Transdermal drug delivery system

1. 10. Transdermal Drug Delivery10. Transdermal Drug Delivery
SystemsSystems
皮 系经 给药 统皮 系经 给药 统

2. ContentsContents
I.I. Factors affecting percutaneous absorptionFactors affecting percutaneous absorption
II.II. Percutaneous absorption enhancerPercutaneous absorption enhancer
III.III. Design features of transdermal drug deliveryDesign features of transdermal drug delivery
systemsystem
IV.IV. Percutaneous absorption modelPercutaneous absorption model
V.V. Advantages and disadvantages of TDDSsAdvantages and disadvantages of TDDSs
VI.VI. Examples of transdermal drug deliver systemsExamples of transdermal drug deliver systems
VII.VII. General clinical considerations in the use ofGeneral clinical considerations in the use of
TDDSsTDDSs

3.  Transdermal drug deliveryTransdermal drug delivery
systems (TDDSs) facilitatesystems (TDDSs) facilitate
the passage of therapeuticthe passage of therapeutic
quantities of drugquantities of drug
substances through thesubstances through the skinskin
and into theand into the generalgeneral
circulationcirculation for theirfor their
systemic effect.systemic effect.
 皮 系 能促 具治经 给药 统 进皮 系 能促 具治经 给药 统 进
量的 物透 皮 ，疗 药 过 肤 进量的 物透 皮 ，疗 药 过 肤 进
入体循 系 作用。环发挥 统入体循 系 作用。环发挥 统

4.  For transdermal drug delivery, itFor transdermal drug delivery, it
is consideredis considered idealideal if the drugif the drug
penetrates through the skin topenetrates through the skin to
the underlying blood supplythe underlying blood supply
without drug buildup in thewithout drug buildup in the
dermal layersdermal layers..
 理想的 皮 系 ， 物经 给药 统时 药理想的 皮 系 ， 物经 给药 统时 药
透入皮 后，能 入血液渗 肤 够进透入皮 后，能 入血液渗 肤 够进
而不在皮下蓄 。积而不在皮下蓄 。积
(3M Transdermal Drug Delivery
http://www.3M.com/DDS)

8. MacrofluxMacroflux®®

9. E-TRANSE-TRANS®®

10. Benefits of TDDSsBenefits of TDDSs
 Eliminates potential pain associated withEliminates potential pain associated with
injectionsinjections
 No first pass metabolism in liverNo first pass metabolism in liver
 Eliminates gastrointestinal side effectEliminates gastrointestinal side effect
 Improves patient compliance due to simpler,Improves patient compliance due to simpler,
pain free deliverypain free delivery
 Potential for home administrationPotential for home administration

11. I. Factors affecting percutaneousI. Factors affecting percutaneous
absorptionabsorption
1. Drug concentration is an important factor.1. Drug concentration is an important factor.
（ 物 度是一个重要因素。）药 浓（ 物 度是一个重要因素。）药 浓
2. The larger the area of application, the more2. The larger the area of application, the more
drug is absorbed.drug is absorbed.
（当 物 用面 大， 皮吸收的 物药 应 积增 经 药（当 物 用面 大， 皮吸收的 物药 应 积增 经 药
量 加。）增量 加。）增

12. 3.3. The aqueous solubility of a drug determines theThe aqueous solubility of a drug determines the
concentration presented to the absorption site,concentration presented to the absorption site,
and the partition coefficient influences the rate ofand the partition coefficient influences the rate of
transport across the absorption site.transport across the absorption site.
物的水溶性决定了吸收部位的 度，分配系药 浓物的水溶性决定了吸收部位的 度，分配系药 浓
数影 吸收部位的 物 速率。响 药 转运数影 吸收部位的 物 速率。响 药 转运
Drugs generally penetrate the skin better in theirDrugs generally penetrate the skin better in their
un-ionized form. Nonpolar drugs tend to acrossun-ionized form. Nonpolar drugs tend to across
the cell barrier through the lipid-rich regions,the cell barrier through the lipid-rich regions,
whereas the polar drugs favor transport betweenwhereas the polar drugs favor transport between
cells.cells.
非解 型的 物透皮效果好。非 性 物易通离 药 极 药非解 型的 物透皮效果好。非 性 物易通离 药 极 药
富含脂 的部位跨越 胞屏障，而 性 物过 质 细 极 药富含脂 的部位跨越 胞屏障，而 性 物过 质 细 极 药
通 胞 。则 过细 转运通 胞 。则 过细 转运

13. 4.4. Drugs with molecular weights of 100 to 800Drugs with molecular weights of 100 to 800
and adequate lipid and aqueous solubilityand adequate lipid and aqueous solubility
can permeate skin. The ideal molecularcan permeate skin. The ideal molecular
weight of a drug for transdermal drugweight of a drug for transdermal drug
delivery is believed to bedelivery is believed to be 400 or less400 or less..
分子量在分子量在 100100 和和 800800 之 并且具有一定间之 并且具有一定间
的脂溶性和水溶性的 物能 透入皮 。药 渗 肤的脂溶性和水溶性的 物能 透入皮 。药 渗 肤
理想的 皮吸收系 的 物分子量经 统 药 应为理想的 皮吸收系 的 物分子量经 统 药 应为
400400 或更小。或更小。

14. 5. Hydration of the skin generally favors5. Hydration of the skin generally favors
percutaneous absorption. The TDDS acts aspercutaneous absorption. The TDDS acts as
an occlusive moisture barrier through whichan occlusive moisture barrier through which
sweat cannot pass, increasing skin hydration.sweat cannot pass, increasing skin hydration.
皮 的水和作用通常有利于 皮吸肤 经皮 的水和作用通常有利于 皮吸肤 经
收。收。 TDDSTDDS 可以作 隔 湿气的屏障（汗水为 绝可以作 隔 湿气的屏障（汗水为 绝
不能通 ），使皮 水合化程度 加。过 肤 增不能通 ），使皮 水合化程度 加。过 肤 增

15. 6. Percutaneous absorption appears to be6. Percutaneous absorption appears to be
greater when the TDDS is applied to a sitegreater when the TDDS is applied to a site
with a thin horny layer than with a thick one.with a thin horny layer than with a thick one.
TDDSTDDS 在角 薄的部位比角 厚的部位质层 质层在角 薄的部位比角 厚的部位质层 质层
皮吸收好。经皮吸收好。经
7. Generally, the longer the medicated7. Generally, the longer the medicated
application is permitted to remain in contactapplication is permitted to remain in contact
with the skin, the greater is the total drugwith the skin, the greater is the total drug
absorption.absorption.
一般而言， 物 用的 越 ，即与皮药 应 时间 长 肤一般而言， 物 用的 越 ，即与皮药 应 时间 长 肤
接触 越 ， 物吸收 量越多。时间 长 药 总接触 越 ， 物吸收 量越多。时间 长 药 总

16. II. Percutaneous absorption enhancersII. Percutaneous absorption enhancers
There is great interest amongThere is great interest among
pharmaceutical scientists to developpharmaceutical scientists to develop
chemical permeation enhancers andchemical permeation enhancers and
physical methods that can increasephysical methods that can increase
percutaneous absorption of therapeuticpercutaneous absorption of therapeutic
agents.agents.

17. 1.1. Chemical enhancersChemical enhancers
A chemical skin penetration enhancerA chemical skin penetration enhancer
increases skin permeability by reversiblyincreases skin permeability by reversibly
damaging or altering the physicochemicaldamaging or altering the physicochemical
nature of the stratum corneum to reducenature of the stratum corneum to reduce
its diffusional resistance.its diffusional resistance.
化学吸收促 通 通 可逆地改 角进剂 过 过 变化学吸收促 通 通 可逆地改 角进剂 过 过 变
的理化状 ，降低 散阻力而提高质层 态 扩的理化状 ，降低 散阻力而提高质层 态 扩
皮 透率。肤渗皮 透率。肤渗

18. Increased hydration of the stratum corneumIncreased hydration of the stratum corneum
A change in the structure of the lipids and lipoproteinsA change in the structure of the lipids and lipoproteins
in the intercellular channelsin the intercellular channels
solvent actionsolvent action
oror
denaturationdenaturation

19. More than 275 chemical compounds have beenMore than 275 chemical compounds have been
cited in the literature as skin penetrationcited in the literature as skin penetration
enhancers; they includeenhancers; they include
 acetone, azoneacetone, azone （ ）氮酮（ ）氮酮 ,,
 dimethyl acetamidedimethyl acetamide （二甲基乙 ）酰胺（二甲基乙 ）酰胺 , dimethyl, dimethyl
formamideformamide （二甲基甲 ）酰胺（二甲基甲 ）酰胺 ,,
 dimethyl sulfoxide (DMSO),dimethyl sulfoxide (DMSO), 二甲基亚砜二甲基亚砜
 ethanol,ethanol,
 oleic acid,oleic acid, 油酸油酸
 polyethylene glycol, propylene glycolpolyethylene glycol, propylene glycol （丙二醇）（丙二醇） ,,
 sodium lauryl sulfatesodium lauryl sulfate （月桂醇硫酸 ）钠（月桂醇硫酸 ）钠 ..

20. The selection of a permeation enhancerThe selection of a permeation enhancer
should be based onshould be based on
 its efficacy in enhancing skin permeationits efficacy in enhancing skin permeation
 its dermal toxicityits dermal toxicity
 its physicochemical and biologicits physicochemical and biologic
compatibility with the system’s othercompatibility with the system’s other
components.components.

21. 2. Iontophoresis and sonophoresis2. Iontophoresis and sonophoresis
Iontophoresis is deliveryIontophoresis is delivery
of a charged chemicalof a charged chemical
compound across thecompound across the
skin membrane using anskin membrane using an
electrical field.electrical field.
（ 子 入法是指在离 导 电场（ 子 入法是指在离 导 电场
作用下， 荷的化合带电作用下， 荷的化合带电
物 入皮 粘膜的一导 肤 种物 入皮 粘膜的一导 肤 种
方法。）方法。）

22. Iontophoresis-Iontophoresis-
enhancedenhanced
transdermaltransdermal
delivery hasdelivery has
shown someshown some
promise as apromise as a
means ofmeans of peptidepeptide
and proteinand protein
administration.administration.

23. A number of drugs have been the subject ofA number of drugs have been the subject of
iontophoretic studies, they includeiontophoretic studies, they include
 lidocainelidocaine
 dexamethasonedexamethasone
 amino acids,amino acids,
 peptidespeptides
 insulininsulin
 VerapamilVerapamil （ 拉 米）维 帕（ 拉 米）维 帕
 PropranololPropranolol （普 洛 ）萘 尔（普 洛 ）萘 尔

24.  SonophoresisSonophoresis, is a process that, is a process that
exponentially increases the absorption ofexponentially increases the absorption of
topical compounds (transdermal delivery)topical compounds (transdermal delivery)
with high-frequency ultrasound.with high-frequency ultrasound.
 Sonophoresis occurs because ultrasoundSonophoresis occurs because ultrasound
waves stimulate micro-vibrations within thewaves stimulate micro-vibrations within the
skin epidermis and increase the overallskin epidermis and increase the overall
kinetic energy of molecules making upkinetic energy of molecules making up
topical agents.topical agents.

25. Limited permeation due to lipid barrier
of the skin
Enhanced permeation by disruption of lipid
barrier cavitation

26.  It is thought that high-frequency ultrasoundIt is thought that high-frequency ultrasound
can influence the integrity of the stratumcan influence the integrity of the stratum
corneum and thus affect its penetrability.corneum and thus affect its penetrability.
Among the agents examined areAmong the agents examined are
 hydrocortisone,hydrocortisone,
 lidocaine,lidocaine,
 salicylic acidsalicylic acid
in such formulations as gels, creams, andin such formulations as gels, creams, and
lotions.lotions.

27. III. Design features of transdermal drugIII. Design features of transdermal drug
delivery systemsdelivery systems
TDDSs are designed to support the passageTDDSs are designed to support the passage
of drug substances from the surface of theof drug substances from the surface of the
skin through its various layers and into theskin through its various layers and into the
systemic circulation.systemic circulation.
（将 物 成 皮 系 能使 物透药 设计 经 给药 统 药 过（将 物 成 皮 系 能使 物透药 设计 经 给药 统 药 过
皮 表面、穿 皮 的不同 入体循肤 过 肤 层进皮 表面、穿 皮 的不同 入体循肤 过 肤 层进
）。环）。环

28. Transdermal drug delivery systems may beTransdermal drug delivery systems may be
constructed of a number of layers, includingconstructed of a number of layers, including
1)1) an occlusive backing membranean occlusive backing membrane to protect theto protect the
system from environmental entry and from loss ofsystem from environmental entry and from loss of
drug from the system or moisture from the skin;drug from the system or moisture from the skin;
2)2) the drugthe drug at the skin-site;at the skin-site;
3)3) a release linera release liner, which is removed before application, which is removed before application
and enables drug release;and enables drug release;
4)4) an adhesive layeran adhesive layer to maintain contact with the skinto maintain contact with the skin
after application.after application.

29. Technically, TDDSs mayTechnically, TDDSs may
be categorized into twobe categorized into two
types,types,
1) Monolithic1) Monolithic （整体型）（整体型）
 Monolithic systemsMonolithic systems
incorporate a drugincorporate a drug
matrix layer betweenmatrix layer between
backing and frontalbacking and frontal
layers.layers.
（整体型在背 和正面衬层（整体型在背 和正面衬层
中 含 骨架 ）间为 药 层中 含 骨架 ）间为 药 层
1. Foil covertrip 2. Drug matrix
3. Release liner 4. Foil baseplate
5. Microporous tape 6. Absorbent
Pad 7. Occlusive overlay

30.  The drug-matrix layer is composed of aThe drug-matrix layer is composed of a
polymeric material in which the drug ispolymeric material in which the drug is
dispersed.dispersed.
（ 物药（ 物药 -- 骨架 由分散有 物的聚合物 成）层 药 组骨架 由分散有 物的聚合物 成）层 药 组
 The polymer matrix controls the rate at whichThe polymer matrix controls the rate at which
the drug is released for percutaneousthe drug is released for percutaneous
absorption.absorption.
（聚合物骨架控制 皮吸收 物的 放速率）经 药 释（聚合物骨架控制 皮吸收 物的 放速率）经 药 释

31.  In the preparation of monolithic systems, theIn the preparation of monolithic systems, the
drug and the polymer are dissolved ordrug and the polymer are dissolved or
blended together, cast as the matrix, andblended together, cast as the matrix, and
dried.dried.
（在制 整体型 ， 物和聚合物一起溶解备 时 药（在制 整体型 ， 物和聚合物一起溶解备 时 药
或混合，作 骨架并干燥）。为或混合，作 骨架并干燥）。为

32. 2) Membrane-controlled systems.2) Membrane-controlled systems.
 Transderm-Nitro, Transderm-Scop
 Form-fill-seal from lamination process

33. Membrane-controlled transdermal systemsMembrane-controlled transdermal systems
are designed to contain a drug reservoir, orare designed to contain a drug reservoir, or
pouch, usually in liquid or gel form, a rate-pouch, usually in liquid or gel form, a rate-
controlling membrane, and backing,controlling membrane, and backing,
adhesive, and protecting layers.adhesive, and protecting layers.
（膜控型 皮 系 有 物经 给药 统设计为 药 储库（膜控型 皮 系 有 物经 给药 统设计为 药 储库
或 囊，通常以液 或粘 存在，含有药 态 胶态或 囊，通常以液 或粘 存在，含有药 态 胶态
控 膜、背 、粘 和保 。）释 衬层 胶层 护层控 膜、背 、粘 和保 。）释 衬层 胶层 护层

34.  Membrane-controlled systems have theMembrane-controlled systems have the
advantage over monolithic systems in that asadvantage over monolithic systems in that as
long as the drug solution in the reservoirlong as the drug solution in the reservoir
remains saturated, the release rate of drugremains saturated, the release rate of drug
through the controlling membrane remainsthrough the controlling membrane remains
constant.constant.
 膜控型比整体型的 点在于，只要 物优 药 贮膜控型比整体型的 点在于，只要 物优 药 贮
中溶液保持 和， 物通 控 膜的速库 饱 药 过 释中溶液保持 和， 物通 控 膜的速库 饱 药 过 释
率保持恒定。率保持恒定。

36. Delivery
Modifier
s
Micro-Delivery
Systems
Proprietary Drug
Delivery Systems &
Designs
Polymer
Technologies
Patch System
Designs

39. IV. Percutaneous absorption modelsIV. Percutaneous absorption models
1.1. In vivo studiesIn vivo studies
In vivo skin penetration studies may beIn vivo skin penetration studies may be
undertaken for one or more of theundertaken for one or more of the
following purposes:following purposes:
1)1) To verify and quantify the cutaneousTo verify and quantify the cutaneous
bioavailability of a topically applied drug.bioavailability of a topically applied drug.
2)2) To verify and quantify the systemicTo verify and quantify the systemic
bioavailability of a transdermal drug.bioavailability of a transdermal drug.

40. 3) To establish bioequivalence of different3) To establish bioequivalence of different
topical formulations of the same drugtopical formulations of the same drug
substance.substance.
4) To determine the incidence and degree of4) To determine the incidence and degree of
systemic toxicologic risk following topicalsystemic toxicologic risk following topical
application of a specific drug or drugapplication of a specific drug or drug
product.product.
5) To relate resultant blood levels of drug in5) To relate resultant blood levels of drug in
human to systemic therapeutic effects.human to systemic therapeutic effects.

41.  The most relevant studies are performed inThe most relevant studies are performed in
humans, however, animal models may behumans, however, animal models may be
used insofar as they may be effective asused insofar as they may be effective as
predictors of human response.predictors of human response.
 Biologic samples used in drug penetrationBiologic samples used in drug penetration
and drug absorption studies includeand drug absorption studies include skinskin
sectionssections,, venous blood from the applicationvenous blood from the application
sitesite,, blood from the systemic circulationblood from the systemic circulation,,
andand excreta (urine, feces, and expired air)excreta (urine, feces, and expired air)..

42. 2. In vitro studies2. In vitro studies
 Skin permeation may be tested in vitro usingSkin permeation may be tested in vitro using
various skin tissues (human or animal wholevarious skin tissues (human or animal whole
skin, dermis or epidermis) in a diffusion cell.skin, dermis or epidermis) in a diffusion cell.
 In vitro penetration studies using humanIn vitro penetration studies using human
skin are limited because of difficulties ofskin are limited because of difficulties of
procurement, storage, expense, andprocurement, storage, expense, and
variation in permeation.variation in permeation.
 Animal skins are much more permeableAnimal skins are much more permeable
than human skin. One alternative that hasthan human skin. One alternative that has
been shown to be effective is shed snakebeen shown to be effective is shed snake
skinskin （蛇 ）蜕（蛇 ）蜕 ..

43.  The material may be used in cell cultureThe material may be used in cell culture
studies or in standard diffusion cells.studies or in standard diffusion cells.
 Diffusion cell systems are employed in vitroDiffusion cell systems are employed in vitro
to quantify the release rates of drugs fromto quantify the release rates of drugs from
topical preparations.topical preparations.
 In these systems,In these systems, skin membranesskin membranes oror
synthetic membranessynthetic membranes may be employed asmay be employed as
barriers to the flow of drug and vehicle tobarriers to the flow of drug and vehicle to
simulate the biologic system.simulate the biologic system.

45. V. Advantages and disadvantages of TDDSsV. Advantages and disadvantages of TDDSs
The advantages of TDDSs are:The advantages of TDDSs are:
1.1. They can avoid gastrointestinal drugThey can avoid gastrointestinal drug
absorption difficulties caused byabsorption difficulties caused by
gastrointestinal pH, enzymatic activity andgastrointestinal pH, enzymatic activity and
drug interactions with food, drink, or otherdrug interactions with food, drink, or other
orally administered drugs.orally administered drugs.
2.2. They can substitute for oral administrationThey can substitute for oral administration
of medication when that route is unsuitable,of medication when that route is unsuitable,
as in instances of vomiting and/or diarrhea.as in instances of vomiting and/or diarrhea.

46. 3.3. They avoid the first-pass effect, that is, theThey avoid the first-pass effect, that is, the
initial pass of a drug substance through theinitial pass of a drug substance through the
systemic and portal circulation followingsystemic and portal circulation following
gastrointestinal absorption, theraby possiblygastrointestinal absorption, theraby possibly
avoiding the drug’s deactivation by digestiveavoiding the drug’s deactivation by digestive
and liver enzymes.and liver enzymes.
4. The systems are noninvasive, avoiding the4. The systems are noninvasive, avoiding the
inconvenience of parenteral therapy.inconvenience of parenteral therapy.

47. 5. They provide extended therapy with a single5. They provide extended therapy with a single
application, thereby improving patientapplication, thereby improving patient
compliance over other dosage formscompliance over other dosage forms
requiring more frequent doserequiring more frequent dose
administration.administration.
6. The activity of drugs having short half-lives6. The activity of drugs having short half-lives
is extended through the reservoir of drugis extended through the reservoir of drug
present in the therapeutic delivery systempresent in the therapeutic delivery system
and its controlled release characteristics.and its controlled release characteristics.

48. 7. Drug therapy may be terminated rapidly by7. Drug therapy may be terminated rapidly by
removal of the application from the surfaceremoval of the application from the surface
of the skin.of the skin.
8. Ease of rapid identification of the8. Ease of rapid identification of the
medication in emergencies (e.g.,medication in emergencies (e.g.,
nonresponsive, unconscious, or comatosenonresponsive, unconscious, or comatose
patient) due to the physical presence,patient) due to the physical presence,
features and identifying-markings on thefeatures and identifying-markings on the
TDDS.TDDS.

49. The disadvantages of TDDSs are:The disadvantages of TDDSs are:
1.1. Only relatively potent drugs are suitableOnly relatively potent drugs are suitable
candidates for transdermal delivery due to thecandidates for transdermal delivery due to the
natural limits of drug entry imposed by the skin’snatural limits of drug entry imposed by the skin’s
impermeability.impermeability.
（由于皮 的不透 性， 有部分活性大的 物肤 过 仅 药 适（由于皮 的不透 性， 有部分活性大的 物肤 过 仅 药 适
合制成 皮 。）经 给药合制成 皮 。）经 给药
2.2. Some patients may develop contact dermatitis atSome patients may develop contact dermatitis at
the site of application due to one or more of thethe site of application due to one or more of the
system components, necessitatingsystem components, necessitating
discontinuation.discontinuation.
（一些病人在用 部位可 生接触性皮炎，无法药 产 继（一些病人在用 部位可 生接触性皮炎，无法药 产 继
用 。）续 药用 。）续 药

50. VI. Examples of transdermal drugVI. Examples of transdermal drug
delivery systemsdelivery systems
1.1. Transdermal scopolamineTransdermal scopolamine
 It was the first TDDS to receiveIt was the first TDDS to receive
FDA approval.FDA approval.
 The Transderm-Scop system is aThe Transderm-Scop system is a
circular flat patch 0.2 mm thickcircular flat patch 0.2 mm thick
and 2.5 cmand 2.5 cm22
in area.in area.

51.  The TDDS contains 1.5 mg of scopolamineThe TDDS contains 1.5 mg of scopolamine
and is designed to deliver approximately 1and is designed to deliver approximately 1
mg of scopolamine at an approximatelymg of scopolamine at an approximately
constant rate to the systemic circulation overconstant rate to the systemic circulation over
the 3 day life-time of the system.the 3 day life-time of the system.
 The patch is worn in a hairless area behindThe patch is worn in a hairless area behind
the ear. Because of the small size of thethe ear. Because of the small size of the
patch, the system is unobtrusive,patch, the system is unobtrusive,
convenient, and well accepted by theconvenient, and well accepted by the
patient.patient.

52. 2. Transdermal Nitroglycerin2. Transdermal Nitroglycerin
A number of nitroglycerin-containingA number of nitroglycerin-containing
TDDSs have been developed, includingTDDSs have been developed, including
 Deponit (Schwarz)Deponit (Schwarz)
 Minitran (3M Pharmaceuticals)Minitran (3M Pharmaceuticals)
 Nitro-Dur (Key)Nitro-Dur (Key)
 Transderm-Nitro (Novartis)Transderm-Nitro (Novartis)
Each of these products maintainsEach of these products maintains
nitroglycerin drug delivery for 24 hours afternitroglycerin drug delivery for 24 hours after
application.application.

53.  Nitroglycerin is used widely in theNitroglycerin is used widely in the
prophylacticprophylactic （ 防）预（ 防）预 treatment oftreatment of
angina.angina.
 It has a relatively low dose, short plasmaIt has a relatively low dose, short plasma
half-life, high peak plasma levels, andhalf-life, high peak plasma levels, and
inherentinherent （固有的）（固有的） side effects whenside effects when
taken sublingually, a popular route.taken sublingually, a popular route.
 It is rapidly metabolized by the liver whenIt is rapidly metabolized by the liver when
taken orally, this first-pass effect is bypassedtaken orally, this first-pass effect is bypassed
by the transdermal route.by the transdermal route.

54.  The various nitroglycerin TDDSs control theThe various nitroglycerin TDDSs control the
rate of drug delivery through a membranerate of drug delivery through a membrane
and/or controlled release from the matrix orand/or controlled release from the matrix or
reservoir.reservoir.
 The rate of drug release depends on theThe rate of drug release depends on the
system. In thesystem. In the Transderm-Nitro systemTransderm-Nitro system,,
nitroglycerin 0.02 mg is delivered per hournitroglycerin 0.02 mg is delivered per hour
for every square centimeter of patch, whereasfor every square centimeter of patch, whereas
in thein the Deponit systemDeponit system, each square, each square
centimeter delivers approximately 0.013 mgcentimeter delivers approximately 0.013 mg
of nitroglycerin per hour.of nitroglycerin per hour.

55.  Not all nitroglycerin systems have the sameNot all nitroglycerin systems have the same
construction. For example, the Transderm-construction. For example, the Transderm-
Nitro TDDS is a four-layer drug pouchNitro TDDS is a four-layer drug pouch
system, whereas the Deponit TDDS is a thinsystem, whereas the Deponit TDDS is a thin
two-layer matrix system resembling.two-layer matrix system resembling.
 Patients should be given explicitPatients should be given explicit
instructions regarding the use ofinstructions regarding the use of
nitroglycerin transdermal systems.nitroglycerin transdermal systems.
Generally, these TDDSs are placed on theGenerally, these TDDSs are placed on the
chest, back, upper arms, or shoulders.chest, back, upper arms, or shoulders.

56.  The patient should understand that physicalThe patient should understand that physical
exercise and elevated ambient temperatures,exercise and elevated ambient temperatures,
such as in a sauna, may increase thesuch as in a sauna, may increase the
absorption of nitroglycerin.absorption of nitroglycerin.

57. 3. Transdermal clonidine3. Transdermal clonidine
 The first transdermal system forThe first transdermal system for
hypertension, Catapres TTS (clonidinehypertension, Catapres TTS (clonidine
transdermal therapeutic system, Boehringertransdermal therapeutic system, Boehringer
Ingelheim), was marketed in 1985.Ingelheim), was marketed in 1985.
 Clonidine lends itself to transdermal deliveryClonidine lends itself to transdermal delivery
because of its lipid solubility, high volume ofbecause of its lipid solubility, high volume of
distribution, and therapeutic effectiveness indistribution, and therapeutic effectiveness in
low plasma concentrations.low plasma concentrations.
 The TDDS provides controlled release ofThe TDDS provides controlled release of
clonidine.clonidine.

58.  Catapres TTS is available in several sizes,Catapres TTS is available in several sizes,
with the amount of drug releasedwith the amount of drug released
proportional to the patch size.proportional to the patch size.
 To ensure constant release over the 7-dayTo ensure constant release over the 7-day
use period, the drug content is greater thanuse period, the drug content is greater than
the total amount of drug delivered.the total amount of drug delivered.
 Catapres TTS is available in several sizes,Catapres TTS is available in several sizes,
with the amount of drug releasedwith the amount of drug released
proportional to the patch size.proportional to the patch size.

59.  Clonidine flows in the direction of the lowerClonidine flows in the direction of the lower
concentration at a constant rate limited by aconcentration at a constant rate limited by a
rate-controlling membrane.rate-controlling membrane.
 The system is applied to the hairless area ofThe system is applied to the hairless area of
intact skin on the upper outer arm or chest.intact skin on the upper outer arm or chest.

60. 4. Transdermal Nicotine4. Transdermal Nicotine
 Nicotine TDDSs are used as adjuncts inNicotine TDDSs are used as adjuncts in
smoking cessation programs.smoking cessation programs.
 In a blinded study, users of nicotine TDDSsIn a blinded study, users of nicotine TDDSs
are more than twice as likely to quit smokingare more than twice as likely to quit smoking
than individuals wearing a placebo patch.than individuals wearing a placebo patch.
 The nicotine TDDSs provide sustained bloodThe nicotine TDDSs provide sustained blood
levels of nicotine as “nicotine-replacement-levels of nicotine as “nicotine-replacement-
therapy” to help the patient establish andtherapy” to help the patient establish and
sustain remission from smoking.sustain remission from smoking.

61.  The commercially available patches containThe commercially available patches contain
from 7 to 22 mg of nicotine for dailyfrom 7 to 22 mg of nicotine for daily
application during the course of treatmentapplication during the course of treatment
ranging from about 6 to 12 weeks.ranging from about 6 to 12 weeks.
 A nicotine TDDS usually is applied to theA nicotine TDDS usually is applied to the
arm or upper front torso, with patientsarm or upper front torso, with patients
advised not to smoke when wearing theadvised not to smoke when wearing the
system.system.
 Some of the nicotine replacement programsSome of the nicotine replacement programs
provide a gradual reduction in nicotineprovide a gradual reduction in nicotine
dosage form during the treatment program.dosage form during the treatment program.

62. 5. Transdermal Estradiol5. Transdermal Estradiol
 The Estraderm TDDS delivers 17The Estraderm TDDS delivers 17ββ-estradiol-estradiol
through a rate-limiting membranethrough a rate-limiting membrane
continuously upon application to intact skin.continuously upon application to intact skin.
 Two systems provide delivery of 0.05 or 0.1Two systems provide delivery of 0.05 or 0.1
mg estradiol per day.mg estradiol per day.

63.  Estradiol is indicated for the treatment ofEstradiol is indicated for the treatment of
moderate to severe vasomotor symptomsmoderate to severe vasomotor symptoms
associated with menopause, femaleassociated with menopause, female
hypogonadismhypogonadism （性腺功能 退）减（性腺功能 退）减 , female, female
castrationcastration （女性卵 切除 ）巢 术（女性卵 切除 ）巢 术 , primary, primary
ovarian failureovarian failure （原 性卵 功能衰竭）发 巢（原 性卵 功能衰竭）发 巢 ,,
and atrophicand atrophic (( 萎 ）缩萎 ）缩 conditions caused byconditions caused by
deficient endogenous estrogen production,deficient endogenous estrogen production,
such as atrophic vaginitis and kraurosissuch as atrophic vaginitis and kraurosis
value.value.

64. Transdermal administration producesTransdermal administration produces
therapeutic serum levels of estradiol withtherapeutic serum levels of estradiol with
lower circulating levels of estrone andlower circulating levels of estrone and
estrone conjugates than does oral therapyestrone conjugates than does oral therapy
and requires a smaller total dose.and requires a smaller total dose.
 The systemic side effects from oralThe systemic side effects from oral
estrogens can be reduced by using theestrogens can be reduced by using the
transdermal dosage forms.transdermal dosage forms.

65. 6. Transdermal testosterone6. Transdermal testosterone
 Testosterone transdermal systems, TestodermTestosterone transdermal systems, Testoderm
(Alza) and Androderm (SmithKline Beecham),(Alza) and Androderm (SmithKline Beecham),
are available with various delivery rates asare available with various delivery rates as
hormone replacement therapy in men whohormone replacement therapy in men who
have an absence or deficiency of testosterone.have an absence or deficiency of testosterone.
 The TDDS is applied daily, usually in theThe TDDS is applied daily, usually in the
morning to mimic endogenous testosteronemorning to mimic endogenous testosterone
release.release.
 Optimum serum levels are reached within 2 toOptimum serum levels are reached within 2 to
4 hours after application. The patch is worn 224 hours after application. The patch is worn 22
to 24 hours daily for 6 to 8 weeks.to 24 hours daily for 6 to 8 weeks.

66. 7. Other transdermal therapeutic systems7. Other transdermal therapeutic systems
 DiltiazemDiltiazem 地 硫卓尔地 硫卓尔
 Isosorbide dinitrateIsosorbide dinitrate 硝酸 山梨醇异硝酸 山梨醇异
 PropranololPropranolol 普奈洛尔普奈洛尔
 NifedipineNifedipine 硝 地平苯硝 地平苯
 MepindololMepindolol 甲 洛吲 尔甲 洛吲 尔
 VerapamilVerapamil 拉 米维 帕拉 米维 帕

67.  Cardiovascular agents,Cardiovascular agents,
 levonorgestrel/estradiollevonorgestrel/estradiol for hormonalfor hormonal
contraceptioncontraception,,
 Physostigmine(Physostigmine( 毒扁豆碱毒扁豆碱 ), xanomeline (), xanomeline ( 占 美诺占 美诺
林林 )for)for Alzheimer’s disease therapyAlzheimer’s disease therapy,,
 Naltrexone(Naltrexone( 曲纳 酶曲纳 酶 ) and methadone for) and methadone for
substancesubstance addictionaddiction,,
 BuspironeBuspirone （丁螺环酮（丁螺环酮）） forfor anxietyanxiety ，，
 BupropionBupropion （安非他 ）酮（安非他 ）酮 forfor smokingsmoking
cessationcessation ，，
 PapaverinePapaverine （罂粟碱）（罂粟碱） forfor male impotencemale impotence ，，

68. VII. General clinical considerations inVII. General clinical considerations in
the use of TDDSsthe use of TDDSs
The patient should be advised of theThe patient should be advised of the
following general guidelines along withfollowing general guidelines along with
product-specific instructions in the use ofproduct-specific instructions in the use of
TDDSs.TDDSs.
1. Percutaneous absorption may vary with the1. Percutaneous absorption may vary with the
site of application.site of application.
2. TDDSs should be applied to clean, dry skin2. TDDSs should be applied to clean, dry skin
that is relatively free of hair and not oily,that is relatively free of hair and not oily,
irritated, inflamed, broken, or callused.irritated, inflamed, broken, or callused.

69. 3. Use of skin lotion should be avoided at the3. Use of skin lotion should be avoided at the
application site, because lotions affect skinapplication site, because lotions affect skin
hydration and can alter the partitionhydration and can alter the partition
coefficient between the drug and the skin.coefficient between the drug and the skin.
4. TDDSs should not be physically altered by4. TDDSs should not be physically altered by
cutting, since this destroys the integrity ofcutting, since this destroys the integrity of
the system.the system.
5. A TDDS should be removed from its5. A TDDS should be removed from its
protective package, with care not to tear orprotective package, with care not to tear or
cut into the unit.cut into the unit.

70. 6. A TDDS should be placed at a site that will6. A TDDS should be placed at a site that will
not subject it to being rubbed off bynot subject it to being rubbed off by
clothing or movement.clothing or movement.
7. A TDDS should be worn for the full period7. A TDDS should be worn for the full period
stated in the product’s instructions.stated in the product’s instructions.
Following that period, it should be removedFollowing that period, it should be removed
and replaced with a fresh system as directed.and replaced with a fresh system as directed.
8. The patient or caregiver should be8. The patient or caregiver should be
instructed to cleanse the hands thoroughlyinstructed to cleanse the hands thoroughly
before and after applying a TDDS.before and after applying a TDDS.

71. 9. if the patient exhibits sensitivity or9. if the patient exhibits sensitivity or
intolerance to a TDDS or if undue skinintolerance to a TDDS or if undue skin
irritation results, the patient should seekirritation results, the patient should seek
reevaluation.reevaluation.
10. Upon removal, a used TDDS should be10. Upon removal, a used TDDS should be
folded in half with the adhesive layerfolded in half with the adhesive layer
together so that it cannot be reused.together so that it cannot be reused.

72. QuestionsQuestions
1. Explain shortly1. Explain shortly
- transdermal drug delivery systems- transdermal drug delivery systems
- iontophoresis- iontophoresis
- sonophoresis- sonophoresis
- percutaneous absorption enhancers- percutaneous absorption enhancers
2. What factors could affect percutaneous drug2. What factors could affect percutaneous drug
absorption?absorption?
3. How to increase percutaneous absorption of drug by3. How to increase percutaneous absorption of drug by
physical and chemical methods?physical and chemical methods?
4. What types of drugs could be designed as TDDSs4. What types of drugs could be designed as TDDSs
and how?and how?

73. 5. How to design transdermal drug delivery systems?5. How to design transdermal drug delivery systems?
6. How to study the percutaneous absorption of drug6. How to study the percutaneous absorption of drug
using in vitro and in vivo models?using in vitro and in vivo models?
6. What are the characteristics of transdermal drug6. What are the characteristics of transdermal drug
delivery systems?delivery systems?
7. How many different types of transdermal7. How many different types of transdermal
nitroglycerin are in the market? Explain theirnitroglycerin are in the market? Explain their
characteristics respectively.characteristics respectively.
8. What are the clinical considerations in the use of8. What are the clinical considerations in the use of
TDDSs?TDDSs?