TRANSDERMAL DRUG DELIVERY

PRESENTED BY..SUSHMITAM PHARM

Transdermal drug delivery can deliver drugs via the skin portal to systemic circulation at a predetermined rate and maintain clinically effective concentrarion over a prolonged period of time.

INTRODUCTION

Percutaneous Absorption The absorption of substances from

outside the skin to positions beneath the skin, including entrance into the blood stream

Penetration of the Skin by DrugsDrugs may penetrate intact skin after

topical application (a)through the walls of the hair follicles,(b) through the sweat glands or the sebaceous glands, (c) or between the cells of the horny layer.

Are designed to support the passage of drug substances from the surface of the skin, through its various layers, and into the systemic circulation.

TRANSDERMAL DELIVERY SYSTEMS

The main route for the penetration of drug is generally through the epidermal layers, rather than through the hair follicles or the gland ducts, because the surface area of the latter is rather minute compared to the area of the skin.

PENETRATION OF THE SKIN BY DRUGS

The percutaneous absorption of a drug generally results from direct penetration of the drug through the stratum corneum. Permeation of the laminate barriers in stratum

corneum can occur by diffusion via:

1. Transcellular penetration (across the cells)2. Intercellular penetration (between the cells)3. Transappendageal penetration (via hair follicles, sweat and sebum glands, and pilosebaceous apparatus)

Sebaceous glandCorneocytes

Intracellular lipid Transappendageal routeIntercellular route

Sweat ductHair follicle

Intracellular lipidmatrix

Epidermis

Dermis

Subcutaneous layer

STRUCTURE OF SKIN

Epidermis: The outer layer of skin is made up of Stratified Squamous epithelial cells. Epidermis is thickest in palms and soles.The stratum corneum forms the outer most layer (10-15µm thick ) which consists of many layers of compacted , flattened, dehydrated keratinized cells. Keratin contains cells called as Corneosites. Stratum corneum layer forms permeability barrier for external environment. 8

DERMIS: The dermis is made up of regular network of robust collagen fibers of fairly uniform thickness with regularly placed cross striations .This network or the gel structure is responsible for the elastic properties of the skin.It is supplied by blood to convey nutrients, remove waste & regulate body temp. Drug is well absorbed by this route.Upper portion of the dermis is formed into ridges containing lymphatics and nerve endings. 9

STRUCTURE OF SKIN

SUBCUTANEOUS TISSUE:

This is a sheet of the fat containing areolar tissue known as the superficial fascia attaching the dermis to the underlying structures .SKIN APPENDAGES:

Sweat glands produces sweat of pH 4-6.8 & absorbs drugs, secretes proteins, lipids and antibodies. Its function is to control heat.HAIR FOLLICLES

They have sebaceous glands which produces sebum and includes glycerides, cholesterol and squalene. 10

STRUCTURE OF SKIN

MECHANISM OF ABSORPTION THROUGH SKIN

Mechanism involved is passive diffusion This can be expressed by FICK’s LAW of DIFFUSION dq = D K A ( c1 – c2 ) dt h

dq /dt = rate of diffusion D = diffusion co-efficient K = partition co- efficient A = surface area of membrane H = thickness of membrane

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ROUTES OF DRUG ABSORPTION THROUGH SKIN

Trans follicular route

Trans epidermal route

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ROUTES OF DRUG ABSORPTION THROUGH SKIN

Trans follicular route: Fractional area available through this route is 0.1 % Human skin contains 40-70 hair follicles, 200 to 250

sweat glands on every sq.cm. of skin area. Mainly water soluble substance are diffused faster

through appendages than that of other layers. Sweat glands and hair follicles act as a shunt i.e. easy

pathway for diffusion through rate limiting ST corneum.

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ROUTES OF DRUG ABSORPTION THROUGH SKIN

Trans Epidermal route Epidermal barrier function mainly resides in horny layer The viable layer may metabolize, inactivate or activate a

prodrug. Dermal capillary contains many capillaries so residence

time of drug is only one minute. Within stratum corneum molecule may penetrate either

transcellularly or intercellular. Intracellular region is filled with lipid rich amorphous

material.

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ROUTES OF DRUG ABSORPTION THROUGH SKIN

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ADVANTAGESAvoidance of first pass metabolismAvoidance of gastro intestinal incompatibilityPredictable and extended duration of activityProvides utilization of drugs with short biological half livesNarrow therapeutic window Improving physiological and pharmacological response

Avoiding the fluctuation in drug levelsMaintain plasma concentration of potent drugsGreater patient compliance due to elimination of multiple dosing profileAbility to deliver drug more selectively to a specific siteProvide suitability for self administrationEnhance therapeutic efficacy

The drug must have some desirable physicochemical properties for penetration through stratum corneum.The transdermal delivery will be very difficult, if the drug dose required is more than 10 mg/day for their therapeutic application.Only relatively potent drugs are suitable candidates for TDDS.The barrier function of the skin changes from one site to another on the same person, from person to person and with age.

DISADVANTAGES

•Polymer matrix / Drug reservoir. •Drug. •Permeation enhancers. •Pressure sensitive adhesive (PSA). •Backing laminates.•Release liner.

BASIC COMPONENTS OF TDDS

POLYMER MATRIX / DRUG RESERVOIR

•Natural Polymers :Cellulose Derivatives, Zein, Gelatin, Shellac,Waxes, Gums and Chitosan.•SyntheticsElastomers:Polyisobutylene,Silicon Rubber, Nitrile,Acrylonitrile, Neoprene,Butylrubber.•SyntheticPolymers:Polyvinyl Alcohol,Polyvinylchloride,Polyethylene, Polypropylene,Polyacrylate, Polyamide,Polyurea,Polyvinylpyrrolidone.

PERMEATION ENHANCERS

Chemical Enhancers•Increasing the drug permeability through the skin by causing reversible damage to the SC.•Conditioning the SC to promote drug diffusion.•Increasing the partition coefficient of the drug to promote its release from the vehicle into the skin.Materials used to enhance absorption: surfactants, azone,dimethylsulfoxide(DMSO),dimethylacetamide, alcohol, acetone, propylene glycol, and polyethylene glycol.

Physical Enhancers: Iontophoresis Sonophoresis

Iontophoresis involves the delivery of charged chemical compounds across the skin membrane using an applied electrical field.Examples: lidocaine, amino acids/peptides/insulin, verapamil,

and propanolol

Sonophoresis, or high-frequency ultrasound, is also being studied as a means to enhance transdermal drug deliveryExamples: hydrocortisone, lidocaine, and salicylic acid in such formulations as gels, creams and lotions

PRESSURE SENSITIVE ADHESIVES(PSA)

A PSA maintains an intimate contact betweenpatch and the skin surface. It should adhere withnot more than applied finger pressure, beaggressively and permanently tachy, and exert astrong holding force. For example polyacrylates,polyisobutylene and silicon based adhesives.

BACKING LAMINATE

The primary function of the backing laminate is to provide support.Backing layer should be chemical resistant and excipient compatible because the prolonged contact between the backing layer and the excipient may cause the additives to leach out or may lead to diffusion of excipient,drug or penetration enhancer through the layer.

EXAMPLES of some backing material are Aluminium vapor coated layer,polyethylene,PVC films etc.

RELEASE LINER

During storage the patch is covered by a protective liner that is removed and discharged immediately before the application of the patch to skin. It is therefore regarded as a part of the primary packaging material rather than a part of dosage form for delivering the drug. Typically, release liner is composed of a base layer which may be non-occlusive(e.g. paper fabric) or occlusive (e.g.polyethylene, polyvinylchloride) and a release coating layer made up of silicon or teflon.

Backing Drug in adhesive Membrane Drug in adhesive Linear

FACTORS AFFECTING TRANSDERMAL PERMEABILITY

Physico chemical properties of parent molecule Solubility and partition co- efficient pH condition Penetrant concentration Physico chemical properties of drug delivery system Release characteristic Composition of drug delivery system Permeation enhancer used

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Physiological and pathological condition of skin Lipid film Skin hydration Skin temperature Effect of vehicle Pathological injury to skin

Biological factors Skin age Thickness of S. Corneum Skin condition

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Solubility and partition co- efficient: Solubility of a drug influences its ability to penetrate the skin. pKa is index of solubility of drug in vehicle and ST corneum has influence on transfer of drug from vehicle to skin.Drug solubility determines concentration presented to absorption site which will effect rate and extent of absorption. Skin permeation can be enhanced by increasing lipophilic character of drug, so that drug penetrates through STC but not through epidermis due to decreased water solubility. Drug which is lipid & water soluble is favored.

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pH & penetration concentration: Moderate pH is favorable because if solutions with high or low pH will result in destruction to the skin.

Higher the concentration of the drug in vehicle faster the absorption.

At higher concentrations than solubility the excess solid drug will function as a reservoir and helps to maintain a constant drug constitution for prolonged period of time.

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EVALUATION OF TRANSDERMAL PATCH

1.Physicochemical evaluation.2. In vitro evaluation.3. In vivo evaluation.

PHYSICOCHEMICAL EVALUATION

•Appearance.•Thickness.•Uniformity of weight.•Drug content determination.•Rolling ball tack test.•Thumb Tack test.•Skin Irritation study.•Moisture content.•%Moisture Uptake.•Tensile Strength.

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Thickness of the patch

The thickness of the drug prepared patch is measured by using a digital micrometer at different point of patch and determines the average thickness and standard deviation for the same to ensure the thickness of the prepared patch

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Content uniformity test 10 patches are selected and content is determined for individual patches. If 9 out of 10 patches have content between 85% to 115% of the specified value and one has content not less than 75% to 125% of the specified value , then transdermal patches pass the test of content uniformity. But if 3 patches have content in the range of 75% to 125%,then additional 20 patches are tested for drug content. If these 20 patches have range from 85% to 115%, then the transdermal patches pass the test

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Drug content determination

An accurately weighed portion of film (above 100 mg) is dissolved in 100 mL of suitable solvent in which drug is soluble and then the solution is shaken continuously for 24 h in shaker incubator. Then the wholesolution is sonicated. After sonication and subsequent filtration, drug in solution is estimated spectrophotometrically byappropriate dilution

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Moisture content:

The prepared films are weighed individually and kept in a desiccators containing calcium chloride at room temperature for 24 h. The films are weighed again after a specified interval until they show a constant weight. The percent moisture content is calculated using following formula. Initial wt. – Final Wt. % Moisture content = ---------------------------------X100 Final weight

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Moisture Uptake:

Weighed film sare kept in a desiccator at room temperature for 24 h. These are then taken out and exposed to 84% relative humidityusing saturated solution of Potassium chloride in a desiccator until a constantweight is achieved. % moisture uptake is calculated as given below. Final weight – Initial weight% moisture uptake =---------------------------------- X 100 Initial weight

TENSILE STRENGTH

To determine tensile strength , polymeric films are sandwiched separately by corked linear iron plates

One end of the films is kept fixed with the help of an iron screen and other end is connected to a freely movable thread over a pulley

1 2 3 4 5 6 7 8 9 10 11 12

WeightPulleyFilm

Thread

The weights are added gradually to the pan attached with the hanging end of the thread

A pointer on the thread is used to measure the elongation of the film. The weight just sufficient to break the film is noted

Tensile strength= F/a.b (1+L/l)

F= is the force required to break a=width of film b=thickness of film; L= length of filml=elongation of film at break point.

IN VITRO DRUG STUDIES

•The Paddle over Disc(USP apparatus 5)•The Cylinder modified USP Basket(USP apparatus 6)•The reciprocating disc(USP apparatus 7)

IN VIVO STUDIES

.Animal models. •Human volunteers.

APPLICATIONS OF TRANSDERMALPATCHES

•The highest selling transdermal patch in the United States is the nicotine patch, which releases nicotine in controlled doses to help with cessation of tobacco smoking.•Nitroglycerin patches are sometimes prescribed for the treatment of angina in lieu of sublingual pills.•The anti-hypertensive drug Clonidine is available in transdermal patch form.•Transdermal form of the MAOI selegiline, became the first transdermal delivery agent for an antidepressant.

EXAMPLES OF TDD SYSTEMS

1. Clonidine - Catapress -TTSFour-layered patch:(1) backing layer of

pigmented polyester film (2) drug reservoir of clonidine, mineral oil, polyisobutylene, and colloidal silicon dioxide, (3) a microporous polypropylene membrane controlling the rate of drug delivery, and (4) an adhesive formulation of agents

Uses: antihypertensive clonidine at a constant rate for 7 days, once a week dosing in the upper arm or torso.

2. Estradiol - Estraderm Four layered patch: (1) transparent polyester film,

(2) drug reservoir of estradiol and alcohol gelled with hydroxypropyl cellulose, (3) an ethylenevinyl acetate copolymer membrane, and (4) an adhesive formulation of light mineral and

polyisobutylene.Uses: design to release 17 B-estradiol continuously.

Applied twice weekly over a cycle of 3 weeks. The patch is generally applied to the abdomen,

altering sites with each application.

3. Nicotine - NicotrolMulti-layered rectangular patch: (1)outer backing of laminated polyester film, (2) rate-controlling adhesive, nonwoven material, and nicotine, (3) disposable liner removed prior to use - Aid in smoking cessation programs.

It is used as a temporary aid for smoking-cessation programs. It helps to control the symptoms of nicotine withdrawal (irritability, headache, fatigue, insomnia) and thus helps you to concentrate on overcoming the psychological and behavioral aspects of your smoking habit.

4.Nitroglycerin - Nitro - Dur Nitroglycerin in a gel like matrix composed of glycerin, water, lactose, polyvinyl alcohol, povidone and sodium citrate sealed in a polyester foil polyethylene laminate.

Use: to provide controlled release of nitroglycerin continuously for a 24 hour period. Patches are applied to inner part of upper arm, shoulders, or chest.

This is a band-aid-like patch inserted on your gum to numb it before an injection

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