(T1030-04-22) Codelivery of Hydrophobic and Hydrophilic Drugs with PLGA-Tipped Hydrogel-Forming Hybrid Microneedle Patches

Purpose: Microneedle patches, an array of tiny needles, have been employed to overcome the skin’s barrier, the stratum corneum, to deliver drugs into the skin in a minimally invasive fashion. However, the tiny size of the needles in the patches limits the drug loading in conventional microneedle designs. Hydrogel-forming microneedles (HFM) readily imbibe skin interstitial fluid upon skin insertion to form continuous hydrogel conduits from attached patch-type water-soluble drug reservoirs, holding the potential to overcome the limitations of other microneedle designs [1]. However, their use to deliver hydrophobic compounds may be challenging. Herein, we propose a novel approach to deliver a hydrophilic drug (levofloxacin hydrochloride, LEX) through a reservoir-integrated HFM patch that is aligned with hydrophobic drug (amphotericin B, AMB) loaded poly(lactic-co-glycolic acid) (PLGA) tips using dissolvable polymer polyvinylpyrrolidone (PVP) for linking the two layers. Once inserted into the skin, the PVP layer dissolves in the skin interstitial fluid, thus depositing PLGA tips with hydrophobic drugs in the skin. HFM imbibe the skin interstitial fluid and create pathways for hydrophilic drugs to pass through from the drug reservoir to the skin (Figure 1). Codelivery of both hydrophobic and hydrophilic drugs would be achieved using one single patch.

Methods: The hybrid patches were fabricated by aligning the PLGA tips and HFM together. First, HFM were prepared by casting aqueous blends containing 20% w/w Gantrez S-97, 7.5% w/w PEG 10,000 and 3% w/w Na₂CO₃ on silicone moulds (11 × 11 conical array, 800 μm in height, 300 μm in base diameter with a 600 μm interspacing), after which they were air-dried for 48 h and crosslinked at 80°C for 24 h (Figure 2A). The LEX reservoir was a directly compressed tablet containing 150 mg of 80% w/w LEX, 10% w/w mannitol and 10% w/w croscarmellose sodium. PLGA tips were cast three times using 10 µL of tip solution containing 75 mg AMB and 25 mg PLGA in 1 mL of DMSO on silicone moulds (11 × 11 conical array, 600 μm in height, 300 μm in base diameter with a 600 μm interspacing). A PVP solution (40% w/w) was then cast on the moulds with PLGA tips inside and then a pre-formed HFM was aligned carefully by gentle manual force (Figure 2A). This PLGA tipped HFM patch was used in combination with the tablet reservoir in the following ex vivo and in vivo studies by adding10 µL of water to the back of HFM to initiate adhesion to the LEX tablet reservoir.

An ex vivo skin permeation study was performed on Franz-diffusion cells using full-thickness neonatal porcine skin. The hybrid patches were inserted into the skin using manual force for 30 s. The release of both drugs was monitored by taking receiver samples at different time points. After 24 h, the drugs deposited in the skin samples were extracted and analysed by HPLC-UV. An in vivo dermatokinetics study was performed using Balb/c mice. One hybrid patch was applied to the back of the mouse and 10 µL of water was added to the back of the hybrid patch, followed by an attachment of LEX tablet reservoir. At pre-determined time points, skin samples from the site of patch application were collected from each animal. These in vivo samples were analysed for drug content using HPLC-UV.

Results: Hybrid patches were fabricated successfully with three-layer structures: PLGA tips, PVP layer and HFM base, as shown in Figure 2. Ex vivo skin deposition at 24 h for hybrid patches (0.5 cm²) was shown to be 54.28 ± 17.64 µg for AMB and 602.64 ± 130.42 µg for LEX, respectively (Figure 3B). AMB reached 14.79 ± 7.02 µg (Figure 3C) and LEX achieved 507.53 ± 321.49 µg (Figure 3D) in the receiver compartment per patch of 0.5 cm² area after 24-hour application. In vivo dermatokinetics in Balb/c mice (Figure 3E) showed that a hybrid patch applied for 24 h could achieve 4-day release of AMB at AUC of 405.20 ± 94.17 µg*h/mL and 2-day release of LEX at AUC of 50.29 ± 28.68 µg*h/mL in the skin (Figure 3F). These results showed co-administration capabilities of the hybrid patches both ex vivo and in vivo.

Conclusion: Novel PLGA tipped HFM was successfully formulated and characterized. This work provides significant evidence regarding the successful codelivery over two days of a hydrophobic drug and a hydrophilic drug using a single dose of hybrid patches both ex vivo and in vivo. These findings highlight the versatility of the hybrid patch systems, overcome the limitations of conventional HFM and greatly increase the range and scope of the type of drugs that is deliverable using one patch, with ensuing benefits for industry, healthcare providers and, ultimately, patients. Pharmacodynamics studies should be then conducted using a proper animal model.

References: Donnelly RF., McCrudden MTC., Alkilani AZ., Larrañeta E., McAlister E., Courtenay AJ., et al. Hydrogel-forming microneedles prepared from “super swelling” polymers combined with lyophilised wafers for transdermal drug delivery. PLoS One 2014;9(10):e111547. Doi: 10.1371/journal.pone.0111547.


Figure 1. Schematic illustration of the hybrid microneedle patches. The hybrid microneedle patches were consisted of three parts. Hydrogel-forming microneedle base (HFM) was aligned with PLGA tips containing AMB with PVP layer. After application on the skin, a directly compressed tablet was attached on the back of the patch. PVP layer dissolved quickly after insertion into the skin and HFM swell after imbibing the skin interstitial fluid. The swollen HFM acted as a pathway for LEX tablet and delivered LEX to the skin. After removal of the patches, PLGA tips with AMB and LEX were deposited in the skin.


Figure 2. (A)Schematic illustration of hybrid patches fabrication process. (B) Microscope pictures of a hybrid patch. Scale bar, 2 mm. (C) detailed tips of a hybrid patch. Scale bar, 500 µm. (D) SEM scanning of the tips in a hybrid patch. Scale bar, 500 µm. (E) SEM scanning of a hybrid patch. Scale bar, 2 mm.


Figure 3. Drug delivery capabilities of hybrid patches. (A) Schematic illustration of ex vivo skin permeation and deposition studies using Franz cell diffusion cells. A hybrid patch was inserted into the full thickness porcine skin. The samples from the receiver compartment were collected over 24 h for skin permeation study. After 24 h application, the skin sample was analysed for skin deposition study. (B) Skin deposition study results of one hybrid patch. Mean + S.D., n = 6. (C) Skin permeation results of AMB for hybrid patches. Mean + S.D., n = 6. (D) Skin permeation results of LEX for hybrid patches. Mean + S.D., n = 6. (E) In vivo dermatokinetics study scheme for hybrid patches. One hybrid patch was applied on the back of a Balb/c mouse and the skin samples were collected at different time points. (F) In vivo dermatokinetics results Mean + S.D., n = 5.