Jaydatt K Jadhav et al.

, IJSID, 2012, 2 (6), 204-217

ISSN:2249-5347

IJSID

International Journal of Science Innovations and Discoveries

An International peer Review Journal for Science

Available online through www.ijsidonline.info Jaydatt K Jadhav1* S.A. Sreenivas2

REVIEW ON CHEMICAL PERMEATION ENHANCER USED IN TRANSDERMAL DRUG DELIVERY SYSTEM scholar, Pharmaceutical Sciences Department, J.J.T. University,Chudela, Jhunjhunu, Rajasthan, India;
2Grurunanak

Institute of Pharmacy, Ibrahimpatnam. Dist. RR, Hydrabad, AP, India.

Received: 03-12-2012 Accepted: 29-12-2012

complexity of transdermal drug delivery. Elucidation of the biochemical enhancing the percutaneous penetration of poorly absorbed drugs. Skin as an important site of drug application for both local and systemic effects However in

composition and functioning of the intrinsic diffusion barrier of the stratum corneum has prompted investigation of chemical and physical means of enhancement technology is a challenging development that would increase the drug through skin can be enhanced by chemical penetration enhancement enhancement technology for transdermal drug delivery as well as the probable mechanism of action. enhancers Keywords: Transdermal delivery; skin; percutaneous penetration; chemical skin, the stratum corneum is the main barrier for drug penetration. Penetration

It is clear that scientists are now only beginning to comprehend the

Address: Name: Jaydatt K Jadhav Place: Jhunjhunu, Rajasthan, India E-mail: jaydatt_jadhav@ rediffmail.com

number of drugs available for transdermal administration. The permeation of methods. In this review, we have discussed the chemical penetration INTRODUCTION

INTRODUCTION

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numbers of drugs are being added to the list of therapeutic agents that can be delivered to the systemic circulation via skin. Transdermal delivery of drugs through the skin to the systemic circulation provides a convenient route of for systemic effects, the comprehensive morphological, biophysical and physicochemical properties of the skin are drug release can be achieved by transdermal drug delivery systems which can deliver medicines via the skin portal administration is recognized as one of the potential route for the local and systemic delivery of drugs. Transdermal

administration for a variety of clinical indications 1.In order to deliver therapeutic agents through the human skin approach evolves, which facilitates the drug release into systemic circulation at a pre-determined rates. Controlled to systemic circulation at a predetermined rate over a prolonged period of time. The transdermal route of delivery not only provides controlled, constant administration of the drug, but also allows continuous input of drugs with short biological half-lives and eliminates pulsed entry into systemic circulation, which often causes efficiency and maintenance of steady plasma level of the drug sustained drug delivery, reduced frequency of administration, reduced side effects and improved patient compliance . Routes of penetration through the skin 3, 4, 5

Currently, transdermal drug delivery is one of the most promising methods for drug application. Increasing INTRODUCTION

to be considered. To address these problems in controlled release drug delivery system, a novel drug delivery

undesirable side effects. In comparison to conventional pharmaceutical dosage forms, transdermal drug delivery system offer many advantages2, such as elimination of first pass metabolism, enhancement of therapeutic Flynn has described the process of percutaneous absorption as follows: when a drug system is applied

topically, the drug diffuses passively out of its carrier or vehicle and into the surface tissue of the skin specifically A concentration gradient is thus established across the skin, which essentially terminates at the outer reaches of

and most importantly the stratum corneum and the sebum filled pilo sebaceous gland ducts. A net mass movement continues through the full thickness of the stratum corneum and ducts into the viable epidermis and dermal strata. concentration of the drug is maintained at the plane where drug reaches the capillaries and is diluted into the concentrations of some drugs may be obtained by reason of the fact that the epidermis is without a direct blood epidermis Barry and Williams have described the attributes of the ideal penetration enhancer. CHEMICAL PERMEATION ENHANCERS [6] It should be nontoxic, non-irritating, and non-allergenic. general system. Once the drug is in general circulation it distributes very rapidly, and gives reasonable rates of

the skins microcirculation in the dermal layer. The systemic circulation acts as a sink for the drug and near zero systemic metabolism and elimination, i.e. there is generally systemic build up. Thus relatively high epidermal

supply and the concentration gradient from the outer surface to the microcirculation cuts directly through the It should be pharmacologically inert, possessing no action of itself at receptor sites anywhere in the body.
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 Upon removal of the enhancer, the horny layer should be immediately and fully recover its normal barrier property. to the environment by diffusion out of the skin.

The barrier function of the skin should reduce in one direction only. Endogenous materials should not be lost

Onset of action should be rapid, and duration of activity should be predictable and suitable for the drug used.
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The accelerant should be chemically and physically compatible with all drugs and adjuvants to be formulated in 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. FUNCTION OF PERMEATION ENHANCER [7] It should readily formulate into dermatological preparations, transdermal devices, and skin adhesives. topical preparations and devices.

Figure 1: A multilayer skin model showing sequence of Transdermal Permeation of drug for systemic delivery

Lipid disruption: The enhancers change the structure of stratum corneum lipid organization and make it sulfoxide (DMSO) and alcohols. and open up the dense protein structure and make it more permeable. through the stratum corneum

permeable to drugs. Many enhancers operate mainly in this way [e.g. Azone, terpenes, fatty acids, dimethyl Partitioning promotion: Many solvents change the solution properties of the horny layer and thus increase the
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On the basis of lipid protein partitioning concept, there are three main functions of penetration enhancers

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

partitioning of a drug, co enhancer and co solvent. Ethanol increases the penetration of nitro-glycerin and estradiol

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Solvents: Water, alcohols, alkyl methyl sulfoxide (dimethyl sulfoxide), dimethyl acetamide and dimethyl CHEMICAL CLASSES OF PERMEATION ENHANCERS [8] formamide, etc Azones Terpenes, terpenoids and essential oils Pyrrolidones Fatty acids and esters Surfactants Bile salts Miscellaneous chemicals Prodrug approach WATER [9] primary measures to increase the penetration of both hydrophilic and lipophilic permeate. Free water within the tissue could alter the solubility of a permeate in the stratum corneum. Also increased skin hydration may swell and may not always increase drug permeation. ALCOHOLS [10, 11, 12, 13,] These include alkanols, alkenols, glycols, polyglycols and glycerols. Alcohols can enhance skin permeation Water is the most natural penetration enhancer. Usually, hydration of the stratum corneum is one of the

open up the compact structure of the stratum corneum, leading to an increase in penetration. But Raised hydration by a variety of mechanisms such as extraction of lipids and proteins, swelling of the stratum corneum or improving drug partitioning into the skin or solubility of the drug in the formulation. Ethanol increases the permeation of Propylene glycol promotes the flux of heparin sodium and verapamil hydrochloride. Its mechanisms of action are

ketoprofen from a gel-spray formulation and triethanolamine salicylate from a hydrophilic emulsion base. enhances the partitioning of papaverine Short-chain glycerides are also effective as permeation enhancers (e.g., TCP). For instance, glycerin tricaprylate (caprylic acid triglyceride) in combination with ethanol is used as a solvent fluidity of the lipoidal membrane of the stratum corneum. SULPHOXIDES AND SIMILAR CHEMICALS [14-21] system. TCP is an excellent hydrophobic vehicle and promoted the permeability of tegafur combined with ethanol. chain glyceride, increased the permeation of papaverine hydrochloride by almost 820 times by increasing the

probably similar to those suggested above for ethanol. Short chain glycerides, for instance, glyceryl monocaprylate Glyceryl monocaprylate enhanced the partitioning of papaverine across hairless rat skins. Sefsol 318, a medium-

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Structure - Dimethyl sulphoxides (DMSO)

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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 the material onto the skin can be tasted in the mouth within a second. Although DMSO is an excellent accelerant, it > 60% DMSO are needed for optimum enhancement efficacy. DMSO may also extract lipids, making the horny layer conformation, from _helical to shee. AZONE [22, 23, 24, 25,]

been applied topically to treat systemic inflammation. DMSO works rapidly as a penetration enhancer - spillage of more permeable by forming aqueous channels. The mechanism of the sulphoxide penetration enhancers is widely

Dimethyl sulphoxides (DMSO) is one of the earliest and most widely studied penetration enhancers. It is a
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does create problems. The effect of the enhancer is concentration-dependent and generally co solvents containing used to denature protein and, on application to human skin, has been shown to change the intercellular keratin

penetration of large range of drugs like indomethacin, urea, methadone, 5-fluorouracil, propanol hydrochloride. Azone increases penetration through stratum corneum by affecting the both lipophilic and hydrophilic route of in human epidermis is an order of magnitude smaller than for mouse skin with the duration of Azone treatment required to achieve the full effect in human epidermis being twice that for mouse skin. ESSENTIAL OILS, TERPENES AND TERPENOIDS [26] possesses lipid-fluidizing ability and shows a strong facilitating effect on drug permeation. The peak permeability

penetration. Azone by increasing the fluidity of layer and partition in the aqueous region helps in increasing the penetration of hydrophilic drugs. An experiment on transdermal permeation of beta-blockers revealed that azone

For transdermal drug delivery, azone is one of the major classes of permeation enhancers. It enhances the

Structure -Azone (laurocapran; 1-dodecylazacycloheptan-2-one)

Essential oils, terpenes and terpenoids components of essential oils defined and classified by the isoprene rule.

They are designated as generally recognized as safe (GRAS) by FDA. These chemicals have been mostly used in

perfumery and other cosmetics. Mostly in numbers of monoterpenes enhance the permeation of various drugs in transdermal drug delivery. Carvone and eucarvone are classified as ketone monoterpene and terpenoids,
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Terpenes and terpenoids are appropriate skin penetration enhancers with low toxicity and irritancy.

Structure limonene and menthone

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respectively.The essential oils of eucalyptus, chenopodium and ylang-ylang have been used to be effective
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penetration enhancers for 5-flouorouracil transversing human skin. PYRROLIDONES [27, 28, 29]

pyrrolidone enhances permeation through the polar route of the skin by increasing the diffusivity, and reduces

passage through the non polar route by decreasing diffusivity and partitioning. Pyrrolidones have been used as as a penetration enhancer for captopril when used into a matrix type transdermal patch. FATTY ACIDS AND ESTERS [30, 31]

permeation enhancers for various molecules with hydrophilic (e.g. 5-fluorouracil and sulphaguanidine) and lipophilic (betamethasone-17- benzoate and progesterone) permeate. In recent studies, higher flux enhancements have been studied for the hydrophilic molecules. Recently N-methyl-2-pyrrolidone is working with limited success

2-pyrrolidone and N-methyl-2-pyrrolidone are the most widely used enhancers of this group. 2-

Structure - 2-pyrrolidone and N-methyl-2-pyrrolidone

been seen that unsaturated fatty acids are more effective in enhancing percutaneous absorption of drugs than their Moreover, they have a greater enhancing effect on lipophilic drugs. Addition of oleic acid to an Ethanol: water whereas addition of the same to ethanol: TCP (50:50) produced no enhancement across hairless rat skin. It was suggested that viscous TCP reduced the thermodynamic activity of oleic acid. Oleic acid was found to be the most

saturated counterparts. Chi et al. reported an increase of 6.5-fold to 17.5-fold in the permeation rate of flurbiprofen through rat skin by unsaturated fatty acids, while no significant increase was observed with saturated fatty acids.

A large number of fatty acids and their esters have been used as permeation enhancers. A general trend has

Structure cetyl lactate and oleic acid

(50:50) co-solvent system markedly improved the skin permeation of zalcitabine, didanosine, and zidovudine, efficient enhancer for piroxicam, followed by linoleic acid. Sodium oleate was found to be a better permeation enhancer than oleyl oleate when tested on indomethacin and urea. The fatty acid extract of cod liver oil was found palmitoleic acid, which resulted in a 640-fold increase in hydrocortisone flux through hairless mouse skin.

to be as good a permeation enhancer as oleic acid. The most effective transdermal penetration enhancer was

Incorporation of pure cod liver oil in a PG vehicle did not improve the hydrocortisone permeability, suggesting that the unsaturated fatty acids have to be in the free form to be able to act as skin permeation enhancers. A 1- hr. preInternational Journal of Science Innovations and Discoveries, Volume 2, Issue 6, November-December 2012

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treatment of rabbit abdomen skin with 10% oleic acid in PG greatly enhanced the absorption of piroxicam from its
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gel.

SURFACE ACTIVE AGENTS [30, 6]

membranes contributing to the overall penetration enhancement of compounds. Cationic surfactants are more destructive to skin tissues causing a greater increase in flux than anionic surfactants. The latter, in turn, produce function of the stratum corneum as a result of removal of water soluble agents that act as plasticizers. Sodium lauryl sulphate has been implicated in reversible lipid modification with resultant disorganization of the stratum and bound or micellar form of the enhancer. BILE SALTS [32]

greater increases in flux than non-ionic surfactants. Anionic surfactants may function by alteration of the barrier

Surface active agents function primarily by adsorption at interfaces and thus interact with biological

Structure -Sodium lauryl sulfate.

corneum and enhanced per meation. In addition, non-ionic surfactants are purported to be able to emulsify sebum, enhancement generated by these compounds may be dependent on the ability of drug to partition between the free desoxycholic and cholic acids, and of the free choleic acids (HCOL) to enhance the transcutaneous penetration of skin permeability of both steroids by producing structural modifications of the stratum corneum.

consequently altering partitioning potential of drugs in favour of enhanced permeation. The permeation The potential of sodium choleate, an ox bile extract containing the sodium salts of taurocholic, glycoeolic,

progesterone and prednisolone, was evaluated by using excised hairless mouse skin. HCOL was found to increase

CYCLODEXTRINS [33, 34]

resultant increase in their solubility, particularly in aqueous solutions. However, cyclodextrins alone were
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Cyclodextrins are biocompatible substances that can form inclusion complexes with lipophilic drugs with a

Structure -2-hydroxypropyl--cyclodextrin

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determined be to less effective as penetration enhancers than when combined with fatty acids and propylene
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glycol.

MONOOLEIN [35, 36, 37]

associate. Monoolein is able to form a discontinuous cubic liquid crystalline phase that can be used as a drug

delivery system. Monoolein concentration influences its skin penetration enhancing ability. Monoolein concentrations from 5-70% (in propylene glycol formulations) on the topical delivery of cyclosporine A using excised porcine skin, found at a lower concentration of 5%, monoolein could improve only the topical delivery of Further increase in its concentrations from 20% to 70% resulted in an increase in the topical delivery of monoolein is non-toxic but it produces skin irritation in some cases. PHOSPHOLIPIDS [38, 39, 40]

Monoolein is a monoglyceride, biodegradable polar lipid, insoluble in water and has the property to self-

Structure- Monoolein

cyclosporine A, while a 10% concentration enhanced both topical and transdermal delivery of the model drug. lamellar structure of the bilayers in the stratum corneum, which leads to increased lipid fluidity in the stratum corneum. However, it may remove skin ceramides and solubilize lipophilic compounds in the skin. Although

cyclosporine A, but a decrease in the transdermal delivery of drug. Monoolein may function by disruption of the

is based on the lipid mixing between liposomes and stratum corneum lipid bilayer. Different phospholipids, however, promote in different way drug permeation and affect differently the partitioning of drugs into the lipid (distearoylphosphatidyl choline), are not able to do this. Phospholipids, e.g. fluid-state EPC (L-a-phosphatidylcholine from egg yolk), may diffuse into the stratum corneum

bilayer, which explains the differences between phospholipids in promoting the dermal drug delivery.

Phospholipid penetrates the surface of stratum corneum lipid bilayer, and the enhancer effect of liposomes Structure-L-a-phosphatidylcholine

and enhance dermal and transdermal drug penetration, while many other phospholipids, e.g. gel-state DSPC

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OXAZOLIDINONES [41, 42, 43]

Oxazolidinones have been synthesized such as 4-benzyloxazolidin-2-one, 4-decyloxazolidin-2-one, 3-acetyl-4decyloxazolidin-2-one, decyloxazolidin-2-one and used as chemical penetration enhancers. These are high molecular weight compounds, and have structural features similar to natural components (sphingosine and ceramide lipids) found in the upper and personal care products.The mechanism of action of oxazolidinones may involve the interaction with stratum of various active ingredients. Permeation Enhancer Azone Pyrrolidones Sulphoxides Essential oil TABLE 1: Review Of Permeation Enhancers Use In Different Research Works [44, 45, 46] Effect of Azone on Shuangwu traumatic Formula Cardiovascular effects Transdermally delivered bupranolol in rabbits Title of paper The results shows effective penetration enhancement was achieved by 3% (w/w) Azone Result corneum lipids and can fluidize the bilayer lipids in the stratum corneum, thereby enhancing the skin penetration Improve in the transdermal permeation of the Shangwu traumatic formula by chemical penetration enhancers Conclusion chemical penetration enhancers increased the in vivo delivery of buspropanol Chemical penetration enhancer is used to enhance the delivery of therapeutically effective dose of the drug through the skin skin layers. These are odourless and nonstaining in nature which makes them preferable choice for use in cosmetic 3-methyl-4-decyloxazolidin-2-one, 3-methyl-4-benzyloxazolidin-2-one, and 5-

Oxazolidinones are a class of compounds containing 2- oxazolidone as part of the structure. Several Structure-3-acetyl-4-decyloxazolidin-2-one

Formulation and Evaluation of transdermal patches of Ropinirole HCl. Essential oils were evaluated penetration enhancers towards 5- fluorouracil using excised human skin

The results of this study penetration enhancers in the TDDS increased the in vivo delivery of buspropanol, thereby increased the beta-blocking activity of buspropanol by 5060% higher than control. Formulation containing DMSO was highest (194 g/cm2/h) as compared to ethanol (170 g/cm2/h) and SLS (178 g/cm2/h). Highest permeation coefficient was achieving using DMSO in formulation.

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Eucalyptus and Chenopodium both are very effective, causing a near 30- fold increase in drug permeability coefficient. Ylang ylang was mildly effective (8-fold increase) and anise had little activity (3-fold increase)

Essential oil used as Chemical penetration enhancer increase in drug permeability coefficient

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Permeation Enhancer

TABLE 2: Review Of Permeation Enhancers Use In Different Research Works [47, 48, 49, 50]
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Title of paper

Oxazolidinones Monoolein Fatty Acid

Feasibility of transdermal delivery of Fluoxetine To examine the in vitro penetration of cisplatin (CIS) through porcine skin in the presence of different conc. Of monoolein (MO) The penetration and retention of cortisol into the skin layers

SR-38 is new and proprietary Oxazolidinones class permeation. Enhancers has been reported to fluidization of the bilayer lipids in skin, thereby consequential enhanced permeation various compounds. Result MO did not act as an authentic penetration enhancer for CIS, but it improved the drug partition to the receptor solution improving CIS transdermal permeation.

The oxazolidinones was act as good feasibility agent and also increase permeation various compounds.

Conclusion

Phospholipid

It is evident that for the transderma1 route to be effective for systemic drug delivery, particularly if the permeate

of interest is poorly absorbed via the skin portal, a penetration enhancer of some form is necessary. The role of the penetration enhancer is to reversibly alter the barrier properties of the skin by improved fluidity of the membrane delivery, with the result that skin will become one of major routes of drug administration in the next decade. enhancement effects with minimal skin irritation. 1. rapidly developing field which would significantly increase the number of drugs suitable for transdermal drug

The entire field of transdermal drug delivery and especially permeation enhancement is still in its infancy.

Saturated anionic phospholipids enhance transdermal transport by electroporation

These unique polymers may also be used as penetration enhancers in combination with other drugs of therapeutic interest for topical orTDDS In the presence of 1 mg/ml DMPS in the the use of lipid enhancer transport milieu, the flux of FITCincreases the upper size Dextran-4k was enhanced by 80-fold limit of transportable and reached 175 g/cm2/min. Thus, the chemicals use of lipid enhancer increases the upper size limit of transportable chemicals. CONCLUSION Linoleic acid + polyamine D 400 polymer achieve statistically higher cortisol penetration through the skin when compared to the commercial standard or the vehicle control.

The monoolein alone less effective but it improved the drug partition to the receptor solution improving CIS transdermal permeation.

structures or by facilitation of drug solubility within the skin. Hence, Skin permeation enhancement technology is a Research in this area has proved the usefulness of chemical penetration enhancers in the enhancement of drug permeation through skin. The chemical penetration enhancement methods discussed in this review are promising. Jain N, K, Controlled and Novel drug delivery system, 1 edition, New Delhi, CBS Publications, 1997, 27-36.
st

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