Oral medication dose form alteration: Patient factors and the effects of adding thickened fluids

159 Pages·2016·3.08 MB·English

Oral medication dose form alteration:
Patient factors and the effects of adding thickened fluids

Chandramouli Radhakrishnan
BPharm, MSc

A thesis submitted for the degree of Doctor of Philosophy at
The University of Queensland in 2016
School of Pharmacy
Abstract
Solid oral dosage forms such as tablets and capsules are often crushed and mixed with foods or
fluids to aid drug delivery for those who cannot or prefer not to swallow them whole. Some
people have a physiological problem limiting swallowing (dysphagia), and their fluids are
thickened to ensure safe swallowing; these thickened fluids are also used to deliver crushed
medication in replacement of water. This thesis explores the issues surrounding the swallowing
of whole tablets and capsules, their modification by crushing and the influence of co-
administration with thickened fluids on absorption pharmacokinetics. The literature review
(Chapter 1) examines the physiology and pathophysiology of swallowing and considers the
particular issues surrounding swallowing tablets and capsules. It also explores the possible
consequences of crushing the medications and mixing the powder with vehicles such as jam,
honey, yoghurt and thickened water.
This thesis contains two sections. In Section A (Chapter 2), the potential influence of
psychological issues, oral sensation, sensory effect and motor ability of an individual on
swallowing pills was investigated. It is hypothesised that swallowing tablets and capsules will
be an issue in people with a memory of gagging on food and medication, strong gag reflex,
heightened taste sensation, or who tend to chew their food for extended periods.
Volunteers (153) completed a written survey and one–on-one assessments. Psychological issues
were addressed by questions on memory of choking incidents on food or medication, and
regularity of medication use. Sensory effects were assessed by measuring the person’s gag
reflex, taste receptor density, size of the mouth (mallampati classification), and on food
neophobia. Motor effects were assessed as efficiency in chewing a jelly snake. Finally, the
volunteers were observed swallowing a capsule and the quantity of water used, and head
position was recorded.
In the survey, 33% of the population reported that they have had trouble swallowing medication.
These people were more likely to have choked on medication in the past, have a smaller mouth
cavity, and a medium or high taste receptor density. There was no relationship between trouble
swallowing medication and gag reflex, food neophobia, chewing efficiency, quantity of water
used to swallow, and head position.
In Section B (Chapters 3, 4, and 5), the effect of crushing medication and mixing with water
thickened with a commercial thickening agent on absorption pharmacokinetics was studied.
Paracetamol tablets were used as the model drug, and saliva samples were used to measure the
PK profile. Chapter 3 assessed the inter- and intra-individual variability as the coefficient of
variation of paracetamol in saliva. Volunteers took whole tablets of paracetamol (2 x 500 mg)
on two different days separated by a week. Saliva production was stimulated using citric acid
and paracetamol levels in the saliva were measured using high-performance liquid
chromatography. Non-compartmental pharmacokinetic analyses were performed, and no
significant variation (Wilcoxon signed - rank test) between the days for the total area under the
curve (AUC ) and concentration maximum (C ) was observed. Hence, the use of
(0-8 h),Saliva max
saliva as a matrix is reproducible and reliable.
Chapter 4, tested, the hypothesis that the rate of drug absorption will be significantly slowed,
and the maximum drug concentration reached will be reduced when a drug is crushed and mixed
with thickened fluid in comparison to the whole tablet, crushed tablet delivered in water, and
crushed tablet mixed with jam. This was based on in vitro tests, in which the use of
commercially available thickened fluids (thickness level 900) as a vehicle for delivering crushed
tablets causes a reduction in drug dissolution in comparison to mixing with jam, water, or
dissolution of the whole tablet.
The effect of the delivery vehicle on paracetamol absorption was investigated in Chapter 4. In
this randomized study, 20 healthy volunteers received paracetamol (2 x 500 mg) on four
occasions, either as crushed tablets with water, crushed tablets with jam, crushed tablets with
thickened fluid (level 900), or whole tablets with water. Participants used 250 ml of water to
rinse their mouths, swallowed the rinsing, and thoroughly cleaned their teeth. Non-
compartmental PK analysis was conducted using linear trapezoidal rule method. The 90%
confidence limits of AUC for all three formulations was within the recommended
(0-8 h),Saliva
limits (80% - 125%) and therefore could be considered to be bioequivalent for this parameter.
However, for C only crushed tablets in jam may be regarded as bioequivalent to whole tablet,
max,
while C for crushed tablets with water or thickened water were not within the recommended
max,
limits (80% - 125%).
In vitro and in vivo correlation (IVIVC) is often used in the process of pharmaceutical
development. This involves using in vitro data to predict the possible in vivo concentration
profile. In Chapter 5, IVIVC was used to predict the possible concentration time profile of
crushed paracetamol delivered with three different levels of thickening agent. The IVIVC model
was developed using in vitro dissolution data, and in vivo absorption data from Chapter 4, for
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whole tablets, crushed tablets in water and crushed tablets in jam. In vitro dissolution data was
used to predict the in vivo concentration time profile of crushed paracetamol tablets thickened
fluid at thickness level 150, 400 and 900. The simulation was then compared with the in vivo
data obtained in Chapter 4 using thickness level 900. The IVIVC simulation overestimated the
reduction in rate of absorption resulting from crushing and mixing with thickened fluid at level
900.
In conclusion (Chapter 6), subjects who were classified as supertasters, have smaller mouth
cavity and who have choked on medication in the past are most likely to find it difficult to
swallow tablets and capsules as a whole. Future work could further investigate these
relationships and consider the methods that people use to swallow their medications. In vivo
assessment of paracetamol release from thickened water found indications for an alteration in
the timing of the peak concentration but not in total concentration absorbed. Future research
should be conducted with dysphagic as well as healthy subjects because of the differences in
their swallowing functions. Finally, IVIVC indicated that a standard dissolution test is not
predictive of drug absorption from thickened fluid and more work is required to investigate
using a more physiologically-based model system.
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Declaration by author
This thesis is composed of my original work, and contains no material previously published or
written by another person except where due reference has been made in the text. I have clearly
stated the contribution by others to jointly-authored works that I have included in my thesis.
I have clearly stated the contribution of others to my thesis as a whole, including statistical
assistance, survey design, data analysis, significant technical procedures, professional editorial
advice, and any other original research work used or reported in my thesis. The content of my
thesis is the result of work I have carried out since the commencement of my research higher
degree candidature and does not include a substantial part of work that has been submitted to
qualify for the award of any other degree or diploma in any university or other tertiary
institution. I have clearly stated which parts of my thesis, if any, have been submitted to qualify
for another award.
I acknowledge that an electronic copy of my thesis must be lodged with the University Library
and, subject to the policy and procedures of The University of Queensland, the thesis be made
available for research and study in accordance with the Copyright Act 1968 unless a period of
embargo has been approved by the Dean of the Graduate School.
I acknowledge that copyright of all material contained in my thesis resides with the copyright
holder(s) of that material. Where appropriate I have obtained copyright permission from the
copyright holder to reproduce material in this thesis.

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Publications during candidature
Conference abstracts
Delivering crushed tablets using thickened fluids: salivary paracetamol concentration indicate
an effect on absorption. In Proceedings of the 9th World Meeting on Pharmaceutics,
Biopharmaceutics and Pharmaceutical Technology. 2014 March 31-April. Lisbon, Portugal. P-
222 (Oral presentation)
Delivering crushed paracetamol tablets using thickened fluids: Does it alter the
pharmacokinetics? In Proceedings of the 5th Pharmaceutical Sciences World Congress. 2014
April 13-16 Melbourne, Australia. P-015 (Poster)
Delivering crushed paracetamol tablets using thickened fluids: Does it alter the
pharmacokinetics? In Proceedings of Australasian Pharmaceutical Sciences Association, 2014
December 5 – 7 121 (Oral presentation)
Delivering crushed paracetamol tablets using thickened fluids: can in vitro-in vivo (IVIVC)
make accurate predictions from dissolution tests? In Proceedings of Australasian
Pharmaceutical Sciences Association, 2014 December 5 – 7 P-189 (Poster)
Determining the prevalence and reason for medication swallowing difficulties in the general
population. In Proceedings of Australasian Pharmaceutical Sciences Association, 2011
December 11 – 14 (Poster)
Publications included in this thesis
No publications included

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Contributions by others to the thesis
My supervisors Associate Professor Kathryn Steadman, Professor Lisa Nissen, and Dr. Julie
Cichero were responsible for the overarching conception and design of the project and
contributed to experimental design, analysis and feedback on drafts of manuscripts for
publication and thesis chapters.
Dr. Heather Smyth (The University of Queensland), contributed to the design and execution of
the survey in Chapter 2. Dr Stephanie Reuter Lange (University of South Australia) and Mr
Aaron Basing (The University of Queensland) contributed to data analysis of Chapters 4. Ms
Aisha Raidhan (School of Pharmacy, King’s College of London) helped to conduct the survey
in Chapter 2.

Statement of parts of the thesis submitted to qualify for the award of another degree

None

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Acknowledgements
I would like to express my special appreciation and thanks to my advisor Associate Professor
Kathryn Steadman, who has been a great mentor for me. I would like to thank her for
encouraging me during my research and for allowing helping me to hone my skills as a research
scientist. I would like to thank my committee members, Dr. Julie Cichero (Adjunct Senior
Lecturer, School of Pharmacy, The University of Queensland), and Professor Lisa Nissen
(Head of School of Clinical Sciences, Faculty of Health, Queensland University of
Technology). I would like to extend special thanks for your valuable comments that helped
improve my research work.
I would also like to thank Dr. Heather Smyth (Research Fellow, CNAFS, The University of
Queensland) and Dr. Stephanie Reuter Lange (Senior Research Fellow, UNISA) for their
contributions towards my PhD thesis. I would like to extend my thanks to Mr. Aaron Basing
(Associate Lecturer, School of Pharmacy, The University of Queensland) and Dr. Giridhar
Tirucherai (Director, Clinical Pharmacology & Pharmacometrics, Bristol-Myers Squibb) for
assisting me with modelling and simulation work. My fellow staff and the students from the
School of Pharmacy deserve a special mentioning for they have been there to support me in
every stage of my study, including participation in my Clinical Trials.
My sincere thanks to CERTARA, for providing me access to the modelling software (Phoenix
WINNONLIN) and Dr. Geraldine Elliott (R&D Director at Imaginot Pty Ltd) for sharing data
for my PhD thesis.
I would like to acknowledge The University of Queensland for offering me Australian
Postgraduate Award and the School of Pharmacy for the travel grant to assist with attending the
9th World Meeting on Pharmaceutics, Biopharmaceutics, and Pharmaceutical Technology in
Lisbon, Portugal and financial support with living expenses scholarship.
Words cannot express how grateful I am to my parents and my kids for all of the sacrifices and
compromises they have made in this process. I would also like to thank all my friends (Juliana,
Nahid, Karnaker, and Ganesh) who have been very supportive of me to strive towards my goal.
Last but not the least, I am very grateful to my wife who has been understanding and stood by
my side through all my ups and downs during the years while encouraging me to maintain my
focus in pursuing my PhD, and taking care of the family in my absence.
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Keywords
Swallowing issues, drug delivery, dysphagia, dosage form modification, IVIVC, thickened
fluids,

Australian and New Zealand Standard Research Classifications (ANZSRC)
ANZSRC code: 111502, Clinical Pharmacology and Therapeutics, 30%
ANZSRC code: 111503, Clinical Pharmacy and Pharmacy Practice, 40%
ANZSRC code: 111504, Pharmaceutical Sciences, 30%
Fields of Research (FoR) Classification
FoR code: 1115, Pharmacology and Pharmaceutical Sciences, 100%

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Table of contents
Abstract ........................................................................................................... i
Declaration by author ...................................................................................... iv
Publications during candidature ........................................................................ v
Publications included in this thesis ................................................................... v
Contributions by others to the thesis ................................................................ vi
Statement of parts of the thesis submitted to qualify for the award of another degree
....................................................................................................................... vi
Acknowledgements ........................................................................................ vii
Keywords ..................................................................................................... viii
Australian and New Zealand Standard Research Classifications (ANZSRC) .... viii
Fields of Research (FoR) Classification ......................................................... viii
Table of contents ............................................................................................. ix
List of Tables ............................................................................................... xiii
List of Figures............................................................................................... xvi
List of Abbreviations ..................................................................................... xix
Section A: Medication swallowing difficulties in the general population……………….31
2 Determining the prevalence and reasons for medication swallowing difficulties in the
general population ................................................................................................................. 32
2.1 Introduction .............................................................................................................. 33
2.2 Materials and Methods ............................................................................................. 37
2.2.1 Population ........................................................................................................... 37
2.3 Study Design ............................................................................................................ 37
2.3.1 Phase 1 – Psychological contribution to medication swallowing issues ............ 37
2.3.2 Phase 2 – Oral sensory contributions to medication swallowing issues ............ 38
2.3.2.1 Gag reflex .................................................................................................... 38
2.3.2.2 Modified Mallampati classification ............................................................ 39
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