Transdermal delivery of vitamin K using dissolving microneedles for the prevention of vitamin K deficiency bleeding

Abstract

Vitamin K deficiency within neonates can result in vitamin K deficiency bleeding. Ensuring that newborns receive vitamin K is particularly critical in places where access to health care and blood products and transfusions is limited. The World Health Organization recommends that newborns receive a 1 mg intramuscular injection of vitamin K at birth. Evidence from multiple surveillance studies shows that the introduction of vitamin K prophylaxis reduces the incidence of vitamin K deficiency bleeding. Despite these recommendations, coverage of vitamin K prophylactic treatment in low-resource settings is limited. An intramuscular injection is the most common method of vitamin K administration in neonates. In low- and middle-income countries, needle sharing may occur, which may result in the spread of bloodborne diseases. The objective of our study was to investigate the manufacture of microneedles for the delivery of vitamin K. Following microneedle fabrication, we performed insertion studies to assess the microneedle's mechanical properties. Results indicate that vitamin K in a microneedle array was successfully delivered in vitro across neonatal porcine skin with 1.80 ± 0.08 mg delivered over 24 h. Therefore, this initial study shows that microneedles do have the potential to prevent vitamin K deficiency bleeding. Future work will assess delivery of vitamin K in microneedle array in vivo.

Keywords: Dissolving microneedles (MN); Less economically developed countries (LEDCs); Transdermal drug delivery; Vitamin K; Vitamin K deficiency bleeding (VKDB).

Graphical abstract

Fig. 1

Light microscope images of vitamin K MN formulations. a) MN formulated from 20% w/w Gantrez® S-97 in 100% ethanol produced a large number of bubbles throughout the array. b) MN formulated from 20% w/w PVP in 100% ethanol produced a brittle needle, although all the needles did form. c) MN formulated from 20% w/w PVP in deionised water, containing 5% w/w Tween 80® produced a very brittle needle. Some needles did not form either. d) MN formulated from 20% w/w Gantrez® S-97 and 5% w/w Tween® 80 created a strong array with fully formed needles.

Fig. 2

a) Compression analysis of vitamin K MN arrays, formulated from 20% w/w Gantrez® S-97 and 5% w/w Tween® 80, at day 0. Before compression, needle height was 0.517 ± 0.057 mm (means ± SD, n = 3). After a 32 N force was applied, needle height was 0.480 ± 0.072 mm. b) Comparison of vitamin K MN arrays subjected to RH 43% or RH 86% for 3 days. At RH 43%, before and after compression, needle height was 0.468 ± 0.065 mm and 0.415 ± 0.103 mm respectively (means ± SD, n = 3). RH 86% resulted in needle heights of 0.449 ± 0.093 mm and 0.427 ± 0.086 mm, before and after compression (means ± SD, n = 3). c) Images of the first 3 layers of Parafilm M® used to measure insertion of a vitamin K MN array at day 0. Layers 1 and 2 show 100% needle penetration, with 72% needle penetration through the third layer. d) Number of Parafilm M® layers penetrated and percentage holes created in each layer to enable calculation of mean insertion depth for 3 MN conditions.

Fig. 3

FTIR analysis showing a) Dissolving MN array containing 20% w/w Gantrez® S-97 and 5% w/w Tween® 80 formulated in deionised water. b) Tween® 80. c) Vitamin K. d) Dissolving vitamin K MN array containing 20% w/w Gantrez® S-97, 5% w/w Tween® 80 and 5.14 ± 0.7 mg vitamin K.

Fig. 4

a) Optical coherence tomography image of a dissolving vitamin K MN array following manual insertion into neonatal porcine skin. b) In vitro cumulative permeation profile of vitamin K across dermatomed 350 µm neonatal porcine skin using a dissolving MN prepared from aqueous blends containing 20% w/w Gantrez® S-97 and 5% w/w Tween® 80 over 24 h (means ± SD, n = 3).