Enhancement
`
`171111111 by
`Elka T0111t0u
`
`Brian W.Ba11y
`
`--.1.'-.1--l11.1|-
`
`.
`
`'
`
`CRC Press
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`Noven Pharmaceuticals, Inc.
`EX2011
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`Mylan Tech, Inc. v. Noven Pharma. Inc.
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`Library ofCongress Cataloging—in—Publicetion Data
`
`Enhancement in drug delivery i edited by Elka Touitou. Brian W. Barry.
`p. ; crn.
`includes bibliographical references and index.
`lSBN (1—3493-3203—6
`1. Drug delivery systems. 2. Drugs—Dosage forms. 3. Drugs-Physiological transport. 4. Absorption
`(Physiology) L Touitou. Elks. 1942‘ IL Barry. Brian W.. 1939-
`{DNLM: 1. Drug Administration Routes. 2. Adjuvants, Pharmaceutic. 3. Drug Delivery Systems. WB
`346 E58 20061
`
`R5199.5.E54 2006
`615'.l-—dc22
`
`2.005045582
`
`Taylor 8: Francis Group
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`200? by Taylor & Francis Group. LLC
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`httptflwwwmrcpressmom
`
`

`

`M 1
`
`Chemical Permeation
`Enhancement
`
`Adrian C. Williams and Brian W. Barry
`
`CONTENTS
`
`Introduction ............................................................................................................. 233
`12.1
`122 Background .............................................................................................................. 234
`12.3 Major Classes of Chemical Penetration Enhancers.................................................. 234
`12.3.1 Water ......................................................................................................... 235
`12.3.2
`Sulfoxides and Similar Chemicals.............................................................. 237
`12.3.3
`Azone ........................................................................................................ 238
`12.3.4
`Pyrrolidones ............................................................................................... 239
`12.3.5
`Fatty Acids ................................................................................................ 240
`12.3.6
`Alcohols, Fatty Alcohols, and Glycols ...................................................... 242
`
`Surfactants .......................................
`12.3.7
`243
`Urea ........................................................................................................... 244
`12.3.8
`12.3.9
`Essential Oils, Terpenes, and Terpenoids .................................................. 244
`12.3.10 Phospholipids ............................................................................................ 246
`12.3.11 Ceramide Analogs247
`12.3.12 Solvents at High Concentrations ............................................................... 24?
`12.3.13 Metabolic Interventions ............................................................................. 247
`12.3.14 Enhancer Combinations ............................................................................ 24’?
`[2.4 General Comments on Penetration Enhancers ........................................................ 248
`References .......................................................................................................................... 251
`
`12.1
`
`INTRODUCTION
`
`Among the myriad strategies employed to increase both the amount 01' a therapeutic agent
`traversing the skin and the range of drugs that can be effectively delivered through this 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 preparations for as long as pastes, poultices, creams, and ointmcnts
`have been applied to skin, though it is only over the last four decades that enhancers have
`been employed deliberately ior 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
`
`
`
`

`

`243
`
`Enhancement in Drug Delivery
`
`increased the skin permeability to macromolecules, such as
`mixtures of enhancers that
`heparin, luteinizing hormone—releasing hormone, and an oligonuclcotides, 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).
`Futttre work may elucidate why the areas of potency hot spots were so 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 may play a crucial role.
`Instead of using a screening approach, with its heavy workload, investigators have tried
`other techniques. Many studies demonstrated that a rule-based approach to enhancement was
`fraught with difficulties; enhancer combinations in different vehicles for specific permeants
`traversing a particular membrane thus tend to be evaluated on a caseby—case basis [72,73].
`However, attempts have been made at a more rational approach to enhancer selection.
`applying quantitative (and qualitative) structure—activity relationships to penetration cn-
`hancers [i447]. 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
`'1"he list of materials that have been used as penetration enhancers as discussed above is not
`exhaustive but is intended to illustrate the range ofagents that have been employed for facilitating
`transdermal drug delivery. Several common themes emerge from these considerations:
`
`1. It is difficult to select rationally a penetration enhancer for a given permeant. Accelerant
`potencies appear to be drug specific, or at host. may be predictive for a series of
`per-meants 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 agents is unpredictable.
`2. Penetration enhancements through animal skins, and rodent tissues in particular, are
`generally considerably greater than those obtained with human skin, 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
`Raman spectroscopy to monitor the penetration of DMSO through volunteer skin [78].
`3. Accelerants tend to work well with cosolvents such as PG or ethanol. 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—dependent effect. This is shown clearly
`by azone, which is effective in promoting the transderma] flux of many drugs when
`used at 1% in PG but which is 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 intcreellular lipid domains to reduce the barrier resistance of the bilayer
`lipids. Disruption to the lipid bilayers could be homogeneous where the enhancer
`
`
`
`

`

`elivery
`
`_
`
`Chemical Permeation Enhancement
`
`249
`
`(a)
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`FIGURE 12.7 The two most potent SCOPE formulations. {a} A mixture of sodium laureth sulfate with
`phcnyl pipcrazine and (b) a combination of sodium monolaurale with N—Iauroyl saroosine. (From
`Karande, P., Jain, A. and Mitragotri, S. Na: Bforedmoi’ 22:192, 2004.)
`
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`Main-ERM-
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`

`

`250
`
`Enhancement in Drug Delivery
`
`distributes evenly within the complex bilayer lipids, but sometimes the aceelerant
`will be heterogeneously concentrated within domains of the bilayer lipids. Such a
`pooling phenomenon has been shown for oleic acid, terpenes, and Azone, and is
`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 permeant within
`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 mechanisms of action have been embraced within a general scheme to 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. [SO—433]]. A very recent, interesting and novel approach assumes that chemical
`accelerants perturb the stratum corneum barrier by lipid extraction or fluidization of the
`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 screened in silico for testing
`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 drug delivery.
`In addition, penetration enhancement can 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 through the membrane could drag the
`permeant with it. though this concept is somewhat controversial and remains to be
`proven.
`{iii} Solubilizing the permeant in the donor (c.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 or to stabilize a dispersion, and a
`terpene as a fragrance material. The efficacies of some topical preparations, particularly
`those long established, are probably due to penetration enhancement by these types of
`agents, although the commercial preparations are not claimed to incorporate an agent
`specifically for its enhancing ability.
`
`(ii)
`
`
`
`