Pediatr Drugs 2004; 6 (2): 127-131ORIGINAL RESEARCH ARTICLE 1174-5878/04/0002-0127/$31.00/0

© 2004 Adis Data Information BV. All rights reserved.

Flavor and Taste of LansoprazoleStrawberry-Flavored Delayed-Release OralSuspension Preferred over RanitidinePeppermint-Flavored Oral SyrupIn Children Aged Between 5–11 Years

Vasundhara Tolia,1 Gary Johnston,2 Julie Stolle2 and Chang Lee2

1 Children’s Hospital of Michigan, Detroit, Michigan, USA2 TAP Pharmaceutical Products Inc., Lake Forest, Illinois, USA

Objective: To compare the flavor and taste preference of two acid-inhibitory therapies in healthy children agedAbstractbetween 5–11 years.Methods: A single-site, single-blind, taste test trial was conducted in which 111 children participated afterparental consent. One teaspoonful (5mL) of lansoprazole delayed-release oral suspension (strawberry-flavored)and ranitidine oral syrup (peppermint-flavored) were provided to each child with a 10-minute break betweensamples. Children tasted the sample, swished it in their mouth for 10 seconds, and then expectorated the sample.Spring water and crackers were used to clear the palate between samples. After each sampling, children wereobserved for facial expressions and asked to rate their degree of liking of each sample based on a 5-point facialhedonic scale (5 = like it very much, 1 = dislike it very much). Likes, dislikes, and product preference wererecorded.Results: Of the 56 female and 54 male children who tasted both samples, 95% (105/110) preferred lansoprazole.Taste and flavor were the most often cited reasons for preferring lansoprazole (61 and 17 children, respectively)while three children preferred the flavor of ranitidine oral syrup. Lansoprazole received a higher mean likingrating compared with ranitidine (mean liking scores of 4.1 and 2.2, respectively). There was no significantdifference in the preference for lansoprazole between age groups and gender with the degree of liking scoresranging between 3.5–4.4. Forty-two children disliked the texture of the lansoprazole oral suspension, citing thegranules (31/110), thickness (7/110), or consistency/texture (4/110), specifically.Conclusion: After sampling both products, 95% of children preferred the flavor and taste of the strawberry-flavored lansoprazole delayed-release oral suspension compared with the peppermint-flavored ranitidine oralsyrup.

Acid-related diseases such as gastroesophageal reflux disease The use of proton pump inhibitor (PPI) therapy has had asignificant impact on the treatment of a wide variety of acid-(GERD) are common in adults as well as among children. Therelated diseases, including GERD,[3] erosive esophagitis,[4] gastricprevalence of GERD symptoms such as heartburn and regurgita-and duodenal ulcers,[5-7] and nonsteroidal anti-inflammatory drug-tion are 1.8 and 2.3%, respectively, in children aged between 3–9induced gastropathy.[5,8-10] PPIs have consistently demonstrated

years. The frequency of these same symptoms increases to 5.2 andsuperior gastric acid suppression compared with the histamine H2-

8.5%, respectively, in children aged between 10–17 years.[1] Al- receptor antagonists (H2RAs).though the incidence of GERD is higher in adults, it has been In children, the effective treatment of acid-related diseases suchspeculated that reflux that begins in childhood begets a lifelong as GERD may be dependent upon several additional factors be-problem with variable symptoms.[2] sides therapeutic efficacy. These factors include product availabil-

128 Tolia et al.

ity as an oral solution instead of a solid capsule/tablet and taste (figure 1), using hypothetical situations to familiarize the childrenacceptance of the solution. Among the PPIs, the US FDA currently with the scale before taste testing was conducted. Water samplesapproves only lansoprazole and omeprazole for use in pediatric were used to practise swishing and expectorating.patients. Both products are available as capsules containing enter- Flavor and taste preferences were determined by administeringic-coated granules. Lansoprazole may be sprinkled in fruit juices, a single-blind taste test of lansoprazole delayed-release oral sus-apple sauce, or yogurt prior to administration, and omeprazole pension and ranitidine oral syrup to healthy children. The rani-may be sprinkled in apple sauce prior to administration.[11,12]

tidine oral syrup was dispensed as a single-strength dose of 75mgLansoprazole is also available as delayed-release, enteric-coated

per 5mL from the bottle. The lansoprazole oral suspension wasgranules which, when mixed with tap water and swirled, become a

reconstituted with distilled water to a concentration of 15mg perstrawberry-flavored oral suspension. Among the currently avail-

30mL and was administered to each child within 15 minutes.able H2RAs, ranitidine, cimetidine, and famotidine are available

These are commercially available standard concentrations of theseas oral liquid dosage formulations. Of the three, ranitidine and

medications. Samples were prepared by a registered nurse in afamotidine are preferred for the treatment of children as they have

separate area of the study site to maintain blinding. Each child wasa lower potential for drug interactions compared with cimeti-

presented with one teaspoonful (5mL) of lansoprazole and rani-dine.[13]

tidine in 30mL plastic sample cups by the interviewer. The agentsTo our knowledge there have been no studies published com- were presented one at a time with the order of the sample presenta-

paring the taste acceptance and preference of acid-inhibitory ther- tion randomized according to a computer generated sequence (S-apy preparations among children. A visual analog scale, a standard Plus Version 6.0 Professional Release 2, Insightful Corporation,tool for quantification, modified by including a facial hedonic Seattle, WA) and balanced across the participants. The childrenscale has been used in prior studies of antimicrobial agents to tasted the samples, swished for 10 seconds, and then expectorated.assess their palatability.[14-16] We performed a prospective study in Between samples, spring water and crackers were provided tochildren to compare the flavor and taste preferences of two widely clear the palate. Ten minutes elapsed between the first and secondused, oral gastric acid inhibitory preparations: lansoprazole straw- sample in order to minimize a carry over effect.berry-flavored delayed-release oral suspension and ranitidine pep-

Immediately after each test dose, the child was asked to ratepermint-flavored oral syrup.their degree of liking using the visual analog scale that incorporat-ed a 5-point facial hedonic scale. Children were asked what their

Methodsproduct preference was following the administration of both sam-ples. Subjects were observed for facial expressions and for com-ments on likes and dislikes, and comments on why one agent wasSetting and Subject Eligibilitypreferred over the other were recorded.

The study was conducted at a contract research organization A registered nurse and physician were available throughout thesite (TIAX LLC, Cambridge, MA). Subjects were recruited by the study to ensure the safety of the children. Any adverse eventcontract research organization from a large respondent database. occurring during the taste testing session was recorded.Male and female children aged between 5–11 years, with a mini-mum weight of 16.8kg, in good health, with no food or drug

Ethicsallergies, and not currently requiring treatment with any prescrip-tion or over-the-counter medications were eligible for participa-tion. The upper limit of the age range in this study was chosen The study center’s institutional review board approved thebecause most children over 11 years of age are able to swallow study. Informed consent was obtained from parents or guardiansintact tablets or capsules. Parents or guardians consulted the and assent was obtained from all children prior to taste testing.participant’s physician to ensure that participation did not poseany unreasonable risk to the child. The study was conducted inhalf-hour sessions with no more than four children participating ineach session.

Determination of Taste Acceptance and Preference

All interviews were conducted on a one-on-one basis. Theinterviewers practised the use of the 5-point facial hedonic scale

Dislike itvery much

Dislike ita little

Like ita little

Notsure

Like itvery much

54321

Fig. 1. The visual analog scale that incorporated a 5-point facial hedonicscale.

© 2004 Adis Data Information BV. All rights reserved. Pediatr Drugs 2004; 6 (2)

Flavour and Taste Preference of Lansoprazole versus Ranitidine 129

several children reported liking “nothing” about the ranitidine oralsyrup. The majority of dislikes regarding lansoprazole oral suspen-sion were related to its texture, while the dislikes for ranitidine oralsyrup were primarily related to its taste.

The average liking score for lansoprazole oral suspension was4.1 ‘like it a little’ (95% CI 3.9, 4.4) compared with the averageliking score of 2.2 ‘dislike it a little’ (95% CI 2.0, 2.5) withranitidine oral syrup. Slightly lower scores, although still signifi-cantly greater with lansoprazole oral suspension compared withranitidine oral syrup, were recorded for each product in the mo-

Table I. Demographics of children enrolled

Characteristic No. of participants (%)

Gender

Male 54 (49.1)

Female 56 (50.9)

Age groups

5–6y 27 (24.5)

7–8y 32 (29.1)

9–11y 51 (46.4)nadic, first-position only analysis (3.7 for lansoprazole oral sus-pension compared with 2.4 for ranitidine oral syrup).Statistical Analysis

On a sequential-monadic basis, the oral suspension of lan-Data are presented as mean values. The taste scores from the soprazole delayed-release granules was ‘liked’ significantly more

visual analog scale with facial hedonic measures were analyzed (p < 0.05) than the ranitidine oral syrup. Overall, 79% of childrenusing analysis of variance (ANOVA). Sequential-monadic hedon- liked the taste of lansoprazole oral suspension ‘very much’ or ‘aic ratings (both samples) were analyzed using two-way ANOVA. little’ compared with the 20% of children tasting ranitidine oralMonadic, first-position only measures were analyzed using one- syrup (table II).way ANOVA. The presence of gender and age effects and the Responses to the liking rating were higher with lansoprazoleinteraction of age and gender were examined by nesting respon- oral suspension compared with ranitidine oral syrup whendents within these class variables and applying a repeated measure analysed by the children’s gender and age group (figure 2). Over-ANOVA. Significance was at the 0.05 level with a 90% power to all, lansoprazole oral suspension received liking scores betweenperceive a difference. Preference measures were analyzed using a 3.5–4.4 for all gender and age groups compared with 2.0–2.5 withproportions test to determine if there was a significant difference ranitidine oral syrup. No significant difference was observed be-in preference between the samples. Facial expressions and open- tween the age groups or between the genders. No adverse eventsended comments on likes and dislikes as well as reasons for why were reported during the course of the study.samples were preferred were recorded, tabulated, and summarizedby product. Discussion

Among pediatric patients the flavor and taste acceptability of aResultsmedication, particularly that of oral liquid preparations, is essen-

A total of 111 children participated in the study and 110 tasted tial for treatment compliance and a successful outcome. Severalboth samples. One child tasted the ranitidine oral syrup first and comparative taste acceptability and preference studies involvingthen refused to taste the lansoprazole sample and was released oral antimicrobial suspensions have been performed in chil-from the study. There was a uniform distribution between the dren.[14,15,17] Although other H2RAs are also available as flavoredgenders and a comparable number of children of each age rangewere represented (table I).

Of the 110 children who tasted both agents (56 females and 54males), 95% (105/110) of the children preferred lansoprazole oralsuspension and 5% (5/110) preferred ranitidine oral syrup. Thechildren’s preference was consistent with their degree of liking asrated by the hedonic scale, with the preferred product being ratedhigher. Taste and flavor were the most often cited reasons whychildren preferred lansoprazole oral suspension (taste, n = 61;specific flavor mentioned, n = 17). Three children reported thatthey preferred ranitidine oral syrup due to its flavor. One childpreferred ranitidine oral syrup because it did not have “little whitegranules” and one child preferred ranitidine oral syrup because itwas “not as bad as the first” sample. The most common commentsregarding what the child liked about the respective samples wererelated to flavor and taste for the lansoprazole oral suspension and

Table II. Responses to the liking rating for lansoprazole and ranitidinea

Degree of liking Lansoprazole oral Ranitidine oralsuspension syrupno. of participants (%) no. of participants (%)

Like it very much 56 (51) 8 (7)

Like it a little 31 (28) 14 (13)

Not sure 12 (11) 22 (20)

Dislike it a little 4 (4) 19 (17)

Dislike it very much 7 (6) 47 (43)

Total 110 (100) 110 (100)

Mean score 4.1 2.2

a Following each sample children were asked “which face or wordsbest describes what you thought about the taste of this sampleoverall”.

© 2004 Adis Data Information BV. All rights reserved. Pediatr Drugs 2004; 6 (2)

130 Tolia et al.

strawberry- and cherry-flavored agents are generally preferredover bubble gum-, banana-, strawberry/banana-, and fruit-flavoredagents.[14,16,17] Studies comparing the taste preference of variousfruit- versus mint-flavored antacid preparations in liquid and tabletforms have been conducted in adults with results that were similarto our findings.[19-22] In one study, antacids of cherry or lemonflavor tended to be preferred over mint-flavored agents[9] whereasan orange-flavored tablet was chosen overwhelmingly in anotherstudy.[1] Oral texture and consistency perception and preferenceare dependent upon the size, shape, and hardness of the particles inaqueous suspensions.[23] As illustrated in this study, four childrencited the white “specks” and “little crunchy balls” as what they

0

1

2

3

4

5

LansoprazoleRanitidine

Fem

ales 5

−6y

Fem

ales 7

−8y

Fem

ales 9

−11y

Male

s 5−6

y

Male

s 7−8

y

Male

s 9−1

1y

Fig. 2. Lansoprazole and ranitidine product liking scores, by gender andage. Scale: 5 = like it very much, 4 = like it a little, 3 = not sure, 2 = dislike ita little, 1 = dislike it very much. liked about lansoprazole, while 31 children reported that they did

not like the white “stuff/balls”. Whether or not the preference ofliquid preparations, to our knowledge this is the first blinded, strawberry-flavored lansoprazole oral suspension would havecomparative taste acceptability and preference evaluation per- changed with greater exposure was not evaluated in this study.formed between oral formulations of agents in the PPI and H2RA While historically the H2RAs were considered the first line ofclasses of acid-suppressive therapies. treatment for acid-related disorders, a number of studies have

found that a tolerance effect to these compounds develops overOf the 110 children who ranged in age from 5–11 years, 95%time with the need for increasing doses to achieve continuedpreferred the taste of the strawberry-flavored lansoprazole oralsymptom relief.[24-26] A great number of studies in adults havesuspension to the peppermint-flavored ranitidine oral syrup. Drugsdemonstrated that PPIs are more effective compared with H2RAsor formulations induce abnormalities of taste by processes not yetin relieving the signs and symptoms of acid-related diseases asfully understood. To improve the palatability of oral medications,well as maintaining the healing of esophageal mucosa.[4,5,27,28]it is common to use a flavoring agent to enhance the sensoryCase series of children treated with omeprazole and lansoprazoleappeal of formulations for children. Often the chemical propertieshave shown superior symptom relief as well as effectiveness inand flavor of a drug dictate the selection of a flavoring agent, as ithealing esophagitis.[29-33] A multicenter trial using lansoprazole inmust effectively mask the unpleasant taste of the drug while notchildren demonstrated an excellent efficacy and safety profile withadversely affecting its stability or bioavailability. Ranitidine is aminimal adverse events.[34,35] Their improved efficacy and wellwell known bitter tasting stimulus[18] and this may overall explaindocumented safety profile combined with the results of this oralthe inability to mask the taste despite the use of flavoring.solution palatability study provides supportive evidence for theA likely assumption would be that this flavor and taste prefer-use of PPIs, such as lansoprazole, in children as well as adults whoence, albeit among healthy children, would translate into improvedare unable to swallow solid oral dosage formulations.medication compliance among those with gastroesophageal disor-

Other factors that warrant consideration and support the use ofders. Further studies are needed to verify this assumption. WhilePPIs in children include ease of administration. In addition to thesome of the older children enrolled in this study may be able toavailability of lansoprazole granules for oral suspension, the enter-ingest solid oral dosage formulations of both of these agents, ouric-coated granules contained in lansoprazole can also be sprinkledgoal was to assess flavor and taste preferences of these two liquidonto soft foods, liquid dietary supplements, or fruit juices prior toformulations that may be applicable clinically to children andingestion, and omeprazole granules can be sprinkled onto appleadolescents who may not be able to swallow capsules and/orsauce. The frequency of dose administration is also a criticaltablets.component of a patient’s adherence to treatment; PPIs such as

The preference of an oral suspension is dependent upon manylansoprazole and omeprazole are administered once daily com-

factors, including flavor, taste, texture, as well as other factorspared with two- to three-times daily administration with ranitidine.

related to diet and exposure time. Variations in diet (e.g. cultural orcomposition) as well as initial versus repeated exposure to a flavor Conclusionmay result in differences in children’s flavor preference as well aschanges in flavor preference over time. While we studied a healthy The flavor and taste of strawberry-flavored lansoprazole enter-volunteer population of children from one geographic area, who ic-coated granules for oral suspension was preferred to that ofwere given a single sample of each acid secretory inhibitor prepa- peppermint-flavored ranitidine oral syrup in a population ofration, we noted results that were similar to those of other investi- healthy children. This flavor and taste preference may result ingators. In taste tests of oral antimicrobial agents in children, the greater medication compliance among children who require long-

© 2004 Adis Data Information BV. All rights reserved. Pediatr Drugs 2004; 6 (2)

Flavour and Taste Preference of Lansoprazole versus Ranitidine 131

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Correspondence and offprints: Dr Vasundhara Tolia, Children’s Hospital of267-70Michigan, 3901 Beaubien Boulevard, Detroit, MI 48201, USA.17. Powers JL, Gooch WM, Oddo LP. Comparison of the palatability of the oralE-mail: vtolia@med.wayne.edususpension of cefdinir vs amoxicillin/clavulanate potassium, cefprozil and

© 2004 Adis Data Information BV. All rights reserved. Pediatr Drugs 2004; 6 (2)