TransdermalDrug Delivery

systems

R. Dinarvand, PhD

Professor of Pharmaceutics

Transdermal Drug Delivery Systems Transdermal Drug Delivery Systems (TDDS)(TDDS)

Diffusion of the drug through skin into the systemic circulation for distribution and therapeutic effect

Most TDD systems use passive delivery

Note the difference with topical dosage forms

Advantages of TDDSAdvantages of TDDS

Reduces first-pass metabolism effect and Reduces first-pass metabolism effect and GI incompatibilityGI incompatibility

Sustains therapeutic drug levelsSustains therapeutic drug levels Permits self-administrationPermits self-administration Non-invasive (no needles or injections)Non-invasive (no needles or injections) Improves patient complianceImproves patient compliance Reduces side effectsReduces side effects Allows removal of drug sourceAllows removal of drug source Long acting drug deliveryLong acting drug delivery

Limitations of TDDSLimitations of TDDS

• Poor diffusion of large molecules

• Skin irritation

• Only suitable for very potent drugs

• Skin is not for drug delivery!

• More expensive than oral drugs

TDDS marketTDDS marketItem 2003 2004 2005 2006 2007 2008

1 Contraception 35 60 100 220 440 631

2 Hypertension 220 235 265 295 330 473

3 Estradiol 550 600 660 750 840 1204

4 Methylphenidate 35 50 75 125 220 315

5 New Prescription 10 25 50 150 350 502

6 Skin Care 50 60 80 90 110 158

7 Testosterone 130 145 155 175 190 272

8 Narcotic Analgesic 750 800 900 1000 1100 1577

9 Nitroglycerin 360 410 440 490 560 803

Total 2140 2385 2725 3295 4140 5934

Skin structureSkin structure

Epidermis structureEpidermis structure

• basal layer: single layer; columnar; keratin 5/14; only skin cells that can divide stem cells transient amplifying cells (50% of basal cells) divide several times differentiate

• stratum spinosum: 3-10 cells thick (largest layer); keratin 1/10 migrate towards surface lose water, form desmosomes, become larger and flatter

• stratum granulosum: 2-3 cells thick; organelles begin degrading keratinocytes with keratohyaline granules: contain proflaggrin flaggrin (component of stratum corneum)

• stratum corneum (cornified layer): 15 cells thick; flat, polyhedral cells (corneocytes); no organelles or nuclei cytosol: mostly keratin filaments and flaggrin; encased in protein shell (involucrin, loricrin) lipid enriched membranes make up the extracellular space ‘mortar’ between keratinocytes; provides water barrier

Epidermis structureEpidermis structure

Skin functionsSkin functionsBody appearance and shape

Protection from mechanical impact (i.e. pressure, stroke) thermic impact (i.e. heat, cold) chemical impact (i.e. acids) microorganisms (bacteria, viruses, fungi) UV-radiation water loss

Immune functionBesides providing a biological barrier against microorganisms through its acidic pH-value, the skin is immunologically active through defense mechanisms in epidermis and dermis.

Temperature regulationThrough sweat-producing glands and the evaporation of sweat and water, the body temperature is controlled. Another mechanism for rapid cooling is vasodilation (widening of blood vessels). Through vasoconstriction (narrowing of blood vessels), heat loss is prevented.

SensationThrough nerve endings and receptors in the skin, sensations such as touch, pain, heat or cold are processes

Vitamin productionThe skin produces Vitamin D through exposure to ultraviolet radiation in sunlight.

Social-interactiveThrough paling, blushing and other expressions regulated by the autonomic nervous system, the skin serves as a communication system.

Drug transport mechanismDrug transport mechanism

Through skin pores, hair follicle, glandsThrough skin pores, hair follicle, glandsThrough cellsThrough cells

IntercellularIntercellular Intracellular (transcellular)Intracellular (transcellular)

Therapies That Use Transdermal Therapies That Use Transdermal Delivery of DrugsDelivery of Drugs

Therapy Drug Delivered by TDD

Motion Sickness ScopolamineAnti-angina NitroglycerineHypertension ClonidineSmoking Cessation NicotineHormone Replacement Therapy

EstradiolEstradiol/ProgestinTestosterone

Pain Management FentanylLidocaine

Permeability Coefficient Is the Critical Permeability Coefficient Is the Critical Predictor of Transdermal DeliveryPredictor of Transdermal Delivery

Transport = Flux = (mg/cmTransport = Flux = (mg/cm22/sec) = P x A x (C/sec) = P x A x (Cdd – C – Crr))

Permeability Coefficient = P = Permeability Coefficient = P = D x KD x K (cm/sec) (cm/sec) hh

Where Where A = Surface area of patchA = Surface area of patchD = Diffusivity of drug in membrane (skin)D = Diffusivity of drug in membrane (skin)K = Partition coefficient (patch/skin)K = Partition coefficient (patch/skin)C = Concentration in donor or receptor C = Concentration in donor or receptor

(patch or skin)(patch or skin)h = Thickness of membrane (skin)h = Thickness of membrane (skin)

Attributes of a Passive TDD Drug Attributes of a Passive TDD Drug CandidateCandidate

Daily dose (< 20 mg/day)Daily dose (< 20 mg/day)

Half-life (10 hours or less)Half-life (10 hours or less)

Molecular weight (< 500 daltons)Molecular weight (< 500 daltons)

Melting point (< 200 Melting point (< 200 ooC)C)

Skin permeabilitySkin permeability

Lipid solubility Lipid solubility [partition coefficient (Log P) between –1.0 and 4][partition coefficient (Log P) between –1.0 and 4]

Toxicology profileToxicology profile

(non-irritating and non-sensitizing to skin)(non-irritating and non-sensitizing to skin)

TDD System Design FactorsTDD System Design Factors

Therapeutic indicationTherapeutic indication

Desired drug delivery profileDesired drug delivery profile

- Dose level, duration, etc.- Dose level, duration, etc.

Skin adhesion profileSkin adhesion profile

Application siteApplication site

Ease of applicationEase of application

Patch size, shape, appearance, comfortPatch size, shape, appearance, comfort

Wear periodWear period

PackagingPackaging

Patch disposalPatch disposal

Patch costPatch cost

TDDS designsTDDS designs

Membrane control systemsMembrane control systems

Skin control systemsSkin control systems

TDD Patches: A System of ComponentsTDD Patches: A System of Components

Components must be chemically and Components must be chemically and physically compatiblephysically compatibleDrug formulation may or may not include Drug formulation may or may not include excipientsexcipientsBacking: provides protection from external Backing: provides protection from external factors during application periodfactors during application periodMembrane: moderates rate of drug releaseMembrane: moderates rate of drug releaseAdhesive: maintains contact with patient’s skin; Adhesive: maintains contact with patient’s skin; incorporates drug and excipients in drug-in-incorporates drug and excipients in drug-in-adhesive TDD systemsadhesive TDD systemsLiner: protects patch during storage; is Liner: protects patch during storage; is removed prior to applicationremoved prior to application

Component/CompositionComponent/Composition

Matrix devicesMatrix devices

Active agent in polymeric membrane, Active agent in polymeric membrane, adhesive, solvent, penetration enhancer, adhesive, solvent, penetration enhancer, backing,backing,

Reservoir devicesReservoir devices

Active agent, gelling agent or excipient, Active agent, gelling agent or excipient, solvent, penetration enhancer, adhesive, solvent, penetration enhancer, adhesive, membrane, backing, release linermembrane, backing, release liner

Matrix

Reservoir

TDD Patch ConstructionTDD Patch Construction

TDD Patch Construction ComparisonTDD Patch Construction Comparison

Matrix Reservoir

Simplified patch construction

Complicated patch construction

Complex formulation Simplified formulation

Skin controlled delivery Membrane moderated delivery

Thinner construction Multiple layers

Excellent skin conformability

Poor skin conformability

Efficient utilization of size Requires extended size

Low dose dumping potential Dose dumping potential

Additional Development StagesAdditional Development Stages

Clinical evaluationClinical evaluation

Formulation and manufacturing scale-Formulation and manufacturing scale-upup

Stability studiesStability studies

Analytical evaluationAnalytical evaluation

Regulatory submission and approvalRegulatory submission and approval

Transdermal System Design: Transdermal System Design: What’s Ahead?What’s Ahead?

Delivery of larger molecules using enhanced passive Delivery of larger molecules using enhanced passive and active delivery systemsand active delivery systems

Materials and formulations to reduce skin irritation, Materials and formulations to reduce skin irritation, enhance the adhesion profile, and improve comfort enhance the adhesion profile, and improve comfort and wearand wear

Patch designs with specialized drug delivery profilesPatch designs with specialized drug delivery profiles

Patches with features that aid in application and usePatches with features that aid in application and use

User and environmentally-friendly packaging User and environmentally-friendly packaging designsdesigns

IontophoresisIontophoresis

Non-invasive, needle-free

Rapid onset and cessation kinetics

Controlled, programmable and titratable drug delivery capabilities

Ability to provide smooth, variable or bolus plasma levels, singly or in combination, all in a single delivery system

Enhanced transdermal delivery for a broad range of compounds, including large drug molecules such as peptides and oligonucleotides

Minimal variability in the delivery profiles among patients and body sites

Potential for enhanced patient compliance and

control

IontophoresisIontophoresis

• Non-invasive, needle-free

• Rapid onset and cessation kinetics

• Controlled, programmable and titratable drug delivery capabilities

• Ability to provide smooth, variable or bolus plasma levels, singly or in combination, all in a single delivery system

• Enhanced transdermal delivery for a broad range of compounds, including large drug molecules such as peptides and oligonucleotides

• Minimal variability in the delivery profiles among patients and body sites

• Potential for enhanced patient compliance and control

SCIENTIFIC BASIS OF IONTOPHORESIS

The Nernst-Planck equation, seen below, is the traditional relationship accepted for describing transport of an ionic species across a membrane:

J = DzVFC/kT+ Cu - D(dC/dx)

where J = molar flux

D = diffusivity coefficient

C = the concentration (molar)

u = the convective flow of water

T = temperature

k = Boltzman's constant z = charge on the species

V = electric field F = Faraday's constant

PhonophresisPhonophresisPhonophoresis is the introduction of substances into the body by ultrasonic energy. Unlike iontophoresis which involves the transfer of ions into the tissue, phonophoresis transmits molecules - a different process although similar in concept.

Some of the common chemicals compounded for phonophoresis include:

Betamethasone Dipropionate

Dexamethasone

Dexamethasone / Lidocaine

Fluocinonide

Hydrocortisone

Hydrocortisone /Lidocaine

Ketoprofen / Naproxen

Piroxicam / Sodium Salicylate

How it worksHow it works

Sonophoresis facts:Sonophoresis facts:• Sonophoresis has been shown to be effective in the

formation of microscopic aqueous channels (Lacunae) through the bilayers of the epidermis.

• The optimum frequency range of the “sonic” waveform to achieve this is in the region of 20-25Khz with power outputs of less than 125mW/cm2. This waveform is pulsed for very short periods (typically 100ms) usually once per second.

• Sonophoresis has been shown to be even more effective when combined with iontophoresis, with further spectacular increases in the efficiency (up to 4000%) of active ingredient absorption in to the lower levels of the epidermis

Product Indication Transdermal HRT  

EstrogenVivelle® and Menorest®/Femiest®

Menopausal Symptoms

EstrogenVivelle® and Menorest®/Femiest

Osteoporosis

Second Generation Estrogen:Vivelle-Dot®/stradot®

Menopausal Symptoms

Second Generation Estrogen:Vivelle-Dot®/stradot®

Osteoporosis

Third Generation Estrogen Menopausal Symptoms/ Osteoporosis

Combination:Estrogen/Progestin CombiPatch®/Estalis®

 

Menopausal Symptoms

Second Generation Combination Estrogen/Progestin

Menopausal Symptoms/ Osteoporosis

Methyltestosterone Female Libido

Methylphenidate/MethyPatch®

Attention Deficit Hyperactivity Disorder

Lidocaine/DentiPatch® Dental Pain Control

overviewoverviewA cataplasm (TDDS) containing biphenylacetic acid as the antirheumatic pain deadener is marketed in Japan as SelTouch by Teikoku and has an area of 10 cm by 14 cm. It utilizes an aqueous gel which acts both as the adhesive and reservoir for the active.  This is a popular dosage form in China and Japan, and this size is typical of their commercial cataplasm patches.

 Patents can be found by searching the key words "Patch" and "Plaster" at USPTO.

 The general (ideal) criteria for selecting drugs for transdermal delivery as follows:

Molecular weight should be less than 500 da

Dose shoule be less than 10 mg

Log P should be between 1-3

Even if the the log P is less than 1 and the dose is potent , still it may be possible to delivery transdermally by manipulating the

patch size.

The selection of drugs for transdermal delivery is more often than not dictated by the clinical need and particularly drugs having short half life and which undergo First pass elimination may be suitable candidates

 The dose of the drug depend upon many variables,

solubility, kind of TDDS, Pka, Partition coeff...etc..