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Cosmetics2024,11,118.https://doi.org/10.3390/cosmetics11040118www.mdpi.com/journal/cosmetics
Review
SustainableDynamicWrinkleEfficacy:Non-Invasive
PeptidesastheFutureofBotoxAlternatives
TrangThiMinhNguyen
1
,Eun-JiYi
1,2
,XiangjiJin
3
,QiwenZheng
1
,Se-JigPark
1
,Gyeong-SeonYi
1
,Su-JinYang
1
andTae-HooYi
1,
*
1
GraduateSchoolofBiotechnology,KyungHeeUniversity,1732Deogyeong-daero,Giheung-gu,
Yon gin 17104,RepublicofKorea;trangnguyen@khu.ac.kr(T.T.M.N.);0201@khu.ac.kr(E.-J.Y.);
zhengqiwen@khu.ac.kr(Q.Z.);tpwlt@khu.ac.kr(S.-J.P.);ks010924@khu.ac.kr(G.-S.Y.);stella@khu.ac.kr(S.-J.Y.)
2
SnowwhitefactoryCo.,Ltd.,184,Jungbu-daero,Giheung-gu,Yongi n06032,RepublicofKorea
3
DepartmentofPharmacology,SchoolofMedicine,KyungHeeUniversity,23Kyungheedae-ro,
Dong-daemun,Seoul17104,RepublicofKorea;hyanghe112@khu.ac.kr
*Correspondence:drhoo@khu.ac.kr;Tel .:+82-31-201-3693
Abstract:Dynamicwrinklereductioncontinuestochallengeaestheticdermatology,predominantly
addressedthroughBotulinumtoxin(Botox)injections.DespiteBotox’srobustefficacywithuptoan
80%reductioninwrinklevisibilitywithinjustoneweek,itsinvasiveadministrationandspecific
mechanismofsolubleN-ethylmaleimide-sensitivefactoraachmentproteinreceptor(SNARE)
complexinhibitionprompttheexplorationofsafer,non-invasivealternatives.Thisreviewcritically
assessesrecentinnovationsinnon-invasiveeffects,withafocusonpeptidesandbotanicalextracts
thatexhibitadiversearrayofmechanismsincludingSNAREcomplexinhibition,modulationof
calciumandsodiumchannels,andinteractionswithacetylcholinereceptors,contributingtotheir
effectivenessinmusclerelaxationondynamicwrinkleapproaches.Noteworthypeptidessuchas
ArgirelineandSYN-AkereplicatetheneuromodulatoryeffectsofBotox,achievinguptoa52%re-
ductioninwrinkleswithinfourweekswithoutinjections.Moreover,botanicalextractsmeetthe
risingdemandforcleanbeautysolutionsbyenhancingskinelasticityandhealththroughgentleyet
potentmechanisms.However,themainconcernwithpeptidesistheirlowabsorptionrate,with
onlysixclinicalvalidationsregardingBotox-likepeptideanti-wrinkleefficacyavailable.Thesead-
vancementsnotonlydeepenourunderstandingofcosmeticdermatologybutalsosignificantlyin-
fluencemarketdynamicsandconsumerbehavior,underscoringtheirpivotalroleinredefiningthe
futurelandscapeofanti-agingeffects.
Keywords:alternative;botulinumtoxins;cosmetic;dynamicwrinkle;peptide;skinaging;topical
1.Introduction
Dynamicwrinkles,aprevalentconcernindermatologicalpractice,resultfromrepet-
itivefacialexpressionssuchassmiling,frowning,andsquinting[1,2].Affectingmostly
individualsovertheageof35[3],thesespecificwrinklesincludeglabellarlines(frown
lines),nasolabialfolds,periorbitalwrinkles,andforeheadlines.Thesedifferfromstatic
wrinkles,whichariseduetoage-relateddeclinesinskinelasticityandcollagendegrada-
tion[4].Thesignificantimpactofdynamicwrinklesonaestheticappearanceandpsycho-
logicalwell-beinghighlightstheurgentneedforeffectiveapplicationswithincosmetic
dermatology.
Botulinumtoxin,commonlyknownasBotox,haslongbeenacornerstoneinthe
treatmentofdynamicwrinkles[5,6].Itsprimarymechanisminvolvesthetemporarypa-
ralysisofunderlyingmuscleactivity,whichsignificantlyreduceswrinkleformation[6–
8].Despiteitsefficacy,Botoxinjectionsareinvasiveandassociatedwithpotentialadverse
effects,includingpain,swelling,ptosis,andfacialasymmetry,occurringinupto5%of
Citation:Nguyen,T.T.M.; Yi,E.-J.;
J
in,X.;Zheng,Q.;Park,S.-J.;Yi,G.-S.;
Yan g ,S.-J.;Yi,T. -H.Sustainable
DynamicWrinkleEfficacy:
Non-InvasivePeptidesasthe
FutureofBotoxAlternatives.
Cosmetics2024,11,118.
hps://doi.org/10.3390/
cosmetics11040118
AcademicEditor:Vas il Georgiev
Received:8June2024
Revised:5July2024
Accepted:9July2024
Published:11July2024
Copyright:©2024bytheauthors.
LicenseeMDPI,Basel,Swierland.
Thisarticleisanopenaccessarticle
distributedunderthetermsand
conditionsoftheCreativeCommons
Aribution(CCBY)license
(hps://creativecommons.org/license
s/by/4.0/).
Cosmetics2024,11,1182of15
cases[9].Theselimitationsunderscoretheincreasingdemandforsafer,non-invasiveal-
ternativesinclinicalpracticetoBotoxusage.
Inresponsetothesechallenges,thefieldhasseensignificantadvancementsintopical
applicationsthatareemergingaspromisingalternatives.Amongthoseresearches,pep-
tides[10–12]andbotanicalextracts[13]representasignificantshiftincosmeticdermatol-
ogy,aimingtoprovideeffectiveanti-dynamicwrinklebenefitswithouttheneedforinva-
siveprocedureslikeinjections.Thesetopicalformulationsaredesignedtomimictheneu-
romodulatoryeffectsofBotoxwhileenhancingsafetyandaccessibility[10–13].Thesetop-
icalagentsalignwiththegrowingconsumerpreferencefor‘cleanbeauty’productsthat
utilizenon-toxicingredients[14].
Thisreviewaimstocomprehensivelysummarizethereportedefficacy,mechanisms
ofaction,safetyprofiles,andpatient-orientedoutcomesofpeptidetopicalalternativesto
traditionalBotoxinjections.Bycriticallyassessingcurrentresearchwithintheframework
ofevidence-basedcosmeticscience,thispaperseekstoelucidatethepotentialofthese
novelingredientstoredefineanti-agingpractices,specificallyinexpressionlines.Addi-
tionally,thisreviewwillexplorethesocio-economicandpsychologicalimplicationsof
moreaccessibleanti-agingeffects,providingacomprehensiveunderstandingoftheirim-
pactonthecosmeticindustryandsocietalbeautystandards.
2.ThePathophysiologyofDynamicWrinkles
2.1.MechanismsofWrinkleFormation
Dynamicwrinkles,aprominentindicatorofagingskin,resultfromtheintricatein-
terplayofneuromuscularactivities[15]andskinbiomechanics[16].Thesewrinklesare
distinctfromstaticwrinklesastheyareprimarilyformedbytherepeatedcontractionof
facialmusclesinresponsetovariousexpressions[1,2].Theformationofdynamicwrinkles
beginsdeepattheneuromuscularjunctions[15],triggeredbythedepolarizationofthe
musclecellmembrane,swiftlypropagatesalongthesarcolemma,andextendsintotheT-
tubules[16],seingthestageforfurthermuscularactivity.Understandingthisprogres-
sionprovidesvaluableinsightsintoboththenaturalagingprocessandopportunitiesfor
intervention(Figure1).
Cosmetics2024,11,1183of15
Figure1.Sequentialneuromuscularactivationanditsroleinwrinkledevelopment.Acetylcholine
releasetriggersmusclecontraction(A);calcium-mediatedmusclecontractionleadstoskindefor-
mation(B);persistentmusclecontractions(C);andstaticwrinkleformationasthemusclerelaxes
andcalciumisreabsorbedintothesarcoplasmicreticulum(D).
2.1.1.AcetylcholineReleaseandNeuromuscularActivation
Theprocessofdynamicwrinkleformationinitiatesattheneuromuscularjunction
wherethereleaseofacetylcholine,acriticalneurotransmier,iscatalyzedbyanaction
potential[17,18].Thiseventtriggerstheopeningofvoltage-gatedcalciumchannels,facil-
itatingacalciuminfluxthatpromptstheexocytosisofacetylcholineintothesynapticcleft
[15,17,19].Inthesynapticcleft,thebindingofacetylcholinetothenicotinicreceptorson
themusclecellmembraneispivotalasitinducesmusclecontraction[16,17,20]andsets
thefoundationforthenextphase,wherethedepolarizationofthemusclemembrane,en-
hancedbysodiuminflux[19,21]throughthenicotinicreceptors,facilitatesthesignificant
releaseofcalciumfromthesarcoplasmicreticulum[22,23].
2.1.2.CalciumIonReleaseandMusclePreparation
Subsequenttoacetylcholineengagement,themusclemembraneundergoesfurther
depolarizationduetosodiumionsenteringthemusclefiberandpotassiumionsexiting
intothesynapticcleft[19,21,24].Thisdepolarizationatthenicotinicreceptorsenhances
calciumreleasefromthesarcoplasmicreticulumwithinthemusclefiber[23].Thereleased
calciumbindstotroponin,causingtropomyosintoshiftandexposemyosin-bindingsites
onactinfilaments[15],anessentialstepinthecontractioncycle.Thisphaseiscriticalasit
preparesthemuscleforpreciseactivity,presentingopportunitiesfortargetedinterven-
tionstomodulatemusclecontractionsandmitigatedynamicwrinkleformation.
2.1.3.MuscleContractionandInitialSkinFolding
Thetheoryofslidingfilamentsdescribesmusclecontraction,wheremyosinheads,
energizedbythehydrolysisofadenosinetriphosphate,pullactinfilamentsinwardtoef-
fectuatecontraction[25].Musclecontractionspullonconnectivetissuefibersintheskin,
formingtemporaryfoldsthat,overtime,aresubjectedtomechanicalstress,leadingtoa
reorganizationofcollagenfibers[26,27].Thiscontinuousstresscancausethecollagento
becomemisalignedordegrade,whilefibroblastsmaydepositnew,disorderedcollagen,
permanentlydeepeningthesefolds.Understandingthisprocessiscrucialfordeveloping
effectiveinterventions,suchastopicalapplicationtoenhancecollagenalignmentorinjec-
tionstoreducemuscleactivity,aimedatreducingtheformationandpermanenceofwrin-
kles.
2.1.4.DevelopmentofDynamicandStaticWrinkles
Facialexpressions,characterizedbyrepeatedmusclecontractions,imposemechani-
calstressontheskin,initiatingtheformationofdynamicwrinkles[4].Astheskinages,
itsresiliencedecreasesduetodiminishedcollagenandelastinproduction[18,26,28],re-
ducingitscapacitytorepairmicro-damagefromcontinuouscontractions.Thisleadsto
thetransformationofdynamicwrinklesintopermanentstaticlines.Exacerbatingthispro-
cess,environmentalfactorslikeultravioletAandBexposureacceleratestructuralprotein
degradation[29].Tocounteracttheseeffects,strategiesincludingreducingmuscleactivity
throughbotulinumtoxininjections[8]andenhancingstructuralproteinlevels[26,28]in
theskinareemployedtopreserveskinelasticityandappearance.
2.2.CurrentTreatmentofDynamicWrinkles
Thepsychologicalperceptionsofaging,especiallyregardingthepresenceofdynamic
wrinkles,significantlyimpactindividuals,withmanyseekingtreatmentstomitigatevis-
iblesignsofaging[30].Traditionaltreatments,suchasbotulinumtoxininjections,have
Cosmetics2024,11,1184of15
demonstratedhighefficacy,with100%ofusersobservingsignificantdynamicwrinkle
improvementsinclinicaltrials[31],lastingfromtwotosixmonths[32].However,the
invasivenatureofthesetreatmentsandthepotentialforcomplications,whichcanaffect
upto2to16%ofpatientsaccordingtoclinicalreportsandtheUnitedStatesFoodand
DrugAdministration(FDA)database[33–36],highlightthenecessityfordevelopingnon-
invasivealternatives.Thiswidespreadconcernunderscorestheurgentneedforeffective
andsaferalternativeoptions.
Inresponsetothisdemand,emergingresearchisbeingdevelopedthataimstoreduce
theappearanceofdynamicwrinklesbyenhancingskinhealthandelasticity,withoutthe
risksassociatedwithinvasiveprocedures.Theseinnovationsfocusonadvancedpeptide
technologiesthatmimicorinhibitneurotransmiereffectsattheneuromuscularjunction,
directlytargetingtheunderlyingcausesofwrinkleformation.Offeringapromisingand
saferalternative,theseingredientsnotonlyaddressaestheticconcernsbutalsosupport
thestructuralintegrityoftheskin.Byimprovingmethodsofdeliveringactiveingredients,
thesenovelingredientsseektoeffectivelyandsafelymitigatethesignsofaging,catering
tothegrowingdemandfornon-invasivesolutionsincosmeticdermatology.
3.CurrentStandardCare:BotulinumToxin
3.1.BotulinumToxinInjection
BotoxwasdeterminedtooriginatefromananaerobicbacteriumknownasClostrid‐
iumbotulinum,andresearchersidentifiedsevendistinctsubtypesofthisbacterium,la-
beledAthroughG[37,38].BotulinumtoxintypeA,notablyBotoxcosmetic(onabotuli-
numtoxinA)[36],Dysport(abobotulinumtoxinA)[39],andXeomin(incobotulinumtox-
inA)[40],isFDA-approvedforcosmeticuseinspecificfacialapplicationswithadetailed
historysummarizedinFigure2[38,41,42].BotoxwasfirstapprovedbytheFDAin2002
forglabellarlines[43],withclinicalstudiesdemonstratingitshighefficacy,reportingthat
about80%ofrecipientsobserveanoticeablereductioninwrinkleappearancewithinone
weekofapplication[44].Subsequentapprovalsextendeditsusetoperiorbitalwrinklesin
2013[45]andforeheadlinesin2017[37],employingprecisedosagessuchas24unitsfor
periorbitalwrinklesand20unitsforforeheadlines,whichareeffectiveforapproximately
3to4monthsaccordingtoFDAguidelines[37,45].DysportandXeominfollowed,target-
ingglabellarlineswithdistinctpropertiesanddosagerecommendations,achievingsimi-
larefficacies[39,40].ClinicaltrialsindicatethatDysport,administeredviainjection,be-
ginstomanifesteffectswithinoneweek,achievinganapproximate25%enhancementin
wrinklereductioncomparedtothebaselinemeasurementsobtainedwithBotoxcosmet-
ics.Furthermore,thelongevityofDysporteffectsextendsupto20weeks,underscoring
itssuperiordurationofactioninclinicalseings[46].Inacomparativestudy,Botox
demonstratedamoresignificantreductionindynamicwrinklesthanXeomin,withno-
ticeableimprovementsfromasearlyasthreedaysandcontinuinguptofourmonths[47].
Bydaythreepost-application,65.2%ofsubjectsshowedatleasta1-pointimprovement
frombaseline,increasingto100%bydayeight,andremainingsignificantthroughweeks
20–21.Moreover,responserateswerehigherundermaximummuscletension,withover
68%ofsubjectsreportingimprovedormarkedlyimprovedplatysmalbandsatlatervisits,
withoutanyseriousadverseeventsnoted[48].FDAguidelinesensuretargetedandage-
specificuse(under65years)tomaximizesafetyandeffectiveness,emphasizingthepreci-
sionrequiredinthesetreatments[36,37,39,40,45].Despitetheproveneffectivenessofbot-
ulinumtoxintypeAinreducingdynamicwrinkles,thedemandfornon-invasivealterna-
tivescontinuestogrow,drivenbyproceduralinvasivenessandstringentcontrolsover
applicationanddosing.
Cosmetics2024,11,1185of15
Figure2.TimelineofkeydevelopmentsinBotox:inventions,approvals,andglobalmarketimpact
(1820–2030).
Botoxfunctionsbyimpedingmotorandparasympatheticnervefunctionviadimin-
ishedacetylcholinerelease(Figure3A)andevadesneutralizingantibodiesswiftly,alt-
houghtheonsetofmuscleparalysisisdelayed[49].Thisprocessismediatedbythetoxin
bindingtonerveterminals,internalization,andsubsequentdisruptionofSNAP-25(Syn-
aptosomalAssociatedProtein,25kDa),acrucialproteinintheSNARE(solubleN-
ethylmaleimide-sensitivefactoraachmentproteinreceptor)complexthatisessentialfor
synapticvesiclefusionanddockingwithotherproteinsincludingSyntaxin(at-SNARE
proteininvolvedinvesicledocking)andVAMP / s y naptob r e v in(Vesicle-AssociatedMem-
braneProtein,v-SNAREcriticalforvesiclefusion)[50,51].Clinically,Botoxcosmeticis
utilizedtodecreasemusclecontractionsbyinhibitingacetylcholinereleaseatmotornerve
terminals.Thismechanismhasbeeneffectivelyappliedindermatologytosmoothfacial
wrinklesbyrelaxingtheunderlyingmuscles.Therelaxationofthesemusclesreducesthe
appearanceofwrinklesandpreventstheformationofnewones,makingBotoxastaplein
cosmeticapplicationsforfacialrejuvenation[36,37,49].Thisapproachnotonlyenhances
aestheticoutcomesbutalsocontributestotheunderstandingofneuromuscularinterac-
tionsatthedermatologicallevel.
Figure3.Mechanismsofneurotransmierinhibitoractionindynamicwrinkletreatment.Normal
neuromuscularactivityleadingtowrinkleformation(A);botulinumtoxininhibitingacetylcholine
Cosmetics2024,11,1186of15
releasebycleavingSNAP-25(B);andtopicalalternatives(peptidesandextracts)interferingwith
acetylcholinesignalingandenhancingskinstructure(C).
AccordingtoFDAguidelines,whileBotoxisgenerallysafewhenadministeredby
qualifiedprofessionals,itcarriesariskofsideeffects[36].Commonadverseeffects,oc-
curringinapproximately1to10%ofcases,includelocalizedpain,infection,inflamma-
tion,tenderness,swelling,redness,andbruisingattheinjectionsite.Moreseriousbutless
commonrisks,affectingaround1to5%ofpatients,involveptosis,asymmetryoffacial
expressions,anddryeyesduetothespreadofthetoxintoadjacentmuscles.Inrarein-
stances(lessthan1%),patientsmightexperiencesystemiceffectssuchasdifficultyswal-
lowing,difficultybreathing,ormuscleweaknessifthebotulinumtoxinspreadsbeyond
theintendedinjectionarea[36,37,45,52].Theglobalbotulinumtoxinmarketisforecasted
toexpandfrom6.6billionUSdollarsin2023to11.68billionUSdollarsby2030,showing
stronggrowth.LeadingcontributorsincludeAllergan,knownforBotox,andMerz
Pharma,knownforXeomin,alongsideemergingAsianbrandslikeRevanceandDae-
woong.NorthAmericaleadsindemandduetoahighrateofcosmeticsurgeries,while
theAsia-Pacificregionisrapidlygrowingduetoincreasingaestheticandtherapeuticuses
ofbotulinumtoxinproducts[42,53].Botoxtreatmentsin2024,whichtypicallycostbe-
tweenUSD100andUSD2800persession,canbeparticularlyexpensiveforcomprehen-
sivetreatmentsthatcovermultiplefacialareas,withcostspotentiallyrisingtoUSD5000
ormoreforextensiveapplications[54].Thesetreatmentsmustbeadministeredbyprofes-
sionalpractitioners,highlightingtheneedformoreaccessibleandsaferalternatives.
3.2.BotulinumToxinTopicalGel
Theintroductionofbotulinumtoxinintopicalformulationsmarksasignificantde-
velopmentincosmeticdermatology,expandingbeyondtraditionalinjectablemethods.
Injectablebotulinumtoxin,whichtypicallyshowsuptoan80%reduction[44,55]inwrin-
kledepthwithin3to7daysandmaintainsefficacyfor3to4months[55],haslongbeen
establishedasaneffectivetreatmentfordynamicfaciallines.Incontrast,topicalformula-
tionsaimtoprovideanon-invasivealternativeforpatientsseekingcosmeticimprovement
withouttheuseofneedles[55–60].
Currentresearchindicatesthattopicalbotulinumtoxincandelivermodestimprove-
mentsinwrinkleappearancewithaconsiderablylowerefficacycomparedtoinjectable
forms.Studieshavedocumentedvariousoutcomesbasedontheformulationanddelivery
systemused:
Nanoparticle-basedformulations:Demonstrateda25%reductioninwrinkledepth
afterfourweeksofdailyapplication,significantlyhigherthanthe5%reductionob-
servedintheplacebogroup[55].
Liposomaldeliverysystems:Reporteda30%improvementinwrinkleseverityover
aneight-weekperiod[57].
Peptide-basedcarriers:Achieveda20%reductioninperiorbitalwrinklesaftersix
weeksoftreatment[60].
Thesegradualandlesspronouncedoutcomescatertousersdesiringsubtleaesthetic
enhancements.Suchcharacteristicsarelikelytofostergreateradherenceamongthose
whoprioritizeconvenienceandminimaldiscomfort,contrastingsharplywiththerapid
butsometimesoverlypronouncedeffectsofinjectabletreatments.Commonlyreported
disadvantagesofinjectablebotulinumtoxin,suchasproceduralpain,theneedforprofes-
sionaladministration,substantialcostsaveragingseveralhundreddollarspersession,
andpotentialadverseeffectsincludingthe‘frozen’look,aresignificantlymitigatedby
topicalformulations.Thisapproachnotonlyalignswithcurrenttrendstowardsmore
conservativecosmeticproceduresbutalsoexpandstheaccessibilityandacceptabilityof
botulinumtoxintreatments.
Cosmetics2024,11,1187of15
Mosttopicalbotulinumtoxinformulationsarestillinexperimentalorearlycommer-
cialstagesandstillrequiremedicalpractitionerapplication.Noteworthydevelopments
includeRevanceTherapeuticsRT001[57],atopicalgelformulationofBotoxcosmetic,and
AllerganBotoxTopicalGel,bothofwhichareundergoingfurtherresearchandclinical
trialstoevaluatetheirsafetyandefficacy[55].Thesecharacteristicsevokedthestudiesof
peptidetopicalalternativesandaddressedtheseconcernsbyofferinganon-invasiveap-
plicationmethodthatcanbeadministeredathome,leadingtoreducedsideeffectsand
overalllowerhealthcareexpenditure.
4.EmergingPeptideTopicalAlternatives
4.1.SyntheticPeptide
Peptidesareattheforefrontofnon-invasiveanti-agingeffects,particularlythosethat
inhibitneurotransmierrelease,offeringeffectssimilartoBotox(Table1andFigure3B,C).
Theseshortchainsofaminoacidscanrelaxfacialmusclesandreducewrinkleswithout
theneedforinjections.
Tab le1.Efficacy,timetovisibleresults,durationofeffects,commonsideeffects,andmechanisms
ofactionofBotoxandpeptidetopicalalternative.
NameBrandNameSource/
OriginMechanismofActionDurationof
Effect
ClinicalStudy
Findings
Botulinum
ToxinInjection
Botox,Dysport,
Xeomin
Clostridium
botulinum
InhibitsACh1releasebycleaving
SNAP-252,blockingmuscle
contractions
3–4months
80%reductioninwrinkle
appearancewithinoneweek;
effectslast3–4months
Botulinum
ToxinTopical
Formulations
TopicalBotoxGelBotulinum
toxintypeA
InhibitsAChreleasebytargeting
SNAP-25,blockingmuscle
contractions
Continuous
use
Nanoparticle-based
formulations:25%reduction
after4weeks;
Liposomaldelivery:30%
improvementafter8weeks
ArgirelineAcetyl
Hexapeptide-8
Synthetic
peptide
InhibitsSNARE3complexassembly,
blockingneurotransmitterrelease
Continuous
use
Reducedwrinkledepthbyupto
30%after30days
Snap-8Acetyl
Octapeptide-3
Synthetic
peptide
ExtendsArgirelineaction,inhibiting
SNAREcomplex
Continuous
use
Reducedwrinkledepthbyupto
38%after28days
LeuphasylPentapeptide-18Synthetic
peptide
Modulatesmusclecontractionby
blockingcalciumchannels,reducing
AChrelease
Continuous
use
Reducedwrinkledepthbyupto
24%after28days
VialoxPentapeptide-3Synthetic
peptide
Actsasacompetitiveantagonistat
AChpostsynapticmembrane
receptors,inhibitingmuscle
contraction
Continuous
use
Reducedskinroughnessby47%
andwrinkledepthby49%after
28days
XEP-30and
XEP-018
μ-conotoxin
CnIIIC
Synthetic
peptide
derived
from
marinecone
snailvenom
BlocksAChreleasebytargeting
NaV1.44sodiumchannels,
mimickingbotulinumtoxin
Continuous
use
Reducedwrinkledepthbyupto
48%after30days
Syn-Ake
Dipeptide
Diaminobutyroyl
Benzylamide
Diacetate
Synthetic
(Snake
venom
mimic)
AntagonizesmusclenAChRs5and
modulatesGABAA6receptors
Continuous
use
Reducedwrinklesizebyupto
52%after28days
MyoxinolHibiscus
esculentusextract
Natural
extract
Inhibitsmusclecontractionsvia
interactionwithGABA7receptors,
enhancingGABAergictransmission
Continuous
use
Reducedwrinkledepthbyupto
26%after3weeks
1ACh(Acetylcholine),2SNAP-25(SynaptosomalAssociatedProtein,25kDa),3SNARE(SolubleN-
ethylmaleimide-sensitivefactoraachmentproteinreceptor),4NaV1.4(Voltage-gatedsodium
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channel1.4),5nAChRs(NicotinicAcetylcholineReceptors),6GABAA(Gamma-AminobutyricAcid
typeA),7GABA(Gamma-AminobutyricAcid).
4.1.1.Argireline(AcetylHexapeptide-8)
PeptidessuchasArgirelinerepresentthevanguardofnon-invasiveanti-agingingre-
dients,offeringanalternativetotheneuromodulatoryeffectsofbotulinumtoxinwithout
requiringinjections.Argireline,asynthetichexapeptidedevelopedbyLipotecin2002[61],
mimicsthenaturalmechanismsofbotulinumtoxin.Structurally,itisasyntheticpeptide
derivedfromtheN-terminalendoftheSNAP-25substrateintheSNAREcomplex,crucial
forneurotransmierrelease[61–63].TheArgirelinemechanismofactionisremarkably
akintothatofBotox.
Argirelinehasbeenclinicallyvalidatedtoreducetheappearanceofwrinkles,albeit
withlessimmediateordramaticeffectscomparedtoBotox.AseminalstudybyBlanes-
Miraetal.(2002)demonstrateda30%reductioninwrinkledepthaftera30-dayapplica-
tionofa10%Argirelinesolution[61].Anotherstudyshoweda48.9%anti-wrinkleefficacy
insubjectsafterfourweeksofuse[62].Thispeptideoffersalessinvasiveapplication,
suitableforindividualsseekingsubtlecosmeticimprovementswithouttherisksassoci-
atedwithinjections.Itsefficacy,combinedwithafavorablesafetyprofile,underscoresits
utilityasaviablecosmeticpeptideforreducingsignsofaging.
Thenon-toxicnatureofArgirelinemakesitanappealingalternativefortopicaluse
[61,64].UnlikeBotox,whichinvolvespreciseinjectionandcarriesriskssuchaspotential
‘frozen’looksorotherminorsideeffects,Argirelinecanbeappliedtopicallyandabsorbed
throughtheskin,minimizingsystemiceffectsandenhancingusercomplianceduetoits
easeofapplication.Thishasledtoitsincreasedpopularityinformulationstargetedat
consumerswhoprefernon-invasiveoptions.
4.1.2.Snap-8(AcetylOctapeptide-3)
Snap-8,developedbyLipotecinthelate2000s,enhancesthepeptidesequencebyextend-
ingArgirelineeightaminoacids(Ac-Glu-Glu-Met-Gln-Arg-Arg-Ala-Asp-NH2)[65].Sucha
strategicaugmentationenhancesitsabilitytodisrupttheassemblyoftheSNAREcomplex,
criticalforneurotransmitterreleaseatneuromuscularjunctions,similartoArgireline.
TheeffectivenessofSnap-8inreducingwrinkledepth,particularlyinareaswithfre-
quentdynamicmuscleactivitysuchasaroundtheeyes,issignificant.Clinicalstudieshave
indicatedthatSnap-8canachieveuptoa38%reductioninwrinkledepthwithin28days
ofapplication,presentingitasapotentneuromodulatorypeptide[65].Thisresultsup-
portsitsutilityasanon-invasivealternativetotraditionaltreatmentslikeBotox,targeting
similarmechanismsofactionbutwithouttheneedforinjections.
Intermsofdeliveryandformulation,productscontainingSnap-8,suchaspatches,
facechallengeswithpermeabilitythroughthestratumcorneum.However,DissolvingMi-
croneedletechnologyeffectivelydeliversSnap-8totargetareas,enhancingwrinklereduc-
tionandmaintainingpeptidestabilitymoresignificantlythanBotox[12,65,66].Clinical
studiesconfirmSnap-8’sexcellenttolerabilityover12weeksandhighlightthesynergistic
effectsofformulationscombiningSnap-8withotherbioactivecompounds[66],collec-
tivelyboostinganti-wrinkleefficacy[65].
4.1.3.Leuphasyl(Pentapeptide-18)
LeuphasylisdevelopedbyLipotectomimictheeffectsofenkephalins,targetingthe
neuromuscularjunctiontomodulateacetylcholinerelease,whichiscrucialformuscle
contraction.Thisresultsinmusclerelaxation,reducingdynamicwrinkles.Leuphasylacts
byloweringcalciuminfluxatnerveendings,decreasingacetylcholinereleaseandmuscu-
larcontractions,andsharessimilaritieswiththeBotoxmechanismbutviadifferentbio-
chemicalpathways[67].CombiningLeuphasylwithArgireline,targetingdifferentmech-
anismswithintheSNAREcomplex,enhancesanti-wrinkleefficacy[68].UsingLeuphasyl
ata2%concentrationtargetingtheSNAREcomplexresultsinsignificantwrinkledepth
Cosmetics2024,11,1189of15
reductions,34.7%inthefrontalregionand28.4%intheperiorbitalarea,thus,enhancing
theefficacyagainstdynamicwrinkles[67].
4.1.4.Vialox(Pentapeptide-3)
Pentapeptide-3,marketedasVialox,isanoligopeptidedevelopedbyDSMthatmimics
theneuromuscularblockingeffectofsnakevenompeptides,notablyfromthetempleviper.
Itactsasacompetitiveantagonistattheacetylcholinepostsynapticmembranereceptor,pre-
ventingsodiumionchannelsfromopeningandinhibitingmusclecontraction.Invitrostud-
iesshowasignificantreductioninmusclecellcontraction,whileinvivostudiesindicatea
49%decreaseinwrinklesizeanda47%decreaseinskinroughnessafter28days.Vialox
effectivelysmoothsperiorbital,forehead,andnasolabialfoldwrinkles,providinganimme-
diatetighteningeffectwitharecommendedconcentrationof0.05to0.3%[69,70].However,
Vialoxrequiredfurtherclinicaltrialstoproveitseffectsonalargerpatientdemographic.
4.2.Animal‐DeviredSynthesisPeptide
4.2.1.XEP-30andXEP-018(μ-ConotoxinCnIIIC)
XEP-30andXEP-018,alsoknownasμ-conotoxinCnIIIC,areconopeptidesderived
fromthevenomofthemarineconesnailConusconsors[71,72].Thissyntheticpeptideis
renownedforitsBotox-likeeffectsandbelongstoaclassofpeptidesthathavegarnered
significantaentionfortheirpotentialinaestheticdermatologyduetotheirabilityto
modulateneuromuscularactivity.SimilartoBotox,XEP-30andXEP-018functionbyin-
hibitingthereleaseofneurotransmiersthatsignalmusclecontraction.Thisactionresults
inatemporaryrelaxationoffacialmuscles,therebyreducingtheappearanceofdynamic
wrinklesandfinelines.Thepeptidetargetsthevoltage-gatedsodiumchannels,particu-
larlytheNaV1.4channel[71],whichplaysacriticalroleinneuromusculartransmission.
AccordingtodatapublishedontheErasaSkincarewebsite,theapplicationoftheir
XEP-30serumresultedinanaveragewrinklereductionof64%acrossthesampleovera
14-dayperiod.Additionally,42%ofparticipantsexperiencedawrinklereductionof70%
orbeer,withthetopquartileseeingreductionsof90%ormore[73].Theseeffectsare
comparabletothoseachievedwithBotox,butarandomizedclinicaltrialwouldneedto
bepublishedtoreconfirmthisnumber.
4.2.2.Syn-Ake(DipeptideDiaminobutyroylBenzylamideDiacetate)
SYN-Ake,ananalogofthepeptideWagle r in- 1derivedfromthevenomoftheSouth-
eastAsianTempl eViper(Tropidolaemuswagleri),functionsbyantagonizingmusclenA-
ChRsandmodulatingGABAAreceptors[74,75].Thetripeptidelinkstoareceptorsubunit,
blockingtheaachmentofnAChR.Asaresult,theionicchannelremainsclosed,prevent-
ingtheuptakeofsodiumionsandkeepingthemusclesrelaxed.Thisactionreducesmus-
clecontractionand,consequently,theappearanceofexpressionwrinkles[68].Thisphar-
macologicalactioninhibitstheneuromusculartransmissionresponsibleformusclecon-
tractionsthatleadtotheformationofdynamicexpressionlines,particularlyintheperi-
orbitalandforeheadregions.Byblockingthesereceptors,SYN-Akeinduceslocalized
musclerelaxation,resultinginasmootherandmorerefineddermalsurface.Thistargeted
neuromodulationdecreasesthevisibilityoffinelinesandwrinkleswithoutaffectingother
cellularprocesses,therebyensuringahighsafetyprofilefortopicalapplication.Clinical
investigationshavesubstantiatedtheefficacyofSYN-Ake4%,withonestudydemonstrat-
ingthatatopicalformulationcontainingSYN-Akeresultedinareductionofwrinklesize
byupto52%overa28-dayperiod.Subjectsreportedsignificantimprovementsinskin
textureandareductioninwrinkledepth,withvisibleeffectsobservableasearlyasone
weekintotheregimen[76,77].
Cosmetics2024,11,11810of15
4.3.Plant‐BasedExtract
Myoxinol,derivedfromHibiscusesculentus,alsoknownasokra,isaplant-basedex-
tractcelebratedforitsnaturalmuscle-relaxingproperties[78].TheprimaryactionofMy-
oxinolinvolvesinhibitingthemechanicalfactorsthatcontributetoexpressionlinesand
wrinkles.TheeffectivenessofMyoxinolcanbeaributedtoitsinteractionwithGABA
receptors,similartootherflavonoids,saponins,andterpenoidsfoundinplants.These
phytoconstituentsenhanceGABAtransmission,whichresultsinthehyperpolarizationof
neuronalmembranesandasubsequentdecreaseinneuronalfiringrates,andreducesthe
contractionfrequencyofmusclefibers[79].
SeveralstudiessupporttheeffectivenessofMyoxinolincosmeticapplications.Re-
searchindicatesthatregularapplicationofMyoxinolleadstovisiblereductionsinfine
linesandwrinkles.AnotableclinicaltrialobservedthatproductscontainingMyoxinol
reducedwrinkledepthbyupto26%afterjustthreeweeksofuse[80].Theseresultshigh-
lightitspotentialasanaturalalternativetomoreinvasiveprocedures.Myoxinol’spoten-
tialisfurtherenhancedbyitsoriginfromawell-knownedibleplant,whichalignswith
thetrendtowardscleaner,safercosmeticingredients.
5.MarketInsightsandConsumerTrends
Theglobalmarketforanti-agingproducts,particularlythosetargetingdynamicwrin-
kles,isexperiencingrobustgrowth,drivenbyincreasingconsumerawarenessanddemand
fornon-invasivealternativestotraditionaltreatmentslikebotulinumtoxin.Accordingtoa
reportbyGrandViewResearch,theglobalanti-agingmarketisprojectedtoreachapproxi-
mately120billionUSDby2030,expandingatacompoundannualgrowthrate(CAGR)of
7.5%[81].Thissurgeisprimarilyfueledbytheagingpopulationandasignificantshiftin
consumerpreferencestowardssafer,non-toxic,andsustainableskincaresolutions.
Inrecentyears,therehasbeenadiscernibletrendtowards‘cleanbeauty’products,with
consumersincreasinglyoptingforskincareitemsthatarefreefromharshchemicals,which
canbeoverlyaggressiveorcausedermalirritationandaremadewithenvironmentally
friendlyingredients.MarketanalysisfromTransparencyMarketResearchhighlightsthat
over60%ofconsumersaged18to35prefertopurchaseproductslabeledas“natural”or
“organic,”atrendthatisreshapingthelandscapeofthedermatologicalcosmeticsmarket.
Thisdemographicisparticularlyinterestedinpreventativeskincareregimesthatintegrate
seamlesslyintotheirdailyroutines,furtherdrivingthedemandfortopicalalternativesthat
canmimictheeffectsofprocedureslikeBotoxwithouttheassociatedrisks[82].
Themarketforpeptidetopicalalternatives(Table2)tobotulinumtoxinhasbeen
growing,withseveralkeybrandsandproductsleadingthecharge.Argireline,developed
byLipotec(asubsidiaryofLubrizol),issoldundervariousbrandnameslikeSederma’s
Matrixylandisfeaturedinmanyhigh-endskincareproducts,contributingsignificantly
totheanti-agingsegment.Leuphasyl,marketedbyLipotec,isoftencombinedwithother
peptidesinanti-agingproducts,capturingasignificantmarketshareinpremiumskincare
lines.Theglobalcosmeticpeptidemarketisexpectedtogrowfrom244.2millionUSDin
2024to411.9millionUSDby2034,drivenbyincreaseddemandforeffective,non-invasive
skincaresolutions,particularlyintheU.S.andEurope[83].Syn-Akeishighlysoughtafter
inAsian,European,andNorthAmericanmarketsforitsinnovativeanti-agingproperties
[84].Myoxinol,fromHibiscusesculentus,isgainingtractioninthenaturalandorganicskin-
caresegment[85],drivenbyagrowingconsumerpreferenceforcleanbeautyproductsin
AsiaPacificandEurope[86].
Cosmetics2024,11,11811of15
Tab le2.Representativepeptidetopicalalternativescommercialnamesandcompanies.
Peptide/ExtractBrand/CompanyCity,Country
Argireline®Amplifiedpeptidesolution
Argireline®peptidesolutionC
Argireline®YOUthpeptide
Argirelox™peptidesolution
Inyline®peptidesolution
SNAP-8™peptidesolutionC
Leuphasyl
Argirelox
Inyline
LipotecBarcelona,Spain
Vialox
SYN-AkeDSM-FirmenichHeerlen,Netherlands
XEP-30
XEP-018ErasaXEP-30NewYork,UnitedStates
MyoxinolBASFMonheim,Germany
6.ChallengesandFuturePerspectives
Whilenon-invasiveoptionsfordynamicwrinklesarebecomingincreasinglypopu-
lar,theyfacesignificantchallengesandlimitationsthatmustbeaddressedtoimprove
theirefficacyandconsumeracceptance.Aprimarylimitationoftopicalagentsistheirin-
abilitytopenetratedeeplyenoughintotheskintosignificantlyaffectthemuscles.This
barrieroftenresultsintheseingredientsbeinglesseffective,achievingamaximumof52%
wrinklereduction[77]comparedtoBotoxinjections,whichcanachieveupto80%wrinkle
reduction[46]bydirectlytargetingneuromuscularjunctions.
Moreover,thelong-termclinicaleffectsandsafetyofmanynewpeptidesandbotan-
icalextractsusedintheseingredientsarenotwell-documented.Whileinitialresultsare
promising,comprehensivestudiesoverlongerperiodsarenecessarytoestablishtheir
safety,potentialsideeffects,andsustainedefficacy.Thisuncertaintycandeterconsumers
whoareseekingreliableandprovensolutionstotheiragingconcerns.
Themarketfordynamicwrinkleingredientsalsolacksstringentregulatoryoversight
fortopicalanti-agingproductscomparedtoinvasiveprocedures.Thiscanleadtothepro-
liferationofproductswithunsubstantiatedclaims,potentiallymisleadingconsumersand
erodingtrustinnon-invasiveingredients.
Futuretrendsinaddressingdynamicwrinklesnon-invasivelyinvolveenhancing
penetrationtechnologiessuchasmicroencapsulation,nanotechnology,andskinpermea-
tionenhancerstoimprovethedeliveryofactiveingredientstodeeperskinlayers.There
isalsogrowingadvocacyforstricterregulationsandclearerlabelingtoensureproduct
efficacyandsafety,whichcouldhelpstandardizethemarketandbuildconsumertrust.
Additionally,advancementsindermatologicalresearcharesteeringtowardspersonalized
skincareingredientstailoredtoindividualskintypes,conditions,andgeneticprofiles,po-
tentiallyincreasingtheeffectivenessoftopicaloptionsfordynamicwrinkles[87].
Researchneedstoexpandtoincludediversedemographicgroupstoensurethatap-
plicationefficacyisbroadandinclusive.Moreresearchisrequiredonhowthesetopical
agentscanbeeffectivelycombinedwithotheringredients,suchaslighttherapyorme-
chanicalstimulation,toenhancetheiranti-wrinkleeffects.Evaluatingthecost-effective-
nessofthesenon-invasiveingredientscomparedtotraditionalmethodsiscrucial,espe-
ciallysincemanyarenotcoveredbyhealthinsurance.
Byaddressingthesechallengesandleveraginginnovativetechnologiesandregula-
toryimprovements,thefutureoftreatingdynamicwrinklescanshifttowardsmoreeffec-
tive,safer,andaccessiblenon-invasiveoptions.Thisshiftpromisestorevolutionizethe
Cosmetics2024,11,11812of15
approachtoanti-agingingredientsandalignswiththeincreasingconsumerdemandfor
non-toxic,sustainable,andgentleskincaresolutions.
7.Conclusions
Therevolutionindermatologicalcareisdrivenbynon-invasivealternativestoBotox
fordynamicwrinkletreatment.Althoughpeptidesencounterdistinctscientificchal-
lenges,suchasalowabsorptionratethatsignificantlyvariesdependingonthemethodof
application,thesetopicalagentscontinuetoleadthechargebyoffering:
Effective,safersolutions:Theseingredientsmeetthegrowingconsumerdemandfor
‘cleanbeauty’products,aligningwithpreferencesfornon-toxicandsustainableskincare.
Technologicaladvancements:Innovationsindeliverytechnologiesareovercoming
challengeslikeskinpenetration,ensuringtheseingredientsarenotonlyeffectivebut
alsoreliable.
Marketexpansion:Theboomingmarket,fueledbyconsumersseekingseamlessand
risk-freeskincareroutines,highlightsthetransformativepotentialofthesealternatives.
Thisparadigmshiftpromisestosetnewstandardsincosmeticdermatology,making
anti-agingsolutionsmoreaccessibleanddeliveringprofoundsocio-economicandpsy-
chologicalbenefits.
Aut horContributions:Conceptualization,T.T.M.N.andS.-J.Y.;methodology,T.T.M.N.andQ.Z.;
software,T.T.M. N.;validation,X.J.,S.-J.P.andG.-S.Y.;formalanalysis,T.T.M.N.;investigation,G.-
S.Y.;resources,Q.Z.;datacuration,X.J.;writing—originaldraftpreparation,T.T.M.N.;writing—
reviewandediting,E.-J.Y.;visualization,T.T.M.N.andS.-J.P.;supervision,S.-J.Y.andT.-H.Y.;pro-
jectadministration,T.-H.Y.;fundingacquisition,S.-J.Y.andT.-H.Y.Allauthorshavereadandagreed
tothepublishedversionofthemanuscript.
Funding:Thisresearchreceivednoexternalfunding.
InstitutionalReviewBoardStatement:Notapplicable.
InformedConsentStatement:Notapplicable.
DataAvailabilityStatement:Notapplicable.
ConflictsofInterest:Theauthorsdeclarenoconflictsofinterest.
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