ISSN   0974-3618  (Print)                    www.rjptonline.org

            0974-360X (Online)

 

 

REVIEW ARTICLE

 

The Structure of Skin and Transdermal Drug Delivery System- A Review

 

Sajid Ali, Maryam Shabbir, Nabeel Shahid

Faculty of Pharmacy, The University of Lahore, Lahore, Pakistan

*Corresponding Author E-mail: sajidalichishti@hotmail.com

 

ABSTRACT:

Transdermal drug delivery system (TDDS) provides various merits over conventional drug delivery systems such as oral delivery and injections including avoidance of hepatic first pass metabolism, reduction of pain, and possible sustained release of drug. Still, transdermal passage of molecule is tedious due to less permeability of stratum corneum (SC), the outermost layer of the skin. In its intact state the skin is a formidable barrier, resistant to chemicals and tissue-harmful ultraviolet rays and virtually impenetrable to the life threatening microorganisms. The stratum corneum (SC) develops a thin, tough, relatively impermeable membrane which usually provides the rate limiting step in transdermal drug delivery system. To overcome this barrier function chemical permeation enhancers (CPEs) are used that facilitate the absorption of permeate through the skin by temporarily decreasing the impermeability of the skin. The present review article highlights the different layer of skin and the passage of drug through a transdermal patch into the stratum corneum for local or systematic effect.

              

KEYWORDS: Skin, transdermal drug delivery system, permeation enhancers, transcellular route, intercellular route.

 

 


INTRODUCTION:

Transdermal drug delivery systems (TDDS) are defined as self-contained, discrete dosage forms which, when applied to the intact skin, deliver the drug(s), through the skin, at a controlled rate to the systemic circulation1. A transdermal patch or skin patch is a medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through the skin and into the bloodstream2.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Received on 05.10.2014       Modified on 27.10.2014

Accepted on 12.11.2014      © RJPT All right reserved

Research J. Pharm. and Tech. 8(2): Feb. 2015; Page 103-109

DOI: 10.5958/0974-360X.2015.00019.0

 

The first transdermal system, Transderm Scop (Baxter), was approved by Food and Drug Administration in 1979 for the prevention of nausea and vomiting associated with travel, particularly at sea. In a broad sense, the term transdermal drug delivery system (TDDS) includes all topically administered drug formulations intended to deliver the active ingredient into the general circulation. Transdermal drug delivery systems (TDDS) have been designed to provide controlled continuous delivery of drugs via the skin to the systemic circulation. Adhesive patches and transdermal drug delivery system (TDDS) of defined shape and size are marketed for systemic action and are intended for treatment or prevention of a systemic disease. Drug released from transdermal drug delivery system (TDDS) is absorbed through the stratum corneum (SC), epidermis and dermis into the blood circulation and transported to target tissue to achieve therapeutic effect. Ideally, entire of the drug should penetrate through the skin to the underlying blood supply without any drug accumulation in the layers of the skin for successful Transdermal deliver3,4.

 

Transdermal drug delivery systems (TDDS) are considered new drug delivery systems and often involve a demonstration of clinical safety and effectiveness of the drug. Transdermal drug delivery system (TDDS) are considered control release dosage forms and should scientifically support in vivo and in vitro claims for controlled release features and should assure in vivo and in vitro reproducibility. As transdermal drug delivery system (TDDS) are regarded as new dosage form for the potent drugs thus it has to be approved based on clinical safety and efficacy studies5. Although TDDS was introduced more than 200 years ago4, it is only recently that the method appears to have reached a practical stage6. Closely related term is percutaneous delivery, which is transportation of drugs into the tissues, with an attempt to avoid systemic effects. The concept of percutaneous absorption of drugs was given by Stoughton in 19897.

 

The Skin

The skin often has been referred to as the largest of the body organs: an average adult’s skin has a surface area of about 2m2.The ease with which some drugs can pass through the skin barrier into the circulating blood means that the transdermal route of medication is a possible substitute to the oral route. However, the number of drugs available as marketed transdermal drug products is limited to those that display the correct physicochemical and pharmacokinetic properties which facilitate their effective delivery across the skin8.

 

When a transdermal patch is applied to the human skin, it may retain the drug or active substance on the surface of the skin, without any absorption, e.g. in case of cosmetics and antiseptics or it may allow the drug permeation through the skin into the deeper regions i.e. dermis and the epidermis. These formulations are also called diadermal or endodermal formulations. The third enviable function is to have the drug absorbed systematically9.

 

Skin is one of the most readily accessible organs of the human body10. There are two kinds of human skin; one that is hair-less such as soles of foot and palms of hand, and the other kind which bears hair and sebaceous glands such as arms and face11. The structure of skin is given in Figure 1.

 

Taxonomical classification

The skin is divided taxonomically into three scales; namely micro scale, meso scale and macro scale. The components of cell and layers of skin constitutes the micro scale as they can only be seen under the microscope and cannot be differentiated or identified with human eye.  The meso scale comprises of skin features, hair, freckles, moles, scale comprises of skin features, hair, freckles, moles pores, skin surface and wrinkles as they can be seen with the naked eye and more clearly under the micro-scale if necessary. The macro scale comprises of body regions and body parts. The skin morphology and appearance appears different at different parts of the body12.

 

Histological classification

The skin is divided histologically into the epidermis, the dermis, and the hypodermis; which collectively forms a cover against external agent and loss of water from the body.

 

Epidermis

Non-viable epidermis and viable epidermis together makes up the epidermis13. Stratum corneum is known as the non-viable epidermis whereas the layer below the stratum corneum is called viable epidermis. The viable epidermis is made of various sublayers of epidermis which collectively is 50-100 µm thick and cells in this layer are held together by tonofibrils14.  Blood capillaries and nerve fibers reach the epidermis by passing through the dermis and subcutaneous fat layer3. The main cell of the epidermis is the keratinocytes which make up 95% of the total cells present in the epidermis. These cells ascend from the epidermal basement membrane towards the skin surface, fashioning several definite layers during its transit. The separate layers of the epidermis are formed by the differing stages of keratin maturation11. The epidermis has the following sublayers:

 

Stratum basale (basal cell layer)

It is the deepest sublayer of the epidermis and is composed of a single layer of basal cells. Keratinocytes are produced in this sublayer. Stratum basale forms the boundary to the dermis. It holds approximately 8% of the water in the epidermis. With aging, stratum basale becomes thinner and loses the ability to retain water. Melanocytes also lie in this layer.

 

Stratum spinosum (prickle cell layer)

It refers to the 10 to 20 layers that lie on top of the basal cell layer. Basal cells, through the process of turn-over, make their shape somewhat flatter and form these layers. These cells are hence called prickle cells and have little spines on the outside of their membrane. The thickness of this sublayer is from 50 to 150 µm.

 

Stratum granulosum (granular cell layer)

It is composed of 2 to 4 granular cell layers. The thickness of this layer is 3 µm. In this sublayer, cornification or keratinization of keratinocytes begins. In this process, organelles such as nuclei and mitochondria start to resolve. Cells become increasingly filled with keratin fibers and contain less moisture as compared to basal and prickle cell layers. The shape of these cells becomes much flatter during this process.

 

Stratum lucidum (clear layer)

It can only be found in soles and palms. Its cells become flatter and more densely packed during turn-over12.

 

Stratum corneum (horny layer)

The outermost layer of the skin, the stratum corneum, is responsible for the barrier function of the skin15. It is also known as non-viable epidermis14. The stratum corneum is 10-15 µm in thickness and is made up of dead flattened corneocytes which is surrounded by an extracellular matrix of lipid13. Corneocytes are the final product of mortal differentiation of epidermal keratinocytes, and are constantly renewed16. It is an interface between the body and the outer environment. It conceals different enzymes which aid in its healthy maintenance. It also helps to regulate the exchange of moisture and oxygen with the external environment17. The chief route of permeation is around the corneocytes. Therefore, the larger the size of corneocytes the longer will be the route for the permeation. Corneocyte size relies upon the site on the body e.g. the size of corneocyte is smaller in the skin of the face as compared to the arm18. The cells are joined together by desmosomes which maintains the cohesiveness of the layer19.

 

The stratum corneum is composed of approximately 40% protein, mostly keratin, and 40% water, with the balance of lipid components. On the surface of the skin is a film of emulsified material which is composed of a complex blend of sweat, sebum, and desquamating cells of epidermis. However, this layer offers little obstruction for the drug to permeate3. The major lipid classes in human stratum corneum involve ceramides, cholesterol and saturated long chain fatty acids15, 19. Another essential component of stratum corneum is water which acts as a plasticizer and prevents cracking and provides flexibility20.

 

Dermis

Once drug molecule is through the stratum corneum, it may pass through the deeper epidermal tissues and enter into the dermis. It is mainly made of fibrous tissues and is 1-2 mm thick. The dermis has a rich supply of blood vessels from where the drug gets absorbed into the general circulation (Samantha Andrews et al., 2012). Sebaceous glands, sweat glands, and hair follicles rises to the surface of the skin from dermis and subcutaneous layer where they originates3. The skin surface of human is recognized to contain an average of 10-70 hair follicles and 200-250 sweat glands on every centimeter square of the skin area10. The dermis has the following sublayers:

 

Papillary layer

It is the upper sublayer of the dermis that clearly segregates from the epidermis. Papillary layer is a loosely connected tissue and includes a large amount of nerve fibers, capillaries, water and cells (e.g. fibroblasts). In this sublayer, collagen fibers form a finer network than those of the reticular layer.

 

Reticular layer

It constitutes the lower part of the dermis and represents a continuous transition to the subcutis or hypodermis. Reticular layer has a denser and thicker network as compared to the papillary layer and includes fewer nerve fibers and capillaries. In this sublayer, collagen fibers are aggregated into thick bundles which are mostly aligned parallel to the surface of skin12.

 

Hypodermis

Subcutis, or hypodermis in histology, is the third layer beneath the dermis. Subcutis is an elastic layer and includes a large amount of fat cells that work as a shock absorber for blood vessels and nerve endings. The thickness of this layer is 4 to 9 mm on average. However, the actual thickness differs from person to person and it also depends on the body region12.

Figure 1.1: Structure of skin11

 

Routes of skin penetration

The main route of transport for water-soluble molecules is transcellular21. It involves the passage through the cytoplasm of corneocytes and lipid arrangement of the stratum corneum9. The pathway of transport for lipid-soluble molecules is intercellular; it implicates the passage apparently through the endogenous lipid within the stratum corneum21. The transcellular and intercellular route is collectively known as transepidermal route14, 22.


composition of stratum corneum.jpg

Figure 2: Transepidermal route23


However, it is an oversimplification of the situation as each route cannot be viewed in segregation. A molecule crossing via the transcellular route must partition into and diffuse through the keratinocytes, but in order to move to the next keratinocytes, the molecule must partition into and diffuse through the estimated 4-20 lipid lamellae between each keratinocyte. This series of partitioning into and diffusing across multiple hydrophilic and hydrophobic regions is unfavorable for most drugs10, 20.

 

Solute molecules may penetrate the skin through the hair follicles, sweat duct or through the sebaceous glands. These passages are collectively known as shunt or appendageal route21. It is generally accepted that the skin appendages comprises of approximately 0.1% of fractional area for drug permeation. Thus the main focus is to develop permeation strategies through the stratum corneum rather than through the appendages3, 20.

 

The passage through damaged skin is increased over normal skin. For example, skin with a disrupted epidermal layer will allow up to 80% of hydrocortisone to pass through the surface into the dermis as compared to 1% through intact skin21.

 

Two factors are involved in percutaneous absorption of drug; partitioning of active constituent between the vehicle and skin, and diffusion of active constituent in the stratum corneum. Percutaneous absorption is defined as penetration of substance into different layers of skin and permeation across the skin into systemic circulation. The percutaneous absorption is a step wise including: Penetration: the entry of a substance into a particular layer; Permeation: the penetration from one layer into another, which is different both functionally and structurally from the first layer; Absorption: the uptake of a substance into systemic circulation24.

 

In case of transdermal drug delivery system the transdermal absorption occurs through a slow process of diffusion which is driven by the gradient between the high concentration of drug in the drug delivery system and the zero concentration prevailing in the skin. Thus the delivery system must be kept in continuous contact with the skin for a considerable time25.

 

Methods of Modifying Barrier Properties of Stratum Corneum

The methods employed for modifying the barrier properties of the stratum corneum to enhance drug penetration and absorption through the skin may be classified into the following categories

·        Chemical enhancement

·        Physical enhancement

·        Biochemical enhancement

·        Supersaturation enhancement

·        Bioconvertable prodrug26

 

 

 

Advantages of TDDSs27-30

1.      The novel matrix formulation provide for the preservation of moderately uniform concentration of diffusible drug in the formulation, thereby avoiding the formation of drug-depleted regions within the topical formulation and helping to ensure relatively constant drug-release rate.

2.      Skin occlusion by the water-impermeable backing film aids systemic efficacy by increasing skin hydration and temperature with a subsequent increase in the rate and extent of skin permeation.

3.      The inclusion of skin penetration enhancers in the transdermal drug delivery system serve to decrease diffusional resistance and increase transport.

4.      The skin, particularly the stratum corneum, provides a large (1-2m2) surface area for drug diffusion

5.      Transdermal administration, as compared to other routes, is moderately noninvasive and helps in avoidance of the inconvenient parenteral therapy.

6.      Patients are willing to accept the use of a simple-looking patch as it can be easily applied and removed.

7.      Transdermal drug delivery system can avoid gastrointestinal drug absorption difficulties caused by gastrointestinal pH, enzymatic activity, interactions with food, drink and other orally administered drugs.

8.      They can be alternated for oral administration of medication when that route is not suitable, as with vomiting and diarrhea.

9.      They avoid the first-pass effect i.e. deactivation by digestive and liver enzymes of the initial pass of drug substance through the systemic and portal circulation following gastrointestinal absorption.

10.    They provide extended therapy with a single application thus improving compliance over most of the other dosage forms requiring more frequent dose administration.

11.    The activity of drugs having a short half-life is extended through the reservoir of drug in the therapeutic delivery system.

12.    Drug therapy may be terminated rapidly by removal of the patch from the surface of the skin.

13.    Patches can be self-administered.

14.    The transdermal patches avoid peak and trough drug levels and provides longer, multiday dosing interval.

15.    They have an ability to deliver drug at a more specific site.

16.    The transdermal drug delivery system allows an opportunity for the utilization of drug candidate with short half-life and low therapeutic index.

17.    The patches are easily identified in case of emergencies e.g. for unresponsive, comatose patients, because of their physical presence, features and identifying marks (Loan Honeywell Nguyen et al., 2005; Meghan Wilkosz et al., 2003).

 

Disadvantages10, 28, 31

1.      The increased residence time of patch on the skin surface leads to an increased incidence of skin maceration and adverse cutaneous reactions.

2.      Relatively potent drugs are suitable candidates for transdermal delivery because of the natural limits of drug entry imposed by the skin’s permeability. Effective skin permeation is limited to relatively small (<1 kD), lipophilic drug molecule.

3.      The increased residence time of patch may increase the chances of localized bacterial population.

4.      The transdermal drug delivery system is not suitable for drug with high doses.

5.      Adhesion of patch on skin may vary according to the patch size, skin type and environmental conditions.

6.      Patch location, age and person to person variability may play an important role in release of drug from the system.

7.      Some patients may develop severe skin allergic reactions to transdermal patches.

8.      Many drugs with a hydrophilic structure permeate the skin too slowly to be of therapeutic benefit.

9.      Damage to a transdermal patch can result in poor control over the release of drug.

10.    Drugs that have high melting point are poor candidates for transdermal drug delivery system due to their low solubility both in water and fat.

 

Penetration enhancer

Penetration enhancers are also known as accelerants, sorption promoter32 or permeation enhancer33. The barrier function is essential for the protective role of stratum corneum but at the same time it may hinder the transdermal delivery of drug through it34. As the major route of drug is through the intracellular channels, the lipid section is a viable determinant in the first step of absorption3.

 

Mechanism of action

Chemical permeation enhancers can work by one or more of the following three principle mechanisms:

·        Relaxation of the extremely ordered lipid structure of the stratum corneum.

·        Interacting with aqueous domain of bilayer of lipid.

·        Enhanced partition of the drug, by addition of co-enhancer or solvent into the stratum corneum.

 

Chemical permeation enhancers exert their effect through above modifications in the skin structure. Various Chemical permeation enhancers interact with the polar head groups through hydrogen bonding and ionic interactions. The resultant disruption of the lipid hydration spheres and change in head group properties cause the relaxation at the head portion. This relaxation can decrease the resistances of this lipid enriched domain for polar molecules. Another aspect can be an increase in the volume of the water layer resulting in more water flow to the tissue, a process known as solvent swelling, leading to increased cross sectional area for diffusion of polar molecules. A portion of free water becomes available, besides the water in structure, at the lipid interface. This process can also occur due to simple hydration.

 

With increased concentrations of solvents e.g. dimethylsulfoxide (DMSO), dimethylacetamide (DMA), and diethyltoluamide (DEET), propylene glycol (PG), a direct effect may be a temporal alteration in chemical composition of the bulk. In such cases so much of the solvent penetrates the aqueous domain of the tissue that it turns a good solvent for substances like corticosteroids and estradiol etc. Simply the resultant partition now privileges a raised percentage of the drug in the tissue. The solvent then is transferred into the dermis along with the drug due to concentration gradient thus created. Chemical permeation enhancers can also modify lipid bilayer by their insertion into the hydrophobic tails, disturbing compacting and permitting facilitated passage of lipid permeants. Further the addition of co-enhancers and solvents can show enhanced permeability of the drugs, probably by synergism35, 36, 37.

 

Fluidization of lipid bilayer

Penetration enhancers such as dimethyl sulphoxide (DMSO), alcohols and fatty acids have been demonstrated to modify the barrier property by fluidizing or loosening highly ordered bilayer structure of stratum corneum thus increasing its permeability. They do this function by forming microcavities or permeable pores within the lipid bilayer which increases the free volume ratio hence increasing the diffusion coefficient of the drug. These enhancers may also modify protein material in bilayer structure to enhance permeability34.

 

Lipid disruption

In some cases the penetration enhancers penetrates into and mix homogeneously with the lipids. They disorganize the intercellular lipids thereby forming aqueous channels within the stratum corneum which increases the permeability13.

 

Interaction with keratin

The penetration enhancers, such as DMSO, urea and surfactants, can also interact with the keratin filaments present in corneocytes which leads to disruption within the cell thereby increasing diffusion coefficient and permeability39.

 

Increased partitioning and solubility in stratum corneum

Penetration enhancers like ethanol and polyethylene glucol (PG) increases solubility within the stratum corneum because they shift the solubility parameter (δ) of the skin closer to their solubility parameter by disrupting the stratum corneum. This increases the miscibility and hence alters the partition coefficient20, 39.


 

Figure 3: Action of penetration enhancers within the intercellular lipid domain38


 

Ideal properties of penetration enhancer32, 37, 39, 40

The ideal properties of penetration enhancers are:

·        It should be pharmacologically inert.

·        It is should be nontoxic, nonirritating, and non-allergenic to the skin.

·        It should produce rapid onset of action; predictable and suitable duration of action for the drug used

·        Following removal of the enhancer, the stratum corneum should immediately and fully recover its normal barrier property.

·        The barrier function of the skin should decrease in one direction only i.e., they should permit therapeutic agents into the body and efflux of endogenous materials should not occur

·        It should be chemically and physically compatible with the delivery system.

·        It should be non-damaging to viable cells.

·        Inexpensive and cosmetically.

·        Penetration enhancer used should be economical.

 


Figure 4: Possible mechanisms of action of skin penetration enhancers41



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