3 Transdermal Drug Delivery Devices

Philip W. Ledger, PhD, and Kirstin C. Nichols, MA

From ALZA Corporation, Palo Alto, Califwnia

The concept of transdermal delivery is not new, but until recently, its therapeutic application was restricted to creams and ointments which are messy and difficult to apply uniformly to ensure reproducible dosing. In the late 197Os, technology was developed that permitted the construction of multicomponent devices embodying the ability to provide precise transdermal delivery in a convenient dosage form.1 Soon thereafter, the first modern “Transdermal Drug Delivery Device” was brought to the market. This product was an adhesive skin patch capable of delivering the antiemetic scopolamine at a controlled, predetermined rate for 3 days of motion sickness prophylaxis. It has been followed by several other transdermal delivery devices. Concurrently, there has been an explosion of interest in the field of novel forms of drug delivery in general, and transdermal delivery in particular. Because pharmacokinetic and physicochemical principles involved in transdermal delivery are discussed in other sections of this publication and extensive reviews on various aspects of transdermal drug delivery273 have recently appeared, here we will describe existing commercial transdermal delivery devices and will speculate on the future of transdermal delivery devices.

Drug Selection and the Advantages ot Transdermal Controlled Delivery

Development of each transdermal dosage form must be based on the physicochemical, pharmacokinetic, and pharmacodynamic properties of the drug to be delivered. Because a drug must exhibit a permeation rate through the skin that is high enough to attain therapeutic levels in the systemic circulation, the smaller the dose of drug required, the more likelihood there is of achieving therapeutic levels, and a dose of about 10 mg per day is generally considered to be an upper limit for passive transdermal delivery. At a given rate of permeation, the active area of the transdermal system will determine what dose is delivered to the body. For practical reasons, the dose necessary to establish desired plasma levels must not require that the device exceed an acceptable size. This relationship between area and dose is exploited by marketing devices of different areas to provide several dosage strengths.

25

20 Ledger and Nichols

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UI ti

4:

s Q 6.0- c- TACHYCARDIA

z

I.M. INJECTIONS

- DROWSINESS

- ORYMOUTH

1 TTS-SCOPOLAMINE ANTI-EMESIS

I I

0 10 I --&______+

20 *LA

z MOTION SICKNESS BRADYCARDIA

60 70 72 t t t

TIME /hr)

FIG. 3-l. Excretion of scopolamine following a single appiication of Transderm-ScGp@ or repeated intra-

muscular injections of scopolamine [at vertical arrow] in humans. Urinary excretion of free scopolamine L 9.5 310.9~/;, (avg. f SE.) df total drug administered

Transdermal delivery bypasses the portal circulation thereby eliminating hepatic first pass metabolism. Therefore, drugs with short half lives due to high hepatic metabolism are particularly appropriate for transdermal delivery. Correspondingly, drugs with long half lives are not strong candidates for transdermal delivery, as their delivery by this mode presents less advantage over oral dosage forms.

If the rate at which a transdermal device releases drug in V&O is greater than the rate of permeation of the drug through the skin, entry of drug into the systemic circulation wiI1 depend largely on skin permeability. Because of wide interindividual variation in permeability,‘l” such delivery is clearly not completely controlled. True controlled trans- dermaf delivery depends on the system having more control over drug flux than the most impermeable skin. For a rapidly permeating drug, this can be achieved by the use of a rate-controlling membrane which has a greater resistance to drug flow than does the epidermis. Rate-controlled systems greatly expanded the value of transdermal drugdelivery by increasingcontrol over blood drug concentrations to increase selectivity of

drug actions. Side effects frequently asso- ciated with peaks in plasma concentrations (Fig. X-l) were reduced, and therapeutic efficacy was enhanced by etiminating troughs of plasma concentration.

Another important advantage of transder- mal therapy which is probably of foremost importance in patient acceptance is conven- ience and the associated increased patient compliance. This is well illustrated by experience with Catapres-TTS@, which contains enough antihypertensive medication for 7 days in a single patch a few centimeters square.

The Biological Interface

Even though transdermal therapy has significant advantages, it has to be recognized that it is not without its attendant disadvan- tages. Biological reactions to the entry of foreign substances can occur and are manifest as localized irritation or contact dermatitis.‘; For obvious reasons, devices showing unac- ceptably high levels of irritation have never reached the market. A low incidence of skin reactions to devices currently marketed has

July-September 1989 Volume 7 Number 3 Transdermal Drua Deliverv 27

been reported. Reactions include irritation and sensitization to adhesives or other system components7 9s as well as contact dermatitis from the therapeutic agents being delivered.9 The latter phenomenon can show unusual onset kinetics. For example, sensitization to clonidine in Catapres-TTS has been found to occur in 25%-40% of patients, but this frequency is only reached after several months of use.10 Either irritation or contact dermatitis can preclude further use of a particular system by a patient. It has been shown, however, that in most cases of sensitization to transdermal clonidine (Catapres-TTS), patients can safely transfer to oral treatment.11

Electrotransport

Electrotransport, or iontophoresis, uses an electrical potential to enhance the passage of drug through the skin. The experimental study of electrotransport has a long history, and the technique has been applied in numerous clinical situations.12~13 Despite this clinical experience with electrotransport, current commercial applications remain limited.

Technology and Applications

All transdermal systems have certain com- ponents in common: A backing membrane to contain the system and to prevent drug release to the environment and influx of water from the environment; a drug reservoir to store the drug in a stable form for the amount of time the system is to be worn; a drug- release mechanism (energy source); a delivery portal to allow the drug released from the system to access the skin; an adhesive to keep the system in adequate contact with the skin; and a peelable protective liner to ensure the system does not begin to deliver the drug until applied to the skin (Fig. 3-2). Marketed passive transdermal delivery systems can be categorized into two basic types: matrix and membrane-controlled. In matrix systems, the drug is present in the reservoir as a semisolid

solution or a dispersion. Membrane- controlled systems have an additional rate- controlling membrane to limit drug release. A recent review provides detailed informa- tion on materials used in commercial trans- dermal devices.14

Matrix Devices

In these devices, drug release is determined by solution diffusion of a drug through its polymer matrix. Molecular and structural factors of the drug-polymer matrix will determine drug release (eg, polarity, glass transition temperature, bonding, the effect of drug and excipients on the polymer chains, and the drug concentration per unit area).15

Polymer Matrix Diffusion-Controlled

The drug reservoir of these systems is formed by dispersing solid drug into a polymer. This polymer-drug mixture is molded into a disk that will release the drug and then mounted onto a drug-impermeable plastic backing. A hypoallergenic micropor- ous adhesive is spread around the periphery of the drug reservoir containing the disk. The disk contacts the skin directly and is held in place by its wet nature and by the adhesive

A

C

L1 BACKING

DRUG RESERVOIR

ADHESIVE-DRUG

RESERVOIR

B

ADHESIVE

PROTECTIVE LINER

RATE-CONTROLLING

MEMBRANE

FIG. 3-2. Construction of four basic types of trans- dermal systems. A) Polymer matrix. B) Adhesive- dispersion monolith. C) Multilaminate. 0) Form-fill and seal.

28 Ledger and Nichols

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rim. Nitro-Dur, a nitroglycerin system, is Membrane Permeation- formulated with this technology. Controlled Systems

Adhesive Dispersion-Type Multilaminate Systems

In these systems, the drug is dispersed in an adhesive polymer such as polyisobutylene or polyacrylate. This drug-containing adhe- sive is spread by hot melt or solvent casting onto a flat sheet of a drug-impermeable backing to form a drug reservoir. Systems manufactured in this manner will not have a constant rate of drug release.16 Frandol@, an isosorbide dinitrate-releasing tape, and Nitro-Dur II@, a nitroglycerin-releasing system, are adhesive dispersion type trans- dermal delivery systems. Both systems are indicated for angina prophylaxis.

To produce relatively constant drug release, Chien has proposed modifying adhesive dispersion systems by loading the drug in several adhesive layers at different concentrations to form a gradient. This proportional loading would achieve constant release by compensating for the time- dependent decrease in drug diffusion that occurs during drug depletion.iti

Micro-Reservoir Dissolution-Controlled

These delivery systems are a combination of the reservoir and dispersion type systems. Systems are manufactured by homogeneously dispersing a water-soluble polymer (eg. polyethylene glycol) containing a suspension of solid drug into a silicone elastomer. Tiny spheres of drug reservoirs are created by forcing the drug containing the water-soluble polymer into the lipophilic polymer. To stabilize the dispersion, the polymer chains are immediately cross-linked and a medi- cated polymer disk of desired surface area and thickness is created. The system is completed by placing the disk at the center of an adhesive pad backed by a drug- impermeable laminate. Drug release can be designed to be partition controlled or matrix diffusion controlled. Nitrodisc. a nitro- glycerin system, is an example of this . .

The drug and adhesive layers of these systems are prepared by dissolving adhesive polymers in an appropriate vehicle and adding a drug to each solution. These drug- containing solutions are deposited as a thin, continuous film and passed through a series of evaporating ovens. The protective liner, the microporous polypropylene control mem- brane, and backing layer are all laminated together with the drug and adhesive layers. A rotary die-cutting press cuts individual dosage forms. Transderm-Stop and Catapres- TTS are examples of multilaminate systems. Because both scopolamine and clonidine permeate skin relatively easily, the rate- controlling membranes prevent the systems from releasing too much drug to individuals with highly permeable skin, The dosage form delivers 0.5 mg of scopolamine to protect against motion sickness for 3 days after a single application’7 Catapres-TTS delivers clonidine in 0.1, 0.2, or 0.3 mg daily doses for 7 days to control hypertension. Catapres- TTS reduces the principal side effects associated with oral clonidine (drowsiness and dry mouth) and simplifies the regimen to enhance compliance.is

The drug is incorporated into the adhesive of both Catapres-TTS and Transderm-Stop to provide initial drug release when the systems are first applied to the skin. This loading dose helps overcome the delay of achieving therapeutic plasma drug concen- trations created by the binding of drug to skin sites and loading of body volume of distribution.

Form-Fill and Seal Systems

These systems, whose classification em- bodies their mode of construction, have a semisolid or liquid drug reserovir (fluid gel reservoir) sealed between the backing and the rate-controlling membrane. Transderm-

technology.” Nitro and Estraderm are examples of mar-

July-September 1989 Volume 7 Number 3 Transdermal Drug Delivery 29

keted products using this technology. Transderm-Nitro is applied on the chest once daily to treat angina symptoms. Systems release 0.5 mg of nitroglycerin for every square centimeter, and four different size systems are rated to release 2.5, 5, 10, or 15 mg of nitroglycerin over 24 hours.19

Estraderm was developed to bypass the first-pass metabolism of oral 17p-estradiol, the hormone identical to that produced by the ovaries, for estrogen replacement and treat- ment of perimenopausal symptoms. Estra- derm is a form-fill-seal, membrane-controlled system. Two systems (10 and 20 ems) are designed to deliver 0.05 or 0.1 mg of estradiol each day in vivo for up to 4 days.20 To enhance transport of estradiol through the skin, the drug reservoir also contains 0.03 ml of ethanol for every 4 mgof estradiol. The 4-day duration of drug delivery allows women to maintain a twice-weekly dosing schedule.

Electrically Assisted Active Drug Delivery Device

Phoresor II, an iontophoretic system, uses electric current to transport anti- inflammatory drugs and local anesthetics through the skin. Percutaneous absorption is regulated by the strength of the current. The Phoresor II has a microprocessor to supply a controlled electrical current to a preinjected drug capsule electrode placed on the skin. After the time and current are set, drug delivery begins within approximately 10 minutes, and the unit conducts selfdiagnostic tests throughout the set time. A liquid crystal display shows the current dosage rate, dosage calculation, and the treatment time remain- ing. The 9 volt battery lasts for about 35 treatments.

A more recent appearance on the market is Lectro Patch, an iontophoretic device which, like Phoresor II, has a reservoir to be filled with a desired drug. Several additional iontophoretic devices have been patented, and many companies are reputed to be developing iontophoretic devices. Despite the proven efficacy of commercially available iontopho-

retie devices,21 they appear inconvenient and are not yet used extensively.

Transdermal Devices in Development

There are likely to be many more trans- dermal delivery devices marketed in the near future. In late 1988, Riker Labs, a subsidiary of 3M, received permission to market another transdermal nitroglycerin patch. Two Trans- dermal Therapeutic Systems developed by ALZA Corporation are awaiting approval from the Food and Drug Administration: fentayl, a potent opioid, that relieves moder- ate to severe pain, and testosterone, which provides hormone replacement for androgen- deficient males. Other transdermal systems now in late clinical trials include: nicotine, to treat smoking addiction (Elan); clonidine, to treat hypertension (Bolar); estradiol and norethisterone acetate for female hormone replacement (Ciba-Geigy); and an antiviral to treat herpes simplex (Research Medical). A large number of companies have reported development of many other transdermal systems incorporating a wide variety of drugs.

Future Directions

The future of transdermal delivery lies mainly in the ability to overcome its existing limitations. For example, the exploitation of drugs with low percutaneous flux may be achieved by the codelivery of permeation enhancers which modify the structural or physiochemical nature of the stratum cor- neum and thereby enhance passive permea- tion. To date, the only material serving this function in a commercial system is ethanol, although numerous agents have been studied experimentally. Although one advantage of controlled transdermal delivery is often the maintenance of a constant rate of drug delivery, there are instances in which pulsa- tile delivery may be advantageous. The feasibility of such devices has been demonstrated.22

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Electrotranspori

Increased acceptance of transdermal elec- trotransport will depend to a large extent on the miniaturization of devices to make their use more convenient. Greater enhancement of permeation and more elaborate system control could significantly increase the potential applications for electrotransport. In addition to facilitating the delivery of low molecular weight drugs showing poor passive permeation, electrotransport should be of use in delivering higher molecular weight mole- cules such as peptides and proteins.‘:’

The possibilities for system control of transdermal drug delivery are greater with electrotransport than with passive diffusion. Patterned and/or on-demand delivery would appear to present few obstacles in light of the sophistication of existing microelectronic circuitry. More exciting, and probably not too remote a possibility, is the construction of a delivery device linking a sensor that monitors a physiological parameter (eg, blood glucose or heart rate) with a feedback mechanism to regulate drug delivery from a transdermal electrotransport device.

have been well established therapeutic agents. There has been much experimental investigation into the use of specially designed prodrugs for transdermal delivery.27 A simple example would be a prodrug which is a nonactive modification of an existing drug with more favorable permeation character- istics than the parent drug. The modifications of the prodrugs allow them to be readily metabolized into the active drug. If intended for systemic delivery, this biotransformation can occur in the skin or elsewhere in the body. Ingenious variations of this principle could, by taking advantage of the biotransforming ability of the skin itself, favor the formation of active drug in the skin for local, topical delivery of poorly permeating substances.“8

The Biological Barrier

Phonophoresis

The use of ultrasound to rnassagc the skin to enhance percutaneous absorption of drugs (phonophoresis, sonophoresis, ultrasono- phoresis) was first described in 1954. Pho- nophoresis has been used most extensively with hydrocortisone. but has also been used with interferon. antibiotics, and nonsteroidal anti-inflammatories. Skauen and %entner”J reviewed ire c*ic~J and ir/ /,it~o phonophoresis. effects of ultrasound on living tissue. and the effects of ultrasound on the drugs. IjnIike earlier studies, recent studies on phonophort,- sis of lignocaine, prilocaine, and fluocinolone acetonide”“y”G have been double-blind placebo-controlled, and the authors suggest that phonophoresis may have benefit in the enhancement of localized drug therapies.

Whatever technological advances occur in transdermal drug delivery, one major limita- tion, the biological interface, may remain hard to overcome. As mentioned above, (sontact sensitization and irritation are problems frequently encountered in the tlevelopment of transdermal delivery systems and occasionally with already marketed !Ievices. Reduction of these problems by strategies such as the incorporation of caorticosteroids or inhibitors of drug metab- olism have been suggested.” As yet, however. no practical applications of such strategies have appeared on the market. The immediate future of transdermal delivery is undoubtedly closely linked to our ability to at least Jlnderstand, and ultimately manipulate, biological phenomena such as local immune responses.

References

Prodrugs

Ibrry HW Transdermal drug dt,l~very. In: Johnson I’ J,loyti ~.Jones .JG. eds. L)rug drlivcry systems: Fundamentals and techniques. Chichester. England: b:llis Horwuod IAd.. 1988:200-223.

To date, those drugs incorporated into commercial transdermal delivery devices

Ilwrt~ I., (‘hwn YW Transdermal drug delivery: a rv\ ~t’v vf pharmaceutics. pharmacokinetics. and

July-September 1989 Volume 7 Number 3 Transdermal Drua Deliverv 31

pharmacodynamics. Crit Rev Ther Drug Carrier Sys. 1988;4:285-349.

4. Feldmann RJ, Maibach HI. Regional variation in percutaneous penetration of 14C cortisol in man. J Invest Dermatol. 1967;48:181-183.

5. Scheuplein RJ, Blank IH. Permeability of the skin. Physiol Rev. 1971;51:702-747.

6. Schmidt RJ. Cutaneous side effects in transdermal drug delivery: Avoidance strategies. In: Hadgraft J, Guy RH, eds. Transdermal drug delivery: developmen- tal issues and research initiatives. New York: Marcel Dekker, Inc., 1989:83-97.

7. Letendre PW, Barr C, Wilkens K. Adverse derma- tologic reaction to transdermal nitroglycerin. Drug Intell Clin Pharm. 1984;18:69-70.

8. Schwartz BK, Clendenning WE. Allergic contact dermatitis from hydroxypropyl cellulose in a trans- dermal estradiol patch. Contact Dermatitis. 1988;18:106-107.

9. Fisher AA. Dermatitis due to transdermal therapeutic systems. Cutis. 1984;34:526-531.

10. Dick JB, Northridge DB, Lawson AA. Skin reactions to long-term transdermal clonidine. Lancet. 1987;1:516-.

11. Maibach HI. Oral substitution in patients sensitized by transdermal clonidine treatment. Contact Derma- titis. 1987;16:1-8.

12. Banga AK, Chien YW. Iontophoretic delivery of drugs: fundamentals, developments and biomedical applica- tions. J Control Rel. 1988;7:1-24.

13. Sloan JB, Soltani K. Iontophoresis in dermatology: a review. J Am Acad Dermatol. 1986;15:671-684.

14. Baker RW, Heller J. Materials selection for transder- ma1 delivery systems. In: Hadgraft J, Guy RH, eds. Transdermal drug delivery: developmental issues and research initiatives. New York: Marcel Dekker, Inc., 1989:293-311.

15. Monkhouse DC, Huq AS. Transdermal drug delivery -problems and promises. Drug Develop Indust Pharm. 1988;14:183-209.

16. Chien YW. Developmentof transdermal drug delivery systems. Drug Develop Indust Pharm. 1987;13:589- 651.

17. Price NM, Schmitt LG, McGuire J. Shaw J, Trobough G. Transdermal scopolamine in the prevention of motion sickness at sea. Clin Pharmacol Ther. 1981;29:414-419.

18. Weber MA. Transdermal antihypertensive therapy: clinical and metabolic considerations. Am Heart J. 1986;112:906-912.

19. Imhof PR. Anti-angina1 therapy with transdermal nitroglycerin. In: Prescott LF and Nimmo WS, eds. Rate Control in Drug Therapy. New York: Churchill Livingstone Inc., 1985:201-214.

20. Powers MS, Schenkel L, Darley PE, Good WR, Balestra JC, Place VP. Pharmacokinetics and phar- macodynamics of transdermal dosage forms of 17p- estradiol: comparison with conventional oral estrogens used for hormone replacement. Am J Ob Gyn. 1985;152:1099-1106.

21. Bezzant JL, Stephen RL, Petelenz TJ, Jacobsen SC. Painless cauterization of spider veins with the use of iontophoretic local anesthesia. J Am Acad Dermatol. 1988;19:867-875.

22. Baker RW, Farrant J. Current U.S. patents. J Control Rel. 1988;7:187-191.

23. Tyle P, Kari B. Iontopheretic (sic) Devices. In: Tyle P, ed. Drug delivery devices: fundamentals and applications. New York: Marcel Dekker, Inc., 1988:421-454.

24. Skauen DM, Zentner GM. Phonophoresis. Int J Pharmaceutics. 1984;20:235-245.

25. Benson HAE, McElnay JC. Harland R. Phonophoresis of lignocaine and prilocaine from Emla cream. Int J Pharmaceutics. 1988;44:65-69.

26. McElnay JC, Kennedy TA, Harland R. The influence of ultrasound on the percutaneous absorption of fluocinolone acetonide. Int J Pharmaceutics 1987;40:105-110.

27. Higuchi WI. Prodrugs in transdermal delivery. In: Kydonieus AG, Berner B, eds. Transdermal delivery of drugs III, Boca Raton, FL: CRC Press, 1987:43- 83.

28. Tauber U. Drug metabolism in the skin: advantages and disadvantages. In: Hagdraft J and Guy RH, eds. Transdermal drug delivery: developmental issues and research initiatives. New York: Marcel Dekker, Inc., 1989:99-111.

Address for correspondence: Philip W. Ledger, PhD, ALZA Corporation, 950 Page Mill Road, P.O. Box 10950, Palo Alto, CA 94303-0802.