approaches for the design of transdermal drug delivery
TRANSCRIPT
APPROACHES FOR THE DESIGN OF TRANSDERMAL DRUG DELIVERY
SYSTEM
PRESENTED BY,VINEETHA K
DEPT. OF PHARMACEUTICS1st M.PHARM
NGSMIPS
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CONTENTSINTRODUCTIONADVANTAGESDISADVANTAGES
BASIC COMPONENTS
APPROACHES USED IN DEVELOPMENT OF
TDDS
REFERENCES
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INTRODUCTION• Definition:
Transdermal drug delivery is defined as a self contained discrete dosage form, which when applied to the intact skin, will deliver the drug at a controlled rate to the systemic circulation.
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BRIEF HISTORY OF TDDS.The NDDS may involve a new dosage form e.g., from thrice
a day dosage to once a day dosage form or developing a patch form in place of injections.
Throughout the past 2 decades, the transdermal patch has become a proven technology that offers a variety of significant clinical benefits over other dosage forms.
Because transdermal drug delivery offers controlled release of the drug into the patient, it enables a steady blood-level profile, resulting in reduced systemic side effects and, sometimes, improved efficacy over other dosage forms
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Transdermal drug delivery system was first introduced more than 20 years ago.
The technology generated tremendous excitement and interest amongst major pharmaceutical companies in the 1980s and 90s.
First transdermal patch was approved in 1981 to prevent the nausea and vomiting associated with motion sickness, the FDA has approved, throughout the past 22 years, more than 35 transdermal patch products, spanning 13 molecules.
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POTENTIAL BENEFITS OF TRANSDERMAL DRUG DELIVERY (ADVANTAGES)
• Controlled delivery resulting in more reliable and predictable blood levels.
• Easy to use.
• Avoids GIT absorption problems for drugs.
• Avoids First Pass hepatic metabolism of drugs.
• More improved and convenient, patient compliance.
• Self medication is possible.
• Reduces frequency of dosing.
• Rapid termination in case of toxicity is possible
• Maintains therapeutic level for 1 to 7 days.6
DISADVANTAGES• Daily dose of more than 10mg is not possible.
• Barrier function changes from person to person and within the same person.
• Local irritation is a major problem.
• Drug with long half life can not be formulated in TDDS.
• Uncomfortable to wear.
• May not be economical.
• Heat, cold, sweating (perspiring) and showering prevent the patch from sticking to the surface of the skin for more than one day. A new patch has to be applied daily
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Routes of drug absorption through skin
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ROUTES OF PERCUTANEOUS PERMEATION.
1. Trans epidermal: -passage of drugs through epidermis. Intracellular (transcellular pathway): in and across cell. Intercellular (paracellular pathway): between 2 cells.
2. Trans apendageal: -through one or more appendages, hair
follicles, pores etc. Trans follicular(shunt pathway): - avoids passing through stratum corneum,
pass through hair follicles and directly into sebaceous gland.
Trans eccrine: -through the sweat gland. 9
COMPONENTS:COMPONENT OF TRANSDERMAL DEVICE INCLUDE:
1) POLYMER MATRIX(RATE CONTROLLING POLYMER)
2) THE DRUG
3) PERMEATION ENHANCER
4) ADHESIVE
5) BACKING LAYER.
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Basic components of Transdermal drug delivery
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1.RATE CONTROLLING POLYMER.
Rate controlling polymer is in the form of membrane or matrix.
It is responsible for control of release by diffusion of drug through the rate controlling membrane or rate controlling matrix.
LIST OF POLYMERS USED:
NATURAL POLYMERS: Cellulose derivatives, Zein, Gelatin, Shellac, Waxes, Gums & Natural rubber
SYNTHETIC ELASTOMER : Polysiloxane, Silicon rubber, Nitrile, Acrylonitryle, Butyl rubber, Styrene butadiene rubber.
SYNTHETIC POLYMER : Poly vinyl alcohol, Poly vinyl chloride, Polyethylene, Poly propylene, Poly urea, PVP, Polymethacrylate
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2.DRUGFor successful developing transdermal delivery, drug should be chosen with great care physicochemical properties
1. Mol. wt. less than 1000 Daltons
2. Affinity for both lipophilic & hydrophilic phase
3. Drug should have low melting point.
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BIOLOGICAL PROPERTIES:
It should be potent with daily dose of few mg/ day.Half life of drug should be short.Non irritant to skin.
3.PERMEATION ENHANCERSAre compounds which are used to improve or alter the
permeability of skin by altering the barrier function of the skin. Some of these compounds might alter the structure of membrane.
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THERE ARE FOUR GROUPS OF PERMEATION ENHANCERS.:
1.Solvents: methanol, ethanol, DMSO, DMF(dimethyl formamide), propylene glycol, glycerol.
2.Surfactants : An ionic:dioctyl sulfosuccinate, sodium lauryl sulphate. Cationic : sodium glycolate, sodium taurocolate. Non ionic : pluronic CF 127,pluronic F-68.3. Binary systems: propylene glycol4. Misc. compounds: calcium thioglycolate
4. ADHESIVES. It is an important component which is necessary for attachment
of TDDS.
The fastening of all transdermal devices to the skin has been
done by using a pressure sensitive adhesive which can be
positioned on the face of the device or in the back of the device
and extending peripherally.
Both adhesive systems should fulfill the following criteria
(i)Should adhere to the skin aggressively, should be easily removed.
(ii)Should not leave an unwashable residue on the skin.
(iii) Should not irritate or sensitize the skin.
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5.Backing membrane They are flexible and provide a good bond to the drug
reservoir, prevent the drug from leaving the dosage form through top.
It is an impermeable membrane that protects the product during the use on the skin.
Contains formulation throughout shelf-life and during wear period
Must be compatible with formulation (non adsorptive) Printable E.g.: Metallic plastic laminate , plastic backing
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APPROACHES FOR THE DESIGN OF TRANSDERMAL DRUG DELIVERY SYSTEM.
1. POLYMER MEMBRANE PERMEATION CONTROLLED SYSTEM
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The drug reservoir is encapsulated in a shallow compartment.
Bounded by drug impermeable metallic plastic laminate backing layer .
A thin layer of drug compatible, hypoallergenic adhesive polymer. e.g. ethylene vinyl acetate copolymer.
External surface of polymer membrane there is a thin layer of pressure sensitive adhesive such as polyisobutylene.
Adhesive layer is further protected by released liner of peel off strip until it is ready to use.
Drug release takes place by 0 order kinetics.
Drug release controlled by controlling partition coefficient of drug, diffusivity & thickness of polymer membrane.
Dose dumping may occur if there is defect or tear in polymer resulting in toxic effect.
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E.g.Transderm nitro: Nitroglycerine releasing trans dermal system for once a day medication for angina pectoris – 2 layered patch.
a) A backing layer of aluminized plastic.
b) Drug reservoir containing nitroglycerine adsorbed on lactose, colloidal silicon dioxide & silicone medical fluid.
c) Ethylene or vinyl acetate copolymer.
d) Silicon adhesive. Transderm Scop: Scopolamine-releasing transdermal system
for 72 hr, prophylaxis of motion sickness. Catapres -TTS: Clonidine releasing transdermal system for 7 day therapy of hypertension. Estraderm: Estradiol-releasing transdermal system for treatment of menopausal syndrome for 3-4 days.
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The intrinsic rate of the drug release from this type of drug delivery system is defined by
Pm and pa respectively defined as:
Where, Km/r and ka/m are the partition coefficient for the interfacial partitioning of the drug from reservoir to the membrane and from the membrane to adhesive layer respectively. Dm and Da are diffusion coefficient and hm and ha are the thickness
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Substituting the pm and pa equation in equation 1
Which define the intrinsic rate of drug release from a membrane moderated drug delivery system.
2. POLYMER MATRIX DIFFUSION CONTROLLED TDDS SYSTEM
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The drug reservoir is obtained by homogenous dispersion of drug in hydrophilic or lipophilic rate controlling polymer .
Followed by cross linking of polymer chains.Or the drug & polymer is dissolved in common
solvent followed by evaporation of solvent in the mould under vaccum or at elevated temperature.
A medicated disc is obtained is glued onto an occlusive base plate in a shallow compartment made from drug impermeable backing layer.
Adhesive is applied along the circumference of the patch to form adhesive rim around the medicated disc.
Advantage is no dose dumping.Drug release will not be 0 order.
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E.g. of this type of system is nitro- dur I and nitro- dur II. for continuous transdermal fusion of nitroglycerine at a daily dose of 0.5 mg/cm2 for therapy of angina pectoris.Nitro dur II is modified version of I in which the drug is dispersed in acrylic based polymer adhesive with a resinous cross linking agent which result in much thinner and more elegant patch.
The rate of drug release from this type of system is defined as:
A is the initial drug loading dose dispersed in the polymer matrix and Cp and Dp are the solubility and diffusivity of the drug in the polymer respectively.Since only the drug species dissolved in the polymer can release .
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3.ADHESIVE DISPERSION-TYPE SYSTEM
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Drug reservoir is prepared by directly dispersing drug in rate controlling adhesive polymer like polyacrylate.
This medicated adhesive is coated onto a flat sheet of drug impermeable metallic plastic laminate by solvent casting or as a hot melt thereby producing a single drug reservoir layer.
Simplest of all transderm patches & thinnest. E.g. : Nitrodur 2- contains nitroglycerin.
This system can be modified by applying onto the medicated adhesive layer thin layers of non medicated rate controlling pressure sensitive adhesive layer to form adhesive diffusion controlled system.
E.g.: Frandol tape- isosorbide dinitrate.
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The rate of drug release in this system is defined by
where,
Ka/r is partition coefficient for the interfacial partitioning of the drug from the reservoir layer to adhesive layer
4.GRADIENT CONTROLLED TDDS
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R1> R2>R3
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Contains several adhesive layer with varying loading level of the drug to form a multilaminate adhesive device.
Adhesive layer closer to the backing layer may contain highest level of than the layer furthest away next to the skin there by creating a gradient of drug loading a multilaminate device forming a drug reservoir gradient control system.
Advantage is that they provide a zero order drug release.
E.g. : Deponit system- nitroglycerin
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The rate of drug release from this drug reservoir gradient controlled system is given by:
Thickness of the adhesive layer for drug molecules to diffuse through increases with time h(t)
5.MICRORESERVIOR TYPE OR MICROSEALED DISSOLUTION CONTROLLED SYSTEM
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Silicon elastomer the lipophillic polymer is used for dispersion technique to form unleachable microscopic sphere of drug reservoir.
The quick stabilization occur by cross linking of the polymer chain which produced medicated polymer disc with a constant surface area and fixed thickness according to requirement of drug release.
Extra coating is available as a biocompatible polymer to modify the mechanism and rate of drug release.
A trans dermal therapeutic system is produced by positioning the medicated disc at the centrally and surrounded bit with an adhesive rim.
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It is successfully utilized in the preparation of nitro-disc, a nitroglycerine releasing trans dermal therapeutic system used in angina pectoris.This system followed zero order release of drug without the danger of dose dumping.The rate of release of drugs of the micro reservoir system is defined by,
Where, m=a/b is the ratio of the bulk of the elution medium over drug solubility of the same medium and b is the ratio of drug concentration at the outer edge of the polymer coating for the drug solubility in the same polymer composition. n is the ratio of the drug concentration at the inner layer of the interfacial barrier over drug solubility in the polymer matrix.
Dl, Dp and Dd and hl, hp and hd; are diffusivities and thickness of liquid layer surrounding the drug particle, polymer coating membrane surrounding the polymer matrix and the hydrodynamic diffusion layer surrounding the polymer coating .
Kl, km and kp are the partition coefficient for the interfacial partitioning of the drug from the liquid compartment to the polymer matrix, from the polymer matrix to the polymer coating membrane and from the polymer coating membrane to the elution solution respectively
Sl and SP are the solubility of the drug in the liquid compartment and in the polymer matrix respectively.
The release of drug from this system can follow either a partition control or matrix diffusion control process depending upon the relative magnitudes of Sl and SP
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6. TRANSDERMAL DELIVERY OF THE MACROMOLECULE
Macromolecules such as Hormones, interferons, bioactive peptides can be delivered by Trans dermal delivery system.
The devices used for this purpose are divided in to two categories….
1. Devices based on ethylene vinyl acetate copolymers (EVAc).
2. Devices based on silicone elastomer.
This both the system utilize one common concept i.e.
Matrix must have channel to facilitate the release of macro molecule
This device is used as implants 36
RECENT APPROACHES1. IONTOPHORESIS:This method involves the application of a low level
electric current either directly to the skin or indirectly via the dosage form in order to enhance permeation of a topically applied therapeutic agent
Built-in battery layerComparable in size to a normal transdermal patch. e.g. : The Lectro PatchTreatment time : 20 minRecommended maximum current : 4mALidocaine (local anesthesia), dexamethasone (arthritis),
hydrocortisone (arthritis), acetic acid (calcified tendinitis) etc.
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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
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The technique offers number of advantages like: The benefits of bypassing hepatic first pass effect. Higher patient complianceDelivery of ionized and unionized drugs Enabling continuous or pulsatile delivery of drug Permitting easier termination of drug deliveryOffering better control over the amount of drug delivered Restoration of the skin barrier function without producing
severe skin irritationImproving the delivery of polar molecules as well as high
molecular weight compounds Ability to be used for systemic delivery or local (topical)
delivery of drugs
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2.Electroporation: Transient high-voltage electrical pulses, to cause rapid permeabilization
of the stratum corneum through which large and small peptides, oligonucleotides and other drugs can pass in significant amounts.
This method involves the application of high voltage pulses to the skin which has been suggested to induce the formation of transient pores. High voltages (100 V) and short treatment durations (milliseconds) are most frequently employed.
Other electrical parameters that affect permeation rate include pulse properties such as waveform, rate and number.
The technology has been successfully used to enhance the skin permeability of molecules with differing lipophilicity and size (i.e. small molecules, proteins, peptides and oligonucleotides) including biopharmaceuticals with molecular weights greater than 7kDA.23
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3.Microneedle-based DevicesThe very first microneedle systems,
described in 1976, consisted of a drug reservoir and a plurality of projections (microneedles 50 to 100 mm long) extending from the reservoir, which the stratum corneum and epidermis to deliver the drug.
The ALZA Corp. has recently commercialized a microneedle technology named Macroflux which can either be used in combination with a drug reservoir or by dry coating the drug on the microprojection array24, the latter being better for intracutaneous immunization
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4.Abrasion:The abrasion technique involves the direct removal or
disruption of the upper layers of the skin to facilitate the permeation of topically applied medicaments.
Some of these devices are based on techniques employed by dermatologists for superficial skin resurfacing (e.g. microdermabrasion) which are used in the treatment of acne, scars, hyperpigmentaion and other skin blemishes.
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5 .Needle-less InjectionThis is reported to involve a pain-free method of
administering drugs to the skin. Over the years, there have been numerous examples of
both liquid (Ped-O-Jet, Iject, Biojector2000, Medi-jector and Intraject) and powder (PMED device formerly known as Powderject injector) systems.
The latter device has been reported to successfully deliver testosterone, lidocaine hydrochloride and macromolecules such as calcitonin and insulin.
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6.Laser RadiationThis method involves direct and controlled
exposure of a laser to the skin which results in the ablation of the stratum corneum without significantly damaging the underlying epidermis.
Removal of the stratum corneum using this method has been shown to enhance the delivery of lipophilic and hydrophilic drugs.
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7.MicroporationMicroporation involves the use of microneedles that are
applied to the skin so that they pierce only the stratum corneum and increase skin permeability.
Microneedles are needles that are 10 to 200 µm in height and 10 to 50 µm in width.
Microneedles do not stimulate the nerves, so the patient does not experience pain or discomfort.
They are usually drug coated projections of solid silicon or hollow, drug filled metal needles.
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8. Sonophoresis: The application of high frequency ultrasound to enhance drug penetration.
Examples:. Lidocaine, hydrocortisone, salicylic acid. Sonophoresis is a process that exponentially increases the absorption of
semisolid topical compounds (transdermal delivery) into the epidermis, dermis and skin appendages.
Sonophoresis occurs because ultrasound waves stimulate micro-vibrations within the skin epidermis and increase the overall kinetic energy of molecules making up topical agents.
Application of ultrasound to the skin increases its permeability (sonophoresis) and enables the delivery of various substances into and through the skin
Sonophoresis, or ultrasound, creates holes in the skin, and allows fluids to travel into or out of the body.
When sound is emitted at a particular frequency, the sound waves disrupt the lipid bilayers. This method can be used for delivery of steroids, systemic drugs such as Insulin and antigens for vaccination.
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REFERENCES.1. Joseph RR, Vincent HLL. Controlled drug
delivery. 2nd Edn. Newyork : Marcel Dekker INC;1987.523-549 p.
2. Chein YW. Novel drug delivery system.2nd Edn. Newyork : Marcel Dekker INC;1992.301-344 p.
3. Guy RH, Hadgraft J. Transdermal drug delivery system.2nd Edn. Newyork : Informa health care;2003.1-25 p.
