Analysis of Bead Sizes for MR Capsules Labeled for Sprinkle

Nagavelli, Laxma R.; Lionberger, Robert; Sayeed, Vilayat A.; Yu, Lawrence X.; Allgire, James F.; Smith, Anjanette P.; Wokovich, Anna M.; Westenberger, Benjamin J.; Buhse, Lucinda F.

doi:10.1208/s12249-010-9529-2

Cited by 10 publications

(5 citation statements)

References 6 publications

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“…Several formulation features of DR/ER-MPH contribute to its consistent MPH release rates despite altered evening food intake. Tiny microbeads (<1 mm in diameter), such as DR/ER-MPH, are rapidly emptied from the stomach (Davis et al 1986) and, as such, expected to be minimally affected by food-induced effects on gastric emptying (Nagavelli et al 2010). Based on the properties of the DR and ER layers, initial dissolution and absorption of MPH are not dependent on any single factor, such as pH or variations in gastrointestinal transit (Childress et al 2018), both factors that can be affected by food.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of HLD200, a Delayed-Release and Extended-Release Methylphenidate: Evaluation of Dose Proportionality, Food Effect, Multiple-Dose Modeling, and Comparative Bioavailability with Immediate-Release Methylphenidate in Healthy Adults

Liu

Gobburu

Po³

et al. 2019

Journal of Child and Adolescent Psychopharmacology

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Objectives: HLD200, an oral, once-daily, evening-dosed, delayed-release, and extended-release methylphenidate (DR/ER-MPH), was designed to provide efficacy from the early morning, throughout the day, and into the evening to individuals with attention-deficit/hyperactivity disorder. The objectives were to evaluate DR/ER-MPH pharmacokinetic (PK) properties in healthy adults, including dose proportionality, food effect, the potential of accumulation using multiple-dose modeling, and bioavailability compared to an immediate-release MPH (IR MPH). Methods: Three open-label, single-dose, crossover studies were conducted, all with a 7-day washout between treatments. In Study I, 20 subjects received evening-dosed DR/ER-MPH (20 and 100 mg) followed by a medium-fat breakfast; 13 subjects received a subsequent 100-mg dose of DR/ER-MPH followed by a low-fat breakfast. In Study II, 18 subjects were evaluated after receiving evening-dosed DR/ER-MPH (100 mg) under 3 conditions: immediately after a high-fat meal, sprinkled on applesauce, and in a fasted state. In Study III, 11 and 12 subjects received evening-dosed DR/ER-MPH (100 mg) and morning-dosed IR MPH (20 mg), respectively. Results: DR/ER-MPH demonstrated dose proportionality between 20- and 100-mg doses. DR/ER-MPH PK parameters were not significantly affected by breakfast content or by sprinkling capsule contents. A high-fat meal immediately preceding evening dosing did not affect total MPH exposure but lowered peak MPH exposure by 14% and 11% versus fasted and sprinkled states, and time to peak exposure was delayed by ∼2.5 hours; these PK differences are unlikely to be clinically significant. Based on multiple-dose simulations using data from Study I, negligible accumulation of DR/ER-MPH was predicted. The relative bioavailability for DR/ER-MPH compared to IR MPH was 73.9%. No serious adverse events (AEs) were reported, and the observed AEs were consistent with MPH. There were no discontinuations in Studies I and III, but three participants withdrew in Study II due to AEs. Conclusions: Evening-dosed DR/ER-MPH demonstrated dose proportionality and can be administered with or without food. Significant accumulation is unlikely with multiple dosing.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of HLD200, a Delayed-Release and Extended-Release Methylphenidate: Evaluation of Dose Proportionality, Food Effect, Multiple-Dose Modeling, and Comparative Bioavailability with Immediate-Release Methylphenidate in Healthy Adults

Liu

Gobburu

Po³

et al. 2019

Journal of Child and Adolescent Psychopharmacology

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“…They report that this size should ensure adequate mouthfeel and reduce the risk of inadvertent chewing although it is not stated whether this is based on adults or a paediatric population. The multiparticulate sizes used in approved modified release capsules labelled for sprinkling on food was reported; the majority of products had multiparticulate sizes of <1.5 mm …”

Section: Discussionmentioning

confidence: 99%

“…The multiparticulate sizes used in approved modified release capsules labelled for sprinkling on food was reported; the majority of products had multiparticulate sizes of <1.5 mm. [57] The administration may also impact upon the mouthfeel, for example products administered directly into the mouth are likely to feel more gritty than those mixed with soft food before administration. Lopez et al [58] assessed the mouthfeel of spherical cellulose multiparticulates dispersed in liquids in young adults using a VAS from very smooth to very gritty.…”

Section: Particle Size Texture and Hardnessmentioning

confidence: 99%

Evidence of acceptability of oral paediatric medicines: a review

Mistry

Batchelor

2017

Journal of Pharmacy and Pharmacology

125

109

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Objectives The aim of this review was to map the currently available evidence on acceptability of oral paediatric medicines to aid in the selection of suitable platform formulations for the development of new acceptable paediatric products. Methods This process used a defined search strategy of indexed publications and included methods to assess the quality of the evidence retrieved. Key findings Taste/palatability was the most extensively studied area of paediatric medicine acceptability yet standard methods or criteria that define what is classed as acceptable to children is still to be defined. There have been many reports on the acceptability of medicines to paediatric populations yet major gaps in the acceptability knowledge base exist including the shape and dimensions of tablets, minitablets and capsules swallowed whole in infants and children; size and overall volume of multiparticulates; volume of liquids completely swallowed in infants and children; duration of retention within the oral cavity, size and taste of orodispersible tablets, lozenges and chewable tablets and the number of solid units dosed at each time point. Conclusions The review highlights where further information is required to support knowledge around acceptability of age-appropriate medicines. An algorithm to aid in selection of a formulation that is likely to be acceptable based on the age range to be treated by the medicine is presented as a result of this review. IntroductionThere is much evidence to support the need for age-appropriate medicines to treat paediatric patients. Pharmaceutical products for the paediatric population have a number of considerations that may not apply to adult products. In particular, the acceptability of a product needs to be clearly defined for paediatric populations and this is currently an area of great interest.The importance and incentive to study the acceptability, including palatability, of paediatric formulations was discussed in the reflection paper [1] and endorsed in the latest European Paediatric guideline on pharmaceutical development of formulations for paediatric use.[2] Before this regulatory change, there was no requirement for medicines to be demonstrated to be acceptable to children. Guidance issued by the European Medicines Agency (EMA) in 2013 states that patient acceptability must be an integral part of paediatric formulation development and described in the paediatric investigation plan (PIP).[3] Acceptability has previously been defined as 'an overall ability of the patient and caregiver (defined as "user") to use a medicinal product as intended (or authorised)'.[4] The palatability of paediatric medicines is one of the most important formulation factors in the acceptability of liquid medicines with potential to influence adherence to therapeutic regimens and outcomes.[5] Palatability has been defined as, 'the overall appreciation of a (often oral) medicine by organoleptic properties such as vision (appearance), smell, taste, aftertaste and mouth feel (e.g. texture, cooli...

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“…However, such hydrocortisone suspensions are not licensed, the hydrocortisone content may be inconsistent leading to treatment failures [30], and may contain sucrose, which can have adverse effects on teeth with long-term use [31]. Food is chewed to <2 mm [32]; therefore, sprinkling beads of smaller size onto food should not cause problems swallowing. Furthermore, sprinkling of medication may have advantages in improving adherence and facilitate caregiving of patients with swallowing difficulties.…”

Section: Discussionmentioning

confidence: 99%

Hydrocortisone Granules Are Bioequivalent When Sprinkled Onto Food or Given Directly on the Tongue

Daniel

Digweed

Quirke

et al. 2019

Journal of the Endocrine Society

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Background Immediate-release hydrocortisone granules in capsules for opening in pediatric-appropriate doses have recently been licensed for children with adrenal insufficiency. This study evaluated the bioavailability of hydrocortisone granules administered as sprinkles onto soft food and yogurt compared with direct administration to the back of the tongue. Methods Randomized, 3-period crossover study in 18 dexamethasone-suppressed healthy men. In each period, the fasted participants received 5 mg hydrocortisone granules either directly to the back of the tongue or sprinkled onto soft food (applesauce), or yogurt, followed by 240 mL of water. Serum cortisol was measured by liquid chromatography tandem mass spectometry. Results The cortisol geometric mean maximum concentration (Cmax) and area under the curve (AUC) for direct administration, sprinkles onto yogurt, and sprinkles onto soft food were: Cmax 428, 426, 427 nmol/L and AUC0-inf 859, 886, 844 h × nmol/L, and AUC0-t 853, 882, 838 h × nmol/L respectively. The 90% CI for the ratios of Cmax, AUC0-inf and AUC0-t for administration with soft food or yogurt to direct administration were well within the bioequivalent range, 80% to 125%. Median time to Cmax (Tmax) was similar between methods of administration: 0.63 hours administered directly, 0.75 hours on soft food and 0.75 hours on yogurt. No adverse events occurred during the study. Conclusions Hydrocortisone granules administered as sprinkles onto soft food or yogurt but not mixed with these foods are bioequivalent to those administered directly to the back of the tongue. Carers, parents, or patients may choose to administer hydrocortisone granules either directly or sprinkled onto soft food or yogurt.

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Analysis of Bead Sizes for MR Capsules Labeled for Sprinkle

Cited by 10 publications

References 6 publications

Pharmacokinetics of HLD200, a Delayed-Release and Extended-Release Methylphenidate: Evaluation of Dose Proportionality, Food Effect, Multiple-Dose Modeling, and Comparative Bioavailability with Immediate-Release Methylphenidate in Healthy Adults

Pharmacokinetics of HLD200, a Delayed-Release and Extended-Release Methylphenidate: Evaluation of Dose Proportionality, Food Effect, Multiple-Dose Modeling, and Comparative Bioavailability with Immediate-Release Methylphenidate in Healthy Adults

Evidence of acceptability of oral paediatric medicines: a review

Hydrocortisone Granules Are Bioequivalent When Sprinkled Onto Food or Given Directly on the Tongue

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