Powder Technology 322 (2017) 402–416

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Powder Technology

journal homepage: www.elsevier.com/locate/powtec

Review

Delivery systems for cosmetics - From manufacturing to the skin of

natural antioxidants
Raquel Costa a, Lúcia Santos b,⁎
a
Chemical Engineering Department, Faculty of Engineering, University of Porto
b
LEPABE – Laboratory for Process Engineering, Environment, Biotechnology and Energy, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal

a r t i c l e i n f o a b s t r a c t

Article history: Delivery systems are extensively used in cosmetic products. This literature review describes some of the delivery
Received 7 October 2016 systems used in the cosmetic industry, some general considerations about their presence and incorporation in
Received in revised form 1 July 2017 cosmetic formulations, as well as their skin interactions. This review also covers the manufacturing process of
Accepted 27 July 2017
a cosmetic cream formulation, including basic ingredients, natural antioxidants in particular. In addition, future
Available online 2 August 2017
perspectives, recent concerns, and further work regarding the cosmetic industry are also described.
Keywords:
Natural antioxidants present health benefits such as anti-ageing, anti-inflammatory, anti-carcinogenic, and anti-
Delivery systems microbial properties that potentiate their use in cosmetic products. Furthermore, they can also be used as preser-
Cosmetics vatives since they avoid the lipid oxidation that usually occurs in cosmetic products. However, antioxidants may
Antioxidants have stability issues and difficulties in crossing the transdermal barrier. Delivery systems can be used to protect
Skin sensitive active ingredients from degradation and to grant a target and controlled release. Several types of delivery
Anti-ageing systems (e.g. liposomes, niosomes, transfersomes, lipid nanoparticles, polymeric microparticles and nanoparticles)
Personal care have been used in cosmetic formulations. The use of delivery systems may improve the penetration of the antiox-
idant. Skin interaction with the different delivery systems depends mostly on their size, flexibility and composition.
Moreover, delivery systems should be easily incorporated in the cosmetic formulation leading to a final uniform
and sensorially attractive product for the costumer. New concerns about environmental impact or animal welfare
are emerging with respect to the cosmetic development, manufacturing and quality control.
© 2017 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403
2. Basic cream formulation ingredients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403
2.1. Antioxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403
3. Cream manufacturing process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404
4. Delivery systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405
4.1. Liposomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405
4.1.1. Niosomes, transfersomes, ethosomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406
4.2. Lipid nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407
4.3. Polymeric nanoparticles and microparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407
5. Skin interaction with delivery systems- illustrative studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408
6. Incorporation of delivery systems in cosmetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410
7. Latest delivery systems in the cosmetic industry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411
8. Trends and future work on the field of cosmetics and delivery systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412
9. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413

⁎ Corresponding author.
E-mail address: lsantos@fe.up.pt (L. Santos).

https://doi.org/10.1016/j.powtec.2017.07.086
0032-5910/© 2017 Elsevier B.V. All rights reserved.
 R. Costa, L. Santos / Powder Technology 322 (2017) 402–416
1. Introduction
Cosmetics have been used since the Egyptian times, where the color
from minerals and plants was applied as eye make-up. According
to manuscripts, some of the substances were toxic, even though
they were used to treat eye and skin illnesses. The first cold cream (an
emulsion of beeswax, vegetable oil and water) was invented in the 2nd
century by Galen, a Greek physician. Nowadays, the cosmetic concept
is certainly very different from back then, although some of the ingredi-
ents are still the same [1]. In fact, according to European definition, cos-
metics are “any substance or mixture intended to be placed in contact
with the external parts of the human body or with the teeth and the mu-
cous membranes of the oral cavity to clean them, change their appear-
ance, protect them, keep them in good condition or correcting body
odors.” Therefore, a wide variety of products are included in the cosmetic
category: make-up powders, toilet soaps, perfumes, shower prepara-
tions, depilatories, deodorants and antiperspirants, products for external
intimate hygiene, skin, hair, oral and nail care products. However, this
definition is not universal. Some products that are considered as cos-
metics in Europe (sunscreen products, anticavity toothpastes, antiperspi-
rants, antidandruff preparations, skin protectants and hair restorers)
may be classified as over-the-counter drugs in the USA since the cosmet-
ic definition is somehow narrower [2].
Currently, skin care products represent billions of euros in the cos-
metic market. Consumer requirements are becoming very demanding
since a facial cream, for instance, must have cleansing, smoothing, restor-
ing, reinforcing and protecting properties besides its hydrating function.
However, consumer necessities are not uniform and static: older people
are usually more concerned about the preventive and therapeutic effects
of a cosmetic formulation instead of appearance changing effects. Typi-
cally, the promotion of a skin care product involves a skin positive effect
(e.g. anti-ageing, antioxidant properties), performed by an active ingre-
dient (e.g. resveratrol, vitamin E), delivered by a vehicle (e.g. cream, lo-
tion), using a recent technology (e.g. nanoparticles, liposomes) [3].
Therefore, the development of cosmetic products should contemplate
an integrative approach, not only focused on the formulation process,
but also on the consumer perception and requirements, as well as mar-
keting strategies, in order to produce a successful product.
To build consumer trust and to commercialize the product it is neces-
sary to assure the safety of all the excipients. According to the legislation,
safety concerns are manufacturer's responsibility [2]. Nevertheless, there
is a considerable number of studies evaluating the safety of cosmetic in-
gredients and their concentration in cosmetic formulations [4,5]. Actual-
ly, the basic composition of a cosmetic cream is well known in the art,
and generally it comprises the use of common excipients that must be
properly listed on the product label. Active ingredients are probably
one of the key factors that makes the difference between thousands of
products claiming to have the same purpose.
2. Basic cream formulation ingredients
Most of the cosmetic formulations for skin care are an oil-water
emulsion (O/W), a water-oil emulsion (W/O) or a double emulsion
(oil-water-oil or water-oil-water). From a dermatological perspective,
the W/O emulsion is a better choice, since the lipid film formed on the
skin favors the oil-soluble active ingredients. Usually, lotions are com-
posed of an O/W emulsion, since they have a higher water content
than creams. O/W emulsions are also more appreciated by the consum-
er for being less greasy. On the other hand, they may cause a cooling
sensation due to the water evaporation [6].
Basic cream formulations with skin hydration function are typically
composed of simple ingredients, such as emollients (10–40%), humec-
tants (1–5%), thickeners (0.1–0.5%), emulsifiers (1–6%), stabilizers
(0.01–0.2%), preservatives (0.01–0.5%) and neutralizers (0.01–0.05%)
[7]. Biological active ingredients such as antioxidants, anti-acne sub-
stances, sunscreens can also be incorporated to add some value to the
403
product. The use of fragrances and dyes may turn the product more at-
tractive to the consumer.
Simple emollients are hydrophobic compounds used to prevent the
water evaporation from the skin by forming an occlusive film. Humec-
tants are hydrophilic compounds that attract water to the stratum
corneum, compensating the reduced number of natural moisturizing fac-
tors [8]. Thickeners are used to control the texture and rheological prop-
erties of the formulation [9]. However, it is important to note that
emollients, humectants and emulsifiers also play a role in the rheological
behavior and sensorial properties of the formulation [10]. Emulsifiers are
molecules that comprise both hydrophobic and hydrophilic characteris-
tics; therefore, they do not tend to be soluble in only one of the phases,
but to collect at the interface of both phases, promoting the emulsion.
Emulsifiers can either be ionic or non-ionic. The first ones can be divided
in cationic and anionic, depending on the head charge [11]. Theoretically,
non-ionic emulsifiers can be selected through the HLB (hydrophilic-lipo-
philic balance) number which measures the balance between the hydro-
philic and lipophilic part of the molecule. However, the solution given by
this system is not always the most suitable, since it has to be considered
against the compatibility with other ingredients, the formulation viscosi-
ty, and the size of the emulsion droplets that can affect creaming rate or
phase splitting. Experimental procedures to determine the best emulsi-
fiers are based in a mixture, combining a pair of emulsifiers, with high
and low HLB values, and the desired sample. Then, it is necessary to ob-
serve which HLB value leads to a stable emulsion [7]. Finally, stabilizers
and preservatives are used to prolong the product shelf-life and promote
its stability. Preservatives are compounds that inhibit the growth of mi-
croorganisms while stabilizers maintain the physicochemical integrity of
the product [12,13].
The use of natural ingredients in cosmetic formulations is actually a
rising interest among scientific community, cosmetic industry, and
consumers. Such ingredients can be natural emollients, UV-filters, anti-
oxidants, or any other natural substances that may add value to the prod-
uct. In the last years, products claiming anti-ageing properties with
antioxidants in their formulation have been surging in the market.
2.1. Antioxidants
Antioxidants are molecules capable of oxidizing themselves before or
instead of other molecules. They are compounds or systems that can in-
teract with free radicals and terminate a chain reaction before vital mol-
ecules are damaged [14]. The use of antioxidants is described in food,
cosmetics, beverages, pharmaceuticals and even in feed industry. They
may be used as supplements and active ingredients with health benefits,
or as stabilizers [15].
Antioxidants can be either synthetic or natural, and both are included
in cosmetic formulations [16]. Synthetic antioxidants (e.g. butylated
hydroxyanisole (BHA), butylated hydroxytoluene (BHT]), and propyl
gallate) are largely used since they are easily produced leading to
lower prices [15]. However, some studies suggest that a high consump-
tion of synthetic antioxidants results in potential health risks [16]. De-
spite the market leading by synthetic antioxidants, the demand for
natural antioxidants have been increasing in the last few years and it is
expected to continue. This trend can be explained by a crescent consum-
er preference for organic and natural products, since they use less addi-
tives and may have less side effects than synthetic ingredients [17].
Natural antioxidants used in the cosmetic industry include a great
number of substances and extracts that can be obtained from a variety
of plants, grains, fruits (Table 1), and are able to reduce the skin oxidative
stress or protect the product from oxidative degradation [18].
Reactive oxygen species (ROS) are one of the major causes of oxida-
tive stress which enhances the skin ageing process [19]. Intrinsic ageing
is associated with the natural process of ageing while extrinsic ageing is
related to external factors (e.g. air pollution, UV-radiation, pathogenic
microorganisms) that affect the ageing process. Photo-ageing is probably
the main reason of ROS production. Several potential skin targets (e.g.
404 R. Costa, L. Santos / Powder Technology 322 (2017) 402–416

Table 1
Examples of the more widely used natural antioxidants in cosmetic formulations.

Classification Antioxidant Source Chemical Structure Kow Reference

Vitamin C Apple, bayberry, broccoli, citrus peel, garlic, peppermint, spearmint 1.9 [14,20–22]
Vitamins
Olives and olive oil, palm oil, pumpkin seeds, sunflower seeds
Vitamin E 12.2 [14,21,23]
nd sunflower oil

Black pepper, onions, curly kale, leeks, broccoli, blueberry, red

Quercetin 1.5 [17,24–26]
wine and tea

Red wine, grape berry skins and seeds, peanuts, dried roots of
Polyphenols Resveratrol 3.1 [27]
plant Polygonum cuspidatum

Rosmarinic acid Peppermint, rosemary, marjoram, sage, thyme, 1.8 [28]

Lycopene Apricots, grapefruit, guava, watermelon, papaya and carrots 16.6 [14,29,30]

Carotenoids
Lutein Spinach, leaf lettuce, peas, oranges, kale, Zea mays, carrot 7.9 [14,31–33]

lipids, DNA, proteins) have been found to interact with ROS [34]. Fig. 1
was adapted from Masaki and presents some of the potential oxidative
stress effects on the skin [35]. Antioxidant molecules can be enzymes or
low molecular weight antioxidants (LMWA) that can act by donating an
electron to reactive species thus interrupting the radical chain reaction,
by preventing the reactive oxidants formation, or by acting as metal che-
lators, oxidative enzyme inhibitors or cofactors of enzymes [19,36].
Antioxidants can also be used as stabilizers, avoiding the rancidity of
lipid ingredients. In fact, lipid oxidation is present not only in cosmetic
products but also in the human body. Therefore, antioxidants may have
multiple functions when they are present in the product. In the initiation
phase of lipid oxidation, the number of radicals is expanded. During the
propagation phase, molecular oxygen and fatty acid radicals react, lead-
ing to the formation of hydroperoxide products. Hydroperoxides are un-
stable and can degrade to produce radicals that will accelerate the
propagation reaction. The termination phase is dominated by reactions
between radicals [37]. Antioxidants can prevent lipid oxidation by
reacting with lipid and peroxy radicals, converting them to more stable
and non-radical products. Antioxidants are also able to reduce hydroper-
oxides to hydroxy compounds, deplete molecular oxygen, deactivate sin-
glet oxygen, remove prooxidative metal ions, replenish hydrogen to other
antioxidants, and absorb UV light [19,38]. According to literature, antiox-
idants can also be involved in cancer treatments, since the production of
reactive oxygen species is altered during tumorigenesis [39,40]. They
also have anti-inflammatory and anti-microbial properties [41].
Nevertheless, antioxidants have some limitations that narrow their
inclusion in all types of products mentioned above. Some antioxidants
are used in the form of extracts, which can cause allergenic reactions
and give some taste or smell to the product [42,43]. For topical applica-
tion in particular, the ability to cross the dermal barrier could be a chal-
lenge for some antioxidants. This difficulty is explained by the distinct
composition of the different skin layers [44,45]. Furthermore, according
to literature, the stability of antioxidants may be influenced by light, pH,
temperature and oxygen [46–48]. They can also react with other matrix
compounds, degrade, and lose their activity [49]. Therefore, the incor-
poration step during the manufacturing process of a cream formulation
must be carefully analyzed to guarantee the stability of the antioxidant.
3. Cream manufacturing process
The manufacturing process of cream formulations typically starts
with the preparation of two separate phases: the oily phase and the
aqueous phase (Fig. 2). Then, the two phases are mixed together to
form the emulsion. Usually, the oily phase is composed of emollients,
emulsifiers, and any other organic soluble substance that is not volatile
or sensitive to temperature. Those substances can vary from natural

Fig. 1. Possible skin oxidative stress effects.

 R. Costa, L. Santos / Powder Technology 322 (2017) 402–416
extracts, antioxidants, preservatives, to film formers. The aqueous phase
usually contains thickener agents, humectants, buffers, or any other
excipient that is soluble in water and thermal resistant [50]. After prepa-
ration of both phases, they are homogenized until a uniform single phase
dispersion is formed. The stirring speed is an important factor to consider
and it should be kept constant when a scale up to industrial production is
performed. Typically, the stirring speed should be under 10,000 rpm to
avoid the breakdown of the thickener carbon chains. The stirring can
lead to bubble formation, therefore the use of a homogenizer with vacu-
um lines or a de-airing step should be added to the process. At laboratory
scale, sonication can be used to remove the bubbles from the formulation
[7]. Further treatments are sometimes necessary to achieve a uniform
dispersion and a size reduction of the ingredients.
The manufacturing of a cosmetic product is mostly based on empiric
experience, therefore a final process flow chart is usually obtained after
several tests and experiments. However, some properties can be readily
associated with the excipients and operational conditions used: 1) if the
emulsion does not form rapidly, different emulsifiers or a higher concen-
tration of emulsifiers should be used; 2) if the oily phase splits, emulsi-
fiers with lower HLB values should probably be selected. On the other
hand, if the water phase splits out, emulsifiers with higher HLB values
must be used; 3) when a solids suspension is involved in the formula,
the use of polymeric emulsifiers must be considered; 4) if the formula-
tion viscosity is low, solid emollients at room temperature can be helpful;
5) emollient concentration (liquid or solid) can also be responsible for
the greasy or sticky feeling of the formulation; 6) The smoothness of
the cream can be achieved through the reduction of the droplet size by
increasing the stirring speed of the homogenizer [7].
Time, mechanical energy, and pressure are operational conditions
that must be controlled in order to have consistent batches. The cooling
of the formulation can be done naturally (which is more suitable for lab-
oratory scale) or using a heat exchanger. The temperature must be
cooled down until a suitable value for the incorporation of the volatile
or thermal sensitive ingredients. The cooling rate can affect the final
product quality and should, therefore, be investigated [9,50]. The ad-
justment of pH can be performed at the end of the formulation or by
adding the neutralizing agent generally to the aqueous phase [7,51].
Some excipients can be sensitive to pH modifications, therefore a careful
choice of the cosmetic ingredient should be made to assure stability. The
filtration step is used to clarify the product, assuring that no sediments
possibly resulting from the cosmetic ingredients are found in the final
formulation. The filter press is probably the most used filtration equip-
ment in the cosmetic industry [52].
As aforementioned, the incorporation of sensitive ingredients, such
as antioxidants, during the manufacturing process, could be a critical as-
pect of producing a new product. To overcome this limitation, delivery
systems may be used, since they can protect sensitive ingredients
Fig. 2. Example of a simplified process flow chart of a cosmetic cream formulation.
405
from degradation and control their release during manufacturing, as-
suring their stability.
4. Delivery systems
Delivery systems are engineered technologies used to carry an active
ingredient, promoting a controlled and targeted delivery. Human skin
acts as a barrier against the permeation of exogenous molecules. Delivery
systems are able to enhance the permeation of the active ingredient
through the skin layers, controlling its concentration in the formulation
and in the skin. For a cosmetic purpose, it is a major concern to keep
the active ingredient in the superficial skin layers and avoid the systemic
absorption [53]. Burst and sustained release are two major features that
should be associated with cosmetic delivery systems. Burst release is im-
portant to improve the penetration of active molecules, while sustained
release becomes important when the active ingredient is irritating at
high concentrations, or when it is needed to supply the skin for long pe-
riods of time [54]. Moreover, the active ingredient protection is another
advantage of using delivery systems. The shelf life required for a cosmetic
product is usually no b 2 years. Therefore, ingredients sensitive to exter-
nal conditions, like light, oxygen, and heat, must be protected to ensure
the stability of the product. In addition, delivery systems can also prevent
the reaction between the encapsulated ingredient and other molecules
in the product matrix [55]. Product appearance and flow properties
may also be improved, enhancing its handling, usage and storage. Unde-
sirable organoleptic properties can be masked and the evaporation of
volatile ingredients can be controlled with delivery systems. These tech-
nologies can also be used to reduce the amount of ingredient in the for-
mulation, becoming a cost saving alternative.
Several types of delivery systems can be found in cosmetic products.
They may be divided into vesicular systems (liposomes, niosomes,
transfersomes), emulsions (microemulsions and nanoemulsions), and
particulate systems (microparticles, nanoparticles) [53]. Table 2 presents
some examples of commercialized cosmetic products containing natural
ingredient loaded delivery systems.
4.1. Liposomes
Described in the mid-sixties, liposomes were used in cosmetic in-
dustry by Christian Dior - Capture™. Nowadays, liposomes present a
large number of applications in different sectors such as food, cosmetic
and pharmaceutical industries [56]. Liposomes are vesicles with a
hydrophilic core and surrounded by at least one phospholipid bilayer.
Diverse liposomes can be formed with different sizes and bilayers:
small unilamellar vesicles (SUV) (10–100 nm), large unilamellar vesi-
cles (LUV) (100–3000 nm), multilamellar vesicles (MLV) (N1000 nm)
where more than one bilayer is present, and even multivesicular
406 R. Costa, L. Santos / Powder Technology 322 (2017) 402–416
liposomes (MVL) [57]. Despite their hydrophilic core, liposomes can ac-
commodate hydrophobic, hydrophilic or amphiphilic molecules. Hy-
drophobic molecules are entrapped between the lipid bilayer whereas
hydrophilic ingredients can be encapsulated in the core. Amphiphilic
molecules stay in the water/lipid surface according to their affinity to
the liposome components [58].
Liposomes have caught the attention of researchers as a promising
delivery system due to its biocompatibility, biodegradability, low toxici-
ty, easy preparation, prolonged circulation time, and the ability of extend
products shelf life. On the other hand, poorly water-soluble drugs incor-
porated in the lipid bilayer are often rapidly released, which limits the
potential of liposomes for hydrophobic molecules [59]. The lack of phys-
ical and chemical stability due to lipid oxidation and hydrolysis are other
drawbacks of this delivery system [60].
Generally, liposome formation involves the dispersion of the lipid
molecules in an aqueous phase to form the vesicles. The production
and preparation of liposomes can be performed through mechanical
methods (film methods, sonication, microfluidization, extrusion),
replacement of organic solvents by aqueous media methods (ethanol in-
jection, proliposome-liposome, reverse-phase evaporation), and deter-
gent removal methods. Nevertheless, only some of those methods are
suitable for a large-scale production since liposomes have to be produced
in a controlled, stable and reproducible way. Film methods are difficult to
scale up (to several tens of liter) and they create vesicles with different
sizes which can lead to an expensive and time consuming production,
due to the need of further processing for a defined liposomal suspension.
Microfluidization operates at pressures between 0 and 200 bar and with
a precise control of the temperature with cooling and heating systems.
This technique allows a large scale and sterile production of liposomes.
Extrusion methods are also applied and they are characterized by high
reproducibility. However, the clogging of extrusion membranes can
lead to a time consuming process and generates high product losses.
The reverse-phase evaporation method is characterized by a high encap-
sulation rate. However, two of the possible drawbacks are the remaining
solvent and the necessity of appropriate shear mixing devices and
pumps for a large scale production [61]. Finally, the preparation of lipo-
somes through ethanol injection based methods is extensively reported
in literature. In general terms, such techniques are often easy to scale
up and produce reproducible results with respect to vesicle diameters
and encapsulation rates. Liposome size and encapsulation rate can be
controlled by the operating parameters such as the lipid concentration
in ethanol, the injection whole diameter, the injection pressure, and
the flow rate of the aqueous phase [64].
Diverse delivery systems based on liposomes were developed:
niosomes, transfersomes, ethosomes, dendrossomes, among others.
Table 2
Commercialized cosmetic products with natural ingredients loaded delivery systems [56,62,63].
Trade name Active ingredient
delivery system
Revitalift Pro-Retinol A
Nanosome
Bioperformance Crème Super Régénérante Absolue Gamma linolenic acid
Nanocapsules
Rénergie Microlift Micro filters (silica and protein)
Nanoparticles
Rovisome ACE Plus Ascorbyl palmitate, tocopherol, retinol
Liposome
Lipobelle Soyaglycone Genstein
Liposome
Cutanova Nano Repair Q10 Cream Coenzyme Q10
Nanostructured lipid carriers
Collagen Stimulator Factor MAP® Vitamin C
Nanocapsules
Nano Gold® Energizing Cream 24-karat gold (natural protein)
Nanoparticles
Platinum Silver Nanocolloid® line products Botanicals and coenzyme Q10
Nanoparticles
4.1.1. Niosomes, transfersomes, ethosomes
Niosomes were originally developed in the seventies for cosmetic in-
dustry, although nowadays a wide range of applications can be also
found in the pharmaceutical field. They are biodegradable and biocom-
patible vesicles composed of nonionic surfactants and, in some cases,
cholesterol or its derivatives [65]. Cholesterol is used as an additive
agent interacting with the hydrophilic head of the nonionic [66]. It affects
some properties of the vesicle such as entrapment efficiency, storage
time, release, and stability [67]. Cholesterol improves the stability of
the surfactant bilayer, since it increases the gel-liquid transition temper-
ature of the niosome. In order to stabilize niosomes, charged molecules
can be added to the bilayer [68]. These additives are useful to prevent ag-
gregation, increase encapsulation efficiency, and enhance skin perme-
ation. Niosome research interest arose from the ability of overcoming
some of the liposome limitations. Nonionic surfactants give higher versa-
tility to the vesicular structures and they are less expensive than phos-
pholipids. Niosomes are also easier to prepare than liposomes due to
the surfactant resistance to air oxidation and high temperatures. Regard-
ing skin permeation, niosomes present a more effective delivery by top-
ical application. Niosomal formulations usually present an improved
sustained release and higher stability than liposomal formulations [65].
However, some of the drawbacks are common for both liposomal and
niosomal vesicles since, during dispersion, both of them are at risk of ag-
gregation, fusion, drug leakage, or hydrolysis of encapsulated drugs [69].
Some of the preparation methods used for niosomes are the thin film hy-
dration method, the organic solvent injection method, the reverse-phase
evaporation method and the bubble method. In the film hydration meth-
od, the surfactants and other additives such as cholesterol are dissolved
in an organic solvent in a round bottomed flask. Then, the solvent is
evaporated using a rotary vacuum evaporator and a thin film is formed
on the inside wall. An aqueous solution (e.g. water or PBS), containing
the active ingredients, is added and the dry film is hydrated above the
transition temperature of the surfactant. During hydration, MLV are
formed [67].
Transfersomes are deformable vesicles, first developed in 1991, com-
posed of phospholipids and an edge activator. The edge activator is usu-
ally a single chain surfactant, with a high radius of curvature, able to
decrease bilayer stiffness [70]. This elastic behavior avoids the vesicle
rupture and it is responsible for its penetration into the skin. Phospholip-
id hydrophilicity leads to xerophobia (tendency to avoid dry surround-
ing). Therefore, for the vesicles to remain maximally swollen on the
skin surface, they try to follow the hydration gradient, moving to the
deeper skin. Edge activator accumulation at the high stress sites allows
the deformation of the vesicle, due to their tendency for curved struc-
tures, and its penetration [71,72]. Phospholipids are the main constituent
Proposed use Brand
Anti-wrinkle L’Oréal
_ Lancôme
Anti-ageing moisturizer Lancôme
Anti-ageing, wrinkle reduction Rovi Cosmetics International GmbH
Antioxidant Mibelle Biochemistry
Revitalizing, anti-ageing Dr. Rimpler GmbH
Stimulation of collagen production Cosmetochem
Anti-ageing, Neiman Marcus
anti-inflammation
Anti-wrinkles, DHC Skincare
anti-ageing
 R. Costa, L. Santos / Powder Technology 322 (2017) 402–416
while surfactants range between 10 and 25% and the solvent alcohol
composition is between 3 and 10%. A wide range of molecules (e.g. pep-
tides, antioxidants, DNA) can be successfully entrapped in transfersomes.
Transfersome preparation involves simple procedures, easy to scale up
and with acceptable additives [73]. The two main techniques are
vortexing-sonication and rotary evaporation–sonication. In vortexing-
sonication method, a PBS mixture of lipids, edge activator, and active in-
gredient, is vortexed until a milky suspension is obtained. The suspen-
sion is then sonicated and extruded through a polycarbonate
membrane. In the rotary evaporation sonication method, lipids and the
edge activator are dissolved in a blend of chloroform and methanol
(2:1, v/v). Then, the solvent is removed using rotary evaporation under
reduced pressure at 400 °C. The deposited lipid film is hydrated with a
solution containing the active ingredient while the flask is rotated during
one hour at room temperature. The resulting vesicles are left to swell, at
room temperature, and then sonicated and extruded through a sandwich
of polycarbonate membrane [74].
Ethosomes are phospholipid vesicles with high concentrations of eth-
anol (20–50%) first developed in 1997. The commercialization of
ethosome technology began in 2000 [75]. As well as transfersomes, this
delivery system has high deformability and it is able to penetrate the
skin. It is believed that ethanol acts as permeation enhancer, since it af-
fects the bilayer structure of the stratum corneum. The interaction of
the vesicle with the disrupted stratum corneum may forge a penetration
pathway [76]. Compared to liposomes, ethosomes are able to deliver the
entrapped ingredient more deeply in the skin and typically they exhibit a
smaller size, higher entrapment efficiency and improved stability [77]. As
opposed to transfersomes, ethosomes are able to improve the skin deliv-
ery under occlusive and non-occlusive conditions [78]. Some of the main
drawbacks of this delivery system are its instability due to oxidative deg-
radation and the lack of purity of natural phospholipids that affects its
public acceptance [73]. The preparation of ethosomes involves two con-
ventional methods, the hot and cold methods, but classic mechanical dis-
persion method and transmembrane pH-gradient active loading method
are also reported. In cold method, the lipid material is dissolved in etha-
nol, at room temperature, with vigorous stirring. Then, propylene glycol
or other polyol is added to the mixture that is afterward heated up to 30
°C. Water of the same temperature is added slowly to the previous mix-
ture. After stirred and cooled at room temperature, the preparation may
be sonicated or extruded to obtain the desired size. The active ingredient
can be dissolved in water or ethanol, depending on its properties. In hot
method, the lipids are dispersed in water at 40 °C until a colloidal solu-
tion is obtained. Ethanol and glycol are also heated separately up to 40
°C and then added to the aqueous phase. After that, the same procedure
of cold method should be followed to obtain the intended size. Large
amounts of ethosomal formulation can be easily prepared, since it does
not required complex and specific equipment [79].
4.2. Lipid nanoparticles
Lipid nanoparticles are an O/W nanoemulsion colloidal dispersion
where the liquid oil is replaced by a solid lipid, in case of solid lipid nano-
particles (SLNs), or a blend of solid and liquid lipids, for the formation of
nanostructured lipid carriers (NLCs). SLNs were first developed, in the
early nineties, and they are generally composed of 0.1% (w/w) to 30%
(w/w) of solid lipid dispersed in an aqueous medium and, if required,
stabilized with 0.5% (w/w) to 5% (w/w) of surfactant. Their mean size
is between 40 and 1000 nm. On the other hand, NLCs are a combination
of solid and liquid lipids in ratio of 70:30 up to 99.9:0.1. A depression in
the melting point is observed for NLCs due to the presence of the liquid
oil, however, they still form a solid matrix at body temperature. Three
different types of NLCs can be formed: imperfect, amorphous and multi-
ple type. The imperfect type structure results from using different mole-
cules that lead to the formation of imperfections, which in turn allow the
accommodation of the active ingredient. The amorphous type structure
results from avoiding the crystallization process leading to an
407
amorphous state. Finally, the multiple type structure corresponds to an
oil-solid lipid-water dispersion where oil nanocompartments are inside
a solid lipid matrix [80]. Several different techniques are described in lit-
erature to produce lipid nanoparticles: high pressure homogenization,
microemulsion technique, emulsification-solvent evaporation,
emulsification-solvent diffusion method, solvent injection (or solvent
displacement) method, phase inversion, multiple emulsion technique,
ultra-sonication and membrane contractor technique [81]. High pressure
homogenization is one of the most used methods and it starts with the
dispersion or dissolution of the active ingredient in the melted lipids.
Then, if hot high pressure homogenization method is performed, the
melted lipids are dispersed in a hot surfactant solution of the same tem-
perature, by high speed stirring. The resulting emulsion is then passed
through a high pressure homogenizer, at the same temperature. On the
other hand, if cold high pressure homogenization is performed, the
melted lipids containing the active ingredient are cooled down until so-
lidification. After that, the mass is crushed, ground, and dispersed in a
cold surfactant solution. A cold pre-suspension of micronized lipid parti-
cles is formed and passed through a high pressure homogenizer at room
temperature [82]. High pressure homogenization has several advantages
comparing to other methods since it is easy to scale up, it does not use
organic solvents and requires a short production time. Furthermore,
high pressure homogenizers are used in pharmaceutical industries, so,
no regulatory problems exist for the production of cosmetic preparations
[81].
SLNs show burst and sustained release, which are both important for
cosmetic application [56,83]. Under optimized conditions, they are able
to entrap both hydrophilic and lipophilic active ingredients. Neverthe-
less, they are claimed to possess a low drug loading capacity due to the
SLN crystalline structure, and they can undergo polymorphic transition
[84]. NLCs are characterized by a less ordered solid lipid matrix due to
the presence of liquid and solid lipid blend. This structure is able to incor-
porate higher amounts of the active ingredient, since it can be located be-
tween the fatty acid chains, between the lipid layers and also in the lipid
matrix imperfections. Additionally, the higher order degree of the struc-
ture also leads to a faster expulsion of the active ingredient. Therefore,
NLCs minimize the expulsion of the active ingredient and increase the
drug loading capacity, overcoming some of the problems of SLNs [80].
The typical raw materials used for the preparation of lipid nanoparti-
cles are GRAS (Generally Recognized As Safe), therefore no problems of
biocompatibility or toxicity are associated [85]. Furthermore, some au-
thors suggest using SLNs and NLCs as delivery systems for sunscreen for-
mulations, since these nanoparticles also have protective effect from the
sun. Several cosmetic products with SLNs and NLCs are already commer-
cially available [81]. Some of the main drawbacks of lipid nanoparticles
are the general tendency for aggregation when combined with some in-
gredients, and gelation behavior associated with SLNs. However, NLCs
present an improved physical stability in suspension comparing to
SLNs [84]. Compared to liposomes, lipid nanoparticles have slower deg-
radation rate in vivo, which provides a better protection and controlled
release of the encapsulated molecules, apart from a more cost-effective
production on large scale [86].
4.3. Polymeric nanoparticles and microparticles
Nano/microparticles are used to entrap active ingredients, either in-
side (core material) or scattered among the particle's own material
(shell material) [87]. The exact definition of nanoparticles and
microparticles is not consensual among authors. Some researchers con-
sider that the nanoparticle size should range between 1 and 100 nm,
while others claim that it must range between 1 and 1000 nm [88,89].
Nano/microparticle is a general term comprising both nano/micro-
spheres and nano/microcapsules. Nano/microspheres consist of a dis-
persion of the active ingredient in the polymeric matrix, whereas
nano/microcapsules are reservoirs where distinct domains of core and
wall material are present [90]. One of the main purposes of this
408 R. Costa, L. Santos / Powder Technology 322 (2017) 402–416
procedure is the creation of a physical barrier that avoids the contact of
the active agent with the external matrix, protecting sensitive sub-
stances from moisture, pH, light, oxygen, and other molecules present
in the matrix [91]. Nanoparticles in particular can be applied as preser-
vatives and antibacterial agents in cosmetics [92].
The preparation of nano/microparticles may be performed by the
same methods (i.e. evaporation or extraction of the solvent, interfacial
polymerization, spray drying), with controlled operational conditions,
in order to obtain the desired product [93,94]. Spray drying is one of
the mostly used microencapsulation techniques [28]. A solution, a sus-
pension, or an emulsion containing the core material and the shell ma-
terial is homogenized and then fed to a spray drying equipment. Then,
the process can be divided in three steps: (1) atomization of the liquid
solution, (2) contact of the fine droplets with a hot gas stream to evap-
orate the solvent, (3) separation and collection of the powder. Spray
drying is a relatively simple process, with a low operation cost, easy to
scale up, and it can operate in continuous. However, some of the main
drawbacks of this method are the high cost of the equipment, the low
overall thermal efficiency, and the possibility of loss of low boiling
point substances. The final product may not have a uniform size and
may need further processing to agglomerate the resulting fine powder
[95,96]. A wide variety of encapsulating agents can be used, extending
from synthetic to natural. Its choice should be made according to the
particle application, the selected core material, the physical and chemi-
cal stability, the required particle size, the release mechanism, and the
manufacturing costs [92,95]. Occasionally, a combination of wall mate-
rials, and crosslinking agents, are used to achieve the desired properties
[93]. Crosslinking agents are molecules capable of establishing ionic or
covalent bonds with the encapsulation agent (i.e. polymer), building a
sort of network, and altering some of the proprieties of the microparti-
cles, particularly the release behavior [97].
Nanoparticles have a greater tendency to aggregate due to their high
surface area and the type of interaction that they can establish with each
other [98]. Additionally, particle size also interferes with the release of
the active ingredient. Active ingredients entrapped in smaller particles
have greater access to the external phase, which can lead to a faster re-
lease by diffusion, a faster penetration of water into the particle, and a
lower drug loading. The adsorption of molecules on the surface also oc-
curs during particle formation, and it is more accentuated the smaller
the particle is. On the other hand, smaller particles may have a better
binding per unit of particle mass than larger ones, which could be useful
to adhere to the skin [99].
In fact, understanding skin physiology and the interactions of the dif-
ferent delivery systems with it is essential for a correct selection of the
most suitable delivery system, as well as its materials and preparation
method. Table 3 presents some examples of studies of natural ingredient
loaded delivery systems with cosmetic relevance.
5. Skin interaction with delivery systems- illustrative studies
One of the main problems of topical application of active ingredients
is the impermeability of the stratum corneum barrier. In order to have
the desired effect, the active ingredient not only has to cross this barrier,
but a sufficient amount must also reach the deeper layers of the skin.
The difficulty of deep penetration can be observed in Junyaprasert
et al. study. The authors described the incorporation of ellagic acid in
niosomal formulations obtained from the mixture of Span 60 and
Tween 60. Human skin and Franz diffusion cells were used to perform
the skin transdermal flux and distribution assays using phosphate buff-
er (pH 5.5) and isopropyl alcohol as the receptor medium. Ellagic acid
from niosomal formulations was found both in the receptor medium
and in the epidermis. On the other hand, when the solution of ellagic
acid was tested, ellagic acid was only found in the epidermis, but not
in the receptor medium. Concerning the distribution of ellagic acid
throughout the skin layers, a higher amount of antioxidant was ob-
served in the epidermis layer (including the stratum corneum) than in
the dermis. The solution of free ellagic acid was only able to penetrate
in the stratum corneum in low amounts [100]. The passage through
the stratum corneum is limited to low-molecular weight molecules
(b500 Da), preferably uncharged, and with partition coefficient (Kow)
values between 1 and 3. Delivery systems have to be smaller than
5–7 nm to potentially diffuse throughout the fluid lipidic bilayers, or
smaller than 36 nm to eventually go through the aqueous pores [45,
101]. Nanoparticles are able to make close contact with superficial junc-
tions of the stratum corneum, creating channels through corneocytes
islands, thus allowing the dispersion of the active ingredient [119]. Ve-
sicular delivery systems are frequently reported in cosmetic formula-
tions. Their dimensions can range between the nano and the micro
scale. Roughly speaking, they can be divided in elastic, flexible, and de-
formable systems, or in rigid ones. Vesicular systems can deliver the ac-
tive ingredient just by releasing it from the vesicle, they can enhance the
transdermal passage due to interactions with the stratum corneum, and
they can fuse and exchange lipid material with the stratum corneum,
transferring the active ingredient to the skin (Fig. 3) [71]. Intact vesicu-
lar skin penetration is more associated with deformable systems, since
they can squeeze through the interclusters and intercorneocytes path-
ways using the hydrating gradient as driving force [120,121]. Deform-
able vesicles are often smaller than rigid ones, which also justifies why
they are frequently found deeper in the skin. Zhang, Y. et al. compared
the use of liposomes and ethosomes for skin delivery of psoleren, a nat-
ural substance used for psoriasis therapy. Franz diffusion cells and rat
skin were used for penetration studies. Ethosomes showed higher
amounts of psoleren in deeper layers of the skin (3.50 times) and an im-
proved skin deposition than liposomes (2.15 times). These results may
be explained by the intact penetration of ethosomes in the skin [122].
The penetration of active substances and nano delivery systems is
also possible through the pilosebaceous units. The corneocytes barrier
in the lower hair follicle infundibulum seems to be crumbly and smaller,
which makes this area more susceptible to penetration. Hair follicle
infundibulum can also act as reservoir for nano and micro sized particles.
It is suggested that larger particles release high concentrations of the ac-
tive ingredient to the follicle duct, from where it can be after released,
while smaller particles (b40 nm) can pass through the disrupted skin
barrier [123]. The hair follicle can be considered as an invagination of
the epidermis extended deep to the dermis layer, thus providing a
greater improvement of penetration surface area. The hair growth
cycle can influence the penetration of active ingredients [124]. Kang
et al. tested the penetration of genistein-loaded elastic liposomes in
hair and hairless skin from rat and mouse, respectively. A decreasing
permeation rate of genistein and skin deposition levels in hairless skin
was more evident for elastic niosomes, which may suggest that hair fol-
licles can work as reservoir of genistein [106].
Rigid particulate system penetration (SLNs, NLCs, micro/nano parti-
cles) mostly depends on the particle size, its composition and charge
being less significant [101]. Nano sized particles (b100 nm), due to
water evaporation after application on the skin, are able to form an occlu-
sive film that increases the hydration of the stratum corneum, which
consequently leads to the formation of gaps between corneocytes.
Hydration also affects the partitioning of the active agent into the stra-
tum corneum [119]. In fact, the particle occlusive capacity may also be af-
fected by the loaded substance. Okonogi et al. described the impact of
lycopene drug loading on skin occlusive properties of NLCs. The results
evidenced that the occlusive properties of the NCLs increased with the
particle drug loading, which confirms that the encapsulated ingredient
may play an important role in the occlusive properties of the film.
These results can be explained by the nanocrystalline characteristics of
lycopene and the formed lipid film [125]. The study performed by
Kamel et al., encapsulating rutin in NLC's as well, presented the same re-
lation between the drug loading and the occlusive properties of the
nanoparticles [113]. Loading natural ingredients into delivery systems
may also have an effect on the product performance comparing to the
unloaded formulations. Kaur et al. tested the efficacy of ethosomal,
 R. Costa, L. Santos / Powder Technology 322 (2017) 402–416 409

Table 3
Examples of studies that tested the transdermal flux, skin penetration and/or incorporated the delivery system in a cosmetic vehicle.

Encapsulated Active Material Preparation method Delivery system Main Results Ref
ingredient ingredient (size)
class

1. Lipoid S 75, - Entrapment efficiency: 61.69% to 85.21% for ethosomes, 89.55%

1. n.s.
ethanol and propylene for liposomes and 81.93% for transfersomes.
2. Conventional 1. Ethosome
glycol - Ethosomes showed superior skin targeting both in vitro and
Antioxidant Apigenin mechanical dispersion 2. Liposome [102]
2. Lipoid S 75 in vivo.
3. Conventional 3. Transfersome
3. Lipoid S 75 and - Ethosomes produced the strongest effect on UVB-induced skin
mechanical dispersion
Tween-80 inflammation.

- Entrapment efficiency: 87.2%.

- Initial burst release up to 16 h followed by controlled release
Nanoparticle
Antioxidant Apigenin PLGA1 Solvent displacement for up to 72 h. [103]
(101 nm)
- Loaded nanoparticles produced better effects than free
apigenin.

- Entrapment efficiency: 78.16% for berberine and 70.28% for

Microcapsule
Berberine gallic acid.
Antioxidant Agar/gelatin n.s. (17 μm and 22 [104]
Gallic acid - In vitro drug delivery of berberine from microcapsule treated
μm)
textiles into the nude mice skin.

1. Sorbitan monostearate,
- Entrapment efficiency: 1.35% to 26.75%.
Ellagic acid polyethylene glycol Reverse-phase Niosome
Antioxidant - The penetration of EA from niosomes depended on the vesicle [100]
(EA) 2. Sorbitan monosterarate, evaporation (124-752 nm)
size, the amount of EA entrapped and the solvents added.
cholesterol

- Entrapment efficiency: 55% and 24% for pure gallic acid and gallic
Elastic: Tween 61, acid in the semi purified fraction in elastic niosomes; 30% and 20%
cholesterol, ethanol Modified chloroform Niosome for pure gallic acid and gallic acid in the semi purified fraction in
Antioxidant Gallic acid [105]
Non-elastic: Tween 61, film (200-400) non-elastic niosomes.
cholesterol, PBS - Elastic niosomes exhibited higher amount of gallic acid
through rat skin.

1. Soya - Entrapment efficiency: 80% for liposome and for transfersomes.

phosphatidylcholine - Percutaneous delivery of elastic liposomes was influenced by
Rotary evaporation and 1. Liposome
Antioxidant Genistein 2. Soya existence of hair follicles. [106]
extrusion method 2. Transfersome
phosphatidylcholine and - The greater permeation rate and deposition values of genistein
sodium deoxycholate were observed from the elastic liposomes in haired skin.

Lipid - Drug loading: 12.1%

Antioxidant Quercetin Tristearin and PC2 n.s. microparticle - Quercetin release from the microparticles did not exhibit [107]
(10-45μm) burst-effect phenomena.

- Entrapment efficiency: 33-57% for rutin, 25-40% for quercetin,

approximately.
Phosphatidylcholine,
Quercetin Liposome (144 - Rutin had better in vitro release properties while quercetin
Antioxidant ceramide-3, cholesterol Thin-film hydration [108]
Rutin nm) demonstrated greater skin permeability.
and oleic acid
- Liposome-in-hydrogel complex systems improved skin
permeability.

Chitosan - Drug loading: 4.1%.

Lipid
Tristearin and Melt emulsification and - Chitosan coating changed the LM3 surface charge.
Antioxidant Resveratrol Microparticles [109]
hydrogenated sonication - Significant enhancement in the in vivo permeation of
(6 μm)
phosphatidylcholine resveratrol.

- Entrapment efficiency: 51% to 53%

Cetylpalmitate and Hot melt SLN
Antioxidant Resveratrol - The presence of tetradecyl-c-cyclodextrin in SLN formulation [110]
tricaprin homogenization (379-472 nm)
improved nanoparticle characteristics.

- Entrapment efficiency: 22 to78%

Rosmarinic Emulsion solvent Microsphere - Emulsions containing RA-loaded PCL4 microspheres showed a
Antioxidant Poly(ε-caprolactone) [111]
acid (RA) evaporation (~ 7-15 um) better long-term stability of the RA compared with those
containing only RA.

Rosmarinic Emulsion solvent Niosome - Entrapment efficiency: 50% to 65%

Antioxidant Sorbitan and cholesterol [112]
acid evaporation (814 nm) - After 24 h, the release was 49.81±1.76% for niosomal gel.

White soft paraffin and - Entrapment efficiency: 89.18% to 96.96%

Liquid paraffin, pifil® GC or - Progressive increase in occlusive properties of the tested
NLC
Antioxidant Rutin (RT) Gelucire®50/13, or Plurol® Probe sonication formulations from 6 to 48 h. [113]
(85-319 nm)
stearique WL 1009, or - An initially rapid release during the first 6 h (burst effect).
Tefose® 2000 CG - No significant effect of RT concentration on sun-blocking.

- Drug loading: 37% to 58%.

Phosphatidylcholine and
Anticellulite Caffeine Thin film hydration Liposome - Higher skin permeation of liposomal cabopol gel formulation. [114]
cholesterol
- Liposomes stored at 2 to 8 °C were more stable.
1. Film hydration 1. Liposome - Entrapment efficiency: 45.2% for liposomes, 70.4% for ethosomes
1. Soya PC2 and CH5
2. Cold method (213-262 nm) and 82.3% for transfersomes.
Curcuma 2. Soya PC2 and ethanol
Extract 3. Modified lipid film 2. Ethosome - The cream efficacy was in the order: transfersomal N ethosomal [115]
longa 3. Soya lecithin and sodium
hydration (rotary (167-195 nm) N liposomal N free C. longa N empty transfersome N empty
deoxycholate
evaporation) 3. Transfersome ethosome N empty liposome N base cream.
(176-199 nm)

(continued on next page)

410 R. Costa, L. Santos / Powder Technology 322 (2017) 402–416
Table 3 (continued)
Encapsulated Active Material Preparation method
ingredient ingredient
class
1. Thin film hydration
1. Tween 61, cholesterol
2. Water–oil–water
Enzyme Papain and sodium cholate
emulsion solvent
2. PLGA1
evaporation
Garcinia
Ethylcellulose blended
Extract mangostana Solvent displacement
methylcellulose
(GML)
Rice bran Sorbitan monostearate and
Extract n.s.
oil Poly(ε-caprolactone)
n.s.- not specified; 1PLGA- Poly(lactic-co-glycolic acid).
n.s.- not specified; 2 PC-phosphatidylcholine; 3LM- lipid microparticle; 4PCL- polycaprolactone.
n.s.- not specified; 5CH- cholesterol.
transfersomal, and liposomal cream formulations with unloaded
and loaded delivery systems (C. longa extract). Cream formulation
efficacy tests were performed in human volunteers through the
evaluation of skin hydration and sebum content. The best cream perfor-
mance was the following, in descending: transfersomal N ethosomal N li-
posomal N free C. longa N empty transfersome N empty ethosome N
empty liposome N base cream. These results suggested that unloaded de-
livery systems had a positive impact on skin hydration and sebum con-
tent but the encapsulation of the natural extract created a synergetic
effect [115]. Delivery systems' performance and skin interaction may
also be modified using a combination of two different active ingredients.
Friedrich et al. encapsulated curcumin and resveratrol both separately
and together. The penetration of resveratrol was improved when co-
encapsulated with curcumin due to interactions of curcumin with the
stratum corneum that facilitated the skin absorption of resveratrol [126].
Safety assessments for nano-particulate systems are important for
consumers' acceptance of this technology and were frequently found in
literature. Oliveira et al. performed in vitro cytotoxicological assays in
human keratinocyte cells and in vivo skin tolerance to rutin loaded gela-
tin nanoparticles in cosmetic sun protective formulations. Results con-
firmed the safety of the tested delivery system [127]. Some studies also
investigated the uptake of the delivery system by human keratinocytes.
Moulaoui et al. tested the uptake of ethosomes and phospholipid vesicles
carrying Fraxinnus angustifolia extract. Results showed a faster internali-
zation of ethosomes, but both types of delivery systems were uptaked
[128].
After understanding how the active ingredient is delivered to the skin
and assuring the safety of both the active ingredients and the delivery
system, it is important to incorporate them in the cosmetic vehicle for
a new characterization of the final product. In fact, the incorporation of
the delivery system in a cosmetic formulation should be kept in mind
since the first development steps of a new carrier.
6. Incorporation of delivery systems in cosmetics
The incorporation in cosmetic formulations of delivery systems is
perhaps one of the most critical aspects in the development of a new
product, since it requires a lot of experiment once it is not universal for
every product. Furthermore, after incorporation it is necessary to guaran-
tee a uniform product, sensorially attractive for the costumer, and with a
long-term stability. Additionally, cosmetic formulations may change
after application to the skin due to interactions with skin or evaporation
of volatile compounds. Experimental formulations must then be tested
regarding its spreadability, rheological properties, color changes, pH
changes, and storage temperatures.
Delivery system Main Results Ref
(size)
- Papain loaded elastic niosomes in gel formulation exhibited
1. Niosome
accumulated amounts and higher fluxes than non-elastic
2. Nanosphere [116]
niosomes.
(221–520 nm)
- No irritation on rabbit skin.
- Entrapment efficiency: 99%.
- Drug loading: 49.73%.
n.s. - Encapsulated and free GML in the cream base penetrated [117]
deeper into hair follicles but encapsulated distributed more
homogeneously on the stratum corneum.
Lipid-core
- This formulation was able to prevent ear edema induced by
Nanocapsule [118]
UVB irradiation by 60 ± 9%.
(200 nm)
Delivery systems can be directly incorporated in the final product,
in the aqueous phase, or in the oily phase. Moreover, they can be firstly
incorporated in gels or dissolved in solutions or slurries that are
then admixed during product manufacturing. A phenolic extract of
Helichrysum stoechas (L.) Moench was encapsulated in polycaprolactone
diol and incorporated in a base moisturizer. The base moisturizer was
prepared by the conventional O/W emulsion. The lyophilized micropar-
ticles had to be dispersed in the oily phase of the moisturizer preparation
to avoid agglomeration. Microparticles were observed in the moisturizer
base as individual particles [129]. On the other hand, quercetin was
entrapped in lipid core microparticles, which were incorporated in the
aqueous phase of a cream formulation. The encapsulation of quercetin
prevented its degradation and long term stability tests demonstrated
that microencapsulation improved the chemical stability of the antioxi-
dant when it was present in a cream [107]. The incorporation in the
final product of an aqueous solution containing the delivery system
often requires a reduction in the water content of the initial formulation.
The same assumption should be taken when the delivery system's
aqueous solution is added to the aqueous phase in the beginning of the
manufacturing process. When SLNs and NLCs are considered, the incor-
poration may lead to a viscosity increase and so, occasionally, it is neces-
sary to reduce the lipid content of the initial formulation [80]. In fact,
regarding the rheological properties, for instance, cosmetic cream formu-
lations may be characterized by a non-Newtonian behavior, since it is
desired to decrease the viscosity of a semisolid formulation when it
is spread on the skin (i.e. an external force is applied). Furthermore,
Newtonian systems such as liquids or emulsions may not form occlusion
films, since they spread rapidly, affecting the effectiveness of the formu-
lation [118]. A good stability after the rheological tests is also important
since it indicates that the product will remain stable even while it is
rubbed into skin.
Another concern is the amount of active ingredient present in the
final cosmetic formulation. Usually during the process, the formulations
are diluted 10 to 20 times. Typically, in the final formulation, the particle
concentration should be 2–4% while the active ingredient concentration
should be 0.05–0.10% [130]. For a successful delivery of an active ingredi-
ent to the skin its thermodynamic activity should be considered. The
thermodynamic activity of an active ingredient describes its tendency
to escape (i.e. driving force) from the cosmetic vehicle to the skin. Con-
sidering no interaction between the skin and the cosmetic vehicle, the
higher the thermodynamic activity, the higher the active ingredient
flux to the skin. In subsaturated vehicles, the thermodynamic activity is
directly dependent on the concentration and activity coefficient of the
active ingredient. In saturated vehicles, the thermodynamic activity is
at unity regardless the concentration or the cosmetic formulation. The
 R. Costa, L. Santos / Powder Technology 322 (2017) 402–416
Active
ingredient
Vesicle
A B
A. Fusion and lipid material exchange with stratum corneum
B. Enhancement of the transdermal passage
C. Free release from the vesicle
D. Intact vesicular skin penetration (only flexible vesicles)
Fig. 3. Possible action mechanisms of vesicles as skin drug delivery systems.
solubility is a factor that affects the thermodynamic activity: considering
the same concentration of an active ingredient in two cosmetic vehicles,
the thermodynamic activity of the active ingredient will be higher when
its solubility is lower. Finally, supersaturated vehicles may be also formu-
lated. In this case, the thermodynamic activity of the active ingredient is
greater than the unity and the flux increases with the saturation degree
[131,132].Taking into account all these considerations, delivery systems
should be incorporated in a proper cosmetic vehicle and at a such con-
centration that on one hand, the active ingredient must be released to
maximize the transdermal flux but on the other hand, stability problems
of the formulations must be avoided.
Polymeric microparticles and nanoparticles may be incorporated ac-
cording to their affinity to form a dispersion and avoid agglomeration.
They can be added as a powder, a slurry, or a wet cake. Powder micro-
particles can be directly incorporated, or firstly dispersed in a solvent.
Mechanical stirring and temperature are important factors to take
into account, since they can influence the integrity of the particles
and lead to the release of the active encapsulated ingredient during
manufacturing [133].
The cosmetic industry is experiencing a big expansion, with ingredi-
ents and technologies being constantly introduced in the market to
overcome some limitations and to create innovative formulations.
Furthermore, new concerns not solely based on product efficacy and
safety are surging in the cosmetic industry.
7. Latest delivery systems in the cosmetic industry
Apart from the delivery systems already described in this review,
there are other technologies that have been explored by the cosmetic
industry, now with a rising interest in the encapsulation of natural
ingredients.
Cubosomes are nanostructured liquid crystalline particles, with a
cubic crystallographic symmetry, formed by self-assembly of amphi-
philic molecules when combined in certain proportions [134]. Some ad-
vantages of cubosomes are the use of biocompatible molecules, the
thermodynamic stability, the encapsulation of hydrophobic, hydrophilic
and amphiphilic substances and the potential for controlled release
through functionalization. The manufacturing of cubosomes can be
done through top-down or bottom-up approaches using a colloidal sta-
bilizer. The bottom-up strategy is more suitable for large scale
411
C D
production and has several advantages comparing to the top-down ap-
proach as it requires less energy input, it allows working with thermo-
sensitive materials, it produces smaller particles with longer-term sta-
bility and with similar or better properties than the ones fabricated by
the top-down approach [135]. This technology caught the attention
not only of the scientific community but also of cosmetic brands such
as L'Oréal or Procter and Gamble [134,136–138].
Another delivery system now used in the cosmetic industry is called
dendrimer. This is a highly branched polymer-based delivery system
with a compact, symmetric and spherical shape. If correctly prepared
they are monodisperse and present several other unique characteristics:
the loading capacity can be altered by changing the generation
number, the physico-chemical properties (e.g. solubility) as well as
the dendrimer-membrane interactions can be controlled through the
manipulation of the surface functionalities, and unlike the linear poly-
mers, the viscosity reaches a maximum value and then decreases with
the molecular weight. This last feature may be highly desirable for
the cosmetic formulators since it may allow an easier handling and in-
corporation in the formulation [139,140]. Typically, dendrimers are
synthetized through a divergent or convergent assembly. The main ad-
vantages of the convergent approach are the precise control over the
molecular weight and a precise location and number of the functionali-
ties. Nevertheless, it is difficult to synthetize dendrimers by the conver-
gent approach in a large scale since the protection of the active site is
required [141]. The incorporation of natural antioxidants in dendrimers
was found in literature [142,143]. Furthermore, several patents of well-
known brands (e.g. L'Oréal, Revlon) claim to use this technology in dif-
ferent kinds of cosmetic products [45].
Nanocrystals are another delivery system firstly introduced in the
market in 2007 with the natural antioxidants rutin and hesperidin.
Originally, nanocrystals were developed to dissolve poorly soluble active
ingredients through crystallization processes, where crystalline particles
of the ingredient were formed within the nanometer range. Therefore,
the nanocrystals are composed of around 100% of the active ingredient
itself with some polymers or surfactants to stabilize. Due to their high
surface area/volume ratio, nanocrystals are able to increase the satura-
tion solubility of the active ingredient and the dissolution rate of the par-
ticles [144]. Furthermore, some natural antioxidant nanocrystals seem to
have higher antioxidant activity than their water soluble derivatives
[145]. The incorporation of this delivery system is simply made by
412 R. Costa, L. Santos / Powder Technology 322 (2017) 402–416
adding an aqueous nanocrystal concentrate to the final dermal formula-
tion, assuring that the nanocrystal concentration is high enough to work
as depot of the active ingredient (i.e. avoid dissolution of nanocrystals)
but not too high for obvious cost reasons [146]. As well as the cubosomes,
nanocrystals can be prepared using bottom-up or top-down approaches.
The last one is industrially more relevant, although it has some draw-
backs such as long operation times and high energy consumption,
which may induce the phase transition of the active ingredient.
Bottom-up approaches have a potential risk of contamination with resid-
ual solvent, besides it is a very complex process [144].
The aforementioned technologies represent some of the recent
work that have been done in the cosmetic industry. Accordingly, there
is still a lot to explore and to investigate for a better understanding
and application of these delivery systems. For instance, there are some
further studies that should be done regarding the improvement of the
loading capacity and the controlled release of cubosomes through
functionalization. One possible approach to explore this topic is by
adding some surfactant molecules that will act as anchors, controlling
and retarding the release of water soluble active ingredients that were
encapsulated [135]. Some more additional work, this time regarding
the nanocrystals, remains in the development of a method to prepare
nanocrystals from medium soluble active ingredients and compare
their performance with the pure solution of the active ingredient.
Nanocrystals of soluble ingredients are also useful because some of
the active ingredients may have a skin penetration rate dependent on
its concentration in the applied cosmetic formulation. As long as the ac-
tive ingredient penetrates the skin, its concentration in the formulation
decreases as well as their ability to penetrate. Therefore, nanocrystals
can be used as depots to keep the active ingredient concentration gradi-
ent and skin penetration steady [145]. Finally, although it was suggested
as future work for dendrimers, the combination of the aforementioned
delivery systems with each other could be applied to most of the tech-
nologies described in this review and can bring interesting findings
and applications [141].
8. Trends and future work on the field of cosmetics and
delivery systems
Cosmetics are used since ancient times and their purpose has been a
combination of therapeutic effects with the desire for beauty [1]. In fact,
according to literature, besides the positive effect on skin health,
cosmetics, in particular make-up, play an important role in social interac-
tion and attractiveness [147,148]. Currently, people are very concerned
with their personal image, which gives the opportunity to develop inno-
vative and appealing products [149]. Actually, new and more effective in-
gredients are one of the main consumers' requests. Natural ingredients,
as is the case of antioxidants, have been increasing their popularity in
the last years and new sources and types of raw materials have been
matter of recent studies. To obtain the bioactive compounds or extracts,
extraction methods need to be optimized and developed in order to dis-
cover safe, ecological, and profitable ways of extracting a wide variety of
compounds, considering their different intrinsic physical-chemical prop-
erties [150]. Additionally, the transformation of some industrial by-
products in safe and suitable raw materials for other industries has
been reported for several areas, and cosmetic industry is not an exception
[151,152]. The speed with which ingredients are introduced in cosmetic
products raises the concern about their safety. However, not only new in-
gredients are subjected to safety assessments. Conventional ingredients
are also being tested using more recent technologies in order to define
new concentration limits and to quantify their presence in commercial
products. Accordingly, cosmetic market experiences a dynamic behavior,
in constant evolution, and therefore companies must be prepared to fol-
low the legislation changes and adapt their products to the new trends.
Nevertheless, currently the consumer perspective is not only focused
on the final product and the positive effects that it may have on its own
health. New concerns about the environmental impact of the cosmetic
development, manufacturing and quality control procedures are surging.
In fact, new analytical methods (frequently used in quality control tests)
claiming to be ecofriendly have been recently described [153]. Europe
Cosmetics (the Personal Care Association) has also made an effort to
work with its members to persuade cosmetic manufacturing companies
to engage in sustainable practices, including the adoption of Life Cycle
Assessment and eco-design of products. Some studies report the pres-
ence and toxicity of cosmetic ingredients in wastewater effluents, fish
tissues and surface water, which can lead to bioaccumulation and
biomagnification problems. The replacement of some synthetic and
toxic cosmetic ingredients by natural ingredients could be a solution to
overcome this problem. However, a careful analysis should be performed
to evaluate the real environmental impact of such replacement. First, it is
necessary to verify if the cosmetic product ingredient really represents
an important contribution to the whole environmental impact of the
final product. Second, an evaluation of the real benefit of using a bio-
based raw material instead of the cosmetic ingredient, i.e. the chemical
processes needed to transform the bio-based raw material into a cosmet-
ic ingredient. Finally, it is necessary to evaluate if the functional perfor-
mance of the bio-based ingredient may affect the dosage and the
effectiveness of the formulation [154]. Animal rights are now another
concern of cosmetic industry and consumers. During the past years, an-
imals have been used for testing cosmetic ingredients and formulations
to assess their safety and performance. However, European Union pub-
lished the 7th Amendment (Directive 2003/15/EC) to the Cosmetic Di-
rective (Directive76/768/EEC) calling for a marketing ban, from March
2013, on cosmetic products that contain ingredients tested on animals
for toxicity and toxicokinetics. Therefore, efforts have been made to de-
velop in vitro, in chemico and in silico models to replace animal testing
since it is necessary to assure product safety and efficacy [155,156].
The development of new delivery systems should also follow the
aforementioned concerns regarding the use of green technologies and
non-toxic environmental materials. In addition, the development of de-
livery systems still has some more goals to achieve. Although skin phys-
iology is relatively well known, further studies should be performed for a
better understanding of the dominant permeation pathways, as well as
the interactions of each delivery system material with the skin. Long-
term use of delivery systems (e.g. nanoparticles) is still unknown, and
their effects should be assessed since they may disturb the physiologic
function of the skin. Actually, safety evaluations are essential for a better
public acceptance of new technologies. Additionally, one of the major
challenges is the process scale-up. Delivery systems should use materials
with reasonable prices in order to pass from the laboratory scale to the
industrial and commercial production [157]. Moreover, the methods
must be developed and optimized in order to obtain a uniform and re-
producible outcome. In fact, uniform and reproducible delivery systems
are not only required in terms of size but also with respect to the drug
loading, controlled release, and stability [158]. The preparation method
should also be adaptable to new market trends and legislation, while
also being able to encapsulate new ingredients. The interactions and be-
havior of different materials that compose a delivery system should be
well studied and documented, since most of the times the selection of en-
capsulating agent is made by trial and error [159]. A deeper study of
these characteristics would provide more information for a more rational
and logical choice of the encapsulating agents. Furthermore, the line be-
tween cosmetic and pharmaceutical products is becoming blurrier. De-
livery systems have been used for both purposes and cosmetic
products are increasingly required to have some health benefit. This is ac-
tually confirmed by the emergence of cosmeceuticals or nutricosmetics
[160,161]. The combination of cosmetic action with textile using delivery
systems is also a new trend [162].
Therefore, the use of delivery systems in cosmetic field is a promising
technology for an improved performance of the products, by increasing
the stability of sensitive ingredients such as natural antioxidants, by de-
creasing its dosage in formulation, and by controlling and targeting the
delivery.
 R. Costa, L. Santos / Powder Technology 322 (2017) 402–416
9. Conclusion
Natural ingredients, in particular natural antioxidants, are gaining
popularity among cosmetic consumers. They can be entrapped into de-
livery systems to improve their skin penetration and to overcome
some stability problems associated with antioxidants. Delivery systems
may be able to protect a sensitive active ingredient while the product
is stored, only releasing it when it is applied on the skin, thus allowing
a controlled and targeted release. Mechanical forces, pH, or temperature
could be used as triggers to promote the liberation. Several types of de-
livery systems may be used in cosmetic formulation and each one of
them has some drawbacks and advantages. The interaction of each deliv-
ery system with the skin mainly depends on in its composition, flexibil-
ity, and size. The incorporation of the delivery system in a cream
formulation must be performed assuring the stability of both of them
in order to obtain a successful product. Despite the success of the delivery
systems and its incorporation in already commercialized products, some
challenges still remain to overcome. New concerns about environmental
impact or animal welfare are surging with respect to the cosmetic devel-
opment, manufacturing, and quality control. With regard to delivery sys-
tems, eventually, the main limitation and future work resides in the
passage from the laboratory scale to industrial production.
To conclude, the usage of delivery systems is a promising technology
and arouses great attention from the scientific community due to the
large number of publications in this field.
Acknowledgements
This work was financially supported by the projects POCI-01-0145-
FEDER-006939 (Laboratory for Process Engineering, Environment,
Biotechnology and Energy – UID/EQU/00511/2013) funded by the
European Regional Development Fund (ERDF), through COMPETE2020 -
Programa Operacional Competitividade e Internacionalização (POCI)
and by national funds, through FCT - Fundação para a Ciência e a
Tecnologia and NORTE-01-0145-FEDER-000005 – LEPABE-2-ECO-
INNOVATION, supported by North Portugal Regional Operational
Programme (NORTE 2020), under the Portugal 2020 Partnership
Agreement, through the European Regional Development Fund (ERDF).
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