Milk as a medium for pediatric formulations: Experimental findings and regulatory aspects

Soulele, Konstantina; Macheras, Panos

doi:10.1016/j.ijpharm.2015.05.015

Cited by 11 publications

(8 citation statements)

References 12 publications

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“…We have previously gained a new understanding of milk as a pediatric drug delivery system for poorly water-soluble drugs by considering the impact of digestion on the lipid species produced and their subsequent interaction with drugs during the digestion process. − Full cream milk typically contains 3.5–4.0% w/v fat, of which about 98% are triglycerides and could potentially serve as a lipid-based formulation for the delivery of poorly water-soluble drugs for pediatric acceptability. − Previous reports have shown that administration of clofazimine with fat-containing food can improve the oral bioavailability, although the results are highly variable. , Administration of clofazimine with a high-fat meal, for example, has been shown to improve the bioavailability of clofazimine compared to fasting . Clofazimine should therefore be taken with food or milk, as recommended by WHO, although the effects of milk on the solubilization of clofazimine are unclear and no bioavailability studies have been conducted.…”

Section: Introductionmentioning

confidence: 99%

Solid-State Behavior and Solubilization of Flash Nanoprecipitated Clofazimine Particles during the Dispersion and Digestion of Milk-Based Formulations

et al. 2019

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Clofazimine, a drug previously used to treat leprosy, has recently been identified as a potential new drug for the treatment for cryptosporidiosis: a diarrheal disease that contributes to 500 000 infant deaths a year in developing countries. Rapid dissolution and local availability of the drug in the small intestine is considered key to the treatment of the infection. However, the commercially available clofazimine formulation (Lamprene) is not well-suited to pediatric use, and therefore reformulation of clofazimine is desirable. Development of clofazimine nanoparticles through the process of flash nanoprecipitation (FNP) has been previously shown to provide fast and improved drug dissolution rates compared to clofazimine crystals and Lamprene. In this study, we investigate the effects of milk-based formulations (as possible pediatric-friendly vehicles) on the in vitro solubilization of clofazimine formulated as either lecithin- or zein/casein-stabilized nanoparticles. Milk and infant formula were used as the lipid vehicles, and time-resolved synchrotron X-ray scattering was used to monitor the presence of crystalline clofazimine in suspension during in vitro lipolysis under intestinal conditions. The study confirmed faster dissolution of clofazimine from all the FNP formulations after the digestion of infant formula was initiated, and a reduced quantity of fat was required to achieve similar levels of drug solubilization compared to the reference drug material and the commercial formulation. These attributes highlight not only the potential benefits of the FNP approach to prepare drug particles but also the fact that enhanced dissolution rates can be complemented by considering the amount of co-administered fat in lipid-based formulations to drive the solubilization of poorly soluble drugs.

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Section: Introductionmentioning

confidence: 99%

Solid-State Behavior and Solubilization of Flash Nanoprecipitated Clofazimine Particles during the Dispersion and Digestion of Milk-Based Formulations

et al. 2019

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“…Development of products using milk still remains a major hurdle [29]. Although spray dried milk powder and freeze dried milk [30,31] have been previously studied as vehicles for poorly water-soluble drugs, albeit in a dissolution context, their use has not progressed into products.…”

Section: Resultsmentioning

confidence: 99%

The impact of digestion is essential to the understanding of milk as a drug delivery system for poorly water soluble drugs

Boyd

Salim

Ramirez

et al. 2018

Journal of Controlled Release

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Milk has previously been considered as a potential lipid-based drug delivery system for poorly water soluble drugs but it has never gained significant attention. This is in part because relying on solubility in lipid-based formulations (in this case milk) does not provide a complete picture of the behavior of such systems upon digestion. Herein, we demonstrate using time resolved X-ray scattering that the digestion of milk is actually crucial to the solubilisation of a poorly water-soluble drug, halofantrine. Halofantrine was chosen because its behaviour in lipid-based formulations has been widely investigated and because of its close structural relationship to lumefantrine, an antimalarial drug of current interest for the treatment of paediatric malaria. The transformation of the drug from a crystalline solid form in suspension in milk, to a solubilised form as a direct consequence of lipolysis highlights that consideration of digestion of the milk lipids as a critical process that influences drug solubilisation and availability for absorption is vital.

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“…(10,11) A novel "Nipple Shield Delivery System" (NSDS) has been proposed as a means to address some of these challenges, with preliminary proof-of-concept in vitro simulation studies and non-clinical user-acceptability studies conducted in the past five years. (12 -16) This thin disposable device (Figure 1), in one format, could be adapted from an existing nipple shield breastfeeding aid to contain a fast dispersible or rapidly disintegrating tablet, and placed over the mother's breast just before infant feeding (12).…”

Section: A Potential Solution To the Paediatric Drug Product Technolomentioning

confidence: 99%

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

Kendall¹,

Lenoir²,

Gerrard³

et al. 2017

Pharm Res

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PurposeNeonates 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 MethodsZinc 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 ResultsPresently 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. ConclusionThese 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. words (limit 250) KEY WORDS:Nipple Shield Delivery System, Slug Mucosal Irritation Assay, Skin Tolerability, Tablet INTRODUCTION Identifying the paediatric drug product technology gapThe development of age appropriate medicines which deliver an active pharmaceutical ingredient (API) to children at the required rate and extent is a complex process. Neonates are a particularly challenging sub-population to address for formulation scientists due to issues including dysphagia, taste aversion, and the need for frequent dose modifications. (1) Liquid formulations have been typically the dosage forms of choice for paediatric drug administration, but are often not practical in developing countries because of high cost, lack of access to refrigeration, contamination issues and limited shelf life.(2 -4) They may also be unpalatable and contain undesirable or unsafe preservatives and solvents. (5) Solid oral dosage forms for infants are often scaled down from adult doses, and there is currently a debate on the limitations of clinical work performed to demonstrate suitability of the dose to the infant. (6, 7) Dispersible tablets can also be used, but require clean sources of water for reconstitution. They also require administration device...

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Milk as a medium for pediatric formulations: Experimental findings and regulatory aspects

Cited by 11 publications

References 12 publications

Solid-State Behavior and Solubilization of Flash Nanoprecipitated Clofazimine Particles during the Dispersion and Digestion of Milk-Based Formulations

Solid-State Behavior and Solubilization of Flash Nanoprecipitated Clofazimine Particles during the Dispersion and Digestion of Milk-Based Formulations

The impact of digestion is essential to the understanding of milk as a drug delivery system for poorly water soluble drugs

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

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