(737e) Novel Validation Method Development for a Drug Delivery Device Used during Breastfeeding

4.5 million infants die every year. Many of these deaths can easily be prevented, with existing medications, if hygienic and effective paediatric formulations were available. In low-resource settings, the need for medications, which do not require refrigeration, can easily be accurately dosed, and can be hygienically administered is especially high, due to electricity, potable water, and literacy limitations. Breastfeeding infants are especially in need of appropriate drug and delivery device combinations, considering few drug delivery systems are commercially available specifically for this population, and infant compliance can be low.

We are responding by developing a novel device for administering medications or nutrients to infants, and in vitro validation methods for characterising itâ??s efficacy. The device, when worn by a mother during breastfeeding, releases active pharmaceutical ingredients contained in the device into the milk directly consumed by the infant. It therefore has many potential advantages. For example, by suspending the medication or nutrient into the breast milk directly, and since it could be disposable, it overcomes the need for potable water as a suspension or cleaning fluid. It contains a solid dosage form, and therefore does not require refrigeration. Since the device is pre-loaded with medication a mother does not need to be literate to measure out a dose. Furthermore, since it is used during breastfeeding, infants may find it to be a more natural means of receiving medicine than conventional spoons or syringes.

Several validation methods have been used and developed in optimising the device design and potential corresponding dosage forms. These include a breastfeeding simulation apparatus, a novel infant tongue peristalsis simulation apparatus, and a novel tablet disintegration characterisation method using texture analysis.

The breastfeeding simulation apparatus was used to assess the release from the device of several dosage forms containing zinc, used in the treatment for diarrhoeal disease. The apparatus mimics maternal lactation, by flowing human milk through a silicone breast mimic. The milk then passes through the device loaded with the therapeutic insert, and then is sucked by a modified breast pump, at pressures physiologically representative of breastfeeding, into an exit line from which samples are collected with a fraction collector. The generated breast milk samples supplemented with zinc, collected over a simulated breastfeed are then analysed via inductively coupled optical emission spectrometry to test drug release rates from the drug delivery system. Zinc release over the course of 20 minutes, more than the time typically used during breastfeeding, in the simulations for four rapidly disintegrating tablet formulations ranged from 32-51%, indicating further formulation optimisation is needed.

An infant tongue mimic system was developed to simulate in vitro the peristaltic motions and associated pressures exerted from an infant tongue during breastfeeding. The system was used to characterise the potential effects of tongue movement on the disintegration of model tablets from the drug delivery system. The tongue mimic system includes a modified peristaltic pump equipped with a novel tongue mimic, a piezoresistive sensor for pressure measurements, a tube for holding the tablet under model breastfeeding flow conditions, and an adjustable palate mimic, allowing for pressure to the tablet to be modified based on clinical data. The release profiles of the model compound, sulforhodamine B, measured at two rotational values possible during breastfeeding for two potential compression values, representative of two potential tongue strengths of infants were statistically different (P=0.0013 and P<0.001, using 2-way ANOVA with matching for the lower and higher compression values respectively). For breastfeeding rotational rates representing non-nutritive breastfeeding, compression amount was found to be a significant factor (P=0.0162). In addition to being useful for characterising dosage forms for the device under the influence of tongue motion during suckling, this system could be useful in characterising other oral dosage forms or products.

Disintegration characterisation in human milk of potential tablet formulations is critical for screening dosage form appropriateness for the device. Therefore, a texture analysis disintegration method was also developed to analytically characterise tablet disintegration in opaque media. This method was developed to overcome visibility challenges which would be associated with use of the USP disintegration test with human milk. In this method, a texture analyser applies a load to a rapidly disintegrating tablet immersed in opaque media, and load data is collected over time as the tablet disintegrates, with fluctuations in the load indicating tablet fracturing. An in-house tablet formulation of a rapidly disintegrating tablet, and a commercially available tablet formulation were characterised in water, bovine, and human milk. These were found by one-way ANOVA to have statistically different disintegration times in each media (P<0.0001). This system is useful in characterising other tablet formulations for the device, and may be useful in the characterisation of other materials in opaque media.

Further work aims to continue testing various designs of the drug delivery system, as well as other formulations of corresponding dosage forms, to optimise the release of active pharmaceutical agent from the device.