Patient acceptability, safety and access: A balancing act for selecting age-appropriate oral dosage forms for paediatric and geriatric populations.

TL;DR: This review provides a comprehensive and up-to-date analysis of oral dosage forms considering key aspects of formulation design including dosage considerations, ease of use, tolerability and safety, manufacturing complexity, stability, supply and cost.

About: This article is published in International Journal of Pharmaceutics.The article was published on 2017-07-11 and is currently open access. It has received 68 citations till now.

Summary

1. Introduction

• Patient centric pharmaceutical drug product design may be described as "the process of identifying the comprehensive needs of individuals or the target patient population and utilizing the identified needs to design pharmaceutical drug products that provide the best overall benefit to risk profile for that target population over the intended duration of treatment" (Stegemann et al., 2016) .
• There is still very limited evidence based data which can be used to provide specific recommendations.
• In addition, the relative cost and supply of the product are important considerations..
• The aim of this review is to provide a comparison of different oral dosage forms according to these three criteria in order to assist pharmaceutical product formulators to select and develop the most suitable product for paediatric and geriatric patients.

2. Factors to consider for paediatric/geriatric oral dosage form design

• In designing a drug product intended for use in paediatrics or older adults, all typical considerations of adult dosage form development apply.
• As for any drug product, API properties which can impact the selection of dosage form include for example biopharmaceutical classification, physico-chemical properties, stability, dose and required release rate (Kuentz et al., 2016) .
• Hence, additional factors need to be taken into account when developing products for these groups.
• The ease of use of a medicinal product (including dose flexibility), is one aspect that affects its overall acceptability to patients, and in this review, this broader concept of patient acceptability has been considered instead.
• It can have a significant impact on patient adherence and therefore safe and effective therapy, and should be considered for all patients, including older adults.

3. Acceptability

• Oral dosage forms may be divided into those which provide flexible doses, such as liquids and multiparticulates, and those which provide unit doses, such as tablets and capsules.
• In the current review, studies that generated evidence in dosage form acceptability are presented in Table 3 according to different age groups including children and older adults.
• For the purpose of this review, the sub-division of the older population was not included in Table 3 , due to the limited studies conducted in this patient population compared to those in children.
• Similar to liquid formulations, the effect of administration volume together with other attributes of the dosage form (e.g. palatability) on patient acceptance needs further investigation.
• The acceptability of tablets (> 5 mm) and capsules in children and older adults is largely determined by the ability to swallow the dosage form intact.

4. Safety

• Patient safety is of great importance, and when selecting a dosage form, the safety and tolerability of the dosage form type and the required excipients used must be assessed, in particular for the younger and older age groups.
• Oral liquids commonly require the inclusion of functional excipients that may have unfavourable safety and toxicity characteristics for young and older patients, as described above, depending on their level of use and duration of treatment.
• In contrast, oral liquids, effervescent, (oro) dispersible and chewable dosage forms, and oral films, generally require the utilisation of taste masking techniques to improve their palatability.
• Whilst the risk associated with required excipients is relatively higher for liquid products than oral solid products, choking is another potential safety risk in using oral medicines for paediatric and older patients.
• Similar risks of mis-dosing to those described above for oral liquids are applicable to multiparticulates, unless they are presented in unit dose formats such as sachets.

5. Access

• Along with key considerations associated with patient acceptability and safety, enabling access to the medicine is fundamental, for patients of all ages.
• A comparison of anticipated relative cost, stability risk, manufacturing complexity and supply chain challenges of various oral dosage forms compared to conventional tablets is provided in Table 4 .
• Such products may require protection from moisture (via moisture protective packaging) to enable adequate shelf life.
• As with ODTs, complexity of manufacture depends on the technology used, and is also related to number of unit processes required.
• Soft gel capsules are generally used for liquid fill, for example lipid-based formulations for poorly soluble APIs and high potency APIs where content uniformity can be problematic.

6. Other dosage forms and Innovations

• This review has focussed on commonly used and well-known oral dosage forms, however the authors have investigated a number of other novel formats, but little information, if any, appears to be available on their patient acceptability.
• In Japan, an agar-based jelly (Swallowing Aid Jelly ("Magic Jelly")) has been developed to assist medicine administration in both elderly and paediatric patients (Ryukakusan Co. Ltd, https://www.ryukakusan.co.jp/productjelly/en).
• In European Nordic countries and Germany, a special coating (MEDCOAT®) is available that can be applied to tablets and capsules by patients to assist swallowing.
• The development of printed medicines has gained interest in recent years, and may offer the potential for personalised medicines whereby the dose of API and product properties are tailored to the patient.
• This product utilises ZipDose® technology whereby powder blend is deposited as a single layer, and an aqueous binding fluid is applied.

7. Conclusions

• This review provides a comprehensive comparison of various oral dosage forms relating to evidence-based patient acceptability, safety and access, to assist pharmaceutical product formulators to select and develop the most suitable product for their intended patient population.
• It is recognised that patient acceptability may be influenced by many factors, but the availability of such information in the public domain would facilitate pharmaceutical product design.
• In the case of neonates, infants and young children, this has often led to the need to utilise juvenile animal data (when available), to support their use.
• Similarly, it is suggested that companies and excipient suppliers are encouraged to make public their safety data on excipients, for example by sharing it via the EuPFI Safety and Toxicity of Excipients in Paediatrics database (Salunke et al., 2013) .
• The evaluation of the accessibility (stability, ease/cost of development, manufacture and supply) of the oral dosage forms has highlighted that those with the most favourable access, for example conventional tablets, may not necessarily be the most acceptable for all patients.

Figures

Table 2 Comparison of key features of oral dosage forms* 139

Table 1 Factors to consider for the selection of an oral dosage form 137

Table 3 Literature-based evidence for patient acceptability of oral dosage forms according to age 332

Table 4 Relative cost, stability risk, manufacturing complexity and supply chain 548 challenges of various oral dosage forms compared to conventional tablets 549

Frequently asked questions

Q1. What are the contributions in this paper?

This review provides a 36 comprehensive and up-to-date analysis of oral dosage forms considering key aspects of 37 formulation design including dosage considerations, ease of use, tolerability and safety, 38 manufacturing complexity, stability, supply and cost. Safety considerations including excipients and potential risk of administration 41 errors of the different dosage forms are also discussed, together with possible manufacturing 42 and supply challenges.