Adv Ther (2022) 39:5351–5375

https://doi.org/10.1007/s12325-022-02319-7

REVIEW

Use of Retinoids in Topical Antiaging Treatments:

A Focused Review of Clinical Evidence
for Conventional and Nanoformulations
Daniela Milosheska . Robert Roškar

Received: August 17, 2022 / Accepted: September 6, 2022 / Published online: October 11, 2022
Ó The Author(s) 2022

ABSTRACT From a formulation perspective, retinoids pose a

challenge to researchers as a result of their
Nowadays, numerous skincare routines are used proven instability, low penetration, and poten-
to rejuvenate aging skin. Retinoids are one of tial for skin irritation. Therefore, novel delivery
the most popular ingredients used in antiaging systems based on nanotechnology are being
treatments. Among the representatives of reti- developed to overcome the limitations of con-
noids, tretinoin is considered the most effective ventional formulations and improve user com-
agent with proven antiaging effects on the skin pliance. In this review, the clinical evidence for
and can be found in formulations approved as retinoids in conventional and nanoformula-
medicines for topical treatment of acne, facial tions for topical antiaging treatments was eval-
wrinkles, and hyperpigmentation. Other reti- uated. In addition, an overview of the
noids present in topical medicines are used for comparison clinical trials between tretinoin and
various indications, but only tazarotene is also other retinoids is presented. In general, there is
approved as adjunctive agent for treatment of a lack of evidence from properly designed clin-
facial fine wrinkling and pigmentation. The ical trials to support the claimed efficacy of the
most commonly used retinoids such as retinol, most commonly used retinoids as antiaging
retinaldehyde, and retinyl palmitate are con- agents in cosmeceuticals. Of the other retinoids
tained in cosmeceuticals regulated as cosmetics. contained in medicines, tazarotene and ada-
Since clinical efficacy studies are not required palene have clinically evaluated antiaging
for marketing cosmetic formulations, there are effects compared to tretinoin and may be con-
concerns about the efficacy of these retinoids. sidered as potential alternatives for antiaging
treatments. The promising potential of retinoid
nanoformulations requires a more comprehen-
sive evaluation with additional studies to sup-
port the preliminary findings.

D. Milosheska Keywords: Antiaging; Clinical evidence;

INSLAB, Maribor, Slovenia Cosmeceuticals; Nanoformulations; Retinoids;
Retinol; Tretinoin
R. Roškar (&)
University of Ljubljana, Faculty of Pharmacy,
Aškerčeva cesta 7, 1000 Ljubljana, Slovenia
e-mail: robert.roskar@ffa.uni-lj.si
5352 Adv Ther (2022) 39:5351–5375

photoaging includes regular use of sunscreens

Key Summary Points and a combination of retinoids and antioxi-
dants [6, 7].
Tretinoin is the retinoid present in The retinoid family consists of both natu-
medicines for topical application with the rally occurring and synthetic analogues of reti-
strongest clinical evidence of antiaging nol (vitamin A). The anti-wrinkle effects of
activity. topically applied formulations containing reti-
noids are based on the promotion of ker-
Tazarotene and adapalene may be atinocyte proliferation and collagen synthesis,
considered as tretinoin alternatives for improvement of the epidermal barrier, inhibi-
antiaging treatments. tion of collagen degradation, transdermal water
Clinical evidence is lacking for retinoids loss (TEWL), and metalloproteinase activity
contained in cosmeceuticals for topical [8, 9]. Retinoids act through retinoic acid (RAR-
antiaging treatments. a, -b, -c) and retinoid-X receptors (RXR-a, -b, -c)
[1]. Considering the molecular structure and
Novel formulations based on receptor selectivity, retinoids are classified into
nanotechnology are being developed to four generations as shown in Table 1.
overcome the major drawbacks of retinoid After topical application, retinyl esters are
use. hydrolyzed to retinol; consequently, retinol is
Further evaluation with in vivo testing and converted to biologically active retinoic acid
clinical trials are needed to support the (tretinoin) via retinaldehyde by dehydrogenases
preclinical results for the developed in a two-step oxidation process [10, 11]. Accord-
nanoformulations containing retinoids. ing to their metabolic pathway, retinoid activity
of the first-generation representatives increases in
the following order: retinyl esters \\ retinol \
retinaldehyde \ retinoic acid, while the tolerance
ranking is reversed: retinyl esters [ retinol =
retinaldehyde [[ retinoic acid (Fig. 1) [11].
INTRODUCTION Therefore, when topically applied, retinol, reti-
naldehyde, and retinol esters must be converted
Skin aging is manifested in clinical features such to a biologically active form—tretinoin, while
as wrinkles, dermal atrophy, and decreased other retinoids are active compounds in their
elasticity as a result of various processes at the specific form [12].
molecular level stimulated by intrinsic and Tretinoin, alitretinoin, adapalene, tazar-
extrinsic sources, leading to degenerative otene, bexarotene, and trifarotene are found in
changes and decreased amount of functional topical formulations approved as medicines for
components of the skin [1, 2]. Although skin various indications such as acne or psoriasis. In
aging is a natural process due to the chrono- addition, tretinoin and tazarotene are the only
logical aging of the human body, photoaging by retinoids with approved indications for treat-
UV radiation is identified as the most important ment of photoaged skin as an adjunctive
extrinsic factor that accelerates the process treatment.
through the effects of the generated reactive Commercial cosmetics (cosmeceuticals) usu-
oxygen species [3–5]. ally contain retinol, retinaldehyde, or retinyl
Nowadays, antiaging skin treatments are a esters. The term cosmeceuticals is used for cos-
hot topic that encompasses various approaches metic products with active ingredients for
to rejuvenate and improve skin condition and which ‘‘drug-like’’ effects on skin structure and
appearance. Among the variety of treatments, function are claimed and are distinguished as a
topical retinoids are one of the most commonly subgroup between cosmetic products and topi-
used active ingredients for which there is clini- cal prescription medicines [13]. However,
cal evidence. The well-known strategy against because of their classification as cosmeceuticals,
Adv Ther (2022) 39:5351–5375 5353

Table 1 Retinoid generations

1st generation 2nd generation 3rd generation 4th generation
Tretinoin (all-trans-retinoic acid) Etretinate Tazarotene Trifarotene
Isotretinoin (13-cis-retinoic acid) Acitretin Adapalene Seletinoid G
Alitretinoin (9-cis-retinoic acid) Motretinate Bexarotene
Retinol (all-trans-retinol, vitamin A)
Retinal (retinaldehyde)
Retinyl palmitate
Retinyl propionate
Retinyl acetate
Retinyl retinoate
Retinyl N-formyl aspartamate

Fig. 1 Representation of retinoid activity and tolerance considering the metabolic pathway

no rigorous pre-market safety or efficacy testing dermatitis, the application of retinoids around
is required [14]. Because retinoids present as the eyes may cause ocular discomfort and dry
active ingredients in cosmeceuticals must be eye syndrome because of their influence on the
converted to tretinoin after application, ocular surface and meibomian gland structure
researchers question their efficacy compared to [17].
tretinoin [14]. Another issue associated with the use of
Although retinoids are among the most retinoids is potential teratogenicity. Retinoid
commonly used antiaging and depigmenting teratogenicity has been confirmed for orally
ingredients in cosmetics [15], their use is asso- ingested retinoids, while concerns about reti-
ciated with the issues of low penetration and noid embryopathy after topical application are
common side effects such as skin irritation due based on published case reports [18]. Panchaud
to their physicochemical properties and proven et al. [18] conducted a prospective, controlled,
instability. The side effects of topically applied multicenter observational study and evaluated
retinoids are generally dose-dependent and the incidence of congenital malformations
manifest as ‘‘retinoid dermatitis’’ or skin irrita- associated with topical retinoid use during the
tion at the application site [16]. In addition to first trimester. Results did not confirm an
5354 Adv Ther (2022) 39:5351–5375

increased risk of retinoid embryopathy. Other manufacturing, and diverse chemical and for-
authors also conducted meta-analyses and mulation landscape [29]. Various lipid-based
reviews of epidemiologic data and concluded delivery systems have been investigated for
that retinoid embryopathy or other adverse different retinoids [30–32]. Liposomes are the
pregnancy outcomes are unlikely with topical most studied nanomaterial [26], while hydro-
exposure during pregnancy [19, 20]. However, gels and nanoemulgels are the most promising
on the basis of current knowledge and available semisolid cosmetic formulations for dermal
data, it can be concluded that the use of topical application of lipid-based nanoparticles [33].
retinoids during pregnancy cannot be advised The lipid-based nanoparticles are considered
because of lack of evidence to support this safe colloidal carriers for the delivery of poorly
decision. soluble active ingredients through the skin,
The mechanisms of retinoid side effects at because the excipients used for the formulation
the molecular level are not fully elucidated [21]. are biodegradable and approved for topical
Generally, in cases where the active ingredient application [34, 35]. However, there is still
is used in the formulation at a low concentra- controversy about the toxicity and safety of
tion and the patient’s skin shows intolerance, it using nanomaterials in cosmeceuticals [36].
is recommended to stop retinoid treatment [22]. Although nanomaterials may be present in
Representatives of non-selective retinoids (first formulations as active ingredients, rheology
generation) are associated with a higher inci- modifiers, or carriers, their use and role in
dence of side effects [23]. marketed cosmetics generally remain undis-
Researchers are continuously focusing on the closed because of the current mistrust towards
development of new retinoid molecules and their application [26]. Usually, nanoparticles are
stable formulations that are effective and well mentioned in some technical information
tolerated to overcome the drawbacks associated about the manufacturing process or on the
with the use of retinoids. product packaging if they are intentionally
synthesized or added to the formulation [26].
Nanoformulations Consequently, the identification of commer-
cially available cosmetics based on nanotech-
Novel nanotechnology-based formulations are nology is quite challenging. Moreover, there is a
being developed and tested to improve retinoid recognized need for research into the efficacy
efficacy and overcome post-topical application and safety with precise guidelines for manufac-
problems. In general, nanotechnology approa- turing, advertising, nanotoxicological testing,
ches are used to improve the chemical and and safe use of nanocosmetics [27, 28, 33, 36,
photochemical stability of the active ingredient, 37].
increase penetration, modify its release from the In this review, the clinical evidence for reti-
formulation, and achieve satisfactory efficacy noids used for topical antiaging treatments is
with minimal skin irritation [24–26]. critically discussed. Also, an overview of the
The use of nanotechnology in antiaging comparison clinical trials between the topical
cosmetics is the fastest growing segment in the formulations with tretinoin as a gold standard
skin care industry. These formulations include and other retinoids is presented. In addition,
lipid-based, polymer-based, metal-based, and the clinical evidence for the antiaging efficacy
other nanosystems (dendrimers, fullerenes, and of recently developed retinoid nanoformula-
nanocrystals) [27, 28]. Among them, lipid-based tions is addressed.
delivery systems (solid lipid nanoparticles This article is based on previously conducted
(SLNs), nanostructured lipid carriers (NLCs), studies and does not contain any new studies
liposomes, and nanoemulsions) are considered with human participants or animals performed
advantageous compared to other nanosystems by any of the authors.
owing to their low toxicity, high drug
loading capacity, biodegradability, large-scale
Adv Ther (2022) 39:5351–5375 5355

CLINICAL EVIDENCE There is no consensus on the duration of treti-

noin therapy. It is recommended that initial
1st Generation treatment is followed by long-term mainte-
nance therapy with regular application of the
retinoid at lower concentrations and/or less
Tretinoin
frequently [46].
Tretinoin (all-trans-retinoic acid) is considered
Besides formulations with low tretinoin
the gold standard for clinically effective topical
content, nanotechnology-based formulations
retinoids used in antiaging treatments. Treti-
are also being tested to provide sustained release
noin is the most potent and best studied reti-
and minimize adverse effects. Another reason
noid for its antiaging properties [38]. Topical
for developing nanoformulations of tretinoin is
tretinoin formulations (concentrations ranging
its proven instability in the presence of light
from 0.01% to 0.1%; the most commonly used
and oxygen [48]. Isotretinoin is the main
are 0.025%, 0.05%, or 0.1%) are approved as
degradation product of tretinoin when exposed
prescription medicines for the treatment of
to light [49].
acne vulgaris, facial wrinkles, and hyperpig-
Different types of nanocarriers with tretinoin
mentation. Numerous clinical studies have
have been developed [50–60]. In most studies,
confirmed the efficacy of tretinoin in the treat-
in vitro permeation studies and drug release
ment of photoaging skin [39–45]. The long-
tests were performed. Some authors have also
term safety and efficacy of 0.05% tretinoin in
performed in vivo skin irritation tests in rats
the treatment of moderate to severe facial
[50, 56] or rabbits [52] comparing the developed
photodamage were evaluated in a 2-year pla-
nanoformulations with conventional formula-
cebo-controlled clinical trial involving 204
tions containing tretinoin. Overall, prolonged
subjects [45]. The study results suggest that
release of the active ingredient, improved sta-
long-term use of 0.05% tretinoin emollient
bility, and reduced irritation were achieved. In
cream with a once-daily application is a safe and
addition, Yamaguchi et al. [56], who developed
effective treatment.
CaCO3-coated nanomicelles containing treti-
Although the most commonly used formu-
noin, evaluated the anti-wrinkle properties of
lations for the treatment of aging skin contain
the formulation by performing in vivo study in
0.05% tretinoin, the optimal concentration,
mice. The results showed better pharmacologi-
application regimen, and duration of treatment
cal effects of the nanoformulation (0.1%) com-
must be individualized by considering the bal-
pared to the tretinoin–Vaseline ointment
ance between efficacy and irritation [12]. Gen-
(0.1%), including thicker epidermis and over-
erally, tretinoin at a concentration of 0.025% is
expression of heparin-binding epidermal
considered therapeutically effective with a rea-
growth factor mRNA as well as increased pro-
sonable safety profile [46]. Because the retinoid
duction of hyaluronan between epidermal lay-
response is dose-dependent, some studies com-
ers [56].
pared the performance of formulations with
Nasrollahi et al. [60] also studied for the first
different concentrations [42–44]. Generally, the
time in vivo the safety of two formulations
formulations with lower concentrations resul-
containing tretinoin (0.05%)—nanoemulsions
ted in less pronounced but significant
and NLCs—by conducting a 1-week controlled
improvement in the clinical and histologic
clinical trial with 20 volunteers. The tested for-
characteristics of the treated photoaged skin
mulations were reasonably safe for topical
with a lower incidence of adverse effects com-
application on the basis of the evaluated
pared to the higher concentrations. To avoid a
parameters: skin pH, erythema index, skin
retinoid dermatitis reaction, it is recommended
hydration, and TEWL. Similarly, Lima et al. [55]
to start treatment with a lower concentration of
conducted a clinical study and evaluated skin
the active ingredient and gradually increase the
irritation of the developed gel formulation
concentration to a tolerable level by using
containing tretinoin NLCs (0.05%) compared to
moisturizers to keep the skin hydrated [47].
the marketed tretinoin (0.05%). Twenty-eight
5356 Adv Ther (2022) 39:5351–5375

participants were enrolled in the study over a potential and physicochemical instability [67].
4-week period, and by measuring TEWL, as a Therefore, some authors have developed
non-invasive physiological measure of skin nanoformulations with isotretinoin to over-
barrier function, it was shown that skin irrita- come the problems associated with the use of
tion was higher with the conventional tretinoin conventional topical formulations, but most are
formulation. Since the performed studies intended for acne treatment [67–73].
included only a small number of participants Raza et al. [69] developed a hydrogel for-
over a short time with application to the fore- mulation containing isotretinoin-loaded NLCs
arm, the formulations need further (0.05%) for the treatment of photoaged skin.
investigation. The formulation was evaluated by in vivo study
The main goal of developing innovative for its antiaging efficacy on extrinsically pho-
nano-delivery systems containing tretinoin is to toaged mouse skin by assessing the biochemical
provide a safe formulation with satisfactory user and macroscopic properties of the skin in
compliance [61]. However, to date, there is no comparison to two commercially available for-
commercially available nanoformulation with mulations containing tretinoin and isotretinoin
tretinoin on the market. [69]. The nanoformulation with isotretinoin
was better tolerated and more effective com-
Isotretinoin pared to the evaluated commercial formula-
Isotretinoin is a cis-isomer of retinoic acid tions. However, the concentration of the active
approved for oral administration in capsules for ingredients in the compared formulations was
the treatment of acne, with a well-documented not clearly stated. Further studies are needed to
adverse effect profile ranging from xerosis to confirm the promising potential of the devel-
teratogenicity [62]. The efficacy of isotretinoin oped nanoformulation.
(0.1% or 0.05%) for topical application in anti-
aging treatments of photodamaged skin has Alitretinoin
been investigated in several studies [63–66]. Alitretinoin is a retinoid that binds to all sub-
Maddin et al. [63] conducted a 36-week, multi- classes of RARs and RXRs [74]. Alitretinoin gel at
center, double-blind, placebo-controlled study doses of 0.1% and 0.05% is approved as a
with 800 patients and showed that the appli- medicine for the topical treatment of Kaposi’s
cation of 0.1% isotretinoin cream improved the sarcoma. To our knowledge, the efficacy of 0.1%
overall appearance of photodamaged skin alitretinoin gel in the treatment of photoaged
compared to the vehicle-controlled group. skin has been studied only in one small,
Similar results were presented by Griffiths et al. 16-week open-label pilot study with 20 partici-
[66], who conducted a 6-month, multicenter, pants [75]. The formulation improved evaluated
randomized, double-blind, vehicle-controlled skin parameters, but with a high incidence of
clinical trial involving 346 subjects with pho- side effects.
todamaged skin. It was confirmed that the
application of 0.05% isotretinoin in combina- Retinol
tion with sunscreens improved the appearance Retinol is a compound with multifunctional
of the fine wrinkles associated with photoaged effects on photodamaged skin, including
skin [66]. The results were consistent with pre- induced production of hyaluronic acid, colla-
viously performed studies by other authors gen, and elastin, as well as epidermal prolifera-
[64, 65]. It can be concluded that most of the tion and differentiation [76–78].
performed studies about topical application of Compared to tretinoin, retinol is about ten-
isotretinoin for photodamaged skin showed fold less potent [10, 14]. For example, retinol at
statistically significant improvement in the a concentration of 0.25% is considered to be as
overall appearance of the skin including fine effective as 0.025% tretinoin, without signifi-
lines and pigmentation. cant side effects and irritation [79]. The maxi-
However, the use of topical isotretinoin for- mum recommended concentration of retinol in
mulations is limited because of skin irritation
Adv Ther (2022) 39:5351–5375 5357

hand and face creams and other leave-on or two-fold lower compared to tretinoin. Addi-
rinse-off cosmetics is 0.3% [80]. tionally, the efficacy of 0.1% retinol formula-
Compared to other retinoids in cosmeceuti- tion in the reduction of facial wrinkles was
cals, retinol is the most evaluated by random- confirmed by facial image analysis in a 12-week
ized, double-blind, vehicle-controlled, whole, study that included 41 healthy women [89]. The
or split-face clinical trials [81]. Formulations study did not include a control group.
with different retinol concentrations (from Retinol is often combined with other active
0.075% to 0.5%) have been evaluated for their ingredients to achieve synergistic effects and
antiaging efficacy. Some authors reported sta- positive clinical results. Bouloc et al. [90] com-
tistically significant improvements in the pared the efficacy of a commercial cosmetic
assessed parameters compared to vehicle product with 0.2% retinol and 2% tetrahydro-
[82–85], while others did not confirm positive jasmonic acid to a 0.025% tretinoin formula-
treatment outcome [86]. However, as suggested tion. Results indicated that formulations
by Spierings [81], considering the limitations of provided comparable effects but the retinol
the performed studies, the wide range of con- formulation was better tolerated and perceived
centrations used, and the declared conflicts of by participants (Table 2).
interest in the sponsored studies, it is ques- Recently, Chien et al. [91] published a study
tionable whether the positive study results truly in which a topical formulation containing a
reflect the efficacy of the active ingredient in combination of three retinoids (1.1%: retinol
the product. (1%), retinyl acetate (0.05%), and retinyl
To prove the efficacy of retinol, some authors palmitate (0.05%)) was compared in terms of
have also conducted comparison clinical studies antiaging efficacy and tolerability with a topical
with tretinoin. Babcock et al. [87] conducted a tretinoin formulation (0.02%), involving
clinical study and compared the efficacy of patients with moderate to severe facial photo-
three sustained-release cosmetic formulations damage. The study suggests that cosmeceuticals
containing 0.25%, 0.5%, or 1.0% retinol with containing a combination of retinol and retinyl
prescription creams containing 0.025%, 0.05%, esters may have a comparable antiaging effect
or 0.1% tretinoin. No statistically significant to tretinoin (Table 2).
differences were found in the assessed efficacy Performed clinical studies for the antiaging
parameters between retinol and tretinoin for- efficacy of retinol have limitations including
mulations [87] (Table 2). Recently, a 12-week, small sample size and lack of a vehicle control
double-blind, controlled clinical trial was per- group which limits the robustness of the results
formed comparing the performance of three and the validity of the conclusions. Studies for
retinol serums (0.25%, 0.5%, 1.0%) and treti- topical treatments need to be vehicle controlled
noin creams (0.025%, 0.05%, 0.1%) by follow- as vehicle alone can also produce significant
ing a step-up protocol to increase the dose of improvements on the skin [81]. However, in
the applied formulation in combination with a practice vehicle-controlled clinical studies are
moisturizer [88]. The retinol formulations per- rare.
formed equivalent to or better than the treti- The need for stabilization of retinol formu-
noin creams. lations is well known because of its sensitivity to
Kong et al. [89] evaluated the effects on the light, oxygen, heat, and heavy metals [80, 92]. A
epidermis of the weekly application of 0.1% recent study that evaluated the stability of 12
tretinoin, 0.1% retinol, and a base formulation commercially available products with declared
on the forearm under occlusion for 1 day during retinoids confirmed the instability of retinoids
a 4-week period in six participants. Compared in almost all cosmetic products by long-term
to the vehicle control group, both 0.1% retinol and accelerated stability testing [92]. It is rec-
and 0.1% tretinoin formulation significantly ommended that retinol in cosmetics is stabi-
increased epidermal thickness and upregulated lized through appropriate formulation, since
the genes for collagen type I and III [89]. How- retinol in cosmetic formulations is generally
ever, the retinol effects were approximately stable for less than 6 months if manufactured
Table 2 Comparison clinical studies: tretinoin vs other topical retinoids in retinoid formulations used in facial antiage treatments
5358

Retinoid Clinical study Duration Subjects Comparison Evaluated parameters Results References
Retinol Randomized, 12 weeks 65 Retinol 0.25%, 0.5%, and Overall photodamage, fine Statistically significant [87]
double-blind, 1.0%, vs tretinoin lines/wrinkles, coarse improvements from
split-face 0.025%, 0.05% and lines/wrinkles, skin tone baseline in all efficacy
comparison 0.1% brightness, mottled parameters. No
clinical study pigmentation, tactile statistically significant
roughness differences in efficacy
between the formulations
was observed
Retinol Randomized, 3 months 120 Retinol 0.2%/ Clinical efficacy evaluations Both products improved [90]
parallel, double- tetrahydrojasmonic of wrinkles (frontal and considerably wrinkles,
blind, whole-face, acid 2% cream vs glabellar area, eyes area, mottled pigmentation,
controlled clinical tretinoin 0.025% cream nasolabial fold), pores, pores, and global
study mottled pigmentation and photodamage. No
global photodamage statistically significant
Three-dimensional differences between both
measurements of the products were observed
periorbital skin relief
(wrinkles, fine lines, and
skin texture) was
performed
Retinol Double-blinded, 24 weeks 24 Formulation with retinol Wrinkles, pigmentation, No significant differences in [91]
single-center, (1%), retinyl acetate yellowing, and overall efficacy between the
parallel-arm, (0.05%), and retinyl clinical severity of the retinoid formulation and
whole-face, palmitate (0.05%) vs photodamage as scored on tretinoin 0.02% in
comparison study tretinoin 0.02% the Griffiths scale for Griffiths photoaging
assessment of the global scores
photodamage
Adv Ther (2022) 39:5351–5375
Table 2 continued
Retinoid Clinical study Duration Subjects Comparison Evaluated parameters Results References

Retinaldehyde Randomized, 44 weeks 125 Retinaldehyde 0.05% vs Optical profilometry of skin Significant reduction of the [107]
double-blind, tretinoin 0.05% vs silicone replica, assessing wrinkle and roughness
vehicle-controlled, vehicle for deepness and features
whole-face clinical roughness of the wrinkles No statistically significant
trial
Adv Ther (2022) 39:5351–5375

differences between the

treatment groups at any
assessment time point was
observed
Retinaldehyde Randomized, 12 weeks 30 Retinaldehyde proretinal Evaluation of skin aging Retinaldehyde [110]
double-blind, hydrogel containing (fine lines and wrinkles) nanoformulation showed
split-face 0.025% retinoid vs and seven skin parameters, better antiaging efficacy in
comparison study 0.025% tretinoin namely surface, volume, the evaluated parameters
hydrogel energy, entropy, compared to tretinoin
homogeneity, contrast,
and variance values
Adapalene Multicenter, 24 weeks 128 0.3% adapalene gel vs Evaluation of the global Significant improvement of [158]
randomized, 0.05% tretinoin cream cutaneous photoaging, the evaluated parameters:
investigator- periorbital and forehead global cutaneous
blinded, whole- wrinkles, ephelides/ photoaging, periorbital
face, parallel- melanosis and actinic and forehead wrinkles,
group comparison keratosis ephelides/melanosis, and
study actinic keratosis
No statistically significant
difference between the
treatments was observed
5359
Table 2 continued
5360

Retinoid Clinical study Duration Subjects Comparison Evaluated parameters Results References

Tazarotene Prospective weekly 24 weeks 349 0.01%, 0.025%, 0.05%, Fine wrinkling, mottled Significant improvement [150]
multicenter, and 0.1% tazarotene hyperpigmentation, was observed for the
investigator- cream vs 0.05% lengthiness, irregular mottled
masked, whole- tretinoin emollient vs depigmentation, tactile hyperpigmentation, fine
face, randomized, vehicle roughness, coarse wrinkling, and the overall
vehicle-controlled, wrinkling, telangiectasia, integrated assessment of
parallel group pore size, elastosis, actinic the individual signs of
study keratoses, and overall photodamage compared
integrated assessment of to vehicle. Tazarotene
the individual signs of 0.05% and tretinoin
photodamage 0.05% produced
comparable results.
Tazarotene 0.1% was the
most effective among the
tested formulations
Tazarotene Multicenter, double- 24 weeks 173 0.1% tazarotene vs 0.05% Fine wrinkling, mottled Tazarotene 0.1% cream [151]
blind, tretinoin emollient hyperpigmentation, coarse offers significantly faster
randomized, cream wrinkling, irregular improvement compared
whole-face, depigmentation, to tretinoin 0.05%
parallel-group lentigines, elastosis, tactile emollient cream in the
study roughness, telangiectasia, treatment of
and actinic keratoses photodamaged skin
Tazarotene efficacy was
significantly better for fine
wrinkling and the overall
integrated assessment of
photodamage, mottled
hyperpigmentation, and
coarse wrinkling
Adv Ther (2022) 39:5351–5375
Adv Ther (2022) 39:5351–5375 5361

under an inert atmosphere and stored, for Clinical studies evaluating the antiaging
example, in aluminum tubes at 20 °C or below effects of nanoformulations containing retinol
[80]. Considering that such products are not are lacking.
manufactured and stored in this way in prac-
tice, the validity of the results from the per- Retinaldehyde
formed studies is questionable and cannot be As a natural precursor of retinoic acid with a
attributed solely to the retinol effect [81]. favorable activity/tolerance ratio after topical
However, the stability of retinoids in cosmetics application, retinaldehyde is considered the
is formulation-dependent and must be evalu- most effective retinoid in cosmeceuticals
ated on a case-by-case basis [92]. In addition, [11, 99, 100]. Oxidation of retinaldehyde to
Temova Rakuša et al. [93] evaluated the con- tretinoin is differentiation-dependent and more
tent-related quality of 35 commercially avail- efficiently performed by differentiated ker-
able cosmetic products containing retinol and atinocytes [101, 102]. The low irritation profile
other retinoids (mainly retinyl palmitate) and of retinaldehyde is due to the limited capacity
found significant inconsistencies in labeling of keratinocytes, since topically applied reti-
and deviations from the declared content, e.g., naldehyde does not bind to retinoid receptors,
a very low content or a much higher concen- but is predominantly converted to retinyl esters
tration than the maximum concentration rec- and only a small fraction is metabolized to tre-
ommended by the Scientific Committee on tinoin, which is responsible for the biological
Consumer Safety at the European Commission. activity [101, 103]. It is considered that skin
Considering the study findings and the fact that irritation is partly a result of the receptors’
most cosmetic products do not indicate the ‘‘overload’’ with non-physiological amounts of
active ingredient content on the packaging, exogenous tretinoin [102] and with retinalde-
which is important for assessment of the pro- hyde as a precursor this process is prevented
duct safety and efficacy, stricter regulations and [100, 101].
quality controls are recommended [93]. Compared to retinol esters, the efficacy of
Different methods are being investigated to retinaldehyde in antiaging treatments is sup-
improve the stability of retinol cosmetic for- ported by stronger evidence. Several studies
mulations, including nanotechnology. Conse- evaluated the efficacy of retinaldehyde on aged
quently, various nanoformulations with retinol and photoaged skin [104–106]. Only Creidi
have been developed [94–98]. Boskabadi et al. et al. [107] performed a comparison clinical
[94] developed SLNs with retinol (0.5%) by study and evaluated the efficacy and tolerability
ultrasonication procedure and incorporated of 0.05% retinaldehyde cream compared to
them into gel formulations. The results of the 0.05% tretinoin cream and vehicle in patients
in vitro cytotoxicity, in vitro permeation, and with photodamaged skin (Table 2). Both for-
in vivo skin irritation testing in rats were mulations were effective on the basis of the
favorable, suggesting that SLNs could be suit- assessed changes of the wrinkle and roughness
able carriers for topical delivery of retinol. Jun features, but tretinoin caused more local irrita-
et al. [96] developed a cream containing vac- tion and lower compliance in patients. How-
uum-assisted lipid nanoparticles with retinol ever, no statistically significant differences in
(0.1% or 0.3%) and evaluated the permeation assessed parameters were observed between
properties of the formulation in an in vitro retinaldehyde and tretinoin or between reti-
study on porcine skin and its effects on a naldehyde and vehicle group (Table 2).
reconstructed 3D human skin model. The Recently, Kwon et al. [108] conducted a
developed formulation with retinol-loaded lipid 3-month randomized, double-blind, controlled
nanocarriers exhibited beneficial properties clinical trial comparing the efficacy of 0.1% and
such as improved penetration, low irritation 0.05% retinaldehyde creams in 40 women. The
profile, and increased epidermis thickness data showed improvement in photoaged skin in
compared to the other tested formulations in terms of hydration, wrinkles, skin roughness,
the study [96]. and reduction in TEWL, although no vehicle
5362 Adv Ther (2022) 39:5351–5375

control group was included. The only statisti- Further studies are needed to evaluate the
cally significant difference between the two clinical efficacy of retinaldehyde in various
groups was observed in the melanin index, cosmetic formulations.
which was higher in 0.1% retinaldehyde group
[108]. Retinyl Palmitate
Formulations containing retinaldehyde at a Retinyl palmitate (RP) is the most abundant
concentration of 0.05% are considered effective form of retinol esters found endogenously in
and well tolerated [100]. Topical application of the skin [113]. As a thermally stable alternative
retinaldehyde, even when applied at higher to retinol, it is widely used in antiaging cos-
concentrations or during a longer period, is also metics. However, compared to retinol, RP is
not associated with detectable change in the more prone to photodegradation [114]. It has
constitutive levels of plasma retinoids due to been shown that RP can be a prooxidant under
skin metabolism [109]. Retinaldehyde is also a certain conditions, such as photo-irradiation,
highly unstable molecule prone to autooxida- through its toxic photodegradation products,
tion and photooxidation [110]. Various formu- generation of reactive oxygen species, induc-
lations based on nanotechnology are being tion of lipid peroxidation, and DNA damage
developed for retinaldehyde as a compound [113, 115]. In addition, there is evidence that
with high antiaging potential and physico- topical application of cosmetics containing RP
chemical instability. may enhance UVR-induced photococarcino-
Pisetpackdeekul et al. [110] developed genesis [116]. The long-term consequences of
proretinal nanoparticles for controlled release the use of RP-containing cosmetics have not
of retinaldehyde by grafting retinaldehyde on been thoroughly investigated [117]. However,
chitosan. The formulation was stability tested on the basis of current knowledge and available
and evaluated for its irritation potential and data, RP is considered a safe cosmetic ingredient
histological changes in the skin by performing when used in current practice and at the rec-
tests on rats and human volunteers. In addition, ommended concentrations of 0.05% in body
the antiaging efficacy of the hydrogel formula- lotions and 0.3% (retinol equivalents) in creams
tion with proretinal nanoparticles was evalu- and leave-on or rinse-off products [80]. RP at a
ated in comparison with a 0.025% tretinoin concentration of 0.6% is half as active com-
hydrogel (Table 2). The controlled release of the pared to 0.25% retinol [79].
active ingredient resulted in improved stimula- No published clinical study has exclusively
tion of the epidermal proliferation with mini- investigated the use of RP as an antiaging agent
mized side effects [110]. Similarly, by under normal conditions of use. There is also
performing an in vitro cytotoxicity study on only one published study that compared the
keratinocytes, an in vivo skin irritation, and a antiaging effects of two different commercial
biological activity study on rats’ skin, Lim- cosmetic products containing RP [118]. How-
charoen et al. [111] suggested that proretinal ever, the RP content in the formulations was
nanoparticles can be used as an effective system not disclosed. In general, most of the studies
for sustained delivery of retinaldehyde. that evaluated the efficacy of retinol esters as
Nayak et al. [112] developed NLCs loaded antiaging agents in cosmetics have method-
with coenzyme Q10 and retinaldehyde (0.05%) ological issues and limitations [119, 120].
and evaluated the efficacy and safety of differ- Therefore, there is a clear lack of evidence from
ent formulations with in vitro release and adequately designed and controlled clinical tri-
cytotoxicity, ex vivo skin permeation, and als to support the use of RP for antiaging
in vivo skin irritation and therapeutic efficacy purposes.
testing on wrinkles in mice. The NLCs gel for- Nevertheless, RP is a very popular cosmetic
mulation with both active ingredients showed a ingredient and there is ongoing research to
significant reduction in wrinkles and better improve its stability and efficacy through various
safety profile than other tested formulations. formulation approaches, including nanoformu-
lations [54, 121–128], microencapsulation
Adv Ther (2022) 39:5351–5375 5363

[124, 129], or combination with other ingredi- compared to retinol and RP, as shown by Bjerke
ents such as pectin [124, 130]. Most of the et al. [132] in in vitro and ex vivo skin models. It
developed formulations have been evaluated is also the first retinyl ester that has been clini-
by various in vitro or ex vivo tests, including cally evaluated by Green et al. [133], who per-
release and skin permeation studies [54, 121, formed a double-blind, randomized, placebo-
124, 125, 127, 128, 131], skin irritation test controlled 48-week study with retinyl propi-
[123], in vitro safety profile and in vitro antioxi- onate cream (0.15%). Although minimal
dant activity [126]. Some authors went a step improvement trends were noted in photoaged
further and evaluated the developed formulations skin, no statistically significant effects were
with in vivo studies. Jeon et al. [128] developed observed compared to vehicle. Some studies
SLNs with RP and incorporated them in hydrogel showed that combining retinyl propionate with
(1000 IU/g and 2500 IU/g as active vitamin A, RP other agents may increase its efficacy in anti-
content). The formulations were evaluated with aging treatments [134, 135]. To our knowledge,
in vivo anti-wrinkle study in mice. On the basis of no published studies are addressing the incor-
the results, it was suggested that SLNs with RP can poration of retinyl propionate into nanotech-
be used for the development of effective anti- nology delivery systems. In light of recent
wrinkle formulations. Moreover, Pena-Rodrı́guez findings identifying retinyl propionate as a
et al. [122] developed transfersomes with RP compound with pronounced antiaging poten-
(1.1%) integrated into liposome membrane with a tial, further research is needed.
predicted shelf life of 36 months. The in vitro
study showed increased penetration of RP into the Retinyl Acetate
skin compared to the formulation with free RP. In Retinyl acetate is a popular retinoid derivative
addition, an in vivo study including six volunteers used as a commercial cosmetic ingredient in
evaluated the compatibility with the skin of the antiaging products [136]. To date, no published
emulsion prepared with RP transfersomes (0.55%) clinical study has evaluated the antiaging effi-
[122]. Measurements of TEWL and penetration of cacy of retinyl acetate as a single active ingre-
RP into the stratum corneum showed that the dient in a topical formulation. Retinyl acetate
emulsion with RP transfersomes did not affect the has been studied as a cocarcinogen, but the
skin integrity. All studies performed showed current evidence on its effects on photocar-
beneficial properties of the developed topical cinogenesis does not provide a consistent
nanoformulations such as improved formulation mechanistic explanation for the results of dif-
stability, higher penetration, and low skin irrita- ferent studies [115]. Arayachukeat et al. [136]
tion. Similar to other retinoids contained in developed polymeric nanoparticles containing
nanoformulations, comprehensive in vivo and retinyl acetate to improve the photostability of
clinical studies of RP formulations are needed, as the compound. The results showed that the
most published studies include only in vitro delivery of retinyl acetate to the dermis could be
evaluations. achieved by a suitable polymeric carrier.
Interestingly, there is no published, well-de-
signed clinical study that confirms the antiag- Retinyl Retinoate
ing effects of RP on the skin, but compared to Retinyl retinoate was synthesized by a conden-
other retinoids, it is a very popular compound sation reaction between retinol and retinoic
for developing new formulations. Overall, there acid to achieve improved photostability [137].
is a lack of clinical evidence supporting the use The compound is considered more stable and
of RP as an antiaging agent in both conven- less irritating compared to other first-generation
tional and nanoformulations. retinoid derivatives with comparable ability to
induce hyaluronan production [138]. The effi-
Retinyl Propionate cacy of retinyl retinoate in the treatment of fine
Retinyl propionate is a retinyl ester that is wrinkles in photoaged skin is also supported by
considered to have a stronger retinoid activity clinical data [139–141]. Considering that the
5364 Adv Ther (2022) 39:5351–5375

performed studies have limitations, including a with mild to moderate adverse effects [146].
small sample size, further studies are needed to Kang et al. [147] conducted a 24-week, multi-
prove the potential of retinyl retinoate as an center, double-blind, randomized, vehicle-con-
antiaging agent. trolled, parallel-group study involving 568
Lee et al. [142] developed different nanofor- patients with photodamaged skin. The once-
mulations with retinyl retinoate and investi- daily 0.1% tazarotene cream was significantly
gated in vitro the active ingredient release. The more effective than the vehicle in reducing fine
study suggests that NLCs may be a suitable de- wrinkles, mottled hyperpigmentation, lentigi-
livery system for topical application of retinyl nes, irregular depigmentation, apparent pore
retinoate. size, elastosis, tactile roughness, and the overall
assessment of photodamage [147]. The results
Retinyl N-Formyl Aspartamate were consistent with the previously published
Retinyl N-formyl aspartamate is a retinoid studies [148, 149].
derivative with higher photostability and lower Some authors also performed clinical com-
irritation potential compared to retinol [143]. parison studies with tretinoin. Kang et al. [150]
Its efficacy on photoaged skin was investigated conducted a clinical study and compared the
in a 24-week, prospective, single-blind, ran- efficacy of different concentrations of tazar-
domized, controlled split-face study with 24 otene creams with 0.05% tretinoin cream. The
participants [144]. The retinyl N-formyl aspar- 0.1% tazarotene cream was as effective as stan-
tamate cream was well tolerated when applied dard tretinoin cream and produced only mild to
twice daily and significantly improved the moderate side effects (Table 2). Similar results
assessed parameters compared to vehicle. How- were obtained in a study conducted by Lowe
ever, the study has limitations, including small et al. [151], suggesting that 0.1% tazarotene
sample size. cream may provide comparable efficacy with a
Overall, there is a lack of evidence support- faster improvement compared to 0.05% treti-
ing the use of the commonly used retinyl esters noin cream (Table 2). Compared to tretinoin,
in antiaging cosmetics (RP, retinyl propionate, tazarotene has been associated with a more
retinyl retinoate, retinyl acetate). frequent occurrence of a burning sensation on
the skin, but only during the first week of
2nd Generation treatment [151].
To our knowledge, there are no recent clini-
cal trials on tazarotene in antiaging treatments,
Currently, second-generation retinoids are not
and most published studies examine its efficacy
used as active ingredients in formulations for
in the treatment of acne.
topical application [145].
Generally, the conducted studies suggest
that topical treatments with tazarotene and
3rd Generation tretinoin have similar tolerability and frequency
of adverse effects, although tazarotene, as a
Tazarotene representative of the selective retinoids, is
Tazarotene is a prodrug of tazarotenic acid with expected to be better tolerated. In practice, tre-
selectivity toward RAR-b and RAR-c but not tinoin is well established and commonly used
toward RXRs [22]. It is currently regulated as for the treatment of aged skin. Considering the
medicine and approved in topical formulations similar performance of the two agents in anti-
(0.045%, 0.05%, or 0.1%) for the treatment of aging treatments, perhaps the higher price is
psoriasis and acne. Also, the 0.1% formulation one of the reasons why tazarotene formulations
of tazarotene is approved as an adjunctive agent are not as widely used in clinical practice as
for the treatment of facial fine wrinkling, pig- tretinoin.
mentation, and benign lentigines. Although tazarotene has confirmed potential
The use of 0.1% tazarotene for treatment of for antiaging treatments, new nanotechnology-
photodamage is considered safe and effective based formulations are being evaluated for
Adv Ther (2022) 39:5351–5375 5365

other indications such as wound healing [152] gel, bexarotene is used for topical treatment of
and psoriasis [153]. IA and IB persistent or refractory cutaneous
T cell lymphoma. To our knowledge, there is no
Adapalene published study that has investigated the use of
The activity of adapalene is selectively mediated bexarotene in antiaging treatments.
via RAR-b and RAR-c receptors [154]. In topical
formulations at a concentration of 0.1% or 4th Generation
0.3%, adapalene is used to treat acne with
clinically confirmed efficacy and tolerability but Trifarotene
is also used off-label for treatment of photoag- Trifarotene is currently approved in topical
ing [155]. Kang et al. [156] conducted a formulations as a 0.005% cream for the treat-
prospective, randomized, controlled, masked, ment of acne [162]. Its efficacy and safety profile
two-center, parallel-group study and evaluated for acne treatment is also being clinically eval-
the efficacy of adapalene gel at two concentra- uated [163, 164]. Trifarotene, as a selective RAR-
tions (0.1% and 0.3%) compared with vehicle in c agonist with greater than 20-fold higher
patients with actinic keratoses and solar lentig- selectivity over RAR-a and RAR-b receptors, has
ines. The 9-month study showed that adapalene confirmed depigmenting and antipigmenting
significantly improved the assessed parameters activity in animal models [165]. It is suggested
of the photoaged skin with acceptable tolerabil- that trifarotene, as a selective agonist of RAR-c
ity compared to the vehicle-treated group. (the predominant isoform in the dermis), has
Herane et al. [157] also recommended 0.3% potential for the treatment of photoaging, as it
adapalene gel as an effective and safe treatment may activate the same pathways induced by
for facial photodamage, as demonstrated by the tretinoin [166]. On the basis of the results from
6-month open-label study in Chilean women preclinical studies, trifarotene is expected to
with cutaneous photoaging, although no vehi- have a better profile compared to earlier gener-
cle control group was included in the study. ation retinoids. However, to date, there is no
In addition, a comparison study conducted published comparison clinical study that
by Bagatin et al. [158] showed that the clinical directly evaluates the superiority of trifarotene
efficacy of 0.3% adapalene gel was comparable in terms of efficacy and tolerability. Therefore,
to 0.05% tretinoin cream (Table 2). Therefore, the use of trifarotene as an antiaging agent
0.3% adapalene gel is recommended as an requires further research and clinical evalua-
effective treatment in patients with mild or tion. Since it is a new generation of retinoids,
moderate photoaging [158]. Pinto et al. [54] new formulations are also likely to be developed
developed NLCs formulation with 0.1% ada- in near future.
palene by miniemulsion method and performed
an in vitro release experiment using the equi- Seletinoid G
librium dialysis method. The new formulation Seletinoid G is a synthetic retinoid with selec-
showed favorable properties from a technolog- tivity toward RAR-c [22]. Kim et al. [23] con-
ical perspective, but further studies are needed ducted an in vivo study in which formulations
to reveal the potential of the formulation for containing 1% seletinoid G, 0.1% tretinoin, or
antiaging treatments. Other nanoformulations vehicle were applied occlusively to the buttock
containing adapalene are being developed and skin of 17 participants for 4 days. The results
evaluated specifically for the treatment of acne showed that seletinoid G affected the expres-
[159, 160]. sion of the assessed extracellular matrix pro-
teins and connective tissue-degrading enzymes
Bexarotene similarly to tretinoin, and it was suggested that
Bexarotene is a selective agonist of all RXRs it could repair altered connective tissue in old
subtypes with a complex and not yet fully skin and inhibit UV-induced collagen defi-
evaluated mechanism of action [161]. As a 1% ciency in young skin [23]. Similarly, a skin
5366 Adv Ther (2022) 39:5351–5375

irritation test with three different concentra- and tazarotene are regulated as medicines that
tions of seletinoid G (0.25%, 0.5%, and 0.1%) are also used for antiaging indications. Ada-
and tretinoin (0.025%, 0.05%, and 0.1%) was palene and tazarotene are recommended as
also performed on six volunteers [23]. alternatives to tretinoin in patients with sensi-
Seletinoid G showed no irritation on the treated tive skin [47]. Retinol is the most clinically
area compared to tretinoin. However, the studied retinoid in cosmetics, while retinalde-
results cannot be generalized because the study hyde is considered the most promising. On the
has some limitations. A recent in vitro study has other hand, retinyl palmitate is the most pop-
also shown that seletinoid G is a potent com- ular model compound for the development of
pound for antiaging treatments without signif- new formulations, although its use as an anti-
icant side effects, as it improves skin barrier aging agent is not supported by clinical evi-
function by promoting keratinocyte migration dence. Also, there is a lack of clinical evidence
and restoring abnormal collagen deposition in for the antiaging efficacy of the other retinyl
the dermis [167]. To date, there is no published esters since most of the performed studies have
clinical study investigating the antiaging effect limitations, such as a small number of partici-
of seletinoid G under normal conditions of use. pants and/or a lack of a vehicle control group.
Although seletinoid G shows promising results In general, placebo-controlled double-blind
as an antiaging agent, its potential has yet to be studies as a standard in clinical research are
evaluated. lacking for cosmetics [168]. Considering the
limitations of the clinical studies performed, the
use of retinoid cosmetics as a tretinoin equiva-
DISCUSSION lent is not justified and evidence-based. Our
findings are consistent with previous studies
Clinical Evidence for Conventional that also suggested that in the case of cosme-
Formulations ceuticals, the positive study outcome cannot be
considered relevant information for clinical
Cosmeceuticals containing retinoids are freely decision-making because most of the performed
available on the market compared to the pre- studies have significant methodological issues
scribed formulations regulated as medicines. and deficiencies in study design that limit the
Customers expect cosmeceuticals to offer pen- relevance of the results [81, 168].
etration of the active ingredient into the skin Although the cosmetic market is constantly
and clinical effects after topical application [13]. growing and many products are marketed with
However, cosmeceuticals are not regulated as unrealistic claims, there is a lack of validated
medicines in terms of safety, quality, and effi- methods for evaluation of the product efficacy
cacy and often contain ingredients for which and safety through comprehensive and stan-
there is no clinical evidence to support their use dardized testing. As a result of the competi-
[14]. The results of published studies suggest tiveness of the cosmetic industry and short
that tretinoin, included in formulations regu- product development cycles, cosmeceuticals are
lated as medicines, is the most well-established being marketed with little or no clinical evalu-
retinoid with solid evidence of antiaging effi- ation. Therefore, there is a need for trustworthy
cacy and approved indications for treatment of evidence from high-quality designed clinical
wrinkles and photoaging. studies that can guide clinicians in their deci-
Overall, there is limited evidence from clin- sion-making about treatment options and not
ical research evaluating the antiaging efficacy of just serve as promotional material for the cos-
other retinoids compared to tretinoin as the metics industry.
gold standard. Comparisons with tretinoin by
whole or split-face clinical studies are per-
formed for retinol, retinaldehyde, adapalene,
and tazarotene. Only retinol and retinaldehyde
are found in cosmeceuticals, while adapalene
Adv Ther (2022) 39:5351–5375 5367

Clinical Evidence for Nanoformulations Overall, the development of targeted delivery

systems with efficiently incorporated active
Overall there is a lack of clinical studies evalu- ingredients, low irritability when applied to the
ating the safety and efficacy of nanoformula- skin, and control over the potential toxicity of
tions compared to conventional formulations. the used nanomaterials is complex.
From the literature review, most of the per- In general, nanoformulations containing
formed studies evaluated the nanoformulations retinoids are advantageous compared to con-
containing retinoids by in vitro/in vivo perme- ventional formulations because they are more
ation tests and in vivo irritation tests. To our stable, penetrate the skin better, produce a
knowledge, only one study including human modified release of the active ingredient at the
volunteers clinically evaluated the antiaging site of action, and cause fewer side effects and
effect of the developed nanoformulation with irritation. The results of the performed studies
retinaldehyde and compared it with tretinoin highlight the promising potential of nanofor-
[110]. mulations for topical delivery, but the prelimi-
One of the reasons for the small number of nary results need to be supported by additional
nanoformulations on the market is the lack of in vivo testing and clinical studies. However,
robust in vitro studies with confirmed in vitro/ translating the results into clinical practice and
in vivo correlations that can be used instead of scaling up the production are challenging
clinical studies [169]. Currently, the risk/benefit because most studies use small batch formula-
ratio of the topical nanoformulations is evalu- tions. Since most published results are from
ated on a case-by-case basis because of the lack preclinical studies, there is a need for compre-
of harmonized quality standards and regulatory hensive clinical evidence for evaluation of the
frameworks [169]. Since clinical trials are not benefits and risks of nanoformulations for
required for cosmetics, there is also a lack of topical use. The use of retinoids containing
evidence to support the claimed efficacy of nanoformulations for topical antiaging treat-
cosmetic nanoformulations. ments requires further research.
The use of nanomaterials in cosmetics
requires a comprehensive safety assessment, as
exposure via topical application may pose a risk
CONCLUSION
for adverse effects from insoluble and persistent
Most of the performed studies emphasized the
nanoparticles that can reach unintended sites in
importance of an appropriate combination of
the body and interact with biological entities at
active ingredients, excipients, and technologi-
the molecular level [170]. One way to bridge the
cal processes to obtain a stable cosmetic product
current gap between research and commercial-
that is effective and well tolerated. When a
ization of innovations and realize the full
suitable formulation is used, significant clinical
potential of new delivery systems is to imple-
effects on the skin are obtained as with treti-
ment analytical and in vitro/in vivo evaluation
noin, but with fewer side effects. Consequently,
strategies for their characterization [171].
such a formulation leads to better user compli-
As a result of restrictive regulations in some
ance and satisfaction. However, considering the
countries, researchers are also looking for alter-
limitations of the performed studies, there is a
natives to animal testing. For example, the
need for additional studies that will provide
Cosmetics Regulation (EC) No. 1223/2009 in
new information and insights to support the
Europe prohibits animal testing for cosmetics
use of different retinoids in antiaging
and marketing of cosmetic ingredients/products
treatments.
tested on animals since March 2013 [170].
Therefore, toxicological data must be obtained
from scientifically validated alternatives such as
in vitro and ex vivo studies, in silico models,
and the use of physiologically based pharma-
cokinetic and toxicokinetic modeling [170].
5368 Adv Ther (2022) 39:5351–5375

ACKNOWLEDGEMENTS regulation or exceeds the permitted use, you

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