Professional Documents
Culture Documents
Cosmet.
Chem.,32, 327-338(November1981)
Evaluation
of efficacy
of antidandruff
agents
EBERHARD FUTTERER, PH.D., Hoechst
Aktiengesellschaft,
Postfach
80 0320,D-6230FrankfurtiM.80, [VestGermany.
Received
January14, 1981.Presented
at theNationalConvention
of
theItalian Society
of Cosmetic
Chemists,
Milan, Italy,November
14,
1980.
Synopsis
The"half-head"
technique
canbeusedasa suitable
andreliable
methodforcomparative
evaluation
of the
efficacy
of antidandruff
agents.Two modesof experimental
designwhichdifferin schedule
andscoring
systemare described.
Data aregivenfor shampoos
and creamrinsescontaining
the new antidandruff
agent PIROCTONE OLAMINE [1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone
ethanolamine
salt]in comparison
to thecorresponding
nonmedicated
formulations
aswellasto thesame
shampoo
bases
containing
ZINC PYRITHIONEasa knownefficacious
antidandruff
agent.Piroctone
olaminehasbeendemonstrated
to be highlyeffectivein the treatmentof dandruffand moreeffective
thanzincpyrithione
at thesameconcentration
(p < 0.05).An appreciable
effecton skinlipidregeneration
ratecouldnot be measured.
A tentativeexplanation
for the oftenperceived
increase
in scalpandhair
oiliness
aftertheuseof antidandruff
products
isadvanced.
INTRODUCTION
328
The experimental
designin the half-headtechniqueallowsthe directcomparison
of
two products,
preferably
shampoos,
in the samesubjectat the sametimeon a double
blindbasis.
Theapplications
of theproducts,
oneproductto eachhalfof thehead,are
done by professional
hairdressers.
The selectionof the subjectswith moderateor
severedandruffand the assessment
of dandruffbeforetreatmentstarted,duringthe
testperiod,andafterthe lasttreatmentareperformedby dermatologists.
For studies
doneto satisfyregulatoryrequirements
the contralateral
siteshouldbe reserved
for a
placebo(vehiclecontrol)formulation.
In claimsubstantiation
studies
or screening
tests
it is usuallyeconomically
advantageous
to pairreference
andexperimental
samples
at
contralateral
sites.Althoughthetestpanelconsists
of onlya relatively
smallnumberof
subjects,
25to 30hasbeenfoundto beadequate,
a statistically
significant
resultcanbe
obtained.Basedon our experiencewe can recommendtwo suitableprocedural
modifications
whichdifferin the frequencyof treatment,test duration,and dandruff
scoringsystem.
PROCEDURE
A. ONCE
WEEKLY
SHAMPOOING--SIX-WEEK
SCHEDULE
Day
-7
-1
Inactiveshampoo
Testshampoo
Inactive or
Treatment
14
21
28
35
42
reference
shampoo
Grade
The subjects
of bothsexesarerandomlyallocatedto two treatmentgroupssuchthat
thegroupmeandandruffscores
performed
by oneandthesameexaminer
throughout
the trial and the numbersin the two groupsare approximately
equal.One group
received
the experimental
producton the rightsideof the headandthe othergroup
received
it on theleft side.The placeboor the reference
productwasappliedto each
headon thealternative
side.After pretreatment
with an inactiveshampoofor the first
eightdaysto achievebaselinelevelsthesubjects
arethenshampooed
onceweeklyfor
six weeks.This frequencyis usedto inducea situationwhichprovidesthe most
difficultconditionsfor the shampoo,
particularly
in suchbasictrialsin whichthe
effectiveness
of an activevs.an inactiveshampoo
(vehiclecontrol)shouldbestudied.
EFFICACY
OF
ANTIDANDRUFF
AGENTS
329
Shampooing
consists
of two latherings
with 5-10 ml shampoo
according
to thelength
andthickness
of thehairfor oneminutewith rinsingbetweenandafterwards.
Sixdays
after the pretreatment
and sevendaysafter shampooing
duringthe treatmentperiod
the degreeof dandruffis assessed
for four quadrantsof the scalpin termsof the
proportionof the scalpaffectedandseverity
usingthefollowingcriteria:
Area ofquadrantaffected
Less than 10% .................................................................
10-30% .............................................................................
30-50% .............................................................................
50-70% .............................................................................
Severity
Smallflakesresembling
a
coarsegreyishwhitepowder.......................................
1
Intermediate
...................................................................
Largeflakesveryloosely
attachedto the scalpand
givingan irregularwhitish
surface ............................................................................. 3
Intermediate
...................................................................
Flakesapparently
congealed
together
into yellowishplatesadhering
to the scalp,sometimes
with
evidenceof exudateand erythema.............................
5
B.
10 SHAMPOO
TREATMENTS--EIGHT-WEEK
SCHEDULE
330
+ = 1 = slightdandruff
(+) = 0, 2 = dandruffno longerdetectable
for testpersons;
the grader
stilloccasionally
findssome
scales
b= 0
EXPERIMENTAL
AND
= completelyfreefrom dandruff
RESULTS
Usingtheprocedures
described
on the half-head
technique
antidandruff
efficacy
trials
have been performedwith shampoosand creamrinsescontainingPIROCTONE
OLAMINE [1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone
ethanolamine salt] in comparisonwith the respectivevehiclebaseas well as to the same
shampoobasecontainingZINC PYRITHIONE (zinc 2-pyridinthiol-1
-oxide)as a
knownefficacious
antidandruff
agent(Figure1).The shampoobasecomposition
used
in the followingdescribed
testsconsisted
of:
Sodiumalkylethersulfate(28%)...............
60.0%(w/w)
Coconutfattyaciddiethanolamide
.......... 3.0%(w/w) .
Pearlescing
agentconcentrate
...................
3.0%(w/w)
Perfume.........................................................
q.s.
Sodiumchloride..........................................
q.s.
Water....................................................
ad 100.0%(w/w)
The cream rinse
basecontainedthe followingconstituents:
Cetylalcohol................................................
2.1%(w/w)
Stearylalcohol.............................................
1.6%(w/w)
Mineraloil ....................................................
1.2%(w/w)
Sodiumlaurylethersulfate(28%).............2.0%(w/w)
Sorbitol(70%)...............................................
0.5%(w/w)
Perfume.........................................................
0.4%(w/w)
Water....................................................
ad 100.0%(w/w)
Is
CH3
_.CH3
CH
32I.
0
],,C
=CHic
H
CH
3 CH2
A
O-
o .....zn -- S
H3N-CH-CHOH
EFFICACY
OF
ANTIDANDRUFF
AGENTS
331
EXAMPLE
30
Treatments
...- &
2G
22
18
14
lO
-1
14
28
42
= 0.75%PO shampoo;
&----& = placebo.
Comparison
of themeandandruffscores
observed
beforethefirsttreatment
andseven
daysafterthe lasttreatmentrevealeda meanreductionof 54.5%associated
with PO
compared
to a meanincrease
of 9.9%in dandruffon theareaof thescalptreatedwith
the inactiveshampoo.
The differences
betweenthe effectsof thetwo treatments
were
highlysignificant
on treatmentDay 14,28and42. The significance
of changes
in mean
dandruff scoreswithin treatmentas well as of differencesamong such changes
betweentreatmentswas assessed
by an analysisof varianceappropriate
to a paired
design.Furthermore
thisresultclearlydemonstrates
that the critisismof the utilization
of half-headapplications
by reasonof supposed
translocation
of the activeoverthe
scalpisnot justified
(2b).Thereasons
thatthetranslocation
of PO whichispresent
in
solubleform did not take placecouldbe the carefultestperformance
or the good
substantivity
of PO to skinandhair(7).
332
II
MeanDandruffScores
andSignificance
of Differences
Between
InitialMeanScores
andCurrentScores
After
WeeklyTreatments
DaysSinceStartof Half-HeadTreatment
a
Day - 1
Mean score
Day 14
24.3
24.4
26.8
21.7
5.2
<0.001
Initial score
minus current score
% decrease or
--2.5
increase
2.7
- 10.3
pb
11.1
<0.01
<0.01
Day 28
Mean score
Initial score
27.8
16.1
-- 3.5
8.3
Day 42
pb
26.7
11.1
-- 2.4
13.3
pb
minus current
score
11.8
<0.001
15.7
<0.001
% decrease
or increase
- 14.4
<0.001
34.0
<0.001
--9.9
54.5
NS c
<0.001
A = 0.75%
(w/w)PO shampoo
B = placeboshampoo
bHighly
significant
CNotsignificant
EXAMPLE
II
(placebo).
After latheringon both sideswith a shampoocontaining
0.2%PO and
rinsingwith wateronehalf of the headwastreatedwith a creamrinsecontaining
0.3%
PO whichwasrinsedoff ten minutesafterthe application.
In the samewaythe other
side was treated with the cream rinse base alone. From the Table III it can be seen that
afterten treatments
in 8 weeksthe percentage
reductionfrom initialdandruffscore
was92.7%usingcreamrinsewith 0.3%PO asagainst64.7%whenplacebocreamrinse
Table
III
Effectof Treatments
withShampoo
Followed
byCreamRinseonDandruff
andPercentage
Reductions
from
Initial Level After Ten Treatments
MeanDandruffScore
TestProducts
for Treatments
Shampoo 0.2%PO
Cream rinse 0.3 % PO
Shampoo 0.2%PO
Cream
rinse
(placebo)
aSignificant
(p < 0.05).A = 28.0%.
Change:
8-week/10
8-weekScore
Initial
Treatments
Minus Initial
% Decrease a
2.32
0.17
-2.15
92.7%
2.32
0.82
--1.50
64.7%
EFFICACY
OF ANTIDANDRUFF
AGENTS
333
wasused.Boththe differences
betweenthe eight-week
scoresandthe initialscoresin
the two treatmentsandthe greaterreductionassociated
with the treatmentwith cream
rinsecontaining
PO in comparison
withtheeffectof treatment
withtheplacebocream
rinseweresignificant
(p < 0.05).The statistical
analysis
wasperformedby usinga
one-sided-sign-test
considering
only thosesubjectswho exhibitscorechanges.There
is significance
whena sufficiently
largeproportionof subjectswith lower scoresis
increased.
From this trial one candeduce:1. That PO incorporated
in a creamrinse
vehicleis likewiseeffectiveagainstdandruff;2. That 0.2%PO incorporatedin a
shampoobasehasalreadya distinctantidandruffefficacy;and 3. That a combined
treatmentwith a shampoocontaining
0.2%PO followedby an application
of a cream
rinsecontaining0.3%PO hasan excellentantidandruffeffect.
EXAMPLE
Ill
ApplyingProcedureB, a comparative
trial wasperformedin 26 subjectswith PO and
ZPT, bothactiveingredients
usedin the sameconcentration
of 0.5%andincorporated
into the sameshampoobase.As Figure3 andthe datain TableIV show,both agents
Postt
Treatment
[llll
reatment
I 1
Time
(weeks)
0.5%(w/w) PO
produceda sharpandaccumulative
decrease
in averagedandruffscores,
PO havingthe
greatereffect.After eighttreatments
in a six-weekperiodthe averagegradechange
was 81.7%with PO and 68.6%with ZPT. Thesechangesin mean dandruffscores
related to the initial scores as well as the difference of 13.1% between the reduction in
dandruffassociated
with PO andthe reductionobtainedwith ZPT wereshownby an
one-sided-sign-test
to be significant
(p < 0.05).Further,this trialsrevealeda slight
increase
in dandruffaftertwo weeksof placebouseon both halvesof the scalp
previously
treatedwith activeshampoos.
Thistesthasbeenrepeatedseveraltimeswith
similar results.
334
IV
Effectof TestProducts
onDandruffandPercentage
Reduction
fromOriginalLevelAfterEightTreatments
MeanDandruffScore
a
Change
8-week
O.5%(w/w)
n = 2 with
Active
Agent
PO
ZPT
1-week
2-week
4-week
6-week
Initial n = 2
n= 4
n= 6
n= 8
0.63
0.87
0.54
0.90
0.42
0.72
2.29
2.29
1.29
1.20
Placebo from
6-week
Score
Minus
- 1.87
- 1.57
81.7%
68.6%
n = Numberof treatments
resp.posttreatments.
bSignificant
(p< 0.05).
A = 13.1%.
EXAMPLE
IV
0.50%(w/w) PO
0.75%(w/w) ZPT
Initial
2.08
2.08
6-week/8Treatments
2-week/2Posttreatments
0.54
0.62
Change
8-weekScore
MinusInitial
--1.54
-- 1.46
%decrease
74%
70%
EFFICACY
OF ANTIDANDRUFF
AGENTS
335
lOO
IPost
treatment
Treatment
80
6.0
uE
20
12
16
Time
(weeks)
Table
VI
Effectof 0.75%
(w/w)PO Shampoo
on Dandruff
in a TwelveWeekTreatment
PeriodFollowed
byFourweek Placebo Use
Treatment
Posttreatment
Initial
Mean score
4-week
2.49
8-week
12-week
4-week
1.21
0.93
0.77
0.70
- 1.28
- 1.56
- 1.72
- 1.79
51.4
62.7
69.1
71.9
Initial score
% decrease
Table
VII
Subjective
Judgement
of ScalpOiliness
After12-week
Treatment
With0.75%PO Shampoo
No. (Percentage)
of Subjects
witha Refattening
Rate
Initial
Refattening
Rate
Strong
Moderate
After
12-week
Treatment
Judged
as:
Intensified
Diminished
Unchanged
10
(52.6%)
(26.7%)
Normal
(22.2%)
336
VIII
EffectonSkinSurface
LipidsRegeneration
AfterTreatment
TwiceDailyfor FourWeekswith0.1%PO in
Aqueous
Isopropanol
Resp.withAqueous
Isopropanol
Alone
SkinSurface
LipidsLevel
120minAfterDefatting
/J,g/cm
2(t= 10)
Test Product
0.1%(w/w) PO in
5096
(w/w) aqueous
isopropanol
50%(w/w)aqueous
isopropanol
Before
Treatment
AfterTreatment
Changein Fat
Regeneration
/.tg/cm
2
40.7
36.8
-- 3.9
-- 9.6
39.1
36.1
--3.0
--7.7
thereis no significant
difference
in the effecton skinlipidsregeneration
ratebetween
the testproductandplacebo.The reductions
measured
in both casesare due to the
isopropanol
andareclinicallynot relevant.
This finding seemsto be partiallyin contradictionto the panelists'judgement
specified
in TableVII. Similarcontradictory
resultshavebeenreportedaftercontinued
useof shampoos
containing
selenium
sulfideor ZPT. Whereas
in a comparative
study
in 134 subjectsneitherseleniumsulfideshampoonor ZPT shampooproducedan
appreciable
effectonthegreasiness
of thescalp(11),therearemanyothermentions
in
the literaturethat increased
hair and scalpoilinessin a significant
numberof users
resultingfromuseof selenium
sulfideandZPT shampoos
is an importantsideeffect
(12-15).Sinceseveral
studies
haveshownno apparent
correlation
between
thelevelof
dandruffandoiliness
of the scalp(11, 16),no suitableexplanation
for thisphenomenon hasyet beenadvanced.However,it may be that the causefor the increasein
greasiness
canbereferedto a simplephysical
effect.Dandruffisthe summation
of two
processes;
an increased
productionof hornycellsand desquamation
in largerflakes.
Thesescales
or squamae
areaggregates
of coherent
hornymaterialwitha considerable
contentof lipidsexcreted
bysebaceous
glands(17).Byproducing
a greaterquantityof
hornycellsand desquamating
largescalessoakedwith lipidsa dandruffsubjectwill
consequently
losea certainamountof lipidswhichotherwise
wouldremainon the
scalpand hair when dandruffhad been controlledby the use of an efficacious
antidandruff
product.Althoughthe activeingredientactuallydid not influencethe
sebumproductionof the sebaceous
glands,the subjectmightinevitablyobserve
that
the hair becomes
greasier.
This is true particularly
for suchsubjectswhichhaveby
naturea veryoily condition.Justthat we haveseenin our study.
EFFICACY
OF
ANTIDANDRUFF
AGENTS
337
CONCLUSION
Antidandruffefficacystudieshavebeenperformedusinghalf-scalp
applications
with
differentmodifications
asto experimental
designand systemof clinicalgrading.This
techniquehasprovedto be a suitableand reliablemethodfor antidandruffefficacy
evaluation
and allowsthe directcomparative
appraisal
of efficacyof two materialson
the sameindividual.By eliminationof the effectsof changesin the individualand in
the environment
a statistically
significant
resultcanbe obtainedwith a relativelysmall
numberof subjects.
Antidandrufftrials with the new antidandruffagent PIROCTONE
OLAMINE
which is
presentin the formulations
(shampoo,
creamrinse)usedin solutionhaveshownthat
thisproductexhibitsan excellentantidandruff
effectiveness
whichsurpasses
at same
concentrationthat of ZINCPYRITHIONE
as a known efficaciousand extensivelyused
antidandruff
agent.In a sebumexcretionratestudyusinga half-sidedesignPiroctone
olaminedid not revealan appreciable
effecton skinlipidsregeneration.
A tentative
explanation
for the oftenperceived
increase
in scalpandhairoilinesss
afterthe useof
antidandruff
productscouldbe the failingof the lossof skinlipidsby desquamating
cells.
REFERENCES
(1) B. Idson,Laboratory
andclinicalevaluation
of antidandruff
preparations,
J. Soc.Cosmet.
Chem.24,
395-398(1973).
d) G. P. Heilgemeir,
Kopfschuppung
andderenquantitativer
Nachweis,
/i'rztl.Kosmetologie
9,
183-189(1979).
(3) P. Finkelstein
andK. Laden,An objectivemethodfor evaluation
of dandruffseverity,
J $oc.Cosmet.
Chem.19, 669-673(1968);F. C. Roia and R. W. Vanderwyk,Residentmicrobialflora of the human
scalpandits relationship
to dandruff,
J. $oc.Cosmet.
Chem.20, 113-134(1969).
(4) H. Tronnier,Zum Nachweisder Wirkungvon Haarbehandlungsund Pflegepriiparaten,
Parfmerie
und Kosmetik56, 31-39(1975).
(5) H. EberhardtundG. Trieb,Die Schuppendicke
alsMassfiir die WirkungvonAntischuppenprliparat-
en,,4'rztl.
Kosmetologie
9, 11-14(1979);
H. Eberhardt,
Messmethoden
zurPriifung
derWirkung
von
Antischuppenpriiparaten,
Fette-$eifen-Anstrichmitte182,
Nr. t, 37-40(1980).
(6) G. DietrichundV. BiSllert,Praxisnahe
Priifmethodef'drWirkstoffegegenvermehrteSchuppung
der
Kopfhaut,
,4'rztl.
Kosmetologie
10,34-45(1980).
(7) K. L&zschandJ. Herok, Radiometrische
Untersuchungen
zur Substantivitiit
desAntischuppenmittels Piroctonolaminan Humanhaar,Proc. 11th Intern.IFSCC Congress
"Cosmetics:
Researchand
Technology,"Venice-Lido,September
23-26,1980;Preprints--Vol.I, pp 103-125.
(8) By Prof.Dr. med.HagenTronnier,Directorof the Dermatological
Clinic,Dortmund.
(9) By Dr. VerenaKentsch,Dermatologicalandpoliclinicof the FreeUniversity,Berlin(Director:Prof.
Dr. med.G. Stiittgen).
(10) H. Schaefer,
The quantitative
differentiation
of sebumexcretionusingphysicalmethods,
J. $oc.
Cosmet.
Chem.24, 331-353(1973).
(tt) N. Orentreich,
E. H. Taylor,R. A. Berger,andR. Auerbachs,
Comparative
studyof two antidandruff
preparations,.].
Pharm.Sci.58, No. t0, 1279-1280(1969).
(12) W. R. Markland,Medicateddandruffshampoos,
NordaBrieJ5No. 473,May 1976.
338