Development, Evaluation, and Pharmacokinetic Assessment of Polymeric Microarray Patches for Transdermal Delivery of Vancomycin Hydrochloride.

Methicillin-resistant Staphylococcus aureus (MRSA) can cause harmful and potentially deadly infections. Vancomycin remains the first-line antibiotic treatment for MRSA-derived infections. Nevertheless, as a peptide drug, it is poorly absorbed when administered orally because of its high molecular weight and low permeability in the gastrointestinal tract and is therefore administered intravenously for the treatment of systemic diseases. In order to circumvent some of the many drawbacks associated with intravenous injection, other routes of drug delivery should be investigated. One of the strategies which has been employed to enhance transdermal drug delivery is based on microarray patches (MAPs). This work, for the first time, describes successful transdermal delivery of vancomycin hydrochloride (VCL) using dissolving MAPs (DMAPs) and hydrogel-forming MAPs (HFMAPs). VCL was formulated into DMAPs and reservoirs [film dosage forms, lyophilized wafers, and compressed tablets (CSTs)] using excipients such as poly(vinyl pyrrolidone), poly(vinyl alcohol), sodium hyaluronate, d-sorbitol, and glycerol. In this study, HFMAPs were manufactured using aqueous blends containing poly(methylvinyl ether-co-maleic acid) cross-linked by esterification with poly(ethylene glycol). The VCL-loaded CSTs (60% w/w VCL) were the most promising reservoirs to be integrated with HFMAPs based on the physicochemical evaluations performed. Both HFMAPs and DMAPs successfully delivered VCL in ex vivo studies with the percentage of drug that permeated across the neonatal porcine skin recorded at 46.39 ± 8.04 and 7.99 ± 0.98%, respectively. In in vivo studies, the area under the plasma concentration time curve from time zero to infinity (AUC0-∞) values of 162.04 ± 61.84 and 61.01 ± 28.50 µg h/mL were achieved following the application of HFMAPs and DMAPs, respectively. In comparison, the AUC0-∞ of HFMAPs was significantly greater than that of the oral administration control group, which showed an AUC0-∞ of 30.50 ± 9.18 µg h/mL (p < 0.05). This work demonstrates that transdermal delivery of VCL is feasible using DMAPs and HFMAPs and could prove effective in the treatment of infectious diseases caused by MRSA, such as skin and soft tissue infections, lymphatic-related infections, and neonatal sepsis.

Two-Photon Polymerisation 3D Printing of Microneedle Array Templates with Versatile Designs: Application in the Development of Polymeric Drug Delivery Systems.

PURPOSE: To apply a simple and flexible manufacturing technique, two-photon polymerisation (2PP), to the fabrication of microneedle (MN) array templates with high precision and low cost in a short time. METHODS: Seven different MN array templates were produced by 2PP 3D printing, varying needle height (900-1300 µm), shape (conical, pyramidal, cross-shaped and with pedestal), base width (300-500 µm) and interspacing (100-500 µm). Silicone MN array moulds were fabricated from these templates and used to produce dissolving and hydrogel-forming MN arrays. These polymeric MN arrays were evaluated for their insertion in skin models and their ability to deliver model drugs (cabotegravir sodium and ibuprofen sodium) to viable layers of the skin (ex vivo and in vitro) for subsequent controlled release and/or absorption. RESULTS: The various templates obtained with 2PP 3D printing allowed the reproducible fabrication of multiple MN array moulds. The polymeric MN arrays produced were efficiently inserted into two different skin models, with sharp conical and pyramidal needles showing the highest insertion depth values (64-90% of needle height). These results correlated generally with ex vivo and in vitro drug delivery results, where the same designs showed higher drug delivery rates after 24 h of application. CONCLUSION: This work highlights the benefits of using 2PP 3D printing to prototype variable MN array designs in a simple and reproducible manner, for their application in drug delivery.

The Use of a Pressure-Indicating Sensor Film to Provide Feedback upon Hydrogel-Forming Microneedle Array Self-Application In Vivo.

PURPOSE: To evaluate the combination of a pressure-indicating sensor film with hydrogel-forming microneedle arrays, as a method of feedback to confirm MN insertion in vivo. METHODS: Pilot in vitro insertion studies were conducted using a Texture Analyser to insert MN arrays, coupled with a pressure-indicating sensor film, at varying forces into excised neonatal porcine skin. In vivo studies involved twenty human volunteers, who self-applied two hydrogel-forming MN arrays, one with a pressure-indicating sensor film incorporated and one without. Optical coherence tomography was employed to measure the resulting penetration depth and colorimetric analysis to investigate the associated colour change of the pressure-indicating sensor film. RESULTS: Microneedle insertion was achieved in vitro at three different forces, demonstrating the colour change of the pressure-indicating sensor film upon application of increasing pressure. When self-applied in vivo, there was no significant difference in the microneedle penetration depth resulting from each type of array, with a mean depth of 237 µm recorded. When the pressure-indicating sensor film was present, a colour change occurred upon each application, providing evidence of insertion. CONCLUSIONS: For the first time, this study shows how the incorporation of a simple, low-cost pressure-indicating sensor film can indicate microneedle insertion in vitro and in vivo, providing visual feedback to assure the user of correct application. Such a strategy may enhance usability of a microneedle device and, hence, assist in the future translation of the technology to widespread clinical use.

Intradermal delivery of the antiretroviral drugs cabotegravir and rilpivirine by dissolving microarray patches: Investigation of lymphatic uptake.

The lymphatic system possesses the main viral replication sites in the body following viral infection. Unfortunately, current antiretroviral agents penetrate the lymph nodes insufficiently when administered orally and, therefore, cannot access the lymphatic system sufficiently to interrupt this viral replication. For this reason, novel drug delivery systems aimed at enhancing the lymphatic uptake of antiretroviral drugs are highly desirable. Dissolving polymeric microarray patches (MAPs) may help to target the lymph intradermally. MAPs are intradermal drug delivery systems used to deliver many types of compounds. The present work describes a novel work investigating the lymphatic uptake of two anti-HIV drugs: cabotegravir (CAB) and rilpivirine (RPV) when delivered intradermally using dissolving MAPs containing nanocrystals of both drugs. Maps were formulated using NCs obtained by solvent-free milling technique. The polymers used to prepare the NCs of both drugs were PVA 10 Kda and PVP 58 Kda. Both NCs were submitted to the lyophilization process and reconstituted with deionized water to form the first layer of drug casting. Backing layers were developed for short application times and effective skin deposition. In vivo biodistribution profiles of RPV and CAB after MAP skin application were investigated and compared with the commercial intramuscular injection using rats. After a single application of RPV MAPs, a higher concentration of RPV was delivered to the axillary lymph nodes (AL) (Cmax 2466 ng/g - Tmax 3 days) when compared with RPV IM injection (18 ng/g - Tmax 1 day), while CAB MAPs delivered slightly lower amounts of drug to the AL (5808 ng/g in 3 days) when compared with CAB IM injection (9225 ng/g in 10 days). However, CAB MAPs delivered 7726 ng/g (Tmax 7 days) to the external lumbar lymph nodes, which was statistically equivalent to IM delivery (Cmax 8282 ng/g - Tmax 7 days). This work provides strong evidence that MAPs were able to enhance the delivery of CAB and RPV to the lymphatic system compared to the IM delivery route.

Hydrogel-forming microneedles enhance transdermal delivery of metformin hydrochloride.

We investigated, for the first time, the potential for a hydrogel-forming microneedle (MN) patch to deliver the high-dose drug metformin HCl transdermally in a sustained manner. This may minimize some gastrointestinal side effects and small intestine absorption variations associated with oral delivery. Patches (two layers) were assembled from a lyophilised drug reservoir layer, with the MN layer made from aqueous blend of 20% w/w poly (methylvinylether-co-maleic acid) crosslinked by esterification with 7.5% w/w poly (ethylene glycol) 10,000 Da. >90% of metformin was recovered from homogeneous drug reservoirs. Drug reservoir dissolution time in PBS (pH 7.4) was <10 min. MN penetrated a validated skin model Parafilm® M consistently. Permeation of metformin HCl across dermatomed neonatal porcine skin in vitro was enhanced by using MN. The combined MN and metformin HCl reservoir patch (containing 75 mg or 50 mg metformin HCl, respectively) delivered 9.71 ±â€¯2.22 mg and 10.04 ±â€¯1.92 mg at 6 h, respectively, and 28.15 ±â€¯2.37 mg and 23.25 ±â€¯3.58 mg at 24 h, respectively.In comparison, 0.34 ±â€¯0.39 mg and 0.85 ±â€¯0.68 mg was delivered at 6 h, respectively, and 0.39 ±â€¯0.39 mg and 1.01 ±â€¯0.84 mg was delivered at 24 h, respectively, from a control set-up employing only the drug reservoirs. In vivo, metformin HCl was detected in rat plasma at 1 h post MN application at a concentration of 0.62 ±â€¯0.51 µg/mL, increasing to 3.76 ±â€¯2.58 µg/ml at 3 h. A maximal concentration of 3.77 ±â€¯2.09 µg/ml was achieved at 24 h. Css was 3.2 µg/mL. Metformin transdermal bioavailability using MNs was estimated as 30%.Hydrogel-forming MN are a promising technology that has demonstrated successful transdermal delivery of metformin HCl. Potential clearly exists for administration of other high-dose drugs using this system.

Design and physicochemical characterisation of novel dissolving polymeric microneedle arrays for transdermal delivery of high dose, low molecular weight drugs.

We describe formulation and evaluation of novel dissolving polymeric microneedle (MN) arrays for the facilitated delivery of low molecular weight, high dose drugs. Ibuprofen sodium was used as the model here and was successfully formulated at approximately 50% w/w in the dry state using the copolymer poly(methylvinylether/maleic acid). These MNs were robust and effectively penetrated skin in vitro, dissolving rapidly to deliver the incorporated drug. The delivery of 1.5mg ibuprofen sodium, the theoretical mass of ibuprofen sodium contained within the dry MN alone, was vastly exceeded, indicating extensive delivery of the drug loaded into the baseplates. Indeed in in vitro transdermal delivery studies, approximately 33mg (90%) of the drug initially loaded into the arrays was delivered over 24h. Iontophoresis produced no meaningful increase in delivery. Biocompatibility studies and in vivo rat skin tolerance experiments raised no concerns. The blood plasma ibuprofen sodium concentrations achieved in rats (263µgml(-1) at the 24h time point) were approximately 20 times greater than the human therapeutic plasma level. By simplistic extrapolation of average weights from rats to humans, a MN patch design of no greater than 10cm(2) could cautiously be estimated to deliver therapeutically-relevant concentrations of ibuprofen sodium in humans. This work, therefore, represents a significant progression in exploitation of MN for successful transdermal delivery of a much wider range of drugs.

Hydrogel-forming microneedles prepared from "super swelling" polymers combined with lyophilised wafers for transdermal drug delivery.

We describe, for the first time, hydrogel-forming microneedle arrays prepared from "super swelling" polymeric compositions. We produced a microneedle formulation with enhanced swelling capabilities from aqueous blends containing 20% w/w Gantrez S-97, 7.5% w/w PEG 10,000 and 3% w/w Na2CO3 and utilised a drug reservoir of a lyophilised wafer-like design. These microneedle-lyophilised wafer compositions were robust and effectively penetrated skin, swelling extensively, but being removed intact. In in vitro delivery experiments across excised neonatal porcine skin, approximately 44 mg of the model high dose small molecule drug ibuprofen sodium was delivered in 24 h, equating to 37% of the loading in the lyophilised reservoir. The super swelling microneedles delivered approximately 1.24 mg of the model protein ovalbumin over 24 h, equivalent to a delivery efficiency of approximately 49%. The integrated microneedle-lyophilised wafer delivery system produced a progressive increase in plasma concentrations of ibuprofen sodium in rats over 6 h, with a maximal concentration of approximately 179 µg/ml achieved in this time. The plasma concentration had fallen to 71±6.7 µg/ml by 24 h. Ovalbumin levels peaked in rat plasma after only 1 hour at 42.36±17.01 ng/ml. Ovalbumin plasma levels then remained almost constant up to 6 h, dropping somewhat at 24 h, when 23.61±4.84 ng/ml was detected. This work represents a significant advancement on conventional microneedle systems, which are presently only suitable for bolus delivery of very potent drugs and vaccines. Once fully developed, such technology may greatly expand the range of drugs that can be delivered transdermally, to the benefit of patients and industry. Accordingly, we are currently progressing towards clinical evaluations with a range of candidate molecules.