TRANSDERMAL DRUG DELIVERY SYSTEMS

ROHIT GOYALM.PHARMACYSECTION-2

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Transdermal Drug Delivery system

CONTENTSIntroductionA brief review of skin structurePathway of transdermal permeationTypes of transdermal patchesPenetration enhancersProducts in the market

DEFINITION:-• These systems are used when our aim is to

deliver drugs through skin in a predetermined controlled fashion the result is transdermal drug delivery.

• ADVANTAGES:-• 1.Avoidence of risks and inconveniences of I.V

therapy.• 2.Reduce side effects due to optimization of the

blood concentration time profile.

MORE ADVANTAGES:-

• Drugs with very short half life. eg is NITROGLYCERIN when administered as transdermal patch release medicament at constant rate for a time period more than that obtainable with oral formulations.

• First pass metabolism in the liver and GI tract is avoided.

• Drugs with narrow therapeutic indices can be safely administered since better control of release is possible.

• Reduced need for active administration (some patches can last 7 days).

• The patch is noninvasive and dosage can be stopped by removal.

• Easy to apply and to monitor.

DISADVANTAGES:-

1.Drug dose is large.2.Drug has large molecular size.3.Drug is metabolized in skin.4.Drug is highly lipophilic and hydrophilic5.Drug undergoes degradation in skin.6.Drug is skin sensitizing and irritating.

A brief review of skin structure

STRUCTURE AND FUNCTION OF HUMAN SKINHuman skin is the largest organ of the human body providing

around 10% of the body mass of an average person and it covers an average area of 1.7m2. Whilst such a large and easily accessible organ apparently offers ideal and multiple sites to administer therapeutic agents for both local and systemic actions, human skin is a highly efficient self-repairing barrier designed to keep ‘the insides in and the outside out.’

The human skin consists of- 1.EPIDERMIS—*Stratum corneum*Stratum germinativum* Stratum spinosum* Stratum granulosum* Stratum lucidum 2. Dermis-The Dermis consists of two sub-layers:

* The Papillary dermis and* The Reticular dermis

The skin can be considered to have four distinct layers of tissue

1. Non-viable epidermis (stratum corneum)2. Viable epidermis3. Viable dermis4. Subcutaneous connective tissue (hypodermis)

Stratum Corneum:

stratum corneum comprises only around 10 µm thick when dry, although it may swell to several times this thickness when wet

stratum corneum serves to regulate water loss from the body whilst preventing the entry of harmful materials including microorganisms

The barrier nature of the stratum corneum depends critically on its unique constituents; 75-80% is protein, 5-15% is lipid with 5-10%

The stratum corneum is the outermost layer of the epidermis and is composed mainly of dead cells that lack nuclei.These are sloughed off during the day and replaced by new cells from the stratum germinativum.There is a high proportion of keratin, an insoluble protein, with a high proportion of disulfide bridges (from cysteine), and also a high level of glycine and alanine residues that allow strong H-bonds to neighbouring amino acids.

Stratum germinativum:

deepest layer of the epidermis new cells are generated for the renewal of the epidermal

layers of the skin. mitotic division is responsible for the generation of the new

epidermal skin cells.A newly formed cell will undergo a progressive maturation

called keratinisation as it migrates to the surface of the skin

Stratum spinosum:

The stratum spinosum (also known as the spinous layer or prickle cell layer) is found on top of the basal layer.

Stratum spinosumlayer consists of two to six rows of keratinocytes.

Stratum granulosum:

one to three cell layers thick the stratum granulosum contains enzymes that begin degradation of the viable cell components such as the nuclei and organelles. The granular cells are so called because they acquire granular structures

DERMIS:

The dermis is typically 3-5 mm thick and is the major component of human skin. It is composed of a network of connective tissue predominantly collagen fibrils providing support and elastic tissue providing flexibility

Subcutaneous Fat Layer:

The subcutaneous fat layer bridges between the overlying dermis and the underlying body constituents

This layer of adipose tissue principally serves to insulate the body and to provide mechanical protection against physical shock

What kind of drugs can be incorporated into a patch?

Compounds with low logP[partition coeff.] will not diffuse into skin lipids

However, compounds with high logP also have difficulties, this time associated with their diffusion out of the stratum corneum.

The accepted range of logP values is between 1 and 3.

Table 2.5- List of Selected Prescription Transdermal Products

DRUG NAME EXAMPLES OF BRAND NAME

Fentanyl Duragesic Clonidine catapres TTS Nicotine Nicoderm CQ, Nicotrol Nitroglycerine Nitro-Dur, Deponit Testosterone Testoderm TTS Estradiol Climara,Combipatch Scopolamine Transderm scop Oxybutynin Awaiting FDA approval Methylphenidate Awaiting FDA approval

Types of transdermal drug delivery systems

1.Monolithic(matrix)systems2.Reservior(membrane)systems3.Monolithic-reservior systems4.Microreservior type systems5.Drug in adhesive type systems

IMPORTANT NOTE:-

• The choice of these systems for controlling drug release depends upon the major rate limiting step in the absorption of drug from such devices.The two rate-limiting steps are:-

• 1.Rate of drug diffusion from the device R• 2.Rate of drug permeation through the stratum

corneum R’• The overall rate of drug transport is proportional

to the sum(R+R’).

1.Monolithic(matrix)systems:-

These systems are used when R’ is the rate –controlling step(R’<R) and drug has a large therapeutic index so that overdosing does not precipitate toxic reactions.The categories of matrix devices are-one in which drug is dissolved(below saturation levels) in the polymer matrix and other in which the drug is dispersed(much above saturation levels).

2.Reservior(membrane)systems:-

These are used when drug permeation rate is rapid and absoption should therefore by controlled by controlling drug realease(R<R’).It is suitable for potent drugs with low therapeutic indices where monitoring drug levels in a narrow range is essential.

3.Monolithic-reservior systems:-

It is basically a device having drug release kinetics intermediate between monolithic and reservior systems.Here the drug-polymer matrix is layered by a rate-controlling membrane.Release is controlled by diffusion of

drug through a thicker layer of polymer matrix.

Micro reservoir type transdermal patch(s):

The drug reservoir is formed by suspending the drug solids in an aqueous solution of water miscible drug solubilizer e.g. polyethylene glycol. The drug suspension is homogenously dispersed by a high shear mechanical force in lipophillic polymer, forming thousands of unleachable microscopic drug reservoirs (micro reservoirs). The dispersion is quickly stabilized by immediately cross linking the polymer chains in-situ which produces a medicated polymer disc of a specific area and fixed thickness. Occlusive base plate mounted between the medicated disc and adhesive form backing prevents the loss of drug through the backing membrane. This system is exemplified by development of Nitrodisc®.

4.Drug in adhesive type transdermal patch

LIMITATIONS:-

A major limitation of transdermal drug delivery system is poor skin penetrability of several drugs.This problem can be overcome by use of penetration enhancers such as

1.GLYCEROL2.PROPYLENE GLYCOL3.SODIUM LAURYL SULPHATE4.DIMETHYL SULPHOXIDE.

Some transdermal delivery systems available in market:-

Transdermal drug delivery Purpose System

MATRIX :- 1.Nitro-Dur In angina pectoris for 1

day RESERVIOR:- 1.Transderm Nitro In angina attack for 1 day 2.Catapress TTS In Hypertension for 1

week MATRIX-RESERVIOR:- 1.Nitrodisc Transdermal

administration for 1 day

NOVEL METHODS IN TOPICAL/TRANSDERMAL DRUG DELIVERY

New dosage forms and drug delivery systems providing

excellent improvement in drug therapy are termed as novel drug delivery systems. These are termed novel, due to recent development with satisfactory results in the field of drug delivery (Juliano et al., 1980). Some of these novel advanced transdermal technologies include (Prausnitz & Allen, 1998):

• Penetration enhancers• Iontophoresis• Electroporation and sonophoresis• Microfabricated microneedles and microchips• Vesicular approaches

PENETRATION ENHANCING TECHNIQUES

1.Chemical permeation enhancers:-

A substance that will increase the permeability of the epithelial barrier by modifying its structure also termed as accelerants or sorption promoters-can enhance drug flux.

Ideal Penetration Enhancer:- 1.Non-toxic, non-irritating, non-allergenic.

2.Immediate onset of increased permeability.

3.Immediate recovery of normal barrier properties upon

removed(reversible).

4.Physically and Chemically compatible with a wide

range of drugs.

Permeation enhancers used for TDDS

CategoryCategory ExampleExample

Solvents Solvents                        

Anionic Anionic surfactants surfactants

Nonionic Nonionic surfactants surfactants

   

Essential oils Essential oils                    

Methanol Methanol Ethanol Ethanol

Dimethyl sulfoxide Dimethyl sulfoxide Propylene glycol Propylene glycol 2- Pyrrolidone 2- Pyrrolidone

Isopropyl myristate Isopropyl myristate Laurocapram Laurocapram

Sodium lauryl Sodium lauryl sulfate sulfate

Sorbitan Sorbitan monolaurate monolaurate

Pluronic Pluronic

Cardamom oil Cardamom oil Caraway oil, Lemon Caraway oil, Lemon

oil oil

2.Iontophoresis:-

The electrical driving of charged molecules into tissue, passes a small direct current (approximately 0.5 mA/cm2) through a drug containing electrode in contact with the skin. The most popular electrodes are based on the silver/silver chloride redox couple.

Three main mechanisms enhance molecular transport: Charged species are driven primarily by electrical repulsion

from the driving electrode. Flow of electric current may increase the permeability of skin

and Electro-osmosis may affect uncharged molecules and large polar

peptides.

Limitations: Hair follicle damage is possible.

The basic principle of iontophoresis is that a small electric current is applied to the skin. This provides the driving force to primarily enable penetration of charged molecules into the skin. A drug reservoir is placed on the skin under the active electrode with the same charge as the penetrant. A indifferent counter electrode is positioned elsewhere on the body. The active electrode effectively repels the active substance and forces it into the skin . This simple electrorepulsion is known as the main mechanism responsible for penetration enhancement by iontophoresis. The number of charged molecules which are moved across the barrier correlates directly to the applied current and thus can be controlled by the current density. Other factors include the possibility to increase the permeability of the skin barrier in the presence of a flow of electric current and electroosmosis. Electroosmosis results when an electric field is applied to a charged membrane such as the skin and causes a solvent flow across this membrane. This stream of solvent carries along with it dissolved molecules. It enhances the penetration of neutral and especially polar substances

Iontophoresis

Iontophoretic Patches

Drawbacks of Iontophoresis:-

Inspite of its extensive application the drawbacks associated with the technology include the possibility of electric shock, skin irritation, burns and cost of treatment. Recent efforts in this technology have resulted in the design of iontophoretic electrodes, which avoids burns. The technique has gained acceptance for local therapy. Its application for systemic medication will require further research to elucidate simple means of drug delivery

3. Electroporation:-

The drawbacks associated with chemical enhancers and iontophoresis can be overcome to a certain extent by electroporation technology developed in recent years. This technology has been developed to overcome the most daunting challenges of transdermal drug delivery. The process involves the application of transient high voltage electrical pulse to cause rapid dissociation of the stratum corneum through which large and small peptides, oligonucleotides and other drugs can pass in significant amounts . The degree of enhancement achieved in vitro is related to the applied voltage, number and duration of the pulses offering the possibility of a controllable phenomenon.

• Skin electroporation (electropermeabilization) creates transient aqueous pores in the

lipid by application of high voltage of electrical pulses of approximately 100–1000 V/Cm for short time(milliseconds). These pores provide pathways for drug penetration that travel straight through the horny layer.

Electroporation

Sonophoresis:-

Another technique besides electroporation attempting to overcome the challenges of transdermal drug delivery involves the usage of high frequency ultrasound waves. The application of low frequency ultrasound was shown to increase the permeability of human skin to many drugs including high molecular weight proteins by several orders of magnitude thus making transdermal administration of these molecules potentially feasible. Low-frequency ultrasound is thus potential non-invasive technology for transdermal drug delivery.

Despite the excitement these findings have provoked it is necessary to maintain an appropriate perspective until several basic questions are answered with respect to mechanism

Sonophoresis

MICRONEEDLES

Microneedles are needles that are 10 to 200 µm in height and 10 to 50 µm in width They are solid or hollow and are connected to a reservoir which contains the active principle.

Needles of approximately with or without centre hollow channels are placed onto the skin surface so that they penetrate the stratum corneum and epidermis without reaching the nerve endings present in the upper dermis.

Microneedle arrays are applied to the skin surface so that they pierce the upper epidermis far enough to increase skin permeability and allow drug delivery, but too short to cause any pain to the receptors in the dermis. Therefore there is no limitation concerning polarity and molecular weight of the delivered molecules.

Products in the market:-

1.Clonidine

Works as an agonist of adrenaline at the presynaptic 2 adrenergic Product name = Catapres-TTS®

used to treat hypertension

2.Ethinylestradiol(EO)and Norelgestromin(N)

Product name = Ortho-Evra®

Used for ContraceptionType of patch = Drug-in-AdhesiveFrequency of application = weekly

OH

H

H H

Ethinylestradiol (an estrogen)

HO N

OH

H H

HO

H H

Norelgestromin (a progestin)

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3.Lidocaine

Product Name = Lidoderm®

Used for: analgesia of postheretic neuralgia (PHN), a painful condition caused by the varicella zoster virus (herpes zoster = shingles)

Type of Patch = Reservoir Frequency of Application = Daily

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4.Nicotine

Product name = Habitrol®, Nicoderm – CQ®, Nicotrol®, Prostep®

Used for: Smoking cessationFrequency of administration = Daily

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5.Nitroglycerin

Works by producing nitric oxide (NO), which then acts as a vasodilator

Product Names = Nitro-Dur®, Transderm-Nitro®

Used for: AnginaType of Patch = Nitro-Dur is Drug-in-adhesive Nitrodisc is reservoirFrequency of administration = Daily

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6.Estradiol

Product Name = Alora®, Climara®, Esclim®, Estraderm®, FemPatch®, Vivelle®, Vivelle-DOT®

Used for: Hormone replacementType of Patch: Drug-in-adhesiveFrequency of application = weekly

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7.Estradiol + Norethindrone

Product name = CombiPatch®

Used for: Hormone Replacement

O

OH

H H

H H

Norethindrone

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8.Oxybutynin

Works as competitive antagonist of the muscarinic acetycholine receptor

Product name = Oxytrol®

Used for: Overactive bladder (antispasmodic)Type of Patch: Drug-in-adhesiveFrequency of application = twice a week

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9.Scopolamine

Works as competitive antagonist of acetylcholine at the muscarinic receptor

Product Name = Transderm Scop®

Used for: Motion Sickness

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10.Lidocaine + Epinephrine

Product name = LidositeUsed for: Dermal anesthesiaType of Patch = Reservoir,

iontophoretic.Epinephrine acts as vasoconstrictor, thus prolonging the duration of action of lidocaine (by delaying resorption) at the site

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11.Testosterone

Product Names = Androderm®, Testoderm TTS®, Testoderm®

Used for: Hypogonadism

Currently available medications for transdermal delivery

DrugDrug Trade Trade namename

Type of Type of transdermtransdermal patchal patch

ManufacturerManufacturer IndicationIndication

Fentanyl Fentanyl Duragesic Duragesic Reservoir Reservoir Alza / Janssen Alza / Janssen Pharmaceutica Pharmaceutica

Moderate/ Severe pain Moderate/ Severe pain

NitroglycNitroglycerine erine

Deponit Deponit Minitran Minitran Nitrodisc Nitrodisc Nitrodur Nitrodur TransderTransdermNitro mNitro

Drug in Drug in adhesive adhesive Drug in Drug in

adhesive adhesive Micro Micro

reservoir reservoir Matrix Matrix

Reservoir Reservoir

Schwarz Pharma Schwarz Pharma 3M Pharmaceuticals 3M Pharmaceuticals

Searle, USA Searle, USA Key Pharmaceuticals Key Pharmaceuticals

Alza/Novartis Alza/Novartis

Angina Pectoris Angina Pectoris

Nicotine Nicotine Prostep Prostep Nicotrol Nicotrol

    Habitraol Habitraol

Reservoir Reservoir Drug in Drug in

adhesive adhesive    

Drug in Drug in adhesive adhesive

ElanCorp/Lederie ElanCorp/Lederie Labs Labs

Cygnus Inc./McNeil Cygnus Inc./McNeil Consumer Products Consumer Products

Ltd. Ltd. Novartis Novartis

Smoking Cessation Smoking Cessation

Testosterone Testosterone Androderm Androderm

   

Testoderm Testoderm

TTS TTS

Reservoir Reservoir

   

Reservoir Reservoir

Thera Tech/ Thera Tech/

GlaxoSmithKline GlaxoSmithKline

Alza Alza

HypogonadisHypogonadis

m in males m in males

Clonidine Clonidine Catapres-TTS Catapres-TTS Membrane matrix Membrane matrix

hybrid type hybrid type

Alza/Boehinger Alza/Boehinger

Ingelheim Ingelheim

Hypertension Hypertension

Lidocaine Lidocaine Lidoderm Lidoderm Drug in adhesive Drug in adhesive Cerner Multum, Inc. Cerner Multum, Inc. Anesthetic Anesthetic

Scopolamine Scopolamine Transderm Transderm

Scop Scop

Membrane matrix Membrane matrix

hybrid type hybrid type

Alza/Novartis Alza/Novartis Motion Motion

sickness sickness

Estradiol Estradiol

   

   

   

   

   

Ethinyl Ethinyl

Estradiol Estradiol

   

Climara Climara

   

Vivelle Vivelle

Estraderm Estraderm

Esclim Esclim

   

Ortho Evra Ortho Evra

Drug in adhesive Drug in adhesive

   

Drug in adhesive Drug in adhesive

Reservoir Reservoir

Drug in adhesive Drug in adhesive

   

Drug in adhesive Drug in adhesive

3M Pharmaceuticals/ 3M Pharmaceuticals/

Berlex Labs Berlex Labs

Noven Noven

Pharma/Novartis Pharma/Novartis

Alza/Novartis Alza/Novartis

Women First Women First

Healthcare, Inc. Healthcare, Inc.

Johnson & Johnson Johnson & Johnson

Postmenstrual Postmenstrual

Syndrome Syndrome

THANKS