NANOSTRUCTURED SYSTEMS CONTAINING ESSENTIAL OIL OF LAVENDER: CURRENT OVERVIEW AND FUTURE PERSPECTIVES SISTEMAS NANOESTRUTURADOS CONTENDO ÓLEO ESSENCIAL DE LAVANDA: VISÃO ATUAL E PERSPECTIVAS FUTURAS

The wide variety of aromatic plants and their use represent great economic value worldwide, due to the numerous therapeutic properties available. The Lavandula genus stands out in the world economy, mainly due to the production of essential oil, which can be extracted from its leaves or flowers, being widely used in the cosmetic, food and pharmaceutical industries. However, the therapeutic properties of this essential oil can be impaired due to its low aqueous solubility, high volatility and low physical-chemical stability. The association of essential oil with nanostructured systems can be a promising and efficient alternative to overcome these limitations, providing greater stability of the active compounds, protection against oxidation, photodegradation and thermal degradation processes, and thus, promoting a potential enhancement of efficiency. Thus, the objective of the study was to carry out a review of the literature about the available research that uses nanostructured systems to encapsulate the essential oil of different lavender species. The search was carried out in April 2020, in the electronic databases Web of Science, PubMed and ScienceDirect. The descriptors and keywords used were: nano *, lavender, Lavandula, followed by the Boolean operators AND; OR, and the year of publication of the articles was not defined. Eight articles were found that adequately met the inclusion criteria, which were published between the years 2017 to 2020. From the results found, it is believed that nanotechnology can be a promising alternative to protect the active compounds of lavender essential oil against factors that can impair their stability, as well as, guarantee or even increase their effectiveness, with the possibility of decreasing dose and consequently side effects.


INTRODUCTION
The use of plants and their active compounds in traditional medicine has been prescribed for decades for the treatment of various disorders and diseases FERNANDES, 2010;SHOKRI et al., 2017). One of these promising natural compounds are essential oils (EOs), produced from the secondary metabolism of plants, and have different therapeutic properties, such as antibacterial, antifungal, antiviral, antioxidant, anticancer, immunomodulatory activities, in addition to analgesic and anti-inflammatory actions. inflammatory (BAKKALI et al., 2008;BONA et al., 2016). According to the International Organization for Standardization (ISO), the term "essential oil" is defined as a "product obtained from a natural raw material of vegetable origin, by steam distillation, by mechanical processes of the citrus fruit epicarp or by distillation. dry, after separation of the aqueous phase -if any -by physical processes" (ISO 9235, 2013), and to be used in the health area, they must comply with national pharmacopoeias (BILIA et al., 2014).
EOs are volatile liquids, fat-soluble and soluble in organic solvents, with a density generally lower than that of water (BURT, 2004). They can be synthesized by all the organs of the plant, that is, buds, flowers, leaves, stems, branches, seeds, fruits, roots, wood or bark, and are stored in secretory cells, cavities, channels, epidermal cells or glandular trichomes (KAMATOU et al., 2008;SELL, 2010). Its composition is directly related to planting conditions, altitude, soil, fertilization and rainfall volume (PROBST, 2012), in addition to the plant organ, age and stage of the vegetative cycle (ANGIONI et al., 2006), factors that may present differences in composition in EOs in plants of the same species (PROBST, 2012).
They are characteristically formed by a mixture of dozens of complex and aromatic chemical compounds that are capable of attributing a great diversity of performance (CALO et al., 2015).
Despite all the characteristics and potentialities, EOs have some limitations, such as easy degradation of their constituents, due to oxidation, isomerization, cyclization or dehydrogenation reactions, triggered enzymatically or chemically (SCOTT, 2005), which can be influenced by conditions during processing and storage, after distillation and in the course of subsequent manipulation of the EO itself (SCHWEIGGERT; CARLE;SCHIEBER, 2007). In addition, these products have high volatility, and can easily decompose, due to direct exposure to heat, humidity, light or oxygen (TUREK, 2013).
The association of EOs with nanosystems seems to be efficient to control the release of active compounds, increase the physical stability of active substances, protect them from interactions with the environment, decrease volatility, reduce toxicity and thus, increase cellular absorption mechanisms (RAVI, 2000;BILIA et al., 2014). The authors Ziani et al., (2011) andDonsi et al., (2011) believe that EOs incorporated in nanoemulsions promote an increase in permeability in the membrane, due to the increase in its surface area, which makes it possible to reduce the concentration of the constituents to obtain an equivalent or even greater effect than in conventional emulsions (LIANG et al., 2012;SALVIA-TRUJILLO et al., 2013).
Based on information from studies on the different and important effects provided by the lavender EO, as well as the possibility of increasing its stability and guaranteeing or enhancing its effect when associated with nanometric systems, it is necessary to search the current literature for studies that use nanotechnology as a way to improve the performance of lavender EO and allow its use in the clinic safely and effectively, which was the objective of the present study. Disciplinarum Scientia. Série: Naturais e Tecnológicas, Santa Maria, v. 21, n. 3, p. 67-88, 2020.

METHODOLOGY
This study is characterized as exploratory, of the literature review type. The search for the studies took place in April 2020, in the electronic databases Web of Science, PubMed, ScienceDirect.
The keywords and keywords used were: nano*, lavender, Lavandula, followed by the Boolean AND operators; OR, the year of publication of the articles was not defined.
The selection of studies included in this review was carried out in three distinct stages. The first consisted of searching the selected databases, in the second step, a critical reading of the abstracts of the studies selected in the previous step was carried out, to confirm whether they met the inclusion criteria, and the third step consisted of a complete reading of the selected studies in the previous steps.
All stages of the methodological quality analysis of the articles were carried out by two independent and blind evaluators.
Full articles were included in this review, which addressed the use of nanostructured systems in the encapsulation of lavender EO. Literature review studies and pilot studies were excluded from the sample, as well as studies that used lavender EO in the same nanostructured system together with some active compound. The following characteristics of publications were recorded: year of publication, name of the author (s), nanocarrier, major component of the lavender EO and objective of the study.

RESULTS AND DISCUSSION
It is noteworthy that the objective of the study was to search the literature for research that used nanotechnology as a way to improve the functional performance only of the lavender OE, without any other associated compound, as explained previously in the inclusion criteria. In addition, it is noteworthy that other articles that used nanotechnology to encapsulate lavender in the form of extract were identified in the current literature (PEREIRA et al., 2015), as well as studies that associated the lavender EO with other compounds, such as Silver (AgNPs) (BELOVA et al., 2019;ELEMIKE et al., 2017), gold (AuNPs) (JADCZAK et al., 2019), clotrimazole (CARBONE et al., 2019) and ferulic acid (CARBONE et al., 2020).
Thus, the studies found in the present literature review that used nanotechnology as a way to improve the functional performance of only the lavender EO are shown in the flowchart below ( Figure 1). Disciplinarum Scientia. Série: Naturais e Tecnológicas, Santa Maria, v. 21, n. 3, p. 67-88, 2020.  The publications that comprised the sample of the present study were published between the years 2017 to 2020, and are shown in Table 1.     Major constituents of R. officinalis EO were identified as camphor (39.46%) and 1.8-cineol (14.63%), and L. dentata EO was 1.8-cineol (68.59 %) and β-pinene (11.53%). The average diameter of the nanoparticles was 226 nm, polydispersity index of 0.197 and zeta potential of 54 mV for nanocapsules containing R. officinalis and 235 nm, polydispersity index 0.214 and zeta potential 50 mV for nanocapsules containing L. dentata OE. Both formulations showed homogeneous size distribution and remained stable for 8 weeks at 25 ± 2 °C. The encapsulation efficiency was determined by GC-FID and presented values of 59% and 41% of the total EO of R. officinalis and L. dentata, respectively.
The authors believe they have developed a simple, repeatable and reproducible method, being an analytical tool for the simultaneous quantification of the main components of EO loaded in an Eudragit EPO nanocapsule, as well as a monitoring tool for biological assays. However, it is important to emphasize that the encapsulation of a complex natural product, such as OE, is a process that represents greater difficulty compared to the encapsulation of a drug and requires studies to optimize the (11.22%) and camphor (7.88%), and the EO of R. officinalis were 1.8-cineole (15.96%), α-pinene (13.38%) and camphor (7.87%).
The in vitro anti-leishmanial activities of the nanoemulsions of L. angustifolia and R. officinalis, as well as of EOs, were investigated against the standard strain of L. major. For the free and nanoemulsified L. angustifolia EO, the effective concentration was reached with IC 50 = 0.11 μL/mL. For the free R. officinalis EO the concentration was effective with IC 50 = 0.26 uL/mL and when nanoemulsified it presented IC 50 = 0.08 μL/mL. In addition, during the amastigote stage assay, L. angustifolia and R.
officinalis EOs and both nanoemulsions were effective at 0.12 μL/mL and 0.06 μL/mL, respectively, in infected macrophages. The results were compared with MA, with IC 50 = 197 mg/mL and demonstrated that the EOs and the nanoemulsions of L. angustifolia and R. officinalis are more effective than the MA.
In addition, the cytotoxicity assay employing macrophages did not reveal toxicity in the host cells at the mentioned concentrations of IC 50 . was used as a type of unsaturated lipid vehicle, and as a biodegradable wall material, whey protein (WPI) was used. The L. angustifolia EO was used in the proportions of 1: 0.5, 1: 1, 1: 1.5 and 1: 2, (w/w). The encapsulation efficiency (EE) was determined by GC-FID and the oil was extracted by Clevenger distillation.
The average droplet diameter was 129 nm, the polydispersity index was 0.151 and the zeta potential -42 mV. The formulation showed a slight change in the droplet size, polydispersity index and zeta potential after 28 days of storage at ambient temperature. The nanoemulsion was stable against the aggregation and coalescence processes in thermal destabilizing stresses similar to those that can be exposed in commercial storage conditions ( intermedia EO, however 10 mL of L. intermedia hydrolate was used as the organic phase. A control nanoemulsion was also prepared with the same procedure, but using Labrafac as the oil phase. The formulations were evaluated by solvent-free gas chromatography coupled with the mass spectrometry (GC-MS) method, to determine the chemical composition of the vapor phase of the L.
intermediaria EO and the hydrolate of L. intermediaria in free and nanoemulsified form. Nanoemulsions were also evaluated for antibacterial activity against E. coli (G -) and B. cereus (G +).
The average droplet diameter of the nanoemulsion containing the L. intermediaria EO was 479.1 nm with a polydispersity index of 0.110, the zeta potential was not reported in the study. The formulation remained physically stable for more than a month after preparation, but it was not informed at which storage temperature. The average droplet diameter of the nanoemulsion containing the L. intermediate hydrolate was 225.4 nm with a polydispersity index of 0.098, which is lower than that obtained in the nanoemulsion, a fact that is justified because the hydrolate contains a small amount of EO components dissolved in water, therefore, when it was used for the preparation of the nanoemulsion, a very low volume ratio between EO and water was present in the system.
In relation to the main constituents of the L. intermediaria EO were linalool (35.8%) and 1.8-cineole (19.8%), followed by α-pinene (8.7%) and linalyl acetate (7, 5% Both nanoemulsions proved to be effective when tested against E. coli and B. cereus, and a potentiation of antimicrobial activity was observed when the L. intermediaria EO was in the nanoemulsified form. As for the L. intermediaria hydrolate, the results were even more promising, since only the nanoemulsified hydrolate showed antibacterial activity against the strains mentioned, while the free form was inactive. Therefore, the authors concluded that nanoemulsions are interesting vehicles for improving the biological activity of the L. intermediaria EO, especially of the hydrolate of L. intermediaria, expanding its potential for application in the pharmaceutical, cosmetic and food fields. The results indicated that C. cyminum EO was more effective than L. angustifolia EO in relation to toxicity after 24 h of treatment in the three mentioned pests. The mean lethal concentration values (LC 50 ) for the 48-hour treatment revealed that in most cases there were no differences between EOs and insect susceptibility, except for O. surinamenensis. However, when nanoencapsulated, C. cyminum was more toxic to O. surinamenensis and T. castaneum after 24 hours of exposure, however there was no difference in toxicity and susceptibility in the nanoencapsulated oils tested in 48 hours. The fumigation Disciplinarum Scientia. Série: Naturais e Tecnológicas, Santa Maria, v. 21, n. 3, p. 67-88, 2020. 77 toxicity of free and nanoencapsulated EOs showed that C. cyminum and L. angustifolia were toxic to pests. Among the three stored pests, the highest and the lowest susceptibility were observed after 24 hours of exposure of S. granarius and T. castaneum to the tested oils, respectively. In addition, the authors tested toxicity by sublethal fumigation to decrease the concentrations of nanoencapsulated EO and phosphine gas. In this bioassay, the mixture of C. cyminum oil and phosphine gas nanocapsules caused synergistic effects in the three pests. In addition, the combination of L. angustifolia and phosphine EO nanocapsules promoted additive effects in S. granarius and T. castaneum.
The results obtained prove that the union of phosphine with nanoencapsulated EO resulted in a decrease in lethal concentrations to achieve higher mortality rates compared to treatments with phosphine alone. The study authors believe that the combination of the nanoencapsulated form of EO with reduced amounts of phosphine could be used as an ideal method for pest control of stored products. The antioxidant capacity in eliminating DPPH radicals depends on the specific composition of the oil, which is affected by a huge number of different factors, such as geographical location, plant variety, climatic and seasonal variations, nutrition and addition of fertilizers in addition to stress during growth (BONA et al., 2016). It is possible that the presence of high amounts of terpenes in L. intermedia (linalool 30% and linalyl acetate 38%) and R. officinalis (1.8 cineol > 50%), with a very low amount of phenolic compounds, is responsible for the lack of antioxidant activity observed for these tested Mediterranean EOs (CARBONE et al., 2018).
Thus, the authors concluded that Mediterranean EOs can be successfully used as components of the NLC matrix prepared by the laboratory scale PIT method. In addition, NLC maintained the same physicochemical properties after being produced. The results of in vitro biological experiments allowed us to infer that Mediterranean EOs, due to their relevant anti-inflammatory activity, can be proposed as active ingredients and oily components of NLC, increasing biocompatibility and reducing the cytotoxicity of pure oils (CARBONE et al., 2018).
In the study by Velmurugan et al. (2017), it was decided to produce nanospheres containing Citrus sinensis EO and nanospheres containing L. angustifolia EO with the aim of infusing the leather.
The concentration of non-ionic surfactant (Triton X-100) ranged from 0.2 to 1 (1%). The authors used chitosan and acrylic acid as wall material using the emulsion polymerization technique, established by the same research group in previous studies (PUNITHA et al., 2015). Nanospheres were characterized and leathers infused with EOs were studied for physical and organoleptic properties, morphology, washability test, perception and porosity assessment.
The nanospheres containing C. sinensis or L. angustifolia EOs exhibited a bimodal and trimodal size distribution with an average of 213.6 nm and 273.8 nm and with the polydispersity index of 0.69 and 1, respectively. The major components of L. angustifolia EO were linalool and linalyl acetate and C. sinensis was pinene, followed by sabinae and mircene.
The authors observed that L. angustifolia EO nanospheres maintain better EO content and content than encapsulated nanospheres with C. sinensis EO. In contrast, the nanospheres loaded with oil of C. sinensis have a higher oil load compared to the nanospheres loaded with oil of L. angustifolia.
This is believed to be due to the greater loss/volatility of C. sinensis oil during the encapsulation process (LI et al., 2005).
The authors observed that both droplets of EOs dispersed evenly and presented a distinct spherical shape surrounded by the wall material, which can be identified by the contrasting nature of the oil and the wall material. On the other hand, the encapsulated L. angustifolia EO showed surface imperfections with different shapes and sizes, presenting nanospherical agglomeration, which may corroborate with the trimodal distribution. It was observed that the organoleptic properties, such as softness, fullness and smoothness, are better in leather infused with C. sinensis EO than in leather infused with L. angustifolia EO, whereas the color uniformity has not changed in leather.
When performing the thermogravimetric analysis, it was identified that the moisture loss (initial degradation) for both is 248 °C. The loss of residual oil and its constituents was observed at 457 °C. The degradation of the core material and the complete evaporation of the oil were recorded above 550 °C, thus demonstrating that the wall material plays a predominant role in oil retention at high temperatures (above 100 °C) and can be applied in thermal coatings. The EOs used in this study also showed antimicrobial efficacy, and the nanosphere containing L. angustifolia has greater antimicrobial activity against certain bacteria such as Bacillus cereus and Bacillus subtilis and fungi such The diameter of the nanoparticles between the studies ranged from 104 nm to 479 nm, the smallest diameter being obtained in the research by Shokri et al. (2017), who developed nanoemulsions containing L. angustifolia EO, using the Homogenization technique by Ultrasound. The largest diameter, on the other hand, was observed in the study by Garzoli et al. (2020), which also produced nanoemulsion, but used the species of L. intermediaria using the Solvent Displacement technique.
Regarding the polydispersity index, the values ranged from 0.110 to 1, with the largest polydispersity index observed in the study by Velmurugan et al. (2017), which produced nanospheres containing L. angustifolia EO, which showed surface imperfections with different shapes, sizes and nanospherical agglomeration, as well as trimodal distribution. It is known that the polydispersity index values should be in the range of 0.15 to 0.3 to indicate homogeneity and stability (MOHANRAJ; CHEN, 2006), results not found in the study by Velmurugan et al. (2017). The values for zeta potential were negative in most studies, ranging from -42 mV to -15.8 mV, only in one study the zeta potential value was positive (50 mV), due to the use of the Eudragit EPO polymer that has cationic characteristics (SINGH et al., 2015).
Regarding the lavender species used in the studies, the L. angustifolia species was the most researched, followed by L. intermedia and L. dentata. The major component in studies that used and L. intermediate, it was 1,8-cineol and linalool, respectively. It is believed that most authors chose to use the L. angustifolia species because there are several studies that prove different activities of its major component, linalool, such as anti-inflammatory (PEANA et al., 2002), antimicrobial (PARK et al., 2012 and antioxidant , as well as sedative (SUGAWARA et al., 1998), anxiolytic (SOUTO-MAIOR et al., 2011), anticonvulsant (ELISABETSKY et al., 1999, analgesic (LI et al., 2016) and local anesthetic (ZALACHORAS et al., 2010). Food supplements containing linalool showed efficacy in the treatment of anxiety disorders, through clinical trials (KASPER et al., 2010). In addition, the preparation of capsules containing L. angustifolia EO has been licensed in Germany for the treatment of anxiety disorders (UEHLEKE et al., 2012).

CONCLUSION
It can be concluded with this review that the research that associated lavender EO to nanostructured systems obtained an increase in the effectiveness of EO, as well as a decrease in toxicity and greater physical-chemical stability of its components. The main species of lavender used was L. angustifolia, which due to its major component linanol, has shown great therapeutic efficacy.
Regarding nanosystems, it was observed that most studies produced nanoemulsions, as they believe to be a promising nanocarrier to be associated with the lavender EO, with the aim of improving the release of bioactive components, as well as increasing its effectiveness. Therefore, it is believed that nanotechnology can be a promising alternative to protect the active compounds against external factors, as well as to guarantee or even increase their effectiveness, with the possibility of reducing the dose and consequently of the side effects. It is also worth noting that the nanostructured formulations are water-based, and thus, they can enable the use of these by-products in the clinic.