Delivery systems for cosmetics - From manufacturing to the skin of natural
antioxidants

Raquel Costa, Lúcia Santos

PII: S0032-5910(17)30632-0
DOI: doi:10.1016/j.powtec.2017.07.086
Reference: PTEC 12728

To appear in: Powder Technology

Received date: 7 October 2016

Revised date: 1 July 2017
Accepted date: 27 July 2017

Please cite this article as: Raquel Costa, Lúcia Santos, Delivery systems for cosmetics
- From manufacturing to the skin of natural antioxidants, Powder Technology (2017),
doi:10.1016/j.powtec.2017.07.086

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DELIVERY SYSTEMS FOR COSMETICS - FROM MANUFACTURING TO THE SKIN OF

NATURAL ANTIOXIDANTS

Raquel Costa a, Lúcia Santos b*

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a

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Chemical Engineering Department, Faculty of Engineering, University of Porto
b
LEPABE – Laboratory for Process Engineering, Environment, Biotechnology and

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Energy, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465,

Porto, Portugal

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*Corresponding author: Tel.: +351 22 5081682, Fax: +351 22 508 1440, e-mail

address: lsantos@fe.up.pt
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Highlights
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 Natural antioxidants can be used both as preservatives and as active ingredients

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 Delivery systems can be used to overcome some limitations of natural antioxidants

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 Skin interaction may depend on the delivery system size, elasticity and composition
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 Integration of delivery systems in a cream should assure the stability of both.

 Environmental or animal welfare concerns are surging in the cosmetic industry

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Abstract

Delivery systems are extensively used in cosmetic products. This literature review

describes some of the delivery systems used in the cosmetic industry, , some general

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considerations about their presence and incorporation in cosmetic formulations, as well as their

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skin interactions. This review also covers the manufacturing process of a cosmetic cream

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formulation, including basic ingredients, natural antioxidants in particular. In addition, future

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perspectives, recent concerns, and further work regarding the cosmetic industry are also

described.

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Natural antioxidants presenthealth benefits such as anti-ageing, anti-inflammatory, anti-

carcinogenic, and anti-microbial properties that potentiate their use in cosmetic products.
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Furthermore, they can also be used as preservatives since they avoid the lipid oxidation that

usually occurs in cosmetic products. However, antioxidants may have stability issues and
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difficulties in crossing the transdermal barrier. Delivery systems can be used to protect sensitive
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active ingredients from degradation and to grant a target and controlled release. Several types of

delivery systems (e.g. liposomes, niosomes, transfersomes, lipid nanoparticles, polymeric

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microparticles and nanoparticles) have been used in cosmetic formulations. The use of delivery
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systems may improve the penetration of the antioxidant. Skin interaction with the different

delivery systems depends mostly on their size, flexibility and composition. Moreover, delivery
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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.

Key words: delivery systems; cosmetics; antioxidants; skin; anti-ageing; personal care
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Contents

1. Introduction .............................................................................................................. 4
2. Basic cream formulation ingredients ........................................................................ 5

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2.1. Antioxidants ....................................................................................................... 6

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3. Cream manufacturing process .................................................................................. 8

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4. Delivery Systems .................................................................................................... 10
4.1. Liposomes ........................................................................................................ 11

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4.1.1. Niosomes, Transfersomes, Ethosomes ..................................................... 12
4.2. Lipid Nanoparticles .......................................................................................... 15

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4.3. Polymeric Nanoparticles and Microparticles ................................................... 17
5. Skin interaction with delivery systems- illustrative studies ................................... 19
6. Incorporation of delivery systems in cosmetics ..................................................... 22
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7. Latest delivery systems in the cosmetic industry ................................................... 24
8. Trends and future work on the field of cosmetics and delivery systems ................ 27
9. Conclusion .............................................................................................................. 30
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Acknowledgements ........................................................................................................ 31
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References of the article ................................................................................................. 32

References of the Tables................................................................................................. 51
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List of Figures ................................................................................................................. 57

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List of Tables .................................................................................................................. 57

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1. Introduction

Cosmetics have been used since the Egyptian times, where the color from minerals and

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plants was applied as eye make-up. According to manuscripts, some of the substances were

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toxic, even though they were used to treat eye and skin illnesses. The first cold cream (an

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emulsion of beeswax, vegetable oil and water) was invented in the 2nd century by Galen, a

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Greek physician. Nowadays, the cosmetic concept is certainly very different from back then,

although some of the ingredients are still the same [1]. In fact, according to European definition,

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cosmetics are ―any substance or mixture intended to be placed in contact with the external parts
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of the human body or with the teeth and the mucous membranes of the oral cavity to clean them,

change their appearance, 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,
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toilet soaps, perfumes, shower preparations, depilatories, deodorants and antiperspirants,

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products for external intimate hygiene, skin, hair, oral and nail care products. However, this
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definition is not universal. Some products that are considered as cosmetics in Europe (sunscreen
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products, anticavity toothpastes, antiperspirants, antidandruff preparations, skin protectants and

hair restorers) may be classified as over-the-counter drugs in the USA since the cosmetic
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definition is somehow narrower [2].

Currently, skin care products represent billions of euros in the cosmetic market. Consumer

requirements are becoming very demanding since a facial cream, for instance, must have

cleansing, smoothing, restoring, 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. Typically , the promotion of a skin care product involves a skin

positive effect (e.g. anti-ageing, antioxidant properties), performed by an active ingredient (e.g.

resveratrol, vitamin E), delivered by a vehicle (e.g. cream, lotion), using a recent technology

(e.g. nanoparticles, liposomes) [3]. Therefore, the development of cosmetic products should
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contemplate an integrative approach, not only focused on the formulation process, but also on

the consumer perception and requirements, as well as marketing strategies, in order to produce a

successful product.

To build consumer trust and to commercialize the product it is necessary to assure the safety

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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

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of cosmetic ingredients and their concentration in cosmetic formulations [4,5]. Actually, the

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basic composition of a cosmetic cream is well known in the art, and generally it comprises the

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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
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claiming to have the same purpose.

2. Basic cream formulation ingredients

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Most of the cosmetic formulations for skin care are an oil-water emulsion (O/W), a water-
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oil emulsion (W/O) or a double emulsion (oil-water-oil or water-oil-water). From a

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dermatological perspective, the W/O emulsion is a better choice, since the lipid film formed on
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the skin favors the oil-soluble active ingredients. Usually, lotions are composed of an O/W

emulsion, since they have a higher water content than creams. O/W emulsions are also more
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appreciated by the consumer 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%), humectants (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 substances, sunscreens can also be

incorporated to add some value to the product. The use of fragrances and dyes may turn the

product more attractive to the consumer.

Simple emollients are hydrophobic compounds used to prevent the water evaporation from

the skin by forming an occlusive film. Humectants are hydrophilic compounds that attract water
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to the stratum corneum, compensating the reduced number of natural moisturizing factors [8].

Thickeners are used to control the texture and rheological properties 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

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molecules that comprise both hydrophobic and hydrophilic characteristics; therefore, they do

not tend to be soluble in only one of the phases, but to collect at the interface of both phases,

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promoting the emulsion. Emulsifiers can either be ionic or non-ionic. The first ones can be

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divided in cationic and anionic, depending on the head charge [11]. Theoretically, non-ionic

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emulsifiers can be selected through the HLB (hydrophilic-lipophilic balance) number which

measures the balance between the hydrophilic and lipophilic part of the molecule. However, the
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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 viscosity, and the size of the

emulsion droplets that can affect creaming rate or phase splitting. Experimental procedures to
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determine the best emulsifiers 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 observe which HLB value
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leads to a stable emulsion [7]. Finally, stabilizers and preservatives are used to prolong the
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product shelf-life and promote its stability. Preservatives are compounds that inhibit the growth

of microorganisms while stabilizers maintain the physicochemical integrity of the product

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[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, antioxidants, or any other natural substances that may add value to the

product. 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 interact with free radicals and terminate a

chain reaction before vital molecules are damaged [14]. The use of antioxidants is described in
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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

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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 consumption of

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synthetic antioxidants results in potential health risks [16]. Despite the market leading by

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synthetic antioxidants, the demand for natural antioxidants have been increasing in the last few

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years and it is expected to continue. This trend can be explained by a crescent consumer

preference for organic and natural products, since they use less additives and may have less
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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
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reduce the skin oxidative stress or protect the product from oxidative degradation [18].

Reactive oxygen species (ROS) are one of the major causes of oxidative stress which
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enhances the skin ageing process [19]. Intrinsic ageing is associated with the natural process of
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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
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reason of ROS production. Several potential skin targets (e.g. lipids, DNA, proteins) have been

found to interact with ROS [20]. Figure 1 was adapted from Masaki and presents some of the

potential oxidative stress effects on the skin [21]. 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 chelators, oxidative enzyme inhibitors or cofactors of enzymes [19,22].

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
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phase, molecular oxygen and fatty acid radicals react, leading to the formation of hydroperoxide

products. Hydroperoxides are unstable and can degrade to produce radicals that will accelerate

the propagation reaction. The termination phase is dominated by reactions between radicals

[23]. Antioxidants can prevent lipid oxidation by reacting with lipid and peroxy radicals,

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converting them to more stable and non-radical products. Antioxidants are also able to reduce

hydroperoxides to hydroxy compounds, deplete molecular oxygen, deactivate singlet oxygen,

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remove prooxidative metal ions, replenish hydrogen to other antioxidants, and absorb UV light

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[19,24]. According to literature, antioxidants can also be involved in cancer treatments, since

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the production of reactive oxygen species is altered during tumorigenesis [25,26]. They also

have anti-inflammatory and anti-microbial properties [27].

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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 [28,29]. For topical application
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in particular, the ability to cross the dermal barrier could be a challenge for some antioxidants.

This difficulty is explained by the distinct composition of the different skin layers [30,31].
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Furthermore, according to literature, the stability of antioxidants may be influenced by light,

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pH, temperature and oxygen [32–34]. They can also react with other matrix compounds,

degrade, and lose their activity [35]. Therefore, the incorporation step during the manufacturing
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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 (Figure 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 extracts, antioxidants, preservatives, to
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film formers. The aqueous phase usually contains thickener agents, humectants, buffers, or any

other excipient that is soluble in water and thermal resistant [36]. After preparation 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

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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,

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therefore the use of a homogenizer with vacuum lines or a de-airing step should be added to the

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process. At laboratory scale, sonication can be used to remove the bubbles from the formulation

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[7]. Further treatments are sometimes necessary to achieve a uniform dispersion and a size

reduction of the ingredients.

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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
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emulsion does not form rapidly, different emulsifiers or a higher concentration of emulsifiers

should be used; 2) if the oily phase splits, emulsifiers with lower HLB values should probably
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be selected. On the other hand, if the water phase splits out, emulsifiers with higher HLB values
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must be used; 3) when a solids suspension is involved in the formula, the use of polymeric

emulsifiers must be considered; 4) if the formulation viscosity is low, solid emollients at room
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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 laboratory 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

[9,36]. The adjustment of pH can be performed at the end of the formulation or by adding the
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neutralizing agent generally to the aqueous phase [7,37]. 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

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probably the most used filtration equipment in the cosmetic industry [38].

As aforementioned, the incorporation of sensitive ingredients, such as antioxidants, during

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the manufacturing process, could be a critical aspect of producing a new product. To overcome

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this limitation, delivery systems may be used, since they can protect sensitive ingredients from

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degradation and control their release during manufacturing, assuring their stability.
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4. Delivery Systems

Delivery systems are engineered technologies used to carry an active ingredient, promoting
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a controlled and targeted delivery. Human skin acts as a barrier against the permeation of
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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
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skin. For a cosmetic purpose, it is a major concern to keep the active ingredient in the
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superficial skin layers and avoid the systemic absorption [39]. Burst and sustained release are

two major features that should be associated with cosmetic delivery systems. Burst release is
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important 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 periods of time [40]. Moreover, the active ingredient protection is

another advantage of using delivery systems. The shelf life required for a cosmetic product is

usually no less than 2 years. Therefore, ingredients sensitive to external 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 [41]. Product appearance and flow properties may also be improved,

enhancing its handling, usage and storage. Undesirable organoleptic properties can be masked
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and the evaporation of volatile ingredients can be controlled with delivery systems. These

technologies can also be used to reduce the amount of ingredient in the formulation, becoming a

cost saving alternative.

Several types of delivery systems can be found in cosmetic products. They may be divided

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into vesicular systems (liposomes, niosomes, transfersomes), emulsions (microemulsions and

nanoemulsions), and particulate systems (microparticles, nanoparticles) [39]. Table 2 presents

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some examples of commercialized cosmetic products containing natural ingredient loaded

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delivery systems.

4.1. Liposomes
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Described in the mid-sixties, liposomes were used in cosmetic industry by Christian Dior -

CaptureTM. Nowadays, liposomes present a large number of applications in different sectors

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such as food, cosmetic and pharmaceutical industries [42]. Liposomes are vesicles with a
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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
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unilamellar vesicles (LUV) (100-3000 nm), multilamellar vesicles (MLV) (> 1000 nm) where
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more than one bilayer is present, and even multivesicular liposomes (MVL) [43]. Despite their

hydrophilic core, liposomes can accommodate hydrophobic, hydrophilic or amphiphilic

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molecules. Hydrophobic 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 [44].

Liposomes have caught the attention of researchers as a promising delivery system due to its

biocompatibility, biodegradability, low toxicity, easy preparation, prolonged circulation time,

and the ability of extend products shelf life. On the other hand, poorly water-soluble drugs

incorporated in the lipid bilayer are often rapidly released, which limits the potential of

liposomes for hydrophobic molecules [45]. The lack of physical and chemical stability due to

lipid oxidation and hydrolysis are other drawbacks of this delivery system [46].
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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 injection, proliposome-

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liposome, reverse-phase evaporation), and detergent removal methods. Nevertheless, only some

of those methods are suitable for a large-scale production since liposomes have to be produced

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in a controlled, stable and reproducible way. Film methods are difficult to scale up (to several

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tens of liter) and they create vesicles with different sizes which can lead to an expensive and

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time consuming production, due to the need of further processing for a defined liposomal

suspension. Microfluidization operates at pressures between 0-200 bar and with a precise
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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
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to a time consuming process and generates high product losses. The reverse-phase evaporation

method is characterized by a high encapsulation rate. However, two of the possible drawbacks
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are the remaining solvent and the necessity of appropriate shear mixing devices and pumps for a
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large scale production [47]. Finally, the preparation of liposomes through ethanol injection

based methods is extensively reported in literature. In general terms, such techniques are often
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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 [48].

Diverse delivery systems based on liposomes were developed: niosomes, transfersomes,

ethosomes, dendrossomes, among others.

4.1.1. Niosomes, Transfersomes, Ethosomes

Niosomes were originally developed in the seventies for cosmetic industry, although
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nowadays a wide range of applications can be also found in the pharmaceutical field. They are

biodegradable and biocompatible vesicles composed of nonionic surfactants and, in some cases,

cholesterol or its derivatives [49]. Cholesterol is used as an additive agent interacting with the

hydrophilic head of the nonionic [50]. It affects some properties of the vesicle such as

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entrapment efficiency, storage time, release, and stability [51]. Cholesterol improves the

stability of the surfactant bilayer, since it increases the gel-liquid transition temperature of the

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niosome. In order to stabilize niosomes, charged molecules can be added to the bilayer [52].

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These additives are useful to prevent aggregation, increase encapsulation efficiency, and

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enhance skin permeation. Niosome research interest arose from the ability of overcoming some

of the liposome limitations. Nonionic surfactants give higher versatility to the vesicular
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structures and they are less expensive than phospholipids. Niosomes are also easier to prepare

than liposomes due to the surfactant resistance to air oxidation and high temperatures.

Regarding skin permeation, niosomes present a more effective delivery by topical application.
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Niosomal formulations usually present an improved sustained release and higher stability than

liposomal formulations [53]. However, some of the drawbacks are common for both liposomal
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and niosomal vesicles since, during dispersion, both of them are at risk of aggregation, fusion,
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drug leakage, or hydrolysis of encapsulated drugs [54]. Some of the preparation methods used

for niosomes are the thin film hydration method, the organic solvent injection method, the
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reverse-phase evaporation method and the bubble method. In the film hydration method, 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 [51].

Transfersomes are deformable vesicles, first developed in 1991, composed of phospholipids

and an edge activator. The edge activator is usually a single chain surfactant, with a high radius

of curvature, able to decrease bilayer stiffness [55]. This elastic behavior avoids the vesicle

rupture and it is responsible for its penetration into the skin. Phospholipid hydrophilicity leads
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to xerophobia (tendency to avoid dry surrounding). 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 structures, and its penetration [56,57]. Phospholipids

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are the main constituent while surfactants range between 10-25% and the solvent alcohol

composition is between 3-10%. A wide range of molecules (e.g. peptides, antioxidants, DNA)

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can be successfully entrapped in transfersomes. Transfersome preparation involves simple

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procedures, easy to scale up and with acceptable additives [58]. The two main techniques are

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vortexing-sonication and rotary evaporation–sonication. In vortexing-sonication method, a PBS

mixture of lipids, edge activator, and active ingredient, is vortexed until a milky suspension is
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obtained. The suspension 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
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under reduced pressure at 400 ºC. The deposited lipid film is hydrated with a solution

containing the active ingredient while the flask is rotated during one hour at room temperature.
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The resulting vesicles are left to swell, at room temperature, and then sonicated and extruded
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through a sandwich of polycarbonate membrane [59] .

Ethosomes are phospholipid vesicles with high concentrations of ethanol (20-50%) first
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developed in 1997. The commercialization of ethosome technology began in 2000 [60]. 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 affects the bilayer structure of

the stratum corneum. The interaction of the vesicle with the disrupted stratum corneum may

forge a penetration pathway [61]. 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 [62]. As opposed to transfersomes, ethosomes are

able to improve the skin delivery under occlusive and non-occlusive conditions [63]. Some of

the main drawbacks of this delivery system are its instability due to oxidative degradation and

the lack of purity of natural phospholipids that affects its public acceptance [58]. The
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preparation of ethosomes involves two conventional methods, the hot and cold methods, but

classic mechanical dispersion method and transmembrane pH-gradient active loading method

are also reported. In cold method, the lipid material is dissolved in ethanol, at room temperature,

with vigorous stirring. Then, propylene glycol or other polyol is added to the mixture that is

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afterward heated up to 30 ºC. Water of the same temperature is added slowly to the previous

mixture. After stirred and cooled at room temperature, the preparation may be sonicated or

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extruded to obtain the desired size. The active ingredient can be dissolved in water or ethanol,

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depending on its properties. In hot method, the lipids are dispersed in water at 40 ºC until a

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colloidal solution is obtained. Ethanol and glycol are also heated separately up to 40 ºC and

then added to the aqueous phase. After that, the same procedure of cold method should be
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followed to obtain the intended size. Large amounts of ethosomal formulation can be easily

prepared, since it does not required complex and specific equipment [64].
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4.2. Lipid Nanoparticles

Lipid nanoparticles are an O/W nanoemulsion colloidal dispersion where the liquid oil is
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replaced by a solid lipid, in case of solid lipid nanoparticles (SLNs), or a blend of solid and
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liquid lipids, for the formation of nanostructured lipid carriers (NLCs). SLNs were first
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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 multiple type. The imperfect type structure results from using

different molecules 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 amorphous state. Finally, the multiple type structure
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corresponds to an oil-solid lipid-water dispersion where oil nanocompartments are inside a solid

lipid matrix [65]. Several different techniques are described in literature to produce lipid

nanoparticles: high pressure homogenization, microemulsion technique, emulsification-solvent

evaporation, emulsification-solvent diffusion method, solvent injection (or solvent

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displacement) method, phase inversion, multiple emulsion technique, ultra-sonication and

membrane contractor technique [66]. High pressure homogenization is one of the most used

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methods and it starts with the dispersion or dissolution of the active ingredient in the melted

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lipids. Then, if hot high pressure homogenization method is performed, the melted lipids are

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dispersed in a hot surfactant solution of the same temperature, by high speed stirring. The

resulting emulsion is then passed through a high pressure homogenizer, at the same temperature.
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On the other hand, if cold high pressure homogenization is performed, the melted lipids

containing the active ingredient are cooled down until solidification. After that, the mass is

crushed, ground, and dispersed in a cold surfactant solution. A cold pre-suspension of

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micronized lipid particles is formed and passed through a high pressure homogenizer at room

temperature [67]. High pressure homogenization has several advantages comparing to other
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methods since it is easy to scale up, it does not use organic solvents and requires a short
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production time. Furthermore, high pressure homogenizers are used in pharmaceutical

industries, so, no regulatory problems exist for the production of cosmetic preparations [66].
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SLNs show burst and sustained release, which are both important for cosmetic application

[68,69]. Under optimized conditions, they are able to entrap both hydrophilic and lipophilic

active ingredients. Nevertheless, they are claimed to possess a low drug loading capacity due to

the SLN crystalline structure, and they can undergo polymorphic transition [70]. 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 incorporate higher amounts of the active ingredient, since it can

be located between the fatty acid chains, between the lipid layers and also in the lipid matrix

imperfections. Additionally, the higher order degree of the structure also leads to a faster

expulsion of the active ingredient. Therefore, NLCs minimize the expulsion of the active
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ingredient and increase the drug loading capacity, overcoming some of the problems of SLNs

[65].

The typical raw materials used for the preparation of lipid nanoparticles are GRAS

(Generally Recognized As Safe), therefore no problems of biocompatibility or toxicity are

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associated [71]. Furthermore, some authors suggest using SLNs and NLCs as delivery systems

for sunscreen formulations, since these nanoparticles also have protective effect from the sun.

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Several cosmetic products with SLNs and NLCs are already commercially available [66]. Some

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of the main drawbacks of lipid nanoparticles are the general tendency for aggregation when

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combined with some ingredients, and gelation behavior associated with SLNs. However, NLCs

present an improved physical stability in suspension comparing to SLNs [70]. Compared to

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liposomes, lipid nanoparticles have slower degradation 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 [72].

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4.3. Polymeric Nanoparticles and Microparticles

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Nano/microparticles are used to entrap active ingredients, either inside (core material) or
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scattered among the particle’s own material (shell material) [73]. The exact definition of
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nanoparticles and microparticles is not consensual among authors. Some researchers consider

that the nanoparticle size should range between 1 and 100 nm, while others claim that it must

range between 1-1000 nm [74,75]. Nano/microparticle is a general term comprising both

nano/microspheres and nano/microcapsules. Nano/microspheres consist of a dispersion of the

active ingredient in the polymeric matrix, whereas nano/microcapsules are reservoirs where

distinct domains of core and wall material are present [76]. One of the main purposes of this

procedure is the creation of a physical barrier that avoids the contact of the active agent with the

external matrix, protecting sensitive substances from moisture, pH, light, oxygen, and other

molecules present in the matrix [77]. Nanoparticles in particular can be applied as preservatives

and antibacterial agents in cosmetics [78].

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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 [79,80]. Spray drying is

one of the mostly used microencapsulation techniques [81]. A solution, a suspension, or an

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emulsion containing the core material and the shell material is homogenized and then fed to a

spray drying equipment. Then, the process can be divided in three steps: (1) atomization of the

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liquid solution, (2) contact of the fine droplets with a hot gas stream to evaporate the solvent, (3)

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separation and collection of the powder. Spray drying is a relatively simple process, with a low

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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,
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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 [82,83].

A wide variety of encapsulating agents can be used, extending from synthetic to natural. Its
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choice should be made according to the particle application, the selected core material, the

physical and chemical stability, the required particle size, the release mechanism, and the
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manufacturing costs [78,82]. Occasionally, a combination of wall materials, and crosslinking

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agents, are used to achieve the desired properties [79]. Crosslinking agents are molecules

capable of establishing ionic or covalent bonds with the encapsulation agent (i.e. polymer),
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building a sort of network, and altering some of the proprieties of the microparticles,

particularly the release behavior [84].

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 [85]. 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 release by

diffusion, a faster penetration of water into the particle, and a lower drug loading. The

adsorption of molecules on the surface also occurs during particle formation, and it is more

accentuated the smaller the particle is. On the other hand, smaller particles may have a better
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binding per unit of particle mass than larger ones, which could be useful to adhere to the skin

[86].

In fact, understanding skin physiology and the interactions of the different delivery systems

with it is essential for a correct selection of the most suitable delivery system, as well as its

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materials and preparation method. Table 3 presents some examples of studies of natural

ingredient loaded delivery systems with cosmetic relevance.

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5. Skin interaction with delivery systems- illustrative studies

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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
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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
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described the incorporation of ellagic acid in niosomal formulations obtained from the mixture
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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 buffer (pH 5.5) and isopropyl alcohol
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as the receptor medium. Ellagic acid from niosomal formulations was found both in the receptor
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medium and in the epidermis. On the other hand, when the solution of ellagic acid was tested,
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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

observed 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

[87]. The passage through the stratum corneum is limited to low-molecular weight molecules

(<500 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 [31,88].

Nanoparticles are able to make close contact with superficial junctions of the stratum corneum,

creating channels through corneocytes islands, thus allowing the dispersion of the active
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ingredient [89]. Vesicular delivery systems are frequently reported in cosmetic formulations.

Their dimensions can range between the nano and the micro scale. Roughly speaking, they can

be divided in elastic, flexible, and deformable systems, or in rigid ones. Vesicular systems can

deliver the active ingredient just by releasing it from the vesicle, they can enhance the

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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

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(Figure 3) [56]. Intact vesicular skin penetration is more associated with deformable systems,

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since they can squeeze through the interclusters and intercorneocytes pathways using the

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hydrating gradient as driving force [90,91]. Deformable vesicles are often smaller than rigid

ones, which also justifies why they are frequently found deeper in the skin. Zhang, Y. et al.
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compared the use of liposomes and ethosomes for skin delivery of psoleren, a natural 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
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improved skin deposition than liposomes (2.15 times). These results may be explained by the

intact penetration of ethosomes in the skin [92].

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The penetration of active substances and nano delivery systems is also possible through the
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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
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infundibulum can also act as reservoir for nano and micro sized particles. It is suggested that

larger particles release high concentrations of the active ingredient to the follicle duct, from

where it can be after released, while smaller particles (less than 40 nm) can pass through the

disrupted skin barrier [93]. 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 [94]. 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 follicles can work as reservoir of genistein [95].

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Rigid particulate system penetration (SLNs, NLCs, micro/nano particles) mostly depends on

the particle size, its composition and charge being less significant [88]. Nano sized particles

(less than 100 nm), due to water evaporation after application on the skin, are able to form an

occlusive film that increases the hydration of the stratum corneum, which consequently leads to

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the formation of gaps between corneocytes. Hydration also affects the partitioning of the active

agent into the stratum corneum [89]. In fact, the particle occlusive capacity may also be affected

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by the loaded substance. Okonogi et al. described the impact of lycopene drug loading on skin

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occlusive properties of NLCs. The results evidenced that the occlusive properties of the NCLs

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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
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the nanocrystalline characteristics of lycopene and the formed lipid film [96]. The study

performed by Kamel et al, encapsulating rutin in NLC’s as well, presented the same relation

between the drug loading and the occlusive properties of the nanoparticles [97]. Loading natural
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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,
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transfersomal, and liposomal cream formulations with unloaded and loaded delivery systems (C.
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longa extract). Cream formulation efficacy tests were performed in human volunteers through

the evaluation of skin hydration and sebum content. The best cream performance was the
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following, in descending: transfersomal > ethosomal > liposomal > free C. longa > empty

transfersome > empty ethosome > empty liposome > base cream. These results suggested that

unloaded delivery systems had a positive impact on skin hydration and sebum content but the

encapsulation of the natural extract created a synergetic effect [98]. 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 [99].
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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

gelatin nanoparticles in cosmetic sun protective formulations. Results confirmed the safety of

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the tested delivery system [100]. Some studies also investigated the uptake of the delivery

system by human keratinocytes. Moulaoui et al. tested the uptake of ethosomes and

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phospholipid vesicles carrying Fraxinnus angustifolia extract. Results showed a faster

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internalization of ethosomes, but both types of delivery systems were uptaked [101].

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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
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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.

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6. Incorporation of delivery systems in cosmetics

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The incorporation in cosmetic formulations of delivery systems is perhaps one of the most
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critical aspects in the development of a new product, since it requires a lot of experiment once it
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is not universal for every product . Furthermore, after incorporation it is necessary to guarantee

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 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

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incorporated in a base moisturizer. The base moisturizer was prepared by the conventional

O/W emulsion. The lyophilized microparticles 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 [102]. On the other hand, quercetin was entrapped in

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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

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tests demonstrated that microencapsulation improved the chemical stability of the antioxidant

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when it was present in a cream [103]. The incorporation in the final product of an aqueous

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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
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solution is added to the aqueous phase in the beginning of the manufacturing process. When

SLNs and NLCs are considered, the incorporation may lead to a viscosity increase and so,

occasionally, it is necessary to reduce the lipid content of the initial formulation [65]. In fact,
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regarding the rheological properties, for instance, cosmetic cream formulations may be

characterized by a non-Newtonian behavior, since it is desired to decrease the viscosity of a

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semisolid formulation when it is spread on the skin (i.e. an external force is applied).
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Furthermore, Newtonian systems such as liquids or emulsions may not form occlusion films,

since they spread rapidly, affecting the effectiveness of the formulation [104]. A good stability
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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% [105]. In fact, for a successful delivery of an active

ingredient 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. Considering no interaction between the skin and the cosmetic

vehicle, the higher the thermodynamic activity, the higher the active ingredient flux to the skin.
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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 solubility is a

factor that affects the thermodynamic activity: considering the same concentration of an active

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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 formulated.

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In this case, the thermodynamic activity of the active ingredient is greater than the unity and

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the flux increases with the saturation degree [106,107].Taking into account all these

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considerations, delivery systems should be incorporated in a proper cosmetic vehicle and at a

such concentration that on one hand, the active ingredient must be released to maximize the
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transdermal flux but on the other hand, stability problems of the formulations must be avoided.

Polymeric microparticles and nanoparticles may be incorporated according to their affinity

to form a dispersion and avoid agglomeration. They can be added as a powder, a slurry, or a wet
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cake. Powder microparticles can be directly incorporated, or firstly dispersed in a solvent.

Mechanical stirring and temperature are important factors to take into account, since they can
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influence the integrity of the particles and lead to the release of the active encapsulated
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ingredient during manufacturing [108].

The cosmetic industry is experiencing a big expansion, with ingredients and technologies
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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

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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

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symmetry, formed by self-assembly of amphiphilic molecules when combined in certain

proportions [109]. Some advantages of cubosomes are the use of biocompatible molecules, the

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thermodynamic stability, the encapsulation of hydrophobic, hydrophilic and amphiphilic

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substances and the potential for controlled release through functionalization. The manufacturing

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of cubosomes can be done through top-down or bottom-up approaches using a colloidal

stabilizer. The bottom-up strategy is more suitable for large scale production and has several
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advantages comparing to the top-down approach as it requires less energy input, it allows

working with thermo-sensitive materials, it produces smaller particles with longer-term stability

and with similar or better properties than the ones fabricated by the top-down approach [110].
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This technology caught the attention not only of the scientific community but also of cosmetic

brands such as L’Oréal or Procter and Gamble [109,111–113]

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Another delivery system now used in the cosmetic industry is called dendrimer. This is a
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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
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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 polymers, 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 incorporation in the formulation[114,115]. Typically, dendrimers are synthetized

through a divergent or convergent assembly. The main advantages of the convergent approach

are the precise control over the molecular weight and a precise location and number of the

functionalities. Nevertheless, it is difficult to synthetize dendrimers by the convergent approach

in a large scale since the protection of the active site is required [116]. The incorporation of
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natural antioxidants in dendrimers was found in literature [117,118]. Furthermore, several

patents of well-known brands (e.g. L’Oreal, Revlon) claim to use this technology in different

kinds of cosmetic products [31].

Nanocrystals are another delivery system firstly introduced in the market in 2007 with the

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natural antioxidants rutin and hesperidin. Originally, nanocrystals were developed to dissolve

poorly soluble active ingredients through crystallization processes, where crystalline particles of

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the ingredient were formed within the nanometer range. Therefore, the nanocrystals are

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composed of around 100% of the active ingredient itself with some polymers or surfactants to

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stabilize. Due to their high surface area/volume ratio, nanocrystals are able to increase the

saturation solubility of the active ingredient and the dissolution rate of the particles [119].
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Furthermore, some natural antioxidant nanocrystals seem to have higher antioxidant activity

than their water soluble derivatives [120]. The incorporation of this delivery system is simply

made by adding an aqueous nanocrystal concentrate to the final dermal formulation, assuring
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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 [121]. As well as the
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cubosomes, nanocrystals can be prepared using bottom-up or top-down approaches. The last
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one is industrially more relevant, although it has some drawbacks such as long operation times

and high energy consumption, which may induce the phase transition of the active ingredient.
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Bottom-up approaches have a potential risk of contamination with residual solvent, besides it is

a very complex process [119].

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 [110]. Some

more additional work, this time regarding the nanocrystals, remains in the development of a
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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 active

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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

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concentration gradient and skin penetration steady [120]. Finally, although it was suggested as

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future work for dendrimers, the combination of the aforementioned delivery systems with each

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other could be applied to most of the technologies described in this review and can bring

interesting findings and applications [116].

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8. Trends and future work on the field of cosmetics and delivery systems
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Cosmetics are used since ancient times and their purpose has been a combination of
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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
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interaction and attractiveness [122,123]. Currently, people are very concerned with their
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personal image, which gives the opportunity to develop innovative and appealing products
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[124]. Actually, new and more effective ingredients 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 discover safe, ecological, and profitable ways of extracting a wide variety

of compounds, considering their different intrinsic physical-chemical properties [125].

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 [126,127]. The speed with which ingredients are introduced in cosmetic products

raises the concern about their safety. However, not only new ingredients are subjected to safety
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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 follow the legislation changes and adapt their products

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to the new trends.

Nevertheless, currently the consumer perspective is not only focused on the final product

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and the positive effects that it may have on its own health. New concerns about the

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environmental impact of the cosmetic development, manufacturing and quality control

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procedures are surging. In fact, new analytical methods (frequently used in quality control tests)

claiming to be ecofriendly have been recently described [128]. Europe Cosmetics (the Personal
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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 presence and toxicity of
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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
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cosmetic ingredients by natural ingredients could be a solution to overcome this problem.

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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
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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 cosmetic ingredient. Finally, it is necessary to evaluate if the functional performance of

the bio-based ingredient may affect the dosage and the effectiveness of the formulation [129].

Animal rights are now another concern of cosmetic industry and consumers. During the past

years, animals have been used for testing cosmetic ingredients and formulations to assess their

safety and performance. However, European Union published the 7th Amendment (Directive

2003/15/EC) to the Cosmetic Directive (Directive76/768/EEC) calling for a marketing ban,

from March 2013, on cosmetic products that contain ingredients tested on animals for toxicity
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and toxicokinetics. Therefore, efforts have been made to develop in vitro, in chemico and in

silico models to replace animal testing since it is necessary to assure product safety and efficacy

[130,131].

The development of new delivery systems should also follow the aforementioned concerns

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regarding the use of green technologiesand non-toxic environmental materials. In addition, the

development of delivery systems still has some more goals to achieve. Although skin

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physiology is relatively well known, further studies should be performed for a better

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understanding of the dominant permeation pathways, as well as the interactions of each delivery

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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
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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
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the industrial and commercial production [132]. Moreover, the methods must be developed and

optimized in order to obtain a uniform and reproducible outcome. In fact, uniform and
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reproducible delivery systems are not only required in terms of size but also with respect to the
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drug loading, controlled release, and stability [133]. The preparation method should also be

adaptable to new market trends and legislation, while also being able to encapsulate new
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ingredients. The interactions and behavior of different materials that compose a delivery system

should be well studied and documented, since most of the times the selection of encapsulating

agent is made by trial and error [134]. A deeper study of these characteristics would provide

more information for a more rational and logical choice of the encapsulating agents.

Furthermore, the line between cosmetic and pharmaceutical products is becoming blurrier.

Delivery systems have been used for both purposes and cosmetic products are increasingly

required to have some health benefit. This is actually confirmed by the emergence of

cosmeceuticals or nutricosmetics [135,136]. The combination of cosmetic action with textile

using delivery systems is also a new trend [137].

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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 decreasing its dosage in formulation, and by controlling and targeting

the delivery.

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9. Conclusion

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Natural ingredients, in particular natural antioxidants, are gaining popularity among

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cosmetic consumers. They can be entrapped into delivery systems to improve their skin

penetration and to overcome some stability problems associated with antioxidants. Delivery
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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.
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Mechanical forces, pH, or temperature could be used as triggers to promote the liberation.
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Several types of delivery systems may be used in cosmetic formulation and each one of them

has some drawbacks and advantages. The interaction of each delivery system with the skin
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mainly depends on in its composition, flexibility, and size. The incorporation of the delivery
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system in a cream formulation must be performed assuring the stability of both of them in order
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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

development, manufacturing, and quality control. With regard to delivery systems, 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 large number of publications in this field.
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Acknowledgements

This work was financially supported by the projects POCI-01-0145-FEDER-006939

NU
(Laboratory for Process Engineering, Environment, Biotechnology and Energy –

UID/EQU/00511/2013) funded by the European Regional Development Fund (ERDF), through

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COMPETE2020 - Programa Operacional Competitividade e nternacionaliza o (POC ) and by

national funds, through CT - unda o para a Ci ncia e a Tecnologia and NORT ‐ 01‐
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0145‐ FEDER‐ 000005 – LEPABE-2-ECO-INNOVATION, supported by North Portugal

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Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership
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Agreement, through the European Regional Development Fund (ERDF).

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List of Figures

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Figure 1 Possible skin oxidative stress effects

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Figure 2 Example of a simplified process flow chart of a cosmetic cream formulation

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Figure 3 Possible action mechanisms of vesicles as skin drug delivery systems

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List of Tables
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Table 1 Examples of the more widely used natural antioxidants in cosmetic formulations
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Table 2 Commercialized cosmetic products with natural ingredients loaded delivery systems
Table 3 Examples of studies that tested the transdermal flux, skin penetration and/or incorporated the delivery system in a cosmetic vehicle
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Table 1 Examples of the more widely used natural antioxidants in cosmetic formulations
Classification Antioxidant Source Chemical Structure Kow Reference

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Apple, bayberry, broccoli, citrus peel, garlic, peppermint,
Vitamin C 1.9 [1–4]

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spearmint
Vitamins

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Olives and olive oil, palm oil, pumpkin seeds, sunflower seeds
Vitamin E 12.2 [1,3,5]
and sunflower oil

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Black pepper, onions, curly kale, leeks, broccoli, blueberry,
Quercetin 1.5 [6–9]
red wine and tea

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Red wine, grape berry skins and seeds, peanuts, dried roots of
Polyphenols Resveratrol 3.1 [10]
plant Polygonum cuspidatum

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Rosmarinic acid Peppermint, rosemary, marjoram, sage, thyme, 1.8 [11]
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Lycopene Apricots, grapefruit, guava, watermelon, papaya and carrots 16.6 [1,12,13]

Carotenoids
Lutein Spinach, leaf lettuce, peas, oranges, kale, zea mays, carrot 7.9 [1,14–16]
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References

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[1] M. Oroian, I. Escriche, Antioxidants: Characterization, natural sources, extraction and analysis, Food Res. Int. 74 (2015) 10–36.
doi:10.1016/j.foodres.2015.04.018.

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[2] L. Zhang, S. Lerner, W. V Rustrum, G.A. Hofmann, Electroporation-mediated topical delivery of vitamin C for cosmetic applications,

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[4] I. Raska, A. Toropov, Comparison of QSPR models of octanol/water partition coefficient for vitamins and non vitamins., Eur. J. Med.
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L.R. Gaspar, P.M.B.G.M. Campos, Photostability and efficacy studies of topical formulations containing UV-filters combination and
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[6] M.E. Embuscado, Spices and herbs: Natural sources of antioxidants - A mini review, J. Funct. Foods. 18 (2015) 811–819.
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[7] A. Munin, F. Edwards-Lévy, Encapsulation of natural polyphenolic compounds; a review., Pharmaceutics. 3 (2011) 793–829.
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[8] E.J. Park, J.-Y. Kim, M.S. Jeong, K.Y. Park, K.H. Park, M.W. Lee, S.S. Joo, S.J. Seo, Effect of topical application of quercetin-3-O-(2″-
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gallate)-α-l-rhamnopyranoside on atopic dermatitis in NC/Nga mice., J. Dermatol. Sci. 77 (2015) 166–72.

doi:10.1016/j.jdermsci.2014.12.005.

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[9] S. Jeon, C.Y. Yoo, S.N. Park, Improved stability and skin permeability of sodium hyaluronate-chitosan multilayered liposomes by Layer-

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by-Layer electrostatic deposition for quercetin delivery., Colloids Surf. B. Biointerfaces. 129 (2015) 7–14.
doi:10.1016/j.colsurfb.2015.03.018.

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[10] L. Kuršvietienė, . Stanevičienė, A. Mongirdienė, J. Bernatonienė, Multiplicity of effects and health benefits of resveratrol, Medicina (B.

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[14] X.-Y. Qv, Z.-P. Zeng, J.-G. Jiang, Preparation of lutein microencapsulation by complex coacervation method and its physicochemical
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[15] A. Alves-Rodrigues, A. Shao, The science behind lutein., Toxicol. Lett. 150 (2004) 57–83. doi:10.1016/j.toxlet.2003.10.031.

[16] K. Mitri, R. Shegokar, S. Gohla, C. Anselmi, R.H. Müller, Lipid nanocarriers for dermal delivery of lutein: preparation, characterization,
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Active ingredient
Trade name Proposed use Brand

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delivery system

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Pro-Retinol A
Revitalift Anti-wrinkle L’Oreal
Nanosome

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Bioperformance Crème Super Gamma linolenic acid
_ Lancôme
Régénérante Absolue Nanocapsules

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Micro filters (silica and protein)
Rénergie Microlift Antiaging Moisturizer Lancôme

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Nanoparticles
Ascorbyl palmitate, tocopherol, retinol Rovi Cosmetics
Rovisome ACE Plus Anti-aging, wrinkle reduction

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Liposome International GmbH

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Genstein
Lipobelle Soyaglycone Antioxidant Mibelle Biochemistry
Liposome

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Coenzyme Q10
Cutanova Nano Repair Q10 Cream CE
Nanostructured lipid carriers
Revitalizing, anti-aging Dr. Rimpler GmbH

Vitamin C
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Collagen Stimulator Factor MAP® Stimulation of collagen production Cosmetochem
Nanocapsules
24-karat gold (natural protein) Anti-aging,
Nano Gold® Energizing Cream Neiman Marcus
Nanoparticles anti-infl ammation
Platinum Silver Nanocolloid® line Botanicals and coenzyme Q10 Anti-wrinkles,
DHC Skincare
products Nanoparticles anti-aging
Table 2 Commercialized cosmetic products with natural ingredients loaded delivery systems [1] [2][3]
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References

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[1] L. Montenegro, Nanocarriers for skin delivery of cosmetic antioxidants, 2 (2014) 73–92.

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[2] I.P. Kaur, M. Kapila, R. Agrawal, Role of novel delivery systems in developing topical antioxidants as therapeutics to combat
photoageing, Ageing Res. Rev. 6 (2007) 271–288. doi:10.1016/j.arr.2007.08.006.

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[3] D. Li, Z. Wu, N. Martini, J. Wen, Advanced carrier systems in cosmetics and cosmeceuticals: A review, J. Cosmet. Sci. 62 (2011) 549–
563.

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Table 3 Examples of studies that tested the transdermal flux, skin penetration and/or incorporated the delivery system in a cosmetic vehicle
Encapsulated Active Preparation Delivery system
Material Main Results Ref

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ingredient class ingredient method (size)

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1. n.s. - Entrapment efficiency: 61.69% to 85.21% for
2. Conventional ethosomes, 89.55% for liposomes and 81.93%
1. Lipoid S 75,

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mechanical 1. Ethosome for transfersomes.
ethanol and propylene glycol
dispersion 2. Liposome - Ethosomes showed superior skin targeting both [1]
2. Lipoid S 75
3. Conventional 3. Transfersome in vitro and in vivo.
3. Lipoid S 75 and Tween-80

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Apigenin mechanical - Ethosomes produced the strongest effect on
dispersion UVB-induced skin inflammation.
- Entrapment efficiency: 87.2%.

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- Initial burst release up to 16 h followed by
Solvent Nanoparticle

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PLGA1 controlled release for up to 72 h. [2]
displacement (101 nm)
- Loaded nanoparticles produced better effects
than free apigenin.
- Entrapment efficiency: 78.16% for berberine

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Berberine and 70.28% for gallic acid.
Antioxidant Microcapsule

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Agar/gelatin n.s. - In vitro drug delivery of berberine from [3]
Gallic acid (17 µm and 22 µm)
microcapsule treated textiles into the nude mice
skin.

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1. Sorbitan monostearate, - Entrapment efficiency: 1.35% to 26.75%.
Ellagic acid polyethylene glycol
(EA) 2. sorbitan monosterarate,
CE Reverse-phase
evaporation
Niosome
(124-752 nm)
- The penetration of EA from niosomes
depended on the vesicle size, the amount of EA
[4]
cholesterol entrapped and the solvents added.
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- Entrapment efficiency: 55% and 24% for pure

Elastic: Tween 61,
cholesterol, ethanol
Gallic acid
Non-elastic: Tween 61,
cholesterol, PBS
n.s.- not specified; 1PLGA- poly(lactic-co-glycolic acid)
gallic acid and gallic acid in the semi purified
Modified Niosome fraction in elastic niosomes; 30% and 20% for
pure gallic acid and gallic acid in the semi [5]
chloroform film (200-400 )
purified fraction in non-elastic niosomes.
- Elastic niosomes exhibited higher amount of
gallic acid through rat skin.
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Encapsulated Active Preparation Delivery system

ingredient class Material Main Results Ref
ingredient method (size)

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- Entrapment efficiency: 80% for liposome and

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for transfersomes.
1. soya phosphatidylcholine Rotary evaporation - Percutaneous delivery of elastic liposomes was
1. Liposome

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Genistein 2. soya phosphatidylcholine and extrusion influenced by existence of hair follicles. [6]
2. Transfersome
and sodium deoxycholate method - The greater permeation rate and deposition
values of genistein were observed from the

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elastic liposomes in haired skin.
- Drug loading: 12.1%
Lipid microparticle
Quercetin Tristearin and PC2 n.s. - Quercetin release from the microparticles did [7]

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(10-45µm)
not exhibit burst-effect phenomena.

Phosphatidylcholine,
Quercetin
ceramide-3, cholesterol and
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- Entrapment efficiency: 33-57% for rutin, 25-
40% for quercetin, approximately.
- Rutin had better in vitro release properties
Liposome
Thin-film hydration [8]

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Rutin (144 nm) while quercetin demonstrated greater skin
oleic acid permeability.

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- Liposome-in-hydrogel complex systems
Antioxidant improved skin permeability.

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- Drug loading: 4.1%.
Chitosan CE Lipid - Chitosan coating changed the LM 3 surface
Melt emulsification
Tristearin and hydrogenated Microparticles charge. [9]
and sonication
phosphatidylcholine (6 µm) - Significant enhancement in the in vivo
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Resveratrol permeation of resveratrol.
- Entrapment efficiency: 51% to 53%
Cetylpalmitate Hot melt SLN - The presence of tetradecyl-c-cyclodextrin in [10]
and tricaprin homogenization (379-472 nm) SLN formulation improved nanoparticle
characteristics.
- Entrapment efficiency: 22 to78%
- Emulsions containing RA-loaded PCL4
Rosmarinic Emulsion solvent Microsphere
poly(ε-caprolactone) microspheres showed a better long-term stability [11]
acid (RA) evaporation (~ 7-15 um) of the RA compared with those containing only
RA.
n.s.- not specified; 2 PC-phosphatidylcholine; 3LM- Lipid microparticle; 4PCL- Polycaprolactone
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Encapsulated Active Preparation Delivery system

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ingredient method (size)

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- Entrapment efficiency: 50% to 65%
Rosmarinic Emulsion solvent Niosome
Sorbitan and cholesterol - After 24 h, the release was 49.81±1.76% for [12]

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acid evaporation (814 nm)
niosomal gel.
- Entrapment efficiency: 89.18% to 96.96%

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Antioxidant White soft paraffin and - Progressive increase in occlusive properties of
Liquid paraffin, pifil® GC the tested formulations from 6-48 h.
NLC
Rutin (RT) or Gelucire®50/13, or Probe sonication - An initially rapid release during the first 6 h [13]
(85-319 nm)

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Plurol® stearique WL 1009, (burst effect).
or Tefose® 2000 CG - Nosignificant effect of RT concentration on

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sun-blocking.
- Drug loading: 37% to 58%.
Phosphatidylcholine and - Higher skin permeation of liposomal cabopol gel

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Anticellulite Caffeine Thin film hydration Liposome [14]
cholesterol formulation.
- Liposomes stored at 2 to 8 °C were more stable.

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1. Liposome - Entrapment efficiency: 45.2% for liposomes,
1. Film hydration 70.4% for ethosomes and 82.3% for

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5 (213-262 nm)
1. soya PC and CH transfersomes.
2. Cold method
Extract
Curcuma
longa
2. soya PC and ethanol
3. soya lecithin and sodium
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3. modified lipid
film hydration
2. Ethosome
(167-195 nm)
- The cream efficacy was in the order:
transfersomal > ethosomal > liposomal > free C.
[15]
deoxycholate 3. Transfersome
(rotary evaporation) longa > empty transfersome > empty ethosome >
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(176-199 nm) empty liposome > base cream.
1. Thin film
- Papain loaded elastic niosomes in gel
1. Tween 61, cholesterol and hydration 1. Niosome
formulation exhibited accumulated amounts and
Enzyme Papain sodium cholate 2. Water–oil–water 2. Nanosphere [16]
higher fluxes than non-elastic niosomes.
2. PLGA1 emulsion solvent (221–520 nm)
- No irritation on rabbit skin.
evaporation
- Entrapment efficiency: 99%.
- Drug loading: 49.73%.
Garcinia
Ethylcellulose blended Solvent - Encapsulated and free GML in the cream base
Extract mangostana n.s. [17]
methylcellulose displacement penetrated deeper into hair follicles but
(GML)
encapsulated distributed more homogeneously
on the stratum corneum.
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n.s.- not specified; 5CH- cholesterol

Encapsulated Active Preparation Delivery system
Material Main Results Ref

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ingredient class ingredient method (size)

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Lipid-core
Rice bran Sorbitan monostearate and - This formulation was able to prevent ear edema
Extract n.s. Nanocapsule [18]
oil Poly(ε-caprolactone) induced by UVB irradiation by 60 ± 9%.

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(200 nm)

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with sun protective potential, J. Photochem. Photobiol. B Biol. 153 (2015) 59–66.
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recuperating the ultraviolet radiation-damaged skin, J. Cosmet. Dermatol. 10

(2011) 260–265. doi:10.1111/j.1473-2165.2011.00586.x.
[16] A. Manosroi, C. Chankhampan, W. Manosroi, J. Manosroi, Transdermal
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[17] A. Tachaprutinun, M.C. Meinke, H. Richter, P. Pan-In, S.
Wanichwecharungruang, F. Knorr, J. Lademann, A. Patzelt, Comparison of the

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form, Eur. J. Pharm. Biopharm. 86 (2014) 307–313.

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doi:10.1016/j.ejpb.2013.12.001.
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Graphical Abstract

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Delivery systems used in the cosmetic industry, their skin interactions and production
were covered. The manufacturing of cream formulations with delivery systems, as well
as product testing were also presented, with illustrative studies along the text. Recent
trends and work on the field of cosmetics and delivery systems were explored.

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