A nipple shield delivery system for oral drug delivery to breastfeeding infants: Microbicide delivery to inactivate HIV

https://doi.org/10.1016/j.ijpharm.2012.05.035Get rights and content

Abstract

A new drug delivery method for infants is presented which incorporates an active pharmaceutical ingredient (API)-loaded insert into a nipple shield delivery system (NSDS). The API is released directly into milk during breastfeeding. This study investigates the feasibility of using the NSDS to deliver the microbicide sodium dodecyl sulfate (SDS), with the goal of preventing mother-to-child transmission (MTCT) of HIV during breastfeeding in low-resource settings, when there is no safer alternative for the infant but to breastfeed. SDS has been previously shown to effectively inactivate HIV in human milk. An apparatus was developed to simulate milk flow through and drug release from a NSDS. Using this apparatus milk was pulsed through a prototype device containing a non-woven fiber insert impregnated with SDS and the microbicide was rapidly released. The total SDS release from inserts ranged from 70 to 100% of the average 0.07 g load within 50 ml (the volume of a typical breastfeed). Human milk spiked with H9/HIVIIIB cells was also passed through the same set-up. Greater than 99% reduction of cell-associated HIV infectivity was achieved in the first 10 ml of milk. This proof of concept study demonstrates efficient drug delivery to breastfeeding infants is achievable using the NSDS.

Graphical abstract

Cross sectional diagram of milk leaving breast passing through nipple shield delivery system insert.

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Introduction

There is no single suitable drug and nutrient delivery method available for infants or young children (Kearns et al., 2003). In developing countries where medical infrastructure is often scarce, pediatric drug and nutrient delivery systems face numerous challenges in supply, stability, sterility, distribution, and dosing (Knoppert, 2009, WHO, 2010c). Liquid formulations are often the principal method of pediatric drug delivery, but are ill-adapted due to high-cost and lack of access to refrigeration or potable water for reconstitution (UNICEF and WHO, 2010). When liquid formulations are not available, a solid dosage form is often the only available method for administration of medicine. Many current medicines are only available in adult strength, so safe and accurate dosing for an infant is complicated (Pandolfini and Bonati, 2005, Stoltenberg et al., 2010). Additionally, liquid formulations can be unpalatable especially for young infants and may require undesirable toxic excipients, such as preservatives and solvents. There is a clear need for formulations that are appropriate, safe, and effective for children.

One clear example of the need for appropriate medicine for infants in developing countries is in the prevention of mother-to-child transmission (MTCT) of HIV in breastfeeding. Of the approximately 500,000 infants per year who are infected with HIV from their mothers, it is estimated that 200,000 infants are infected through breastfeeding (Chasela et al., 2010), with 90% of MTCT occurring in sub-Saharan Africa (UNAIDS, 2008). WHO policy on breastfeeding states that, ‘… when replacement feeding is acceptable, feasible, affordable, sustainable and safe, avoidance of all breastfeeding by HIV infected mothers is recommended …’ (WHO, 2010b). This condition is often not met, and breastfeeding in low-resource settings has been shown to significantly increase infant survival (Brahmbhatt and Gray, 2003). In light of this, recent WHO guidelines recommend the continued use of oral anti-retroviral (ARV) drugs by the mother and/or the infant to prevent HIV transmission through breastfeeding (WHO, 2010a). However, widespread distribution of ARVs does not yet exist in sub-Saharan Africa and ARV use can lead to side effects and resistant strains of the virus if infection still occurs (Zeh et al., 2011).

As an alternative approach, the administration of edible microbicides into expressed infected milk which is then delivered to the baby has been previously considered (Hartmann et al., 2006a). Sodium dodecyl (or lauryl) sulfate (SDS), an anionic surfactant, is a candidate for use as an edible microbicide with anti-HIV activity in human milk. It has been demonstrated that 0.1–1 wt% SDS rapidly kills sexually transmitted pathogens, including HIV in media (Howett et al., 2000, Howett et al., 1999, Krebs et al., 2000, Krebs et al., 1999). A concentration of 0.1 wt% SDS has been demonstrated to rapidly inactivate cell free and cell-associated HIV in human milk (Hartmann et al., 2005, Tuaillon et al., 2009). This concentration is safe for infant use, based on a maximum acceptable infant oral exposure to SDS of 1 g/kg (of infant)/day and a biochemical analysis of the effect of SDS on milk content (Hartmann et al., 2006a, Hartmann et al., 2006b). Another benefit of SDS is its broad antiviral activity by solubilizing lipid membranes; therefore unlike many anti-viral compounds SDS is strain independent and unlikely to drive HIV mutation to a resistant form (Hartmann et al., 2006b).

Given that delivery of SDS during breastfeeding may be an effective method of reducing viral load in milk and preventing MTCT of HIV, we propose a new method to deliver SDS to infants during breastfeeding that also overcomes many of the general challenges associated with frequent drug delivery to infants. The concept is to incorporate a drug-impregnated insert into a nipple shield worn by a mother during breastfeeding (Fig. 1), where during suckling, a drug is released directly into the milk (Gerrard, 2011, Sokal et al., 2009). Nipple shields, typically a single molding of silicone, are available at low cost and are used to aid mothers and/or infants during breastfeeding, typically to reduce pain or nipple damage, or to assist latching on (Riordan, 2005). The NSDS would have an insert containing a dose of the API in dried form. In the studies reported in this publication, NSDS inserts were made from non-woven fiber, representing a flexible, high surface area support for drug incorporation. The mother would wear the NSDS as her child breastfeeds, and as milk passes through the insert the API would be released directly into the milk and pass to the infant. The insert could be placed inside the NSDS prior to each feed or the NSDS could be preloaded with the insert prior to the mother obtaining the device, and be entirely disposable after one use. Alternatively, the NSDS could be washed, disinfected, and reloaded with another insert for reuse.

This study had two aims: firstly to determine the kinetics of drug release into milk from a NSDS insert during a pulsed flow that mimics breastfeeding; and secondly to establish whether the release of SDS from a NSDS into human milk can inactivate HIV within the fluid.

Section snippets

Formulation of non-woven fiber inserts with SDS

To make the NSDS inserts, 10 mm diameter discs of a medical grade non-woven cellulosic (viscose) and polyester based fiber matrix with a 2.75 mm thickness and area density of 300 g/m2 (Bathfelt, Texel, Québec, Canada) were soaked in a 30 wt% SDS (Reagent Plus > 98.5% purity, Sigma–Aldrich, UK) solution at 60 °C for 10 s. They were then air dried at room temperature on a mesh. After 72 h drying their weight stabilized with a final weight gain of 0.07 g (standard deviation 0.01 g, n = 13). This fiber grade

Release of the edible microbicide SDS from NSDS inserts

The release of SDS from a NSDS insert in a mimicked breastfeeding simulation environment was studied using the apparatus outlined in Section 2.2 and Fig. 2d. This was performed to provide evidence of the influence of the physiological variables within breastfeeding that could influence drug release from a NSDS. Preliminary experiments determined a suitable apparatus to mimic drug release from a drug-loaded NSDS insert. Conditions of milk flow through an NSDS insert resembling breastfeeding were

Drug release into milk from the NSDS

Parameters that are expected to influence release kinetics of an API from a NSDS are: drug form, support material/excipients, flow conditions and solvent type. For this study where flow conditions and milk type were changed the greatest variation in release behavior was seen between the differing milk types, with goat's milk producing the most rapid SDS release rate. Understanding in detail the effect of milk composition on release kinetics will be important for controlled release into human

Conclusion

A sustained release of the edible microbicide SDS into HIV infected milk during breastfeeding from a NSDS placed over the mother's breast, is proposed to be an effective method for oral delivery of microbicides to prevent MTCT of HIV. This study has demonstrated that a NSDS can deliver SDS into milk from a non-woven fiber insert at non-toxic microbicidal concentrations. It has also demonstrated that SDS release using the NSDS is capable of rapidly inactivating significant amounts of

Acknowledgments

We are grateful to the Bill and Melinda Gates Foundation, the Clinton Foundation (Clinton Global Initiative), the UK EPSRC, Cambridge University and King's College (Cambridge University), Pembroke College (Cambridge University) – UC Berkeley Exchange, and the International Design Development Summit for financial support and advice. We thank Wobbly Bottom Farm, Hertfordshire for their supply of goat's milk and Pauline Sakamoto of the Milk Bank, Santa Clara Valley Medical Centre (San Jose,

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