Needleless administration of advanced therapies into the skin via the appendages using a hypobaric patch

Abstract

Advanced therapies are commonly administered via injection even when they act within the skin tissue, and this increases the chances of off-target effects. Here we report the use of a skin patch containing a hypobaric chamber that induces skin dome formation to enable needleless delivery of advanced therapies directly into porcine, rat, and mouse skin. Finite element method modeling showed that the hypobaric chamber in the patch opened the skin appendages by 32%, thinned the skin, and compressed the appendage wall epithelia. These changes allowed direct delivery of an H1N1 vaccine antigen and a diclofenac nanotherapeutic into the skin. Fluorescence imaging and infrared mapping of the skin showed needleless delivery via the appendages. The in vivo utility of the patch was demonstrated by a superior immunoglobulin G response to the vaccine antigen in mice compared to intramuscular injection and a 70% reduction in rat paw swelling in vivo over 5 h with diclofenac without skin histology changes.

Keywords: advanced therapeutics; drug delivery; needleless delivery; skin; vaccine.

Fig. 1.

A schematic showing the proposed clinical use of the patch with the hypobaric chamber loaded with the drug-containing formulation and applied to the skin.

Fig. 2.

(A) The FEM model geometry. (B) A three-dimensional FEM model image of application of 500 mbar using the hypobaric chamber. (C) A FEM cross-sectional image of angular and radial strain components. (D) A FEM visualization of the hair follicle deformation during hypobaric chamber application. (E) A photograph of the skin dome formed on porcine skin ex vivo using a hypobaric chamber at 500 mbar. (F) Confocal microscopic images of the skin appendages (i) without hypobaric pressure and (ii) with hypobaric pressure. (G) The mean relative difference in diameter of the skin appendages at different hypobaric conditions compared to atmospheric pressure (asterisk indicates significantly different from atmospheric pressure of ≈1,018 mbar). Data in G are ± SEM (n = 3).

Fig. 3.

In vitro percutaneous penetration of (A) diclofenac diethylamine gel using porcine skin over 24 h with (+) or without (−) the application of the hypobaric chamber patch. Two concentrations were used: 0.5 mM when the drugs were monomers and 151 mM when the drugs were nanoaggregates. Data represent the mean ± SD (n = 5). ER represents the ratio between the amount of drug found using the patch vs. without the patch when the drugs were presented as nanoaggegates. Epid is the epiderms, Derm is the dermis, and Trans is transdermal. Student’s t test with *P < 0.01 and **P < 0.001. (B) The infrared mapping images of the skin with and without the application of the patch containing the hypobaric chamber showing collagen (based on 1,341-cm⁻¹ peak, integration range 1,355 to 1,325 cm⁻¹), lipid (based on 2,851-cm⁻¹ peak, integration range 2,860 to 2,840 cm⁻¹) and diclofenac (based on 1,306-cm⁻¹ peak, integration range 1,315 to 1,295 cm⁻¹) distribution in the skin lateral slices.

Fig. 4.

(A–C) The delivery of FTIC-dextran with (+) and without (−) the patch using a hypobaric pressure of 500 mbar: (A) 10 kDa FITC-dextran, (B) 70 kDa FITC-dextran, or (C) 150 kDa FITC-dextran. Skin deposition and permeation data represent mean ± SD (n = 5). ER was the ratio of dextran in the tissue with vs. without the hypobaric chamber patch. One-way ANOVA statistics applied (A–C) with *P < 0.05 and ***P < 0.001. (D) Confocal microscopy imaging (20× objective) of the skin (control) and the skin after the application of FITC-dextran (label is green) 10 kDa (Left) and 150 kDa (Right) with and without the hypobaric chamber patch. (E) The amount of H1N1 antigen delivered into the skin and blood noninvasively using the patch with two different application protocols data represents mean + 1 SD, n = 3 with *P < 0.05. (F) IgG response to the H1N1 antigen delivery into the skin using −4.5 psi for 20 min; data are mean + 1 SD, n = 3 with *P < 0.05.

Fig. 5.

(A) Skin histology with and without the hypobaric patch application in healthy and inflamed rat paw skin. (B) TEWL after the application of the hypobaric patch. (C) Antiinflammatory activity of diclofenac diethylamine nanoaggregates formulated in a gel (43 mM) on rat carrageenan-induced paw edema without (−) and with (+) the patch. (D) The area under the curve of the swelling data *P < 0.001 (Mann–Whitney U test or analysis of variance, Bonferroni post hoc test); data are the mean ± SD (n = 5).