Factors influencing derm1a1I penetration of drugsl

I. Bi ological factors:
1
mical
II. Physicoche1
1. Skin, con1dition
1
factors:
I
1. Skin hydiration
2. Skin a,ge
d pH
2, Temperature an1
3. Bl1ood f101w
3.. Diffusion coefffcient
41 Regional skin site
4. Drug concentraition
5. Skin metabolism
5.. PartitioJ1 coeffic1ient
1

6. Species difference. ■._ I ll

6. · . - I . ze Ii - ' .

shape.
BIOLOGICAL FACTORS:
l ~Sltln condltlon 1

► The intact, h1 ealthy skin is a to ug·h barrie1r but acids and! alkalis
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injure bal'l'iier cellls and 'thereb·y promote penetratfo n1.

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►Mixtures of non-polar and polar solvents,, su ch as chlo1 rolorm an1d

1 1

m ethanol, remove th1e llipid fract:ion a11nd molecules 1

1 1
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pa:s·s miore easilyHI
► 1D1isease alters skin condition, skin inflamed,, with loss 0 f stratum 1

cor-neum th1us permeability increases .

>if orgain thiic kened, wlth1cams, calluses an d warts, drug permeation
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dec re a·se~
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Z. Slc1ln age
► Skiln o·f the y0 un1 and the el derly is more pe rm1
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1
eable tha1n adult 1

tissue.
► Children aire more sus1c1
eptibl e to thie t:oxic effects of dru1s land
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chemicals., because of their greater surface area per unit body

wei.ght;.thus pote·n t 'topical sterioids, Causes .severe si de-effects and
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d eat h.
1 1 1
 3.Blood flow:
►An increased blood f;low could reduce the amount of time a
penetrant remains in the dermis, and also raise the concentration
gradient across the skin.
► In clinically hyperaemic disease damages the skin barrier and
increase absorption.
4 . Regional skin sites :
► Variations in permeability depend on the thickness and nature of
the stratum corneum and the density of skin appendages.
► Absorption changes with substance, volunteer and site.
► Permeabilities depend on thickness of stratum corneum and the
overall thickness of the tissue.
► Plantar and palmar callus may be 400-600 µm thick compared to
10-20 µm for other sites.
► The hyoscine Transderm system employs in postauricular skin {i.e .
behind the ear) because the layers of stratum corneum are thinner
► Facial skin in general is more permeable than other body sites
 5. Skin m,emb alism:
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►Thie sikin m1
etabol iz,es :steroid hor,m1ones, chemic,al carcino,1e,n:s ,an d
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1
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some druss.
►·This is advantage to prodl1rulgs.
► .Skin can metabolize 5,% of topical dlrugs..

&. Spetjes di/ferenc-es:

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rats ,and ra lbblts ,are used to as,sess p ercutaneous abs01

► 1Mice., 1 1 1
rption,.
bu1t th1eir skins have m1ore ha1ir tol lliclles than lhu1man skin land they
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lack sweat gla nd.s~

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► Hairless mouse, monkey and pig skins are mos,t like that of
hu1man s,. 1

►· Hl airless rat andl fuzzy guii1nea pi,1 may b e better models for
1

h1uman.s,
:► To 01bta1in skin1penietration data1it is best to use lh 11uman ski·n
 J. Dif/uilo11n cae/fident,:
►The diffusi0nal speed 0·f a molleculle depends mainly 01 n 'the stat e of
1
1 1

matter of the 1 med1ium .

► In gases, diffusion coeffic·i e nts a1
1
re large,than liquids
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►· l 1n skin, the dli ffusiviti es reaclh1their lbwest valu es wlthi1

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1
n the,
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compacted stratum C0rnaum matrix.

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),,The diffusion coefficient. of ,a dfiug in a to1 pica1ll ve·hicile depends 0n1

the properties, of the d1 ru1 ,and the diffusion me,1
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di1um an1
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d on the
interaction between them ..
4. Drug iconcentn,t/on:
► Dru1 permeation a1 n1d fl1ux of sol1ute i's p ro portional to thie
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conce1n trati0,n gradient across the barir1

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ier.
► dru1 1 pe1 rmeation fo llaw.s, Fick s law, saturated donor solution give,s,
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maximum flux .
.
► 1pH change, comp lex form1
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n, or the presence of surfa1
a ti01 ctants1c
micell es, or co:solvenls modify th @ effective partiit i01
1 1
n coeffi1cie1n t
5. P.a·ttitian caelficie.nt(K}:
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> The partition coeffircient Is important in establishirng the flux of a

drug throu,gh the stratum corn eum~
► Drugi (K<1) are water so 1uble,, (K.>·1)1are oii l soluble t
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►· Polar CDs,alvent, m1
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·ixtures such as p1ropylene glyco:I wi1th water,

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pr0 duce siaturatedl drug solu1tions a1nd ma·ximiize the 1

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concentrati101n
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gradi ent across the stiratum cornarum.

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►· Surfact.ints d isrupti0 n1io f intercelllular lipriid 1

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e st1ratum
packing in th1
corn1eu1m, aict ars penetrat'ion E1
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nh an cers.
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► Complex formationr0f dru1 increases the appa rent partitio1

1
n
coeffici1e nt may promote drug abs,orption ~
6. Molecular slz·e and shape,:
>·Absorptio1 n is apparentl·y inversely·1 related to molll1ecular ·w·e is·h t~
► Smalll mole·cules pe1 ate fasteir than large ones~,
n1etr1
► It is 1
more d1ifficult to determ1ine the effect of' molecul ar shape, as it
1
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is related to panirtion c.oefficient.

M eth1ods of Pregaration of 0 in1tm1ents & Creams
1 1

iturati 0n
l , Tr1 1 1

2,. Fusio1
n
3.. Ch em1icall reaction
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4,. E1
mu1ll sification
Meth adis of Pre]J,aration of Pa:stes
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1.. Tri't uratian

2. Fusion
Methiod of Preparation of G1
1

els
Gen1e1ral method
1. Tritru ration Method
Widely used method!
F'o r extemporan eous pre1
1 parat1
1 1i 0n ,o f oin1t1
me·nts.

When the b1
a1se i.s soft and me,dicam1ent is solid insolulb le
1 1

Small amio unt of IH1

quid to in corporated in t'h e base
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Advanta1e·
ixins· a,sl welll as siz1e redu:c ti1011
Involves m1

Proce dure::
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1.. R.educe·th1e sollid rm edicament:to fi ne p ow·d er

1
1
1

2. Me di·cam,e nt 'is mlxed with srmalll amount of base on ointme,nt slab

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with a stainless steel srpatulla untill a homo,geneous pro1duct is

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·for,m ed.,
3 .. A.d d rema1
i nin1
g quantities of ba,se with uniform mixing

4 . lnco 17porat@ any !liquid iin1n!d.i l!nt. if 1pres1e nt

1

(m10rtar and pestlle to lbe us e d i1n case of l1arge 1quantity of lliquid)

1 1 1 1 11

E1.: 1
Pr·epare and dispense 100 ,I af ,s ulphur alnrt •m ent
1 1

R.
Sublimed sullphur, finelly sifted - 10 1
1 1

Siimple oi1
n1tment
1
- 901
Prep11re a1n alnlment
rectlan - A pply the oi1n tment to,·th1e affected area as di1rected1.
Dl1 1
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2. Fu,sio1n method:
.S,u itabl e 'When oi·ntment b ase ,c·onitains, number- of·solid in1re,dients
1
1 1 1

of diffe1rent m1elting·poi1nts..
Procedure:
1. Ointment baise are me,1lt.ed in1decr1asi1n1 order of t 1hei1r meltin1
1 1

po,irnt.

2.. H1ighest merlt.in1,g point: should be m1elted first, low m,ettiin1:point

next. ,
3. This av oids over heat,i ng a,f su11bstance,s of l10 W' mell ting point
1 1

cament slowlly to the 1mell t1e,d mass

4. lnc,arporate med i111

.5,. Stir'thor01u ghly untilll ma,ss cools d own a1

1
n1d homoseneoius
product is fonmed .
6. Liquid ingradia,nts or iaquaous sulbstanica sh01
1 1

u1ld be heated to the 1

me1lted b1a,se.s before, ad1dition.

sa11me t emperature as the 1
1

7. If not, wax or soJids wUI C0 0I dow1n quickly an1d get ,sep arated
1 1
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PreEa1utlons:
► Strriing is 1d one co,n1ti.nously- ho1m o,ge.neous mass
► Vigoiro 1us stirring sh0u1ld be avoided to p1reve1n t en'trapment: of air
1 1 1 1

,► Rap1 id cooling sh10 ulld 1b1e arvoided 't0 get a1uniforim prod1uct_
1 1 1

►To re,mo~e the dust or forei1n pa11rticles strain throu11h musH1

n1cloth
Ee: Prep,ara aind dlis pen1se liJO .I of Citrimide,ain1tment
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R.
Cetlimi de - ·1 1
1

Cet:ostearyl allc:ohol - 10 g
White so-ft paraffin -10 1 1

Uquidl para1ffin -2 9 B
1
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Pure wa·ter - SO ,I
Prac:edrulre:
t m ent ba1ses 'in decre,asin.1 order of M1Pt..
1~ Mlelrt oin1 1
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2. Dissolve cetrimide in w·ate r and heat the so1li1u ti 0 1n ,

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1
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3i Mix cetrimi,de :so lu1tion to hot molten mass and .stir.

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31. Chemica1I reactio n method
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Pre1
p1aration of some Diintment involves ch@miicall reactii ons
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!Elg - (a)lodlin:e ointment (iodi1

ne free form)
(b)l 0diilile 0intme1
1
n t (iodin e comb,ined form with101
1
i ntment b,ase,)
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lalOintments 1conlain1in1 freeriadline

► l01dine is sti·g htl'Y s oluble in faits
1
andl velgetable oils.
.
► Readil¥ solulble is potass,i um iod iide :so,lution1 in water due to
1

format1i0n1of 1
polyi,od1ides (KIii. 12• IKI.. 212_1 Kil ..312 )
►· Poly i0dides are, 1
1 1
re1dlily sollubll e in water, al co,hol rand glycer1
1 1
in ,~
► These soluti 0 1n 1s may hie incorporait ed 'With t h1
1
e 1m o1lten abs,orption
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type oi1
n1t:1 n t bas,e.
me1
l lb1J Ointm,ents containing combined lod ine 1

ixedl oils an1d ma1n1y 'f its o:btained firom vese table and anim all s01
F1 1
1 urces
contain u,nsart1
urated co,n,s,t ituents
lodi1ne combinres, witih doubl e bonds
1

HI + 12 (Olleil: acid)
CH 3 (CH 2)1 C1H:=CH {CH2 ) 7 C001

CH 3 (CH 2) 1 CHI.OHi (CH 2 ) 7 COOH (Di-i,0 d0 steari'c aciid)

1
1

1 1 1
r da1
ree iodiine is not availlable, So 0 lntm1ents, appe,a1
F1 rk, ,greeni1sh bla1ck
1

in colour
Leaves na sta,ln w1h1
e11 rubbe,d int0 tihe slkin, Hence know1n ais non-
1

stainin1 1
iodin1 ointment
4. E1
m1ulsif1
i1cation m1ethod
1. Facts, o:ils and waxes an mel1ted together 'to ,a temp eratur1@ an1d 7 00c,.
1
1 1

2. Aque,o u,s sollution of the

1 heait stabrle, 'Wate,r soluble co,m1pou,n ds i:s
1

1
also hea,t edl to, the ,s,amie temp.erature,IM
3. Aque 0 us Solution is slowly adde d to the me,lted bases, with
1 1 1

rc ontinuou's ,s tirring u1
n til ljOOIII..
m ulslfyin,s age1n t i:s nee,ded to,make a1stable ermulsion
E1 1

'Water s1oluble soap,S1aire commonly used1as emulsifier to r se1

m i,sol1idl o/w
1

emulsions..
Combirnation of t 1 nolamin1e stea11ra1te soap a1nd cetyl allcohol is used
rietha11 1

in c/w' em1ul,sion
IBee,s, wax and divalent c:alcium ions 1
us,,ed in w1/o e1m ulsion.1
 IPre,garation of Gels:
·1~ Us,u,allry pliepared by addin1 t hiicken·1ng agen1t
1

met hyl eel lu lose

ex:Tia1,aca11nth ;Carboxy1 1
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2.. Thi1cikenin1 a11en1t is, adde,d t0 aqueous solution in w 1hich dru1 has
1

t 0 be dissolved
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3jj Mass is triturated in a1mortar u1

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n1til a smiio oth 1p roduct is obta1ined
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4. When colou11
redl drug to be 'incorporated glass mortar is used
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,5. Whole grum is p1refe·rredl to powdered gurm ·t o get cl1ear

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p1 rati0n of' uniform c.o,nsi1sten1cy

repa1