Transdermal delivery of gentamicin using dissolving microneedle arrays for potential treatment of neonatal sepsis

Abstract

Neonatal infections are a leading cause of childhood mortality in low-resource settings. World Health Organization guidelines for outpatient treatment of possible serious bacterial infection (PSBI) in neonates and young infants when referral for hospital treatment is not feasible include intramuscular gentamicin (GEN) and oral amoxicillin. GEN is supplied as an aqueous solution of gentamicin sulphate in vials or ampoules and requires health care workers to be trained in dose calculation or selection of an appropriate dose based on the patient's weight band and to have access to safe injection supplies and appropriate sharps disposal. A simplified formulation, packaging, and delivery method to treat PSBI in low-resource settings could decrease user error and expand access to lifesaving outpatient antibiotic treatment for infants with severe infection during the neonatal period. We developed dissolving polymeric microneedles (MN) arrays to deliver GEN transdermally. MN arrays were produced from aqueous blends containing 30% (w/w) of GEN and two polymers approved by the US Food and Drug Administration: sodium hyaluronate and poly(vinylpyrrolidone). The arrays (19 × 19 needles and 500 μm height) were mechanically strong and were able to penetrate a skin simulant to a depth of 378 μm. The MN arrays were tested in vitro using a Franz Cell setup delivering approximately 4.45 mg of GEN over 6 h. Finally, three different doses (low, medium, and high) of GEN delivered by MN arrays were tested in an animal model. Maximum plasma levels of GEN were dose-dependent and ranged between 2 and 5 μg/mL. The time required to reach these levels post-MN array application ranged between 1 and 6 h. This work demonstrated the potential of dissolving MN arrays to deliver GEN transdermally at therapeutic levels in vivo.

Novel Hydrogel-Forming Microneedle Array for Intradermal Vaccination in Mice Using Ovalbumin as a Model Protein Antigen

“…This resulted in a percentage reduction in MN height of approximately 6.04% (dissolving MN) and 5.68% (hydrogel-forming MN). These results are consistent with our previous work with other MN designs[11,13]. Importantly, the MNs did not shatter during compression, nor did the needles appear to bend when examined microscopically.The insertion properties of both MN types were also investigated to ensure MNs could consistently penetrate the validated skin model, Parafilm M ® and thus, be used for successful vaccination of mice in subsequent experiments.…”

Design, Formulation, and Evaluation of Novel Dissolving Microarray Patches Containing Rilpivirine for Intravaginal Delivery

“…This study builds upon work previously carried out in our research group, where we described the formulation, development and in vivo testing of dissolving microarray patches (MAPs) incorporating RPV LA for intradermal delivery . MAPs are micrometer‐scale devices, which have undergone extensive research in the fields of intradermal drug and vaccine delivery and have also been used in combination with nanosuspensions but had never before been used in the delivery of a LA nanosuspension, the potential of which we had previously theorized . An integral part of the present study, carried out with colleagues in PATH, involved conducting preliminary market research, early in the design concept phase, to inform the potential acceptability of MAPs for delivery of HIV PrEP intravaginally.…”

Advances in the Formulations of Microneedles for Manifold Biomedical Applications

“…Differing from the above biodegradable MNs that permit sustained drug release, dissolving MNs offer a burst release profile. The representative polymers are hyaluronic acid (HA),8a,40 carboxymethlycellulose (CMC),8b,41 polyacrylic acid (PAA),8d PVA, PVP, sucrose, starch, trehalose,41a DNA, and their mixtures 41a,46. McCrudden and co‐workers designed a dissolving MN patch for the transdermal delivery of painkiller, ibuprofen by screening a range of food and drug administration (FDA) regulated polymers and their combinations to maximize the drug loading and mechanical properties.…”

“…These MN platforms have been intensively explored for transdermal drug delivery in the treatment of both local and systemic diseases 1c,12. They function as carriers for small molecular drugs, peptides and proteins (e.g., insulin, vaccines, and antibodies),8a,14 oligonucleotides,11d and nanomedicines10a,b and deliver them into peripheral tissues like skin, eyes, mouth, vascular wall, vagina etc . Recently, MNs also receive attention from medical diagnosis and health monitoring, as they can easily access skin interstitial fluid (ISF) that is formed by blood transcapillary filtration and contains numerous biomarkers of clinical interest .…”