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Current Drug Delivery, 2012, 9, 219-230

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Novel Penetration Enhancers for Skin Applications: A Review Rabinarayan Parhi*, Padilama Suresh, Sumant Mondal and Posa Mahesh Kumar GITAM Institute of Pharmacy, GITAM University, Gandhi Nagar Campus, Rushikunda, Visakhapatnam-530045, Andhra Pradesh, India

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Abstract: The use of topical formulation is popular over the past decade due to extensive researches made in the field of transdermal drug delivery. As a result, an increasing number of drugs are being added to the list of therapeutic agents that can be delivered to systemic circulation through the skin. Commonly available dosage forms for the topical application are creams, ointments, gels, patches etc. The therapeutic benefits of the above topical formulations are limited due to barrier property of stratum corneum (SC). The use of chemical penetration enhancers (CPEs) is one of the long standing approach to overcome the barrier property of SC. Numerous class of novel compounds have been evaluated for penetration enhancement activity, including soft enhancement for percutaneous absorption (SEPA), for example, 2 N-nonyl-1,3dioxolanes, N-acetyle prolinate esters (such as pentyl- and octyl-N-acetyle prolinate), alkyldiloxanes (e.g., 1-Alkyl-3-b-D glucopyranosyl-1,1,3,3-tetramethyl disiloxanes), transcarbam (such as 5-(dodecyloxycarbonyl) pentylammonium-5(dodecyloxycarbonyl) pentylcarbamate), iminosulfurane (like N-hexyl,N-benzoyl-S,S-dimethylimino-sulfuranes), capsaicin derivatives (e.g., Nonivamide), cinnamene compounds (such as cinnamic acid, cinnamaldehyde etc), terpenes (like clove and basil oil) and synergestic combination of penetration enhancers (SCOPE). We briefly describe about the anatomy of skin. Potential mechanisms of action of above novel PEs along with adverse reactions associated with traditional PEs are also considered in this review.

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Transdermal drug administration is a more viable alternative to conventional oral route due to following advantages; (i) low metabolic activity of skin as compared to gastrointestinal tract and liver (ii) elimination of variable rate of absorption (iii) delivering the drug directly to the inflamed site and thereby producing high local concentration (iv) noninvasiveness (v) improved owner compliance with drug administration (vi) prolonged drug levels in blood stream (vii) minimize inter- and intra-patient variation (viii) allows effective use of drug with short biological half-life and (ix) easy termination of drug administration [1-4].

of microneedle) and chemical methods (penetration enhancers) can be utilized to alter the barrier properties of the skin and the percutaneous permeation rate of drugs [7-10]. Of these approaches, co-administration of skin PEs, which will reversibly diminish the barrier property, is most widely used due to the lack of pain at application site [11]. The extent of absorption through different layers of skin is systemically more important when we consider drugs applied to the skin for [3]:

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1. INTRODUCTION

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Keywords: Stratum corneum, penetration enhancers, soft enhancement for percutaneous absorption, bilipid layer.

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The skin is the largest organ of the body, accounting for more than 10% of body mass. It has important protective and homeostatic roles and is generally regarded as a critical protective barrier to the external environment [5]. Stratum corneum, the outermost layer of the epidermis, is the principle rate limitation to transdermal drug delivery. The combination of intercellular lipid along with highly keratinized intracellular environment makes the SC a very effective barrier to drug penetration [6]. To be therapeutically beneficial, the barrier properties of skin must be modified such that the drug can be administered at a rate sufficiently high to achieve a therapeutically effective level at the proper site. Both physical (sonophoresis, iontophoresis, electroporation and the use *Address correspondence to this author at the Department of Pharmaceutics, GITAM Institute of Pharmacy, GITAM University, Gandhi Nagar Campus, Rushikonda, Visakhapatnam-530045, Andhra Pradesh, India; Tel: 09052983544; E-mail- [email protected]

1-/12 $58.00+.00

1) Local effects (e.g., corticosteroids for dermatitis) 2) Transport through the skin for systemic effects (e.g., fentanyl, nicotine, oestradiol and testosterone patches) 3) Surface action (e.g., sunscreens and anti-infectives) 4) Targeting deeper tissues (e.g., non-steroidal antiinflammatory agents for muscle inflammation) and 5) The case of accidental exposure (e.g., solvents in the workplace, agricultural chemical, or allergens). Although many chemicals have been evaluated as PEs in human or animal skins, to date none has proven to be ideal. Some of the more desirable properties for PEs acting within skin have been given as [12]: 1) They should be non-toxic, non-irritating and nonallergenic. 2) The action should be immediate and the effect should be both predictable and reproducible. 3) They should have no pharmacological activity within the body i.e. should not bind to receptor sites. © 2012 Bentham Science Publishers

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4) The PEs should work unidirectionally, i.e. should allow therapeutic agents into the body, while preventing the loss of endogenous material from the body.

and non-keratinocytes including Langerhans cells. Dendritic antigen-presenting cells have a role in skin sensitization and keratinocyte proliferation and Merkel cells are found in the basal region and function as sensory receptors for the peripheral nervous system [14-16]. Keratinocytes are anchored to the basement membrane by hemidesmosomes and to other keratinocytes by desmosomes [17,18].

5) When removed from the skin, barrier properties should return both rapidly and fully. 6) The PEs should be appropriate for formulation into diverse topical preparations, thus should be compatible with both excipients and drugs.

Keratinocytes are surrounded by a continuous lipid phase known as the intercellular lipid. These are comprised primarily of cholesterol, ceramides and free fatty acids. These sphingolipids are arranged as multiple lamellar structures and the arrangement led to the popular ‘bricks and mortar’ model of the SC [19,20]. This creates a highly lipophilic barrier which prevents excessive water loss to the environment and protects against the transdermal penetration of drug molecules [21,22].

7) They should be cosmetically acceptable with an appropriate skin ‘feel’. Still, CPEs provide several advantages such as design flexibility with formulation chemistry, application over large surface area in the form of patch, gel etc, and the absence of external physical delivery mechanism. However, these are usually not selective towards SC lipids and eventually affect the viable epidermal cells, thereby inducing irritation by interstitial release of cytokins and by triggering other inflammatory response. In addition, development of transdermal products of macromolecules is hindered by low skin permeability [13]. In this article, we reviewed some new investigated PEs and discuss their possible mechanism of action.

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2.3. Subcutaneous

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The subcutaneous is mainly composed of adipocytes with fewer fibroblasts, endothelial cells and macrophages. It connects to the dermis by collagen and elastin fibres. Its major role is to carry the vessels and nerves that supply the skin [25].

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The human skin comprises three tissue layers: the cellular epidermis, the underlying dermis, and the subcutaneous. Each layer is physically and functionally distinct with appendages, including hair follicles, sweat ducts and sebaceous glands (Fig. (1)).

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2. OVERVIEW OF THE ANATOMY OF SKIN

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The dermis is a vascularized collagen-rich connective tissue containing mucopolysaccharides collectively known as the ground substance. The main cell type is the fibroblast, which produces connective tissue. Mast cells are contained within the dermis, although the number of cells and the contents of the granules (histamine, heparin or serotonin) vary depending on species and on region of the body [23]. Vascular supply provides nutrient to dermal tissue and nerve supply to the dermis is functioning in response to the perception of pain, pressure and temperature [24].

3. PERMEATION PATHWAYS THROUGH SKIN The basic requirement of a transdermal drug delivery system is for the drug to penetrate the SC, the outermost layer of the skin, which is comprised of keratin-rich cells embedded in multiple lipid bilayer. In general, the drug has two potential routes (Fig. (2)) to entry in the inner tissue of the skin. The different pathways are as follows: a) Transappendageal route •

Via the eccrine gland



Via the pilosebaceous unit (Hair follicle and Sebaceous gland)

Fig. (1). The typical structure of mammalian skin.

b) Transepidermal route 2.1. Epidermis



Via transcellular route

The multilayered epidermis can be classified into SC and viable epidermis. SC constitutes of dead cells, whereas four layers (stratum germinativum, stratum spinosum, stratum granulosum and stratum lucidum) are recognized in viable epidermis which represent different stages of differentiation, ranging from the proliferating cells of the stratum germinativum to the terminally differentiated cells of the SC. There are two types of cells, keratinocytes comprising melanocytes



Via intercellular route (Polar route through lipid bilayer)

4. MECHANISMS OF PENETRATION ENHANCERS According to the Lipid protein partitioning (LPP) theory, enhancers would act by one or more of three main mechanisms [26]:

Novel Penetration Enhancers for Skin Applications: A Review

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Skin Surface

Stratum Corneum

Transcellular

Intercellular Transappendageal

Fig. (2). Possible routes of solute transport through the epidermis.

1) Disruption of the highly ordered structure of SC lipid with an increase in intercellular diffusivity. This mechanism is shown by terpenes, azones [26,27].

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5) Effects on protein junctions, such as desmosomes, involved in squamae cohesion.

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6) Alternation of partitioning between SC components and the lipid in the diffusion pathway.

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The modes of action of PEs in general are complex. At clinically acceptable concentrations, most promoters interact with intercellular lipid domain of SC. Solute and/or solvent diffuse through the lipid region will then increase the fluidity of the intercellular lipids by interaction with the lipid tails (lipophilic enhancer and/or, with the disruption polar head groups (polar enhancers). This leads to extraction of lipids and/or change in polarity of the intercellular lipid. These effects may then result in formation of pools or vesicles through associations of polar solvents, or the more lipophilic solvents in the lipid tail region (Fig. (3)). With some enhancers, especially hygroscopic agents, the desmosomes and protein-like bridges may damaged, leading to fissuring of intercellular lipid and splitting of SC squames as shown in Fig. (4). Under severe conditions, especially with surfactants and polar solvents, solutes may enter into corneocytes cytosol with disruption of keratin protein and vacuolization as a result (Fig. (5)).

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4) Disruption of corneocyte envelope.

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The above LPP model extended to include the following [30,31]:

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3) Improvement in partitioning of a drug into SC by coenhancer, or cosolvent such as propylene glycol, and ethanol [29].

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2) Interaction with intracellular protein to enhance penetration through corneocytes. Example- dimethylsulfoxide, dimethylformamide, pyrrolidones [28].

Aprotic solvents enhance the permeation of many drugs, including antifungal, barbiturate, steroids and local ansthetics. However, the popularity was gradually decreased due to side effects like erythema, scaling, contact urticaria, stinging and burning sensation caused by them [32]. In addition, DMSO produces foul odour on the breath because of its conversion to metabolite, dimethyl sulphide. Furthermore, it was proved that the DMF caused irreversible membrane damage in human skin [33]. Azone (1-dodecylazacycloheptan-2-one or laurocapram) was the first molecule specifically designed as a skin PE. It is an excellent PE in the sense that it is promoting the permeation of both hydrophilic and lipophilic drugs. However, histopathological study showed that it is causing irritation mainly in the epidermis of human beings. This was further confirmed by the fact that neutrophils were present in the epidermis after application of azone [34]. The severity of irritation caused by azone is less in comparison to aprotic solvents. Similarly, erythema is common in pyrrolidone compounds, for example, N-methyl pyrrolidone (NMP), and 2-pyrrolidone (2P)). In addition, NMP was showing toxic hygroscopic contact reaction [35]. The application of surfactants (anionic and cationic) is limited due to their potentiality to damage human skin. Furthermore, SLS is a powerful irritant and increased the transepidemeral water loss in human volunteer’s in vivo [36]. Concentration dependant penetration enhancement was evident with ethanol, when used as co-solvent to water. However, diffusion of salicylate ion, across human epidermal membranes was promoted up to an ethanol:water composition of 0.63, whereas higher levels of the alcohol decreased permeation [37]. Terpens are very safe and effective class of PE, obtained from natural sources. They cause no skin toxicity or if any, only mild irritation. Even terpenes, which are considered to be skin irritants, did not cause long lasting erythema. For more updated information regarding various terpens as skin PE, readers can refer excellent review by Aqil M. et al. (2007) [38].

5. PROBLEMS ASSOCIATED WITH TRADITIONAL PENETRATION ENHANCERS Ancient PEs tended to be disruptive agents that destroy SC and were non-specific in their penetration enhancement activity. These included earliest and most widely used aprotic solvents (dimethylsulfoxide (DMSO), dimethylformamide (DMF) and Dimethylacetamide (DMAC)), azone, pyrrolidone, surfactant and alcohol.

6. NOVEL PENETRATION ENHANCERS 6.1. Soft Enhancement for Percutaneous Absorption (SEPA) SEPA is an acronym for Soft Enhancement of Percutaneous Absorption, where soft communicates that the absorption enhancement is temporary and reversible due to rapid breakdown of the enhancer. SEPA indicates a family of PEs which

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Fig. (3). Disruption of the highly ordered structure of SC lipid with an increase in intercellular diffusivity [25].

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Normal corneocytes in Stratum corrneum

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Fissure

Spliting of corneoccytes squamae

Denaaturation of Keeratin

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Orientation of Keratin K

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Fig. (4). Action at Desmosomes and Protein structures.

Solvent Entryy

Corneocyte

Vacuooles

Fig. (5). Action on the corneocytes.

includes dioxolanes and dioxanes group. All the members of SEPA family consist of carbon, hydrogen and oxygen molecules without nitrogen molecule to minimize the risk of being metabolized to potential toxic compound. One of the examples of SEPA molecules is 2-n-nonyl1,3- dioxolanes (ND), which designated as SEPA 0009

(Fig. (6)). It is an amphiphilic molecule with the property of reversibly altering the lipid structure of the SC. SEPA disorders the SC lipids to increase fluidity which allows drugs of lower molecular weight to pass through the skin without making path for bacteria and viruses. In addition, with increased disorderness it also modifies the protein hydrophobic interaction which further enhances the permeation [39].

Novel Penetration Enhancers for Skin Applications: A Review

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Current Drug Delivery, 2012, Vol. 9, No. 2

its head (dioxolane ring) level along with the head groups and the aliphatic chain is parallel with the acyl chains of the phospholipids. It was able to add bulkiness to the acyl chain and thus compensated for the bulkiness of the head groups. Thus, the chains will no longer tilt, which can explain the absence of the pre-transition of lipid in SEM study. In addition, ND, a dioxolanes derivative, can create hydrogen bonds with each of two adjacent DPPC molecules. This can immobilize the phospholipids and thus add more structure to the bilayer. This can explain the increase in the transition and the apparent increase in the enthalpy of the main transition. The behavior of ND in DPPC liposomes suggested that ND could work as a penetration retarder rather than penetration enhancer [44]. There are contrary reports exist on the penetration enhancing and retarding effect of SEPA.

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H3C Fig. (6). 2-(1 nonyl)-1,3-dioxolane.

SEPA enhances the penetration of one or more members of drug category, including NSAIDs, vasodilators, corticosteroids, anesthetic, antimicrobial and antiviral. It is generally used in the concentration range of 5% to 10%, but it can be used up to 20% without any side effects. SEPA can be formulated in various formulations such as creams, ointment, gel, emulsions, lotions, solutions, microemulsion, patches, lacquers, topical films and sprays. Opteron, AndroGel and EcoNail are some of the marketed products containing SEPA [40].

6.2. N-acetyl Prolinate Esters

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N-acetyl prolinate esters are a series of novel PEs, which were synthesized from L-proline by acetylation with acetic anhydrate and followed by esterification with N-alkanol in the presence of acid [45]. The series of N-acetyl prolinate esters with alkyl side chain length of 5-18 is shown in the Fig. (7). These PEs act by disrupting the lipid packing in the intercellular bilayers of SC [46].

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Diani AR. et al. (1995) reported that ND influences the topical delivery of minoxidil by stimulation of scalp hair growth in the balding stumptail macaque. In their study, an inch2 area of balding scalp of female monkey was topically treated for 5 days/week with minoxidil-SEPA (2.5% minoxidil, weight/volume in 10% SEPA, 25% propylene glycol and 65% isopropyl alcohol), Rogaine® topical solution (2% minoxidil, weight/volume in 20% propylene glycol, 60% ethanol and 20% water) and respective vehicles (without drug) for 16 week via paintbrush application. Scalp hair was collected by shaving at 4-week intervals. The shaved hair was filtered, weighed and recorded as the change from baseline. The minoxidil-SEPA groups displayed a significant increase in hair weight compared to their respective vehicles at the aforesaid interval. To conform above fact, 24 hr urine samples were collected at steady-state and analyzed by high performance liquid chromatography to assess urinary excretion of total minoxidil in each of the four drug treated groups. A 2.8-fold elevation of minoxidil urine concentration was found in minoxidil-SEPA treated groups as compared to the Rogaine® group [41].

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Morganti F. et al. (1999) investigated the effect of SEPA on SC by Fourier transform infrared (FT-IR), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). A significant change in position and intensity of IR absorption band and DSC thermal transition of SC lipids were observed. In addition, there was loosening of SC cell packing observed by SEM analysis [42]. These modifications were reversed after SEPA was removed from the site of application. These results clearly demonstrate that SEPA is able to modify the structure of the lipid matrix of SC. In another study, ND increased the permeation of dapiprazole synergistically with propylene glycol, when hairless mouse skin was taken as model membrane [43]. This finding was attributed to the different mechanism of action shown by ND (increasing fluidity of SC lipid) and propylene glycol (partitioning). The mechanism of ND was studied by using SC lipid liposomes and probed phospholipid. Dipalmitoyl phosphatidyl choline (DPCC) was used as a model membrane and the results have shown that ND can fit into the bilayer lipid with

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Compound

R

PNAP

-C5H11

ONAP

-C8H17

DNAP

-C10H21

UNAP

-C11H23

DDNAP

-C12H25

HDNAP

-C16H33

Oleyl-NAP

-C18H35

Fig. (7). List of N-acetyle prolinate ester.

A series of alkyl side chain (length of 5-18 carbon) esters of N-acetylproline were synthesized and their penetration enhancement activity on model drugs (benazepril and hydrocortisone) was investigated. The order of enhancement ratio for benazepril through hairless mouse skin was found to be C18=C11> C12> C16> C10> C8=C5=control when used at 5% concentration level. However, only compounds with alkyl chain length of 10 or greater were effective as enhancers for benazepril. Pentyl- and octyl-esters did not show any enhancement activity. Similarly, the order for hydrocortisone

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attributed to (i) partitioning (ii) diffusion and (iii) defatting effect [49].

was C12=C11 >C18> C10=C8=C5=C16 >control. All the compounds were effective as skin PEs for hydrocortisone. Furthermore, in both the cases, 11- and 12-carbon esters have both the hydrophilic and hydrophobic groups similar to azone, which might have contributed to the activity. In case of 18-carbon ester, the activity was attributed to the presence of cis-double bond which in turn affect the mode of packing in the matrix of SC. This was further confirmed by the SEM study which revealed the higher order of enhancement in case of C18, C12 and C11, may be due to the elimination of lipid transition when treated with SC [46].

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6.4. Transkarbam (T) Transkarbam is a group of carbamic acid salts, derived from -amino acid esters having high transdermal penetration enhancing activity. Most active compound amongst this group is Transkarbam-12 (5-(dodecyloxycarbonyl) pentylammonium-5-(dodecyloxycarbonyl) pentylcarbamate). It was synthesized by the reaction between 6-aminohexanoic acid dodecylester with CO2. The linear and branched transkarbam are shown in the Fig. (8). It is a novel biodegradable permeation enhancer with a wide spectrum of physiochemical property, low toxicity and no dermal irritability [54].

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6.3. Alkyldisiloxane

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PNAP is an effective transdermal PE and is nontoxic at lower dose. It exhibits dose related CNS toxicity at higher doses when compared with azone after intraperitoneal administration [45]. N-Dodecanoyl-L-proline showed highest permeability of hydrocortisone through the hairless mouse skin amongst a series of N-dodecanoyl-L-amino acid methyl esters evaluated [48].

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Ghafourian T. et al. (2004) studied the in vitro enhancement activities of N-acetyl prolinate derivatives towards hydrocortisone and benazepril, using full thickness hairless mouse skin. Saturated drug solutions in propylene glycol with or without enhancers at 5% (w/v) were used as donor phase. They analyzed enhancement ratio for permeability coefficient (Kp), diffusion coefficient (D) and membranevehicle partition co-efficient (Km) for individual drugs using stepwise regression analysis. The result shows that a positive relationship exists between Kp and partition coefficient towards hydrocortisone, which was due to increased enhancement ratio of drug diffusion to the skin by the enhancers with higher lipophilicity and not due to the increased partitioning. In case of benazepril, correlation was observed between partition coefficient and Kp and between partition coefficient and Km. This result is explained as an increased lipophilicity of enhancers leading to higher diffusion of benazepril into the skin. However, HDNAP was an outlier from correlations in both the occasions. This could be due to the methods used for skin permeation studies using this enhancer. Unlike other enhancers, HDNAP was not soluble in propylene glycol, and therefore, ethanol was used as a co-solvent. The ethanol might have induced a synergistic effect with HDNAP [47].

Above enhancers were tested in-vitro for percutaneous penetration of antipyrine and indomethacin by using rat abdominal skin and the result revealed that these compounds increase the enhancing effect of indomethacin and antipyrine (hydrophilic drug) up to 10 times as much as control [49]. Antipyrine permeation through rabbit abdominal skin was evaluated in vitro by using prepared oligodimethylsiloxanes containing glucose (glucopyranosyl terminated ODMS with ether and thioether linkages) or cellobiose moiety as a terminal group. It was found that permeation of the antipyrine through the rat abdominal skin was increased by the addition of glucose substitution but not by cellobiose [50]. The increase in permeation coefficient was observed when ODMS was substituted with pyridine, ammonia [51], quaternary salt [52] and pyrrolidone [53] as compared to the control.

Alkyldisiloxane is a novel class of transdermal PEs where one or more alkyl groups are bonded with two silicon atoms which in turn are linked by oxygen atom. Among those, oligodimethylsiloxanes (ODMSs) is the most widely used and it has polar substituent at one end to give various modified forms. Due to its higher lipophilicity, it remains in SC without penetration into epidermis which decreases the chance of irritation and inflammation. The synthesis of alkyldisiloxanes containing sugar moiety with various alkyl chain lengths were investigated in order to develop a silicone-based transdermal PE. 1-Alkyl-3-b-D-glucopyranosyl1,1,3,3-tetramethyldisiloxanes (Glc–SiCs) were prepared by two-step hydrosilylations of 1-alkene and 1-allyl-b-Dglucose tetraacetate with 1,1,3,3-tetramethyldisiloxane in the presence of bis(benzonitrile)platinum dichloride as the catalyst followed by hydrolysis of the acetyl groups with sodium methoxide. The mechanism of action of alkyldisiloxane was

O R- Linear T8 Octyl T9 nonyl T10 decyl T11 undecyl T12 dodecyl

branched 2a 7-methyloctyl 2b 8-methylnonyl 2c 9-methyldecyl 2d 10-methylundecyl 2e 11-methyldodecyl 2f 8-ethyldecyl 2g 10-ethyldodecyl

Fig. (8). Linear transkarbams T8-T12 and their methyl- and ethylbranched analogs 2a-2g.

Being a carbamic acid salt, T12 is quite unstable in a mildly acidic environment. Thus, in the SC, where fatty acids comprise approximately 10% of the SC lipids and the average pH is 5.5, its polar head decomposed and release a

Novel Penetration Enhancers for Skin Applications: A Review

Current Drug Delivery, 2012, Vol. 9, No. 2

molecule of CO2. The CO2 release in the SC could cause the disruption of the highly ordered lipid lamellae by changing the hydrogen bonding within the polar heads of the lipids and by conformational changes in the molecule of T12. Such disordering of the lipid lamellae would consequently result in an easier drug permeation route through the skin barrier. This theory is further supported by the fact that the free amine, 6-aminohexanoic acid dodecylester, was inactive [55].

compounds and are soluble in a variety of polar and nonpolar solvents, and their solutions remain stable for several months when stored under normal laboratory conditions [66]. The mechanism of action was contributed by several factors such as increasing partition coefficient, interaction between the enhancer and lipids, interaction between the enhancer with protein (by forming hydrogen bond) and optimal molecular size [66]. Song Y, et al. (2005) investigated several new 4-substituted N-benzoyl-S,S-dimethyliminosulfuranes (Fig. (9)). Among all, bromo- and hexyl-substituted analogs were found to be the most effective enhancers when tested in both hairless mouse skin and human cadaver skin. Bromoiminosulfurane showed the highest enhancement activity [66]. This result was supported by the fact that bromoderivative was kinetically trapped in the bilayer lipid which leads to an enhanced residence time of bromo-derivative in the bilayer and therefore to an explanation for the markedly enhanced activity of the bromo-derivative than to that of other halogenated derivatives in the series of iminosulfuranes studied [67].

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Klimentova J, et al. (2006) synthesized two series of compounds, carbonic and carbamic acid esters, and evaluated for penetration enhancement activity using porcine skin in vitro. The maximum activities observed in the compounds where both chains contained ester or amide group in contrast to those with one simple alkyl chain in either carbonates or carbamates. Among all the compounds, PE activity of T12 was exceptional and was connected to lability of its polar head and quite probably arises from its ability to release CO 2 in SC [55]. With methyl and ethyl branching of T, the activity was decreased as compared to linear one and also the activity of the branched alcohols decreased with increasing the chain length [56].

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Iminosulfuranes are the class of PEs which were synthesized by treating DMSO with trifluoroacetic anhydride, followed by the reaction of the resultant product (S, Sdimethyl-S-(trifluoroacetoxy) sulfonium trifluoroacetate) with an appropriate 4-substituted benzamide. Then the compounds were purified by chromatography using silica gel, followed by eluting with dichloromethane or ethanol and crystallized [65]. Iminosulfuranes are crystalline, colorless

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The potent enhancing effect of traditional PE, dimethyl sulfoxide, on skin penetration was first reported in 1964. The mechanisms of action of DMSO include solvent effect, lipid extraction and disruption, and protein configuration change [59-61]. It has been associated with a number of toxicity and irritancy problems, the extent of which was also concentration-dependent, and this made DMSO undesirable for further use as a percutaneous penetration enhancer [62-64].

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6.5. Iminosulfuranes

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A comparison of PE effect was made among T12 with various terminal groups (carbonate, carbamate, amide, ketone and alkyl) and the result indicates that activity of T12 decreased by replacing oxygen with nitrogen in the terminal group. Furthermore, there was a correlation between their solubility in the aqueous donor solution among carbonate, carbamate, amide, ketone and alkyl analogs. This could explain the highest activity of carbonates as it is more soluble in aqueous donor solution. On the other hand, T12 is poorly soluble in donor solution, which testifies a different mechanism of action (disorderness in the SC lipid). It was concluded that ester group is essential for the activity of T12 and its replacement by carbonate and carbamate analogs not only decreases the enhancing potency, but is likely to change the mechanism of action [57]. The penetration enhancement of adefovir with 1% T12 was highest at pH 4 i.e. T12 action on adefovir permeation was connected to pH-dependent increase of diffusion coefficient or decrease of a diffusion path length. It had no effect on solubility and thermodynamic activity of the drug [58].

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R=F R = Br R=I R = n-butyl R = n-hexyl

Fig. (9). Chemical structure of various substituted Iminosulfuranes.

6.6. Capsaicin and Its Derivatives Capsaicin (8-methyl N-vanillyl-6-nonenamide), is a resin, obtained from the plant of capsicum family. It exerts major therapeutic effects on cardiovascular, respiratory, sensory nervous system and used in the treatment of joint inflammation before the penetration enhancement activity was proved [68]. The above activity is related to its antagonistic effect on substance P, neurokinins and calcitonin gene related peptide [69,70]. Mechanism of action of capsaicin is thought to be its ability to insert itself into the lipid bilayer within the intercellular channels and create disruption in their structure. This reduces the diffusional resistance of the intercellular domains [71]. Capsaicin has side effects like severe burning pain, hyperalgesia and erythema, therefore its commercially available concentration is very less (0.025% to 0.075%) and clinical use is limited [72]. To avoid above side effects, potent synthetic analogs like nonivamide (N-nonanoyl vanillyla-

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mide), and sodium nonivamide acetate (SNA) of capsaicin were synthesized (Fig. (10)).

6.7. Cinnamene Compounds Cinnamene compounds (Fig. (11)) are collected from various species of Cinnamon of family Lauraceae. These volatile oils have numerous activities like carminative, flavoring, antiseptic, dentifrice and perfumes.

Pungency and pharmacological profile of nonivamide is similar to that of capsaicin, and is frequently used for the neurophysiological studies [73,74]. Nonivamide had an enhancement effect on ketoprofen through rat skin at very low concentration (0.025%), but the effect did not conspicuously increase with an increase in nonivamide concentration, which attributed to nonivamide acting in concentration independent manner. In addition, when menthol (5%) and nonivamide (0.025%) were used simultaneously, the penetration enhancement was higher than that of menthol or nonivamide alone. Therefore, the menthol and nonivamide provided different mechanisms to enhance the penetration of ketoprofen gel through rat skin, and gave a synergistic effect [75]. A synergistic enhancement of multi-enhancers (nonivamide, menthol and ethanol) through rat skin with reduced skin irritation was also reported [76]. The permeation of free base of capsaicin analog DA-5018 ([N-[3-(3,4-dimethylphenyl) propyl]-4-(2-aminoethoxy)-3-Methoxyphenyl acetamide) into the deeper layers of the skin via the lipoidal (non-polar) pathway was also reported [77,78].

on

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The mechanism of action was attributed to the formation of hydrogen bond between cinnamene compounds and amides (present in the ceramide) and this bond is stronger than that of hydrogen bond present between amides. Cinnamic acid has the greater activity to form hydrogen bond than cinnamic alcohol and cinnamaldehyde, while the activity of cinnamic alcohol to form hydrogen bond is higher than that of cinnamaldehyde. Therefore, the theory of competitive hydrogen bond explained the penetration flux order of ligustrazine hydrochloride through porcine skin. The penetration capacity of functional groups attached to cinnamene is -COOH > -OH > -CHO that implies order of enhancing effect which is cinnamic acid > cinnamic alcohol  cinnamaldehyde [82]. The same result was reported for cinnamic acid when human skin was used as a model membrane [83]. 6.8. Aloe Vera

n

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The proposed mechanism of Aloe vera is related to the molecular weight of the co-formulated active ingredient (Fig. (12)). In a complex solution of aloe vera and drug at saturation, higher the drug size/molecular weight, the permeation

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Aloe vera (Aloe Barbadensis), commonly known as healing plant, is used for various medicinal, cosmetic and nutraceutical preparations [84]. Aloe vera pulp (generally known as inner gel) is an attractive prospect for topical use due to humectant and skin friendly characteristic [85].

bu

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The higher plasma concentration of SNA was obtained in the early period after in vivo transdermal application from hydrophilic ointment. The result may be due to the fact that SNA molecules passed through skin via the intercellular and transappendageal routes since the permeation through the hair follicles is higher than that through SC [79]. The transdermal transport of SNA was increased through rat skin with a pretreatment with cationic surfactant (cetylpyridinium chloride) [80]. In another study, the permeation of SNA was increased by replacing ethanol with n-propanol which could be due to increased SNA solubility and decreased the diffusional barrier property of SC in the presence of n-propanol [81]. CH 3

fo

O

HO

CH 3

N

ot

NH

CH 3

O

Capsaicin

CH 3 O HO

NH CH 3 O

Nonivamide CH3

O

O O

Na O NH CH3 O

Sodium Nonivamide Acetate

Fig. (10). Chemical structure of capsaicin and its derivatives.

Novel Penetration Enhancers for Skin Applications: A Review

Current Drug Delivery, 2012, Vol. 9, No. 2

O H

227

O

O

OH

Cinnamic alcohol

Cinnamyldehyde

Cinnamic acid

Fig. (11). Chemical structure of Cinnamene compounds.

Enhancement Lower enhancement

Higher enhancement

Reduced interaction with enhancing factor

Greater interaction with enhancing factor

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Drug Molecular Weight

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Small

n

Lower Aloe Vera component permeation, Due to high displacement of Aloe Vera

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from pathway

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from pathway

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Higher Aloe Vera component permeation, Due to low displacement of Aloe Vera

Large

tri

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% Aloe Vera permeation

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Fig. (12). Flowchart summarizing the proposed mechanism behind the observed permeation enhancement behavior of Aloe Vera.

Clove oil was obtained from Eugenia Caryophyllata by supercritical fluid technology and was incorporated into topical gel formulation to investigate its penetration activity. The penetration enhancement ratio of clove oil was found to be 7.3, as compared to control at lower concentration of 1% and 5%, when ibuprofen and rabbit skin were used as model drug and model membrane, respectively for permeation study. It is also known that the content of eugenol was nearly 82% and acetyleugenol was 8% in clove oil, therefore, it is most probably that the effects of the oil on enhancing transdermal delivery of ibuprofen are attributed to eugenol and acetyleugenol. Moreover, it acts by increasing the fluidity of the SC lipid [87].

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routes will be more effectively blocked, and a consequence of this is that it will allow increased scope for the drug to interact with the enhancing factor and complex with it before being transported across the skin. This phenomenon can be rationalized in terms of the scope for interaction and complexation of the drug with the enhancing factor present in aloe vera gel, and in terms that it increases thermodynamic activity. Smaller molecules are seemingly less effective at blocking aleo vera from permeation pathways. Thus, if more of an enhancing factor is ‘lost’ from the solution as a result of its permeation, then there will be reduced opportunity for the drug to interact with it, and subsequently less permeation through the skin [86]. 6.9. Terpenes (Clove oil & Basil Oil)

Terpenes are found in essential oils and are comprised of only carbon, hydrogen and oxygen atoms. Of the PEs, terpenes are arguably the most highly advanced and proven category and are classified as generally regarded as safe (GRAS) by the Food and Drug Administration. Numerous terpenes have long been used as medicines, fragrance and flavoring agents. For example, menthol is traditionally used in inhalation pharmaceuticals and has a mild antipruritic effect when incorporated into emollient preparations. It is also used as a fragrance and to flavor toothpastes, peppermint sweets and menthylated cigarettes.

Basil oil, a volatile oil is obtained from the leaves of Ocimum basilicum (Lamiaceae formerly Labiatae family). Linalool (62%) is the major constituent present in basil oil. Basil oil interacts more competitively with the amide groups of the ceramides due the to presence of alcohol group, as the oxygen atom of alcohol group is more electronegative. This leads to the formation of a competitive hydrogen bonding between ceramides of SC and basil oil, leading to the disruption of barrier provided by transverse hydrogen bonding between lipid bilayers, and the creation of new pathways for the molecular permeation. This facilitates the permeation of labetalol hydrochloride across the skin of rat at higher concentration (enhancement ratio of 46.52) in the presence of basil oil at a concentration of 5%, whereas other terpenes

228 Current Drug Delivery, 2012, Vol. 9, No. 2

Parhi et al.

(camphor, clove oil, geraniol and thymol) showed less enhancement than basil oil [88].

tion upon touching the skin because of differential retention in skin. All SCOPE formulations exhibited ‘S’ value greater than 1 with ‘S’ value of 9 as the highest for BDAC:LA, which means positive synergistic effect. They also exhibited irritation potential less than 10. PEs used to enhance permeation of various active ingredients are represented in Table 1.

6.10. Synergistic Combinations of Penetration Enhancers (SCOPE) Several classes of CPEs have been studied for permeation enhancement. However, only few induce a therapeutic enhancement of drug transport. This problem is aggravated for drug having high molecular weight. In addition, potent enhancers are also potent irritants to the skin at the concentration required to induce sufficient penetration enhancement [89]. Thus, improved enhancement by single enhancers inevitably leads to compromise on safety issue.

Clearly above novel PEs (natural or chemical) offer potential advantages in delivering broad range of therapeutic agents (either small or large molecules), ease of administration (as compare to transdermal spray), speed of administration, sustained therapy through specifically designed controlled release product (e.g. patches).

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No doubt there is a large increase in use of topical formulation because of patient compliance. However, there are significant differences in transdermal drug penetration among various species (e.g. mouse, rat, guinea pig, monkey or pig) used in percutaneous testing. In particular, the type and higher density of hair follicles in the animal species may contribute to difference in transdermal drug permeation. In addition, in animal and human many drugs show significant regional differences in transdermal penetration. Apart from the above factors, other parameters like physicochemical properties of the tested compound and delivery systems, possible skin pretreatment and environmental factors are also influencing the permeation of drug through skin. So, there is a need to create correlation between in-vitro/in-vivo data obtained in animals and in humans. It is apparent that if diverse classes of drug are to be delivered via the transdermal route then most will require substantial enhancer augmentation because of generally poor intrinsic diffusivity. The field of transdermal drug delivery, with the use of PEs, has become more prevalent and a growing trend with new discovery of PEs.

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List of Penetration Enhancers with Active Ingredient

Penetration Enhancers

Active Ingredients

References

2-(1-nonyl)-1,3-dioxolane (ND)

Minoxidil Dapiprazole Indomethacin and Alprostadil

[41] [43] [44]

N-acetyl prolinate esters

Alkyl esters of N-acetyl prolinate

Benazepril Hydrocortisone and Estradiol

[45] [46]

Alkyldisiloxane

Glc-Sics

Antipyrine and Indomethacin

[53]

SEPA

N

ot

Group

fo

Table 1.

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To overcome the above problems, new family of safe and potent permeation enhancer designated as Synergestic Combinations of Penetration Enhancers was developed [90]. SCOPE means the combination of novel PEs like sodium laureth sulfate (SLA) with phenyl piperazine (PP), N-lauroyl sarcosine (NSA) with sorbitan monooleate (S20) and benzyl dimethyl dodecyl ammonium chloride (BDAC) with lauric acid (LA). The above SCOPE formulations were incorporated into transdermal patch and then evaluated in vitro for flux enhancement with macromolecules like LHRH (MW1.2 KDa), oligonucleotide (MW-15KDa) and light weight heparin (LMW-10KDa) as model drugs. Upon confirmation of flux enhancement, the formulations were subjected to in vivo study for bioavailability and potential irritation assessement test for safety. Then, a novel technique called in vitro skin impedance guided throughput (INSIGHT) was used to screen the above combinations, followed by quantification of the synergistic effect of enhancers by defining a parameter (S) which quantitatively describe the potency of a binary formulation compared to the weighted mathematical average of the individual potency at the same concentration. These combinations exhibit high potency and lack of irrita-

7. CONCLUSIONS

Transkarbam

Transkarbam-12

Adefovir

[58]

Iminosulfuranes

Bromo- iminosulfurane

Hydrocortisone and Caffeine

[67]

Capsaicin and its derivatives

Capsaicin Nonivamide

Naproxan Ketoprofen

[71] [75]

Cinnamene compounds

Cinnamic acid, cinnamyl alcohol

Ligustrazine hydrochloride

[82]

Glycosides

Aloe vera pulp

Colchicine, Mefenamic acid, Oxybutynin and Quinine

[86]

Terpenes

Clove oil Basil oil

Ibuprofen Labetalol hydrochloride

[87] [88]

SCOPE

Sodium laureth sulfate (SLA) Phenyl Piperazine (PP

LHRH, oligonucleotides, Heparin, Methotrexate

[90]

Novel Penetration Enhancers for Skin Applications: A Review

Current Drug Delivery, 2012, Vol. 9, No. 2 [25]

CONFLICT OF INTEREST None declared.

[26]

ACKNOWLEDGEMENT [27]

None declared. REFERENCES

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Received: June 24, 2011

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Revised: August 17, 2011

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Parhi et al.

Accepted: September 09, 2011

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