Figure 1.
Schematic representation of the concept of combining hydrogel-forming microneedles prepared from super swelling polymers and lyophilised wafer-type drug reservoirs for enhanced transdermal delivery of proteins and high dose low potency drug substances.
Figure 2.
Schematic representation of casting and crosslinking of the super swelling hydrogel films (A), microneedle preparation (B), Texture Analyser set-up for investigation of physical properties of microneedles (C) and Franz cell set-up for in vitro transdermal drug release studies (D).
Panel (E) shows a diagrammatic representation of the measurements recorded from the optical coherence tomographic images of microneedle penetration into excised neonatal porcine skin in vitro, namely; (a) the distance between the lower microneedle base plate and the stratum corneum, (b) the depth of microneedle penetration into the skin and (c) the width of the micropore created in the skin.
Figure 3.
Swelling curve for crosslinked hydrogel films prepared from aqueous blends containing 20% w/w PMVE/MA, 7.5% w/w PEG and 3% Na2CO3 based on the increasing mass of the swelling array expressed as a percentage of the mass of a dry array (Means ± SD, n = 3) (A).
Super swelling microneedle arrays prepared from aqueous blends containing 20% w/w PMVE/MA, 7.5% w/w PEG and 3% Na2CO3 as (B) xerogel and (C) post-swelling for 3 hours in PBS pH 7.4. t/S versus t swelling curves of super swelling hydrogel prepared from aqueous blends containing 20% w/w PMVE/MA, 7.5% w/w PEG and 3% Na2CO3 (Mean ± SD, n = 3) (D). Digital microscope images of super swelling hydrogel-forming MN (prepared from aqueous blends containing 20% w/w PMVE/MA, 7.5% PEG 10,000 and 3% Na2CO3) following the application of different forces (0.05, 0.18, 0.36, 0.71 and 0.9 N/needle). These images are representative of the percentage reduction in the heights of needles on the MN arrays observed following the application of the different forces (Means+SD, n = 3) (E). Digital images showing micropores in excised neonatal porcine skin following application of different forces and subsequent staining with methylene blue solution post microneedle removal (F). Attenuated total reflectance (ATR)-Fourier transform infrared (FTIR) spectra of dry hydrogels prepared from aqueous blends containing: 20% w/w Gantrez S-97, 7.5% w/w PEG 10.000 non crosslinked (a) and crosslinked (b) materials; Na2CO3 (c) and 20% w/w Gantrez S-97, 7.5% w/w PEG 10.000 and 3% w/w Na2CO3 non crosslinked (d) and crosslinked (e) materials. The left panel shows a closer view of the carbonyl region for the same materials. A FTIR Accutrac FT/IR-4100 Series (Jasco, Essex, UK) equipped with MIRacle diamond ATR was used at room temperature. Samples were scanned and recorded in the region of 4000–400 cm−1 at a resolution of 4.0 cm−1. The obtained spectra were an average of 64 scans. A standard smoothing process was applied to all the spectra using the equipment software (G).
Table 1.
Aqueous blends used to prepare hydrogel formulations tested in the current study and the equilibrium swelling of the formed hydrogels (Means ± SD, n = 3).
Figure 4.
False colour 2D still images of super swelling MN arrays immediately following insertion into excised neonatal porcine skin at application forces of 4, 7, 11 or 16 N/array or using manual application.
(Scale bar represents 300 µm in each case) (A). The effect of application force (N/array) upon the resultant penetration depth of super swelling MN arrays in neonatal porcine skin in vitro, expressed as a p [percentage of MN height (Means+S.D., n = 10)]. The penetration parameters of the MN arrays were quantified using optical coherence tomography (B). False colour images of the in vitro swelling profile of MN arrays in excised neonatal porcine skin recorded over a 3 h period, as assessed by optical coherence tomography (Scale bar represents 300 µm in each case) (C). OCT visualisation of the micropores residing within the skin immediately following MN array insertion (0 min) and following 60 min in skin (Scale bar represents 300 µm. in each case) (D).
Table 2.
The effect of force of application upon the resultant penetration characteristics of MN arrays cast from 20% w/w Gantrez S-97, 7.5% w/w PEG 10,000 and 3% w/w Na2CO3, in the geometry 19×19 with height 600 µm, width 300 µm and interspacing at base 50 µm into neonatal porcine skin, (Means ± SD, n = 10).
Table 3.
In vitro swelling of MN arrays (19×19 MN, 600 µm height, 300 µm width at base, 50 µm interspacing at base) upon insertion into neonatal porcine skin, (Means ± SD, n = 15).
Table 4.
Physical properties of lyophilised drug reservoirs.
Figure 5.
The in vitro cumulative permeation profile of ibuprofen sodium across dermatomed 350 µm neonatal porcine skin when delivered using in-dwelling super swelling MN arrays combined with lyophilised drug reservoirs (Means ± S.D., n = 9) (A).
Digital images of the ibuprofen sodium-loaded lyophilised wafers used in in vitro and in vivo experiments and prepared from aqueous blends containing 10% w/w gelatin, 3% w/w mannitol and 40% w/w ibuprofen sodium (B, C). The in vitro cumulative permeation profile of OVA across dermatomed 350 µm neonatal porcine skin when delivered using in-dwelling super swelling MN arrays combined with lyophilised drug reservoirs (Means ± S.D., n = 5) (D). Digital images (E, F)of the OVA-loaded lyophilised wafers used in in vitro and in vivo experiments and prepared from aqueous blends containing 10% w/w gelatin, 40% w/w mannitol, 10% w/w NaCl, 1% w/w sucrose and 0.5% w/w OVA. These active-loaded tablets exhibited high porosities as exemplified in (G).
Figure 6.
Schematic representation of application and retention strategies for rat experiments designed to evaluate in vivo performance of super swelling microneedle arrays (A).
The in vivo plasma profiles of ibuprofen sodium (B) (Means ± S.D., n = 4) and OVA (C) (Means ± S.D., n = 3) following transdermal delivery using super swelling microneedle arrays with lyophilised drug reservoirs. Typical morphology of super swelling microneedles upon removal from rat skin in vivo after 24 hours insertion indicating that, despite extensive swelling, the microneedles are removed intact (D, E).