a smart review on approaches of drug permeation …

Tamta et al. World Journal of Pharmaceutical Research

www.wjpr.net Vol 9, Issue 6, 2020.

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A SMART REVIEW ON APPROACHES OF DRUG PERMEATION

THROUGH TRANSDERMAL FILMS

Yogita Tyagi and Vivek Tamta*

Department of Pharmacy GRD (PG) IMT, Rajpur Road Dehradun-248001, Uttarakhand,

India.

ABSTRACT

This review focuses on the recent advancements in the TDDS which

include iontophoresis, sonophoresis, electroporation, microneedles,

magnetophoresis, photomechanical waves and electron beam

irradiation. Transdermal drug delivery system (TDDS) utilizes the skin

as executable route for drug administration but the foremost barrier

against drug permeability is the stratum corneum and therefore, it

limits therapeutic bioavailability of the bioactive. These advancements

are exhaustively discussed with techniques involved with their

beneficial claims for different categories of bioactive. However, a lot

of research has been carried out in TDDS, still the system has many

pros and cons such as inconsistent drug release, prevention of burst

release formulation and problems related to toxicity. In addition to that, to exploit the TDDS

more efficiently scientists have worked on some combinational approaches for manufacturing

TDDS viz., chemical–iontophoresis, chemical– electroporation, chemical–ultrasound,

iontophoresis–ultrasound, electroporation–iontophoresis electroporation– ultrasound and

pressure waves–chemicals and reported the synergistic effect of the same for safe, effective

and practical use of TDDS. The present article covers all the above-mentioned aspects in

detail and hence the article will assuredly serve as an enlightening tool for the visionaries

working in the concerned area.

KEYWORDS: Transdermal films, Permeation, Bioavailability, Stratum corneum.

1. INTRODUCTION

Transdermal drug delivery system (TDDS) are adhesive drug containing devices of defined

surface area that delivers predetermined amount of drug to the intact skin at the

World Journal of Pharmaceutical Research SJIF Impact Factor 8.084

Volume 9, Issue 6, 619-642. Review Article ISSN 2277– 7105

Article Received on

31 March 2020,

Revised on 21 April 2020,

Accepted on 11 May 2020,

DOI: 10.20959/wjpr20206-17577

*Corresponding Author

Vivek Tamta

Department of Pharmacy

GRD (PG) IMT, Rajpur

Road Dehradun-248001,

Uttarakhand, India.



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preprogrammed rate.[4,5]

The transdermal delivery has gained importance in the recent years.

The TDDS has potential advantages of avoiding hepatic first pass metabolism, maintaining

constant blood levels for longer period of time resulting in a reduction of dosing frequency,

improved bioavailability, decreased gastrointestinal irritation and improved patient

compliance.[6]

Since the early 1980s, transdermal patch dosage form of transdermal therapeutic system

(TTS) has been available commercially. Such a system offers a variety of significant clinical

benefits over other conventional systems. Therefore the TTS is of particular clinical

significance for the prevention and long-term treatment of chronic diseases like

hypertension.[7]

Some of the antihypertensive drugs have already been formulated and

evaluated as transdermal patches but most of them still been unexplored. Transdermal

formulation of antihypertensive drug is promising aspect in near future.

Mortality from heart diseases increases dramatically with age. Hypertension is one of the

main causes of heart disease and, in recent years, the age adjusted hypertension and

hypertensive disease death rates have been increasing.[8]

Consequently, the prevention and

treatment of hypertension is of major social significance.[9]

Hypertension is defined

conventionally as a sustained increase in blood pressure 140/90 mm Hg, a criterion that

characterizes a group of patients whose risk of hypertension-related cardiovascular disease is

high enough to merit medical attention. Actually, the risk of both fatal and nonfatal

cardiovascular disease in adults is lowest with systolic blood pressures of less than 120 mm

Hg and diastolic BP less than 80 mm Hg; these risks increase progressively with higher

systolic and diastolic blood pressures.[10]

Hypertension is directly responsible for 57% of all stroke deaths and 24% of all coronary

heart disease deaths in India. Pooling of Indian epidemiological studies shows that

hypertension is present in 25% urban and 10% rural subjects.[11]

Therefore cost effective

approaches to optimally control blood pressure among Indians are very much needed. Despite

the suitability of TDDS in the treatment of chronic disease like hypertension, the high cost of

antihypertensive patches than conventional products made the target patients to think

twice.[12]

In spite of the high cost of transdermal patches for hypertension treatment, antihypertensive

patch with the established dosage forms reduced the occurrence of hospitalization and



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diagnostic costs. These advantages prepared the target consumers to accept antihypertensive

patches as a costlier alternative to the conventional therapy. Further, the possibility of

achieving controlled zero order absorption, simple mode of administration and the option of

easy withdrawal of dose in case of adverse manifestations make them desirable in

antihypertensive therapy.[13]

During the past few years, interest in the development of novel drug delivery systems for

existing drug molecules has been renewed. The development of a novel delivery system for

existing drug molecules not only improves the drug’s performance in terms of efficacy and

safety but also improves patient compliance and overall therapeutic benefit to a significant

extent.[1]

Transdermal Drug Delivery System (TDDS) are defined as self contained, discrete

dosage forms which are also known as “patches”.[2,3]

when patches are applied to the intact

skin, deliver the drug through the skin at a controlled rate to the systemic

circulation.[4]

TDDS are dosage forms designed to deliver a therapeutically effective amount

of drug across a patient’s skin.[5]

The main objective of transdermal drug delivery system is to deliver drugs into systemic

circulation into the skin through skin at predetermined rate with minimal inter and intra

patient variation.[3]

Currently transdermal delivery is one of the most promising methods for

drug application.[6]

It reduces the load that the oral route commonly places on the digestive

tract and liver. It enhances patient compliances and minimizes harmful side effects of a drug

caused from temporary over dose and is convenience in transdermal delivered drugs that

require only once weakly application.[7]

That will improves bioavailability, more uniform plasma levels, longer duration of action

resulting in a reduction in dosing frequency, reduced side effects and improved therapy due

to maintenance of plasma levels up to the end of the dosing interval compared to a decline in

plasma levels with conventional oral dosage forms.[8]

Transdermal delivery not only provides

controlled, constant administration of drugs, but also allows continuous input of drugs with

short biological half lives and eliminates pulsed entry into systemic circulation, which often

causes undesirable side effects.[3]

Several important advantages of transdermal drug delivery

are limitations of hepatic first pass metabolism, enhancement of therapeutic efficacy and

maintenance of steady plasma level of drug.[1]

The developments of TDDS is a

multidisciplinary activity that encompasses fundamental feasibility studies starting from the

selection of drug molecule to the demonstration of sufficient drug flux in an ex vivo and in



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vivo model followed by fabrication of a drug delivery system that meets all the stringent

needs that are specific to the drug molecule (physicochemical, stability factors), the patient

(comfort and cosmetic appeal), the manufacturer (scale up and manufacturability) and most

important economy.[7]

The first transdermal system, Transderm SCOP was approved by FDA in 1979 for the

prevention of nausea and vomiting associated with travel. Most transdermal patches are

designed to release the active ingredient at a zero order rate for a period of several hours to

days following application to the skin. This is especially advantageous for prophylactic

therapy in chronic conditions.[9]

The evidence of percutaneous drug absorption may be found

through measurable blood levels of the drug, detectable excretion of the drug and its

metabolites in the urine and through the clinical response of the patient to the administered

drug therapy.

1.1.Mechanisms of transdermal permeation

For a systemically active drug to reach a target tissue, it has to possess some physicochemical

properties which facilitate the sorption of the drug through the skin and enter the

microcirculation. The release of a therapeutic agent from Knowledge of skin permeation

kinetics is vital to the successful development of transdermal systems. This permeation can

be possible if the drug possesses certain physico-chemical properties. The rate of permeation

across the skin

dt

dQ is given by.

)1.......().........( rds CCPdt

dQ

Where, Cd = concentration of skin penetrant in the donar compartment (e.g., on the surface of

stratum corneum) Cr = concentration in the receptor compartment (e.g., body) respectively Ps

= the overall permeability constant of the skin tissue to the penetrant.

)2......(....................s

ssss

h

DKP

Where, Ks is the partition coefficient for the interfacial partitioning of the penetrant molecule

from a solution medium or a transdermal therapeutic system onto the stratum corneum,

Dss is the apparent diffusivity for the steady state diffusion of the penetrant molecule through

a thickness of skin tissues and hs is the overall thickness of skin tissues.



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As Ks, Dss and hs are constant under given conditions, the permeability coefficient (Ps) for a

skin penetrant can be considered to be constant.

From Eq.1 it is clear that a constant rate of drug permeation can be obtained only when

Cd>>Cr i.e., the drug concentration at the surface of the stratum corneum (Cd) is constistently

and substantially greater than the drug concentration in the body (Cr). then Eq. 1 becomes:

ds CPdt

dQ.

And the rate of skin permeation dQ/dt) become constant (Cd) become fairly constant

throughout the course of skin permeation.to maintain the (Cd) at a constant value the drug

released rate( Rr) always greater than the rate of skin uptake (Ra)

i.e. Rr>>Ra

by doing so Cd ia maintained at level which is always greater than the equilibrium solubility

of the drug in the stratum corneum and the maximum rate of skin permeation dQ/dt as

expressed by equation (4)

(dQ/dt)m = Ps.Cs

Reached apparently, the magnitude of dQ/dt)m is determined by the skin permeability

coefficient of the drug and its equilibrium solubility in the stratum corneum.

1.2.Types of Transdermal Films

There are five main types of transdermal patches.

1.2.1. Single-layer Drug-in-Adhesive

The adhesive layer of this system also contains the drug. In this type of patch the adhesive

layer not only serves to adhere the various layers together, along with the entire system to the

skin, but is also responsible for the releasing of the drug. The adhesive layer is surrounded by

a temporary liner and a backing.

1.2.2. Multi-layer Drug-in-Adhesive

The multi-layer drug-in-adhesive patch is similar to the single-layer system; the multi-layer

system is different, however, in that it adds another layer of drug-in-adhesive, usually

separated by a membrane (but not in all cases). One of the layers is for immediate release of

the drug and other layer is for control release of drug from the reservoir. This patch also has a



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temporary liner-layer and a permanent backing. The drug release from this depends on

membrane permeability and diffusion of drug molecules.

1.2.3. Reservoir

Unlike the single-layer and multi-layer drug-in-adhesive systems, the reservoir transdermal

system has a separate drug layer. The drug layer is a liquid compartment containing a drug

solution or suspension separated by the adhesive layer. The drug reservoir is totally

encapsulated in a shallow compartment molded from a drug-impermeable metallic plastic

laminate, with a rate-controlling membrane made of a polymer like vinyl acetate on one

surface. This patch is also backed by the backing layer. In this type of system the rate of

release is zero order.

1.2.4. Matrix

The matrix system has a drug layer of a semisolid matrix containing a drug solution or

suspension. The adhesive layer in this patch surrounds the drug layer, partially overlaying it.

Also known as a monolithic device.

1.2.5. Vapour Patch

In a vapour patch, the adhesive layer not only serves to adhere the various layers together but

also to release vapour. Vapour patches release essential oils for up to 6 hours and are mainly

used for decongestion. Other vapour patches on the market improve quality of sleep or aid

in smoking cessation.

1.3.Approaches used in development of TDDS

Several technologies have been successfully developed to provide a rate control over the

release and the transdermal permeation of drugs. These technologies can be classified into

four approaches as follows.

Membrane permeation – controlled systems

Adhesive dispersion – type systems.

Matrix diffusion – controlled systems.

Micro reservoir type or micro sealed dissolution controlled systems.

1.3.1. Membrane permeation – controlled systems: In this type of system, drug reservoir

is encapsulated in a shallow compartment moulded from a drug impermeable metallic plastic

laminate and a rate controlling polymeric membrane which may be micro porous or non-

https://en.wikipedia.org/wiki/Vinyl_acetate

https://en.wikipedia.org/wiki/Smoking_cessation



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porous as shown in fig.4. The drug molecules are permitted to release only through the rate –

controlling polymeric membrane. In the drug reservoir compartment, the drug solids are

either dispersed homogenously in a solid polymer matrix (e.g. Polyisobutylene adhesive) or

suspended in anunbleachable, viscous liquid medium (e.g. Silicon fluids) to form a paste like

suspension. Examples of thissystem are Transderm-nitro, Transderm-scop, Catapresand

Estraderm etc.

Fig 1: Membrane permeation controlled system.

1.3.2. Adhesive Dispersion – Type Systems: This is a simplified form of the membrane-

permeation controlled system. The drug reservoir is formulated by directly dispersing the

drug in an adhesive polymer e.g. Poly (isobutylene) or poly (acrylate) adhesive and then

spreading the medicated adhesive, by solvent casting or hot melt, on to a flat sheet of drug

impermeable metallic plastic backing to form a thin drug reservoir layer. On the top of the

drug reservoir layer, thin layers of non-medicated, rate controlling adhesive polymer of a

specific permeability and constant thickness are applied to produce an adhesive diffusion –

controlled delivery system.

Fig 2: Adhesive dispersion type system.



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1.3.3. Matrix Diffusion- Controlled Systems: In this approach, the drug reservoir is

formed by homogenously dispersing the drug solids in a hydrophilic or lipophillic polymer

matrix. The resultant medicated polymer is then molded into a medicated disc with a defined

surface area and controlled thickness. Drug reservoir containing polymer disc is then pasted

onto an occlusive base plate in a compartment fabricated from a drug-impermeable plastic

backing membrane (fig.6). e.g. Nitro-Door: Delivers nitroglycerin for the treatment of angina

pectoris.

Fig 3: Matrix Diffusion- Controlled Systems.

1.3.4. Micro reservoir type or Micro sealed Dissolution:- The micro reservoir type drug

delivery system can be considered a combination of the reservoir and matrix diffusion type

drug delivery systems. This transfer maltherapeutic system is then produced by positioning

the medicated disc at the centre and surrounding it with an adhesive rim The Matrix system

design is characterized by the inclusion of a semisolid matrix containing a drug solution or

suspension which is in direct contact with the release line.

2. ANATOMY OF TRANSDERMAL DRUG DELIVERY SYSTEMS

2.1. Additives

2.1.1. Release Liner: Important properties for the release liner, the system component that

is removed before application to the skin, include easy removability and excipient resistance.

To maintain potency and predictable delivery characteristics, the liner must be resistant to

drugs within the preparation and to humidity.



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2.1.2. Backing Layer: Backings are chosen for appearance, flexibility and need for

occlusion. Examples of backings are polyester film, polyethylene film and polyolefin film.

Backing Layer is visible after the system is applied; the backing layer should exhibit

excipient resistance, a low moisture vapor transmission rate and nontoxic composition. Non-

excipient-resistant backings may allow leaching of additives from the backing and alteration

of the drug. A low moisture vapor transmission rate is essential to retaining skin moisture and

hydrating the area where by increases drug penetration.

2.1.3. Adhesive Layer: Adhesives are used to maintain intimate contact between the patch

and the skin surface. Many classes of adhesives are available that might be considered for use

with TDDS, although in practice pressure sensitive adhesives (PSAs) are preferred. PSAs are

generally defined as materials that adhere to a substrate with light pressure and which leave

no residual adhesive upon their removal and offer the following advantages.

2.1.4. Overlay: A TDDS may include a drug free adhesive coated film, foam or nonwoven

component designed to be placed over a transdermal patch that has been applied onto the

skin. This overlay secures the medicated patch to the skin of the patient.

2.1.5. Membrane: A membrane may be sealed to the backing to form a pocket to enclose

the drug containing matrix or used as a single layer in the patch construction. The diffusion

properties of the membrane are used to control availability of the drug and/or excipients to

the skin.

2.1.6. Chemical Permeation Enhancers: The skin’s physical structure provides a barrier

that may limit the permeation of some agents. Skin permeation enhancers broaden the range

of drugs that can be delivered transdermally by increasing the penetration of permeants

through enhanced diffusion of the SC and/or by increasing the solubility of the penetrant.

Protein denaturation may disrupt the barrier as many fluidization and randomization of

intercellular lipids or intercellular delamination and expansion. Ideally, a permeation

enhancer functions only to reduce the barrier resistance of the SC and does not damage any

viable cells. The ideal enhancer is: Pharmacologically inert. Nontoxic. Nonirritating.

Nonallergenic. The enhancer should not extract endogenous material out of the skin but

should spread well on skin and have a suitable skin feel. If the substance is a liquid and is to

be used at high volume fractions, it should be a suitable solvent for drugs. Due to their

systemic and localized toxicity, many effective chemical permeation enhancers have not been



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explored yet. Hence natural products have increasingly been used as enhancers due to their

better safety profile. Terpenes are essential oils, which are used as fragrance, flavourings, and

medicines. They have been found effective penetration enhancers for a number of hydrophilic

and lipophilic drugs. Terpenes are highly lipophilic due to their isoprene (C5H8) units. They

are generally recognized as safe (GRAS) by the FDA. They increase the drug diffusivity in

the SC for hydrophilic drugs and they enhance partitioning of drug into the SC for lipophilic

drugs, besides causing increased diffusivity.

2.2. Selection of Drug

Drug should be chosen with great care, various parameters to be considered for the selection

of drug includes.

2.2.1. Physicochemical properties of drug

Should have molecular weight less than 1000 daltons.

Should have affinity for both lipophilic and hydrophilic phase.

Should have low melting point.

2.2.2. Biological properties of drug.

Should be potent with daily dose of few mg.

Should have short half life.

Drug must not induce cutaneous irritation or allergic response.

Drug which degrade in GIT or are inactivated by hepatic first pass effect are suitable

candidates.

Tolerance to drug must be developed under near zero order release profile of transdermal

delivery.

Drugs which have to be administered for long period of time or which causes adverse

effect to non target tissues can also be formulated.

3. ADVANTAGES OF TRANSDERMAL DRUG DELIVERY

Transdermal drug delivery enables the avoidance of gastrointestinal absorption with its

associated pitfalls of enzymatic and pH associated deactivation.

Avoidance of first pass metabolism.

The lack of peaks in plasma concentration can reduce the risk of side effects, thus drugs

that require relatively consistent plasma levels are very good candidate for transdermal

drug delivery.



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As a substitute for oral route.

The patch also permit constant dosing rather than the peaks and valley in medication level

associated with orally administered medication.

Rapid notifications of medication in the event of emergency as well as the capacity to

terminate drug effects rapidly via patch removal.

Avoidance of gastro intestinal incompatibility.

Convenience especially notable in patches that require only once weekly application, such

a simple dosing regimen can aid in patient adherence to drug therapy.

Minimizing undesirable side effects.

Provide utilization of drug with short biological half lives, narrow therapeutic window.

Avoiding in drug fluctuation drug levels.

Inter and intra patient variation.

Termination of therapy is easy at any point of time.

Provide suitability for self-administration.

They are non-invasive, avoiding the inconvenience of parentral therapy.

The activity of drugs having a short half-life is extended through the reservoir of drug in

the therapeutic delivery system and its controlled release.

It is of great advantages in patients who are nauseated or unconscious.

Transdermal patches are better way to deliver substances that are broken down by the

stomach aids, not well absorbed from the gut, or extensively degraded by the liver.

Transdermal patches are cost effective.

4. DISADVANTAGES OF TRANSDERMAL DRUG DELIVERY

Transdermal drug delivery system cannot deliver ionic drugs.

It cannot achieve high drug levels in blood.

It cannot develop for drugs of large molecular size.

It cannot deliver drugs in a pulsatile fashion.

It cannot develop if drug or formulation causes irritation to skin.

Possibility of local irritation at site of application.

May cause allergic reaction.

Sufficient aqueous and lipid solubility, a log P (octanol/ water) between 1 and 3 is

required for permeate to transverse stratum corneum and underlying aqueous layer.

Only potent drugs are suitable candidates for transdermal patch because of the natural

limits of drug entry imposed by the skin’s impermeability.



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Long time adherence is difficult.

5. TRANSDERMAL ROUTE THROUGH SKIN AND DRUG DELIVERY

PROSPECTS

5.1.Description

The skin is the largest organ of the human body which covers a surface area of approximately

2 sq.m. and receives about one third of the blood circulation through the body. It serves as a

permeability barrier against the transdermal absorption of various chemical and biological

agents. It is one of the most readily available organs of the body with a thickness of few

millimeters (2.97 0.28 mm) which,

Separates the underlying blood circulation network from the outside environment

Serves as a barrier against physical, chemical and microbiological attacks.

Acts as a thermostat in maintaining body temperature.

Plays role in the regulation of blood pressure.

Protects against the penetration of UV rays.

Skin is a major factor in determining the various drug delivery aspects like permeation

and absorption of drug across the dermis. The diffusional resistance of the skin is greatly

dependent on its anatomy and ultrastructure

5.2.Anatomy of Skin

The structure of human skin can be categorized into four main layers

The epidermis

The viable epidermis

A non-viable epidermis (Stratum corneum

The overlying dermis

The innermost subcutaneous fat layer (Hypodermis)

5.2.1. The Epidermis

The epidermis is a continually self-renewing, stratified squamous epithelium covering the

entire outer surface of the body and primarily composed of two parts: the living or viable

cells of the malpighian layer (viable epidermis) and the dead cells of the stratum

corneum commonly referred to as the horny layer.[5]

Viable epidermis is further classified

into four distinct layers.[12]

Stratum lucidum

Stratum granulosu



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Stratum spinosu

Stratum basale

Fig. 4: Schematic representation of anatomy of epidermis.

5.2.2. Stratum corneum

This is the outermost layer of skin also called as horny layer. It is the rate limiting barrier that

restricts the inward and outward movement of chemical substances. The barrier nature of the

horny layer depends critically on its constituents: 75-80% proteins, 5-15% lipids, and 5-10%

ondansetron material on a dry weight basis.

Stratum corneum is approximately 10 mm thick when dry but swells to several times when

fully hydrated. It is flexible but relatively impermeable. The architecture of horny layer may

be modeled as a wall-like structure with protein bricks and lipid mortar. It consists of horny

skin cells (corneocytes) which are connected via desmosomes (protein-rich appendages of the

cell membrane). The corneocytes are embedded in a lipid matrix which plays a significant

role in determining the permeability of substance across the skin.[11]

Fig. 5: Schematic representation of microstructure of stratum corneum.



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5.2.3. Viable epidermis

This is situated beneath the stratum corneum and varies in thickness from 0.06 mm on the

eyelids to 0.8mm on the palms. Going inwards, it consists of various layers as stratum

lucidum, stratum granulosum, stratum spinosum, and the stratum basale. In the basale layer,

mitosis of the cells constantly renews the epidermis and this proliferation compensates the

loss of dead horny cells from the skin surface. As the cells produced by the basale layer move

outward, they itself alter morphologically and histochemically, undergoing keratinization to

form the outermost layer of stratum corneum.[14]

Fig. 6: Schematic representation of different layers of epidermis.

5.2.4. Dermis

Dermis is the layer of skin just beneath the epidermis which is 3 to 5 mm thick layer and is

composed of a matrix of connective tissues, which contains blood vessels, lymph vessels, and

nerves. The cutaneous blood supply has essential function in regulation of body temperature.

It also provides nutrients and oxygen to the skin, while removing toxins and waste products.

Capillaries reach to within 0.2 mm of skin surface and provide sink conditions for most

molecules penetrating the skin barrier. The blood supply thus keeps the dermal concentration

of permeate very low, and the resulting concentration difference across the epidermis

provides the essential driving force for transdermal permeation. In terms of transdermal drug

delivery, this layer is often viewed as essentially gelled water, and thus provides a minimal



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barrier to the delivery of most polar drugs, although the dermal barrier may be significant

when delivering highly lipophillic molecules.[13]

5.2.5. Hypodermis

The hypodermis or subcutaneous fat tissue supports the dermis and epidermis. It serves as a

fat storage area. This layer helps to regulate temperature, provides nutritional support and

mechanical protection. It carries principal blood vessels and nerves to skin and may contain

sensory pressure organs. For transdermal drug delivery, drug has to penetrate through all

three layers and reach in systemic circulation.

5.2.6. Percutaneous absorption

Before a topically applied drug can act either locally or systemically, it must penetrate

through stratum corneum. Percutaneous absorption is defined as penetration of substances

into various layers of skin and permeation across the skin into systemic

circulation.[11]

Percutaneous absorption of drug molecules is of particular importance in

transdermal drug delivery system because the drug has to be absorbed to an adequate extent

and rate to achieve and maintain uniform, systemic, therapeutic levels throughout the

duration of use. In general once drug molecule cross the stratum corneal barrier, passage into

deeper dermal layers and systemic uptake occurs relatively quickly and easily.

Fig. 7: Schematic representation of percutaneous permeation.



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The release of a therapeutic agent from a formulation applied to the skin surface and its

transport to the systemic circulation is a multistep process which involves.

Dissolution within and release from the formulation

Partitioning into the skin’s outermost layer, the stratum corneum (SC)

Diffusion through the SC, principally via a lipidic intercellular pathway.

Partitioning from the SC into the aqueous viable epidermis, diffusion through the viable

epidermis and into the upper dermis, uptake into the papillary dermis (capillary system)

and into the microcirculation.

6. ROUTES OF DRUG PENETRATION THROUGH SKIN

In the process of percutaneous permeation, a drug molecule may pass through the epidermis

itself or may get diffuse through shunts, particularly those offered by the relatively widely

distributed hair follicles and eccrine glands as shown in figure 6. In the initial transient

diffusion stage, drug molecules may penetrate the skin along the hair follicles or sweat ducts

and then absorbed through the follicular epithelium and the sebaceous glands. When a steady

state has been reached the diffusion through the intact Stratum corneum becomes the primary

pathway for transdermal permeation.

6.1. Transepidermal route

In transepidermal transport, molecules cross the intact horny layer. Two potential micro-

routes of entry exist, the transcellular (or intracellular) and the intercellular pathway.

Fig. 8: Schematic representation of Transepidermal route.



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Both polar and non-polar substances diffuse via transcellular and intercellular routes by

different mechanisms. The polar molecules mainly diffuse through the polar pathway

consisting of “bound water” within the hydrated stratum corneum whereas the non-polar

molecules dissolve and diffuse through the non-aqueous lipid matrix of the stratum corneum.

Thus the principal pathway taken by a penetrant is decided mainly by the partition coefficient

(log K). Hydrophilic drugs partition preferentially into the intracellular domains, whereas

lipophillic permeants (octanol/water log K > 2) traverse the stratum corneum via the

intercellular route. Most molecules pass the stratum corneum by both routes.[5]

Fig. 9: Possible micro routes for drug penetration across human skin intercellular or

transcellular.

6.2.Transfollicular route (Shunt pathway)

This route comprises transport via the sweat glands and the hair follicles with their associated

sebaceous glands. Although these routes offer high permeability, they are considered to be of

minor importance because of their relatively small area, approximately 0.1% area of the total

skin. This route seems to be most important for ions and large polar molecules which hardly

permeate through the stratum corneum.



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6.3.Barrier functions of the skin

The top layer of skin is most important function in maintaining the effectiveness of the

barrier. Here the individual cells overlie each other and are tightly packed, preventing

bacteria from entry and maintaining the water holding properties of the skin.[14]

Stratum

corneum mainly consists of the keratinized dead cell and water content is also less as

compared to the other skin components. Lipids are secreted by the cells from the base layer

of the skin to the top. These lipid molecules join up and form a tough connective network, in

effect acting as the mortar between the bricks of a wall.

7. IDEAL PROPERTIES OF DRUG CANDIDATE FOR TRANSDERMAL DRUG

DELIVERY

Parameter Properties

Dose Should be low (<20 mg/day)

Half-life in h 10 or less

Molecular weight <400

Partition coefficient Log P (octanol-water) between-1.0 and 4

Skin permeability coefficient >0.5 × 10−3

cm/h

Skin reaction Non irritating and non-sensitizing

Oral bioavailability Low

Therapeutic index Low

7.1.Environmental factors

7.1.1. Sunlight

Due to Sunlight the walls of blood vessels become thinner leading to bruising with only

minor trauma in sun-exposed areas. Also pigmentation: The most noticeable sun-induced

pigment change is a freckle or solar lentigo.

7.1.2. Cold Season

Often result in itchy, dry skin. Skin responds by increasing oil production to compensate for

the weather’s drying effects. A good moisturizer will help ease symptoms of dry skin. Also,

drinking lots of water can keep your skin hydrated and looking radiant.

7.1.3. Air Pollution

Dust can clog pores and increase bacteria on the face and surface of skin, both of which lead

to acne or spots. This affects drug delivery through the skin. Invisible chemical pollutants in

the air can interfere with skin’s natural protection system, breaking down the natural skin’s

oils that normally trap moisture in skin and keep it supple.



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7.1.4. Effect of Heat on Transdermal patch

Heat induced high absorption of transdermal delivered drugs. Patient should be advised to

avoid exposing the patch application site to external heat source like heated water bags, hot

water bottles. Even high body temperature may also increase the transdermally delivered

drugs. In this case the patch should be removed immediately. Transdermal drug patches are

stored in their original packing and keep in a cool, dry place until they are ready to used.

8. VARIOUS METHODS FOR PREPARATION OF TRANSDERMAL DRUG

DELIVERY SYSTEM

8.1.Asymmetric TPX membrane method

A prototype patch can be fabricated by a heat sealable polyester film (type 1009, 3m) with a

concave of 1cm diameter used as the backing membrane. Drug sample is dispensed into the

concave membrane, covered by a TPX {poly (4-methyl-1-pentene)} asymmetric membrane,

and sealed by an adhesive.

8.2. Asymmetric TPX membrane preparation

These are fabricated by using the dry/wet inversion process. TPX is dissolved in a mixture of

solvent (cyclohexane) and nonsolvent additives at 60°c to form a polymer solution. The

polymer solution is kept at 40°C for 24 hrs and cast on a glass plate to a pre-determined

thickness with a gardener knife. After that the casting film is evaporated at 50°C for 30 sec,

then the glass plate is to be immersed immediately in coagulation bath [maintained the

temperature at 25°C]. After 10 minutes of immersion, the membrane can be removed, air dry

in a circulation oven at 50°C for 12 hrs].

8.3. Circular teflon mould method

Solutions containing polymers in various ratios are used in an organic solvent. Calculated

amount of drug is dissolved in half the quantity of same organic solvent. Enhancers in

different concentrations are dissolved in the other half of the organic solvent and then added.

Di-N-butylphthalate is added as a plasticizer into drug polymer solution. The total contents

are to be stirred for 12 h and then poured into a circular teflon mould. The moulds are placed

on a leveled surface and covered with an inverted funnel to control solvent vaporization in a

laminar flow hood model with speed of air 1/2 m /sec. The solvent is allowed to evaporate for

24 h. Before evaluation the dried films are to be stored for another 24 h at 25±0.5 °C in a

desiccators containing silica gel before to eliminate aging effects. These types of films are to

be evaluated within one week of their preparation.



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8.4. Mercury substrate method

In this method drug is dissolved in polymer solution along with plasticizer. The above

solution is to be stirred for 10-15 min to produce a homogeneous dispersion and poured in to

a leveled mercury surface. Then the solution is covered with inverted funnel to control

solvent evaporation.

8.5. By using “EVAC membranes” method

In order to prepare the target transdermal therapeutic system, 1% carbopol reservoir gel,

polyethelene (PE), ethylene vinyl acetate copolymer (EVAC) membranes can be used as rate

control membranes. If the drug is not soluble in water, propylene glycol is used for the

preparation of gel. Drug is dissolved in propylene glycol, carbopol resin will be added to the

above solution and neutralized by using 5% w/w sodium hydroxide solution. The drug (in gel

form) is placed on a sheet of backing layer covering the specified area. A rate controlling

membrane will be placed over the gel and the edges will be sealed by heat to obtain a leak

proof device.

8.6. Aluminium backed adhesive film method

Transdermal drug delivery system may produce unstable matrices if the loading dose is

greater than 10 mg. Aluminium backed adhesive film method is a suitable one for preparation

of same, chloroform is choice of solvent, because most of the drugs as well as adhesive are

soluble in chloroform. The drug is dissolved in chloroform and adhesive material will be

added to the drug solution and dissolved. A custammade aluminium former is lined with

aluminium foil and the ends blanked off with tightly fitting cork blocks.

8.7. By using free film method

Free film of cellulose acetate is prepared by casting on mercury surface. A polymer solution

2% w/w is prepared by using chloroform. Plasticizers are incorporated at a concentration of

40% w/w of polymer weight. Five ml of polymer solution was poured in a glass ring which is

placed over the mercury surface in a glass petri dish. The rate of evaporation of the solvent is

controlled by placing an inverted funnel over the petridish. The film formation is noted by

observing the mercury surface after complete evaporation of the solvent. The dry film will be

separated out and stored between the sheets of wax paper in desiccators until use. Free films

of different thickness can be prepared by changing the volume of the polymer solution.



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9. CHARACTERIZATION OF PREPARED TRANSDERMAL PATCHES

9.1. Physical appearance

All the formulated transdermal patches of Felodipine were visually inspected for colour,

flexibility, homogeneity & smoothness.

9.2. Thickness

The thickness of the formulated patch was measured at 3 different places on a single patch

using screw gauge and average thickness of three readings was calculated.

9.3. Folding endurance

The folding endurance was measured manually for the formulated patches. A strip of patch

(2×2cm2) was cut and repeatedly folded at the same place until it broke. The number of times

the patch could be folded at the same place without breaking or cracking was observed.

9.4. Weight uniformity

To check weight uniformity, three patches from each formulation batch was randomly

selected. Patches of 2×2cm2 were weighed individually on digital balance and average

weight of three patches was calculated.

9.5. Tensile strength

The tensile strength and percent elongation of the prepared films were performed using a

Universal strength testing machine (Hounsfield, slinfold, U.K.). It is consists of two load cell

grips. The upper one was movable and lower one was fixed. The test patch of size (2 x 2cm2)

was fixed between these two cell grips and force was gradually applied till the patch broke.

The tensile strength of patch was taken directly from the dial reading in kg. The tensile

strength was calculated as;

Tensile strength = Tensile load at break/ cross sectional area

9.6. Ex-Vivo Release Studies

9.6.1. Preparation of skin

A full thickness of skin was excised from dorsal site of dead albino rat (150-200gm) and skin

was washed with water. The fatty tissue layer was removed. The outer portion with hairs was

applied with depilatory and allowed to dry. The hairs were scrubbed with the help of wet

cotton and washed with normal saline solution. The skin was kept in phosphate buffer

solution (pH-7.4) in refrigerator until skin was used for release study. Prior to use, the skin



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was allowed to equilibrate with room temperature. After that the skin was mounted between

donor and receptor compartment of cell. The skin was clamped in such a way that the dermal

side will be in contact with receptor medium.

9.6.2. Methodology

Phosphate buffer pH 7.4 was used as receptor solution. The volume of Franz diffusion cell

was 30 ml and temperature was maintained at 37 ± 1°C with the help of hot plate. The

diffusion has been carried out for 24 hours and 1 ml sample was withdrawn at different time

interval for a period of 24 hour. The same volume of phosphate buffer with pH 7.4 was added

to receptor compartment to maintain sink conditions and the samples were analyzed at 239

nm.[13,14]

9.7. Skin Irritation studies

To predict the compatibility between polymeric patch and skin, Draize test for skin irritation

was performed. Skin irritation was performed on healthy rabbits (average weight: 1.5 to 2.5

kg). The dorsal surface (50 cm2) of rabbit was cleaned, and the hair was removed by shaving.

The skin was cleared with rectified spirit. Formalin solution (0.8%) was used as control. The

optimized formulation was placed over the skin and was removed after 24 hours. The resulted

skin reaction was checked for erythema.

9.8. Stability studies

As per ICH guidelines, transdermal patches were subjected to accelerated stability studies.

Optimized formulation was exposed to controlled temperature (40±2 °C) and relative

humidity (75±5 % RH) for a period of 2 months in humidity control oven (Lab Control,

Ajinkya IM 3500 Series, India). After 15, 30 and 60 days the samples were taken out and

analyzed for Physical appearance, folding endurance and ex-vivo drug release.

10. CONCLUSION

To overcome the problems associated with the oral delivery route, transdermal drug delivery

systems are utterly used as an alternative route especially focusing improvements in the

elegance, dosage flexibility and patient compliance. This scenario surely remains continued

in the future and hence leads to more advancement of modern techniques involved for

loading a bioactive in TDDS for overcoming the problems associated with the barrier

properties of the skin. The attractiveness of the transdermal route for application of this

technology is obvious because of the accessibility of the device for adjustment, control and



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removal. New TDDS products, approved by FDA having bioactive under categories that

include hypertension, angina, motion sickness, female menopause, male hypogonadism,

severe pain, local pain control, nicotine dependence, and recently, contraception and urinary

incontinence. These products are gaining worldwide popularity and thus are considered as a

mature technology. These systems bypass many problems that concern with poor oral

bioavailability, side effect associated with high peak or poor compliance due to frequent dose

interval. Much research are still in progress for the development and scale up of TDDS under

categories like, Parkinson's disease, attention deficit and hyperactivity disorder and female

sexual dysfunction.

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a smart review on approaches of drug permeation …

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