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Table of Contents
Year : 2023  |  Volume : 9  |  Issue : 3  |  Page : 258-269

Potential of essential oils as alternative permeation enhancers for transdermal delivery

1 Department of Pharmacognosy, ISF College of Pharmacy, Moga, Punjab, India
2 CCRAS, Ministry of AYUSH, Jhansi, Uttar Pradesh, India

Date of Submission26-Apr-2021
Date of Acceptance04-Nov-2021
Date of Web Publication21-Jul-2022

Correspondence Address:
Dr. Alok Sharma
Department of Pharmacognosy, ISF College of Pharmacy, Moga - 142 001, Punjab
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2311-8571.351508

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Transdermal drug delivery plays a significant part in the drug delivery system when compared to other routes of drug administration. The function of the stratum corneum (SC) is a barrier. Recently, numerous methods have been thrived to improve the perforation of drugs across the skin. The most effective method is to use enhancers since these agents enhance skin permeability. Natural penetration enhancers like essential oils demonstrate higher enhancement activity and are more widely accepted than synthetic penetration enhancers. High potential in the expansion and interaction with the SC intercellular lipids has led to an increasing interest in these oils as penetration enhancers. This article gives an overview of a few essential oils, including their mode of action and important parameters for permeation improvement. The present work can provide essential oils as alternative enhancers, and this could be useful in transdermal administration.

Keywords: Essential oil, natural permeation enhancers, skin, stratum corneum, transdermal drug delivery

How to cite this article:
Mahanty J, Rasheed SH, Kumar S, Singh H, Sharma A. Potential of essential oils as alternative permeation enhancers for transdermal delivery. World J Tradit Chin Med 2023;9:258-69

How to cite this URL:
Mahanty J, Rasheed SH, Kumar S, Singh H, Sharma A. Potential of essential oils as alternative permeation enhancers for transdermal delivery. World J Tradit Chin Med [serial online] 2023 [cited 2023 Sep 25];9:258-69. Available from: https://www.wjtcm.net/text.asp?2023/9/3/258/351508

  Introduction Top

Among other routes of drug administration, the transdermal route plays a critical role as a means to deliver drugs. By evading hepatic first-pass metabolism, this drug prolongs its effects.[1] The DDS has a disadvantage in that SC has a barrier function, and in order to overcome this drawback, skin permeation enhancers are used.[2] A formulation's permeability enhancement is determined by the degree to which it effectively increases the permeability of the skin, mucosa, or a test membrane, and permeation enhancers are the agents that provisionally decrease the skin impermeability. In general, there are three main types of permeation enhancers: physical, synthetic, and natural. The skin's uppermost layer is called the epidermis.[3]

The epidermis is a layer of stratified squamous epithelium that acts as a physical, chemical, and biological barrier.[4] Stratum corneum (SC) is localized on the outermost layer of the epidermis and has two major structural components: coenocytes and inter-corneocyte lipid.[5] Thus, SC, a layer of lethally differentiated cornified cells in the topmost epidermis, forms, which is responsible for the skin's barrier attributes. Keratinocytes provide essential lipid components for skin function during epidermal differentiation. Nevertheless, lipid composition changes substantially from the basal layer to the SC when the keratinocytes pass through the SC.[6] As a result of these changes, phospholipids and glycosphingolipids are exhausted, resulting in an increase in ceramides, cholesterol, free fatty acids, and small amounts of cholesterol sulfates and cholesterol esters.[7] The epidermal permeability barrier influences several cutaneous activities, including epidermal proliferation, differentiation, lipid synthesis, cytokine expression, and innate immunity.[8]

The barrier qualities of transdermal drug administration must be tailored to allow adequate drug absorption to attain effective levels at an appropriate location.[9] The most commonly used method for modifying SC properties has been the use of permeation promoters in the transdermal drug delivery (TDD) system.[10] As compared with conventional synthetic permeation enhancers, natural permeation enhancers (NPEs) provide better permeation and reduced skin irritation. Transdermal application of various essential oils exhibiting alternative permeation enhancer abilities is illustrated in the graphic abstract. So far, there has not been a comprehensive review on the permeation effects of essential oils on SC. A literature review was done to look at achievements in the chemistry, transdermal utilization, and pharmacology of essential oils. Moreover, the present review will provide information about essential oils, their bioactive constituents, and interactions with TDD.[11]

  Skin Anatomy Top

A significant organ in the body, the skin, is composed of many layers that protect the internal parts of the body from the external environment.[12] The epidermis is a stratified, squamous, keratinizing epithelium which is the uppermost layer of skin and constitutes around 90% keratinocytes, which is liable for the barrier properties of the skin, however, the physical properties, shape, and size of keratinocytes alter during migration to the skin surface.[13],[14] The dermis consists primarily of connective tissue and faces the epidermis as a physical barrier for larger molecules. The dermis and epidermis adjoin at a junction, known as the dermal-epidermal junction.[15] The hypodermis is an adipose tissue layer that connects the dermis, aponeurosis, and fasciae of the muscles.[16]

  Permeation Enhancers Top

By decreasing the skin's impermeability, permeation enhancers facilitate the drug absorption across the skin.[17] Enhancing permeation through the interaction of permeation enhancers and polar head groups of lipids is ideal. Due to altered interactions between the lipid–lipid head linker and the wrapping arrangement of the lipids, hydrophilic drugs diffuse more readily. Permeation enhancer increases the content of water molecules within the bilayer, increasing cross-sectional area for polar drug diffusion.[18]

Ideal properties of permeation enhancers

It is important that permeation enhancers be pharmacologically inert, well suited to drugs and excipients, odorless, economical, and have appropriate solvent properties. The ideal permeation enhancers must not deplete body fluids or electrolytes, and the skin must instantly regain its barrier properties.[19] Permeation enhancers must be nonallergic, nonirritating, and nontoxic. Enhancers should allow therapeutic agents to enter the body. Permeation enhancers should be physically and chemically stable, and they should be compatible with formulation and ingredients and must have a reproducible duration of action.[20] A single permeation enhancer alone cannot exhibit all the essential features.

Routes of permeation

A drug can cross the skin barrier via different routes, as demonstrated by Hueber et al.[21] [Figure 1] represents the transepidermal route of drug penetration through the intact skin. A molecule can penetrate the normal intact human skin via the appendageal and transepidermal routes.[21] The appendageal pathway, also known as the shunting route, involves transporting ions and big polar molecules through sweat glands, hair follicles, and their associated sebaceous glands, which is favorable for ions and large polar molecules that rarely travel through the SC.[22] Despite having the highest permeability, these pathways are of marginal significance because they cover only 0.1% of the entire skin area.[23]
Figure 1: The transepidermal route of drug penetration through the intact skin involves the path of molecules via the stratum corneum, an architecturally diverse multilayered and cellular barrier. The intra-cellular path allows the transport of hydrophilic solutes. Whereas, transport via inter-cellular spaces allows diffusion of lipophilic solutes via continuous lipid matrix

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Types of permeation enhancers

Permeation enhancers can be classified as physical, chemical, and natural.[24]

Physical permeation enhancers

By using ultrasonic, magnetic, and physical separation, physical permeation enhancers increase penetration. In order to improve the permeation capability of drugs, multiple methods such as iontophoresis, electroporation, ultrasound, microneedles, and radiofrequency are used.[25] Physical permeation enhancers must be nonallergic and nonirritating in order to be effective, allowing therapeutic compounds to enter the body while avoiding a deficit of biological material in the body. The use of physical permeation enhancers is widely used in pharmaceutical applications to improve the transport of drug molecules. As an example, electroporation is primarily used to initiate DNA into a cell body. Hepatocellular carcinomas (≤3 cm) are commonly treated with radiofrequency ablation.[26]

Chemical penetration enhancers

Chemical permeation enhancers are distinguished by their pharmacological inertness, nonallergen, rapid onset of action, and optimum duration of action, as well as their economic and cosmetic acceptability. Chemical penetration enhancers (CPEs) bind directly to hydrophobic lipid tails and alter their packaging to facilitate fluidity and enhance drug penetration.[27]

A CPE possesses numerous advantages, such as an appropriate rate of permeation for therapeutic efficacy.[28] Transdermal surface formulations were improved in terms of permeation. The CPEs may also be disadvantageous, in that the concentration of distinct drugs is not the same, so the same dosage cannot be used. It is not recommended to use certain permeation enhancers together at different concentrations. In most cases, chemical permeation enhancers are ineffective for medical applications due to their toxicity.[29]

Natural permeation enhancers

These natural penetration enhancers contain mainly glycerides, which are formed from fatty acids and glycerin. Unlike animal fats, most plant-mediated oils are liquid at a specific temperature and contain low concentrations of saturated fats and elevated amounts of unsaturated and monounsaturated fats.[30] Coconut oil is an exception, as it is semi-solid at room temperature and has a high saturated fat content. There are many different kinds of oils, each with its own set of qualities. As shown in [Figure 2], NPEs are classified into terpenes, volatiles, and fixed oils. Monounsaturated, unsaturated, and saturated fatty acids can all be found in plant-based oils. Furthermore, distinct oils have characteristic fatty acid constituents with altering chains of varying lengths and degrees of saturation. Furthermore, some essential oils are unstable, prone to degradation and oxidation, as well as breakdown and microbe growth. Hence, the distinguishing features of distinct oils emphasize the significance of judicious choice for skin moisturization.[31]
Figure 2: Potential natural permeation enhancers: Natural permeation enhancers are new classes of permeation enhancers which include essential oils and may support in enhancing the drug permeation into the stratum corneum. It may be classified into three types of essential oils such as terpenes, volatile oil, and fixed oil

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  Selected Essential Oils as Natural Permeation Enhancers Top

Essential oils or aromatic oils might be considered natural alternatives to chemical enhancers as they include a diverse range of bioactive components.[32] The prevalent compounds such as terpenes and terpenoids are illustrated in [Figure 3]. Besides, [Table 1] also demonstrates a view of the percentage of bioactives in NPEs and their allied applications. Further, [Table 2] summarizes the details about the skin penetration enhancement effect of NPEs.
Figure 3: Essential oils as natural permeation enhancers: The main constituents are terpenes, terpenoids, etc. Essential oils exhibit varied and applicable as natural permeation enhancers

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Table 1: Percentage of bioactives in natural permeation enhancers and their allied applications

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Table 2: Skin penetration enhancement effect of natural permeation enhancers

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Basil oil

Basil oil is extracted from the leaves of Ocimum basilicum, a member of the Lamiaceae family. Methyl chavicol (40%–80%), linalool (5%–10%), 1,8-cineole (1%–7%) and eugenol (1%–10%), ursolic acid (1%–2.5%), and oleanolic acid (0.15%–0.17%) are the chemical constituents present in basil.[35],[36] Ursolic and oleanolic acids play a role in skin permeation enhancement. A rise in keratinocyte differentiation and lipid production is induced by ursolic and oleanolic acids.[5] Basil oil is beneficial for enhancing immune function, protecting against infection, and reducing water retention.[37] Fang et al. studied the effect of basil oil extract on drug penetration through the dorsal skin of Wistar rats using Franz diffusion cells. Both in vitro and in vivo studies were conducted to determine the degree of drug uptake within the skin reservoir. Basil essential oils were evaluated for low and high polarity. Estragole, squalene (triterpene), and sesquiterpene, α-bergamotene, and θ-muurolene make up the low polarity part. Other than estragole, which is oxygenated, the other components were hydrocarbons. Phytol (aliphatic diterpene) was the major compound of the high-polarity portion, others being oxygenated terpenes, including d-linalool, estragole, and butylated hydroxytoluene. Leu et al. discovered that both the proportions improved the skin penetration of indomethacin, however, low-polarity portion improved the permeation more efficiently.[34] Jain et al. found that a preliminary treatment with basil oil improved the skin penetration and absorption of indomethacin. Basil oil acts by enhancing drug absorption across the SC and causing alterations in the skin's physiology. Based on in vivo microdialysis, the low-polarity group had higher subcutaneous indomethacin levels than the standard group, whereas the high-polarity group had negligible indomethacin concentrations. As compared to lipophilic indomethacin, basil essential oil showed lower enhancing activity than hydrophilic 5-fluorouracil (5-FU). The differences between the in vitro and in vivo epidermal deposition experiments appeared to indicate that the high-polarity part was better able to hold the drug inside the skin as compared to the lower polarity portion.[34]

According to Jain et al., basil oil was proven to be more efficient than camphor, geraniol, thymol, or clove oil in enhancing the permeation of aqueous labetalol hydrochloride through rat lower abdominal skin.[38] The ursolic, oleanolic acid along with the solvent system (ethanol-water, 60:40) showed a synergistic effect with complete fluctuating quantities. By forming viable H-bonds among ceramides and terpenes in phytoconstituents, the rigid connections of phospholipid bilayers are loosened, allowing structural permeation to occur. Bioactives with the most electronegative alcoholic class, such as basil oil, react with peptide groups of ceramides, in contrast to bioactives with less electronegative carboxylic groups and their derivatives, such as camphor, which contains a ketone oxygen atom. As compared to camphor, geraniol exhibited a minimum enhancement ratio, even though these essential oils contained more electro donating alcoholic oxygen atoms. According to this study, the physicochemical characteristics of the permeant molecules, as well as those of the enhancer molecules, influence the penetration of a molecule through the peritoneal skin.[38]

Cardamom oil

The ripe fruits of Elettaria cardamomum (Zingiberaceae) are used to extract cardamom oil. It comprises various chemical constituents, namely α-terpineol (45%–55%), myrcene 27%, limonene 8%, menthone 6%, β-phellandrene 3%, 1,8-cineol 2%, sabinene 2%, and heptane 2%.[35] α-terpineol is the main bioactive constituent of cardamom oil. The packing of hydrophobic lipids in the stratum corneum is disrupted as a result. In addition, cardamom oil has been used to treat toothaches and muscular discomfort as an antibacterial and pain reliever.[39] An acetone extraction of cardamom seeds was examined by Yamahara et al., to determine if it affected skin penetration of prednisolone.[40] Acetyl terpineol and terpineol were isolated from acetone extract and fractionated. In comparison with Azone (1-dodecyclazacycloheptan-2-one),[40] the two components, along with further separated compounds, show that prednisolone enhances skin permeation.[40]

According to Williams et al, in vitro, cardamom oil improved the penetration of indomethacin, diclofenac, and piroxicam through abdominal rabbit skin. The skin permeation index was computed using the flux of the enhancer-containing preparation and the flux of the standard preparation without the enhancer. Huang et al., discovered that piroxicam at pH 5.8 and pH 7.4 with 1% cardamom oil had the greatest enhancing effect when compared to indomethacin and diclofenac.[41] At a concentration of 1% cardamom oil, reduced lag times were observed for indomethacin and diclofenac penetration through the epidermis. The findings suggest that, rather than drug solubility in a solvent system, cardamom oil's stimulating action is influenced by its concentration, pH, and physicochemical properties.[41] Huang et al., found that pretreating rabbit abdomen skin for 30 min with 5% cardamom oil in alcohol: water solvent mixture (1:1) increased the peak area of the piroxicam plasma concentration time curve (area under the curve: 0–24) by 67.09 times when compared to nontreated skin. The total bioavailability was found to be 83.23%. Permeation was comparable after 60 min pretreatment and 30 min pretreatment.[42]

Chamomile oil

Chamomile oil is extracted from the flowers of Matricaria chamomilla L., a member of the Asteraceae family. The chemical constituents present in chamomile oil are chamazulene (6.46%), α-bisabolone oxide A (35.74%), (Z)-β-farnesene (6.63%), α-bisabolol oxide A (19.07%), and apigenin (1%–2%). Apigenin is a significant bioactive which enhances skin permeability, keratinocyte differentiation, lipid production, and lamellar body. The oil can also be used for wound healing, including ulcers and sores, anxiety relief, and sleep promotion. Hu et al., evaluated mouse skin permeation after pretreatment with apigenin. The husky appearance of mice's skin did not change after 9 days of topical apigenin therapy. In comparison to vehicle-treated mice, apigenin did not change the transepidermal water loss (TEWL) rates or standard skin surface pH. When compared to vehicle-treated mice, apigenin-treated mice demonstrated little but negligible SC hydration. Variation in baseline TEWL and topical apigenin sped up barrier recovery, which was especially noticeable 4 h after severe barrier disruption. Based on these findings, topical apigenin significantly enhanced epidermal penetration barrier homeostasis in healthy mouse skin.[8]

Citronella oil

Citronella oil is isolated from the leaves of the Cymbopogon nardus plant, which belongs to the Gramineae family. It consists of numerous constituents, such as citronellal (32%–45%), geranyl acetate (3%–8%), geraniol (11%–13%), and limonene (1%–4%). Geraniol is responsible for the enhancement of epidermal permeability.[43] Geraniol disrupts the hydrophobic lipid packing of the SC.[44] Citronella oil is also used therapeutically to get rid of parasites and worms from the digestive tract, as well as for increasing appetite and reducing fluid retention.[33]

The first time citronella was demonstrated to enhance permeation across the abdominal skin of a male Wistar rat by Arellano et al.,[45] The outcomes revealed that geraniol, a bioactive present in citronella oil, was shown to be an effective accelerant for diclofenac sodium. In comparison to nerolidol (14-fold increase) and menthol, geraniol demonstrated a 20-fold increase in skin permeability (11-fold increase). Geraniol has the best increasing effect of all alcohols. Structures with hydrocarbon tails and polar heads disrupt the lipid packaging of the SC layer. In general, terpenes bearing molecules were better at absorbing hydrophilic medicines through the skin, whereas hydrocarbon terpenes were better at absorbing lipophilic drugs via the skin. Drug absorption through the skin is critically affected by the geraniol, physiochemical nature of drugs, as well as the vehicle in preparations. Geraniol is an efficient skin permeation enhancer out of eleven monoterpenes comprising (+)-limonene, (−)-menthone, (+)-terpinen-4-ol, α-terpineol, 1,8-cineole, (+)-carvone, (−)-verbenone, (−)-fenchone, p-cymene, (+)-neomenthol, and geraniol examined to enhance the caffeine penetration across the hairless mouse skin.[45],[46] Hydrocortisone and triamcinolone acetonide are other replica drugs with differing lipophilicities. Essential oils were administered in propylene glycol at 0.4 M about 1 h before the application of drugs. The pretreatment signifies that SC penetration of caffeine was increased. After removing the enhancement influence of propylene glycol on caffeine penetration, geraniol shows an enhancement ratio of 1.76 (15.7 before removing), followed by neomenthol with a 1.52-fold rise (13.6-fold before removing).[47]

Eucalyptus oil

There are about seven hundred species of Eucalyptus in the family Myrtaceae. The eucalyptus oil contains various chemical constituents such as eucalyptol (60%–85%), α-pinene (10%–20%), (+)-limonene (1%–10%), and 4-methylcumene (1%–5%). A main bioactive of eucalyptus oil is 1,8-cineole or eucalyptol, which is liable for the enhancement of skin permeability.[48] It is a colorless cyclic ether and monoterpenoid liquid. It increases the fluidity of SC lipids and has a spicy aroma and taste. As a result, it's used in flavourings, colognes, and cosmetics. In addition, it is also utilized in numerous brands of mouthwash and cough suppressants.[49] Rajan & Vasudevan investigated the use of essential oils to improve skin penetration of the polar drug 5 FU. Using excised human skin, they examined 5 FU's penetration enhancing activity.[50] In this study, the drug permeability coefficient was enhanced by 30 times when eucalyptus oil was used using eucalyptus oil as an enhancer.[50] Moreover, eucalyptus oil works less effectively as a permeation enhancer compared with 1,8-cineole, a main component in eucalyptus. This may be acceptable because the bioactives present in plant essential oils are not at their maximal thermodynamic activity. Furthermore, several essential oils contain bioactives that, through a variety of physiochemical approaches, can restrict transdermal delivery.[51] Karpanen et al. in their study revealed that the main constituent i.e., eucalyptol (1,8-cineole), present in eucalyptus oil improved the permeation effect of drugs, chlorhexidine (2%(w/w) within the dermal and epidermal bottom layer. Researchers found that the mixture of chlorhexidine, isopropyl alcohol (70%), and eucalyptus oil (10%) enhanced the drug permeability within the dermis 2 min after application, in comparison to either chlorhexidine or isopropyl alcohol alone.[52]

Fennel oil

The dried ripe fruit of the Foeniculum vulgare Mill, which belongs to the Umbelliferae family, is used to extract essential fennel oil. The bioactives present in fennel oil are (60%–80%) anethole, (12%–16%) fenchone, (3%–5%) α-pinene, and (2%–5%) estragole.[53] Fennel oil is largely composed of anethole, which is a chemical compound that increases skin permeability. It penetrated the SC and broke down the hydrogen bonds.[54] Fennel oil is also used for treating various digestive problems, such as heartburn, gas, and loss of appetite. In a study, fennel oil was discovered to be an efficient skin permeation enhancer. Das et al. reported that pretreatment of fennel oil with propylene glycol increased the penetration of trazodone hydrochloride; however, pretreatment by fennel oil (10%) in propylene glycol indicated the improvement ratio of 9.25 as compared to the standard. The presence of phytochemicals with variable physicochemical properties and molecular weights (MWs) in different essential oils could be the cause of differences in penetration enhancement ratios. Low boiling degrees and MWs of trans-anethole and 1,8-cineole may contribute to fennel oil's maximal enhancement ratio.[55]

Peppermint oil

Peppermint oil contains menthol, a noteworthy bioactive that plays a key role in enhancing epidermal permeability. Through altering the intercellular packing, it increases skin dissemination and alters the lipid structure.[56] Peppermint oil also has therapeutic effects on digestion, oral hygiene, stress reduction, pain relief, and blood circulation.[57] It is isolated from the leaves of Mentha piperita belonging to the family Lamiaceae. The bioactives present in peppermint oil are menthol (9%–48%), l-menthone (13%–20%), Menthofuran (4.56%-18.2%), 1,8-cineole (2%–5%), pulegone (2%–5%), and methyl ethanoate (4%–10%).[58] In vitro penetration research was performed for evaluating the activity of peppermint oil on the human breast; Nielsen used various concentrations 0.1%–5% (v/v) in aqueous solutions comprising 1% (v/v) Tween, 0.9% (w/v) sodium chloride, and distilled water (H2O). The fluidity of H2O indicates the skin's durability, and a higher flux value indicates impaired skin. The results of this investigation showed that at higher concentrations of oil, H2O flux also increases. However, at lower concentrations, a reduction in H2O permeation was observed, suggesting that the SC has a defensive effect. Peppermint oil was found to have significant effects on skin barrier function, and as a result, it was investigated beyond to predict its action on benzoic acid SC at various concentrations. A finding revealed that peppermint oil was defensive at levels of 0.1% and 1.0% (v/v) against the permeation of hydrophilic drugs.[59]

Olive oil

Olive oil (OO) is extracted from the fruits of Olea europaea. It comprises oleic acid (75%–85%), accompanied by minor amounts of fatty acids including linoleic acid (21%) and palmitic acid (20%). OO has around 200 unique chemical components, such as sterols, triterpenes, alcohols, and phenolic components. Antioxidants of OO are richer in hydrophilic phenols. The antioxidant effects of phenolics are greater than those of Vitamin E.[60] It was reported by Cooke et al. that 52% of newborn nurseries support OO skin therapy.[61] Danby et al. examined the effects of OO and sunflower oil (SFO) for skin barrier in two groups of adult people with or without the etiology of atopic dermatitis (AD).[62] Group 1 comprised six adults with AD, topically administered OO to arm twice a day for at least 5 weeks, whereas another arm was used as a control. The TEWL was 2.3 times higher in Group 1 when olive oil was used to cure both hands instead of control (P = 0.001).[63] And the OO-healed hands had SCs that have been 23% slimmer as compared to control forearms. Whereas Group 2 comprised six adults with a record of AD and other groups (6 adults) without any record of AD, and topically administered OO to one arm and sunflower oil to the alternative arm bis a day for four 28 days. These results from murine animal studies revealed that OO increased skin permeability.[63]

Epidermis barrier function does not develop until a few weeks after the baby is born, hence skin maintenance is needed to assist early neonates' undeveloped skin barrier. An Austrian organization investigated the efficacy of water-based lanolin cream (Bepanthen) versus oil-based lanolin cream (OO cream) or no emollient using arbitrary infants as subjects. Skin dehydration and irritation were measured by using a four-point scale. The water- and oil-based cream group had both significantly reduced flaking and scaling dermatitis in the fourth week, compared to the group that did not achieve soothing. Oil-based cream was more effective than Bepanthen cream in curing dermatitis at weeks 2, 3, and 4. A study by Kiechl-Kohlendorfer et al. showed that OO may be beneficial to the skin of newborns.[64]

Orange peel oil

Orange peel oil is extracted from orange peel. It contains carvone, menthol, and hesperidin. Hesperidin is a major component in orange peel oil. Hesperidin enhances epidermal permeability, keratinocyte differentiation, lipid production, and lamellar body. The medicinal properties of orange peel include lowering blood pressure, improving heart health, and lowering bad cholesterol.[65] In vivo studies of the activity of hesperidin were performed on normal murine skin. Hou et al. first evaluated the mouse skin permeability after pretreatment with hesperidin. The husky appearance of mice did not change after topical application of 2% hesperidin two times daily for at least 6 days. The TEWL, the surface pH, or the SC hydration did not change between the hesperidin- and vehicle-treated groups. The barrier recovery was significantly improved in mice treated with hesperidin at both 2 h and 4 h following severe barrier disturbance with monotonous tape stripping (retrieval rates at 2 h, 11.21 ± 4.64 for vehicle treated and 48.54 ± 4.56 for hesperidin treated, P < 0.0001; at 4 h, 37.41 ± 5.17 for vehicle treated and 60.90 ± 4.58 for hesperidin treated, P < 0.005. N = 12 for all). Thus, hesperidin topical application increased epidermal permeability in mice with normal skin.[66]

Turpentine oil

By distilling oleoresin from Pinus longifolia Roxb belonging to the family Pinaceae, turpentine oil was isolated. The bioactives present in turpentine oil are α-pinene (75%–85%), β-pinene (~3%), and camphene (4%–15%), and limonene (di pentene 5%–15%).[36],[67] Charoo et al. demonstrated that when turpentine oil was combined with a cosolvent of isopropyl and alcohol-propylene glycol, flurbiprofen was permeated more readily in SC. Turpentine oil exhibits the greatest infiltration capacity at a concentration of 5%(v/v) and is more efficient than tulsi at the same concentration. SC layer interruption is the primary reason for this.[68] Turpentine oil was employed to penetrate matrix transdermal patches containing diclofenac diethylamine and to improve flow in ketoconazole transdermal films. The transdermal films made up of ketoconazole distributed curative conditions of the drug in a stable and long-term manner. It acts as a permeation enhancer to improve the permeability of ketoconazole.[69] According to the findings, as the concentration of turpentine oil rises, drug permeability increases as well. It contains essential oils that show a synergistic effect, and it also enhances the permeability of the drug due to the rise in interruption of the SC.[70]

  Effect of Natural Permeation Enhancers Top

Increased TDD of water-soluble drugs can be a consequence of the miscibility and solubility characteristics of enhancers.[71] Leaching of epidermal lipids is the mechanism by which NPEs promote the permeation of oil-soluble drugs. It is important to improve partitioning properties at the SC tissue interface to enhance the permeation of lipophilic compounds.[72] By combining both permeation enhancers and cosolvents, this can be accomplished. Few enhancers tend to cause keratin to swell and remove SC's structural material. Thus, decreasing diffusional resistance and increasing permeability of lipophilic compounds.[62] [Figure 4] briefly highlights the mechanics of NPEs, indicating that they are responsible for interrupting the highly structured lipid arrangement within corneocytes in the SC. Furthermore, they interact with proteins' intercellular regions, altering their conformational state and making SC more drug permeable. Further, [Table 3] compares chemical and NPEs. In addition, modern cosmetics and biological tools are used to investigate and validate the functions of essential oils in SC.[73] The bioactive components of essential oils that increase drug permeability in SC are listed in [Table 4], along with their chemical structures and mechanisms of action.
Figure 4: Natural permeation enhancers transport the drugs through the skin by various mechanisms of action: (a) Interruption of the highly ordered intercellular lipid structure among the corneocytes in the stratum corneum, (b) interaction with intercellular domain of protein, which stimulates their conformational alterations and makes stratum corneum more permeable for drugs, (c) partitioning promotion – many solvents alter the features of the stratum corneum

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Table 3: Comparison between chemical penetration enhancers and natural permeation enhancers

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Table 4: Bioactives of selected essential oils with their structures and mechanism of action

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  Safety of Essential Oils as Permeation Enhancers Top

Biochemical configuration and concentration determine to a large extent the toxicity of Essential oils EO s and their bioactives. Accordingly, noxious and appropriate reports receive a precise response on their safety and use of enhancers for drug penetration. EOs and their bioactive components are quickly absorbed into the bloodstream through the skin and eliminated from the body via urine and feces.[74] Lan et al. revealed key elements present in the essential oils of lavender (linalyl acetate and linalool); cypress oil from aroma bath exhibited increasing transdermal absorption after 10–20 min bathing of mice.[75] The transdermal absorption of limonene from grapefruit oil was detected in mice's blood and brain after 20 min of bathing. It was found that lavender oil's bioactives permeate into the skin of male mice after massaging it for 20 min, and their highest concentration is found in the blood after that time.[75] While major constituents were eliminated from the bloodstream 90 min after the massage. Studies have shown that after topical application of the EOs, the bioactives and their metabolites are continuously metabolized, not accumulated. In this case, EOs were quickly eliminated from the culture, demonstrating their potential as a permeation enhancer.[76]

  Components Influencing the Permeation Enhancing Capability Top

Lipophilicity of the drug

The physicochemical features of drugs, such as lipophilicity, MW, and melting point, are inextricably linked to their penetration into the skin. The recommended logP for a drug to infiltrate the SC is 1–3, with a maximum MW limit of 500.[77] The proposed QSAR model for assessing the drug's skin penetrability is log kp = 6.3 + 0.71 logP0.061 MW, where Kp is the skin penetrability coefficient.[78] Drug lipophilicity is a prevalent factor influencing skin penetrability. A parabolic relation was discovered among logP values of drugs and the ratio of enhancement of NPEs. ER = 4.89 (logP) 2 + 12.34 logP + 25.87, r = 0.682, showing that limonene can achieve the best drug penetration impact. The same results were observed in borneol.[79] When 1% borneol was present, the values were represented by the model ER = 0.46 (logP) 2 + 0.41 logP + 5.18 (r = 0.86); when 3% borneol was present, the values were described by the model ER = 1.57 (logP) 2 + 2.64 logP + 13.58 (r = 0.79). By improving the function of hydrophilic drugs, borneol may achieve optimal penetration. By plotting camphor ER against drug logP values, a parabolic curve emerges. The result describes that hydrophilic drugs are more likely to be detected by NPEs than hydrophobic ones.[80]

Lipophilicity of the natural permeation enhancer

NPEs have lipophilicity that makes it easier to estimate their permeation enhancement effects. NPE phytoconstituents like limonene provide permeation enhancement for lipophilic drugs, whereas a polar group in menthol, 1,8-cineole, enables permeation enhancement for hydrophilic drugs.[81],[82] NPEs with higher logP values were shown to be the most effective for lipophilic drugs as they were easier to combine with SC lipid bilayers and enhanced the reliability of SC's barrier function, allowing for drug skin penetration.[83] The penetration of lipophilic valsartan, menthone, was enhanced most by anethole, one of the phytoconstituents of NPE tested. The less efficient permeation enhancer was eugenol. However, it was noticed that the highest lipophilicity of NPE resulted in the lower partitioning of ondansetron into the SC.[84]

The concentration of the natural permeation enhancer

NPEs at a concentration of 0.4%–5% were employed in the TDD system. An increase in NPE concentration usually enhances the permeation enhancement effect. A rise in the drug's ER values with increased NPE concentration might be ascribed to NPE's capacity to improve skin barrier characteristics, but a decrease in drug permeation at high NPE concentration could be due to the drug's interaction with NPE.[85]

  Conclusion Top

Transdermal drug administration has a number of advantages over oral drug administration, prompting researchers to look at ways to get beyond the skin's barrier function by employing essential oils as NPEs. In recent years, the demand for TDD has been continuously increasing, inspiring numerous researchers to deliver drugs through the skin. It may be unsafe and ineffective to use chemical enhancers with the SC as their action is confined to the upper layers. Chemical enhancers increase drug penetration through the skin with an increase in skin irritation as chemical enhancer concentration is increased in formulation. As a consequence, it is tough to strike the right balance between chemical enhancer safety and effectiveness. Owing to their natural origin, good penetration capacities, few adverse effects, and inexpensive cost, essential oils are good penetration enhancers for TDD systems. Several oils have been shown to enhance the penetration of hydrophilic and lipophilic drugs through the epidermis, and these oils could be employed as safe permeation enhancers to increase transdermal absorption of drugs from topical formulations. To facilitate the commercial manufacturing of future transdermal products that are efficient, more research is required to expand NPEs. Therefore, the absorption of drugs across the skin may be enhanced by essential oils.

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Conflicts of interest

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1], [Table 2], [Table 3], [Table 4]


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