issn: 0975-766x available online through research article ...pooja mathur * et al. /international...

Pooja Mathur * et al. /International Journal Of Pharmacy&Technology

IJPT | June-2011 | Vol. 3 | Issue No.2 | 2373-2401 Page 2373

ISSN: 0975-766X Available Online through Research Article

www.ijptonline.com

VARIOUS PENETRATION ENHANCEMENTS TECHNIQUES IN TRANSDERMAL DRUG DELIVERY

Vinay Valecha1, Pooja Mathur*2, Navneet Syan2, Surender verma3

1B.S.Anangpuria College of Pharmacy, Faridabad-121001, Haryana, India. 2Ganpati Institute of Pharmacy, Bilaspur, Yamunanagar-135102, Haryana, India.

3Institute of pharmaceutical sciences, kurukshetra uiversity, kurukshetra. Email: [email protected]

Received on 06-04-2011 Accepted on 19-04-2011

Abstract

Transdermal drug delivery (TDD) via skin to the systemic circulation provides a convenient route of

administration for a variety of clinical situations. The skin layer stratum corneum is the main barrier for

permeation of drug into the skin. So to pass the stratum corneum and to increase the flux through skin membrane,

different approaches of penetration enhancement are to be used. Transdermal drug technology specialists are

continuing to search for new methods that can effectively and painlessly deliver the larger molecules into the skin.

Several new active rate controlled transdermal drug delivery system (TDDS) technologies (chemical based,

physical based, electrically-based, structure-based, velocity-based, etc.) have been found, developed and

commercialized for the TDD. This review article covers most of the new active transport enhancement

technologies involved in enhancing the transdermal permeation into an effective drug delivery system. An attempt

has been done in depth to cover the penetration enhancement techniques (chemical, physical and various important

approaches) which are useful for a optimized and successful TDD.

Key words: Stratum Corneum, Transdermal Drug Delivery (TDD), Transdermal Drug Delivery System (TDDS)

Introduction

The main focus on specialty pharmaceuticals that add value and patient protection in major pharmaceutical

markets by providing better delivery (e.g. oral controlled-release, inhalation, implant and transdermal


IJPT | June-2011 | Vol. 3 | Issue No.2 | 2373-2401 374

delivery systems) is further pushing the boundaries of the practical applications of basic pharmaceutical research.

Transdermal drug delivery (TDD) is now considered to be a well established technology [1]. Transdermal delivery

of drugs across the skin to the systemic circulation provides a convenient route of administration for a variety of

drugs [2]. Transdermal drug delivery system is capable of delivering those drugs having poor oral bioavailability,

side effects associated with high peaks or poor patient compliance because of high frequent dosing. However, skin

irritation, high manufacturing costs and less than ideal cosmetic appearance is the major draw back of TDD. The

main focus of recent advances with traditional passive TDD systems is on reducing skin irritation and making

products more aesthetically acceptable for patients. Other alternative systems are also in developing stage for

example physical enhancement; they are more focused on the delivery of the larger molecules such as peptides and

nucleotides. For the successful delivery of drugs, the transdermal route gaining the main focus for research in drug

delivery, around 40% of the drug candidate under clinical evaluation are related to transdermal system. The first

transdermal patch was approved in 1981 by FDA. The demand for transdermal products has been rising day by

day and this is likely to continue for the coming future. The number of new TDD products is now increasing very

fast to deliver real therapeutic benefit to patients around the world. More than 35 TDD products have now been

approved for sale in the US, and approximately 16 active ingredients have been approved now for use globally [3].

Some of Currently available marketed preparations of TDDS containing scopolamine (hyoscine) for the treatment

of motion sickness, clonidine and nitroglycerin for cardiovascular disease, fentanyl for chronic pain, nicotine to aid

smoking cessation, oestradiol (alone or in combination with levonorgestrel or norethisterone) for hormone

replacement and testosterone for hypogonadism [2]. A list of marketed preparations is mentioned in table no. 1 [3].

The worldwide transdermal patch market basically focused on the following drugs as- scopolamine (hyoscine),

nitroglycerine, tulobuterol, clonidine, estradiol (with and without norethisterone or levonorgestrel), testosterone,

fentanyl and nicotine [4]. Some of the marketed products of modified TDD technologies have been summarized in

table no. 2.



Table-1: Marketed preparations [3].

Brand Name Company Name Drug product

Climara 3M Pharmaceuticals/Berlex Labs Estradiol

Androderm TheraTech/GlaxoSmithKline Testosterone

Alora TheraTech/Proctol and Gamble Estradiol

Deponit Schwarz-Pharma Nitroglycerin

Duragesic® Alza/Janssen Pharmaceutica Fentanyl

Estraderm Alza/Norvatis Estradiol

Fematrix Ethical Holdings/Solvay Healthcare Ltd. Estrogen

FemPatch Parke-Davis Estradiol

Habitraol Novartis Nicotine

Minitran 3M Pharmaceuticals Nitroglycerin

Nicoderm® Alza/GlaxoSmithKline Nicotine

Nitrodisc Roberts Pharmaceuticals Nitroglycerin

Nitro-dur Key Pharmaceuticals Nitroglycerin

Nuvelle TS Ethical Holdings/Schering Estrogen/Progesterone

Prostep Elan Corp./Lederle Labs Nicotine

Testoderm TTS® Alza Testosterone

Transderm- Scop® Alza/Norvatis Scopolamine

Transderm- Nitro® Alza/Norvatis Nitroglycerin



Table-2: Marketed products of modified TDD technologies [3].

Enhancement

Method

Brand Name Company Name Drug product available/under

consideration

Microprojection,

M acroflux Alza Corporation

Vaccines

Therapeutic

proteins

Iontophoresis E-Trans Alza Corporation Fentanyl

Ultrasound

SonoPrep® Sontra Medical

Corporation

Peptides, Other large

molecules

Ultrasound SonoDermTM Imarx Large molecules (Insulin)

Needleless

injectors

Intraject Weston Medical Vaccines

Needleless

injectors

Powder Ject PowderJect

Pharmaceuticals

Insulin

Medicated

Tattoos

Med-Tat Lipper-Man Ltd. Acetaminophen, Vitamin C

Heat

CHADD Zars, Inc S-Caine (lidocaine and tetracaine)

Laser Radiation Transdermal

laser assisted

delivery

Norwood Abbey Wide range of drugs



ADVANTAGES OF TDDS [5-7]

1. TDDS utilizes the drug candidates having short half-life and low therapeutic index.

2. It reduces the dosing frequency and enhances the patient compliance.

3. Sustained delivery of drugs can be achieved which provides a steady plasma profile and hence reduces

systemic side effects.

4. Reduces the typical dosing schedule to once daily or even once weekly, so improves the patient compliance

5. Avoidance of the first-pass metabolism effect for drugs with poor oral bioavailability.

6. TDD represents a convenient, patient-friendly route for drug delivery with flexibility, allows easily dose

changes according to patient needs and also allows self-regulation of dosing by the patient.

7. TDD requires almost minimal patient cooperation.

8. TDD is accessible to a wide range of patient populations and a highly acceptable option for drug dosing

because of its non-invasive character.

Potential limitations of TDDS

• Pharmacokinetic Issues

The skin has low intrinsic permeability for many high molecular weight, hydrophilic, and/or ionized drugs, which

permeate very slowly to achieve therapeutic drug plasma levels. For maintaining the constant delivery rate, most

of the patches contain 20 times the drug quantity to be absorbed while worn to produce a stable concentration

gradient. However due to such a design which does not allow for pulsatile delivery, the large amounts of drug in

the transdermal devices cannot achieve high drug serum levels [8].

• Safety issues

The used patches must be discarded properly as they still contain drug after removal. The damage to patches via

worn or by exposure to excessive heat (sunlight, electric blankets, hot tubs etc.) affects the drug delivery. It

increases the skin permeability and blood flow, which may leads to toxicity because of increased drug absorption

[9]. Some of the patches (nicotine transderm, nicotine CQ, nicotrol, deponit, androderm) contain traces of



metal, when the patients wearing them undergo magnetic resonance imaging; they have the chances for burns [10].

For transdermal gels and creams transference is a potential issue. Virilization in female sex partners has been

reported with men treated with topical testosterone and in a 2 years old boy a precocious sexual development has

been occurred when exposed to testosterone cream on his father’s arms and back [11]. Application sites most of

the time required to be washed thoroughly with soap and water. With some of the topical preparations, patients

should have to wait for at least two hours for optimal absorption.

• Cutaneous reactions

The skin reactions on application site can result from exposure to the drug, adhesive, or excipients of transdermal

systems for example in the patients treated with testosterone containing patches [12-14]. Contact dermatitis after

the use of a transdermal system may be treated by cleaning the area with bland soap and cool water or topical

corticosteroid or antihistamine can also be used. The irritation associated with repeated patch applications can be

overcome by site rotation, if the reaction is extensive or systemic the use should be discontinued. Transdermal

estrogen patches may be applied to the abdomen, buttock, thigh, or upper arm. No change has been found during

movement from one site to another in serum hormone concentrations [12, 15]. The discontinuation of therapy is

usually found less than 10% in case of intolerable or unmanageable application site reactions with many

transdermal preparations [14-17].

• Patient related issues

The safety issues reported by the Food and Drug Administration related to the use of transdermal systems includes

partial removal of the backing of the patch before application, resulting in under dosing and patients

misunderstanding of the instructions [18]. So the patients should receive clear, concise instructions on skin

preparations, potential application sites, the number of patches to apply at one time and application site rotation if

any. Transdermal delivery systems should be applied with uniform pressure on clean, dry, hairless skin and not to

an oily, inflamed or broken skin. Hair removal with a depilatory agent just before application of a patch can

damage the stratum corneum and alter the drug permeation. Topical products should never be applied



over open wounds or broken skin [19]. Showering, bathing, or excess sweating rarely results in loss of adhesion

and the detachment of transdermal systems. A detachment of estrogen patches occurs during showering or bathing

in 1% to 3% of applications and loss of adhesion with excessive sweating occurs in less than 1% [20].

• Design related issues

Clear patches are popular because they cannot be detected easily on exposed skin. However the lack of visibility

also difficult to locate them when it is time for their removal in addition, differences in units of measure (e.g.

milligrams per hour, milligrams per day, milligrams, micrograms per hour, and milligrams per day per week) also

create confusion for healthcare professionals and patients. Some patches may be cut to adjust the dosage or to

optimize the dosing. Cutting oxybutynin-TDS matrix patches shows no significant effect on the drug

concentration/cm2, drug release, or adhesion, even after storing the patch for up to 7 days [10, 20].

Drug delivery across human skin

It is well documented fact that the skin is the largest and most easily accessible organ of the body for topical and

systemic delivery of drugs [21, 22]. The human skin thickness is approximately 2.97 mm, covers a surface area of

approximately two square meters of our body, having hair follicles about 10-70 on every square centimeter and

sweat glands 200-250 on every square centimeter. Skin is multilayered tissue consisting of epidermis, dermis and

hypodermis. Stratum corneum has compacted, flattened, dehydrated and keratinized cells. They have the water

content of only 20% as compared to other organs having up to 70%. Ointments, gels, creams and medicinal

plasters containing natural herbs are traditional TD preparations. There are currently more than 35 TDD products

approved in the USA for the treatment of various conditions including hypertension, angina, motion sickness,

female menopause, male hypogonadism, severe pain, local pain, nicotine dependence, contraception and urinary

incontinence. There are also several products in late-stage development in new therapeutic areas including,

parkinson’s disease, attention deficit, hyperactivity disorder and female sexual dysfunction [1].

Limitations of skin as a delivery method

• The barrier



The intercellular pathway is widely accepted main route of permeation through the skin for small molecules. For

some compounds the intracellular domain is also important parameter and often several mechanisms might be

working in parallel. It is thought that the organization of lipids in skin layers dictate the required physicochemical

properties of a molecule to ensure its rapid diffusion through the skin. The small molecules with good water and

lipid solubility are generally accepted as suitable candidates for TDDS. These solubility characteristics are often

also indicated by the possession of a low melting point, typically < 200 °C [22-26].

Drug Related Factors

• Partitioning

According to the Fick’s Law, drug related properties that influence flux across the skin are the concentration

gradient of drug within the skin and the diffusivity. The ability of the drug to partition into the skin influenced the

concentration gradient. The octanol-water partition coefficient can be used as reference to predict this partitioning

behavior within the skin. The generally accepted range of logP for maximum permeation is found to be 1-3. The

partitioning of the drug can be improved by increasing the concentration of drug in the applied vehicle or by

manipulating the vehicle to reduce drug solubility. Permeation enhancers can also increase diffusivity of drug [27-

32].

• Diffusivity

The chemical structure of the drug also influences the diffusivity, it occurs basically due to interactions between

the polar head groups of the intercellular lipids and H-bond forming functional groups present in the drug

structure. The number of H-bonding groups in the permeant should not exceed two. The functional properties of

skin also limit the access of drugs into and across the epidermis. The outer layer, stratum corneum, is a main

contributor to the skin’s impermeability. A lot of efforts have to be done in the respective field, for developing

more efficient TDD products [33-35].

Occlusion

To improve the efficiency of TDD systems, traditional TDD products depend mainly on their occlusive nature.



Although the mechanism by which occlusion increases the diffusivity of many drugs is not known, some of the

important effects of occlusion include: water accumulation within the skin, thereby swelling of the corneocytes

and increased water content of the intercellular matrix [36]; increase in skin temperature and decreased evaporative

loss of co- solvents [37]. Occlusion often causes an increased propensity for skin irritation at the application site

might be due to the affects of the accumulated water or to trap sweat [36-38]. Now day’s efforts have been focused

on the development of newer generation products with less potential for this reaction. Occlusive systems also

provide an environment for microbial proliferation. Skin offers the advantages of easy access and large surface

area. However, it also behaves like an effective barrier that limits penetration of large, hydrophilic polypeptides

(Insulin). Stratum corneum is responsible for this impermeability via its lipid rich matrix [39, 40]. Various

methods have been tested to overcome the skin barrier. They can be separated mainly into chemical enhancers and

physical methods (mainly iontophoresis and sonophoresis along with some other useful techniques.

VARIOUS APPROACHES FOR PENETRATION ENHANCEMENTS [2]



PHYSICAL APPROACHES TO OVERCOMING THE BARRIER

The various classes of active systems under development are available as penetration enhancers, which include

iontophoresis, electroporation, microneedles, abrasion, needleless injection, suction, stretching, ultrasound,

magnetophoresis, radio frequency, lasers, photomechanical waves, and temperature manipulation. Some most

commonly employed techniques are as following:

• Iontophoresis

• This technology enhances the drug transport across the skin barrier with the assistance of an electric field.

The mechanisms involve in transdermal iontophoresis include electrophoresis, electroosmosis and electroporation.

Direct current (DC) iontophoresis with a constant current is the most common form of transdermal iontophoretic

drug delivery. It has been suggested that AC can eliminate potential electrochemical burns and also reduce skin

irritation and sensation, which can occur during long iontophoresis application or when an inappropriate electrode

design is used [41-49].

A number of published studies for macromolecules and protein and peptide structures are listed below which

includes: calcitonin, corticotrophin-releasing hormone, delta sleep-inducing peptide, dextran sulphate, inulin,

insulin, vasopressin, gonadotropin releasing hormone, growth hormone-releasing factor, leuprolide acetate,

leutenising hormone releasing hormone, neutral thyrotrophin-releasing hormone, oligonucleotides, parathyroid

hormone. To date, however, clinical studies have been limited only to smaller molecules such as lidocaine,

dexamethasone etofenamate, naproxen, metoclopramide with hydrocortisone, cortisone, vincristine and fentanyl

[46,50-78].

• Electroporation

This method involves the high voltage pulses (10µs–100ms) to the skin that has been suggested to induce transient

pores. High voltages (•100 V) and short time durations (milliseconds) are mostly used. By using this technology

the enhancement in the skin permeability has been successfully used for the molecules with different lipophilicity

and size (i.e. small molecules, proteins, peptides and oligonucleotides) with molecular weights greater that



7kDA. The theory behind the application of electroporation to skin is that the intercellular lipid bilayers of the skin

should behave in the same way as those of cell membranes and be susceptible to pore formation by high voltage

electrical pulsing. Increase in transdermal penetration has been reported in-vitro for various sizes of molecules, for

e.g. Drug molecules as, tetracaine, timolol and fentanyl, cyclosporin A, insulin,dextrans and microspheres [79-

87].

• Ultrasound (sonophoresis and phonophoresis)

The ultrasonic energy has been used to enhance the transdermal delivery of solutes either simultaneously or via

pretreatment. It uses low frequency ultrasound (55 kHz) for an average duration of 15 seconds to enhance the skin

permeability [88]. S. Mitragotri et al., reported in-vitro permeation enhancement of several low molecular weight

drugs under the same ultrasound conditions [89]. D Bommannan and co workers [90,91] found that a 20 min

application of ultrasound (0.2 W/cm2) at a frequency of 2 MHz is not sufficient for enhancing salicylic acid

penetration into the skin. However, 10 MHz ultrasound under the same conditions resulted in a 4-fold increase and

16 MHz ultrasound resulted in about a 2.5 fold increase in transdermal salicylic acid transport.

• Micro needle based devices

The first micro needle system was described in 1976, consisted of a drug reservoir and a plurality of projections

(micro needles 50 to 100 mm long) [92]. Micro needles are tiny micron-sized structures which penetrate to the

upper dermal layers. This delivery method has the advantages like minimally invasive, pain free and lot of

potential for drug delivery across skin. Recently, Kolli and Banga, et al., describes use of soluble maltose micro

needles which dissolve [93].

• Needle-less Injection

These are the devices in which transdermal delivery is achieved by injecting the liquid or solid particles at

supersonic speeds by using a suitable energy source. The mechanism involves forcing of compressed gas (helium)

along with the drug particles through the nozzle, within the jet flow at sufficient velocity for skin penetration [92,

93].



• Controlled heat aided drug delivery system (CHADD)

Skin temperature increases due to heat that leads to increase in microcirculation and blood vessel permeability,

thus facilitating drug transfer to the systemic circulation. Zars, lnc [Salt Lake City, UT, USA] has developed a

technology that takes advantage of heat’s ability to increase transdermal permeation. CHADD is a very small

heating unit that can be placed on top of a traditional transdermal patch. An oxidation reaction in the transdermal

patch provides heat at a limited intensity and duration. The drawbacks of this technology are that heat can slightly

compromise the barrier function of the skin [94].

• Laser radiation

For enhancing topical delivery of drugs lasers are used to remove the stratum corneum barrier by controlled

ablation. This method involves ablation of the stratum corneum with direct and controlled exposure of a laser to

the skin without damaging the epidermis. This method has been successfully used to enhance the delivery of

lipophillic and hydrophilic drugs [95]. However, the structural changes in the skin layers caused by this technique

still need to be studied for safety and reversibility [96, 97].

• Magnetophoresis

To enhance the drug delivery across biological barriers a novel approach magnetophoresis can be used, e.g.

benzoic acid was selected as a drug candidate along with diamagnetic substance and influence of magnetic field

strength on diffusion flux was studied and was found to increase with increasing applied strength [98].

• Combination of electrically based physical enhancement techniques

A number of studies have been investigated for the achievement of a synergistic enhancement effect with a

combination of two techniques in topical delivery. For example, the combination of skin electroporation followed

by iontophoresis has been shown a five times more release of luteinizing hormone over that of iontophoresis alone

[99,100]. An increases flux of salmon calcitonin has been reported by electroporation combined with iontophoresis

through human epidermis compared to each technique used alone [101]. Kost et al., also observed that the

combination of electroporation with ultrasound produces a synergistic interaction, which may be caused by



ultrasound disorganizing stratum corneum lipids to an extent where they were more susceptible to the

electroporation [102]. The heparin flux also increases with combination of low-frequency ultrasound and

iontophoresis across pig skin above that observed for each of the techniques alone [103].

Chemical methods for permeation enhancement

The perfect chemical enhancer in the TDDS is, as reviewed by Barry et al., and Sinha et al., [104, 105].

Considerable efforts have been made on chemicals or combinations of chemicals as penetration enhancers

[106,107]. Chemicals generally interfere with the highly ordered lipid bilayer structure which is a primary barrier

to diffusion of drug. Chemical permeation enhancers are relatively economic, simple in application, easy to

prepare, offer flexibility in their design and allow the freedom of self administration to the patient. The chemical

enhancers can be formulated with the active therapeutic agent as a topical cream or gel, or an adhesive skin patch.

Mechanism of action of chemical permeation enhancers

A variety of complex mechanisms are involved to enhance the permeation across the skin. Chemical enhancers

either extract lipids from the skin, hence creating diffusion pathways for the drug to permeate or they can partition

themselves into the lipid bi-layers thereby disrupting the highly ordered lipid lamellae which results fluidization

[108-110]. Alternately, chemical enhancers can also act by enhancing thermodynamic activity of drug in the

formulation, for e.g., by super saturating the drug in the formulation. Such a classification is purely out of practical

benefits because permeation enhancers can act on skin by a variety of different mechanisms. Depending on their

individual physico chemical properties, chemicals belonging to the same group can act on skin by different

mechanisms. We briefly discuss the most widely accepted permeation enhancers based on their chemical

structures.

• Water

Water is a natural penetration enhancer. Usually, the increased hydration of the stratum corneum increases

transdermal flux of a variety of drugs [111].



• Hydrocarbons

Buyuktimkin et al., reviewed several other hydrocarbons and their effect on skin permeation of a variety of drugs

in their study [110]. Hydrocarbons including alkanes, alkenes, halogenated alkanes, squalane, squalene and

mineral oil have been used as penetration enhancers to increase permeation of a variety of drugs across the skin.

They work by partitioning into the stratum corneum and disrupting the ordered lipid bilayer structure. Alkanes

with 9-10 carbon atoms showed highest skin permeation enhancement of propranolol and diazepam while shorter

alkanes (5-6 carbon atoms) showed highest permeation enhancement of caffeine [112]. In the study squalane and

squalene improved permeation of diclofenac, mineral oil was effective for methyl nicotinate and chloro dodecane

enhances the permeation of timolol maleate [113].

• Alcohols

Alcohols including alkanols, alkenols, glycols, polyglycols and glycerols generally used as vehicles, solvents or

penetration enhancers in TDDS. They enhances skin permeation by a variety of mechanisms such as extraction of

lipids and proteins, swelling of the stratum corneum or improving drug partitioning or solubility of drug [110].

• Acids

Fatty acids are commonly studied in this category. These chemicals enhance transport of drug by partitioning into

the lipid bilayers and disrupting their order, by improving drug partitioning into the stratum corneum and by

forming lipophillic complexes with drugs [114]. Oleic acid is an example in this category that is extensively

studied as a permeation enhancer [115-116].

• Amines and amides

Primary, secondary and tertiary amines and cyclic and acyclic amines or amides have been used successfully in

enhancing skin permeation. They enhance the skin permeation by improving drug partitioning into the skin [114,

1118]. Azone and pyrrolidones are the most extensively studied amides [114].

• Esters

Esters of fatty acids show skin permeation enhancement of a wide variety of drugs in various studies [118-119].



The most widely studied ester is Isopropyl myristate. These chemicals work by partitioning themselves in the

ordered lipid layers of the stratum corneum [118].

• Surfactants

A wide variety of surfactants include anionic, cationic, zwitter ionic and non ionic surfactants are usually used

with a vehicle or solvent system as skin permeation enhancers [118-120]. Their activity depends upon the

hydrophilic to lipophillic balance, charge and lipid tail length [117]. Anionic and non-ionic surfactants are more

widely studied as compare to others surfactants [114].

• Terpenes, terpenoids and essential oils

Terpenes are a popular choice for permeation enhancers in transdermal drug delivery [121-123]. The effect of a

specific terpene on skin depends upon its exact physicochemical properties, particularly its lipophilicity. In general

smaller terpenes with hydrophobic groups are better skin permeation enhancers [118].

• Sulfoxides

Di methyl sulfoxide was the first chemical which was originally used as a solvent to improve drug partitioning into

the skin; however several studies have reported the use of dimethyl sulfoxide as enhancers in other solvent systems

[118].

• Lipids

Phospholipids have been successfully used as permeation enhancers in the form of vesicles, micro emulsions and

micellar systems [124-125]. They can fuse with the lipid bilayers of the stratum corneum in the form of self-

assembled structures such as vesicles or micelles, thereby enhancing partitioning of encapsulated drug as well as

disruption of the ordered bilayer structure [114].

• Miscellaneous

In addition to the above mentioned groups, several other chemical groups have been studied for their ability to

enhance drug transport across the skin as beta cyclodextrins, amino acids and thioacyl derivatives of amino acids,

alkyl amino esters, ketones and oxazolidinones. Enzymes as papain are a relatively new class of



chemicals studied as permeation enhancers [110, 126-130].

• Synergistic mixtures of chemical permeation enhancers

Many classical permeation enhancers include solvents such as water, fatty acids, alcohols, glycols and fatty esters

used in their pure state as permeation enhancers. A number of studies concluded that certain chemicals in a

mixture interact synergistically and induce skin permeation enhancements higher than that by the individual

components [120]. A mixture of two or more solvents is one of the most widely studied formulation design to

facilitate drug transport across the skin layers. The mechanisms behind it may be

(a) change in the thermodynamic activity (e.g., by increasing the degree of saturation in the solvent and, hence,

increasing the escaping tendency) or (b) specific interaction with the stratum corneum, either by increasing the

drug solubility in the stratum corneum or by altering the various transport pathways (i.e., the polar and non polar

pathways) in the stratum corneum [131]. Table no. 3 lists a few mixtures of chemical enhancers.

Table 3: List of various combination solvent mixtures for permeation enhancement

Solvent mixture Active molecule Ref no.

diethylene glycol

monoethyl ether:isopropyl myristate(40:60)

Clebopride 132

ethanol:water(60:40) Ondansetron hydrochloride 117

propylene glycol:ethanol(33:67) Naloxone 133

isopropyl myristate:glyceryl

monocaprylate(90:10)

Pentazocine 118

propylene glycol:lauric acid(90:10) Lipophillic antiestrogens 134

ethanol:tricaprylin(40:60) Tegafur 135

Isopropyl

myristate:n-methyl pyrrolidone(25:75)

Lidocaine 136



menthol:n-methyl pyrrolidone Formoterol fumarate 137

isopropyl myristate:n-methyl pyrrolidone Formoterol fumarate 137

triethylene glycol monomethyl

ether:isopropyl palmitate

Estradiol 138

cineole and oleic acid Zidovudine 139

aqueous solutions of n-lauroyl sarcosine and

ethanol

Fluorescein 110

linoleic, linolenic and arachidonic acid Dapiprazole base (DAP-B) 140

oleyl alcohol and azone Furosemide 141

azone and propylene glycol Clonazepam and lorazepam 142

Miscellaneous techniques

• Prodrugs and ion pairs

The prodrug approach was investigated for the drugs having unfavorable partition coefficients to enhance their

dermal and transdermal delivery. A promoiety was added into the design to increase partition coefficient and hence

solubility and transport of the parent drug in the stratum corneum. Upon reaching the viable epidermis, esterase

releases the parent drug by hydrolysis. The study concluded that the permeability of the very polar 6-mercapto

purine was increased up to 240 times using S-6- acyloxy methyl and 9- dialkyl amino methyl promoieties74.

Permeability of 5-fluorouracil, a polar drug was increased up to 25 times by forming N acyl derivatives. The

prodrug approach has also been investigated for increasing skin permeability of non steroidal anti-inflammatory

drugs, nalbuphine. Formation of lipophillic ion pairs has been investigated to increase stratum corneum penetration

of charged species. This strategy involves adding an oppositely charged species to the charged drug, forming an

ion-pair in which the charges are neutralized so that the complex can partition into and permeate through the

stratum corneum. The ion-pair then dissociates in the aqueous viable epidermis releasing the parent charged drug,



which can diffuse within the epidermal and dermal tissues [143].

• Eutectic systems

The melting point of a drug affect solubility and hence skin penetration. According to solution theory, lower the

melting point, greater the solubility of a material in a given solvent, including skin lipids layers. The 1:1 eutectic

mixture (melting point 18°C) is oil, which is formulated as an oil-in-water emulsion it maximizes the

thermodynamic activity of the local anesthetics. A list of eutectic systems with a penetration enhancer as the

second components has been documented here, for example: Ibuprofen with terpenes, and methyl nicotinate,

propranolol with fatty acids, and lignocaine with menthol. In all cases, the melting point of the drug was depressed

to around or below skin temperature thereby enhancing drug solubility [143].

• Complexes

To enhance aqueous solubility and drug stability complexation of drugs with cyclodextrins has been used mostly.

Cyclodextrins are large molecules, with high molecular weights greater than 1000 Da, therefore would not readily

permeate the skin. Complexation with cyclodextrins has been variously reported to both increase and decrease skin

penetration [143]. Cyclodextrin complexes have been shown to increase the stability, wettability and dissolution of

the lipophillic insect repellent N, N-di methyl- toluamide and the stability and photo stability of sunscreens. It has

been reported that complexation with cyclodextrins can both increase and decrease skin penetration. Loftsson and

Masson et al. concluded that the effect on skin penetration may be related to cyclodextrin concentration, a reduced

flux generally observed at relatively high cyclodextrin concentrations. At higher cyclodextrin concentrations, the

excess cyclodextrin would be expected to complex free drug and hence reduce flux. Shaker et al. recently

concluded that complexation with HP-beta-cyclodextrin had no effect on the flux of cortisone through hairless

mouse skin by either of the proposed mechanisms [144-148].

• Vehicles

To date, the most promising transdermal drug carrier is the recently developed and patented Transfersome® which

penetrates the skin barrier along the transcutaneous moisture gradient. Transfersome carriers can create a



highly concentrated drug depot in the systemic circulation [149]. Liposomes are microscopic bilayer vesicles,

which are usually made of phospholipids (mainly phosphatidyl choline) and cholesterol, contain both hydrophilic

and lipophillic portions and can serve as carriers for polar and non polar drugs. Niosomes have a similar

morphology, but are made of nonionic surfactants, mixed with cholesterol [150]. Transfersomes contain at least

one component to destabilize the lipid bilayers, e.g. Bile salts, poly sorbates, glycolipids, alkyl or acyl poly

ethoxylenes etc. Polypeptides such as calcitonin, insulin, α- and γ- interferon, and, Cu-Zn super oxide dismutase,

serum albumin, and dextrose have been successfully delivered across the skin with transfersome carriers [151].

• Medicated tattoos

Medicated Tattoo (Med-Tat) is a modification of temporary tattoo which contains an active drug substance useful

for transdermal delivery. Med-Tats are a novel means of delivering compounds transdermally and are produced by

Lipper–Man Ltd [Morristown, N.J.]. They are applied to clean, dry skin like temporary tattoos. There is no

predetermined duration of therapy for Med–Tats; instead, a color chart is provided by the manufacturer that can be

compared to the color of the patient’s tattoo to determine when the tattoo should be removed. Drugs and other

compounds used in Med-Tats prototypes are acetaminophen and Vitamin C [3].

• Skin abrasion

The abrasion technique involves the direct removal or disruption of the upper layers of the skin to facilitate the

permeation of topically applied drugs. These devices are based on techniques employed by dermatologists for

superficial skin resurfacing (e.g. micro derma abrasion) which are used in the treatment of acne, scars, hyper

pigmentation and other skin blemishes. Micro scissuining is a process which creates micro channels in the skin by

eroding the impermeable outer layers with sharp microscopic metal granules. Med. Pharm. Ltd. [Charlbury, U.K.]

had developed a novel dermal abrasion device (D3S) for the delivery of difficult to formulate therapeutics ranging

from hydrophilic low molecular weight compounds to biopharmaceuticals. In vitro data have shown that the

application of the device can increase the penetration of angiotensin into the skin compared to untreated human

skin [3,152].



REGULATORY STRATEGY FOR NEW DRUG APPLICATION SUBMISSIONS FOR TDDS [143]

1. A standard irritation and sensitization studies should be performed with the patch itself in animals or humans.

2. Negotiation in the timing and implementation of the toxicology requirements has to be done.

3. FDA should review dermal aspects of the IND and New drug Application (NDA).

4. Primary review should occur at the division that handles the indication under study.

5. Dose ranging studies should be there in Phase II.

6. Single Phase III study could be negotiated.

Conclusion

Transdermal drug delivery is an old technology, due to recent advances in technology and the ability to apply the

drug to the site of action without rupturing the skin membrane, transdermal route is becoming a widely accepted

route of drug administration. Successful transdermal drug delivery requires numerous considerations related to the

nature and function of the site of application in skin. The newer developed API’s are far more active and hence

they need to be delivered in a controlled manner. Modification of transdermal drug delivery systems can enhance

the bioavailability of poorly absorbed drugs. Transdermal drug delivery technologies are becoming one of the

fastest growing sectors in the pharmaceutical industry. The future of transdermal rate controlled drug delivery is

expected to grow day by day, and biomedical application of TDDS is expected to increase along with the

successful development of new approaches. Synergistic systems such as chemical mixtures, physical measures,

combinations of chemicals and various other permeation enhancing systems can be used not only to improve the

potency of permeation enhancers but also their safety factor. Application of developments in nanotechnology

could lead to systems where a single device could monitor drug levels by sampling through the skin and thus

provide controlled delivery of the drug. The safe and effective drug delivery is the aim for each and every new

technology ever explored.



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Corresponding Author:

Pooja Mathur*,

Assistant Professor,

Dept. of Pharmaceutics,

Ganpati Institute of Pharmacy, Bilaspur,

Yamunanagar-135102, Haryana, India.

Email: [email protected]

issn: 0975-766x available online through research article ...pooja mathur * et al. /international...

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