lesions in PsA. In vitro and in vivo skin permeation demonstrated that the inter-layer retained TAC within the skin of ∼100 μm, while the tip-layer delivered DIC up to ∼300 μm into the articular cavity. TD-MN not only efficiently decreased the psoriasis area and severity index scores and recovered the thickened epidermis of imiquimod-induced psoriasis but also alleviated carrageenan/kaolin-induced arthritis even better than DIC injection through reducing joint swelling, muscle atrophy, and cartilage destruction. Importantly, TD-MN significantly inhibited the serum TNF-α and IL-17A in psoriatic and arthritic rats. The results support that this approach represents a promising alternative to multi-administration of different drugs for comorbidity, providing a convenient and effective strategy for meeting the requirements of PsA treatment.


Keywords:

Blank-MN, blank layered MNs; C6, coumarin 6; CLSM, confocal laser scanning microscope; DIC, diclofenac sodium; DIC-MN, layered MNs loading DIC in the tip-layer of needles; Diclofenac sodium; HA, hyaluronic acid; IL-17A, interleukin 17A; IMQ, imiquimod; IVISR, in vivo imaging system; Layered microneedles; MIX-MN, unlayered MNs loading the mixture of DIC and TAC in needles; MN, microneedle; NIC, nicotinamide; NSAIDs, nonsteroidal anti-inflammatory drugs; Need-based drug delivery; OCT, optical coherence tomography; PASI, psoriasis area and severity index; PDMS, polydimethylsiloxane; PVP, polyvinyl pyrrolidone; PsA, psoriatic arthritis; Psoriasis; Psoriatic arthritis; RhB, rhodamine B; SC, stratum corneum; SEM, scanning electron microscope; TAC, tacrolimus; TAC-MN, layered MNs loading TAC in the inter-layer of needles; TD-MN, layered MNs co-loading TAC in the inter-layer of needles and DIC in the tip-layer; TEWL, transepidermal water loss; TNF-α, tumor necrosis factor α; Tacrolimus.

Conflict of interest statement

The authors have no conflicts of interest to declare.

Figures


Image 1



Graphical abstract


Figure 1



Figure 1

Fabrication and characterization of layered MNs. Schematic fabrication process of layered MNs (A). MN arrays and single needle photographed with digital microscopy (B, scale bar = 1 mm) and scanning electron microscopy (C, scale bar = 100 μm). Layered structure of MNs loading RhB in the tip-layer and C6 in the inter-layer photographed with confocal laser scanning microscopy (D, scale bar = 200 μm).


Figure 2



Figure 2

Insertion depth of MNs through Parafilm M® and rat skin in vitro. Percentage of holes created and insertion depth of layered MNs in Parafilm M® layers (A). Data are mean±standard derivation of six determinations. Optical coherence tomography image of insertion depth of rat skin treated with layered MNs in vitro (B). Scale bar = 300 μm.


Figure 3



Figure 3

Confocal laser scanning micrographs via 3D reconstruction of rat skin treated with fluorescent probes loaded layered MNs in vivo. Scale bar = 100 μm.


Figure 4



Figure 4

In vitro permeation behavior of different MN formulations. Permeation profiles of TAC (A) and DIC (B) through rat skin from different MN formulations. Skin retention of TAC (C) and DIC (D) after 24 h permeation from different MN formulations. Each symbol and bar represented the mean ± standard deviation of six determinations. Significant differences were calculated using ANOVA test (∗P < 0.05).


Figure 5



Figure 5

In vivo permeation behavior of different MN formulations. Cumulative permeated amount of TAC (A) and DIC (B) through rat skin, and skin retention of TAC (C) and DIC (D) after 24 h permeation from different MN formulations. Each symbol and bar represented the mean ± standard deviation of six determinations. Significant differences were calculated using ANOVA test (∗P < 0.05).


Figure 6



Figure 6

In vivo imaging of rat knees after treated with layered MNs and intra-articular injection. In vivo images of RhB delivery from layered MNs into the articular cavity of rats throughout 24 h (A); RhB in the articular cavity of rats via intra-articular injection throughout 12 h (B); and the fluorescence intensity with time (C). In the layered MNs treated group, the treated skin covering the articular cavity was removed prior to imaging at each time point; while the treated skin in the intra-articular injection group was removed at 12 h post-injection.


Figure 7



Figure 7

Psoriasis model establishment and treatment. Schematic diagram of protocols of IMQ-induced psoriasis rat model establishment and the treatment (A). The representative skin clinical manifestations throughout model establishment and treatment (B). PASI scores of psoriatic skin lesions treated with different MN formulations (C). TEWL of psoriatic skin lesions treated with different MN formulations (D). Each symbol and bar represented the mean±standard derivation of six determinations. Significant differences were calculated using ANOVA test. P < 0.05 in comparison with the IMQ group; #P < 0.05 in comparison with the IMQ+MIX-MN group.


Figure 8



Figure 8

Arthritis model establishment and treatment. Schematic diagram of protocols of carrageenan/kaolin-induced arthritis rat model establishment and treatment (A and B). Degree of knee joint swelling after treated with different MN formulations throughout the experiment (C). Muscle weight ratio after treated with different MN formulations (D). Each symbol and bar represented the mean±standard derivation of six determinations. Significant differences were calculated using ANOVA test. P < 0.05 in comparison with the IMQ group; #P < 0.05 in comparison with TD-MN group.


Figure 9



Figure 9

Histopathological analysis of the psoriatic rats treated with different MN formulations. Histological analysis of skin after 5 days of anti-psoriatic treatment with different MN formulations (A). The epidermal thickness of skin measured under the microscope (B). The sliced sections were stained with hematoxylin and eosin (magnification 100×). Scale bar = 200 μm. Mean of epidermal thickness was calculated based on 20 random site measurements. Significant differences were calculated using ANOVA test. ∗P < 0.05 in comparison with the IMQ group; #P < 0.05 in comparison with the IMQ+MIX-MN group.


Figure 10



Figure 10

Histopathological analysis of the arthritic rats treated with different MN formulations. Histological analysis of knee joint after 5 days of anti-arthritic treatment with different MN formulations. The sliced sections were stained with hematoxylin and eosin (A) and safranin O-fast green (B) (magnification 100×). Scale bar = 200 μm.


Figure 11



Figure 11

Effects of different MN formulations on serum TNF-α (i) and IL-17A (ii) levels in psoriatic (A) and arthritic (B) rats. Each symbol and bar represented mean±standard derivation of six determinations. Significant differences were calculated using ANOVA test. P < 0.05 in comparison with the positive group (IMQ-induced psoriatic and carrageenan/kaolin-induced arthritic model group); #P < 0.05 in comparison with MIX-MN group; ns, no significant difference with the negative group.

Similar articles

References

    1. Sala M., Elaissari A., Fessi H. Advances in psoriasis physiopathology and treatments: up to date of mechanistic insights and perspectives of novel therapies based on innovative skin drug delivery systems (ISDDS) J Control Release. 2016;239:182–202.



      PubMed

    1. Boehncke W.H., Schön M.P. Psoriasis. Lancet. 2015;386:983–994.



      PubMed

    1. Bata-Csorgo Z., Hammerberg C., Voorhees J.J., Cooper K.D. Flow cytometric identification of proliferative subpopulations within normal human epidermis and the localization of the primary hyperproliferative population in psoriasis. J Exp Med. 1993;178:1271–1281.



      PMC



      PubMed

    1. Nestle F.O., Kaplan D.H., Barker J. Psoriasis. N Engl J Med. 2009;361:496–509.



      PubMed

    1. Ritchlin C.T., Proulx S., Schwarz E.S. Translational perspectives on psoriatic arthritis. J Rheumatol Suppl. 2009;83:30–34.



      PubMed

Dies ist ein automatisch übersetzter Artikel. Er kann nur einer groben Orientierung dienen. Das Original gibt es hier: psoriasis

Gib den ersten Kommentar ab

Schreibe einen Kommentar

Deine E-Mail-Adresse wird nicht veröffentlicht. Erforderliche Felder sind mit * markiert.