Fig. 1. Steps in prolactin synrhasis and &ease. (I) S.vnrhesLs OJ proiacrin messenger RNA, which is st8mrrlared by estrogen and TRH. (2) Synrhesis oy preprokacrin, a larger molecular weighr /or*,. Jrom messenger RNA. IJ bromocriprine decr~st-s pro- lacnn synihesis. it may decnease either srep I or 2. (3) Processing oJ preprolactin and srorage oJprolacrm. (4) Llegradarion oJ prolactin. which is increased 5y chronic twatmenf with dopamrnergic agosurs. i ‘) Release of prolactin Jrom Qhe cell. Release is slow- lawd by TRH and VIP. and inhibited by dopamine.

be caused by more than just prevention of inhibition by dopamine. but the hypo- thalamic factors which serotonin releases to enhance prolactin secretion are not known. Prolactin itself may inhibit pro-

laclin prodtxtion; at least part of this effect appears to be mediated through the hypothalamus.

It is evident that the control of prolac- tin release is complex and depends on many factors, some of which are sum- marized in Fig. 1. The physiological role of these factors is now beginning to be determined. Regulation of pro&tin pro- duction by these factors may occur at several levels including changes in release. synthesis, and stability of prolactin, changes in the sensitivity of cells to factors which influence prolactin produc- tion. and growth of prolactin-producing cells.

Read!- list I Flttcluger. E. and Del Pozo, E. (1971) in

Handbook oJ Experimenral Pharmacologv (Berde. B. and Schild. H. 0. eds) Vol. 49. Springer-Vcrlag. Berlin, Heidelberg and New York, pp. 615-690

2 Frantz. A. G. (1973) in Fronriws in Neuroendo- crrno/ogv (Ganong. W. F. and Martini. L. eds), Oxford Unwersit~ Press, New York, pp. 337-374

3 MacLeod, R. M. (1976) in Frontiers in Neuro- endocrinorogv (Martini. L. and Gaeong. W. F. NW. Vol. IV. Raven Press. New York, pp. 169-I<>4

4 Martin. T. F. J. and Tashjian. A. H. Jr. (1977) in Biochemi~,al Acliolps OJ Hormones, (Litwack. G. cd) Vol. IV, Academic Press, New York, pp. 27&3’)8

TIPS - April, 1980

Mcitcs. J. (1973) in Human Prolarrin(P~steels. J. 1.. and Robyn. C. eds) Excerpt8 Medica. Amsterdam, pp. 105-l 16 Nicoll, 0. S. (1974) in Handbook oJ Ph.vsiolonv. Se&on 7: Eitdocrinolo~v (Knob& E. and Sawyer. W. H. eds) Vol. IV. American Physiological Society, Washington D.C., pp. 253-292 Parkes. D. (1979) N. Ennl. 1. Afed. 301, B73-R78 Rcich1in.S. (1979) N. Engl. J. Med. 300.313-315

Dr Dannies received her Ph.D. UI Brandeis Universiry in 1971 and then wnl 10 Harvard Universiry as Research Fellow. In 1976 she rook up herpresenr posirion as Asstsranr PraJessor PI Yale.

Programmed, systemic drug de ivery by the transdermal route Jane Shaw and John Urquhart ALZA Corpora&n. 950 Page &lill Road, Palo Alto, CaltJornia 94301. U.S.A.

In their recent exposition in TIPS of factors governing percutaneous absorp- tion of drugs, Wepierre a.nd Marty stated that this route has been “little used to obtain systemic effects” despite ,its important advantages over oral admini- stration. They attribute its neglect to its unsuitability for delivery of any but very potent drugs, and “lack of precision regarding the real dose absorbed”.

As advantages of percutaneous deli- very, these authors mention its avoidance of drug deactivation by digestive enzymes or first-pass hepatic metabolism. These advantages, of course, also characterize

parenteral routes such as injections or i.\. infusions. Only the latter, however, offer precise control over the rate of drug entry into the bloodstream. and then only when closely monitored. This paper describes the first rate-controlled ransdermal pharmaceutical product: the transdermal therapeutic system-scopolamine (TTS- sonpolamine). The current indication for its use is prevention of nausea and vomit- ing induced by motion.

The TTS-scopolamine is easily self- administered; it delivers scopolamine at a predetermined rate to the systemic circu- lation through intact skin. Our data in-

dicate that it is functionally the equivalent of a closely controlled i.v. infusion. A notable effect of the rate-control designed into the dosage form is that it confers greatly increased selectivity on the drug’s action.

In conventional dosage forms, scopola- mine’s inherent lack of selectivity of action has severely limited its use for preventing motion sickness, despite its potent anti-emetic action. Given in pulse mode, either orally or intramuscularly, scopolamine produces unpleasant CNS side effects such as drowsiness, giddiness, confusion, memory disturbances, and so forth. These properties suggested that the drug was i?n appropriate candidate for rate controlled delivery through intact skin in a self-applied dosage form; the aim was to program drug entry into the bloodstream at - rate chosen to evoke its anti-emetic effect sel.xtivcly, with minimal elicitation of its undesired side actions.

The use of the principle of rate control to separate the therapeutic effects of drugs from their undesired side actions is a concept that has only recently become feasible for routine use in medical

TIPS - April, I980

practice. Its application has had to await development of data relating blood and tissue concentrations of various agents to their specific pharmacological effects. The recent availability of such informa- tion for some drugs has made it possible to design and develop dosage forms capable of maintaining their concentra- tions at appropriate levels by control of their input rates. The TTS-scopolamine is the first of such development efforts to utilize intact skin as the route for control- led input into the systemic circulation.

Problems of tnnsdermal drug delivery

Transdermal delivery of potent agents for systemic therapy is not new, but its past use has been attended by a number of difficulties, the most serious being its inherent unpredictability. Despite that problem, and the very limited per- meability of skin in general, transdermal drug therapy is unquestionably feasible. The use of ointment or cream prepara- tions of nitroglycerin, anti-inflammatory agents, atId hormones has demonstrated clearly that some potent drugs applied to intact skin can elict adequate systemic therapeutic effects. Such effects are un- predictable for at least three reasons: (1) variation in area and thickness of oint- ment or cream formulations applied by the patient; (2) the inability of such first- order dosage forms (regardless of amount applied) to control the rate of drug release to skin; and (3) wide differences in skin permeability that affect the amount of drug entering the circulation.

In development of a rate-specified dosage form, compensation for differ- ences in skin permeability is a necessity if a controlled drug input rate is to result in predictable blood levels. Permeability of skin to a particular drug formulation can vary not only among skin sites of each individual but also among the same sites of different individuals’. Permeability also varies between sexes and am.ong different age and ethnic group+‘. Moreover, changes in environmental conditions and variations in skin blood flow and sweat gland function can tran- siently change skin permnbility. All of these factors have contributed to variable, unpredictable ra*es oi systemic drug input from ointments or sre ms.

Concept and design of Tl’S-scopolamine

The need, then, was for transdermal dosage form that would: (1) eliminate the possibility of imprecise self-administra- tion and (2) produce predictable blood

levels of scopolamine in plasma tl!=: i;j selectively evoked the therapeutic response. Achieving (2) required that variations in skin permeab lity be pre- vented from interfering with 3 predictable rate of drug input to the circulation. WC therefore designed TTS-scopolamine to deliver drug at a rate lower than even the least permeable of skin can absorb. In that way, the dosage form md not the skin would control the rate of entry of drug ir.to the bloodstream. To arrive at this design we had to define the extent of variations in skin permeability to scopola- mine at various body sites and at the same body sites among different individuals; we also established the effects on permeability of various factors such as occlusion and temperature. These studies are described in detail elsewhereM.

To determine the loweit blood levels of scopolamine providing an adequate anti- nauseant effect, we monitored the drug’s

209

uL :1 concentrations (as reflected in its urinary excretion rates) and its pharma- cological effects at intervals following a 200 pg i.m. dose. (The Royal Navy has utilized this dosage fo prevent motion sickness in lifeboat>‘.) The results are shown in Fig. 1.

To define ihe rate of scopolamine input required to maximize the selectivity of the anti-emetic action, we evaluated trans- dermal scopdamine delivery systems of different areas that delivered the drug at proportionately different rates under a variety of conditions ot motion. These rate-ranging studies indicated that a rate of drug entry into the bloodstream of 5 pg h-’ would maintain therapeutic blood levels. The svstem’s area was fixed at 2.5 cm2 and its scopolamine release rate at 2 p’g cm-? h-‘. That rate is only one fifth of the average permeation rate of drug through postauricular skin at its prevail- ing plysiological temperature of 34’C;

AMNESIA +

CENTRAL NERVOUS SYSTEM EFFECTS +

210

thus, the major control over drug delivery to the systemic circulation resides in the system and not the skin.

in viva, TTS-scopolamine delivers 0.5 mg of the drug in programmed fashion over three days. Approximate!y 14Ul(g of scopolamine is delivered as a priming dose in the first few hours, followed by a constant rate of 5 ug h-t over the re- mainder of the 3 day duration of the product’s functional lifetime. About 100 ug binds to sites in the epidermis beneath the TTSscopoiamine and the remainder of the priming dose serves to bring the blood levels of the drug up to the steady- state value as rapidly as possible. We use the term ‘programmed delivery’ to signify this kinetic sequence of drug delivery.

The system is a thin (0.2 mm thick), muitiiayer unit (Fig. 2) comprising a steady-state reservoir that contains the drug in a gel, sandwiched ‘between an impermeable backing Layer and a rate- controlling microporou s membrane. On the epidermai sidre of thut membrane (Fig. 2) is an adhesive gel layer. also containing scopolamine, which secures the system to the skin and also provides the priming- dose drug reservoir. After the patient places the system on dry, intact skin behind the ear, drug dififuses through skin into capillaries within the dermis, whence it is carried into the geru:ral circulation.

Bioavaihbiity stndy: TTS versus i.v. infosios

To determine whether TTS provided an eract analog to a closely monitored i.v. infusion. we compared urinary excretion

DRUG MOLECULES

BACKING MEMBRANE

/ DRUG RESERVOIR

/ RATE CONTROLLING MlCROPOROUS MEMBRANE

SKIN CONTACT ADHESIVE

SKIN SURFACE

levels of scopolamine prevailing during its dehvery by TTS-scopolamine or a con- trol!ed intravenous infusion at approxi- mately the same rate.

Rates of urinary excretion of scopola- mine peaked within 12-24 h following ITS application, then decreased slightly, and thereafter held constant throughout the remainder of the 72 h wearing of the system (Fig. 3. dashed lines). During i.v. infusion (Fig. 3. solid lines) excretion of unchanged scopdiamine attained a steady rate within the first 12-24 h. which was maintained throughout the 72 h infusion. Drug excretion rates associated with the i-v. infusion and TTS varied significantly only during hours 12-24 of scopolamine administration and after its discontinua- tion (Fig. 3).

During each mode of scopolamine administration. subjects reported a dry mouth as the only significant pharma- cological effect. A moderately dry mouth developed 12-24 h following TTS appli- cation but decreased so that it was barely noticeable at the time of removal of the system. During scopolamine infusion, subjelcts reported experiencing a mildly dry mouth continuously. It appears that the concentration of scopolamine that elicits the dry mouth side-effect is very little higher than that needed to attain protectiou against motion sickness.

The data indicate that TTS-scopoia- mine controlled the drug’s excretion as well as intravenous administration. The higher rate of scopolamine excretion during the first 24 h of TTS use is attri- butable to the initial priming dose pro- vided by incorporation of scopolamine

SWEAT DUCT

BLOOD CAPILLARY

FCT. 2. Wwmauc diawtzm oJconta ledjlow of drw .fr~~n TTS-s;-opoiamine lhrouah tkrn inlo rhe systemic

circulafron.

TIPS - April, I980

into the adhesive contacting the skin. Because skins have differing capacities for concentrating scopolamine, a slight over- shoot or undershoot can occur in the rate of cfrug input during hours 12-24 foilow- ing TTS application. This over/under- shoot is very small with respect to the wide oscillations of urinary excretion seen with intramuscular injections (Fig. I).

Following cessation of transdermal scopolamine administration, the cutaneous depot of drug manifests itself in a rate of urinary excretion that initially declines rather more slowly than the rate observed following cessation of intra- venous administration, a difference that appears to be without pharmacological consequence.

Discussion

The anti-emetic effect of TTS-scopoia- mine has been documented elsewhere for a variety of conditions of motion*J; two- thirds of the people experienced transient dry mouth and one-sixth experienced some drowsiness. Other central effects of scopolamine were observed infrequently, as was mydriasis.

A point deserving emphasis is that, with rate-controlled delivery, the total scopolamine dosage producing a satis- factory therapeutic effect is only about one-fifth of that required with pulse-entry (first-order) dosage forms such as injec- tions. The usual intramuscular dose of scopolamine administered for motion sickness is MO ug, and its 6-hourly repe- tition would presumably be required under conditions of continuous motion. Thus, the total dose over three days from this first-order dosage form would be 2.4 mg v. programmed delivery of 0.5 mg over three days from TTS-scopolamine. In addition to a reduction in total dosage, the TTS-scopolamine avoids dose-related peaks in plasma concentration (reflected by the urinary excretion curve shown in Fig. I). Therein lies the mechanism by which rate-controlled administration in- creases the selectivity of scopolamine’s actions.

Another point deserving emphasis is that the TTS-scopolamine’s duration of 3 days is many times longer than the pharmacokinetic half-life of the drug, which is less than one hourto. The thera- peutic system form, instead of the intrinsic kinetic properties of the drug, provides the therapeutically important attribute of duration of action.

Transdermal therapeutic systems pro- ducts based on the same technology are

TIPS - April, 1980 211

1.2

1.0

0.2

C

i I

--- TTS-scopolamine, programmed to deliver 0.5 mq

over 3 days [n = It

- Conrtnuous intravenous infuslon of scopolamloe.

3.7-6.0 pg/hr (n = 6)

t Scopolamine administratton started

1 Scopolamine admmlstratlon stopped

a Area denotes differrnce in rate of scopolamine

excretion after stoppmg (at 72 hr) intravenous

and transdermal adI Gnisfratlon of the drug.

t o-12 12-24 24-36 36-48

--lb -i- T

___+___. i

--

T

___&_~ I i

I i

48-60 M-72 72-84 84-96 96-108 108-120 1

Time (hrl

Fig. 3. Urinary excretion of scopolamine base during and followinK transdermal and inrr~.~enous crriwm~frarron. Crrne was collecred a~ 1’ h mrerwls rhrouahwr each period of drug adminirtrorion and for 3 days after termination, and was onal_vsed IO determine :he we 0-f ercrtwon of unmrrobolwd scopolonww. The urrnur~ excretion rate of scopolamine is 111% of fhe infravenous delivery rare.

under development with a number of other agents. Drugs deemed most suitable for controlled administration via this route are those active at parenteral rates of administration of 2 mg per day or less. The system is especially applicable to potent agents with narrow therapeutic indices, short half-lives or gastrointestinal absorption problems. In evaluating a candidate drug, it is important to estab- lish that its permeation through skin at feasible sites of application is sufficient to produce an adequate th.erapeutic effect when the drug is administered over an area of skin acceptable 1.0 physician and patient. The, techniques for assessing drug permeation through human skin in vitro and in wivo have been described elsewhere”.

The ubiquity of action of the parasym- patholytic agents suggests that other therapeutically beneficial applications may be found for the rate-controlled delivery of scopolamine. Thus, the TTS- scopolaniine may have a certain value as a clinical pharmacological research tool,

over and above its proven efficacy as a pharmaceutical product.

Reading list 1 Feldman. R. J. and Matbalh, H. I. (196’) J.

Invest. Dermorol. 48. I8l-18.4 2 Momagna, W.. Van Scott, E. J. and Eou&:on.

R. B. (eds) (1972) PhormacoloQI- and rhe Skrn 20th Symposrum on rhe Biology of lhe &II: Adwnwz m B~olo~v of the Z?m Series. Vol. 1, pp. 540-546. AppleIon-Ceatur?-Crorts. Neu York

3 Zbinden. G. (ed) (1976) Prwrprs m To.wo-olo~~. Vol. 2, pp. W-59. Springer-verlas, Nw Vorh

4 Shau. J. E. and Chandrasekaran. S. K. (19’8) ,n Drug Metobotwn Revrews (DiCarlo. F ed). Vol. 8. Marcel Drkker. New Vorh

5 Shaw. J. E., Chandrasekaran. S. K.. Campbell. P. S. and Schmitt. L. G. (1977) III Curuneous Tarieiry (Drill, V. A. and Lazar. P. eds). PP. 83-94. Academic Press, New York

6 Shaa, J. E. and Chandrasekaran. S. li. m ProceedmRs of the Incernarronol ConJerencr on Drum Absorptron, Edinburgh, Scotland. 26-B September I979 (in press)

? Brand. J. J. and Whiningham. P. (1970) Lonwf ii W-234 .-

8 Graybiel. A., Kneplon. J. and Shaw. 1. (1976) AWN. Spuce Envrron. Med. 47. KM-I 100