transdermal drug delivery systems
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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..
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