In vivo studies investigating biodistribution of nanoparticle-encapsulated rhodamine B delivered via dissolving microneedles.

Nanoparticles (NPs) have undergone extensive investigation as drug delivery and targeting vehicles. NP delivery is often via the parenteral route, reliant on administration using hypodermic needles, which can be associated with patient compliance issues and safety concerns. In the recent past, the intradermal delivery of NPs, via novel dissolving microneedle (MN) arrays has garnered interest in the pharmaceutical community. However, published studies using this combinatorial approach have been limited, in that they have focussed on the use of in vitro and ex vivo models only. The current study was designed to answer the fundamental question of how such NPs are distributed in an in vivo murine model, following MN-mediated delivery. Rhodamine B (RhB) was employed as a model tracer dye to facilitate study of biodistribution. Following MN application, RhB was detected in the livers, kidneys, spleens and superficial parotid lymph nodes of the mice. Uptake into the lymphatics was of particular note, as it points towards the potential for utilisation of a minimally-invasive MN delivery strategy in controlled targeting of active drug substances and vaccines to the lymphatics. The use of such a delivery system could, following further development, have far-reaching benefits in enhancement of immunomodulatory and anti-cancer therapies. As a consequence, further investigation of MN/NP combinatorial delivery strategies is warranted.

Microneedle-mediated delivery of donepezil: Potential for improved treatment options in Alzheimer's disease.

Transdermal drug delivery is an attractive route of drug administration; however, there are relatively few marketed transdermal products. To increase delivery across the skin, strategies to enhance skin permeability are widely investigated, with microneedles demonstrating particular promise. Hydrogel-forming microneedles are inserted into the skin, and following dissolution of a drug loaded reservoir and movement of the drug through the created channels, the microneedle array is removed intact, and can then be readily and safely discarded. This study presents the formulation and evaluation of an integrated microneedle patch containing the Alzheimer's drug, donepezil hydrochloride. The integrated patch consisted of hydrogel-forming microneedles in combination with a donepezil hydrochloride containing film. Formulation and characterisation of plasticised films, prepared from poly(vinylpyrrolidone) or poly (methyl vinyl ether co-maleic anhydride/acid) (Gantrez®) polymers, is presented. Furthermore, in vitro permeation of donepezil hydrochloride across neonatal porcine skin from the patches was investigated, with 854.71µg±122.71µg donepezil hydrochloride delivered after 24h, using the optimum patch formulation. Following administration of the patch to an animal model, plasma concentrations of 51.8±17.6ng/mL were obtained, demonstrating the success of this delivery platform for donepezil hydrochloride.

A facile system to evaluate in vitro drug release from dissolving microneedle arrays.

The use of biological tissues in the in vitro assessments of dissolving (?) microneedle (MN) array mechanical strength and subsequent drug release profiles presents some fundamental difficulties, in part due to inherent variability of the biological tissues employed. As a result, these biological materials are not appropriate for routine used in industrial formulation development or quality control (QC) tests. In the present work a facile system using Parafilm M(®) (PF) to test drug permeation performance using dissolving MN arrays is proposed. Dissolving MN arrays containing 196 needles (600 µm needle height) were inserted into a single layer of PF and a hermetic "pouch" was created including the array inside. The resulting system was placed in a dissolution bath and the release of model molecules was evaluated. Different MN formulations were tested using this novel setup, releasing between 40 and 180 µg of their cargos after 6h. The proposed system is a more realistic approach for MN testing than the typical performance test described in the literature for conventional transdermal patches. Additionally, the use of PF membrane was tested either in the hermetic "pouch" and using Franz Cell methodology yielding comparable release curves. Microscopy was used in order to ascertain the insertion of the different MN arrays in the PF layer. The proposed system appears to be a good alternative to the use of Franz cells in order to compare different MN formulations. Given the increasing industrial interest in MN technology, the proposed system has potential as a standardised drug/active agent release test for quality control purposes.

Microneedle-mediated intrascleral delivery of in situ forming thermoresponsive implants for sustained ocular drug delivery.

OBJECTIVES: This paper describes use of minimally invasive hollow microneedle (HMN) to deliver in situ forming thermoresponsive poloxamer-based implants into the scleral tissue to provide sustained drug delivery. METHODS: In situ forming poloxamer formulations were prepared and investigated for their rheological properties. HMN devices 400, 500 and 600 µm in height were fabricated from hypodermic needles (i.e. 27, 29 and 30 G) and tested for depth of penetration into rabbit sclera. Maximum force and work required to expel different volumes of poloxamer formulations was also investigated. Release of fluorescein sodium (FS) from intrasclerally injected implants was also investigated. Optical coherence tomography (OCT) was used to examine implant localisation and scleral pore-closure. KEY FINDINGS: Poloxamer formulations showed Newtonian behaviour at 20°C and pseudoplastic (shear-thinning) behaviour at 37°C. Maximum force and work required to expel different volumes of poloxamer formulations with different needles ranged from 0.158 to 2.021 N and 0.173 to 6.000 N, respectively. OCT showed intrascleral localisation of implants and scleral pore-closure occurred within 2-3 h. Sustain release of FS was noticed over 24 h and varied with depth of implant delivery. CONCLUSIONS: This study shows that the minimally invasive HMN device can localise in situ forming implants in the scleral tissue and provide sustained drug delivery.

Electrically-responsive anti-adherent hydrogels for photodynamic antimicrobial chemotherapy.

The loading of the photosensitisers meso-Tetra (N-methyl-4-pyridyl) porphine tetra tosylate (TMP), methylene blue (MB) and TMP with sodium dodecyl sulphate (SDS) into and release from hydrogels composed of the polyelectrolyte poly(methyl vinyl ether-co-maleic acid) crosslinked in a 2:1 ratio with PEG 10,000 were investigated as a potential rapid photodynamic antimicrobial chemotherapy (PACT) treatment for infected wounds using iontophoresis as a novel delivery method. Photosensitiser uptake was very high; (% TMP uptake; 95.53-96.72%) (% MB uptake; 90.58-93.26%) and was PMVE/MA concentration independent, whilst SDS severely limited TMP uptake (5.93-8.75%). Hydrogel hardness, compressibility and adhesiveness on the dermal surface of neonate porcine skin increased with PMVE/MA concentration and were significantly increased with SDS. The ionic conductivities of the hydrogels increased with PMVE/MA concentration. Drug release was PMVE/MA concentration independent, except for drug release under iontophoteric conditions for MB and TMP (without SDS). In just 15 min, the mean% drug concentrations released of TMP, TMP (with SDS) and MB using an electric current ranged from 22.30 to 64.72 µg ml(-1), 6.37-4.59 µg ml(-1) and 11.73-36.57 µg ml(-1) respectively. These concentrations were in excess of those required to induce complete kill of clinical strains of meticillin-resistant Staphylococcus aureus and Burkholderia cepacia. Thus these results support our contention that the iontophoteric delivery of TMP and MB using anti-adherent, electrically-responsive, PEG-crosslinked PMVE/MA hydrogels are a potential option in the rapid PACT treatment of infected wounds.