10. Transdermal Drug Delive10. Transdermal Drug Delive

ry Systemsry Systems 经皮给药系统经皮给药系统

ContentsContents

I.I. Factors affecting percutaneous absorptionFactors affecting percutaneous absorptionII.II. Percutaneous absorption enhancerPercutaneous absorption enhancerIII.III. Design features of transdermal drug deliveDesign features of transdermal drug delive

ry systemry systemIV.IV. Percutaneous absorption modelPercutaneous absorption modelV.V. Advantages and disadvantages of TDDSsAdvantages and disadvantages of TDDSsVI.VI. Examples of transdermal drug deliver systExamples of transdermal drug deliver syst

emsemsVII.VII. General clinical considerations in the use General clinical considerations in the use

of TDDSsof TDDSs

Transdermal drug deliTransdermal drug delivery systems (TDDSs) fvery systems (TDDSs) facilitate the passage of acilitate the passage of therapeutic quantities therapeutic quantities of drug substances throf drug substances through the ough the skin skin and into and into the the general circulationgeneral circulation for their systemic effecfor their systemic effect. t.

经皮给药系统能促进具治经皮给药系统能促进具治疗量的药物透过皮肤，进疗量的药物透过皮肤，进入体循环发挥系统作用。入体循环发挥系统作用。

For transdermal drug deliFor transdermal drug delivery, it is consideredvery, it is considered ideal ideal iif the drug penetrates throuf the drug penetrates through the skin to the underlyigh the skin to the underlying blood supply ng blood supply without drwithout drug buildup in the dermal laug buildup in the dermal layersyers..

理想的经皮给药系统时，药物理想的经皮给药系统时，药物渗透入皮肤后，能够进入血液渗透入皮肤后，能够进入血液而不在皮下蓄积。而不在皮下蓄积。

(3M Transdermal Drug Deliveryhttp://www.3M.com/DDS)

MacrofluxMacroflux®®

E-TRANSE-TRANS®®

Benefits of TDDSsBenefits of TDDSs Eliminates potential pain associated Eliminates potential pain associated

with injectionswith injections No first pass metabolism in liverNo first pass metabolism in liver Eliminates gastrointestinal side effecEliminates gastrointestinal side effec

tt Improves patient compliance due to Improves patient compliance due to

simpler, pain free deliverysimpler, pain free delivery Potential for home administrationPotential for home administration

I. Factors affecting percutaneous I. Factors affecting percutaneous absorptionabsorption

1. Drug concentration is an important 1. Drug concentration is an important factor.factor.

（药物浓度是一个重要因素。）（药物浓度是一个重要因素。）

2. The larger the area of application, t2. The larger the area of application, the more drug is absorbed.he more drug is absorbed.

（当药物应用面积增大，经皮吸收的药物量（当药物应用面积增大，经皮吸收的药物量增加。）增加。）

3. 3. The aqueous solubility of a drug determiThe aqueous solubility of a drug determines the concentration presented to the anes the concentration presented to the absorption site, and the partition coefficiebsorption site, and the partition coefficient influences the rate of transport across nt influences the rate of transport across the absorption site. the absorption site. 药物的水溶性决定了吸收部位的浓度，分配系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。数影响吸收部位的药物转运速率。Drugs generally penetrate the skin better Drugs generally penetrate the skin better in their un-ionized form. Nonpolar drugs in their un-ionized form. Nonpolar drugs tend to across the cell barrier through thtend to across the cell barrier through the lipid-rich regions, whereas the polar dre lipid-rich regions, whereas the polar drugs favor transport between cells.ugs favor transport between cells.非解离型的药物透皮效果好。非极性药物易通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。则通过细胞转运。

4. 4. Drugs with molecular weights of 10Drugs with molecular weights of 100 to 800 and adequate lipid and aqu0 to 800 and adequate lipid and aqueous solubility can permeate skin. eous solubility can permeate skin. The ideal molecular weight of a druThe ideal molecular weight of a drug for transdermal drug delivery is bg for transdermal drug delivery is believed to be elieved to be 400 or less400 or less..

分子量在分子量在 100100 和和 800800 之间并且具有一定的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想的经皮吸收系统的药物分子量应为 400400或更小。或更小。

5. Hydration of the skin generally favor5. Hydration of the skin generally favors percutaneous absorption. The TDDS s percutaneous absorption. The TDDS acts as an occlusive moisture barrier tacts as an occlusive moisture barrier through which sweat cannot pass, incrhrough which sweat cannot pass, increasing skin hydration.easing skin hydration.

皮肤的水和作用通常有利于经皮吸收。皮肤的水和作用通常有利于经皮吸收。 TDDSTDDS可以作为隔绝湿气的屏障（汗水不能通过），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。使皮肤水合化程度增加。

6. Percutaneous absorption appears to be 6. Percutaneous absorption appears to be greater when the TDDS is applied to a sitgreater when the TDDS is applied to a site with a thin horny layer than with a thice with a thin horny layer than with a thick one.k one.TDDSTDDS 在角质层薄的部位比角质层厚的部位经皮在角质层薄的部位比角质层厚的部位经皮吸收好。吸收好。

7. Generally, the longer the medicated app7. Generally, the longer the medicated application is permitted to remain in contact lication is permitted to remain in contact with the skin, the greater is the total druwith the skin, the greater is the total drug absorption.g absorption.一般而言，药物应用的时间越长，即与皮肤接一般而言，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。触时间越长，药物吸收总量越多。

II. Percutaneous absorption enhaII. Percutaneous absorption enhancersncers

There is great interest among pharThere is great interest among pharmaceutical scientists to develop chemaceutical scientists to develop chemical permeation enhancers and pmical permeation enhancers and physical methods that can increase physical methods that can increase percutaneous absorption of therapeercutaneous absorption of therapeutic agents.utic agents.

1.1. Chemical enhancersChemical enhancersA chemical skin penetration enhanA chemical skin penetration enhancer increases skin permeability by rcer increases skin permeability by reversibly damaging or altering the eversibly damaging or altering the physicochemical nature of the stratphysicochemical nature of the stratum corneum to reduce its diffusionum corneum to reduce its diffusional resistance. al resistance. 化学吸收促进剂通过通过可逆地改变角质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层的理化状态，降低扩散阻力而提高皮肤渗透率。渗透率。

Increased hydration of the stratum corneumIncreased hydration of the stratum corneum

A change in the structure of the lipids and lipoproteins A change in the structure of the lipids and lipoproteins in the intercellular channelsin the intercellular channels

solvent actisolvent action or denaton or denat

urationuration

More than 275 chemical compounds have More than 275 chemical compounds have been cited in the literature as skin penetrabeen cited in the literature as skin penetration enhancers; they include tion enhancers; they include

acetone, azone acetone, azone （氮酮）（氮酮） , , dimethyl acetamide dimethyl acetamide （二甲基乙酰胺）（二甲基乙酰胺） , dim, dim

ethyl formamideethyl formamide （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 glycol polyethylene glycol, propylene glycol （丙（丙

二醇）二醇） , , sodium lauryl sulfate sodium lauryl sulfate （月桂醇硫酸钠）（月桂醇硫酸钠） ..

The selection of a permeation enhanThe selection of a permeation enhancer should be based on cer should be based on

its efficacy in enhancing skin permeits efficacy in enhancing skin permeation ation

its dermal toxicity its dermal toxicity its physicochemical and biologic coits physicochemical and biologic co

mpatibility with the system’s other mpatibility with the system’s other components.components.

2. Iontophoresis and sonophoresi2. Iontophoresis and sonophoresiss

Iontophoresis is deliIontophoresis is delivery of a charged chevery of a charged chemical compound acrmical compound across the skin membraoss the skin membrane using an electrical ne using an electrical field.field.

（离子导入法是指在电场（离子导入法是指在电场作用下，带电荷的化合作用下，带电荷的化合物导入皮肤粘膜的一种物导入皮肤粘膜的一种方法。）方法。）

Iontophoresis-Iontophoresis-enhanced transenhanced transdermal deliverdermal delivery has shown soy has shown some promise as me promise as a means of a means of peppeptide and proteitide and proteinn administratio administration.n.

A number of drugs have been the subjA number of drugs have been the subject of iontophoretic studies, they inclect of iontophoretic studies, they includeude

lidocainelidocaine dexamethasonedexamethasone amino acids, amino acids, peptidespeptides insulininsulin Verapamil Verapamil （维拉帕米）（维拉帕米） Propranolol Propranolol （普萘洛尔）（普萘洛尔）

SonophoresisSonophoresis, is a process that expo, is a process that exponentially increases the absorption of nentially increases the absorption of topical compounds (transdermal delitopical compounds (transdermal delivery) with high-frequency ultrasounvery) with high-frequency ultrasound.d.

Sonophoresis occurs because ultrasSonophoresis occurs because ultrasound waves stimulate micro-vibratioound waves stimulate micro-vibrations within the skin epidermis and incns within the skin epidermis and increase the overall kinetic energy of mrease the overall kinetic energy of molecules making up topical agents.olecules making up topical agents.

Limited permeation due to lipid barrierof the skin

Enhanced permeation by disruption of lipidbarrier cavitation

It is thought that high-frequency ultrIt is thought that high-frequency ultrasound can influence the integrity of tasound can influence the integrity of the stratum corneum and thus affect ithe stratum corneum and thus affect its penetrability.s penetrability.

Among the agents examined are Among the agents examined are hydrocortisone, hydrocortisone, lidocaine, lidocaine, salicylic acidsalicylic acid

in such formulations as gels, creams, in such formulations as gels, creams, and lotions.and lotions.

III. Design features of transdermal III. Design features of transdermal drug delivery systemsdrug delivery systems

TDDSs are designed to support the pTDDSs are designed to support the passage of drug substances from the sassage of drug substances from the surface of the skin through its various urface of the skin through its various layers and into the systemic circulatilayers and into the systemic circulation.on.

（将药物设计成经皮给药系统能使药物透过（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皮肤表面、穿过皮肤的不同层进入体循环）。环）。

Transdermal drug delivery systems may be constructed Transdermal drug delivery systems may be constructed of a number of layers, including of a number of layers, including

1) 1) an occlusive backing membranean occlusive backing membrane to protect the system fr to protect the system from environmental entry and from loss of drug from the om environmental entry and from loss of drug from the system or moisture from the skin;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 and , which is removed before application and

enables drug release;enables drug release;4) 4) an adhesive layeran adhesive layer to maintain contact with the skin after to maintain contact with the skin after

application. application.

Technically, TDDSs Technically, TDDSs may be categorized inmay be categorized into two types, to two types,

1) Monolithic 1) Monolithic （整体（整体型）型）

Monolithic systems iMonolithic systems incorporate a drug mancorporate a drug matrix layer between batrix layer between backing and frontal layecking and frontal layers.rs.

（整体型在背衬层和正面（整体型在背衬层和正面中间为含药骨架层）中间为含药骨架层）

1. Foil covertrip 2. Drug matrix3. Release liner 4. Foil baseplate5. Microporous tape 6. AbsorbentPad 7. Occlusive overlay

The drug-matrix layer is composed of The drug-matrix layer is composed of a polymeric material in which the drua polymeric material in which the drug is dispersed.g is dispersed.

（药物（药物 -- 骨架层由分散有药物的聚合物组成）骨架层由分散有药物的聚合物组成）

The polymer matrix controls the rate The polymer matrix controls the rate at which the drug is released for percat which the drug is released for percutaneous absorption.utaneous absorption.

（聚合物骨架控制经皮吸收药物的释放速率）（聚合物骨架控制经皮吸收药物的释放速率）

In the preparation of monolithic systeIn the preparation of monolithic systems, the drug and the polymer are dissms, the drug and the polymer are dissolved or blended together, cast as the olved or blended together, cast as the matrix, and dried.matrix, and dried.

（在制备整体型时，药物和聚合物一起溶解或（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）。混合，作为骨架并干燥）。

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

Membrane-controlled transdermal sMembrane-controlled transdermal systems are designed to contain a druystems are designed to contain a drug reservoir, or pouch, usually in liquig reservoir, or pouch, usually in liquid or gel form, a rate-controlling memd or gel form, a rate-controlling membrane, and backing, adhesive, and prbrane, and backing, adhesive, and protecting layers.otecting layers.

（膜控型经皮给药系统设计为有药物储库或（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。）释膜、背衬层、粘胶层和保护层。）

Membrane-controlled systems have tMembrane-controlled systems have the advantage over monolithic systemhe advantage over monolithic systems in that as long as the drug solution is in that as long as the drug solution in the reservoir remains saturated, the n the reservoir remains saturated, the release rate of drug through the contrrelease rate of drug through the controlling membrane remains constant.olling membrane remains constant.

膜控型比整体型的优点在于，只要药物贮库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中溶液保持饱和，药物通过控释膜的速率保持恒定。持恒定。

DeliveryModifiers

Micro-DeliverySystems

Proprietary Drug Delivery Systems &

Designs

PolymerTechnologies

Patch SystemDesigns

IV. Percutaneous absorption mIV. Percutaneous absorption modelsodels

1.1. In vivo studiesIn vivo studiesIn vivo skin penetration studies may bIn vivo skin penetration studies may be undertaken for one or more of the foe undertaken for one or more of the following purposes: llowing purposes:

1)1) To verify and quantify the cutaneous To verify and quantify the cutaneous bioavailability of a topically applied dbioavailability of a topically applied drug.rug.

2)2) To verify and quantify the systemic biTo verify and quantify the systemic bioavailability of a transdermal drug.oavailability of a transdermal drug.

3) To establish bioequivalence of differ3) To establish bioequivalence of different topical formulations of the same ent topical formulations of the same drug substance.drug substance.

4) To determine the incidence and deg4) To determine the incidence and degree of systemic toxicologic risk folloree of systemic toxicologic risk following topical application of a specific wing topical application of a specific drug or drug product.drug or drug product.

5) To relate resultant blood levels of dr5) To relate resultant blood levels of drug in human to systemic therapeutic ug in human to systemic therapeutic effects.effects.

The most relevant studies are The most relevant studies are performed in humans, however, performed in humans, however, animal models may be used insofar as animal models may be used insofar as they may be effective as predictors of they may be effective as predictors of human response.human response.

Biologic samples used in drug Biologic samples used in drug penetration and drug absorption penetration and drug absorption studies includestudies include skin sections skin sections, , venous venous blood from the application siteblood from the application site, , blood blood from the systemic circulationfrom the systemic circulation, and , and excreta (urine, feces, and expired air)excreta (urine, feces, and expired air)..

2. In vitro studies2. In vitro studies Skin permeation may be tested in vitrSkin permeation may be tested in vitr

o using various skin tissues (human or o using various skin tissues (human or animal whole skin, dermis or epidermanimal whole skin, dermis or epidermis) in a diffusion cell.is) in a diffusion cell.

In vitro penetration studies using huIn vitro penetration studies using human skin are limited because of difficman skin are limited because of difficulties of procurement, storage, expenulties of procurement, storage, expense, and variation in permeation.se, and variation in permeation.

Animal skins are much more permeabAnimal skins are much more permeable than human skin. One alternative tle than human skin. One alternative that has been shown to be effective is shat has been shown to be effective is shed snake skinhed snake skin （蛇蜕）（蛇蜕） ..

The material may be used in cell The material may be used in cell culture studies or in standard culture studies or in standard diffusion cells.diffusion cells.

Diffusion cell systems are employed Diffusion cell systems are employed in vitro to quantify the release rates in vitro to quantify the release rates of drugs from topical preparations.of drugs from topical preparations.

In these systems, In these systems, skin membranesskin membranes or or synthetic membranessynthetic membranes may be may be employed as barriers to the flow of employed as barriers to the flow of drug and vehicle to simulate the drug and vehicle to simulate the biologic system.biologic system.

V. Advantages and disadvantages of TV. Advantages and disadvantages of TDDSsDDSs

The advantages of TDDSs are:The advantages of TDDSs are:1.1. They can avoid gastrointestinal drug aThey can avoid gastrointestinal drug a

bsorption difficulties caused by gastrbsorption difficulties caused by gastrointestinal pH, enzymatic activity and ointestinal pH, enzymatic activity and drug interactions with food, drink, or drug interactions with food, drink, or other orally administered drugs.other orally administered drugs.

2.2. They can substitute for oral administrThey can substitute for oral administration of medication when that route is ation of medication when that route is unsuitable, as in instances of vomitinunsuitable, as in instances of vomiting and/or diarrhea.g and/or diarrhea.

3. 3. They avoid the first-pass effect, that iThey avoid the first-pass effect, that is, the initial pass of a drug substance ts, the initial pass of a drug substance through the systemic and portal circulhrough the systemic and portal circulation following gastrointestinal absoration following gastrointestinal absorption, theraby possibly avoiding the dption, theraby possibly avoiding the drug’s deactivation by digestive and lirug’s deactivation by digestive and liver enzymes.ver enzymes.

4. The systems are noninvasive, avoidin4. The systems are noninvasive, avoiding the inconvenience of parenteral theg the inconvenience of parenteral therapy.rapy.

5. They provide extended therapy with 5. They provide extended therapy with a single application, thereby a single application, thereby improving patient compliance over improving patient compliance over other dosage forms requiring more other dosage forms requiring more frequent dose administration.frequent dose administration.

6. The activity of drugs having short 6. The activity of drugs having short half-lives is extended through the half-lives is extended through the reservoir of drug present in the reservoir of drug present in the therapeutic delivery system and its therapeutic delivery system and its controlled release characteristics.controlled release characteristics.

7. Drug therapy may be terminated rap7. Drug therapy may be terminated rapidly by removal of the application froidly by removal of the application from the surface of the skin.m the surface of the skin.

8. Ease of rapid identification of the m8. Ease of rapid identification of the medication in emergencies (e.g., nonreedication in emergencies (e.g., nonresponsive, unconscious, or comatose sponsive, unconscious, or comatose patient) due to the physical presence,patient) due to the physical presence, features and identifying-markings o features and identifying-markings on the TDDS.n the TDDS.

The disadvantages of TDDSs are:The disadvantages of TDDSs are:1. 1. Only relatively potent drugs are suitable Only relatively potent drugs are suitable

candidates for transdermal delivery due candidates for transdermal delivery due to the natural limits of drug entry imposto the natural limits of drug entry imposed by the skin’s impermeability.ed 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（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。）合制成经皮给药。）

2. 2. Some patients may develop contact dermSome patients may develop contact dermatitis at the site of application due to one atitis at the site of application due to one or more of the system components, neceor more of the system components, necessitating discontinuation.ssitating discontinuation.

（一些病人在用药部位可产生接触性皮炎，无法继（一些病人在用药部位可产生接触性皮炎，无法继续用药。）续用药。）

VI. Examples of transdermal drug VI. Examples of transdermal drug delivery systemsdelivery systems

1.1. Transdermal scopolamineTransdermal scopolamine

It was the first TDDS to receiIt was the first TDDS to receive FDA approval.ve FDA approval.

The Transderm-Scop system The Transderm-Scop system is a circular flat patch 0.2 mis a circular flat patch 0.2 mm thick and 2.5 cmm thick and 2.5 cm22 in area. in area.

The TDDS contains 1.5 mg of The TDDS contains 1.5 mg of scopolamine and is designed to scopolamine and is designed to deliver approximately 1 mg of deliver approximately 1 mg of scopolamine at an approximately scopolamine at an approximately constant rate to the systemic constant rate to the systemic circulation over the 3 day life-time of circulation over the 3 day life-time of the system.the system.

The patch is worn in a hairless area The patch is worn in a hairless area behind the ear. Because of the small behind the ear. Because of the small size of the patch, the system is size of the patch, the system is unobtrusive, convenient, and well unobtrusive, convenient, and well accepted by the patient.accepted by the patient.

2. Transdermal Nitroglycerin2. Transdermal NitroglycerinA number of nitroglycerin-containing A 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 maintains nitroEach of these products maintains nitroglycerin drug delivery for 24 hours aftglycerin drug delivery for 24 hours after application.er application.

Nitroglycerin is used widely in the propNitroglycerin is used widely in the prophylactic hylactic （预防）（预防） treatment of angina.treatment of angina.

It has a relatively low dose, short plasmIt has a relatively low dose, short plasma half-life, high peak plasma levels, and a half-life, high peak plasma levels, and inherent inherent （固有的）（固有的） side effects when taside effects when taken sublingually, a popular route.ken sublingually, a popular route.

It is rapidly metabolized by the liver whIt is rapidly metabolized by the liver when taken orally, this first-pass effect is ben taken orally, this first-pass effect is bypassed by the transdermal route.ypassed by the transdermal route.

The various nitroglycerin TDDSs contThe various nitroglycerin TDDSs control the rate of drug delivery through rol the rate of drug delivery through a membrane and/or controlled releasa membrane and/or controlled release from the matrix or reservoir.e from the matrix or reservoir.

The rate of drug release depends on tThe rate of drug release depends on the system. In the he system. In the Transderm-Nitro syTransderm-Nitro systemstem, nitroglycerin 0.02 mg is deliver, nitroglycerin 0.02 mg is delivered per hour for every square centimeed per hour for every square centimeter of patch, whereas in the ter of patch, whereas in the Deponit sDeponit systemystem, each square centimeter delive, each square centimeter delivers approximately 0.013 mg of nitroglyrs approximately 0.013 mg of nitroglycerin per hour.cerin per hour.

Not all nitroglycerin systems have the sNot all nitroglycerin systems have the same construction. For example, the Traame construction. For example, the Transderm-Nitro TDDS is a four-layer drug nsderm-Nitro TDDS is a four-layer drug pouch system, whereas the Deponit TDpouch system, whereas the Deponit TDDS is a thin two-layer matrix system resDS is a thin two-layer matrix system resembling.embling.

Patients should be given explicit instrucPatients should be given explicit instructions regarding the use of nitroglycerin tions regarding the use of nitroglycerin transdermal systems.transdermal systems.Generally, these TDDSs are placed on thGenerally, these TDDSs are placed on the chest, back, upper arms, or shoulders.e chest, back, upper arms, or shoulders.

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

3. Transdermal clonidine3. Transdermal clonidine The first transdermal system for hypertThe first transdermal system for hypert

ension, Catapres TTS (clonidine transdeension, Catapres TTS (clonidine transdermal therapeutic system, Boehringer Inrmal therapeutic system, Boehringer Ingelheim), was marketed in 1985.gelheim), was marketed in 1985.

Clonidine lends itself to transdermal delClonidine lends itself to transdermal delivery because of its lipid solubility, high ivery because of its lipid solubility, high volume of distribution, and therapeutic volume of distribution, and therapeutic effectiveness in low plasma concentratieffectiveness in low plasma concentrations.ons.

The TDDS provides controlled release of The TDDS provides controlled release of clonidine.clonidine.

Catapres TTS is available in several siCatapres TTS is available in several sizes, with the amount of drug releasezes, with the amount of drug released proportional to the patch size.d proportional to the patch size.

To ensure constant release over the To ensure constant release over the 7-day use period, the drug content is 7-day use period, the drug content is greater than the total amount of drug greater than the total amount of drug delivered.delivered.

Catapres TTS is available in several siCatapres TTS is available in several sizes, with the amount of drug releasezes, with the amount of drug released proportional to the patch size.d proportional to the patch size.

Clonidine flows in the direction of thClonidine flows in the direction of the lower concentration at a constant re lower concentration at a constant rate limited by a rate-controlling meate limited by a rate-controlling membrane.mbrane.

The system is applied to the hairless The system is applied to the hairless area of intact skin on the upper outer area of intact skin on the upper outer arm or chest.arm or chest.

4. Transdermal Nicotine4. Transdermal Nicotine Nicotine TDDSs are used as adjuncts in sNicotine TDDSs are used as adjuncts in s

moking cessation programs.moking cessation programs. In a blinded study, users of nicotine TDDIn a blinded study, users of nicotine TDD

Ss are more than twice as likely to quit sSs are more than twice as likely to quit smoking than individuals wearing a placemoking than individuals wearing a placebo patch.bo patch.

The nicotine TDDSs provide sustained blThe nicotine TDDSs provide sustained blood levels of nicotine as “nicotine-replacood levels of nicotine as “nicotine-replacement-therapy” to help the patient estabement-therapy” to help the patient establish and sustain remission from smoking. lish and sustain remission from smoking.

The commercially available patches The commercially available patches contain from 7 to 22 mg of nicotine for contain from 7 to 22 mg of nicotine for daily application during the course of daily application during the course of treatment ranging from about 6 to 12 treatment ranging from about 6 to 12 weeks.weeks.

A nicotine TDDS usually is applied to A nicotine TDDS usually is applied to the arm or upper front torso, with the arm or upper front torso, with patients advised not to smoke when patients advised not to smoke when wearing the system.wearing the system.

Some of the nicotine replacement Some of the nicotine replacement programs provide a gradual reduction programs provide a gradual reduction in nicotine dosage form during the in nicotine dosage form during the treatment program.treatment program.

5. Transdermal Estradiol5. Transdermal Estradiol The Estraderm TDDS delivers 17The Estraderm TDDS delivers 17-est-est

radiol through a rate-limiting membradiol through a rate-limiting membrane continuously upon application trane continuously upon application to intact skin.o intact skin.

Two systems provide delivery of 0.05 Two systems provide delivery of 0.05 or 0.1 mg estradiol per day.or 0.1 mg estradiol per day.

Estradiol is indicated for the treatmeEstradiol is indicated for the treatment of moderate to severe vasomotor synt of moderate to severe vasomotor symptoms associated with menopause, mptoms associated with menopause, female hypogonadism female hypogonadism （性腺功能减（性腺功能减退）退） , female castration , female castration （女性卵巢切除（女性卵巢切除术）术） , primary ovarian failure , primary ovarian failure （原发性（原发性卵巢功能衰竭）卵巢功能衰竭） , and atrophic , and atrophic (( 萎缩）萎缩） cconditions caused by deficient endogeonditions caused by deficient endogenous estrogen production, such as atrnous estrogen production, such as atrophic vaginitis and kraurosis value. ophic vaginitis and kraurosis value.

Transdermal administration producTransdermal administration produces therapeutic serum levels of estrades therapeutic serum levels of estradiol with lower circulating levels of esiol with lower circulating levels of estrone and estrone conjugates than dotrone and estrone conjugates than does oral therapy and requires a smallees oral therapy and requires a smaller total dose.r total dose.

The systemic side effects from oral eThe systemic side effects from oral estrogens can be reduced by using the strogens can be reduced by using the transdermal dosage forms.transdermal dosage forms.

6. Transdermal testosterone6. Transdermal testosterone Testosterone transdermal systems, TestoTestosterone transdermal systems, Testo

derm (Alza) and Androderm (SmithKline derm (Alza) and Androderm (SmithKline Beecham), are available with various deliBeecham), are available with various delivery rates as hormone replacement theravery rates as hormone replacement therapy in men who have an absence or deficiepy in men who have an absence or deficiency of testosterone.ncy of testosterone.

The TDDS is applied daily, usually in the The TDDS is applied daily, usually in the morning to mimic endogenous testosteromorning to mimic endogenous testosterone release.ne release.

Optimum serum levels are reached within Optimum serum levels are reached within 2 to 4 hours after application. The patch is 2 to 4 hours after application. The patch is worn 22 to 24 hours daily for 6 to 8 weeks.worn 22 to 24 hours daily for 6 to 8 weeks.

7. Other transdermal therapeutic syste7. Other transdermal therapeutic systemsms

Diltiazem Diltiazem 地尔硫卓地尔硫卓 Isosorbide dinitrate Isosorbide dinitrate 硝酸异山梨醇硝酸异山梨醇 Propranolol Propranolol 普奈洛尔普奈洛尔 Nifedipine Nifedipine 硝苯地平硝苯地平 Mepindolol Mepindolol 甲吲洛尔甲吲洛尔 Verapamil Verapamil 维拉帕米维拉帕米

Cardiovascular agents, Cardiovascular agents, levonorgestrel/estradiol levonorgestrel/estradiol for hormonal confor hormonal con

traceptiontraception, , Physostigmine(Physostigmine( 毒扁豆碱毒扁豆碱 ), xanomeline (), xanomeline ( 占占诺美林诺美林 )for )for Alzheimer’s disease therapyAlzheimer’s disease therapy,,

Naltrexone(Naltrexone(纳曲酶纳曲酶 ) and methadone for su) and methadone for substance bstance addictionaddiction,,

BuspironeBuspirone （丁螺环酮（丁螺环酮）） for for anxietyanxiety ，， Bupropion Bupropion （安非他酮）（安非他酮） for for smoking cessasmoking cessa

tiontion ，， PapaverinePapaverine （罂粟碱） （罂粟碱） for for male impotencemale impotence ，，

VII. General clinical considerationVII. General clinical considerations in the use of TDDSss in the use of TDDSs

The patient should be advised of thThe patient should be advised of the following general guidelines alone following general guidelines along with product-specific instructions g with product-specific instructions in the use of TDDSs.in the use of TDDSs.

1. Percutaneous absorption may vary 1. Percutaneous absorption may vary with the site of application.with the site of application.

2. TDDSs should be applied to clean, d2. TDDSs should be applied to clean, dry skin that is relatively free of hair ry skin that is relatively free of hair and not oily, irritated, inflamed, brand not oily, irritated, inflamed, broken, or callused.oken, or callused.

3. Use of skin lotion should be avoided 3. Use of skin lotion should be avoided at the application site, because lotionat the application site, because lotions affect skin hydration and can alter ts affect skin hydration and can alter the partition coefficient between the he partition coefficient between the drug and the skin.drug and the skin.

4. TDDSs should not be physically alte4. TDDSs should not be physically altered by cutting, since this destroys thred by cutting, since this destroys the integrity of the system.e integrity of the system.

5. A TDDS should be removed from its 5. A TDDS should be removed from its protective package, with care not to tprotective package, with care not to tear or cut into the unit.ear or cut into the unit.

6. A TDDS should be placed at a site 6. A TDDS should be placed at a site that will not subject it to being that will not subject it to being rubbed off by clothing or movement.rubbed off by clothing or movement.

7. A TDDS should be worn for the full 7. A TDDS should be worn for the full period stated in the product’s period stated in the product’s instructions. Following that period, it instructions. Following that period, it should be removed and replaced with should be removed and replaced with a fresh system as directed.a fresh system as directed.

8. The patient or caregiver should be 8. The patient or caregiver should be instructed to cleanse the hands instructed to cleanse the hands thoroughly before and after applying thoroughly before and after applying a TDDS. a TDDS.

9. if the patient exhibits 9. if the patient exhibits sensitivity or intolerance to a sensitivity or intolerance to a TDDS or if undue skin irritation TDDS or if undue skin irritation results, the patient should seek results, the patient should seek reevaluation.reevaluation.

10. Upon removal, a used TDDS 10. Upon removal, a used TDDS should be folded in half with the should be folded in half with the adhesive layer together so that it adhesive layer together so that it cannot be reused.cannot be reused.

QuestionsQuestions1. Explain shortly1. Explain shortly- transdermal drug delivery systems- transdermal drug delivery systems- iontophoresis- iontophoresis- sonophoresis - sonophoresis - percutaneous absorption enhancers- percutaneous absorption enhancers2. What factors could affect percutaneous dru2. What factors could affect percutaneous dru

g absorption?g absorption?3. How to increase percutaneous absorption o3. How to increase percutaneous absorption o

f drug by physical and chemical methods?f drug by physical and chemical methods?4. What types of drugs could be designed as T4. What types of drugs could be designed as T

DDSs and how?DDSs and how?

5. How to design transdermal drug delivery sy5. How to design transdermal drug delivery systems?stems?

6. How to study the percutaneous absorption 6. How to study the percutaneous absorption of drug using in vitro and in vivo models?of drug using in vitro and in vivo models?

6. What are the characteristics of transdermal 6. What are the characteristics of transdermal drug delivery systems?drug delivery systems?

7. How many different types of transdermal ni7. How many different types of transdermal nitroglycerin are in the market? Explain their troglycerin are in the market? Explain their characteristics respectively.characteristics respectively.

8. What are the clinical considerations in the 8. What are the clinical considerations in the use of TDDSs? use of TDDSs?