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Reference Section

a report by

Dr M i l a n R H enz l

Professor Emeritus, Department of Gynecology and Obstetrics, Stanford University School of Medicine

Modern transdermal drug delivery systems are products

of basic pharmaceutical research that took place during

the last third of the 20th century. The first drug

delivered through the skin was dimethyl sulfoxide in

1900, and nitroglycerine ointment was introduced for

the management of angina in 1954; however, these

attempts lacked the proper scientific foundation and

were short-lived.1

The evolution of transdermal drug delivery systems

that had a meaningful impact on the practice of

medicine is intimately linked to the name of Dr

Alejandro Zaffaroni, a US scientist who, in the late

1960s, founded the Alza Corporation (based in

Mountain View, California).The primary focus of this

research corporation was to explore how to deliver

medicines to the target organs in a physiological and

presumably more effective and patient-friendly way.At

that time in the late 1960s this was a pioneering

concept often met with skepticism.2

Today, every worthwhile pharmaceutical corporation

has incorporated into its structure a division devoted to

innovative drug delivery systems. If one could judge the

success of a class of products in our case the

transdermal delivery system by the amount of sales

they generate, the impact of transdermal delivery

systems would be remarkable. Figure 1 shows that, in

1995, the revenue generated by the transdermal

therapeutic systems amounted to US$1.5 billion,

mostly due to the sales of transdermal analgesic and

non-endocrine systems, while endocrine drugs

represented a lesser part of the sales.

In the period between 1995 and 2002, the total fortransdermal delivery systems increased from US$1.5

billion to US$3.2 billion, i.e. by 213%. During the

same time period, the endocrine segment increased

from US$0.6 to US$1.8 billion., i.e. by 300%. The

trend is continuing and it is projected that, in 2008, the

market for all transdermal delivery systems will reach

US$4.5 billion.

The US Food and Drug Administration (FDA)

approved the first transdermal products in 1981.These

were preparations releasing scopalamine for the

prevention of motion sickness and a system releasing

nitroglycerine for the prevention of angina pectoris

associated with coronary artery disease.

Meanwhile, it has been recognized that the skin is an

excellent organ through which molecules of

reproductive steroids can reach the general circulation

rapidly and with relative ease. An intensive effort has

been initiated to develop systems for hormonal

replacement therapy (HRT) both in women and in

men, and the FDA approved the first system-releasing

estradiol (E2) Estraderm in 1986.3

The development of a transdermal system-releasing

testosterone Androderm proceeded more slowly,

although there has been an unsaturated market for

testosterone replacement therapy. In the US,

testosterone deficiency affects approximately one

million men. However, only an estimated 100,000 to

150,000 men have received some sort of treatment.

Serum T concentrations in adult need to be about 100

to 1,000 times higher then concentrations of E2 in

adult women (T 300ng to 1,000ng/dL versus E2 50pg

to 150pg/mL).

Initially, it was not possible to deliver these amounts

of testosterone through the usual sites the skin on

the torso and limbs and alternate routes were

sought. It was realized that the scrotum skin is thethinnest on the body and its unique superficial

vascularity makes it at least five times more permeable

than other skin sites. Later developments enabled the

construction of patches releasing testosterone from the

non-scrotal skin (on the back and thighs).

The Promi se o f T ransdermal Drug De l i ve ry Not Only for Reproduct i ve S te ro ids

Dr Milan R Henzl is currentlyprofessor emeritus at the StanfordUniversity School of Medicine,

Stanford, California. He haspreviously been executive medical

director at Syntex Research in PaloAlto, California, where he was

responsible for the development ofcompounds within the female health

area. Here, Dr Henzl developedbutoconazole (Femstat) , an

antifungal imidazole, from approvalfor prescription to over-the-counteruse. He also developed the single-

day therapy of vaginal fungalinfections with butoconazole

formulated in a special long-acting

cream, which was as effective as theseven-day application of miconazolenitrate cream. In addition, Dr Henzldeveloped nafarelin, a gonadotropin-releasing hormone agonistic analog,

for the management ofendometriosis, precocious puberty

and uterine leiomyomas. He was thefirst to conduct clinical trials with a

non-steroidal, anti-inflammatorydrug, naproxen sodium, for the

treatment of dysmenorrhea. Earlier,he participated in the development

of oral hormonal contraception,principally the minipill. The first

physician to be awarded theChairmans Science Medal, Dr Henzl

has authored 140 publications inscientific, peer-reviewed journals and14 books/monographs/chapters

in textbooks.

1

B U S I N E S S B R I E F I N G : N O R T H A M E R I C A N P H A R M A C O T H E R A P Y

1. M R Henzl and P K Loomba,Transdermal Delivery of Sex Steroids for Hormone Replacement Therapy and Contraception:A

Review of Principles and Practice,J. Reprod. Med., 48 (2003), pp. 525540.

2. A Zaffaroni,Overview and Evolution of Therapeutic Systems,Ann. NY Acad. Sci., 618 (1991), pp. 405421.

3. J E Shaw and S K Chandrasekaran, Skin as a Mode for Systemic Drug Administration, Pharmacology of the Skin II,

Chapter 13, MW Greaves and S Shuster (eds), Berlin, Heidelberg, New York: Springer Verlag, 1989.

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Currently, in the US, there are two transdermal

therapeutic systems for testosterone to be applied to

the skin of the torso and limbs, and four systems to be

applied to the scrotum skin. However, the patches,

irrespective of location, need to be exchanged daily.

Due to the various research problems that had to be

solved, FDA approval of the Androderm patch

occurred only in 1995 close to 10 years after FDAapproval of Estroderm.

The development of percutaneous contraception

presented unique challenges. The patch has to contain

two steroidal hormones an estrogen and a prog-

estogen in amounts that would secure a reasonably

long time for which the patch would still be active. It

was considered that no shorter than a weekly exchange

of the patch would be acceptable to the users. The

steroids would need to be released from the patch

rapidly, in order to attain levels that would effectively

inhibit ovulation and provide control of uterine

bleeding.These levels would need to be maintained at a

steady state until the patch is exchanged.The developers

of the contraceptive patch will have met all these

requirements, as outlined in this article.

The time lag between transdermal HRT and

transdermal contraception is best illustrated by the fact

that the first transdermal contraceptive system Ortho-

Evra was approved by FDA only in 2002.

Rationally, the developers of the contraceptive patch

decided to use ethinylestradiol (EE), a time-tested

estrogen in oral contraceptives. Meanwhile, the

progestogen content in oral contraceptives has been

steadily decreasing without negatively affecting their

efficacy.With respect to transdermal contraception, the

progestogen of interest was norgestimate, since very low

doses of this hormone were used in oral contraceptives.

The oral triphasic treatment schedule utilized daily

doses of norgestimate as low as 0.180mg, which

increased in seven-day increments to 0.215mg/day and

to 0.25mg/day a total of 4.2mg over 21 days.The

daily dose of EE was steady: 35mg x 21 days.1

However, rather than norgestimate, the developers of the

patch decided to use its active metabolite norelgestromin a highly potent progestogen with

minimal metabolic impact.4 The contraceptive

transdermal patch contains 0.75mg EE and 60mg

norelgestromin and has to be changed only once a week.

After application of the patch,steady state concentrations

of both contraceptive hormones are achieved within 48

hours. For EE, these concentrations reach about

50pg/mL; for norelgestromin, the steady-state

concentrations are around 1ng/mL (see Figure 2).1, 4

This system provides a high contraceptive protection

and an acceptable bleeding pattern comparable to and

possibly better than that with low-dose oral

contraceptives. The character of adverse events is

approximately the same as with oral contraceptives;

however, significantly fewer women discontinuecontraceptive patches as a result of adverse events than

do women using oral contraceptives. This could

indicate a higher compliance. Indeed, in randomized

comparative studies, the compliance was significantly

higher in the contraceptive patch group than in the oral

contraception group.5

Extensive studies have largely discredited the presumed

advantages, principally the cardioprotective effects of

The Promise o f Transderma l Drug De l i very Not On ly fo r Reproduct i ve Stero id s


2

Figure 1: Marketing trend for transdermal systems in

the US. The sector with endocrine drugs is increasing

more than the analgesic sector

Figure 2: Rapid absorption and steady state of norelgestromine during

contiguous application of hormonal patches

4. M R Henzl,Norgestimate: From the Laboratory to Three Clinical Indications,J.Reprod.Med., 46 (2001) 7,pp.647661.

From various sources.

Modified from M R Henzl and P K Loomba, Transdermal Delivery of Sex Steroi ds for Hormone Replacemen t Therapy and

Contraception:A Review of Principles and Practice, J. Reprod. Med., 48 (2003),pp. 525540.

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oral HRT. The crucial question has arisen of whether

the transdermal route might obviate the undesired

effects of oral dosing and whether the transdermal route

might even be preferable to the oral HRT.

Drug delivery through the skin offers several

advantages. Hormones delivered transdermally are

not subject to gastrointestinal enzymatic activity andavoid first-pass liver metabolism. Therefore, the

administered amounts can be lower. The bolus oral

dose leads to hepatic over-synthesis of certain

proteins, notably the C-reactive protein and renin

substrate. Oral administration is associated with a

significant decrease in anti-thrombin III activity, but

also with an improved lipid profile decreased low-

density lipoprotein and increased high-density

lipoprotein. Transdermal hormone administration

lacks these effects. On the other hand, a decrease in

factor VII activity, fibrinogen and tr iglycerides levels,

and a lack of effect on C-reactive protein can be

considered as metabolic advantages of transdermal

hormone treatment.

An additional advantage of transdermal hormonal

systems is that they can be self-administered and a single

application can extend the effective therapy for up to

seven days.This is important for hormones with short

half-lives, such as E2. Therapeutic drug levels can be

attained rapidly and with low daily doses. It is

important that, in emergencies, the patch can be

removed and the adverse action rapidly terminated.

The cardinal question is whether the differences in

the metabolic parameters between oral and

transdermal delivery of reproductive hormones

would translate into clinically meaningful disparities

that would make transdermal hormone delivery safer

and even preferable to the oral administration. The

long-term clinical consequences of transdermal drug

delivery have not yet been fully assessed. It would

require large-scale and long-term clinical trials to

evaluate the clinical significance of the lack of

interactions with the liver and other metabolic

differences of the transdermal versus the oral route of

hormonal dosing.6,7

The wide range of indications described for the

transdermal delivery of reproductive hormones was

achieved with transdermal patches. As we have shown

in the preceding paragraphs, the development of these

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Reference Section

Figure 3: Delivering medicinal substances through the skin by means of an

electrical current

Figure 4: Titanium Disk with Microscopic Titanium

Teeth-like Projections

Figure 5: A patch for sustained drug delivery or analyte

extraction by means of sonophuresis

5. M C Audet, M Moreau,W D Koltun,A S Waldbaum, G

Shangold, A C Fisher, and G W Creasy, Evaluation of

Contraceptive Efficacy and Cycle Control of a Transdermal

Contraceptive Patch Versus an Oral Contraceptive: A

Randomised Controlled Trial, JAMA, 285 (2001), pp.

2,3472,354.

This E-TRANS technology can be programmed for continuous, patterned, on-demand or feedback-controlled drug delivery.

Courtesy of Alza Corp.

Modified from M R Henzl and P K Loomba,Transdermal Delivery of Sex Steroids for

Hormone Replacement Therapy and Contraception: A Review of Principl es and

Practice, J. Reprod. Med., 48 (2003),pp. 525540.

From the Mitragotri Research Group (http://drugdelivery.engr.

ucsb.edu/ultrasound_mediated_transdermal2.htm).Accessed Nov. 9, 2003

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patches was laborious and presented a multitude of

intellectual challenges. The length of time that was

necessary to develop individual patches releasing

reproductive hormones for specific clinical conditions

has been the best indicator of the multiple problems

that were encountered and had to be resolved during

their development.Yet, progress in transdermal delivery

of other drugs advanced at a pace that resulted insophisticated systems, compared to which the patch

would seem simple.

The most significant progress in the transdermal drug

delivery technology has involved electrotransport

the use of electric potential to move charged

therapeutic molecules across the skin. Innovations in

electric circuitry and battery technology have enabled

the development of small, integrated, patch-like

systems for the systemic delivery of medicinal agents

(see Figure 3).2 Since the permeation rate of drugs in

electrotransport systems is proportional to the applied

current, the dose of the delivered drug can easily be

manipulated by controlling the electrical current. 1,2

Thus, both a rapid onset of delivery and an

intermittent, pulsatile, and/or on-demand, patient-

controlled dosing can be achieved.3 Such systems are

important in the management of pain, among other

things.The technology enables the delivery of potent,

high-molecular weight entities, including peptides

and proteins.9

Other transdermal innovations include macroflux

technologies utilizing microprojection patches.8 The

main component of the microprojection patch is a

titanium disk affixed to a polymeric adhesive back.

The titanium disk is 8cm2 and consists of an array of

microscopic, titanium, tooth-like microprojections

that are coated with medicinal substances. There are

as many as 300 microprojections per cm2 (see Figure

4). They penetrate just the 10m to 25m-thin layer

of dead cells of the stratum corneum, in which they

create holes microchannels large enough to

permit the transport of large molecules to the

physiologically active deeper layers of the epidermis.

This viable epidermis has no capillaries, however.The

extensive vascular network of the dermis is

immediately adjacent and takes up the medicinal

substances rapidly.The titanium microprojections are

too small to cause pain.

This technology offers a needle-free and painlesstransdermal drug delivery of large-molecular-weight

compounds such as insulin, several peptidic

hormones, and vaccines. Studies are being conducted

with a growth hormone-releasing factor analog,

which is important in the management of Type II

diabetes. With this new system, patients can receive

drugs for 12 weeks.Clinically important are tests with

the delivery of parathyroid hormone by the

macroflux transdermal patch to patients with

osteopenia and osteoporosis.9

Since 1995, it has been known that the application of

low-frequency ultrasound enhances skin permeability,

a phenomenon referred to as low-frequency

sonophoresis.10,11 This technology allows effective

transdermal transmission by means of skin systems not

larger than a wristwatch (see Figure 5). Significant are

experiments with heparin and low-molecular-weight

heparin; however, the technical modification of

sonography also enables the transdermal delivery of

high-molecular-weight compounds.

Low-frequency sonophoresis also offers a promising

development in that it could be modified into a major,

diagnostic, non-invasive method.The sonophoretically

increased permeability of the skin may be used not only

for drug delivery, but also for the collection of

interstitial fluid.The extraction of interstitial fluid can

be accomplished by applying a vacuum and the

collected material can be analyzed for a number of

biological agents. One of the most important clinical

applications of sonophoresis would be to measure

glucose content in the obtained fluid. This would

enable the diabetic patients to monitor their glucose

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4

6. J C Stevenson,D Crook, I F Godsland, B Lees, and M I Whitehead,Oral Versus Transdermal Hormone Replacement Therapy,

Int. J. Fertil. Menopausal Stud., 38 (1993) 1, Suppl., pp. 3035.

7. D Crook,Do We Need Clinical Trials to Test the Ability of Transdermal HRT to Prevent Coronary Heart Disease?, Curr.Control Trials Cardiovasc. Med., 2 (2001) 5, pp. 211214.

8. E R Scott, B J Phipps, R J Gyory, and R V Padmanabhan, Electrotransport Systems for Transdermal Delivery: A Practical

Implementation of Iontophoresis, Handbook of Pharmaceutical Controlled Release Technology, D L Wise (ed.), New

York:Marcel Dekker, 2000, pp. 617659.

9. W Q Lin, M Cormier,A Samiee, A Griffen, B Johnson, C L Teng, G E Hardee, and P E Daddona,Transdermal Delivery

of Antisense Oligonucleotides with Microprojection Patch (Macroflux) Technology, Pharm. Res. 18 (2001) 12, pp.

1,7891,793.

10.S Mitragotri, D Blankschtein, and R Langer, Ultrasound-mediated Transdermal Protein Delivery, Science, 269 (1995)

5,225, pp. 850853.

11. S Mitragotri, M Coleman, J Kost, and R Langer,Analysis of Ultrasonically Extracted Interstitial Fluid as a Predictor of Blood

Glucose Levels,J.Appl. Physiol., 89 (2000), pp. 961966.

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concentrations frequently and to direct the appropriate

therapy accordingly.10,11

Modern computer technology could provide a link

between the system quantitatively analyzing drugs

and/or biological material in the interstitial fluid and

the systems delivering drugs by non-invasive

transdermal means. Such interacting systems could havebuilt-in feedback mechanisms between the drug

concentration in the tissues and transdermal drug

release systems.The amount of the drug released would

then be determined by the concentration of the drug in

the tissues, and the feedback mechanism would be

controlled by a computer chip.

In further developments, one could envision feedback

mechanisms between natural substances such as steroidal

hormones and the therapeutically administered agents,for example gonadotropic hormones and

gonadotrophin-releasing hormone and its analogs.

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Reference Section

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