`
`MANUFACTURE OF
`MEDICINES
`
`THIRD EDITION apprnti
`
`ELSEVIER
`
`Edited by
`Michael E. Aulton
`
`CHURCHILL
`LIVINGSTONE
`
`0001
`
`Noven Pharmaceuticals, Inc.
`EX2006
`Mylan Tech., Inc. v. Noven Pharma., Inc.
`IPR2018-00174
`
`

`

` CHURCHILL
`
`
`
`LIVINGSTONE
`ELSEVIER
`
`An imprint of
`Elsevier Limited
`
`© Harcourt Publishers Limited 2001
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`First edition 1988
`Second edition 200
`Third edition 2007
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`ISBN-13: 9780443101083
`
`International Edition ISBN-13: 9780443 01076
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`A catalogue record for this bouk is available fromthe British Library
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`A catalog
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`Note
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`. Changes in practice, weatinent and drug therapy may become necessary or appropriate. Rea
`to check the most current information provided(i) on procedures featured or(i) by the manufacturerof
`
`
`be administered, to verify the recommended dose or formula, the method and duration of administration, and
`
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`It
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`

` Introduction
`
`
`
`Methods for studying transdermal drug delivery 581
`In vitro methads
`581
`Excised skin
`581
`582
`Artifical membranes
`Release methods without a rate-limiting membrane
`Invive methods
`583
`Histology
`583
`Surface lass
`584
`Microdialysis
`584
`584
`Analysis of body tissues or fluids
`Observation of a pharmacological or physiological
`response
`585
`Physical properties of the skin
`Binassays
`585
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Rational approach to drug delivery to and viathe skin
`Surface treatment
`569
`569
`Stratum corneum treatment
`570
`Skin appendage treatment
`Viable epidermis and dermis treatment
`Transcutaneous immunization
`5/1
`Systemictreatment via transdermal absorption
`Drug transport through the skin
`571
`S3asic principles of diffusion through membranes
`Diffusion process
`5/1
`Complexdiffusional barriers
`Skin transport
`5/3
`5/3
`Routes of penetration
`Sebum andsurface material
`
`5/1
`
`5/1
`
`5/1
`
`5/2
`
`5/73
`
`566
`
`567
`
`Structure, function and topical treatment of human
`skin
`566
`Anatomy and physiology
`Epidermis
`568
`Dermis
`568
`Subcutaneous tissue
`Skin appendages
`568
`Functions of the skin
`568
`Mechanical function
`568
`Protective function
`569
`
`568
`
`569
`
`
`Temperature andpH 5/6
`Diffusion coefficient
`5/7
`Drug concentration
`5/7
`arlition coefficient
`578
`578
`Molecular size and shape
`Ideal molecular properties for drug penetration
`
`5/9
`
`5/79
`Drug permeation through skin
`579
`Stratum corneum rate controlling
`5/9
`Stratum corneum notrate controlling
`580
`Absorption fromsolution: skin 4 perfect sink
`Absorption from suspensions: skin a perfect sink
`
`580
`
`582
`
`585
`
`5/3
`Skin appendages
`573
`Epidermalroute
`General conclusions on drug transport through the skin
`
`574
`
`Maximizing the bioavailability of drugs applied
`toskin 585
`585
`Drug cr prodrug selection
`Properties that influence transdermal delivery 574
`Chemical potential adjustment
`586
`
`Biological factors§575 Hydration 586
`
`Skin condition
`575
`Ultrasound (phonophoresis)
`586
`Skinage
`575
`lontophoresis
`586
`Bloodflow 5/5
`Electroporation
`586
`586
`575
`Regionalskin sites
`Radiofrequency waves
`587
`Skin metabatism 376
`Stratumcorneum removal
`Photomechanical wave 58/
`Species differences
`Microneedle array
`587
`Physicochemical factors
`Skin hydration
`5/6
`Chemical penetration enhancers
`587
`
`
`
`5/6
`576
`
`
`
`

`

`
`
`Delivering the medicament to the diseasedsite is a prob-
`lem with appendage treatment. For example, it is difficult
`to achieve a high antibiotic concentration in a sebaceous
`gland when, as in acne, a horny plug blocks the follicle.
`When delivered throughthe skin, the drug may notbe 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
`eficiently delivers drug to the receptor. However, many
`potentially valuable drugs cannot be used topically as they
`do not readily cross the stratum corneum. Hence, investi-
`galors may use stratagems such as adding chemical pene-
`ation enhancers to diminish this layer’s barrier function
`(discussed later in this chapter). Another approach devel-
`ops prodrugs, which reach the biological
`receptor and
`release the pharmacologically active fragment. Theefficacy
`i many topical steroids depends partly on molecular
`youps which promote percutaneous absorption but which
`my not enhance drug-receptor binding.
`Drug examples include topical steroidal and non-
`yeroidal antiinflammatory agents; corticosteroids may
`iso be used in psoriasis. Antibiotics include those listed
`ove. Anaesthetic drugs such as benzocaine, ametho
`wine and lidocaine reduce pain, and antipruritics and
`itihistamines alleviate itch, but they may cause sensiti-
`ation. Topical 5-fluorouracil and methotrexate eradi-
`“ale premalignant and some malignant skin tumours,
`id Weal psoriasis. The psoralens (particularly in con-
`uiction with ultraviolet light - PUVAtherapy) mitigate
`woriasis, and 5-aminolaevulinic acid (with visible light
`madiation — photodynamic therapy) treats skin cancer.
`
`lonscutaneous immunization
`
`jhe skin has a highly effective immunological surveillance
`al effector system. A new therapy involves developing
`sunsculaneous
`immunization via topical application of
`weine antigens. The process uses an adjuvant such as
`folera toxin added to a vaccine antigen (e.g. diphtheria
`noid) to induce antibodies to the diphtheria toxoid. The
`gjuvant and antigen target Langerhans cells, potent anti-
`«n-presenting cells in the epidermis. Simple application of
`‘evaccine formulation to the skin of experimental animals
`adhuman volunteers has produced positive responses.
`
`oe
`
`stemic treatment via transdermal absorption
`
`erally, in the past we have not used healthy skin as a
`fee route during systemic attacks on disease, with the
`feeworthy exceptions of nitroglycerin and antileprotics.
`body absorbs drugs slowly and incompletely through
`
`the stratum corneumand muchof the preparationis lost by
`washing, by adherence to clothes and by shedding with
`stratum corneumscales, Other problems include marked
`variations in skin permeability with regard to subject, site,
`age and condition, which make control difficult. However,
`in recent years considerable scientific work has led 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 oftreatments appropriate to various skin strata.
`
` THROUGH SKIN
`
`Basic principles of diffusion through membranes
`
`A useful way to study percutaneous absorptionis to con-
`sider, first, how molecules penetrate inert (artificial) mem-
`branes and then move onto the special situation of skin
`transport. An understanding of the basic principles ofper-
`meation through membranesis also valuable inall other
`arcas 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 controlled-release formulations and
`drug targeting.
`
`Diffusion process
`
`In passive diffusion, matter moves from one region of a
`system to another following random molecular motion.
`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 transferof diffusing substance per unit area ofa sec-
`{ion is proportional to the concentration gradient meas-
`ured normal
`to the section. This is expressed as Fick’s
`First Lawof Diffusion, Eqn 38.1:
`oC
`(38.1)
`J=~—D95~
`where J is the rate of transferper unit area of surface (the
`flux), C is the concentration of diffusing substance, x is
`the space coordinate measured normalto the section, and
`Dis the diffusion coefficient. The negative sign indicates
`that the flux is in the direction of decreasing concentra-
`tion, i.e. downthe concentration gradient. In many situa-
`tions D is constant but
`in more complex materials, D
`depends markedly on concentration; its dimensions are
`(length)*(time)"', often specified as em? s7!.
`Fick’s First Lawcontains three variables, J, C and x, of
`which J is additionally a multiple variable, dm/dz, where
`m is amount and ¢ is time. We therefore usually employ
`Fick’s Second Law, which reduces the number ofvari-
`ables by one. For the common experimental situation in
`
`571
`
`
`
`

`

`
`
`
`
`-a
`
`DOSAGE FORM DESIGN AND MANUFACTURE
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`572
`
`the concentration
`i.e.
`which diffusion is unidirectional,
`gradient is only along the x-axis, Eqn 38.2 expresses
`Fick’s Second Lawas:
`
`D
`
`(38.2)
`
`lin
`
`jac
`dC _
`ax?
`or
`Manyexperimental designs employ a membrane separat-
`ing two compartments, with a concentration gradient
`operating during a runand‘sink’ conditions (essentially
`zero concentration) prevailing in the receptor compart-
`ment. If we measure the cumulative mass of diffusant, #7,
`which passes per unit area through the membrane as a
`function oftime, we obtainthe plot shownin Figure 38.3.
`At long timesthe plot approaches a straight line and from
`its slope we obtain the steady flux, di/di (Eqn 38.3):
`
`dm _ DO, K
`(38.3)
`dt
`h
`_
`Here C,,is the constant concentration of drug in the donor
`solution, K is
`the partition coefficient of the solute
`between the membraneandthe bathing solution, and Ais
`the thickness of the membrane.
`If a steady-state plot is extrapolated to the time axis,
`the intercept so obtained at m = 0is the lag time, L:
`= he6D
`From Eqn38.4, D is estimated provided that the mem-
`brane thickness, /, is available. Knowing these parame-
`ters and C,, and measuring di/dt, Eqn 38.3 provides one
`way ofassessing K. Eqn 38.3 shows whythis perme-
`ation procedure may be referred to as a zero-order
`process. By analogy with chemical kinetic operations,
`Eqn38.3 represents a zero-order process with a rate con-
`stant of DK/h.
`
`L
`
`(38.4)
`
`
`
`Ae Time
`
`Fig. 38.3. The time course for absorption for the simple zero-
`order flux case obtained by plotting m, the cumulative arnount of
`diffusant crossing unit area of membrane, as a function of time.
`Steady state is achieved when the plot becomes linear; extrapolation
`of the linear portion to the time axis yields the lag time L.
`
`
`Sometimes with biological membranes (suchas ti
`we camnol separate the value of D fromthat ofK. Wi
`then often employ a composite parameter, the permet)
`ity coefficient, R where P = KD or P = KD/h. The hig
`definition is used when /i
`is uncertain, e.g. diffusg
`through skin.
`
`Complex diffusional barriers
`
`Barriers in series The treatment above deals on}
`with the simple situation in which diffusion occursin|
`single isotropic medium. However, skin is a hetero
`neous multilayer tissue and in percutaneous absorplia
`the concentration gradient develops over severalstr
`Wecan treat skin in terms of a laminate, eachlayera
`which contributes a diffusional resistance, R, whicht
`directly proportional to the layer thickness, A, and is inti
`rectly proportional to the productofthe layerdiffusivity
`D, and the partition coefficient, K, with respectto th
`external phase. The total diffusional resistanceofall
`layers in a three-ply membrane such as skin (stratun
`corneum, viable epidermis and dermis) is givenby th
`expression:
`1
`h,
`hy
`hy
`t= Pi~ DR, * DR * DSK,
`Here RF,is the total resistance to permeation, P., is th
`thickness-weighted permeability coefficient, and th
`numerals refer to the separate skin layers.
`[f one segment has a much greater resistance than th
`other layers (e.g. the stratum corneum compared with th
`viable epidermis or dermis) then the single high-resist
`ance phase determines the composite barrier properties
`Then P, = K, D,/h,, where the subscript
`[
`refers to ty
`resistant phase.
`Barriers in parallel Shunts and pores. suchas hai
`follicles and sweat glands, pierce human skin (se
`Fig. 38.1).
`Investigators often idealize this comple
`structure and consider the simple situation in which th
`diffusional mediumconsists of two or more diffusiona
`pathways linked in parallel. Then the total diffusiona
`flux perunit area of composite, /,, is the sum oftheindi
`vidual fluxes through the separate routes. Thus:
`
`(83
`
`386
`p= HS t+fyd ge
`where /,, 7,, etc., denote the fractional areas for eachdif
`fusional route andJ,, J,, etc., are the fluxes perunit are
`of each separate route. In general, for independentlinea
`parallel pathways during stcadystate diffusion:
`
`(38.7,
`JrHCOoh, Pit fy Pat ...)
`where P,, P,,... represent the thickness-weightedperme
`ability coefficients.
`If only one route allows diffusant to pass, i.e. the othe
`
`routes are impervious, then the solution reduces to thi
`
`

`

`
`
`
`Effect on skin permeability
`Delivery system
`Examples/constituents
`Markedincrease
`Plastic film. unperforated water
`nost
`Prevents water lass; full hydration
`proofplaster
`
`Occlusive dressing
`
`
`
`
`
`
`
`
`
`can
`lince
`jture
`
`ure
`skin
`vent
`pt of
`
`tion
`Toss
`biate
`
`lines
`ition
`trate
`lhey
`| the
`ions,
`
`(flux
`may
`
`lter-
`
`Occlusive patch
`
`Most transdermal patches
`
`Prevents water loss: full hydration
`
`Marked increase
`
`Marked increase
`Parattins. oils, fats, waxes. fatty acids
`Prevents waterloss: may produce
`Lipophilic material
`and alcohols. esters. silicones
`
`full hydration
`Prevents water loss. marked
`Marked increase
`Anhydrouslipid material plus
`hydration
`water/oil emulsifiers
`
`
`Absorption base
`
`Anhyrous lipid material plus
`Emulsifying base
`oil/water emulsifiers
`
`
`Marked increase
`Prevents water loss: marked
`hydration
`
`
`Increase
`Retardswaterloss: raised hydration
`Oily creams
`Water/oil emulsian
`
`
`Slight increase?
`Maydonate water: slight hydration
`Aqueous creams
`Oil/water emulsion
`increase
`
`
`Humectant
`Water-soluble bases, glycerol
`May withdraw water; decreased
`Can decrease or act as
`
`glycos
`hydration
`penetration enhancer
`
`Powder
`
`Clays. organics, inorganics,
`shake lotions
`
`Aid water evaporation; decreased
`excess hydration
`
`Little effect on stratum
`comeum
`
`Diffusion coefficient
`
`Drug concentration
`
`The diffusional! speed of a molecule depends mainlyon
`the state of matter of the medium. In gases and air, dif-
`fusion coefficients are large because the void space
`available to the molecules is great compared to their
`size, and the mean free path between molecularcolli-
`sions is big. In liquids, the free volume is much smaller,
`mean free paths are decreased, and diffusion coefficients
`are much reduced.
`In skin, the diffusivities drop pro-
`sressively and reachtheir lowest values within the com-
`pacted stratum corneum matrix. For
`a 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 onthe interaction
`between them.
`However, the measured value of D mayreflect infiu-
`ences other than intrinsic mobility. For example, some
`drug may bind and become immobilized withinthe stra-
`tum corneumandthis process affects the magnitude of D
`as determined from the lag time (Eqn 38.4). However,
`regardless of such complications,
`the value of D
`measures the penetration rate of a molecule under speci-
`fied conditions andis therefore useful to know.
`
`It was seen previously that the flux of solute is propor-
`tional to the concentration gradient across the entire bar-
`rier phase (Eqn 38.3). Thus, drug permeation usually
`follows Fick’s Law. One requirement for maximal flux in
`a thermodynamically stable situation is that the donor
`solution should be saturated. A formulator can optimize
`the solubility of a drug such as a corticosteroid by con-
`trolling the solvent composition of the vehicle. Then a
`saturated solution maybe obtainedat a selected concen-
`tration of the drug by experimenting with aseries ofsol
`vents or, more usually, by blending twoliquids to form a
`miscible binary mixture with suitable solvent properties.
`Althoughthe concentration differential is usually con-
`sideredto be the driving force for diffusion, the chemical
`potential gradient oractivity gradient is actually the fun-
`damental parameter. Often the distinction is unimportant
`but sometimes we must considerit. Thus, the thermody-
`namic activity of a penetrant in the donor phase orthe
`membrane maybe radically altered by, for example, pH
`change, complex formation or the presence ofsurfac-
`tants, micelles or cosolvents. Such factors also modify
`the effective partition coefficient.
`
`577
`
`
`
`