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Pharmacology & Pharmacy
Essential oils (EOs) have stability problems, including volatility, oxidation, photosensitivity, heat sensitivity, humidity sensitivity, pH sensitivity, and ion sensitivity. A drug delivery system is an effective way to stabilize EOs, especially due to the protective effect of polymeric drug carriers. Polysaccharides are frequently employed as drug carrier materials because they are highly safe, come in a variety of forms, and have plentiful sources.
- polysaccharides
- essential oil
- drug delivery system
- stability
1. Introduction
Essential oil (EO) is a mixture of volatile and hydrophobic liquid that can be distilled with water vapor [1] (p. 226). It is biologically and medicinally active. Its pharmacological effects include anti-inflammatory, antimicrobial, anticancer, antiaging, antinociceptive, and neuroprotective properties [2,3,4]. After their synthesis from plastids, EO naturally accumulates in secretory structures such as oil cells, oil canals, oil chambers, granular hair, etc. [5]. However, it is volatile and loses its active constituents after extraction due to environmental factors such as light, heat, humidity, oxygen, etc. Hence, it is difficult to ensure efficacy and long-term preservation, which creates a huge challenge for EO preparations and other applications. Li et al. [6] studied the process of EO preparation and found that in contrast to crushing, concentration, and drying operations, the extraction process resulted in heat transformation and accelerated the volatilization of components. In their study, they also stated that the volatile components could be retained more when the raw powder of the plant was directly used to replace EO in the preparation, indicating that the plant cell structures were conducive to the stability of the EO. In other words, the stabilization of EO naturally depends on encapsulation and other protective effects of plant cell structures. Gao Bo et al. [7] defined raw powder as a raw material in EO preparation using the “unification of drugs and excipients” method, and also found that Humagsolan tablets that contain Angelica EO and are prepared using the unification of drugs and an excipient method are more stable than Humagsolan tablets prepared using the inclusion and spraying methods, which use extracted EOs as raw materials. Basically, the authors proposed that pulverization could be used as a drug preparation process that preserves the integrity of the plant cell wall while completely encapsulating EO. Further, the period of expiration (t0.9) of Humagsolan tablets prepared with raw Angelica powders was 6.7 and 2.7 times longer than that of EO-spraying tablets and cyclodextrin inclusion, respectively, proving that the structures of plant cells are protective of EO.
In fact, EO possesses antioxidant activities after being extracted, which means that EO is able to fight against environmental factors by itself [8]; however, this ability is low without plant cell protection, causing EO to easily lose flavor and even become darker and resin-like in preservation. Hence, carrier technology is widely used to improve the stability of EO. Compared with antioxidants and packaging, etc., carrier technology is more flexible and efficient. EO carrier technology is a type of drug delivery system that uses different materials to improve the stability of EO [9]. The different types of EO drug carriers, such as microemulsion, microspheres, etc., are usually polymeric [10,11,12]. Polymer materials are macromolecular compounds chiefly bonded by a great number of repeat units, which can carry various drug molecules based on large modules and long chains or network structures [13,14] (pp. 1, 11). The EO is encapsulated in the polymeric carrier structure, so that the artificial carrier system replaces the EO’s natural state in plant cells and achieves stability of the EO in vitro in the form of preparations; herein, this is based on the biomimetic concept.
Polysaccharides are carbohydrate polymers made up of lots of monosaccharide units [15] (p. 97). Polysaccharides are safe, biodegradable, and have abundant natural sources [16]; thus, they have become the preferred polymeric materials for EO drug delivery systems. Most of the polysaccharide carrier materials are extracted from plants (except for chitosan, which is mainly derived from animal shells) and, therefore, the composition of EO carriers is similar to the natural state of EO. That is, the polysaccharide-based delivery systems have a good ability to encapsulate EO and an advantage in the controlled release of EO, as is the case in plant tissues. For example, the content of EO is high in the early stage of plant flowering in order to provide nutrients, while at the end of the flowering stage, the release of EO is high to attract insect pollination [17]. The polysaccharide carriers can also provide different release properties due to their designation as a drug delivery system, ensuring that the EO reaches its target cells stably.
2. Applications of Polysaccharide-Based Drug Carriers in Stabilization of Essential Oil
Polysaccharides can improve the stability of EOs through different plant biomimetic carrier technologies, including volatility, oxidation, photosensitivity, heat sensitivity, humidity sensitivity, and impurity (such as pH and metal ion) sensitivity. The different structures of polysaccharide materials advance through different techniques and form different types of carriers. For example, gum arabic is a good O/W emulsifying agent due to its hydrophilic carbohydrate chains with numerous hydroxyl groups and the hydrophobic amino acid residues, such as proline, in the glycoprotein [32,33]; starch, cellulose and chitosan have high crystallinity and also vary in their derivatives, allowing for the formation of encapsulation carrier systems with good performance [34,35,36]; sodium alginate, pectin, and pullulan have good water solubility, sodium alginate and pectin have gel properties, and the latter has better elasticity, making them suitable substrates to promote the formation of semi-finished products [37,38,39].
2.1. Applications of Polysaccharide Materials in Essential Oil Biomimetic Drug Delivery Systems Based on Emulsification
2.1.1. Gum Arabic
Gum arabic contains 70% polysaccharides, 2% proteins, and cations such as calcium, magnesium, and potassium. There are various monosaccharides in gum arabic, providing both hydrophilic and hydrophobic groups. Hence, gum arabic is effective in its amphiphilicity and is mainly used as a natural O/W emulsifying agent. Through emulsification, gum arabic may develop a smoother EO in vitro release curve within 25 h than cyclodextrin inclusion, while also guaranteeing a smaller particle size, higher yield, and higher encapsulation efficiency (EE%) [40]. Additionally, compared with other emulsifying agents like tween 80 and lecithin, a gum arabic-based emulsion system could have minimal zeta-potential change after loading EO. However, its particle size change in 28 days was the highest, showing that its emulsifying ability was weaker than that of tween 80 and lecithin under an emulsifier/oil mass of 0.5 [41]. Hence, it is always suggested that it is used with other emulsifying agents such as pectin, sodium alginate, gelatin, etc. [29] (pp. 104–105). Moreover, hydrophobic Nile red is used to label the contents of milk droplets, and it has shown directly that gum arabic forms a well-sealed interface film layer, which further supports the statement that the gum arabic emulsion system may provide a strong enough biomimetic protective effect of heterogenous dispersion on EO [42].
Recently, gum arabic has been modified to slow down the digestion rate of oil in emulsion. The esterification of gum arabic with octenyl succinic anhydride (OSA) is preferred instead of aging modification and protein modification. The ability of OSA gum arabic to be emulsified in terms of stabilization is as high as of 20 wt% oil at a low concentration of 0.6 wt%, and breakage of the emulsions did not occur in 40 days of storage in 25–90 °C [43]. When OSA gum arabic was applied to cinnamon oil, the results showed that the particle size of the cinnamon oil emulsion was effectively reduced by OSA gum arabic, and the particle size of the emulsion droplets basically remained the same during storage, showing that it has great potential and that it is feasible to prepare a stable EO emulsion using OSA gum arabic [44].
According to a recent study [45], in the determination of structural changes of amphiphilic substances of gum arabic at the oil–water interface, it was stated that the emulsifying property of gum arabic was related to the electrostatic repulsion of glucuronic acid against highly branched molecule chains. Additionally, it should also be noted that the composition of proteins in gum arabic may also significantly affect its amphiphilicity and determine its emulsifying ability. Hence, the characterization of zeta-potential, particle size, polymer dispersity index, and other parameters is important for indicating the quality of EO–gum arabic-based emulsion systems. By all accounts, the characteristics of an emulsification drug delivery system based on gum arabic are simple, that is, only simple mixing is needed as the preparation method and the composition is simple, including EO, gum arabic, and water. Generally, gum arabic can emulsify 10–20 wt% of EO, but the regularity and pattern of its protection of volatile components of EO need to be further elucidated.
2.1.2. Others
Gums such as xanthan gum, tragacanth, and guar gum are polysaccharides similar to gum arabic in terms of their chemical properties. Traditionally, they play the role of O/W emulsifying agents in drug delivery systems of EOs. Their emulsifying processes are basically same as that of gum arabic, that is, they form an interface film layer due to the hydrophobic and hydrophilic functional groups in their molecular structures. However, their emulsifying abilities are commonly weaker than that of gum arabic due to the absence of amphiphilic protein. According to our search, we found that the gums stated above tend to be used with synthetic emulsifiers to disperse the oil–water system [46]. Since their application as the main emulsifying agents in EO drug delivery systems is thought to be limited, they are not discussed in detail, but from another perspective, these gums are able to form gel-based or film-based delivery systems of EO.
2.2. Applications of Polysaccharide Materials in Essential Oil Biomimetic Drug Delivery Systems Based on Encapsulation
2.2.1. Starch
Starch is made up of maltobiose. In its preparation, gelatinization is often required to promote the dissolution of starch molecular chains, and hence, the chains stretch and tangle to form a networking hydrocolloid carrier system. Recently, EO loading capacity (LC%) is generally more than 15%, while the EE% is above 70%. Similar to gum arabic, esterified OSA starch with better hydrophobicity is frequently used to ensure an adequate LC% of EO. For ginger EO, the protection by OSA starch by its microcapsule, which was determined using a general heat stability test for 10 days, could be increased by 40% [47]. On the other hand, when an intact yeast cell wall was used as the wall material to encapsulate ginger oil, the stability of the carrier in a baking experiment was only increased by 9%, showing that the biomimetic level of OSA starch is probably better than that of the cell walls of microorganisms [48].
In addition, porous starch, another example of modified starch, can be used as a new adsorber for the solidification of EO instead of traditional cyclodextrin. Porous starch with a hollow structure can adsorb small molecules of EO in its large surface area via van der Waals forces. As simple as the self-assembly of emulsification, only a mixing process is needed for the absorption of EO by porous starch, and recently, it was found that EO-loaded powder can be directly compressed into tablets. Further, the aroma map of volatile compounds in the obtained powder and tablet became significantly smoother, demonstrating another benefit of starch in improving the stability of EO from the perspective of production [49]. Additionally, it was found that the EO absorbed by porous starch can be further processed into microcapsules by combining them with other polysaccharides as wall materials. The time required for the complete release of EO could be prolonged by eight times, proving that the involvement of porous starch was conducive to optimizing EO stability in an encapsulated carrier system [50].
In fact, the mechanism of starch in improving EO stability is related to the helix chain of starch, and there are a lot of hydrophilic hydroxyl groups on the outer surface of the helix chain. Thus, the inner of helix chains are hydrophobic channels, allowing the entry of small molecules of EO. Recently, it was reported that the entrance process is caused by the presence of EO molecules, which alter the conformational isomerism of starch, trapping the EO molecules between the helices. The starch-based carriers are then entangled and the EO molecules are spontaneously encapsulated in the molecules, which gives the starch carrier system the advantages of needing fewer excipients and simple preparation.
2.2.2. Cellulose
Cellulose is made up of cellobiose. Since its repeating unit is a rigid molecule that is water-insoluble, modified cellulose is needed and mainly used in EO preparation (for example, ethyl cellulose). In the encapsulation of EO, ethyl cellulose was used to construct a polymeric matrix, and the result showed that the UV absorbance of EO basically remained unchanged after 90 days of storage. Additionally, a photostability test showed that cellulose reduce the photosensitivity of EO by half, enhancing EO’s resistance to the light exposure with the help of cellulose [51]. As a composite wall material, cellulose nanocrystal was used. Two types of lemon fragrance microcapsules were prepared using chitosan-sodium tripolyphosphate and chitosan-cellulose nanocrystals, respectively, through the ion cross-linking method, and the result of thermogravimetric analysis (TGA) showed that the weight loss of the latter was always smaller than the former in the water evaporation and flavor escape stages. While in the weightless stage of the thermal degradation of wall material, the maximum degradation temperature of the latter is higher than that of the former, indicating that cellulose forms a thicker carrier wall, which is comparable in thickness to the walls of plant cells like parenchymal cells and even cork cells, so that cellulose is often found to be more effective in preventing instabilities caused by heat, etc. [52].
In the last 20 years, another source of cellulose, bacterial cellulose, has been developed. Its chemical structures are the same as those of plant cellulose, but it is purer, more designable, and more controllable, has better physiochemical properties, and is also definitely safe [53]. Although there are no reports on the application of bacterial cellulose-based EO delivery systems, bacterial cellulose nanocrystal has been used as stabilizer to prepare hydrophobic alfacalcidol Pickering emulsion. It was found that the particle size of emulsion droplets decreased as the cellulose concentration increased, indicating that bacterial cellulose can improve the stability of hydrophobic drugs through emulsification [54]. Hence, it is feasible to stabilize EO via carrier technology.
In fact, as the main composition of the plant cell wall, cellulose highly mimics the encapsulation of EOs by the plant’s tissue structure; thus, it can have an LC% of 35–88% but an EE% ranging from 13–74% due to EO compatibility and other factors such as the preparation method [51,55]. Studies [56,57] have shown that after the encapsulation of EOs, the release of EOs no longer depends on their own vapor pressure and boiling points, but relies on the nature of the encapsulation material, that is, cellulose, which has its own stability and is easier to cross-link due to its rigid molecular structure. Therefore, the carrier has strong stability against environmental influences such as heat, light, and humidity, and there are many reports on its combination with other materials in the stabilization of EO.
2.2.3. Chitosan
Chitosan is made up of chitobiose. It is mainly derived from animal shells but is as rigid and stable as plant cellulose. The protective effects of chitosan towards EO were investigated, and the TGA results showed that the weight loss of oil-loaded chitosan nanoparticles was below 20%, while that of EO was around 90% [58]. The difference between chitosan and cellulose is an amino group at the C2 position. The amino group, which can be protonated under weak acidic conditions, will carry a positive charge, resulting in different properties of the EO delivery system. For example:
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Bioadhesion: Since chitosan can be protonated in acidic conditions, it can adhere to the surface of various negatively charged cell membranes such as red blood cells and mucosal cells. Then, it can swell to form an in vivo–in situ smart gel [61], resulting in a hemostasis effect, mucoadhesion, targeted drug delivery, and other drug properties. It can also capture bacteria through this electrostatic attraction and synergistically improve the microorganism inhibition of EO.
Recently, derivatives of chitosan have been needed to satisfy the demands of various drug delivery properties. Among them, the modification of trimethyl chitosan has been the most popular. When N,N,N-trimethyl chitosan was used to prepare Ocimum gratissimum EO nanoparticles, the LC% and EE% of the nanoparticles were increased by about 10%, while the cumulative release in 24 h under different pH conditions was also increased by 10–20%, compared with unmodified chitosan-based nanoparticles, showing that N,N,N-trimethyl chitosan is conducive to the formation of a highly mimicked system [62]. Moreover, chitosan, oligochitosan, trimethyl chitosan, and carboxymethyl chitosan were, respectively used as raw material to form new carrier system of hydrophobic curcumin liposomes. It was proven that the trimethyl chitosan carrier system had the strongest corneal permeability, demonstrating that chitosan EO preparations have great potential in corneal drug delivery as well as mucosal drug delivery [63].
Chitosan is the only natural basic amino polysaccharide [64]. Its EO drug delivery systems recently showed LC% values of 6–70% and EE% values of 29–90% [58,60,61,62,65]. As a result of the high LC% and EE%, we deduce that the positive charge of chitosan probably mimics the electrical property of the plant cell membrane to a certain extent. There is a lack of in-depth research on the EO encapsulation mechanism of chitosan, but it is mainly believed that its foundation is closely related to the properties of its amino group. Generally, it is still emphasized that the presence of amino cations plays the main role in EO encapsulation. By adjusting the pH of the system, EO drug delivery systems based on chitosan can be characterized by resistance to environmental factors such as pH and ions. Moreover, the positive charge allows for the designation of a targeted drug delivery system and transdermal drug delivery system due to its influence on cell permeability, etc. [66].
2.2.4. Others
Inulin is another polysaccharide that has improved EO stability through the encapsulation technique. However, a study investigated EO stability improvement by OSA starch, inulin, chitosan, and other wall materials in the preparation of microalgal oil microcapsules, and found that the regularity of inulin as the main carrier in improving the stability of EO was poor [67]. Additionally, inulin has rarely been used in EO delivery systems in previous years, so it will not be discussed in depth.
2.3. Applications of Polysaccharide Materials in Essential Oil Biomimetic Drug Delivery Systems Based on Solidification
2.3.1. Sodium Alginate
Sodium alginate is made up of M units (β-D-mannuronic acid) and G units (α-L-guluronic acid) in the form of triblock copolymers with GM, GG, and MM repeating units. In the presence of divalent cations, sodium ions from the G units will be displaced to form a calcium alginate gel network, leading to the stacking of G units and the formation of an egg-shaped molecular structure known as the egg box model. The three-dimensional gel network structure of the egg box model will take on the role of EO encapsulation during the forming stage [68]. Instead of general gelling and filming agents [69], the special gelation mechanism of sodium alginate is currently used to develop injectable gels [70]. Eucalyptus EO cyclodextrin inclusion powder was redissolved and swollen in sodium alginate solution, and then, CaCl2 solution was quickly injected after tracheal intubation. Hence, an ion-sensitive in situ gel could be formed in the lung and shown via in vivo fluorescence imaging. The full dissolution time of the EO-gel delivery system was more than 12 h, indicating that the sodium alginate could effectively provide slow release of the drug in the lesion through the multiprotection of powdering, follow up by in situ gelation [71].
As a sodium salt, sodium alginate is hydrophilic and so limits LE% for hydrophobic drugs like EOs. There have been many studies on the modification of sodium alginate, but no drug delivery systems that use EOs as raw materials and are based on modified sodium alginate have been investigated. Positively, acylated sodium alginate loaded with hydrophobic emodin was proven to increase LE% by 4–10% and slow down 36 h cumulative drug release by 6–15%, showing the potential of sodium alginate for the biomimetic protection of hydrophobic EOs [72].
In fact, as natural polymers, blocks of sodium alginate molecules are randomly interweaved in different proportions; hence the crystalline regions and three-dimensional structures are not stable at all. Inter- and intra-batch variability may disadvantage the stable production of related drug delivery systems. As a result, the LE% ranges from 9 to 36%, and the EE% ranges from 57 to 95% [73,74,75,76]. However, it is interesting to find that the COONa groups could cause acidity in sodium alginate, which contrasts with chitosan. Therefore, sodium alginate, which is negatively charged, is often used with chitosan to prepare a dense encapsulation drug delivery system through the combination of complex coacervates and interfacial interaction methods. The complex carrier’s wall structure will include an inner layer of polysaccharide, middle layer of polyelectrolyte film (formed through the attraction of the opposite charges of chitosan and sodium alginate), and outer layer of another polysaccharide [73,77,78,79].
2.3.2. Pectin
Pectin is made up of three kinds of galacturonic acid as repeating units, and it possesses various functional groups with different chemical properties. For instance, pectin is amphiphilic since it has acetyl, ferulic acid ester, carboxyl, and other groups, and therefore, it is an emulsifying agent [80]. Additionally, pectin has many ions like sodium, potassium, calcium, etc., causing it to easily form ion cross-linking gel via a substitution reaction. In pharmaceutical excipients, it can be divided into high-methoxy (HM) and low-methoxy (LM) pectin, which differ in their gelation properties. HM pectin normally forms a gel through non-covalent bonding in galacturonic acid regions, while LM pectin can form an egg-shaped molecular structure like calcium alginate gel, with more binding sites and stronger binding strength. Commonly, HM pectin performs better than LM pectin in emulsification systems. A rheological study found that the viscosity of an HM pectin delivery system increased as the ratio of pectin/emulsion increases, and showed that the multiprotection of pectin firstly forms an emulsion, and then, becomes a semi-solid gel due to the increase in networking degree [81]. Meanwhile, in emulsification, microcapsule powder was added into a pectin and gelatin solution, respectively, to compare their gelling ability. It was found that pectin increased the hardness of the microcapsule powder by 30%, which is twice that of gelatin, and could release EO for at least 3h [82].
The physical strength of highly esterified natural pectin gel is not as good as that of LM pectin; hence, the research on pectin modification focuses on the reduction in the methyl esterification degree and improvement of the water absorption property [83]. However, esterification has allowed pectin to be more compatible with hydrophobic EOs. The chemical proportions of EOs are basically the same before and after their preparation [84]. HM pectin can also improve the thermal stability and pharmacological activity of EO multiple times [85]. Therefore, compared with LM pectin, HM pectin is generally used in carrier systems to improve the stability of EOs, while other modified pectins are rarely used.
In fact, the mechanism of pectin in improving the stability of EO is complex, and its application in EO is rare. According to the available data, the LE% is only 4%, and the EE% is only 25%. However, recent studies have shown that the mechanism of pectin in improving the stability of EOs is related to the molecular weight of pectin, the degree of esterification of pectin, the galacturonic acid cross-links between pectin chains, and the interactions between pectin and other molecules (such as EO and emulsifying agent molecules) [86]. In addition, there are various types of EO and pectin. For example, cinnamon oil may be different in chemical composition since it can be extracted from different parts of plants, such as the inner bark and leaves, while pectin can be derived from different medicinal plants [87,88]. So, it should be noted that the protective effect is easily affected by plant source, preparation method, etc., leading to variation in drug carriers. Usually, EO drug delivery systems based on pectin are in the form of emugels [89]. The complex carrier highly mimics the multi-protection of plant EOs. This dosage form has the advantage of simplifying the formulation and process method, and the EO proportion is similar before and after the preparation due to the high degree of esterification. This is beneficial to the internal balance and function of EOs.
2.3.3. Pullulan
Pullulan is a maltotriose trimer that does not have a gelling property, but it has good elasticity and solubility. Its solution is electrically neutral, and hence, it is often used as a filming agent to solidify EO emulsion or encapsulation. Clove EO nanoemulsion and Pickering emulsion were prepared and, respectively, added into a matrix solution made using pullulan/gelatin to form a thin film composite. As a result, when the film solutions were kept at low temperature, room temperature, and body temperature, the release curve showed continuous growth in 72 h, indicating that the volatility of clove EO was slow and incomplete, that is, the retention rate was always maintained at a high level [90].
The modification of pullulan focuses on increasing its hydrophobicity to reduce the moisture absorption of pullulan and to promote its compatibility for hydrophobic drugs. A variety of methoxylated whey protein isolate–pullulan composite aerogels was prepared to adsorb clove EO, all of which delayed the total release rate of EO differently [91]. However, there are no reports on the application of modified pullulan thin layer composites in the stabilization of EO.
Recently, the application of pullulan in the solidification of EO intermediate carriers has been rare, and hence, there is a lack of the experimental studies that show its LE% and EE%. However, it is a fact that pullulan can further stabilize EO through plant biomimetic technologies, especially via filming, since a lot of hydroxyl groups on its surface allow pullulan to form intermolecular hydrogen bonds with cross-linking agents, proteins, and other substances to construct dense network structures of EO carriers [92].
This entry is adapted from the peer-reviewed paper 10.3390/polym15163338
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