Available online on 15.10.2021 at http://jddtonline.info

Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research

Copyright  © 2021 The  Author(s): This is an open-access article distributed under the terms of the CC BY-NC 4.0 which permits unrestricted use, distribution, and reproduction in any medium for non-commercial use provided the original author and source are credited

Open Access  Full Text Article                                                                                                                                          Review Article 

A Comprehensive Review on Natural Products as Chemical Penetration Enhancer 

Das Sudip1*, Sen Gupta Koushik2

1 Department of Pharmaceutics, Himalayan Pharmacy Institute, Majhitar, Rangpo, East Sikkim, India, 737136.

2  Department of Pharmaceutical Technology, University of North Bengal, Raja Rammohunpur, Darjeeling, West Bengal, 734014, India

Article Info:

_________________________________________

Article History:

Received 17 August 2021      

Reviewed 23 September 2021

Accepted 28 September 2021  

Published 15 October 2021  

_________________________________________

Cite this article as: 

Das S, Sen Gupta K, A Comprehensive Review on Natural Products as Chemical Penetration Enhancer, Journal of Drug Delivery and Therapeutics. 2021; 11(5-S):176-187

DOI: http://dx.doi.org/10.22270/jddt.v11i5-S.5077         

_________________________________________

*Address for Correspondence:  

Mr. Sudip Das, Department of Pharmaceutics, Himalayan Pharmacy Institute, Majhitar, Rangpo, East Sikkim, India, 737136.

Abstract

______________________________________________________________________________________________________

The drug delivery within the stratum corneum of the skin prevails a challenging area for the pharmaceutical field, especially to the formulation scientists. Several investigations revealed that the lipid domain, which is the integral component of the transport barrier, must be breached if it is to be delivered transdermally at an appropriate rate. In particular, transdermal drug delivery has intrigued researchers with multiple suggestions because multiple dosing or insufficient drug delivery or characteristics of various drugs often results in low therapeutic effects. The application of permeation or penetration enhancers may prolong the number of drugs that can be offered topically. The application of any natural permeation enhancer is innoxious over the artificial permeation enhancers. The natural permeation enhancers are investigated, so notably include essential oils, terpenes, terpenoids, fatty acid esters, etc., have a certain effect in the transdermal drug delivery system. Despite decades of investigation on the natural chemical penetration enhancer, the researchers could not establish the effectiveness of natural penetration enhancers clinically due to the lack of in vivo models. Several factors, like solubility, solvent selection, experimental models, etc., has restricted the application and development of natural penetration enhancers in topical drug delivery systems, especially in the patches. Therefore, further investigation needs to do on skin irritation to decide natural penetration enhancers controlling optimum enhancement effects with minimal skin irritation. This review gives a comprehensive literature survey on naturally obtained chemical penetration enhancers and their future possibilities.

Keywords: Topical Drug delivery system, Natural products, Penetration enhancer, Stratum corneum, In vivo models. 

 


 

1. INTRODUCTION

The expansion of controlled release drug delivery systems has generated exceptional interest in pharmaceutical science from the last few years [1, 2, 3]. In particular, transdermal drug delivery has intrigued researchers with multiple suggestions because multiple dosing or insufficient drug delivery or characteristics of various drugs often results in low therapeutic effects [4, 5, 6]. Amid these techniques, films or patches, and gels have been extensively designed for skin diseases or topical care in the last few decades. These dosage forms can also incorporate drugs for therapeutic applications [7, 8, 9]. Films or patches have the advantages of being a drug reservoir, adhesive properties, and precise performance at a targeted site on the skin surface, thereby prolonging the drug release and improving therapeutic effects. However, the fixed size and shape of these dosage forms are constraints, especially for patients in some restrictive conditions.

In contrast to films, the hydrogel structure is flexible and easy to practice [10, 11]. The drug delivery within the stratum corneum of the skin prevails a challenging area for the pharmaceutical field, especially to the formulation scientists. The stratum corneum of the skin restricts the drug permeation through the skin. Several investigations revealed that the lipid domain, which is the integral component of the transport barrier, must be breached if it is to be delivered transdermally at an appropriate rate. Therefore, skin permeation enhancement in the transdermal drug delivery system is presently an important sphere of pharmaceutical and toxicological investigation [12].

The application of permeation or penetration enhancers may prolong the number of drugs that can be offered topically. Several techniques have also been proposed, e.g., physical (phonophoresis, electroporation, iontophoresis, magnetophoresis, microfabricated needle, and laser technologies, etc.), chemical (synthesis of lipophilic analog, delipidization of stratum corneum, co-administration of penetration enhancers, colloidal formulations such as liposomes, niosomes, and microemulsions), biochemical, supersaturation, etc. to enhance the permeation of the drug molecule across the skin barrier [12]. Chemical techniques are also introduced in utilizing chemical excipients, which can reversibly alter the structure of the stratum corneum. The chemical enhancer may improve the solubility within the stratum corneum or increase the lipid fluidity with the intracellular bilayers [12]. The role of penetration enhancer embodiment in topical formulations would allow the delivery of high molecular weight of drugs through the stratum corneum will be well documented and validated shortly [12].

1.1. Strategies involved in permeation process across stratum corneum (SC)

Stratum corneum is a thin heterogeneous layer consisting of keratinized epidermal cells, and separated by an intracellular lipid domain [13]. This composition of the corneocytes within the lipid-protein matrix resembled a brick wall, with the corneocytes being the bricks, and the lipid-protein matrix is the mortar [14]. The dead cells overlap with each other by some enzymes and are typically embedded in an intracellular matrix of a complex mixture of lipids [14]. There are several mechanisms by which a drug molecule can penetrate across the stratum corneum (SC). The most common pathways for penetrating SC involved intercellular, transcellular, appendageal routes, etc., which can be studied in the pharmacodynamic domain. The appendageal route is not considered a significant pathway for drug permeation because sweat glands and hair follicles only occupied 0.1% of the total surface of the human skin [15]. However, drug delivery via this route may be relevant for the permeation of slowly diffusing compounds and very high molecular weight substances, such as nanoparticles [15]. 

The intercellular spaces or route is another most encouraging route of drug molecule permeation over the transcellular space in the most empirical studies. The thickness of the SC is much more inferior than the diffusional pathlength. The diffusional pathlength involves persistent diffusion of the drug molecule and can restrict between polar head groups and alkyl chains of the intercellular lipids [16]. The diffusion mechanism includes the penetration of drug molecules from a higher concentration to one of the lower concentrations. Fick’s first law of diffusion can describe steady-state diffusion where the rate of transfer or flux (J) of the diffusive substance is proportional to the velocity of the molecular movement within the diffusion layer (diffusion co-efficient, D), and the concentration gradient is estimated over the membrane [16]. Various drug molecules may interact with the different skin layers in the route of percutaneous penetration, appearing in limited absorption [14, 17]. These interplays may be in the form of reversible/irreversible binding to individual structures in the biological tissue, such as the SC keratin and specific sites in the skin to produce a physiological response (e.g., therapeutic activity or an allergic reaction) [17]. Drug binding is distinguished from drug accumulation or retention in the different compartments; thus, high molecular weight drug partition limits the drug diffusivity across the SC. A further possibility is that both processes may provide to the skin's reservoir capacity for certain compounds, e.g., steroids [14, 17].

1.2. Ideal characteristics of permeation enhancer

The penetration or permeation enhancer is also known as accelerants or sorption promoters, which regulate the drug molecule penetration without affecting the viable cells. The most well-known mechanism of penetration enhancers associated with the reversibly altering of the physiochemical nature of the SC to defeat its diffusion resistance. Various literature pieces were reviewed and noticed that the ideal characteristics of a permeation enhancer include non-toxicity, non-sensitizing, non-irritating, rapid activity with predictable and reproducible, pharmacologically inert, chemical compatible, etc. [18].

The permeation enhancer should not extricate the endogenous material of the skin but should have specific spreadable properties on the skin surface. The enhancer should have the same solubility profile as that of the skin. It should be removed completely after the removal of the transdermal systems. If the substance is a liquid and used at high-volume fractions, it should be a suitable solvent for drugs [18]. The mechanism of permeation enhancer involved solubilizing the skin-tissue components, interaction with intracellular lipids leads to disruption of lamellar structure, interaction with intracellular proteins leads to trouble in the corneocyte layer, enhanced partition co-efficient of the drug molecule, using co-enhancer or cosolvents in the SC [19-21]. However, there is no before-mentioned penetration enhancer to possess all the above parameters. The principal task of drug delivery scientists is to decrease the toxicity and sensitizing effect of the permeation enhancer while selecting the transdermal drug delivery system.

2. CHEMICAL PENETRATION/PERMEATION ENHANCER

In the last few decades, a considerable number of compounds have been reported as a penetration enhancer. Hence the studies of various chemical penetration enhancers are very imperative to develop any transdermal or topically utilized drug delivery system. On the other hand, the classification of different chemical enhancers is also notable for experimentation.

2.1. Natural products as skin permeation enhancer

The absorption of drugs within the percutaneous route is quite challenging, and hence adequate natural and synthetic permeation enhancer widely used in transdermal drug delivery systems. The application of any natural permeation enhancer is innoxious over the artificial permeation enhancers, considering the most common synthetic permeation enhancers such as DMSO, DMF, ionic surfactants, etc., are connected with unpleasant and toxic side effects [22, 23]. The natural permeation enhancers are investigated, so notably include essential oils, terpenes, terpenoids, fatty acid esters, etc., have a certain effect in the transdermal drug delivery system. It has been demonstrated after several studies that iontophoresis in combination with enhancers (e.g., linolenic acid) modified the highly compact cells of the stratum corneum into a looser network of filaments, disrupted the keratin pattern, and resulted in swelling of stratum corneum cell layers of human epidermis, thus enhancing the flux of medication through human epidermis [24].

2.1.1. Essential oils, terpenes, and terpenoids

Naturally occurring terpenes are the most convenient volatile oils constituted of hydrocarbons and oxygenated derivatives such as alcohols and their glycosides, ethers, aldehydes, and phenols, ketones, oxides, carboxylic acids, and esters [25]. Terpenes are the most popular clinically efficient permeation enhancer used in transdermal drug delivery systems due to their following advantages such as reversible alteration in the SC, percutaneous absorption enhancement, low toxicity, low irritational effect, etc. [26]. The physicochemical properties and chemical structure of the terpenes intensify the permeation activity of the terpenes. The permeability co-efficient of the various terpenes has been studied tentatively using human and animals’ skin and found the larger value of Log P is more efficient than the smaller Log P value of terpenes [27]. It has also been found that liquid terpenes can obtain more hydrogen bonds with SC and produce a more beneficial permeation effect than the solid terpenes. Triterpenes and tetra-terpenes generally have a poor penetration effect than other terpenes, while aldehyde or ester functional group improves their performance [28].

Polar terpenes comprising oxygen molecules were found to be more potent for hydrophilic drugs than the lipophilic terpenes. Smaller terpenes tended to be more intense than the larger terpenes. Hydrocarbons terpenes with lipophilic drug combinations are more effective in the transdermal drug delivery system [29, 30]. However, smaller alcoholic unsaturated terpenes are a desirable candidate for the permeation of hydrophilic drugs. Besides, polar bi-cyclic terpenes with oxygen molecules exhibited a lesser permeation effect than other cyclic terpenes. Various terpenes such as 1,8-cineole, menthol, limonene, etc., were effective in multiple in vivo skin permeation models [31-33]. Other prototypes of terpenes such as monoterpenes, sesquiterpenes, etc., are also investigated in topical drug delivery systems and affirmed not effective than polar terpenes. The various studies examined the possible reasons, e.g., diffusional area, the concentration of the terpenes used, etc. have not emerged as conventional penetration enhancers. Even for menthol, the available literature does not provide substantial evidence that it can enhance topical or transdermal drug delivery in humans [34-36].

Cornwell et al., reviewed the effect of 12 sesquiterpenes on the permeation of 5-flurouracil in human skin. The absorption of 5-flurouracil was increased by using sesquiterpenes saturated in dimethyl isosorbide [37]. Several transdermal systems containing L-menthol, generally obtained from peppermint oil, are also effective for regulating hormones and drugs. Some investigators also mixed L-menthol with the drug moiety to make a eutectic mixture. The initial melting point drops, leading to more absorption of the drug molecule by enhancing the formulation's solubility. By increasing the drug solubility, L-menthol alters the SC barrier [38, 39]. 

2.1.2. Saponins

Saponins are also termed natural surfactants utilized extensively in the transdermal drug delivery system. Saponins are generally derived from glycosides occurring in plants containing steroidal or triterpenoid aglycone to which one or more sugar chains are connected [40, 41]. Generally, saponins molecules are arranged with hydrophobic molecules or moieties encompassing the outer parameter resulting in lesions in the membrane plane due to micelle-like aggregations [42]. A comprehensive investigation was done on the mechanism of saponins and found that it can develop pores in the membranes, leading to long-lasting effects and permeating large-sized molecules, e.g., ferritin [41, 42]. Saponins may combine with the polar heads of membrane phospholipids and hydroxyl groups of cholesterol, leading to micelle-like aggregates. Furthermore, their hydrophobic interior of the bilayers may also conjugate with a hydrophobic aglycone backbone. Both of these outcomes may contribute to the alteration of the lipid environment and hence improve absorption [43, 44].

Saponins comprise of hemolytic movement, which is correlated with the association of saponins with steroids, particularly cholesterol. The hemolytic capability of saponins displaces significantly with the structure of glycoside, and it includes bringing down of interfacial strain between the fluid and lipid periods of the erythrocyte film about the emulsification of the lipids and their subsequent discharge from the layer [45]. Saponins are holding of one side chain group, additionally upgrading potential in examination with saponins containing two sugars [12]. Then again, expanding the measure of sugar side chains grew the film porousness for calcium particles [46-48]. In this manner, the upshots from past examinations reveal that the hemolytic movement and upgrading potential saturation might be because of the blend of target layer synthesis, the saponin side chain(s), and the design of the aglycone [49]. The consequences of the past examinations done by the specialists on skin penetration improvement uncover that saponins have the potential to promote the porousness of different cured medications (model pervades, for example, aceclofenac, gentamicin sulfate, and carvedilol, diclofenac sodium.

2.1.3. Fatty acids

Fatty acids have been adopted as permeation enhancers and have been effective and safe in transdermal drug delivery systems. Fatty acids generally consist of an aliphatic hydrocarbon chain along with a terminal carboxylic acid group. The saturated or unsaturated aliphatic chain length, in the number, position, and configuration of double bonds, may differ from one another. They have a more exalted capacity increasing for the absorption of lipophilic drugs [50, 51]. Fatty acids appear to be clinically satisfactory penetration enhancers as designated by the following benefits, i.e., the non-irritational effect on the skin, no-toxicity, wide range of compatibility, very high skin flux, etc. The fatty acids in transdermal formulations appear to reduce skin irritation and sensitization, which is a further prevalent problem associated with some medications [50, 51].

A numeral number of investigations has clearly illustrated that the length of the alkyl chain of the fatty acids affects percutaneous drug absorption [52]. Pieces of evidence from several studies have revealed that the enhancing effects of saturated fatty acids were greatest for C10 and C12 fatty acids. Besides, the activator activity was influenced by the saturation of binding and affirmed that long-chain unsaturated fatty acids showed an improvement over the analogous saturated fatty acids [50]. In addition, branching fatty acids appear to affect their permeation enhancement activity. It was determined that PUFA linoleic, alpha-linolenic acids and arachidonic acids are polyunsaturated fatty acids in nature to improve skin penetration stronger than the mono-unsaturated fatty acids. A general trend was observed that the unsaturated fatty acids effectively enhance the percutaneous absorption of drugs, their saturated counterparts [53].   The improvement effects of fatty acid on penetration through the stratum corneum are dependent on the structure. They have associated a balance between the permeability of pure fatty acids through the stratum corneum and the interaction of acid skin lipids. The fatty acid concentrations also resemble to influence their improvement activities. The permeability of the skin meloxicam through the human cadaver skin increased as the concentration of oleic acid increased 0.4 to 1% [53]. Percutaneous drug absorption has been increased by a wide variety of long-chain fatty acids, the most popular of oleic acid. It is fascinating to record that many of the penetration enhancers such as azones containing saturated or unsaturated hydrocarbon chains and some structure-activity relationship (SAR) were interpreted by some researchers and affirmed that using a wide range of fatty acids, acids, alcohols, sulfoxides, surfactants and amides as enhancers is also effective [53, 54].

2.1.4. Herbal extracts

Herbal extracts are the most expensive materials in today’s society. The nature of the herbal extracts is non-toxic, biocompatible, biodegradable in the body, and hence the use of these materials has lots of advantages. Some of the herbal extracts have the ability to penetrate the SC without any penetration enhancer. In vivo investigations on the penetration, the study showed flavonoids such as flavones, apigenin, chamomile, luteolin, apigenin, and 7-O-beta-glucoside, etc., could not only absorbed the skin surface but also penetrate without the proximity of any penetration enhancer. Hence, these materials are important for the topical drug delivery system [55]. According to the various skin permeation study with Franz diffusion cell apparatus, alkaloids showed an effective skin permeation model that permeates 5-fluorouracil and benzoic acid. In the in vivo studies of skin permeation, the methanolic extract of Coptis japonica results in three alkaloids, e.g., berberine, effectively coptisine, and palmatine, which showed improved skin permeation of hydrophilic permeant 5-fluorouracil [56].

Papain is the most common cysteine protease enzyme isolated from Carica papaya, was investigated in vitro and in vivo skin permeation study of low molecular weight heparin. The investigators suggested that the combined administration of heparin's low molecular weight with papain can be a new approach to improved heparin administration and bioavailability [57]. Another study was investigated to check the permeability of the compounds based on a different range of lipophilicity, such as ether extract of Senkyu. The investigation revealed that the ether extract of Senkyu had improved the permeability in vitro and in vivo with the same patency rate. It was concluded that natural compounds having high lipophilicity could permeate the mouse skin in vivo due to the accumulation property. Thus, the ether extract of Senkyu can be used to improve the lipophilicity of moderate lipophilic compounds [58]. The permeation of the aceclofenac drug through human cadaver skin is also challenging, and thus, the study of the piperine materials improved the permeation. The FTIR study confirmed the involvement of partial biphasic SC lipids and interaction with keratin presence in the SC was the possible mechanism to enhance the transdermal permeation of aceclofenac by piperine molecules [59].

The enhanced permeation characteristics of capsaicin by azones as the permeation enhancer may benefit transdermal drug delivery systems. It was determined that increased penetration occurred when the animal skin was treated with azones as capsaicin, which can able to alter the SC layer in the skin [60]. Aloe vera gel was also found to increase the skin penetration depending upon the enhancement ratio and molecular weight of the compound and could be a possible alternative to use in the transdermal drug delivery system. The penetration effect of the aloe gel was demonstrated through the probable pull effect of complexes formed between the compound and thus enhance the permeation. Still, it was also asserted that the proposed mechanism of action has to be further investigated and authenticated. Some of the A. vera gel constituents can penetrate the skin, which was interestingly reliant on the molecular weight of the co-applied compounds. The higher the co-applied compound's molecular weight, the less the gel components were transported across the skin. This was demonstrated by the probable displacement of Aloe vera components from the penetration pathways, whereby restraining the permeation of the gel components more efficiently than the smaller compounds. Related to the analysis for intestinal drug absorption enhancement, Aloe vera gel could conceivably be utilized as a penetration enhancement agent for the transdermal delivery of drugs if established to be effective and safe [61].

Any herbal extract used as a penetration enhancer in the transdermal drug delivery system may work by two simple mechanisms: (a) herbal extracts improve the solubility of the drug within SC by altering the partition co-efficient and (b) increases the lipophilicity of the drug molecule in the SC layer, thus disrupting the lipid layer of the skin. Lignins are the cellulose content that can be used for penetration through the skin. Aloe Vera can absorb into all the skin layers, which may further increase the penetration of certain drug molecules across the skin, as lignins can penetrate the toughened areas of the skin [62].

2.1.5. Urea

Urea is a potent chemical substance that can also be adopted as a permeation enhancer in the transdermal drug delivery systems. Urea promotes the transdermal permeation by forming hydrophilic diffusion channels by facilitating hydration of the stratum corneum. Urea can increase the water content in the SC layer by acting as a humectant and retained the SC fluidity, which is a great disadvantage. Cyclical urea permeation enhancers are biodegradable and nontoxic molecules consisting of a polar parent moiety and a long chain alkyl ester group. As a result, penetration enhancement may be a consequence of both hydrophilic activity and lipid disruption mechanisms [63].

Some investigators analyzed the permeation effect of urea by using corneometry even when applied in a formulation with reduced water activity. A subsequent study was also performed to investigate the molecular characteristics of the SC layer's keratin and macroscopic properties after adding the urea to dehydrated SC and corneocytes. This study results strengthened the hypothesis that urea functioned as a natural endogenous humectant by replacing water in low humidity conditions and maintained a fluidic SC. At more than 10% of concentration, urea acts as emollient or keratolytic action. At higher concentrations (>10%), urea exerts an emollient/keratolytic action. These studies showed that formulations with a high concentration of urea could treat ichthyosis and other hyperkeratotic conditions. Some studies suggested that urea could dissolve keratin at high concentrations by promoting the breakdown of hydrogen bonds. Further investigations have shown that urea can induce keratin conformational changes, causing the protein structure [63, 64].

2.1.6. Esters from natural sources

In chemistry, an ester is a chemical compound, generally derived from organic or inorganic acid, in which an alkoxy group replaces at least one hydroxyl group. Usually, esters are derived from carboxylic acid and alcohol. Many esters, such as a fatty acid ester of glycerol, are important esters in the biological division. Esters that are low molecular weight can be found in essential oils or vegetable oils. The most prevalent ester of ethanol and acetic acid is the ethyl acetate, which has been reviewed for transdermal penetration enhancers. Although the mechanism of action was not well understood, and the use of this molecule in transdermal preparation is not innoxious from the toxicity and sensitivity point of the landscape [65]. Sucrose ester is a very common surface-active agent which is generally practiced in several cosmeceutical products. Depending upon the composition, sucrose esters exist as solid, liquid, and waxy materials. Their properties are determined by the degree of fatty acid esterification and the nature of esterified fatty acid molecules in the sucrose. Furthermore, the shorter the fatty acid chain, the better the water solubility; thus, di and higher esters are generally not water-soluble and can be adequately used in transdermal preparation [66]. Various studies revealed that the effectiveness of sucrose laurate as a penetration enhancer in transdermal patches incorporated poorly water-soluble drugs. Sucrose laurate hydrogel was formulated and investigated as a percutaneous delivery system of poorly water-soluble drugs and found an effective penetration enhancer when investigated in vivo [66].

The effects of sucrose esters on the permeability of the human stratum corneum and the percutaneous penetration of 4- hydroxybenzonitrile were investigated. Studies found that the hydrophilic sucrose oleate and sucrose laurate in water or Transcutol® found effective. Treatment of the skin with 2% SE in Transcutol® significantly increased the extent of 4-hydroxybenzonitrile penetration relative to the control. When skin treated with these formulations was examined spectroscopically, the C-H asymmetric and symmetric stretching bands of the lipid methylene groups were characterized by decreased absorbances and frequency shifts to higher wavenumbers. These effects on the stratum corneum lipids and 4-hydroxybenzonitrile penetration were more pronounced for sucrose laureate when combined with Transcutol®. These results showed that the combination of SEs and Transcutol® could temporarily alter the stratum corneum barrier properties, thereby promoting drug penetration if used in transdermal patches [67].

Several alkyl esters such as methyl acetate, ethyl acetate, butyl acetate, methyl propionate, ethyl propionate, methyl valerate, etc., were investigated as skin permeation enhancers for some drug molecules. The steady-state flux of the drug molecule as measured in vitro through excised rat skin was enhanced about more folds by ethyl acetate, methyl acetate, and methyl propionate relative to that from various solvents. Thus, using these esters as penetration enhancers in the transdermal drug delivery system is quite useful [68, 69]. Examples of these several chemical penetration enhancer findings are represented in Table 1 within vivo approach.


 

 

Table 1: List of naturally obtained chemical penetration enhancer used for topical drug delivery system.

Class

Permeation enhancer

Probable model drugs/permeant

Probable model type/skin type

Ref

Terpenes

Alpha-terpinol

Lidocaine

Porcine

[69]

Carvone

Nicorandil,     ondansetron hydrochloride,     nimodipine,  nicorandil

Neonatal rat epidermis,     EVA 2825 membrane,  epidermal membrane

[70-74]

Menthol

ligustrazine, Osthole,     paeonol,  Risperidone, 5-fluorouracil

Modified Franz diffusion cell experiment, porcine skin, in vitro permeation studies and coarse-grained molecular dynamics.

[75-79]

Anethole

Valsartan,     selegiline hydrochloride,     Etodolac

Rat skin, modified horizontal diffusion cells through cellulose membrane and rat skin.

[80-82]

Menthone

Valsartan,     ligustrazine hydrochloride, tamoxifen,     Halobetasol propionate

Rat skin, porcine skin, human skin on Franz cells.

[80,83-85]

Eugenol

Valsartan,     glibenclamide and glipizide,     tamoxifen

Rat skin, in vitro permeation study, porcine epidermis.

[80,86,87]

α-Bisabolol

Propranolol hydrochloride,     5-fluorouracil

Rat skin, Human skin samples.

[88,89]

Borneol

Propranolol hydrochloride,     borneol,  curcumine,  ligustrazine

Modified Franz diffusion cells through piglet skin, epidermal keratinocyte HaCaT and dermal fibroblast CCC-HSF-1 cell cultures, rat skin in vitro, in vitro porcine dorsal skin.

[90-93]

Verbenon-e

Genistein,     valsartan,  propranolol hydrochloride

In vitro human skin, rat skin and human cadaver skin, rat and human cadaver skin.

[94-96]

Pulegone

Zidovudine,     osthole, tetramethylpyrazine, ferulic acid, puerarin and geniposide,  arginine vasopressin,  insulin

Rat skin, rat skin, rat skin.

[97-100]

Saponins and Herbal extracts

Glycyrrhiza glabra

(glycyrrhizin)

Diclofenac sodium

Abdominal rat skin.

[101]

Glycyrrhizin

Carvedilol

Rat epidermis.

[102]

Asparagus racemosus

Carvedilol

Rat epidermis.

[103]

Aloe vera

Caffeine

Porcine ear skin.

[104]

Aloe vera

Mefenamic acid

Porcine ear skin.

[104]

Aloe vera

Colchicines

Porcine ear skin.

[104]

Aloe vera

Oxybutynin

Porcine ear skin.

[104]

Aloe vera

Quinine

Porcine ear skin.

[104]

Quillaja saponaria and

Acanthophyllum squarrusom

Gentamicin sulfate

Shed snake-skin and liposomal membranes.

[105]

Coptis japonica and

It’s alkaloidal

Isolates.

5-fluorouracil

Human skin.

[106]

Senkyu (Ligustici chuanxiong

Rhizome)

Herbal extracts

Hairless mouse skin.

[107]

Asiaticoside (ASI)

-

Ex vivo skin permeation.

[108]

Fatty acids

Oleic Acid

 

Zinc phthalocyanine, Lamotrigine, Caffeine

Suine ear skin, Human skin.

[109-111]

Linoleic acid

Bupivacaine, Insulin, Arginine Vasopressin, glimepiride

In vitro permeation, ex vivo study, rat skin, modified Franz diffusion cell.

[112-115]

Lauric acid

Ondansetron, phenmetrazine, Alprazolam

Human cadaver skin.

[116-118]

palmitic acid

5-fluorouracil, Diclofenac, Ketorolac tromethamine

Microwave-treated skins, ex vivo and in vivo drug permeation, rat skin

[119-121]

Linoleic acid, oleic acid,

margaric acid, cis-11,14-eicosadienoic acid, stearic acid

Carvedilol

Rat skin.

[122]

Caprylic acid

Pranoprofen

Rat skin.

[123]

Palmitic acid, oleic acid

Diclofenac

Rat skin.

[124]

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Essential oils

Eucalyptus, anise, chenopodium, ylang ylang oils

5-fluorouracil

Excised human skin

[125]

Eucalyptus, peppermint,

turpentine oils

5-fluorouracil

Excised human skin.

[126]

Turpentine oil

Ibuprofen

Cellulose membrane, excised rabbit abdominal skin.

[127]

Rosemary, ylang, lilacin, peppermint oils

Aminophylline

Human skin.

[128]

Ylang, lavender, orange, nutmeg, chamomile, sage, eucalyptus, ginger, peppermint oils

p-aminobenzoic acid.

Human skin.

[129]

Basil oil

Labetolol hydrochloride

Rat abdominal skin.

[130]

Tulsi, Turpentine oils

Flurbiprofen

Rat skin.

[131]

Eryngium bungee essential oil

Piroxicam

Rat skin.

[132]

Fennel, eucalyptus,

citronella, mentha oils

Trazodone hydrochloride

Mouse epidermis.

[133]

Ajuput, niaouli, cardamom, orange, melissa, myrtle oils

Estradiol

Hairless mouse skin.

[134]

Niaouli oil

Estradiol

Hairless mouse skin.

[135]

Turpentine, eucalyptus,

peppermint oils

Ketoconazole

Pig skin.

[136]

Eucalyptus oil

Chlorhexidine digluconate

Full-thickness human skin.

[137]

Thyme, petit

grain, basil oils

Nitrendipine

Rat abdominal skin and human cadaver skin.

[138]

Alpinia oxyphylla oil

Indomethacin

Dorsal skin of rats.

[139]

Basil oil

Indomethacin

Dorsal skin of rats.

[140]

Cardamom oil

Indomethacin, diclofenac, piroxicam

Rabbit abdominal skin.

[141]

Peppermint, tea

tree, eucalyptus

oils

Benzoic acid

Human breast or abdominal skin.

[142]

Black cumin, tulsi, clove, eucalyptus oils.

Carvedilol

Excised rat abdominal skin.

[143]

 


 

3. FUTURE PROSPECTIVE

The supreme skin penetration enhancer should be stable, non-toxic, non-irritating, and, most importantly, should have the ability to permeate the stratum corneum. The permeation enhancer should be harmonious with the other excipients, especially the drugs present in the system. The release or diffusion mechanism of the drug candidate should not hinder by the incorporation of natural permeation enhancers in topical drug delivery systems. Despite decades of investigation on the natural chemical penetration enhancer, the researchers could not establish the effectiveness of natural penetration enhancers clinically. Several factors like solubility, solvent selection, experimental models, etc., restrict the application and development of natural penetration enhancers in topical drug delivery systems, especially in the patches. The effectiveness of human skin for characterization purposes is quite difficult due to regulatory ethics and constraints. Though, the porcine skin is also seemed to be effective and can be used as a surrogate for characterization purposes. The physicochemical nature of the natural penetration enhancers should be considered properly before selection for the formulation development. The dose of the penetration enhancer and the crystalline nature in the skin surface’s temperature is a big concern, especially when used for transdermal drug delivery systems. There are some other scopes where natural penetration enhancers can be used along with other penetration enhancers; thus, the synergistic effect will systematically enhance the ultimate activity of the patches in biomedical applications. Some penetration enhancers generally utilized for any cosmetics preparation can also be studies for transdermal systems. The progressions in analytical techniques are also important to characterize the compatibility of the penetration enhancer with other excipients and the mechanical nature of the formulated patches. Thus, no penetration enhancer will not create any irritation on the skin surfaces. The scientist should concentrate on how the irritational effect can be reduced and should concern the cost of the product concurrently. Thus, more improved in vivo models are also required to justify the effectiveness and adverse effects of the transdermal systems as only in vitro studies cannot prognosticate the irritational impact on the skin.

4. CONCLUSION

The penetration of large molecules through the skin is a big concern for drug delivery society. Though the use of natural chemical penetration enhancers is quite effective from the delivery point of view, but the irritational effect is again a big concern. The higher concentration of chemical enhancers in formulation increases drug transport across the skin but is proportionally related to their ability to cause skin irritation. Therefore, it is very complicated and challenging to maintain the concentration and adverse effect of penetration enhancers in topical drug delivery systems. Various essential oils, terpenes, fatty acids, and esters from natural sources have been used in cosmetics over time. The applications of these penetration enhancers in the drug delivery system can improve and resolve the drawbacks, especially in transdermal drug delivery systems. Various research has been performed by the top institutional societies throughout the world and has confirmed the potency or effectiveness of natural chemical penetration enhancers in the drug delivery systems except for mild irritational effects on the skin. Therefore, further investigation needs to do on skin irritation to decide natural penetration enhancers controlling optimum enhancement effects with minimal skin irritation.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

FUNDING

Not applicable. 

ACKNOWLEDGMENTS

Declared none.

REFERENCES

1. Bruneau M, Bennici S, Brendle J, Dutournie P, Limousy L, Pluchon S. Systems for stimuli-controlled release: Materials and applications. J Controlled Release 2019; 294:355-371. https://doi.org/10.1016/j.jconrel.2018.12.038

2. Weiser JR, Saltzman WM. Controlled release for local delivery of drugs: Barriers and models. J Controlled Release 2014; 190:664-673 https://doi.org/10.1016/j.jconrel.2014.04.048

3. Kim H, Lee JH, Kim JE, Kim YS, et al. Micro-/nano-sized delivery systems of ginsenosides for improved systemic bioavailability. J Ginseng Res 2018; 42:361-369. https://doi.org/10.1016/j.jgr.2017.12.003

4. Waghule T, Singhvi G, Dubey SK, Pandey MM, et al. Microneedles: A smart approach and increasing potential for transdermal drug delivery system. Biomed Pharmacother 2019; 109:1249-1258. https://doi.org/10.1016/j.biopha.2018.10.078

5. Rai VK, Mishra N, Yadav KS, Yadav NP. Nanoemulsion as pharmaceutical carrier for dermal and transdermal drug delivery: Formulation development, stability issues, basic considerations and applications. J Controlled Release 2018; 270:203-225. https://doi.org/10.1016/j.jconrel.2017.11.049

6. Kathe K, Kathpalia H. Film forming systems for topical and transdermal drug delivery. Asian J Pharm Sci 2017; 12:487-497. https://doi.org/10.1016/j.ajps.2017.07.004

7. Kim H, Kim JT, Barua S, Yoo SY, et al. Seeking better topical delivery technologies of moisturizing agents for enhanced skin moisturization. Expert Opin Drug Delivery 2018; 15:17-31. https://doi.org/10.1080/17425247.2017.1306054

8. Barua S, Lee DI, Kim H, Jo K, Yeo S, et al. Solid Lipid Nanoparticles of Serine Designed by Evaluating Affinity of Solid Lipids to Stratum Corneum for Enhanced Skin Hydration in Combination with Reed Root Extract. Bull Korean Chem Soc 2018; 39:220-226. https://doi.org/10.1002/bkcs.11371

9. Engelke L, Winter G, Engert J. Application of water-soluble polyvinyl alcohol-based film patches on laser microporated skin facilitates intradermal macromolecule and nanoparticle delivery. Eur J Pharm Biopharm 2018; 128:119-130. https://doi.org/10.1016/j.ejpb.2018.04.008

10. Carter P, Narasimhan B, Wang Q. Biocompatible nanoparticles and vesicular systems in transdermal drug delivery for various skin diseases. Int J Pharm 2019; 555:49-62. https://doi.org/10.1016/j.ijpharm.2018.11.032

11. Santos LF, Correia IJ, Silva AS, Mano JF. Biomaterials for drug delivery patches. Eur J Pharm Sci 2018; 118:49-66. https://doi.org/10.1016/j.ejps.2018.03.020

12. Woldemichael GM, Wink M. Identification and biological activities of triterpenoid saponins from Chenopodium quinoa. J Agric Food Chem 2001; 49: 2327-2332. https://doi.org/10.1021/jf0013499

13. Menon GK, Cleary GW, Lane ME. The structure and function of the stratum corneum. Int J Pharm 2012; 435:3-9. https://doi.org/10.1016/j.ijpharm.2012.06.005

14. Michaels AS, Chandrasekaran SK, Shaw JE. Drug permeation through human skin: theory and in vitro experimental measurement. AIChE J 1975; 21:985-996. https://doi.org/10.1002/aic.690210522

15. Lademann J, Richter H, Schanzer S, Knorr F, Meinke M, Sterry W, Patzelt A. Penetration and storage of particles in human skin: perspectives and safety aspects. Eur J Pharm Biopharm 2011; 77:465-468. https://doi.org/10.1016/j.ejpb.2010.10.015

16. Albery WJ, Hadgraft J. Percutaneous absorption: in vivo experiments. J Pharm Pharmacol 1979: 31:140-147. https://doi.org/10.1111/j.2042-7158.1979.tb13456.x

17. Vickers CFH. Existence of reservoir in the stratum corneum: experimental proof. Arch Dermatol 1963: 88:20-23. https://doi.org/10.1001/archderm.1963.01590190026002

18. Barry BW. Dermatological formulation: percutaneous absorption. Mercel Dekker, New York, Volume 18, 1983; pp. 225-238.

19. Barry BW. Mode of action of penetration enhancers in human skin. J Controlled Release 1987; 6:85-97. https://doi.org/10.1016/0168-3659(87)90066-6

20. Barry BW. Modern methods of promoting drug absorption through the skin. Mol Asp Med 1991; 12:195-241. https://doi.org/10.1016/0098-2997(91)90002-4

21. Guy RH, Hadgraft J. The effect of penetration enhancers on the kinetics of percutaneous absorption. J Controlled Release 1987; 5:43-51. https://doi.org/10.1016/0168-3659(87)90036-8

22. Kanikkannan N, Singh M. Skin permeation enhancement effect and skin irritation of saturated fatty alcohols. Int J Pharm 2002; 248(1-2):219-228. https://doi.org/10.1016/S0378-5173(02)00454-4

23. Kligman AM. Topical pharmacology and toxicology of dimethylsulfoxide. J Am Med Assoc 1965; 193:796-804. https://doi.org/10.1001/jama.1965.03090100042010

24. Ben-Shabat S, Baruch N, Sintov AC. Conjugates of unsaturated fatty acids with propylene glycol as potentially less irritant skin penetration enhancers. Drug Dev Ind Pharm 2007; 33:1169-1175. https://doi.org/10.1080/03639040701199258

25. Barry BW, Williams AC. Terpenes as skin penetration enhancers. In: Walters KA, Hadgraft J (eds) Pharmaceutical skin penetration enhancement. Marcel Dekker, New York, 1995; pp. 95-111.

26. Barry BW. The LPP theory of skin penetration enhancement. In vitro percutaneous absorption: principles, fundamentals and applications. CRC Press, Florida, 1991; pp. 165-185.

27. Aqil M, Ahad A, Sultana Y, Ali A. Status of terpenes as skin permeation enhancers. Drug Discov Today 2007; 12:1061-1067. https://doi.org/10.1016/j.drudis.2007.09.001

28. Kang L, Yap CW, Lim PFC, Chen YZ, Ho PC, Chan YW, et al. Formulation development of transdermal dosage form: quantitative structure activity relationship model for predicting activity of terpenes that enhance drug penetration through human skin. J Controlled Release 2007; 120:211-219. https://doi.org/10.1016/j.jconrel.2007.05.006

29. Kunta JR, Goskonda VR, Brotherton HO, Khan MA, Reddy IK. Effect of menthol and related terpenes on the percutaneous absorption of propranolol across excised hairless mouse skin. J Pharm Sci 1997; 86:1369-1373. https://doi.org/10.1021/js970161+

30. Woldemichael GM, Wink M. Identification and biological activities of triterpenoid saponins from Chenopodium quinoa. J Agric Food Chem 2001; 49:2327-2332. https://doi.org/10.1021/jf0013499

31. Jain R, Aqil M, Ahad A, Ali S, Khar RK. Basil oil is a promising skin permeation enhancer for transdermal delivery of labetalol hydrochloride. Drug Dev Ind Pharm 2008; 34:384-389. https://doi.org/10.1080/03639040701657958

32. Williams AC, Barry BW. The enhancement index concept applied to terpene penetration enhancer for human skin and model lipophilic (oestradiol) and hydrophilic (5 fluorouracil) drugs. Int J Pharm 1991; 74:157-168. https://doi.org/10.1016/0378-5173(91)90232-D

33. Yamane MA, Williams AC, Barry BW. Effect of terpenes and oleic acid as skin penetratin enhancers toward 5-Fluorouracil as assessed with time; permeation partitioning and differential scanning calorimetry. Int J Pharm 1995; 116:237-251. https://doi.org/10.1016/0378-5173(94)00312-S

34. Williams AC, Barry BW. Terpenes and the lipid-protein-partitioning theory of skin penetration enhancement. Pharm Res 1991; 8:17-24. https://doi.org/10.1023/A:1015813803205

35. Yamane MA, Williams AC, Barry BW. Terpene penetration enhancers in propylene glycol/water co-solvent systems: effectiveness and mechanism of action. J Pharm Pharmacol 1995; 47:978-989. https://doi.org/10.1111/j.2042-7158.1995.tb03282.x

36. Cornwell PA, Barry BW. Sesquiterpene components of volatile oils as skin penetration enhancers for the hydrophilic permeant 5-fluorouracil. J Pharm Pharmacol 1994; 46:261-269. https://doi.org/10.1111/j.2042-7158.1994.tb03791.x

37. Olivella MS, Lhez L, Pappano NB, Debattista NB. Effects of dimethylformamide and L-menthol permeation enhancers on transdermal delivery of quercetin. Pharm Dev Technol 2007; 12(5): 481484. https://doi.org/10.1080/10837450701481207

38. Nagai N, Ogata F, Yamaguchi M, et al. Combination with l-Menthol Enhances Transdermal Penetration of Indomethacin Solid Nanoparticles. Int J Mol Sci 2019; 20(15): 3644. https://doi.org/10.3390/ijms20153644

39. Melzig MF, Bader G, Loose R. Investigations of the mechanism of membrane activity of selected triterpenoid saponins. Planta Med 2001; 67:43-48. https://doi.org/10.1055/s-2001-10632

40. Plock A, Sokolowska-Kohler W, Presber W. Application of flow cytometry and microscopical methods to characterize the effect of herbal drugs on leishmania spp. Exp Parasitol 2001; 97:141-153. https://doi.org/10.1006/expr.2001.4598

41. Seeman P, Cheng D, Iles GH. Structure of membrane holes in osmotic and saponin hemolysis. J Cell Biol 1973; 56:519-527. https://doi.org/10.1083/jcb.56.2.519

42. Brain K, Hadgraft J, Al-Shatalebi M. Membrane modification in activity of plant molluscicides. Planta Med 1990; 56:663. https://doi.org/10.1055/s-2006-961323

43. Brown MB, Martin GP, Jones SA, Akomeah FK. Dermal and transdermal drug delivery system: current and future prospects. Drug Deliv 2006; 13:175-187. https://doi.org/10.1080/10717540500455975

44. Hostettmann K, Marston A. Chemistry and pharmacology of natural products: Saponins. Cambridge University Press, Cambridge. 1995; pp. 234-284

45. Yamasaki Y, Ito K, Enomoto Y, Sutko JL. Alterations by saponins of passive Ca2? permeability and Na?-Ca2? Exchange activity of canine cardiac sarcolemmal vesicles. Biochem Biophys Acta 1987; 897:481-487. https://doi.org/10.1016/0005-2736(87)90445-7

46. Deng S, May BH, Zhang AL, Lu C, Xue CC. Topical herbal medicine combined with pharmacotherapy for psoriasis: a systematic review and meta-analysis. Arch Dermatol Res 2013; 305:179-189. https://doi.org/10.1007/s00403-013-1316-y

47. Kage M, Tokudome Y, Hashimoto F. Permeation of hyaluronan tetrasaccharides through hairless mouse skin: an in vitro and in vivo study. Arch Dermatol Res 2013; 305:69-77. https://doi.org/10.1007/s00403-012-1252-2

48. Francis G, Kerem Z, Makkar HP, Becker K. The biological action of saponins in animal systems: a review. Br J Nutr 2002; 88:587-605. https://doi.org/10.1079/BJN2002725

49. Aungst B. Fatty acids as skin permeation enhancers. In: Smith EW, Maibach HI (eds) Percutaneous penetration enhancers. CRC Press, Florida, 1995; pp. 277-287.

50. Ogiso T, Shintani M. Mechanism for the enhancement effect of fatty acids on the percutaneous absorption of propranolol. J Pharm Sci 1990; 79: 1065-1071. https://doi.org/10.1002/jps.2600791206

51. Morimoto K, Tojima H, Haruta T, Suzuki M, Kakemi M. Enhancing effect of unsaturated fatty acids with various structures on the permeation of indomethacin through rat skin. J Pharm Pharmacol 1996; 48:1133-1137.

https://doi.org/10.1111/j.2042-7158.1996.tb03908.x

52. Aungst BJ, Rogers NJ, Shefter E. Enhancement of naloxone penetration through human skin in vitro using fatty acids, fatty alcohols, surfactants, sulfoxides and amines. Int J Pharm 1986; 33:225-234. https://doi.org/10.1016/0378-5173(86)90057-8

53. Aungst BJ. Structure effect studies of fatty acid isomers as skin penetration enhancers and skin irritant. Pharm Res 1989; 6: 244-247. https://doi.org/10.1023/A:1015921702258

54. Merfort I, Heilmann J, Hagedorn LU, Lippold BC. In vivo skin permeation studies of chamomile flavones. Pharmazie 1994; 49(7):509-511.

55. Namba T, Sekiya K, Toshinal A, Kadota S, Hatanaka T, Katayama K, et al. Study on baths with crude drug. II: the effects of Coptidis rhizoma extracts as skin permeation enhancer. Yakugaku Zasshi 1992; 112(9):638-44. https://doi.org/10.1248/yakushi1947.112.9_638

56. Gabovac V, Schmit ZT, Bernkop SA. Papain: An effective permeation enhances for orally administered low molecular weight heparin. J Pharm Res 2007; 24(5):1001-6. https://doi.org/10.1007/s11095-006-9226-8

57. Namba T, Sekiya K, Kadota S, Hattori M, Katayama K, Koizumi T. Studies on the baths with crude drug: the effects of Senkyu extract as skin penetration enhancer. Yakugaku Zasshi 1992; 112(9):638-644. https://doi.org/10.1248/yakushi1947.112.9_638

58. Shah KK, Shiradkar MR, Bindu VH. Transdermal drug delivery of acleofenac: Effect of piperine and its mechanism of action. Int J Pharm Bio Sci 2011; 2(3):3-7.

59. Saini S, Chauhan SB, Agarwal SS. Recent development in transdermal drug delivery system. J Adv Pharm Educ Res 2014; 4(1): 31-40.

60. Guy RH, Potts RO. Penetration of industrial chemicals across the skin: a predictive model. Am J Ind Med 1993; 23:711-719. https://doi.org/10.1002/ajim.4700230505

61. Rosso A, Zuccaro S. Determination of alkaloids from the colchicines family by reversed-phase high performance liquid chromatography. J. Chromtogr A 1998; 825:96-101. https://doi.org/10.1016/S0021-9673(98)00595-0

62. Roderick BW, Eric WS. The role of percutaneous penetration enhancers. Adv Drug Delivery Rev 1996; 18:295-301. https://doi.org/10.1016/0169-409X(95)00078-L

63. Celleno L. Topical urea in skincare: A review. Dermatologic Therapy 2018; e12690. https://doi.org/10.1111/dth.12690

64. Friend DR. Transdermal delivery of levonorgestrel. Med Res Rev 1991; 11:49-80. https://doi.org/10.1002/med.2610110105

65. Szűts A, Szabó-Révész P. Sucrose esters as natural surfactants in drug delivery systems-A mini-review. Int J Pharm 2012; 433(1-2):1-9. https://doi.org/10.1016/j.ijpharm.2012.04.076

66. Ayala Bravo HA, Quintanar GD, Naik A, Kalia YN, Cornejo-Bravo JM, Ganem-Quintanar A. Effects of sucrose oleate and sucrose laureate on in vivo human stratum corneum permeability. Pharm Res 2003; 20(8):12671273. https://doi.org/10.1023/A:1025013401471

67. Catz P, Friend DR. Alkyl esters as skin permeation enhancers for indomethacin. Int J of Pharm 1989; 55(1):17-23. https://doi.org/10.1016/0378-5173(89)90271-8

68. Friend D, Catz P, Heller J. Simple alkyl esters as skin permeation enhancers. J Controlled Release 1989; 9(1):33-41. https://doi.org/10.1016/0168-3659(89)90031-X

69. Mohammadi-Samani S, Jamshidzadeh A, Montaseri H, Rangbar-Zahedani M, Kianrad R. The effects of some permeability enhancers on the percutaneous absorption of lidocaine. Pak J Pharm Sci. 2010; 23(1):8388.

70. Krishnaiah YS, Nada A. Enantioselective penetration enhancing effect of carvone on the in vitro transdermal permeation of nicorandil. Pharm Dev Technol 2012; 17(5):574582. https://doi.org/10.3109/10837450.2011.557729

71. Krishnaiah YS, Raju V, Shiva Kumar M, Rama B, Raghumurthy V, Ramana Murthy KV. Studies on optimizing in vitro transdermal permeation of ondansetron hydrochloride using nerodilol, carvone, and limonene as penetration enhancers. Pharm Dev Technol 2008; 13(3):177185. https://doi.org/10.1080/10837450801949350

72. Krishnaiah YS, Bhaskar P, Satyanarayana V. Effect of carvone on the permeation of nimodipine from a membrane-moderated transdermal therapeutic system. Pharmazie 2003; 58(8):559563.

73. Krishnaiah YS, Al-Saidan SM, Chandrasekhar DV, Rama B. Effect of nerodilol and carvone on in vitro permeation of nicorandil across rat epidermal membrane. Drug Dev Ind Pharm 2006; 32(4):423435. https://doi.org/10.1080/03639040500528939

74. Varman RM, Singh S. Investigation of effects of terpene skin penetration enhancers on stability and biological activity of lysozyme. AAPS Pharm SciTech 2012; 13(4):10841090. https://doi.org/10.1208/s12249-012-9840-1

75. Dai X, Wang R, Wu Z, et al. Permeation-enhancing effects and mechanisms of borneol and menthol on ligustrazine: A multiscale study using in vitro and coarse-grained molecular dynamics simulation methods. Chem Biol Drug Des 2018; 92(5):18301837. https://doi.org/10.1111/cbdd.13350

76. Yang S, Wang R, Wan G, et al. A Multiscale Study on the Penetration Enhancement Mechanism of Menthol to Osthole. J Chem Inf Model 2016; 56(11):22342242. https://doi.org/10.1021/acs.jcim.6b00232

77. Wang W, Cai Y, Liu Y, Zhao Y, Feng J, Liu C. Microemulsions based on paeonol-menthol eutectic mixture for enhanced transdermal delivery: formulation development and in vitro evaluation. Artif Cells Nanomed Biotechnol 2017; 45(6):16. https://doi.org/10.1080/21691401.2016.1226178

78. Ning Y, Chen X, Yu Z, Liang W, Li F. Delivery of risperidone from gels across porcine skin in vitro and in vivo in rabbits. Pak J Pharm Sci 2018; 31(3):885891.

79. Wang R, Wu Z, Yang S, et al. A Molecular Interpretation on the Different Penetration Enhancement Effect of Borneol and Menthol towards 5-Fluorouracil. Int J Mol Sci 2017; 18(12):2747. https://doi.org/10.3390/ijms18122747

80. Ahad A, Aqil M, Ali A. The application of anethole, menthone, and eugenol in transdermal penetration of valsartan: Enhancement and mechanistic investigation. Pharm Biol 2016; 54(6):10421051. https://doi.org/10.3109/13880209.2015.1100639

81. Krishnaiah YS, Al-Saidan SM, Jayaram B. Effect of nerodilol, carvone and anethole on the in vitro transdermal delivery of selegiline hydrochloride. Pharmazie 2006; 61(1):4653.

82. Tas C, Ozkan Y, Okyar A, Savaser A. In vitro and ex vivo permeation studies of etodolac from hydrophilic gels and effect of terpenes as enhancers. Drug Deliv 2007; 14(7):453459. https://doi.org/10.1080/10717540701603746

83. Wang J, Dong C, Song Z, et al. Monocyclic monoterpenes as penetration enhancers of ligustrazine hydrochloride for dermal delivery. Pharm Dev Technol 2017; 22(4):571577. https://doi.org/10.1080/10837450.2016.1189936

84. Zhao K, Singh S, Singh J. Effect of menthone on the in vitro percutaneous absorption of tamoxifen and skin reversibility. Int J Pharm 2001; 219(1-2):177181. https://doi.org/10.1016/S0378-5173(01)00640-8

85. Carvajal-Vidal P, Mallandrich M, García ML, Calpena AC. Effect of Different Skin Penetration Promoters in Halobetasol Propionate Permeation and Retention in Human Skin. Int J Mol Sci 2017; 18(11):2475. https://doi.org/10.3390/ijms18112475

86. Mutalik S, Udupa N. Effect of some penetration enhancers on the permeation of glibenclamide and glipizide through mouse skin. Pharmazie 2003; 58(12):891894.

87. Zhao K, Singh J. Mechanisms of percutaneous absorption of tamoxifen by terpenes: eugenol, D-limonene and menthone. J Controlled Release 1998; 55(2-3):253260. https://doi.org/10.1016/S0168-3659(98)00053-4

88. Cui Y, Li L, Zhang L, et al. Enhancement and mechanism of transdermal absorption of terpene-induced propranolol hydrochloride. Arch Pharm Res 2011; 34(9):14771485. https://doi.org/10.1007/s12272-011-0909-2

89. Ron Kadir Brian, W Barry. α-Bisabolol, a possible safe penetration enhancer for dermal and transdermal therapeutics. Int J Pharma 1991; 70(1-2):87-94. https://doi.org/10.1016/0378-5173(91)90167-M

90. Zhou W, He S, Yang Y, Jian D, Chen X, Ding J. Formulation, characterization and clinical evaluation of propranolol hydrochloride gel for transdermal treatment of superficial infantile hemangioma. Drug Dev Ind Pharm 2015; 41(7):11091119. https://doi.org/10.3109/03639045.2014.931968

91. Yi QF, Yan J, Tang SY, Huang H, Kang LY. Effect of borneol on the transdermal permeation of drugs with differing lipophilicity and molecular organization of stratum corneum lipids. Drug Dev Ind Pharm 2016; 42(7):10861093. https://doi.org/10.3109/03639045.2015.1107095

92. Gao ZS, Wang L, Zhang M. Effects of penetration enhancers on curcumin transdermal drug delivery. Zhong Yao Cai 2012; 35(1):141144.

93. Zhang CF, Zhan W, Yang ZL, Wang YL. Impacts of bicyclo-monoterpene enhancers on transdermal delivery of ligustrazine. Yao Xue Xue Bao 2010; 45(11):14521458.

94. Chadha G, Sathigari S, Parsons DL, Jayachandra Babu R. In vitro percutaneous absorption of genistein from topical gels through human skin. Drug Dev Ind Pharm 2011; 37(5):498505. https://doi.org/10.3109/03639045.2010.525238

95. Ahad A, Aqil M, Kohli K, Sultana Y, Mujeeb M, Ali A. Role of novel terpenes in transcutaneous permeation of valsartan: effectiveness and mechanism of action. Drug Dev Ind Pharm 2011; 37(5):583596. https://doi.org/10.3109/03639045.2010.532219

96. Ahad A, Aqil M, Kohli K, Sultana Y, Mujeeb M, Ali A. Interactions between novel terpenes and main components of rat and human skin: mechanistic view for transdermal delivery of propranolol hydrochloride. Curr Drug Deliv 2011; 8(2):213224. https://doi.org/10.2174/156720111794479907

97. Narishetty ST, Panchagnula R. Transdermal delivery of zidovudine: effect of terpenes and their mechanism of action. J Controlled Release 2004; 95(3):367379. https://doi.org/10.1016/j.jconrel.2003.11.022

98. Lan Y, Wang J, Li H, et al. Effect of menthone and related compounds on skin permeation of drugs with different lipophilicity and molecular organization of stratum corneum lipids. Pharm Dev Technol 2016; 21(4):389398.

99. Nair VB, Panchagnula R. The effect of pretreatment with terpenes on transdermal iontophoretic delivery of arginine vasopressin. Farmaco 2004; 59(7):575581. https://doi.org/10.1016/j.farmac.2004.02.004

100. Pillai O, Panchagnula R. Transdermal iontophoresis of insulin. V. Effect of terpenes. J Control Release 2003; 88(2):287296. https://doi.org/10.1016/S0168-3659(03)00065-8

101. Nokhodchi A, Nazemiyeh H, Ghafourian T, Hassan-Zahed D, Valizadeh H, Bahary LA. The effect of glycyrrhizin on the release rate and the skin permeation of diclofenac sodium from topical formulations. Farmao 2002; 57(11):883-888. https://doi.org/10.1016/S0014-827X(02)01298-3

102. Sapra B, Jain S, Tiwary AK. Transdermal delivery of carvedilol containing glycyrrhizin and chitosan as permeation enhancers: biochemical, biophysical, microscopic and pharmacodynamic evaluation. Drug Deliv 2008; 15(7):443-454. https://doi.org/10.1080/10717540802327047

103. Sapra B, Jain S, Tiwary AK. Effect of Asparagus racemosus extract on transdermal delivery of carvedilol: a mechanistic study. AAPS Pharm Sci Tech 2009; 10(1):199-210. https://doi.org/10.1208/s12249-009-9198-1

104. Cole L, Heard C. Skin permeation enhancement potential of Aloe vera and a proposed mechanism of action based upon size exclusion and pull effect. Int J Pharm 2007; 333(1-2):10-16. https://doi.org/10.1016/j.ijpharm.2006.09.047

105. Moghimipour E, Sajadi Tabassi SA, Ramazani M, Lobenberg R. Enhanced permeability of gentamicin sulfate through shed snake-skin and liposomal membranes by different enhancers. Iran J Basic Med Sci 2002; 6(1):9-20.

106. Namba T, Sekiya K, Toshinal A, Kadota S, Hatanaka T, Katayama K, et al. Study on baths with crude drug. II: the effects of Coptidis rhizoma extracts as skin permeation enhancer. Yakugaku Zasshi 1995; 115(8):618-625. https://doi.org/10.1248/yakushi1947.115.8_618

107. Namba T, Sekiya K, Kadota S, Hattori M, Katayama K, Koizumi T. Studies on the baths with crude drug: the effects of Senkyu extract as skin penetration enhancer. Yakugaku Zasshi 1992; 112(9):638-644. https://doi.org/10.1248/yakushi1947.112.9_638

108. Li H, Peng Q, Guo Y, Wang X, Zhang L. Preparation and in vitro and in vivo Study of Asiaticoside-Loaded Nanoemulsions and Nanoemulsions-Based Gels for Transdermal Delivery. Int J Nanomedicine 2020; 15:31233136. https://doi.org/10.2147/IJN.S241923

109. da Silva ER, de Freitas ZM, Gitirana Lde B, Ricci-Júnior E. Improving the topical delivery of zinc phthalocyanine using oleic acid as a penetration enhancer: in vitro permeation and retention. Drug Dev Ind Pharm 2011; 37(5):569575. https://doi.org/10.3109/03639045.2010.529144

110. Jafri I, Shoaib MH, Yousuf RI, Ali FR. Effect of permeation enhancers on in vitro release and transdermal delivery of lamotrigine from Eudragit® RS100 polymer matrix-type drug in adhesive patches. Prog Biomater 2019; 8(2):91100. https://doi.org/10.1007/s40204-019-0114-9

111. Abd E, Benson HAE, Roberts MS, Grice JE. Follicular Penetration of Caffeine from Topically Applied Nanoemulsion Formulations Containing Penetration Enhancers: In vitro Human Skin Studies. Skin Pharmacol Physiol 2018; 31(5):252260. https://doi.org/10.1159/000489857

112. Yue Y, Zhao D, Yin Q. Hyaluronic acid modified nanostructured lipid carriers for transdermal bupivacaine delivery: In vitro and in vivo anesthesia evaluation. Biomed Pharmacother 2018; 98:813820. https://doi.org/10.1016/j.biopha.2017.12.103

113. Pillai O, Panchagnula R. Transdermal delivery of insulin from poloxamer gel: ex vivo and in vivo skin permeation studies in rat using iontophoresis and chemical enhancers. J Controlled Release 2003; 89(1):127140. https://doi.org/10.1016/S0168-3659(03)00094-4

114. Nair VB, Panchagnula R. Effect of iontophoresis and fatty acids on permeation of arginine vasopressin through rat skin. Pharmacol Res 2003; 47(6):563569. https://doi.org/10.1016/S1043-6618(03)00016-1

115. Cho CW, Choi JS, Yang KH, Shin SC. Enhanced transdermal controlled delivery of glimepiride from the ethylene-vinyl acetate matrix. Drug Deliv 2009; 16(6):320330. https://doi.org/10.1080/10717540903031084

116. Dimas DA, Dallas PP, Rekkas DM. Ion pair formation as a possible mechanism for the enhancement effect of lauric acid on the transdermal permeation of ondansetron. Pharm Dev Technol 2004; 9(3):311320. https://doi.org/10.1081/PDT-200031449

117. Jiang Y, Murnane KS, Bhattaccharjee SA, Blough BE, Banga AK. Skin Delivery and Irritation Potential of Phenmetrazine as a Candidate Transdermal Formulation for Repurposed Indications. AAPS J 2019; 21(4):70. https://doi.org/10.1208/s12248-019-0335-9

118. Soler LI, Boix A, Lauroba J, Colom H, Domenech J. Transdermal delivery of alprazolam from a monolithic patch: formulation based on in vitro characterization. Drug Dev Ind Pharm 2012; 38(10):11711178. https://doi.org/10.3109/03639045.2011.643893

119. Nawaz A, Wong TW. Microwave as skin permeation enhancer for transdermal drug delivery of chitosan-5-fluorouracil nanoparticles. Carbohydr Polym 2017; 157:906919. https://doi.org/10.1016/j.carbpol.2016.09.080

120. Gaur PK, Purohit S, Kumar Y, Mishra S, Bhandari A. Preparation, characterization and permeation studies of a nanovesicular system containing diclofenac for transdermal delivery. Pharm Dev Technol 2014; 19(1):4854. https://doi.org/10.3109/10837450.2012.751406

121. Kumar P, Singh SK, Mishra DN, Girotra P. Enhancement of ketorolac tromethamine permeability through rat skin using penetration enhancers: An ex-vivo study. Int J Pharm Investig 2015; 5(3):142146. https://doi.org/10.4103/2230-973X.160850

122. Amin S, Mir SR, Kohli K, Ali B, Ali M. A study of the chemical composition of black cumin oil and its effect on penetration enhancement from transdermal formulation. Nat Prod Res 2010; 24(12):115-1151. https://doi.org/10.1080/14786410902940909

123. Cho CW, Choi JS, Yang KH, Shin SC. Enhanced transdermal absorption and pharmacokinetic evaluation of pranoprofen- ethylene-vinyl acetate matrix containing penetration enhancer in rats. Arch Pharm Res 2009; 32(5):747-753. https://doi.org/10.1007/s12272-009-1514-5

124. Kim MJ, Doh HJ, Choi MK, Chung SJ, Shim CK, Kim DD, et al. Skin permeation enhancement of diclofenac by fatty acids. Drug Deliv 2008; 15(6):373-379. https://doi.org/10.1080/10717540802006898

125. Williams AC, Barry BW. Essential oils as novel human skin penetration enhancers. Int J Pharm 1989; 57:R7-R9. https://doi.org/10.1016/0378-5173(89)90310-4

126. Abdullah D, et al. Enhancing effect of essential oils on the penetration of 5-fluorouracil through rat skin. Yao Xue Xue Bao 1996; 31:214-221.

127. Khan NR, et al. Formulation, and physical, in vitro and ex vivo evaluation of transdermal ibuprofen hydrogels containing turpentine oil as penetration enhancer. Pharmazie 2011; 66:849-852.

128. Wang LH, et al. Vehicle and enhancer effects on human skin penetration of aminophylline from cream formulations: evaluation in vivo. J Cosmet Sci 2007; 58:245-254.

129. Wang LH, Chen JX. Study of p-aminobenzoic acid and its metabolites in human volunteers treated with essential oil formulations using attenuated total reflection-Fourier transform infrared spectroscopy and HPLC with fluorometric detection. Microchim Acta 2010; 168:93-98. https://doi.org/10.1007/s00604-009-0255-y

130. Jain R, et al. Basil oil is a promising skin penetration enhancer for transdermal delivery of labetolol hydrochloride. Drug Dev Ind Pharm 2008; 34:384-389. https://doi.org/10.1080/03639040701657958

131. Charoo NA, et al. Improvement in bioavailability of transdermally applied flurbiprofen using tulsi (Ocinum sanctum) and turpentine oil. Colloids Surf B 2008; 65:300-307. https://doi.org/10.1016/j.colsurfb.2008.05.001

132. Saeedi M, Morteza-Semnani K. Penetration-enhancing effect of the essential oil and methanolic extract of Eryngium bungei on percutaneous absorption of piroxicam through rat skin. J Essent Oil Bear Pl 2009; 12:728-741. https://doi.org/10.1080/0972060X.2009.10643782

133. Das MK, et al. Effect of different terpene-containing essential oils on percutaneous absorption of trazodone hydrochloride through mouse epidermis. Drug Deliv 2006; 13:425-431. https://doi.org/10.1080/10717540500395064

134. Monti D, et al. Effect of different terpene-containing essential oils on permeation of estradiol through hairless mouse skin. Int J Pharm 2002; 237:209-214. https://doi.org/10.1016/S0378-5173(02)00032-7

135. Monti D, et al. Niaouli oils from different sources: analysis and influence on cutaneous permeation of estradiol in vitro. Drug Deliv 2009; 16:237-242. https://doi.org/10.1080/10717540902896297

136. Rajan R, Vasudevan DT. Effect of permeation enhancers on the penetration mechanism of transfersomal gel of ketoconazole. J Adv Pharm Technol Res 2012; 3:112-116. https://doi.org/10.4103/2231-4040.97286

137. Karpanen TJ, et al. Enhanced chlorhexidine skin penetration with eucalyptus oil. BMC Infect Dis 2010; 10:278. https://doi.org/10.1186/1471-2334-10-278

138. Mittal A, et al. The effect of penetration enhancers on permeation kinetics of nitrendipine in two different skin models. Biol Pharm Bull 2008; 31:1766-1772. https://doi.org/10.1248/bpb.31.1766

139. Fang JY, et al. Development of sesquiterpenes from alpinia oxyphylla as novel skin permeation enhancers. Eur J Pharm Sci 2003; 19:253- 262. https://doi.org/10.1016/S0928-0987(03)00118-0

140. Fang JY, et al. Essential oils from sweet basil (Ocimum basilicum) as novel enhancers to accelerate transdermal drug delivery. Biol Pharm Bull 2004; 27:1819-1825. https://doi.org/10.1248/bpb.27.1819

141. Huang YB, et al. Cardamom oil as a skin permeation enhancer for indomethacin, piroxicam and diclofenac. Int J Pharm 1995; 126:111-117. https://doi.org/10.1016/0378-5173(95)04104-4

142. Nielsen JB. Natural oils affect the human skin integrity and the percutaneous penetration of benzoic acid dose-dependently. Basic Clin Pharmacol Toxicol 2006; 98:575-581. https://doi.org/10.1111/j.1742-7843.2006.pto_388.x

143. Takayama K, Nagai T. Limonene and related compounds as potential skin penetration promoters. Drug Dev Ind Pharm 1994; 20:677-684. https://doi.org/10.3109/03639049409038325