Ethanol+ @
`Drug 72 @ BS
`—~80 ROP ETHOSOME
`_
`=i
`e295
`
`Enhancement
`in Drug Delivery
`»)
`
`eee
`
`naam Oy]
`Elka Touitou
`
`:
`= Droae
`Cea peten
`
`0001
`
`Noven Pharmaceuticals, Inc.
`EX2011
`Mylan Tech., Inc. v. Noven Pharma., Inc.
`IPR2018-01119
`
`

`

` CRC Press
`
`Enhancementin drug delivery | edited by Elka Touitou, Brian W. Barry.
`p.; cm.
`Includes bibliographical references and index.
`1, Drugdeliverysystems. 2, Drugs--Dosageforms.3. Drugs--Physiologicaltransport.4. Absorption
`ISBN 0-8493-3203-6
`(Physiology) 1. Touitou, Elka, 1942- ILBarry, Brian Wi, 1939-
`(DNLM:1, Drug Administration Routes.2. Adjuvants, Pharmaceutic. 3. DrugDeliverySystems.WB
`340 E58 2006]
`615'.1--de22
`2006045582
`
`RS199.5.E54 2006
`
`Taylor & Francis Group
`6000 Broken Sound Parkway NW, Suite 300
`Boca Raton, FL 33487-2742
`2007 by Taylor & Francis Group, LLC
`CRC Pressis an imprint of Taylor & Francis Group, an Informa business
`Noclaim to original U.S. Government works
`Printed in the United States of America on acid-free paper
`30987654321
`International Standard Book Number-10: 0-8493-3203-6 (Hardcover)
`International Standard Book Number-13: 978-0-§493-3203-6 (Hardcover)
`This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted
`withpermission, and sourcesare indicated. Awidevarietyofreferencesarelisted. Reasonableeffortshave beenmadeto
`publishreliabledataand information,buttheauthorandthepublishercannotassume responsibilityforthevalidityof
`all materials or for the consequences of their use.
`No partofthisbook maybereprinted, reproduced,transmitted,orutilizedin anyformbyanyelectronic,mechanical, or
`othermeans,nowknownorhereafterinvented,includingphotocopying,microfilming, andrecording,orinanyinforma-
`tion storage orretrieval system, without written permission from the publishers.
`For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://
`www.copyright.com/) orcontactthe CopyrightClearanceCenter, Inc. (CCC) 222RosewoodDrive, Danvers, MA01923,
`978-750-8400.CCCisanot-for-profitorganizationthat provideslicensesand registration foravarietyofusers. Fororga-
`nizationsthat havebeen granteda photocopy licensebytheCCC,a separate system ofpaymenthasbeenarranged.
`‘Trademark Notice: Productor corporate names may be trademarks or registered trademarks, and are used onlyfor
`identification and explanation withoutintent to infringe. Library ofCongress Cataloging-in-Publication Data
`
`Visit the Taylor & Francis Website at
`http://www.taylorandfrancis.com
`and the CRC Press Website at
`http://www.crcpress.com
`
`

`

`
`
`1 2 Chemical Permeation
`Enhancement
`
`Adrian C. Williams and Brian W. Barry
`
`CONTENTS
`
`AREORIGIN.occnexsnessmnssninnearnrnaunininnnnnnRuane 233
`FEGL,
`12.2 Background ..........cscesesesssesssesessesessseatsncsesssassasavsasseesesssussussesserearetseveececeeseceeceseeeseees 234
`12.3. Major Classes of Chemical Penetration Enhancers......cc0cccceeeeecceceeeeeceeeeceeceececc...... 234
`12.3.1 Water. ..ecscsessesessesscsssessssesnssssessevensssssesassucisssessansavatesserescensevsscececeesescececescee. 235
`12.3.2
` Sulfoxides and Similar Chemicals..........c..ccccssessesseseccesesessesecscesecceccescesceee. 237
`12.3.3
`AZOME ooeeseecescscssesescssesesesssnsecacecavsrcassusssssssassssssasebasessecesesecesseceeeceeeecececccc. 238
`Y2.3.4—Pyrrolidomes...... eee ceceecsessesscssesesessacscersnsasecseserssstsssssssrsavssuserececcececececees 239
`12.3.5
`Fatty Acids... ccessssseseecsescscssscsssossessrssersatssssvarsustussitasasisasessescececececec. 240
`12.3.6
`Alcohols, Fatty Alcohols, and Glycols...c..cccccsscssssesessessesssssececesesecoseseeseeee. 242
`12.3.7 Surfactants... ccssecesscessceeece
`243
`
`ULC cece cseseseesscesessstseescscsssescsesevasavarstassarassssesesesapavansesesecesceseeececseesesces 244
`L238
`12.3.9
`Essential Oils, Terpenes, and Terpenoids..........2.c.ccsscesessesssseseseeseeeeeseecosees 244
`12,3.10 Phospholipids ..0.....c.ccccssesesssssseesessssessececararsersuesesssavasssesseseeervaveeesescecescecees 246
`12.3.1] Ceramide Analogs ........csesccccscssscssssssecececeesescessesseeversacsveversesseecersecececeeeees..247
`12.3.12 Solvents at High Concentrations .o......0...ceccccsesesscesesscesesseveuesesceeseececsee cesses 247
`12.3.13 Metabolic Interventions............c.ccccccssssssesesessesesesssssssevssesesvereecesseesesseecesees 247
`12.3.14 Enhancer Combinations..........cccccsssssesesssecsssessssssssssssseseecescecececeseeeecececcecee. 247
`[2.4 General Comments on Penetration Enhancer.........sscccsssccssesssseseseevecceceeeececececeeeeae. 248
`References... ccccecsesseevesesesseseesessssssesussvasssssucausesaaucareasarsasassicarsuvaveneisateeseeseseececescececcece 251
`
`12.1.
`
`INTRODUCTION
`
`Amongthe myriad strategies employed to increase both the amountofa therapeutic agent
`traversing the skin and the rangeof drugs that can beeffectively delivered throughthis route,
`lies in the application of chemical penetration enhancers. These agents interact with stratum
`corneum constituents to promote drug flux. Such materials have been used empirically in
`topical and transdermal preparationsforas long as pastes, poultices, creams, and ointments
`have been applied to skin, though it is only over the last four decades that enhancers have
`been employed deliberately for this specific purpose. To date, nearly 400 chemicals have been
`evaluated as penetration enhancers (accelerants, absorption promoters), yet their inclusion
`into topical or transdermal formulations is limited because the underlying mechanisms of
`action of these agents are seldom clearly defined and regulatory approval is costly and
`difficult. Here, we review some applications of the more widely investigated chemical pene-
`tration enhancers and consider some of the complex mechanisms by which they may exert
`their activities.
`
`233
`
`
`
`=Pe
`
`

`

`248
`
`Enhancementin Drug Delivery
`
`increased the skin permeability to macromolecules, such as
`mixtures of enhancers that
`heparin, luteinizing hormone-releasing hormone, and an oligonucleotides, by up to 100-
`fold. The two most successful SCOPE formulations were a mixture of sodium laureth sulfate
`with phenyl piperazine (Figure 12.7a) and a combination of N-lauroyl sarcosine with sorbitan
`monolaurate (Figure 12.7b).
`Future work mayelucidate why the areas of potency hot spots wereso restricted, and the
`fundamental molecular mechanisms producing the enhancement. The molecular structures of
`the most successful SCOPE mixtures, as illustrated in Figure 12.7, suggest that surface-active
`phenomena mayplay a crucialrole.
`Instead of using a screening approach, with its heavy workload,investigators have tried
`other techniques. Manystudies demonstrated that a rule-based approach to enhancement was
`fraught with difficulties; enhancer combinations in different vehicles for specific permeants
`traversing a particular membranethus tend to be evaluated on a case-by-case basis [72,73].
`However, attempts have been made at a more rational approach to enhancerselection,
`applying quantitative (and qualitative) structure-activity relationships to penetration en-
`hancers [74-77]. Naturally, such models depend upon the quality of data used to obtain the
`relationship. Hence inclusion of information derived from, for example, different animal
`models or dosing regimens must be carefully assessed as the generated relationship may
`only be applicable to the specific conditions used in obtaining the input data.
`
`12.4 GENERAL COMMENTS ON PENETRATION ENHANCERS
`The list of materials that have been used as penetration enhancers as discussed aboveis not
`exhaustive butis intendedtoillustrate the range ofagents that have been employedforfacilitating
`transdermal drug delivery. Several common themes emerge from these considerations:
`1. Itis difficult to select rationally a penetration enhancer for a given permeant. Accelerant
`potencies appear to be drug specific, or at best may be predictive for a series of
`permeants with similar physicochemical properties (such as similar partition coeffi-
`cients, molecular weights, and solubilities). Some broad trends are apparent, such as
`the use of hydrocarbon monoterpenes for lipophilic permeants, but
`the level of
`enhancement expected for these agentsis unpredictable.
`2. Penetration enhancements through animal skins, and rodenttissues in particular, are
`generally considerably greater than those obtained with humanskin, correlating with
`the increased barrier resistance of human stratum corneum. Hairless mouse skin is
`particularly fragile and its use may grossly mislead the investigator. Most experiments
`are performed in vitro, although there are exceptions, for example, the use of confocal
`Ramanspectroscopy to monitor the penetration of DMSOthrough volunteer skin [78].
`3. Accelerants tend to work well with cosolvents such as PG orethanol. Synergistic effects
`arise enhancers such as azone,oleic acid (and other fatty acids), and terpenes dissolved
`in, for example, PG.
`4, Many enhancers have a complex concentration-dependenteffect. This is shown clearly
`by azone, whichis effective in promoting the transdermal flux of many drugs when
`used at 1% in PG but whichis far less potent when applied at higher concentrations or
`neat.
`5. Potential mechanisms of action of enhancers are varied, and can range from direct
`effects on the skin to modification of the formulation. Thus, directly acting on the
`skin, enhancers can do the following (see Figure 12.1):
`(i) Modify the intercellular lipid domainsto reduce the barrier resistance ofthe bilayer
`lipids. Disruption to thelipid bilayers could be homogeneous where the enhancer
`
`
`
`

`

`Chemical Permeation Enhancement
`
`249
`
`(a)
`
`d
`
`?
`
`Phenyl piperazine
`
`HO
`
`(b)
`eee
`
`
`
`Sorbitan monolaurate
`
`OH
`
`A-Lauroyl sarcosine
`
`Seeeeun
`
`
`
`FIGURE 12.7 The two most potent SCOPE formulations. (a) A mixture of sodium Jaureth sulfate with
`phenyl piperazine and (b) a combination of sodium monolaurate with N-lauroy! sarcosine. (From
`Karande,P., Jain, A. and Mitragotri, S, Nat Biotechnol 22:192, 2004.)
`
`elivery
`
`ich as
`» 100-
`sulfate
`rbitan
`
`id the
`ires of
`active
`
`: tried
`it was
`leants
`
`12,73].
`ction,
`m en
`in the
`nimal
`» may
`
`is not
`tating
`
`lerant
`ies of
`:oeffi-
`ch as
`‘rel of
`
`r, are
`- with
`<in is
`nents
`focal
`1 [78].
`ffects
`olved
`
`learly
`when
`ms Or
`
`direct
`n the
`
`(layer
`ancer
`
`
`leaee
`
`
`

`

`250
`
`Enhancementin Drug Delivery
`
`distributes evenly within the complex bilayer lipids, but sometimes the accelerant
`will be heterogeneously concentrated within domains ofthe bilayer lipids. Such a
`pooling phenomenon has been shown for oleic acid, terpenes, and Azone, andis
`likely to occur for several similar enhancers considering the range of packing and
`different molecular domains in the stratum corneum lipids. The crystalline/
`gel/liquid crystal domain may fluidize, alter its polarity, separate phase, or have
`lipids extracted.
`(ii) Alter the solvent nature of the stratum corneum so as to modify partitioning of the
`drug, coenhancer, or a cosolvent into the tissue. Many enhancers are good solvents
`and so, for example, the pyrrolidones can increase the amount of permeantwithin
`the skin.
`(iii) Act on the stratum corneum intracellular keratin, denature it, or modify its con-
`formation causing swelling, increased hydration, and vacuolization.
`(iv) Affect
`the desmosomes that maintain cohesion between corneocytes and: other
`protein structures, leading finally to splitting of the stratum corneum.
`The above mechanismsofaction have been embraced within a general schemeto explain
`enhancer effects on stratum corneum,
`termed the lipid- protein-partitioning concept;
`enhancers can act by altering skin lipids and proteins or by affecting partitioning
`behavior [79]. Recent general reviews on skin penetration enhancers have been written
`(see Refs. [80-83]). A very recent, interesting and novel approach assumes that chemical
`accclerants perturb the stratum corneum barrier by lipid extraction or fluidization ofthe
`lipid bilayers, as assessed through Fourier transform infrared spectroscopy [84]. By
`analyzing the underlying molecular forces responsible for irritancy and potency,
`the
`authors isolated inherent constraints that limit performance. Using this knowledge,
`they designed more than 300 potential enhancers, which were screenedin silico fortesting
`in vitro. This publication and a prior paper from the same group [71] represent two ofthe
`most important texts published in recent years in the area of transdermal drugdelivery.
`In addition, penetration enhancementcan be indirect by:
`(i) Modification of thermodynamic activity of the vehicle. Rapid permeation of a good
`solvent such as ethanol from the donor solution, or its evaporation, can leave the
`permeant in a more thermodynamically active state than when all the solvent was
`originally present—even to the point of supersaturation.
`It has been suggested that solvent permeating throughthe membrane could drag the
`permeant withit, though this conceptis somewhat controversial and remains to be
`(iii) Solubilizing the permeant in the donor (e.g., with surfactants), especially where
`solubility is very low as with steroids in aqueous donor solutions, can reduce
`depletion effects and prolong drug permeation.
`6. Many of the chemicals described above are used for alternative reasons within topical
`and transdermal preparations. For example, a dermatological preparation could contain
`PG as a vehicle, a surfactant to solubilize the drug orto stabilize a dispersion, and a
`terpene as a fragrance material. The efficacies of some topical preparations, particularly
`those long established, are probably due to penctration enhancement by these types of
`agents, although the commercial preparations are not claimed to incorporate an agent
`specificallyfor its enhancingability.
`
`proven.
`
`(ii)
`
`
`
`