Download Introduction to Transdermal Drug Delivery

Transdermal
Drug Delivery systems
R. Dinarvand, PhD
Professor of Pharmaceutics
Transdermal Drug Delivery Systems
(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 TDDS
 Reduces first-pass metabolism effect and
GI incompatibility
 Sustains therapeutic drug levels
 Permits self-administration
 Non-invasive (no needles or injections)
 Improves patient compliance
 Reduces side effects
 Allows removal of drug source
 Long acting drug delivery
Limitations 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 market
Item
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
2140
2385
2725
3295
4140
5934
Total
Dermis width: 1-4 mm
Skin structure
Epidermis width: 0.07-0.15 mm
Epidermis structure
Epidermis 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
Skin functions
Body 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 function
Besides providing a biological barrier against microorganisms through its acidic pH-value, the skin is
immunologically active through defense mechanisms in epidermis and dermis.
Temperature regulation
Through 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.
Sensation
Through nerve endings and receptors in the skin, sensations such as touch, pain, heat or cold are processes
Vitamin production
The skin produces Vitamin D through exposure to ultraviolet radiation in sunlight.
Social-interactive
Through paling, blushing and other expressions regulated by the autonomic nervous system, the skin serves as a
communication system.
Drug transport mechanism
Through skin pores, hair follicle, glands
Through cells


Intercellular
Intracellular (transcellular)
Therapies That Use Transdermal
Delivery of Drugs
Therapy
Motion Sickness
Anti-angina
Hypertension
Smoking Cessation
Hormone Replacement
Therapy
Pain Management
Drug Delivered by TDD
Scopolamine
Nitroglycerine
Clonidine
Nicotine
Estradiol
Estradiol/Progestin
Testosterone
Fentanyl
Lidocaine
Permeability Coefficient Is the Critical
Predictor of Transdermal Delivery
Transport = Flux = (mg/cm2/sec) = P x A x (Cd – Cr)
Permeability Coefficient = P = D x K (cm/sec)
h
Where
A = Surface area of patch
D = Diffusivity of drug in membrane (skin)
K = Partition coefficient (patch/skin)
C = Concentration in donor or receptor
(patch or skin)
h = Thickness of membrane (skin)
Attributes of a Passive TDD Drug
Candidate
Daily dose (< 20 mg/day)
Half-life (10 hours or less)
Molecular weight (< 500 daltons)
Melting point (< 200 oC)
Skin permeability
Lipid solubility
[partition coefficient (Log P) between –1.0 and 4]
Toxicology profile
(non-irritating and non-sensitizing to skin)
TDD System Design Factors
Therapeutic indication
Desired drug delivery profile
- Dose level, duration, etc.
Skin adhesion profile
Application site
Ease of application
Patch size, shape, appearance, comfort
Wear period
Packaging
Patch disposal
Patch cost
TDDS designs
Membrane control systems
Skin control systems
TDD Patches: A System of Components
Components must be chemically and
physically compatible
Drug formulation may or may not include
excipients
Backing: provides protection from external
factors during application period
Membrane: moderates rate of drug release
Adhesive: maintains contact with patient’s skin;
incorporates drug and excipients in drug-inadhesive TDD systems
Liner: protects patch during storage; is removed
prior to application
Component/Composition
Matrix devices
Active agent in polymeric membrane,
adhesive, solvent, penetration enhancer,
backing,
Reservoir devices
Active agent, gelling agent or excipient,
solvent, penetration enhancer, adhesive,
membrane, backing, release liner
TDD Patch Construction
Reservoir
Matrix
TDD Patch Construction Comparison
Matrix
Simplified patch
construction
Reservoir
Complicated patch construction
Complex formulation
Skin controlled delivery
Thinner construction
Excellent skin
conformability
Simplified formulation
Membrane moderated delivery
Multiple layers
Poor skin conformability
Efficient utilization of size Requires extended size
Low dose dumping potential Dose dumping potential
Additional Development Stages
Clinical evaluation
Formulation and manufacturing scaleup
Stability studies
Analytical evaluation
Regulatory submission and approval
Transdermal System Design:
What’s Ahead?
Delivery of larger molecules using enhanced passive
and active delivery systems
Materials and formulations to reduce skin irritation,
enhance the adhesion profile, and improve comfort
and wear
Patch designs with specialized drug delivery profiles
Patches with features that aid in application and use
User and environmentally-friendly packaging
designs
Iontophoresis
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
Iontophoresis
• 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
Phonophresis
Phonophoresis 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 works
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
Estrogen
Vivelle® and Menorest®/Femiest®
Menopausal Symptoms
Estrogen
Vivelle® 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
overview
A 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..