Patient-Centred Pharmaceutical Design to Improve Acceptability of Medicines: Similarities and Differences in Paediatric and Geriatric Populations
Identifieur interne : 000E35 ( Pmc/Corpus ); précédent : 000E34; suivant : 000E36Patient-Centred Pharmaceutical Design to Improve Acceptability of Medicines: Similarities and Differences in Paediatric and Geriatric Populations
Auteurs : Fang Liu ; Sejal Ranmal ; Hannah K. Batchelor ; Mine Orlu-Gul ; Terry B. Ernest ; Iwan W. Thomas ; Talia Flanagan ; Catherine TuleuSource :
- Drugs [ 0012-6667 ] ; 2014.
Abstract
Patient acceptability of a medicinal product is a key aspect in the development and prescribing of medicines. Children and older adults differ in many aspects from the other age subsets of population and require particular considerations in medication acceptability. This review highlights the similarities and differences in these two age groups in relation to factors affecting acceptability of medicines. New and conventional formulations of medicines are considered regarding their appropriateness for use in children and older people. Aspects of a formulation that impact acceptability in these patient groups are discussed, including, for example, taste/smell/viscosity of a liquid and size/shape of a tablet. A better understanding of the acceptability of existing formulations highlights opportunities for the development of new and more acceptable medicines and facilitates safe and effective prescribing for the young and older populations.
The online version of this article (doi:10.1007/s40265-014-0297-2) contains supplementary material, which is available to authorized users.
Url:
DOI: 10.1007/s40265-014-0297-2
PubMed: 25274536
PubMed Central: 4210646
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PMC:4210646Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Patient-Centred Pharmaceutical Design to Improve Acceptability of Medicines: Similarities and Differences in Paediatric and Geriatric Populations</title><author><name sortKey="Liu, Fang" sort="Liu, Fang" uniqKey="Liu F" first="Fang" last="Liu">Fang Liu</name><affiliation><nlm:aff id="Aff1">Department of Pharmacy, School of Life and Medical Sciences, University of Hertfordshire, Hatfield, AL10 9AB UK</nlm:aff></affiliation></author><author><name sortKey="Ranmal, Sejal" sort="Ranmal, Sejal" uniqKey="Ranmal S" first="Sejal" last="Ranmal">Sejal Ranmal</name><affiliation><nlm:aff id="Aff2">Department of Pharmaceutics, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX UK</nlm:aff></affiliation></author><author><name sortKey="Batchelor, Hannah K" sort="Batchelor, Hannah K" uniqKey="Batchelor H" first="Hannah K." last="Batchelor">Hannah K. Batchelor</name><affiliation><nlm:aff id="Aff3">Pharmacy, Pharmacology and Therapeutics, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT UK</nlm:aff></affiliation></author><author><name sortKey="Orlu Gul, Mine" sort="Orlu Gul, Mine" uniqKey="Orlu Gul M" first="Mine" last="Orlu-Gul">Mine Orlu-Gul</name><affiliation><nlm:aff id="Aff2">Department of Pharmaceutics, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX UK</nlm:aff></affiliation></author><author><name sortKey="Ernest, Terry B" sort="Ernest, Terry B" uniqKey="Ernest T" first="Terry B." last="Ernest">Terry B. Ernest</name><affiliation><nlm:aff id="Aff4">GlaxoSmithKline, Harlow, Essex CM19 5AW UK</nlm:aff></affiliation></author><author><name sortKey="Thomas, Iwan W" sort="Thomas, Iwan W" uniqKey="Thomas I" first="Iwan W." last="Thomas">Iwan W. Thomas</name><affiliation><nlm:aff id="Aff5">Piramal Healthcare UK Ltd, Morpeth, Northumberland NE61 3YA UK</nlm:aff></affiliation></author><author><name sortKey="Flanagan, Talia" sort="Flanagan, Talia" uniqKey="Flanagan T" first="Talia" last="Flanagan">Talia Flanagan</name><affiliation><nlm:aff id="Aff6">Pharmaceutical Development, AstraZeneca, Macclesfield, Cheshire SK10 2NA UK</nlm:aff></affiliation></author><author><name sortKey="Tuleu, Catherine" sort="Tuleu, Catherine" uniqKey="Tuleu C" first="Catherine" last="Tuleu">Catherine Tuleu</name><affiliation><nlm:aff id="Aff2">Department of Pharmaceutics, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX UK</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">25274536</idno><idno type="pmc">4210646</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4210646</idno><idno type="RBID">PMC:4210646</idno><idno type="doi">10.1007/s40265-014-0297-2</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">000E35</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000E35</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Patient-Centred Pharmaceutical Design to Improve Acceptability of Medicines: Similarities and Differences in Paediatric and Geriatric Populations</title><author><name sortKey="Liu, Fang" sort="Liu, Fang" uniqKey="Liu F" first="Fang" last="Liu">Fang Liu</name><affiliation><nlm:aff id="Aff1">Department of Pharmacy, School of Life and Medical Sciences, University of Hertfordshire, Hatfield, AL10 9AB UK</nlm:aff></affiliation></author><author><name sortKey="Ranmal, Sejal" sort="Ranmal, Sejal" uniqKey="Ranmal S" first="Sejal" last="Ranmal">Sejal Ranmal</name><affiliation><nlm:aff id="Aff2">Department of Pharmaceutics, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX UK</nlm:aff></affiliation></author><author><name sortKey="Batchelor, Hannah K" sort="Batchelor, Hannah K" uniqKey="Batchelor H" first="Hannah K." last="Batchelor">Hannah K. Batchelor</name><affiliation><nlm:aff id="Aff3">Pharmacy, Pharmacology and Therapeutics, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT UK</nlm:aff></affiliation></author><author><name sortKey="Orlu Gul, Mine" sort="Orlu Gul, Mine" uniqKey="Orlu Gul M" first="Mine" last="Orlu-Gul">Mine Orlu-Gul</name><affiliation><nlm:aff id="Aff2">Department of Pharmaceutics, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX UK</nlm:aff></affiliation></author><author><name sortKey="Ernest, Terry B" sort="Ernest, Terry B" uniqKey="Ernest T" first="Terry B." last="Ernest">Terry B. Ernest</name><affiliation><nlm:aff id="Aff4">GlaxoSmithKline, Harlow, Essex CM19 5AW UK</nlm:aff></affiliation></author><author><name sortKey="Thomas, Iwan W" sort="Thomas, Iwan W" uniqKey="Thomas I" first="Iwan W." last="Thomas">Iwan W. Thomas</name><affiliation><nlm:aff id="Aff5">Piramal Healthcare UK Ltd, Morpeth, Northumberland NE61 3YA UK</nlm:aff></affiliation></author><author><name sortKey="Flanagan, Talia" sort="Flanagan, Talia" uniqKey="Flanagan T" first="Talia" last="Flanagan">Talia Flanagan</name><affiliation><nlm:aff id="Aff6">Pharmaceutical Development, AstraZeneca, Macclesfield, Cheshire SK10 2NA UK</nlm:aff></affiliation></author><author><name sortKey="Tuleu, Catherine" sort="Tuleu, Catherine" uniqKey="Tuleu C" first="Catherine" last="Tuleu">Catherine Tuleu</name><affiliation><nlm:aff id="Aff2">Department of Pharmaceutics, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX UK</nlm:aff></affiliation></author></analytic><series><title level="j">Drugs</title><idno type="ISSN">0012-6667</idno><idno type="eISSN">1179-1950</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Patient acceptability of a medicinal product is a key aspect in the development and prescribing of medicines. Children and older adults differ in many aspects from the other age subsets of population and require particular considerations in medication acceptability. This review highlights the similarities and differences in these two age groups in relation to factors affecting acceptability of medicines. New and conventional formulations of medicines are considered regarding their appropriateness for use in children and older people. Aspects of a formulation that impact acceptability in these patient groups are discussed, including, for example, taste/smell/viscosity of a liquid and size/shape of a tablet. A better understanding of the acceptability of existing formulations highlights opportunities for the development of new and more acceptable medicines and facilitates safe and effective prescribing for the young and older populations.</p><sec><title>Electronic supplementary material</title><p>The online version of this article (doi:10.1007/s40265-014-0297-2) contains supplementary material, which is available to authorized users.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Kozarewicz, P" uniqKey="Kozarewicz P">P Kozarewicz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Paradiso, Lm" uniqKey="Paradiso L">LM Paradiso</name></author><author><name sortKey="Roughead, Ee" uniqKey="Roughead E">EE Roughead</name></author><author><name sortKey="Gilbert, Al" uniqKey="Gilbert A">AL Gilbert</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cuzzolin, L" 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Drugs</journal-id><journal-id journal-id-type="iso-abbrev">Drugs</journal-id><journal-title-group><journal-title>Drugs</journal-title></journal-title-group><issn pub-type="ppub">0012-6667</issn><issn pub-type="epub">1179-1950</issn><publisher><publisher-name>Springer International Publishing</publisher-name><publisher-loc>Cham</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">25274536</article-id><article-id pub-id-type="pmc">4210646</article-id><article-id pub-id-type="publisher-id">297</article-id><article-id pub-id-type="doi">10.1007/s40265-014-0297-2</article-id><article-categories><subj-group subj-group-type="heading"><subject>Review Article</subject></subj-group></article-categories><title-group><article-title>Patient-Centred Pharmaceutical Design to Improve Acceptability of Medicines: Similarities and Differences in Paediatric and Geriatric Populations</article-title></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><name><surname>Liu</surname><given-names>Fang</given-names></name><address><phone>+44-1707284273</phone><email>f.liu3@herts.ac.uk</email></address><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Ranmal</surname><given-names>Sejal</given-names></name><xref ref-type="aff" rid="Aff2"></xref></contrib><contrib contrib-type="author"><name><surname>Batchelor</surname><given-names>Hannah K.</given-names></name><xref ref-type="aff" rid="Aff3"></xref></contrib><contrib contrib-type="author"><name><surname>Orlu-Gul</surname><given-names>Mine</given-names></name><xref ref-type="aff" rid="Aff2"></xref></contrib><contrib contrib-type="author"><name><surname>Ernest</surname><given-names>Terry B.</given-names></name><xref ref-type="aff" rid="Aff4"></xref></contrib><contrib contrib-type="author"><name><surname>Thomas</surname><given-names>Iwan W.</given-names></name><xref ref-type="aff" rid="Aff5"></xref></contrib><contrib contrib-type="author"><name><surname>Flanagan</surname><given-names>Talia</given-names></name><xref ref-type="aff" rid="Aff6"></xref></contrib><contrib contrib-type="author"><name><surname>Tuleu</surname><given-names>Catherine</given-names></name><xref ref-type="aff" rid="Aff2"></xref></contrib><aff id="Aff1"><label></label>Department of Pharmacy, School of Life and Medical Sciences, University of Hertfordshire, Hatfield, AL10 9AB UK</aff><aff id="Aff2"><label></label>Department of Pharmaceutics, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX UK</aff><aff id="Aff3"><label></label>Pharmacy, Pharmacology and Therapeutics, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT UK</aff><aff id="Aff4"><label></label>GlaxoSmithKline, Harlow, Essex CM19 5AW UK</aff><aff id="Aff5"><label></label>Piramal Healthcare UK Ltd, Morpeth, Northumberland NE61 3YA UK</aff><aff id="Aff6"><label></label>Pharmaceutical Development, AstraZeneca, Macclesfield, Cheshire SK10 2NA UK</aff></contrib-group><pub-date pub-type="epub"><day>2</day><month>10</month><year>2014</year></pub-date><pub-date pub-type="pmc-release"><day>2</day><month>10</month><year>2014</year></pub-date><pub-date pub-type="ppub"><year>2014</year></pub-date><volume>74</volume><issue>16</issue><fpage>1871</fpage><lpage>1889</lpage><permissions><copyright-statement>© The Author(s) 2014</copyright-statement><license license-type="OpenAccess"><license-p><bold>Open Access</bold>This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.</license-p></license></permissions><abstract id="Abs1"><p>Patient acceptability of a medicinal product is a key aspect in the development and prescribing of medicines. Children and older adults differ in many aspects from the other age subsets of population and require particular considerations in medication acceptability. This review highlights the similarities and differences in these two age groups in relation to factors affecting acceptability of medicines. New and conventional formulations of medicines are considered regarding their appropriateness for use in children and older people. Aspects of a formulation that impact acceptability in these patient groups are discussed, including, for example, taste/smell/viscosity of a liquid and size/shape of a tablet. A better understanding of the acceptability of existing formulations highlights opportunities for the development of new and more acceptable medicines and facilitates safe and effective prescribing for the young and older populations.</p><sec><title>Electronic supplementary material</title><p>The online version of this article (doi:10.1007/s40265-014-0297-2) contains supplementary material, which is available to authorized users.</p></sec></abstract><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© Springer International Publishing Switzerland 2014</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec id="d30e283"><title>Key Points</title><p><table-wrap id="Taba"><table frame="hsides" rules="groups"><tbody><tr><td align="left">Appropriate pharmaceutical design of oral medicines can improve acceptability and patient outcomes in paediatric and geriatric populations.</td></tr><tr><td align="left">Similar considerations should be given to physical characteristics affecting swallowability of tablets and capsules for use in children and older patients.</td></tr><tr><td align="left">Whilst formulation factors such as taste and smell are important features for paediatric medicines, safe swallowing is the key formulation factor in designing medicines for older patients.</td></tr></tbody></table></table-wrap></p></sec><sec id="Sec1" sec-type="intro"><title>Introduction</title><p>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)” [<xref ref-type="bibr" rid="CR1">1</xref>]. This terminology is used as the basis for this review article. Additional consideration is required in developing medicines for young and older patients as their physiological and cognitive responses may differ due to the developing and deteriorating conditions of the body, respectively. Oral administration is the most common route of drug delivery to both young and older patients. However, there are obstacles for young and older patients to accept their oral medicines, e.g. swallowing difficulties or dysphagia, the involvement of caregivers, child recalcitrance and polypharmacy in the older population, to name just a few. While these barriers may not be considered major issues for adults, they could potentially affect adherence in young and older patients. In many cases, oral medicines are modified to ease administration in these patients, ranging from simple removal from packaging to dispensing in a dosette box, to more complex alterations including crushing or splitting of solid oral dosage forms [<xref ref-type="bibr" rid="CR2">2</xref>–<xref ref-type="bibr" rid="CR6">6</xref>]. Altering medication dosage forms, whether for children or adults, leads to unlicensed use of medicines and can potentially change bioavailability, toxicity and stability of the medicines.</p><p>Guidance issued by the European Medicines Agency (EMA) highlighted that acceptability must be an integral part of paediatric formulation development [<xref ref-type="bibr" rid="CR7">7</xref>]. Recently, the EMA Geriatric Expert Group has issued a concept paper on the need for a reflection paper on the quality requirements of medicines for older adults [<xref ref-type="bibr" rid="CR8">8</xref>]. The EMA Quality Working Party is currently looking into drafting the reflection paper. Similar principles might apply to assess the acceptability of medicines in children and older adults; however, a duplicate approach might not be appropriate due to the different patient-centred issues in these two populations. The aim of this review is to highlight the similarities and differences between children and older adults in relation to the acceptability of oral medicines. A detailed analysis of barriers associated with administration of oral medicines guides the choice and development of appropriate medicines to meet the needs of both patient groups (see the Electronic Supplementary Material for a description of the search strategy).</p></sec><sec id="Sec2"><title>Patient-Centred Factors Affecting Acceptability of Oral Medicines</title><p>Table <xref rid="Tab1" ref-type="table">1</xref> summarises the most important patient-related factors that affect oral medication acceptability in children and older adults.<table-wrap id="Tab1"><label>Table 1</label><caption><p>The most important patient-related factors affecting acceptability of oral medications in children and older adults</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left">Factors</th><th align="left">Children</th><th align="left">Older adults</th></tr></thead><tbody><tr><td align="left" colspan="3">Patient characteristics</td></tr><tr><td align="left"> Age</td><td align="left">0–18 years; divided into subgroups according to age [<xref ref-type="bibr" rid="CR17">17</xref>]. A patient’s cognitive development should also be considered in acceptability of medicines</td><td align="left">>65 years; age alone is not the only determinant affecting patients’ health conditions and ability to take medicines; frailty could be more important than age</td></tr><tr><td align="left"> Health conditions</td><td align="left">A single condition is more common than the presence of co-morbidities in paediatric populations</td><td align="left">Co-morbidities are common; medication handling and administration can be affected by many diseases that are highly prevalent such as dementia, Parkinson’s disease, head and neck cancer, and stroke, and common functional conditions, e.g. visual and cognitive impairments and neuromuscular degeneration</td></tr><tr><td align="left"> Disease status</td><td align="left">Acute conditions and long-term illnesses are both present although acute conditions are more common</td><td align="left">Acute conditions and long-term illnesses are both present although chronic conditions are more common</td></tr><tr><td align="left"> Ability to swallow</td><td align="left">Very young children may have difficulties swallowing conventional tablets and capsules</td><td align="left">Dysphagia is common and affects ability to take oral medicines; many age-related conditions can cause swallowing difficulties</td></tr><tr><td align="left" colspan="3">Drug therapy-associated factors</td></tr><tr><td align="left"> Duration of therapy</td><td align="left">Short- and long-term treatments are both required although short-term treatments are more common</td><td align="left">Long-term treatments are common; acceptability to medicines can be affected by treatment outcomes of long-term therapy</td></tr><tr><td align="left"> Concomitant medications</td><td align="left">A single medication for the treatment of a single disease is more common than multiple medications due to the prevalence of acute rather than chronic illness</td><td align="left">Polypharmacy (taking more than 5 medicines at the same time) has high prevalence; the number of medicines taken can affect the preference of dosage forms, e.g. patients taking numerous tablets may prefer fixed-dose combinations</td></tr><tr><td align="left" colspan="3">Social factors</td></tr><tr><td align="left"> Responsibility for medication administration</td><td align="left">Young children are usually helped by caregivers; older children can self-administer medicines</td><td align="left">Independent-living older adults can self-administer medicines; in other cases they can be helped by caregivers</td></tr><tr><td align="left"> Caregivers</td><td align="left">Usually adults including parents/guardians, nursery practitioners and school teachers</td><td align="left">A mixture of different characteristics; could be older-age partners or nursing home/hospital nurses</td></tr><tr><td align="left"> Environments where oral medication administration occurs</td><td align="left">Home, nursery, school, hospital</td><td align="left">Home, residential home, nursing home, hospital</td></tr></tbody></table></table-wrap></p><sec id="Sec3"><title>Patient Characteristics</title><p>There is no such thing as a standard paediatric or geriatric patient. As the physiological and cognitive systems continue to develop or be impaired, chronological age is not the best indicator to predict the characteristics of the patient. Frailty does not always accompany very old age nor do all infants mature at the same rate. The heterogeneity is higher in the older adult group as the definition and recognition of the physiological changes with advanced age is diverse.</p></sec><sec id="Sec4"><title>Drug Therapy-Associated Factors</title><p>The duration of treatment and the required number of medicines potentially increase the complexity of acceptance to medicines in older adults. Many older adults are on multiple medications to treat their multi-morbidities [<xref ref-type="bibr" rid="CR9">9</xref>]. The dose regimen further complicates adherence and acceptance of medicines [<xref ref-type="bibr" rid="CR10">10</xref>]. In this respect, multi-compartment adherence aids are promising in terms of helping patients to remember to take their medicines at the right time [<xref ref-type="bibr" rid="CR11">11</xref>].</p></sec><sec id="Sec5"><title>Socio-Cultural Factors</title><p>In both populations the involvement of a caregiver is common; therefore, there is a need for the directions on usage of a medicine to be clear both to the patient and the caregiver. Older adults living in their own home may be the sole person responsible for their medicine management, whereas seniors living in nursing homes are often helped by formal carers or by nurses at hospitals. The majority of paediatric populations, except adolescents, are typically dependent on their parents/carers to take their medicines. As such, the ability and willingness of the carer to administer a medicine to these patients as intended could determine the acceptability of the medicine and outcome of the treatment [<xref ref-type="bibr" rid="CR12">12</xref>–<xref ref-type="bibr" rid="CR16">16</xref>].</p><p>The acceptability of medicines may be influenced by the setting in which the administration of the medicine takes place. Children with minor diseases may need to take medications during nursery/school hours. Chronically ill children may need to take their regular medicines or medicines for the treatment of acute problems at school. Peer pressure and child recalcitrance are potential factors affecting their acceptance of a medication form in these cases.</p></sec><sec id="Sec6"><title>Dysphagia in Children and Older Adults</title><p>The ability to swallow determines the acceptability of conventional medication forms such as tablets and capsules. Swallowing is a rapid, albeit complex, process that involves two essential actions: bolus transport and airway protection. The process of deglutition is generally divided into three main phases: the oral phase, the pharyngeal phase and the oesophageal phase. Dysphagia is defined as difficulty in swallowing and can occur in both children and older adults [<xref ref-type="bibr" rid="CR18">18</xref>]. While swallowing reflexes can be observed as early as in utero, significant maturation related to deglutition occurs between 6 months and 3 years of age, with complete maturation generally believed to have occurred by 6 years of age [<xref ref-type="bibr" rid="CR19">19</xref>, <xref ref-type="bibr" rid="CR20">20</xref>].</p><p>The prevalence of paediatric dysphagia is difficult to ascertain given the wide variations in how swallowing impairments are defined and the assessment measures used to identify them. The causes of paediatric dysphagia can be medical, developmental, behavioural, psychological, or it may indeed be a multidimensional disorder. Common aetiologies include prematurity, developmental disorders, neurological disorders, reflux and craniofacial abnormalities [<xref ref-type="bibr" rid="CR21">21</xref>, <xref ref-type="bibr" rid="CR22">22</xref>]. Although the exact incidence of dysphagia is unknown, it is reportedly becoming more common given the improved prognosis of pre-mature infants and of children with chronic medical conditions [<xref ref-type="bibr" rid="CR23">23</xref>, <xref ref-type="bibr" rid="CR24">24</xref>]. Nevertheless, it has been reported that as many as 25–45 % of typically developing children and up to 80 % of children with developmental disabilities exhibit some form of feeding disorders [<xref ref-type="bibr" rid="CR21">21</xref>].</p><p>In contrast to children, the natural process of aging is associated with a decline in swallowing function affecting all three phases of deglutition [<xref ref-type="bibr" rid="CR25">25</xref>]. Poor dentition and reduction in masticatory strength in older age are the main causes of increases in oral-phase duration and the amount of oral residue during swallowing. Age-related neuromuscular decline contributes to a delay in triggering pharyngeal swallowing reflex and decreases in bolus movement and clearance in the oesophageal phase. It was estimated that 70–90 % of the older population experience some degree of dysphagia [<xref ref-type="bibr" rid="CR26">26</xref>]. In one study, 87 % of residents in a care home (average age of 87 years) reported mealtime difficulties related to swallowing and 68 % showed signs of dysphagia [<xref ref-type="bibr" rid="CR27">27</xref>]. The prevalence of dysphagia is particularly high in patients with age-related diseases such as Parkinson’s disease (80 %), Alzheimer’s disease (40–70 %) and acute stroke (50 %) [<xref ref-type="bibr" rid="CR28">28</xref>–<xref ref-type="bibr" rid="CR31">31</xref>].</p></sec></sec><sec id="Sec7"><title>Factors Affecting Acceptability of Tablets and Capsules</title><sec id="Sec8"><title>Acceptability of Tablets and Capsules in Children</title><p>The age at which most children acquire the skills to swallow tablets and capsules safely has been the subject of much debate. Early literature widely quotes 6 years as a general age from which these dosage forms may be considered suitable for children [<xref ref-type="bibr" rid="CR32">32</xref>]. Recent evidence suggests that some children may have already acquired the ability to swallow tablets and capsules from an earlier age, or in some cases can be taught using behavioural training interventions. For example, Yeung and Wong [<xref ref-type="bibr" rid="CR33">33</xref>] found that children with HIV as young as 3 years were prescribed stavudine as a solid dosage form. In a recent study in Uganda and Zimbabwe, 36 % of children were able to swallow antiretroviral tablets intact (mean age 3.3 years), while 64 % required them to be crushed or dispersed (mean age 2.9 years) [<xref ref-type="bibr" rid="CR34">34</xref>]. Behavioural techniques to aid swallowing of both tablets and capsules involving children as young as 2–3 years old have also been described; however, such reports are limited to specific diseases and small sample sizes [<xref ref-type="bibr" rid="CR35">35</xref>–<xref ref-type="bibr" rid="CR41">41</xref>].</p><p>Although swallowing ability may be perceived to improve with age, some studies have reported swallowing difficulties in adolescence. In a general paediatric clinic in Denmark, nearly half (43 %) of parents surveyed reported children aged 12 years and younger experienced difficulties taking both liquids and tablets, primarily due to taste and swallowability; problems in administering tablets were more pronounced [<xref ref-type="bibr" rid="CR42">42</xref>]. In a qualitative study, Hansen et al. [<xref ref-type="bibr" rid="CR43">43</xref>] found that more than one-third of adolescents described difficulties in taking oral medications, particularly swallowing tablets, primarily due to taste and size. Polaha et al. [<xref ref-type="bibr" rid="CR44">44</xref>] similarly reported that around one-third of children and adolescents had refused and rejected tablets at least once; interestingly, frequent medication users were more likely to refuse them despite reportedly having better tablet swallowing skills. Difficulties in swallowing have nonetheless been implicated as a barrier to adherence in children in various chronic conditions [<xref ref-type="bibr" rid="CR38">38</xref>, <xref ref-type="bibr" rid="CR45">45</xref>–<xref ref-type="bibr" rid="CR47">47</xref>].</p><p>The ability to swallow tablets and capsules is one of the factors that influence the age at which children convert from liquid to solid formulations. Following analysis of community prescription data in Netherlands, Schirm et al. [<xref ref-type="bibr" rid="CR48">48</xref>] found that the use of tablets and capsules exceeded liquids from the age of 7 years for licensed products, 3 years for off-label medicines and 9 years for unlicensed, pharmacy-compounded medicines. Similarly, in the UK, the average age of conversion from liquid to solid antiretroviral formulations was 7.3 years [<xref ref-type="bibr" rid="CR33">33</xref>]. It is worth noting that many factors can potentially affect this conversion age, e.g. the availability of tablets of the right size and strength for paediatric use and the acceptance of prescribing an unlicensed medicine when an authorised formulation is available. Comparison of the practice in different countries would be an interesting topic for future study.</p><p>The ability of children to swallow tablets and capsules is strongly related to the size of these dosage forms, alongside age. However, current guidance on the suitability of tablet sizes for different age groups in children is based upon anecdotal feedback and perception [<xref ref-type="bibr" rid="CR7">7</xref>]. Direct evidence in this area is scarce and future research in this area is required. Table <xref rid="Tab2" ref-type="table">2</xref> summarises the published evidence on the ability of children to swallow tablets of different dimensions based upon age. Mini-tablets (1–4 mm in diameter) are relatively new dosage forms with considerable promise in paediatrics [<xref ref-type="bibr" rid="CR17">17</xref>, <xref ref-type="bibr" rid="CR49">49</xref>]. Mini-tablets can be administered directly (swallowed whole) or could be labelled for sprinkling onto food. Various research studies have recently assessed the acceptability of mini-tablets in infants and children (Table <xref rid="Tab2" ref-type="table">2</xref>). While these exploratory studies demonstrate their proof of concept, each involved administration of single mini-tablets, whereas multiple mini-tablets are more likely to be used clinically to provide the appropriate dose. Further research is required to demonstrate the application of mini-tablets in practice.<table-wrap id="Tab2"><label>Table 2</label><caption><p>Literature reports on the ability of children to swallow tablets in relation to age and tablet size</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left">Age of children</th><th align="left">Sample size</th><th align="left">Tablet size</th><th align="left">Study outcomes</th><th align="left">References</th></tr></thead><tbody><tr><td align="left">1–9 years</td><td char="." align="char">555</td><td align="left">7 mm ketoprofen tablets</td><td align="left">80 % of parents reported that their children had no problems with swallowing, although administration problems were three times more common in those under 2 years of age than in older children</td><td align="left">[<xref ref-type="bibr" rid="CR50">50</xref>]</td></tr><tr><td align="left">2–11 years</td><td char="." align="char">96</td><td align="left">5 and 8 mm</td><td align="left">1–7 tablets were taken by children over several months. No reports of swallowing difficulties or adverse events</td><td align="left">[<xref ref-type="bibr" rid="CR51">51</xref>]</td></tr><tr><td align="left">6–11 years</td><td char="." align="char">113</td><td align="left">7 mm</td><td align="left">91 % of children aged 6–11 years were able to swallow the tablet; 46 % without training, 38 % trained with an ordinary plastic cup and 7 % with the assistance of a patented pill cup</td><td align="left">[<xref ref-type="bibr" rid="CR41">41</xref>]</td></tr><tr><td align="left">2–6 years</td><td char="." align="char">100</td><td align="left">3 mm mini-tablets</td><td align="left">46 % of 2-year-olds and 87 % of 5-year-olds were able to swallow a single mini-tablet</td><td align="left">[<xref ref-type="bibr" rid="CR52">52</xref>]</td></tr><tr><td align="left">From 6 months</td><td char="." align="char">306</td><td align="left">2 mm coated and uncoated mini-tablets</td><td align="left">Children as young as 6 months old were capable of swallowing the mini-tablets, with acceptability of the mini-tablets superior to 3 mL glucose syrup. Some instances of chewing before deglutition were observed across the various age groups, with around half of children aged 1–3 years swallowing the mini-tablets intact. Two incidences of coughing were reported for coated mini-tablets, both in children below 1 year of age</td><td align="left">[<xref ref-type="bibr" rid="CR53">53</xref>]</td></tr><tr><td align="left">6–30 months</td><td char="." align="char">16</td><td align="left">2 mm enteric-coated pancrelipase mini-tablets</td><td align="left">The mini-tablets were administered with applesauce to the children. Ease of swallowing was rated by parents on a 4-point scale (with 0 corresponding to poor and 3 as excellent). The mean score of the mini-tablets was 1 (fair) to 2 (good)</td><td align="left">[<xref ref-type="bibr" rid="CR54">54</xref>]</td></tr><tr><td align="left">1–4 years</td><td char="." align="char">183</td><td align="left">4 mm uncoated mini-tablets</td><td align="left">The mini-tablets were significantly better accepted than 3 other dosage forms (a powder, suspension and syrup)</td><td align="left">[<xref ref-type="bibr" rid="CR55">55</xref>]</td></tr></tbody></table></table-wrap></p></sec><sec id="Sec9"><title>Acceptability of Tablets and Capsules in Older Patients</title><p>In older patients, age- or disease-related swallowing difficulties affect their ability to take solid oral medicines. In a survey involving 17 community pharmacies from England and Northern Ireland, 60 % of patients aged between 60 and 89 years experienced difficulties in swallowing tablets and capsules [<xref ref-type="bibr" rid="CR56">56</xref>]. A recent study reported that 37.4 % of adult patients (mean age 62 years) attending their general practices had difficulties in swallowing medicines [<xref ref-type="bibr" rid="CR57">57</xref>]. Polypharmacy (taking ≥5 medicines) is common in older patients [<xref ref-type="bibr" rid="CR9">9</xref>]. A study conducted in Switzerland showed that community-dwelling polypharmacy patients (mean age 67 years) reported ongoing (9.0 %) or past (13.4 %) swallowing difficulties that resulted in intentional non-adherence in 23 % of these patients [<xref ref-type="bibr" rid="CR58">58</xref>].</p><p>Anxiety, previous bad experiences and disliking the idea of taking medicines could all contribute to difficulties for older patients in taking tablets and capsules [<xref ref-type="bibr" rid="CR57">57</xref>]. Effortful swallowing, a process of swallowing ‘hard’ using oral and pharyngeal muscles, is commonly advised by speech and language therapists to help dysphagia patients and could increase the oral swallowing pressure to propel the swallowed object more effectively [<xref ref-type="bibr" rid="CR59">59</xref>]. It was shown that targeted training using swallow-related exercises significantly improved swallowing performance of patients with Parkinson’s disease [<xref ref-type="bibr" rid="CR60">60</xref>]. Indeed, some patients with dysphagia found that concentrating on swallowing improved their ability to swallow solid dosage forms [<xref ref-type="bibr" rid="CR61">61</xref>].</p></sec><sec id="Sec10"><title>Factors Affecting Swallowability and Oesophageal Transit of Tablets and Capsules in Adults</title><p>During the swallow process, there is a risk for tablets and capsules to adhere to the oesophagus, causing prolonged or incomplete oesophageal transit. A trapped dosage form can start to disintegrate or dissolve within the oesophagus and cause oesophageal injury, often due to altered local pH or hyper-osmolarity [<xref ref-type="bibr" rid="CR62">62</xref>]. The swallowability and oesophageal transit of tablets and capsules are affected by many physical characteristics of the dosage form. However, literature reports on swallowability of tablets and capsules were typically conducted in the adult population and data from children and older adults are scarce. Difficulties in swallowing and oesophageal retention of tablets and capsules are expected to be magnified in children and older adults; therefore, the findings of studies in adults provide useful guidance. Nevertheless, studies that are directly conducted in paediatric and geriatric populations would be valuable to guide the design of medicines for these patients.</p><p>Tablet size was found to affect the swallowability and oesophageal transit in adults; smaller tablets were considered easier to swallow and showed faster oesophageal transit than larger tablets (Table <xref rid="Tab3" ref-type="table">3</xref>). Shape, density, surface characteristics and type of formulation can all affect the swallowability and oesophageal transit of tablets and capsules (Table <xref rid="Tab3" ref-type="table">3</xref>). Visual aspects of medicines such as colour can be adapted not only to provide an aesthetic dosage form that is acceptable to patients, but to aid users in recognising and differentiating medicines. The colour of tablets is associated with flavour perceptions and there are many reviews on the topic [<xref ref-type="bibr" rid="CR63">63</xref>]. Tablet colour has been linked with taste, where pink is considered to be sweeter than red, and yellow is considered to be salty irrespective of its actual ingredients [<xref ref-type="bibr" rid="CR64">64</xref>]. The colour of a medication has also been connected with specific ailments and can affect patient adherence. A change in tablet colour was associated with non-adherence in adult patients with epilepsy [<xref ref-type="bibr" rid="CR65">65</xref>]. There have been reviews on the effect of colour of tablets and perceptions of efficacy [<xref ref-type="bibr" rid="CR66">66</xref>]. Colour preferences among children have shown to be stereotypically gender dependent [<xref ref-type="bibr" rid="CR67">67</xref>], and they seem to prefer brightly coloured medicines. In older patients, white was seen as the most popular colour choice for tablets; however, those patients who take more than ten tablets every day prefer brighter colours than patients who take fewer tablets [<xref ref-type="bibr" rid="CR68">68</xref>].<table-wrap id="Tab3"><label>Table 3</label><caption><p>Factors affecting swallowability and oesophageal transit of tablets and capsules</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left">Study population</th><th align="left">Outcome measure</th><th align="left">Summary of outcomes</th><th align="left">References</th></tr></thead><tbody><tr><td align="left" colspan="4">Tablet size</td></tr><tr><td align="left"> Male adults aged 24–33 years</td><td align="left">Ease of swallowing</td><td align="left">Swallowing larger tablets required significantly more swallows and more effort in swallowing than smaller tablets</td><td align="left">[<xref ref-type="bibr" rid="CR73">73</xref>]</td></tr><tr><td align="left"> Adults (age range 17–82 years)</td><td align="left">Oesophageal transit</td><td align="left">Smaller tablets have shown faster oesophageal transit than larger tablets</td><td align="left">[<xref ref-type="bibr" rid="CR69">69</xref>, <xref ref-type="bibr" rid="CR74">74</xref>, <xref ref-type="bibr" rid="CR75">75</xref>]</td></tr><tr><td align="left"> Adults (age range 23–77 years)</td><td align="left">Oesophageal transit</td><td align="left">Large tablets (11 mm) showed significantly longer oesophageal transition time than small (5.5 mm) and medium (8 mm) size tablets</td><td align="left">[<xref ref-type="bibr" rid="CR69">69</xref>]</td></tr><tr><td align="left"> Older adults (aged 59–80 years)</td><td align="left">Oesophageal transit</td><td align="left">Oesophageal transit of tablets as small as 4 mm in diameter can be prolonged</td><td align="left">[<xref ref-type="bibr" rid="CR76">76</xref>]</td></tr><tr><td align="left" colspan="4">Tablet shape</td></tr><tr><td align="left"> 84 % participants aged 23–64 years and 15 % aged 65 years or older</td><td align="left">Ease of swallowing</td><td align="left">Arched (curved), oval and oblong tablets were generally easier to swallow than flat round tablets. Oblong tablets were considered difficult to swallow for small tablets</td><td align="left">[<xref ref-type="bibr" rid="CR68">68</xref>]</td></tr><tr><td align="left"> Male adults aged 24–33 years</td><td align="left">Ease of swallowing</td><td align="left">Medium or large tablets were preferred to be oblong or oval, while small round tablets were considered as easy to swallow as other shapes</td><td align="left">[<xref ref-type="bibr" rid="CR73">73</xref>]</td></tr><tr><td align="left"> Adults (age range 17–82 years)</td><td align="left">Oesophageal transit</td><td align="left">Oval tablets were easier to pass through the oesophagus than round tablets, especially when the tablet is large</td><td align="left">[<xref ref-type="bibr" rid="CR69">69</xref>, <xref ref-type="bibr" rid="CR74">74</xref>]</td></tr><tr><td align="left" colspan="4">Film coating</td></tr><tr><td align="left"> Male adults aged 24–33 years</td><td align="left">Ease of swallowing</td><td align="left">A film coating applied to the surface of the tablet was found to make swallowing easier</td><td align="left">[<xref ref-type="bibr" rid="CR73">73</xref>]</td></tr><tr><td align="left"> Adults (age range 17–82 years)</td><td align="left">Oesophageal transit</td><td align="left">Film coatings improve oesophageal transit of both large and small tablets compared to uncoated tablets</td><td align="left">[<xref ref-type="bibr" rid="CR69">69</xref>, <xref ref-type="bibr" rid="CR74">74</xref>]</td></tr><tr><td align="left" colspan="4">Density</td></tr><tr><td align="left"> Adults (age range 17–82 years)</td><td align="left">Oesophageal transit</td><td align="left">Heavy large capsules passed through the oesophagus significantly faster than light large capsules in a standing position</td><td align="left">[<xref ref-type="bibr" rid="CR74">74</xref>]</td></tr><tr><td align="left" colspan="4">Type of formulation</td></tr><tr><td align="left"> Older adults (mean age 66, range 50–79 years)</td><td align="left">Oesophageal transit</td><td align="left">The oesophageal transit time of gelatine capsules was significantly longer than enteric-coated and cellulose-based film-coated tablets</td><td align="left">[<xref ref-type="bibr" rid="CR77">77</xref>, <xref ref-type="bibr" rid="CR78">78</xref>]</td></tr><tr><td align="left"> Adults (age not specified)</td><td align="left">Oesophageal transit</td><td align="left">Barium sulphate tablets were more likely to stick to the oesophagus than capsules of the same drug</td><td align="left">[<xref ref-type="bibr" rid="CR79">79</xref>]</td></tr><tr><td align="left"> Adults (age range 17–82 years)</td><td align="left">Oesophageal transit</td><td align="left">Large capsules passed through the oesophagus significantly faster than uncoated oval tablets and their transit was less affected by the posture of the patient than tablets</td><td align="left">[<xref ref-type="bibr" rid="CR74">74</xref>]</td></tr><tr><td align="left"> Adults (age range 19–80 years)</td><td align="left">Oesophageal transit</td><td align="left">Oesophageal passage of capsules was not affected either by capsule size or the amount of water taken at the same time, both of which had significant influence on the transit of tablets</td><td align="left">[<xref ref-type="bibr" rid="CR69">69</xref>]</td></tr><tr><td align="left" colspan="4">Body position of the patient</td></tr><tr><td align="left"> Adults (age range 17–82 years)</td><td align="left">Oesophageal transit</td><td align="left">Oesophageal transit of tablets and capsules are significantly faster in patients in the standing position than in the supine position</td><td align="left">[<xref ref-type="bibr" rid="CR69">69</xref>, <xref ref-type="bibr" rid="CR74">74</xref>, <xref ref-type="bibr" rid="CR75">75</xref>, <xref ref-type="bibr" rid="CR80">80</xref>, <xref ref-type="bibr" rid="CR81">81</xref>]</td></tr><tr><td align="left" colspan="4">Fluid taken</td></tr><tr><td align="left"> Adults (age range 17–82 years)</td><td align="left">Oesophageal transit</td><td align="left">Tablets and capsules pass through the oesophagus faster when a large quantity of fluid is taken with the medication</td><td align="left">[<xref ref-type="bibr" rid="CR80">80</xref>–<xref ref-type="bibr" rid="CR82">82</xref>]</td></tr><tr><td align="left"> Adults (age range 19–80 years)</td><td align="left">Oesophageal transit</td><td align="left">The most common cause of oesophageal retention of tablets and capsules was the combination of a small volume of water (25 mL) and the supine position. When a large quantity of water (100 mL) was taken, the transit time was significantly shorter for small and large tablets in the supine position and for large tablets in the standing position</td><td align="left">[<xref ref-type="bibr" rid="CR69">69</xref>]</td></tr></tbody></table></table-wrap></p><p>The ability of a patient to swallow tablets and capsules is also affected by patient-related factors. The retention of a tablet or capsule in the oesophagus is affected by the body position of the patient while taking the medicine and the volume of fluid taken with the medication (Table <xref rid="Tab3" ref-type="table">3</xref>). It was recommended that medications should be taken with at least 100 mL of fluid and the patient remains standing for at least 90 s to prevent oesophageal retention [<xref ref-type="bibr" rid="CR69">69</xref>]. Although useful guidance, some older patients may not be able to follow this advice, as they may be bedridden or may have difficulty in swallowing a large amount of fluid [<xref ref-type="bibr" rid="CR70">70</xref>]. Similarly, this volume may be too large for children to take.</p></sec><sec id="Sec11"><title>New ‘Easy-to-Swallow’ Technologies to Aid in Swallowability of Tablets and Capsules</title><p>Several technologies have been developed to aid the swallowing of solid oral dosage forms. A disposable device called MedCoat<sup>®</sup> (Med Coat AB, Stockholm, Sweden) can be used by the patient to apply a thin coat on the tablet before swallowing [<xref ref-type="bibr" rid="CR71">71</xref>]. The coating contains gelatine, sweeteners and flavouring agents and can improve the taste of the tablet. In a clinical trial (average age 30 years), the coating improved the ease of swallowing of tablets, especially bitter-flavoured placebo tablets [<xref ref-type="bibr" rid="CR71">71</xref>]. A similar flavoured spray product Pill Glide<sup>®</sup> (FLAVORx Inc., Columbia, MD, USA) requires the patient to apply the spray to the back of the mouth and tongue before taking tablets or capsules [<xref ref-type="bibr" rid="CR72">72</xref>]. The spray creates a lubricated surface in the mouth and thus facilitates swallowing. Pill Glide<sup>®</sup> has been found to be helpful in adolescents with difficulties in swallowing tablets.</p></sec></sec><sec id="Sec12"><title>Factors Affecting Acceptability of Oral Liquid Dosage Forms</title><p>Oral liquids are generally regarded to be the most appropriate dosage form for children despite having issues including taste masking, portability, stability and the inclusion of excipients that are not always appropriate for all paediatric patients. The challenge in using liquid formulations in older patients, particularly those with dysphagia, is aspiration, which is caused by inadequate protection of the airway during swallowing. The prevalence of aspiration was reported as 51 % in dysphagia patients and 36 % of healthy older adults showed some degree of aspiration during normal swallowing [<xref ref-type="bibr" rid="CR83">83</xref>, <xref ref-type="bibr" rid="CR84">84</xref>].</p><p>Patient acceptability of a liquid dosage form is inevitability affected by many of its characteristics (Table <xref rid="Tab4" ref-type="table">4</xref>). Modifications in these formulation factors can improve swallowing of a liquid by moderating the timing and response of oral, pharyngeal and oesophageal phases.<table-wrap id="Tab4"><label>Table 4</label><caption><p>Factors affecting the swallowability and acceptability of liquid medicines</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left">Study population</th><th align="left">Outcome measures</th><th align="left">Summary of outcomes</th><th align="left">References</th></tr></thead><tbody><tr><td align="left" colspan="4">Taste</td></tr><tr><td align="left"> Healthy young adults</td><td align="left">Swallowing speed</td><td align="left">Sweet, sour and salty tastes reduced the swallowing speed and prolonged oral and pharyngeal swallowing durations compared with neutral tastes</td><td align="left">[<xref ref-type="bibr" rid="CR85">85</xref>]</td></tr><tr><td align="left"> Healthy young adults</td><td align="left">Swallow physiology</td><td align="left">Sweet, sour and salty tastes generated stronger muscle contractions and shorter activation onset times during swallowing than the no-taste conditions</td><td align="left">[<xref ref-type="bibr" rid="CR86">86</xref>]</td></tr><tr><td align="left"> Older adults (aged 65–85 years)</td><td align="left">Swallow physiology</td><td align="left">The effects of sweet, sour and salty tastes on swallow physiology reduced in older adults</td><td align="left">[<xref ref-type="bibr" rid="CR86">86</xref>]</td></tr><tr><td align="left"> Patients with neurogenic dysphagia</td><td align="left">Oropharyngeal swallowing</td><td align="left">A sour bolus reduced the swallow onset time, shortened the pharyngeal delay and transit time, and improved oropharyngeal swallow efficiency</td><td align="left">[<xref ref-type="bibr" rid="CR87">87</xref>]</td></tr><tr><td align="left" colspan="4">Palatability</td></tr><tr><td align="left"> Healthy young adults</td><td align="left">Swallowing physiology</td><td align="left">Palatability of the ingested liquid had little effect on swallowing physiology and performances</td><td align="left">[<xref ref-type="bibr" rid="CR88">88</xref>, <xref ref-type="bibr" rid="CR89">89</xref>]</td></tr><tr><td align="left"> Adults aged 23–71 years</td><td align="left">Oral, pharyngeal and oesophageal transit</td><td align="left">No difference was found on the duration of oral, pharyngeal and oesophageal phases of swallowing between an unpleasant bitter bolus and a pleasant sweet bolus</td><td align="left">[<xref ref-type="bibr" rid="CR90">90</xref>]</td></tr><tr><td align="left"> Older patients with neurogenic dysphagia</td><td align="left">Swallowing performance</td><td align="left">A pleasant sweet–sour mixture did not significantly improve swallowing performances compared with water</td><td align="left">[<xref ref-type="bibr" rid="CR91">91</xref>]</td></tr><tr><td align="left" colspan="4">Oral stimuli</td></tr><tr><td align="left"> Patients with stroke (aged 41–88 years)</td><td align="left">Pharyngeal transit</td><td align="left">The combination of sour taste and cold stimuli was able to improve pharyngeal transit time</td><td align="left">[<xref ref-type="bibr" rid="CR92">92</xref>]</td></tr><tr><td align="left"> Healthy young adults</td><td align="left">Swallow performance</td><td align="left">Carbonated water was able to improve swallowing performances</td><td align="left">[<xref ref-type="bibr" rid="CR88">88</xref>, <xref ref-type="bibr" rid="CR93">93</xref>]</td></tr><tr><td align="left"> Adult patients with neurogenic dysphagia</td><td align="left">Pharyngeal transit and aspiration risk</td><td align="left">Carbonated water significantly improved pharyngeal transit and reduced aspiration and penetration risk scores compared with non-carbonated thin liquid</td><td align="left">[<xref ref-type="bibr" rid="CR94">94</xref>]</td></tr><tr><td align="left" colspan="4">Smell</td></tr><tr><td align="left"> Adults</td><td align="left">5-Point scale on smell (5 being most positive score)</td><td align="left">The smell of different liquid corticosteroid products (prednisolone 1 mg/mL; prednisolone sodium phosphate 1 mg/mL and dexamethasone 0.5 mg/5 mL) was measured. Dexamethasone scored most positively; this may be attributed to the lower concentration, as the taste was not scored more positively than prednisolone</td><td align="left">[<xref ref-type="bibr" rid="CR95">95</xref>]</td></tr><tr><td align="left" colspan="4">Texture</td></tr><tr><td align="left"> Adults</td><td align="left">Effects on palatability</td><td align="left">The texture of liquids was included in a study on the palatability of liquid anti-infectives with acknowledgement that texture can influence palatability of a liquid, although there were no additional details on what textures are acceptable or otherwise</td><td align="left">[<xref ref-type="bibr" rid="CR96">96</xref>]</td></tr><tr><td align="left"> Adults</td><td align="left">5-Point scale on texture (5 being most positive score)</td><td align="left">The texture of different liquid corticosteroid products (prednisolone 1 mg/mL; prednisolone sodium phosphate 1 mg/mL and dexamethasone 0.5 mg/5 mL) was measured. Prednisolone sodium phosphate 1 mg/mL was scored most positively; this may be due to the higher solubility of the salt form making the particle size smaller within the product</td><td align="left">[<xref ref-type="bibr" rid="CR95">95</xref>]</td></tr><tr><td align="left"> Children aged 1–4 years</td><td align="left">Acceptability</td><td align="left">Syrup was more acceptable to children than a suspension using placebo formulation and this is likely related to the taste or texture difference between these formulations</td><td align="left">[<xref ref-type="bibr" rid="CR55">55</xref>]</td></tr><tr><td align="left" colspan="4">Viscosity</td></tr><tr><td align="left"> Healthy young adults</td><td align="left">Oropharyngeal transit</td><td align="left">Increasing the viscosity of the liquid slowed the oropharyngeal transit of the bolus</td><td align="left">[<xref ref-type="bibr" rid="CR97">97</xref>–<xref ref-type="bibr" rid="CR100">100</xref>]</td></tr><tr><td align="left"> Patients with Parkinson’s disease</td><td align="left">Timing and safety of swallow</td><td align="left">Increasing the viscosity of the liquid slowed the oropharyngeal transit of the bolus and reduced aspiration/penetration risk scores by preventing the premature emptying from the mouth before the pharyngeal swallow response</td><td align="left">[<xref ref-type="bibr" rid="CR100">100</xref>]</td></tr><tr><td align="left"> Dysphagia patients with dementia or Parkinson’s disease</td><td align="left">Oesophageal transit</td><td align="left">Both honey-thick and nectar-thick liquids were able to significantly reduce the risk of aspiration in dysphagia patients compared with thin liquids</td><td align="left">[<xref ref-type="bibr" rid="CR101">101</xref>]</td></tr><tr><td align="left" colspan="4">Volume</td></tr><tr><td align="left"> Healthy older adults (aged 61–70 years)</td><td align="left">PAS score</td><td align="left">Increasing the liquid bolus volume increased the risk of aspiration. The PAS score increased significantly with a 20 mL bolus volume compared with 5, 10 and 15 mL volumes</td><td align="left">[<xref ref-type="bibr" rid="CR83">83</xref>]</td></tr><tr><td align="left"> Healthy male adults</td><td align="left">Oral and pharyngeal phases of swallowing</td><td align="left">Higher liquid bolus volumes (2–20 mL) increased difficulty in swallowing, including a longer oral retention time and increased magnitude of structural movement for oropharyngeal clearance</td><td align="left">[<xref ref-type="bibr" rid="CR97">97</xref>]</td></tr><tr><td align="left"> Patients with neurogenic dysphagia</td><td align="left">Ease of swallowing</td><td align="left">A liquid volume of 1 mL was more difficult to swallow by stroke patients than 5 mL volume</td><td align="left">[<xref ref-type="bibr" rid="CR102">102</xref>]</td></tr><tr><td align="left" colspan="4">Administration devices</td></tr><tr><td align="left"> Healthy older adults (aged 61–70 years)</td><td align="left">PAS score</td><td align="left">No difference in PAS scores between cup and straw drinking</td><td align="left">[<xref ref-type="bibr" rid="CR83">83</xref>]</td></tr><tr><td align="left"> Older patients with neurogenic dysphagia</td><td align="left">PAS score</td><td align="left">Drinking from a teaspoon resulted in significantly lower PAS scores than cup drinking</td><td align="left">[<xref ref-type="bibr" rid="CR91">91</xref>]</td></tr><tr><td align="left" colspan="4">Patient posture</td></tr><tr><td align="left"> Patients with oropharyngeal dysphagia; head and neck surgical patients</td><td align="left">Prevention of aspiration</td><td align="left">Head or body postural changes (chin down, chin up, head rotated, head tilted and lying down) eliminated aspiration in 77 % of patients with oropharyngeal dysphagia and 60 % patients who had head and neck surgery</td><td align="left">[<xref ref-type="bibr" rid="CR103">103</xref>, <xref ref-type="bibr" rid="CR104">104</xref>]</td></tr><tr><td align="left"> Dysphagia patients</td><td align="left">Prevention of aspiration</td><td align="left">Chin down posture was effective to prevent 55–64 % of aspiration</td><td align="left">[<xref ref-type="bibr" rid="CR105">105</xref>, <xref ref-type="bibr" rid="CR106">106</xref>]</td></tr><tr><td align="left"> Dysphagia patients</td><td align="left">Prevention of aspiration</td><td align="left">Head rotation was useful in 29 % of patients to prevent aspiration</td><td align="left">[<xref ref-type="bibr" rid="CR105">105</xref>]</td></tr><tr><td align="left"> Healthy adults</td><td align="left">Pharyngeal clearance</td><td align="left">Head rotation reduced the UES resting pressure and prolongs the UES opening, and thus improved pharyngeal clearance during swallowing</td><td align="left">[<xref ref-type="bibr" rid="CR107">107</xref>]</td></tr></tbody></table><table-wrap-foot><p><italic>PAS</italic> Penetration-Aspiration Scale, <italic>UES</italic> upper oesophageal sphincter</p></table-wrap-foot></table-wrap></p><sec id="Sec13"><title>Taste, Smell and Palatability of a Liquid</title><p>Taste is regarded as the most important factor determining the acceptability of a liquid medicine in children. There have been several studies undertaken that investigated the taste of liquid medicines in paediatric populations. These typically use face-rating scoring systems to evaluate the taste in this population and an example study was conducted by Cohen et al. [<xref ref-type="bibr" rid="CR108">108</xref>]. Review articles have been published on this area and the reader is directed to the review by Ernest et al. for additional information [<xref ref-type="bibr" rid="CR109">109</xref>].</p><p>Research has linked smell of a liquid to flavour and it has been argued that the majority of the flavour of food actually comes from its smell [<xref ref-type="bibr" rid="CR110">110</xref>]. It is likely that certain medicines do smell unpleasant, yet there is very limited work done in this area, particularly in linking medication odour to compliance/adherence (Table <xref rid="Tab5" ref-type="table">5</xref>).<table-wrap id="Tab5"><label>Table 5</label><caption><p>Acceptability studies of oral flexible formulations in children and older adults</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left">Study population</th><th align="left">Summary of outcomes</th><th align="left">References</th></tr></thead><tbody><tr><td align="left" colspan="3">Multiparticulates</td></tr><tr><td align="left"> Children (aged 5–16 years)</td><td align="left">In the crossover study comparing a valproate sprinkle formulation with syrup, 9 of 12 parents preferred sprinkles due to their ease of use, while 9 children preferred them due to enhanced palatability, despite the authors reporting a gritty texture</td><td align="left">[<xref ref-type="bibr" rid="CR13">13</xref>]</td></tr><tr><td align="left"> Children (aged 3–14 years)</td><td align="left">Neutral-tasting sodium valproate microgranules were well-accepted and adhered to over 90 days of treatment, although one-fifth of parents reported difficulty administering the drug to their child due to the consistency or mouthfeel of the drug</td><td align="left">[<xref ref-type="bibr" rid="CR126">126</xref>]</td></tr><tr><td align="left"> Children (from 6 months old)</td><td align="left">Microencapsulated iron sprinkles and other micronutrient powders were superior in terms of ease of use, acceptance and adherence compared with other forms such as drops and crushable tablets</td><td align="left">[<xref ref-type="bibr" rid="CR127">127</xref>–<xref ref-type="bibr" rid="CR130">130</xref>]</td></tr><tr><td align="left"> Infants (5–7 months)</td><td align="left">Adherence to ferrous fumarate sprinkles was slightly poorer than for drops, with some parents expressing concerns about the new product and its safety</td><td align="left">[<xref ref-type="bibr" rid="CR131">131</xref>]</td></tr><tr><td align="left"> Adults and older adults (mean age 66 years, range 34–83 years)</td><td align="left">The majority of patients (67 %) preferred chewable tablets compared with sachet for calcium and vitamin D supplements. Sachet was considered to be more time-consuming and more difficult to take than chewable tablets</td><td align="left">[<xref ref-type="bibr" rid="CR132">132</xref>, <xref ref-type="bibr" rid="CR133">133</xref>]</td></tr><tr><td align="left"> Children and adults with phenylketonuria (aged 8–49 years)</td><td align="left">11 of 12 participants preferred a ‘ready to drink’ liquid protein substitute formulation over powder. The liquid formulation was considered easy to take and more convenient to use in different environments than the powder</td><td align="left">[<xref ref-type="bibr" rid="CR132">132</xref>, <xref ref-type="bibr" rid="CR133">133</xref>]</td></tr><tr><td align="left" colspan="3">Dispersible and effervescent tablets</td></tr><tr><td align="left"> Infants and children (aged 3 months to 5 years)</td><td align="left">90 % of caregivers reported that zinc dispersible tablets were as acceptable to their children, or more so, as other medicines, while 84 % were willing to use the medicine again in the future</td><td align="left">[<xref ref-type="bibr" rid="CR134">134</xref>]</td></tr><tr><td align="left"> Children (aged 0–5 years)</td><td align="left">Acceptability and adherence to diarrhoea treatment was more favourable using zinc dispersible tablets. Almost 90 % of children received 10 days’ treatment and two-thirds completed the full 14 days, while only 6.5 % of caregivers reported administration problems (4 % reported vomiting and 2.5 % refusal to take)</td><td align="left">[<xref ref-type="bibr" rid="CR135">135</xref>]</td></tr><tr><td align="left"> Children (aged 4–8 years)</td><td align="left">A citrus-flavoured effervescent tablet was preferred over peppermint-flavoured syrup by more than two-thirds of the children and their caregivers</td><td align="left">[<xref ref-type="bibr" rid="CR136">136</xref>]</td></tr><tr><td align="left"> Parkinson’s disease patients with dysphagia</td><td align="left">The acceptability of a dispersible tablet containing levodopa-benserazide was considered advantageous with regard to ease of administration</td><td align="left">[<xref ref-type="bibr" rid="CR137">137</xref>]</td></tr><tr><td align="left" colspan="3">ODTs</td></tr><tr><td align="left"> Children (aged 6–11 years)</td><td align="left">More than 90 % of the children preferred strawberry-flavoured lansoprazole ODTs over peppermint-flavoured ranitidine syrup</td><td align="left">[<xref ref-type="bibr" rid="CR138">138</xref>]</td></tr><tr><td align="left"> Children (aged 5–11 years)</td><td align="left">The taste of the ondansetron ODTs scored lower than placebo; however, none of the children rejected or spat out the tablet and 87 % were reportedly willing to take it again in the future</td><td align="left">[<xref ref-type="bibr" rid="CR139">139</xref>]</td></tr><tr><td align="left"> Children (aged 6 months to 10 years)</td><td align="left">A randomised clinical trial involved administration of ondansetron ODTs or placebo to children; however, patient acceptability was not assessed as part of the study</td><td align="left">[<xref ref-type="bibr" rid="CR140">140</xref>]</td></tr><tr><td align="left"> Adult patients with depression</td><td align="left">More than 80 % of patients preferred ODTs over conventional tablets</td><td align="left">[<xref ref-type="bibr" rid="CR141">141</xref>, <xref ref-type="bibr" rid="CR142">142</xref>]</td></tr><tr><td align="left"> Older patients with schizophrenia</td><td align="left">Olanzapine ODTs have been shown to improve medication compliance in acutely ill non-compliant patients in nursing homes</td><td align="left">[<xref ref-type="bibr" rid="CR143">143</xref>]</td></tr><tr><td align="left"> Depressed patients older than 85 years</td><td align="left">Mirtazapine ODTs were used for the treatment of depression in these ‘old–old’ patients, and were found to be acceptable and well-tolerated</td><td align="left">[<xref ref-type="bibr" rid="CR144">144</xref>]</td></tr><tr><td align="left"> Older patients with Parkinson’s disease</td><td align="left">In a multicentre, open-label study, more than twice as many patients preferred carbidopa–levodopa ODTs (45 %) compared with conventional tablets (20 %)</td><td align="left">[<xref ref-type="bibr" rid="CR145">145</xref>]</td></tr><tr><td align="left" colspan="3">Chewable tablets</td></tr><tr><td align="left"> Children from the age of 2 years</td><td align="left">The review summarised chewable tablets to be safe and well-tolerated in children from this age</td><td align="left">[<xref ref-type="bibr" rid="CR146">146</xref>]</td></tr><tr><td align="left"> Children (aged 6–11 years)</td><td align="left">82 % of the children and 87 % of their parents preferred a cherry-flavoured chewable montelukast tablet over inhaled therapy, and this formulation resulted in better self-reported adherence</td><td align="left">[<xref ref-type="bibr" rid="CR147">147</xref>]</td></tr></tbody></table><table-wrap-foot><p><italic>ODTs</italic> orally disintegrating tablets</p></table-wrap-foot></table-wrap></p><p>The effect of taste on medication acceptability in older patients has not been extensively investigated compared to the paediatric population. However, the unpleasant taste of liquid medicines was identified as one of the barriers for older patients with dysphagia to taking their medications [<xref ref-type="bibr" rid="CR61">61</xref>]. Swallowing is modulated by the nervous inputs generated from sensory receptors in the oral, pharyngeal and laryngeal regions via trigeminal, glossopharyngeal and vagus nerves [<xref ref-type="bibr" rid="CR111">111</xref>]. Taste, thermal and chemical properties of the ingested fluid act as stimuli of these nerves and are known to affect swallowing activities (Table <xref rid="Tab4" ref-type="table">4</xref>). However, the effect of taste was likely to decrease in older adults due to the reduced taste sensitivity in older individuals [<xref ref-type="bibr" rid="CR112">112</xref>].</p><p>Beneficial effects of a sour bolus, consisting of 50 % lemon juice and water, on the oropharyngeal swallowing in patients with neurogenic dysphagia were reported by Logemann et al. [<xref ref-type="bibr" rid="CR87">87</xref>] (Table <xref rid="Tab4" ref-type="table">4</xref>). It was suggested that the sour taste acted as an “alerting” stimulus and enhanced or altered the sensory input to the nervous system and thus facilitated oropharyngeal swallowing in neurogenic dysphagia patients. The strong sour taste was deemed unpleasant by most participants and changing the liquid into a palatable sweet and sour taste did not significantly improve swallowing [<xref ref-type="bibr" rid="CR91">91</xref>]. It is the challenge for future research to utilise the benefit of the sour taste and improve the palatability in the design of oral liquid medicines to promote safe swallowing in older dysphagic patients.</p></sec><sec id="Sec14"><title>Texture and Viscosity of a Liquid</title><p>The texture and mouth feel of particles is acknowledged as important in food products as it affects mastication and overall taste sensation [<xref ref-type="bibr" rid="CR113">113</xref>]. Grittiness of particles has previously been linked to particles >12 μm [<xref ref-type="bibr" rid="CR113">113</xref>]. Texture effects on acceptability of liquid medicines have not been extensively investigated (Table <xref rid="Tab4" ref-type="table">4</xref>) and it is an important subject for future research.</p><p>The consistency and rheology of the swallowed bolus affect the safety of swallowing [<xref ref-type="bibr" rid="CR114">114</xref>, <xref ref-type="bibr" rid="CR115">115</xref>]. In particular, liquids and thin pastes initiate significantly different muscle activities during swallowing compared with thick pastes, which could be associated with a higher risk of aspiration in dysphagia patients [<xref ref-type="bibr" rid="CR98">98</xref>]. Thin liquids pose a high risk of aspiration due to their lack of resistance to flow and they usually arrive at the hypopharynx before the onset of the pharyngeal swallow. Increasing the viscosity of the liquid slows the oropharyngeal transit of the bolus and thus prevents the premature emptying from the mouth before the pharyngeal swallow response [<xref ref-type="bibr" rid="CR97">97</xref>–<xref ref-type="bibr" rid="CR99">99</xref>].</p></sec><sec id="Sec15"><title>Volume of a Liquid Administered</title><p>Small volumes are normally better tolerated for preparations with known palatability issues, unless a more diluted preparation may allow better taste masking. There are issues in very small volumes of oral liquids for administration in children; these are generally related to the accuracy of dosing relative to the devices available [<xref ref-type="bibr" rid="CR116">116</xref>]. Minimal volumes are normally used when dosing very young children via enteral tubes to ensure that sufficient nutrition can be administered in addition to medication. The typical volume of medicine administered in a child is expected to be swallowable in one unit; therefore, the maximum volume should equate to the volume of a swallow. The volume of a swallow is reported to be 4.5 mL for children from 15 months to 3.5 years of age and this equates to a typical volume of 0.27 mL/kg [<xref ref-type="bibr" rid="CR117">117</xref>].</p><p>The volume of the liquid to be swallowed can affect the safety of swallowing in older adults. A normal sip size for healthy adults has been reported to be in the range of 17–21 mL [<xref ref-type="bibr" rid="CR117">117</xref>, <xref ref-type="bibr" rid="CR118">118</xref>]. However, the sip size is much smaller (9.8 mL ± 6.0) in patients with neurogenic oropharyngeal dysphagia [<xref ref-type="bibr" rid="CR91">91</xref>]. Increasing the liquid bolus volume has been shown to increase the risk of aspiration (Table <xref rid="Tab4" ref-type="table">4</xref>). Interestingly, too small a volume can also be a problem for dysphagia patients to swallow (Table <xref rid="Tab4" ref-type="table">4</xref>) [<xref ref-type="bibr" rid="CR102">102</xref>]. This is likely due to the reduced sensory awareness in these patients and because increased bolus volume increases the sensory input into the nervous system.</p></sec><sec id="Sec16"><title>Administration Devices</title><p>The device used to administer an oral liquid is critical in ensuring that the dose administered is accurate. There are many alternatives available for the delivery of oral liquids including oral syringes, measuring spoons and measuring cups. In general, drinking from a spoon is considered safer for patients with dysphagia than cup and straw drinking (Table <xref rid="Tab4" ref-type="table">4</xref>). The front edge of the bolus was reported to be frequently in the hypopharynx before the initiation of the swallowing during straw drinking and this distal bolus location was associated with greater occurrences of airway penetration in dysphagia patients [<xref ref-type="bibr" rid="CR119">119</xref>].</p></sec><sec id="Sec17"><title>Packaging and Storage</title><p>Preservatives are required in multidose oral preparations; however, preservatives are often associated with bitterness and this needs to be balanced with the overall palatability of the medicine. The safety and toxicity of the preservatives used need careful consideration, particularly for neonates. Packaging liquid medicines in a single-use sachet has benefits in terms of reducing the requirement for preservatives and also increasing the portability of a medicine. This packaging is used within the UK for paracetamol suspensions and Gaviscon<sup>®</sup> products. Anecdotal evidence suggest that carers prefer sachets of certain drugs due to the portability and also eliminating the need for an additional measuring device as the medicine can be transferred directly from the sachet to the patient’s mouth. Oral liquids may require refrigeration, which is a further hurdle for patients who may require frequent administration of a liquid.</p></sec><sec id="Sec18"><title>Patient Posture</title><p>Postural changes of the head and body have been frequently used as compensatory treatments for oropharyngeal dysphagia, especially for eliminating aspiration of thin liquids. The most effective postural techniques include head rotation and chin-down posture—touching the chin to the front of the neck (Table <xref rid="Tab4" ref-type="table">4</xref>) [<xref ref-type="bibr" rid="CR105">105</xref>, <xref ref-type="bibr" rid="CR106">106</xref>, <xref ref-type="bibr" rid="CR120">120</xref>, <xref ref-type="bibr" rid="CR121">121</xref>]. The effectiveness of the chin-down posture in reducing the risk of aspiration is related to a significant narrowing of the laryngeal entrance and a posterior shift of the epiglottis, and thus providing a more effective protection of the airway entrance [<xref ref-type="bibr" rid="CR122">122</xref>–<xref ref-type="bibr" rid="CR124">124</xref>]. This technique was seen to be most helpful in the oldest patients (ages 80–95 years), probably relating to the changes in the natural neck posture with age [<xref ref-type="bibr" rid="CR101">101</xref>]. Head rotation was shown to lateralise the bolus away from the direction of the head turn during swallowing [<xref ref-type="bibr" rid="CR107">107</xref>, <xref ref-type="bibr" rid="CR125">125</xref>]. This technique is therefore useful for patients with unilateral neurologic or structural damage to the pharynx, by bypassing the damaged area and improving the efficiency of swallow. The effect of posture in the very young has not been examined with respect to medicines administration but may be of significant importance for babies and infants who often feed in a horizontal position.</p></sec></sec><sec id="Sec19"><title>Acceptability of Other Flexible Oral Solid Dosage Forms</title><p>Alternatives to liquid medicines are often sought where liquid medicines are not acceptable to patients; for example, where taste issues cannot be overcome, more sophisticated formulation approaches such as encapsulation of drug particles may be required. Many disadvantages associated with taking oral liquids can be avoided by the use of flexible oral solid medicines that are convenient to use by patients who cannot swallow tablets and capsules. Table <xref rid="Tab5" ref-type="table">5</xref> describes studies investigating the acceptability of these formulations in children and older adults and Table <xref rid="Tab6" ref-type="table">6</xref> summarises the advantages and challenges of using these formulations in these patient groups.<table-wrap id="Tab6"><label>Table 6</label><caption><p>Advantages and challenges of using flexible oral solid formulations in children and older adults</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left">Advantages</th><th align="left">Challenges</th></tr></thead><tbody><tr><td align="left" colspan="2">Multiparticulates</td></tr><tr><td align="left"> 1. Infants can start to swallow thick, semi-solid foods from the age of 6 months and administration of multiparticulates mixed with semi-solid food is considered appropriate for children above this age [<xref ref-type="bibr" rid="CR17">17</xref>]</td><td align="left" rowspan="2">1. Grittiness and poor mouth feel [<xref ref-type="bibr" rid="CR13">13</xref>, <xref ref-type="bibr" rid="CR16">16</xref>, <xref ref-type="bibr" rid="CR126">126</xref>]<break></break>2. Lack of knowledge and experience in the use and safety of this formulation amongst parents and carers [<xref ref-type="bibr" rid="CR13">13</xref>, <xref ref-type="bibr" rid="CR16">16</xref>, <xref ref-type="bibr" rid="CR126">126</xref>]<break></break>3. Multiparticulates are considered to be more time-consuming and more difficult to take than liquid formulations and chewable tablets due to the requirement of handling (mixing with food and drink) before administration [<xref ref-type="bibr" rid="CR132">132</xref>, <xref ref-type="bibr" rid="CR133">133</xref>]. This could pose challenges to children and older adults, many of whom rely on caregivers for taking their medicines</td></tr><tr><td align="left"> 2. Multiparticulates can be mixed with semi-solid food for administration to older patients. Swallowing is considered safer with a lower risk of aspiration in dysphagia patients when semi-solid food, such as paste, pudding and rice is swallowed than with liquids [<xref ref-type="bibr" rid="CR148">148</xref>–<xref ref-type="bibr" rid="CR150">150</xref>]</td></tr><tr><td align="left" colspan="2">Dispersible and effervescent tablets</td></tr><tr><td align="left"> 1. These tablets are potentially suitable to be administered to infants under 6 months of age for drug substances and excipients that are compatible with breast milk [<xref ref-type="bibr" rid="CR151">151</xref>]. A ‘nipple shield delivery system’ (NSDS) could facilitate this novel method of infant drug delivery [<xref ref-type="bibr" rid="CR152">152</xref>]</td><td align="left" rowspan="2">1. These formulations usually require the application of a large volume of water, which could be problematic for both children and older patients who find swallowing a large amount of liquid difficult, especially in patients with dysphagia [<xref ref-type="bibr" rid="CR70">70</xref>]<break></break>2. The risk of aspiration in dysphagia patients for swallowing thin liquids resulted from these formulations would need to be considered<break></break>3. Effervescent formulations showed high capacity for tooth erosion, even more so than sugar-containing medicines, which should be considered for long-term use in children and older people [<xref ref-type="bibr" rid="CR154">154</xref>]<break></break>4. Soluble and dispersible formulations often contain a high quantity of sodium and the maximum daily dose of these medications could exceed the recommended daily dietary intake of sodium [<xref ref-type="bibr" rid="CR155">155</xref>]. Prescribing sodium-containing formulations was associated with increased cardiovascular incidents [<xref ref-type="bibr" rid="CR155">155</xref>] and the use of effervescent formulations was responsible for poor blood pressure control in older hypertension patients [<xref ref-type="bibr" rid="CR156">156</xref>]</td></tr><tr><td align="left"> 2. Carbonated water generated by effervescent formulations could potentially improve safe swallowing in dysphagia patients [<xref ref-type="bibr" rid="CR88">88</xref>, <xref ref-type="bibr" rid="CR93">93</xref>, <xref ref-type="bibr" rid="CR153">153</xref>]</td></tr><tr><td align="left" colspan="2">ODTs</td></tr><tr><td align="left"> 1. ODTs are generally acceptable in children and older patients, which is normally associated with their taste, texture, ease of use and reduced concern about difficulties in swallowing [<xref ref-type="bibr" rid="CR141">141</xref>, <xref ref-type="bibr" rid="CR142">142</xref>, <xref ref-type="bibr" rid="CR145">145</xref>]</td><td align="left" rowspan="4">1. The risk of aspiration remains the same in swallowing ODTs as conventional tablets in dysphagia patients [<xref ref-type="bibr" rid="CR157">157</xref>]</td></tr><tr><td align="left"> 2. ODTs are easier to swallow than conventional tablets in dysphagia patients [<xref ref-type="bibr" rid="CR157">157</xref>]. Fewer numbers of swallows, shorter swallowing duration, reduced muscular effort and less fluid assistance are required in swallowing ODTs than conventional tablets</td></tr><tr><td align="left"> 3. The use of ODTs can be beneficial for patients who are purposely non-adherent, particularly in relation to antipsychotic treatments, as it is more difficult to spit the tablet out or hide the formulation in the mouth [<xref ref-type="bibr" rid="CR158">158</xref>]</td></tr><tr><td align="left"> 4. The ease of administration of ODTs can be advantageous to reduce the work burden on nursing staff and caregivers who assist the administration of medicines in older patients [<xref ref-type="bibr" rid="CR143">143</xref>]</td></tr><tr><td align="left" colspan="2">Chewable tablets</td></tr><tr><td align="left"> 1. Many chewable formulations are licensed for use in children from the age of 2 years and were found to be safe and well-tolerated in children from this age [<xref ref-type="bibr" rid="CR146">146</xref>, <xref ref-type="bibr" rid="CR147">147</xref>]</td><td align="left">1. Chewable tablets have the potential for tooth erosion over long-term use [<xref ref-type="bibr" rid="CR154">154</xref>]<break></break>2. Use in older patients could be limited due to the decline in chewing ability<break></break>3. Adverse events are associated with the swallowing of intact or partially chewed chewable tablets, such as intestinal obstruction, ischaemia and perforation [<xref ref-type="bibr" rid="CR159">159</xref>]. The issue can be augmented by the large variation in chewability of commercially available chewable tablets [<xref ref-type="bibr" rid="CR159">159</xref>]</td></tr></tbody></table><table-wrap-foot><p><italic>ODTs</italic> orally disintegrating tablets</p></table-wrap-foot></table-wrap></p><sec id="Sec20"><title>Multiparticulate Dosage Forms</title><p>Multiparticulates include powders, granules and pellets and are usually presented in sachets or capsules that can be reconstituted in a drink to provide solutions or suspensions, or applied onto food as ‘sprinkles’. They can also be further processed to produce other solid formulations including conventional, orally disintegrating or chewable tablets. Based on recent US FDA guidance, multiparticulates that are labelled for administration via sprinkling should have a target size of 2.5 mm, with no more than 10 % variation over this to a maximum size of 2.8 mm [<xref ref-type="bibr" rid="CR160">160</xref>]. These formulations are typically considered as paediatric formulations; however, older patients can also benefit from their use, such as for the treatment of Parkinson’s disease, osteoporosis and phenylketonuria [<xref ref-type="bibr" rid="CR132">132</xref>, <xref ref-type="bibr" rid="CR133">133</xref>, <xref ref-type="bibr" rid="CR161">161</xref>].</p></sec><sec id="Sec21"><title>Dispersible, Soluble and Effervescent Tablets</title><p>Dispersible, soluble and effervescent tablets are solid dosage forms that can be dispersed or dissolved in a liquid to form a solution or suspension. These dosage forms require effective taste masking, as reviewed in Sect. <xref rid="Sec13" ref-type="sec">4.1</xref> relating to oral liquid medicines. These dosage forms are beneficial in the delivery of large doses of active drug substances as they are easier to swallow than large tablets. The acceptability and safety of using dispersible and soluble tablets in older adults, especially those with dysphagia, have not been fully studied. However, effervescent formulations may be a useful technology to promote safe swallowing in older patients due to the production of carbon dioxide in water. Carbonated water has been found to be able to improve swallowing in dysphagia patients by exciting chemical stimulation in the oral cavity (Table <xref rid="Tab4" ref-type="table">4</xref>) [<xref ref-type="bibr" rid="CR88">88</xref>, <xref ref-type="bibr" rid="CR93">93</xref>, <xref ref-type="bibr" rid="CR153">153</xref>]. A national survey in the UK showed that 90 % of the prescribed and issued over-the-counter ‘easy to swallow’ solid formulations were effervescent tablets for long-term use in older people [<xref ref-type="bibr" rid="CR162">162</xref>].</p></sec><sec id="Sec22"><title>Orally Disintegrating Formulations</title><p>Orally disintegrating formulations include tablets, films and thin wafers. These formulations are relatively new innovations in improving patient compliance and acceptance, especially for paediatric and geriatric patients. These preparations may be applicable for use across the paediatric population, including infants and young children; however, evidence of their use and acceptability in these subsets is lacking. A number of orally disintegrating tablet and film formulations have been developed for the treatment of diseases that are common in the older population such as pain, depression, Parkinson’s disease and Alzheimer’s disease [<xref ref-type="bibr" rid="CR163">163</xref>, <xref ref-type="bibr" rid="CR164">164</xref>].</p></sec><sec id="Sec23"><title>Chewable Tablets</title><p>Chewable tablets are another dosage form useful for paediatric and geriatric patients who are unable to swallow conventionally sized monolithic dosage forms intact. In typically developing children, deciduous (primary) teeth begin to erupt from 6 months of age and the complete set of 20 have usually erupted between the ages of 2 and 3 years. Exfoliation of deciduous teeth begins from 6 to 7 years of age, with complete replacement by permanent teeth usually completed by the age of 12–13 years. Recent research suggests continual refinement of chewing skills occurs until at least the age of 3 years, at which time chewing patterns and efficiency also stabilise [<xref ref-type="bibr" rid="CR165">165</xref>].</p><p>Despite the recent popularity of chewable tablets in children, their usage in older adults may be limited due to the deteriorations of chewing ability in this age group. The prevalence of chewing problems was observed to be 40 % among older Tanzanian citizens (aged 50–100 years) [<xref ref-type="bibr" rid="CR166">166</xref>]. In Finland, chewing ability was considered poor in 55 % of long-term hospitalised older individuals and 65 % could eat mashed food only [<xref ref-type="bibr" rid="CR167">167</xref>]. The loss of teeth is regarded as the primary factor accounting for the deterioration of the chewing ability and the possession of more than 20 teeth is essential for retaining good chewing capacity. However, a survey in Japan showed that 65 % of older people (aged 75–100 years) had less than 20 teeth [<xref ref-type="bibr" rid="CR168">168</xref>]. In Denmark, half of the 75- and 85-year-old men and women in a suburban area were edentulous and only 15 % still had more than 20 teeth [<xref ref-type="bibr" rid="CR169">169</xref>]. As a result, chewing problems were shown in three-quarters of those very old men and women who have lost all of their natural teeth.</p></sec><sec id="Sec24"><title>Films and Jellys</title><p>A film formulation provides easy swallow through the application of a dry film that turns into a jelly instantaneously in the mouth by absorbing a small amount of saliva [<xref ref-type="bibr" rid="CR170">170</xref>]. The film consists of an inner layer that contains the active drug and two gelling layers covering the drug layer (Fig. <xref rid="Fig1" ref-type="fig">1</xref>). The dissolution of the drug in the mouth was limited by the gel layer which swells by absorbing water (Fig. <xref rid="Fig2" ref-type="fig">2</xref>). The oesophageal transit of the film was significantly quicker than gelatin capsules [<xref ref-type="bibr" rid="CR170">170</xref>]. The technology may be difficult to use in older people with xerostomia, which is a common symptom in the older population, particularly related to the increased use of medications [<xref ref-type="bibr" rid="CR171">171</xref>]. A drug-containing oral jelly was developed to improve swallowing for older patients [<xref ref-type="bibr" rid="CR172">172</xref>]. The formulation comprises a jelly portion and an air portion which can be pushed to extrude the jelly when opening the package.<fig id="Fig1"><label>Fig. 1</label><caption><p>Schematic structure of the easy-swallowing film formulation (reproduced from Okabe et al. [<xref ref-type="bibr" rid="CR170">170</xref>], with permission)</p></caption><graphic xlink:href="40265_2014_297_Fig1_HTML" id="MO1"></graphic></fig><fig id="Fig2"><label>Fig. 2</label><caption><p>The swelling behaviour of the film formulation in purified water (reproduced from Okabe et al. [<xref ref-type="bibr" rid="CR170">170</xref>], with permission)</p></caption><graphic xlink:href="40265_2014_297_Fig2_HTML" id="MO2"></graphic></fig></p></sec></sec><sec id="Sec25"><title>Acceptability of Dosage Forms Designed for Particular Therapeutic Effects</title><sec id="Sec26"><title>Modified-Release Formulations</title><p>Oral modified-release formulations enable longer and more patient-friendly dosing intervals. This can be beneficial in children to avoid the need to take medicines at school or nursery settings and to improve adherence in older patients. More simplified dose regimens with fewer daily doses have been associated with higher patient adherence [<xref ref-type="bibr" rid="CR10">10</xref>]. It was found that patient adherence was significantly higher with once- and twice-daily regimens than three and four times daily regimens. Further evidence shows that adherence can be improved by switching from twice-daily to once-daily therapy [<xref ref-type="bibr" rid="CR173">173</xref>]. Adherence to antiretroviral therapy was significantly improved when patients were switched from twice-daily to once-daily stavudine treatments for HIV [<xref ref-type="bibr" rid="CR174">174</xref>]. However, for extended-release formulations, patients need to be reminded that doses should be taken at approximately equal time intervals, e.g. the same time of the day for once-daily preparations. Taking doses too far apart or too close together for these formulations may result in decreased efficacy or increased adverse effects.</p><p>Conventionally, modified-release formulations are designed as single-unit dosage forms that contain the active ingredient in a single tablet or capsule. These formulations are challenging for children and older patients to swallow (see Sect. <xref rid="Sec8" ref-type="sec">3.1</xref>). Crushing modified-release tablets prior to administration poses an additional risk of toxicity due to the high level of active drug contents. There have been reports of patient deaths resulting from administrating crushed modified-release tablets to older dysphagia patients [<xref ref-type="bibr" rid="CR175">175</xref>]. Modified-release multiparticulate systems offer a more flexible method for administration to children and older patients and exist as granules, pellets, beads, mini-tablets, microspheres and microcapsules [<xref ref-type="bibr" rid="CR176">176</xref>–<xref ref-type="bibr" rid="CR179">179</xref>]. These multiple-unit modified-release systems can be filled into capsules/sachets or compressed into orally disintegrating tablets as the final dosage form [<xref ref-type="bibr" rid="CR180">180</xref>, <xref ref-type="bibr" rid="CR181">181</xref>].</p></sec><sec id="Sec27"><title>Fixed-Dose Combinations</title><p>Fixed-dose combinations could be useful to reduce pill burden in older patients and could be beneficial for paediatric patients with combined drug therapies such as treatment for HIV. However, this could increase the size of the tablet and cause further swallowing issues. A potential solution could be different coloured pellets that could be mixed together at different strengths by the manufacturer or pharmacist. Fixed-dose combinations in the forms of oral suspensions and dispersible tablets have been proposed in paediatrics for the treatment of HIV [<xref ref-type="bibr" rid="CR182">182</xref>]. Kayitare et al. [<xref ref-type="bibr" rid="CR183">183</xref>] have developed a fixed-dose combination tablet of zidovudine and lamivudine for paediatric use that allows dose flexibility and easy administration to children. The rectangular tablet can be broken into eight subunits for dose adjustment according to body weight and each subunit disintegrates rapidly in a small volume of liquid to aid administration. It was suggested that the tablet is suitable for children from infants (from 1 month old) to adolescents (up to 18 years of age) [<xref ref-type="bibr" rid="CR183">183</xref>].</p></sec></sec><sec id="Sec28"><title>Concluding Remarks</title><p>Children and older adults share similarities in oral medication acceptability, particularly difficulties in swallowing conventional tablets and capsules. Appropriate formulation design and selection affect the acceptability of medicines in these two age groups and have an impact on patient safety, therapeutic outcomes and adherence. However, distinct differences in relation to drug therapy are notable in children and older people, and separate considerations in prescribing and formulation development should be given to the two populations. Whilst taste, smell and palatability are major concerns in developing paediatric formulations, characteristics of a medicine affecting safe swallowing are of significant importance in older patients, especially to prevent oesophageal retention and risk of aspiration. Nevertheless, both the young and older populations benefit enormously from the advances in pharmaceutical technology which offers bespoke and appropriate formulations of choice to meet their needs.</p></sec><sec sec-type="supplementary-material"><title>Electronic supplementary material</title><sec id="Sec29"><supplementary-material content-type="local-data" id="MOESM1"><media xlink:href="40265_2014_297_MOESM1_ESM.docx"><caption><p>Supplementary material 1 (DOCX 35 kb)</p></caption></media></supplementary-material></sec></sec></body><back><fn-group><fn><p>On behalf of European Paediatric Formulation Initiatives (EuPFI).</p></fn></fn-group><ref-list id="Bib1"><title>References</title><ref id="CR1"><label>1.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kozarewicz</surname><given-names>P</given-names></name></person-group><article-title>Regulatory perspectives on acceptability testing of dosage forms in children</article-title><source>Int J Pharm</source><year>2014</year><volume>469</volume><fpage>245</fpage><lpage>248</lpage><pub-id pub-id-type="pmid">24704104</pub-id></element-citation></ref><ref id="CR2"><label>2.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Paradiso</surname><given-names>LM</given-names></name><name><surname>Roughead</surname><given-names>EE</given-names></name><name><surname>Gilbert</surname><given-names>AL</given-names></name><etal></etal></person-group><article-title>Crushing or altering medications: what’s happening residential aged-care facilities?</article-title><source>Australas J Ageing</source><year>2002</year><volume>21</volume><fpage>123</fpage><lpage>1270</lpage></element-citation></ref><ref id="CR3"><label>3.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Cuzzolin</surname><given-names>L</given-names></name><name><surname>Atzei</surname><given-names>A</given-names></name><name><surname>Fanos</surname><given-names>V</given-names></name></person-group><article-title>Off-label and unlicensed prescribing for newborns and children in different settings: a review of the literature and a consideration about drug safety</article-title><source>Expert Opin Drug Saf</source><year>2006</year><volume>5</volume><fpage>703</fpage><lpage>718</lpage><pub-id pub-id-type="pmid">16907660</pub-id></element-citation></ref><ref id="CR4"><label>4.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Richey</surname><given-names>RH</given-names></name><name><surname>Shah</surname><given-names>UU</given-names></name><name><surname>Peak</surname><given-names>M</given-names></name><etal></etal></person-group><article-title>Manipulation of drugs to achieve the required dose is intrinsic to paediatric practice but is not supported by guidelines or evidence</article-title><source>BMC Pediatr</source><year>2013</year><volume>13</volume><fpage>81</fpage><pub-id pub-id-type="pmid">23688279</pub-id></element-citation></ref><ref id="CR5"><label>5.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Standing</surname><given-names>JF</given-names></name><name><surname>Tuleu</surname><given-names>C</given-names></name></person-group><article-title>Paediatric formulations—getting to the heart of the problem</article-title><source>Int J Pharm</source><year>2005</year><volume>300</volume><fpage>56</fpage><lpage>66</lpage><pub-id pub-id-type="pmid">15979830</pub-id></element-citation></ref><ref id="CR6"><label>6.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wright</surname><given-names>D</given-names></name></person-group><article-title>Medication administration in nursing homes</article-title><source>Nurs Stand</source><year>2002</year><volume>16</volume><fpage>33</fpage><lpage>38</lpage><pub-id pub-id-type="pmid">12216309</pub-id></element-citation></ref><ref id="CR7"><label>7.</label><mixed-citation publication-type="other">European Medicines Agency (EMA). 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