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`
`
`Journal of Pharmacy and Pharmacology
`
`Published by The Pharmaceutical Society of Great Britain
`1 Lambeth High Street, London SE1 SJN Telephone 01-735 9141 Telegrams Pharmakon London SE1
`
`EDITOR
`
`J. R. FowLER
`
`EDITORIAL BOARD
`
`Advisory Editors
`
`Professor A. M. BARRETT, The University of Leeds
`
`Dr. B. A. CALLINGHAM, University of Cambridge
`
`Professor P. H. ELWORTHY, The University of Manchester
`
`’
`
`Professor D. W. MATHIESON, University of Bradford
`
`Professor M. J. H. SMITH, King’s College Hospital Medical School, University of London
`
`Other Board Members
`
`Dr. L. C. BLABER, Roche Products Ltd. , Welwyn Garden City
`
`Professor M. R. W. BROWN, The University of Aston in Birmingham
`
`Dr. G. P. CARR, British Pharmacopoeia Commission
`
`Dr. J. H. COLLETT, The University of Manchester
`D. H. DORKEN, Smith Kline & French Ltd., Welwyn Garden City
`
`Professor A. T. FLORENCE, University of Strathciyde
`
`Dr. J. D. PHILLIPSON, School of Pharmacy, University of London
`
`Dr. N. PILPEL, Chelsea College, University of London
`
`Professor R. L. SMITH, St. Mary’s Hospital Medical School, University of London
`
`Professor S. E. SMITH, St. Thomas’ Hospital Medical School, University of London
`
`Secretary
`D. F. LEWIS
`
`Copyright © 1983 Journal of Pharmacy and Pharmacology. The appearance on the code on the first page of a
`article in this Journal indicates the copyright owner’s consent that copies of the article may be made for personal 0
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`Copyright Law. This consent does not extend to other kinds of copying, such as copying for general distribution, f0
`advertising or promotional purposes, for creating new collective works, or for resale.
`
`
`
`Annual subscription for 1983: UK £51.00 (inc. postage); overseas £59.00 (air speeded).
`Single copies £5.00 (overseas £6.00).
`
`Claims for missing copies cannot be considered unless received within three months of publication.
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`

`
`Volume 35 Number 1
`
`
`
`January 1983
`
`"
`'
`Original Papers
`5. MALAMATARis. N. PILPEL
`Tensile strength and compression of coated
`pharmaceutical powders: tablets
`
`1. G. JOLLIFFE. J. M. NEWTON
`The effect of dosator nozzle wall texture on capsule
`filling with the mG2 simulator
`R. H. GUY. J. HADGRAFI. M. J. TAYLOR, 1. w. KELLAWAY
`Release of non—electrolytes from liposomes
`
`L. LENNARD. J. L. MADDOCKS
`Assay of 6—thioguanine nucleotide, a major
`metaboliteof azothiaprine. 6-mercaptopurinc and
`_6-thioguanine, in human red blood cells
`K. YAMA0i<A, T. NAKAGAWA. T. UNO
`Moment analysis for disposition kinetics of several
`cephalosporin antibiotics in rats
`P. LABRUDE, L. VIGNERON
`Stability and functional properties of haemoglobin
`freeze—dried in the presence of four protective
`substances after prolonged storage: dose-effect
`relationships
`K. A. wALTERs. G. L. FLYNN, J. R. MARVEL
`
`Physicochemical characterization of the human
`nail: permeation pattern for water and the
`homologous alcohols and differences with respect
`to the stratum corneum
`
`R. MATHISON
`
`Actions of neurotransmitters and peptides on
`longitudinal and circular muscle of the rat portal
`vein
`
`
`
`. 38-42
`
`T. R. MACGREGOR, M. A. DRUM. s. E. HARRIGAN.
`J. N. wiLEY,R. H. REuNiNG
`Naltrexone metabolism and sustained release
`following administration of an insoluble complex to
`h
`d
`.
`_
`.
`r esus monkeys an guinea pigs
`
`COII1I1”111I11C3.t101'lS
`R. C. ROWE
`
`5 43-44
`
`The orientation and alignment ofparticles in tablet
`film coatings
`
`44-45
`
`J. HARVEY, H. PARisH, P. P. R. H0. J. R. BOOT.
`w. DAWSON
`
`The preferential inhibition ol'5—lipoxygenase
`product formation by benoxaprofen
`
`46-48
`
`48_4g
`
`50-51
`
`52-53
`
`54_56
`
`57-58
`
`59-61
`
`62_64
`
`F. FRANCONLS. MANZlNl.l.S’l‘l~1NDARDI.
`F. BENNARDINI. G. ANTONINI, P. FAii.Li. R. MATUCCI.
`A. GIOTTI
`Differential inhibitory effect of tziurine on
`contractile responses to potassium and
`noradrenaline in rabbit ear artery
`
`1. F. STAMFORD. M. A. CARROLL. A. ClVll€R.
`C. N.
`l-{ENSBY,A.BENNET1‘
`Identification of arachidonate metabolites in
`normal. benign and malignant human mammary
`tissues
`
`s. HARA. T. sAroii. H. KITAGAWA
`Dose-dependence of the effect of hydralazine on
`the central nervous system in rats
`
`1. R. FRY. C. G. wiLsoN
`The effect ofadrenalectomy on hepatic mixed
`function oxidase activity in female rats
`
`R. C. SMALL. V. w. YONG
`The failure of morphine to depress selectively
`non—adrenergic neural inhibition ofthe guinea-pig
`taenia caeci
`
`R. w. FULLER, K. w. PERRY
`Effect ofpergolide on MOPEG sulphate levels in
`rat brain regions
`
`A. IBRAHIM, P. CouvRr.uR. M. ROLAND. P. sFF:isF:R
`New magnetic drug carrier
`
`R. IENTILE, A. DE sARRo. D. ROTIROTI. G. B. DE sARRo.
`G. NISTICO
`Powerful stimulation ofrat caudate nucleus
`adenylate cyclase activity by BW 245C, a
`prostaglandin analogue with prostacyclin-like
`activity
`
`xxxvfi
`
`
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`gCFA[g)mv. Aijacor, IPRZO15-01776 ANACOR EX. 2188 - 3/9
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`'_-,-..-,.__L.,_.,..,.....__.__.
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`
`
`
`coefficients. Such structural influences on physica-
`chemical properties, when considered together with
`relative permeabilities, have helped decipher the
`barrier mechanisms of several membranes (Blank
`1964; Scheuplein 1965; Hwang et al 1976; Ho et al
`1977: Behl et al 1980; Durrheim et al 1980; Flynn et
`al 1981). Previous studies of the alkanol’s permea~ 3
`tion of skin are especially notable as these provide
`evidence that the stratum corneum acts to some
`extent as a hydrophobic continuum (barrier) (Blank
`1964; Scheuplein 1965; Behl et al 1980; Durrheim et
`al 1980; Flynn et al 1981). Similar studies on the j
`human nail plate presented here are comparably };
`revealing as, unlike the stratum corneum, the nail
`becomes less permeable to the n-alkanols as their
`hydrophobicity is increased. At extreme hydro-
`phobicity there is
`increased permeability. The
`mechanistic significance of these general observa-
`tions is considered.
`
`9
`
`75f‘
`*
`
`Apparently, no evidence exists concerning funda-
`mental permeation mechanisms and possible influ-
`ences of chemical structure on transport across the
`nail plate. To an extent its permeability properties
`have been inferred without foundation from the
`
`behaviour of other horny tissues. In order to make a
`priori judgements concerning toxic risk and thera-
`peutic benefit of substances brought in contact with
`the nail, some baseline information on this tissue is
`needed.
`
`We have shown it possible to determine nail plate
`permeability coefficients using standard diffusion
`cell techniques (Walters et al 1981). Results obtained
`for water agreed well with literature data on water
`transpiration through the nail plate (Burch & Winsor
`1946; Spruit 1971; Baden et al 1973). In pursuant
`studies the techniques have been extended to the
`permeation of some n-alkanols. These are useful
`prototype compounds with systematically varying
`oil/water (o/w) distribution coefficients and diffusion
`
`* Correspondence. This work supported through the
`generosity of Ortho Pharmaceutical Corporation, Raritan,
`N.J., U.S.A.
`
`‘r Present address, Fisons Limited, Pharmaceutical Divi-
`sion, Research & Development Laboratories, Bakewell
`Road, Loughborough, Leicestershire LE11 0QY, U.K.
`
`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`J. Pharm. Pharmacol. 1983, 35: 28-33
`Received June 18, 1982
`
`0022-3573/83/010028-06
`©1983 J. Pharm. Ph
`
`Physicochemical characterization of the human nafl
`permeation pattern for water and the homologous
`alcohols and differences with respect to the stratum;
`corneum*
`
`KENNETH A. WALTERST, GORDON L. ELYNN*, AND JOHN R. MARVEL:
`
`College of Pharmacy, University ofMichigan, Ann Arbor, Michigan 48109, U. S./1., and if Dermatological Division, Ortho
`Pharmaceutical Corporation, Raritan, New Jersey, U.S.A.
`
`In order to develop a basic concept of the permeability of the human nail plate and thus
`create a better understanding of the toxic potentials and therapeutic possibilities of
`substances applied to the nail, avulsed cadaver nails have been placed in specially
`constructed diffusion chambers and their permeation by water and the n-alkanols through
`dodecanol, all in high aqueous dilution, has been investigated. The permeability coefficient
`of water is 16-5 X 10—3 cm h*1 and that for methanol is 5-6 X 1&3 cm h"1. Ethanol’s
`permeability coefficient measured 5-8 X 10-3 cm h—1. Permeability coefficients decreased
`systematically thereafter to a low value of 0-27 X 10-3 cm h-1 at n-octanol. The middle
`chain length alkanols, n-pentanol through n-octanol, have similar permeability coefficients
`but n—decanol and n-dodecanol show higher rates of permeation. The data suggest that, as a
`membrane, the hydrated human nail plate behaves like a hydrogel of high ionic strength to
`the polar and semipolar alcohols. Declining permeability rates appear linked to decreased
`partitioning into the complex matrix of the plate as the compounds become hydrophobic.
`The results for n—decanol and n-dodecanol introduce the possibility that a parallel lipid
`pathway exists which favours the permeation of these exceedingly hydrophobic species.
`
`MATERIALS AND METHODS
`
`Materials
`
`Tritiated water and radiolabelled alcohols were
`obtained from New England Nuclear ([3H]water,
`[3H]methanol,
`[14C]ethanol,
`[1“C]butanol), Cali-
`fornia Bionuclear
`([14C]propanol,
`[1“C]pent‘anol¢
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`
`NAIL PERMEATION BY HOMOLOGOUS ALCOHOLS
`
`29
`
`qheptanol, [14C]dodecanol) and ICN ([14C]hex- compound, h is the nail plate thickness and tL is the
`diffusional lag time obtained by linear regression of
`-ml, [14C]octanol, [14C]decanol). All radiolabelled
`the steady state slope of uptake versus time plots.
`pounds were diluted with saline (0-9% NaCl
`The nail plates used in these studies were measured
`gation Solution, Abbott Labs) before use. The
`with a micrometer and averaged 0-54 mm in thick-
`anols were diluted to trace concentrations, 10*‘
`ness.
`
`
`
`tails of the diffusion cell and permeation pro-
`e ures have been given previously (Walters et al
`0 1), Briefly, trimmed human nail plate sections*
`5 re placed between two halves of a diffusion cell. A
`“wn amount of a radiolabelled permeant was
`ced in the donor chamber and samples were taken
`fpredetermined intervals from the receptor cham-
`‘
`. Isotope activity was monitored using a Beckman
`9000 liquid scintillation counter.
`g
`he ‘permeation behaviours of
`[3H]water and
`methanol and [14C]alkanols in dilute solution
`\..._a
`ere followed as a function of time at 37 °C. In all
`es two permeants were applied with different
`iolabels. Generally methanol was run as a tri-
`ed compound along with a 14C—1abelled co-
`meant. Methanol thus served as a reference and it
`
`mportant to note that the increased values for the
`meability coefficient of decanol and dodecanol
`e obtained concurrently with normal methanol
`ata.
`
`ermeability coefficients
`m:
`
`(P) were calculated
`
`_V(dC/dt)
`P ” A. A C
`
`(1)
`
`RESULTS AND DISCUSSION
`
`Permeability coefficients of water and the saline
`diluted n-alkanols are given along with diffusion lag
`times in Table 1. Fig.
`1 shows the relationship
`between the logarithms of the permeability coeffi-
`cients and the alkyl chain lengths of the alcohols. An
`unusual pattern is observed with minimum per-
`meability coefficient values at
`intermediate alkyl
`chain length.
`
`Table 1. Nail plate permeability data for water and
`n-alkanols.
`
`Lag. time
`Permeability-'*
`tL
`coefficient
`(s)
`(cm h-1 X 103)
`Permeant
`900 i 100
`16-5 : 5-9
`6)
`Water
`5-6 : 1-2
`26) 1790 i 200
`Methanol
`5-8 : 3-1
`8
`2730 i 200
`Ethanol
`0-83 : 0-15 4
`4020 : 350
`n-Propanol
`0-61 i 0-27 4
`3470 i 350
`n-Butanol
`0-35 : 0-07 6
`2700 i 250
`n-Pentanol
`0-36 i 0-23 5
`3540 : 300
`n-Hexanol
`0-42 i 0-12 4
`2520 i 300
`n-Heptanol
`0-27 i 0-03 4
`2120 i 150
`n-Octanol
`2-5 i 1-7
`10) 2090 4; 150
`n—Decanol
`n-Dodecanol 4-1
`.4; 2-7
`8)
`2300 i 150
`
`Effective
`diffusionb
`constant
`(Deg) cm? s‘
`X 107
`5-4
`2-7
`1-3
`1-2
`1-4
`1-8
`1-4
`1-9
`2-2
`2-1
`2-1
`
`a. Data include standard deviation and (
`experiments.
`b. From t,_ = fi (Mean value for h = 0-54 mm)
`6D
`
`) number of
`
`Fig. 2 shows the effective diffusivities of the
`permeants in the nail plate tissue as a function of
`alkyl chain length.
`
`Theoretical considerations
`
`The nail plate’s barrier properties are governed by its
`anatomical construction and its physicochemical
`properties and a proposed model must be support-
`able in terms of both. The model developed here,
`although speculative,
`fulfills these requirements.
`The plate consists of a laminate of sheets of
`keratinized cells (Caputo & Dadati 1968; Forslind
`1970; Forslind & Thyresson 1975). Like the stratum
`
`
`
`there V is the volume of the receiver half cell, dC/dt
`the rate of change in concentration in the
`‘ udo-steady state portion of the receiver concen-
`‘ation versus time plot, A is the diffusional area and
`is the concentration differential of permeant
`oss the membrane. V(dC/dt) gives the diffusional
`ux in mass per unit time. The diffusion cells with
`all plate membranes in place were scrupulously
`cked for intercompartmental leakage using sol-
`B. but impenetrable polyethyleneglycol markers
`no leaks were evident.
`
`iffusivities of the permeants in the nail plate
`Ssue were calculated from the non-stationary state
`ods using:
`
`(2)
`
`Where Dcff is the effective diffusivity for a given
`
`“ll Fresh cadaver nails generously supplied by _Dr T. M.
`——
`lchy University of Michigan, School of Medicine.
`
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`
`5
`
`x103(cmh-‘) 5
`Logpermeabilitycoefficient
`
`
`O-l
`
`123456789101112
`Alcohol alkyl chain length
`
`FIG. 1. Relationship between the logarithm of the per-
`meability coefficient and alkyl chain length of the alcohol.
`
`corneum, the cytoplasmic keratin mass is partially
`crystalline and partially amorphous. In section, thin
`lipid seams are seen to separate the cell layers. This
`lipid is from the original cell membranes and is
`apparently supplemented by intercellular deposition
`of so-called membrane coating granules during the
`plate’s formation (Hashimoto et al 1966; Hashimoto
`1971a,b).
`
`6
`
`./Water
`
`
`
`
`
`Effectivediffusionconstant
`
`p
`A
`;
`
`through the cell units stacked upon one another and;
`separated by the intercellular substance, or may flowi
`mainly around the cell contents by way of the.
`interconnecting, extra-cellular lipid network. The5
`first of these possibilities involves alternating pas,
`sages through two distinctly different domains.“
`Based on the lipid content of the nail being totally
`extracellular and 1% of the total volume and on
`individual cell dimensions of 30 um diameter (hexa;
`gonal) and 1 mn thickness, the latter route would
`offer a fractional area for diffusion of 5 X 104. At
`this percentage composition and with these cen
`dimensions,
`the calculated width of the region
`between cells is approximately 100 A, in reasonable
`agreement with ultra-microscopic estimates (Zaias &
`Alvarez 1968; Hashimoto 1971b). Allowance has to
`be made for diffusional path of the extracellular
`route to be tortuous, having a path length up to, but
`not exceeding, 15 times (1/2 cell diameter), the nail’s
`width.
`
`The following equation can be formulated to
`describe flux across the nail plate as described using
`the general principles outlined by Flynn et al (1974):
`
`{L
`r,
`"
`J
`_ 1, ______._ __
`
`ZR, + ERM + RL JA
`
`A
`
`C
`
`(3)
`
`Here I is the total flux (mass/time), A, is the area of
`application, and fc and fL are the fractional areas
`available for
`the transcellular and lipid routes
`respectively. The terms RC and RM are the summed
`resistances of the two types of lamina encountered
`transcellularly while RL is the resistance of the
`extracellular lipid route. The term AC is the driving
`force for the mass transfer process measured as the
`concentration difference across the nail plate.
`Equation 3 can be made more explicit by including
`the estimated fractional areas and by defining the
`resistances in terms of effective thicknesses (h),
`diffusivities within phases (D), and partition coeffi-
`cients (K):
`
`L ~
`A
`
`0-9995DcDMKcKM
`DMKM2h, +D,1<,2hM
`
`+
`
`(4)
`
`
`
`
`
`it
`I
`ii
`i
`L;
`l
`
`.
`
`30
`
`Ix) O
`
`K. A. WALTERS ET AL
`
`The above picture allows consideration of diff“
`
`
`
`123456789101112
`
`Alcohol alkyl chain length
`
`5 X 10—4DMKM_._, i C
`
`FIG. 2. Effecive diffusivities of the permeants as a function
`of alkyl chain length of the alcohol.
`
`The subscript c is used to indicate the intracellular
`protein domain and the subscript M the extracellular
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`
`
`of the n-alkanols (including water at n = 0) is shown ‘
`in Fig. 1. From water to n-octanol permeability
`coefficients decrease systematically and by an overall
`factor of about 60. This observation rules out the
`
`possibility that a lipid pathway is involved for these
`permeants. Over the same alkyl chain length span
`diffusivities are also decreasing, but only several-
`fold. The lag time based diffusivities are on the order
`10-7 cm? s-1,
`a magnitude which is physically
`plausible.
`'
`A nominal molecular size sensitivity for diffusivity
`is evident considering the narrow spread in apparent
`Dc (Deffective) values. Thus, there must be another
`cause for the decline in the permeability coefficients
`with increasing chain length. According to equation
`5 partitioning provides the only alternative basis for
`the declining trend; it would be necessary for the
`partition coefficients between the protein domain of
`the nail (keratin) and the external water to decrease
`about 25-fold. To our knowledge there is no
`precedent for such behaviour in a mass transfer
`framework under circumstances where the external
`
`media are aqueous. There are, however, some
`observations supporting the concept that the keratin
`matrix has a decreasing ability to dissolve the
`alkanols as the homologous series is ascended.
`Tillman & Higuchi (1961) note that the solvating and
`softening abilities of solvents for callus strips are in
`the order water > methanol >> ethanol. A great
`deal of work has been done on the sorption of
`solvents into hair and wool fibres and, according to
`Harrison & Speakman (1958), the fine structure of
`wool seems to be inaccessible to molecules larger
`than n-propanol. On the basis of the present work, it
`would appear that exclusion associated with increas-
`ing hydrophobicity is more a thermodynamic than _a
`kinetic (molecular size) phenomenon. Hair (wool),
`callus and nail seem to have more in common
`
`chemically and physically with each other than they
`do with the stratum corneum (Baden 1970; Baden et
`al 1973) and thus inferences drawn from the cited
`works have good probability of being applicable to
`the nail. Furthermore, at 1(}7 cm2 s-1 the effective
`diffusivities are too large for an approximately
`25-fold factor to be incorporated and hidden in some
`complex way. It therefore appears that, to a rough
`first approximation, the nail plate acts as a concen-
`trated hydrogel to the alkanol permeants through
`n-octanol. The behaviour suggests there is a positive
`free energy change accompanying the transfer of a
`methylene group from the external, water medium
`to the intracellular protein phase.
`Skin permeation of the alkanols through n-octanol
`
`nation 5 gives the flux per unit area for typical
`meants in terms of physically meaningful mass
`nsfer parameters. The bracketed quality is a
`rnplex mass transfer coefficient or ‘permeability
`fficient’. Using the symbol P for the permeability
`fficient,
`the statement J/A = PAC, applies
`rierally for such mass transfer systems. The opera-
`e parallel pathways are indicated by the two
`larate collections of terms comprising P.
`The permeability coefficient profile for a homolo-
`us series of permeants will depend upon how the
`fusivities and partition coefficients in equation 5
`" affected by variation of length of the alkyl chain.
`s impossible to predict how Dc and Kc might be
`acted as very little is known about solubility and
`lecular mobility in the nail’s dense, semicrystal-
`e protein phases. Based on general considerations
`y-nn et al 1974) and on partitioning behaviour of
`g chain fatty acids between the nail plate and
`ter (Baden 1970), KM may be assumed to follow
`general o/w homologue partitioning pattern:
`
`log KM_,, = log KM_O + am
`
`(6)
`
`ere KM.“ is the partition coefficient of the homo-
`ue of chain length n between a water immiscible
`ase and water and log KMO is the Y-intercept of a
`tKM‘,, versus n. The term, 717, is the slope of the
`Ug'K versus 11 plot. The nature of the intercellular
`terial is such that n20-3 and therefore KM.“ can
`be expected to grow in an exponential fashion as the
`alkyl chain is extended.
`
`Relative permeability of the n-alkanols through nail
`Plate and stratum corneum
`The alkyl chain length dependency of permeability
`
`NAIL PERMEATION BY HOMOLOGOUS ALCOHOLS
`
`31
`
`domain. The quantities he and hM are the
`med thicknesses of the cytoplasmic laminae and
`brane lamellae passed through transcellularly.
`“ded together these yield the total nail plate
`igkness. Common values of diffusivity (DM) and
`a..i.OC3 CO
`efficient (KM) are given for the lipid
`gnents of the two distinct routes but the 2hM<<hL
`in in the absence of a significant tortuosity factor.
`]y,
`for all but
`the most polar permeants,
`1KM2hc>>DcKCEhM as DC<DM (likely) and
`M<<2hC. Therefore:
`
`1
`
`-1 A 7
`
`{O-9995DCKC+5 >< HHDMKMT A C (5)
`
`Ehc
`
`hL
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`32
`
`K. A. WALTERS ET AL
`
`estimated, ie, P z fLDMKM/hM, and KM is about
`6000. This value is certainly not too large considering
`the extended length of the alkyl chain.
`
`is strikingly different (Blank 1964; Scheuplein 1965;
`Behl et al 1980; Durrheim et al 1980; Flynn et al
`1981). As the alkyl chain length is
`increased,
`permeability coefficients also ‘increase, with the
`increase being essentially exponential past ethanol.
`Such behaviour signifies that the stratum corneum
`functions for the most part as a hydrophobic mem~
`brane to these permeants, with increased perme-
`ability coefficients the result of increased partition-
`ing into some critical hydrophobic phase within the
`horny structure. The stratum corneum’s far greater
`lipid content undoubtedly plays a role here, setting
`its membrane behaviour apart from that of the nail
`and perhaps other cornified tissues.
`The striking increase in nail plate permeability
`coefficients from n-octanol to n-dodecanol signals a
`change in diffusional mechanism. Now permeability
`is increasing with increased hydrophobicity of the
`permeants,
`an unmistakable indication of
`the
`emergence of a functionally lipid pathway. Equa-
`tions 4 and 5 were formulated with such a route in
`
`mind, namely a route through the intercellular
`seams,
`with
`the
`collection
`of
`terms,
`5 X 10-4DMKM,hL, representing the route’s diffusive
`contribution. Regardless of whether the placement
`of the lipid pathway is anatomically proper,
`the
`route’s essential trait is an exponentially increasing
`distributioning with increased alkyl chain length, as
`described in equation 6. Even a fractionally minor
`lipid route will assume rate-controlling proportions
`at an appropriately long alkyl chain length providing
`no other competitive pathway has a partitioning
`sensitivity. The transition to lipid pathway control
`occurs with but a slight increase in effective diffusiv-
`ity based on the effective diffusivities of n-decanol
`and n-dodecanol. It would appear that the route is
`not tortuous as these effective diffusivities do not
`
`allow for great non—linearity in path. The appearance
`of this route so late on the alkyl chain length profile is
`consistent with its limited fractional area, which we
`estimate to be about 1/100 of that of the same
`
`pathway in stratum corneum. With a methylene unit
`partitioning factor (315) of 20-3 as suggested by
`literature data (Baden 1970),
`the alkyl fragment
`necessary to place the permeation process into
`extracellular control would have to be five to six
`
`carbons longer than it would for the stratum cor-
`neum, and this is very close to what is experimentally
`observed. Assuming a fractional area of 5 X 1(H
`and otherwise using the permeability data in Table 1,
`the partition coefficient between the extracellular
`lipid substance and water necessary to account for
`dodecanol’s high permeability coefficient can be
`
`
`
`It seems likely to us that the alkanol permeability
`pattern of the nail plate reflects general nail behav-
`
`iour and thus suggests how other low molecular
`weight organics might permeate. If this supposition
`is true, then very polar compounds might be surpris-
`ingly easily delivered through the nail plate to
`underlying tissues. The fact that urea can be used to
`chemically loosen and separate the nail plate from its
`bed is a supporting observation (Farber & South
`1978). The low incidence of problems associated
`with the use of powerful hydrophobic organic
`i
`solvents in nail laquer seems equally reinforcing.
`Certainly toxic and irritant properties of substances .3
`measured via patch tests on skin cannot be extrapol-
`ated to the nail. Moreover, physicochemical criteria op
`governing the selection of therapeutic candidates t0 ‘
`treat nail disorders would seem to be very different
`from the established criteria used for drug selection
`for the skin.
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`
`
`
`It is thus evident that the nail plate as a membrane.
`behaves in a manner widely different from the:
`epidermis (stratum corneum). There are other djf;
`ferences. The absolute rate of water transpiration“
`through the nail is faster than through the intact skin
`(,~.«.10 times) and, if the rate is thickness-normalized;
`the ratio is approximately 1000 in favour of the nail.
`Over a wide polarity range nail plate permeability is
`inversely related to polarity while the reverse is true
`for the stratum corneum. The declining nail plate
`permeability appears related to decreasing affinity gf
`the keratin matrix for the higher alkanols. Attempgs
`to confirm this supposition by way of equilibrium
`partitioning were not entirely successful.
`At extreme hydrophobicities (2Cg) a new path.
`way for diffusion through the nail becomes evident,
`And from n-octanol
`to n-dodecanol equilibrium
`partition coefficients
`increased exponentially,
`a
`trend generally supportive of the lipid character of
`the route. A partition coefficient for n-dodecanolof
`131 i 24 was obtained. If it is assumed that this Cm ,
`homologue is concentrated exclusively in the lipid
`domain, which overall
`is estimated to occupy
`approximately 0-01 volume fraction, then dodecan-
`ol’s intrinsic partition coefficient would be 13 000.
`This value is only a little over twice the value
`computed from the permeability coefficient using a
`fractional area for diffusion of 5 X 1(H. Given all
`uncertainties, this is in reasonable if not fortuitous
`accord.
`
`,
`
`
`
`’
`
`.
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`

`
`
`
`st. Derm. 55: 115-122
`
`(1973)
`
`,1, H. P. (1970) J. Inve
`n H. P,, Goldsmith, L. A., Fleming, B.
`uchim. Biophys. Acta. 322: 269-278
`Q R., Flynn,' G. L., Kurihara, T., Smith, W.,
`‘gguchi, W. I., Ho, N. F. H., Pierson, C. L. (1980) J.
`est. Derm. 75: 346-352
`: 415-420
`k, 1. H. (1964) Ibid. 43
`G. E., Winsor, T. (1946) Arch. Derm. Syph. 51:
`hv
`M1
`to, R. , Dadati, E. (1968) Arch. Klin. Exp. Derm. 231:
`44-354
`gfi-irheim, H., Flynn, G. L., Higuchi, W. I., Behl, C. R.
`(1980) J. Pharm. Sci., 69: 781-786
`er, E. M., South, D. A. (1978) Cutis 22. 689-692
`m, G, L., Durrheim, H., Higuchi, W. I.
`(1981) J.
`iliiharm. Sci. 70: 52-56
`11, G. L., Yalkowsky, S. H., Roseman, T. J. (1974)
`Ibid. 63: 479-510
`. (1970) Acta. Derm. Venereol 50: 161-168
`. (1975) Arch. Derm. Forsch.
`
`NAIL PERMEATION BY HOMOLOGOUS ALCOHOLS
`REFERENCES
`
`33
`
`Harrison, D., Speakman, J. B. (1958) Textile Res. J. 28:
`1005-1007
`
`Hashimoto, K. (1971a) Ultrastructure Res. 36: 391-410
`Hashimoto, K. (1971b) Arch. Derm. Forsch. 240: 1-22
`Hashimoto, K., Bernard, G. G., Nelson, R., Lever, W. F.
`(1966) J. Invest. Derm. 47: 205-217
`Ho, N. F. H., Park, J. Y., Morozowich, W.,Higuchi, W. I.
`(1977) In: Roche, E. B. (ed.) ‘Design of Biopharmaceut-
`ical Properties through Prodrugs & Analogs. American
`Pharmaceutical Association, Washington, pp 136-227
`Hwang, S., Owada, E., Yotsunganagi, T., Suhardja, L.,
`Ho, N. F. H., Flynn, G. L., Higuchi, W. I. (1976) J.
`Pharm. Sci. 65: 1574-1578
`
`Scheuplein, R. J. (1965) J. Invest. Derm. 45: 334-346
`Spruit, D. (1971) Ibid. 56: 359-361
`Tillman, W. J., Higuchi, T. (1961) J. Invest. Derm. 37:
`87-92
`
`Walters, K. A., Flynn, G. L., Marvel, J. R.
`Invest. Derm. 76: 76-79
`Zaias, N., Alvarez, J. (1968) J. Invest. Derm. 51: 120-136
`
`(1981) J.
`
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