Arch Dermatol Res (2014) 306:419–426 DOI 10.1007/s00403-014-1445-y

REVIEW ARTICLE

Natural products as potential drug permeation enhancer in transdermal drug delivery system Umesh K. Patil • Richa Saraogi

Received: 20 May 2012 / Revised: 23 December 2013 / Accepted: 10 January 2014 / Published online: 31 January 2014 Ó Springer-Verlag Berlin Heidelberg 2014

Abstract Permeation enhancers are defined as substances that are capable of promoting penetration of drugs into skin and transdermal therapeutic systems offers a more reliable mean of administering drug through the skin. Skin is a natural barrier so it is necessary to employ enhancement strategies to improve topical bioavailability. This review explores that natural products have got potential to enhance the permeation of the drug through skin by reversibly reducing the skin barrier resistance. The use of natural products is the most reliable means of permeation enhancement of transdermally administered drugs and permits the delivery of broader classes of drugs through the stratum corneum. They are safe, non-toxic, pharmacologically inert, non-irritating, and non-allergenic to use as permeation enhancers. The present review initially highlights the current status of natural products on the basis of SAR studies which have shown significant enhancer activities. Keywords Fatty acids  Herbal extracts  QSAR  SAR  Skin penetration enhancers  Stratum corneum  Terpenes

Introduction Extensive research during the past two decades has revealed that transdermal drug delivery has attracted U. K. Patil (&) Department of Pharmaceutical Sciences, Dr. Harisingh Gaur University, Sagar 470003, MP, India e-mail: [email protected] R. Saraogi College of Pharmacy, SR Group of Institutes, Ambabai, Jhansi 284003, UP, India

considerable attention as regards of its many potential advantages. It offers comfortable, convenient, and noninvasive way to administer drugs. The variable rates of absorption and metabolism encountered in other conventional routes of administration are avoided [19]. The greatest obstacle in the transdermal drug delivery is stratum corneum, as it provides a rate-limiting step for the delivery of most of the drugs. Many studies showed that lipid domain, 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 of a drug is presently an important area of pharmaceutical and toxicological research. The use of permeation enhancers has expanded the number of drugs that can be administered transdermally and many different approaches have been developed to overcome the impervious nature of the stratum corneum by various physical, chemical, biochemical, supersaturation, and bioconvertable prodrug enhancement strategies. The physical strategies involve phonophoresis, electroporation, iontophoresis, magnetophoresis, micro fabricated needle, and laser technologies. The chemical strategies involve synthesis of lipophilic analogue, delipidization of stratum corneum, co administration of penetration enhancers, colloidal formulations such as liposomes, niosomes, and microemulsions [71]. Out of these strategies, a popular technique is the use of chemical permeation enhancers, which alters reversibly the permeability barrier of the stratum corneum [73]. Chemical enhancers are currently believed to improve solubility within the stratum corneum or increase lipid fluidity of the intracellular bilayers (Fig. 1). The role of penetration enhancer inclusion in topical formulations has been well documented and undoubtedly, in the future, would permit the delivery of broader classes of drugs through the stratum corneum.

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Fig. 1 Potential routes of drug permeation through human skin: transappendaged and transcellular (intercellular and intracellular routes) permeation routes

Chemical permeation enhancer and its ideal characteristics

3. 4.

The permeation enhancer is known as accelerants or sorption promoters which enhance drug flux without damaging viable cells. They are added to the topical formulations to increase skin permeability by reversibly altering the physiochemical nature of the stratum corneum to reduce its diffusion resistance. The contribution of chemical penetration enhancers have been reviewed [8] which states that the ideal enhancer should be 1. 2. 3. 4. 5. 6.

nontoxic, non-allergenic, and non-irritating, pharmacologically inert, rapid-acting with predictable and reproducible activity, unidirectional, chemically compatible and easily formulated into a variety of systems, and cosmetically acceptable with suitable skin feel.

The enhancer should have a solubility parameter similar to that of skin. It should return rapidly and completely too normal, when removed from the skin surface. The enhancer should not extract endogenous material out of the skin but should spread well on skin and have a suitable skin feel. If the substance is a liquid and is to be used at high-volume fractions, it should be a suitable solvent for drugs [8]. Mode of action of penetration enhancers Skin permeation enhancers may exert their effects through one or a combination of the following mechanisms [9, 11, 29]: 1. 2.

By solubilizing the skin-tissue components. Interaction with intercellular lipids leading to disruption of the highly ordered lamellar structure.

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Interaction with intracellular protein to promote permeation of drugs through the corneocyte layer. Improved partition of the drugs, co-enhancers or cosolvents into the stratum corneum.

The latter three mechanisms have been described as the lipid-protein-partition (LLP) theory [10, 12]. In this theory, various possible locations of enhancer action within the intercellular and intracellular regions of stratum corneum have been proposed. In the intercellular region, three active sites where a penetration enhancer may act to enhance the permeation of permeants have been suggested. These three active areas are the area of polar head groups of the lipids, the aqueous regions between the lipid head groups, and the lipid region of the hydrophobic tails within the bilayers. In the case of the intracellular region, since the intercellular region of the stratum corneum is composed of keratin, penetration enhancers such as surfactants and aprotic solvents may interact with polar head group of the keratin. These interactions result in the reduction of the binding forces between protein molecules, thereby changing the conformations of the protein helices [12]; in addition to the LLP theory, an alternative mechanism has been proposed [30], in which an enhancer may alter the solvent nature of viable epidermis and dermal tissue and promote the partitioning of lipophilic drug from the stratum corneum into the deeper layer of the skin. The mechanism of action can be assessed further by considering to Fick’s law of diffusion: dm=dt ¼ D Co K=h; where dm/dt is the flux per unit area, Co is the constant concentration of drug in donor solution, K is the partition coefficient of the solute between the membrane and the bathing solution, D is the diffusion coefficient, and h is thickness of membrane [31]. From the above equation, it is

Arch Dermatol Res (2014) 306:419–426 Table 1 Types of chemical penetration enhancers classified by functional groups and chemical structures [11, 15, 38, 69]

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permeation flux of drug molecules across the skin, possess various problems associated with them when employed at concentrations necessary for achieving the desired target. For example, DMSO and DMF are the concentrationdependent enhancers and at relative high concentrations, they cause reversible denaturation of keratin and lead to keratolysis with symptoms of erythema, scaling, contact uticaria, stinging, and burning sensation [43, 65]. Alcohols are the effective penetration enhancers but can dissolve the skin lipids resulting in dryness and decrease in the threshold of skin [39]. The use of azone promotes the absorption of polar solutes but is not satisfactorily effective on human skins [15]. Hence, in recent years efforts have been directed at identifying safe and effective penetration enhancers from both natural products and synthetic chemicals which can be classified as generally regarded as safe (GRAS) by Food and Drug Administration (FDA), such as essential oils and terpenes, and polymeric enhancers [1, 2].

Types

Examples

Alcohols

Ethanol, 1-octanol, 1-hexanol, 1-decanol, Lauryl alcohol, Linolenyl alcohol

Azone and derivatives

Azone (Laurocapram, 1-dodecylazacyclo heptan-2-one), 1-alkyl- or 1-alkenylaza cycloalkanones

Fatty acid esters

Cetyl lactate, butyl acetate, isopropyl myristate

Fatty acids

Alkanoic acids, oleic acid, lauric acid, capric acid

Glycols

Propylene glycol, polyethylene glycol 400

Oxazolidinones

4-decyloxazolidin-2-one, 3-acetyl-4Decyloxazol idin -2-one

Pyrrolidones

2-pyrrolidone, N-methyl-2-pyrrolidone, 1-lauryl-2- Pyrrolidone

Sulfoxides and similar compounds

Dimethylsulfoxide, Dimethylacetamide, Dimethyl formamide

Surfactants

Sorbitan monopalmitate, Sorbitan trioleate, Cetyl trimethyl ammonium bromide

Terpenes

Nerolidol, Farnesol, Carvone, Menthone

Urea and derivatives

Urea, 1-dodecylurea, 1-dodecyl-3-methyl urea, 1- Dodecyl -3- Methylthiourea

Natural products as skin permeation enhancers

Water

Water

Various investigations have been done to examine the possibilities of the percutaneous delivery of drugs and efforts have been directed at identifying safe and effective enhancers from both natural products and synthetic chemicals. Since the use of many chemical enhancers such as DMSO, DMF, azone, ionic surfactants is also associated with unpleasant and toxic side effects [39, 43, 65], in recent years there has been a search for natural compounds as permeation enhancers to improve drug permeation that also exhibit low toxicity while maintaining their enhancing activity. The natural permeation enhancers studied so far include essential oils, terpenes, terpenoids, fatty acid esters, fatty acid glycols, and herbal extracts. It has been concluded after several studies that iontophoresis in combination with enhancers (e.g. linolenic acid) transformed 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 increasing the flux of medication through human epidermis [14].

clear that the ideal properties of a molecule that would penetrate stratum corneum depends on the magnitude of passive diffusion process which depends on the integrity and efficacy of the epidermal barrier and also influenced by the drug itself. Drugs with low molecular weight (below 800 Daltons) with a high water and lipid solubility show the greatest penetration [7]. Both, vehicle containing applied drugs and degree of hydration of stratum corneum are considered as the important factors in permeation. The vehicle that contains the applied drug is considered as an important factor in permeation: occluding the epidermis increases its water content, enhancing drug absorption. Classification of penetration enhancers A large number of compounds have been reported to increase the penetration of drugs through the skin and, therefore, a simple, relevant system for classification of compounds is essential for systemic study and applied research. Classification of chemical enhancers based on their chemical structures is shown in Table 1. Problems associated with chemical permeation enhancers Extensive research during the past two decades has revealed that chemical penetration enhancers, despite showing satisfactory performance in enhancing the

Essential oils, terpenes, and terpenoids Terpenes are a series of naturally occurring volatile oils that are composed of hydrocarbons and their oxygenated derivatives such as alcohols and their glycosides, ethers, aldehydes, phenols, ketones, oxides, carboxylic acids, and esters. The basic chemical structure consists of a number of repeated units of isoprene, C5H8, in a head-to-tail orientation to form linear chains or rings [13]. Terpenes appear

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to be clinically acceptable penetration enhancers as indicated by following advantages [12]: 1. 2. 3. 4.

High percutaneous enhancement ability, Reversible effect on the lipids of SC, Good evidence of freedom from toxicity, and Less toxic with low irritancy potential.

Recently, natural and synthetic terpenoids have attracted great interest as safe and effective penetration enhancers [57, 66]. Further, quite a few terpenes are included in the list of GRAS agents issued by US FDA [66]. Hence, their satisfactory performance in enhancing the permeation of drug molecules across the skin has been intensively investigated as penetration enhancers. The chemical structures of terpenes and the physicochemical properties of the drugs play an important role in the permeation enhancing activity of terpenes [4]. Permeability coefficient of various terpenes have been determined experimentally using human skin and the results suggest that terpenes with larger Log p values were more effective enhancers than those with smaller Log p. It has also been observed that the liquid terpenes could form more number of hydrogen bonds with intercellular lipids of SC and produce better enhancing effects than solid terpenes. Triterpenes and tetra-terpenes generally had poor penetration effect than other terpenes, while presence of aldehyde or ester functional group increases their efficiency [37]. Reports indicate that the oxygen containing polar terpenes (e.g. carvacrol, menthol) were found to be more potent for hydrophilic drugs (e.g. propranolol hydrochloride) than the lipophilic terpenes (e.g. limonene, p-methene) [45]. It has been suggested that hydrocarbon

monoterpenes should be used for lipophilic permeants and smaller terpenes tended to be more active than the larger terpenes [71]. Furthermore, smaller alcoholic terpenes with a higher degree of unsaturation appeared to be good candidates for enhancing the permeation of hydrophilic drugs. In addition, oxygen-containing terpenes with a bicyclic structure displayed a lesser permeation-enhancing effect. According to skin permeation studies using diffusion cells and excised animal skin, it was found that terpenes such as 1,8-cineole, menthol, and limonene were effective in enhancing the skin penetration of model permeants such as oestradiol, 5-fluorouracil, and labetalol hydrochloride [36, 70, 72]. A variety of terpenes have been shown to increase the percutaneous absorption of both hydrophilic and lipophilic drugs. Examples of these investigations are given in Table 2. Fatty acids Fatty acids consist of an aliphatic hydrocarbon chain and a terminal carboxylic acid group. They differ in their aliphatic chain length, which is either saturated or un-saturated, in the number, position, and configuration of double bonds and may have branching and other substituents. A large number of fatty acids have been used as permeation enhancers and have proven to be effective and safe sorption promoters. They have a greater enhancing potential for the absorption of the lipophilic drugs. Fatty acids, as a skin permeation enhancer, appear to be clinically acceptable penetration enhancers as indicated by following advantages: 1. 2. 3.

Very high skin flux, No skin irritation or sensitization problems, and Compatibility with a wide variety of drugs.

Table 2 Studies of terpenes as skin permeation enhancers Permeant

Surfactant

Skin

References

Lidocaine

Alpha-terpinol

Porcine

[50]

5-fluorouracil

Carvone, 1, 8 cineol, thymol

Porcine

[26]

Caffeine

11-terpenes-terpineol, e.g. terpen-4-ol, neomenthol, geraniol

Mouse

[28]

Ketoprofen

Limonene, cineole, menthol

Rat

[60]

Haloperidol

Carvacrol, linalool, a-terpineol

Human

[67]

Mefenamic acid

1,8-cineole

Porcine ear

[32]

Diclofenac sodium

Nerolidol, farnesol, carvone, menthone and limonene oxide

Rat

[5]

Ketotifen

Menthol, limonene

Hairless mouse

[41]

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The fatty acids in transdermal formulations appear to reduce the skin irritation and sensitization which is most common problem associated with some drugs. A wide variety of long-chain fatty acids have a potential utility as skin permeation enhancers. The enhancing effects of fatty acids depend on several factors, including the 1. 2. 3. 4.

Physicochemical nature of the permeants, Vehicle used to deliver permeants, The fatty acid selected, and Chemical structures of the fatty acid [6, 55].

A number of investigations have clearly demontrated that the alkyl chain length of fatty acids affected percutaneous drug absorption [51]. Evidences from several studies have revealed that the enhancing effects of saturated fatty acids were greatest for C10 and C12 fatty acids [7, 44, 55]. Also, the enhancer activity was influenced by the bond saturation and was found that the unsaturated long-chain

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Table 3 Studies of fatty acids having potential role as skin permeation enhancers Permeants

Surfactant

Skin

References

Flurbiprofen

Unsaturated fatty acids: oleic acid, linoleic acid, linolenic acid

Wistar rat

[24]

Lidocaine

Conjugates of unsaturated fatty acids (e.g. Oleic acid, linoleic acid, linolenic acid) with propylene glycol

Porcine

[14]

LHRH

Lauric acid, palmitic acid, oleic acid, linoleic acid (10 % in ethanol)

Porcine

[16]

Piroxicam

Lauric acid, myristic acid

Rat

[34]

Carvedilol

Linoleic acid, oleic acid, margaric acid, cis11,14-eicosadienoic acid, stearic acid

Rat

[3]

Estradiol

Fatty acid commonly used in cosmetics and topical formulations

Human epidermal membrane

[35]

Loratadine

Linoleic acid

Rat

[20]

Pranoprofen

Caprylic acid

Rat

[21]

Diclofenac

Palmitic acid, oleic acid

Rat

[40]

fatty acids showed a greater enhancement than the analogous saturated fatty acids [6]. Moreover, the branching of fatty acids appeared to affect their enhancing permeation activity [7]. It has been found that PUFA-linoleic, alphalinolenic acid, and arachidonic acids which are polyunsaturated fatty acids in nature enhance skin permeation stronger than monounsaturated fatty acids. A general trend has been seen that unsaturated fatty acids are more effective in enhancing percutaneous absorption of drugs than their saturated counterparts [19]. The enhancement effects of fatty acids on penetration through the stratum corneum are structure-dependent, and are associated with the existence of a balance between the permeability of pure fatty acids across stratum corneum and the interaction of the acids to skin lipids. Concentrations of fatty acids also seem to influence their enhancing activities. The skin permeation of Meloxicam through human cadaver skin was found to increase as the concentration of oleic acid increased from 0.4 to 1 %. A variety of fatty acids have been shown to increase the percutaneous absorption of both hydrophilic and lipophilic drugs. Examples of these investigations are given in Table 3.

are attached. They are characterized as natural surfactant and hence acquire great potential for use as percutaneous permeation enhancers [46, 59]. A large number of biological activities ascribed to saponins are their action on membrane. It has been revealed by previous findings that saponins’s specific ability for pore formation in membranes has resulted in their widespread use in physiological research, as they contribute long-lasting effects and these membranes were permeable to large molecules, e.g. ferritin for longer periods [22, 42, 46, 47, 56, 63, 64]. Probably, the saponin molecules arranged in ring with their hydrophobic moieties combine with cholesterol around the outer parameter resulting in lesions in the plane of membrane, due to micelle-like aggregations [64]. On the other hand, several studies illustrate that insertion of the aglycone into the lipid bilayer is independent of the presence of cholesterol. Saponins may interact with the polar heads of membrane phospholipids and the—OH group of cholesterol through—OH groups at C3 or C28, which results in the ability of the latter to form micelle-like aggregates. Moreover, their hydrophobic aglycone backbone could intercalate into the hydrophobic interior of the bilayers. Both of these effects may contribute to the alteration of the lipid environment around membrane proteins [17, 18]. Saponins consist of hemolytic activity which is probably associated with the interaction of saponins with the steroids, especially cholesterol. The hemolytic potential of saponins varies considerably with the structure of glycoside, and its phenomenon involves lowering of interfacial tension between the aqueous and lipid phases of the erythrocyte membrane, resulting in the emulsification of the lipids and their subsequent release from the membrane [33]. Saponins consisting of one side chain posses more enhancing potential in comparison with saponins containing two sugars [71]. On the other hand, increasing the amount of sugar side chains increased the membrane permeability for calcium ions [74–77]. Thus, the results from previous studies reveal that the haemolytic activity and enhancing potential permeation may be due to the combination of target membrane composition, the type of the saponin side chain(s), and the nature of the aglycone [25]. The results of the previous investigations done by the researchers on skin permeation enhancement reveal that saponins possess potential to enhance the permeability of various medicated drugs (model permeates) such as aceclofenac, gentamicin sulfate, and carvedilol, diclofenac sodium. Examples of these findings are illustrated in the Table 4.

Saponins Herbal extracts Saponins constitute a highly diverse group of glycosides occurring in plants, which posses either a steroidal or a triterpenoid aglycone to which one or more sugar chains

Herbal extracts have the ability to penetrate the skin surface fast. In vivo skin penetration investigations of

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Table 4 Studies of saponins and other herbal extracts having potential role as skin permeation enhancers Permeants

Herbal Extracts (Surfactant)

Skin

Diclofenac sodium

Glycyrrhiza glabra (glycyrrhizin)

Abdominal rat skin

[54]

Carvedilol

Glycyrrhizin

Rat epidermis

[61]

Carvedilol

Asparagus racemosus

Rat epidermis

[62]

Caffeine

Aloe vera

Porcine ear skin

[23]

Mefenamic acid

Aloe vera

Porcine ear skin

[23]

Colchicines Oxybutynin

Aloe vera Aloe vera

Porcine ear skin Porcine ear skin

[23] [23]

Quinine

Aloe vera

Porcine ear skin

[23]

Gentamicin sulfate

Quillaja saponaria and Acanthophyllum squarrusom Coptis japonica and its alkaloidal isolates

Shed snake-skin and liposomal membranes

[49]

Human skin

[53]

Hairless mouse skin

[52]

5fluorouracil Herbal extracts

Senkyu (Ligustici Chuanxiong Rhizome)

References

the chamomile flavones apigenin, luteolin, and apigenin 7-o-beta-glucoside concluded that the flavonoids are not only absorbed at the skin surface, but also penetrate into deeper skin layers. This is and important feature for their topical uses [48]. According to skin permeation studies using diffusion cells and excised animal skin, it was found that alkaloids were effective for enhancing the skin permeation of model permeants such as 5-fluorouracil and benzoic acid. In in vitro studies, it have been revealed that methanol extract of Coptis japonica and its three alkaloidal isolates (berberine, coptisine, and palmatine) enhance effectively the skin permeation of hydrophilic permeant 5-fluorouracil [53]. Another study has been done to investigate the permeability of natural herbal compounds of different range of lipophilicity through hairless mouse skin and the effect of the certain herbal extract called Senkyu (Ligustici Chuanxiong Rhizome) ether extract (SEE) as permeability enhancer. The investigation revealed that SEE enhanced the permeability of the herbal ingredient that has moderate permeability rate. It was observed that the effect of SEE in vivo was similar to that obtained in the in vitro experiment. It was concluded that the natural compounds having high lipophilicity sufficiently permeated into the hairless mouse skin owing to their accumulative property, and the SEE enhanced the permeability of the moderately lipophilic compounds into the skin [52]. Examples of some of

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the herbal extracts acting as skin permeation enhancers are illustrated in the Table 4. Criteria for the use of natural products as skin permeation enhancers The selection of a specific enhancer for given permeants has remained challenging. It has been proposed that physicochemical properties of selected enhancers must be compared with those of the permeants [58] as there are reports indicating that the potency of skin penetration enhancers might be drug specific [68, 69]. It is generally recognized that structures and physiochemical properties of the chemical enhancers govern their penetration enhancement potencies. With the aid of structure–activity relationship (SAR) studies, prediction of enhancer potency may be possible for a series of permeants with similar physicochemical properties. SAR can be used to correlate the enhancing potency of chemical enhancer with its structure or physiochemical parameters, such as molecular shape, size, molecular geometry, solubility parameter, electronic effect, hydrophilicity, and lipophilicity [38]. Besides SAR, the quantitative structure–activity relationship (QSAR) technique has been employed to explore the structural requirements of chemical penetration enhancers towards different drugs [27]. QSAR has been explored for relating the skin permeation of compounds to their physicochemical properties. In 1990, Flynn compiled skin permeability coefficients across human skin from different literature sources and identified Log p as the most important factor for determining the permeability coefficients. The subsequent QSAR studies raised interest in using QSAR for modeling skin permeation. These QSAR models provide an insight into the mechanism of skin penetration and guidance for predicting permeability of new compounds.

Conclusion Skin permeation enhancement technology is a rapidly developing field which would significantly increase the number of drugs suitable for transdermal drug delivery, with the result that skin will become one of major routes of drug administration in the next decade. Elucidation of the biochemical composition and functioning of the intrinsic diffusion barrier of the stratum corneum has prompted investigation of chemical and physical means of enhancing the percutaneous penetration of poorly absorbed drugs. Research in this area has proved the usefulness of chemical penetration enhancers in the enhancement of drug permeation through skin. The role of natural penetration enhancer inclusion in topical formulations has been well documented

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and will undoubtedly, in the future, permit the delivery of broader classes of drugs through the stratum corneum. Further researches should focus on skin irritation with a view to selecting natural penetration enhancers possessing optimum enhancement effects with minimal skin irritation.

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