Skin Structure

1
Skin Structure
2
Outline

• Skin anatomy
• Transdermal drug delivery and transport
  mechanisms
• Advantages and disadvantages
• Ficks 1st law
• Skin controlled drug input vs system controlled
• Transdermal device components
• Type of transdermal devices
• Transdermals on market
• Patient counseling

3
Skin Barrier Function

• Microbiological barrier
• Chemical barrier
• Radiation barrier
• Heat barrier and temperature regulation
• Electric barrier

4
Skin Structure
5
Scopolamine Transdermal AbsorptionPenetrated
through epidermis is rate-determining
Scopolamine is for motion sickness. Scop is the
1st transdermal device.
6
Strutum Corneum (SC)
7
Stratum Corneum (SC)(15-25 layers of dead cells)
8
Stratum Corneum (SC)SC is not uniform
Sole Lower leg Forehead Upper Thigh Lower arm
dorsal Palm Lower arm ventral Upper
arm Paraumbilical region Shoulder blade Axilla
(armpit)
9
ScopolamineLocation of the patch is important
10
Stratum Corneum (SC)
SC is in a dynamic state
11
Epidermal Proliferation Unit (EPU)
12
Effect of Age on SC Permeability
13
Effect of age on skin permeability
14
Water content/moisture effect
15
Structure of Stratum Corneum
16
Role of lipids in the formation of epidermal
laminar granules
From Transdermal Drug Delivery, Hadgrafft Guy
17
Unique Lipid Composition in SC
18
Unique lipid composition in the S.C.
Comparison of mammalian epidermal lipids
19
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20
Outline

• Skin anatomy
• Transdermal drug delivery and transport
  mechanisms
• Advantages and disadvantages
• Ficks 1st law
• Skin controlled drug input vs system controlled
• Transdermal device components
• Type of transdermal device
• Transdermals on market
• Patient counseling

21
Absorption pathways through SC
22
Outline

• Skin anatomy
• Transdermal drug delivery and transport
  mechanisms
• Advantages and disadvantages
• Ficks 1st law
• Skin controlled drug input vs system controlled
• Transdermal device components
• Type of transdermal device
• Transdermals on market
• Patient counseling

23
Advantages of Transdermal Delivery

• Bypass hepatic first pass
• Bypass gastrointestinal incompatibility
• Reduce side effects
• Provide predictable and extended duration of
  activity
• Greater patient compliance
• Reversibility of drug delivery for removal
• Minimize inter- and intrapatient variation

24
Hepatic First Pass Effect
25
Advantages of Transdermal Delivery

• Bypass hepatic first pass
• Bypass gastrointestinal incompatibility
• Reduce side effects
• Provide predictable and extended duration of
  activity
• Greater patient compliance
• Reversibility of drug delivery for removal
• Minimize inter- and intrapatient variation

26
GI Incompatibility
pH 1-3
pH 5-7
pH 7-8
pH 6.5
27
Advantages of Transdermal Delivery(continued)

• Self administration
• Can use drugs with short half-life
• Administration of drugs with narrow therapeutic
  window
• Zero order release
• Controlled release for accurate dosing
• Control of plasma levels of potent drugs

28
Half-Life of Some Transdermally Delivered Drugs

• Clonidine 12 7 h
• Fentanyl 3.7 0.4 h
• Nicotine 2.0 0.7 h
• Nitroglycerin 2.3 0.6 min
• Scopolamine 2.9 1.2 h
• Estradiol 1.8-3.7 h

The activity of these drugs can be extended
through the reservoir of the drugs present in the
transdermal delivery devices.
29
Advantages of Transdermal Delivery(continued)

• Self administration
• Can use drugs with short half-life
• Administration of drugs with narrow therapeutic
  window
• Zero order release
• Controlled release for accurate dosing
• Control of plasma levels of potent drugs

30
DTPA to chelate radioactive materials
31
Drug Release from Transdermal Patches
http//www.worldpharmaweb.com/ddcr/aut03/article6.
pdfsearch'transdermal20patch20zero20order20r
elease'
32
Disadvantages of Transermal Delivery

• Permeation of drugs through human skin is limited
• - Stratum corneum is the rate-limiting
  factor
• - Only potent drugs that do not require
  high plasma levels are suitable for
  delivery
• Skin irritation from adhesives, API, excipients
  and enhancers
• -- Contact allergic dermatitis (involves host
  immunological activity)
• -- Contact irritant dermatitis (direct toxic
  injury to cell membranes, cytoplasm or nuclei)
• Poor adhesive of transdermal devices

33
Definition

• Allergic contact dermatitis is an itchy skin
  condition caused by an allergic reaction to
  material in contact with the skin. It arises some
  hours after contact with the responsible
  material, and settles down over some days
  providing the skin is no longer in contact with
  it.
• Allergic contact dermatitis is distinct from
  irritant contact dermatitis, in which a similar
  skin condition is caused by excessive contact
  with irritants. Irritants include water, soaps,
  detergents, solvents, acids, alkalis, and
  friction. Irritant contact dermatitis may affect
  anyone, providing they have had enough exposure
  to the irritant.
• Allergy is the term given to a reaction by a
  small number of people to a substance (known as
  the allergen) which is harmless to those who are
  not allergic to it. Only small quantities of
  allergen are necessary to induce the reaction.
  Contact allergy occurs predominantly from the
  allergen on the skin rather than from internal
  sources or food. The first contact does not
  result in allergy often the person has been able
  to touch the material for many years without
  adverse reaction.

http//dermnetnz.org/dermatitis/contact-allergy.ht
ml
34
Outline

• Skin anatomy
• Transdermal drug delivery and transport
  mechanisms
• Advantages and disadvantages
• Ficks 1st law
• Skin controlled drug input vs system controlled
• Transdermal device components
• Type of transdermal device
• Transdermals on market
• Patient counseling

35
Passive Diffusion

• Definition Diffusion of substances across a
  membrane without the aid of another molecule or
  energy

http//bio.winona.msus.edu/berg/ANIMTNS/PassDiff.h
tm
36
Simple Passive Diffusion(driven by concentration
gradient)
http//bio.winona.msus.edu/berg/ANIMTNS/PassDiff.h
tm
37
Ficks First Law
J dM/(Adt) (mass/area/time) Flux (J) The
quantity of material (M) flowing through a
cross-section of a barrier (A) in unit time
(dt) J KD/h (Co-Ci) K Soct/Swater
(solubility of drug in Octanol/in water)
D Diffusion coefficient (area/time)
h thickness of the barrier (cm) C
concentration of drugs in each side of the
barrier.
38
Ficks First Law
J KD/h (Co-Ci) P (Co Ci) P KD/h
permeability coefficient K partition
coefficient (Relative SOLUBILITY in the membrane
and surrounding medium) D diffusion
coefficient (SPEED with which molecule can move
through a medium includes size and shape) D is
not a constant. It may change in value with
increased concentration, by temp, pressure,
solvent properties, and chemical nature of the
drug. h thickness of membrane (Implies "P" is
unique for each membrane)
39
Ficks First Law

• At steady state
• Input rate output rate
• Assume initial Ci 0 (sink condition)
• J (dM/dt)/A P Co
• Input rate dM/dt A P Co

40
Ficks First Law

• Output rate elimination rate Cls x Cpss
• Cls systemic clearance (V/time)
• The Clearance (Cl) of a drug is the volume
  of plasma from which the drug is completely
  removed per unit time. The amount eliminated is
  proportional to the concentration of the drug in
  the blood.
• Cpss Steady state plasma concentration
• When input rate output rate
• A P Co Cls Cpss
• Cpss A P Co /Cls

41
Estimation of P and S
Log P -2.72 0.71 log Koct 0.0061 MW Log S
- log Koct 1.11 ? Sf (mp T)/4.577 (273 T)
0.54 P permeation coefficient
S Co solubility ? Sf
entropy of formation m.p. melting
point T temperature
42
Effect of Melting Temperature on Permeability
From Transdermal Drug Delivery, Hadgraft Guy,
1989
43
Relationship Between K and J
J (dM/dt)/A P Co
Kp P permeability coefficient, Sw S Co
solubility in water
44
LogKoct of selected compounds

• Fentanyl 4.7
• Nicotine 1.17
• Nitroglycerin 2.0
• Scopolamine 1.24
• Estradiol 2.69
• Hydrocortisone 1.53

45
An example calculation

• Nitroglycerin
• MW 227, log Koct 2.05, Sw 5 mg/mL
• Log Kp -2.72 0.712.05-0.0061227 -2.6492
• Kp 0.0023 cm/h
• Jmax Kp Co 0.0023 5 11.5 mg/cm2/h
• Dose in 24 h from a 10 cm2 patch 11.5 24 10
  2.76 mg/day
• Systems on the market 5 mg/day

46
Another example

• Your favorite cpd, needs about 10 mg per day
• MW 268, log Koct 4.09 Sw 0.1 mg/ml
• logKp -2.72 0.71 4.09 0.0061268
• Kp 0.0354 cm/h
• Jmax Kp Sw 0.1 0.0354 0.00354 mg/cm2/h
• Dose of a 10 cm2 patch for 24 0.003541024
  0.85 mg
• To reach enough, one needs an area of 117702 cm2
• The total surface area of an adult human is only
  about 1.6-2 m2

47
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48
Outline

• Skin anatomy
• Transdermal drug delivery and transport
  mechanisms
• Advantages and disadvantages
• Ficks 1st law
• Skin controlled drug input vs system controlled
• Transdermal device components
• Type of transdermal devices
• Transdermals on market
• Patient counseling

49
Skin Controlled vs. Delivery System Controlled
Drug Input

• Skin controlled drug input system
  controlled drug input system

No rate controlling membrane
System controls the rate
Transderm-Scopolamine
Nitrodisc
50
Outline

• Skin anatomy
• Transdermal drug delivery and transport
  mechanisms
• Advantages and disadvantages
• Ficks 1st law
• Skin controlled drug input vs system controlled
• Transdermal device components
• Type of transdermal devices
• Transdermals on market
• Patient counseling

51
Basic Components of Transdermal Devices

• Polymeric matrix or matrices
• Drug (Pharmaceutically Active Ingredient)
• Permeation enhancers and other excipients
• Adhesives

52
Polymer Matrix or Matrices

• Support and regulate the release of the drug
• Over 50 various polymers which are either
  natural, synthetic elastomers, or synthetic
  polymers (see next page)
• Polyvinylpyrrolidone (PVP),
  ethylene-vinyl acetate copolymer, porous
  polypropylene, polyester
• Factors to consider
• -MW, chemical functionality
• -Should not react with the drug
• -Polymer and its degradation products
  must be non-toxic
• -Must not decompose in storage or use
• -Must be easily manufactured
• -Must be pharmacologically inert
• -Should be colorless, tasteless, and
  odorless
• -Should not be to costly

53
Matrix Materials

• Polymer (polypropylene, polyester)
• Cross-linked polymer
• Co-polymer
• Ethylene-vinyl acetate copolymer (EVA)
  (Estraderm)
• Poly (Vinyl alcohol)-co-(vinyl pyrrolidone)
  (Nitro-Dur)
• Polymer blend (PVA-PVP)

54
Ethylene-Vinyl Acetate Copolymer (EVA)Control of
release rate by modifying copolymer
55
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56
Drugs for Transdermal Delivery

• Be potent (10 mg to mg per day)
• Short half-life
• Narrow therapeutic window
• Lipophilicity/Hydrophilicity (predicted by
  Partition coefficient, K)
• MW and size of molecules
• Extent of skin binding
• 1st pass effect is high
• Non-irritating to the skin
• Clinical necessity for steady state delivery

57
Transdermally Delivered Drugs Should be Potent

• When input rate output rate
• A P Co Cls Cpss
• Cpss A P Co /Cls
• Co Cls Cpss / (A P)

58
Relationship Between K and J
59
Characteristics of Enhancers and Other Excipients

• Pharmacologically inert
• Non-toxic, non-irritating, non-allergenic
• Reliable and predictable
• Immediate recovery of the skin
• (reversible disruption of the skin)
• Compatible with the API

60
Enhancers and Other Excipients

• Lipophilic solvents
• Dimethylsulfoxide (DMSO)
• Dimethylformamide (DMF)
• 2-Pyrrvolidinone
• Surface active agents
• Sodium lauryl sulfate (SDS)
• Dodecyl methyl sulfoxide
• Two component system
• Propylene glycol-oleic acid
• 1,4 butane diol-linoleic acid

61
penetration enhancers
62
Some Chemical Enhancers
http//www.macrochem.com/site/pdf/SEPA.pdfsearch
'Azone20penetration20enhancer'
63
Phenolic compound permeability as a function of
relative humidity
Water is an ideal permeation enhancer
Filled circle Benzyl alcohol Open circle
phenol Triangle o-chlorophenol.
64
Water As An Enhancer
Hydration causes corneocyte swelling and keratin
bundle dissociation
65
Water As An EnhancerSwelling of corneocytes
66
Azone
Azone
Dodecylazacycloheptan-2-one or laurocapram
67
Structure of Azone
Azone
N-0915
68
Permeation of metronidazole through human skin
69
SEPASoft Enhancement of Percutaneous Absorption
Minoxidil is for hair growth
70
Effect of SEPA on Stratum Corneum
http//www.macrochem.com/site/pdf/SEPA.pdfsearch
'Azone20penetration20enhancer'
71
Cell Membrane
http//cellbio.utmb.edu/cellbio/membrane_intro.htm
Architecture
72
Mechanisms of Permeation Enhancement
73
Pharmaceutical Skin Penetration Enhancement, Ed.
KA Waters, J Hadgraft, 1993
74
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75
Physical Approaches to Enhance Permeability

• Needle-Syringe injection (Parenterals)
• Needle-free injection (PowderJet, BioJet)
• Tape stripping
• Iontophoresis
• Sonophoresis
• Electrophoresis
• Microneedle

76
Tape Stripping(removal of layers of stratum
corneum)
From 17 layers to 9 layers
77
Percutaneous Penetration of PEG 1000 Oligomers
Through Tape Stripped Mouse Skin (TEWL
transepidermal water loss)
Tsui et al., Arch Dermatol Res. 2003
295(4)169-74.
78
Removing S.C. to enhance vaccination efficiency
Vaccine. 2001, 20(1-2)42-8.
79
Needle-Free Injection
www.bioject.com and www.powderject.com
80
Biojector led to enhanced immune responses
J. Biotech. and EJPB.
81
Iontophoresis

• Mechanisms
• Electrophoresis
• Electro-osmosis
• Increased permeability

A transdermal delivery system in which a
substance, charged or uncharged, is propelled
through the skin by a low electrical current.
This method can be used to drive a drug across
the skin barrier, as is done with pilocarpine to
stimulate sweating in the sweat chloride test for
cystic fibrosis. Iontophoresis can also be used
in the reverse direction to draw a molecule
through the skin.
82
Iontophoresis Enhances Drug Permeation
L iontophoresis of insulin to decrease glucose
level
R iontophoresis of Luteinizing Hormone (LH)
83
Sonophoresis
Ultrasonic refers to sound waves whose frequency
is gt20 KHz Sonophoresis the movement of drugs
through living skin and into soft tissue under
the influence of an ultrasonic perturbation
Merino et al. J Pharm Sci. 2003 92(6)1125-37.
84
Fish vaccination
85
Microneedles
86
Adhesives

• Pressure sensitive adhesive
• Peripheral adhesive
• Face adhesive
• Factors to consider with adhesives
• Non-irritating/non-toxic
• Adhere to skin aggressively during dosing
• Easily removable
• Excellent contact with skin

87
Peripheral Adhesion
88
Face Adhesive
Polypropylene
Polyacrylic copolymer
Deponit Glyceryl Trinitrate
89
Pressure sensitive adhesion

• Pressure-sensitive adhesives can be defined as "a
  distinct category of adhesive tapes that in dry
  form are aggressive and permanently tacky at room
  temperature." PSAs will adhere to a variety of
  substrates when applied with pressure do not
  require activation by water, heat, or solvents
  and have sufficient cohesive strength to be
  handled with the fingers. The primary mode of
  bonding for a PSA is not chemical or mechanical
  but rather a polar attraction to the substrate,
  and always requires pressure to achieve
  sufficient wet-out onto the surface to provide
  adequate adhesion.

http//www.devicelink.com/mpb/archive/98/01/002c.h
tml
90
Fundamentals of adhesion

• The measured surface energy of the adhesive must
  be equal to less than that of the human skin.
• Kinetic requirement the material must possess
  sufficient mobility at room temperature. Under
  the condition of application, the adhesive must
  be able to flow sufficiently.
• Easily removable
• Must not leave any residue behind on the skin.

91
The critical surface tension of skin clean skin
is 28-29 dynes/cm
92
ADHESIVE PERFORMANCE FACTORS

• Tack how easily (in term of applied pressure)
  and how quickly a given adhesive can be applied
  on the skin
• Peel adhesion How difficult it is to remove the
  adhesive once it has been attached firmly
• Shear strength A measure of cohesive strength,
  reflects the ability of the adhesive to peel
  cleanly away from the substrate without leaving a
  residue
• http//www.devicelink.com/mpb/archive/98/01/002c.h
  tml

93
Adhesion requirements
The matrix systems are advantageous in that the
entire system can be made to be thin and elegant,
and being comfortable to wear. Also, there is
more flexibility in choosing the backing layer.
94
Adhesives for skin contact

• PIB-based adhesives (polyisobutylene)
• Acylic adhesives (dominates the medical PSA
  market)
• A mixture of hard and soft polymers
• Silicone-based PSAs
• long chain polydimethylsiloxane (PDMS) (Tg
  -140oC) benzene-soluble silicate resin.

95
Outline

• Skin anatomy
• Transdermal drug delivery and transport
  mechanisms
• Advantages and disadvantages
• Ficks 1st law
• Skin controlled drug input vs system controlled
• Transdermal device components
• Type of transdermal devices
• Transdermals on market
• Patient counseling

96
Type of Transdermal Devices
97
Membrane-Moderated (Reservoir)
Estraderm
Transderm-Nitro
98
Membrane-Moderated (Reservoir)
99
Drug-In-Adhesive
Glyceryl Trinitrate
100
Deponit Glyceryl Trinitrate
101
Monolithic Single Layer
Polypropylene
Polyacrylic copolymer
Deponit Glyceryl Trinitrate
102
Matrix - Monolithic Microreservoirs
103
3 M Transdermal Delivery Systems
104
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105
Outline

• Skin anatomy
• Transdermal drug delivery and transport
  mechanisms
• Advantages and disadvantages
• Ficks 1st law
• Skin controlled drug input vs system controlled
• Transdermal device components
• Type of transdermal devices
• Transdermals on market
• Patient counseling

106
Nature Reviews Drug Discovery 3, 115-124 (2004)
doi10.1038/nrd1304
107
http//www.3m.com/us/healthcare/manufacturers/dds/
pdf/DDT_Transdermal.pdfsearch'transdermal20drug
20delivery'
108
Catapres-TTS (Clonidine)
Estraderm (estradiol)
109
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110
17b-Estradiol

• A natural hormone used for the relief of
  post-menopausal syndromes and osteoporosis.
• Oral dosed undergoes significant 1st pass
• Short half-life 1 hr
• Not substantially metabolized by skin
• Convenient once to twice a week dosing on the
  trunk (abdomen, buttock)
• ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER
  

111
Estradiol

• Estraderm (Ciba) Release rate Surface area
  Total Estradiol
• (mg/day) (cm2)
  (mg)
• 0.05
  10.0 4.0
• 0.10
  20.0 8.0
• Climara (Berlex) 0.05
  12.5 3.9
• (0.0.25-0.1 six) 0.10
  25.0 7.8
• Vivelle (Novogyne) 0.025 2.5
  0.39
• 0.0375
  3.75 0.589
• 0.05
  5.0 0.78
• 0.075
  7.5 1.17
• 0.1
  10.0 1.56

112
Vivelle-Dot

• Vivelle-Dot contains estradiol in a
  multipolymeric adhesive. The system is designed
  to release estradiol continuously upon
  application to intact skin.
• A translucent polyolefin film
• An adhesive formulation containing estradiol,
  acrylic adhesive, silicone adhesive, oleyl
  alcohol, povidone, and dipropylene glycol
• A polyester release liner

113
Climara Dose Proportionality Study
6.5 cm2, 2.0 mg, 0.025 mg/d 12.5 cm2, 3.8 mg 0.5
mg/d
114
Effect of Application Sites on the Absorption
Single dose of 25 cm2 for a week in 38 menopausal
women (climara).
115
Evaluation of Once or Twice a week Dosing
12.5 cm2 Climara patch once or 3- and 4-day
applications of a 10 cm2 twice-a-week Estraderm
patch
116
Same vs. Alternative Sites
12.5 cm2 Climara patch
117
Transdermal Scopolamine

• Antimuscarinic drug, natural ingredient found in
  belladonna plant used for motion sickness
• 1st transdermal drug device approved by FDA
• Non-irritating
• Potent drug 200 mg
• Short-half life (2.9 1.2 h),
  anticholinergic side-effects when given orally

118

• Scopolamine
• MW 303.35, pKa 7.55-7.81.
• The Transderm Scop film 0.2 mm thick and 2.5
  cm2
• (1) Backing layer of tan-colored, aluminized,
  polyester film
• (2) Drug reservoir light mineral oil, and
  polyisobutylene
• (3) Rate controlling microporous polypropylene
  membrane
• (4) Adhesive formulation of mineral oil,
  polyisobutylene, and scopolamine.
• (5) A protective peel strip of siliconized
  polyester, which covers the adhesive layer

119
Clonidine

• An antihypertensive agent
• Oral drug undergoes significant 1st pass
• Highly lipid soluble
• Low therapeutic concentration (0.2-2
  ng/mL)
• Once a week

120
Nitroglycerin

• Antianginal drug used for prevention of angina
  pectoris due to coronary artery disease
• A Vasodilator
• Very short-half life (min)
• Extensive 1st pass
• Low dose (Cpss 1.2 10 ng/mL)
• Tolerance is common for long term use
• Side-effects include headache,
  dizziness, and hypotension, and skin
  irritation
• Transderm-Nitro (Novartis)
• Nitro-Dur (key)
• Deponit (Schwarz Pharma)

121
Deponit
122
Nicotine Patches

• To provide nicotine replacement therapy to obtain
  plasma levels of nicotine that would prevent or
  lessen the severity of the withdrawal symptoms
• Nicoderm (SKB) Release rate Surface
  area Total nicotine
• (mg/d)
  (cm2) (mg)
• 21
  22 114
• 14
  15 78
• 7
  7
  36
• Prostep (Berlex) 22
  7 30
• 11
  3.5 15
• Nicotrol (McNeil) 15
  30 24.9
• Habitrol (Basel) 21
  30 52.5
• 14
  20 35
• 7
  10 17.5

123
Nicotine Transdermals
124
Fentanyl (Duragesic)
DURAGESIC (fentanyl transdermal system) is a
transdermal system providing continuous systemic
delivery of fentanyl, a potent opioid analgesic,
for 72 hours. The chemical name is
N-Phenyl-N-(1-2-phenylethyl-4-piperidyl)
propanamide.
125
Fentanyl Duragesic

• The amount of fentanyl released from each system
  per hour is proportional to the surface area (25
  µg/h per 10 cm2)..
• DURAGESIC is a rectangular transparent unit
  comprising a protective liner and four functional
  layers. 1) a backing layer of polyester film 2)
  a drug reservoir of fentanyl and alcohol USP
  gelled with hydroxyethyl cellulose 3) an
  ethylene-vinyl acetate copolymer membrane that
  controls the rate of fentanyl delivery to the
  skin surface and 4) a fentanyl containing
  silicone adhesive. Before use, a protective liner
  covering the adhesive layer is removed and
  discarded.
• Do not cut or damage DURAGESIC. If the
  DURAGESIC system is cut, controlled drug
  delivery will not be possible

126
Oxytrol (Oxybutynin) for Overactive Bladder (OAB)
Layer 1 (Backing Film) is a thin flexible
polyester/ethylene-vinyl acetate film that
provides the matrix system with occlusivity and
physical integrity and protects the adhesive/drug
layer. Layer 2 (Adhesive/Drug Layer) is a cast
film of acrylic adhesive containing oxybutynin
and triacetin, USP. Layer 3 (Release Liner) is
two overlapped siliconized polyester strips that
are peeled off and discarded by the patient prior
to applying the matrix system.
127

• OXYTROL Oxybutynin Transdermal System
• OXYTROL is designed to deliver oxybutynin
  continuously and consistently over a 3- to 4-day
  interval after application to intact skin.
  OXYTROL is available as a 39 cm2 system
  containing 36 mg of oxybutynin. It has a nominal
  in vivo delivery rate of 3.9 mg oxybutynin per
  day through skin of average permeability
• Oxybutynin is an antispasmodic, anticholinergic
  agent.

128
Lidoderm (Endo Pharm)

• Lidoderm (lidocaine patch 5) is comprised of an
  adhesive material containing 5 lidocaine, which
  is applied to a non-woven polyester felt backing
  and covered with a polyethylene terephthalate
  (PET) film release liner. The release liner is
  removed prior to application to the skin. The
  size of the patch is 10 cm x 14 cm.
• Each adhesive patch contains 700 mg of lidocaine
  in an aqueous base.
• The Lidoderm patch is the only topical analgesic
  indicated to treat the pain of postherpetic
  neuralgia (PHN). 
• 12-hour once-daily dosing up to 3 patches at a
  time

129
Lidoderm for Postherpetic Neurogalia (PHN)

• PHN is the pain after the rash from shingles
  is gone
• Shingles are caused by chicken-pox infection
  of nerves
• Pain can last for 6 months
• Zostrix cream
• five-six times a day. It will take two to
  three weeks of use before the cream will start to
  work

130
Iontocaine (Iomed)
Drug Concentration List No. Container
Size Lidocaine HCl Epinephrine 018-71
Fliptop Vial 30 ml 2
1100,000
131
Iontocaine

• Lidocaine stabilizes the neuronal membrane by
  inhibiting the ionic fluxes required for the
  initiation and conduction of impulses, thereby
  effecting local anesthetic action. Epinephrine
  increases the depth and duration of anesthesia,
  presumably because of its vasoconstrictor
  activity, which decreases the rate of removal of
  lidocaine from the site of administration.
• Duration of anesthesia varied between 42 minutes
  to 110 minutes
• Doses of more than 40 mAmin (e.g., mA, 10 min)
  are not recommended.

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Ortho-Evra (Ortho-McNeil Pharm)

• The ORTHO EVRA birth control patch is a highly
  effective, weekly hormonal birth control patch
  that is worn on the skin to prevent pregnancy.
  The patch is worn for one week and replaced on
  the same day of the week for three consecutive
  weeks, with the fourth week "patch-free." ORTHO
  EVRA combines the efficacy of the birth control
  pill with once-a-week dosing.
• ORTHO EVRA contains two types of hormones
  estrogen (ethinyl estradiol) and progestin
  (norelgestromin). Once you apply the Patch to
  your body, low doses of these hormones are
  continuously transferred through your skin and
  into your bloodstream to help prevent pregnancy.
  
• ORTHO EVRA can be worn in several discreet
  locations buttock, abdomen, upper torso, or
  upper outer arm.

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Ortho-Evra for Birth Control
134
Testosterone
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Outline

• Skin anatomy
• Transdermal drug delivery and transport
  mechanisms
• Advantages and disadvantages
• Ficks 1st law
• Skin controlled drug input vs system controlled
• Transdermal device components
• Type of transdermal devices
• Transdermals on market
• Patient counseling

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Patient Instructions

• Wash your hands with soap and water before
  applying patch. Dry hands completely.
• Clean the area chosen with soap and water. Rinse
  and wipe the area completely dry with a clean
  tissue.
• Apply the patch at the same times of day.
• Apply to a non-hairy area of the body.
• Do not apply the patch on skin folds or wear
  under tight clothing.
• Do not use the same spot all the time but rotate
  to different areas.
• Do not apply a patch directly after showering,
  bathing, or swimming.
• Open the package and remove and throw away the
  protective backing. Do not touch the sticky side.
• Do not cut the patches.
• Attach the patch to the skin and press firmly in
  place for 10-15 sec. Run your finger along the
  outside edge of the patch to seal it.
• Remove the throw away the patch after the
  specified time or before applying the next patch.
• Repeat the above procedure.

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Topics

• Which layer of the skin is the rate-limiting
  layer for drug penetration?
• Characteristics of stratum corneum
• Ficks law, flux, relationship between flux and
  other parameters
• Advantages and disadvantages of TDD
• Requirements for drugs that can be delivered by
  the transdermal routes
• Permeation enhancers
• Transdermal devices
• Transdermals on the market

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In Vitro Methods
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In Vivo Methods
Surface residue In skin (tape stripping) In
systemic circulation In the excreta
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Surface residues
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Microdialysis