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 500μm height) were mechanically strong and were able to penetrate a skin simulant to a depth of 378μm. The MN arrays were tested in vitro using a Franz Cell setup delivering approximately 4.45mg of GEN over 6h. 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 5μg/mL. The time required to reach these levels post-MN array application ranged between 1 and 6h. This work demonstrated the potential of dissolving MN arrays to deliver GEN transdermally at therapeutic levels in vivo.
Highlights
Neonatal infections, including sepsis, are a significant cause of childhood mortality in low-resource settings; they cause an estimated 26% to 36% of the neonatal deaths that occur globally in low- to middle-income countries [1,2]
The initial objective of this work was to formulate well-formed MNs using biocompatible materials approved by the US Food and Drug Administration (FDA) with high drug loading of GEN
We formulated numerous dissolving MNs using water-soluble biocompatible or biodegradable polymers to investigate their compatibility with a high dose of GEN (30% w/w). Some polymers, such as PVP [25], poly(vinyl alcohol) (PVA) [33,34], sodium hyaluronate [35,36] and Gantrez® copolymers [12,24,25,37,38] have frequently been used as matrices in the formation of dissolving MNs
Summary
Neonatal infections, including sepsis, are a significant cause of childhood mortality in low-resource settings; they cause an estimated 26% to 36% of the neonatal deaths that occur globally in low- to middle-income countries [1,2]. GEN for injection is presented as an aqueous solution of gentamicin sulphate in vials or ampoules. It has a narrow therapeutic index and, like other aminoglycosides, it is potentially ototoxic and nephrotoxic. The elimination half-life of GEN in neonates and children depends on the patient age [6,7,8]. When this drug is administered to neonates, careful dose calculation and close monitoring are required to prevent GEN-induced toxicity. Close monitoring of GEN concentration in serum should be conducted, but this is not commonly available in low-resource settings and is currently not part of the WHO recommendations for the outpatient setting
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