A review of the potential therapeutic and cosmetic use of propolis in topical formulations

CHEMICAL COMPOSITION OF PROPOLIS

The diverse natural source of propolis has to some extent precluded the establishment of a “common propolis formulation” with well-defined components. Most importantly, depending on the season and also on the region from where it is being collected, it may vary. What seems to be consistent when several types of propolis were analyzed is that they all have a certain amount of total phenolic compounds and total flavonoids (Table 1). Additionally, higher phenolic and flavonoid composition has been positively correlated to the ability of free radical scavenging in propolis from Argentina, Japan, Greece, and Cyprus, but not in propolis from Morocco or Brazil. Phenolic compounds have received a good deal of attention in recent years, among the various classes of naturally occurring antioxidants, particularly because they inhibit lipid peroxidation and lipoxygenase in vitro, and show reducing properties. These characteristics play an important role in the neutralization or sequestration of free radicals and in transition metal chelation, acting both in the initiation and propagation steps of the oxidative process. The phenolic compounds of plants can be further classified into many categories like simple phenol, phenolic acids (a derivate of benzoic acids and cinnamic), coumarin, flavonoid, stilbene, condensable and hydrolyzable tannins, lignans, and lignins (Sousa et al., 2007).

Table 1. Total polyphenol and flavonoid content of propolis from different regions and countries. [Click here to view]

Phenolic constituents and antioxidant activity of propolis from Melipona interrupta and Melipona seminigra, two species of Amazonian stingless bees from the north of Brazil were studied. Both methanol and ethanol propolis extracts from M. interrupta showed higher content of phenolic compounds and greater antioxidant activity in relation to extracts of propolis produced M. seminigra. The analysis of propolis species showed promising results for antioxidant activities to the prevention of diseases of the local population (Silva et al., 2013).

In recent studies, the Brazilian red propolis was characterized by Liquid Chromatography-Orbitrap-Fourier Transforming Mass Spectometry and many molecules were found such as elemicin, isolemicin, methyl isoeugenol, methyl eugenol, formononetin, biochanin A, isoliquiritigenin, medicarpin, homopterocarpan, quercetin, and vestitol that allow it to be distinguished from other types of Brazilian propolis (Mendonça et al., 2015).

Similarly, Greek propolis, from different parts of the country, has been recently reanalyzed for its biochemical composition as well as for its antioxidant potential (Kasiotis et al., 2017). Of the eight different types analyzed, the total phenolic content varied from 113–181 mg/g. The total flavonoid content ranged from 46–86mg/g. The free radical scavenging activity was also measured in the same samples by the DPPH assay. By this method, IC50 values could be found to be as low as 1.19 μg/ml and were no bigger than 16 μg/ml. The authors also evaluated quantitatively the constituents of the eight types of Greek propolis and over 25 different ones were found. Pynocembrin and chrysin were the only ones found in all eight types. Other components found were galangin, gallic acid, p-coumaric acid. Caffeic acid, caffeic acid phenethyl ester, and quercetin were found in five, six, and five samples, respectively.

Savka and collaborators (Savka et al., 2015) reported the analyses of eight different types of propolis, collected in different regions of the United States of America (e.g., Nevada, Minnesota, and Louisiana). These authors deliberately chose regions with differing climates, such as cold (northern regions), wet (southeast), and dry (southwest), and tested propolis samples originating from these regions. Upon gas chromatography-mass spectrophotometry analyses, they were able to categorize compounds into eight different classes. Some of them, such as cinnamic acid derivatives, were present in all samples analyzed. Others, on the other hand, such as phenolic glycerides were present only in the samples from Minnesota and New York, but not in those from Nevada, for instance.

In summary, the chemical composition of propolis is highly dependent on its region and the local flora, which in turn is directly influenced by its macro- and micro-climate. Plants found in dry versus wet, perennial versus seasonal plants will most likely give rise to different kinds of propolis. However, all of them contain varying amounts of polyphenols and flavonoids, which warrant the biological activities of propolis.

PROPOLIS BIOLOGICAL ACTIVITIES

Due to its diverse therapeutic properties, and its composition chemical richness, propolis has become a focus of interest in many areas of scientific research, seeking to discover new therapies to treat many diseases like diabetes, tumor, bacterial infections, allergic rhinitis, and ulcers. (Sforcin et al., 2011). Propolis active compounds have antibacterial, antifungal, antiviral, anti-inflammatory, antioxidant, anti-tumor, immunomodulatory, hepatoprotective, antidiabetic, and healing properties (Fig. 1) (Chan et al., 2013; Hu et al., 2005; Khalil, 2006; Marquele et al., 2005;Zhang et al., 2016). Its essential oil also contains terpenoids, aromatic and aliphatic compounds that exhibit antibacterial activity (Garedew et al., 2004; Melliou et al., 2007) and inhibits lipid peroxidation (Gregory et al., 2007; Gregory et al., 2008). In this review, we focus solely on the use of propolis topically, whether it is for therapeutic or for cosmetic purposes.

Antioxidant properties

The antioxidant activity of propolis has been observed in topical formulations to prevent and treat skin diseases, as well as aging (Fig. 1). A healthy skin depends upon the balanced presence of free oxygen radicals, of which high levels can cause cell death and aging.

Free radicals are defined as any species that contains one or more unpaired electrons, capable of existing independently (Halliwell and Gutteridge, 2016). Oxygen in its ground state has two unpaired electrons and can act as an oxidizing agent (Pietta, 2000).

In addition, ROS are generated by all aerobic cells, as by-products of various metabolic reactions and in response to different stimuli (Aliev et al., 2008; Bennett et al., 2009). Under specific stress conditions, the ROS levels exceed the antioxidant capacity of a cell, establishing an imbalanced condition referred to as oxidative stress. This situation can be derived from a reduction in the antioxidant defense system due to the depletion of components of this system or mutations that compromise its functions. Oxidative stress can also result from the increased production of ROS due to exposure to the compounds that generate them and/or activate ROS systems and/or hypertoxic conditions or both (Costa and Moradas-Ferreira, 2001).

Figure 1. Topical activities of propolis. Propolis has been shown to exert biological activities that are interesting to human health. Herein the topical use of propolis and its properties are discussed, such as antioxidant, antimicrobial, cosmetic stabilizer, wound healing and sunscreen. [Click here to view]

Polyphenols and flavonoids (the major constituents of propolis) can also act by different antioxidant mechanisms, including the inhibition of the enzymes involved in the formation of reactive oxygen species (xanthine oxidase, protein kinase C, lipoxygenase, cyclooxygenase, and oxidation of nicotinamide adenine dinucleotide). It has also been described to chelate trace elements (free iron or copper), which are potential enhancers of the generation of free radicals, or to act even as stabilizers of these radicals involved in oxidative processes by forming complexes with them (Daleprane et al., 2013; Pietta, 2000). Even though propolis has many active compounds that have already been investigated for various organic disorders, only few reports have focused on its antioxidant biological responses in topical formulations.

A study by Mouhoubi-Tafinine et al. (2016) compared honey with propolis found in a region of Algeria, regarding its antioxidant activity. The extracts of propolis presented significantly higher activity than honey. The antioxidant activity measured through the reduction test indicated higher activity in propolis in extracts with methanol, showing the relation of phenolic components and antioxidant activity.

A functional emulsion with 11 compounds extracted from Brazilian red propolis containing echium oil (omega 3), alpha-linolenic acid, stearidonic acid, and plant sterol esters, with or without phenolic compounds, was analyzed. Oxidative markers, such as hydroperoxides, thiobarbituric acid reactive substances, and phytosterol oxidation products were evaluated. Their oxygen radical absorbance capacity was also tested. Researchers found that synapic acid and rutain, both present at high quantities in the ethanolic extract of propolis from Alagoas, a northeastern state of Brazil, showed the same antioxidant activity as tert-butylhydroquinone (standard antioxidant) and should be further investigated as a potential natural antioxidant that could be applied in a functional emulsion (Freires et al., 2016).

In addition, the antioxidant activity of propolis can be used to evaluate its functional activity in topical formulations or to evaluate the release of its active principles from such formulations. (Marquele-Oliveira et al., 2007). One of the theoretical concerns regarding phytotherapeutic research, however, has been toward the development of active ingredient release studies and formulations, when propolis components could interfere with each other, showing antagonistic or synergistic activities. In practice, these concerns could be rapidly overcome. The use of crude ethanolic, aqueous, or methanolic propolis extracts showed that synergic action seemed to enhance the results obtained when other known antioxidants were used, even if certain constituents could already present antioxidant action by themselves.

USE OF PROPOLIS IN COSMETIC FORMULATIONS

USE OF PROPOLIS IN PHARMACEUTICAL FORMULATION

There are some studies about the use of propolis in pharmaceutical formulation. In the area of nanoparticles, there is a study about the immunological activity of propolis flavonoids liposome in vitro and in vivo. The propolis was extracted with ethanol 95% and then dried in vacuum to obtain flavonoids. The propolis flavonoids liposome was prepared with ethanol injection method and the encapsulation efficiency was 91%. This study found valuable information regarding the possibility of the use of propolis flavonoids liposome as a potential adjuvant in the immune modulatory function (Tao et al., 2014).

Microemulsion and nanoemulsion using propolis as active ingredient consist other possibilities in pharmaceutical formulations. Zilius et al. (2016) formulated microemulsion using PEG-8 caprylic/capric glycerides (Labrasol) and ethanolic propolis extracts, aiming at delivering propolis phenolic compounds ex vivo in to the skin. Their results with this o/w microemulsion were interesting because the phenolic compounds were found predominantly in the lipid phase of microemulsion minimizing their availability at the surface of the skin. In this light, they considered this formulation as potential antioxidant that could be applied for reduced deleterious effects of oxidative stress on biological systems (Zilius et al., 2016).

A work with nanoemulsions based on aqueous propolis and lycopene extract was conducted to evaluate the harmlessness of the propolis-lycopene system and to determine the photoprotection capacity of natural substances in nanoemulsion. This work was performed through the evaluation of level skin changes and anti-inflammatory action. Aqueous extract of propolis was obtained by refluxing 100 g of propolis powder and 250 ml of water, lycopene was obtained from ripe tomatoes. The nanoemulsions were prepared with both substances and the results showed that this system exhibited moisturizer characteristic that improves the ability of the skin to defend against sunlight (Butnariu and Giuchici, 2011).

Novel aqueous formulation of propolis spray was evaluated for its topical anti-inflammatory activity in comparison with two other commercial propolis-based sprays, a hydroalcohol spray and hydroglyceric one used for topical treatment of inflammatory conditions of the oropharyngeal cavity. The results obtained demonstrated the topical anti-inflammatory activity of the novel aqueous formulation of Actichelated^® propolis in comparison with two commercial formulations (Sosa et al., 2007).

Propolis formulation is used in common cold, upper respiratory tract infections, and flu-like infection. A study (Shinmei et al., 2009) about potentials uses of propolis mention the administration of Brazilian propolis in sneezing and nasal rubbing in experimental allergic rhinitis in mice model. The authors concluded that propolis may be effective in the inhibition of histamine release. Studying 46 human patients with mild-to-moderate asthma, who used an aqueous extract of propolis 13% using for 2 months, Khayyal et al. (2003) reported a reduced incidence and severity of nocturnal attacks. Pharmaceutical formulation with ethanolic propolis extract and polymers like Carbopol 934P, poloxamer 407, or gelatine were designed for the treatment of oral mucosa diseases and the data obtained indicate a potentially useful role in this treatment (Wagh, 2013).

Table 2. Reported side effects of propolis (case reports). [Click here to view]

Another type of use for propolis is lozenges and toothpaste. There are reports that this kind of formulation causes acute oral mucositis with ulceration. Because of allergic reactions in some people, the use of these products should be done with care. A case report of a 77-year-old man draws attention to the side effects because at time of the examination, the tongue was reddened and painful and there was desquamation of mucosal surface of the lower lip with tags of detached tissue, and the lips were swollen and inflamed (Hay and Greig, 1990).

SIDE EFFECTS OF PROPOLIS

The uses of both oral and topical propolis has been considered overall safe, and propolis has been considered nontoxic at doses of approximately 1.4 mg/kg and day or 70 mg/day.

It is interesting to note that the genotoxic activity that has been tested on propolis has been deemed to be non-genotoxic. The ethanolic extract of Brazilian propolis has been subjected to such studies in different models, such as Allium cepa (Roberto et al., 2016) and Chinese hamster ovary cells mammalian cells (Santos et al., 2014). In the former work, the genotoxic activity of ethanolic extract of propolis was assessed by the presence of micronuclei and chromosomal aberrations. Not only propolis did not induce genotoxic damage but also it protected against methyl methanesulfonate. The work by Santos et al. (2014) analyzed several aspects of the ethanolic extract of propolis, in addition to the genotoxic potential. This extract was considered to be non-genotoxic and even to show some protective activity against gamma-irradiation-induced DNA damage (50% reduction). As for cytotoxicity, at lower concentrations tested (50 μg/ml), propolis seemed to induce cell proliferation or at least to reduce irradiation-induced necrosis. Interestingly, post-irradiation treatment with higher concentrations (200 μg/ml) induced necrosis at 24 and 48 hours, but not at 72 hours. Although further studies are clearly necessary, these results indicate that propolis may not be safe in all the possible settings.

There have been cases of allergies to propolis reported (Table 2). These cases are most frequently contact dermatitis, found in beehive handlers, but other reports are also available. Matos et al. (2014) reported a case of contact dermatitis at the temporal portions of the face, forehead, and cheeks of a 69-year-old woman. She had used honey for cosmetic purposes, and dermatitis was confirmed with patch application. Later, when questioned, the beekeeper/honey producer admitted adding propolis to the honey provided, as a means of preservative, due to its antimicrobial activity. Two different other cases of cheilitis due to allergic reaction to propolis (as confirmed by patch test for 3–7 days) have been reported in patients who consumed honey (Nyman and Hangvall, 2016; Pasolini et al., 2004). It should be pointed that although propolis is not commonly found in honey, the addition of propolis to this food and use in cosmetic products has been increasing. Two additional cases of stomatitis were reported by Garrido Fernandez et al. (2004) when propolis was given as oral tablets. In these cases, symptoms were resolved with glucocorticoids and anti-histaminic medication.

Whether propolis by itself could serve a sensitizing agent is debatable. Since propolis composition may vary, some types of propolis may have the potential to cause an allergic reaction, whereas others may not. It is believed that among the known components of some propolis, 3-methyl-2-butenyl-caffeate and phenyl-ethyl caffeate may play a direct role in sensitization. Other components such as benzyl salicylate and benzyl cinnamate may have a supporting role (de Groot 2013).

Propolis-induced dermatitis had previously only been known to beekeepers, and in most cases, the occurrence of such cases was underreported. A series of reports have addressed the frequency of allergic reactions both in beekeepers as well as in the general population, and the prevalence of positive patch test reactions to propolis has reached 1.9%–3.5%. This has led the authors of these reports to advocate propolis inclusion in the baseline series (Henschel et al., 2002; Rajpara et al., 2009; Wilkinson et al., 2019). With the increasing inclusion of propolis in cosmetic products, it will be interesting to follow up the reports on allergic reactions, both in beekeepers as well as in the general population. As a final note to propolis-induced allergies, propolis, and mainly, two of its most frequently found components (pinocembrin and chrysin), have been reported to combat allergic reactions in in vitro and in vivo models. (Choi et al., 2017; Gu et al., 2017; Hanieh et al., 2017). The use of propolis to treat allergic reactions, although promising and interesting, is still incipient and falls beyond the scope of this review.

FINAL CONSIDERATIONS

Propolis may be a promising alternative in the treatment of some diseases according to a number of studies that have proven many of its therapeutic activities. Some studies, however, are still missing. For instance, it is not known if propolis could have teratogenic activity, thus preventing its usage by pregnant women. Additionally, given the existing cases of contact dermatitis, it would be beneficial to investigate whether constant exposure would increase the cases of allergic reactions, and if so, in which conditions.

On the other hand, the antioxidant, healing, antibacterial, antitumor, and anti-inflammatory activities of propolis may be more effectively used in the development of new research. Particularly, the pharmaceutical and cosmetic areas could benefit from this product, which could result in better disease treatment and the improvement of cosmetics with esthetic aspects, in regard to photoprotection and possibly make-up with anti-aging purposes. As propolis is a natural substance and with various activities, as already has been seen in existing publications, it is expected that it will be used in new pharmaceuticals and/or cosmetics available to the population, thus offering effective and safe treatment options.

CONFLICT OF INTEREST

The authors declared that they have no conflict of interest.

FINANCIAL SUPPORT

None.

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