Use of Model-Informed Drug Development to Streamline Development of Long-Acting Products: Can These Successes Be Translated to Long-Acting Hormonal Contraceptives?

Long-acting contraceptives are the most effective reversible contraceptive methods. Increasing patients' access to these contraceptives may translate into fewer unintended pregnancies and lead to substantial individual and public health benefits. However, development of long-acting products can be complex and challenging. This review provides (a) an overview of representative development programs for long-acting antipsychotics as cases for conceptual translation to long-acting contraceptives, (b) several case examples on how modeling and simulation have been used to streamline the development of long-acting products, and (c) examples of challenges andopportunities in developing long-acting contraceptives and information on how exposure-response relationships of commonly used progestins may enable regulators and developers to rely on prior findings of effectiveness and safety from an approved contraceptive to streamline the development of long-acting contraceptives. The US Food and Drug Administration is seeking assistance from stakeholders to provide data from studies in which pharmacokinetic and pharmacodynamic or clinical outcomes of hormonal contraceptives were evaluated and not previously submitted.

Contraceptive and Infertility Target DataBase: a contraceptive drug development tool for targeting and analysis of human reproductive specific tissues†.

The long and challenging drug development process begins with discovery biology for the selection of an appropriate target for a specific indication. Target is a broad term that can be applied to a range of biological entities such as proteins, genes, and ribonucleic acids (RNAs). Although there are numerous databases available for mining biological entities, publicly available searchable, downloadable databases to aid in target selection for a specific disease or indication (e.g., developing contraceptives and infertility treatments) are limited. We report the development of the Contraceptive and Infertility Target DataBase (https://www.citdbase.org), which provides investigators an interface to mine existing transcriptomic and proteomic resources to identify high-quality contraceptive/infertility targets. The development of similar databases is applicable to the identification of targets for other diseases and conditions.

Using the Slug Mucosal Irritation Assay to Investigate the Tolerability of Tablet Excipients on Human Skin in the Context of the Use of a Nipple Shield Delivery System.

PURPOSE: Neonates are particularly challenging to treat. A novel patented drug delivery device containing a rapidly disintegrating tablet held within a modified nipple shield (NSDS) was designed to deliver medication to infants during breastfeeding. However concerns exist around dermatological nipple tolerability with no pharmaceutical safety assessment guidance to study local tissue tolerance of the nipple and the areola. This is the first Slug Mucosal Irritation (SMI) study to evaluate irritancy potential of GRAS excipients commonly used to manufacture rapidly disintegrating immediate release solid oral dosage form METHODS: Zinc sulphate selected as the antidiarrheal model drug that reduces infant mortality, was blended with functional excipients at traditional levels [microcrystalline cellulose, sodium starch glycolate, croscarmellose sodium, magnesium stearate]. Slugs were exposed to blends slurried in human breast milk to assess their stinging, itching or burning potential, using objective values such as mucus production to categorize irritation potency RESULTS: Presently an in vivo assay, previously validated for prediction of ocular and nasal irritation, was used as an alternative to vertebrate models to anticipate the potential maternal dermatological tolerability issues to NSDS tablet components. The excipients did not elicit irritancy. However, mild irritancy was observed when zinc sulphate was present in blends. CONCLUSION: These promising good tolerability results support the continued investigation of these excipients within NSDS rapidly disintegrating tablet formulations. Topical local tolerance effects being almost entirely limited to irritation, the slug assay potentially adds to the existing preformulation toolbox, and may sit in between the in vitro and existing in vivo assays.

Reducing infectivity of HIV upon exposure to surfaces coated with N,N-dodecyl, methyl-polyethylenimine.

The infectivity of high-titer, cell-free HIV in culture media and human milk is rapidly reduced upon exposure to polyethylene slides painted with the linear hydrophobic polycation N,N-dodecyl,methyl-polyethylenimine (DMPEI). Accompanying viral p24 protein and free viral RNA analysis of solutions exposed to DMPEI-coated surfaces suggests that virion attachment to the polycationic surface and its subsequent inactivation are the likely mechanism of this phenomenon.

Attitudes toward a novel breastfeeding-mediated drug and nutrient delivery system: A qualitative study.

The objective of this study was to determine the attitudes and impressions of breastfeeding mothers and healthcare practitioners towards a device concept integrating breastfeeding with infant drug and nutrient administration. This was an exploratory qualitative study involving 20 breastfeeding mothers and 6 healthcare practitioners from the Suffolk and Middlesex County areas of Massachusetts, USA each individually interviewed. Interview transcription of the semi-structured interviews by an independent service began during data collection, and data coding into major themes continued until and after data saturation was reached. Repeated medication delivery with a reusable product was highlighted as a potential use case for the device concept; ease of use and cleaning as well as cost, familiarity with the method, and infant response were identified as critical considerations. Participants questioned device suitability with liquid formulations (as opposed to non-liquid), while potential advantages over alternative medication delivery technology like oral syringes were identified, including a more "natural" feeling. Most participants had prior knowledge of, or personal experience with, devices like commercially available nipple shields. Attitudes towards the NSDS were not determined by experience with nipple shields, however. The participants' prior exposure to nipple shields is in contrast to related studies in Kenya and South Africa where commercial nipple shields were not widely known and where specific concerns surrounding potential community stigma to an unknown device were raised by participants.

Innovations in Pediatric Drug Formulations and Administration Technologies for Low Resource Settings.

Despite advances in regulations and initiatives to increase pediatric medicine development, there is still an unmet need for age-appropriate medicines for children. The availability of pediatric formulations is particularly lacking in resource poor areas, due to, for example, area-specific disease burden and financial constraints, as well as disconnected supply chains and fragmented healthcare systems. The paucity of authorized pediatric medicines often results in the manipulation and administration of products intended for adults, with an increased risk of mis-dosing and adverse reactions. This article provides an overview of the some of the key difficulties associated with the development of pediatric medicines in both high and low resource areas, and highlights shared and location specific challenges and opportunities. The utilization of dispersible oral dosage forms and suppositories for low and middle-income countries (LMICs) are described in addition to other platform technologies that may in the future offer opportunities for future pediatric medicine development for low resource settings.

An assessment of infant medication administration and storage practices in selected communities in the Vhembe District of Limpopo Province, South Africa.

BACKGROUND: Effective infant medication administration and storage is a major public health challenge outlined by the World Health Organization. These challenges may be exacerbated in rural or limited-resource areas. AIM: The aim of this study was to investigate infant medication administration and storage practices. SETTING: This study took place in selected communities in the Vhembe District of Limpopo Province, South Africa. METHOD: Data was collected through 39 semi-structured interviews with infant caretakers and rural health workers. Interviews were recorded when permission was given by participants. Interviews were transcribed and coded using grounded theory and Tesch's model of data analysis. Themes were agreed upon through consensus discussions with the researchers and an independent coder. RESULTS: Six themes that affect current infant medication administration and storage practices in the Vhembe District were identified: access to infant healthcare, the role of health workers, the devices used in the administration of infant medication, reluctance of the infant to take the medication, storage and reuse of infant medication in the rural home and hygiene practices surrounding infant medication administration. CONCLUSIONS: Many factors were found to affect infant medication administration and storage practices in in the Vhembe District. Substantial evidence was found to suggest that the relationship between rural health workers and infant caretakers strongly influences these practices: a great amount of reliance and trust is placed in the health worker. Ensuring proper dosage of infant medication in the rural household arose as a main concern of participants. Reuse of medication in the home and home hygiene practices surrounding infant medication administration are areas of potential future research. This future research may further inform recommendations for infant medication administration and storage practices in the Vhembe District.

Mimicking the Impact of Infant Tongue Peristalsis on Behavior of Solid Oral Dosage Forms Administered During Breastfeeding.

An in vitro simulation system was developed to study the effect of an infant's peristaltic tongue motion during breastfeeding on oral rapidly disintegrating tablets in the mouth, for use in rapid product candidate screening. These tablets are being designed for use inside a modified nipple shield worn by a mother during breastfeeding, a proposed novel platform technology to administer drugs and nutrients to breastfeeding infants. In this study, the release of a model compound, sulforhodamine B, from tablet formulations was studied under physiologically relevant forces induced by compression and rotation of a tongue mimic. The release profiles of the sulforhodamine B in flowing deionized water were found to be statistically different using 2-way ANOVA with matching, when tongue mimic rotation was introduced for 2 compression levels representing 2 tongue strengths (p = 0.0013 and p < 0.0001 for the lower and higher compression settings, respectively). Compression level was found to be a significant factor for increasing model compound release at rotational rates representing nonnutritive breastfeeding (p = 0.0162). This novel apparatus is the first to simulate the motion and pressures applied by the tongue and could be used in future infant oral product development.

Characterisation of zinc delivery from a nipple shield delivery system using a breastfeeding simulation apparatus.

Zinc delivery from a nipple shield delivery system (NSDS), a novel platform for administering medicines to infants during breastfeeding, was characterised using a breastfeeding simulation apparatus. In this study, human milk at flow rates and pressures physiologically representative of breastfeeding passed through the NSDS loaded with zinc-containing rapidly disintegrating tablets, resulting in release of zinc into the milk. Inductively coupled plasma optical emission spectrometry was used to detect the zinc released, using a method that does not require prior digestion of the samples and that could be applied in other zinc analysis studies in breast milk. Four different types of zinc-containing tablets with equal zinc load but varying excipient compositions were tested in the NSDS in vitro. Zinc release measured over 20 minutes ranged from 32-51% of the loaded dose. Total zinc release for sets tablets of the same composition but differing hardness were not significantly different from one another with P = 0.3598 and P = 0.1270 for two tested pairs using unpaired t tests with Welch's correction. By the same test total zinc release from two sets of tablets having similar hardness but differing composition were also not significantly significant with P = 0.2634. Future zinc tablet composition and formulation optimisation could lead to zinc supplements and therapeutics with faster drug release, which could be administered with the NSDS during breastfeeding. The use of the NSDS to deliver zinc could then lead to treatment and prevention of some of the leading causes of child mortality, including diarrheal disease and pneumonia.

Acceptability of a nipple shield delivery system administering antiviral agents to prevent mother-to-child transmission of HIV through breastfeeding.

BACKGROUND: Breastfeeding is a route of mother-to-child transmission (MTCT) of the human immunodeficiency virus (HIV). The World Health Organization recommends antiretroviral (ARV) prophylaxis as the best method to prevent mother-to-child transmission of HIV (PMTCT) during breastfeeding. The nipple shield delivery system (NSDS) is being developed as an accessible method to deliver ARVs to infants and PMTCT during breastfeeding. The NSDS can potentially circumvent hygiene and storage issues in delivering drugs to infants in low-resource settings. OBJECTIVES: The primary objective was to determine acceptability of the NSDS for PMTCT in Kenya. Secondary objectives included assessing mothers' understanding of MTCT and identifying cultural and implementation issues that might affect NSDS acceptability. METHODS: Eleven focus group discussions were conducted, each group consisting of 7 to 12 participants. Seven focus group discussions consisted of HIV-positive mothers, 2 included grandmothers/mothers-in-law, and 2 included fathers/husbands. Ten in-depth interviews were also conducted with individual maternal/child health care providers. Topics included infant feeding and HIV stigma, as well as safety, effectiveness, and feasibility of the NSDS. Device prototypes were used in discussions. RESULTS: Participants felt that the NSDS could be trusted if validated scientifically and promoted by health care professionals. HIV-related stigma, access, efficacy, and hygiene were identified as important considerations for acceptance. CONCLUSION: The NSDS is a potentially acceptable method of PMTCT during breastfeeding. Further studies are needed to confirm acceptability, safety, and efficacy. For NSDS adoption to PMTCT, strategies will need to be developed to minimize HIV-related stigma and to ensure that continuous hygiene of the device is maintained.

Characterising the disintegration properties of tablets in opaque media using texture analysis.

Tablet disintegration characterisation is used in pharmaceutical research, development, and quality control. Standard methods used to characterise tablet disintegration are often dependent on visual observation in measurement of disintegration times. This presents a challenge for disintegration studies of tablets in opaque, physiologically relevant media that could be useful for tablet formulation optimisation. This study has explored an application of texture analysis disintegration testing, a non-visual, quantitative means of determining tablet disintegration end point, by analysing the disintegration behaviour of two tablet formulations in opaque media. In this study, the disintegration behaviour of one tablet formulation manufactured in-house, and Sybedia Flashtab placebo tablets in water, bovine, and human milk were characterised. A novel method is presented to characterise the disintegration process and to quantify the disintegration end points of the tablets in various media using load data generated by a texture analyser probe. The disintegration times in the different media were found to be statistically different (P<0.0001) from one another for both tablet formulations using one-way ANOVA. Using the Tukey post-hoc test, the Sybedia Flashtab placebo tablets were found not to have statistically significant disintegration times from each other in human versus bovine milk (adjusted P value 0.1685).

Modeling the physiological factors that affect drug delivery from a nipple shield delivery system to breastfeeding infants.

An apparatus was designed to mimic lactation from a human breast. It was used to determine the influence of milk fat content and flow rate, and suction pulse rate of a breastfeeding infant upon the release of a model compound from a nipple shield delivery system (NSDS). The NSDS would be worn by a mother to deliver drugs and nutrients to her infant during breastfeeding. Sulforhodamine B dye (SB) was used as model compound and formulated as a dispersible tablet to be placed within the NSDS. Increasing suction pulse rate from 30 to 120 pulses/min clearly correlated with increased cumulative release of SB for the same volume of milk passed through the NSDS. No distinct correlation was found between flow rates (1, 5, and 8 mL/min) and SB release, possibly because of competing factors controlling release rate at different flow rates. A highly similar SB release rate into two fat content fluids (2.9 and 4.2 wt %) was observed for identical flow conditions. This proof of concept study outlines a novel method to mimic lactation from a breast, and future studies will lead to effective methods to identify key physiological factors that influence drug release from a NSDS.

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

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/HIV(IIIB) 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.