Volatile Oils from Natural Plants: Promising Penetration Enhancers for Biological Barriers

Abstract

Drug delivery often faces challenges from biological barriers, including the skin and mucosa. Penetration enhancers (PEs) are commonly employed to improve the delivery of poorly permeable drugs. Among them, volatile oils derived from natural plants have emerged as promising candidates due to their rapid action, minimal side effects, and high efficiency. This paper provides a brief introduction to biological barriers and highlights the potential of volatile oils as PEs and their underlying mechanisms. Their role in improving transdermal and transmucosal drug delivery has been explored by a comprehensive review of recent research, which provides valuable insights into their future application in pharmaceutical formulations.

Keywords

volatile oils - penetration enhancer - biological barriers - transdermal delivery - mucosal delivery

Introduction

Biological barriers, such as the skin and mucosa, play a critical role in maintaining homeostasis in the body by regulating water balance, gas exchange, nutrient absorption, excretion, and infection prevention,[1] yet pose significant challenges to drug delivery, limiting the efficiency of many therapeutic agents.[2] The dense structure of the skin and the dynamic environment of the mucosa impede drug permeability. The development of innovative drug delivery methods is essential.[3] Strategies that have been developed focus on the use of chemical, physical, biological, and nanotechnology-based approaches.[4] Among them, chemical penetration enhancers (PEs) like surfactants, organic solvents (e.g., ethanol and propylene glycol), and fatty acids (e.g., oleic acid and linoleic acid) are commonly used to improve drug absorption.[5] Synthetic PEs are also included; however often suffer from limitations such as low specificity, potential toxicity, and limited biocompatibility.

Volatile oils derived from natural plants offer an appealing alternative for PEs. These oils have garnered considerable attention due to their strong penetration-enhancing effects, broad availability, and synergistic interactions with drugs.[6] Monoterpenes and sesquiterpenes extracted from plant volatile oils are the main permeation enhancers. In general, terpenes with polar functional groups enhance the permeability of water-soluble drugs, while lipophilic terpenes are more effective for lipid-soluble drugs.[7] It is also recorded in ancient books that “Pungent spice enlightenment, consciousness restore resuscitation and leading the medicine upwards.” The record perfectly summarises the characteristics of pungent and hot essential oils in enhancing penetration.[8] Despite the potential of volatile oils, the mechanisms underlying the penetration-enhancing effects remain inadequately understood, and their application in drug delivery is still evolving. This paper aims to provide a comprehensive review of volatile oils as natural PEs, focusing on their mechanisms, applications, and future potential in improving transdermal and transmucosal drug delivery systems.

Biological Barriers

Mucosal Barrier

Mucosa, including ocular, nasal, oral, and intestinal mucosa, is a widely distributed protective barrier in the body. These nonkeratinized membranes are rich in capillaries, making them crucial sites for drug absorption, albeit with inherent challenges to permeability.[9]

The ocular mucosa that hinders drug delivery primarily includes the tear film and cornea ([Fig. 1A]). The tear film is approximately 3 to 10 μm thick and consists of an outer lipid layer, a middle aqueous layer, and an inner mucin layer, which dilutes drugs through tear secretion.[10] The cornea consists of an epithelial layer, stroma, and endothelium, which pose additional challenges in ocular drug delivery. The epithelium is lipid-rich and hinders the passage of hydrophilic drugs, whereas the stroma, which is a hydrophilic layer constituting 90% of corneal thickness, limits the passage of lipophilic drugs.[11] Mucins above the epithelial layer further complicate drug absorption and reduce ocular bioavailability.[12] The relatively insensitive response of ocular immune response makes ocular administration a viable route for delivering proteins and other drugs with poor oral bioavailability.[13]

Fig. 1 Mucosal barrier structure. (A) Ocular mucosal barrier. (B) Nasal mucosal barrier. (C) Oral mucosal barrier. (D) Intestinal mucosal barrier.

The nasal mucosa has low enzyme activity, but high ciliated cell density and mucus production, and forms a multilayered barrier to drug delivery.[14] [15] It includes a mucous layer, epithelium, and basement membrane ([Fig. 1B]). The nasal mucosa is divided into vestibular, respiratory, and olfactory according to structure and function.[16] The mucus layer and ciliated epithelium form a physical barrier that prevents drug penetration. The clearance of mucociliary limits the residence time of drugs, which require rapid diffusion for effective absorption.[17] Chemical barriers consisting of enzymes further restrict permeability.

The oral mucosa comprises the epithelium, lamina propria, and submucosa ([Fig. 1C]) and is further divided into buccal, sublingual, hard palate, and gingival mucosa based on regions and specific characteristics.[18] Physiological characteristics of the oral mucosa are critical in determining the rate of drug absorption.[19] Nonkeratinized areas, like the buccal and sublingual mucosa, facilitate drug absorption. Buccal mucosa is thicker than the sublingual mucosa, and thus has poorer permeability for drugs.[20] Lipids secreted by membrane particles reside in the intercellular space of the granular layer, constitute the main barrier to drug delivery in the oral mucosa.[21] The basement membrane also restricts the entry of hydrophilic drugs into the lamina propria. Enzymes and immune proteins on the surface of oral epithelium form an enzymatic barrier and a diffusion barrier.[22] The permeability of oral mucosa is generally intermediate between that of skin and gastrointestinal mucosa, making it a viable but complex route for drug delivery.

The intestinal mucosa, lining the digestive tract from the esophagus to the rectum, forms mechanical, chemical, biological, and immune barriers to drug delivery ([Fig. 1D]). Enhancing drug delivery across this barrier requires overcoming physical, enzymatic, and metabolic constraints. Mechanical barriers, like epithelial cells and tight junctions, block harmful substances while regulating permeability.[23] [24] Chemical barriers include gastric acid and digestive enzymes. The immune barrier mainly consists of intestinal mucosal lymphoid tissue with secreted immunoglobulin A. The biological barriers involve gut flora and immune components.[25] These collectively impede the absorption of a drug, particularly for molecules with poor gastrointestinal stability and permeability.

Skin Barrier

The skin is the largest organ of the human body and serves as an important protective barrier to maintain homeostasis and prevent external harm. Its structure consists of the epidermis, dermis, subcutaneous tissue, and appendages ([Fig. 2]).[26] Among these, the epidermis plays a central role in drug absorption, with the stratum corneum, the outermost layer, acting as the primary barrier. This layer consists of tightly packed keratinocytes embedded in intercellular lipids, forming a “brick-and-mortar” structure that effectively limits the penetration of external substances.[27] The hydrophobic nature of the stratum corneum makes hydrophilic drugs particularly challenging to penetrate, while excessively lipophilic drugs may also struggle to move beyond this layer.

Fig. 2 Skin structure.

The skin chemical barrier is mainly dependent on epidermal pH and antimicrobial peptides. Abnormal pH value disrupts skin barrier function by disrupting the stratum corneum and the distribution of intercellular lipids.[28] The skin immune barrier refers to innate immunity, triggered by various immune cells and active molecules in response to an invasion. This forms a skin immune barrier.[29] Drugs are absorbed through the skin mainly through the stratum corneum, sweat gland orifices, etc. The stratum corneum accounts for over 90% of the total absorption capacity of the skin. The drug enters the dermis through the stratum corneum and reaches blood vessels, and enters systemic circulation. The stratum corneum structure is dense in the skin layer and lacks blood and lymphatic vessels, thereby limiting transdermal absorption of pharmaceutical preparations.[30]

The barrier function of the skin is further reinforced by its chemical, microbial, and immune components. The chemical barrier inhibits pathogen growth and contributes to barrier integrity. The microbial barrier, composed of commensal microorganisms, acts as the first line of defense against external insults, while the immune barrier involves innate and adaptive immune responses mediated by skin-resident cells. Together, these features ensure the skin resilience but also pose significant challenges to transdermal drug delivery.

Volatile Oils and their Permeation-Enhancing Effects

Volatile Oils

Volatile oils, also known as essential oils, are aromatic substances extracted from plants and, in rare cases, animals.[31] These oils have been utilized for centuries in traditional medicine systems across cultures for their therapeutic properties and unique ability to enhance drug absorption. The composition of volatile oil is complex. It may consist of dozens to hundreds of compounds, most of which are aliphatic, aromatic, and terpenoids and their oxygen-containing derivatives. Historical records indicate that ancient Egyptians used rudimentary distillation methods to obtain volatile oils for aromatherapy, cosmetics, and medicinal purposes.[32] In Traditional Chinese Medicine (TCM), the concept of “aromatherapy and disease prevention” was first introduced in the Yellow Emperor's Inner Canon, which highlighted the health-preserving effects of aromatic herbs.[33] Common sources of volatile oils include herbs such as mint, clove, and angelica, which are widely used in TCM formulations.[34]

Volatile oils are composed of complex mixtures of terpenes, sesquiterpenes, and other aromatic compounds, with their specific properties determined by their functional groups. The versatility of volatile oils allows them to facilitate drug transport across both lipophilic and hydrophilic barriers. Additionally, their small molecular size and ability to disrupt lipid bilayers make them particularly effective as natural PEs. Volatile oils have several advantages when compared to the synthetic enhancers. They are derived from widely available natural sources, exhibit low toxicity and minimal irritation, and often have synergistic therapeutic effects when combined with active drugs. These attributes make them highly attractive for pharmaceutical applications, where they can enhance drug permeability while contributing additional benefits such as anti-inflammatory or antimicrobial effects. With the ability to promote transdermal and transmucosal delivery, volatile oils represent a promising solution to overcoming the challenges posed by biological barriers.

The Mechanisms for the Enhanced Permeation

The mechanisms of volatile oils primarily involve modifying the structural and functional properties of biological barriers.[35] [36] For mucosal permeability, volatile oils can reduce mucus viscosity and improve drug diffusion in the mucus layer by improving the rheological properties of the mucus layer. They can also alter the intercellular lipid arrangement within the epithelial layer, expanding the paracellular pathway for drug transport, enhancing the fluidity of cell membranes, and facilitating transcellular absorption ([Fig. 3]). [Fig. 4] shows the mechanisms in enhancing skin permeation. Volatile oils disrupt the orderly arrangement of lipids in the stratum corneum and increase its permeability.[37] Its mechanism is mainly reflected in the following two aspects. First, volatile oils can change the microstructure of the stratum corneum. Specifically, a proportion of volatile oils establishes continuous hydrogen bonding with lipid molecular head groups, which disrupts the intrinsic hydrogen bonding network within intercellular lipids. This molecular interaction leads to structural disorganization and increased porosity of the stratum corneum, thereby compromising the epidermal barrier integrity.[38] Secondly, volatile oils show a pronounced molecular affinity for the cholesterol constituents within the stratum corneum's lipid architecture. This preferential molecular interaction induces enhanced fluidization of the lamellar bilayer structure, which ultimately facilitates a marked augmentation in transdermal drug permeation kinetics. They can also interact with keratin within keratinocytes, altering the conformation of the protein and loosening the tight structure of the cuticle and creating pathways for drug movement.[39] Furthermore, volatile oils promote skin microcirculation and enhance the distribution of drugs from the epidermis into systemic circulation while altering the skin surface charge to improve drug uptake.

Fig. 3 Mechanism of mucosa penetration. (A) Reduce mucosal mucus concentration. (B) Promote Intercellular route. (C) Promote transcellular route.

Fig. 4 Mechanism of skin penetration. (A) Destroy the orderly arrangement of stratum corneum lipids. (B) Change the conformation of keratin. (C) Improve microcirculation.

Transmucosal Drug Delivery

Ocular Mucosa

Volatile oils, such as menthol and borneol, have shown great potential to overcome this biological barrier. Their mechanisms involve enhancing the fluidity of the lipid bilayer in the corneal epithelium and increasing cell membrane permeability ([Table 1]).[40] [41] [42] Ouyang et al investigated the effect of menthol on the permeability of baicalin in isolated rabbit corneas and found that 0.1% menthol improved the apparent permeability coefficient by 52.05 times without causing notable irritation.[40] Similarly, Song et al demonstrated through in vitro and in vivo corneal models that borneol enhanced the corneal permeability of sinomenine hydrochloride.[41] These findings underscore the ability of volatile oils to improve drug delivery across the ocular mucosa.

Table 1 A summary of volatile oils in promoting mucosal permeability

Volatile oils	Alone/combined use	Mucosal species	Model drugs	Dosage form	Irritation	Experimental setup	In vitro/in vivo	Permeation ratio/permeation factor (ER)	Apparent permeability coefficient (P app)	Transdermal rate (J ss, µg/cm/h)	Time lag (h)	Permeability coefficient (K P)	Other parameters	Ref.
0.1% menthol	Alone	In vitro rabbit cornea	Baicalin	Solution	Blinks: 7.8 ± 0.96 times	Modified vertical Franz diffusion cell	In vitro	52.05	22.72 × 10 cm/s					[40]
0.04% borneol	Alone	In vitro rabbit cornea	Sinomenine hydrochloride	Solution		Franz diffusion pool; microdialyzers	In vitro/in vivo		2.39 ± 0.41 cm/s				AUC0-t: 41.14 ± 6.02 mg/mL·min; C max: 0.37 ± 0.01 mg/mL	[41]
0.1% menthol	Alone	SD rat cornea	Ozone	Solution			In vivo						MDA content: 4.03 ± 1.03 nmol/mgprot; SOD content: 369.10 ± 116.05 U/mgprot	[42]
0.15% borneol	Alone	Rabbits, dog sheep, and other nasal mucosa	Cobra neurotoxin	Solution			In vitro						Number of radioactive liquid flashes (cpm): 2,110 ± 17 (rabbit); 1,490 ± 11 (dogs); 2,230 ± 12 (sheep)	[43]
4% menthol	Alone/Combined	SD rat nasal mucosa	Insulin	Solution			In vivo						Rate of change in blood glucose: 68.05 ± 17% (3 h); AUC: 34.64 ± 20.32%·h; bioavailability: 13.41%	[44]
0.5% menthol	Alone	Nasal mucosa of rats	Furosemide	Solution			In vivo						Absorption rate constant: 0.04 min; urine onset: 23.33 ± 3.04 min	[45]
60 μg/mL menthol	Alone	Calu-3 cells	Puerarin	Solution	0-60 μg/mL (1:0.5)	Chopstick electrodes and epithelial voyometry (EMD Millipore, Billerica, Massachusetts, United States)	In vitro	1.15	A: cell apex. B: basolateral side. 1.78 × 10 cm/s (A-B); 2.06 × 10 cm/s (B-A)					[46]
50 μg/mL menthol	Alone	Rat nasal epithelial cells	Puerarin	Solution	0-50 μg/mL (1:0.5)	Chopstick electrodes and epithelial voyometry (EMD Millipore, Billerica, MA, United States).	In vitro	1.03	A: cell apex. B: basolateral side. 2.15 × 10 cm/s (A-B); 2.20 × 10 cm/s (B-A)					[47]
4.76% limonene	Alone	Porcine cheek tissue mucosa (cheek area)	Bentronidazole solution	Solution		Franz diffusion pool	In vitro	4.9		12.53 ± 2.39	2.84	(25.10 ± 4.80) × 10 cm/h		[49]
0.1 mg/mL menthol	Alone	Porcine cheek tissue epithelial mucosa	Nucleoside analogue dideoxycytidine	Solution		Horizontal diffusion cell	In vitro	1.98			6.41	(8.13 ± 0.77) × 10 cm/s		[50]
0.1 mL/mL clove oil	Mix for use	SD rats	Echinacoside	Solution			In vivo						C max: 2.89 ± 0.48 μg/L; T max: 100.00 ± 15.49 min; AUC0-24: 899.9 ± 74.1 μg/L·min; AUC0-∞: 1,141.271 ± 286.613 μg/L·min	[52]
3% borneol/menthol microemulsion	Mix for use	SD rats	Soy flavonoids	Solution			In vivo						C max: 300.81 ± 38.46 ng/mL; T max: 1.00 ± 0.16 h; AUC0-12: 1,355.87 ± 202.23 ng/h/mL;	[53]
0.72 μL/mL Angelica volatile oil	Alone	SD rat valgus intestinal sac; Caco-2 cell model	Baicalin; puerarin	Solution			In vivo/in vitro		Baicalin in vivo: 24.83 ± 0.36 (× 10 cm/s); cell: 8.15 ± 3.88 (× 10 cm/s). Puerarin in vivo: (10.80 ± 1.96)× 10 cm/s					[54]
0.72 μL/mL Angelica volatile oil	Alone	SD rat valgus intestinal sac	Baicalin	Solution			In vivo		24.83 ± 0.36 (×10 cm/s)					[55]
0.2% menthol	Alone	Frog dorsal skin	Ciprofloxacin	Solution		Dual-chamber transdermal diffusion device	In vitro			11.89 ± 1.44				[57]
5 mg/mL menthol	Alone	Isolated frog skin	Puerarin	Solution		TP-5 intelligent transdermal tester	In vitro		6.21 ± 1.34 × 10 cm/min					[58]

Abbreviations: AUC, area under the curve; C _max, peak concentration; MDA, malondialdehyde; SD rats, Sprague–Dawley rats; SOD, superoxide dismutase; T _max, time to peak.

Nasal Mucosa

Volatile oils, such as menthol and borneol, have the ability to enhance drug permeability across the nasal mucosa ([Table 1]). For instance, Liu et al studied the effects of borneol on the nasal absorption of I-cobratoxin in rabbits, dogs, and sheep, and found that borneol significantly improved the absorption and overcame the poor baseline permeability of the toxin.[43] Wang et al pretreated diabetic rats with menthol before intranasal insulin administration and observed a seven-fold increase in pharmacological bioavailability compared to untreated controls.[44] These studies highlight the effectiveness of volatile oils in enhancing drug absorption through the nasal mucosa.

Mucosal permeability assays can be performed by in vivo animal experiments and in vitro mucosal tissues. However, there are some limitations; the results of the in vivo experiment are significantly affected by experimental animal species, administration site, mucosal status, etc. Similarly, in vitro animal studies are also related to permeability in mucosal tissues; the results of in vitro mucosal membranes may be inaccurate due to enzyme inactivation and low metabolic activity. The experiments can be performed using an in vitro cell model. Among these, Calu-3 cells derived from human respiratory epithelium and animal nasal epithelium are often used to assess nasal mucosal permeability.[45] For an in vitro permeability test on a cell model, the safe dose of volatile oils should be considered by investigating their cytotoxicity. The cells' transepithelial resistance (TEER) should be evaluated by a chopstick electrode and epithelial voltmeter. The permeability was assessed by the permeability enhancement ratio (ER) and two-way apparent permeability coefficient (P _app) ([Table 1]).[46] [47] For example, Zhang et al selected the appropriate menthol concentration (60 μg/mL, 50 μg/mL) for their preliminary study of menthol stimulation experiment with Calu-3 cell monolayers (used as a nasal mucosa model) and rat nasal epithelial cells.[46] [47] They characterised puerarin transport through the cell model and evaluated the absorption efficiency of puerarin after co-administration with paeoniflorin and menthol. The result showed that puerarin was poorly transported alone, mainly by passive diffusion through the cell monolayer. When puerarin was combined with paeoniflorin, there was no significant change in the P _app of puerarin; however, when combined with menthol, the P _app of puerarin was significantly improved (p < 0.05), suggesting that due to drug compatibility, the tight junction was opened, weakening the epithelial cells' barrier ability and facilitating puerarin transportation.

Oral Mucosa

Volatile oils have demonstrated significant potential in improving oral mucosal drug delivery by enhancing both transcellular and paracellular pathways.[48] Mechanistically, they facilitate drug transport by increasing the fluidity of the lipid bilayer in epithelial cells and disrupting intercellular lipids ([Table 1]).[49] [50] For instance, Amaral et al investigated the effects of eugenol, carvacrol, and limonene on the permeability of benzyl nitrate (BZN) through porcine buccal mucosa.[49] The result showed that the permeability coefficient of BZN was increased by 2.6, 2.9, and 4.9 times, respectively. Limonene showed the strongest enhancing effects, mainly due to its interaction with the nonpolar regions of the buccal epithelium. Similarly, Shojaei et al demonstrated that menthol enhanced the permeability of the hydrophilic nucleoside analog, dideoxycytidine, across porcine buccal mucosa, with significant increases observed at concentrations as low as 0.1 mg/mL.[50] The mechanism for this might be related to the increased partition coefficient of terpenes.

Intestinal Mucosa

Compared to other intestinal absorption enhancers, including surfactants, bile acids, chelating agents, and fatty acids,[51] volatile oils from natural plants have low irritation toxicity and can improve the intestinal absorption of active ingredients, thereby improving the curative effect. Intestinal permeability experiments can be performed using in vitro inverted intestine, in vivo intestinal perfusion, and Caco-2 cell models. The permeability-enhancing effect can be investigated using the pharmacokinetic parameters like C _max, T _max, AUC, and permeability coefficient ([Table 1]).[52] [53] [54] [55] For example, Shen et al studied the absorption behavior of echinacoside (ECH) using an in vitro inverted intestinal sac model and an in situ single-pass intestinal perfusion model.[52] Pharmacokinetic methods were used to assess the effects of verapamil and clove oil on the bioavailability of ECH in vivo. The results showed that additional treatment of verapamil and clove oil increased the bioavailability of ECH by 1.37-fold (p < 0.05) and 2.36-fold (p < 0.001), respectively, when compared with the ECH group. Shen et al[53] used the rat-isolated intestinal membrane diffusion chamber system to evaluate the effects of a borneol/menthol eutectic mixture (25:75) and microemulsion daidzein absorption in rat-isolated intestinal membranes, and performed pharmacokinetic studies in rats. The results showed that both the borneol/menthol eutectic mixture and microemulsion enhanced daidzein absorption, with the relative bioavailability increasing by 1.5 and 3.65 times, respectively, when compared with daidzein suspension. The volatile oils might increase the fluidity of the polar head region and relax cell membrane tight junctions, thereby improving drug absorption in the intestinal mucosa.[56] However, the exact mechanism of how the volatile oils cross the intestinal mucosal barrier has not been fully explored.

Frog skin is widely used in the experiment of volatile oils promoting mucosal penetration because there is no complete “modeling” technology to support the isolated ocular, nasal, and digestive tract mucosa at present. ([Table 1]). For example, Zhao et al conducted an in vitro mucosal absorption test via a two-compartment transdermal diffusion device and calculated the permeability coefficient.[57] They found that 0.2% menthol could significantly reduce the permeability coefficient of ciprofloxacin mucosal absorption and enhance its reservoir effect. Li et al conducted an in vitro mucosal permeability test on isolated bullfrog abdominal skin using a Franz diffusion cell.[58] They further investigated the effects of different concentrations of menthol on the P _app of puerarin, and the result showed that menthol had a significant promoting effect when the concentration reached 5 mg/mL, and the P _app value was (6.21 ± 1.34) × 10 cm/min.

Transdermal Drug Delivery

Transdermal drug delivery is efficient in administering medications by steadily releasing them and avoiding the digestive system, but the barrier of skin complicates absorption. PEs, like naturally derived volatile oils, help drugs pass through the skin, providing safety, effectiveness, and extra therapeutic benefits.[59]

Patches and Pastes

A patch is a thin layer made from drugs and polymers, and is ideal for drugs with strong effects, molecular weights under 1000, and suitable oil-water partition coefficients. Transdermal absorption enhancers are designed to open stratum corneum pores, improve bilayer fluidity, and boost drug penetration, and are crucial.[38]

Volatile oils from natural plants are typically PEs, sometimes combined with azone and propylene glycol to boost transdermal permeation, with permeability ranging from 1.21 to 3.22 ([Table 2]).[60] [61] [62] [63] [64] For instance, Luo et al used a modified Franz diffusion cell with nude mouse skin as transdermal barriers to study the effect of 5% clove oil on transdermal permeation of ligustrazine phosphate, achieving a cumulative amount of 3.96 mg/cm² over 12 hours and an enhancement rate of 3.22 when compared with the negetaive control and surpassed the positive control laurocapram,[63] indicating the patch's superior transdermal effectiveness. The study also discovered that transdermal absorption enhancers boost absorption, with combined enhancers being more effective. Yu et al found that using 2% menthol, 1% azone, and 2% propylene glycol together significantly improved the transdermal penetration of active ingredients in Sumei Slimming Paste.[64]

Table 2 Different Chinese medicine volatile oil to promote skin penetration related experiments

Volatile oils	Single/combined	Skin type	Model drugs	Dosage form	Stimulation experiments	Device	In vitro/in vivo	Transdermal rate (J ss, µg/cm/h)	Permeability (Q, µg/cm)	Time lag (h)	Permeability ratio/permeation factor (ER)	Other parameters	Ref.
1% cinnamyl alcohol	Alone	Big-eared rabbit back	Flurbiprofen	Patches		Horizontal horizontal double-chamber diffusion tank	In vitro	8.42 ± 1.24	24 h: 205.04 ± 29.28	3.87	1.52		[60]
5% villous amomum fruit oil; 3% tsao-ko amomum fruit oil; 10% white cardamom oil	Alone	Kunming mouse abdomen	Total strychnine base	Patches		TK-12B transdermal diffusion tester	In vitro	1,039; 951; 907	4 h: 1,989.30 ± 529.10; 2,230.60 ± 661.10; 2,227.60 ± 886.10		1.21; 1.23; 1.38		[61]
10% tsao-ko amomum fruit oil	Alone	Kunming mouse abdomen	Rotondine	Patches		Modified Franz diffusion cell	In vitro	421.00 ± 43.00	12 h: 4,914.00		1.28		[62]
5% Clove volatile oil	Alone	Nude mice	Ligustrazine phosphate	Patches		TK-12B transdermal diffusion tester	In vitro	295.20 ± 67.90	12 h: 3,964.20 ± 621.30		3.22		[63]
2% menthol + 1% nitrogen ketone + 2% propylene glycol	Mix for use	Ex vivo rat skin	Oleanolic acid	Patches		MSD-1200 transdermal absorption meter	In vitro	172.00 ± 17.00			1.76		[64]
1% menthol	Alone	Kunming mouse abdomen	Naringin	Plasters		TK-12B transdermal diffusion tester	In vitro	3.91			3.48		[67]
1% borneol + 1% menthol + 2% camphor	Mix for use	Ex vivo mice; Strat-M™ Artificial membranes	Patriarch hempting	Plasters		RYJ-12B drug transdermal diffusion tester	In vitro	4.45; 2.39	72 h: 33.85; 15.96	1.41; 0.49	4.25; 1.74		[68]
8% borneol + menthol eutectic mixture	Mix for use	Ex vivo rat skin	Ligustrazine hydrochloride	Gel patches		Horizontal Franz diffusion cell	In vitro	389.76		0.64	5.81		[69]
Citrus peel volatile oil	Alone	New Zealand rabbit back	Piperine	Cataplasm		Improved Franz release pool (homemade)	In vitro		8 h: 6.01 ± 0.37				[70]
2% menthol	Alone	Guinea pig back	Diclofenac potassium	Cataplasm		TP-3 smart transdermal diffusion meter	In vitro	35.06	12 h: 434.26				[71]
0.5% white mustard oil	Alone	Rat back	Cnidium monnieri gel	Gels		Modified Franz diffusion cell	In vitro	16.61			2.1		[74]
0.5% white mustard oil	Alone	Rat back	Berberine hydrochloride gel	Gels		Modified Franz diffusion cell	In vitro	7.27			2.42		[75]
Chuanxiong volatile oil	Alone	SD rat abdomen	Flurbiprofen gel	Gels		Franz diffusion cell device	In vitro	144.68 ± 16.73					[76]
15% Chuanxiong volatile oi	Alone	New Zealand rabbit back	Flurbiprofen gel	Gels		Laser Doppler flow tester	In vivo					Cutaneous blood perfusion: 272 ± 89.6 bPU	[77]
3% farnesol + 10% isopropanol	Mix for use	In vitro suckling pigs	Pronell hydrochloride gel	Gels		Modified Franz diffusion cell	In vitro	132.38	24 h: 2,946.00 ± 774.40	1.77	2.09		[78]
1% borneol + 1% menthol	Mix for use	SD rat abdomen	Sophodine; Marine	Gels		RYJ-6B drug transdermal diffusion experimenter	In vitro	505.00 ± 7.00; 479.00 ± 5.00	24 h: 6,858 ± 80; 7,018 ± 87		4.4; 3.65		[79]
3% menthol	Single/mixed	Mouse abdomen	Lidocaine gel	Gels		Modified Franz diffusion cell	In vitro		6 h: 14,768 ± 1430			Permeability coefficient (mg/h): 1.947 ± 0.23	[80]
5% menthol	Alone	Ex vivo rat skin	Tinidazole gel	Gels		Franz diffusion pool	In vitro		24 h: 623.4 ± 65.0				[81]
5% menthol	Alone	Ex vivo rat skin	A sprig of artemisin	Gels		Modified Franz diffusion cell method	In vitro/in vivo	8.82 ± 0.86		28.90 ± 9.04	4.48	AUC: 2,263.71 ± 720.61 (μg·L/h); t 0.5: 18.92 ± 7.01 h; T max: 4.2 ± 2.49 h; C max: 116.91 ± 27.09 μg/L	[82]
Zanthoxylum pepper volatile oil microemulsion gel	Alone	SD rat abdomen	Ostholemine; Ligustrazine; Ferulic acid; Puerarin; Genipine	Microemulsion gel	Less irritating to the skin demonstrating by a HE staining	TK-24B Drug Transdermal Diffusion Tester	In vitro	Ostholerin: 3.94 ± 1.10; Ligustrazine: 82.41 ± 15.02; Ferulic acid: 26.13 ± 8.08; Puerarin: 51.43 ± 10.22; Genipine: 101.88 ± 23.98	Ostholemine 24 h: 84.22 ± 23.20; Ligustrazine 24 h: 2,029.89 ± 356.65; Ferulic acid 24 h: 820.04 ± 36.96; Puerarin 24 h: 1,385.08 ± 103.46; Genipine 24 h: 2,713.30 ± 203.69	Ostholemine: 2.59 ± 1.32; Ligustrazine: 3.85 ± 1.06; Ferulic acid: 6.44 ± 2.50; Puerarin: 2.80 ± 1.90; Genipine: 101.88 ± 23.98	Ostholemine: 4.28; Ligustrazine: 9.64; Ferulic acid: 90.1; Puerarin: 1,028.6; Genipine: 926.19		[83]
2% nitrogen ketone + 1% Camellia oleifera shoots volatile oil	Mix and use	SD rat abdomen	Triptolide alcohol; Meloxicam	Creams	No acute toxicity and irritation; no skin allergy	TG-6A Diffusion Experimenter	In vitro	0.12 ± 0.03; 3.20 ± 0.30	12 h: 1.48 ± 0.20; 38.36 ± 0.50				[88]
5% menthol	Alone	Kunming mouse abdomen	Dexamethasone acetate	Creams		Modified simple cabs	In vitro		6 h: 205.90 ± 14.58				[89]
3% menthol + 3% borneol	Mix and use	Kunming mouse abdomen	Curcuma; Gemarone	Ointment		Modified Franz diffusion cell	In vitro	30.02; 68.78			1.85; 2.13		[90]
5% borneol	Alone	SD rats	Gallic acid; Curry Latin	Ointment	No irritation to the skin	Franz transdermal diffusion pool	In vitro	46.3; 3.1	24 h: 1,163.60 ± 23.50; 73.80 ± 2.80		1.73; 1.82		[91]
5% peppermint oil	Alone	Rat abdominal skin	Glucosamine hydrochloride	Solution		Modified Franz diffusion cell	In vitro	95.50 ± 30.55			7.38		[93]
1% litseae fructus oil; 3% dried Ginger volatile oil; 5% magnolia flos volatile oil	Alone	Kunming mouse abdomen	Ligustrazine phosphate	Solution		TK.12B Transdermal Diffusion Tester	In vitro	207; 166; 205	4 h: 916; 740; 933		1.27; 1.5; 1.15		[94]
5% borneol; 5% menthol	Alone	SD rat dorsal	Hook vine	Solution		RYJ-6A Drug Transdermal Diffusion Tester	In vitro	0.92 ± 0.05; 0.87 ± 0.03			2.24; 1.95		[95]
5% borneol; 5% menthol	Alone	SD rat dorsal	Gastrodia	Solution		RYJ-6A Transdermal Diffusion Tester	In vitro	17.49; 14.27	24 h: 406.76; 322.94				[96]
5% Bergamot volatile oil	Alone	Big-eared rabbit back	Ligustrazine	Solution	The mean 2-hour erythema score was 0.38	TP-6 Intelligent Transdermal Tester	In vitro	484.66 ± 69.03		2.23 ± 0.28	14.52		[97]
Saposhnikoviae; Euodia rutaecarpa; Saussurea lappa	Alone	Nude mouse skin	Ibuprofen	Solution		Franz-TT6 transdermal absorptive instrument	In vitro	9.92 ± 1.32; 10.56 ± 1.52; 9.32 ± 1.20	12 h: 1,023.49 ± 18.63; 871.36 ± 16.79; 682.44 ± 15.38		3.02; 3.55; 2.88		[98]
Saposhnikoviae; Euodia rutaecarpa; Saussurea lappa	Alone	Nude mouse skin	Ibuprofen	Solution		Franz-TT6 transdermal absorptive instrument	In vitro	10.76 ± 1.43; 9.78 ± 1.28; 9.13 ± 1.12	12 h: 868.42 ± 16.32; 1,019.12 ± 15.21; 690.43 ± 14.32		3.02; 3.54; 2.40		[99]
Euodia rutaecarpa; Saposhnikoviae	Alone	Nude mouse abdomen	Ibuprofen	Solution		TP-3A Transdermal Diffusion Tester	In vitro	86.20 ± 0.87; 74.89 ± 1.63	12 h: 1,016.53 ± 11.05; 863.63 ± 18.73		3.46; 3.00		[100]
5% Resina Liquidambaris volatile oil	Alone	Rabbit belly	Tinidazole	Solution		Homemade transdermal device	In vitro		24 h: 4,052.00 ± 3.00				[101]
5% white Mustard volatile oil	Alone	Wistar rat abdomen	Fumarate ethyl; Asaroctan; Ephedrine hydrochloride; Baicalin	Solution		Franz diffusion cell device	In vitro	11.23; 23.22; 2.90; 5.49	24 h: 253.81 ± 6.95; 549.33 ± 21.92; 69.87 ± 2.29; 130.23 ± 12.22		4.56; 7.04; 3.34; 7.97		[102]
7% litseae fructus oil	Alone	Mouse abdomen	Rotondine	Solution		TK-12B transdermal diffuser instrument	In vitro	1,066.7	4 h: 4,979.80		1.2		[103]
2% eucalyptus oil	Alone	SD rats	Ligustrazine	Solution		Valia-Chien horizontal diffusion tank	In vitro					Permeability coefficient: 123.47 ± 2.42 (cm/h)	[104]
2%, 5% Angelica sinensis volatile oil (A); 2%, 5% Clove volatile oil (B)	Alone	Kunming mouse abdomen	(1) Tanshinone II.A; (2) Puerarin; (3) Ginsenoside Rg1	Solution		TT-06 Transdermal Absorbor, Franz Diffusion Cell	In vitro	(1) Tanshinone II.A 5% A: 6.66; 5% B: 6.72; (2) Puerarin 5% A: 20.24; 5% B: 9.79; (3) Ginsenosides Rg1 5% A: 3.11; 5% B: 2.35	(1) Tanshinone II.A 8 h 5% A: 50.32 ± 6.33; 5% B: 53.11 ± 3.61; (2) Puerarin 8 h 5% A: 160.42 ± 0.60; 5% B: 78.45 ± 6.97; (3) Ginsenosides Rg1 8 h 5% A: 25.91 ± 3.79; 2% B: 19.43 ± 0.94		(1) Tanshinone II.A A: 3.36; B: 4.06; (2) Puerarin A: 9.13; B: 4.42; (3) Ginsenoside Rg1 A: 16.30; B:12.30		[105]
1% Angelica sinensis volatile oil	Alone	SD rat abdomen	Resveratrol	Solution		Franz diffusion pool	In vitro	6.51 ± 2.11	8 h: 129.00 ± 8.14		3.29		[106]
2% Angelica sinensis volatile oil	Alone	The lower part of the xiphoid process in nude mice	Ferulic acid	Solution		Valia-Chien Horizontal Diffusion Tank	In vitro					Permeability coefficient: 184.87 ± 11.473 (cm/h)	[107]
Clove volatile oil; Clove volatile oil + nitrogen ketone	Single/mixed	SD rat dorsal	Diclofenac sodium	Solution		Transdermal absorption diffusion device	In vitro	106.08 ± 31.10; 152.31 ± 27.33			1.89; 2.71		[108]
5% Clove volatile oil	Alone	New Zealand white rabbit back; Wistar Rats; Kunming mice	Tanshinone II.A	Solution	Skin irritation response score is 0; The volatile oil is not irritating	Modified Franz diffusion cell	In vitro	6.72	8 h: 53.11 ± 3.61		4.06		[109]
Patchouli volatile oil	Alone	SD rat dorsal	Diclofenac sodium	Solution		Homemade transdermal absorption diffusion device	In vitro	87.87 ± 15.91		0.55 ± 2.11	1.56	9.338 ± 2.951 (cm/h)	[110]
Tangerine peel oil (A); Zedoary turmeric oil (B)	Alone	Nude mouse abdomen	(1) Baicalin; (2) Wogonin; (3) Baicalein; (4) Total flavonoids	Solution		TK-6H Transdermal Diffusion Tester	In vitro	(1) Baicalin A: 2.53 ± 0.42; B: 0.94 ± 0.17; (2) Woscutellin A: 0.280 ± 0.068; B: 0.12 ± 0.02; (3) Baicalin A: 2.04 ± 0.38; B: 0.84 ± 0.18; (4) Total flavonoids A: 4.75 ± 0.87; B: 1.91 ± 0.37			(1) Baicalin A: 4.34; B: 1.61; (2) Woscutellin A: 3.27; B: 1.43; (3) Baicalin A: 2.75; B: 1.13; (4) Total flavonoids: A: 3.37; B: 1.32		[111]
1,8-Eucalyptol; 4-Terpineol; Camphor; menthol; α-Terpineol; carvone	Alone	SD rat abdomen	Ibuprofen	Solution	HaCaT cell half inhibition (μg/mL): 1,702.00; 717.71; 1,285.26; 405.65; 424.75; 420.00	Franz diffusion pool	In vitro	74.50 ± 9.29; 89.39 ± 19.40; 43.07 ± 3.12; 75.27 ± 3.59; 47.33 ± 8.89; 73.06 ± 8.73		0.97 ± 0.18; 1.09 ± 0.71; 1.85 ± 0.42; 2.08 ± 0.72; 1.55 ± 0.29; 0.29 ± 0.61	3.20; 3.84; 1.85; 3.23; 2.03; 3.14		[112]
Menthol	Alone	Rabbit back skin; Exfoliate the skin	Metronidazole	Solution		Multiple two-chamber diffusion cell units with self-improvements	In vitro	38.19 ± 1.82; 61.94 ± 4.23					[113]
5% Notopterygium volatile oil	Alone	Kunming mouse abdomen	Rhubarbin vine	Solution		Modified Franz transdermal absorptive instrument	In vitro	277.53 ± 65.81	24 h: 6,166.96 ± 317.30		1.11		[114]
5% Notopterygium volatile oil	Alone	Nude mouse abdomen	Rhubarbin vine	Solution		Modified Franz transdermal absorptimeter	In vitro	170.93 ± 39.81	24 h: 1,947.13 ± 586.28		698.88		[115]
5% Notopterygium volatile oil	Alone	Kunming mouse abdomen	Strychnine	Solution		Modified Franz transdermal absorptive instrument	In vitro	271.60 ± 35.50	24 h: 5,516.50 ± 713.90		1.36		[116]
1% cinnamon oil	Alone	SD rat dorsal	Strychnine; Strychnine	Solution		HC-188 Transdermameter, MSE-1600 Franz Diffusion Cell	In vitro	19.65 ± 2.31; 18.38 ± 2.15	12 h: 195.31 ± 57.98; 199.74 ± 34.34	1.57 ± 0.27; 1.70 ± 0.51	3.54; 2.55		[117]
3% Olibanum volatile oil (A); 3% Myrrh volatile oil (B)	Single/mixed	Kunming mouse abdomen	(1) Strychnine; (2) Strychnine; (3) Ephedrine hydrochloride	Solution		Modified Franz diffusion cell	In vitro	(1) Strychnine A: 45.54; B: 41.43; Pairs: 45.68; Mixed: 35.94; (2) Strychnine A: 96.74; B: 98.69; Pairs: 85.08; Mixed: 92.58; (3) Ephedrine hydrochloride A: 38.25; B: 36.75; Pairs: 37.61; Mixed: 35.50	(1) Nux strychnine 12 h A: 114.85 ± 7.19; B: 113.40 ± 27.58; Pairs: 120.69 ± 21.44; Mix: 97.71 ± 6.98; (2) Strychnine 12 h: A: 291.09 ± 11.37; B: 288.42 ± 9.47; Pairs: 268.78 ± 30.27; Mix: 249.90 ± 10.08 (3) Ephedrine hydrochloride 12 h A: 114.22 ± 7.99; B: 105.49 ± 12.02; Pairs: 112.55 ± 4.86; Mix: 96.18 ± 5.18	(1) Strychnine A: 0.73; B: 0.21; Pairs: 0.50; Mix: 0.34; (2) Strychnine A: 0.24; B: 0.18; Pairs: 0.31; Mix: 0.62 (3) Ephedrine hydrochloride A: 0.08; B: 0.54; Pairs: 0.09; Mix: 0.75	(1) Strychnine A: 2.13; B: 1.94; Pairs: 2.14; Mix: 1.68; (2) Strychnine A: 1.58; B: 1.61; Pairs:1.55; Mix: 1.51; (3) Ephedrine hydrochloride A: 3.5; B: 3.29; Pairs: 3.37; Mix: 3.18		[118]
3% Olibanum volatile oil (A); 3% Myrrh volatile oil (B)	Single/mixed	Kunming mouse abdomen	Chuanxiong	Solution		TT-6D transdermal diffusion tester	In vitro	A: 2.56; B: 2.75; Monomix: 2.42; Mixed mention: 2.76	24 h: A: 57.80 ± 2.86; B: 63.34 ± 4.56; Monomix: 54.17 ± 4.40; Mixed mention: 62.52 ± 7.79	A: 1.45; B: 2.02; Monomix: 1.91; Mixed mention: 2.44	A: 7.68; B: 8.26; Monomix: 7.26; Mixed mention: 8.28		[119]
1% borneol	Alone	Mouse skin	VB1	Solution		TT-6 Transdermal Diffusion Tester	In vitro	14.49	24 h: 322.59 ± 201.10		12.66		[120]
1% Cnidium monnieri volatile oil (A); 1% borneol (B); 1% menthol (C)	Single/mixed	Rabbit back	Metronidazole	Solution		Homemade transdermal absorption device	In vitro	A: 52.89 ± 6.57; B: 52.26 ± 7.38; C: 63.58 ± 8.08; A + B: 70.06 ± 6.62; A + C: 71.82 ± 7.57			A: 2.21; B: 2.19; C: 2.66; A + B: 2.93; A + C: 3.01		[121]
1% Cnidium monnieri volatile oil; 1% Cnidium monnieri volatile oil + 1% nitrogen ketone	Single/mixed	Rabbit back	Metronidazole	Solution		Dual-chamber transdermal diffusion device	In vitro	52.89 ± 6.57; 79.44 ± 8.14			2.21; 3.32		[123]
1% Cnidium monnieri volatile oil; 1% Cnidium monnieri volatile oil + 5% oleic acid	Single/mixed	Rabbit back	Diclofenac sodium	Solution		Homemade transdermal absorption device	In vitro	63.50 ± 9.60; 44.30 ± 4.90					[124]
5% Asarum volatile oil	Alone	Kunming mouse abdomen	Rhubarbin vine	Solution		TT-6 transdermal absorptive instrument	In vitro	219.89 ± 19.99	24 h: 5,276.62 ± 813.06		1.03		[125]
5% Asarum volatile oil	Alone	Nude mouse abdomen	Cranial pain	Solution		TT-6 transdermal absorptive instrument	In vitro	284.29 ± 18.08	24 h: 5,722.78 ± 250.21		37.09		[126]
5% Asarum volatile oil	Alone	Kunming mouse abdomen	Cranial pain	Solution		TT-6 transdermal absorptive instrument	In vitro	678.60 ± 48.50	24 h: 16,601.80 ± 2,061.80		1.36		[127]
5% Cyperus volatile oil	Alone	SD rat abdomen	Clonrazepam	Solution		Modified Franz diffusion cell	In vitro	10.32 ± 0.2329	24 h: 229.30 ± 2.68		3.18		[128]
5% Cyperus volatile oil	Alone	SD rat abdomen	Paracetamol	Solution		TT-6 transdermal absorptive instrument	In vitro	2.17	24 h: 51.76 ± 1.77		3.07		[129]
5% Cyperus volatile oil	Alone	SD rat abdomen	Indomethacin	Solution		TT-6 Transdermal Absorptive Instrument	In vitro	3.67	24 h: 86.98 ± 1.69		0.94		[130]
3% Euodia rutaecarpa volatile oil	Alone	Kunming mouse abdomen	Marine	Solution		YB-P6 transdermal tester	In vitro	136.50 ± 4.89	12 h: 1,319.65 ± 31.80	1.89 h	6.79		[131]
2% Clove volatile oil	Alone	Nude mouse abdomen	5-Fluorouracil	Solution		Double-chamber diffusion tank	In vitro	656.29 ± 139.37			110.48		[132]
4% menthol; 4% borneol; 4% muskone	Alone	SD rat abdomen	Phloretin	Solution		Franz YB-P6 Intelligent Transdermal Experimenter	In vitro	10.57; 8.97; 2.99	12 h: 118.12 ± 8.14; 101.69 ± 7.17; 33.75 ± 5.07		13.56; 6.54; 3.46		[133]
2% menthol	Alone	Rabbit back	Metronidazole	Solution		Two-chamber diffusion tank in vitro experimental setup	In vitro	43.36 ± 2.66		3.02 ± 0.96			[133] [134]
5% menthol	Alone	Laboratory dogs	Terbinafine hydrochloride	Solution		Vertical Franz diffusion cell	In vitro	0.19	24 h: 4.79 ± 0.17	-0.41	1.72		[135]
5% menthol	Alone	Pekingese dorsal thorax waist	Ketoconazole	Solution		Vertical Franz diffusion cell	In vitro	0.58			2.21 ± 0.08		[136]
1% nitrogen ketone + 1% menthol; 1% menthol	Single/mixed	Rabbits	Ciclopirox olamine; salicylic acid	Solution		Modified vertical double-chamber in vitro transdermal experimental setup	In vitro	116.99 ± 3.80; 163.35 ± 1.39			3.22; 1.98		[137]
2% borneol	Alone	SD rat abdomen	Fumarate ethyl	Solution		Franz in vitro drug release device	In vitro	4.63		6.9	1.56	Permeability coefficient: 0.0186 (cm/h)	[138]
Propylene glycol + peppermint (1:1)	Mix and use	Kunming mice	Oxapizin	Solution		Modified Franz diffusion device	In vitro	257.17 ± 15.86			6.66		[139]
1% nitrogen ketone + 2% borneol + 2% menthol	Mix and use	Mice; Strat-M™Artificial membranes	Icariin	solution		RYJ-12B drug transdermal diffusion tester	In vitro	0.5; 0.04	11.05; 1.06				[140]
5% menthol	Alone	Dorsal thorax and waist of experimental dogs	Ketoconazole; Terbinafine hydrochloride	Solution		Vertical transdermal diffuser	In vitro	0.58; 0.19			2.21 ± 0.08; 1.72		[141]
2,000 mg/mL menthol	Alone	SD rat dorsal	5-Fluorouracil	Solution		Dual-chamber transdermal diffusion device	In vitro	187.35 ± 37.79					[142]
1% borneol; 1% menthol; 1% nitrogen ketone + 1% borneol; 1% nitrogen ketone + 1% menthol	Single/mixed	Rabbit back	Metronidazole	Solution		Dual-chamber transdermal diffusion device	In vitro	52.26 ± 7.38; 63.58 ± 8.80; 72.70 ± 7.14; 75.70 ± 6.84			2.19; 2.66; 3.04; 3.17		[143]
2% borneol + 2% menthol	Mix and use	Mouse back; Strat-M Artificial membranes	Ferulic acid	Solution		RYJ-12B drug transdermal diffusion tester	In vitro	7.81; 8.23	24 h: 34.32; 34.79	1.41; 0.06			[144]
2% menthol + 4% nitrogen ketone + 5% propylene glycol + 60% ethanol	Mix and use	New Zealand rabbits	Chlorpromazine hydrochloride	Solution		Self-made in vitro transdermal experimental device	In vitro	10.77 ± 1.66					[145]
1% menthol	Alone	SD rat dorsal	Diclofenac sodium	Solution		Homemade dual-chamber transdermal diffusion device	In vitro	36.80 ± 12.80		0.02 ± 0.04	1.87		[146]
5% nepeta oil; 5% menthol	Alone	SD rat abdomen	Cnidium monnieri	Solution		Valia-Chien diffusion pool	In vitro	2.28; 2.52	12 h: 38.48 ± 4.57; 18.45 ± 2.73	0.89; 0.45	3.09; 3.41		[146] [147]
5% menthol	Alone	Nitrocellulose membranes	A sprig of artemisin	Solution		TK-12B Transdermal Diffusion Instrument	In vitro	1.19 ± 0.03			1.76		[148]
5% menthol	Alone	Ex vivo rat skin	Ostholemine; Ligustrazine; Ferulic acid; Puerarin; Genipine	Solution		Franz diffusion pool	In vitro	6.19 ± 2.36; 489.12 ± 132.76; 240.40 ± 71.17; 111.33 ± 22.04; 174.95 ± 34.14	24 h: 201.43 ± 20.26; 9,115.90 ± 884.32; 7,563.98 ± 1,343.71; 2,599.38 ± 614.99; 3,417.39 ± 913.75	5.03 ± 0.72; 4.97 ± 0.66; 5.67 ± 0.73; 5.39 ± 0.34; 5.26 ± 0.73	3.68; 24.33; 147.48; 2226.6; 1749.5		[149]
2% menthol + 1% nitrogen ketones	Mix and use	In vitro rabbit skin	Indomethacin; Diclofenac sodium	Solution		Two-chamber diffusion tank	In vitro	151.38 ± 9.92; 67.42 ± 2.74		4.75 ± 0.78; 7.75 ± 2.82	6.92; 2.56		[150]
1% menthol	Alone	Ex vivo rat skin	Paeoniflorin	Solution		Two-chamber diffusion tank	In vitro	18.67			3.3		[151]
0.02 kg/L menthol	Alone	In vitro rabbit skin	Diclofenac sodium	Solution		Improve the two-chamber diffusion tank on your own	In vitro	29.60 ± 5.40					[152]
3% menthol	Alone	Ex vivo rat skin	salicylic acid	Solution		Two-chamber diffusion tank	In vitro	239 ± 57	24 h: 3080 ± 670				[153]
2% menthol + 1% nitrogen ketones	Mix and use	In vitro rabbit skin	Indomethacin	Solution		Two-chamber diffusion tank	In vitro	151.4 ± 9.9	720.4 ± 151.4	4.8 ± 0.8			[154]
2% menthol + 1% nitrogen ketones (A); 2% menthol + 5% oleic acid (B); 2% menthol + 10% propylene glycol (C)	Mix and use	In vitro rabbit skin	5-Fluorouracil	Solution		Dual-chamber transdermal diffusion device	In vitro	A: 178.00 ± 18.00; B: 133.00 ± 9.00; C: 173.00 ± 16.00			A: 1.76; B: 1.32; C: 1.71		[155]
2% menthol + 2% nitrogen ketones (A); 2% menthol + 10% propylene glycol (B)	Mix and use	In vitro rabbit skin	Diclofenac sodium	Solution		Multiple two-chamber diffusion tanks	In vitro		24 h: A: 995.40 ± 57.50; B: 836.40 ± 20.80				[156]
3% menthol + 3% camphor	Mix and use	In vitro rabbit skin	Niacinamide	Solution		Two-chamber diffusion tank	In vitro					Transdermal percentage: 24 h: 52.4 ± 9.8%	[157]
3% borneol + 3% menthol	Mix and use	Ex vivo rat skin	Sinomenine	Solution		Double-chamber diffusion tank	In vitro	97.40 ± 10.32			3.23		[158]
4% menthol	Alone	Pigeon skin	Ivermectin	Solution		Two-chamber diffusion tank	In vitro	49.82 ± 3.73	12 h: 646.50 ± 34.91				[159]
3% Artemisia annua essential oil	Alone	Nude mouse back	Triptolide	Nanoemulsion		Franz diffusion pool	In vitro	0.93 ± 0.04		1.88 ± 0.15	10.3		[160]
Clove volatile oil (A); Cinnamon volatile oil (B)	Alone	New Zealand rabbit	Amygdalin	Films		Franz frees the pool	In vitro					Absorption value A: A: 0.837 B: 0.816	[161]
Asarum volatile oil	Alone	SD rat dorsal	Sinapine	Extracts		TK-12D transdermal diffuser	In vitro		24 h: 97.77 ± 16.61; 13.24 ± 9.85				[162]
3% menthol	Alone	Kunming mice	Qufeng Huoluo Spray	Sprays		TP-6 Intelligent Transdermal Experimenter	In vitro	11.6				Transmittance per unit area: 26.35%	[163]

Abbreviations: AUC, area under the curve; C _max, peak concentration; SD rat, Sprague–Dawley rats; t _0.5, elimination half-life; T _max, time to peak.

Plaster is a local or systemic patch preparation for skin application made of drugs, substrates, and carriers.[65] Originally called cataplasm, the gel paste coated drug with a hydrophilic matrix that permits high drug loading, good gas permeability, and minimal irritation.[66] In addition to azone, volatile oils like menthol, borneol, camphor, and citrus peel oils are also strong penetrating agents. These oils can be used alone or mixed in plasters, achieving penetration ratios of 1.74-5.81 ([Table 2]).[67] [68] [69] Yin et al used a Franz diffusion cell and an HPLC method to study the in vitro transdermal absorption of naringin in Sanwei Dieda Fengshi Plaster and assessed the enhancing effects of different PEs.[67] The results showed that the addition of PEs like menthol, propylene glycol, and azone significantly boosted the absorption rate of naringin, with menthol being the most effective, followed by propylene glycol and azone. The penetration can be enhanced by combining two or more PEs in a transdermal drug delivery system. Evidence also suggested that roles of volatile oils in enhancing penetration in cataplasm.[70] [71]

Gels

Gels are a semi-solid dosage form containing drugs and a suitable matrix.[72] Small doses, low molecular weight, and potent drugs must be selected for transdermal use; however, many drugs do not meet these criteria. Therefore, enhancing drug bioavailability requires improving transdermal absorption.[73] To enhance transdermal drug absorption, PEs like white mustard oil, chuanxiong oil, pepper oil, menthol, and borneol are commonly used. In vivo pharmacokinetic experiments measured parameters such as area under the curve (AUC), elimination half-life (t _0.5), time to peak (T _max), and peak concentration (C _max). Laser Doppler was used to measure skin blood perfusion and assess the penetration of plant-derived volatile oils into drugs. In vitro studies using modified Franz diffusion cells showed that the volatile oils increased drug release from the gel, leading to an increase in permeability of the gels by approximately 2.09 to 4.48 times ([Table 2]).[74] [75] [76] [77] [78] [79] [80] [81] [82] [83] [84] [85] [86] [87] [88] [89] [90] [91] [92] [93] [94] Xu et al assessed the effect of menthol and azone on percutaneous permeation of lidocaine in gel through a Franz diffusion cell method and an orthogonal test on isolated mouse skin and Strat-M membrane, measuring cumulative permeation per unit area over 72 hours.[80] They found that a mix of 1% menthol, 1% borneol, and 2% camphor achieved the best penetration.

The types and doses of PEs in prescriptions influence the transdermal effects of drugs differently. For instance, the volatile oil extracted from Ligusticum chuanxiong has a unique pro-permeability effect when combined with borneol and menthol. It was shown that these volatile oils could enhance the removal of flurbiprofen from the skin layers to the capillaries by promoting blood flow in the skin.[77] Li et al discovered that 1% borneol and 1% menthol effectively enhanced the penetration of sophoridine and matrine in Sophora alopecuroides gel by disrupting the stratum corneum and increasing gaps between epidermal cells.[89]

Natural plant microemulsion gel system combines the properties of microemulsions and gels to enhance solubility, stability, and absorption efficiency of drugs. Liu and colleagues encapsulated a drug in Zanthoxylum bungeanum essential oil microemulsion gel and studied its in vitro transdermal behavior using a modified Franz diffusion cell method.[84] Differential scanning calorimetry (DSC) was used to assess the impact of Zanthoxylum bungeanum essential oil and its microemulsion gel on stratum corneum molecules and microstructure, and it was found that both lipophilic and hydrophilic drugs were able to penetrate effectively.

Ointments

An ointment is a semi-solid form combining drugs with a suitable base, used for lubrication, protection, and local treatment, and some have systemic effects. It is a classic preparation, with inclusivity, portability, and efficacy.[86]

Transdermal absorbents are needed to enhance the effectiveness of the ointment. Common enhancers are chemicals like azone and naturals like menthol and borneol. Volatile oils are effective, affordable, and have minimal side effects. They combine the drug and adjuvant effect of the base to promote skin penetration and provide therapeutic benefits.[87] Volatile oils from natural plant are widely used to enhance drug penetration in ointments, with a permeability enhancement factor of approximately 1.738 to 2.130, as measured by the modified Franz diffusion cell ([Table 2]).[88] [89] [90] [91] Cui et al discovered that 5% borneol enhanced the penetration of gallic acid and corilagin in Phyllanthus emblica ointment without causing significant skin irritation after 1 and 24 hours.[91] Borneol helped reduce pathogenic heat in the blood, improving radioactive skin erythema and pigmentation. In the study, borneol, when used in Yuganzi ointment, not only boosted penetration but also improved skin conditions and alleviated damage.

Herbal volatile oils are different from general PEs due to their unique medicinal and pharmacodynamic properties. The ointment can be optimized for efficacy and therapeutic goals by taking advantage of the dual role of volatile oils in enhancing penetration and providing a synergistic effect.

Drug Solution

Solutions are commonly used for transdermal delivery due to their ease of preparation and versatility. However, drug absorption may be limited by the intact skin, making PEs crucial for improving delivery efficiency.[92]

In the study examining the penetration effects of volatile oils from TCM, the PEs can be borneol, menthol, clove, frankincense, and myrrh oils. The model drugs usually included anti-inflammatory agents like ibuprofen and diclofenac; antibacterial drugs like tinidazole, metronidazole, and ketoconazole; and TCM components like ligustrazine, strychnine, brucine, and ephedrine hydrochloride. Franz diffusion cells and other in vitro devices were employed to measure parameters like transdermal rate and permeability. Menthol, borneol, clove, and similar volatile oils from TCM can effectively enhance the skin penetration of drug solutions. The ERs for menthol, borneol, and clove oil concentrations range from 1.72 to 2,226.60, 1.56 to 12.66, and 1.89 to 110.48, respectively ([Table 2]).[93] [94] [95] [96] [97] [98] [99] [100] [101] [102] [103] [104] [105] [106] [107] [108] [109] [110] [111] [112] [113] [114] [115] [116] [117] [118] [119] [120] [121] [122] [123] [124] [125] [126] [127] [128] [129] [130] [131] [132] [133] [134] [135] [136] [137] [138] [139] [140] [141] [142] [143] [144] [145] [146] [147] [148] [149] [150] [151] [152] [153] [154] [155] [156] [157] [158] [159] Wang et al observed that higher concentrations of menthol significantly increased puerarin' steady-state flow rate (J_ss) and 24-hour cumulative penetration (Q_24h).[149] In the experiment, the penetration ER reached 2226.60 with the addition of 5% menthol, suggesting a strong in vitro transdermal penetration. Isolated animal skin models were used in most studies, but fixing skin in vivo is challenging. This is because the drug ingredients are affected by subcutaneous blood flow, temperature, and stress responses, which keeps most of the studies at the preclinical stage.

Other Transdermal Preparations

Transdermal preparations are frequently paired with films, sprays, nanoemulsions, and other forms containing volatile oils from TCM to enhance absorption ([Table 2]).[160] [161] [162] [163] Zhu et al discovered that the essential oil of Artemisia annua or its nanoemulsion enhanced penetration more effectively than celastrol by affecting the structure and thermodynamic properties of the skin.[160] Lu et al found that essential oils of cinnamon and clove significantly enhanced the penetration of amygdalin.[161] Zhang et al reported that 3% menthol was more effective than the same concentration of borneol and azone in improving the penetration of bergenin in Qufeng Huoluo spray.[163]

Conclusion and Prospects

The involvement of volatile oils as PEs in transdermal and transmucosal drug delivery offers significant potential to overcome the limitations posed by biological barriers. These volatile oils function by altering the lipid structure of the stratum corneum and increasing membrane fluidity, thereby improving drug absorption. The efficacy of natural plant volatile oils, their good biocompatibility and low toxicity, along with their capacity to enhance drug penetration across biological barriers through multiple mechanisms and their inherent biological activities, including antibacterial, anti-inflammatory, and antioxidant properties, enable them to act synergistically with therapeutic agents, making them alternatives to synthetic PEs.

The study highlights that volatile oils such as menthol, borneol, and clove oil can substantially improve the permeability of various drugs in different formulations, including patches, gels, ointments, solutions, and more innovative systems like nanoemulsions and transdermal films. Beyond their role as PEs, volatile oils have other benefits, such as anti-inflammatory, antimicrobial, and soothing properties, which can improve patient compliance and therapeutic outcomes.

However, despite the compelling evidence supporting the use of volatile oils, there are still many safety and efficacy issues that need to be addressed. Based on the natural plant volatile oils mentioned in the article, the more studied ones in terms of human toxicity and irritation include cinnamon, clove, peppermint, and camphor. Cinnamon is very safe in food preparation, but skin sensitization has been occasionally reported. Cinnamon promotes dermatitis when added to perfumes and oral sensitization when added to oral care products, but the toxicity of the compounds is dose-dependent. The toxicity of cinnamon is only due to specific compounds that exert their toxic effects only at concentrations higher than 3 g/3 kg.[164] Eugenol, which is contained in the volatile oil of cloves, has been shown to cause adverse reactions in flavor ingredients and dental products, including skin irritation, ulcer formation, dermatitis, and slow healing, and in rare cases even anaphylactic shock. This compound is one of the most common and recognized allergens for consumers of fragrances in the EU. The potential of eugenol and clove leaf oil to induce delayed skin hypersensitivity or to trigger reactions due to preexisting skin sensitization in men was assessed. However, analysis of human patch test data suggested that there is little potential for eugenol alone or clove oil to induce these effects.[165] In clinical trials investigating the effects of peppermint oil on inflammatory bowel syndrome, where peppermint oil was typically administered in high doses with a maximum daily dose of 540 mg, only a few adverse events have been reported. The adverse reactions observed were primarily mild and transient and included heartburn, dry mouth, hiccups, a peppermint-like flavor, rash, dizziness, headache, and, rarely, increased appetite. For menthol, the Food and Drug Administration has approved over-the-counter topical concentrations of up to 16% menthol, with an estimated lethal dose range of 50 to 150 mg/kg body weight in humans via oral administration. In vitro and in vivo studies have demonstrated their safety, with most studies showing low toxicity to humans.[166] [167] For camphor, its ingestion demonstrated adverse effects including neurotoxicity, hepatotoxicity, and granulomatous hepatitis, according to the relatively small amount of clinical data available. The lethal dose and dose range for adults under certain circumstances is 50 to 500 mg/kg. Doses of 2 g or more result in toxic effects, whereas 4 g results in death.[168] [169]

The following challenges are particularly prominent. First, essential oils consist of a wide range of volatile organic compounds. This intricate chemical composition can induce ingredient interactions that may cause toxicity or irritation, thereby posing a risk to the safety of prolonged usage. Secondly, some specific components may interact with other drugs by interfering with metabolic pathways (such as inhibiting or inducing cytochrome P450 enzyme system), resulting in decreased or increased efficacy and affecting therapeutic effects. In addition, most of the current studies focus on the short-term effects of volatile oils and lack long-term clinical data support. Therefore, determining the optimal concentration of volatile oils to maximise benefits without causing adverse reactions is still a key scientific issue.

In view of the above problems, we suggest that future research should focus on comprehensive studies to address these gaps: (1) comprehensive toxicological assessments to systematically evaluate the safety profiles of essential oils across varying dosage regimens and exposure durations; (2) development of evidence-based usage guidelines derived from existing scientific literature to mitigate risks associated with prolonged high-concentration applications; (3) implementation of standardized manufacturing protocols, encompassing rigorous production criteria and quality control measures, coupled with enhanced market surveillance systems to ensure product purity, minimize adulteration, and prevent environmental contamination. By addressing these considerations, volatile oils can be more effectively integrated into clinical practice, enhancing drug delivery strategies and ultimately improving patient outcomes.

Conflict of Interest

None declared.

^# These authors contributed equally to this work.

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Publication History

Received: 16 December 2024

Accepted: 15 July 2025

Article published online:
01 September 2025