challenges of sensory evaluation (palatability ... · dr catherine tuleu ucl school of pharmacy...
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Dr Catherine Tuleu UCL School of Pharmacy
Reader, Department of Pharmaceutics
&
Director, Centre for Paediatric Pharmacy Research
Challenges of sensory evaluation
(palatability/acceptability) of pharmaceutical
products for adults and children
IFST Sensory Science Group Conference June 16 2016
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- Acceptability and
Palatability of medicines
-Methodological similarity/differences with food sensory research
a case study: ‘to select or not to select’ - Moving towards non human tools?
- Opportunities for sensory analysis during the
development of (paediatric) medicines
- The EU paediatric medicine regulation: 9
years down the line
Today’s snapshot
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• Acceptability is an overall ability of the patient and caregiver
(defined as ‘user’) to use a medicinal product as intended (or
authorised).
vs
• Acceptability of a medicinal product is likely to have a significant
impact on the patient’s adherence and consequently is likely to
have an impact on safety and efficacy of the product.
Official (regulatory) definitions
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Characteristics of medicinal product
• Palatability (one of the main but not exclusive elements)
• appearance (e.g. colour, shape, embossing, etc.)
• swallowability (size/shape, integrity of dosage form (e.g. coating)
• Required dose (e.g. dosing volume, number of tablets, break marks,
etc.)
• Required dosing frequency and duration of treatment
• Actual mode of administration
• Complexity of modification prior to administration (if required)
• Selected administration device (if any)
• Container closure system (primary and secondary)
(physical and behavioural) age appropriate / clinically relevant
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• Palatability is defined as the overall appreciation of a (often oral) medicine by
organoleptic properties such as vision (appearance), smell, taste, aftertaste
and mouth feel (e.g. texture, cooling, heating, trigeminal response), and possibly
also sound (auditory clues).
• It is determined by the characteristics of the components (Active Substance and
Excipients) and the way the active substance is formulated into a medicine.
• Palatability is also relevant for other routes of administration e.g. buccal, nasal,
inhalation use, and whenever the product may contact the taste receptors
indirectly e.g. by deposition in the throat, post nasal run off, etc.
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Children DO NOT think that the worse
a medication taste, the better it works!
A survey of 500 parents [Ascent Pediatrics,
Inc.] indicated that ~50% of children refuse
to take their medication at some time and
that, for the 75% of those who were
noncompliant, the reason reported was
related to a drug's taste. C.-P. Milne et al, Clin Ther 2008 30 (11) 2133-2145
Taste was the most commonly reported
barrier to medicines administration
affecting 35% (188/542) of all prescribed
oral formulations, and associated with 64%
(54/85) of formulations that were refused. Venables, R., Int J Pharm, 480 (2015) 55-62.
Palatability remains one of the key reasons
for rejection of medication in young children.
A survey of over 800 paediatricians on
barriers to treatment completion for
children with acute/chronic illnesses:
Frequency of dosing (96%/91%)
Unpleasant taste (91%/84%)
Side effects of medication (88%/88%) American Society of Pediatrics; 2000
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Is the future bright?
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Since January 2007 the Paediatric Regulation came into force
in EU and obliges pharmaceutical companies to develop
paediatric medicines
8 A system of OBLIGATIONS and INCENTIVES
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PIP
Early in development (end of phase 1 in adults)
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11
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•
“It is recommended that taste assessment is conducted hand-
in-hand with formulation development”…catch 22!
Adult Program
• Taste as criteria for compound selection?
• Phase I studies – adult.
Paediatric Program
• In vitro methods?
• Adult volunteers?
• Part of the pediatric clinical studies.
• Other means and confirm post marketing
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Later phase ‘panels’
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Regulatory expectations?
“The choice of the method and the acceptance criteria, as
proposed by the applicant, should be described and justified for the
intended aim. The suitability of the chosen method and the
appropriateness of the limits to be applied should be discussed and
justified in terms of benefit-risk considerations
…including risks at population level (e.g. emergence of resistance),
and should take account of the characteristics of the target age
group, the condition relevant to the medicine, incidental and multiple
use and co-medication”
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Several methods described in the literature
BUT knowledge still fragmented
an internationally harmonized method has not yet been developed
iUK
Numerous aspects need to be further explored, including:
• design of studies incl. number of subjects involved, questionnaires to patients and/or caregivers, type of scales used etc.
• acceptance criteria
• eg 100% 80%? What % is ‘acceptable’?
http://www.paediatricscienceuk.com
P.R.O.
2016
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‘…voluntary full consumption within the maximum offering time…’
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What to learn from the modern sensory and
consumer science of food industry?
Formulation development - earlier phase
and panels of healthy adult volunteers
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• The market
– Pharma (small) vs Food (Big)
– Global
– Development geared towards more developed countries where there is less
kids
– Rx market not driven by competitive sales (excl. OTC)
• Soft food to administer medicines (as administration vehicle/taste masking effect)?
• Flavouring? Level of sweetness acceptance…
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Pharma vs Food
• Start point….Endpoint
• Product attribute
– limited
– can’t be attractive (Rx)
• Product quality for testing:
– GMP
BAD (bitter, metallic…
AVERSIVE) OK
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Panel healthy (sick) volunteers)
Socio-demographics
Age (direct vs proxi measurement)
Environment (parents) influence
gender, genetics…
Methodology
- Swallow /swirl-spit
- 5ml?->15ml?
5sec?->15 sec?
- Single vs repeated exposure(compliance)
End point
Product development
Benchmarking – generics!
Degree of liking (preference) =many
naïve subjects
Vs
Degree of tolerance (acceptability) = few
trained subject (patients?)
QC
Methodology
Questionnaires/ Scale used
stats
Setting
is it a CT?
Pain scale
3yo+, self report Wong & Baker, 1988
P.R.O.
iUK
2016 n=6 n=5
Aversiveness scale
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YES (Phase 1 study) O) NO
NO
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ISO guideline on participant training(/selection?) methodology
Intra-individual Variability
Retrospective analysis of 3 studies
selection on quinine
Sample APIs
Study 1 N=21 males and females Quinine hydrochloride
Caffeine citrate
Diclofenac sodium
Sildenafil citrate
Paracetamol
Study 2 n=48 males and females Quinine hydrochloride
Study 3 n=48 males Quinine hydrochloride
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To select or not to select…
Rationale for selecting participants:
-For lowest [quinine] all ratings <25
-For highest [quinine] all >75
-Range between two ratings of the same
concentration no greater than 50
6 participants “sensitive” (the first 6) the remaining 15 as “non-sensitive
inter-individual variability
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To select or not to select…
“sensitivity selection” to quinine did not necessarily result in participants being
significantly more sensitive to other APIs
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Need for screening tools for taste assessment at different stages of the drug
development process EARLY PHASE
Pre-candidate
stage? Selection of salt? Formulation?
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Thanks to my group for their hard work! …And still smiling…
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https://www.ucl.ac.uk/pharmacy/people/academic-research-staff-profiles/catherine-tuleu
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Back up slides
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–Obligation : data in children agreed as per binding Paediatric Investigation Plan (PIP)
End of phase I
Or Waiver from the requirement
Or Deferral of the timing of the studies
Discuss all subsets
–Paediatric Committee (PDCO) at the EMA
–FORMULATION WORKING GROUP
–Reward (incentives) for paediatric studies conducted
if information included in the product information (SPC)
even if clinical trial do not show efficacy
3 pilars
ICH E11
For formulators
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Solid dosage forms = smaller is nicer?
Ready to use
(mono, multidose Packaging -Device)
Require manipulation
(reconstitution, sprinkle)
Intermediate for SODF
(compaction, API combination)
Dosage
forms
Swallow-
ability
Dosing
flexibility
Taste
masking
Modified
release
Chemical
stability
Excipients
tolerability
Liquids
Solids
Multi-
particulates
Powder
Granules
Pellets
Minitablets
1 to <4mm
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Mouthfeel of dispersible tablets
excipients (coprocessed or not)
- Tribology
- BATA model
- Texture aids?
- Swallowability models
- Gastrointestinal transit of non
disintegrating MP
iUK
ACCEPT
MP
mouthfeel
Birmingham
Thinktank
(P Mistry, Dr
H Batchelor)
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Acceptability of mouthfeel of
Multiparticulate study