Assessing the risk of a clinically significant infection from a Microneedle Array Patch (MAP) product.

Microneedle Array Patches (MAPs) are an emerging dosage form that creates transient micron-sized disruptions in the outermost physical skin barrier, the stratum corneum, to facilitate delivery of active pharmaceutical ingredients to the underlying tissue. Numerous MAP products are proposed and there is significant clinical potential in priority areas such as vaccination. However, since their inception scientists have hypothesized about the risk of a clinically significant MAP-induced infection. Safety data from two major Phase 3 clinical trials involving hundreds of participants, who in total received tens of thousands of MAP applications, does not identify any clinically significant infections. However, the incumbent data set is not extensive enough to make definitive generalizable conclusions. A comprehensive assessment of the infection risk is therefore advised for MAP products, and this should be informed by clinical and pre-clinical data, theoretical analysis and informed opinions. In this article, a group of key stakeholders identify some of the key product- and patient-specific factors that may contribute to the risk of infection from a MAP product and provide expert opinions in the context of guidance from regulatory authorities. Considerations that are particularly pertinent to the MAP dosage form include the specifications of the finished product (e.g. microbial specification), it's design features, the setting for administration, the skill of the administrator, the anatomical application site, the target population and the clinical context. These factors, and others discussed in this article, provide a platform for the development of MAP risk assessments and a stimulus for early and open dialogue between developers, regulatory authorities and other key stakeholders, to expedite and promote development of safe and effective MAP products.

Formulation Approach that Enables the Coating of a Stable Influenza Vaccine on a Transdermal Microneedle Patch.

A trivalent influenza split vaccine was formulated at high concentration for coating on the transdermal microneedle system. Monovalent vaccine bulks of three influenza strains, two influenza A strains, and one B strain were diafiltrated, concentrated, and lyophilized. The lyophilized powder of each vaccine strain was separately reconstituted and subsequently combined into a coating formulation of high concentration trivalent vaccine. The formulation process converted the monovalent vaccine bulks with low hemagglutinin (HA) concentrations 0.1 mg/mL into a viscous, emulsion containing HA at ~50 mg/mL. This physically stable emulsion demonstrated viscosity 1 poise and 30° contact angle for effective, homogeneous coating on each microneedle. Evaluation of the vaccine antigen HA by SRID and SDS-PAGE/Western blot showed that HA remained stable throughout the vaccine transdermal microneedle system manufacturing process and 1-year ambient storage (25°C). Anti-influenza antibody responses were evaluated by ELISA and hemagglutination inhibition (HAI) assay after primary and booster immunization with the vaccine-coated transdermal microneedle systems at either 25-µg or 40-µg total HA. The results showed the induction of serum anti-influenza IgG and anti-HA neutralizing antibodies after primary immunization and significant titer rises after booster immunization for both doses, indicating the dry-coated trivalent vaccine delivered by transdermal microneedle system elicited both primary and recall antibody responses against all three antigen strains. The study demonstrates that the transdermal microneedle system provides an attractive alternative for influenza vaccine delivery with key advantages such as preservative-free and room-temperature storage.

Development of a novel zolmitriptan intracutaneous microneedle system (Qtrypta™) for the acute treatment of migraine.

M207 is an investigational intracutaneous microneedle therapeutic system for nonoral zolmitriptan delivery. In a Phase I trial, M207 provided faster absorption with a higher 2 h exposure than oral zolmitriptan. In the pivotal trial evaluating efficacy, tolerability and safety in moderate-to-severe migraine attacks, M207 3.8 mg was superior to placebo in providing freedom from headache pain (42 vs 14%) and freedom from most bothersome symptom (68 vs 43%) 2 h post-dose. Treatment-emergent adverse events were mild and transient and most commonly concerned the application site. In post hoc analyses: pain freedom was sustained in approximately 1/3 of patients; efficacy was observed in migraine headaches that are typically more difficult to treat.

Effect of Skin Model on In Vitro Performance of an Adhesive Dermally Applied Microarray Coated with Zolmitriptan.

Franz cell studies, utilizing different human skin and an artificial membrane, evaluating the influence of skin model on permeation of zolmitriptan coated on an array of titanium microprojections, were evaluated. Full thickness and dermatomed ex vivo human skin, as well as a synthetic hydrophobic membrane (Strat-M®), were assessed. It was found that the choice of model demonstrated different absorption kinetics for the permeation of zolmitriptan. For the synthetic membrane only 11% of the zolmitriptan coated dose permeated into the receptor media, whilst for the dermatomed skin 85% permeated into the receptor. The permeation of zolmitriptan through full thickness skin had a significantly different absorption profile and time to maximum flux in comparison to the dermatomed skin and synthetic model. On the basis of these results dermatomed skin may be a better estimate of in vivo performance of drug-coated metallic microprojections.

Pharmacokinetics and Skin Tolerability of Intracutaneous Zolmitriptan Delivery in Swine Using Adhesive Dermally Applied Microarray.

Adhesive Dermally Applied Microarray (ADAM) is a new drug-delivery system that uses microprojections (340-µm long) for intracutaneous drug self-administration. We formulated zolmitriptan, a well-accepted and commonly used migraine medication, for administration using ADAM. In vivo studies were conducted in female prepubescent Yorkshire pigs using ADAM 1.9-mg zolmitriptan applied to the inner thigh and left in place for 1 h. Pharmacokinetic studies showed that the ADAM 1.9-mg zolmitriptan was delivered with high efficiency (85%) and high absolute bioavailability (77%). Furthermore, in vivo evaluation showed a rapid systemic absorption with a median Tmax of 15 min. Skin biopsies of the treatment sites showed a mean depth of microprojection penetration of 105.4 ± 3.6 µm. Mass spectrometry imaging showed that the zolmitriptan after 1 h of patch wear time was predominantly localized to the dermis. ADAM zolmitriptan was well tolerated with a transient mild-to-moderate erythema response. The findings in these studies, particularly the rapid zolmitriptan absorption profile after intracutaneous administration, provided validation to advance ADAM zolmitriptan development.