(4
`
`Pharmaceutical Press Pharmaceutics -
`
`
`
`Yvonne Perrie
`Thomas Rades
`
`CELGENE 2016
`APOTEX v. CELGENE
`IPR2023-00512
`
`
`
`Drug Delivery
`and Targeting
`
`

`

`
`
`

`

`
`Pharmaceutics:
`Drug Delivery
`and Targeting
`
`
`
`bao=Meadoga)
`Chair in Drug Delivery
`Aston Pharmacy School
`Aston University, Birmingham, UK
`
`Thomas Rades
`Chair in Pharmaceutical Sciences
`The New Zealand National School of Pharmacy
`University of Otago, Dunedin, New Zealand
`
`
`
`London P Chicago
`
`h i”
`
`uealee
`
`Pharmaceutical Press
`
`

`

`Published by the Pharmaceutical Press
`An imprint of RPS Publishing
`1 Lambeth High Street, London SE1 7JN, UK
`100 South Atkinson Road, Suite 200, Grayslake, IL 60030-7820, USA
`
`© Pharmaceutical Press 2010
`(RP) is a trade mark of RPS Publishing
`RPS Publishing is the publishing organisation of the Royal Pharmaceutical
`Society of Great Britain
`
`First published 2010
`
`Typeset by Thomson Digital, Naida, India
`Printed in Great Britain by TJ International, Padstow, UK
`
`ISBN 978 0 85369 762 6
`
`All rights reserved. No part of this publication may be reproduced, stored
`in a retrieval system, or transmitted in any form or by any means, without
`the prior written permission of the copyright holder.
`The publisher makes no representation, express or implied, with regard
`to the accuracy of the information contained in this book and cannot accept
`any legal responsibility or liability for any errors or omissions that may be
`made.
`The right of Yvonne Perrie and Thomas Rades to be identified as the
`authors of this work has been asserted by them in accordance with the
`Copyright, Designs and Patents Act, 1988.
`
`A catalogue record for this book is available from the British Library.
`
`£:j
`
`FSC
`Mi)ted Sources
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`
`

`

`Introduction to the FASTtrack series
`Preface
`About the authors
`
`vii
`viii
`
`X
`
`3
`
`4
`
`1. Controlling drug delivery ................ 1
`1
`Introduction
`Differentiating delivery systems according to
`their physical state
`Differentiating delivery systems according to
`their route of administration
`Differentiating drug delivery systems
`according to their mechanism
`of drug release
`Immediate release
`Modified release
`Drug absorption
`Mechanisms of drug absorption
`Summary
`Self-assessment
`Further reading
`
`7
`8
`10
`14
`16
`18
`20
`24
`
`2. Immediate-release drug delivery
`systems I: increasing the solubility and
`dissolution rate of drugs ............... 25
`25
`Introduction
`Improving drug delivery by increasing the
`solubility and dissolution rate of the drug
`How to determine the dissolution rate
`of a drug
`Super disintegrants
`Summary
`Self-assessment
`Reference
`Further reading
`
`49
`50
`50
`50
`56
`56
`
`26
`
`The biopharmaceutics classification
`system
`The maximum absorbable dose
`Drug absorption
`Barriers to drug absorption
`Strategies to overcome the barriers to
`drug absorption
`Summary
`Self-assessment
`Further reading
`
`59
`62
`63
`64
`
`66
`68
`68
`70
`
`4. Delayed-release drug delivery
`systems ............................... 71
`71
`Introduction
`72
`Small intestine-specific delivery
`77
`Colon-specific drug delivery
`80
`Summary
`81
`Self-assessment
`83
`Further reading
`
`5. Sustained-release delivery
`systems ............................... 85
`85
`Introduction
`Suitable drug candidates for
`sustained-release dosage forms
`Dissolution-based sustained-release
`dosage forms
`Gastroretentive drug delivery systems
`Diffusion-based sustained-release
`dosage forms
`Summary
`Self-assessment
`Further reading
`
`87
`
`89
`90
`
`97
`110
`110
`115
`
`3. Immediate-release drug delivery systems II:
`increasing the permeability and
`absorption of drugs .................... 59
`59
`Introduction
`
`6. Controlled-release dosage forms . .... 117
`117
`Introduction
`Polymer membrane permeation-
`controlled systems
`
`120
`
`V
`
`

`

`vi
`
`Contents
`
`Polymer matrix diffusion-controlled
`systems
`Activation-modulated controlled drug
`delivery systems
`Feedback-regulated controlled drug
`delivery systems
`Conclusions
`Self-assessment
`Reference
`Further reading
`
`123
`
`127
`
`134
`136
`136
`139
`139
`
`7. Site-directed drug targeting . ......... 141
`141
`General principles of drug targeting
`Requirements for effective drug
`targeting
`Physiological and biological barriers to
`drug targeting
`Types of drug targeting
`Cellular uptake and intracellular routing
`of the drug
`
`145
`150
`
`154
`
`142
`
`Summary
`Self-assessment
`Further reading
`
`156
`156
`160
`
`8. Carriers for drug targeting ........... 161
`161
`Options for drug targeting systems
`Modification of the drug to promote
`targeting- prodrugs
`Soluble macromolecular drug carriers to
`promote targeting
`Colloidal and particulate drug delivery
`systems
`Summary
`Self-assessment
`Further reading
`
`165
`
`176
`205
`205
`213
`
`162
`
`Answers to self-assessment
`Mind maps
`Index
`
`215
`217
`222
`
`

`

`F ASTtrack is a new series of revision guides created for undergraduate pharmacy
`students. The books are intended to be used in conjunction with textbooks and
`reference books as an aid to revision to help guide students through their exams. They
`provide essential information required in each particular subject area. The books will
`also be useful for pre-registration trainees preparing for the Royal Pharmaceutical
`Society of Great Britain's (RPSGB's) registration examination, and to practising
`pharmacists as a quick reference text.
`
`The content of each title focuses on what pharmacy students really need to know in
`order to pass exams. Features include*:
`concise bulleted information
`key points
`tips for the student
`multiple choice questions (MCQs) and worked examples
`case studies
`simple diagrams.
`
`The titles in the F ASTtrack series reflect the full spectrum of modules for the
`undergraduate pharmacy degree.
`
`Titles include:
`Complementary and Alternative Medicine
`Managing Symptoms in the Pharmacy
`Pharmaceutical Compounding and Dispensing
`Pharmaceutics: Dosage Form and Design
`Pharmaceutics: Drug Delivery and Targeting
`Pharmacology
`Physical Pharmacy (based on Florence & Attwood's Physicochemical Principles
`of Pharmacy)
`Therapeutics
`
`There is also an accompanying website which includes extra MCQs, further title
`information and sample content:
`www.fasttrackpharmacy.com.
`
`If you have any feedback regarding this series, please contact us at
`feedback@fasttrackpharmacy.com.
`
`*Note: not all features are in every title in the series.
`
`vii
`
`

`

`The best drugs can't exert their beneficial effects if they are not reaching their
`target site in the body at an appropriate concentration and for a sufficient
`length of time. It is clear that if a tablet is still in the package it is of no benefit for the
`patient. Less obvious is that this may also be the case after the tablet has been
`swallowed.
`In the stomach the tablet might not disintegrate and the drug might not be
`released from the dosage form. Or the drug simply has too low aqueous solubility
`in the gastrointestinal fluids. If the drug is not in solution it will (generally) not be
`able to overcome the epithelial membranes of the gastrointestinal tract and it
`cannot enter into the body and reach the target site of its activity. How can we
`improve the solubility of poorly water-soluble drugs?
`Some drugs chemically or enzymatically degrade in the stomach. Others
`lead to gastric irritation. How can these drugs still be administered via
`the oral route?
`In other cases the drug may dissolve very fast and is absorbed very quickly from
`the gastrointestinal tract. Whilst this seems a good thing (and indeed it often is),
`it can lead to high plasma concentration peaks of the drug followed by fast
`elimination of the drug, and consequently a short duration of action. So the
`patient has to take the drug very frequently and there will be strong fluctuations in
`the plasma concentration of the drug over time. Can we formulate a dosage form
`to improve this situation?
`Some drugs cannot be delivered by the oral route as they are metabolised in the
`liver, before reaching the systemic circulation. What can be done?
`Again other drugs may have a strong side-effect profile, which may prohibit
`efficient treatment. Can we improve this situation, and direct the drug to its target
`site, rather than having it distributed evenly throughout the body?
`This book tries to answer these and other questions in a concise and structured
`way. We will systematically review important concepts and facts relating to the
`delivery and targeting of drugs. The emphasis of this book has not been placed on the
`anatomical routes of delivery, but instead on the principles of drug release and
`targeting, namely: immediate release, delayed release, sustained release, controlled
`release and targeted release. Because of its overwhelming importance in drug
`delivery today, we have placed some focus on oral delivery (for immediate release,
`delayed release, sustained release), but other routes of delivery will also be covered
`where appropriate (for controlled and targeted release). Relevant examples of
`delivery systems will be given throughout the book with a focus on delivery systems
`that have actually reached clinical reality.
`
`viii
`
`

`

`Preface
`
`ix
`
`This book aims to highlight differences and principles in a concise way
`(including some mind maps at the end of the book), and so we have to apologise to the
`experts in the field if we have drawn boundaries for clarity where a grey zone
`is more appropriate. In the words of Picasso, however, we feel that students
`should know the boundaries before they can (and should) cross them.
`
`Yvonne Perrie
`Thomas Rades
`July 2009
`
`

`

`Professor YVONNE FERRIE is the Chair in Drug Delivery within Aston Pharmacy
`School, Aston University, Birmingham, UK. She has a BSc (first-class honours) in
`Pharmacy (1994) from Strathclyde University, Scotland and registered with the
`Royal Pharmaceutical Society of Great Britain in 1995.
`In 1998 Yvonne received her PhD from the University of London, UK where
`she investigated the use of liposomes for gene delivery under the supervision of
`Professor Gregory Gregoriadis. After working for a newly established drug delivery
`company, Lipoxen, Yvonne joined Aston University as a lecturer in 2000 and
`since 2007 holds the Chair in Drug Delivery.
`Yvonne is currently the Associate Dean for Learning and Teaching within the
`School of Life and Health Science and was previously awarded the Aston University
`Teaching Excellence Award.
`Yvonne's research is focused on the development of particulate carrier systems
`to facilitate the delivery of drugs and vaccines and aims to provide practical solutions
`to current healthcare problems. Yvonne is also Editor in Chief of the Journal of
`Liposome Research.
`
`Professor THOMAS RADEs is the Chair in Pharmaceutical Sciences at the National
`School of Pharmacy, University of Otago, New Zealand. He has a BSc in Pharmacy
`from the University of Hamburg, Germany and is a registered pharmacist.
`In 1994 Thomas received a PhD from the University of Braunschweig, Germany
`for his work on thermotropic and lyotropic liquid crystalline drugs. After working as a
`research scientist in Preclinical Development and Formulation at F. Hoffmann-La
`Roche in Basel, Switzerland, he became Senior Lecturer in Pharmaceutical
`Sciences at Otago in 1999 and since 2003 holds the Chair in Pharmaceutical Sciences.
`For his undergraduate and postgraduate teaching in pharmaceutics he was
`awarded the University of Otago Teaching Excellence Award and the New Zealand
`Tertiary Teaching Excellence Award for Sustained Excellence.
`Thomas has developed an international reputation for his research in drug delivery
`and physical characterisation of drugs. He has currently published more than 175
`papers in international peer review journals. His research interests include
`nanoparticles as delivery systems for drugs and vaccines, and the solid state of drugs
`and dosage forms.
`
`X
`
`

`

`

`

`

`

`

`

`4
`
`Pharmaceutics: Drug Delivery
`
`Tips
`
`Here are some examples of ho
`dosage forms in their simplest terms
`can be differentiated according to the
`and dispersion of their phases:
`rug solution is a one-phase
`stem as the dissolved drug does
`not fulfil
`equirements for a
`phase. In a solution the
`lecularly dispersed dru
`separa out to form larger
`he concentration
`g is not changed (e.g.
`evaporation of the solvent)
`environmental conditions
`(e.g. temperature) are constant.
`■ A suspension is
`phase
`system containi
`ntinu
`liquid phase an
`ispe
`phase.
`n emulsion is a
`se system
`containing two liquid phases, one
`dispersed and one continuous.
`1111 Ointmentsaregenerallytwo-phase
`or multiphase gels, with at least
`two continuous phases (usually a
`crystalline or liquid crystalline
`surfactant phase and a · 'd
`phase).
`■ Creams additionally conta a
`water phase which may be
`dispersed (water-in-oil ere
`continuous (oil-in-water cream).
`11 Tablets are essentially com pressed
`powers, and might thus be
`classified as containing a solid and
`gaseous continuous phase. Of
`ourse a tablet contains several
`olid phases, as drug particles are
`usually present together
`· o
`solid phases (e.g. filler, bin er
`disintegrant, glidant and lubricant
`particles).
`
`used to form the liposomes will determine if a
`liposomal dispersion is a suspension (if the
`lipids are in a crystalline state) or an emulsion
`(if the lipids are in a fluid, liquid crystalline
`state).
`It is important to note that the presence of a
`dispersed phase will lead to physical instability
`in the system. For example, in an oil-in-water
`emulsion, the dispersed oil droplets have a larger
`interfacial area to the water than if the droplets
`had coalesced into one large continuous phase.
`This increased interfacial area leads to an
`increased interfacial free energy, according to the
`relationship:
`
`where Gi is the interfacial free energy of the
`system, A is the interfacial area between the
`dispersed phase (here the oil droplets) and the
`continuous phase (here the water phase) and y is
`the interfacial tension between the two phases.
`The interfacial free energy of the system (here the
`emulsion) can be minimised by coalescence of
`the droplets into larger droplets and finally into
`one continuous oil phase, as this maximally
`reduces the total interfacial area. This is of course
`undesirable from a formulation viewpoint.
`Coalescence of droplets in an emulsion is a
`pharmaceutical instability, but from a
`thermodynamic viewpoint the system has been
`stabilised, as the interfacial free energy has been
`reduced. In practical terms an emulsion is
`pharmaceutically stabilised by adding
`emulsifiers to the systems, that either lower the
`interfacial tension (note: if y gets smaller, Gi will
`get smaller), or that act as a physical barrier
`against coalescence. In either case, increasing the
`interfacial area will still increase the surface free
`energy.
`
`Differentiating delivery systems according
`to their route of administration
`
`Another way of differentiating dosage forms is according to their site or
`route of administration. Drugs can be administered directly into the
`
`

`

`

`

`6
`
`Pharmaceutics:
`
`specialised sites for absorption. There are
`many mucosal membranes that can be used for
`drug administration. Of the highest importance
`are the mucosal membranes of the
`gastrointestinal tract, allowing oral drug
`delivery. The suitability and convenience of
`this route of delivery make oral dosage forms
`the most common of all drug delivery systems.
`Also the buccal, sublingual, rectal and vaginal
`mucosa and indeed the lung and nasal mucosal
`membranes can act as absorption sites. For
`all of these mucosal membranes dosage
`forms have been developed, such as buccal
`and sublingual tablets, suppositories, vaginal rings, inhalers and nasal
`sprays, to name a few.
`If drug delivery systems are designed to give a local drug effect and
`not systemic activity, they can be described as topical delivery
`systems. This is the case for many dermal dosage forms.
`
`Oral drug delivery
`As stated above, the oral route is the most popular route to administer
`drugs. However, some factors should be considered when looking to
`administer drugs via this route. In particular the transit time in the
`gastrointestinal tract may vary considerably:
`between patients and within the same patient, with the gastric
`residence time being the most variable
`with the state of the dosage form (liquid dosage forms are emptied
`out of the stomach faster than solid dosage forms)
`with the fasted or fed state of the patient.
`The pH conditions in the gastrointestinal tract also vary considerably,
`from a low pH in the stomach (1.5-2 in the fasted state to around 5 in
`the fed state) to a higher pH in the small and large intestine. The pH in
`the small intestine varies from 4 to 7, with an average value of
`approximately 6.5. This may affect stability and will influence the degree
`of ionisation of ionisable drugs which in turn will influence their
`absorption (unionised forms of drugs are usually taken up better than
`ionised forms of the same drug) and solubility (unionised forms are
`usually less soluble than ionised forms of the same drug).
`
`First-pass metabolism
`Importantly, drugs that are taken up into the body through the
`gastrointestinal mucosa will be transported to the liver via the portal
`vein before going into general circulation. As the liver is the main
`metabolic organ of the body, if the drug is susceptible to metabolic
`degradation in the liver, this may considerably reduce the activity of
`
`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`and hence possible drug absorption routes, are lined with epithelial
`tissue. For example, drugs administered orally must cross the epithelium
`of the gastrointestinal tract before they can enter the systemic circulation.
`
`Barriers to drug absorption
`Epithelia are tissues composed of one or more
`layers of cells. These layers are supported by a
`basement membrane which lies on top of the
`supporting connective tissue. The function of
`epithelial cells includes absorption, secretion
`and protection and is dependent on their location
`within the body. The epithelia are classified by
`their:
`Shape
`1.
`a. Squamous - these cells have a flat
`(squashed) shape.
`b. Columnar - these are narrow, tall cells.
`c. Cuboidal -these cells have a cubic shape,
`intermediate between squamous and
`columnar.
`
`Stratification (number of cell layers}
`2.
`a. Simple - single layer of cells, termed epithelium.
`b. Stratified - multiple layers.
`
`Specialisation - some epithelia will have a specialised function
`3.
`a. Keratinised cells contain keratin protein to improve the strength of
`the barrier.
`b. Ciliated cells have apical membrane extensions that can increase
`the overall absorption area and rhythmically beat to move mucus.
`
`Mucus
`Many of the epithelial linings considered as absorption sites have a
`mucus layer coating. Mucus is synthesised and secreted by goblet cells
`which are a specialised type of columnar epithelial cells. Mucus is viscous in
`nature and is composed of highly glycosylated peptides known as mucins
`and inorganic salts in water. The main role of mucus is to protect and lubricate
`the epithelial lining. In the respiratory tract it supports mucociliary clearance,
`by trapping substances and removing them through the mucociliary
`escalator. In the gastrointestinal tract, mucus both protects the stomach from
`the acidic conditions therein and helps lubricate the passage of food.
`However, in terms of drug delivery, mucus serves as a physical barrier
`to absorption. A substance must first diffuse across the mucus barrier
`before it can reach the epithelia and be absorbed. Therefore the viscosity
`and thickness of the mucus layer and any interactions the drug and/or
`delivery system may have with the mucus must be considered.
`
`

`

`

`

`Controlling drug delivery
`
`17
`
`Fick's first law of diffusion states that
`the amount of a solute, for example a
`drug in solution, passing across a unit
`area, for exam
`the lipid bilayerof
`th
`· I b
`r (flux, J, units:
`, is proportional to the
`concentration difference across this
`unit area (dC/dx, units: kgm-4
`). T
`proportional constant is O (units:
`m2 s-1 ) and the
`rtitio
`1cient
`d
`is K.
`
`st
`occurs along the concentration
`gradient, i.e. from higher
`concentration of the solute to lower
`concentration. This equation applies
`to steady-state conditions. Diffusion is
`discussed in more depth in Chapter 5.
`
`ps
`Examples of carri r- ediated
`drug transport
`111 Facilitated diffusion: riboflavin
`and vitamin 86 are ab
`a facilitat
`ional
`transport.
`■ Active absorption: levodopa 1s
`bsorbed by active absorption via
`.. , "" ,..., ...... ,· ... transporters.
`
`from high to low concentration. The rate of
`diffusion is governed by Fick's law. Low(cid:173)
`molecular-weight drugs are absorbed by passive
`diffusion and factors controlling the rate of
`diffusion include:
`■ drug concentration
`■ partition coefficient of the drug
`■ area of absorptive tissue.
`In particular the lipophilicity of the drug is
`important since the drug must diffuse across the
`cell membrane and an optimum partition
`coefficient is usually observed for passive
`diffusion processes.
`Carrier-mediated transport
`This form of transport involves specific carrier
`proteins present in the cell membranes. Carrier(cid:173)
`mediated transport can either act with a
`concentration gradient (facilitated diffusion) or
`against a concentration gradient (active
`absorption). For active absorption, as the
`transport is working against a concentration
`gradient, energy is required.
`Any molecules, including drug molecules,
`which are similar to the natural substrate of
`the carrier protein are transported across the
`cell membrane. As this process involves a
`carrier protein, the mechanism is saturable
`at high concentrations and uptake via this
`route can be inhibited by competing
`substrates.
`
`Endocytosis
`This process involves internalisation of
`substances by engulfment by the cell membrane
`which forms membrane-based vesicles within
`the cell, known as endosomes. This allows larger molecules
`or particulates to enter the cell. There are several types of
`endocytosis:
`■ Receptor-mediated endocytosis: substances interact with specific
`surface receptors. As this involves receptors, the process is
`saturable. Drugs bind to receptors on the surface of the cell. This
`promotes invagination and vesicle formation in the cell. Within
`these vesicles, known as endosomes, the contents are subjected
`to low-pH conditions and digestive enzymes which can result in
`drug degradation/inactivation.
`
`

`

`

`

`Controlling drug delivery
`
`19
`
`g is in the gastrointestinal tract
`II outside the body.
`
`lfa
`it i
`
`allow the effective, safe, and reliable application of the drug to
`the patient.
`For the development of dosage forms the formulation scientist
`needs to optimise the bioavailability of the drug. This means
`the delivery systems should allow and facilitate the drug to reach its
`target site in the body. For example, a tablet formulation containing an
`antihypertensive drug must disintegrate in the gastrointestinal tract,
`the drug needs to dissolve and the dissolved drug needs to permeate
`across the mucosa! membrane of the gastrointestinal tract into the
`body.
`Whilst some drugs are meant to act locally,
`e.g. in the oral cavity, in the gastrointestinal
`tract, in the eye or on the skin, nevertheless
`the prime role of the drug delivery system is
`to allow the drug to reach its target site.
`Another role of the delivery systems is to
`allow the safe application of the drug. This
`includes that the drug in the formulation must
`be chemically, physically and microbiologically
`stable. Side-effects of the drug and drug
`interactions should be avoided or minimised
`by the use of suitable drug delivery
`systems. The delivery systems also need to
`improve the patient's compliance with the
`pharmacotherapy by the development of
`convenient applications. For example, one can
`improve patient compliance by developing an
`oral dosage form where previously
`only parenteral application was
`possible.
`Finally, the delivery system needs
`to be reliable and its formulation needs to
`be technically feasible. This means the
`pharmaceutical quality of the delivery systems
`needs to be assured, drug release from the system needs
`to be reproducible and the influence of the body on drug release
`should be minimised (for example, food effects after oral
`administration). However, for any application of a drug delivery
`system on the market, the dosage form needs to be produced
`in large quantities and at low costs to make affordable medicines
`available. Therefore, it is also necessary to investigate the
`feasibility of the developed systems to be scaled up from
`the laboratory to the production scale. Figure 1. 7 summarises the
`key attributes to be optimised to develop a drug into a
`medicine.
`
`Some confusion may arise from the
`use of the expression targeted drug
`delivery systems. In this book we
`define targeted delivery system as
`systems that allow selec
`of the drug to a specific
`he body to
`or specific cells insi
`tion. If the
`achieve a targeted
`rele
`of the drug rom t e dosage
`rgeted to a specific organ,
`terns may be better called
`'very systems (although
`t ors define only dermal
`some
`application of dosage forms as being
`topical).
`
`

`

`

`

`Questions
`1. Indicate which one of the following statements is not correct:
`a. The drug delivery system can play a vital role in controlling the
`pharmacological effect of the drug.
`b. The drug delivery system can influence the pharmacokinetic profile
`of the drug, the rate of drug release, the site and duration of drug action
`and subsequently the side-effect profile.
`c. An optimal drug delivery system ensures that the active drug
`is available at the site of action for the correct time and
`duration.
`d. The drug concentration at the appropriate site should be below the
`minimal effective concentration (MEC).
`e. The concentration interval between the MEC and the minimal toxic
`concentration (MTC) is known as the therapeutic range.
`
`2. Indicate which one of the following statements is not correct:
`a. A simple emulsion contains two liquid phases (oil and water).
`b.
`In a water-in-oil emulsion, the oil phase is dispersed and the water
`phase is continuous.
`c. A simple suspension contains a liquid and a solid phase.
`d.
`In a suspension the solid phase is dispersed and the liquid phase is
`continuous.
`In most multiphase dosage forms one or more phases are dispersed,
`whilst other phases are continuous.
`
`e.
`
`3. Indicate which one of the following statements is not correct:
`a. Dispersing one phase into the other will lead to a larger interfacial area
`between the two phases.
`b. A larger interfacial area between the two phases leads to an
`increased interfacial free energy, according to the relationship:
`Gi Ay.
`In the equation Gi Ay, Gi is the interfacial free energy of the system.
`In the equation Gi Ay, A is the interfacial area between the dispersed
`phase and the continuous phase.
`In the equation Gi Ay, y is the surface tension of the continuous
`phase.
`
`c.
`d.
`
`e.
`
`4. Indicate which one of the following statements is not correct:
`a. The most important route of drug administration into the body is
`through mucosa! membranes.
`b. Mucosa! membranes are a stronger barrier to drug uptake than the
`skin.
`c. The mucosa! membranes of the small intestine are specialised sites
`for absorption.
`d. There are many mucosa! membranes that can be used for drug
`administration.
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`22
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`Pharmaceutics:
`
`e. Absorption of drugs through the mucosa! membranes of the
`gastrointestinal tract allows for oral drug delivery.
`
`b.
`
`5. Indicate which one of the following statements is not correct:
`a. Drugs that are taken up into the body through the gastrointestinal
`mucosa will be transported to the liver via the portal vein before going
`into general circulation.
`If the drug is susceptible to metabolic degradation in the liver, this
`may considerably enhance the activity of the drug. This phenomenon
`is known as the hepatic first-pass effect.
`c. The rectal route may also show varying degrees of the first-pass effect.
`d.
`In other routes of administration (intravenous, vaginal, nasal, buccal
`and sublingual) the drug is distributed in the body before reaching the
`liver.
`e. Whilst the liver is the main metabolic organ of the body, metabolism
`may also take place in the gastrointestinal lumen and indeed in the
`mucosal membranes.
`
`6. Indicate which one of the following statements is not correct:
`a. Many dosage forms are designed to release the drug immediately after
`administration. This is useful if a fast onset of action is required for
`therapeutic reasons.
`b. The onset of action is very fast for intravenous injections and
`infusions and a pharmacological effect may be seen in a matter of
`seconds after administration.
`c. The onset of action is fast for oral delivery of immediate-release
`dosage forms, such as simple tablets, and a pharmacological effect
`may be seen in a matter of minutes to hours.
`d. If the drug has a long biological half-life, the time interval between
`administrations may be short, requiring frequent dosing and
`potentially leading to low patient compliance and suboptimal
`therapeutic outcome.
`e. Uptake of a drug through the mucosa! membranes may be due to
`passive diffusion or by receptor-mediated active transport
`mechanisms.
`
`7. Indicate which one of the following statements is not correct:
`a. Delayed-release dosage forms can be defined as systems formulated to
`release the active ingredient at a time other than immediately after
`administration.
`b. Colon-specific dosage forms are developed for the treatment of local
`and systemic diseases in the colon, including colorectal cancer and
`Crohn's disease.
`In the plasma concentration versus time profile of a delayed-release
`oral dosage form Cm.ax (but not T max) is strongly dependent on the
`gastric emptying times.
`
`c.
`
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`

`d. Delayed-release systems can be used to protect the drug from
`degradation in the low-pH environment of the stomach.
`e. Delayed-release systems can be used to protect the stomach from
`irritation by the drug.
`
`c.
`
`8. Indicate which one of the following statements is not correct:
`a. The release kinetics of the drugs from sustained-release matrix
`systems often follows a first-order kinetics.
`b. The release kinetics of the drugs from sustained-release reservoir
`systems often follows a zero-order kinetics.
`If the release of the drug from the dosage form is sustained such that
`the release takes place throughout the entire gastrointestinal tract,
`one can reduce Cm.ax and prolong the time interval of drug
`concentration in the therapeutic range.
`d. The use of sustained-release dosage forms may reduce the frequency
`of dosing, for example from three times a day to once a day.
`e. Sustained-release dosage forms can achieve their release
`characteristics by the use of suitable polymers.
`
`9. Indicate which one of the following statements is not correct:
`a.
`In contrast to sustained-release forms, controlled-release systems
`are designed to lead to predictable and constant plasma
`concentrations, independently of the biological environment of the
`application site.
`b. Controlled-release systems are controlling the drug concentration in
`the body, not just the release of the drug from the dosage form.
`c. Controlled-release systems are used in a variety of
`administration routes, including transdermal, oral and vaginal
`administration.
`In contrast to sustained-release forms, in controlled-release systems
`the dose is of less importance than the release rate from the
`therapeutic system.
`e. Controlled-release systems are target-specific, which means they
`'exclusively' deliver the drug to the target organ inside the body.
`
`d.
`
`10. Indicate which one of the following statements is not correct:
`a.
`In drug absorption, passive diffusion involves the diffusion of drugs
`across the cell membrane and is driven by a concentration gradient,
`with drugs moving from high to low concentration.
`b. Carrier-mediated transport involves specific carrier proteins present
`in the cell membranes and can act either with a concentration
`gradient (facilitated diffusion) or against a concentration gradient
`(active absorption).
`c. Endocytosis involves internalisation of substances by engulfment by
`the cell