transdermal drug delivery system [tdds]

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Transdermal Drug Delivery System [TDDS] 12/25/21 SAGAR KISHOR SAVALE 1

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Page 1: Transdermal Drug Delivery System [TDDS]

Transdermal Drug Delivery System [TDDS]

05/01/23SAGAR KISHOR SAVALE1

Page 2: Transdermal Drug Delivery System [TDDS]

Contents:-

Introduction to TDDS’s

Basic Components of TDDS’s

Factors of TDDS

Penetration Enhancements

Percutaneous Absorption

Approaches used in TDDS’s

Production of TDDS’s

Model Drug Selection Criteria

Evaluation of TDDS05/01/23SAGAR KISHOR SAVALE2

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A] Introduction to TDDS’s-Management of illness through medication has entered an era of rapid growth. A variety of means by which drugs are delivered to the human body for the therapy such as tablets, capsules, injections, aerosols, creams, ointments, suppositories, liquids etc. are referred as a conventional drug formulations.

Among many pharmaceutical dosage forms, continuous intravenous infusion at preprogrammed rate has been recognized as a superior mode of drug delivery.

At present, the most common form of delivery of drugs is the oral route. It has the notable advantage of easy administration.

Contd...

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But these delivery systems having some Drawbacks-Oral- poor bioavailability hepatic metabolism (first pass) tendency to produce rapid blood level spikes need of high and/or frequent dosing

Intravenous- These mode of drug delivery entails certain risks and therefore necessities hospitalization of the patients and close medical supervision of the medication.

To overcome these difficulties there is a need for the development of new drug delivery system which will improve the therapeutic efficacy and safety of drugs by more precisely.

Contd...

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The integument as an organ The integument as an organ,

and is an alternative name for skin.

The integumentary system includes the skin and the skin derivatives hair, nails, and glands.

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The Integument Is the largest system of the body

16% of body weight, 1.5 to 2m2 in area, The integument is made up of two parts:

1. Cutaneous membranea. Epidermis– Superficial epitheliumb. Dermis – underlying CT with blood supply

2. Accessory structuresa. Hairb. Nailsc. Exocrine Glands

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Protection First line of defense against

Bacteria Viruses

Protects underlying structures from Ultraviolet (UV) radiation Dehydration

Vitamin D production Needed for calcium absorption

Sensation Sensory receptors

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Body temperature regulationIf too hot

Dermal blood vessels dilate Vessels carry more blood to surface so heat can escape

If too cold Dermal blood vessels constrict Prevents heat from escaping

ExcretionSmall amounts of waste products are lost

through perspiration

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Understanding how the skin can function in these many ways starts with understanding the structure of the 3 layers of skin

The Epidermis Epithelial tissue

Dermis Dense connective tissue proper – irregular

Hypodermis Subcutaneous tissue- loose connective tissue

proper and adipose tissue

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Epidermis

Dermis

Hypodermis or

subcutaneous layer

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The Epidermis Is a vascular stratified squamous epithelium

Nutrients and oxygen diffuse from capillaries in the dermis

Cells of the EpidermisKeratinocytes

Contain large amounts of keratinAre the most abundant cells in the epidermis

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The structural relationship andinterface between the epidermisand underlying dermis. Theproportions of the various layersdiffer with the location sampled.

Dermis

Epidermis

Epidermalridge

Dermalpapilla

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Thin SkinCovers most of the body Has four layers of keratinocytes

Thick SkinCovers the palms of the hands and soles of

the feetHas five layers of keratinocytes

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Structures of the Epidermis The five strata of keratinocytes in thick

skin From basal lamina to free surface

1. Stratum basale2. Stratum spinosum3. Stratum granulosum4. Stratum lucidum5. Stratum corneum

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Thick skin LM 210

Surface

Stratumcorneum

Stratumlucidum

Stratumgranulosum

StratumspinosumStratum basaleBasementmembrane

DermisPapillary layer of dermis

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Stratum BasaleIs attached to basement membrane by

hemidesmosomesForms a strong bond between epidermis and

dermisForms epidermal ridges (e.g., fingerprints) Dermal papillae (tiny mounds)

Increase the area of basement membraneStrengthen attachment between epidermis and dermis

Has many basal cells or germinative cells

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Thick skin SEM 25

Epidermalridge

Pores of sweatgland ducts

Epidermal ridges

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Stratum Spinosum — the “spiny layer”Produced by division of stratum basaleEight to ten layers of keratinocytes bound by

desmosomesCells shrink until cytoskeletons stick out (spiny)Continue to divide, increasing thickness of

epitheliumContain dendritic (Langerhans) cells, active in

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Stratum Granulosum — the “grainy layer” Stops dividing, starts producing

Keratin A tough, fibrous protein Makes up hair and nails

Keratohyalin Dense granulesCross-link keratin fibers

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Stratum Lucidum — the “clear layer”Found only in thick skinCovers stratum granulosum

Stratum Corneum — the “horn layer”Exposed surface of skin 15 to 30 layers of keratinized cellsWater resistantShed and replaced every 2 weeks

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The Dermis Located between

epidermis and subcutaneous layer

Anchors epidermal accessory structures (hair follicles, sweat glands)

Two components1. Outer papillary layer 2. Deep reticular layer

Der

mis

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The Papillary LayerConsists of areolar tissueContains smaller capillaries, lymphatics, and

sensory neuronsHas dermal papillae projecting between

epidermal ridgesThe Reticular Layer

Consists of dense irregular connective tissueContains larger blood vessels, lymphatic

vessels, and nerve fibersContains collagen and elastic fibersContains connective tissue proper 05/01/23SAGAR KISHOR SAVALE26

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An inflammation of the papillary layerCaused by

infection, radiation, mechanical irritation, or chemicals (e.g., poison ivy)

Characterized by itch or pain

CharacteristicsStrong, due to collagen fibersElastic, due to elastic fibersFlexible

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Hair

Papillarylayer

Reticularlayer

Cutaneousplexus

Papillaryplexus

Epidermalridges

Dermalpapillae

Capillary loopof papillary

plexus

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The Hypodermis (Subcutaneous Layer)Lies below the integumentStabilizes the skinAllows separate movement Made of elastic areolar and adipose tissuesConnected to the reticular layer of integument

by connective tissue fibersDeposits of Subcutaneous Fat

Distribution patterns determined by hormones

Reduced by cosmetic liposuction (lipoplasty)

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Transdermal Drug Delivery System

Contd...

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One of the methods most often utilized has been transdermal delivery - meaning transport of therapeutic substances through the skin for systemic effect in the form of patches that deliver drugs for systemic effects at a predetermined and controlled rate.

Definition- When the aim is to deliver drugs through skin in a predetermined & controlled release fashion, it is known transdermal drug delivery system.

It is a polymeric drug delivery system which contains drug either in a reservoir with a rate – controlling membrane or dispersed in polymer matrix.

Contd...

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Comparison between IV, Oral and TDDs:-I V Oral TDD

Reduced Liver First pass effect

Yes No Yes

Constant Drug Levels

Yes No Yes

Self-administration

No Yes Yes

Unrestricted Patient Activity

No Yes Yes

Non-invasive No Yes Yes

Contd...

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Advantages of Transdermal system:-

Dosage intervals not limited by gastric transit time.Avoid the first- pass effect.Noninvasive.Allows effective use of drug with short biological half- life.Drugs with narrow therapeutic indices can be safely administered. Drug therapy may be terminated rapidly by removal of the application from the surface of the skin.Self administration is possible.Single application has capacity for multi-day therapy, thereby improving patient compliance.Easy to prepare and easy to transport.

Contd...

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Disadvantages of Transdermal system:-

Only potent drugs are suitable Candidate.Unsuitable for drugs that irritate or sensitize the skin.These systems include variation in absorption efficiency at different sites of skinMaintaining contact between device & skin can be problem.Barrier function of skin changes from one site to another on same person, from person to person & with age.Some Patients develop contact dermatitis at the site of application.

Contd...

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These Route is Unsuitable when:-

Drug dose is large. Drug has large molecular size. Drug is skin sensitizing and irritating. Drug is highly lipophilic or hydrophilic.

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B] Basic Components Of Transdermal System:-

Polymer matrix / Drug reservoirDrugPenetration enhancersPressure sensitive adhesive (PSA)Backing laminatesRelease linerOther excipients like plasticizers and solvents

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Polymer matrix / Drug reservoir:-

Control the release of the drug. Prepared by dispersion. Should have biocompatibility and chemical compatibility.

Natural Polymer Synthetic Elastomer Synthetic Polymer

Gelatin Neoprene Polyethylene

Gum Arabic Silicone rubber Polystyrene

Starch Butyl rubber PVC

Shellac Chloroprene PVP

zein Polysiloxane Polyster

Contd...

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Drug:-

The foremost requirement of TDDS is that the drug possesses the right mix of physicochemical and biological properties.Biological properties-

Therapeutic IndexBiological half lifeSkin toxicity

Physicochemical properties-Mol. WtPartition coefficientDrug stabilityMelting point

Contd...

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Penetration Enhancers:-Two types of principles have been employed to increase drug permeation (and drug absorption) through skin: chemical and physical.

Chemical enhancers-Substance exist which temporarily diminish the

impermeability of the skin, known also as accelerants or sorption promoters.Examples-Sulphoxides and similar chemicals, Azone, Pyrrolidones, Fatty acids, Essential oils, terpenes, terpenoids, Oxazolidodienes and Urea.

Physical enhancers- Physical enhancement technologies have taken off

where the limitations of chemical enhancement have been reached. Methodologies involved in the physical transdermal delivery including: •Electrically-based techniques: iontophoresis, electroporation, ultrasound, photomechanical wave,•Structure-based techniques: microneedles, and •Velocity-based techniques: jet-propulsion

Contd...

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Pressure Sensitive Adhesives (PSA):-

A PSA is a material that helps in maintaining an intimate contact between transdermal system and the skin surface.It can be positioned on the face of the deviceSome widely used pressure sensitive adhesives are-

PolyisobutylenePolyacrylatesSilicones

Contd...

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Backing Laminate:-Hold and protect the drug reservoir from exposure to atmosphere.Avoid loss of drugAccept printing High flexibilityGood oxygen transmission and a high moisture vapor transmission rateExamples- vinyl, polyethylene and polyester films.

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. Part of primary packagingBase layer -Non-occlusive (e.g. paper fabric) or occlusive (e.g. polyethylene, polyvinylchloride).Release coating layer- silicon or Teflon.

Contd...

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Other Excipients:-Various solvents used to prepare drug reservoirEx- chloroform, methanol, acetone, isopropanol and dichloromethane.

Plasticizers are also added to provide plasticity to the transdermal patch.Ex- dibutylpthalate, triethylcitrate, polyethylene glycol and propylene glycol

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Factors affecting Transdermal permeation

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C] Penetration Enhancement:-Skin structure as it relates to drug penetration:-

The skin is a multilayered organ, complex in structure and function. It is composed of-Outer epidermis (outermost layered called STRATUM CORNEUM)Viable epidermis (stratum lucidum, stratum granulosum, stratum spinosum and stratum germinotive)Dermis

Contd...

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Enhancers:-Three pathways for drug penetration through the skin-Polar (cause protein conformational change or solvent swelling).Non-polar (alter the rigidity of lipid structure which substantially increase diffusion).Polar/non-polar (altering the multilaminated pathway for penetrants).

Contd...

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Classification Of Penetration Enhancement

Chemical

Physical

1. Sulphoxides and similar chemicals

2. Azone3. Pyrrolidones4. Fatty acids5. Essential oils,

terpenes and terpenoids

6. Oxazolidodienes7. Urea

A] Electrically based techniques-1. Iontophoresis2. Electroporation3. Ultrasound (sonophoresis)4. Photochemical waves5. Laser Ablation6. Combination of electrically based physical enhancement technique and chemical enhancers. B] Structured based technique-1. Micro needles C] Velocity based technique-1. Jet-propelled particles

Contd...

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Chemical Penetration Enhancement:-

Ideal characteristics of chemical penetration enhancers

Non-toxic, non-irritating and non-allergenicThe activity and duration of effect should be both predictable and reproducible.No pharmacological activity within the body.UnidirectionalBarrier properties should return to normal.Cosmetically acceptable with an appropriate skin feel.

Mechanism of chemical penetration enhancement:- Disruption of the highly ordered structure of stratum corneum lipid.Interaction with intercellular protein.Improved partition of the drug, co enhancer or solvent into the stratum corneum.

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1. Sulphoxides and similar chemicals:-

Aprotic solvent, colourless, odourless and hydroscopic It is known as ‘Universal Solvent’ for TDDs. The effect is concentration-dependant (›60% ) Cause erythema, denaturing of skin, burning sensation. Ex- showing a 12-fold increase in the flux of caffeine

permeating across a DMF-treated human skin, but it also shows irreversible damage to skin.

2. Azone:-

Azone (1-dodecylazacycloheptan-2-one or laurocapran) Colourless, odourless liquid with a melting point of -7 ºC Smooth, oily but yet non-greasyfeel. Soluble in most of organic solvent. Effect showing in 0.1-5% (more often between 1-3%)

Contd...

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3. Pyrrolidones:-

Used as permeation enhancers for numerous molecules including hydrophilic (e.g. mannitol and 5-flurouracil) and lipophilic (progesterone and hydrocortisone) permeants.Ex-N-methyl-2 pyrolidone was employed with limited success as a penetration enhancer for captopril when formulated in a matrix-type transdermal patch.

4. Fatty acids:-

Percutaneous absorption can be increased by long-chain fatty acids such as oleic acid.Ex- Oleic acid increase the flux 28 fold of salicylic acid and 56 of 5-flourouracil.

5. Essential oils, terpenes and terpenoids:-

It is used as medicinal use as well as flavoring agent and fragrance agent.Ex- Chenopodium found to be effective penetration enhancers for 5-flouorouracil transversing human skin.

Contd...

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6. Oxazolidinones:-

Potential for use in many cosmetic and personal care product formulations.It having ability to localize co-administered drug in skin layers, resulting in low systemic permeation.Ex- 4-decyloxazolidin-2-one -localize the delivery of retinoic acid and diclofenac sodium in skin layers.

7. Urea

Cyclic urea permeation enhancers are biodegradable and non-toxic molecules.Enhancement mechanism by lipid disruption mechanism.

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Physical Penetration Enhancement:-1. Iontophoresis:-

It acts by repulsion effect between charged electrode and solute(drug reservoir)Applied electric current of 0.5mA/cm2

Low M.W (‹500 Da)Ex- Lidocaine, metoclopramide plus hydrocortisone, vincristine etc,.

Contd...

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2. Electroporation:-

Process involves the application of large transmembrane voltages caused by electrical pulses (10μs–100ms).It cause formation of transient pores in the membrane that allow the passage for drug.Induce steady-state transport through skin with in minute.Controllable through manipulation of electrical pulse.

Contd...

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3. Ultrasound (or sonophoresis):-

Traditionally associated with physiotherapy, sports medicine and medical imaging than TDDs.It produces physical air pressure above topical skin.Deliver drug in low frequency range 20 kHz. (less than used in physiotherapy 1MHz)

Contd...

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4. Photochemical Waves:-

It also known as laser generated stress wavesPWs are the pressure pulses produced by ablation of a material target.It is not much more attention.

5. Laser Ablation:-

The use of lasers to remove the stratum corneum barrier by controlled ablation.It is reported that use of LAs on pig Stratum corneum- hydrocortisone.

6. Combination of electrically based physical enhancement technique and chemical enhancers.

Contd...

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Structured- based technique:-

Microneedle:-

They create a physical pathway through the upper epidermis to increase skin permeability.Made up of siliconSilicon needles individual measuring about 150μm in length and 80μm base diameter and fabricated on array of 3x3 mm (400 needles).

Contd...

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Velocity based technique-

Jet-propelled particles:-

It propel the drug into the skin.High velocity jet (100m/s) of compressed gas (helium).

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Absorbed in Surface of sebum

Transdermal

Trans follicular

Intracellular Pathway Intercellular Pathway

Stratum Corneum

Pilosebaceous Unit Eccrine Gland

Sebaceous GlandHair Follicles

Dermis

Microcirculation

Viable Epidermis

Percutaneous absorptionDrug can releases from dosage from

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Generally, drug absorption into the skin occurs by passive diffusion.

The rate of drug transport across the stratum corneum follows fick’s first law of diffusion.

dm/dt = J = d a k/h Where,

dm / dt = J = rate of diffusion / study state flux.d = diffusion coefficient.a = surface area of membrane.k = partial coefficient between the stratum corneum and the vehicle.h = diffusional path length / membrane thickness.

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In other words, the rate of drug transport depends not only on its aqueous solubility,

But is also directly proportional to its oil/water partition coefficient, its concentration in the formulation vehicle, and the surface area of the skin to which it is exposed;

It is inversely proportional to the thickness of the stratum corneum.

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D] Approaches Used in TDDs:-Approache

s

A) According to drug release mechanisms:-1. Matrix-diffusion controlled TDDS’s2. Membrane-permeation controlled TDDS’s3. Microreservoir type or Micro sealed dissolution controlled TDDS’s4. Adhesive dispersion type TDDS’s

B) According to rate controlling step:-1. Those control the rate of drug delivery to skin.2. Those allow the skin to control the rate of drug absorption.

C) According to polymer:-1. Hydrophilic or hydro gel system2. Hydrophobic or occlusion system

Contd...

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a] According to drug release mechanisms:-

1. Matrix-diffusion controlled TDDS’s:- Drug Reservoir- Dispersing drug particles in a

hydrophilic or lipophilic polymer matrix which is accomplished by:

Homogeneously mixing of grounded particlesLiquid

polymer

Highly viscous base polymer

Blending of particle with rubbery polymer

Molded in medicated discAlso by dissolving Drug and Polymer in common

solvent solvent evaporation method

Pasted on occlusive base plate

Impermeable plastic membrane

Contd...

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Example:- Nitroglycerin-releasing transdermal therapeutic system (Nitro-Dur ) for therapy of angina pectoris at a daily dose of 5mg/cm2.

Contd...

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2. Membrane-permeation controlled TDDS’s:-Drug reservoir- Grounded Drug particles

Dispersed in solid polymer matrix

Suspended in viscous liquid medium (silicon)

Rate-controlling polymeric membrane (EVA)

Adhesive polymer (silicon, PA)

The release of Drug from the system by rate- controlling polymer.Achieved by Polymer composition, permeability coefficient and thickness.

Contd...

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Examples:-•Nitroglycerine –releasing transdermal system (once a day for angina pectoris)•Scopolamine-releasing transdermal system (72hrs for motion sickness)•Clonidine-releasing transdermal system (7 days for hypertension)

The constant release of the drug is the major advantages of these approaches.

Contd...

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3. Microreservoir type or Micro sealed dissolution controlled TDDS’s:-It can be considered as a combination of the reservoir and matrix diffusion type drug delivery systems.Drug reservoir:- Drug particle

Drug suspension

Dispersing in a lipophilic polymer (silicon) by high dispersion technique

Spheres of DRMedicated disc

Surrounded by adhesive film

Aqueous solution (water-soluble liq. Polymer)

Contd...

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Example- Nitrodisc for angina pectoris (0.5mg/cm2 OD)The release of drug from this system can follow either a partition control or matrix diffusion-control process.

Contd...

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4. Adhesive dispersion type TDDS’s:-

Simple form of Membrane-permeation controlled TDDs.

Drug reservoir:- Drug particleDispersed in adhesive polymer (poly (isobutylene) or poly(acrylate) )

Medicated disc (solvent casting or hot melt)Impermeable film

Example-Isosorbide dinitrate,releasing TDDs for angina pectoris (OD)

Contd...

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b] According to rate controlling step:-

Those they control the rate of drug delivery to the skin. Potent, for maintaining MEC

Those that allow the skin to control the rate of drug absorption.

Having wide range of plasma drug concentration.c] According to polymer:-

Hydrophilic or hydro gel system:-Drug release by swelling mechanism.Patch of these type absorb water from the skin.Causes skin irritation & burning sensation.

Contd...

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Hydrophobic or occlusion system:-

Prevent losing of water from the skin.Swelling of Horny layer at skin surface.Increases the temperature and resulting in increase in molecular motion & skin permeation & decrease in protein network density.Causes sweat retention syndrome, irritation reaction.

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Production of TDDS’s:-There are 3 main steps in production of TDDS’s:-

Contd...

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General Scheme for Production :-

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Outline of Production of TDDS’s:-

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E] Model Drug Selection Criteria:-Most drugs are not suitable candidate for Transdermal drug delivery for one or more reason-

‘Easy to deliver’ drugs have already been commercialized into TDDs.To date 10 drugs out of 100 have been commercialized into TDDs.More than 35 patches spanning 13 molecules present in market.

For successfully developing a transdermal drug delivery system, the drug should be chosen with great care. The drug possesses the right mix of physicochemical and biological properties for transdermal drug delivery.

Contd...

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The following are some desirable properties of a drug for Selection of drug for transdermal delivery:-

Biological Properties:-Therapeutic Index:- Narrow therapeutic indexFirst-pass metabolism- drug which goes extensive to First-pass metabolism.Biological Half Life- Short (10hrs or less)Skin Toxicity- Should not irritant and sensitizing to skin.Dose- less than 20mg/day.Immunogenicity- Drug should not stimulate on immune reaction.

Contd...

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Physicochemical Properties:-Molecular Weight:- less than 500 Daltons.Partition coefficient- Should have octanol-water partition coefficient (LogP) value in range 1.0- 4.0 .Drug StabilitySkin permeability coefficient- greater than 0.5x10 cm/hr.Melting point- low (2000 F).

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Sr. No.

Evaluation Parameters

1 Percentage of Moisture Absorption

2 Percentage of Moisture Loss3 Thickness of Film4 Weight Variation5 Drug Content6 In vitro drug release study7 In vivo drug release study8 Stability test9 Sterility test10 Tensile strength11 Water Absorption test

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Physicochemical Evaluation of Transdermal Patches Thickness - travelling microscope, dial/screw gauge,

micrometer

Weight variation – weigh 10 patches

Drug content – by suitable validated analytical method

Folding endurance – repeatedly folding at same point until it break . The number of times it could be folded is its folding endurance value.

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Content uniformity- 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.

Microscopic study- SEM

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•Microscopic study- SEM

88

Microscopic view of gestodene TDDS

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Swellability-The degree of swelling (% S) was calculated using the formula

S (%) = Wt – Wo/Wo x 100Where S is percent swelling Wt is the weight of patch at time t and W o is

the weight of patch at time zeroSurface pH-Hardness-Physical appearance

All the Transdermal patches were visually inspected for color, clarity, flexibility, and smoothness

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Flatness one strip is cut from the centre and two from each side of patches. The length of each strip is measured and variation in length is measured by determining percent constriction. Zero percent constriction is equivalent to 100 percent flatness.

% constriction =[(I1-I2)/I1]X100 I2 = Final length of each strip I1 = Initial length of each strip Percentage of moisture content % Moisture content = Initial weight – Final weight X

100 Final weight  

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Percentage of moisture uptake-

% moisture uptake = Final weight – Initial weight X 100                                                 Initial weight Water Vapor Transmission study- WVT  = W/ ST                        W is the increase in weight in 24 h; S is area of

film exposed (cm2); T is exposure time .Tensile strength- Tensile strength= F/a.b (1+L/l)                      F is the force required to break; a is width of film; b is

thickness of film; L is length of film; l is elongation of film at break point

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Peel Adhesion properties Tack properties

I. Thumb tack testII. Rolling ball testIII. Quick stick (Peel tack) testIV. Probe tack test

Shear Strength

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05/01/23SAGAR KISHOR SAVALE93Figure: 1 Peel Adhesion Test

In this test, the force required to remove an adhesive coating form a test substrate is referred to as peel adhesion.

Molecular weight of adhesive polymer, the type and amount of additives are the variables that determined the peel adhesion properties.

A single tape is applied to a stainless steel plate or a backing membrane of choice and then tape is pulled from the substrate at a 180°C angle, and the force required for tape removed is measured.

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It is the ability of the polymer to adhere to substrate with little contact pressure. Tack is dependent on molecular weight and composition of polymer as well as on the use of tackifying resins in polymer

The force required to remove thumb from adhesive is a measure of tack.

This test measures the softness of a polymer.

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05/01/23SAGAR KISHOR SAVALE95 Figure: 2 Rolling ball tack test

In this test, stainless steel ball of 7/16 inches in diameter is released on an inclined track so that, it rolls down and comes into contact with horizontal, upward facing adhesive (Figure: 2).

The distance the ball travels along the adhesive provides the measurement of tack, which is expressed in inch

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Figure: 3 Quick stick (peel-tack) test

In this test, the tape is pulled away from the substrate at 90ºC at a speed of 12 inches/min. The peel force required breaking the bond between adhesive and substrate is measured (Figure-3) and recorded as tack value, which is expressed in ounces or grams per inch width .

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05/01/23SAGAR KISHOR SAVALE97Figure: 4 Probe Tack test

In this test, the tip of a clean probe with a defined surface roughness is brought into contact with adhesive, and when a bond is formed between probe and adhesive. The subsequent removal of the probe mechanically breaks it (Figure-4). The force required to pull the probe away from the adhesive at fixed rate is recorded as tack and it is expressed in grams.

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05/01/23SAGAR KISHOR SAVALE98 Figure: 5 Shear strength properties

Shear strength is the measurement of the cohesive strength of an adhesive polymer i.e. device should not slip on application determined by measuring the time it takes to pull an adhesive coated tape off a stainless plate.

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Comparison in In vitro and In vivo Transdermal permeation rates

Permeation rates (mcg/cm2/day) In vitro In vivo

Drugs Delivery systems

Hairless mouse

Human cadaver

Nitroglycerin

Nitro disc 435.6 - 713.0

Nitro dur 400.1 487.9 411.6Transderm- nitro

349.2 461.5 427.9

Deponit 269.5 - 282.5

Estradiol Estraderm 9.6 6.5 5.0Clonidine Catapres-

TTS68.9 49.2 38.9

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According to the International Conference on

Harmonization (ICH) guidelines by storing the TDDS

samples at 40± 2°C and 75 ± 5% RH for 6 months.

The samples were withdrawn at 0, 30, 60, 90 and

180 days and analyzed for drug content by suitable

analytical technique.

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Toxicological Evaluation-a) Contact dermatitis 1. contact irritant dermatitis 2. ten day primary irritation test 3. twenty one day irritation test 4. laser doppler 5. evaporative water loss measurement 6. contact allergic dermatitis b) Growth of microorganisms 1. localized superficial infections 2. miliaria(prickly heat)

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REGULATORY STRATEGY FOR INVESTIGATIONAL NEW DRUG (IND) APPLICATION AND NEW DRUG APPLICATION SUBMISSIONS FOR TDDS

Standard irritation and sensitization studies should be performed with the patch itself in

animals/humans. Negotiate the timing and implementation of the toxicology requirements. The dermatology division at FDA should review dermal aspects of the IND and New drug

Application(NDA). Primary review should occur at the division that handles the indication under study. Dose ranging studies be required in Phase 2. Single Phase 3 study could be negotiated.

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Drug Trade name Type of

transdermal patch

Manufacturer Indication

Fentanyl Duragesic Reservoir Alza / Janssen Pharmaceuticals Analgesic

Nitroglycerine

Deponit

Minitran

Nitro disc

Nitro- dur

Transderm-Nitro

Drug in adhesive

Drug in adhesive

Micro reservoir

Matrix

Reservoir

Schwarz Pharma

3M Pharmaceuticals

Searle, USA

Key Pharmaceuticals

Alza/Novartis

Angina Pectoris

Scopolamine Transderm- Scop Membrane matrix hybrid type Alza/Novartis Motion sickness

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References:-Chein, Y W, 1992, Novel Drug Delivery System, 2nd edition, vol-14, Marcel Dekker Inc, New York, pp- 301-314.Banker, G S, & Rhodes, C T, 2002, Modern Pharmaceutics, 4th edition, vol-121, Marcel Dekker Inc, New York, pp. 187-192.Hsieh, D S, 1994, Drug Permeation Enhancement, theory and

application, vol-62, Marcel Dekker Inc, New York, pp. 3-23.Roberts, M S, & Walters, K A, 1998, Dermal Absorption and

Toxicity Assessment, vol-91, Marcel Dekker Inc, New York, pp 297-309 371-375.Walters, K A, 2002, Dermatological and Transdermal

Formulation,vol-119, Marcel Dekker Inc, New York, pp 1-14 337-339.Brahmankar, D M & Jaiswal, S B, 2005, Biopharmaceutics and

Pharmacokinetics A Treatise, Vallabh prakashan, Delhi, pp-365-369.

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Sachan, N.K, et al, 2009, Transdermal Approaches in drug delivery, Der Pharmacia Lettre, pp 4-47.Heather, A E, 2005, Transdermal Drug Delivery: Penetration Enhancement Techniques, Current Drug delivery, vol-2, pp 23-33.Kandavilli, S, et al, 2002, Polymers used in Transdermal Drug delivery System, Pharmaceutical Technologies, pp 62-80.Pathan, B I, et al, 2009, Chemical Penetration Enhancers for Transdermal Drug delivery System, Tropical Journal of

Pharmaceutical Research, pp 173-179.Cross, S E, et al, 2004, Physical Enhancement of Transdermal Drug Application: Is Delivery Technology Keeping up with Pharmaceutical Development?, Current Drug Delivery, pp 81-92.Aggarwal, G, 2009, Development, Fabrication and Evaluation of Transdermal Drug Delivery System - A Review, Pharmainfo, Vol. 7 Issue 5.

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