Transcript chapter 10

10. Transdermal Drug Delivery
Systems
经皮给药系统
Contents
I.
II.
III.
IV.
V.
VI.
VII.
Factors affecting percutaneous absorption
Percutaneous absorption enhancer
Design features of transdermal drug delivery
system
Percutaneous absorption model
Advantages and disadvantages of TDDSs
Examples of transdermal drug deliver systems
General clinical considerations in the use of
TDDSs
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Transdermal drug delivery
systems (TDDSs) facilitate
the passage of therapeutic
quantities
of
drug
substances through the skin
and into the general
circulation
for
their
systemic effect.
经皮给药系统能促进具治
疗量的药物透过皮肤，进
入体循环发挥系统作用。

For transdermal drug delivery, it
is considered ideal if the drug
penetrates through the skin to
the underlying blood supply
without drug buildup in the
dermal layers.

理想的经皮给药系统时，药物
渗透入皮肤后，能够进入血液
而不在皮下蓄积。
(3M Transdermal Drug Delivery
http://www.3M.com/DDS)
Macroflux®
E-TRANS®
Benefits of TDDSs
 Eliminates potential pain associated with
injections
 No first pass metabolism in liver
 Eliminates gastrointestinal side effect
 Improves patient compliance due to simpler,
pain free delivery
 Potential for home administration
I. Factors affecting percutaneous
absorption
1. Drug concentration is an important factor.
（药物浓度是一个重要因素。）
2. The larger the area of application, the more
drug is absorbed.
（当药物应用面积增大，经皮吸收的药物量
增加。）
3. The aqueous solubility of a drug determines the
concentration presented to the absorption site,
and the partition coefficient influences the rate
of transport across the absorption site.
药物的水溶性决定了吸收部位的浓度，分配系
数影响吸收部位的药物转运速率。
Drugs generally penetrate the skin better in their
un-ionized form. Nonpolar drugs tend to across
the cell barrier through the lipid-rich regions,
whereas the polar drugs favor transport between
cells.
非解离型的药物透皮效果好。非极性药物易通
过富含脂质的部位跨越细胞屏障，而极性药物
则通过细胞转运。
4. Drugs with molecular weights of 100 to 800
and adequate lipid and aqueous solubility
can permeate skin. The ideal molecular
weight of a drug for transdermal drug
delivery is believed to be 400 or less.
分子量在100和800之间并且具有一定的脂
溶性和水溶性的药物能渗透入皮肤。理想
的经皮吸收系统的药物分子量应为400或
更小。
5. Hydration of the skin generally favors
percutaneous absorption. The TDDS acts as
an occlusive moisture barrier through which
sweat cannot pass, increasing skin hydration.
皮肤的水和作用通常有利于经皮吸收。TDDS
可以作为隔绝湿气的屏障（汗水不能通过），
使皮肤水合化程度增加。
6. Percutaneous absorption appears to be
greater when the TDDS is applied to a site
with a thin horny layer than with a thick one.
TDDS在角质层薄的部位比角质层厚的部位经
皮吸收好。
7. Generally, the longer the medicated
application is permitted to remain in contact
with the skin, the greater is the total drug
absorption.
一般而言，药物应用的时间越长，即与皮肤
接触时间越长，药物吸收总量越多。
II. Percutaneous absorption enhancers
There
is
great
interest
among
pharmaceutical scientists to develop
chemical permeation enhancers and
physical methods that can increase
percutaneous absorption of therapeutic
agents.
1.
Chemical enhancers
A chemical skin penetration enhancer
increases skin permeability by reversibly
damaging or altering the physicochemical
nature of the stratum corneum to reduce
its diffusional resistance.
化学吸收促进剂通过通过可逆地改变角质
层的理化状态，降低扩散阻力而提高皮肤
渗透率。
Increased hydration of the stratum corneum
solvent action
or
denaturation
A change in the structure of the lipids and lipoproteins
in the intercellular channels
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More than 275 chemical compounds have been
cited in the literature as skin penetration
enhancers; they include
acetone, azone （氮酮）,
dimethyl acetamide （二甲基乙酰胺）, dimethyl
formamide（二甲基甲酰胺）,
dimethyl sulfoxide (DMSO), 二甲基亚砜
ethanol,
oleic acid, 油酸
polyethylene glycol, propylene glycol （丙二醇）,
sodium lauryl sulfate （月桂醇硫酸钠）.
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The selection of a permeation enhancer
should be based on
its efficacy in enhancing skin permeation
its dermal toxicity
its physicochemical and biologic
compatibility with the system’s other
components.
2. Iontophoresis and sonophoresis
Iontophoresis is delivery
of a charged chemical
compound across the
skin membrane using an
electrical field.
（离子导入法是指在电场
作用下，带电荷的化合
物导入皮肤粘膜的一种
方法。）
Iontophoresisenhanced
transdermal
delivery has
shown some
promise as a
means of peptide
and protein
administration.
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A number of drugs have been the subject of
iontophoretic studies, they include
lidocaine
dexamethasone
amino acids,
peptides
insulin
Verapamil （维拉帕米）
Propranolol （普萘洛尔）
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Sonophoresis, is a process that
exponentially increases the absorption of
topical compounds (transdermal delivery)
with high-frequency ultrasound.
Sonophoresis occurs because ultrasound
waves stimulate micro-vibrations within the
skin epidermis and increase the overall
kinetic energy of molecules making up
topical agents.
Limited permeation due to lipid barrier
of the skin
Enhanced permeation by disruption of lipid
barrier cavitation
It is thought that high-frequency ultrasound
can influence the integrity of the stratum
corneum and thus affect its penetrability.
Among the agents examined are
 hydrocortisone,
 lidocaine,
 salicylic acid
in such formulations as gels, creams, and
lotions.

III. Design features of transdermal drug
delivery systems
TDDSs are designed to support the passage
of drug substances from the surface of the
skin through its various layers and into the
systemic circulation.
（将药物设计成经皮给药系统能使药物透过
皮肤表面、穿过皮肤的不同层进入体循
环）。
Transdermal drug delivery systems may be
constructed of a number of layers, including
1) an occlusive backing membrane to protect the
system from environmental entry and from loss of
drug from the system or moisture from the skin;
2) the drug at the skin-site;
3) a release liner, which is removed before application
and enables drug release;
4) an adhesive layer to maintain contact with the skin
after application.
Technically, TDDSs may
be categorized into two
types,
1) Monolithic （整体型）
 Monolithic
systems
incorporate
a
drug
matrix layer between
backing and frontal
layers.
（整体型在背衬层和正面
中间为含药骨架层）
1. Foil covertrip 2. Drug matrix
3. Release liner 4. Foil baseplate
5. Microporous tape 6. Absorbent
Pad 7. Occlusive overlay
The drug-matrix layer is composed of a
polymeric material in which the drug is
dispersed.
（药物-骨架层由分散有药物的聚合物组成）

The polymer matrix controls the rate at which
the drug is released for percutaneous
absorption.
（聚合物骨架控制经皮吸收药物的释放速率）
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In the preparation of monolithic systems, the
drug and the polymer are dissolved or
blended together, cast as the matrix, and
dried.
（在制备整体型时，药物和聚合物一起溶解或
混合，作为骨架并干燥）。
2) Membrane-controlled systems.
 Transderm-Nitro, Transderm-Scop
 Form-fill-seal from lamination process
Membrane-controlled transdermal systems
are designed to contain a drug reservoir, or
pouch, usually in liquid or gel form, a ratecontrolling membrane, and backing,
adhesive, and protecting layers.
（膜控型经皮给药系统设计为有药物储库或
药囊，通常以液态或粘胶态存在，含有控
释膜、背衬层、粘胶层和保护层。）

Membrane-controlled systems have the
advantage over monolithic systems in that as
long as the drug solution in the reservoir
remains saturated, the release rate of drug
through the controlling membrane remains
constant.
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膜控型比整体型的优点在于，只要药物贮
库中溶液保持饱和，药物通过控释膜的速
率保持恒定。
Delivery
Modifiers
Proprietary Drug
Delivery Systems &
Designs
Polymer
Technologies
Patch System
Designs
Micro-Delivery
Systems
IV. Percutaneous absorption models
1.
1)
2)
In vivo studies
In vivo skin penetration studies may be
undertaken for one or more of the
following purposes:
To verify and quantify the cutaneous
bioavailability of a topically applied drug.
To verify and quantify the systemic
bioavailability of a transdermal drug.
3) To establish bioequivalence of different
topical formulations of the same drug
substance.
4) To determine the incidence and degree of
systemic toxicologic risk following topical
application of a specific drug or drug
product.
5) To relate resultant blood levels of drug in
human to systemic therapeutic effects.

The most relevant studies are performed in
humans, however, animal models may be
used insofar as they may be effective as
predictors of human response.

Biologic samples used in drug penetration
and drug absorption studies include skin
sections, venous blood from the application
site, blood from the systemic circulation,
and excreta (urine, feces, and expired air).
2. In vitro studies
 Skin permeation may be tested in vitro using
various skin tissues (human or animal whole
skin, dermis or epidermis) in a diffusion cell.
 In vitro penetration studies using human
skin are limited because of difficulties of
procurement, storage, expense, and
variation in permeation.
 Animal skins are much more permeable
than human skin. One alternative that has
been shown to be effective is shed snake
skin（蛇蜕）.
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The material may be used in cell culture
studies or in standard diffusion cells.
Diffusion cell systems are employed in vitro
to quantify the release rates of drugs from
topical preparations.
In these systems, skin membranes or
synthetic membranes may be employed as
barriers to the flow of drug and vehicle to
simulate the biologic system.
V. Advantages and disadvantages of TDDSs
The advantages of TDDSs are:
1. They can avoid gastrointestinal drug
absorption difficulties caused by
gastrointestinal pH, enzymatic activity and
drug interactions with food, drink, or other
orally administered drugs.
2. They can substitute for oral administration
of medication when that route is unsuitable,
as in instances of vomiting and/or diarrhea.
3. They avoid the first-pass effect, that is, the
initial pass of a drug substance through the
systemic and portal circulation following
gastrointestinal absorption, theraby possibly
avoiding the drug’s deactivation by digestive
and liver enzymes.
4. The systems are noninvasive, avoiding the
inconvenience of parenteral therapy.
5. They provide extended therapy with a single
application, thereby improving patient
compliance over other dosage forms
requiring more frequent dose administration.
6. The activity of drugs having short half-lives
is extended through the reservoir of drug
present in the therapeutic delivery system
and its controlled release characteristics.
7. Drug therapy may be terminated rapidly by
removal of the application from the surface
of the skin.
8. Ease of rapid identification of the
medication in emergencies (e.g.,
nonresponsive, unconscious, or comatose
patient) due to the physical presence,
features and identifying-markings on the
TDDS.
The disadvantages of TDDSs are:
1. Only relatively potent drugs are suitable
candidates for transdermal delivery due to the
natural limits of drug entry imposed by the
skin’s impermeability.
（由于皮肤的不透过性，仅有部分活性大的药物适
合制成经皮给药。）
2. Some patients may develop contact dermatitis at
the site of application due to one or more of the
system components, necessitating
discontinuation.
（一些病人在用药部位可产生接触性皮炎，无法继
续用药。）
VI. Examples of transdermal drug
delivery systems
1.
Transdermal scopolamine

It was the first TDDS to receive
FDA approval.

The Transderm-Scop system is a
circular flat patch 0.2 mm thick
and 2.5 cm2 in area.
 The
TDDS contains 1.5 mg of scopolamine
and is designed to deliver approximately 1
mg of scopolamine at an approximately
constant rate to the systemic circulation over
the 3 day life-time of the system.
 The patch is worn in a hairless area behind
the ear. Because of the small size of the
patch, the system is unobtrusive, convenient,
and well accepted by the patient.
2. Transdermal Nitroglycerin
A number of nitroglycerin-containing
TDDSs have been developed, including
 Deponit (Schwarz)
 Minitran (3M Pharmaceuticals)
 Nitro-Dur (Key)
 Transderm-Nitro (Novartis)
Each of these products maintains
nitroglycerin drug delivery for 24 hours after
application.
 Nitroglycerin
is used widely in the
prophylactic （预防） treatment of angina.
 It
has a relatively low dose, short plasma
half-life, high peak plasma levels, and
inherent （固有的） side effects when taken
sublingually, a popular route.
 It
is rapidly metabolized by the liver when
taken orally, this first-pass effect is bypassed
by the transdermal route.
 The
various nitroglycerin TDDSs control the
rate of drug delivery through a membrane
and/or controlled release from the matrix or
reservoir.
 The rate of drug release depends on the
system. In the Transderm-Nitro system,
nitroglycerin 0.02 mg is delivered per hour
for every square centimeter of patch,
whereas in the Deponit system, each square
centimeter delivers approximately 0.013 mg
of nitroglycerin per hour.
 Not
all nitroglycerin systems have the same
construction. For example, the TransdermNitro TDDS is a four-layer drug pouch
system, whereas the Deponit TDDS is a thin
two-layer matrix system resembling.
 Patients should be given explicit
instructions regarding the use of
nitroglycerin transdermal systems.
Generally, these TDDSs are placed on the
chest, back, upper arms, or shoulders.
 The
patient should understand that physical
exercise and elevated ambient temperatures,
such as in a sauna, may increase the
absorption of nitroglycerin.
3. Transdermal clonidine
 The first transdermal system for
hypertension, Catapres TTS (clonidine
transdermal therapeutic system, Boehringer
Ingelheim), was marketed in 1985.
 Clonidine lends itself to transdermal
delivery because of its lipid solubility, high
volume of distribution, and therapeutic
effectiveness in low plasma concentrations.
 The TDDS provides controlled release of
clonidine.
 Catapres
TTS is available in several sizes,
with the amount of drug released
proportional to the patch size.
 To ensure constant release over the 7-day
use period, the drug content is greater than
the total amount of drug delivered.
 Catapres TTS is available in several sizes,
with the amount of drug released
proportional to the patch size.
 Clonidine
flows in the direction of the lower
concentration at a constant rate limited by a
rate-controlling membrane.
 The
system is applied to the hairless area of
intact skin on the upper outer arm or chest.
4. Transdermal Nicotine
 Nicotine TDDSs are used as adjuncts in
smoking cessation programs.
 In a blinded study, users of nicotine TDDSs
are more than twice as likely to quit smoking
than individuals wearing a placebo patch.
 The nicotine TDDSs provide sustained blood
levels of nicotine as “nicotine-replacementtherapy” to help the patient establish and
sustain remission from smoking.
 The
commercially available patches contain
from 7 to 22 mg of nicotine for daily
application during the course of treatment
ranging from about 6 to 12 weeks.
 A nicotine TDDS usually is applied to the
arm or upper front torso, with patients
advised not to smoke when wearing the
system.
 Some of the nicotine replacement programs
provide a gradual reduction in nicotine
dosage form during the treatment program.
5. Transdermal Estradiol
 The Estraderm TDDS delivers 17-estradiol
through
a
rate-limiting
membrane
continuously upon application to intact skin.
 Two systems provide delivery of 0.05 or 0.1
mg estradiol per day.
 Estradiol
is indicated for the treatment of
moderate to severe vasomotor symptoms
associated
with
menopause,
female
hypogonadism （性腺功能减退）, female
castration （ 女 性 卵 巢 切 除 术） , primary
ovarian failure （原发性卵巢功能衰竭）,
and atrophic (萎缩）conditions caused by
deficient endogenous estrogen production,
such as atrophic vaginitis and kraurosis
value.
Transdermal
administration
produces
therapeutic serum levels of estradiol with
lower circulating levels of estrone and
estrone conjugates than does oral therapy
and requires a smaller total dose.
 The
systemic side effects from oral
estrogens can be reduced by using the
transdermal dosage forms.
6. Transdermal testosterone
 Testosterone transdermal systems, Testoderm
(Alza) and Androderm (SmithKline Beecham),
are available with various delivery rates as
hormone replacement therapy in men who
have an absence or deficiency of testosterone.
 The TDDS is applied daily, usually in the
morning to mimic endogenous testosterone
release.
 Optimum serum levels are reached within 2 to
4 hours after application. The patch is worn 22
to 24 hours daily for 6 to 8 weeks.
7. Other transdermal therapeutic systems
 Diltiazem
地尔硫卓
 Isosorbide dinitrate 硝酸异山梨醇
 Propranolol 普奈洛尔
 Nifedipine 硝苯地平
 Mepindolol 甲吲洛尔
 Verapamil 维拉帕米
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Cardiovascular agents,
levonorgestrel/estradiol for hormonal
contraception,
Physostigmine(毒扁豆碱), xanomeline (占诺美
林)for Alzheimer’s disease therapy,
Naltrexone(纳曲酶) and methadone for substance
addiction,
Buspirone（丁螺环酮）for anxiety，
Bupropion （安非他酮） for smoking cessation，
Papaverine（罂粟碱） for male impotence，
VII. General clinical considerations in
the use of TDDSs
The patient should be advised of the
following general guidelines along with
product-specific instructions in the use of
TDDSs.
1. Percutaneous absorption may vary with the
site of application.
2. TDDSs should be applied to clean, dry skin
that is relatively free of hair and not oily,
irritated, inflamed, broken, or callused.
3. Use of skin lotion should be avoided at the
application site, because lotions affect skin
hydration and can alter the partition
coefficient between the drug and the skin.
4. TDDSs should not be physically altered by
cutting, since this destroys the integrity of
the system.
5. A TDDS should be removed from its
protective package, with care not to tear or
cut into the unit.
6. A TDDS should be placed at a site that will
not subject it to being rubbed off by
clothing or movement.
7. A TDDS should be worn for the full period
stated in the product’s instructions.
Following that period, it should be removed
and replaced with a fresh system as directed.
8. The patient or caregiver should be
instructed to cleanse the hands thoroughly
before and after applying a TDDS.
9. if the patient exhibits sensitivity or
intolerance to a TDDS or if undue skin
irritation results, the patient should seek
reevaluation.
10. Upon removal, a used TDDS should be
folded in half with the adhesive layer
together so that it cannot be reused.
Questions
1. Explain shortly
- transdermal drug delivery systems
- iontophoresis
- sonophoresis
- percutaneous absorption enhancers
2. What factors could affect percutaneous drug
absorption?
3. How to increase percutaneous absorption of drug
by physical and chemical methods?
4. What types of drugs could be designed as TDDSs
and how?
5. How to design transdermal drug delivery systems?
6. How to study the percutaneous absorption of drug
using in vitro and in vivo models?
6. What are the characteristics of transdermal drug
delivery systems?
7. How many different types of transdermal
nitroglycerin are in the market? Explain their
characteristics respectively.
8. What are the clinical considerations in the use of
TDDSs?