The development of transdermal hormone replacement therapy

The perimenopause, the time leading up to the menopause or final menses, has been recognised through the ages as a time of significant change. Symptoms of gradual reduction in female hormone production are common and experienced by many women.

For some these, symptoms can be debilitating, affecting all aspects of daily living. There is little reference to early remedies in the literature; indeed menopause has only become a concern with the increase in lifespan associated with better nutrition and improved healthcare over the past two centuries.

The average age of menopause has been consistently around age 51 whilst average age of death has increased from mid 20s in medieval times to 84 years today. Even when menopausal problems were apparent, there was little help available. Thomas Graham wrote in his book published in 1837, “The

Diseases of Females”, that with the exception for attention to diet and exercise, “little or nothing is required for the management of ordinary cases”.

Women were thought to be ruled by their hormones, and thus inferior to men, making menopause a shameful secret. It was only in the later 19th century that scientists began experimenting with various animal extracts in the search for the “fountain of youth”. The Merck Manual of 1899 describes a preparation known as “Ovariin” which was a coarse brown powder taken orally, essentially the dried and pulverised ovaries of a cow. Research continued; notably Drs Allen and Doisy.

Working together between 1923 and 1938 they identified oestrogen and its effects, followed by the other female hormones and their relationship to each other. Pharmaceutical companies were quick to spot possible market opportunities in menopause, menstruation problems, infertility and contraception and also hoped to address problems such as wrinkles and thinning hair! Scientists were recruited by the drug industry and the first commercial oestrogen was available in 1930. This was “Emmenin”, produced from urine obtained from late-pregnant women in Canada. Although marketed as the first effective oestrogen, an alternative source was quickly required as there were problems with high cost, taste and odour!

A better source was found in pregnant mares urine and this was marketed by the company Ayerst (which became Wyeth) as Premarin, its name derived from the source. This has been available for nearly 70 years now.

Other oestrogens followed with ethinyl oestradiol being synthesised in Germany by the company Schering in 1938, still the leading oestrogen used in contraception, and diethylstilbestrol synthesised in the same year in the UK by Charles Dodds. He made the formulation available freely, believing that pharmaceutical companies should not profit from scientific work. Many companies applied to manufacture DES (diethylstilbestrol) as it was off patent even thought Dodds himself already had concerns about possible cancer and miscarriage risks.

All these preparations to date had been oral formulations with no consideration of alternative delivery methods. Although effective HRT had really been made available in 1941 with DES, prescribing was not widespread until the 1960s when the change in womens role in society brought the menopause and hence the benefits of HRT to the fore.

Several books were written at that time which highlighted the improvement in both emotional and physical wellbeing for middle-aged women, indeed HRT was regarded as a panacea for all midlife issues. The prominent American gynaecologist, Dr Robert Wilson, promoted the use of oestrogen in his book “Feminine Forever” as a means of combating the “living decay” of menopause and advocated the use of oestrogen from “puberty to the grave”, advice which is not recommended now. Drug prescriptions increased steadily with Premarin being the number one drug in the US by 1992 . The use of HRT remained popular despite a significant scare in the 1970s in the USA when the link between unopposed oestrogen and endometrial cancer was demonstrated.

Despite providing an excellent treatment for many women, oral preparations are not without drawbacks. Daily dosing is required, which is a disadvantage for some menopausal women with memory problems! Any oral preparation must be absorbed from the digestive tract, then passes to the liver via the portal system and is metabolised before reaching the target organs. This increases the workload on the liver and affects the dose eventually delivered. The higher total dose required may give rise to oestrogenic side-effects including nausea, breast tenderness, headaches and leg cramps. Women with malabsorption problems may simply not absorb sufficient drug doses to achieve an adequate response.

Other routes of administration have become possible, but obviously need to be convenient and confer advantages over the oral route in order to be worthwhile. Research into transdermal administration had been going on throughout the 1970s but had several difficulties to overcome. Earlier, skin had been thought of as an impermeable protective barrier. However it has been shown that many drugs can diffuse through the thin layer of tissue separating the outside world from the capillary network lying just below the skin surface.

The first transdermal delivery systems were launched in 1979 and the next decade saw the development of ten further transdermal delivery systems (TTDS) containing different drugs. The drug company ALZA in the US led the market with brands including Estraderm, Duragesic, and Transderm-Nitro. They also produced patches for delivery of nicotine and analgesics, and anti-nausea drugs.

The main advantage of transdermal delivery relates to the controlled absorption rate giving predictable, uniform plasma levels, and improved bioavailability. The lower overall dose tends to result in fewer side effects. A transdermal patch is easy and painless to apply and equally simple to discontinue by removing the patch, should administration no longer be required, for example prior to surgery. A simple system tends to improve patient compliance particularly with weekly patches.

In order for a drug to be administered via the passive adhesive transdermal route, it must fulfill several requirements; the drug must be of low molecular weight, non-ionic, have adequate solubility in both oil and water; it must have a low melting point and be potent (dose in mg per day). Oestrogen meets all these requirements and several types of patch have been developed, the earliest being the reservoir patch, and the matrix patch.

The technology applied to formulate a “simple patch” cannot be underestimated; each patch contains several layers each performing a specific function. Permeation enhancers are used to increase the permeability of the stratum corneum to enable a higher therapeutic level of drug to pass through. These chemicals alter the protein and lipid layers improving permeability. Pressure sensitive adhesives are used to attach the patch to the skin and so have to be strong enough to adhere quickly to the skin surface with only finger pressure but reasonably easy to remove without leaving a sticky residue behind.

In fact, the biggest problem with transdermal patches is the possibility of skin sensitivity to the adhesive. This can cause irritation, itching and redness, sometimes leaving a raised wheal. This is a common reason for patient discontinuation. The reservoir patch consists of the drug itself suspended in a clear releasable solvent such as ethanol, which is sandwiched between a rate controlling membrane and a backing laminate.

The rate controlling membrane is non-porous, so that the drug is released by diffusing directly through the material. The solubility of the drug and the thickness of this rate controlling membrane will therefore affect the rate of drug release. The impermeable backing laminate must be flexible and compatible with the drug within the reservoir such that the drug does not leach out through the backing layer and reduce the amount of drug delivered through the adhesive.

A release liner is part of the packaging required to prevent the drug being released until it is used by the patient, when it is removed and the patch stuck on to the skin. The brand “Estraderm” is a well known reservoir patch now licensed for manufacture by the company Novartis.

The most common transdermal patch used in hormone therapy replacement is the adhesive type patch where the drug is directly incorporated into the organic solvent based pressure sensitive adhesive solution. This is then cast as a thin film and dried to evaporate the solvent, leaving a dried adhesive matrix film containing the drug and excipients. This is sandwiched between the backing layer, and the release liner which is used to package the patch until used. It has been shown that patient compliance is improved due to ease of remembering once weekly patch application and improved cosmetic appearance, and better adhesion. Several drug-in-adhesive patches are currently available, “Estradot” and “Evorel” amongst them.

One of the technological challenges to extending this method of delivery is that larger molecules such as proteins and peptides are too large to pass through the skin.

It is for this reason that progesterone, a large molecule compared to oestrogen, was not immediately suitable for use in transdermal patches. However using electricity or ultrasound can help to “push” the molecules through the skin. Iontophoresis involves passing a direct electrical current between two electrodes on the skin surface whilst phonophoresis uses ultrasonic frequencies to help transfer high molecular weight drugs through the skin.

Since transdermal therapy first became available nearly 30 years ago, studies have confirmed differences in clinical response between oral and transdermal therapy.

It has been shown that oestrogen has an adverse impact on the clotting cascade and may provoke venous thrombotic events (VTE). Several well known papers were published in the Lancet in 1996 establishing an increased relative risk of developing VTE of 2-4 in current HRT users. However the Estradiol Clotting Factor Study group identified a difference in effect between oral and transdermal administration. Oral oestrogens appeared to impair the balance between procoagulant factors and antithrombotic mechanisms, whilst transdermal delivery has no effect on haemostasis. Thus it would seem prudent to avoid the oral route in women with previous history or at higher risk of VTE, and use patches as the first choice for therapy instead.

The impact of oestrogens and mode of delivery on lipid levels has also undergone signficant scrutiny. Early studies appeared to show that oestrogen reduced the risk of cardiovascular disease, thought to be mediated by reduction of low density lipo-proteins and increasing circulating levels of high density lipoproteins and triglycerides.

These findings were not confirmed in several larger studies most notably the Womens Health Initiative in 2002. The difference in these study results may depend in part on the method of drug delivery, as these larger studies all looked at oral treatment. During oral therapy, the level of oestrodiol in the liver sinusoids is 4-5 times the physiological level circulating throughout the rest of the body. This localised high level increases the amount of acute-phase inflammatory proteins such as C-reactive protein and procoagulant factors, and also several enzymes involved in plaque disruption; these markers are not elevated in transdermal administration as the oestrogen passes directly into the systemic circulation thus avoiding the first-pass hepatic effect.

Bypassing the liver results in more stable oestradiol levels without the supraphysiological effects on these inflammatory markers. Again it may be prudent to use transdermal delivery for those women who are at higher risk for cardiovascular disease such as diabetes mellitus, on medication which alters hepatic enzyme function or known impaired hepatic function. There are currently two trials ongoing which are investigating whether the beneficial effects of transdermal therapy at physiological levels, can be shown to have better clinical outcomes long term (the KEEPS Kronos Early Estrogen Prevention Study and ELITE, Early versus Late Intervention Trial with Estradiol).

Hormone therapy has certainly developed enormously since the early days of grinding up dried bovine ovaries, to the current state-of-the-art transdermal therapy now available. The future may bring yet more improved, tailored hormone replacement therapy delivery systems, increasing the benefits whilst reducing risks to a minimum.

References

1. Thomas Graham “The Diseases of Females” (1837)
2. Merck & Co, Merck Manual of Diagnosis and Therapy 54 (1899)
3. Robert Meyer “The Bitter Pill” (1983)
4. Robert A. Wilson “Feminine Forever” (1966)
5. Robert A. Wilson “Feminine Forever” (1966)
6. http:// www.wyeth.com/about
7. Rees M, Stevenson J et al. “Management of the Menopause” British Menopause Society, May 2009
8. Sugino M et al. Skin permeation and transdermal delivery systems of drugs: history to overcome barrier function in stratUm corneum. Yakugaku Asshi. 2009 Dec: 129(12) 1453-8
9. http://www.pharmiweb.com/News/Pressreleases Jan 2003
10. Aggarwhal G. Development, fabrication and evaluation of transdermal drug delivery systems – a review. Pharmainfo.net. Oct 2009
11. Lake Y, Pinnock S. Improved patient acceptability with a transdermal drug in adhesive oestradiol patch. J Obstet Gynecol 2000, 40: 313-316
12. Daly E, Vessey MP et al. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 1996; 348(9033): 977-980
13. Jick H, Derby LE, Myers MW et al. Risk of hospital admission for idiopathic venous thromboembolism among users of postmenopausal oestrogens. Lancet 1996; 348 (9033): 981-3
14. Anonymous. Effects of haemostasis of hormone replacement therapy with transdermal oestradiol and oral sequential medroxyprogesterone acetate.The Writing Group for the Estradiol Clotting Factors Study. Thromb Haemost 1996; 75:476-80
15. Canonico M et al. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens:the ESTHER study. Circulation 2007 115(7):840-5
16. Menon DV, Vongpatanasin W. Effects of transdermal estrogen replacement therapy on cardiovascular risk factors.Treat Endocrinol. 2006;5(1):37-51
17. Goodman MP. Are all estrogens created equal? A review of oral vs transdermal therapy. J Womens Health 2011 0ct 19 (epub ahead of print)

Articles