chemical penetration enhancers- a review

www.wjpps.com Vol 3 Issue 2 2014.

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Shelke et al. World Journal of Pharmacy and Pharmaceutical Sciences

CHEMICAL PENETRATION ENHANCERS- A REVIEW

Shelke Suvarna Jagannath*, Shinkar Dattatraya Manohar1,

Saudagar Ravindra Bhanudas2

*1Department of Pharmaceutics, KCT’s RGS College of Pharmacy, Anjeneri, Nashik.422

213.Maharashtra, India. 2Department of Pharmaceutical Chemistry, KCT’s RGS College of Pharmacy, Anjeneri,

Nashik.422213.Maharashtra.

ABSTRACT

The transdermal route has been identified as one of the highly potential

routes of systemic drug delivery and provide the advantages of

escaping of the first-pass effect, ease of use and withdrawal (in case of

side effects), and better patient compliance.Skin as an important site of

drug application for both local and systemic effects. However, the

major limitation of this route is the difficulty of permeation of drug

through the skin. To improve the transdermal drug delivery,

penetration enhancers are used which penetrate into skin to reversibly

decrease the barrier resistance. Chemical enhancers that aid absorption

of co-administered moieties are currently believed to improve

solubility within the stratum corneum or increase lipid fluidity of the

intracellular bilayers. This review concern with the detail information

of advantages, mechanism of action of chemical penetration enhancer and different chemical

penetration enhancers used in transdermal drug delivery.

Keywords- Transdermal drug delivery, Skin, Chemical penetration enhancers.

INTRODUCTION

Transdermal route offers several potential advantages over conventional routes like

avoidance of first pass metabolism, predictable and extended duration of activity, minimizing

under able side effects, utility of short half-life drugs, improving physiological and

pharmacological response, avoiding the fluctuation in drug levels, inter and intra patient

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Article Received on 10 November 2013, Revised on 03 December 2013, Accepted on 05 January 2014

*Correspondence for

Author:

Suvarna Jagannath Shelke

Department of Pharmaceutics,

KCT’s RGS College of

Pharmacy, Anjeneri,

Nashik.422 213.Maharashtra,

India.


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valuations, and most importantly, it provides patient convenience. But one of the major

problems in transdermal drug delivery is the low penetration rate through the outer most layer

of skin [1].

The skin is a largest single organ of the body. Drug delivery through skin is one of the major

functions of the skin. But skin serves as a barrier for the drugs to pass through it [2].

Percutaneous absorption involves the passage of the drug molecule from the skin surface into

the stratum corneum under the influence of a concentration gradient and its subsequent

diffusion through the stratum corneum and underlying epidermis, through the dermis, and

into the blood circulation. The skin behaves as a passive barrier to the penetrant molecule.

The stratum corneum provides the greatest resistance to penetration, and it is the rate-limiting

step in percutaneous absorption [3].

PENETRATION ENHANCER

Penetration enhancers are the agents which help in the absorption of penetrant through the

skin by temporarily lowers the impermeability of the skin. Ideally, these substances should be

pharmacologically inert, nonirritating, nontoxic, non-allergenic, and compatible with the

drugs and excipients, odorless, tasteless, colorless, and inexpensive and also have good

solvent properties. The enhancer should not show the loss of body fluids, electrolytes, and

other endogenous materials, and on its removal the skin should quickly regain its barrier

nature. No single penetration enhancer having all the required properties [4].

The stratum corneum is the site of activity of the chemical penetration enhancers. Whilst the

mechanisms by which these compounds are thought to promote permeation are now only

beginning to be elucidated, their activity is thought to be a result of multiple effects within

the diverse biochemical environments of this layer. We currently believe that most chemical

enhancers are active by spatial disruption of the normally ordered arrangement of the

intercellular molecules. It is the uniform, ordered nature of this biochemical, especially lipid

bilayers, which maintain and promote the diffusional resistance of the barrier. In addition,

modification of the intracellular environment of the coenocyte may also be influential in the

penetration of certain classes of drug. The range of the biochemical components found in the

barrier layers suggests that penetration enhancer chemicals from diverse family groups

should be effective in promoting percutaneous penetration. The range of chemical enhancers

that have been researched to date is vast; a review of the most promising enhancers from the

different classes has already been presented [5].


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IDEAL CHARACTERISTICS OF CHEMICAL PENETRATION ENHANCERS [6, 7]

Barry and Williams have described the attributes of the ideal penetration enhancer.

They should have no pharmacological activity within the body. i.e. should not bind to

receptor sites.

It should be nontoxic, non-irritating, and non-allergenic.

Onset of action should be rapid, and duration of activity should be predictable and

suitable for the drug used.

Upon removal of the enhancer, the horny layer should be immediately and fully recover

its normal barrier property.

When removed from the skin, barrier properties should return both rapidly and fully.

The accelerant should be chemically and physically compatible with all drugs and

adjuvants to be formulated in topical preparations and devices.

If liquid and to be used at high volume fractions, it should be suitable solvent for drugs.

It should spread well on the skin, with a suitable skin “feel”.

It should readily formulate into dermatological preparations, transdermal devices, and

skin adhesives.

MECHANISM OF CHEMICAL PENETRATION ENHANCEMENT [8]

Penetration enhancers may act by one or more of three main mechanisms,

1. Disruption of the highly ordered structure of stratum corneum lipid.

2. Interaction with intercellular protein.

3. Improved partition of the drug, coenhancer or solvent into the stratum corneum.

The enhancer act by altering one of three pathways. The key to altering the polar pathway is

to cause protein conformational change or solvent swelling. The fatty acid enhancers

increased the fluidity of the lipid protein portion of the stratum corneum. Some enhancers act

on both polar and nonpolar pathway by altering the multilaminate pathway for penetration.

Enhancers can increase the drug diffusivity through skin proteins. The type of enhancer

employed has a significant impact on the design and development of the product. A useful

way to consider factors affecting drug permeation rate through the stratum corneum is via the

simple equation given below for steady state flux. If we plot the cumulative mass of

diffusion, m, passing per unit area through the membrane , at long time the graph approaches

linearity and its slope its yield the steady flux dm/dt,

dm/dt = D Co K /h---------------------------- (1)


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WhereCo 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. From the above equation, we deduce the ideal properties of a

molecule that would penetrate stratum corneum well. These are:

Low molecular mass, preferably less than 600Da, when D tends to be high.

Adequate solubility in oil and water so that membrane concentration gradient may be

high.

High but balanced (optimal) K (if too large, may inhibit clearance by viable tissue).

Low melting point, correlating with good solubility as predicted by ideal solubility

theory.

FUNCTION OF PERMEATION ENHANCER [9]

On the basis of lipid protein partitioning concept, there are three main functions of

penetration enhancers

Lipid disruption: The enhancers change the structure of stratum corneum lipid organization

and make it permeable to drugs. Many enhancers operate mainly in this way e.g. Azone,

terpenes, fatty acids, dimethyl sulfoxide (DMSO) and alcohols.

Protein modification: Ionic surfactants, decyl methyl sulfoxide and DMSO interact with

keratin in corneocytes and open up the dense protein structure and make it more permeable.

Partitioning promotion: Many solvents change the solution properties of the horny layer

and thus increase the partitioning of a drug, co enhancer and co solvent. Ethanol increases the

penetration of nitro-glycerin and estradiol through the stratum corneum.

CHEMICAL CLASSES OF PERMEATION ENHANCERS

A. Cyclodextrines

B. Sulfoxides

C. Alcohols

D. Alkanes

E. Surface active agent

F. Fatty acids

G. Esters

H. Essential oil, terpenes and terpenoids

I. Amines and Amides

1) Urea


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2) Dimethylacetamide and dimethylformamide

3) Pyrrolidones

L. Azone

Cyclodextrin

Cyclodextrines are biocompatible substances that can form inclusion complexes with

lipophilic drugs with a resultant increase in their solubility, particularly in aqueous solutions

[10]. However,cyclodextrins alone were determined be to less effective as penetration

enhancers than when combined with fatty acids and propylene glycol [11].Cyclodextrins are

large molecules, with molecular weights greater than 1000Daltons, therefore it would be

expected that they would not readily permeate the skin. Complexation with cyclodextrins has

been variously reported to both increase and decrease skin penetration [12, 13]. In a recent

review of the available data, Lofts son and Mass on concluded that the effect on skin

penetration may be related to cyclodextrin concentration, with reduced flux generally

observed at relatively high cyclodextrin concentrations, whilst low cyclodextrin

concentrations resulting in increased flux [14].

Sulfoxides and similar chemicals

Dimethyl sulphoxides (DMSO) is one of the earliest and most widely studied penetration

enhancers. It is a powerful aportic solvent which hydrogen bonds with itself rather than with

water. It is colourless, odourless and is hydroscopic and is often used in many areas of

pharmaceutical sciences as a “universal solvent”. DMSO alone has been applied topically to

treat systemic inflammation. DMSO works rapidly as a penetration enhancer - spillage of the

material onto the skin can be tasted in the mouth within a second. Although DMSO is an

excellent accelerant, it does create problems. The effect of the enhancer is concentration-

dependent and generally cosolvents containing > 60% DMSO are needed for optimum

enhancement efficacy [15]. However, at these relative high concentrations, DMSO can cause

erythema and wheal of the stratum corneum. Denaturing of some skin proteins results in

erythema, scaling, contact urticarial, stinging and burning sensation [16]. Since DMSO is

problematic for use as a penetration enhancer, researchers have investigated a similar

chemically-related material as an accelerant. Dimethylacetamide (DMAC) and

dimethylformamide (DMF) are similarly powerful aportic solvents. However, South well and

Barry, showing a 12-fold increase in the flux of caffeine permeating across a DMF-treated

human skin, concluded that the enhancer caused irreversible membrane damage [17]. DMF


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irreversibly damages human skin membranes but has been found in vivo to promote the

bioavailability of betamethasone-17-benzoate as measured by vasoconstrictor assay [18, 19].

Alcohol

Alcohols may influence transdermal penetration by a number of mechanisms. The alkyl chain

length of the alkanols (fatty alcohols) is an important parameter in the promotion of

permeation enhancement. Augmentation appears to increase as the number of carbon units

increases, up to a limiting value. In addition, lower molecular weight alkanols are thought to

act as solvents, enhancing the solubility of drugs in the matrix of the stratum corneum [20].

Disruption of the stratum corneum integrity through extraction of biochemical by the more

hydrophobic alcohols almost certainly also contributes to enhanced mass transfer through this

tissue [21]. Ethanol is the most commonly used alcohol as a transdermal penetration

enhancer. The molecular complexity of different glycol molecules is a determinant of their

efficacy as permeation enhancers. Solubility of the drug in the delivery vehicle is markedly

influenced by the number of ethylene oxide functional groups on the enhancer molecule; this

solubility modification may either enhance or retard transdermal flux depending on the

specific drug and delivery environment. The activity of propylene glycol (PG) is thought to

result from solvation of α keratin within the stratum corneum; the occupation of

proteinaceous hydrogen bonding sites reducing drug-tissue binding and thus promoting

permeation [22]. Ethanol acts as a penetration enhancer by extracting large amounts of

stratum corneum lipids. It also increases the number of free sulphydryl groups of keratin in

the stratum corneum proteins. Usually, pretreatment of skin with ethanol increases the

permeation of hydrophilic compounds, while it decreases that of hydrophobic ones [23].

Alkanes

Long chain alkanes (C-C) have been shown to enhance skin permeability by non-destructive

alteration of the stratum corneum barrier [24]. These findings were confirmed in studies in

which nonane was investigated as an enhancer, although there must be some destructive

solubilization and biochemical extraction caused by these lipophilic solvents [25].

Surfactants

Many surfactants are capable of interacting with the stratum corneumto increase the

absorption of drugs and other active compounds from products applied to the skin. Skin

penetration measurements are valuable in quantifying these effects and observing the

influence of surfactant chemistry and concentration. A surfactant interacts with skin by


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depositing onto the stratum corneum, there by disorganizing its structure. Then surfactant can

solubilize or remove lipids or water-soluble constituents in or on the surface of the stratum

corneum. Finally it can be transported into and through the stratum corneum. This last effect

is related to the surfactant and stratum corneum protein interaction and epidermal keratin

denaturation [26].

Examples [27]

Anionic surfactants- sodium lauryl sulfate, sodium laureth sulfate

Cationic surfactants- quaternary ammonium chloride

Non-ionic surfactants-Span 20, Span 80, Tween 80

Fatty acids

Selective perturbation of the intercellular lipid bilayers in the stratum corneum appears to be

the major mode of enhancing activity of the fatty acids [28]. Oleic acid is common mono-

saturated fatty acid and is reported to increase the permeation of lipophilic drug through skin

and buccal mucosa by transdermal cellular pathway. Most of these molecule when apply onto

the skin surface permeate along the stratum corneum lipid domain and the organization of

these regions is very important for the barrier function of the skin [29].

Esters

Esters such as ethyl acetate are relatively polar, hydrogen bonding compounds that may

enhance permeation in a similar manner to the sulphoxides and formamides by penetrating

into the stratum corneum and increasing the lipid fluidity by disruption of lipid packing [30].

A similar mode of action is proposed for isopropyl myristate. The lipophilic esters may

influence partitioning between vehicle and skin by solubilization effects [31].

Essential oil, terpenes and terpenoids

Terpenes are present in naturally occurring volatile oils appears to be clinically acceptable

enhancer. Moreover, the wide variety of terpenes have been shown to increase the

percutaneous absorption of number of drugs or terpenes, the naturally occurring volatile oils,

are considered as clinically acceptable penetration enhancers as indicated by high

percutaneous enhancement ability, reversible effect on the lipids stratum corneum and low

cutaneous irritancy at lower concentration (1-5%). Moreover, terpenes have been shown to

increase the skin permeation of a number of drugs. A number of terpenes are used such as

cyclic mono-terpenes limonene and cineole hydrocarbons and alcohols, menthols, ketones,


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camphor, carvone are used as penetration enhancers. Camphor is readily absorbed through

the skin and produces a feeling of cooling. Eugenol is component of clove, may reduce the

ability to feel and react to painful stimulation. Menthol is an organic compound made

synthetically obtained from peppermint or other mint oils. Menthol has ability to chemically

trigger the cold sensitive. Cineole has been used to promote the percutaneous absorption of

several lipophilic drug through hairless mouse skin. [32]

Amines and Amides

a) Urea

Urea promotes transdermal permeation by facilitating hydration of the stratum corneum and

by the formation of hydrophilic diffusion channels within the barrier. Cyclic urea permeation

enhancers are biodegradable andnon-toxic molecules consisting of a polar parent moiety and

a long chain alkyl ester group. As a result, enhancement mechanism may be a consequence of

both hydrophilic activity and lipid disruption mechanism [33].

b) Dimethylacetamide and dimethylformamide-

These compounds are less potent penetration enhancing chemical alternatives to DMSO. At

low concentrations their activity as enhancers is a result of partitioning into the keratin

regions. At higher concentrations they increase lipid fluidity by disruption of lipid packing as

a result of solvation shell formation around the polar head groups of the lipids [34].

c) Pyrrolidones

Pyrrolidone and its derivatives are reported to interact with both keratin and with lipids in the

skin. Azone is known to show significant accelerant effects at low concentrations for both

hydrophilic and hydrophobic drugs and is one of the few enhancers that have been developed

commercially. Differential scanning calorimetric studies have shown that azone affects lipid

structures of the stratum corneum [35].

Azone

Azone (1-dodecylazacycloheptan-2-one or laurocapram) was the first molecule or agent

which was specifically designed as a skin penetration enhancer. Azone possesses a smooth,

oily but yet non greasy feel. It is a colorless, odorless liquid with a melting point of -7 °C.

Azone is a highly lipophilic material and it is soluble in and also compatible with the most

organic solvents including alcohol and propylene glycol. It increased the skin transport of a

wide variety of drugs including steroids, antibiotics and antiviral agents. Azone is basically


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most effective at low concentration. Usually it is employed typically between 0.1- 5% but

more often between 1- 3%. Azone partitions into the bilayer lipid for disrupting their packing

arrangement but also integrated into the lipid this process is opposite to be homogeneous. It

may exist as dispersed within the barrier lipoid or separate domains within the bilayer [36]

Table no.1- Examples of Chemical penetration enhancers reported in literature [37-49]

Sr.No. Name of Drug Penetration Enhancers Reference

1 Sodium salicylate Azone Hadgraft et al.(1985)

2 Flurbiprofen Azone Ma et al.(2010)

3 Leuprolide Urea Lu et al. ( 1992)

4 Haloperidol Urea Vaddi et al.( 2009)

5 Morphine Surfactants Monti et al.(2001)

6 Retinol Surfactants Mélot et al.( 2009)

7 Verapamil hydrochloride Terpenes Güngör et al. (2008)

8 Minoxidil Terpenes Mura et al.(2009)

10 Daphnetin Fatty acids Wen et al.(2009)

11 Nitrendipin Fatty acids Mittal et al. ( 2008)

13 Tizanidine hydrochloride Alcohols Mutalik et al. (2009)

14 Propanolol Pyrrolidones Amnuaikit et al. (2005)

16 Itraconazole cyclodextrins Shah et.al. (2012)

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chemical penetration enhancers- a review

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