THIRD EDITION
`
`
`THE DESIGNAND”
`MANUFACTURE OF
`MEDICINES
`
`ELsmER
`
`Edited by
`Michael E.Aulton
`
`CH C RCH ILL
`LIVINGSTONE
`
`Noven Pharmaceuticals, Inc.
`EX2006
`
`0001
`
`Mylan Tech., Inc. v. Noven Pharma, Inc.
`lPR2018—00174
`
`
`
`

`

` CHURCHILL
`
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`ELSEVIER
`
`www.elsevierheulth.l:0m
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`\X/brking together [0 grow
`[ibrarics in developing courzu'ics
`\m’w.c|tc\.'c|.:am \\\\w..\t>:li:.li‘i.1 _
`2
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`
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`salt.- ntoyaé
`ELSEVIER
`'
`'-
`Sabre. Foundation
`lrom sustainab'e fora-515
`paper manufactured
`i't'lllln‘d .n IJ.|11‘__‘tlt'l\-
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`

`

`Introduction
`
`566
`
`56?
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`565
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`5.76
` Temperature and pf |
`
`br'x'
`Dl:lt:S'OI1CGEl‘-1EIFPF‘T
`Structure. function and topical treatment of human
`
`5!!
`Urug concentration
`skin
`566
`EYE;
`in l'LirJ" Luellicienl
`anatomy and physiologyi
`578
`Molecalar Size and shape:
`Epldi’T'T'JEi
`568
`Idea: molecular a'operl e5 for drug peitel'iaiiort
`Dennis
`568
`Subcutaneoustissue
`Sk:n appeincages
`568
`-J-tct'ons ot the skin
`568
`lfechariicalfc'ction
`568
`Prclecliuefuncliun
`559
`
`5?9
`
`5}”?
`Drug permeation through skin
`5?"?
`St'atum corneum rate ccrtrol‘ing
`5N
`St'atum cornoum not ”ate ccrtroltng
`580
`Abscrptior from solution skin a perfect sirk
`Abecrpiinr‘ from suspension? sk-n a perfect sink
`
`580
`
`569
`
`Methods for studying transdermal drug delivery 531
`!.n wtro motrcds
`581
`Excisec skin
`5-3]
`582
`Arlilic al rtteittbr'artes
`Release methods wthout a rate—ti ‘i'liiii‘ig trienbi on ie
`In VIVC metnoj;
`583
`Histology
`583
`Surface .055
`581i
`MicrodialySIS
`581i
`58f—
`Analyse otbc-cy Lissues or fluids
`Observation of a pharmacoocical or physiological
`res-ponee
`585
`Pnysmal properties of the sxih
`Bioassays
`585
`
`585
`
`582
`
`Qafional approach to drug deli-Joint to and via the sk '
`Surface treatment
`569
`559
`Sritlurtt coi'itoum treatment
`5m
`Skin epicencage treatment
`\tieiulo opider'rtis arc dermis treatment
`Transcutaneous immunization
`5H
`Systemic treatment we transdernnat absorption
`Drug transport through the skin
`53”
`.jasic principles of ditfu5ion througl‘ r-“tembrartes
`Diffustoi: process
`571
`Complex d:ffu5!onal barriors
`Skirt transport
`5Y3
`573
`Routes ofpenetration
`Sodom and sur’ece material
`
`5?1
`
`5?1
`
`571
`
`5t?
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`5??
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`573
`Skin appendages
`5?3
`Enidermal ro_r_e
`General conclusions on drug transport through the skin
`
`5%
`
`Properties that influence transdermal delivery 5?”.
`Bologicalfaciors
`575
`Skinccr‘diliun
`57"5
`Skinaee
`575
`Bluurlflow 5TB
`Regionalskinsitos
`Skinmetahoiisrn
`
`5?5
`576
`
`586
`
`586
`
`Maximizing the hioavailahility of drugs applied
`toskin 585
`585
`Drug or prodrug selection
`Chemical ootential adjustmen:
`Hydration
`586
`Ultrasound{phonupltureszs}
`Ionlcpl‘oresis
`586
`Flo-:trono'atmn
`586
`586
`Redio‘roquoncywavc-s
`58?
`Sli alum corneuni removal
`
`Photomecinankolwovo
`58.tr
`Species differences
`596
`
`Mzcroneedle air-.33;
`587
`Pltysicochorr‘icalfactors
`57’6
`
`587
`Chemical penetrat or enhancers
`Skinhyc'raiion
`bib
`
`
`565
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`

`

`
`
`Delivering the medicament to the diseased site is a prob-
`leni wrth appendage treatment. For example. it is dil'iicult
`In achieve a high antibiotic concentration in a sebaceous
`gland when. as in acne. a homy plug blocks the follicle.
`When delivered through the skin. the drug may not he suf-
`ficiently hydrophobic to partition from the water—rich
`viable epidermis and dermis into the sebum—filled gland.
`
`Viable epidermis and dermis treatment
`
`We can treat many diseases prOVided that the preparation
`:i'lit'ienlly delivers drug to the receptor. However, many
`rtrrertliully valuable drugs cannot be used topically as they
`in not readily cross the Stratum cor'neutrr. Hence, investi—
`gulurs may use stratagems such as adding chemical pene-
`Iartion enhancers to diminish this layer’s barrier function
`Itiiscussctl later in this chapter). Another approach devel—
`ups prodr'ugs. which reach the biological
`receptor and
`release the pharmacologicall y active fragment. The efiieaey
`u:
`runny topical steroids depends partly on molecular
`groups which promote percutaneous absorption but. which
`may not enhance drug—receptor binding.
`Drug examples include topical steroidal and non-
`‘a‘rttitlttl antiinfltiniIttatory agents; corticosteroids may
`risttbC used in psoriasis. Antibiotics include those listed
`one. Anaesthetic drugs such as benzocaine. arnetho
`.".||tlL' and lidocaine reduce pain, and antiprurities and
`nti
`.slamines alleviate itch. but they may cause sensiti—
`uriuri. Topical 5—fluorouracil and methotrexatc eradi—
`:.-tc prematignanl arid some malignant skirt
`tumours.
`to! treat psoriasis. The psoralcns (particularly in con—
`_.'nctiou with ultraviolet light — I’UVA therapy] mitigate
`:zrrriasis. and 5—aminolaevulinie acid (with visible light
`satiation — photodynamic therapy} treats skin cancer.
`
`iranscutaneous immunization
`
`he skirt has a highly effective immunological surveillance
`al effector system. A new therapy involves developing
`:Jttsculancous
`immunization via topical application of
`it"t'lllL‘ antigens. The process uses an adjuvaut such as
`intern toxin added to a vaccine antigen (cg. diphtheria
`-'-trrirli to induce antibodies to the diphtheria tosoid. The
`ii|'_'\'.l|'tl and antigen target Langerhans cells, potent anti—
`ltn‘pTL’fiCI‘tting cells in the epidermis. Simple application of
`intaccine formulation to the skin of experimental zutirnals
`sl human volunteers has produced positive responses.
`
`'lrsternic treatment Vin tronsdermot absorption
`
`eraily. in the past we have not used healthy skin as a
`_ gruutc during systemic attacks on disease. with the
`'
`.ewnrthy esceptions of nitroglycerin and antileprotics.
`body absorbs drugs slowly and incompletely through
`
`the stratum conteum and much ot‘tlte preparation is lost by
`washing. by adherence to clothes and by shedding with
`stratum corneurn scales. Other problems include marked
`variations in skin pel'lneahilily with regard to subject. site.
`age and condition. which make control difficult. l-[oweverz
`in recent years considerable scientilie work has leti to the
`route being used to treat several conditions by means of
`transdermal patches (discussed later in this chapter}.
`Figure 38.2 illustrates drug penetration routes and
`examples of treatments appropriate to various skin strata.
`
` .__t_-_r__rjtouGH stun
`
`Basic principles of diffusion through membranes
`
`A useful way to study pei'cutaneous absorption is to con—
`sider. first. how molecules penetrate inert (artificial) mem—
`branes and then move on to the special situation of skin
`transport. An understanding ofthe basic principles ol'per--
`location lhr'ougli membranes is also valuable itt all other
`areas of biopharmaceutics — oral. buccal. rectal. nasal.
`lung. vaginal. uterine.
`injection or eye. The underlying
`mathematics are also relevant to dosage form design, par—
`ticularly sustained— or contrt'illet'l—r'elease forrrnrlations and
`drug targeting.
`
`Diffusion process
`
`in passive diffusion. matter moves from one region of a
`system to another following random molecular rrtotion.
`The basic hypothesis underlying the mathematical theory
`for isotropic materials (which have identical structural
`and diffusional properties in all directions} is that the rate
`of transfer of diffusing substance per unit area oi‘ a sec—
`tion is proportional to the concentration gradient meas—
`ured normal
`to the section. This is expressed as Fiek’s
`First Law of Diffusion. Eqn 38.1:
`8C
`(38.”
`J=_DE
`where J is the rate of transfer per unit area ot‘surfaee (the
`flux). C is the concentration of diffusing substance. I is
`the space coordinate measured normal to the section, and
`D is the diffusion coefficient. The negative sign indicates
`that the flux is in the direction ot’ decreasing concetrtra—
`tion, i.e. down the concentration gradient. In many situa-
`tions 1’)
`is constant hill
`in more complex materials. i)
`depends markedly on concentration: its dimensions are
`(length)3(timei”i. often specified as cm"! s".
`Fisk's First Law contains three variables, J, C and I. of
`which J is additionally a multiple variable, dinidr. where
`m is amount and r is time. We therefore usually employ
`Fiek‘s Second Law, which reduces the number of vari—
`ables by one. For the common experimental situation in
`
`571
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`If a steady—state plot is extrapolated to the time axis.
`the intercept so ohtaincd at or : {l is the lag time. f,:
`it:
`I.
`(38.4)
`— 61.5
`Front Eqn 38.4. f) is estimated provided that the mem—
`brane thickness. h. is available. Knowing these parame—
`ters and C”. and measuring dinldt. Eqn 38.3 provides one
`way of assessing K. Eqn 38.3 shows why this perine—
`ation procedure may he referred to as a zero-order
`process. By analogy with chemical kinetic operations.
`EL] I1 38.3 represents :-1 IND-Oftlflr process with a rate con—
`stant of DK/t’r.
`
`
`
`* l
`
`"
`
`Time
`
`Fig. 38.3 The Ti‘ne course for absorption for the simple zero—
`order flux case obtained by plotting m. t‘te cumulative amount of
`dillLJSdeL crossing unit area of membrane, as a function of time.
`Steady state is achieved when the plot becomes linear; extrapolation
`oftlie linear pn'tion to the time axis yields the lag time L.
`
`
`
`572
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`' "'fi————fi
`
`DOSAGE FORM DESlGN AND MANUFACTURE
`
`the concentratitm
`i.e.
`which diffusion is unidirectional.
`gradient is only along the .r-asis. Hon 38.2 expresses
`Fick‘s Second Law as:
`
`D
`
`{38.3}
`
`1-.
`
`8 t:
`fig =
`a..~.--’
`3’
`Many experimental designs emplOy a membrane separat—
`ing two cotttparttnents, with a concentration gradient
`operating during a run and ‘sink‘ conditions (essentially
`zero concentration] prevailing in the receptor compart—
`rnertl. If we measure the cumulative Ittass of diffusant. in.
`which passes per unit area through the membrane as a
`function of time. we obtain the plot shown in Figure 38.3.
`At long times the plot approaches a straight line and from
`its slope we obtain the steady this. din/d! (Eon 38.3):
`
`DC K
`{38.3)
`[1:3
`(3:1 =
`Here C” is the constant concentration of drug in the donor
`solution. K is
`the partition coefficient of the solute
`between the membrane and the bathing solution. and h is
`the thickness of the membrane.
`
`
`Sometimes with biological membranes tscclt i131
`we cannot separate the value of i.) from that affix:
`then often employ a composite parameter. the herniati-
`it y coefficient. R where P = Kt) or P = KD/r'r. The |r.::.
`definition is used when it
`is uncertain. eg. dift'uis:
`through skin.
`
`Complex diffusional barriers
`
`Barriers in series The treatment ahoyc deals (all
`with. the simple situation in which diffusion oecursini
`single isotropic medium.
`llowex-‘er. skin is a Itetctogt
`ncous multilayer tissue and in percutaneous altsr-tplia
`the concentration gradient develops over several stnn
`We can treat skirt in terms of a laminate, each layer
`which contributes a diffusional resistance, R. whirlii
`directly proportional to the layer thickness. ft. and is ittli
`rectly proportional to the product of the layer diffusivity
`D. and the partition coefficient. K. with respect [elm
`external phase. The total diffusional resistance of ill in
`layers in a three—ply membrane such as skin tstrntttn
`corneum.
`t-iahle epidermis and dermis} is git-en b}'thi
`expression:
`
`it.
`fr.
`ltl
`|
`”Tea- or. “—le Tr
`llerc If... is the total resistance to permeation, P.. is tht
`thickness—Weighted permeability coefficient. and llll
`numerals refer to the separate skin layers.
`[1' one segment has a much greater resistance [.tflll th
`other layers leg. the stratum cornenm cotnparedwittttiti
`viable epidermis or dermis) then the single [ugh-resist
`ance phase determines the composite barrier properties
`Then PT 2 it" ler‘tl. where the subscript
`l
`refers to iiti
`resistant phase.
`Barriers in parallel Shunts and pores. such as hat
`follicles anti sweat glands, pierce human skin (so
`Fig. 38.1].
`Investigators often ideali‘xe this cantata:
`structure and consider the simple situation in which llll
`diffusional medium consists of two or more diffusion
`Pfllhways linked in parallel. Then the total diffusion:
`llux per unit area of composite. Jr is the sum oftlte ltttll
`\-'idua| fluxes: through the separate routeS.Tl1us:
`
`335'
`
`J. r r”. .r. +_r2 J1...
`
`[38.6
`
`Wl'ICI'SfE. f3. etc. denote the fractional areas for caclttiif
`l'usional route and .II. J_,_, etc., are the fluxes per utzit are:
`of each separate route. In general, for independent lino.
`parallel pathways during steady state diffusion:
`
`J... = cut r. P, if. r3+ ...)
`
`oat:
`
`where Fl. P1,... represent the thickness—weiglned peraic
`ability coefficients.
`If only one route allows dil'l'usant to pass. i.e. the nth-c:
`routes are impervious. then the solution reduces to tltt
`
`
`
`

`

`
`
`
`Effect on skin permeability
`Delivery system
`Examples/constituents
`. In
`M df'kE't'i rtf rea sc-
`, ost
`
`Dre-lustre dressing
`
`
`F‘tastlc film |. orcertorated eater
`piuol' plaster
`
`?Jre‘.ent' water 102.3. full hydr alien
`
`
`
`ult
`
`
`
`can
`ince
`fiure
`
`tody
`.ture
`skin
`uent
`ti of
`
`
`
`llrrluswe patch
`
`Most trarlscer'mal patches
`
`Prevents ne'er logs iJ.l li-.-di'at:on
`
`lv‘ler'aed increase
`
`Absorption hat-t:
`
`Marked mired-.9
`.fals oases falls-50d)
`Paraffin; oil
`Pro-rents 'J-jIEl' loss roe; produce
`LIprhllit; material
`and alcohol: esters ElllliLinl-j‘.
`
`I'ul h'ft‘iI'J-tltil"
`Prevents water to.» marked
`Mar Iced- iritrea so
`.r‘arih-rdraus lipid material plus
`hvd- ulion
`-'.".*.tE!i.-':- l E'l‘l’ltliSIilE‘f:
`
`
`Anhyrnus lipc materl‘ttplu
`El‘ltL‘lEilylf‘lg 'ease
`Odin-rater emulsifiers
`
`Market: Increase
`loo-3 marked
`Potent-2 .zalE'l
`h-rdrallun
`
`
`increase
`Retard .. water less lfill'it-Ki hydration
`.lon
`t'v‘Jtt'T’bll PI'TlLJi
`Olly crowns
`
`
`Dilfvater emulsion
`Slqi‘lllllCIUtJSfT-J
`Me» donate .'.'ater. sliqt‘t i‘.'.'dl'-'51.=Cll‘.
`Aqueous cream;
`increase
`
`
`Humectant
`Water—soluble b1..-ES. gtsturot
`Ma; -.-.rri-idrorv naiPt. t'lecrea .90
`Cat: lit-t I ease or act as
`
`gl-rcos
`tour-am:
`penetration when: or
`
`Littie effect on so atom
`Aid -.'.-'..JiCr c-voporatlon. decree .pd
`flaw orqorut 3. loorqarirs.
`pov'der
`CCI'Hf-‘Ill'l'
`shake totlonz
`etc-“s“. hyrirel ion
`
`
`Diffusion coefficient
`
`Drug concentration
`
`The diffusional speed of a molecule depends mainly on
`the state of matter of the medium. in gases and till'. dif—
`fusion coefficients are large because the void space
`available to the molecules is grout compared to their-
`size, and the mean free path between molecular colli—
`sions is big. In liquids, the free volume is much smaller.
`mean free paths are decreased. and diffusion cocflicients
`are much reduced,
`in skin. the dift‘tlsivities drop pro-
`gressively and reach their lowest values within the corn—
`patcletl
`stratum corneum matrix.
`lior
`rt constant
`temperature. the diffusion coefficient of a drug in a top—
`ical vehicle or in skin depends on the properties of the
`drug and the diffusion medium and on the interaction
`between them.
`However, the. measured value of i) may reflect influ—
`ences other than intrinsic mohility. For example, some
`drug may bind and become immobilized within the stra—
`tt'm comeum and this process affects the magnitude of l)
`as determined from the lag time (Eon 38.4). However,
`regardless of such tzoniplicalions.
`the value oi~ D
`measures the penetration rate of a molecule under speci—
`licd conditions and is therefore useful to know.
`
`It was seen previously that the “lift of solute is propor—
`tional to the concentration gradient across the entire bar—
`rier phase [Eon 38.3).
`'l'hus. drug permeation usually
`follows Fick's law. One requirement for maximal [his in
`a thermodynamicalIv stahle situation is that the donor
`solution should be saturated. A fot'mulator can optimize
`the solubility of a drug such as a corticosteroid by con—
`trolling the solvent composition of the vehicle. Then a
`saturated solution may be obtained at a selected concen—
`tration of the drug by experimenting with a series of so]
`vents or. more usually. by blending two liquids to form a
`miscible binary mixture with suitable solvent properties.
`Although the concentration differential is usually con—
`sidered to be the driving force for diffusion. the chemical
`potential gradient or activity gradient is actually the futi—
`damental parameter. Often the distinction is unimportant
`but sometimes we must consider 1L Thus, the thermody—
`namic activin of a penetrant in the donor phase or the
`membrane may he radically altered by. for example, pli
`change. complex formation or the presence of surfac-
`tants. micelles or cosolvents. Such factors also modify
`the effective partition coefficient.
`
`577
`
`
`
`