5. Strategies and solutions

many plant extracts showed preliminary natural UV filter activity and, in the same manner,

Table 1 summarizes a selection of the abovementioned plants, lichens, and pure molecules

Major constituent(s) Main effect(s)

ECG—()-epicatechin-3-gallate, EGC—() epigallocatechin, EGCG—()-

epigallocatechin-3-gallate

Rutin, kaempferol, quercetin, and its glycosylated derivatives and cinnamic acid derivatives

Lipid fraction n.r. UV absorber

Catechin, epicatechin, taxifolin, caffeic, ferulic, p-hydroxybenzoic, vanillic, gallic, and protocatechuic acid

Lipid fraction Linoleic acid, palmitic acid

Rutin, narcissin Prevent UV irradiation-

Pelargonidin Antioxidant, reduces

induced oxidative stress

UV absorber, emollient

Antioxidant, reduces UVB-induced skin erythema, free-radicalscavenging effect

UVB-induced skin erythema, antiinflammatory, diminishing DNA damage on UVA-induced

skin damage

(TEWL)

n. r. Inhibits UV-B irradiation-

photo damage and transepidermal water loss

Reduces UVB-induced skin erythema, freeradical-scavenging effect

induced inflammation and oxidative stress of the skin Antioxidant, decreases oxidative damages of the skin

Anticarcinogenic, anti-inflammatory, photostabilizing capacity

compound(s)

Polyphenol, flavonoid

Phenolic compounds, flavonols

and hydrolyzable tannins

Glycine max Seeds Soybean cake Soy isoflavone Genistein Antioxidant, reduces skin

compounds, polyphenols, procyanidin derivatives

Flavonoids and polyphenolic compounds

antioxidant properties and/or synergistic photoprotective effects.

Plant extract Type of

Camellia sinensis n.r. n.r. Polyphenols EC—()epicatechin,

Plant name Plant

Calendula officinalis

50 Herbal Medicine

Coffea genus (10 species)

Fragaria x ananassa

Pimenta pseudocaryophyllus part(s) used

Green dry coffee beans

Culcitium reflexum Leaf Ethanolic

Moringa oleifera Seeds Petroleum ether

extract

Pinus pinaster Bark Picnogenol Phenolic

Leaves Ethanolic extract

Flower Hydroalcoholic extract

> Chloroform extract

extract

Fruits n.r. Anthocyanins

which have been mentioned at least in two different types of research.

UV light is recognized by the US National Institute of Environmental Health Sciences, as the main etiological agent of a large number of skin cancers, sunburns, and oxidative stress (US Tenth Report on Carcinogens). Despite controversial data about photo-irritation, photosensitization, and contact dermatitis, synthetic and mineral sunscreens are used to prevent UVinduced skin damage and are very common in several skin care formulations. More often than not, the etiology of a skin disease is multifactorial and includes DNA damages, inflammatory processes, oxidative stress from ROS, lipid peroxidation, etc. All the abovementioned causes need a multi-target approach, which is impossible to obtain with a "magic-bullet" molecule and neither in a blend of UVA/UVB/UVC filters. All synergic photoprotective claims may be integrated with a proven formulation strategy (oleosomes and/or other encapsulation technologies, coatings or stabilizers, film thickness, etc.) in order to stabilize and/or boost the suncare herbal ingredients.

Moreover, in view of the increased demand of natural, herbal ingredients, sunscreens will be the next trend for photoprotective formulations. To this end, it is mandatory to develop natural sunscreen formulations based on a sound scientific investigation to sustain safe and effective products. In these regards, in our laboratory, we have very recently developed a rational approach considering the synergistic properties that a good candidate should possess: proven UVB/UVA absorption capability, antioxidant effects, protection against DNA and other free radical cellular structure-mediated damages, potential synergic protective mechanisms, and, finally, good toxicological profiles and proven formulation efficacy. As a matter of fact, several herbal/natural molecules may provide, in theory, these activities. Herbal extracts are naturally composed of mixtures of synergistic ingredients developed by plants through the evolution process (i.e., polyphenols), to allow the earlier marine organisms to colonize the terrestrial environment inferring resistance to high UV-induced oxidative stress. Taking this into account, as the synthetic strategy goes toward the design of multifunctional molecules inspired by the above natural mechanism [7], herbal sunscreen goes in the same direction but starts from the other side that already is available in the phytocomplex. The weak point of this latter approach is the investigation strategy, often incomplete, that makes literature data not useful. To further complicate the picture, it must be noted that different portions of the plant may be used (leaves, bark, roots, owers, seeds, or fruits), they can be dried either in air or using instruments, and they can be cut or ground into particles and then extracted with either water or organic solvents at different herbs to solvent ratio (i.e., 1:4, w/v). But also fresh herbs are used; in this case, the herb to solvent ratio is usually 1:1. The extraction process might be different in function of the characteristics (physical and chemical) of the ingredients. Thus, the same approach for different compounds cannot be devised. Also, steam distillation is used in the preparation and extraction of essential oils from botanical materials. New technologies, i.e., supercritical carbon dioxide extraction technology, membrane separation technology, enzymatic extraction methods, and so on, are emerging, further complicating the pattern of the relative observed activities.

Taking all this into account, only a few studies on herbal extracts really match the abovementioned strategy. An ideal approach (Figure 1) should involve three different steps, typical of drug development:


Figure 1. A rational process in suncare active ingredients discovery from herbal extracts.

Guidelines for the Development of Herbal-Based Sunscreen

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53

processes, oxidative stress from ROS, lipid peroxidation, etc. All the abovementioned causes need a multi-target approach, which is impossible to obtain with a "magic-bullet" molecule and neither in a blend of UVA/UVB/UVC filters. All synergic photoprotective claims may be integrated with a proven formulation strategy (oleosomes and/or other encapsulation technologies, coatings or stabilizers, film thickness, etc.) in order to stabilize and/or boost the suncare

Moreover, in view of the increased demand of natural, herbal ingredients, sunscreens will be the next trend for photoprotective formulations. To this end, it is mandatory to develop natural sunscreen formulations based on a sound scientific investigation to sustain safe and effective products. In these regards, in our laboratory, we have very recently developed a rational approach considering the synergistic properties that a good candidate should possess: proven UVB/UVA absorption capability, antioxidant effects, protection against DNA and other free radical cellular structure-mediated damages, potential synergic protective mechanisms, and, finally, good toxicological profiles and proven formulation efficacy. As a matter of fact, several herbal/natural molecules may provide, in theory, these activities. Herbal extracts are naturally composed of mixtures of synergistic ingredients developed by plants through the evolution process (i.e., polyphenols), to allow the earlier marine organisms to colonize the terrestrial environment inferring resistance to high UV-induced oxidative stress. Taking this into account, as the synthetic strategy goes toward the design of multifunctional molecules inspired by the above natural mechanism [7], herbal sunscreen goes in the same direction but starts from the other side that already is available in the phytocomplex. The weak point of this latter approach is the investigation strategy, often incomplete, that makes literature data not useful. To further complicate the picture, it must be noted that different portions of the plant may be used (leaves, bark, roots, owers, seeds, or fruits), they can be dried either in air or using instruments, and they can be cut or ground into particles and then extracted with either water or organic solvents at different herbs to solvent ratio (i.e., 1:4, w/v). But also fresh herbs are used; in this case, the herb to solvent ratio is usually 1:1. The extraction process might be different in function of the characteristics (physical and chemical) of the ingredients. Thus, the same approach for different compounds cannot be devised. Also, steam distillation is used in the preparation and extraction of essential oils from botanical materials. New technologies, i.e., supercritical carbon dioxide extraction technology, membrane separation technology, enzymatic extraction methods, and so

on, are emerging, further complicating the pattern of the relative observed activities.

Taking all this into account, only a few studies on herbal extracts really match the abovementioned strategy. An ideal approach (Figure 1) should involve three different steps, typical

1. Extraction and characterization of the properties of the extracts (i.e., composition, UV

2. In vitro evaluation of synergic physiological activity (i.e., lenitive, antiradical, antioxidant,

3. Formulation strategies, new vehicles development, stabilization, and SPF evaluation

herbal ingredients.

52 Herbal Medicine

of drug development:

etc.).

absorption, mutagenicity, cytotoxicity).

in vitro and on volunteers.

Figure 1. A rational process in suncare active ingredients discovery from herbal extracts.

In our opinion, step 3 represents the main lack of evidence in order to develop a natural sunscreen product. Despite an improving number of recent studies regarding the incorporation of antioxidants into sunscreen [25, 27, 28], none of the researches we reviewed include herbal products and more sophisticated formulations, as nanostructured lipid carrier, elastic niosomes, nanoparticles, microemulsion, etc. We recommend this way as an essential trend for "green" sunscreen research.

Due to the growing interest in herbal remedies, there is also a significant amount of data available on herbal ingredients (i.e., public databases containing analysis, efficacy tests,

Guidelines for the Development of Herbal-Based Sunscreen

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55

It is already possible, based on existing proofs, to envisage a stage of discovery from herbal ingredients, which includes the preparation of extract (by the same standardized methods) eventual isolation, structure/composition elucidation, and in vitro bioactivity evaluation. In the case of sunscreens, the class of compounds behaving abilities of solar radiation absorption and antioxidant capacities are well known (i.e., polyphenols); what is not known is how much the mixture of other ingredients present in the extract may contribute to the sunscreen activity with complementary mechanisms (i.e., booster activity). This implies that the evaluation of activity in vivo must be conducted for each single extract. As recently reviewed by Si-Yuan Pan et al., the herbal preparation may contain "hundreds" of active compounds, and in addition, the concentrations of some of them might be exceedingly low and thus insufficient for conducting in vivo studies on isolated molecules. They report that from 1960 to 1982 and from over 100,000 crude tested extracts (deriving from more than 30.00 plants) only two compounds, Taxol and camptothecin, were developed into marketable therapeutics [33].

Based on the experience from random trials and observations in animals, ancient people acquired the knowledge of using herbs to treat illnesses. However, herbs used in traditional medicines constitute only a small portion of naturally occurring plants; thus, a large part of

In this chapter, we presented a systematic approach based on our experiences and proposed it as a possible standard approach in this field. The steps mentioned in Figure 1 have to be considered as an initial set of guidelines needed for the development of herbal-based sunscreen. The end result is a complete and rational methodology for the research and development of herbal sunscreen. The authors consider it to be essential to match the initial in vitro studies about UV filter activities with synergic biological activities (antioxidant, anti-inflammatory, inhibitory UVinduced damage effect, etc.) and formulation strategies (boosters, encapsulation, etc.). A solid response in each step may be considered a complete strategy. Finally, regarding natural products and traditional knowledge, an eco-friendly and sustainable approach can complete the investi-

We believe that our contribution will be useful to expedite the discovery of sunfilters from

This work was supported by the University of Ferrara (Bando FIR-2016 to Silvia Vertuani) and Ambrosialab srl, Ferrara (Grant 2017). We thank Anna Maria Brincat (Clubclass Residential

herbs. With a solid discovery approach, chances of success will greatly increase.

gation process and the management of the industrial supply chains.

extracts preparation) even in relation to their molecular targets [33].

work still remains to be developed.

7. Conclusion

Acknowledgements
